TWI386392B - Sulfonyl-substituted bicyclic compounds as modulators of ppar - Google Patents

Description

一種可作為過氧小體增生活化受體調控劑的磺酸基取代雙環化合物 Sulfonic acid-substituted bicyclic compound as a regulator of peroxisome proliferator-activated receptor

本發明係關於一種新的磺酸基取代的雙環芳香基衍生物(sulfonyl-substituted bicyclic aryl derivatives)以及藉由調控細胞核受體中介過程以使用該化合物治療不同疾病的方法，尤其是指過氧小體增生活化受體(peroxisome proliferator activated receptors,PPARs)所中介的過程。 The present invention relates to a novel sulfonyl-substituted bicyclic aryl derivatives and a method for treating different diseases by using the compound by regulating a nuclear receptor intermediate process, especially for small peroxygen The process by which peroxisome proliferator activated receptors (PPARs) are intervened.

過氧小體增生物是一群結構上多樣的化合物，當處理在哺乳動物時，不僅引起肝和腎過氧小體在大小和數量上的劇烈增加，還經由β-氧化(β-oxidation)循環所需的酵素表現量增加而伴隨過氧小體代謝脂肪酸能力的增加，請見Lazarow and Fujiki,Ann.Rev.Cell Biol.1：489-530(1985)、Vamecq and Draye,Essays Biochem.24：1115-225(1989)及Nelali et al.,Cancer Res.48：5316-5324(1988)。可活化或與其他一或多個過氧小體增生活化受體相互作用的化合物已被揭露在動物模式下而可調控三酸甘油脂和膽固醇。這類化合物包含纖維酸系(fibrate class)的降血脂藥、除草劑及磷苯二甲酸鹽可塑劑(phthalate plasticizers)，請見Reddy and Lalwani,Crit.Rev.Toxicol.12：1-58(1983)。過氧小體增生也可被飲食或生理因素引起，如高脂肪飲食和待在寒冷環境中。 Peroxisome-enhancing organisms are a group of structurally diverse compounds that, when treated in mammals, cause not only a dramatic increase in the size and number of liver and kidney peroxygen bodies, but also a beta-oxidation cycle. The increased amount of enzyme required is accompanied by an increase in the ability of the peroxygen to metabolize fatty acids, see Lazarow and Fujiki, Ann. Rev. Cell Biol. 1: 489-530 (1985), Vamecq and Draye, Essays Biochem. 24: 1115-225 (1989) and Nelali et al., Cancer Res. 48:5316-5324 (1988). Compounds that can activate or interact with other one or more peroxisome proliferator-activated receptors have been disclosed to modulate triglycerides and cholesterol in animal mode. Such compounds include a fibrate class of hypolipidemic agents, herbicides, and phthalate plasticizers, see Reddy and Lalwani, Crit. Rev. Toxicol. 12:1-58 ( 1983). Peroxisome proliferation can also be caused by diet or physiological factors, such as a high-fat diet and staying in a cold environment.

PPAR調控的生物過程就是對PPAR受體配體產生反應的受體 調控的過程，或是受體組合調控的過程。這些過程例如為：血脂的傳送和脂肪酸的代謝、胰島素敏感性和血糖濃度的調控，而這些都和低血糖症(hypoglycemia)及高胰島素症(hyperinsulinemia)有關(如：起因於異常的胰臟β細胞功能、胰島素分泌腫瘤(insulin secreting tumors)及/或胰島素自體抗體、胰島素受體或對胰臟β細胞有刺激性的自體抗體所造成的自體免疫性低血糖症)、導致動脈粥狀硬化的巨噬細胞分化、發炎反應、腫瘤的形成、過度增生及脂肪細胞分化。 The biological process regulated by PPAR is the receptor that responds to PPAR receptor ligands. The process of regulation, or the process of receptor regulation. These processes are, for example, the transmission of blood lipids and the metabolism of fatty acids, insulin sensitivity and regulation of blood glucose levels, which are associated with hypoglycemia and hyperinsulinemia (eg, due to abnormal pancreatic beta) Cellular function, insulin secreting tumors and/or insulin autoantibodies, insulin receptors or autoimmune hypoglycemia caused by stimulating autoantibodies to pancreatic beta cells), leading to atherosclerosis Sclerosing macrophage differentiation, inflammatory response, tumor formation, hyperproliferation, and adipocyte differentiation.

PPAR的亞型包含PPAR-alpha、PPAR-delta(也已知為NUC1、PPAR-beta和FAAR)以及兩種PPAR-gamma異構物。這些PPAR可經由連接到DNA序列片段(稱作PPAR反應序列，PPRE)調控目標基因的表現。迄今，PPRE的序列已在數種編碼為調節脂肪代謝的蛋白質基因的促進子中鑑定出，證實了PPAR扮演一個關鍵角色在脂肪生成的訊號傳遞和脂肪的體內平衡上。 The subtype of PPAR comprises PPAR-alpha, PPAR-delta (also known as NUC1, PPAR-beta and FAAR) and two PPAR-gamma isomers. These PPARs can regulate the expression of a target gene via a DNA sequence fragment (referred to as a PPAR reaction sequence, PPRE). To date, the sequence of PPRE has been identified in several promoters encoding protein genes that regulate fat metabolism, confirming that PPAR plays a key role in the signaling of fat production and the homeostasis of fat.

端看這機制，藉這機制過氧小體增生物執行它們多效作用，這機制是藉由鑑定出被該化合物活化的細胞核荷爾蒙受體超級家族成員所得到的，請見Isseman and Green,Nature 347-645-650(1990)。受體PPAR-alpha(或PPAR-α)，隨後被指出被不同中、長鏈脂肪酸活化且除了刺激編碼大鼠醯基輔酶A(acyl-CoA)及水解酶-脫氫酶(hydratase-dehydrogenase)基因的表現外，還刺激兔子的細胞色素P450 4A6(一種脂肪酸ω羥化酶)，請見Gottlicher et al.,Proc.Natl.Acad.Sci.USA 89：4653-4657(1992)、Tugwood et al., EMBO J 11：433-439(1992)、Bardot et al.,Biochem.Biophys.Res.Comm.192：37-45(1993)、Muerhoff et al.,J Biol.Chem.267：19051-19053(1992)及Marcus et al.,Proc.Natl.Acad Sci.USA 90(12)：5723-5727(1993)。 Looking at this mechanism, this mechanism is used to perform their pluripotency by peroxisomes, which is obtained by identifying members of the nuclear hormone receptor superfamily activated by the compound, see Isseman and Green, Nature 347-645-650 (1990). The receptor PPAR-alpha (or PPAR-alpha) was subsequently identified as being activated by different medium and long chain fatty acids and in addition to stimulation encoding rat 醯 酶 酶 酶 ( 及 及 及 及 及 及 及 hydr hydr hydr hydr hydr hydr hydr hydr hydr hydr hydr hydr hydr hydr hydr hydr hydr hydr hydr hydr hydr hydr hydr In addition to gene expression, rabbit cytochrome P450 4A6 (a fatty acid ω hydroxylase) is also stimulated, see Gottlicher et al., Proc. Natl. Acad. Sci. USA 89:4653-4657 (1992), Tugwood et al ., EMBO J 11: 433-439 (1992), Bardot et al., Biochem. Biophys. Res. Comm . 192: 37-45 (1993), Muerhoff et al., J Biol. Chem. 267: 19051-19053 (1992) and Marcus et al., Proc. Natl. Acad Sci. USA 90(12): 5723-5727 (1993).

細胞核受體PPAR-gamma(或PPAR-γ)的活化子，如胰鳥素增敏劑(troglitazone)，在臨床上已經證實可以提升胰鳥素的作用，減少血中糖份並且有較小且明顯效用在減少第二型糖尿病病人身上血液中三酸甘油脂濃度，請見D.E.Kelly et al.,Curr.Opin.Endocrinol.Diabetes,90-96,5(2),(1998)、M.D.Johnson et al.,Ann.Pharmacother.,337-348,32(3),(1997)及M.Leutenegger et al.,Curr.Ther.Res.,403-413,58(7),(1997)。 The activator of the nuclear receptor PPAR-gamma (or PPAR-γ), such as troglitazone, has been clinically proven to enhance the action of tryptatin, reduce blood sugar and is small and Significant utility in reducing blood triglyceride concentrations in patients with type 2 diabetes, see DEKelly et al., Curr . Opin . Endocrinol. Diabetes, 90-96, 5(2), (1998), MD Johnson et al. , Ann. Pharmacother. , 337-348, 32(3), (1997) and M. Leutenegger et al., Curr. Ther. Res., 403-413 , 58(7), (1997).

因PPAR-delta(或PPAR-δ)普遍的表達且選擇性配體不易取得，一開始不如其他PPAR受到注意。然而，基因研究及近來PPAR-δ激動劑合成的發展都協助揭示其作為在脂肪酸分解和能量平衡有影響的調控劑的角色。脂肪組織和肌肉的研究上都已揭露PPAR-δ代謝的功能。脂肪組織中PPAR-δ活化形式的轉基因表現產生對遺傳上或高脂肪飲食所引起肥胖、高血脂(hyperlipidemia)及組織皮脂腺病(tissue steatosis)有抗性的瘦老鼠。活化的受體會引起脂肪酸代謝及體內溫度平衡所需的基因。有趣的是，用來脂肪儲存與合成的PPAR-γ目標基因的轉錄保持不變。同樣，PPAR-δ缺陷的小鼠給予高脂肪飲食顯示能量解偶聯的降低與肥胖的傾向。而且，這些資料證實PPAR-δ是脂肪燃燒的關鍵調節子、扮演 著一種相對於PPAR-γ脂肪儲存功能的角色。因此，儘管它們演化上及結構上是相近的，PPAR-γ和PPAR-δ調控不同的基因網路。在骨骼肌中，PPAR-δ同樣正向調整脂肪氧化和能量消耗，程度上遠多於少量表現的PPAR-α，請見Evans RM et al 2004 Nature Med 1-7,10(4),2004。 Due to the widespread expression of PPAR-delta (or PPAR-δ) and the difficulty of obtaining selective ligands, it was not as noticeable as other PPARs at first. However, both genetic research and recent developments in PPAR-delta agonist synthesis have helped to uncover its role as a regulator of effects in fatty acid breakdown and energy balance. The function of PPAR-delta metabolism has been revealed in studies of adipose tissue and muscle. Transgenic expression of the PPAR-delta activated form in adipose tissue produces lean mice that are resistant to obesity, hyperlipidemia, and tissue steatosis caused by genetic or high fat diets. Activated receptors cause genes required for fatty acid metabolism and temperature balance in vivo. Interestingly, the transcription of the PPAR-γ target gene used for fat storage and synthesis remained unchanged. Similarly, administration of a PPAR-delta-deficient mouse to a high-fat diet showed a reduced propensity for energy uncoupling and obesity. Moreover, these data confirm that PPAR-δ is a key regulator of fat burning and plays a role relative to the PPAR-γ fat storage function. Thus, although they are evolutionary and structurally similar, PPAR-γ and PPAR-δ regulate different gene networks. In skeletal muscle, PPAR-δ also positively regulates fat oxidation and energy expenditure to a greater extent than PPAR-α, as described in Evans RM et al 2004 Nature Med 1-7, 10(4), 2004.

PPAR-δ在身體裡被廣泛地表現且被認為是用在治療血脂異常(dyslipidemia)和其他疾病有價值的分子標的。例如，在近期胰島素抗性的肥胖恆河猴的研究上，一種有潛力和選擇性的PPAR-delta化合物顯示出在劑量反應的方式下能有效降低VLDL和增加HDL。 PPAR-δ is widely expressed in the body and is considered to be a valuable molecular marker for the treatment of dyslipidemia and other diseases. For example, in a recent study of insulin-resistant obese rhesus monkeys, a potential and selective PPAR-delta compound has been shown to be effective in reducing VLDL and increasing HDL in a dose-responsive manner.

因為3種PPAR的異構物其全都已顯示重要的角色在體內的能量平衡上及其他人類身體上重要的生物過程，並被顯示出為在治療代謝和其他疾病的重要的分子標的，請見Willson,et al.J.Med.Chem.43：527-550,2000，所以本技術領域想要發展出有足夠能力與這些PPAR異構物相互作用的化合物，或是有效性選擇地針對單一種PPAR異構物作用的化合物，特別是PPAR-δ。這種化合物將會有廣泛的用途，例如在治療或預防肥胖、糖尿病、血脂異常或新陳代謝X症候群(metabolic sybdrome X)或其他的用途上。 Because the three PPAR isomers have all shown important roles in the body's energy balance and other important biological processes on the human body, and have been shown to be important molecular markers in the treatment of metabolism and other diseases, see Willson, et al. J. Med. Chem. 43: 527-550, 2000, so it is desirable in the art to develop compounds that have sufficient capacity to interact with these PPAR isomers, or to selectively target a single species. A compound that acts as a PPAR isomer, especially PPAR-δ. Such compounds will have a wide range of uses, for example in the treatment or prevention of obesity, diabetes, dyslipidemia or metabolic sybdrome X or other uses.

數種PPAR調控的藥物已經被證實使用在人體上。Fenofibrate和gemfibrozil(皆為降血脂藥物)皆為PPAR-γ的調控劑；pioglitazone(Actos,Takeda Pharmaceuticals and Eli Lill)和rosiglitazon(Avandia,GlaxcoSmithKline)都是PPAR-α的調控劑。然而，這些化合物均有 潛在的致癌傾向，且在囓齒類動物中已證實有增生功能而導致不同的癌症(PPAR-α調控劑導致大腸直腸癌、膀胱癌，PPAR-γ調控劑導致肝癌)。因此，發現出缺乏這些傾向的PPARs調控劑是有必要的。 Several PPAR-regulated drugs have been shown to be used in humans. Both Fenofibrate and gemfibrozil (both hypolipidemic drugs) are modulators of PPAR-γ; pioglitazone (Actos, Takeda Pharmaceuticals and Eli Lill) and rosiglitazon (Avandia, GlaxcoSmithKline) are modulators of PPAR-α. However, these compounds have Potential carcinogenic tendency, and proliferative function has been demonstrated in rodents leading to different cancers (PPAR-α modulators lead to colorectal cancer, bladder cancer, PPAR-γ modulators lead to liver cancer). Therefore, it has been found that PPARs modulators lacking these tendencies are necessary.

本發明係關於磺酸基取代的雙環化合物，其作為PPAR的調控劑，和治療代謝失調的方法。本發明的一具體內容是有如結構式(I)的化合物： The present invention relates to sulfonic acid substituted bicyclic compounds which act as modulators of PPAR and methods of treating metabolic disorders. A specific aspect of the invention is a compound of formula (I):

或是其鹽類、酯類或前導藥物(prodrug)，其中：A是一飽和或不飽和的碳氫化合物鏈(hydrocarbon chain)，或是一含雜原子的碳氫化合物鏈，且有3至5個原子形成一5至7員環；G₁是共價連接到A的一原子環(在可利用的位置上)，且選自-(CR¹R²)_n-、-Z(CR¹R²)_n-、-(CR¹R²)_nZ-、-(CR¹R²)_rZ(CR¹R²)_s-組成的群組；Z是O、S或NR；n是0、1或2；r與s是0或1； R¹和R²是分別獨立選自氫、鹵素、低烷基、低雜烷基、低烷氧基及低全鹵烷基組成的群組，或者可一起組成一環烷基；X₁、X₂和X₃是分別獨立選自氫、低烷基、環烷基、鹵素、全鹵烷基、羥基、低烷氧基、硝基、氰基及NH₂組成的群組；G₂是選自包含飽和或不飽和的環烷基或是雜環烷基連接子組成的群組，且視需要地經X₄和X₅取代；X₄和X₅是分別獨立選自氫、烷基、鹵素、低全鹵烷基、羥基、烷氧基、硝基、氰基、NH₂及CO₂R組成的群組；R是低烷基和氫；G₃是選自一單鍵、一雙鍵、-(CR³R⁴)_m-、羰基和-(CR³R⁴)_mCR³=CR⁴-組成的群組；m是0、1或2；R³和R⁴是分別獨立選自氫、低烷基、低烷氧基、視需要地經取代的芳香基、低全鹵烷基、硝基及氰基組成的群組；G₄是選自氫、視需要地經取代的芳香基、雜芳香基、環烷基、環雜烷基、環雜芳香基及環烯基組成的群組，且G₃是一單鍵時，G₄可共價連接到G₂。 Or a salt, ester or prodrug thereof, wherein: A is a saturated or unsaturated hydrocarbon chain, or a hetero atom-containing hydrocarbon chain, and has 3 to 5 atoms form a 5 to 7 membered ring; G ₁ is an atomic ring covalently bonded to A (at the available position) and is selected from -(CR ¹ R ² ) _n -, -Z (CR ¹ R ² ) _n -, -(CR ¹ R ² ) _n Z-, -(CR ¹ R ² ) _r Z(CR ¹ R ² ) _s - group of components; Z is O, S or NR; n is 0 , 1 or 2; r and s are 0 or 1; R ¹ and R ² are each independently selected from the group consisting of hydrogen, halogen, lower alkyl, lower heteroalkyl, lower alkoxy and lower perhaloalkyl Or may together form a cycloalkyl group; X ₁ , X ₂ and X ₃ are each independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, halogen, perhaloalkyl, hydroxy, lower alkoxy, nitro, cyanide a group consisting of a group of NH ₂ and G ₂ is selected from the group consisting of a saturated or unsaturated cycloalkyl group or a heterocycloalkyl linker, and optionally substituted with X ₄ and X ₅ ; X ₄ And X ₅ are independently selected from the group consisting of hydrogen, alkyl, halogen, low perhaloalkyl, hydroxy, alkoxy, nitro, cyano, a group consisting of NH ₂ and CO ₂ R; R is a lower alkyl group and hydrogen; G ₃ is selected from a single bond, a double bond, -(CR ³ R ⁴ ) _m -, a carbonyl group, and -(CR ³ R ⁴ _m CR ³ =CR ⁴ - group consisting of; m is 0, 1 or 2; R ³ and R ⁴ are independently selected from hydrogen, lower alkyl, lower alkoxy, optionally substituted aryl a group consisting of a low perhaloalkyl group, a nitro group, and a cyano group; G ₄ is an aromatic group selected from hydrogen, optionally substituted, a heteroaryl group, a cycloalkyl group, a cycloheteroalkyl group, or a cycloheteroaryl group. And a group consisting of a cycloalkenyl group, and when G ₃ is a single bond, G ₄ may be covalently bonded to G ₂ .

另一種觀點，當G₄是氫，G₃是一視需要地經相同或不同芳香基或雜芳香基雙重取代的烷基。 Another point of view, when G ₄ is hydrogen, G ₃ is an alkyl group which is optionally substituted by the same or different aryl or heteroaryl groups.

本發明的另一種觀點是如結構式(I)的化合物，其中A是一有3個原子的鏈並形成一5員環。 Another aspect of the invention is a compound of formula (I) wherein A is a chain of 3 atoms and forms a 5 membered ring.

本發明的另一種觀點是如結構式(I)的化合物，其中A是一有 3個原子的鏈，而且在形成A的鏈中3個原子中至少有1個原子是雜原子，如氮、氧及硫。 Another aspect of the invention is a compound of formula (I) wherein A is one A chain of 3 atoms, and at least 1 of the 3 atoms in the chain forming A is a hetero atom such as nitrogen, oxygen and sulfur.

本發明的另一觀點是有如結構式(II)、(III)和(IV)的化合物： Another aspect of the invention is a compound of formula (II), (III) and (IV):

本發明的另一觀點是有如下面結構式的化合物： Another aspect of the invention is a compound having the formula:

本發明的另一觀點是有如下面結構式的化合物： Another aspect of the invention is a compound having the formula:

本發明的另一觀點是有如下面結構式的化合物： Another aspect of the invention is a compound having the formula:

本發明的另一觀點是有如下面結構式的化合物： Another aspect of the invention is a compound having the formula:

本發明的另一觀點是本發明的化合物，其中：G₁是-(CR¹R²)_n-，其中若A是一3碳鏈，n是0或1；G₂是一有下面結構的環狀基元： Another aspect of the invention is a compound of the invention, wherein: G ₁ is -(CR ¹ R ² ) _n -, wherein if A is a 3 carbon chain, n is 0 or 1; G ₂ is a structure having the following structure Cylindrical element:

其中Y₁和Y₂分別獨立是氮或碳-X₆；X₄和X₅是分別獨立選自氫、烷基、雜烷基、鹵素、低鹵烷基、羥基、烷氧基、硝基、氰基、NH₂和CO₂R組成的群組，其中R是低烷基和氫；p是1、2或3；W是獨立選自-CX₄X₅、N-X₇及一與Y₂一起形成一雙鍵的基元組成的群組；W中的X₄和X₅取代基是獨立選自在G₂其他地方表達的X₄與X₅取代基，因此G₂可經1到4種不同的取代基取代；X₆是選自氫、烷基、羥基、烷氧基、氰基、鹵素、低全鹵烷基以及NH₂組成的群組，或者都沒有，當與Y₁或Y₂形成一雙鍵時；進一步地，若當X₆是烷基、烷氧基或低全鹵烷基時，然後此群組可能有機會連接到G₄；X₇是選自氫、烷基、烷氧基、低全鹵烷基組成的群組，或者都沒有，當與Y₂形成一雙鍵時。 Wherein Y ₁ and Y ₂ are each independently nitrogen or carbon-X ₆ ; X ₄ and X ₅ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, halogen, lower haloalkyl, hydroxy, alkoxy, nitro a group consisting of cyano, NH ₂ and CO ₂ R, wherein R is a lower alkyl group and hydrogen; p is 1, 2 or 3; W is independently selected from -CX ₄ X ₅ , NX ₇ and one and Y ₂ a group consisting of a single bond together; the X ₄ and X ₅ substituents in W are independently selected from the X ₄ and X ₅ substituents expressed elsewhere in G ₂ , so G ₂ can be 1 to 4 Substituted by a different substituent; X ₆ is selected from the group consisting of hydrogen, alkyl, hydroxy, alkoxy, cyano, halogen, lower perhaloalkyl, and NH ₂ , or none, when with Y ₁ or Y _{2 when} a double bond is formed; further, if X ₆ is an alkyl group, an alkoxy group or a low perhaloalkyl group, then this group may have a chance to be attached to G ₄ ; X ₇ is selected from hydrogen, alkyl A group consisting of alkoxy groups, low perhaloalkyl groups, or none, when forming a double bond with Y ₂ .

本發明的另一個觀點是本發明的化合物，其中A包含一有3個原子的鏈，並且形成一5員環。 Another aspect of the invention is a compound of the invention wherein A comprises a chain of 3 atoms and forms a 5 membered ring.

本發明的另一個觀點是本發明的化合物，其中G₃是一單鍵。 Another aspect of the present invention is a compound of the invention wherein G ₃ is a single bond.

本發明的另一個觀點是本發明的化合物，其中p=2，W=-CX₄X₅-或一與Y₂一起形成一雙鍵的基元；Y₁=N。 Another aspect of the invention is a compound of the invention wherein p = 2, W = -CX ₄ X ₅ - or a moiety which together with Y ₂ forms a double bond; Y ₁ = N.

本發明的其他觀點是本發明的化合物，其中G₄是視需要地經取代的苯基或視需要地經取代的吡啶基。 Other aspect of the present invention is a compound of the invention wherein G ₄ is optionally substituted phenyl or optionally substituted pyridyl.

本發明的另一觀點是本發明的化合物，其中G₄是經鹵素、低全鹵烷基或全鹵烷氧基單一或雙重取代。 Another aspect of the present invention is a compound of the invention wherein G ₄ is twofold substituted by halogen, lower perhaloalkyl or a single full or haloalkoxy.

本發明的另一觀點是本發明的化合物，其中R¹和R²是分別獨立選自氫、甲基、乙基、丙基組成的群組，或可一起形成環丙基、環丁基、環戊基、或環己基。 Another aspect of the invention is a compound of the invention, wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, or may together form a cyclopropyl, cyclobutyl, Cyclopentyl, or cyclohexyl.

本發明的其他觀點是本發明的化合物，其中R¹和R²分別是氫。 Other aspect of the present invention is a compound of the present invention, wherein R ¹ and R ² are each hydrogen.

本發明的其他觀點是本發明的化合物，其中X₁、X₂、X₃是分別獨立選自氫、甲基、乙基、丙基和鹵素組成的群組。 A further aspect of the invention is a compound of the invention wherein X ₁ , X ₂ , X ₃ are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl and halogen.

本發明的其他觀點是本發明的化合物，其中X₁、X₂、X₃是分別獨立選自氫和甲基組成的群組。 A further aspect of the invention is a compound of the invention wherein X ₁ , X ₂ , X ₃ are each independently selected from the group consisting of hydrogen and methyl.

本發明的其他觀點是結構式如下的化合物： Other aspects of the invention are compounds of the formula:

其中：G₁是選自-(CR¹R²)_n-和-(CR¹R²)_nO-組成的群組； n是0、1或2；R¹和R²是獨立選自氫、氟、低烷基、低雜烷基、低烷氧基和低全鹵烷基組成的群組，或是R¹與R²可一起形成一環烷基；X₁，X₂，和X₃是分別獨立選自氫、低烷基、環烷基、鹵素、全鹵烷基、羥基、低烷氧基、硝基、氰基及NH₂組成的群組；X₄和X₅是分別獨立選自氫、烷基、鹵素、低全鹵烷基、羥基、烷氧基、硝基、氰基、NH₂和CO₂R組成的群組，或者X₄與X₅可一起組成一碳環；R是選自低烷基和氫組成的群組；G₃是選自一單鍵、一雙鍵、-(CR³R⁴)_m-、羰基和-(CR³R⁴)_mCR³=CR⁴-組成的群組；m是0、1、或2；R³和R⁴分別獨立是氫、低烷基、低烷氧基、視需要地經取代的芳香基、低全鹵烷基、氰基和硝基；G₄是選自氫、視需要地經取代的芳香基、雜芳香基、環烷基、環烯基組成的群組。 Wherein: G ₁ is a group selected from the group consisting of -(CR ¹ R ² ) _n - and -(CR ¹ R ² ) _n O-; n is 0, 1 or 2; and R ¹ and R ² are independently selected from hydrogen a group consisting of fluorine, a lower alkyl group, a lower heteroalkyl group, a lower alkoxy group, and a lower perhaloalkyl group, or R ¹ and R ² may together form a cycloalkyl group; X ₁ , X ₂ , and X ₃ Is a group independently selected from the group consisting of hydrogen, a lower alkyl group, a cycloalkyl group, a halogen, a perhaloalkyl group, a hydroxyl group, a lower alkoxy group, a nitro group, a cyano group, and an NH ₂ group; X ₄ and X ₅ are independently independent a group consisting of hydrogen, alkyl, halogen, low perhaloalkyl, hydroxy, alkoxy, nitro, cyano, NH ₂ and CO ₂ R, or X ₄ and X ₅ may together form a carbocyclic ring ; R is selected from the group consisting of a lower alkyl group and hydrogen; G ₃ is selected from the group consisting of a single bond, a double bond, -(CR ³ R ⁴ ) _m -, a carbonyl group, and -(CR ³ R ⁴ ) _m CR ³ =CR ⁴ - group consisting of; m is 0, 1, or 2; R ³ and R ⁴ are each independently hydrogen, lower alkyl, lower alkoxy, optionally substituted aryl, lower perhalogen a group, a cyano group and a nitro group; G ₄ is a group selected from the group consisting of hydrogen, an optionally substituted aryl group, a heteroaryl group, a cycloalkyl group, and a cycloalkenyl group.

其他觀點是結構式(I)的化合物，其中G₁是-(CR¹R²-)n-，而n是0或1。 Other views are compounds of formula (I) wherein G ₁ is -(CR ¹ R ² -)n- and n is 0 or 1.

本發明的其他觀點是本發明的化合物，其中R¹和R²是分別獨立選自氫、甲基、乙基、丙基組成的群組，或者也可一起形成一環丙基。 Other aspect of the present invention is a compound of the present invention, wherein R ¹ and R ² are each independently selected from the group of hydrogen, methyl, ethyl, propyl composition, or may form a cyclopropyl group.

本發明的其他觀點是本發明的化合物，其中R¹和R²分別 是氫。 Other aspect of the present invention is a compound of the present invention, wherein R ¹ and R ² are each hydrogen.

本發明的其他觀點是本發明的化合物，其中X₁、X₂和X₃是分別獨立選自氫、鹵素、低烷基和低烷氧基組成的群組。 A further aspect of the invention is a compound of the invention wherein X ₁ , X ₂ and X ₃ are each independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy.

本發明的其他觀點是本發明的化合物，其中G₃是一單鍵。 Other aspect of the present invention is a compound of the invention wherein G ₃ is a single bond.

本發明的其他觀點是本發明的化合物，其中G₄有一選自下面群組的結構式： Other aspect of the present invention is a compound of the present invention wherein G ₄ has a structural formula selected from the following group:

其中q是1到3而X₈和X₉是分別獨立選自氫、低全鹵烷氧基、烷基、鹵素、低全鹵烷基、羥基、烷氧基、硝基、氰基、NH₂及CO₂R組成的群組，其中R是低烷基和氫；本發明的另一觀點是藉由以下的結構式表達的化合物：本發明的其他觀點是本發明的化合物，其係為hPPAR-delta調控劑。 Wherein q is 1 to 3 and X ₈ and X ₉ are each independently selected from the group consisting of hydrogen, lower perhaloalkoxy, alkyl, halogen, lower perhaloalkyl, hydroxy, alkoxy, nitro, cyano, NH a group consisting of ₂ and CO ₂ R, wherein R is a lower alkyl group and hydrogen; another aspect of the invention is a compound expressed by the following structural formula: a further aspect of the invention is a compound of the invention, which is hPPAR-delta modulator.

本發明的其他觀點是藥學組成物，其包含本發明的化合物，即hPPAR-delta調控劑。 A further aspect of the invention is a pharmaceutical composition comprising a compound of the invention, i.e., an hPPAR-delta modulator.

本發明的其他觀點是藥學組成物，其進一步包含了藥物可接受的賦形劑或載劑。 A further aspect of the invention is a pharmaceutical composition further comprising a pharmaceutically acceptable excipient or carrier.

本發明的另一觀點是本發明的化合物或藥學組成物，其係藉由調控hPPAR-delta治療疾病或改善狀態。 Another aspect of the invention is a compound or pharmaceutical composition of the invention which is used to treat a disease or to improve a condition by modulating hPPAR-delta.

本發明的另一觀點是本發明的化合物或藥學組成物，其係藉由調控hPPAR-delta用於疾病治療或狀態改善，其中所謂調控hPPAR-delta的疾病或狀態是血脂異常、新陳代謝X症候群、心臟衰竭、高膽固醇血症、心血管疾病、第二型糖尿病、第一型糖尿病、胰島素抗性、高血脂、肥胖、厭食或貪食症、發炎反應和神經性厭食症。 Another aspect of the present invention is a compound or pharmaceutical composition of the present invention for use in the treatment of disease or a state improvement by modulating hPPAR-delta, wherein the disease or condition regulating hPPAR-delta is dyslipidemia, metabolic X syndrome, Heart failure, hypercholesterolemia, cardiovascular disease, type 2 diabetes, type 1 diabetes, insulin resistance, hyperlipidemia, obesity, anorexia or bulimia, inflammatory response and anorexia nervosa.

本發明的另一觀點是本發明的化合物或藥學組成物，其用於製造藥劑，此藥劑藉由調控hPPAR-delta用於預防或治療疾病或狀態改善。 Another aspect of the invention is a compound or pharmaceutical composition of the invention for use in the manufacture of a medicament for the prevention or treatment of a disease or condition by modulating hPPAR-delta.

本發明的其他觀點是具功能性細胞試驗得到EC₅₀少於5μM值的化合物、其藥學上可接受的前導藥物、藥學上活性代謝物、或藥學上可接受的鹽。 Other aspect of the present invention is a functional cellular assay with compound ₅₀ to give values of less than 5μM EC, a pharmaceutically acceptable preamble drugs, pharmaceutically active metabolite, or pharmaceutically acceptable salt thereof.

本發明的另一觀點是一種提高患者HDL的方法，其包含投與治療量的本發明化合物。 Another aspect of the invention is a method of increasing HDL in a patient comprising administering a therapeutic amount of a compound of the invention.

本發明的另一觀點是hPPAR-delta調控劑用於製造藥劑的用途，此藥劑是在病人需要的時，用於提升其HDL。 Another aspect of the invention is the use of an hPPAR-delta modulator for the manufacture of a medicament for boosting its HDL when required by a patient.

本發明的另一觀點是治療患者第二型糖尿病、減少患者胰島素抗性或降低患者血壓的方法，其包含投與治療量的本發明具結構式(I)的化合物。 Another aspect of the invention is a method of treating a patient with type 2 diabetes, reducing insulin resistance in a patient, or reducing blood pressure in a patient comprising administering a therapeutic amount of a compound of formula (I) of the invention.

本發明的另一觀點是有結構式(I)的hPPAR-delta調控劑化 合物用於製造藥劑的用途，此藥劑是在病人需要時，用於治療其第二型糖尿病、減少其胰島素抗性或降低其血壓。 Another aspect of the invention is the hPPAR-delta modulating agent of formula (I) The use of a composition for the manufacture of a medicament for treating a second type of diabetes, reducing its insulin resistance or lowering its blood pressure when needed by a patient.

本發明的另一觀點是減少患者LDLc的方法，其包含投與治療量的本發明任何化合物。 Another aspect of the invention is a method of reducing LDLc in a patient comprising administering a therapeutic amount of any of the compounds of the invention.

本發明的另一觀點是本發明hPPAR-delta調控劑化合物用於製造藥劑的用途，此藥劑是在病人需要時，用於降低其LDLc。 Another aspect of the invention is the use of the hPPAR-delta modulator compounds of the invention for the manufacture of a medicament for reducing LDLc when required by a patient.

本發明的另一觀點是將患者LDL分子從低密度的LDL轉換到正常密度LDL的方法，其包含了投與治療量的hPPAR-delta調控劑化合物。 Another aspect of the invention is a method of converting a patient LDL molecule from a low density LDL to a normal density LDL comprising administering a therapeutic amount of a hPPAR-delta modulator compound.

本發明的另一觀點是hPPAR-delta調控劑化合物用於製造藥劑的用途，此藥劑是在病人需要時將LDL分子大小從低密度轉換到正常密度。 Another aspect of the invention is the use of a hPPAR-delta modulator compound for the manufacture of a medicament for converting LDL molecular size from low density to normal density when required by a patient.

本發明的另一觀點是治療患者包含血管疾病、冠狀心臟疾病、腦血管疾病及末梢血管疾病等動脈粥狀硬化疾病的方法，其包含投與治療量的本發明hPPAR-delta調控劑化合物。 Another aspect of the invention is a method of treating a atherosclerotic disease comprising vascular disease, coronary heart disease, cerebrovascular disease, and peripheral vascular disease in a patient comprising administering a therapeutic amount of a hPPAR-delta modulator compound of the invention.

本發明的另一觀點是本發明hPPAR-delta調控劑化合物用於製造治療動脈粥狀硬化疾病的藥劑，此藥劑是在病人需要時，用於治療包含血管疾病、冠狀心臟疾病、腦血管疾病、末梢血管疾病等疾病。 Another aspect of the present invention is that the hPPAR-delta modulator compound of the present invention is used for the manufacture of an agent for treating atherosclerotic diseases, which is used for treating vascular diseases, coronary heart diseases, cerebrovascular diseases, and Diseases such as peripheral vascular disease.

本發明的另一觀點是治療患者包含類風濕性關節炎、氣喘、骨關節炎和自體免疫疾病等發炎疾病的方法，其包含投與治療量的本發明的hPPAR-delta調控劑化合物。 Another aspect of the invention is a method of treating a patient comprising an inflammatory disease, such as rheumatoid arthritis, asthma, osteoarthritis, and an autoimmune disease, comprising administering a therapeutic amount of a hPPAR-delta modulator compound of the invention.

本發明的另一觀點是本發明hPPAR-delta調控劑化合物用於製造治療發炎疾病的藥劑的用途，此藥劑是在病人需要時，用於治療包含類風濕性關節炎、氣喘、骨關節炎和自體免疫疾病等發炎疾病。 Another aspect of the present invention is the use of the hPPAR-delta modulator compound of the present invention for the manufacture of a medicament for treating an inflammatory disease, which is for treating a patient comprising rheumatoid arthritis, asthma, osteoarthritis and An inflammatory disease such as an autoimmune disease.

本發明的另一觀點是治療hPPAR-delta調控疾病或狀態的方法，包含投與有效治療量的本發明化合物，或其藥學上可接受的鹽類、酯類、醯胺類或前導藥物。 Another aspect of the invention is a method of treating hPPAR-delta to modulate a disease or condition comprising administering a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, guanamine or prodrug thereof.

本發明的另一觀點是調控過氧小體增生活化受體(PPAR)功能的方法，包含以本發明的化合物接觸上述PPAR，並監測細胞型態的改變、細胞的增生、該PPAR的活性、或是該PPAR與自然連接物的連接。 Another aspect of the invention is a method of modulating the function of a peroxisome proliferator-activated receptor (PPAR) comprising contacting a compound of the invention with the PPAR described above, and monitoring changes in cell type, cell proliferation, activity of the PPAR Or the connection of the PPAR to the natural connection.

本發明的另一觀點是調控過氧小體增生活化受體(PPAR)的方法，其中PPAR是選自包含有PPAR-alpha、PPAR-delta及PPAR-gamma的群組。 Another aspect of the invention is a method of modulating a peroxisome proliferator-activated receptor (PPAR), wherein the PPAR is selected from the group consisting of PPAR-alpha, PPAR-delta, and PPAR-gamma.

本發明的另一觀點是治療疾病的方法，其包含確認病人的需求，然後投與該病人有效治療量的本發明化合物，其中該疾病是選自於包含肥胖、糖尿病、高胰島素血症、新陳代謝X症候群、多囊性卵巢症候群、更年期、氧化壓力相關的失調、組織傷害的發炎反應、肺氣腫的發病、局部缺血相關的器官傷害、阿黴素(doxorubicin)引起的心臟傷害、藥物引起的肝中毒、動脈硬化、以及高毒性的肺部傷害。 Another aspect of the invention is a method of treating a condition comprising confirming a patient's needs and then administering to the patient a therapeutically effective amount of a compound of the invention, wherein the disease is selected from the group consisting of obesity, diabetes, hyperinsulinemia, metabolism X syndrome, polycystic ovarian syndrome, menopause, oxidative stress-related disorders, inflammatory response to tissue damage, onset of emphysema, ischemic-related organ damage, doxorubicin-induced heart damage, drug-induced Hepatic poisoning, arteriosclerosis, and highly toxic lung damage.

木發明的另一觀點是化合物，其用於調控過氧小體增生活化 受體的功能，該PPAR較好是選自於包含有PPAR-α、PPAR-δ及PPAR-γ的群組。 Another aspect of the invention of wood is a compound for regulating the activation of peroxisome proliferation Preferably, the PPAR is selected from the group consisting of PPAR-α, PPAR-δ, and PPAR-γ.

本發明的另一觀點是化合物或組成物，其是藉由調控像是PPAR-α、PPAR-δ及PPAR-γ等PPAR用於治療疾病或狀態改善，其中疾病或狀態是血脂異常、新陳代謝X症候群、心臟衰竭、高膽固醇血症、心血管疾病、第二型糖尿病、第一型糖尿病、胰島素抗性高血脂症、肥胖、暴食與厭食、發炎反應和神經性厭食症。 Another aspect of the invention is a compound or composition for the treatment of a disease or condition by the modulation of PPARs such as PPAR-[alpha], PPAR-[delta] and PPAR-[gamma], wherein the disease or condition is dyslipidemia, metabolism X Syndrome, heart failure, hypercholesterolemia, cardiovascular disease, type 2 diabetes, type 1 diabetes, insulin resistance hyperlipidemia, obesity, binge eating and anorexia, inflammatory response, and anorexia nervosa.

本發明的另一觀點是化合物或組成物，其是用來製造藥劑，此藥劑是藉由調控像是PPAR-α、PPAR-δ及PPAR-γ等PPAR用於治療疾病或狀態改善。 Another aspect of the invention is a compound or composition for the manufacture of a medicament for the treatment of a disease or condition by modulation of PPAR such as PPAR-[alpha], PPAR-[delta] and PPAR-[gamma].

本發明揭露一種經酸類或酯類基元，及磺酸基元取代的雙環母分子部分，其可調控至少一種PPAR的功能。於此描述的化合物可活化PPAR-delta和PPAR-gamma、PPAR-alpha和PPAR-delta或所有三種PPAR的亞型，或是顯著地活化hPPAR-gamma、hPPAR-alpha或hPPAR-delta。 The present invention discloses a bicyclic parent molecular moiety substituted with an acid or ester moiety, and a sulfonic acid moiety, which modulates the function of at least one PPAR. The compounds described herein activate PPAR-delta and PPAR-gamma, PPAR-alpha and PPAR-delta or all three PPAR subtypes, or significantly activate hPPAR-gamma, hPPAR-alpha or hPPAR-delta.

本發明係為一種調控至少一種過氧小體增生活化受體功能的方法，包括以如文中所示的結構式I的化合物與PPAR接觸。而細胞表現型的改變、細胞增生、PPAR的活性、PPAR的表現量或PPAR與自然連接物的連接等變化是可以被監測。這樣的方法可以是疾病治療、生物學試驗、細胞試驗或生化試驗等模式。 The invention is a method of modulating the function of at least one peroxisome proliferator-activated receptor comprising contacting a compound of formula I as shown herein with a PPAR. Changes in cell phenotype, cell proliferation, PPAR activity, PPAR performance, or the association of PPAR with natural linkers can be monitored. Such a method may be a mode of disease treatment, biological test, cell test or biochemical test.

本發明描述一種治療疾病的方法，包含確認病人的需求以及投與有效治療量如文中所示的結構式I化合物。因此，在某些具體實施上，本發明的方法治療的疾病可選自包含以下的群組：肥胖、糖尿病、高胰島素血症、新陳代謝X症候群、多囊性卵巢症候群、更年期、氧化壓力相關的失調、組織傷害的發炎反應、肺炎腫的發病、局部缺血相關的器官傷害、阿黴素引起的心臟傷害、藥物引起的肝中毒、動脈硬化和高毒性的肺部傷害。 The present invention describes a method of treating a disease comprising confirming the patient's needs and administering a therapeutically effective amount of a compound of formula I as shown herein. Thus, in certain embodiments, the disease treated by the methods of the invention may be selected from the group consisting of obesity, diabetes, hyperinsulinemia, metabolic X syndrome, polycystic ovarian syndrome, menopause, oxidative stress-related Disorders, inflammatory responses to tissue damage, onset of pneumonia, organ damage associated with ischemia, heart damage caused by doxorubicin, drug-induced liver toxicity, arteriosclerosis, and highly toxic lung damage.

另一觀點，本發明係關於一種調控至少一種過氧小增生活化受體功能的方法，包含以如文中所示的結構式I化合物與PPAR接觸。細胞表現型的改變、細胞增生、PPAR的活性、或PPAR與自然連接物的連接等變化都可以被監測。這樣的方法可以是疾病治療、生物學試驗、細胞試驗或生化試驗等的模式。在某些具體實施上，PPAR可選自包含有PPAR-α、PPAR-δ和PPAR-γ的群組。 In another aspect, the invention relates to a method of modulating the function of at least one peroxired small hyperplastic activated receptor comprising contacting a compound of formula I as shown herein with a PPAR. Changes in cell phenotype, cell proliferation, PPAR activity, or the attachment of PPAR to natural linkers can all be monitored. Such a method may be a mode of disease treatment, biological test, cell test or biochemical test. In certain implementations, the PPAR can be selected from the group consisting of PPAR-α, PPAR-δ, and PPAR-γ.

本說明書所使用的名詞其意思如下：本文中單獨或組合使用的「醯基」乙詞，是指一結合到烯基、烷基、芳香基、環烷基、雜芳香基、雜環或其他基元的羰基，而與羰基鍵結的原子是碳。乙醯基是指-C(=O)CH₃基。 The terms used in this specification have the following meanings: The term "mercapto" as used herein, alone or in combination, means a bond to an alkenyl group, an alkyl group, an aryl group, a cycloalkyl group, a heteroaryl group, a heterocyclic ring or the like. The carbonyl group of the motif, and the atom bonded to the carbonyl group is carbon. Ethylene is a -C(=O)CH ₃ group.

本文中單獨或組合使用的「烯基」乙詞，意指一直鏈或支鏈的碳氫殘基且有一或多個雙鍵並含有2到20個碳原子。單獨或組合的經取代的烯基是指一烷基，其視需要地經如此處定義的芳香基和雜環取代。亞烯基(Alkenylene)意指一連接在二或多個位置上的碳-碳雙鍵系統，如亞乙烯基(ethenylene)[(-CH=CH-)]。合適的烯 基例子包含乙烯基、丙烯基、2-甲基丙烯基、1,4-丁二烯基等。 The term "alkenyl" as used herein, alone or in combination, means a straight or branched hydrocarbon residue having one or more double bonds and containing from 2 to 20 carbon atoms. Substituted alkenyl, alone or in combination, refers to a monoalkyl group which is optionally substituted with an aryl group and a heterocyclic ring as defined herein. Alkenylene means a carbon-carbon double bond system attached at two or more positions, such as ethenylene [(-CH=CH-)]. Suitable alkene Examples of the group include a vinyl group, a propenyl group, a 2-methylpropenyl group, a 1,4-butadienyl group and the like.

本文中單獨或組合使用的「烷氧基」乙詞，意指一烷基醚殘基，其中烷基如前定義。合適的烷基醚殘基例子包含甲氧基、乙氧基、n-丙氧基、異丙氧基、n-丁氧基、異丁氧基、二級丁氧基、三級丁氧基、乙氧基乙氧基、甲氧基丙氧基乙氧基、乙氧基戊氧基乙氧基乙氧基等。 The term "alkoxy" as used herein, alone or in combination, means a monoalkyl ether residue wherein alkyl is as previously defined. Examples of suitable alkyl ether residues include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, bis-butoxy, tert-butoxy Ethoxyethoxy, methoxypropoxyethoxy, ethoxypentyloxyethoxyethoxy and the like.

本文中單獨或組合使用的「烷氧基烷氧基」乙詞，意指一透過另一烷氧基連接到母分子部分的烷氧基。 The term "alkoxyalkoxy" as used herein, alone or in combination, means an alkoxy group which is attached to the parent molecular moiety through another alkoxy group.

本文中單獨或組合使用的「烷氧基烷基」乙詞，意指一透過一烷基連接到母分子部分的烷氧基。 The term "alkoxyalkyl" as used herein, alone or in combination, means an alkoxy group which is attached to the parent molecular moiety through a monoalkyl group.

本文中單獨或組合使用的「烷氧基羰基」乙詞，意指一透過一羰基連接到母分子部分的烷氧基。 The term "alkoxycarbonyl" as used herein, alone or in combination, means an alkoxy group which is attached to the parent molecular moiety through a carbonyl group.

本文中單獨或組合使用的「烷基」乙詞，意指一直鏈或支鏈的烷基殘基，且含有1到20個碳原子。單獨或組合的經取代的烷基，意指一烷基殘基，其視需要地經如此處定義的芳香基和雜環取代。烷基殘基的例子包括甲基、乙基、n-丙基、異丙基、n-丁基、異丁基、二級丁基、三級丁基、戊基、異戊基、己基、辛基、壬基等。 The term "alkyl" as used herein, alone or in combination, means a straight or branched alkyl residue and contains from 1 to 20 carbon atoms. Substituted alkyl, alone or in combination, means a monoalkyl residue which is optionally substituted with an aryl group and a heterocyclic ring as defined herein. Examples of alkyl residues include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tert-butyl, pentyl, isopentyl, hexyl, Xinji, Yanji and so on.

本文中單獨或組合使用的「烷胺基」乙詞，意指一透過一烷基連接到母分子部分的胺基。 The term "alkylamino" as used herein, alone or in combination, means an amine group attached to the parent molecular moiety through a monoalkyl group.

本文中單獨或組合使用的「伸烷基(alkylene)」乙詞，意指一衍生自連接在二或多個位置的直鏈或支鏈的碳氫化合物的飽和脂 肪基(saturated aliphatic group)，如次甲基(-CH₂-)。 The term "alkylene" as used herein, alone or in combination, means a saturated aliphatic group derived from a straight or branched hydrocarbon chain attached at two or more positions. Such as methine (-CH ₂ -).

本文中單獨或組合使用的「烷基羰基」和「烷醯基」乙詞，意指一透過一羰基連接到母分子部分的烷基。 As used herein, the terms "alkylcarbonyl" and "alkyl", alone or in combination, mean an alkyl group attached to the parent molecular moiety through a carbonyl group.

本文中單獨或組合使用的「亞烷基(alkylidene)」乙詞，意指一烯基，其中碳-碳雙鍵的一碳原子屬於與烯基連接的基元。 The term "alkylidene" as used herein, alone or in combination, means an alkenyl group wherein one carbon atom of the carbon-carbon double bond is a moiety attached to an alkenyl group.

本文中單獨或組合使用的「烷磺基」乙詞，意指一透過一磺酸基連接到母分子部分的烷基。 The term "alkylsulfonyl" as used herein, alone or in combination, means an alkyl group attached to the parent molecular moiety through a monosulfonic acid group.

本文中單獨或組合使用的「烷硫基」乙詞，意指一烷基硫醚(R-S-)殘基，其中烷基乙詞如前定義。合適的烷基硫醚殘基例子包含甲硫基、乙硫基、n-丙硫基、異丙硫基、n-丁硫基、異丁硫基、二級-丁硫基、三級-丁硫基、乙氧基乙硫基、甲氧基丙氧基乙硫基、乙氧基戊氧基乙氧基乙硫基等。 The term "alkylthio" as used herein, alone or in combination, means a monoalkyl sulfide (R-S-) residue wherein alkyl is as defined above. Examples of suitable alkyl sulfide residues include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tertiary - Butylthio, ethoxyethylthio, methoxypropoxyethylthio, ethoxypentyloxyethoxyethylthio and the like.

本文中單獨或組合使用的「炔基」乙詞，意指一長鏈或支鏈的碳氫化合物殘基，且有一或多個三鍵結合且較好含有2到20個碳原子。單獨或組合的經取代的炔基，係指一烷基殘基，其視需要地經如此處定義的芳香基和雜環取代。伸炔基(alkynylene)意指連接在兩個位置的碳-碳三鍵，如次乙炔基(ethynylene)(-C≡C-)。炔基殘基的例子包含乙炔基、丙炔基、丁炔基等。 The term "alkynyl" as used herein, alone or in combination, means a long chain or branched hydrocarbon residue having one or more triple bonds and preferably from 2 to 20 carbon atoms. Substituted alkynyl, alone or in combination, refers to a monoalkyl residue which is optionally substituted with an aryl group and a heterocyclic ring as defined herein. Alkynylene means a carbon-carbon triple bond attached at two positions, such as ethynylene (-C≡C-). Examples of the alkynyl residue include an ethynyl group, a propynyl group, a butynyl group and the like.

本文中單獨或組合使用的「醯胺基(amido)」乙詞，意指一如下所述且透過一羰基連接到母分子部分的胺基。本文中單獨或組合使用的「C-胺基(C-amido)」乙詞，意指有R如本文定義的-C(=O)-NR₂基。本文中單獨或組合使用的「N-胺基(N-amido)」乙 詞，意指有R如本文定義的RC(=O)NH基。 The term "amido" as used herein, alone or in combination, means an amine group which is attached to the parent molecular moiety through a carbonyl group as described below. The term "C-amido" as used herein, alone or in combination, means having the radical -C(=O)-NR ₂ as defined herein. The term "N-amido" as used herein, alone or in combination, means R having RC(=O)NH as defined herein.

