TWI449702B - Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents - Google Patents

Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents Download PDF

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TWI449702B
TWI449702B TW101124999A TW101124999A TWI449702B TW I449702 B TWI449702 B TW I449702B TW 101124999 A TW101124999 A TW 101124999A TW 101124999 A TW101124999 A TW 101124999A TW I449702 B TWI449702 B TW I449702B
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phenyl
cycloalkyl
heteroaryl
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TW201402568A (en
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Rajan Anand
James M Apgar
Tesfaye Biftu
Ping Chen
Lin Chu
Vincent J Colandrea
Guizhen Dong
James F Dropinski
Danqing Feng
Jacqueline D Hicks
Jinlong Jiang
Alexander J Kim
Kenneth J Leavitt
Bing Li
Xiaoxia Qian
Iyassu Sebhat
Lan Wei
Robert R Wilkening
Zhicai Wu
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Merck Sharp & Dohme
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作為抗糖尿病劑之新穎環氮雜苯并咪唑衍生物Novel cyclic azabenzimidazole derivatives as antidiabetic agents

糖尿病之特徵為在空腹狀態下或在口服葡萄糖耐受性測試期間投與葡萄糖之後血漿葡萄糖含量升高(高血糖症)。在1型糖尿病或胰島素依賴性糖尿病(IDDM)中，患者產生極少或不產生胰島素，而胰島素為調控葡萄糖之利用之激素。在2型糖尿病或非胰島素依賴性糖尿病(NIDDM)中，胰臟中之胰島細胞仍產生胰島素。2型糖尿病患者對胰島素在包括肌肉、肝臟及脂肪組織之主要胰島素敏感性組織中刺激葡萄糖及脂質代謝的作用具有抗性。此等患者常常具有正常的胰島素含量，且可能患有高胰島素血症(血漿胰島素含量升高)，因為其藉由分泌較高量之胰島素來補償胰島素之有效性降低(Polonsky,Int.J.Obes.Relat.Metab.Disord.24增刊2：S29-31,2000)。胰島素抗性並非主要由胰島素受體之數目減少引起，而是由尚未完全瞭解之胰島素受體結合後缺陷引起。此對胰島素之反應性的缺乏使得胰島素介導之對肌肉中葡萄糖吸收、氧化及儲存的活化不足，且使得胰島素介導之對脂肪組織中脂肪分解以及對肝臟中葡萄糖產生及分泌的抑制不足。最終，患者可能因無法適當地補償胰島素抗性而患上糖尿病。在人類中，胰小島(pancreatic islet)內之β細胞最初藉由增加胰島素輸出來補償胰島素抗性。2型糖尿病因β細胞群之增加不足(或實際上衰減)而發作顯然係由於β細胞凋亡相對於非糖尿病性胰島素抗性個體增加之故(Butler等人，Diabetes 52：102-110,2003)。Diabetes is characterized by elevated plasma glucose levels (hyperglycemia) following administration of glucose in the fasting state or during the oral glucose tolerance test. In type 1 diabetes or insulin-dependent diabetes mellitus (IDDM), patients produce little or no insulin, and insulin is a hormone that regulates the utilization of glucose. In type 2 diabetes or non-insulin dependent diabetes (NIDDM), islet cells in the pancreas still produce insulin. Type 2 diabetic patients are resistant to the effects of insulin on glucose and lipid metabolism in major insulin-sensitive tissues including muscle, liver and adipose tissue. These patients often have normal insulin levels and may have hyperinsulinemia (increased plasma insulin levels) because they compensate for the reduced effectiveness of insulin by secreting higher amounts of insulin (Polonsky, Int. J. Obes.Relat.Metab.Disord.24 Supplement 2: S29-31, 2000). Insulin resistance is not primarily caused by a decrease in the number of insulin receptors, but by defects in insulin receptor binding that are not fully understood. This lack of reactivity to insulin renders insulin-mediated activation of glucose uptake, oxidation, and storage in muscle insufficient, and insulin-mediated inhibition of lipolysis in adipose tissue and inhibition of glucose production and secretion in the liver. Eventually, the patient may develop diabetes due to the inability to properly compensate for insulin resistance. In humans, beta cells in the pancreatic islet initially compensate for insulin resistance by increasing insulin output. The onset of type 2 diabetes due to insufficient (or indeed attenuated) increase in beta cell population is apparently due to an increase in beta cell apoptosis relative to non-diabetic insulin resistant individuals (Butler et al., Diabetes) 52: 102-110, 2003).

持久或不受控制之高血糖症與增加且早發之發病率及死亡率相關。異常之葡萄糖穩態常常與肥胖症、高血壓，及脂質、脂蛋白及脂蛋白元代謝改變，以及其他代謝疾病及血液動力學疾病直接及間接相關。2型糖尿病患者患上大血管及微血管併發症之風險顯著增加，該等併發症包括動脈粥樣硬化、冠狀動脈性心臟病、中風、周邊血管疾病、高血壓、腎病變、神經病變及視網膜病變。因此，對葡萄糖穩態、脂質代謝、肥胖症及高血壓的有效治療性控制在糖尿病之臨床管理及治療方面至關重要。Prolonged or uncontrolled hyperglycemia is associated with increased morbidity and mortality from early onset. Abnormal glucose homeostasis is often directly and indirectly related to obesity, hypertension, and metabolic changes in lipids, lipoproteins, and lipoproteins, as well as other metabolic and hemodynamic diseases. Patients with type 2 diabetes have a significantly increased risk of macrovascular and microvascular complications, including atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. . Therefore, effective therapeutic control of glucose homeostasis, lipid metabolism, obesity, and hypertension is critical in the clinical management and treatment of diabetes.

具有胰島素抗性之患者常常展現若干症狀，統稱為X症候群或代謝症候群。患有代謝症候群之患者發生動脈粥樣硬化及冠狀動脈性心臟病之風險增加。Patients with insulin resistance often exhibit several symptoms, collectively referred to as X syndrome or metabolic syndrome. Patients with metabolic syndrome have an increased risk of developing atherosclerosis and coronary heart disease.

存在若干可用於2型糖尿病之治療，其各自具有自身的侷限及潛在風險。身體鍛煉及減少飲食熱量攝入常常顯著改善糖尿病病狀，且為通常所推薦之對2型糖尿病及與胰島素抗性相關之糖尿病前期病狀的第一線治療。因久坐生活方式根深蒂固及過量消耗食物、尤其含有大量脂肪及碳水化合物之食物，此治療之順應性一般極差。對糖尿病之藥理學治療已主要集中於三個病理生理學領域：(1)肝臟葡萄糖產生(雙胍，諸如苯乙雙胍(phenformin)及二甲雙胍(metformin))；(2)胰島素抗性(PPAR促效劑，諸如羅格列酮(rosiglitazone)、曲格列酮(troglitazone)、恩格列酮(engliazone)、巴格列酮(balaglitazone)、MCC-555、萘格 列酮(netoglitazone)、T-131、LY-300512、LY-818及吡格列酮(pioglitazone))；(3)胰島素分泌(磺醯脲，諸如甲苯磺丁脲(tolbutamide)、格列吡嗪(glipizide)及格列美脲(glimipiride))；(4)腸促胰島素激素模擬物(GLP-1衍生物及類似物，諸如艾塞那肽(exenatide)及利拉魯肽(liraglitide))；及(5)腸促胰島素激素降解抑制劑(DPP-4抑制劑，諸如西他列汀(sitagliptin))。There are several treatments available for type 2 diabetes, each with its own limitations and potential risks. Physical exercise and reduced calorie intake often significantly improve the condition of diabetes and are the first recommended first-line treatment for type 2 diabetes and pre-diabetic conditions associated with insulin resistance. The responsiveness of this treatment is generally poor due to sedentary lifestyle entrenched and excessive consumption of food, especially foods that contain large amounts of fat and carbohydrates. Pharmacological treatment of diabetes has focused on three areas of pathophysiology: (1) hepatic glucose production (biguana, such as phenformin and metformin); (2) insulin resistance (PPAR efficacies) Agents such as rosiglitazone, troglitazone, engliazone, bagliglitazone, MCC-555, naprox Intravenous secretion (sulfonylurea, such as tolbutamide, glipizide) And glimepiride; (4) incretin hormone mimetics (GLP-1 derivatives and analogs, such as exenatide and liraglitide); and (5) Incretin hormone degradation inhibitor (DPP-4 inhibitor, such as sitagliptin).

許多當前的糖尿病治療具有不當副作用。苯乙雙胍及二甲雙胍可誘發乳酸酸中毒、噁心/嘔吐及腹瀉。二甲雙胍相比苯乙雙胍具有較低副作用風險且被廣泛地開處方用於治療2型糖尿病。當前投入市場之PPAR γ促效劑在減少血漿葡萄糖及血色素A1C方面適度有效，且不能大幅改良脂質代謝或脂質型態。磺醯脲及相關胰島素促泌素即使在葡萄糖含量較低時亦可促使胰島素分泌，從而導致低血糖症，此在嚴重狀況下可能致命。因此，必須小心控制胰島素促泌素的投與。仍需要藉由新穎作用機制起作用且展現較少副作用之糖尿病治療。Many current diabetes treatments have undue side effects. Phenformin and metformin can induce lactic acidosis, nausea/vomiting, and diarrhea. Metformin has a lower risk of side effects than phenformin and is widely prescribed for the treatment of type 2 diabetes. The currently marketed PPAR gamma agonist is moderately effective in reducing plasma glucose and hemoglobin A1C and does not significantly improve lipid metabolism or lipid profile. Sulfaquine urea and related insulin secretagogues promote insulin secretion even at low glucose levels, leading to hypoglycemia, which can be fatal under severe conditions. Therefore, care must be taken to control the administration of insulin secretagogue. There is still a need for diabetes treatment that works by a novel mechanism of action and exhibits fewer side effects.

AMP活化之蛋白激酶(AMPK)已被鑑別為碳水化合物及脂肪酸代謝之調控劑，其對環境及營養性應激作出反應來幫助維持能量平衡。有跡象表明，AMPK之活化藉由減少葡萄糖生成及重新脂質生成(脂肪酸及膽固醇合成)以及藉由增加脂肪酸氧化及骨骼肌葡萄糖吸收而對脂質及葡萄糖代謝產生許多有利作用。藉由AMPK引起之磷酸化抑制ACC會使脂肪酸合成減少及脂肪酸氧化增加，而藉由 AMPK引起之磷酸化抑制HMG-CoA還原酶會使膽固醇合成減少(Carling,D.等人，FEBS Letters 223：217(1987))。AMP-activated protein kinase (AMPK) has been identified as a regulator of carbohydrate and fatty acid metabolism that responds to environmental and trophic stress to help maintain energy balance. There are indications that AMPK activation has many beneficial effects on lipid and glucose metabolism by reducing glucose production and re-lipid production (fatty acid and cholesterol synthesis) and by increasing fatty acid oxidation and skeletal muscle glucose uptake. Inhibition of ACC by phosphorylation by AMPK results in reduced fatty acid synthesis and increased fatty acid oxidation. Phosphorylation by AMPK inhibits HMG-CoA reductase and reduces cholesterol synthesis (Carling, D. et al., FEBS Letters 223:217 (1987)).

在肝臟中，AMPK活化使得脂肪酸及膽固醇合成減少，從而抑制肝臟葡萄糖產生且增加脂肪酸氧化。已顯示，AMP活化之蛋白激酶在肝臟及肌肉中經由甘油-3-磷酸醯基轉移酶調控三醯基甘油合成及脂肪酸氧化(Muoio,D.M.等人，Biochem.J.338：783(1999))。已顯示，AMPK之另一受質，亦即肝細胞核因子-4α，涉及於1型成年發病型糖尿病中(Leclerc,I.等人，Diabetes 50：1515(2001))。據信經AMPK活化來調控之其他過程包括刺激骨骼肌中之葡萄糖轉運以及調控肝臟中脂肪酸及葡萄糖代謝之關鍵基因(Hardie,D.G.及Hawley,S.A.,Bioessays 23：1112(2001)；Kemp,B.E.等人，Biochem.Soc.Transactions 31：162(2003)；Musi,N.及Goodyear,L.J..Current Drug Targets-Immune,Endocrine and Metabolic Disorders 2：119(2002)；Lochhead,P.A.等人，Diabetes 49：896(2000)；及Zhou,G.等人，J.of Clin.Invest.108：1167(2001)。In the liver, AMPK activation reduces fatty acid and cholesterol synthesis, thereby inhibiting hepatic glucose production and increasing fatty acid oxidation. It has been shown that AMP-activated protein kinase regulates trimethyl glycerol synthesis and fatty acid oxidation via glycerol-3-phosphate thiotransferase in the liver and muscle (Muoio, DM et al, Biochem. J. 338: 783 (1999)) . It has been shown that another receptor for AMPK, hepatocyte nuclear factor-4 alpha, is involved in type 1 adult onset diabetes (Leclerc, I. et al., Diabetes 50: 1515 (2001)). Other processes that are believed to be regulated by AMPK activation include stimulation of glucose transport in skeletal muscle and regulation of key genes in fatty acids and glucose metabolism in the liver (Hardie, DG and Hawley, SA, Bioessays 23:1112 (2001); Kemp, BE, etc. Human, Biochem. Soc. Transactions 31: 162 (2003); Musi, N. and Goodyear, LJ. Current Drug Targets-Immune, Endocrine and Metabolic Disorders 2: 119 (2002); Lochhead, PA et al., Diabetes 49: 896 (2000); and Zhou, G. et al., J. of Clin. Invest. 108: 1167 (2001).

活體內研究已證實，在肥胖症及2型糖尿病之齧齒動物模型中短期及長期投與AICAR(一種AMPK活化劑)均產生以下有利作用：1)胰島素抗性糖尿病(ob/ob)小鼠中之葡萄糖穩態改良；2)ob/ob及db/db小鼠中之血糖濃度降低且在投藥8週後血糖下降35%；及3)在顯示胰島素抗性症候群特徵之大鼠中代謝紊亂減少及血壓下降(Bergeron,R.等人，Diabetes 50：1076(2001)；Song,S.M.等人，Diabetologia 45：56(2002)；Halseth,A.E.等人，Biochem.and Biophys.Res.Comm.294：798(2002)；及Buhl,E.S.等人，Diabetes 51：2199(2002))。在肥胖型Zucker(fa/fa)大鼠中進行7週AICAR投藥之另一研究使得血漿三酸甘油酯及游離脂肪酸減少；HDL膽固醇增加；及葡萄糖代謝正常化，如由口服葡萄糖耐受性測試所評估(Minokoshi,Y.等人，Nature 415：339(2002))。在轉殖基因小鼠之骨骼肌中表現顯性負性AMPK已證實，AICAR對刺激葡萄糖轉運之作用取決於AMPK活化(Mu,J.等人，Molecular Cell 7：1085(2001))。In vivo studies have demonstrated that short-term and long-term administration of AICAR (an AMPK activator) in the rodent model of obesity and type 2 diabetes produces the following beneficial effects: 1) Insulin-resistant diabetes (ob/ob) mice Glucose homeostasis improvement; 2) decreased blood glucose concentration in ob/ob and db/db mice and decreased blood glucose by 35% after 8 weeks of administration; and 3) decreased metabolic disorder in rats showing insulin resistance syndrome characteristics And blood pressure drop (Bergeron, R. et al., Diabetes 50: 1076 (2001); Song, SM et al, Diabetologia 45:56 (2002); Halseth, A.E., et al., Biochem. and Biophys. Res. Comm. 294: 798 (2002); and Buhl, E.S. et al., Diabetes 51: 2199 (2002)). Another study of 7-week AICAR administration in obese Zucker (fa/fa) rats resulted in a decrease in plasma triglycerides and free fatty acids; an increase in HDL cholesterol; and normalization of glucose metabolism, as measured by oral glucose tolerance Assessed (Minokoshi, Y. et al., Nature 415:339 (2002)). The presence of dominant negative AMPK in skeletal muscle of transgenic mice has demonstrated that the effect of AICAR on stimulating glucose transport is dependent on AMPK activation (Mu, J. et al., Molecular Cell 7: 1085 (2001)).

新近資料亦表明，AMPK活化涉及於抗糖尿病藥物二甲雙胍之降糖及降脂作用中。已顯示，糖尿病藥物二甲雙胍可在高濃度下於活體內活化AMPK(Zhou,G.等人，J.of Clin.Invest.108：1167(2001)；Musi,N.等人，Diabetes 51：2074(2002))。Recent data also indicate that AMPK activation is involved in the hypoglycemic and lipid-lowering effects of the antidiabetic drug metformin. It has been shown that the diabetes drug metformin can activate AMPK in vivo at high concentrations (Zhou, G. et al, J. of Clin. Invest. 108: 1167 (2001); Musi, N. et al., Diabetes 51: 2074 ( 2002)).

基於此等研究，預期活體內活化肝臟中之AMPK可使肝臟葡萄糖輸出減少、總體葡萄糖穩態改良、脂肪酸及膽固醇合成減少，及脂肪酸氧化增加。預期刺激骨骼肌中之AMPK使得葡萄糖吸收及脂肪酸氧化增加，從而引起葡萄糖穩態改良及胰島素作用改良。最終，所引起之能量消耗增加應使體重減輕。亦已報導血壓降低為AMPK活化之結果。Based on these studies, it is expected that activation of AMPK in the liver in vivo can reduce hepatic glucose output, overall glucose homeostasis, decreased fatty acid and cholesterol synthesis, and increased fatty acid oxidation. It is expected that stimulating AMPK in skeletal muscle will increase glucose absorption and fatty acid oxidation, resulting in glucose homeostasis and insulin action improvement. Ultimately, the resulting increase in energy consumption should result in weight loss. It has also been reported that blood pressure reduction is the result of AMPK activation.

脂肪酸合成增加為許多腫瘤細胞之特徵，因此，經由AMPK活化來減少脂肪酸合成亦可適用作癌症療法。AMPK活化亦可適用於治療腦部缺血事件(Blazquez,C.等 人，J.Neurochem.73：1674(1999))；防止反應性氧物質造成損害(Zhou,M.等人，Am.J.Physiol.Endocrinol.Metab.279：E622(2000))；及改良局部循環系統(Chen,Z.-P.等人，AMP-activated protein kinase phosphorylation of endothelial NO synthase.FEBS Letters 443：285(1999))。Fatty acid synthesis is characteristic of many tumor cells, and therefore, reduction of fatty acid synthesis via AMPK activation can also be applied as a cancer therapy. AMPK activation can also be used to treat brain ischemic events (Blazquez, C. et al. Human, J. Neurochem. 73: 1674 (1999)); prevention of damage caused by reactive oxygen species (Zhou, M. et al., Am. J. Physiol. Endocrinol. Metab. 279: E622 (2000)); Circulatory system (Chen, Z.-P. et al., AMP-activated protein kinase phosphorylation of endothelial NO synthase. FEBS Letters 443:285 (1999)).

預期活化AMPK之化合物適用於藉由改良葡萄糖及脂質代謝以及藉由減輕體重來治療2型糖尿病、肥胖症、高血壓、血脂異常、癌症及代謝症候群，以及心血管疾病，諸如心肌梗塞及中風。需要具有適合用作人類用醫藥品之藥物動力學及藥效學特性的有效AMPK活化劑。Compounds that activate AMPK are expected to be useful for treating type 2 diabetes, obesity, hypertension, dyslipidemia, cancer and metabolic syndrome, and cardiovascular diseases such as myocardial infarction and stroke by improving glucose and lipid metabolism and by reducing body weight. There is a need for an effective AMPK activator having pharmacokinetic and pharmacodynamic properties suitable for use as a pharmaceutical for human use.

苯并咪唑化合物揭示於WO 2010/051206、WO 2010/051176、WO 2010/047982、WO 2010/036613、WO 93/07124、WO 95/29897、WO 98/39342、WO 98/39343、WO 00/03997、WO 00/14095、WO 01/53272、WO 01/53291、WO 02/092575、WO 02/40019、WO 03/018061、WO 05/002520、WO 05/018672、WO 06/094209、US 6,312,662、US 6,489,476、US 2005/0148643、DE 3 316 095、JP 6 298 731、EP 0 126 030、EP 0 128 862、EP 0 129 506及EP 0 120 403中。AMPK活化劑揭示於WO 08/006432、WO 05/051298、WO 05/020892、US 2007/015665、US 2007/032529、US 2006/287356及US 2005/038068中。Benzimidazole compounds are disclosed in WO 2010/051206, WO 2010/051176, WO 2010/047982, WO 2010/036613, WO 93/07124, WO 95/29897, WO 98/39342, WO 98/39343, WO 00/03997 , WO 00/14095, WO 01/53272, WO 01/53291, WO 02/092575, WO 02/40019, WO 03/018061, WO 05/002520, WO 05/018672, WO 06/094209, US 6,312,662, US 6, 489, 476, US 2005/0148643, DE 3 316 095, JP 6 298 731, EP 0 126 030, EP 0 128 862, EP 0 129 506 and EP 0 120 403. AMPK activators are disclosed in WO 08/006432, WO 05/051298, WO 05/020892, US 2007/015665, US 2007/032529, US 2006/287356, and US 2005/038068.

本發明係關於結構式I之新穎苯并咪唑衍生物： 及其醫藥學上可接受之鹽。結構式I之化合物及其實施例為AMP活化之蛋白激酶(AMPK)之活化劑且適用於治療、預防及抑制由活化AMP活化之蛋白激酶所介導之疾病、病症及病狀，諸如2型糖尿病、胰島素抗性、高血糖症、血脂異常、脂質失調、肥胖症、高血壓、代謝症候群及動脈粥樣硬化。The present invention relates to novel benzimidazole derivatives of structural formula I: And pharmaceutically acceptable salts thereof. Compounds of structural formula I and examples thereof are activators of AMP-activated protein kinase (AMPK) and are useful for treating, preventing, and inhibiting diseases, disorders, and conditions mediated by activated AMP-activated protein kinases, such as type 2 Diabetes, insulin resistance, hyperglycemia, dyslipidemia, lipid disorders, obesity, hypertension, metabolic syndrome, and atherosclerosis.

本發明亦關於包含本發明化合物及醫藥學上可接受之載劑的醫藥組合物。本發明亦關於藉由投與本發明化合物及醫藥組合物來治療、控制或預防有需要之個體中對活化AMP活化之蛋白激酶起反應之病症、疾病及病狀的方法。本發明亦關於本發明化合物之用途，其係用於製造適用於治療對活化AMP活化之蛋白激酶起反應之疾病、病症及病狀的藥物。本發明亦關於藉由投與本發明化合物以及治療有效量之已知適用於治療疾病、病症及病狀之另一藥劑來治療此等疾病、病症及病狀。本發明另外係關於製備本發明化合物之方法。The invention also relates to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier. The invention also relates to a method of treating, controlling or preventing a condition, disease, and condition in response to activation of an AMP-activated protein kinase in a subject in need thereof by administering a compound of the invention and a pharmaceutical composition. The invention also relates to the use of a compound of the invention for the manufacture of a medicament useful for the treatment of diseases, disorders and conditions which are responsive to activation of AMP-activated protein kinases. The invention also relates to the treatment of such diseases, disorders and conditions by administering a compound of the invention and a therapeutically effective amount of another agent known to be useful in the treatment of diseases, disorders and conditions. The invention further relates to a process for the preparation of a compound of the invention.

本發明係關於結構式I之新穎化合物： 或其醫藥學上可接受之鹽，其中：T係選自由以下組成之群：CR3 、N及N-氧化物；U係選自由以下組成之群：CR1 、N及N-氧化物；V係選自由以下組成之群：CR2 、N及N-氧化物；W係選自由以下組成之群：CR4 、N及N-氧化物，其限制條件為T、U、V及W中之至少一者為N或N-氧化物；X不存在或選自：(1)-CH2 -，(2)-CHF-，(3)-CF2 -，(4)-S-，(5)-O-，(6)-O-CH2 -，(7)-NH-，(8)-C(O)-，(9)-NHC(O)-，(10)-C(O)NH-，(11)-NHSO2 -，(12)-SO2 NH-，及(13)-CO2 -，其中各CH2 未經取代或經1或2個選自以下之取代基取代：羥基、鹵素、NH2 、C1-6 烷基、CO2 H、CO2 C1-6 烷基、COC1-6 烷基、苯基及-CH2 苯基，且其中各NH未經取代或 經1個選自以下之取代基取代：C1-6 烷基、CO2 H、CO2 C1-6 烷基、COC1-6 烷基、苯基及-CH2 苯基；Y係選自：(1)C3-10 環烷基，(2)C3-10 環烯基，(3)C2-10 環雜烷基，(4)C2-10 環雜烯基，(5)芳基，及(6)雜芳基，其中環烷基、環烯基、環雜烷基、環雜烯基、芳基及雜芳基未經取代或經1、2、3或4個選自Rb 之取代基取代；Z係選自：(1)側氧基(oxo)，(2)-CN，(3)-CF3 ，(4)-C1-6 烷基，(5)-(CH2 )t -鹵素，(6)-(CH2 )n COC1-6 烷基，(7)-(CH2 )n CO2 H，(8)-(CH2 )n OCOH，(9)-(CH2 )n CO2 Ri ，(10)-(CH2 )n OCORi ，(11)-(CH2 )n OH，(12)-(CH2 )n C(O)N(Rg )2 ， (13)-(CH2 )n C(O)(CH2 )n N(Rg )2 ，(14)-(CH2 )n OC(O)(CH2 )n N(Rg )2 ，(15)-(CH2 )n NHC(O)C1-6 烷基，(16)-(CH2 )n NHSO2 Ri ，(17)-(CH2 )n SO2 C1-6 烷基，(18)-(CH2 )n SO2 NHRg ，(19)-(CH2 )n SO2 NHC(O)Ri ，(20)-(CH2 )n SO2 NHCO2 Ri ，(21)-(CH2 )n SO2 NHCON(Rg )2 ，(22)-(CH2 )n C(O)NHSO2 Ri ，(23)-(CH2 )n NHC(O)N(Rg )2 ，(24)-(CH2 )n C3-10 環烷基-CO2 Re ，(25)雜芳基，(26)-C2-10 環雜烯基，及(27)-C2-10 環雜烷基，其中各CH2 未經取代或經1或2個選自C1-6 烷基、-OH及-NH2 之取代基取代，其中各NH未經取代或經1個選自Rc 之取代基取代，且其中烷基、環烷基、環雜烷基、環雜烯基、芳基及雜芳基各自未經取代或經1、2、3或4個選自Rc 之取代基取代；R1 及R2 各自係獨立地選自：(1)氫，(2)鹵素，(3)CN， (4)CF3 ，(5)-C1-6 烷基，(6)-C2-6 烯基，(7)-C2-6 炔基，(8)-(CH2 )p C3-10 環烷基，(9)-(CH2 )p C3-7 環烷基-芳基，(10)-(CH2 )p C3-7 環烷基-雜芳基，(11)-(CH2 )p C4-10 環烯基，(12)-(CH2 )p C4-7 環烯基-芳基，(13)-(CH2 )p C4-7 環烯基-雜芳基，(14)-(CH2 )p C2-10 環雜烷基，(15)-(CH2 )p C2-10 環雜烯基，(16)-(CH2 )p 芳基，(17)-(CH2 )p 芳基-C1-8 烷基，(18)-(CH2 )p 芳基-C2-8 烯基，(19)-(CH2 )p 芳基-C2-8 炔基-C1-8 烷基，(20)-(CH2 )p 芳基-C2-8 炔基-C3-7 環烷基，(21)-(CH2 )p 芳基-C2-8 炔基-C3-7 環烯基，(22)-(CH2 )p 芳基-C2-8 炔基-C2-10 環雜烷基，(23)-(CH2 )p 芳基-C2-8 炔基-C2-10 環雜烯基，(24)-(CH2 )p 芳基-C2-8 炔基-芳基，(25)-(CH2 )p 芳基-C2-8 炔基-雜芳基，(26)-(CH2 )p 芳基-C3-7 環烷基，(27)-(CH2 )p 芳基-C2-10 環雜烷基， (28)-(CH2 )p 芳基-C2-10 環雜烯基，(29)-(CH2 )p 芳基-芳基，(30)-(CH2 )p 芳基-雜芳基，(31)-(CH2 )p 雜芳基，(32)-C2-6 烯基-烷基，(33)-C2-6 烯基-芳基，(34)-C2-6 烯基-雜芳基，(35)-C2-6 烯基-C3-7 環烷基，(36)-C2-6 烯基-C3-7 環烯基，(37)-C2-6 烯基-C2-7 環雜烷基，(38)-C2-6 烯基-C2-7 環雜烯基，(39)-C2-6 炔基-(CH2 )1-3 -O-芳基，(40)-C2-6 炔基-烷基，(41)-C2-6 炔基-芳基，(42)-C2-6 炔基-雜芳基，(43)-C2-6 炔基-C3-7 環烷基，(44)-C2-6 炔基-C3-7 環烯基，(45)-C2-6 炔基-C2-7 環雜烷基，(46)-C2-6 炔基-C2-7 環雜烯基，及(47)-C(O)NH-(CH2 )0-3 苯基，其中各CH2 未經取代或經1或2個選自以下之取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，其中烷基、烯基、炔基、環烷基、環烯基、環雜烷基、環雜烯基、苯基、芳基及雜芳基各自 未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代，其限制條件為R1 及R2 中之至少一者以及R1 及R2 中僅一者係選自由以下組成之群：氫、鹵素、-CN、-CF3 、-C1-6 烷基、-C2-6 烯基及-C2-6 炔基；R3 及R4 係各自獨立地選自：(1)氫，(2)鹵素，(3)-C1-6 烷基，(4)-C2-6 烯基，(5)-C2-6 炔基，(6)-C3-10 環烷基，(7)-C3-10 環烯基，(8)芳基，(9)雜芳基，(10)-CN，(11)-CF3 ，(12)-OH，(13)-OC1-6 烷基，(14)-NH2 ，(15)-NHC1-6 烷基，(16)-N(C1-6 烷基)2 ，(17)-SC1-6 烷基，(18)-SOC1-6 烷基，(19)-SO2 C1-6 烷基， (20)-NHSO2 C1-6 烷基，(21)-NHC(O)C1-6 烷基，(22)-SO2 NHC1-6 烷基，及(23)-C(O)NHC1-6 烷基；R5 係選自：(1)氫，(2)-C1-6 烷基，(3)-CH2 CO2 H，及(4)-CH2 CO2 C1-6 烷基；各Ra 係獨立地選自由以下組成之群：(1)-(CH2 )m -鹵素，(2)側氧基，(3)-(CH2 )m OH，(4)-(CH2 )m N(Rj )2 ，(5)-(CH2 )m NO2 ，(6)-(CH2 )m CN，(7)-C1-6 烷基，(8)-(CH2 )m CF3 ，(9)-(CH2 )m OCF3 ，(10)-O-(CH2 )m -OC1-6 烷基，(11)-(CH2 )m C(O)N(Rj )2 ，(12)-(CH2 )m C(=N-OH)N(Rj )2 ，(13)-(CH2 )m OC1-6 烷基，(14)-(CH2 )m O-(CH2 )m -C3-7 環烷基， (15)-(CH2 )m O-(CH2 )m -C2-7 環雜烷基，(16)-(CH2 )m O-(CH2 )m -芳基，(17)-(CH2 )m O-(CH2 )m -雜芳基，(18)-(CH2 )m SC1-6 烷基，(19)-(CH2 )m S(O)C1-6 烷基，(20)-(CH2 )m SO2 C1-6 烷基，(21)-(CH2 )m SO2 C3-7 環烷基，(22)-(CH2 )m SO2 C2-7 環雜烷基，(23)-(CH2 )m SO2 -芳基，(24)-(CH2 )m SO2 -雜芳基，(25)-(CH2 )m SO2 NHC1-6 烷基，(26)-(CH2 )m SO2 NHC3-7 環烷基，(27)-(CH2 )m SO2 NHC2-7 環雜烷基，(28)-(CH2 )m SO2 NH-芳基，(29)-(CH2 )m SO2 NH-雜芳基，(30)-(CH2 )m NHSO2 -C1-6 烷基，(31)-(CH2 )m NHSO2 -C3-7 環烷基，(32)-(CH2 )m NHSO2 -C2-7 環雜烷基，(33)-(CH2 )m NHSO2 -芳基，(34)-(CH2 )m NHSO2 NH-雜芳基，(35)-(CH2 )m N(Rj )-C1-6 烷基，(36)-(CH2 )m N(Rj )-C3-7 環烷基，(37)-(CH2 )m N(Rj )-C2-7 環雜烷基，(38)-(CH2 )m N(Rj )-C2-7 環雜烯基， (39)-(CH2 )m N(Rj )-芳基，(40)-(CH2 )m N(Rj )-雜芳基，(41)-(CH2 )m C(O)Rf ，(42)-(CH2 )m C(O)N(Rj )2 ，(43)-(CH2 )m N(Rj )C(O)N(Rj )2 ，(44)-(CH2 )m CO2 H，(45)-(CH2 )m OCOH，(46)-(CH2 )m CO2 Rf ，(47)-(CH2 )m OCORf ，(48)-(CH2 )m C3-7 環烷基，(49)-(CH2 )m C3-7 環烯基，(50)-(CH2 )m C2-6 環雜烷基，(51)-(CH2 )m C2-6 環雜烯基，(52)-(CH2 )m 芳基，及(53)-(CH2 )m 雜芳基，其中各CH2 未經取代或經1或2個選自以下之取代基取代：側氧基、-(CH2 )0-3 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基，且其中烷基、環烷基、環烯基、環雜烷基、環雜烯基、芳基及雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-5 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-SO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基；各Rb 係獨立地選自：(1)氫，(2)-C1-6 烷基，(3)-C3-6 環烷基，(4)-C3-6 環烯基，(5)-C2-6 環雜烷基，(6)-C2-6 環雜烯基，(7)芳基，(8)雜芳基，(9)-(CH2 )t -鹵素，(10)-(CH2 )s -OH，(11)-NO2 ，(12)-NH2 ，(13)-NH(C1-6 烷基)，(14)-N(C1-6 烷基)2 ，(15)-OC1-6 烷基，(16)-(CH2 )q CO2 H，(17)-(CH2 )q CO2 C1-6 烷基，(18)-CF3 ，(19)-CN，(20)-SO2 C1-6 烷基，及(21)-(CH2 )s CON(Re )2 ， 其中各CH2 未經取代或經1或2個鹵素取代，且其中烷基、環烷基、環烯基、環雜烷基、環雜烯基、芳基及雜芳基各自未經取代或經1、2或3個鹵素取代；各Rc 係獨立地選自：(1)鹵素，(2)側氧基，(3)-(CH2 )r OH，(4)-(CH2 )r N(Re )2 ，(5)-(CH2 )r CN，(6)-C1-6 烷基，(7)-CF3 ，(8)-C1-6 烷基-OH，(9)-OCH2 OC1-6 烷基，(10)-(CH2 )r OC1-6 烷基，(11)-OCH2 芳基，(12)-(CH2 )r SC1-6 烷基，(13)-(CH2 )r C(O)Rf ，(14)-(CH2 )r C(O)N(Re )2 ，(15)-(CH2 )r CO2 H，(16)-(CH2 )r CO2 Rf ，(17)-(CH2 )r C3-7 環烷基，(18)-(CH2 )r C2-6 環雜烷基，(19)-(CH2 )r 芳基，及(20)-(CH2 )r 雜芳基， 其中各CH2 未經取代或經1或2個選自以下之取代基取代：側氧基、-OH、-CN、-N(Rh )2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基及雜芳基，且其中烷基、環烷基、環雜烷基、芳基及雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-OH、-CN、-N(Rh )2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基及雜芳基；Re 、Rg 及Rh 各自係獨立地選自：(1)氫，(2)-C1-6 烷基，及(3)-O-C1-6 烷基，其中烷基未經取代或經1、2、3或4個選自以下之取代基取代：-OH、側氧基、鹵素、C1-6 烷基、-OC1-6 烷基、-NH2 、-NH(C1-6 烷基)及-N(C1-6 烷基)2 ；各Rj 係獨立地選自：(1)氫，(2)C1-6 烷基，(3)C3-6 環烷基，(4)-C(O)Ri ，及(5)-SO2 Ri ，其中烷基及環烷基未經取代或經1、2、3或4個選自以下之取代基取代：-OH、側氧基、鹵素、C1-6 烷基、-OC1-6 烷基、-NH2 、-NH(C1-6 烷基)及-N(C1-6 烷基)2 ； Rf 及Ri 各自係獨立地選自：(1)C1-6 烷基，(2)C4-7 環烷基，(3)C4-7 環烯基，(4)C3-7 環雜烷基，(5)C3-7 環雜烯基，(6)芳基，及(7)雜芳基，其中烷基、環烷基、環烯基、環雜烷基、環雜烯基、芳基及雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-OH、-CN、-NH2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基及雜芳基；n為0、1、2、3或4；m為0、1、2、3或4；p為0、1、2或3；q為0、1、2、3或4；r為0、1或2；s為0、1、2、3或4；且t為0、1、2、3或4。The present invention relates to novel compounds of structural formula I: Or a pharmaceutically acceptable salt thereof, wherein: T is selected from the group consisting of CR 3 , N and N-oxide; and U is selected from the group consisting of CR 1 , N and N-oxide; The V system is selected from the group consisting of CR 2 , N and N-oxides; the W system is selected from the group consisting of CR 4 , N and N-oxides, the restrictions being T, U, V and W At least one of them is N or N-oxide; X is absent or selected from: (1)-CH 2 -, (2)-CHF-, (3)-CF 2 -, (4)-S-, ( 5) -O-, (6)-O-CH 2 -, (7)-NH-, (8)-C(O)-, (9)-NHC(O)-, (10)-C(O NH-, (11)-NHSO 2 -, (12)-SO 2 NH-, and (13)-CO 2 -, wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from : hydroxy, halogen, NH 2 , C 1-6 alkyl, CO 2 H, CO 2 C 1-6 alkyl, COC 1-6 alkyl, phenyl and -CH 2 phenyl, and wherein each NH is not Substituted or substituted with one substituent selected from the group consisting of C 1-6 alkyl, CO 2 H, CO 2 C 1-6 alkyl, COC 1-6 alkyl, phenyl and -CH 2 phenyl; Y Is selected from the group consisting of: (1) C 3-10 cycloalkyl, (2) C 3-10 cycloalkenyl, (3) C 2-10 cycloheteroalkyl, (4) C 2-10 cycloheteroyl, (5) aryl, and (6) An aryl group wherein a cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl group is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R b ; Z is selected from the group consisting of: (1) pendant oxo (oxo), (2)-CN, (3)-CF 3 , (4)-C 1-6 alkyl, (5)-(CH 2 ) t -halogen , (6)-(CH 2 ) n COC 1-6 alkyl, (7)-(CH 2 ) n CO 2 H, (8)-(CH 2 ) n OCOH, (9)-(CH 2 ) n CO 2 R i , (10)-(CH 2 ) n OCOR i , (11)-(CH 2 ) n OH, (12)-(CH 2 ) n C(O)N(R g ) 2 , (13 )-(CH 2 ) n C(O)(CH 2 ) n N(R g ) 2 , (14)-(CH 2 ) n OC(O)(CH 2 ) n N(R g ) 2 , (15 )-(CH 2 ) n NHC(O)C 1-6 alkyl, (16)-(CH 2 ) n NHSO 2 R i , (17)-(CH 2 ) n SO 2 C 1-6 alkyl, (18)-(CH 2 ) n SO 2 NHR g , (19)-(CH 2 ) n SO 2 NHC(O)R i , (20)-(CH 2 ) n SO 2 NHCO 2 R i , (21 )-(CH 2 ) n SO 2 NHCON(R g ) 2 ,(22)-(CH 2 ) n C(O)NHSO 2 R i ,(23)-(CH 2 ) n NHC(O)N(R g ) 2 , (24)-(CH 2 ) n C 3-10 cycloalkyl-CO 2 R e , (25) heteroaryl, (26)-C 2-10 cycloheteroalkenyl, and (27) -C 2-10 cycloheteroalkyl group, wherein each of CH 2 unsubstituted or substituted by 1 or 2 substituents selected from C 1-6 alkyl, -OH and -NH 2 taken of Substituent group, wherein each is unsubstituted or NH selected one of the substituents R c, and wherein the alkyl, cycloalkyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl, each non- Substituted or substituted with 1, 2, 3 or 4 substituents selected from R c ; R 1 and R 2 are each independently selected from: (1) hydrogen, (2) halogen, (3) CN, (4) CF 3 , (5)-C 1-6 alkyl, (6)-C 2-6 alkenyl, (7)-C 2-6 alkynyl, (8)-(CH 2 ) p C 3-10 ring Alkyl, (9)-(CH 2 ) p C 3-7 cycloalkyl-aryl, (10)-(CH 2 ) p C 3-7 cycloalkyl-heteroaryl, (11)-(CH 2 ) p C 4-10 cycloalkenyl, (12)-(CH 2 ) p C 4-7 cycloalkenyl-aryl, (13)-(CH 2 ) p C 4-7 cycloalkenyl-heteroaryl Base, (14)-(CH 2 ) p C 2-10 cycloheteroalkyl, (15)-(CH 2 ) p C 2-10 cycloheteroalkenyl, (16)-(CH 2 ) p aryl, (17)-(CH 2 ) p aryl-C 1-8 alkyl, (18)-(CH 2 ) p aryl-C 2-8 alkenyl, (19)-(CH 2 ) p aryl- C 2-8 alkynyl-C 1-8 alkyl, (20)-(CH 2 ) p aryl-C 2-8 alkynyl-C 3-7 cycloalkyl, (21)-(CH 2 ) p Aryl-C 2-8 alkynyl-C 3-7 cycloalkenyl, (22)-(CH 2 ) p aryl-C 2-8 alkynyl-C 2-10 cycloheteroalkyl, (23)- (CH 2) p -C 2-8 alkynyl aryl -C 2-10 cycloheteroalkenyl (24) - (CH 2) p -C 2-8 alkynyl aryl - aryl, (25) - (CH 2 ) p -C 2-8 alkynyl aryl - heteroaryl, (26) - ( CH 2 ) p aryl-C 3-7 cycloalkyl, (27)-(CH 2 ) p aryl-C 2-10 cycloheteroalkyl, (28)-(CH 2 ) p aryl-C 2 -10 cycloheteroalkenyl, (29)-(CH 2 ) p aryl-aryl, (30)-(CH 2 ) p aryl-heteroaryl, (31)-(CH 2 ) p heteroaryl , (32)-C 2-6 alkenyl-alkyl, (33)-C 2-6 alkenyl-aryl, (34)-C 2-6 alkenyl-heteroaryl, (35)-C 2 -6 alkenyl-C 3-7 cycloalkyl, (36)-C 2-6 alkenyl-C 3-7 cycloalkenyl, (37)-C 2-6 alkenyl-C 2-7 cyclohexane , (38)-C 2-6 alkenyl-C 2-7 cycloheteroalkenyl, (39)-C 2-6 alkynyl-(CH 2 ) 1-3 -O-aryl, (40)- C 2-6 alkynyl-alkyl, (41)-C 2-6 alkynyl-aryl, (42)-C 2-6 alkynyl-heteroaryl, (43)-C 2-6 alkynyl- C 3-7 cycloalkyl, (44)-C 2-6 alkynyl-C 3-7 cycloalkenyl, (45)-C 2-6 alkynyl-C 2-7 cycloheteroalkyl, (46) -C 2-6 alkynyl-C 2-7 cycloheteroalkenyl, and (47)-C(O)NH-(CH 2 ) 0-3 phenyl wherein each CH 2 is unsubstituted or via 1 or 2 Substituted by a substituent selected from the group consisting of halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl, and -N (C 1 -6 alkyl) 2, Alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, phenyl, aryl and heteroaryl are each unsubstituted or 1, 2, 3 or 4 R a is independently selected from the substituents, with the proviso that R 1 and R 2 in the 2, only one line is selected from at least one of R and R 1 and the group consisting of: hydrogen, halogen, -CN, -CF 3 , -C 1-6 alkyl, -C 2-6 alkenyl and -C 2-6 alkynyl; R 3 and R 4 are each independently selected from: (1) hydrogen, (2) halogen, (3)-C 1-6 alkyl, (4)-C 2-6 alkenyl, (5)-C 2-6 alkynyl, (6)-C 3-10 cycloalkyl, (7)-C 3-10 cycloalkenyl, (8) aryl, (9) heteroaryl, (10)-CN, (11)-CF 3 , (12)-OH, (13)-OC 1-6 alkyl, (14) -NH 2 , (15)-NHC 1-6 alkyl, (16)-N(C 1-6 alkyl) 2 , (17)-SC 1-6 alkyl, (18)-SOC 1 -6 alkyl, (19)-SO 2 C 1-6 alkyl, (20)-NHSO 2 C 1-6 alkyl, (21)-NHC(O)C 1-6 alkyl, (22)- SO 2 NHC 1-6 alkyl, and (23)-C(O)NHC 1-6 alkyl; R 5 is selected from: (1) hydrogen, (2)-C 1-6 alkyl, (3) -CH 2 CO 2 H, and (4)-CH 2 CO 2 C 1-6 alkyl; each R a is independently selected from the group consisting of: (1)-(CH 2 ) m -halogen, (2 ) Group, (3) - (CH 2 ) m OH, (4) - (CH 2) m N (R j) 2, (5) - (CH 2) m NO 2, (6) - (CH 2) m CN,(7)-C 1-6 alkyl, (8)-(CH 2 ) m CF 3 , (9)-(CH 2 ) m OCF 3 , (10)-O-(CH 2 ) m - OC 1-6 alkyl, (11)-(CH 2 ) m C(O)N(R j ) 2 , (12)-(CH 2 ) m C(=N-OH)N(R j ) 2 , (13)-(CH 2 ) m OC 1-6 alkyl, (14)-(CH 2 ) m O-(CH 2 ) m -C 3-7 cycloalkyl, (15)-(CH 2 ) m O-(CH 2 ) m -C 2-7cycloheteroalkyl , (16)-(CH 2 ) m O-(CH 2 ) m -aryl, (17)-(CH 2 ) m O-(CH 2 ) m -heteroaryl, (18)-(CH 2 ) m SC 1-6 alkyl, (19)-(CH 2 ) m S(O)C 1-6 alkyl, (20)-(CH 2 ) m SO 2 C 1-6 alkyl, (21)-(CH 2 ) m SO 2 C 3-7 cycloalkyl, (22)-(CH 2 ) m SO 2 C 2-7 cycloheteroalkyl , (23)-(CH 2 ) m SO 2 -aryl, (24)-(CH 2 ) m SO 2 -heteroaryl, (25)-(CH 2 ) m SO 2 NHC 1-6 alkyl, (26)-(CH 2 ) m SO 2 NHC 3-7 cycloalkyl, (27)-(CH 2 ) m SO 2 NHC 2-7 cycloheteroalkyl, (28)-(CH 2 ) m SO 2 NH-aryl, (29)-(CH 2 ) m SO 2 NH-heteroaryl, (30)-(CH 2 ) m NHSO 2 -C 1-6 alkyl, (31)-(CH 2 ) m NHSO 2 -C 3-7 cycloalkyl, (32) - (CH 2 ) m NHSO 2 -C 2-7 cycloheteroalkyl , (33) - (CH 2 ) m NHSO 2 - aryl, (34) - (CH 2 ) m NHSO 2 NH- heteroaryl, (35) - (CH 2 ) m N (R j) -C 1 -6 alkyl, (36)-(CH 2 ) m N(R j )-C 3-7 cycloalkyl, (37)-(CH 2 ) m N(R j )-C 2-7 cyclohexane Base, (38)-(CH 2 ) m N(R j )-C 2-7cycloheteroalkenyl , (39)-(CH 2 ) m N(R j )-aryl, (40)-(CH 2 ) m N(R j )-heteroaryl, (41)-(CH 2 ) m C(O)R f , (42)-(CH 2 ) m C(O)N(R j ) 2 , ( 43)-(CH 2 ) m N(R j )C(O)N(R j ) 2 , (44)-(CH 2 ) m CO 2 H, (45)-(CH 2 ) m OCOH, (46 )-(CH 2 ) m CO 2 R f , (47)-(CH 2 ) m OCOR f , (48)-(CH 2 ) m C 3-7 cycloalkyl, (49)-(CH 2 ) m C 3-7 cycloalkenyl, (50)-(CH 2 ) m C 2-6 cycloheteroalkyl, (51)-(CH 2 ) m C 2-6 cycloheteroalkenyl, (52)-(CH 2) m aryl, and (53) - (CH 2) m heteroaryl, wherein each of the CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from the substituents: oxo, - (CH 2) 0-3 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl , halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl Base and CH 2 Aryl, and wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted by 1, 2, 3 or 4 Base substitution: pendant oxy, -(CH 2 ) 0-5 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C 1 -6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -SO 2 C 1-6 Alkyl, -C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl; each R b is independently selected from: (1) hydrogen, (2)-C 1 -6 alkyl, (3)-C 3-6 cycloalkyl, (4)-C 3-6 cycloalkenyl, (5)-C 2-6 cycloheteroalkyl, (6)-C 2-6 Cycloheteroalkenyl, (7) aryl, (8) heteroaryl, (9)-(CH 2 ) t -halogen, (10)-(CH 2 ) s -OH, (11)-NO 2 , ( 12) -NH 2 , (13)-NH(C 1-6 alkyl), (14)-N(C 1-6 alkyl) 2 , (15)-OC 1-6 alkyl, (16)- (CH 2 ) q CO 2 H, (17)-(CH 2 ) q CO 2 C 1-6 alkyl, (18)-CF 3 , (19)-CN, (20)-SO 2 C 1-6 An alkyl group, and (21)-(CH 2 ) s CON(R e ) 2 , wherein each CH 2 is unsubstituted or substituted with 1 or 2 halogens, and wherein alkyl, cycloalkyl, cycloalkenyl, ring Heteroalkyl, Heteroalkenyl, aryl, and heteroaryl, each unsubstituted or substituted with 1, 2 or 3 halogen; each R c are independently selected: (1) halogen, (2) oxo, (3) - (CH 2 ) r OH, (4)-(CH 2 ) r N(R e ) 2 , (5)-(CH 2 ) r CN, (6)-C 1-6 alkyl, (7)-CF 3 , (8)-C 1-6 alkyl-OH, (9)-OCH 2 OC 1-6 alkyl, (10)-(CH 2 ) r OC 1-6 alkyl, (11)-OCH 2 Aryl, (12)-(CH 2 ) r SC 1-6 alkyl, (13)-(CH 2 ) r C(O)R f , (14)-(CH 2 ) r C(O)N( R e ) 2 , (15)-(CH 2 ) r CO 2 H, (16)-(CH 2 ) r CO 2 R f , (17)-(CH 2 ) r C 3-7 cycloalkyl, ( 18) -(CH 2 ) r C 2-6cycloheteroalkyl , (19)-(CH 2 ) r aryl, and (20)-(CH 2 ) r heteroaryl, wherein each CH 2 is unsubstituted Or substituted with 1 or 2 substituents selected from the group consisting of: pendant oxy, -OH, -CN, -N(R h ) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3-7 cycloalkyl and heteroaryl, and wherein alkyl, cycloalkyl, The cycloheteroalkyl, aryl and heteroaryl groups are unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of pendant oxy, -OH, -CN, -N(R h ) 2 , -C 1-6 Group, -OC 1-6 alkyl, halo, -CH 2 F, -CHF 2, -CF 3, -CO 2 H, -CO 2 C 1-6 alkyl, -C 3-7 cycloalkyl, and heteroaryl An aryl group; R e , R g and R h are each independently selected from the group consisting of: (1) hydrogen, (2)-C 1-6 alkyl, and (3)-OC 1-6 alkyl, wherein the alkyl group is not Substituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of: -OH, pendant oxy, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH (C 1-6 alkyl) and -N(C 1-6 alkyl) 2 ; each R j is independently selected from: (1) hydrogen, (2) C 1-6 alkyl, (3) C 3 a -6 cycloalkyl group, (4)-C(O)R i , and (5)-SO 2 R i wherein the alkyl group and the cycloalkyl group are unsubstituted or 1, 2, 3 or 4 are selected from the group consisting of Substituents substituted: -OH, pendant oxy, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl) and -N (C 1- 6 alkyl) 2 ; R f and R i are each independently selected from: (1) C 1-6 alkyl, (2) C 4-7 cycloalkyl, (3) C 4-7 cycloalkenyl, (4) C 3-7 cycloheteroalkyl, (5) C 3-7 cycloheteroalkenyl, (6) aryl, and (7) heteroaryl, wherein alkyl, cycloalkyl, cycloalkenyl, The cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl groups are unsubstituted or selected from 1, 2, 3 or 4 Under the substituents: oxo, -OH, -CN, -NH 2, -C 1-6 alkyl, -OC 1-6 alkyl, halo, -CH 2 F, -CHF 2, -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3-7 cycloalkyl, and heteroaryl; n is 0, 1, 2, 3 or 4; m is 0, 1, 2, 3 Or 4; p is 0, 1, 2 or 3; q is 0, 1, 2, 3 or 4; r is 0, 1 or 2; s is 0, 1, 2, 3 or 4; and t is 0, 1, 2, 3 or 4.

在本發明之一個實施例中，本發明係關於結構式I之新穎化合物： 或其醫藥學上可接受之鹽，其中：T係選自由以下組成之群：CR3 、N及N-氧化物；U係選自由以下組成之群：CR1 、N及N-氧化物；V係選自由以下組成之群：CR2 、N及N-氧化物；W係選自由以下組成之群：CR4 、N及N-氧化物，其限制條件為T、U、V及W中之至少一者為N或N-氧化物；X不存在或選自：-CH2 -、-CHF-、-CF2 -、-S-、-O-、-O-CH2 -、-NH-、-C(O)-、-NHC(O)-、-C(O)NH-、-NHSO2 -、-SO2 NH-及-CO2 -，其中各CH2 未經取代或經1或2個選自以下之取代基取代：羥基、鹵素、NH2 、C1-6 烷基、CO2 H、CO2 C1-6 烷基、COC1-6 烷基、苯基及-CH2 苯基，且其中各NH未經取代或經1個選自以下之取代基取代：C1-6 烷基、CO2 H、CO2 C1-6 烷基、COC1-6 烷基、苯基及-CH2 苯基；Y係選自：C3-10 環烷基、C3-10 環烯基、C2-10 環雜烷基、C2-10 環雜烯基、芳基及雜芳基，其中環烷基、環烯基、環雜烷基、環雜烯基、芳基及雜芳基未經取代或經1、2、3或4個選自Rb 之取代基取代；Z係選自：側氧基、-CN、-CF3 、-C1-6 烷基、-(CH2 )t -鹵素、-(CH2 )n COC1-6 烷基、-(CH2 )n CO2 H、-(CH2 )n OCOH、-(CH2 )n CO2 Ri 、-(CH2 )n OCORi 、-(CH2 )n OH、-(CH2 )n C(O)N(Rg )2 、-(CH2 )n C(O)(CH2 )n N(Rg )2 、-(CH2 )n OC(O)(CH2 )n N(Rg )2 、-(CH2 )n NHC(O)C1-6 烷基、-(CH2 )n NHSO2 Ri 、-(CH2 )n SO2 C1-6 烷基、-(CH2 )n SO2 NHRg 、-(CH2 )n SO2 NHC(O)Ri 、-(CH2 )n SO2 NHCO2 Ri 、-(CH2 )n SO2 NHCON(Rg )2 、-(CH2 )n C(O)NHSO2 Ri 、-(CH2 )n NHC(O)N(Rg )2 、-(CH2 )n C3-10 環烷基-CO2 Re 、雜芳基、-C2-10 環雜烯基及-C2-10 環雜烷基，其中各CH2 未經取代或經1或2個選自C1-6 烷基、-OH及-NH2 之取代基取代，其中各NH未經取代或經1個選自Rc 之取代基取代，且其中烷基、環烷基、環雜烷基、環雜烯基、芳基及雜芳基各自未經取代或經1、2、3或4個選自Rc 之取代基取代；R1 及R2 各自係獨立地選自：氫、鹵素、CN、CF3 、-C1-6 烷基、-C2-6 烯基、-C2-6 炔基、-(CH2 )p C3-10 環烷基、-(CH2 )p C3-7 環烷基-芳基、-(CH2 )p C3-7 環烷基-雜芳基、-(CH2 )p C4-10 環烯基、-(CH2 )p C4-7 環烯基-芳基、-(CH2 )p C4-7 環烯基-雜芳基、-(CH2 )p C2-10 環雜烷基、-(CH2 )p C2-10 環雜烯基、-(CH2 )p 芳基、-(CH2 )p 芳基-C3-7 環烷基、-(CH2 )p 芳基-C2-7 環雜烷基、-(CH2 )p 芳基-芳基、-(CH2 )p 芳基-雜芳基、-(CH2 )p 雜芳基、-C2-6 烯基-烷基、-C2-6 烯基-芳基、-C2-6 烯基-雜芳基、-C2-6 烯基-C3-7 環烷基、-C2-6 烯基-C3-7 環烯基、-C2-6 烯基-C2-7 環雜烷基、-C2-6 烯基-C2-7 環雜烯基、-C2-6 炔基-(CH2 )1-3 -O-芳基、-C2-6 炔基-烷基、-C2-6 炔基-芳基、-C2-6 炔基-雜芳基、-C2-6 炔基-C3-7 環烷基、-C2-6 炔基-C3-7 環烯基、-C2-6 炔基-C2-7 環雜烷基、-C2-6 炔基-C2-7 環雜烯基及-C(O)NH-(CH2 )0-3 苯基，其中各CH2 未經取代或經1或2個選自以下之 取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，其中烷基、烯基及炔基各自未經取代或經1、2或3個選自以下之取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，且其中環烷基、環烯基、環雜烷基、環雜烯基、苯基、芳基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代，其限制條件為R1 及R2 中之至少一者以及R1 及R2 中僅一者係選自由以下組成之群：氫、鹵素、-CN、-CF3 、-C1-6 烷基、-C2-6 烯基及-C2-6 炔基；R3 及R4 係各自獨立地選自：氫、鹵素、-C1-6 烷基、-C2-6 烯基、-C2-6 炔基、-C3-10 環烷基、-C3-10 環烯基、芳基、雜芳基、-CN、-CF3 、-OH、-OC1-6 烷基、-NH2 、-NHC1-6 烷基、-N(C1-6 烷基)2 、-SC1-6 烷基、-SOC1-6 烷基、-SO2 C1-6 烷基、-NHSO2 C1-6 烷基、-NHC(O)C1-6 烷基、-SO2 NHC1-6 烷基及-C(O)NHC1-6 烷基；R5 係選自：氫、-C1-6 烷基、-CH2 CO2 H及-CH2 CO2 C1-6 烷基；各Ra 係獨立地選自由以下組成之群：鹵素、側氧基、-(CH2 )m OH、-(CH2 )m N(Rj )2 、-(CH2 )m NO2 、-(CH2 )m CN、-C1-6 烷基、-(CH2 )m CF3 、-(CH2 )m OCF3 、-OCH2 OC1-6 烷基、-(CH2 )m C(O)N(Rj )2 、-(CH2 )m C(=N-OH)N(Rj )2 、-(CH2 )m OC1-6 烷基、-(CH2 )m O-(CH2 )m -C3-7 環烷基、-(CH2 )m O-(CH2 )m -C2-7 環雜烷基、-(CH2 )m O-(CH2 )m -芳基、-(CH2 )m O-(CH2 )m -雜芳 基、-(CH2 )m SC1-6 烷基、-(CH2 )m S(O)C1-6 烷基、-(CH2 )m SO2 C1-6 烷基、-(CH2 )m SO2 C3-7 環烷基、-(CH2 )m SO2 C2-7 環雜烷基、-(CH2 )m SO2 -芳基、-(CH2 )m SO2 -雜芳基、-(CH2 )m SO2 NHC1-6 烷基、-(CH2 )m SO2 NHC3-7 環烷基、-(CH2 )m SO2 NHC2-7 環雜烷基、-(CH2 )m SO2 NH-芳基、-(CH2 )m SO2 NH-雜芳基、-(CH2 )m NHSO2 -C1-6 烷基、-(CH2 )m NHSO2 -C3-7 環烷基、-(CH2 )m NHSO2 -C2-7 環雜烷基、-(CH2 )m NHSO2 -芳基、-(CH2 )m NHSO2 NH-雜芳基、-(CH2 )m C(O)Rf 、-(CH2 )m C(O)N(Rj )2 、-(CH2 )m N(Rj )C(O)N(Rj )2 、-(CH2 )m CO2 H、-(CH2 )m OCOH、-(CH2 )m CO2 Rf 、-(CH2 )m OCORf 、-(CH2 )m C3-7 環烷基、-(CH2 )m C3-7 環烯基、-(CH2 )m C2-6 環雜烷基、-(CH2 )m C2-6 環雜烯基、-(CH2 )m 芳基及-(CH2 )m 雜芳基，其中各CH2 未經取代或經1或2個選自以下之取代基取代：側氧基、-(CH2 )0-3 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基，且其中烷基、環烷基、環烯基、環雜烷基、環雜烯基、芳基及雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-3 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-SO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基；各Rb 係獨立地選自：氫、-C1-6 烷基、-C3-6 環烷基、-C3-6 環 烯基、-C2-6 環雜烷基、-C2-6 環雜烯基、芳基、雜芳基、-(CH2 )t -鹵素、-(CH2 )s -OH、-NO2 、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-OC1-6 烷基、-(CH2 )q CO2 H、-(CH2 )q CO2 C1-6 烷基、-CF3 、-CN、-SO2 C1-6 烷基及-(CH2 )s CON(Re )2 ，其中各CH2 未經取代或經1或2個鹵素取代，且其中烷基、環烷基、環烯基、環雜烷基、環雜烯基、芳基及雜芳基各自未經取代或經1、2或3個鹵素取代；各Rc 係獨立地選自：鹵素、側氧基、-(CH2 )r OH、-(CH2 )r N(Re )2 、-(CH2 )r CN、-C1-6 烷基、-CF3 、-C1-6 烷基-OH、-OCH2 OC1-6 烷基、-(CH2 )r OC1-6 烷基、-OCH2 芳基、-(CH2 )r SC1-6 烷基、-(CH2 )r C(O)Rf 、-(CH2 )r C(O)N(Re )2 、-(CH2 )r CO2 H、-(CH2 )r CO2 Rf 、-(CH2 )r C3-7 環烷基、-(CH2 )r C2-6 環雜烷基、-(CH2 )r 芳基及-(CH2 )r 雜芳基，其中各CH2 未經取代或經1或2個選自以下之取代基取代：側氧基、-OH、-CN、-N(Rh )2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基及雜芳基，且其中烷基、環烷基、環雜烷基、芳基及雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-OH、-CN、-N(Rh )2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基及雜芳基；Re 、Rg 及Rh 各自係獨立地選自：氫、-C1-6 烷基及-O-C1-6 烷基，其中烷基未經取代或經1、2、3或4個選自以下之取代基取代：-OH、側氧基、鹵素、C1-6 烷基、-OC1-6 烷基、-NH2 、-NH(C1-6 烷基)及-N(C1-6 烷基)2 ；各Rj 係獨立地選自：氫、C1-6 烷基、C3-6 環烷基、-C(O)Ri 及-SO2 Ri ，其中烷基及環烷基未經取代或經1、2、3或4個選自以下之取代基取代：-OH、側氧基、鹵素、C1-6 烷基、-OC1-6 烷基、-NH2 、-NH(C1-6 烷基)及-N(C1-6 烷基)2 ；Rf 及Ri 各自係獨立地選自：C1-6 烷基、C4-7 環烷基、C4-7 環烯基、C3-7 環雜烷基、C3-7 環雜烯基、芳基及雜芳基，其中烷基、環烷基、環烯基、環雜烷基、環雜烯基、芳基及雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-OH、-CN、-NH2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基及雜芳基；n為0、1、2、3或4；m為0、1、2、3或4；p為0、1、2或3；q為0、1、2、3或4；r為0、1或2；s為0、1、2、3或4；且t為0、1、2、3或4。In one embodiment of the invention, the invention relates to novel compounds of structural formula I: Or a pharmaceutically acceptable salt thereof, wherein: T is selected from the group consisting of CR 3 , N and N-oxide; and U is selected from the group consisting of CR 1 , N and N-oxide; The V system is selected from the group consisting of CR 2 , N and N-oxides; the W system is selected from the group consisting of CR 4 , N and N-oxides, the restrictions being T, U, V and W At least one of them is N or N-oxide; X is absent or selected from: -CH 2 -, -CHF-, -CF 2 -, -S-, -O-, -O-CH 2 -, -NH -, -C(O)-, -NHC(O)-, -C(O)NH-, -NHSO 2 -, -SO 2 NH- and -CO 2 -, wherein each CH 2 is unsubstituted or passed through 1 Or two substituents selected from the group consisting of: hydroxy, halogen, NH 2 , C 1-6 alkyl, CO 2 H, CO 2 C 1-6 alkyl, COC 1-6 alkyl, phenyl and -CH a phenyl group, wherein each NH is unsubstituted or substituted with one substituent selected from the group consisting of C 1-6 alkyl, CO 2 H, CO 2 C 1-6 alkyl, COC 1-6 alkyl, Phenyl and -CH 2 phenyl; Y is selected from: C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 2-10 cycloheteroalkyl, C 2-10 cycloheteroalkenyl, aryl And a heteroaryl group, wherein a cycloalkyl group, a cycloalkenyl group, a cycloheteroalkyl group, a cycloheteroalkenyl group Aryl and heteroaryl unsubstituted or substituted with 1,2, 3 or 4 substituents selected from the substituents R b; the Z is selected from: oxo, -CN, -CF 3, -C 1-6 alkyl , -(CH 2 ) t -halogen, -(CH 2 ) n COC 1-6 alkyl, -(CH 2 ) n CO 2 H, -(CH 2 ) n OCOH, -(CH 2 ) n CO 2 R i , -(CH 2 ) n OCOR i , -(CH 2 ) n OH, -(CH 2 ) n C(O)N(R g ) 2 , -(CH 2 ) n C(O)(CH 2 n N(R g ) 2 , -(CH 2 ) n OC(O)(CH 2 ) n N(R g ) 2 , -(CH 2 ) n NHC(O)C 1-6 alkyl, -( CH 2 ) n NHSO 2 R i , -(CH 2 ) n SO 2 C 1-6 alkyl, -(CH 2 ) n SO 2 NHR g , -(CH 2 ) n SO 2 NHC(O)R i , -(CH 2 ) n SO 2 NHCO 2 R i , -(CH 2 ) n SO 2 NHCON(R g ) 2 , -(CH 2 ) n C(O)NHSO 2 R i , -(CH 2 ) n NHC (O)N(R g ) 2 , -(CH 2 ) n C 3-10 cycloalkyl-CO 2 R e , heteroaryl, -C 2-10 cycloheteroalkenyl and -C 2-10 ring hetero An alkyl group, wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from C 1-6 alkyl, -OH and -NH 2 wherein each NH is unsubstituted or 1 is selected from R c Substituted with a substituent, and wherein each of the alkyl, cycloalkyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl groups is unsubstituted or Substituted by 1, 2, 3 or 4 substituents selected from R c ; each of R 1 and R 2 is independently selected from the group consisting of: hydrogen, halogen, CN, CF 3 , -C 1-6 alkyl, -C 2 -6 alkenyl, -C 2-6 alkynyl, -(CH 2 ) p C 3-10 cycloalkyl, -(CH 2 ) p C 3-7 cycloalkyl-aryl, -(CH 2 ) p C 3-7 cycloalkyl-heteroaryl, -(CH 2 ) p C 4-10 cycloalkenyl, -(CH 2 ) p C 4-7 cycloalkenyl-aryl, -(CH 2 ) p C 4-7 cycloalkenyl-heteroaryl, -(CH 2 ) p C 2-10 cycloheteroalkyl, -(CH 2 ) p C 2-10 cycloheteroalkenyl, -(CH 2 ) p aryl, -(CH 2 ) p aryl-C 3-7 cycloalkyl, -(CH 2 ) p aryl-C 2-7 cycloheteroalkyl, -(CH 2 ) p aryl-aryl, -(CH 2 ) paryl -heteroaryl, -(CH 2 ) p heteroaryl, -C 2-6 alkenyl-alkyl, -C 2-6 alkenyl-aryl, -C 2-6 alkenyl- Heteroaryl, -C 2-6 alkenyl-C 3-7 cycloalkyl, -C 2-6 alkenyl-C 3-7 cycloalkenyl, -C 2-6 alkenyl-C 2-7 ring hetero Alkyl, -C 2-6 alkenyl-C 2-7 cycloheteroalkenyl, -C 2-6 alkynyl-(CH 2 ) 1-3 -O-aryl, -C 2-6 alkynyl-alkane , -C 2-6 alkynyl-aryl, -C 2-6 alkynyl-heteroaryl, -C 2-6 alkynyl-C 3-7 cycloalkyl, -C 2-6 alkynyl-C 3-7 cycloalkenyl, -C 2-6 alkynyl-C 2-7 cycloheteroalkyl, -C 2-6 alkynyl- a C 2-7 cycloheteroalkenyl group and a -C(O)NH-(CH 2 ) 0-3 phenyl group, wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl and -N(C 1-6 alkyl) 2 , wherein alkyl, alkene And alkynyl groups are each unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkane a group, -NHC 1-6 alkyl and -N(C 1-6 alkyl) 2 , and wherein cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, phenyl, aryl and heteroaryl group each unsubstituted or substituted by three or four of independently selected R a substituents, with the proviso that in R 1 and R 2 in at least one of R 1 and R 2, and only one of Is selected from the group consisting of hydrogen, halogen, -CN, -CF 3 , -C 1-6 alkyl, -C 2-6 alkenyl and -C 2-6 alkynyl; each of R 3 and R 4 Independently selected from: hydrogen, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-10 cycloalkyl, -C 3-10 cycloalkenyl , aryl, heteroaryl, -CN, -CF 3, -OH, -OC 1-6 alkyl, -NH 2, -NHC 1-6 alkyl, -N (C 1-6 alkyl ) 2, -SC 1-6 alkyl, -SOC 1-6 alkyl, -SO 2 C 1-6 alkyl, -NHSO 2 C 1-6 alkyl, -NHC (O) C 1-6 alkyl , -SO 2 NHC 1-6 alkyl and -C(O)NHC 1-6 alkyl; R 5 is selected from the group consisting of: hydrogen, -C 1-6 alkyl, -CH 2 CO 2 H, and -CH 2 CO 2 C 1-6 alkyl; each R a is independently selected from the group consisting of halogen, pendant oxy, -(CH 2 ) m OH, -(CH 2 ) m N(R j ) 2 , -( CH 2 ) m NO 2 , -(CH 2 ) m CN, -C 1-6 alkyl, -(CH 2 ) m CF 3 , -(CH 2 ) m OCF 3 , -OCH 2 OC 1-6 alkyl , -(CH 2 ) m C(O)N(R j ) 2 , -(CH 2 ) m C(=N-OH)N(R j ) 2 , -(CH 2 ) m OC 1-6 alkyl , -(CH 2 ) m O-(CH 2 ) m -C 3-7 cycloalkyl, -(CH 2 ) m O-(CH 2 ) m -C 2-7 cycloheteroalkyl, -(CH 2 m O-(CH 2 ) m -aryl, -(CH 2 ) m O-(CH 2 ) m -heteroaryl, -(CH 2 ) m SC 1-6 alkyl, -(CH 2 ) m S(O)C 1-6 alkyl, -(CH 2 ) m SO 2 C 1-6 alkyl, -(CH 2 ) m SO 2 C 3-7 cycloalkyl, -(CH 2 ) m SO 2 C 2-7 cycloheteroalkyl, -(CH 2 ) m SO 2 -aryl, -(CH 2 ) m SO 2 -heteroaryl, -(CH 2 ) m SO 2 NHC 1-6 alkyl, - (CH 2 ) m SO 2 NHC 3-7 cycloalkyl, -(CH 2 ) m SO 2 NHC 2-7 cycloheteroalkyl, -( CH 2 ) m SO 2 NH-aryl, -(CH 2 ) m SO 2 NH-heteroaryl, -(CH 2 ) m NHSO 2 -C 1-6 alkyl, -(CH 2 ) m NHSO 2 - C 3-7 cycloalkyl, -(CH 2 ) m NHSO 2 -C 2-7 cycloheteroalkyl, -(CH 2 ) m NHSO 2 -aryl, -(CH 2 ) m NHSO 2 NH-hetero Base, -(CH 2 ) m C(O)R f , -(CH 2 ) m C(O)N(R j ) 2 , -(CH 2 ) m N(R j )C(O)N(R j ) 2 , -(CH 2 ) m CO 2 H, -(CH 2 ) m OCOH, -(CH 2 ) m CO 2 R f , -(CH 2 ) m OCOR f , -(CH 2 ) m C 3 -7 cycloalkyl, -(CH 2 ) m C 3-7 cycloalkenyl, -(CH 2 ) m C 2-6 cycloheteroalkyl, -(CH 2 ) m C 2-6 cycloheteroalkenyl, -(CH 2 ) m aryl and -(CH 2 ) m heteroaryl, wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of pendant oxy, -(CH 2 ) 0 -3 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, Halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl And CH 2 heteroaryl, and wherein the alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl groups are unsubstituted or 1, 2, 3 or 4 Substituted by a substituent selected from the group consisting of a pendant oxy group, -(CH 2 ) 0-3 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -SO 2 C 1-6 alkyl, -C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl; each R b is independently selected from: hydrogen, -C 1- 6 alkyl, -C 3-6 cycloalkyl, -C 3-6 cycloalkenyl, -C 2-6 cycloheteroalkyl, -C 2-6 cycloheteroalkenyl, aryl, heteroaryl, - (CH 2 ) t -halogen, -(CH 2 ) s -OH, -NO 2 , -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -OC 1-6 alkyl, -(CH 2 ) q CO 2 H, -(CH 2 ) q CO 2 C 1-6 alkyl, -CF 3 , -CN, -SO 2 C 1-6 alkyl and -( CH 2 ) s CON(R e ) 2 , wherein each CH 2 is unsubstituted or substituted with 1 or 2 halogens, and wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, The aryl and heteroaryl are each unsubstituted or substituted by 1, 2 or 3 halogens; each R c is independently selected from the group consisting of: halogen, pendant oxy, -(CH 2 ) r OH, -(CH 2 ) r N(R e ) 2 , -(CH 2 ) r CN, -C 1-6 alkyl, -CF 3 , -C 1-6 alkyl-OH, -OCH 2 OC 1-6 alkyl, -(CH 2 ) r OC 1-6 alkyl, -OCH 2 aryl, -(CH 2 ) r SC 1-6 alkyl, -(CH 2 ) r C(O)R f , -(CH 2 ) r C(O)N(R e ) 2 , -(CH 2 ) r CO 2 H, -(CH 2 ) r CO 2 R f , -(CH 2 ) r C 3-7 cycloalkyl, -(CH 2 ) r C 2-6 cycloheteroalkyl, -(CH 2 ) r aryl and -(CH 2 ) r heteroaryl, wherein Each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of pendant oxy, -OH, -CN, -N(R h ) 2 , -C 1-6 alkyl, -OC 1- 6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3-7 cycloalkyl and heteroaryl, and wherein the alkane The base, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of pendant oxy, -OH, -CN, -N (R h ) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkane a group, a -C 3-7 cycloalkyl group and a heteroaryl group; each of R e , R g and R h is independently selected from the group consisting of hydrogen, -C 1-6 alkyl and -OC 1-6 alkyl, wherein the alkane The base is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: -OH, Alkoxy, halo, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2, -NH (C 1-6 alkyl), and -N (C 1-6 alkyl) 2; each R j Is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, -C(O)R i and -SO 2 R i , wherein the alkyl and cycloalkyl are unsubstituted or passed through , 2, 3 or 4 substituents selected from the group consisting of: -OH, pendant oxy, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH (C 1-6 Alkyl) and -N(C 1-6 alkyl) 2 ; R f and R i are each independently selected from: C 1-6 alkyl, C 4-7 cycloalkyl, C 4-7 cycloalkenyl , C 3-7 cycloheteroalkyl, C 3-7 cycloheteroalkenyl, aryl and heteroaryl, wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl And the heteroaryl group is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of pendant oxy, -OH, -CN, -NH 2 , -C 1-6 alkyl, -OC 1 -6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3-7 cycloalkyl and heteroaryl; n is 0, 1, 2, 3 or 4; m is 0, 1, 2, 3 or 4; p is 0, 1, 2 or 3; q is 0, 1, 2, 3 or 4; r is 0, 1 or 2;s is 0, 1, 2, 3 or 4; and t is 0, 1, 2, 3 or 4.

在本發明之另一實施例中，T係選自由以下組成之群：-CR3 -、N及N-氧化物。在此實施例之一類別中，T為-CR3 -。在此實施例之另一類別中，T係選自由以下組成之群：N及N-氧化物。在此實施例之另一類別中，T為N。在此實施例之另一類別中，T為N-氧化物。Group embodiment, T is selected from the group consisting of the following In another embodiment of the present invention consisting of: -CR 3 -, N-oxide and N-. In one of the categories of this embodiment, T is -CR 3 -. In another class of this embodiment, the T system is selected from the group consisting of N and N-oxides. In another category of this embodiment, T is N. In another class of this embodiment, T is an N-oxide.

在本發明之另一實施例中，U係選自由以下組成之群：-CR1 -、N及N-氧化物。在此實施例之一類別中，U為-CR1 -。在此實施例之另一類別中，U係選自由以下組成之群：N及N-氧化物。在此實施例之另一類別中，U為N。在此實 施例之另一類別中，U係選自由以下組成之群：N-氧化物。In another embodiment of the invention, the U is selected from the group consisting of -CR 1 -, N and N-oxide. In one of the categories of this embodiment, U is -CR 1 -. In another class of this embodiment, the U is selected from the group consisting of N and N-oxides. In another category of this embodiment, U is N. In another class of this embodiment, the U is selected from the group consisting of N-oxides.

在本發明之另一實施例中，V係選自由以下組成之群：-CR2 -、N及N-氧化物。在此實施例之一類別中，V為-CR2 -。在此實施例之另一類別中，V係選自由以下組成之群：N及N-氧化物。在此實施例之另一類別中，V為N。在此實施例之另一類別中，V為N-氧化物。Embodiment, V is selected from the group consisting of the group consisting of In another embodiment of the present invention: -CR 2 -, N-oxide and N-. In one of the categories of this embodiment, V is -CR 2 -. In another class of this embodiment, the V system is selected from the group consisting of N and N-oxides. In another category of this embodiment, V is N. In another class of this embodiment, V is an N-oxide.

在本發明之另一實施例中，W係選自由以下組成之群：-CR4 -、N及N-氧化物。在此實施例之一類別中，W係選自由以下組成之群：-CR4 -。在此實施例之另一類別中，W係選自由以下組成之群：N及N-氧化物。在此實施例之另一類別中，W為N。在此實施例之另一類別中，W為N-氧化物。In another embodiment of the invention, W is selected from the group consisting of -CR 4 -, N and N-oxide. In one of the categories of this embodiment, the W system is selected from the group consisting of -CR 4 -. In another class of this embodiment, the W system is selected from the group consisting of N and N-oxides. In another category of this embodiment, W is N. In another class of this embodiment, W is an N-oxide.

在本發明之另一實施例中，T及W之一為N或N-氧化物，U為CR1 且V為CR2 ，其限制條件為若W為N或N-氧化物，則R1 係選自氫、鹵素、-CN、-CF3 、-C1-6 烷基、-C2-6 烯基及-C2-6 炔基，且若T為N或N-氧化物，則R2 係選自氫、鹵素、-CN、-CF3 、-C1-6 烷基、-C2-6 烯基及-C2-6 炔基。In another embodiment of the invention, one of T and W is N or N-oxide, U is CR 1 and V is CR 2 , with the constraint that if W is N or N-oxide, then R 1 Is selected from the group consisting of hydrogen, halogen, -CN, -CF 3 , -C 1-6 alkyl, -C 2-6 alkenyl, and -C 2-6 alkynyl, and if T is N or N-oxide, then R 2 is selected from the group consisting of hydrogen, halogen, -CN, -CF 3 , -C 1-6 alkyl, -C 2-6 alkenyl, and -C 2-6 alkynyl.

在本發明之另一實施例中，T及W之一為N或N-氧化物，U為CR1 且V為CR2 ，其限制條件為若W為N或N-氧化物，則R1 為鹵素，且若T為N或N-氧化物，則R2 為鹵素。In another embodiment of the invention, one of T and W is N or N-oxide, U is CR 1 and V is CR 2 , with the constraint that if W is N or N-oxide, then R 1 Is a halogen, and if T is N or an N-oxide, then R 2 is a halogen.

在本發明之另一實施例中，T為N或N-氧化物；U為-CR1 -；V為-CR2 -；且W為-CR4 -。在此實施例之一類別中，T為N或N-氧化物；U為-CR1 -；V為-CR2 -，其中R2 為鹵素；且 W為-CR4 -。在此實施例之另一類別中，T為N；U為-CR1 -；V為-CR2 -，其中R2 為鹵素；且W為-CR4 -。In another embodiment of the invention, T is N or N-oxide; U is -CR 1 -; V is -CR 2 -; and W is -CR 4 -. In one class of this embodiment, T is N or N-oxide; U is -CR 1 -; V is -CR 2 -, wherein R 2 is halogen; and W is -CR 4 -. In another class of this embodiment, T is N; U is -CR 1 -; V is -CR 2 -, wherein R 2 is halogen; and W is -CR 4 -.

在本發明之另一實施例中，T及W之一為N或N-氧化物，U為CR1 且V為CR2 ，其限制條件為若W為N或N-氧化物，則R1 為鹵素，且若T為N或N-氧化物，則R2 為氯。In another embodiment of the invention, one of T and W is N or N-oxide, U is CR 1 and V is CR 2 , with the constraint that if W is N or N-oxide, then R 1 Is a halogen, and if T is N or an N-oxide, then R 2 is chlorine.

在本發明之另一實施例中，T為N或N-氧化物，U為CR1 ，V為CR2 ，且W為CR4 。在此類別之一子類中，T為N，U為CR1 ，V為CR2 ，且W為CR4 。在此類別之另一子類中，T為N，U為CR1 ，V為CR2 ，W為CR4 ，且R2 為鹵素。在此類別之另一子類中，T為N，U為CR1 ，V為CR2 ，W為CR4 ，且R2 為氯。在此類別之另一子類中，T為N，U為CR1 ，V為CR2 ，W為CR4 ，R2 為氯，且R4 為氫。In another embodiment of the invention, T is N or an N-oxide, U is CR 1 , V is CR 2 , and W is CR 4 . In one of the subclasses of this category, T is N, U is CR 1 , V is CR 2 , and W is CR 4 . In another subclass of this class, T is N, U is CR 1 , V is CR 2 , W is CR 4 , and R 2 is halogen. In another subclass of this class, T is N, U is CR 1 , V is CR 2 , W is CR 4 , and R 2 is chlorine. In another subclass of this class, T is N, U is CR 1 , V is CR 2 , W is CR 4 , R 2 is chlorine, and R 4 is hydrogen.

在本發明之另一實施例中，X不存在。In another embodiment of the invention, X does not exist.

在本發明之另一實施例中，X係選自：-CH2 -、-CHF-、-CF2 -、-S-、-O-、-O-CH2 -、-NH-、-C(O)-、-NHC(O)-、-C(O)NH-、-NHSO2 -、-SO2 NH-及-CO2 -，其中各CH2 未經取代或經1或2個選自以下之取代基取代：羥基、鹵素、NH2 、C1-6 烷基、CO2 H、CO2 C1-6 烷基、COC1-6 烷基、苯基及-CH2 苯基，且其中各NH未經取代或經1個選自以下之取代基取代：C1-6 烷基、CO2 H、CO2 C1-6 烷基、COC1-6 烷基、苯基及-CH2 苯基。在此實施例之一類別中，X不存在或選自：-CH2 -、-CHF-、-CF2 -、-S-、-O-、-O-CH2 -及-NH-。在此實施例之另一類別中，X不存在或選自：-CH2 -、-O-及-O-CH2 -。在此實施例之另一類別中，X不存在或選自：-O-及-O- CH2 -。在此實施例之另一類別中，X係選自：-O-及-O-CH2 -。在此實施例之另一類別中，X為-O-。在此實施例之另一類別中，X為-O-CH2 -。在此實施例之另一類別中，X不存在或選自：-C(O)-、-NHC(O)-、-C(O)NH-、-NHSO2 -、-SO2 NH-及-CO2 -。In another embodiment of the present invention, X is selected from the group consisting of: -CH 2 -, -CHF-, -CF 2 -, -S-, -O-, -O-CH 2 -, -NH-, -C (O)-, -NHC(O)-, -C(O)NH-, -NHSO 2 -, -SO 2 NH- and -CO 2 -, wherein each CH 2 is unsubstituted or selected by 1 or 2 Substituted from the following substituents: hydroxy, halogen, NH 2 , C 1-6 alkyl, CO 2 H, CO 2 C 1-6 alkyl, COC 1-6 alkyl, phenyl and -CH 2 phenyl, And wherein each NH is unsubstituted or substituted with one substituent selected from the group consisting of C 1-6 alkyl, CO 2 H, CO 2 C 1-6 alkyl, COC 1-6 alkyl, phenyl and CH 2 phenyl. In one of the classes of this embodiment, X is absent or selected from the group consisting of: -CH 2 -, -CHF-, -CF 2 -, -S-, -O-, -O-CH 2 -, and -NH-. In this embodiment another class of embodiments, X is absent or is selected from: -CH 2 -, - O-, and -O-CH 2 -. In this embodiment another class of embodiments, X is absent or is selected from: -O- and -O- CH 2 -. In this embodiment another class of embodiments, X is selected from: -O- and -O-CH 2 -. In another class of this embodiment, X is -O-. In this embodiment another class of embodiments, X is -O-CH 2 -. In another class of this embodiment, X is absent or selected from the group consisting of: -C(O)-, -NHC(O)-, -C(O)NH-, -NHSO 2 -, -SO 2 NH- and -CO 2 -.

在本發明之另-實施例中，X為-O-。In another embodiment of the invention, X is -O-.

在本發明之另一實施例中，Y係選自：C3-10 環烷基、C3-10 環烯基、C2-10 環雜烷基、C2-10 環雜烯基、芳基及雜芳基，其中環烷基、環烯基、環雜烷基、環雜烯基、芳基及雜芳基未經取代或經1、2、3或4個選自Rb 之取代基取代。在此實施例之一類別中，Y係選自：C3-10 環烷基、C2-10 環雜烷基及芳基，其中環烷基、環雜烷基及芳基未經取代或經1、2、3或4個選自Rb 之取代基取代。在此實施例之另一類別中，Y係選自：C3-10 環烷基、C2-10 環雜烷基及苯基，其中環烷基、環雜烷基及苯基未經取代或經1、2、3或4個選自Rb 之取代基取代。在此實施例之另一類別中，Y係選自：環己基、環丁基、環丙基、環戊基、吡咯啶、哌啶、四氫呋喃、四氫哌喃及苯基，其中環烷基、環雜烷基及苯基未經取代或經1、2、3或4個選自Rb 之取代基取代。In another embodiment of the present invention, Y is selected from the group consisting of C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 2-10 cycloheteroalkyl, C 2-10 cycloheteroalkenyl, aromatic And heteroaryl, wherein cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted by 1, 2, 3 or 4 selected from R b Substituted. In one class of this embodiment, Y is selected from the group consisting of: C 3-10 cycloalkyl, C 2-10 cycloheteroalkyl, and aryl, wherein cycloalkyl, cycloheteroalkyl, and aryl are unsubstituted or Substituted by 1, 2, 3 or 4 substituents selected from R b . In another class of this embodiment, Y is selected from the group consisting of C 3-10 cycloalkyl, C 2-10 cycloheteroalkyl, and phenyl, wherein cycloalkyl, cycloheteroalkyl, and phenyl are unsubstituted Or substituted with 1, 2, 3 or 4 substituents selected from R b . In another class of this embodiment, Y is selected from the group consisting of cyclohexyl, cyclobutyl, cyclopropyl, cyclopentyl, pyrrolidine, piperidine, tetrahydrofuran, tetrahydropyran, and phenyl, wherein cycloalkyl The cycloheteroalkyl and phenyl groups are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R b .

在此實施例之另一類別中，Y係選自：C3-7 環烷基及芳基，其中環烷基及芳基各自未經取代或經1、2、3或4個選自Rb 之取代基取代。在此類別之一子類中，Y係選自：環己基及苯基，其中環烷基及苯基各自未經取代或經1、2、3或4個選自Rb 之取代基取代。In another class of this embodiment, Y is selected from the group consisting of: C 3-7 cycloalkyl and aryl, wherein the cycloalkyl and aryl are each unsubstituted or 1, 2, 3 or 4 are selected from R Substituted by b . In a subclass of this class, Y is selected from the group consisting of cyclohexyl and phenyl, wherein the cycloalkyl and phenyl are each unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R b .

在此實施例之另一類別中，Y為芳基，其中各芳基未經取代或經1、2、3或4個選自Rb 之取代基取代。在此類別之一子類中，Y為苯基，其中各苯基未經取代或經1、2、3或4個選自Rb 之取代基取代。In another class of this embodiment, Y is aryl wherein each aryl group is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R b . In a subclass of this class, Y is phenyl wherein each phenyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R b .

在此實施例之另一類別中，Y係選自：C3-10 環烷基，其中各環烷基未經取代或經1、2、3或4個選自Rb 之取代基取代。在此類別之一子類中，Y為環己基，其中各環己基未經取代或經1、2、3或4個選自Rb 之取代基取代。In another class of this embodiment, Y is selected from the group consisting of: C 3-10 cycloalkyl, wherein each cycloalkyl group is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R b . In a subclass of this class, Y is cyclohexyl wherein each cyclohexyl group is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R b .

在本發明之另一實施例中，Y係選自：C3-7 環烷基、C2-10 環雜烷基及苯基，其中環烷基、環雜烷基及苯基各自未經取代或經1、2、3或4個選自Rb 之取代基取代。在此實施例之一類別中，Y係選自：環丁基、環己基、1,4：3,6-二去水-D-甘露糖醇、四氫哌喃及苯基，其中環丁基、環己基、四氫哌喃及苯基各自未經取代或經1、2、3或4個選自Rb 之取代基取代。在此實施例之另一類別中，Y係選自：環丁基、環己基、1,4：3,6-二去水-D-甘露糖醇、2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃、四氫哌喃及苯基，其中環丁基、環己基、四氫哌喃及苯基各自未經取代或經1、2、3或4個選自Rb 之取代基取代。在此實施例之另一類別中，Y係選自：環丁基、環己基、2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃、四氫哌喃及苯基，其中環丁基、環己基、四氫哌喃及苯基各自未經取代或經1、2、3或4個選自Rb 之取代基取代。In another embodiment of the present invention, Y is selected from the group consisting of C 3-7 cycloalkyl, C 2-10 cycloheteroalkyl, and phenyl, wherein cycloalkyl, cycloheteroalkyl, and phenyl are each not Substituted or substituted with 1, 2, 3 or 4 substituents selected from R b . In one of the embodiments, Y is selected from the group consisting of: cyclobutyl, cyclohexyl, 1,4:3,6-dide-D-mannitol, tetrahydropyran, and phenyl, wherein cyclopentane The group, cyclohexyl, tetrahydropyran and phenyl are each unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R b . In another class of this embodiment, Y is selected from the group consisting of: cyclobutyl, cyclohexyl, 1,4:3,6-dide-D-mannitol, 2,3,3a,5,6, 6a-hexahydrofuro[3,2-b]furan, tetrahydropyran and phenyl, wherein cyclobutyl, cyclohexyl, tetrahydropyran and phenyl are each unsubstituted or 1, 2, 3 or Four substituents selected from R b are substituted. In another class of this embodiment, Y is selected from the group consisting of: cyclobutyl, cyclohexyl, 2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan, tetrahydroperylene And phenyl, wherein each of cyclobutyl, cyclohexyl, tetrahydropyran and phenyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R b .

在本發明之另一實施例中，Y係選自：C2-10 環雜烷基， 其中各環雜烷基未經取代或經1、2、3或4個選自Rb 之取代基取代。在此實施例之一類別中，Y為六氫呋喃并[3,2-b]呋喃。在此實施例之另一類別中，Y為2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃。In another embodiment of the present invention, Y is selected from the group consisting of: C 2-10 cycloheteroalkyl, wherein each cycloheteroalkyl group is unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from R b Replace. In one of the classes of this embodiment, Y is hexahydrofuro[3,2-b]furan. In another class of this embodiment, Y is 2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan.

在本發明之另一實施例中，Z係選自：側氧基、-CN、-CF3 、-C1-6 烷基、-(CH2 )t -鹵素、-(CH2 )n COC1-6 烷基、-(CH2 )n CO2 H、-(CH2 )n OCOH、-(CH2 )n CO2 Ri 、-(CH2 )n OCORi 、-(CH2 )n OH、-(CH2 )n C(O)N(Rg )2 、-(CH2 )n C(O)(CH2 )n N(Rg )2 、-(CH2 )n OC(O)(CH2 )n N(Rg )2 、-(CH2 )n NHC(O)C1-6 烷基、-(CH2 )n NHSO2 Ri 、-(CH2 )n SO2 C1-6 烷基、-(CH2 )n SO2 NHRg 、-(CH2 )n SO2 NHC(O)Ri 、-(CH2 )n SO2 NHCO2 Ri 、-(CH2 )n SO2 NHCON(Rg )2 、-(CH2 )n C(O)NHSO2 Ri 、-(CH2 )n NHC(O)N(Rg )2 、-(CH2 )n C3-10 環烷基-CO2 Re 、雜芳基、-C2-10 環雜烯基及-C2-10 環雜烷基，其中各CH2 未經取代或經1或2個選自C1-6 烷基、-OH及-NH2 之取代基取代，其中各NH未經取代或經1個選自Rc 之取代基取代，且其中烷基、環烷基、環雜烷基、環雜烯基、芳基及雜芳基各自未經取代或經1、2、3或4個選自Rc 之取代基取代。 N COC (CH 2) - oxo, -CN, -CF 3, -C 1-6 alkyl, - (CH 2) t - halogen: In another embodiment of the present invention, Z is selected from 1-6 alkyl, -(CH 2 ) n CO 2 H, -(CH 2 ) n OCOH, -(CH 2 ) n CO 2 R i , -(CH 2 ) n OCOR i , -(CH 2 ) n OH, -(CH 2 ) n C(O)N(R g ) 2 , -(CH 2 ) n C(O)(CH 2 ) n N(R g ) 2 , -(CH 2 ) n OC(O (CH 2 ) n N(R g ) 2 , -(CH 2 ) n NHC(O)C 1-6 alkyl, -(CH 2 ) n NHSO 2 R i , -(CH 2 ) n SO 2 C 1-6 alkyl, -(CH 2 ) n SO 2 NHR g , -(CH 2 ) n SO 2 NHC(O)R i , -(CH 2 ) n SO 2 NHCO 2 R i , -(CH 2 ) n SO 2 NHCON(R g ) 2 , -(CH 2 ) n C(O)NHSO 2 R i , -(CH 2 ) n NHC(O)N(R g ) 2 , -(CH 2 ) n C 3 a -10 cycloalkyl-CO 2 R e , a heteroaryl group, a -C 2-10 cycloheteroalkenyl group, and a -C 2-10 cycloheteroalkyl group, wherein each CH 2 is unsubstituted or selected from 1 or 2 Substituted with a substituent of C 1-6 alkyl, -OH and -NH 2 wherein each NH is unsubstituted or substituted with one substituent selected from R c , and wherein alkyl, cycloalkyl, cycloheteroalkyl , cycloheteroalkenyl, aryl and heteroaryl, each unsubstituted or substituted by 3 or 4 substituents selected from the substituents R c

在此實施例之一類別中，Z係選自：側氧基、-CN、-CF3 、-C1-6 烷基、-(CH2 )t -鹵素、-(CH2 )n COC1-6 烷基、-(CH2 )n CO2 H、-(CH2 )n OCOH、-(CH2 )n CO2 Ri 、-(CH2 )n OCORi 、-(CH2 )n OH、-(CH2 )n C(O)N(Rg )2 、-(CH2 )n C(O)(CH2 )n N(Rg )2 、-(CH2 )n OC(O)(CH2 )n N(Rg )2 、-(CH2 )n NHC(O)C1-6 烷基、-(CH2 )n NHSO2 Ri 、-(CH2 )n SO2 C1-6 烷基、-(CH2 )n SO2 NHRg 、 -(CH2 )n SO2 NHC(O)Ri 、-(CH2 )n SO2 NHCO2 Ri 、-(CH2 )n SO2 NHCON(Rg )2 、-(CH2 )n C(O)NHSO2 Ri 、-(CH2 )n NHC(O)N(Rg )2 、-(CH2 )n C3-10 環烷基-CO2 Re 、雜芳基、-C2-10 環雜烯基及-C2-10 環雜烷基，其中各CH2 未經取代或經1或2個選自C1-6 烷基、-OH及-NH2 之取代基取代，其中各NH未經取代或經1個選自Rc 之取代基取代，且其中烷基、環烷基、環雜烷基、環雜烯基及雜芳基各自未經取代或經1、2、3或4個選自Rc 之取代基取代。In one embodiment of this category embodiment, Z is selected from: oxo, -CN, -CF 3, -C 1-6 alkyl, - (CH 2) t - halogen, - (CH 2) n COC 1 -6 alkyl, -(CH 2 ) n CO 2 H, -(CH 2 ) n OCOH, -(CH 2 ) n CO 2 R i , -(CH 2 ) n OCOR i , -(CH 2 ) n OH , -(CH 2 ) n C(O)N(R g ) 2 , -(CH 2 ) n C(O)(CH 2 ) n N(R g ) 2 , -(CH 2 ) n OC(O) (CH 2 ) n N(R g ) 2 , -(CH 2 ) n NHC(O)C 1-6 alkyl, -(CH 2 ) n NHSO 2 R i , -(CH 2 ) n SO 2 C 1 -6 alkyl, -(CH 2 ) n SO 2 NHR g , -(CH 2 ) n SO 2 NHC(O)R i , -(CH 2 ) n SO 2 NHCO 2 R i , -(CH 2 ) n SO 2 NHCON(R g ) 2 , -(CH 2 ) n C(O)NHSO 2 R i , -(CH 2 ) n NHC(O)N(R g ) 2 , -(CH 2 ) n C 3- 10 cycloalkyl-CO 2 R e , heteroaryl, -C 2-10 cycloheteroalkenyl and -C 2-10 cycloheteroalkyl, wherein each CH 2 is unsubstituted or 1 or 2 selected from C Substituted with a substituent of 1-6 alkyl, -OH and -NH 2 wherein each NH is unsubstituted or substituted with one substituent selected from R c , and wherein alkyl, cycloalkyl, cycloheteroalkyl, The cycloheteroalkenyl and heteroaryl groups are each unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R c .

在本發明此實施例之另一類別中，Z係選自：側氧基、-CF3 、-C1-6 烷基、-(CH2 )t -鹵素、-(CH2 )n COC1-6 烷基、-(CH2 )n CO2 H、-(CH2 )n OH、-(CH2 )n C(O)N(Rg )2 、-(CH2 )n C(O)(CH2 )n N(Rg )2 、-(CH2 )n SO2 C1-6 烷基及雜芳基，其中各CH2 未經取代或經1或2個選自C1-6 烷基、-OH及-NH2 之取代基取代，其中各NH未經取代或經1個選自Rc 之取代基取代，且其中烷基及雜芳基各自未經取代或經1、2、3或4個選自Rc 之取代基取代。In this embodiment of the present invention, another class of embodiments, Z is selected from: oxo, -CF 3, -C 1-6 alkyl, - (CH 2) t - halogen, - (CH 2) n COC 1 -6 alkyl, -(CH 2 ) n CO 2 H, -(CH 2 ) n OH, -(CH 2 ) n C(O)N(R g ) 2 , -(CH 2 ) n C(O) (CH 2 ) n N(R g ) 2 , —(CH 2 ) n SO 2 C 1-6 alkyl and heteroaryl, wherein each CH 2 is unsubstituted or 1 or 2 is selected from C 1-6 Substituted with a substituent of an alkyl group, -OH and -NH 2 wherein each NH is unsubstituted or substituted with one substituent selected from R c , and wherein the alkyl group and the heteroaryl group are each unsubstituted or 1, 2 , 3 or 4 substituents selected from R c are substituted.

在本發明此實施例之另一類別中，Z係選自：側氧基、-CF3 、-C1-6 烷基、-(CH2 )t -鹵素、-(CH2 )n COC1-6 烷基、-(CH2 )n OCOH、-(CH2 )n CO2 H、-(CH2 )n OH、-(CH2 )n C(O)N(Rg )2 、-(CH2 )n C(O)(CH2 )n N(Rg )2 、-(CH2 )n OC(O)(CH2 )n N(Rg )2 及-(CH2 )n SO2 C1-6 烷基，其中各CH2 未經取代或經1或2個選自C1-6 烷基、-OH及-NH2 之取代基取代，其中各NH未經取代或經1個選自Rc 之取代基取代，且其中各烷基未經取代或經1、2、3或4個選自Rc 之取代基取代。In this embodiment of the present invention, another class of embodiments, Z is selected from: oxo, -CF 3, -C 1-6 alkyl, - (CH 2) t - halogen, - (CH 2) n COC 1 -6 alkyl, -(CH 2 ) n OCOH, -(CH 2 ) n CO 2 H, -(CH 2 ) n OH, -(CH 2 ) n C(O)N(R g ) 2 , -( CH 2 ) n C(O)(CH 2 ) n N(R g ) 2 , -(CH 2 ) n OC(O)(CH 2 ) n N(R g ) 2 and -(CH 2 ) n SO 2 a C 1-6 alkyl group, wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from C 1-6 alkyl, -OH and -NH 2 wherein each NH is unsubstituted or passed through 1 Substituted with a substituent selected from R c , and wherein each alkyl group is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R c .

在本發明此實施例之另一類別中，Z係選自：側氧基、-CF3 、-CH3 、-CH2 F、-COCH3 、-CO2 H、-OH、-CH2 OH、-CH(CH3 )OH、-C(CH3 )2 OH、-C(O)N(OCH3 )(CH3 )、-C(O)(CH2 )NH2 、-OC(O)CH(CH3 )NH2 及-SO2 CH3 ，其中各CH2 未經取代或經1或2個選自C1-6 烷基、-OH及-NH2 之取代基取代，其中各NH未經取代或經1個選自Rc 之取代基取代，且其中各烷基未經取代或經1、2、3或4個選自Rc 之取代基取代。In this embodiment of the present invention, another class of embodiments, Z is selected from: oxo, -CF 3, -CH 3, -CH 2 F, -COCH 3, -CO 2 H, -OH, -CH 2 OH , -CH(CH 3 )OH, -C(CH 3 ) 2 OH, -C(O)N(OCH 3 )(CH 3 ), -C(O)(CH 2 )NH 2 , -OC(O) CH(CH 3 )NH 2 and -SO 2 CH 3 wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from C 1-6 alkyl, -OH and -NH 2 wherein each NH Substituted or substituted with one substituent selected from R c , and wherein each alkyl group is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R c .

在本發明此實施例之另一類別中，Z係選自：側氧基、-CF3 、-C1-6 烷基、-(CH2 )t -鹵素、-(CH2 )n CO2 H、-(CH2 )n OH及-(CH2 )n SO2 C1-6 烷基，其中各CH2 未經取代或經1或2個選自C1-6 烷基、-OH及-NH2 之取代基取代，其中各NH未經取代或經1個選自Rc 之取代基取代，且其中各烷基未經取代或經1、2、3或4個選自Rc 之取代基取代。在本發明此實施例之另一類別中，Z係選自：側氧基、-CF3 、-CH3 、-CH2 F、-CO2 H、-OH、-CH2 OH、-CH(CH3 )OH、-C(CH3 )2 OH及-SO2 CH3 ，其中各CH2 未經取代或經1或2個選自C1-6 烷基、-OH及-NH2 之取代基取代，且其中各烷基未經取代或經1、2、3或4個選自Rc 之取代基取代。In this embodiment of the present invention, another class of embodiments, Z is selected from: oxo, -CF 3, -C 1-6 alkyl, - (CH 2) t - halogen, - (CH 2) n CO 2 H, -(CH 2 ) n OH and -(CH 2 ) n SO 2 C 1-6 alkyl, wherein each CH 2 is unsubstituted or one or two selected from C 1-6 alkyl, -OH and a substituent substituted with -NH 2 wherein each NH is unsubstituted or substituted with 1 substituent selected from R c , and wherein each alkyl group is unsubstituted or 1, 2, 3 or 4 is selected from R c Substituent substitution. In this embodiment of the present invention, another class of embodiments, Z is selected from: oxo, -CF 3, -CH 3, -CH 2 F, -CO 2 H, -OH, -CH 2 OH, -CH ( CH 3 )OH, -C(CH 3 ) 2 OH and -SO 2 CH 3 wherein each CH 2 is unsubstituted or substituted by 1 or 2 selected from C 1-6 alkyl, -OH and -NH 2 Substituent, and wherein each alkyl group is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R c .

在本發明此實施例之另一類別中，Z係選自：側氧基、-CF3 、-CH3 、-CH2 F、-CO2 H、-OH、-CH2 OH、-CH(CH3 )OH、-C(CH3 )2 OH及-SO2 CH3 。In this embodiment of the present invention, another class of embodiments, Z is selected from: oxo, -CF 3, -CH 3, -CH 2 F, -CO 2 H, -OH, -CH 2 OH, -CH ( CH 3 ) OH, -C(CH 3 ) 2 OH and -SO 2 CH 3 .

在此實施例之另一類別中，Z係選自：側氧基、CN、-(CH2 )n CO2 H、-(CH2 )n CO2 Ri 及-(CH2 )n OH。在此類別之一子類中，Z係選自：側氧基、CN、-CO2 H、-CO2 Ri 及-OH。In another class of this embodiment, the Z system is selected from the group consisting of: pendant oxy, CN, -(CH 2 ) n CO 2 H, -(CH 2 ) n CO 2 R i , and -(CH 2 ) n OH. In a subclass of this class, the Z system is selected from the group consisting of: pendant oxy, CN, -CO 2 H, -CO 2 R i and -OH.

在此實施例之另一類別中，Z係選自：-(CH2 )n CO2 H及-(CH2 )n CO2 Ri 。在此類別之一子類中，Z係選自：-CO2 H及-CO2 Ri 。In another class of this embodiment, the Z system is selected from the group consisting of: -(CH 2 ) n CO 2 H and -(CH 2 ) n CO 2 R i . In one subcategory of this category, the Z series is selected from the group consisting of: -CO 2 H and -CO 2 R i .

在本發明之另一實施例中，Z係選自：-(CH2 )n CO2 H及-(CH2 )n OH，其中各CH2 未經取代或經1或2個選自C1-6 烷基、-OH及-NH2 之取代基取代，且其中各NH未經取代或經1個選自Rc 之取代基取代。在此實施例之一類別中，Z係選自：-(CH2 )n CO2 H及-(CH2 )n OH，其中各CH2 未經取代或經1或2個選自C1-6 烷基及-OH之取代基取代。在此實施例之另一類別中，Z係選自：-(CH2 )n CO2 H及-(CH2 )n OH。在此實施例之另一類別中，Z係選自：-CO2 H、-OH、-CH2 OH及-C(CH3 )2 OH。在此實施例之另一類別中，Z係選自：-CO2 H、-CH2 OH及-C(CH3 )2 OH。In another embodiment of the present invention, the Z system is selected from the group consisting of: -(CH 2 ) n CO 2 H and -(CH 2 ) n OH, wherein each CH 2 is unsubstituted or 1 or 2 is selected from C 1 Substituents of -6 alkyl, -OH and -NH 2 are substituted, and wherein each NH is unsubstituted or substituted with one substituent selected from R c . In one class of this embodiment, the Z series is selected from the group consisting of: -(CH 2 ) n CO 2 H and -(CH 2 ) n OH, wherein each CH 2 is unsubstituted or 1 or 2 is selected from C 1- Substituents of 6 alkyl and -OH are substituted. In another class of this embodiment, the Z system is selected from the group consisting of: -(CH 2 ) n CO 2 H and -(CH 2 ) n OH. In another class of this embodiment, the Z system is selected from the group consisting of: -CO 2 H, -OH, -CH 2 OH, and -C(CH 3 ) 2 OH. In another class of this embodiment, the Z system is selected from the group consisting of: -CO 2 H, -CH 2 OH, and -C(CH 3 ) 2 OH.

