TW201600520A

TW201600520A - Heterocyclic compound

Info

Publication number: TW201600520A
Application number: TW104102066A
Authority: TW
Inventors: 川崎昌紀; 味上達; 中村信二; 根来伸行; 池田周平; 芦沢朋子; 圓井省吾; 谷口孝彦
Original assignee: 武田藥品工業股份有限公司
Priority date: 2014-05-20
Filing date: 2015-01-22
Publication date: 2016-01-01
Also published as: AR099145A1

Abstract

A compound represented by the formula (I): wherein each symbol is as described in the SPECIFICATION, or a salt thereof has a PDE2A inhibitory action, and is useful as a prophylactic or therapeutic drug for schizophrenia, Alzheimer's disease and the like.

Description

雜環化合物 Heterocyclic compound

本發明有關具有PDE2A選擇性抑制作用，而且有用於作為作為精神***症、阿茲海默症及類似者之預防性或治療性藥物之含氮雜環化合物。 The present invention relates to a nitrogen-containing heterocyclic compound having a PDE2A selective inhibitory action and which is useful as a prophylactic or therapeutic drug for schizophrenia, Alzheimer's disease and the like.

(本發明之背景) (Background of the invention)

環狀核苷酸磷酸雙酯酶(PDE)為藉由控制其分解速率而調節第二傳訊者(即，環狀腺嘌呤核苷單磷酸(cAMP)和環狀鳥嘌呤核苷單磷酸(cGMP))之細胞濃度之酶。PDE為由21個基因所編碼之酶的超家族，而且根據結構和功能性質細分成11種不同的家族。PDE酶選擇性地催化cAMP及/或cGMP之3’-酯鍵之水解，形成不起作用的5’-單磷酸酯。在基質特異性之基準上，PDE家族可進一步分類成三個群組：i)cAMP-PDE(PDE4、PDE7以及PDE8)，ii)cGMP-PDE(PDE5、PDE6以及PDE9)，以及iii)雙基質PDE(PDE1、PDE2、PDE3、PDE10以及PDE11)。 Cyclic Nucleotide Phosphodiesterase (PDE) regulates second courier (ie, cyclic adenine nucleoside monophosphate (cAMP) and cyclic guanine nucleoside monophosphate (cGMP) by controlling its rate of decomposition )) The enzyme concentration of the cell. PDE is a superfamily of enzymes encoded by 21 genes and is subdivided into 11 different families based on structural and functional properties. The PDE enzyme selectively catalyzes the hydrolysis of the 3'-ester bond of cAMP and/or cGMP to form an inactive 5'-monophosphate. On the basis of matrix specificity, the PDE family can be further classified into three groups: i) cAMP-PDE (PDE4, PDE7, and PDE8), ii) cGMP-PDE (PDE5, PDE6, and PDE9), and iii) dual matrix PDE (PDE1, PDE2, PDE3, PDE10, and PDE11).

cAMP和cGMP實質上涉及每種生理過程之調節，諸如，促發炎介質產生和作用、離子通道功能、肌肉鬆弛、學習和記憶形成、分化、細胞凋亡、脂質生成、肝醣分解以及葡萄糖新生成。尤其是，在神經元中，此等第二傳訊者在調節突觸傳導中以及神經元分化和存活方面具有重要角色(非專利文件1)。藉由cAMP和cGMP調節此等過程伴隨著蛋白質激酶A(PKA)和蛋白質激酶G(PKG)之活化，其接著磷酸化各式各樣的基質，包含調節各式各樣的生理過程之轉錄因子、離子通道以及受體。響應於細胞外信號傳遞和cAMP和cGMP藉由PDE之降解，細胞內cAMP和cGMP濃度似乎為短暫地、空間地以及功能性地由腺核苷酸環化酶和鳥苷酸環化酶之調節所劃分(非專利文件2)。PDE在細胞中提供降解環狀核苷酸cAMP和cGMP之唯一手段，因此PDE在環狀核苷酸信號傳遞中扮演重要角色。從而，PDE可為多種治療性藥物之有希望的目標。 cAMP and cGMP essentially involve the regulation of each physiological process, such as the production and action of inflammatory mediators, ion channel function, muscle relaxation, learning and memory formation, differentiation, apoptosis, lipid production, Hepatic glycolysis and new glucose production. In particular, in neurons, these second couriers play an important role in regulating synaptic transmission as well as neuronal differentiation and survival (Non-Patent Document 1). Modulation of these processes by cAMP and cGMP is accompanied by activation of protein kinase A (PKA) and protein kinase G (PKG), which in turn phosphorylate a wide variety of substrates, including transcription factors that regulate a wide variety of physiological processes. , ion channels and receptors. In response to extracellular signaling and degradation of cAMP and cGMP by PDE, intracellular cAMP and cGMP concentrations appear to be transiently, spatially, and functionally regulated by adenosine cyclase and guanylate cyclase. Divided (Non-Patent Document 2). PDE provides the only means of degrading cyclic nucleotides cAMP and cGMP in cells, so PDE plays an important role in circular nucleotide signaling. Thus, PDE can be a promising target for a variety of therapeutic drugs.

磷酸雙酯酶2A(PDE2A)為水解cAMP和cGMP兩者之雙基質酶。其係組織成四個結構域、N-端、GAF-A、GAF-B以及催化結構域，而且作用為同型二聚體(homodimer)。PDE2A催化活性係藉由cGMP結合受到異位刺激。GAF-B結構域以高親和力和高選擇性結合cGMP。構形變化是由PDE2A同型二聚體中之cGMP結合所造成，其造成酶之催化活性增加數倍或更高(非專利文件3至6)。相反地，尚未知cAMP刺激PDE2A催化活性之體內實例。此外，cAMP與GAF-B結構域之結合親和力為30至100倍低於cGMP(非專利文件6和7)。PDE2A活性可於其中細胞cGMP濃度提高之條件下變成功能性地顯著，顯示酶之GAF結構域調節之生理角色。 Phosphodiesterase 2A (PDE2A) is a dual matrix enzyme that hydrolyzes both cAMP and cGMP. It is organized into four domains, N-terminal, GAF-A, GAF-B and catalytic domain, and acts as a homodimer. PDE2A catalytic activity is ectopically stimulated by cGMP binding. The GAF-B domain binds cGMP with high affinity and high selectivity. The conformational change is caused by the cGMP binding in the PDE2A homodimer, which causes the catalytic activity of the enzyme to increase several times or more (Non-Patent Documents 3 to 6). In contrast, in vivo examples of cAMP-stimulated PDE2A catalytic activity are not known. Furthermore, the binding affinity of cAMP to the GAF-B domain is 30 to 100 times lower than cGMP (Non-Patent Documents 6 and 7). PDE2A activity can become functionally significant under conditions in which the concentration of cellular cGMP is increased, indicating the physiological role of the regulation of the GAF domain of the enzyme.

PDE2A是於廣泛多種組織中表現，而且於腦中高度表現。蛋白質原先從心臟、肝臟、腎上腺、血小板、內皮細胞以及巨噬細胞純化(非專利文件8至13)。在腦中，尾狀葉、依核、皮質(額骨、頂骨以及顯骨)以及海馬迴中的PDE2A mRNA濃度最高，而且PDE2A mRNA在其他腦區域中為至少10倍較低的表現(非專利文件14)。這暗示PDE2A可控制對於學習和記憶形成重要之區域中的神經元內cAMP和cGMP濃度。 PDE2A is expressed in a wide variety of tissues and is highly expressed in the brain. The protein was originally purified from heart, liver, adrenal gland, platelets, endothelial cells, and macrophages (Non-Patent Documents 8 to 13). In the brain, PDE2A mRNA is highest in caudate, nucleus, cortex (frontal, parietal, and osseous) and hippocampal gyrus, and PDE2A mRNA is at least 10-fold lower in other brain regions (non-patented) Document 14). This suggests that PDE2A can control cAMP and cGMP concentrations in neurons in areas important for learning and memory formation.

PDE2A之抑制造成可改善認知功能之cAMP和cGMP濃度之增加。在皮質神經元和海馬迴切片兩者中，PDE2A抑制劑在鳥苷酸環化酶活化劑之存在下有力地增加cGMP濃度，而且亦在氟斯克寧(forskolin)之存在下增加cAMP濃度(非專利文件15)。亦發現響應於弱的強直刺激，PDE2A抑制劑有力地增加海馬迴切片中之長期增益效應(LTP)之誘導。這對切片中LTP之效果暗示PDE2A抑制對體內學習和記憶具有正面影響(非專利文件15)。事實上，相同PDE2A抑制劑在大鼠中增加對新穎物體和社會認知任務兩者之記憶力(retention)，而且改善3、12以及24月齡大鼠的物體記憶和物體認知任務。其亦衰減亞慢性經PCP處理之大鼠中之維度外-維度內(ED/ID)認知任務之維度外(ED)變換不足(非專利文件15至17)。此等結果暗示PDE2A抑制可經由cAMP和cGMP調節之信號傳遞串列之增益作用促進學習和記憶過程。 Inhibition of PDE2A results in an increase in cAMP and cGMP concentrations that improve cognitive function. In both cortical neurons and hippocampal gyrus, PDE2A inhibitors potently increase cGMP concentrations in the presence of guanylate cyclase activators and also increase cAMP concentrations in the presence of forskolin (non- Patent Document 15). It has also been found that PDE2A inhibitors potently increase the induction of long-term gain effects (LTP) in hippocampal re-slices in response to weak tonic stimulation. The effect of LTP in this pair of slices suggests that PDE2A inhibition has a positive effect on learning and memory in vivo (Non-Patent Document 15). In fact, the same PDE2A inhibitor increased the retention of both novel and social cognitive tasks in rats, and improved object memory and object recognition tasks in 3, 12, and 24 month old rats. It also attenuates the extra-dimensional (ED) transformation of the dimension-external-dimensional (ED/ID) cognitive task in subchronic PCP-treated rats (Non-Patent Documents 15 to 17). These results suggest that PDE2A inhibition can facilitate learning and memory processes via the gain effects of cAMP and cGMP regulated signaling sequences.

藉由PDE2A抑制而增加的cGMP濃度亦可影響焦慮和壓力相關事件。PDE2A抑制劑減少氧化壓力，而且誘發NADPH氧化酶次單元在經氧化壓力誘發劑處理之小鼠中之表現。其經由NADPH氧化酶途徑改善提高之十字迷宮、露地以及探洞試驗中之焦慮狀行為(非專利文件18)。另外，PDE2A抑制劑亦在提高之十字迷宮和探洞試驗中對非應激小鼠之行為產生抗焦慮之效果(非專利文件19)。PDE2A可為治療不僅認知不足，亦可為神經精神和神經退化性疾病中之焦慮之新穎生理目標。 Increased cGMP concentration by PDE2A inhibition can also Affect anxiety and stress related events. PDE2A inhibitors reduced oxidative stress and induced the performance of NADPH oxidase subunits in mice treated with oxidative stress inducing agents. It improves the anxiety-like behavior in the elevated maze, open field, and caving test via the NADPH oxidase pathway (Non-Patent Document 18). In addition, PDE2A inhibitors also have an anxiolytic effect on the behavior of non-stressed mice in the elevated plus maze and cavities (Non-Patent Document 19). PDE2A can be used to treat not only cognitive deficits, but also novel physiological targets for anxiety in neuropsychiatric and neurodegenerative diseases.

腦中之此等獨特分布和功能表示PDE2A代表治療神經精神和神經退化性疾病(特別是精神***症和阿茲海默症)之重要新穎目標。 These unique distributions and functions in the brain indicate that PDE2A represents an important novel goal in the treatment of neuropsychiatric and neurodegenerative diseases, particularly schizophrenia and Alzheimer's disease.

專利文件1描述式I所示之化合物(其為雜環化合物)： Patent Document 1 describes a compound of formula I which is a heterocyclic compound:

其中各符號係如專利文件1中所定義，係ATK激酶抑制劑，而且有用於治療癌症。 Each of these symbols is an ATK kinase inhibitor as defined in Patent Document 1, and is useful for treating cancer.

專利文件2描述式(I)所示之化合物(其為雜環化合物)： Patent Document 2 describes a compound represented by the formula (I) which is a heterocyclic compound:

其中各符號係如專利文件2中所定義，係CRTH2受體調控劑，而且有用於治療氣喘、鬱血、過敏性鼻炎以及COPD。 Each symbol is a CRTH2 receptor modulator as defined in Patent Document 2, and is useful for the treatment of asthma, stagnation, allergic rhinitis, and COPD.

專利文件3描述式I所示之化合物(其為雜環化合物)： Patent Document 3 describes a compound of formula I which is a heterocyclic compound:

其中各符號係如專利文件3中所定義，係蛋白質激酶-1抑制劑，而且有用於治療癌症。 Each of these symbols is a protein kinase-1 inhibitor as defined in Patent Document 3, and is useful for treating cancer.

專利文件4描述式所示之化合物(其為雜環化合物)： Patent Document 4 describes a compound of the formula (which is a heterocyclic compound):

其中各符號係如專利文件4中所定義，係PDE3A抑制劑，而且有用於治療呼吸道疾病(COPD、氣喘等)和高血壓。 Wherein each symbol is as defined in Patent Document 4, It is a PDE3A inhibitor and is used to treat respiratory diseases (COPD, asthma, etc.) and hypertension.

專利文件5描述式(1)所示之化合物(其為雜環化合物)： Patent Document 5 describes a compound represented by the formula (1) which is a heterocyclic compound:

其中各符號係如專利文件5中所定義，是蛋白質激酶抑制劑，而且有用於治療癌症及類似者。 Each of these symbols is a protein kinase inhibitor as defined in Patent Document 5, and is useful for treating cancer and the like.

專利文件6描述式(I)所示化合物(其為雜環化合物)：其中各符號係如專利文件6中所定義，是JNK調控劑，有用於治療糖尿病和相關疾病。 Patent Document 6 describes a compound of the formula (I) which is a heterocyclic compound: Each of these symbols, as defined in Patent Document 6, is a JNK modulator and is useful for the treatment of diabetes and related diseases.

專利文件7描述式I所示之化合物(其為雜環化合物)： Patent Document 7 describes a compound of formula I which is a heterocyclic compound:

其中各符號係如專利文件7中所定義，為鉀離子通道阻斷劑。 Each symbol is as defined in Patent Document 7, It is a potassium ion channel blocker.

專利文件8描述式XXVIII所示化合物(其為雜環化合物)； Patent Document 8 describes a compound of the formula XXVIII which is a heterocyclic compound;

其中各符號係如專利文件8中所定義，是合成中間體。 Each symbol is a synthetic intermediate as defined in Patent Document 8.

專利文件9描述下式之雜環化合物： Patent Document 9 describes a heterocyclic compound of the formula:

其中各符號係如專利文件9中所定義，是PDE4抑制劑，而且有用於治療發炎和過敏疾病。 Each of these symbols, as defined in Patent Document 9, is a PDE4 inhibitor and is useful in the treatment of inflammatory and allergic diseases.

專利文件10描述式(1)所示化合物(其為雜環化合物)：Ar ¹ (Alk ^a ) _r L ¹ Ar ² CH(R ¹ )C(R ^a )(R ^a')R (1) Patent Document 10 describes a compound represented by the formula (1) which is a heterocyclic compound: Ar ¹ (Alk ^a ) _r L ¹ Ar ² CH(R ¹ )C(R ^a )(R ^a ' )R (1)

其中各符號係如專利文件10中所定義，是α 4黏合素抑制劑，而且有用於免疫發炎和發炎疾病之預防。 Each of these symbols, as defined in Patent Document 10, is an alpha 4 binder inhibitor and is useful for the prevention of immune inflammatory and inflammatory diseases.

專利文件11描述式(II)所示化合物(其為雜環化合物)： Patent Document 11 describes a compound of the formula (II) which is a heterocyclic compound:

其中各符號係如專利文件11中所定義，是合成起始材料化合物。 Each of the symbols is a synthetic starting material compound as defined in Patent Document 11.

亦已知以下化合物(CAS登記號：1422628-80-5)。 The following compounds are also known (CAS Registry Number: 1422628-80-5).

[文件列表] [document list] [專利文件] [Patent Document]

專利文件1：WO 2012/178124 Patent Document 1: WO 2012/178124

專利文件2：WO 2012/087861 Patent Document 2: WO 2012/087861

專利文件3：WO 2011/044157 Patent Document 3: WO 2011/044157

專利文件4：WO 2010/097410 Patent Document 4: WO 2010/097410

專利文件5：WO 2009/026276 Patent Document 5: WO 2009/026276

專利文件6：WO 2007/125405 Patent Document 6: WO 2007/125405

專利文件7：WO 2006/015159 Patent Document 7: WO 2006/015159

專利文件8：WO 2004/056823 Patent Document 8: WO 2004/056823

專利文件9：WO 2005/058892 Patent Document 9: WO 2005/058892

專利文件10：WO 00/32575 Patent Document 10: WO 00/32575

專利文件11：JP-A-6-145169 Patent Document 11: JP-A-6-145169

[非專利文件] [Non-patent document]

非專利文件1：Nat. Rev. Drug Discov. 2006、vol. 5: 660-670 Non-Patent Document 1: Nat. Rev. Drug Discov. 2006, vol. 5: 660-670

非專利文件2：Circ. Res. 2007、vol. 100: 950-966 Non-Patent Document 2: Circ. Res. 2007, vol. 100: 950-966

非專利文件3：J. Biol. Chem. 1971、vol. 246: 3841-3846 Non-Patent Document 3: J. Biol. Chem. 1971, vol. 246: 3841-3846

非專利文件4：J. Biol. Chem. 1973、vol. 248: 1334-1340 Non-Patent Document 4: J. Biol. Chem. 1973, vol. 248: 1334-1340

非專利文件5：PNAS 2005、vol. 99: 13260-13265 Non-Patent Document 5: PNAS 2005, vol. 99: 13260-13265

非專利文件6：British J. Pharmacol. 2010、vol. 161: 1645-1660 Non-Patent Document 6: British J. Pharmacol. 2010, vol. 161: 1645-1660

非專利文件7：J. Biol. Chem. 2004、vol. 279: 37928-37938 Non-Patent Document 7: J. Biol. Chem. 2004, vol. 279: 37928-37938

非專利文件8：J. Biol. Chem. 1982、vol. 257: 1973-1979 Non-Patent Document 8: J. Biol. Chem. 1982, vol. 257: 1973-1979

非專利文件9：J. Biol. Chem. 1983、vol. 258: 12526-12533 Non-Patent Document 9: J. Biol. Chem. 1983, vol. 258: 12526-12533

非專利文件10：Phosphodiesterase Inhibitors、Academic Press: 21-40 Non-Patent Document 10: Phosphodiesterase Inhibitors, Academic Press: 21-40

非專利文件11：Rev. Physiol. Biochem. Pharmacol. 1999、vol. 135: 67-104 Non-Patent Document 11: Rev. Physiol. Biochem. Pharmacol. 1999, vol. 135: 67-104

非專利文件12：Cell Signal 2004、vol. 16: 365-374 Non-Patent Document 12: Cell Signal 2004, vol. 16: 365-374

非專利文件13：J. Histochem. Cytochem. 2009、vol. 57: 933-949 Non-Patent Document 13: J. Histochem. Cytochem. 2009, vol. 57: 933-949

非專利文件14：Neuropharmacology 2010、vol. 59: 367-374 Non-Patent Document 14: Neuropharmacology 2010, vol. 59: 367-374

非專利文件15：Neuropharmacology 2004、vol. 47: 1081-1092 Non-Patent Document 15: Neuropharmacology 2004, vol. 47: 1081-1092

非專利文件16：Mol. Neurobiol. 2010、vol. 41: 129-137 Non-Patent Document 16: Mol. Neurobiol. 2010, vol. 41: 129-137

非專利文件17：Neuropharmacology 2012、vol. 62: 1182-1190 Non-Patent Document 17: Neuropharmacology 2012, vol. 62: 1182-1190

非專利文件18：J. Pharmacol. Exp. Ther. 2008、vol. 326: 369-379 Non-Patent Document 18: J. Pharmacol. Exp. Ther. 2008, vol. 326: 369-379

非專利文件19：J. Pharmacol. Exp. Ther. 2009、vol. 331: 690-699 Non-Patent Document 19: J. Pharmacol. Exp. Ther. 2009, vol. 331: 690-699

本發明旨在提供具有PDE2A選擇性抑制作用，而且有用於作為用於精神***症、阿茲海默症及類似者的預防性或治療性藥物的化合物。 The present invention is intended to provide a compound having PDE2A selective inhibitory action and which is useful as a prophylactic or therapeutic drug for schizophrenia, Alzheimer's disease and the like.

本案發明者已進行密集研究，並且發現爾後描述的式(I)所示之化合物出乎意料地具有優異的PDE2A選擇性抑制作用，因此，係有用於作為精神***症、阿茲海默症及類似者之預防性或治療性藥物，而基於此等發現完成本發明。 The inventors of the present invention have conducted intensive studies and found that the compound of the formula (I) described later unexpectedly has an excellent PDE2A selective inhibitory action and is therefore useful for schizophrenia, Alzheimer's disease and The present invention has been completed based on such findings as prophylactic or therapeutic drugs.

據此，本發明係如下。 Accordingly, the present invention is as follows.

[1]一種式(I)所示之化合物或其鹽： [1] A compound of the formula (I) or a salt thereof:

其中環A為吡唑環；環B為嘧啶環，其係經1至3個選自下列之取代基取代：(1)C_1-6烷基，(2)視需要經1至3個C_1-6烷基取代之***基，以及(3)視需要經1至3個C_1-6烷基取代之吡啶基；環D為經C_1-6烷氧基取代之苯環，該C_1-6烷氧基視需要經1至3個鹵素原子取代；X為碳原子；L為鍵結；以及Y為下式所表示之基團： Wherein ring A is a pyrazole ring; ring B is a pyrimidine ring substituted by 1 to 3 substituents selected from the group consisting of: (1) C _1-6 alkyl, (2) 1 to 3 C as needed _{a 1-6} alkyl-substituted triazolyl group, and (3) a pyridyl group optionally substituted with 1 to 3 C _1-6 alkyl groups; and a ring D is a benzene ring substituted with a C _1-6 alkoxy group, The C _1-6 alkoxy group is optionally substituted by 1 to 3 halogen atoms; X is a carbon atom; L is a bond; and Y is a group represented by the following formula:

環R²為氫原子；R³為C_1-6烷基；以及 R⁴為C_1-6烷基。 Ring R ² is a hydrogen atom; R ³ is a C _1-6 alkyl group; and R ⁴ is a C _1-6 alkyl group.

[2]一種化合物或其鹽，該化合物係N-((1S)-2-羥基-2-甲基-1-(4-(三氟甲氧基)苯基)丙基)-5-(6-甲基吡啶-3-基)吡唑并[1,5-a]嘧啶-3-甲醯胺。 [2] A compound or a salt thereof, which is N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-5-( 6-Methylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.

[3]一種化合物或其鹽，該化合物係N-((1S)-2-羥基-2-甲基-1-(4-(三氟甲氧基)苯基)丙基)-6-甲基-5-(4-甲基-1H-1,2,3-***-1-基)吡唑并[1,5-a]嘧啶-3-甲醯胺。 [3] A compound or a salt thereof, which is N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-6- 5-[4-Methyl-1H-1,2,3-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.

[4]一種化合物或其鹽，該化合物係N-((1S)-2-羥基-2-甲基-1-(4-(三氟甲氧基)苯基)丙基)-6-甲基-5-(3-甲基-1H-1,2,4-***-1-基)吡唑并[1,5-a]嘧啶-3-甲醯胺。 [4] A compound or a salt thereof, which is N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-6- 5-[3-methyl-1H-1,2,4-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.

[5]一種藥劑，包括上述[1]至[4]中任一項所述之化合物或其鹽。 [5] A pharmaceutical agent, which comprises the compound of any one of the above [1] to [4] or a salt thereof.

[6]如上述[5]所述之藥劑，其為磷酸雙酯酶2A抑制劑。 [6] The agent according to [5] above, which is a phosphodiesterase 2A inhibitor.

[7]如上述[5]所述之藥劑，其為用於精神***症之預防性或治療性藥物。 [7] The agent according to the above [5], which is a prophylactic or therapeutic drug for schizophrenia.

[8]上述[1]至[4]中任一項所述之化合物或其鹽，係用於預防或治療精神***症。 [8] The compound according to any one of the above [1] to [4] or a salt thereof for use in the prevention or treatment of schizophrenia.

[9]一種抑制哺乳動物中之磷酸雙酯酶2A之方法，包括對該哺乳動物投藥有效量的上述[1]至[4]中任一項所述之化合物或其鹽。 [9] A method of inhibiting phosphodiesterase 2A in a mammal, which comprises administering to the mammal an effective amount of the compound of any one of the above [1] to [4] or a salt thereof.

[10]一種預防或治療哺乳動物之精神***症之方法，包括對該哺乳動物投藥有效量的上述[1]至[4]中任一項所述之化合物或其鹽。 [10] A method of preventing or treating schizophrenia in a mammal, comprising administering an effective amount of the compound according to any one of the above [1] to [4] or a salt thereof.

[11]一種上述[1]至[4]中任一項所述之化合物或其鹽於製造精神***症之預防性或治療性藥物之用途。 [11] A compound according to any one of the above [1] to [4] or a salt thereof The use of prophylactic or therapeutic drugs for schizophrenia.

根據本發明，可提供具有PDE2A選擇性抑制作用，而且有用於作為精神***症、阿茲海默症及類似者之預防性或治療性藥物之化合物。 According to the present invention, a compound having a PDE2A selective inhibitory action and a prophylactic or therapeutic drug for schizophrenia, Alzheimer's disease and the like can be provided.

第1圖為顯示恐懼情境條件試驗中受試化合物對MK-801誘發之異常之改善效果之圖。化合物A為從實施例1-II中獲得之化合物(30mg/kg，p.o.)，化合物B為從實施例2-II中獲得之化合物(30mg/kg，p.o.)，以及化合物C為實施例3中獲得之化合物(30mg/kg，p.o.)。 Fig. 1 is a graph showing the effect of the test compound on the MK-801-induced abnormality in the fear situation test. Compound A is a compound obtained from Example 1-II (30 mg/kg, po), Compound B is a compound obtained from Example 2-II (30 mg/kg, po), and Compound C is Example 3. The compound obtained (30 mg/kg, po).

(本發明之詳細說明) (Detailed description of the invention)

本發明係以下詳述。 The invention is described in detail below.

以下詳述用於本說明書之各取代基之定義。除非另行註明，否則各取代基具有以下定義。 The definitions of the various substituents used in the present specification are detailed below. Each substituent has the following definitions unless otherwise noted.

本說明書中，"鹵素原子"之實例包含氟、氯、溴以及碘。 In the present specification, examples of the "halogen atom" include fluorine, chlorine, bromine, and iodine.

本說明書中，"C_1-6烷基"之實例包含甲基、乙基、丙基、異丙基、丁基、異丁基、第二丁基、第三丁基、戊基、異戊基、新戊基、1-乙基丙基、己基、異己基、1,1-二甲基丁基、2,2-二甲基丁基、3,3-二甲基丁基以及2-乙基丁基。 In the present specification, examples of the "C _1-6 alkyl group" include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, second butyl group, tert-butyl group, pentyl group, and isoprene. Base, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2- Ethyl butyl.

本說明書中，"C_1-6烷氧基"之實例包含甲氧基、乙氧基、丙氧基、異丙氧基、丁氧基、異丁氧基、第二丁氧基、第三丁氧基、戊氧基以及己氧基。 In the present specification, examples of the "C _1-6 alkoxy group" include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a second butoxy group, and a third. Butoxy, pentyloxy and hexyloxy.

本說明書中，"視需要經鹵化之C_1-6烷氧基"之實例包含視需要具有1至7個，較佳為1至5個鹵素原子之C_1-6烷氧基。其具體實例包含甲氧基、二氟甲氧基、三氟甲氧基、乙氧基、2,2,2-三氟乙氧基、丙氧基、異丙氧基、丁氧基、4,4,4-三氟丁氧基、異丁氧基、第二丁氧基、戊氧基以及己氧基。 In the present specification, "the optionally halogenated C _1-6 alkoxy" and examples thereof include optionally having 1-7, preferably a C 1 to 5 halogen atoms ₆ alkoxy. Specific examples thereof include a methoxy group, a difluoromethoxy group, a trifluoromethoxy group, an ethoxy group, a 2,2,2-trifluoroethoxy group, a propoxy group, an isopropoxy group, a butoxy group, and 4 4,4-Trifluorobutoxy, isobutoxy, second butoxy, pentyloxy and hexyloxy.

式(I)中之各符號之定義係於以下詳述。 The definition of each symbol in the formula (I) is as detailed below.

環A為吡唑環。 Ring A is a pyrazole ring.

環B為嘧啶環，其係經1至3個選自下列取代基取代之：(1)C_1-6烷基(例如，甲基)，(2)視需要經1至3個C_1-6烷基(例如，甲基)取代之***基(例如，1,2,3-***基、1,2,4-***基)，以及(3)視需要經1至3個C_1-6烷基(例如，甲基)取代之吡啶基。 Ring B is a pyrimidine ring which is substituted with 1 to 3 substituents selected from the group consisting of: (1) C _1-6 alkyl (eg, methyl), (2) 1 to 3 C _{1- a 6-} alkyl (eg, methyl)-substituted triazolyl group (eg, 1,2,3-triazolyl, 1,2,4-triazolyl), and (3) 1 to 3 C as needed _{a 1-6} alkyl (eg, methyl) substituted pyridyl group.

稠合環AB較佳為吡唑并[1,5-a]嘧啶環，其視需要經1至3個選自下列之取代基取代：(1)C_1-6烷基(例如，甲基)，(2)視需要經1至3個C_1-6烷基(例如，甲基)取代之***基(例如，1,2,3-***基、1,2,4-***基)，以及(3)視需要經1至3個C_1-6烷基(例如，甲基)取代之吡啶基。 The fused ring AB is preferably a pyrazolo[1,5-a]pyrimidine ring which is optionally substituted with 1 to 3 substituents selected from the group consisting of: (1) a C _1-6 alkyl group (for example, a methyl group) And (2) a triazolyl group substituted with 1 to 3 C _1-6 alkyl groups (for example, methyl group) as desired (for example, 1,2,3-triazolyl, 1,2,4-triazole) And (3) a pyridyl group substituted with 1 to 3 C _1-6 alkyl groups (for example, methyl group) as needed.

環D為經C_1-6烷氧基(例如，甲氧基)取代之苯環，該C_1-6烷氧基視需要經1至3個鹵素原子(例如，氟原子)取代。 By ring D is C _1-6 alkoxy (e.g., methoxy) substituent of a benzene ring, the C _1-6 alkoxy optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atom).

X為碳原子。 X is a carbon atom.

L為鍵結。 L is the bond.

Y為式所表示之基團： Y is a group represented by the formula:

其中R²為氫原子；R³為C_1-6烷基(例如，甲基)；以及R⁴為C_1-6烷基(例如，甲基)。 Wherein R ² is a hydrogen atom; R ³ is a C _1-6 alkyl group (for example, a methyl group); and R ⁴ is a C _1-6 alkyl group (for example, a methyl group).

化合物(I)之較佳實例包含以下化合物。 Preferred examples of the compound (I) include the following compounds.

[化合物A] [Compound A]

化合物(I)，其中環A為吡唑環；環B為嘧啶環，其係經1至3個選自下列之取代基取代：(1)C_1-6烷基，(2)視需要經1至3個C_1-6烷基取代之***基，以及(3)視需要經1至3個C_1-6烷基取代之吡啶基；環D為經C_1-6烷氧基取代之苯環，該C_1-6烷氧基視需要經1至3個鹵素原子取代；X為碳原子；L為鍵結；以及 Y為式所表示之基團： Compound (I) wherein ring A is a pyrazole ring; ring B is a pyrimidine ring substituted by 1 to 3 substituents selected from the group consisting of: (1) C _1-6 alkyl, (2) optionally 1 to 3 C _1-6 alkyl-substituted triazolyl groups, and (3) pyridyl groups optionally substituted with 1 to 3 C _1-6 alkyl groups; ring D is substituted by C _1-6 alkoxy groups a benzene ring, the C _1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms; X is a carbon atom; L is a bond; and Y is a group represented by the formula:

其中R²為氫原子；R³為C_1-6烷基；R⁴為C_1-6烷基。 Wherein R ² is a hydrogen atom; R ³ is a C _1-6 alkyl group; and R ⁴ is a C _1-6 alkyl group.

作為化合物(I)之實例，較佳為N-((1S)-2-羥基-2-甲基-1-(4-(三氟甲氧基)苯基)丙基)-5-(6-甲基吡啶-3-基)吡唑并[1,5-a]嘧啶-3-甲醯胺，N-((1S)-2-羥基-2-甲基-1-(4-(三氟甲氧基)苯基)丙基)-6-甲基-5-(4-甲基-1H-1,2,3-***-1-基)吡唑并[1,5-a]嘧啶-3-甲醯胺，以及N-((1S)-2-羥基-2-甲基-1-(4-(三氟甲氧基)苯基)丙基)-6-甲基-5-(3-甲基-1H-1,2,4-***-1-基)吡唑并[1,5-a]嘧啶-3-甲醯胺，以及其鹽類。 As an example of the compound (I), N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-5-(6) is preferred. -methylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, N-((1S)-2-hydroxy-2-methyl-1-(4-(three Fluoromethoxy)phenyl)propyl)-6-methyl-5-(4-methyl-1H-1,2,3-triazol-1-yl)pyrazolo[1,5-a] Pyrimidine-3-carbamide, and N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-6-methyl-5 -(3-Methyl-1H-1,2,4-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, and salts thereof.

式(I)所示之化合物之鹽之實例包含金屬鹽、銨鹽、與有機鹼之鹽、與無機酸之鹽、與有機酸之鹽、與鹼性或酸性胺基酸之鹽及類似者。 Examples of the salt of the compound represented by the formula (I) include a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like. .

金屬鹽之較佳實例包含鹼性金屬鹽，諸如，鈉鹽、鉀鹽及類似者；鹼土金屬鹽，諸如，鈣鹽、鎂鹽、鋇鹽及類似者；鋁鹽及類似者。 Preferred examples of the metal salt include basic metal salts such as sodium salts, potassium salts and the like; alkaline earth metal salts such as calcium salts, magnesium salts, barium salts and the like; aluminum salts and the like.

與有機鹼之鹽之較佳實例包含與三甲胺、三乙胺、吡啶、甲吡啶、2,6-二甲基吡啶、乙醇胺、二乙醇胺、三乙醇胺、環己胺、二環己胺、N,N’-二苯甲基乙二胺及類似者之鹽。 Preferred examples of the salt with an organic base include trimethylamine, triethylamine, pyridine, methylpyridine, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N. , N'-diphenylmethylethylenediamine and similar salts.

與無機酸之鹽之較佳實例包含與鹽酸、氫溴酸、硝酸、硫酸、磷酸及類似者之鹽。 Preferred examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.

與有機酸之鹽之較佳實例包含與甲酸、乙酸、三氟乙酸、鄰苯二甲酸、反丁烯二酸、草酸、酒石酸、順丁烯二酸、檸檬酸、琥珀酸、蘋果酸、甲磺酸、苯磺酸、對甲苯磺酸及類似者之鹽。 Preferred examples of the salt with an organic acid include with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, and Sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.

與鹼性胺基酸之鹽之較佳實例包含與精胺酸、離胺酸、鳥胺酸及類似者之鹽，以及與酸性胺基酸之鹽之較佳實例包含與天冬胺酸、麩胺酸及類似者之鹽。 Preferred examples of the salt with a basic amino acid include salts with arginine, lysine, ornithine and the like, and preferred examples of the salt with an acidic amino acid include aspartic acid, A salt of glutamic acid and the like.

上述鹽中，較佳為醫藥上可接受之鹽。 Among the above salts, preferred are pharmaceutically acceptable salts.