本文中單獨或組合使用的「胺基」乙詞，意指NR^aR^b，其中R^aR^b是獨立選自氫、烯基、烷氧基、烷氧基烷基、烷氧基羰基、烷基、烷基羰基、芳香基、芳香烯基、芳香烷基、環烷基、鹵烷基羰基、(NR^cR^d)烷基羰基、雜芳香基、雜芳香烯基、雜芳香烷基、雜環、雜環烯基及雜環烷基，其中芳香基、雜芳香烷基的芳香基部分、芳香烷基、雜芳香基、雜芳香烯基的雜芳香基部分、雜芳香烷基的雜芳香基部分、雜環、雜環烯基的雜環部分以及雜環烷基的雜環部分都可經一、二、三、四或五個取代基取代，而這些取代基是獨立選自烯基、烷氧基、烷氧基烷基、烷基、氰基、鹵素、鹵烷氧基、鹵烷基、羥基、羥基烷基(hydroxy-alkyl)、硝基和氧基。 The term "amino" as used herein, alone or in combination, means NR ^a R ^b , wherein R ^a R ^b is independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, Alkyl, alkylcarbonyl, aryl, aromatic alkenyl, arylalkyl, cycloalkyl, haloalkylcarbonyl, (NR ^c R ^d )alkylcarbonyl, heteroaryl, heteroaromatic alkenyl, heteroarylalkyl , heterocyclic, heterocycloalkenyl and heterocycloalkyl, wherein the aryl group, the aromatic moiety of the heteroaromatic alkyl group, the arylalkyl group, the heteroaryl group, the heteroaromatic moiety of the heteroaromatic alkenyl group, the heteroaromatic alkyl group The heteroaryl moiety, the heterocyclic ring, the heterocyclic moiety of the heterocycloalkenyl group, and the heterocyclic moiety of the heterocycloalkyl group may be substituted by one, two, three, four or five substituents, and these substituents are independently selected from Alkenyl, alkoxy, alkoxyalkyl, alkyl, cyano, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxy-alkyl, nitro and oxy.

本文中單獨或組合使用的「胺基烷基」乙詞，意指一透過一烷基連接到母分子部分的胺基。 The term "aminoalkyl" as used herein, alone or in combination, means an amine group attached to the parent molecular moiety through an alkyl group.

本文中單獨或組合使用的「胺基羰基」和「胺甲醯基(carbamoyl)」乙詞，意指一經胺基取代的羰基，其中胺基可選自含烷基、芳香基、芳香烷基、環烷基、環烷基烷基殘基等取代基的一級-胺基或二級-胺基。 The terms "aminocarbonyl" and "carbamoyl" as used herein, alone or in combination, mean carbonyl substituted by an amine group, wherein the amine group may be selected from alkyl, aryl, arylalkyl groups. a primary-amino group or a secondary-amino group of a substituent such as a cycloalkyl group or a cycloalkylalkyl group.

本文中單獨或組合使用的「芳香烷基」和「芳香烷氧基」乙詞，意指如前定義的烷基或烷氧基殘基，且其中至少有1個氫原子經下文提到的芳香基殘基取代。因此，「芳香基」包含如苯甲基、2-苯乙基、二苯甲基甲基、羥基苯基甲基、甲基苯基甲基以及二苯 基甲基等取代基，而「芳香烷氧基(aryloxy)」包含如苯甲基氧基、二苯基甲氧基、4-甲氧基苯基甲氧基等取代基。 The words "aromatic alkyl" and "aromatic alkoxy" as used herein, alone or in combination, mean alkyl or alkoxy residues as defined above, and wherein at least one of the hydrogen atoms is as indicated below. The aryl group is substituted. Therefore, "aromatic group" includes, for example, benzyl, 2-phenylethyl, benzhydrylmethyl, hydroxyphenylmethyl, methylphenylmethyl, and diphenyl. A substituent such as a methyl group, and "aryloxy" includes a substituent such as a benzyloxy group, a diphenylmethoxy group or a 4-methoxyphenylmethoxy group.

本文中單獨或組合使用的「芳香環氧羰基(aralkoxycarbonyl)」乙詞，意指結構式芳香烷基-O-C(O)-的殘基，其中「芳香烷基」如前定義。芳香環氧羰基殘基的例子是苯甲基氧基羰基(Z或Cbz)和4-甲氧基苯基甲氧基羰基(MOS)。 The term "aralkoxycarbonyl" as used herein, alone or in combination, means a residue of the structural arylalkyl-O-C(O)-, wherein "aromatic alkyl" is as defined above. Examples of aromatic epoxycarbonyl residues are benzyloxycarbonyl (Z or Cbz) and 4-methoxyphenylmethoxycarbonyl (MOS).

本文中單獨或組合使用的「芳香烷醯基(aralkanoyl)」乙詞，意指一衍生自經像苯甲醯基(benzoyl)、苯乙醯基(phenylacetyl)、3-苯丙醯基(3-phenylpropionyl)(又稱氫桂皮醯基，hydrocinnamoyl)、4-苯基丁醯基(4-phenylbutyryl)、(2-萘基)乙醯基、4-氯氫桂皮醯基(4-chlorohydrocinnamoyl)、4-胺基氫桂皮醯基(4-aminohydrocinnamoyl)、4-甲氧基氫桂皮醯基(4-methoxyhydroeinnamoyl)等芳香基取代的烷羧酸的醯基殘基。「芳香醯基(aroyl)」乙詞，意指一衍生自芳香羧酸的醯基殘基，而芳香基如前定義。芳香醯基的例子包含經取代或不經取代的苯甲醯基、萘甲醯基，像是苯甲醯基、4-氯苯甲醯基、4-羧基苯甲醯基、4-(苯甲基氧基羰基)苯甲醯基、1-萘甲醯基、2-萘甲醯基、6-羰基-2-萘甲醯基、6-(苯甲基氧基羰基)-2-萘甲醯基、3-苯甲基氧基-2-萘甲醯基、3-羥基-2-萘甲醯基、3-(苯甲基氧基甲醯胺基)-2-萘甲醯基等。 The term "aralkanoyl" as used herein, alone or in combination, means derived from benzoyl, phenylacetyl, 3-phenylpropenyl (3). -phenylpropionyl) (also known as hydrogen cinnamoyl), 4-phenylbutyryl, (2-naphthyl)ethenyl, 4-chlorohydrocinnamoyl, 4- a sulfhydryl residue of an aromatic-substituted alkanecarboxylic acid such as 4-aminohydrocinnamoyl or 4-methoxyhydroeinnamoyl. "Aroyl" means a sulfhydryl residue derived from an aromatic carboxylic acid, and the aryl group is as defined above. Examples of the aromatic fluorenyl group include a substituted or unsubstituted benzamidine group, a naphthylmethyl group, such as a benzamidine group, a 4-chlorobenzylidene group, a 4-carboxybenzylidene group, a 4-(benzene group). Methyloxycarbonyl)benzhydryl, 1-naphthylmethyl, 2-naphthylmethyl, 6-carbonyl-2-naphthylmethyl, 6-(benzyloxycarbonyl)-2-naphthalene Mercapto, 3-benzyloxy-2-naphthylmethyl, 3-hydroxy-2-naphthylmethyl, 3-(benzyloxycarbamoyl)-2-naphthylmethyl Wait.

本文中單獨或組合使用的「芳香基」乙詞，意指一苯基、或雙環或三環稠環系統，其中一或多個綢環是苯基。雙環稠環系統的例子為一稠合如本文定義的環烷基或另一苯基的苯基。三環稠 環系統的例子為一稠合如本文定義的環烷基或另一苯基的雙環稠環系統。芳香基的代表例包含，但不限於，3-乙醯胺基苯基、4-乙醯胺基苯基、2-胺基-3-甲基苯基、3-胺基-1-萘甲醯基、6-胺基-2-萘甲醯基、3-胺苯基、4-(三級-丁氧基)苯基、4-氯苯基、4,6-二甲氧基-2-萘甲醯基、4-氟苯基、4-羥基苯基、2-甲基-3-乙醯胺基苯基、2-甲基-3-胺苯基、蒽基(anthracenyl)、薁基(azulenyl)、2,4-二甲基-3-胺苯基、茀基(fluorenyl)、二氫茚基(indanyl)、茚基(indenyl)、4-甲氧基苯基、3-甲基-4-胺苯基、3-甲基-4-羥基苯基、3-甲基-4-甲氧基苯基、1-萘甲醯基、2-萘甲醯基、3-硝基苯基、苯基、哌嗪苯基、p-甲苯基(p-tolyl)、四氫萘甲醯基(tetrahydronaphthyl)、4-三氟甲氧基苯基及4-三氟甲基苯基。本發明的芳香基可視需要地經一、二、三、四或五個取代基取代，而這些取代基是獨立選自烷氧基、烷氧基羰基、烷基、烷基羰基、烷基羰基胺基、烷氧基羰基、烷基亞磺醯基(alkylsulfinyl)、烷基亞磺醯基胺基、烷磺基、烷磺基胺基、烷硫基、醯胺基、胺基、胺基烷醯基、胺基羰基、芳香環氧羰基胺基、芳香基、芳香環氧羰基、烷氧基羰基胺基、芳香羰基、芳香胺基羰基、芳香氧基、芳香亞磺醯基、芳香亞磺醯基胺基、芳香磺基、芳香磺基胺基、芳香硫基、羧基、氰基、經雙取代的醯胺基、經雙取代的胺基、經雙取代的胺基羰基、鹵烷基、鹵烷氧基、鹵烷基亞磺醯基、鹵烷基亞磺醯基胺基、鹵烷磺基、鹵烷磺基胺基、鹵烷硫基、鹵素、雜環、肼基(hydrazinyl)、肼基羰基、羥基、硝基、磺酸鹽、磺酸、經三取代的矽基(silyl)、-C(=NOH)NH₂、 -C(=NH)NH₂等。而其中芳香基、芳香烷氧基的芳香基部分、芳香烷基的芳香基部分、芳香羰基的芳香基部分、雜芳香基、雜芳香烷氧基的雜芳香基部分、雜芳香烷基的雜芳香基部分、雜環、雜環烷氧基的雜環部分、雜環烷基的雜環部分更可進一步地經1、2、3、4或5個取代基取代，而此取代基是獨立選自烯基、烷氧基、烷基、鹵素、鹵烷氧基、鹵烷基、羥基、羥基烷基及硝基。 The term "aromatic" as used herein, alone or in combination, means a monophenyl or bicyclic or tricyclic fused ring system wherein one or more of the rings is phenyl. An example of a bicyclic fused ring system is a phenyl group fused to a cycloalkyl group as defined herein or another phenyl group. An example of a tricyclic fused ring system is a bicyclic fused ring system fused to a cycloalkyl group as defined herein or another phenyl group. Representative examples of the aryl group include, but are not limited to, 3-ethylaminophenyl, 4-ethylaminophenyl, 2-amino-3-methylphenyl, 3-amino-1-naphthyl Indenyl, 6-amino-2-naphthylmethyl, 3-aminophenyl, 4-(tertiary-butoxy)phenyl, 4-chlorophenyl, 4,6-dimethoxy-2 -naphthylmethyl, 4-fluorophenyl, 4-hydroxyphenyl, 2-methyl-3-ethylaminophenyl, 2-methyl-3-aminephenyl, anthracenyl, anthracene Azulenyl, 2,4-dimethyl-3-amine phenyl, fluorenyl, indanyl, indenyl, 4-methoxyphenyl, 3-methyl 4-Aminophenyl, 3-methyl-4-hydroxyphenyl, 3-methyl-4-methoxyphenyl, 1-naphthylmethyl, 2-naphthylmethyl, 3-nitro Phenyl, phenyl, piperazine phenyl, p-tolyl, tetrahydronaphthyl, 4-trifluoromethoxyphenyl and 4-trifluoromethylphenyl. The aryl group of the present invention may optionally be substituted with one, two, three, four or five substituents independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyl. Amine, alkoxycarbonyl, alkylsulfinyl, alkylsulfinylamino, alkylsulfonyl, alkylsulfonylamino, alkylthio, decylamino, amine, amine Alkyl fluorenyl, aminocarbonyl, aromatic epoxycarbonylamino, aryl, aromatic epoxycarbonyl, alkoxycarbonylamino, aromatic carbonyl, aromatic aminocarbonyl, aromatic oxy, aromatic sulfinyl, aromatic Sulfhydrylamino group, aromatic sulfo group, aromatic sulfoamino group, aromatic thio group, carboxyl group, cyano group, disubstituted guanylamino group, disubstituted amine group, disubstituted aminocarbonyl group, halothane Alkyl, haloalkoxy, haloalkylsulfinyl, haloalkylsulfinylamino, haloalkylsulfonyl, haloalkylsulfonylamino, haloalkylthio, halogen, heterocyclic, fluorenyl Hydrazinyl), mercaptocarbonyl, hydroxy, nitro, sulfonate, sulfonic acid, trisubstituted silyl, -C(=NOH)NH ₂ , -C(=NH)NH ₂ and the like. Wherein an aromatic group, an aromatic moiety of an aromatic alkoxy group, an aromatic moiety of an aromatic alkyl group, an aromatic moiety of an aromatic carbonyl group, a heteroaromatic group, a heteroaromatic moiety of a heteroaromatic alkoxy group, or a heteroaromatic alkyl group The aromatic moiety, the heterocyclic ring, the heterocyclic moiety of the heterocycloalkoxy group, and the heterocyclic moiety of the heterocycloalkyl group may be further substituted with 1, 2, 3, 4 or 5 substituents, and the substituent is independent It is selected from the group consisting of alkenyl, alkoxy, alkyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl and nitro.

本文中單獨或組合使用的「芳香烯基」乙詞，意指一透過一烯基連接到母分子部分的芳香基。 The term "aromatic alkenyl" as used herein, alone or in combination, means an aromatic group attached to the parent molecular moiety through an alkenyl group.

本文中單獨或組合使用的「芳香烷氧基」乙詞，意指一透過一烷氧基連接到母分子部分的芳香基。 The term "aromatic alkoxy" as used herein, alone or in combination, means an aromatic group attached to the parent molecular moiety through an alkoxy group.

本文中單獨或組合使用的「芳香烷基」乙詞，意指一透過一烷基連接到母分子部分的芳香基。 The term "aromatic alkyl" as used herein, alone or in combination, means an aromatic group attached to the parent molecular moiety through a monoalkyl group.

本文中單獨或組合使用的「芳香烷胺基」乙詞，意指一透過一取代氫原子的氮原子連接到母分子的芳香胺基。 The term "aromatic alkylamino" as used herein, alone or in combination, means an aromatic amine group attached to the parent molecule through a nitrogen atom of a substituted hydrogen atom.

本文中單獨或組合使用的「芳香亞烷基(arylalkylidene)」乙詞，意指一透過一亞烷基連接到母分子部分的芳香基。 The term "arylalkylidene" as used herein, alone or in combination, means an aromatic group attached to the parent molecular moiety through an alkylene group.

本文中單獨或組合使用的「芳香烷硫基」乙詞，意指一透過一硫原子連接到母分子部分的芳香烷基。 The term "aromatic alkylthio" as used herein, alone or in combination, means an aromatic alkyl group attached to the parent molecular moiety through a sulfur atom.

本文中單獨或組合使用的「芳香烷基」乙詞，意指一透過一烷基連接到母分子部分的芳香基。 The term "aromatic alkyl" as used herein, alone or in combination, means an aromatic group attached to the parent molecular moiety through a monoalkyl group.

本文中單獨或組合使用的「芳香羰基」乙詞，意指一透過一羰基連接到母分子部分的芳香基。 The term "aromatic carbonyl" as used herein, alone or in combination, means an aryl group attached to the parent molecular moiety through a carbonyl group.

本文中單獨或組合使用的「芳香氧基」乙詞，意指一透過一氧原子連接到母分子部分的芳香基。 The term "aromatic oxy" as used herein, alone or in combination, means an aryl group attached to the parent molecular moiety through an oxygen atom.

本文中單獨或組用使用的「芳香磺基」乙詞，意指一透過一磺酸基連接到母分子部分的芳香基。 The term "aromatic sulfo" as used herein, alone or in combination, means an aromatic group attached to the parent molecular moiety through a monosulfonic acid group.

本文中單獨或組合使用的「芳香硫基」乙詞，意指一透過一硫原子連接到母分子部分的芳香基。 The term "aromatic thio" as used herein, alone or in combination, means an aryl group attached to the parent molecular moiety through a sulfur atom.

本文中單獨或組合使用的「苯並基(benzo)」乙詞，意指一衍生自苯的二價殘基C₆H₄=。其例子包括苯並噻吩(benzothiophene)、苯並咪唑(benzimidazole)。 The term "benzo" as used herein, alone or in combination, means a divalent residue derived from benzene, C ₆ H ₄ =. Examples thereof include benzothiophene and benzimidazole.

本文中單獨或組合使用的「O-胺甲醯基(carbamyl)」乙詞，意指具R如本文定義的-OC(=O)-NR基，。 The term "O-aminocarbamyl" as used herein, alone or in combination, means -C(=O)-NR, as defined herein, R.

本文中單獨或組合使用的「N-胺基碳酸」乙詞，意指具R如本文定義的ROC(=O)NH基。 The term "N-aminocarbacarbonate" as used herein, alone or in combination, means R.sup.6 (=O)NH group as defined herein.

本文中單獨使用的「羰基」乙詞，包含醛基[-(C=O)-H]，而組合使用時，其是-C=O-基。 The term "carbonyl" used herein alone, includes the aldehyde group [-(C=O)-H], and when used in combination, it is a -C=O- group.

本文中使用的「羧基」乙詞，意指-C(O)OH或對應的羧酸根陰離子，如羧酸鹽。「O-羧基」意指具R如本文定義的RC(=O)O-基。「C-羧基」意指具R如本文定義的-C(=O)OR基。 As used herein, the term "carboxy" means -C(O)OH or a corresponding carboxylate anion such as a carboxylate. "O-carboxy" means an RC(=O)O- group having R as defined herein. "C-carboxy" means a radical -R(=O)OR as defined herein.

本文中單獨或組合使用的「氰基」乙詞，意指-CN。 The term "cyano" as used herein, alone or in combination, means -CN.

本文中單獨或組合使用的「環烷基」乙詞，意指飽和或部分飽和的單環、雙環、三環烷基殘基，其中每一環的一基元較好含有3到12碳原子且可能是視需要地經如本文定義的芳香基取代的 苯並基稠環系統。環烷基的例子包含環丙基、環丁基、環戊基、環己基、環庚基、八氫萘甲醯基、2,3-二氫-1H-茚基、金剛烷基(adamantyl)。本文中「雙環」及「三環」意圖包含雙稠環系統，如十氫化萘(decahydonapthalene)、八氫化萘(octahydronapthalene)，也可以是多環飽和或不飽和的型態。後者所述的異構物的例子為雙環[2,2,2]辛烷(bicyclo[2,2,2]octane)、雙環[2,2,2]辛烷(bicyclo[2,2,2]octane)、雙環[1,1,1]戊烷(bicyclo[1,1,1]pentane)、莰酮(camphor)和雙環[3,2,1]辛烷(bicyclo[3,2,1]octane)。 The term "cycloalkyl" as used herein, alone or in combination, means a saturated or partially saturated monocyclic, bicyclic, tricyclic alkyl residue wherein one element of each ring preferably contains from 3 to 12 carbon atoms and May be optionally substituted with an aryl group as defined herein Benzo fused ring system. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl . As used herein, "bicyclic" and "tricyclic" are intended to include double fused ring systems such as decathydon apthalene, octahydronapthalene, or polycyclic saturated or unsaturated forms. Examples of the isomers described in the latter are bicyclo[2,2,2]octane (bicyclo[2,2,2]octane), bicyclo[2,2,2]octane (bicyclo[2,2,2 Octoctane, bicyclo[1,1,1]pentane, camphorone, and bicyclo[3,2,1]octane (bicyclo[3,2,1] ]octane).

本文中單獨或組合使用的「環烷基烷基」乙詞，意指如前文定義且經如前文定義的環烷基殘基取代的烷基。環烷基烷基的例子可包括環丙基甲基、環丁基甲基、環戊基甲基、環己基甲基、1-環戊基乙基、1-環己基乙基、2-環戊基乙基、2-環己基乙基、環丁基丙基、環戊基丙基、環己基丁基等。 The term "cycloalkylalkyl" as used herein, alone or in combination, means an alkyl group as defined above and substituted with a cycloalkyl residue as defined above. Examples of the cycloalkylalkyl group may include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cyclopentylethyl, 1-cyclohexylethyl, 2-cyclopentyl Ethyl, 2-cyclohexylethyl, cyclobutylpropyl, cyclopentylpropyl, cyclohexylbutyl and the like.

本文中單獨或組合使用的「環烷基羰基」乙詞，意指一具一環烷基-(C=O)-結構式的醯基，其中「環烷基」乙詞如前文定義，如環丙基羰基、環己基羰基、金剛烷基羰基、1,2,3,4-四氫-2-萘基、2-乙醯胺-1,2,3,4-四氫-2-萘基、1-羥基-1,2,3,4-四氫-6-萘基等。 The term "cycloalkylcarbonyl" as used herein, alone or in combination, means a fluorenyl group having a monocycloalkyl-(C=O)-formula wherein "cycloalkyl" is as defined above, eg, Propylcarbonyl, cyclohexylcarbonyl, adamantylcarbonyl, 1,2,3,4-tetrahydro-2-naphthyl, 2-acetamidamine-1,2,3,4-tetrahydro-2-naphthyl , 1-hydroxy-1,2,3,4-tetrahydro-6-naphthyl and the like.

本文中單獨或組合使用的「酯」乙詞，意指一連接有羰基的烷氧基、芳香氧基、環烷氧基、雜芳香氧基及雜環氧基。 The term "ester" as used herein, alone or in combination, means an alkoxy group, an aryloxy group, a cycloalkoxy group, a heteroaryloxy group and a heterocyclic oxy group to which a carbonyl group is bonded.

本文中單獨或組合使用「醚」乙詞，意指一連接二基元於碳原子的氧基。 The term "ether" is used herein, alone or in combination, to mean an oxy group attached to a two-membered carbon atom.

本文中單獨或組合使用的「鹵素」乙詞，意指氟、氯、溴或 碘。 The term "halogen" as used herein, alone or in combination, means fluoro, chloro, bromo or iodine.

本文中單獨或組合使用的「鹵烷氧基」乙詞，意指一透過一氧原子連接到母分子部分的鹵烷基。 The term "haloalkoxy" as used herein, alone or in combination, means a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

本文中單獨或組合使用的「鹵烷基」乙詞，意指一如前文定義且一或多個氫原子經鹵素取代的烷基。鹵伸烷基意指一連接到兩或多個位置的鹵烴基(halohydrocarbyl)。例子包括氟亞甲基(-CFH-)、二氟亞甲基(-CF₂-)、氯亞甲基(-CHCl-)等。鹵烷基殘基的例子包含氯甲基、1-溴乙基、氟甲基、二氟甲基、三氟甲基、1,1,1-三氟乙基、全氟癸基等。 The term "haloalkyl" as used herein, alone or in combination, means an alkyl group as defined above and substituted with one or more hydrogen atoms via a halogen. Haloalkyl means a halohydrocarbyl attached to two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF ₂ -), chloromethylene (-CHCl-), and the like. Examples of the haloalkyl residue include a chloromethyl group, a 1-bromoethyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 1,1,1-trifluoroethyl group, a perfluorodecyl group and the like.

本文中單獨或組合使用的「鹵烷基羰基」乙詞，意指一透過一羰基連接到母分子部分的鹵烷基。 The term "haloalkylcarbonyl" as used herein, alone or in combination, means a haloalkyl group attached to the parent molecular moiety through a carbonyl group.

本文中單獨或組合使用的「雜烷基」乙詞，意指一穩定直鏈或支鏈、環狀的碳氫化合物殘基或其組合，其是完全飽和或含有1至3級的不飽和，並由所述數目的碳原子及1至3個選自於氧、氮、硫的雜原子所組成，其中氧、硫係視需要地被氧化，氮係視需要地被季銨化。雜原子氧、氮、硫可位於雜烷基內部的任一位置中。任何二雜原子可為連續的，例如-CH₂-NH-OCH₃-。 The term "heteroalkyl" as used herein, alone or in combination, means a stable straight or branched chain, cyclic hydrocarbon residue or a combination thereof which is fully saturated or contains 1 to 3 stages of unsaturation. And consisting of the number of carbon atoms and 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, wherein oxygen and sulfur are optionally oxidized, and nitrogen is optionally quaternized. The heteroatom oxygen, nitrogen, sulfur may be located at any position within the heteroalkyl group. Any two heteroatoms may be consecutive, for example, -CH ₂ -NH-OCH ₃ -.

本文中單獨或組合使用的「雜芳香基」乙詞，意指一芳香5或6員環，其中至少一原子選自氮、氧和硫，而其餘原子為碳。5員環具有二雙鍵，而6員環具有三雙鍵。雜芳香基是透過一可取代的環中碳原子或氮原子連接到母分子部分。「雜芳香基」乙詞包含一系統，其中一雜芳香基環稠合至一如此處定義的芳香基或雜 環、或是另一雜環基。雜芳香基的例子包含苯噻吩基、苯並二唑基(benzoxadiazolyl)、苯並呋喃基、苯並咪唑基、苯並***基、思啉基(cinnolilyl)、呋喃基、咪唑基、吲哚基、異噁唑基、異喹啉基、異噻唑基、萘啶基、噁二唑基、噁唑基、嘌呤基、噻唑基、噻吩并吡啶基、噻吩基、噻唑基、噻二唑基、吡啶基、噠嗪基、嘧啶基、吡嗪基、吡唑基、吡咯基、吡啶並[2,3-d]嘧啶基、吡咯並[2,3-b]吡啶基、喹唑啉基、喹啉基、噻吩並[2,3-c]吡啶基、四唑基、三嗪基等。本發明的雜芳香基可視需要地經一、兩、三、四或五個取代基取代，而這些取代基是獨立選自烯基、烷氧基、烷氧基烷基、烷氧基羰基、烷基、炔基、烷基羰基、胺基、胺基烷基、芳香基、芳香烷氧基、芳香烷基、芳香烷硫基、芳香炔基、芳香氧基、羧基、氰基、環烷基、鹵素、鹵烷氧基、鹵烷基、二級-雜芳香基、雜芳香烷氧基、雜芳香烷基、雜環、(雜環)烷氧基、(雜環)烷基、肼基、肼基羰基、羥基、羥基烷基、硝基、氧基，其中芳香基、芳香烷氧基的芳香基部分、芳香烷基的芳香基部分、芳香烷硫基的芳香基部分、芳香炔基的芳香基部分、芳香氧基的芳香基部分、二級-雜芳香基、雜芳香烷氧基的雜芳香基部分、雜芳香烷基的雜芳香基部分、雜環、雜環烷氧基的雜環部分、(雜環)烷基的的雜環部分更可進一步視需要地經1、2、3、4或5個取代基取代，而此取代基是獨立選自烯基、烷氧基、烷氧基烷基、烷基、氰基、鹵素、鹵烷氧基、鹵烷基、羥基、羥基烷基、硝基及氧基。 The term "heteroaromatic" as used herein, alone or in combination, means an aromatic 5 or 6 membered ring wherein at least one atom is selected from the group consisting of nitrogen, oxygen and sulfur, and the remaining atoms are carbon. The 5-member ring has two double bonds, while the 6-member ring has three double bonds. A heteroaryl group is attached to the parent molecular moiety through a carbon or nitrogen atom in a substitutable ring. The term "heteroaromatic" includes a system wherein a heteroaromatic ring is fused to an aromatic or heteroatom as defined herein. Ring, or another heterocyclic group. Examples of heteroaryl groups include phenylthienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolilyl, furyl, imidazolyl, anthracene. , isoxazolyl, isoquinolyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, indolyl, thiazolyl, thienopyridyl, thienyl, thiazolyl, thiadiazolyl , pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl , quinolyl, thieno[2,3-c]pyridyl, tetrazolyl, triazinyl and the like. The heteroaromatic group of the present invention may be optionally substituted with one, two, three, four or five substituents which are independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, Alkyl, alkynyl, alkylcarbonyl, amine, aminoalkyl, aryl, arylalkoxy, arylalkyl, arylalkylthio, arylalkynyl, aryloxy, carboxy, cyano, naphthenic Base, halogen, haloalkoxy, haloalkyl, secondary-heteroaryl, heteroaromatic alkoxy, heteroaromatic alkyl, heterocyclic, (heterocyclic) alkoxy, (heterocyclic) alkyl, anthracene Base, mercaptocarbonyl, hydroxy, hydroxyalkyl, nitro, oxy, wherein the aryl group, the aryl moiety of the aryl alkoxy group, the aryl moiety of the arylalkyl group, the aryl moiety of the arylalkylthio group, the aromatic alkyne The aromatic moiety of the group, the aromatic moiety of the aromatic oxy group, the secondary-heteroaryl group, the heteroaryl moiety of the heteroaromatic alkoxy group, the heteroaromatic moiety of the heteroaromatic alkyl group, the heterocyclic ring, the heterocycloalkoxy group The heterocyclic moiety, the heterocyclic moiety of the (heterocyclic)alkyl group may be further substituted with 1, 2, 3, 4 or 5 substituents as needed. And the substituent is independently selected from alkenyl, alkoxy, alkoxyalkyl, alkyl, cyano, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro and oxy .

本文中單獨或組合使用的「雜芳香烯基」乙詞，意指一透過 一烯基連接到母分子部分的雜芳香基。 The term "heteroaromatic alkenyl" as used herein, alone or in combination, means A monoalkenyl group attached to the heteroaryl group of the parent molecular moiety.

本文中單獨或組合使用的「雜芳香烷基烷氧基」乙詞，意指一透過一烷氧基連接到母分子部分的雜芳香基。 The term "heteroarylalkylalkoxy" as used herein, alone or in combination, means a heteroaryl group attached to the parent molecular moiety through an alkoxy group.

本文中單獨或組合使用的「雜芳香烷基」乙詞，意指一透過一烷基連接到母分子部分的雜芳香基。 The term "heteroarylalkyl" as used herein, alone or in combination, means a heteroaryl group which is attached to the parent molecular moiety through a monoalkyl group.

本文中單獨或組合使用的「雜芳香亞烷基」乙詞，意指一透過一亞烷基連接到母分子部分的雜芳香基。 The term "heteroaromatic alkylene" as used herein, alone or in combination, means a heteroaryl group which is attached to the parent molecular moiety through a monoalkylene group.

本文中單獨或組合使用的「雜芳香氧基」乙詞，意指一透過一氧原子連接到母分子部分的雜芳香基。 The term "heteroaryloxy" as used herein, alone or in combination, means a heteroaryl group attached to the parent molecular moiety through an oxygen atom.

本文中單獨或組合使用的「雜芳香磺基」乙詞，意指一透過一磺酸基連接到母分子部分的雜芳香基。 The term "heteroaromatic sulfo" as used herein, alone or in combination, means a heteroaromatic group attached to the parent molecular moiety through a monosulfonic acid group.

本文中單獨或組合使用的「雜環」乙詞，意指一飽和或部分飽和的單環、雙環、或三環的雜環殘基，且包含至少1個，較佳是1到4個、更佳是1到2個氮、氧或硫原子環成員，並有較佳是3到8員環於每環中，更佳是3到7員環在每個環中，而最佳是5到6員環在每個環中。5員環有0或1個雙鍵，而6、7員環有0、1或2個雙鍵。本發明的雜環是透過於環中可取代的碳原子或氮原子連接母分子。「雜環」意圖包含碸、亞碸、三級氮環成員的N-氧化物、碳環的稠環系統、苯並基的稠環系統。「雜環」乙詞也包含一雜環稠合一如本文定義的芳香基或另一雜環的系統。本發明雜環的例子包含氮丙啶基、四氫吖唉基、1,3-苯並二氧基、二氰異吲哚基、二氫異喹啉基、二氫思啉基、二氫苯并二氧基、二氫[1,3] 唑并[4,5b]吡啶基、苯並噻唑基、二氫吲哚基、二氫吡啶基、1,3-二噁烷基、1,4-二噁烷基、1,3-二氧戊環基、異吲哚啉基、嗎啉基、哌嗪基、吡咯烷基、四氫吡啶基、啶基、噻嗎啉基等。本發明的雜環可視需要地經一、二、三、四或五個取代基取代，而這些取代基是獨立選自烯基、烷氧基、烷氧基烷基、烷氧基羰基、烷基、炔基、烷基羰基、胺基、胺基烷基、芳香基、芳香烷氧基、芳香烷基、芳香亞烷基、氰基、(環烷基)亞烷基、鹵素、鹵烷氧基、鹵烷基、雜芳香基、雜芳香烷氧基、雜芳香烷基、雜芳香亞烷基、亞胺基羥基、二級-雜環、雜環烷氧基、(雜環)烷基、雜環亞烷基、羥基、羥基烷基、硝基、氧基，其中芳香基、芳香烷氧基的芳香基部分、芳香烷基的芳香基部分、雜芳香基、雜芳香烷氧基的雜芳香基部分、雜芳香亞烷基的雜芳香基部分、雜芳香烷基的雜芳香基部分、雜芳香亞烷基的雜芳香基部分、二級-雜環、雜環烷氧基的雜環部分、雜環烷基的雜環部分及雜環亞烷基的雜環部分更可進一步視需要地經1、2、3、4或5個取代基取代，而此取代基是獨立選自烯基、烷氧基、烷氧基烷基、烷基、氰基、鹵素、鹵烷氧基、鹵烷基、羥基、羥基烷基、硝基及氧基。 The term "heterocyclic" as used herein, alone or in combination, means a saturated or partially saturated monocyclic, bicyclic or tricyclic heterocyclic residue and includes at least one, preferably from 1 to 4, More preferably, it is one to two nitrogen, oxygen or sulfur atom ring members, and preferably has 3 to 8 member rings in each ring, more preferably 3 to 7 member rings in each ring, and most preferably 5 Go to the 6-member ring in each ring. The 5-member ring has 0 or 1 double-key, while the 6- and 7-member rings have 0, 1 or 2 double keys. The heterocyclic ring of the present invention is bonded to the parent molecule through a carbon atom or a nitrogen atom which may be substituted in the ring. The "heterocyclic ring" is intended to include an N-oxide of a ruthenium, an anthracene, a tertiary nitrogen ring member, a fused ring system of a carbocyclic ring, and a fused ring system of a benzo group. The term "heterocyclic" also encompasses a system wherein a heterocyclic ring is fused to an aromatic group or another heterocyclic ring as defined herein. Examples of the heterocyclic ring of the present invention include aziridine, tetrahydroindenyl, 1,3-benzodioxy, dicyanoisoindenyl, dihydroisoquinolinyl, dihydrosinyl, dihydrogen. Benzodioxy, dihydro[1,3] Zizo[4,5b]pyridyl, benzothiazolyl, indanyl, dihydropyridyl, 1,3-dioxyl, 1,4-dioxyl, 1,3-dioxo Pentocyclo, isoindolyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridyl, pyridine, morpholinyl and the like. The heterocycle of the present invention may be optionally substituted with one, two, three, four or five substituents which are independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkane Base, alkynyl group, alkylcarbonyl group, amine group, aminoalkyl group, aryl group, arylalkoxy group, arylalkyl group, aromatic alkylene group, cyano group, (cycloalkyl)alkylene group, halogen, halogen Oxyl, haloalkyl, heteroaryl, heteroaromatic alkoxy, heteroarylalkyl, heteroaromatic alkylene, imidohydroxy, secondary-heterocyclic, heterocycloalkoxy, (heterocyclic) alkane a heterocyclic alkylene group, a hydroxyl group, a hydroxyalkyl group, a nitro group, an oxy group, wherein the aryl group, the aryl moiety of the aryl alkoxy group, the aryl moiety of the arylalkyl group, the heteroaryl group, the heteroaromatic alkoxy group a heteroaromatic moiety, a heteroaromatic moiety of a heteroaromatic alkylene group, a heteroaromatic moiety of a heteroaromatic alkyl group, a heteroaromatic moiety of a heteroaromatic alkylene group, a secondary-heterocyclic ring, a heterocycloalkoxy group The heterocyclic moiety, the heterocyclic moiety of the heterocycloalkyl group, and the heterocyclic moiety of the heterocycloalkylene group may be further substituted by 1, 2, 3, 4 or 5 as needed. Substituted, and the substituent is independently selected from alkenyl, alkoxy, alkoxyalkyl, alkyl, cyano, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro and oxygen base.

本文中單獨或組合使用的「雜環烯基」乙詞，意指一透過一烯基連接到母分子部分的雜環。 The term "heterocycloalkenyl" as used herein, alone or in combination, means a heterocyclic ring which is attached to the parent molecular moiety through an alkenyl group.

本文中單獨或組合使用的「雜環烷氧基」乙詞，意指一透過一氧原子連接到母分子部分的雜環。 The term "heterocycloalkoxy" as used herein, alone or in combination, means a heterocyclic ring which is attached to the parent molecular moiety through an oxygen atom.

本文中單獨或組合使用的「雜環烷基」乙詞，意指一如前面 定義且經如前定義的雜環取代一個氫原子的烷基，如吡咯基甲基、四氫噻吩甲基、吡啶甲基等。 The term "heterocycloalkyl" as used herein, alone or in combination, means as before An alkyl group which is defined by a heterocyclic ring as defined above and substituted with a hydrogen atom, such as pyrrolylmethyl, tetrahydrothiophenemethyl, pyridylmethyl and the like.

本文中單獨或組合使用的「雜環亞烷基」乙詞，意指一透過一亞烷基連接到母分子部分的雜環。 The term "heterocycloalkylene" as used herein, alone or in combination, means a heterocyclic ring which is attached to the parent molecular moiety through a monoalkylene group.

本文中單獨或組合使用的「肼基」乙詞，意指兩個藉一單鍵連接的胺基，如：-N-N-。 The term "thiol" as used herein, alone or in combination, means two amine groups bonded by a single bond, such as: -N-N-.

本文中單獨或組合使用的「氫離子基(hydrido)」乙詞，意指一氫取代基，例如-H。 The term "hydrido" as used herein, alone or in combination, means a hydrogen substituent such as -H.

本文中單獨或組合使用的「羥基」乙詞，意指OH。 The term "hydroxy" as used herein, alone or in combination, means OH.

本文中單獨或組合使用的「羥基烷基」乙詞，意指一透過一烷基連接到母分子部分的羥基。 The term "hydroxyalkyl" as used herein, alone or in combination, means a hydroxy group attached to the parent molecular moiety through an alkyl group.

本文中單獨或組合使用的「亞胺基」乙詞，意指=N-。 The term "imine" as used herein, alone or in combination, means =N-.

本文中單獨或組合使用的「亞胺基羥基」乙詞，意指=N(OH)及=NO-。片語「在主鏈中」，意指起始於一個基團與本發明化合物的連接點的最長的連續或毗連的碳原子鏈。 The term "imine hydroxy" as used herein, alone or in combination, means =N(OH) and =NO-. The phrase "in the main chain" means the longest continuous or contiguous chain of carbon atoms starting from the point of attachment of a group to a compound of the invention.

「異氰酸基」乙詞，意指-NCO基。 The word "isocyanato" refers to the -NCO group.

「異硫氰酸基」乙詞意指NCS基。 The term "isothiocyanato" refers to the NCS group.

片語「原子直鏈」，意指獨立選自碳、氮、氧和硫的最長原子直鏈。 The phrase "atomic straight chain" means the longest atomic straight chain independently selected from carbon, nitrogen, oxygen and sulfur.

本文中單獨或組合使用的「低烷基」乙詞，意指一包含1到6個碳原子的烷基。 The term "low alkyl" as used herein, alone or in combination, means an alkyl group containing from 1 to 6 carbon atoms.

「硫醇烷基」乙詞，意指一具R和R’如本文定義的R’SR基。 The term "thiolalkyl" refers to an R'SR group, as defined herein, R and R'.

「硫醇硫醇基」乙詞，意指一具R如本文定義的RSR’S-基。 The term "thiol thiol" means a RR'S- group as defined herein.

「硫醇基」乙詞，意指一具R如本文定義的RS基。 The term "thiol" refers to an RS group as defined herein.

「零」乙詞，意指一孤電子對。 The word "zero" means a lone pair.

本文中單獨或組合使用的「-NR^cR^d」乙詞，意指二個基R^c與R^d，此二基是透過氮原子連接至母分子部分。R^c與R^d是分別獨立選自氫和烷基。 The term "-NR ^c R ^d " as used herein, alone or in combination, means two radicals R ^c and R ^d which are attached to the parent molecular moiety through a nitrogen atom. R ^c and R ^d are each independently selected from the group consisting of hydrogen and alkyl.

本文中單獨或組合使用的「(NR^cR^d)烷基」乙詞，意指一透過一烷基連接到母分子部分的-NR^cR^d基。 The term "(NR ^c R ^d )alkyl" as used herein, alone or in combination, means a -NR ^c R ^d group attached to the parent molecular moiety through an alkyl group.

本文中單獨或組合使用的「(NR^cR^d)烷基羰基」乙詞，意指一透過羰基連接到母分子部分的NR^cR^d烷基。 The term "(NR ^c R ^d )alkylcarbonyl" used herein, alone or in combination, means an NR ^c R ^d alkyl group attached to the parent molecular moiety through a carbonyl group.

本文中單獨或組合使用的「硝基」乙詞，意指-NO₂。 The term "nitro" as used herein, alone or in combination, means -NO ₂ .

本文中單獨或組合使用的「氧基(oxy)」乙詞，意指-O-。 The term "oxy" as used herein, alone or in combination, means -O-.

本文中單獨或組合使用的「氧基(oxo)」乙詞，意指=O。 The term "oxo" as used herein, alone or in combination, means =0.

本文中單獨或組合使用的「全鹵烷氧基」乙詞，意指一所有氫原子經鹵素取代的烷氧基。 The term "perhaloalkoxy" as used herein, alone or in combination, means an alkoxy group in which all hydrogen atoms are replaced by a halogen.

本文中單獨或組合使用的「全鹵烷基」乙詞，意指一所有氫原子經鹵素取代的烷基。 The term "perhaloalkyl" as used herein, alone or in combination, means an alkyl group in which all hydrogen atoms are replaced by a halogen.

本文中單獨或組合使用的「殘基」乙詞，意指一取代基或一在連接點的基元。 The term "residue" as used herein, alone or in combination, means a substituent or a motif at a point of attachment.

單獨使用或本文未另定義的「取代的」乙詞，意指連接1到4個選自下列的取代基：烷基、烷基羰基、烷氧基、鹵素、羥基、胺基、硝基、氰基、硫基、鹵烷基、羧基、烷氧基羰基、環烷基、 雜環、烷醯胺基、胺基醯胺基、醯胺基、胺基羰基、芳香羰基、芳香基、芳香氧基、烷氧基羰基、芳香烷氧基羰基、烷氧基羰基胺基、胺基、經雙取代的胺基、經取代的胺基羰基、經取代的醯胺基、經雙取代的醯胺基、芳香烷氧基羰基胺基、烷硫基、烷基亞磺基、烷磺基、烷硫基、芳香基亞磺基、芳香磺基、芳香硫基、雜環、磺酸鹽、磺酸和經三取代的矽基。本文中單獨或組合使用的「磺酸鹽」、「磺酸」、「磺酸的」乙詞，意指-SO₃H基且如磺酸的陰離子係以鹽類形式。 "Substituted", used alone or not otherwise defined herein, means 1 to 4 substituents selected from the group consisting of alkyl, alkylcarbonyl, alkoxy, halo, hydroxy, amine, nitro, Cyano, thio, haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl, heterocyclic, alkanoylamino, aminoguanamine, decylamino, aminocarbonyl, aromatic carbonyl, aryl, aromatic Oxyl, alkoxycarbonyl, arylalkoxycarbonyl, alkoxycarbonylamino, amine, disubstituted amine, substituted aminocarbonyl, substituted guanamine, disubstituted guanidine Amine, aromatic alkoxycarbonylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylthio, arylsulfinyl, aromatic sulfo, aromatic thio, heterocyclic, sulfonate, Sulfonic acid and trisubstituted fluorenyl. The term "sulfonate", "sulfonic acid", or "sulfonic acid" as used herein, alone or in combination, means that the -SO ₃ H group and the anion such as a sulfonic acid are in the form of a salt.

本文中單獨或組合使用的「磺醯基」乙詞，意指-S和-S-。 The term "sulfonyl" used herein, alone or in combination, means -S and -S-.

本文中單獨或組合使用的「亞磺基」乙詞，意指-S(O)-。 The term "sulfinyl" as used herein, alone or in combination, means -S(O)-.

本文中單獨或組合使用的「磺酸基」乙詞，意指-SO₂-。 The term "sulfonic acid group" as used herein, alone or in combination, means -SO ₂ -.

本文中單獨或組合使用的「N-磺醯胺基」乙詞，意指一具R如本文定義的RS(=O)₂NH-基。 The term "N-sulfonylamino" as used herein, alone or in combination, means an R(=O) ₂ NH- group, as defined herein.

本文中單獨或組合使用的「S-磺醯胺基」，意指一具R如本文定義的-S(=O)₂NR₂基。 As used herein, "S-sulfonylamino", alone or in combination, means a radical of the formula -S(=O) ₂ NR ₂ as defined herein.

本文中單獨或組合使用「硫氫基」或「硫基」乙詞，意指-S-基或是氧原子經硫原子取代的醚基。硫基的氧化衍生物，實際上是亞磺基和磺基也包含在硫氫基和硫基的定義中。 The term "sulfhydryl" or "thio" is used herein, alone or in combination, to mean an -S- group or an ether group in which an oxygen atom is substituted with a sulfur atom. The oxidized derivatives of the thio group, in fact, the sulfinyl group and the sulfo group are also included in the definition of the sulfhydryl group and the thio group.

本文中單獨或組合使用的「硫醚基」乙詞，意指一橋接兩母分子部分碳原子的硫基。 The term "thioether group" as used herein, alone or in combination, means a thio group which bridges a carbon atom of a portion of two parent molecules.

本文中單獨或組合使用的「硫醇」乙詞，意指-SH基。 The term "thiol" as used herein, alone or in combination, means -SH group.

本文中單獨使用的「硫胺甲醯基」乙詞包含硫甲醯基 [-(C=S)-H]，而組合使用時，其是-C=S-基。 The term "thiamine thiol" used alone in this article contains thiomethyl thiol [-(C=S)-H], and when used in combination, it is a -C=S- group.

「N-硫胺甲醯基」乙詞，意指具R如本文定義的ROC(=S)NH-基。 The term "N-thiamine-methyl" refers to a RC(=S)NH- group having R as defined herein.

「O-硫胺甲醯基」乙詞，意指具R如本文定義的-OC(=S)-NR基。 The term "O-thiamine-methyl" refers to an -OC(=S)-NR group having R as defined herein.

「硫氰酸」乙詞，意指-CNS基。 The term "thiocyanate" means -CNS.

「三鹵甲烷磺醯胺基」乙詞，意指X為一鹵素且具R如本文定義的X₃CS(=O)₂NR-基。 The term "trihalomethanesulfonamido" means X is a halogen and has the R ₃ CS(=O) ₂ NR- group as defined herein.

「三鹵甲烷磺基」乙詞，意指具X為一鹵素的X₃CS(=O)₂-基。 The term "trihalomethanesulfonyl" means an X ₃ CS(=O) ₂ - group having X as a halogen.

「三鹵甲氧基」乙詞，意指具X為一鹵素的X₃CO-基。 The term "trihalomethoxy" refers to an X ₃ CO- group having X as a halogen.

本文中單獨或組合使用的「經三取代的矽基」乙詞，意指一在三原子價以本文「經取代的胺基」所定義的基團取代的矽氧基。例子包括三甲基矽基、正丁基二甲基矽基、三苯基矽基等。 The term "trisubstituted fluorenyl" as used herein, alone or in combination, means a fluorenyloxy group substituted at a trivalent valent as defined herein by the "substituted amino group". Examples include trimethylsulfonyl, n-butyldimethylhydrazino, triphenylsulfonyl and the like.

當記載取代基而未對取代限制時，經取代與不經取代的形式都被包含。當取代基限定於「經取代的」時，經取代的形式是有特殊意涵的。 When a substituent is described without being limited by substitution, both substituted and unsubstituted forms are included. When a substituent is limited to "substituted", the substituted form has a particular meaning.

本發明的化合物可以存在為治療上可接受的鹽類。 The compounds of the invention may exist as therapeutically acceptable salts.

本文中使用的「治療上可接受的鹽」乙詞，代表本發明化合物的鹽類或兩性離子的型式，其可以是水溶性、脂溶性或可分散性的，且是適合治療疾病，而不帶毒性、疼痛或過敏反應，並有等量合理的利益/風險比，對意欲使用的用途是有效的。鹽類可以在化合物的最後分離和純化製備或藉一胺基與一合適的酸反應而 分離。代表性的酸加成鹽含有醋酸鹽、己二酸鹽、海藻酸鹽、檸檬酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、重硫酸鹽、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、二葡萄糖酸鹽、甘油磷酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、甲酸鹽、延胡索酸鹽、鹽酸鹽、溴酸鹽、碘酸鹽、2-羥基乙基磺酸鹽、乳酸鹽、馬來酸鹽、均三甲苯磺酸鹽、甲基磺酸鹽、萘甲醯基磺酸鹽、菸鹼酸鹽、2-萘磺酸鹽、草酸鹽、巴母酸鹽、果膠酸鹽、過硫酸鹽、3-苯丙酸鹽、苦味酸鹽、三甲基乙酸鹽、丙酸鹽、丁二酸鹽、酒石酸鹽、三氯乙酸鹽、三氟乙酸鹽、磷酸鹽、麩胺酸鹽、重碳酸鹽、對-甲苯磺酸鹽、十一酸鹽。同樣地，本發明化合物中的胺基可以被下列季胺化：甲基、乙基、丙基和丁基的氯化物、溴化物和碘化物；二甲基、二乙基、二丁基和二戊基的磺酸鹽；癸基、十二烷基、十四烷基和甾基的氯化物、溴化物和碘化物；和苯甲基和苯乙基的溴化物。用來形成治療上可接受加成鹽的酸其例子包含：無機酸，像是鹽酸、溴酸、硫酸和磷酸；及有機酸，像是草酸、馬來酸、丁二酸、檸檬酸。 As used herein, the term "therapeutically acceptable salt", which refers to a salt or zwitterionic form of a compound of the invention, may be water soluble, fat soluble or dispersible, and is suitable for treating diseases without With toxicity, pain or allergic reactions, and an equal reasonable benefit/risk ratio, it is effective for the intended use. Salts can be prepared at the final isolation and purification of the compound or by reacting an amine group with a suitable acid. Separation. Representative acid addition salts contain acetate, adipate, alginate, citrate, aspartate, benzoate, besylate, disulfate, butyrate, camphoric acid Salt, camphor sulfonate, digluconate, glycerol phosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, bromate, iodate, 2-hydroxyl Ethyl sulfonate, lactate, maleate, mesitylene sulfonate, methane sulfonate, naphthyl sulfonate, nicotinic acid salt, 2-naphthalene sulfonate, oxalate , palmitate, pectate, persulfate, 3-phenylpropionate, picrate, trimethylacetate, propionate, succinate, tartrate, trichloroacetate, three Fluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonate, eleven acid salt. Likewise, the amine groups in the compounds of the invention may be aminated by the following quaternary groups: chlorides, bromides and iodides of methyl, ethyl, propyl and butyl; dimethyl, diethyl, dibutyl and Sulfonates of dipentyl; chlorides, bromides and iodides of decyl, dodecyl, tetradecyl and decyl; and bromides of benzyl and phenethyl. Examples of the acid used to form the therapeutically acceptable addition salt include inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid and phosphoric acid; and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid.