在本發明之另一實施例中，Z為-CO2 H。In another embodiment of the present invention, Z is -CO 2 H.

在本發明之另一實施例中，Z係選自：-(CH2 )n OH，其中各CH2 未經取代或經1或2個選自C1-6 烷基、-OH及-NH2 之取代基取代，且其中各NH未經取代或經1個選自Rc 之取代基取代。在此實施例之一類別中，Z係選自：-(CH2 )n OH，其中各CH2 未經取代或經1或2個選自C1-6 烷基及-OH之取代基取代。在此實施例之另一類別中，Z係選自：-(CH2 )n OH。在此實施例之另一類別中，Z係選自：-OH、-CH2 OH及-C(CH3 )2 OH。In another embodiment of the invention, the Z series is selected from the group consisting of: -(CH 2 ) n OH wherein each CH 2 is unsubstituted or 1 or 2 selected from C 1-6 alkyl, -OH and -NH Substituent 2 is substituted, and wherein each NH is unsubstituted or substituted with one substituent selected from R c . In one class of this embodiment, the Z system is selected from the group consisting of: -(CH 2 ) n OH, wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from C 1-6 alkyl and -OH . In another class of this embodiment, the Z series is selected from the group consisting of: -(CH 2 ) n OH. In this embodiment another class of embodiments, Z is selected from: -OH, -CH 2 OH and -C (CH 3) 2 OH.

在本發明之另一實施例中，Z係選自：-(CH2 )t -鹵素及-(CH2 )n OH，其中各CH2 未經取代或經1或2個選自C1-6 烷 基、-OH及-NH2 之取代基取代。在此實施例之一類別中，Z係選自：-(CH2 )t -鹵素及-(CH2 )n OH。在此實施例之一類別中，Z係選自：-鹵素及-OH。在此實施例之另一類別中，Z係選自：氟及-OH。在此實施例之另一類別中，Z為鹵素。在此實施例之另一類別中，Z為氟。在此實施例之另一類別中，Z為-OH。In another embodiment of the present invention, the Z system is selected from the group consisting of: -(CH 2 ) t -halogen and -(CH 2 ) n OH, wherein each CH 2 is unsubstituted or 1 or 2 is selected from C 1- Substituents of 6 alkyl, -OH and -NH 2 are substituted. In one of the classes of this embodiment, the Z system is selected from the group consisting of: -(CH 2 ) t -halogen and -(CH 2 ) n OH. In one of the classes of this embodiment, the Z system is selected from the group consisting of: -halogen and -OH. In another class of this embodiment, the Z system is selected from the group consisting of: fluorine and -OH. In another class of this embodiment, Z is a halogen. In another class of this embodiment, Z is fluorine. In another class of this embodiment, Z is -OH.

在本發明之另一實施例中，Z係選自：-(CH2 )n CO2 H、-(CH2 )t -鹵素及-(CH2 )n OH，其中各CH2 未經取代或經1或2個選自C1-6 烷基、-OH及-NH2 之取代基取代，且其中各NH未經取代或經1個選自Rc 之取代基取代。在此實施例之一類別中，Z係選自：-(CH2 )n CO2 H、-(CH2 )t -鹵素及-(CH2 )n OH，其中各CH2 未經取代或經1或2個選自C1-6 烷基及-OH之取代基取代。在此實施例之另一類別中，Z係選自：-(CH2 )n CO2 H、鹵素及-(CH2 )n OH。在此實施例之另一類別中，Z係選自：-CO2 H、F、-OH、-CH2 OH及-C(CH3 )2 OH。在此實施例之另一類別中，Z係選自：-CO2 H、F、-OH、-CH2 OH及-C(CH3 )2 OH。In another embodiment of the present invention, the Z system is selected from the group consisting of: -(CH 2 ) n CO 2 H, -(CH 2 ) t -halogen, and -(CH 2 ) n OH, wherein each CH 2 is unsubstituted or Substituted by 1 or 2 substituents selected from C 1-6 alkyl, -OH and -NH 2 , and wherein each NH is unsubstituted or substituted with 1 substituent selected from R c . In one class of this embodiment, the Z system is selected from the group consisting of: -(CH 2 ) n CO 2 H, -(CH 2 ) t -halogen, and -(CH 2 ) n OH, wherein each CH 2 is unsubstituted or One or two substituents selected from C 1-6 alkyl and -OH are substituted. In another class of this embodiment, the Z system is selected from the group consisting of: -(CH 2 ) n CO 2 H, halogen, and -(CH 2 ) n OH. In another class of this embodiment, the Z system is selected from the group consisting of: -CO 2 H, F, -OH, -CH 2 OH, and -C(CH 3 ) 2 OH. In another class of this embodiment, the Z system is selected from the group consisting of: -CO 2 H, F, -OH, -CH 2 OH, and -C(CH 3 ) 2 OH.

在本發明之另一實施例中，R1 及R2 各自係獨立地選自：氫、鹵素、CN、CF3 、-C1-6 烷基、-C2-6 烯基、-C2-6 炔基、-(CH2 )p C3-10 環烷基、-(CH2 )p C3-7 環烷基-芳基、-(CH2 )p C3-7 環烷基-雜芳基、-(CH2 )p C4-10 環烯基、-(CH2 )p C4-7 環烯基-芳基、-(CH2 )p C4-7 環烯基-雜芳基、-(CH2 )p C2-10 環雜烷基、-(CH2 )p C2-10 環雜烯基、-(CH2 )p 芳基、-(CH2 )p 芳基-C3-7 環烷基、-(CH2 )p 芳基-C2-7 環雜烷基、-(CH2 )p 芳基-芳基、 -(CH2 )p 芳基-雜芳基、-(CH2 )p 雜芳基、-C2-6 烯基-烷基、-C2-6 烯基-芳基、-C2-6 烯基-雜芳基、-C2-6 烯基-C3-7 環烷基、-C2-6 烯基-C3-7 環烯基、-C2-6 烯基-C2-7 環雜烷基、-C2-6 烯基-C2-7 環雜烯基、-C2-6 炔基-(CH2 )1-3 -O-芳基、-C2-6 炔基-烷基、-C2-6 炔基-芳基、-C2-6 炔基-雜芳基、-C2-6 炔基-C3-7 環烷基、-C2-6 炔基-C3-7 環烯基、-C2-6 炔基-C2-7 環雜烷基、-C2-6 炔基-C2-7 環雜烯基及-C(O)NH-(CH2 )0-3 苯基，其中各CH2 未經取代或經1或2個選自以下之取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，其中烷基、烯基及炔基各自未經取代或經1、2或3個選自以下之取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，且其中環烷基、環烯基、環雜烷基、環雜烯基、苯基、芳基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代，其限制條件為R1 及R2 中之至少一者以及R1 及R2 中僅一者係選自由以下組成之群：氫、鹵素、-CN、-CF3 、-C1-6 烷基、-C2-6 烯基及-C2-6 炔基。在本發明此實施例之一類別中，R1 及R2 各自係獨立地選自：鹵素、-(CH2 )p C4-10 環烯基、-(CH2 )p 芳基、-(CH2 )p 芳基-C3-7 環烷基、-(CH2 )p 芳基-C2-7 環雜烷基、-(CH2 )p 芳基-芳基、-(CH2 )p 芳基-雜芳基、-(CH2 )p 雜芳基、-C2-6 炔基-芳基，其中各CH2 未經取代或經1或2個選自以下之取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，其中各炔基未經取代或經1、2或3個選自以下之取代基取代：鹵 素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，且其中環烷基、環烯基、環雜烷基、芳基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代，其限制條件為R1 及R2 中之至少一者以及R1 及R2 中僅一者係選自由鹵素組成之群。In another embodiment of the present invention, R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, CN, CF 3 , —C 1-6 alkyl, —C 2-6 alkenyl, —C 2 . -6 alkynyl, -(CH 2 ) p C 3-10 cycloalkyl, -(CH 2 ) p C 3-7 cycloalkyl-aryl, -(CH 2 ) p C 3-7 cycloalkyl- Heteroaryl, -(CH 2 ) p C 4-10 cycloalkenyl, -(CH 2 ) p C 4-7 cycloalkenyl-aryl, -(CH 2 ) p C 4-7 cycloalkenyl-hetero Aryl, -(CH 2 ) p C 2-10 cycloheteroalkyl, -(CH 2 ) p C 2-10 cycloheteroalkenyl, -(CH 2 ) p aryl, -(CH 2 ) p aryl -C 3-7 cycloalkyl, -(CH 2 ) p aryl-C 2-7 cycloheteroalkyl, -(CH 2 ) p aryl-aryl, -(CH 2 ) p aryl-heteroaryl , -(CH 2 ) p heteroaryl, -C 2-6 alkenyl-alkyl, -C 2-6 alkenyl-aryl, -C 2-6 alkenyl-heteroaryl, -C 2- 6 alkenyl-C 3-7 cycloalkyl, -C 2-6 alkenyl-C 3-7 cycloalkenyl, -C 2-6 alkenyl-C 2-7 cycloheteroalkyl, -C 2-6 Alkenyl-C 2-7cycloheteroalkenyl , -C 2-6 alkynyl-(CH 2 ) 1-3 -O-aryl, -C 2-6 alkynyl-alkyl, -C 2-6 alkyne -aryl, -C 2-6 alkynyl-heteroaryl, -C 2-6 alkynyl-C 3-7 cycloalkyl, -C 2-6 alkynyl-C 3-7 cycloalkenyl, - C 2-6 alkynyl -C 2-7 cycloalkyl heteroalkyl, -C 2-6 alkynyl -C 2-7 cycloheteroalkyl Group, and -C (O) NH- (CH 2 ) 0-3 phenyl, wherein each of the CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from the group: halogen, CF 3, -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl and -N(C 1-6 alkyl) 2 , wherein the alkyl, alkenyl and alkynyl groups are not Substituted or substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 An alkyl group and -N(C 1-6 alkyl) 2 , and wherein each of the cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, phenyl, aryl and heteroaryl groups is unsubstituted or three or four of independently selected R a substituents, with the proviso that R 1 and R 2 in the 2, only one line is selected from at least one of R and R 1 and the group consisting of Hydrogen, halogen, -CN, -CF 3 , -C 1-6 alkyl, -C 2-6 alkenyl and -C 2-6 alkynyl. In a class of this embodiment of the invention, R 1 and R 2 are each independently selected from the group consisting of: halo, -(CH 2 ) p C 4-10 cycloalkenyl, -(CH 2 ) p aryl, -( CH 2 ) p aryl-C 3-7 cycloalkyl, -(CH 2 ) p aryl-C 2-7 cycloheteroalkyl, -(CH 2 ) p aryl-aryl, -(CH 2 ) Paryl -heteroaryl, -(CH 2 ) p heteroaryl, -C 2-6 alkynyl-aryl, wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: Halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl and -N(C 1-6 alkyl) 2 , each of which The alkynyl group is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, - NHC 1-6 alkyl and -N(C 1-6 alkyl) 2 , and wherein each of the cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl and heteroaryl groups is unsubstituted or 1, 2 three or four of independently selected R a substituents, with the proviso that R 1 and R 2 in the 2, only one line is selected from at least one of R and R 1 and the group consisting of halogen composition.

在本發明此實施例之另一類別中，R1 及R2 各自係獨立地選自：鹵素、-C4-10 環烯基、-芳基、-芳基-C3-7 環烷基、-芳基-C2-7 環雜烷基、-芳基-芳基、-芳基-雜芳基、-雜芳基、-C2-6 炔基-芳基，其中各炔基未經取代或經1、2或3個選自以下之取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，且其中環烷基、環烯基、環雜烷基、芳基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代，其限制條件為R1 及R2 中之至少一者以及R1 及R2 中僅一者係選自由鹵素組成之群。在本發明此實施例之另一類別中，R1 及R2 各自係獨立地選自：鹵素、-C4-10 環烯基、-苯基、-苯基-C3-7 環烷基、-苯基-C2-7 環雜烷基、-苯基-雜芳基、-雜芳基、-C2-6 炔基-苯基，其中各炔基未經取代或經1、2或3個選自以下之取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，且其中環烷基、環烯基、環雜烷基、苯基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代，其限制條件為R1 及R2 中之至少一者以及R1 及R2 中僅一者係選自由鹵素組成之群。在本發明此實施例之另一類別中，R1 及R2 各自係獨立 地選自：Cl、F、環己烯基、-苯基、苯基-環丙基、苯基-哌嗪、苯基-吡咯啶、-苯基-苯基、苯基-三唑、苯基-噻唑、苯基-吡唑、苯基-噁二唑、苯基-呋喃、-吡啶、苯并間二氧雜環戊烯、吲哚、氮雜吲哚、苯并呋喃、苯并吡唑、苯并二噁烷、四氫異喹啉、氮雜苯并咪唑、-C2 炔基-苯基，其中各炔基未經取代或經1、2或3個選自以下之取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，且其中環烷基、環烯基、環雜烷基、苯基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代，其限制條件為R1 及R2 中之至少一者以及R1 及R2 中僅一者係選自由Cl及F組成之群。在本發明此實施例之另一類別中，R1 及R2 各自係獨立地選自：Cl、環己烯基、-苯基、苯基-環丙基、苯基-哌嗪、苯基-吡咯啶、-苯基-苯基、苯基-三唑、苯基-噻唑、苯基-吡唑、苯基-噁二唑、苯基-呋喃、-吡啶、苯并間二氧雜環戊烯、吲哚、氮雜吲哚、苯并呋喃、苯并吡唑、苯并二噁烷、四氫異喹啉、-C2 炔基-苯基，其中各炔基未經取代或經1、2或3個選自以下之取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，且其中環烷基、環烯基、環雜烷基、苯基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代，其限制條件為R1 及R2 中之至少一者以及R1 及R2 中僅一者為Cl。In another class of this embodiment of the invention, R 1 and R 2 are each independently selected from the group consisting of: halo, -C 4-10 cycloalkenyl, -aryl, -aryl-C 3-7 cycloalkyl , -Aryl-C 2-7 cycloheteroalkyl, -aryl-aryl, -aryl-heteroaryl, -heteroaryl, -C 2-6 alkynyl-aryl, wherein each alkynyl group is not Substituted or substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1- 6 alkyl and -N(C 1-6 alkyl) 2 , and wherein each of the cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl and heteroaryl groups is unsubstituted or 1, 2, 3 or 4 R a independently selected from the substituents, with the proviso that R 1 and R 2 in the 2, only one line is selected from at least one of R and R 1 and the group consisting of halogen composition. In another class of this embodiment of the invention, R 1 and R 2 are each independently selected from the group consisting of: halo, -C 4-10 cycloalkenyl, -phenyl, -phenyl-C 3-7 cycloalkyl , -phenyl-C 2-7 cycloheteroalkyl, -phenyl-heteroaryl, -heteroaryl, -C 2-6 alkynyl-phenyl, wherein each alkynyl group is unsubstituted or 1, 2 Or 3 substituents selected from the group consisting of halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl, and -N ( C 1-6 alkyl) 2 , and wherein each of the cycloalkyl, cycloalkenyl, cycloheteroalkyl, phenyl and heteroaryl groups is unsubstituted or 1, 2, 3 or 4 independently selected from R a the substituents of the group consisting of with the proviso that only one of the two lines selected from the group consisting of halogen in R 1 and R 2 and at least one of R 1 and R. In another class of this embodiment of the invention, R 1 and R 2 are each independently selected from the group consisting of: Cl, F, cyclohexenyl, -phenyl, phenyl-cyclopropyl, phenyl-piperazine, Phenyl-pyrrolidine, -phenyl-phenyl, phenyl-triazole, phenyl-thiazole, phenyl-pyrazole, phenyl-oxadiazole, phenyl-furan, -pyridine, benzodioxine Heterocyclopentene, anthracene, azaindole, benzofuran, benzopyrazole, benzodioxane, tetrahydroisoquinoline, azabenzimidazole, -C 2 alkynyl-phenyl, wherein Each alkynyl group is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl and -N(C 1-6 alkyl) 2 , and wherein each of the cycloalkyl, cycloalkenyl, cycloheteroalkyl, phenyl and heteroaryl groups is unsubstituted or 1, 2 , 3, or 4 substituents independently selected from the substituents R a, with the proviso that R 1 and R 2 and at least one of the R 1 and R 2 only one selected from the group consisting of the group consisting of F and Cl. In another class of this embodiment of the invention, R 1 and R 2 are each independently selected from the group consisting of: Cl, cyclohexenyl, -phenyl, phenyl-cyclopropyl, phenyl-piperazine, phenyl - pyrrolidine, -phenyl-phenyl, phenyl-triazole, phenyl-thiazole, phenyl-pyrazole, phenyl-oxadiazole, phenyl-furan, -pyridine, benzodioxole Pentene, anthracene, azaindole, benzofuran, benzopyrazole, benzodioxane, tetrahydroisoquinoline, -C 2 alkynyl-phenyl, wherein each alkynyl group is unsubstituted or 1, 2 or 3 substituents selected from the group consisting of halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl and -N(C 1-6 alkyl) 2 , and wherein each of the cycloalkyl, cycloalkenyl, cycloheteroalkyl, phenyl and heteroaryl groups is unsubstituted or independently selected 1, 2, 3 or 4 since the R a substituents, with the proviso that R 1 and R 2 in at least one of the 2 and only one of R 1 and R is Cl.

在本發明此實施例之另一類別中，R1 係獨立地選自： -(CH2 )p C4-10 環烯基、-(CH2 )p 芳基、-(CH2 )p 芳基-C3-7 環烷基、-(CH2 )p 芳基-C2-7 環雜烷基、-(CH2 )p 芳基-芳基、-(CH2 )p 芳基-雜芳基、-(CH2 )p 雜芳基、-C2-6 炔基-芳基，其中各CH2 未經取代或經1或2個選自以下之取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，其中各炔基未經取代或經1、2或3個選自以下之取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，且其中環烷基、環烯基、環雜烷基、芳基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代，且R2 係選自由鹵素組成之群。在本發明此實施例之另一類別中，R1 係獨立地選自：-C4-10 環烯基、-芳基、-芳基-C3-7 環烷基、-芳基-C2-7 環雜烷基、-芳基-芳基、-芳基-雜芳基、-雜芳基、-C2-6 炔基-芳基，其中各炔基未經取代或經1、2或3個選自以下之取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，且其中環烷基、環烯基、環雜烷基、芳基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代，且R2 係選自由鹵素組成之群。在本發明此實施例之另一類別中，R1 係獨立地選自：-C4-10 環烯基、-苯基、-苯基-C3-7 環烷基、-苯基-C2-7 環雜烷基、-苯基-雜芳基、-雜芳基、-C2-6 炔基-苯基，其中各炔基未經取代或經1、2或3個選自以下之取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，且其中環烷基、環烯 基、環雜烷基、苯基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代，且R2 係選自由鹵素組成之群。在本發明此實施例之另一類別中，R1 係獨立地選自：環己烯基、-苯基、苯基-環丙基、苯基-哌嗪、苯基-吡咯啶、-苯基-苯基、苯基-三唑、苯基-噻唑、苯基-吡唑、苯基-噁二唑、苯基-呋喃、-吡啶、苯并間二氧雜環戊烯、吲哚、氮雜吲哚、苯并呋喃、苯并吡唑、苯并二噁烷、四氫異喹啉、-C2 炔基-苯基，其中各炔基未經取代或經1、2或3個選自以下之取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，且其中環烷基、環烯基、環雜烷基、苯基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代，且R2 係選自由Cl及F組成之群。在本發明此實施例之另一類別中，R1 係獨立地選自：環己烯基、-苯基、苯基-環丙基、苯基-哌嗪、苯基-吡咯啶、-苯基-苯基、苯基-三唑、苯基-噻唑、苯基-吡唑、苯基-噁二唑、苯基-呋喃、-吡啶、苯并間二氧雜環戊烯、吲哚、氮雜吲哚、苯并呋喃、苯并吡唑、苯并二噁烷、四氫異喹啉、-C2 炔基-苯基，其中各炔基未經取代或經1、2或3個選自以下之取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，且其中環烷基、環烯基、環雜烷基、苯基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代，且R2 為Cl。In another class of this embodiment of the invention, R 1 is independently selected from the group consisting of: -(CH 2 ) p C 4-10 cycloalkenyl, -(CH 2 ) p aryl, -(CH 2 ) p aryl -C 3-7 cycloalkyl, -(CH 2 ) p aryl-C 2-7 cycloheteroalkyl, -(CH 2 ) p aryl-aryl, -(CH 2 ) p aryl-hetero An aryl group, -(CH 2 ) p heteroaryl group, -C 2-6 alkynyl-aryl group, wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl and -N(C 1-6 alkyl) 2 , wherein each alkynyl group is unsubstituted Or substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkane And -N(C 1-6 alkyl) 2 , and wherein each of the cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl and heteroaryl groups is unsubstituted or 1, 2, 3 or 4 independent Substituents selected from R a are substituted, and R 2 is selected from the group consisting of halogens. In another class of this embodiment of the invention, R 1 is independently selected from: -C 4-10 cycloalkenyl, -aryl, -aryl-C 3-7 cycloalkyl, -aryl-C 2-7cycloheteroalkyl , -aryl-aryl, -aryl-heteroaryl, -heteroaryl, -C 2-6 alkynyl-aryl, wherein each alkynyl group is unsubstituted or 2 or 3 substituents selected from the group consisting of halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl and -N (C 1-6 alkyl) 2 , and wherein each of the cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl and heteroaryl groups is unsubstituted or 1, 2, 3 or 4 independently selected from R the group substituted with a substituent, and R 2 is selected from the group consisting of the group consisting of halogen. In another class of this embodiment of the invention, R 1 is independently selected from the group consisting of: -C 4-10 cycloalkenyl, -phenyl, -phenyl-C 3-7 cycloalkyl, -phenyl-C 2-7cycloheteroalkyl , -phenyl-heteroaryl, -heteroaryl, -C 2-6 alkynyl-phenyl, wherein each alkynyl group is unsubstituted or 1, 2 or 3 is selected from the group consisting of Substituted substituents: halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl, and -N(C 1-6 alkyl ) 2, and wherein the cycloalkyl, cycloalkenyl, cycloheteroalkyl, phenyl and heteroaryl, each unsubstituted or substituted by three or four of independently selected R a substituents, and R 2 is selected from the group consisting of halogens. In another class of this embodiment of the invention, R 1 is independently selected from the group consisting of cyclohexenyl, -phenyl, phenyl-cyclopropyl, phenyl-piperazine, phenyl-pyrrolidine, -benzene Base-phenyl, phenyl-triazole, phenyl-thiazole, phenyl-pyrazole, phenyl-oxadiazole, phenyl-furan, -pyridine, benzodioxole, anthracene, Azaindole, benzofuran, benzopyrazole, benzodioxane, tetrahydroisoquinoline, -C 2 alkynyl-phenyl, wherein each alkynyl group is unsubstituted or 1, 2 or 3 Substituted by a substituent selected from the group consisting of halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl, and -N (C 1- 6 alkyl) 2 , and wherein each of the cycloalkyl, cycloalkenyl, cycloheteroalkyl, phenyl and heteroaryl groups is unsubstituted or substituted 1, 2, 3 or 4 independently from R a Substituted, and R 2 is selected from the group consisting of Cl and F. In another class of this embodiment of the invention, R 1 is independently selected from the group consisting of cyclohexenyl, -phenyl, phenyl-cyclopropyl, phenyl-piperazine, phenyl-pyrrolidine, -benzene Base-phenyl, phenyl-triazole, phenyl-thiazole, phenyl-pyrazole, phenyl-oxadiazole, phenyl-furan, -pyridine, benzodioxole, anthracene, Azaindole, benzofuran, benzopyrazole, benzodioxane, tetrahydroisoquinoline, -C 2 alkynyl-phenyl, wherein each alkynyl group is unsubstituted or 1, 2 or 3 Substituted by a substituent selected from the group consisting of halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl, and -N (C 1- 6 alkyl) 2 , and wherein each of the cycloalkyl, cycloalkenyl, cycloheteroalkyl, phenyl and heteroaryl groups is unsubstituted or substituted 1, 2, 3 or 4 independently from R a Substituted, and R 2 is Cl.

在本發明之另一實施例中，R1 及R2 各自係獨立地選自： 鹵素、-C4-10 環烯基、-苯基、-苯基-C3-7 環烷基、-苯基-C2-7 環雜烷基、-苯基-芳基、-苯基-雜芳基、-雜芳基及-C2-6 炔基-苯基，其中各炔基未經取代或經1、2或3個選自以下之取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，且其中環烷基、環烯基、環雜烷基、苯基、芳基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代，其限制條件為R1 及R2 中之至少一者以及R1 及R2 中僅一者係選自由鹵素組成之群。在該實施例之另一類別中，R1 及R2 各自係獨立地選自：鹵素、-苯基-C2-7 環雜烷基及-苯基-芳基，其中環雜烷基、芳基及苯基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代，其限制條件為R1 及R2 中之至少一者以及R1 及R2 中僅一者係選自由鹵素組成之群；或其醫藥學上可接受之鹽。在該實施例之另一類別中，R1 及R2 各自係獨立地選自：鹵素、-苯基-吡咯啶及-苯基-苯基，其中吡咯啶及苯基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代，其限制條件為R1 及R2 中之至少一者以及R1 及R2 中僅一者係選自由鹵素組成之群；或其醫藥學上可接受之鹽。在該實施例之另一類別中，各R1 係獨立地選自：-苯基-C2-7 環雜烷基及-苯基-芳基，其中環雜烷基、芳基及苯基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代，且R2 係選自由鹵素組成之群；或其醫藥學上可接受之鹽。在該實施例之另一類別中，各R1 係獨立地選自：-苯基-C2-7 環雜烷基及-苯基-苯基，其中環雜烷基及苯 基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代，且R2 係選自由鹵素組成之群；或其醫藥學上可接受之鹽。在該實施例之另一類別中，各R1 係獨立地選自：-苯基-吡咯啶及-苯基-苯基，其中吡咯啶及苯基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代，且R2 係選自由鹵素組成之群；或其醫藥學上可接受之鹽。In another embodiment of the present invention, R 1 and R 2 are each independently selected from the group consisting of: halogen, -C 4-10 cycloalkenyl, -phenyl, -phenyl-C 3-7 cycloalkyl, - Phenyl-C 2-7 cycloheteroalkyl, -phenyl-aryl, -phenyl-heteroaryl, -heteroaryl and -C 2-6 alkynyl-phenyl, wherein the alkynyl group is unsubstituted Or substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkane And -N(C 1-6 alkyl) 2 , and wherein each of the cycloalkyl, cycloalkenyl, cycloheteroalkyl, phenyl, aryl and heteroaryl groups is unsubstituted or 1, 2, 3 or four of independently selected R a substituents, with the proviso that R 1 and R 2 in the 2, only one line is selected from at least one of R and R 1 and the group consisting of halogen composition. In another class of this embodiment, R 1 and R 2 are each independently selected from the group consisting of: halo, -phenyl-C 2-7 cycloheteroalkyl, and -phenyl-aryl, wherein cycloheteroalkyl, aryl group and phenyl are each unsubstituted or three or four of independently selected R a substituents, with the proviso that R 1 and R 2 in at least one of R 1 and R 2, and Only one of them is selected from the group consisting of halogen; or a pharmaceutically acceptable salt thereof. In another class of this embodiment, each of R 1 and R 2 is independently selected from the group consisting of halogen, -phenyl-pyrrolidine, and -phenyl-phenyl, wherein pyrrolidine and phenyl are each unsubstituted or three or four of independently selected R a substituents group consisting of with the proviso that only one of the two lines selected from the group consisting of halogen in R 1 and R 2 and at least one of R 1 and R Or a pharmaceutically acceptable salt thereof. In another class of this embodiment, each R 1 is independently selected from the group consisting of: -phenyl-C 2-7 cycloheteroalkyl and -phenyl-aryl, wherein cycloheteroalkyl, aryl, and phenyl Each is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R a , and R 2 is selected from the group consisting of halogen; or a pharmaceutically acceptable salt thereof. In another class of this embodiment, each R 1 is independently selected from the group consisting of: -phenyl-C 2-7 cycloheteroalkyl and -phenyl-phenyl, wherein the cycloheteroalkyl and phenyl are each Substituted or substituted with 1, 2, 3 or 4 substituents independently selected from R a and R 2 is selected from the group consisting of halogen; or a pharmaceutically acceptable salt thereof. In another class of this embodiment, each R 1 is independently selected from the group consisting of: -phenyl-pyrrolidine and -phenyl-phenyl, wherein pyrrolidine and phenyl are each unsubstituted or 1, 2, 3 Or 4 substituents independently selected from R a , and R 2 is selected from the group consisting of halogen; or a pharmaceutically acceptable salt thereof.

在本發明此實施例之另一類別中，R2 係獨立地選自：-(CH2 )p C4-10 環烯基、-(CH2 )p 芳基、-(CH2 )p 芳基-C3-7 環烷基、-(CH2 )p 芳基-C2-7 環雜烷基、-(CH2 )p 芳基-芳基、-(CH2 )p 芳基-雜芳基、-(CH2 )p 雜芳基、-C2-6 炔基-芳基，其中各CH2 未經取代或經1或2個選自以下之取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，其中各炔基未經取代或經1、2或3個選自以下之取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，且其中環烷基、環烯基、環雜烷基、芳基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代，且R1 係選自由鹵素組成之群。在本發明此實施例之另一類別中，R2 係獨立地選自：-C4-10 環烯基、-芳基、-芳基-C3-7 環烷基、-芳基-C2-7 環雜烷基、-芳基-芳基、-芳基-雜芳基、-雜芳基、-C2-6 炔基-芳基，其中各炔基未經取代或經1、2或3個選自以下之取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，且其中環烷基、環烯基、環雜烷基、芳基及雜芳基各自未經取代或 經1、2、3或4個獨立地選自Ra 之取代基取代，且R1 係選自由鹵素組成之群。在本發明此實施例之另一類別中，R2 係獨立地選自：-C4-10 環烯基、-苯基、-苯基-C3-7 環烷基、-苯基-C2-7 環雜烷基、-苯基-苯基、-苯基-雜芳基、-雜芳基、-C2-6 炔基-苯基，其中各炔基未經取代或經1、2或3個選自以下之取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，且其中環烷基、環烯基、環雜烷基、苯基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代，且R1 係選自由鹵素組成之群。在本發明此實施例之另一類別中，R2 係獨立地選自：環己烯基、-苯基、苯基-環丙基、苯基-哌嗪、苯基-吡咯啶、-苯基-苯基、苯基-三唑、苯基-噻唑、苯基-吡唑、苯基-噁二唑、苯基-呋喃、-吡啶、苯并間二氧雜環戊烯、吲哚、氮雜吲哚、苯并呋喃、苯并吡唑、苯并二噁烷、四氫異喹啉、-C2 炔基-苯基，其中各炔基未經取代或經1、2或3個選自以下之取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，且其中環烷基、環烯基、環雜烷基、苯基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代，且R1 係選自由Cl及F組成之群。在本發明此實施例之另一類別中，R2 係獨立地選自：環己烯基、-苯基、苯基-環丙基、苯基-哌嗪、苯基-吡咯啶、-苯基-苯基、苯基-三唑、苯基-噻唑、苯基-吡唑、苯基-噁二唑、苯基-呋喃、-吡啶、苯并間二氧雜環戊烯、吲哚、氮雜吲 哚、苯并呋喃、苯并吡唑、苯并二噁烷、四氫異喹啉、-C2 炔基-苯基，其中各炔基未經取代或經1、2或3個選自以下之取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，且其中環烷基、環烯基、環雜烷基、苯基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代，且R1 為Cl。In another class of this embodiment of the invention, the R 2 is independently selected from the group consisting of: -(CH 2 ) p C 4-10 cycloalkenyl, -(CH 2 ) p aryl, -(CH 2 ) p aryl -C 3-7 cycloalkyl, -(CH 2 ) p aryl-C 2-7 cycloheteroalkyl, -(CH 2 ) p aryl-aryl, -(CH 2 ) p aryl-hetero An aryl group, -(CH 2 ) p heteroaryl group, -C 2-6 alkynyl-aryl group, wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl and -N(C 1-6 alkyl) 2 , wherein each alkynyl group is unsubstituted Or substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkane And -N(C 1-6 alkyl) 2 , and wherein each of the cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl and heteroaryl groups is unsubstituted or 1, 2, 3 or 4 independent Substituents selected from R a are substituted, and R 1 is selected from the group consisting of halogen. In another class of this embodiment of the invention, the R 2 is independently selected from: -C 4-10 cycloalkenyl, -aryl, -aryl-C 3-7 cycloalkyl, -aryl-C 2-7cycloheteroalkyl , -aryl-aryl, -aryl-heteroaryl, -heteroaryl, -C 2-6 alkynyl-aryl, wherein each alkynyl group is unsubstituted or 2 or 3 substituents selected from the group consisting of halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl and -N (C 1-6 alkyl) 2 , and wherein each of the cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl and heteroaryl groups is unsubstituted or 1, 2, 3 or 4 independently selected from R the group substituted with a substituent, and R 1 is selected from the group consisting of the group consisting of halogen. In another class of this embodiment of the invention, the R 2 is independently selected from the group consisting of: -C 4-10 cycloalkenyl, -phenyl, -phenyl-C 3-7 cycloalkyl, -phenyl-C 2-7cycloheteroalkyl , -phenyl-phenyl, -phenyl-heteroaryl, -heteroaryl, -C 2-6 alkynyl-phenyl, wherein each alkynyl group is unsubstituted or passed through 2 or 3 substituents selected from the group consisting of halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl and -N (C 1-6 alkyl) 2 , and wherein each of the cycloalkyl, cycloalkenyl, cycloheteroalkyl, phenyl and heteroaryl groups is unsubstituted or independently selected from 1, 2, 3 or 4 the group substituted with a substituent, and R 1 is selected from the group consisting of the group consisting of halogen. In another class of this embodiment of the invention, the R 2 is independently selected from the group consisting of cyclohexenyl, -phenyl, phenyl-cyclopropyl, phenyl-piperazine, phenyl-pyrrolidine, -benzene Base-phenyl, phenyl-triazole, phenyl-thiazole, phenyl-pyrazole, phenyl-oxadiazole, phenyl-furan, -pyridine, benzodioxole, anthracene, Azaindole, benzofuran, benzopyrazole, benzodioxane, tetrahydroisoquinoline, -C 2 alkynyl-phenyl, wherein each alkynyl group is unsubstituted or 1, 2 or 3 Substituted by a substituent selected from the group consisting of halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl, and -N (C 1- 6 alkyl) 2 , and wherein each of the cycloalkyl, cycloalkenyl, cycloheteroalkyl, phenyl and heteroaryl groups is unsubstituted or substituted 1, 2, 3 or 4 independently from R a Substituted, and R 1 is selected from the group consisting of Cl and F. In another class of this embodiment of the invention, the R 2 is independently selected from the group consisting of cyclohexenyl, -phenyl, phenyl-cyclopropyl, phenyl-piperazine, phenyl-pyrrolidine, -benzene Base-phenyl, phenyl-triazole, phenyl-thiazole, phenyl-pyrazole, phenyl-oxadiazole, phenyl-furan, -pyridine, benzodioxole, anthracene, Azaindole, benzofuran, benzopyrazole, benzodioxane, tetrahydroisoquinoline, -C 2 alkynyl-phenyl, wherein each alkynyl group is unsubstituted or 1, 2 or 3 Substituted by a substituent selected from the group consisting of halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl, and -N (C 1- 6 alkyl) 2 , and wherein each of the cycloalkyl, cycloalkenyl, cycloheteroalkyl, phenyl and heteroaryl groups is unsubstituted or substituted 1, 2, 3 or 4 independently from R a Substituted, and R 1 is Cl.

在本發明之另一實施例中，各R1 係獨立地選自：-(CH2 )p 芳基-C1-8 烷基、-(CH2 )p 芳基-C2-8 烯基、-(CH2 )p 芳基-C2-8 炔基-C1-8 烷基、-(CH2 )p 芳基-C2-8 炔基-C3-7 環烷基、-(CH2 )p 芳基-C2-8 炔基-C3-7 環烯基、-(CH2 )p 芳基-C2-8 炔基-C2-10 環雜烷基、-(CH2 )p 芳基-C2-8 炔基-C2-10 環雜烯基、-(CH2 )p 芳基-C2-8 炔基-芳基、-(CH2 )p 芳基-C2-8 炔基-雜芳基、-(CH2 )p 芳基-C2-10 環雜烷基、-(CH2 )p 芳基-C2-10 環雜烯基、-(CH2 )p 芳基-芳基及-(CH2 )p 芳基-雜芳基，其中各CH2 未經取代或經1或2個選自以下之取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，其中烷基、烯基、炔基、環烷基、環烯基、環雜烷基、環雜烯基、芳基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代。In another embodiment of the invention, each R 1 is independently selected from the group consisting of: -(CH 2 ) p aryl-C 1-8 alkyl, -(CH 2 ) p aryl-C 2-8 alkenyl , -(CH 2 ) p aryl-C 2-8 alkynyl-C 1-8 alkyl, -(CH 2 ) p aryl-C 2-8 alkynyl-C 3-7 cycloalkyl, -( CH 2 ) p aryl-C 2-8 alkynyl-C 3-7 cycloalkenyl, -(CH 2 ) p aryl-C 2-8 alkynyl-C 2-10 cycloheteroalkyl, -(CH 2) p -C 2-8 alkynyl aryl -C 2-10 cycloalkyl heteroalkenyl, - (CH 2) p -C 2-8 alkynyl aryl - aryl, - (CH 2) p aryl - C 2-8 alkynyl-heteroaryl, -(CH 2 ) p aryl-C 2-10 cycloheteroalkyl, -(CH 2 ) p aryl-C 2-10 cycloheteroalkenyl, -(CH 2 ) paryl -aryl and -(CH 2 ) p aryl-heteroaryl, wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from halogen, CF 3 , -OH , -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl and -N(C 1-6 alkyl) 2 , wherein alkyl, alkenyl, alkynyl The cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl groups are each unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R a .

在本發明之另一實施例中，各R1 係獨立地選自：-(CH2 )p 芳基-C2-8 炔基-C1-8 烷基、-(CH2 )p 芳基-C2-8 炔基-C3-7 環烷基、-(CH2 )p 芳基-C2-8 炔基-C2-10 環雜烷基、-(CH2 )p 芳基-C2-10 環雜烯基、-(CH2 )p 芳基-芳基及-(CH2 )p 芳基-雜芳基，其中各CH2 未經取代或經1或2個選自以下之取代基取代：鹵 素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，其中烷基、炔基、環烷基、環雜烷基、環雜烯基、芳基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代。In another embodiment of the present invention, each R 1 is independently selected from the group consisting of: -(CH 2 ) p aryl-C 2-8 alkynyl-C 1-8 alkyl, -(CH 2 ) p aryl -C 2-8 alkynyl-C 3-7 cycloalkyl, -(CH 2 ) p aryl-C 2-8 alkynyl-C 2-10 cycloheteroalkyl, -(CH 2 ) p aryl - C 2-10 cycloheteroalkenyl, -(CH 2 ) p aryl-aryl and -(CH 2 ) p aryl-heteroaryl, wherein each CH 2 is unsubstituted or selected from 1 or 2 below Substituted substituents: halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl, and -N(C 1-6 alkyl ) 2, wherein alkyl, alkynyl, cycloalkyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl, each unsubstituted or substituted with 1,2, 3, or 4 substituents independently selected from R a The substituent is substituted.

在本發明之另一實施例中，各R1 係獨立地選自：-苯基-C2-8 炔基-C1-8 烷基、-苯基-C2-3 炔基-C3-7 環烷基、-苯基-C2-3 炔基-C2-10 環雜烷基、-苯基-C2-10 環雜烯基、聯苯及-苯基-雜芳基，其中烷基、炔基、環烷基、環雜烷基、環雜烯基、苯基、聯苯及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代。In another embodiment of the invention, each R 1 is independently selected from the group consisting of: -phenyl-C 2-8 alkynyl-C 1-8 alkyl, -phenyl-C 2-3 alkynyl-C 3 -7 cycloalkyl, -phenyl-C 2-3 alkynyl-C 2-10 cycloheteroalkyl, -phenyl-C 2-10 cycloheteroalkenyl, biphenyl and -phenyl-heteroaryl, Wherein alkyl, alkynyl, cycloalkyl, cycloheteroalkyl, cycloheteroalkenyl, phenyl, biphenyl and heteroaryl are each unsubstituted or 1, 2, 3 or 4 independently selected from R a The substituent is substituted.

在本發明之另一實施例中，各R1 係獨立地選自：-苯基-C2 炔基C1-5 烷基、-苯基-C2-3 炔基-C3-7 環烷基、-苯基-C2-3 炔基-C2-10 環雜烷基、-苯基-C2-10 環雜烯基、聯苯及-苯基-雜芳基，其中烷基、炔基、環烷基、環雜烷基、苯基、聯苯、環雜烯基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代。在本發明之另一實施例中，各R1 係獨立地選自：苯基-C2 炔基C1-5 烷基、苯基-C2-3 炔基-C3-7 環烷基、苯基-C2-3 炔基-C2-10 環雜烷基、苯基-二氫吡咯并[3,4-c]吡唑、聯苯、苯基-吡啶，其中烷基、炔基、環烷基、環雜烷基、苯基、聯苯、二氫吡咯并[3,4-c]吡唑及吡啶各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代。在本發明之另一實施例中，各R1 係獨立地選自：苯基-C2 炔基-CH(OH)CH3 、苯基-C2 炔基-CH2 CH2 OH、苯基-C2 炔基-C(CH3 )2 OH、苯基-C2 炔基-CH2 OH、苯基-C2 炔 基-CH2 CH2 CH2 OH、苯基-C2 炔基-(CH2 )4 CH3 、苯基-C2 炔基-CH2 CH2 -NH-嘧啶及苯基-C2 炔基-CH2 OCH2 CH2 OCH3 、苯基-C2 炔基-環戊基、苯基-C2 炔基-環戊基-OH、苯基-C3 炔基-環戊基、苯基-C2 炔基-環己基、苯基-C3 炔基-嗎啉、苯基-C2 炔基-哌啶、苯基-C3 炔基-吡咯啶-OH、苯基-C3 炔基-哌嗪-CH3 、苯基-4,6-二氫吡咯并[3,4-c]吡唑、苯基-4,6-二氫吡咯并[3,4-c]吡唑-CH2 C(CH3 )2 OH、苯基-4,6-二氫吡咯并[3,4-c]吡唑-CH2 C(CH3 )2 F、苯基-4,6-二氫吡咯并[3,4-c]吡唑-CH2 環丙基、苯基-4,6-二氫吡咯并[3,4-c]吡唑-CH2 CF3 及苯基-4,6-二氫吡咯并[3,4-c]吡唑-SO2 NH-環丙基、聯苯、聯苯-吡唑、聯苯-吡唑-CH3 、聯苯-吡唑-環丙基、聯苯-吡唑-CH2 C(CH3 )2 OH、聯苯-咪唑、聯苯-咪唑-CH3 、聯苯-噁唑、聯苯-噁二唑、聯苯-噁二唑-CH3 、聯苯-噁二唑-環丙基、聯苯-噁二唑-CF3 、聯苯-噁二唑-OH、聯苯-噻唑、聯苯-三唑、聯苯-四唑、聯苯-二氫咪唑、聯苯-四氫嘧啶、苯基-吡啶、苯基-吡啶-三唑、苯基-吡啶-四唑、苯基-吡啶-吡唑及苯基-吡啶-吡唑-CH2 C(CH3 )2 OH。In another embodiment of the invention, each R 1 is independently selected from the group consisting of: -phenyl-C 2 alkynyl C 1-5 alkyl, -phenyl-C 2-3 alkynyl-C 3-7 ring Alkyl, -phenyl-C 2-3 alkynyl-C 2-10 cycloheteroalkyl, -phenyl-C 2-10 cycloheteroalkenyl, biphenyl and -phenyl-heteroaryl, wherein alkyl , alkynyl, cycloalkyl, cycloheteroalkyl, phenyl, biphenyl, cycloheteroalkenyl and heteroaryl are each unsubstituted or 1, 2, 3 or 4 independently selected from R a substituents Replace. In another embodiment of the invention, each R 1 is independently selected from the group consisting of: phenyl-C 2 alkynyl C 1-5 alkyl, phenyl-C 2-3 alkynyl-C 3-7 cycloalkyl , phenyl-C 2-3 alkynyl-C 2-10 cycloheteroalkyl, phenyl-dihydropyrrolo[3,4-c]pyrazole, biphenyl, phenyl-pyridine, wherein alkyl, alkyne The base, cycloalkyl, cycloheteroalkyl, phenyl, biphenyl, dihydropyrrolo[3,4-c]pyrazole and pyridine are each unsubstituted or independently selected from 1, 2, 3 or 4 Substituent for R a is substituted. In another embodiment of the invention, each R 1 is independently selected from the group consisting of: phenyl-C 2 alkynyl-CH(OH)CH 3 , phenyl-C 2 alkynyl-CH 2 CH 2 OH, phenyl -C 2 alkynyl-C(CH 3 ) 2 OH, phenyl-C 2 alkynyl-CH 2 OH, phenyl-C 2 alkynyl-CH 2 CH 2 CH 2 OH, phenyl-C 2 alkynyl- (CH 2 ) 4 CH 3 , phenyl-C 2 alkynyl-CH 2 CH 2 -NH-pyrimidine and phenyl-C 2 alkynyl-CH 2 OCH 2 CH 2 OCH 3 , phenyl-C 2 alkynyl- Cyclopentyl, phenyl-C 2 alkynyl-cyclopentyl-OH, phenyl-C 3 alkynyl-cyclopentyl, phenyl-C 2 alkynyl-cyclohexyl, phenyl-C 3 alkynyl-? Porphyrin, phenyl-C 2 alkynyl-piperidine, phenyl-C 3 alkynyl-pyrrolidine-OH, phenyl-C 3 alkynyl-piperazine-CH 3 , phenyl-4,6-dihydropyrrole And [3,4-c]pyrazole, phenyl-4,6-dihydropyrrolo[3,4-c]pyrazole-CH 2 C(CH 3 ) 2 OH, phenyl-4,6-di Hydropyrrolo[3,4-c]pyrazole-CH 2 C(CH 3 ) 2 F, phenyl-4,6-dihydropyrrolo[3,4-c]pyrazole-CH 2 cyclopropyl, Phenyl-4,6-dihydropyrrolo[3,4-c]pyrazole-CH 2 CF 3 and phenyl-4,6-dihydropyrrolo[3,4-c]pyrazole-SO 2 NH - cyclopropyl, biphenyl, biphenyl - pyrazole, biphenyl - pyrazole -CH 3, biphenyl - pyrazole - cyclopropyl, biphenyl - pyrazol -CH 2 C ( CH 3 ) 2 OH, biphenyl-imidazole, biphenyl-imidazole-CH 3 , biphenyl-oxazole, biphenyl-oxadiazole, biphenyl-oxadiazole-CH 3 , biphenyl-oxadiazole-ring Propyl, biphenyl-oxadiazole-CF 3 , biphenyl-oxadiazole-OH, biphenyl-thiazole, biphenyl-triazole, biphenyl-tetrazole, biphenyl-dihydroimidazole, biphenyl-tetra Hydropyrimidine, phenyl-pyridine, phenyl-pyridine-triazole, phenyl-pyridine-tetrazole, phenyl-pyridine-pyrazole and phenyl-pyridine-pyrazole-CH 2 C(CH 3 ) 2 OH.

在本發明之另一實施例中，各R1 係獨立地選自：-苯基-C2-10 環雜烯基、聯苯、-苯基-雜芳基，其中環雜烯基、苯基、聯苯及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代。在此實施例之一類別中，各R1 係獨立地選自：-苯基-二氫吡咯并[3,4-c]吡唑、聯苯、-苯基-吡啶，其中苯基、二氫吡咯并[3,4-c]吡唑、聯苯及吡啶各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取 代。在此類別之一子類中，各R1 係獨立地選自：苯基-4,6-二氫吡咯并[3,4-c]吡唑、苯基-4,6-二氫吡咯并[3,4-c]吡唑-CH2 C(CH3 )2 OH、苯基-4,6-二氫吡咯并[3,4-c]吡唑-CH2 C(CH3 )2 F、苯基-4,6-二氫吡咯并[3,4-c]吡唑-CH2 環丙基、苯基-4,6-二氫吡咯并[3,4-c]吡唑-CH2 CF3 及苯基-4,6-二氫吡咯并[3,4-c]吡唑-SO2 NH-環丙基、聯苯、聯苯-吡唑、聯苯-吡唑-CH3 、聯苯-吡唑-環丙基、聯苯-吡唑-CH2 C(CH3 )2 OH、聯苯-咪唑、聯苯-咪唑-CH3 、聯苯-噁唑、聯苯-噁二唑、聯苯-噁二唑-CH3 、聯苯-噁二唑-環丙基、聯苯-噁二唑-CF3 、聯苯-噁二唑-OH、聯苯-噻唑、聯苯-三唑、聯苯-四唑、聯苯-二氫咪唑、聯苯-四氫嘧啶、苯基-吡啶、苯基-吡啶-三唑、苯基-吡啶-四唑、苯基-吡啶-吡唑及苯基-吡啶-吡唑-CH2 C(CH3 )2 OH。In another embodiment of the present invention, each R 1 is independently selected from the group consisting of: -phenyl-C 2-10 cycloheteroalkenyl, biphenyl, -phenyl-heteroaryl, wherein cycloheteroalkenyl, benzene The base, biphenyl and heteroaryl are each unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from R a . In one class of this embodiment, each R 1 is independently selected from the group consisting of: -phenyl-dihydropyrrolo[3,4-c]pyrazole, biphenyl, -phenyl-pyridine, wherein phenyl, Hydropyrrolo[3,4-c]pyrazole, biphenyl and pyridine are each unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from R a . In a subclass of this class, each R 1 is independently selected from the group consisting of: phenyl-4,6-dihydropyrrolo[3,4-c]pyrazole, phenyl-4,6-dihydropyrrole [3,4-c]pyrazole-CH 2 C(CH 3 ) 2 OH, phenyl-4,6-dihydropyrrolo[3,4-c]pyrazole-CH 2 C(CH 3 ) 2 F Phenyl-4,6-dihydropyrrolo[3,4-c]pyrazole-CH 2 cyclopropyl,phenyl-4,6-dihydropyrrolo[3,4-c]pyrazole-CH 2 CF 3 and phenyl-4,6-dihydropyrrolo[3,4-c]pyrazole-SO 2 NH-cyclopropyl, biphenyl, biphenyl-pyrazole, biphenyl-pyrazole-CH 3 , biphenyl-pyrazole-cyclopropyl, biphenyl-pyrazole-CH 2 C(CH 3 ) 2 OH, biphenyl-imidazole, biphenyl-imidazole-CH 3 , biphenyl-oxazole, biphenyl-caca oxadiazole, biphenyl - oxadiazole -CH 3, biphenyl - oxadiazole - cyclopropyl, biphenyl - oxadiazole -CF 3, biphenyl - oxadiazole -OH, biphenyl - thiazole, biphenyl Triazole, biphenyl-tetrazole, biphenyl-dihydroimidazole, biphenyl-tetrahydropyrimidine, phenyl-pyridine, phenyl-pyridine-triazole, phenyl-pyridine-tetrazole, phenyl-pyridine- Pyrazole and phenyl-pyridine-pyrazole-CH 2 C(CH 3 ) 2 OH.

在本發明之另一實施例中，R1 及R2 各自係獨立地選自：鹵素、-C4-10 環烯基、-苯基、苯基-C2-8 炔基-C1-8 烷基、苯基-C2-3 炔基-C3-7 環烷基、苯基-C2-3 炔基-C2-10 環雜烷基、-苯基-C3-7 環烷基、-苯基-C2-7 環雜烷基、苯基-C2-10 環雜烯基、-苯基-芳基、-苯基-雜芳基、-雜芳基及-C2-6 炔基-苯基，且其中烷基、炔基、環烷基、環烯基、環雜烷基、環雜烯基、苯基、芳基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代，其限制條件為R1 及R2 中之至少一者以及R1 及R2 中僅一者係選自鹵素；或其醫藥學上可接受之鹽。In another embodiment of the present invention, R 1 and R 2 are each independently selected from the group consisting of: halogen, -C 4-10 cycloalkenyl, -phenyl, phenyl-C 2-8 alkynyl-C 1- 8- alkyl, phenyl-C 2-3 alkynyl-C 3-7 cycloalkyl, phenyl-C 2-3 alkynyl-C 2-10 cycloheteroalkyl, -phenyl-C 3-7 ring Alkyl, -phenyl-C 2-7 cycloheteroalkyl, phenyl-C 2-10 cycloheteroalkenyl, -phenyl-aryl, -phenyl-heteroaryl, -heteroaryl and -C 2-6 alkynyl-phenyl, and wherein alkyl, alkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, phenyl, aryl and heteroaryl are each unsubstituted or three or four of independently selected R a substituents, with the proviso that R 1 and R 2 in the 2, only one of the lines and at least one of R 1 and R is selected from halogen; or A pharmaceutically acceptable salt.

在本發明之另一實施例中，R1 係獨立地選自：-C4-10 環 烯基、-苯基、苯基-C2 炔基C1-5 烷基、苯基-C2-3 炔基-C3-7 環烷基、苯基-C2-3 炔基-C2-10 環雜烷基、-苯基-C3-7 環烷基、-苯基-C2-7 環雜烷基、苯基-C2-10 環雜烯基、-苯基-苯基、-苯基-雜芳基、-雜芳基及-C2-6 炔基-苯基，其中烷基、炔基、環烷基、環烯基、環雜烷基、環雜烯基、苯基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代。在本發明之另一實施例中，R1 係獨立地選自：-苯基-C2-7 環雜烷基、-苯基-C2-10 環雜烯基、-苯基-苯基及-苯基-雜芳基，其中環雜烷基、環雜烯基、雜芳基及苯基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代。In another embodiment of the present invention, R 1 is independently selected from the group consisting of: -C 4-10 cycloalkenyl, -phenyl, phenyl-C 2 alkynyl C 1-5 alkyl, phenyl-C 2 -3 alkynyl-C 3-7 cycloalkyl, phenyl-C 2-3 alkynyl-C 2-10 cycloheteroalkyl, -phenyl-C 3-7 cycloalkyl, -phenyl-C 2 -7 cycloheteroalkyl, phenyl-C 2-10 cycloheteroalkenyl, -phenyl-phenyl, -phenyl-heteroaryl, -heteroaryl and -C 2-6 alkynyl-phenyl, Wherein alkyl, alkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, phenyl and heteroaryl are each unsubstituted or 1, 2, 3 or 4 independently selected from R the substituents a. In another embodiment of the present invention, R 1 is independently selected from the group consisting of: -phenyl-C 2-7 cycloheteroalkyl, -phenyl-C 2-10 cycloheteroalkenyl, -phenyl-phenyl and - phenyl - heteroaryl, wherein cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl and phenyl are each unsubstituted or three or four of independently selected R a substituents .

在本發明之另一實施例中，R3 及R4 係各自獨立地選自：氫、鹵素、-C1-6 烷基、-C2-6 烯基、-C2-6 炔基、-C3-10 環烷基、-C3-10 環烯基、芳基、雜芳基、-CN、-CF3 、-OH、-OC1-6 烷基、-NH2 、-NHC1-6 烷基、-N(C1-6 烷基)2 、-SC1-6 烷基、-SOC1-6 烷基、-SO2 C1-6 烷基、-NHSO2 C1-6 烷基、-NHC(O)C1-6 烷基、-SO2 NHC1-6 烷基及-C(O)NHC1-6 烷基。In another embodiment of the present invention, R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, -C 3-10 cycloalkyl, -C 3-10 cycloalkenyl, aryl, heteroaryl, -CN, -CF 3 , -OH, -OC 1-6 alkyl, -NH 2 , -NHC 1 -6 alkyl, -N(C 1-6 alkyl) 2 , -SC 1-6 alkyl, -SOC 1-6 alkyl, -SO 2 C 1-6 alkyl, -NHSO 2 C 1-6 Alkyl, -NHC(O)C 1-6 alkyl, -SO 2 NHC 1-6 alkyl, and -C(O)NHC 1-6 alkyl.

在本發明之另一實施例中，各R3 不存在或獨立地選自：氫、鹵素、-C1-6 烷基、-C2-6 烯基、-C2-6 炔基、-C3-10 環烷基、-C3-10 環烯基、芳基、雜芳基、-CN、-CF3 、-OH、-OC1-6 烷基、-NH2 、-NHC1-6 烷基、-N(C1-6 烷基)2 、-SC1-6 烷基、-SOC1-6 烷基、-SO2 C1-6 烷基、-NHSO2 C1-6 烷基、-NHC(O)C1-6 烷基、-SO2 NHC1-6 烷基及-C(O)NHC1-6 烷基。在此實施例之一類別中，各R3 係獨立地選自：氫、鹵素、-C1-6 烷 基、-C2-6 烯基、-C2-6 炔基、-C3-10 環烷基、-C3-10 環烯基、芳基、雜芳基、-CN、-CF3 、-OH、-OC1-6 烷基、-NH2 、-NHC1-6 烷基、-N(C1-6 烷基)2 、-SC1-6 烷基、-SOC1-6 烷基、-SO2 C1-6 烷基、-NHSO2 C1-6 烷基、-NHC(O)C1-6 烷基、-SO2 NHC1-6 烷基及-C(O)NHC1-6 烷基。在此實施例之另一類別中，各R3 係獨立地選自：氫、鹵素、-C1-6 烷基、-C2-6 烯基、-C2-6 炔基、-CN、-CF3 、-OH、-OC1-6 烷基、-NH2 、-NHC1-6 烷基、-N(C1-6 烷基)2 、-SC1-6 烷基、-SOC1-6 烷基、-SO2 C1-6 烷基、-NHSO2 C1-6 烷基、-NHC(O)C1-6 烷基、-SO2 NHC1-6 烷基及-C(O)NHC1-6 烷基。在此實施例之另一類別中，各R3 係獨立地選自：氫、鹵素、-C1-6 烷基、-CN、-CF3 、-OH、-OC1-6 烷基、-NH2 、-NHC1-6 烷基及-N(C1-6 烷基)2 。在此實施例之另一類別中，各R3 係獨立地選自：氫、鹵素、-C1-6 烷基、-CN、-CF3 、-OH及-OC1-6 烷基。在此實施例之另一類別中，各R3 係獨立地選自：氫及-C1-6 烷基。在此實施例之另一類別中，各R3 為氫。在此實施例之另一類別中，各R3 為-C1-6 烷基。In another embodiment of the invention, each R 3 is absent or independently selected from the group consisting of: hydrogen, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, - C 3-10 cycloalkyl, -C 3-10 cycloalkenyl, aryl, heteroaryl, -CN, -CF 3 , -OH, -OC 1-6 alkyl, -NH 2 , -NHC 1- 6 alkyl, -N(C 1-6 alkyl) 2 , -SC 1-6 alkyl, -SOC 1-6 alkyl, -SO 2 C 1-6 alkyl, -NHSO 2 C 1-6 alkane A group, -NHC(O)C 1-6 alkyl, -SO 2 NHC 1-6 alkyl, and -C(O)NHC 1-6 alkyl. In one class of this embodiment, each R 3 is independently selected from the group consisting of: hydrogen, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3- 10 cycloalkyl, -C 3-10 cycloalkenyl, aryl, heteroaryl, -CN, -CF 3 , -OH, -OC 1-6 alkyl, -NH 2 , -NHC 1-6 alkyl , -N(C 1-6 alkyl) 2 , -SC 1-6 alkyl, -SOC 1-6 alkyl, -SO 2 C 1-6 alkyl, -NHSO 2 C 1-6 alkyl, - NHC(O)C 1-6 alkyl, -SO 2 NHC 1-6 alkyl and -C(O)NHC 1-6 alkyl. In another class of this embodiment, each R 3 is independently selected from the group consisting of hydrogen, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -CN, -CF 3 , -OH, -OC 1-6 alkyl, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -SC 1-6 alkyl, -SOC 1 -6 alkyl, -SO 2 C 1-6 alkyl, -NHSO 2 C 1-6 alkyl, -NHC(O)C 1-6 alkyl, -SO 2 NHC 1-6 alkyl, and -C ( O) NHC 1-6 alkyl. In another class of this embodiment, each R 3 is independently selected from the group consisting of: hydrogen, halogen, -C 1-6 alkyl, -CN, -CF 3 , -OH, -OC 1-6 alkyl, - NH 2 , -NHC 1-6 alkyl and -N(C 1-6 alkyl) 2 . In this embodiment another class of embodiments, each of R 3 are independently selected from: hydrogen, halo, -C 1-6 alkyl, -CN, -CF 3, -OH and -OC 1-6 alkyl. In another class of this embodiment, each R 3 is independently selected from the group consisting of hydrogen and -C 1-6 alkyl. In another class of this embodiment, each R 3 is hydrogen. In another class of this embodiment, each R 3 is -C 1-6 alkyl.

在本發明之另一實施例中，R3 為氫或不存在。在此實施例之一類別中，R3 為氫。在本發明此實施例之另一類別中，R3 不存在。In another embodiment of the present invention, R 3 is hydrogen or absent. In one of the classes of this embodiment, R 3 is hydrogen. In this embodiment of the present invention, another class of embodiments, R 3 is absent.

在本發明之另一實施例中，各R4 不存在或獨立地選自：氫、鹵素、-C1-6 烷基、-C2-6 烯基、-C2-6 炔基、-C3-10 環烷基、-C3-10 環烯基、芳基、雜芳基、-CN、-CF3 、-OH、-OC1-6 烷基、-NH2 、-NHC1-6 烷基、-N(C1-6 烷基)2 、-SC1-6 烷基、 -SOC1-6 烷基、-SO2 C1-6 烷基、-NHSO2 C1-6 烷基、-NHC(O)C1-6 烷基、-SO2 NHC1-6 烷基及-C(O)NHC1-6 烷基。在此實施例之一類別中，各R4 係獨立地選自：氫、鹵素、-C1-6 烷基、-C2-6 烯基、-C2-6 炔基、-C3-10 環烷基、-C3-10 環烯基、芳基、雜芳基、-CN、-CF3 、-OH、-OC1-6 烷基、-NH2 、-NHC1-6 烷基、-N(C1-6 烷基)2 、-SC1-6 烷基、-SOC1-6 烷基、-SO2 C1-6 烷基、-NHSO2 C1-6 烷基、-NHC(O)C1-6 烷基、-SO2 NHC1-6 烷基及-C(O)NHC1-6 烷基。在此實施例之另一類別中，各R4 係獨立地選自：氫、鹵素、-C1-6 烷基、-C2-6 烯基、-C2-6 炔基、-CN、-CF3 、-OH、-OC1-6 烷基、-NH2 、-NHC1-6 烷基、-N(C1-6 烷基)2 、-SC1-6 烷基、-SOC1-6 烷基、-SO2 C1-6 烷基、-NHSO2 C1-6 烷基、-NHC(O)C1-6 烷基、-SO2 NHC1-6 烷基及-C(O)NHC1-6 烷基。在此實施例之另一類別中，各R4 係獨立地選自：氫、鹵素、-C1-6 烷基、-CN、-CF3 、-OH、-OC1-6 烷基、-NH2 、-NHC1-6 烷基及-N(C1-6 烷基)2 。在此實施例之另一類別中，各R4 係獨立地選自：氫、鹵素、-C1-6 烷基、-CN、-CF3 、-OH及-OC1-6 烷基。在此實施例之另一類別中，各R4 係獨立地選自：氫及-C1-6 烷基。在此實施例之另一類別中，各R4 為氫。在此實施例之另一類別中，各R4 為-C1-6 烷基。In another embodiment of the invention, each R 4 is absent or independently selected from the group consisting of: hydrogen, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, - C 3-10 cycloalkyl, -C 3-10 cycloalkenyl, aryl, heteroaryl, -CN, -CF 3 , -OH, -OC 1-6 alkyl, -NH 2 , -NHC 1- 6 alkyl, -N(C 1-6 alkyl) 2 , -SC 1-6 alkyl, -SOC 1-6 alkyl, -SO 2 C 1-6 alkyl, -NHSO 2 C 1-6 alkane A group, -NHC(O)C 1-6 alkyl, -SO 2 NHC 1-6 alkyl, and -C(O)NHC 1-6 alkyl. In one class of this embodiment, each R 4 is independently selected from the group consisting of: hydrogen, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3- 10 cycloalkyl, -C 3-10 cycloalkenyl, aryl, heteroaryl, -CN, -CF 3 , -OH, -OC 1-6 alkyl, -NH 2 , -NHC 1-6 alkyl , -N(C 1-6 alkyl) 2 , -SC 1-6 alkyl, -SOC 1-6 alkyl, -SO 2 C 1-6 alkyl, -NHSO 2 C 1-6 alkyl, - NHC(O)C 1-6 alkyl, -SO 2 NHC 1-6 alkyl and -C(O)NHC 1-6 alkyl. In another class of this embodiment, each R 4 is independently selected from the group consisting of hydrogen, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -CN, -CF 3 , -OH, -OC 1-6 alkyl, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -SC 1-6 alkyl, -SOC 1 -6 alkyl, -SO 2 C 1-6 alkyl, -NHSO 2 C 1-6 alkyl, -NHC(O)C 1-6 alkyl, -SO 2 NHC 1-6 alkyl, and -C ( O) NHC 1-6 alkyl. In another class of this embodiment, each R 4 is independently selected from the group consisting of: hydrogen, halogen, -C 1-6 alkyl, -CN, -CF 3 , -OH, -OC 1-6 alkyl, - NH 2 , -NHC 1-6 alkyl and -N(C 1-6 alkyl) 2 . In another class of this embodiment, each R 4 is independently selected from the group consisting of hydrogen, halogen, -C 1-6 alkyl, -CN, -CF 3 , -OH, and -OC 1-6 alkyl. In another class of this embodiment, each R 4 is independently selected from the group consisting of hydrogen and -C 1-6 alkyl. In another class of this embodiment, each R 4 is hydrogen. In another class of this embodiment, each R 4 is -C 1-6 alkyl.

在本發明之另一實施例中，R4 為氫或不存在。在此實施例之一類別中，R4 為氫。在本發明此實施例之另一類別中，R4 不存在。In another embodiment of the present invention, R 4 is hydrogen or absent. In one of the classes of this embodiment, R 4 is hydrogen. In another class of this embodiment of the invention, R 4 is absent.

在本發明之另一實施例中，R5 係選自由以下組成之群： 氫、-C1-6 烷基、-CH2 CO2 H及-CH2 CO2 C1-6 烷基。在此實施例之一類別中，R5 係選自由以下組成之群：氫及-C1 烷基。在此實施例之另一類別中，R5 為氫。In another embodiment of the present invention, R 5 is selected from the group consisting of hydrogen, -C 1-6 alkyl, -CH 2 CO 2 H, and -CH 2 CO 2 C 1-6 alkyl. In one embodiment categories in this embodiment, R 5 selected from the group consisting of the group consisting of: hydrogen, and -C 1 alkyl. In this embodiment another class of the embodiments, R 5 is hydrogen.

在本發明之另一實施例中，Ra 係獨立地選自由以下組成之群：-(CH2 )m -鹵素、側氧基、-(CH2 )m OH、-(CH2 )m N(Rj )2 、-(CH2 )m NO2 、-(CH2 )m CN、-C1-6 烷基、-(CH2 )m CF3 、-(CH2 )m OCF3 、-O-(CH2 )m -OC1-6 烷基、-(CH2 )m C(O)N(Rj )2 、-(CH2 )m C(=N-OH)N(Rj )2 、-(CH2 )m OC1-6 烷基、-(CH2 )m O-(CH2 )m -C3-7 環烷基、-(CH2 )m O-(CH2 )m -C2-7 環雜烷基、-(CH2 )m O-(CH2 )m -芳基、-(CH2 )m O-(CH2 )m -雜芳基、-(CH2 )m SC1-6 烷基、-(CH2 )m S(O)C1-6 烷基、-(CH2 )m SO2 C1-6 烷基、-(CH2 )m SO2 C3-7 環烷基、-(CH2 )m SO2 C2-7 環雜烷基、-(CH2 )m SO2 -芳基、-(CH2 )m SO2 -雜芳基、-(CH2 )m SO2 NHC1-6 烷基、-(CH2 )m SO2 NHC3-7 環烷基、-(CH2 )m SO2 NHC2-7 環雜烷基、-(CH2 )m SO2 NH-芳基、-(CH2 )m SO2 NH-雜芳基、-(CH2 )m NHSO2 -C1-6 烷基、-(CH2 )m NHSO2 -C3-7 環烷基、-(CH2 )m NHSO2 -C2-7 環雜烷基、-(CH2 )m NHSO2 -芳基、-(CH2 )m NHSO2 NH-雜芳基、-(CH2 )m N(Rj )-C1-6 烷基、-(CH2 )m N(Rj )-C3-7 環烷基、-(CH2 )m N(Rj )-C2-7 環雜烷基、-(CH2 )m N(Rj )-C2-7 環雜烯基、-(CH2 )m N(Rj )-芳基、-(CH2 )m N(Rj )-雜芳基、-(CH2 )m C(O)Rf 、-(CH2 )m C(O)N(Rj )2 、-(CH2 )m N(Rj )C(O)N(Rj )2 、-(CH2 )m CO2 H、-(CH2 )m OCOH、-(CH2 )m CO2 Rf 、-(CH2 )m OCORf 、-(CH2 )m C3-7 環烷基、-(CH2 )m C3-7 環烯基、-(CH2 )m C2-6 環雜烷基、-(CH2 )m C2-6 環雜烯基、-(CH2 )m 芳基及-(CH2 )m 雜芳基，其中各CH2 未經取代或經1或2個選自以下之取代基取代：側氧基、-(CH2 )0-3 OH 、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基，且其中烷基、環烷基、環烯基、環雜烷基、環雜烯基、芳基及雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-5 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-SO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基。In another embodiment of the present invention, R a is independently selected from the group consisting of: -(CH 2 ) m -halogen, pendant oxy, -(CH 2 ) m OH, -(CH 2 ) m N (R j ) 2 , —(CH 2 ) m NO 2 , —(CH 2 ) m CN, —C 1-6 alkyl, —(CH 2 ) m CF 3 , —(CH 2 ) m OCF 3 ,- O-(CH 2 ) m -OC 1-6 alkyl, -(CH 2 ) m C(O)N(R j ) 2 , -(CH 2 ) m C(=N-OH)N(R j ) 2 , -(CH 2 ) m OC 1-6 alkyl, -(CH 2 ) m O-(CH 2 ) m -C 3-7 cycloalkyl, -(CH 2 ) m O-(CH 2 ) m -C 2-7 cycloheteroalkyl, -(CH 2 ) m O-(CH 2 ) m -aryl, -(CH 2 ) m O-(CH 2 ) m -heteroaryl, -(CH 2 ) m SC 1-6 alkyl, -(CH 2 ) m S(O)C 1-6 alkyl, -(CH 2 ) m SO 2 C 1-6 alkyl, -(CH 2 ) m SO 2 C 3 -7 cycloalkyl, -(CH 2 ) m SO 2 C 2-7 cycloheteroalkyl, -(CH 2 ) m SO 2 -aryl, -(CH 2 ) m SO 2 -heteroaryl, -( CH 2 ) m SO 2 NHC 1-6 alkyl, -(CH 2 ) m SO 2 NHC 3-7 cycloalkyl, -(CH 2 ) m SO 2 NHC 2-7 cycloheteroalkyl, -(CH 2 m SO 2 NH-aryl, -(CH 2 ) m SO 2 NH-heteroaryl, -(CH 2 ) m NHSO 2 -C 1-6 alkyl, -(CH 2 ) m NHSO 2 -C 3 -7 cycloalkyl, -(CH 2 ) m NHSO 2 -C 2-7 cycloheteroalkyl, -(CH 2 m NHSO 2 -aryl, -(CH 2 ) m NHSO 2 NH-heteroaryl, -(CH 2 ) m N(R j )-C 1-6 alkyl, -(CH 2 ) m N(R j )-C 3-7 cycloalkyl, -(CH 2 ) m N(R j )-C 2-7 cycloheteroalkyl, -(CH 2 ) m N(R j )-C 2-7 ring Alkenyl, -(CH 2 ) m N(R j )-aryl, -(CH 2 ) m N(R j )-heteroaryl, -(CH 2 ) m C(O)R f , -(CH 2 ) m C(O)N(R j ) 2 , -(CH 2 ) m N(R j )C(O)N(R j ) 2 , -(CH 2 ) m CO 2 H, -(CH 2 m OCOH, -(CH 2 ) m CO 2 R f , -(CH 2 ) m OCOR f , -(CH 2 ) m C 3-7 cycloalkyl, -(CH 2 ) m C 3-7 cycloolefin , -(CH 2 ) m C 2-6 cycloheteroalkyl, -(CH 2 ) m C 2-6 cycloheteroalkenyl, -(CH 2 ) m aryl and -(CH 2 ) m heteroaryl Wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of pendant oxy, -(CH 2 ) 0-3 OH , -CN, -NH 2 , -NH(C 1-6 Alkyl), -N(C 1-6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, —CO 2 C 1-6 alkyl, —C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl, and wherein alkyl, cycloalkyl, cycloalkenyl Base, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl Unsubstituted or substituted by 3 or 4 substituents selected from the substituents: oxo, - (CH 2) 0-5 OH , -CN, -NH 2, -NH (C 1-6 alkyl , -N(C 1-6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H -CO 2 C 1-6 alkyl, -SO 2 C 1-6 alkyl, -C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl.

在本發明之另一實施例中，各Ra 係獨立地選自由以下組成之群：鹵素、側氧基、-(CH2 )m OH、-(CH2 )m N(Rj )2 、-(CH2 )m NO2 、-(CH2 )m CN、-C1-6 烷基、-(CH2 )m CF3 、-(CH2 )m OCF3 、-OCH2 OC1-6 烷基、-(CH2 )m C(O)N(Rj )2 、-(CH2 )m C(=N-OH)N(Rj )2 、-(CH2 )m OC1-6 烷基、-(CH2 )m O-(CH2 )m -C3-7 環烷基、-(CH2 )m O-(CH2 )m -C2-7 環雜烷基、-(CH2 )m O-(CH2 )m -芳基、-(CH2 )m O-(CH2 )m -雜芳基、-(CH2 )m SC1-6 烷基、-(CH2 )m S(O)C1-6 烷基、-(CH2 )m SO2 C1-6 烷基、-(CH2 )m SO2 C3-7 環烷基、-(CH2 )m SO2 C2-7 環雜烷基、-(CH2 )m SO2 -芳基、-(CH2 )m SO2 -雜芳基、-(CH2 )m SO2 NHC1-6 烷基、-(CH2 )m SO2 NHC3-7 環烷基、-(CH2 )m SO2 NHC2-7 環雜烷基、-(CH2 )m SO2 NH-芳基、-(CH2 )m SO2 NH-雜芳基、-(CH2 )m NHSO2 -C1-6 烷基、-(CH2 )m NHSO2 -C3-7 環烷基、-(CH2 )m NHSO2 -C2-7 環雜烷基、-(CH2 )m NHSO2 -芳基、-(CH2 )m NHSO2 NH-雜芳基、-(CH2 )m C(O)Rf 、-(CH2 )m C(O)N(Rj )2 、-(CH2 )m N(Rj )C(O)N(Rj )2 、-(CH2 )m CO2 H、-(CH2 )m OCOH 、-(CH2 )m CO2 Rf 、-(CH2 )m OCORf 、-(CH2 )m C3-7 環烷基、-(CH2 )m C3-7 環烯基、-(CH2 )m C2-6 環雜烷基、-(CH2 )m C2-6 環雜烯基、-(CH2 )m 芳基及-(CH2 )m 雜芳基，其中各CH2 未經取代或經1或2個選自以下之取代基取代：側氧基、-(CH2 )0-3 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基，且其中烷基、環烷基、環烯基、環雜烷基、環雜烯基、芳基及雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-3 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-SO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基。In another embodiment of the present invention, each R a is independently selected from the group consisting of halogen, pendant oxy, -(CH 2 ) m OH, -(CH 2 ) m N(R j ) 2 , -(CH 2 ) m NO 2 , -(CH 2 ) m CN, -C 1-6 alkyl, -(CH 2 ) m CF 3 , -(CH 2 ) m OCF 3 , -OCH 2 OC 1-6 Alkyl, -(CH 2 ) m C(O)N(R j ) 2 , -(CH 2 ) m C(=N-OH)N(R j ) 2 , -(CH 2 ) m OC 1-6 Alkyl, -(CH 2 ) m O-(CH 2 ) m -C 3-7 cycloalkyl, -(CH 2 ) m O-(CH 2 ) m -C 2-7 cycloheteroalkyl, -( CH 2 ) m O-(CH 2 ) m -aryl, -(CH 2 ) m O-(CH 2 ) m -heteroaryl, -(CH 2 ) m SC 1-6 alkyl, -(CH 2 m S(O)C 1-6 alkyl, -(CH 2 ) m SO 2 C 1-6 alkyl, -(CH 2 ) m SO 2 C 3-7 cycloalkyl, -(CH 2 ) m SO 2 C 2-7 cycloheteroalkyl, -(CH 2 ) m SO 2 -aryl, -(CH 2 ) m SO 2 -heteroaryl, -(CH 2 ) m SO 2 NHC 1-6 alkyl , -(CH 2 ) m SO 2 NHC 3-7 cycloalkyl, -(CH 2 ) m SO 2 NHC 2-7 cycloheteroalkyl, -(CH 2 ) m SO 2 NH-aryl, -(CH 2 ) m SO 2 NH-heteroaryl, -(CH 2 ) m NHSO 2 -C 1-6 alkyl, -(CH 2 ) m NHSO 2 -C 3-7 cycloalkyl, -(CH 2 ) m NHSO 2 -C 2-7 cycloheteroalkyl, - (CH 2) m NHSO 2 - aryl , - (CH 2) m NHSO 2 NH- heteroaryl, - (CH 2) m C (O) R f, - (CH 2) m C (O) N (R j) 2, - (CH 2) m N(R j )C(O)N(R j ) 2 , -(CH 2 ) m CO 2 H, -(CH 2 ) m OCOH , -(CH 2 ) m CO 2 R f , -(CH 2 m OCOR f , -(CH 2 ) m C 3-7 cycloalkyl, -(CH 2 ) m C 3-7 cycloalkenyl, -(CH 2 ) m C 2-6 cycloheteroalkyl, -( CH 2 ) m C 2-6 cycloheteroalkenyl, -(CH 2 ) m aryl and -(CH 2 ) m heteroaryl, wherein each CH 2 is unsubstituted or substituted by 1 or 2 selected from Base substitution: pendant oxy, -(CH 2 ) 0-3 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C 1 -6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3-7 naphthenic a base, a phenyl group, a CH 2 phenyl group, a heteroaryl group and a CH 2 heteroaryl group, and wherein the alkyl group, the cycloalkyl group, the cycloalkenyl group, the cycloheteroalkyl group, the cycloheteroalkenyl group, the aryl group and the heteroaryl group are not Substituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of: pendant oxy, -(CH 2 ) 0-3 OH, -CN, -NH 2 , -NH(C 1-6 alkyl ), -N(C 1-6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -SO 2 C 1-6 alkyl, -C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl base.

在此實施例之一類別中，各Ra 係獨立地選自由以下組成之群：鹵素、-(CH2 )m OH、-(CH2 )m N(Rj )2 、-(CH2 )m CN、-C1-6 烷基、-(CH2 )m CF3 、-(CH2 )m OCF3 、-(CH2 )m C(O)N(Rj )2 、-(CH2 )m OC1-6 烷基、-(CH2 )m O-(CH2 )m -C3-7 環烷基、-(CH2 )m O-(CH2 )m -C2-7 環雜烷基、-(CH2 )m SO2 C1-6 烷基、-(CH2 )m SO2 C2-7 環雜烷基、-(CH2 )m SO2 NHC1-6 烷基、-(CH2 )m SO2 NHC3-7 環烷基、-(CH2 )m NHSO2 -C1-6 烷基、-(CH2 )m C(O)Rf 、-(CH2 )m CO2 H、-(CH2 )m CO2 Rf 、-(CH2 )m C3-7 環烷基，其中各CH2 未經取代或經1或2個選自以下之取代基取代：側氧基、-(CH2 )0-3 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、 -OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基，且其中烷基、環烷基及環雜烷基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-3 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-SO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基。In one class of this embodiment, each R a is independently selected from the group consisting of: halogen, -(CH 2 ) m OH, -(CH 2 ) m N(R j ) 2 , -(CH 2 ) m CN, -C 1-6 alkyl, -(CH 2 ) m CF 3 , -(CH 2 ) m OCF 3 , -(CH 2 ) m C(O)N(R j ) 2 , -(CH 2 m OC 1-6 alkyl, -(CH 2 ) m O-(CH 2 ) m -C 3-7 cycloalkyl, -(CH 2 ) m O-(CH 2 ) m -C 2-7 ring Heteroalkyl, -(CH 2 ) m SO 2 C 1-6 alkyl, -(CH 2 ) m SO 2 C 2-7 cycloheteroalkyl, -(CH 2 ) m SO 2 NHC 1-6 alkyl , -(CH 2 ) m SO 2 NHC 3-7 cycloalkyl, -(CH 2 ) m NHSO 2 -C 1-6 alkyl, -(CH 2 ) m C(O)R f , -(CH 2 m CO 2 H, -(CH 2 ) m CO 2 R f , -(CH 2 ) m C 3-7 cycloalkyl, wherein each CH 2 is unsubstituted or has 1 or 2 substituents selected from the group consisting of Substitution: pendant oxy, -(CH 2 ) 0-3 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C 1- 6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3-7 cycloalkyl , phenyl, CH 2 phenyl, heteroaryl and heteroaryl-CH 2, and wherein the alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted 2, 3 or 4 Substituents from the group consisting of: oxo, - (CH 2) 0-3 OH , -CN, -NH 2, -NH (C 1-6 alkyl), - N (C 1-6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -SO 2 C 1-6 alkyl, -C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl.

在此實施例之另一類別中，各Ra 係獨立地選自由以下組成之群：鹵素、-(CH2 )m OH、-N(Rj )2 、-CN、-C1-6 烷基、-(CH2 )m CF3 、-OCF3 、-(CH2 )m C(O)N(Rj )2 、-(CH2 )m OC1-6 烷基、-(CH2 )m O-(CH2 )m -C3-7 環烷基、-(CH2 )m O-(CH2 )m -C2-7 環雜烷基、-SO2 C1-6 烷基、-SO2 C2-7 環雜烷基、-SO2 NHC1-6 烷基、-SO2 NHC3-7 環烷基、-NHSO2 -C1-6 烷基、-C(O)Rf 、-CO2 H、-CO2 Rf 、-C3-7 環烷基，其中各CH2 未經取代或經1或2個選自以下之取代基取代：側氧基、-(CH2 )0-3 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基，且其中烷基、環烷基及環雜烷基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-3 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-SO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳 基及CH2 雜芳基。In another class of this embodiment the group of embodiments, each R a is independently selected from the group consisting of lines consisting of: halogen, - (CH 2) m OH , -N (R j) 2, -CN, -C 1-6 alkyl , -(CH 2 ) m CF 3 , -OCF 3 , -(CH 2 ) m C(O)N(R j ) 2 , -(CH 2 ) m OC 1-6 alkyl, -(CH 2 ) m O-(CH 2 ) m -C 3-7 cycloalkyl, -(CH 2 ) m O-(CH 2 ) m -C 2-7 cycloheteroalkyl, -SO 2 C 1-6 alkyl, -SO 2 C 2-7 cycloheteroalkyl, -SO 2 NHC 1-6 alkyl, -SO 2 NHC 3-7 cycloalkyl, -NHSO 2 -C 1-6 alkyl, -C(O)R f , -CO 2 H, -CO 2 R f , -C 3-7 cycloalkyl, wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of pendant oxy, -(CH 2 ) 0-3 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 Alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3-7 cycloalkyl, phenyl, CH 2 phenyl, a heteroaryl group and a CH 2 heteroaryl group, wherein the alkyl group, the cycloalkyl group and the cycloheteroalkyl group are unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of pendant oxy groups, -( CH 2 ) 0-3 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 ,- C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -SO 2 C 1 1-6 alkyl, -C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and heteroaryl-CH 2.

在此實施例之另一類別中，各Ra 係獨立地選自由以下組成之群：鹵素、-(CH2 )m OH、-N(Rj )2 、-CN、-C1-6 烷基、-(CH2 )m CF3 、-OCF3 、-(CH2 )m C(O)N(Rj )2 、-(CH2 )m OC1-6 烷基、-(CH2 )m O-(CH2 )m -C3-7 環烷基、-(CH2 )m O-(CH2 )m -C2-7 環雜烷基、-SO2 C1-6 烷基、-SO2 C2-7 環雜烷基、-SO2 NHC1-6 烷基、-SO2 NHC3-7 環烷基、-NHSO2 -C1-6 烷基、-C(O)Rf 、-CO2 H、-CO2 Rf 、-C3-7 環烷基，其中各CH2 未經取代或經1或2個選自以下之取代基取代：-OH、-C1-6 烷基、-OC1-6 烷基及鹵素，且其中烷基、環烷基及環雜烷基未經取代或經1、2、3或4個選自以下之取代基取代：-C1-6 烷基、鹵素、-SO2 C1-6 烷基及-C3-7 環烷基。In another class of this embodiment, each R a is independently selected from the group consisting of: halo, -(CH 2 ) m OH, -N(R j ) 2 , -CN, -C 1-6 alkane , -(CH 2 ) m CF 3 , -OCF 3 , -(CH 2 ) m C(O)N(R j ) 2 , -(CH 2 ) m OC 1-6 alkyl, -(CH 2 ) m O-(CH 2 ) m -C 3-7 cycloalkyl, -(CH 2 ) m O-(CH 2 ) m -C 2-7 cycloheteroalkyl, -SO 2 C 1-6 alkyl, -SO 2 C 2-7 cycloheteroalkyl, -SO 2 NHC 1-6 alkyl, -SO 2 NHC 3-7 cycloalkyl, -NHSO 2 -C 1-6 alkyl, -C(O)R f , -CO 2 H, -CO 2 R f , -C 3-7 cycloalkyl, wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: -OH, -C 1- 6 alkyl, -OC 1-6 alkyl and halogen, and wherein the alkyl, cycloalkyl and cycloheteroalkyl groups are unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from: -C 1-6 alkyl, halogen, -SO 2 C 1-6 alkyl and -C 3-7 cycloalkyl.

在此實施例之另一類別中，各Ra 係獨立地選自由以下組成之群：F、Cl、Br、-C(CH3 )2 OH、-OH、-CH2 OH、-CH(OH)CHF2 、CH(OH)CF3 、-(CH2 )2 C(CH3 )2 -OH、-N(CH3 )2 、-CN、-CH3 、-CH2 CH3 、-C(CH3 )3 、-CF3 、-CH2 CF3 、-OCF3 、-C(O)NH-環丙基、-OCH2 CH3 、-OCH3 、-O(CH2 )3 -SO2 CH3 、OCH2 CH2 F、-CH2 OCH3 、-O-環丁基、-O-環戊基、-O-氮雜環丁烷、-O-CH2 -二氧雜環戊烷、-SO2 CH(CH3 )2 、-SO2 CH3 、-SO2 -吡咯啶、-SO2 -氮雜環丁烷、-SO2 NHCH3 、-SO2 NHC(CH3 )3 、-SO2 NH-環丙基、-NHSO2 -CH3 、-C(O)CH(CH3 )2 、C(O)-吡咯啶、-C(O)-嗎啉、-CO2 H、-CO2 -CH(CH3 )2 、-CO2 -C(CH3 )3 及環丙基，其中各CH2 未經取代或經1或2個選自以下之取代基取代：-OH、-C1-6 烷基、-OC1-6 烷基及鹵素，且其中 烷基、環烷基及環雜烷基未經取代或經1、2、3或4個選自以下之取代基取代：-C1-6 烷基、鹵素、-SO2 C1-6 烷基及-C3-7 環烷基。In another class of this embodiment, each R a is independently selected from the group consisting of F, Cl, Br, -C(CH 3 ) 2 OH, -OH, -CH 2 OH, -CH(OH CHF 2 , CH(OH)CF 3 , -(CH 2 ) 2 C(CH 3 ) 2 -OH, -N(CH 3 ) 2 , -CN, -CH 3 , -CH 2 CH 3 , -C( CH 3) 3, -CF 3, -CH 2 CF 3, -OCF 3, -C (O) NH- cyclopropyl, -OCH 2 CH 3, -OCH 3 , -O (CH 2) 3 -SO 2 CH 3 , OCH 2 CH 2 F, -CH 2 OCH 3 , -O-cyclobutyl, -O-cyclopentyl, -O-azetidine, -O-CH 2 -dioxolane , -SO 2 CH(CH 3 ) 2 , -SO 2 CH 3 , -SO 2 -pyrrolidine, -SO 2 -azetidine, -SO 2 NHCH 3 , -SO 2 NHC(CH 3 ) 3 , -SO 2 NH-cyclopropyl, -NHSO 2 -CH 3 , -C(O)CH(CH 3 ) 2 , C(O)-pyrrolidine, -C(O)-morpholine, -CO 2 H, -CO 2 -CH(CH 3 ) 2 , -CO 2 -C(CH 3 ) 3 and a cyclopropyl group, wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: -OH, -C 1-6 alkyl, -OC 1-6 alkyl and halogen, and wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from Substitution: -C 1-6 alkyl, halogen, -SO 2 C 1-6 alkane And -C 3-7 cycloalkyl.

在此實施例之另一類別中，各Ra 係獨立地選自由以下組成之群：F、Cl、Br、-C(CH3 )2 OH、-OH、-CH2 OH、-CH(OH)CHF2 、CH(OH)CF3 、-(CH2 )2 C(CH3 )2 -OH、-N(CH3 )2 、-CN、-CH3 、-CH2 CH3 、-C(CH3 )3 、-CF3 、-CH2 CF3 、-OCF3 、-C(O)NH-環丙基、-OCH2 CH3 、-OCH3 、-O(CH2 )3 -SO2 CH3 、OCH2 CH2 F、-CH2 OCH3 、-O-環丁基、-O-環戊基、-O-氮雜環丁烷、-O-CH2 -二氧雜環戊烷、-SO2 CH(CH3 )2 、-SO2 CH3 、-SO2 -吡咯啶、-SO2 -氮雜環丁烷、-SO2 NHCH3 、-SO2 NHC(CH3 )3 、-SO2 NH-環丙基、-NHSO2 -CH3 、-C(O)CH(CH3 )2 、C(O)-吡咯啶、-C(O)-嗎啉、-CO2 H、-CO2 -CH(CH3 )2 、-CO2 -C(CH3 )3 及環丙基。In another class of this embodiment, each R a is independently selected from the group consisting of F, Cl, Br, -C(CH 3 ) 2 OH, -OH, -CH 2 OH, -CH(OH CHF 2 , CH(OH)CF 3 , -(CH 2 ) 2 C(CH 3 ) 2 -OH, -N(CH 3 ) 2 , -CN, -CH 3 , -CH 2 CH 3 , -C( CH 3) 3, -CF 3, -CH 2 CF 3, -OCF 3, -C (O) NH- cyclopropyl, -OCH 2 CH 3, -OCH 3 , -O (CH 2) 3 -SO 2 CH 3 , OCH 2 CH 2 F, -CH 2 OCH 3 , -O-cyclobutyl, -O-cyclopentyl, -O-azetidine, -O-CH 2 -dioxolane , -SO 2 CH(CH 3 ) 2 , -SO 2 CH 3 , -SO 2 -pyrrolidine, -SO 2 -azetidine, -SO 2 NHCH 3 , -SO 2 NHC(CH 3 ) 3 , -SO 2 NH-cyclopropyl, -NHSO 2 -CH 3 , -C(O)CH(CH 3 ) 2 , C(O)-pyrrolidine, -C(O)-morpholine, -CO 2 H, -CO 2 -CH(CH 3 ) 2 , -CO 2 -C(CH 3 ) 3 and cyclopropyl.

在本發明之另一實施例中，Ra 係獨立地選自由以下組成之群：鹵素、側氧基、-(CH2 )m OH、-(CH2 )m N(Rj )2 、-(CH2 )m NO2 、-(CH2 )m CN、-C1-6 烷基、-(CH2 )m CF3 、-(CH2 )m OCF3 、-OCH2 OC1-6 烷基、-OCH2 -芳基、-(CH2 )m C(=N-OH)N(Rj )2 、-(CH2 )m OC1-6 烷基、-(CH2 )m O-芳基、-(CH2 )m SC1-6 烷基、-(CH2 )m S(O)C1-6 烷基、-(CH2 )m SO2 C1-6 烷基、-(CH2 )m SO2 C3-7 環烷基、-(CH2 )m SO2 C2-7 環雜烷基、-(CH2 )m SO2 -芳基、-(CH2 )m SO2 -雜芳基、-(CH2 )m SO2 NHC1-6 烷基、-(CH2 )m SO2 NHC3-7 環烷基、-(CH2 )m SO2 NHC2-7 環雜烷基、-(CH2 )m SO2 NH-芳基、-(CH2 )m SO2 NH-雜芳基、-(CH2 )m NHSO2 -C1-6 烷基、 -(CH2 )m NHSO2 -C3-7 環烷基、-(CH2 )m NHSO2 -C2-7 環雜烷基、-(CH2 )m NHSO2 -芳基、-(CH2 )m NHSO2 NH-雜芳基、-(CH2 )m C(O)Rf 、-(CH2 )m C(O)N(Rj )2 、-(CH2 )m N(Rj )C(O)N(Rj )2 、-(CH2 )m CO2 H、-(CH2 )m OCOH、-(CH2 )m CO2 Rf 、-(CH2 )m OCORf 、-(CH2 )m C3-7 環烷基、-(CH2 )m C3-7 環烯基、-(CH2 )m C2-6 環雜烷基、-(CH2 )m C2-6 環雜烯基、-(CH2 )m 芳基及-(CH2 )m 雜芳基，其中各CH2 未經取代或經1或2個選自以下之取代基取代：側氧基、-(CH2 )0-3 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基，且其中烷基、環烷基、環烯基、環雜烷基、環雜烯基、芳基及雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-3 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基。In another embodiment of the present invention, R a is independently selected from the group consisting of halogen, pendant oxy, -(CH 2 ) m OH, -(CH 2 ) m N(R j ) 2 ,- (CH 2 ) m NO 2 , -(CH 2 ) m CN, -C 1-6 alkyl, -(CH 2 ) m CF 3 , -(CH 2 ) m OCF 3 , -OCH 2 OC 1-6 alkane , -OCH 2 -aryl, -(CH 2 ) m C(=N-OH)N(R j ) 2 , -(CH 2 ) m OC 1-6 alkyl, -(CH 2 ) m O- Aryl, -(CH 2 ) m SC 1-6 alkyl, -(CH 2 ) m S(O)C 1-6 alkyl, -(CH 2 ) m SO 2 C 1-6 alkyl, -( CH 2 ) m SO 2 C 3-7 cycloalkyl, -(CH 2 ) m SO 2 C 2-7 cycloheteroalkyl, -(CH 2 ) m SO 2 -aryl, -(CH 2 ) m SO 2 -heteroaryl, -(CH 2 ) m SO 2 NHC 1-6 alkyl, -(CH 2 ) m SO 2 NHC 3-7 cycloalkyl, -(CH 2 ) m SO 2 NHC 2-7 ring Heteroalkyl, -(CH 2 ) m SO 2 NH-aryl, -(CH 2 ) m SO 2 NH-heteroaryl, -(CH 2 ) m NHSO 2 -C 1-6 alkyl, -(CH 2 ) m NHSO 2 -C 3-7 cycloalkyl, -(CH 2 ) m NHSO 2 -C 2-7 cycloheteroalkyl, -(CH 2 ) m NHSO 2 -aryl, -(CH 2 ) m NHSO 2 NH-heteroaryl, -(CH 2 ) m C(O)R f , -(CH 2 ) m C(O)N(R j ) 2 , -(CH 2 ) m N(R j )C (O)N(R j ) 2 , -(CH 2 ) m CO 2 H, -( CH 2 ) m OCOH, -(CH 2 ) m CO 2 R f , -(CH 2 ) m OCOR f , -(CH 2 ) m C 3-7 cycloalkyl, -(CH 2 ) m C 3-7 Cycloalkenyl, -(CH 2 ) m C 2-6cycloheteroalkyl , -(CH 2 ) m C 2-6cycloheteroalkenyl , -(CH 2 ) m aryl and -(CH 2 ) m An aryl group wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of pendant oxy, -(CH 2 ) 0-3 OH, -CN, -NH 2 , -NH (C 1 -6 alkyl), -N(C 1-6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , - CO 2 H, —CO 2 C 1-6 alkyl, —C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl, and wherein alkyl, cycloalkyl, The cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl groups are unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of pendant oxy groups, -(CH 2 ) 0-3 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl , halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl And CH 2 heteroaryl.

在此實施例之一類別中，各Ra 係獨立地選自由以下組成之群：鹵素、-(CH2 )m OH、-(CH2 )m N(Rj )2 、-(CH2 )m CN、-C1-6 烷基、-(CH2 )m CF3 、-(CH2 )m OC1-6 烷基、-(CH2 )m SO2 C1-6 烷基、-(CH2 )m SO2 C2-7 環雜烷基、-(CH2 )m SO2 NHC1-6 烷基、-(CH2 )m SO2 NHC3-7 環烷基、-(CH2 )m NHSO2 -C1-6 烷基、-(CH2 )m C(O)Rf 及-(CH2 )m CO2 H，其中各CH2 未經取代或經1或2個選自以下之取代基取代：側氧基、-(CH2 )0-3 OH、-CN 、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基，且其中烷基、環烷基及環雜烷基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-3 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基。In one class of this embodiment, each R a is independently selected from the group consisting of: halogen, -(CH 2 ) m OH, -(CH 2 ) m N(R j ) 2 , -(CH 2 ) m CN, -C 1-6 alkyl, -(CH 2 ) m CF 3 , -(CH 2 ) m OC 1-6 alkyl, -(CH 2 ) m SO 2 C 1-6 alkyl, -( CH 2 ) m SO 2 C 2-7 cycloheteroalkyl, -(CH 2 ) m SO 2 NHC 1-6 alkyl, -(CH 2 ) m SO 2 NHC 3-7 cycloalkyl, -(CH 2 m NHSO 2 -C 1-6 alkyl, -(CH 2 ) m C(O)R f and -(CH 2 ) m CO 2 H, wherein each CH 2 is unsubstituted or selected from 1 or 2 Substituted by the following substituents: pendant oxy, -(CH 2 ) 0-3 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3- a 7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl group, and wherein the alkyl, cycloalkyl and cycloheteroalkyl groups are unsubstituted or 1, 2, 3 or 4 selected Substituted from the following substituents: pendant oxy, -(CH 2 ) 0-3 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halo, -CH 2 F, -CHF 2, -CF 3 -CO 2 H, -CO 2 C 1-6 alkyl.

在此類別之一子類中，各Ra 係獨立地選自由以下組成之群：鹵素、-(CH2 )m OH、-N(Rj )2 、-CN、-C1-6 烷基、-CF3 、-OC1-6 烷基、-SO2 C1-6 烷基、-SO2 C2-7 環雜烷基、-SO2 NHC1-6 烷基、-SO2 NHC3-7 環烷基、-NHSO2 -C1-6 烷基、-C(O)Rf 及-CO2 H，其中烷基、環烷基及環雜烷基各自未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-3 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基。在此類別之另一子類中，各Ra 係獨立地選自由以下組成之群：F、Cl、-CH2 OH、-OH、-N(CH3 )2 、-CN、-CH3 、-CF3 、-OCH3 、-OCH2 CH3 、-C(OH)(CH3 )2 、-CH(OH)CHF2 、-CH(OCH3 )CH3 、-SO2 CH3 、-SO2 CH(CH3 )2 、-SO2 -氮雜環丁烷、-SO2 -吡咯啶、-SO2 NH-第三丁基、-SO2 NH-環丙基、-NHSO2 CH3 、-C(O)CH(CH3 )2 及-CO2 H，其中各CH2 未經取代或經1或2個選自以下之取代基取代：側氧基、-(CH2 )0-3 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基，且其中烷基、環烷基及環雜烷基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-3 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基。在此類別之一子類中，各Ra 係獨立地選自由以下組成之群：F、Cl、-CH2 OH、-OH、-N(CH3 )2 、-CN、-CH3 、-CF3 、-OCH3 、-OCH2 CH3 、-C(OH)(CH3 )2 、-CH(OH)CHF2 、-CH(OCH3 )CH3 、-SO2 CH3 、-SO2 CH(CH3 )2 、-SO2 -氮雜環丁烷、-SO2 -吡咯啶、-SO2 NH-第三丁基、-SO2 NH-環丙基、-NHSO2 CH3 、-C(O)CH(CH3 )2 及-CO2 H。在此實施例之另一類別中，各Ra 係獨立地選自由以下組成之群：-SO2 C1-6 烷基及-NHSO2 -C1-6 烷基，其中烷基未經取代或經1、2或3個選自以下之取代基取代：側氧基、-(CH2 )0-3 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H及-CO2 C1-6 烷基。在此類別之一子類中，各Ra 係獨立地選自由以下組成之群：-SO2 CH3 、-SO2 CH(CH3 )2 及-NHSO2 CH3 ，其中各烷基未經取代或經1、2或3個選自以下之取代基取代：側氧基、-(CH2 )0-3 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H及-CO2 C1-6 烷基。在此類別之另一子類中，各Ra 係獨立地選自由以下組成之 群：-SO2 CH3 、-SO2 CH(CH3 )2 及-NHSO2 CH3 。在此類別之另一子類中，各Ra 係獨立地選自由以下組成之群：-SO2 CH3 及-NHSO2 CH3 。In a subclass of this class, each R a is independently selected from the group consisting of: halo, -(CH 2 ) m OH, -N(R j ) 2 , -CN, -C 1-6 alkyl , -CF 3 , -OC 1-6 alkyl, -SO 2 C 1-6 alkyl, -SO 2 C 2-7 cycloheteroalkyl, -SO 2 NHC 1-6 alkyl, -SO 2 NHC 3 a -7 cycloalkyl group, -NHSO 2 -C 1-6 alkyl group, -C(O)R f and -CO 2 H, wherein the alkyl group, the cycloalkyl group and the cycloheteroalkyl group are each unsubstituted or passed through 2, 3 or 4 substituents selected from the group consisting of: pendant oxy, -(CH 2 ) 0-3 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1- 6 alkyl. In another subclass of this class, each R a is independently selected from the group consisting of F, Cl, -CH 2 OH, -OH, -N(CH 3 ) 2 , -CN, -CH 3 , -CF 3 , -OCH 3 , -OCH 2 CH 3 , -C(OH)(CH 3 ) 2 , -CH(OH)CHF 2 , -CH(OCH 3 )CH 3 , -SO 2 CH 3 , -SO 2 CH(CH 3 ) 2 , -SO 2 -azetidine, -SO 2 -pyrrolidine, -SO 2 NH-tert-butyl, -SO 2 NH-cyclopropyl, -NHSO 2 CH 3 , -C(O)CH(CH 3 ) 2 and -CO 2 H, wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of pendant oxy, -(CH 2 ) 0-3 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl, and wherein the alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or three or four of the substituents selected from: oxo, - (CH 2) 0- 3 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen , -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1 -6 alkyl. In a subclass of this class, each R a is independently selected from the group consisting of F, Cl, -CH 2 OH, -OH, -N(CH 3 ) 2 , -CN, -CH 3 , - CF 3 , -OCH 3 , -OCH 2 CH 3 , -C(OH)(CH 3 ) 2 , -CH(OH)CHF 2 , -CH(OCH 3 )CH 3 , -SO 2 CH 3 , -SO 2 CH(CH 3 ) 2 , -SO 2 -azetidine, -SO 2 -pyrrolidine, -SO 2 NH-tert-butyl, -SO 2 NH-cyclopropyl, -NHSO 2 CH 3 ,- C(O)CH(CH 3 ) 2 and -CO 2 H. In another class of this embodiment, each R a is independently selected from the group consisting of -SO 2 C 1-6 alkyl and -NHSO 2 -C 1-6 alkyl, wherein the alkyl group is unsubstituted Or substituted with 1, 2 or 3 substituents selected from the group consisting of: pendant oxy, -(CH 2 ) 0-3 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N (C 1-6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H and -CO 2 C 1-6 alkyl. In a subclass of this class, each R a is independently selected from the group consisting of -SO 2 CH 3 , -SO 2 CH(CH 3 ) 2 and -NHSO 2 CH 3 , wherein each alkyl group is not Substituted or substituted with 1, 2 or 3 substituents selected from the group consisting of: pendant oxy, -(CH 2 ) 0-3 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), - N(C 1-6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H and -CO 2 C 1-6 alkyl. In another subclass of this class, each R a is independently selected from the group consisting of -SO 2 CH 3 , -SO 2 CH(CH 3 ) 2 , and -NHSO 2 CH 3 . In another subclass of this class, each R a is independently selected from the group consisting of -SO 2 CH 3 and -NHSO 2 CH 3 .

在本發明之另一實施例中，各Ra 係獨立地選自由以下組成之群：-(CH2 )m CN、-(CH2 )m NHSO2 -C1-6 烷基及-(CH2 )m SO2 C1-6 烷基。在此實施例之一類別中，各Ra 係獨立地選自由以下組成之群：-CN、-NHSO2 -C1-6 烷基及-SO2 C1-6 烷基。在此實施例之另一類別中，各Ra 係獨立地選自由以下組成之群：-CN、-NHSO2 CH3 及-SO2 C1-6 烷基。In another embodiment of the invention, each R a is independently selected from the group consisting of: -(CH 2 ) m CN, -(CH 2 ) m NHSO 2 -C 1-6 alkyl and -(CH 2 ) m SO 2 C 1-6 alkyl. In one class of this embodiment, each R a is independently selected from the group consisting of -CN, -NHSO 2 -C 1-6 alkyl, and -SO 2 C 1-6 alkyl. In another class of this embodiment, each R a is independently selected from the group consisting of -CN, -NHSO 2 CH 3 and -SO 2 C 1-6 alkyl.

在本發明之另一實施例中，各Ra 係獨立地選自由以下組成之群：-(CH2 )m CN、-(CH2 )m NHSO2 -C1-6 烷基及-(CH2 )m SO2 C1-6 烷基。在此實施例之一類別中，各Ra 係獨立地選自由以下組成之群：-CN、-NHSO2 -C1-6 烷基及-SO2 C1-6 烷基。在此實施例之另一類別中，各Ra 係獨立地選自由以下組成之群：-CN、-NHSO2 CH3 、-SO2 CH3 及-SO2 CH(CH3 )2 。在此實施例之另一類別中，各Ra 係獨立地選自由以下組成之群：-CN、-NHSO2 CH3 及-SO2 CH3 。In another embodiment of the invention, each R a is independently selected from the group consisting of: -(CH 2 ) m CN, -(CH 2 ) m NHSO 2 -C 1-6 alkyl and -(CH 2 ) m SO 2 C 1-6 alkyl. In one class of this embodiment, each R a is independently selected from the group consisting of -CN, -NHSO 2 -C 1-6 alkyl, and -SO 2 C 1-6 alkyl. In another class of this embodiment, each R a is independently selected from the group consisting of -CN, -NHSO 2 CH 3 , -SO 2 CH 3 , and -SO 2 CH(CH 3 ) 2 . In another class of this embodiment, each R a is independently selected from the group consisting of -CN, -NHSO 2 CH 3 and -SO 2 CH 3 .