化合物(I)之前藥表示由於活體中生理條件下與酶、胃酸等之反應而轉化成化合物(I)之化合物，亦即，根據酶之氧化、還原、水解等轉化成化合物(I)之化合物；由於胃酸等而藉由水解轉化成化合物(I)之化合物。 The compound (I) is a compound which is converted into a compound (I) by a reaction with an enzyme, a gastric acid or the like under physiological conditions in a living body, that is, a compound which is converted into the compound (I) according to oxidation, reduction, hydrolysis or the like of the enzyme. a compound which is converted into the compound (I) by hydrolysis due to gastric acid or the like.

用於化合物(I)之前藥可為藉由使化合物(I)中之胺基經歷醯化、烷化或磷酸化而獲得之化合物(例如，藉由使化合物(I)中之胺基經歷二十烷醯化、丙胺醯化、戊基胺基羰化、(5-甲基-2-側氧基-1,3-二氧雜環戊烯-4-基)甲氧基羰化、四氫呋喃化、咯啶基甲基化、三甲基乙醯氧基甲基化以及第三丁基化等而獲得之化合物)；使化合物(I) 中之羥基經歷醯化、烷化、磷酸化或硼化而獲得之化合物(例如，藉由使化合物(I)中之羥基經歷乙醯化、十六醯化、丙醯化、三甲基乙醯化、琥珀醯化、反丁烯二醯化、丙胺醯化、二甲基胺基甲基羰化等而獲得之化合物)；藉由使化合物(I)中之羧基經歷酯化或醯胺化而獲得之化合物(例如，藉由使化合物(I)中之羧基經歷C_1-6烷基酯化、苯基酯化、羧基甲基酯化、二甲基胺基甲基酯化、三甲基乙醯氧基甲基酯化、乙氧基羰氧基乙基酯化、酞基酯化、(5-甲基-2-側氧基-1,3-二氧雜環戊烯-4-基)甲基酯化、環己氧基羰基乙基酯化以及甲基醯胺化等而獲得之化合物)及類似者。其中，較佳為使用經C_1-6烷基(諸如，甲基、乙基、第三丁基及類似者酯化之化合物(I)中之羧基)。此等化合物可藉由本質上已知之方法自化合物(I)產生。 The prodrug for the compound (I) may be a compound obtained by subjecting an amine group in the compound (I) to deuteration, alkylation or phosphorylation (for example, by subjecting the amine group in the compound (I) to two Decadecylation, propylamine oximation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonylation, tetrahydrofuran a compound obtained by cyclization, methylation, trimethylacetoxymethylation, and tertiary butylation; or subjecting a hydroxyl group in the compound (I) to deuteration, alkylation, phosphorylation or a compound obtained by boronation (for example, by subjecting a hydroxyl group in the compound (I) to acetylation, hexadecanization, propylation, trimethylacetamidine, amber oximation, and antibutene dimerization a compound obtained by subjecting propylamine, dimethylaminomethylcarbonylation or the like to a compound obtained by subjecting a carboxyl group in the compound (I) to esterification or guanidation (for example, by causing a compound ( The carboxyl group in I) undergoes C _1-6 alkyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, trimethyl ethoxymethyl methyl esterification, ethoxylation Carboethoxyethyl esterification, Esterification, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl esterification, cyclohexyloxycarbonylethyl esterification, and methylguanamine Compounds obtained by crystallization, etc.) and the like. Among them, it is preferred to use a carboxyl group in the compound (I) which is esterified with a C _1-6 alkyl group such as a methyl group, an ethyl group, a tert-butyl group or the like. These compounds can be produced from compound (I) by a method known per se.

化合物(I)之前藥可為在Development of Pharmaceutical Products、vol.7、Molecular Design、163-198、Hirokawa Shoten(1990)中描述之在生理條件下轉化成化合物(I)之化合物。 The compound (I) prodrug may be a compound which is converted into the compound (I) under physiological conditions as described in Development of Pharmaceutical Products, vol. 7, Molecular Design, 163-198, Hirokawa Shoten (1990).

除非另行註明，以下反應方案中之化合物中之各符號如上定義。只要不會抑制反應，描述於反應方案中之各化合物可形成鹽。此鹽之實例包含彼等與化合物(I)之鹽類似者。 Unless otherwise indicated, each symbol in the compounds of the following reaction schemes is as defined above. Each compound described in the reaction scheme can form a salt as long as it does not inhibit the reaction. Examples of such salts include those similar to those of the compound (I).

雖然各步驟中獲得之化合物可以反應混合物之形式直接用作下一個反應之粗產物，其亦可根據習知方法從反應混合物單離，而且進一步藉由分離手段(諸如，再結晶、蒸餾、層析術及類似者)而容易純化。 Although the compound obtained in each step can be directly used as the crude product of the next reaction in the form of a reaction mixture, it can be isolated from the reaction mixture according to a conventional method, and further by means of separation (for example, Recrystallization, distillation, chromatography and the like) are easy to purify.

本發明之化合物之產生方法係於以下描述。 The method of producing the compound of the present invention is as described below.

化合物(I)可藉由本質上已知之方法製造，例如，反應方案1至反應方案11中顯示之製造方法或與其類似之方法。 The compound (I) can be produced by a method known per se, for example, the production method shown in Reaction Scheme 1 to Reaction Scheme 11 or a method analogous thereto.

以下各產生方法中，用於化合物(I)之製造之各起始材料化合物可形成鹽。此鹽之實例包含彼等與化合物(I)之鹽類似者。 In each of the following production methods, each of the starting material compounds used in the production of the compound (I) can form a salt. Examples of such salts include those similar to those of the compound (I).

欲用於化合物(I)之製造之各起始材料化合物可直接以反應混合物之形式用作下一個反應之粗產物。化合物亦可根據習知方法從反應混合物單離，而且可藉由本質上已知之手段(諸如，萃取、濃縮、中和、過濾、蒸餾、再結晶、層析術及類似者)而純化。欲用於上述再結晶之溶劑之實例包含水、醇類、醚類、烴類、醯胺類、鹵化烴類、腈類、酮類、酯類、亞碸類、有機酸及類似者。此等溶劑可單獨使用或兩種或更多種溶劑可以適合的比率混合，例如，1：1至1：10之比率。另外，作為其中之化合物，可商購產物直接使用，或可亦使用藉由本質上已知之方法或與其類似之方法產生之化合物。 The respective starting material compounds to be used in the production of the compound (I) can be used as the crude product of the next reaction as the reaction mixture. The compound can also be isolated from the reaction mixture according to conventional methods, and can be purified by means known per se, such as extraction, concentration, neutralization, filtration, distillation, recrystallization, chromatography and the like. Examples of the solvent to be used in the above recrystallization include water, alcohols, ethers, hydrocarbons, guanamines, halogenated hydrocarbons, nitriles, ketones, esters, oximes, organic acids, and the like. These solvents may be used singly or two or more solvents may be mixed in a suitable ratio, for example, a ratio of 1:1 to 1:10. Further, as the compound therein, a commercially available product may be used as it is, or a compound produced by a method known per se or a method similar thereto may also be used.

當化合物(I)和化合物(I)之製造中間體具有可轉化之官能基(例如，羧基、胺基、羥基、羰基、巰基、C_1-6烷氧基-羰基、C_6-14芳氧基-羰基、C_7-16芳烷氧基-羰基、磺酸基、鹵素原子、視需要鹵化之C_1-6烷基磺醯氧基、氰基、胺基羰基、氧硼基等)時，可藉由以本質上已知之方法或與其類似之方法轉化此等官能基而製造多種化合物。 When the intermediate of the production of the compound (I) and the compound (I) has a functional group which can be converted (for example, a carboxyl group, an amine group, a hydroxyl group, a carbonyl group, a thiol group, a C _1-6 alkoxy group, a carbonyl group, a C _6-14 aryloxy group) a base-carbonyl group, a C _7-16 aralkyloxy-carbonyl group, a sulfonic acid group, a halogen atom, a C _1-6 alkylsulfonyloxy group optionally halogenated, a cyano group, an aminocarbonyl group, an oxyboron group, etc.) A plurality of compounds can be produced by converting such functional groups by a method known per se or a method analogous thereto.

羧基可藉由對視需要經保護之胺基及類似者藉由諸如，酯化、還原、醯胺化、轉化反應之反應而轉化。 The carboxyl group can be converted by reacting an amine group as desired and the like by, for example, esterification, reduction, amidation, or conversion reaction.

胺基可藉由諸如，醯胺化、磺醯化、亞硝化、烷化、芳基化、亞醯胺化及類似者之反應而轉化。 The amine group can be converted by, for example, amide amination, sulfonation, nitrosation, alkylation, arylation, hydrazide, and the like.

羥基可藉由諸如，酯化、胺甲醯化、磺醯化、烷化、氟化、芳基化、氧化、鹵化及類似者之反應而轉化。 The hydroxyl group can be converted by, for example, esterification, amine methylation, sulfonation, alkylation, fluorination, arylation, oxidation, halogenation, and the like.

羰基可藉由諸如，還原、氧化、氟化、亞胺化(包含肟化、腙化)、(硫)酮化、烷叉基化、硫羰化及類似者之反應而轉化。 The carbonyl group can be converted by, for example, reduction, oxidation, fluorination, imidization (including deuteration, deuteration), (thio)ketolation, alkylidization, thiocarbonylation, and the like.

巰基可藉由諸如，烷化、氧化及類似者之反應而轉化。 The thiol group can be converted by, for example, alkylation, oxidation, and the like.

C_1-6烷氧基-羰基、C_6-14芳氧基-羰基及C_7-16芳烷氧基-羰基可藉由諸如，還原、水解及類似者之反應而轉化。 The C _1-6 alkoxy-carbonyl group, the C _6-14 aryloxy-carbonyl group and the C _7-16 aralkyloxy-carbonyl group can be converted by, for example, reduction, hydrolysis and the like.

磺酸基可藉由諸如，磺醯胺化、還原及類似者之反應而轉化。 The sulfonic acid group can be converted by, for example, sulfoximation, reduction, and the like.

鹵素原子可藉由諸如，多種親核性取代反應、多種偶合反應及類似者之反應而轉化。 The halogen atom can be converted by, for example, a plurality of nucleophilic substitution reactions, various coupling reactions, and the like.

視需要經鹵化之C_1-6烷基磺醯氧基可藉由諸如，多種親核性取代反應、多種偶合反應及類似者之反應而轉化。 The C _1-6 alkylsulfonyloxy group which is halogenated as needed may be converted by, for example, a plurality of nucleophilic substitution reactions, various coupling reactions, and the like.

氰基可藉由諸如，還原、水解及類似者之反應而轉化。 The cyano group can be converted by, for example, reduction, hydrolysis, and the like.

胺基羰基可藉由諸如，脫水、還原及類似者之反應而轉化。 The aminocarbonyl group can be converted by, for example, dehydration, reduction, and the like.

氧硼基可藉由諸如，氧化、多種偶合反應及類似者之反應而轉化。 The boron boron group can be exemplified by, for example, oxidation, various coupling reactions, and the like. The reaction is converted.

前述各別反應中，當獲得游離形式之化合物時，其可根據習知方法轉化成鹽。當化合物以鹽獲得時，其可根據習知方法轉化成游離形式或其他鹽。 In the foregoing respective reactions, when a compound in a free form is obtained, it can be converted into a salt according to a conventional method. When the compound is obtained as a salt, it can be converted into a free form or other salt according to conventional methods.

此等官能基可根據本質上已知之方法轉化，例如，Comprehensive Organic Transformations,Second Edition,Wiley-VCH,Richard C.Larock中描述之方法及類似者。 Such functional groups can be converted according to methods known per se, for example, the methods described in Comprehensive Organic Transformations, Second Edition, Wiley-VCH, Richard C. Larock, and the like.

化合物(I)之製造方法之各反應和起始材料化合物之合成之各反應中，當起始材料化合物具有胺基、羧基、羥基、羰基、羰基或巰基作為取代基時，通常用於胜肽化學之保護基及類似者可導入此等基團。如需要，反應之後，目標化合物可藉由保護基而獲得移除。 In the respective reactions of the respective methods for the production of the compound (I) and the synthesis of the starting material compound, when the starting material compound has an amine group, a carboxyl group, a hydroxyl group, a carbonyl group, a carbonyl group or a thiol group as a substituent, it is usually used for a peptide. Chemical protecting groups and the like can be introduced into these groups. If desired, the target compound can be removed by a protecting group after the reaction.

至於胺基保護基，使用例如，甲醯基、C_1-6烷基-羰基(例如，乙醯基、乙基羰基等)、苯基羰基、C_1-6烷基-氧基羰基(例如，甲氧基羰基、乙氧基羰基、第三丁氧基羰基(Boc)等)、烯丙氧基羰基(Alloc)、苯氧基羰基、茀基甲氧基羰基(Fmoc)、C_7-10芳烷基-羰基(例如，苯甲基羰基等)、C_7-10芳烷基-氧基羰基(例如，苯甲氧基羰基(Z)等)、C_7-10芳烷基(例如，苯甲基等)、2-(三甲基矽基)乙氧基甲基(SEM)、三苯甲基、酞醯基、N,N-二甲基胺基伸甲基、烯丙基、第三丁基及類似者，其各視需要具有取代基。至於此等取代基，使用苯基、鹵素原子(例如，氟、氯、溴、碘等)、C_1-6烷基-羰基(例如，甲基羰基、乙基羰基、丁基羰基等)、硝基及類似者。取代基之數目為約1至3。 As the amino protecting group, for example, a decyl group, a C _1-6 alkyl-carbonyl group (for example, an ethyl fluorenyl group, an ethylcarbonyl group, etc.), a phenylcarbonyl group, a C _1-6 alkyl-oxycarbonyl group (for example, , methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl (Boc), etc., allyloxycarbonyl (Alloc), phenoxycarbonyl, fluorenylmethoxycarbonyl (Fmoc), C _{7- 10} aralkyl-carbonyl (eg, benzylcarbonyl, etc.), C _7-10 aralkyl-oxycarbonyl (eg, benzyloxycarbonyl (Z), etc.), C _7-10 aralkyl (eg, , benzyl, etc.), 2-(trimethylsulfonyl)ethoxymethyl (SEM), trityl, decyl, N,N-dimethylaminomethyl, allyl, The third butyl group and the like, each having a substituent as needed. As such substituents, a phenyl group, a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), a C _1-6 alkyl-carbonyl group (for example, methylcarbonyl group, ethylcarbonyl group, butylcarbonyl group, etc.), Nitro and similar. The number of substituents is from about 1 to 3.

至於羧基保護基，使用例如，C_1-6烷基(例如，甲基、乙基、正丙基、異丙基、正丁基、第三丁基等)、烯丙基、苯甲基、苯基、三苯甲基、三烷基矽基、及類似者，其各視需要具有取代基。至於此等取代基，使用鹵素原子(例如，氟、氯、溴、碘等)、甲醯基、C_1-6烷基-羰基(例如，乙醯基、乙基羰基、丁基羰基等)、硝基及類似者。取代基之數目為約1至3。 As the carboxy protecting group, for example, a C _1-6 alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, etc.), allyl, benzyl, A phenyl group, a trityl group, a trialkyl fluorenyl group, and the like, each having a substituent as needed. As such substituents, a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), a decyl group, a C _1-6 alkyl-carbonyl group (for example, an ethyl fluorenyl group, an ethylcarbonyl group, a butylcarbonyl group, etc.) is used. Nitro and similar. The number of substituents is from about 1 to 3.

至於羥基之保護基，使用例如，C_1-6烷基(例如，甲基、乙基、正丙基、異丙基、正丁基、第三丁基等)、C_7-10芳烷基(例如，苯甲基等)、甲醯基、C_1-6烷基-羰基(例如，乙醯基、乙基羰基等)、苯甲醯基、C_7-10芳烷基-羰基(例如，苯甲基羰基等)、四氫哌喃基、呋喃基、矽基及類似者，其各視需要具有取代基。至於此等取代基，使用鹵素原子(例如，氟、氯、溴、碘等)、C_1-6烷基(例如，甲基、乙基、正丙基等)、苯基、C_7-10芳烷基(例如，苯甲基等)、C_1-6烷氧基(例如，甲氧基、乙氧基、正丙氧基等)、硝基及類似者。取代基之數目為約1至4。 As the protecting group for a hydroxyl group, for example, a C _1-6 alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, etc.), a C _7-10 aralkyl group is used. (eg, benzyl, etc.), indolyl, C _1-6 alkyl-carbonyl (eg, ethyl ethenyl, ethylcarbonyl, etc.), benzamyl, C _7-10 aralkyl-carbonyl (eg , benzylcarbonyl, etc.), tetrahydropyranyl, furyl, fluorenyl and the like, each having a substituent as needed. As such substituents, a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), a C _1-6 alkyl group (e.g., methyl, ethyl, n-propyl, etc.), a phenyl group, a C _{7-10 are used.} An aralkyl group (e.g., benzyl group, etc.), a C _1-6 alkoxy group (e.g., methoxy, ethoxy, n-propoxy, etc.), a nitro group, and the like. The number of substituents is from about 1 to 4.

保護羰基之實例包含環狀縮醛(例如，1,3-二噁烷)、非環狀縮醛(例如，二-C_1-6烷基縮醛)及類似者。 Examples of the protective carbonyl group include a cyclic acetal (for example, 1,3-dioxane), an acyclic acetal (for example, a di-C _1-6 alkyl acetal), and the like.

巰基保護基之實例包含C_1-6烷基、苯基、三苯甲基、C_7-10芳烷基(例如，苯甲基)、C_1-6烷基-羰基、苯甲醯基、C_7-10芳烷基-羰基(例如，苯甲基羰基)、C_1-6烷氧基-羰基、C_6-14芳氧基-羰基(例如，苯氧基羰基)、C_7-14芳烷氧基-羰基(例如，苯甲氧基羰基、9-茀基甲氧基羰基)、2-四氫哌喃基、 C_1-6烷基胺基-羰基(例如，甲基胺基羰基、乙基胺基羰基)及類似者。此等保護基視需要經選自鹵素原子、C_1-6烷基、C_1-6烷氧基以及硝基之1至3個取代基取代。 Examples of mercapto protecting groups include C _1-6 alkyl, phenyl, trityl, C _7-10 aralkyl (eg, benzyl), C _1-6 alkyl-carbonyl, benzhydryl, C _7-10 aralkyl-carbonyl (for example, benzylcarbonyl), C _1-6 alkoxy-carbonyl, C _6-14 aryloxy-carbonyl (for example, phenoxycarbonyl), C _7-14 Aralkyloxy-carbonyl (for example, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), 2-tetrahydropyranyl, C _1-6 alkylamino-carbonyl (for example, methylamino) Carbonyl, ethylaminocarbonyl) and the like. These protecting groups are preferably substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, and a nitro group.

此等保護基可藉由本質上已知之方法導入或移除，例如，Greene’s Protective Organic Transformations,4th Edition,Wiley-Interscience,Theodora W.Greene,Peter G.M.Wuts中描述之方法及類似者。具體而言，可描述使用酸、鹼、紫外線、肼、苯基肼、N-甲基二硫胺甲酸鈉、四丁基氟化銨、乙酸鈀、三烷基矽基鹵化物(例如，三甲基矽基碘化物、三甲基矽基溴化物)及類似者之方法、還原方法及類似者。 Such protecting groups can be introduced or removed by methods known per se, for example, those described in Greene's Protective Organic Transformations, 4th Edition, Wiley-Interscience, Theodora W. Greene, Peter G. M. Wuts, and the like. Specifically, the use of an acid, a base, an ultraviolet ray, a hydrazine, a phenyl hydrazine, a sodium N-methyldithiocarbamate, a tetrabutylammonium fluoride, a palladium acetate, a trialkyl fluorenyl halide (for example, a top three) can be described. A method based on sulfhydryl iodide, trimethylsulfonium bromide, and the like, a reduction method, and the like.

當化合物(I)是以組態異構物、非鏡像異構物、構形物及類似者存在時，其可各藉由已知手段單離。當化合物(I)含有光學異構物時，可藉由以一般光學解析度之手段解析消旋物而獲得光學活性形式((+)形式、(-)形式)獲得。 When the compound (I) is present as a configurational isomer, a non-image isomer, a configuration, and the like, it may each be separated by a known means. When the compound (I) contains an optical isomer, it can be obtained by analyzing the racemate by a general optical resolution to obtain an optically active form ((+) form, (-) form).

當化合物(I)含有光學異構物、立體異構物、位向異構物、旋轉異構體或互變異構物時，此等者亦涵蓋於化合物(I)中，而且可根據合成方法和本質上已知之方法獲得為單一產物。 When the compound (I) contains an optical isomer, a stereoisomer, a meta isomer, a rotamer or a tautomer, these are also encompassed in the compound (I), and may be synthesized according to the method. And methods known per se are obtained as a single product.

例如，光學解析度之方法可為本質上已知之方法，諸如，分段再結晶方法、掌性管柱方法、非鏡像異構物方法等。 For example, the method of optical resolution may be a method known per se, such as a segmentation recrystallization method, a palm column method, a non-image isomer method, and the like.

1)分段再結晶方法 1) Segmentation recrystallization method

一種其中形成具有光學活性化合物(例如，(+)-杏仁酸、(-)-杏仁酸、(+)-酒石酸、(-)-酒石酸、(+)-1-苯乙胺、(-)-1-苯乙胺、辛可寧、(-)-辛可尼汀、馬錢子鹼等)之消旋物或其鹽之方法，該消旋物或其鹽係藉由分段再結晶方法分離，且若期望，進行中和步驟以產生游離之光學異構物。 One in which an optically active compound is formed (for example, (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1-phenylethylamine, (-)- a method of a racemate of 1-phenylethylamine, cinchonine, (-)-cinchonine, strychnine, or the like, or a salt thereof, the racemate or a salt thereof by a method of segmental recrystallization Separation, and if desired, a neutralization step to produce free optical isomers.

2)掌性管柱方法 2) palm tube method

一種其中對管柱(掌性管柱)施用消旋物或其鹽以分離光學異構物而允許分離。在液體層析術之情況下，例如，對掌性管柱(諸，ENALTIO-OVM(由Tosoh Corporation所製造)、CHIRAL系列(由所製造Daicel Chemical Industries、Ltd.)及類似者施用光學異構物之混合物，以及單獨或以摻合物之方式以作為溶析液之水、多種緩衝劑(例如，磷酸鹽緩衝劑等)和有機溶劑(例如，乙醇、甲醇、異丙醇、乙腈、三氟乙酸、二乙胺等)展開以分離光學異構物。氣體層析術之情況下，例如，使用掌性管柱(諸如，CP-Chirasil-DeX CB(由GL Sciences Inc.所製造)及類似者以允許分離。 One in which a racemate or a salt thereof is applied to a column (a palm column) to separate optical isomers to allow separation. In the case of liquid chromatography, for example, optical isomerism is applied to a palmar column (such as ENALTIO-OVM (manufactured by Tosoh Corporation), CHIRAL series (manufactured by Daicel Chemical Industries, Ltd.), and the like. a mixture of substances, as a solvent for the eluent alone or in a blend, a plurality of buffers (for example, a phosphate buffer, etc.) and an organic solvent (for example, ethanol, methanol, isopropanol, acetonitrile, three Fluoroacetic acid, diethylamine, etc.) are developed to separate optical isomers. In the case of gas chromatography, for example, a palmar string (such as CP-Chirasil-DeX CB (manufactured by GL Sciences Inc.) and Similar to allow separation.

3)非鏡像異構物方法 3) Non-image isomer method

一種其中藉由與光學活性試劑之化學反應而將消旋物混合物製備成非鏡像異構物混合物，該混合物係藉由典型的分離手段(例如，分段再結晶方法、層析術方法等)及類似者而製造成單一物質，以及進行化學處理(諸如，水解反應及類似者)以分離光學活性試劑部分，藉此獲得光學異構物。例如，當化合物(I)在分子中含有羥基或一級或二級胺基時，化合物和光學活性有機酸(例如，MTPA[α-甲氧基- α-(三氟甲基)苯基乙酸]、(-)-甲氧基乙酸等)及類似者經歷縮合反應以分別產生酯化合物或醯胺化合物之非鏡像異構物。當化合物(I)具有羧基時，化合物和光學活性胺或光學活性醇試劑經歷縮合反應以分別產生醯胺化合物或酯化合物之非鏡像異構物。將經分離之非鏡像異構物以酸水解反應或鹼水解反應而轉化成原始化合物之光學異構物。 A mixture in which a racemic mixture is prepared as a non-imagewise isomer by chemical reaction with an optically active agent, by a typical separation means (eg, a staged recrystallization method, a chromatographic method, etc.) And a similar substance is produced as a single substance, and a chemical treatment such as a hydrolysis reaction and the like is carried out to separate the optically active reagent portion, thereby obtaining an optical isomer. For example, when the compound (I) contains a hydroxyl group or a primary or secondary amine group in the molecule, the compound and the optically active organic acid (for example, MTPA[ α -methoxy- α- (trifluoromethyl)phenylacetic acid] , (-)-methoxyacetic acid, etc.) and the like undergo a condensation reaction to produce a non-image isomer of the ester compound or the guanamine compound, respectively. When the compound (I) has a carboxyl group, the compound and the optically active amine or optically active alcohol reagent undergo a condensation reaction to respectively produce a non-image isomer of the guanamine compound or the ester compound. The isolated non-Spiegelmer is converted to the optical isomer of the original compound by acid hydrolysis or base hydrolysis.

本發明之化合物之製造方法中描述之溶劑、酸以及鹼係解釋如下。 The solvent, acid and base described in the production method of the compound of the present invention are explained below.

至於"溶劑"，可使用例如，"醇類"、"醚類"、"烴類"、"醯胺類"、"鹵化烴"、"腈類"、"酮類"、"酯類"、"亞碸類"、"水"及類似者。 As the "solvent", for example, "alcohol", "ether", "hydrocarbon", "melamine", "halogenated hydrocarbon", "nitrile", "ketone", "ester", "Aachen", "water" and the like.

"醇類"之實例包含甲醇、乙醇、1-丙醇、2-丙醇、第三丁基醇及類似者。 Examples of the "alcohol" include methanol, ethanol, 1-propanol, 2-propanol, t-butyl alcohol, and the like.

"醚類"之實例包含二乙基醚、二異丙基醚、二苯基醚、四氫呋喃、1,4-二噁烷、1,2-二甲氧基乙烷、第三丁基甲基醚及類似者。 Examples of the "ether" include diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and tert-butyl methyl ether. Similar.

"烴類"之實例包含"芳香族烴類"和"飽和烴類"。"芳香族烴類"之實例包含苯、甲苯及類似者。"飽和烴類"之實例包含環己烷、己烷、石油醚及類似者。 Examples of "hydrocarbons" include "aromatic hydrocarbons" and "saturated hydrocarbons". Examples of "aromatic hydrocarbons" include benzene, toluene, and the like. Examples of "saturated hydrocarbons" include cyclohexane, hexane, petroleum ether, and the like.

"醯胺類"之實例包含N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、N-甲基吡咯啶酮、六甲基磷酸三醯胺及類似者。 Examples of "melamines" include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, trimethylamine hexamethylphosphate, and the like.

"鹵化烴"之實例包含二氯甲烷、三氯甲烷、四氯化碳、1,2-二氯乙烷、氯苯、三氟甲基苯及類似者。 Examples of "halogenated hydrocarbons" include dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, trifluoromethylbenzene, and the like.

"腈類"之實例包含乙腈、丙腈及類似者。 Examples of "nitrile" include acetonitrile, propionitrile and the like.

"酮類"之實例包含丙酮、乙基甲基酮及類似者。 Examples of "ketones" include acetone, ethyl methyl ketone and the like.

"酯類"之實例包含乙酸乙酯、乙酸第三丁酯及類似者。 Examples of "esters" include ethyl acetate, t-butyl acetate, and the like.

"亞碸類"之實例包含二甲基亞碸及類似者。 Examples of "Athene" include dimethyl hydrazine and the like.

"酸"之實例包含"有機酸"、"無機酸"、"路易士酸"及類似者。 Examples of "acid" include "organic acid", "mineral acid", "Louis acid" and the like.

"有機酸"之實例包含甲酸、乙酸、丙酸、三氟乙酸、檸檬酸、甲磺酸、對甲苯磺酸及類似者。 Examples of the "organic acid" include formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.

"無機酸"之實例包含鹽酸、硫酸及類似者。 Examples of the "mineral acid" include hydrochloric acid, sulfuric acid, and the like.

"路易士酸"之實例包含三氯化硼、三溴化硼及類似者。 Examples of "Louis acid" include boron trichloride, boron tribromide, and the like.

"鹼"之實例包含"無機鹼"、"鹼性鹽"、"芳香族胺"、"三級胺"、"鹼金屬氫化物"、"鹼金屬"、"金屬醯胺類"、"烷基金屬"、"芳基金屬"、"金屬烷氧化物"及類似者。 Examples of "base" include "inorganic base", "basic salt", "aromatic amine", "tribasic amine", "alkali metal hydride", "alkali metal", "metal amide", "alkane" Base metal "," aryl metal", "metal alkoxide" and the like.

"無機鹼"之實例包含氫氧化鈉、氫氧化鉀、氫氧化鋰、氫氧化鋇及類似者。 Examples of the "inorganic base" include sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, and the like.

"鹼性鹽"之實例包含碳酸鈉、碳酸鉀、碳酸銫、碳酸氫鈉、乙酸鈉、磷酸三鉀、乙酸銨及類似者。 Examples of the "basic salt" include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, sodium acetate, tripotassium phosphate, ammonium acetate, and the like.

"芳香族胺"之實例包含吡啶、2,6-二甲基吡啶及類似者。 Examples of "aromatic amines" include pyridine, 2,6-lutidine, and the like.

"三級胺"之實例包含三乙胺、三丙基胺、三丁基胺、二異丙基乙基胺、環己基二甲基胺、4-二甲基胺基吡啶、N,N-二甲基苯胺、N-甲基哌啶、N-甲基吡咯啶、N-甲基嗎啉、1,8-二氮雜雙環[5.4.0]十一-7-烯及類似者。 Examples of "tribasic amines" include triethylamine, tripropylamine, tributylamine, diisopropylethylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N- Dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene and the like.

"鹼金屬氫化物"之實例包含氫化鈉、氫化鉀及類似者。 Examples of the "alkali metal hydride" include sodium hydride, potassium hydride, and the like.

"鹼金屬"之實例包含鈉、鋰、鉀及類似者。 Examples of "alkali metals" include sodium, lithium, potassium, and the like.

"金屬醯胺類"之實例包含醯胺鈉、二異丙基醯胺鋰、六甲基二矽胺化鋰及類似者。 Examples of the "metal amide" include sodium amide, lithium diisopropyl guanamine, lithium hexamethyldiamine, and the like.

"烷基金屬"之實例包含丁基鋰、第二丁基鋰、第三丁基鋰及類似者。 Examples of the "alkyl metal" include butyl lithium, t-butyl lithium, t-butyl lithium, and the like.

"芳基金屬"之實例包含苯基鋰及類似者。 Examples of "aryl metal" include phenyl lithium and the like.

"金屬烷氧化物"之實例包含甲氧化鋰、乙氧化鈉、第三丁氧化鈉、第三丁氧化鉀及類似者。 Examples of "metal alkoxide" include lithium pentoxide, sodium ethoxide, sodium tributoxide, potassium third potassium hydride, and the like.

其中L¹為離去基，而且其他符號係如以上定義。 Wherein L ¹ is a leaving group, and other symbols are as defined above.

化合物(2)可以可商購之產品獲得，或可藉由本質上已知之方法或與其類似之方法製造。 The compound (2) can be obtained from commercially available products, or can be produced by a method known per se or a method analogous thereto.

L¹之離去基之實例包含羥基、鹵素原子、視需要鹵化之C_1-6烷基磺醯氧基、視需要鹵化之C_1-6烷氧基、視需要經取代之芳氧基、視需要經取代之芳烷氧基、1-1H-咪唑基及類似者，優先為羥基、鹵素原子以及C_1-2烷氧基。 Examples of the leaving group of L ¹ include a hydroxyl group, a halogen atom, a C _1-6 alkylsulfonyloxy group optionally halogenated, a C _1-6 alkoxy group optionally halogenated, an optionally substituted aryloxy group, The aralkyloxy group, the 1-1H-imidazolyl group and the like which are optionally substituted are preferably a hydroxyl group, a halogen atom and a C _1-2 alkoxy group.

<步驟1> <Step 1>

化合物(1)可藉由化合物(2)與化合物(3)之縮合反應而製造。 Compound (1) can be obtained by condensation reaction of compound (2) with compound (3) Manufacturing.

<步驟1-1> <Step 1-1>

化合物(2)(其中L¹為羥基)與化合物(3)之縮合是在縮合劑之存在下於不會不利地影響溶劑之反應中進行。縮合劑之實例包含通常已知的縮合劑，諸如，碳二亞胺縮合試劑(例如，二環己基碳二亞胺(DCC)、二異丙基碳二亞胺(DIC)、N-乙基-N’-3-二甲基胺基丙基碳二亞胺以及其鹽酸鹽(WSC、WSC-HCl、EDCI)及類似者)、磷酸縮合試劑(例如，苯并***-1-基氧基-參(二甲基胺基)鏻六氟磷酸鹽(BOP)、疊氮磷酸二苯酯(DPPA)及類似者)、N,N’-羰基二咪唑、2-甲基-6-硝基苯甲酸酐、四氟硼酸2-氯-1,3-二甲基咪唑鎓、2-氯-1-甲基吡啶鎓、N,N-二甲基胺磺醯基氯化物、2-氯-4,6-二甲氧基三、4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基-嗎啉鎓氯化物及類似者。 The condensation of the compound (2) (wherein L ¹ is a hydroxyl group) with the compound (3) is carried out in the presence of a condensing agent in a reaction which does not adversely affect the solvent. Examples of the condensing agent include generally known condensing agents such as carbodiimide condensing agents (for example, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), N-ethyl -N'-3-dimethylaminopropyl carbodiimide and its hydrochloride (WSC, WSC-HCl, EDCI) and the like), a phosphoric acid condensation reagent (for example, benzotriazol-1-yl) Oxy-paraxyl (dimethylamino)phosphonium hexafluorophosphate (BOP), diphenylphosphoryl azide (DPPA) and the like), N,N'-carbonyldiimidazole, 2-methyl-6- Nitrobenzoic anhydride, 2-chloro-1,3-dimethylimidazolium tetrafluoroborate, 2-chloro-1-methylpyridinium, N,N-dimethylaminesulfonyl chloride, 2- Chloro-4,6-dimethoxy three , 4-(4,6-dimethoxy-1,3,5-three 2-yl)-4-methyl-morpholinium chloride and the like.

當碳二亞胺縮合試劑、2-甲基-6-硝基苯甲酸酐及類似者用作縮合劑時，於所需處，反應效率可藉由使用適合的縮合促進劑(例如，1-羥基-7-氮雜苯并***、1-羥基苯并***、N-羥基琥珀醯亞胺、N-羥基鄰苯二甲醯亞胺、4-二甲基胺基吡啶等)而改善。當磷酸縮合試劑(例如，苯并***-1-基氧基-參(二甲基胺基)鏻六氟磷酸鹽(BOP)、疊氮磷酸二苯酯(DPPA)及類似者)、2-甲基-6-硝基苯甲酸酐及類似者用作縮合劑時，反應效率通常可藉由添加有機胺鹼，諸如，三乙胺、二異丙基乙基胺及類似者而改善。 When a carbodiimide condensation reagent, 2-methyl-6-nitrobenzoic anhydride, and the like are used as a condensing agent, the reaction efficiency can be achieved by using a suitable condensation accelerator (for example, 1- Improved by hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide, 4-dimethylaminopyridine, etc.) . As a phosphoric acid condensation reagent (for example, benzotriazol-1-yloxy-parade (dimethylamino)phosphonium hexafluorophosphate (BOP), diphenylphosphoryl azide (DPPA) and the like), 2 When methyl-6-nitrobenzoic anhydride and the like are used as a condensing agent, the reaction efficiency can usually be improved by adding an organic amine base such as triethylamine, diisopropylethylamine and the like.