鹼加成鹽類可在化合物的最後分離和純化時藉由一羧基與一像是金屬氫氧化物、金屬碳酸鹽及金屬重酸鹽等合適的鹼反應，或是與氨或有機的一級、二級或三級胺反應而製備。治療上可接受鹽類的陽離子包括鋰、鈉、鉀、鈣、鎂、鋁及無毒性的四級胺陽離子如銨離子、四甲基銨離子、四乙基銨離子、甲胺、二甲胺、三甲胺、三乙胺、二乙胺、乙胺、三丁胺、吡啶、N,N-二甲基苯胺、N-甲基哌啶、N-甲基嗎啉、二環己胺、普魯卡因、二苯甲胺、 N,N-二苯基苯乙胺、1-二苯羥甲胺及N,N’-二苯基乙烯二胺。其他適用於鹼加成鹽形成的有機胺代表例包括乙烯二胺、乙醇胺、二乙醇胺、哌啶和哌嗪。 The base addition salt can be reacted with a suitable base such as a metal hydroxide, a metal carbonate or a metal heavy acid salt, or with an ammonia or organic first stage, in the final separation and purification of the compound. Prepared by a secondary or tertiary amine reaction. Cations for therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, aluminum and non-toxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine , trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, general Rucaine, diphenylamine, N,N-diphenylphenethylamine, 1-diphenylhydroxymethylamine and N,N'-diphenylethylenediamine. Other representative examples of organic amines suitable for the formation of base addition salts include ethylene diamine, ethanolamine, diethanolamine, piperidine and piperazine.

本發明化合物也可以治療上可接受的前導藥物存在。「治療上可接受的前導藥物」乙詞意指那些適合用在病人中的前導藥物或兩性離子，其是無毒性、疼痛或過敏反應，並有等量合理的與利益/風險比，對意欲使用的用途是有效的。「前導藥物」乙詞意指在活體內轉換成結構式(I)母化合物的化合物，如在血液中水解。當任何變數、取代基或名詞(如：芳香基、雜環、R¹²)在結構式或一般結構中出現超過一次時，其每次出現時的意義是不同於其餘出現時的意義。同理，只要取代基或變數的組合導致可靠的組合，這樣的組合是允許的。 The compounds of the invention may also be present in the form of a therapeutically acceptable prodrug. The term "therapeuticly acceptable lead drug" means the lead drug or zwitterion that is suitable for use in a patient. It is non-toxic, painful or allergic, and has an equal reasonable benefit/risk ratio. The purpose of use is valid. The term "lead drug" means a compound which is converted in vivo to a parent compound of the formula (I), such as hydrolysis in blood. When any variable, substituent or noun (eg, aryl, heterocycle, R ¹² ) occurs more than once in a structural formula or general structure, its meaning at each occurrence is different from the meaning of the remaining occurrence. By the same token, such combinations are permissible as long as the combination of substituents or variables results in a reliable combination.

因為碳-碳雙鍵的存在於本化合物中，本發明思量著碳-碳雙鍵周圍取代基的排列所造成的不同幾何異構物以及其混合型。必須暸解的是本發明包含兩個異構物或其混合物，而其是擁有抑制蛋白質激酶的能力。這些取代基被命名為E或Z結構，其中E表示是在碳-碳雙鍵相對側的高秩序取代基，而Z表示是在碳-碳雙鍵同一側的高秩序取代基。 Because of the presence of carbon-carbon double bonds in the present compounds, the present invention contemplates the different geometric isomers and their hybrid forms resulting from the arrangement of substituents around the carbon-carbon double bond. It must be understood that the invention encompasses two isomers or mixtures thereof which possess the ability to inhibit protein kinases. These substituents are designated as E or Z structures, where E represents a high order substituent on the opposite side of the carbon-carbon double bond and Z represents a high order substituent on the same side of the carbon-carbon double bond.

不對稱中心存在本發明的化合物上。這些中心被命名為”R”或”S”，其係視圍繞在對掌性的碳原子取代基構型而定。應該瞭解的是本發明包含所有立體化學異構物形式，或其混合物，而其是具有抑制蛋白質激酶的能力。化合物的個別立體異構物可從商業 上取得的含對掌中心的起始原料合成而製備得到，或是藉製備對應物產品的混合物，再藉像是轉換成異構物混合物的分離方式，又藉分離或再結晶、色層分離的技術、或是用對掌色層分離管柱對對應物直接分離而製備得到。特殊立體化學的起始化合物不是商業上可取得就是本技術已知技藝可製得的。 Asymmetric centers are present on the compounds of the invention. These centers are designated "R" or "S" depending on the configuration of the carbon atom substituents surrounding the palm. It will be appreciated that the invention encompasses all stereochemically isomeric forms, or mixtures thereof, which are capable of inhibiting protein kinases. Individual stereoisomers of compounds are available from commercial Prepared by synthesizing the starting material containing the center of the palm, or by preparing a mixture of the corresponding product, and then by means of separation into a mixture of isomers, by separation or recrystallization, chromatography The technique is either prepared by directly separating the counterparts from the separation column of the palm color layer. Starting compounds of particular stereochemistry are not commercially available or can be made by techniques known in the art.

「複合治療」意指投與兩種以上治療劑來治療一本揭露提到的治療狀態或疾病，例如：動脈硬化、疼痛、發炎、偏頭痛、瘤增生、血管新生造成的狀態或疾病等。這樣的投與包含在實質上同步行為中共同投與這些治療劑，例如在一具固定比例活性組成的膠囊中，或是在多個不同各別有活性組合的膠囊中。此外，這樣的投與還包含在連續行為中使用每一種治療劑。於其他案例中，養生治療法將提供治療此處提到的狀態或疾病時藥物組合的有益功效。 "Complex therapy" means administration of two or more therapeutic agents to treat a treatment state or disease as disclosed, such as arteriosclerosis, pain, inflammation, migraine, neoplastic hyperplasia, conditions or diseases caused by angiogenesis. Such administration involves co-administering these therapeutic agents in substantially synchronized behavior, such as in a capsule having a fixed ratio of active composition, or in a plurality of capsules each having a separate active combination. In addition, such administration also involves the use of each therapeutic agent in a continuous manner. In other cases, the regimen will provide the beneficial effects of the combination of drugs in the treatment of the conditions or diseases mentioned herein.

「視需要地經取代(optionally substituted)」乙詞，意指前頭基可經取代或不經取代。經取代時，視需要地經取代的基團其取代基的組群不受限制地包括一或多個獨立選自下列組群或命名子集的取代基：(C₁-C₆)烷基、(C₂-C₆)烯基、(C₂-C₆)炔基、(C₁-C₆)雜烷基、(C₁-C₆)鹵烷基、(C₂-C₆)鹵烯基、(C₂-C₆)鹵炔基、(C₃-C₆)環烷基、苯基、(C₁-C₆)烷氧基、苯氧基、(C₁-C₆)鹵烷氧基、胺基、(C₁-C₆)烷胺基、(C₁-C₆)烷硫基、苯基-硫-、氧基、(C₁-C₆)羧酯基、(C₁-C₆)羧基醯胺基、(C₁-C₆)醯氧基、氫原子、鹵素、氰基、硝基、胺基、疊氮基(N₃)、甲胺基、二甲胺基、硫醇基(SH)、甲硫基(SCH₃)、羥 基、甲氧基(OCH₃)、三氟甲氧基(OCF₃)、甲基、三氟甲基、乙醯基(C(O)CH₃)、甲酸甲酯基(CO₂CH₃)、羧基、醯胺基、吡啶基、噻吩、呋喃基、(C₁-C₆)氨基甲酯基(carbamte)、及(C₁-C₆)脲基(urea)。視需要地經取代的基團可能是未經取代的(即-CH2CH₃)、經完全取代的(即-CF₂CF₃)、經單一取代的(即-CH₂CH₂F)、或經單一取代至完全取代之間的(即-CH₂CF₃)。 "optionally substituted" means that the primordial group may be substituted or unsubstituted. When substituted, an optionally substituted group wherein the group of substituents includes, without limitation, one or more substituents independently selected from the group consisting of: (C ₁ -C ₆ )alkyl (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ )alkynyl, (C ₁ -C ₆ )heteroalkyl, (C ₁ -C ₆ )haloalkyl,(C ₂ -C ₆ ) Haloalkenyl, (C ₂ -C ₆ )halynynyl, (C ₃ -C ₆ )cycloalkyl, phenyl, (C ₁ -C ₆ )alkoxy, phenoxy, (C ₁ -C ₆ Haloalkoxy, amine, (C ₁ -C ₆ )alkylamino, (C ₁ -C ₆ )alkylthio, phenyl-sulfo-, oxy, (C ₁ -C ₆ )carboxylate (C ₁ -C ₆ )carboxyguanidino, (C ₁ -C ₆ )methoxy, hydrogen, halogen, cyano, nitro, amine, azide (N ₃ ), methylamino, Dimethylamino, thiol (SH), methylthio (SCH ₃ ), hydroxyl, methoxy (OCH ₃ ), trifluoromethoxy (OCF ₃ ), methyl, trifluoromethyl, acetamidine Base (C(O)CH ₃ ), methyl formate (CO ₂ CH ₃ ), carboxyl, decylamino, pyridyl, thiophene, furyl, (C ₁ -C ₆ )carbamte, And (C ₁ -C ₆ )urea (urea). Optionally substituted groups may be unsubstituted (i.e., -CH2CH _3), it was fully substituted (i.e., -CF ₂ CF _3), substituted by a single (i.e., -CH ₂ CH ₂ F), or with Single substitution to complete substitution (ie -CH ₂ CF ₃ ).

「前導藥物」乙詞意指一在活體內更有活性的化合物。 The term "leading drug" means a compound that is more active in vivo.

於此所述，病人的「治療」是意圖包含預防方法。 As described herein, the "treatment" of a patient is intended to include a method of prevention.

任何名詞在本文沒有明確定義被視為可以被熟悉本技藝人士所了解的。 Any noun is not explicitly defined herein and is considered to be understood by those skilled in the art.

單獨出現並無數字稱號的R或R’，意指一選自包含烷基、環烷基、芳香基、雜芳香基(透過一環中碳連接)以及雜環烷基(透過一環中碳連接)群組的視需要地經取代的基元。 R or R' having no numerical design appears alone, meaning that one selected from the group consisting of an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group (linked through a carbon in a ring), and a heterocycloalkyl group (through a carbon bond in a ring) An optionally substituted primitive of a group.

「單鍵」乙詞，意指一介於二原子的化學鍵，或是一當鍵結的原子被視為較大次結構的一部分時，而介於二基元的化學鍵。 The term "single bond" means a chemical bond between two atoms, or a chemical bond between two atoms when the bonded atom is considered to be part of a larger structure.

在實例中，G₃被視為「一單鍵」，這種構造如下呈現(右邊)是有意圖的：指定G₃瓦解成一單鍵連接G₂和G₄。 In the example, G ₃ is considered to be "a single bond", and this configuration is presented as follows (right) is intentional: designating G _{3 to} collapse into a single bond connection G ₂ and G ₄ .

「活化」乙詞，意指增加PPAR的細胞功能。 The word "activation" means increasing the cellular function of PPAR.

「抑制」乙詞，意指降低PPAR的細胞功能。PPAR的功能可以 是與自然連接體的作用或催化活性。 "Suppress" the word "meaning" to reduce the cellular function of PPAR. PPAR function can It is the interaction or catalytic activity with a natural linker.

「調控」乙詞，意指本發明一種化合物改變PPAR功能的能力。調控劑可以活化PPAR的活性。「調控」乙詞，也意指藉由增加或減少一複合體形成在PPAR和自然連接體間的或然率而調控PPAR的功能。調控劑可增加一複合體形成在PPAR和自然連接體間的或然率，或可據暴露於PPAR的化合物濃度而增加或減少一複合體形成在PPAR和自然連接體間的或然率，或可減少一複合體形成在PPAR和自然連接體間的或然率。 By "control", it is meant the ability of a compound of the invention to alter the function of PPAR. Modulators can activate the activity of PPAR. The term "regulation" also means regulating the function of PPAR by increasing or decreasing the probability of a complex forming between a PPAR and a natural linker. The modulator may increase the likelihood that a complex forms between the PPAR and the natural linker, or may increase or decrease the likelihood of a complex formed between the PPAR and the natural linker depending on the concentration of the compound exposed to the PPAR, or may reduce a complex The body forms a probability between the PPAR and the natural linker.

「監測」乙詞，意指觀察添加本發明化合物到細胞後其效果的方法。效果可證實在細胞型態上的改變、細胞的增生、PPAR的活性或PPAR和自然連接體的作用。當然地，「監測」乙詞，包含偵測是否改變有發生。「複合治療」意指投與兩種以上治療劑來治療一本揭露提到的治療狀態或疾病，例如：動脈硬化、疼痛、發炎、偏頭痛、瘤增生、血管新生造成的狀態或疾病等。這樣的投與包含在實質上同步行為中共同投與這些治療劑，例如在一具固定比例活性組成的膠囊中，或是在多個不同各別有活性組合的膠囊中。此外，這樣的投與還包含在連續行為中使用每一種治療劑。於其他案例中，養生治療法將提供治療此處提到的狀態或疾病時藥物組合的有益功效。 By "monitoring", it is meant a method of observing the effect of adding a compound of the invention to a cell. The effect can be confirmed in cell type changes, cell proliferation, PPAR activity or the role of PPAR and natural linkers. Of course, the word "monitoring" includes detecting whether a change has occurred. "Complex therapy" means administration of two or more therapeutic agents to treat a treatment state or disease as disclosed, such as arteriosclerosis, pain, inflammation, migraine, neoplastic hyperplasia, conditions or diseases caused by angiogenesis. Such administration involves co-administering these therapeutic agents in substantially synchronized behavior, such as in a capsule having a fixed ratio of active composition, or in a plurality of capsules each having a separate active combination. In addition, such administration also involves the use of each therapeutic agent in a continuous manner. In other cases, the regimen will provide the beneficial effects of the combination of drugs in the treatment of the conditions or diseases mentioned herein.

「視需要地經取代(optionally substituted)」乙詞，意指前頭基可經取代或不經取代。經取代時，視需要地經取代的基團其取代基的組群不受限制地包括一或多個獨立選自下列組群或命名子集 的取代基：(C₁-C₆)烷基、(C₂-C₆)烯基、(C₂-C₆)炔基、(C₁-C₆)雜烷基、(C₁-C₆)鹵烷基、(C₂-C₆)鹵烯基、(C₂-C₆)鹵炔基、(C₃-C₆)環烷基、苯基、(C₁-C₆)烷氧基、苯氧基、(C₁-C₆)鹵烷氧基、胺基、(C₁-C₆)烷胺基、(C₁-C₆)烷硫基、苯基-硫-、氧基、(C₁-C₆)羧酯基、(C₁-C₆)羧基醯胺基、(C₁-C₆)醯氧基、氫原子、鹵素、氰基、硝基、胺基、疊氮基(N₃)、甲胺基、二甲胺基、硫醇基(SH)、甲硫基(SCH₃)、羥基、甲氧基(OCH₃)、三氟甲氧基(OCF₃)、甲基、三氟甲基、乙醯基(C(O)CH₃)、甲酸甲酯基(CO₂CH₃)、羧基、醯胺基、吡啶基、噻吩、呋喃基、(C₁-C₆)氨基甲酯基(carbamte)、及(C₁-C₆)脲基(urea)。視需要地經取代的基團可能是未經取代的(即-CH2CH₃)、經完全取代的(即-CF₂CF₃)、經單一取代的(即-CH₂CH₂F)、或經單一取代至完全取代之間的(即-CH₂CF₃)。 "optionally substituted" means that the primordial group may be substituted or unsubstituted. When substituted, an optionally substituted group wherein the group of substituents includes, without limitation, one or more substituents independently selected from the group consisting of: (C ₁ -C ₆ )alkyl (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ )alkynyl, (C ₁ -C ₆ )heteroalkyl, (C ₁ -C ₆ )haloalkyl,(C ₂ -C ₆ ) Haloalkenyl, (C ₂ -C ₆ )halynynyl, (C ₃ -C ₆ )cycloalkyl, phenyl, (C ₁ -C ₆ )alkoxy, phenoxy, (C ₁ -C ₆ Haloalkoxy, amine, (C ₁ -C ₆ )alkylamino, (C ₁ -C ₆ )alkylthio, phenyl-sulfo-, oxy, (C ₁ -C ₆ )carboxylate (C ₁ -C ₆ )carboxyguanidino, (C ₁ -C ₆ )methoxy, hydrogen, halogen, cyano, nitro, amine, azide (N ₃ ), methylamino, Dimethylamino, thiol (SH), methylthio (SCH ₃ ), hydroxyl, methoxy (OCH ₃ ), trifluoromethoxy (OCF ₃ ), methyl, trifluoromethyl, acetamidine Base (C(O)CH ₃ ), methyl formate (CO ₂ CH ₃ ), carboxyl, decylamino, pyridyl, thiophene, furyl, (C ₁ -C ₆ )carbamte, And (C ₁ -C ₆ )urea (urea). Optionally substituted groups may be unsubstituted (i.e., -CH2CH _3), it was fully substituted (i.e., -CF ₂ CF _3), substituted by a single (i.e., -CH ₂ CH ₂ F), or with Single substitution to complete substitution (ie -CH ₂ CF ₃ ).

此處使用的「PPAR調控劑」乙詞，意指一化合物，其具有關於後文記載的標的(TARGET NAME)分析測得的標的活性不超過100μM，更典型地不超過50μM的IC₅₀。「IC₅₀」是指減少酶的活性至半衰期的抑制劑濃度。本發明代表性的化合物已被發現具備對抗PPAR的抑制能力。本發明的化合物較好是具有關於PPAR分析測得的PPAR活性不超過10μM的IC₅₀，更好是不超過5μM的IC₅₀，甚至更好是不超過1μM的IC₅₀，最好是不超過200nM的IC₅₀。 The term "PPAR modulator" as used herein, means a compound having an IC _{50 of} not more than 100 μM, more typically not more than 50 μM, as measured by the TARGET NAME analysis described hereinafter. "IC ₅₀ " refers to the concentration of an inhibitor that reduces the activity of the enzyme to half-life. Representative compounds of the invention have been found to possess the ability to inhibit PPAR. Compounds of the invention preferably has a measured analysis on PPAR PPAR activity does not exceed IC ₅₀ 10μM, more preferably not more than the IC ₅₀ 5μM, even more preferably does not exceed IC ₅₀ 1μM, preferably not more than 200nM IC ₅₀ .

於此所述，病人的「治療」是意圖包含預防方法。「病人」乙詞包含人、牛、犬、山羊、綿羊、豬和兔。 As described herein, the "treatment" of a patient is intended to include a method of prevention. The word "patient" includes humans, cows, dogs, goats, sheep, pigs and rabbits.

本文中使用的「有效治療量」乙詞，意指一被投與的化合物 劑量，其可舒緩一或多個被治療疾病或狀態的症狀達某一程度。關於糖尿病或血脂異常的治療，有效治療量意指劑量可產生下列功效：(1)有效降低血糖濃度；(2)使脂肪正常化，例如三酸甘油脂、低密度脂蛋白；(3)舒緩一或多個此疾病的疾病或狀態的症狀達某一程度；及/或(4)提升HDL。 As used herein, the term "effective therapeutic amount" means a compound that is administered. A dose that relieves the symptoms of one or more of the diseases or conditions being treated to a certain extent. For the treatment of diabetes or dyslipidemia, a therapeutically effective amount means that the dose produces the following effects: (1) effective reduction of blood glucose concentration; (2) normalization of fat, such as triglyceride, low density lipoprotein; (3) soothing One or more symptoms of the disease or condition of the disease to a certain extent; and/or (4) elevated HDL.

「促進」或「促進的」，意指在效力或持續時間上增加或延長需要的效果。因此，關於促進治療劑的效力，「促進」乙詞，意指在效力或持續時間上增加或延長同一系統中其他治療劑的效力。本文中使用的「有效增強量」意指一適當用來增強在一需要的系統中其他治療劑效力的劑量。用於病人時，有效於此用處的劑量是視疾病或狀態的嚴重性及成因、先前治療、病人的健康狀態、對藥物的反應及醫師的判斷而不同。於本技術領域，透過例行實驗決定有效增強量是被完善考量的。 "Promoting" or "promoting" means increasing or prolonging the effect required in terms of effectiveness or duration. Thus, with regard to promoting the efficacy of a therapeutic agent, "promoting" the term means increasing or prolonging the effectiveness of other therapeutic agents in the same system in terms of potency or duration. As used herein, "effective boosting amount" means a dose that is suitably used to enhance the efficacy of other therapeutic agents in a desired system. When used in a patient, the dosage effective for this use will vary depending on the severity and cause of the disease or condition, prior treatment, the health of the patient, the response to the drug, and the judgment of the physician. In the technical field, it is determined by routine experimentation that the effective enhancement amount is considered.

除非另有說明，當取代基意指「視需要地經取代」，代表著此取代基是一可被一或多個獨立選自下列基團取代的基團：烷基、環烷基、芳香基、雜芳香基、雜脂環(heteroalicyclic)、羥基、烷氧基、全鹵烷氧基(較好是全氟烷氧基)、一或二鹵烷氧基、芳香烷基、硫醇基、烷硫基、芳香硫基、氰基、鹵素、羰基、硫羰基、O-胺甲醯基、N-胺甲醯基、O-硫胺甲醯基、N-硫胺甲醯基、C-醯胺基、N-醯胺基、S-磺醯胺基、N-磺醯胺基、C-羧基、O-羧基、異氰酸基、硫氰酸基、異硫氰酸基、硝基、全鹵烷基、全氟烷基、矽基、三鹵甲烷磺醯胺基、胺基含經單一或二取代的胺基及其被保護的 衍生物。保護基(即可形成上述取代基的保護衍生物)已為本技術領域所習知的且可參考像是前文Green and Wuts的文獻。 Unless otherwise indicated, when a substituent means "optionally substituted," it is meant that the substituent is a group which may be substituted by one or more groups independently selected from the group consisting of alkyl, cycloalkyl, aromatic. Base, heteroaromatic, heteroalicyclic, hydroxy, alkoxy, perhaloalkoxy (preferably perfluoroalkoxy), mono or dihaloalkoxy, arylalkyl, thiol , alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-amine, mercapto, N-amine, thiol, O-thiamine, N-thiamine, C - amidino group, N-nonylamino group, S-sulfonylamino group, N-sulfonylamino group, C-carboxyl group, O-carboxyl group, isocyanate group, thiocyanate group, isothiocyanate group, nitrate Group, perhaloalkyl, perfluoroalkyl, decyl, trihalomethanesulfonylamino, amine group containing a mono- or disubstituted amine group and protected thereof derivative. Protecting groups (i.e., protective derivatives which form the above substituents) are well known in the art and reference is made to the literature such as Green and Wuts.

本發明的分子具體實施例可具有一或多個對掌性的中心以及每個中心可以以R或S構型存在。本發明包含所有的非鏡像異構物、對掌性異構物、差象異構物等形式也包含其混合物。假如需要，立體異構物可由本技術領域已知的方法製得，例如利用對掌性色層分析管柱分離立體異構物。另外，本發明的化合物可以以幾何異構物存在。本發明包含所有順式(cis)、反式(trans)、syn、anti、E形、Z形異構物也包含其混合物。 Molecular embodiments of the invention may have one or more centers of palmarity and each center may exist in the R or S configuration. The invention encompasses all forms of non-image isomers, palmitic isomers, poor image isomers, and the like, as well as mixtures thereof. If desired, the stereoisomers can be prepared by methods known in the art, for example, by separating the stereoisomers using a palm color analysis column. Additionally, the compounds of the invention may exist as geometric isomers. The invention encompasses all cis, trans, syn, anti, E, Z isomers as well as mixtures thereof.

在某種情況，化合物可以以互變異構體形式存在。所有互變異構體包含在結構式I，而且被本發明所提供。 In some cases, the compounds may exist in tautomeric forms. All tautomers are included in Structural Formula I and are provided by the present invention.

除此之外，本發明的化合物可以以非溶解形式存在，也可以以溶解在治療上可接受溶劑如水或乙醇等的溶解形式存在。一般來說，溶解形式被認為在本發明目的上是等同於非溶解形式。 In addition to this, the compounds of the present invention may exist in an undissolved form or in a dissolved form dissolved in a therapeutically acceptable solvent such as water or ethanol. In general, the dissolved form is considered equivalent to the undissolved form for the purposes of the present invention.

另一觀點，本發明係關於一種治療疾病的方法，其包含確認病人的需求，以及投與病人有效治療量的如此處所述的結構式I化合物。 In another aspect, the invention is directed to a method of treating a condition comprising determining a patient's need, and administering to the patient a therapeutically effective amount of a compound of formula I as described herein.

PPAR的第三亞型，PPAR-δ(NUC1)，是在身體中被廣泛地表現並已顯示為一在治療血脂異常和其他疾病上有價值的分子標的。例如，在近期胰島素抗性的肥胖恆河猴的研究上，一種有潛力和選擇性的PPAR-δ化合物顯示出在劑量反應的方式下可以有效降低VLDL和提高HDL，請參見Oliver et al.,Proc.Natl.Acad.Sci.U. S.A.98：5305,2001。同樣地，在近期野生型及HDL缺乏(ABCA1^-/-)老鼠的研究上，另一種有潛力和選擇性的PPAR-δ化合物已顯示出可以減低部分小腸內膽固醇的吸收，並伴隨著降低膽固醇吸收蛋白NPC1L1的表現，請參見van der Veen et al.,J.Lipid Res.2005 46：526-534。 The third subtype of PPAR, PPAR-δ (NUC1), is widely expressed in the body and has been shown to be a valuable molecular marker in the treatment of dyslipidemia and other diseases. For example, in a recent study of insulin-resistant obese rhesus monkeys, a potential and selective PPAR-delta compound has been shown to effectively reduce VLDL and increase HDL in a dose-response manner, see Oliver et al. USA 98: 5305, 2001. Proc. Natl. Acad. Sci. Similarly, in recent studies of wild-type and HDL-deficient (ABCA1 ^-/- ) mice, another potential and selective PPAR-δ compound has been shown to reduce cholesterol absorption in some small intestines, accompanied by lowering cholesterol. For the performance of the absorption protein NPC1L1, see van der Veen et al., J. Lipid Res. 2005 46:526-534.

本發明的化合物是藉由調控hPPAR-delta來治療疾病或改善狀態。藉由PPAR-delta調控並使用此類化合物和組成物的特定疾病和狀態包含但並不限定於，血脂異常、X症狀、心臟衰竭、高膽固醇血症、心血管疾病、第二型糖尿病、第一型糖尿病、胰島素抗性、高血脂、肥胖、厭食或貪食症、發炎反應和神經性厭食症。其它的指示包含疤的縮小及傷口癒合。 The compounds of the invention are used to treat disease or improve condition by modulating hPPAR-delta. Specific diseases and conditions regulated and used by PPAR-delta for such compounds and compositions include, but are not limited to, dyslipidemia, X symptoms, heart failure, hypercholesterolemia, cardiovascular disease, type 2 diabetes, Type 1 diabetes, insulin resistance, hyperlipidemia, obesity, anorexia or bulimia, inflammatory response and anorexia nervosa. Other indications include the reduction of tendon and wound healing.

本發明的化合物也可用來(a)提升患者的HDL；(b)治療患者的第二型糖尿病、降低患者的胰島素抗性或降低患者的血壓；(c)降低患者LDLc；(d)轉移患者的LDL分子大小從低密度到正常密度的LDL；(e)降低患者膽固醇的吸收或增加患者膽固醇的釋放；(f)降低患者NPC1L1的表現；(g)治療患者包含血管疾病、冠狀心臟疾病、腦血管疾病和末梢血管疾病等動脈粥狀硬化疾病；以及(h)治療患者包含類風濕性關節炎、氣喘、骨關節炎和自體免疫疾病等發炎疾病。 The compounds of the invention may also be used to (a) enhance a patient's HDL; (b) treat a patient's type 2 diabetes, reduce the patient's insulin resistance or reduce the patient's blood pressure; (c) reduce the patient's LDLc; (d) metastasize the patient LDL molecules range in size from low to normal density LDL; (e) reduce cholesterol absorption in patients or increase cholesterol release in patients; (f) reduce the performance of patients with NPC1L1; (g) treat patients with vascular disease, coronary heart disease, An atherosclerotic disease such as cerebrovascular disease and peripheral vascular disease; and (h) treatment of patients with inflammatory diseases such as rheumatoid arthritis, asthma, osteoarthritis, and autoimmune diseases.

本發明的化合物也可用在治療、改良或預防疾病或狀態，其是選自於包含肥胖、糖尿病、高胰島素血症、新陳代謝X症候群、多囊性卵巢症候群、更年期、氧化壓力相關的失調、組織傷害的 發炎反應、肺氣腫的發病、局部缺血相關的器官傷害、阿黴素引起的心臟傷害、藥物引起的肝中毒、動脈硬化及高毒性的肺部傷害。 The compounds of the invention may also be used in the treatment, amelioration or prevention of diseases or conditions selected from the group consisting of obesity, diabetes, hyperinsulinemia, metabolic X syndrome, polycystic ovarian syndrome, menopause, oxidative stress related disorders, tissues Injured Inflammatory response, onset of emphysema, organ damage associated with ischemia, heart damage caused by doxorubicin, drug-induced hepatotoxicity, arteriosclerosis, and highly toxic lung injury.

包含此處提到的化合物的組成物可用來預防及/或治療。在治療的應用上，投與有效劑量組成物到一已感染PPAR中介、調控或涉及的疾病或狀態的病人來治癒或部分遏止疾病或狀態的症狀，這些疾病或狀態包含但不限於代謝疾病或狀態的病狀。有效於此用處的劑量是視疾病或狀態的嚴重性及成因、先前治療、病人的健康狀態、對藥物的反應及醫師的判斷而不同(如劑量逐漸增加的臨床試驗)。 Compositions comprising the compounds mentioned herein are useful for prevention and/or treatment. In therapeutic applications, an effective dosage composition is administered to a patient who has been infected, regulated or involved in a disease or condition associated with PPAR to cure or partially arrest the symptoms of the disease or condition, including but not limited to metabolic diseases or The condition of the state. The dosage effective for this use will vary depending on the severity and cause of the disease or condition, prior treatment, the health of the patient, the response to the drug, and the judgment of the physician (e.g., clinical trials with increasing doses).

在預防的應用上，投與包含此處提到的化合物的組成物到可能會感染或具高風險的PPAR中介、調控或涉及的疾病或狀態的病人，而這些疾病或狀態包含但不限於代謝疾病或狀態的病狀。這樣的劑量定義為「預防上有效量或劑量」。在這個用途，確切的量也是視病人的健康狀態、體重而不同。於本技術領域，透過例行實驗(如劑量逐漸增加的臨床試驗)決定預防上有效量是被完善考量的。 In the context of prophylaxis, administration of a composition comprising a compound referred to herein to a patient or a disease or condition that may be infected or at high risk of PPAR mediation, regulation or involvement, including but not limited to metabolism The condition of the disease or condition. Such a dose is defined as "prophylactically effective amount or dose". In this use, the exact amount varies depending on the patient's state of health and weight. In the art, routine testing (such as clinical trials with increasing doses) determines that the effective amount of prevention is well considered.

一旦病人的狀態有所改善時，如需要，投與維持的劑量。隨後，根據症狀，劑量或投與頻率，或兩者，可減少至被改善的疾病或狀態維持的程度。當症狀已經被減緩到所需的程度，治療可以終止。然而，於任何症狀復發時，病人可以要求長時間的間歇性治療。 Once the patient's condition has improved, the dose is maintained as needed. Subsequently, depending on the symptoms, the dose or frequency of administration, or both, it can be reduced to the extent that the disease or condition is improved. When the symptoms have been slowed to the desired level, treatment can be terminated. However, in the event of any recurrence of symptoms, the patient may require intermittent treatment for a prolonged period of time.

特定治療劑的量將會與如此的劑量相符，且會依不同的因素而有所不同，如特殊的化合物、疾病狀態和其嚴重性、患者或需要此治療的主人的狀態特性(例如體重)但仍可以根據案例周圍的特殊環境以本技術熟知的方式例行性地決定，包含，例如：被投與的特殊治療劑投與的途徑、被治療的狀態、以及被治療的患者或主人。然而，一般來說，成人治療所採用的劑量將會典型地位在每天0.02-5000毫克，較佳地是每天1-1500毫克。所需的劑量可被合適地以單一劑量表現，或在適當間隔投與分別劑量，例如每天二、三、四或更多的次劑量。 The amount of a particular therapeutic agent will be consistent with such a dose and will vary depending on factors such as the particular compound, the condition and severity of the condition, or the conditional characteristics of the patient or the owner in need of such treatment (eg, weight) However, it can still be routinely determined in a manner well known in the art, depending on the particular circumstances surrounding the case, including, for example, the route by which the particular therapeutic agent is administered, the condition being treated, and the patient or owner being treated. However, in general, the dosage for adult treatment will typically be between 0.02 and 5000 mg per day, preferably between 1 and 1500 mg per day. The desired dose can be suitably presented in a single dose, or separate doses administered at appropriate intervals, for example two, three, four or more sub-doses per day.

在某些例子，投與至少一於此處所需的化合物(或藥學上可接受的酸類、酯類、胺類、前導藥物或溶劑)並複合其他治療劑是適當的。經由這個例子，假如一病人接受此處的化合物經歷到的副作用其中一種是高血壓，投與抗高血壓治療劑並複合起初的治療劑是適當的。或是經由這個例子，任一此處提到的化合物的治療功效可透過投與佐藥來提升(亦即佐藥本身只有些微的治療功效，但複合其他治療劑後，對病人的整體治療功效可能提升)。或是經由這個例子，病人經歷到的功效可藉由投與此處提到的化合物及另一也具治療功效的治療劑(其包含養生治療法)來增加。或是經由這個例子，在牽涉投與此處描述的一化合物對糖尿病的治療中，增強的治療功效可能藉由提供病人另一糖尿病治療劑而發生。在任何案例中，不管被治療的疾病或狀態，病人經歷到的整體功效可以是二治療劑簡單附加的或病人經歷到協同作用的功 效。 In certain instances, it may be appropriate to administer at least one of the compounds (or pharmaceutically acceptable acids, esters, amines, prodrugs or solvents) required herein and in combination with other therapeutic agents. By way of this example, if a patient receives a side effect experienced by a compound herein, one of which is hypertension, it is appropriate to administer an antihypertensive therapeutic with a combination of the original therapeutic agent. Or via this example, the therapeutic efficacy of any of the compounds mentioned herein can be enhanced by administration of an adjuvant (ie, the adjuvant itself has only a slight therapeutic effect, but after combining other therapeutic agents, the overall therapeutic efficacy of the patient May improve). Or via this example, the efficacy experienced by the patient can be increased by administering a compound as referred to herein and another therapeutic agent that also has therapeutic efficacy, which includes a regimen of health care. Or via this example, in the treatment of diabetes involving a compound described herein, enhanced therapeutic efficacy may occur by providing the patient with another diabetes therapeutic. In any case, regardless of the disease or condition being treated, the overall efficacy experienced by the patient may be the simple addition of the second therapeutic agent or the patient's experience of synergy. effect.

特別的是，可能的複合治療不被限制的例子包含結構式I化合物與：(a)statin和/或其他降血脂藥物，例如MTP抑制劑和LDLR正向調控劑；(b)抗糖尿病藥物，例如metformin、磺醯脲、或PPAR-gamma、PPAR-alpha和PPAR-alpha/gamma調控劑(例如噻唑烷二酮，如Pioglitazone和telmisartan)；(c)抗高血壓藥物，例如血管收縮素的拮抗劑(如telmisartan)、鈣離子通道拮抗劑，(如lacidipine)和ACE抑制劑(如enalapril)。 In particular, examples of possible combination therapy are not limited to include a compound of formula I with: (a) statin and/or other hypolipidemic agents, such as MTP inhibitors and LDLR positive modulators; (b) anti-diabetic agents, For example, metformin, sulfonylurea, or PPAR-gamma, PPAR-alpha and PPAR-alpha/gamma modulators (such as thiazolidinediones such as Pioglitazone and telmisartan); (c) antagonism of antihypertensive drugs such as angiotensin Agents (such as telmisartan), calcium channel antagonists (such as lacidipine) and ACE inhibitors (such as enalapril).

在任何案例中，多重治療藥物(其中之一是在這裡描述的化合物之一)也許可以以任何順序或同時地被投與。假如是同時地，多重治療藥物以單一、聯合形式或多重的形式被提供(經由這個例子，以單一藥片或兩分開的藥片)。治療劑之一也許可以多種劑量的形式被提供，或兩者都以多種劑量的形式被提供。假如不是同時地，多種劑量用藥時間點也許會從多於零周到少於四周之間而改變。 In any case, multiple therapeutic drugs (one of which is one of the compounds described herein) may be administered in any order or simultaneously. If at the same time, multiple therapeutic agents are provided in a single, combined or multiple form (via this example, a single tablet or two separate tablets). One of the therapeutic agents may be provided in a variety of dosage forms, or both in a variety of dosage forms. If not simultaneously, the timing of multiple doses may vary from more than zero weeks to less than four weeks.

合適的投與途徑也許包含，例如：口部、直腸的、黏膜間、肺部、眼部或腸部的投與；腸胃外的傳遞，包含肌肉內的、皮下的、靜脈的、脊髓的注射，還有椎管內、直接腦室內、腹腔的、鼻內的或眼內的注射。 Suitable routes of administration may include, for example, oral, rectal, intermucosal, pulmonary, ocular or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, spinal injection There are also intraspinal, direct intraventricular, intraperitoneal, intranasal or intraocular injections.

擇一地，可以局部地投與化合物而非全身性地，例如，經常以儲存或持續釋放的劑型直接地注射化合物到器官。再者，可以投與藥物於標靶性的藥物傳遞系統如於表面有器官特異性抗體的 微脂體。微脂體會以器官為標的並選擇地被器官吸收。 Alternatively, the compound can be administered topically rather than systemically, for example, the compound is often injected directly into the organ in a dosage form that is stored or sustained release. Furthermore, drugs can be administered to targeted drug delivery systems such as organ-specific antibodies on the surface. Microlipids. The liposomes are organ-targeted and selectively absorbed by the organ.

本發明的藥學組成物可以以已知的方式製造，例如：依常見的混合、溶解、造粒、膜衣錠的製造、磨碎、乳化、膠囊化、封裝或壓縮的流程。 The pharmaceutical compositions of the present invention can be made in a known manner, for example, according to the usual mixing, dissolving, granulating, film ingot manufacturing, milling, emulsifying, encapsulating, encapsulating or compressing processes.

根據本發明使用的藥學組成物因此可以使用一或多個生理上可接受的載劑的方式製備，此載劑包含促進活性化合物變成藥理上使用的調劑過程的賦形劑及助劑。適當劑型是取決於投與途徑的選擇。任何已知的技術、賦形劑及助劑是作為適當的及本技術瞭解的，如前面的Remington’s Pharmaceutical Sciences。 The pharmaceutical compositions used in accordance with the present invention may thus be prepared by the use of one or more physiologically acceptable carriers which comprise excipients and auxiliaries which facilitate the formulation of the active compound into a pharmacologically acceptable formulation. The appropriate dosage form is the choice depending on the route of administration. Any known techniques, excipients, and auxiliaries are known as appropriate and in the art, such as Remington's Pharmaceutical Sciences, supra.

對於靜脈注射，本發明的藥物也能製備於水溶液中，較佳地生理上可相容的緩衝液，如Hank’s溶液、Ringer’s溶液或生理食鹽水緩衝液。對於黏膜間的投與，適用於穿越壁障的滲透劑可被用在此劑型中。這類的滲透劑在本技術是已知的。對於腸胃外的注射，本發明的藥物可以製備在水溶液或非水溶液中，較佳地是利用生理上可相容的緩衝液或賦形劑。這類的賦形劑是本技術已知的。 For intravenous injection, the medicament of the present invention can also be prepared in an aqueous solution, preferably a physiologically compatible buffer such as Hank's solution, Ringer's solution or physiological saline buffer. For intermucosal administration, penetrants suitable for crossing the barrier can be used in this dosage form. Such penetrants are known in the art. For parenteral injection, the medicament of the invention may be prepared in an aqueous or non-aqueous solution, preferably using a physiologically compatible buffer or excipient. Excipients of this type are known in the art.

對於口部的投藥，化合物可藉由結合活性化合物與本技術已知的藥學上可接受的載劑或賦形劑而立即配製。這類的載劑使本發明的化合物配製成藥片、粉末、藥丸、糖衣錠、膠囊、液體、凝膠、含藥糖漿、萬能藥、漿料、懸浮液等，以用於被治療病人的口部攝取。口服的藥學調劑可藉由混合一或多個賦形劑或一或多個本發明的化合物、視需要地研磨得到的混合物及如需要在添 加合適的助劑後處理混合物以得到藥片或糖衣錠核心而獲致。合適的賦形劑特別是填充劑，如包含乳糖、蔗糖、甘露蜜醇或山梨醇的糖類；纖維素調劑，如玉米、澱粉，小麥澱粉、稻米澱粉、馬鈴薯澱粉、明膠、天然龍膠、甲基纖維素、微晶纖維素、羥丙基甲基纖維素、鈉羧甲基纖維素；或其他，如聚乙烯吡咯烷酮(PVP或povidone)或磷酸鈣。假如需要，可添加崩解劑，如交聯的甲基纖維素鈉、聚乙烯吡咯烷酮、瓊酯、或海藻酸、或者是其鹽，像是藻酸鈉。 For oral administration, the compounds can be formulated immediately by combining the active compound with a pharmaceutically acceptable carrier or excipient known in the art. Such carriers allow the compounds of the present invention to be formulated into tablets, powders, pills, dragees, capsules, liquids, gels, medicated syrups, panacea, slurries, suspensions, and the like, for use in the mouth of a patient being treated Ingestion. A pharmaceutical formulation for oral administration can be prepared by mixing one or more excipients or one or more compounds of the invention, optionally grinding the mixture, and if desired The mixture is treated with a suitable adjuvant to obtain a tablet or dragee core. Suitable excipients are, in particular, fillers, such as sugars comprising lactose, sucrose, mannitol or sorbitol; cellulose conditioners such as corn, starch, wheat starch, rice starch, potato starch, gelatin, natural longan, a Cellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If necessary, a disintegrating agent such as crosslinked methylcellulose sodium, polyvinylpyrrolidone, agarate, or alginic acid, or a salt thereof such as sodium alginate may be added.

提供合適的外膜給糖衣錠核心。為了這個目的，濃縮的糖溶液可以被使用，其視需要地包含***膠、滑粉、聚乙烯吡咯烷酮、carbopol膠、聚乙二醇及/或二氧化鈦、漆溶液、以及合適的有機溶劑或溶劑混合物。合成染料或顏料也可添加在藥片或是膜衣錠外膜，用來分辨或特徵化活性化合物劑量的不同組合。 A suitable outer membrane is provided to the core of the dragee. For this purpose, a concentrated sugar solution may be used, optionally containing gum arabic, slippery powder, polyvinylpyrrolidone, carbopol gum, polyethylene glycol and/or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. . Synthetic dyes or pigments may also be added to the outer film of the tablet or film ingot to distinguish or characterize different combinations of active compound doses.

口服的藥學調劑包含凝膠製成的推入配合膠囊，以及凝膠和塑化劑(如甘油和山梨醇)製成的軟密封膠囊。推入配合膠囊可以包含在添加劑中的活性原料，添加劑具有如乳糖的填充劑、如澱粉的連接劑、及/或如滑粉或鎂硬酯酸的潤滑劑，並視需要地包含固化劑。在軟膠囊中，活性化合物可溶解或懸浮在合適的液體中，如脂肪油、液態石蠟或液態聚乙二醇。此外，固化劑也可被添加。所有口服的劑型都應該是適於這種投與的劑量。 Oral pharmaceutical formulations include gel-fitted push-fit capsules, as well as soft, sealed capsules made of gels and plasticizers such as glycerin and sorbitol. The push-fit capsule may comprise an active ingredient in an additive having a filler such as lactose, a linker such as starch, and/or a lubricant such as slip powder or magnesium stearate, and optionally a curing agent. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid such as a fatty oil, liquid paraffin or liquid polyethylene glycol. In addition, a curing agent can also be added. All oral dosage forms should be those suitable for such administration.

對於口服或舌下投與，組成物也可以習知方式製備的藥片、錠劑或凝膠的形式服用。 For oral or sublingual administration, the composition can also be administered in the form of tablets, lozenges or gels prepared in a conventional manner.

對於吸入投與，根據本發明使用的化合物是合宜地以呈現於使用合適推進器的加壓包裝或噴霧器的噴劑劑型被投遞，而推進器，如二氯二氟甲烷、三氯氟甲烷、四氟二氯乙烷、二氧化碳或其他適合的氣體。在加壓噴霧的案例中，劑量單元可藉由提供一閥控制來投遞計算好的劑量來決定。用於吸入器或吹藥器像是明膠的膠囊和藥包可被製備含有化合物的粉末混合物以及如乳糖或澱粉等合適的粉末基材。 For administration by inhalation, the compounds used according to the invention are conveniently delivered in a spray formulation presented as a pressurized pack or nebulizer using a suitable pusher, such as dichlorodifluoromethane, trichlorofluoromethane, Tetrafluorodichloroethane, carbon dioxide or other suitable gas. In the case of a pressurized spray, the dosage unit can be determined by providing a valve control to deliver the calculated dose. Capsules and sachets for use in an inhaler or insufflator such as gelatin can be prepared as a powder mixture containing the compound and a suitable powder base such as lactose or starch.

化合物也可製備用來以注射腸胃外的方式投與如以快速注射或持續注入。注射的劑型也可以單元劑量形式表示，如有添加防腐劑的安瓿或多劑容器。組成物也可為這些形式如懸浮液、溶液或於油或水溶液載體中的乳膠，而且也包含配製劑，如懸浮劑、安定劑及/或分散劑。 The compounds may also be prepared for administration in a parenteral manner such as by rapid injection or continuous infusion. Dosage forms for injection may also be presented in unit dosage form, such as ampoules or multi-dose containers with added preservatives. The composition may also be in the form of a suspension, solution or emulsion in an oil or aqueous carrier, and also includes formulations such as suspending, stabilizing and/or dispersing agents.

腸胃外的藥物劑型包含在水溶形式下的活性化合物水溶液。此外，活性化合物的懸浮液也可被製備成適當的油性注射懸浮液。合適的脂溶性溶劑或載體包含如芝麻油的脂肪油，或如油酸乙酯或三酸甘油酯的合成脂肪酸酯，或微脂體。水溶液的注射懸浮液也可含有提升懸浮液黏性的物質，如鈉羧甲基纖維素、山梨醇或蔔萄聚糖。視需要地，懸浮液也可含有提升化合物溶解度的適當安定劑或藥劑，而允許製造高濃縮的溶液。 A parenteral pharmaceutical dosage form comprises an aqueous solution of the active compound in a water soluble form. Furthermore, suspensions of the active compounds can also be prepared in a suitable oily injection suspension. Suitable fat-soluble solvents or vehicles comprise fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. The injection suspension of the aqueous solution may also contain substances which enhance the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compound, while permitting the manufacture of highly concentrated solutions.

擇一地，活性原料也可在使用前是以粉末的形式以與合適載體(如：無菌的無熱的水)組合。 Alternatively, the active material may be combined in a powder form with a suitable carrier (e.g., sterile, non-thermal water) prior to use.

化合物也可製備成直腸的組成物，例如栓劑或灌腸劑，如含 有合宜的栓劑基質(如可可脂或甘油)。 The compound may also be prepared as a rectal composition, such as a suppository or enemas, such as There is a suitable suppository base (such as cocoa butter or glycerin).

除了先前所描述的劑型外，化合物也可被製備成儲存調劑。長效型劑型可藉由植入(例如皮下的或肌肉內的)或藉由肌肉注射的方式被投與。因此，舉例來說，化合物可與適當的高分子或疏水性的物質(例如製備成於可接受的油脂中的乳膠)或離子交換樹酯製備，或是製備成微溶性的衍生物(例如製備成微溶性鹽類)。 In addition to the dosage forms previously described, the compounds can also be prepared as storage conditioners. Long-acting dosage forms can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be prepared with suitable polymeric or hydrophobic materials (for example, latexes prepared in acceptable oils and fats) or ion exchange resins, or prepared as sparingly soluble derivatives (eg, prepared) Become a slightly soluble salt).

本發明疏水性化合物載劑是一包括苯甲基乙醇、非極性介面活性劑、水可混溶的有機聚合物及水溶液相的共溶劑系統。共溶劑系統可以是10%乙醇、10%聚乙烯乙二醇300、10%聚乙烯乙二醇40蓖麻油(PEG-40蓖麻油)及70%水溶液。共溶劑系統可溶解疏水性化合物，且其本身於全身性投與時能產生低毒性。自然地，共溶劑系統之比例可被考慮地改變而不破壞其溶解性及毒性等特性。再者，共溶劑成份本質可被改變：例如，PEG-40蓖麻油可被其他低毒性的非極性介面活性劑替代；聚乙烯乙二醇300的比例大小可被改變；其他生物相容的聚合物可替代聚乙烯乙二醇，如聚乙烯吡咯烷酮；且其他醣類或多醣也許可以包含在水溶液中。 The hydrophobic compound carrier of the present invention is a cosolvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase. The cosolvent system can be 10% ethanol, 10% polyethylene glycol 300, 10% polyethylene glycol 40 castor oil (PEG-40 castor oil) and a 70% aqueous solution. The cosolvent system dissolves hydrophobic compounds and itself produces low toxicity when administered systemically. Naturally, the proportion of the cosolvent system can be considered to change without destroying its solubility and toxicity characteristics. Furthermore, the nature of the cosolvent component can be altered: for example, PEG-40 castor oil can be replaced by other low toxicity non-polar surfactants; the proportion of polyethylene glycol 300 can be varied; other biocompatible polymerizations The substance may be substituted for polyethylene glycol, such as polyvinylpyrrolidone; and other sugars or polysaccharides may be included in the aqueous solution.

擇一地，其他疏水性藥學化合物的傳遞系統亦適用。微脂體和乳膠是已知的疏水性藥物傳遞載體或載劑的例子。某些有機溶劑如N-甲基吡咯烷酮也可能被使用，雖然通常需較大毒性的代價。此外，化合物可利用持續釋放系統傳遞，如含治療劑的固態疏水性聚合物的半滲透性基質。不同的持續釋放材料已建立且為熟知此項技術者所知道的。持續釋放膠囊可根據其化學特性釋放 化合物達數星期甚至超過100天。根據治療劑的化學性質及生物穩定性，穩定蛋白質的額外策略亦可被使用。 Alternatively, delivery systems for other hydrophobic pharmaceutical compounds are also suitable. Liposomes and latexes are examples of known hydrophobic drug delivery vehicles or carriers. Certain organic solvents such as N-methylpyrrolidone may also be used, although generally at the expense of greater toxicity. In addition, the compounds can be delivered using a sustained release system, such as a semipermeable matrix of a solid hydrophobic polymer containing a therapeutic agent. Different sustained release materials have been established and are known to those skilled in the art. Sustained release capsules can be released according to their chemical properties The compound can last for weeks or even more than 100 days. Additional strategies for stabilizing proteins can also be used depending on the chemical nature and biostability of the therapeutic agent.