在本發明之另一實施例中，各Ra 係獨立地選自由以下組成之群：-(CH2 )m CN及-(CH2 )m SO2 C1-6 烷基。在此實施例之一類別中，各Ra 係獨立地選自由以下組成之群：-CN及-SO2 C1-6 烷基。在此實施例之另一類別中，各Ra 係獨立地選自由以下組成之群：-CN及-SO2 CH3 。In another embodiment of the invention, each R a is independently selected from the group consisting of -(CH 2 ) m CN and -(CH 2 ) m SO 2 C 1-6 alkyl. In one class of this embodiment, each R a is independently selected from the group consisting of -CN and -SO 2 C 1-6 alkyl. In another class of this embodiment, each R a is independently selected from the group consisting of -CN and -SO 2 CH 3 .

在本發明之另一實施例中，Ra 係獨立地選自由以下組成之群：-(CH2 )m -鹵素、-(CH2 )m OH、-(CH2 )m CF3 、-O-(CH2 )m - OC1-6 烷基、-(CH2 )m SO2 NHC3-7 環烷基、-(CH2 )m N(Rj )-雜芳基、-(CH2 )m C3-7 環烷基、-(CH2 )m C2-6 環雜烯基及-(CH2 )m 雜芳基，其中各CH2 未經取代或經1或2個選自以下之取代基取代：側氧基、-(CH2 )0-3 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基，且其中烷基、環烷基、環雜烯基及雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-5 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-SO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基。在此實施例之一類別中，各CH2 未經取代或經1或2個選自以下之取代基取代：-C1-6 烷基，且烷基、環烷基、環雜烯基及雜芳基各自未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-5 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-SO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基。在此實施例之另一類別中，各CH2 未經取代或經1或2個選自以下之取代基取代：-C1-6 烷基，且烷基、環烷基、環雜烯基及雜芳基各自未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-5 OH、-C1-6 烷基、-CF3 及-C3-7 環烷基。在此實施例之另一類別中，各CH2 未經取代或經1或2 個選自以下之取代基取代：-CH3 ，且烷基、環烷基、環雜烯基及雜芳基各自未經取代或經1、2、3或4個選自以下之取代基取代：-OH、-CH2 C(CH3 )2 OH、-CH3 、CH2 CH3 、CH(CH3 )2 、-CF3 、環丙基、環己基及環戊基。在此實施例之另一類別中，各雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：-CH2 C(CH3 )2 OH。In another embodiment of the present invention, R a is independently selected from the group consisting of: -(CH 2 ) m -halogen, -(CH 2 ) m OH, -(CH 2 ) m CF 3 , -O -(CH 2 ) m - OC 1-6 alkyl, -(CH 2 ) m SO 2 NHC 3-7 cycloalkyl, -(CH 2 ) m N(R j )-heteroaryl, -(CH 2 a m C 3-7 cycloalkyl, -(CH 2 ) m C 2-6 cycloheteroalkenyl and -(CH 2 ) m heteroaryl, wherein each CH 2 is unsubstituted or selected from 1 or 2 Substituted by the following substituents: a pendant oxy group, -(CH 2 ) 0-3 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3- a 7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl group, and wherein the alkyl, cycloalkyl, cycloheteroalkenyl and heteroaryl groups are unsubstituted or 1, 2, 3 Or 4 substituents selected from the group consisting of: pendant oxy, -(CH 2 ) 0-5 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 Alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl , -SO 2 C 1-6 alkyl, -C 3-7 cycloalkyl, phenyl, CH 2 phenyl , heteroaryl and CH 2 heteroaryl. In one class of this embodiment, each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of: -C 1-6 alkyl, and alkyl, cycloalkyl, cycloheteroalkenyl and The heteroaryl groups are each unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of pendant oxy, -(CH 2 ) 0-5 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -SO 2 C 1-6 alkyl, -C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl base. In another class of this embodiment, each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of: -C 1-6 alkyl, and alkyl, cycloalkyl, cycloheteroalkenyl And the heteroaryl groups are each unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of pendant oxy, -(CH 2 ) 0-5 OH, -C 1-6 alkyl, -CF 3 and -C 3-7 cycloalkyl. In another class of this embodiment, each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of: -CH 3 , and alkyl, cycloalkyl, cycloheteroalkenyl, and heteroaryl Each is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of: -OH, -CH 2 C(CH 3 ) 2 OH, -CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , -CF 3 , cyclopropyl, cyclohexyl and cyclopentyl. In another class of this embodiment, each heteroaryl group is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of: -CH 2 C(CH 3 ) 2 OH.

在本發明之另一實施例中，Ra 係獨立地選自由以下組成之群：-CH2 CH2 F、-OH、-CH2 CH2 OH、-CH2 C(CH3 )2 OH、-CH2 CF3 、-OCH2 CH2 OCH3 、-SO2 NH環丙基、-NH-嘧啶、-CH2 環丙基、2,5二氫1H咪唑、1,4,5,6-四氫嘧啶、咪唑、噁唑、噻唑、三唑、四唑及噁二唑，其中各CH2 未經取代或經1或2個選自以下之取代基取代：-C1-6 烷基，且其中烷基、環烷基、環雜烯基及雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-5 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-SO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基。在此實施例之一類別中，各CH2 未經取代或經1或2個選自以下之取代基取代：-C1-6 烷基，且烷基、環烷基、環雜烯基及雜芳基各自未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-5 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-SO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基 及CH2 雜芳基。在此實施例之另一類別中，各CH2 未經取代或經1或2個選自以下之取代基取代：-C1-6 烷基，且烷基、環烷基、環雜烯基及雜芳基各自未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-5 OH、-C1-6 烷基、-CF3 及-C3-7 環烷基。在此實施例之另一類別中，各CH2 未經取代或經1或2個選自以下之取代基取代：-CH3 ，且烷基、環烷基、環雜烯基及雜芳基各自未經取代或經1、2、3或4個選自以下之取代基取代：-OH、-CH2 C(CH3 )2 OH、-CH3 、CH2 CH3 、CH(CH3 )2 、-CF3 、環丙基、環己基及環戊基。在此實施例之另一類別中，各雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：-CH2 C(CH3 )2 OH。In another embodiment of the present invention, R a is independently selected from the group consisting of: -CH 2 CH 2 F, -OH, -CH 2 CH 2 OH, -CH 2 C(CH 3 ) 2 OH, -CH 2 CF 3 , -OCH 2 CH 2 OCH 3 , -SO 2 NH cyclopropyl, -NH-pyrimidine, -CH 2 cyclopropyl, 2,5 dihydro 1H imidazole, 1,4,5,6- Tetrahydropyrimidine, imidazole, oxazole, thiazole, triazole, tetrazole and oxadiazole, wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: -C 1-6 alkyl, And wherein the alkyl group, cycloalkyl group, cycloheteroalkenyl group and heteroaryl group are unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of pendant oxy group, -(CH 2 ) 0-5 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -SO 2 C 1-6 alkyl, -C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl. In one class of this embodiment, each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of: -C 1-6 alkyl, and alkyl, cycloalkyl, cycloheteroalkenyl and The heteroaryl groups are each unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of pendant oxy, -(CH 2 ) 0-5 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -SO 2 C 1-6 alkyl, -C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl base. In another class of this embodiment, each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of: -C 1-6 alkyl, and alkyl, cycloalkyl, cycloheteroalkenyl And the heteroaryl groups are each unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of pendant oxy, -(CH 2 ) 0-5 OH, -C 1-6 alkyl, -CF 3 and -C 3-7 cycloalkyl. In another class of this embodiment, each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of: -CH 3 , and alkyl, cycloalkyl, cycloheteroalkenyl, and heteroaryl Each is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of: -OH, -CH 2 C(CH 3 ) 2 OH, -CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , -CF 3 , cyclopropyl, cyclohexyl and cyclopentyl. In another class of this embodiment, each heteroaryl group is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of: -CH 2 C(CH 3 ) 2 OH.

在本發明之另一實施例中，Ra 係獨立地選自由以下組成之群：-(CH2 )m OH及-(CH2 )m 雜芳基，其中各CH2 未經取代或經1或2個選自以下之取代基取代：側氧基、-(CH2 )0-3 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基，且其中雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-5 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-SO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基。在此實施例之一類別中，各CH2 未經取代或經1或2個選自以下之取代基取代：-C1-6 烷基，且各雜芳基未經取代或經 1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-5 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-SO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基。在此實施例之另一類別中，各CH2 未經取代或經1或2個選自以下之取代基取代：-C1-6 烷基，且各雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-5 OH、-C1-6 烷基、-CF3 及-C3-7 環烷基。在此實施例之另一類別中，各CH2 未經取代或經1或2個選自以下之取代基取代：-CH3 ，且各雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：-OH、-CH2 C(CH3 )2 OH、-CH3 、CH2 CH3 、CH(CH3 )2 、-CF3 、環丙基、環己基及環戊基。在此實施例之另一類別中，各雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：-CH2 C(CH3 )2 OH。In another embodiment of the present invention, R a is independently selected from the group consisting of -(CH 2 ) m OH and -(CH 2 ) m heteroaryl, wherein each CH 2 is unsubstituted or passed through 1 Or 2 substituents selected from the group consisting of: pendant oxy, -(CH 2 ) 0-3 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 Alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl a -C 3-7 cycloalkyl group, a phenyl group, a CH 2 phenyl group, a heteroaryl group, and a CH 2 heteroaryl group, and wherein the heteroaryl group is unsubstituted or 1, 2, 3 or 4 selected from the group consisting of Substituent substitution: pendant oxy, -(CH 2 ) 0-5 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -SO 2 C 1- 6 alkyl, -C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl. In one class of this embodiment, each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: -C 1-6 alkyl, and each heteroaryl is unsubstituted or 1, 2 , 3 or 4 substituents selected from the group consisting of: pendant oxy, -(CH 2 ) 0-5 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N (C 1 -6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 Alkyl, -SO 2 C 1-6 alkyl, -C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl. In another class of this embodiment, each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of: -C 1-6 alkyl, and each heteroaryl is unsubstituted or passed through 2, 3 or 4 substituents selected from the group consisting of pendant oxy, -(CH 2 ) 0-5 OH, -C 1-6 alkyl, -CF 3 and -C 3-7 cycloalkyl. In another class of this embodiment, each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: -CH 3 , and each heteroaryl is unsubstituted or 1, 2, 3 or Substituted by four substituents selected from the group consisting of: -OH, -CH 2 C(CH 3 ) 2 OH, -CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , -CF 3 , cyclopropyl, cyclohexyl And cyclopentyl. In another class of this embodiment, each heteroaryl group is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of: -CH 2 C(CH 3 ) 2 OH.

在本發明之另一實施例中，Ra 係獨立地選自由以下組成之群：-OH、-CH2 CH2 OH、-CH2 C(CH3 )2 OH、吡唑、咪唑、噁唑、噻唑、三唑、四唑及噁二唑，其中各CH2 未經取代或經1或2個選自以下之取代基取代：側氧基、-(CH2 )0-3 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基，且其中雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-5 OH、-CN、-NH2 、-NH(C1-6 烷 基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-SO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基。在此實施例之一類別中，各CH2 未經取代或經1或2個選自以下之取代基取代：-C1-6 烷基，且各雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-5 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-SO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基。在此實施例之另一類別中，各CH2 未經取代或經1或2個選自以下之取代基取代：-C1-6 烷基，且各雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-5 OH、-C1-6 烷基、-CF3 及-C3-7 環烷基。在此實施例之另一類別中，各CH2 未經取代或經1或2個選自以下之取代基取代：-CH3 ，且各雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：-OH、-CH2 C(CH3 )2 OH、-CH3 、CH2 CH3 、CH(CH3 )2 、-CF3 、環丙基、環己基及環戊基。在此實施例之另一類別中，各雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：-CH2 C(CH3 )2 OH。In another embodiment of the present invention, R a is independently selected from the group consisting of: -OH, -CH 2 CH 2 OH, -CH 2 C(CH 3 ) 2 OH, pyrazole, imidazole, oxazole , thiazole, triazole, tetrazole and oxadiazole, wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of pendant oxy, -(CH 2 ) 0-3 OH, -CN , -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F , -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl And wherein the heteroaryl group is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of pendant oxy, -(CH 2 ) 0-5 OH, -CN, -NH 2 , -NH (C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -SO 2 C 1-6 alkyl, -C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 Heteroaryl. In one class of this embodiment, each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: -C 1-6 alkyl, and each heteroaryl is unsubstituted or 1, 2 , 3 or 4 substituents selected from the group consisting of: pendant oxy, -(CH 2 ) 0-5 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N (C 1 -6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 Alkyl, -SO 2 C 1-6 alkyl, -C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl. In another class of this embodiment, each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of: -C 1-6 alkyl, and each heteroaryl is unsubstituted or passed through 2, 3 or 4 substituents selected from the group consisting of pendant oxy, -(CH 2 ) 0-5 OH, -C 1-6 alkyl, -CF 3 and -C 3-7 cycloalkyl. In another class of this embodiment, each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: -CH 3 , and each heteroaryl is unsubstituted or 1, 2, 3 or Substituted by four substituents selected from the group consisting of: -OH, -CH 2 C(CH 3 ) 2 OH, -CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , -CF 3 , cyclopropyl, cyclohexyl And cyclopentyl. In another class of this embodiment, each heteroaryl group is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of: -CH 2 C(CH 3 ) 2 OH.

在本發明之另一實施例中，Ra 係獨立地選自由以下組成之群：-(CH2 )m -鹵素、-(CH2 )m OH、-(CH2 )m -N(Rj )2 、-(CH2 )m -CN、-(CH2 )m C1-6 烷基、-(CH2 )m OCF3 、-(CH2 )m C(O)N(Rj )2 、-(CH2 )m O-(CH2 )m -C3-7 環烷基、-(CH2 )m O-(CH2 )m -C2-7 環雜 烷基、-(CH2 )m SO2 C1-6 烷基、-(CH2 )m SO2 C2-7 環雜烷基、-(CH2 )m SO2 NHC1-6 烷基、-(CH2 )m NHSO2 -C1-6 烷基、-(CH2 )m C(O)Rf 、-(CH2 )m CO2 H、-(CH2 )m CO2 Rf 、-(CH2 )m CF3 、-O-(CH2 )m -OC1-6 烷基、-(CH2 )m SO2 NHC3-7 環烷基、-(CH2 )m N(Rj )-雜芳基、-(CH2 )m C3-7 環烷基、-(CH2 )m C2-6 環雜烯基及-(CH2 )m 雜芳基，其中各CH2 未經取代或經1或2個選自以下之取代基取代：側氧基、-(CH2 )0-3 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基，且其中烷基、環烷基、環雜烷基、環雜烯基及雜芳基各自未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-5 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-SO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基。在此實施例之一類別中，各Ra 係獨立地選自由以下組成之群：F、Cl、Br、-C(CH3 )2 OH、-OH、-CH2 OH、-CH2 CH2 OH、-CH2 C(CH3 )2 OH、-CH(OH)CHF2 、CH(OH)CF3 、-(CH2 )2 C(CH3 )2 -OH、-N(CH3 )2 、-CN、-CH3 、-CH2 CH3 、-C(CH3 )3 、-CF3 、-CH2 CF3 、-OCF3 、-C(O)NH-環丙基、-OCH2 CH3 、-OCH3 、-O(CH2 )3 -SO2 CH3 、OCH2 CH2 F、-CH2 OCH3 、-O-環丁基、-O-環戊基、-O-氮雜環丁烷、-O-CH2 -二氧雜環戊烷、-SO2 CH(CH3 )2 、-SO2 CH3 、-SO2 -吡咯啶、-SO2 -氮雜環丁烷、-SO2 NHCH3 、-SO2 NHC(CH3 )3 、 -SO2 NH-環丙基、-NHSO2 -CH3 、-C(O)CH(CH3 )2 、C(O)-吡咯啶、-C(O)-嗎啉、-CO2 H、-CO2 -CH(CH3 )2 、-CO2 -C(CH3 )3 、環丙基、吡唑、咪唑、噁唑、噻唑、三唑、四唑及噁二唑，其中各雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-5 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-SO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基。In another embodiment of the present invention, R a is independently selected from the group consisting of: -(CH 2 ) m -halogen, -(CH 2 ) m OH, -(CH 2 ) m -N(R j 2 , -(CH 2 ) m -CN, -(CH 2 ) m C 1-6 alkyl, -(CH 2 ) m OCF 3 , -(CH 2 ) m C(O)N(R j ) 2 , -(CH 2 ) m O-(CH 2 ) m -C 3-7 cycloalkyl, -(CH 2 ) m O-(CH 2 ) m -C 2-7 cycloheteroalkyl, -(CH 2 m SO 2 C 1-6 alkyl, -(CH 2 ) m SO 2 C 2-7 cycloheteroalkyl, -(CH 2 ) m SO 2 NHC 1-6 alkyl, -(CH 2 ) m NHSO 2 -C 1-6 alkyl, -(CH 2 ) m C(O)R f , -(CH 2 ) m CO 2 H, -(CH 2 ) m CO 2 R f , -(CH 2 ) m CF 3 , -O-(CH 2 ) m -OC 1-6 alkyl, -(CH 2 ) m SO 2 NHC 3-7 cycloalkyl, -(CH 2 ) m N(R j )-heteroaryl, -(CH 2 ) m C 3-7 cycloalkyl, -(CH 2 ) m C 2-6 cycloheteroalkenyl and -(CH 2 ) m heteroaryl, wherein each CH 2 is unsubstituted or 1 or Substituted by two substituents selected from the group consisting of pendant oxy, -(CH 2 ) 0-3 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkane 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3-7 cycloalkyl, phenyl, CH 2 phenyl , CH 2 hetero aryl group and heteroaryl group, and wherein alkyl, cycloalkyl, cycloheteroalkyl, cycloheteroalkenyl, and heteroaryl, each unsubstituted or substituted by 3 or 4 selected from Substituents substituted: pendant oxy, -(CH 2 ) 0-5 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 ,- C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -SO 2 C 1 -6 alkyl, -C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl. In one class of this embodiment, each R a is independently selected from the group consisting of F, Cl, Br, -C(CH 3 ) 2 OH, -OH, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 C(CH 3 ) 2 OH, -CH(OH)CHF 2 , CH(OH)CF 3 , -(CH 2 ) 2 C(CH 3 ) 2 -OH, -N(CH 3 ) 2 , -CN, -CH 3 , -CH 2 CH 3 , -C(CH 3 ) 3 , -CF 3 , -CH 2 CF 3 , -OCF 3 , -C(O)NH-cyclopropyl, -OCH 2 CH 3 , -OCH 3 , -O(CH 2 ) 3 -SO 2 CH 3 , OCH 2 CH 2 F, -CH 2 OCH 3 , -O-cyclobutyl, -O-cyclopentyl, -O-nitrogen Heterocyclobutane, -O-CH 2 -dioxolane, -SO 2 CH(CH 3 ) 2 , -SO 2 CH 3 , -SO 2 -pyrrolidine, -SO 2 -azetidine , -SO 2 NHCH 3 , -SO 2 NHC(CH 3 ) 3 , -SO 2 NH-cyclopropyl, -NHSO 2 -CH 3 , -C(O)CH(CH 3 ) 2 , C(O)- Pyrrolidine, -C(O)-morpholine, -CO 2 H, -CO 2 -CH(CH 3 ) 2 , -CO 2 -C(CH 3 ) 3 , cyclopropyl, pyrazole, imidazole, oxazole , thiazole, triazole, tetrazole and oxadiazole, wherein each heteroaryl group is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of pendant oxy, -(CH 2 ) 0- 5 OH, -CN, -NH 2, -NH (C 1-6 alkyl), - N (C 1-6 alkyl ) 2, -C 1-6 alkyl, -OC 1-6 alkyl, halo, -CH 2 F, -CHF 2, -CF 3, -CO 2 H, -CO 2 C 1-6 alkyl, - SO 2 C 1-6 alkyl, -C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl.

在本發明之另一實施例中，Ra 係獨立地選自由以下組成之群：-(CH2 )m -鹵素、N(Rj )2 、-CN、-C1-6 烷基、-(CH2 )m OH、-(CH2 )m CF3 、-O-(CH2 )m -OC1-6 烷基、-C(O)Rf 、-CO2 H、-(CH2 )m SO2 NHC3-7 環烷基、-NHSO2 -C1-6 烷基、-(CH2 )m N(Rj )-雜芳基、-(CH2 )m C3-7 環烷基、-(CH2 )m C2-6 環雜烯基及-(CH2 )m 雜芳基，其中各CH2 未經取代或經1或2個選自以下之取代基取代：側氧基、-(CH2 )0-3 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基，且其中烷基、環烷基、環雜烷基、環雜烯基及雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-5 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-SO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基。在此實施例之一類別中，各Ra 係獨立地選 自由以下組成之群：F、Cl、-OH、-CH2 OH、-CH2 CH2 OH、-CH2 C(CH3 )2 OH、-N(CH3 )2 、-CN、-CH3 、-CF3 、-OCH3 、-OCH2 CH3 、-C(OH)(CH3 )2 、-CH(OH)CHF2 、-CH(OCH3 )CH3 、-SO2 CH3 、-SO2 CH(CH3 )2 、-SO2 -氮雜環丁烷、-SO2 -吡咯啶、-SO2 NH-第三丁基、-SO2 NH-環丙基、-NHSO2 CH3 、-C(O)CH(CH3 )2 、-CO2 H、吡唑、咪唑、噁唑、噻唑、三唑、四唑及噁二唑，其中各CH2 未經取代或經1或2個選自以下之取代基取代：-C1-6 烷基，且各雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-5 OH、-C1-6 烷基、-CF3 及-C3-7 環烷基。In another embodiment of the present invention, R a is independently selected from the group consisting of: -(CH 2 ) m -halogen, N(R j ) 2 , -CN, -C 1-6 alkyl, - (CH 2 ) m OH, -(CH 2 ) m CF 3 , -O-(CH 2 ) m -OC 1-6 alkyl, -C(O)R f , -CO 2 H, -(CH 2 ) m SO 2 NHC 3-7 cycloalkyl, -NHSO 2 -C 1-6 alkyl, -(CH 2 ) m N(R j )-heteroaryl, -(CH 2 ) m C 3-7 naphthenic a group, -(CH 2 ) m C 2-6 cycloheteroalkenyl and -(CH 2 ) m heteroaryl, wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of: side oxygen a group, -(CH 2 ) 0-3 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl, and wherein alkyl, cycloalkyl, cycloheteroalkyl, cycloheteroalkenyl and heteroaryl are unsubstituted or 1, 2, 3 or 4 Substituted by a substituent selected from the group consisting of a pendant oxy group, -(CH 2 ) 0-5 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -SO 2 C 1-6 alkyl, -C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 Heteroaryl. In one class of this embodiment, each R a is independently selected from the group consisting of F, Cl, -OH, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 C(CH 3 ) 2 OH, -N(CH 3 ) 2 , -CN, -CH 3 , -CF 3 , -OCH 3 , -OCH 2 CH 3 , -C(OH)(CH 3 ) 2 , -CH(OH)CHF 2 , -CH(OCH 3 )CH 3 , -SO 2 CH 3 , -SO 2 CH(CH 3 ) 2 , -SO 2 -azetidine, -SO 2 -pyrrolidine, -SO 2 NH-third , -SO 2 NH-cyclopropyl, -NHSO 2 CH 3 , -C(O)CH(CH 3 ) 2 , -CO 2 H, pyrazole, imidazole, oxazole, thiazole, triazole, tetrazole and Oxadiazole wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: -C 1-6 alkyl, and each heteroaryl is unsubstituted or 1, 2, 3 or 4 Substituents selected from the group consisting of pendant oxy, -(CH 2 ) 0-5 OH, -C 1-6 alkyl, -CF 3 and -C 3-7 cycloalkyl.

在本發明之另一實施例中，Ra 係獨立地選自由以下組成之群：-(CH2 )m OH、-(CH2 )m CN、-(CH2 )m NHSO2 -C1-6 烷基、-(CH2 )m SO2 C1-6 烷基及-(CH2 )m 雜芳基，其中各CH2 未經取代或經1或2個選自以下之取代基取代：-C1-6 烷基，且各雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-5 OH、-C1-6 烷基、-CF3 及-C3-7 環烷基。In another embodiment of the present invention, R a is independently selected from the group consisting of: -(CH 2 ) m OH, -(CH 2 ) m CN, -(CH 2 ) m NHSO 2 -C 1- a 6 alkyl group, a -(CH 2 ) m SO 2 C 1-6 alkyl group, and a -(CH 2 ) m heteroaryl group, wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of: -C 1-6 alkyl, and each heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of pendant oxy, -(CH 2 ) 0-5 OH, -C 1-6 alkyl, -CF 3 and -C 3-7 cycloalkyl.

在本發明之另一實施例中，Ra 係獨立地選自由以下組成之群：-OH、-CH2 CH2 OH、-CH2 C(CH3 )2 OH、-CN、-NHSO2 CH3 及-SO2 CH3 、吡唑、咪唑、噁唑、噻唑、三唑、四唑及噁二唑，其中各CH2 未經取代或經1或2個選自以下之取代基取代：-C1-6 烷基，且各雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-5 OH、-C1-6 烷基、-CF3 及-C3-7 環烷基。In another embodiment of the present invention, R a is independently selected from the group consisting of: -OH, -CH 2 CH 2 OH, -CH 2 C(CH 3 ) 2 OH, -CN, -NHSO 2 CH 3 and -SO 2 CH 3 , pyrazole, imidazole, oxazole, thiazole, triazole, tetrazole and oxadiazole, wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of: - C 1-6 alkyl, and each heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of pendant oxy, -(CH 2 ) 0-5 OH, -C 1 -6 alkyl, -CF 3 and -C 3-7 cycloalkyl.

在本發明之另一實施例中，各Rb 係獨立地選自：氫、-C1-6 烷基、-C3-6 環烷基、-C3-6 環烯基、-C2-6 環雜烷基、-C2-6 環雜烯基、芳基、雜芳基、-(CH2 )t -鹵素、-(CH2 )s -OH、-NO2 、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-OC1-6 烷基、-(CH2 )q CO2 H、-(CH2 )q CO2 C1-6 烷基、-CF3 、-CN、-SO2 C1-6 烷基及-(CH2 )s CON(Re )2 ，其中各CH2 未經取代或經1或2個鹵素取代，且其中烷基、環烷基、環烯基、環雜烷基、環雜烯基、芳基及雜芳基各自未經取代或經1、2或3個鹵素取代。In another embodiment of the invention, each R b is independently selected from the group consisting of: hydrogen, -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 3-6 cycloalkenyl, -C 2 -6 cycloalkyl heteroalkyl, -C 2-6 cycloheteroalkyl, aryl, heteroaryl, - (CH 2) t - halogen, - (CH 2) s -OH , -NO 2, -NH 2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -OC 1-6 alkyl, -(CH 2 ) q CO 2 H, -(CH 2 ) q CO 2 C 1-6 alkyl, -CF 3 , -CN, -SO 2 C 1-6 alkyl and -(CH 2 ) s CON(R e ) 2 , wherein each CH 2 is unsubstituted or has 1 or 2 halogens Substituted, and wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are each unsubstituted or substituted with 1, 2 or 3 halogens.

在此實施例之一類別中，各Rb 係獨立地選自：氫、-C1-6 烷基、-(CH2 )t -鹵素、-(CH2 )s -OH、-NO2 、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-OC1-6 烷基、-(CH2 )q CO2 H、-(CH2 )q CO2 C1-6 烷基、-CF3 、-CN、-SO2 C1-6 烷基及-(CH2 )s CON(Re )2 ，其中各CH2 未經取代或經1或2個鹵素取代，且其中各烷基未經取代或經1、2或3個鹵素取代。在此實施例之一類別中，各Rb 係獨立地選自：氫、-C1-6 烷基、-(CH2 )t -鹵素、-(CH2 )s -OH、-NO2 、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-OC1-6 烷基、-(CH2 )q CO2 H、-(CH2 )q CO2 C1-6 烷基、-CF3 、-CN、-SO2 C1-6 烷基及-(CH2 )s CON(Re )2 ，其中各CH2 未經取代或經1或2個鹵素取代，且其中各烷基未經取代或經1、2或3個鹵素取代。在此實施例之另一類別中，各Rb 係獨立地選自：氫、-C1-6 烷基、-(CH2 )t -鹵素、-(CH2 )s -OH、-CO2 H及-CO2 C1-6 烷基，其中各CH2 未經取代或經1或2個鹵素取代，且其中各烷基未經取代或經1、2或3個鹵素 取代。在此實施例之另一類別中，各Rb 係獨立地選自：氫、-C1-6 烷基、-(CH2 )t -鹵素、-(CH2 )s -OH、-CO2 H及-CO2 C1-6 烷基，其中各CH2 未經取代或經1或2個鹵素取代，且其中各烷基未經取代或經1、2或3個鹵素取代。在此實施例之另一類別中，各Rb 係獨立地選自：氫、-CH3 、-CH2 F、-CH2 OH、-C(CH3 )2 -OH、-CO2 H及-CO2 C(CH3 )3 ，其中各CH2 未經取代或經1或2個鹵素取代，且其中各烷基未經取代或經1、2或3個鹵素取代。In one class of this embodiment, each R b is independently selected from the group consisting of: hydrogen, -C 1-6 alkyl, -(CH 2 ) t -halogen, -(CH 2 ) s -OH, -NO 2 , -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -OC 1-6 alkyl, -(CH 2 ) q CO 2 H, -(CH 2 ) q CO 2 C 1-6 alkyl, -CF 3 , -CN, -SO 2 C 1-6 alkyl and -(CH 2 ) s CON(R e ) 2 , wherein each CH 2 is unsubstituted or passed through 1 Or 2 halogen substitutions, and wherein each alkyl group is unsubstituted or substituted with 1, 2 or 3 halogens. In one class of this embodiment, each R b is independently selected from the group consisting of: hydrogen, -C 1-6 alkyl, -(CH 2 ) t -halogen, -(CH 2 ) s -OH, -NO 2 , -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -OC 1-6 alkyl, -(CH 2 ) q CO 2 H, -(CH 2 ) q CO 2 C 1-6 alkyl, -CF 3 , -CN, -SO 2 C 1-6 alkyl and -(CH 2 ) s CON(R e ) 2 , wherein each CH 2 is unsubstituted or passed through 1 Or 2 halogen substitutions, and wherein each alkyl group is unsubstituted or substituted with 1, 2 or 3 halogens. In another class of this embodiment, each R b is independently selected from the group consisting of: hydrogen, -C 1-6 alkyl, -(CH 2 ) t -halogen, -(CH 2 ) s -OH, -CO 2 H and -CO 2 C 1-6 alkyl, wherein each CH 2 is unsubstituted or substituted with 1 or 2 halogens, and wherein each alkyl group is unsubstituted or substituted with 1, 2 or 3 halogens. In another class of this embodiment, each R b is independently selected from the group consisting of: hydrogen, -C 1-6 alkyl, -(CH 2 ) t -halogen, -(CH 2 ) s -OH, -CO 2 H and -CO 2 C 1-6 alkyl, wherein each CH 2 is unsubstituted or substituted with 1 or 2 halogens, and wherein each alkyl group is unsubstituted or substituted with 1, 2 or 3 halogens. In another class of this embodiment, each R b is independently selected from the group consisting of: hydrogen, —CH 3 , —CH 2 F, —CH 2 OH, —C(CH 3 ) 2 —OH, —CO 2 H, and -CO 2 C(CH 3 ) 3 wherein each CH 2 is unsubstituted or substituted with 1 or 2 halogens, and wherein each alkyl group is unsubstituted or substituted with 1, 2 or 3 halogens.

在本發明之另一實施例中，各Rb 係獨立地選自：氫、-C1-6 烷基及-(CH2 )s -OH。在此實施例之一類別中，各Rb 係獨立地選自：氫、-CH3 、-OH及-CH2 OH。在此實施例之一類別中，各Rb 係獨立地選自：氫、-CH3 及-CH2 OH。In another embodiment of the invention, each R b is independently selected from the group consisting of hydrogen, -C 1-6 alkyl, and -(CH 2 ) s -OH. In one class of this embodiment, each R b is independently selected from the group consisting of: hydrogen, -CH 3 , -OH, and -CH 2 OH. In one class of this embodiment, each R b is independently selected from the group consisting of: hydrogen, -CH 3 and -CH 2 OH.

在本發明之另一實施例中，各Rc 係獨立地選自：鹵素、側氧基、-(CH2 )r OH、-(CH2 )r N(Re )2 、-(CH2 )r CN、-C1-6 烷基、-CF3 、-C1-6 烷基-OH、-OCH2 OC1-6 烷基、-(CH2 )r OC1-6 烷基、-OCH2 芳基、-(CH2 )r SC1-6 烷基、-(CH2 )r C(O)Rf 、-(CH2 )r C(O)N(Re )2 、-(CH2 )r CO2 H、-(CH2 )r CO2 Rf 、-(CH2 )r C3-7 環烷基、-(CH2 )r C2-6 環雜烷基、-(CH2 )r 芳基及-(CH2 )r 雜芳基，其中各CH2 未經取代或經1或2個選自以下之取代基取代：側氧基、-OH、-CN、-N(Rh )2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基及雜芳基，且其中烷基、環烷基、環雜烷基、芳基及雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-OH、-CN、-N(Rh )2 、-C1-6 烷基、 -OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基及雜芳基。在此實施例之一類別中，各Rc 係獨立地選自：鹵素、側氧基、-(CH2 )r OH、-(CH2 )r N(Re )2 、-(CH2 )r CN、-C1-6 烷基、-CF3 、-C1-6 烷基-OH、-OCH2 OC1-6 烷基、-(CH2 )r OC1-6 烷基、-(CH2 )r SC1-6 烷基、-(CH2 )r C(O)Rf 、-(CH2 )r C(O)N(Re )2 、-(CH2 )r CO2 H及-(CH2 )r CO2 Rf ，其中各CH2 未經取代或經1或2個選自以下之取代基取代：側氧基、-OH、-CN、-N(Rh )2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基及雜芳基，且其中烷基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-OH、-CN、-N(Rh )2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H及-CO2 C1-6 烷基。在此實施例之一類別中，各Rc 係獨立地選自：鹵素、側氧基、-OH、-N(Re )2 、-CN、-C1-6 烷基、-CF3 、-C1-6 烷基-OH、-OC1-6 烷基、-SC1-6 烷基、-C(O)Rf 、-C(O)N(Re )2 、-CO2 H及-CO2 Rf ，其中烷基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-OH、-CN、-N(Rh )2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H及-CO2 C1-6 烷基。在此實施例之另一類別中，各Rc 係獨立地選自：鹵素、側氧基、-OH、-N(Re )2 、-CN、-C1-6 烷基、-CF3 、-C1-6 烷基-OH及-OC1-6 烷基，其中烷基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-OH、-CN、-N(Rh )2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H及-CO2 C1-6 烷基。In another embodiment of the invention, each R c is independently selected from the group consisting of: halogen, pendant oxy, -(CH 2 ) r OH, -(CH 2 ) r N(R e ) 2 , -(CH 2 r CN, -C 1-6 alkyl, -CF 3 , -C 1-6 alkyl-OH, -OCH 2 OC 1-6 alkyl, -(CH 2 ) r OC 1-6 alkyl, - OCH 2 aryl, -(CH 2 ) r SC 1-6 alkyl, -(CH 2 ) r C(O)R f , -(CH 2 ) r C(O)N(R e ) 2 , -( CH 2 ) r CO 2 H, -(CH 2 ) r CO 2 R f , -(CH 2 ) r C 3-7 cycloalkyl, -(CH 2 ) r C 2-6 cycloheteroalkyl, -( CH 2 ) r aryl and -(CH 2 ) r heteroaryl, wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of pendant oxy, -OH, -CN, -N (R h ) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkane a group, a -C 3-7 cycloalkyl group and a heteroaryl group, and wherein the alkyl group, the cycloalkyl group, the cycloheteroalkyl group, the aryl group and the heteroaryl group are unsubstituted or 1, 2, 3 or 4 are selected from Substituted by the following substituents: pendant oxy, -OH, -CN, -N(R h ) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3, -CO 2 H, -CO 2 C 1-6 alkyl, -C 3-7 cycloalkyl, and heteroaryl In one class of this embodiment, each R c is independently selected from the group consisting of: halogen, pendant oxy, -(CH 2 ) r OH, -(CH 2 ) r N(R e ) 2 , -(CH 2 ) r CN, -C 1-6 alkyl, -CF 3 , -C 1-6 alkyl-OH, -OCH 2 OC 1-6 alkyl, -(CH 2 ) r OC 1-6 alkyl, -( CH 2 ) r SC 1-6 alkyl, -(CH 2 ) r C(O)R f , -(CH 2 ) r C(O)N(R e ) 2 , -(CH 2 ) r CO 2 H And -(CH 2 ) r CO 2 R f , wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of pendant oxy, -OH, -CN, -N(R h ) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3 -7 cycloalkyl and heteroaryl, and wherein the alkyl group is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of pendant oxy, -OH, -CN, -N (R h 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H and -CO 2 C 1-6 alkyl. In one class of this embodiment, each R c is independently selected from the group consisting of: halogen, pendant oxy, -OH, -N(R e ) 2 , -CN, -C 1-6 alkyl, -CF 3 , -C 1-6 alkyl-OH, -OC 1-6 alkyl, -SC 1-6 alkyl, -C(O)R f , -C(O)N(R e ) 2 , -CO 2 H And -CO 2 R f , wherein the alkyl group is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of pendant oxy, -OH, -CN, -N(R h ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H and -CO 2 C 1-6 alkyl. In another class of this embodiment, each R c is independently selected from the group consisting of: halogen, pendant oxy, -OH, -N(R e ) 2 , -CN, -C 1-6 alkyl, -CF 3 , -C 1-6 alkyl-OH and -OC 1-6 alkyl, wherein the alkyl group is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of pendant oxy groups, -OH, -CN, -N(R h ) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H and -CO 2 C 1-6 alkyl.

在本發明之另一實施例中，Re 、Rg 及Rh 各自係獨立地選自：氫、-C1-6 烷基及-O-C1-6 烷基，其中烷基未經取代或經1、2、3或4個選自以下之取代基取代：-OH、側氧基、鹵素、C1-6 烷基、-OC1-6 烷基、-NH2 、-NH(C1-6 烷基)及-N(C1-6 烷基)2 。在本發明此實施例之一類別中，Re 、Rg 及Rh 各自係獨立地選自：氫、-CH3 及-OCH3 ，其中烷基未經取代或經1、2、3或4個選自以下之取代基取代：-OH、側氧基、鹵素、C1-6 烷基、-OC1-6 烷基、-NH2 、-NH(C1-6 烷基)及-N(C1-6 烷基)2 。In another embodiment of the present invention, R e , R g and R h are each independently selected from the group consisting of hydrogen, —C 1-6 alkyl and —OC 1-6 alkyl, wherein the alkyl group is unsubstituted or Substituted by 1, 2, 3 or 4 substituents selected from the group consisting of: -OH, pendant oxy, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH (C 1 -6 alkyl) and -N(C 1-6 alkyl) 2 . In a class of this embodiment of the invention, R e , R g and R h are each independently selected from the group consisting of: hydrogen, —CH 3 and —OCH 3 , wherein the alkyl group is unsubstituted or 1, 2, 3 or Substituted by four substituents selected from the group consisting of -OH, pendant oxy, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl) and - N(C 1-6 alkyl) 2 .

在本發明之另一實施例中，各Re 係獨立地選自：氫、-C1-6 烷基及-O-C1-6 烷基，其中烷基未經取代或經1、2、3或4個選自以下之取代基取代：-OH、側氧基、鹵素、C1-6 烷基、-OC1-6 烷基、-NH2 、-NH(C1-6 烷基)及-N(C1-6 烷基)2 。在本發明此實施例之一類別中，各Re 係獨立地選自：氫、-CH3 及-OCH3 ，其中烷基未經取代或經1、2、3或4個選自以下之取代基取代：-OH、側氧基、鹵素、C1-6 烷基、-OC1-6 烷基、-NH2 、-NH(C1-6 烷基)及-N(C1-6 烷基)2 。In another embodiment of the invention, each R e is independently selected from the group consisting of hydrogen, -C 1-6 alkyl, and -OC 1-6 alkyl, wherein the alkyl group is unsubstituted or 1, 2, 3 Or 4 substituents selected from the group consisting of: -OH, pendant oxy, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl) and -N(C 1-6 alkyl) 2 . In a class of this embodiment of the invention, each R e is independently selected from the group consisting of hydrogen, —CH 3 and —OCH 3 , wherein the alkyl group is unsubstituted or 1, 2, 3 or 4 selected from the group consisting of Substituent substitution: -OH, pendant oxy, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl) and -N (C 1-6 Alkyl) 2 .

在本發明之另一實施例中，各Rg 係獨立地選自：氫、-C1-6 烷基及-O-C1-6 烷基，其中烷基未經取代或經1、2、3或4個選自以下之取代基取代：-OH、側氧基、鹵素、C1-6 烷基、-OC1-6 烷基、-NH2 、-NH(C1-6 烷基)及-N(C1-6 烷基)2 。在本發明此實施例之一類別中，各Rg 係獨立地選自：氫、-CH3 及-OCH3 ，其中烷基未經取代或經1、2、3或4個選自以下之取代基取代：-OH、側氧基、鹵素、C1-6 烷 基、-OC1-6 烷基、-NH2 、-NH(C1-6 烷基)及-N(C1-6 烷基)2 。In another embodiment of the invention, each R g is independently selected from the group consisting of hydrogen, -C 1-6 alkyl, and -OC 1-6 alkyl, wherein the alkyl group is unsubstituted or 1, 2, 3 Or 4 substituents selected from the group consisting of: -OH, pendant oxy, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl) and -N(C 1-6 alkyl) 2 . In a class of this embodiment of the invention, each R g is independently selected from the group consisting of: hydrogen, -CH 3 and -OCH 3 wherein the alkyl group is unsubstituted or 1, 2, 3 or 4 selected from the group consisting of Substituent substitution: -OH, pendant oxy, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl) and -N (C 1-6 Alkyl) 2 .

在本發明之另一實施例中，各Rh 係獨立地選自：氫、-C1-6 烷基及-O-C1-6 烷基，其中烷基未經取代或經1、2、3或4個選自以下之取代基取代：-OH、側氧基、鹵素、C1-6 烷基、-OC1-6 烷基、-NH2 、-NH(C1-6 烷基)及-N(C1-6 烷基)2 。在本發明此實施例之一類別中，各Rh 係獨立地選自：氫、-CH3 及-OCH3 ，其中烷基未經取代或經1、2、3或4個選自以下之取代基取代：-OH、側氧基、鹵素、C1-6 烷基、-OC1-6 烷基、-NH2 、-NH(C1-6 烷基)及-N(C1-6 烷基)2 。In another embodiment of the invention, each R h is independently selected from the group consisting of hydrogen, -C 1-6 alkyl, and -OC 1-6 alkyl, wherein the alkyl group is unsubstituted or 1, 2, 3 Or 4 substituents selected from the group consisting of: -OH, pendant oxy, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl) and -N(C 1-6 alkyl) 2 . In this embodiment of the present invention, one embodiment categories, each R h are independently selected from: hydrogen, -CH 3 and -OCH 3, wherein alkyl is unsubstituted or 3 or 4 selected from the Substituent substitution: -OH, pendant oxy, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl) and -N (C 1-6 Alkyl) 2 .

在本發明之另一實施例中，Re 、Rg 及Rh 各自係獨立地選自：氫及C1-6 烷基，其中烷基未經取代或經1、2、3或4個選自以下之取代基取代：-OH、側氧基、鹵素、C1-6 烷基、-OC1-6 烷基、-NH2 、-NH(C1-6 烷基)及-N(C1-6 烷基)2 。在此實施例之一類別中，各Re 係獨立地選自：氫及C1-6 烷基，其中烷基未經取代或經1、2或3個選自以下之取代基取代：-OH、側氧基、鹵素、C1-6 烷基、-OC1-6 烷基、-NH2 、-NH(C1-6 烷基)及-N(C1-6 烷基)2 。在此類別之一子類中，Re 為氫。在此類別之另一子類中，Re 為C1-6 烷基。在此實施例之另一類別中，各Rg 係獨立地選自：氫及C1-6 烷基，其中烷基未經取代或經1、2或3個選自以下之取代基取代：-OH、側氧基、鹵素、C1-6 烷基、-OC1-6 烷基、-NH2 、-NH(C1-6 烷基)及-N(C1-6 烷基)2 。在此類別之一子類中，Rg 為氫。在此類別之另一子類中，Rg 為C1-6 烷基。在此實施例之另一類別中，各Rh 係獨立地選自：氫及C1-6 烷基，其 中烷基未經取代或經1、2或3個選自以下之取代基取代：-OH、側氧基、鹵素、C1-6 烷基、-OC1-6 烷基、-NH2 、-NH(C1-6 烷基)及-N(C1-6 烷基)2 。在此類別之一子類中，Rh 為氫。在此類別之另一子類中，Rh 為C1-6 烷基。In another embodiment of the present invention, R e , R g and R h are each independently selected from the group consisting of hydrogen and C 1-6 alkyl, wherein the alkyl group is unsubstituted or 1, 2, 3 or 4 Substituted by a substituent selected from the group consisting of -OH, pendant oxy, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), and -N ( C 1-6 alkyl) 2 . In one class of this embodiment, each R e is independently selected from the group consisting of: hydrogen and C 1-6 alkyl, wherein the alkyl group is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of: - OH, pendant oxy, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl) and -N(C 1-6 alkyl) 2 . In one of the subclasses of this category, R e is hydrogen. In another subclass of this class, R e is C 1-6 alkyl. In another class of this embodiment, each R g is independently selected from the group consisting of: hydrogen and C 1-6 alkyl, wherein the alkyl group is unsubstituted or substituted with 1, 2 or 3 substituents selected from: -OH, pendant oxy, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl) and -N(C 1-6 alkyl) 2 . In one of the subclasses of this category, Rg is hydrogen. In another subclass of this class, R g is C 1-6 alkyl. In another class of this embodiment, each R h is independently selected from the group consisting of hydrogen and C 1-6 alkyl, wherein the alkyl group is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of: -OH, pendant oxy, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl) and -N(C 1-6 alkyl) 2 . In one of the subclasses of this category, Rh is hydrogen. In another subclass of this class, R h is C 1-6 alkyl.

在本發明之另一實施例中，各Rj 係獨立地選自：氫、C1-6 烷基、C3-6 環烷基、-C(O)Ri 及-SO2 Ri ，其中烷基及環烷基未經取代或經1、2、3或4個選自以下之取代基取代：-OH、側氧基、鹵素、C1-6 烷基、-OC1-6 烷基、-NH2 、-NH(C1-6 烷基)及-N(C1-6 烷基)2 。在此實施例之一類別中，各Rj 係獨立地選自：氫、C1-6 烷基及C3-6 環烷基，其中烷基及環烷基未經取代或經1、2、3或4個選自以下之取代基取代：-OH、側氧基、鹵素、C1-6 烷基、-OC1-6 烷基、-NH2 、-NH(C1-6 烷基)及-N(C1-6 烷基)2 。在此實施例之另一類別中，各Rj 係獨立地選自：氫、-CH3 及環丙基，其中甲基及環丙基未經取代或經1、2、3或4個選自以下之取代基取代：-OH、側氧基、鹵素、C1-6 烷基、-OC1-6 烷基、-NH2 、-NH(C1-6 烷基)及-N(C1-6 烷基)2 。In another embodiment of the invention, each R j is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, -C(O)R i and -SO 2 R i , wherein the alkyl and cycloalkyl groups unsubstituted or substituted with 3 or 4 selected from the substituents: -OH, oxo, halo, C 1-6 alkyl, -OC 1-6 alkyl a group, -NH 2 , -NH(C 1-6 alkyl) and -N(C 1-6 alkyl) 2 . In one class of this embodiment, each R j is independently selected from the group consisting of hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl, wherein the alkyl and cycloalkyl are unsubstituted or 1, 2 , 3 or 4 substituents selected from the group consisting of: -OH, pendant oxy, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl And -N(C 1-6 alkyl) 2 . In another class of this embodiment, each R j is independently selected from the group consisting of hydrogen, -CH 3 and cyclopropyl, wherein the methyl and cyclopropyl groups are unsubstituted or 1, 2, 3 or 4 are selected Substituted from the following substituents: -OH, pendant oxy, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl) and -N (C 1-6 alkyl) 2 .

在本發明之另一實施例中，各Rj 係獨立地選自：氫、C1-6 烷基、C3-6 環烷基、-C(O)Ri 及-SO2 Ri ，其中烷基及環烷基未經取代或經1、2、3或4個選自以下之取代基取代：-OH、側氧基、鹵素、C1-6 烷基、-OC1-6 烷基、-NH2 、-NH(C1-6 烷基)及-N(C1-6 烷基)2 。在此實施例之一類別中，各Rj 係獨立地選自：氫、C1-6 烷基、-C(O)Ri 及-SO2 Ri ，其中烷基未經取代或經1、2、3或4個選自以下之取代基取代：-OH、側 氧基、鹵素、C1-6 烷基、-OC1-6 烷基、-NH2 、-NH(C1-6 烷基)及-N(C1-6 烷基)2 。在此實施例之另一類別中，各Rj 係獨立地選自：氫及C1-6 烷基，其中烷基未經取代或經1、2、3或4個選自以下之取代基取代：-OH、側氧基、鹵素、C1-6 烷基、-OC1-6 烷基、-NH2 、-NH(C1-6 烷基)及-N(C1-6 烷基)2 。在此實施例之另一類別中，各Rj 係獨立地選自：氫及C1-6 烷基。在此實施例之另一類別中，Rj 為氫。在此實施例之另一類別中，Rj 為C1-6 烷基，其中烷基未經取代或經1、2或3個選自以下之取代基取代：-OH、側氧基、鹵素、C1-6 烷基、-OC1-6 烷基、-NH2 、-NH(C1-6 烷基)及-N(C1-6 烷基)2 。在此實施例之另一類別中，Rj 為C1-6 烷基。In another embodiment of the invention, each R j is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, -C(O)R i and -SO 2 R i , wherein the alkyl and cycloalkyl groups unsubstituted or substituted with 3 or 4 selected from the substituents: -OH, oxo, halo, C 1-6 alkyl, -OC 1-6 alkyl a group, -NH 2 , -NH(C 1-6 alkyl) and -N(C 1-6 alkyl) 2 . In one class of this embodiment, each R j is independently selected from the group consisting of: hydrogen, C 1-6 alkyl, -C(O)R i and -SO 2 R i , wherein the alkyl group is unsubstituted or , 2, 3 or 4 substituents selected from the group consisting of: -OH, pendant oxy, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH (C 1-6 Alkyl) and -N(C 1-6 alkyl) 2 . In another class of this embodiment, each R j is independently selected from the group consisting of hydrogen and C 1-6 alkyl, wherein the alkyl group is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Substituted: -OH, pendant oxy, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl) and -N(C 1-6 alkyl ) 2 . In another class of this embodiment, each R j is independently selected from the group consisting of hydrogen and C 1-6 alkyl. In another class of this embodiment, R j is hydrogen. In this embodiment another class of the embodiments, R j is C 1-6 alkyl, wherein alkyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from the substituents: -OH, oxo, halo C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl) and -N(C 1-6 alkyl) 2 . In another class of this embodiment, R j is C 1-6 alkyl.

在本發明之另一實施例中，Rf 及Ri 各自係獨立地選自：C1-6 烷基、C4-7 環烷基、C4-7 環烯基、C3-7 環雜烷基、C3-7 環雜烯基、芳基及雜芳基，其中烷基、環烷基、環烯基、環雜烷基、環雜烯基、芳基及雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-OH、-CN、-NH2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基及雜芳基。在此實施例之一類別中，Rf 及Ri 各自係獨立地選自：C1-6 烷基及C3-7 環雜烷基，其中烷基及環雜烷基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-OH、-CN、-NH2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基及雜芳基。在此實施例之另一類別中，Rf 及Ri 各自係獨立地選自：C1-6 烷基及C3-7 環雜烷 基，其中烷基及環雜烷基未經取代或經1、2或3個選自以下之取代基取代：側氧基、-OH、-CN、-NH2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H及-CO2 C1-6 烷基。在此實施例之另一類別中，Rf 及Ri 各自係獨立地選自：-CH(CH3 )2 、-C(CH3 、嗎啉、吡咯啶及哌嗪，其中烷基、嗎啉、吡咯啶及哌嗪各自未經取代或經1、2或3個選自以下之取代基取代：側氧基、-OH、-CN、-NH2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H及-CO2 C1-6 烷基。In another embodiment of the present invention, each of R f and R i is independently selected from the group consisting of: C 1-6 alkyl, C 4-7 cycloalkyl, C 4-7 cycloalkenyl, C 3-7 ring a heteroalkyl group, a C 3-7 cycloheteroalkenyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the cycloalkenyl group, the cycloheteroalkyl group, the cycloheteroalkenyl group, the aryl group and the heteroaryl group are not Substituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of: pendant oxy, -OH, -CN, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3-7 cycloalkyl and heteroaryl. In one embodiment of this category embodiment, R f, and each R i are independently selected: C 1-6 alkyl group and a C 3-7 cycloalkyl heteroalkyl, wherein alkyl and cycloheteroalkyl are unsubstituted or substituted 1, 2, 3 or 4 substituents selected from the group consisting of: pendant oxy, -OH, -CN, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3-7 cycloalkyl and heteroaryl. In another class of this embodiment, R f and R i are each independently selected from the group consisting of: C 1-6 alkyl and C 3-7 cycloheteroalkyl, wherein alkyl and cycloheteroalkyl are unsubstituted or Substituted by 1, 2 or 3 substituents selected from the group consisting of pendant oxy, -OH, -CN, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H and -CO 2 C 1-6 alkyl. In another class of this embodiment, each of R f and R i is independently selected from the group consisting of: -CH(CH 3 ) 2 , -C(CH 3 , morpholine, pyrrolidine, and piperazine, wherein alkyl, The porphyrin, pyrrolidine and piperazine are each unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of pendant oxy, -OH, -CN, -NH 2 , -C 1-6 alkyl, - OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H and -CO 2 C 1-6 alkyl.

在本發明之另一實施例中，各Rf 係獨立地選自：C1-6 烷基、C4-7 環烷基、C4-7 環烯基、C3-7 環雜烷基、C3-7 環雜烯基、芳基及雜芳基，其中烷基、環烷基、環烯基、環雜烷基、環雜烯基、芳基及雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-OH、-CN、-NH2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基及雜芳基。在此實施例之一類別中，各Rf 係獨立地選自：C1-6 烷基及C3-7 環雜烷基，其中烷基及環雜烷基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-OH、-CN、-NH2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基及雜芳基。在此實施例之另一類別中，各Rf 係獨立地選自：C1-6 烷基及C3-7 環雜烷基，其中烷基及環雜烷基未經取代或經1、2或3個選自以下之取代基取代：側氧基、-OH、-CN、-NH2 、-C1-6 烷基、-OC1-6 烷基、鹵素、 -CH2 F、-CHF2 、-CF3 、-CO2 H及-CO2 C1-6 烷基。在此實施例之另一類別中，各Rf 係獨立地選自：-CH(CH3 )2 、-C(CH3 、嗎啉、吡咯啶及哌嗪，其中烷基、嗎啉、吡咯啶及哌嗪各自未經取代或經1、2或3個選自以下之取代基取代：側氧基、-OH、-CN、-NH2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H及-CO2 C1-6 烷基。In another embodiment of the invention, each Rf is independently selected from the group consisting of: C1-6 alkyl, C4-7 cycloalkyl, C4-7 cycloalkenyl, C3-7 cycloheteroalkyl , C 3-7 cycloheteroalkyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of: pendant oxy, -OH, -CN, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3-7 cycloalkyl and heteroaryl. In one class of this embodiment, each R f is independently selected from the group consisting of: C 1-6 alkyl and C 3-7 cycloheteroalkyl, wherein alkyl and cycloheteroalkyl are unsubstituted or 1, 2 , 3 or 4 selected from the substituents: oxo, -OH, -CN, -NH 2, -C 1-6 alkyl, -OC 1-6 alkyl, halo, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3-7 cycloalkyl and heteroaryl. In another class of this embodiment, each Rf is independently selected from the group consisting of: C1-6 alkyl and C3-7 cycloheteroalkyl, wherein the alkyl and cycloheteroalkyl are unsubstituted or passed through 2 or 3 substituents selected from the group consisting of: pendant oxy, -OH, -CN, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, - CHF 2 , -CF 3 , -CO 2 H and -CO 2 C 1-6 alkyl. In this embodiment another class of embodiments, each R f are independently selected: -CH (CH 3) 2, -C (CH 3, morpholine, pyrrolidine and piperazine, where alkyl, morpholine, pyrrole piperidine and piperazine are each unsubstituted or substituted by 1, 2 or 3 substituents selected from the substituents: oxo, -OH, -CN, -NH 2, -C 1-6 alkyl, -OC 1- 6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H and -CO 2 C 1-6 alkyl.

在本發明之另一實施例中，各Ri 係獨立地選自：C1-6 烷基、C4-7 環烷基、C4-7 環烯基、C3-7 環雜烷基、C3-7 環雜烯基、芳基及雜芳基，其中烷基、環烷基、環烯基、環雜烷基、環雜烯基、芳基及雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-OH、-CN、-NH2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基及雜芳基。在此實施例之一類別中，各Ri 係獨立地選自：C1-6 烷基及C3-7 環雜烷基，其中烷基及環雜烷基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-OH、-CN、-NH2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基及雜芳基。在此實施例之另一類別中，各Ri 係獨立地選自：C1-6 烷基及C3-7 環雜烷基，其中烷基及環雜烷基未經取代或經1、2或3個選自以下之取代基取代：側氧基、-OH、-CN、-NH2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H及-CO2 C1-6 烷基。在此實施例之另一類別中，各Ri 係獨立地選自：-CH(CH3 )2 、-C(CH3 、嗎啉、吡咯啶及哌嗪，其中烷基、嗎啉、吡咯啶及哌嗪各 自未經取代或經1、2或3個選自以下之取代基取代：側氧基、-OH、-CN、-NH2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H及-CO2 C1-6 烷基。In another embodiment of the present invention, each R i is independently selected from the group consisting of: C 1-6 alkyl, C 4-7 cycloalkyl, C 4-7 cycloalkenyl, C 3-7 cycloheteroalkyl , C 3-7 cycloheteroalkenyl, aryl and heteroaryl, wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or 1, 2, 3 or 4 substituents selected from the group consisting of: pendant oxy, -OH, -CN, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3-7 cycloalkyl and heteroaryl. In one class of this embodiment, each R i is independently selected from the group consisting of: C 1-6 alkyl and C 3-7 cycloheteroalkyl, wherein alkyl and cycloheteroalkyl are unsubstituted or 1, 2 , 3 or 4 substituents selected from the group consisting of: pendant oxy, -OH, -CN, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3-7 cycloalkyl and heteroaryl. In another class of this embodiment, each R i is independently selected from the group consisting of: C 1-6 alkyl and C 3-7 cycloheteroalkyl, wherein alkyl and cycloheteroalkyl are unsubstituted or passed through 2 or 3 substituents selected from the group consisting of: pendant oxy, -OH, -CN, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, - CHF 2 , -CF 3 , -CO 2 H and -CO 2 C 1-6 alkyl. In another class of this embodiment, each R i is independently selected from the group consisting of: -CH(CH 3 ) 2 , -C(CH 3 , morpholine, pyrrolidine, and piperazine, wherein alkyl, morpholine, pyrrole The pyridine and piperazine are each unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of pendant oxy, -OH, -CN, -NH 2 , -C 1-6 alkyl, -OC 1- 6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H and -CO 2 C 1-6 alkyl.

在此實施例之另一類別中，Rf 及Ri 各自係獨立地選自：C1-6 烷基，其中烷基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-OH、-CN、-NH2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基及雜芳基。在此實施例之另一類別中，Rf 及Ri 各自係獨立地選自：C4-7 環烷基、C4-7 環烯基、C3-7 環雜烷基、C3-7 環雜烯基、芳基及雜芳基，其中環烷基、環烯基、環雜烷基、環雜烯基、芳基及雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-OH、-CN、-NH2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基及雜芳基。In another class of this embodiment, R f and R i are each independently selected from: C 1-6 alkyl, wherein alkyl is unsubstituted or substituted by 1, 2, 3 or 4 selected from Base substitution: pendant oxy, -OH, -CN, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3-7 cycloalkyl and heteroaryl. In another class of this embodiment, each of R f and R i is independently selected from the group consisting of: C 4-7 cycloalkyl, C 4-7 cycloalkenyl, C 3-7 cycloheteroalkyl, C 3 - a 7- ring heteroalkenyl, aryl and heteroaryl group wherein the cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl groups are unsubstituted or 1, 2, 3 or 4 Substituted by a substituent selected from the group consisting of pendant oxy, -OH, -CN, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3-7 cycloalkyl and heteroaryl.

在本發明之另一實施例中，n為0、1、2、3或4。在此實施例之一類別中，n為1、2或3。在此實施例之另一類別中，n為0、1或2。在此實施例之另一類別中，n為0。在此實施例之另一類別中，n為1。在此實施例之另一類別中，n為2。In another embodiment of the invention, n is 0, 1, 2, 3 or 4. In one of the categories of this embodiment, n is 1, 2 or 3. In another category of this embodiment, n is 0, 1, or 2. In another category of this embodiment, n is zero. In another category of this embodiment, n is one. In another category of this embodiment, n is 2.

在本發明之另一實施例中，m為0、1、2、3或4。在此實施例之一類別中，m為0、1、2或3。在此實施例之另一類別中，m為1、2或3。在此實施例之另一類別中，m為0、1或2。在此實施例之另一類別中，m為0或1。在此實施例之另一類別中，m為0。在此實施例之另一類別中，m為 1。In another embodiment of the invention, m is 0, 1, 2, 3 or 4. In one of the categories of this embodiment, m is 0, 1, 2 or 3. In another category of this embodiment, m is 1, 2 or 3. In another category of this embodiment, m is 0, 1, or 2. In another category of this embodiment, m is 0 or 1. In another category of this embodiment, m is zero. In another category of this embodiment, m is 1.

在本發明之另一實施例中，p為0、1、2或3。在此實施例之一類別中，p為1、2或3。在此實施例之另一類別中，p為0、1或2。在此實施例之另一類別中，p為0或2。在此實施例之另一類別中，p為0。在此實施例之另一類別中，p為1。在此實施例之另一類別中，p為2。In another embodiment of the invention, p is 0, 1, 2 or 3. In one of the categories of this embodiment, p is 1, 2 or 3. In another category of this embodiment, p is 0, 1, or 2. In another category of this embodiment, p is 0 or 2. In another category of this embodiment, p is zero. In another category of this embodiment, p is one. In another category of this embodiment, p is two.

在本發明之另一實施例中，q為0、1、2、3或4。在此實施例之一類別中，q為1、2或3。在此實施例之另一類別中，q為0、1或2。在此實施例之另一類別中，q為1或2。在此實施例之另一類別中，q為0。在此實施例之另一類別中，q為1。在此實施例之另一類別中，q為2。In another embodiment of the invention, q is 0, 1, 2, 3 or 4. In one of the categories of this embodiment, q is 1, 2 or 3. In another category of this embodiment, q is 0, 1, or 2. In another category of this embodiment, q is 1 or 2. In another category of this embodiment, q is zero. In another category of this embodiment, q is one. In another category of this embodiment, q is two.

在本發明之另一實施例中，r為0、1或2。在此實施例之一類別中，r為0或1。在此實施例之另一類別中，r為0。在此實施例之另一類別中，r為1。在此實施例之另一類別中，r為2。In another embodiment of the invention, r is 0, 1, or 2. In one of the categories of this embodiment, r is 0 or 1. In another category of this embodiment, r is zero. In another category of this embodiment, r is one. In another category of this embodiment, r is two.

在本發明之另一實施例中，s為0、1、2、3或4。在此實施例之一類別中，s為0、1、2或3。在此實施例之一類別中，s為0、1或2。在此實施例之另一類別中，s為0或1。在此實施例之另一類別中，s為1或2。在此實施例之另一類別中，s為0或2。在此實施例之另一類別中，s為0。在此實施例之另一類別中，s為1。在此實施例之另一類別中，s為2。在此實施例之另一類別中，s為3。In another embodiment of the invention, s is 0, 1, 2, 3 or 4. In one of the categories of this embodiment, s is 0, 1, 2 or 3. In one of the categories of this embodiment, s is 0, 1, or 2. In another category of this embodiment, s is 0 or 1. In another category of this embodiment, s is 1 or 2. In another category of this embodiment, s is 0 or 2. In another category of this embodiment, s is zero. In another category of this embodiment, s is one. In another category of this embodiment, s is two. In another category of this embodiment, s is three.

在本發明之另一實施例中，t為0、1、2、3或4。在此實施例之一類別中，t為0、1、2或3。在此實施例之一類別 中，t為0、1或2。在此實施例之另一類別中，t為0或1。在此實施例之另一類別中，t為1或2。在此實施例之另一類別中，t為0或2。在此實施例之另一類別中，t為0。在此實施例之另一類別中，t為1。在此實施例之另一類別中，t為2。在此實施例之另一類別中，t為3。In another embodiment of the invention, t is 0, 1, 2, 3 or 4. In one of the categories of this embodiment, t is 0, 1, 2 or 3. In one of the categories of this embodiment Medium, t is 0, 1, or 2. In another category of this embodiment, t is 0 or 1. In another category of this embodiment, t is 1 or 2. In another category of this embodiment, t is 0 or 2. In another category of this embodiment, t is zero. In another category of this embodiment, t is one. In another category of this embodiment, t is two. In another category of this embodiment, t is three.

本發明之另一實施例係關於結構式I之化合物，其中：T為N；U為-CR1 -；V為-CR2 -；W為-CR4 -；X係選自：(1)-O-，及(2)-O-CH2 -；Y係選自：(1)C3-10 環烷基，(2)C2-10 環雜烷基，及(3)苯基，其中環烷基、環雜烷基及苯基未經取代或經1、2、3或4個選自Rb 之取代基取代；Z係選自：(1)側氧基，(2)-CF3 ，(3)-C1-6 烷基，(4)-(CH2 )t -鹵素， (5)-(CH2 )n CO2 H，(6)-(CH2 )n OH，及(7)-(CH2 )n SO2 C1-6 烷基，其中各CH2 未經取代或經1或2個選自C1-6 烷基、-OH及-NH2 之取代基取代，且其中各烷基未經取代或經1、2、3或4個選自Rc 之取代基取代；R1 係獨立地選自：(1)-C4-10 環烯基，(2)-苯基，(3)苯基-C2 炔基C1-5 烷基，(4)苯基-C2-3 炔基-C3-7 環烷基，(5)苯基-C2-3 炔基-C2-10 環雜烷基，(6)-苯基-C3-7 環烷基，(7)-苯基-C2-7 環雜烷基，(8)苯基-C2-10 環雜烯基，(9)-苯基-苯基、(10)-苯基-雜芳基，(11)-雜芳基，及(12)-C2-6 炔基-苯基，其中烷基、炔基、環烷基、環烯基、環雜烷基、環雜烯基、苯基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代；R2 係選自鹵素；R4 為氫；且 R5 為氫；或其醫藥學上可接受之鹽。Another embodiment of the invention is directed to a compound of formula I, wherein: T is N; U is -CR 1 -; V is -CR 2 -; W is -CR 4 -; X is selected from: (1) -O-, and (2)-O-CH 2 -; Y is selected from the group consisting of: (1) C 3-10 cycloalkyl, (2) C 2-10 cycloheteroalkyl, and (3) phenyl, Wherein the cycloalkyl, cycloheteroalkyl and phenyl are unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from R b ; Z is selected from the group consisting of: (1) pendant oxy, (2)- CF 3 , (3)-C 1-6 alkyl, (4)-(CH 2 ) t -halogen, (5)-(CH 2 ) n CO 2 H, (6)-(CH 2 ) n OH, And (7)-(CH 2 ) n SO 2 C 1-6 alkyl, wherein each CH 2 is unsubstituted or has 1 or 2 substituents selected from C 1-6 alkyl, -OH and -NH 2 Substituted, and wherein each alkyl group is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R c ; R 1 is independently selected from: (1)-C 4-10 cycloalkenyl, 2) -phenyl, (3) phenyl-C 2 alkynyl C 1-5 alkyl, (4) phenyl-C 2-3 alkynyl-C 3-7 cycloalkyl, (5) phenyl- C 2-3 alkynyl-C 2-10 cycloheteroalkyl, (6)-phenyl-C 3-7 cycloalkyl, (7)-phenyl-C 2-7 cycloheteroalkyl, (8) Phenyl-C 2-10 cycloheteroalkenyl, (9)-phenyl-phenyl, (10)-phenyl-heteroaryl, (11)-heteroaryl, and (1 2) -C 2-6 alkynyl-phenyl, wherein alkyl, alkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, phenyl and heteroaryl are each unsubstituted or 1, 2, 3 or 4 substituents independently selected from R a ; R 2 is selected from halogen; R 4 is hydrogen; and R 5 is hydrogen; or a pharmaceutically acceptable salt thereof.

本發明之另一實施例係關於結構式I之化合物，其中：T為N；U為-CR1 -；V為-CR2 -；W為-CR4 -；X為-O-；Y係選自C2-10 環雜烷基，其中各環雜烷基未經取代或經1、2、3或4個選自Rb 之取代基取代；Z係選自：-(CH2 )t -鹵素及-(CH2 )n OH；R1 係獨立地選自：(1)苯基-C2-8 炔基-C1-8 烷基，(2)苯基-C2-3 炔基-C3-7 環烷基，(3)苯基-C2-3 炔基-C2-10 環雜烷基，(4)苯基-C2-10 環雜烯基，(5)聯苯，及(6)苯基-雜芳基，其中烷基、炔基、環烷基、環雜烷基、環雜烯基、苯基、聯苯及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代；R2 係選自鹵素；R4 為氫；且R5 為氫； 或其醫藥學上可接受之鹽。Another embodiment of the invention is directed to a compound of formula I, wherein: T is N; U is -CR 1 -; V is -CR 2 -; W is -CR 4 -; X is -O-; Selected from a C 2-10 cycloheteroalkyl group, wherein each cycloheteroalkyl group is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R b ; Z is selected from the group consisting of: -(CH 2 ) t -halogen and -(CH 2 ) n OH; R 1 is independently selected from: (1) phenyl-C 2-8 alkynyl-C 1-8 alkyl, (2) phenyl-C 2-3 alkyne Benzyl -C 3-7 cycloalkyl, (3) phenyl-C 2-3 alkynyl-C 2-10 cycloheteroalkyl, (4) phenyl-C 2-10 cycloheteroyl, (5) Biphenyl, and (6) phenyl-heteroaryl, wherein alkyl, alkynyl, cycloalkyl, cycloheteroalkyl, cycloheteroalkenyl, phenyl, biphenyl and heteroaryl are each unsubstituted or 1, 2, 3 or 4 substituents independently selected from R a ; R 2 is selected from halogen; R 4 is hydrogen; and R 5 is hydrogen; or a pharmaceutically acceptable salt thereof.

本發明之另一實施例係關於結構式I之化合物，其中：T為N；U為-CR1 -；V為-CR2 -；W為-CR4 -；X係選自：(1)-O-，及(2)-O-CH2 -；Y係選自：(1)C3-10 環烷基，(2)C2-10 環雜烷基，及(3)苯基，其中環烷基、環雜烷基及苯基未經取代或經1、2、3或4個選自Rb 之取代基取代；Z係選自：(1)側氧基，(2)-CF3 ，(3)-C1-6 烷基，(4)-(CH2 )t -鹵素，(5)-(CH2 )n CO2 H，(6)-(CH2 )n OH，及(7)-(CH2 )n SO2 C1-6 烷基，其中各CH2 未經取代或經1或2個選自C1-6 烷基、-OH及-NH2 之取代基取代，其中各NH未經取代或經1個選自Rc 之取代基取代，且其中各烷基未經取代或經1、2、3或4個選自Rc 之取代基取代；R1 係獨立地選自：(1)-C4-10 環烯基，(2)-苯基，(3)-苯基-C3-7 環烷基，(4)-苯基-C2-7 環雜烷基，(5)-苯基-苯基，(6)-苯基-雜芳基，(7)-雜芳基，及(8)-C2-6 炔基-苯基，其中各炔基未經取代或經1、2或3個選自以下之取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，且其中環烷基、環烯基、環雜烷基、苯基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代；R2 係選自：鹵素；R4 為氫；且R5 為氫；或其醫藥學上可接受之鹽。Another embodiment of the invention is directed to a compound of formula I, wherein: T is N; U is -CR 1 -; V is -CR 2 -; W is -CR 4 -; X is selected from: (1) -O-, and (2)-O-CH 2 -; Y is selected from the group consisting of: (1) C 3-10 cycloalkyl, (2) C 2-10 cycloheteroalkyl, and (3) phenyl, Wherein the cycloalkyl, cycloheteroalkyl and phenyl are unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from R b ; Z is selected from the group consisting of: (1) pendant oxy, (2)- CF 3 , (3)-C 1-6 alkyl, (4)-(CH 2 ) t -halogen, (5)-(CH 2 ) n CO 2 H, (6)-(CH 2 ) n OH, And (7)-(CH 2 ) n SO 2 C 1-6 alkyl, wherein each CH 2 is unsubstituted or has 1 or 2 substituents selected from C 1-6 alkyl, -OH and -NH 2 substituents, wherein each is unsubstituted or NH selected one of the substituents R c, and wherein each alkyl unsubstituted or substituted with 1,2, 3 or 4 substituents selected from the substituents R c; R 1 Is independently selected from the group consisting of: (1)-C 4-10 cycloalkenyl, (2)-phenyl, (3)-phenyl-C 3-7 cycloalkyl, (4)-phenyl-C 2- 7 -cycloheteroalkyl, (5)-phenyl-phenyl, (6)-phenyl-heteroaryl, (7)-heteroaryl, and (8)-C 2-6 alkynyl-phenyl, Wherein each alkynyl group is unsubstituted or 1, 2 or 3 is selected from the following Substituent substitution: halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl, and -N(C 1-6 alkyl) 2, and wherein the cycloalkyl, cycloalkenyl, cycloheteroalkyl, phenyl and heteroaryl, each unsubstituted or substituted by three or four of independently selected R a substituents; R & lt 2 It is selected from the group consisting of: halogen; R 4 is hydrogen; and R 5 is hydrogen; or a pharmaceutically acceptable salt thereof.

本發明之另一實施例係關於結構式I之化合物，其中：T為N；U為-CR1 -； V為-CR2 -；W為-CR4 -；X為-O-；Y係選自：(1)C3-7 環烷基，(2)C2-10 環雜烷基，及(3)苯基，其中環烷基、環雜烷基及苯基各自未經取代或經1、2、3或4個選自Rb 之取代基取代；Z係選自：(1)-(CH2 )n CO2 H，(2)-(CH2 )t -鹵素，及(3)-(CH2 )n OH，其中各CH2 未經取代或經1或2個選自C1-6 烷基及-OH之取代基取代；或其醫藥學上可接受之鹽。 R1 係獨立地選自：(1)-苯基-C2-7 環雜烷基，(2)苯基-C2-10 環雜烯基，(3)-苯基-苯基，及(4)苯基-雜芳基，其中環雜烷基、環雜烯基、雜芳基及苯基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代；R2 係選自鹵素；R4 為氫；且 R5 為氫；或其醫藥學上可接受之鹽。Another embodiment of the invention is directed to a compound of formula I, wherein: T is N; U is -CR 1 -; V is -CR 2 -; W is -CR 4 -; X is -O-; Selected from: (1) C 3-7 cycloalkyl, (2) C 2-10 cycloheteroalkyl, and (3) phenyl, wherein the cycloalkyl, cycloheteroalkyl and phenyl are each unsubstituted or Substituted by 1, 2, 3 or 4 substituents selected from R b ; Z is selected from the group consisting of: (1)-(CH 2 ) n CO 2 H, (2)-(CH 2 ) t -halogen, and 3) -(CH 2 ) n OH wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from C 1-6 alkyl and -OH; or a pharmaceutically acceptable salt thereof. R 1 is independently selected from the group consisting of: (1)-phenyl-C 2-7 cycloheteroalkyl, (2) phenyl-C 2-10 cycloheteroalkenyl, (3)-phenyl-phenyl, and (4) A phenyl-heteroaryl group, wherein a cycloheteroalkyl group, a cycloheteroalkenyl group, a heteroaryl group and a phenyl group are each unsubstituted or 1, 2, 3 or 4 substituents independently selected from R a Substituted; R 2 is selected from halogen; R 4 is hydrogen; and R 5 is hydrogen; or a pharmaceutically acceptable salt thereof.

本發明之另一實施例係關於結構式I之化合物，其中：T為N；U為-CR1 -；V為-CR2 -；W為-CR4 -；X為-O-；Y係選自C2-10 環雜烷基，其中各環雜烷基未經取代或經1、2、3或4個選自Rb 之取代基取代；Z係選自：-(CH2 )n OH；R1 係獨立地選自：(1)-苯基-C2-10 環雜烯基，(2)聯苯，及(3)苯基-雜芳基，其中環雜烯基、苯基、聯苯及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代；R2 係選自鹵素；R4 為氫；且R5 為氫；或其醫藥學上可接受之鹽。Another embodiment of the invention is directed to a compound of formula I, wherein: T is N; U is -CR 1 -; V is -CR 2 -; W is -CR 4 -; X is -O-; Selected from a C 2-10 cycloheteroalkyl group, wherein each cycloheteroalkyl group is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R b ; Z is selected from the group consisting of: -(CH 2 ) n OH; R 1 is independently selected from the group consisting of: (1)-phenyl-C 2-10 cycloheteroalkenyl, (2) biphenyl, and (3) phenyl-heteroaryl, wherein cycloheteroalkenyl, benzene The base, biphenyl and heteroaryl are each unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from R a ; R 2 is selected from halogen; R 4 is hydrogen; and R 5 is hydrogen Or a pharmaceutically acceptable salt thereof.

本發明之另一實施例係關於結構式I之化合物，其中：T為N；U為-CR1 -； V為-CR2 -；W為-CR4 -；X為-O-；Y係選自：(1)C3-7 環烷基，(2)C2-10 環雜烷基，及(3)苯基，其中環烷基、環雜烷基及苯基各自未經取代或經1、2、3或4個選自Rb 之取代基取代；Z係選自：(1)-(CH2 )n CO2 H，及(2)-(CH2 )n OH，其中各CH2 未經取代或經1或2個選自C1-6 烷基及-OH之取代基取代；R1 係選自：(1)-苯基-C2-7 環雜烷基，及(2)-苯基-苯基，其中環雜烷基及苯基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代；R2 係選自：鹵素；R4 為氫；且R5 為氫；或其醫藥學上可接受之鹽。Another embodiment of the invention is directed to a compound of formula I, wherein: T is N; U is -CR 1 -; V is -CR 2 -; W is -CR 4 -; X is -O-; Selected from: (1) C 3-7 cycloalkyl, (2) C 2-10 cycloheteroalkyl, and (3) phenyl, wherein the cycloalkyl, cycloheteroalkyl and phenyl are each unsubstituted or Substituted by 1, 2, 3 or 4 substituents selected from R b ; Z is selected from the group consisting of: (1)-(CH 2 ) n CO 2 H, and (2)-(CH 2 ) n OH, each of which CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from C 1-6 alkyl and -OH; R 1 is selected from: (1)-phenyl-C 2-7 cycloheteroalkyl, (2)-Phenyl-phenyl, wherein the cycloheteroalkyl and phenyl are each unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from R a ; R 2 is selected from: halogen ; R 4 is hydrogen; and R 5 is hydrogen; or a pharmaceutically acceptable salt thereof.

在本發明之另一實施例中，本發明係關於結構式Ia之化 合物： 或其醫藥學上可接受之鹽。In another embodiment of the invention, the invention relates to a compound of formula Ia: Or a pharmaceutically acceptable salt thereof.

在本發明之另一實施例中，本發明係關於結構式Ib之化合物： 或其醫藥學上可接受之鹽。In another embodiment of the invention, the invention relates to a compound of formula Ib: Or a pharmaceutically acceptable salt thereof.

在本發明之另一實施例中，本發明係關於結構式Ic之化合物： 或其醫藥學上可接受之鹽。In another embodiment of the invention, the invention relates to a compound of formula Ic: Or a pharmaceutically acceptable salt thereof.

在本發明之另一實施例中，本發明係關於結構式Id之化合物： 或其醫藥學上可接受之鹽。In another embodiment of the invention, the invention relates to a compound of formula Id: Or a pharmaceutically acceptable salt thereof.

結構式I之化合物包括結構式Ia、Ib、Ic及Id之化合物及其醫藥學上可接受之鹽、水合物及溶劑合物。Compounds of formula I include compounds of formula Ia, Ib, Ic and Id, and pharmaceutically acceptable salts, hydrates and solvates thereof.

適用作AMP蛋白激酶活化劑之本發明化合物之說明性而非限制性實例為以下化合物： 及其醫藥學上可接受之鹽。Illustrative, non-limiting examples of compounds of the invention suitable for use as AMP protein kinase activators are the following compounds: And pharmaceutically acceptable salts thereof.

「烷基」以及其他具有字首「烷」之基團(諸如烷氧基、烷醯基)意謂具有至多10個碳之碳鏈，其可為直鏈或分支鏈或其組合。烷基之實例包括甲基、乙基、正丙基、異丙基、丁基、異丁基、第二丁基及第三丁基、戊基、己 基、庚基、辛基、壬基及其類似基團。"Alkyl" and other groups having the prefix "alk" (such as alkoxy, alkano) mean a carbon chain having up to 10 carbons which may be straight or branched or a combination thereof. Examples of the alkyl group include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a butyl group, an isobutyl group, a second butyl group, and a tributyl group, a pentyl group, and a hexyl group. Base, heptyl, octyl, decyl and the like.

「烯基」意謂具有至多10個碳且含有至少一個碳碳雙鍵之碳鏈且其可為直鏈或分支鏈或其組合。烯基之實例包括乙烯基、烯丙基、異丙烯基、戊烯基、己烯基、庚烯基、1-丙烯基、2-丁烯基、2-甲基-2-丁烯基及其類似基團。在本發明之一個實施例中，烯基為乙烯基。"Alkenyl" means a carbon chain having up to 10 carbons and containing at least one carbon-carbon double bond and which may be a straight or branched chain or a combination thereof. Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl and Its similar group. In one embodiment of the invention, the alkenyl group is a vinyl group.

「炔基」意謂具有至多10個碳且含有至少一個碳碳參鍵之碳鏈且其可為直鏈或分支鏈或其組合。在一個實施例中，C2-8 炔基意謂具有2至8個碳且含有一個碳碳參鍵之碳鏈。炔基之實例包括乙炔基、炔丙基、3-甲基-1-戊炔基、2-庚炔基及其類似基團。在本發明之一個實施例中，炔基為乙炔基。在另一實施例中，炔基為炔丙基。"Alkynyl" means a carbon chain having up to 10 carbons and containing at least one carbon-carbon reference and which may be a straight or branched chain or a combination thereof. In one embodiment, C 2-8 alkynyl means a carbon chain having 2 to 8 carbons and containing a carbon-carbon bond. Examples of alkynyl groups include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like. In one embodiment of the invention, the alkynyl group is an ethynyl group. In another embodiment, the alkynyl group is a propargyl group.

「環烷基」意謂各自具有3至14個碳原子之單環或雙環或橋連飽和碳環。環烷基之實例包括環丙基、環丁基、環戊基、環己基、環庚基、環辛基及十氫萘基，及其類似基團。在本發明之一個實施例中，環烷基係選自環戊基及環己基。在本發明之另一實施例中，環烷基係選自環丙基、環戊基及環己基。"Cycloalkyl" means a monocyclic or bicyclic or bridged saturated carbocyclic ring each having from 3 to 14 carbon atoms. Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and a decahydronaphthyl group, and the like. In one embodiment of the invention, the cycloalkyl group is selected from the group consisting of cyclopentyl and cyclohexyl. In another embodiment of the invention, the cycloalkyl group is selected from the group consisting of cyclopropyl, cyclopentyl and cyclohexyl.

「環烯基」意謂各自具有3至14個碳原子且含有至少一個雙鍵之非芳族單環或雙環或橋連碳環。環烷基之實例包括環丙烯基、環丁烯基、環戊烯基、環己烯基、環庚烯基、環辛烯基、十氫萘基、雙環[2.2.1]庚-5-烯-2-基及其類似基團。"Cycloalkenyl" means a non-aromatic monocyclic or bicyclic or bridged carbocyclic ring each having from 3 to 14 carbon atoms and containing at least one double bond. Examples of cycloalkyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, decahydronaphthyl, bicyclo [2.2.1] g--5- Alken-2-yl and the like.

「環雜烷基」意謂各自具有2至14個碳原子且含有1、 2、3、4或5個選自N、NH、O及S之雜原子的非芳族單環或雙環或橋連飽和碳環。在一個實施例中，C2-10 環雜烷基意謂具有2至10個碳原子且含有1、2、3、4或5個選自N、NH、O及S之雜原子的非芳族單環或雙環或橋連飽和碳環。環雜烷基之實例包括四氫呋喃基、氮雜環丁烷基、全氫氮呯基、二氫呋喃基、二噁烷基、噁烷基、嗎啉基、1,4-二噻烷基、哌嗪基、哌啶基、1,3-二氧雜環戊烷基、咪唑啶基、咪唑啉基、吡咯啉基、吡咯啶基、哌喃基、四氫哌喃基、二氫哌喃基、氧硫雜環戊烷基、二硫雜環戊烷基、1,3-二噻烷基、氧硫雜環己烷基、硫代嗎啉基、二氧離子基異噻唑啶基、氮雜環庚基、二氮雜雙環[3.2.1]-辛烷及六氫吲唑基。環雜烷基環可在環碳及/或環氮上經取代。在本發明之一個實施例中，環雜烷基係選自哌啶、吡咯啶、噁唑啶、1,3-噁唑啶-2,4-二酮、噻唑啶、1,3-噻唑啶-2,4-二酮、咪唑啶及乙內醯脲，及其類似物。在本發明之另一實施例中，環雜烷基係選自：嗎啉、吡咯啶、哌嗪及哌啶。在本發明之另一實施例中，環雜烷基為吡咯啶。"Cycloheteroalkyl" means a non-aromatic monocyclic or bicyclic ring or bridge each having from 2 to 14 carbon atoms and containing 1, 2, 3, 4 or 5 heteroatoms selected from N, NH, O and S. Even saturated carbon rings. In one embodiment, C 2-10 cycloheteroalkyl means a non-aryl having 2 to 10 carbon atoms and containing 1, 2, 3, 4 or 5 heteroatoms selected from N, NH, O and S. A family of monocyclic or bicyclic or bridged saturated carbocycles. Examples of cycloheteroalkyl groups include tetrahydrofuranyl, azetidinyl, perhydroazinyl, dihydrofuranyl, dioxoalkyl, acetoalkyl, morpholinyl, 1,4-dithiaalkyl, Piperazinyl, piperidinyl, 1,3-dioxolyl, imidazolidinyl, imidazolinyl, pyrrolinyl, pyrrolidinyl, piperidyl, tetrahydropyranyl, dihydropyran Base, oxathiolane, dithiolanyl, 1,3-dithiazide, oxathiolanyl, thiomorpholinyl, dioxyisoisothiazolidinyl, Azacycloheptyl, diazabicyclo[3.2.1]-octane and hexahydrocarbazolyl. The cycloheteroalkyl ring can be substituted on the ring carbon and/or the ring nitrogen. In one embodiment of the invention, the cycloheteroalkyl group is selected from the group consisting of piperidine, pyrrolidine, oxazolidine, 1,3-oxazolidine-2,4-dione, thiazolidine, 1,3-thiazopyridine -2,4-dione, imidazolium and beta-urea, and analogs thereof. In another embodiment of the invention, the cycloheteroalkyl group is selected from the group consisting of morpholine, pyrrolidine, piperazine, and piperidine. In another embodiment of the invention, the cycloheteroalkyl group is pyrrolidine.

在另一實施例中，C2-10 環雜烷基為具有2至10個碳原子且含有1或2個選自O之雜原子的非芳族雙環飽和碳環。在本發明之另一實施例中，環雜烷基為二去水-甘露糖醇。在本發明之另一實施例中，環雜烷基為1,4：3,6-二去水-甘露糖醇。在本發明之另一實施例中，環雜烷基為1,4：3,6-二去水-D-甘露糖醇。在本發明之另一實施例中，環雜烷基為六氫呋喃并[3,2-b]呋喃。在此實施例之一類別中，環 雜烷基為2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃。In another embodiment, the C 2-10 cycloheteroalkyl group is a non-aromatic bicyclic saturated carbocyclic ring having 2 to 10 carbon atoms and containing 1 or 2 heteroatoms selected from O. In another embodiment of the invention, the cycloheteroalkyl group is di-deso-mannitol. In another embodiment of the invention, the cycloheteroalkyl group is 1,4:3,6-di-dehydrate-mannitol. In another embodiment of the invention, the cycloheteroalkyl group is 1,4:3,6-di-deso-D-mannitol. In another embodiment of the invention, the cycloheteroalkyl group is hexahydrofuro[3,2-b]furan. In one class of this embodiment, the cycloheteroalkyl group is 2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan.

「環雜烯基」意謂各自具有2至14個碳原子，含有至少一個雙鍵且含有1、2、3、4或5個選自N、NH、O及S之雜原子的非芳族單環或雙環或橋連環。環雜烯基之實例包括1,2,4-噁二唑-5-酮、1,2,4-噻二唑-5-酮、1,2,4-三唑-3-酮及1,2,3,6-四氫吡啶、二氫-1,3,4-噁二唑及[1,6]-二氫吡啶，及其類似物。在本發明之一個實施例中，環雜烯基為二氫-1,3,4-噁二唑。在本發明之另一實施例中，環雜烯基為[1,6]-二氫吡啶。"Cycloheteroalkenyl" means a non-aromatic group each having from 2 to 14 carbon atoms, containing at least one double bond and containing 1, 2, 3, 4 or 5 heteroatoms selected from N, NH, O and S Single or double ring or bridged ring. Examples of cycloheteroalkenyl groups include 1,2,4-oxadiazol-5-one, 1,2,4-thiadiazol-5-one, 1,2,4-triazol-3-one, and 1, 2,3,6-tetrahydropyridine, dihydro-1,3,4-oxadiazole and [1,6]-dihydropyridine, and the like. In one embodiment of the invention, the cycloheteroalkenyl group is dihydro-1,3,4-oxadiazole. In another embodiment of the invention, the cycloheteroalkenyl group is [1,6]-dihydropyridine.

在另一實施例中，C2-10 環雜烯基為具有2至10個碳原子且含有1、2或3個選自N及NH之雜原子的非芳族雙環碳環。在此實施例之一類別中，環雜烯基為二氫吡咯并[3,4-c]吡唑。在此實施例之另一類別中，環雜烯基為4,6-二氫吡咯并[3,4-c]吡唑。In another embodiment, the C 2-10 cycloheteroalkenyl group is a non-aromatic bicyclic carbon ring having 2 to 10 carbon atoms and containing 1, 2 or 3 heteroatoms selected from N and NH. In one class of this embodiment, the cycloheteroalkenyl group is dihydropyrrolo[3,4-c]pyrazole. In another class of this embodiment, the cycloheteroalkenyl group is 4,6-dihydropyrrolo[3,4-c]pyrazole.

在另一實施例中，C2-6 環雜烯基為具有2至6個碳原子且含有1或2個選自N及NH之雜原子的非芳族雙環碳環。在此實施例之一類別中，環雜烯基為二氫咪唑或四氫嘧啶。在此實施例之另一類別中，環雜烯基為2,5二氫-1H-咪唑或1,4,5,6-四氫嘧啶。在此實施例之另一類別中，環雜烯基為二氫咪唑。在此實施例之另一類別中，環雜烯基為2,5二氫-1H-咪唑。在此實施例之另一類別中，環雜烯基為四氫嘧啶。在此實施例之另一類別中，環雜烯基為1,4,5,6-四氫嘧啶。In another embodiment, the C 2-6 cycloheteroalkenyl group is a non-aromatic bicyclic carbon ring having 2 to 6 carbon atoms and containing 1 or 2 heteroatoms selected from N and NH. In one class of this embodiment, the cycloheteroalkenyl group is a dihydroimidazole or a tetrahydropyrimidine. In another class of this embodiment, the cycloheteroalkenyl group is 2,5 dihydro-1H-imidazole or 1,4,5,6-tetrahydropyrimidine. In another class of this embodiment, the cycloheteroalkenyl group is a dihydroimidazole. In another class of this embodiment, the cycloheteroalkenyl group is 2,5 dihydro-1H-imidazole. In another class of this embodiment, the cycloheteroalkenyl group is a tetrahydropyrimidine. In another class of this embodiment, the cycloheteroalkenyl group is a 1,4,5,6-tetrahydropyrimidine.

「芳基」意謂含有5至14個碳原子且至少一個環為芳族 之單環、雙環或三環系統。因此，芳基包括芳族環與非芳族環(諸如環烷基或環烯基環)稠合之環系統。芳基之實例包括苯基、萘、聯苯、茚滿及5,6,7,8-四氫萘及其類似物。在本發明之一個實施例中，芳基為苯基、萘、聯苯、茚滿及5,6,7,8-四氫萘。在本發明之另一實施例中，芳基為苯基、萘、茚滿及5,6,7,8-四氫萘。在此實施例之一個類別中，芳基為苯基及萘。在此實施例之另一類別中，芳基為苯基。在此實施例之另一類別中，芳基為萘。"Aryl" means 5 to 14 carbon atoms and at least one ring is aromatic Single, double or triple ring system. Thus, an aryl group includes a ring system in which an aromatic ring is fused to a non-aromatic ring such as a cycloalkyl or cycloalkenyl ring. Examples of the aryl group include phenyl, naphthalene, biphenyl, indan and 5,6,7,8-tetrahydronaphthalene and the like. In one embodiment of the invention, the aryl group is phenyl, naphthalene, biphenyl, indan and 5,6,7,8-tetrahydronaphthalene. In another embodiment of the invention, the aryl group is phenyl, naphthalene, indane and 5,6,7,8-tetrahydronaphthalene. In one class of this embodiment, the aryl group is phenyl and naphthalene. In another class of this embodiment, the aryl group is a phenyl group. In another class of this embodiment, the aryl group is naphthalene.

「雜芳基」意謂含有5至14個碳原子且含有1、2、3、4或5個選自N、NH、O及S之雜原子且至少一個含雜原子之環為芳族的單環、雙環或三環系統。因此，雜芳基包括含雜原子之芳族環與非芳族環(諸如環烷基、環烯基、環雜烷基或環雜烯基環)稠合之環系統，且亦包括芳基環與含雜原子之非芳族環(諸如環雜烷基或環雜烯基環)稠合之環系統。雜芳基之實例包括：吡唑、吡啶、吡嗪、嘧啶、噻唑、噻吩、苯并咪唑、喹啉、異喹啉、吲哚、吲唑、咔唑、苯并三唑、苯并呋喃、苯并噻唑、苯并噻吩、苯并異噁唑、噁唑、呋喃、苯并噁唑、異噁唑、吲哚啉、異吲哚啉、四唑、咪唑、噁二唑、噻二唑、三唑、苯并噻唑、苯并吡唑、咪唑并吡啶、苯并間二氧雜環戊烯、二氫吡啶、二氫吡咯并吡啶、二氫苯并噁嗪、苯并間二氧雜環戊烯、苯并二氧雜環己烯、吡咯并吡啶、三唑并吡啶、二氫吡啶并噁嗪、二氫苯并噁嗪、二氫吲哚、二氫異吲哚、二氫苯并咪唑、二氫喹啉、四氫異喹啉、四氫環戊二烯并吲哚、 四氫喹喏啉及四氫吡啶。在本發明之一個實施例中，雜芳基係選自：咪唑、吡唑、吡啶、吡嗪、嘧啶、噻唑、噻吩、苯并咪唑、喹啉、異喹啉、吲哚、吲唑、咔唑、苯并三唑、苯并呋喃、苯并噻唑、苯并[b]噻吩、苯并[d]異噁唑、3,4-二氫-2H-苯并[1,4]噁嗪、苯并[1,3]二氧雜環戊烯、苯并[1,4]二氧雜環己烯、1H-吡咯并[2,3-b]吡啶、1,6-二氫-吡啶、[1,2,4]三唑并[4,3-a]吡啶、3,4二氫吡啶并[3,2-b][1,4]噁嗪、3,4-二氫-2H-1,4-苯并噁嗪、2,3-二氫-1H-吲哚、2,3-二氫-1H-異吲哚、2,3-二氫苯并咪唑、1,2-二氫喹啉、1,2,3,4-四氫異喹啉、1,2,3,4-四氫環戊二烯并[b]吲哚、1,2,3,4-四氫喹喏啉及1,2,3,6-四氫吡啶。在本發明之另一實施例中，雜芳基為四唑。在另一實施例中，雜芳基係選自：吡唑、吡啶、嘧啶、異噁唑、咪唑、噁唑、三唑、四唑、噁二唑、噻唑、噻二唑及苯并噁唑。在本發明之另一實施例中，雜芳基為四唑。"Heteroaryl" means a radical containing from 5 to 14 carbon atoms and containing 1, 2, 3, 4 or 5 heteroatoms selected from N, NH, O and S and at least one heteroatom-containing ring being aromatic Single, double or triple ring system. Thus, a heteroaryl group includes a ring system in which an aromatic ring containing a hetero atom is fused to a non-aromatic ring such as a cycloalkyl, cycloalkenyl, cycloheteroalkyl or cycloheteroalkenyl ring, and also includes an aryl group. A ring system in which a ring is fused to a non-aromatic ring containing a hetero atom such as a cycloheteroalkyl or cycloheteroalkenyl ring. Examples of heteroaryl groups include: pyrazole, pyridine, pyrazine, pyrimidine, thiazole, thiophene, benzimidazole, quinoline, isoquinoline, indole, oxazole, oxazole, benzotriazole, benzofuran, Benzothiazole, benzothiophene, benzisoxazole, oxazole, furan, benzoxazole, isoxazole, porphyrin, isoporphyrin, tetrazole, imidazole, oxadiazole, thiadiazole, Triazole, benzothiazole, benzopyrazole, imidazopyridine, benzodioxol, dihydropyridine, dihydropyrrolopyridine, dihydrobenzoxazine, benzodioxane Pentene, benzodioxine, pyrrolopyridine, triazolopyridine, dihydropyridoxazine, dihydrobenzoxazine, indoline, dihydroisoindole, dihydrobenzo Imidazole, dihydroquinoline, tetrahydroisoquinoline, tetrahydrocyclopentadienyl, Tetrahydroquinoxaline and tetrahydropyridine. In one embodiment of the invention, the heteroaryl is selected from the group consisting of: imidazole, pyrazole, pyridine, pyrazine, pyrimidine, thiazole, thiophene, benzimidazole, quinoline, isoquinoline, indole, oxazole, indole Azole, benzotriazole, benzofuran, benzothiazole, benzo[b]thiophene, benzo[d]isoxazole, 3,4-dihydro-2H-benzo[1,4]oxazine, Benzo[1,3]dioxole, benzo[1,4]dioxine, 1H-pyrrolo[2,3-b]pyridine, 1,6-dihydro-pyridine, [1,2,4]triazolo[4,3-a]pyridine, 3,4 dihydropyrido[3,2-b][1,4]oxazine, 3,4-dihydro-2H- 1,4-benzoxazine, 2,3-dihydro-1H-indole, 2,3-dihydro-1H-isoindole, 2,3-dihydrobenzimidazole, 1,2-dihydrogen Quinoline, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydrocyclopenta[b]indole, 1,2,3,4-tetrahydroquinoline Porphyrin and 1,2,3,6-tetrahydropyridine. In another embodiment of the invention, the heteroaryl is a tetrazole. In another embodiment, the heteroaryl is selected from the group consisting of pyrazole, pyridine, pyrimidine, isoxazole, imidazole, oxazole, triazole, tetrazole, oxadiazole, thiazole, thiadiazole, and benzoxazole. . In another embodiment of the invention, the heteroaryl is a tetrazole.

「鹵素」包括氟、氯、溴及碘。在本發明之一個實施例中，鹵素係選自氟、氯及溴。在本發明之另一實施例中，鹵素係選自氟及氯。在本發明之另一實施例中，鹵素為氟。在本發明之另一實施例中，鹵素為氯。"Halogen" includes fluorine, chlorine, bromine and iodine. In one embodiment of the invention, the halogen is selected from the group consisting of fluorine, chlorine and bromine. In another embodiment of the invention, the halogen is selected from the group consisting of fluorine and chlorine. In another embodiment of the invention, the halogen is fluorine. In another embodiment of the invention, the halogen is chlorine.

當任何變數(例如R1 、Ra 等)在任何組分或式I中出現一次以上時，其在每次出現時之定義獨立於其在每一其他出現情況下之定義。又，只有當取代基及/或變數之組合產生穩定化合物時，方可允許該等組合。取代基變數中橫跨一鍵之波浪線表示連接點。When any variable (e.g. R 1, R a, etc.) occurs more than one time in any constituent or in Formula I, its definition on each occurrence is independent of its definition at every other occurrence of the situation. Again, such combinations are only permitted if a combination of substituents and/or variables results in a stable compound. The wavy line across a bond in the substituent variable represents the point of attachment.

依據本發明中所用之標準命名法，首先描述指定側鏈之末端部分，繼之以朝向連接點之鄰近官能基。舉例而言，C1-5 烷基羰基胺基C1-6 烷基取代基等效於： In accordance with the standard nomenclature used in the present invention, the terminal portion of the designated side chain is first described, followed by the adjacent functional groups toward the point of attachment. For example, a C 1-5 alkylcarbonylamino C 1-6 alkyl substituent is equivalent to:

在選擇本發明化合物時，一般技術者應瞭解，將依照化學結構連接性及穩定性之熟知原理來選擇各種取代基，亦即R1 、R2 等。In selecting a compound of the invention, one of ordinary skill will appreciate that various substituents, i.e., R 1 , R 2 , etc., will be selected in accordance with well-known principles of chemical structure connectivity and stability.

術語「經取代」應視為包括由指定取代基進行之多重取代。在揭示或主張多個取代基部分之情況下，經取代之化合物可獨立地經一或多個所揭示或所主張之取代基部分單取代或多取代。獨立地經取代意謂(兩個或兩個以上)取代基可相同或不同。The term "substituted" shall be taken to include multiple substitutions by a given substituent. Where a plurality of substituent moieties are disclosed or claimed, the substituted compound may be independently mono- or polysubstituted by one or more of the disclosed or claimed substituent moieties. Substituting independently means that the (two or more) substituents may be the same or different.

式I化合物可含有一或多個不對稱中心，且因此可以外消旋體及外消旋混合物、單一對映異構體、非對映異構體混合物及個別非對映異構體之形式存在。本發明意欲包涵式I化合物之所有該等異構形式。The compounds of formula I may contain one or more asymmetric centers and may therefore be in the form of racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. presence. The invention is intended to encompass all such isomeric forms of the compounds of formula I.

本文所述之一些化合物含有烯系雙鍵，且除非另有規定，否則其意欲包括E及Z幾何異構體。Some of the compounds described herein contain an olefinic double bond and are intended to include both E and Z geometric isomers unless otherwise specified.

互變異構體定義為經歷質子自化合物之一個原子快速移位至化合物之另一原子的化合物。本文所述之一些化合物可以具有不同氫連接點之互變異構體形式存在。此種實例可為酮及其烯醇形式，稱為酮-烯醇互變異構體。式I化合物涵蓋個別互變異構體以及其混合物。A tautomer is defined as a compound that undergoes a rapid shift of a proton from one atom of a compound to another atom of the compound. Some of the compounds described herein may exist in tautomeric forms with different hydrogen attachment points. Such an example may be in the form of a ketone and its enol, known as a keto-enol tautomer. The compounds of formula I encompass individual tautomers as well as mixtures thereof.

在通式I之化合物中，原子可展現其天然同位素豐度，或可人工增濃一或多個原子之特定同位素，該特定同位素具有相同原子序數，但原子質量或質量數不同於自然界中主要發現之原子質量或質量數。本發明意欲包括結構式I之化合物之所有適合的同位素變化。舉例而言，氫(H)之不同同位素形式包括氕(1 H)及氘(2 H)。氕為自然界中所發現之主要氫同位素。氘增濃可提供某些治療優勢，諸如增加活體內半衰期或減少劑量需求，或可提供適用作表徵生物樣品之標準物的化合物。經同位素增濃之結構式I之化合物可在不進行過度實驗之情況下，藉由熟習此項技術者熟知之習知技術或藉由類似於本文中之流程及實例所述之製程，使用適當經同位素增濃之試劑及/或中間物來製備。In a compound of formula I, an atom may exhibit its natural isotopic abundance, or a specific isotope of one or more atoms may be artificially enriched, the specific isotope having the same atomic number, but the atomic mass or mass number is different from that in nature. The atomic mass or mass found. The present invention is intended to include all suitable isotopic variations of the compounds of structural formula I. For example, different isotopic forms of hydrogen (H) include deuterium ( 1 H) and deuterium ( 2 H). It is the main hydrogen isotope found in nature. Indole enrichment may provide certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide compounds suitable for use as standards for characterizing biological samples. Isotopically enriched compounds of formula I may be suitably employed without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described herein. Prepared by isotope-enriched reagents and/or intermediates.

可藉由例如自適合溶劑(例如MeOH或乙酸乙酯或其混合物)中分步結晶來將式I化合物分離成對映異構體之非對映異構體對。可藉由習知方式，例如藉由使用光學活性胺作為解析劑或在對掌性HPLC管柱上將由此獲得之對映異構體對分離成個別立體異構體。The compound of formula I can be separated into the diastereomeric pairs of the enantiomers by, for example, fractional crystallization from a suitable solvent such as MeOH or ethyl acetate or mixtures thereof. The thus obtained enantiomeric pair can be separated into individual stereoisomers by conventional means, for example by using an optically active amine as a resolving agent or on a palmitic HPLC column.

或者，可藉由使用光學純之起始物質或具有已知組態之試劑進行立體特異性合成來獲得通式I之化合物之任何對映異構體。Alternatively, any enantiomer of a compound of formula I can be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.

此外，本發明化合物之一些結晶形式可以多晶型物形式存在，且該等形式意欲包括在本發明中。另外，一些本發明化合物可與水或常見有機溶劑形成溶劑合物。該等溶劑 合物涵蓋於本發明之範疇內。Furthermore, some of the crystalline forms of the compounds of the invention may exist in polymorphic forms, and such forms are intended to be included in the present invention. Additionally, some of the compounds of the invention may form solvates with water or common organic solvents. Such solvents The compositions are encompassed within the scope of the invention.