當化合物(3)形成鹽時，這反應通常是藉由添加鹼而進行。此鹼之實例包含三級胺、鹼性鹽、金屬氫錯合物化合物及類似者。此等鹼通常是以每1莫耳之化合物(3)為約1至100莫耳，較佳為約1至10莫耳之含量使用。 When the compound (3) forms a salt, the reaction is usually carried out by adding a base. Row. Examples of the base include a tertiary amine, a basic salt, a metal hydrogen complex compound, and the like. These bases are usually used in an amount of from about 1 to 100 moles, preferably from about 1 to 10 moles, per 1 mole of the compound (3).

化合物(3)通常是以每1莫耳之化合物(2)為以約0.1至10莫耳，較佳為約0.5至2莫耳之含量使用。欲使用之縮合劑通常是以每1莫耳之化合物(2)為約0.1至10莫耳，較佳為約1至3莫耳之含量使用。上述縮合促進劑和鹼通常是以每1莫耳之化合物(2)為約0.1至10莫耳，較佳為約0.3至3莫耳之含量使用。 The compound (3) is usually used in an amount of about 0.1 to 10 moles, preferably about 0.5 to 2 moles per 1 mole of the compound (2). The condensing agent to be used is usually used in an amount of about 0.1 to 10 moles, preferably about 1 to 3 moles per 1 mole of the compound (2). The above condensation accelerator and base are usually used in an amount of from about 0.1 to 10 moles, preferably from about 0.3 to 3 moles per 1 mole of the compound (2).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，鹵化烴類、醯胺類、亞碸類、醚類、腈類、酯類、烴類、水及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as a halogenated hydrocarbon, a guanamine, an anthracene, an ether, a nitrile, an ester, a hydrocarbon, water, and the like. , mixed solvents and the like.

雖然反應時間取決於欲使用之試劑和溶劑而改變，通常為約0.1至48小時，較佳為約0.5至24小時。 Although the reaction time varies depending on the reagent and solvent to be used, it is usually from about 0.1 to 48 hours, preferably from about 0.5 to 24 hours.

反應溫度通常為約0至200℃，較佳為約20至100℃。 The reaction temperature is usually from about 0 to 200 ° C, preferably from about 20 to 100 ° C.

<步驟1-2> <Step 1-2>

化合物(2)(其中L¹為羥基除外之離去基)和化合物(3)之縮合，且較佳為化合物(2)(其中L¹為C_1-2烷氧基除外之離去基)和化合物(3)之縮合是在不會不利地影響反應的溶劑中進行，而且如需要則添加鹼。 Compound (2) (except where L ¹ is a leaving group of a hydroxyl group) and the compound (3) and condensed, and preferably the compound (2) (wherein L ¹ is C _1-2 alkoxy exception of the leaving group) The condensation with the compound (3) is carried out in a solvent which does not adversely affect the reaction, and a base is added if necessary.

欲於此使用之鹼之實例包含三級胺、芳香族胺、鹼性鹽及類似者。鹼通常是以每1莫耳之化合物(2)為約0.1至10莫耳，較佳為約0.3至3莫耳之含量使用。 Examples of the base to be used herein include a tertiary amine, an aromatic amine, a basic salt, and the like. The base is usually used in an amount of about 0.1 to 10 moles, preferably about 0.3 to 3 moles per 1 mole of the compound (2).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，鹵化烴、醯胺類、醚類、腈類、酯類、烴類、水及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as a halogenated hydrocarbon, a guanamine, an ether, a nitrile, an ester, a hydrocarbon, water, and the like, a mixed solvent thereof, and Similar.

雖然反應時間取決於欲使用之試劑和溶劑，通常為約0.1至48小時，較佳為約0.5至24小時。 Although the reaction time depends on the reagent and solvent to be used, it is usually from about 0.1 to 48 hours, preferably from about 0.5 to 24 hours.

反應溫度為約-40至200℃，較佳為約0至100℃。 The reaction temperature is about -40 to 200 ° C, preferably about 0 to 100 ° C.

<步驟1-3> <Step 1-3>

化合物(2)(其中L¹為羥基除外之離去基)和化合物(3)之縮合，且較佳為化合物(2)(其中L¹為C_1-2烷氧基除外之離去基)和化合物(3)之縮合是在有機鋁試劑之存在下，在不會不利地影響反應之溶劑中進行。有機鋁試劑之實例包含通常為已知試劑，諸如，三甲基鋁、三乙基鋁、二甲基氯化鋁、二異丁基鋁氫化物及類似者。 Compound (2) (except where L ¹ is a leaving group of a hydroxyl group) and the compound (3) and condensed, and preferably the compound (2) (wherein L ¹ is C _1-2 alkoxy exception of the leaving group) The condensation with the compound (3) is carried out in the presence of an organoaluminum reagent in a solvent which does not adversely affect the reaction. Examples of the organoaluminum reagent include generally known reagents such as trimethylaluminum, triethylaluminum, dimethylaluminum chloride, diisobutylaluminum hydride, and the like.

有機鋁試劑通常是以每1莫耳之化合物(2)約0.1至10莫耳，較佳為約1至3莫耳之含量使用。 The organoaluminum reagent is usually used in an amount of about 0.1 to 10 moles, preferably about 1 to 3 moles per 1 mole of the compound (2).

至於這反應，如需要，可使用適合的活化劑，諸如，鹽酸及類似者。 As for this reaction, a suitable activator such as hydrochloric acid and the like can be used as needed.

當化合物(3)形成鹽，諸如，鹽酸鹽及類似者時，這反應可藉由添加鹼以抑制諸如鹽酸及類似者之活化劑之作用而進行。此鹼之實例包含三級胺、鹼性鹽、金屬氫錯合物化合物及類似者。此等活化劑和鹼通常是每1莫耳之化合物(3)為約1至100莫耳，較佳為約1至10莫耳之含量使用。 When the compound (3) forms a salt such as a hydrochloride and the like, the reaction can be carried out by adding a base to inhibit the action of an activator such as hydrochloric acid and the like. Examples of the base include a tertiary amine, a basic salt, a metal hydrogen complex compound, and the like. These activators and bases are usually used in an amount of from about 1 to 100 moles, preferably from about 1 to 10 moles, per 1 mole of the compound (3).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，鹵化烴、烴類及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although only The solvent is not particularly limited, and is preferably, for example, a solvent such as a halogenated hydrocarbon, a hydrocarbon, and the like, a mixed solvent thereof, and the like.

反應溫度為約0至200℃，較佳為約20至100℃。 The reaction temperature is from about 0 to 200 ° C, preferably from about 20 to 100 ° C.

化合物(17)係反應方案1中之化合物(3)(其中-L-Y為-C(R³)(R⁴)-OH)，其可藉由例如反應方案2中顯示之方法或與其類似之方法產生。 Compound (17) is a compound (3) in Reaction Scheme 1 (wherein -LY is -C(R ³ )(R ⁴ )-OH), which can be obtained by, for example, the method shown in Reaction Scheme 2 or a method analogous thereto produce.

其中R⁵為胺基保護基，R⁶為羧基保護基，以及其他符號如以上定義。 Wherein R ⁵ is an amino protecting group, R ⁶ is a carboxy protecting group, and the other symbols are as defined above.

化合物(4)可以可商購之產品獲得，或可藉由本質上已知之方法或與其類似之方法製造，以及化合物(11)可以可商購之產品獲得。 The compound (4) can be obtained from a commercially available product, or can be produced by a method known per se or a method analogous thereto, and the compound (11) can be obtained from a commercially available product.

<步驟2> <Step 2>

化合物(5)可藉由使化合物(4)經歷史特烈卡(Strecker)反應而製造。 Compound (5) can be produced by subjecting compound (4) to a historical Strecker reaction.

這反應通常縮合化合物(4)和氨或其等同者以及氰化氫或其等同者，導致對應的α-胺基腈(5)。 This reaction typically condenses compound (4) with ammonia or its equivalent as well as hydrogen cyanide or its equivalent, resulting in the corresponding a-amino nitrile (5).

氨之等同者之實例包含氯化銨、碳酸銨、苯甲基胺及類似者。氨或其等同者通常是以每1莫耳之化合物(4)為約1至50莫耳，較佳為約1至10莫耳之含量使用。 Examples of the equivalent of ammonia include ammonium chloride, ammonium carbonate, benzylamine, and the like. Ammonia or its equivalent is usually used in an amount of from about 1 to 50 moles, preferably from about 1 to 10 moles per 1 mole of compound (4).

氰化氫之等同者之實例包含氰化鈉、氰化鉀、三甲基矽基氰化物及類似者。氰化氫或其等同者通常是以每1莫耳之化合物(4)為約1至50莫耳，較佳為約1至10莫耳之含量使用。 Examples of the equivalent of hydrogen cyanide include sodium cyanide, potassium cyanide, trimethyldecyl cyanide, and the like. The hydrogen cyanide or its equivalent is usually used in an amount of from about 1 to 50 moles, preferably from about 1 to 10 moles per 1 mole of the compound (4).

如需要，這反應可藉由添加路易士酸，諸如，四異丙醇鈦(IV)及類似者而進行。路易士酸通常是以每1莫耳之化合物(4)為約0.05至50莫耳，較佳為約0.1至10莫耳之含量使用。 This reaction can be carried out by adding a Lewis acid such as titanium (IV) tetraisopropoxide and the like, if necessary. The Lewis acid is usually used in an amount of about 0.05 to 50 moles, preferably about 0.1 to 10 moles per 1 mole of the compound (4).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，醇類、鹵化烴、醚類、烴類、腈類、水及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as an alcohol, a halogenated hydrocarbon, an ether, a hydrocarbon, a nitrile, water, or the like. It is a mixed solvent and the like.

雖然反應時間取決於欲使用之試劑和溶劑，通常約0.1至100小時，較佳為約0.5至48小時。 Although the reaction time depends on the reagent and solvent to be used, it is usually about 0.1 to 100 hours, preferably about 0.5 to 48 hours.

反應溫度為約-78至200℃，較佳為約-78至100℃。 The reaction temperature is about -78 to 200 ° C, preferably about -78 to 100 ° C.

<步驟3> <Step 3>

化合物(6)可藉由保護化合物(5)之胺基而製造。 The compound (6) can be produced by protecting the amine group of the compound (5).

此保護基之實例包含第三丁氧基羰基(Boc)、苯甲氧基羰基(Z)及類似者。 Examples of such a protecting group include a third butoxycarbonyl group (Boc), a benzyloxycarbonyl group (Z), and the like.

這步驟中之導入保護基可藉由本質上已知之方法進行，例如Greene’s Protective Groups in Organic Synthesis,4^th Edition,Wiley-Interscience,Theodora W.Greene,Peter G.M.Wuts中描述之方法及類似者。 This step of introducing the protective group may be carried out by methods known in nature, for example, Greene's Protective Groups in Organic Synthesis, 4 th Edition, Wiley-Interscience, Theodora W.Greene, the method described in Peter GMWuts and the like.

<步驟4> <Step 4>

化合物(7)可從化合物(6)製造。 Compound (7) can be produced from Compound (6).

這反應可藉由本質上已知之方法進行，例如，Synthesis,vol.12,pp.949-950、1989中描述之方法或與其類似之方法。例如，可描述使用碳酸鉀和水性過氧化氫及類似者之反應。 This reaction can be carried out by a method known per se, for example, the method described in Synthesis, vol. 12, pp. 949-950, 1989 or a method analogous thereto. For example, the reaction using potassium carbonate and aqueous hydrogen peroxide and the like can be described.

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，亞碸類、醇類、水及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as an anthraquinone, an alcohol, water, and the like, a mixed solvent thereof, and the like.

雖然反應時間取決於欲使用之試劑和溶劑，通常為約0.1至100小時，較佳為約0.5至36小時。 Although the reaction time depends on the reagent and solvent to be used, it is usually from about 0.1 to 100 hours, preferably from about 0.5 to 36 hours.

反應溫度為約-30至150℃，較佳為約0至120℃。 The reaction temperature is about -30 to 150 ° C, preferably about 0 to 120 ° C.

<步驟5> <Step 5>

化合物(10)可藉由使化合物(7)經歷水解反應而製造。 Compound (10) can be produced by subjecting compound (7) to a hydrolysis reaction.

這反應係根據習知方法進行，而且使用酸或鹼。 This reaction is carried out according to a conventional method, and an acid or a base is used.

酸之實例包含無機酸、有機酸及類似者。鹼之實例包含無機鹼、鹼性鹽及類似者。此等酸和鹼通常是以每1莫耳之化合物(7)為約0.5至100莫耳，較佳為約1至20莫耳之含量使用。 Examples of the acid include inorganic acids, organic acids, and the like. Examples of the base include inorganic bases, basic salts, and the like. These acids and bases are usually used in an amount of from about 0.5 to 100 moles, preferably from about 1 to 20 moles per 1 mole of the compound (7).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，醇類、醚類、水及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as an alcohol, an ether, water, and the like, a mixed solvent thereof, and the like.

雖然反應時間取決於欲使用之試劑和溶劑，通常約0.1至100小時，較佳為約0.1至48小時。 Although the reaction time depends on the reagent and solvent to be used, it is usually about 0.1 to 100 hours, preferably about 0.1 to 48 hours.

反應溫度為約-10至200℃，較佳為約0至150℃。 The reaction temperature is about -10 to 200 ° C, preferably about 0 to 150 ° C.

<步驟6> <Step 6>

化合物(8)可從化合物(4)製造。 Compound (8) can be produced from Compound (4).

這反應可藉由本質上已知之方法進行，例如，ORGANIC PREPARATIONS AND PROCEDURES INT.,vol.36,pp.391-443、2004中描述之方法與其類似之方法進行。 This reaction can be carried out by a method known per se, for example, the method described in ORGANIC PREPARATIONS AND PROCEDURES INT., vol. 36, pp. 391-443, 2004, and the like.

例如，可描述使用碳酸銨和氰化鉀及類似者之方法。 For example, a method using ammonium carbonate and potassium cyanide and the like can be described.

用於這反應之碳酸銨通常是以每1莫耳之化合物(4)為約0.5至50莫耳，較佳為約1至10莫耳之含量使用。用於這反應之氰化鉀通常是以每1莫耳之化合物(4)為約1至50莫耳，較佳為約1至5莫耳之含量使用。 The ammonium carbonate used in this reaction is usually used in an amount of about 0.5 to 50 moles, preferably about 1 to 10 moles per 1 mole of the compound (4). The potassium cyanide used in this reaction is usually used in an amount of about 1 to 50 moles, preferably about 1 to 5 moles per 1 mole of the compound (4).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，醇類、水及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although only The solvent is not particularly limited, and is preferably, for example, a solvent such as an alcohol, water, and the like, a mixed solvent thereof, and the like.

雖然反應時間取決於欲使用之試劑和溶劑，通常為約0.5至72小時，較佳為約0.5至12小時。 Although the reaction time depends on the reagent and solvent to be used, it is usually from about 0.5 to 72 hours, preferably from about 0.5 to 12 hours.

反應溫度為約0至150℃，較佳為約20至100℃。 The reaction temperature is from about 0 to 150 ° C, preferably from about 20 to 100 ° C.

<步驟7> <Step 7>

化合物(9)可藉由使化合物(8)經歷水解反應而製造。 Compound (9) can be produced by subjecting compound (8) to a hydrolysis reaction.

這反應是以步驟5中之相同方式進行。 This reaction was carried out in the same manner as in the step 5.

<步驟8> <Step 8>

化合物(10)可藉由保護化合物(9)之胺基而製造。 The compound (10) can be produced by protecting the amine group of the compound (9).

這反應是以步驟3中之相同方式進行。 This reaction was carried out in the same manner as in the step 3.

<步驟9> <Step 9>

化合物(12)可藉由使化合物(10)與化合物(11)反應而製造。 The compound (12) can be produced by reacting the compound (10) with the compound (11).

(i)這反應是在縮合劑之存在下於對反應呈惰性之溶劑中進行。縮合劑之實例包含通常已知的縮合劑，諸如，碳二亞胺縮合試劑(例如，二環己基碳二亞胺(DCC)、二異丙基碳二亞胺(DIC)、N-乙基-N’-3-二甲基胺基丙基碳二亞胺以及其鹽酸鹽(WSC、WSC-HCl、EDCI)及類似者)、磷酸縮合試劑(例如，苯并***-1-基氧基-參(二甲基胺基)鏻六氟磷酸鹽(BOP)、疊氮磷酸二苯酯(DPPA)及類似者)、N,N’-羰基二咪唑、2-甲基-6-硝基苯甲酸酐、2-氯-1,3-二甲基咪唑鎓四氟硼酸酯、2-氯-1-甲基吡啶鎓、N,N-二甲基胺磺醯基氯化物、2-氯-4,6-二甲氧基三、4-(4,6-二甲氧基-1,3,5- 三-2-基)-4-甲基-嗎啉鎓氯化物及類似者。 (i) This reaction is carried out in the presence of a condensing agent in a solvent inert to the reaction. Examples of the condensing agent include generally known condensing agents such as carbodiimide condensing agents (for example, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), N-ethyl -N'-3-dimethylaminopropyl carbodiimide and its hydrochloride (WSC, WSC-HCl, EDCI) and the like), a phosphoric acid condensation reagent (for example, benzotriazol-1-yl) Oxy-paraxyl (dimethylamino)phosphonium hexafluorophosphate (BOP), diphenylphosphoryl azide (DPPA) and the like), N,N'-carbonyldiimidazole, 2-methyl-6- Nitrobenzoic anhydride, 2-chloro-1,3-dimethylimidazolium tetrafluoroborate, 2-chloro-1-methylpyridinium, N,N-dimethylaminesulfonyl chloride, 2-chloro-4,6-dimethoxy three , 4-(4,6-dimethoxy-1,3,5-three 2-yl)-4-methyl-morpholinium chloride and the like.

當使用碳二亞胺縮合試劑(例如，二環己基碳二亞胺(DCC)、二異丙基碳二亞胺(DIC)、N-乙基-N’-3-二甲基胺基丙基碳二亞胺和其鹽酸鹽(WSC、WSC-HCl、EDCI)及類似者)、2-甲基-6-硝基苯甲酸酐及類似者作為縮合劑時，反應效率可藉由於所需處使用適合之縮合促進劑(例如，1-羥基-7-氮雜苯并***、1-羥基苯并***、N-羥基琥珀醯亞胺、N-羥基鄰苯二甲醯亞胺、4-二甲基胺基吡啶等)而改善。當使用磷酸縮合試劑(例如，苯并***-1-基氧基-參(二甲基胺基)鏻六氟磷酸鹽(BOP)、疊氮磷酸二苯酯(DPPA)及類似者)、2-甲基-6-硝基苯甲酸酐及類似者作為縮合劑時，反應效率通常可添加有機胺鹼，諸如，三乙胺、二異丙基乙基胺及類似者而改善。當化合物(11)形成鹽時，這反應通常藉由添加鹼而進行。此鹼之實例包含三級胺、鹼性鹽、金屬氫錯合物化合物及類似者。此等鹼通常是以每1莫耳之化合物(11)為約1至100莫耳，較佳為約1至10莫耳之含量使用。 When using a carbodiimide condensation reagent (for example, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), N-ethyl-N'-3-dimethylaminopropyl When the carbodiimide and its hydrochloride (WSC, WSC-HCl, EDCI) and the like), 2-methyl-6-nitrobenzoic anhydride and the like are used as a condensing agent, the reaction efficiency can be utilized Suitable condensation promoters are required (for example, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide) , 4-dimethylaminopyridine, etc.) improved. When a phosphoric acid condensation reagent (for example, benzotriazol-1-yloxy-gin(dimethylamino)phosphonium hexafluorophosphate (BOP), diphenylphosphoryl azide (DPPA) and the like), When 2-methyl-6-nitrobenzoic anhydride and the like are used as a condensing agent, the reaction efficiency can be usually improved by adding an organic amine base such as triethylamine, diisopropylethylamine and the like. When the compound (11) forms a salt, the reaction is usually carried out by adding a base. Examples of the base include a tertiary amine, a basic salt, a metal hydrogen complex compound, and the like. These bases are usually used in an amount of from about 1 to 100 moles, preferably from about 1 to 10 moles, per 1 mole of the compound (11).

化合物(11)通常是以每1莫耳之化合物(10)為約1至10莫耳，較佳為約1至2莫耳之含量使用。縮合劑通常是以每1莫耳之化合物(10)為約0.1至10莫耳，較佳為約1至3莫耳之含量使用。上述縮合促進劑和鹼通常是以每1莫耳之化合物(10)為約0.1至10莫耳，較佳為約0.3至3莫耳之含量始用。 The compound (11) is usually used in an amount of about 1 to 10 moles, preferably about 1 to 2 moles per 1 mole of the compound (10). The condensing agent is usually used in an amount of about 0.1 to 10 moles, preferably about 1 to 3 moles per 1 mole of the compound (10). The above condensation accelerator and base are usually used in an amount of about 0.1 to 10 moles, preferably about 0.3 to 3 moles per 1 mole of the compound (10).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，鹵化烴、醯胺類、亞碸類、醚類、腈類、酯類、烴類、水及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although only The solvent is not particularly limited, and is preferably, for example, a solvent such as a halogenated hydrocarbon, a guanamine, an anthracene, an ether, a nitrile, an ester, a hydrocarbon, water, or the like, Mixed solvents and the like.

<步驟10> <Step 10>

化合物(13)可自化合物(10)製造。 Compound (13) can be produced from Compound (10).

這反應是例如根據習知方法進行，而且使用亞磺醯氯、草醯氯及類似者。此等試劑通常是以每1莫耳之化合物(10)為約1至100莫耳，較佳為約1至30莫耳之含量使用。 This reaction is carried out, for example, according to a conventional method, and uses sulfinium chloride, grass chloroform, and the like. These agents are usually used in an amount of from about 1 to 100 moles, preferably from about 1 to 30 moles per 1 mole of the compound (10).

這反應有利地不在溶劑中或在對反應呈惰性之溶劑中進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，鹵化烴、烴類及類似者或其混合溶劑。 This reaction is advantageously carried out in a solvent or in a solvent inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as a halogenated hydrocarbon, a hydrocarbon, and the like or a mixed solvent thereof.

雖然反應時間取決於欲使用之試劑和溶劑，通常為約0.1至100小時，較佳為約0.1至24小時。 Although the reaction time depends on the reagent and solvent to be used, it is usually from about 0.1 to 100 hours, preferably from about 0.1 to 24 hours.

反應溫度為約-20至150℃，較佳為約0至100℃。 The reaction temperature is about -20 to 150 ° C, preferably about 0 to 100 ° C.

<步驟11> <Step 11>

化合物(12)可藉由使化合物(13)與化合物(11)反應而製造。 Compound (12) can be produced by reacting compound (13) with compound (11).

化合物(11)通常是以每1莫耳之化合物(13)為約1至50莫耳，較佳為約1至5莫耳之含量使用。 The compound (11) is usually used in an amount of about 1 to 50 moles, preferably about 1 to 5 moles per 1 mole of the compound (13).

當化合物(11)形成鹽時，這反應通常是藉由添加鹼而進行。此鹼之實例包含三級胺、鹼性鹽、金屬氫錯合物化合物及類似者。此等鹼通常是以每1莫耳之化合物(11)為約1至100莫耳，較佳為約1至10莫耳之含量使用。 When the compound (11) forms a salt, the reaction is usually carried out by adding a base. Examples of the base include a tertiary amine, a basic salt, a metal hydrogen complex compound, and the like. These bases are usually used in an amount of from about 1 to 100 moles, preferably from about 1 to 10 moles, per 1 mole of the compound (11).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，鹵化烴、醯胺類、亞碸類、醚類、腈類、酯類、烴類及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as a halogenated hydrocarbon, a guanamine, an anthracene, an ether, a nitrile, an ester, a hydrocarbon, and the like, and a mixture thereof. Solvents and the like.

反應溫度為約-30至150℃，較佳為約0至100℃。 The reaction temperature is about -30 to 150 ° C, preferably about 0 to 100 ° C.

<步驟12> <Step 12>

化合物(14)可藉由使化合物(12)與用於導入R⁴之取代基之有機金屬試劑反應而製造。 The compound (14) can be produced by reacting the compound (12) with an organometallic reagent for introducing a substituent of R ⁴ .

此有機金屬試劑之實例包含有機鎂、有機鋰及類似者。此等試劑通常是以每1莫耳之化合物(14)為約1至50莫耳，較佳為約1至5莫耳之含量使用。 Examples of such organometallic reagents include organomagnesium, organolithium, and the like. Such agents are generally employed at a level of from about 1 to 50 moles, preferably from about 1 to 5 moles, per 1 mole of compound (14).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，鹵化烴、醚類、烴類及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as a halogenated hydrocarbon, an ether, a hydrocarbon, and the like, a mixed solvent thereof, and the like.

反應溫度為約-100至100℃，較佳為約-40至50℃。 The reaction temperature is about -100 to 100 ° C, preferably about -40 to 50 ° C.

<步驟13> <Step 13>

化合物(15)可自化合物(14)製造。 Compound (15) can be produced from Compound (14).

(i)當化合物(15)(其中R³為取代基)製造時，這反應是以步驟12中之相同方式進行。 (i) When the compound (15) wherein R ³ is a substituent is produced, the reaction is carried out in the same manner as in the step 12.

(ii)當化合物(15)(其中R³為氫原子)製造時，這反應是在還原劑之存在下於對反應呈惰性之溶劑中進行。還原劑之實例包含鋁氫化物、二異丁基鋁氫化物、鋰鋁氫化物及類似者。 (ii) When the compound (15) wherein R ³ is a hydrogen atom is produced, the reaction is carried out in the presence of a reducing agent in a solvent inert to the reaction. Examples of the reducing agent include aluminum hydride, diisobutyl aluminum hydride, lithium aluminum hydride, and the like.

此等還原劑通常是以相對於化合物(14)為約0.25至10莫耳，較佳為約0.5至5莫耳之含量使用。 These reducing agents are usually used in an amount of from about 0.25 to 10 moles, preferably from about 0.5 to 5 moles, per mole of the compound (14).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，醚類、鹵化烴、烴類及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, an ether, a halogenated hydrocarbon, a hydrocarbon, and the like, a mixed solvent thereof, and the like.

雖然反應時間取決於欲使用之試劑和溶劑，通常為約0.1至72小時，較佳為約0.5至24小時。 Although the reaction time depends on the reagent and solvent to be used, it is usually from about 0.1 to 72 hours, preferably from about 0.5 to 24 hours.

反應溫度為約-40至150℃，較佳為約-20至100℃。 The reaction temperature is about -40 to 150 ° C, preferably about -20 to 100 ° C.

<步驟14> <Step 14>

化合物(16)可藉由化合物(10)之羧基保護而製造。 The compound (16) can be produced by protecting the carboxyl group of the compound (10).

此保護基之實例包含甲基、乙基、正丙基、異丙基、正丁基、第三丁基、苯甲基及類似者。 Examples of such protecting groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, benzyl and the like.

這步驟中之導入保護基可藉由本質上已知之方法進行，例如，Greene’s Protective Groups in Organic Synthesis,4^th Edition,Wiley-Interscience,Theodora W.Greene,Peter G.M.Wuts et al.中描述之方法。 This step of introducing the protective group may be carried out by methods known in nature, e.g., Greene's Protective Groups in Organic Synthesis , 4 th Edition, Wiley-Interscience, Theodora W.Greene, Peter GMWuts et al. In the method described.

<步驟15> <Step 15>

化合物(15)(其中R³和R⁴皆為取代基)可藉由使化合物(16)與用於導入R³和R⁴之取代基之有機金屬試劑反應而製造。 The compound (15) wherein R ³ and R ⁴ are both a substituent can be produced by reacting the compound (16) with an organometallic reagent for introducing a substituent of R ³ and R ⁴ .

這反應是以與步驟12中相同之方式進行。 This reaction was carried out in the same manner as in the step 12.

<步驟16> <Step 16>

化合物(17)可藉由移除化合物(15)之胺基保護基而製造。 Compound (17) can be produced by removing the amine protecting group of Compound (15).

這步驟中移除保護基可藉由本質上已知之方法進行，例如，Greene’s Protective Groups in Organic Synthesis,4^th Edition,Wiley-Interscience,Theodora W.Greene,Peter G.M.Wuts et al.中描述之方法。 This removal of the protecting group in step may be performed by methods known in nature, e.g., Greene's Protective Groups in Organic Synthesis , 4 th Edition, Wiley-Interscience, Theodora W.Greene, Peter GMWuts et al. In the method described.

化合物(17)係反應方案1中之化合物(3)(其中-L-Y為-C(R³)(R⁴)-OH)，其可藉由例如反應方案3中顯示之方法或與其類似之方法產生。 Compound (17) is a compound (3) in Reaction Scheme 1 (wherein -LY is -C(R ³ )(R ⁴ )-OH), which can be obtained by, for example, the method shown in Reaction Scheme 3 or a method analogous thereto produce.

反應方案3 Reaction Scheme 3

其中L²為離去基，而且其他符號係如以上定義。 Wherein L ² is a leaving group, and the other symbols are as defined above.

L²之離去基之實例包含鹵素原子、視需要鹵化之C_1-6烷基磺醯氧基、視需要經取代之芳基磺醯氧基及類似者。 Examples of the leaving group of L ² include a halogen atom, a C _1-6 alkylsulfonyloxy group optionally halogenated, an optionally substituted arylsulfonyloxy group, and the like.

化合物(18)和化合物(19)可以可商購之產品獲得，或可藉由本質上已知之方法或與其類似之方法製造。 The compound (18) and the compound (19) can be obtained from commercially available products, or can be produced by a method known per se or a method analogous thereto.

<步驟17> <Step 17>

化合物(20)可藉由使化合物(18)和化合物(19)經歷交叉偶合反應而製造。 Compound (20) can be produced by subjecting compound (18) and compound (19) to a cross-coupling reaction.

這反應是根據習知方法進行，而且使用過渡金屬觸媒和鹼。 This reaction is carried out according to a conventional method, and a transition metal catalyst and a base are used.

過渡金屬觸媒之實例包含鈀觸媒及類似者。鈀觸媒之實例包含雙(三-第三丁基膦)鈀(0)、參(二苯亞甲基丙酮)二鈀(0)及類似者。過渡金屬觸媒是以每1莫耳之化合物(18)為約0.01至5莫耳，較佳為約0.03至0.5莫耳之含量使用。鹼之實例包含有機鹼、無機鹼、鹼性鹽及類似者。此等鹼通常是以每1莫耳之化合物(18)為約0.5至100莫耳，較佳為約1至20莫耳之含量使用。化合物(19)通常是以每1莫耳之化合物(18)為約0.5至50莫耳，較佳為約0.9至10莫耳之含量使用。 Examples of transition metal catalysts include palladium catalysts and the like. Examples of the palladium catalyst include bis(tri-tert-butylphosphine)palladium(0), ginseng(dibenzylideneacetone)dipalladium(0) and the like. The transition metal catalyst is used in an amount of from about 0.01 to 5 moles, preferably from about 0.03 to 0.5 moles per 1 mole of the compound (18). Examples of the base include an organic base, an inorganic base, a basic salt, and the like. These bases are usually from about 0.5 to 100 moles per 1 mole of compound (18), preferably It is used in an amount of about 1 to 20 moles. The compound (19) is usually used in an amount of from about 0.5 to 50 moles, preferably from about 0.9 to 10 moles per 1 mole of the compound (18).

這反應亦在不起作用的氣體(例如，氬氣或氮氣)氣氛或在膦配位體之共存在下於氣流中進行。此膦配位體之實例包含三-第三丁基膦及類似者。此等膦配位體通常是以每1莫耳之過渡金屬觸媒為約0.1至10莫耳，較佳為約0.5至5莫耳之含量使用。 This reaction is also carried out in a gas stream in an inactive gas (for example, argon or nitrogen) atmosphere or in the presence of a phosphine ligand. Examples of such phosphine ligands include tri-tert-butylphosphine and the like. These phosphine ligands are typically employed at a level of from about 0.1 to 10 moles, preferably from about 0.5 to 5 moles, per 1 mole of transition metal catalyst.

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，烴類、醚類、腈類、水及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as a hydrocarbon, an ether, a nitrile, water, and the like, a mixed solvent thereof, and the like.

雖然反應時間取決於欲使用之試劑和溶劑，通常為約0.1至100小時，較佳為約0.1至72小時。 Although the reaction time depends on the reagent and solvent to be used, it is usually from about 0.1 to 100 hours, preferably from about 0.1 to 72 hours.

<步驟18> <Step 18>

化合物(21)可自化合物(20)製造。 Compound (21) can be produced from Compound (20).

<步驟19> <Step 19>

化合物(17)可藉由去保護化合物(21)之二苯基伸甲基而製造。 The compound (17) can be produced by deprotecting the diphenylmethyl group of the compound (21).

這步驟中移除保護基可藉由本質上已知之方法進行，例如，Greene’s Protective Groups in Organic Synthesis,4^th Edition,Wiley-Interscience,Theodora W.Greene,Peter G.M. Wuts et al.中描述之方法。 This step may be carried out by removal of the protecting group methods known in nature, e.g., Greene's Protective Groups in Organic Synthesis , 4 th Edition, Wiley-Interscience, Theodora W.Greene, Peter GM Wuts et al. In the method described.

<步驟20> <Step 20>

化合物(22)可藉由使化合物(20)經歷水解反應而製造。 Compound (22) can be produced by subjecting compound (20) to a hydrolysis reaction.

<步驟21> <Step 21>

化合物(23)可自化合物(22)製造。 Compound (23) can be produced from Compound (22).

這反應可以步驟9中之相同方式進行。 This reaction can be carried out in the same manner as in the step 9.

<步驟22> <Step 22>

化合物(24)可藉由使化合物(23)與用於導入R⁴之取代基之有機金屬試劑反應而製造。 The compound (24) can be produced by reacting the compound (23) with an organometallic reagent for introducing a substituent of R ⁴ .

<步驟23> <Step 23>

化合物(21)可自化合物(24)製造。 Compound (21) can be produced from Compound (24).

這反應可以步驟13中之相同方式進行。 This reaction can be carried out in the same manner as in the step 13.

化合物(29)係反應方案1中之化合物(3)(其中-L-Y為-CH₂-OR¹)，其可藉由反應方案4中顯示之方法顯示於或與其類似之方法產生。 Compound (29) is a compound (3) in Reaction Scheme 1 (wherein -LY is -CH ₂ -OR ¹ ) which can be produced by the method shown in Reaction Scheme 4 or in a similar manner.

反應方案4 Reaction Scheme 4

其中R⁷為羥基、視需要經取代之C_1-3烷氧基或視需要經取代之苯甲基，而且其他符號係如上定義。 Wherein R ⁷ is hydroxy, optionally substituted C _1-3 alkoxy or optionally substituted benzyl, and the other symbols are as defined above.

化合物(25)、化合物(33)以及化合物(4)可以可商購之產品獲得，或可藉由本質上已知之方法或與其類似之方法製造。 The compound (25), the compound (33), and the compound (4) can be obtained from commercially available products, or can be produced by a method known per se or a method analogous thereto.

<步驟24> <Step 24>

化合物(26)可藉由溴化化合物(25)而製造。 Compound (26) can be produced by brominating compound (25).

此溴化劑之實例包含溴、苯基三甲基銨三溴化物、N-溴琥珀醯亞胺及類似者。此等溴化劑通常是以每1莫耳之化合物(25)為約0.5至2莫耳，較佳為約0.8至1.5莫耳之含量使用。 Examples of such brominating agents include bromine, phenyltrimethylammonium tribromide, N-bromosuccinimide, and the like. These brominating agents are usually used in an amount of about 0.5 to 2 moles, preferably about 0.8 to 1.5 moles per 1 mole of the compound (25).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，有機酸類、醇類、醚類、醯胺類、鹵化烴、烴類、水及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as an organic acid, an alcohol, an ether, a guanamine, a halogenated hydrocarbon, a hydrocarbon, water, or the like, a mixed solvent thereof, and Similar.