許多本發明的化合物可以被提供為具有藥學上相容之相對離子的鹽類。藥學上相容之相對的鹽類可由許多酸類形成，此酸類包括但不限定於氯化氫根、硫酸根、醋酸根、乳酸根、酒石酸根、蘋果酸、琥珀酸根等。鹽類在水溶液或其他中性溶劑中的溶解度是較在游離酸類或鹼類形式中的溶解度高。使用本發明化合物的鹽類包括但不限定於醋酸鈣、氫氯酸、磷酸、硫酸、氫氧化鈉、氫氧化鉀、醋酸鎂、對甲苯亞磺酸鹽。鹽類可藉由接觸本發明化合物於適當純淨或在不活潑的溶劑中的酸類製備以生成本發明的鹽類形式。在較佳實施例中，對甲苯亞磺酸是使用於揭露的化合物。在一更佳實施例中，實施例81可以與對甲苯亞磺酸接觸生成本發明對甲苯磺酸鹽的形式，而形成4-[2,6-順-二甲基-4-(4-三氯甲氧-苯基)-哌嗪-1-磺酸基]-二氫茚-2-(R)-羧酸-對甲苯亞磺酸鹽。 Many of the compounds of the invention may be provided as salts having pharmaceutically compatible relative ions. Pharmaceutically compatible relative salts can be formed from a wide variety of acids including, but not limited to, hydrogen chloride, sulfate, acetate, lactate, tartrate, malic acid, succinate, and the like. The solubility of salts in aqueous solutions or other neutral solvents is higher than in free acid or base forms. Salts using the compounds of the invention include, but are not limited to, calcium acetate, hydrochloric acid, phosphoric acid, sulfuric acid, sodium hydroxide, potassium hydroxide, magnesium acetate, p-toluenesulfinate. Salts can be prepared by contacting the compounds of the invention in an acid which is suitably pure or in an inert solvent to form the salt forms of the invention. In a preferred embodiment, p-toluenesulfinic acid is the compound used in the disclosure. In a more preferred embodiment, Example 81 can be contacted with p-toluenesulfinic acid to form the p-toluenesulfonate salt of the present invention to form 4-[2,6-cis-dimethyl-4-(4- Trichloromethoxy-phenyl)-piperazine-1-sulfonyl]-indoline-2-(R)-carboxylic acid-p-toluenesulfinate.

本申請案所引用的美國或國外的所有文獻、專利或申請案於此經引用被併入，如同於此被寫入。 All documents, patents, or applications filed in the U.S.A.S.

下列圖解將用來實現本發明。 The following illustrations will be used to implement the invention.

圖解一Graphic one

從二氫茚-2-醋酸、二氫茚-2-羧酸、二氫茚-1-羧酸或6-甲氧基二氫茚-1-醋酸的酯頭基來製備不同的二氫茚-羧酸。首先以純氯磺酸氯磺酸化二氫茚。當使用空間上被阻礙的哌嗪時，藉由於室溫或升溫下與合適的哌嗪或呱啶反應而引起磺醯胺的形成。最後，使用鋰氫氧化物而完成酯基元的鹼水解。 Preparation of different indoline from the ester head group of indoline-2-acetic acid, indoline-2-carboxylic acid, indoline-1-carboxylic acid or 6-methoxyindoline-1-acetate -carboxylic acid. The indoline is first sulfonated with pure chlorosulfonic acid. When sterically hindered piperazine is used, the formation of sulfonamide is caused by reaction with a suitable piperazine or acridine at room temperature or elevated temperature. Finally, alkali hydrolysis of the ester moiety is accomplished using lithium hydroxide.

圖解二Illustration two

利用一相似於使用LHMDS和碘化甲烷達成初始甲基化加成 的方式合成甲基化的二氫茚-羧酸(圖解二)。 Utilizing a similarity to the use of LHMDS and methyl iodide to achieve initial methylation addition The way to synthesize methylated indoline-carboxylic acid (Scheme 2).

圖解三Graphic three

圖解三概述本發明的吲哚-1-基具體例的合成。首先使用氯磺酸氯磺酸化1-(2,3-二氫-吲哚-1-基)-乙醇，接著藉由與合適的哌嗪或呱啶反應而形成磺醯胺。隨後藉由在酸性條件下移除乙醯保護基再藉由吲哚的DDQ氧化來得到吲哚。以甲基溴醋酸N-烷基化吲哚並進一步地以鋰氫氧化物水解而提供所需的羧酸。 Scheme 3 summarizes the synthesis of the indol-1-yl specific examples of the present invention. First, 1-(2,3-dihydro-indol-1-yl)-ethanol is sulfonated with chlorosulfonic acid, followed by reaction with the appropriate piperazine or acridine to form the sulfonamide. The oxime is then obtained by removing the acetamidine protecting group under acidic conditions and oxidizing by argon DDQ. N-alkylated hydrazine with methyl bromoacetate and further hydrolyzed with lithium hydroxide provides the desired carboxylic acid.

圖解四Graphic four

圖解四的化合物顯示了一磺醯胺取代在吲哚的6-位置。先以1-(5-溴-2,3-二氫-吲哚-1-基)-乙醇氯磺酸化，接著以合適的哌嗪或呱啶形成磺醯胺而得到6-磺醯胺-5-溴吲哚。隨著以在1,4-二氧陸圜中的濃縮氯化氫移除乙醯保護基，接續利用DDQ氧化產生吲哚頭基。以甲基溴醋酸N-烷基化吲哚後，使用鋰氫氧化物水解酯類。依次地，在水解步驟前，在氫氣氛圍下以10%Pd/C進行5-溴官能氫化而得到6-磺醯胺-吲哚。 The compound of Scheme 4 shows that the sulfonamide is substituted at the 6-position of hydrazine. Sulfonated with 1-(5-bromo-2,3-dihydro-indol-1-yl)-ethanol, followed by formation of the sulfonamide with the appropriate piperazine or acridine to give 6-sulfonamide- 5-bromoindole. As the ethyl hydrazine protecting group is removed with concentrated hydrogen chloride in 1,4-dioxane, the hydrazine group is subsequently oxidized by DDQ. After N-alkylated hydrazine with methyl bromoacetate, the esters are hydrolyzed using lithium hydroxide. In turn, 5-bromo-functional hydrogenation was carried out at 10% Pd/C under a hydrogen atmosphere to give 6-sulfonamide-oxime before the hydrolysis step.

圖解五Graphic five

圖解五描述了一連結G₂-G₄基元形成本發明中間產物具體例的一般方法，以及一以水解方式切斷受酸保護的中間產物而產生本發明具體例的一般方法。 Scheme 5 describes a general method for forming a G ₂ -G ₄ moiety to form a specific example of the intermediate product of the present invention, and a general method for producing a specific example of the present invention by hydrolyzing the acid-protected intermediate product.

圖解六Graphic six

圖解六描述了一製備本發明6-甲氧基-苯並噻吩具體例的一般方法。 Scheme 6 describes a general method for preparing a specific example of the 6-methoxy-benzothiophene of the present invention.

圖解七Graphic seven

圖解七描繪出一製備本發明苯並噻吩具體例的一般方法。幾種圖解表達出一使用磺酸親電子基及氮親核基製備一磺醯胺鍵。這樣一來，可透過模組方式引入廣泛多樣的G₂-G₃-G₄基團。 Scheme 7 depicts a general method for preparing specific examples of the benzothiophenes of the present invention. Several diagrams express the use of a sulfonic acid electrophilic group and a nitrogen nucleophilic group to prepare a monosulfonamide linkage. In this way, a wide variety of G ₂ -G ₃ -G ₄ groups can be introduced through the module.

圖解八Illustration eight

圖解八概述了從連接鹵素化的芳香基G₄基團與適當的哌嗪或呱啶來合成不同的G₂-G₃-G₄基團。藉由與氯磺酸化的二氫茚-羧酸酯頭基反應(見圖解一)引起磺醯胺的形成。最後，使用鋰氫氧化物完成酯基元的鹼水解。 Scheme 8 outlines the synthesis of different G ₂ -G ₃ -G ₄ groups from a halogenated aryl G ₄ group with an appropriate piperazine or acridine. The formation of sulfonamide is caused by reaction with a chlorosulfonated indoline-carboxylate head group (see Scheme 1). Finally, alkali hydrolysis of the ester moieties is accomplished using lithium hydroxide.

圖解九Illustration nine

圖解九概述了實施例79的合成。 Scheme 9 summarizes the synthesis of Example 79.

實施例Example 實施例1和實施例2Embodiment 1 and Embodiment 2 {5-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-基}-醋酸和{4-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-基}-醋酸：{5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-yl}-acetic acid and {4-[4-(4-trifluoro) Methyl-phenyl)-piperazin-1-sulfonyl]-indan-2-yl}-acetic acid:

步驟1：step 1:

{5-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-基}-醋酸甲酯和{4-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-基}-醋酸甲酯：於0℃中，加入二氫茚基-2-醋酸甲酯(1.0克，5.26毫莫耳)至攪拌中的5毫升氯磺酸溶液。在0℃下持續攪拌該溶液0.5小時，然後置於室溫下3小時。緩緩加入得到的溶液至冰層上並以二乙醇(3X 100毫升)萃取。乾燥(硫酸鈉)此混合有機層並濃縮以提供一5-氯磺酸基-二氫茚-2-醋酸甲酯和4-氯磺酸基-二氫茚-2-醋酸甲酯的混合物(1.38克，4.78毫莫耳，91%)，且不需要進一步地純化此混合磺酸基的氯化物混合物即可用於下個步驟。溶解磺酸基的氯化物溶夜(370毫克，1.28毫莫耳)於乾四氫呋喃(THF)(10毫升)。加入1-(4-三氟甲基苯基)哌嗪(315毫克，1.37毫莫耳)、三乙基胺(600微升，4.3毫莫耳)和DMAP(催化量)至此溶液。在室溫下持續攪拌反 應液1小時，並以矽膠快速管柱色層分析法濃縮且直接純化，來分離位向異構物(在己烷下的25%醋酸乙酯)而提供潔淨無色油狀的{5-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-基}-醋酸甲酯(118毫克，19%)和{4-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-基}-醋酸甲酯(40毫克，6%)。 {5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-yl}-acetate and {4-[4-(4- Trifluoromethyl-phenyl)-piperazine-1-sulfonic acid]-indan-2-yl}-acetic acid methyl ester: at 0 ° C, dihydroindenyl-2-acetic acid methyl ester (1.0) Gram, 5.26 mmol) to 5 ml of chlorosulfonic acid solution in stirring. The solution was continuously stirred at 0 ° C for 0.5 hours and then left at room temperature for 3 hours. The resulting solution was slowly added to the ice layer and extracted with diethanol (3×100 mL). The mixed organic layer was dried (sodium sulfate) and concentrated to give a mixture of methyl 5-chlorosulfonic acid-dihydroindole-2-acetate and methyl 4-chlorosulfonic acid-dihydroindole-2-acetate ( 1.38 g, 4.78 mmol, 91%), and the chloride mixture of this mixed sulfonic acid group was not further purified and used in the next step. The sulfonate-soluble chloride was dissolved in night (370 mg, 1.28 mmol) in dry tetrahydrofuran (THF) (10 mL). 1-(4-Trifluoromethylphenyl)piperazine (315 mg, 1.37 mmol), triethylamine (600 μL, 4.3 mmol) and DMAP (catalytic amount) were added to this solution. The reaction solution was continuously stirred at room temperature for 1 hour, and concentrated by silica gel chromatography and directly purified to isolate the isomer (25% ethyl acetate in hexane) to provide a clean, colorless oil. {5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-yl}-acetic acid methyl ester (118 mg, 19%) {4-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-yl}-acetic acid methyl ester (40 mg, 6%).

{5-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-基}-醋酸甲酯{5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-yl}-methyl acetate

¹H NMR(400 MHz,CDCl₃)δ 7.57(s,1H),7.56(d,1H),7.45(d,2H),7.33(d,1H),6.87(d,2H),3.69(s,3H),3.33(m,4H),3.21(dd,2H),3.14(m,4H),2.95(m,1H),2.71(dd,2H),2.52(d,2H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57 (s, 1H), 7.56 (d, 1H), 7.45 (d, 2H), 7.33 (d, 1H), 6.87 (d, 2H), 3.69 (s, 3H), 3.33 (m, 4H), 3.21 (dd, 2H), 3.14 (m, 4H), 2.95 (m, 1H), 2.71 (dd, 2H), 2.52 (d, 2H).

{4-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-基}-醋酸甲酯{4-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonic acid]-indan-2-yl}-methyl acetate

¹H NMR(400 MHz,CDCl₃)δ 7.60(d,1H),7.40(d,2H),7.42(d,1H),7.31(dd,1H),6.88(d,2H),3.69(s,3H),3.52(dd,1H),3.31(m,4H),3.23(m,4H),3.20(m,1H),2.93(m,2H),2.70(m,1H),2.50(m,2H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.60 (d, 1H), 7.40 (d, 2H), 7.42 (d, 1H), 7.31 (dd, 1H), 6.88 (d, 2H), 3.69 (s, 3H), 3.52 (dd, 1H), 3.31 (m, 4H), 3.23 (m, 4H), 3.20 (m, 1H), 2.93 (m, 2H), 2.70 (m, 1H), 2.50 (m, 2H) ).

步驟2：Step 2:

{5-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-基}-醋酸：{5-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-sulfonyl]-indan-2-yl}-acetic acid:

將{5-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-基}-醋酸甲酯(118毫克，0.245毫莫耳)溶解於四氫呋喃(THF)(10毫升) 中。加入1M氫氧化鋰(5毫升)於此混合溶液中且在室溫下持續攪拌3小時。TLC表示此反應已完成。以Dowex 50WX4-50熄滅此反應混合物直到變為中性，再過濾以提供白色固體的純{5-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-基}-醋酸(112毫克，98%)。更可進一步藉矽膠快速管柱色層分析法(二氯甲烷/甲醇/醋酸95：5：0.1)純化此產物。¹H NMR(400 MHz,MeOH-d₄)δ 7.60(s,1H),7.56(d,1H),7.45(d,2H),7.41(d,1H),7.00(d,2H),3.32(m,4H),3.22(m,2H),3.17(m,4H),2.88(m,1H),2.72(m,2H),2.47(d,2H)；LCMS：468.8(M+1)⁺。 {5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-yl}-acetic acid methyl ester (118 mg, 0.245 mmol) Dissolved in tetrahydrofuran (THF) (10 mL). 1 M lithium hydroxide (5 ml) was added to the mixed solution and stirring was continued at room temperature for 3 hours. TLC indicates that this reaction has been completed. The reaction mixture was quenched with Dowex 50WX4-50 until neutral, then filtered to afford pure <5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonic acid as a white solid. -Indoline-2-yl}-acetic acid (112 mg, 98%). Further, the product was further purified by silica gel flash column chromatography (dichloromethane/methanol/acetic acid 95:5:0.1). ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 7.60 (s, 1H), 7.56 (d, 1H), 7.45 (d, 2H), 7.41 (d, 1H), 7.00 (d, 2H), 3.32 ( m, 4H), 3.22 (m , 2H), 3.17 (m, 4H), 2.88 (m, 1H), 2.72 (m, 2H), 2.47 (d, 2H); LCMS: 468.8 (m + 1) +.

{4-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-基}-醋酸：{4-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-yl}-acetic acid:

根據步驟2的流程合成化合物{4-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-基}-醋酸(>99%)。¹H NMR(400 MHz,MeOH-d₄)δ 7.60(d,1H),7.52(d,2H),7.51(d,1H),7.31(t,1H),7.15(d,2H),3.53(dd,1H),3.42(m,4H),3.25(m,4H),3.20(m,1H),3.00(dd,1H),2.87(m,1H),2.72(m,1H),2.47(m,2H)；LCMS：468.8(M+1)⁺。 The compound {4-[4-(4-trifluoromethyl-phenyl)-piperazin-1-sulfonyl]-dihydroindol-2-yl}-acetic acid (>99%) was synthesized according to the procedure of Step 2. . ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 7.60 (d, 1H), 7.52 (d, 2H), 7.51 (d, 1H), 7.31 (t, 1H), 7.15 (d, 2H), 3.53 ( Dd,1H), 3.42 (m, 4H), 3.25 (m, 4H), 3.20 (m, 1H), 3.00 (dd, 1H), 2.87 (m, 1H), 2.72 (m, 1H), 2.47 (m) , 2H); LCMS: 468.8 (M+1) ⁺ .

實施例3Example 3

{5-[4-(3,4-二氯苯基)-哌嗪-1-磺酸基]-二氫茚-2-基}-醋酸：{5-[4-(3,4-Dichlorophenyl)-piperazine-1-sulfonyl]-indan-2-yl}-acetic acid:

使用3,4-(二氯苯基)-哌嗪並根據實施例1的流程合成化合物{5-[4-(3,4-二氯苯基)-哌嗪-1-磺酸基]-二氫茚-2-基}-醋酸。¹H NMR(400 MHz,MeOH-d₄)δ 7.60(s,1H),7.56(d,1H),7.42(d,1H),7.29(d,1H),7.04(d,1H),6.83(dd,1H),3.31(m,2H),3.23(m,4H),3.18(m,1H),3.08(m,3H),2.90(m,1H),2.74(m,2H),2.46(d,2H)；LCMS：468.8(M+1)⁺。 The compound {5-[4-(3,4-dichlorophenyl)-piperazine-1-sulfonate]- was synthesized according to the procedure of Example 1 using 3,4-(dichlorophenyl)-piperazine. Dihydroindol-2-yl}-acetic acid. ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 7.60 (s, 1H), 7.56 (d, 1H), 7.42 (d, 1H), 7.29 (d, 1H), 7.04 (d, 1H), 6.83 ( Dd,1H), 3.31 (m, 2H), 3.23 (m, 4H), 3.18 (m, 1H), 3.08 (m, 3H), 2.90 (m, 1H), 2.74 (m, 2H), 2.46 (d) , 2H); LCMS: 468.8 (M+1) ⁺ .

實施例4Example 4

{4-[4-(3,4-二氯苯基)-哌嗪-1-磺酸基]-二氫茚-2-基}-醋酸：{4-[4-(3,4-Dichlorophenyl)-piperazin-1-sulfonyl]-indan-2-yl}-acetic acid:

使用3,4-(二氯苯基)-哌嗪並根據實施例1的流程合成化合物{4-[4-(3,4-二氯苯基)-哌嗪-1-磺酸基]-二氫茚-2-基}-醋酸。¹H NMR(400 MHz,MeOH-d₄)δ 7.59(d,1H),7.52(d,1H),7.38(dd,1H),7.29(d,1H),7.04(d,1H),6.85(dd,1H),3.50(dd,1H),3.20(m,8H),2.98 (dd,1H),2.86(m,1H),2.72(dd,1H),2.48(m,1H),2.18(m,2H)；LCMS：468.9(M+1)⁺。 The compound {4-[4-(3,4-dichlorophenyl)-piperazine-1-sulfonate]- was synthesized according to the procedure of Example 1 using 3,4-(dichlorophenyl)-piperazine. Dihydroindol-2-yl}-acetic acid. ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 7.59 (d, 1H), 7.52 (d, 1H), 7.38 (dd, 1H), 7.29 (d, 1H), 7.04 (d, 1H), 6.85 ( Dd,1H), 3.50 (dd, 1H), 3.20 (m, 8H), 2.98 (dd, 1H), 2.86 (m, 1H), 2.72 (dd, 1H), 2.48 (m, 1H), 2.18 (m) , 2H); LCMS: 468.9 (M+1) ⁺ .

實施例5 Example 5

5-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸：5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid:

使用二氫茚-2-羧酸甲酯並根據實施例1的流程合成化合物5-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸。¹H NMR(400 MHz,MeOH-d₄)δ 7.64(s,1H),7.60(d,1H),7.46(d,2H),7.46(m,1H),7.01(d,2H),3.41(m,1H),3.30(m,8H),3.10(m,4H)。 The compound 5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indoline was synthesized according to the procedure of Example 1 using methyl indoline-2-carboxylate. 2-carboxylic acid. ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 7.64 (s, 1H), 7.60 (d, 1H), 7.46 (d, 2H), 7.46 (m, 1H), 7.01 (d, 2H), 3.41 ( m, 1H), 3.30 (m, 8H), 3.10 (m, 4H).

實施例6 Example 6

4-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸：4-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid:

使用二氫茚-2-羧酸甲酯並根據實施例1的流程合成化合物4-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸。¹H NMR (400 MHz,MeOH-d₄)δ 7.63(d,1H),7.53(d,1H),7.46(d,2H),7.40(t,1H),7.03(d,2H),3.58-3.56(m,2H),3.42-3.34(m,5H),3.32-3.18(m,6H)；LCMS：455.0(M+1)⁺。 Synthesis of the compound 4-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indoline using the indoline-2-carboxylic acid methyl ester according to the procedure of Example 1. 2-carboxylic acid. ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 7.63 (d, 1H), 7.53 (d, 1H), 7.46 (d, 2H), 7.40 (t, 1H), 7.03 (d, 2H), 3.58- 3.56 (m, 2H), 3.42-3.34 (m, 5H), 3.32-3.18 (m, 6H); LCMS: 455.0 (m + 1) +.

實施例7 Example 7

5-[4-(3,4-二氯苯基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸：5-[4-(3,4-Dichlorophenyl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid:

使用二氫茚-2-羧酸甲酯及3,4-(二氯苯基)-哌嗪並根據實施例1的流程合成化合物5-[4-(3,4-二氯苯基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸。¹H NMR(400 MHz,MeOH-d₄)δ 7.61(s,1H),7.56(d,1H),7.42(d,1H),7.28(d,1H),7.03(d,1H),6.89(dd,1H),3.30(m,1H),3.28(m,4H),3.32(m,4H),3.08(m,4H)。 The compound 5-[4-(3,4-dichlorophenyl)- was synthesized according to the procedure of Example 1 using methyl indoline-2-carboxylate and 3,4-(dichlorophenyl)-piperazine. Piperazine-1-sulfonate]-indoline-2-carboxylic acid. ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 7.61 (s, 1H), 7.56 (d, 1H), 7.42 (d, 1H), 7.28 (d, 1H), 7.03 (d, 1H), 6.89 ( Dd, 1H), 3.30 (m, 1H), 3.28 (m, 4H), 3.32 (m, 4H), 3.08 (m, 4H).

實施例8 Example 8

4-[4-(3,4-二氯苯基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸：4-[4-(3,4-Dichlorophenyl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid:

使用二氫茚-2-羧酸甲酯及3,4-(二氯苯基)-哌嗪並根據實施例1的流程合成化合物4-[4-(3,4-二氯苯基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸。¹H NMR(400 MHz,MeOH-d₄)δ 7.62(d,1H),7.54(d,1H),7.40(t,1H),7.30(d,1H),7.06(d,1H),6.86(dd,1H),3.57-3.55(m,2H),3.42-3.34(m,1H),3.32-3.29(m,2H),3.26-3.16(m,8H)；LCMS：454.9(M+1)⁺。 The compound 4-[4-(3,4-dichlorophenyl)- was synthesized according to the procedure of Example 1 using methyl indoline-2-carboxylate and 3,4-(dichlorophenyl)-piperazine. Piperazine-1-sulfonate]-indoline-2-carboxylic acid. ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 7.62 (d, 1H), 7.54 (d, 1H), 7.40 (t, 1H), 7.30 (d, 1H), 7.06 (d, 1H), 6.86 ( Dd,1H),3.57-3.55(m,2H),3.42-3.34(m,1H),3.32-3.29(m,2H),3.26-3.16(m,8H);LCMS:454.9(M+1) ⁺ .

實施例9 Example 9

5-[4-(4-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸：5-[4-(4-Trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid:

使用二氫茚-2-羧酸甲酯及1-[5-(三氟甲基)-吡啶-2-基)-哌嗪並根據實施例1的流程合成此化合物5-[4-(4-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸。¹H NMR(400 MHz,MeOH-d₄)δ 8.01(s,1H),7.69(d,1H),7.61(s,1H),7.56(d,1H),7.41(d,1H),6.85(d,1H),3.75(m,3H),3.32(m,1H),3.31(m,3H),3.28(m,3H),3.05(m,3H)；LCMS：455.9(M+1)⁺。 This compound 5-[4-(4) was synthesized according to the procedure of Example 1 using methyl indoline-2-carboxylate and 1-[5-(trifluoromethyl)-pyridin-2-yl)-piperazine. -Trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonate]-indoline-2-carboxylic acid. ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 8.01 (s, 1H), 7.69 (d, 1H), 7.61 (s, 1H), 7.56 (d, 1H), 7.41 (d, 1H), 6.85 ( d, 1H), 3.75 (m , 3H), 3.32 (m, 1H), 3.31 (m, 3H), 3.28 (m, 3H), 3.05 (m, 3H); LCMS: 455.9 (m + 1) +.

實施例10 Example 10

4-[4-(3,4-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸：4-[4-(3,4-Trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid:

使用二氫茚-2-羧酸甲酯和1-[5-(三氟甲基)-吡啶-2-基)-哌嗪並根據實施例1的流程合成化合物4-[4-(3,4-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸。¹H NMR(400 MHz,MeOH-D₄)δ 8.35(s,1H),7.74(d,1H),7.65(d,1H),7.55(d,1H),7.42(t,1H),6.90(d：1H),3.78(m,4H),3.59(d,2H),3.41(m,1H),3.34(m,2H),3.20(m,4H)；LCMS：456.0(M+1)⁺。 Synthesis of compound 4-[4-(3, using methyl indoline-2-carboxylate and 1-[5-(trifluoromethyl)-pyridin-2-yl)-piperazine according to the procedure of Example 1. 4-Trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid. ¹ H NMR (400 MHz, MeOH-D ₄ ) δ 8.35 (s, 1H), 7.74 (d, 1H), 7.65 (d, 1H), 7.55 (d, 1H), 7.42 (t, 1H), 6.90 ( d: 1H), 3.78 (m , 4H), 3.59 (d, 2H), 3.41 (m, 1H), 3.34 (m, 2H), 3.20 (m, 4H); LCMS: 456.0 (m + 1) +.

實施例11和實施例12 Example 11 and Example 12

4-[4-(4-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-2-(R)-羧酸和4-[4-(4-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-2-(S)-羧酸：4-[4-(4-Trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfo]-indoline-2-(R)-carboxylic acid and 4-[4-(4 -trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-2-(S)-carboxylic acid:

使用對掌性HPLC解析實施例10的4-[4-(4-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸外消旋混合物以提供純對掌異 構物4-[4-(4-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-2-(R)-羧酸和4-[4-(4-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-2-(S)-羧酸。 The 4-[4-(4-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonic acid]-indoline-2-carboxylic acid external elimination of Example 10 was analyzed using a palm HPLC. Spin mixture to provide pure palm Structure 4-[4-(4-Trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfo]-indoline-2-(R)-carboxylic acid and 4-[4- (4-Trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-2-(S)-carboxylic acid.

實施例13和實施例14 Example 13 and Example 14

2-甲基-5-[4-(5-三氟甲基-吡啶2-基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸和2-甲基-4-[4-(5-三氟甲基-吡啶2-基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸：2-methyl-5-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonic acid]-indoline-2-carboxylic acid and 2-methyl-4- [4-(5-Trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid: 步驟1step 1

2-甲基-二氫茚-2-羧酸甲酯：Methyl 2-methyl-indoline-2-carboxylate:

溶解二氫茚-2-羧酸甲酯(550毫克，3.125毫莫耳)在THF(20毫升)中。於-78℃下，注入LiHMDS(THF中的1M溶液，3.75毫升)至反應混合物中。在-78℃下攪拌此溶液15分鐘，再加熱至0℃持溫15分鐘，然後置於-78℃持溫15分鐘。注入甲基碘(250微升，4.01毫莫 耳)於此反應混合物，然後在-78℃下攪拌15分鐘，於室溫下攪拌30分鐘，再以飽和氯化氨熄滅。以二甲酯稀釋此溶液並以飽和碳酸氫鈉、鹵水洗滌，再乾燥(硫酸鎂)、過瀘及濃縮。接著以矽膠快速管柱色層分析法純化粗混合物以提供白色固體的2-甲基-二氫茚-2-羧酸甲酯(52毫克，9%)。¹H NMR(400 MHz,CDCl₃)δ 7.16(m,4H),3.72(t,3H),3.48(d,2H),2.81(d,2H),1.36(s,3H)。 Methyl indoline-2-carboxylate (550 mg, 3.125 mmol) was dissolved in THF (20 mL). LiHMDS (1 M solution in THF, 3.75 ml) was poured into the reaction mixture at -78 °C. The solution was stirred at -78 ° C for 15 minutes, heated to 0 ° C for 15 minutes, and then held at -78 ° C for 15 minutes. Methyl iodide (250 μL, 4.01 mmol) was injected into the reaction mixture, followed by stirring at -78 ° C for 15 minutes, stirring at room temperature for 30 minutes, and quenching with saturated ammonium chloride. The solution was diluted with dimethyl ester and washed with saturated sodium bicarbonate, brine, dried (MgSO4) The crude mixture was purified by silica gel flash chromatography to afford ethyl 2-methyl-dihydroindole-2-carboxylate as a white solid (52 mg, 9%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.16 (m, 4H), 3.72 (t, 3H), 3.48 (d, 2H), 2.81 (d, 2H), 1.36 (s, 3H).

步驟2Step 2

2-甲基-5-[4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸：2-methyl-5-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid:

使用1-[5-三氟甲基-吡啶-2-基]-哌嗪及2-甲基-二氫茚-2-羧酸甲酯並根據實施例1的流程合成化合物2-甲基-5-[4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸。¹H NMR(400 MHz,MeOH-d₄)δ 8.30(s,1H),7.70(dd,1H),7.61(s,1H),7.58(d,1H),7.41(d,1H),6.86(d,1H),3.74(s,4H),3.50(dd,2H),3.06(m,4H),2.90(dd,2H),1.35(s,3H)；LCMS：470.5(M+1)⁺。 Synthesis of compound 2-methyl- using 1-[5-trifluoromethyl-pyridin-2-yl]-piperazine and methyl 2-methyl-indoline-2-carboxylate according to the procedure of Example 1. 5-[4-(5-Trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid. ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 8.30 (s, 1H), 7.70 (dd, 1H), 7.61 (s, 1H), 7.58 (d, 1H), 7.41 (d, 1H), 6.86 ( d,1H), 3.74 (s, 4H), 3.50 (dd, 2H), 3.06 (m, 4H), 2.90 (dd, 2H), 1.35 (s, 3H); LCMS: 470.5 (M+1) ⁺ .

2-甲基-4-[4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸：2-methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid:

使用1-[5-(三氟甲基-吡啶)-2-基)-哌嗪和2-甲基-二氫茚-2-羧酸甲酯並根據實施例1的流程合成化合物2-甲基-4-[4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸。¹H NMR(400 MHz,MeOH-d₄)δ 8.32(s,1H),7.74(dd,1H),7.61(d,1H),7.50(d,1H),7.39(t,1H),6.92(d,1H),3.90(m,1H),3.75(m,5H),3.50(d,1H),3.19(m,4H),2.91(d,1H),1.40(s,3H)；LCMS：470.0(M+1)⁺。 Synthesis of compound 2-A using 1-[5-(trifluoromethyl-pyridine)-2-yl)-piperazine and 2-methyl-indoline-2-carboxylic acid methyl ester according to the procedure of Example 1. 4-[4-(5-Trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid. ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 8.32 (s, 1H), 7.74 (dd, 1H), 7.61 (d, 1H), 7.50 (d, 1H), 7.39 (t, 1H), 6.92 ( d,1H), 3.90 (m, 1H), 3.75 (m, 5H), 3.50 (d, 1H), 3.19 (m, 4H), 2.91 (d, 1H), 1.40 (s, 3H); LCMS: 470.0 (M+1) ⁺ .

實施例15 Example 15

5-[4-(3-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸：5-[4-(3-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid:

使用二氫茚-2-羧酸甲酯及1-(3-三氟甲基苯基)-哌嗪並根據實施例1的流程合成化合物5-[4-(3-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫化茚-2-羧酸。¹H NMR(400 MHz,MeOH-d₄)δ 7.65(s,1H), 7.60(d,1H),7.45(d,1H),7.38(t,1H),7.15(d,1H),7.08(d,1H),3.41(m,1H),3.30(m,8H),3.11(m,4H)。 Synthesis of compound 5-[4-(3-trifluoromethyl-benzene) according to the procedure of Example 1 using methyl indoline-2-carboxylate and 1-(3-trifluoromethylphenyl)-piperazine Base)-piperazine-1-sulfonate]-indan-2-carboxylic acid. ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 7.65 (s, 1H), 7.60 (d, 1H), 7.45 (d, 1H), 7.38 (t, 1H), 7.15 (d, 1H), 7.08 ( d, 1H), 3.41 (m, 1H), 3.30 (m, 8H), 3.11 (m, 4H).

實施例16 Example 16

4-[4-(3-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸：4-[4-(3-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid:

使用二氫茚-2-羧酸甲酯和1-(3-三氟甲基-苯基)-哌嗪並根據實施例1的流程合成化合物4-[4-(3-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸。¹H NMR(400 MHz,MeOH-d₄)δ 7.62(d,1H),7.53(d,1H),7.39(dd,1H),7.40(m,1H),7.16(d,1H),7.16(s,1H),7.09(d,1H),3.57(m,2H),3.36(m,1H),3.30(m,6H),3.23(m,4H)。 The compound 4-[4-(3-trifluoromethyl-) was synthesized according to the procedure of Example 1 using methyl indoline-2-carboxylate and 1-(3-trifluoromethyl-phenyl)-piperazine. Phenyl)-piperazine-1-sulfonate]-indoline-2-carboxylic acid. ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 7.62 (d, 1H), 7.53 (d, 1H), 7.39 (dd, 1H), 7.40 (m, 1H), 7.16 (d, 1H), 7.16 ( s, 1H), 7.09 (d, 1H), 3.57 (m, 2H), 3.36 (m, 1H), 3.30 (m, 6H), 3.23 (m, 4H).

實施例17和實施例18 Example 17 and Example 18 5-[4-(4-三氟甲基-苯基)-3,6-二氫-2H-吡啶-1-磺酸基]-二氫茚-2-羧酸和4-[4-(4-三氟甲基-苯基)-3,6-二氫-2H-吡啶-1-磺酸基]-二氫茚-2-羧酸：5-[4-(4-Trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridine-1-sulfo]-indoline-2-carboxylic acid and 4-[4-( 4-Trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridine-1-sulfonic acid]-indoline-2-carboxylic acid:

步驟1step 1

1-苯甲基-4-(4-三氟甲基-苯基)-1,2,3,6-四氫-吡啶：1-Benzyl-4-(4-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine:

於-78℃下，以液滴方式添加於四氫呋喃(50毫升)中的4-碘三氟甲苯(2.97克，10.92毫莫耳)至於四氫呋喃(50毫升)中的n-BuLi(7.5毫升，1.6 M，12毫莫耳)超過半小時。攪拌此反應混合物30分鐘，同時添加於四氫呋喃(10毫升)中的N-苯甲基-4-哌啶酮(2.13克，11.69毫莫耳)超過10分鐘。在-78℃下持續攪拌30分鐘後，靜置隔夜。以飽和氯化銨熄滅此反應並分離出有機層。以四氫呋喃萃取水層，而乾燥(硫酸鎂)、過濾及濃縮組合的有機層而得到褐色油。接著，溶解粗產物於濃縮的氯化氫(30毫升)及1,4-二氧陸圜中並於100℃下攪拌隔夜。倒入反應液至飽和的碳酸氫鈉並以乙酸乙酯(3X200毫升)萃取。乾燥(硫酸鎂)組合的有機層、過濾及濃縮。以矽膠快速管柱色層分析法純化產物以得到1-苯甲基-4-(4-三氟甲基-苯基)-1,2,3,6-四氫-吡啶。¹H NMR(400 MHz,CDCl₃)δ 7.61(d,2H),7.52(d,2H),7.40(m,5H),6.21(m,1H),3.70(s,2H),3.25(q,2H), 2.78(t,2H),2.62(m,2H)；LCMS：318.4(M+1)⁺。 Add 4-Iodobenzotrifluoride (2.97 g, 10.92 mmol) in tetrahydrofuran (50 mL) to n-BuLi (7.5 mL, 1.6) in tetrahydrofuran (50 mL) at -78 °C. M, 12 millimoles) for more than half an hour. The reaction mixture was stirred for 30 minutes while adding N -benzyl-4-piperidinone (2.13 g, 11.69 mmol) in tetrahydrofuran (10 mL) over 10 min. After stirring at -78 ° C for 30 minutes, it was allowed to stand overnight. The reaction was quenched with saturated ammonium chloride and the organic layer was separated. The aqueous layer was extracted with THF, dried (MgSO.sub.4), filtered and concentrated. Next, the crude product was dissolved in concentrated hydrogen chloride (30 ml) and 1,4-dioxane and stirred at 100 ° C overnight. The reaction mixture was poured into EtOAc EtOAc (EtOAc) The combined organic layers were dried (MgSO4), filtered and concentrated. The product was purified by silica gel flash chromatography to give 1-benzyl-4-(4-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.61 (d, 2H), 7.52 (d, 2H), 7.40 (m, 5H), 6.21. (m, 1H), 3.70 (s, 2H), 3.25 (q, 2H), 2.78 (t, 2H ), 2.62 (m, 2H); LCMS: 318.4 (m + 1) +.

步驟2Step 2

4-(4-三氟甲基-苯基)-1,2,3,6-四氫-吡啶(氯化氫)：4-(4-Trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine (hydrogen chloride):

溶解1-苯甲基-4-(4-三氟甲基-苯基)-1,2,3,6-四氫-吡啶於四氫呋喃(10毫升)中。冷卻反應液至-20℃並加入在四氫呋喃(2毫升)中的1-氯乙基氯甲酸(0.5毫升)。在-10℃下攪拌此反應液3小時並濃縮。加入甲醇(10毫升)至粗混合物並迴流2小時。移除溶劑以提供4-(4-三氟甲基-苯基)-1,2,3,6-四氫-吡啶(氯化氫)，而不需進一步純化。¹H NMR(400 MHz,DMSO-d₆)δ 9.40(s,2H),7.74(m,4H),6.39(m,1H),3.79(m,2H),3.33(m,2H),2.74(m,2H)。 Dissolved 1-benzyl-4-(4-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine in tetrahydrofuran (10 mL). The reaction solution was cooled to -20 ° C and EtOAc (EtOAc) The reaction solution was stirred at -10 °C for 3 hours and concentrated. Methanol (10 mL) was added to the crude mixture and refluxed for 2 h. The solvent was removed to give 4-(4-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine (hydrogen chloride) without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.40 (s, 2H), 7.74 (m, 4H), 6.39 (m, 1H), 3.79 (m, 2H), 3.33 (m, 2H), 2.74 ( m, 2H).

步驟3Step 3

5-[4-(4-三氟甲基-苯基)-3,6-二氫-2H-吡啶-1-磺酸基]-二氫茚-2-羧酸：5-[4-(4-Trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridine-1-sulfonyl]-indoline-2-carboxylic acid:

使用二氫茚-2-羧酸甲酯和4-(4-三氟甲基-苯基)-1,2,3,6-四氫-吡啶並根據實施例1的流程製備化合物5-[4-(4-三氟甲基-苯基)-3,6-二氫-2H-吡啶-1-磺酸基]-二氫化茚-2-羧酸。¹H NMR(400 MHz,CDCl₃)δ 7.66(m,2H),7.57(d,2H),7.39(m,3H),6.06(m,1H),3.79(m,2H),3.50-3.26(m,7H),2.63(m,2H)；LCMS：451.9(M+1)⁺。 Preparation of compound 5-- using methyl indoline-2-carboxylate and 4-(4-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine according to the procedure of Example 1. 4-(4-Trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridine-1-sulfonic acid]-indane-2-carboxylic acid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.66 (m, 2H), 7.57 (d, 2H), 7.39 (m, 3H), 6.06 (m, 1H), 3.79 (m, 2H), 3.50-3.26 ( m, 7H), 2.63 (m , 2H); LCMS: 451.9 (m + 1) +.

4-[4-(4-三氟甲基-苯基)-3,6-二氫-2H-吡啶-1-磺酸基]-二氫茚-2-羧酸：4-[4-(4-Trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridine-1-sulfonyl]-indoline-2-carboxylic acid:

使用二氫茚-2-羧酸甲酯和4-(4-三氟甲基-苯基)-1,2,3,6-四氫-吡啶並根據實施例1的流程製備化合物4-[4-(4-三氟甲基-苯基)-3,6-二氫-2H-吡啶-1-磺酸基]-二氫茚-羧酸。¹H NMR(400 MHz,CDCl₃)δ 7.69(d,1H),7.57(d,2H),7.44(d,1H),7.41(d,2H),7.34(t,1H),6.08(m,1H),3.89(m,2H),3.80-3.31(m,7H),2.61(m,2H)；LCMS：451.9(M+1)⁺。 Preparation of compound 4- using the procedure for the procedure of Example 1 using methyl indoline-2-carboxylate and 4-(4-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine 4-(4-Trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridine-1-sulfonic acid]-indoline-carboxylic acid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.69 (d, 1H), 7.57 (d, 2H), 7.44 (d, 1H), 7.41 (d, 2H), 7.34 (t, 1H), 6.08 (m, 1H), 3.89 (m, 2H ), 3.80-3.31 (m, 7H), 2.61 (m, 2H); LCMS: 451.9 (m + 1) +.

實施例19 Example 19

6-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indoline-1-carboxylic acid:

使用二氫茚-1-羧酸甲酯並根據實施例1的流程製備化合物6-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,DMSO-d₆)δ 12.71(s,1H),7.75(s,1H),7.65(d,1H),7.57(d,1H),7.53(d,2H),7.06(d,2H),4.17(t,1H),3.40(m,4H),3.03(m,6H),2.36(m,2H)；LCMS：454.9(M+1)⁺。 Preparation of compound 6-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indoline using the procedure of Example 1 using methyl indoline-1-carboxylate 1-carboxylic acid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.71 (s, 1H), 7.75 (s, 1H), 7.65 (d, 1H), 7.57 (d, 1H), 7.53 (d, 2H), 7.06 ( d, 2H), 4.17 (t , 1H), 3.40 (m, 4H), 3.03 (m, 6H), 2.36 (m, 2H); LCMS: 454.9 (m + 1) +.

實施例20 Example 20

6-[4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[4-(5-Trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-1-carboxylic acid:

使用二氫茚-1-羧酸甲酯和1-[5-(三氟甲基)-吡啶-2-基]-哌嗪並根據實施例1的流程製備化合物6-[4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,CDCl₃)δ 8.35(s,1H),7.83(s,1H),7.64(dd,1H),7.61(dd,1H),7.39(d,1H),6.61(d； 1H),4.13(t,1H),3.75(m,4H),3.23-3.10(m,1H),3.11(m,4H),3.40-2.94(m,1H),2.48(m,2H)。 Preparation of compound 6-[4-(5- using methyl dihydroindole-1-carboxylate and 1-[5-(trifluoromethyl)-pyridin-2-yl]-piperazine according to the procedure of Example 1. Trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonate]-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.35 (s, 1H), 7.83 (s, 1H), 7.64 (dd, 1H), 7.61 (dd, 1H), 7.39 (d, 1H), 6.61 (d; 1H), 4.13 (t, 1H), 3.75 (m, 4H), 3.23-3.10 (m, 1H), 3.11 (m, 4H), 3.40-2.94 (m, 1H), 2.48 (m, 2H).

實施例21 Example 21

6-(4-苯甲基[1,3]二氧基-5-基-哌嗪-1-磺酸基)-二氫茚-1-羧酸：6-(4-Benzyl[1,3]dioxy-5-yl-piperazine-1-sulfonic acid)-indoline-1-carboxylic acid:

使用1-(3,4-亞甲基二氧苯甲基)哌嗪和二氫茚-1-羧酸甲酯並根據實施例1的流程合成化合物6-(4-苯甲基[1,3]二氧基-5-基-哌嗪-1-磺酸基)-二氫茚-1-羧酸。¹H NMR(400 MHz,MeOH-D₄)δ 7.77(s,1H)7.60(dd,1H),7.47(d,1H),6.78(s,1H),6.73(m,2H),5.90(s,2H),4.11(t,1H),3.16-3.09(m,1H),3.04-2.96(m,5H),2.58-2.55(m,4H),2.45-2.39(m,2H)；LCMS。 Synthesis of the compound 6-(4-benzylidene [1, using 1-(3,4-methylenedioxybenzyl)piperazine and indoline-1-carboxylic acid methyl ester according to the procedure of Example 1. 3] Dioxy-5-yl-piperazine-1-sulfonate)-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, MeOH-D ₄ ) δ 7.77 (s, 1H) 7.60 (dd, 1H), 7.47 (d, 1H), 6.78 (s, 1H), 6.73 (m, 2H), 5.90 (s) , 2H), 4.11 (t, 1H), 3.16-3.09 (m, 1H), 3.04 - 2.96 (m, 5H), 2.58 - 2.55 (m, 4H), 2.45 - 2.39 (m, 2H);

實施例22 Example 22

6-[4-(4-三氟甲基-苯基)-3,6-雙氫-2H-吡啶-1-磺酸基]-二氫茚-1-羧酸：6-[4-(4-Trifluoromethyl-phenyl)-3,6-dihydro-2 H -pyridine-1-sulfonyl]-indoline-1-carboxylic acid:

使用二氫茚-1-羧酸甲酯並根據實施例17的流程合成化合物6-[4-(4-三氟甲基-苯基)-3,6-雙氫-2H-吡啶-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,DMSO-d₆)δ 12.72(s,1H),7.80(s,1H),7.73-7.69(m,3H),7.61(d,2H),7.55(d,1H),6.28(m,1H),4.16(t,1H),3.72(m,2H),3.26(t,2H),3.12-2.92(m,2H),2.62(m,2H),2.36(2H)；LCMS：451.9(M+1)⁺。 The compound 6-[4-(4-trifluoromethyl-phenyl)-3,6-dihydro-2 H -pyridine-1 was synthesized according to the procedure of Example 17 using methyl dihydroindole-1-carboxylate. - sulfonic acid]-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.72 (s, 1H), 7.80 (s, 1H), 7.73 - 7.69 (m, 3H), 7.61 (d, 2H), 7.55 (d, 1H), 6.28(m,1H), 4.16(t,1H), 3.72(m,2H), 3.26(t,2H),3.12-2.92(m,2H), 2.62(m,2H), 2.36(2H);LCMS :451.9(M+1) ⁺ .

實施例23 Example 23

6-[2-(s)-甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[2-(s)-Methyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonic acid]-indoline-1-carboxylic acid: 步驟1step 1

3-(s)-甲基-1-(5-三氟甲基-吡啶-2-基)-哌嗪：3-(s)-methyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine:

於100℃下在甲苯中(10毫升)攪拌2-溴-5-三氟甲基-吡啶 (1.06g，4.69毫莫耳)、(S)-(+)-2-甲基哌嗪(1.03克，10.28毫莫耳)以及三乙胺(1.5毫升，10.76毫莫耳)26小時。冷卻反應液至室溫，以乙酸乙酯稀釋(150毫升)並以水和鹵水清洗。乾燥(硫酸鎂)有機層、過濾及濃縮。以自動矽膠快速管柱色層分析純化粗混合物(梯度洗提液0-20% MeOH/dichloromethane)來提供黃色固體的3-(S)-甲基-1-(5-三氟甲基-吡啶-2-基)-哌嗪(926毫克，81%)。¹H NMR(400 MHz,CDCl₃)δ 8.38(s,1H),7.62(dd,1H),7.63(d,1H),4.29-4.20(m,2H),3.16-3.12(m,1H),3.02-2.85(m,3H),2.64-2.52(m,2H),1.18(d,3H)。 Stir 2-bromo-5-trifluoromethyl-pyridine (1.06 g, 4.69 mmol), ( S )-(+)-2-methylpiperazine (1.03) in toluene (10 mL) at 100 °C. Gram, 10.28 millimoles) and triethylamine (1.5 ml, 10.76 mmol) for 26 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (150 ml) and washed with water and brine. The organic layer was dried (MgSO4), filtered and concentrated. The crude mixture was purified by automated gel column chromatography (gradient elution 0-20% MeOH/dichloromethane) to afford 3-( S )-methyl-1-(5-trifluoromethyl-pyridine as a yellow solid. 2-yl)-piperazine (926 mg, 81%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (s, 1H), 7.62 (dd, 1H), 7.63 (d, 1H), 4.29 - 4.20 (m, 2H), 3.16 - 3.12 (m, 1H), 3.02-2.85 (m, 3H), 2.64-2.52 (m, 2H), 1.18 (d, 3H).

步驟2Step 2

6-[2-(S)-甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[2-( S )-Methyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-1-carboxylic acid:

使用3-(S)-甲基-1-(5-三氟甲基-吡啶-2-基)-哌嗪以及二氫茚-1-羧酸甲酯並根據實施例1的流程合成化合物6-[2-(S)-甲基-4-(5-三氟甲基-吡啶-基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,MeOH-d₄)δ 8.33(s,1H),7.90(d,1H,J=5.89 Hz),7.71-7.67(m, 1H),7.62-7.57(m,1H),7.35-7.31(m,1H),6.58-6.52(m,1H),4.27-3.96(m,4H),3.80-3.69(m,1H),3.37-3.21(m,2H),3.15-2.92(m,3H),2.52-2.40(m,2H),1.11-1.08(m,3H)；LCMS：470.1(M+1)⁺。 Synthesis of compound 6 according to the procedure of Example 1 using 3-(S)-methyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine and methyl indoline-1-carboxylate -[2-( S )-Methyl-4-(5-trifluoromethyl-pyridinyl)-piperazine-1-sulfonic acid]-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 8.33 (s, 1H), 7.90 (d, 1H, J = 5.89 Hz), 7.71-7.67 (m, 1H), 7.62-7.57 (m, 1H), 7.35-7.31 (m, 1H), 6.58-6.52 (m, 1H), 4.27-3.96 (m, 4H), 3.80-3.69 (m, 1H), 3.37-3.21 (m, 2H), 3.15-2.92 (m , 3H), 2.52-2.40 (m, 2H), 1.11-1.08 (m, 3H); LCMS: 470.1 (M+1) ⁺ .

實施例24 Example 24

6-[2-(R)-甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[2-(R)-Methyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonic acid]-indoline-1-carboxylic acid:

使用3-(R)-甲基-1-(5-三氟甲基-吡啶-2-基)-哌嗪和二氫茚-1-羧酸甲酯並根據實施例1的流程合成化合物6-[2-(R)-甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,MeOH-d₄)δ 8.33(s,1H),7.90(d,1H),7.71-7.67(m,1H),7.62-7.57(m,1H),7.35-7.31(m,1H),6.58-6.52(m,1H),4.27-3.96(m,4H),3.80-3.69(m,1H),3.37-3.21(m,2H),3.15-2.92(m,3H),2.52-2.40(m,2H),1.11-1.08(m,3H)；LCMS：470.0(M+1)⁺。 Synthesis of compound 6 according to the procedure of Example 1 using 3-(R)-methyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine and methyl indoline-1-carboxylate -[2-(R)-Methyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 8.33 (s, 1H), 7.90 (d, 1H), 7.71-7.67 (m, 1H), 7.62-7.57 (m, 1H), 7.35-7.31 (m) , 1H), 6.58-6.52 (m, 1H), 4.27-3.96 (m, 4H), 3.80-3.69 (m, 1H), 3.37-3.21 (m, 2H), 3.15-2.92 (m, 3H), 2.52 -2.40 (m, 2H), 1.11-1.08 (m, 3H); LCMS: 470.0 (m + 1) +.

實施例25 Example 25

6-[3-(R)-甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸6-[3-(R)-Methyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonic acid]-indoline-1-carboxylic acid 步驟1step 1

4-苯甲基-2-(R)-甲基-1-(5-三氟甲基-吡啶-2-基)-哌嗪：4-Benzyl-2-(R)-methyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine:

使用1-苯甲基-3-(R)-甲基-哌嗪並根據實施例1(步驟23)的流程合成化合物4-苯甲基-2-(R)-甲基-1-(5-三氟甲基-吡啶-2-基)-哌嗪。¹H NMR(400 MHz,MeOH-D₄)δ 8.38(s,1H),7.76(dd,1H),6.90(d,1H),4.80-4.70(m,1H),4.36-4.32(m,1H),3.30-3.16(m,4H),3.20-2.92(m,1H),1.29(d,3H)；LCMS：336.1(M+1)⁺。 The compound 4-benzyl-2-(R)-methyl-1-(5) was synthesized according to the procedure of Example 1 (Step 23) using 1-benzyl-3-(R)-methyl-piperazine. -Trifluoromethyl-pyridin-2-yl)-piperazine. ¹ H NMR (400 MHz, MeOH-D ₄ ) δ 8.38 (s, 1H), 7.76 (dd, 1H), 6.90 (d, 1H), 4.80-4.70 (m, 1H), 4.36-4.32 (m, 1H) ), 3.30-3.16 (m, 4H) , 3.20-2.92 (m, 1H), 1.29 (d, 3H); LCMS: 336.1 (m + 1) +.