投與呈對映異構純之調配物形式之本發明化合物一般較佳。可藉由許多習知方法中之任一者將外消旋混合物分離成其個別對映異構體。此等方法包括對掌性層析；用對掌性助劑衍生化，繼而藉由層析或結晶進行分離；及使非對映異構性鹽分步結晶。It is generally preferred to administer a compound of the invention in the form of an enantiomerically pure formulation. The racemic mixture can be separated into its individual enantiomers by any of a number of conventional methods. Such methods include palm chromatography; derivatization with a palmitic aid, followed by chromatography or crystallization; and crystallization of the diastereomeric salt in portions.

術語「醫藥學上可接受之鹽」係指自醫藥學上可接受之無毒鹼或酸(包括無機鹼或有機鹼及無機酸或有機酸)製備之鹽。衍生自無機鹼之鹽包括鋁鹽、銨鹽、鈣鹽、銅鹽、鐵鹽、亞鐵鹽、鋰鹽、鎂鹽、錳鹽、亞錳鹽、鉀鹽、鈉鹽、鋅鹽及其類似鹽。銨鹽、鈣鹽、鎂鹽、鉀鹽及鈉鹽尤佳。衍生自醫藥學上可接受之有機無毒鹼之鹽包括以下胺之鹽：一級胺、二級胺及三級胺、經取代之胺(包括天然存在之經取代胺)、環胺及鹼性離子交換樹脂，諸如精胺酸、甜菜鹼(betaine)、咖啡鹼(caffeine)、膽鹼、N,N'-二苄基乙二胺、二乙胺、2-二乙基胺基乙醇、2-二甲基胺基乙醇、乙醇胺、乙二胺、N-乙基-嗎啉、N-乙基哌啶、還原葡糖胺(glucamine)、葡糖胺(glucosamine)、組胺酸、海卓胺(hydrabamine)、異丙胺、離胺酸、甲基還原葡糖胺、嗎啉、哌嗪、哌啶、聚胺樹脂、普魯卡因(procaine)、嘌呤、可可豆鹼(theobromine)、三乙胺、三甲胺、三丙胺、緩血酸胺(tromethamine)及其類似物。術語「醫藥學上可接受之鹽」另外包括所有可接受之鹽，諸如乙酸鹽、三氟乙酸鹽、乳糖酸鹽、苯磺酸鹽、月桂酸鹽、苯甲酸鹽、蘋 果酸鹽、碳酸氫鹽、順丁烯二酸鹽、硫酸氫鹽、杏仁酸鹽、酒石酸氫鹽、甲磺酸鹽、硼酸鹽、甲基溴化物、溴化物、甲基硝酸鹽、乙二胺四乙酸鈣、甲基硫酸鹽、樟腦磺酸鹽、黏液酸鹽(mucate)、碳酸鹽、萘磺酸鹽、氯化物、硝酸鹽、棒酸鹽(clavulanate)、N-甲基還原葡糖胺鹽、檸檬酸鹽、銨鹽、二鹽酸鹽、油酸鹽、乙二胺四乙酸鹽、草酸鹽、乙二磺酸鹽、雙羥萘酸鹽(pamoate)(恩波酸鹽(embonate))、依託酸鹽(estolate)、棕櫚酸鹽、乙磺酸鹽、泛酸鹽、反丁烯二酸鹽、磷酸鹽/二磷酸鹽、葡庚糖酸鹽、聚半乳糖醛酸鹽、葡糖酸鹽、水楊酸鹽、麩胺酸鹽、硬脂酸鹽、乙內醯胺苯胂酸鹽(glycollylarsanilate)、硫酸鹽、己基間苯二酚鹽(hexylresorcinate)、次乙酸鹽(subacetate)、海卓胺鹽、丁二酸鹽、氫溴酸鹽、丹寧酸鹽(tannate)、鹽酸鹽、酒石酸鹽、羥基萘甲酸鹽、茶氯酸鹽(teoclate)、碘化物、甲苯磺酸鹽、異硫代羥酸鹽(isothionate)、三乙碘化物(triethiodide)、乳酸鹽、盤尼酸鹽(panoate)、戊酸鹽及其類似鹽，其可作為用於改變溶解度或水解特徵之劑型使用或可用於持續釋放調配物或前藥調配物中。The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganese, potassium, sodium, zinc and the like. salt. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases include the salts of the following amines: primary amines, secondary amines and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines and basic ions Exchange resin, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-di Methylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, chlordamine Hydrabamine), isopropylamine, lysine, methyl-reducing glucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, guanidine, theobromine, triethylamine , trimethylamine, tripropylamine, tromethamine and the like. The term "pharmaceutically acceptable salts" additionally includes all acceptable salts such as acetate, trifluoroacetate, lactobionate, besylate, laurate, benzoate, apple ALT, bicarbonate, maleate, hydrogen sulphate, mandelate, hydrogen tartrate, methanesulfonate, borate, methyl bromide, bromide, methyl nitrate, ethylene Amine tetraacetate, methyl sulfate, camphor sulfonate, mucate, carbonate, naphthalene sulfonate, chloride, nitrate, clavulanate, N-methyl reduced glucose Amine salt, citrate, ammonium salt, dihydrochloride, oleate, ethylenediaminetetraacetate, oxalate, ethanedisulfonate, pamoate (enpo acid salt) Embnate (), estolate, palmitate, ethanesulfonate, pantothenate, fumarate, phosphate/diphosphate, glucoheptonate, polygalacturonate , gluconate, salicylate, glutamate, stearate, glycollylarsanilate, sulfate, hexylresorcinate, hypoacetate Subacetate), succinate, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate, tea chlorate Iodide, toluenesulfonate, isothionate, triethiodide, lactate, panoate, valerate and the like, which can be used as Dosage forms that alter solubility or hydrolysis characteristics are used or can be used in sustained release formulations or prodrug formulations.

應瞭解，如本文所用，提及式I化合物亦欲包括醫藥學上可接受之鹽。It will be appreciated that as used herein, reference to a compound of formula I is also intended to include a pharmaceutically acceptable salt.

本發明化合物為AMP活化之蛋白激酶之活化劑。本發明之治療方法包含如下方法：藉由投與需要該治療之患者無毒、治療有效量之活化AMPK活化之蛋白激酶之本發明化 合物來活化AMPK活化之蛋白激酶及治療AMPK活化之蛋白激酶介導之疾病。The compounds of the invention are activators of AMP-activated protein kinases. The method of treatment of the present invention comprises the method of inactivating a protein kinase that activates AMPK-activated by a non-toxic, therapeutically effective amount of a patient in need of such treatment. Compounds activate AMPK-activated protein kinases and treat AMPK-activated protein kinase-mediated diseases.

AMP活化之蛋白激酶(AMPK)為由催化性α次單元以及調控性β及γ次單元構成之異三聚酶。存在兩種編碼α次單元與β次單元之同功異型物(α1、α2、β1及β2)之基因及三種編碼γ次單元之同功異型物(γ1、γ2及γ3)之基因，從而產生12種可能的異三聚組合。α2同功異型物主要見於骨骼肌及心肌AMPK中；α1同功異型物與α2同功異型物見於肝臟AMPK中；而α1同功異型物AMPK主要存在於胰小島β細胞中。詳言之，結構式I之化合物為AMP活化之蛋白激酶之至少一種異三聚同功異型物的活化劑。AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme composed of a catalytic alpha subunit and a regulatory beta and gamma subunit. There are two genes encoding the isoforms (α1, α2, β1, and β2) of the α-subunit and the β-subunit, and three genes encoding the isoforms (γ1, γ2, and γ3) of the γ-subunit, thereby generating 12 possible heterotrimeric combinations. The α2 isoforms are mainly found in skeletal muscle and myocardial AMPK; α1 isoforms and α2 isoforms are found in liver AMPK; and α1 isoforms AMPK are mainly found in pancreatic islet β cells. In particular, the compound of structural formula I is an activator of at least one heterotrimeric isoform of an AMP-activated protein kinase.

「活化劑」為增強完全磷酸化之AMPK之活性(下游受質磷酸化)或增加AMPK磷酸化之化合物。An "activator" is a compound that enhances the activity of fully phosphorylated AMPK (downstream phosphorylation) or increases AMPK phosphorylation.

本發明化合物有效治療及預防對活化AMP活化之蛋白激酶起反應之疾病、病症及病狀，包括(但不限於)：2型糖尿病、胰島素抗性、高血糖症、肥胖症、高胰島素血症、葡萄糖不耐、動脈粥樣硬化、代謝症候群、高血壓、高肝臟葡萄糖輸出、高血糖濃度、非酒精性脂肪變性肝炎、對缺血及再灌注損傷之保護，及脂質失調，諸如血脂異常、血漿三酸甘油酯含量升高、游離脂肪酸含量升高、膽固醇含量升高、低密度脂蛋白(LDL)含量高及高密度脂蛋白(HDL)含量低。該等化合物亦適用於治療癌症、低氧症及糖皮質激素誘發之細胞凋亡。The compounds of the present invention are effective for the treatment and prevention of diseases, disorders and conditions responsive to activation of AMP-activated protein kinases, including but not limited to: type 2 diabetes, insulin resistance, hyperglycemia, obesity, hyperinsulinemia , glucose intolerance, atherosclerosis, metabolic syndrome, hypertension, high liver glucose output, hyperglycemia, nonalcoholic steatosis, protection against ischemia and reperfusion injury, and lipid disorders, such as dyslipidemia, Increased plasma triglyceride levels, elevated free fatty acid levels, elevated cholesterol levels, high LDL content, and low HDL levels. These compounds are also suitable for the treatment of cancer, hypoxia and glucocorticoid-induced apoptosis.

一或多種以下疾病可藉由將治療有效量之式I化合物或 其醫藥學上可接受之鹽投與需要治療之患者來治療：(1)非胰島素依賴性糖尿病(2型糖尿病)；(2)高血糖症；(3)代謝症候群；(4)肥胖症；(5)高膽固醇血症；(6)高三酸甘油酯血症(富含三酸甘油酯之脂蛋白含量升高)；(7)混合性或糖尿病性血脂異常；(8)低HDL膽固醇；(9)高LDL膽固醇；(10)動脈粥樣硬化；及(11)高血壓。One or more of the following diseases can be achieved by treating a therapeutically effective amount of a compound of formula I or The pharmaceutically acceptable salt is administered to patients in need of treatment: (1) non-insulin dependent diabetes (type 2 diabetes); (2) hyperglycemia; (3) metabolic syndrome; (4) obesity; (5) hypercholesterolemia; (6) hypertriglyceridemia (increased triglyceride-rich lipoprotein); (7) mixed or diabetic dyslipidemia; (8) low HDL cholesterol; (9) high LDL cholesterol; (10) atherosclerosis; and (11) hypertension.

又，式I化合物可用於製造用以治療一或多種上述疾病之藥物。Further, the compounds of formula I are useful in the manufacture of a medicament for the treatment of one or more of the above mentioned conditions.

化合物用途之一個實施例係有關藉由將治療有效量投與需要治療之患者來治療一或多種以下疾病：(1)2型糖尿病；(2)高血糖症；(3)代謝症候群；(4)肥胖症；(5)高膽固醇血症；及(6)高血壓。One embodiment of the use of a compound relates to the treatment of one or more of the following diseases by administering a therapeutically effective amount to a patient in need of treatment: (1) type 2 diabetes; (2) hyperglycemia; (3) metabolic syndrome; Obesity; (5) hypercholesterolemia; and (6) hypertension.

該等化合物亦可用於製造用以治療一或多種上述疾病之藥物。The compounds can also be used in the manufacture of a medicament for the treatment of one or more of the above mentioned conditions.

預期化合物可有效減少糖尿病患者以及葡萄糖耐受性異常及/或具有糖尿病前期病狀之非糖尿病患者體內的葡萄糖及脂質。化合物可改善糖尿病患者或糖尿病前期患者常出現之高胰島素血症，此係藉由調節此等患者常出現之血清葡萄糖含量波動來達成。化合物亦可有效治療或減輕胰島素抗性。化合物可有效治療或預防妊娠期糖尿病。Compounds are expected to be effective in reducing glucose and lipids in diabetic patients as well as in glucose-tolerant and/or non-diabetic patients with pre-diabetic conditions. Compounds can improve hyperinsulinemia, which is common in diabetic patients or pre-diabetic patients, by adjusting the fluctuations in serum glucose levels that are commonly seen in these patients. The compounds are also effective in treating or reducing insulin resistance. The compound is effective in treating or preventing gestational diabetes.

如本文所述之化合物、組合物、方法及藥物亦可有效降低與代謝症候群相關之不良後遺症的風險，且降低發生動脈粥樣硬化之風險、延遲動脈粥樣硬化發作及/或降低動脈粥樣硬化後遺症之風險。動脈粥樣硬化之後遺症包括心 絞痛、跛行、心臟病發作、中風及其他後遺症。藉由保持高血糖症處於控制下，該等化合物亦可有效延遲或預防血管再狹窄及糖尿病性視網膜病變。The compounds, compositions, methods, and medicaments described herein are also effective in reducing the risk of adverse sequelae associated with metabolic syndrome, and reducing the risk of developing atherosclerosis, delaying the onset of atherosclerosis, and/or reducing atherosclerosis. The risk of sequelae of hardening. Atherosclerosis sequelae including heart Colic, lameness, heart attack, stroke and other sequelae. These compounds are also effective in delaying or preventing vascular restenosis and diabetic retinopathy by keeping hyperglycemia under control.

本發明化合物亦可用於改良或恢復β細胞功能，因此其可適用於治療1型糖尿病或者延遲或預防2型糖尿病患者對胰島素療法的需求。The compounds of the invention may also be used to improve or restore beta cell function, and thus may be useful in the treatment of type 1 diabetes or in delaying or preventing the need for insulin therapy in patients with type 2 diabetes.

本發明化合物治療之其他可能成果包括(但不限於)：1)脂肪酸合成減少；2)脂肪酸氧化及酮生成增加；3)膽固醇合成、脂質生成及三酸甘油酯合成減少；4)血糖含量及濃度降低；5)葡萄糖穩態改良；6)葡萄糖代謝正常化；7)血壓降低；8)HDL增加；9)血漿三酸甘油酯減少；10)游離脂肪酸減少；11)肝臟葡萄糖輸出減少；12)胰島素作用改良；13)血壓降低；14)胰島素敏感性改良；15)抑制肝臟葡萄糖輸出；15)抑制重新脂質生成；16)刺激肌肉葡萄糖吸收；17)調節由胰臟β細胞分泌胰島素；及16)體重減輕。Other possible outcomes of treatment with the compounds of the invention include, but are not limited to, 1) reduced fatty acid synthesis; 2) increased fatty acid oxidation and ketone production; 3) reduced cholesterol synthesis, lipid production, and triglyceride synthesis; 4) blood glucose levels and Reduced concentration; 5) glucose homeostasis improvement; 6) normalization of glucose metabolism; 7) decreased blood pressure; 8) increased HDL; 9) decreased plasma triglyceride; 10) decreased free fatty acid; 11) decreased liver glucose output; Insulin effect improvement; 13) blood pressure reduction; 14) insulin sensitivity improvement; 15) inhibition of liver glucose output; 15) inhibition of re-lipidogenesis; 16) stimulation of muscle glucose absorption; 17) regulation of secretion of insulin by pancreatic beta cells; 16) Weight loss.

化合物一般可有效治療一或多種以下疾病：(1)2型糖尿病(亦稱為非胰島素依賴性糖尿病或NIDDM)、(2)高血糖症、(3)葡萄糖耐受性異常、(4)胰島素抗性、(5)肥胖症、(6)脂質失調、(7)血脂異常、(8)高脂質血症、(9)高三酸甘油酯血症、(10)高膽固醇血症、(11)低HDL含量、(12)高LDL含量、(13)動脈粥樣硬化及其後遺症、(14)血管再狹窄、(15)腹型肥胖症、(16)視網膜病變、(17)代謝症候群、(18)高血壓(high blood pressure/hypertension)，及(19)胰島素抗性。Compounds are generally effective in the treatment of one or more of the following conditions: (1) type 2 diabetes (also known as non-insulin dependent diabetes or NIDDM), (2) hyperglycemia, (3) abnormal glucose tolerance, and (4) insulin Resistance, (5) obesity, (6) lipid disorders, (7) dyslipidemia, (8) hyperlipidemia, (9) hypertriglyceridemia, (10) hypercholesterolemia, (11) Low HDL content, (12) high LDL content, (13) atherosclerosis and its sequelae, (14) vascular restenosis, (15) abdominal obesity, (16) retinopathy, (17) metabolic syndrome, ( 18) High blood pressure/hypertension, and (19) insulin resistance.

本發明之一個態樣提供一種治療及控制混合性或糖尿病性血脂異常、高膽固醇血症、動脈粥樣硬化、低HDL含量、高LDL含量、高脂質血症及/或高三酸甘油酯血症之方法，其包含投與需要該治療之患者治療有效量之式I化合物。該化合物可單獨使用或宜與膽固醇生物合成抑制劑一起投與，尤其HMG-CoA還原酶抑制劑，諸如洛伐他汀(lovastatin)、辛伐他汀(simvastatin)、羅素他汀(rosuvastatin)、普伐他汀(pravastatin)、氟伐他汀(fluvastatin)、阿托伐他汀(atorvastatin)、立伐他汀(rivastatin)、伊伐他汀(itavastatin)或ZD-4522。該化合物亦宜與其他降低脂質之藥物組合使用，諸如膽固醇吸收抑制劑(例如固烷醇酯(stanol ester)；固醇醣苷(sterol glycoside)，諸如替奎安(tiqueside)；及氮雜環丁酮(azetidinone)，諸如依折麥布(ezetimibe))、ACAT抑制劑(諸如阿伐麥布(avasimibe))、CETP抑制劑(例如安特普(anacetrapib)、托徹普(torcetrapib)，及公開的申請案WO 2005/100298、WO 2006/014413及WO 2006/014357中所述者)、菸酸及菸酸受體促效劑、膽汁酸錯隔劑、微粒體三酸甘油酯轉運抑制劑，及膽汁酸再吸收抑制劑。此等組合治療可有效治療或控制一或多種選自由以下組成之群的相關病狀：高膽固醇血症、動脈粥樣硬化、高脂質血症、高三酸甘油酯血症、血脂異常、高LDL及低HDL。One aspect of the present invention provides a method of treating and controlling mixed or diabetic dyslipidemia, hypercholesterolemia, atherosclerosis, low HDL content, high LDL content, hyperlipidemia, and/or triglycerideemia A method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I. The compound may be administered alone or in combination with a cholesterol biosynthesis inhibitor, particularly an HMG-CoA reductase inhibitor such as lovastatin, simvastatin, rosuvastatin, pravastatin. (pravastatin), fluvastatin, atorvastatin, rivastatin, itavastatin or ZD-4522. The compound is also preferably used in combination with other lipid lowering agents, such as cholesterol absorption inhibitors (e.g., stanol esters; sterol glycoside, such as tiqueside; and azetidin) Azetidinone, such as ezetimibe, ACAT inhibitors (such as avasimibe), CETP inhibitors (such as anacetrapib, torcetrapib, and public) Applications described in WO 2005/100298, WO 2006/014413, and WO 2006/014357), niacin and niacin receptor agonists, bile acid spacers, microsomal triglyceride transport inhibitors, And bile acid reuptake inhibitors. Such combination therapy is effective for treating or controlling one or more related conditions selected from the group consisting of hypercholesterolemia, atherosclerosis, hyperlipidemia, hypertriglyceridemia, dyslipidemia, high LDL And low HDL.

本發明亦關於藉由投與本發明之化合物及醫藥組合物來治療、控制或預防2型糖尿病之方法及藥物。本發明亦關於藉由組合投與本發明化合物與治療有效量之已知適用於 治療2型糖尿病之另一藥劑來治療、控制或預防2型糖尿病之方法及藥物。本發明亦關於藉由單獨或組合投與本發明之化合物及醫藥組合物來治療、控制或預防糖尿病相關病症之方法及藥物。本發明亦關於治療及預防糖尿病前期個體之糖尿病的方法及藥物，此係藉由單獨或組合投與本發明之化合物及醫藥組合物來達成。The invention also relates to methods and medicaments for the treatment, management or prevention of type 2 diabetes by administering the compounds and pharmaceutical compositions of the invention. The invention also relates to the use of a compound of the invention in combination with a therapeutically effective amount as known to apply to Another agent for treating type 2 diabetes to treat, control or prevent type 2 diabetes. The invention also relates to methods and medicaments for the treatment, management or prevention of diabetes-related disorders by administering the compounds and pharmaceutical compositions of the invention, alone or in combination. The present invention also relates to a method and a medicament for treating and preventing diabetes in a pre-diabetic individual, which are achieved by administering the compound of the present invention and a pharmaceutical composition, either singly or in combination.

本發明亦關於藉由投與本發明之化合物及醫藥組合物來治療、控制或預防肥胖症之方法及藥物。本發明亦關於藉由組合投與本發明化合物與治療有效量之已知適用於治療肥胖症之另一藥劑來治療、控制或預防肥胖症之方法及藥物。本發明亦關於藉由單獨或組合投與本發明之化合物及醫藥組合物來治療、控制或預防肥胖症相關病症之方法及藥物。本發明亦關於藉由單獨或組合投與本發明之化合物及醫藥組合物來治療及預防過重個體之肥胖症的方法及藥物。該等化合物亦適用於治療肥胖症相關病症，或與過量食物攝入相關之飲食障礙及與其相關之併發症，包括左心室肥大；以及治療或預防其他哺乳動物種類(包括犬及貓)之肥胖症。The present invention also relates to methods and medicaments for treating, controlling or preventing obesity by administering the compounds and pharmaceutical compositions of the present invention. The invention also relates to methods and medicaments for the treatment, management or prevention of obesity by administering a compound of the invention in combination with a therapeutically effective amount of another agent known to be useful in the treatment of obesity. The invention also relates to methods and medicaments for the treatment, management or prevention of obesity-related disorders by administering the compounds and pharmaceutical compositions of the invention, alone or in combination. The present invention also relates to methods and medicaments for treating and preventing obesity in overweight individuals by administering the compounds and pharmaceutical compositions of the present invention, alone or in combination. The compounds are also suitable for the treatment of obesity-related disorders, or dietary disorders associated with excessive food intake and associated complications, including left ventricular hypertrophy; and treatment or prevention of obesity in other mammalian species, including dogs and cats. disease.

本發明亦關於藉由投與本發明之化合物及醫藥組合物來治療、控制或預防高血糖症之方法及藥物。本發明亦關於藉由組合投與本發明化合物與治療有效量之已知適用於治療高血糖症之另一藥劑來治療、控制或預防高血糖症之方法及藥物。The present invention also relates to methods and medicaments for treating, controlling or preventing hyperglycemia by administering the compounds and pharmaceutical compositions of the present invention. The invention also relates to methods and medicaments for the treatment, management or prevention of hyperglycemia by administering a compound of the invention in combination with a therapeutically effective amount of another agent known to be useful in the treatment of hyperglycemia.

本發明亦關於藉由投與本發明之化合物及醫藥組合物來 治療、控制或預防胰島素抗性之方法及藥物。本發明亦關於藉由組合投與本發明化合物與治療有效量之已知適用於治療胰島素抗性之另一藥劑來治療、控制或預防胰島素抗性之方法及藥物。The invention also relates to administration of a compound of the invention and a pharmaceutical composition Methods and medicaments for treating, controlling or preventing insulin resistance. The invention also relates to methods and medicaments for the treatment, management or prevention of insulin resistance by administering a compound of the invention in combination with a therapeutically effective amount of another agent known to be useful in the treatment of insulin resistance.

本發明亦關於藉由投與本發明之化合物及醫藥組合物來治療、控制或預防脂質失調之方法及藥物。本發明亦關於藉由組合投與本發明化合物與治療有效量之已知適用於治療脂質失調之另一藥劑來治療、控制或預防脂質失調之方法及藥物。本發明亦關於藉由單獨或組合投與本發明之化合物及醫藥組合物來治療、控制或預防血脂異常相關病症及脂質失調相關病症之方法及藥物。The invention also relates to methods and medicaments for treating, managing or preventing lipid disorders by administering the compounds and pharmaceutical compositions of the invention. The invention also relates to methods and medicaments for the treatment, management or prevention of lipid disorders by administering a compound of the invention in combination with a therapeutically effective amount of another agent known to be useful in the treatment of lipid disorders. The present invention also relates to methods and medicaments for treating, controlling or preventing dyslipidemia-related disorders and lipid-related disorders by administering the compounds and pharmaceutical compositions of the present invention, alone or in combination.

本發明亦關於藉由投與本發明之化合物及醫藥組合物來治療、控制或預防動脈粥樣硬化之方法及藥物。本發明亦關於藉由組合投與本發明化合物與治療有效量之已知適用於治療動脈粥樣硬化之另一藥劑來治療、控制或預防動脈粥樣硬化之方法及藥物。本發明亦關於藉由單獨或組合投與本發明之化合物及醫藥組合物來治療、控制或預防動脈粥樣硬化相關病症之方法及藥物。The invention also relates to methods and medicaments for treating, controlling or preventing atherosclerosis by administering the compounds and pharmaceutical compositions of the invention. The invention also relates to methods and medicaments for the treatment, management or prevention of atherosclerosis by administering a compound of the invention in combination with a therapeutically effective amount of another agent known to be useful in the treatment of atherosclerosis. The invention also relates to methods and medicaments for the treatment, management or prevention of atherosclerosis-related disorders by administering the compounds and pharmaceutical compositions of the invention, alone or in combination.

本發明亦關於藉由投與本發明之化合物及醫藥組合物來治療、控制或預防高血壓之方法及藥物。本發明亦關於藉由組合投與本發明化合物與治療有效量之已知適用於治療高血壓之另一藥劑來治療、控制或預防高血壓之方法及藥物。本發明亦關於藉由單獨或組合投與本發明之化合物及醫藥組合物來治療、控制或預防高血壓相關病症之方法及 藥物。本發明亦關於藉由單獨或組合投與本發明之化合物及醫藥組合物來治療及預防高血壓前期個體之高血壓的方法及藥物。The invention also relates to methods and medicaments for treating, controlling or preventing hypertension by administering the compounds and pharmaceutical compositions of the invention. The invention also relates to methods and medicaments for treating, managing or preventing hypertension by administering a compound of the invention in combination with a therapeutically effective amount of another agent known to be useful in the treatment of hypertension. The present invention also relates to a method for treating, controlling or preventing a hypertension-related disorder by administering a compound of the present invention and a pharmaceutical composition, alone or in combination, and drug. The present invention also relates to methods and medicaments for treating and preventing hypertension in a prehypertensive individual by administering the compounds and pharmaceutical compositions of the present invention, alone or in combination.

本發明亦關於藉由投與本發明之化合物及醫藥組合物來治療、控制或預防代謝症候群之方法及藥物。本發明亦關於藉由組合投與本發明化合物與治療有效量之已知適用於治療代謝症候群之另一藥劑來治療代謝症候群之方法及藥物。The present invention also relates to methods and medicaments for treating, controlling or preventing metabolic syndrome by administering the compounds and pharmaceutical compositions of the present invention. The invention also relates to methods and medicaments for treating metabolic syndrome by administering a compound of the invention in combination with a therapeutically effective amount of another agent known to be useful in the treatment of metabolic syndrome.

在使用重組人類AMPK複合物之酶活化分析(參見生物實例1)中，T、U、V及W中之至少一者為N或N-氧化物之本發明化合物與T為CR3 ，U為CR1 -，V為CR2 且W為CR4 之化合物相比，具有意想不到之效力增加益處。In an enzyme activation assay using recombinant human AMPK complex (see Biological Example 1), at least one of T, U, V and W is an N or N-oxide compound of the invention and T is CR 3 , U is CR 1 -, V is CR 2 and W is a compound of CR 4 with an unexpected increase in potency.

另外，T、U、V及W中之至少一者為N或N-氧化物之本發明化合物與T為CR3 ，U為CR1 -，V為CR2 且W為CR4 之化合物相比，具有意想不到之與人類血漿蛋白結合減少的益處。活體內藥理活性與未結合於血漿蛋白之藥物的濃度相關。血漿蛋白藉助於其高濃度來控制血漿中及與血漿平衡之區室中未結合於血漿蛋白之藥物的濃度，藉此有效衰減活體內藥物效力(參見Trainor,G.L.(2007),Expert Opin.Drug Discov.2(1),51-64)。未結合於血漿蛋白之藥物的濃度較高使得活體內藥理活性增強。由於本發明化合物之效力增加及其在血漿中之未結合分數較高，故預期該等化合物在較低血漿暴露下展現降低葡萄糖之功效。Further, the compound of the present invention in which at least one of T, U, V and W is an N or N-oxide is compared with a compound wherein T is CR 3 , U is CR 1 -, V is CR 2 and W is CR 4 There is an unexpected benefit of reduced binding to human plasma proteins. The pharmacological activity in vivo is related to the concentration of the drug that is not bound to plasma proteins. Plasma proteins, by virtue of their high concentrations, control the concentration of drugs that are not bound to plasma proteins in plasma and plasma-balanced compartments, thereby effectively attenuating in vivo drug potency (see Trainor, GL (2007), Expert Opin. Drug Discov. 2 (1), 51-64). Higher concentrations of drugs that are not bound to plasma proteins result in enhanced pharmacological activity in vivo. Due to the increased potency of the compounds of the invention and their higher unbound fraction in plasma, these compounds are expected to exhibit reduced glucose efficacy at lower plasma exposures.

如本文所用之術語「糖尿病」包括胰島素依賴性糖尿病 (亦即IDDM，亦稱為1型糖尿病)與非胰島素依賴性糖尿病(亦即NIDDM，亦稱為2型糖尿病)。1型糖尿病或胰島素依賴性糖尿病為絕對缺乏胰島素之結果，胰島素為調控葡萄糖利用之激素。2型糖尿病或胰島素非依賴性糖尿病(亦即非胰島素依賴性糖尿病)常常在胰島素含量正常或甚至升高之情況下發生，且似乎為組織不能對胰島素作出適當反應之結果。大多數2型糖尿病患者亦為肥胖的。本發明組合物適用於治療1型糖尿病與2型糖尿病兩者。術語「與肥胖症相關之糖尿病」係指由肥胖症引起或起因於肥胖症之糖尿病。該等組合物對於治療2型糖尿病尤其有效。本發明組合物亦適用於治療及/或預防妊娠期糖尿病。The term "diabetes" as used herein includes insulin-dependent diabetes (ie IDDM, also known as type 1 diabetes) and non-insulin dependent diabetes (ie NIDDM, also known as type 2 diabetes). Type 1 diabetes or insulin-dependent diabetes is the result of an absolute lack of insulin, a hormone that regulates glucose utilization. Type 2 diabetes or insulin-independent diabetes (i.e., non-insulin-dependent diabetes) often occurs with normal or even elevated insulin levels and appears to be the result of a tissue that does not respond appropriately to insulin. Most patients with type 2 diabetes are also obese. The compositions of the invention are useful in the treatment of both type 1 diabetes and type 2 diabetes. The term "obesity associated with obesity" refers to diabetes caused by or caused by obesity. These compositions are particularly effective for treating type 2 diabetes. The compositions of the invention are also suitable for the treatment and/or prevention of gestational diabetes.

糖尿病之特徵在於空腹血漿葡萄糖含量大於或等於126 mg/dl。患糖尿病個體之空腹血漿葡萄糖含量大於或等於126 mg/dl。糖尿病前期個體為罹患前期糖尿病之個體。前期糖尿病之特徵在於大於或等於110 mg/dl且小於126 mg/dl之異常空腹血漿葡萄糖(FPG)含量；或葡萄糖耐受性異常；或具有胰島素抗性。糖尿病前期個體為空腹葡萄糖異常(空腹血漿葡萄糖(FPG)含量大於或等於110 mg/dl且小於126 mg/dl)；或葡萄糖耐受性異常(2小時血漿葡萄糖含量140 mg/dl且<200 mg/dl)；或具有胰島素抗性，使得發生糖尿病之風險增加的個體。Diabetes is characterized by a fasting plasma glucose content greater than or equal to 126 mg/dl. Fasting plasma glucose levels in individuals with diabetes are greater than or equal to 126 mg/dl. Individuals with pre-diabetes are individuals with pre-diabetes. Pre-diabetes is characterized by abnormal fasting plasma glucose (FPG) levels greater than or equal to 110 mg/dl and less than 126 mg/dl; or abnormal glucose tolerance; or insulin resistance. Pre-diabetes individuals have fasting glucose abnormalities (fasting plasma glucose (FPG) levels greater than or equal to 110 mg/dl and less than 126 mg/dl); or impaired glucose tolerance (2 hours plasma glucose levels) 140 mg/dl and <200 mg/dl); or individuals with insulin resistance that increase the risk of developing diabetes.

糖尿病之治療涉及投與本發明之化合物或組合以治療患糖尿病個體。一個治療成果可為降低葡萄糖含量升高之個體體內的葡萄糖含量。另一治療成果可為降低胰島素含量 升高之個體體內的胰島素含量。另一治療成果可為降低血漿三酸甘油酯升高之個體體內的血漿三酸甘油酯。另一治療成果為降低具有高LDL膽固醇含量之個體體內的LDL膽固醇。另一治療成果可為增加具有低HDL膽固醇含量之個體體內的HDL膽固醇。另一治療成果為增加胰島素敏感性。另一治療成果可為增強葡萄糖不耐個體之葡萄糖耐受性。又一治療成果可為降低胰島素抗性增加或胰島素含量升高之個體的胰島素抗性。糖尿病、尤其與肥胖症相關之糖尿病的預防涉及投與本發明之化合物或組合以預防有需要之個體之糖尿病發作。需要預防糖尿病之個體為過重或肥胖之糖尿病前期個體。Treatment of diabetes involves administration of a compound or combination of the invention to treat a diabetic individual. One therapeutic outcome may be to reduce the amount of glucose in an individual with elevated glucose levels. Another treatment outcome can be to reduce insulin levels The insulin content of an elevated individual. Another therapeutic outcome may be plasma triglycerides in individuals with elevated plasma triglycerides. Another therapeutic outcome is the reduction of LDL cholesterol in individuals with high LDL cholesterol levels. Another therapeutic outcome may be to increase HDL cholesterol in individuals with low HDL cholesterol levels. Another treatment outcome is increased insulin sensitivity. Another therapeutic outcome may be to enhance glucose tolerance in individuals with glucose intolerance. A further therapeutic outcome may be to reduce insulin resistance in individuals with increased insulin resistance or elevated insulin levels. Prevention of diabetes, particularly diabetes associated with obesity, involves administering a compound or combination of the invention to prevent the onset of diabetes in an individual in need thereof. Individuals in need of prevention of diabetes are pre-diabetic individuals who are overweight or obese.

術語「糖尿病相關病症」應理解為意謂與糖尿病相關、由糖尿病引起或起因於糖尿病之病症。糖尿病相關病症之實例包括視網膜損傷、腎病及神經損傷。The term "diabetes-related disorder" is understood to mean a condition associated with diabetes, caused by or caused by diabetes. Examples of diabetes related disorders include retinal damage, kidney disease, and nerve damage.

如本文所用之術語「動脈粥樣硬化」涵蓋由在相關醫學領域中從業之醫師識別及瞭解之血管疾病及病狀。動脈粥樣硬化性心血管疾病、冠狀動脈性心臟病(亦稱為冠狀動脈疾病或缺血性心臟病)、腦血管疾病及周邊血管疾病為動脈粥樣硬化之所有臨床表現，且因此由術語「動脈粥樣硬化」及「動脈粥樣硬化性疾病」所涵蓋。可投與包含治療有效量之抗肥胖劑以及治療有效量之抗高血壓劑的組合以預防或降低冠狀動脈性心臟病事件、腦血管事件或間歇性跛行發生或復發(可能性存在)的風險。冠狀動脈性心臟病事件欲包括CHD死亡、心肌梗塞(亦即心臟病發作)及冠 狀動脈血管重建程序(coronary revascularization procedure)。腦血管事件欲包括缺血性或出血性中風(亦稱為腦血管意外)及短暫缺血性發作。間歇性跛行係周邊血管疾病之臨床表現。如本文所用之術語「動脈粥樣硬化性疾病事件」欲涵蓋冠狀動脈性心臟病事件、腦血管事件及間歇性跛行。預期先前曾經歷一或多次非致命性動脈粥樣硬化性疾病事件的人係存在此種事件復發之可能性者。術語「動脈粥樣硬化相關病症」應理解為意謂與動脈粥樣硬化相關、由動脈粥樣硬化引起或起因於動脈粥樣硬化之病症。The term "atherosclerosis" as used herein encompasses vascular diseases and conditions that are recognized and understood by physicians practicing in the relevant medical field. Atherosclerotic cardiovascular disease, coronary heart disease (also known as coronary artery disease or ischemic heart disease), cerebrovascular disease, and peripheral vascular disease are all clinical manifestations of atherosclerosis, and are therefore termed Covered by "atherosclerosis" and "atherosclerotic disease". A combination comprising a therapeutically effective amount of an anti-obesity agent and a therapeutically effective amount of an anti-hypertensive agent to prevent or reduce the risk of coronary heart disease events, cerebrovascular events, or intermittent claudication or recurrence (possibility of possibility) . Coronary heart disease events include CHD death, myocardial infarction (ie heart attack) and crown Coronary revascularization procedure. Cerebrovascular events are intended to include ischemic or hemorrhagic strokes (also known as cerebrovascular accidents) and transient ischemic attacks. Intermittent claudication is a clinical manifestation of peripheral vascular disease. The term "atherosclerotic disease event" as used herein is intended to cover coronary heart disease events, cerebrovascular events, and intermittent claudication. People who have previously experienced one or more non-fatal atherosclerotic disease events are expected to have the possibility of recurrence of such events. The term "atherosclerosis-related disorder" is understood to mean a condition associated with atherosclerosis, caused by atherosclerosis or caused by atherosclerosis.

如本文所用之術語「高血壓」包括本態性或原發性高血壓，其中病因未知或其中高血壓係歸因於一種以上病因，諸如心臟與血管中之變化；及繼發性高血壓，其中病因已知。繼發性高血壓之病因包括(但不限於)肥胖症；腎病；激素失調；使用某些藥物，諸如口服避孕藥、皮質類固醇、環孢素(cyclosporin)及其類似物。術語「高血壓」涵蓋收縮壓與舒張壓水準均升高(140 mmHg/90 mmHg)之高血壓；及孤立性收縮性高血壓，其中僅收縮壓升至大於或等於140 mmHg，而舒張壓小於90 mmHg。正常血壓可定義為收縮壓小於120 mmHg且舒張壓小於80 mmHg。高血壓個體為患有高血壓之個體。高血壓前期個體為血壓介於120 mmHg/80 mmHg與139 mmHg/89 mmHg之間的個體。一個治療成果為降低高血壓個體之血壓。高血壓之治療涉及投與本發明之化合物及組合以治療高血壓個體之高血壓。高血壓相關病症之治療涉及投與本發明之化合物或 組合以治療高血壓相關病症。高血壓或高血壓相關病症之預防涉及將本發明之組合投與高血壓前期個體以預防高血壓或高血壓相關病症發作。此處，高血壓相關病症與高血壓相關、由高血壓引起或起因於高血壓。高血壓相關病症之實例包括(但不限於)：心臟病、心臟衰竭、心臟病發作、腎衰竭及中風。The term "hypertension" as used herein includes primordial or essential hypertension in which the cause is unknown or in which hypertension is attributed to more than one cause, such as changes in the heart and blood vessels; and secondary hypertension, wherein The cause is known. The causes of secondary hypertension include, but are not limited to, obesity; kidney disease; hormonal imbalance; the use of certain drugs, such as oral contraceptives, corticosteroids, cyclosporin, and the like. The term "hypertension" covers both systolic and diastolic blood pressure levels ( 140 mmHg/ Hypertension of 90 mmHg); and isolated systolic hypertension, in which only systolic blood pressure rises to greater than or equal to 140 mmHg, and diastolic blood pressure is less than 90 mmHg. Normal blood pressure can be defined as a systolic blood pressure of less than 120 mmHg and a diastolic blood pressure of less than 80 mmHg. Hypertensive individuals are individuals with high blood pressure. Individuals with prehypertension are individuals with blood pressures between 120 mmHg/80 mmHg and 139 mmHg/89 mmHg. One treatment outcome is to lower the blood pressure of individuals with high blood pressure. Treatment of hypertension involves administering the compounds and combinations of the invention to treat hypertension in a subject with hypertension. Treatment of a condition associated with hypertension involves administration of a compound or combination of the invention to treat a condition associated with hypertension. Prevention of hypertension or hypertension related conditions involves administering a combination of the invention to a prehypertensive individual to prevent the onset of hypertension or hypertension related conditions. Here, a hypertension-related disorder is associated with hypertension, caused by hypertension, or caused by hypertension. Examples of hypertension related conditions include, but are not limited to, heart disease, heart failure, heart attack, kidney failure, and stroke.

血脂異常及脂質失調為脂質代謝病症，包括以一或多種脂質(亦即膽固醇及三酸甘油酯)及/或脂蛋白元(亦即脂蛋白元A、B、C及E)及/或脂蛋白(亦即由脂質及使脂質於血液中循環之脂蛋白元形成之大分子複合物，諸如LDL、VLDL及IDL)之異常濃度為特徵的各種病狀。高脂質血症與脂質、LDL及VLDL膽固醇及/或三酸甘油酯之異常高的含量相關。血脂異常之治療涉及將本發明之組合投與血脂異常個體。血脂異常之預防涉及將本發明之組合投與血脂異常前期個體。血脂異常前期個體為脂質含量高於正常值，但尚未出現血脂異常之個體。Dyslipidemia and lipid disorders are lipid metabolic disorders, including one or more lipids (ie, cholesterol and triglycerides) and/or lipoproteins (ie, lipoproteins A, B, C, and E) and/or lipids. Various conditions characterized by abnormal concentrations of proteins (i.e., macromolecular complexes formed by lipids and lipoproteins that circulate lipids in the blood, such as LDL, VLDL, and IDL). Hyperlipidemia is associated with an abnormally high content of lipids, LDL and VLDL cholesterol and/or triglycerides. Treatment of dyslipidemia involves administering a combination of the invention to a dyslipidemia individual. Prevention of dyslipidemia involves administering a combination of the invention to a pre- dyslipidemia individual. Individuals with pre-dyslipidemia were individuals with higher lipid content than normal, but no dyslipidemia.

術語「血脂異常相關病症」及「脂質失調相關病症」應理解為意謂與血脂異常或脂質失調相關、由血脂異常或脂質失調引起或起因於血脂異常或脂質失調之病症。血脂異常相關病症及脂質失調相關病症之實例包括(但不限於)：高脂質血症、高三酸甘油酯血症、高膽固醇血症、高密度脂蛋白(HDL)含量低、低密度脂蛋白(LDL)血漿含量高、動脈粥樣硬化及其後遺症、冠狀動脈或頸動脈疾病、心臟病發作及中風。The terms "dyslipidemia-related disorder" and "lipid-disorder-related disorder" are understood to mean disorders associated with dyslipidemia or lipid disorders, caused by dyslipidemia or lipid disorders, or caused by dyslipidemia or lipid disorders. Examples of dyslipidemia-related disorders and lipid-related disorders include, but are not limited to, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low-density lipoprotein (HDL) levels, low-density lipoprotein ( LDL) high plasma levels, atherosclerosis and its sequelae, coronary or carotid artery disease, heart attack and stroke.

如本文所用之術語「肥胖症」為存在過量體脂肪之病狀。肥胖症之操作型定義係基於身體質量指數(BMI)，其以每平方公尺身高之體重(kg/m2 )計算。「肥胖症」係指其他方面健康之個體之身體質量指數(BMI)大於或等於30 kg/m2 的病狀，或患有至少一種共存疾病之個體之BMI大於或等於27 kg/m2 的病狀。「肥胖個體」為身體質量指數(BMI)大於或等於30 kg/m2 且其他方面健康之個體，或BMI大於或等於27 kg/m2 且患有至少一種共存疾病之個體。過重個體為有患肥胖症風險之個體。「有患肥胖症風險之個體」為BMI為25 kg/m2 至小於30 kg/m2 且其他方面健康之個體，或BMI為25 kg/m2 至小於27 kg/m2 且患有至少一種共存疾病之個體。The term "obesity" as used herein refers to a condition in which excess body fat is present. The operational definition of obesity is based on body mass index (BMI), which is calculated as body weight per square meter (kg/m 2 ). "obesity" means a condition in which a healthy individual has a body mass index (BMI) greater than or equal to 30 kg/m 2 , or an individual having at least one comorbid condition has a BMI greater than or equal to 27 kg/m 2 Symptoms. An "obese individual" is an individual whose body mass index (BMI) is greater than or equal to 30 kg/m 2 and otherwise healthy, or an individual having a BMI greater than or equal to 27 kg/m 2 and having at least one comorbid condition. Overweight individuals are individuals at risk for obesity. "Individuals at risk of obesity" are individuals with a BMI of 25 kg/m 2 to less than 30 kg/m 2 and otherwise healthy, or a BMI of 25 kg/m 2 to less than 27 kg/m 2 and at least An individual with a coexisting disease.

在亞洲人中在較低身體質量指數(BMI)下發生與肥胖症相關之風險增加。在包括日本之亞洲國家，「肥胖症」係指患有至少一種需要減輕體重或應藉由減輕體重來改善之肥胖症誘發性或肥胖症相關性共存疾病的個體具有大於或等於25 kg/m2 之BMI的病狀。在包括日本之亞洲國家，「肥胖個體」係指患有至少一種需要減輕體重或應藉由減輕體重來改善之肥胖症誘發性或肥胖症相關性共存疾病的個體，其BMI大於或等於25 kg/m2 。在亞洲-太平洋地區，「有患肥胖症風險之個體」為BMI大於23 kg/m2 至小於25 kg/m2 之個體。An increased risk of obesity is associated with lower body mass index (BMI) among Asians. In Asian countries including Japan, "obesity" refers to an individual having at least one obesity-induced or obesity-related comorbidity disease that requires weight loss or improved by weight loss to have greater than or equal to 25 kg/m. 2 BMI symptoms. In Asian countries including Japan, "obese individuals" refers to individuals with at least one obesity-induced or obesity-related comorbidity disease that requires weight loss or which should be improved by weight loss, with a BMI greater than or equal to 25 kg. /m 2 . In the Asia-Pacific region, individuals with a risk of obesity are individuals with a BMI greater than 23 kg/m 2 to less than 25 kg/m 2 .

如本文所用之術語「肥胖症」意欲涵蓋所有上述肥胖症定義。The term "obesity" as used herein is intended to encompass all of the above definitions of obesity.

肥胖症誘發性或肥胖症相關性共存疾病包括(但不限於)糖尿病、非胰島素依賴性糖尿病(即，2型糖尿病)、與肥胖症相關之糖尿病、葡萄糖耐受性異常、空腹葡萄糖異常、胰島素抗性症候群、血脂異常、高血壓、與肥胖症相關之高血壓、高尿酸血症、痛風、冠狀動脈疾病、心肌梗塞、心絞痛、睡眠呼吸暫停症候群、匹克威克症候群(Pickwickian syndrome)、脂肪肝、腦梗塞、腦血栓、短暫缺血性發作、畸形障礙、變形性關節炎、腰痛、月經病及不孕症。共存疾病尤其包括：高血壓、高脂質血症、血脂異常、葡萄糖不耐、心血管疾病、睡眠呼吸暫停及其他肥胖症相關病狀。Obesity-induced or obesity-related comorbidities include, but are not limited to, diabetes, non-insulin-dependent diabetes (ie, type 2 diabetes), obesity-associated diabetes, impaired glucose tolerance, fasting glucose abnormalities, insulin Resistance syndrome, dyslipidemia, hypertension, obesity-related hypertension, hyperuricemia, gout, coronary artery disease, myocardial infarction, angina pectoris, sleep apnea syndrome, Pickwickian syndrome, fatty liver , cerebral infarction, cerebral thrombosis, transient ischemic attack, malformation disorder, deformed arthritis, low back pain, menstrual disease and infertility. Coexisting diseases include, in particular, hypertension, hyperlipidemia, dyslipidemia, glucose intolerance, cardiovascular disease, sleep apnea and other obesity-related conditions.

肥胖症及肥胖症相關病症之治療涉及投與本發明化合物以減輕或維持肥胖個體之體重。一個治療成果可為使肥胖個體之體重相對於即將投與本發明化合物之前該個體之體重減輕。另一治療成果可為防止先前因飲食、鍛煉或藥物療法而損失之體重出現體重再增長。另一治療成果可為降低肥胖症相關疾病之發生率及/或嚴重程度。治療宜使個體減少食物或熱量攝入，包括減少總體食物攝入，或減少特定膳食組分(諸如碳水化合物或脂肪)之攝入；及/或抑制養分吸收；及/或抑制代謝率降低；及減輕有需要之患者之體重。治療亦可改變代謝率，諸如提高代謝率而非抑制代謝率降低，或提高代謝率以及抑制代謝率降低；及/或使通常由體重損失引起之代謝抗性降至最低。Treatment of obesity and obesity-related disorders involves administration of a compound of the invention to reduce or maintain the weight of an obese individual. One therapeutic outcome may be to reduce the body weight of the obese individual relative to the weight of the individual prior to administration of the compound of the invention. Another treatment outcome may be to prevent weight gain from losing weight previously lost due to diet, exercise, or medication. Another therapeutic outcome may be to reduce the incidence and/or severity of obesity-related diseases. Treatment should reduce the individual's food or calorie intake, including reducing overall food intake, or reducing the intake of specific dietary components (such as carbohydrates or fats); and/or inhibiting nutrient absorption; and/or inhibiting metabolic rate reduction; And reduce the weight of patients in need. Treatment can also alter metabolic rates, such as increasing metabolic rate rather than inhibiting metabolic rate reduction, or increasing metabolic rate and inhibiting metabolic rate reduction; and/or minimizing metabolic resistance typically caused by weight loss.

肥胖症及肥胖症相關病症之預防涉及投與本發明化合物 以減輕或維持有患肥胖症風險之個體的體重。一個預防成果可為使有患肥胖症風險之個體的體重相對於即將投與本發明化合物之前該個體的體重減輕。另一預防成果可為防止先前因飲食、鍛煉或藥物療法而損失之體重出現體重再增長。若在有患肥胖症風險之個體的肥胖症發作之前施以治療，則另一預防成果可為防止肥胖症發生。若在有患肥胖症風險之個體的肥胖症發作之前施以治療，則另一預防成果可為降低肥胖症相關病症之發生率及/或嚴重程度。此外，若開始對已肥胖之個體進行治療，則該治療可防止以下肥胖症相關病症的發生、發展或嚴重程度加劇：諸如(但不限於)動脈硬化、II型糖尿病、多囊性卵巢疾病、心血管疾病、骨關節炎、皮膚病症、高血壓、胰島素抗性、高膽固醇血症、高三酸甘油酯血症及膽石病。Prevention of obesity and obesity-related disorders involves administration of a compound of the invention To reduce or maintain the weight of an individual at risk for obesity. One preventative outcome may be to reduce the body weight of an individual at risk of obesity relative to the weight of the individual prior to administration of the compound of the invention. Another preventive outcome can be to prevent weight gain from losing weight previously lost due to diet, exercise, or medication. If treatment is given before the onset of obesity in an individual at risk for obesity, another preventive outcome can be to prevent obesity. If treatment is given prior to the onset of obesity in an individual at risk for obesity, another preventive outcome may be to reduce the incidence and/or severity of obesity-related conditions. In addition, if treatment is initiated on obese individuals, the treatment may prevent the onset, progression, or severity of obesity-related conditions such as, but not limited to, arteriosclerosis, type 2 diabetes, polycystic ovarian disease, Cardiovascular disease, osteoarthritis, skin disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia and cholelithiasis.

本文中之肥胖症相關病症與肥胖症相關、由肥胖症引起或起因於肥胖症。肥胖症相關病症之實例包括暴食及貪食症、高血壓、糖尿病、血漿胰島素濃度升高及胰島素抗性、血脂異常、高脂質血症、子宮內膜癌、乳癌、前列腺癌及結腸癌、骨關節炎、阻塞性睡眠呼吸暫停、膽石病、膽結石、心臟病、心律異常及心律不整、心肌梗塞、充血性心臟衰竭、冠狀動脈性心臟病、猝死、中風、多囊性卵巢疾病、顱咽管瘤、普來德-威利症候群(Prader-Willi Syndrome)、弗勒利希氏症候群(Frohlich's syndrome)、GH缺乏個體、正常變異型身材矮小、特納氏症候群(Turner's syndrome)，及顯示代謝活性降低或以總無脂肪質量百分 比表示之靜態能量消耗減小的其他病理狀況(例如患有急性淋巴母細胞白血病之兒童)。肥胖症相關病症之其他實例為代謝症候群(亦稱為X症候群)、胰島素抗性症候群、性功能障礙與生殖功能障礙(諸如不孕症、男性性腺低能症及女性多毛症)、胃腸運動障礙(諸如肥胖症相關胃-食道逆流)、呼吸障礙(諸如肥胖-換氣不足症候群(匹克威克症候群))、心血管病症、發炎(諸如全身性血管結構發炎)、動脈硬化、高膽固醇血症、高尿酸血症、下背痛、膽囊疾病、痛風及腎癌。本發明化合物亦適用於降低肥胖症之繼發結果的風險，諸如降低左心室肥大之風險。Obesity-related conditions herein are associated with obesity, caused by obesity, or caused by obesity. Examples of obesity-related disorders include binge eating and bulimia, hypertension, diabetes, elevated plasma insulin levels and insulin resistance, dyslipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer and colon cancer, bone and joint Inflammation, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heart rhythm and arrhythmia, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, polycystic ovarian disease, craniopharynx Tuberculosis, Prader-Willi Syndrome, Frohlich's syndrome, GH-deficient individuals, normal variant short stature, Turner's syndrome, and showing metabolism Reduced activity or percentage of total fat-free mass Other pathological conditions that indicate a decrease in static energy expenditure (eg, children with acute lymphoblastic leukemia). Other examples of obesity-related disorders are metabolic syndrome (also known as X syndrome), insulin resistance syndrome, sexual dysfunction and reproductive dysfunction (such as infertility, male gonadal dysfunction and female hirsutism), gastrointestinal dyskinesia ( Such as obesity-related gastro-esophageal reflux, respiratory disorders (such as obesity-deficiency syndrome (Pickwick syndrome)), cardiovascular disorders, inflammation (such as systemic vascular structural inflammation), arteriosclerosis, hypercholesterolemia, Hyperuricemia, lower back pain, gallbladder disease, gout and kidney cancer. The compounds of the invention are also suitable for reducing the risk of secondary outcomes of obesity, such as reducing the risk of left ventricular hypertrophy.

式I化合物亦適用於治療或預防貓及狗之肥胖症及肥胖症相關病症。同樣地，術語「哺乳動物」包括伴侶動物，諸如貓及狗。The compounds of formula I are also suitable for the treatment or prevention of obesity and obesity-related disorders in cats and dogs. Similarly, the term "mammal" includes companion animals such as cats and dogs.

術語「代謝症候群」(亦稱為X症候群)定義於Third Report of the National Cholesterol Education Program Expert Panel on Detection,Evaluation and Treatment of High Blood Cholesterol in Adults(Adult Treatment Panel III或ATP III),National Institutes of Health,2001,NIH出版物第01-3670號.E.S.Ford等人，JAMA，第287卷(3),2002年1月16日，第356-359頁中。簡言之，若某人患有三種或三種以上下列病症，則將其定義為患有代謝症候群：腹型肥胖症、高三酸甘油酯血症、低HDL膽固醇、高血壓及高空腹血漿葡萄糖。關於此等病症之標準定義於ATP-III中。代謝症候群之治療涉及將本發明之組合投與患有代謝 症候群之個體。代謝症候群之預防涉及將本發明之組合投與患有定義代謝症候群之病症中之兩者的個體。患有定義代謝症候群之病症中之兩者的個體為已發生定義代謝症候群之病症中之兩者，但尚未發生定義代謝症候群之病症中之三者或三者以上的個體。The term "metabolic syndrome" (also known as X syndrome) is defined in the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III or ATP III), National Institutes of Health , 2001, NIH Publication No. 01-3670. ES Ford et al., JAMA, Vol. 287 (3), January 16, 2002, pp. 356-359. In short, if a person has three or more of the following conditions, it is defined as having metabolic syndrome: abdominal obesity, hypertriglyceridemia, low HDL cholesterol, hypertension, and high fasting plasma glucose. The criteria for these conditions are defined in ATP-III. Treatment of metabolic syndrome involves administering a combination of the invention to have metabolism Individuals of the syndrome. Prevention of metabolic syndrome involves administering a combination of the invention to an individual having both of the conditions defining the metabolic syndrome. An individual having two of the conditions defining the metabolic syndrome is one in which two of the conditions defining the metabolic syndrome have occurred, but three or more of the conditions defining the metabolic syndrome have not occurred.

左心室肥大(LVH)係基於左心室質量指數(LVMI)及相對壁厚(RWT)來鑑別。左心室質量指數定義為左心室質量(公克)除以體表面積(平方公尺)。相對壁厚定義為2×後壁厚度/左心室舒張末直徑。正常LVMI值通常為85，且正常RWT約為0.36。患有LVH之雄性個體的LVMI大於131 g/m2 ；患有LVH之雌性個體的LVMI大於100 g/m2 。LVMI值升高之個體為LVMI介於85 g/m2 與131 g/m2 之間的雄性個體，或LVMI介於85 g/m2 與100 g/m2 之間的雌性個體。Left ventricular hypertrophy (LVH) is identified based on left ventricular mass index (LVMI) and relative wall thickness (RWT). The left ventricular mass index is defined as the left ventricular mass (grams) divided by the body surface area (square meters). The relative wall thickness is defined as 2 x posterior wall thickness / left ventricular end diastolic diameter. The normal LVMI value is typically 85 and the normal RWT is approximately 0.36. Male subjects with LVH have an LVMI greater than 131 g/m 2 ; female individuals with LVH have an LVMI greater than 100 g/m 2 . Individuals with elevated LVMI values were male individuals with LVMI between 85 g/m 2 and 131 g/m 2 , or female individuals with LVMI between 85 g/m 2 and 100 g/m 2 .

心臟肥大或左心室肥大之治療涉及將本發明之組合投與患有心臟肥大或左心室肥大之個體。心臟肥大或左心室肥大之預防涉及投與本發明之組合以降低或維持LVMI值升高之個體的LVMI或防止具有正常LVMI值之個體的LVMI增加。Treatment of cardiac hypertrophy or left ventricular hypertrophy involves administering a combination of the invention to an individual having cardiac hypertrophy or left ventricular hypertrophy. Prevention of cardiac hypertrophy or left ventricular hypertrophy involves administration of a combination of the invention to reduce or maintain LVMI in an individual with an elevated LVMI value or to prevent an increase in LVMI in an individual with a normal LVMI value.

心臟肥大或左心室肥大之一個治療成果可為心室質量下降。心臟肥大或左心室肥大之另一治療成果可為心室質量之增加速率降低。心臟肥大或左心室肥大之另一治療成果可為心室壁厚減小。心臟肥大或左心室肥大之另一治療成果可為心室壁厚之增加速率降低。One treatment outcome for cardiac hypertrophy or left ventricular hypertrophy can result in decreased ventricular quality. Another treatment for cardiac hypertrophy or left ventricular hypertrophy can reduce the rate of increase in ventricular mass. Another treatment for cardiac hypertrophy or left ventricular hypertrophy can result in a reduction in ventricular wall thickness. Another treatment for cardiac hypertrophy or left ventricular hypertrophy can reduce the rate of increase in ventricular wall thickness.

術語化合物之「投與(administration of)」及或「投與一 種(administering a)」化合物應理解為意謂向需要治療之個體或哺乳動物提供本發明化合物或本發明化合物之前藥。The term "administration of" and or "investment one" An "administering a" compound is understood to mean a compound of the invention or a compound of the invention prior to administration to an individual or mammal in need of treatment.

投與結構式I之化合物以實施本發明治療方法係藉由將有效量之結構式I之化合物投與需要該治療或預防之哺乳動物來進行。經由使用熟知風險因素來確定對根據本發明方法進行預防性投藥的需求。在最終分析中，由負責該病例之醫師或獸醫來確定個別化合物之有效量，但該有效量視以下因素而定：諸如欲治療之確切疾病、患者所患疾病及其他疾病或病狀之嚴重程度、所選投藥途徑、患者可能同時需要之其他藥物及治療，及處於醫師判斷中之其他因素。Administration of a compound of formula I to practice a method of the invention is carried out by administering an effective amount of a compound of formula I to a mammal in need of such treatment or prevention. The need for prophylactic administration of the method according to the invention is determined via the use of well-known risk factors. In the final analysis, the effective amount of the individual compound is determined by the physician or veterinarian responsible for the case, but the effective amount depends on factors such as the exact disease to be treated, the patient's disease, and other serious diseases or conditions. The extent, the route of administration chosen, the other medications and treatments that the patient may need at the same time, and other factors at the discretion of the physician.

本發明化合物對此等疾病或病症之適用性可在文獻中已報導之動物疾病模型中證實。The suitability of the compounds of the invention for such diseases or conditions can be demonstrated in animal disease models reported in the literature.

式I化合物之預防或治療劑量的量值當然應隨欲治療病狀之性質或嚴重程度以及特定式I化合物及其投藥途徑而變化。該量值亦應根據個別患者之年齡、體重及反應而變化。一般而言，日劑量範圍為每公斤哺乳動物體重約0.001毫克至約100毫克，較佳為每公斤0.01毫克至約50毫克且最佳為每公斤0.1毫克至10毫克，以單次或分次劑量投與。另一方面，在一些狀況下，可能有必要使用超出此等界限之劑量。The amount of the prophylactic or therapeutic dose of the compound of formula I will of course vary depending on the nature or severity of the condition to be treated and the particular compound of formula I and its route of administration. This amount should also vary depending on the age, weight and response of the individual patient. In general, the daily dose ranges from about 0.001 mg to about 100 mg per kg of mammalian body weight, preferably from 0.01 mg to about 50 mg per kg and most preferably from 0.1 mg to 10 mg per kg, in single or divided portions. Dosage is administered. On the other hand, in some cases it may be necessary to use doses that exceed these limits.

對於採用供靜脈內投與之組合物的用法，適合劑量範圍為每日每公斤體重約0.001毫克至約100毫克式I化合物，在一個實施例中為約0.01毫克至約50毫克，且在另一實施例 中為0.1毫克至10毫克。For use with compositions for intravenous administration, a suitable dosage range is from about 0.001 mg to about 100 mg of the compound of formula I per kg of body weight per day, in one embodiment from about 0.01 mg to about 50 mg, and in another An embodiment In the range of 0.1 mg to 10 mg.

在採用口服組合物之狀況下，適合劑量範圍為例如每日約0.01毫克至約1000毫克式I化合物。在一個實施例中，該範圍為每日約0.1毫克至約10毫克。對於經口投藥，組合物較佳以錠劑形式提供，該等錠劑含有0.01至1,000毫克，較佳0.01、0.05、0.1、0.5、1、2、2.5、3、4、5、6、7、8、9、10、12、12.5、15、20、25、30、40、50、100、250、500、750或1000毫克活性成分，以對欲治療之患者依症狀調整劑量。In the case of oral compositions, suitable dosages are, for example, from about 0.01 mg to about 1000 mg of the compound of formula I per day. In one embodiment, the range is from about 0.1 mg to about 10 mg per day. For oral administration, the compositions are preferably provided in the form of a tablet containing from 0.01 to 1,000 mg, preferably 0.01, 0.05, 0.1, 0.5, 1, 2, 2.5, 3, 4, 5, 6, 7 8, 9, 10, 12, 12.5, 15, 20, 25, 30, 40, 50, 100, 250, 500, 750 or 1000 mg of active ingredient to adjust the dosage to the patient to be treated.

本發明之另一態樣提供醫藥組合物，其包含式I化合物及醫藥學上可接受之載劑。如醫藥組合物中之術語「組合物」欲涵蓋包含活性成分及構成載劑之惰性成分(醫藥學上可接受之賦形劑)的產物，以及由任何兩種或兩種以上成分組合、複合或聚集，或由一或多種成分解離，或由一或多種成分進行其他類型之反應或相互作用而直接或間接產生的任何產物。因此，本發明之醫藥組合物涵蓋藉由混合式I化合物、其他活性成分及醫藥學上可接受之賦形劑而製成的任何組合物。Another aspect of the invention provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier. The term "composition" as used in the pharmaceutical composition is intended to cover the product comprising the active ingredient and the inert ingredients (pharmaceutically acceptable excipients) which comprise the carrier, and the combination or combination of any two or more components. Or agglomerated, or any product that is directly or indirectly produced by one or more decompositions, or other types of reactions or interactions by one or more components. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of formula I, other active ingredients, and pharmaceutically acceptable excipients.

可採用任何適合投藥途徑向哺乳動物，尤其人類或伴侶動物(諸如狗或貓)提供有效劑量之本發明化合物。舉例而言，可採用經口、經直腸、局部、非經腸、經眼、經肺及經鼻投藥途徑，及其類似途徑。劑型包括錠劑、糖衣錠、分散液、懸浮液、溶液、膠囊、乳膏、軟膏、氣霧劑及其類似劑型。An effective amount of a compound of the invention may be provided to a mammal, especially a human or companion animal, such as a dog or cat, using any suitable route of administration. For example, oral, transrectal, topical, parenteral, transocular, transpulmonary, and nasal routes of administration, and the like can be employed. Dosage forms include lozenges, dragees, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.

本發明之醫藥組合物包含式I化合物或其醫藥學上可接受之鹽作為活性成分，且亦可含有醫藥學上可接受之載劑及視情況存在之其他治療成分。「醫藥學上可接受」意謂載劑、稀釋劑或賦形劑必須與調配物之其他成分相容且對其接受者無害。該等組合物包括適於經口、經直腸、局部、非經腸(包括皮下、肌肉內及靜脈內)、經眼(眼部)、經肺(氣霧劑吸入)或經鼻投與之組合物，不過在任何既定狀況下之最適合途徑應視所治療病狀之性質及嚴重程度以及活性成分之性質而定。該等組合物宜以單位劑型提供且藉由製藥技術中熟知之任何方法製備。The pharmaceutical compositions of the present invention comprise a compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient, and may also contain a pharmaceutically acceptable carrier and, where appropriate, other therapeutic ingredients. "Pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient. Such compositions include those suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), transocular (ocular), transpulmonary (aerosol inhalation) or nasal administration. The composition, however, the most suitable route under any given conditions will depend on the nature and severity of the condition being treated and the nature of the active ingredient. These compositions are preferably presented in unit dosage form and are prepared by any methods known in the pharmaceutical art.

對於藉由吸入投藥，本發明化合物宜以氣霧劑噴霧呈現形式自加壓包裝或噴霧器傳遞，或以可進行調配之粉末形式傳遞且粉末組合物可藉助於吹入粉末吸入器裝置吸入。用於吸入之較佳傳遞系統為定劑量吸入(metered dose inhalation，MDI)氣霧劑，其可調配成式I化合物於適合推進劑(諸如碳氟化合物或烴)中之懸浮液或溶液；及乾粉吸入(dry powder inhalation，DPI)氣霧劑，其可調配成存在或不存在其他賦形劑之式I化合物之乾粉。For administration by inhalation, the compounds of the invention are preferably delivered from a pressurized pack or nebulizer in the form of an aerosol spray, or as a powder which can be formulated and the powder composition can be inhaled by means of a blown powder inhaler device. A preferred delivery system for inhalation is a metered dose inhalation (MDI) aerosol which can be formulated as a suspension or solution of a compound of formula I in a propellant such as a fluorocarbon or a hydrocarbon; A dry powder inhalation (DPI) aerosol which can be formulated as a dry powder of a compound of formula I in the presence or absence of other excipients.

式I化合物之適合的局部調配物包括經皮裝置、氣霧劑、乳膏、溶液、軟膏、凝膠、洗劑、敷粉(dusting powder)及其類似物。含有本發明化合物之局部用醫藥組合物通常包括與醫藥學上可接受之媒劑混合的約0.005重量%至5重量%之活性化合物。適用於投與本發明化合物之經皮皮膚貼片包括一般技術者已知之貼片。Suitable topical formulations of the compounds of formula I include transdermal devices, aerosols, creams, solutions, ointments, gels, lotions, dusting powders and the like. The topical pharmaceutical compositions containing a compound of the invention typically comprise from about 0.005% to about 5% by weight of active compound in admixture with a pharmaceutically acceptable vehicle. Transdermal skin patches suitable for administration to the compounds of the invention include patches known to those of ordinary skill in the art.

在實際使用中，可根據習知醫藥混配技術將式I化合物作為與醫藥載劑精細混合之活性成分加以組合。視例如經口或非經腸(包括靜脈內)投藥所需之製劑的形式而定，載劑可呈多種形式。在製備用於口服劑型之組合物時，可採用任何常用醫藥介質，在諸如懸浮液、酏劑及溶液之口服液體製劑之狀況下為諸如水、二醇、油、醇、調味劑、防腐劑、著色劑及其類似物；或在諸如散劑、膠囊及錠劑之口服固體製劑之狀況下載劑為諸如澱粉、糖、微晶纖維素、稀釋劑、成粒劑、潤滑劑、黏合劑、崩解劑及其類似物，其中固體口服製劑優於液體製劑。由於錠劑及膠囊易於投與，故其代表最有利之口服單位劑型，在此種狀況下顯然採用固體醫藥載劑。必要時，可由標準水性或非水性技術將錠劑包覆包衣。In actual use, the compound of formula I can be combined as an active ingredient in admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on, for example, the form of the preparation required for oral or parenteral (including intravenous) administration. In the preparation of a composition for oral dosage form, any of the usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols, flavoring agents, preservatives, in the case of oral liquid preparations such as suspensions, elixirs and solutions. , colorants and the like; or in the case of oral solid preparations such as powders, capsules and lozenges, the downloading agent is such as starch, sugar, microcrystalline cellulose, diluent, granulating agent, lubricant, binder, collapse Decomposers and analogs thereof, wherein the solid oral preparation is superior to the liquid preparation. Because tablets and capsules are easy to administer, they represent the most advantageous oral unit dosage form, in which case solid pharmaceutical carriers are obviously employed. If desired, the tablet may be coated by standard aqueous or non-aqueous techniques.

除上文所陳述之常用劑型以外，式I化合物亦可由控制釋放方式及/或傳遞裝置投與，諸如美國專利第3,845,770號、第3,916,899號、第3,536,809號、第3,598,123號、第3,630,200號及第4,008,719號中所述者。In addition to the usual dosage forms set forth above, the compounds of formula I may also be administered by controlled release means and/or delivery devices, such as U.S. Patent Nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123, 3,630,200 and Said in 4,008,719.

適於經口投與之本發明醫藥組合物可以如下形式呈現：個別單位，諸如膠囊(包括定時釋放及持續釋放調配物)、丸劑、扁囊劑、散劑、顆粒劑或錠劑，各自含有預定量之活性成分；散劑或顆粒劑；或於水性液體、非水性液體中之溶液或懸浮液、水包油乳液或油包水液體乳液，包括酏劑、酊劑、溶液、懸浮液、糖漿及乳液。該等組合物可藉由任何製藥方法製備，但所有方法皆包括使活性成分與由 一或多種必要成分構成之載劑締合的步驟。一般而言，組合物係藉由將活性成分與液體載劑或細粉狀固體載體或兩者均勻且精細地混合，接著在必要時使產物成形為所要呈現形式來製備。舉例而言，錠劑可藉由視情況與一或多種附屬成分一起壓製或模製來製備。壓製錠劑可藉由在適合機器中壓製視情況與黏合劑、潤滑劑、惰性稀釋劑、表面活性劑或分散劑混合的呈自由流動形式(諸如粉末或顆粒)之活性成分來製備。模製錠劑可藉由在適合機器中模製經惰性液體稀釋劑濕潤之粉末狀化合物之混合物來製得。理想地，各錠劑、扁囊劑或膠囊含有約0.01至1,000毫克，尤其0.01、0.05、0.1、0.5、1.0、2、2.5、3、4、5、6、7、8、9、10、12、15、25、30、40、50、75、100、125、150、175、180、200、225、250、500、750及1,000毫克活性成分，以對欲治療之患者依症狀調整劑量。The pharmaceutical compositions of the present invention suitable for oral administration can be presented in the form of individual units, such as capsules (including timed release and sustained release formulations), pills, cachets, powders, granules or lozenges, each containing a predetermined Amount of active ingredient; powder or granule; or solution or suspension in aqueous liquid, non-aqueous liquid, oil-in-water emulsion or water-in-oil liquid emulsion, including elixirs, tinctures, solutions, suspensions, syrups and lotions . The compositions can be prepared by any of the methods of pharmacy, but all methods include the active ingredient A step of association of carriers comprising one or more essential ingredients. In general, the compositions are prepared by uniformly and finely mixing the active ingredient with a liquid carrier or a finely divided solid carrier or both, and, if necessary, shaping the product into the desired form. For example, lozenges can be prepared by compression or molding, as appropriate, with one or more accessory ingredients. Pressed lozenges can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granule, optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersing agent. Molded lozenges can be prepared by molding in a suitable machine a mixture of powdered compound moistened with an inert liquid diluent. Desirably, each tablet, cachet or capsule contains from about 0.01 to 1,000 mg, especially 0.01, 0.05, 0.1, 0.5, 1.0, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 25, 30, 40, 50, 75, 100, 125, 150, 175, 180, 200, 225, 250, 500, 750, and 1,000 mg of active ingredient to adjust the dosage to the patient to be treated.

投與本發明化合物之其他適合方式包括在封閉或不封閉之情況下注射、靜脈內快速注射或輸注、腹膜內投藥、皮下投藥、肌肉內投藥、鼻內投藥及局部投藥。Other suitable means of administering a compound of the invention include injection, intravenous bolus injection or infusion, intraperitoneal administration, subcutaneous administration, intramuscular administration, intranasal administration, and topical administration, with or without closure.

包含上文所述任何化合物及醫藥學上可接受之載劑的醫藥組合物例示本發明。藉由將上文所述之任何化合物與醫藥學上可接受之載劑組合而製成的醫藥組合物亦例示本發明。本發明說明一種製備醫藥組合物之方法，其包含將上文所述之任何化合物與醫藥學上可接受之載劑組合。Pharmaceutical compositions comprising any of the compounds described above and a pharmaceutically acceptable carrier are illustrative of the invention. The invention is also exemplified by a pharmaceutical composition prepared by combining any of the compounds described above with a pharmaceutically acceptable carrier. The present invention describes a method of preparing a pharmaceutical composition comprising combining any of the compounds described above with a pharmaceutically acceptable carrier.

劑量可以單次日劑量投與，或總日劑量可以每日兩次、三次或四次之分次劑量投與。此外，基於選擇供投藥之個 別化合物之特性，劑量可依較低頻率投與，例如每週一次、每週兩次、每月一次等。對於較低頻率投藥，單位劑量當然應相應地較大。The dose can be administered in a single daily dose, or the total daily dose can be administered in divided doses of two, three or four times daily. In addition, based on the choice of drugs for administration The characteristics of other compounds, the dose can be administered at a lower frequency, such as once a week, twice a week, once a month, and the like. For lower frequency administration, the unit dose should of course be correspondingly larger.

當經由鼻內途徑、經皮途徑、由直腸或陰道栓劑或經連續靜脈內溶液投藥時，劑量投與當然應在整個給藥方案中為連續而非間歇的。When administered via an intranasal route, a transdermal route, a rectal or vaginal suppository, or a continuous intravenous solution, the dosage administration should of course be continuous rather than intermittent throughout the dosage regimen.

以下為式I化合物之代表性醫藥劑型之實例： The following are examples of representative pharmaceutical dosage forms of the compounds of formula I:

式I化合物可與用於治療/預防/抑制或改善式I化合物所適用之疾病、病症或病狀的其他藥物組合使用。該等其他藥物可依其常用途徑及用量，與式I化合物同時或依序投與。當式I化合物與一或多種其他藥物同時使用時，除式I 化合物以外亦含有該等其他藥物之醫藥組合物較佳。因此，本發明之醫藥組合物包括除式I化合物以外亦含有一或多種其他活性成分之醫藥組合物。可與式I化合物組合之其他活性成分之實例包括(但不限於)：其他抗糖尿病劑、抗血脂異常劑及抗高血壓劑、抗肥胖劑及食慾抑制劑，其可各別地投與或在同一醫藥組合物中投與。The compounds of formula I can be used in combination with other drugs for the treatment/prevention/suppression or amelioration of the disease, disorder or condition to which the compound of formula I is applied. These other drugs may be administered simultaneously or sequentially with the compound of formula I, according to their usual route and amount. When a compound of formula I is used in combination with one or more other drugs, Pharmaceutical compositions containing such other drugs in addition to the compounds are preferred. Accordingly, the pharmaceutical compositions of the present invention comprise a pharmaceutical composition comprising one or more additional active ingredients in addition to a compound of formula I. Examples of other active ingredients which may be combined with a compound of formula I include, but are not limited to, other anti-diabetic agents, anti-dyslipidemic agents and anti-hypertensive agents, anti-obesity agents and appetite suppressants, which may be administered separately or It is administered in the same pharmaceutical composition.

本發明亦提供一種治療或預防AMPK活化之蛋白激酶(AMPK)介導之疾病的方法，該方法包含投與需要該治療或有發生AMPK介導之疾病風險的患者一定量之AMPK活化劑及一定量之一或多種活性成分，使得其一起產生有效緩解作用。The invention also provides a method for treating or preventing AMPK-activated protein kinase (AMPK) mediated diseases, comprising administering to a patient in need of such treatment or a risk of developing an AMPK-mediated disease a certain amount of an AMPK activator and a certain amount One or more of the active ingredients are combined such that they together produce an effective palliative effect.

在本發明之另一態樣中，提供一種醫藥組合物，其包含AMPK活化劑及一或多種活性成分，以及至少一種醫藥學上可接受之載劑或賦形劑。In another aspect of the invention, a pharmaceutical composition comprising an AMPK activator and one or more active ingredients, and at least one pharmaceutically acceptable carrier or excipient is provided.

因此，根據本發明之另一態樣，提供AMPK活化劑及一或多種活性成分之用途，其係用於製造用以治療或預防AMPK介導之疾病的藥物。因此，在本發明之又一或替代性態樣中，提供一種包含呈組合製劑形式之AMPK活化劑及一或多種活性成分的產物，以在治療或預防AMPK介導之疾病中同時、各別或依序使用。此種組合製劑可例如呈雙包裝(twin pack)形式。Thus, in accordance with another aspect of the invention, there is provided the use of an AMPK activator and one or more active ingredients for the manufacture of a medicament for the treatment or prevention of an AMPK mediated disease. Thus, in yet another or alternative aspect of the invention, there is provided a product comprising an AMPK activator in the form of a combined preparation and one or more active ingredients for simultaneous, separate treatment in the treatment or prevention of AMPK mediated diseases Or use in order. Such a combined preparation may, for example, be in the form of a twin pack.

應瞭解，為了治療或預防糖尿病、肥胖症、高血壓、代謝症候群、血脂異常、癌症、動脈粥樣硬化及其相關病症，本發明化合物可與有效治療彼病症之另一醫藥劑聯合 使用。It will be appreciated that for the treatment or prevention of diabetes, obesity, hypertension, metabolic syndrome, dyslipidemia, cancer, atherosclerosis and related disorders, the compounds of the invention may be combined with another pharmaceutical agent effective in the treatment of the condition use.

本發明亦提供一種治療或預防糖尿病、肥胖症、高血壓、代謝症候群、血脂異常、癌症、動脈粥樣硬化及其相關病症之方法，該方法包含投與需要該治療之患者一定量之本發明化合物及一定量之有效治療彼病症之另一醫藥劑，使得其一起產生有效緩解作用。The invention also provides a method of treating or preventing diabetes, obesity, hypertension, metabolic syndrome, dyslipidemia, cancer, atherosclerosis and related disorders, the method comprising administering to a patient in need of such treatment a quantity of the invention The compound and an amount of another pharmaceutical agent effective to treat the condition together result in an effective palliative effect.

本發明亦提供一種治療或預防糖尿病、肥胖症、高血壓、代謝症候群、血脂異常、癌症、動脈粥樣硬化及其相關病症之方法，該方法包含投與需要該治療之患者一定量之本發明化合物及一定量之適用於治療彼特定病狀之另一醫藥劑，使得其一起產生有效緩解作用。The invention also provides a method of treating or preventing diabetes, obesity, hypertension, metabolic syndrome, dyslipidemia, cancer, atherosclerosis and related disorders, the method comprising administering to a patient in need of such treatment a quantity of the invention The compound and an amount of another pharmaceutical agent suitable for treating a particular condition result in an effective mitigating effect.

適於與本發明化合物組合使用之醫藥劑包括(但不限於)：Pharmaceutical agents suitable for use in combination with the compounds of the invention include, but are not limited to:

(a)抗糖尿病劑，諸如(1)PPARγ促效劑類，諸如格列酮(glitazone)(例如環格列酮(ciglitazone)、達格列酮(darglitazone)、恩格列酮(englitazone)、伊沙列酮(isaglitazone)(MCC-555)、吡格列酮(ACTOS)、羅格列酮(AVANDIA)、曲格列酮、利格列酮(rivoglitazone)、BRL49653、CLX-0921、5-BTZD、GW-0207、LG-100641、R483及LY-300512及其類似物，以及WO 97/10813、97/27857、97/28115、97/28137、97/27847、03/000685及03/027112中所揭示之化合物，及SPPARMS(選擇性PPARγ調節劑)，諸如T131(Amgen)、FK614(Fujisawa)、萘格列酮及美格達森(metaglidasen))；(2)雙胍類，諸如丁雙胍(buformin)、二甲雙胍及苯乙雙 胍，及其類似物；(3)蛋白質酪胺酸磷酸酯酶1B(PTP-1B)抑制劑類，諸如ISIS 113715、A-401674、A-364504、IDD-3、IDD 2846、KP-40046、KR61639、MC52445、MC52453、C7、OC-060062、OC-86839、OC29796、TTP-277BC1，以及WO 04/041799、04/050646、02/26707、02/26743、04/092146、03/048140、04/089918、03/002569、04/065387、04/127570及US 2004/167183中所揭示之彼等藥劑；(4)磺醯脲類，諸如乙醯苯磺醯環己脲(acetohexamide)、氯磺丙脲(chlorpropamide)、特泌胰(diabinese)、格列本脲(glibenclamide)、格列吡嗪、優降糖(glyburide)、格列美脲(glimepiride)、甲磺吡脲(gliclazide)、格列戊脲(glipentide)、格列喹酮(gliquidone)、格列索脲(glisolamide)、妥拉磺脲(tolazamide)及甲苯磺丁脲，及其類似物；(5)美格替耐(meglitinide)類，諸如瑞格列奈(repaglinide)、米格列奈(metiglinide)(GLUFAST)及那格列奈(nateglinide)，及其類似物；(6)α葡糖苷水解酶抑制劑類，諸如醣祿(acarbose)、脂解素(adiposine)、卡格列波糖(camiglibose)、乙格列酯(emiglitate)、米格列醇(miglitol)、伏格列波糖(voglibose)、帕地黴素Q(pradimicin-Q)、薩保菌素(salbostatin)、CKD-711、MDL-25,637、MDL-73,945及MOR 14，及其類似物；(7)α-澱粉酶抑制劑類，諸如澱粉酶抑肽(tendamistat)、萃他丁(trestatin)及A1-3688，及其類似物；(8)胰島素促泌素類，諸如利諾格列(linogliride)、那格列奈、米格列奈(GLUFAST)、ID1101 A-4166及其類 似物；(9)脂肪酸氧化抑制劑類，諸如氯莫克舍(clomoxir)及乙莫克舍(etomoxir)，及其類似物；(10)A2拮抗劑類，諸如咪格列唑(midaglizole)、伊格列哚(isaglidole)、德格列哚(deriglidole)、咪唑克生(idazoxan)、依諾克生(earoxan)及氟洛克生(fluparoxan)，及其類似物；(11)胰島素或胰島素模擬物類，諸如柏子仁(biota)、LP-100、諾和瑞(novarapid)、地特胰島素(insulin detemir)、賴脯胰島素(insulin lispro)、甘精胰島素(insulin glargine)、胰島素鋅懸浮液(中效胰島素(lente)及長效胰島素(ultralente))、Lys-Pro胰島素、GLP-1(17-36)、GLP-1(73-7)(胰島素調理素(insulintropin))、GLP-1(7-36)-NH2 艾塞那肽/腸促胰島素類似物4(Exendin-4)、艾塞那肽LAR、利拉魯肽、AVE0010、CJC 1131、BIM51077、CS 872、THO318、BAY-694326、GP010、ALBUGON(與白蛋白融合之GLP-1)、HGX-007(Epac促效劑)、S-23521，及WO 04/022004、WO 04/37859中所揭示之化合物，及其類似物；(12)非噻唑啶二酮類，諸如JT-501及法格列紮(farglitazar)(GW-2570/GI-262579)，及其類似物；(13)PPARα/γ雙重促效劑類，諸如AVE 0847、CLX-0940、GW-1536、GW1929、GW-2433、KRP-297、L-796449、LBM 642、LR-90、LY510919、MK-0767、ONO 5129、SB 219994、TAK-559、TAK-654、677954(GlaxoSmithkline)、E-3030(Eisai)、LY510929(Lilly)、AK109(Asahi)、DRF2655(Dr.Reddy)、DRF8351(Dr.Reddy)、MC3002(Maxocore)、TY51501(ToaEiyo)、 法格列紮、那格列紮(naveglitazar)、莫格列紮(muraglitazar)、培格列紮(peliglitazar)、替格列紮(tesaglitazar)(GALIDA)、瑞格列紮(reglitazar)(JT-501)、西格列紮(chiglitazar)，及WO 99/16758、WO 99/19313、WO 99/20614、WO 99/38850、WO 00/23415、WO 00/23417、WO 00/23445、WO 00/50414、WO 01/00579、WO 01/79150、WO 02/062799、WO 03/033481、WO 03/033450、WO 03/033453中所揭示者；及(14)胰島素、胰島素模擬物及其他胰島素增敏藥；(15)VPAC2受體促效劑類；(16)GLK調節劑類，諸如PSN105、RO 281675、RO 274375，及WO 03/015774、WO 03/000262、WO 03/055482、WO 04/046139、WO 04/045614、WO 04/063179、WO 04/063194、WO 04/050645中所揭示者，及其類似物；(17)類視黃素(retinoid)調節劑類，諸如WO 03/000249中所揭示者；(18)GSK 3β/GSK 3抑制劑類，諸如4-[2-(2-溴苯基)-4-(4-氟苯基-1H-咪唑-5-基]吡啶、CT21022、CT20026、CT-98023、SB-216763、SB410111、SB-675236、CP-70949、XD4241，及WO 03/037869、03/03877、03/037891、03/024447、05/000192、05/019218中所揭示之彼等化合物，及其類似物；(19)肝糖磷酸化酶(HGLPa)抑制劑類，諸如AVE 5688、PSN 357、GPi-879，WO 03/037864、WO 03/091213、WO 04/092158、WO 05/013975、WO 05/013981、US 2004/0220229及JP 2004-196702中所揭示者，及其類似物；(20)ATP消耗促進劑類，諸如WO 03/007990中所揭示者；(21)PPARγ促效劑與 二甲雙胍之固定組合，諸如AVANDAMET；(22)PPAR泛促效劑(pan agonist)類，諸如GSK 677954；(23)GPR40(G蛋白偶合受體40)，亦稱為SNORF 55，諸如BG 700，及WO 04/041266、04/022551、03/099793中所揭示者；(24)GPR119(G蛋白偶合受體119，亦稱為RUP3；SNORF 25)，諸如RUP3、HGPRBMY26、PFI 007、SNORF 25；(25)腺苷受體2B拮抗劑類，諸如ATL-618、AT1-802、E3080，及其類似物；(26)肉鹼棕櫚醯基轉移酶抑制劑類，諸如ST 1327及ST 1326，及其類似物；(27)果糖1,6-雙磷酸酯酶抑制劑類，諸如CS-917、MB7803，及其類似物；(28)升糖素(glucagon)拮抗劑類，諸如AT77077、BAY 694326、GW 4123X、NN2501，及WO 03/064404、WO 05/00781、US 2004/0209928、US 2004/029943中所揭示者，及其類似物；(30)葡萄糖-6-磷酸酶抑制劑類；(31)磷酸烯醇丙酮酸羧激酶(PEPCK)抑制劑類；(32)丙酮酸脫氫酶激酶(PDK)活化劑類；(33)RXR促效劑類，諸如MC1036、CS00018、JNJ 10166806，及WO 04/089916、US 6759546中所揭示者，及其類似物；(34)SGLT抑制劑類，諸如AVE 2268、KGT 1251、T1095/RWJ 394718；(35)BLX-1002；(36)α葡糖苷酶抑制劑類；(37)升糖素受體促效劑類；(38)葡萄糖激酶活化劑類；39)GIP-1；40)胰島素促泌素；41)GPR-40促效劑類，諸如TAK-875、5-[4-[[(1R)-4-[6-(3-羥基-3-甲基丁氧基)-2-甲基吡啶-3-基]-2,3-二氫-1H-茚-1-基]氧基]苯基]異噻唑-3-醇1-氧化物、5-(4-((3-(2,6-二甲基-4-(3-(甲 基磺醯基)丙氧基)苯基)苯基)甲氧基)苯基)異噻唑-3-醇1-氧化物、5-(4-((3-(2-甲基-6-(3-羥基丙氧基)吡啶-3-基)-2-甲基苯基)甲氧基)苯基)異噻唑-3-醇1-氧化物，及5-[4-[[3-[4-(3-胺基丙氧基)-2,6-二甲基苯基]苯基]甲氧基]苯基]異噻唑-3-醇1-氧化物，及WO 11/078371中所揭示者。(a) an anti-diabetic agent such as (1) a PPAR gamma agonist such as glitazone (eg, ciglitazone, darglitazone, englitazone, Isaristazone (MCC-555), pioglitazone (ACTOS), rosiglitazone (AVANDIA), troglitazone, rivoglitazone, BRL49653, CLX-0921, 5-BTZD, GW -0207, LG-100641, R483 and LY-300512 and the like, and as disclosed in WO 97/10813, 97/27857, 97/28115, 97/28137, 97/27847, 03/000685 and 03/027112 Compounds, and SPPARMS (selective PPAR gamma modulators), such as T131 (Amgen), FK614 (Fujisawa), napoglitazone, and metaglidasen); (2) biguanides, such as buformin, Metformin and phenformin, and analogs thereof; (3) protein tyrosinate phosphatase 1B (PTP-1B) inhibitors, such as ISIS 113715, A-401674, A-364504, IDD-3, IDD 2846, KP-40046, KR61639, MC52445, MC52453, C7, OC-060062, OC-86839, OC29796, TTP-277BC1, and WO 04/041799, 04/050646, 02/26707, 02/26743, 04/092146, 03/ 048140, And their agents disclosed in 04/089918, 03/002569, 04/065387, 04/127570, and US 2004/167183; (4) sulfonylureas, such as acetohexamide, chlorine Chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, Glitnoteide, gliquidone, glisolamide, tolazamide, and tolbutamide, and analogs thereof; (5) meltelidine ( Meglitinide), such as repaglinide, metiglinide (GLUFAST) and nateglinide, and analogues thereof; (6) alpha glucoside hydrolase inhibitors, such as Acarbose, adiposine, camiglibose, emiglitate, miglitol, voglibose, dispalatus Pradimicin-Q, salbostatin, CKD-711, MDL-25,637, MDL-73,945 and MOR 14, and their analogues; (7) alpha-amylase inhibitors, such as amylase Suppress (tendamistat), trestatin and A1-3688, and analogues thereof; (8) insulin secretagogues such as linogliride, nateglinide, mitiglinide (GLUFAST) , ID1101 A-4166 and its analogs; (9) fatty acid oxidation inhibitors, such as clomoxir and etomoxir, and analogs thereof; (10) A2 antagonists, such as Midaglizole, isaglidole, deriglidole, idazoxan, earoxan, and fluparoxan, and the like (11) Insulin or insulin mimics such as biota, LP-100, novarapid, insulin detemir, insulin lispro, insulin glinc (insulin) Glargine), zinc suspension of insulin (lente and long-acting insulin), Lys-Pro insulin, GLP-1 (17-36), GLP-1 (73-7) (insulin opsonin ( insulintropin)), GLP-1 ( 7-36) -NH 2 exenatide / exenatide 4 (exendin-4), exenatide LAR, liraglutide, AVE0010, CJC 1131, BIM51 077, CS 872, THO318, BAY-694326, GP010, ALBUGON (GLP-1 fused to albumin), HGX-007 (Epac agonist), S-23521, and WO 04/022004, WO 04/37859 Compounds disclosed, and analogs thereof; (12) non-thiazolidinediones such as JT-501 and farglitazar (GW-2570/GI-262579), and analogs thereof; (13) PPARα/γ dual agonists, such as AVE 0847, CLX-0940, GW-1536, GW1929, GW-2433, KRP-297, L-796449, LBM 642, LR-90, LY510919, MK-0767, ONO 5129 , SB 219994, TAK-559, TAK-654, 677954 (GlaxoSmithkline), E-3030 (Eisai), LY510929 (Lilly), AK109 (Asahi), DRF2655 (Dr. Reddy), DRF8351 (Dr. Reddy), MC3002 ( Maxocore), TY51501 (ToaEiyo), Fagliza, naveglitazar, mugligliza, peliglitazar, tesaglitazar (GALIDA), Reggae Reglitazar (JT-501), chiglitazar, and WO 99/16758, WO 99/19313, WO 99/20614, WO 99/38850, WO 00/23415, WO 00/23417, WO 00/23445, WO 00/50414, WO 01/00579, WO 01/79150, WO 02/0 62799, WO 03/033481, WO 03/033450, WO 03/033453; and (14) insulin, insulin mimetic and other insulin sensitizers; (15) VPAC2 receptor agonist; (16) GLK modulators, such as PSN105, RO 281675, RO 274375, and WO 03/015774, WO 03/000262, WO 03/055482, WO 04/046139, WO 04/045614, WO 04/063179, WO 04/063194 , as disclosed in WO 04/050645, and analogs thereof; (17) retinoid-modulating agents, such as those disclosed in WO 03/000249; (18) GSK 3β/GSK 3 inhibitors , such as 4-[2-(2-bromophenyl)-4-(4-fluorophenyl-1H-imidazol-5-yl]pyridine, CT21022, CT20026, CT-98023, SB-216763, SB410111, SB- 675236, CP-70949, XD4241, and their compounds disclosed in WO 03/037869, 03/03877, 03/037891, 03/024447, 05/000192, 05/019218, and the like; (19) liver Sugar phosphorylase (HGLPa) inhibitors, such as AVE 5688, PSN 357, GPi-879, WO 03/037864, WO 03/091213, WO 04/092158, WO 05/013975, WO 05/013981, US 2004/ 0220229 and JP 2004-196702, and their analogues; (20) ATP Consumption promoters, such as those disclosed in WO 03/007990; (21) a fixed combination of a PPAR gamma agonist with metformin, such as AVANDAMET; (22) a PPAR pan agonist, such as GSK 677954; 23) GPR40 (G protein coupled receptor 40), also known as SNORF 55, such as BG 700, and those disclosed in WO 04/041266, 04/022551, 03/099793; (24) GPR119 (G protein coupled receptor) 119, also known as RUP3; SNORF 25), such as RUP3, HGPRBMY26, PFI 007, SNORF 25; (25) adenosine receptor 2B antagonists, such as ATL-618, AT1-802, E3080, and analogs thereof; (26) carnitine palmitoyl transferase inhibitors such as ST 1327 and ST 1326, and analogs thereof; (27) fructose 1,6-bisphosphatase inhibitors such as CS-917, MB7803, and An analogue thereof; (28) a glucagon antagonist such as AT77077, BAY 694326, GW 4123X, NN2501, and WO 03/064404, WO 05/00781, US 2004/0209928, US 2004/029943 Revealers, and their analogs; (30) glucose-6-phosphatase inhibitors; (31) phosphoenolpyruvate carboxykinase (PEPCK) inhibitors; (32) pyruvate dehydrogenase kinase (PDK) live (33) RXR agonists, such as MC1036, CS00018, JNJ 10166806, and those disclosed in WO 04/089916, US 6,759,546, and analogs thereof; (34) SGLT inhibitors, such as AVE 2268 , KGT 1251, T1095/RWJ 394718; (35) BLX-1002; (36) alpha glucosidase inhibitors; (37) glucomannin receptor agonists; (38) glucokinase activators; GIP-1; 40) insulin secretagogue; 41) GPR-40 agonist, such as TAK-875, 5-[4-[[(1R)-4-[6-(3-hydroxy-3-) Methylbutoxy)-2-methylpyridin-3-yl]-2,3-dihydro-1H-indol-1-yl]oxy]phenyl]isothiazol-3-ol 1-oxide, 5-(4-((3-(2,6-Dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)phenyl)methoxy)phenyl)isothiazole- 3-alcohol 1-oxide, 5-(4-((3-(2-methyl-6-(3-hydroxypropoxy)pyridin-3-yl)-2-methylphenyl)methoxy) Phenyl)isothiazol-3-ol 1-oxide, and 5-[4-[[3-[4-(3-aminopropoxy)-2,6-dimethylphenyl]phenyl Methoxy]phenyl]isothiazol-3-ol 1-oxide, and as disclosed in WO 11/078371.