雖然反應時間取決於欲使用之試劑和溶劑，通常為約0.1至100小時，較佳為約0.1至48小時。 Although the reaction time depends on the reagent and solvent to be used, it is usually from about 0.1 to 100 hours, preferably from about 0.1 to 48 hours.

反應溫度為約-30至200℃，較佳為約0至100℃。 The reaction temperature is about -30 to 200 ° C, preferably about 0 to 100 ° C.

<步驟25> <Step 25>

化合物(27)可自化合物(26)製造。 Compound (27) can be produced from Compound (26).

(i)這反應藉由例如，使化合物(26)與期望的醇(R¹OH)在碳酸銀(I)或氧化亞鐵(I)和三氟化硼二乙基醚錯合物之存在下反應而進行。 (i) by reacting, for example, the presence of compound (26) with the desired alcohol (R ¹ OH) in silver (I) or ferrous oxide (I) and boron trifluoride diethyl ether complex The reaction is carried out.

碳酸銀(I)和氧化亞鐵(I)通常是以每1莫耳之化合物(26)為約1至10莫耳，較佳為約1至5莫耳之含量使用。 The silver (I) carbonate and the ferrous iron (I) are usually used in an amount of from about 1 to 10 moles, preferably from about 1 to 5 moles per 1 mole of the compound (26).

三氟化硼二乙基醚錯合物通常是以每1莫耳之化合物(26)為約1至10莫耳，較佳為約1至5莫耳之含量使用。 The boron trifluoride diethyl ether complex is usually used in an amount of about 1 to 10 moles, preferably about 1 to 5 moles per 1 mole of the compound (26).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，對應於R¹OH的醇類、醚類、鹵化烴、烴類及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as an alcohol, an ether, a halogenated hydrocarbon, a hydrocarbon, and the like corresponding to R ¹ OH, a mixed solvent thereof, and the like.

反應溫度為約-30至150℃，較佳為約0至80℃。 The reaction temperature is about -30 to 150 ° C, preferably about 0 to 80 ° C.

(ii)這反應亦可藉由使化合物(26)與期望的醇(R¹OH)在鹼之存在下反應而進行。 (ii) This reaction can also be carried out by reacting the compound (26) with a desired alcohol (R ¹ OH) in the presence of a base.

此鹼之實例包含三級胺、鹼性鹽、金屬氫錯合物化合物、金屬烷氧化物、金屬醯胺類、烷基金屬、芳基金屬及類似者。此等鹼通常是以每1莫耳之化合物(26)為約1至10莫耳，較佳為約1至5莫耳之含量使用。 Examples of the base include a tertiary amine, a basic salt, a metal hydrogen complex compound, a metal alkoxide, a metal decylamine, an alkyl metal, an aryl metal, and the like. These bases are usually used in an amount of from about 1 to 10 moles, preferably from about 1 to 5 moles, per 1 mole of the compound (26).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，對應R¹OH的醇類、醚類、醯胺類、亞碸類、鹵化烴、烴類及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as an alcohol, an ether, a guanamine, an anthracene, a halogenated hydrocarbon, a hydrocarbon, or the like corresponding to R ¹ OH. It is a mixed solvent and the like.

<步驟26> <Step 26>

化合物(28a)或化合物(28b)可藉由使化合物(27)與化合物(33)反應而製造。 The compound (28a) or the compound (28b) can be produced by reacting the compound (27) with the compound (33).

(i)化合物(28a)可藉由化合物(27)與化合物(33)之脫水縮合反應而製造。 (i) The compound (28a) can be produced by a dehydration condensation reaction of the compound (27) with the compound (33).

化合物(33)通常是以每1莫耳之化合物(27)為約1至10莫耳，較佳為約1至5莫耳之含量使用。 The compound (33) is usually used in an amount of about 1 to 10 moles, preferably about 1 to 5 moles per 1 mole of the compound (27).

當化合物(33)形成鹽時，這反應是通常藉由添加鹼而進行。此鹼之實例包含三級胺、芳香族胺、鹼性鹽、無機鹼、鹼金屬氫化物、金屬烷氧化物及類似者。此等鹼通常是以每1莫耳之化合物(33)為約1至10莫耳，較佳為約1至5莫耳之含量使用。 When the compound (33) forms a salt, the reaction is usually carried out by adding a base. Examples of the base include a tertiary amine, an aromatic amine, a basic salt, an inorganic base, an alkali metal hydride, a metal alkoxide, and the like. These bases are usually used in an amount of from about 1 to 10 moles, preferably from about 1 to 5 moles, per 1 mole of the compound (33).

這反應亦可藉由對系統添加脫水劑，諸如，分子篩及類似者，或對甲苯磺酸、氯化鋅、氯化磷醯、三氟化硼、四氯化鈦、乙酸、三氟乙酸及類似者，或藉由使用迪安-斯達克(Dean-Stark)及類似者移除系統產生之水或此等之組合而促進。 This reaction can also be carried out by adding a dehydrating agent to the system, such as molecular sieves and the like, or p-toluenesulfonic acid, zinc chloride, phosphonium chloride, boron trifluoride, titanium tetrachloride, acetic acid, trifluoroacetic acid and Similarly, or by using Dean-Stark and the like to remove water produced by the system or a combination of these.

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，醇類、醚類、烴類、酯類及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although only The solvent is not particularly limited, and is preferably, for example, a solvent such as an alcohol, an ether, a hydrocarbon, an ester, and the like, a mixed solvent thereof, and the like.

(ii)化合物(28b)可藉由化合物(27)和化合物(33)之還原胺化反應而製造(例如，描述於Jikken Kagaku Kouza,4th Edition,vol.20,pp.282-284,366-368(The Chemical Society of Japan ed.)；J.Am.Chem.Soc.,vol.93,pp.2897-2904、1971；Synthesis,p.135、1975及類似者)。 (ii) Compound (28b) can be produced by reductive amination reaction of compound (27) and compound (33) (for example, as described in Jikken Kagaku Kouza, 4th Edition, vol. 20, pp. 282-284, 366-368 ( The Chemical Society of Japan ed.); J. Am. Chem. Soc., vol. 93, pp. 2897-2904, 1971; Synthesis, p. 135, 1975 and the like).

這反應中，化合物(28b)是藉由使藉由化合物(27)與化合物(33)之脫水反應而形成之亞胺形式經歷還原反應而獲得。 In this reaction, the compound (28b) is obtained by subjecting the imine form formed by the dehydration reaction of the compound (27) to the compound (33) to undergo a reduction reaction.

化合物(33)通常是以每1莫耳之化合物(27)為約1至10莫耳，較佳為約1至3莫耳之含量使用。 The compound (33) is usually used in an amount of about 1 to 10 moles, preferably about 1 to 3 moles per 1 mole of the compound (27).

上述脫水反應亦可藉由對系統添加脫水劑，諸如，分子篩及類似者，或對甲苯磺酸、氯化鋅、氯化磷醯、三氟化硼、四氯化鈦、乙酸、三氟乙酸及類似者，或藉由使用迪安-斯達克及類似者移除系統產生之水或此等之組合而促進。 The above dehydration reaction can also be carried out by adding a dehydrating agent to the system, such as molecular sieves and the like, or p-toluenesulfonic acid, zinc chloride, phosphonium chloride, boron trifluoride, titanium tetrachloride, acetic acid, trifluoroacetic acid. And the like, or by using Dean Stark and the like to remove water produced by the system or a combination of these.

還原反應是根據習知方法進行，而且通常使用還原劑。還原劑之實例包含金屬氫化物，諸如，鋁氫化物、二異丁基鋁氫化物、三正丁氫化物及類似者；金屬氫錯合物化合物，諸如，氰基硼氰化鈉、三乙醯氧基硼氫化鈉、硼氫化鈉、鋰鋁氫化物及類似者；硼烷錯合物，諸如，硼烷四氫呋喃錯合物、硼烷二甲基硫化物錯合物、甲吡啶-硼烷錯合物及類似者；烷基硼烷，諸如，己基硼烷、二異戊基硼烷及類似者及類似者。 The reduction reaction is carried out according to a conventional method, and a reducing agent is usually used. Examples of the reducing agent include metal hydrides such as aluminum hydride, diisobutylaluminum hydride, tri-n-butyl hydride, and the like; metal hydrogen complexes Compounds such as sodium cyanoborohydride, sodium triethoxy borohydride, sodium borohydride, lithium aluminum hydride and the like; borane complexes such as borane tetrahydrofuran complex, borane II Methyl sulfide complex, pyrithion-borane complex and the like; alkylboranes such as hexylborane, diisoamylborane and the like and the like.

此等還原劑通常是以每1莫耳之化合物(27)為約0.25至10莫耳，較佳為約0.5至5莫耳之含量使用。 These reducing agents are usually used in an amount of from about 0.25 to 10 moles, preferably from about 0.5 to 5 moles per 1 mole of the compound (27).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，鹵化烴、醇類、醚類、腈類、酯類、烴類、醯胺類、有機酸類及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as a halogenated hydrocarbon, an alcohol, an ether, a nitrile, an ester, a hydrocarbon, a guanamine, an organic acid, or the like. It is a mixed solvent and the like.

雖然反應時間取決於欲使用之試劑和溶劑，通常為約0.1至100小時，較佳為約0.5至24小時。 Although the reaction time depends on the reagent and solvent to be used, it is usually from about 0.1 to 100 hours, preferably from about 0.5 to 24 hours.

反應溫度為約-20至200℃，較佳為約0至100℃。 The reaction temperature is about -20 to 200 ° C, preferably about 0 to 100 ° C.

<步驟27> <Step 27>

化合物(29)可自化合物(28a)或化合物(28b)製造。 Compound (29) can be produced from compound (28a) or compound (28b).

(i)這反應是藉由例如，使用觸媒，諸如，鈀-碳、氫氧化鈀、鈀黑、二氧化鉑、雷尼鎳、雷尼鈷及類似者而進行。此等觸媒通常是以相對於化合物(28a)或化合物(28b)為約1至1000重量%，較佳為約5至300重量%之含量使用。 (i) This reaction is carried out, for example, by using a catalyst such as palladium-carbon, palladium hydroxide, palladium black, platinum dioxide, Raney nickel, Raney cobalt, and the like. These catalysts are usually used in an amount of from about 1 to 1000% by weight, preferably from about 5 to 300% by weight, based on the compound (28a) or the compound (28b).

這反應亦使用非氣態氫之多種氫來源進行。此氫來源之實例包含甲酸、甲酸銨、三乙基甲酸銨、亞膦酸鈉、肼及類似者。此等氫來源通常是每1莫耳之化合物(28a)或化合物(28b)以為約1至10莫耳，較佳為約1至5莫耳之含量使用。 This reaction is also carried out using a variety of hydrogen sources other than gaseous hydrogen. Examples of such hydrogen sources include formic acid, ammonium formate, ammonium triethylformate, sodium phosphinate, hydrazine, and the like. These hydrogen sources are usually per 1 mole of compound (28a) or The compound (28b) is used in an amount of from about 1 to 10 moles, preferably from about 1 to 5 moles.

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，鹵化烴、醇類、醚類、酯類、有機酸類、醯胺類及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as a halogenated hydrocarbon, an alcohol, an ether, an ester, an organic acid, a guanamine or the like, a mixed solvent thereof and the like. .

雖然反應時間取決於欲使用之試劑和溶劑，通常為約0.1至100小時，較佳為約0.5至50小時。 Although the reaction time depends on the reagent and solvent to be used, it is usually from about 0.1 to 100 hours, preferably from about 0.5 to 50 hours.

(ii)化合物(29)可藉由例如，使化合物(28a)或化合物(28b)(其中R⁷為羥基或視需要經取代之C_1-3烷氧基)經歷還原反應而製造。 (ii) The compound (29) can be produced, for example, by subjecting the compound (28a) or the compound (28b) (wherein R ⁷ is a hydroxyl group or, if necessary, a substituted C _1-3 alkoxy group) to a reduction reaction.

還原劑之實例包含硼烷錯合物、金屬氫錯合物化合物及類似者。 Examples of the reducing agent include a borane complex, a metal hydrogen complex compound, and the like.

此等還原劑通常是以每1莫耳之化合物(28a)或化合物(28b)為約0.25至100莫耳，較佳為約0.5至10莫耳之含量使用。 These reducing agents are usually used in an amount of from about 0.25 to 100 moles, preferably from about 0.5 to 10 moles per 1 mole of the compound (28a) or the compound (28b).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，醚類、醇類、水及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as an ether, an alcohol, water, and the like, a mixed solvent thereof, and the like.

反應溫度為約-50至150℃，較佳為約-20至100℃。 The reaction temperature is about -50 to 150 ° C, preferably about -20 to 100 ° C.

<步驟28> <Step 28>

化合物(30)可藉由使化合物(4)經歷Wittig反應及類似者而產生。 Compound (30) can be produced by subjecting Compound (4) to a Wittig reaction and the like.

這反應是藉由例如，使化合物(4)與從甲基(三苯基)鏻鹽和鹼製備之磷偶極體反應而進行。 This reaction is carried out, for example, by reacting the compound (4) with a phosphorus dipole prepared from a methyl (triphenyl) phosphonium salt and a base.

此鹼之實例包含金屬烷氧化物、烷基金屬、鹼金屬氫化物、金屬醯胺類及類似者。此等鹼通常是以每1莫耳之化合物(4)約1至10莫耳，較佳為約1至5莫耳為之含量使用。 Examples of the base include metal alkoxides, metal alkyls, alkali metal hydrides, metal guanamines, and the like. These bases are usually used in an amount of from about 1 to 10 moles, preferably from about 1 to 5 moles per 1 mole of the compound (4).

甲基(三苯基)鏻鹽通常是以之每1莫耳之化合物(4)為約1至10莫耳，較佳為約1至5莫耳之含量使用。 The methyl (triphenyl) phosphonium salt is usually used in an amount of about 1 to 10 moles, preferably about 1 to 5 moles per 1 mole of the compound (4).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，醚類、鹵化烴、烴類、亞碸類及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as an ether, a halogenated hydrocarbon, a hydrocarbon, an anthraquinone or the like, a mixed solvent thereof and the like.

雖然反應時間取決於欲使用之試劑和溶劑，通常為約0.1至48小時，較佳為約0.1至24小時。 Although the reaction time depends on the reagent and solvent to be used, it is usually from about 0.1 to 48 hours, preferably from about 0.1 to 24 hours.

反應溫度為約-78至100℃，較佳為約0至100℃。 The reaction temperature is about -78 to 100 ° C, preferably about 0 to 100 ° C.

<步驟29> <Step 29>

化合物(31)可藉由使化合物(30)與氧化劑反應而製造。 Compound (31) can be produced by reacting compound (30) with an oxidizing agent.

此氧化劑之實例包含3-氯過苯甲酸、過乙酸及類似者。 Examples of such oxidizing agents include 3-chloroperbenzoic acid, peracetic acid, and the like.

此等氧化劑通常是以每1莫耳之化合物(30)為約1至10莫耳，較佳為約1至5莫耳之含量使用。 These oxidizing agents are usually used in an amount of from about 1 to 10 moles, preferably from about 1 to 5 moles, per 1 mole of the compound (30).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，鹵化烴、有機酸、酯類、醚類、烴類、腈類、水及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent. For example, halogenated hydrocarbons, organic acids, esters, ethers, hydrocarbons, nitriles, water and the like, mixed solvents thereof and the like.

反應溫度為約-78至150℃，較佳為約-20至80℃。 The reaction temperature is about -78 to 150 ° C, preferably about -20 to 80 ° C.

<步驟30> <Step 30>

化合物(32)可藉由使化合物(31)與期望的醇(R¹OH)在鹼之存在反應而製造。 Compound (32) can be produced by reacting compound (31) with a desired alcohol (R ¹ OH) in the presence of a base.

鹼之實例包含從R¹OH製備金屬烷氧化物、鹼性鹽、金屬氫錯合物化合物、三級胺及類似者。此等鹼通常是以每1莫耳之化合物(31)為約1至100莫耳，較佳為約1至10莫耳之含量使用。 Examples of the base include a metal alkoxide, a basic salt, a metal hydrogen complex compound, a tertiary amine, and the like from R ¹ OH. These bases are usually used in an amount of from about 1 to 100 moles, preferably from about 1 to 10 moles, per 1 mole of the compound (31).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，對應於R¹OH的醇類、醯胺類、鹵化烴、醚類、烴類、腈類、水及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as an alcohol corresponding to R ¹ OH, a guanamine, a halogenated hydrocarbon, an ether, a hydrocarbon, a nitrile, water, and the like. , mixed solvents and the like.

<步驟31> <Step 31>

化合物(27)可藉由使化合物(32)經歷氧化反應而製造。 Compound (27) can be produced by subjecting compound (32) to an oxidation reaction.

這反應是根據習知方法進行，而且使用氧化劑。 This reaction is carried out according to a conventional method, and an oxidizing agent is used.

氧化劑之實例包含金屬鹽和金屬氧化物，諸如，氧化鉻(VI)、氯鉻酸吡啶鎓、二氧化錳及類似者；有機氧化劑，諸如，鄰碘醯基苯甲酸(IBX)、1,1,1-三乙醯氧基-1,1-二氫-1,2-苯并碘雜氧雜環戊-3(1H)-酮(戴斯-馬丁過碘烷)及類似者。此等氧化劑通常是以每1莫耳之化合物(32)為約1至100莫耳，較佳為約1至50莫耳之含量使用。 Examples of the oxidizing agent include metal salts and metal oxides such as chromium (VI) oxide, pyridinium chlorochromate, manganese dioxide, and the like; organic oxidizing agents, For example, o-iodohydrazinobenzoic acid (IBX), 1,1,1-triethoxymethoxy-1,1-dihydro-1,2-benzoxiooxacyclo-3(1H)-one (Dess-Martin periodine) and the like. These oxidizing agents are usually used in an amount of from about 1 to 100 moles, preferably from about 1 to 50 moles per 1 mole of the compound (32).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，鹵化烴、芳香族烴類、飽和烴類、腈類、酯類、醚類、亞碸類、水及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as a halogenated hydrocarbon, an aromatic hydrocarbon, a saturated hydrocarbon, a nitrile, an ester, an ether, an anthraquinone, water, and the like. , mixed solvents and the like.

反應溫度為約-78至150℃，較佳為約-78至100℃。 The reaction temperature is about -78 to 150 ° C, preferably about -78 to 100 ° C.

化合物(37)係反應方案1中之化合物(3)，其中-L-Y為-CH₂CH₂-OR¹，可藉由例如，顯示於反應方案5中顯示之方法或與其類似之方法而產生。 Compound (37) is the compound (3) in Reaction Scheme 1, wherein -LY is -CH ₂ CH ₂ -OR ¹ , which can be produced, for example, by the method shown in Reaction Scheme 5 or a method analogous thereto.

其中各符號係如上定義。 Each symbol is as defined above.

化合物(33)和化合物(34)可以可商購之產品獲得，或可藉由本質上已知之方法或與其類似之方法製造。 The compound (33) and the compound (34) can be obtained from commercially available products, or can be produced by a method known per se or a method analogous thereto.

<步驟32> <Step 32>

化合物(35)可藉由使化合物(34)與期望的醇(R¹OH)反應在鈀(II)觸媒之存在下反應而製造。 Compound (35) can be produced by reacting compound (34) with a desired alcohol (R ¹ OH) in the presence of a palladium (II) catalyst.

鈀(II)觸媒之實例包含氯化雙(乙腈)鈀、氯化鈀、乙酸鈀及類似者。此等鈀(II)觸媒通常是以每1莫耳之化合物(34)為約0.005至1莫耳，較佳為約0.01至1莫耳之含量使用。 Examples of the palladium (II) catalyst include bis(acetonitrile)palladium chloride, palladium chloride, palladium acetate, and the like. These palladium (II) catalysts are generally used in an amount of from about 0.005 to 1 mole, preferably from about 0.01 to 1 mole, per 1 mole of the compound (34).

醇(R¹OH)通常是以每1莫耳之化合物(34)為約1至10莫耳，較佳為約1至3莫耳之含量使用。 The alcohol (R ¹ OH) is usually used in an amount of about 1 to 10 moles, preferably about 1 to 3 moles per 1 mole of the compound (34).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，鹵化烴、對應R¹OH之醇類、醚類、烴類及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as a halogenated hydrocarbon, an alcohol corresponding to R ¹ OH, an ether, a hydrocarbon, and the like, a mixed solvent thereof, and the like.

雖然反應時間取決於欲使用之試劑和溶劑，通常為約0.5至48小時，較佳為約1至24小時。 Although the reaction time depends on the reagent and solvent to be used, it is usually from about 0.5 to 48 hours, preferably from about 1 to 24 hours.

反應溫度為約0至100℃，較佳為約20至80℃。 The reaction temperature is from about 0 to 100 ° C, preferably from about 20 to 80 ° C.

<步驟33> <Step 33>

化合物(36a)或化合物(36b)可藉由使化合物(35)與化合物(33)反應而製造。 The compound (36a) or the compound (36b) can be produced by reacting the compound (35) with the compound (33).

這反應是以步驟26中之相同方式進行。 This reaction was carried out in the same manner as in step 26.

<步驟34> <Step 34>

化合物(37)可自(36a)或化合物(36b)化合物製造。 Compound (37) can be produced from (36a) or compound (36b).

這反應是以步驟27中之相同方式進行。 This reaction was carried out in the same manner as in step 27.

化合物(42)係反應方案1中之化合物(3)(其中-L-Y為-CH₂-C(R³)(R⁴)-OH)，其可藉由例如顯示於反應方案6中顯示方法之或與其類似之方法製造。 Compound (42) is a compound (3) in Reaction Scheme 1 (wherein -LY is -CH ₂ -C(R ³ )(R ⁴ )-OH), which can be represented, for example, by the method shown in Reaction Scheme 6. Or manufactured in a similar way.

其中各符號係如上定義。 Each symbol is as defined above.

化合物(4)可以可商購之產品獲得，或可藉由本質上已知之方法或與其類似之方法製造。 The compound (4) can be obtained from commercially available products, or can be produced by a method known per se or a method analogous thereto.

<步驟35> <Step 35>

化合物(38)可自化合物(4)製造。 Compound (38) can be produced from Compound (4).

這反應是藉由，例如，使氨或其等同者與丙二酸反應進行。此氨之等同者之實例包含乙酸銨、氯化銨、六甲基二矽胺烷及類似者。氨和其等同者通常是以每1莫耳之化合物(4)為約1至100莫耳，較佳為約1至10莫耳之含量使用。 This reaction is carried out, for example, by reacting ammonia or its equivalent with malonic acid. Examples of the equivalent of this ammonia include ammonium acetate, ammonium chloride, hexamethyldioxane, and the like. Ammonia and its equivalent are usually used in an amount of from about 1 to 100 moles, preferably from about 1 to 10 moles per 1 mole of compound (4).

丙二酸通常是以每1莫耳之化合物(4)為約1至100莫耳，較佳為約1至5莫耳含量使用。 Malonic acid is usually used in an amount of from about 1 to 100 moles, preferably from about 1 to 5 moles, per 1 mole of the compound (4).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，鹵化烴、醇類、醚類、烴類、醯胺類、水及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as a halogenated hydrocarbon, an alcohol, an ether, a hydrocarbon, a guanamine, water, and the like, a mixed solvent thereof, and the like.

反應溫度為約0至200℃，較佳為約20至150℃。 The reaction temperature is from about 0 to 200 ° C, preferably from about 20 to 150 ° C.

<步驟36> <Step 36>

化合物(39)可藉由保護化合物(38)之羧基而製造。 The compound (39) can be produced by protecting the carboxyl group of the compound (38).

這反應是以步驟14中之相同方式進行。 This reaction was carried out in the same manner as in step 14.

<步驟37> <Step 37>

化合物(40)可藉由保護化合物(39)之胺基而製造。 The compound (40) can be produced by protecting the amine group of the compound (39).

<步驟38> <Step 38>

化合物(41)可自化合物(40)製造。 Compound (41) can be produced from compound (40).

<步驟39> <Step 39>

化合物(42)可藉由移除化合物(41)之胺基保護基而製造。 Compound (42) can be produced by removing the amine protecting group of compound (41).

這反應是以步驟16中之相同方式進行。 This reaction was carried out in the same manner as in the step 16.

化合物(47)係反應方案1中之化合物(2)，其中稠合環AB為在6-位置具有R⁹之吡唑并[1,5-a]嘧啶，而且L¹為羥基，可藉由例如，反應方案7中顯示之方法或與其類似之方法而產生。 Compound (47) is a compound (2) in Reaction Scheme 1, wherein the fused ring AB is a pyrazolo[1,5-a]pyrimidine having R ⁹ at the 6-position, and L ¹ is a hydroxyl group, For example, the method shown in Reaction Scheme 7 or a method similar thereto is produced.

反應方案7 Reaction Scheme 7

其中R⁸為氫原子或羧基保護基，R⁹為氫原子、視需要經取代之C_1-6烷基、視需要經取代之C_1-6烷氧基、單-或二-C_1-6烷基胺基、鹵素原子或氰基，R¹⁰為氰基或視需要經取代之氧硼基，R¹¹為視需要經取代之C_1-6烷基，L³和L⁴各為離去基，以及其他符號係如上定義。 Wherein R ⁸ is a hydrogen atom or a carboxy protecting group, R ⁹ is a hydrogen atom, optionally substituted C _1-6 alkyl group, optionally substituted C _1-6 alkoxy group, mono- or di-C _{1- a 6} alkylamino group, a halogen atom or a cyano group, R ¹⁰ is a cyano group or an optionally substituted oxygen boron group, R ¹¹ is a C _1-6 alkyl group optionally substituted, and L ³ and L ^{4 are} each Debase, and other symbols are as defined above.

R¹⁰之“視需要經取代之氧硼基”之實例包含視需要經兩個羥基、四甲基乙烯二氧基及類似者取代之氧硼基。 Examples of the "optionally substituted oxyboron group" of R ¹⁰ include an oxyboron group optionally substituted with two hydroxy groups, a tetramethylethylenedioxy group, and the like.

L³之離去基之實例包含視需要經取代之C_1-3烷氧基、視需要經取代之C_1-3二烷基胺基及類似者。 The leaving group L of Example ³ to include the optionally substituted a C _1-3 alkoxy group, the optionally substituted C _1-3 dialkylamino, and the like.

L⁴之離去基之實例包含鹵素原子、視需要經鹵化之C_1-6烷基磺醯氧基、視需要經C_1-6烷基取代之C_6-10芳基磺醯氧基及類似者。 Examples of the leaving group of L ⁴ include a halogen atom, a C _1-6 alkylsulfonyloxy group optionally halogenated, a C _6-10 arylsulfonyloxy group optionally substituted by a C _1-6 alkyl group, and Similar.

化合物(43)、化合物(44)、化合物(45)、化合物(48)及化合物(53)可以可商購之產品獲得，或可藉由本質上已知之方法或與其類似之方法製造。 The compound (43), the compound (44), the compound (45), the compound (48) and the compound (53) can be obtained from commercially available products, or can be produced by a method known per se or a method analogous thereto.

<步驟40> <Step 40>

化合物(46)(其中R⁸為羧基保護基)可藉由使化合物(43)(其中R⁸為羧基保護基)與化合物(44)或化合物(45)反應而製造。 Compound (46) wherein R ⁸ is a carboxy protecting group can be produced by reacting compound (43) wherein R ⁸ is a carboxy protecting group with compound (44) or compound (45).

化合物(44)或化合物(45)通常是以每1莫耳之化合物(43)為約0.5至10莫耳，較佳為約1至5莫耳之含量使用。 The compound (44) or the compound (45) is usually used in an amount of about 0.5 to 10 moles, preferably about 1 to 5 moles per 1 mole of the compound (43).

這反應亦是藉由添加酸或鹼而進行。此酸之實例包含有機酸及類似者。此鹼之實例包含三級胺及類似者。此等酸或鹼通常是以每1莫耳之化合物(43)為約0.5至50莫耳，較佳為約1至10莫耳之含量使用。 This reaction is also carried out by adding an acid or a base. Examples of the acid include organic acids and the like. Examples of such bases include tertiary amines and the like. These acids or bases are usually used in an amount of from about 0.5 to 50 moles, preferably from about 1 to 10 moles per 1 mole of compound (43).

這反應有利地不在溶劑中或在對反應呈惰性之溶劑中進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，醇類、醚類、鹵化烴、烴類、有機酸類、無機酸類及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent or in a solvent inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as an alcohol, an ether, a halogenated hydrocarbon, a hydrocarbon, an organic acid, an inorganic acid, and the like, a mixed solvent thereof, and the like.

<步驟41> <Step 41>

化合物(47)可藉由使化合物(43)(其中R⁸為氫原子)與化合物(44)或化合物(45)反應而製造。 Compound (47) is prepared by reacting the compound (43) (wherein R ⁸ is a hydrogen atom) is manufactured with the compound (44) or compound (45) reaction.

這反應通常是以與步驟40中之相同方式進行。 This reaction is usually carried out in the same manner as in the step 40.

<步驟42> <Step 42>

化合物(47)可藉由使化合物(46)經歷水解反應而製造。 Compound (47) can be produced by subjecting compound (46) to a hydrolysis reaction.

<步驟43> <Step 43>

化合物(50)(其中R⁸為羧基保護基)可藉由使化合物(46)(其中R⁹為鹵素原子)和氰化鋅(48)或雙(戊醯)二硼(bis(pinacolato)diboron)(49)在鈀觸媒之存在下經歷偶合反應而製造。 Compound (50) wherein R ⁸ is a carboxy protecting group can be obtained by allowing compound (46) (wherein R ⁹ is a halogen atom) and zinc cyanide (48) or bis(pentacolato) diboron (49) is produced by undergoing a coupling reaction in the presence of a palladium catalyst.

氰化鋅(48)通常是以每1莫耳之化合物(46)約0.5至10莫耳，較佳為約1至5莫耳之含量使用。再者，鋅金屬可適當添加。鋅金屬通常是以每1莫耳之化合物(46)為約0.005至10莫耳，較佳為約0.01至5莫耳之含量使用。 The zinc cyanide (48) is usually used in an amount of from about 0.5 to 10 moles, preferably from about 1 to 5 moles per 1 mole of the compound (46). Further, zinc metal can be added as appropriate. The zinc metal is usually used in an amount of from about 0.005 to 10 moles, preferably from about 0.01 to 5 moles per 1 mole of the compound (46).

雙(戊醯)二硼(49)通常是以每1莫耳之化合物(46)為約1至10莫耳，較佳為約1至5莫耳之含量使用。這反應通常是在鹼之存在下進行。鹼之實例包含鹼性鹽及類似者。 The bis(pentamidine) diboron (49) is usually used in an amount of about 1 to 10 moles, preferably about 1 to 5 moles per 1 mole of the compound (46). This reaction is usually carried out in the presence of a base. Examples of the base include a basic salt and the like.

鈀觸媒之實例包含乙酸鈀(II)、參(二苯亞甲基丙酮)二鈀(0)、肆(三苯基膦)鈀(0)、雙(三-第三丁基膦)鈀(0)、雙(三苯基膦)鈀(II)氯化物、[1,1’-雙(二苯基膦基)二茂鐵]鈀(II)氯化物及類似者。此等鈀觸媒通常是以每1莫耳之化合物(46)為約0.005至1莫耳，較佳為約0.01至1莫耳之含量使用。 Examples of the palladium catalyst include palladium (II) acetate, bis(diphenylmethyleneacetone) dipalladium (0), ruthenium (triphenylphosphine) palladium (0), bis(tri-tert-butylphosphine) palladium. (0), bis(triphenylphosphine)palladium(II) chloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride and the like. These palladium catalysts are generally used in an amount of from about 0.005 to 1 mole, preferably from about 0.01 to 1 mole per 1 mole of compound (46).

這反應通常是在不起作用的氣體(例如，氬氣或氮氣)氣氛或氣流中於膦配位體之共存在下進行。膦配位體之實例包含三-第三丁基膦、三苯基膦、1,1’-雙(二苯基膦基)二茂鐵及類似者。此等膦配位體通常是以每1莫耳之鈀觸媒為約0.1至10莫耳，較佳為約0.5至5莫耳之含量使用。 This reaction is usually carried out in the presence of a phosphine ligand in an inert gas (for example, argon or nitrogen) atmosphere or gas stream. Examples of phosphine ligands include tri-t-butylphosphine, triphenylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, and the like. These phosphine ligands are generally employed at a level of from about 0.1 to 10 moles, preferably from about 0.5 to 5 moles per 1 mole of palladium catalyst.

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，醯胺類、醚類、烴類、亞碸類及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although only The solvent is not particularly limited, and is preferably, for example, a solvent such as a guanamine, an ether, a hydrocarbon, an anthraquinone or the like, a mixed solvent thereof and the like.

雖然反應時間取決於欲使用之試劑和溶劑，通常為約0.5至100小時，較佳為約1至48小時。 Although the reaction time depends on the reagent and solvent to be used, it is usually from about 0.5 to 100 hours, preferably from about 1 to 48 hours.

<步驟44> <Step 44>

化合物(47)(其中R⁹為氰基)可藉由使化合物(50)(其中R¹⁰為氰基)經歷水解反應而製造。 Compound (47) wherein R ⁹ is a cyano group can be produced by subjecting compound (50) wherein R ¹⁰ is a cyano group to a hydrolysis reaction.

<步驟45> <Step 45>

化合物(51)可藉由使化合物(50)(其中R¹⁰為視需要經取代之氧硼基)與氧化劑反應而製造。 The compound (51) can be produced by reacting the compound (50) wherein R ¹⁰ is an optionally substituted oxygen boron group with an oxidizing agent.

此氧化劑之實例包含過氧化氫水、Oxone(註冊商標)、過硼酸鈉、羥基胺、三級胺-N-氧化物、氧及類似者。此氧化劑通常是以每1莫耳之化合物(50)為約1至100莫耳，較佳為約1至30莫耳之含量使用。 Examples of such an oxidizing agent include hydrogen peroxide water, Oxone (registered trademark), sodium perborate, hydroxylamine, tertiary amine-N-oxide, oxygen, and the like. The oxidizing agent is usually used in an amount of from about 1 to 100 moles, preferably from about 1 to 30 moles per 1 mole of the compound (50).

這反應中，亦可添加鹼或過渡金屬觸媒。此鹼之實例包含無機鹼、鹼性鹽、三級胺及類似者。此等鹼通常是以每1莫耳之化合物(50)為約1至100莫耳，較佳為約1至50莫耳之含量使用。此過渡金屬觸媒之實例包含硫酸銅(II)、氧化亞銅(I)、溴化銅(II)、氯化銅(II)、乙酸銅(II)及類似者。此等過渡金屬觸媒通常是以每1莫耳之化合物(50)為約0.01至10莫耳，較佳為約0.05至1莫耳之含量使用。 In this reaction, a base or a transition metal catalyst may also be added. Examples of the base include inorganic bases, basic salts, tertiary amines, and the like. These bases are usually used in an amount of from about 1 to 100 moles, preferably from about 1 to 50 moles per 1 mole of the compound (50). Examples of the transition metal catalyst include copper (II) sulfate, copper (I) oxide, copper (II) bromide, copper (II) chloride, copper (II) acetate, and the like. These transition metal catalysts are generally used in an amount of from about 0.01 to 10 moles, preferably from about 0.05 to 1 mole per 1 mole of compound (50).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，醯胺類、醚類、腈類、鹵化烴、烴類、醇類及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as a guanamine, an ether, a nitrile, a halogenated hydrocarbon, a hydrocarbon, an alcohol, and the like, a mixed solvent thereof, and the like. .

雖然反應時間取決於欲使用之試劑和溶劑，通常為約0.1至100小時，較佳為約0.5至48小時。 Although the reaction time depends on the reagent and solvent to be used, it is usually from about 0.1 to 100 hours, preferably from about 0.5 to 48 hours.