步驟2Step 2

2-(R)-甲基-1-(5-三氟甲基-吡啶-2-基)-哌嗪：2-(R)-Methyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine:

於氫氣氛圍(50psi)下攪拌4-苯甲基-2-(R)-甲基-1-(5-三氟甲基-吡啶-2-基)-哌嗪(175毫克，0.522毫莫耳)以及乙醇(5毫升)中的10%Pd/C(催化劑)3天。透過一矽藻土過濾反應混合液並經由矽膠管柱色層分析純化(梯度洗提液：在二氯甲烷中的0-20%甲醇)以提供一所需的產物(117毫克，99%)。¹H NMR(400 MHz,MeOH-D₄)δ 8.39(s,1H),7.60(dd,1H),7.39-7.28(m,5H),6.58(d,1H),4.49(br s,1H),4.10(br d,1H),3.62(br d,1H),3.47(br d,1H),3.24(br t,1H),2.95(br d,1H),2.77(br d,1H),2.35-2.15(m,2H),1.25(d,3H)；LCMS：246.1(M+1)⁺。 Stir 4-benzyl-2-( R )-methyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine (175 mg, 0.522 mmol) under a hydrogen atmosphere (50 psi) And 10% Pd/C (catalyst) in ethanol (5 ml) for 3 days. The reaction mixture was filtered through a pad of EtOAc (EtOAc) elute elute . ¹ H NMR (400 MHz, MeOH-D ₄ ) δ 8.39 (s, 1H), 7.60 (dd, 1H), 7.39-7.28 (m, 5H), 6.58 (d, 1H), 4.49 (br s, 1H) , 4.10 (br d, 1H), 3.62 (br d, 1H), 3.47 (br d, 1H), 3.24 (br t, 1H), 2.95 (br d, 1H), 2.77 (br d, 1H), 2.35 -2.15 (m, 2H), 1.25 (d, 3H); LCMS: 246.1 (m + 1) +.

步驟3Step 3

6-[3-(R)-甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[3-(R)-Methyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonic acid]-indoline-1-carboxylic acid:

使用2-(R)-甲基-1-(5-三氟甲基-吡啶-2-基)-哌嗪和二氧茚-1-羧酸甲酯並根據實施例1的流程合成化合物6-[3-(R)-甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,MeOH-D₄)δ 8.33(s,1H),7.80(s,1H),7.72-7.62(m,2H),7.46 (dd,1H),6.80(dd,1H),4.76-4.66(m,1H),4.28(br d,1H),4.14(br t,1H),3.79(br d,1H),3.61(br d,1H),3.29-3.20(m,1H),3.16-3.06(m,1H),3.03-2.94(m,1H),2.56-2.32(m,4H),1.26(m,3H)；LCMS：470.0(M+1)⁺。 Synthesis of compound 6 according to the procedure of Example 1 using 2-(R)-methyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine and methyl dioxan-1-carboxylate -[3-(R)-Methyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, MeOH-D ₄ ) δ 8.33 (s, 1H), 7.80 (s, 1H), 7.72-7.62 (m, 2H), 7.46 (dd, 1H), 6.80 (dd, 1H), 4.76-4.66(m,1H), 4.28(br d,1H), 4.14(br t,1H), 3.79(br d,1H), 3.61(br d,1H), 3.29-3.20(m,1H), 3.16-3.06 (m, 1H), 3.03-2.94 (m, 1H), 2.56-2.32 (m, 4H), 1.26 (m, 3H); LCMS: 470.0 (m + 1) +.

實施例26 Example 26 6-[4-(3-氟-4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[4-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indoline-1-carboxylic acid:

步驟1step 1

4-(3-氟-4-三氟甲基-苯基)-哌嗪-1-羧酸正丁酯：4-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid n-butyl ester:

溶解正丁基-1-哌嗪-羧酸(740毫克，3.05毫莫耳)以及2-溴-5-三氟甲基-吡啶(530毫克，2.85毫莫耳)在無水甲苯中(6毫升，脫氣)。另一方面，置入三(二苯亞甲基丙酮)二鈀(0)(152毫克，0.17毫莫耳)、1,3-二(2,6-二-i-丙基苯基)咪唑氯化物(283毫克，0.67毫莫耳)和t-丁氧化鈉(400毫克，4.2毫莫耳)於一配有間隔的試瓶中。 此「催化」試瓶配置有神奇攪拌棒並經乾燥氮氣沖洗。轉移反應溶液至催化試瓶內，並於100下℃攪拌混合液5小時。之後，結合反應溶液及20毫升的己烷/EtOAc(2：1)並通過矽藻土層。濃縮得到的濾液並使用矽膠色層分析純化(0-20% EtOAc/己烷)，而得到853毫克(86%)的濾渣4-(3-氟-4-三氟甲基-苯基)-哌嗪-1-羧酸正丁酯。¹H NMR(400 MHz.CDCl₃)δ 7.44-7.40(m,1H),6.65-6.58(m,2H),3.59-3.56(m,4H),3.27-3.25(m,4H),1.49(s,9H)。 Dissolve n-butyl-1-piperazine-carboxylic acid (740 mg, 3.05 mmol) and 2-bromo-5-trifluoromethyl-pyridine (530 mg, 2.85 mmol) in dry toluene (6 mL) , degassing). On the other hand, tris(diphenylmethyleneacetone)dipalladium (0) (152 mg, 0.17 mmol), 1,3-bis(2,6-di- i -propylphenyl)imidazole was placed. Chloride (283 mg, 0.67 mmol) and t -butoxide (400 mg, 4.2 mmol) were placed in a separate vial. This "catalytic" test bottle is equipped with a magic stir bar and rinsed with dry nitrogen. The reaction solution was transferred to a catalytic test bottle, and the mixture was stirred at 100 ° C for 5 hours. Thereafter, the reaction solution was combined with 20 ml of hexane/EtOAc (2:1) and passed through a layer of diatomaceous earth. The resulting filtrate was concentrated and purified using EtOAc (EtOAc:EtOAc) elute Piperazine-1-carboxylic acid n-butyl ester. ¹ H NMR (400 MHz.CDCl ₃ ) δ 7.44-7.40 (m, 1H), 6.65-6.58 (m, 2H), 3.59-3.56 (m, 4H), 3.27-3.25 (m, 4H), 1.49 (s , 9H).

步驟2Step 2

4-(3-氟-4-三氟甲基-苯基)-哌嗪：4-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine:

室溫下於三氟醋酸/二氯甲烷(5毫升，25% v/v)混合液中攪拌4-(3-氟-4-三氟甲基-苯基)-哌嗪-1-羧酸正丁酯(853毫克，2.45毫莫耳)20分鐘。反應混合物與25毫升的二氯甲烷(DCM)混合，並以飽和碳酸氫鈉(2x10毫升)以及鹵水清洗。以無水硫酸鈉乾燥產生的二氯甲烷層，並濃縮產生粗胺。進一步地以矽膠色層分析純化(梯度沖提液在二氯甲烷中的0-10%甲醇)以提供4-(3-氟-4-三氟甲基-苯基)-哌嗪。此產物進一步地用於下面步驟。 Stirring 4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid in a mixture of trifluoroacetic acid/dichloromethane (5 mL, 25% v/v) at room temperature N-butyl ester (853 mg, 2.45 mmol) for 20 minutes. The reaction mixture was mixed with 25 ml of dichloromethane (DCM) and washed with saturated sodium hydrogen sulfate (2×10 mL) and brine. The resulting dichloromethane layer was dried over anhydrous sodium sulfate and concentrated to give a crude amine. Further purified by gelatin chromatography (0-10% methanol in dichloromethane) to afford 4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazine. This product was further used in the next step.

步驟3Step 3

6-[4-(3-氟-4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[4-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indoline-1-carboxylic acid:

使用1-(3-氟-4-三氟甲基-苯基)-哌嗪及二氫茚-1-羧酸甲酯並根據實施例1的流程合成化合物6-[4-(3-氟-4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,MeOH-D₄)δ 7.81(s,1H),7.66-7.63(m,1H),7.49-7.38(m,2H),6.78-6.75(m,2H),4.14(t,1H),3.39-3.36(m,4H),3.16-3.07(m,5H),3.03-2.95(m,1H),2.46-2.39(m,2H)；LCMS：472.9(M+1)⁺。 Synthesis of compound 6-[4-(3-fluoro) using 1-(3-fluoro-4-trifluoromethyl-phenyl)-piperazine and indoline-1-carboxylic acid methyl ester according to the procedure of Example 1. -4-Trifluoromethyl-phenyl)-piperazine-1-sulfonate]-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, MeOH-D ₄ ) δ 7.81 (s, 1H), 7.66-7.63 (m, 1H), 7.49-7.38 (m, 2H), 6.78-6.75 (m, 2H), 4.14 (t) , 1H), 3.39-3.36 (m, 4H), 3.16-3.07 (m, 5H), 3.03 - 2.95 (m, 1H), 2.46-2.39 (m, 2H); LCMS: 472.9 (M+1) ⁺ .

實施例27 Example 27

6-[順-2,6-二甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[cis-2,6-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonic acid]-indoline-1-carboxylic acid:

使用順-2,6-二甲基哌嗪並根據實施例23的流程合成化合物6-[順-2,6-二甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫 茚-1-羧酸。¹H NMR(400 MHz,MeOH-d₄)δ 8.31(s,1H),7.89(s,1H),7.70(d,1H),7.58(dd,1H),7.31(d,1H),6.54(d,1H),4.34-4.26(m,1H),4.20-4.05(m,2H),3.99(t,2H),3.13-2.91(m,4H),2.52-2.36(m,2H),1.37(d,6H)；LCMS：484.0(M+1)⁺。 Synthesis of compound 6-[cis-2,6-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl) according to the procedure of Example 23 using cis-2,6-dimethylpiperazine - piperazine-1-sulfonate]-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 8.31 (s, 1H), 7.89 (s, 1H), 7.70 (d, 1H), 7.58 (dd, 1H), 7.31 (d, 1H), 6.54 ( d,1H),4.34-4.26(m,1H), 4.20-4.05(m,2H),3.99(t,2H),3.13-2.91(m,4H),2.52-2.36(m,2H), 1.37( d,6H); LCMS: 484.0 (M+1) ⁺ .

實施例28 Example 28 6-[順-2,6-二甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-1-甲基-二氫茚-1-羧酸：6-[cis-2,6-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-sulfonate]-1-methyl-indoline-1 -carboxylic acid:

步驟1step 1

1-甲基-二氫茚-1-羧酸甲酯：Methyl 1-methyl-indoline-1-carboxylate:

使用二氫茚-1-羧酸甲酯(67%)並根據實施例13的流程製備化合物1-甲基-二氫茚-1-羧酸甲酯。¹H NMR(400 MHz,CDCl₃)δ 7.32-7.16(m,4H),3.66(s,3H),3.11-3.04(m,1H),2.97-2.90(m,1H), 2.76-2.70(d,1H),1.99-1.92(m,1H),1.55(s,3H)。 The compound 1-methyl-indoline-1-carboxylic acid methyl ester was prepared according to the procedure of Example 13 using methyl dihydroindole-1-carboxylate (67%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.32-7.16 (m, 4H), 3.66 (s, 3H), 3.11-3.04 (m, 1H), 2.97-2.90 (m, 1H), 2.76-2.70 (d , 1H), 1.99-1.92 (m, 1H), 1.55 (s, 3H).

步驟2Step 2

6-[順-2,6-二甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-1-甲基-二氫茚-1-羧酸：6-[cis-2,6-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-sulfonate]-1-methyl-indoline-1 -carboxylic acid:

使用1-甲基-二氫茚-1-羧酸甲酯以及2,6-二甲基哌嗪並根據實施例27的流程合成化合物6-[順-2,6-二甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-1-甲基-二氫茚-1-羧酸。¹H NMR(400 MHz,MeOH-d₄)δ 8.26(s,1H),7.96(dd,1H),7.65(dd,1H),7.32(d,1H),4.30-4.22(m,1H),4.18-4.11(m,1H),4.04-3.98(m,1H),3.35(s,3H),3.08-2.92(m,4H),2.76-2.70(m,1H),2.04-1.97(m,1H),1.55(s,3H),1.36-1.33(m,6H)；LCMS：498.1(M+1)⁺。 Synthesis of compound 6-[cis-2,6-dimethyl-4- using methyl 1-methyl-indoline-1-carboxylate and 2,6-dimethylpiperazine according to the procedure of Example 27. (5-Trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonate]-1-methyl-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 8.26 (s, 1H), 7.96 (dd, 1H), 7.65 (dd, 1H), 7.32 (d, 1H), 4.30-4.22 (m, 1H), 4.18-4.11 (m, 1H), 4.04-3.98 (m, 1H), 3.35 (s, 3H), 3.08-2.92 (m, 4H), 2.76-2.70 (m, 1H), 2.04-1.97 (m, 1H) ), 1.55 (s, 3H) , 1.36-1.33 (m, 6H); LCMS: 498.1 (m + 1) +.

實施例29Example 29 {6-甲氧基-5-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-1-基}-醋酸：{6-Methoxy-5-[4-(4-trifluoromethyl-phenyl)-piperazin-1-sulfonyl]-indan-1-yl}-acetic acid:

步驟1step 1

(6-甲氧基-亞二氫茚-1-基)-醋酸乙酯：(6-methoxy-indanidin-1-yl)-ethyl acetate:

溶解6-甲氧基-二氫茚-1-酮(5.02克，30.95亳莫耳)以及三乙基磷酸醋酸(15.5毫升，78.13毫莫耳)在THF(20毫升)中並緩慢地添加至乙醇(850微升)及氫化鈉(油中的60%分散液，2.5克)的混合液。在70℃下攪拌得到的漿料隔夜。以二乙基酯稀釋得到的粗混合物，並以水與鹵水清洗，再以硫酸鈉乾燥、過濾和濃縮。以矽膠快速管柱色層分析(在乙基醋酸的5：1己烷)純化產物而提供E/Z異構物(~1：1)混合物的(6-甲氧基-亞二氫茚-1-基)-醋酸乙酯(3.18克，47%)。E/Z異構物(~1：1)混合物¹H NMR(400 MHz,CDCl₃)δ 7.37(d,1H)7.27(d,1H),7.09(d,1H),6.99(dd,1H),6.97(d,1H),6.81(dd,1H),6.50(m,1H),6.31-6.30(m,1H),4.27(quart,2H),4.22(quart,2H),3.87(s,3H),3.86(s,3H),3.60(m,2H),3.36-3.33(m,4H),3.05-3.02(m,2H),1.37(t,3H),1.31(t,3H)。 Dissolve 6-methoxy-indan-1-one (5.02 g, 30.95 mmol) and triethylphosphoric acid (15.5 mL, 78.13 mmol) in THF (20 mL) and slowly add to A mixture of ethanol (850 microliters) and sodium hydride (60% dispersion in oil, 2.5 grams). The resulting slurry was stirred at 70 ° C overnight. The resulting crude mixture was diluted with diethyl ether and washed with water and brine, dried over sodium sulfate, filtered and concentrated. The product was purified by silica gel flash column chromatography (5:1 hexane in ethyl acetate) to provide (6-methoxy-dihydroindole) as a mixture of E/Z isomers (~1:1). 1-Base)-ethyl acetate (3.18 g, 47%). E/Z isomer (~1:1) mixture ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37 (d, 1H) 7.27 (d, 1H), 7.09 (d, 1H), 6.99 (dd, 1H) , 6.97 (d, 1H), 6.81 (dd, 1H), 6.50 (m, 1H), 6.31-6.30 (m, 1H), 4.27 (quart, 2H), 4.22 (quart, 2H), 3.87 (s, 3H) ), 3.86 (s, 3H), 3.60 (m, 2H), 3.36-3.33 (m, 4H), 3.05-3.02 (m, 2H), 1.37 (t, 3H), 1.31 (t, 3H).

步驟2Step 2

(6-甲氧基-二氫茚-1-基)-醋酸乙酯：(6-Methoxy-dihydroindol-1-yl)-ethyl acetate:

溶解(6-甲氧基-亞二氫茚-1-基)-醋酸乙酯(3.18克，14.5毫莫耳)在甲醇(30毫升)中。添加催化量的10% Pd/C而在氫氣氛圍下攪拌反應混合液2小時。透過矽藻土過濾反應混合液而提供純無色油狀的(6-甲氧基-二氫茚-1-基)-醋酸乙酯(2.98克，94%)。LCMS：235.0(M+1)⁺。 (6-Methoxy-indanidin-1-yl)-ethyl acetate (3.18 g, 14.5 mmol) was dissolved in methanol (30 mL). A catalytic amount of 10% Pd/C was added and the reaction mixture was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through EtOAc (EtOAc) (EtOAc) LCMS: 235.0 (M+1) ⁺ .

步驟3Step 3

{6-甲氧基-5-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-1-基}-醋酸{6-Methoxy-5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-1-yl}-acetic acid

使用(6-甲氧基-二氫茚-1-基)-醋酸乙酯並根據實施例1的流程合成化合物{6-甲氧基-5-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-1-基}-醋酸。¹H NMR(400 MHz,MeOH-d₄)δ 7.67(s,1H)7.46(d,2H),7.10(s,1H),7.01(d,2H),3.89(s,3H),3.57(quint.,1H),3.30 (m,8H),2.96-2.78(m,3H),2.49-2.37(m,2H),1.85-1.76(m,1H)；LCMS：498.9(M+1)⁺。 The compound {6-methoxy-5-[4-(4-trifluoromethyl-benzene) was synthesized according to the procedure of Example 1 using (6-methoxy-indan-1-yl)-ethyl acetate. Base)-piperazine-1-sulfonic acid]-indan-1-yl}-acetic acid. ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 7.67 (s, 1H) 7.46 (d, 2H), 7.10 (s, 1H), 7.01 (d, 2H), 3.89 (s, 3H), 3.57 (quint , 1H), 3.30 (m, 8H), 2.96-2.78 (m, 3H), 2.49-2.37 (m, 2H), 1.85-1.76 (m, 1H); LCMS: 498.9 (M+1) ⁺ .

實施例30Example 30

{5-[4-(3,4-二氯-苯基)-哌嗪-1-磺酸基]-6-甲氧基-二氫茚-1-基}-醋酸：{5-[4-(3,4-Dichloro-phenyl)-piperazine-1-sulfo]-6-methoxy-indan-1-yl}-acetic acid:

使用3,4二氯苯基哌嗪並根據實施例29的流程合成{5-[4-(3,4-二氯-苯基)-哌嗪-1-磺酸基]-6-甲氧基-二氫茚-1-基}-醋酸。¹H NMR(400 MHz,MeOH-d₄)δ 7.64(s,1H)7.28(d,1H),7.14-7.12(s,1H),7.04(d,1H),6.85(dd,1H),3.90(s,3H),3.60(quint.,1H),3.30-3.27(m,4H),3.19-3.17(m,4H),2.95-2.76(m,2H),2.60(dd,1H),2.43-2.33(m,2H),1.85-1.76(m,1H)；LCMS：498.8(M+1)⁺。 Synthesis of {5-[4-(3,4-dichloro-phenyl)-piperazine-1-sulfonate]-6-methoxy by 3,4-dichlorophenylpiperazine according to the procedure of Example 29. Base-dihydroindol-1-yl}-acetic acid. ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 7.64 (s, 1H) 7.28 (d, 1H), 7.14, 7.12 (s, 1H), 7.04 (d, 1H), 6.85 (dd, 1H), 3.90 (s, 3H), 3.60 (quint., 1H), 3.30-3.27 (m, 4H), 3.19-3.17 (m, 4H), 2.95-2.76 (m, 2H), 2.60 (dd, 1H), 2.43- 2.33 (m, 2H), 1.85-1.76 (m, 1H); LCMS: 498.8 (m + 1) +.

實施例31Example 31 {5-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-吲哚-1-基}-醋酸：{5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-acetic acid: 步驟1step 1

1-{5-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-2,3-二氫-吲哚-1-基}-乙醇：1-{5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonate]-2,3-dihydro-indol-1-yl}-ethanol:

根據實施例1的流程(89%)合成化合物1-{5-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-2,3-二氫-吲哚-1-基}-乙醇。¹H NMR(400 MHz,CDCl₃)δ 8.43(d 1H),7.62(d,1H)7.57(s,1H),7.47(d,2H),6.88(d,2H),4.16(t,2H),3.35(m,4H),3.28(t,2H),3.15(m,4H),2.27(s,3H)；LCMS：454.0(M+1)⁺。 The compound 1-{5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-indole was synthesized according to the procedure of Example 1 (89%).哚-1-yl}-ethanol. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.43 (d 1H), 7.62 (d, 1H) 7.57 (s, 1H), 7.47 (d, 2H), 6.88 (d, 2H), 4.16 (t, 2H) , 3.35 (m, 4H), 3.28 (t, 2H), 3.15 (m, 4H), 2.27 (s, 3H); LCMS: 454.0 (m + 1) +.

步驟2Step 2

5-{4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基}-2,3-二氫-1H-吲哚：5-{4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonate}-2,3-dihydro-1H-indole:

在1,4-二氧陸圜(5毫升)和濃縮氯化氫(2.5毫升)中迴流1-{5-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-2,3-二氫-吲哚-1-基}-乙醇2小時。接著以二氯甲烷稀釋反應液，並以1N氯化氫、飽和碳酸鈉沖再乾燥(Na₂SO₄)、過濾及濃縮而提供灰白色固體5-{4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基}-2,3-二氫-1H-吲哚(1.03g，75%)。¹H NMR(400 MHz,CDCl₃)δ 7.48-7.20(m,4H),6.88(d,2H),6.60(d,1H),3.70(t,2H),3.36-3.33(m,4H),3.15-3.12(m,4H),3.10(t,2H)。 1-{5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonate was refluxed in 1,4-dioxane (5 mL) and concentrated hydrogen chloride (2.5 mL) ]-2,3-Dihydro-indol-1-yl}-ethanol for 2 hours. The reaction was then diluted with dichloromethane, 1N hydrogen chloride and is, then washed with saturated sodium carbonate, dried (Na ₂ SO _4), filtered, and concentrated to provide an off-white solid 5- {4- (4-trifluoromethyl-phenyl) - - piperazine-1-sulfonate}-2,3-dihydro-1H-indole (1.03 g, 75%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.48-7.20 (m, 4H), 6.88 (d, 2H), 6.60 (d, 1H), 3.70 (t, 2H), 3.36-3.33 (m, 4H), 3.15-3.12 (m, 4H), 3.10 (t, 2H).

步驟3Step 3

5-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-1H-吲哚：5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonate]-1H-indole:

溶解5-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-2,3-二氫-1H-吲哚(180毫克，0.44毫莫耳)在二氯甲烷(10毫升)中。添加DDQ(100毫克，0.44毫莫耳)並在室溫下攪拌4小時。濃縮反應液並以矽膠快速管柱色層分析(在己烷的45%乙基醋酸)純化，而提供白色固體5-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-1-H-吲哚(70%)。¹H NMR(400 MHz,DMSO-D₆)δ 11.72(s,1H),8.07(s,1H)7.65(d,1H),7.62-7.61(m,1H),7.52-7.48(m,3H),7.04(d,2H),6.71(m,1H),3.40-3.36(m,4H),3.02-2.99(m,4H)。 Dissolved 5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonate]-2,3-dihydro-1H-indole (180 mg, 0.44 mmol) in two In methyl chloride (10 ml). DDQ (100 mg, 0.44 mmol) was added and stirred at room temperature for 4 hours. The reaction mixture was concentrated and purified with EtOAc EtOAc (EtOAc:EtOAc -sulfonate]-1-H-indole (70%). ¹ H NMR (400 MHz, DMSO-D ₆ ) δ 11.72 (s, 1H), 8.07 (s, 1H) 7.65 (d, 1H), 7.62-7.61 (m, 1H), 7.52-7.48 (m, 3H) , 7.04 (d, 2H), 6.71 (m, 1H), 3.40-3.36 (m, 4H), 3.02 - 2.99 (m, 4H).

步驟4Step 4

{5-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-吲哚-1-基}醋酸甲酯：{5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}acetic acid methyl ester:

於70℃下在乙腈(10毫升)中攪拌5-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-1H-吲哚(60毫克，0.15毫莫耳)、甲基溴醋酸(16微升，0.18毫莫耳)以及碳酸銫(95毫克，0.29毫莫耳)過夜。以乙基醋酸稀釋反應混合物，再以水、鹵水沖洗，以Na₂SO₄乾燥並濃縮而提供黃色油狀{5-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-吲哚-1-基}醋酸甲酯(>99%)。¹H NMR(400 MHz,CDCl₃)δ 8.11(d,1H)7.60(dd,1H),7.43(d,2H),7.36(d,1H),7.24(d,1H),6.83(d,2H),6.90(d,1H),4.91(s,2H),3.76(s,3H),3.32-3.30(m,4H),3.15-3.13(m,4H)。 Stir 5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonate]-1H-indole (60 mg, 0.15 mmol) in acetonitrile (10 mL) at 70 °C Ear), methyl bromide (16 μL, 0.18 mmol) and cesium carbonate (95 mg, 0.29 mmol) overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over Na ₂ SO ₄ and concentrated to afford white crystals of 5-[4-(4-trifluoromethyl-phenyl)-piperazine-1 -Mercaptosyl]-indol-1-yl}methyl acetate (>99%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (d, 1H) 7.60 (dd, 1H), 7.43 (d, 2H), 7.36 (d, 1H), 7.24 (d, 1H), 6.83 (d, 2H) ), 6.90 (d, 1H), 4.91 (s, 2H), 3.76 (s, 3H), 3.32-3.30 (m, 4H), 3.15-3.13 (m, 4H).

步驟5Step 5

{5-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-吲哚-1-基}醋酸：{5-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-sulfonyl]-indol-1-yl}acetic acid:

根據實施例1的流程水解化合物{5-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-吲哚-1-基}-醋酸甲酯。¹H NMR(400 MHz,CDCl₃)δ 8.08(d,1H)7.70(dd,1H),7.60(d,1H),7.53(m,3H),7.04(d,2H),6.74(d,1H),5.16(s,2H),3.39(m,4H),3.01(m,4H)。 The compound {5-[4-(4-trifluoromethyl-phenyl)-piperazin-1-sulfonyl]-indol-1-yl}-methyl acetate was hydrolyzed according to the procedure of Example 1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.08 (d, 1H) 7.70 (dd, 1H), 7.60 (d, 1H), 7.53 (m, 3H), 7.04 (d, 2H), 6.74 (d, 1H) ), 5.16 (s, 2H), 3.39 (m, 4H), 3.01 (m, 4H).

實施例32Example 32

{5-溴-6-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-吲哚-1-基}-醋酸：{5-Bromo-6-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-acetic acid:

使用1-(5-溴-2,3-二氫-吲哚-1-基)-乙醇為起始原料並根據實施例31的流程合成{5-溴-6-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-吲哚-1-基}-醋酸。¹H NMR(400 MHz,CDCl₃)δ 8.14(s,1H)7.95(s,1H),7.46(d,2H),7.28(d,1H),6.88(d,2H),6.56(d,1H),4.94(s,2H),3.44-3.42(m,4H),3.28-3.26(m,4H)。 Using 5-(5-bromo-2,3-dihydro-indol-1-yl)-ethanol as starting material and synthesizing {5-bromo-6-[4-(4-tri) according to the procedure of Example 31 Fluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-acetic acid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.14 (s, 1H) 7.95 (s, 1H), 7.46 (d, 2H), 7.28 (d, 1H), 6.88 (d, 2H), 6.56 (d, 1H) ), 4.94 (s, 2H), 3.44 - 3.42 (m, 4H), 3.28-3.26 (m, 4H).

實施例33Example 33

{5-溴-6-[4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-吲哚-1-基}-醋酸：{5-Bromo-6-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-sulfonyl]-indol-1-yl}-acetic acid:

使用1-(5-溴-2,3-二氫-吲哚-1-基)-乙醇以及1-[5-(三氟甲基-吡啶-2-基]哌嗪並根據實施例26的流程合成{5-溴-6-[4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-吲哚-1-基}-醋酸。¹H NMR(400 MHz,CDCl₃)δ 8.24(s,1H)8.07(s,1H),7.87(s,1H),7.63(dd,1H),7.23(d, 1H),6.61(d,1H),6.46(d,1H),5.30(s,2H),3.66-3.63(m,4H),3.34-3.32(m,4H)。 1-(5-Bromo-2,3-dihydro-indol-1-yl)-ethanol and 1-[5-(trifluoromethyl-pyridin-2-yl)piperazine were used and according to Example 26 The procedure synthesizes {5-bromo-6-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfo]-indol-1-yl}-acetic acid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.24 (s, 1H) 8.07 (s, 1H), 7.87 (s, 1H), 7.63 (dd, 1H), 7.23 (d, 1H), 6.61 (d, 1H), 6.46 (d, 1H), 5.30 (s, 2H), 3.66-3.63 (m, 4H), 3.34-3.32 (m, 4H).

實施例34Example 34

{6-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-吲哚-1-基}-醋酸{6-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-acetic acid 步驟1step 1

{5-溴-6-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-吲哚-1-基}-醋酸甲酯：{5-Bromo-6-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-methyl acetate:

使用1-(5-溴-2,3-二氫-吲哚-1-基)-乙醇為起始原料並根據實施例31的流程合成化合物{5-溴-6-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-吲哚-1-基}-醋酸甲酯。¹H NMR(400 MHz,CDCl₃)δ 8.13(s,1H)7.98(s,1H),7.47(d,2H),7.31(d,1H),6.90(d,2H),6.58(d,1H),4.11(dd,2H),3.79(s,3H),3.45(m,4H),3.32(m,4H)。 The compound {5-bromo-6-[4-(4-) was synthesized according to the procedure of Example 31 using 1-(5-bromo-2,3-dihydro-indol-1-yl)-ethanol as a starting material. Trifluoromethyl-phenyl)-piperazine-1-sulfoyl]-indol-1-yl}-methyl acetate. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.13 (s, 1H) 7.98 (s, 1H), 7.47 (d, 2H), 7.31 (d, 1H), 6.90 (d, 2H), 6.58 (d, 1H) ), 4.11 (dd, 2H), 3.79 (s, 3H), 3.45 (m, 4H), 3.32 (m, 4H).

步驟2Step 2

{6-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-吲哚-1-基}-醋酸甲酯：{6-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-methyl acetate:

在氫氣氛圍下攪拌{5-溴-6-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-吲哚-1-基}-醋酸甲酯(135亳克，0.24毫莫耳)、三乙胺基(40微升0.29毫莫耳)和10%Pd/C(催化劑)，直到所有起始原料不見。透過矽藻土過濾反應液、濃縮並藉由快速管柱色層分析純化(在乙基乙酸的60%己烷)而提供乾淨油狀的{6-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-吲哚-1-基}-醋酸甲酯(96毫克，83%)。¹H NMR(400 MHz,CDCl₃)δ 7.76(d,1H)7.75(d,1H),7.51(dd,1H),7.44(dd,2H),7.31(d,1H),6.84(d,2H),6.67(d,1H),4.11(dd,2H),3.78(s,3H),3.33(m,4H),3.16(m,4H)。 Stirring {5-bromo-6-[4-(4-trifluoromethyl-phenyl)-piperazin-1-sulfonyl]-indol-1-yl}-methyl acetate under a hydrogen atmosphere (135亳克, 0.24 mmol, triethylamine (40 μl 0.29 mmol) and 10% Pd/C (catalyst) until all starting materials are not visible. The reaction solution was filtered through celite, concentrated and purified by flash column chromatography (60% hexanes in ethyl acetate) to afford a crude oil of &quot;6-[4-(4-trifluoromethyl-) Phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-methyl acetate (96 mg, 83%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.76 (d, 1H) 7.75 (d, 1H), 7.51 (dd, 1H), 7.44 (dd, 2H), 7.31 (d, 1H), 6.84 (d, 2H) ), 6.67 (d, 1H), 4.11 (dd, 2H), 3.78 (s, 3H), 3.33 (m, 4H), 3.16 (m, 4H).

步驟3Step 3

{6-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-吲哚-1-基}-醋酸：{6-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-acetic acid:

根據實施例1(87%)的流程水解{6-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-吲哚-1-基}-醋酸甲酯。¹H NMR(400 MHz,CDCl₃)δ 7.93(d,1H)7.82(d,1H),7.67(d,1H),7.50(d,2H),7.42(dd,1H),7.03(d,2H),6.60(d,1H),5.20(s,2H),3.37(m,4H),3.02(m,4H)。 Hydrolysis of {6-[4-(4-trifluoromethyl-phenyl)-piperazin-1-sulfonate]-indol-1-yl}-methyl acetate according to the procedure of Example 1 (87%) . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.93 (d, 1H) 7.82 (d, 1H), 7.67 (d, 1H), 7.50 (d, 2H), 7.42 (dd, 1H), 7.03 (d, 2H) ), 6.60 (d, 1H), 5.20 (s, 2H), 3.37 (m, 4H), 3.02 (m, 4H).

實施例35Example 35

{6-[4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-吲哚-1-基}醋酸：{6-[4-(5-Trifluoromethyl-pyridin-2-yl)-piperazin-1-sulfonyl]-indol-1-yl}acetic acid:

使用1-[5-(三氟甲基)-吡啶-2-基]哌嗪並根據實施例34的流程合成化合物{6-[4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-吲哚-1-基}醋酸。¹H NMR(400 MHz,CDCl₃)δ 8.31(s,1H),7.73(d,1H)7.72(s,1H),7.58(dd,1H),7.48(dd,1H),7.30(d,1H),6.64(d,1H),6.56(d,1H),4.93(s,2H),3.74(m,4H),3.10(m,4H).)；LCMS：468.9(M+1)⁺。 The compound {6-[4-(5-trifluoromethyl-pyridin-2-yl) was synthesized according to the procedure of Example 34 using 1-[5-(trifluoromethyl)-pyridin-2-yl]piperazine. - piperazine-1-sulfonate]-indol-1-yl}acetic acid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (s, 1H), 7.73 (d, 1H) 7.72 (s, 1H), 7.58 (dd, 1H), 7.48 (dd, 1H), 7.30 (d, 1H) ), 6.64 (d, 1H) , 6.56 (d, 1H), 4.93 (s, 2H), 3.74 (m, 4H), 3.10 (m, 4H)); LCMS:. 468.9 (m + 1) +.

根據圖解六和圖解七製備實施例36-37。 Examples 36-37 were prepared according to Scheme 6 and Scheme 7.

實施例36Example 36 步驟1step 1

4-(3-甲氧基-苯基磺酸基)-3-氧基-丁酸乙酯的合成：Synthesis of 4-(3-methoxy-phenylsulfonyl)-3-oxy-butyric acid ethyl ester:

緩慢地加入在20毫升乙腈中的4-氯乙醯乙酸乙酯(8.75克，71.2毫莫耳)溶液至在20毫升乙腈中的3-甲氧基苯硫醇(9.69克，71.2毫莫耳)及碳酸銫(46.4克，14.2毫莫耳)混合液超過5分鐘。 室溫下攪拌混合液2小時，然後以矽藻土過濾。蒸發濾液提供靜置時固化的油脂。溶解殘留物於EtOAc中，接著以水、鹵水清洗溶液並以硫酸鈉乾燥。蒸發溶劑提供14.0克所需的酯類。¹H NMR(400 MHz,CDCl₃)δ 7.20(t,1H),6.90(d,1H),6.87(s,1H),6.79(d,1H),4.20(q,2H),3.82(s,2H),3.79(s,3H),3.63(s,2H),1.26(t,3H)。 A solution of 4-chloroacetic acid ethyl acetate (8.75 g, 71.2 mmol) in 20 ml of acetonitrile was slowly added to 3-methoxybenzenethiol (9.69 g, 71.2 mmol) in 20 ml of acetonitrile. And a mixture of barium carbonate (46.4 grams, 14.2 millimoles) for more than 5 minutes. The mixture was stirred at room temperature for 2 hours and then filtered over Celite. The evaporated filtrate provides a grease that solidifies upon standing. The residue was dissolved in EtOAc then washed with water and brine and dried over sodium sulfate. Evaporation of the solvent provided 14.0 g of the desired ester. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.20 (t, 1H), 6.90 (d, 1H), 6.87 (s, 1H), 6.79 (d, 1H), 4.20 (q, 2H), 3.82 (s, 2H), 3.79 (s, 3H), 3.63 (s, 2H), 1.26 (t, 3H).

步驟2Step 2

(6-甲氧基-苯並[b]噻吩-3-基)-醋酸乙酯的合成：Synthesis of (6-methoxy-benzo[b]thiophen-3-yl)-acetic acid ethyl ester:

室溫下將步驟1(7.0克，26.0毫莫耳)的化合物緩慢地加入到甲烷磺酸(100毫升)中。攪拌產生的溶液20分鐘並以液滴的方式加入到冰上(250克)。以EtOAc萃取水層混合物兩次。以鹵水、飽 和碳酸氫鈉沖洗有機層，再以Na₂SO₄烘乾。在移除溶劑後，以矽膠色層分析純化(3：7 EtOAc/己烷)殘留物而提供4.33克所要的化合物VIb。 Step 1 (7.0 g, 26.0 mmol) of compound was slowly added to methanesulfonic acid (100 mL) at room temperature. The resulting solution was stirred for 20 minutes and added to ice (250 g) as droplets. The aqueous layer mixture was extracted twice with EtOAc. The organic layer was washed with brine and saturated sodium bicarbonate and dried over Na ₂ SO ₄ . After removal of the solvent, it was purified to silica gel layer chromatography (3: 7 EtOAc / hexanes) the residue to provide the desired compound 4.33 g VIb.

步驟3Step 3

(7-氯磺酸-6甲氧基-苯並[b]噻吩-3-基)-醋酸乙酯的合成：Synthesis of (7-chlorosulfonic acid-6-methoxy-benzo[b]thiophen-3-yl)-acetic acid ethyl ester:

添加氯磺酸(0.56毫升，8.0毫莫耳)至在10毫升DCM中的步驟2(VI-B)(1.0克，4.0毫莫耳)化合物溶液。室溫下攪拌產生的混合物4小時。在真空下蒸發溶劑，然後溶解殘留物在EtOAc。以碳酸鈉、鹵水清洗溶液，再以硫酸鈉烘乾。蒸發溶液而提供50毫克所要的化合物VIc。¹H NMR(400 MHz,CDCl₃)δ 8.08(d,1H),7.38(s,1H),6.90(d,1H),4.21(q,2H),4.02(s,2H),4.01(s,3H),1.24(t,3H)。 Add chlorosulfonic acid (0.56 mL, 8.0 mmol) to step 2 (VI-B) (1.0 g, 4.0 mmol) compound in 10 mL DCM. The resulting mixture was stirred at room temperature for 4 hours. The solvent was evaporated in vacuo then the residue was takenEtOAcEtOAc. The solution was washed with sodium carbonate and brine and dried over sodium sulfate. The solution was evaporated to provide 50 mg of the desired compound VIc. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.08 (d, 1H), 7.38 (s, 1H), 6.90 (d, 1H), 4.21 (q, 2H), 4.02 (s, 2H), 4.01 (s, 3H), 1.24 (t, 3H).

步驟4Step 4

{6-甲氧基-7-[4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-苯並[b]{6-Methoxy-7-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonate]-benzo[b] 噻吩-3-基}-醋酸乙酯的合成：Synthesis of thiophen-3-yl}-ethyl acetate:

先加入1-[5-(三氟甲基)-2-吡啶基]哌嗪(32毫克，0.14毫莫耳)到在THF(2毫升)中的步驟3(50毫克，0.14毫莫耳)化合物溶液，再加入三乙胺(39微升，0.28毫莫耳)。室溫下攪拌反應液4小時。蒸發溶劑，再以矽膠色層分析純化殘留物而提供22毫克所需要的化合物。 First add 1-[5-(trifluoromethyl)-2-pyridyl]piperazine (32 mg, 0.14 mmol) to step 3 (50 mg, 0.14 mmol) in THF (2 mL) The compound solution was further added with triethylamine (39 μL, 0.28 mmol). The reaction solution was stirred at room temperature for 4 hours. The solvent was evaporated and the residue was purified eluting with EtOAc (EtOAc)

步驟5Step 5

{6-甲氧基-7-[4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-苯並[b]噻吩-3-基}-醋酸：{6-Methoxy-7-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonic acid]-benzo[b]thiophen-3-yl}-acetic acid :

先溶解步驟4VId(22毫克，0.041毫莫耳)的化合物在2毫升THF/MeOH(3：1)中，接著加入1N氫氧化鋰(5.0當量)。在40℃下攪拌產生的混合物3小時。在氮氣下蒸發有機溶劑而以水(2毫升)稀釋殘留物。以***(2毫升)分離水層。移除有機層後，以1N氯化氫(5.0當量)中和水層，接著以乙酸乙酯(5毫升)萃取。以水、鹵水清洗有機層，再以硫酸鈉烘乾。移除溶劑而提供實施例36的化合物。¹H NMR(400 MHz,CDCl₃)δ 8.32(s,1H),8.38(s,1H),7.78(d,1H),7.61(d,1H),7.22(s,1H),6.60(m,1H),4.01(s,2H),3.98(s,3H),3.77(m,4H),3.22(m,4H)。 The compound of Step 4 VId (22 mg, 0.041 mmol) was dissolved in 2 mL THF / MeOH (3:1) followed by 1N lithium hydroxide (5.0 eq.). The resulting mixture was stirred at 40 ° C for 3 hours. The organic solvent was evaporated under nitrogen and the residue was diluted with water (2 mL). The aqueous layer was separated with diethyl ether (2 mL). After the organic layer was removed, the aqueous layer was evaporated,jjjjjjjjjj The organic layer was washed with water and brine and dried over sodium sulfate. The solvent of Example 36 was provided by removing the solvent. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (s, 1H), 8.38 (s, 1H), 7.78 (d, 1H), 7.61 (d, 1H), 7.22 (s, 1H), 6.60 (m, 1H), 4.01 (s, 2H), 3.98 (s, 3H), 3.77 (m, 4H), 3.22 (m, 4H).

實施例37Example 37 步驟1step 1

苯並[b]噻吩-3-基-醋酸甲酯的合成：Synthesis of benzo[b]thiophen-3-yl-acetate:

添加濃縮氯化氫(催化劑量)到一在甲醇中的2-苯並[b]噻吩-3-基醋酸(4.0克)溶液中。在80℃下迴流產生的溶液4小時。在真空中移除溶劑而溶解殘留物於EtOAc中。以水、鹵水清洗溶液，再以Na₂SO₄乾燥。在減壓下移除溶劑後，提供了甲基酯。¹H NMR(400 MHz,CDCl₃)δ 7.90(d,1H),7.80(d,1H),7.40(m,2H),7.39(s,1H),3.91(s,2H),3.75(s,3H)。 Concentrated hydrogen chloride (catalyst amount) was added to a solution of 2-benzo[b]thiophen-3-ylacetic acid (4.0 g) in methanol. The resulting solution was refluxed at 80 ° C for 4 hours. The solvent was removed in vacuo to dissolve the residue in EtOAc. The solution was washed with water and brine and dried over Na ₂ SO ₄ . After removal of the solvent under reduced pressure, a methyl ester is provided. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.90 (d, 1H), 7.80 (d, 1H), 7.40 (m, 2H), 7.39 (s, 1H), 3.91 (s, 2H), 3.75 (s, 3H).

步驟2Step 2

(5-氯磺酸基-苯並[b]噻吩-3-基}-醋酸甲酯的合成：Synthesis of (5-chlorosulfonyl-benzo[b]thiophen-3-yl}-acetic acid methyl ester:

根據使用來製備中間產物VIc的方法(圖解VI)製備中間產物VIIb。¹H NMR(400 MHz,CDCl₃)δ 8.60(s,1H),8.02(d,1H),8.00(d, 1H),7.80(s,1H),3.99(s,2H),3.78(s,3H)。 The intermediate product VIIb was prepared according to the method (Illustration VI) used to prepare the intermediate product VIc. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.60 (s, 1H), 8.02 (d, 1H), 8.00 (d, 1H), 7.80 (s, 1H), 3.99 (s, 2H), 3.78 (s, 3H).

步驟3Step 3

{5-[4-(5-三氟甲基-吡啶-2-基)哌嗪-1-磺酸基]-苯並[b]噻吩-3-基}-醋酸甲酯的合成：Synthesis of {5-[4-(5-trifluoromethyl-pyridin-2-yl)piperazine-1-sulfonic acid]-benzo[b]thiophen-3-yl}-acetic acid methyl ester:

根據用來製備中間產物VId的方法(圖解VI)製備中間產物VIIc。 The intermediate product VIIc was prepared according to the method used to prepare the intermediate product VId (Scheme VI).

步驟4Step 4

{5-[4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-苯並[b]噻吩-3-基}-醋酸的合成：Synthesis of {5-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonic acid]-benzo[b]thiophen-3-yl}-acetic acid:

根據用來製備實施例36化合物的方法製備實施例37的化合物。¹H NMR(400 MHz,CDCl₃)δ 8.33(s,1H),8.32(s,1H),7.87(d,1H),7.78(d,1H),7.65(s,1H),7.62(d,1H),6.59(d,1H),3.93(s,2H),3.78(m,4H),3.14(m,4H)。 The compound of Example 37 was prepared according to the procedure used to prepare the compound of Example 36. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (s, 1H), 8.32 (s, 1H), 7.78 (d, 1H), 7.78 (d, 1H), 7.65 (s, 1H), 7.62 (d, 1H), 6.59 (d, 1H), 3.93 (s, 2H), 3.78 (m, 4H), 3.14 (m, 4H).

實施例38 Example 38

6-[2,2-二甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1羧酸的合成：Synthesis of 6-[2,2-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-1 carboxylic acid:

使用2,2-二甲基-4-(5-三氟甲基-吡啶-2-基)哌嗪並根據用來製備實施例23的方法製備實施例38的化合物。¹H NMR(400 MHz.CDCl₃)δ 8.36(s,1H),7.91(s,1H),7.71(d,1H),7.61(d,1H)7.36-7.31(m,1H),6.52(d,1H),4.15-4.11(m,1H),3.73-3.53(m,6H),3.18-3.12(m,1H),3.10-2.95(m,1H),2.54-2.42(m,2H),1.39(s,6H).ESMS(M+H)：484.1。 The compound of Example 38 was prepared according to the method used to prepare Example 23 using 2,2-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)piperazine. ¹ H NMR (400 MHz.CDCl ₃ ) δ 8.36 (s, 1H), 7.91 (s, 1H), 7.71 (d, 1H), 7.61 (d, 1H) 7.36-7.31 (m, 1H), 6.52 (d) , 1H), 4.15-4.11 (m, 1H), 3.73-3.53 (m, 6H), 3.18-3.12 (m, 1H), 3.10-2.95 (m, 1H), 2.54-2.42 (m, 2H), 1.39 (s, 6H). ESMS (M+H): 484.1.

實施例39Example 39

(R)-4-(3-羧基-二氫茚-5-磺酸基)-1-(5-三氟甲基-吡啶-2-基)-哌嗪-2-羧酸甲酯的合成：Synthesis of (R)-4-(3-carboxy-indoline-5-sulfonate)-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine-2-carboxylic acid methyl ester :

使用1-(5-三氟甲基-吡啶-2-基)-哌嗪並根據用來製備實施例26的方法製備實施例39的化合物。¹H NMR(400MHz,CD₃OD)δ 8.37(m,1H),7.85(s,1H),7.80(d,1H),7.69(d,1H),7.52(d,1H),6.94(d,1H),5.55(m,1H),4.33-4.29(m,1H),4.20-4.11(m,2H),3.84-3.81(m,1H),3.74(s,3H),3.47-3.41(m,1H),3.20-3.14(m,1H),3.07-2.99(m,1H),2.65-2.61(m,1H),2.51-2.42(m,3H).ESMS(M+H)：514.0。 The compound of Example 39 was prepared using 1-(5-trifluoromethyl-pyridin-2-yl)-piperazine according to the procedure used for the preparation of Example 26. _{^{1 H NMR (400MHz, CD 3}} OD) δ 8.37 (m, 1H), 7.85 (s, 1H), 7.80 (d, 1H), 7.69 (d, 1H), 7.52 (d, 1H), 6.94 (d, 1H), 5.55 (m, 1H), 4.33-4.29 (m, 1H), 4.20-4.11 (m, 2H), 3.84-3.81 (m, 1H), 3.74 (s, 3H), 3.47-3.41 (m, 1H), 3.20-3.14 (m, 1H), 3.07-2.99 (m, 1H), 2.65-2.61 (m, 1H), 2.51-2.42 (m, 3H). ESMS (M+H): 514.0.

實施例40Example 40

(S)-4-(3-羧基-二氫茚-5-磺酸基)-1-(5-三氟甲基-吡啶-2-基)-哌嗪-2-羧酸甲酯的合成：Synthesis of (S)-4-(3-carboxy-indoline-5-sulfonate)-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine-2-carboxylic acid methyl ester :

使用1-(5-三氟甲基-吡啶-2-基)-哌嗪並根據用來製備實施例26的方法製備實施例38的化合物。¹H NMR(400MHz,CDCl₃)δ 8.35(m,1H),7.85(s,1H),7.69-7.62(m,2H),7.41(d,1H),6.68-6.01(m,1H),5.53(m,1H),4.35(d,1H),4.16-4.13(m,1H),3.90-3.82(m,2H),3.74(s,3H),3.60-3.51(m,1H),3.19-3.11(m,1H),3.03-2.95(m,1H),2.64-2.60(m,1H),2.52-2.46(m,3H).ESMS(M+H)：514.0。 The compound of Example 38 was prepared using 1-(5-trifluoromethyl-pyridin-2-yl)-piperazine according to the procedure used for the preparation of Example 26. _{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.35 (m, 1H), 7.85 (s, 1H), 7.69-7.62 (m, 2H), 7.41 (d, 1H), 6.68-6.01 (m, 1H), 5.53 (m, 1H), 4.35 (d, 1H), 4.16-4.13 (m, 1H), 3.90-3.82 (m, 2H), 3.74 (s, 3H), 3.60-3.51 (m, 1H), 3.19-3.11 (m, 1H), 3.03 - 2.95 (m, 1H), 2.64 - 2.60 (m, 1H), 2.52 - 2.46 (m, 3H). ESMS (M+H): 514.0.

實施例41 Example 41

3{5-[4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-苯並[b]噻吩-3-基}-醋酸：3{5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfo]-benzo[b]thiophen-3-yl}-acetic acid:

使用1-(4-三氟甲基-苯基)-哌嗪並根據實施例37的流程而製備之。¹H NMR(400 MHz,CDCl₃)δ 8.34(s,1H),7.90(d,1H),7.76(d,1H),7.65(s,1H),7.45(d,2H),6.85(d,2H),3.94(s,2H),3.34(m,4H),3.20(m,4H)。 This was prepared according to the procedure of Example 37 using 1-(4-trifluoromethyl-phenyl)-piperazine. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34 (s, 1H), 7.90 (d, 1H), 7.76 (d, 1H), 7.65 (s, 1H), 7.45 (d, 2H), 6.85 (d, 2H), 3.94 (s, 2H), 3.34 (m, 4H), 3.20 (m, 4H).