(b)抗血脂異常劑，諸如(1)膽汁酸錯隔劑類，諸如消膽胺(cholestyramine)、考來維侖(colesevelem)、考來替潑(colestipol)、交聯聚葡萄糖之二烷基胺基烷基衍生物、Colestid®、LoCholest®及Questran®，及其類似物；(2)HMG-CoA還原酶抑制劑類，諸如阿托伐他汀、伊伐他汀、匹伐他汀(pitavastatin)、氟伐他汀、洛伐他汀、普伐他汀、立伐他汀、辛伐他汀、羅素他汀(ZD-4522)及其他他汀(statin)類，尤其辛伐他汀；(3)HMG-CoA合成酶抑制劑類；(4)膽固醇吸收抑制劑類，諸如FMVP4(Forbes Medi-Tech)、KT6-971(Kotobuki Pharmaceutical)、FM-VA12(Forbes Medi-Tech)、FM-VP-24(Forbes Medi-Tech)、固烷醇酯、β-植固醇(beta-sitosterol)、固醇醣苷(諸如替奎安)及氮雜環丁酮(諸如依折麥布)，及WO 04/005247中所揭示者，及其類似物；(5)醯基輔酶A-膽固醇醯基轉移酶(ACAT)抑制劑類，諸如阿伐麥布、依魯麥布(eflucimibe)、帕替麥布(pactimibe)(KY505)、SMP 797(Sumitomo)、SM32504(Sumitomo)，及WO 03/091216中所揭示者，及其類似物；(6)CETP抑制劑類，諸如安特普、JTT 705(Japan Tobacco)、托徹普、CP 532,632、BAY63-2149(Bayer)、SC 591、SC 795及其類 似物；(7)角鯊烯合成酶抑制劑類；(8)抗氧化劑類，諸如普羅布可(probucol)及其類似物；(9)PPARα促效劑類，諸如苄氯貝特(beclofibrate)、苯紮貝特(bezafibrate)、環丙貝特(ciprofibrate)、氯貝特(clofibrate)、依託貝特(etofibrate)、非諾貝特(fenofibrate)、吉卡賓(gemcabene)及吉非羅齊(gemfibrozil)、GW 7647、BM 170744(Kowa)、LY518674(Lilly)、GW590735(GlaxoSmithkline)、KRP-101(Kyorin)、DRF10945(Dr.Reddy)、NS-220/R1593(Nippon Shinyaku/Roche)、ST1929(Sigma Tau)、MC3001/MC3004(MaxoCore Pharmaceuticals)、吉卡賓鈣(gemcabene calcium)、其他纖維酸衍生物(諸如Atromid®、Lopid®及Tricor®)，及US 6,548,538中所揭示者，及其類似物；(10)FXR受體調節劑類，諸如GW 4064(GlaxoSmithkline)、SR 103912、QRX401、LN-6691(Lion Bioscience)，及WO 02/064125、WO 04/045511中所揭示者，及其類似物；(11)LXR受體調節劑類，諸如GW 3965(GlaxoSmithkline)、T9013137及XTCO179628(X-Ceptor Therapeutics/Sanyo)，及WO 03/031408、WO 03/063796、WO 04/072041中所揭示者，及其類似物；(12)脂蛋白合成酶抑制劑類，諸如菸酸；(13)腎素血管收縮素系統抑制劑類；(14)PPARδ部分促效劑類，諸如WO 03/024395中所揭示者；(15)膽汁酸再吸收抑制劑類，諸如BARI 1453、SC435、PHA384640、S8921、AZD7706及其類似物；及膽汁酸錯隔劑類，諸如考來維侖(WELCHOL/CHOLESTAGEL)、考來替潑、消膽胺，及交聯聚葡萄糖之二烷基胺基烷基 衍生物；(16)PPARδ促效劑類，諸如GW 501516(Ligand,GSK)、GW 590735、GW-0742(GlaxoSmithkline)、T659(Amgen/Tularik)、LY934(Lilly)、NNC610050(Novo Nordisk)，以及WO 97/28149、WO 01/79197、WO 02/14291、WO 02/46154、WO 02/46176、WO 02/076957、WO 03/016291、WO 03/033493、WO 03/035603、WO 03/072100、WO 03/097607、WO 04/005253、WO 04/007439及JP10237049中所揭示者，及其類似物；(17)三酸甘油酯合成抑制劑類；(18)微粒體三酸甘油酯轉運(MTTP)抑制劑類，諸如英普他派(implitapide)、LAB687、JTT130(Japan Tobacco)、CP346086，及WO 03/072532中所揭示者，及其類似物；(19)轉錄調節劑類；(20)角鯊烯環氧酶抑制劑類；(21)低密度脂蛋白(LDL)受體誘導劑類；(22)血小板凝集抑制劑類；(23)5-LO或FLAP抑制劑類；及(24)菸酸受體促效劑類，包括HM74A受體促效劑；(25)PPAR調節劑類，諸如WO 01/25181、WO 01/79150、WO 02/79162、WO 02/081428、WO 03/016265、WO 03/033453中所揭示者；(26)菸酸結合之鉻，如WO 03/039535中所揭示；(27)經取代之酸衍生物，如WO 03/040114中所揭示；(28)輸注型HDL，諸如LUV/ETC-588(Pfizer)、APO-A1 Milano/ETC216(Pfizer)、ETC-642(Pfizer)、ISIS301012、D4F(Bruin Pharma)、合成三聚ApoA1、靶向泡沫細胞之Bioral Apo A1，及其類似物；(29)IBAT抑制劑類，諸如BARI143/HMR145A/HMR1453(Sanofi-Aventis)、PHA384640E(Pfizer)、S8921(Shionogi)、 AZD7806(AstrZeneca)、AK105(Asah Kasei)，及其類似物；(30)Lp-PLA2抑制劑類，諸如SB480848(GlaxoSmithkline)、659032(GlaxoSmithkline)、677116(GlaxoSmithkline)，及其類似物；(31)影響脂質組成之其他藥劑，包括ETC1001/ESP31015(Pfizer)、ESP-55016(Pfizer)、AGI1067(AtheroGenics)、AC3056(Amylin)、AZD4619(AstrZeneca)；及 (c)抗高血壓劑，諸如(1)利尿劑類，諸如噻嗪類(thiazide)，包括氯噻酮(chlorthalidone)、氯噻嗪(chlorthiazide)、二氯苯磺胺(dichlorophenamide)、氫氟噻嗪(hydroflumethiazide)、吲達帕胺(indapamide)及氫氯噻嗪(hydrochlorothiazide)；亨氏環利尿劑(loop diuretic)，諸如布美他尼(bumetanide)、利尿酸(ethacrynic acid)、呋喃苯胺酸(furosemide)及托西邁(torsemide)；鉀助減劑(potassium sparing agent)，諸如阿米洛利(amiloride)及胺苯喋啶(triamterene)；及醛固酮拮抗劑，諸如螺內酯(spironolactone)、依普利酮(epirenone)及其類似物；(2)β-腎上腺素激導性阻斷劑類，諸如醋丁洛爾(acebutolol)、阿替洛爾(atenolol)、倍他洛爾(betaxolol)、貝凡洛爾(bevantolol)、比索洛爾(bisoprolol)、波吲洛爾(bopindolol)、卡替洛爾(carteolol)、卡維地洛(carvedilol)、塞利洛爾(celiprolol)、艾司洛爾(esmolol)、茚諾洛爾(indenolol)、美托洛爾(metaprolol)、納多洛爾(nadolol)、奈必洛爾(nebivolol)、噴布洛爾(penbutolol)、品多洛爾(pindolol)、普萘洛爾(propanolol)、索他洛爾(sotalol)、特他洛爾(tertatolol)、替利洛爾(tilisolol)及噻嗎洛爾(timolol)， 及其類似物；(3)鈣通道阻斷劑類，諸如胺氯地平(amlodipine)、阿雷地平(aranidipine)、阿折地平(azelnidipine)、巴尼地平(barnidipine)、貝尼地平(benidipine)、苄普地爾(bepridil)、西尼地平(cinaldipine)、氯維地平(clevidipine)、地爾硫卓(diltiazem)、依福地平(efonidipine)、非洛地平(felodipine)、戈洛帕米(gallopamil)、伊拉地平(isradipine)、拉西地平(lacidipine)、來米地平(lemildipine)、樂卡地平(lercanidipine)、尼卡地平(nicardipine)、硝苯地平(nifedipine)、尼伐地平(nilvadipine)、尼莫地平(nimodepine)、尼索地平(nisoldipine)、尼群地平(nitrendipine)、馬尼地平(manidipine)、普拉地平(pranidipine)及維拉帕米(verapamil)，及其類似物；(4)血管收縮素轉化酶(ACE)抑制劑類，諸如貝那普利(benazepril)、卡托普利(captopril)、西拉普利(cilazapril)、地拉普利(delapril)、依拉普利(enalapril)、福辛普利(fosinopril)、咪達普利(imidapril)、賴諾普利(losinopril)、莫西普利(moexipril)、喹那普利(quinapril)、喹普利拉(quinaprilat)、雷米普利(ramipril)、培哚普利(perindopril)、哌多普利(perindropril)、喹尼普利(quanipril)、螺普利(spirapril)、替諾普利(tenocapril)、群多普利(trandolapril)及佐芬普利(zofenopril)，及其類似物；(5)中性肽鏈內切酶抑制劑類，諸如奧馬曲拉(omapatrilat)、坎沙曲(cadoxatril)及依卡曲爾(ecadotril)、法西多曲(fosidotril)、山帕曲拉(sampatrilat)、AVE7688、ER4030及其類似物；(6)內皮素(endothelin)拮抗劑類，諸如替唑生坦(tezosentan)、 A308165及YM62899，及其類似物；(7)血管舒張劑類，諸如肼屈嗪(hydralazine)、可樂寧(clonidine)、敏樂定(minoxidil)及菸鹼醇(nicotinyl alcohol)、菸鹼酸(nicotinic acid)或其鹽，及其類似物；(8)血管緊張素II受體拮抗劑類，諸如坎地沙坦(candesartan)、依普羅沙坦(eprosartan)、厄貝沙坦(irbesartan)、洛沙坦(losartan)、普拉沙坦(pratosartan)、他索沙坦(tasosartan)、替米沙坦(telmisartan)、纈沙坦(valsartan)及EXP-3137、FI6828K及RNH6270，及其類似物；(9)α/β腎上腺素激導性阻斷劑類，如尼普洛爾(nipradilol)、阿羅洛爾(arotinolol)及胺磺洛爾(amosulalol)，及其類似物；(10)α1阻斷劑類，諸如特拉唑嗪(terazosin)、烏拉地爾(urapidil)、哌唑嗪(prazosin)、布那唑嗪(bunazosin)、曲馬唑嗪(trimazosin)、多沙唑嗪(doxazosin)、萘哌地爾(naftopidil)、吲哚哌胺(indoramin)、WHIP 164及XEN010，及其類似物；(11)α2促效劑類，諸如洛非西定(lofexidine)、噻美尼定(tiamenidine)、莫索尼定(moxonidine)、利美尼定(rilmenidine)及胍那苄(guanobenz)，及其類似物；(12)醛固酮抑制劑及其類似物；(13)血管生成素-2結合劑(angiopoietin-2-binding agent)類，諸如WO 03/030833中所揭示者；及 (d)抗肥胖劑，諸如(1)5HT(血清素)轉運體抑制劑類，諸如帕羅西汀(paroxetine)、氟西汀(fluoxetine)、氟苯丙胺(fenfluramine)、氟伏沙明(fluvoxamine)、含曲林(sertraline)及丙咪嗪(imipramine)，及WO 03/00663中所揭示者；以及 血清素/去甲腎上腺素再吸收抑制劑類，諸如西布曲明(sibutramine)(MERIDIA/REDUCTIL)；及多巴胺吸收抑制劑/去甲腎上腺素吸收抑制劑，諸如鹽酸雷達法辛(radafaxine hydrochloride)、353162(GlaxoSmithkline)及其類似物；(2)NE(去甲腎上腺素)轉運體抑制劑類，諸如GW 320659、地昔帕明(despiramine)、他舒普侖(talsupram)及諾米芬辛(nomifensine)；(3)CB1(類大麻酚-1受體)拮抗劑/反向促效劑類，諸如泰倫那班(taranabant)、利莫那班(rimonabant)(ACCOMPLIA Sanofi Synthelabo)、SR-147778(Sanofi Synthelabo)、AVE1625(Sanofi-Aventis)、BAY 65-2520(Bayer)、SLV 319(Solvay)、SLV326(Solvay)、CP945598(Pfizer)、E-6776(Esteve)、O1691(Organix)、ORG14481(Organon)、VER24343(Vernalis)、NESS0327(Univ of Sassari/Univ of Cagliari)，及美國專利第4,973,587號、第5,013,837號、第5,081,122號、第5,112,820號、第5,292,736號、第5,532,237號、第5,624,941號、第6,028,084號及第6,509367號，及WO 96/33159、WO 97/29079、WO 98/31227、WO 98/33765、WO 98/37061、WO 98/41519、WO 98/43635、WO 98/43636、WO 99/02499、WO 00/10967、WO 00/10968、WO 01/09120、WO 01/58869、WO 01/64632、WO 01/64633、WO 01/64634、WO 01/70700、WO 01/96330、WO 02/076949、WO 03/006007、WO 03/007887、WO 03/020217、WO 03/026647、WO 03/026648、WO 03/027069、WO 03/027076、WO 03/027114、WO 03/037332、WO 03/040107、WO 04/096763、 WO 04/111039、WO 04/111033、WO 04/111034、WO 04/111038、WO 04/013120、WO 05/000301、WO 05/016286、WO 05/066126及EP-658546中所揭示者，及其類似物；(4)胃內激素(ghrelin)促效劑/拮抗劑類，諸如BVT81-97(BioVitrum)、RC1291(Rejuvenon)、SRD-04677(Sumitomo)、未醯化胃內激素(TheraTechnologies)，及WO 01/87335、WO 02/08250、WO 05/012331中所揭示者，及其類似物；(5)H3(組織胺H3)拮抗劑/反向促效劑類，諸如硫丙咪胺(thioperamide)、N-(4-戊烯基)胺基甲酸3-(1H-咪唑-4-基)丙酯、氯苄普特(clobenpropit)、碘苯普特(iodophenpropit)、莫普西凡(imoproxifan)、GT2394(Gliatech)及A331440，及WO 02/15905中所揭示者，及O-[3-(1H-咪唑-4-基)丙醇]胺基甲酸酯(Kiec-Kononowicz,K.等人，Pharmazie,55：349-55(2000))、含哌啶之組織胺H3受體拮抗劑(Lazewska,D.等人，Pharmazie,56：927-32(2001))、二苯甲酮衍生物及相關化合物(Sasse,A.等人，Arch.Pharm.(Weinheim)334：45-52(2001))、經取代之N-苯基胺基甲酸酯(Reidemeister,S.等人，Pharmazie,55：83-6(2000))，及普西凡(proxifan)衍生物(Sasse,A.等人，J.Med.Chem..43：3335-43(2000))，及組織胺H3受體調節劑，諸如WO 03/024928及WO 03/024929中所揭示者；(6)黑色素濃集激素1受體(MCH1R)拮抗劑類，諸如T-226296(Takeda)、T71(Takeda/Amgen)、AMGN-608450、AMGN-503796(Amgen)、856464(GlaxoSmithkline)、A224940(Abbott)、A798(Abbott)、ATC0175/AR224349(Arena Pharmaceuticals)、GW803430(GlaxoSmithkline)、NBI-1A(Neurocrine Biosciences)、NGX-1(Neurogen)、SNP-7941(Synaptic)、SNAP9847(Synaptic)、T-226293(Schering Plough)、TPI-1361-17(Saitama Medical School/University of California Irvine)，及WO 01/21169、WO 01/82925、WO 01/87834、WO 02/051809、WO 02/06245、WO 02/076929、WO 02/076947、WO 02/04433、WO 02/51809、WO 02/083134、WO 02/094799、WO 03/004027、WO 03/13574、WO 03/15769、WO 03/028641、WO 03/035624、WO 03/033476、WO 03/033480、WO 04/004611、WO 04/004726、WO 04/011438、WO 04/028459、WO 04/034702、WO 04/039764、WO 04/052848、WO 04/087680，及日本專利申請案第JP 13226269號、第JP 1437059號、第JP 2004315511號中所揭示者，及其類似物；(7)MCH2R(黑色素濃集激素2R)促效劑/拮抗劑類；(8)NPY1(神經肽Y Y1)拮抗劑類，諸如BMS205749、BIBP3226、J-115814、BIBO 3304、LY-357897、CP-671906及GI-264879A，及美國專利第6,001,836號以及WO 96/14307、WO 01/23387、WO 99/51600、WO 01/85690、WO 01/85098、WO 01/85173及WO 01/89528中所揭示者；(9)NPY5(神經肽Y Y5)拮抗劑類，諸如152,804、S2367(Shionogi)、E-6999(Esteve)、GW-569180A、GW-594884A(GlaxoSmithkline)、GW-587081X、GW-548118X、FR 235,208、FR226928、FR 240662、FR252384、1229U91、GI-264879A、CGP71683A、C-75(Fasgen)、LY- 377897、LY366377、PD-160170、SR-120562A、SR-120819A、S2367(Shionogi)、JCF-104及H409/22，及美國專利第6,140,354號、第6,191,160號、第6,258,837號、第6,313,298號、第6,326,375號、第6,329,395號、第6,335,345號、第6,337,332號、第6,329,395號及第6,340,683號，及EP-01010691、EP-01044970及FR252384，及PCT公開案第WO 97/19682號、第WO 97/20820號、第WO 97/20821號、第WO 97/20822號、第WO 97/20823號、第WO 98/27063號、第WO 00/107409號、第WO 00/185714號、第WO 00/185730號、第WO 00/64880號、第WO 00/68197號、第WO 00/69849號、第WO 01/09120號、第WO 01/14376號、第WO 01/85714號、第WO 01/85730號、第WO 01/07409號、第WO 01/02379號、第WO 01/02379號、第WO 01/23388號、第WO 01/23389號、第WO 01/44201號、第WO 01/62737號、第WO 01/62738號、第WO 01/09120號、第WO 02/20488號、第WO 02/22592號、第WO 02/48152號、第WO 02/49648號、第WO 02/051806號、第WO 02/094789號、第WO 03/009845號、第WO 03/014083號、第WO 03/022849號、第WO 03/028726號、第WO 05/014592號、第WO 05/01493號，及Norman等人，J.Med.Chem.43：4288-4312(2000)中所揭示之彼等化合物；(10)瘦素(leptin)，諸如重組人類瘦素(PEG-OB，Hoffman La Roche)及重組甲硫胺醯基人類瘦素(Amgen)；(11)瘦素衍生物，諸如專利第5,552,524號、第5,552,523號、第5,552,522號、第5,521,283號，及WO 96/23513、 WO 96/23514、WO 96/23515、WO 96/23516、WO 96/23517、WO 96/23518、WO 96/23519及WO 96/23520中所揭示者；(12)類鴉片(opioid)拮抗劑類，諸如納美芬(nalmefene)(Revex®)、3-甲氧基納曲酮(3-methoxynaltrexone)、納洛酮(naloxone)及納曲酮(naltrexone)，及WO 00/21509中所揭示者；(13)食慾激素受體(orexin)拮抗劑，諸如SB-334867-A(GlaxoSmithkline)，及WO 01/96302、01/68609、02/44172、02/51232、02/51838、02/089800、02/090355、03/023561、03/032991、03/037847、04/004733、04/026866、04/041791、04/085403中所揭示者，及其類似物；(14)BRS3(鈴蟾素(bombesin)受體亞型3)促效劑類；(15)CCK-A(膽囊收縮素-A(cholecystokinin-A))促效劑類，諸如AR-R 15849、GI 181771、JMV-180、A-71378、A-71623、PD170292、PD 149164、SR146131、SR125180、布他濱地(butabindide)，及US 5,739,106中所揭示者；(16)CNTF(睫狀神經營養因子(ciliary neurotrophic factor))，諸如GI-181771(Glaxo-SmithKline)、SR146131(Sanofi Synthelabo)、布他濱地及PD170,292、PD 149164(Pfizer)；(17)CNTF衍生物類，諸如阿索開(axokine)(Regeneron)，及WO 94/09134、WO 98/22128及WO 99/43813中所揭示者；(18)GHS(生長激素促泌素受體)促效劑類，諸如NN703、海沙瑞林(hexarelin)、MK-0677、SM-130686、CP-424,391、L-692,429及L-163,255，及美國專利第6358951號、美國專利申請案第2002/049196號及第2002/022637號，及WO 01/56592及WO 02/32888中 所揭示者；(19)5HT2c(血清素受體2c)促效劑類，諸如APD3546/AR10A(Arena Pharmaceuticals)、ATH88651(Athersys)、ATH88740(Athersys)、BVT933(Biovitrum/GSK)、DPCA37215(BMS)、IK264、LY448100(Lilly)、PNU 22394、WAY 470(Wyeth)、WAY629(Wyeth)、WAY161503(Biovitrum)、R-1065、VR1065(Vernalis/Roche)、YM 348，及美國專利第3,914,250號，及PCT公開案01/66548、02/36596、02/48124、02/10169、02/44152、02/51844、02/40456、02/40457、03/057698、05/000849中所揭示者，及其類似物；(20)Mc3r(黑皮素3受體(melanocortin 3 receptor))促效劑類；(21)Mc4r(黑皮素4受體)促效劑類，諸如CHIR86036(Chiron)、CHIR915(Chiron)、ME-10142(Melacure)、ME-10145(Melacure)、HS-131(Melacure)、NBI72432(Neurocrine Biosciences)、NNC 70-619(Novo Nordisk)、TTP2435(Transtech)，及PCT公開案WO 99/64002、00/74679、01/991752、01/0125192、01/52880、01/74844、01/70708、01/70337、01/91752、01/010842、02/059095、02/059107、02/059108、02/059117、02/062766、02/069095、02/12166、02/11715、02/12178、02/15909、02/38544、02/068387、02/068388、02/067869、02/081430、03/06604、03/007949、03/009847、03/009850、03/013509、03/031410、03/094918、04/028453、04/048345、04/050610、04/075823、04/083208、04/089951、05/000339，及EP 1460069及US 2005049269及JP 2005042839中所揭示者，及其類似物；(22)單胺再吸收 抑制劑類，諸如西布曲明(Meridia®/Reductil®)及其鹽，及美國專利第4,746,680號、第4,806,570號及第5,436,272號，及美國專利公開案第2002/0006964號，及WO 01/27068及WO 01/62341中所揭示之彼等化合物；(23)血清素再吸收抑制劑類，諸如右旋氟苯丙胺(dexfenfluramine)、氟西汀，以及美國專利第6,365,633號，及WO 01/27060及WO 01/162341中所揭示者；(24)GLP-1(升糖素樣肽1)促效劑類；(25)托吡酯(Topiramate)(Topimax®)；(26)植物藥理學化合物57(phytopharm compound 57)(CP 644,673)；(27)ACC2(乙醯基-CoA羧基酶-2)抑制劑類；(28)β3(β腎上腺素激導性受體3)促效劑類，諸如拉非貝隆(rafebergron)/AD9677/TAK677(Dainippon/Takeda)、CL-316,243、SB 418790、BRL-37344、L-796568、BMS-196085、BRL-35135A、CGP12177A、BTA-243、GRC1087(Glenmark Pharmaceuticals)、GW 427353(鹽酸索拉貝隆(solabegron hydrochloride))、Trecadrine、Zeneca D7114、N-5984(Nisshin Kyorin)、LY-377604(Lilly)、KT07924(Kissei)、SR 59119A，及美國專利第5,705,515號、第US 5,451,677號，及WO 94/18161、WO 95/29159、WO 97/46556、WO 98/04526WO 98/32753、WO 01/74782、WO 02/32897、WO 03/014113、WO 03/016276、WO 03/016307、WO 03/024948、WO 03/024953、WO 03/037881、WO 04/108674中所揭示者，及其類似物；(29)DGAT1(二醯甘油醯基轉移酶1)抑制劑類；(30)DGAT2(二醯甘油醯基轉移酶2)抑制劑類；(31) FAS(脂肪酸合成酶)抑制劑類，諸如淺藍菌素(Cerulenin)及C75；(32)PDE(磷酸二酯酶)抑制劑類，諸如茶鹼(theophylline)、己酮可可鹼(pentoxifylline)、紮普司特(zaprinast)、西地那非(sildenafil)、胺利酮(amrinone)、米利酮(milrinone)、西洛他胺(cilostamide)、咯利普蘭(rolipram)及西洛司特(cilomilast)，以及WO 03/037432、WO 03/037899中所述者；(33)甲狀腺激素β促效劑類，諸如KB-2611(KaroBioBMS)，及WO 02/15845及日本專利申請案第JP 2000256190號中所揭示者；(34)UCP-1(解偶合蛋白1)、UCP-2或UCP-3活化劑類，諸如植烷酸(phytanic acid)、4-[(E)-2-(5,6,7,8-四氫-5,5,8,8-四甲基-2-萘基)-1-丙氧基]苯甲酸(TTNPB)及視黃酸(retinoic acid)，及WO 99/00123中所揭示者；(35)醯基雌激素類，諸如del Mar-Grasa,M.等人，Obesity Research,9：202-9(2001)中所揭示之油醯基雌酮(oleoyl-estrone)；(36)糖皮質激素受體拮抗劑類，諸如CP472555(Pfizer)、KB 3305，及WO 04/000869、WO 04/075864中所揭示者，及其類似物；(37)11β HSD-1(11-β羥基類固醇脫氫酶1型)抑制劑類，諸如BVT 3498(AMG 331)、BVT 2733、3-(1-金剛烷基)-4-乙基-5-(乙硫基)-4H-1,2,4-三唑、3-(1-金剛烷基)-5-(3,4,5-三甲氧基苯基)-4-甲基-4H-1,2,4-三唑、3-金剛烷基-4,5,6,7,8,9,10,11,12,3a-十氫-1,2,4-三唑并[4,3-a][11]輪烯，及WO 01/90091、01/90090、01/90092、02/072084、04/011410、04/033427、04/041264、04/027047、04/056744、04/065351、04/089415、 04/037251中所揭示之彼等化合物，及其類似物；(38)SCD-1(硬脂醯基-CoA去飽和酶-1)抑制劑類；(39)二肽基肽酶IV(DPP-4)抑制劑類，諸如異白胺酸噻唑啶(isoleucine thiazolidide)、纈胺酸吡咯啶(valine pyrrolidide)、西他列汀(Januvia)、沙格列汀(saxagliptin)、阿格列汀(alogliptin)、NVP-DPP728、LAF237(維格列汀(vildagliptin))、P93/01、TSL 225、TMC-2A/2B/2C、FE 999011、P9310/K364、VIP 0177、SDZ 274-444、GSK 823093、E 3024、SYR 322、TS021、SSR 162369、GRC 8200、K579、NN7201、CR 14023、PHX 1004、PHX 1149、PT-630、SK-0403，及WO 02/083128、WO 02/062764、WO 02/14271、WO 03/000180、WO 03/000181、WO 03/000250、WO 03/002530、WO 03/002531、WO 03/002553、WO 03/002593、WO 03/004498、WO 03/004496、WO 03/005766、WO 03/017936、WO 03/024942、WO 03/024965、WO 03/033524、WO 03/055881、WO 03/057144、WO 03/037327、WO 04/041795、WO 04/071454、WO 04/0214870、WO 04/041273、WO 04/041820、WO 04/050658、WO 04/046106、WO 04/067509、WO 04/048532、WO 04/099185、WO 04/108730、WO 05/009956、WO 04/09806、WO 05/023762、US 2005/043292及EP 1 258 476中所揭示之化合物；(40)脂肪酶抑制劑類，諸如四氫利普司他汀(tetrahydrolipstatin)(奧利司他(orlistat)/XENICAL)、ATL962(Alizyme/Takeda)、GT389255(Genzyme/Peptimmune)、Triton WR1339、RHC80267、利普司他汀(lipstatin)、茶皂 素(teasaponin)及二乙基香豆素磷酸酯(diethylumbelliferyl phosphate)、FL-386、WAY-121898、Bay-N-3176、纈胺內酯(valilactone)、厄斯特欣(esteracin)、厄比內酯A(ebelactone A)、厄比內酯B(ebelactone B)及RHC 80267，及WO 01/77094、WO 04/111004及美國專利第4,598,089號、第4,452,813號、第5,512,565號、第5,391,571號、第5,602,151號、第4,405,644號、第4,189,438號及第4,242,453中所揭示者，及其類似物；(41)脂肪酸轉運體抑制劑類；(42)二羧酸轉運體抑制劑類；(43)葡萄糖轉運體抑制劑類；及(44)磷酸轉運體抑制劑類；(45)食慾抑制雙環化合物類，諸如1426(Aventis)及1954(Aventis)，及WO 00/18749、WO 01/32638、WO 01/62746、WO 01/62747及WO 03/015769中所揭示之化合物；(46)肽YY及PYY促效劑類，諸如PYY336(Nastech/Merck)、AC162352(IC Innovations/Curis/Amylin)、TM30335/TM30338(7TM Pharma)、PYY336(Emisphere Tehcnologies)、聚乙二醇化肽YY3-36，WO 03/026591、04/089279中所揭示者，及其類似物；(47)脂質代謝調節劑類，諸如山楂酸(maslinic acid)、高根二醇(erythrodiol)、熊果酸(ursolic acid)、熊果醇(uvaol)、樺木酸(betulinic acid)、樺木腦(betulin)及其類似物，及WO 03/011267中所揭示之化合物；(48)轉錄因子調節劑類，諸如WO 03/026576中所揭示者；(49)Mc5r(黑皮素5受體)調節劑類，諸如WO 97/19952、WO 00/15826、WO 00/15790、US 20030092041中所揭示者，及其類似物；(50)腦源性神經營 養因子(BDNF)；(51)Mc1r(黑皮素1受體調節劑)，諸如LK-184(Proctor & Gamble)及其類似物；(52)5HT6拮抗劑類，諸如BVT74316(BioVitrum)、BVT5182c(BioVitrum)、E-6795(Esteve)、E-6814(Esteve)、SB399885(GlaxoSmithkline)、SB271046(GlaxoSmithkline)、RO-046790(Roche)及其類似物；(53)脂肪酸轉運蛋白4(FATP4)；(54)乙醯基-CoA羧基酶(ACC)抑制劑類，諸如CP640186、CP610431、CP640188(Pfizer)；(55)C末端生長激素片段類，諸如AOD9604(Monash Univ/Metabolic Pharmaceuticals)及其類似物；(56)調酸素(oxyntomodulin)；(57)神經肽FF受體拮抗劑類，諸如WO 04/083218中所揭示者，及其類似物；(58)澱粉素(amylin)促效劑類，諸如斯美林(Symlin)/普蘭林肽(pramlintide)/AC137(Amylin)；(59)蝴蝶亞仙人掌(Hoodia)及佛頭玉仙人掌(trichocaulon)提取物類；(60)BVT74713及其他腸脂質食慾抑制劑類；(61)多巴胺促效劑類，諸如布普品(bupropion)(WELLBUTRIN/GlaxoSmithkline)；(62)唑尼沙胺(zonisamide)(ZONEGRAN/Dainippon/Elan)，及其類似物；及 (e)適於與本發明化合物組合使用之食慾抑制劑包括(但不限於)阿米雷斯(aminorex)、安非克羅拉(amphechloral)、安非他命(amphetamine)、苄非他明(benzphetamine)、氯苯丁胺(chlorphentermine)、氯苄雷司(clobenzorex)、氯福雷司(cloforex)、氯胺雷司(clominorex)、氯特胺(clortermine)、塞可啶(cyclexedrine)、右旋氟苯丙胺、右旋安非他命 (dextroamphetamine)、安非拉酮(diethylpropion)、苯托雷司(diphemethoxidine)、N-乙基安非他命(N-ethylamphetamine)、芬布酯(fenbutrazate)、氟苯丙胺(fenfluramine)、非尼雷司(fenisorex)、芬普雷司(fenproporex)、氟多雷司(fludorex)、氟胺雷司(fluminorex)、糠基甲基安非他命(furfurylmethylamphetamine)、左苯丙胺(levamfetamine)、左法哌酯(levophacetoperane)、嗎吲哚(mazindol)、美芬雷司(mefenorex)、甲胺苯丙酮(metamfepramone)、甲安非他命(methamphetamine)、去甲假麻黃(norpseudoephedrine)、噴托雷司(pentorex)、苯甲曲嗪(phendimetrazine)、芬美曲嗪(phenmetrazine)、芬特明(phentermine)、苯丙醇胺(phenylpropanolamine)、匹西雷司(picilorex)及諾美婷及其醫藥學上可接受之鹽。一類尤其適合之食慾抑制劑為鹵化安非他命衍生物，包括氯苯丁胺、氯福雷司、氯特胺、右旋氟苯丙胺、氟苯丙胺、匹西雷司及西布曲明，及其醫藥學上可接受之鹽。與本發明化合物組合使用之特定鹵化安非他命衍生物包括：氟苯丙胺及右旋氟苯丙胺，及其醫藥學上可接受之鹽。(b) anti-dyslipidemic agents, such as (1) bile acid spacers, such as cholestyramine, colesevelem, colestipol, cross-linked polydextrose dioxane Aminoalkyl derivatives, Colestid®, LoCholest® and Questran®, and their analogues; (2) HMG-CoA reductase inhibitors such as atorvastatin, ivavastatin, pitavastatin , fluvastatin, lovastatin, pravastatin, rivastatin, simvastatin, rositastatin (ZD-4522) and other statins, especially simvastatin; (3) inhibition of HMG-CoA synthase (4) Cholesterol absorption inhibitors such as FMVP4 (Forbes Medi-Tech), KT6-971 (Kotobuki Pharmaceutical), FM-VA12 (Forbes Medi-Tech), FM-VP-24 (Forbes Medi-Tech) , stanol esters, beta-sitosterol, sterol glycosides (such as tiqueside), and azetidinone (such as ezetimibe), and those disclosed in WO 04/005247, And its analogues; (5) 醯Kymase A-cholesterol thiotransferase (ACAT) inhibitors, such as avasamib, eflucimibe, pactimibe (K Y505), SMP 797 (Sumitomo), SM32504 (Sumitomo), and those disclosed in WO 03/091216, and analogs thereof; (6) CETP inhibitors such as Antep, JTT 705 (Japan Tobacco), Chep, CP 532, 632, BAY63-2149 (Bayer), SC 591, SC 795 and their like (7) squalene synthetase inhibitors; (8) antioxidants such as probucol and its analogues; (9) PPARα agonists such as beclofibrate ), bezafibrate, ciprofibrate, clofibrate, etofibrate, fenofibrate, gemcabene and gemfibrozil (gemfibrozil), GW 7647, BM 170744 (Kowa), LY518674 (Lilly), GW590735 (GlaxoSmithkline), KRP-101 (Kyorin), DRF10945 (Dr. Reddy), NS-220/R1593 (Nippon Shinyaku/Roche), ST1929 (Sigma Tau), MC3001/MC3004 (MaxoCore Pharmaceuticals), gemcabene calcium, other fibric acid derivatives (such as Atromid®, Lopid®, and Tricor®), and those disclosed in US 6,548,538, and the like (10) FXR receptor modulators, such as those disclosed in GW 4064 (GlaxoSmithkline), SR 103912, QRX401, LN-6691 (Lion Bioscience), and WO 02/064125, WO 04/045511, and the like (11) LXR receptor modulators such as GW 3965 (GlaxoSmithkline), T9013137 and XTCO179628 (X-Ceptor Therapeutics /Sanyo), and as disclosed in WO 03/031408, WO 03/063796, WO 04/072041, and analogs thereof; (12) lipoprotein synthetase inhibitors, such as niacin; (13) renin blood vessels Champin system inhibitors; (14) PPAR delta partial agonists, such as those disclosed in WO 03/024395; (15) bile acid reuptake inhibitors such as BARI 1453, SC435, PHA384640, S8921, AZD7706 and Analogs thereof; and bile acid spacers such as WELCHOL/CHOLESTAGEL, colestipol, cholestyramine, and dialkylaminoalkyl cross-linked polydextrose Derivatives; (16) PPAR delta agonists such as GW 501516 (Ligand, GSK), GW 590735, GW-0742 (GlaxoSmithkline), T659 (Amgen/Tularik), LY934 (Lilly), NNC610050 (Novo Nordisk), and WO 97/28149, WO 01/79197, WO 02/14291, WO 02/46154, WO 02/46176, WO 02/076957, WO 03/016291, WO 03/033493, WO 03/035603, WO 03/072100, WO 03/097607, WO 04/005253, WO 04/007439, and JP 10237049, and their analogs; (17) triglyceride synthesis inhibitors; (18) microsomal triglyceride transport (MTTP) Inhibitors, such as those disclosed in implitapide, LAB687, JTT130 (Japan Tobacco), CP346086, and WO 03/072532, and analogs thereof; (19) transcriptional regulators; (20) Squalene epoxidase inhibitors; (21) low density lipoprotein (LDL) receptor inducers; (22) platelet aggregation inhibitors; (23) 5-LO or FLAP inhibitors; Niacin receptor agonists, including HM74A receptor agonists; (25) PPAR modulators, such as WO 01/25181, WO 01/79150, WO 02/79162, WO 02/081428, WO 03/ 016265, disclosed in WO 03/033453 (26) niacin-bound chromium, as disclosed in WO 03/039535; (27) substituted acid derivatives as disclosed in WO 03/040114; (28) infused HDL, such as LUV/ETC- 588 (Pfizer), APO-A1 Milano/ETC216 (Pfizer), ETC-642 (Pfizer), ISIS301012, D4F (Bruin Pharma), synthetic trimeric ApoA1, Bioral Apo A1 targeting foam cells, and the like; 29) IBAT inhibitors such as BARI143/HMR145A/HMR1453 (Sanofi-Aventis), PHA384640E (Pfizer), S8921 (Shionogi), AZD7806 (AstrZeneca), AK105 (Asah Kasei), and the like; (30) Lp-PLA2 inhibitors such as SB480848 (GlaxoSmithkline), 659032 (GlaxoSmithkline), 677116 (GlaxoSmithkline), and the like; (31) Other agents that affect lipid composition, including ETC1001/ESP31015 (Pfizer), ESP-55016 (Pfizer), AGI1067 (AtheroGenics), AC3056 (Amylin), AZD4619 (AstrZeneca); (c) antihypertensive agents, such as (1) diuretics, such as thiazide, including chlorthalidone, chlorthiazide, dichlorophenamide, hydrofluorothiazide Hydroflumethiazide, indapamide, and hydrochlorothiazide; loop diuretic, such as bumetanide, ethacrynic acid, furosemide, and Tosemide; potassium sparing agent, such as amiloride and triamterene; and aldosterone antagonists, such as spironolactone, eplerenone ( Epirenone and its analogues; (2) β-adrenergic blockers such as acebutolol, atenolol, betaxolol, Bevano (bevantolol), bisoprolol, bopindolol, carteolol, carvedilol, celiprolol, esmolol ), indenolol, metaprolol, nadolol (nado) Lol), nebivolol, penbutolol, pindolol, propanolol, sotalol, tertatolol , tilisolol and timolol, And analogues thereof; (3) calcium channel blockers such as amlodipine, aranidipine, azelnidipine, barnidipine, benidipine , bepridil, cinaldipine, clevidipine, diltiazem, efenidipine, felodipine, gallopamil, Isradipine, lacidipine, lemildipine, lercanidipine, nicardipine, nifedipine, nilvadipine, niche Nimodepine, nisoldipine, nitrendipine, manidipine, pranidipine, and verapamil, and analogs thereof; (4) Angiotensin-converting enzyme (ACE) inhibitors, such as benazepril, captopril, cilazapril, deLapril, enalapril Elenapril), fosinopril, imidapril, lisino Losinopril, moexipril, quinapril, quinaprilat, ramipril, perindopril, piperidril (perindropril), quanipril, spirapril, tenocapril, trandolapril and zofenopril, and analogues thereof; Neutral endopeptidase inhibitors, such as omapatrilat, cadoxatril and ecadotril, fosidotril, sampatrilat , AVE7688, ER4030 and its analogues; (6) endothelin antagonists, such as tezosentan, A308165 and YM62899, and their analogs; (7) vasodilators, such as hydralazine, clonidine, minoxidil, nicotinyl alcohol, nicotinic acid ( Nicotinic acid) or a salt thereof, and analogs thereof; (8) angiotensin II receptor antagonists such as candesartan, eprosartan, irbesartan, Losartan, pratosartan, tasosartan, telmisartan, valsartan, and EXP-3137, FI6828K, and RNH6270, and the like (9) alpha/beta adrenergic antagonists such as nipradil, arotinolol and amosulalol, and analogs thereof; (10) Alpha 1 blockers, such as terazosin, urapidil, prazosin, bunazosin, trimazosin, doxazosin ), naftopidil, indoramin, WHIP 164 and XEN010, and analogues thereof; (11) alpha 2 agonists, such as lofexid (lofexidi) Ne), tiamenidine, moxonidine, rilmenidine, and guanobenz, and analogs thereof; (12) aldosterone inhibitors and analogs thereof; 13) an angiopoietin-2 binding agent, such as disclosed in WO 03/030833; (d) anti-obesity agents, such as (1) 5HT (serotonin) transporter inhibitors, such as paroxetine, fluoxetine, fenfluramine, fluvoxamine, Containing sertraline and imipramine, and as disclosed in WO 03/00663; Serotonin/norepinephrine reuptake inhibitors, such as sibutramine (MERIDIA/REDUCTIL); and dopamine absorption inhibitor/norepinephrine absorption inhibitors, such as radafaxine hydrochloride , 353162 (GlaxoSmithkline) and its analogues; (2) NE (norepinephrine) transporter inhibitors such as GW 320659, despiramine, talsupram and nomifensine (nomifensine); (3) CB1 (cannabinoid-1 receptor) antagonists/reverse agonists such as taranabant, rimonabant (ACCOMPLIA Sanofi Synthelabo), SR -147778 (Sanofi Synthelabo), AVE1625 (Sanofi-Aventis), BAY 65-2520 (Bayer), SLV 319 (Solvay), SLV326 (Solvay), CP945598 (Pfizer), E-6776 (Esteve), O1691 (Organix), ORG14481 (Organon), VER 24343 (Vernalis), NESS 0327 (Univ of Sassari/Univ of Cagliari), and U.S. Patent Nos. 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736, 5,532,237, 5,624,941 No. 6,028,084 and 6,509367, and WO 96/3315 9. WO 97/29079, WO 98/31227, WO 98/33765, WO 98/37061, WO 98/41519, WO 98/43635, WO 98/43636, WO 99/02499, WO 00/10967, WO 00/ 10968, WO 01/09120, WO 01/58869, WO 01/64632, WO 01/64633, WO 01/64634, WO 01/70700, WO 01/96330, WO 02/076949, WO 03/006007, WO 03/ 007887, WO 03/020217, WO 03/026647, WO 03/026648, WO 03/027069, WO 03/027076, WO 03/027114, WO 03/037332, WO 03/040107, WO 04/096763, And as disclosed in WO 04/111039, WO 04/111033, WO 04/111034, WO 04/111038, WO 04/013120, WO 05/000301, WO 05/016286, WO 05/066126, and EP-658546, Analogs; (4) ghrelin agonists/antagonists, such as BVT81-97 (BioVitrum), RC1291 (Rejuvenon), SRD-04677 (Sumitomo), undeuterated stomach hormone (TheraTechnologies), And those disclosed in WO 01/87335, WO 02/08250, WO 05/012331, and analogs thereof; (5) H3 (histamine H3) antagonists/reverse agonists, such as thiopropamine ( Thioperamide), 3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate, clobenpropit, iodophenpropit, mopuxifan Imoproxifan), GT2394 (Gliatech) and A331440, and those disclosed in WO 02/15905, and O-[3-(1H-imidazol-4-yl)propanol]carbamate (Kiec-Kononowicz, K. Et al, Pharmazie, 55: 349-55 (2000)), piperidine-containing histamine H3 receptor antagonist (Lazewska, D. et al, Pharmazie, 56: 927-32 (2001)), benzophenone Derivatives and related compounds (Sasse, A. et al., Arch. Pharm. (Weinheim) 334: 45-52 (2001)), substituted N-phenyl carbamates (Reidemeister, S. et al., Pharmazie, 55: 83-6 (2000)), and proxifan derivatives (Sasse, A. et al., J. Med. Chem.. 43: 3335-43 (2000)), and histamine H3 receptor modulators, such as those disclosed in WO 03/024928 and WO 03/024929; (6) Melanin Concentration Hormone 1 Receptor (MCH1R) Antagonists such as T-226296 (Takeda), T71 (Takeda/Amgen), AMGN-608450, AMGN-503796 (Amgen), 856464 (GlaxoSmithkline), A224940 (Abbott), A798 (Abbott), ATC0175/AR224349 (Arena Pharmaceuticals), GW803430 (GlaxoSmithkline), NBI-1A (Neurocrine Biosciences), NGX-1 (Neurogen), SNP-7941 (Synaptic), SNAP9847 (Synaptic), T-226293 (Schering Plough), TPI-1361-17 (Saitama Medical School/University of California Irvine), and WO 01/21169, WO 01/82925, WO 01/87834, WO 02/051809, WO 02/06245, WO 02/076929, WO 02/076947, WO 02/04433, WO 02/51809, WO 02/083134, WO 02/094799, WO 03/004027, WO 03/13574, WO 03/15769, WO 03/028641, WO 03/035624, WO 03/033476, WO 03/033480, WO 04/004611, WO 04/004726, WO 04/011438, WO 04/028459, WO 04/034702, WO 04/039764, WO 04/052848, WO 04/087680, and Japanese Patent Application No. JP 13226269, JPY 1437059, JP 2004315511, and the like; (7) MCH2R (melanin-concentrating hormone 2R) agonist/antagonist; (8) NPY1 (neuropeptide Y Y1) antagonist Classes such as BMS 205749, BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, and GI-264879A, and U.S. Patent No. 6,001,836 and WO 96/14307, WO 01/23387, WO 99/51600 , as disclosed in WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528; (9) NPY5 (neuropeptide Y Y5) antagonists, such as 152,804, S2367 (Shionogi), E-6999 (Esteve), GW-569180A, GW-594884A (GlaxoSmithkline), GW-587081X, GW-548118X, FR 235, 208, FR226928, FR 240662, FR252384, 1229U91, GI-264879A, CGP71683A, C-75 (Fasgen), LY- 377897, LY366377, PD-160170, SR-120562A, SR-120819A, S2367 (Shionogi), JCF-104, and H409/22, and U.S. Patent Nos. 6,140,354, 6,191,160, 6,258,837, 6,313,298, 6,326,375 No. 6,329,395, 6,335,345, 6,337,332, 6,329,395 and 6,340,683, and EP-01010691, EP-01044970 and FR252384, and PCT Publication No. WO 97/19682, WO 97/20820 , WO 97/20821, WO 97/20822, WO 97/20823, WO 98/27063, WO 00/107409, WO 00/185714, WO 00/185730, WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO 01/14376, WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO 01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO 01/62738, WO 01/09120, WO 02/20488, WO 02/22592, WO 02/48152, WO 02/49648, WO 02/051806, WO 02 /094789, WO 03/009845, WO 03/014083, WO 03/022849, WO 03/028726, WO 05/014592, WO 05/01493, and Norman et al, J. Med. Chem. 43: 4288-4312 ( (2000) leptin, such as recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant methylthioguanidine human leptin (Amgen); (11) Leptin derivatives, such as Patent Nos. 5,552,524, 5,552,523, 5,552,522, 5,521,283, and WO 96/23513, WO 96/23514, WO 96/23515, WO 96/23516, WO 96/23517, WO 96/23518, WO 96/23519 and WO 96/23520; (12) opioid antagonists , such as nalmefene (Revex®), 3-methoxynaltrexone, naloxone, and naltrexone, and those disclosed in WO 00/21509 (13) an orexin receptor antagonist, such as SB-334867-A (GlaxoSmithkline), and WO 01/96302, 01/68609, 02/44172, 02/51232, 02/51838, 02/089800, 02/090355, 03/023561, 03/032991, 03/037847, 04/004733, 04/026866, 04/041791, 04/085403, and the like; (14) BRS3 (bell Bombesin) receptor subtype 3) agonist; (15) CCK-A (cholecystokinin-A) agonist, such as AR-R 15849, GI 181771, JMV-180, A -71378, A-71623, PD170292, PD 149164, SR146131, SR125180, butabindide, and US 5,739,106; (16) CNTF (ciliary neurotrophic factor), such as GI-181771 (Glaxo-SmithKline), SR146131 (Sanofi Synthe Labo), citridin and PD 170, 292, PD 149164 (Pfizer); (17) CNTF derivatives, such as axokine (Regeneron), and WO 94/09134, WO 98/22128 and WO 99 (438) GHS (growth hormone secretagogue receptor) agonists, such as NN703, hexarelin, MK-0677, SM-130686, CP-424, 391, L- 692, 429 and L-163, 255, and U.S. Patent No. 6,358,951, U.S. Patent Application Serial Nos. 2002/049196 and 2002/022637, and WO 01/56592 and WO 02/32888 Revealed; (19) 5HT2c (serotonin receptor 2c) agonists such as APD3546/AR10A (Arena Pharmaceuticals), ATH88651 (Athersys), ATH88740 (Athersys), BVT933 (Biovitrum/GSK), DPCA37215 (BMS) , IK264, LY448100 (Lilly), PNU 22394, WAY 470 (Wyeth), WAY629 (Wyeth), WAY161503 (Biovitrum), R-1065, VR1065 (Vernalis/Roche), YM 348, and US Patent No. 3,914,250, and PCT Published in the publications 01/66548, 02/36596, 02/48124, 02/10169, 02/44152, 02/51844, 02/40456, 02/40457, 03/057698, 05/000849, and the like (20) Mc3r (melanocortin 3 receptor) agonist; (21) Mc4r (melanocortin 4 receptor) agonist, such as CHIR86036 (Chiron), CHIR915 (Chiron) , ME-10142 (Melacure), ME-10145 (Melacure), HS-131 (Melacure), NBI72432 (Neurocrine Biosciences), NNC 70-619 (Novo Nordisk), TTP2435 (Transtech), and PCT Publication WO 99/64002 , 00/74679, 01/991752, 01/0125192, 01/52880, 01/74844, 01/70708, 01/70337, 01/91752, 01/010842, 02/059095, 02/059107, 02/059108, 02 /059117, 02/062766 , 02/069095, 02/12166, 02/11715, 02/12178, 02/15909, 02/38544, 02/068387, 02/068388, 02/067869, 02/081430, 03/06604, 03/007949, 03 /009847, 03/009850, 03/013509, 03/031410, 03/094918, 04/028453, 04/048345, 04/050610, 04/075823, 04/083208, 04/089951, 05/000339, and EP 1460069 And those disclosed in US 2005049269 and JP 2005042839, and analogs thereof; (22) monoamine reabsorption Inhibitors, such as sibutramine (Reuteril®) and its salts, and U.S. Patent Nos. 4,746,680, 4,806,570 and 5,436,272, and U.S. Patent Publication No. 2002/0006964, and WO 01/ 27068 and their compounds disclosed in WO 01/62341; (23) serotonin reuptake inhibitors, such as dexfenfluramine, fluoxetine, and U.S. Patent No. 6,365,633, and WO 01/27060 And those disclosed in WO 01/162341; (24) GLP-1 (glycin-like peptide 1) agonist; (25) Topiramate (Topimax®); (26) Phytopharmacological compound 57 ( Phytopharm compound 57) (CP 644,673); (27) ACC2 (acetyl-CoA carboxylase-2) inhibitors; (28) β3 (β-adrenergic receptor 3) agonists, such as pull Rafebergron/AD9677/TAK677 (Dainippon/Takeda), CL-316, 243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, GRC1087 (Glenmark Pharmaceuticals) , GW 427353 (solabegron hydrochloride), Trecadrine, Zeneca D7114, N-5984 (Nisshin Kyorin), LY-377604 (Lilly), K T07924 (Kissei), SR 59119A, and U.S. Patent No. 5,705,515, U.S. Patent No. 5,451,677, and WO 94/18161, WO 95/29159, WO 97/46556, WO 98/04526 WO 98/32753, WO 01/74782, WO 02/32897, WO 03/014113, WO 03/016276, WO 03/016307, WO 03/024948, WO 03/024953, WO 03/037881, WO 04/108674, and the like; DGAT1 (dimeric glycerol thiol transferase 1) inhibitors; (30) DGAT2 (diglycerol thiol transferase 2) inhibitors; (31) FAS (fatty acid synthase) inhibitors, such as cerulenin and C75; (32) PDE (phosphodiesterase) inhibitors, such as theophylline, pentoxifylline, Zaprenast, sildenafil, amrinone, milrinone, cilostamide, rolipram, and cilomilast And, as described in WO 03/037432, WO 03/037899; (33) thyroid hormone beta agonists, such as KB-2611 (Karo BioBMS), and WO 02/15845 and Japanese Patent Application No. JP 2000256190 (34) UCP-1 (decoupled protein 1), UCP-2 or UCP-3 activators, such as phytanic acid, 4-[(E)-2-(5, 6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propoxy]benzoic acid (TTNPB) and retinoic acid, and WO 99 (00) Mercapto-estrogens, such as del Mar-Grasa, M. et al., Obesity Research, 9: 202-9 (2001), oleoyl- ketone (oleoyl- Estrone); (36) glucocorticoid receptor antagonists such as CP472555 (Pfizer), KB 3305, and WO 04/00 0869, WO 04/075864, and analogs thereof; (37) 11β HSD-1 (11-beta hydroxysteroid dehydrogenase type 1) inhibitors, such as BVT 3498 (AMG 331), BVT 2733, 3-(1-adamantyl)-4-ethyl-5-(ethylthio)-4H-1,2,4-triazole, 3-(1-adamantyl)-5-(3,4 ,5-trimethoxyphenyl)-4-methyl-4H-1,2,4-triazole, 3-adamantyl-4,5,6,7,8,9,10,11,12, 3a-decahydro-1,2,4-triazolo[4,3-a][11]bornene, and WO 01/90091, 01/90090, 01/90092, 02/072084, 04/011410, 04 /033427, 04/041264, 04/027047, 04/056744, 04/065351, 04/089415, Their compounds, and their analogs, disclosed in 04/037251; (38) SCD-1 (stearylsulfonyl-CoA desaturase-1) inhibitors; (39) dipeptidyl peptidase IV (DPP) -4) Inhibitors, such as isotrecine thiazolidide, valine pyrrolidide, jasulide, saxagliptin, alogliptin ( Alogliptin), NVP-DPP728, LAF237 (vildagliptin), P93/01, TSL 225, TMC-2A/2B/2C, FE 999011, P9310/K364, VIP 0177, SDZ 274-444, GSK 823093 , E 3024, SYR 322, TS021, SSR 162369, GRC 8200, K579, NN7201, CR 14023, PHX 1004, PHX 1149, PT-630, SK-0403, and WO 02/083128, WO 02/062764, WO 02/ 14271, WO 03/000180, WO 03/000181, WO 03/000250, WO 03/002530, WO 03/002531, WO 03/002553, WO 03/002593, WO 03/004498, WO 03/004496, WO 03/ 005766, WO 03/017936, WO 03/024942, WO 03/024965, WO 03/033524, WO 03/055881, WO 03/057144, WO 03/037327, WO 04/041795, WO 04/071454, WO 04/ 0214870, WO 04/041273, WO 04/041820, WO 04/050658, WO 04/0 46106, WO 04/067509, WO 04/048532, WO 04/099185, WO 04/108730, WO 05/009956, WO 04/09806, WO 05/023762, US 2005/043292, and EP 1 258 476 a compound; (40) a lipase inhibitor such as tetrahydrolipstatin (orlistat/XENICAL), ATL962 (Alizyme/Takeda), GT389255 (Genzyme/Peptimmune), Triton WR1339, RHC80267, lipstatin, tea soap Teasaponin and diethylumbelliferyl phosphate, FL-386, WAY-121898, Bay-N-3176, valilactone, esteracin, erby Lactone A (ebelactone A), ebelactone B and RHC 80267, and WO 01/77094, WO 04/111004, and U.S. Patent Nos. 4,598,089, 4,452,813, 5,512,565, 5,391,571. Nos. 5,602,151, 4,405,644, 4,189,438 and 4,242,453, and analogs thereof; (41) fatty acid transporter inhibitors; (42) dicarboxylic acid transporter inhibitors; (43) glucose Transporter inhibitors; and (44) phosphate transporter inhibitors; (45) appetite-suppressing bicyclic compounds such as 1426 (Aventis) and 1954 (Aventis), and WO 00/18749, WO 01/32638, WO 01 /62746, compounds disclosed in WO 01/62747 and WO 03/015769; (46) peptide YY and PYY agonists, such as PYY336 (Nastech/Merck), AC162352 (IC Innovations/Curis/Amylin), TM30335/ TM30338 (7TM Pharma), PYY336 (Emisphere Tehcnologies), pegylated peptide YY3-36, WO 03/026591, 04/089279 Showers, and their analogs; (47) lipid metabolism regulators such as maslinic acid, erythrodiol, ursolic acid, ursolic acid (uvaol), betulinic acid ( Betulinic acid), betulin and its analogues, and the compounds disclosed in WO 03/011267; (48) transcription factor modulators, such as those disclosed in WO 03/026576; (49) Mc5r (black) Peelin 5 receptor) modulators, such as those disclosed in WO 97/19952, WO 00/15826, WO 00/15790, US 20030092041, and the like; (50) Brain-derived gods Factor (BDNF); (51) Mc1r (melanocortin 1 receptor modulator), such as LK-184 (Proctor & Gamble) and its analogs; (52) 5HT6 antagonists, such as BVT74316 (BioVitrum), BVT5182c (BioVitrum), E-6795 (Esteve), E-6814 (Esteve), SB399885 (GlaxoSmithkline), SB271046 (GlaxoSmithkline), RO-046790 (Roche) and the like; (53) fatty acid transporter 4 (FATP4); (54) Ethyl-CoA carboxylase (ACC) inhibitors such as CP640186, CP610431, CP640188 (Pfizer); (55) C-terminal growth hormone fragments such as AOD9604 (Monash Univ/Metabolic Pharmaceuticals) and the like (56) oxyntomodulin; (57) neuropeptide FF receptor antagonists, such as those disclosed in WO 04/083218, and analogs thereof; (58) amyloid agonists, Such as, for example, Symlin/pramlintide/AC137 (Amylin); (59) Hoodia and trichocaulon extracts; (60) BVT74713 and other intestinal lipid appetites Inhibitors; (61) dopamine agonists, such as bupropion (WELLBUTRIN/GlaxoSmithkline); (62) zonisamide (zonisamid) e) (ZONEGRAN/Dainippon/Elan), and analogues thereof; (e) Appetite suppressants suitable for use in combination with the compounds of the invention include, but are not limited to, aminorex, amphhechloral, amphetamine, benzphetamine, Chlorphentermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dextroflufenamide Right-handed amphetamine (dextroamphetamine), diethylpropion, diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine, fenisorex ), fenproporex, fludodex, fluminorex, furfurylmethylamphetamine, levafetamine, levophacetoperane, Maz (mazindol), mefenorex, metamfepramone, methamphetamine, norpseudoephedrine, pentorex, benzomethazine Phendimetrazine), phenmetrazine, phentermine, phenylpropanolamine, picilorex and normetene, and pharmaceutically acceptable salts thereof. A particularly suitable appetite suppressant is a halogenated amphetamine derivative, including chlorpheniramine, chlorflurans, clopidogrel, dextroflufenamide, flumethamine, piridis and sibutramine, and its medicine Acceptable salt. Specific halogenated amphetamine derivatives for use in combination with the compounds of the invention include: flufenip and dextroflufenamide, and pharmaceutically acceptable salts thereof.

與本發明化合物組合使用之特定化合物包括：辛伐他汀、美伐他汀(mevastatin)、依折麥布、阿托伐他汀、西他列汀、二甲雙胍、西布曲明、奧利司他、奎尼克(Qnexa)、托吡酯、納曲酮、布普品、芬特明及洛沙坦、洛沙坦與氫氯噻嗪。與本發明化合物組合使用之特定CB1拮抗劑/反向促效劑包括：WO 03/077847中所揭示者，包括：N-[3-(4-氯苯基)-2(S)-苯基-1(S)-甲基丙基]-2-(4-三氟甲基-2-嘧啶 氧基)-2-甲基丙醯胺、N-[3-(4-氯苯基)-2-(3-氰基苯基)-1-甲基丙基]-2-(5-三氟甲基-2-吡啶氧基)-2-甲基丙醯胺、N-[3-(4-氯苯基)-2-(5-氯-3-吡啶基)-1-甲基丙基]-2-(5-三氟甲基-2-吡啶氧基)-2-甲基丙醯胺，及其醫藥學上可接受之鹽；以及WO 05/000809中所揭示者，包括以下：3-{1-[雙(4-氯苯基)甲基]氮雜環丁烷-3-亞基}-3-(3,5-二氟苯基)-2,2-二甲基丙腈、1-{1-[1-(4-氯苯基)戊基]氮雜環丁烷-3-基}-1-(3,5-二氟苯基)-2-甲基丙-2-醇、3-((S)-(4-氯苯基){3-[(1S)-1-(3,5-二氟苯基)-2-羥基-2-甲基丙基]氮雜環丁烷-1-基}甲基)苯甲腈、3-((S)-(4-氯苯基){3-[(1S)-1-(3,5-二氟苯基)-2-氟-2-甲基丙基]氮雜環丁烷-1-基}甲基)苯甲腈、3-((4-氯苯基){3-[1-(3,5-二氟苯基)-2,2-二甲基丙基]氮雜環丁烷-1-基}甲基)苯甲腈、3-((1S)-1-{1-[(S)-(3-氰基苯基)(4-氰基苯基)甲基]氮雜環丁烷-3-基}-2-氟-2-甲基丙基)-5-氟苯甲腈、3-[(S)-(4-氯苯基)(3-{(1S)-2-氟-1-[3-氟-5-(4H-1,2,4-三唑-4-基)苯基]-2-甲基丙基}氮雜環丁烷-1-基)甲基]苯甲腈及5-((4-氯苯基){3-[(1S)-1-(3,5-二氟苯基)-2-氟-2-甲基丙基]氮雜環丁烷-1-基}甲基)噻吩-3-甲腈，及其醫藥學上可接受之鹽；以及：3-[(S)-(4-氯苯基)(3-{(1S)-2-氟-1-[3-氟-5-(5-側氧基-4,5-二氫-1,3,4-噁二唑-2-基)苯基]-2-甲基丙基}氮雜環丁烷-1-基)甲基]苯甲腈、3-[(S)-(4-氯苯基)(3-{(1S)-2-氟-1-[3-氟-5-(1,3,4-噁二唑-2-基)苯基]-2-甲基丙基}氮雜環丁烷-1-基)甲基]苯甲腈、3-[(S)-(3-{(1S)-1-[3-(5-胺基-1,3,4-噁二唑-2-基)-5-氟 苯基]-2-氟-2-甲基丙基}氮雜環丁烷-1-基)(4-氯苯基)甲基]苯甲腈、3-[(S)-(4-氰基苯基)(3-{(1S)-2-氟-1-[3-氟-5-(5-側氧基-4,5-二氫-1,3,4-噁二唑-2-基)苯基]-2-甲基丙基}氮雜環丁烷-1-基)甲基]苯甲腈、3-[(S)-(3-{(1S)-1-[3-(5-胺基-1,3,4-噁二唑-2-基)-5-氟苯基]-2-氟-2-甲基丙基}氮雜環丁烷-1-基)(4-氰基苯基)甲基]苯甲腈、3-[(S)-(4-氰基苯基)(3-{(1S)-2-氟-1-[3-氟-5-(1,3,4-噁二唑-2-基)苯基]-2-甲基丙基}氮雜環丁烷-1-基)甲基]苯甲腈、3-[(S)-(4-氯苯基)(3-{(1S)-2-氟-1-[3-氟-5-(1,2,4-噁二唑-3-基)苯基]-2-甲基丙基}氮雜環丁烷-1-基)甲基]苯甲腈、3-[(1S)-1-(1-{(S)-(4-氰基苯基)[3-(1,2,4-噁二唑-3-基)苯基]-甲基}氮雜環丁烷-3-基)-2-氟-2-甲基丙基]-5-氟苯甲腈、5-(3-{1-[1-(二苯基甲基)氮雜環丁烷-3-基]-2-氟-2-甲基丙基}-5-氟苯基)-1H-四唑、5-(3-{1-[1-(二苯基甲基)氮雜環丁烷-3-基]-2-氟-2-甲基丙基}-5-氟苯基)-1-甲基-1H-四唑、5-(3-{1-[1-(二苯基甲基)氮雜環丁烷-3-基]-2-氟-2-甲基丙基}-5-氟苯基)-2-甲基-2H-四唑、3-[(4-氯苯基)(3-{2-氟-1-[3-氟-5-(2-甲基-2H-四唑-5-基)苯基]-2-甲基丙基}氮雜環丁烷-1-基)甲基]苯甲腈、3-[(4-氯苯基)(3-{2-氟-1-[3-氟-5-(1-甲基-1H-四唑-5-基)苯基]-2-甲基丙基}氮雜環丁烷-1-基)甲基]苯甲腈、3-[(4-氰基苯基)(3-{2-氟-1-[3-氟-5-(1-甲基-1H-四唑-5-基)苯基]-2-甲基丙基}氮雜環丁烷-1-基)甲基]苯甲腈、3-[(4-氰基苯基)(3-{2-氟-1-[3-氟-5-(2-甲基-2H-四唑-5-基)苯基]-2-甲基丙基}氮雜環丁烷-1-基)甲基]苯甲腈、5-{3-[(S)-{3- [(1S)-1-(3-溴-5-氟苯基)-2-氟-2-甲基丙基]氮雜環丁烷-1-基}(4-氯苯基)甲基]苯基}-1,3,4-噁二唑-2(3H)-酮、3-[(1S)-1-(1-{(S)-(4-氯苯基)[3-(5-側氧基-4,5-二氫-1,3,4-噁二唑-2-基)苯基]甲基}氮雜環丁烷-3-基)-2-氟-2-甲基丙基]-5-氟苯甲腈、3-[(1S)-1-(1-{(S)-(4-氰基苯基)[3-(5-側氧基-4,5-二氫-1,3,4-噁二唑-2-基)苯基]甲基}氮雜環丁烷-3-基)-2-氟-2-甲基丙基]-5-氟苯甲腈、3-[(1S)-1-(1-{(S)-(4-氰基苯基)[3-(1,3,4-噁二唑-2-基)苯基]甲基}氮雜環丁烷-3-基)-2-氟-2-甲基丙基]-5-氟苯甲腈、3-[(1S)-1-(1-{(S)-(4-氯苯基)[3-(1,3,4-噁二唑-2-基)苯基]甲基}氮雜環丁烷-3-基)-2-氟-2-甲基丙基]-5-氟苯甲腈、3-((1S)-1-{1-[(S)-[3-(5-胺基-1,3,4-噁二唑-2-基)苯基](4-氯苯基)甲基]氮雜環丁烷-3-基}-2-氟-2-甲基丙基)-5-氟苯甲腈、3-((1S)-1-{1-[(S)-[3-(5-胺基-1,3,4-噁二唑-2-基)苯基](4-氰基苯基)甲基]氮雜環丁烷-3-基}-2-氟-2-甲基丙基)-5-氟苯甲腈、3-[(1S)-1-(1-{(S)-(4-氰基苯基)[3-(1,2,4-噁二唑-3-基)苯基]甲基}氮雜環丁烷-3-基)-2-氟-2-甲基丙基]-5-氟苯甲腈、3-[(1S)-1-(1-{(S)-(4-氯苯基)[3-(1,2,4-噁二唑-3-基)苯基]甲基}氮雜環丁烷-3-基)-2-氟-2-甲基丙基]-5-氟苯甲腈、5-[3-((S)-(4-氯苯基){3-[(1S)-1-(3,5-二氟苯基)-2-氟-2-甲基丙基]氮雜環丁烷-1-基}甲基)苯基]-1,3,4-噁二唑-2(3H)-酮、5-[3-((S)-(4-氯苯基){3-[(1S)-1-(3,5-二氟苯基)-2-氟-2-甲基丙基]氮雜環丁烷-1-基}甲基)苯基]-1,3,4-噁二唑-2(3H)-酮、4-{(S)-{3-[(1S)-1-(3,5-二氟苯基)-2-氟-2-甲基丙基]氮雜環丁烷-1- 基}[3-(5-側氧基-4,5-二氫-1,3,4-噁二唑-2-基)苯基]甲基}-苯甲腈，及其醫藥學上可接受之鹽。Specific compounds used in combination with the compounds of the invention include: simvastatin, mevastatin, ezetimibe, atorvastatin, sitagliptin, metformin, sibutramine, orlistat, quinine Qnexa, topiramate, naltrexone, buppe, phentermine and losartan, losartan and hydrochlorothiazide. Specific CB1 antagonists/reverse agonists for use in combination with the compounds of the invention include those disclosed in WO 03/077847, including: N-[3-(4-chlorophenyl)-2(S)-phenyl -1(S)-methylpropyl]-2-(4-trifluoromethyl-2-pyrimidine Oxy)-2-methylpropanamide, N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-three Fluoromethyl-2-pyridyloxy)-2-methylpropanamide, N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropane 2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide, and pharmaceutically acceptable salts thereof; and as disclosed in WO 05/000809, including the following :3-{1-[Bis(4-chlorophenyl)methyl]azetidin-3-yl}-3-(3,5-difluorophenyl)-2,2-dimethyl Propionitrile, 1-{1-[1-(4-chlorophenyl)pentyl]azetidin-3-yl}-1-(3,5-difluorophenyl)-2-methylpropane 2-ol, 3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-hydroxy-2-methylpropyl Azetidine-1-yl}methyl)benzonitrile, 3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorobenzene) 2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)benzonitrile, 3-((4-chlorophenyl){3-[1-(3, 5-difluorophenyl)-2,2-dimethylpropyl]azetidin-1-yl}methyl)benzonitrile, 3-((1S)-1-{1-[(S )-(3-cyanophenyl)(4-cyanophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile , 3-[(S)-(4-chlorophenyl)(3-{(1S) 2-fluoro-1-[3-fluoro-5-(4H-1,2,4-triazol-4-yl)phenyl]-2-methylpropyl}azetidin-1-yl )methyl]benzonitrile and 5-((4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl] Azetidin-1-yl}methyl)thiophene-3-carbonitrile, and a pharmaceutically acceptable salt thereof; and: 3-[(S)-(4-chlorophenyl)(3-{ (1S)-2-fluoro-1-[3-fluoro-5-(5-sided oxy-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]-2 -methylpropyl}azetidin-1-yl)methyl]benzonitrile, 3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1 -[3-Fluoro-5-(1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile ,3-[(S)-(3-{(1S)-1-[3-(5-Amino-1,3,4-oxadiazol-2-yl)-5-fluoro Phenyl]-2-fluoro-2-methylpropyl}azetidin-1-yl)(4-chlorophenyl)methyl]benzonitrile, 3-[(S)-(4-cyanide Phenylphenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(5-o-oxy-4,5-dihydro-1,3,4-oxadiazole-2 -yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile, 3-[(S)-(3-{(1S)-1-[3 -(5-Amino-1,3,4-oxadiazol-2-yl)-5-fluorophenyl]-2-fluoro-2-methylpropyl}azetidin-1-yl) (4-cyanophenyl)methyl]benzonitrile, 3-[(S)-(4-cyanophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5 -(1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile, 3-[(S) -(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(1,2,4-oxadiazol-3-yl)phenyl]-2- Methylpropyl}azetidin-1-yl)methyl]benzonitrile, 3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3- (1,2,4-oxadiazol-3-yl)phenyl]-methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzamide Nitrile, 5-(3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorophenyl)- 1H-tetrazole, 5-(3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorobenzene Base)-1-methyl-1H-tetrazole, 5- (3-{1-[1-(Diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorophenyl)-2-methyl -2H-tetrazole, 3-[(4-chlorophenyl)(3-{2-fluoro-1-[3-fluoro-5-(2-methyl-2H-tetrazol-5-yl)phenyl) ]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile, 3-[(4-chlorophenyl)(3-{2-fluoro-1-[3-fluoro -5-(1-Methyl-1H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile, 3-[( 4-cyanophenyl)(3-{2-fluoro-1-[3-fluoro-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-2-methylpropyl} Azetidin-1-yl)methyl]benzonitrile, 3-[(4-cyanophenyl)(3-{2-fluoro-1-[3-fluoro-5-(2-methyl) -2H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile, 5-{3-[(S)-{3 - [(1S)-1-(3-Bromo-5-fluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}(4-chlorophenyl)methyl] Phenyl}-1,3,4-oxadiazol-2(3H)-one, 3-[(1S)-1-(1-{(S)-(4-chlorophenyl)[3-(5 -Sideoxy-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methyl Propyl]-5-fluorobenzonitrile, 3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(5-sideoxy-4,5) -dihydro-1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluoro Benzoonitrile, 3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(1,3,4-oxadiazol-2-yl)phenyl] Methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile, 3-[(1S)-1-(1-{(S)- (4-chlorophenyl)[3-(1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methyl Propyl]-5-fluorobenzonitrile, 3-((1S)-1-{1-[(S)-[3-(5-amino-1,3,4-oxadiazol-2-yl) Phenyl](4-chlorophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile, 3-((1S) 1-{1-[(S)-[3-(5-Amino-1,3,4-oxadiazol-2-yl)phenyl](4-cyanophenyl)methyl]aza Cyclobutane-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile, 3- [(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(1,2,4-oxadiazol-3-yl)phenyl]methyl}azacyclocycle Butyl-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile, 3-[(1S)-1-(1-{(S)-(4-chlorophenyl) [3-(1,2,4-oxadiazol-3-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5- Fluorobenzonitrile, 5-[3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-) Propyl]azetidin-1-yl}methyl)phenyl]-1,3,4-oxadiazole-2(3H)-one, 5-[3-((S)-(4) -Chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl) Phenyl]-1,3,4-oxadiazol-2(3H)-one, 4-{(S)-{3-[(1S)-1-(3,5-difluorophenyl)-2 -fluoro-2-methylpropyl]azetidin-1- [3-(5-Sideoxy-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]methyl}-benzonitrile, and its pharmaceutically acceptable Accept the salt.

與本發明化合物組合使用之特定NPY5拮抗劑包括：3-側氧基-N-(5-苯基-2-吡嗪基)-螺[異苯并呋喃-1(3H),4'-哌啶]-1'-甲醯胺、3-側氧基-N-(7-三氟甲基吡啶并[3,2-b]吡啶-2-基)-螺[異苯并呋喃-1(3H),4'-哌啶]-1'-甲醯胺、N-[5-(3-氟苯基)-2-嘧啶基]-3-側氧基螺[異苯并呋喃-1(3H),4'-哌啶]-1'-甲醯胺、反-3'-側氧基-N-(5-苯基-2-嘧啶基)螺[環己烷-1,1'(3'H)-異苯并呋喃]-4-甲醯胺、反-3'-側氧基-N-[1-(3-喹啉基)-4-咪唑基]螺[環己烷-1,1'(3'H)-異苯并呋喃]-4-甲醯胺、反-3-側氧基-N-(5-苯基-2-吡嗪基)螺[4-氮雜異苯并呋喃-1(3H),1'-環己烷]-4'-甲醯胺、反-N-[5-(3-氟苯基)-2-嘧啶基]-3-側氧基螺[5-氮雜異苯并呋喃-1(3H),1'-環己烷]-4'-甲醯胺、反-N-[5-(2-氟苯基)-2-嘧啶基]-3-側氧基螺[5-氮雜異苯并呋喃-1(3H),1'-環己烷]-4'-甲醯胺、反-N-[1-(3,5-二氟苯基)-4-咪唑基]-3-側氧基螺[7-氮雜異苯并呋喃-1(3H),1'-環己烷]-4'-甲醯胺、反-3-側氧基-N-(1-苯基-4-吡唑基)螺[4-氮雜異苯并呋喃-1(3H),1'-環己烷]-4'-甲醯胺、反-N-[1-(2-氟苯基)-3-吡唑基]-3-側氧基螺[6-氮雜異苯并呋喃-1(3H),1'-環己烷]-4'-甲醯胺、反-3-側氧基-N-(1-苯基-3-吡唑基)螺[6-氮雜異苯并呋喃-1(3H),1'-環己烷]-4'-甲醯胺、反-3-側氧基-N-(2-苯基-1,2,3-三唑-4-基)螺[6-氮雜異苯并呋喃-1(3H),1'-環己烷]-4'-甲醯胺，及其醫藥學上可接受之鹽及酯。Specific NPY5 antagonists for use in combination with the compounds of the invention include: 3-sided oxy-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1 (3H), 4'-piperidin Acridine-1'-carbamamine, 3-sided oxy-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2-yl)-spiro[isobenzofuran-1 ( 3H), 4'-piperidine]-1'-formamide, N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxooxyspiro[isobenzofuran-1 ( 3H), 4'-piperidine]-1'-formamide, trans-3'-o-oxy-N-(5-phenyl-2-pyrimidinyl)spiro[cyclohexane-1,1' ( 3'H)-isobenzofuran]-4-carboxamide, trans-3'-sideoxy-N-[1-(3-quinolinyl)-4-imidazolyl]spiro[cyclohexane- 1,1'(3'H)-isobenzofuran]-4-carboxamide, trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4-aza Isobenzofuran-1 (3H), 1'-cyclohexane]-4'-formamide, trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-side oxygen Base snail [5-aza isobenzofuran-1 (3H), 1'-cyclohexane]-4'-formamide, trans-N-[5-(2-fluorophenyl)-2-pyrimidine 3-yloxy snail [5-aza isobenzofuran-1 (3H), 1'-cyclohexane]-4'-carbenamide, trans-N-[1-(3,5 -difluorophenyl)-4-imidazolyl-3-oxooxyspiro[7-azaisobenzofuran-1(3H), 1'-cyclohexane]-4'-carbenamide, anti - 3-Phenoxy-N-(1-phenyl-4-pyrazolyl)spiro[4-azaisobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide , trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxooxyspiro[6-azaisobenzofuran-1(3H), 1'-cyclohexane ]-4'-carbamamine, trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran-1 (3H), 1'- Cyclohexane]-4'-formamide, trans-3-oxo-N-(2-phenyl-1,2,3-triazol-4-yl)spiro[6-aza isophthalate Furan-1 (3H), 1'-cyclohexane]-4'-formamide, and pharmaceutically acceptable salts and esters thereof.

與本發明化合物組合使用之特定ACC-1/2抑制劑包括：1'-[(4,8-二甲氧基喹啉-2-基)羰基]-6-(1H-四唑-5-基)螺[烷-2,4'-哌啶]-4-酮、特戊酸(5-{1'-[(4,8-二甲氧基喹啉-2-基)羰基]-4-側氧基螺[烷-2,4'-哌啶]-6-基}-2H-四唑-2-基)甲酯、5-{1'-[(8-環丙基-4-甲氧基喹啉-2-基)羰基]-4-側氧基螺[烷-2,4'-哌啶]-6-基}菸鹼酸、1'-(8-甲氧基-4-嗎啉-4-基-2-萘甲醯基)-6-(1H-四唑-5-基)螺[烷-2,4'-哌啶]-4-酮及1'-[(4-乙氧基-8-乙基喹啉-2-基)羰基]-6-(1H-四唑-5-基)螺[烷-2,4'-哌啶]-4-酮，及其醫藥學上可接受之鹽及酯。與本發明化合物組合使用之特定MCH1R拮抗劑化合物包括：1-{4-[(1-乙基氮雜環丁烷-3-基)氧基]苯基}-4-[(4-氟苄基)氧基]吡啶-2(1H)-酮、4-[(4-氟苄基)氧基]-1-{4-[(1-異丙基氮雜環丁烷-3-基)氧基]苯基}吡啶-2(1H)-酮、1-[4-(氮雜環丁烷-3-基氧基)苯基]-4-[(5-氯吡啶-2-基)甲氧基]吡啶-2(1H)-酮、4-[(5-氯吡啶-2-基)甲氧基]-1-{4-[(1-乙基氮雜環丁烷-3-基)氧基]苯基}吡啶-2(1H)-酮、4-[(5-氯吡啶-2-基)甲氧基]-1-{4-[(1-丙基氮雜環丁烷-3-基)氧基]苯基}吡啶-2(1H)-酮及4-[(5-氯吡啶-2-基)甲氧基]-1-(4-{[(2S)-1-乙基氮雜環丁烷-2-基]甲氧基}苯基)吡啶-2(1H)-酮，或其醫藥學上可接受之鹽。Specific ACC-1/2 inhibitors for use in combination with the compounds of the invention include: 1'-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(1H-tetrazole-5- Snail Alkano-2,4'-piperidin-4-one, pivalic acid (5-{1'-[(4,8-dimethoxyquinolin-2-yl)carbonyl)-4-oxooxy screw[ Alkano-2,4'-piperidine]-6-yl}-2H-tetrazol-2-yl)methyl ester, 5-{1'-[(8-cyclopropyl-4-methoxyquinoline- 2-yl)carbonyl]-4-sideoxyspiro[ Alkano-2,4'-piperidine]-6-yl}nicotinic acid, 1'-(8-methoxy-4-morpholin-4-yl-2-naphthylmethyl)-6-(1H -tetrazole-5-yl) snail [ Alkano-2,4'-piperidin-4-one and 1'-[(4-ethoxy-8-ethylquinolin-2-yl)carbonyl]-6-(1H-tetrazole-5- Snail Alkano-2,4'-piperidin-4-one, and pharmaceutically acceptable salts and esters thereof. Specific MCH1R antagonist compounds for use in combination with the compounds of the invention include: 1-{4-[(1-ethylazetidin-3-yl)oxy]phenyl}-4-[(4-fluorobenzyl) Ethyl]pyridine]-2(1H)-one, 4-[(4-fluorobenzyl)oxy]-1-{4-[(1-isopropylazetidin-3-yl) Oxy]phenyl}pyridine-2(1H)-one, 1-[4-(azetidin-3-yloxy)phenyl]-4-[(5-chloropyridin-2-yl) Methoxy]pyridine-2(1H)-one, 4-[(5-chloropyridin-2-yl)methoxy]-1-{4-[(1-ethylazetidin-3- Alkyloxy]phenyl}pyridine-2(1H)-one, 4-[(5-chloropyridin-2-yl)methoxy]-1-{4-[(1-propylazetidine) Alkyl-3-yl)oxy]phenyl}pyridine-2(1H)-one and 4-[(5-chloropyridin-2-yl)methoxy]-1-(4-{[(2S)- 1-Ethylazetidin-2-yl]methoxy}phenyl)pyridine-2(1H)-one, or a pharmaceutically acceptable salt thereof.

與本發明化合物組合使用之特定DP-IV抑制劑係選自Januvia，7-[(3R)-3-胺基-4-(2,4,5-三氟苯基)丁醯基]-3-(三氟甲基)-5,6,7,8-四氫-1,2,4-三唑并[4,3-a]吡嗪。詳言之，式I之化合物宜與7-[(3R)-3-胺基-4-(2,4,5-三氟苯基)丁醯 基]-3-(三氟甲基)-5,6,7,8-四氫-1,2,4-三唑并[4,3-a]吡嗪及其醫藥學上可接受之鹽組合。The specific DP-IV inhibitor used in combination with the compounds of the invention is selected from the group consisting of Januvia, 7-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanyl]-3-( Trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine. In particular, the compound of formula I is preferably associated with 7-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butane. 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine and pharmaceutically acceptable salts thereof combination.

與本發明化合物組合使用之特定H3(組織胺H3)拮抗劑/反向促效劑包括：WO 05/077905中所揭示者，包括：3-{4-[(1-環丁基-4-哌啶基)氧基]苯基}-2-乙基吡啶并[2,3-d]-嘧啶-4(3H)-酮、3-{4-[(1-環丁基-4-哌啶基)氧基]苯基}-2-甲基吡啶并[4,3-d]嘧啶-4(3H)-酮、2-乙基-3-(4-{3-[(3S)-3-甲基哌啶-1-基]丙氧基}苯基)吡啶并[2,3-d]嘧啶-4(3H)-酮、2-甲基-3-(4-{3-[(3S)-3-甲基哌啶-1-基]丙氧基}苯基)吡啶并[4,3-d]嘧啶-4(3H)-酮、3-{4-[(1-環丁基-4-哌啶基)氧基]苯基}-2,5-二甲基-4(3H)-喹唑啉酮、3-{4-[(1-環丁基-4-哌啶基)氧基]苯基}-2-甲基-5-三氟甲基-4(3H)-喹唑啉酮、3-{4-[(1-環丁基-4-哌啶基)氧基]苯基}-5-甲氧基-2-甲基-4(3H)-喹唑啉酮、3-{4-[(1-環丁基哌啶-4-基)氧基]苯基}-5-氟-2-甲基-4(3H)-喹唑啉酮、3-{4-[(1-環丁基哌啶-4-基)氧基]苯基}-7-氟-2-甲基-4(3H)-喹唑啉酮、3-{4-[(1-環丁基哌啶-4-基)氧基]苯基}-6-甲氧基-2-甲基-4(3H)-喹唑啉酮、3-{4-[(1-環丁基哌啶-4-基)氧基]苯基}-6-氟-2-甲基-4(3H)-喹唑啉酮、3-{4-[(1-環丁基哌啶-4-基)氧基]苯基}-8-氟-2-甲基-4(3H)-喹唑啉酮、3-{4-[(1-環戊基-4-哌啶基)氧基]苯基}-2-甲基吡啶并[4,3-d]嘧啶-4(3H)-酮、3-{4-[(1-環丁基哌啶-4-基)氧基]苯基}-6-氟-2-甲基吡啶并[3,4-d]嘧啶-4(3H)-酮、3-{4-[(1-環丁基-4-哌啶基)氧基]苯基}-2-乙基吡啶并[4,3-d]嘧啶-4(3H)-酮、6-甲氧基-2-甲基-3-{4-[3- (1-哌啶基)丙氧基]苯基}吡啶并[3,4-d]嘧啶-4(3H)-酮、6-甲氧基-2-甲基-3-{4-[3-(1-吡咯啶基)丙氧基]苯基}吡啶并[3,4-d]嘧啶-4(3H)-酮、2,5-二甲基-3-{4-[3-(1-吡咯啶基)丙氧基]苯基}-4(3H)-喹唑啉酮、2-甲基-3-{4-[3-(1-吡咯啶基)丙氧基]苯基}-5-三氟甲基-4(3H)-喹唑啉酮、5-氟-2-甲基-3-{4-[3-(1-哌啶基)丙氧基]苯基}-4(3H)-喹唑啉酮、6-甲氧基-2-甲基-3-{4-[3-(1-哌啶基)丙氧基]苯基}-4(3H)-喹唑啉酮、5-甲氧基-2-甲基-3-(4-{3-[(3S)-3-甲基哌啶-1-基]丙氧基}苯基)-4(3H)-喹唑啉酮、7-甲氧基-2-甲基-3-(4-{3-[(3S)-3-甲基哌啶-1-基]丙氧基}苯基)-4(3H)-喹唑啉酮、2-甲基-3-(4-{3-[(3S)-3-甲基哌啶-1-基]丙氧基}苯基)吡啶并[2,3-d]嘧啶-4(3H)-酮、5-氟-2-甲基-3-(4-{3-[(2R)-2-甲基吡咯啶-1-基]丙氧基}苯基)-4(3H)-喹唑啉酮、2-甲基-3-(4-{3-[(2R)-2-甲基吡咯啶-1-基]丙氧基}苯基)吡啶并[4,3-d]嘧啶-4(3H)-酮、6-甲氧基-2-甲基-3-(4-{3-[(2R)-2-甲基吡咯啶-1-基]丙氧基}苯基)-4(3H)-喹唑啉酮、6-甲氧基-2-甲基-3-(4-{3-[(2S)-2-甲基吡咯啶-1-基]丙氧基}苯基)-4(3H)-喹唑啉酮，及其醫藥學上可接受之鹽。Particular H3 (histamine H3) antagonists/reverse agonists for use in combination with the compounds of the invention include those disclosed in WO 05/077905, including: 3-{4-[(1-cyclobutyl-4- Piperidinyl)oxy]phenyl}-2-ethylpyrido[2,3-d]-pyrimidin-4(3H)-one, 3-{4-[(1-cyclobutyl-4-piperidin) Pyridyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one, 2-ethyl-3-(4-{3-[(3S)- 3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one, 2-methyl-3-(4-{3-[ (3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 3-{4-[(1-ring) Butyl-4-piperidinyloxy]phenyl}-2,5-dimethyl-4(3H)-quinazolinone, 3-{4-[(1-cyclobutyl-4-piperidin) Pyridyl)oxy]phenyl}-2-methyl-5-trifluoromethyl-4(3H)-quinazolinone, 3-{4-[(1-cyclobutyl-4-piperidinyl) Oxy]phenyl}-5-methoxy-2-methyl-4(3H)-quinazolinone, 3-{4-[(1-cyclobutylpiperidin-4-yl)oxy Phenyl}-5-fluoro-2-methyl-4(3H)-quinazolinone, 3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}- 7-fluoro-2-methyl-4(3H)-quinazolinone, 3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-methoxy -2-methyl-4(3H)- Oxazolinone, 3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-fluoro-2-methyl-4(3H)-quinazolinone, 3 -{4-[(1-Cyclobutylpiperidin-4-yl)oxy]phenyl}-8-fluoro-2-methyl-4(3H)-quinazolinone, 3-{4-[ (1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one, 3-{4-[(1 -cyclobutylpiperidin-4-yl)oxy]phenyl}-6-fluoro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one, 3-{4-[ (1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[4,3-d]pyrimidin-4(3H)-one, 6-methoxy-2- Methyl-3-{4-[3- (1-piperidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one, 6-methoxy-2-methyl-3-{4-[3 -(1-pyrrolidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one, 2,5-dimethyl-3-{4-[3-( 1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone, 2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl }-5-trifluoromethyl-4(3H)-quinazolinone, 5-fluoro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl} -4(3H)-quinazolinone, 6-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)- Quinazolinone, 5-methoxy-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4 ( 3H)-quinazolinone, 7-methoxy-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl) -4(3H)-quinazolinone, 2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyridin[ 2,3-d]pyrimidine-4(3H)-one, 5-fluoro-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy Phenyl)-4-(3H)-quinazolinone, 2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}benzene Pyridyl[4,3-d]pyrimidin-4(3H)-one, 6-methoxy-2-methyl-3-(4-{3-[(2R)-2-) Pyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone, 6-methoxy-2-methyl-3-(4-{3-[(2S)-2 -Methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone, and a pharmaceutically acceptable salt thereof.

與本發明化合物組合使用之特定CCK1R促效劑包括：3-(4-{[1-(3-乙氧基苯基)-2-(4-甲基苯基)-1H-咪唑-4-基]羰基}-1-哌嗪基)-1-萘甲酸、3-(4-{[1-(3-乙氧基苯基)-2-(2-氟-4-甲基苯基)-1H-咪唑-4-基]羰基}-1-哌嗪基)-1-萘甲酸、3-(4-{[1-(3-乙氧基苯基)-2-(4-氟苯基)-1H-咪唑-4-基]羰基}-1-哌嗪基)-1-萘甲酸、3-(4-{[1-(3-乙氧基苯基)-2- (2,4-二氟苯基)-1H-咪唑-4-基]羰基}-1-哌嗪基)-1-萘甲酸及3-(4-{[1-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)-2-(4-氟苯基)-1H-咪唑-4-基]羰基}-1-哌嗪基)-1-萘甲酸，及其醫藥學上可接受之鹽。Specific CCK1R agonists for use in combination with the compounds of the invention include: 3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazole-4- Carbonyl}-1-piperazinyl-1-naphthoic acid, 3-(4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl) -1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid, 3-(4-{[1-(3-ethoxyphenyl)-2-(4-fluorobenzene) -1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid, 3-(4-{[1-(3-ethoxyphenyl)-2- (2,4-difluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic acid and 3-(4-{[1-(2,3-dihydro) -1,4-benzodioxan-6-yl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthalene Formic acid, and pharmaceutically acceptable salts thereof.

與本發明化合物組合使用之特定MC4R促效劑包括：1)(5S)-1'-{[(3R,4R)-1-第三丁基-3-(2,3,4-三氟苯基)哌啶-4-基]羰基}-3-氯-2-甲基-5-[1-甲基-1-(1-甲基-1H-1,2,4-三唑-5-基)乙基]-5H-螺[呋喃并[3,4-b]吡啶-7,4'-哌啶]；2)(5R)-1'-{[(3R,4R)-1-第三丁基-3-(2,3,4-三氟苯基)-哌啶-4-基]羰基}-3-氯-2-甲基-5-[1-甲基-1-(1-甲基-1H-1,2,4-三唑-5-基)乙基]-5H-螺[呋喃并[3,4-b]吡啶-7,4'-哌啶]；3)2-(1'-{[(3S,4R)-1-第三丁基-4-(2,4-二氟苯基)吡咯啶-3-基]羰基}-3-氯-2-甲基-5H-螺[呋喃并[3,4-b]吡啶-7,4'-哌啶]-5-基)-2-甲基丙腈；4)1'-{[(3S,4R)-1-第三丁基-4-(2,4-二氟苯基)吡咯啶-3-基]羰基}-3-氯-2-甲基-5-[1-甲基-1-(1-甲基-1H-1,2,4-三唑-5-基)乙基]-5H-螺[呋喃并[3,4-b]吡啶-7,4'-哌啶]；5)N-[(3R,4R)-3-({3-氯-2-甲基-5-[1-甲基-1-(1-甲基-1H-1,2,4-三唑-5-基)乙基]-1'H,5H-螺[呋喃并[3,4-b]吡啶-7,4'-哌啶]-1'-基}羰基)-4-(2,4-二氟苯基)-環戊基]-N-甲基四氫-2H-哌喃-4-胺；6)2-[3-氯-1'-({(1R,2R)-2-(2,4-二氟苯基)-4-[甲基(四氫-2H-哌喃-4-基)胺基]-環戊基}-羰基)-2-甲基-5H-螺[呋喃并[3,4-b]吡啶-7,4'-哌啶]-5-基]-2-甲基-丙腈；及其醫藥學上可接受之鹽。Specific MC4R agonists for use in combination with the compounds of the invention include: 1) (5S)-1'-{[(3R,4R)-1-t-butyl-3-(2,3,4-trifluorobenzene) Benzylpiperidin-4-yl]carbonyl}-3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazole-5- Ethyl]-5H-spiro[furo[3,4-b]pyridine-7,4'-piperidine]; 2)(5R)-1'-{[(3R,4R)-1- Tributyl-3-(2,3,4-trifluorophenyl)-piperidin-4-yl]carbonyl}-3-chloro-2-methyl-5-[1-methyl-1-(1 -methyl-1H-1,2,4-triazol-5-yl)ethyl]-5H-spiro[furo[3,4-b]pyridine-7,4'-piperidine]; 3)2 -(1'-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-3-chloro-2-methyl -5H-spiro[furo[3,4-b]pyridine-7,4'-piperidine]-5-yl)-2-methylpropanenitrile; 4) 1'-{[(3S,4R)- 1-t-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-3-chloro-2-methyl-5-[1-methyl-1-(1 -methyl-1H-1,2,4-triazol-5-yl)ethyl]-5H-spiro[furo[3,4-b]pyridine-7,4'-piperidine]; 5)N -[(3R,4R)-3-({3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazole-5-) Ethyl]-1'H,5H-spiro[furo[3,4-b]pyridine-7,4'-piperidine]-1'-yl}carbonyl)-4-(2,4-di Fluorophenyl)-cyclopentyl]-N-methyltetrahydro-2H-pyran 4-amine; 6) 2-[3-chloro-1'-({(1R,2R)-2-(2,4-difluorophenyl)-4-[methyl(tetrahydro-2H-piperidin)喃-4-yl)amino]-cyclopentyl}-carbonyl)-2-methyl-5H-spiro[furo[3,4-b]pyridine-7,4'-piperidine]-5-yl ]-2-methyl-propionitrile; and pharmaceutically acceptable salts thereof.

適合之神經激肽-1(neurokinin-1，NK-1)受體拮抗劑宜與 本發明之AMP激酶活化劑一起使用。用於本發明之NK-1受體拮抗劑詳盡描述於此項技術中。用於本發明之特定神經激肽-1受體拮抗劑包括：(±)-(2R3R,2S3S)-N-{[2-環丙氧基-5-(三氟甲氧基)-苯基]甲基}-2-苯基哌啶-3-胺、2-(R)-(1-(R)-(3,5-雙(三氟甲基)-苯基)乙氧基)-3-(S)-(4-氟苯基)-4-(3-(5-側氧基-1H,4H-1,2,4-三唑基)甲基)嗎啉、阿瑞吡坦(aperpitant)、CJ17493、GW597599、GW679769、R673、RO67319、R1124、R1204、SSR146977、SSR240600、T-2328及T2763，或其醫藥學上可接受之鹽。Suitable neurokinin-1 (NK-1) receptor antagonists should be The AMP kinase activators of the invention are used together. The NK-1 receptor antagonists useful in the present invention are described in detail in the art. Specific neurokinin-1 receptor antagonists for use in the present invention include: (±)-(2R3R, 2S3S)-N-{[2-cyclopropoxy-5-(trifluoromethoxy)-phenyl ]methyl}-2-phenylpiperidin-3-amine, 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)- 3-(S)-(4-fluorophenyl)-4-(3-(5-o-oxy-1H,4H-1,2,4-triazolyl)methyl)morpholine, aprepitant (aperpitant), CJ17493, GW597599, GW679769, R673, RO67319, R1124, R1204, SSR146977, SSR240600, T-2328 and T2763, or a pharmaceutically acceptable salt thereof.

術語「治療有效量」意謂將引發研究者、獸醫、內科醫師或其他臨床醫師所尋求的組織、系統、動物或人類之生物或醫學反應，包括所治療病症之症狀減輕的結構式I之化合物之量。本發明之新穎治療方法係針對熟習此項技術者已知之病症。術語「哺乳動物」包括人類，及伴侶動物，諸如狗及貓。The term "therapeutically effective amount" means a compound of formula I which will elicit a biological or medical response of a tissue, system, animal or human being sought by a researcher, veterinarian, physician or other clinician, including amelioration of the symptoms of the condition being treated. The amount. The novel therapeutic methods of the present invention are directed to conditions known to those skilled in the art. The term "mammal" includes humans, as well as companion animals such as dogs and cats.

式I化合物與第二活性成分之重量比可變化且將視各成分之有效劑量而定。一般而言，將使用各自之有效劑量。因此，舉例而言，當式I化合物與DPIV抑制劑組合時，式I化合物與DPIV抑制劑之重量比一般將在約1000：1至約1：1000、較佳約200：1至約1：200之範圍內。式I化合物與其他活性成分之組合一般亦將處於前述範圍內，但在各種狀況下，應使用各活性成分之有效劑量。The weight ratio of the compound of formula I to the second active ingredient can vary and will depend on the effective dosage of the ingredients. In general, the respective effective dose will be used. Thus, for example, when a compound of formula I is combined with a DPIV inhibitor, the weight ratio of the compound of formula I to the DPIV inhibitor will generally range from about 1000:1 to about 1:1000, preferably from about 200:1 to about 1: Within the range of 200. Combinations of a compound of formula I with other active ingredients will generally also be within the foregoing ranges, but in each case an effective amount of each active ingredient will be employed.

本發明之結構式I之化合物可根據以下流程、中間物及實例之程序使用適當物質來製備，且進一步由以下特定實 例例示。此外，藉由利用本文所含之揭示內容中所述之程序，一般技術者可容易地製備本文所主張之其他本發明化合物。然而，實例中所說明之化合物不應理解為形成視作本發明之唯一種類。實例進一步說明有關製備本發明化合物之細節。熟習此項技術者將易於瞭解，以下製備程序之條件及製程的已知變化可用於製備此等化合物。本發明化合物一般以其醫藥學上可接受之鹽(諸如本文先前所述之鹽)形式分離。使用胺及羧酸官能基之保護基來促進所要反應及使不當反應降至最少已有充分文獻記載。移除保護基所需之條件見於標準教科書中，諸如Greene,T及Wuts,P.G.M.,Protective Groups in Organic Synthesis,John Wiley & Sons,Inc.,New York,NY,1991。CBZ及BOC為有機合成中之常用保護基，且其移除條件為熟習此項技術者所知。除非另有註釋，否則所有溫度皆為攝氏度。質譜(MS)係藉由電噴霧離子質譜分析來量測。The compound of the formula I of the present invention can be prepared by using an appropriate substance according to the following procedures, intermediates and examples, and further by the following specific An example is given. In addition, other compounds of the invention as claimed herein can be readily prepared by one of ordinary skill in the art by utilizing the procedures set forth in the disclosure herein. However, the compounds illustrated in the examples are not to be construed as forming the only species considered to be the invention. The examples further illustrate details regarding the preparation of the compounds of the invention. Those skilled in the art will readily appreciate that known variations in the conditions and processes of the following preparative procedures can be used to prepare such compounds. The compounds of the invention are generally isolated in the form of their pharmaceutically acceptable salts, such as the salts previously described herein. The use of protecting groups for amine and carboxylic acid functional groups to promote the desired reaction and to minimize undesired reactions has been well documented. The conditions required to remove the protecting group are found in standard textbooks such as Greene, T and Wuts, P. G. M., Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., New York, NY, 1991. CBZ and BOC are commonly used protecting groups in organic synthesis, and their removal conditions are known to those skilled in the art. All temperatures are in degrees Celsius unless otherwise noted. Mass spectrometry (MS) was measured by electrospray ion mass spectrometry.

對本發明化合物之製備之描述中所用之縮寫：ACN為乙腈；AcOH為乙酸；C為碳；CV為管柱體積；DAST為三氟化(二乙基胺基)硫；DBU為1,8-二氮雜雙環[5.4.0]十一碳-7-烯；DIBAL-H為氫化二異丁基鋁；DCM為二氯甲烷；DIPEA為二異丙基乙胺；DMA為二甲基縮乙醛；DME為1,2-二甲氧基乙烷；DMF為二甲基甲醯胺；DMSO為二甲亞碸；dppf DCM錯合物為1,1'-雙(二苯基-膦基)二茂鐵二氯甲烷錯合物；Et2 O為乙醚；EtOAc為乙酸乙酯；dppf為1,1'-雙(二苯基-膦基)二茂鐵；EtOH為乙醇；Et3 N為三乙 胺；h為小時；HPLC為高壓液相層析；ISCO Rf 為經由中壓液相層析，使用Teledyne ISCO RediSep®管柱測定之Rf ；異甘露糖醇(isomannide)為1,4：3,6-二去水-甘露糖醇；KOAc為乙酸鉀；L為公升；LC/MS及LC-MS為液相層析/質譜分析；KOTMS為三甲基矽醇鉀；LAH為氫化鋰鋁；M為莫耳濃度；ml及mL為毫升；Me為甲基；MeCN為乙腈；MeI為碘代甲烷；MeMgBr為溴化甲基鎂；MeOH為甲醇；MgBr為溴化鎂；min為分鐘；mmol為毫莫耳；m-CPBA為間氯過苯甲酸；MTBE為第三丁基甲基醚；N為當量濃度；NaOAc為乙酸鈉；NBS為N-溴代丁二醯胺；NIS為N-碘代丁二醯胺；PPh3 為三苯基膦；PhSiH為苯基矽烷；wt%為重量百分比；psi為磅/平方吋；RT及rt為室溫；Rt為滯留時間；羅謝爾氏鹽(Rochelles' Salt)為酒石酸鉀鈉；SEM為2-(三甲基矽烷基)乙氧基甲基；SEMCl為2-(三甲基矽烷基)-乙氧基甲基氯；TBAF為氟化四丁基銨；TMS為三甲基矽烷基；TFA為三氟乙酸；且THF為四氫呋喃。Abbreviations used in the description of the preparation of the compounds of the invention: ACN is acetonitrile; AcOH is acetic acid; C is carbon; CV is column volume; DAST is trifluoro (diethylamino) sulfur; DBU is 1,8- Diazabicyclo[5.4.0]undec-7-ene; DIBAL-H is diisobutylaluminum hydride; DCM is dichloromethane; DIPEA is diisopropylethylamine; DMA is dimethyl condensed Aldehyde; DME is 1,2-dimethoxyethane; DMF is dimethylformamide; DMSO is dimethyl hydrazine; dppf DCM complex is 1,1'-bis(diphenyl-phosphino) a ferrocene dichloromethane complex; Et 2 O is diethyl ether; EtOAc is ethyl acetate; dppf is 1,1'-bis(diphenyl-phosphino)ferrocene; EtOH is ethanol; Et 3 N is triethylamine; H is hour; HPLC high pressure liquid chromatography; ISCO R f via medium pressure liquid chromatography using a column RediSep® measurement of Teledyne ISCO R f; isomannide (isomannide) of 1 , 4:3,6-di-dehydrate-mannitol; KOAc is potassium acetate; L is liter; LC/MS and LC-MS are liquid chromatography/mass spectrometry; KOTMS is potassium trimethylnonoxide; LAH Lithium aluminum hydride; M is molar concentration; ml and mL are milliliters; Me is methyl; MeCN is acetonitrile; MeI is Methanation methane; MeMgBr is methyl magnesium bromide; MeOH is methanol; MgBr is magnesium bromide; min is minute; mmol is millimolar; m-CPBA is m-chloroperbenzoic acid; MTBE is third butyl methyl ether; Is an equivalent concentration; NaOAc is sodium acetate; NBS is N-bromosuccinamine; NIS is N-iodobutanediamine; PPh 3 is triphenylphosphine; PhSiH is phenylnonane; wt% is weight percent ; psi is pounds per square inch; RT and rt are room temperature; Rt is residence time; Rochelles' Salt is sodium potassium tartrate; SEM is 2-(trimethyldecyl)ethoxylated SEMCl is 2-(trimethyldecyl)-ethoxymethyl chloride; TBAF is tetrabutylammonium fluoride; TMS is trimethyldecylalkyl; TFA is trifluoroacetic acid; and THF is tetrahydrofuran.

微波(MW)反應係使用單模式操作型Biotage Emrys Optimizer，在密封反應瓶中，於保持恆定之指定固定溫度下維持規定反應時間來進行。中壓液相層析(MPLC)純化係使用預先裝填有35-60微米矽膠之Teledyne ISCO RediSep®正相管柱來進行。LC-MS系統含有以正離子模式操作且接收0.1 mL/min流率之Applied Biosystems API150EX MS與接收0.1 mL/min流率之Shimadzu UV偵測器。除非有規定，否則LC條件為溶劑A=含0.03% TFA之乙 腈；溶劑B=含0.05% TFA之水；流率=10 mL/min；管柱：Chromolith Performance RP-18e，100×4.6 mm；梯度程式：min(%B)0(95)，1.6(5)，2.6(5)，2.7(95)，3.0(95)。除非有規定，否則1 H NMR係於DMSO-d6 中在300 MHz或500 MHz下獲得，且光譜係使用CD2 HS(O)CD3 (δ 2.504)作為參考線內標以單位δ記錄。C、H、N微量分析係由Robertson Microlit Laboratories,Inc.,Madison,NJ進行。The microwave (MW) reaction was carried out using a single mode operation type Biotage Emrys Optimizer in a sealed reaction flask maintained at a predetermined fixed temperature maintained at a constant constant temperature. Medium pressure liquid chromatography (MPLC) purification was carried out using a Teledyne ISCO RediSep® normal phase column pre-filled with 35-60 micron silicone. The LC-MS system contained an Applied Biosystems API 150 EX MS operating in positive ion mode and receiving a flow rate of 0.1 mL/min with a Shimadzu UV detector receiving a flow rate of 0.1 mL/min. Unless otherwise specified, LC conditions are solvent A = acetonitrile with 0.03% TFA; solvent B = water with 0.05% TFA; flow rate = 10 mL/min; column: Chromolith Performance RP-18e, 100 x 4.6 mm; Gradient program: min (% B) 0 (95), 1.6 (5), 2.6 (5), 2.7 (95), 3.0 (95). 1 H NMR was obtained in DMSO-d 6 at 300 MHz or 500 MHz, and the spectra were recorded in units of δ using CD 2 HS(O)CD 3 (δ 2.504) as a reference line internal standard, unless otherwise specified. C, H, N microanalysis was performed by Robertson Microlit Laboratories, Inc., Madison, NJ.

以下反應流程說明可用於合成本發明所述之結構式I之化合物的方法。除非另有指示，否則所有取代基如上文所定義。可採用基於有機合成文獻中已知之合成轉化的若干策略來製備通式I之標題化合物。The following reaction scheme illustrates a process that can be used to synthesize the compounds of structural formula I described herein. Unless otherwise indicated, all substituents are as defined above. The title compound of formula I can be prepared using several strategies based on synthetic transformations known in the art of organic synthesis.

中間物1Intermediate 1

6-氯-5-碘-2-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶6-chloro-5-iodo-2-(methylsulfonyl)-1H-imidazo[4,5-b]pyridine

步驟A5,6-二氯-3-硝基吡啶-2-胺 。向5-氯-3-硝基吡啶-2-胺(16 g，92 mmol)於AcOH(70 mL)中之溶液中添加N-氯 代丁二醯亞胺(14.8 g，111 mmol)。在80℃下隔夜攪拌混合物3小時，冷卻至室溫，用MeOH(30 mL)稀釋且過濾。用AcOH、水洗滌固體殘餘物，接著乾燥，得到呈白色固體狀之所要產物，其未經進一步純化即用於下一步驟中。LC-MS：C5 H3 Cl2 N3 O2 計算值208.0，觀測值m/e：208.07(M+H)+ (Rt 1.48/5 min)。Step A 5,6-Dichloro-3-nitropyridin-2-amine . To a solution of 5-chloro-3-nitropyridin-2-amine (16 g, 92 mmol) in EtOAc (EtOAc) (EtOAc) The mixture was stirred at 80 &lt;0&gt;C overnight for 3 h, cooled to rt then diluted with EtOAc EtOAc The solid residue was washed with EtOAc (EtOAc)EtOAc. LC-MS: C 5 H 3 Cl 2 N 3 O 2 calcd 208.0, observed m / e: 208.07 (M + H) + (Rt 1.48 / 5 min).

步驟B5-氯-6-碘-3-硝基吡啶-2-胺 。向5,6-二氯-3-硝基吡啶-2-胺(15 g，72.1 mmol)於AcOH(70 mL)中之溶液中添加碘化鈉(43.2 g，149.9 mmol)。在90℃下攪拌混合物2小時，冷卻至室溫，用水(70 mL)稀釋且過濾。用水洗滌固體殘餘物，接著在真空下乾燥，得到呈淺黃色固體狀之所要產物，其未經進一步純化即用於下一步驟中。LC-MS：C5 H3 ClIN3 O2 計算值299.45，觀測值m/e：299.94(M+H)+ (Rt 2.18/5 min)。Step B 5-Chloro-6-iodo-3-nitropyridin-2-amine . To a solution of 5,6-dichloro-3-nitropyridin-2-amine (15 g, 72.1 mmol) in AcOH (70 mL), sodium iodide (43.2 g, 149.9 mmol). The mixture was stirred at 90 &lt;0&gt;C for 2 h, cooled to rt and diluted with water &lt The solid residue was washed with EtOAc (EtOAc)EtOAc. LC-MS: C 5 H 3 ClIN 3 O 2 calcd 299.45, observed m / e: 299.94 (M + H) + (Rt 2.18 / 5 min).

步驟C5-氯-6-碘吡啶-2,3-二胺 。向5-氯-6-碘-3-硝基吡啶-2-胺(18.9 g，63.1 mmol)於EtOH(100 mL)中之懸浮液中添加二水合氯化錫(II)(57 g，252 mmol)。在70℃下加熱混合物0.5小時。使反應物(rxn)升溫至室溫，且用150 mL水與60 g KF之漿液處理並攪拌0.5小時。接著將混合物分配於乙酸乙酯(300 mL)與水(300 mL)之間。用鹽水洗滌乙酸乙酯層，經硫酸鎂乾燥，且經100 g矽膠襯墊過濾。濃縮濾液且在真空下乾燥，得到灰白色固體，其未經進一步純化即用於下一步驟中。LC-MS：C5 H5 ClIN3 計算值269.47，觀測值m/e：269.99(M+H)+ (Rt 1.35/5 min)。Step C 5-Chloro-6-iodopyridine-2,3-diamine . To a suspension of 5-chloro-6-iodo-3-nitropyridin-2-amine (18.9 g, 63.1 mmol) in EtOH (100 mL) was added tin(II) chloride dihydrate (57 g, 252 Mm). The mixture was heated at 70 ° C for 0.5 hours. The reaction (rxn) was allowed to warm to room temperature and was treated with 150 mL of water and 60 g of KF slurry and stirred for 0.5 hour. The mixture was then partitioned between ethyl acetate (300 mL) and water (300 mL). The ethyl acetate layer was washed with brine, dried over magnesium sulfate and filtered th The filtrate was concentrated and dried <RTI ID=0.0> LC-MS: C 5 H 5 ClIN 3 calcd 269.47, observed m / e: 269.99 (M + H) + (Rt 1.35 / 5 min).

步驟D6-氯-5-碘-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-硫酮 。將DMAP(15.4 g，126 mmol)添加至5-氯-6-碘吡啶-2,3-二胺(17 g，63.1 mmol)之THF(200 mL)溶液中。接著在氮氣下經由加料漏斗逐滴添加硫光氣(4.9 mL，63.1 mmol)，且在室溫下攪拌1小時。接著將混合物分配於乙酸乙酯(500 mL)與2 N HCl(100 mL)之間。用鹽水洗滌乙酸乙酯層，經硫酸鎂乾燥且濃縮，得到呈白色粉末狀之所要產物，其未經進一步純化即用於下一步驟中。LC-MS：C6 H3 ClIN3 S計算值311.5，觀測值m/e：311.91(M+H)+ (Rt 1.69/5 min)。Step D 6-Chloro-5-iodo-1,3-dihydro-2H-imidazo[4,5-b]pyridine-2-thione . DMAP (15.4 g, 126 mmol) was added to a solution of 5-chloro-6-iodopyridine-2,3-diamine (17 g, 63.1 mmol) in THF (200 mL). Subsequently, thiophosgene (4.9 mL, 63.1 mmol) was added dropwise via an addition funnel under nitrogen, and stirred at room temperature for 1 hour. The mixture was then partitioned between ethyl acetate (500 mL) and 2N EtOAc (100 mL). The ethyl acetate layer was washed with EtOAc (EtOAc m. LC-MS: C 6 H 3 ClIN 3 S calcd 311.5, observed m / e: 311.91 (M + H) + (Rt 1.69 / 5 min).

步驟E6-氯-5-碘-2-(甲基硫基)-1H-咪唑并[4,5-b]吡啶 。在室溫下，將6-氯-5-碘-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-硫酮(11.0 g，35.3 mmol)及KOH(2.38 g，42.4 mmol)於乙醇(200 mL)中之懸浮液攪拌0.5小時。接著添加碘甲烷(2.2 mL，35.3 mmol)，且在室溫下攪拌反應物1小時。在真空中移除乙醇，且將所得殘餘物分配於乙酸乙酯(250 mL)與2 N HCl(50 mL)之間。用鹽水洗滌乙酸乙酯層，經硫酸鎂乾燥，經100 g矽膠襯墊過濾且濃縮，得到呈白色固體狀之所要產物。LC-MS：C7 H5 ClIN3 S計算值325.56，觀測值m/e：325.88(M+H)+ (Rt 2.05/5 min)。Step E 6-Chloro-5-iodo-2-(methylthio)-1H-imidazo[4,5-b]pyridine . 6-Chloro-5-iodo-1,3-dihydro-2H-imidazo[4,5-b]pyridine-2-thione (11.0 g, 35.3 mmol) and KOH (2.38 g) at room temperature The suspension in 42.4 mmol) in ethanol (200 mL) was stirred for 0.5 h. Methyl iodide (2.2 mL, 35.3 mmol) was then added and the mixture was stirred at room temperature for 1 hour. Ethanol was removed in vacuo and the residue was partitioned between ethyl acetate (250 mL) and 2 N EtOAc The ethyl acetate layer was washed with EtOAc (EtOAc m. LC-MS: C 7 H 5 ClIN 3 S calcd 325.56, observed m / e: 325.88 (M + H) + (Rt 2.05 / 5 min).

步驟F6-氯-5-碘-2-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶 。將過硫酸氫鉀(oxone)(20.8 g，33.8 mmol)添加至6-氯-5-碘-2-(甲基硫基)-1H-咪唑并[4,5-b]吡啶(5.0 g，15.4 mmol)之乙腈(100 mL)/水(100 mL)懸浮液中，且在室溫下 攪拌反應物18小時。經燒結玻璃漏斗過濾懸浮液，且將濾液分配於乙酸乙酯與飽和硫酸氫鈉之間。用鹽水洗滌乙酸乙酯層，經硫酸鎂乾燥且濃縮，得到呈白色固體狀之標題化合物，其未經進一步純化即用於後續步驟中。溶解性阻礙了純化且此物質按原樣使用。LC-MS：C7 H5 ClN3 O2 S計算值357.56，觀測值m/e：357.07(M+H)+ (Rt 1.36/4 min)。1 H NMR δ(ppm)(DMSO-d6 )：8.44(1 H,s),3.53(3 H,s)。Step F 6-Chloro-5-iodo-2-(methylsulfonyl)-1H-imidazo[4,5-b]pyridine . Add oxone (20.8 g, 33.8 mmol) to 6-chloro-5-iodo-2-(methylthio)-1H-imidazo[4,5-b]pyridine (5.0 g, 15.4 mmol) of a suspension of acetonitrile (100 mL) / water (100 mL), and the mixture was stirred at room temperature for 18 hours. The suspension was filtered through a sintered glass funnel and the filtrate was partitioned between ethyl acetate and saturated sodium hydrogen sulfate. The ethyl acetate layer was washed with EtOAc EtOAc m. Solubility hinders purification and this material is used as is. LC-MS: C 7 H 5 ClN 3 O 2 S Calcd 357.56, observed m / e: 357.07 (M + H) + (Rt 1.36 / 4 min). 1 H NMR δ (ppm) (DMSO-d 6 ): 8.44 (1H, s), 3.53 (3H, s).