反應溫度為約-40至150℃，較佳為約-10至100℃。 The reaction temperature is about -40 to 150 ° C, preferably about -10 to 100 ° C.

<步驟46> <Step 46>

化合物(52)可藉由使化合物(51)與化合物(53)反應而製造。 Compound (52) can be produced by reacting compound (51) with compound (53).

這反應是在鹼之存在下進行。此鹼之實例包含鹼性鹽、芳香族胺、三級胺、鹼金屬氫化物、金屬醯胺類及類似者。此等鹼通常是以每1莫耳之化合物(51)為約1至50莫耳，較佳為約1至10莫耳之含量使用。 This reaction is carried out in the presence of a base. Examples of the base include a basic salt, an aromatic amine, a tertiary amine, an alkali metal hydride, a metal decylamine, and the like. These bases are usually used in an amount of from about 1 to 50 moles, preferably from about 1 to 10 moles, per 1 mole of the compound (51).

化合物(53)通常是以每1莫耳之化合物(51)為約1至50莫耳，較佳為約1至10莫耳之含量使用。 The compound (53) is usually used in an amount of about 1 to 50 moles, preferably about 1 to 10 moles per 1 mole of the compound (51).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，醯胺類、醚類、腈類、鹵化烴、烴類、亞碸類、酮類及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as a guanamine, an ether, a nitrile, a halogenated hydrocarbon, a hydrocarbon, an anthracene, a ketone, or the like, a mixture thereof. Solvents and the like.

反應溫度為約-100至150℃，較佳為約-40至100℃。 The reaction temperature is about -100 to 150 ° C, preferably about -40 to 100 ° C.

<步驟47> <Step 47>

化合物(47)(其中R⁹為視需要經取代之C_1-6烷氧基)可藉由使化合物(52)經歷水解反應而製造。 Compound (47) wherein R ⁹ is optionally substituted C _1-6 alkoxy group can be produced by subjecting compound (52) to a hydrolysis reaction.

化合物(59)係反應方案1中之化合物(2)，其中稠合環AB為於5-位置具有R¹²且於6-位置具有R⁹之吡唑并[1,5-a]嘧啶，以及L¹為羥基，可藉由例如，反應方案8中顯示之方法或與其類似之方法而產生。 Reaction Scheme 1 The compound (2) Compound (59) system, wherein the fused ring AB is at the 5-position with R ¹² and having at the 6-position of R ⁹ and pyrazolo [1,5-a] pyrimidine, and L ¹ is a hydroxyl group which can be produced, for example, by the method shown in Reaction Scheme 8 or a method analogous thereto.

其中R¹²為視需要經取代之烴基、視需要經取代之C_1-6烷氧基、鹵素原子、氰基、視需要經取代之胺基或視需要經取代之雜環基，以及其他符號係如上定義。 Wherein R ¹² is optionally substituted hydrocarbyl, optionally substituted C _1-6 alkoxy, halogen atom, cyano group, optionally substituted amino group or optionally substituted heterocyclic group, and other symbols Is defined as above.

化合物(54)、化合物(55)以及化合物(60)可以可商購之產品獲得，或可藉由本質上已知之方法或與其類似之方法產生。 The compound (54), the compound (55) and the compound (60) can be obtained from commercially available products, or can be produced by a method known per se or a method analogous thereto.

<步驟48> <Step 48>

化合物(56)可藉由使化合物(54)與化合物(55)在酸之存在下反應而製造。 Compound (56) can be produced by reacting compound (54) with compound (55) in the presence of an acid.

此酸之實例包含有機酸類及類似者。 Examples of such acids include organic acids and the like.

此等酸通常是以每1莫耳之化合物(54)為約0.5至200莫耳，較佳為1至100莫耳之含量使用。 These acids are usually used in an amount of from about 0.5 to 200 moles, preferably from 1 to 100 moles per 1 mole of the compound (54).

化合物(55)通常是以每1莫耳之化合物(54)約1至10莫耳，較佳為約1至5莫耳之含量使用。 The compound (55) is usually used in an amount of about 1 to 10 moles, preferably about 1 to 5 moles per 1 mole of the compound (54).

這反應有利地不在溶劑中或在對反應呈惰性之溶劑中進行。 This reaction is advantageously carried out in a solvent or in a solvent inert to the reaction.

雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，鹵化烴、芳香族烴類、飽和烴類、腈類、醚類及類似者、其混合溶劑及類似者。 Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as a halogenated hydrocarbon, an aromatic hydrocarbon, a saturated hydrocarbon, a nitrile, an ether, and the like, a mixed solvent thereof, and the like.

<步驟49> <Step 49>

化合物(57)可藉由包括使化合物(56)與鹵化劑反應之方法(A)或包括使用三苯基膦和鹵素來源鹵化化合物(56)之方法(B)而製造。 The compound (57) can be produced by a method (A) comprising reacting the compound (56) with a halogenating agent or a method (B) comprising using a triphenylphosphine and a halogen-derived halogenated compound (56).

(i)當使用方法(A)時，鹵化劑之實例包含氧基氯化磷、亞磺醯氯及類似者。此等鹵化劑通常是以每1莫耳之化合物(56)為約1至200莫耳，較佳為約1至50莫耳之含量使用。 (i) When the method (A) is used, examples of the halogenating agent include phosphorus oxychloride, sulfinium chloride and the like. These halogenating agents are usually used in an amount of from about 1 to 200 moles, preferably from about 1 to 50 moles per 1 mole of the compound (56).

這反應亦可藉由添加鹼而促進。此鹼之實例包含三級胺及類似者。此等鹼通常是以每1莫耳之化合物(56)為約0.5至50莫耳，較佳為約1至5莫耳之含量使用。 This reaction can also be promoted by the addition of a base. Examples of such bases include tertiary amines and the like. These bases are usually used in an amount of from about 0.5 to 50 moles, preferably from about 1 to 5 moles per 1 mole of compound (56).

這反應亦可藉由添加醯胺類而促進。此醯胺類之實例包含N,N-二甲基甲醯胺及類似者。此等醯胺類通常是以每1莫耳之化合物(56)為約0.01至10莫耳，較佳為約0.1至5莫耳之含量使用。 This reaction can also be promoted by the addition of guanamines. Examples of such guanamines include N,N-dimethylformamide and the like. These guanamines are generally used in an amount of from about 0.01 to 10 moles, preferably from about 0.1 to 5 moles per 1 mole of compound (56).

這反應有利地不在溶劑中或在對反應呈惰性之溶劑中進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，鹵化烴、芳香族烴類、飽和烴類、腈類、醚類及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent or in a solvent inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as a halogenated hydrocarbon, an aromatic hydrocarbon, a saturated hydrocarbon, a nitrile, an ether, and the like, a mixed solvent thereof, and the like.

雖然反應時間取決於欲使用之試劑和溶劑，通常為約0.1至200小時，較佳為約0.5至150小時。 Although the reaction time depends on the reagent and solvent to be used, it is usually from about 0.1 to 200 hours, preferably from about 0.5 to 150 hours.

(ii)當使用方法(B)時，可使用四氯化碳或四溴化碳作為鹵素來源。 (ii) When using the method (B), carbon tetrachloride or carbon tetrabromide may be used as a halogen source.

鹵素來源通常是以每1莫耳之化合物(56)約1至50莫耳，較佳為約1至10莫耳之含量使用。 The halogen source is usually used in an amount of from about 1 to 50 moles, preferably from about 1 to 10 moles per 1 mole of compound (56).

三苯基膦通常是以每1莫耳之化合物(56)約1至50莫耳，較佳為約1至10莫耳之含量使用。 Triphenylphosphine is usually used in an amount of from about 1 to 50 moles, preferably from about 1 to 10 moles per 1 mole of compound (56).

這反應藉由使用對反應呈惰性之溶劑而有利地進行。 This reaction is advantageously carried out by using a solvent which is inert to the reaction.

<步驟50> <Step 50>

化合物(58)可使藉由使化合物(57)經歷還原反應而製造。 Compound (58) can be produced by subjecting compound (57) to a reduction reaction.

此還原劑之實例包含鋅粉劑、鋅-銅合金粉劑及類似者。此等還原劑通常是以每1莫耳之化合物(57)為約1至50莫耳，較佳為約1至10莫耳之含量使用。 Examples of the reducing agent include zinc powder, zinc-copper alloy powder, and the like. These reducing agents are usually used in an amount of from about 1 to 50 moles, preferably from about 1 to 10 moles, per 1 mole of the compound (57).

這反應亦可藉由添加適合的添加劑而促進。此添加劑之實例包含氯化鈉、氨及類似者。可使用此等添加劑之混合物。此等添加劑通常是以每1莫耳之化合物(57)為約1至200莫耳，較佳為約1至100莫耳之含量使用。 This reaction can also be promoted by the addition of suitable additives. Examples of such additives include sodium chloride, ammonia, and the like. Mixtures of such additives can be used. These additives are usually used in an amount of from about 1 to 200 moles, preferably from about 1 to 100 moles, per 1 mole of the compound (57).

這反應亦可藉由氫化反應而進行。在這情況下，使用例如，觸媒，諸如，鈀碳、氫氧化鈀碳、鈀黑、鉑碳、二氧化鉑、雷尼鎳、雷尼鈷及類似者。此等觸媒通常是以每1莫耳之化合物(57)為約5至1000重量%，較佳為約10至300重量%之含量使用。 This reaction can also be carried out by a hydrogenation reaction. In this case, for example, a catalyst such as palladium carbon, palladium hydroxide carbon, palladium black, platinum carbon, platinum dioxide, Raney nickel, Raney cobalt, and the like is used. These catalysts are usually used in an amount of from about 5 to 1000% by weight, preferably from about 10 to 300% by weight, per 1 mole of the compound (57).

氫化反應亦可藉由使用非氣態氫之多種氫來源而進行。此氫來源之實例包含甲酸、甲酸銨、三乙基甲酸銨、亞膦酸鈉、肼及類似者。此等氫來源通常是以每1莫耳之化合物(57)為約1至10莫耳，較佳為約1至5莫耳之含量使用。 The hydrogenation reaction can also be carried out by using a plurality of hydrogen sources other than gaseous hydrogen. Examples of such hydrogen sources include formic acid, ammonium formate, ammonium triethylformate, sodium phosphinate, hydrazine, and the like. These hydrogen sources are usually used in an amount of from about 1 to 10 moles, preferably from about 1 to 5 moles, per 1 mole of the compound (57).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，芳香族烴類、醇類、酯類、飽和烴類、醚類、有機酸類、無機酸類、醯胺類、水及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as an aromatic hydrocarbon, an alcohol, an ester, a saturated hydrocarbon, an ether, an organic acid, an inorganic acid or a guanamine. Water and the like, mixed solvents and the like Like.

<步驟51> <Step 51>

化合物(59)可藉由使化合物(58)經歷水解反應而製造。 Compound (59) can be produced by subjecting compound (58) to a hydrolysis reaction.

<步驟52> <Step 52>

化合物(61)可藉由使化合物(54)與化合物(60)反應而製造。 Compound (61) can be produced by reacting compound (54) with compound (60).

這反應是以與步驟48中相同之方式進行。 This reaction was carried out in the same manner as in the step 48.

<步驟53> <Step 53>

化合物(62)可自化合物(61)製造。 Compound (62) can be produced from compound (61).

這反應是以與步驟49中相同之方式進行。 This reaction was carried out in the same manner as in the step 49.

<步驟54> <Step 54>

化合物(63)可自化合物(62)製造。 Compound (63) can be produced from Compound (62).

這反應是以步驟50中之相同方式進行。 This reaction was carried out in the same manner as in the step 50.

<步驟55> <Step 55>

化合物(58)可自化合物(63)製造。 Compound (58) can be produced from compound (63).

(i)化合物(58)(其中R¹²為視需要經取代之烴基或視需要經取代之雜環基)可藉由Suzuki-Miyaura偶合反應、Stille偶合反應及類似者製造。偶合反應可藉由本質上已知之方法進行，例如，Topics in Current Chemistry 219.Cross-Coupling Reactions：A Practical Guide、Springer-Verlag、Norio Miyaura et al.中描述之方法及類似者或與其類似之方法。 (i) Compound (58) wherein R ¹² is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group can be produced by a Suzuki-Miyaura coupling reaction, a Stille coupling reaction, and the like. The coupling reaction can be carried out by a method known per se, for example, the method described in Topics in Current Chemistry 219. Cross-Coupling Reactions: A Practical Guide, Springer-Verlag, Norio Miyaura et al., and the like or the like. .

(ii)化合物(58)(其中R¹²為視需要經取代之胺基或視需要經取代之雜環基(例如，咯啶-1-基、嗎啉基、1H-吡唑-1-基)、視需要經取代之C_1-6烷氧基)可產生藉由本質上已知的親核性取代反應或Buchwald-Hartwig偶合反應進行。Buchwald-Hartwig偶合反應可藉由本質上已知之方法進行，例如，Topics in Current Chemistry 219.Cross-Coupling Reactions：A Practical Guide、Springer-Verlag、Norio Miyaura et al.中描述之方法及類似者或與其類似之方法。 (ii) the compound (58) (wherein R ¹² is an optionally substituted amino group or an optionally substituted heterocyclic group (for example, a pyridin-1-yl group, a morpholinyl group, a 1H-pyrazol-1-yl group) And optionally substituted C _1-6 alkoxy) can be produced by a nucleophilic substitution reaction or a Buchwald-Hartwig coupling reaction which is known per se. The Buchwald-Hartwig coupling reaction can be carried out by a method known per se, for example, the method described in Topics in Current Chemistry 219. Cross-Coupling Reactions: A Practical Guide, Springer-Verlag, Norio Miyaura et al. A similar approach.

化合物(69)係反應方案1中之化合物(1)，其中稠合環AB為吡唑并[4,3-c]吡啶-4(5H)-酮，可藉由，例如，反應方案9中顯示之方法或與其類似之方法產生。 Compound (69) is the compound (1) in Reaction Scheme 1, wherein the fused ring AB is pyrazolo[4,3-c]pyridine-4(5H)-one, which can be, for example, in Reaction Scheme 9 The method of display or a method similar thereto is produced.

其中R¹³為羥基之保護基，M¹CN為用於導入氰基之有機金屬試劑，而且其他符號係如上定義。 Wherein R ¹³ is a protecting group for a hydroxyl group, M ¹ CN is an organometallic reagent for introducing a cyano group, and the other symbols are as defined above.

化合物(64)和化合物(70)可以可商購之產品獲得，或可藉由本質上已知之方法或與其類似之方法製造。 The compound (64) and the compound (70) can be obtained from commercially available products, or can be produced by a method known per se or a method analogous thereto.

<步驟56> <Step 56>

化合物(65)可藉由使化合物(64)與一氧化碳和R⁶OH在過渡金屬觸媒下反應而產生。 Compound (65) can be produced by reacting compound (64) with carbon monoxide and R ⁶ OH under a transition metal catalyst.

過渡金屬觸媒之實例包含乙酸鈀(II)、參(二苯亞甲基丙酮)二鈀(0)、雙(三-第三丁基膦)鈀(0)、雙(三苯基膦)鈀(II)氯化物、[1,1’-雙(二苯基膦基)二茂鐵]鈀(II)氯化物及類似者。此等鈀觸媒通常是以每1莫耳之化合物(64)為約0.005至1莫耳，較佳為約0.01至1莫耳之含量使用。 Examples of transition metal catalysts include palladium (II) acetate, bis(dibenzylideneacetone) dipalladium (0), bis(tri-tert-butylphosphine)palladium (0), bis(triphenylphosphine). Palladium (II) chloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) chloride and the like. These palladium catalysts are generally used in an amount of from about 0.005 to 1 mole, preferably from about 0.01 to 1 mole per 1 mole of compound (64).

這反應通常是藉由使用鹼而進行。鹼之實例包含三級胺及類似者。 This reaction is usually carried out by using a base. Examples of the base include tertiary amines and the like.

這反應是在一氧化碳氣氛下進行。一氧化碳壓力通常是約1至100大氣壓力，較佳為約1至20大氣壓力。 This reaction is carried out under a carbon monoxide atmosphere. The carbon monoxide pressure is usually from about 1 to 100 atmospheres, preferably from about 1 to 20 atmospheres.

這反應亦在膦配位體之共存在下進行。此膦配位體之實例包含三-第三丁基膦、三苯基膦、1,1’-雙(二苯基膦基)二茂鐵及類似者。此等膦配位體通常是以每1莫耳之鈀觸媒為約1至10莫耳，較佳為約1至5莫耳之含量使用。 This reaction is also carried out in the presence of a phosphine ligand. Examples of such phosphine ligands include tri-t-butylphosphine, triphenylphosphine, 1,1'-bis(diphenylphosphino)ferrocene and the like. These phosphine ligands are generally employed at a level of from about 1 to 10 moles, preferably from about 1 to 5 moles, per 1 mole of palladium catalyst.

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，醯胺類、烴類、對應R⁶OH之醇類、醚類及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as a guanamine, a hydrocarbon, an alcohol corresponding to R ⁶ OH, an ether and the like, a mixed solvent thereof and the like.

雖然反應時間取決於欲使用之試劑和溶劑，通常是約0.5至100小時，較佳為約1至48小時。 Although the reaction time depends on the reagent and solvent to be used, it is usually from about 0.5 to 100 hours, preferably from about 1 to 48 hours.

<步驟57> <Step 57>

化合物(66)可藉由使化合物(64)與金屬氰化物(70)反應而產生。 Compound (66) can be produced by reacting compound (64) with metal cyanide (70).

金屬氰化物(70)通常是以每1莫耳之化合物(64)為約0.5至10莫耳，較佳為約1至5莫耳之含量使用。 The metal cyanide (70) is usually used in an amount of from about 0.5 to 10 moles, preferably from about 1 to 5 moles per 1 mole of the compound (64).

這反應可在加合物，諸如，碘化銅、溴化鎳及類似者之共存在下進行。 This reaction can be carried out in the presence of an adduct such as copper iodide, nickel bromide and the like.

這反應可藉由使化合物(64)與金屬氰化物(70)在金屬觸媒，諸如，鈀觸媒及類似者之存在反應而進行。 This reaction can be carried out by reacting the compound (64) with the metal cyanide (70) in the presence of a metal catalyst such as a palladium catalyst and the like.

可描述包含乙酸鈀(II)、參(二苯亞甲基丙酮)二鈀(0)、肆(三苯基膦)鈀(0)、雙(三-第三丁基膦)鈀(0)、雙(三苯基膦)鈀(II)氯化物、[1,1’-雙(二苯基膦基)二茂鐵]鈀(II)氯化物及類似者之鈀觸媒之實例。此等鈀觸媒通常是以每1莫耳之化合物(64)為約0.005至1莫耳，較佳為約0.01至1莫耳之含量使用。 It can be described that palladium(II) acetate, bis(dibenzylideneacetone)dipalladium(0), ruthenium (triphenylphosphine)palladium(0), bis(tri-tert-butylphosphine)palladium(0) Examples of bis(triphenylphosphine)palladium(II) chloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride and similar palladium catalysts. These palladium catalysts are generally used in an amount of from about 0.005 to 1 mole, preferably from about 0.01 to 1 mole per 1 mole of compound (64).

觸媒反應通常是於不起作用的氣體(例如，氬氣或氮氣)氣氛中或氣流中在膦配位體之共存下進行。此膦配位體之實例包含三-第三丁基膦、三苯基膦、1,1’-雙(二苯基膦基) 二茂鐵及類似者。此等膦配位體通常是以每1莫耳之鈀觸媒為約1至10莫耳，較佳為約1至5莫耳之含量使用。再者，如適當可添加鋅金屬。鋅金屬通常是以每1莫耳之化合物(64)為約0.005至10莫耳，較佳為約0.01至5莫耳之含量使用。 The catalyst reaction is usually carried out in the presence of an inactive gas (for example, argon or nitrogen) or in a gas stream in the coexistence of a phosphine ligand. Examples of such phosphine ligands include tri-t-butylphosphine, triphenylphosphine, 1,1'-bis(diphenylphosphino) Ferrocene and similar. These phosphine ligands are generally employed at a level of from about 1 to 10 moles, preferably from about 1 to 5 moles, per 1 mole of palladium catalyst. Further, zinc metal may be added as appropriate. The zinc metal is usually used in an amount of from about 0.005 to 10 moles, preferably from about 0.01 to 5 moles per 1 mole of the compound (64).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，醯胺類、醚類、烴類及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as a guanamine, an ether, a hydrocarbon, and the like, a mixed solvent thereof, and the like.

<步驟58> <Step 58>

化合物(67)可藉由使化合物(65)經歷水解反應而製造。 Compound (67) can be produced by subjecting compound (65) to a hydrolysis reaction.

<步驟59> <Step 59>

化合物(67)可藉由使化合物(66)經歷水解反應而製造。 Compound (67) can be produced by subjecting compound (66) to a hydrolysis reaction.

這反應是以步驟4和步驟5中之相同方式進行。 This reaction was carried out in the same manner as in Step 4 and Step 5.

<步驟60> <Step 60>

化合物(68)可藉由使化合物(67)與化合物(3)經歷縮合反應而製造。 Compound (68) can be produced by subjecting compound (67) to compound (3) to undergo a condensation reaction.

這反應是以步驟1中之相同方式進行。 This reaction was carried out in the same manner as in the step 1.

<步驟61> <Step 61>

化合物(69)可藉由使化合物(68)經歷去保護反應而製造。 Compound (69) can be produced by subjecting compound (68) to a deprotection reaction Made.

化合物(68)之保護基之移除可藉由本質上已知之方法進行，例如，Greene’s Protective Groups in Organic Synthesis,4^th Edition,Wiley-Interscience,Theodora W.Greene,Peter G.M.Wuts et al.中描述之方法或與其類似之方法，例如，可描述使用酸或鹼、氫化反應及類似者之方法。 Removing (68) the protective group of the compound may be carried out by methods known in nature, e.g., Greene's Protective Groups in Organic Synthesis , 4 th Edition, Wiley-Interscience, Theodora W.Greene, Peter GMWuts et al. Described the The method or a method analogous thereto can, for example, describe an acid or a base, a hydrogenation reaction, and the like.

反應方案1中之化合物(2)中，化合物(81)可藉由例如，反應方案10中顯示之方法或與其類似之方法製造。 In the compound (2) in Reaction Scheme 1, the compound (81) can be produced, for example, by the method shown in Reaction Scheme 10 or a method analogous thereto.

其中Z¹為CR^Z1(R^Z1為氫原子、鹵素原子、視需要經取代之烴基、視需要經取代之C_1-6烷氧基、視需要經取代之胺基、氰基或視需要經取代之雜環基)所表示之基團或氮原子，Z²為CR^Z2(R^Z2為氫原子、鹵素原子、視需要經取代之烴基、視需要經取代之C_1-6烷氧基、視需要經取代之胺基、氰基或視需要經取代之雜環基)所表示之基團或氮原子，Z³為CR^Z3(R^Z3為氫原子、鹵素原子、視需要經取代之烴基、視需要經取代之C_1-6烷氧基、視需要經取代之胺基、氰基、視需要經取代之C_1-6烷基-羰基或視需要經取代之雜環基)所表示之基團或氮原子，R¹⁴為羰基保護基，而且其他符號係如上定義。 Wherein Z ¹ is CR ^Z1 (R ^Z1 is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted C _1-6 alkoxy group, an optionally substituted amino group, a cyano group or, if necessary, a group represented by a substituted heterocyclic group or a nitrogen atom, and Z ² is CR ^Z2 (R ^Z2 is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted C _1-6 alkoxy group, a group represented by a substituted amino group, a cyano group or an optionally substituted heterocyclic group, or a nitrogen atom, and Z ³ is CR ^Z3 (R ^Z3 is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group) , if desired, a substituted C _1-6 alkoxy group, optionally substituted amino group, cyano group, optionally substituted C _1-6 alkyl-carbonyl group or optionally substituted heterocyclic group) The group or the nitrogen atom, R ¹⁴ is a carbonyl protecting group, and the other symbols are as defined above.

R¹⁴之羰基保護基之實例包含環狀縮醛(例如，1,3-二噁烷)、非環狀縮醛(例如，二-C_1-6烷基縮醛)及類似者。 Examples of the carbonyl protecting group for R ¹⁴ include a cyclic acetal (for example, 1,3-dioxane), an acyclic acetal (for example, a di-C _1-6 alkyl acetal), and the like.

化合物(71)、化合物(72)以及化合物(76)可以可商購之產品獲得，或可藉由本質上已知之方法或與其類似之方法製造。 The compound (71), the compound (72) and the compound (76) can be obtained from commercially available products, or can be produced by a method known per se or a method analogous thereto.

<步驟62> <Step 62>

化合物(73)可藉由使化合物(71)與化合物(72)反應而製造。 Compound (73) can be produced by reacting compound (71) with compound (72).

化合物(72)通常是以每1莫耳之化合物(71)為約1至100莫耳，較佳為約1至10莫耳之含量使用。 The compound (72) is usually used in an amount of from about 1 to 100 moles, preferably from about 1 to 10 moles per 1 mole of the compound (71).

這反應是藉由鹼之存在下而進行。此鹼之實例包含三級胺、芳香族胺、鹼金屬氫化物、金屬醯胺類、鹼性鹽、金屬烷氧化物及類似者。此等鹼通常是以每1莫耳之化合物(71)為約1至100莫耳，較佳為約1至10莫耳之含量使用。 This reaction is carried out by the presence of a base. Examples of the base include a tertiary amine, an aromatic amine, an alkali metal hydride, a metal amide, a basic salt, a metal alkoxide, and the like. These bases are usually used in an amount of from about 1 to 100 moles, preferably from about 1 to 10 moles, per 1 mole of the compound (71).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，鹵化烴、芳香族胺、醯胺類、醇類、醚類、腈類、烴類、亞碸類及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent. For example, halogenated hydrocarbons, aromatic amines, decylamines, alcohols, ethers, nitriles, hydrocarbons, anthraquinones and the like, mixed solvents thereof and the like.

<步驟63> <Step 63>

化合物(74)可藉由使化合物(73)經歷酸水解反應而製造。 Compound (74) can be produced by subjecting compound (73) to an acid hydrolysis reaction.

此酸之實例包含有機酸、無機酸及類似者。此等酸通常是以每1莫耳之化合物(73)為約1至200莫耳，較佳為約10至100莫耳之含量使用。 Examples of the acid include organic acids, inorganic acids, and the like. These acids are usually used in an amount of from about 1 to 200 moles, preferably from about 10 to 100 moles per 1 mole of the compound (73).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，鹵化烴、醚類、腈類、烴類及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as a halogenated hydrocarbon, an ether, a nitrile, a hydrocarbon, and the like, a mixed solvent thereof, and the like.

<步驟64> <Step 64>

化合物(75)可藉由還原化合物(74)之硝基而製造。 Compound (75) can be produced by reducing the nitro group of compound (74).

可藉由本質上已知之方法進行將硝基轉化成胺基，例如，Reductions in Organic Chemistry,Second Edition,The American Chmical Society,1996中描述之方法或與其類似之方法，例如，可描述氫化反應、使用金屬或金屬鹽之反應及類似者。 The conversion of a nitro group to an amine group can be carried out by a method known per se, for example, the method described in Reductions in Organic Chemistry, Second Edition, The American Chmical Society, 1996, or a method analogous thereto, for example, a hydrogenation reaction can be described, Use metal or metal salt Should be similar.

<步驟65> <Step 65>

化合物(77)可藉由使化合物(76)經歷水解反應而製造。 Compound (77) can be produced by subjecting compound (76) to a hydrolysis reaction.

<步驟66> <Step 66>

化合物(78)可藉由使化合物(75)和化合物(77)經歷縮合反應而製造。 Compound (78) can be produced by subjecting compound (75) and compound (77) to a condensation reaction.

<步驟67> <Step 67>

化合物(79)可藉由移除化合物(78)之羰基保護基而製造。 Compound (79) can be produced by removing the carbonyl protecting group of Compound (78).

羰基保護基之移除可藉由本質上已知之方法進行，例如，Greene’s Protective Groups in Organic Synthesis,4^th Edition,Wiley-Interscience,Theodora W.Greene,Peter G.M.Wuts et al.中描述之方法或與其類似之方法。 Removal of the carbonyl protecting group may be carried out by methods known in nature, e.g., Greene's Protective Groups in Organic Synthesis , 4 th Edition, Wiley-Interscience, Theodora W.Greene, Peter GMWuts et al. , Or a method analogous thereto described in the The method.

這反應是藉由，例如，使用酸及類似者之方法進行。 This reaction is carried out, for example, by using an acid or the like.

<步驟68> <Step 68>

化合物(80)可自化合物(79)製造。 Compound (80) can be produced from compound (79).

這反應是使用鹼進行。此鹼之實例包含鹼性鹽、芳香族胺、三級胺、金屬烷氧化物、金屬醯胺類、鹼金屬氫化物、二級胺及類似者。 This reaction is carried out using a base. Examples of the base include a basic salt, an aromatic amine, a tertiary amine, a metal alkoxide, a metal decylamine, an alkali metal hydride, a secondary amine, and the like.

二級胺之實例包含咯啶、哌啶及類似者。 Examples of secondary amines include pyridinium, piperidine and the like.

此等鹼通常是以相對於化合物(79)為約1至100莫耳，較佳為約1至50莫耳之含量使用。 These bases are usually used in an amount of from about 1 to 100 moles, preferably from about 1 to 50 moles, per mole of the compound (79).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，溶劑，諸如，鹵化烴、醚類、腈類、烴類、醯胺類、亞碸類及類似者、其混合溶劑及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a solvent such as a halogenated hydrocarbon, an ether, a nitrile, a hydrocarbon, a guanamine, an anthraquinone or the like, a mixed solvent thereof and the like. By.

<步驟69> <Step 69>

化合物(81)可藉由使化合物(80)經歷水解反應而製造。 Compound (81) can be produced by subjecting compound (80) to a hydrolysis reaction.

反應方案1中之化合物(2)中，化合物(84)可藉由，例如，反應方案11中顯示之方法或與其類似之方法而製造。 In the compound (2) in Reaction Scheme 1, the compound (84) can be produced, for example, by the method shown in Reaction Scheme 11 or a method analogous thereto.

其中R¹⁵為視需要經取代之C_1-6烷基，而且其他符號係如上定義。 Wherein R ¹⁵ is a C _1-6 alkyl group which is optionally substituted, and the other symbols are as defined above.

化合物(83)可以可商購之產品獲得，或可藉由本質上已知之方法或與其類似之方法製造。 The compound (83) can be obtained from commercially available products, or can be produced by a method known per se or a method analogous thereto.

<步驟70> <Step 70>

化合物(82)可藉由使化合物(56)與化合物(83)反應而製造。 Compound (82) can be produced by reacting compound (56) with compound (83).

化合物(83)通常是以每1莫耳之化合物(56)為約1至50莫耳，較佳為約1至10莫耳之含量使用。 The compound (83) is usually used in an amount of about 1 to 50 moles, preferably about 1 to 10 moles per 1 mole of the compound (56).

這反應是藉由鹼之存在下而進行。此鹼之實例包含鹼性鹽、三級胺、鹼金屬氫化物、金屬醯胺及類似者。此等鹼通常是以每1莫耳之化合物(56)為約0.5至50莫耳，較佳為約1至10莫耳之含量使用。 This reaction is carried out by the presence of a base. Examples of the base include a basic salt, a tertiary amine, an alkali metal hydride, a metal decylamine, and the like. These bases are usually used in an amount of from about 0.5 to 50 moles, preferably from about 1 to 10 moles per 1 mole of compound (56).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，例如，醚類、烴類、醯胺類、鹵化烴、腈類、亞碸類及類似者。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, for example, ethers, hydrocarbons, guanamines, halogenated hydrocarbons, nitriles, fluorenes, and the like.

雖然反應時間取決於欲使用之試劑和溶劑，通常為約0.1至72小時，較佳為約0.5至36小時。 Although the reaction time depends on the reagent and solvent to be used, it is usually from about 0.1 to 72 hours, preferably from about 0.5 to 36 hours.

反應溫度為約-80至150℃，較佳為約-40至120℃。 The reaction temperature is about -80 to 150 ° C, preferably about -40 to 120 ° C.

<步驟71> <Step 71>

化合物(84)可藉由使化合物(82)經歷水解反應而製造。 Compound (84) can be produced by subjecting compound (82) to a hydrolysis reaction.

反應方案8中之化合物(63)亦可藉由，例如，反應方案12中顯示之方法或與其類似之方法而產生。 Compound (63) in Reaction Scheme 8 can also be produced, for example, by the method shown in Reaction Scheme 12 or a method analogous thereto.

反應方案12 Reaction Scheme 12

其中各符號係如上定義。 Each symbol is as defined above.

化合物(85)、化合物(88)以及化合物(91)可以可商購之產品獲得，或可藉由本質上已知之方法或與其類似之方法製造。 The compound (85), the compound (88) and the compound (91) can be obtained from commercially available products, or can be produced by a method known per se or a method analogous thereto.

<步驟72> <Step 72>

化合物(86)可藉由溴化化合物(85)而製造。 Compound (86) can be produced by brominating compound (85).

此溴化劑之實例包含溴、苯基三甲基三溴化銨及類似者。此等溴化劑通常是以每1莫耳之化合物(85)為約0.5至5莫耳，較佳為約1至2莫耳之含量使用。 Examples of such brominating agents include bromine, phenyltrimethylammonium tribromide, and the like. These brominating agents are usually used in an amount of from about 0.5 to 5 moles, preferably from about 1 to 2 moles per 1 mole of compound (85).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，醇類、醚類、醯胺類、酯類、鹵化烴、烴類及類似者或其混合溶劑。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, an alcohol, an ether, a guanamine, an ester, a halogenated hydrocarbon, a hydrocarbon, and the like or a mixed solvent thereof.

反應溫度為約-20至100℃，較佳為約0至50℃。 The reaction temperature is about -20 to 100 ° C, preferably about 0 to 50 ° C.

<步驟73> <Step 73>

化合物(87)可藉由使化合物(86)與鹼反應而製造。 Compound (87) can be produced by reacting compound (86) with a base.

此鹼之實例包含金屬烷氧化物、鹼性鹽及類似者。此等鹼通常是以每1莫耳之化合物(86)為約1至20莫耳，較佳為約1至5莫耳之含量使用。 Examples of the base include metal alkoxides, basic salts, and the like. These bases are usually used in an amount of from about 1 to 20 moles, preferably from about 1 to 5 moles per 1 mole of compound (86).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，對應R¹⁴OH的醇類、醯胺類、鹵化烴、烴類及類似者或其混合溶劑。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, an alcohol corresponding to R ¹⁴ OH, a guanamine, a halogenated hydrocarbon, a hydrocarbon, and the like or a mixed solvent thereof.

雖然反應時間取決於欲使用之試劑和溶劑，通常為約0.1至48小時，較佳為約1至24小時。 Although the reaction time depends on the reagent and solvent to be used, it is usually from about 0.1 to 48 hours, preferably from about 1 to 24 hours.

反應溫度為約-20至100℃，較佳為約0至80℃。 The reaction temperature is about -20 to 100 ° C, preferably about 0 to 80 ° C.

<步驟74> <Step 74>

化合物(89)可藉由使反應化合物(88)甲基等同者而製造。 Compound (89) can be produced by making the reaction compound (88) methyl equivalent.

此甲醯基等同者之實例包含N,N-二甲基甲醯胺二甲基縮醛、第三丁氧基雙(二甲基胺基)甲烷、原甲酸三甲酯、原甲酸三乙酯及類似者。此等甲醯基等同者通常是以每1莫耳之化合物(88)為約0.5至100莫耳，較佳為約1至10莫耳之含量使用。 Examples of such a fluorenyl equivalent include N,N-dimethylformamide dimethyl acetal, third butoxy bis(dimethylamino)methane, trimethyl orthoformate, and triethyl orthoformate. Ester and similar. Such a fluorenyl equivalent is usually used in an amount of from about 0.5 to 100 moles, preferably from about 1 to 10 moles per 1 mole of the compound (88).