實施例42Example 42

{5-[2-甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-苯並[b]噻吩-3-基}-醋酸：{5-[2-Methyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonic acid]-benzo[b]thiophen-3-yl}-acetic acid:

使用1-(5-三氟甲基-吡啶-2-基)-哌嗪並根據實施例37的流程製備之。¹H NMR(400 MHz,CDCl₃)δ 8.38(s,1H),8.32(s,1H),7.82(m,2H),7.63(s,1H),7.55(d,1H),6.48(d,1H),4.29(m,1H),4.18(d,1H),4.02(d,1H),3.92(s,2H),3.79(d,1H),3.28(m,2H),3.02(t,1H),1.10(d,3H)。 This was prepared according to the procedure of Example 37 using 1-(5-trifluoromethyl-pyridin-2-yl)-piperazine. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (s, 1H), 8.32 (s, 1H), 7.82 (m, 2H), 7.63 (s, 1H), 7.55 (d, 1H), 6.48 (d, 1H), 4.29 (m, 1H), 4.18 (d, 1H), 4.02 (d, 1H), 3.92 (s, 2H), 3.79 (d, 1H), 3.28 (m, 2H), 3.02 (t, 1H) ), 1.10 (d, 3H).

實施例43Example 43

{5-[2,6-二甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-苯並[b]噻吩-3-基}-醋酸：{5-[2,6-Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl} -acetic acid:

使用2,6-二甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪並根據實施例37的流程製備之。¹H NMR(400 MHz,CDCl₃)δ 8.37(s,1H),8.29(s,1H),7.81(m,2H),7.62(s,1H),7.52(d,1H),6.44(d,1H),4.27(m,2H),3.96(t,2H),3.91(s,2H),3.03(dd,2H),1.39(d,6H)。 This was prepared according to the procedure of Example 37 using 2,6-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 8.29 (s, 1H), 7.81 (m, 2H), 7.62 (s, 1H), 7.52 (d, 1H), 6.44 (d, 1H), 4.27 (m, 2H), 3.96 (t, 2H), 3.91 (s, 2H), 3.03 (dd, 2H), 1.39 (d, 6H).

實施例44Example 44

{5-[2,5-二甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-苯並[b]噻吩-3-基}-醋酸：{5-[2,5-Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl} -acetic acid:

使用2,5-二甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪並根據實施例37的流程製備之。¹H NMR(400 MHz,CDCl₃)δ 8.39(s,1H),8.37(s,1H),7.87(d,1H),7.79(d,1H),7.64(s,1H),7.61(d,1H),6.57(d,1H),4.63(m,1H),4.31(m,1H),4.05(d,1H),3.94(s,2H),3.61(d,1H),3.37(m,2H),1.21(d,3H),0.96(d,3H)。 This was prepared according to the procedure of Example 37 using 2,5-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.39 (s, 1H), 8.37 (s, 1H), 7.78 (d, 1H), 7.79 (d, 1H), 7.64 (s, 1H), 7.61 (d, 1H), 6.57 (d, 1H), 4.63 (m, 1H), 4.31 (m, 1H), 4.05 (d, 1H), 3.94 (s, 2H), 3.61 (d, 1H), 3.37 (m, 2H) ), 1.21 (d, 3H), 0.96 (d, 3H).

實施例45 Example 45

6-[4-(2-氟-4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[4-(2-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indoline-1-carboxylic acid:

根據實施例26的流程合成化合物6-[4-(2-氟-4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,CD₃OD)δ 7.83(s,1H),7.65(dd,1H),7.51(d,1H),7.38(d,1H),7.32(dd,1H),7.14-7.10(m,1H),4.15(t,1H),3.30-3.20(m,4H),3.20-3.15(m,1H),3.14-3.10(m,4H),3.09-2.96(m,1H),2.49(q,2H)；LCMS 472.5(M+1)⁺。 The compound 6-[4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazine-1-sulfo]-indoline-1-carboxylic acid was synthesized according to the procedure of Example 26. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.83 (s, 1H), 7.65 (dd, 1H), 7.51 (d, 1H), 7.38 (d, 1H), 7.32 (dd, 1H), 7.14-7.10 (m, 1H), 4.15 (t, 1H), 3.30-3.20 (m, 4H), 3.20-3.15 (m, 1H), 3.14-3.10 (m, 4H), 3.09-2.96 (m, 1H), 2.49 (q, 2H); LCMS 472.5 (M+1) ⁺ .

實施例46 Example 46

6-[4-(3,4-二氯-苯基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[4-(3,4-Dichloro-phenyl)-piperazine-1-sulfonyl]-indoline-1-carboxylic acid:

根據實施例26的流程製備化合物6-[4-(3,4-二氯-苯基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,CD₃OD)δ 7.84(s,1H),7.70(d,1H),7.54(d,1H),7.34-7.29(m,1H),7.10-7.06(m,1H),6.90-6.84(m,1H),4.38(t,1H),3.30-3.22(m,4H),3.21-3.25(m,1H),3.24-3.10(m,4H),3.20-2.99(m,1H),2.50(q,2H)；LCMS 455.5 (M+1)⁺。 The compound 6-[4-(3,4-dichloro-phenyl)-piperazine-1-sulfo]-indoline-1-carboxylic acid was prepared according to the procedure of Example 26. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.84 (s, 1H), 7.70 (d, 1H), 7.54 (d, 1H), 7.34-7.29 (m, 1H), 7.10-7.06 (m, 1H) , 6.90-6.84 (m, 1H), 4.38 (t, 1H), 3.30-3.22 (m, 4H), 3.21-3.25 (m, 1H), 3.24-3.10 (m, 4H), 3.20-2.99 (m, 1H), 2.50 (q, 2H); LCMS 455.5 (M+1) ⁺ .

實施例47Example 47

步驟1step 1

1-(2-氟-4-三氟甲基-苯基)-哌嗪：1-(2-Fluoro-4-trifluoromethyl-phenyl)-piperazine:

使用哌嗪及1-溴-2-氟-4-三氟甲基-苯甲基並根據實施例26步驟1的流程合成化合物1-(2-氟-4-三氟甲基-苯基)-哌嗪。 Synthesis of the compound 1-(2-fluoro-4-trifluoromethyl-phenyl) according to the procedure of Step 1 of Example 26 using piperazine and 1-bromo-2-fluoro-4-trifluoromethyl-benzyl. -Piperazine.

步驟2Step 2 {5-[4-(2-氟-4-三氟甲基-苯基)-哌嗪-1-磺酸基]-苯並[b]噻吩-3-基}-醋酸：{5-[4-(2-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-sulfo]-benzo[b]thiophen-3-yl}-acetic acid:

使用上面步驟1得到的1-(2-氟-4-三氟甲基-苯基)-哌嗪並根據實施例37的流程合成化合物{5-[4-(2-氟-4-三氟甲基-苯基)-哌嗪-1-磺酸基]-苯並[b]噻吩-3-基}-醋酸。¹H NMR(400 MHz,CD₃OD)δ 8.44(s,1H),8.04(d,1H),7.82(s,1H),7.78(dd,1H),7.46-7.38(m,1H),6.80-8.72(m,2H),3.98(s,2H),3.42-3.32(m,4H),3.19-3.10(m, 4H)；LCMS 502.5(M+1)⁺。 The compound {5-[4-(2-fluoro-4-trifluoro) was synthesized according to the procedure of Example 37 using 1-(2-fluoro-4-trifluoromethyl-phenyl)-piperazine obtained in the above step 1 Methyl-phenyl)-piperazine-1-sulfonate]-benzo[b]thiophen-3-yl}-acetic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 8.04 (d, 1H), 7.82 (s, 1H), 7.78 (dd, 1H), 7.46-7.38 (m, 1H), 6.80 - 8.72 (m, 2H), 3.98 (s, 2H), 3.42-3.32 (m, 4H), 3.19-3.10 (m, 4H); LCMS 502.5 (M+1) ⁺ .

實施例48Example 48

{5-[4-(3-氟-4-三氟甲基-苯基)-哌嗪-1-磺酸基]-苯並[b]噻吩-3-基}-醋酸：{5-[4-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-sulfo]-benzo[b]thiophen-3-yl}-acetic acid:

根據實施例47的流程合成化合物{5-[4-(3-氟-4-三氟甲基-苯基)-哌嗪-1-磺酸基]-苯並[b]噻吩-3-基}-醋酸。¹H NMR(400 MHz,CD₃OD)δ 8.40(s,1H),8.10(d,1H),7.81(s,1H),7.78(dd,1H),7.46-7.39(m,1H),6.80-8.72(m,2H),4.00(s,2H),3.40-3.31(m,4H),3.18-3.10(m,4H)；LCMS 502.5(M+1)⁺。 The compound {5-[4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazine-1-sulfo]-benzo[b]thiophen-3-yl was synthesized according to the procedure of Example 47 }-acetic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.40 (s, 1H), 8.10 (d, 1H), 7.81 (s, 1H), 7.78 (dd, 1H), 7.46-7.39 (m, 1H), 6.80 - 8.72 (m, 2H), 4.40 (s, 2H), 3.40 - 3.31 (m, 4H), 3.18 - 3.10 (m, 4H); LCMS 502.5 (M+1) ⁺ .

實施例49 Example 49

6-[4-(3,4-二氯-苯基)-2,6-順-二甲基-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[4-(3,4-Dichloro-phenyl)-2,6-cis-dimethyl-piperazine-1-sulfonic acid]-indoline-1-carboxylic acid:

使用2,6-順-二甲基-哌嗪和4-溴-1,2-二氯-甲苯並根據實施例 26步驟1和3的流程合成化合物6-[4-(3,4-二氯-苯基)-2,6-順-二甲基-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,CD₃OD)δ 7.83(d,1H),7.67-7.62(m,1H),7.38(dd,1H),7.19(d,1H),6.82(d,1H),6.65(dd,1H),4.30-4.21(m,1H),4.20-4.10(m,2H),3.25-3.20(m,2H),3.19-3.10(m,1H),3.08-2.89(m,1H),2.65-2.56(m,2H),2.45-2.39(m,2H),1.48(d,3H),1.45(d,3H)；LCMS 483.4(M+1)⁺。 Synthesis of compound 6-[4-(3,4-di) according to the procedure of steps 1 and 3 of Example 26 using 2,6-cis-dimethyl-piperazine and 4-bromo-1,2-dichloro-toluene. Chloro-phenyl)-2,6-cis-dimethyl-piperazine-1-sulfonate]-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.83 (d, 1H), 7.67-7.62 (m, 1H), 7.38 (dd, 1H), 7.19 (d, 1H), 6.82 (d, 1H), 6.65 (dd, 1H), 4.30-4.21 (m, 1H), 4.20-4.10 (m, 2H), 3.25-3.20 (m, 2H), 3.19-3.10 (m, 1H), 3.08-2.89 (m, 1H) , 2.65-2.56 (m, 2H), 2.45-2.39 (m, 2H), 1.48 (d, 3H), 1.45 (d, 3H); LCMS 483.4 (m + 1) +.

實施例50 Example 50

6-[4-(3-氯-4-三氟甲基-苯基)-2,6-順-二甲基-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[4-(3-Chloro-4-trifluoromethyl-phenyl)-2,6-cis-dimethyl-piperazine-1-sulfonic acid]-indoline-1-carboxylic acid:

使用2,6-順-二甲基-哌嗪和4-溴-2-氯-1-三氟甲基-甲苯並根據實施例26步驟1和3的流程合成化合物6-[4-(3-氯-4-三氟甲基-苯基)-2,6-順-二甲基-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,CD₃OD)δ 7.87(s,1H),7.69(d,1H),7.45(d,1H),7.38(d,1H),6.85(s,1H),6.72(d,1H),4.28-4.21(m,1H),4.18-4.10(m,1H),4.08(t,1H),3.48-3.40(m,1H),3.38-3.18(m,3H),3.10-2.89(m,2H),2.48-2.38(m,2H),1.42(m,3H)1.40(d,3H)；LCMS 516.9(M+1)⁺。 Synthesis of compound 6-[4-(3) using 2,6-cis-dimethyl-piperazine and 4-bromo-2-chloro-1-trifluoromethyl-toluene according to the procedure of steps 26 and 3 of Example 26. -Chloro-4-trifluoromethyl-phenyl)-2,6-cis-dimethyl-piperazine-1-sulfonic acid]-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.87 (s, 1H), 7.69 (d, 1H), 7.45 (d, 1H), 7.38 (d, 1H), 6.85 (s, 1H), 6.72 (d) , 1H), 4.28-4.21 (m, 1H), 4.18-4.10 (m, 1H), 4.08 (t, 1H), 3.48-3.40 (m, 1H), 3.38-3.18 (m, 3H), 3.10-2.89 (m, 2H), 2.48-2.38 ( m, 2H), 1.42 (m, 3H) 1.40 (d, 3H); LCMS 516.9 (m + 1) +.

實施例51 Example 51

6-[2,6-順-二甲基-4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[2,6-cis-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indoline-1-carboxylic acid:

使用2,6-順-二甲基-哌嗪和1-溴-4-三氟甲氧基-甲苯並根據實施例26步驟1和3的流程合成化合物6-[2,6-順-二甲基-4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,CD₃OD)δ 7.88(s,1H),7.70(d,1H),7.40(d,1H),7.10(d,2H),6.89(d,2H),4.30-4.20(m,1H),4.19-4.09(m,2H),3.30-3.20(m,2H),3.19-3.10(m,1H),3.08-2.98(m,1H),2.65-2.56(m,2H),2.45-2.39(m,2H),1.50(d,3H),1.45(d,3H)；LCMS 498.5(M+1)⁺。 Synthesis of compound 6-[2,6-cis-di using 2,6-cis-dimethyl-piperazine and 1-bromo-4-trifluoromethoxy-toluene according to the procedure of steps 26 and 3 of Example 26. Methyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfo]-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.88 (s, 1H), 7.70 (d, 1H), 7.40 (d, 1H), 7.10 (d, 2H), 6.89 (d, 2H), 4.30-4.20 (m, 1H), 4.19-4.09 (m, 2H), 3.30-3.20 (m, 2H), 3.19-3.10 (m, 1H), 3.08-2.98 (m, 1H), 2.65-2.56 (m, 2H) , 2.45-2.39 (m, 2H), 1.50 (d, 3H), 1.45 (d, 3H); LCMS 498.5 (m + 1) +.

實施例52 Example 52

6-[4-(3,4-二氯-苯基)-3-(S)-甲基-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[4-(3,4-Dichloro-phenyl)-3-(S)-methyl-piperazine-1-sulfonyl]-indoline-1-carboxylic acid:

使用3-(S)-甲基-哌嗪-1-羧酸正丁酯和4-溴-1,2-氯-甲苯並根據實施例26的流程合成化合物6-[4-(3,4-二氯-苯基)-3-(S)-甲基-哌嗪 -1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,CD₃OD)δ 7.88(s,1H),7.65(d,1H),7.45(d,1H),7.32(d,1H),7.15-6.94(m,1H),6.78-6.72(m,1H),4.20-4.10(m,1H),4.10-4.00(m,2H),3.70-3.60(m,1H),3.45-3.40(m,1H),3.30-3.21(m,2H),3.20-3.11(m,1H),3.10-2.90(m,1H),2.75-2.60(m,1H)2.48-2.40(m,2H),1.20(d,3H)；LCMS 469.4(M+1)⁺。 Synthesis of compound 6-[4-(3,4) using 3-(S)-methyl-piperazine-1-carboxylic acid n-butyl ester and 4-bromo-1,2-chloro-toluene according to the procedure of Example 26. -Dichloro-phenyl)-3-(S)-methyl-piperazine-1-sulfonate]-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.88 (s, 1H), 7.65 (d, 1H), 7.45 (d, 1H), 7.32 (d, 1H), 7.15-6.94 (m, 1H), 6.78 -6.72 (m, 1H), 4.20-4.10 (m, 1H), 4.10-4.00 (m, 2H), 3.70-3.60 (m, 1H), 3.45-3.40 (m, 1H), 3.30-3.21 (m, 2H), 3.20-3.11 (m, 1H), 3.10-2.90 (m, 1H), 2.75-2.60 (m, 1H) 2.48-2.40 (m, 2H), 1.20 (d, 3H); LCMS 469.4 (M+ 1) ⁺ .

實施例53 Example 53

6-[3-(S)-甲基-4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[3-(S)-Methyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonic acid]-indoline-1-carboxylic acid:

使用3-(S)-甲基-哌嗪-1-羧酸正丁酯以及1-溴-4-三氟甲氧基-甲苯並根據實施例26的流程合成化合物6-[3-(S)-甲基-4-(4-三氟甲氧基-苯)-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,CD₃OD)δ 7.81(s,1H),7.66(d,1H),7.50(d,1H),7.62(d,2H),6.98-6.93(m,2H),4.18(t,1H),4.00-3.90(m,1H),3.60-3.55(m,1H),3.35-3.25(m,3H),3.20-3.10(m,1H),3.10-3.00(m,1H),2.85-2.75(m,1H),2.70-2.60(m,1H)2.40(q,2H),1.10(d,3H)；LCMS 484.5(M+1)⁺。 Synthesis of compound 6-[3-(S) using 3-(S)-methyl-piperazine-1-carboxylic acid n-butyl ester and 1-bromo-4-trifluoromethoxy-toluene according to the procedure of Example 26. )-Methyl-4-(4-trifluoromethoxy-benzene)-piperazine-1-sulfo]-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.81 (s, 1H), 7.66 (d, 1H), 7.50 (d, 1H), 7.62 (d, 2H), 6.98-6.93 (m, 2H), 4.18 (t, 1H), 4.00-3.90 (m, 1H), 3.60-3.55 (m, 1H), 3.35-3.25 (m, 3H), 3.20-3.10 (m, 1H), 3.10-3.00 (m, 1H) , 2.85-2.75 (m, 1H), 2.70-2.60 (m, 1H) 2.40 (q, 2H), 1.10 (d, 3H); LCMS 484.5 (M+1) ⁺ .

實施例54 Example 54

6-[4-(3-氟-4-三氟甲基-苯基)-3-(S)-甲基-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[4-(3-Fluoro-4-trifluoromethyl-phenyl)-3-(S)-methyl-piperazine-1-sulfonyl]-indoline-1-carboxylic acid:

使用3-(S)-甲基-哌嗪-1-羧酸正丁酯並根據實施例26的流程合成化合物6-[4-(3-氟-4-三氟甲基-苯基)-3-(S)-甲基-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,CD₃OD)δ 7.80(s,1H),7.70(d,1H),7.50(d,1H),7.41-7.31(m,2H),7.20-7.10(m,1H),4.20-4.10(m,1H),3.90-3.78(m,1H),3.50-3.40(m,1H),3.39-3.20(m,3H),3.19-3.10(m,1H),3.09-2.98(m,2H),2.80-2.70(m,1H),2.42-2.25(m,2H),1.10(d,3H)；LCMS 486.5(M+1)⁺。 The compound 6-[4-(3-fluoro-4-trifluoromethyl-phenyl)- was synthesized according to the procedure of Example 26 using 3-(S)-methyl-piperazine-1-carboxylic acid n-butyl ester. 3-(S)-Methyl-piperazine-1-sulfonate]-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.80 (s, 1H), 7.70 (d, 1H), 7.50 (d, 1H), 7.41-7.31 (m, 2H), 7.20-7.10 (m, 1H) , 4.20-4.10 (m, 1H), 3.90-3.78 (m, 1H), 3.50-3.40 (m, 1H), 3.39-3.20 (m, 3H), 3.19-3.10 (m, 1H), 3.09-2.98 ( m, 2H), 2.80-2.70 (m , 1H), 2.42-2.25 (m, 2H), 1.10 (d, 3H); LCMS 486.5 (m + 1) +.

實施例55 Example 55

6-[3-(S)-甲基-4-(5-三氟甲基-苯基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[3-(S)-Methyl-4-(5-trifluoromethyl-phenyl-pyridin-2-yl)-piperazine-1-sulfonic acid]-indoline-1-carboxylic acid :

使用3-(S)-甲基-哌嗪-1-羧酸正丁酯以及2-溴-5-三氟甲基-吡啶並根據實施例26的流程合成化合物6-[3-(S)-甲基-4-(5-三氟甲基 -苯基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,CD₃OD)δ 8.38(s,1H),7.83(s 1H),7.78-7.72(m,1H),7.65(d,1H),7.50-7.40(m,1H),6.85-6.80(m,1H),4.80-4.70(m,1H),4.30(d,1H),4.20-4.10(m,2H),3.81(d,1H),3.60(d,1H),2.35-2.24(m,1H),3.20-3.11(m,1H),3.10-2.98(m,1H),2.60-2.45(m,1H)2.42-2.25(m,2H),1.40-1.20(m,3H)；LCMS 469.5(M+1)⁺。 Synthesis of compound 6-[3-(S) according to the procedure of Example 26 using 3-(S)-methyl-piperazine-1-carboxylic acid n-butyl ester and 2-bromo-5-trifluoromethyl-pyridine. -Methyl-4-(5-trifluoromethyl-phenyl-pyridin-2-yl)-piperazine-1-sulfonic acid]-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (s, 1H), 7.83 (s 1H), 7.78-7.72 (m, 1H), 7.65 (d, 1H), 7.50-7.40 (m, 1H), 6.85-6.80 (m, 1H), 4.80-4.70 (m, 1H), 4.30 (d, 1H), 4.20-4.10 (m, 2H), 3.81 (d, 1H), 3.60 (d, 1H), 2.35- 2.24(m,1H), 3.20-3.11(m,1H), 3.10-2.98(m,1H), 2.60-2.45(m,1H)2.42-2.25(m,2H),1.40-1.20(m,3H) ; LCMS 469.5 (M+1) ⁺ .

實施例56 Example 56

6-[4-(3-氯-4-三氟甲基-苯基)-2-乙基-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[4-(3-Chloro-4-trifluoromethyl-phenyl)-2-ethyl-piperazine-1-sulfonic acid]-indoline-1-carboxylic acid:

使用2-乙基-哌嗪以及4-溴-2-氯-1-三氟甲基-甲苯並根據實施例26步驟1和3的流程合成化合物6-[4-(3-氯-4-三氟甲基-苯基)-2-乙基-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,CD₃OD)δ 7.90(d,1H),7.72(t,1H),7.45(dd,1H),7.38(dd,1H),6.87(dd,1H),6.70(dd,1H),4.12-4.02(m,1H),4.01-3.93(m,1H),3.98-3.76(m,1H),3.58-3.42(m,2H),3.41-3.29(m,1H),3.11-3.02(m,1H),3.00-2.82(m,2H),2.82-2.62(m,1H),2.46-2.36(m,2H),1.76-1.56(m,2H),1.00-0.92(m 3H)；LCMS 516.9(M+1)⁺。 Synthesis of compound 6-[4-(3-chloro-4-) using 2-ethyl-piperazine and 4-bromo-2-chloro-1-trifluoromethyl-toluene according to the procedure of Steps 1 and 3 of Example 26. Trifluoromethyl-phenyl)-2-ethyl-piperazine-1-sulfonate]-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.90 (d, 1H), 7.72 (t, 1H), 7.45 (dd, 1H), 7.38 (dd, 1H), 6.87 (dd, 1H), 6.70 (dd , 1H), 4.12-4.02 (m, 1H), 4.01-3.93 (m, 1H), 3.98-3.76 (m, 1H), 3.58-3.42 (m, 2H), 3.41-3.29 (m, 1H), 3.11 -3.02 (m, 1H), 3.00-2.82 (m, 2H), 2.82-2.62 (m, 1H), 2.46-2.36 (m, 2H), 1.76-1.56 (m, 2H), 1.00-0.92 (m 3H ); LCMS 516.9 (M+1) ⁺ .

實施例57Example 57

化合物6-[2-乙基-4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-二氫茚-1羧酸：Compound 6-[2-Ethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfo]-indoline-1carboxylic acid:

使用2-乙基-哌嗪以及1-溴-4-三氟甲氧基-甲苯並根據實施例26步驟1和3的流程合成化合物6-[2-乙基-4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,CD₃OD)δ 7.90(s,1H),7.79-7.73(m,1H),7.47-7.38(m,1H),7.08(d,2H),6.88-6.81(m,2H),4.12(q,1H),3.99-3.90(m,1H),3.88-3.76(m,1H),3.44-3.24(m,3H),3.16-3.08(m,1H),3.02-2.92(m,1H),2.69-2.50(m,2H),2.48-2.36(m,2H),1.82-1.66(m,2H),0.95(t,3H)；LCMS 498.5(M+1)⁺。 The compound 6-[2-ethyl-4-(4-trifluoro) was synthesized according to the procedure of Steps 1 and 3 of Example 26 using 2-ethyl-piperazine and 1-bromo-4-trifluoromethoxy-toluene. Methoxy-phenyl)-piperazine-1-sulfonate]-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.90 (s, 1H), 7.79-7.73 (m, 1H), 7.47-7.38 (m, 1H), 7.08 (d, 2H), 6.88-6.81 (m, 2H), 4.12 (q, 1H), 3.99-3.90 (m, 1H), 3.88-3.76 (m, 1H), 3.44-3.24 (m, 3H), 3.16-3.08 (m, 1H), 3.02-2.92 ( m, 1H), 2.69-2.50 (m , 2H), 2.48-2.36 (m, 2H), 1.82-1.66 (m, 2H), 0.95 (t, 3H); LCMS 498.5 (m + 1) +.

實施例58 Example 58

6-[4-(3,4-二氯-苯基)-2-乙基-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[4-(3,4-Dichloro-phenyl)-2-ethyl-piperazine-1-sulfonyl]-indoline-1-carboxylic acid:

使用2-乙基-哌嗪和4-溴-1,2-二氯-甲苯並根據實施例26步驟 1和3的流程合成化合物6-[4-(3,4-二氯-苯基)-2-乙基-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,CD₃OD)δ 7.84(s,1H),7.68-7.64(m,1H),7.39-7.32(m,1H),7.19(dd,1H),6.82(dd,1H),6.68-6.62(m,1H),4.10(q,1H),3.98-3.83(m,1H),3.81-3.71(m,1H),3.30-3.20(m,3H),3.12-3.02(m,1H),3.00-2.90(m,1H),2.70-2.60(m,2H),2.40-2.30(m,2H),1.55-1.51(m,2H),0.98(t,3H)；LCMS 483.4(M+1)⁺。 Synthesis of compound 6-[4-(3,4-dichloro-phenyl) according to the procedure of steps 1 and 3 of Example 26 using 2-ethyl-piperazine and 4-bromo-1,2-dichloro-toluene. 2-Ethyl-piperazine-1-sulfonate]-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.84 (s, 1H), 7.68-7.64 (m, 1H), 7.39-7.32 (m, 1H), 7.19 (dd, 1H), 6.82 (dd, 1H) , 6.68-6.62 (m, 1H), 4.10 (q, 1H), 3.98-3.83 (m, 1H), 3.81-3.71 (m, 1H), 3.30-3.20 (m, 3H), 3.12-3.02 (m, 1H), 3.00-2.90 (m, 1H), 2.70-2.60 (m, 2H), 2.40-2.30 (m, 2H), 1.55-1.51 (m, 2H), 0.98 (t, 3H); LCMS 483.4 (M +1) ⁺ .

實施例59 Example 59

6-[2-乙基-4-(3-氟-4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[2-ethyl-4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indoline-1-carboxylic acid:

使用2-乙基-哌嗪並根據實施例26步驟1及3的流程合成化合物6-[2-乙基-4-(3-氟-4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,CD₃OD)δ 7.84(s,1H),7.98-7.83(m,1H),7.79(d,1H),7.51-7.48(m,1H),6.71-6.60(m,2H),4.09-3.91(m,2H),3.86-3.76(m,1H),3.60-3.44(m,2H),3.30-3.20(m,1H),3.14-3.01(m,1H),2.98-2.88(m,2H),2.80-2.62(m,1H),2.52-2.46(m,2H),1.74-1.58(m,2H),0.98-0.90(m,3H)；LCMS 500.5(M+1)⁺。 Synthesis of compound 6-[2-ethyl-4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazine using 2-ethyl-piperazine and following the procedure of steps 1 and 3 of Example 26. 1-sulfonate]-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.84 (s, 1H), 7.98-7.83 (m, 1H), 7.79 (d, 1H), 7.51-7.48 (m, 1H), 6.71-6.60 (m, 2H), 4.09-3.91 (m, 2H), 3.86-3.76 (m, 1H), 3.60-3.44 (m, 2H), 3.30-3.20 (m, 1H), 3.14-3.01 (m, 1H), 2.98- 2.88 (m, 2H), 2.80-2.62 (m, 1H), 2.52-2.46 (m, 2H), 1.74-1.58 (m, 2H), 0.98-0.90 (m, 3H); LCMS 500.5 (M+1) ⁺ .

實施例60 Example 60

6-[2-乙基-4-(2-氟-4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[2-Ethyl-4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indoline-1-carboxylic acid:

使用2-乙基-哌嗪以及1-溴-2-氟-4-三氟甲基-甲苯並根據實施例26步驟1和3的流程合成化合物6-[2-乙基-4-(2-氟-4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,CD₃OD)δ 8.10(s,1H),7.78-7.70(m,1H),7.50-7.40(m,1H),7.36-7.28(m,2H),7.10-6.99(m,1H),4.12(t,1H),4.00-3.80(m,2H),3.50-3.22(m,3H),3.20-3.15(m,1H),3.14-3.05(m,1H),2.75-2.50(m,2H),2.45(q,2H),1.72-1.50(m,2H),1.01-0.95(m,3H)；LCMS 500.5(M+1)⁺。 Synthesis of compound 6-[2-ethyl-4-(2) using 2-ethyl-piperazine and 1-bromo-2-fluoro-4-trifluoromethyl-toluene according to the procedure of Steps 1 and 3 of Example 26. -Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-sulfonate]-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.10 (s, 1H), 7.78-7.70 (m, 1H), 7.50-7.40 (m, 1H), 7.36-7.28 (m, 2H), 7.10-6.99 ( m, 1H), 4.12 (t, 1H), 4.00-3.80 (m, 2H), 3.50-3.22 (m, 3H), 3.20-3.15 (m, 1H), 3.14-3.05 (m, 1H), 2.75- 2.50 (m, 2H), 2.45 (q, 2H), 1.72-1.50 (m, 2H), 1.01-0.95 (m, 3H); LCMS 500.5 (m + 1) +.

實施例61 Example 61

6-[4-(3,4-二氯-苯基)-(S)-甲基-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[4-(3,4-Dichloro-phenyl)-(S)-methyl-piperazin-1-sulfonyl]-indoline-1-carboxylic acid:

使用2-(S)-甲基-哌嗪以及4-溴-1,2-二氯-甲苯並根據實施例26 步驟1和3的流程合成化合物6-[4-(3,4-二氯-苯基)-(S)-甲基-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,CD₃OD)δ 7.88(s,1H),7.74-7.68(m,1H),7.41(t,1H),7.28-7.24(m,1H),6.94(dd,1H),6.78-6.72(m,1H),4.22-4.14(m,1H),4.13-4.07(m,1H),3.78-3.70(m,1H),3.50-3.40(m,1H),3.16-3.04(m,2H),3.02-2.92(m,1H),2.90-2.84(m,1H),2.76-2.64(m,2H),2.46-2.32(m,2H),1.02(d,3H)；LCMS 469.4(M+1)⁺。 Synthesis of compound 6-[4-(3,4-dichloro) using 2-(S)-methyl-piperazine and 4-bromo-1,2-dichloro-toluene according to the procedure of Steps 1 and 3 of Example 26. -Phenyl)-(S)-methyl-piperazine-1-sulfonate]-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.88 (s, 1H), 7.74-7.68 (m, 1H), 7.41 (t, 1H), 7.28-7.24 (m, 1H), 6.94 (dd, 1H) , 6.78-6.72 (m, 1H), 4.22-4.14 (m, 1H), 4.13-4.07 (m, 1H), 3.78-3.70 (m, 1H), 3.50-3.40 (m, 1H), 3.16-3.04 ( m, 2H), 3.02-2.92 (m, 1H), 2.90-2.84 (m, 1H), 2.76-2.64 (m, 2H), 2.46-2.32 (m, 2H), 1.02 (d, 3H); LCMS 469.4 (M+1) ⁺ .

實施例62 Example 62

6-[2-(S)-甲基-4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[2-(S)-Methyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonic acid]-indoline-1-carboxylic acid:

使用2-(S)-甲基-哌嗪以及1-溴-4-三氟甲氧基-甲苯並根據實施例26步驟1和3的流程合成化合物6-[2-(S)-甲基-4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,CD₃OD)δ 7.89(s,1H),7.73-7.69(m,1H),7.45-7.40(m,1H),7.11-7.06(m,2H),6.92-6.87(m,2H),4.22-4.16(m,1H),4.13-4.07(m,1H),3.78-3.70(m,1H),3.51-3.41(m,1H),3.16-3.06(m,2H),3.02-2.92(m,1H),2.86-2.79(m,1H),2.73-2.61(m,2H),2.45-2.38(m,2H),1.20(d,3H)；LCMS 484.5(M+1)⁺。 Synthesis of compound 6-[2-(S)-methyl using 2-(S)-methyl-piperazine and 1-bromo-4-trifluoromethoxy-toluene according to the procedure of Steps 1 and 3 of Example 26. 4-(4-Trifluoromethoxy-phenyl)-piperazine-1-sulfonic acid]-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.89 (s, 1H), 7.73-7.69 (m, 1H), 7.45-7.40 (m, 1H), 7.11-7.06 (m, 2H), 6.92-6.87 ( m, 2H), 4.22-4.16 (m, 1H), 4.13-4.07 (m, 1H), 3.78-3.70 (m, 1H), 3.51-3.41 (m, 1H), 3.16-3.06 (m, 2H), 3.02-2.92 (m, 1H), 2.86-2.79 (m, 1H), 2.73-2.61 (m, 2H), 2.45-2.38 (m, 2H), 1.20 (d, 3H); LCMS 484.5 (M+1) ⁺ .

實施例63 Example 63

6-[4-(3-氟-4-三氟甲氧基-苯基)-2-(S)-甲基-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[4-(3-Fluoro-4-trifluoromethoxy-phenyl)-2-(S)-methyl-piperazine-1-sulfonyl]-indoline-1-carboxylic acid:

使用2-(S)-甲基-哌嗪並根據實施例26步驟1和3的流程合成化合物6-[4-(3-氟-4-三氟甲基-苯基)-2-(S)-甲氧基-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,CD₃OD)δ 7.87(d,1H),7.71-7.62(m,1H),7.41-7.32(m,2H),6.68-6.58(m,2H),4.23-4.16(m,1H),4.14-4.02(m,1H),3.80-3.69(m,1H),3.66-3.47(m,1H),3.43-3.34(m,2H),3.12-3.01(m,2H),2.99-2.80(m,2H),2.45-2.36(m,2H),1.20-1.00(m,3H)；LCMS 486.5(M+1)⁺。 Synthesis of the compound 6-[4-(3-fluoro-4-trifluoromethyl-phenyl)-2-(S) using 2-(S)-methyl-piperazine according to the procedure of Steps 1 and 3 of Example 26. )-Methoxy-piperazine-1-sulfonate]-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.87 (d, 1H), 7.71-7.62 (m, 1H), 7.41-7.32 (m, 2H), 6.68-6.58 (m, 2H), 4.23-4.16 ( m, 1H), 4.14 - 4.02 (m, 1H), 3.80-3.69 (m, 1H), 3.66-3.47 (m, 1H), 3.43 - 3.34 (m, 2H), 3.12-3.01 (m, 2H), 2.99-2.80 (m, 2H), 2.45-2.36 (m, 2H), 1.20-1.00 (m, 3H); LCMS 486.5 (m + 1) +.

實施例64 Example 64

6-[3-乙基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[3-ethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonic acid]-indoline-1-carboxylic acid:

使用3-乙基-哌嗪-1-羧酸正丁酯以及2-溴-5-三氟甲基-吡啶並根據實施例的流程合成化合物6-[3-乙基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,CD₃OD)δ 8.30(s,1H),7.80(s,1H),7.69-7.60(m,2H),7.50-7.40(m,1H)6.90-6.80(m,1H),4.60-4.50(m,1H),4.43-4.35(m,1H),4.15-4.05(m,1H),3.80(d,2H),3.35-3.20(m,2H),3.19-3.10(m,1H),3.10-3.00(m,1H),2.50-2.40(m,3H),1.99-1.60(m,2H),1.01-0.93(m,3H)；LCMS 483.5(M+1)⁺。 The compound 6-[3-ethyl-4-(5-) was synthesized according to the procedure of the example using 3-ethyl-piperazine-1-carboxylic acid n-butyl ester and 2-bromo-5-trifluoromethyl-pyridine. Trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonate]-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.30 (s, 1H), 7.80 (s, 1H), 7.69-7.60 (m, 2H), 7.50-7.40 (m, 1H) 6.90-6.80 (m, 1H) ), 4.60-4.50 (m, 1H), 4.43-4.35 (m, 1H), 4.15-4.05 (m, 1H), 3.80 (d, 2H), 3.35-3.20 (m, 2H), 3.19-3.10 (m , 1H), 3.10-3.00 (m, 1H), 2.50-2.40 (m, 3H), 1.99-1.60 (m, 2H), 1.01-0.93 (m, 3H); LCMS 483.5 (M+1) ⁺ .

實施例65 Example 65

6-[3,5-順-二甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[3,5-cis-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonic acid]-indoline-1-carboxylic acid:

使用3,5-順-二甲基-哌嗪-1-羧酸正丁酯和2-溴-5-三氟甲基-吡啶並根據實施例26的流程合成化合物6-[3,5-順-二甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,CD₃OD)δ 8.05(s,1H),7.51(s,1H),7.40-7.30(m,2H),7.18(d,1H)6.46(d,1H),4.35-4.25(m,1H),3.25(t,1H),3.41-3.32(m,1H),3.08-3.02(m,2H),2.98-2.88(m,1H),2.86-2.78(m,1H),2.74-2.64(m,1H),2.24-2.16(m,1H),2.15-2.08(m,2H),1.03(d,3H),1.02(d, 3H)；LCMS 483.5(M+1)⁺。 The compound 6-[3,5- was synthesized according to the procedure of Example 26 using n-butyl 3,5-cis-dimethyl-piperazine-1-carboxylate and 2-bromo-5-trifluoromethyl-pyridine. Cis-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfo]-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.05 (s, 1H), 7.51 (s, 1H), 7.40-7.30 (m, 2H), 7.18 (d, 1H) 6.46 (d, 1H), 4.35- 4.25 (m, 1H), 3.25 (t, 1H), 3.41-3.32 (m, 1H), 3.08-3.02 (m, 2H), 2.98-2.88 (m, 1H), 2.86-2.78 (m, 1H), 2.74-2.64 (m, 1H), 2.24-2.16 (m, 1H), 2.15-2.08 (m, 2H), 1.03 (d, 3H), 1.02 (d, 3H); LCMS 483.5 (m + 1) +.

實施例66 Example 66

6-(5-三氟甲基-3,6-二氫-2H-[2,4]二吡啶基-1-磺酸基)-二氫茚-1-羧酸：6-(5-Trifluoromethyl-3,6-dihydro-2H-[2,4]dipyridyl-1-sulfonyl)-indoline-1-carboxylic acid: 步驟1step 1

以氮氣清洗2-碘-5-三氟甲基吡啶(2.2克，8.0毫莫耳)及吡啶-4-溴酸(1.0克，8.8毫莫耳)在甲醇(8毫升)及甲苯(30毫升)的溶液5分鐘，接著添加Pd(PPh₃)₄(0.2克)以及水溶液2M Na₂CO₃(4毫升)。加熱逆流混合液7小時。冷卻反應液到室溫後，以過濾的方式移除固體而在真空下濃縮濾液。溶解殘留物於EtOAc(20毫升)中並以鹵水沖洗。在真空下濃縮有機溶液，並以管柱色層分析純化，而提供微黃粉末的所要化合物。 2-Iodo-5-trifluoromethylpyridine (2.2 g, 8.0 mmol) and pyridine-4-bromo acid (1.0 g, 8.8 mmol) in methanol (8 mL) and toluene (30 mL) The solution was allowed to stand for 5 minutes, followed by the addition of Pd(PPh ₃ ) ₄ (0.2 g) and aqueous 2M Na ₂ CO ₃ (4 mL). The countercurrent mixture was heated for 7 hours. After cooling the reaction mixture to room temperature, the solid was removed by filtration and the filtrate was concentrated under vacuum. The residue was dissolved in EtOAc (20 mL)EtOAc. The organic solution was concentrated under vacuum and purified by column chromatography to afford the desired compound as a yellow powder.

步驟2Step 2

添加溴甲苯(0.2克，1.2毫莫耳)到步驟1(0.23克，1.1毫莫耳)化合物在DMF(10毫升)中的溶液。隨後加熱混合物到95℃ 8小時。反應混合物降溫到室溫後，慢慢地倒入***(500毫升)，而攪拌混合物過夜。以過濾方式移除微黃色結晶產物且並乾燥以得到所要的化合物(0.2克)。 Add bromotoluene (0.2 g, 1.2 mmol) to a solution of step 1 (0.23 g, 1.1 mmol) compound in DMF (10 mL). The mixture was then heated to 95 ° C for 8 hours. After the reaction mixture was cooled to room temperature, diethyl ether (500 ml) was poured slowly, and the mixture was stirred overnight. The yellowish crystalline product was removed by filtration and dried to give the desired compound (0.2 g).

步驟3Step 3

於-52℃下添加硼氫化鈉(0.1克)到一步驟2產物(0.2克)在甲醇(10毫升)中的溶液。攪拌反應混合物30分鐘。在真空下濃縮反應混合物。溶解殘餘物在***(10毫升)中以及以水(10毫升)清洗。以無水鈉硫酸鹽乾燥後，移除溶劑而提供黃色固態的所需化合物(150毫克)。 Sodium borohydride (0.1 g) was added at -52 °C to a solution of the product from step 2 (0.2 g) in methanol (10 mL). The reaction mixture was stirred for 30 minutes. The reaction mixture was concentrated under vacuum. The residue was dissolved in diethyl ether (10 mL) and water (10 mL). After drying over anhydrous sodium sulfate, the solvent was removed to give the desired compound (150 mg) as a yellow solid.

步驟4Step 4

於-52℃下以液滴方式添加氯甲酸乙酯(0.3克)到一步驟3產物(150毫克)在二氯甲烷(10毫升)中的溶液。在0℃下攪拌混合物40分鐘。在真空下濃縮反應混合物。溶解殘餘物在甲醇(10毫升)中並加熱逆流1小時。冷卻反應混合物到室溫並在真空下濃縮。溶解殘餘物在二氯甲烷(20毫升)及三乙基胺(0.5毫升)中並添加甲基2-(5-氯磺酸基-2-甲基苯基)醋酸(0.3克)。在室溫下攪拌過夜後，以鹵水(3x20毫升)沖洗混合物，再以硫酸鈉乾燥並在真空下濃縮。以管柱色層分析純化殘餘物而提供白色固態的所需化合物(100毫克)。 A solution of the ethyl chloroformate (0.3 g) was added dropwise at -52 °C to a product of step 3 (150 mg) in dichloromethane (10 mL). The mixture was stirred at 0 ° C for 40 minutes. The reaction mixture was concentrated under vacuum. The residue was dissolved in methanol (10 mL) and heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was dissolved in dichloromethane (20 mL) and triethylamine (0.5 mL) and ethyl 2-(5-chlorosulfonyl-2-methylphenyl)acetic acid (0.3 g). After stirring at room temperature overnight, the mixture was washed with brine (3×20 mL) The residue was purified by column chromatography to give the desired compound (100 mg).

步驟5Step 5

0℃下以液滴方式添加2M氫氧化納溶液(2毫升)到一步驟4產物(100毫克)在四氫呋喃中的溶液。暖化反應混合物到室溫並攪 拌直到用完所有起始原料。在真空下濃縮反應混合物。殘餘物被變酸以2M氯化氫酸化殘餘物到pH3並以EtOAc萃取。以硫酸鈉乾燥有機溶液，並在真空下濃縮溶劑而提供本標題化合物(60毫克)。¹H NMR(400 MHz,CD₃OD)δ 8.77(s,1H),8.04-8.00(m,1H),7.88(s,1H),7.73-7.64(m,2H),7.47(d,1H)6.78(s,1H),4.13(t,1H),3.85-3.81(m,1H),3.36-3.27(m,2H),3.14-3.05(m,2H),3.04-2.93(m,1H),2.75-2.67(m,2H),2.42(q,2H)；LCMS 452.5(M+1)⁺。 A 2 M sodium hydroxide solution (2 mL) was added dropwise at 0 ° C to a solution of the product from step 4 (100 mg) in tetrahydrofuran. The reaction mixture was warmed to room temperature and stirred until all starting materials were used up. The reaction mixture was concentrated under vacuum. The residue was acidified to aq. The organic solution was dried <RTI ID=0.0> ¹ H NMR (400 MHz, CD ₃ OD) δ 8.77 (s, 1H), 8.04-8.00 (m, 1H), 7.78 (s, 1H), 7.73-7.64 (m, 2H), 7.47 (d, 1H) 6.78(s,1H), 4.13(t,1H), 3.85-3.81(m,1H), 3.36-3.27(m,2H),3.14-3.05(m,2H),3.04-2.93(m,1H), 2.75-2.67 (m, 2H), 2.42 (q, 2H); LCMS 452.5 (m + 1) +.

實施例67 Example 67

6-[4-(5-三氟甲基-吡啶-2-基)-[1,4]二氮-1-磺酸基]-二氫茚-1-羧酸：6-[4-(5-Trifluoromethyl-pyridin-2-yl)-[1,4]diazo-1-sulfonyl]-indoline-1-carboxylic acid:

使用[1,4]二氮以及2-溴-5-三氟甲基-吡啶並根據實施例23的流程合成化合物6-[4-(5-三氟甲基-吡啶-2-基)-[1,4]二氮-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,CD₃OD)δ 8.26(s,1H),7.81(s,1H),7.66-7.56(m,2H),7.25(d,1H),6.65(d,1H),4.06(t,1H),3.92-3.86(m,1H),3.84-3.76(m,1H),3.75-3.70(m,1H),3.54-3.44(m,2H),3.38-3.24(m,3H),3.10-3.02(m,1H),2.98-2.88(m,1H),2.48-2.36(m,2H),1.96-1.88(m,2H)；LCMS 469.5(M+1)⁺。 The compound 6-[4-(5-trifluoromethyl-pyridin-2-yl)- was synthesized according to the procedure of Example 23 using [1,4]diazide and 2-bromo-5-trifluoromethyl-pyridine. [1,4]Dinitro-1-sulfonyl]-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.26 (s, 1H), 7.81 (s, 1H), 7.66-7.56 (m, 2H), 7.25 (d, 1H), 6.65 (d, 1H), 4.06 (t, 1H), 3.92-3.86 (m, 1H), 3.84-3.76 (m, 1H), 3.75-3.70 (m, 1H), 3.54-3.44 (m, 2H), 3.38-3.24 (m, 3H) , 3.10-3.02 (m, 1H), 2.98-2.88 (m, 1H), 2.48-2.36 (m, 2H), 1.96-1.88 (m, 2H); LCMS 469.5 (M+1) ⁺ .

實施例68 Example 68

6-[2,6-(S,S)-二甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[2,6-(S,S)-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-1- carboxylic acid:

使用2,6-(S,S)-二甲基-哌嗪以及2-溴-5-三氟甲基-吡啶並根據實施例26步驟1和3的流程合成化合物6-[2,6-(S,S)-二甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(非鏡相異構物~1：1,400 MHz,CD₃OD)δ 8.25(s,1H),8.24(s,1H)7.95(s,1H),7.90(s,1H),7.70-7.60(m,4H),7.35(d,1H)7.25(d,1H),6.70(d,1H)6.50(d,1H),4.30-4.19(m,4H),4.15(t,1H)4.01(t,1H),3.80-3.60(m,4H),3.62-3.52(m,2H),3.43-3.25(m,2H),3.15-2.80(m,4H),2.25-2.15(m,4H),1.38(d,6H),1.30(d,6H)；LCMS 483.8(M+1)⁺。 Synthesis of compound 6-[2,6- according to the procedure of Steps 1 and 3 of Example 26 using 2,6-(S,S)-dimethyl-piperazine and 2-bromo-5-trifluoromethyl-pyridine. (S,S)-Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-1-carboxylic acid. ¹ H NMR (non-mirrible isomer ~ 1:1, 400 MHz, CD ₃ OD) δ 8.25 (s, 1H), 8.24 (s, 1H) 7.95 (s, 1H), 7.90 (s, 1H), 7.70- 7.60 (m, 4H), 7.35 (d, 1H) 7.25 (d, 1H), 6.70 (d, 1H) 6.50 (d, 1H), 4.30-4.19 (m, 4H), 4.15 (t, 1H) 4.01 ( t,1H), 3.80-3.60 (m, 4H), 3.62-3.52 (m, 2H), 3.43-3.25 (m, 2H), 3.15-2.80 (m, 4H), 2.25-2.15 (m, 4H), 1.38 (d, 6H), 1.30 (d, 6H); LCMS 483.8 (M + 1) +.

實施例69 Example 69

6-[3,5-(S,S)二甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[3,5-(S,S)dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-1-carboxylate acid:

使用3,5-(S,S)-二甲基-哌嗪-1-羧酸正丁酯以及2-溴-5-三氟甲基-吡啶並根據實施例26的流程合成化合物6-[3,5-(S,S)二甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,CD₃OD)δ 8.38-8.30(m,1H),7.90(s,1H),7.80-7.65(m,2H),7.45(d,1H)6.65(d,1H),4.65-4.55(m,1H),4.43-4.32(m,2H),4.20-4.10(m,1H)3.70-3.58(m,3H),3.20-3.10(m,1H),3.09-3.00(m,1H),2.58-2.38(m,2H),1.05(d,3H),1.02(d,3H)；LCMS 483.5(M+1)⁺。 Synthesis of compound 6-[3,5-(S,S)-dimethyl-piperazine-1-carboxylic acid n-butyl ester and 2-bromo-5-trifluoromethyl-pyridine according to the procedure of Example 26 3,5-(S,S)dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.38-8.30 (m, 1H), 7.90 (s, 1H), 7.80-7.65 (m, 2H), 7.45 (d, 1H) 6.65 (d, 1H), 4.65-4.55 (m, 1H), 4.43-4.32 (m, 2H), 4.20-4.10 (m, 1H) 3.70-3.58 (m, 3H), 3.20-3.10 (m, 1H), 3.09-3.00 (m, 1H), 2.58-2.38 (m, 2H ), 1.05 (d, 3H), 1.02 (d, 3H); LCMS 483.5 (m + 1) +.

實施例70 Example 70

6-[2,6-順-二甲基-4-(3-氟-4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[2,6-cis-dimethyl-4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazine-1-sulfonic acid]-indoline-1-carboxylic acid:

根據實施例71的流程合成6-[2,6-順-二甲基-4-(3-氟-4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,CD₃OD)δ 7.87(s,1H),7.70(dd,1H),7.38-7.34(m,2H),6.62(s,1H),6.59(d,1H),4.26-4.22(m,1H),4.16-4.10(m,1H),4.08(t,1H),3.47(d,2H),3.10-3.02(m,1H),2.97-2.88(m,3H),2.40(q,2H),1.42(d,3H),1.40(d,2H)。 Synthesis of 6-[2,6-cis-dimethyl-4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazine-1-sulfonate]-dihydrogen according to the procedure of Example 71茚-1-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.87 (s, 1H), 7.70 (dd, 1H), 7.38-7.34 (m, 2H), 6.62 (s, 1H), 6.59 (d, 1H), 4.26 -4.22 (m, 1H), 4.16-4.10 (m, 1H), 4.08 (t, 1H), 3.47 (d, 2H), 3.10-3.02 (m, 1H), 2.97-2.88 (m, 3H), 2.40 (q, 2H), 1.42 (d, 3H), 1.40 (d, 2H).