中間物2Intermediate 2

6-氯-5-碘-2-(甲基磺醯基)-1-{[2-(三甲基矽烷基)乙氧基]甲基}-咪唑并[4,5-b]吡啶 。在0℃下於氮氣氛圍下，將SEM-Cl(2.48 mL，14 mmol)添加至中間物1(5.0 g，14 mmol)及三乙胺(2.92 mL，21 mmol)之THF(100 mL)溶液中。經30分鐘使反應物升溫至室溫。將反應物分配於乙酸乙酯與飽和氯化銨水溶液之間。用水、鹽水洗滌有機層，經硫酸鎂乾燥且濃縮。利用BiotageTM 100G SNAP濾筒且採用線性梯度：0%至20% EtOAc/己烷繼之以20%至100% EtOAc/己烷對所得殘餘物進行急驟層析，得到呈澄清油狀之標題化合物。LC-MS：C13 H19 ClN3 O3 SSi計算值487.8，觀測值m/e：428.9(M+H)+ (Rt 2.54/4 min)。 6-chloro-5-iodo-2- (methyl-sulfo acyl) -1 - {[2- (trimethyl silicon alkyl) ethoxy] methyl} - imidazo [4,5-b] pyridine. Add SEM-Cl (2.48 mL, 14 mmol) to Intermediate 1 (5.0 g, 14 mmol) and triethylamine (2.92 mL, 21 mmol) in THF (100 mL) in. The reaction was allowed to warm to room temperature over 30 min. The reaction was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with water and brine, dried over magnesium sulfate Using Biotage TM 100G SNAP cartridge and using a linear gradient: 0% to 20% EtOAc / hexanes followed by 20% to 100% EtOAc / hexane resulting residue was subjected to flash chromatography to give a clear oil of the title compound . LC-MS: C 13 H 19 ClN 3 O 3 SSi calcd 487.8, observed m / e: 428.9 (M + H) + (Rt 2.54 / 4 min).

中間物3Intermediate 3

5-[(6-氯-5-碘-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H咪唑并[4,5-b]吡啶-2-基)氧基]-2-甲基苯甲酸甲酯 。在室溫下於氮氣氛圍下，將碳酸銫(2.67 g，8.2 mmol)添加至中間物2(1.6 g，3.28 mmol)及5-羥基-2-甲基苯甲酸甲酯(0.82 g，4.92 mmol)之DMA(10 mL)溶液中。攪拌反應物15分鐘，接著分配於乙酸乙酯與10%檸檬酸水溶液之間。用水、鹽水洗滌有機層，經硫酸鎂乾燥且濃縮。利用BiotageTM 100G SNAP濾筒且採用線性梯度：0%至100% EtOAc/己烷對所得殘餘物進行急驟層析，得到呈白色固體狀之標題化合物。LC-MS：C21 H25 ClN3 O4 Si計算值573.89，觀測值m/e：573.93(M+H)+ (Rt 2.92/4 min)。 5-[(6-chloro-5-iodo-1-{[2-(trimethyldecyl)ethoxy]methyl}-1H imidazo[4,5-b]pyridin-2-yl)oxy Methyl 2-methylbenzoate . Cesium carbonate (2.67 g, 8.2 mmol) was added to intermediate 2 (1.6 g, 3.28 mmol) and methyl 5-hydroxy-2-methylbenzoate (0.82 g, 4.92 mmol) at room temperature under nitrogen. ) in DMA (10 mL) solution. The reaction was stirred for 15 min then partitioned between ethyl acetate and 10% aqueous EtOAc. The organic layer was washed with water and brine, dried over magnesium sulfate Using Biotage TM 100G SNAP cartridge and using a linear gradient: 0% to 100% EtOAc / hexane resulting residue was subjected to flash chromatography to give a white solid of the title compound. LC-MS: C 21 H 25 ClN 3 O 4 Si calcd 573.89, observed m / e: 573.93 (M + H) + (Rt 2.92 / 4 min).

中間物4Intermediate 4

反-4-[(6-氯-5-碘-1-{丙-2-烯-1-基}-1H咪唑并[4,5-b]吡啶-2-基]氧基}環己烷甲酸乙酯 。在室溫下，將氫化鈉(475 mg，19.8 mmol)添加至中間物1(5.9 g，16.5 mmol)及烯丙基溴(1.7 mL，19.8 mmol)之DMF溶液中。在室溫下攪拌反應物16小時。接著依序用4-羥基環己烷甲酸乙酯(10.64 mL，66 mmol)及DBU(9.95 mL，66 mmol)處理反應物。將反應物分配於EtOAc與10%檸檬酸水溶液之間。用水、鹽水洗滌EtOAc層，經硫酸鎂乾燥且濃縮。利用BiotageTM 100G SNAP濾筒且採用梯度：0%至20% EtOAc/己烷對所 得殘餘物進行急驟層析，得到呈無色油狀之標題化合物，其在真空乾燥隔夜後凝固。LC-MS：C18 H21 ClN3 O3 計算值489.7，觀測值m/e：489.9(M+H)+ (Rt 2.75/4 min)。 Trans-4-[(6-chloro-5-iodo-1-{prop-2-en-1-yl}-1H imidazo[4,5-b]pyridin-2-yl]oxy}cyclohexane Ethyl formate . Sodium hydride (475 mg, 19.8 mmol) was added to a solution of intermediate 1 (5.9 g, 16.5 mmol) and allyl bromide (1.7 mL, 19.8 mmol) in DMF at room temperature. The reaction was stirred with EtOAc (EtOAc) (EtOAc)EtOAc. . aqueous citric acid between water, EtOAc layer was washed with brine, dried over magnesium sulfate and concentrated using a Biotage TM 100G SNAP cartridge and gradient: 0% to 20% EtOAc / hexane resulting residue was subjected to flash chromatography to give The title compound was obtained as a colorless oil, which was solidified after vacuum drying overnight. LC-MS: C 18 H 21 ClN 3 O 3 calc. 489.7, observed m/e: 489.9 (M+H) + (Rt 2.75/4 Min).

中間物5Intermediate 5

反-4-{[(5-(4-溴苯基)-6-氯-1-{丙-2-烯-1-基}-1H咪唑并[4,5-b]吡啶-2-基]氧基}環己烷甲酸乙酯 。在室溫下於氮氣氛圍下，將1,1'-雙(二苯基膦基)二茂鐵-二氯化鈀(II)二氯甲烷錯合物(183 mg，0.22 mmol)添加至中間物4(550 mg，1.12 mmol)、4-溴苯基酸(271 mg，1.35 mmol)及碳酸銫(1.1 g，3.37 mmol)之DMSO(5 mL)溶液中。加熱反應物至90℃，維持3小時，接著分配於EtOAc與10%檸檬酸水溶液之間。用水及鹽水洗滌有機層，經硫酸鎂乾燥且濃縮。利用BiotageTM 50G SNAP濾筒且採用線性梯度：0%至100% EtOAc/己烷對所得殘餘物進行急驟層析，得到呈白色固體狀之標題化合物。LC-MS：C24 H25 BrClN3 O3 計算值518.8，觀測值m/e：520.3(M+H)+ (Rt 1.4/2 min)。 Trans-4-{[(5-(4-bromophenyl)-6-chloro-1-{prop-2-en-1-yl}-1H imidazo[4,5-b]pyridin-2-yl Ethyl}ethyl cyclohexanecarboxylate . 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) chloride dichloride was mixed at room temperature under a nitrogen atmosphere. (183 mg, 0.22 mmol) added to intermediate 4 (550 mg, 1.12 mmol), 4-bromophenyl Acid (271 mg, 1.35 mmol) and cesium carbonate (1.1 g, 3.37 mmol) in DMSO (5 mL). The reaction was heated to 90 &lt;0&gt;C for 3 h then partitioned between EtOAc and 10% aqueous EtOAc. The organic layer was washed with water and brine, dried over magnesium sulfate Using Biotage TM 50G SNAP cartridge and using a linear gradient: 0% to 100% EtOAc / hexane resulting residue was subjected to flash chromatography to give a white solid of the title compound. LC-MS: C 24 H 25 BrClN 3 O 3 calcd 518.8, observed m / e: 520.3 (M + H) + (Rt 1.4 / 2 min).

中間物6Intermediate 6

5-(聯苯-4-基)-6-氯-2-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶5-(biphenyl-4-yl)-6-chloro-2-(methylsulfonyl)-1H-imidazo[4,5-b]pyridine

將中間物1(50 g，140 mmol)、4-聯苯酸(33.2 g，168 mmol)及磷酸三鉀(89 g，212.3 mmol)溶解於THF(500 mL)及水(50 mL)中，接著用N2 充氣20分鐘。將乙酸鈀(3.14 g，14.0 mmol)及正丁基二金剛烷基膦(Catacxium A，10 g，28 mmol)於THF(30 mL)中之溶液用N2 充氣20分鐘，接著添加至中間物1、聯苯酸及鹼之混合物中。加熱反應物至45℃，維持18小時。再將乙酸鈀(3.14 g，14.0 mmol)及正丁基二金剛烷基膦(Catacxium A，10 g，28 mmol)於THF(30 mL)中之等分試樣用N2 充氣20分鐘，且添加至反應混合物中。在45℃下維持24小時後，冷卻反應物至室溫，且用EtOAc及鹽水稀釋。濃縮有機層，且用THF/MTBE濕磨，得到呈褐色固體狀之標題化合物。LC-MS：C19 H14 ClN3 O2 S計算值383.05；觀測值m/e：383.9(M+H)+ (Rt 2.01/4 min)。Intermediate 1 (50 g, 140 mmol), 4-biphenyl Acid (33.2 g, 168 mmol) and tripotassium phosphate (89 g, 212.3 mmol) was dissolved in THF (500 mL) and water (50 mL), followed by the inflator 20 minutes with N 2. A solution of palladium acetate (3.14 g, 14.0 mmol) and n-butyldiamantylphosphine (Catacxium A, 10 g, 28 mmol) in THF (30 mL) was then agitated with N 2 for 20 min then added to the intermediate 1, biphenyl In a mixture of acid and base. The reaction was heated to 45 ° C for 18 hours. An aliquot of palladium acetate (3.14 g, 14.0 mmol) and n-butyldiamantylphosphine (Catacxium A, 10 g, 28 mmol) in THF (30 mL) was then inflated with N 2 for 20 min. Add to the reaction mixture. After 24 hours at 45 ° C, the reaction was cooled to rt and diluted with EtOAc & brine. The organic layer was concentrated with EtOAc EtOAc m. LC-MS: C 19 H 14 ClN 3 O 2 S Calcd 383.05; Observed m / e: 383.9 (M + H) + (Rt 2.01 / 4 min).

實例1Example 1

5-{[5-(聯苯-4-基)-6-氯-1H咪唑并[4,5-b]吡啶-2-基]氧基}-2-甲基苯甲酸5-{[5-(biphenyl-4-yl)-6-chloro-1Himidazo[4,5-b]pyridin-2-yl]oxy}-2-methylbenzoic acid

步驟A. 在室溫下於氮氣氛圍下，將1,1'-雙(二苯基膦基)二茂鐵-二氯化鈀(II)二氯甲烷錯合物(142 mg，0.17 mmol)添加至中間物3(200 mg，0.35 mmol)、4-聯苯酸(104 mg，0.52 mmol)及氫氧化鋰(20 mg，0.87 mmol)之二噁烷(1.8 mL)/水(0.2 mL)溶液中。加熱反應物至80℃，維持20分鐘，接著分配於乙酸乙酯與10%檸檬酸水溶液之間。用水、鹽水洗滌有機層，經硫酸鎂乾燥且濃縮。利用BiotageTM 10G SNAP濾筒且採用線性梯度：0%至100% EtOAc/己烷對所得殘餘物進行急驟層析，得到呈白色固體狀之5-{[5-(聯苯-4-基)-6-氯-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H咪唑并[4,5-b]吡啶-2-基]氧基}-2-甲基苯甲酸甲酯。LC-MS：C33 H34 ClN3 O4 Si計算值600.18，觀測值m/e：600.93(M+H)+ (Rt 3.2/4 min)。Step A. 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) chloride dichloromethane complex (142 mg, 0.17 mmol) at room temperature under a nitrogen atmosphere. Add to Intermediate 3 (200 mg, 0.35 mmol), 4-biphenyl Acid (104 mg, 0.52 mmol) and lithium hydroxide (20 mg, 0.87 mmol) in dioxane (1.8 mL) / water (0.2 mL). The reaction was heated to 80 ° C for 20 minutes and then partitioned between ethyl acetate and 10% aqueous EtOAc. The organic layer was washed with water and brine, dried over magnesium sulfate Using Biotage TM 10G SNAP cartridge and using a linear gradient: 0% to 100% EtOAc / hexane resulting residue was subjected to flash chromatography to give a white solid of 5 - {[5- (biphenyl-4-yl) -6-Chloro-1-{[2-(trimethyldecyl)ethoxy]methyl}-1H imidazo[4,5-b]pyridin-2-yl]oxy}-2-methyl Methyl benzoate. LC-MS: C 33 H 34 ClN 3 O 4 Si calcd 600.18, observed m / e: 600.93 (M + H) + (Rt 3.2 / 4 min).

步驟B. 在80℃下，將5-{[5-(聯苯-4-基)-6-氯-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H咪唑并[4,5-b]吡啶-2-基]氧基}-2-甲基苯甲酸甲酯(140 mg，0.23 mmol)及飽和硫酸氫鉀(0.27 mL)之甲酸(2.7 mL，70.4 mmol)溶液攪拌1小時。 將反應物分配於EtOAc與鹽水之間。分離有機層且濃縮，得到呈白色固體狀之5-{[5-(聯苯-4-基)-6-氯-1H咪唑并[4,5-b]吡啶-2-基]氧基}-2-甲基苯甲酸甲酯，其未經進一步純化即用於下一步驟中。LC-MS：C27 H20 ClN3 O3 計算值469.89，觀測值m/e：470.2(M+H)+ (Rt 2.3/4 min)。Step B. 5-{[5-(Biphenyl-4-yl)-6-chloro-1-{[2-(trimethyldecyl)ethoxy]methyl}-1H at 80 °C Methyl imidazo[4,5-b]pyridin-2-yl]oxy}-2-methylbenzoate (140 mg, 0.23 mmol) and saturated aqueous potassium hydrogen sulfate (0.27 mL) (2.7 mL, 70.4 The mmol solution was stirred for 1 hour. The reaction was partitioned between EtOAc and brine. The organic layer was separated and concentrated to give 5-{[5-(biphenyl-4-yl)-6-chloro-1H imidazo[4,5-b]pyridin-2-yl]oxy} as a white solid. Methyl 2-methylbenzoate, which was used in the next step without further purification. LC-MS: C 27 H 20 ClN 3 O 3 calcd 469.89, observed m / e: 470.2 (M + H) + (Rt 2.3 / 4 min).

步驟C. 將2N KOH(1.1 mL，2.2 mmol)添加至5-{[5-(聯苯-4-基)-6-氯-1H咪唑并[4,5-b]吡啶-2-基]氧基}-2-甲基苯甲酸甲酯(104 mg，0.22 mmol)之甲醇(10 mL)溶液中，且在80℃下攪拌反應物2小時。將反應物分配於EtOAc與10%檸檬酸水溶液之間。分離有機層，用鹽水洗滌，經硫酸鎂乾燥且濃縮。利用BiotageTM 10G SNAP濾筒且採用梯度：0%至100% EtOAc/己烷對所得殘餘物進行急驟層析，得到呈白色固體狀之標題化合物。LC-MS：C26 H18 ClN3 O3 計算值455.89，觀測值m/e：456.2(M+H)+ (Rt 2.0/4 min)。1 H NMR δ(ppm)(DMSO-d6 )：8.00(1H,s),7.82(1H,m)7.79-7.69(7H,m),7.48(2 H,m),7.38(2 H,m),2.56(3 H,s)。Step C. Add 2N KOH (1.1 mL, 2.2 mmol) to 5-{[5-(biphenyl-4-yl)-6-chloro-1H imidazo[4,5-b]pyridin-2-yl] A solution of methyl oxy}-2-methylbenzoate (104 mg, 0.22 mmol) in methanol (10 mL). The reaction was partitioned between EtOAc and 10% aqueous EtOAc. The organic layer was separated, washed with brine, dried over magnesium sulfate Using Biotage TM 10G SNAP cartridge and gradient: 0% to 100% EtOAc / hexane resulting residue was subjected to flash chromatography to give a white solid of the title compound. LC-MS: C 26 H 18 ClN 3 O 3 calcd 455.89, observed m / e: 456.2 (M + H) + (Rt 2.0 / 4 min). 1 H NMR δ (ppm) (DMSO-d 6 ): 8.00 (1H, s), 7.82 (1H, m) 7.79-7.69 (7H, m), 7.48 (2 H, m), 7.38 (2 H, m ), 2.56 (3 H, s).

實例29Example 29

反-4-{[(5-(聯苯-4-基)-6-氯-1H咪唑并[4,5-b]吡啶-2-基]氧基}環己烷甲酸Trans-4-{[(5-(biphenyl-4-yl)-6-chloro-1H imidazo[4,5-b]pyridin-2-yl]oxy}cyclohexanecarboxylic acid

步驟A.反-4-{[(5-(聯苯-4-基)-6-氯-1H咪唑并[4,5-b]吡啶-2-基]氧基}環己烷甲酸乙酯 。在室溫下於氮氣氛圍下，將1,1'-雙(二苯基膦基)二茂鐵-二氯化鈀(II)二氯甲烷錯合物(1.0 g，1.22 mmol)添加至中間物4(3.0 g，6.13 mmol)、4-聯苯酸(1.46 g，7.35 mmol)及碳酸銫(1.99 g，18.4 mmol)之DMSO(50 mL)溶液中。加熱反應物至90℃，維持2小時。將反應物保持於氮氣下，接著添加苯基矽烷(2.27 mL，18.4 mmol)，且在90℃下攪拌反應物1小時。冷卻至室溫後，用EtOAc(200 mL)稀釋反應物，且傾倒至10%檸檬酸水溶液(200 mL)中。用水及鹽水洗滌有機層，經硫酸鎂乾燥且濃縮。利用BiotageTM 100G SNAP濾筒且採用線性梯度：0%至100%乙酸乙酯/己烷對所得殘餘物進行急驟層析，得到呈結晶白色固體狀之反-4-{[(5-(聯苯-4-基)-6-氯-1H咪唑并[4,5-b]吡啶-2-基]氧基}環己烷甲酸乙酯。LC-MS：C27 H26 ClN3 O3 計算值475.9，觀測值m/e：476.4(M+H)+ (Rt 1.5/2 min)。Step A. trans-4 - {[(5- (biphenyl-4-yl) -6-chloro -1H-imidazo [4,5-b] pyridin-2-yl] oxy} cyclohexanecarboxylate Add 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) chloride dichloromethane complex (1.0 g, 1.22 mmol) to a nitrogen atmosphere at room temperature. Intermediate 4 (3.0 g, 6.13 mmol), 4-biphenyl Acid (1.46 g, 7.35 mmol) and cesium carbonate (1.99 g, 18.4 mmol) in DMSO (50 mL). The reaction was heated to 90 ° C for 2 hours. The reaction was kept under nitrogen then phenyl decane (2.27 mL, 18.4 mmol) was then weighed and the After cooling to room temperature, the reaction was diluted with EtOAc (EtOAc) The organic layer was washed with water and brine, dried over magnesium sulfate Using Biotage TM 100G SNAP cartridge and using a linear gradient: 0-100% ethyl acetate / hexane resulting residue was subjected to flash chromatography to give a crystalline white solid of trans-4 - {[(5- (biphenyl Ethyl phenyl-4-yl)-6-chloro-1Himidazo[4,5-b]pyridin-2-yl]oxy}cyclohexanecarboxylate. LC-MS: C 27 H 26 ClN 3 O 3 Value 475.9, observed m/e: 476.4 (M+H) + (Rt 1.5/2 min).

步驟B. 將三甲基矽醇鉀(1.48 g，11.5 mmol)添加至反-4-{[(5-(聯苯-4-基)-6-氯-1H咪唑并[4,5-b]吡啶-2-基]氧基} 環己烷甲酸乙酯(2.5 g，5.25 mmol)之THF(10 mL)溶液中，且在室溫下攪拌反應物16小時。接著將反應混合物分配於EtOAc與10%檸檬酸水溶液之間。用鹽水洗滌有機層，經硫酸鎂乾燥，且在用THF(40 mL)清洗下濃縮。濃縮經合併之有機層，接著用乙腈(50 mL)濕磨，得到呈灰白色固體狀之標題化合物。LC-MS：C25 H22 ClN3 O3 計算值447.9，觀測值m/e：448.4(M+H)+ (Rt 1.15/2 min)。1 H NMR δ(ppm)(DMSO-d6 )：7.91(1 H,s),7.78-7.71(6 H,m),7.49(2 H,t,J=7.60 Hz),7.39(1 H,t,J=7.38 Hz),5.02-4.95(1 H,m),2.35-2.27(1 H,m),2.24(2 H,m),1.99(2 H,m),1.57-1.46(4 H,m)。Step B. Potassium trimethyl decoxide (1.48 g, 11.5 mmol) was added to trans-4-{[(5-(biphenyl-4-yl)-6-chloro-1H imidazo[4,5-b a solution of ethyl pyridin-2-yl]oxy}cyclohexanecarboxylate (2.5 g, 5.25 mmol) in THF (10 mL). The organic layer was washed with EtOAc EtOAc (EtOAc m. off-white solid of the title compound .LC-MS: C 25 H 22 ClN 3 O 3 calcd 447.9, observed m / e: 448.4 (m + H) + (Rt 1.15 / 2 min) 1 H NMR δ (. Ppm) (DMSO-d 6 ): 7.91 (1 H, s), 7.78-7.71 (6 H, m), 7.49 (2 H, t, J = 7.60 Hz), 7.39 (1 H, t, J = 7.38) Hz), 5.02-4.95 (1 H, m), 2.35-2.27 (1 H, m), 2.24 (2H, m), 1.99 (2H, m), 1.57-1.46 (4H, m).

實例74Example 74

反-4-[(6-氯-5-{3-氰基-4-[(3-甲基氮雜環丁烷-3-基)氧基]苯基}-1H-咪唑并[4,5-b]吡啶-2-基)氧基]環己烷甲酸Trans-4-[(6-chloro-5-{3-cyano-4-[(3-methylazetidin-3-yl)oxy]phenyl}-1H-imidazo[4, 5-b]pyridin-2-yl)oxy]cyclohexanecarboxylic acid

步驟A. 將中間物4溶解於DMSO(3.7 mL)中，且依序添加碳酸銫(1996 mg，6.13 mmol)、3-氰基-4-氟苯基酸(674 mg，4.08 mmol)及1,1'-雙(二苯基膦基)二茂鐵-二氯化鈀(II)二氯甲烷錯合物(149 mg，0.204 mmol)。加熱反應物至80℃且攪拌4小時。用檸檬酸(3 mL，10% w/v)淬滅反應。收集有機層，在真空中濃縮，接著經由急驟層析(40 g 管柱，0%至50% EtOAc/己烷)純化，得到呈褐色固體狀之反-4-{[6-氯-5-(3-氰基-4-氟苯基)-1-(丙-2-烯-1-基)-1H-咪唑并[4,5-b]吡啶-2-基]氧基}環己烷甲酸乙酯。Step A. Dissolve Intermediate 4 in DMSO (3.7 mL) and add cesium carbonate (1996 mg, 6.13 mmol), 3-cyano-4-fluorophenyl Acid (674 mg, 4.08 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) chloride methylene chloride complex (149 mg, 0.204 mmol). The reaction was heated to 80 ° C and stirred for 4 hours. The reaction was quenched with citric acid (3 mL, 10% w/v). The organic layer was collected, EtOAc (EtOAc m. (3-cyano-4-fluorophenyl)-1-(prop-2-en-1-yl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy}cyclohexane Ethyl formate.

步驟B. 向反-4-{[6-氯-5-(3-氰基-4-氟苯基)-1-(丙-2-烯-1-基)-1H-咪唑并[4,5-b]吡啶-2-基]氧基}環己烷甲酸乙酯(980 mg，2.029 mmol)於DMSO(4 mL)中之溶液中依序添加1,1'-雙(二苯基膦基)二茂鐵-二氯化鈀(II)二氯甲烷錯合物(148 mg，0.203 mmol)及苯基矽烷(220 mg，2.029 mmol)。在90℃下加熱反應物1小時。接著冷卻反應物，用檸檬酸(10% w/v，5 mL)淬滅，接著用EtOAc(2×10 mL)萃取。收集有機層，乾燥，接著在真空中濃縮。經由急驟層析(40 g管柱，40 mL/min流速，0%至100% EtOAc/己烷)純化殘餘物，得到呈黃色泡沫狀之反-4-{[6-氯-5-(3-氰基-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-2-基]氧基}-環己烷甲酸乙酯。Step B. To trans-4-{[6-chloro-5-(3-cyano-4-fluorophenyl)-1-(prop-2-en-1-yl)-1H-imidazo[4, Addition of 1,1'-bis(diphenylphosphine) to a solution of ethyl 5-b]pyridin-2-yl]oxy}cyclohexanecarboxylate (980 mg, 2.029 mmol) in DMSO (4 mL) Base) ferrocene-palladium(II) dichloride methylene chloride complex (148 mg, 0.203 mmol) and phenyl decane (220 mg, 2.029 mmol). The reaction was heated at 90 ° C for 1 hour. The reaction was then cooled with EtOAc (EtOAc (EtOAc) The organic layer was collected, dried and then concentrated in vacuo. The residue was purified by flash chromatography eluting eluting elut elut elut elut elut elut elut -Cyano-4-fluorophenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy}-cyclohexanecarboxylic acid ethyl ester.

步驟C. 向反-4-{[6-氯-5-(3-氰基-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-2-基]氧基}環己烷甲酸乙酯(30 mg，0.075 mmol)於DMSO(400 μL)中之溶液中添加碳酸銫(48.9 mg，0.150 mmol)及3-甲基氮雜環丁烷-3-醇(2.55 mg，0.150 mmol)。經4小時加熱反應物至90℃。冷卻反應物，接著用檸檬酸淬滅，且用EtOAc萃取。添加LiOH(100 μL，0.200 mmol)，且攪拌反應物隔夜。接著用檸檬酸(2 mL，10% w/v)淬滅反應，且用EtOAc(2×5 mL)萃取。合併有機層且在真空中濃縮，得到粗殘餘物，經由逆相HPLC純化該殘餘物，得到呈白色粉末狀之標題化合物。LC-MS： C24 H24 ClN5 O4 計算值481.2，觀測值m/e：482.1(M+H)+ (Rt 0.8/2 min)。Step C. To the trans-4-{[6-chloro-5-(3-cyano-4-fluorophenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy} ring To a solution of ethyl hexanecarboxylate (30 mg, 0.075 mmol) in DMSO (400 μL) was added cesium carbonate (48.9 mg, 0.150 mmol) and 3-methylazetidin-3-ol (2.55 mg, 0.150 mmol). The reaction was heated to 90 ° C over 4 hours. The reaction was cooled, then quenched with EtOAc andEtOAcEtOAc. LiOH (100 μL, 0.200 mmol) was added and the mixture was stirred overnight. The reaction was quenched with EtOAc (2 mLEtOAcEtOAc The combined organic layers were concentrated with EtOAc EtOAc m. LC-MS: C 24 H 24 ClN 5 O 4 calculated 481.2, observed m / e: 482.1 (M + H) + (Rt 0.8 / 2 min).

實例79Example 79

反-4-({6-氯-5-[4'-(甲基磺醯基)聯苯-4-基]-1H-咪唑并[4,5-b]吡啶-2-基}氧基)環己烷甲酸Trans-4-({6-chloro-5-[4'-(methylsulfonyl)biphenyl-4-yl]-1H-imidazo[4,5-b]pyridin-2-yl}oxy Cyclohexanecarboxylic acid

步驟A. 在室溫下於氮氣氛圍下，將1,1'-雙(二苯基膦基)二茂鐵-二氯化鈀(II)二氯甲烷錯合物(260 mg，0.32 mmol)添加至中間物5(550 mg，1.06 mmol)、4-(甲基磺醯基)苯基酸(233 mg，1.17 mmol)及2 M磷酸三鉀(1.59 mL，3.18 mmol)之二噁烷(6 mL)溶液中。加熱反應物至80℃，維持4小時。接著添加苯基矽烷(688 mg，6.36 mmol)，且在80℃下攪拌反應物1小時。冷卻至室溫後，用EtOAc(200 mL)稀釋反應物，且傾倒至10%檸檬酸水溶液(200 mL)中。分離有機層，用水及鹽水洗滌，經硫酸鎂乾燥且濃縮。利用BiotageTM 50G SNAP濾筒且以0%至100% EtOAc/己烷溶離對所得殘餘物進行急驟層析，得到呈淺黃色油狀之反-4-({6-氯-5-[4'-(甲基磺醯基)-聯苯-4-基]-1H咪唑并[4,5-b]吡啶-2-基}氧基)環己烷甲酸乙酯。LC-MS：C28 H28 ClN3 O5 S計算值554.05，觀測值m/e：555.04(M+H)+ (Rt 2.2/4 min)。Step A. 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) chloride dichloromethane complex (260 mg, 0.32 mmol) at room temperature under a nitrogen atmosphere. Add to Intermediate 5 (550 mg, 1.06 mmol), 4-(methylsulfonyl)phenyl Acid (233 mg, 1.17 mmol) and 2 M tripotassium phosphate (1.59 mL, 3.18 mmol) in dioxane (6 mL). The reaction was heated to 80 ° C for 4 hours. Phenylnonane (688 mg, 6.36 mmol) was then added and the reaction was stirred at 80 ° C for 1 h. After cooling to room temperature, the reaction was diluted with EtOAc (EtOAc) The organic layer was separated, washed with water and brine, dried Using Biotage TM 50G SNAP cartridge and from 0% to 100% EtOAc / hexanes eluting The residue was subjected to flash chromatography to give a pale yellow oil of the trans-4 - ({6-chloro-5- [4 ' -(Methylsulfonyl)-biphenyl-4-yl]-1H imidazo[4,5-b]pyridin-2-yl}oxy)cyclohexanecarboxylic acid ethyl ester. LC-MS: C 28 H 28 ClN 3 O 5 S calcd 554.05, observed m / e: 555.04 (M + H) + (Rt 2.2 / 4 min).

步驟B. 將三甲基矽醇鉀(278 mg，2.16 mmol)添加至反-4-({6-氯-5-[4'-(甲基磺醯基)聯苯-4-基]-1H咪唑并[4,5-b]吡啶-2-基}氧基)環己烷甲酸乙酯(240 mg，0.43 mmol)之四氫呋喃(3 mL)溶液中，且在室溫下攪拌混合物16小時。將反應混合物分配於EtOAc與10%檸檬酸水溶液之間。分離有機層，用鹽水洗滌，經硫酸鎂乾燥且濃縮。用乙腈(10 mL)濕磨所得粗產物，得到呈灰白色固體狀之標題化合物。LC-MS：C26 H24 ClN3 O5 S計算值526.0，觀測值m/e：526.3(M+H)+ (Rt 0.8/2 min)。1 H NMR δ(ppm)(DMSO-d6 )：8.03-7.99(5 H,m),7.86(2 H,d,J=8.16 Hz),7.79(2 H,d,J=8.12 Hz),5.01-4.97(1 H,m),2.30(1 H,m),2.24(3 H,d,J=10.17 Hz),2.00(3 H,m),1.58-1.49(4 H,m)。Step B. Potassium trimethyl decoxide (278 mg, 2.16 mmol) was added to trans-4-({6-chloro-5-[4'-(methylsulfonyl)biphenyl-4-yl]- To a solution of 1H imidazo[4,5-b]pyridin-2-yl}oxy)cyclohexanecarboxylate (240 mg, 0.43 mmol) in THF (3 mL) . The reaction mixture was partitioned between EtOAc and 10% aqueous EtOAc. The organic layer was separated, washed with brine, dried over magnesium sulfate The crude product was triturated with EtOAc (EtOAc) LC-MS: C 26 H 24 ClN 3 O 5 S calcd 526.0, observed m / e: 526.3 (M + H) + (Rt 0.8 / 2 min). 1 H NMR δ (ppm) (DMSO-d 6 ): 8.03-7.99 (5 H, m), 7.86 (2H, d, J = 8.16 Hz), 7.79 (2H, d, J = 8.12 Hz), 5.01-4.97 (1 H, m), 2.30 (1 H, m), 2.24 (3H, d, J = 10.17 Hz), 2.00 (3H, m), 1.58-1.49 (4H, m).

實例111Example 111

(3-{[5-(聯苯-4-基)-6-氯-1H-咪唑并[4,5-b]吡啶-2-基]氧基}環丁烷-1,1-二基)二甲醇 。在氮氣下於周圍溫度下，向2,2'-(3-{[5-(聯苯-4-基)-6-氯-1H-咪唑并[4,5-b]吡啶-2-基]氧基}環丁烷-1,1-二基)二乙酸二乙酯(實例73之酯前驅物，590 mg，1.14 mmol)於無水THF(13.0 mL)中之經攪拌溶液中添加整份氫化鋰鋁(215 mg，5.67 mmol)。混合物展現放熱，且在周圍溫度下將其攪拌45分鐘。用無水THF(20 mL)稀釋混合物，且冷卻至5℃。逐滴添加飽和氯化銨水溶液直至氣體停止釋出。接著用羅謝爾氏鹽飽和水溶液(50 mL)稀釋混合物，且攪拌2小時。用乙酸乙酯(3×150 mL)萃取混合物。合併有機層，且用羅謝爾氏鹽飽和水溶液(3×70 mL)及鹽水(100 mL)洗滌。經CeliteTM 薄襯墊過濾有機層，且在減壓下濃縮。在高真空下於50℃下乾燥所得白色固體1小時，得到標題化合物。LC-MS：C24 H22 ClN3 O3 計算值435.13，觀測值m/e：436.19(M+H)+ (Rt 2.0/4.0 min)。1 H NMR δ(ppm)(DMSO-d6 )：7.90(1H,s),7.77-7.72(6H,m),7.49(2H,t,J=7.6 Hz),7.39(1H,6,J=7.2 Hz),5.27(1H,t,7.1 Hz),4.74(1H,t,5.4 Hz),4.67(1H,t,5.5 Hz),3.41(2H,d,5.3 Hz),3.34(2H,d,5.3 Hz),2.30(2H,m),2.07(2H,m)。 (3-{[5-(Biphenyl-4-yl)-6-chloro-1H-imidazo[4,5-b]pyridin-2-yl]oxy}cyclobutane-1,1-diyl ) Dimethanol . To 2,2'-(3-{[5-(biphenyl-4-yl)-6-chloro-1H-imidazo[4,5-b]pyridin-2-yl at ambient temperature under nitrogen Diethyl oxy]cyclobutane-1,1-diyl)diacetate (ester precursor of Example 73, 590 mg, 1.14 mmol) in dry THF (13.0 mL) Lithium aluminum hydride (215 mg, 5.67 mmol). The mixture exhibited an exotherm and was stirred at ambient temperature for 45 minutes. The mixture was diluted with anhydrous THF (20 mL) and cooled to 5 °C. A saturated aqueous solution of ammonium chloride was added dropwise until the gas ceased to evolve. The mixture was then diluted with a saturated aqueous solution of Rochelle's salt (50 mL) and stirred for 2 hours. The mixture was extracted with ethyl acetate (3×150 mL). The organic layers were combined and washed with a saturated aqueous solution of &lt;RTI ID=0.0&gt;&gt; The organic layer was filtered through a pad of Celite (s) and concentrated under reduced pressure. The resulting white solid was dried under high vacuum at 50 °C for one hour to give the title compound. LC-MS: C 24 H 22 ClN 3 O 3 calcd 435.13, observed m / e: 436.19 (M + H) + (Rt 2.0 / 4.0 min). 1 H NMR δ (ppm) ( DMSO-d 6): 7.90 (1H, s), 7.77-7.72 (6H, m), 7.49 (2H, t, J = 7.6 Hz), 7.39 (1H, 6, J = 7.2 Hz), 5.27 (1H, t, 7.1 Hz), 4.74 (1H, t, 5.4 Hz), 4.67 (1H, t, 5.5 Hz), 3.41 (2H, d, 5.3 Hz), 3.34 (2H, d, 5.3 Hz), 2.30 (2H, m), 2.07 (2H, m).

實例130Example 130

2-[順-3-({6-氯-5-[4'-(甲基磺醯基)聯苯-4-基]-1H-咪唑并[4,5-b]吡啶-2-基}氧基)環丁基]丙-2-醇 。在0℃下，向順-3-({6-氯-5-[4'-(甲基磺醯基)-聯苯-4-基]-1H-咪唑并[4,5-b]吡啶-2-基}氧基)環丁烷甲酸乙酯(實例110之前驅物，19 mg，0.036 mmol)於0.5 mL無水THF中之溶液中添加100 μL MeMgBr溶液(3.0 M之THF溶液，0.3 mmol)。在0℃下攪拌所得澄清溶液46分鐘，接著藉由添加飽和氯化銨水溶液淬滅。接著將混合物分配於EtOAc與水之間。用EtOAc反萃取含水部分一次。再用飽和氯化銨水溶液洗滌經合併之有機萃取物一次，用鹽水洗滌一次，經Na2 SO4 乾燥，過濾且 濃縮。在BiotageTM 10 g SNAP濾筒上，以含0%至20% EtOAc之己烷之線性梯度對所得粗物質進行層析。合併所要溶離份，得到呈白色泡沫狀之所要產物。LC-MS：C26 H26 ClN3 O4 S計算值=511.13，觀測值m/e：512.2(M+H)+ (Rt 1.97/4 min)。1 H NMR(500 MHz,CDCl3 )：δ 11.21(s,1 H),8.04(d,J=8.0 Hz,2 H)；7.92(s,1 H)；7.87-7.80(m,4 H)；7.71(d,J=7.9 Hz,2 H)；5.20(s,1 H)；3.12(s,3 H)；2.46(s,2 H)；2.11(s,2 H)；1.94(m,1 H)；1.11(s,6 H)。 2-[cis-3-({6-chloro-5-[4'-(methylsulfonyl)biphenyl-4-yl]-1H-imidazo[4,5-b]pyridin-2-yl }oxy)cyclobutyl]propan-2-ol . To cis-3-({6-chloro-5-[4'-(methylsulfonyl)-biphenyl-4-yl]-1H-imidazo[4,5-b]pyridine at 0 °C Ethyl 2-methyl}oxy)cyclobutanecarboxylate (Previous Example 110, 19 mg, 0.036 mmol) in 0.5 mL of dry THF was added 100 μL of MeMgBr solution (3.0 M in THF, 0.3 mmol) ). The resulting clear solution was stirred at 0 ° C for 46 min then quenched by the addition of saturated aqueous ammonium chloride. The mixture was then partitioned between EtOAc and water. The aqueous fraction was back extracted with EtOAc. Then saturated aqueous ammonium chloride solution of the combined organic extracts were once washed once with brine, dried over Na 2 SO 4, filtered and concentrated. On Biotage TM 10 g SNAP cartridge, containing 0-20% linear gradient of EtOAc in hexanes The resulting crude material was chromatographed. The desired fractions were combined to give the desired product as a white foam. LC-MS: C 26 H 26 ClN 3 O 4 S calculated = 511.13, observed m / e: 512.2 (M + H) + (Rt 1.97 / 4 min). 1 H NMR (500 MHz, CDCl 3 ): δ 11.21 (s, 1 H), 8.04 (d, J = 8.0 Hz, 2 H); 7.92 (s, 1 H); 7.87-7.80 (m, 4 H) ; 7.71 (d, J = 7.9 Hz, 2 H); 5.20 (s, 1 H); 3.12 (s, 3 H); 2.46 (s, 2 H); 2.11 (s, 2 H); 1.94 (m, 1 H); 1.11 (s, 6 H).

實例137Example 137

步驟A：反-4-{[5-(聯苯-4-基)-6-氯-1H咪唑并[4,5-b]吡啶-2-基]-氧基}環己烷甲醛 。在N2 下於-78℃下，向實例29之酯前驅物(200 mg，0.420 mmol)於THF(10 mL)中之溶液中添加DIBAL-H之甲苯溶液(0.364 ml，0.546 mmol)。在-78℃下攪拌混合物2小時，接著再添加DIBAL-H(0.840 ml，1.261 mmol)。攪拌反應物隔夜(自-78℃至-20℃)，接著在-78℃下藉由添加數滴飽和NH4 Cl淬滅。形成沈澱物且藉由經CeliteTM 過濾而移除。在減壓下濃縮濾液，藉由在矽膠Biotage 25S上，以EtOAc/異己烷(梯度自20%至65%)溶離進行管柱層析來純化所得殘餘物，得到呈白色固體狀之標題化合物。LC-MS：C25 H22 ClN3 O2 計算值431.914，觀測值m/e：432.14(M+H)+ (Rt 3.54/5.5 min)。 Step A: trans-4-{[5-(biphenyl-4-yl)-6-chloro-1H imidazo[4,5-b]pyridin-2-yl]-oxy}cyclohexanecarbaldehyde . Under N 2 at -78 deg.] C, the toluene solution of DIBAL-H (0.364 ml, 0.546 mmol) ( 10 mL) in a solution of the ester precursor to Example 29 of (200 mg, 0.420 mmol) in THF. The mixture was stirred at -78 °C for 2 hours, then DIBAL-H (0.840 ml, 1.261 mmol) was then added. The reaction was stirred overnight (from -78 ° C to -20 ° C) then quenched by addition of a few drops of saturated NH 4 Cl at -78 °C. A precipitate formed and was filtered by Celite TM was removed. The filtrate was concentrated under reduced pressure. EtOAcjjjjjjjj LC-MS: C 25 H 22 ClN 3 O 2 Calcd 431.914, observed m / e: 432.14 (M + H) + (Rt 3.54 / 5.5 min).

步驟B：1-(反-4-{[5-(聯苯-4-基)-6-氯-1H咪唑并[4,5-b] 吡啶-2-基]-氧基}環己基乙醇 。在N2 下於0℃下，向步驟A之產物(70 mg，0.162 mmol)於THF(10 mL)中之溶液中添加溴化甲基鎂之乙醚溶液(0.108 ml，0.324 mmol)。在0℃下攪拌混合物15分鐘，接著在室溫下攪拌2小時。在0℃下藉由添加數滴飽和NH4 Cl淬滅反應。形成沈澱物且藉由經CeliteTM 過濾而移除。在減壓下濃縮濾液，且藉由製備型TLC，以EtOAc/異己烷(6：4)溶離來純化所得殘餘物，得到呈兩種異構體之1：1混合物形式之標題化合物。LC-MS：C26 H26 ClN3 O2 計算值447.957，觀測值m/e：448.21(M+H)+ (Rt 3.59/5.5 min)。1 H NMR δ(ppm)(CD3 OD)：7.78(1H,s),7.68-7.75(6H,m),7.46(2H,t,J=7.5 Hz),7.36(1H,t,J=7.5 Hz),4.96(1H,m),3.54(1H,qn,J=6.0 Hz),2.05(1 H,m),1.86(1 H,m),1.55(2 H,m),1.21-1.40(3 H,m),1.17(3 H,d,J=6 Hz)。 Step B: 1-(trans-4-{[5-(biphenyl-4-yl)-6-chloro-1H imidazo[4,5-b] pyridin-2-yl]-oxy}cyclohexylethanol in under N 2 at 0 ℃, diethyl ether was added methyl magnesium bromide solution (0.108 ml, 0.324 mmol) in THF (10 mL) to a solution of the product of step A (70 mg, 0.162 mmol). in the mixture was stirred for 15 minutes at 0 ℃, followed by stirring for 2 hours at room temperature by the addition of a few drops of saturated at 0 ℃ reaction was quenched with NH 4 Cl. A precipitate formed and was removed by filtration through Celite TM. Save the The filtrate was concentrated, and the residue was purified eluting elut elut elut elut elut elut elut elut elut C 26 H 26 ClN 3 O 2 calc. 447.957, observed m/e: 448.21. (M+H) + (Rt 3.59/5.5 min). 1 H NMR δ (ppm) (CD 3 OD): 7.78 (1H, s), 7.68-7.75 (6H, m), 7.46 (2H, t, J = 7.5 Hz), 7.36 (1H, t, J = 7.5 Hz), 4.96 (1H, m), 3.54 (1H, qn, J =6.0 Hz), 2.05 (1 H, m), 1.86 (1 H, m), 1.55 (2 H, m), 1.21-1.40 (3 H, m), 1.17 (3 H, d, J = 6 Hz ).

實例139Example 139

步驟A：5-(聯苯-4-基)-6-氯-2-{[反-4-(氟甲基)環己基]氧基}-1H咪唑并[4,5-b]吡啶 。在-78℃下，向醇(55.6 mg，0.128 mmol)於CH2 Cl2 (10 ml)中之經攪拌溶液中添加DAST(0.085 ml，0.641 mmol)，且在室溫下攪拌混合物2小時。粗產物自溶液中沈澱且藉由過濾來分離。藉由管柱層析，以EtOAC/己烷(1/1)溶離來純化粗產物，得到呈白色固體狀之標題化合物。LC-MS：C25 H23 ClFN3 O計算值435.921，觀測值m/e：436.15(M+H)+ (Rt 3.86/5.5 min)。1 H NMR δ(ppm)(CD3 OD)：7.78(1H,s),7.67-7.77(6H,m),7.46(2H,t,J=7.5 Hz),7.36(1H,t,J=7.5 Hz),4.99(1H,m),4.33(1H,d,6.0 Hz),4.23(1H,d,6.0 Hz),2.35(2 H,m),1.93(2 H,m),1.58(2 H,m),1.21-1.42(3 H,m)。 Step A: 5-(Biphenyl-4-yl)-6-chloro-2-{[trans-4-(fluoromethyl)cyclohexyl]oxy}-1H imidazo[4,5-b]pyridine . DAST (0.085 ml, 0.641 mmol) was added to a stirred solution of MeOH (55.6 mg, 0.128 mmol) in CH 2 Cl 2 (10 ml), and the mixture was stirred at room temperature for 2 hours. The crude product precipitated from the solution and was isolated by filtration. The crude product was purified by EtOAc EtOAc elut elut elut elut LC-MS: C 25 H 23 ClFN 3 O Calcd 435.921, observed m / e: 436.15 (M + H) + (Rt 3.86 / 5.5 min). 1 H NMR δ (ppm) (CD 3 OD): 7.78 (1H, s), 7.67-7.77 (6H, m), 7.46 (2H, t, J = 7.5 Hz), 7.36 (1H, t, J = 7.5 Hz), 4.99 (1H, m), 4.33 (1H, d, 6.0 Hz), 4.23 (1H, d, 6.0 Hz), 2.35 (2 H, m), 1.93 (2 H, m), 1.58 (2 H , m), 1.21-1.42 (3 H, m).

實例140Example 140

(2R,3S,5R)-5-[[6-氯-5-(4-苯基苯基)-1H-咪唑并[4,5-b]吡啶-2-基]氧基]-2-(羥甲基)四氫哌喃-3-醇(2R,3S,5R)-5-[[6-chloro-5-(4-phenylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2- (hydroxymethyl) tetrahydropyran-3-ol

步驟A：2-[[6-氯-2-甲基磺醯基-5-(4-苯基苯基)咪唑并[4,5-b]吡啶-1-基]甲氧基]乙基-三甲基-矽烷 。向中間物6(4 g，10.42 mmol)於THF(21 mL)中之0℃溶液中添加三乙胺(1.89 mL，13.5 mmol)及SEM-Cl(2.03 mL，11.4 mmol)。使反應物升溫至室溫且攪拌15分鐘，接著用EtOAc及水稀釋。用EtOAc(×2)萃取水層，且用鹽水洗滌經合併之萃取物，經Na2 SO4 乾燥，過濾且濃縮。藉由管柱層析，使用以5%至50% EtOAc/己烷梯度溶離之BiotageTM 100 g管柱純化所得粗物質。收集含有產物之溶離份且在真空中濃縮，得到呈白色固體狀之所要產物。LC-MS：C25 H28 ClN3 O3 SSi計算值513.13，觀測值m/e：514.16(M+H)+ (Rt 1.4/2.0 min)。 Step A: 2-[[6-Chloro-2-methylsulfonyl-5-(4-phenylphenyl)imidazo[4,5-b]pyridin-1-yl]methoxy]ethyl - Trimethyl-decane . Triethylamine (1.89 mL, 13.5 mmol) and SEM-Cl (2.03 mL, 11.4 mmol) were added to EtOAc (EtOAc) The reaction was allowed to warm to room rt and stirred 15 min then diluted with EtOAc & water. With EtOAc (× 2) and the aqueous layer was extracted, washed with brine and the combined extracts were dried over Na 2 SO 4, filtered and concentrated. By column chromatography using Biotage TM between 5% and 50% EtOAc / hexanes eluting a gradient of 100 g of the resulting crude material was purified column. The product-containing fractions were collected and concentrated in vacuo to give the desired product as a white solid. LC-MS: C 25 H 28 ClN 3 O 3 SSi calcd 513.13, observed m / e: 514.16 (M + H) + (Rt 1.4 / 2.0 min).

步驟B：2-[[2-[[(4aR,7R,8aS)-2-苯基-4,4a,6,7,8,8a-六氫哌喃并[3,2-d][1,3]二氧雜環己烯-7-基]氧基]-6-氯-5-(4-苯基苯基)咪唑并[4,5-b]吡啶-1-基]甲氧基]乙基-三甲基-矽烷 。將1,5-去水-4,6-O-亞苄基-3-去氧-D-葡糖醇(266 mg，1.125 mmol，Carbosynth，CAS編號：152613-20-2)、來自步驟A之2-[[6-氯-2-甲基磺醯基-5-(4-苯基苯基)咪唑并[4,5-b]吡啶-1-基]甲氧基]乙基-三甲基-矽烷(386 mg，0.75 mmol)及碳酸銫(489 mg，1.5 mmol)溶解於DMF(1.5 mL) 中。在室溫下攪拌反應混合物3小時，接著用水及EtOAc稀釋。分離水層，用EtOAc(×1)萃取，且用飽和NaHCO3 及鹽水洗滌經合併之有機層，經Na2 SO4 乾燥，過濾且濃縮。藉由管柱層析，使用以20%至80% EtOAc：己烷坡度(ramp)溶離之BiotageTM 25 g管柱純化所得粗物質。收集含有產物之溶離份且在真空中濃縮，得到呈白色泡沫狀之所要產物。LC-MS：C37 H40 ClN3 O5 Si計算值669.24，觀測值m/e：670.34(M+H)+ (Rt 1.4/2.0 min)。 Step B: 2-[[2-[[(4aR,7R,8aS)-2-phenyl-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1 ,3]dioxine-7-yl]oxy]-6-chloro-5-(4-phenylphenyl)imidazo[4,5-b]pyridin-1-yl]methoxy ] Ethyl-trimethyl-decane . 1,5-desmethyl-4,6-O-benzylidene-3-deoxy-D-glucitol (266 mg, 1.125 mmol, Carbosynth, CAS number: 152613-20-2), from step A 2-[[6-Chloro-2-methylsulfonyl-5-(4-phenylphenyl)imidazo[4,5-b]pyridin-1-yl]methoxy]ethyl-tri Methyl-decane (386 mg, 0.75 mmol) and cesium carbonate (489 mg, 1.5 mmol) were dissolved in DMF (1.5 mL). The reaction mixture was stirred at room temperature for 3 hr then diluted with water and EtOAc. The aqueous layer was combined organic layers were washed with brine and saturated NaHCO 3 was separated and extracted with EtOAc (× 1), and dried over Na 2 SO 4, filtered and concentrated. By column chromatography using 20% to 80% EtOAc: Biotage TM hexane gradient (RAMP) 25 g column eluting the crude material was purified. The product-containing fractions were collected and concentrated in vacuo to give the desired product as a white foam. LC-MS: C 37 H 40 ClN 3 O 5 Si Calcd 669.24, observed m / e: 670.34 (M + H) + (Rt 1.4 / 2.0 min).

步驟C：(2R,3S,5R)-5-[[6-氯-5-(4-苯基苯基)-1H-咪唑并[4,5-b]吡啶-2-基]氧基]-2-(羥甲基)四氫哌喃-3-醇Step C: (2R,3S,5R)-5-[[6-chloro-5-(4-phenylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy] -2-(hydroxymethyl)tetrahydropyran-3-ol

將來自步驟B之2-[[2-[[(4aR,7R,8aS)-2-苯基-4,4a,6,7,8,8a-六氫哌喃并[3,2-d][1,3]二氧雜環己烯-7-基]氧基]-6-氯-5-(4-苯基苯基)咪唑并[4,5-b]吡啶-1-基]甲氧基]乙基-三甲基-矽烷(190 mg，0.283 mmol)溶解於4 M HCl之二噁烷溶液(4 mL，16 mmol)中。在室溫下攪拌反應物3小時，且再添加4 M HCl之二噁烷溶液(2 mL，8 mmol)。再攪拌反應物1小時，接著用EtOAc稀釋，且用3 M NaOH及飽和NaHCO3 中和。分離水層，用EtOAc(×2)萃取，且用鹽水洗滌經合併之萃取物，經Na2 SO4 乾燥，過濾且濃縮。藉由管柱層析，使用以10%至100% EtOAc/己烷繼之以0%至5% MeOH/CH2 Cl2 溶離之BiotageTM 25 g管柱純化所得粗物質。收集含有所要產物之溶離份且在真空中濃縮。使所得泡沫狀物自MeCN/水中冷凍乾燥，得到呈白色固體狀之標題化合物。LC-MS：C24 H22 ClN3 O4 計算值451.13，觀測值m/e：452.13 (M+H)；(Rt 2.9/5.5 min)；1 H NMR δ(ppm)(CD3 OD)：7.82(S,1H),7.74-7.68(m,6H),7.46(t,J=7.5 Hz,2H),7.36(t,J=7.5 Hz,1H),5.12(七重峰，J=5.5 Hz,1H),4.34(ddd,J=10.5,5.0,1.5 Hz,1H),3.88(dd,J=12.0,2.0 Hz,1H),3.67-3.59(m,2H),3.37(t,J=10 Hz,1H),3.18-3.15(m,1H),2.76-2.74(m,1H),1.69(q,J=11.0 Hz,1H)。2-[[2-[[4aR,7R,8aS)-2-phenyl-4,4a,6,7,8,8a-hexahydropyrano[3,2-d] from step B [1,3]dioxine-7-yl]oxy]-6-chloro-5-(4-phenylphenyl)imidazo[4,5-b]pyridin-1-yl]- Ethyl]ethyl-trimethyl-decane (190 mg, 0.283 mmol) was dissolved in 4 M EtOAc in dichloromethane (4 mL, 16 mmol). The reaction was stirred at room temperature for 3 h and aq. EtOAc (EtOAc &lt The reaction was stirred for 1 hour and then diluted with EtOAc, and washed with 3 M NaOH and neutralized with saturated NaHCO 3. The aqueous layer was separated and extracted with EtOAc (× 2), washed with brine and the combined extracts were dried over Na 2 SO 4, filtered and concentrated. By column chromatography using 10% to 100% EtOAc / hexanes followed by 0% to 5% MeOH / CH 2 Cl 2 solution of 25 g Biotage TM from the resulting crude material was purified by column. The fractions containing the desired product were collected and concentrated in vacuo. The resulting foam was lyophilized from MeCN / water to afford title compound. LC-MS: C 24 H 22 ClN 3 O 4 calcd 451.13, observed m / e: 452.13 (M + H); (Rt 2.9 / 5.5 min); 1 H NMR δ (ppm) (CD 3 OD): 7.82(S,1H),7.74-7.68(m,6H), 7.46(t,J=7.5 Hz,2H), 7.36(t,J=7.5 Hz,1H), 5.12 (seven peak, J=5.5 Hz, 1H), 4.34 (ddd, J = 10.5, 5.0, 1.5 Hz, 1H), 3.88 (dd, J = 12.0, 2.0 Hz, 1H), 3.67-3.59 (m, 2H), 3.37 (t, J = 10 Hz) , 1H), 3.18-3.15 (m, 1H), 2.76-2.74 (m, 1H), 1.69 (q, J = 11.0 Hz, 1H).

實例159Example 159

1,4：3,6-二去水-2-O-[5-(聯苯-4-基)-6-氯-1H-咪唑并[4,5-b]吡啶-2-基]-D-甘露糖醇1,4:3,6-di-dehydro-2-O-[5-(biphenyl-4-yl)-6-chloro-1H-imidazo[4,5-b]pyridin-2-yl]- D-mannitol

步驟A：1,4：3,6-二去水-2-O-[5-(聯苯-4-基)-6-氯-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-咪唑并[4,5-b]吡啶-2-基]-5-O-[第三丁基(二甲基)矽烷基]-D-甘露糖醇與1,4：3,6-二去水-2-O-[5-(聯苯-4-基)-6-氯-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-咪唑并[4,5-b]吡啶-2-基]-D-甘露糖醇 之混合物 Step A: 1,4:3,6-di-dehydro-2-O-[5-(biphenyl-4-yl)-6-chloro-1-{[2-(trimethyldecyl)ethoxy Methyl}-1}-imidazo[4,5-b]pyridin-2-yl]-5-O-[t-butyl(dimethyl)decyl]-D-mannitol with 1, 4:3,6-di-dehydrated 2-O-[5-(biphenyl-4-yl)-6-chloro-1-{[2-(trimethyldecyl)ethoxy]methyl} a mixture of -1H-imidazo[4,5-b]pyridin-2-yl]-D-mannitol

在室溫下，將2-[[6-氯-2-甲基磺醯基-5-(4-苯基苯基)咪唑并[4,5-b]吡啶-1-基]甲氧基]乙基-三甲基-矽烷(來自實例147步驟A，2023 mg，3.93 mmol)、1,4：3,6-二去水-2-O-[第三丁基(二甲基)矽烷基]-D-甘露糖醇(2049 mg，7.87 mmol，來自WuXi PharmaTech Co.,Ltd.)及DBU(1.186 mL，7.87 mmol)於DMA(30 mL)中之混合物攪拌隔夜。接著用EtOAc萃取粗混合物，且用水洗滌。經無水硫酸鈉乾燥有機層，且在減壓下濃縮。藉由在矽膠BiotageTM 40M上，以5%至100% EtOAc：己烷坡度溶離進行管柱層析來純化所得殘餘物。收集含有產物之溶離份且在真空中濃縮，得到呈白色固體狀之所要產物。LC-MS：C36 H48 ClN3 O5 Si2 計算值693.28，觀測值m/e：694.05(M+H)+ (Rt 3.17/4.0 min)，及C30 H34 ClN3 O5 Si計算值579.20，觀測值m/e：579.97(M+H)+ (Rt 2.59/4.0 min)。2-[[6-Chloro-2-methylsulfonyl-5-(4-phenylphenyl)imidazo[4,5-b]pyridin-1-yl]methoxy at room temperature Ethyl-trimethyl-decane (from Example 147, Step A, 2023 mg, 3.93 mmol), 1,4:3,6-di-dehydro-2-O-[t-butyl(dimethyl)decane A mixture of the base of -D-mannitol (2049 mg, 7.87 mmol, from WuXi PharmaTech Co., Ltd.) and DBU (1.186 mL, 7.87 mmol) in DMA (30 mL) was stirred overnight. The crude mixture was then extracted with EtOAc and washed with water. The organic layer was dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by column chromatography on silica gel Biotage (TM) 40M eluting with 5% to 100% EtOAc: hexanes. The product-containing fractions were collected and concentrated in vacuo to give the desired product as a white solid. LC-MS: calcd for C 36 H 48 ClN 3 O 5 Si 2 693.28, observed m/e: 694.05 (M+H) + (Rt 3.17/4.0 min), and C 30 H 34 ClN 3 O 5 Si Value 579.20, observed m/e: 579.97 (M+H) + (Rt 2.59 / 4.0 min).

步驟B：1,4：3,6-二去水-2-O-[5-(聯苯-4-基)-6-氯-1H-咪唑并[4,5-b]吡啶-2-基]-D-甘露糖醇 。將步驟A之產物(2160 mg，1.695 mmol)溶解於甲酸(27 mL)中，且添加飽和硫酸氫鉀水溶液(3 mL，1.695 mmol)。在室溫下攪拌反應物隔夜，接著冷卻至0℃，且用NaOH(50/50%，以重量計)鹼化至pH=12。用THF(10 mL)稀釋混合物，且在室溫下攪拌45分鐘。用2 N HCl將所得混合物酸化至pH=7，且用EtOAc萃取。用水洗滌經合併之有機層兩次，用鹽水洗滌一次，接著經無水硫酸鈉乾燥，過濾且濃縮，得到粗產物。藉由在矽膠BiotageTM 40 M上，以CH2 Cl2 /EtOH/NH4 =95/4/1(梯度自5%至9%)溶離進行管柱層析來純化粗產物，得到粗產物，使其自CH2 Cl2 /MeOH中再結晶，得到呈白色固體狀之標題化合物。LC-MS：C24 H20 ClN3 O4 計算值449.11，觀測值m/e：449.96(M+H)(Rt 3.2/5.5 min)；1 H NMR δ(ppm)(DMSO-d6 )：7.91(S,1H),7.70-7.80(m,6H),7.48(t,J=7.5 Hz,2H),7.38(t,J=7.5 Hz,1H),5.47(qt,J=6.0 Hz,1H),5.05-4.90(m,br,1H),4.82(t,J=5.0 Hz,1H),4.35(t,J=5.0 Hz,1H),4.20-4.00(m,2H),3.90(m,1H),3.77(t,J=7.5 Hz,1H),3.42(t,J=8.5 Hz,1H)。 Step B: 1,4:3,6-di-dehydro-2-O-[5-(biphenyl-4-yl)-6-chloro-1H-imidazo[4,5-b]pyridine-2- Base]-D-mannitol . The product of Step A (2160 mg, 1. 495 mmol) was dissolved in EtOAc (EtOAc) The reaction was stirred at room temperature overnight then cooled to 0 ° C and basified to pH = 12 with NaOH (50 / 50% by weight). The mixture was diluted with THF (10 mL) and stirred at room temperature for 45 min. The resulting mixture was acidified to pH = 7 with 2 N EtOAc andEtOAc. The combined organic layers were washed twice with EtOAc (EtOAc)EtOAc. On silica gel by Biotage TM 40 M, in CH 2 Cl 2 / EtOH / NH 4 = 95/4/1 ( gradient from 5-9%) by column chromatography eluting crude product was purified to give the crude product, since it CH 2 Cl 2 / MeOH recrystallized to give a white solid of the title compound. LC-MS: C 24 H 20 ClN 3 O 4 calcd 449.11, observed m / e: 449.96 (M + H) (Rt 3.2 / 5.5 min); 1 H NMR δ (ppm) (DMSO-d 6): 7.91(S,1H), 7.70-7.80(m,6H), 7.48(t,J=7.5 Hz,2H), 7.38(t,J=7.5 Hz,1H),5.47(qt,J=6.0 Hz,1H ), 5.05-4.90 (m, br, 1H), 4.82 (t, J = 5.0 Hz, 1H), 4.35 (t, J = 5.0 Hz, 1H), 4.20 - 4.00 (m, 2H), 3.90 (m, 1H), 3.77 (t, J = 7.5 Hz, 1H), 3.42 (t, J = 8.5 Hz, 1H).

中間物7Intermediate 7

(3R,3aR,6R,6aR)-6-[5-(4-溴苯基)-6-氯-1-(2-三甲基矽烷基乙氧基甲基)咪唑并[4,5-b]吡啶-2-基]氧基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇(3R,3aR,6R,6aR)-6-[5-(4-bromophenyl)-6-chloro-1-(2-trimethyldecyloxymethyl)imidazo[4,5- b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol

步驟A5-(4-溴苯基)-6-氯-2-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶 。將肆(三苯基膦)鈀(PalladiumTetrakis)(1.63 g，1.411 mmol)添加至中間物1(10.08 g，28.2 mmol)、4-溴苯基酸(6.23 g，31.0 mmol)及磷酸鉀(18.44 g，87 mmol)於二噁烷(150 mL)及水(30 mL)中之經攪拌混濁溶液中。使反應混合物脫氣(3×)且置於氮氣下，隨後加熱至100℃。17小時後，冷卻反應混合物至室溫，隨後在減壓下蒸發。用甲苯(2×60 mL)洗提所得殘餘物，得到呈棕色/ 白色固體狀之產物，其未經進一步純化即用於下一步驟中。LC-MS：C13 H9 BrClN3 O2 S計算值384.93,386.93，觀測值m/e：385.81,387.84(M+H)+ (Rt 1.15/2 min)。Step A 5-(4-Bromophenyl)-6-chloro-2-(methylsulfonyl)-1H-imidazo[4,5-b]pyridine . Palladium Tetrakis (1.63 g, 1.411 mmol) was added to Intermediate 1 (10.08 g, 28.2 mmol), 4-bromophenyl The acid (6.23 g, 31.0 mmol) and potassium phosphate (18.44 g, 87 mmol) were dissolved in turd in dioxane (150 mL) and water (30 mL). The reaction mixture was degassed (3x) and placed under nitrogen then heated to 100 °C. After 17 hours, the reaction mixture was cooled to room temperature and then evaporated under reduced pressure. The residue was purified with EtOAc (EtOAc)EtOAc LC-MS: C 13 H 9 BrClN 3 O 2 S Calcd 384.93,386.93, observed m / e: 385.81,387.84 (M + H) + (Rt 1.15 / 2 min).

步驟B2-[[5-(4-溴苯基)-6-氯-2-甲基磺醯基-咪唑并[4,5-b]吡啶-1-基]甲氧基]乙基-三甲基-矽烷 。將N,N-二異丙基乙胺(15 mL，86 mmol)添加至來自前一步驟之未純化5-(4-溴苯基)-6-氯-2-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶於THF(150 mL)中之經攪拌懸浮液中。在冰浴中冷卻反應混合物至0℃，隨後經9分鐘緩慢添加SEM-Cl(10 mL，56.4 mmol)。添加完成後10分鐘，自冰浴中移出反應混合物，且使其升溫至室溫。16小時後，添加水(200 mL)，隨後分配反應混合物。用EtOAc(3×200 mL)萃取水層。合併有機層，用鹽水(1×100 mL)洗滌，經Na2 SO4 乾燥，過濾，且在減壓下蒸發，得到黃色/棕色固體。利用兩個165 g二氧化矽RediSep Rf ®管柱且採用0%至30% EtOAc/己烷梯度並保持30% EtOAc/己烷對固體進行急驟層析，得到呈黃色固體狀之所要產物。LC-MS：C19 H23 BrClN3 O3 SSi計算值515.01,517.01，觀測值m/e：515.85,517.86(M+H)+ (Rt 1.33/2 min)。Step B 2-[[5-(4-Bromophenyl)-6-chloro-2-methylsulfonyl-imidazo[4,5-b]pyridin-1-yl]methoxy]ethyl- Trimethyl-decane . Add N,N-diisopropylethylamine (15 mL, 86 mmol) to the unpurified 5-(4-bromophenyl)-6-chloro-2-(methylsulfonyl) from the previous step -1H-Imidazo[4,5-b]pyridine in THF (150 mL) in a stirred suspension. The reaction mixture was cooled to 0.degree. C. in an ice bath then SEM-CI (10 mL, 56.4 mmol) was slowly added over 9 min. Ten minutes after the addition was completed, the reaction mixture was removed from the ice bath and allowed to warm to room temperature. After 16 hours, water (200 mL) was added and then the mixture was partitioned. The aqueous layer was extracted with EtOAc (3×200 mL). The organic layers were combined, dried and washed with brine (1 × 100 mL) with over Na 2 SO 4, filtered, and evaporated under reduced pressure to give a yellow / brown solid. Silicon dioxide using two 165 g RediSep R f ® column and using 0% to 30% EtOAc / hexanes gradient and held 30% EtOAc / hexane solid was flash chromatographed, to give a yellow solid of the desired product. LC-MS: C 19 H 23 BrClN 3 O 3 SSi Calcd 515.01,517.01, observed m / e: 515.85,517.86 (M + H) + (Rt 1.33 / 2 min).

步驟C(3R,3aR,6R,6aR)-6-[5-(4-溴苯基)-6-氯-1-(2-三甲基矽烷基乙氧基甲基)咪唑并[4,5-b]吡啶-2-基]氧基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇 。將DBU(4.2 mL，27.9 mmol)添加至異甘露糖醇(4.11 g，28.1 mmol)於DMF(60 mL)中之經攪拌溶液中。反應混合物為黃色溶 液，將其在室溫下攪拌。經54分鐘，將2-[[5-(4-溴苯基)-6-氯-2-甲基磺醯基-咪唑并[4,5-b]吡啶-1-基]甲氧基]乙基-三甲基-矽烷(4.78 g，9.25 mmol)於DMF(34 mL)中之懸浮液逐滴添加至反應混合物中。1.5小時後，將反應混合物分配於EtOAc(500 mL)與水(200 mL)之間。用水(4×100 mL)及鹽水(1×100 mL)洗滌有機層，經Na2 SO4 乾燥，過濾，且在減壓下蒸發，得到黃色泡沫狀物。利用120 g二氧化矽RediSep Rf ®管柱且採用0%至70% EtOAc/己烷梯度並保持70% EtOAc/己烷對泡沫狀物進行急驟層析，得到呈白色泡沫狀之標題化合物。LC-MS：C24 H29 BrClN3 O5 Si計算值581.07,583.07，觀測值m/e：582.20,584.23(M+H)+ (Rt 1.32/2 min)。Step C (3R,3aR,6R,6aR)-6-[5-(4-bromophenyl)-6-chloro-1-(2-trimethyldecyloxymethyl)imidazo[4, 5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol . DBU (4.2 mL, 27.9 mmol) was added to a stirred solution of iso-mannitol (4.11 g, 28.1 mmol) in DMF (60 mL). The reaction mixture was a yellow solution which was stirred at room temperature. 2-[[5-(4-Bromophenyl)-6-chloro-2-methylsulfonyl-imidazo[4,5-b]pyridin-1-yl]methoxy] over 54 minutes A suspension of ethyl-trimethyl-decane (4.78 g, 9.25 mmol) in DMF (34 mL) was added dropwise to the reaction mixture. After 1.5 hours the reaction mixture was partitioned between EtOAc (EtOAc) The organic layer was washed with water (4 × 100 mL) and brine (1 × 100 mL), dried over Na 2 SO 4, filtered, and evaporated under reduced pressure to give a yellow foam. Silicon dioxide using 120 g RediSep R f ® column and using 0% to 70% EtOAc / hexanes gradient and held 70% EtOAc / hexane foam was flash chromatographed to afford the title compound as a white foam. LC-MS: C 24 H Calcd 581.07,583.07 29 BrClN 3 O 5 Si, observed value m / e: 582.20,584.23 (M + H) + (Rt 1.32 / 2 min).

中間物8Intermediate 8

(3R,3aR,6R,6aR)-6-[6-氯-5-[4-(4,4,5,5-四甲基-1,3,2-二氧硼 -2-基)苯基]-1-(2-三甲基矽烷基乙氧基甲基)咪唑并[4,5-b]吡啶-2-基]氧基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇 (3R,3aR,6R,6aR)-6-[6-chloro-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) -2-yl)phenyl]-1-(2-trimethyldecyl ethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5 ,6,6a-hexahydrofuro[3,2-b]furan-3-ol

將1,1'-雙(二苯基膦基)二茂鐵-二氯化鈀(II)二氯甲烷錯合物(0.5137 g，0.629 mmol)添加至中間物7(3.1823 g，5.46 mmol)、雙(頻哪醇根基)二硼(4.09 g，16.11 mmol)及乙酸鉀(2.79 g，28.4 mmol)於二噁烷(50 mL)中之經攪拌懸浮液中。使反應混合物脫氣(3×)且置於氮氣下，隨後加熱至80℃。2小時後，冷卻反應混合物至室溫，隨後分配於EtOAc(200 mL)、水(200 mL)及足量鹽水之間以打碎乳液。用EtOAc(3×100 mL)萃取水層。合併有機層，用鹽水(1×100 mL)洗滌，經Na2 SO4 乾燥，過濾，且在減壓下蒸發，得到暗棕色殘餘物。利用120 g二氧化矽RediSep Rf ®管柱且採用0%至70% EtOAc/己烷梯度並保持70% EtOAc/己烷對殘餘物進行急驟層析，得到呈白色泡沫狀之標題化合物。LC-MS：C30 H41 BClN3 O7 Si計算值629.25，觀測值m/e：630.46(M+H)+ (Rt 1.34/2 min)。Add 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) chloride dichloromethane complex (0.5137 g, 0.629 mmol) to intermediate 7 (3.1823 g, 5.46 mmol) A stirred suspension of bis(pinacolyl)diboron (4.09 g, 16.11 mmol) and potassium acetate (2.79 g, 28.4 mmol) in dioxane (50 mL). The reaction mixture was degassed (3x) and placed under nitrogen then heated to 80. After 2 hours, the reaction mixture was cooled to room temperature then partitioned between EtOAc (200 mL) and water (200 mL) The aqueous layer was extracted with EtOAc (3×100 mL). The organic layers were combined, washed with brine (1 × 100 mL), dried over Na 2 SO 4, filtered, and evaporated under reduced pressure to give a dark brown residue. Silicon dioxide using 120 g RediSep R f ® column and using 0% to 70% EtOAc / hexanes gradient and held 70% EtOAc / hexanes residue was subjected to flash chromatography to afford the title compound as a white foam. LC-MS: C 30 H 41 BClN 3 O 7 Si calcd 629.25, observed m / e: 630.46 (M + H) + (Rt 1.34 / 2 min).

中間物9Intermediate 9

(3R,3aR,6R,6aR)-6-[5-[4-(5-溴-2-吡啶基)苯基]-6-氯-1-(2-三甲基矽烷基乙氧基甲基)咪唑并[4,5-b]吡啶-2-基]氧基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇(3R,3aR,6R,6aR)-6-[5-[4-(5-bromo-2-pyridyl)phenyl]-6-chloro-1-(2-trimethyldecylalkylethoxy) Imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol

將肆(三苯基膦)鈀(189.5 mg，0.164 mmol)添加至中間物8(0.98 g，1.556 mmol)、2,5-二溴吡啶(375.5 mg，1.585 mmol)及碳酸鈉(669.9 mg，6.32 mmol)於1,4-二噁烷(80 mL)及水(20 mL)中之經攪拌混濁溶液中。使反應混合物脫氣(3×)且置於氮氣下，隨後加熱至80℃。2小時後，冷卻反應混合物至室溫，隨後分配於EtOAc(150 mL)與水(150 mL)之間。用EtOAc(3×75 mL)萃取水層。合併有機層，用鹽水(1×100 mL)洗滌，經Na2 SO4 乾燥，過濾，且在減壓下蒸發，得到琥珀色泡沫狀物。利用80 g二氧化矽RediSep Rf ®管柱且採用0%至80% EtOAc/己烷梯度並保持80% EtOAc/己烷對泡沫狀物進行急驟層析，得到呈白色固體狀之標題化合物。LC-MS：C29 H32 BrClN4 O5 Si計算值658.1,660.1，觀測值m/e：659.36,661.33(M+H)+ (Rt 1.33/2 min)。肆(triphenylphosphine)palladium (189.5 mg, 0.164 mmol) was added to Intermediate 8 (0.98 g, 1.565 mmol), 2,5-dibromopyridine (375.5 mg, 1.585 mmol) and sodium carbonate (669.9 mg, 6.32 mmol) in a stirred turbid solution in 1,4-dioxane (80 mL) and water (20 mL). The reaction mixture was degassed (3x) and placed under nitrogen then heated to 80. After 2 hours, the reaction mixture was cooled to EtOAc then EtOAc (EtOAc) The aqueous layer was extracted with EtOAc (3×75 mL). The organic layers were combined, washed with brine (1 × 100 mL), dried over Na 2 SO 4, filtered, and evaporated under reduced pressure to give an amber foam. Silicon dioxide using a 80 g RediSep R f ® column and using 0% to 80% EtOAc / hexanes gradient and held 80% EtOAc / hexane foam was flash chromatographed to afford the title compound as a white solid. LC-MS: C 29 H 32 BrClN 4 O 5 Si Calcd 658.1,660.1, observed m / e: 659.36,661.33 (M + H) + (Rt 1.33 / 2 min).

中間物10Intermediate 10

(3R,3aR,6R,6aR)-6-[5-[4-(6-溴-3-吡啶基)苯基]-6-氯-1-(2-三甲基矽烷基乙氧基甲基)咪唑并[4,5-b]吡啶-2-基]氧基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇 。將肆(三苯 基膦)鈀(134.9 mg，0.117 mmol)添加至中間物8(625.8 mg，0.993 mmol)、2-溴-5-碘吡啶(313.1 mg，1.103 mmol)及磷酸鉀(631.3 mg，2.97 mmol)於1,4-二噁烷(8 mL)及水(2 mL)中之經攪拌混濁溶液中。使反應混合物脫氣(3×)且置於氮氣下，隨後加熱至80℃。7.5小時後，冷卻反應混合物至室溫，隨後分配於EtOAc(150 mL)與水(150 mL)之間。用EtOAc(3×75 mL)萃取水層。合併有機層，用鹽水(1×100 mL)洗滌，經Na2 SO4 乾燥，過濾，且在減壓下蒸發，得到琥珀色泡沫狀物。利用40 g二氧化矽RediSep Rf ®管柱且採用0%至80% EtOAc/己烷梯度並保持80% EtOAc/己烷對泡沫狀物進行急驟層析，自乙醇及苯中凍乾後得到呈灰白色固體狀之標題化合物。LC-MS：C29 H32 BrClN4 O5 Si計算值658.1,660.1，觀測值m/e：659.30,661.33(M+H)+ (Rt 1.31/2 min)。 (3R,3aR,6R,6aR)-6-[5-[4-(6-bromo-3-pyridyl)phenyl]-6-chloro-1-(2-trimethyldecylalkylethoxy) Imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol . Palladium (triphenylphosphine) palladium (134.9 mg, 0.117 mmol) was added to Intermediate 8 (625.8 mg, 0.993 mmol), 2-bromo-5-iodopyridine (313.1 mg, 1.103 mmol) and potassium phosphate (631.3 mg) , 2.97 mmol) in a stirred turbid solution in 1,4-dioxane (8 mL) and water (2 mL). The reaction mixture was degassed (3x) and placed under nitrogen then heated to 80. After 7.5 hours, the reaction mixture was cooled to EtOAc then EtOAc (EtOAc) The aqueous layer was extracted with EtOAc (3×75 mL). The organic layers were combined, washed with brine (1 × 100 mL), dried over Na 2 SO 4, filtered, and evaporated under reduced pressure to give an amber foam. Silicon dioxide using a 40 g RediSep R f ® column and using 0% to 80% EtOAc / hexanes gradient and held 80% EtOAc / hexane foam was flash chromatographed to obtain ethanol from benzene and lyophilized The title compound is obtained as a white solid. LC-MS: C 29 H 32 BrClN 4 O 5 Si Calcd 658.1,660.1, observed m / e: 659.30,661.33 (M + H) + (Rt 1.31 / 2 min).

中間物11Intermediate 11

4-[4-[2-[[(3R,3aR,6R,6aR)-3-羥基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-6-基]氧基]-6-氯-1H-咪唑并[4,5-b]吡啶-5-基]苯基]苯甲腈4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6 -yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]benzonitrile

步驟A4-[4-[2-[[(3R,3aR,6R,6aR)-3-羥基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-6-基]氧基]-6-氯-1-(2-三甲基矽烷 基乙氧基甲基)咪唑并[4,5-b]吡啶-5-基]苯基]苯甲腈 。將LiOH(0.22 mL，0.660 mmol)及1,1'-雙(二苯基膦基)-二茂鐵-二氯化鈀(II)二氯甲烷錯合物(24.1 mg，0.030 mmol)添加至中間物7(153.1 mg，0.263 mmol)及4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)苯甲腈(126.4 mg，0.552 mmol)於1,4-二噁烷(2.1 mL)及水(0.31 mL)中之經攪拌溶液中。使反應混合物脫氣(3×)且置於氮氣下，隨後加熱至80℃。16小時後，冷卻反應混合物至室溫，隨後分配於EtOAc(40 mL)與水(40 mL)之間。用EtOAc(2×20 mL)萃取水層。合併有機層，用鹽水(1×20 mL)洗滌，經Na2 SO4 乾燥，過濾，且在減壓下蒸發，得到棕色殘餘物。藉由急驟層析，利用4 g二氧化矽RediSep Rf ®管柱及以下條件：0%至60% EtOAc/己烷梯度，保持60% EtOAc/己烷，60%至70% EtOAc/己烷梯度且保持70% EtOAc/己烷來純化此物質。合併所要溶離份，在減壓下蒸發，且自乙醇及苯中凍乾，得到呈黃色固體狀之所要化合物。LC-MS：C31 H33 ClN4 O5 Si計算值604.19，觀測值m/e：605.21(M+H)+ (Rt 1.31/2 min)。Step A 4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan 6-yl] oxy] -6-chloro-1- (2-methyl-ethoxymethyl silane-yl) imidazo [4,5-b] pyridin-5-yl] phenyl] benzonitrile . Add LiOH (0.22 mL, 0.660 mmol) and 1,1'-bis(diphenylphosphino)-ferrocene-palladium(II) chloride dichloromethane complex (24.1 mg, 0.030 mmol) to Intermediate 7 (153.1 mg, 0.263 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Benzylcarbonitrile (126.4 mg, 0.552 mmol) in 1,4-dioxane (2.1 mL) and water (0.31 mL). The reaction mixture was degassed (3x) and placed under nitrogen then heated to 80. After 16 h, the reaction mixture was cooled to EtOAc EtOAc (EtOAc) The aqueous layer was extracted with EtOAc (2×20 mL). The organic layers were combined, washed with brine (1 × 20 mL), dried over Na 2 SO 4, filtered, and evaporated under reduced pressure to give a brown residue. By flash chromatography, 4 g of ruthenium RediSep R f ® column and the following conditions: 0% to 60% EtOAc / hexane gradient, 60% EtOAc / hexanes, 60% to 70% EtOAc / hexane The material was purified by gradient and 70% EtOAc / hexanes. The desired fractions are combined, evaporated under reduced pressure and lyophilized from EtOAc (EtOAc). LC-MS: C 31 H 33 ClN calcd 604.19 4 O 5 Si, observed value m / e: 605.21 (M + H) + (Rt 1.31 / 2 min).

步驟B4-[4-[2-[[(3R,3aR,6R,6aR)-3-羥基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-6-基]氧基]-6-氯-1H-咪唑并[4,5-b]吡啶-5-基]苯基]苯甲腈 。在攪拌下，將4-[4-[2-[[(3R,3aR,6R,6aR)-3-羥基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-6-基]氧基]-6-氯-1-(2-三甲基矽烷基乙氧基甲基)咪唑并[4,5-b]吡啶-5-基]苯基]苯甲腈(49.4 mg，0.082 mmol)、甲酸(1.0 mL，26.1 mmol)及飽和KHSO4 水溶液(0.06 mL)之混合物加熱至 40℃。6.5小時後，冷卻反應混合物至室溫且置於冰箱中隔夜，接著在冰浴中冷卻至0℃。藉由添加5 N NaOH(5.2 mL，26 mmol)將pH值調整至pH 14。將THF(2 mL)添加至反應混合物中，自冰浴中移出該混合物且使其升溫至室溫。在室溫下攪拌45分鐘後，藉由添加2 N HCl將pH值調整至7。將反應混合物分配於EtOAc(30 mL)與水(30 mL)之間。用EtOAc(2×20 mL)萃取水層。合併有機層，用鹽水(1×20 mL)洗滌，經Na2 SO4 乾燥，過濾，且在減壓下蒸發，得到淺黃色固體。藉由逆相HPLC(C-18)，使用30×150 mm SunfireTM 管柱且以20%至100%乙腈/水+0.05% TFA梯度，繼而以100%乙腈+0.05% TFA沖洗液溶離來純化，自乙醇及苯中凍乾後得到呈白色固體狀之標題化合物。LC-MS：C25 H19 ClN4 O4 計算值474.11，觀測值m/e：475.12(M+H)+ (Rt 1.15/2 min)。Step B 4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan -6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]benzonitrile . 4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuran [3,2-] with stirring b]furan-6-yl]oxy]-6-chloro-1-(2-trimethyldecyloxymethyl)imidazo[4,5-b]pyridin-5-yl]phenyl] benzonitrile (49.4 mg, 0.082 mmol), a mixture of formic acid (1.0 mL, 26.1 mmol) and saturated KHSO 4 aqueous solution (0.06 mL) of was heated to 40 ℃. After 6.5 hours, the reaction mixture was cooled to room temperature and placed in a refrigerator overnight, then cooled to 0 ° C in an ice bath. The pH was adjusted to pH 14 by the addition of 5 N NaOH (5.2 mL, 26 mmol). THF (2 mL) was added to the mixture and the mixture was removed from iced water and warmed to room temperature. After stirring at room temperature for 45 minutes, the pH was adjusted to 7 by the addition of 2 N HCl. The reaction mixture was partitioned between EtOAc (30 mL)EtOAc. The aqueous layer was extracted with EtOAc (2×20 mL). The organic layers were combined, washed with brine (1 × 20 mL), dried over Na 2 SO 4, filtered, and evaporated under reduced pressure to give a pale yellow solid. By reverse phase HPLC (C-18), using 30 × 150 mm Sunfire TM column and 20% to 100% acetonitrile / water gradient + 0.05% TFA, followed by a rinse liquid purified eluting with 100% acetonitrile + 0.05% TFA The title compound is obtained as a white solid. LC-MS: C 25 H 19 ClN 4 O 4 calcd 474.11, observed m / e: 475.12 (M + H) + (Rt 1.15 / 2 min).

中間物12Intermediate 12

1-(1-(4-溴苯基)-1H-吡唑-4-基)-2-甲基丙-2-醇1-(1-(4-bromophenyl)-1H-pyrazol-4-yl)-2-methylpropan-2-ol

步驟A2-(1H-吡唑-4-基)乙酸甲酯 。在氮氣下，將2-(1H-吡唑-4-基)乙酸(970 mg，7.69 mmol)置於無水甲醇(80 mL)中。對混合物進行音波處理直至固體完全溶解。經30分鐘，向此溶液中逐滴添加三甲基矽烷基重氮甲烷於己烷中之2.0 M溶液(3.85 mL，7.69 mmol)。添加稍過量之三甲基矽烷基重氮甲烷直至持續呈黃色。在室溫下攪拌混合物20 分鐘，接著在減壓下濃縮。使用以10管柱體積含0%至5%甲醇之二氯甲烷且以5%甲醇保持10管柱體積來溶離之Biotage 25 g矽膠濾筒對所得橙色油狀物進行層析。合併產物溶離份且在減壓下濃縮，得到呈澄清無色油狀之所要化合物。1 H NMR δ(ppm)(CDCl3 )：7.54(2H,s),3.70(3H,s),3.55(2H,s)。Step A 2-(1H-Pyrazol-4-yl)acetic acid methyl ester . 2-(1H-Pyrazol-4-yl)acetic acid (970 mg, 7.69 mmol) was taken in anhydrous methanol (80 mL). The mixture was sonicated until the solids were completely dissolved. To this solution was added dropwise a 2.0 M solution of trimethylsulfonyldiazomethane in hexane (3.85 mL, 7.69 mmol) over 30 min. A slight excess of trimethyldecyl diazomethane was added until it continued to appear yellow. The mixture was stirred at room temperature for 20 minutes and then concentrated under reduced pressure. The resulting orange oil was chromatographed using a Biotage 25 g silica gel cartridge eluting with 10 column volumes containing 0% to 5% methanol in dichloromethane and 10 column volumes in 5% methanol. The product was combined and concentrated under reduced pressure to give the desired compound as crystals. 1 H NMR δ (ppm) (CDCl 3 ): 7.54 (2H, s), 3.70 (3H, s), 3.55 (2H, s).

步驟B2-甲基-1-(1H-吡唑-4-基)丙-2-醇 。在氮氣下，將2-(1H-吡唑-4-基)乙酸甲酯(700 mg，4.99 mmol)置於無水THF(100 mL)中。冷卻混合物至0℃，且經5分鐘逐滴添加3.0 M MeMgBr溶液(15.38 mL，46.10 mmol)。使混合物升溫至室溫。16小時後，將混合物傾倒至飽和碳酸氫鈉水溶液(100 mL)中。用EtOAc(4×100 mL)萃取混合物。用鹽水(100 mL)洗滌經合併之有機層，經硫酸鈉乾燥，且在減壓下濃縮。使用以15管柱體積含0%至10%甲醇之二氯甲烷且以10%甲醇保持5管柱體積來溶離之Biotage 25 g矽膠濾筒對所得橙色油狀物進行層析。合併產物溶離份且在減壓下濃縮，得到呈白色固體狀之所要產物。1 H NMR δ(ppm)(CDCl3 )：7.40(2H,s),2.63(2H,s),1.21(6H,s)。Step B 2-Methyl-1-(1H-pyrazol-4-yl)propan-2-ol . Methyl 2-(1H-pyrazol-4-yl)acetate (700 mg, 4.99 mmol) was taken in anhydrous THF (100 mL). The mixture was cooled to 0 ° C and 3.0 M MeMgBr solution (15.38 mL, 46.10 mmol) was added dropwise over 5 min. The mixture was allowed to warm to room temperature. After 16 hours, the mixture was poured into saturated aqueous sodium bicarbonate (100 mL). The mixture was extracted with EtOAc (4×100 mL). The combined organic layers were washed with brine (100 mL) dry The resulting orange oil was chromatographed using a Biotage 25 g silica gel cartridge eluting with 15 column volumes of dichloromethane containing 0% to 10% methanol and keeping 5 column volumes with 10% methanol. The product was combined and concentrated under reduced pressure to give the desired product. 1 H NMR δ (ppm) (CDCl 3 ): 7.40 (2H, s), 2.63 (2H, s), 1.21. (6H, s).

步驟C1-(1-(4-溴苯基)-1H-吡唑-4-基)-2-甲基丙-2-醇 。在氮氣下，將2-甲基-1-(1H-吡唑-4-基)丙-2-醇(21 mg，0.15 mmol)、乙酸銅(II)(27 mg，0.15 mmol)及4-溴苯基酸(30 mg，0.15 mmol)置於1,2-二氯乙烷(1 mL)中。添加4A分子篩(約20 mg)及吡啶(36 μL，36 mg，0.45 mmol)。在50℃下攪拌混合物9小時，同時對大氣開放。冷卻混合 物至室溫，經CeliteTM 過濾，用甲醇清洗，且在減壓下濃縮。使用以30管柱體積含0%至5%甲醇之二氯甲烷溶離之Biotage 50 g(2×25 g，串聯)矽膠濾筒對所得橙色油狀物進行層析。合併所要產物溶離份且在減壓下濃縮，得到無色油狀物(25 mg，54%)。LC-MS：C13 H15 BrN20 計算值295.17，觀測值m/e：296.87(M+H)+ (Rt 1.75/4 min)。1 H NMR δ(ppm)(CDCl3 )：7.77(1H,s),7.58(1H,s),7.55(4H,s),2.67(2H,s),1.26(6H,s)。Step C 1-(1-(4-Bromophenyl)-1H-pyrazol-4-yl)-2-methylpropan-2-ol . 2-Methyl-1-(1H-pyrazol-4-yl)propan-2-ol (21 mg, 0.15 mmol), copper (II) acetate (27 mg, 0.15 mmol) and 4- Bromophenyl The acid (30 mg, 0.15 mmol) was taken in 1,2-dichloroethane (1 mL). 4A molecular sieve (about 20 mg) and pyridine (36 μL, 36 mg, 0.45 mmol) were added. The mixture was stirred at 50 ° C for 9 hours while being open to the atmosphere. The mixture was cooled to room temperature, filtered through Celite TM, washing with methanol, and concentrated under reduced pressure. The resulting orange oil was chromatographed using a Biotage 50 g (2 x 25 g, tandem) silica gel cartridge eluting with a 30 column volume containing 0% to 5% methanol in dichloromethane. The product was dissolved in EtOAc (EtOAc m. LC-MS: 13 H 15 BrN 20 calcd 295.17 C, observed value m / e: 296.87 (M + H) + (Rt 1.75 / 4 min). 1 H NMR δ (ppm) (CDCl 3 ): 7.77 (1H, s), 7.58 (1H, s), 7.55 (4H, s), 2.67 (2H, s), 1.26 (6H, s).

實例163Example 163

(3R,3aR,6R,6aR)-6-[[6-氯-5-[4-(4-吡唑-1-基苯基)苯基]-1H-咪唑并[4,5-b]吡啶-2-基]氧基]-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-(4-pyrazol-1-ylphenyl)phenyl]-1H-imidazo[4,5-b] Pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol

步驟A(3R,3aR,6R,6aR)-6-[6-氯-5-[4-(4-吡唑-1-基苯基)苯基]-1-(2-三甲基矽烷基乙氧基甲基)咪唑并[4,5-b]吡啶-2-基]氧基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇 。將(4-吡唑-1-基苯基)酸(127 mg，0.675 mmol)、1,1'-雙(二苯基膦基)二茂鐵-二氯化鈀(II)二氯甲烷錯合物(45.9 mg，0.056 mmol)及LiOH(0.469 mL，1.407 mmol)添加至中間物7(328 mg，0.563 mmol)於1,4-二噁烷(3 mL)及水(0.8 mL)中之經攪拌混合物中。將反應混合物置於氮氣下，隨後加 熱至90℃。2小時後，冷卻反應混合物至室溫，隨後分配於EtOAc(50 mL)與飽和氯化銨水溶液(50 mL)之間。用EtOAc(2×50 mL)萃取水層。合併有機層，用鹽水(1×50 mL)洗滌，經Na2 SO4 乾燥，過濾，且在減壓下蒸發。利用矽膠BiotageTM 25S管柱且採用0%至80% EtOAc/己烷梯度對所得殘餘物進行急驟層析，得到呈淡黃色固體狀之所要化合物。LC-MS：C33 H36 ClN5 O5 Si計算值645.22，觀測值m/e：646.48(M+H)+ (Rt 1.32/2 min)。Step A (3R,3aR,6R,6aR)-6-[6-Chloro-5-[4-(4-pyrazol-1-ylphenyl)phenyl]-1-(2-trimethyldecyl) Ethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3 - Alcohol . Will (4-pyrazol-1-ylphenyl) Acid (127 mg, 0.675 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) chloride complex (45.9 mg, 0.056 mmol) and LiOH (0.469) </ RTI></RTI><RTIgt;</RTI><RTIgt;</RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt; The reaction mixture was placed under nitrogen and then heated to 90 °C. After 2 hours, the reaction mixture was cooled to EtOAc EtOAc (EtOAc) The aqueous layer was extracted with EtOAc (2×50 mL). The organic layers were combined, washed with brine (1 × 50 mL), dried over Na 2 SO 4, filtered, and evaporated under reduced pressure. Silica gel column using Biotage TM 25S and using 0% to 80% EtOAc / hexanes gradient resulting residue was subjected to flash chromatography to give a pale yellow solid of the desired compound. LC-MS: C 33 H 36 ClN 5 O 5 Si Calcd 645.22, observed m / e: 646.48 (M + H) + (Rt 1.32 / 2 min).

步驟B(3R,3aR,6R,6aR)-6-[[6-氯-5-[4-(4-吡唑-1-基苯基)苯基]-1H-咪唑并[4,5-b]吡啶-2-基]氧基]-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇 。組合甲酸(3 mL，78 mmol)、飽和KHSO4 水溶液(0.33 mL，0.289 mmol)及(3R,3aR,6R,6aR)-6-[6-氯-5-[4-(4-吡唑-1-基苯基)苯基]-1-(2-三甲基矽烷基乙氧基甲基)咪唑并[4,5-b]吡啶-2-基]氧基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇(187 mg，0.289 mmol)。在60℃下攪拌反應混合物隔夜。在冰浴中冷卻反應混合物至0℃。藉由添加含NaOH(3120 mg，78 mmol)之水(5 mL)將反應混合物之pH值調整至>11。將THF(5 mL)添加至反應混合物中，接著自冰浴中移出反應物且使其升溫至室溫。30分鐘後，藉由添加濃鹽酸將反應混合物之pH值調整至6。將反應混合物分配於EtOAc(100 mL)與水(50 mL)之間。用EtOAc(2×100 mL)萃取水層。合併有機層，用鹽水(1×50 mL)洗滌，經Na2 SO4 乾燥，過濾，且在減壓下蒸發。藉由製備型逆相HPLC(C-18)，使用19×100 mm SunfireTM 管柱且 以10%至90%乙腈/水+0.05% TFA梯度，繼而以90%乙腈/水+0.05% TFA沖洗液溶離來純化所得殘餘物。合併所要溶離份，在減壓下蒸發，且自乙腈及水中凍乾，得到呈白色固體狀之標題化合物。LC-MS：C27 H22 ClN5 O4 計算值515.14，觀測值m/e：515.92(M+H)+ (Rt 1.16/2 min)；1 H NMR δ(ppm)(CD3 OD)：8.30(d,J=2.5 Hz,1H),7.87(m,4H),7.85(s,1H),7.79(m,4H),7.77(d,J=1.5 Hz,1H),6.58(t,J=2 Hz,1H),5.56(qt,J=5 Hz,1H),4.99(t,J=5.3 Hz,1H),4.49(t,J=5.3 Hz,1H),4.28-4.31(m,1H),4.19(dd,J=5.5 Hz,10.5 Hz,1H),4.12(dd,J=4.5 Hz,10 Hz,1H),3.92(t,J=7.5 Hz,1H),3.62(t,J=8.8 Hz,1H)。Step B (3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-(4-pyrazol-1-ylphenyl)phenyl]-1H-imidazo[4,5- b] Pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol . Combined formic acid (3 mL, 78 mmol), saturated aqueous KHSO 4 (0.33 mL, 0.289 mmol) and (3R,3aR,6R,6aR)-6-[6-chloro-5-[4-(4-pyrazole- 1-ylphenyl)phenyl]-1-(2-trimethyldecyloxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a, 5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (187 mg, 0.289 mmol). The reaction mixture was stirred at 60 ° C overnight. The reaction mixture was cooled to 0 ° C in an ice bath. The pH of the reaction mixture was adjusted to >11 by the addition of water (5 mL) containing NaOH (3120 mg, 78 mmol). THF (5 mL) was added to the reaction mixture, then the mixture was taken from iced water and warmed to room temperature. After 30 minutes, the pH of the reaction mixture was adjusted to 6 by the addition of concentrated hydrochloric acid. The reaction mixture was partitioned between EtOAc (EtOAc) The aqueous layer was extracted with EtOAc (2×100 mL). The organic layers were combined, washed with brine (1 × 50 mL), dried over Na 2 SO 4, filtered, and evaporated under reduced pressure. By preparative reverse phase HPLC (C-18), using 19 × 100 mm Sunfire TM column and 10% to 90% acetonitrile / water gradient + 0.05% TFA, followed by a rinse in 90% acetonitrile / water + 0.05% TFA The resulting residue was purified by liquid dissolution. The title compound was obtained as a white solid. LC-MS: C 27 H 22 ClN 5 O 4 calcd 515.14, observed m / e: 515.92 (M + H) + (Rt 1.16 / 2 min); 1 H NMR δ (ppm) (CD 3 OD): 8.30 (d, J = 2.5 Hz, 1H), 7.87 (m, 4H), 7.85 (s, 1H), 7.79 (m, 4H), 7.77 (d, J = 1.5 Hz, 1H), 6.58 (t, J = 2 Hz, 1H), 5.56 (qt, J = 5 Hz, 1H), 4.99 (t, J = 5.3 Hz, 1H), 4.49 (t, J = 5.3 Hz, 1H), 4.28 - 4.31 (m, 1H) ), 4.19 (dd, J = 5.5 Hz, 10.5 Hz, 1H), 4.12 (dd, J = 4.5 Hz, 10 Hz, 1H), 3.92 (t, J = 7.5 Hz, 1H), 3.62 (t, J = 8.8 Hz, 1H).

如上文所示，在用於製備實例163之1,1'-雙(二苯基膦基)二茂鐵-二氯化鈀(II)二氯甲烷錯合物偶合反應期間，異甘露糖醇起始物質未經保護(R=H)或經TBS保護(R=OTBS)。觀測到TBS基團在反應期間實質上脫除，得到未經保護之醇。As shown above, during the complex coupling reaction of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) chloride methylene chloride used in the preparation of Example 163, isomannitol The starting material is unprotected (R = H) or protected by TBS (R = OTBS). It was observed that the TBS group was substantially removed during the reaction to give an unprotected alcohol.

實例164Example 164

(3R,3aR,6R,6aR)-6-[[6-氯-5-[4-[4-(1-甲基咪唑-2-基)苯基]苯基]-1H-咪唑并[4,5-b]吡啶-2-基]氧基]-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[4-(1-methylimidazol-2-yl)phenyl]phenyl]-1H-imidazo[4 ,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol

步驟A(3R,3aR,6R,6aR)-6-[[5-(4-溴苯基)-6-氯-1H-咪唑并[4,5-b]吡啶-2-基]氧基]-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇 。將甲酸(4.5 mL，117 mmol)、飽和KHSO4 水溶液(0.5 mL，0.940 mmol)及中間物7(548 mg，0.940 mmol)之混合物在60℃下加熱隔夜。在冰浴中冷卻反應混合物至0℃。藉由添加含NaOH(4680 mg，117 mmol)之水(10 mL)將反應混合物之pH值調整至>pH 11。將THF(10 mL)添加至反應混合物中，自冰浴中移出混合物且使其升溫至室溫。30分鐘後，藉由添加濃鹽酸將反應混合物之pH值調整至pH 6。用EtOAc(3×80 mL)萃取反應混合物。合併有機層，用鹽水(1×100 mL)洗滌，經Na2 SO4 乾燥，過濾，且在減壓下蒸發。利用矽膠BiotageTM 25 M管柱且採用0%至10% MeOH/DCM梯度對所得殘餘物進行急驟層析，得到呈白色固體狀之所要產物。LC-MS：C18 H15 BrClN3 O4 計算值450.99,452.99，觀測值m/e：452.00,454.02(M+H)+ (Rt 1.14/2 min)。Step A (3R,3aR,6R,6aR)-6-[[5-(4-Bromophenyl)-6-chloro-1H-imidazo[4,5-b]pyridin-2-yl]oxy] -2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol . The (548 mg, 0.940 mmol) of a mixture of formic acid (4.5 mL, 117 mmol), saturated aqueous KHSO 4 (0.5 mL, 0.940 mmol) and intermediate 7 was heated overnight at 60 ℃. The reaction mixture was cooled to 0 ° C in an ice bath. The pH of the reaction mixture was adjusted to >pH 11 by the addition of water (10 mL) containing NaOH (4680 mg, 117 mmol). THF (10 mL) was added to the reaction mixture, the mixture was removed from iced water and warmed to room temperature. After 30 minutes, the pH of the reaction mixture was adjusted to pH 6 by the addition of concentrated hydrochloric acid. The reaction mixture was extracted with EtOAc (3×40 mL). The organic layers were combined, washed with brine (1 × 100 mL), dried over Na 2 SO 4, filtered, and evaporated under reduced pressure. The residue was flash chromatographed using EtOAc EtOAc ( EtOAc ) LC-MS: C 18 H 15 BrClN 3 O 4 Calcd 450.99,452.99, observed m / e: 452.00,454.02 (M + H) + (Rt 1.14 / 2 min).

步驟B(3R,3aR,6R,6aR)-6-[[6-氯-5-[4-[4-(1-甲基咪唑-2-基)苯基]苯基]-1H-咪唑并[4,5-b]吡啶-2-基]氧基]-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇 。將1-甲基-2-[4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)苯基]咪唑(26.4 mg，0.093 mmol)、1,1'-雙(二苯基膦基)二茂鐵-二氯化鈀 (II)二氯甲烷錯合物(6.33 mg，7.75 μmol)及LiOH(0.065 mL，0.194 mmol)添加至(3R,3aR,6R,6aR)-6-[[5-(4-溴苯基)-6-氯-1H-咪唑并[4,5-b]吡啶-2-基]氧基]-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇(35.1 mg，0.078 mmol)於1,4-二噁烷(3 mL)及水(0.8 mL)中之經攪拌混合物中。將反應混合物置於氮氣下且加熱至90℃。2小時後，冷卻反應混合物至室溫，隨後分配於EtOAc(30 mL)與飽和NH4 Cl(30 mL)之間。用EtOAc(1×30 mL)萃取水層。合併有機層，用鹽水(1×40 mL)洗滌，經Na2 SO4 乾燥，過濾，且在減壓下蒸發。藉由製備型薄層層析，使用500微米20 cm×20 cm矽膠板(使用10% MeOH/DCM展開)純化所得殘餘物。藉由製備型逆相HPLC(C-18)，使用19×100 mm SunfireTM 管柱且以10%至90%乙腈/水+0.05% TFA梯度，繼而以90%乙腈/水+0.05% TFA沖洗液溶離來進一步純化自板中分離之物質。合併所要溶離份，在減壓下濃縮，且自乙腈及水中凍乾，得到呈白色固體狀之標題化合物。LC-MS：C28 H24 ClN5 O4 計算值529.15，觀測值m/e：530.28(M+H)+ (Rt 1.00/2 min)；1 H NMR δ(ppm)(CD3 OD)：8.04(d,J=8 Hz,2H),7.81-7.88(m,7H),7.69(d,J=1.5 Hz,1H),7.66(d,J=2.0 Hz,1H),5.55(qt,J=5.5 Hz,1H),4.97(t,J=5.3 Hz,1H),4.47(t,J=5.0 Hz,1H),4.28-4.29(m,1H),4.17(dd,J=5.8 Hz,10.3 Hz,1H),4.11(dd,J=4.5 Hz,10.0 Hz,1H),3.99(s,3H),3.90(t,J=7.5 Hz,1H),3.62(t,J=8.5 Hz,1H)。Step B (3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[4-(1-methylimidazol-2-yl)phenyl]phenyl]-1H-imidazole [4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol . 1-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) -2-yl)phenyl]imidazole (26.4 mg, 0.093 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) chloride complex (6.33 mg , 7.75 μmol) and LiOH (0.065 mL, 0.194 mmol) were added to (3R,3aR,6R,6aR)-6-[[5-(4-bromophenyl)-6-chloro-1H-imidazo[4, 5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (35.1 mg, 0.078 mmol) Stirred mixture in 1,4-dioxane (3 mL) and water (0.8 mL). The reaction mixture was placed under nitrogen and heated to 90 °C. After 2 hours, the reaction mixture was cooled to room temperature, then partitioned between EtOAc and saturated NH 4 Cl (30 mL) ( 30 mL). The aqueous layer was extracted with EtOAc (1×30 mL). The organic layers were combined, washed with brine (1 × 40 mL), dried over Na 2 SO 4, filtered, and evaporated under reduced pressure. The resulting residue was purified by preparative thin layer chromatography using a 500 micron 20 cm x 20 cm silica gel (developed using 10% MeOH / DCM). By preparative reverse phase HPLC (C-18), using 19 × 100 mm Sunfire TM column and 10% to 90% acetonitrile / water gradient + 0.05% TFA, followed by a rinse in 90% acetonitrile / water + 0.05% TFA The liquid is dissolved to further purify the material separated from the plate. The title compound was obtained as a white solid. LC-MS: C 28 H 5 O 4 Calcd 24 ClN 529.15, observed value m / e: 530.28 (M + H) + (Rt 1.00 / 2 min); 1 H NMR δ (ppm) (CD 3 OD): 8.04 (d, J = 8 Hz, 2H), 7.81-7.88 (m, 7H), 7.69 (d, J = 1.5 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 5.55 (qt, J = 5.5 Hz, 1H), 4.97 (t, J = 5.3 Hz, 1H), 4.47 (t, J = 5.0 Hz, 1H), 4.28-4.29 (m, 1H), 4.17 (dd, J = 5.8 Hz, 10.3 Hz, 1H), 4.11 (dd, J = 4.5 Hz, 10.0 Hz, 1H), 3.99 (s, 3H), 3.90 (t, J = 7.5 Hz, 1H), 3.62 (t, J = 8.5 Hz, 1H) .