這反應可藉由添加劑而促進。此添加劑之實例包含有機酸、路易士酸、金屬烷氧化物、三級胺及類似者。此等添加劑通常是以每1莫耳之化合物(88)為約0.01至10莫耳，較佳為約0.05至5莫耳之含量使用。 This reaction can be promoted by an additive. Examples of such additives include organic acids, Lewis acids, metal alkoxides, tertiary amines, and the like. These additives are usually used in an amount of from about 0.01 to 10 moles, preferably from about 0.05 to 5 moles per 1 mole of the compound (88).

這反應有利地不在溶劑中或在對反應呈惰性之溶劑中進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，醯胺類、酯類、鹵化烴、烴類、有機酸類、無水乙酸及類似者或其混合溶劑。 This reaction is advantageously not in the solvent or in a solvent inert to the reaction In progress. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, guanamines, esters, halogenated hydrocarbons, hydrocarbons, organic acids, anhydrous acetic acid, and the like or a mixed solvent thereof.

反應溫度為約-20至250℃，較佳為約0至200℃。 The reaction temperature is about -20 to 250 ° C, preferably about 0 to 200 ° C.

<步驟75> <Step 75>

化合物(54)可自化合物(89)製造。 Compound (54) can be produced from compound (89).

這反應是藉由，例如，使化合物(89)與肼、肼單水合物、肼水溶液及類似者反應而進行。此等肼通常是以每1莫耳之化合物(89)為約0.5至10莫耳，較佳為約1至3莫耳之含量使用。 This reaction is carried out, for example, by reacting the compound (89) with hydrazine, hydrazine monohydrate, an aqueous hydrazine solution and the like. These oximes are usually used in an amount of from about 0.5 to 10 moles, preferably from about 1 to 3 moles per 1 mole of compound (89).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，醯胺類、醚類、鹵化烴、烴類、醇類及類似者或其混合溶劑。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a guanamine, an ether, a halogenated hydrocarbon, a hydrocarbon, an alcohol, and the like or a mixed solvent thereof.

反應溫度為約0至150℃，較佳為約10至100℃。 The reaction temperature is from about 0 to 150 ° C, preferably from about 10 to 100 ° C.

<步驟76> <Step 76>

化合物(90)可藉由使化合物(87)與化合物(54)在鹼之存在下反應而製造。 Compound (90) can be produced by reacting compound (87) with compound (54) in the presence of a base.

此鹼之實例包含鹼性鹽、金屬烷氧化物及類似者。此等鹼通常是以每1莫耳之化合物(54)為約0.5至10莫耳，較佳為約1至3莫耳之含量使用。 Examples of the base include a basic salt, a metal alkoxide, and the like. These bases are usually used in an amount of from about 0.5 to 10 moles, preferably from about 1 to 3 moles per 1 mole of compound (54).

化合物(87)通常是每1莫耳之化合物(54)以為約0.5至10莫耳，較佳為約1至3莫耳之含量使用。 The compound (87) is usually used in an amount of about 0.5 to 10 moles, preferably about 1 to 3 moles per 1 mole of the compound (54).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，醯胺類、醚類、鹵化烴、烴類、腈類及類似者或其混合溶劑。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a guanamine, an ether, a halogenated hydrocarbon, a hydrocarbon, a nitrile or the like or a mixed solvent thereof.

反應溫度為約-20至150℃，較佳為約0至110℃。 The reaction temperature is about -20 to 150 ° C, preferably about 0 to 110 ° C.

<步驟77> <Step 77>

化合物(90)亦可藉由使化合物(54)與化合物(91)反應而製造。 Compound (90) can also be produced by reacting compound (54) with compound (91).

這反應是以步驟76中之相同方式進行。 This reaction is carried out in the same manner as in step 76.

<步驟78> <Step 78>

化合物(63)可藉由使化合物(90)與鹵化劑或三苯基膦及鹵素來源反應而產生。 Compound (63) can be produced by reacting compound (90) with a halogenating agent or triphenylphosphine and a halogen source.

化合物(97)係反應方案8中之化合物(59)，其中R¹²為視需要經取代之1H-1,2,3-***-1-基，亦可藉由，例如，反應圖13中描述之方法或與其類似之方法而產生。 Compound (97) is a compound (59) in Reaction Scheme 8, wherein R ¹² is an optionally substituted 1H-1,2,3-triazol-1-yl group, and may also be reacted, for example, by the reaction in FIG. The method of description or a method similar thereto is produced.

反應方案13 Reaction Scheme 13

其中R¹⁶和R¹⁷各獨立為氫原子或視需要經取代之烴基，而且其他符號係如上定義。 Wherein R ¹⁶ and R ^{17 are} each independently a hydrogen atom or a hydrocarbon group optionally substituted, and the other symbols are as defined above.

化合物(94)和化合物(95)可以可商購之產品獲得，或可藉由本質上已知之方法或與其類似之方法製造。 The compound (94) and the compound (95) can be obtained from commercially available products, or can be produced by a method known per se or a method analogous thereto.

<步驟79> <Step 79>

化合物(92)可自化合物(90)製造。 Compound (92) can be produced from compound (90).

(i)化合物(92)(其中L²為鹵素原子)可藉由使化合物(90)與鹵化劑或三苯基膦及鹵素來源反應而製造。 (i) Compound (92) wherein L ² is a halogen atom can be produced by reacting compound (90) with a halogenating agent or triphenylphosphine and a halogen source.

(ii)化合物(92)(其中L²為視需要鹵化之C_1-6烷基磺醯氧基、視需要經取代之芳基磺醯氧基及類似者)可藉由使對應的磺醯氯或磺酸酐與化合物(90)反應而產生。 (ii) the compound (92) wherein L ² is a C _1-6 alkylsulfonyloxy group optionally substituted, an optionally substituted arylsulfonyloxy group and the like may be obtained by reacting the corresponding sulfonium sulfonate Chlorine or a sulfonic acid anhydride is produced by reacting with the compound (90).

對應的磺醯氯或磺酸酐通常是以每1莫耳之化合物(90)為約1至50莫耳，較佳為約1至10莫耳之含量使用。 The corresponding sulfonium chloride or sulfonic anhydride is usually used in an amount of from about 1 to 50 moles, preferably from about 1 to 10 moles per 1 mole of the compound (90).

這反應是藉由鹼之存在下而進行。此鹼之實例包含芳香族胺、三級胺及類似者。此等鹼通常是以每1莫耳之化合物(90)為約1至50莫耳，較佳為約1至10莫耳之含量使用。 This reaction is carried out by the presence of a base. Examples of the base include aromatic amines, tertiary amines, and the like. These bases are usually used in an amount of from about 1 to 50 moles, preferably from about 1 to 10 moles, per 1 mole of the compound (90).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，醯胺類、酯類、鹵化烴、烴類、醚類、腈類、芳香族胺及類似者或其混合溶劑。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although only The solvent is not particularly limited, and is preferably, for example, a guanamine, an ester, a halogenated hydrocarbon, a hydrocarbon, an ether, a nitrile, an aromatic amine, and the like or a mixed solvent thereof.

<步驟80> <Step 80>

化合物(93)可藉由使化合物(92)與疊氮化物反應而製造。 Compound (93) can be produced by reacting compound (92) with an azide.

此疊氮化物之實例包含疊氮化鈉、四-正丁基疊氮化銨及類似者。此等疊氮化物通常是以每1莫耳之化合物(92)為約1至10莫耳，較佳為約1至3莫耳之含量使用。 Examples of the azide include sodium azide, tetra-n-butylammonium azide, and the like. Such azides are generally used at a level of from about 1 to 10 moles, preferably from about 1 to 3 moles, per 1 mole of compound (92).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，醯胺類、腈類、醇類、亞碸類及類似者或其混合溶劑。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, a guanamine, a nitrile, an alcohol, an anthraquinone or the like or a mixed solvent thereof.

反應溫度為約0至150℃，較佳為約0至100℃。 The reaction temperature is from about 0 to 150 ° C, preferably from about 0 to 100 ° C.

<步驟81> <Step 81>

化合物(93)可藉由使化合物(90)與疊氮化劑反應而製造。 Compound (93) can be produced by reacting compound (90) with an azide agent.

此疊氮化劑之實例包含二苯基磷氧基疊氮化物及類似者。此等疊氮化劑通常是以每1莫耳之化合物(90)為約1至30莫耳，較佳為約1至15莫耳之含量使用。 Examples of the azide agent include diphenylphosphoryl azide and the like. These azide agents are generally used in an amount of from about 1 to 30 moles, preferably from about 1 to 15 moles, per 1 mole of compound (90).

這反應是藉由鹼之存在下而進行。此鹼之實例包含芳香族胺、三級胺及類似者。此等鹼通常是以每1莫耳之化合物(90)為約1至50莫耳，較佳為約1至20莫耳之含量使用。 This reaction is carried out by the presence of a base. Examples of the base include aromatic amines, tertiary amines, and the like. These bases are usually used in an amount of from about 1 to 50 moles, preferably from about 1 to 20 moles, per 1 mole of the compound (90).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，醚類、醯胺類、烴類、鹵化烴、腈類及類似者或其混合溶劑。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, an ether, a guanamine, a hydrocarbon, a halogenated hydrocarbon, a nitrile or the like or a mixed solvent thereof.

<步驟82> <Step 82>

化合物(96)可藉由使化合物(93)與化合物(94)或化合物(95)反應而製造。 Compound (96) can be produced by reacting compound (93) with compound (94) or compound (95).

(i)當化合物(93)與化合物(94-I)反應時，這反應是使用鹼進行。此鹼之實例包含鹼金屬氫化物、金屬醯胺類、烷基金屬、芳基金屬、金屬烷氧化物及類似者。此等鹼通常是以每1莫耳之化合物(93)為約1至10莫耳，較佳為約1至5莫耳之含量使用。 (i) When the compound (93) is reacted with the compound (94-I), the reaction is carried out using a base. Examples of the base include alkali metal hydrides, metal guanamines, metal alkyls, aryl metals, metal alkoxides, and the like. These bases are usually used in an amount of from about 1 to 10 moles, preferably from about 1 to 5 moles per 1 mole of the compound (93).

化合物(94-I)通常是以每1莫耳之化合物(93)為約1至10莫耳，較佳為約1至5莫耳之含量使用。 The compound (94-I) is usually used in an amount of about 1 to 10 moles, preferably about 1 to 5 moles per 1 mole of the compound (93).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，醚類、醯胺類、烴類、鹵化烴、亞碸類及類似者或其混合溶劑。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, an ether, a guanamine, a hydrocarbon, a halogenated hydrocarbon, an anthraquinone or the like or a mixed solvent thereof.

雖然反應時間取決於欲使用之試劑和溶劑，通常為約 0.1至48小時，較佳為約1至24小時。 Although the reaction time depends on the reagents and solvents to be used, it is usually about It is from 0.1 to 48 hours, preferably from about 1 to 24 hours.

反應溫度為約-78至150℃，較佳為約-78至120℃。 The reaction temperature is about -78 to 150 ° C, preferably about -78 to 120 ° C.

(ii)當化合物(93)與化合物(94-II)反應時，化合物(94-II)通常是以每1莫耳之化合物(93)為約1至10莫耳，較佳為約1至3莫耳之含量使用。 (ii) When compound (93) is reacted with compound (94-II), compound (94-II) is usually about 1 to 10 moles, preferably about 1 to 1 mole per mole of compound (93). 3 mole content is used.

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，醚類、醯胺類、烴類、鹵化烴、酯類、腈類及類似者或其混合溶劑。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, an ether, a guanamine, a hydrocarbon, a halogenated hydrocarbon, an ester, a nitrile or the like or a mixed solvent thereof.

(iii)當化合物(93)與化合物(95)反應時，化合物(95)通常是以每1莫耳之化合物(93)為約1至20莫耳，較佳為約1至10莫耳之含量使用。 (iii) When compound (93) is reacted with compound (95), compound (95) is usually about 1 to 20 moles, preferably about 1 to 10 moles per 1 mole of compound (93). The content is used.

這反應係藉由銅觸媒而加速。此銅觸媒之實例包含碘化亞銅(I)及類似者。此等銅觸媒通常是以每1莫耳之化合物(93)為約0.01至5莫耳，較佳為約0.05至0.5莫耳之含量使用。 This reaction is accelerated by a copper catalyst. Examples of the copper catalyst include cuprous iodide (I) and the like. These copper catalysts are usually used in an amount of from about 0.01 to 5 moles, preferably from about 0.05 to 0.5 moles per 1 mole of the compound (93).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，醚類、醯胺類、烴類、鹵化烴及類似者或其混合溶劑。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, an ether, a guanamine, a hydrocarbon, a halogenated hydrocarbon, and the like or a mixed solvent thereof.

反應溫度為約0至200℃，較佳為約10至170℃。 The reaction temperature is from about 0 to 200 ° C, preferably from about 10 to 170 ° C.

<步驟83> <Step 83>

化合物(97)可藉由使化合物(96)經歷去保護反應而製造。 Compound (97) can be produced by subjecting compound (96) to a deprotection reaction.

化合物(96)之保護基之移除可藉由本質上已知之方法進行，例如，Greene’s Protective Groups in Organic Synthesis,4^th Edition,Wiley-Interscience,Theodora W.Greene,Peter G.M.Wuts et al.中描述之方法或與其類似之方法，可描述例如，使用酸之方法、氫化反應、使用過渡金屬觸媒之方法及類似者。 Removing (96) the protective group of the compound may be carried out by methods known in nature, e.g., Greene's Protective Groups in Organic Synthesis , 4 th Edition, Wiley-Interscience, Theodora W.Greene, Peter GMWuts et al. Described the The method or a method analogous thereto can describe, for example, a method using an acid, a hydrogenation reaction, a method using a transition metal catalyst, and the like.

反應方案1中之化合物(1)中，化合物(100)亦可藉由，例如，反應方案14中顯示之方法於或與其類似之方法而產生。 In the compound (1) in Reaction Scheme 1, the compound (100) can also be produced by, for example, the method shown in Reaction Scheme 14 or a method analogous thereto.

其中各符號係如上定義。 Each symbol is as defined above.

<步驟83> <Step 83>

化合物(98)可藉由使化合物(56)經歷水解反應而製造。 Compound (98) can be produced by subjecting compound (56) to a hydrolysis reaction.

<步驟84> <Step 84>

化合物(99)可藉由使化合物(98)和化合物(3)經歷縮合反應而製造。 Compound (99) can be produced by subjecting compound (98) and compound (3) to a condensation reaction.

<步驟85> <Step 85>

化合物(100)可藉由使化合物(99)與化合物(83)反應而製造。 The compound (100) can be produced by reacting the compound (99) with the compound (83).

這反應是以步驟70中之相同方式進行。 This reaction is carried out in the same manner as in step 70.

反應方案1中之化合物中，化合物(104)亦可藉由，例如，反應方案15中顯示之方法或與其類似之方法而產生。 Among the compounds of Reaction Scheme 1, Compound (104) can also be produced by, for example, the method shown in Reaction Scheme 15 or a method analogous thereto.

其中各符號係如上定義。 Each symbol is as defined above.

<步驟86> <Step 86>

化合物(101)可藉由使化合物(90)經歷水解反應而製造。 Compound (101) can be produced by subjecting compound (90) to a hydrolysis reaction.

<步驟87> <Step 87>

化合物(102)可藉由使化合物(101)與鹵化劑反應或使用三苯基膦和鹵素來源而製造。 Compound (102) can be produced by reacting compound (101) with a halogenating agent or using a source of triphenylphosphine and halogen.

<步驟88> <Step 88>

化合物(103)可藉由使化合物(102)與化合物(3)反應而製造。 Compound (103) can be produced by reacting compound (102) with compound (3).

這反應是使用鹼進行。此鹼之實例包含三級胺、芳香族胺、鹼性鹽及類似者。此等鹼通常是以每1莫耳之化合物(102)為約1至50莫耳，較佳為約1至5莫耳之含量使用。 This reaction is carried out using a base. Examples of the base include a tertiary amine, an aromatic amine, a basic salt, and the like. These bases are usually used in an amount of from about 1 to 50 moles, preferably from about 1 to 5 moles per 1 mole of the compound (102).

這反應在對反應呈惰性之溶劑中有利地進行。雖然只要反應能進行，此溶劑並不特別限制，較佳為例如，醚類、醯胺類、烴類、鹵化烴、腈類、芳香族胺類及類似者或其混合溶劑。 This reaction is advantageously carried out in a solvent which is inert to the reaction. Although the solvent is not particularly limited as long as the reaction proceeds, it is preferably, for example, an ether, a guanamine, a hydrocarbon, a halogenated hydrocarbon, a nitrile, an aromatic amine, and the like or a mixed solvent thereof.

反應溫度為約-40至150℃，較佳為約0至100℃。 The reaction temperature is about -40 to 150 ° C, preferably about 0 to 100 ° C.

<步驟89> <Step 89>

化合物(104)可自化合物(103)製造。 Compound (104) can be produced from compound (103).

這反應是以步驟55中之相同方式進行。 This reaction was carried out in the same manner as in the step 55.

<步驟90> <Step 90>

化合物(104)可藉由使化合物(58)與化合物(3)反應而製造。 Compound (104) can be produced by reacting compound (58) with compound (3).

這反應是以步驟1至3中之相同方式進行。 This reaction was carried out in the same manner as in the steps 1 to 3.

藉由各上述製造方法而獲得之化合物(I)可藉由已知手段，諸如，濃縮、減壓下濃縮、溶劑萃取、結晶、再結晶、相轉移、層析術及類似者單離和純化。用於各上述製造方法之各別起始材料化合物可藉由已知手段與類似的前述手段單離和純化。或者，此等反應混合物形式之起始材料化合物可不用單離而直接用作下一個步驟之起始材料。 The compound (I) obtained by each of the above production methods can be isolated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, and the like. . The respective starting material compounds used in each of the above production methods can be isolated and purified by known means and similar means as described above. Alternatively, the starting material compound in the form of such a reaction mixture can be used as the starting material for the next step without isolation.

當化合物(I)含有異構物，諸如，光學異構物、立體異構物、位向異構物、旋轉異構體及類似者，化合物(I)中亦涵蓋任何異構物以及其混合物。例如，當化合物(I)具有光學異構物時，化合物(I)中亦涵蓋從消旋物解析之光學異構物。此等異構物可藉由本質上已知的合成手段或分離手段(例如，濃縮、溶劑萃取、管柱層析術、再結晶等)、光學解析方法(例如，分段再結晶方法、掌性管柱方法、非鏡像異構物方法等)及類似者獲得為各別產物。 When the compound (I) contains an isomer such as an optical isomer, a stereoisomer, a meta isomer, a rotamer and the like, any isomer and a mixture thereof are also encompassed in the compound (I). . For example, when the compound (I) has an optical isomer, the optical isomer which is resolved from the racemate is also encompassed in the compound (I). Such isomers may be synthesized by synthetic means or separation means (eg, concentration, solvent extraction, column chromatography, recrystallization, etc.), optical resolution methods (eg, segmental recrystallization methods, palms) The column method, the non-image isomer method, etc.) and the like are obtained as individual products.

化合物(I)可為結晶。甚至若化合物(I)為單一結晶形式或混合結晶形式，其可提供本發明之化合物(I)。結晶可藉由施用本質上已知之結晶方法而產生結晶。 Compound (I) may be crystalline. Even if the compound (I) is in a single crystalline form or a mixed crystalline form, it can provide the compound (I) of the present invention. Crystallization can be crystallized by applying a crystallization method known per se.

化合物(I)可為溶劑合物(例如，水合物等)或非溶劑合物(例如，非水合物等)，這兩者皆涵蓋中化合物(I)。 The compound (I) may be a solvate (for example, a hydrate or the like) or an unsolvate (for example, a non-hydrate or the like), both of which cover the intermediate compound (I).

化合物(I)亦涵蓋經同位素(例如，²H、³H、¹³C、¹⁴C、¹⁸F、³⁵S、¹²⁵I等)及類似者標誌或取代之化合物。 Compound (I) also encompasses compounds which are labeled or substituted by isotopes (e.g., ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁸ F, ³⁵ S, ¹²⁵ I, etc.) and the like.

化合物(I)亦涵蓋氘轉化形式，其中¹H轉化成²H(D)。 Compound (I) also encompasses a ruthenium conversion form in which ¹ H is converted to ² H (D).

經同位素標誌或取代之化合物(I)可使用作為，例如，用於正子放射斷層造影術(PET)之作為示蹤劑(PET示蹤劑)，而且有用於，諸如，醫學診斷及類似者之領域中。 The isotope-labeled or substituted compound (I) can be used as, for example, It is used as a tracer (PET tracer) for positron emission tomography (PET) and is used in fields such as medical diagnostics and the like.

由於本發明之化合物具有優異的PDE2A抑制作用，其顯示低毒性(例如，光毒性、急性毒性、慢性毒性、基因毒性、生殖毒性、心臟毒性、藥物交互作用、致癌性等，特別為光毒性)，有優異的安定性(特別為代謝安定性)和體內動力學(吸收性、分布、代謝、***等)，而且進一步顯示高溶解度，有用於作為醫藥產物。本發明之化合物對哺乳動物(例如，小鼠、大鼠、倉鼠、兔、貓、狗、牛、馬、綿羊、猴、人等)具有PDE2A抑制作用，而且可使用作為下列疾病和病徵之預防性或治療性藥物：(1)精神障礙(例如，短期性精神障礙、共享型精神障礙)，(2)由酒精、***、***、古柯鹼、***、肥胖、吸入劑、鴉片類或苯環己哌啶誘發之精神病，(3)妄想症，(4)焦慮異常，(5)運動障礙，(6)情緒障礙，(7)重度憂鬱症，(8)疊加在精神障礙(包含妄想症和精神***症)上之重度憂鬱症，(9)輕度、中度或重度類型之重度憂鬱發作，(10)躁狂或混合情感性發作，(11)輕躁狂情感性發作， (12)有典型特徵之抑鬱發作，(13)有憂鬱特徵之抑鬱發作，(14)有緊張型特徵之抑鬱發作，(15)產後初始之情感性發作；(16)中風後抑鬱，(17)低落性情感疾患，(18)輕鬱症，(19)自閉症；(20)藥物成癮，(21)神經退化性異常，(22)與腦創傷相關之神經退行性疾病，(23)與中風相關之神經退行性疾病，(24)與腦梗塞相關之神經退行性疾病，(25)與低血糖症相關之神經退行性疾病，(26)與癲癇發作相關之神經退行性疾病，(27)與神經毒素中毒相關之神經退行性疾病，(28)多系統萎縮症，(29)阿滋海默症，(30)失智症，(31)多發性梗塞失智症，(32)酒精性失智症或與其他藥物相關之失智症，(33)與顱內腫瘤或腦創傷相關之失智症，(34)與杭丁頓氏舞蹈症或帕金森式症相關之失智症，(35)與AIDS相關之阿滋海默症， (36)額顯葉阿滋海默症，(37)譫妄，(38)失憶性疾患，(39)創傷後壓力異常，(40)智力遲鈍，(41)學習異常(例如，閱讀障礙、數學障礙或書寫表現之障礙)，(42)注意力缺損/過動症；(43)與年齡相關之知能缺損，(44)經前情緒障礙，(45)精神***症之精神病後抑鬱障礙，(46)雙極性情感疾病(包含第一型雙極性情感疾病和第二型雙極性情感疾病)，(47)循環性情感疾患，(48)帕金森式症，(49)杭丁頓氏舞蹈症，(50)妄想症，(51)精神***症(正性病徵、負性病徵、認知功能異常為主要病徵)(例如，偏執型精神***症、混亂型精神***症、緊張型精神***症、未定型精神***症、殘留型精神***症)，(52)類精神***症異常，(53)妄想型或憂鬱型***情感性疾病，(54)偏執型人格障礙症， (55)***型人格障礙症，(56)肥胖，(57)代謝症候群，(58)非胰島素依賴型糖尿病(NIDDM)，(59)葡萄糖耐受不良，(60)肺炎，(61)骨關節炎，(62)偏頭痛，(63)脆弱X染色體症候群。 Since the compound of the present invention has excellent PDE2A inhibition, it exhibits low toxicity (for example, phototoxicity, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity, etc., especially phototoxicity) It has excellent stability (especially for metabolic stability) and in vivo kinetics (absorbability, distribution, metabolism, excretion, etc.), and further shows high solubility, and is used as a pharmaceutical product. The compound of the present invention has PDE2A inhibitory action on mammals (e.g., mouse, rat, hamster, rabbit, cat, dog, cow, horse, sheep, monkey, human, etc.), and can be used as a prophylaxis for the following diseases and symptoms Sexual or therapeutic drugs: (1) mental disorders (eg, short-term mental disorders, shared mental disorders), (2) alcohol, amphetamines, marijuana, ***e, ecstasy, obesity, inhalants, opium Or phencyclidine-induced psychosis, (3) delusions, (4) anxiety disorders, (5) dyskinesias, (6) mood disorders, (7) severe depression, (8) superimposed on mental disorders (including Severe depression on paranoia and schizophrenia, (9) mild, moderate or severe type of severe depression, (10) mania or mixed emotional seizures, (11) savage emotional episodes, (12) Depressive episodes with typical characteristics, (13) Depressive episodes with depression characteristics, (14) Depressive episodes with stressful characteristics, (15) Initial emotional episodes after delivery; (16) Post-stroke depression, (17) ) low-lying emotional disorders, (18) mild depression, (19) autism; (20) drug addiction, (21) neurodegenerative abnormalities, (22) neurodegenerative diseases associated with brain trauma, (23) Neurodegenerative diseases associated with stroke, (24) neurodegenerative diseases associated with cerebral infarction, (25) neurodegenerative diseases associated with hypoglycemia, (26) neurodegenerative diseases associated with seizures, ( 27) Neurodegenerative diseases associated with neurotoxin poisoning, (28) Multiple system atrophy, (29) Alzheimer's disease, (30) Dementia, (31) Multiple infarction dementia, (32) Alcoholic dementia or dementia associated with other drugs, (33) Dementia associated with intracranial or brain trauma, (34) Dementia associated with Huntington's disease or Parkinson's disease Disease, (35) Alzheimer's disease associated with AIDS, (36) frontal lobe Alzheimer's disease, (37) sputum, (38) amnesic disorder, (39) post-traumatic stress abnormalities, (40) mental retardation, (41) learning abnormalities (eg, dyslexia, mathematics) Obstacles to impediment or written performance), (42) attention deficit/hyperactivity disorder; (43) age-related cognitive impairment, (44) premenstrual mood disorder, (45) post-psychiatric depression for schizophrenia, 46) Bipolar affective disorders (including first-type bipolar affective disorder and second-type bipolar affective disorder), (47) circulatory affective disorder, (48) Parkinson's disease, (49) Huntington's disease (50) paranoia, (51) schizophrenia (positive sexual symptoms, negative sexual signs, cognitive dysfunction as the main symptoms) (for example, paranoid schizophrenia, chaotic schizophrenia, nervous schizophrenia, Untyped schizophrenia, residual schizophrenia, (52) schizophrenia abnormalities, (53) delusional or melancholic schizoaffective disorders, (54) paranoid personality disorder, (55) schizophrenic personality disorder, (56) obesity, (57) metabolic syndrome, (58) non-insulin-dependent diabetes mellitus (NIDDM), (59) glucose intolerance, (60) pneumonia, (61) bone and joint Inflammation, (62) migraine, (63) fragile X chromosome syndrome.

特別地，本發明之化合物有用於預防或治療精神***症和阿茲海默症。 In particular, the compounds of the invention are useful for the prevention or treatment of schizophrenia and Alzheimer's disease.

由於本發明之化合物有優異的代謝安定性，預期其對上述疾病甚至在低劑量時顯示優異的治療效果。此外，本發明之化合物有優異的腦內轉移率。 Since the compound of the present invention has excellent metabolic stability, it is expected to exhibit an excellent therapeutic effect on the above diseases even at a low dose. Furthermore, the compounds of the invention have excellent intracerebral transfer rates.

由於本發明之化合物顯示低毒性，含有本發明之化合物之醫藥組成物(後文中稱為“本發明之藥劑”)可根據本質上已知之方法(例如，日本藥典中描述之方法等)作為醫藥製劑之製造方法，以例如錠劑(包含糖衣錠劑、膜衣錠劑、舌下錠劑、口內崩解錠劑、頰及類似者)、粒劑、粉劑、丸劑、囊劑(包含軟膠囊、微膠囊)、喉錠、糖漿、液體、乳劑、懸浮液、控釋製劑(例如，速釋製劑、持釋製劑、持釋微膠囊)、氣溶膠、膜(例如，口內崩解膜、口腔黏膜-黏著劑膜)、注射劑(例如，皮下注射劑、靜脈內注射劑、肌肉內注射劑、腹腔內注射劑)、點滴輸注、經皮吸收型製劑、軟膏、洗劑、黏著製劑、栓劑(例如，直腸栓劑、***栓劑)、片劑、鼻製劑、肺製劑(吸入劑)、眼藥水及類似者之形式，口服或非經口地(例如，靜脈內、肌肉內、皮下、器官內、鼻內、皮內、滴注、大腦內、直腸內、***內、腹腔內以及腫瘤內投藥、腫瘤附近之投藥以及對病灶直接投藥)安全地單獨投藥或生理上可接受之載體與混合而投藥。 Since the compound of the present invention exhibits low toxicity, the pharmaceutical composition containing the compound of the present invention (hereinafter referred to as "the agent of the present invention") can be used as a medicine according to a method known per se (for example, a method described in the Japanese Pharmacopoeia). The preparation method of the preparation, for example, a tablet (including a sugar-coated tablet, a film-coated tablet, a sublingual tablet, an intraoral disintegrating tablet, a buccal and the like), a granule, a powder, a pill, a capsule (including a soft capsule) , microcapsules), throat lozenges, syrups, liquids, emulsions, suspensions, controlled release preparations (eg, immediate release preparations, sustained release preparations, sustained release microcapsules), aerosols, membranes (eg, intraoral disintegration membranes, Oral mucosa-adhesive film), injection (for example, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), infusion, percutaneous suction Forming preparations, ointments, lotions, adhesive preparations, suppositories (eg, rectal suppositories, vaginal suppositories), tablets, nasal preparations, lung preparations (inhalation), eye drops, and the like, orally or parenterally (eg, intravenous, intramuscular, subcutaneous, intra-organ, intranasal, intradermal, instillation, intracerebral, intrarectal, intravaginal, intraperitoneal, and intratumoral administration, administration near the tumor, and direct administration to the lesion) The drug is administered alone or in combination with a physiologically acceptable carrier.

上述“生理上可接受之載體”可以多種習知用作製劑材料之有機或無機載體材料所例示，例如，用於固體製劑之賦形劑、潤滑劑、結合劑以及崩解劑；或用於液體製劑之溶劑、助溶劑、懸浮劑、等滲劑、緩衝劑、安慰劑及類似者。此外，當需要時，亦可於適當時使用適當量的一般添加劑，諸如，防腐劑、抗氧化劑、著色劑、甜味劑、吸附劑、濕潤劑及類似者。 The above "physiologically acceptable carrier" can be exemplified by various organic or inorganic carrier materials which are conventionally used as formulation materials, for example, excipients, lubricants, binders and disintegrants for solid preparations; or Solvents, solubilizers, suspending agents, isotonic agents, buffers, placebos and the like of liquid preparations. Further, when necessary, an appropriate amount of a general additive such as a preservative, an antioxidant, a colorant, a sweetener, an adsorbent, a wetting agent, and the like may also be used as appropriate.

賦形劑之實例包含乳糖、蔗糖、D-甘露醇、D-山梨醇、澱粉、α-澱粉、玉米澱粉、糊精、結晶纖維素、低經取代之羥基丙基纖維素、鈉羧基甲基纖維素、***膠、聚三葡萄糖、輕質無水矽酸、合成矽酸鋁、鋁矽酸鎂及類似者。 Examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, alpha -starch, corn starch, dextrin, crystalline cellulose, low substituted hydroxypropylcellulose, sodium carboxymethyl Cellulose, gum arabic, polytriglucose, light anhydrous citric acid, synthetic aluminum citrate, magnesium aluminosilicate and the like.

潤滑劑之實例包含硬脂酸鎂、硬脂酸鈣、滑石、膠質氧化矽及類似者。 Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal cerium oxide, and the like.

黏合劑之實例包含α-澱粉、結晶纖維素、蔗糖、***膠、D-甘露醇、海藻糖、糊精、聚三葡萄糖、羥基丙基纖維素、羥基丙基甲基纖維素、聚乙烯基吡咯啶酮、澱粉、蔗糖、明膠、甲基纖維素、羧基甲基纖維素、羧基甲基纖維素鈉及類似者。 Examples of the binder include α -starch, crystalline cellulose, sucrose, gum arabic, D-mannitol, trehalose, dextrin, polytriglucose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl Pyrrolidone, starch, sucrose, gelatin, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, and the like.

崩解劑之實例包含乳糖、蔗糖、澱粉、羧基甲基纖維素、羧基甲基纖維素鈣、交聯羧甲基纖維素鈉、羧基甲基澱粉鈉、輕質無水矽酸、低經取代之羥基丙基纖維素及類似者。 Examples of disintegrants include lactose, sucrose, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium carboxymethyl starch, light anhydrous citric acid, low substituted Hydroxypropyl cellulose and the like.

溶劑之實例包含注射用水、生理食鹽水、林格式(Ringer’s)注射劑、酒精、丙二醇、聚乙二醇、聚乙烯二醇、芝麻油、玉米油、橄欖油、棉籽油及類似者。 Examples of the solvent include water for injection, physiological saline, Ringer's injection, alcohol, propylene glycol, polyethylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like.

助溶劑之實例包含聚乙二醇、丙二醇、D-甘露醇、海藻糖、苯甲酸苯甲酯、乙醇、參胺基甲烷、膽固醇、三乙醇胺、碳酸鈉、檸檬酸鈉、水楊酸鈉、乙酸鈉及類似者。 Examples of the co-solvent include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, ginsyl methane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, Sodium acetate and the like.

懸浮劑之實例包含界面活性劑，諸如，硬脂醯三乙醇胺、月桂基硫酸鈉、月桂基胺基丙酸、卵磷脂、氯化苄烷銨、氯化本索寧、甘油單硬脂酸酯及類似者；親水性聚合物，諸如，聚乙烯基醇、聚乙烯基吡咯啶酮、羧基甲基纖維素鈉、甲基纖維素、羥基甲基纖維素、羥基乙基纖維素、羥基丙基纖維素、聚山梨醇酯、聚氧基乙烯氫化蓖麻油及類似者；及類似者。 Examples of suspending agents include surfactants such as stearin triethanolamine, sodium lauryl sulfate, lauryl alanine, lecithin, benzalkonium chloride, benzinine chloride, glyceryl monostearate And similar; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl Cellulose, polysorbate, polyoxyethylene hydrogenated castor oil and the like; and the like.

等滲劑之實例包含葡萄糖、D-山梨醇、氯化鈉、甘油、D-甘露醇及類似者。 Examples of isotonic agents include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, and the like.

緩衝劑之實例包含緩衝溶液，諸如，磷酸鹽、乙酸鹽、碳酸鹽、檸檬酸鹽及類似者。 Examples of buffers include buffer solutions such as phosphates, acetates, carbonates, citrates, and the like.

安慰劑之實例包含苯甲醇及類似者。 Examples of placebos include benzyl alcohol and the like.

防腐劑之實例包含對羥基苯甲酸鹽、氯丁醇、苯甲醇、苯乙醇酒精、去氫乙酸、山梨酸及類似者。 Examples of the preservative include p-hydroxybenzoate, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid, and the like.

抗氧化劑之實例包含亞硫酸鹽、抗壞血酸、α-生育酚及類似者。 Examples of the antioxidant include sulfite, ascorbic acid, α -tocopherol, and the like.