實施例71 Example 71

6-[4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[4-(4-Trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indoline-1-carboxylic acid:

使用1-(4-三氟甲氧基-苯基)-哌嗪並根據實施例26的流程合成化合物6-[4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,CDCl₃)δ 7.85(s,1H),7.66(dd,1H),7.41(d,1H),7.12(d,2H),6.95(d,2H),4.15(t,1H),3.40-3.08(m,9H),3.04-2.96(m,1H),2.56-2.42(m,2H)；LCMS 471.5(M+1)⁺。 Synthesis of compound 6-[4-(4-trifluoromethoxy-phenyl)-piperazine-1- using 1-(4-trifluoromethoxy-phenyl)-piperazine according to the procedure of Example Sulfo]]-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85 (s, 1H), 7.66 (dd, 1H), 7.41 (d, 1H), 7.12 (d, 2H), 6.95 (d, 2H), 4.15 (t, 1H), 3.40-3.08 (m, 9H), 3.04-2.96 (m, 1H), 2.56-2.42 (m, 2H); LCMS 471.5 (M+1) ⁺ .

實施例72 Example 72

6-[2-乙基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[2-ethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-1-carboxylic acid:

根據實施例26步驟1(使用2-乙基-哌嗪以及2-氯-5-三氟甲基-吡啶)和步驟3(使用3-乙基-1-(5-三氟甲基-吡啶-2-基)的流程合成 化合物6-[2-乙基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,CDCl₃)δ 8.32(s,1H),7.92(s,1H),7.72(t,1H),7.58(t,1H),7.36-7.31(m,1H),6.54-6.48(m,1H),4.20-4.05(m,3H),3.99-3.93(m,1H),3.85-3.73(m,1H),3.32-3.20(m,1H),3.16-2.82(m,4H),2.54-2.38(m,2H),1.62-1.48(m,2H),0.90(q,3H)；LCMS 484.0(M+1)⁺。 Step 1 according to Example 26 (using 2-ethyl-piperazine and 2-chloro-5-trifluoromethyl-pyridine) and Step 3 (using 3-ethyl-1-(5-trifluoromethyl-pyridine) The synthesis of the compound 2-[2-ethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-1- ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (s, 1H), 7.92 (s, 1H), 7.72 (t, 1H), 7.58 (t, 1H), 7.36-7.31 (m, 1H) , 6.54-6.48 (m, 1H), 4.20-4.05 (m, 3H), 3.99-3.93 (m, 1H), 3.85-3.73 (m, 1H), 3.32-3.20 (m, 1H), 3.16-2.82 ( m, 4H), 2.54-2.38 (m , 2H), 1.62-1.48 (m, 2H), 0.90 (q, 3H); LCMS 484.0 (m + 1) +.

實施例73 Example 73

6-[3,3-二甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[3,3-Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-1-carboxylic acid:

使用2,2-二甲基-1-(5-三氟甲基-吡啶-2-基)-哌嗪並根據實施例26的流程合成化合物6-[3,3-二甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,CDCl₃)δ 8.47(s,1H),7.85(s,1H),7.66-7.62(m,2H),7.40(d,1H),6.86(d,1H),4.15(t,1H),3.61(br s,2H),3.25-3.12(m,3H),3.05-2.96(m,1H),2.92(s,2H),2.57-2.41(m,2H),1.44(s,6H)；LCMS 483.9(M+1)⁺。 The compound 6-[3,3-dimethyl-4- was synthesized according to the procedure of Example 26 using 2,2-dimethyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine. (5-Trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.47 (s, 1H), 7.85 (s, 1H), 7.66-7.62 (m, 2H), 7.40 (d, 1H), 6.86 (d, 1H), 4.15 ( t,1H), 3.61 (br s, 2H), 3.25-3.12 (m, 3H), 3.05-2.96 (m, 1H), 2.92 (s, 2H), 2.57-2.41 (m, 2H), 1.44 (s) , 6H); LCMS 483.9 (M + 1) ⁺ .

實施例74 Example 74

6-[4-(3-氯-4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[4-(3-Chloro-4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indoline-1-carboxylic acid:

使用1-(3-氯-4-三氟甲基-苯基)-哌嗪並根據實施例26的流程合成化合物6-[4-(3-氯-4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz,CDCl₃)δ 8.47(s,1H),7.85(s,1H),7.66-7.62(m,2H),7.40(d,1H),6.86(d,1H),4.15(t,1H),3.61(br s,2H),3.25-3.12(m,3H),3.05-2.96(m,1H),2.92(s,2H),2.57-2.41(m,2H),1.44(s,6H)；LCMS 483.9(M+1)⁺。 Synthesis of compound 6-[4-(3-chloro-4-trifluoromethyl-phenyl) according to the procedure of Example 26 using 1-(3-chloro-4-trifluoromethyl-phenyl)-piperazine - piperazine-1-sulfonate]-indoline-1-carboxylic acid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.47 (s, 1H), 7.85 (s, 1H), 7.66-7.62 (m, 2H), 7.40 (d, 1H), 6.86 (d, 1H), 4.15 ( t,1H), 3.61 (br s, 2H), 3.25-3.12 (m, 3H), 3.05-2.96 (m, 1H), 2.92 (s, 2H), 2.57-2.41 (m, 2H), 1.44 (s) , 6H); LCMS 483.9 (M + 1) ⁺ .

實施例75 Example 75

6-[2,6-順-二甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1-(S)-羧酸：6-[2,6-cis-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-1-(S)- carboxylic acid:

藉由掌性HPLC(chiralcel OD-H 0.46 x 15 cm Hex/IPA 96：4(v/v)with 0.1% TFA，流速1毫升/分鐘)分離外消旋物而得到化合物6-[2,6-順-二甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二 氫茚-1-(S)-羧酸。LCMS 482.1(M-1)^-。 The racemate was isolated by palm chromatography (chiralcel OD-H 0.46 x 15 cm Hex/IPA 96:4 (v/v) with 0.1% TFA, flow rate 1 ml/min) to give compound 6-[2,6 -cis-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfo]-indoline-1-(S)-carboxylic acid. LCMS 482.1 (M-1) ^- .

實施例76 Example 76

6-[2,6-順-二甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1-(R)-羧酸：6-[2,6-cis-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-sulfonyl]-indoline-1-(R)- carboxylic acid:

藉由掌性HPLC(chiralcel OD-H 0.46 x 15 cm Hex/IPA 96：4(v/v)with 0.1% TFA，流速1毫升/分鐘)分離外消旋物而得到化合物6-[2,6-順-二甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1-(R)-羧酸。LCMS 482.0(M-1)^-。 The racemate was isolated by palm chromatography (chiralcel OD-H 0.46 x 15 cm Hex/IPA 96:4 (v/v) with 0.1% TFA, flow rate 1 ml/min) to give compound 6-[2,6 -cis-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfo]-indoline-1-(R)-carboxylic acid. LCMS 482.0 (M-1) ^- .

實施例77Example 77

步驟1step 1 3,5-順-二甲基-1-(5-三氟甲基-吡啶-2-基)-哌嗪：3,5-cis-dimethyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine:

使用2,6-二甲基哌嗪並根據實施例23的流程合成化合物3,5-順-二甲基-1-(5-三氟甲基-吡啶-2-基)-哌嗪。 The compound 3,5-cis-dimethyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine was synthesized according to the procedure of Example 23 using 2,6-dimethylpiperazine.

步驟2Step 2 4-[2,6-順-二甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸：4-[2,6-cis-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid:

使用二氫茚-2-羧酸甲酯以及從上面步驟得到的3,5-順-二甲基-1-(5-三氟甲基-吡啶-2-基)-哌嗪並根據實施例1的流程合成化合物4-[2,6-順-二甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸。 Using methyl indoline-2-carboxylate and 3,5-cis-dimethyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine obtained from the above procedure and according to the examples Synthesis of the compound 4-[2,6-cis-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-2 -carboxylic acid.

實施例78 Example 78

4-[2,6-二甲基-4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸：4-[2,6-Dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid:

使用3,8-二氮-雙環[3,2,1]辛烷-8-羧酸正丁酯以及2-氯-5-三氟甲基-吡啶並根據實施例26的流程合成化合物4-[2,6-二甲基-4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸。¹H NMR(400 MHz,CD₃OD)δ 8.33(s,1H),7.94(s,1H),7.79(dd,1H),7.72(dd,1H),7.46(d,1H),6.79(d,1H),4.40-4.30(m,3H),3.17-3.09(m,3H), 3.05-2.97(m,2H),2.43(q,2H),1.60-1.36(m,4H)；LCMS 482.5(M+1)⁺。 Synthesis of compound 4- using 3,8-diaza-bicyclo[3,2,1]octane-8-carboxylic acid n-butyl ester and 2-chloro-5-trifluoromethyl-pyridine according to the procedure of Example 26. [2,6-Dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.33 (s, 1H), 7.94 (s, 1H), 7.79 (dd, 1H), 7.72 (dd, 1H), 7.46 (d, 1H), 6.79 (d) , 1H), 4.40-4.30 (m, 3H), 3.17-3.09 (m, 3H), 3.05-2.97 (m, 2H), 2.43 (q, 2H), 1.60-1.36 (m, 4H); LCMS 482.5 ( M+1) ⁺ .

實施例79Example 79

步驟1step 1

1,2-二(溴甲基)-3-硝基苯(nitrobenzene) 1,2 -di(bromomethyl)-3-nitrobenzene (nitrobenzene)

倒入20克1,2-二甲基-3-硝基苯(0.13莫耳)、50克N-溴琥珀醯亞胺(0.28莫耳)、5克偶氮雙(3.0莫耳)及200毫升的二氯甲烷至5毫升的三角瓶中。在氮氣下以120瓦的散光燈照射18小時而對和緩迴流發生作用。然後，冷卻混合物並透過過濾移除沉澱的琥珀醯亞胺。濃縮濾液且藉由矽膠色層分析純化(在己烷中的5-50% CH₂Cl₂)以得到2.6克白色固態物(64%)。 Pour 20 g of 1,2-dimethyl-3-nitrobenzene (0.13 mol), 50 g of N-bromosuccinimide (0.28 mol), 5 g of azobis (3.0 mol) and 200 Dilute the dichloromethane into a 5 ml flask. Irradiation at reflux with a 120 watt astigmatism lamp for 18 hours under nitrogen. Then, the mixture was cooled and the precipitated amber imine was removed by filtration. The filtrate was concentrated and purified by silica gel layer chromatography (in hexanes 5-50% CH ₂ Cl ₂₎ to give 2.6 g of white solids (64%).

步驟2Step 2

二甲基-4-硝基二氫茚-2,2-二羧酸：Dimethyl-4-nitroindoline-2,2-dicarboxylic acid:

小部份地添加0.84克60%的氫化鈉(0.021莫耳)到一溶夜，而此溶液為在室溫下、氮氣下被攪拌在15.0毫升***中的5.0毫升甲烷(因為金屬鈉不可取得，因此使用氫化鈉)。完成添加後，攪拌近於澄清的無色溶液5分鐘。然後添加1.3克二甲基丙二酸酯，而得到微混濁的無色溶液。迅速地添加3.1克1,2-二(溴甲基)3-硝基苯懸浮體，而立即得到懸浮在暗綠色溶液的沉澱物。藉由過濾移除沉澱物並濃縮濾液。以矽膠(在己烷中的20-100%CH₂Cl₂)純化殘餘物以得到1.93克灰白色固態物(67%)。 A small portion of 0.84 g of 60% sodium hydride (0.021 mol) was added to a solution of the night, and this solution was 5.0 ml of methane stirred in 15.0 ml of diethyl ether at room temperature under nitrogen (because metal sodium is not available). Therefore, sodium hydride is used). After the addition was completed, the nearly clear, colorless solution was stirred for 5 minutes. Then, 1.3 g of dimethylmalonate was added to obtain a slightly turbid colorless solution. A suspension of 3.1 g of 1,2-bis(bromomethyl)3-nitrobenzene was quickly added, and a precipitate suspended in a dark green solution was immediately obtained. The precipitate was removed by filtration and the filtrate was concentrated. In silicone (in hexanes 20-100% CH ₂ Cl ₂₎ to give the residue was purified by an off-white solid was 1.93 g (67%).

步驟3Step 3

甲基-4-硝基二氫茚-2-羧基：Methyl-4-nitroindoline-2-carboxyl:

於氮氣及160℃下加熱有4.84克的二甲基-4-硝基二氫茚-2,2-二羧基(0.167莫耳)、0.84克氯化鋰(0.0198莫耳)、1.1毫升的水及18毫升的二甲基亞碸的混合物2小時。隨後冷卻並在高真空下移除二甲基亞碸。以矽膠(在己烷中的10-100%CH₂Cl₂)純化殘餘物以得到2.5克白色固態物(65%)。 4.74 g of dimethyl-4-nitroindoline-2,2-dicarboxyl (0.167 mol), 0.84 g of lithium chloride (0.0198 mol), 1.1 ml of water were heated under nitrogen at 160 °C. And a mixture of 18 ml of dimethyl hydrazine for 2 hours. It was then cooled and the dimethyl hydrazine was removed under high vacuum. In silica gel (10-100% CH ₂ Cl ₂ in hexanes) the residue was purified to obtain 2.5 g of a white solid product (65%).

步驟4Step 4

甲基-4-胺基二氫茚-2-羧酸：Methyl-4-aminoindoline-2-carboxylic acid:

於55psi的氫氣下搖晃有2.4克的甲基-4-硝基二氫茚-2-羧基(0.11莫耳)、1.1克10%的碳上鈀及15毫升的乙酸乙酯的混合物1小時。隨後過濾混合物並濃縮濾液而產生2.07克的白色固態物(100%)。 A mixture of 2.4 g of methyl-4-nitroindan-2-carboxyl (0.11 mol), 1.1 g of 10% palladium on carbon and 15 ml of ethyl acetate was shaken under 55 psi of hydrogen for 1 hour. The mixture was then filtered and the filtrate was concentrated to give a white solid (100%).

步驟5Step 5

甲基-4-氯磺酸基-2-羧基：Methyl-4-chlorosulfonate-2-carboxyl:

於-5℃水浴中冷卻包含2.5克甲基-4-胺基二氫茚-2-羧基(0.013莫耳)、12.5毫升的乙腈以及12.5毫升的水的混合物。添加2.6毫升的濃縮氯化氫(0.014莫耳)。以液滴的方式添加1克在5毫升水中的硝酸鈉(0.021莫耳)逾20分鐘。在添加完畢後，攪拌溶液20分鐘。隨後轉移到一具有冰水有套漏斗。以液滴的方式添加一在氮氣及55℃下攪拌的溶液，此溶液為在20毫升的水中的4.2克鉀硫黃酸鹽(0.026莫耳)。添加發生後，一沒有添加的暗層浮升到 偶氮離子溶液的表層。在添加完成後，在55℃下攪拌混合液30分鐘，隨後冷卻再以40毫升的乙基醋酸萃取。乾燥有機層(硫酸鎂)並濃縮。裝載殘餘物在80毫升的矽膠中，其中矽膠是被泥漿填充在乙烷中。先以100毫升的己烷再以在己烷中的1-50%CH₂Cl₂的50毫升分餾物洗提，以產生1.3克的琥珀油(33%)。 A mixture containing 2.5 grams of methyl-4-aminoindoline-2-carboxyl (0.013 moles), 12.5 milliliters of acetonitrile, and 12.5 milliliters of water was cooled in a water bath at -5 °C. Add 2.6 ml of concentrated hydrogen chloride (0.014 mol). Add 1 gram of sodium nitrate (0.021 mole) in 5 ml of water as droplets for more than 20 minutes. After the addition was completed, the solution was stirred for 20 minutes. It was then transferred to a funnel with ice water. A solution of nitrogen and 55 ° C was added as a droplet, which was 4.2 g of potassium thioate (0.026 mol) in 20 ml of water. After the addition occurred, a dark layer that was not added floated to the surface of the azo ion solution. After the addition was completed, the mixture was stirred at 55 ° C for 30 minutes, then cooled and extracted with 40 ml of ethyl acetate. The organic layer was dried (MgSO4) and concentrated. The loading residue was taken up in 80 ml of silicone, which was filled with mud in hexane. It was first eluted with 100 ml of hexane and 50 ml of a 1-50% CH ₂ Cl ₂ in hexane to yield 1.3 g of amber oil (33%).

劇烈地搖晃有3.6克在30毫升四氯化碳的上述化合物和10毫升水的混合物並冷卻到3℃。一定的速率充溢氯氣使溫度維持在10℃下。在轉化完成後，分離不同的相而二氯甲烷萃取水層。乾燥(硫酸鎂)組成的有機層並濃縮以產生4.0克的黃色油脂(>100%)。 A mixture of 3.6 g of the above compound in 30 ml of carbon tetrachloride and 10 ml of water was shaken vigorously and cooled to 3 °C. The chlorine gas is filled at a certain rate to maintain the temperature at 10 °C. After the conversion was completed, the different phases were separated and the aqueous layer was extracted with dichloromethane. The organic layer consisting of dry (MgSO4) was concentrated and concentrated to give &lt

步驟6Step 6

4-[2,6-順-二甲基-4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-甲酯：4-[2,6-cis-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indoline-2-methyl ester:

氮氣下加熱有有2.13克的A(0.0078莫耳)、3.0克的B-C(0.0109莫耳)、20毫升的乙腈以及3.0克的碳酸鉀(0.0217莫耳)的混合物至60℃並攪拌20小時。隨後過濾混合物並濃縮濾液。以矽膠(在己烷中的5-50%CH₂Cl₂)純化殘餘物以得到2.64克黏性的黃色油脂 (66%)。 A mixture of 2.13 grams of A (0.0078 moles), 3.0 grams of BC (0.0109 moles), 20 milliliters of acetonitrile, and 3.0 grams of potassium carbonate (0.0217 moles) was heated to 60 ° C and stirred for 20 hours under nitrogen. The mixture was then filtered and the filtrate was concentrated. In silicone (in hexane 5-50% CH ₂ Cl ₂₎ to give the residue was purified as a yellow viscous oil 2.64 g (66%).

步驟7Step 7 4-[2,6-順-二甲基-4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸：4-[2,6-cis-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid:

加入在最微量水中(大約2.5毫升)的0.14克氫氧化鋰(0.0057莫耳)溶液至經室溫攪拌並在最少量THF(大約15毫升)中的2.64克KLYP060甲酯(0.0052莫耳)溶液。覆蓋此混合液並在室溫下攪拌12小時。HPLC檢測顯示出反應有85%完成，如此添加額外的0.020克氫氧化鋰(0.125總當量)並持續攪拌達3小時。隨後濃縮而移除THF以及分離在EtOAc和水中。以0.54毫升濃縮的氯化氫處理水層。隨後以乙酸乙酯萃取。乾燥(硫酸鎂)有機層並濃縮而產生2.38克黃色非結晶形固體(93%)。 Add 0.14 g of lithium hydroxide (0.0057 mol) in the minimum amount of water (about 2.5 ml) to a solution of 2.64 g of KLYP060 methyl ester (0.0052 mol) in a minimum amount of THF (about 15 ml) at room temperature. . The mixture was covered and stirred at room temperature for 12 hours. HPLC analysis showed 85% completion of the reaction, so an additional 0.020 grams of lithium hydroxide (0.125 total equivalents) was added and stirring was continued for 3 hours. It was then concentrated to remove THF and separated in EtOAc and water. The aqueous layer was treated with 0.54 mL of concentrated hydrogen chloride. It was then extracted with ethyl acetate. The organic layer was dried (MgSO.sub.4).

實施例80 Example 80

4-[2,6-順-二甲基-4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-(S)-羧酸：4-[2,6-cis-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfo]-indoline-2-(S)-carboxylic acid :

藉由掌性HPLC(chiralpak ASH 0.46 x 15 cm Hex/IPA 94：6(v/v)with 0.1% TFA，流速1毫升/分鐘)分離外消旋物而得到化合物4-[2,6-順-二甲基-4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-(S)-羧酸。LCMS 497.1(M-1)^-。 The racemate was isolated by palm chromatography (chiralpak ASH 0.46 x 15 cm Hex/IPA 94:6 (v/v) with 0.1% TFA, flow rate 1 ml/min) to give compound 4-[2,6-cis. -Dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfo]-indoline-2-(S)-carboxylic acid. LCMS 497.1 (M-1) ^- .

實施例81 Example 81

4-[2,6-順-二甲基-4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-(R)-羧酸：4-[2,6-cis-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazin-1-sulfonyl]-indoline-2-(R)-carboxylic acid :

藉由掌性HPLC(chiralpak ASH 0.46 x 15 cm Hex/IPA 94：6(v/v)with 0.1% TFA，流速1毫升/分鐘)分離外消旋物而得到化合物4-[2,6-順-二甲基-4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基-二氫茚-2-(R)-羧酸。LCMS 497.1(M-1)^-。 The racemate was isolated by palm chromatography (chiralpak ASH 0.46 x 15 cm Hex/IPA 94:6 (v/v) with 0.1% TFA, flow rate 1 ml/min) to give compound 4-[2,6-cis. -Dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl-indoline-2-(R)-carboxylic acid. LCMS 497.1 (M-1) ^- .

實施例82 Example 82

4-[4-(3-氯-4-三氟甲氧基-苯基)-2,6-順-二甲基-哌嗪-1-磺酸基]-二氫茚-2-羧酸：4-[4-(3-Chloro-4-trifluoromethoxy-phenyl)-2,6-cis-dimethyl-piperazine-1-sulfonyl]-indoline-2-carboxylic acid :

使用4-溴-2-氯-1-三氟甲基-甲苯並根據實施例79的流程合成化合物4-[4-(3-氯-4-三氟甲氧基-苯基)-2,6-順-二甲基-哌嗪-1-磺酸基]-二氫茚-2-羧酸。¹H NMR(400 MHz,CD₃OD)δ 7.70(d,1H),7.50-7.42(m,2H),7.32(t,1H),6.94(d,1H)6.82(m,1H),4.25-4.18(m,1H),4.11-4.01(m,1H)3.62-3.52(m,4H),3.41-3.32(m,1H),3.29-3.24(m,2H),3.03(dd,1H),2.94(m,1H)1.45(d,3H),1.43(d,3H)；LCMS 517.0(M+1)⁺。 The compound 4-[4-(3-chloro-4-trifluoromethoxy-phenyl)-2 was synthesized according to the procedure of Example 79 using 4-bromo-2-chloro-1-trifluoromethyl-toluene. 6-cis-dimethyl-piperazine-1-sulfonate]-indoline-2-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.70 (d, 1H), 7.50-7.42 (m, 2H), 7.32 (t, 1H), 6.94 (d, 1H) 6.82 (m, 1H), 4.25- 4.18(m,1H),4.11-4.01(m,1H)3.62-3.52(m,4H),3.41-3.32(m,1H), 3.29-3.24(m,2H),3.03(dd,1H),2.94 (m, 1H) 1.45 (d , 3H), 1.43 (d, 3H); LCMS 517.0 (m + 1) +.

實施例83 Example 83

4-[4-(3-氟-4-三氟甲基-苯基)-2,6-順-二甲基-哌嗪-1-磺酸基]-二氫茚-2-羧酸：4-[4-(3-Fluoro-4-trifluoromethyl-phenyl)-2,6-cis-dimethyl-piperazine-1-sulfonyl]-indoline-2-carboxylic acid:

使用1-溴-3-氟-4-三氟甲基-甲苯並根據實施例79的流程合成化合物4-[4-(3-氟-4-三氟甲基-苯基)-2,6-順-二甲基-哌嗪-1-磺酸基]-二氫茚-2-羧酸。¹H NMR(400 MHz,CD₃OD)δ 7.20(d,1H),7.40(d,1H),7.44-7.32(m,2H),6.74(s,1H)6.72-6.67(m,1H), 4.26-4.20(m,1H),4.10-4.02(m,1H)3.66-3.58(m,2H),3.54(d,2H),3.42-3.34(m,2H),3.30-3.25(m,1H),3.01(dd,1H),2.94(m,1H)1.46(d,3H),1.40(d,3H)；LCMS 500.5(M+1)⁺。 The compound 4-[4-(3-fluoro-4-trifluoromethyl-phenyl)-2,6 was synthesized according to the procedure of Example 79 using 1-bromo-3-fluoro-4-trifluoromethyl-toluene. -cis-dimethyl-piperazine-1-sulfonate]-indoline-2-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.20 (d, 1H), 7.40 (d, 1H), 7.44 - 7.32 (m, 2H), 6.74 (s, 1H) 6.72-6.67 (m, 1H), 4.26-4.20 (m, 1H), 4.10-4.02 (m, 1H) 3.66-3.58 (m, 2H), 3.54 (d, 2H), 3.42-3.34 (m, 2H), 3.30-3.25 (m, 1H) , 3.01 (dd, 1H), 2.94 (m, 1H) 1.46 (d, 3H), 1.40 (d, 3H); LCMS 500.5 (M+1) ⁺ .

實施例84 Example 84

5-[2,6-順-二甲基-4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸：5-[2,6-cis-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid:

使用二氫茚-2-羧酸甲酯以及3,5-二甲基-1-(4-三氟甲氧基-苯基)-哌嗪(使用2,6-順-二甲基哌嗪以及1-溴-4-三氟甲氧基-甲苯並根據實施例26步驟1的流程所製得的)並根據實施例1的流程合成化合物5-[2,6-順-二甲基-4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸。¹H NMR(400 MHz,CD₃OD)δ 7.72(s,1H),7.66(d,1H),7.37(d,1H),7.09(d,2H),6.87(d,2H),4.22-4.12(m,2H),3.41-3.25(m,7H),2.64-2.58(m,2H),1.46(d,6H)；LCMS 499.5(M+1)⁺。 Use of indoline-2-carboxylic acid methyl ester and 3,5-dimethyl-1-(4-trifluoromethoxy-phenyl)-piperazine (using 2,6-cis-dimethylpiperazine) And 1-bromo-4-trifluoromethoxy-toluene and prepared according to the procedure of Step 1 of Example 26) and synthesizing compound 5-[2,6-cis-dimethyl- according to the procedure of Example 1. 4-(4-Trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.72 (s, 1H), 7.66 (d, 1H), 7.37 (d, 1H), 7.09 (d, 2H), 6.87 (d, 2H), 4.22-4.12 (m, 2H), 3.41-3.25 (m, 7H), 2.64 - 2.58 (m, 2H), 1.46 (d, 6H); LCMS 499.5 (M+1) ⁺ .

實施例85 Example 85

6-[4-(4-二氟甲氧基-3-甲基-苯基)-2,6-二甲基-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[4-(4-Difluoromethoxy-3-methyl-phenyl)-2,6-dimethyl-piperazine-1-sulfonic acid]-indoline-1-carboxylic acid:

使用二氫茚-1-羧酸甲酯並根據實施例1的流程製備化合物6-[4-(4-二甲氧基-3-甲基-苯基)-2,6-二甲基-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(CD₃OD)ppm.7.82(s,1H),7.72(dd,1H),7.39(dd,1H),6.93(d,1H),6.72(s,1H),6.65(d,1H),6.60(t,1H),4.15(m,2H),3.69(s,2H),3.22(d,2H),3.09(m,1H),2.97(m,1H)2.58(dd,1H),2.48(dd,1H),2.42(m,2H),2.19(s,3H),1.45(d,6H)。 The compound 6-[4-(4-dimethoxy-3-methyl-phenyl)-2,6-dimethyl- was prepared according to the procedure of Example 1 using methyl dihydroindole-1-carboxylate. Piperazine-1-sulfonate]-indoline-1-carboxylic acid. ¹ H NMR (CD ₃ OD) ppm.7.82 (s, 1H), 7.72 (dd, 1H), 7.39 (dd, 1H), 6.93 (d, 1H), 6.72 (s, 1H), 6.65 (d, 1H) ), 6.60(t,1H), 4.15(m,2H), 3.69(s,2H), 3.22(d,2H), 3.09(m,1H), 2.97(m,1H)2.58(dd,1H), 2.48 (dd, 1H), 2.42 (m, 2H), 2.19 (s, 3H), 1.45 (d, 6H).

實施例86 Example 86

6-[2,3-二甲基-4-(5-三氟甲基-1-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[2,3-Dimethyl-4-(5-trifluoromethyl-1-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-1-carboxylic acid:

根據實施例37的流程製備化合物6-[2,3-二甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸。¹H NMR(400 MHz, CDCl₃),δ(ppm)：8.33(s,1H),7.85(d,1H),7.62(d,1H),7.56(t,1H),7.29(d,1H),6.43(dd,1H),4.37(m,1H),4.11(m,3H),3.20(m,2H),3.08(m,3H),2.45(m,2H),1.41(dd,3H,1.18(dd,3H)。 The compound 6-[2,3-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfo]-indoline was prepared according to the procedure of Example 37. 1-carboxylic acid. ¹ H NMR (400 MHz, CDCl ₃ ), δ (ppm): 8.33 (s, 1H), 7.85 (d, 1H), 7.62 (d, 1H), 7.56 (t, 1H), 7.29 (d, 1H) , 6.43 (dd, 1H), 4.37 (m, 1H), 4.11 (m, 3H), 3.20 (m, 2H), 3.08 (m, 3H), 2.45 (m, 2H), 1.41 (dd, 3H, 1.18) (dd, 3H).

實施例87Example 87

{5-[2,3-二甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-苯並[b]噻吩-3-基}-醋酸：{5-[2,3-Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl} -acetic acid:

根據實施例37的流程製備化合物{5-[2,3-二甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-苯並[b]噻吩-3-基}-醋酸。¹H NMR(400 MHz,CDCl₃),δ(ppm)：)：8.29(s,1H),8.28(s,1H),7.76(m,2H),7.59(s,1H),7.48(d,1H),6.34(d,1H),4.39(m,1H),3.98(m,2H),3.88(s,2H),3.37(m,1H),3.25(m,1H),3.15(m,1H),1.44(d,3H),1.18(d,3H)。 The compound {5-[2,3-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-benzo[,] was prepared according to the procedure of Example 37. b] thiophen-3-yl}-acetic acid. ¹ H NMR (400 MHz, CDCl ₃ ), δ (ppm):): 8.29 (s, 1H), 8.28 (s, 1H), 7.76 (m, 2H), 7.59 (s, 1H), 7.48 (d, 1H), 6.34 (d, 1H), 4.39 (m, 1H), 3.98 (m, 2H), 3.88 (s, 2H), 3.37 (m, 1H), 3.25 (m, 1H), 3.15 (m, 1H) ), 1.44 (d, 3H), 1.18 (d, 3H).

實施例88Example 88

步驟1step 1 3,5二甲基-1-(4-三氟甲氧基-苯基)-哌嗪：3,5-Dimethyl-1-(4-trifluoromethoxy-phenyl)-piperazine:

根據實施例79的流程合成化合物3,5-二甲基-1-(4-三氟甲氧基-苯基)-哌嗪。 The compound 3,5-dimethyl-1-(4-trifluoromethoxy-phenyl)-piperazine was synthesized according to the procedure of Example 79.

步驟2Step 2 {6-[2,6-二甲基-4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-吲哚-1-基}-醋酸：{6-[2,6-Dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazin-1-sulfonyl]-indol-1-yl}-acetic acid:

使用從步驟1取得的3,5-二甲基-1-(4-三氟甲氧基-苯基)-哌嗪並根據實施例34的流程合成化合物{6-[2,6-二甲基-4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-吲哚-1-基}-醋酸。¹H NMR(400 MHz,CD₃OD)δ7.89(s,1H),7.71(d,1H),7.52(dd,1H),7.44(d,1H),7.05(d,2H),6.84(d,2H),6.58(d,1H),5.02(s,2H),4.23-4.19(m,2H),3.27(d,2H),2.55(dd,2H),1.46(d,6H)；LCMS 512.6(M+1)⁺。 The compound {6-[2,6-dimethyl) was synthesized according to the procedure of Example 34 using 3,5-dimethyl-1-(4-trifluoromethoxy-phenyl)-piperazine obtained from the step 1. 4-(4-Trifluoromethoxy-phenyl)-piperazin-1-sulfonyl]-indol-1-yl}-acetic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.89 (s, 1H), 7.71 (d, 1H), 7.52 (dd, 1H), 7.44 (d, 1H), 7.05 (d, 2H), 6.84 ( d, 2H), 6.58 (d, 1H), 5.02 (s, 2H), 4.23-4.19 (m, 2H), 3.27 (d, 2H), 2.55 (dd, 2H), 1.46 (d, 6H); LCMS 512.6 (M+1) ⁺ .

實施例89 Example 89

4-[4-(5-三氟甲氧基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸：4-[4-(5-Trifluoromethoxy-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid:

使用二氫茚-2-羧酸甲酯並根據實施例1的流程製備化合物4-[4-(5-三氟甲氧基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸。H NMR(CD₃OD)δ 8.02(d,1H),7.60(d,1H),7.51(d,1H),7.46(m,1H),7.38(t,1H),6.82(d,1H),3.62(m,3H),3.55(d,2H)：3.16(m,8H)。 Preparation of the compound 4-[4-(5-trifluoromethoxy-pyridin-2-yl)-piperazine-1-sulfonate] using the indoline-2-carboxylic acid methyl ester and following the procedure of Example 1. - Indoline-2-carboxylic acid. H NMR (CD ₃ OD) δ 8.02 (d, 1H), 7.60 (d, 1H), 7.51 (d, 1H), 7.46 (m, 1H), 7.38 (t, 1H), 6.82 (d, 1H), 3.62 (m, 3H), 3.55 (d, 2H): 3.16 (m, 8H).

實施例90Example 90

{6-[4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-吲哚-1-基}-醋酸：{6-[4-(4-Trifluoromethoxy-phenyl)-piperazin-1-sulfonyl]-indol-1-yl}-acetic acid:

根據實施例34的流程自1-(4-三氟甲氧基-苯基)-哌嗪製備{6-[4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-吲哚-1-基}-醋酸甲酯。在室溫下攪拌含有{6-[4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-吲哚-1-基}-醋酸甲酯(45毫克，0.09毫莫耳)、1M氫氧化鋁(2毫升)、四氫呋喃(6毫升)和甲醇(2毫升)的混合液3小時。將反應物倒入1M氯化氫(50毫升)並以乙酸乙酯(40毫升2)萃取。乾燥組成的有機萃取，並過濾及濃縮而產生{6-[4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基}-吲哚-1-基}-醋酸。¹H NMR(400 MHz,DMSO-d6)：δ 7.89(s,1H),7.77(d,1H),7.63(d,1H),7.38(d,1H),7.14(d,2H),6.93(d,2H),6.61(d,1H),5.19(s,2H),3.23-3.15(m,4H),3.03-2.95(m,4H)； MS(ESI)：483.7(M+H)。 Preparation of {6-[4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonate from 1-(4-trifluoromethoxy-phenyl)-piperazine according to the procedure of Example 34 Acidic]-indol-1-yl}-methyl acetate. Stirring at room temperature containing {6-[4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfo]-indol-1-yl}-methyl acetate (45 mg, A mixture of 0.19 mmoles, 1M aluminum hydroxide (2 mL), tetrahydrofuran (6 mL) and methanol (2 mL). The reaction was poured into 1M EtOAc (EtOAc)EtOAc. Drying the organic extract of the composition, and filtering and concentrating to give {6-[4-(4-trifluoromethoxy-phenyl)-piperazin-1-sulfonyl}-indol-1-yl}-acetic acid . ¹ H NMR (400 MHz, DMSO-d6): δ 7.89 (s, 1H), 7.77 (d, 1H), 7.63 (d, 1H), 7.38 (d, 1H), 7.14 (d, 2H), 6.93 ( d, 2H), 6.61 (d, 1H), 5.19 (s, 2H), 3.23 - 3.15 (m, 4H), 3.03 - 2.95 (m, 4H); MS (ESI): 483.7 (M+H).

實施例91Example 91

{6-[4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-2,3-二氫-吲哚-1-基}-醋酸：{6-[4-(4-Trifluoromethoxy-phenyl)-piperazin-1-sulfonate]-2,3-dihydro-indol-1-yl}-acetic acid:

室溫下加入三乙基矽烷(0.13毫升，0.77毫莫耳)至一含{6-[4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基}-2,3-二氫-吲哚-1-基}-醋酸甲酯(82毫克，0.16毫莫耳)以及三氟醋酸(4毫升)的溶液。1小時後，加入更多的三乙基矽烷(0.2毫升，1.2毫莫耳)。在額外的4小時後，將反應物倒入1.2M氫氧化鈉(50毫升)並以二氯甲烷(30毫升3)萃取。乾燥組成的有機萃取物，並過濾、濃縮，再以矽膠色層分析純化(4：1→3：2；己烷：乙酸乙酯)而產生{6-[4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-2,3-二氫-吲哚-1-基}-醋酸甲酯：MS(ESI)：500.1(M+H)。根據實施例1步驟2的流程水解{6-[4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-2,3-二氫-吲哚-1-基}-醋酸甲酯，而產生{6-[4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-2,3-二氫-吲哚-1-基}-醋酸。¹H NMR(400 MHz,DMSO-d6)：δ 7.24(d,1H),7.19(d,2H),6.98(d,2H),6.93(d,1H),6.68(s,1H),4.05(s,2H),3.57(t,2H), 3.24-3.17(m,4H),3.03(t,2H),3.00-2.94(m,4H)；MS(ESI)：486.1(M+H)。 Add triethyl decane (0.13 ml, 0.77 mmol) to a solution containing {6-[4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonate}-2 at room temperature , a solution of methyl 3-dihydro-indol-1-yl}-acetate (82 mg, 0.16 mmol) and trifluoroacetic acid (4 mL). After 1 hour, more triethyl decane (0.2 mL, 1.2 mmol) was added. After an additional 4 hours, the reaction was poured into EtOAc EtOAc. The organic extracts are dried, filtered, concentrated, and purified by gelatin chromatography (4:1→3:2; hexane:ethyl acetate) to give {6-[4-(4-trifluoromethoxy) Methyl-phenyl)-piperazine-1-sulfonate]-2,3-dihydro-indol-1-yl}-methyl acetate: MS (ESI): 500.1 (M+H). Hydrolysis of {6-[4-(4-trifluoromethoxy-phenyl)-piperazin-1-sulfonate]-2,3-dihydro-indole-1- according to the procedure of Example 2, Step 2. {-}-methyl acetate, resulting in {6-[4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonate]-2,3-dihydro-indole-1- Base}-acetic acid. ¹ H NMR (400 MHz, DMSO-d6): δ 7.24 (d, 1H), 7.19 (d, 2H), 6.98 (d, 2H), 6.93 (d, 1H), 6.68 (s, 1H), 4.05 ( s, 2H), 3.57 (t, 2H), 3.24-3.17 (m, 4H), 3.03 (t, 2H), 3.00 - 2.94 (m, 4H); MS (ESI): 486.1 (M+H).

實施例92 Example 92

4-[4-(4-氯-苯基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸：4-[4-(4-Chloro-phenyl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid:

根據實施例1的流程自1-(4-氯-苯基)-哌嗪以及4-氯磺酸基-二氫茚-2-羧酸甲酯製備化合物4-[4-(4-氯-苯基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸。¹H NMR(400 MHz,DMSO-d6)：δ 7.58(d,1H),7.56(d,1H),7.43(t,1H),7.23(d,2H),6.92(d,2H),3.50-3.41(m,2H),3.40-3.29(m,1H),3.28-3.13(m,6H),3.12-3.04(m,4H)；MS(ESI)：420.9(M+H)。 Preparation of compound 4-[4-(4-chloro-) from 1-(4-chloro-phenyl)-piperazine and methyl 4-chlorosulfonyl-indoline-2-carboxylate according to the procedure of Example 1. Phenyl)-piperazine-1-sulfonate]-indoline-2-carboxylic acid. ¹ H NMR (400 MHz, DMSO-d6): δ 7.58 (d, 1H), 7.56 (d, 1H), 7.43 (t, 1H), 7.23 (d, 2H), 6.92 (d, 2H), 3.50- 3.41 (m, 2H), 3.40-3.29 (m, 1H), 3.28-3.13 (m, 6H), 3.12-3.04 (m, 4H); MS (ESI): 420.9 (M+H).

實施例93 Example 93

4-[2-(S)-甲基-4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸：4-[2-(S)-Methyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid:

根據實施例1的流程自3-(S)-甲基-1-(4-三氟甲氧基-苯基)-哌嗪以及4-氯磺酸基-二氫茚-2-羧酸甲酯製備4-[2-(S)-甲基-4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸]-二氫化茚-2-羧酸。¹H NMR(400 MHz,DMSO-d6)：δ 7.65(d,1H),7.53(d,1H),7.38(t,1H),7.18(d,2H),6.98-6.92(m,2H),4.15-4.00(m,1H),3.60-3.12(m,9H),2.83-2.75(m,1H),2.64-2.50(m,1H),1.18(d,3H)；MS(ESI)：485.3(M+H)。 According to the procedure of Example 1, from 3-(S)-methyl-1-(4-trifluoromethoxy-phenyl)-piperazine and 4-chlorosulfonyl-indoline-2-carboxylic acid A The ester was prepared as 4-[2-(S)-methyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonic acid]-indan-2-carboxylic acid. ¹ H NMR (400 MHz, DMSO-d6): δ 7.65 (d, 1H), 7.53 (d, 1H), 7.38 (t, 1H), 7.18 (d, 2H), 6.98-6.92 (m, 2H), 4.15-4.00 (m, 1H), 3.60-3.12 (m, 9H), 2.83-2.75 (m, 1H), 2.64-2.50 (m, 1H), 1.18 (d, 3H); MS (ESI): 485.3 ( M+H).

實施例94 Example 94

4-[2-(S)-甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸：4-[2-(S)-Methyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid:

根據實施例1的流程從3-(S)-甲基-1-(5-三氟甲基-吡啶-2-基)- 哌嗪和4-氯磺酸基-二氫茚-2-羧酸甲酯製備化合物4-[2-(S)-甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸。¹H NMR(400 MHz,DMSO-d6)：δ 8.3&(s,1H),7.82-7.76(m,1H),7.65(d,1H),7.52(d,1H),7.37(t,1H),6.93-6.88(m,1H),4.35-4.18(m,2H),4.18-4.02(m,1H),3.60-3.46(m,1H),3.45-3.10(m,7H),2.97-2.80(m,1H),1.06-1.01(m,3H)；MS(ESI)：470.0(M+H)。 From 3-(S)-methyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine and 4-chlorosulfonyl-indoline-2-carboxylate according to the procedure of Example 1. Preparation of the compound methyl 4-[2-(S)-methyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-2- carboxylic acid. ¹ H NMR (400 MHz, DMSO-d6): δ 8.3 & (s, 1H), 7.82-7.76 (m, 1H), 7.65 (d, 1H), 7.52 (d, 1H), 7.37 (t, 1H) , 6.93-6.88 (m, 1H), 4.35-4.18 (m, 2H), 4.18-4.02 (m, 1H), 3.60-3.46 (m, 1H), 3.45-3.10 (m, 7H), 2.97-2.80 ( m, 1H), 1.06-1.01 (m, 3H); MS (ESI): 470.0 (M+H).

實施例95Example 95

步驟1step 1

3,5-二甲基-1-(4-三氟甲氧基-苯甲基)-哌嗪：3,5-Dimethyl-1-(4-trifluoromethoxy-benzyl)-piperazine:

化合物3,5-二甲基-1-(4-三氟甲氧基-苯甲基)-哌嗪被合成藉由取得2,6-二甲基哌嗪(1.0克，8.77毫莫耳)並且在室溫下加入至一正攪拌在二氯甲烷(30毫升)中的4-(三氟甲氧基)-苯甲醛(776微升，4.3毫莫耳)溶液。一小時後，加入三乙醯氧基氫硼化鈉(2.45克，8.77毫莫耳)到混合物。在室溫下攪拌溶液另四小時，直到反 應完成(TLC)。濃縮反應物並以乙酸乙酯稀釋，再以1N氯化氫(2 X 50毫升)萃取。以氫氧化鈉中和水層並以乙酸乙酯(3 X 50毫升)萃取。乾燥有機層(硫酸鈉)，並濃縮而提供潔淨油脂狀的3,5-二甲基-1-(4-三氟甲氧基-苯甲基)-哌嗪(1.01克，80%)。¹H NMR(400 MHz,CD₃OD)δ 7.42(d,2H),7.23(d,2H),3.54(s,2H),2.98-2.88(m,2H),2.82-2.74(m,2H),1.69(t,2H),1.05(d,6H)；LCMS 289.5(M+1)⁺。 The compound 3,5-dimethyl-1-(4-trifluoromethoxy-benzyl)-piperazine was synthesized by obtaining 2,6-dimethylpiperazine (1.0 g, 8.77 mmol). It was then added to a solution of 4-(trifluoromethoxy)-benzaldehyde (776 μL, 4.3 mmol) which was stirred in dichloromethane (30 mL). One hour later, sodium triethoxysulfonium borohydride (2.45 g, 8.77 mmol) was added to the mixture. The solution was stirred at room temperature for another four hours until the reaction was complete (TLC). The reaction was concentrated and diluted with EtOAc EtOAc (EtOAc) The aqueous layer was neutralized with sodium hydroxide and extracted with ethyl acetate (3 X 50 mL). The organic layer was dried (sodium sulfate) and concentrated to afford 3,5-dimethyl-1-(4-trifluoromethoxy-benzyl)-piperazine (1.01 g, 80%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.42 (d, 2H), 7.23 (d, 2H), 3.54 (s, 2H), 2.98-2.88 (m, 2H), 2.82-2.74 (m, 2H) , 1.69 (t, 2H), 1.05 (d, 6H); LCMS 289.5 (M + 1) +.

步驟2Step 2 4-[2,6-二甲基-4-(4-三氟甲氧基-苯甲基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸：4-[2,6-Dimethyl-4-(4-trifluoromethoxy-benzyl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid:

根據實施例1步驟1和3的流程合成化合物4-[2,6-二甲基-4-(4-三氟甲氧基-苯甲基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸。¹H NMR(400 MHz,CD₃OD)δ 7.74-7.64(m,4H),7.47(d,1H),7.39-7.28(m,2H),4.42(s,2H),4.21-2.18(m,2H),3.50-3.34(m,5H),3.33-3.19(m,4H),1-56(d,6H)；LCMS 497.5(M+1)⁺。 The compound 4-[2,6-dimethyl-4-(4-trifluoromethoxy-benzyl)-piperazine-1-sulfonate]-di was synthesized according to the procedures of steps 1 and 3 of Example 1. Hydroquinone-2-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.74-7.64 (m, 4H), 7.47 (d, 1H), 7.39-7.28 (m, 2H), 4.42 (s, 2H), 4.21-2.18 (m, 2H), 3.50-3.34 (m, 5H ), 3.33-3.19 (m, 4H), 1-56 (d, 6H); LCMS 497.5 (m + 1) +.

實施例96 Example 96

4-[2,6-二甲基-4-(4-三氟甲基-苯甲基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸：4-[2,6-Dimethyl-4-(4-trifluoromethyl-benzyl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid:

使用4-(三氟甲基)-苯甲醛並根據實施例95的流程合成化合物4-[2，6-二甲基-4-(4-三氟甲氧基-苯甲基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸。¹H NMR(400 MHz,CD₃OD)δ 7.78-7.62(m,5H),7.47(d,1H),7.32(t,1H),4.41(s,2H),4.21-2.15(m,2H),3.52-3.36(m,5H),3.34-3.22(m,4H),1.52(d,6H)；LCMS 497.5(M+1)⁺。 4-(2,6-Dimethyl-4-(4-trifluoromethoxy-benzyl)-piperazine was synthesized according to the procedure of Example 95 using 4-(trifluoromethyl)-benzaldehyde. 1-sulfonate]-indoline-2-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.78-7.62 (m, 5H), 7.47 (d, 1H), 7.32 (t, 1H), 4.41 (s, 2H), 4.21-2.15 (m, 2H) , 3.52-3.36 (m, 5H), 3.34-3.22 (m, 4H), 1.52 (d, 6H); LCMS 497.5 (m + 1) +.

實施例97 Example 97

4-[4-(4-三氟甲基-苯甲基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸：4-[4-(4-Trifluoromethyl-benzyl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid:

使用哌嗪以及4-(三氟甲基)-苯甲醛並根據實施例95的流程合成化合物4-[4-(4-三氟甲氧基-苯甲基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸。¹H NMR(400 MHz,CD₃OD)δ 7.82-7.73(m,4H),7.62(d,1H),7.54(d,1H),7.38(t,1H),4.47(s,2H),3.54-3.48(m,5H),3.46-3.35(m,2H),3.32-3.22(m,6H)；LCMS 469.5(M+1)⁺。 Synthesis of the compound 4-[4-(4-trifluoromethoxy-benzyl)-piperazine-1-sulfonic acid using piperazine and 4-(trifluoromethyl)-benzaldehyde according to the procedure of Example 95 Base]-indoline-2-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.82-7.73 (m, 4H), 7.62 (d, 1H), 7.54 (d, 1H), 7.38 (t, 1H), 4.47 (s, 2H), 3.54 - 3.48 (m, 5H), 3.46-3.35 (m, 2H), 3.32-3.22 (m, 6H); LCMS 469.5 (M+1) ⁺ .

實施例98 Example 98

4-[4-(4-三氟甲氧基-苯甲基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸：4-[4-(4-Trifluoromethoxy-benzyl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid:

使用哌嗪並根據實施例95的流程合成化合物4-[4-(4-三氟甲氧基-苯甲基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸。¹H NMR(400 MHz,CD₃OD)δ 7.70-7.60(m,3H),7.54(d,1H),7.42-7.33(m,3H),4.41(s,2H),3.54-3.48(m,5H),3.46-3.35(m,2H),3.32-3.22(m,6H)；LCMS 484.9(M+1)⁺。 The compound 4-[4-(4-trifluoromethoxy-benzyl)-piperazin-1-sulfonyl]-indoline-2-carboxylic acid was synthesized according to the procedure of Example 95 using piperazine. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.70-7.60 (m, 3H), 7.54 (d, 1H), 7.42-7.33 (m, 3H), 4.41 (s, 2H), 3.54-3.48 (m, 5H), 3.46-3.35 (m, 2H ), 3.32-3.22 (m, 6H); LCMS 484.9 (m + 1) +.

實施例99Example 99

步驟1step 1

6-溴-吡啶-3-醇(6-Bromo-pyridin-3-ol)：6-Bromo-pyridin-3-ol (6-Bromo-pyridin-3-ol):

加入有THF(180毫升)中的6-溴吡啶-3-基溴酸(9.5克，43.48毫莫耳)溶液至一250毫升的圓底燒瓶。邊攪拌邊以液滴式的方式加入過氧化氫(8.8克，98.35毫莫耳)至前述混合物，當冷卻到0℃ 後超過10分鐘。邊攪拌邊以液滴式的方式加入醋酸到前述混合物，當冷卻到0℃超過5分鐘。使產生的溶液產生反應，並攪拌過夜，同時溫度保持在室溫。以TLC(EtOAc/PE=1：1)監測反應過程。產物藉由先加入亞硫酸氫鈉再加入碳酸氫鈉而沉澱。以80毫升EtOAc萃取產生的溶液三次，組合有機層並以硫酸鎂乾燥，再藉由於真空下使用旋轉脫水器的蒸發方式濃縮。得到7克(88%)白色固態物的6-溴吡啶-3-醇。且測得6-溴吡啶-3-醇的Rf值為0.5。 A solution of 6-bromopyridin-3-ylbromide (9.5 g, 43.48 mmol) in THF (180 mL) was added to a 250 mL round bottom flask. Hydrogen peroxide (8.8 g, 98.35 mmol) was added dropwise to the mixture while stirring, while cooling to 0 ° C After more than 10 minutes. Acetic acid was added to the aforementioned mixture in a dropletwise manner while stirring, and cooled to 0 ° C for more than 5 minutes. The resulting solution was allowed to react and stirred overnight while maintaining the temperature at room temperature. The course of the reaction was monitored by TLC (EtOAc / PE = 1:1). The product was precipitated by first adding sodium hydrogen sulfite followed by sodium hydrogencarbonate. The resulting solution was extracted three times with 80 mL of EtOAc. EtOAc was evaporated and evaporated and evaporated. 7 g (88%) of 6-bromopyridin-3-ol as a white solid were obtained. Further, the Rf value of 6-bromopyridin-3-ol was measured to be 0.5.