＊ 在用於製備表10中之實例164-170之1,1'-雙(二苯基膦基)二茂鐵-二氯化鈀(II)二氯甲烷錯合物偶合反應期間，異甘露糖醇起始物質未經保護(呈-OH形式)或經TBS保護(呈-OTBS形式)。觀測到TBS基團在反應期間實質上脫除，得到未經保護之醇(-OH)。在表10中之實例164-170之質譜項中標註出TBS保護的使用。 * Different mannose during the coupling reaction of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) chloride complex prepared for the preparation of Examples 164-170 in Table 10 The sugar alcohol starting material is unprotected (in the form of -OH) or protected by TBS (in the form of -OTBS). It was observed that the TBS group was substantially removed during the reaction to give an unprotected alcohol (-OH). The use of TBS protection is noted in the mass spectral term of Examples 164-170 in Table 10.

使用WO 2011/028455中所述之程序且對熟習此項技術者已知之程序進行修改，來製備實例171-178之偶合反應中所用的未經取代之二氫吡咯并[3,4-c]吡唑起始物質。實例173使用區位異構體1-(環丙基甲基)-5,6-二氫-4H-吡咯并[3,4-c]吡唑與2-(環丙基甲基)-5,6-二氫-4H-吡咯并[3,4-c]吡唑之混合物作為起始物質。實例177係由起始物質2,4,5,6-四氫吡咯并[3,4-c]吡唑得到。實例176使用N-乙基-5,6-二氫-4H-吡咯并[3,4-c]吡唑-2-磺醯胺作為起始物質；N-乙基-5,6-二氫-4H-吡咯并[3,4-c]吡唑-2-磺醯胺之磺醯胺在反應條件下水解，得到實例176。The unsubstituted dihydropyrrolo[3,4-c] used in the coupling reaction of Examples 171-178 was prepared using the procedure described in WO 2011/028455 and modified by procedures known to those skilled in the art. Pyrazole starting material. Example 173 uses the positional isomer 1-(cyclopropylmethyl)-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole and 2-(cyclopropylmethyl)-5, A mixture of 6-dihydro-4H-pyrrolo[3,4-c]pyrazole was used as the starting material. Example 177 was obtained from the starting material 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole. Example 176 uses N-ethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-sulfonamide as the starting material; N-ethyl-5,6-dihydrogen The sulfonamide of -4H-pyrrolo[3,4-c]pyrazole-2-sulfonamide was hydrolyzed under the reaction conditions to give Example 176.

實例171Example 171

(3R,3aR,6R,6aR)-6-[[6-氯-5-[4-[2-(2-羥基-2-甲基-丙基)-4,6-二氫吡咯并[3,4-c]吡唑-5-基]苯基]-1H-咪唑并[4,5-b]吡啶-2-基]氧基]-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[2-(2-hydroxy-2-methyl-propyl)-4,6-dihydropyrrolo[3 ,4-c]pyrazol-5-yl]phenyl]-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-six Hydrofurop[3,2-b]furan-3-ol

步驟A(3R,3aR,6R,6aR)-6-[6-氯-5-[4-[2-(2-羥基-2-甲基-丙基)-4,6-二氫吡咯并[3,4-c]吡唑-5-基]苯基]-1-(2-三甲基矽烷基乙氧基甲基)咪唑并[4,5-b]吡啶-2-基]氧基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇 。在室溫下於氮氣氛圍下，將參(二亞苄基丙酮)二鈀(0)(3.8 mg，0.0041 mmol)及1-苯基-2-(二-第三丁基膦基)-1H-吡咯(3.0 mg，0.010 mmol)於二噁烷(0.2 mL)中之混合物攪拌30分鐘。將1-(5,6-二氫-4H-吡咯并[3,4-c]吡唑-2-基)-2-甲基-丙-2-醇、2,2,2-三氟乙酸(68.7 mg，0.233 mmol)、2 M K3 PO4 水溶液(0.2 mL，0.4 mmol)及中間物7(72.0 mg，0.124 mmol)於二噁烷(1.2 mL)中之溶液添加至上述催化劑中，且用氮氣覆蓋混合物並置於110℃油浴中20小時。將所得混合物添加至乙酸乙酯(30 mL)及水(20 mL)中，分離有機層，用飽和氯化鈉水溶液(1×10 mL)洗滌，經無水硫酸鎂乾燥，過濾，且蒸發得到油狀物。將殘餘物溶解於乙酸乙酯中且置放於製備型二氧化矽板(1×1000u)上，使該板展開且以乙酸乙酯溶離UV活性物譜帶(active band)，蒸發後得到油狀物。LC-MS：C33 H43 ClN6 O6 Si計算值682.27，觀測值m/e：683.57(M+H)+ (Rt 1.25/2.0 min)。Step A (3R, 3aR, 6R, 6aR)-6-[6-chloro-5-[4-[2-(2-hydroxy-2-methyl-propyl)-4,6-dihydropyrrolo[ 3,4-c]pyrazol-5-yl]phenyl]-1-(2-trimethyldecyloxyethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy -2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol . Phenyl (dibenzylideneacetone) dipalladium (0) (3.8 mg, 0.0041 mmol) and 1-phenyl-2-(di-tert-butylphosphino)-1H at room temperature under a nitrogen atmosphere A mixture of pyrrole (3.0 mg, 0.010 mmol) in dioxane (0.2 mL) was stirred for 30 min. 1-(5,6-Dihydro-4H-pyrrolo[3,4-c]pyrazol-2-yl)-2-methyl-propan-2-ol, 2,2,2-trifluoroacetic acid (68.7 mg, 0.233 mmol), 2 MK 3 PO 4 aqueous solution (0.2 mL, 0.4 mmol) and a solution of intermediate 7 (72.0 mg, 0.124 mmol) in dioxane (1.2 mL) were added to the above catalyst, and The mixture was covered with nitrogen and placed in a 110 ° C oil bath for 20 hours. The mixture was added to ethyl acetate (30 mL) EtOAc (EtOAc)EtOAc. Shape. The residue was dissolved in ethyl acetate and placed on a preparative ceria board (1 x 1000 u). The plate was developed and the UV active band was dissolved in ethyl acetate. Shape. LC-MS: C 33 H 43 ClN 6 O 6 Si calcd 682.27, observed m / e: 683.57 (M + H) + (Rt 1.25 / 2.0 min).

步驟B(3R,3aR,6R,6aR)-6-[[6-氯-5-[4-[2-(2-羥基-2-甲基-丙基)-4,6-二氫吡咯并[3,4-c]吡唑-5-基]苯基]-1H-咪唑 并[4,5-b]吡啶-2-基]氧基]-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇 。將(3R,3aR,6R,6aR)-6-[6-氯-5-[4-[2-(2-羥基-2-甲基-丙基)-4,6-二氫吡咯并[3,4-c]吡唑-5-基]苯基]-1-(2-三甲基矽烷基乙氧基甲基)咪唑并[4,5-b]吡啶-2-基]氧基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇(48.8 mg，0.07 mmol)、甲酸(1.5 mL)及飽和KHSO4 水溶液(0.2 mL)之混合物在周圍溫度下攪拌40分鐘，接著置於冰箱中。18小時後，將反應混合物分配於EtOAc(50 mL)與飽和碳酸氫鈉水溶液(25 mL)之間。用EtOAc(2×20 mL)萃取水層。合併有機層，用鹽水(1×10 mL)洗滌，經MgSO4 乾燥，過濾，且在減壓下蒸發。將殘餘物溶解於MeOH(1 mL)中，且經15分鐘添加7滴3 N NaOH水溶液。藉由逆相HPLC(C-18)，使用30×150 mm SunfireTM 管柱且以20%至80%乙腈/水梯度溶離來純化混合物，凍乾後得到呈淡黃色固體狀之標題化合物。LC-MS：C27 H29 ClN6 O5 計算值552.19，觀測值m/e：553.44(M+H)+ (Rt 1.09/2.0 min)；1 H NMR δ(ppm)(CD3 OD)：7.96(s,1H),7.62(d,1H),7.52(s,1H),6.81(d,1H),5.59(m,1H),4.98(dd,1H),4.48(dd,1H),4.30(m,1H),4.16(m,2H),4.14(s,2H),3.91(dd,1H),3.60(dd,1H)及1.20(s,6H)。Step B (3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[2-(2-hydroxy-2-methyl-propyl)-4,6-dihydropyrrole [3,4-c]pyrazol-5-yl]phenyl]-1H-imidazo [4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a - hexahydrofuro[3,2-b]furan-3-ol . (3R,3aR,6R,6aR)-6-[6-chloro-5-[4-[2-(2-hydroxy-2-methyl-propyl)-4,6-dihydropyrrolo[3 ,4-c]pyrazol-5-yl]phenyl]-1-(2-trimethyldecyloxyethoxy)imidazo[4,5-b]pyridin-2-yl]oxy- 2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (48.8 mg, 0.07 mmol), formic acid (1.5 mL) and saturated aqueous KHSO 4 (0.2 mL) The mixture was stirred at ambient temperature for 40 minutes and then placed in a refrigerator. The reaction mixture was partitioned between EtOAc (50 mL)EtOAc. The aqueous layer was extracted with EtOAc (2×20 mL). The organic layers were combined, dried and washed with brine (1 × 10 mL) over with MgSO 4, filtered, and evaporated under reduced pressure. The residue was dissolved in MeOH (1 mL) and aq. The mixture was purified by EtOAc ( EtOAc ) eluting LC-MS: C 27 H 29 ClN 6 O 5 calcd 552.19, observed m / e: 553.44 (M + H) + (Rt 1.09 / 2.0 min); 1 H NMR δ (ppm) (CD 3 OD): 7.96 (s, 1H), 7.62 (d, 1H), 7.52 (s, 1H), 6.81 (d, 1H), 5.59 (m, 1H), 4.98 (dd, 1H), 4.48 (dd, 1H), 4.30 (m, 1H), 4.16 (m, 2H), 4.14 (s, 2H), 3.91 (dd, 1H), 3.60 (dd, 1H) and 1.20 (s, 6H).

實例179Example 179

(3R,3aR,6R,6aR)-6-[[6-氯-5-[4-(6-吡唑-1-基-3-吡啶基)苯基]-1H-咪唑并[4,5-b]吡啶-2-基]氧基]-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-(6-pyrazol-1-yl-3-pyridyl)phenyl]-1H-imidazo[4,5 -b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol

步驟A(3R,3aR,6R,6aR)-6-[6-氯-5-[4-(6-吡唑-1-基-3-吡啶基)苯基]-1-(2-三甲基矽烷基乙氧基甲基)咪唑并[4,5-b]吡啶-2-基]氧基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇 。將5-溴-2-吡唑-1-基-吡啶(0.879 g，3.92 mmol)、1,1'- 雙(二苯基膦基)二茂鐵-二氯化鈀(II)二氯甲烷錯合物(0.267 g，0.327 mmol)及LiOH(2.72 mL，8.17 mmol)添加至中間物8(2.06 g，3.27 mmol)於1,4-二噁烷(9 mL)及水(2.4 mL)中之經攪拌混合物中。將反應混合物置於氮氣下，接著加熱至90℃。4小時後，冷卻反應混合物至室溫，隨後分配於飽和氯化銨水溶液(200 mL)與EtOAc(150 mL)之間。用EtOAc(2×150 mL)萃取水層。合併有機層，用鹽水(1×100 mL)洗滌，經Na2 SO4 乾燥，過濾，且在減壓下蒸發。利用矽膠BiotageTM 40 M管柱且採用0%至80% EtOAc/己烷梯度對所得殘餘物進行急驟層析，得到呈淡黃色固體狀之所要產物。LC-MS：C32 H35 ClN6 O5 Si計算值646.21，觀測值m/e：647.53(M+H)+ (Rt 1.32/2 min)。Step A (3R,3aR,6R,6aR)-6-[6-Chloro-5-[4-(6-pyrazol-1-yl-3-pyridyl)phenyl]-1-(2-trimethyl) Alkyl ethoxymethyl) imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b] Furan-3-ol . 5-Bromo-2-pyrazol-1-yl-pyridine (0.879 g, 3.92 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) chloride The complex (0.267 g, 0.327 mmol) and LiOH (2.72 mL, 8.17 mmol) were added to Intermediate 8 (2.06 g, 3.27 mmol) in 1,4-dioxane (9 mL) and water (2.4 mL) It is stirred in the mixture. The reaction mixture was placed under nitrogen and then heated to 90 °C. After 4 hours, the reaction mixture was cooled to EtOAc EtOAc m. The aqueous layer was extracted with EtOAc (2×150 mL). The organic layers were combined, washed with brine (1 × 100 mL), dried over Na 2 SO 4, filtered, and evaporated under reduced pressure. Silica gel using Biotage TM 40 M column and using 0% to 80% EtOAc / hexanes gradient resulting residue was subjected to flash chromatography to give a pale yellow solid of the desired product. LC-MS: C 32 H 35 ClN 6 O 5 Si Calcd 646.21, observed m / e: 647.53 (M + H) + (Rt 1.32 / 2 min).

步驟B(3R,3aR,6R,6aR)-6-[[6-氯-5-[4-(6-吡唑-1-基-3-吡啶基)苯基]-1H-咪唑并[4,5-b]吡啶-2-基]氧基]-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇 。將甲酸(6 mL，156 mmol)、飽和KHSO4 水溶液(0.66 mL，2.58 mmol)及(3R,3aR,6R,6aR)-6-[6-氯-5-[4-(6-吡唑-1-基-3-吡啶基)苯基]-1-(2-三甲基矽烷基乙氧基甲基)咪唑并[4,5-b]吡啶-2-基]氧基-2,3,3a,5,6,6a-六氫-呋喃并[3,2-b]呋喃-3-醇(1.67 g，2.58 mmol)之混合物在60℃下攪拌隔夜，接著在冰浴中冷卻至0℃。藉由添加含NaOH(6.24 g，156 mmol)之水(5 mL)將反應混合物之pH值調整至pH>11。將THF(10 mL)添加至反應混合物中，且自冰浴中移出反應物並使其升溫至室溫。30分鐘後，藉由添加濃鹽酸將反應混合物之pH值調整至 pH 6。分離兩相混合物。在減壓下濃縮有機層及所得白色沈澱物，再溶解於DMSO中且過濾，隨後藉由製備型逆相HPLC(C-18)，使用19×100 mm SunfireTM 管柱且以10%至90%乙腈/水+0.05% TFA梯度，繼而以90%乙腈/水+0.05% TFA沖洗液溶離來純化。合併所要溶離份，且在減壓下蒸發。用MeOH洗滌所得殘餘物且自乙腈及水中凍乾，得到呈白色固體狀之標題化合物。LC-MS：C26 H21 ClN6 O4 計算值516.13，觀測值m/e：517.22(M+H)+ (Rt 1.16/2 min)；1 H NMR δ(ppm)(CD3 OD)：8.80(d,J=2.5 Hz,1H),8.67(d,J=2.0 Hz,1H),8.30(dd,J=2.8 Hz,8.5 Hz,1H),8.06(d,J=9.0 Hz,1H),7.81-7.83(m,6H),6.84(t,J=2.3 Hz,1H),5.56(qt,J=5.5 Hz,1H),4.99(t,J=5.3 Hz,1H),4.49(t,J=5.0 Hz,1H),4.28-4.32(m,1H),4.19(dd,J=6.0 Hz,10 Hz,1H),4.13(dd,J=4.8 Hz,10.3 Hz,1H),3.92(dd,J=7.0 Hz,J=8.0 Hz,1H),3.62(t,J=8.5 Hz,1H)。Step B (3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-(6-pyrazol-1-yl-3-pyridyl)phenyl]-1H-imidazo[4 , 5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol . Formic acid (6 mL, 156 mmol), saturated aqueous KHSO 4 (0.66 mL, 2.58 mmol) and (3R,3aR,6R,6aR)-6-[6-chloro-5-[4-(6-pyrazole- 1-yl-3-pyridyl)phenyl]-1-(2-trimethyldecyloxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3 , a mixture of 3a, 5,6,6a-hexahydro-furo[3,2-b]furan-3-ol (1.67 g, 2.58 mmol) was stirred at 60 ° C overnight, then cooled to 0 in an ice bath. °C. The pH of the reaction mixture was adjusted to pH > 11 by adding water (5 mL) containing NaOH (6.24 g, 156 mmol). THF (10 mL) was added to the reaction mixture and the mixture was taken from iced water and warmed to room temperature. After 30 minutes, the pH of the reaction mixture was adjusted to pH 6 by the addition of concentrated hydrochloric acid. The two phase mixture was separated. The organic layer was concentrated and the resulting white precipitate under reduced pressure, then dissolved in DMSO and filtered, followed by preparative reverse-phase HPLC (C-18), using 19 × 100 mm Sunfire TM column and 90 to 10% The % acetonitrile/water + 0.05% TFA gradient was then purified by dissolving in 90% acetonitrile/water + 0.05% TFA rinse. The desired fractions were combined and evaporated under reduced pressure. The residue was washed with EtOAc (EtOAc) LC-MS: C 26 H 21 ClN 6 O 4 calcd 516.13, observed m / e: 517.22 (M + H) + (Rt 1.16 / 2 min); 1 H NMR δ (ppm) (CD 3 OD): 8.80 (d, J = 2.5 Hz, 1H), 8.67 (d, J = 2.0 Hz, 1H), 8.30 (dd, J = 2.8 Hz, 8.5 Hz, 1H), 8.06 (d, J = 9.0 Hz, 1H) , 7.81 - 7.83 (m, 6H), 6.84 (t, J = 2.3 Hz, 1H), 5.56 (qt, J = 5.5 Hz, 1H), 4.99 (t, J = 5.3 Hz, 1H), 4.49 (t, J=5.0 Hz, 1H), 4.28-4.32 (m, 1H), 4.19 (dd, J=6.0 Hz, 10 Hz, 1H), 4.13 (dd, J=4.8 Hz, 10.3 Hz, 1H), 3.92 (dd , J = 7.0 Hz, J = 8.0 Hz, 1H), 3.62 (t, J = 8.5 Hz, 1H).

如上文所示，在用於製備實例179之偶合反應期間，異甘露糖醇未經保護(R=H)或經TBS保護(R=TBS)。觀測到TBS基團在反應期間實質上脫除，得到未經保護之醇(R=H)。As indicated above, during the coupling reaction used to prepare Example 179, the isomannitol was unprotected (R=H) or TBS protected (R=TBS). It was observed that the TBS group was substantially removed during the reaction to give an unprotected alcohol (R = H).

實例180Example 180

(3R,3aR,6R,6aR)-6-[[6-氯-5-[4-[4-(1,2,4-三唑-1-基)苯基]苯基]-1H-咪唑并[4,5-b]吡啶-2-基]氧基]-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[4-(1,2,4-triazol-1-yl)phenyl]phenyl]-1H-imidazole And [4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol

步驟A(3R,3aR,6R,6aR)-6-[6-氯-5-[4-[4-(1,2,4-三唑-1-基)苯基]苯基]-1-(2-三甲基矽烷基乙氧基甲基)咪唑并[4,5-b]吡啶-2-基]氧基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇 。將1-(4-溴苯基)-1,2,4-三唑(0.557 g，2.486 mmol)、肆(三苯基膦)鈀(0.383 g，0.331 mmol)及磷酸鉀(1.407 g，6.63 mmol)添加至中間物8(1.044 g，1.657 mmol)於二噁烷(9 mL)及水(2.4 mL)中之經攪拌混合物中。將反應混合物置於氮氣下，隨後加熱至90℃。4小時後，冷卻反應混合物至室溫，接著分配於EtOAc(100 mL)與飽和氯化銨水溶液(100 mL)之間。用乙酸乙酯(2×100 mL)萃取水層。合併有機層，用鹽水(1×50 mL)洗滌，經Na2 SO4 乾燥，過濾，且在減壓下蒸發。利用矽膠BiotageTM 40 M管柱且採用0%至100% EtOAc/己烷梯度對所得殘餘物進行急驟層析，得到呈淡黃色固體狀之所要產物。LC-MS：C32 H35 ClN6 O5 Si計算值646.21，觀測值m/e：647.01(M+H)+ (Rt 1.26/2 min)。Step A (3R,3aR,6R,6aR)-6-[6-chloro-5-[4-[4-(1,2,4-triazol-1-yl)phenyl]phenyl]-1- (2-trimethyldecyl ethoxymethyl) imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuran[3 , 2-b]furan-3-ol . 1-(4-Bromophenyl)-1,2,4-triazole (0.557 g, 2.486 mmol), hydrazine (triphenylphosphine) palladium (0.383 g, 0.331 mmol) and potassium phosphate (1.407 g, 6.63) Methyl) was added to a stirred mixture of intermediate 8 (1.044 g, 1.657 mmol) in dioxane (9 mL) and water (2.4 mL). The reaction mixture was placed under nitrogen and then heated to 90 °C. After 4 hours, the reaction mixture was cooled to EtOAc EtOAc (EtOAc) The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layers were combined, washed with brine (1 × 50 mL), dried over Na 2 SO 4, filtered, and evaporated under reduced pressure. Silica gel using Biotage TM 40 M column and using 0% to 100% EtOAc / hexanes gradient resulting residue was subjected to flash chromatography to give a pale yellow solid of the desired product. LC-MS: C 32 H 35 ClN 6 O 5 Si Calcd 646.21, observed m / e: 647.01 (M + H) + (Rt 1.26 / 2 min).

步驟B(3R,3aR,6R,6aR)-6-[[6-氯-5-[4-[4-(1,2,4-三唑-1-基)苯基]苯基]-1H-咪唑并[4,5-b]吡啶-2-基]氧基]- 2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇 。製成甲酸(3 mL，68.8 mmol)、飽和KHSO4 水溶液(0.33 mL，1.777 mmol)及(3R,3aR,6R,6aR)-6-[6-氯-5-[4-[4-(1,2,4-三唑-1-基)苯基]苯基]-1-(2-三甲基矽烷基乙氧基甲基)咪唑并[4,5-b]吡啶-2-基]氧基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇(1.15 g，1.777 mmol)之混合物。在60℃下攪拌反應混合物隔夜，接著在冰浴中冷卻至0℃。藉由添加含NaOH(2.75 g，68.8 mmol)之水(5 mL)將反應混合物之pH值調整至pH>11。將THF(5 mL)添加至反應混合物中，且自冰浴中移出反應物並使其升溫至室溫。30分鐘後，藉由添加濃鹽酸將反應混合物之pH值調整至pH 6。分離兩相混合物。在減壓下濃縮有機層及已形成之所得白色沈澱物，再溶解於DMSO中且過濾，隨後藉由製備型逆相HPLC(C-18)，使用19×100 mm SunfireTM 管柱且以10%至90%乙腈/水梯度+0.05% TFA，繼而以90%乙腈/水+0.05% TFA沖洗液溶離來純化。合併所要溶離份，且在減壓下蒸發。用MeOH洗滌所得殘餘物且自乙腈及水中凍乾，得到呈白色固體狀之標題化合物。LC-MS：C26 H21 ClN6 O4 計算值516.13，觀測值m/e：516.85(M+H)+ (Rt 1.11/2 min)；1 H NMR δ(ppm)(CD3 OD)：9.17(s,1H),8.21(s,1H),7.82-7.97(m,4H),7.78-7.80(m,5H),5.56(qt,J=5.5 Hz,1H),4.98(t,J=5.3 Hz,1H),4.49(t,J=5 Hz,1H),4.28-4.32(m,1H),4.19(dd,J=6.0 Hz,10.0 Hz,1H),4.12(dd,J=5.0 Hz,10.0 Hz,1H),3.92(dd,J=7.0 Hz,8.0 Hz,1H),3.62(t,J=8.8 Hz,1H)。Step B (3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[4-(1,2,4-triazol-1-yl)phenyl]phenyl]-1H -Imidazo[4,5-b]pyridin-2-yl]oxy] -2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol . Made of formic acid (3 mL, 68.8 mmol), saturated KHSO 4 (0.33 mL, 1.773 mmol) and (3R,3aR,6R,6aR)-6-[6-chloro-5-[4-[4-(1) , 2,4-triazol-1-yl)phenyl]phenyl]-1-(2-trimethyldecyloxyethoxymethyl)imidazo[4,5-b]pyridin-2-yl] A mixture of oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (1.15 g, 1.777 mmol). The reaction mixture was stirred at 60 ° C overnight, then cooled to 0 ° C in an ice bath. The pH of the reaction mixture was adjusted to pH > 11 by the addition of water (5 mL) containing NaOH (2.75 g, 68.8 mmol). THF (5 mL) was added to the reaction mixture and the mixture was taken from iced water and warmed to room temperature. After 30 minutes, the pH of the reaction mixture was adjusted to pH 6 by the addition of concentrated hydrochloric acid. The two phase mixture was separated. The organic layer was concentrated under reduced pressure and the resulting white precipitate formed was redissolved in DMSO and filtered, followed by preparative reverse-phase HPLC (C-18), using 19 × 100 mm Sunfire TM column and at 10 The % to 90% acetonitrile/water gradient + 0.05% TFA was then purified by dissolving in 90% acetonitrile/water + 0.05% TFA rinse. The desired fractions were combined and evaporated under reduced pressure. The residue was washed with EtOAc (EtOAc) LC-MS: C 26 H 21 ClN 6 O 4 calcd 516.13, observed m / e: 516.85 (M + H) + (Rt 1.11 / 2 min); 1 H NMR δ (ppm) (CD 3 OD): 9.17(s,1H), 8.21(s,1H),7.82-7.97(m,4H),7.78-7.80(m,5H),5.56(qt,J=5.5 Hz,1H),4.98(t,J= 5.3 Hz, 1H), 4.49 (t, J = 5 Hz, 1H), 4.28-4.32 (m, 1H), 4.19 (dd, J = 6.0 Hz, 10.0 Hz, 1H), 4.12 (dd, J = 5.0 Hz) , 10.0 Hz, 1H), 3.92 (dd, J = 7.0 Hz, 8.0 Hz, 1H), 3.62 (t, J = 8.8 Hz, 1H).

如上文所示，在用於製備實例180之偶合反應期間，異甘露糖醇起始物質未經保護(R=H)或經TBS保護(R=TBS)。觀測到TBS基團在反應期間實質上脫除，得到未經保護之醇(R=H)。As indicated above, during the coupling reaction used to prepare Example 180, the isomannitol starting material was unprotected (R=H) or TBS protected (R=TBS). It was observed that the TBS group was substantially removed during the reaction to give an unprotected alcohol (R = H).

＊ 在用於製備表12中之實例181-197之偶合反應期間，異甘露糖醇起始物質未經保護(呈-OH形式)或經TBS保護(呈-OTBS形式)。觀測到TBS基團在反應期間實質上脫除，得到未經保護之醇(-OH)。在表12中之實例181-197之 質譜項中標註出TBS保護的使用。 * During the coupling reaction used to prepare Examples 181-197 in Table 12, the isomannitol starting material was unprotected (in the form of -OH) or protected by TBS (in the form of -OTBS). It was observed that the TBS group was substantially removed during the reaction to give an unprotected alcohol (-OH). The use of TBS protection is noted in the mass spectral term of Examples 181-197 in Table 12.

實例198Example 198

(3R,3aR,6R,6aR)-6-[[6-氯-5-[4-(5-吡唑-1-基-2-吡啶基)苯基]-1H-咪唑并[4,5-b]吡啶-2-基]氧基]-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-(5-pyrazol-1-yl-2-pyridyl)phenyl]-1H-imidazo[4,5 -b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol

步驟A(3R,3aR,6R,6aR)-6-[6-氯-5-[4-(5-吡唑-1-基-2-吡啶基)苯基]-1-(2-三甲基矽烷基乙氧基甲基)咪唑并[4,5-b]吡啶-2-基]氧基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇 。將中間物9(81.0 mg，0.123 mmol)、吡唑(11.2 mg，0.165 mmol)、磷酸鉀(76.1 mg，0.359 mmol)及碘化銅(I)(5.0 mg，0.026 mmol)之混合物抽真空，且用氮氣(3×)回填。添加反-(1R,2R)-N,N'-雙甲基-1,2-環己二胺(10 μl，0.063 mmol)及DMF(0.25 mL)，且在攪拌下加熱懸浮液至110℃。24小時後，冷卻反應混合物至室溫，接著經CeliteTM 襯墊過濾，且用EtOAc(75 mL)清洗。用水(3×30 mL)及鹽水(1×20 mL)洗滌濾液，經Na2 SO4 乾燥，過濾，且在減壓下蒸發，得到琥珀色殘餘物。使用兩個500微米20 cm×20 cm矽膠板(使用80% EtOAc/己烷展開)對殘餘物進行製備型薄層層析，得到呈無色殘餘物形式之所要產物。LC-MS：C32 H35 ClN6 O5 Si計算值646.21，觀測值m/e：647.45 (M+H)+ (Rt 1.27/2 min)。Step A (3R,3aR,6R,6aR)-6-[6-Chloro-5-[4-(5-pyrazol-1-yl-2-pyridyl)phenyl]-1-(2-trimethyl) Alkyl ethoxymethyl) imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b] Furan-3-ol . A mixture of Intermediate 9 (81.0 mg, 0.123 mmol), pyrazole (11.2 mg, 0.165 mmol), potassium phosphate (76.1 mg, 0.359 mmol) and copper (I) iodide (5.0 mg, 0.026 mmol) was evaporated. And backfill with nitrogen (3 x). Add trans-(1R,2R)-N,N'-bismethyl-1,2-cyclohexanediamine (10 μl, 0.063 mmol) and DMF (0.25 mL) and heat the suspension to 110 ° C with stirring . After 24 hours, the reaction mixture was cooled to room temperature and then filtered through a Celite TM pad, and washed with EtOAc (75 mL). Washed with water (3 × 30 mL) and brine (1 × 20 mL) The filtrate was washed, dried over Na 2 SO 4, filtered, and evaporated under reduced pressure to give an amber residue. The residue was subjected to preparative thin layer chromatography using two 500 micron 20 cm x 20 cm silica gel plates (developed with 80% EtOAc/hexanes) to afford the desired product as a colorless residue. LC-MS: C 32 H 35 ClN 6 O 5 Si Calcd 646.21, observed m / e: 647.45 (M + H) + (Rt 1.27 / 2 min).

步驟B(3R,3aR,6R,6aR)-6-[[6-氯-5-[4-(5-吡唑-1-基-2-吡啶基)苯基]-1H-咪唑并[4,5-b]吡啶-2-基]氧基]-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇 。在攪拌下，將(3R,3aR,6R,6aR)-6-[6-氯-5-[4-(5-吡唑-1-基-2-吡啶基)苯基]-1-(2-三甲基矽烷基乙氧基甲基)咪唑并[4,5-b]吡啶-2-基]氧基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇(32.7 mg，0.051 mmol)、甲酸(1.0 mL，26.1 mmol)及飽和KHSO4 水溶液(0.05 mL)之混合物加熱至40℃。16.5小時後，冷卻反應混合物至室溫，接著在冰浴中冷卻至0℃。藉由添加5 N NaOH(5.8 mL，29 mmol)將反應混合物之pH值調整至pH 14。將THF(2 mL)添加至反應混合物，自冰浴中移出混合物且使其升溫至室溫。1.5小時後，藉由添加2 N HCl將反應混合物之pH值調整至pH 6。將反應混合物分配於EtOAc(30 mL)與水(30 mL)之間。用EtOAc(2×20 mL)萃取水層。合併有機層，用鹽水(1×20 mL)洗滌，經Na2 SO4 乾燥，過濾，且在減壓下蒸發，得到白色殘餘物。藉由逆相HPLC(C-18)，使用30×150 mm SunfireTM 管柱且以20%至70%乙腈/水+0.05% TFA梯度，繼而以70%乙腈/水+0.05% TFA沖洗液溶離來純化殘餘物，隨後自乙醇及苯中凍乾，得到呈白色固體狀之標題化合物。LC-MS：C26 H21 ClN6 O4 計算值516.13，觀測值m/e：517.35(M+H)+ (Rt 1.11/2 min)；1 H NMR δ(ppm)(CD3 OD)：9.21(d,J=2.6 Hz,1H),8.52(dd,J=2.6 Hz,8.6Hz,1H),8.47(d,J=2.6 Hz,1H),8.24(d,J=8.7 Hz,1H), 8.19(d,J=8.4 Hz,2H),8.04(s,1H),7.89(d,J=8.3 Hz,2H),7.87(d,J=1.8 Hz,1H),6.66(t,J=2.2 Hz,1H),5.61(qt,J=5.2 Hz,1H),4.99(t,J=5.2 Hz,1H),4.48(t,J=5.1 Hz,1H),4.28-4.32(m,1H),4.18(d,J=5.1 Hz,2H),3.91(dd,J=6.8 Hz,8.2 Hz,1H),3.61(t,J=8.6,1H)。Step B (3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-(5-pyrazol-1-yl-2-pyridyl)phenyl]-1H-imidazo[4 , 5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol . (3R,3aR,6R,6aR)-6-[6-chloro-5-[4-(5-pyrazol-1-yl-2-pyridyl)phenyl]-1-(2) -trimethyldecyl ethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuran [3,2 -b] furan-3-ol (32.7 mg, 0.051 mmol), a mixture of formic acid (1.0 mL, 26.1 mmol) and saturated KHSO 4 aqueous solution (0.05 mL) of was heated to 40 ℃. After 16.5 hours, the reaction mixture was cooled to room temperature then cooled to 0 ° C in an ice bath. The pH of the reaction mixture was adjusted to pH 14 by the addition of 5 N NaOH (5.8 mL, 29 mmol). THF (2 mL) was added to the reaction mixture and the mixture was taken from iced water and warmed to room temperature. After 1.5 hours, the pH of the reaction mixture was adjusted to pH 6 by the addition of 2 N HCl. The reaction mixture was partitioned between EtOAc (30 mL)EtOAc. The aqueous layer was extracted with EtOAc (2×20 mL). The organic layers were combined, washed with brine (1 × 20 mL), dried over Na 2 SO 4, filtered, and evaporated under reduced pressure to give a white residue. By reverse phase HPLC (C-18), using 30 × 150 mm Sunfire TM column and with 20-70% acetonitrile / water gradient + 0.05% TFA, then with 70% acetonitrile / water + 0.05% TFA rinse liquid fractions The residue was purified by EtOAc (EtOAc): LC-MS: C 26 H 21 ClN 6 O 4 calcd 516.13, observed m / e: 517.35 (M + H) + (Rt 1.11 / 2 min); 1 H NMR δ (ppm) (CD 3 OD): 9.21 (d, J = 2.6 Hz, 1H), 8.52 (dd, J = 2.6 Hz, 8.6 Hz, 1H), 8.47 (d, J = 2.6 Hz, 1H), 8.24 (d, J = 8.7 Hz, 1H) , 8.19 (d, J = 8.4 Hz, 2H), 8.04 (s, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.87 (d, J = 1.8 Hz, 1H), 6.66 (t, J = 2.2 Hz, 1H), 5.61 (qt, J = 5.2 Hz, 1H), 4.99 (t, J = 5.2 Hz, 1H), 4.48 (t, J = 5.1 Hz, 1H), 4.28-4.32 (m, 1H) , 4.18 (d, J = 5.1 Hz, 2H), 3.91 (dd, J = 6.8 Hz, 8.2 Hz, 1H), 3.61 (t, J = 8.6, 1H).

實例202Example 202

(3R,3aR,6R,6aR)-6-[[6-氯-5-[4-[5-[4-(2-羥基-2-甲基-丙基)吡唑-1-基]-2-吡啶基]苯基]-1H-咪唑并[4,5-b]吡啶-2-基]氧基]-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[5-[4-(2-hydroxy-2-methyl-propyl)pyrazol-1-yl]- 2-pyridyl]phenyl]-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuran [3,2 -b]furan-3-ol

步驟A2-[1-[6-[4-[2-[[(3R,3aR,6R,6aR)-3-羥基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-6-基]氧基]-6-氯-1-(2-三甲基矽烷基乙氧基甲基)咪唑并[4,5-b]吡啶-5-基]苯基]-3-吡啶基]吡唑-4-基]乙酸 。在8 mL小瓶中，向中間物9(196.6 mg，0.298 mmol)、2-(1H-吡唑-4-基)乙酸甲酯(87.2 mg，0.622 mmol)、磷酸鉀(191.9 mg，0.904 mmol)及碘化銅(I)(11.9 mg，0.062 mmol)之混合物中添加反-(1R,2R)-N,N'-雙甲基-1,2-環己二胺(20.0 μl，0.127 mmol)及DMF(0.6 mL)。加熱所得懸浮液至110℃。24小時後，冷卻反應混合物至室溫，隨後分配於EtOAc(50 mL)與2 N HCl(50 mL)之間。過濾兩相混合物，且收集固體。分配兩相濾液，同時用EtOAc(2×30 mL)洗滌固體。使用此等EtOAc洗滌液中之每一者萃取水層。合併有機層，用鹽水(1×30 mL)洗滌，經Na2 SO4 乾燥，過濾，且在減壓下蒸發，得到黃色殘餘物。將殘餘物溶解於EtOAc(50 mL)及水(20 mL)中。分配兩相混合物，且用EtOAc(1×50 mL)萃取水層。合併有機層，用 鹽水(1×20 mL)洗滌，經MgSO4 乾燥，過濾，且在減壓下蒸發，得到黃色殘餘物。用MeOH(30 mL)洗滌經過濾之固體，將其與處理所得之殘餘物合併且在減壓下蒸發，得到黃色殘餘物。藉由逆相HPLC(C-18)，使用30×150 mm SunfireTM 管柱且以20%至100%乙腈/水+0.05% TFA梯度，繼而以100%乙腈+0.05% TFA沖洗液溶離來純化殘餘物，得到呈黃色殘餘物形式之所要化合物。LC-MS：C34 H37 ClN6 O7 Si計算值704.22，觀測值m/e：705.32(M+H)+ (Rt 1.20/2 min)。Step A 2-[1-[6-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuran[3 ,2-b]furan-6-yl]oxy]-6-chloro-1-(2-trimethyldecylethoxyethoxymethyl)imidazo[4,5-b]pyridin-5-yl] Phenyl]-3-pyridyl]pyrazol-4-yl]acetic acid . In an 8 mL vial, intermediate 9 (196.6 mg, 0.298 mmol), methyl 2-(1H-pyrazol-4-yl)acetate (87.2 mg, 0.622 mmol), potassium phosphate (191.9 mg, 0.904 mmol) And a mixture of copper (I) iodide (11.9 mg, 0.062 mmol) was added with trans-(1R,2R)-N,N'-bismethyl-1,2-cyclohexanediamine (20.0 μl, 0.127 mmol) And DMF (0.6 mL). The resulting suspension was heated to 110 °C. After 24 hours, the reaction mixture was cooled to EtOAc then EtOAc (EtOAc) The two phase mixture was filtered and the solid was collected. The two phase filtrate was partitioned while the solid was washed with EtOAc (2×30 mL). The aqueous layer was extracted using each of these EtOAc washes. The organic layers were combined, washed with brine (1 × 30 mL), dried over Na 2 SO 4, filtered, and evaporated under reduced pressure to give a yellow residue. The residue was dissolved in EtOAc (50 mL)EtOAc. The biphasic mixture was partitioned and the aqueous layer was extracted with EtOAc EtOAc. The organic layers were combined, washed with brine (1 × 20 mL), dried MgSO 4, filtered, and evaporated under reduced pressure to give a yellow residue. The filtered solid was washed with MeOH (30 mL). By reverse phase HPLC (C-18), using 30 × 150 mm Sunfire TM column and 20% to 100% acetonitrile / water gradient + 0.05% TFA, followed by a rinse liquid purified eluting with 100% acetonitrile + 0.05% TFA The residue gives the desired compound as a yellow residue. LC-MS: C 34 H 37 ClN 6 O 7 Si calcd 704.22, observed m / e: 705.32 (M + H) + (Rt 1.20 / 2 min).

步驟B2-[1-[6-[4-[2-[[(3R,3aR,6R,6aR)-3-羥基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-6-基]氧基]-6-氯-1-(2-三甲基矽烷基乙氧基甲基)咪唑并[4,5-b]吡啶-5-基]苯基]-3-吡啶基]吡唑-4-基]乙酸甲酯 。將TMS-重氮甲烷(2 M之己烷溶液，0.15 mL，0.300 mmol)添加至2-[1-[6-[4-[2-[[(3R,3aR,6R,6aR)-3-羥基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-6-基]氧基]-6-氯-1-(2-三甲基矽烷基乙氧基甲基)-咪唑并[4,5-b]吡啶-5-基]苯基]-3-吡啶基]吡唑-4-基]乙酸(27.3 mg，0.039 mmol)於MeOH(0.5 mL)及DCM(0.5 mL)中之經攪拌溶液中。在室溫下攪拌反應混合物。3.5小時後，在減壓下蒸發反應混合物，得到呈黃色殘餘物形式之所要化合物。此物質未經進一步純化即用於下一步驟中。LC-MS：C35 H39 ClN6 O7 Si計算值718.23，觀測值m/e：719.31(M+H)+ (Rt 1.26/2 min)。Step B 2-[1-[6-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuran[3 ,2-b]furan-6-yl]oxy]-6-chloro-1-(2-trimethyldecylethoxyethoxymethyl)imidazo[4,5-b]pyridin-5-yl] Methyl phenyl]-3-pyridyl]pyrazol-4-yl]acetate . Add TMS-diazomethane (2 M in hexanes, 0.15 mL, 0.300 mmol) to 2-[1-[6-[4-[2-[[(3R,3aR,6R,6aR)-3- Hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1-(2-trimethyldecylalkyl) Oxymethyl)-imidazo[4,5-b]pyridin-5-yl]phenyl]-3-pyridyl]pyrazol-4-yl]acetic acid (27.3 mg, 0.039 mmol) in MeOH (0.5 mL And a stirred solution in DCM (0.5 mL). The reaction mixture was stirred at room temperature. After 3.5 hours, the reaction mixture was evaporated under reduced pressure to give the desired compound. This material was used in the next step without further purification. LC-MS: C 35 H 39 ClN calcd 718.23 6 O 7 Si, observed value m / e: 719.31 (M + H) + (Rt 1.26 / 2 min).

步驟C(3R,3aR,6R,6aR)-6-[6-氯-5-[4-[5-[4-(2-羥基-2-甲基-丙基)吡唑-1-基]-2-吡啶基]苯基]-1-(2-三甲基矽烷基乙 氧基甲基)咪唑并[4,5-b]吡啶-2-基]氧基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇 。將溴化甲基鎂(0.2 mL，0.600 mmol)添加至來自步驟B之2-[1-[6-[4-[2-[[(3R,3aR,6R,6aR)-3-羥基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-6-基]氧基]-6-氯-1-(2-三甲基矽烷基乙氧基甲基)咪唑并[4,5-b]吡啶-5-基]苯基]-3-吡啶基]吡唑-4-基]乙酸甲酯於THF(1 mL)中之經攪拌溶液中。在室溫下攪拌反應混合物。2.5小時後，將反應混合物分配於EtOAc(40 mL)與飽和NH4 Cl水溶液(40 mL)之間。用EtOAc(2×20 mL)萃取水層。合併有機層，用鹽水(1×20 mL)洗滌，經Na2 SO4 乾燥，過濾，且在減壓下蒸發，得到黃色殘餘物。藉由逆相HPLC(C-18)，使用30×150 mm SunfireTM 管柱且以20%至100%乙腈/水+0.05% TFA梯度，繼而以100%乙腈+0.05% TFA沖洗液溶離來純化殘餘物，得到呈黃色殘餘物形式之所要化合物。LC-MS：C36 H43 ClN6 O6 Si計算值718.27，觀測值m/e：719.52(M+H)+ (Rt 1.23/2 min)。Step C (3R,3aR,6R,6aR)-6-[6-chloro-5-[4-[5-[4-(2-hydroxy-2-methyl-propyl)pyrazol-1-yl] -2-pyridinyl] phenyl] -1- (2-methyl silicone alkyl ethoxy methyl) imidazo [4,5-b] pyridin-2-yl] oxy -2,3,3a, 5,6,6a-hexahydrofuro[3,2-b]furan-3-ol . Add methylmagnesium bromide (0.2 mL, 0.600 mmol) to 2-[1-[6-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2) from step B ,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1-(2-trimethyldecylalkylethoxy Methyl imidazo[4,5-b]pyridin-5-yl]phenyl]-3-pyridyl]pyrazol-4-yl]acetate in THF (1 mL). The reaction mixture was stirred at room temperature. After 2.5 hours, the reaction mixture was partitioned between EtOAc (40 mL) and saturated aqueous NH 4 Cl (40 mL) between. The aqueous layer was extracted with EtOAc (2×20 mL). The organic layers were combined, washed with brine (1 × 20 mL), dried over Na 2 SO 4, filtered, and evaporated under reduced pressure to give a yellow residue. By reverse phase HPLC (C-18), using 30 × 150 mm Sunfire TM column and 20% to 100% acetonitrile / water gradient + 0.05% TFA, followed by a rinse liquid purified eluting with 100% acetonitrile + 0.05% TFA The residue gives the desired compound as a yellow residue. LC-MS: C 36 H 43 ClN 6 O 6 Si calcd 718.27, observed m / e: 719.52 (M + H) + (Rt 1.23 / 2 min).

步驟D(3R,3aR,6R,6aR)-6-[[6-氯-5-[4-[5-[4-(2-羥基-2-甲基-丙基)吡唑-1-基]-2-吡啶基]苯基]-1H-咪唑并[4,5-b]吡啶-2-基]氧基]-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇 。在攪拌下，將(3R,3aR,6R,6aR)-6-[6-氯-5-[4-[5-[4-(2-羥基-2-甲基-丙基)吡唑-1-基]-2-吡啶基]苯基]-1-(2-三甲基矽烷基乙氧基-甲基)咪唑并[4,5-b]吡啶-2-基]氧基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇(10.1 mg，0.014 mmol)、甲酸(1.0 mL，26.1 mmol)及飽和KHSO4 水溶液 (0.05 mL)之混合物加熱至40℃。16小時後，冷卻反應混合物至室溫，隨後在冰浴中冷卻至0℃。藉由添加5 N NaOH(5.8 mL，29.0 mmol)將反應混合物之pH值調整至pH 14。將THF(2 mL)添加至反應混合物中，且自冰浴中移出反應物並使其升溫至室溫。30分鐘後，藉由添加2 N HCl將反應混合物之pH值調整至pH 7。將反應混合物分配於EtOAc(30 mL)與水(20 mL)之間。用EtOAc(2×20 mL)萃取水層。合併有機層，用鹽水(1×20 mL)洗滌，經MgSO4 乾燥，過濾，且在減壓下蒸發，得到白色殘餘物。將此物質溶解於DMSO/MeOH中，且藉由逆相HPLC(C-18)，使用30×150 mm SunfireTM 管柱且以20%至100%乙腈/水+0.05% TFA梯度，繼而以100%乙腈+0.05% TFA沖洗液溶離來純化。合併所要溶離份，在減壓下蒸發，且自乙醇及苯中凍乾，得到呈淺黃色固體狀之標題化合物。LC-MS：C30 H29 ClN6 O5 計算值588.19，觀測值m/e：589.28(M+H)+ (Rt 1.10/2 min)；1 H NMR δ(ppm)(CD3 OD)：9.15(d,J=2.5 Hz,1H),8.46(dd,J=2.7 Hz,8.9 Hz,1H),8.26(s,1H),8.19(d,J=8.7 Hz,1H),8.14(d,J=8.4 Hz,2H),7.97(s,1H),7.86(d,J=8.4 Hz,1H),7.73(s,1H),5.58(qt,J=5.2 Hz,1H),4.98(t,J=5.2 Hz,1H),4.47(t,J=5.0 Hz,1H),4.27-4.31(m,1H),4.17(dd,J=5.4 Hz,10.2 Hz,1H),4.14(dd,J=4.7 Hz,10.2 Hz,1H),3.91(m,1H),3.60(t,J=8.6 Hz,1H),2.73(s,2H),1.25(s,6H)。Step D (3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[5-[4-(2-hydroxy-2-methyl-propyl)pyrazol-1-yl ]-2-pyridyl]phenyl]-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuran [3] , 2-b]furan-3-ol . (3R,3aR,6R,6aR)-6-[6-chloro-5-[4-[5-[4-(2-hydroxy-2-methyl-propyl)pyrazole-1 with stirring -yl]-2-pyridyl]phenyl]-1-(2-trimethyldecyloxyethoxy-methyl)imidazo[4,5-b]pyridin-2-yl]oxy-2, 3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (10.1 mg, 0.014 mmol), formic acid (1.0 mL, 26.1 mmol) and saturated aqueous KHSO 4 (0.05 mL) The mixture was heated to 40 °C. After 16 hours, the reaction mixture was cooled to room temperature and then cooled to 0 ° C in an ice bath. The pH of the reaction mixture was adjusted to pH 14 by the addition of 5 N NaOH (5.8 mL, 29.0 mmol). THF (2 mL) was added to the reaction mixture and the mixture was taken from iced water and warmed to room temperature. After 30 minutes, the pH of the reaction mixture was adjusted to pH 7 by the addition of 2 N HCl. The reaction mixture was partitioned between EtOAc (30 mL)EtOAc. The aqueous layer was extracted with EtOAc (2×20 mL). The organic layers were combined, washed with brine (1 × 20 mL), dried MgSO 4, filtered, and evaporated under reduced pressure to give a white residue. This material was dissolved in DMSO / MeOH, and the by reverse phase HPLC (C-18), using 30 × 150 mm Sunfire TM column and 20% to 100% acetonitrile / water gradient + 0.05% TFA, then with 100 The % acetonitrile + 0.05% TFA rinse was dissolved to purify. The title compound was obtained as a pale yellow solid. LC-MS: C 30 H 29 ClN 6 O 5 calcd 588.19, observed m / e: 589.28 (M + H) + (Rt 1.10 / 2 min); 1 H NMR δ (ppm) (CD 3 OD): 9.15 (d, J = 2.5 Hz, 1H), 8.46 (dd, J = 2.7 Hz, 8.9 Hz, 1H), 8.26 (s, 1H), 8.19 (d, J = 8.7 Hz, 1H), 8.14 (d, J = 8.4 Hz, 2H), 7.97 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.73 (s, 1H), 5.58 (qt, J = 5.2 Hz, 1H), 4.98 (t, J = 5.2 Hz, 1H), 4.47 (t, J = 5.0 Hz, 1H), 4.27 - 4.31 (m, 1H), 4.17 (dd, J = 5.4 Hz, 10.2 Hz, 1H), 4.14 (dd, J = 4.7 Hz, 10.2 Hz, 1H), 3.91 (m, 1H), 3.60 (t, J = 8.6 Hz, 1H), 2.73 (s, 2H), 1.25 (s, 6H).

實例203Example 203

(3R,3aR,6R,6aR)-6-[[6-氯-5-[4-[6-(1,2,4-三唑-1-基)-3-吡啶基]苯基]-1H-咪唑并[4,5-b]吡啶-2-基]氧基]-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[6-(1,2,4-triazol-1-yl)-3-pyridyl]phenyl]- 1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol

步驟A(3R,3aR,6R,6aR)-6-[6-氯-5-[4-[6-(1,2,4-三唑-1-基)-3-吡啶基]苯基]-1-(2-三甲基矽烷基乙氧基甲基)咪唑并[4,5-b]吡啶-2-基]氧基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇 。在氮氣下，向中間物10(89.7 mg，0.136 mmol)、1,2,4-三唑(11.5 mg，0.167 mmol)、碘化銅(I)(5.4 mg，0.028 mmol)及磷酸鉀(71.8 mg，0.338 mmol)之混合物中添加反-(1R,2R)-N,N'-雙甲基-1,2-環己二胺(10 μl，0.063 mmol)及DMF(0.27 mL)。在攪拌下，加熱所得懸浮液至110℃。25小時後，冷卻反應混合物至室溫，接著經CeliteTM 襯墊過濾，且用EtOAc(75 mL)清洗。用水(3×20 mL)及鹽水(1×20 mL)洗滌濾液，經Na2 SO4 乾燥，過濾，且在減壓下蒸發，得到淺黃色殘餘物。藉由製備型薄層層析，使用500微米20 cm×20 cm矽膠板(使用85% EtOAc/己烷展開)純化殘餘物，得到無色殘餘物。藉由逆相HPLC(C-18)，使用30×150 mm SunfireTM 管柱且以20%至100%乙腈/水+0.05% TFA梯度，繼而以100%乙腈+0.05% TFA沖洗液溶離來進一步純化殘餘物，得到呈無色殘餘物形式之所要化合物。 LC-MS：C31 H34 ClN7 O5 Si計算值647.21，觀測值m/e：648.45(M+H)+ (Rt 1.27/2 min)。Step A (3R, 3aR, 6R, 6aR)-6-[6-chloro-5-[4-[6-(1,2,4-triazol-1-yl)-3-pyridyl]phenyl] 1-(2-trimethyldecylethoxyethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuran And [3,2-b]furan-3-ol . Intermediate 10 (89.7 mg, 0.136 mmol), 1,2,4-triazole (11.5 mg, 0.167 mmol), copper (I) iodide (5.4 mg, 0.028 mmol) and potassium phosphate (71.8) under nitrogen. To a mixture of mg, 0.338 mmol) was added trans-(1R,2R)-N,N'-bismethyl-1,2-cyclohexanediamine (10 μl, 0.063 mmol) and DMF (0.27 mL). The resulting suspension was heated to 110 ° C with stirring. After 25 hours, the reaction mixture was cooled to room temperature and then filtered through a Celite TM pad, and washed with EtOAc (75 mL). Washed with water (3 × 20 mL) and brine (1 × 20 mL) The filtrate was washed, dried over Na 2 SO 4, filtered, and evaporated under reduced pressure to give a pale yellow residue. The residue was purified by preparative EtOAc (EtOAc) eluting By reverse phase HPLC (C-18), using 30 × 150 mm Sunfire TM column and 20% to 100% acetonitrile / water gradient + 0.05% TFA, then with 100% acetonitrile + 0.05% TFA further rinsing liquid fractions The residue is purified to give the desired compound as a colourless residue. LC-MS: C 31 H 34 ClN 7 O 5 Si Calcd 647.21, observed m / e: 648.45 (M + H) + (Rt 1.27 / 2 min).

步驟B(3R,3aR,6R,6aR)-6-[[6-氯-5-[4-[6-(1,2,4-三唑-1-基)-3-吡啶基]苯基]-1H-咪唑并[4,5-b]吡啶-2-基]氧基]-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇 。Step B (3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[6-(1,2,4-triazol-1-yl)-3-pyridyl]phenyl -1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3- Alcohol .

將(3R,3aR,6R,6aR)-6-[6-氯-5-[4-[6-(1,2,4-三唑-1-基)-3-吡啶基]苯基]-1-(2-三甲基矽烷基乙氧基甲基)咪唑并[4,5-b]吡啶-2-基]氧基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇(29.2 mg，0.045 mmol)、甲酸(1.0 mL，26.1 mmol)及飽和KHSO4 水溶液(0.05 mL)之混合物加熱至40℃。15小時後，冷卻反應混合物至室溫，隨後在冰浴中冷卻至0℃。藉由添加5 N NaOH(5.8 mL，29.0 mmol)將反應混合物之pH值調整至pH 14。將THF(2 mL)添加至反應混合物中，且自冰浴中移出反應物並使其升溫至室溫。30分鐘後，藉由添加2 N HCl將反應混合物之pH值調整至pH 6。將反應混合物分配於EtOAc(40 mL)與水(30 mL)之間。用EtOAc(2×20 mL)萃取水層。合併有機層，用鹽水(1×20 mL)洗滌，經Na2 SO4 乾燥，過濾，且在減壓下蒸發，得到白色殘餘物。藉由逆相HPLC(C-18)，使用30×150 mm SunfireTM 管柱且以20%至80%乙腈/水+0.05% TFA梯度，繼而以80%乙腈/水+0.05% TFA沖洗液溶離來純化殘餘物，隨後自乙醇及苯中凍乾，得到呈灰白色固體狀之標題化合物。LC-MS：C25 H20 ClN7 O4 計算值517.13，觀測值m/e：518.30(M+H)+ (Rt 1.10/2 min)；1 H NMR δ(ppm)(CD3 OD)：9.42 (s,1H),8.89(d,J=2.2 Hz,1H),8.39(dd,J=2.4 Hz,8.6 Hz,1H),8.25(s,1H),8.07(d,J=8.5 Hz,1H),7.97(s,1H),7.86(m,4H),5.59(qt,J=5.2 Hz,1H),4.99(t,J=5.2 Hz,1H),4.48(t,J=5.0 Hz,1H),4.28-4.32(m,1H),4.14-4.20(m,2H),3.92(dd,J=6.8 Hz,8.2 Hz,1H),3.61(t,J=8.7 Hz,1H)。(3R,3aR,6R,6aR)-6-[6-chloro-5-[4-[6-(1,2,4-triazol-1-yl)-3-pyridyl]phenyl]- 1-(2-trimethyldecylethoxyethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuran [3,2-b] furan-3-ol (29.2 mg, 0.045 mmol), a mixture of formic acid (1.0 mL, 26.1 mmol) and saturated KHSO 4 aqueous solution (0.05 mL) of was heated to 40 ℃. After 15 hours, the reaction mixture was cooled to room temperature and then cooled to 0 ° C in an ice bath. The pH of the reaction mixture was adjusted to pH 14 by the addition of 5 N NaOH (5.8 mL, 29.0 mmol). THF (2 mL) was added to the reaction mixture and the mixture was taken from iced water and warmed to room temperature. After 30 minutes, the pH of the reaction mixture was adjusted to pH 6 by the addition of 2 N HCl. The reaction mixture was partitioned between EtOAc (40 mL The aqueous layer was extracted with EtOAc (2×20 mL). The organic layers were combined, washed with brine (1 × 20 mL), dried over Na 2 SO 4, filtered, and evaporated under reduced pressure to give a white residue. By reverse phase HPLC (C-18), using 30 × 150 mm Sunfire TM column and with 20-80% acetonitrile / water gradient + 0.05% TFA, then with 80% acetonitrile / water + 0.05% TFA rinse liquid fractions The residue was purified by EtOAc (EtOAc): LC-MS: C 25 H 20 ClN 7 O 4 calcd 517.13, observed m / e: 518.30 (M + H) + (Rt 1.10 / 2 min); 1 H NMR δ (ppm) (CD 3 OD): 9.42 (s, 1H), 8.89 (d, J = 2.2 Hz, 1H), 8.39 (dd, J = 2.4 Hz, 8.6 Hz, 1H), 8.25 (s, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.97 (s, 1H), 7.86 (m, 4H), 5.59 (qt, J = 5.2 Hz, 1H), 4.99 (t, J = 5.2 Hz, 1H), 4.48 (t, J = 5.0 Hz, 1H), 4.28-4.32 (m, 1H), 4.14-4.20 (m, 2H), 3.92 (dd, J = 6.8 Hz, 8.2 Hz, 1H), 3.61 (t, J = 8.7 Hz, 1H).

實例206Example 206

(3R,3aR,6R,6aR)-6-[[6-氯-5-[4-[6-[4-(2-羥基-2-甲基-丙(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[6-[4-(2-hydroxy-2-methyl-propyl) 基)吡唑-1-基]-3-吡啶基]苯基]-1H-咪唑并[4,5-b]吡啶-2-基]氧基]-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇Pyrazol-1-yl]-3-pyridyl]phenyl]-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6, 6a-hexahydrofuro[3,2-b]furan-3-ol

步驟A2-[1-[5-[4-[2-[[(3R,3aR,6R,6aR)-3-羥基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-6-基]氧基]-6-氯-1-(2-三甲基矽烷基乙氧基甲基)咪唑并[4,5-b]吡啶-5-基]苯基]-2-吡啶基]吡唑-4-基]乙酸 。在氮氣下，向2-(1H-吡唑-4-基)乙酸甲酯(36.9 mg，0.263 mmol)、中間物10(147.3 mg，0.223 mmol)、磷酸鉀(152.9 mg，0.720 mmol)及碘化銅(I)(8.8 mg，0.046 mmol)之混合物中添加反-(1R,2R)-N,N'-雙甲基-1,2-環己二胺(15 μl，0.095 mmol)及DMF(0.45 mL)。在攪拌下，加熱所得懸浮液至110℃。24小時後，冷卻反應混合物至室溫，隨後分配於EtOAc(100 mL)與2 N HCl(30 mL)之間。經CeliteTM 襯墊過濾兩相混合物。將來自CeliteTM 襯墊頂部之固體溶解於DMA中，且與兩相濾液合併。藉由過濾水層收集所得固體。用水(3×30 mL)及鹽水(1×30 mL)洗滌有機層。經Na2 SO4 乾燥有機層，過濾，且在減壓下蒸發，得到淺黃色殘餘物。將藉由過濾水層收集之固體及來自有機層之殘餘物溶解於DMSO及MeOH中，且藉由製備型逆相HPLC(C-18)，使用30×150 mm SunfireTM 管柱且以20%至100%乙腈/水+0.05% TFA梯度，繼而以100%乙腈+0.05% TFA沖洗液溶離來純化。合併所要溶離份且在減壓下蒸發，得到呈黃色殘餘物形式之標題化合物。LC-MS：C34 H37 ClN6 O7 Si計算值704.22，觀測值m/e：705.13(M+H)+ (Rt 1.24/2 min)。Step A 2-[1-[5-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuran[3 ,2-b]furan-6-yl]oxy]-6-chloro-1-(2-trimethyldecylethoxyethoxymethyl)imidazo[4,5-b]pyridin-5-yl] Phenyl]-2-pyridyl]pyrazol-4-yl]acetic acid . Methyl 2-(1H-pyrazol-4-yl)acetate (36.9 mg, 0.263 mmol), intermediate 10 (147.3 mg, 0.223 mmol), potassium phosphate (152.9 mg, 0.720 mmol) and iodine under nitrogen Add anti-(1R,2R)-N,N'-bismethyl-1,2-cyclohexanediamine (15 μl, 0.095 mmol) and DMF to a mixture of copper (I) (8.8 mg, 0.046 mmol) (0.45 mL). The resulting suspension was heated to 110 ° C with stirring. After 24 hours, the reaction mixture was cooled to EtOAc EtOAc (EtOAc) The two phase mixture was filtered through a pad of Celite (TM) . The solid from the top of the Celite (TM) liner was dissolved in DMA and combined with the two phase filtrate. The resulting solid was collected by filtration of a water layer. The organic layer was washed with water (3×30 mL) and brine (1×30 mL). The organic layer was dried over Na 2 SO 4, filtered, and evaporated under reduced pressure to give a pale yellow residue. The solid was collected by filtration, and the aqueous layer from the organic layer, the residue was dissolved in DMSO and MeOH and purified by prep reverse phase HPLC (C-18), using 30 × 150 mm Sunfire TM column and 20% Purification by 100% acetonitrile/water + 0.05% TFA gradient followed by dissolution with 100% acetonitrile + 0.05% TFA rinse. The title compound was obtained as a yellow residue. LC-MS: C 34 H 37 ClN 6 O 7 Si calcd 704.22, observed m / e: 705.13 (M + H) + (Rt 1.24 / 2 min).

步驟B2-[1-[5-[4-[2-[[(3R,3aR,6R,6aR)-3-羥基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-6-基]氧基]-6-氯-1-(2-三甲基矽烷基乙氧基甲基)咪唑并[4,5-b]吡啶-5-基]苯基]-2-吡啶基]吡唑-4-基]乙酸甲酯 。將TMS-重氮甲烷(2 M之己烷溶液，0.06 mL，0.120 mmol)添加至2-[1-[5-[4-[2-[[(3R,3aR,6R,6aR)-3-羥基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-6-基]氧基]-6-氯-1-(2-三甲基矽烷基乙氧基甲基)-咪唑并[4,5-b]吡啶-5-基]苯基]-2-吡啶基]吡唑-4-基]乙酸(60.4 mg，0.086 mmol)於MeOH(1 mL)中之經攪拌懸浮液中。將DCM(0.6 mL)添加至反應混合物中，得到黃色溶液。再將TMS-重氮甲烷(2 M之己烷溶液，0.04 mL，0.080 mmol)添加至反應混合物中。1小時後，在減壓下蒸發反應混合物，得到黃色殘餘物。藉由製備型薄層層析，使用兩個500微米20 cm×20 cm矽膠板(使用75% EtOAc/己烷展開)純化殘餘物，得到呈無色殘餘物形式之標題化合物。LC-MS：C35 H39 ClN6 O7 Si計算值718.23，觀測值m/e：719.03(M+H)+ (Rt 1.29/2 min)。Step B 2-[1-[5-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuran[3 ,2-b]furan-6-yl]oxy]-6-chloro-1-(2-trimethyldecylethoxyethoxymethyl)imidazo[4,5-b]pyridin-5-yl] Methyl phenyl]-2-pyridyl]pyrazol-4-yl]acetate . Add TMS-diazomethane (2 M in hexanes, 0.06 mL, 0.120 mmol) to 2-[1-[5-[4-[2-[[(3R,3aR,6R,6aR)-3- Hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1-(2-trimethyldecylalkyl) Oxymethyl)-imidazo[4,5-b]pyridin-5-yl]phenyl]-2-pyridyl]pyrazol-4-yl]acetic acid (60.4 mg, 0.086 mmol) in MeOH (1 mL In the stirred suspension. DCM (0.6 mL) was added to the reaction mixture to give a yellow solution. TMS-diazomethane (2 M in hexanes, 0.04 mL, 0.080 mmol) was then added to the mixture. After 1 hour, the reaction mixture was evaporated under reduced pressure to give a yellow residue. The residue was purified by preparative EtOAc EtOAc (EtOAc) LC-MS: C 35 H 39 ClN calcd 718.23 6 O 7 Si, observed value m / e: 719.03 (M + H) + (Rt 1.29 / 2 min).

步驟C2-[1-[5-[4-[2-[[(3R,3aR,6R,6aR)-3-羥基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-6-基]氧基]-6-氯-1H-咪唑并[4,5-b]吡啶-5-基]苯基]-2-吡啶基]吡唑-4-基]乙酸 。在攪拌下，將2-[1-[5-[4-[2-[[(3R,3aR,6R,6aR)-3-羥基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-6-基]氧基]-6-氯-1-(2-三甲基矽烷基-乙氧基甲基)咪唑并[4,5-b]吡啶-5-基]苯基]-2-吡啶基]吡唑-4-基]乙酸甲酯(28.5 mg，0.040 mmol)、甲酸(1.0 mL，26.1 mmol)及飽和KHSO4 水溶液(0.05 mL)之混合物加熱至 40℃。16小時後，冷卻反應混合物至室溫，隨後分配於EtOAc(40 mL)與飽和NaHCO3 水溶液(40 mL)之間。在分配期間形成白色沈澱物。用EtOAc(2×20 mL)萃取水層。合併有機層且用鹽水(1×20 mL)洗滌。將2 N HCl(20 mL)添加至鹽水層中，從而溶解白色沈澱物。用經合併之有機層再分配鹽水/2 N HCl層。合併水層，且藉由添加2 N HCl將pH值調整至約pH 3。用EtOAc(3×20 mL)萃取經合併之水層。用鹽水(1×20 mL)洗滌經合併之EtOAc萃取物，隨後與初始有機層合併。經Na2 SO4 乾燥經合併之有機層，過濾，且在減壓下蒸發，得到呈淺黃色殘餘物形式之2-[1-[5-[4-[2-[[(3R,3aR,6R,6aR)-3-羥基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-6-基]氧基]-6-氯-1H-咪唑并[4,5-b]吡啶-5-基]苯基]-2-吡啶基]吡唑-4-基]乙酸與2-[1-[5-[4-[2-[[(3R,3aR,6R,6aR)-3-羥基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-6-基]氧基]-6-氯-1H-咪唑并[4,5-b]吡啶-5-基]苯基]-2-吡啶基]吡唑-4-基]乙酸甲酯之混合物。此殘餘物未經進一步純化即用於下一步驟中。LC-MS：C28 H23 ClN6 O6 計算值574.14，觀測值m/e：574.90(M+H)+ (Rt 1.11/2 min)。Step C 2-[1-[5-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuran[3 ,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]-2-pyridyl]pyrazole-4- Base] acetic acid . 2-[1-[5-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuran under stirring) And [3,2-b]furan-6-yl]oxy]-6-chloro-1-(2-trimethyldecyl-ethoxymethyl)imidazo[4,5-b]pyridine- Mixture of methyl 5-phenyl]phenyl]-2-pyridyl]pyrazol-4-yl]acetate (28.5 mg, 0.040 mmol), formic acid (1.0 mL, 26.1 mmol) and saturated aqueous KHSO 4 (0.05 mL) Heat to 40 °C. After 16 hours, the reaction mixture was cooled to room temperature, then partitioned between EtOAc and saturated aqueous NaHCO 3 (40 mL) (40 mL) . A white precipitate formed during the dispensing. The aqueous layer was extracted with EtOAc (2×20 mL). The organic layers were combined and washed with brine (1×20 mL). 2 N HCl (20 mL) was added to the brine layer to dissolve a white precipitate. The brine/2 N HCl layer was redistributed with the combined organic layers. The aqueous layers were combined and the pH was adjusted to approximately pH 3 by the addition of 2N HCl. The combined aqueous layers were extracted with EtOAc (3×20 mL). The combined EtOAc extracts were washed with brine (1×20 mL) and then combined with EtOAc. Dried over Na 2 SO 4 the combined organic layers were, filtered, and evaporated under reduced pressure to give a pale yellow residue forms of 2- [1- [5- [4- [ 2 - [[(3R, 3aR, 6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazole [4,5-b]pyridin-5-yl]phenyl]-2-pyridyl]pyrazol-4-yl]acetic acid and 2-[1-[5-[4-[2-[[(3R, 3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H- A mixture of imidazo[4,5-b]pyridin-5-yl]phenyl]-2-pyridyl]pyrazol-4-yl]acetic acid methyl ester. This residue was used in the next step without further purification. LC-MS: C 28 H 23 ClN 6 O 6 Calc 574.14, observed m / e: 574.90 (M + H) + (Rt 1.11 / 2 min).

步驟D2-[1-[5-[4-[2-[[(3R,3aR,6R,6aR)-3-羥基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-6-基]氧基]-6-氯-1H-咪唑并[4,5-b]吡啶-5-基]苯基]-2-吡啶基]吡唑-4-基]乙酸甲酯 。將TMS-重氮甲烷(2 M之己烷溶液，25 μl，0.050 mmol)添加至來自步驟C之2-[1-[5-[4-[2-[[(3R,3aR,6R,6aR)-3-羥基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-6-基]氧基]-6-氯-1H- 咪唑并[4,5-b]吡啶-5-基]苯基]-2-吡啶基]吡唑-4-基]乙酸與2-[1-[5-[4-[2-[[(3R,3aR,6R,6aR)-3-羥基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-6-基]氧基]-6-氯-1H-咪唑并[4,5-b]吡啶-5-基]苯基]-2-吡啶基]吡唑-4-基]乙酸甲酯之混合物(23.1 mg)於MeOH(0.7 mL)及DCM(0.7 mL)中之經攪拌混濁溶液中。再將MeOH(0.5 mL)、DCM(0.7 mL)及TMS-重氮甲烷(20 μl，0.040 mmol)添加至反應混合物中，且在室溫下攪拌反應混合物。50分鐘後，再將TMS-重氮甲烷(20 μl，0.040 mmol)添加至反應混合物中。35分鐘後，在減壓下蒸發反應混合物，得到呈白色固體狀之標題化合物，其未經進一步純化即用於下一步驟中。LC-MS：C29 H25 ClN6 O6 計算值588.15，觀測值m/e：588.95(M+H)+ (Rt 1.15/2 min)。Step D 2-[1-[5-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuran[3 ,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]-2-pyridyl]pyrazole-4- Methyl acetate . Add TMS-diazomethane (2 M in hexanes, 25 μl, 0.050 mmol) to 2-[1-[5-[4-[2-[[(3R,3aR,6R,6aR) from step C )-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4, 5-[5-[5-[4-[2-[[(3R,3aR,6R) , 6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[ a mixture of methyl 4,5-b]pyridin-5-yl]phenyl]-2-pyridyl]pyrazol-4-yl]acetate (23.1 mg) in MeOH (0.7 mL) and DCM (EtOAc) It is stirred in a turbid solution. MeOH (0.5 mL), DCM (0.7 mL) and TMS-diazomethane (20 μl, 0.040 mmol) were then added to the reaction mixture and the mixture was stirred at room temperature. After 50 minutes, TMS-diazomethane (20 μl, 0.040 mmol) was added to the reaction mixture. After 35 minutes, the title compound was crystalljjjjjjjjjjj LC-MS: C 29 H 25 ClN 6 O 6 Calc 588.15, observed m / e: 588.95 (M + H) + (Rt 1.15 / 2 min).

步驟E(3R,3aR,6R,6aR)-6-[[6-氯-5-[4-[6-[4-(2-羥基-2-甲基-丙基)吡唑-1-基]-3-吡啶基]苯基]-1H-咪唑并[4,5-b]吡啶-2-基]氧基]-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇 。將溴化甲基鎂(0.13 mL，0.390 mmol)逐滴添加至來自步驟D之2-[1-[5-[4-[2-[[(3R,3aR,6R,6aR)-3-羥基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-6-基]氧基]-6-氯-1H-咪唑并[4,5-b]吡啶-5-基]苯基]-2-吡啶基]吡唑-4-基]乙酸甲酯於THF(1 mL)中之經攪拌溶液中。在室溫下攪拌反應混合物。1小時後，再將溴化甲基鎂(0.05 mL，0.15 mmol)添加至反應混合物中。1小時後，將反應混合物分配於EtOAc(40 mL)與飽和NH4 Cl水溶液(40 mL)之間。用EtOAc(2×20 mL)萃取水 層。合併有機層，用鹽水(1×20 mL)洗滌，經Na2 SO4 乾燥，過濾，且在減壓下蒸發，得到淺黃色殘餘物。藉由逆相HPLC(C-18)，使用30×150 mm SunfireTM 管柱且以20%至100%乙腈/水+0.05% TFA梯度，繼而以100%乙腈+0.05% TFA沖洗液溶離來純化，隨後自乙醇及苯中凍乾，得到呈白色固體狀之標題化合物。LC-MS：C30 H29 ClN6 O5 計算值588.19，觀測值m/e：588.95(M+H)+ (Rt 1.13/2 min)；1 H NMR δ(ppm)(CD3 OD)：8.78(寬單峰，1H),8.50(寬單峰，1H),8.28(dd,J=2.0 Hz,8.6 Hz,1H),8.02(寬雙峰，J=8.6 Hz,1H),7.93(s,1H),7.81-7.85(m,4H),7.69(寬單峰，1H),5.58(qt,J=5.3 Hz,1H),4.99(t,J=5.2 Hz,1H),4.48(t,J=5.0 Hz,1H),4.28-4.32(m,1H),4.18(dd,J=5.6 Hz,10.3 Hz,1H),4.14(dd,J=4.7 Hz,10.2 Hz,1H),3.92(dd,J=6.9 Hz,8.3 Hz,1H),3.61(t,J=8.6 Hz,1H),2.73(s,2H),1.25(s,6H)。Step E (3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[6-[4-(2-hydroxy-2-methyl-propyl)pyrazol-1-yl) ]-3-pyridyl]phenyl]-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuran [3] , 2-b]furan-3-ol . Methylmagnesium bromide (0.13 mL, 0.390 mmol) was added dropwise to 2-[1-[5-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy) from step D -2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridine Methyl 5-amino]phenyl]-2-pyridyl]pyrazol-4-yl]acetate in THF (1 mL). The reaction mixture was stirred at room temperature. After 1 hour, methylmagnesium bromide (0.05 mL, 0.15 mmol) was added to the reaction mixture. After 1 hour, the reaction mixture was partitioned between EtOAc (40 mL) and saturated aqueous NH 4 Cl (40 mL) between. The aqueous layer was extracted with EtOAc (2×20 mL). The organic layers were combined, washed with brine (1 × 20 mL), dried over Na 2 SO 4, filtered, and evaporated under reduced pressure to give a pale yellow residue. By reverse phase HPLC (C-18), using 30 × 150 mm Sunfire TM column and 20% to 100% acetonitrile / water gradient + 0.05% TFA, followed by a rinse liquid purified eluting with 100% acetonitrile + 0.05% TFA It is then lyophilized from ethanol and benzene to give the title compound as a white solid. LC-MS: C 30 H 29 ClN 6 O 5 calcd 588.19, observed m / e: 588.95 (M + H) + (Rt 1.13 / 2 min); 1 H NMR δ (ppm) (CD 3 OD): 8.78 (width unimodal, 1H), 8.50 (width unimodal, 1H), 8.28 (dd, J = 2.0 Hz, 8.6 Hz, 1H), 8.02 (width doublet, J = 8.6 Hz, 1H), 7.93 (s , 1H), 7.81-7.85 (m, 4H), 7.69 (wide unimodal, 1H), 5.58 (qt, J = 5.3 Hz, 1H), 4.99 (t, J = 5.2 Hz, 1H), 4.48 (t, J=5.0 Hz, 1H), 4.28-4.32 (m, 1H), 4.18 (dd, J=5.6 Hz, 10.3 Hz, 1H), 4.14 (dd, J=4.7 Hz, 10.2 Hz, 1H), 3.92 (dd , J = 6.9 Hz, 8.3 Hz, 1H), 3.61 (t, J = 8.6 Hz, 1H), 2.73 (s, 2H), 1.25 (s, 6H).

實例207Example 207

(3R,3aR,6R,6aR)-6-[[6-氯-5-[4-[4-(1H-四唑-5-基)苯基]苯基]-1H-咪唑并[4,5-b]吡啶-2-基]氧基]-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[4-(1H-tetrazol-5-yl)phenyl]phenyl]-1H-imidazo[4, 5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol

在攪拌下，將中間物11(27.9 mg，0.059 mmol)、疊氮基 三甲基錫(153.5 mg，0.746 mmol)及甲苯(1 mL)之混合物加熱至110℃。16小時後，冷卻反應混合物至室溫。藉由製備型薄層層析，使用兩個1000微米20 cm×20 cm矽膠板(使用90：9：1 DCM/MeOH/乙酸展開)純化反應混合物，得到白色固體。藉由製備型薄層層析，使用500微米20 cm×20 cm矽膠板(使用90：9：1 DCM/MeOH/乙酸展開兩次)再次純化產物，得到白色固體。藉由逆相HPLC(C-18)，使用30×150 mm SunfireTM 管柱且以20%至100%乙腈/水+0.05% TFA梯度，繼而以100%乙腈+0.05% TFA沖洗液溶離來進一步純化此物質。合併所要溶離份，在減壓下蒸發，且自乙醇及苯中凍乾，得到呈白色固體狀之標題化合物。LC-MS：C25 H20 ClN7 O4 計算值517.13，觀測值m/e：518.20(M+H)+ (Rt 1.08/2 min)；1 H NMR δ(ppm)(CD3 OD)：8.14(d,J=8.3 Hz,2H),7.95(d,J=8.3 Hz,2H),7.87(s,1H),7.79-7.84(m,4H),5.56(qt,J=5.3 Hz,1H),4.97(t,J=5.2 Hz,1H),4.47(t,J=5.0 Hz,1H),4.26-4.30(m,1H),4.17(dd,J=5.7 Hz,10.1 Hz,1H),4.12(dd,J=4.8 Hz,10.3 Hz,1H),3.90(dd,J=7.0 Hz,8.3 Hz,1H),3.60(t,J=8.6 Hz,1H)。A mixture of Intermediate 11 (27.9 mg, 0.059 mmol), azide trimethyltin (153.5 mg, 0.746 mmol) and toluene (1 mL) was heated to 110 °C with stirring. After 16 hours, the reaction mixture was cooled to room temperature. The reaction mixture was purified by preparative thin layer chromatography using two 1000 micron 20 cm x 20 cm silica gel plates (developed with 90:9:1 DCM / MeOH / acetic acid) to afford a white solid. The product was re-purified by preparative thin layer chromatography using a 500 micron 20 cm x 20 cm silica gel (twisted with 90:9:1 DCM / MeOH / acetic acid) to afford a white solid. By reverse phase HPLC (C-18), using 30 × 150 mm Sunfire TM column and 20% to 100% acetonitrile / water gradient + 0.05% TFA, then with 100% acetonitrile + 0.05% TFA further rinsing liquid fractions This material was purified. The title compound was obtained as a white solid. LC-MS: C 25 H 20 ClN 7 O 4 calcd 517.13, observed m / e: 518.20 (M + H) + (Rt 1.08 / 2 min); 1 H NMR δ (ppm) (CD 3 OD): 8.14 (d, J = 8.3 Hz, 2H), 7.95 (d, J = 8.3 Hz, 2H), 7.87 (s, 1H), 7.79-7.84 (m, 4H), 5.56 (qt, J = 5.3 Hz, 1H) ), 4.97 (t, J = 5.2 Hz, 1H), 4.47 (t, J = 5.0 Hz, 1H), 4.26 - 4.30 (m, 1H), 4.17 (dd, J = 5.7 Hz, 10.1 Hz, 1H), 4.12 (dd, J = 4.8 Hz, 10.3 Hz, 1H), 3.90 (dd, J = 7.0 Hz, 8.3 Hz, 1H), 3.60 (t, J = 8.6 Hz, 1H).

實例208Example 208

(3R,3aR,6R,6aR)-6-[[6-氯-5-[4-[4-(2,5-二氫-1H-咪唑-2-(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[4-(2,5-dihydro-1H-imidazol-2-) 基)苯基]苯基]-1H-咪唑并[4,5-b]吡啶-2-基]氧基]-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-醇Phenyl]phenyl]-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuran[3,2 -b]furan-3-ol

在攪拌下，將中間物11(28.4 mg，0.060 mmol)、乙二胺(0.5 mL，7.46 mmol)及二硫化碳(6 μl，0.100 mmol)之混合物加熱至50℃。18小時後，冷卻反應混合物至室溫，隨後在減壓下蒸發，得到黃色固體。藉由逆相HPLC(C-18)，使用30×150 mm SunfireTM 管柱且以20%至100%乙腈/水+0.05% TFA梯度，繼而以100%乙腈+0.05% TFA沖洗液溶離來純化固體，隨後自乙醇及苯中凍乾，得到呈白色固體狀之標題化合物。LC-MS：C27 H24 ClN5 O4 計算值517.15，觀測值m/e：518.14(M+H)+ (Rt 0.98/2 min)；1 H NMR δ(ppm)(CD3 OD)：7.96-8.01(m,4H),7.81-7.85(m,5H),5.55(qt,J=5.4 Hz,1H),4.97(t,J=5.2 Hz,1H),4.47(t,J=5.0 Hz,1H),4.26-4.30(m,1H),4.09-4.19(m,6H),3.90(t,J=7.0 Hz,1H),3.60(t,J=8.6 Hz,1H)。A mixture of Intermediate 11 (28.4 mg, 0.060 mmol), ethylenediamine (0.5 mL, 7.46 mmol) and carbon disulfide (6 μl, 0.100 mmol) was heated to 50 °C with stirring. After 18 hours, the reaction mixture was cooled to room temperature then evaporated then evaporated By reverse phase HPLC (C-18), using 30 × 150 mm Sunfire TM column and 20% to 100% acetonitrile / water gradient + 0.05% TFA, followed by a rinse liquid purified eluting with 100% acetonitrile + 0.05% TFA The title compound was obtained as a white solid. LC-MS: C 27 H 24 ClN 5 O 4 calcd 517.15, observed m / e: 518.14 (M + H) + (Rt 0.98 / 2 min); 1 H NMR δ (ppm) (CD 3 OD): 7.96-8.01(m,4H),7.81-7.85(m,5H),5.55(qt,J=5.4 Hz,1H),4.97(t,J=5.2 Hz,1H),4.47(t,J=5.0 Hz , 1H), 4.26-4.30 (m, 1H), 4.09-4.19 (m, 6H), 3.90 (t, J = 7.0 Hz, 1H), 3.60 (t, J = 8.6 Hz, 1H).

實例213Example 213

2-[[(3R,3aR,6S,6aS)-6-氟-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-基]氧基]-6-氯-5-(4-苯基苯基)-1H-咪唑并[4,5-b]吡啶2-[[(3R,3aR,6S,6aS)-6-fluoro-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]oxy] -6-chloro-5-(4-phenylphenyl)-1H-imidazo[4,5-b]pyridine

步驟A2-[[2-[[(3R,3aR,6S,6aS)-6-氟-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-基]氧基]-6-氯-5-(4-苯基苯基)咪唑并[4,5-b]吡啶-1-基]甲氧基]乙基-三甲基-矽烷 。在冰浴中，將來自實例159步驟A之中間物(85.8 mg，0.148 mmol)於DCM(1.5 mL)中之經攪拌溶液(在20 mL塑膠小瓶中)冷卻至 0℃。將DAST(0.12 mL，0.908 mmol)逐滴添加至反應混合物中。10分鐘後，自冰浴中移出反應混合物且使其升溫至室溫。21.5小時後，在冰浴中冷卻反應混合物至0℃，隨後緩慢添加飽和NaHCO3 水溶液(30 mL)。用EtOAc(3×30 mL)萃取所得兩相懸浮液。合併有機層，經Na2 SO4 乾燥，過濾，且在減壓下蒸發，得到琥珀色殘餘物。利用4 g二氧化矽RediSep Rf ®管柱且採用0%至50% EtOAc/己烷梯度並保持50% EtOAc/己烷對殘餘物進行急驟層析，得到呈無色殘餘物形式之所要化合物。LC-MS：C30 H33 ClFN3 O4 Si計算值581.19，觀測值m/e：582.21(M+H)+ (Rt 1.41/2 min)。Step A 2-[[2-[[(3R,3aR,6S,6aS)-6-fluoro-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3 -yl]oxy]-6-chloro-5-(4-phenylphenyl)imidazo[4,5-b]pyridin-1-yl]methoxy]ethyl-trimethyl-decane . The intermediate (85.8 mg, 0.148 mmol) from Example 159, Step A, was taken from a stirred solution (in a 20 mL plastic vial) to 0&lt;0&gt;C. DAST (0.12 mL, 0.908 mmol) was added dropwise to the reaction mixture. After 10 minutes, the reaction mixture was removed from the ice bath and allowed to warm to room temperature. After 21.5 hours, the reaction mixture was cooled in an ice bath to 0 deg.] C, followed by the slow addition of a saturated aqueous NaHCO 3 (30 mL). The resulting two phase suspension was extracted with EtOAc (3 x 30 mL). The organic layers were combined, dried over Na 2 SO 4, filtered, and evaporated under reduced pressure to give an amber residue. Silicon dioxide using 4 g RediSep R f ® column and using 0% to 50% EtOAc / hexanes gradient and held 50% EtOAc / hexanes residue was subjected to flash chromatography to give a colorless residue in the form of the desired compound. LC-MS: C 30 H 33 ClFN 3 O 4 Si calcd 581.19, observed m / e: 582.21 (M + H) + (Rt 1.41 / 2 min).

步驟B2-[[(3R,3aR,6S,6aS)-6-氟-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-基]氧基]-6-氯-5-(4-苯基苯基)-1H-咪唑并[4,5-b]吡啶 。在攪拌下，將2-[[2-[[(3R,3aR,6S,6aS)-6-氟-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-3-基]氧基]-6-氯-5-(4-苯基苯基)咪唑并[4,5-b]吡啶-1-基]甲氧基]乙基-三甲基-矽烷(23.2 mg，0.040 mmol)、甲酸(1.0 mL，26.1 mmol)及飽和KHSO4 水溶液(0.05 mL)之混合物加熱至40℃。4小時後，冷卻反應混合物至室溫，隨後在減壓下濃縮。將經濃縮之反應混合物分配於EtOAc(20 mL)與飽和NaHCO3 水溶液(20 mL)之間。用EtOAc(2×20 mL)萃取水層。合併有機層，經Na2 SO4 乾燥，過濾，且在減壓下蒸發，得到無色殘餘物。藉由逆相HPLC(C-18)，使用30×150 mm SunfireTM 管柱且以20%-100%乙腈/水+0.05% TFA梯度，繼而以100%乙腈+0.05% TFA沖洗液溶離來純化殘餘物，隨後自乙醇及苯 中凍乾，得到呈白色固體狀之標題化合物。LC-MS：C24 H19 ClFN3 O3 計算值451.11，觀測值m/e：452.14(M+H)+ (Rt 1.23/2 min)；1 H NMR δ(ppm)(CD3 OD)：7.86(s,1H),7.71-7.75(m,4H),7.69(d,J=7.3 Hz,2H),7.46(t,J=7.7 Hz,2H),7.36(t,J=7.4 Hz,1H),5.59(qt,J=4.8 Hz,1H),5.13(dd,J=2.4 Hz,50.4 Hz,1H),5.13(t,J=5.3 Hz,1H),4.67(dd,J=5.0 Hz,11.4 Hz,1H),4.11(t,J=11.5 Hz,1H),4.03-4.08(m,2H),3.97(ddd,J=2.5 Hz,11.3 Hz,41.1,1H)。Step B 2-[[(3R,3aR,6S,6aS)-6-fluoro-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]oxy -6-chloro-5-(4-phenylphenyl)-1H-imidazo[4,5-b]pyridine . 2-[[2-[[(3R,3aR,6S,6aS)-6-fluoro-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]] Furan-3-yl]oxy]-6-chloro-5-(4-phenylphenyl)imidazo[4,5-b]pyridin-1-yl]methoxy]ethyl-trimethyl- Silane (23.2 mg, 0.040 mmol), a mixture of formic acid (1.0 mL, 26.1 mmol) and saturated KHSO 4 aqueous solution (0.05 mL) of was heated to 40 ℃. After 4 hours, the reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The concentrated the reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO 3 (20 mL) (20 mL) . The aqueous layer was extracted with EtOAc (2×20 mL). The organic layers were combined, dried over Na 2 SO 4, filtered, and evaporated under reduced pressure to give a colorless residue. By reverse phase HPLC (C-18), using 30 × 150 mm Sunfire TM column and 20% -100% acetonitrile / water gradient + 0.05% TFA, followed by a rinse liquid purified eluting with 100% acetonitrile + 0.05% TFA The residue was lyophilized from ethanol and EtOAc afforded the title compound. LC-MS: C 24 H 19 ClFN 3 O 3 calcd 451.11, observed m / e: 452.14 (M + H) + (Rt 1.23 / 2 min); 1 H NMR δ (ppm) (CD 3 OD): 7.86(s,1H), 7.71-7.75(m,4H), 7.69(d,J=7.3 Hz,2H), 7.46(t,J=7.7 Hz,2H),7.36(t,J=7.4 Hz,1H ), 5.59 (qt, J = 4.8 Hz, 1H), 5.13 (dd, J = 2.4 Hz, 50.4 Hz, 1H), 5.13 (t, J = 5.3 Hz, 1H), 4.67 (dd, J = 5.0 Hz, 11.4 Hz, 1H), 4.11 (t, J = 11.5 Hz, 1H), 4.03-4.08 (m, 2H), 3.97 (ddd, J = 2.5 Hz, 11.3 Hz, 41.1, 1H).

中間物13Intermediate 13

5-(4-溴苯基)-3-(三氟甲基)-1,2,4-噁二唑 。將羰基二咪唑(202 mg，1.244 mmol)添加至4-溴苯甲酸(208.4 mg，1.037 mmol)於無水二氯甲烷(2 mL)中之溶液中。接著添加2,2,2-三氟-N'-羥基-乙脒(173 mg，1.348 mmol)，且在室溫下攪拌混合物1小時。蒸發混合物，且將所得殘餘物溶解於甲苯(2 mL)中並在100℃油浴中加熱18小時。蒸發溶液，且在矽膠Biotage 25S上，以EtOAc/異己烷(含0%至5% EtOAc之己烷)溶離來純化殘餘物，得到呈淡黃色油狀之標題化合物。1 H NMR δ(ppm)(CDCl3 )：8.08(d,2H)及7.76(d,2H)。 5-(4-Bromophenyl)-3-(trifluoromethyl)-1,2,4-oxadiazole . Carbonyldiimidazole (202 mg, 1.244 mmol) was added to a solution of 4-bromobenzoic acid (208.4 mg, 1.037 mmol) in anhydrous dichloromethane (2 mL). Then 2,2,2-trifluoro-N'-hydroxy-acetamidine (173 mg, 1.348 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was evaporated, and the obtained residue was crystalljjjjjjjjjj The solution was evaporated and the residue was purified eluting elut elut elut elut elut elut 1 H NMR δ (ppm) (CDCl 3 ): 8.08 (d, 2H) and 7.76 (d, 2H).

中間物14Intermediate 14

3-(4-溴苯基)-5-環丙基-1,2,4-噁二唑 。將三乙胺(0.204 mL，1.463 mmol)及環丙烷羰基氯(0.089 mL，0.976 mmol)添加至4-溴-N'-羥基-苄脒(104.9 mg，0.488 mmol)於二氯甲烷(2 mL)中之經攪拌混合物中，且在室溫下攪拌混合物30分鐘。蒸發混合物，溶解於甲苯中且再蒸發。將所得殘餘物溶解於甲苯(3 mL)中，且在110℃油浴中加熱18小時。蒸發且藉由製備型TLC純化所得混合物，得到標題化合物。LC-MS：C11 H9 BrN2 O計算值263.99，觀測值m/e：265.18/267.18(M+H)+ (Rt 1.25/2 min)。 3-(4-Bromophenyl)-5-cyclopropyl-1,2,4-oxadiazole . Add triethylamine (0.204 mL, 1.463 mmol) and cyclopropanecarbonyl chloride (0.089 mL, 0.976 mmol) to 4-bromo-N'-hydroxy-benzylhydrazine (104.9 mg, 0.488 mmol) in dichloromethane (2 mL The mixture was stirred and the mixture was stirred at room temperature for 30 minutes. The mixture was evaporated, dissolved in toluene and evaporated. The resulting residue was dissolved in toluene (3 mL) and then warm Evaporation and purification of the mixture obtained by preparative TLC afford LC-MS: C 11 H 9 BrN 2 O Calcd 263.99, observed m / e: 265.18 / 267.18 ( M + H) + (Rt 1.25 / 2 min).

中間物15Intermediate 15

5-(4-溴苯基)-2-(((3R,3aR,6R,6aS)-6-((第三丁基二甲基矽烷基)氧基)六氫呋喃并[3,2-b]呋喃-3-基)氧基)-6-氯-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶 。在氮氣下，將5-(4-溴苯基)-6-氯-2-(甲基磺醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶(2.00 g，3.87 mmol)及(3R,3aR,6R,6aS)-6-((第三丁基二甲基矽烷基)氧基)六氫呋喃并[3,2-b]呋喃-3-醇(2.02 g，7.74 mmol)置於無水DMF(15 mL)中。接著添加碳酸銫(3.78 g，11.61 mmol)， 且在室溫下攪拌混合物2小時。接著將混合物傾倒至水(200 mL)中，且用乙酸乙酯(2×150 mL)萃取。用鹽水(100 mL)洗滌經合併之有機層，經硫酸鈉乾燥，且在減壓下濃縮，得到暗色油狀物。使用以含0%至75%乙酸乙酯之1：1二氯甲烷/己烷混合物溶離之Biotage 100 g矽膠濾筒對該油狀物進行層析。合併所要產物溶離份且在減壓下濃縮，得到呈灰白色固體狀之標題化合物。LC-MS：C30 H43 BrClN3 O5 Si2 計算值697.21，觀測值m/e：698.17(M+H)+ (Rt 3.19/4 min)。 5-(4-bromophenyl)-2-(((3R,3aR,6R,6aS)-6-((t-butyldimethylmethylalkyl)oxy)hexahydrofuran[3,2- b]furan-3-yl)oxy)-6-chloro-1-((2-(trimethyldecyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine . 5-(4-Bromophenyl)-6-chloro-2-(methylsulfonyl)-1-((2-(trimethyldecyl)ethoxy)methyl)- under nitrogen 1H-imidazo[4,5-b]pyridine (2.00 g, 3.87 mmol) and (3R,3aR,6R,6aS)-6-((t-butyldimethylmethylalkyl)oxy)hexahydrofuran [3,2-b]furan-3-ol (2.02 g, 7.74 mmol) was taken in anhydrous DMF (15 mL). Then cesium carbonate (3.78 g, 11.61 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was poured into water (200 mL) and extracted with EtOAc EtOAc. The combined organic layers were washed with EtOAc EtOAc m. The oil was chromatographed using a Biotage 100 g silica gel cartridge eluted with a mixture of 0% to 75% ethyl acetate in 1:1 dichloromethane/hexane. The title compound was obtained as a white solid. LC-MS: C 30 H 43 BrClN 3 O 5 Si 2 calcd 697.21, observed m / e: 698.17 (M + H) + (Rt 3.19 / 4 min).

中間物16Intermediate 16

將雙(頻哪醇根基)二硼(1.573 g，6.20 mmol)、1,1'-雙(二苯基膦基)二茂鐵-二氯化鈀(II)二氯甲烷錯合物(0.337 g，0.413 mmol)及乙酸鉀(1.014 g，10.33 mmol)添加至[(3R,3aR,6R,6aS)-3-[5-(4-溴苯基)-6-氯-1-(2-三甲基矽烷基乙氧基甲基)咪唑并[4,5-b]吡啶-2-基]氧基-2,3,3a,5,6,6a-六氫呋喃并[3,2-b]呋喃-6-基]氧基-第三丁基-二甲基-矽烷(中間物15，1.44 g，2.065 mmol)於DMF(15 mL)中之經攪拌溶液中。在80℃油浴中加熱混合物18小時，且在冷卻至室溫後，用EtOAc(100 mL)稀釋，經CeliteTM 過濾，且用乙酸乙 酯(100 mL)洗滌過濾襯墊。用鹽水(100 mL)洗滌經合併之有機層，經Na2 SO4 乾燥，過濾，且在減壓下蒸發。藉由在矽膠Biotage 40 M上，以EtOAc/異己烷(含0%至30% EtOAc之己烷)溶離進行管柱層析來純化所得殘餘物，得到呈淡黃色固體狀之標題化合物。LC-MS：C36 H55 BClN3 O7Si2 計算值743.34，觀測值m/e：744.52(M+H)+ (Rt 1.53/2 min)。Bis (pinacol) diboron (1.573 g, 6.20 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) chloride complex (0.337 g, 0.413 mmol) and potassium acetate (1.014 g, 10.33 mmol) were added to [(3R,3aR,6R,6aS)-3-[5-(4-bromophenyl)-6-chloro-1-(2- Trimethyldecyl ethoxymethyl) imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuran [3,2- b] A solution of furan-6-yloxy-t-butyl-dimethyl-decane (Intermediate 15, 1.44 g, 2.065 mmol) in DMF (15 mL). Was heated at 80 deg.] C oil bath mixture for 18 hours and, after cooling to room temperature, diluted with EtOAc (100 mL), filtered through Celite TM, and the filter pad was washed with ethyl acetate (100 mL). With brine (100 mL) the combined organic layers were washed, dried over Na 2 SO 4, filtered, and evaporated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc LC-MS: C 36 H 55 BClN 3 O7Si 2 calcd 743.34, observed m / e: 744.52 (M + H) + (Rt 1.53 / 2 min).

中間物17Intermediate 17

2-溴-5-(四唑-1-基)吡啶 。將疊氮化鈉(241.6 mg，3.72 mmol)及原甲酸三乙酯(1.0 mL，6.01 mmol)添加至5-胺基-2-溴吡啶(511.8 mg，2.96 mmol)於乙酸(3 mL，52.4 mmol)中之經攪拌溶液中，且將反應混合物加熱至80℃。7小時後，冷卻反應混合物至室溫，隨後在減壓下蒸發。將所得紅色/棕色固體分配於EtOAc(50 mL)與水(50 mL)之間。用EtOAc(2×50 mL)萃取水層。合併有機層，用1 N HCl(2×50 mL)、飽和NaHCO3 水溶液(1×50 mL)及鹽水(1×50 mL)洗滌，經Na2 SO4 乾燥，過濾，且在減壓下蒸發，得到琥珀色固體。利用40 g二氧化矽RediSep Rf ®管柱且採用0%至2% MeOH/DCM梯度並保持2% MeOH/DCM對該固體進行急驟層析，得到呈淡黃色固體狀之標題化合物。LC-MS：C6 H4 BrN5 計算值224.97,226.96，觀測值m/e：226.22,228.21(M+H)+ (Rt 0.42/2 min)。 2-bromo-5-(tetrazol-1-yl)pyridine . Add sodium azide (241.6 mg, 3.72 mmol) and triethyl orthoformate (1.0 mL, 6.01 mmol) to 5-amino-2-bromopyridine (511.8 mg, 2.96 mmol) in acetic acid (3 mL, 52.4 The stirred solution was stirred in mmol) and the reaction mixture was heated to 80 °C. After 7 hours, the reaction mixture was cooled to room temperature and then evaporated under reduced pressure. The resulting red/brown solid was partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (2×50 mL). The organic layers were combined, (2 × 50 mL), saturated aqueous NaHCO 3 (1 × 50 mL) and brine (1 × 50 mL) and washed with 1 N HCl, dried over Na 2 SO 4, filtered, and evaporated under reduced pressure , to get an amber solid. Silicon dioxide using a 40 g RediSep R f ® column and using 0% to 2% MeOH / DCM gradient and held 2% MeOH / DCM The solid was flash chromatographed to afford the title compound as a pale yellow solid. LC-MS: C 6 H 4 BrN 5 calcd 224.97,226.96, observed m / e: 226.22,228.21 (M + H) + (Rt 0.42 / 2 min).

中間物18Intermediate 18

1-甲基-2-[4-(4,4,5,5-四甲基-1,3,2-二氧硼 -2-基)苯基]咪唑 。在油浴中於85℃下，將在DMSO(660 mL)中之2-(4-溴苯基)-1-甲基-1H-咪唑(71.1 g，300 mmol，1當量)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1,3,2-二氧硼(83.8 g，329.92 mmol，1.1當量)、dppfPdCl2 (6.6 g，9.03 mmol，0.03當量)及KOAc(88.2 g，900 mmol，3當量)之溶液攪拌隔夜。冷卻反應混合物，接著藉由添加1200 mL水淬滅。用二氯甲烷(2×500 mL)萃取所得溶液。合併有機層，經無水硫酸鎂乾燥，且在真空下濃縮。將所得殘餘物施加於矽膠管柱上且以乙酸乙酯/石油醚(1：5-1：2)溶離，得到呈灰色粉末狀之標題化合物。LC-MS：C16 H21 BN2 O2 計算值284.17，觀測值m/e：285(M+H)+ ；1 H NMR δ(ppm)(CDCl3 )：7.89(2H,d,J=8.0 Hz),7.65(2H,d,J=8.0 Hz),7.14(1H,d,J=1.2 Hz),6.97(1H,d,J=1.2 Hz),3.76(3H,s),1.36(12H,s)。 1-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron -2-yl)phenyl]imidazole . 2-(4-Bromophenyl)-1-methyl-1H-imidazole (71.1 g, 300 mmol, 1 eq.), 4, 4 in DMSO (660 mL) in an oil bath at 85 °C ,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboron -2-yl)-1,3,2-dioxaboron A solution of (83.8 g, 329.92 mmol, 1.1 eq.), dppfPdCl 2 (6.6 g, 9.03 mmol, 0.03 eq.) and KOAc (88.2 g, 900 mmol, 3 eq.) was stirred overnight. The reaction mixture was cooled and then quenched by the addition of 1200 mL water. The resulting solution was extracted with dichloromethane (2 x 500 mL). The organic layers were combined, dried over anhydrous magnesium The resulting residue was applied to a EtOAc EtOAc EtOAc (EtOAc) LC-MS: C 16 H 21 BN 2 O 2 calc. 284.17, observed m / e: 285 (M + H) +; 1 H NMR δ (ppm) (CDCl 3): 7.89 (2H, d, J = 8.0 Hz), 7.65 (2H, d, J = 8.0 Hz), 7.14 (1H, d, J = 1.2 Hz), 6.97 (1H, d, J = 1.2 Hz), 3.76 (3H, s), 1.36 (12H) , s).

中間物19Intermediate 19

可根據中間物18所述之程序自2-(4-溴苯基)噻唑製備中間物19。Intermediate 19 can be prepared from 2-(4-bromophenyl)thiazole according to the procedure described for Intermediate 18.

中間物20Intermediate 20

可藉由使[6-(1H-咪唑-2-基)-3-吡啶基]酸與SEMCl反應來製備中間物20。By [6-(1H-imidazol-2-yl)-3-pyridyl] The intermediate 20 was prepared by reacting an acid with SEMCl.

中間物21Intermediate 21

可藉由使N,N' -雙(二甲基胺基亞甲基)-肼與6-氯吡啶-3-胺反應來製備中間物21。Intermediate 21 can be prepared by reacting N,N' -bis(dimethylaminomethylene)-hydrazine with 6-chloropyridin-3-amine.

中間物22Intermediate 22

3-(4-溴苯基)-1-環丙基-吡唑 。在90℃下，將3-(4-溴苯基)-1H-吡唑(302 g，1.35 mol)、環丙基酸(233 g，2.71 mol)、乙酸銅(II)(246 g，1.35 mol)、4-(二甲基胺基)吡啶(662 g，5.42 mol)、碳酸銫(1103 g，3.39 mol)及1,4-二噁烷(8 L)之溶液攪拌36小時。冷卻反應混合物至室溫，隨後經CeliteTM 過濾，用EtOAc(4 L)洗滌。用2 N HCl將濾液酸化至pH 5。用EtOAc(12 L)萃取水層。合併有機層，用鹽水洗滌，經MgSO4 乾燥，過濾，且在減壓下蒸發。在ISCO 1500 g管柱上，以0%至20% EtOAc/庚烷梯度溶離來純化所得殘餘物，得到標題化合物。LC-MS：C12 H11 BrN2 計算值262.01,264.01，觀測值m/e：263.04,265.06(M+H)+ (Rt 1.19/2 min)。 3-(4-Bromophenyl)-1-cyclopropyl-pyrazole . 3-(4-bromophenyl)-1H-pyrazole (302 g, 1.35 mol), cyclopropyl at 90 ° C Acid (233 g, 2.71 mol), copper (II) acetate (246 g, 1.35 mol), 4-(dimethylamino)pyridine (662 g, 5.42 mol), cesium carbonate (1103 g, 3.39 mol) and A solution of 1,4-dioxane (8 L) was stirred for 36 hours. The reaction mixture was cooled to room temperature, then filtered through Celite TM, washing with EtOAc (4 L). The filtrate was acidified to pH 5 with 2 N HCl. The aqueous layer was extracted with EtOAc (12 L). The organic layers were combined, washed with brine, dried over MgSO 4, filtered, and evaporated under reduced pressure. The resulting residue was purified eluting with EtOAc EtOAc EtOAc LC-MS: C 12 H 11 BrN 2 calc 262.01,264.01, observed m / e: 263.04,265.06 (M + H) + (Rt 1.19 / 2 min).