著色劑之實例包含水溶性食物焦油色素(例如，食用色素紅色第2號和第3號、食用色素黃色第4號和第5號、食用色素藍色第1號和第2號等)、水不溶性色淀類染料(例如，前述水溶性食物焦油色素之鋁鹽)、天然染料(例如，β-胡蘿蔔素、葉綠素、氧化鐵紅色)及類似者。 Examples of the coloring agent include water-soluble food tar pigments (for example, food coloring red No. 2 and No. 3, food coloring yellow Nos. 4 and No. 5, food coloring blue Nos. 1 and No. 2, etc.), water Insoluble lake-based dyes (for example, the aforementioned aluminum salts of water-soluble food tar pigments), natural dyes (for example, β-carotene, chlorophyll, iron oxide red) and the like.

甜味劑之實例包含糖精鈉、甘草酸二鉀、阿斯巴甜、甜菊及類似者。 Examples of the sweetener include sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia, and the like.

雖然本發明之藥劑中之本發明之化合物之含量取決於劑量形式、本發明之化合物之劑量及類似者而改變，其為例如，整個藥劑之約0.01至100重量%，較佳為約0.1至95重量%。 Although the amount of the compound of the present invention in the agent of the present invention varies depending on the dosage form, the dose of the compound of the present invention and the like, it is, for example, about 0.01 to 100% by weight of the entire pharmaceutical agent, preferably about 0.1 to 95% by weight.

雖然本發明之化合物之劑量取決於投藥對象、投藥路徑、目標疾病、病徵及類似者而改變，其對精神***症病患(成人，約60kg體重)口服投藥時，通常為約0.1至約20mg/kg體重，較佳為約0.2至約10mg/kg體重，更佳為為約0.5至約10mg/kg體重，而且根據病徵每天期望地投藥約一至數(例如，1至3)份之劑量。 Although the dose of the compound of the present invention varies depending on the subject to be administered, the route of administration, the target disease, the condition and the like, it is usually from about 0.1 to about 20 mg when administered orally to a schizophrenia patient (adult, about 60 kg body weight). The body weight/kg is preferably from about 0.2 to about 10 mg/kg body weight, more preferably from about 0.5 to about 10 mg/kg body weight, and a dose of about one to several (e.g., one to three) parts is desirably administered per day depending on the condition.

本發明之化合物可作為單一活性物質投藥，或可與其他藥劑組合投藥，諸如，用於治療精神障礙 (特別為精神***症以及雙極性情感疾患)、強迫症、重鬱症、帕金森式症、阿茲海默症、認知異常、記憶喪失及類似者之其他藥物(後文中簡稱為合併用藥物)。 The compounds of the invention may be administered as a single active substance or may be administered in combination with other agents, such as for the treatment of mental disorders (especially for schizophrenia and bipolar emotional disorders), obsessive-compulsive disorder, severe depression, Parkinson's disease, Alzheimer's disease, cognitive abnormalities, memory loss, and other drugs (hereinafter referred to as combined drugs) .

合併用藥物之實例包含尼古丁α 7促效劑、尼古丁α 7部分促效劑、尼古丁α 7正向異位性調控劑、PDE2抑制劑、PDE4抑制劑、PDE5抑制劑、PDE10抑制劑、其他PDE抑制劑、鈣離子阻斷劑、毒蕈鹼m1和m2調控劑、腺苷受體調控劑、安帕金、甘胺酸轉運蛋白1抑制劑、NMDA-R調控劑、mGluR調控劑、多巴胺調控劑、羥色胺調控劑、選擇性羥色胺再吸收抑制劑、羥色胺以及正腎上腺素再吸收抑制劑、正腎上腺素以及多巴胺再吸收抑制劑、三重再吸收抑制劑、***素調控劑、膽鹼酯酶抑制劑(例如，多奈派齊、利伐斯的明、加蘭他敏)及類似者。 Examples of combined drugs include nicotine α 7 agonist, nicotine α 7 partial agonist, nicotine α 7 positive atopic modulator, PDE2 inhibitor, PDE4 inhibitor, PDE5 inhibitor, PDE10 inhibitor, other PDE Inhibitors, calcium blockers, muscarinic m1 and m2 modulators, adenosine receptor modulators, ampamycin, glycine transporter 1 inhibitors, NMDA-R modulators, mGluR modulators, dopamine regulation Agent, serotonin modulator, selective serotonin reuptake inhibitor, serotonin and norepinephrine reuptake inhibitor, norepinephrine and dopamine reuptake inhibitor, triple reuptake inhibitor, cannabinoid modulator, cholinesterase inhibition Agents (eg, Donepez, rivastigmine, galantamine) and the like.

此外，合併用藥物之實例包含，但不限於，其他適合精神***症藥物(例如，氟哌啶醇(Haloperidol)、氯氮平(Clozapine)、奧氮平(Olanzapine)、理思必妥(Risperidone)、阿立哌唑(Aripiprazole)、齊拉西酮(Ziprasidone)、帕利酮(Paliperidone)、富馬酸奎硫平(Quetiapine fumarate)等)、雙極性情感疾患藥物(例如，鋰、奧氮平、阿立哌唑、丙戊酸等)、帕金森式症藥物(例如，左旋多巴、溴隱亭(Bromocriptine)、培高利特(Pergolide)、普拉克索(Pramipexole)、托卡朋(Tolcapone)、丙環定(Procyclidine)、三己苯尼迪(Trihexyphenidyl)、苯扎托品(Benztropine)等)、用於治療重鬱症之劑(例如，阿米替林(Amitriptyline)、丙咪(Imipramine)、去甲丙咪丙咪(Desipramine)、去甲替林(Nortriptyline)、帕羅西汀(Paroxetine)、氟西汀(Fluoxetine)、舍曲林(Sertraline)、丁氨苯丙酮(Bupropion)、艾司西酞普蘭(Escitalopram)、米氮平(Mirtazapine)、萬拉法辛(Venlafaxine)、度洛西汀(Duloxetine)等)、用於治療阿茲海默症之劑(例如，加蘭他敏(Galantamine)、塔克林(Tacrine)、多奈派齊(Donepezil)、利伐斯的明(Rivastigmine)、美金剛烷(Memantine)、新托平(Neotropin)、思吉寧(Selegiline)、***、氯碘羥喹(Clioquinol)等)、用於治療失智症之劑(例如，硫利達(Thioridazine)、氟哌啶醇、理思必妥、塔克林、多奈派齊、利伐斯的明等)、用於治療癲癇之劑(例如，苯妥英(Phenytoin)、***(Phenobarbital)、卡馬西平(Carbamazepine)、丙戊酸、乙琥胺(Ethosuximide)、加巴噴丁(Gabapentin)、索菲酮(Solfeton)、非爾氨(Felbatol)等)、用於治療多發性硬化症之劑(例如，托特羅定(Tolterodine)、奧昔布寧(Oxybutynin)、氧可酮(Oxycodone)、干擾素β-1b、干擾素β-1a、硫唑嘌呤(Azathioprine)、氨甲蝶呤(Methotrexate)、格拉默(Glatiramer)等)、用於治療杭丁頓氏舞蹈症之劑(例如，阿米替林(Amitriptyline)、丙咪(Imipramine)、去甲丙咪丙咪(Desipramine)、去甲替林(Nortriptyline)、帕羅西汀(Paroxetine)、氟西汀(Fluoxetine)、舍曲林(Sertraline)、丁苯那(Terabenazine)、氟哌啶醇、氯丙(Chlorpromazine)、硫利達(Thioridazine)、舒必利(Sulpiride)、奎硫平、氯氮平、理思必妥等)、有用於治療糖尿病之劑[例如，PPAR配位體(例如，促效劑或拮抗劑，諸如羅格列酮(Rosiglitazone)、曲格列酮(Troglitazone)、皮利酮(Pioglitazone)等)、胰島素促泌素(例如，磺醯脲藥物，諸如，格列本脲(Glyburide)、格列美脲(Glimepiride)、氯磺丙脲(Chlopropamide)、甲苯磺丁脲(Tolbutamide)、格列吡(Glipizide)等以及非磺醯基促泌素)、α-葡萄醣苷酶抑制劑(例如，阿卡波糖、米格列醇(Miglitol)、伏利波糖等)、胰島素敏化劑(例如，PPAR-γ促效劑(例如，格列酮類)；雙胍類、PTP-1B抑制劑、DPP-IV抑制劑、11 β-HSD抑制劑等)、肝臟葡萄糖排出量降低之化合物(例如，升糖素拮抗劑以及二甲雙胍(例如，庫魯化錠(Glucophage)、庫魯化錠XR等))、胰島素以及胰島素衍生物(包含胰島素之長和短作用形式兩者和胰島素調配物)]、抗肥胖藥物[例如，β-3促效劑、CB-1促效劑、神經胜肽Y5抑制劑、睫狀神經營養因子以及衍生物(例如，阿索開(Axokine))、食慾抑制劑(例如，***(Sibutramine))、脂肪酶抑制劑(例如，奧利司他(Orlistat))等]。 Further, examples of the combined drug include, but are not limited to, other drugs suitable for schizophrenia (for example, haloperidol, clozapine, olanzapine, risperidone (Risperidone) ), Aripiprazole, Ziprasidone, Paliperidone, Quetiapine fumarate, etc., bipolar affective drugs (eg, lithium, azide) Paclitaxel, valproic acid, etc. Tolcapone), Procyclidine, Trihexyphenidyl, Benztropine, etc., for the treatment of severe depression (eg, Amitriptyline, Ami) (Imipramine), mitopromidazole (Desipramine), Nortriptyline, Paroxetine, Fluoxetine, Sertraline, Bupropion, Escitalopram, Rice Mirtazapine, Venlafaxine, Duloxetine, etc., agents for the treatment of Alzheimer's disease (eg, Galantamine, Tacrine) ), Donepezil, Rivastigmine, Memantine, Neotropin, Selegiline, Estrogen, Clioquinol Etc., for the treatment of dementia (for example, sulphur (Thioridazine), haloperidol, risperidone, tacrine, donepezil, rivastigmine, etc.), agents for the treatment of epilepsy (eg, Phenytoin, phenobarbital ( Phenobarbital), Carbamazepine, valproic acid, Ethosuximide, Gabapentin, Solfeton, Felbatol, etc., for the treatment of multiple sclerosis Agents (for example, Tolterodine, Oxybutynin, Oxycodone, Interferon beta-1b, Interferon beta-1a, Azathioprine, Methotrexate) (Methotrexate), Glatiramer, etc., for the treatment of Huntington's disease (eg, Amitriptyline, Ami) (Imipramine), mitopromidazole (Desipramine), Nortriptyline, Paroxetine, Fluoxetine, Sertraline, Butenaline (Terabenazine), haloperidol, chloropropyl (Chlorpromazine), sulphide (Thioridazine), Sulpiride, quetiapine, clozapine, risperidone, etc., agents for the treatment of diabetes [eg, PPAR ligands (eg, agonists or antagonists, such as Rogge) Rosiglitazone, Troglitazone, Pioglitazone, etc., insulin secretagogues (eg, sulfonylurea drugs such as Glyburide, Glimepiride (Glyburide) Glimepiride), Chlopropamide, Tolbutamide, Glipizide (Glipizide) and the like as well as non-sulfostyl-secretin), α -glucosidase inhibitors (for example, acarbose, miglitol, voltose, etc.), insulin sensitizers (for example) , PPAR-γ agonists (eg, glitazones); biguanides, PTP-1B inhibitors, DPP-IV inhibitors, 11 β-HSD inhibitors, etc.), compounds with reduced hepatic glucose excretion (eg, Glucagon antagonists and metformin (eg, Glucophage, Kuru, XR, etc.), insulin, and insulin derivatives (including both long and short forms of insulin and insulin formulations), Anti-obesity drugs [eg, beta-3 agonists, CB-1 agonists, neuropeptide Y5 inhibitors, ciliary neurotrophic factors and derivatives (eg, Axokine), appetite suppressants ( For example, Sibutramine, lipase inhibitors (eg, Orlistat), etc.].

本發明之組合劑之投藥形式不特別限制，而且本發明之化合物和合併用藥物僅需要於投藥時組合。此投藥模式之實例包含以下者：(1)投藥藉由同時加工本發明之化合物與合併用藥物而獲得之單一製劑，(2)以相同投藥路徑，同時投藥已分別產生之本發明之化合物之兩種製劑和合併用藥物，(3)以交錯方式和相同投藥路徑，已分別產生之本發明之化合物之兩種製劑和合併用藥物，(4)以不同投藥路徑，同時投藥已分別產生之本發明之化合物之兩種製劑和合併用藥物，(5)以交錯方式和不同投藥路徑(例如，以本發明之化合物和合併用藥物之順序或以相反順序投藥)及類似者，投藥已分別產生之本發明之化合物之兩種製劑和合併用藥物。 The administration form of the composition of the present invention is not particularly limited, and the compound of the present invention and the combined drug need only be combined at the time of administration. Examples of the administration mode include the following: (1) administration of a single preparation obtained by simultaneously processing a compound of the present invention and a combined drug, and (2) simultaneous administration of a compound of the present invention which has been separately produced by the same administration route Two preparations and combined drugs, (3) in a staggered manner and the same route of administration, respectively, the hair that has been produced separately Two preparations of the compound of the compound and the combined drug, (4) simultaneously administering the two preparations of the compound of the present invention and the combined drug separately produced in different administration routes, (5) in a staggered manner and different administration routes (for example) In the case of the compound of the present invention and the combination drug or in the reverse order, and the like, the two preparations of the compound of the present invention and the combined drug which have been separately produced are administered.

此等投藥形式彙總如下，簡稱為本發明之合併用藥物。 These administration forms are summarized as follows, and are simply referred to as the combined drugs of the present invention.

當投藥本發明之合併用藥物時，可同時投藥合併用藥物和本發明之化合物。另外，本發明之化合物可在合併用藥物投藥投藥之後投藥，而且合併用藥物可在投藥本發明之化合物之後投藥。當以交錯方式投藥時，投藥時間取決於欲投藥之活性成分、劑量形式以及投藥方法而改變。 When the combined drug of the present invention is administered, the combined drug and the compound of the present invention can be administered simultaneously. Further, the compound of the present invention can be administered after administration of a combined drug, and the combined drug can be administered after administration of the compound of the present invention. When administered in a staggered manner, the time of administration varies depending on the active ingredient to be administered, the dosage form, and the method of administration.

例如，當首先投藥合併用藥物或其醫藥組成物時，本發明之化合物或其醫藥組成物可在投藥合併用藥物或其醫藥組成物之後之1分鐘至3天內，較佳為10分鐘至1天內，更佳為為15分鐘至1小時內投藥。另外，當首先投藥本發明之化合物或其醫藥組成物時，合併用藥物或其醫藥組成物可在投藥本發明之化合物或其醫藥組成物之後之1分鐘至1天內，較佳為10分鐘至6小時內，更佳為15分鐘至1小時內投藥。 For example, when the drug or a pharmaceutical composition thereof is administered first, the compound of the present invention or a pharmaceutical composition thereof may be administered within 1 minute to 3 days, preferably 10 minutes, after administration of the drug or a pharmaceutical composition thereof. It is better to administer within 15 minutes to 1 hour within 1 day. Further, when the compound of the present invention or a pharmaceutical composition thereof is administered first, the combined drug or a pharmaceutical composition thereof may be administered within 1 minute to 1 day, preferably 10 minutes after administration of the compound of the present invention or a pharmaceutical composition thereof. It is better to administer within 15 minutes to 1 hour within 6 hours.

當合併用藥物不會造成副作用之問題時，可以任何劑量投藥。雖然合併用藥物之劑量取決於劑量形式、投藥對象、投藥路徑、目標疾病、病徵及類似者而改變，其對精神***症病患(成人，約60kg體重)口服投藥時，通常為例如約0.1至約20mg/kg體重，較佳為約0.2至約10mg/kg體重，更佳為約0.5至約10mg/kg體重，而且根據病徵期望每天投藥約一至數(例如，1至3)份劑量。 When the combined drug does not cause side effects, it can be administered at any dose. Although the dose of the combined drug depends on the dosage form, the subject, the route of administration, the target disease, the symptoms, and the like. Orally, when administered orally to a schizophrenia patient (adult, about 60 kg body weight), it is usually, for example, about 0.1 to about 20 mg/kg body weight, preferably about 0.2 to about 10 mg/kg body weight, more preferably about 0.5 to About 10 mg/kg body weight, and about one to several (e.g., 1 to 3) doses are administered per day depending on the condition.

當本發明之化合物與合併用藥物組合使用時，考慮到兩種藥物之相反效果，其劑量可減少至安全範圍內。 When the compound of the present invention is used in combination with a combination drug, the dose can be reduced to a safe range in consideration of the opposite effects of the two drugs.

本發明之合併用藥物顯示低毒性，例如，本發明之化合物或(及)上述合併用藥物可根據本質上已知之方法與生理上可接受之載體例如錠劑(包含糖衣錠劑、膜衣錠劑及類似者)、粉劑、丸劑、囊劑(包含軟膠囊)、液體、乳劑、懸浮液、注射劑、栓劑、持釋製劑(例如，舌下錠劑、微囊劑等)、硬膏劑、口內崩解錠劑、口服可崩解膜及類似者混合，以產生可安全地口服或非經口地投藥(例如，皮下、局部、直腸、靜脈內投藥等)之醫藥組成物。 The combined medicament of the present invention exhibits low toxicity, for example, the compound of the present invention or (and) the above-mentioned combined medicament can be administered according to a method known per se to a physiologically acceptable carrier such as a tablet (including a dragee, a film-coated tablet) And similar), powders, pills, capsules (including soft capsules), liquids, emulsions, suspensions, injections, suppositories, sustained release preparations (eg, sublingual tablets, microcapsules, etc.), plasters, intraoral The disintegrating tablet, the orally disintegrable film and the like are mixed to produce a pharmaceutical composition which can be safely administered orally or parenterally (for example, subcutaneous, topical, rectal, intravenous, etc.).

可用於製造本發明醫藥上可接受的載體之組合藥物為與上述彼等用於本發明之藥劑者相同。 Combinations of the drugs which can be used in the manufacture of the pharmaceutically acceptable carrier of the present invention are the same as those described above for use in the present invention.

本發明之組合藥物中之本發明之化合物與合併用藥物之間之混合比率可基於投藥對象、投藥路徑、目標疾病及類似者而適當地選擇。 The mixing ratio between the compound of the present invention and the drug for combination in the combination drug of the present invention can be appropriately selected depending on the administration target, the administration route, the target disease, and the like.

若組合兩種或更多種藥物，本發明之組合藥物中之合併用藥物可以適當比例組合。 When two or more drugs are combined, the combined drugs in the combination drug of the present invention may be combined in an appropriate ratio.

合併用藥物之劑量可基於臨床上使用之劑量而適當地選擇。另外，本發明之化合物與合併用藥物之間之混合比率可基於投藥對象、投藥路徑、目標疾病、病徵、組合物等而適當地選擇。例如，若投藥對象為人類，合併用藥物可以範圍為相對於1重量份之本發明之化合物之約0.01至100重量份之含量使用。 The dose of the combined drug can be appropriately selected based on the dose used clinically. In addition, the mixing ratio between the compound of the present invention and the combined drug can be based on the administration target, the administration route, the target disease, the symptom, and the composition. Wait and choose as appropriate. For example, if the administration target is a human, the combined drug may be used in an amount ranging from about 0.01 to 100 parts by weight based on 1 part by weight of the compound of the present invention.

例如，雖然本發明之組合劑中之本發明之化合物之含量取決於製劑形式而改變，其通常為整個製劑之約0.01至99.9重量%，較佳為約0.1至50重量%、更佳為為約0.5至20重量%。 For example, although the content of the compound of the present invention in the composition of the present invention varies depending on the form of the preparation, it is usually from about 0.01 to 99.9% by weight, preferably from about 0.1 to 50% by weight, more preferably from about 0.1 to 50% by weight, based on the total amount of the preparation. About 0.5 to 20% by weight.

本發明之組合劑中之合併用藥物之含量取決於製劑形式而改變，而且通常為整個製劑之約0.01至99.9重量%，較佳為約0.1至50重量%，進一步較佳為約0.5至20重量%。 The amount of the combined drug in the composition of the present invention varies depending on the form of the preparation, and is usually about 0.01 to 99.9% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight of the entire preparation. weight%.

雖然添加劑(諸如，本發明之組合劑中之載體及類似者)之含量取決於製劑之形式而改變，其通常為基於整個製劑之約1至99.99重量%，較佳為約10至90重量%。 Although the amount of the additive (such as the carrier in the composition of the present invention and the like) varies depending on the form of the preparation, it is usually from about 1 to 99.99% by weight, preferably from about 10 to 90% by weight based on the entire preparation. .

當分別製備本發明之化合物與合併用藥物時，可採用相同內容。 The same contents can be employed when the compound of the present invention and the drug for combination are separately prepared.

由於劑量可於多種上述條件下改變，少於該劑量之劑量可為充足或可需要以超過上述範圍之劑量投藥。 Since the dosage can be varied under a variety of the above conditions, less than the dose can be sufficient or it may be necessary to administer the dose in excess of the above range.

實施例 Example

本發明係藉由參考僅例示且不應被理解為限制性之實施例、調配例以及實驗例而於以下詳述，而且本發明可在本發明之範疇內改變。以下實施例中，“室溫” 通常表示約10℃至約35℃。表示混合溶劑之比率為體積混合比率，除非另行註明。%表示重量%，除非另行註明。 The invention is described in detail below with reference to the examples, the examples, and the examples, which are intended to be illustrative only, and the invention may be modified within the scope of the invention. In the following examples, "room temperature" It generally represents from about 10 ° C to about 35 ° C. Indicates that the ratio of the mixed solvent is the volume mixing ratio unless otherwise stated. % means % by weight unless otherwise stated.

矽膠管柱層析術中，NH表示胺基丙基矽烷鍵結之矽膠之使用。HPLC(高效能液體層析術)中，C18表示鍵結之矽膠之使用。洗析溶劑之比率為體積混合比率，除非另行註明。 In the rubber column chromatography, NH represents the use of an aminopropyl decane-bonded silicone. In HPLC (High Performance Liquid Chromatography), C18 indicates the use of bonded silicone. The ratio of elution solvent is the volume mixing ratio unless otherwise stated.

¹H NMR(質子核磁共振譜)係藉由傅利葉轉換型NMR測量。不描述羥基、胺基及類似者之質子之寬廣和未辨識之峰。 ¹ H NMR (proton nuclear magnetic resonance spectrum) was measured by Fourier transform type NMR. Broad and unrecognized peaks of protons of hydroxyl groups, amine groups and the like are not described.

以下參考例和實施例中，質譜(MS)、核磁共振譜(NMR)以及熔點係藉由以下儀器測量。 In the following Reference Examples and Examples, mass spectrometry (MS), nuclear magnetic resonance spectrum (NMR), and melting point were measured by the following instruments.

MS(質譜)係以LC/MS(液體層析圖質譜儀)測量。至於游離化方法，則使用API(大氣壓力游離化、大氣壓力化學游離化)方法或ESI(電噴霧游離化)方法。數據表示所測之值(實測值)。通常，觀察到分子離子峰。在具有胺基(-NH₂)之化合物之情況下，可觀察到NH₃移除之後作為碎體離子之峰。在鹽之情況下，通常觀察到分子離子峰或游離形式之碎體離子峰。 MS (mass spectrometry) was measured by LC/MS (liquid chromatogram mass spectrometer). As for the dissociation method, an API (atmospheric pressure release, atmospheric pressure chemical release) method or an ESI (electrospray ionization) method is used. The data represents the measured value (measured value). Typically, molecular ion peaks are observed. In the case of a compound having an amine group (-NH ₂ ), a peak as a fragment ion after NH ₃ removal can be observed. In the case of a salt, a molecular ion peak or a free form of fragment ion peak is usually observed.

實施例1-I Example 1-I N-((1S)-2-羥基-2-甲基-1-(4-(三氟甲氧基)苯基)丙基)-5-(6-甲基吡啶-3-基)吡唑并[1,5-a]嘧啶-3-甲醯胺 N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-5-(6-methylpyridin-3-yl)pyrazole And [1,5-a]pyrimidine-3-carboxamide A)5-羥基吡唑并[1,5-a]嘧啶-3-羧酸乙酯 A) Ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate

在3-胺基-1H-吡唑-4-羧酸乙酯(15.0g)和3-乙氧基-2-丙烯酸乙酯(21.0mL)於N,N-二甲基甲醯胺(322mL)之溶液中添加碳酸銫(56.7g)。將反應混合物於100℃攪拌隔夜，添加水，以及依序添加乙酸以將pH調整至約4。將獲得之固體藉由過濾而收集，而且以水清洗而產生標題化合物(17.1g)。 Ethyl 3-amino-1H-pyrazole-4-carboxylate (15.0 g) and ethyl 3-ethoxy-2-propenoate (21.0 mL) in N,N-dimethylformamide (322 mL) Solution Barium carbonate (56.7 g) was added thereto. The reaction mixture was stirred overnight at 100 ° C, water was added, and acetic acid was added sequentially to adjust the pH to about 4. The obtained solid was collected by filtration and washed with water to give the title compound (17.1 g).

¹H NMR(300MHz,DMSO-d₆)δ 1.28(3H,t,J=7.0Hz),4.27(2H,q,J=6.9Hz),6.14(1H,d,J=7.9Hz),8.13(1H,s),8.56(1H,d,J=7.9Hz),11.75(1H,brs)。 ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.28 (3H, t, J = 7.0 Hz), 4.27 (2H, q, J = 6.9 Hz), 6.14 (1H, d, J = 7.9 Hz), 8.13 ( 1H, s), 8.56 (1H, d, J = 7.9 Hz), 11.75 (1H, brs).

B)5-羥基吡唑并[1,5-a]嘧啶-3-羧酸 B) 5-Hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylic acid

在5-羥基吡唑并[1,5-a]嘧啶-3-羧酸乙酯(20.8g)、四氫呋喃(223mL)和乙醇(111mL)之混合物中添加2M氫氧化鈉水溶液(201mL)。將反應混合物於50℃攪拌隔夜，而且使有機溶劑於減壓下蒸發。在殘質中添加2M鹽酸(201mL)，將沉澱之固體藉由過濾而收集，而且以水/乙醇清洗而產生標題化合物(17.7g)。 A 2 M aqueous sodium hydroxide solution (201 mL) was added to a mixture of ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (20.8 g), tetrahydrofuran (223 mL) and ethanol (111 mL). The reaction mixture was stirred at 50 ° C overnight, and the organic solvent was evaporated. 2M Hydrochloric acid (201 mL) was added to the residue, and the precipitated solid was collected by filtration and washed with water/ethanol to give the title compound (17.7 g).

MS(API-)：[M-H]^-177.9。 MS (API-): [MH] ^- 177.9.

C)5-氯吡唑并[1,5-a]嘧啶-3-羰基氯化物 C) 5-Chloropyrazo[1,5-a]pyrimidine-3-carbonyl chloride

在5-羥基吡唑并[1,5-a]嘧啶-3-羧酸(4.24g)中添加***(50mL)，並且緩慢地添加N,N-二異丙基乙基胺(13.6mL)。將反應混合物於迴流下加熱3小時，而且於減壓下蒸發***。在殘質中添加乙酸乙酯，混合物冷卻至0℃，添加水，將混合物以乙酸乙酯萃取。萃取物以水和飽和鹽水清洗且過濾通過矽膠墊，而且溶劑於減壓下蒸發以產生標題化合物(3.07g)。 Phosphorus oxychloride (50 mL) was added to 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylic acid (4.24 g), and N,N-diisopropylethylamine was slowly added ( 13.6 mL). The reaction mixture was heated under reflux for 3 hours, and phosphorus oxychloride was evaporated under reduced pressure. Ethyl acetate was added to the residue, the mixture was cooled to 0 ° C, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and aq.

¹H NMR(300MHz,DMSO-d₆)δ 7.37(1H,d,J=7.2Hz), 8.61(1H,s),9.30(1H,d,J=7.2Hz)。 ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.37 (1H, d, J = 7.2 Hz), 8.61 (1H, s), 9.30 (1H, d, J = 7.2 Hz).

D)(S)-5-氯-N-(2-羥基-2-甲基-1-(4-(三氟甲氧基)苯基)丙基)吡唑并[1,5-a]嘧啶-3-甲醯胺 D) (S)-5-Chloro-N-(2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)pyrazolo[1,5-a] Pyrimidine-3-carboxamide

在5-氯吡唑并[1,5-a]嘧啶-3-羰基氯化物(1.07g)、(S)-1-胺基-2-甲基-1-(4-(三氟甲氧基)苯基)丙-2-醇鹽酸鹽(1.42g)以及乙腈(20mL)之混合物中添加三乙胺(1.60mL)。將反應混合物於室溫攪拌3小時，添加水，以及將混合物以乙酸乙酯萃取。將將萃取物以飽和鹽水清洗，以無水硫酸鈉乾燥，以及使溶劑於減壓下蒸發。殘質經由矽膠管柱層析術(己烷/乙酸乙酯)純化，而且所得固體以二異丙基醚清洗以產生標題化合物(1.76g)。 In 5-chloropyrazolo[1,5-a]pyrimidin-3-carbonyl chloride (1.07g), (S)-1-amino-2-methyl-1-(4-(trifluoromethoxy) Triethylamine (1.60 mL) was added to a mixture of phenyl)propan-2-ol hydrochloride (1.42 g) and acetonitrile (20 mL). The reaction mixture was stirred at room temperature for 3 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc)

MS(API+)：[M+H]⁺429.1. MS (API+): [M+H] ⁺ 429.1.

E)N-((1S)-2-羥基-2-甲基-1-(4-(三氟甲氧基)苯基)丙基)-5-(6-甲基吡啶-3-基)吡唑并[1,5-a]嘧啶-3-甲醯胺 E) N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-5-(6-methylpyridin-3-yl) Pyrazolo[1,5-a]pyrimidine-3-carboxamide

於室溫，在(S)-5-氯-N-(2-羥基-2-甲基-1-(4-(三氟甲氧基)苯基)丙基)吡唑并[1,5-a]嘧啶-3-甲醯胺(55.0mg)、2-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡啶(43.9mg)、碳酸鉀(26.6mg)、甲苯(4mL)以及水(0.4mL)之混合物中添加雙(二-第三丁基(4-二甲基胺基苯基)膦)二氯鈀(II)(9.1mg)。將反應混合物於氮氣氛下攪拌，而且於150℃使用微波爐25分鐘，以及經由矽膠管柱層析術(己烷/乙酸乙酯)純化。所得固體以己烷/乙酸乙酯清洗以產生標題化合物(39.3mg)。 (S)-5-Chloro-N-(2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)pyrazolo[1,5 at room temperature -a]pyrimidine-3-carbamide (55.0 mg), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- Addition of bis(di-tert-butyl(4-dimethylaminophenyl) to a mixture of 2-yl)pyridine (43.9 mg), potassium carbonate (26.6 mg), toluene (4 mL) and water (0.4 mL) Phosphine) dichloropalladium (II) (9.1 mg). The reaction mixture was stirred under a nitrogen atmosphere, and was applied to a microwave oven at 150[deg.] C. for 25 min and purified by EtOAc (hexane/ethyl acetate). The resulting solid was washed with EtOAc /EtOAcEtOAc

MS(API+)：[M+H]+486.2。 MS (API+): [M+H]+486.2.

1H NMR(300MHz,DMSO-d6)δ 1.03(3H,s),1.33(3H,s),2.60(3H,s),4.93(1H,d,J=8.3Hz),5.19(1H,s),7.23-7.33(2H,m),7.48-7.59(3H,m),7.98(1H,d,J=7.5Hz),8.50(1H,s),8.81(1H,dd,J=8.3、2.3Hz),9.24(1H,d,J=8.7Hz),9.41(1H,d,J=7.5Hz),9.54(1H,d,J=2.3Hz)。 1H NMR (300MHz, DMSO-d6) δ 1.03 (3H, s), 1.33 (3H, s), 2.60 (3H, s), 4.93 (1H, d, J = 8.3 Hz), 5.19 (1H, s), 7.23-7.33(2H,m), 7.48-7.59(3H,m), 7.98(1H,d,J=7.5Hz), 8.50(1H,s),8.81(1H,dd,J=8.3,2.3Hz) , 9.24 (1H, d, J = 8.7 Hz), 9.41 (1H, d, J = 7.5 Hz), 9.54 (1H, d, J = 2.3 Hz).

實施例1-II Example 1-II N-((1S)-2-羥基-2-甲基-1-(4-(三氟甲氧基)苯基)丙基)-5-(6-甲基吡啶-3-基)吡唑并[1,5-a]嘧啶-3-甲醯胺 N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-5-(6-methylpyridin-3-yl)pyrazole And [1,5-a]pyrimidine-3-carboxamide A)5-羥基吡唑并[1,5-a]嘧啶-3-羧酸乙酯 A) Ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate

將3-胺基-1H-吡唑-4-羧酸乙酯(10.7g)、3-乙氧基丙烯酸乙酯(15mL)和碳酸銫(33.8g)於N,N-二甲基甲醯胺(200mL)中之混合物於110℃攪拌18小時。使溶劑於減壓下蒸發，以及將殘質以水稀釋及以乙酸酸化。沉澱之固體藉由過濾而收集，以水清洗，以及乾燥以產生標題化合物(13.7g)。 3-Amino-1H-pyrazole-4-carboxylic acid ethyl ester (10.7 g), 3-ethoxyethyl acrylate (15 mL) and cesium carbonate (33.8 g) in N,N-dimethylformamidine The mixture in the amine (200 mL) was stirred at 110 ° C for 18 h. The solvent was evaporated under reduced pressure, and the residue was diluted with water and acidified with acetic acid. The precipitated solid was collected by filtration, washed with water and dried to give the title compound (13.7 g).

1H NMR(300MHz,DMSO-d6)δ 1.28(3H、t、J=7.2Hz),4.27(2H,q,J=7.2Hz),6.15(1H,d,J=7.9Hz),8.13(1H,s),8.56(1H,d,J=7.9Hz),11.77(1H,brs)。 1H NMR (300MHz, DMSO-d6) δ 1.28 (3H, t, J = 7.2 Hz), 4.27 (2H, q, J = 7.2 Hz), 6.15 (1H, d, J = 7.9 Hz), 8.13 (1H, s), 8.56 (1H, d, J = 7.9 Hz), 11.77 (1H, brs).

B)5-氯吡唑并[1,5-a]嘧啶-3-羧酸乙酯 B) ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate

將5-羥基吡唑并[1,5-a]嘧啶-3-羧酸乙酯(18.0g)懸浮於乙腈(40mL)，於室溫添加***(40mL)，以及使混合物於氮氣氛下於110℃攪拌4小時。反應混合物冷卻，而且於減壓下濃縮。殘質以乙酸乙酯稀釋及以碳酸氫鈉水溶液中和，而且不溶性材料以矽藻土濾除。濾液之有機層經矽膠墊純化，以及使溶劑於減壓下蒸發。沉澱之固體以乙酸乙酯/二異丙基醚清洗以產生標題化合物(14.1g)。母液進一步於減壓下濃縮，而且產生之固體以乙酸乙酯/二異丙基醚清洗以產生標題化合物(2.40g)。 Ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (18.0 g) was suspended in acetonitrile (40 mL), phosphorus oxychloride (40 mL) was added at room temperature, and the mixture was applied to nitrogen The mixture was stirred at 110 ° C for 4 hours under an atmosphere. The reaction mixture was cooled and concentrated under reduced pressure. The residue was diluted with ethyl acetate and neutralized with aqueous sodium bicarbonate, and the insoluble material was filtered over Celite. Organic layer of filtrate The silicone pad was purified and the solvent was evaporated under reduced pressure. The precipitated solid was washed with ethyl acetate / diisopropyl ether to afford the title compound (14.1 g). The mother liquor was further concentrated under reduced pressure and EtOAcqqqqqqq

¹H NMR(300MHz,CDCl₃)δ 1.42(3H、t、J=7.2Hz),4.43(2H,q,J=7.2Hz),6.99(1H,d,J=7.2Hz),8.56(1H,s),8.63(1H,d,J=7.2Hz)。 ^{_{1 H NMR (300MHz, CDCl 3}} ) δ 1.42 (3H, t, J = 7.2Hz), 4.43 (2H, q, J = 7.2Hz), 6.99 (1H, d, J = 7.2Hz), 8.56 (1H, s), 8.63 (1H, d, J = 7.2 Hz).