步驟2Step 2

2-溴-5-三氟甲氧基-吡啶：加入6-溴吡啶-3-醇(2.5克，14.37毫莫耳)至一50毫升的密封管中。加入過氯甲烷(6.6克，42.86毫莫耳)。添加五氟化銻(101克，465.44毫莫耳)到此混合物。持續攪拌八小時使得產生的溶液產生反應，同時溫度在油浴中維持在150℃。冷卻到室溫後，注入反應混合物到冰水中。以飽和的氫氧化鉀調整溶液pH值到7。以100毫升EtOAc萃取產生的溶液2次，而合併有機層並以硫酸鎂乾燥再藉由於真空下使用旋轉脫水器的蒸發方式濃縮。產生0.1克(2.9%)黃色固態物的2-溴-5-(三氟甲氧基)-吡啶。 2-Bromo-5-trifluoromethoxy-pyridine: 6-bromopyridin-3-ol (2.5 g, 14.37 mmol) was added to a 50 mL sealed tube. Add perchloroform (6.6 g, 42.86 mmol). Antimony pentafluoride (101 g, 465.44 mmol) was added to the mixture. Stirring was continued for eight hours to allow the resulting solution to react while maintaining the temperature at 150 ° C in the oil bath. After cooling to room temperature, the reaction mixture was poured into ice water. The pH of the solution was adjusted to 7 with saturated potassium hydroxide. The resulting solution was extracted twice with 100 mL EtOAc. EtOAc was evaporated and evaporated. 0.1 g (2.9%) of 2-bromo-5-(trifluoromethoxy)-pyridine was obtained as a yellow solid.

步驟3Step 3

3,5-二甲基-1-(5-三氟甲氧基-吡啶-2-基)-哌嗪：3,5-Dimethyl-1-(5-trifluoromethoxy-pyridin-2-yl)-piperazine:

加入2-溴-5-(三氟甲氧基)吡啶(120毫克，0.50毫莫耳)至一50毫升的圓底燒瓶。添加2,6-二甲基哌嗪(220毫克，1.96毫莫耳)到此混合物。接著加入碳酸鉀(270毫克，1.96毫莫耳)。加入DMF(10毫升)到此混合物。使產生的溶液產生反應，並攪拌3小時，而溫度保持在140℃的油浴中。以TLC(CH₂Cl₂/MeOH=1：10)監測反應過程。冷卻產生的溶液至室溫。加入10毫升EtOAc和10毫升的水。以硫酸鎂乾燥油層，並以蒸發方式濃縮。藉由通過有10：1二氯甲烷/甲醇溶劑系統洗提的管柱純化殘餘物。產生白色固態物的0.1克2-(2,6-二甲基哌嗪)-5-(三氟甲氧基)吡啶。 2-Bromo-5-(trifluoromethoxy)pyridine (120 mg, 0.50 mmol) was added to a 50 mL round bottom flask. 2,6-Dimethylpiperazine (220 mg, 1.96 mmol) was added to the mixture. Potassium carbonate (270 mg, 1.96 mmol) was then added. DMF (10 mL) was added to the mixture. The resulting solution was allowed to react and stirred for 3 hours while maintaining the temperature in an oil bath at 140 °C. In _{TLC (CH 2 Cl 2 / MeOH} = 1: 10) to monitor the reaction. The resulting solution was cooled to room temperature. 10 ml of EtOAc and 10 ml of water were added. The oil layer was dried over magnesium sulfate and concentrated by evaporation. The residue was purified by column eluting with a 10: 1 dichloromethane / methanol solvent. 0.1 g of 2-(2,6-dimethylpiperazine)-5-(trifluoromethoxy)pyridine was obtained as a white solid.

步驟4Step 4 4-[2,6-二甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸：4-[2,6-Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid:

根據實施例1步驟1和3的流程合成化合物4-[2,6-二甲基-4-(5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸。¹H NMR(400 MHz,CD₃OD)δ 7.98(s,1H),7.71(d,1H),7.47-7.42(m,2H),7.33(t,1H),6.77(d,1H),4.24-4.18(m,1H),4.12-4.00(m,3H),3.56-3.52(m,2H),3.41-3.25(m,3H),3.03(dd,1H),2.95(dd,1H), 1.39(d,6H)；LCMS 500.5(M+1)⁺。 The compound 4-[2,6-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonate]- was synthesized according to the procedure of steps 1 and 3 of Example 1. Indoline-2-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.98 (s, 1H), 7.71 (d, 1H), 7.47-7.42 (m, 2H), 7.33 (t, 1H), 6.77 (d, 1H), 4.24 -4.18(m,1H),4.12-4.00(m,3H),3.56-3.52(m,2H),3.41-3.25(m,3H),3.03(dd,1H),2.95(dd,1H), 1.39 (d, 6H); LCMS 500.5 (M + 1) ⁺ .

實施例100Example 100

{5-[2,6-二甲基-4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-苯並[b]噻吩-3-基}-醋酸：{5-[2,6-Dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-acetic acid :

使用2,6-二甲基哌嗪以及1-溴-4-三氟甲氧基甲苯並根據實施例47的流程合成化合物{5-[2,6-二甲基-4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-苯並[b]噻吩-3-基}-醋酸。H NMR(400 MHz,CD₃OD)δ 8.46(s,1H),7.94(d,1H),7.84(d,1H),7.73(s,1H),7.04(d,2H)；6.81(d,2H),4.24-4.20(m,2H),3.91(s,2H),3.27-3.25(m,2H),2.56(dd,2H),1.47(d,6H)；LCMS 528.9(M+1)⁺。 The compound {5-[2,6-dimethyl-4-(4-tri) was synthesized according to the procedure of Example 47 using 2,6-dimethylpiperazine and 1-bromo-4-trifluoromethoxytoluene. Fluoromethoxy-phenyl)-piperazine-1-sulfonate]-benzo[b]thiophen-3-yl}-acetic acid. H NMR (400 MHz, CD ₃ OD) δ 8.46 (s, 1H), 7.94 (d, 1H), 7.84 (d, 1H), 7.73 (s, 1H), 7.04 (d, 2H); 6.81 (d, 2H), 4.24-4.20 (m, 2H), 3.91 (s, 2H), 3.27-3.25 (m, 2H), 2.56 (dd, 2H), 1.47 (d, 6H); LCMS 528.9 (M+1) ⁺ .

實施例101 Example 101

4-[2,6-二甲基-4-(4-三氟甲基磺醯基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸：4-[2,6-Dimethyl-4-(4-trifluoromethylsulfonyl-phenyl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid:

使用2,6-二甲基哌嗪以及1-溴-4-(三氟甲基磺醯基)-甲苯並根 據實施例26的流程合成化合物4-[2,6-二甲基-4-(4-三氟甲基磺醯基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸。¹H NMR(400 MHz,CD₃OD)δ 7.71(d,1H),7.50-7.44(m,3H),7.33(t,1H),6.91(d,2H),4.22-4.19(m,1H),4.06-4.02(m,1H),3.62-3.50(m,4H),3.41-3.22(m,3H),2.91(dd,1H),2.82(dd,1H),1.45(d,6H)；LCMS 514.9(M+1)⁺。 The compound 4-[2,6-dimethyl-4- was synthesized according to the procedure of Example 26 using 2,6-dimethylpiperazine and 1-bromo-4-(trifluoromethylsulfonyl)-toluene. (4-Trifluoromethylsulfonyl-phenyl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.71 (d, 1H), 7.50-7.44 (m, 3H), 7.33 (t, 1H), 6.91 (d, 2H), 4.22-4.19 (m, 1H) , 4.06-4.02 (m, 1H), 3.62-3.50 (m, 4H), 3.41-3.22 (m, 3H), 2.91 (dd, 1H), 2.82 (dd, 1H), 1.45 (d, 6H); LCMS 514.9 (M+1) ⁺ .

實施例102 Example 102

4-[4-(-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸：4-[4-(-Trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indoline-2-carboxylic acid:

使用1-溴-4-(三氟甲氧基)-甲苯並根據實施例26的流程合成化合物4-[4-(-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸。¹H NMR(400 MHz,CD₃OD)δ 7.61(d,1H),7.52(d,1H),7.38(t,1H),7.10(d,2H),6.96(d,2H),3.59-3.54(m,2H),3.42-3.27(m,3H),3.25-3.18(m,8H)；LCMS 470.9(M+1)⁺。 The compound 4-[4-(-trifluoromethoxy-phenyl)-piperazine-1-sulfonate was synthesized according to the procedure of Example 26 using 1-bromo-4-(trifluoromethoxy)-toluene. ]-Indoline-2-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.61 (d, 1H), 7.52 (d, 1H), 7.38 (t, 1H), 7.10 (d, 2H), 6.96 (d, 2H), 3.59-3.54 (m, 2H), 3.42-3.27 ( m, 3H), 3.25-3.18 (m, 8H); LCMS 470.9 (m + 1) +.

實施例103 Example 103

6-[4-(2,4-二氯-苯基)-2,6-二甲基-哌嗪-1-磺酸基]-二氫茚-2-羧酸：6-[4-(2,4-Dichloro-phenyl)-2,6-dimethyl-piperazine-1-sulfonyl]-indoline-2-carboxylic acid:

根據實施例37中的流程製備本化合物。¹H NMR(400 MHz,CDCl₃),δ 7.90(s,1H),7.72(d,1H),7.36(d,1H),7.35(s,1H),7.10(d,1H),6.80(d,1H),4.25(m,1H),4.11(m,2H),3.17(m,1H),2.99(m,3H),2.64(dd,1H),2.47(m,3H),1.55(d,6H)。 The present compound was prepared according to the procedure in Example 37. ¹ H NMR (400 MHz, CDCl ₃ ), δ 7.90 (s, 1H), 7.72 (d, 1H), 7.36 (d, 1H), 7.35 (s, 1H), 7.10 (d, 1H), 6.80 (d) , 1H), 4.25 (m, 1H), 4.11 (m, 2H), 3.17 (m, 1H), 2.99 (m, 3H), 2.64 (dd, 1H), 2.47 (m, 3H), 1.55 (d, 6H).

實施例104 Example 104

6-[2,6-二甲基-4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸：6-[2,6-Dimethyl-4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indoline-1-carboxylic acid:

根據實施例37的流程製備本化合物。¹H NMR(400 MHz,CDCl₃),δ 7.89(s,1H),7.77(d,1H),7.42(d,2H),7.32(d,1H),6.78(d,2H),4.26(m,1H),4.11(m,2H),3.36(m,2H),309(m,1H),2.94(m,1H),2.83(m,1H),2.77(m,1H),2.44(m,2H),1.44(d,6H)。 The present compound was prepared according to the procedure of Example 37. ¹ H NMR (400 MHz, CDCl ₃ ), δ 7.89 (s, 1H), 7.77 (d, 1H), 7.42 (d, 2H), 7.32 (d, 1H), 6.78 (d, 2H), 4.26 (m) , 1H), 4.11 (m, 2H), 3.36 (m, 2H), 309 (m, 1H), 2.94 (m, 1H), 2.83 (m, 1H), 2.77 (m, 1H), 2.44 (m, 2H), 1.44 (d, 6H).

實施例105 Example 105

4-[2,6-二甲基-4-(4-三氟甲基-苯基)-哌嗪-1-磺酸基]-二氫茚-1-羧酸：4-[2,6-Dimethyl-4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indoline-1-carboxylic acid:

根據實施例37的流程製備本化合物。¹H NMR(400 MHz,CDCl₃)δ 7.73(s,1H),7.45(d,2H),7.40(d,1H),7.30(d,1H),6.84(d,2H),4.23(m,1H),4.06(m,1H),3.58(m,2H),3.39(m,3H),3.28(m,2H),2.92(dd,1H),2.83(dd,1H),1.48(dd,6H)。 The present compound was prepared according to the procedure of Example 37. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.73 (s, 1H), 7.45 (d, 2H), 7.40 (d, 1H), 7.30 (d, 1H), 6.84 (d, 2H), 4.23 (m, 1H), 4.06 (m, 1H), 3.58 (m, 2H), 3.39 (m, 3H), 3.28 (m, 2H), 2.92 (dd, 1H), 2.83 (dd, 1H), 1.48 (dd, 6H) ).

實施例106Example 106

步驟1step 1

1-(4-正-丁基-苯基)-順-3.5-二甲基-哌嗪：1-(4-n-butyl-phenyl)-cis-3.5-dimethyl-piperazine:

加入4-(正-丁基)溴甲苯(1.86克，8.7毫莫耳)到一在甲苯(35毫升)中的順-2,6-二甲基哌嗪(1克，8.7毫莫耳)溶液，隨後分別加入BINAP(0.81克，1.3毫莫耳)以及t-BuONa(1.5克，15.6毫莫耳)。對產生的混合物除氣兩次。隨後，加入三(二並苄基丙酮)二鈀(Pd₂(dba)₃)(0.79克，0.87毫莫耳)，並加熱混合物到100℃而過夜。以TLC監控轉換過程。冷卻反應燒瓶到室溫，並在分離漏斗中沖洗。以乙酸乙酯(3x100毫升)萃取，後以水(1x100毫升)、鹵水(1x50毫升)沖洗，再以硫酸鈉乾燥並在真空下濃縮而產生粗產物，粗產物再經由以二氯甲烷中的甲烷洗提的矽膠管柱色層分析而純化，以提供0.8克的產物。¹H NMR(400 MHz,CDCl₃)δ 7.29-7.26(m,2H),6.88-6.86(m,2H),3.49-3.46(m,2H),3.08-3.00(m,2H),2.33-2.27(m,2H),2.15(1H,br),1.29(s,9H),1.13(d,6H)。 Add 4-(n-butyl)bromotoluene (1.86 g, 8.7 mmol) to a cis-2,6-dimethylpiperazine (1 g, 8.7 mmol) in toluene (35 mL) The solution was then separately added to BINAP (0.81 g, 1.3 mmol) and t- BuONa (1.5 g, 15.6 mmol). The resulting mixture was degassed twice. Subsequently, tris(dibenzylbenzylacetate)dipalladium (Pd ₂ (dba) ₃ ) (0.79 g, 0.87 mmol) was added, and the mixture was heated to 100 ° C overnight. The conversion process is monitored by TLC. The reaction flask was cooled to room temperature and rinsed in a separating funnel. Extracted with ethyl acetate (3×100 mL), EtOAc (EtOAc)EtOAc. The methane eluted gel column chromatography was purified to provide 0.8 g of product. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.29-7.26 (m, 2H), 6.88-6.86 (m, 2H), 3.49-3.46 (m, 2H), 3.08-3.00 (m, 2H), 2.33 - 2.27 (m, 2H), 2.15 (1H, br), 1.29 (s, 9H), 1.13 (d, 6H).

步驟2Step 2 4-[4-(4-正-丁基-苯基)-順-2,6-二甲基-哌嗪-1-磺酸基]-二氫茚-2-羧酸：4-[4-(4-n-butyl-phenyl)-cis-2,6-dimethyl-piperazine-1-sulfonyl]-indoline-2-carboxylic acid:

使用從上述步驟1得到的二氫茚-2-羧酸甲酯和1-(4-正-丁基-苯基)-順-3,5-二甲基-哌嗪並根據實施例1的流程合成化合物4-[4-(4-正-丁基-苯基)-順-2,6-二甲基-哌嗪-1-磺酸基]-二氫茚-2-羧酸。¹H NMR(400 MHz,CD₃OD)δ 7.71(d,1H),7.47(d,1H),7.34(t,1H),7.24(d,2H),6.81(d,2H),4.16-4.14(m,1H),4.02-4.00(m,1H),3.54(d,2H),3.34-3.26(m,5H),2.67(dd,1H),2.59(dd,1H),1.51(d,3H),1.50(d,3H),1.26(s,9H)。 Using the indoline-2-carboxylic acid methyl ester obtained from the above step 1 and 1-(4-n-butyl-phenyl)-cis-3,5-dimethyl-piperazine and according to Example 1 The procedure synthesizes the compound 4-[4-(4-n-butyl-phenyl)-cis-2,6-dimethyl-piperazine-1-sulfonyl]-indoline-2-carboxylic acid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.71 (d, 1H), 7.47 (d, 1H), 7.34 (t, 1H), 7.24 (d, 2H), 6.81 (d, 2H), 4.16-4. (m, 1H), 4.02-4.00 (m, 1H), 3.54 (d, 2H), 3.34-3.26 (m, 5H), 2.67 (dd, 1H), 2.59 (dd, 1H), 1.51 (d, 3H) ), 1.50 (d, 3H), 1.26 (s, 9H).

實施例107Example 107

步驟1step 1

(4,6-二氯-吡啶-3-基)-甲醇：(4,6-dichloro-pyridin-3-yl)-methanol:

加入Et₂O(200毫升)至一500毫升的三頸圓底燒瓶。分數次地加入鋰鋁四氫(2.4克，64毫莫耳)到前述混合物中，同時冷卻到0℃。分數次地加入氯化鋁(17克，128毫莫耳)到前述混合物中，同時冷卻到0℃。導入氮氣。隨後邊攪拌邊以液滴的方式加入在Et₂O(100毫升)中的甲基4,6-二氯尼古丁酸(13.1克，64毫莫耳)溶液，同時冷卻到0℃。邊攪拌邊使產生的溶液反應1小時，同時溫度維持在一油浴中的迴流。以TLC(EtOAc/PE=1：1)監測反應流程。加入100毫升的水/冰熄滅反應混合液。以500毫升EtOEt萃取產生的溶液二次，合併有機層，並以硫酸鈉乾燥，再於真空下使用旋轉脫水器的蒸發方式濃縮。得到4.5克(43%)黃色固態物的(4,6-二氯吡啶-3-基)甲醇。一射頻0.3的(4,6-二氯吡啶-3-基)甲烷被觀察 到。且測得(4,6-二氯吡啶-3-基)甲烷的Rf值為0.3。 Et ₂ O (200 mL) was added to a 500 mL 3-neck round bottom flask. Lithium aluminum tetrahydrogen (2.4 g, 64 mmol) was added in portions to the previous mixture while cooling to 0 °C. Aluminum chloride (17 g, 128 mmol) was added in portions to the previous mixture while cooling to 0 °C. Introduce nitrogen. A solution of methyl 4,6-dichloronicotonic acid (13.1 g, 64 mmol) in Et ₂ O (100 mL) was then added dropwise with stirring while cooling to 0 °C. The resulting solution was reacted for 1 hour while stirring while maintaining the reflux in an oil bath. The reaction was monitored by TLC (EtOAc / PE = 1:1). The reaction mixture was quenched by the addition of 100 ml of water/ice. The resulting solution was extracted twice with 500 ml of EtOEt, and the organic layers were combined, dried over sodium sulfate, and evaporated. 4.5 g (43%) of a yellow solid (4,6-dichloropyridin-3-yl)methanol was obtained. A radio frequency of 0.3 (4,6-dichloropyridin-3-yl)methane was observed. Further, the (4,6-dichloropyridin-3-yl)methane was found to have an Rf value of 0.3.

步驟2Step 2

2,4-二氯-5-三氯甲基-吡啶：加入(4,6-二氯吡啶-3-基)甲烷(7克，39毫莫耳)至100毫升圓底燒瓶。加入四氯化碳(200毫升)到該混合物。邊攪拌邊以液滴的方式加入二氯硫醯(120毫升)到前述的混合物。邊攪拌邊使產生的溶液反應過夜，同時溫度保持在迴流。以TLC(CH2C12/PE=1：1)監測反應過程。於真空下使用旋轉脫水器的蒸發方式濃縮混合物。藉由增加碳酸氫鈉(2N)來調整pH值到8。以100毫升的EtOAc萃取產生的溶液二次，並合併有機層以在硫酸鈉乾燥。藉由一有1：4二氯甲烷：聚乙烯溶劑系統洗提的管柱而純化殘餘物。得到1.2克(12%)白色結晶的2,4-二氯-5-(三氯甲基)吡啶。且測得2.4-二氯-5-(三氯甲基)吡啶的Rf值為0.5。 2,4-Dichloro-5-trichloromethyl-pyridine: (4,6-Dichloropyridin-3-yl)methane (7 g, 39 mmol) was added to a 100 mL round bottom flask. Carbon tetrachloride (200 ml) was added to the mixture. Dichlorothiazide (120 ml) was added as a droplet to the above mixture while stirring. The resulting solution was allowed to react overnight while stirring while maintaining the temperature at reflux. The reaction was monitored by TLC (CH2C12 / PE = 1:1). The mixture was concentrated under vacuum using a rotary dehydrator. The pH was adjusted to 8 by increasing sodium bicarbonate (2N). The resulting solution was extracted twice with 100 mL of EtOAc. The residue was purified by a column eluted with a 1:4 dichloromethane: polyethylene solvent system. 1.2 g (12%) of 2,4-dichloro-5-(trichloromethyl)pyridine as white crystals were obtained. Further, the Rf value of 2.4-dichloro-5-(trichloromethyl)pyridine was measured to be 0.5.

步驟3Step 3

2,4-二氯-5-三氟甲基-吡啶：2,4-Dichloro-5-trifluoromethyl-pyridine:

加入2,4-二氯-5-(三氟甲基)吡啶(0.9克，3.00毫莫耳)至100毫 升的清洗過的密封管內，並維持在一不活潑的氮氣氛圍中。加入SbF5(7克，30.00毫莫耳)到這個混合物。邊攪拌邊使產生的溶液反應1小時，同時溫度維持在150℃的油浴中。在水浴中冷卻反應混合物。藉由加入50克的水/冰熄滅反應混合物。經由添加碳酸氫鈉來調整pH值到8。以100毫升的EtOAc萃取產生的溶液二次，而合併有機層並以硫酸鎂乾燥，然後在真空下使用旋轉脫水器的蒸發方式濃縮。產生0.5克(62.5%)褐色油脂的2,4-二氯-5-(三氟甲基)-吡啶。 Add 2,4-dichloro-5-(trifluoromethyl)pyridine (0.9 g, 3.00 mmol) to 100 m Rin the cleaned sealed tube and maintain it in an inert nitrogen atmosphere. SbF5 (7 grams, 30.00 millimoles) was added to this mixture. The resulting solution was allowed to react for 1 hour while stirring while maintaining the temperature in an oil bath at 150 °C. The reaction mixture was cooled in a water bath. The reaction mixture was quenched by the addition of 50 g of water/ice. The pH was adjusted to 8 via the addition of sodium bicarbonate. The resulting solution was extracted twice with 100 mL of EtOAc and organic layers were combined and dried over magnesium sulfate and evaporated. 0.5 g (62.5%) of a brown oil of 2,4-dichloro-5-(trifluoromethyl)-pyridine was produced.

步驟4Step 4

1-(4-氯-5-三氟甲基-吡啶-2-基)-3,5-二甲基-哌嗪：1-(4-Chloro-5-trifluoromethyl-pyridin-2-yl)-3,5-dimethyl-piperazine:

加入2,4-二氯-5-(三氟甲基)吡啶(800毫克，3.70毫莫耳)至100毫升的圓底燒瓶。加入2,6-二甲基哌嗪(800毫克，7.14毫莫耳)到該混合物。接續加入碳酸鉀(1.0克，7.25毫莫耳)。也加入DMF(15毫升)到該混合物。邊攪拌邊使產生的溶液發生反應2小時，而溫度維持在140℃的油浴中。藉由添加50毫升的冰/水熄滅這反應混合物。以50毫升的EtOAc萃取產生的溶液一次，而合併有機層並以硫酸鎂乾燥，再於真空下使用旋轉脫水器的蒸發方式被蒸發濃縮。透過一具10：1二氯甲烷/甲醇溶劑系統洗提的管柱純化殘餘 物。產生0.2克(18%)黃色固態物的1-(4-氯-5-(三氟甲基)吡啶-2-基)-3,5-二甲基哌嗪。 2,4-Dichloro-5-(trifluoromethyl)pyridine (800 mg, 3.70 mmol) was added to a 100 mL round bottom flask. 2,6-Dimethylpiperazine (800 mg, 7.14 mmol) was added to the mixture. Potassium carbonate (1.0 g, 7.25 mmol) was added. DMF (15 mL) was also added to the mixture. The resulting solution was allowed to react for 2 hours while stirring, while maintaining the temperature in an oil bath at 140 °C. The reaction mixture was quenched by the addition of 50 mL of ice/water. The resulting solution was extracted once with 50 mL of EtOAc. EtOAc was evaporated and evaporated. Purification of residue through a column eluted with a 10:1 dichloromethane/methanol solvent system Things. 0.2 g (18%) of a yellow solid of 1-(4-chloro-5-(trifluoromethyl)pyridin-2-yl)-3,5-dimethylpiperazine was obtained.

步驟5Step 5 4-[4-(4-氯-5-三氟甲基-吡啶-2-基)-2,6-二甲基-哌嗪-1-磺酸基]-二氫茚-2-羧酸：4-[4-(4-Chloro-5-trifluoromethyl-pyridin-2-yl)-2,6-dimethyl-piperazine-1-sulfonic acid]-indoline-2-carboxylic acid :

使用二氫茚-2-羧酸甲酯並根據實施例1步驟1和3的流程製備化合物4-[4-(4-氯-5-三氟甲基-吡啶-2-基)-2,6-二甲基-哌嗪-1-磺酸基]-二氫茚-2-羧酸。¹H NMR(CD₃OD)δ 8.26(s,1H),7.67(d,1H),7.42(d,1H),7.29(t,1H),6.86(s,1H)4.22(m,1H),4.08(d,2H),3.52(d,2H),3.34(m,2H),3.24(m,2H),3.17(dd,2H),1.36(d,6H)。 The compound 4-[4-(4-chloro-5-trifluoromethyl-pyridin-2-yl)-2 was prepared according to the procedure of steps 1 and 3 of Example 1 using methyl indane-2-carboxylate. 6-Dimethyl-piperazin-1-sulfonyl]-indoline-2-carboxylic acid. ¹ H NMR (CD ₃ OD) δ 8.26 (s, 1H), 7.67 (d, 1H), 7.42 (d, 1H), 7.29 (t, 1H), 6.86 (s, 1H) 4.22 (m, 1H), 4.08 (d, 2H), 3.52 (d, 2H), 3.34 (m, 2H), 3.24 (m, 2H), 3.17 (dd, 2H), 1.36 (d, 6H).

實施例108Example 108 生物活性Biological activity

為了解活化PPAR亞型的能力(轉活化試驗)，在CV-1細胞中進行過渡性轉染試驗來篩選化合物。使用一先前建立的嵌合受體系統以與相同合成反應序列上的受體亞型其相對轉錄活性作比較，並預防內生性受體的活化免於結果的解釋複雜化。例子可見於Lehmann,J.M.；Moore,L.B.；Smith-Oliver,T.A；Wilkinson,W.O.；Willson,T.M.；Kliewer,S.A.An antidiabetic Thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor δ (PPARδ),J.Biol.Chem.,1995,270,12953-6。融合老鼠和人類PPAR-alpha、PPAR-gamma和PPAR-delta的配體連接區域到酵母菌轉錄因子GAL4 DNA結合區域。將個別的PPAR嵌合體過渡性地轉染至CV-1細胞，此嵌合體結合具有含4或5個GAL4 DNA結合區域的報導構築體，以驅動螢光酵素的表達。8-16小時後，重新置放細胞到多孔分析盤並將培養液換成無酚-紅並含5%去脂牛血清的DME培養液。重新置放4小時後，以化合物或1%的DMSO處理細胞20-24小時。以Britelite(Perkin Elmer)分析螢光酵素的活性，此分析是依照廠商的說明書，並以Perkin Elmer Viewlux或Molecular Devices Acquest測量(例子請看Kliewer,S.A.et.al. To understand the ability to activate PPAR isoforms (transactivation assay), transient transfection assays were performed in CV-1 cells to screen for compounds. The use of a previously established chimeric receptor system to compare the relative transcriptional activity of receptor subtypes on the same synthetic reaction sequence and to prevent activation of endogenous receptors is not complicated by the interpretation of the results. Examples can be found in Lehmann, JM; Moore, LB; Smith-Oliver, TA; Wilkinson, WO; Willson, TM; Kliewer, SAAn antidiabetic Thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor δ (PPARδ), J. Biol. Chem., 1995 , 270 , 12953-6. The ligand-ligated region of mouse and human PPAR-alpha, PPAR-gamma and PPAR-delta was fused to the yeast transcription factor GAL4 DNA binding region. Individual PPAR chimeras were transiently transfected into CV-1 cells, which bind to reporter constructs containing 4 or 5 GAL4 DNA binding regions to drive expression of luciferase. After 8-16 hours, the cells were repositioned into a multi-well assay plate and the culture was changed to DME medium without phenol-red and containing 5% delipidated bovine serum. After re-disposition for 4 hours, cells were treated with compound or 1% DMSO for 20-24 hours. Fluorescent enzyme activity was analyzed by Britelite (Perkin Elmer) according to the manufacturer's instructions and measured by Perkin Elmer Viewlux or Molecular Devices Acquest (see Kliewer, SAet.al. for an example).

Cell 1995,83,813-819)。使用Rosiglitazone在PPARδ分析中作為正控制。使用Wy-14643和GW7674在PPARδ分析中作為正控制。使用GW501516在PPARδ分析中作為正控制。 Cell 1995, 83, 813-819). Rosiglitazone was used as a positive control in the PPARδ analysis. Wy-14643 and GW7674 were used as positive controls in the PPARδ analysis. GW501516 was used as a positive control in the PPARδ analysis.

檢測實施例1-107的化合物並測量有關他們EC₅₀值以及調控PPAR-alpha、PPAR-gamma及PAR-delta效力的生物活性，如在表二中所示者。 Example 1-107 compound of detection and measurement of EC ₅₀ values and their relevant regulatory PPAR-alpha, PPAR-gamma biological activity and potency of PAR-delta, as those shown in Table II.

從上面所描述，一技巧純熟的人可以簡單的查明發明的必要特徵，惟以上所述者，僅為本創作之較佳實施例而已，當不能限定本創作實施之範圍，即凡依本創作申請專利範圍所作之均等變化與修飾等，皆應仍屬本創作之專利涵蓋範圍意圖保護之範疇。 From the above description, a skilled person can easily ascertain the necessary features of the invention, but the above is only a preferred embodiment of the present invention, and cannot limit the scope of the implementation of the present invention. Equal changes and modifications to the scope of the patent application for creation shall remain within the scope of the intended protection of the scope of the patent.

Claims (45)

一種化合物，係具有式(I)的結構： 其中，A係為具3個原子的飽和或不飽和碳氫化合物鏈，而形成5員環；G₁係共價連接A之一環原子於可利用的位置上，且G₁為一單鍵或-CR¹R²-；R¹及R²係分別獨立選自於由氫、鹵素、C1-C6烷基、C1-C6雜烷基、C1-C6烷氧基及C1-C6全鹵烷基所組成的群組；X₁、X₂及X₃係分別獨立選自於由氫、C1-C6烷基、鹵素、C1-C20全鹵烷基、羥基、C1-C6烷氧基、硝基、氰基及NH₂所組成的群組；G₂係為一環狀基元並具有下述結構： 其中，Y₁係為N； Y₂係為N或C-X₆；X₆係選自於由氫、C1-C20烷基、羥基、C1-C20烷氧基、氰基、鹵素、C1-C6全鹵烷基及NH₂所組成的群組，或者當與Y₂形成一雙鍵時，X₆係為無；X₄及X₅係分別獨立選自於由氫、C1-C20烷基、鹵素、C1-C6全鹵烷基、羥基、C1-C20烷氧基、硝基、氰基、NH₂及CO₂R所組成的群組；R係為C1-C6烷基或氫；p係為2；W係為-CX₄X₅-；G₃係為一單鍵或-CR³R⁴-；R³及R⁴係分別獨立選自於由氫、C1-C6烷基、C1-C6烷氧基、視需要地經取代的芳香基、C1-C6全鹵烷基、硝基及氰基所組成的群組；G₄係選自於由苯基及5或6員單環雜芳香基所組成的群組；其中，5或6員單環雜芳香基中有一或二個原子係選自於N或S的雜原子，且苯基或5或6員單環雜芳香基係為視需要地經取代的；又其中，術語「雜烷基」，意謂由所述碳原子數目以及1至3個選自於氧、氮或硫的雜原子所組成；術語「視需要地經取代的」，意謂經一或多個選自於由下列群組組 成的取代基取代：C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6雜烷基、C1-C6鹵烷基、C2-C6鹵烯基、C2-C6鹵炔基、C3-C6環烷基、苯基、C1-C6烷氧基、苯氧基、C1-C6鹵烷氧基、胺基、C1-C6烷胺基、C1-C6烷硫基、苯基-硫-、氧基、C1-C6羧酯基、C1-C6羧基醯胺基、C1-C6醯氧基、氫、鹵素、CN、NO₂、NH₂、N₃、NHCH₃、N(CH₃)₂、SH、SCH₃、OH、OCH₃、OCF₃、CH₃、CF₃、C(O)CH₃、CO₂CH₃、CO₂H、C(O)NH₂、吡啶基、噻吩基、呋喃基、C1-C6胺基甲酯基及C1-C6脲基。 A compound having the structure of formula (I): Wherein, A is a saturated or unsaturated hydrocarbon chain having 3 atoms, and forms a 5-membered ring; G ₁ is covalently bonded to a ring atom of A at an available position, and G ₁ is a single bond or -CR ¹ R ² -; R ¹ and R ² are each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy and C1-C6 perhaloalkyl. a group consisting of; X ₁ , X ₂ and X ₃ are each independently selected from hydrogen, C1-C6 alkyl, halogen, C1-C20 perhaloalkyl, hydroxy, C1-C6 alkoxy, nitro a group consisting of cyano and NH ₂ ; G ₂ is a cyclic element and has the following structure: Wherein Y ₁ is N; Y ₂ is N or CX ₆ ; X ₆ is selected from hydrogen, C1-C20 alkyl, hydroxyl, C1-C20 alkoxy, cyano, halogen, C1-C6 a group consisting of a haloalkyl group and a NH ₂ group, or when a double bond is formed with Y ₂ , the X ₆ system is absent; and the X ₄ and X ₅ groups are independently selected from hydrogen, a C1-C20 alkyl group, and a halogen. a group consisting of C1-C6 perhaloalkyl, hydroxy, C1-C20 alkoxy, nitro, cyano, NH ₂ and CO ₂ R; R is a C1-C6 alkyl or hydrogen; p is 2; W is -CX ₄ X ₅ -; G ₃ is a single bond or -CR ³ R ⁴ -; R ³ and R ⁴ are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 a group consisting of an alkoxy group, an optionally substituted aryl group, a C1-C6 perhaloalkyl group, a nitro group, and a cyano group; the G ₄ group is selected from a phenyl group and a 5- or 6-membered monocyclic aromatic group. a group consisting of: wherein one or two of the 5 or 6 membered monocyclic heteroaryl groups are selected from a hetero atom of N or S, and the phenyl or 5 or 6 membered monocyclic heteroaryl is Desirably substituted; wherein, the term "heteroalkyl" means the number of carbon atoms and 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur. Composition; the term "optionally substituted" means substituted by one or more substituents selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl. , C1-C6 heteroalkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, phenyl, C1-C6 alkoxy, phenoxy, C1-C6 haloalkoxy group, amine group, C1-C6 alkylamino group, C1-C6 alkylthio group, phenyl-sulfur-, oxy group, C1-C6 carboxylate group, C1-C6-carboxy-nonylamino group, C1 -C6 methoxy, hydrogen, halogen, CN, NO ₂ , NH ₂ , N ₃ , NHCH ₃ , N(CH ₃ ) ₂ , SH, SCH ₃ , OH, OCH ₃ , OCF ₃ , CH ₃ , CF ₃ , C(O)CH ₃ , CO ₂ CH ₃ , CO ₂ H, C(O)NH ₂ , pyridyl, thienyl, furyl, C1-C6 aminomethyl ester and C1-C6 urea. 如請求項第1項所述之化合物，其具有下列化學式： The compound of claim 1, which has the following chemical formula: 如請求項第2項所述之化合物，其具有下列化學式： The compound of claim 2, which has the following chemical formula: 如請求項第2項所述之化合物，其具有下列化學式： The compound of claim 2, which has the following chemical formula: 如請求項第1項所述之化合物，其中G₃係為一單鍵。 The compound of claim 1, wherein G ₃ is a single bond. 如請求項第1項所述之化合物，其中G₄係經鹵素、C1-C6全氟烷基、C1-C6全氟烷氧基、C1-C6一氟烷氧基或C1-C6二氟烷氧基單一或雙重取代。 The compound of claim 1, wherein the G ₄ is halogen, C1-C6 perfluoroalkyl, C1-C6 perfluoroalkoxy, C1-C6-fluoroalkoxy or C1-C6 difluoroalkane. The oxy group is mono- or double-substituted. 如請求項第1項所述之化合物，其中Y₂係為N。 The compound of claim 1, wherein the Y ₂ is N. 如請求項第1項所述之化合物，其中G₄係為苯基或吡啶基。 The compound of claim 1, wherein G ₄ is phenyl or pyridyl. 如請求項第8項所述之化合物，其中G₄係經鹵素、C1-C6全氟烷基、C1-C6全氟烷氧基、C1-C6一氟烷氧基或C1-C6二氟烷氧基單一或雙重取代。 The compound of claim 8, wherein the G ₄ is halogen, C1-C6 perfluoroalkyl, C1-C6 perfluoroalkoxy, C1-C6-fluoroalkoxy or C1-C6 difluoroalkane. The oxy group is mono- or double-substituted. 如請求項第1項所述之化合物，其中R¹和R²係分別獨立選自於由氫、甲基、乙基及丙基所組成的群組。 The compound of claim 1, wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen, methyl, ethyl and propyl. 如請求項第10項所述之化合物，其中R¹和R²係為氫。 The compound of claim 10, wherein R ¹ and R ² are hydrogen. 如請求項第1項所述之化合物，其中X₁、X₂及X₃係分別獨立選自於由氫、C1-C6烷基、鹵素及C1-C20全鹵烷基所組成的群組。 The compound of claim 1, wherein X ₁ , X ₂ and X ₃ are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen and C1-C20 perhaloalkyl. 如請求項第12項所述之化合物，其中X₁、X₂及X₃係分別獨立選自於由氫、甲基所組成的群組。 The compound of claim 12, wherein X ₁ , X ₂ and X ₃ are each independently selected from the group consisting of hydrogen and methyl. 一種化合物，係具有選自於由下列群組所組成的結構： 其中，G₁係為一單鍵或-CR¹R2-；R¹及R²係分別獨立選自於由氫、氟、C1-C6烷基、C1-C6雜烷基、C1-C6烷氧基及C1-C6全鹵烷基所組成的群組；X₁、X₂及X₃係分別獨立選自於由氫、C1-C6烷基、鹵素、C1-C20全鹵烷基、羥基、C1-C6烷氧基、硝基、氰基及NH₂所組成的群 全鹵烷基、羥基、C1-C6烷氧基、硝基、氰基及NH₂所組成的群組；X₄及X₅係分別獨立選自於由氫、C1-C20烷基、鹵素、C1-C6全鹵烷基、羥基、C1-C20烷氧基、硝基、氰基、NH₂及CO₂R所組成的群組；R係為C1-C6烷基或氫；G₃係為一單鍵或-CR³R⁴-；R³與R⁴係分別獨立選自於由氫、C1-C6烷基、C1-C6烷氧基、視需要地經取代的芳香基、C1-C6全鹵烷基、硝基及氰基所組成的群組；G₄係選自於由苯基及5或6員單環雜芳香基所組成的群組；其中，5或6員單環雜芳香基中有一或二個原子係選自於N或S的雜原子，且苯基或5或6員單環雜芳香基係為視需要地經取代的；又其中，術語「雜烷基」，意謂由所述碳原子數目以及1至3個選自於氧、氮或硫的雜原子所組成；術語「視需要地經取代的」，意謂經一或多個選自於由下列群組組成的取代基取代：C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6雜烷基、C1-C6鹵烷基、C2-C6鹵烯基、C2-C6鹵炔基、C3-C6環烷基、苯基、C1-C6烷氧基、苯氧基、C1-C6鹵烷氧基、胺基、C1-C6烷胺基、C1-C6烷硫基、苯基-硫-、氧基、C1-C6羧酯基、 N₃、NHCH₃、N(CH₃)₂、SH、SCH₃、OH、OCH₃、OCF₃、CH₃、CF₃、C(O)CH₃、CO₂CH₃、CO₂H、C(O)NH₂、吡啶基、噻吩基、呋喃基、C1-C6胺基甲酯基及C1-C6脲基。 A compound having a structure selected from the group consisting of: Wherein G ₁ is a single bond or -CR ¹ R2-; R ¹ and R ² are each independently selected from the group consisting of hydrogen, fluorine, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy a group consisting of a C1-C6 perhaloalkyl group; X ₁ , X ₂ and X ₃ are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, C1-C20 perhaloalkyl, hydroxy, group C1-C6 alkoxy group, a nitro group, a cyano group consisting of NH ₂ and perhaloalkyl, hydroxy, C1-C6 alkoxy, nitro, cyano and consisting of NH _2; X ₄ and X ₅ is independently selected from the group consisting of hydrogen, C1-C20 alkyl, halogen, C1-C6 perhaloalkyl, hydroxy, C1-C20 alkoxy, nitro, cyano, NH ₂ and CO ₂ R a group; R is a C1-C6 alkyl group or hydrogen; G ₃ is a single bond or -CR ³ R ⁴ -; R ³ and R ⁴ are each independently selected from hydrogen, C1-C6 alkyl, a group consisting of a C1-C6 alkoxy group, an optionally substituted aryl group, a C1-C6 perhaloalkyl group, a nitro group and a cyano group; the G ₄ group is selected from the group consisting of a phenyl group and a 5 or 6 member a group consisting of a cycloheteroaryl group; wherein one or two of the 5 or 6 membered monocyclic heteroaryl groups are selected from a hetero atom of N or S, and the phenyl group or a 5 or 6 membered single ring An aromatic group is optionally substituted; wherein, the term "heteroalkyl" means consisting of the number of carbon atoms and one to three heteroatoms selected from oxygen, nitrogen or sulfur; the term ""Substituted as desired" means substituted by one or more substituents selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hetero Alkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, phenyl, C1-C6 alkoxy, phenoxy, C1-C6 haloalkyl alkoxy, amino, C1-C6 alkyl group, C1-C6 alkylthio, phenyl - S -, oxo, C1-C6 carboxylic acid ester _{group, N 3, NHCH 3, N} (CH 3) 2, SH , SCH ₃ , OH, OCH ₃ , OCF ₃ , CH ₃ , CF ₃ , C(O)CH ₃ , CO ₂ CH ₃ , CO ₂ H, C(O)NH ₂ , pyridyl, thienyl, furyl, C1-C6 aminomethyl ester group and C1-C6 urea group. 如請求項第14項所述之化合物，其中X₁及X₂中至少一者不為氫。 The compound of claim 14, wherein at least one of X ₁ and X ₂ is not hydrogen. 如請求項第15項所述之化合物，其中X₄及X₅中至少一者係為C1-C6烷基。 The compound of claim 15, wherein at least one of X ₄ and X ₅ is a C1-C6 alkyl group. 如請求項第16項所述之化合物，其中X₄及X₅中至少一者係為甲基。 The compound of claim 16, wherein at least one of X ₄ and X ₅ is a methyl group. 如請求項第17項所述之化合物，其中X₄及X₅均為甲基。 The compound of claim 17, wherein X ₄ and X ₅ are both methyl. 如請求項第18項所述之化合物，其中X₄及X₅係分別連接至哌嗪環的2號及6號位置。 The compound of claim 18, wherein X ₄ and X ₅ are attached to positions 2 and 6 of the piperazine ring, respectively. 如請求項第18項所述之化合物，其中X₄及X₅係分別連接至哌嗪環的3號及5號位置。 The compound of claim 18, wherein X ₄ and X ₅ are attached to positions 3 and 5 of the piperazine ring, respectively. 如請求項第18項所述之化合物，其中X₄及X₅係分別連接至哌 嗪環的5號及6號位置。 The compound of claim 18, wherein X ₄ and X ₅ are attached to positions 5 and 6 of the piperazine ring, respectively. 如請求項第18項所述之化合物，其中X₄及X₅係為順式排列。 The compound of claim 18, wherein X ₄ and X ₅ are in cis arrangement. 如請求項第22項所述之化合物，其係為4-[順-2,6-二甲基-4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-羧酸。 The compound of claim 22, which is 4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonate ]-Indoline-2-carboxylic acid. 如請求項第22項所述之化合物，其係為4-[順-2,6-二甲基-4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-(R)-羧酸。 The compound of claim 22, which is 4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonate ]-Indoline-2-(R)-carboxylic acid. 如請求項第22項所述之化合物，其係為4-[順-2,6-二甲基-4-(4-三氟甲氧基-苯基)-哌嗪-1-磺酸基]-二氫茚-2-(S)-羧酸。 The compound of claim 22, which is 4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonate ]-Indoline-2-(S)-carboxylic acid. 如請求項第14項所述之化合物，其中R¹及R²係分別獨立選自於由氫、甲基、乙基及丙基所組成的群組。 The compound of claim 14, wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen, methyl, ethyl and propyl. 如請求項第26項所述之化合物，其中R¹及R²係為氫。 The compound of claim 26, wherein R ¹ and R ² are hydrogen. 如請求項第14項所述之化合物，其中X₁、X₂及X₃係分別獨立選自於由氫、C1-C6烷基、鹵素及C1-C6烷氧基所組成的群組。 The compound of claim 14, wherein X ₁ , X ₂ and X ₃ are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, and C1-C6 alkoxy. 如請求項第14項所述之化合物，其中G₃係為一單鍵。 The compound of claim 14, wherein G ₃ is a single bond. 如請求項第14項所述之化合物，其中G₄係具有選自於由下列群組所組成的結構： 其中，q係為1、2或3；X₈及X₉係分別獨立選自於由氫、C1-C6烷基、鹵素、C1-C6全鹵烷基、C1-C6全氟烷氧基、C1-C6一氟烷氧基、C1-C6二氟烷氧基、羥基、C1-C6烷氧基、硝基、氰基、NH₂及CO₂CH₃所組成的群組。 The compound of claim 14, wherein the G ₄ system has a structure selected from the group consisting of: Wherein q is 1, 2 or 3; X ₈ and X ₉ are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, C1-C6 perhaloalkyl, C1-C6 perfluoroalkoxy, a group consisting of C1-C6 monofluoroalkoxy, C1-C6 difluoroalkoxy, hydroxy, C1-C6 alkoxy, nitro, cyano, NH ₂ and CO ₂ CH ₃ . 一種化合物，係為4-[2,6-順-二甲基-4-(4-三氯甲氧-苯基)-哌嗪-1-磺酸基]-二氫茚-2-(R)-羧酸-對甲苯亞磺酸鹽。 A compound which is 4-[2,6-cis-dimethyl-4-(4-trichloromethoxy-phenyl)-piperazine-1-sulfonyl]-indoline-2-(R) )-carboxylic acid-p-toluenesulfinate. 一種化合物，係具有選自於由下列群組所組成的結構： A compound having a structure selected from the group consisting of: 如請求項第1、23、24、25及31項中任一項所述之化合物，其具細胞中經過渡性轉染試驗得到EC₅₀少於5μM值。 The requested item and a compound according to any of the first 31 1,23,24,25 which has cells by transient transfection experiments to give a value of less than 5μM EC _50. 一種hPPAR-δ調控劑，係含如請求項第1、23、24、25及31項中任一項所述之化合物。 A hPPAR-delta modulator comprising the compound of any one of claims 1, 23, 24, 25 and 31. 一種藥學組成物，係含如請求項第1、23、24、25及31項中任一項所述之化合物。 A pharmaceutical composition comprising the compound of any one of claims 1, 23, 24, 25 and 31. 如請求項第35項所述之藥學組成物，更含有藥學上可接受的載劑或賦形劑。 The pharmaceutical composition of claim 35, further comprising a pharmaceutically acceptable carrier or excipient. 一種如請求項第1、23、24、25及31項中任一項所述之化合物用於製備藥劑的用途，藥劑係用於治療hPPAR-δ所調控的疾病或改善hPPAR-δ所調控的狀態。 The use of a compound according to any one of claims 1, 23, 24, 25 and 31 for the preparation of a medicament for the treatment of a disease modulated by hPPAR-δ or for the modulation of hPPAR-δ status. 如請求項第37項所述之用途，其中hPPAR-δ所調控的疾病或狀態係為血脂異常、新陳代謝X症候群、心臟衰竭、高膽固醇血症、心血管疾病、第二型糖尿病、第一型糖尿病、胰島素抗性、高血脂、肥胖、厭食症、貪食症、發炎反應或神經性厭食症。 The use according to claim 37, wherein the disease or condition regulated by hPPAR-δ is dyslipidemia, metabolic X syndrome, heart failure, hypercholesterolemia, cardiovascular disease, type 2 diabetes, first type Diabetes, insulin resistance, hyperlipidemia, obesity, anorexia, bulimia, inflammatory response or anorexia nervosa. 如請求項第38項所述之用途，其中發炎反應係為類風濕性關 節炎、氣喘、骨關節炎或自體免疫疾病。 The use of claim 38, wherein the inflammatory response is rheumatoid Inflammation, asthma, osteoarthritis or autoimmune diseases. 一種如請求項第1、23、24、25及31項中任一項所述之化合物用於製備藥劑的用途，藥劑係於患者需要時用於提升其HDL。 A use of a compound according to any one of claims 1, 23, 24, 25 and 31 for the preparation of a medicament for use in boosting HDL of a patient. 一種如請求項第1、23、24、25及31項中任一項所述之化合物用於製備藥劑的用途，藥劑係於患者需要時用於治療其第二型糖尿病、降低其胰島素抗性或降低其血壓。 A use of a compound according to any one of claims 1, 23, 24, 25 and 31 for the preparation of a medicament for the treatment of a second type of diabetes and a reduction of insulin resistance thereof when the patient desires Or lower its blood pressure. 一種如請求項第1、23、24、25及31項中任一項所述之化合物用於製備藥劑的用途，藥劑係於患者需要時用於降低其LDLc。 A use of a compound according to any one of claims 1, 23, 24, 25 and 31 for the preparation of a medicament for use in reducing LDLc when required by a patient. 一種如請求項第1、23、24、25及31項中任一項所述之化合物用於製備藥劑的用途，藥劑係於患者需要時用於將其LDL分子大小從低密度轉換成正常密度。 A use of a compound according to any one of claims 1, 23, 24, 25 and 31 for the preparation of a medicament for converting a LDL molecular size from a low density to a normal density when required by a patient . 一種如請求項第1至32項任一項所述之化合物用於製備藥劑的用途，藥劑係於患者需要時用於治療動脈粥狀硬化疾病，而動脈粥狀硬化疾病包含血管疾病、冠狀心臟疾病、腦血管疾病或末梢血管疾病。 The use of a compound according to any one of claims 1 to 32 for the preparation of a medicament for treating an atherosclerotic disease when the patient desires, and the atherosclerotic disease comprises a vascular disease, a coronary heart Disease, cerebrovascular disease or peripheral vascular disease. 一種如請求項第1至32項任一項所述之化合物用於製備藥劑的 用途，藥劑係用於治療肥胖、糖尿病、高胰島素血症、新陳代謝X症候群、多囊性卵巢症候群、更年期、氧化壓力相關的失調、組織傷害的發炎反應、肺氣腫的發病、局部缺血相關的器官傷害、阿黴素引起的心臟傷害、藥物引起的肝中毒、動脈硬化或高毒性的肺部傷害。 A compound according to any one of claims 1 to 32 for use in the preparation of a medicament Uses, for the treatment of obesity, diabetes, hyperinsulinemia, metabolic X syndrome, polycystic ovarian syndrome, menopause, oxidative stress-related disorders, inflammatory response to tissue damage, onset of emphysema, ischemia-related Organ damage, heart damage caused by doxorubicin, drug-induced liver toxicity, arteriosclerosis or highly toxic lung damage.