實例214Example 214

(3R,3aR,6R,6aR)-6-((6-氯-5-(4-(哌啶-4-基乙炔基)苯基)-1H-咪唑并[4,5-b]吡啶-2-基)氧基)六氫呋喃并[3,2-b]呋喃-3-醇(3R,3aR,6R,6aR)-6-((6-chloro-5-(4-(piperidin-4-ylethynyl)phenyl)-1H-imidazo[4,5-b]pyridine- 2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol

步驟A：4-((4-(2-(((3R,3aR,6R,6aS)-6-((第三丁基二甲基矽烷基)氧基)六氫呋喃并[3,2-b]呋喃-3-基)氧基)-6-氯-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-5-基)苯基)乙炔基)哌啶-1-甲酸第三丁酯 Step A: 4-((4-(2-((3R,3aR,6R,6aS)-6-((t-butyldimethylmethylalkyl)oxy)hexahydrofuro[3,2- b]furan-3-yl)oxy)-6-chloro-1-((2-(trimethyldecyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine- 3-butyl)phenyl)ethynyl)piperidine-1-carboxylic acid tert-butyl ester

在氮氣下，將5-(4-溴苯基)-2-(((3R,3aR,6R,6aS)-6-((第三丁基二甲基矽烷基)氧基)六氫呋喃并[3,2-b]呋喃-3-基)氧基)-6-氯-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶(中間物15，63 mg，0.090 mmol)、4-乙炔基-哌啶-1-甲酸第三丁酯(23 mg，0.108 mmol)、雙(三苯基膦)二氯化鈀(II)(10 mg，0.014 mmol)及碘化銅(I)(1.4 mg，0.007 mmol)置於無水三乙胺(0.5 mL)中。在乾冰/丙酮浴中冷卻混合物的同時，施加高真空，隨後引入氮氣(3×)。自冰浴中移出混合物，用鐵氟龍(teflon)蓋密封，且加熱至50℃，維持24小時。冷卻至室溫後，經CeliteTM 過濾混合物，且用乙酸乙酯清洗直至濾液無色。接著在減壓下濃縮濾液，得到橙色油狀物，其未經進一步純化即直接用於下一步驟 中。LC-MS：C42 H61 ClN4 O7 Si2 計算值824.38，觀測值m/e：825.45(M+H)+ (Rt 3.34/4 min)。5-(4-Bromophenyl)-2-(((3R,3aR,6R,6aS)-6-((t-butyldimethylmethyl)alkyl)oxy) hexahydrofuran under nitrogen [3,2-b]furan-3-yl)oxy)-6-chloro-1-((2-(trimethyldecyl)ethoxy)methyl)-1H-imidazo[4,5 -b]pyridine (intermediate 15, 63 mg, 0.090 mmol), 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (23 mg, 0.108 mmol), bis(triphenylphosphine)palladium dichloride (II) (10 mg, 0.014 mmol) and copper (I) iodide (1.4 mg, 0.007 mmol) were taken in anhydrous triethylamine (0.5 mL). While the mixture was cooled in a dry ice/acetone bath, a high vacuum was applied, followed by introduction of nitrogen (3x). The mixture was removed from the ice bath, sealed with a teflon lid and heated to 50 ° C for 24 hours. After cooling to room temperature, the mixture was filtered through Celite TM, and washed with ethyl acetate until the filtrate was colorless. The filtrate was then concentrated under reduced pressure to give abr. LC-MS: C 42 H 61 ClN 4 O 7 Si 2 calcd 824.38, observed m / e: 825.45 (M + H) + (Rt 3.34 / 4 min).

步驟B：(3R,3aR,6R,6aR)-6-((6-氯-5-(4-(哌啶-4-基乙炔基)苯基)-1H-咪唑并[4,5-b]吡啶-2-基)氧基)六氫呋喃并[3,2-b]呋喃-3-醇 Step B: (3R,3aR,6R,6aR)-6-((6-chloro-5-(4-(piperidin-4-ylethynyl)phenyl)-1H-imidazo[4,5-b Pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol

在氮氣下，將來自步驟A之未純化之4-((4-(2-(((3R,3aR,6R,6aS)-6-((第三丁基二甲基矽烷基)氧基)-六氫呋喃并[3,2-b]呋喃-3-基)氧基)-6-氯-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-5-基)苯基)乙炔基)哌啶-1-甲酸第三丁酯(0.090 mol理論值)置於甲酸(1.0 mL)中。添加硫酸氫鉀飽和水溶液(0.2 mL)，且在50℃下攪拌混合物4小時。冷卻混合物至室溫。接著用甲醇(5 mL)稀釋混合物，在冰浴中冷卻至5℃，且使用6 N NaOH水溶液鹼化至pH 14。在pH 14下攪拌混合物10分鐘，接著逐滴添加濃鹽酸水溶液直至pH值為pH 7。將混合物傾倒至飽和碳酸氫鈉水溶液(40 mL)中，且用乙酸乙酯(2×70 mL)萃取。在減壓下濃縮經合併之有機層。將所得黃色固體溶解於DMSO中，且使用以含0%至60%乙腈之水(0.1% TFA)經10分鐘溶離之Gilson逆相製備型HPLC進行層析。合併所要產物溶離份，在-78℃下冷凍，且凍乾至乾燥，得到黃色固體。LC-MS：C25 H25 ClN4 O4 計算值480.16，觀測值m/e：481.14(M+H)+ (Rt 1.43/4 min)。1 H NMR δ(ppm)(CD3 OD)：7.80(1H,s),7.62(2H,d,J=8.5 Hz),7.49(2H,d,J=8.5 Hz),5.53(1H,m),4.95(1H,t,J=5.5 Hz),4.46(1H,t, J=5.0 Hz),4.27(1H,m),4.15(1H,dd,J=9.5,6.0 Hz),4.09(1H,dd,J=10.0,4.9 Hz),3.88(1H,dd,J=8.0,7.0 Hz),3.58(1H,t,J=8.5 Hz),3.42(2H,m),3.18(2H,m),3.09(1H,m),2.17(2H,m),1.96(2H,m)。Unpurified 4-((4-(2-(3R,3aR,6R,6aS)-6-((t-butyldimethyl)alkyl)oxy) from Step A under nitrogen -Hexahydrofuro[3,2-b]furan-3-yl)oxy)-6-chloro-1-((2-(trimethyldecyl)ethoxy)methyl)-1H-imidazole And [4,5-b]pyridin-5-yl)phenyl)ethynyl)piperidine-1-carboxylic acid tert-butyl ester (0.090 mol of theory) was placed in formic acid (1.0 mL). A saturated aqueous solution of potassium hydrogensulfate (0.2 mL) was added, and the mixture was stirred at 50 ° C for 4 hours. The mixture was cooled to room temperature. The mixture was then diluted with MeOH (5 mL), cooled to 5 &lt;0&gt;C in an ice bath and basified to pH 14 using aqueous 6 N NaOH. The mixture was stirred at pH 14 for 10 minutes, then a concentrated aqueous solution of hydrochloric acid was added dropwise until pH was pH 7. The mixture was poured into aq. EtOAc (EtOAc) The combined organic layers were concentrated under reduced pressure. The resulting yellow solid was dissolved in DMSO and chromatographed using a Gilson reverse phase preparative HPLC eluting with 0% to 60% acetonitrile in water (0.1% TFA) over 10 min. The fractions of the desired product were combined, frozen at -78 ° C, and lyophilized to dryness to give a yellow solid. LC-MS: C 25 H 25 ClN 4 O 4 calcd 480.16, observed m / e: 481.14 (M + H) + (Rt 1.43 / 4 min). 1 H NMR δ (ppm) (CD 3 OD): 7.80 (1H, s), 7.62 (2H, d, J = 8.5 Hz), 7.49 (2H, d, J = 8.5 Hz), 5.53 (1H, m) , 4.95 (1H, t, J = 5.5 Hz), 4.46 (1H, t, J = 5.0 Hz), 4.27 (1H, m), 4.15 (1H, dd, J = 9.5, 6.0 Hz), 4.09 (1H, Dd, J = 10.0, 4.9 Hz), 3.88 (1H, dd, J = 8.0, 7.0 Hz), 3.58 (1H, t, J = 8.5 Hz), 3.42 (2H, m), 3.18 (2H, m), 3.09 (1H, m), 2.17 (2H, m), 1.96 (2H, m).

或者，可根據以下程序製備(3R,3aR,6R,6aR)-6-((6-氯-5-(4-(哌啶-4-基乙炔基)苯基)-1H-咪唑并[4,5-b]吡啶-2-基)氧基)六氫呋喃并[3,2-b]呋喃-3-醇：Alternatively, (3R, 3aR, 6R, 6aR)-6-((6-chloro-5-(4-(piperidin-4-ylethynyl)phenyl)-1H-imidazo[4] can be prepared according to the following procedure ,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol:

步驟A：(3R,3aR,6R,6aR)-6-((5-(4-溴苯基)-6-氯-1H-咪唑并[4,5-b]吡啶-2-基)氧基)六氫呋喃并[3,2-b]呋喃-3-醇。 Step A: (3R,3aR,6R,6aR)-6-((5-(4-bromophenyl)-6-chloro-1H-imidazo[4,5-b]pyridin-2-yl)oxy ) hexahydrofuro[3,2-b]furan-3-ol.

在氮氣下，將(3R,3aR,6R,6aR)-6-((5-(4-溴苯基)-6-氯-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-2-基)氧基)六氫呋喃并[3,2-b]呋喃-3-醇(中間物7，527 mg，0.904 mmol)置於甲酸(2.5 mL)中。添加硫酸氫鉀飽和水溶液(0.4 mL)，且在50℃下攪拌所得混合物9小時。冷卻混合物，且緩慢添加至飽和碳酸氫鈉水溶液(200 mL)中。用乙酸乙酯(2×150 mL)萃取混合物，且在減壓下濃縮。將所得白色固體溶解於甲醇(5 mL)中，且用3 N氫氧化鈉水溶液(2 mL)鹼化。在室溫下攪拌混合物10分鐘，接著用1 N鹽酸水溶液(6 mL)中和。將混合物傾倒至飽和碳酸氫鈉水溶液(25 mL)中，且用乙酸乙酯(2×50 mL)萃取。經硫酸鈉乾燥經合併之有機層，且在減壓下濃縮。使用以含0%至5%甲醇之二氯甲烷經20分鐘溶離之Biotage 25 g矽膠濾筒對所得白色固體進行層析。合併產物溶離份，在減壓下濃縮，且在高真空下乾燥，獲得白色固體。LC-MS：C18 H15 BrClN3 O4 計算值452.69，觀測值m/e：454.02(M+H)+ (Rt 1.84/4 min)。(3R, 3aR, 6R, 6aR)-6-((5-(4-bromophenyl)-6-chloro-1-((2-(trimethyldecyl))ethoxy)) Methyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (Intermediate 7,527 mg, 0.904 mmol ) was placed in formic acid (2.5 mL). A saturated aqueous solution of potassium hydrogensulfate (0.4 mL) was added, and the mixture was stirred at 50 ° C for 9 hours. The mixture was cooled and slowly added to saturated aqueous sodium bicarbonate (200 mL). The mixture was extracted with ethyl acetate (2×150 mL) and evaporated. The resulting white solid was dissolved in MeOH (5 mL)EtOAcEtOAc The mixture was stirred at room temperature for 10 minutes and then neutralized with 1N aqueous hydrochloric acid (6 mL). The mixture was poured into a saturated aqueous solution of sodium bicarbonate (25 mL) and ethyl acetate (2×50 mL). The combined organic layers were dried with sodium sulfate and evaporated The resulting white solid was chromatographed using a Biotage 25 g silica gel cartridge eluting with 0% to 5% methanol in dichloromethane over 20 min. The product was combined and concentrated under reduced pressure and dried under high vacuum to afford a white solid. LC-MS: C 18 H 15 BrClN 3 O 4 calcd 452.69, observed m / e: 454.02 (M + H) + (Rt 1.84 / 4 min).

步驟B：(3R,3aR,6R,6aR)-6-((6-氯-5-(4-(哌啶-4-基乙炔基)苯基)-1H-咪唑并[4,5-b]吡啶-2-基)氧基)六氫呋喃并[3,2-b]呋喃-3-醇 。在氮氣下，將(3R,3aR,6R,6aR)-6-((5-(4-溴苯基)-6-氯-1H-咪唑并[4,5-b]吡啶-2-基)氧基)六氫呋喃并[3,2-b]呋喃-3-醇(25 mg，0.055 mmol)、4-乙炔基哌啶(10.5 mg，0.072 mmol)、碘化銅(I)(2.1 mg，0.011 mmol)、氯(三-第三丁基)-2[-(2'-胺基-1,1'-聯苯)]鈀(II)(5.7 mg，0.011 mmol，藉由與J.AM.CHEM.SOC.2010,132,14073-14075中所述之程序類似之程序製備)及碳酸銫(54.0 mg，0.166 mmol)置於無水、經脫氣之甲苯(138 μl)及二甲基乙醯胺(138 μl)中。在50℃下攪拌混合物2小時。用二甲基甲醯胺(0.7 mL)稀釋所得殘餘物，接著經濾盤(filter disc)(0.45微米)過濾。藉由逆相HPLC純化法，使用含0%至100%乙腈之水經10分鐘純化該物質。在減壓下濃縮所要產物溶離份，得到呈灰白色固體狀之標題化合物。LC-MS：C25 H25 ClN4 O4 計算值480.16，觀測值m/e：481.14(M+H)+ (Rt 1.43/4 min)。1 H NMR δ(ppm)(CD3 OD)：7.80(1H,s),7.62(2H,d,J=8.5 Hz),7.49(2H,d,J=8.5 Hz),5.53(1H,m),4.95(1H,t,J=5.5 Hz),4.46(1H,t,J=5.0 Hz),4.27(1H,m),4.15(1H,dd,J=9.5,6.0 Hz),4.09(1H,dd,J=10.0,4.9 Hz),3.88(1H,dd,J=8.0,7.0 Hz),3.58(1H,t,J=8.5 Hz),3.42(2H,m),3.18(2H,m),3.09(1H,m),2.17(2H,m),1.96(2H,m)。Step B: (3R,3aR,6R,6aR)-6-((6-chloro-5-(4-(piperidin-4-ylethynyl)phenyl)-1H-imidazo[4,5-b Pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol . (3R,3aR,6R,6aR)-6-((5-(4-bromophenyl)-6-chloro-1H-imidazo[4,5-b]pyridin-2-yl) under nitrogen Oxy) hexahydrofuro[3,2-b]furan-3-ol (25 mg, 0.055 mmol), 4-ethynylpiperidine (10.5 mg, 0.072 mmol), copper iodide (I) (2.1 mg , 0.011 mmol), chloro(tri-tert-butyl)-2[-(2'-amino-1,1'-biphenyl)]palladium(II) (5.7 mg, 0.011 mmol, by with J. Prepared in a similar procedure as described in AM.CHEM.SOC. 2010, 132, 14073-14075) and cesium carbonate (54.0 mg, 0.166 mmol) in anhydrous, degassed toluene (138 μl) and dimethyl In acetamide (138 μl). The mixture was stirred at 50 ° C for 2 hours. The resulting residue was diluted with dimethylformamide (0.7 mL) then filtered th The material was purified by reverse phase HPLC purification using water containing 0% to 100% acetonitrile over 10 min. The title compound was obtained as a white solid. LC-MS: C 25 H 25 ClN 4 O 4 calcd 480.16, observed m / e: 481.14 (M + H) + (Rt 1.43 / 4 min). 1 H NMR δ (ppm) (CD 3 OD): 7.80 (1H, s), 7.62 (2H, d, J = 8.5 Hz), 7.49 (2H, d, J = 8.5 Hz), 5.53 (1H, m) , 4.95 (1H, t, J = 5.5 Hz), 4.46 (1H, t, J = 5.0 Hz), 4.27 (1H, m), 4.15 (1H, dd, J = 9.5, 6.0 Hz), 4.09 (1H, Dd, J = 10.0, 4.9 Hz), 3.88 (1H, dd, J = 8.0, 7.0 Hz), 3.58 (1H, t, J = 8.5 Hz), 3.42 (2H, m), 3.18 (2H, m), 3.09 (1H, m), 2.17 (2H, m), 1.96 (2H, m).

生物實例1Biological example 1 AMPKSAMSF(活體外AMPK活化分析)AMPKSAMSF (in vitro AMPK activation assay)

自桿狀病毒表現系統獲得重組人類AMPK複合物1(含有α1β1γ1)。根據製造商之說明書，藉由在草地黏蟲21(spodoptera frugiperda 21)細胞中用AMPK/pBacPak9純系與Baculogold桿狀病毒DNA(Pharmingen)一起共轉染來產生重組病毒。在含有10%血清之格雷氏培養基(Grace's medium)中進行每一輪病毒擴增，持續5天。使用已經歷三輪擴增之病毒進行所有蛋白質產生程序。為表現AMPK複合物，藉由將sf21細胞自含血清儲備液連續稀釋至SF900II培養基中來使其適應於無血清培養基(SF900 II，Invitrogen)，且在27℃下以90 rpm維持於搖瓶中。在無血清條件下於sf21細胞中，藉由三重感染產生重組AMPK酶複合物，每一次單元使用一種重組病毒。在對數期感染細胞(1×106 個細胞/毫升)，感染倍率為約5。用病毒感染72小時後，藉由以10,000×g離心15分鐘來收集細胞。使來自2公升培養物之昆蟲細胞集結粒再懸浮於50 ml溶解緩衝液(20 mM Tris-HCl、50 mM NaCl、50 mM NaF、30 mM Na PPi、0.25 M蔗糖、10 mM ZnCl2 、2 mM DTT、0.4 mg/ml毛地黃皂苷(digitonin))中，且在乾冰乙醇浴中進行兩個冷凍-解凍溶解循環。藉由以10,000×g離心來移除不可溶物質，且使用聚乙二醇(PEG)來部分分離上清液。在2.5% PEG與6% PEG之間沈澱的蛋白質分離部分用於使用藍色瓊脂糖(Blue-Sepharose)步驟之進一步純化(Zhou等人，J.Clin.Invest.108,1167-1174,2001)。Recombinant human AMPK complex 1 (containing α1β1γ1) was obtained from the baculovirus expression system. Recombinant viruses were generated by co-transfection with Baculogold baculovirus DNA (Pharmingen) in PBSK/pBacPak9 pure lines in Spodoptera frugiperda 21 cells according to the manufacturer's instructions. Each round of virus amplification was performed in 10% serum in Grace's medium for 5 days. All protein production procedures were performed using viruses that had undergone three rounds of amplification. To express the AMPK complex, it was adapted to serum-free medium (SF900 II, Invitrogen) by serial dilution of sf21 cells from serum-containing stock into SF900II medium, and maintained in shake flasks at 90 rpm at 27 °C. . Recombinant AMPK enzyme complexes were produced by triple infection in serum-free conditions in sf21 cells, using one recombinant virus per unit. In the log phase infected cells (1 × 10 6 cells / ml), the infection rate was about 5. After 72 hours of infection with the virus, the cells were collected by centrifugation at 10,000 x g for 15 minutes. Resuspend insect cells from 2 liter cultures in 50 ml lysis buffer (20 mM Tris-HCl, 50 mM NaCl, 50 mM NaF, 30 mM Na PPi, 0.25 M sucrose, 10 mM ZnCl 2 , 2 mM) DTT, 0.4 mg/ml digitonin), and two freeze-thaw cycles were performed in a dry ice ethanol bath. The insoluble matter was removed by centrifugation at 10,000 x g, and polyethylene glycol (PEG) was used to partially separate the supernatant. The protein fractions precipitated between 2.5% PEG and 6% PEG were used for further purification using the Blue-Sepharose step (Zhou et al, J. Clin. Invest. 108, 1167-1174, 2001). .

在384孔板中以30 μl體積進行活體外AMPK活化分析。 在微量滴定板中，藉由將15 μl含2×酶之分析緩衝液(20 mM HEPES(pH 7.3)、5 mM MgCl2 、3 mM DTT、0.01% Brij 35及CamK激酶，用以活化AMPK)添加至含有DMSO或化合物之孔中來組建(assembled)酶反應。藉由添加15 μl分析緩衝液中之含200 μM ATP及3.0 μM經螢光標記之SAMS(5-FAM-HMRSAMSGLHLVKRR-COOH)之2×受質混合物來起始反應。在25℃下培育45分鐘後，藉由添加70 μl停止緩衝液(100 mM HEPES(pH 7.3)、40 mM EDTA、0.015% Brij 35)來停止反應。使用Caliper EZ Reader LabChip微流體讀取器(microfluidics reader)評估磷酸化之5-FAM SAMS產物。藉由計算受質及產物之峰高且報導產物/(產物+受質)峰比率來確定產物轉化率。10點滴定數據以最大AMP活化%表示。使用四參數擬合法繪製結果之曲線，且反映50%最大活化之拐點以EC50 報導。所選化合物之最大AMP活化%提供於下表中。In vitro AMPK activation assays were performed in 384-well plates in a volume of 30 μl. In a microtiter plate, 15 μl of assay buffer containing 2× enzyme (20 mM HEPES (pH 7.3), 5 mM MgCl 2 , 3 mM DTT, 0.01% Brij 35 and CamK kinase) was used to activate AMPK) The enzyme reaction is assembled by adding to a well containing DMSO or a compound. The reaction was initiated by the addition of 2 x substrate mixture containing 200 μM ATP and 3.0 μM fluorescently labeled SAMS (5-FAM-HMRSAMSGLHLVKRR-COOH) in 15 μl of assay buffer. After incubation at 25 ° C for 45 minutes, the reaction was stopped by the addition of 70 μl stop buffer (100 mM HEPES (pH 7.3), 40 mM EDTA, 0.015% Brij 35). The phosphorylated 5-FAM SAMS product was evaluated using a Caliper EZ Reader LabChip microfluidics reader. Product conversion was determined by calculating the peak height of the acceptor and product and reporting the product/(product + acceptor) peak ratio. The 10 point titration data is expressed as the maximum AMP activation %. Using a four-parameter curve fitting the results of the draw, and reflect 50% of the maximal activation of the knee to EC 50 report. The maximum AMP activation % of the selected compounds is provided in the table below.

在活體外AMPK活化分析中使用重組人類AMPK複合物1(含有α1β1γ1)測試本發明化合物，包括實例1-229之化合物，且發現其具有大於人類AMPK複合物1(含有α1β1γ1)之50%最大AMP活化，且EC50 值小於10微莫耳濃度。在活體外AMPK活化分析中使用重組人類AMPK複合物1發現，較佳本發明化合物之EC50 值小於0.1微莫耳濃度。Compounds of the invention, including compounds of Examples 1-229, were tested in an in vitro AMPK activation assay using recombinant human AMPK complex 1 (containing α1β1γ1) and found to have a 50% max AMP greater than human AMPK complex 1 (containing α1β1γ1) activation, and the EC 50 value of less than 10 micromolar. Human recombinant AMPK complexes found in an AMPK activation in vitro assay, the compounds of the present invention, the preferred EC 50 value of less than 0.1 micromolar.

所選化合物之最大AMP活化Maximum AMP activation of selected compounds

生物實例2Biological example 2 在db/+小鼠中由AMPK活化劑磷酸化乙醯基CoA羧基酶：Phosphorylation of Ethyl CoA Carboxylase by AMPK Activator in db/+ Mice:

為評估AMPK活化劑增加肝臟及骨骼肌中乙醯基COA羧基酶(ACC)之磷酸化的潛力，在評估前2小時或7小時向db/+小鼠給與AMPK活化劑，在評估時比較經媒劑處理之小鼠與經化合物處理之小鼠之組織中的磷酸化ACC(p-ACC)/總ACC含量。簡言之，使用氣體麻醉，以經由鼻錐投與之1%至4%異氟醚(isoflurane)麻醉小鼠。一旦麻醉， 即移出肝臟及骨骼肌(腓腸肌)之樣品，在液氮中急速冷凍(snap freeze)，且進行均質化。分析勻漿之蛋白質濃度，且使用Meso Scale Discovery之多陣列分析套組來評估等量蛋白質之總ACC及磷酸化ACC(p-ACC)含量。MSD分析板含有塗覆有抗生蛋白鏈菌素(streptavidin)之電極表面。蛋白質樣品結合於抗生蛋白鏈菌素。初級ACC或p-ACC特異性抗體結合於蛋白質，且經MSD SULFO-TAG標記之二級抗體繼而結合於該初級抗體。MSD板之電極表面對電刺激作出反應，且使結合於ACC及p-ACC之SULFO-TAG標記發射與所存在之p-ACC或總ACC之量成比例的光信號。測定各樣品之p-ACC含量/總ACC含量之比率，且經AMPK活化劑處理之小鼠的p-ACC含量/總ACC含量之比率與經媒劑對照物處理之小鼠的比率相比顯著提高(顯著提高以p<0.05之差異描述)。To assess the potential of AMPK activators to increase phosphorylation of acetylcholine COA carboxylase (ACC) in liver and skeletal muscle, AMPK activators were administered to db/+ mice 2 hours or 7 hours prior to evaluation and compared at the time of evaluation. Phosphorylated ACC (p-ACC)/total ACC content in the tissues of vehicle treated mice and compound treated mice. Briefly, mice were anesthetized with gas anesthesia to administer 1% to 4% isoflurane via a nose cone. Once anesthesia, That is, a sample of the liver and skeletal muscle (gastrocnemius muscle) was removed, and snap frozen in liquid nitrogen, and homogenization was performed. The protein concentration of the homogenate was analyzed and the multi-array analysis kit of Meso Scale Discovery was used to assess the total ACC and phosphorylated ACC (p-ACC) content of the equal amounts of protein. The MSD assay plate contains an electrode surface coated with streptavidin. The protein sample binds to streptavidin. The primary ACC or p-ACC specific antibody binds to the protein, and the MSD SULFO-TAG labeled secondary antibody then binds to the primary antibody. The electrode surface of the MSD plate reacts to electrical stimulation and causes the SULFO-TAG tag bound to ACC and p-ACC to emit an optical signal proportional to the amount of p-ACC or total ACC present. The ratio of p-ACC content to total ACC content of each sample was determined, and the ratio of p-ACC content/total ACC content of mice treated with AMPK activator was significantly higher than the ratio of mice treated with vehicle control. Increase (significantly increased by a difference of p < 0.05).

生物實例3Biological example 3 在db/+小鼠中由AMPK活化劑抑制脂肪酸合成(FAS)：Inhibition of fatty acid synthesis (FAS) by AMPK activators in db/+ mice:

為確定AMPK活化劑對肝臟中脂肪酸合成(FAS)的影響，如Sakurai T,Miyazawa S,Shindo Y及T.Hashimoto(Biochim Biophys Acta.1974年9月19日；360(3)：275-88)所述，確定化合物之經口預給藥對併入肝臟三酸甘油酯中之3 H之量的影響。簡言之，在時間=-8小時時，向小鼠(db/+，Jackson Laboratory,Maine)經口給與AMPK活化劑。接著在時間=-1小時時，向小鼠每100 g體重注射0.5 ml含0.15 M NaCl之0.2 mCi3 H水。在時間0時，經由頸椎脫位法處死小鼠，且 收集肝臟以供FAS分析。為分析肝臟之FAS，在90℃下於4 M KOH/50%乙醇溶液中加熱肝臟樣品5小時。接著用己烷萃取肝臟之鹼性水解產物，且用10 M H2 SO4 酸化至pH<2。接著再用己烷自酸化之水解產物中萃取肝臟之脂肪酸，用暖空氣流完全乾燥，接著再懸浮於閃爍流體中，且在β計數器上計數。基於併入肝臟三酸甘油酯中之3 H之量來計算每公克肝臟所合成之脂肪酸的量。在經AMPK活化劑處理之小鼠中合成之經3 H放射性標記之脂肪酸的量顯著低於在對照小鼠中合成之經3 H放射性標記之脂肪酸的量。To determine the effects of AMPK activators on fatty acid synthesis (FAS) in the liver, such as Sakurai T, Miyazawa S, Shindo Y and T. Hashimoto (Biochim Biophys Acta. September 19, 1974; 360(3): 275-88) The effect of oral pre-administration of the compound on the amount of 3 H incorporated into the liver triglyceride is determined. Briefly, AMPK activators were orally administered to mice (db/+, Jackson Laboratory, Maine) at time = -8 hours. Next, at time = -1 hour, mice were injected with 0.5 ml of 0.2 mCi of 3 H water containing 0.15 M NaCl per 100 g of body weight. At time 0, mice were sacrificed by cervical dislocation and livers were collected for FAS analysis. To analyze the FAS of the liver, liver samples were heated in a 4 M KOH/50% ethanol solution at 90 ° C for 5 hours. The alkaline hydrolysate of the liver was then extracted with hexane and acidified to pH < 2 with 10 MH 2 SO 4 . The fatty acids of the liver were then extracted from the acidified hydrolysate with hexane, completely dried with a stream of warm air, then resuspended in a scintillation fluid and counted on a beta counter. The amount of fatty acid synthesized per gram of liver was calculated based on the amount of 3 H incorporated into the liver triglyceride. The amount of 3 H radiolabeled fatty acid synthesized in mice treated with AMPK activator was significantly lower than the amount of 3 H radiolabeled fatty acid synthesized in control mice.

生物實例4Biological example 4 在小鼠中用AMPK活化劑進行活體內療法研究(葡萄糖耐受性測試)：In vivo therapy studies (glucose tolerance test) with AMPK activators in mice:

用有效劑量之AMPK活化之蛋白激酶活化劑同時處理DIO小鼠。DIO mice were treated simultaneously with an effective amount of AMPK-activated protein kinase activator.

材料與方法：使用雄性C57BL/6NT小鼠(Taconic，在開始投與藥物時為16-18週齡)。向小鼠隨意提供水及高脂肪膳食D12492(Research Diet Inc.)。在1週的檢疫與適應期中，將小鼠保持在維持於23±2℃溫度、55±15%相對濕度及12小時光暗循環(7：00-19：00)之動物室中。接著每日兩次在9 AM及5 PM藉由經口管飼法向動物投與媒劑(5 ml/kg含0.5%甲基纖維素之蒸餾水)。9天後，觀測到穩定體重。次日(第-1天)，使小鼠禁食4小時，且尾部抽血以測定葡萄糖及胰島素含量。基於血漿葡萄糖、胰島素含量及體重將動物分組(n=8)。第0天記錄體重及料斗中之食物，隨後起始 化合物給藥。向一組經口投與媒劑，而向第二組每日兩次藉由管飼法投與30 mg/kg(5 ml/kg)劑量本發明之AMPK活化之蛋白激酶活化劑，持續12天。每隔一天量測體重及食物攝入量。第5天，使動物禁食4小時，以在早晨給藥後量測血漿葡萄糖及胰島素含量。第12天，量測體重及食物攝入量，且動物接受其最後一次早晨劑量。使小鼠再次禁食4小時，在設定時間點(t=0分鐘)收集血液，接著經口使用右旋糖(2 g/kg)攻擊(challenge)。由右旋糖攻擊後20分鐘及90分鐘獲取之尾部血液測定血漿葡萄糖及胰島素含量。使用自t=0至t=90分鐘之血漿葡萄糖及胰島素偏移型態對各處理之曲線下面積(AUC)進行積分。自針對餵食D7012之C57BL/6NT小鼠進行校正之AUC數據產生各處理之抑制百分比值。在口服葡萄糖耐受性測試期間，在給與0.1 mg/kg至100 mg/kg範圍內之口服劑量後，較佳本發明化合物顯著減小12天葡萄糖及/或胰島素AUC。Materials and Methods: Male C57BL/6NT mice (Taconic, 16-18 weeks of age at the start of drug administration) were used. The mice were provided with water and a high fat diet D12492 (Research Diet Inc.). During the 1-week quarantine and acclimation period, the mice were maintained in an animal room maintained at a temperature of 23 ± 2 °C, 55 ± 15% relative humidity, and a 12-hour light-dark cycle (7:00-19:00). The vehicle was then administered to the animals by oral gavage twice daily at 9 AM and 5 PM (5 ml/kg distilled water containing 0.5% methylcellulose). After 9 days, a stable body weight was observed. On the next day (Day-1), the mice were fasted for 4 hours and blood was drawn from the tail to determine glucose and insulin levels. Animals were grouped based on plasma glucose, insulin content, and body weight (n=8). Record the weight and food in the hopper on day 0, then start Administration of the compound. The vehicle was administered orally to a group, and the second group was administered twice daily by gavage at a dose of 30 mg/kg (5 ml/kg) of the AMPK-activated protein kinase activator of the present invention for 12 hours. day. Body weight and food intake were measured every other day. On day 5, the animals were fasted for 4 hours to measure plasma glucose and insulin levels after morning dosing. On day 12, body weight and food intake were measured and the animals received their last morning dose. Mice were again fasted for 4 hours, blood was collected at set time points (t = 0 minutes), and then dextrose (2 g/kg) challenge was orally administered. Plasma glucose and insulin levels were determined from the tail blood obtained 20 minutes and 90 minutes after the dextrose challenge. The area under the curve (AUC) of each treatment was integrated using plasma glucose and insulin offset patterns from t=0 to t=90 minutes. Corrected AUC data from C57BL/6NT mice fed D7012 yielded percent inhibition values for each treatment. Preferably, the compounds of the invention significantly reduce 12 days of glucose and/or insulin AUC after administration of an oral dose ranging from 0.1 mg/kg to 100 mg/kg during the oral glucose tolerance test.

生物實例5Biological example 5 在膳食誘發性肥胖(DIO)小鼠中進行短期食物攝入研究：通用程序Short-term food intake studies in diet-induced obesity (DIO) mice: a general procedure

在此等研究中使用成年DIO小鼠。在適應生態飼養條件(受控濕度及溫度，在24小時中光照12小時)至少2天後，自齧齒動物籠中移除食物D12492(Research Diet Inc.)。經口、腹膜內、皮下或靜脈內投與本發明AMPK活化劑或媒劑，隨後將已知量之食物送回至籠中。給藥與提供食物之間的最佳時間間隔係基於化合物之半衰期，該半衰期係基 於化合物之腦濃度達最高的時間。在若干時間間隔下量測食物剩餘量。以各時間間隔內每公克體重攝食之食物公克數計算食物攝入量，且將AMPK活化劑之食慾抑制作用與媒劑之作用相比較。經AMPK活化劑處理之小鼠的食物攝入量顯著小於對照小鼠之食物攝入量。Adult DIO mice were used in these studies. Food D12492 (Research Diet Inc.) was removed from rodent cages after adaptation to ecological feeding conditions (controlled humidity and temperature, 12 hours light in 24 hours) for at least 2 days. The AMPK activator or vehicle of the invention is administered orally, intraperitoneally, subcutaneously or intravenously, and then a known amount of food is returned to the cage. The optimal time interval between administration and food supply is based on the half-life of the compound, which is based on the half-life of the compound. The brain concentration of the compound reaches the highest time. The amount of food remaining was measured at several time intervals. The food intake was calculated as the number of grams of food per gram of body weight fed at each time interval, and the appetite suppression of the AMPK activator was compared to the effect of the vehicle. The food intake of mice treated with AMPK activator was significantly less than that of control mice.

生物實例6Biological example 6 在膳食誘發性肥胖(DIO)小鼠中進行長期重量減輕研究：通用程序Long-term weight loss study in diet-induced obesity (DIO) mice: general procedure

在此等研究中使用成年DIO小鼠。在斷乳時或斷乳後不久，大鼠或小鼠因排他性地獲取含有高於對照膳食中之脂肪及蔗糖比例之脂肪及蔗糖的膳食而變肥胖。用於誘發肥胖症之膳食為研究用膳食(Research Diets)D12451食糧(45%脂肪)。齧齒動物攝取食糧直至其顯著變重且體脂肪比例高於對照膳食大鼠，通常攝取9週。對齧齒動物經口、腹膜內、皮下或靜脈內注射(每日1至4次)或連續輸注本發明AMPK活化劑或媒劑。每日或以更高頻率量測食物攝入量及體重。以各時間間隔內每公克體重攝食之食物公克數計算食物攝入量，且將本發明AMPK活化劑之食慾抑制及重量減輕作用與媒劑之作用相比較。經AMPK活化劑處理之小鼠的重量減輕顯著大於對照小鼠之重量減輕。Adult DIO mice were used in these studies. At the time of weaning or shortly after weaning, the rat or mouse becomes obese by exclusively obtaining a diet containing fat and sucrose higher than the ratio of fat and sucrose in the control diet. The diet used to induce obesity was Research Diets D12451 food (45% fat). Rodents ingest food until they become significantly heavier and have a higher body fat ratio than control diet rats, usually for 9 weeks. The rodent is administered orally, intraperitoneally, subcutaneously or intravenously (1 to 4 times daily) or continuously infused with an AMPK activator or vehicle of the invention. Food intake and body weight are measured daily or at a higher frequency. The food intake was calculated as the number of grams of food per kilogram of body weight fed in each time interval, and the appetite suppression and weight loss effect of the AMPK activator of the present invention was compared with the effect of the vehicle. The weight loss of mice treated with AMPK activator was significantly greater than that of control mice.

儘管已參考本發明之某些特定實施例來描述及說明本發明，但熟習此項技術者應瞭解，在不脫離本發明之精神及範疇的情況下可作出各種改變、修改及替代。舉例而言，由於接受任何適應症治療之哺乳動物對上文所指示之本發 明化合物的反應性有變化，故除上文所闡述之特定劑量以外的有效劑量可能適用。同樣地，所觀測到的特定藥理學反應可根據且取決於所選特定活性化合物或是否存在醫藥學載劑，以及調配物類型及所用投藥模式而變化，且根據本發明之目的及實務涵蓋該等預期之結果變化或差異。因此，預期本發明係由以下申請專利範圍之範疇界定且該等申請專利範圍在合理範圍內廣義地解釋。Although the present invention has been described and illustrated with reference to the specific embodiments of the present invention, it will be understood by those skilled in the art that various changes, modifications and substitutions can be made without departing from the spirit and scope of the invention. For example, a mammal receiving any indication for treatment has the above indicated The reactivity of the compounds of the compounds varies, so that effective dosages other than the specific dosages set forth above may apply. Likewise, the particular pharmacological reaction observed can vary depending on and depending on the particular active compound selected or whether a pharmaceutical carrier is present, as well as the type of formulation and mode of administration employed, and encompasses the purpose and practice in accordance with the present invention. Such as expected changes or differences in results. Accordingly, the invention is intended to be defined by the scope of the appended claims

Claims (21)

一種結構式I之化合物， 或其醫藥學上可接受之鹽，其中：T係N；U係CR1 ；V係CR2 ；W係CR4 ，X係選自：(1)-O-，及(2)-O-CH2 -；Y係選自：(1)C3-10 環烷基，(2)C3-10 環烯基，(3)C2-10 環雜烷基，(4)C2-10 環雜烯基，(5)芳基，及(6)雜芳基，其中環烷基、環烯基、環雜烷基、環雜烯基、芳基及雜芳基未經取代或經1、2、3或4個選自Rb 之取代基取代；Z係選自： (1)側氧基(oxo)，(2)-CF3 ，(3)-C1-6 烷基，(4)-(CH2 )t -鹵素，(5)-(CH2 )n CO2 H，(6)-(CH2 )n OH，及(7)-(CH2 )n SO2 C1-6 烷基，其中各CH2 未經取代或經1或2個選自C1-6 烷基、-OH及-NH2 之取代基取代，且其中烷基係各自未經取代或經1、2、3或4個選自Rc 之取代基取代；R1 及R2 各自係獨立地選自：(1)氫，(2)鹵素，(3)CN，(4)CF3 ，(5)-C1-6 烷基，(6)-C2-6 烯基，(7)-C2-6 炔基，(8)-(CH2 )p C3-10 環烷基，(9)-(CH2 )p C3-7 環烷基-芳基，(10)-(CH2 )p C3-7 環烷基-雜芳基，(11)-(CH2 )p C4-10 環烯基，(12)-(CH2 )p C4-7 環烯基-芳基，(13)-(CH2 )p C4-7 環烯基-雜芳基， (14)-(CH2 )p C2-10 環雜烷基，(15)-(CH2 )p C2-10 環雜烯基，(16)-(CH2 )p 芳基，(17)-(CH2 )p 芳基-C1-8 烷基，(18)-(CH2 )p 芳基-C2-8 烯基，(19)-(CH2 )p 芳基-C2-8 炔基-C1-8 烷基，(20)-(CH2 )p 芳基-C2-8 炔基-C3-7 環烷基，(21)-(CH2 )p 芳基-C2-8 炔基-C3-7 環烯基，(22)-(CH2 )p 芳基-C2-8 炔基-C2-10 環雜烷基，(23)-(CH2 )p 芳基-C2-8 炔基-C2-10 環雜烯基，(24)-(CH2 )p 芳基-C2-8 炔基-芳基，(25)-(CH2 )p 芳基-C2-8 炔基-雜芳基，(26)-(CH2 )p 芳基-C3-7 環烷基，(27)-(CH2 )p 芳基-C2-10 環雜烷基，(28)-(CH2 )p 芳基-C2-10 環雜烯基，(29)-(CH2 )p 芳基-芳基，(30)-(CH2 )p 芳基-雜芳基，(31)-(CH2 )p 雜芳基，(32)-C2-6 烯基-烷基，(33)-C2-6 烯基-芳基，(34)-C2-6 烯基-雜芳基，(35)-C2-6 烯基-C3-7 環烷基，(36)-C2-6 烯基-C3-7 環烯基，(37)-C2-6 烯基-C2-7 環雜烷基， (38)-C2-6 烯基-C2-7 環雜烯基，(39)-C2-6 炔基-(CH2 )1-3 -O-芳基，(40)-C2-6 炔基-烷基，(41)-C2-6 炔基-芳基，(42)-C2-6 炔基-雜芳基，(43)-C2-6 炔基-C3-7 環烷基，(44)-C2-6 炔基-C3-7 環烯基，(45)-C2-6 炔基-C2-7 環雜烷基，(46)-C2-6 炔基-C2-7 環雜烯基，及(47)-C(O)NH-(CH2 )0-3 苯基，其中各CH2 未經取代或經1或2個選自以下之取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，其中烷基、烯基、炔基、環烷基、環烯基、環雜烷基、環雜烯基、苯基、芳基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代，其限制條件為R1 及R2 中之至少一者以及R1 及R2 中僅一者係選自由以下組成之群：氫、鹵素、-CN、-CF3 、-C1-6 烷基、-C2-6 烯基及-C2-6 炔基；R4 係各自獨立地選自：(1)氫，(2)鹵素，(3)-C1-6 烷基，(4)-C2-6 烯基， (5)-C2-6 炔基，(6)-CN，(7)-CF3 ，(8)-OH，(9)-OC1-6 烷基，(10)-NH2 ，(11)-NHC1-6 烷基，(12)-N(C1-6 烷基)2 ，(13)-SC1-6 烷基，(14)-SOC1-6 烷基，(15)-SO2 C1-6 烷基，(16)-NHSO2 C1-6 烷基，(17)-NHC(O)C1-6 烷基，(18)-SO2 NHC1-6 烷基，及(19)-C(O)NHC1-6 烷基；R5 係選自：(1)氫，(2)-C1-6 烷基，(3)-CH2 CO2 H，及(4)-CH2 CO2 C1-6 烷基；各Ra 係獨立地選自由以下組成之群：(1)-(CH2 )m -鹵素，(2)側氧基，(3)-(CH2 )m OH， (4)-(CH2 )m N(Rj )2 ，(5)-(CH2 )m NO2 ，(6)-(CH2 )m CN，(7)-C1-6 烷基，(8)-(CH2 )m CF3 ，(9)-(CH2 )m OCF3 ，(10)-O-(CH2 )m -OC1-6 烷基，(11)-(CH2 )m C(O)N(Rj )2 ，(12)-(CH2 )m C(=N-OH)N(Rj )2 ，(13)-(CH2 )m OC1-6 烷基，(14)-(CH2 )m O-(CH2 )m -C3-7 環烷基，(15)-(CH2 )m O-(CH2 )m -C2-7 環雜烷基，(16)-(CH2 )m O-(CH2 )m -芳基，(17)-(CH2 )m O-(CH2 )m -雜芳基，(18)-(CH2 )m SC1-6 烷基，(19)-(CH2 )m S(O)C1-6 烷基，(20)-(CH2 )m SO2 C1-6 烷基，(21)-(CH2 )m SO2 C3-7 環烷基，(22)-(CH2 )m SO2 C2-7 環雜烷基，(23)-(CH2 )m SO2 -芳基，(24)-(CH2 )m SO2 -雜芳基，(25)-(CH2 )m SO2 NHC1-6 烷基，(26)-(CH2 )m SO2 NHC3-7 環烷基，(27)-(CH2 )m SO2 NHC2-7 環雜烷基， (28)-(CH2 )m SO2 NH-芳基，(29)-(CH2 )m SO2 NH-雜芳基，(30)-(CH2 )m NHSO2 -C1-6 烷基，(31)-(CH2 )m NHSO2 -C3-7 環烷基，(32)-(CH2 )m NHSO2 -C2-7 環雜烷基，(33)-(CH2 )m NHSO2 -芳基，(34)-(CH2 )m NHSO2 NH-雜芳基，(35)-(CH2 )m N(Rj )-C1-6 烷基，(36)-(CH2 )m N(Rj )-C3-7 環烷基，(37)-(CH2 )m N(Rj )-C2-7 環雜烷基，(38)-(CH2 )m N(Rj )-C2-7 環雜烯基，(39)-(CH2 )m N(Rj )-芳基，(40)-(CH2 )m N(Rj )-雜芳基，(41)-(CH2 )m C(O)Rf ，(42)-(CH2 )m C(O)N(Rj )2 ，(43)-(CH2 )m N(Rj )C(O)N(Rj )2 ，(44)-(CH2 )m CO2 H，(45)-(CH2 )m OCOH，(46)-(CH2 )m CO2 Rf ，(47)-(CH2 )m OCORf ，(48)-(CH2 )m C3-7 環烷基，(49)-(CH2 )m C3-7 環烯基，(50)-(CH2 )m C2-6 環雜烷基，(51)-(CH2 )m C2-6 環雜烯基， (52)-(CH2 )m 芳基，及(53)-(CH2 )m 雜芳基，其中各CH2 未經取代或經1或2個選自以下之取代基取代：側氧基、-(CH2 )0-3 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基(CH3 )、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基，且其中烷基、環烷基、環烯基、環雜烷基、環雜烯基、芳基及雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-5 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-SO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基；各Rb 係獨立地選自：(1)氫，(2)-C1-6 烷基，(3)-C3-6 環烷基，(4)-C3-6 環烯基，(5)-C2-6 環雜烷基，(6)-C2-6 環雜烯基，(7)芳基，(8)雜芳基，(9)-(CH2 )t -鹵素，(10)-(CH2 )s -OH， (11)-NO2 ，(12)-NH2 ，(13)-NH(C1-6 烷基)，(14)-N(C1-6 烷基)2 ，(15)-OC1-6 烷基，(16)-(CH2 )q CO2 H，(17)-(CH2 )q CO2 C1-6 烷基，(18)-CF3 ，(19)-CN，(20)-SO2 C1-6 烷基，及(21)-(CH2 )s CON(Re )2 ，其中各CH2 未經取代或經1或2個鹵素取代，且其中烷基、環烷基、環烯基、環雜烷基、環雜烯基、芳基及雜芳基各自未經取代或經1、2或3個鹵素取代；各Rc 係獨立地選自：(1)鹵素，(2)側氧基，(3)-(CH2 )r OH，(4)-(CH2 )r N(Re )2 ，(5)-(CH2 )r CN，(6)-C1-6 烷基，(7)-CF3 ，(8)-C1-6 烷基-OH，(9)-OCH2 OC1-6 烷基， (10)-(CH2 )r OC1-6 烷基，(11)-OCH2 芳基，(12)-(CH2 )r SC1-6 烷基，(13)-(CH2 )r C(O)Rf ，(14)-(CH2 )r C(O)N(Re )2 ，(15)-(CH2 )r CO2 H，(16)-(CH2 )r CO2 Rf ，(17)-(CH2 )r C3-7 環烷基，(18)-(CH2 )r C2-6 環雜烷基，(19)-(CH2 )r 芳基，及(20)-(CH2 )r 雜芳基，其中各CH2 未經取代或經1或2個選自以下之取代基取代：側氧基、-OH、-CN、-N(Rh )2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基及雜芳基，且其中烷基、環烷基、環雜烷基、芳基及雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-OH、-CN、-N(Rh )2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基及雜芳基；Re 、Rg 及Rh 各自係獨立地選自：(1)氫，(2)-C1-6 烷基，及(3)-O-C1-6 烷基，其中烷基未經取代或經1、2、3或4個選自以下之取代基 取代：-OH、側氧基、鹵素、C1-6 烷基、-OC1-6 烷基、-NH2 、-NH(C1-6 烷基)及-N(C1-6 烷基)2 ；各Rj 係獨立地選自：(1)氫，(2)C1-6 烷基，(3)C3-6 環烷基，(4)-C(O)Ri ，及(5)-SO2 Ri ，其中烷基及環烷基未經取代或經1、2、3或4個選自以下之取代基取代：-OH、側氧基、鹵素、C1-6 烷基、-OC1-6 烷基、-NH2 、-NH(C1-6 烷基)及-N(C1-6 烷基)2 ；Rf 及Ri 各自係獨立地選自：(1)C1-6 烷基，(2)C4-7 環烷基，(3)C4-7 環烯基，(4)C3-7 環雜烷基，(5)C3-7 環雜烯基，(6)芳基，及(7)雜芳基，其中烷基、環烷基、環烯基、環雜烷基、環雜烯基、芳基及雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-OH、-CN、-NH2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基及雜芳基； 其中環雜烷基為各自具有2至14個碳原子且含有1、2、3、4或5個選自N、NH、O及S之雜原子的非芳族單環或雙環或橋連飽和碳環；環雜烯基意謂各自具有2至14個碳原子，含有至少一個雙鍵且含有1、2、3、4或5個選自N、NH、O及S之雜原子的非芳族單環或雙環或橋連環；及雜芳基意謂含有5至14個碳原子且含有1、2、3、4或5個選自N、NH、O及S之雜原子且至少一個含雜原子之環為芳族的單環、雙環或三環系統；n為0、1、2、3或4；m為0、1、2、3或4；p為0、1、2或3；q為0、1、2、3或4；r為0、1或2；s為0、1、2、3或4；且t為0、1、2、3或4。a compound of formula I, Or a pharmaceutically acceptable salt thereof, wherein: T is N; U is CR 1 ; V is CR 2 ; W is CR 4 , and X is selected from the group consisting of: (1)-O-, and (2)-O- CH 2 -; Y is selected from the group consisting of: (1) C 3-10 cycloalkyl, (2) C 3-10 cycloalkenyl, (3) C 2-10 cycloheteroalkyl, (4) C 2-10 a cycloheteroalkenyl group, a (5) aryl group, and (6) a heteroaryl group in which a cycloalkyl group, a cycloalkenyl group, a cycloheteroalkyl group, a cycloheteroalkenyl group, an aryl group, and a heteroaryl group are unsubstituted or subjected to 1 , 2, 3 or 4 substituents selected from R b ; Z is selected from the group consisting of: (1) pendant oxo (oxo), (2)-CF 3 , (3)-C 1-6 alkyl, 4) -(CH 2 ) t -halogen, (5)-(CH 2 ) n CO 2 H, (6)-(CH 2 ) n OH, and (7)-(CH 2 ) n SO 2 C 1- a 6 alkyl group in which each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from C 1-6 alkyl, -OH and -NH 2 , and wherein the alkyl groups are each unsubstituted or passed through 1, 2, 3 or 4 substituents selected from R c ; each of R 1 and R 2 is independently selected from: (1) hydrogen, (2) halogen, (3) CN, (4) CF 3 , (5) )-C 1-6 alkyl, (6)-C 2-6 alkenyl, (7)-C 2-6 alkynyl, (8)-(CH 2 ) p C 3-10 cycloalkyl, (9 )-(CH 2 ) p C 3-7 cycloalkyl-aryl, (10)-(CH 2 ) p C 3-7 cycloalkyl-heteroaryl, (11)-(CH 2 ) p C 4-10 cycloalkenyl, (12)-(CH 2 ) p C 4-7 cycloalkenyl-aryl, (13)-(CH 2 ) p C 4-7 cycloalkenyl-heteroaryl (14)-(CH 2 ) p C 2-10 cycloheteroalkyl, (15)-(CH 2 ) p C 2-10 cycloheteroalkenyl, (16)-(CH 2 ) p aryl, (17)-(CH 2 ) p aryl-C 1-8 alkyl, (18)-(CH 2 ) p aryl-C 2-8 alkenyl, (19)-(CH 2 ) p aryl- C 2-8 alkynyl-C 1-8 alkyl, (20)-(CH 2 ) p aryl-C 2-8 alkynyl-C 3-7 cycloalkyl, (21)-(CH 2 ) p Aryl-C 2-8 alkynyl-C 3-7 cycloalkenyl, (22)-(CH 2 ) p aryl-C 2-8 alkynyl-C 2-10 cycloheteroalkyl, (23)- (CH 2 ) p aryl-C 2-8 alkynyl-C 2-10 cycloheteroalkenyl, (24)-(CH 2 ) p aryl-C 2-8 alkynyl-aryl, (25)- (CH 2 ) p aryl-C 2-8 alkynyl-heteroaryl, (26)-(CH 2 ) p aryl-C 3-7 cycloalkyl, (27)-(CH 2 ) p aryl -C 2-10 cycloheteroalkyl, (28)-(CH 2 ) p aryl-C 2-10 cycloheteroalkenyl, (29)-(CH 2 ) p aryl-aryl, (30)- (CH 2 ) p aryl-heteroaryl, (31)-(CH 2 ) p heteroaryl, (32)-C 2-6 alkenyl-alkyl, (33)-C 2-6 alkenyl- Aryl, (34)-C 2-6 alkenyl-heteroaryl, (35)-C 2-6 alkenyl-C 3-7 cycloalkyl, (36)-C 2-6 alkenyl-C 3 -7 cycloalkenyl group, (37) -C 2-6 alkenyl, -C 2-7 cycloalkyl Alkyl, (38) -C 2-6 alkenyl, -C 2-7 alkenyl ring heteroaryl group, (39) -C 2-6 alkynyl, - (CH 2) 1-3 -O- aryl, (40) -C 2-6 alkynyl-alkyl, (41)-C 2-6 alkynyl-aryl, (42)-C 2-6 alkynyl-heteroaryl, (43)-C 2-6 alkynyl -C 3-7 cycloalkyl, (44)-C 2-6 alkynyl-C 3-7 cycloalkenyl, (45)-C 2-6 alkynyl-C 2-7 cycloheteroalkyl, (46 a -C 2-6 alkynyl-C 2-7 cycloheteroalkenyl group, and (47)-C(O)NH-(CH 2 ) 0-3 phenyl group, wherein each CH 2 is unsubstituted or 1 or Substituted by two substituents selected from the group consisting of halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl, and -N (C 1-6 alkyl) 2 , wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, phenyl, aryl and heteroaryl are each unsubstituted or by 3 or 4 substituents independently selected from the substituents R a, with the proviso that R 1 and R 2 in the 2, only one of the at least one selected from the group and R 1 and R consisting of Group: hydrogen, halogen, -CN, -CF 3 , -C 1-6 alkyl, -C 2-6 alkenyl and -C 2-6 alkynyl; R 4 are each independently selected from: (1) hydrogen , (2) halogen, (3)-C 1-6 alkyl, (4)-C 2-6 alkenyl, (5)-C 2-6 alkynyl, ( 6) -CN, (7)-CF 3 , (8)-OH, (9)-OC 1-6 alkyl, (10)-NH 2 , (11)-NHC 1-6 alkyl, (12) -N(C 1-6 alkyl) 2 , (13)-SC 1-6 alkyl, (14)-SOC 1-6 alkyl, (15)-SO 2 C 1-6 alkyl, (16) -NHSO 2 C 1-6 alkyl, (17)-NHC(O)C 1-6 alkyl, (18)-SO 2 NHC 1-6 alkyl, and (19)-C(O)NHC 1- 6 alkyl; R 5 is selected from: (1) hydrogen, (2)-C 1-6 alkyl, (3)-CH 2 CO 2 H, and (4)-CH 2 CO 2 C 1-6 alkane Each R a is independently selected from the group consisting of: (1)-(CH 2 ) m -halogen, (2) pendant oxy, (3)-(CH 2 ) m OH, (4)-( CH 2 ) m N(R j ) 2 , (5)-(CH 2 ) m NO 2 , (6)-(CH 2 ) m CN, (7)-C 1-6 alkyl, (8)-( CH 2 ) m CF 3 , (9)-(CH 2 ) m OCF 3 , (10)-O-(CH 2 ) m -OC 1-6 alkyl, (11)-(CH 2 ) m C(O N(R j ) 2 , (12)-(CH 2 ) m C(=N-OH)N(R j ) 2 , (13)-(CH 2 ) m OC 1-6 alkyl, (14) -(CH 2 ) m O-(CH 2 ) m -C 3-7 cycloalkyl, (15)-(CH 2 ) m O-(CH 2 ) m -C 2-7 cycloheteroalkyl, (16 )-(CH 2 ) m O-(CH 2 ) m -aryl, (17)-(CH 2 ) m O-(CH 2 ) m -heteroaryl, (18)-(CH 2 ) m SC 1 -6 alkyl, (19) - (CH 2 ) m S (O) C 1-6 alkyl, (20) - (CH 2 ) m SO 2 C 1-6 alkyl , (21) - (CH 2 ) m SO 2 C 3-7 cycloalkyl, (22) - (CH 2 ) m SO 2 C 2-7 cycloheteroalkyl, (23) - (CH 2 ) m SO 2 -aryl, (24)-(CH 2 ) m SO 2 -heteroaryl, (25)-(CH 2 ) m SO 2 NHC 1-6 alkyl, (26)-(CH 2 ) m SO 2 NHC 3-7 cycloalkyl, (27)-(CH 2 ) m SO 2 NHC 2-7 cycloheteroalkyl, (28)-(CH 2 ) m SO 2 NH-aryl, (29)-(CH 2 ) m SO 2 NH-heteroaryl, (30)-(CH 2 ) m NHSO 2 -C 1-6 alkyl, (31)-(CH 2 ) m NHSO 2 -C 3-7 cycloalkyl, (32)-(CH 2 ) m NHSO 2 -C 2-7cycloheteroalkyl , (33)-(CH 2 ) m NHSO 2 -aryl, (34)-(CH 2 ) m NHSO 2 NH- Aryl, (35)-(CH 2 ) m N(R j )-C 1-6 alkyl, (36)-(CH 2 ) m N(R j )-C 3-7 cycloalkyl, (37 )-(CH 2 ) m N(R j )-C 2-7cycloheteroalkyl , (38)-(CH 2 ) m N(R j )-C 2-7cycloheteroalkenyl , (39)- (CH 2 ) m N(R j )-aryl, (40)-(CH 2 ) m N(R j )-heteroaryl, (41)-(CH 2 ) m C(O)R f , ( 42) -(CH 2 ) m C(O)N(R j ) 2 , (43)-(CH 2 ) m N(R j )C(O)N(R j ) 2 , (44)-(CH 2 ) m CO 2 H, (45)-(CH 2 ) m OCOH, (46)-(CH 2 ) m CO 2 R f , (47)-(CH 2 ) m OCOR f , (48)-(CH 2) m C 3-7 cycloalkyl, (49) - (CH 2 ) m C 3-7 cycloalkyl Group, (50) - (CH 2 ) m C 2-6 cycloheteroalkyl, (51) - (CH 2 ) m C 2-6 cycloheteroalkyl group, (52) - (CH 2 ) m aryl, and (53) - (CH 2) m heteroaryl, wherein each of the CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from the substituents: oxo, - (CH 2) 0-3 OH , - CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C 1-6 alkyl (CH 3 ), -OC 1-6 alkyl, halogen , -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl, and wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or 1, 2, 3 or 4 are selected from Substituted by the following substituents: a pendant oxy group, -(CH 2 ) 0-5 OH, -CN, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -SO 2 C 1-6 alkyl, -C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl; each R b is independently selected from: (1) hydrogen, (2) -C 1-6 alkyl, (3) -C 3-6 cycloalkyl, (4) -C 3-6 cycloalkenyl, (5) -C 2-6 cycloalkyl Alkyl, (6) -C 2-6 cycloalkyl heteroalkenyl, (7) aryl, (8) heteroaryl, (9) - (CH 2 ) t - halo, (10) - (CH 2 ) s -OH, (11)-NO 2 , (12)-NH 2 , (13)-NH(C 1-6 alkyl), (14)-N(C 1-6 alkyl) 2 , (15)- OC 1-6 alkyl, (16)-(CH 2 ) q CO 2 H, (17)-(CH 2 ) q CO 2 C 1-6 alkyl, (18)-CF 3 , (19)-CN , (20)-SO 2 C 1-6 alkyl, and (21)-(CH 2 ) s CON(R e ) 2 , wherein each CH 2 is unsubstituted or substituted with 1 or 2 halogens, and wherein the alkane The base, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are each unsubstituted or substituted by 1, 2 or 3 halogens; each R c is independently selected from: (1) halogen, (2) pendant oxy group, (3)-(CH 2 ) r OH, (4)-(CH 2 ) r N(R e ) 2 , (5)-(CH 2 ) r CN, (6)-C 1-6 alkyl, (7)-CF 3 , (8)-C 1-6 alkyl-OH, (9)-OCH 2 OC 1-6 alkyl, (10)-(CH 2 ) r OC 1-6 alkyl, (11)-OCH 2 aryl, (12)-(CH 2 ) r SC 1-6 alkyl, (13)-(CH 2 ) r C(O)R f , (14)-(CH 2 ) r C(O)N(R e ) 2 , (15)-(CH 2 ) r CO 2 H, (16)-(CH 2 ) r CO 2 R f , (17 ) - (CH 2) r C 3-7 cycloalkyl, (18) - (CH 2 ) r C 2-6 cycloheteroalkyl, (19) - (CH 2 ) r Group, and (20) - (CH 2) r heteroaryl, wherein each of the CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from the substituents: oxo, -OH, -CN, -N ( R h ) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl a -C 3-7 cycloalkyl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the cycloheteroalkyl group, the aryl group and the heteroaryl group are unsubstituted or 1, 2, 3 or 4 are selected from the group consisting of Substituents substituted: pendant oxy, -OH, -CN, -N(R h ) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3-7 cycloalkyl and heteroaryl; R e , R g and R h are each independently selected from: (1) Hydrogen, (2)-C 1-6 alkyl, and (3)-OC 1-6 alkyl, wherein the alkyl group is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of: - OH, pendant oxy, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl) and -N(C 1-6 alkyl) 2 ; Each R j is independently selected from the group consisting of: (1) hydrogen, (2) C 1-6 alkyl, (3) C 3-6 cycloalkyl, (4)-C(O)R i , and (5) -SO 2 R i , wherein alkyl and cycloalkyl are unsubstituted or passed through 1 , 2, 3 or 4 substituents selected from the group consisting of: -OH, pendant oxy, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH (C 1-6 Alkyl) and -N(C 1-6 alkyl) 2 ; R f and R i are each independently selected from: (1) C 1-6 alkyl, (2) C 4-7 cycloalkyl, ( 3) C 4-7 cycloalkenyl, (4) C 3-7 cycloheteroalkyl, (5) C 3-7 cycloheteroalkenyl, (6) aryl, and (7) heteroaryl, wherein the alkane The group, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of pendant oxy groups , -OH, -CN, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 a C 1-6 alkyl group, a —C 3-7 cycloalkyl group, and a heteroaryl group; wherein the cycloheteroalkyl group has 2 to 14 carbon atoms each and contains 1, 2, 3, 4 or 5 selected from N, Non-aromatic monocyclic or bicyclic or bridged saturated carbocyclic rings of heteroatoms of NH, O and S; cycloheteroalkenyl means each having from 2 to 14 carbon atoms, containing at least one double bond and containing 1, 2, 3 , 4 or 5 non-aromatic monocyclic or bicyclic or bridged rings selected from heteroatoms of N, NH, O and S; and heteroaryl means a monocyclic, bicyclic or tricyclic ring having 5 to 14 carbon atoms and containing 1, 2, 3, 4 or 5 heteroatoms selected from N, NH, O and S and at least one hetero atom-containing ring being aromatic System; n is 0, 1, 2, 3 or 4; m is 0, 1, 2, 3 or 4; p is 0, 1, 2 or 3; q is 0, 1, 2, 3 or 4; r is 0, 1 or 2; s is 0, 1, 2, 3 or 4; and t is 0, 1, 2, 3 or 4. 如請求項1之化合物，其中：T係N；U係CR1 ；V係CR2 ；W係CR4 ，X係選自：(1)-O-，及(2)-O-CH2 -；Y係選自： (1)C3-10 環烷基，(2)C3-10 環烯基，(3)C2-10 環雜烷基，(4)C2-10 環雜烯基，(5)芳基，及(6)雜芳基，其中環烷基、環烯基、環雜烷基、環雜烯基、芳基及雜芳基未經取代或經1、2、3或4個選自Rb 之取代基取代；Z係選自：(1)側氧基，(2)-CF3 ，(3)-C1-6 烷基，(4)-(CH2 )t -鹵素，(5)-(CH2 )n CO2 H，(6)-(CH2 )n OH，及(7)-(CH2 )n SO2 C1-6 烷基，其中各CH2 未經取代或經1或2個選自C1-6 烷基、-OH及-NH2 之取代基取代，且其中烷基係各自未經取代或經1、2、3或4個選自Rc 之取代基取代；R1 及R2 各自係獨立地選自：(1)氫，(2)鹵素，(3)CN，(4)CF3 ， (5)-C1-6 烷基，(6)-C2-6 烯基，(7)-C2-6 炔基，(8)-(CH2 )p C3-10 環烷基，(9)-(CH2 )p C3-7 環烷基-芳基，(10)-(CH2 )p C3-7 環烷基-雜芳基，(11)-(CH2 )p C4-10 環烯基，(12)-(CH2 )p C4-7 環烯基-芳基，(13)-(CH2 )p C4-7 環烯基-雜芳基，(14)-(CH2 )p C2-10 環雜烷基，(15)-(CH2 )p C2-10 環雜烯基，(16)-(CH2 )p 芳基，(17)-(CH2 )p 芳基-C3-7 環烷基，(18)-(CH2 )p 芳基-C2-7 環雜烷基，(19)-(CH2 )p 芳基-芳基，(20)-(CH2 )p 芳基-雜芳基，(21)-(CH2 )p 雜芳基，(22)-C2-6 烯基-烷基，(23)-C2-6 烯基-芳基，(24)-C2-6 烯基-雜芳基，(25)-C2-6 烯基-C3-7 環烷基，(26)-C2-6 烯基-C3-7 環烯基，(27)-C2-6 烯基-C2-7 環雜烷基，(28)-C2-6 烯基-C2-7 環雜烯基， (29)-C2-6 炔基-(CH2 )1-3 -O-芳基，(30)-C2-6 炔基-烷基，(31)-C2-6 炔基-芳基，(32)-C2-6 炔基-雜芳基，(33)-C2-6 炔基-C3-7 環烷基，(34)-C2-6 炔基-C3-7 環烯基，(35)-C2-6 炔基-C2-7 環雜烷基，(36)-C2-6 炔基-C2-7 環雜烯基，及(37)-C(O)NH-(CH2 )0-3 苯基，其中各CH2 未經取代或經1或2個選自以下之取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，其中烷基、烯基及炔基各自未經取代或經1、2或3個選自以下之取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，且其中環烷基、環烯基、環雜烷基、環雜烯基、苯基、芳基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代，其限制條件為R1 及R2 中之至少一者以及R1 及R2 中僅一者係選自由以下組成之群：氫、鹵素、-CN、-CF3 、-C1-6 烷基、-C2-6 烯基及-C2-6 炔基；R4 係各自獨立地選自：(1)氫，(2)鹵素，(3)-C1-6 烷基， (4)-C2-6 烯基，(5)-C2-6 炔基，(6)-CN，(7)-CF3 ，(8)-OH，(9)-OC1-6 烷基，(10)-NH2 ，(11)-NHC1-6 烷基，(12)-N(C1-6 烷基)2 ，(13)-SC1-6 烷基，(14)-SOC1-6 烷基，(15)-SO2 C1-6 烷基，(16)-NHSO2 C1-6 烷基，(17)-NHC(O)C1-6 烷基，(18)-SO2 NHC1-6 烷基，及(19)-C(O)NHC1-6 烷基；R5 係選自：(1)氫，(2)-C1-6 烷基，(3)-CH2 CO2 H，及(4)-CH2 CO2 C1-6 烷基；各Ra 係獨立地選自由以下組成之群：(1)鹵素，(2)側氧基， (3)-(CH2 )m OH，(4)-(CH2 )m N(Rj )2 ，(5)-(CH2 )m NO2 ，(6)-(CH2 )m CN，(7)-C1-6 烷基，(8)-(CH2 )m CF3 ，(9)-(CH2 )m OCF3 ，(10)-OCH2 OC1-6 烷基，(11)-(CH2 )m C(O)N(Rj )2 ，(12)-(CH2 )m C(=N-OH)N(Rj )2 ，(13)-(CH2 )m OC1-6 烷基，(14)-(CH2 )m O-(CH2 )m -C3-7 環烷基，(15)-(CH2 )m O-(CH2 )m -C2-7 環雜烷基，(16)-(CH2 )m O-(CH2 )m -芳基，(17)-(CH2 )m O-(CH2 )m -雜芳基，(18)-(CH2 )m SC1-6 烷基，(19)-(CH2 )m S(O)C1-6 烷基，(20)-(CH2 )m SO2 C1-6 烷基，(21)-(CH2 )m SO2 C3-7 環烷基，(22)-(CH2 )m SO2 C2-7 環雜烷基，(23)-(CH2 )m SO2 -芳基，(24)-(CH2 )m SO2 -雜芳基，(25)-(CH2 )m SO2 NHC1-6 烷基，(26)-(CH2 )m SO2 NHC3-7 環烷基， (27)-(CH2 )m SO2 NHC2-7 環雜烷基，(28)-(CH2 )m SO2 NH-芳基，(29)-(CH2 )m SO2 NH-雜芳基，(30)-(CH2 )m NHSO2 -C1-6 烷基，(31)-(CH2 )m NHSO2 -C3-7 環烷基，(32)-(CH2 )m NHSO2 -C2-7 環雜烷基，(33)-(CH2 )m NHSO2 -芳基，(34)-(CH2 )m NHSO2 NH-雜芳基，(35)-(CH2 )m C(O)Rf ，(36)-(CH2 )m C(O)N(Rj )2 ，(37)-(CH2 )m N(Rj )C(O)N(Rj )2 ，(38)-(CH2 )m CO2 H，(39)-(CH2 )m OCOH，(40)-(CH2 )m CO2 Rf ，(41)-(CH2 )m OCORf ，(42)-(CH2 )m C3-7 環烷基，(43)-(CH2 )m C3-7 環烯基，(44)-(CH2 )m C2-6 環雜烷基，(45)-(CH2 )m C2-6 環雜烯基，(46)-(CH2 )m 芳基，及(47)-(CH2 )m 雜芳基，其中各CH2 未經取代或經1或2個選自以下之取代基取代：側氧基、-(CH2 )0-3 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F 、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基，且其中烷基、環烷基、環烯基、環雜烷基、環雜烯基、芳基及雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-(CH2 )0-3 OH、-CN、-NH2 、-NH(C1-6 烷基)、-N(C1-6 烷基)2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-SO2 C1-6 烷基、-C3-7 環烷基、苯基、CH2 苯基、雜芳基及CH2 雜芳基；各Rb 係獨立地選自：(1)氫，(2)-C1-6 烷基，(3)-C3-6 環烷基，(4)-C3-6 環烯基，(5)-C2-6 環雜烷基，(6)-C2-6 環雜烯基，(7)芳基，(8)雜芳基，(9)-(CH2 )t -鹵素，(10)-(CH2 )s -OH，(11)-NO2 ，(12)-NH2 ，(13)-NH(C1-6 烷基)，(14)-N(C1-6 烷基)2 ，(15)-OC1-6 烷基， (16)-(CH2 )q CO2 H，(17)-(CH2 )q CO2 C1-6 烷基，(18)-CF3 ，(19)-CN，(20)-SO2 C1-6 烷基，及(21)-(CH2 )s CON(Re )2 ，其中各CH2 未經取代或經1或2個鹵素取代，且其中烷基、環烷基、環烯基、環雜烷基、環雜烯基、芳基及雜芳基各自未經取代或經1、2或3個鹵素取代；各Rc 係獨立地選自：(1)鹵素，(2)側氧基，(3)-(CH2 )r OH，(4)-(CH2 )r N(Re )2 ，(5)-(CH2 )r CN，(6)-C1-6 烷基，(7)-CF3 ，(8)-C1-6 烷基-OH，(9)-OCH2 OC1-6 烷基，(10)-(CH2 )r OC1-6 烷基，(11)-OCH2 芳基，(12)-(CH2 )r SC1-6 烷基，(13)-(CH2 )r C(O)Rf ，(14)-(CH2 )r C(O)N(Re )2 ， (15)-(CH2 )r CO2 H，(16)-(CH2 )r CO2 Rf ，(17)-(CH2 )r C3-7 環烷基，(18)-(CH2 )r C2-6 環雜烷基，(19)-(CH2 )r 芳基，及(20)-(CH2 )r 雜芳基，其中各CH2 未經取代或經1或2個選自以下之取代基取代：側氧基、-OH、-CN、-N(Rh )2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基及雜芳基，且其中烷基、環烷基、環雜烷基、芳基及雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-OH、-CN、-N(Rh )2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基及雜芳基；Re 、Rg 及Rh 各自係獨立地選自：(1)氫，(2)-C1-6 烷基，及(3)-O-C1-6 烷基，其中烷基未經取代或經1、2、3或4個選自以下之取代基取代：-OH、側氧基、鹵素、C1-6 烷基、-OC1-6 烷基、-NH2 、-NH(C1-6 烷基)及-N(C1-6 烷基)2 ；各Rj 係獨立地選自：(1)氫，(2)C1-6 烷基， (3)C3-6 環烷基，(4)-C(O)Ri ，及(5)-SO2 Ri ，其中烷基及環烷基未經取代或經1、2、3或4個選自以下之取代基取代：-OH、側氧基、鹵素、C1-6 烷基、-OC1-6 烷基、-NH2 、-NH(C1-6 烷基)及-N(C1-6 烷基)2 ；Rf 及Ri 各自係獨立地選自：(1)C1-6 烷基，(2)C4-7 環烷基，(3)C4-7 環烯基，(4)C3-7 環雜烷基，(5)C3-7 環雜烯基，(6)芳基，及(7)雜芳基，其中烷基、環烷基、環烯基、環雜烷基、環雜烯基、芳基及雜芳基未經取代或經1、2、3或4個選自以下之取代基取代：側氧基、-OH、-CN、-NH2 、-C1-6 烷基、-OC1-6 烷基、鹵素、-CH2 F、-CHF2 、-CF3 、-CO2 H、-CO2 C1-6 烷基、-C3-7 環烷基及雜芳基；n為0、1、2、3或4；m為0、1、2、3或4；p為0、1、2或3；q為0、1、2、3或4；r為0、1或2； s為0、1、2、3或4；且t為0、1、2、3或4；或其醫藥學上可接受之鹽。The compound of claim 1, wherein: T is N; U is CR 1 ; V is CR 2 ; W is CR 4 , and X is selected from the group consisting of: (1)-O-, and (2)-O-CH 2 - Y is selected from the group consisting of: (1) C 3-10 cycloalkyl, (2) C 3-10 cycloalkenyl, (3) C 2-10 cycloheteroalkyl, (4) C 2-10 cyclohexene a (5) aryl group, and (6) a heteroaryl group in which a cycloalkyl group, a cycloalkenyl group, a cycloheteroalkyl group, a cycloheteroalkenyl group, an aryl group, and a heteroaryl group are unsubstituted or 1, 2, 3 or 4 substituents selected from R b ; Z is selected from the group consisting of: (1) pendant oxy, (2)-CF 3 , (3)-C 1-6 alkyl, (4)-(CH 2 T -halogen, (5)-(CH 2 ) n CO 2 H, (6)-(CH 2 ) n OH, and (7)-(CH 2 ) n SO 2 C 1-6 alkyl, each of which CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from C 1-6 alkyl, -OH and -NH 2 , and wherein the alkyl groups are each unsubstituted or 1, 2, 3 or 4 Substituted with a substituent selected from R c ; R 1 and R 2 are each independently selected from: (1) hydrogen, (2) halogen, (3) CN, (4) CF 3 , (5)-C 1-6 Alkyl, (6)-C 2-6 alkenyl, (7)-C 2-6 alkynyl, (8)-(CH 2 ) p C 3-10 cycloalkyl, (9)-(CH 2 ) p C 3-7 cycloalkyl-aryl, (10)-(CH 2 ) p C 3-7 cycloalkyl-heteroaryl, (11)-(CH 2 ) p C 4-10 Cycloalkenyl, (12)-(CH 2 ) p C 4-7 cycloalkenyl-aryl, (13)-(CH 2 ) p C 4-7 cycloalkenyl-heteroaryl, (14)-( CH 2 ) p C 2-10 cycloheteroalkyl, (15)-(CH 2 ) p C 2-10 cycloheteroalkenyl, (16)-(CH 2 ) p aryl, (17)-(CH 2 ) p -C 3-7 cycloalkyl, aryl, (18) - (CH 2 ) p aryl -C 2-7 cycloheteroalkyl, (19) - (CH 2 ) p aryl - aryl, ( 20) -(CH 2 ) p aryl-heteroaryl, (21)-(CH 2 ) p heteroaryl, (22)-C 2-6 alkenyl-alkyl, (23)-C 2-6 Alkenyl-aryl, (24)-C 2-6 alkenyl-heteroaryl, (25)-C 2-6 alkenyl-C 3-7 cycloalkyl, (26)-C 2-6 alkenyl -C 3-7 cycloalkenyl, (27)-C 2-6 alkenyl-C 2-7 cycloheteroalkyl, (28)-C 2-6 alkenyl-C 2-7 cycloheteroalkenyl, 29)-C 2-6 alkynyl-(CH 2 ) 1-3 -O-aryl, (30)-C 2-6 alkynyl-alkyl, (31)-C 2-6 alkynyl-aryl , (32)-C 2-6 alkynyl-heteroaryl, (33)-C 2-6 alkynyl-C 3-7 cycloalkyl, (34)-C 2-6 alkynyl-C 3-7 Cycloalkenyl, (35)-C 2-6 alkynyl-C 2-7 cycloheteroalkyl, (36)-C 2-6 alkynyl-C 2-7 cycloheteroalkenyl, and (37)-C (O)NH-(CH 2 ) 0-3 phenyl wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -O C 1-6 alkyl, -NHC 1-6 alkyl and -N(C 1-6 alkyl) 2 , wherein each of the alkyl, alkenyl and alkynyl groups is unsubstituted or selected from 1, 2 or 3 Substituted by the following substituents: halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl, and -N(C 1-6 alkane yl) 2, and wherein the cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, phenyl, aryl and heteroaryl, each unsubstituted or substituted by 3 or 4 substituents independently selected from since the R a substituents, with the proviso that R 1 and R 2 in the 2, only one line is selected from at least one of R and R 1 and the group consisting of: hydrogen, halogen, -CN, -CF 3 , -C 1-6 alkyl, -C 2-6 alkenyl and -C 2-6 alkynyl; R 4 are each independently selected from: (1) hydrogen, (2) halogen, (3)-C 1 -6 alkyl, (4)-C 2-6 alkenyl, (5)-C 2-6 alkynyl, (6)-CN, (7)-CF 3 , (8)-OH, (9)- OC 1-6 alkyl, (10)-NH 2 , (11)-NHC 1-6 alkyl, (12)-N(C 1-6 alkyl) 2 , (13)-SC 1-6 alkyl , (14)-SOC 1-6 alkyl, (15)-SO 2 C 1-6 alkyl, (16)-NHSO 2 C 1-6 alkyl, (17)-NHC(O)C 1-6 An alkyl group, (18)-SO 2 NHC 1-6 alkyl, and (19)-C(O)NHC 1-6 alkyl; R 5 is selected from the group consisting of: (1) hydrogen, (2)-C 1-6 alkyl, (3)-CH 2 CO 2 H, and (4)-CH 2 CO 2 C 1-6 alkyl; each R a is independently selected from Groups of the following: (1) halogen, (2) pendant oxy, (3)-(CH 2 ) m OH, (4)-(CH 2 ) m N(R j ) 2 , (5)-(CH 2 ) m NO 2 , (6)-(CH 2 ) m CN, (7)-C 1-6 alkyl, (8)-(CH 2 ) m CF 3 , (9)-(CH 2 ) m OCF 3 , (10)-OCH 2 OC 1-6 alkyl, (11)-(CH 2 ) m C(O)N(R j ) 2 , (12)-(CH 2 ) m C(=N-OH N(R j ) 2 , (13)-(CH 2 ) m OC 1-6 alkyl, (14)-(CH 2 ) m O-(CH 2 ) m -C 3-7 cycloalkyl, ( 15)-(CH 2 ) m O-(CH 2 ) m -C 2-7cycloheteroalkyl , (16)-(CH 2 ) m O-(CH 2 ) m -aryl, (17)-( CH 2 ) m O-(CH 2 ) m -heteroaryl, (18)-(CH 2 ) m SC 1-6 alkyl, (19)-(CH 2 ) m S(O)C 1-6 alkane Base, (20)-(CH 2 ) m SO 2 C 1-6 alkyl, (21)-(CH 2 ) m SO 2 C 3-7 cycloalkyl, (22)-(CH 2 ) m SO 2 C 2-7 cycloheteroalkyl, (23)-(CH 2 ) m SO 2 -aryl, (24)-(CH 2 ) m SO 2 -heteroaryl, (25)-(CH 2 ) m SO 2 NHC 1-6 alkyl, (26)-(CH 2 ) m SO 2 NHC 3-7 cycloalkyl, (27)-(CH 2 ) m SO 2 NHC 2-7 cycloheteroalkyl, (28) -(CH 2 ) m SO 2 NH-aryl, (29)-(CH 2 ) m SO 2 NH-heteroaryl, (30)-(CH 2 ) m NHSO 2 -C 1-6 alkyl, (31)-(CH 2 ) m NHSO 2 -C 3-7 cycloalkyl, (32)- (CH 2 ) m NHSO 2 -C 2-7cycloheteroalkyl , (33)-(CH 2 ) m NHSO 2 -aryl, (34)-(CH 2 ) m NHSO 2 NH-heteroaryl, 35)-(CH 2 ) m C(O)R f , (36)-(CH 2 ) m C(O)N(R j ) 2 , (37)-(CH 2 ) m N(R j )C (O)N(R j ) 2 , (38)-(CH 2 ) m CO 2 H, (39)-(CH 2 ) m OCOH, (40)-(CH 2 ) m CO 2 R f , (41 )-(CH 2 ) m OCOR f , (42)-(CH 2 ) m C 3-7 cycloalkyl, (43)-(CH 2 ) m C 3-7 cycloalkenyl, (44)-(CH 2 ) m C 2-6 cycloheteroalkyl, (45)-(CH 2 ) m C 2-6 cycloheteroalkenyl, (46)-(CH 2 ) m aryl, and (47)-(CH 2 a m heteroaryl group, wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of pendant oxy, -(CH 2 ) 0-3 OH, -CN, -NH 2 , -NH (C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F , -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl, and wherein alkyl, ring Alkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl The group is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of pendant oxy, -(CH 2 ) 0-3 OH, -CN, -NH 2 , -NH(C 1-6 Alkyl), -N(C 1-6 alkyl) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -SO 2 C 1-6 alkyl, -C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl; R b is independently selected from the group consisting of: (1) hydrogen, (2)-C 1-6 alkyl, (3)-C 3-6 cycloalkyl, (4)-C 3-6 cycloalkenyl, (5) )-C 2-6 cycloheteroalkyl, (6)-C 2-6 cycloheteroalkenyl, (7) aryl, (8) heteroaryl, (9)-(CH 2 ) t -halogen, ( 10)-(CH 2 ) s -OH, (11)-NO 2 , (12)-NH 2 , (13)-NH(C 1-6 alkyl), (14)-N (C 1-6 alkane 2 )(15)-OC 1-6 alkyl, (16)-(CH 2 ) q CO 2 H, (17)-(CH 2 ) q CO 2 C 1-6 alkyl, (18)- CF 3 , (19)-CN, (20)-SO 2 C 1-6 alkyl, and (21)-(CH 2 ) s CON(R e ) 2 , wherein each CH 2 is unsubstituted or 1 or 2 halogen substituted, and wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are each unsubstituted or substituted with 1, 2 or 3 halogens; R c independent system Selected from: (1) halogen, (2) oxo, (3) - (CH 2 ) r OH, (4) - (CH 2) r N (R e) 2, (5) - (CH 2 r CN,(6)-C 1-6 alkyl, (7)-CF 3 , (8)-C 1-6 alkyl-OH, (9)-OCH 2 OC 1-6 alkyl, (10 )-(CH 2 ) r OC 1-6 alkyl, (11)-OCH 2 aryl, (12)-(CH 2 ) r SC 1-6 alkyl, (13)-(CH 2 ) r C( O) R f , (14)-(CH 2 ) r C(O)N(R e ) 2 , (15)-(CH 2 ) r CO 2 H, (16)-(CH 2 ) r CO 2 R f , (17)-(CH 2 ) r C 3-7 cycloalkyl, (18)-(CH 2 ) r C 2-6 cycloheteroalkyl, (19)-(CH 2 ) r aryl, (20)-(CH 2 ) rheteroaryl , wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of pendant oxy, -OH, -CN, -N(R h ) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3-7 cycloalkyl and heteroaryl, and wherein alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted or have 1, 2, 3 or 4 substituents selected from Substitution: pendant oxy, -OH, -CN, -N(R h ) 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen, -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3- 7 cycloalkyl and heteroaryl; R e , R g and R h are each independently selected from: (1) hydrogen, (2)-C 1-6 alkyl, and (3)-OC 1-6 alkane a group wherein the alkyl group is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of -OH, pendant oxy, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl) and -N(C 1-6 alkyl) 2 ; each R j is independently selected from: (1) hydrogen, (2) C 1-6 alkyl (3) C 3-6 cycloalkyl, (4)-C(O)R i , and (5)-SO 2 R i wherein the alkyl group and the cycloalkyl group are unsubstituted or 1, 2, 3 Or 4 substituents selected from the group consisting of: -OH, pendant oxy, halogen, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl) and -N(C 1-6 alkyl) 2 ; R f and R i are each independently selected from: (1) C 1-6 alkyl, (2) C 4-7 cycloalkyl, (3) C 4 -7 cycloalkenyl, (4) C 3-7 cycloheteroalkyl, (5) C 3-7 cycloheteroalkenyl, (6) aryl, and (7) heteroaryl, wherein alkyl, naphthenic The base, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of pendant oxy groups, -OH, -CN, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, halogen , -CH 2 F, -CHF 2 , -CF 3 , -CO 2 H, -CO 2 C 1-6 alkyl, -C 3-7 cycloalkyl and heteroaryl; n is 0, 1, 2 3 or 4; m is 0, 1, 2, 3 or 4; p is 0, 1, 2 or 3; q is 0, 1, 2, 3 or 4; r is 0, 1 or 2; s is 0, 1, 2, 3 or 4; and t is 0, 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof. 如請求項2之化合物，其中X為-O-；或其醫藥學上可接受之鹽。 The compound of claim 2, wherein X is -O-; or a pharmaceutically acceptable salt thereof. 如請求項2之化合物，其中Y係選自：(1)C3-10 環烷基，(2)C2-10 環雜烷基，及(3)芳基，其中環烷基、環雜烷基及芳基未經取代或經1、2、3或4個選自Rb 之取代基取代；或其醫藥學上可接受之鹽。The compound of claim 2, wherein Y is selected from the group consisting of: (1) C 3-10 cycloalkyl, (2) C 2-10 cycloheteroalkyl, and (3) aryl, wherein cycloalkyl, cyclohexane The alkyl and aryl groups are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R b ; or a pharmaceutically acceptable salt thereof. 如請求項4之化合物，其中Y係選自：(1)C3-7 環烷基，(2)C2-10 環雜烷基，及(3)苯基，其中環烷基、環雜烷基及苯基各自未經取代或經1、2、3或4個選自Rb 之取代基取代；或其醫藥學上可接受之鹽。The compound of claim 4, wherein Y is selected from the group consisting of: (1) C 3-7 cycloalkyl, (2) C 2-10 cycloheteroalkyl, and (3) phenyl, wherein cycloalkyl, cyclohexane The alkyl group and the phenyl group are each unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R b ; or a pharmaceutically acceptable salt thereof. 如請求項2之化合物，其中Z係選自：(1)-(CH2 )n CO2 H，及(2)-(CH2 )n OH，其中各CH2 未經取代或經1或2個選自C1-6 烷基、-OH及-NH2 之取代基取代；或其醫藥學上可接受之鹽。The compound of claim 2, wherein the Z is selected from the group consisting of: (1)-(CH 2 ) n CO 2 H, and (2)-(CH 2 ) n OH, wherein each CH 2 is unsubstituted or 1 or 2 Substituted with a substituent selected from C 1-6 alkyl, -OH and -NH 2 ; or a pharmaceutically acceptable salt thereof. 如請求項1之化合物，其中R1 及R2 各自係獨立地選自： (1)鹵素，(2)-C4-10 環烯基，(3)-苯基，(4)-苯基-C2-8 炔基-C1-8 烷基，(5)-苯基-C2-3 炔基-C3-7 環烷基，(6)-苯基-C2-3 炔基-C2-10 環雜烷基，(7)-苯基-C3-7 環烷基，(8)-苯基-C2-7 環雜烷基，(9)-苯基-C2-10 環雜烯基，(10)-苯基-芳基，(11)-苯基-雜芳基，(12)-雜芳基，及(13)-C2-6 炔基-苯基，且其中烷基、炔基、環烷基、環烯基、環雜烷基、環雜烯基、苯基、芳基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代，其限制條件為R1 及R2 中之至少一者以及R1 及R2 中僅一者係選自鹵素；或其醫藥學上可接受之鹽。The compound of claim 1, wherein each of R 1 and R 2 is independently selected from the group consisting of: (1) halogen, (2)-C 4-10 cycloalkenyl, (3)-phenyl, (4)-phenyl -C 2-8 alkynyl-C 1-8 alkyl, (5)-phenyl-C 2-3 alkynyl-C 3-7 cycloalkyl, (6)-phenyl-C 2-3 alkynyl -C 2-10 cycloheteroalkyl, (7)-phenyl-C 3-7 cycloalkyl, (8)-phenyl-C 2-7 cycloheteroalkyl, (9)-phenyl-C 2 -10 cycloheteroalkenyl, (10)-phenyl-aryl, (11)-phenyl-heteroaryl, (12)-heteroaryl, and (13)-C 2-6 alkynyl-phenyl And wherein alkyl, alkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, phenyl, aryl and heteroaryl are each unsubstituted or 1, 2, 3 or 4 R a is independently selected from the substituents, with the proviso that R 1 and R 2 in the 2, only one of the lines and at least one of R 1 and R is selected from halogen; or a pharmaceutically acceptable salt thereof. 如請求項7之化合物，其中R1 係獨立地選自：(1)-C4-10 環烯基，(2)-苯基，(3)-苯基-C2 炔基C1-5 烷基，(4)-苯基-C2-3 炔基-C3-7 環烷基，(5)-苯基-C2-3 炔基-C2-10 環雜烷基， (6)-苯基-C3-7 環烷基，(7)-苯基-C2-7 環雜烷基，(8)-苯基-C2-10 環雜烯基，(9)-苯基-苯基，(10)-苯基-雜芳基，(11)-雜芳基，及(12)-C2-6 炔基-苯基，其中烷基、炔基、環烷基、環烯基、環雜烷基、環雜烯基、苯基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代；且R2 係選自鹵素；或其醫藥學上可接受之鹽。The compound of claim 7, wherein R 1 is independently selected from the group consisting of: (1)-C 4-10 cycloalkenyl, (2)-phenyl, (3)-phenyl-C 2 alkynyl C 1-5 Alkyl, (4)-phenyl-C 2-3 alkynyl-C 3-7 cycloalkyl, (5)-phenyl-C 2-3 alkynyl-C 2-10 cycloheteroalkyl, (6 )-phenyl-C 3-7 cycloalkyl, (7)-phenyl-C 2-7 cycloheteroalkyl, (8)-phenyl-C 2-10 cycloheteroalkenyl, (9)-benzene -Phenyl, (10)-phenyl-heteroaryl, (11)-heteroaryl, and (12)-C 2-6 alkynyl-phenyl, wherein alkyl, alkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, phenyl and heteroaryl, each unsubstituted or substituted by three or four of independently selected R a substituents; and R 2 is selected from the group From halogen; or a pharmaceutically acceptable salt thereof. 如請求項8之化合物，其中各R1 係獨立地選自：(1)-苯基-C2-7 環雜烷基，(2)-苯基-C2-10 環雜烯基，(3)-苯基-苯基，及(4)-苯基-雜芳基，其中環雜烷基、環雜烯基、雜芳基及苯基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代；且R2 為鹵素；或其醫藥學上可接受之鹽。The compound of claim 8, wherein each R 1 is independently selected from the group consisting of: (1)-phenyl-C 2-7 cycloheteroalkyl, (2)-phenyl-C 2-10 cycloheteroalkenyl, 3) -phenyl-phenyl, and (4)-phenyl-heteroaryl, wherein the cycloheteroalkyl, cycloheteroalkenyl, heteroaryl and phenyl are each unsubstituted or 1, 2, 3 or 4 substituents independently selected from R a ; and R 2 are halogen; or a pharmaceutically acceptable salt thereof. 如請求項2之化合物，其中R1 及R2 各自係獨立地選自：(1)鹵素，(2)-C4-10 環烯基， (3)-苯基，(4)-苯基-C3-7 環烷基，(5)-苯基-C2-7 環雜烷基，(6)-苯基-芳基，(7)-苯基-雜芳基，(8)-雜芳基，及(9)-C2-6 炔基-苯基，其中各炔基未經取代或經1、2或3個選自以下之取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，且其中環烷基、環烯基、環雜烷基、苯基、芳基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代，其限制條件為R1 及R2 中之至少一者以及R1 及R2 中僅一者係選自鹵素；或其醫藥學上可接受之鹽。The compound of claim 2, wherein each of R 1 and R 2 is independently selected from the group consisting of: (1) halogen, (2)-C 4-10 cycloalkenyl, (3)-phenyl, (4)-phenyl -C 3-7 cycloalkyl, (5)-phenyl-C 2-7 cycloheteroalkyl, (6)-phenyl-aryl, (7)-phenyl-heteroaryl, (8)- a heteroaryl group, and (9)-C 2-6 alkynyl-phenyl, wherein each alkynyl group is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl and -N(C 1-6 alkyl) 2 , and wherein cycloalkyl, cycloalkenyl, The cycloheteroalkyl, phenyl, aryl and heteroaryl are each unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from R a , with the limitation of R 1 and R 2 At least one and only one of R 1 and R 2 are selected from halogen; or a pharmaceutically acceptable salt thereof. 如請求項10之化合物，其中R1 係獨立地選自：(1)-C4-10 環烯基，(2)-苯基，(3)-苯基-C3-7 環烷基，(4)-苯基-C2-7 環雜烷基，(5)-苯基-苯基，(6)-苯基-雜芳基，(7)-雜芳基，及(8)-C2-6 炔基-苯基，其中各炔基未經取代或經1、2或3個選自以下之取代基 取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，且其中環烷基、環烯基、環雜烷基、苯基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代；且R2 係選自：鹵素；或其醫藥學上可接受之鹽。The compound of claim 10, wherein R 1 is independently selected from the group consisting of: (1)-C 4-10 cycloalkenyl, (2)-phenyl, (3)-phenyl-C 3-7 cycloalkyl, (4)-Phenyl-C 2-7 cycloheteroalkyl, (5)-phenyl-phenyl, (6)-phenyl-heteroaryl, (7)-heteroaryl, and (8)- C 2-6 alkynyl-phenyl, wherein each alkynyl group is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, CF 3 , -OH, -NH 2 , -C 1-6 Alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl and -N(C 1-6 alkyl) 2 , and wherein cycloalkyl, cycloalkenyl, cycloheteroalkyl, phenyl and hetero The aryl groups are each unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R a ; and R 2 is selected from: halogen; or a pharmaceutically acceptable salt thereof. 如請求項11之化合物，其中各R1 係獨立地選自：(1)-苯基-C2-7 環雜烷基，及(2)-苯基-苯基，其中環雜烷基及苯基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代，且R2 係選自鹵素；或其醫藥學上可接受之鹽。The compound of claim 11, wherein each R 1 is independently selected from the group consisting of: (1)-phenyl-C 2-7 cycloheteroalkyl, and (2)-phenyl-phenyl, wherein the cycloheteroalkyl group The phenyl groups are each unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from R a , and R 2 is selected from halogen; or a pharmaceutically acceptable salt thereof. 如請求項2之化合物，其中R4 為氫；且R5 為氫；或其醫藥學上可接受之鹽。The compound of claim 2, wherein R 4 is hydrogen; and R 5 is hydrogen; or a pharmaceutically acceptable salt thereof. 如請求項1之化合物，其中：T為N；U為-CR1 -；V為-CR2 -；W為-CR4 -；X係選自：(1)-O-，及(2)-O-CH2 -；Y係選自： (1)-C3-10 環烷基，(2)-C2-10 環雜烷基，及(3)-苯基，其中環烷基、環雜烷基及苯基未經取代或經1、2、3或4個選自Rb 之取代基取代；Z係選自：(1)側氧基，(2)-CF3 ，(3)-C1-6 烷基，(4)-(CH2 )t -鹵素，(5)-(CH2 )n CO2 H，(6)-(CH2 )n OH，及(7)-(CH2 )n SO2 C1-6 烷基，其中各CH2 未經取代或經1或2個選自C1-6 烷基、-OH及-NH2 之取代基取代，且其中各烷基未經取代或經1、2、3或4個選自Rc 之取代基取代；R1 係獨立地選自：(1)-C4-10 環烯基，(2)-苯基，(3)-苯基-C2 炔基C1-5 烷基，(4)-苯基-C2-3 炔基-C3-7 環烷基，(5)-苯基-C2-3 炔基-C2-10 環雜烷基，(6)-苯基-C3-7 環烷基，(7)-苯基-C2-7 環雜烷基， (8)-苯基-C2-10 環雜烯基，(9)-苯基-苯基，(10)-苯基-雜芳基，(11)-雜芳基，及(12)-C2-6 炔基-苯基，其中烷基、炔基、環烷基、環烯基、環雜烷基、環雜烯基、苯基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代；R2 係選自鹵素；R4 為氫；且R5 為氫；或其醫藥學上可接受之鹽。The compound of claim 1, wherein: T is N; U is -CR 1 -; V is -CR 2 -; W is -CR 4 -; and X is selected from the group consisting of: (1)-O-, and (2) -O-CH 2 -; Y is selected from the group consisting of: (1)-C 3-10 cycloalkyl, (2)-C 2-10 cycloheteroalkyl, and (3)-phenyl, wherein cycloalkyl, The cycloheteroalkyl and phenyl groups are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R b ; the Z series is selected from: (1) pendant oxy group, (2)-CF 3 , (3) )-C 1-6 alkyl, (4)-(CH 2 ) t -halogen, (5)-(CH 2 ) n CO 2 H, (6)-(CH 2 ) n OH, and (7)- (CH 2 ) n SO 2 C 1-6 alkyl, wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from C 1-6 alkyl, -OH and -NH 2 , and each The alkyl group is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R c ; R 1 is independently selected from: (1)-C 4-10 cycloalkenyl, (2)-phenyl , (3)-phenyl-C 2 alkynyl C 1-5 alkyl, (4)-phenyl-C 2-3 alkynyl-C 3-7 cycloalkyl, (5)-phenyl-C 2 -3 alkynyl-C 2-10 cycloheteroalkyl, (6)-phenyl-C 3-7 cycloalkyl, (7)-phenyl-C 2-7 cycloheteroalkyl, (8)-benzene -C 2-10cycloheteroalkenyl , (9)-phenyl-phenyl, (10)-phenyl-heteroaryl, (11)-heteroaryl, and (12)-C 2-6 alkyne Base-phenyl, Alkyl, alkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, phenyl and heteroaryl, each unsubstituted or substituted by 3 or 4 substituents independently selected from R the group substituted with a substituent; R 2 is selected from halo; R 4 is hydrogen; and R 5 is hydrogen; or a pharmaceutically acceptable salt thereof. 如請求項2之化合物，其中：T為N；U為-CR1 -；V為-CR2 -；W為-CR4 -；X係選自：(1)-O-，及(2)-O-CH2 -；Y係選自：(1)C3-10 環烷基，(2)C2-10 環雜烷基，及(3)苯基， 其中環烷基、環雜烷基及苯基未經取代或經1、2、3或4個選自Rb 之取代基取代；Z係選自：(1)側氧基，(2)-CF3 ，(3)-C1-6 烷基，(4)-(CH2 )t -鹵素，(5)-(CH2 )n CO2 H，(6)-(CH2 )n OH，及(7)-(CH2 )n SO2 C1-6 烷基，其中各CH2 未經取代或經1或2個選自C1-6 烷基、-OH及-NH2 之取代基取代，且其中各烷基未經取代或經1、2、3或4個選自Rc 之取代基取代；R1 係獨立地選自：(1)-C4-10 環烯基，(2)-苯基，(3)-苯基-C3-7 環烷基，(4)-苯基-C2-7 環雜烷基，(5)-苯基-雜芳基，(6)-苯基-苯基，(7)-雜芳基，及(8)-C2-6 炔基-苯基，其中各炔基未經取代或經1、2或3個選自以下之取代基取代：鹵素、CF3 、-OH、-NH2 、-C1-6 烷基、-OC1-6 烷 基、-NHC1-6 烷基及-N(C1-6 烷基)2 ，且其中環烷基、環烯基、環雜烷基、苯基及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代；R2 係選自鹵素；R4 為氫；且R5 為氫；或其醫藥學上可接受之鹽。The compound of claim 2, wherein: T is N; U is -CR 1 -; V is -CR 2 -; W is -CR 4 -; X is selected from the group consisting of: (1)-O-, and (2) -O-CH 2 -; Y is selected from the group consisting of: (1) C 3-10 cycloalkyl, (2) C 2-10 cycloheteroalkyl, and (3) phenyl, wherein cycloalkyl, cyclohexane The base and the phenyl group are unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from R b ; the Z series is selected from: (1) pendant oxy group, (2)-CF 3 , (3)-C 1-6 alkyl, (4)-(CH 2 ) t -halogen, (5)-(CH 2 ) n CO 2 H, (6)-(CH 2 ) n OH, and (7)-(CH 2 n SO 2 C 1-6 alkyl, wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from C 1-6 alkyl, -OH and -NH 2 , and wherein each alkyl group is not Substituted or substituted with 1, 2, 3 or 4 substituents selected from R c ; R 1 is independently selected from: (1)-C 4-10 cycloalkenyl, (2)-phenyl, (3 )-phenyl-C 3-7 cycloalkyl, (4)-phenyl-C 2-7 cycloheteroalkyl, (5)-phenyl-heteroaryl, (6)-phenyl-phenyl, (7)-heteroaryl, and (8)-C 2-6 alkynyl-phenyl, wherein each alkynyl group is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, CF 3 , -OH, -NH 2 , -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl and -N(C 1-6 alkyl) 2 , and wherein each of the cycloalkyl, cycloalkenyl, cycloheteroalkyl, phenyl and heteroaryl groups is unsubstituted or independently selected 1, 2, 3 or 4 since the R a substituents; R 2 is selected from halo; R 4 is hydrogen; and R 5 is hydrogen; or a pharmaceutically acceptable salt thereof. 如請求項2之化合物，其中：T為N；U為-CR1 -；V為-CR2 -；W為-CR4 -；X為-O-；Y係選自：(1)C3-7 環烷基，(2)C2-10 環雜烷基，及(3)苯基，其中環烷基、環雜烷基及苯基各自未經取代或經1、2、3或4個選自Rb 之取代基取代；Z係選自：(1)-(CH2 )n CO2 H，及(2)-(CH2 )n OH，其中各CH2 未經取代或經1或2個選自C1-6 烷基及-OH之取代基取代； R1 係選自：(1)-苯基-C2-7 環雜烷基，及(2)-苯基-苯基，其中環雜烷基及苯基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代；R2 係選自鹵素；R4 為氫；且R5 為氫；或其醫藥學上可接受之鹽。The compound of claim 2, wherein: T is N; U is -CR 1 -; V is -CR 2 -; W is -CR 4 -; X is -O-; and Y is selected from: (1) C 3 -7 cycloalkyl, (2) C 2-10 cycloheteroalkyl, and (3) phenyl wherein cycloalkyl, cycloheteroalkyl and phenyl are each unsubstituted or 1, 2, 3 or 4 Substituted from a substituent selected from R b ; Z is selected from the group consisting of: (1)-(CH 2 ) n CO 2 H, and (2)-(CH 2 ) n OH, wherein each CH 2 is unsubstituted or subjected to 1 or 2 substituents selected from the C 1-6 alkyl and -OH substituents; R & lt 1 selected from: (1) - phenyl -C 2-7 cycloheteroalkyl, and (2) - phenyl - phenyl a group wherein the cycloheteroalkyl group and the phenyl group are each unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from R a ; R 2 is selected from halogen; R 4 is hydrogen; and R 5 Is hydrogen; or a pharmaceutically acceptable salt thereof. 如請求項16之化合物，其係選自： 或其醫藥學上可接受之鹽。The compound of claim 16, which is selected from the group consisting of: Or a pharmaceutically acceptable salt thereof. 如請求項1之化合物，其中：T為N；U為-CR1 -；V為-CR2 -；W為-CR4 -；X為-O-；Y係選自C2-10 環雜烷基，其中各環雜烷基未經取代或經1、2、3或4個選自Rb 之取代基取代；Z係選自：-(CH2 )n OH；R1 係獨立地選自：(1)-苯基-C2-10 環雜烯基，(2)-聯苯，及(3)-苯基-雜芳基，其中環雜烯基、苯基、聯苯及雜芳基各自未經取代或經1、2、3或4個獨立地選自Ra 之取代基取代；R2 係選自鹵素； R4 為氫；且R5 為氫；或其醫藥學上可接受之鹽。The compound of claim 1, wherein: T is N; U is -CR 1 -; V is -CR 2 -; W is -CR 4 -; X is -O-; and Y is selected from C 2-10 ring An alkyl group, wherein each cycloheteroalkyl group is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R b ; Z is selected from the group consisting of: -(CH 2 ) n OH; R 1 is independently selected From: (1)-phenyl-C 2-10 cycloheteroalkenyl, (2)-biphenyl, and (3)-phenyl-heteroaryl, wherein cycloheteroalkenyl, phenyl, biphenyl, and hetero The aryl groups are each unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from R a ; R 2 is selected from halogen; R 4 is hydrogen; and R 5 is hydrogen; or pharmaceutically thereof Acceptable salt. 如請求項18之化合物，其係選自： 或其醫藥學上可接受之鹽。The compound of claim 18, which is selected from the group consisting of: Or a pharmaceutically acceptable salt thereof. 一種組合物，其包含如請求項1之化合物及醫藥學上可接受之載劑。 A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. 一種組合物，其包含如請求項1之化合物及選自辛伐他汀(simvastatin)、依折麥布(ezetimibe)及西他列汀(sitagliptin)之化合物，及醫藥學上可接受之載劑。A composition comprising a compound of claim 1 and a compound selected from the group consisting of simvastatin, ezetimibe, and sitagliptin, and a pharmaceutically acceptable carrier.
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CN101959404A (en) * 2008-02-04 2011-01-26 墨丘瑞医疗有限公司 Single adenosine phosphate activated protein kinase conditioning agent
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