C)5-(6-甲基吡啶-3-基)吡唑并[1,5-a]嘧啶-3-羧酸乙酯 C) ethyl 5-(6-methylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate

將5-氯吡唑并[1,5-a]嘧啶-3-羧酸乙酯(1.7g)、2-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡啶(2g)、磷酸鉀(3.4g)、甲苯(32mL以及水(8mL)之混合物以氬沖洗，於室溫添加雙(二-第三丁基(4-二甲基胺基苯基)膦)二氯鈀(II)(267mg)，以及將反應混合物加熱至110℃和攪拌15小時。反應混合物冷卻，添加水和乙酸乙酯及四氫呋喃，以及濾除不溶性材料。濾液之有機層以飽和鹽水清洗，以無水硫酸鈉乾燥，以及使溶劑於減壓下蒸發。產生之固體以乙酸乙酯/二異丙基醚清洗以產生標題化合物(1.69g)。母液進一步經由矽膠管柱層析術(己烷/乙酸乙酯)純化，而且所得固體以乙酸乙酯/二異丙基醚清洗以產生標題化合物(0.29g)。 Ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (1.7 g), 2-methyl-5-(4,4,5,5-tetramethyl-1,3 , a mixture of 2-dioxaborolan-2-yl)pyridine (2g), potassium phosphate (3.4g), toluene (32mL and water (8mL) was flushed with argon, and double (di- Tributyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (267 mg), and the reaction mixture was heated to 110 ° C and stirred for 15 hours. The reaction mixture was cooled, water and ethyl acetate were added. And the tetrahydrofuran, and the insoluble material was filtered off. The organic layer of the filtrate was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated and evaporated. The title compound (0.29 g) was obtained from m.

MS(API+)：[M+H]⁺283.1。 MS (API+): [M+H] ⁺ 283.1.

D)5-(6-甲基吡啶-3-基)吡唑并[1,5-a]嘧啶-3-羧酸 D) 5-(6-Methylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

將5-(6-甲基吡啶-3-基)吡唑并[1,5-a]嘧啶-3-羧酸乙酯 (1.98g)懸浮於乙醇(15mL)和四氫呋喃(30mL)之混合物，添加2M氫氧化鈉水溶液(7mL)，以及將反應混合物於60℃攪拌18小時。反應混合物之有機溶劑於減壓下蒸發，而且殘質以2M鹽酸酸化。產生之固體藉由過濾而收集，以水清洗，以及乾燥以產生標題化合物(1.8g)。 Ethyl 5-(6-methylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate A mixture of ethanol (15 mL) and tetrahydrofuran (30 mL) was added, and 2M aqueous sodium hydroxide (7 mL) was added, and the mixture was stirred at 60 ° C for 18 hours. The organic solvent of the reaction mixture was evaporated under reduced pressure and the residue was acidified with 2M hydrochloric acid. The resulting solid was collected by filtration, washed with water, and dried to give the title compound (1.8 g).

MS(API+)：[M+H]⁺255.1。 MS (API+): [M+H] ⁺ 255.1.

將5-(6-甲基吡啶-3-基)吡唑并[1,5-a]嘧啶-3-羧酸(2.87g)、(S)-1-胺基-2-甲基-1-(4-(三氟甲氧基)苯基)丙-2-醇鹽酸鹽(3.22g)以及三乙胺(4.72mL)懸浮於乙腈(120mL)，在其中添加1-羥基苯并***(1.83g)和1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(2.60g)，以及將混合物於氮氣氛下於室溫攪拌4小時。在反應混合物中添加水，以及將混合物以乙酸乙酯萃取。將萃取物以飽和鹽水清洗，以及以無水硫酸鈉乾燥，以及使溶劑於減壓下蒸發。殘質經由矽膠管柱層析術(NH、己烷/乙酸乙酯)純化，以及所得之固體從乙酸乙酯/庚烷再結晶以產生標題化合物(3.24g)。母液進一步濃縮，而且所得之固體從乙酸乙酯/庚烷再結晶以產生標題化合物(0.80g)。 5-(6-Methylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (2.87 g), (S)-1-amino-2-methyl-1 -(4-(Trifluoromethoxy)phenyl)propan-2-ol hydrochloride (3.22 g) and triethylamine (4.72 mL) were suspended in acetonitrile (120 mL), and 1-hydroxybenzotriazole was added thereto. Azole (1.83 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.60 g), and the mixture was stirred at room temperature under nitrogen for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc) elute The mother liquor was further concentrated, and the obtained solid was crystallised from ethyl acetate /hexanes to afford title compound (0.80 g).

MS(API+)：[M+H]⁺486.1。 MS (API+): [M+H] ⁺ 486.1.

¹H NMR(300MHz,DMSO-d₆)δ 1.04(3H,s),1.33(3H,s),2.60(3H,s),4.93(1H,d,J=8.5Hz),5.19(1H,s),7.24-7.32(2H,m),7.49-7.58(3H,m),7.98(1H,d,J=7.5Hz),8.50(1H,s), 8.81(1H,dd,J=8.3、2.3Hz),9.24(1H,d,J=8.5Hz),9.41(1H,d,J=7.5Hz),9.54(1H,d,J=2.3Hz)。 ^{1 H NMR (300MHz, DMSO-} d 6) δ 1.04 (3H, s), 1.33 (3H, s), 2.60 (3H, s), 4.93 (1H, d, J = 8.5Hz), 5.19 (1H, s ), 7.24-7.32 (2H, m), 7.49-7.58 (3H, m), 7.98 (1H, d, J = 7.5 Hz), 8.50 (1H, s), 8.81 (1H, dd, J = 8.3, 2.3 Hz), 9.24 (1H, d, J = 8.5 Hz), 9.41 (1H, d, J = 7.5 Hz), 9.54 (1H, d, J = 2.3 Hz).

實施例2-I Example 2-I N-((1S)-2-羥基-2-甲基-1-(4-(三氟甲氧基)苯基)丙基)-6-甲基-5-(4-甲基-1H-1,2,3-***-1-基)吡唑并[1,5-a]嘧啶-3-甲醯胺 N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-6-methyl-5-(4-methyl-1H- 1,2,3-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide A)5,7-二羥基-6-甲基吡唑并[1,5-a]嘧啶-3-羧酸乙酯 A) Ethyl 5,7-dihydroxy-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate

於160℃，將5-胺基-1H-吡唑-4-羧酸乙酯(22.4g)和2-甲基丙二酸二乙酯(24.6mL)及三丁基胺(51.6mL)之混合物攪拌隔夜。冷卻至室溫之後，將混合物倒入1M氫氧化鈉水溶液中，以及以乙酸乙酯清洗兩次。將水層之pH以1M鹽酸調整至1。產生之固體藉由過濾而收集，以水清洗，以及於減壓下乾燥以產生標題化合物(21.0g)。 Ethyl 5-amino-1H-pyrazole-4-carboxylate (22.4 g) and diethyl 2-methylmalonate (24.6 mL) and tributylamine (51.6 mL) at 160 °C The mixture was stirred overnight. After cooling to room temperature, the mixture was poured into 1M aqueous sodium hydroxide and washed twice with ethyl acetate. The pH of the aqueous layer was adjusted to 1 with 1 M hydrochloric acid. The resulting solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (21.0 g).

MS(API+)：[M+H]⁺238.1。 MS (API+): [M+H] ⁺ 238.1.

B)5,7-二氯-6-甲基吡唑并[1,5-a]嘧啶-3-羧酸乙酯 B) Ethyl 5,7-dichloro-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate

將5,7-二羥基-6-甲基吡唑并[1,5-a]嘧啶-3-羧酸乙酯(21.0g)和***(206mL)之混合物於90℃攪拌隔夜，而且於減壓下濃縮。在殘質中添加冰水，以及將混合物以乙酸乙酯萃取。萃取物以飽和鹽水清洗，以及以無水硫酸鎂乾燥。溶劑於減壓下蒸發，而且殘質以乙酸乙酯清洗以產生粗產物(8.12g)。於110℃，將粗產物(2.0g)和***(25.5mL)之混合物攪拌3天。反應混合物於減壓下濃縮，將殘質以乙酸乙酯稀釋且倒入冰水，以及分離有機層。有機層以飽和鹽水清洗，以無水硫酸鎂乾燥，以及使溶劑於減壓下蒸發。殘質經由矽膠管柱層析術(己烷/乙酸乙酯)純化，以產生標題化合物(0.660g)。 A mixture of ethyl 5,7-dihydroxy-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (21.0 g) and phosphorus oxychloride (206 mL) was stirred at 90 ° C overnight. It was also concentrated under reduced pressure. Ice water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. A mixture of the crude product (2.0 g) and phosphorus oxychloride (25.5 mL) was stirred at 110 ° C for 3 days. The reaction mixture was concentrated under reduced pressure. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and solvent Evaporate under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc)

¹H NMR(300MHz,DMSO-d₆)δ 1.32(3H、t、J=7.1Hz),2.49(3H,s),4.31(2H,q,J=7.2Hz),8.69(1H,s)。 ^{1 H NMR (300MHz, DMSO-} d 6) δ 1.32 (3H, t, J = 7.1Hz), 2.49 (3H, s), 4.31 (2H, q, J = 7.2Hz), 8.69 (1H, s).

C)5-氯-6-甲基吡唑并[1,5-a]嘧啶-3-羧酸乙酯 C) ethyl 5-chloro-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate

將5,7-二氯-6-甲基吡唑并[1,5-a]嘧啶-3-羧酸乙酯(660mg)和鋅粉劑(338mg)、濃氨水(2.0mL)、飽和鹽水(6.0mL)以及四氫呋喃(6.0mL)之混合物於室溫攪拌2小時。將反應混合物過濾，以乙酸乙酯清洗，以及分離有機層。有機層以飽和鹽水清洗，以無水硫酸鎂乾燥，以及使溶劑於減壓下蒸發。殘質經由矽膠管柱層析術(己烷/乙酸乙酯)純化，以產生標題化合物(198mg)。 Ethyl 5,7-dichloro-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (660 mg) and zinc powder (338 mg), concentrated aqueous ammonia (2.0 mL), saturated brine ( A mixture of 6.0 mL) and tetrahydrofuran (6.0 mL) was stirred at room temperature for 2 hr. The reaction mixture was filtered, washed with ethyl acetate and organic layer was evaporated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc)

¹H NMR(300MHz,DMSO-d₆)δ 1.31(3H、t、J=7.0Hz),2.36(3H,d,J=1.1Hz),4.30(2H,q,J=7.2Hz),8.59(1H,s),9.34(1H,d,J=0.8Hz)。 ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.31 (3H, t, J = 7.0 Hz), 2.36 (3H, d, J = 1.1 Hz), 4.30 (2H, q, J = 7.2 Hz), 8.59 ( 1H, s), 9.34 (1H, d, J = 0.8 Hz).

D)6-甲基-5-(4-甲基-1H-1,2,3-***-1-基)吡唑并[1,5-a]嘧啶-3-羧酸乙酯 D) Ethyl 6-methyl-5-(4-methyl-1H-1,2,3-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate

將5-氯-6-甲基吡唑并[1,5-a]嘧啶-3-羧酸乙酯(400mg)、4-甲基-1H-1,2,3-***(153mg)、碳酸鉀(277mg)以及N,N-二甲基甲醯胺(5mL)之混合物於室溫攪拌隔夜。將反應混合物於室溫倒入水，以及將混合物以乙酸乙酯萃取。有機層以飽和鹽水清洗，以無水硫酸鎂乾燥，而且於減壓下濃縮。殘質經由矽膠管柱層析術(乙酸乙酯/己烷)純化以產生標題化合物(106mg)。 Ethyl 5-chloro-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (400 mg), 4-methyl-1H-1,2,3-triazole (153 mg), A mixture of potassium carbonate (277 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature overnight. The reaction mixture was poured into water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, evaporated The residue was purified with EtOAc EtOAc (EtOAc)

MS(API+)：[M+H]⁺287.1。 MS (API+): [M+H] ⁺ 287.1.

E)N-((1S)-2-羥基-2-甲基-1-(4-(三氟甲氧基)苯基)丙基)-6-甲基-5-(4-甲基-1H-1,2,3-***-1-基)吡唑并[1,5-a]嘧啶-3-甲醯胺 E) N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-6-methyl-5-(4-methyl- 1H-1,2,3-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

於165℃，將6-甲基-5-(4-甲基-1H-1,2,3-***-1-基)吡唑并[1,5-a]嘧啶-3-羧酸乙酯(105mg)、(S)-1-胺基-2-甲基-1-(4-(三氟甲氧基)苯基)丙-2-醇鹽酸鹽(110mg)、1.8M三甲基鋁-甲苯溶液(0.611mL)以及甲苯(2mL)之混合物於微波照射下攪拌25分鐘。反應混合物冷卻至室溫，添加(S)-1-胺基-2-甲基-1-(4-(三氟甲氧基)苯基)丙-2-醇鹽酸鹽(20mg)，以及將混合物於165℃之微波照射下攪拌20分鐘。於室溫在飽和碳酸氫鈉水溶液中添加反應混合物，以及使混合物過濾通過矽藻土。將濾液以萃取乙酸乙酯。有機層以飽和鹽水清洗且以硫酸鎂乾燥，而且於減壓下濃縮。殘質經由矽膠管柱層析術(乙酸乙酯/己烷)純化以產生標題化合物(29.4mg)。 6-Methyl-5-(4-methyl-1H-1,2,3-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid B at 165 ° C Ester (105 mg), (S)-1-amino-2-methyl-1-(4-(trifluoromethoxy)phenyl)propan-2-ol hydrochloride (110 mg), 1.8 M trimethyl A mixture of a base aluminum-toluene solution (0.611 mL) and toluene (2 mL) was stirred under microwave irradiation for 25 minutes. The reaction mixture was cooled to room temperature, and (S)-1-amino-2-methyl-1-(4-(trifluoromethoxy)phenyl)propan-2-ol hydrochloride (20 mg) was added. The mixture was stirred under microwave irradiation at 165 ° C for 20 minutes. The reaction mixture was added to a saturated aqueous solution of sodium hydrogencarbonate at room temperature, and the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The residue was purified by EtOAc EtOAc (EtOAc)

MS(API+)：[M+H]⁺490.2。 MS (API+): [M+H] ⁺ 490.2.

¹H NMR(300MHz,CDCl₃)δ 1.17(3H,s),1.48(3H,s),1.70(1H,s),2.50(3H,d,J=0.8Hz),2.84(3H,d,J=0.8Hz),5.05(1H,d,J=8.3Hz),7.12-7.22(2H,m),7.38-7.50(2H,m),8.60(1H,s),8.68-8.83(3H,m)。 ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.17 (3H, s), 1.48 (3H, s), 1.70 (1H, s), 2.50 (3H, d, J = 0.8 Hz), 2.84 (3H, d, J =0.8 Hz), 5.05 (1H, d, J = 8.3 Hz), 7.12-7.22 (2H, m), 7.38-7.50 (2H, m), 8.60 (1H, s), 8.68-8.83 (3H, m) .

實施例2-II Example 2-II N-((1S)-2-羥基-2-甲基-1-(4-(三氟甲氧基)苯基)丙基)-6-甲基-5-(4-甲基-1H-1,2,3-***-1-基)吡唑并[1,5-a]嘧啶-3-甲醯胺 N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-6-methyl-5-(4-methyl-1H- 1,2,3-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-methyl Guanamine A)3-胺基-1H-吡唑-4-羧酸第三丁酯 A) 3-Amino-1H-pyrazole-4-carboxylic acid tert-butyl ester

將2-氰基乙酸第三丁酯(24.3g)和1-第三丁氧基-N,N,N',N'-四甲基甲烷二胺(35.5mL)之混合物於室溫攪拌30分鐘。反應混合物於減壓下濃縮以產生2-氰基-3-(二甲基胺基)丙烯酸第三丁酯之粗產物。於70℃，將所得之粗產物和肼單水合物(8.39mL)於甲醇(344mL)之溶液攪拌隔夜。反應混合物冷卻至室溫且倒入水，而且將混合物以乙酸乙酯萃取。有機層以飽和鹽水清洗，以及以無水硫酸鎂乾燥。溶劑於減壓下蒸發而且殘質從二異丙基醚結晶以產生標題化合物(18.6g)。 A mixture of tert-butyl 2-cyanoacetate (24.3 g) and 1-t-butoxy-N,N,N',N'-tetramethylmethanediamine (35.5 mL) was stirred at room temperature 30 minute. The reaction mixture was concentrated under reduced pressure to give a crude product of <RTI ID=0.0>> The resulting crude product and a solution of hydrazine monohydrate (8.39 mL) in methanol (344 mL) were stirred overnight. The reaction mixture was cooled to room temperature and poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure.

MS(API+)：[M+H]⁺ 184.1。 MS (API+): [M+H] ⁺ 184.1.

B)3,3-二甲氧基-2-甲基丙酸甲酯 B) Methyl 3,3-dimethoxy-2-methylpropanoate

於0℃，在甲基丙烯酸甲酯(51.2g)於乙酸乙酯(301mL)之溶液中添加溴(26.2mL)於乙酸乙酯(20mL)之溶液。反應混合物於室溫攪拌16小時，而且添加飽和硫酸鈉水溶液。反應混合物以水稀釋，而且以乙酸乙酯萃取。有機層以飽和鹽水清洗，以無水硫酸鈉乾燥，以及溶劑於減壓下蒸發以產生2,3-二溴-2-甲基丙酸甲酯(143g)。甲氧化鋰於甲醇之28%溶液(213g)以甲醇(221mL)稀釋，加熱至70℃，以及添加所得之粗產物(143g)於甲醇(20mL)之溶液。反應混合物於70℃攪拌3小時，以及以二乙基醚(550mL)和水稀釋。有機層以水和飽和鹽水清洗，以無水硫酸鈉乾燥，以及溶劑於減壓下蒸發以產生標題化合物(39.4g)。 To a solution of methyl methacrylate (51.2 g) in ethyl acetate (301 mL), EtOAc (EtOAc) The reaction mixture was stirred at room temperature for 16 hours and a saturated aqueous solution of sodium sulfate was added. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate A 28% solution of lithium methoxide in methanol (213 g) was diluted with methanol (221 mL), heated to 70 ° C, and a solution of the obtained crude product (143 g) in methanol (20 mL). The reaction mixture was stirred at 70 ° C for 3 hours and diluted with diethyl ether (550 mL) and water. The organic layer was washed with EtOAcq.

¹H NMR(300MHz,CDCl₃)δ 1.17(3H,d,J=7.2Hz),2.71-2.86(1H,m),3.35(3H,s),3.38(3H,s),3.70(3H,s),4.50(1H,d,J=7.7Hz)。 ¹ H NMR (300MHz, CDCl ₃ ) δ 1.17 (3H, d, J = 7.2 Hz), 2.71-2.86 (1H, m), 3.35 (3H, s), 3.38 (3H, s), 3.70 (3H, s ), 4.50 (1H, d, J = 7.7 Hz).

C)5-羥基-6-甲基吡唑并[1,5-a]嘧啶-3-羧酸第三丁酯 C) 3-Hydroxy-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid tert-butyl ester

在3-胺基-1H-吡唑-4-羧酸第三丁酯(6.80g)和3,3-二甲氧基-2-甲基丙酸甲酯(9.03g)於N,N-二甲基甲醯胺(74.2mL)之溶液中添加碳酸銫(21.8g)，而且將反應混合物於100℃攪拌16小時。反應混合物以水稀釋，而且以乙酸調整至約pH 4。產生之固體藉由過濾而收集，以水清洗，以及於減壓下乾燥以產生標題化合物(9.24g)。 In the 3-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (6.80 g) and 3,3-dimethoxy-2-methylpropionic acid methyl ester (9.03 g) in N,N- Cesium carbonate (21.8 g) was added to a solution of dimethylformamide (74.2 mL), and the reaction mixture was stirred at 100 ° C for 16 hours. The reaction mixture was diluted with water and adjusted to about pH 4 with acetic acid. The resulting solid was collected by filtration, washed with water, and dried under vacuo to give the title compound (9.24 g).

MS(API+)：[M+H]⁺250.1。 MS (API+): [M+H] ⁺ 250.1.

D)5-氯-6-甲基吡唑并[1,5-a]嘧啶-3-羧酸第三丁酯 D) 5-Chloro-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid tert-butyl ester

於室溫，在三苯基膦(8.14g)於1,2-二氯乙烷(80.0mL)之溶液中添加四氯化碳(2.92mL)。將反應混合物於氮氣氛下於室溫攪拌30分鐘，而且於室溫添加5-羥基-6-甲基吡唑并[1,5-a]嘧啶-3-羧酸第三丁酯(1.5g)於1,2-二氯乙烷(70mL)之懸浮液。將反應混合物於氮氣氛下於75℃至85℃攪拌4.5小時，而且於減壓下濃縮。殘質以乙酸乙酯和水稀釋，而且將混合物以乙酸乙酯萃取。將萃取物以飽和鹽水清洗，以及以無水硫酸鈉乾燥，以及使溶劑於減壓下蒸發。殘質經由矽膠管柱層析術(己烷/乙酸乙酯)純化，以產生標題化合物(1.54g)。 Carbon tetrachloride (2.92 mL) was added to a solution of triphenylphosphine (8.14 g) in 1,2-dichloroethane (80.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes under nitrogen, and a solution of 5-hydroxy-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid tert-butyl ester (1.5 g) was added at room temperature. A suspension of 1,2-dichloroethane (70 mL). The reaction mixture was stirred at 75 ° C to 85 ° C for 4.5 hours under nitrogen and concentrated under reduced pressure. The residue was diluted with ethyl acetate and water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified with EtOAc EtOAc EtOAc EtOAc

¹H NMR(300MHz,CDCl₃)δ 1.62(9H,s),2.42(3H,d,J=1.1Hz),8.40(1H,s),8.52(1H,d,J=1.1Hz)。 ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.62 (9H, s), 2.42 (3H, d, J = 1.1 Hz), 8.40 (1H, s), 8.52 (1H, d, J = 1.1 Hz).

E)6-甲基-5-(4-甲基-1H-1,2,3-***-1-基)吡唑并[1,5-a]嘧啶-3-羧酸第三丁酯 E) 6-methyl-5-(4-methyl-1H-1,2,3-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid tert-butyl ester

在5-氯-6-甲基吡唑并[1,5-a]嘧啶-3-羧酸第三丁酯(607mg)於N,N-二甲基甲醯胺(39.8mL)之溶液中添加4-甲基-1H-1,2,3-***(208mg)和碳酸鉀(378mg)。將反應混合物於室溫攪拌2小時，添加水，以及將混合物以乙酸乙酯萃取。萃取物以水和飽和鹽水清洗，以無水硫酸鈉乾燥，以及使溶劑於減壓下蒸發。殘質經由矽膠管柱層析術(己烷/乙酸乙酯)純化，以產生標題化合物(167mg)。 In a solution of 5-chloro-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid tert-butyl ester (607 mg) in N,N-dimethylformamide (39.8 mL) 4-Methyl-1H-1,2,3-triazole (208 mg) and potassium carbonate (378 mg) were added. The reaction mixture was stirred at room temperature for 2 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified with EtOAc EtOAc (EtOAc)

MS(API+)：[M+H]⁺315.1。 MS (API+): [M+H] ⁺ 315.1.

F)5-三氮基-6-甲基吡唑并[1,5-a]嘧啶-3-羧酸第三丁酯 F) 5-triazyl-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid tert-butyl ester

於60℃，將5-氯-6-甲基吡唑并[1,5-a]嘧啶-3-羧酸第三丁酯(268mg)、鈉疊氮化物(98mg)以及乙醇(5.00mL)之混合物攪拌隔夜。反應混合物冷卻至室溫，倒入水，以及將混合物以乙酸乙酯萃取。有機層以飽和鹽水清洗，以無水硫酸鎂乾燥，以及溶劑於減壓下蒸發以產生標題化合物(279mg)。所得之粗產物無經純化即可用於下一個反應。 5-Chloro-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid tert-butyl ester (268 mg), sodium azide (98 mg) and ethanol (5.00 mL) at 60 °C The mixture was stirred overnight. The reaction mixture was cooled to room temperature, poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc m. The crude product obtained was used in the next reaction without purification.

MS(API+)：[M+H]⁺ 275.1。 MS (API+): [M+H] ⁺ 275.1.

G)6-甲基-5-(4-甲基-1H-1,2,3-***-1-基)吡唑并[1,5-a]嘧啶-3-羧酸第三丁酯 G) 6-methyl-5-(4-methyl-1H-1,2,3-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid tert-butyl ester

將5-三氮基-6-甲基吡唑并[1,5-a]嘧啶-3-羧酸第三丁酯(239mg)和2-(三苯基正膦亞基)丙醛(291mg)以及四氫呋喃(4.36mL)之混合物於60℃攪拌5小時。反應混合物冷卻至室溫，而且使溶劑於減壓下蒸發。殘質經由矽膠管柱層析術(乙酸乙酯/己烷)純化以產生標題化合物(256mg)。 5-triazyl-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid tert-butyl A mixture of the ester (239 mg) and 2-(triphenylphosphoranylidene)propanal (291 mg) and tetrahydrofuran (4.36 mL) was stirred at 60 ° C for 5 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc)

MS(API+)：[M+H]⁺315.2. MS (API+): [M+H] ⁺ 315.2.

H)N-((1S)-2-羥基-2-甲基-1-(4-(三氟甲氧基)苯基)丙基)-6-甲基-5-(4-甲基-1H-1,2,3-***-1-基)吡唑并[1,5-a]嘧啶-3-甲醯胺 H) N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-6-methyl-5-(4-methyl- 1H-1,2,3-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

於0℃，在6-甲基-5-(4-甲基-1H-1,2,3-***-1-基)吡唑并[1,5-a]嘧啶-3-羧酸第三丁酯(1.12g)於甲苯(50.8mL)之溶液中添加三氟乙酸(29.0mL)。反應混合物於室溫攪拌隔夜，於減壓下濃縮以產生6-甲基-5-(4-甲基-1H-1,2,3-***-1-基)吡唑并[1,5-a]嘧啶-3-羧酸之粗產物(990mg)。在所得之粗產物(987mg)和(1S)-1-胺基-2-甲基-1-(4-(三氟甲氧基)苯基)丙-2-醇鹽酸鹽(1.15g)於N,N-二甲基甲醯胺(127mL)之溶液中添加1-羥基苯并***單水合物(724mg)、1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(897mg)以及三乙胺(2.69mL)。反應混合物於室溫攪拌隔夜，添加水，以及將混合物以乙酸乙酯萃取。萃取物以飽和碳酸氫鈉水溶液、水以及飽和鹽水清洗，以無水硫酸鈉乾燥，以及使溶劑於減壓下蒸發。殘質經由矽膠管柱層析術(己烷/乙酸乙酯)純化，以產生標題化合物(1.54g)。 At 0 ° C in 6-methyl-5-(4-methyl-1H-1,2,3-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid To a solution of tributyl ester (1.12 g) in toluene (50.8 mL) was added trifluoroacetic acid (29.0 mL). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure to give 6-methyl-5-(4-methyl-1H-1,2,3-triazol-1-yl)pyrazole [1,5 -a] Crude product of pyrimidine-3-carboxylic acid (990 mg). The crude product obtained (987 mg) and (1S)-1-amino-2-methyl-1-(4-(trifluoromethoxy)phenyl)propan-2-ol hydrochloride (1.15 g) Add 1-hydroxybenzotriazole monohydrate (724 mg), 1-(3-dimethylaminopropyl)-3-ethylate to a solution of N,N-dimethylformamide (127 mL) Carbodiimide hydrochloride (897 mg) and triethylamine (2.69 mL). The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate, water and saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified with EtOAc EtOAc EtOAc EtOAc

MS(API+)：[M+H]⁺490.2。 MS (API+): [M+H] ⁺ 490.2.

¹H NMR(300MHz,CDCl₃)δ 1.17(3H,s),1.48(3H,s),1.72 (1H,s),2.50(3H,d,J=0.8Hz),2.84(3H,d,J=0.8Hz),5.05(1H,d,J=8.3Hz),7.17(2H,d,J=7.9Hz),7.38-7.48(2H,m),8.60(1H,s),8.67-8.82(3H,m)。 ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.17 (3H, s), 1.48 (3H, s), 1.72 (1H, s), 2.50 (3H, d, J = 0.8 Hz), 2.84 (3H, d, J =0.8 Hz), 5.05 (1H, d, J = 8.3 Hz), 7.17 (2H, d, J = 7.9 Hz), 7.38-7.48 (2H, m), 8.60 (1H, s), 8.67-8.82 (3H , m).

I)N-((1S)-2-羥基-2-甲基-1-(4-(三氟甲氧基)苯基)丙基)-6-甲基-5-(4-甲基-1H-1,2,3-***-1-基)吡唑并[1,5-a]嘧啶-3-甲醯胺 I) N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-6-methyl-5-(4-methyl- 1H-1,2,3-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

將N-((1S)-2-羥基-2-甲基-1-(4-(三氟甲氧基)苯基)丙基)-6-甲基-5-(4-甲基-1H-1,2,3-***-1-基)吡唑并[1,5-a]嘧啶-3-甲醯胺(3.07g)於50℃至60℃溶解於乙酸乙酯(220mL)，而且在50℃至60℃添加己烷(150mL)。反應混合物於室溫攪拌2小時，添加己烷(70mL)，以及將混合物於室溫攪拌10分鐘。產生之固體藉由過濾而收集，而且在減壓下乾燥以產生標題化合物(2.48g)。 N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-6-methyl-5-(4-methyl-1H -1,2,3-Triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (3.07 g) was dissolved in ethyl acetate (220 mL) at 50 ° C to 60 ° C. Further, hexane (150 mL) was added at 50 ° C to 60 ° C. The reaction mixture was stirred at room temperature for 2 hr, hexane (70 mL) was evaporated, and the mixture was stirred at room temperature for 10 min. The resulting solid was collected by filtration and dried under reduced pressure to yield title compound (2.48 g).

MS(API+)：[M+H]⁺490.2。 MS (API+): [M+H] ⁺ 490.2.

¹H NMR(300MHz,CDCl₃)δ 1.17(3H,s),1.48(3H,s),1.74(1H,s),2.50(3H,s),2.84(3H,d,J=0.8Hz),5.05(1H,d,J=8.3Hz),7.17(2H,d,J=7.9Hz),7.40-7.49(2H,m),8.60(1H,s),8.69-8.83(3H,m)。 ^{_{1 H NMR (300MHz, CDCl 3}} ) δ 1.17 (3H, s), 1.48 (3H, s), 1.74 (1H, s), 2.50 (3H, s), 2.84 (3H, d, J = 0.8Hz), 5.05 (1H, d, J = 8.3 Hz), 7.17 (2H, d, J = 7.9 Hz), 7.40-7.49 (2H, m), 8.60 (1H, s), 8.69-8.83 (3H, m).

實施例3 Example 3 N-((1S)-2-羥基-2-甲基-1-(4-(三氟甲氧基)苯基)丙基)-6-甲基-5-(3-甲基-1H-1,2,4-***-1-基)吡唑并[1,5-a]嘧啶-3-甲醯胺 N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-6-methyl-5-(3-methyl-1H- 1,2,4-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide A)3-胺基-1H-吡唑-4-羧酸第三丁酯 A) 3-Amino-1H-pyrazole-4-carboxylic acid tert-butyl ester

於室溫，將2-氰基乙酸第三丁酯(24.3g)和1-第三丁氧基-N,N,N’,N’-四甲基甲烷二胺(35.5mL)之混合物攪拌30分鐘。反應混合物於減壓下濃縮，以產生2-氰基-3-(二甲基胺基)丙烯酸第三丁酯之粗產物。將所得之粗產物和肼單水合物(8.39mL)於甲醇(344mL)之溶液於70℃攪拌隔夜。反應混合物冷卻至室溫，倒入水，以及將混合物以乙酸乙酯萃取。將有機層分離，以飽和鹽水清洗，以及以無水硫酸鎂乾燥。溶劑於減壓下蒸發，而且殘質從異丙基醚結晶以產生標題化合物(18.6g)。 Third butyl cyanoacetate (24.3 g) and 1-third butoxide at room temperature A mixture of benzyl-N,N,N',N'-tetramethylmethanediamine (35.5 mL) was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure to give a crude product of <RTIgt; The resulting crude product and a solution of hydrazine monohydrate (8.39 mL) in methanol (344 mL) The reaction mixture was cooled to room temperature, poured into water, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure.

MS(API+)：[M+H]⁺184.1. MS (API+): [M+H] ⁺ 184.1.

於0℃，在甲基丙烯酸甲酯(51.2g)於乙酸乙酯(301mL)之溶液中添加溴(26.2mL)於乙酸乙酯(20mL)之溶液。反應混合物於室溫攪拌16小時，而且添加飽和硫酸鈉水溶液。反應混合物以水稀釋，而且將混合物以乙酸乙酯萃取。有機層以飽和鹽水清洗，以無水硫酸鈉乾燥，以及將溶劑於減壓下蒸發以產生2,3-二溴-2-甲基丙酸甲酯(143g)之粗產物。甲氧化鋰之28%甲醇溶液(213g)以甲醇(221mL)稀釋，加熱至70℃，以及添加所得之粗產物(143g)於甲醇(20mL)之溶液。將反應混合物於70℃攪拌3小時，以及以二乙基醚(550mL)和水稀釋。有機層以水和飽和鹽水清洗，以無水硫酸鈉乾燥，以及溶劑於減壓下蒸發以產生標題化合物(39.4g)。 To a solution of methyl methacrylate (51.2 g) in ethyl acetate (301 mL), EtOAc (EtOAc) The reaction mixture was stirred at room temperature for 16 hours and a saturated aqueous solution of sodium sulfate was added. The reaction mixture was diluted with water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. A 28% methanol solution of lithium pentoxide (213 g) was diluted with methanol (221 mL), heated to 70 ° C, and a solution of the obtained crude product (143 g) in methanol (20 mL). The reaction mixture was stirred at 70 <0>C for 3 h and diluted with diethyl ether (550 mL) and water. The organic layer was washed with EtOAcq.

¹H NMR(300MHz,CDCl₃)δ 1.17(3H,d,J=7.2Hz),2.71-2.86(1H,m),3.35(3H,s),3.38(3H,s),3.70(3H,s),4.50(1H,d, J=7.7Hz)。 ^{_{1 H NMR (300MHz, CDCl 3}} ) δ 1.17 (3H, d, J = 7.2Hz), 2.71-2.86 (1H, m), 3.35 (3H, s), 3.38 (3H, s), 3.70 (3H, s ), 4.50 (1H, d, J = 7.7 Hz).

MS(API+)：[M+H]⁺250.1 MS (API+): [M+H] ⁺ 250.1

於室溫，在三苯基膦(8.14g)於1,2-二氯乙烷(80.0mL)之溶液中添加四氯化碳(2.92mL)。將反應混合物於氮氣氛下於室溫攪拌30分鐘，而且於室溫添加5-羥基-6-甲基吡唑并[1,5-a]嘧啶-3-羧酸第三丁酯(1.5g)於1,2-二氯乙烷(70mL)之懸浮液。將反應混合物於氮氣氛下於75℃至85℃攪拌4.5小時，而且於減壓下濃縮。殘質以水稀釋，而且以乙酸乙酯萃取。將萃取物以飽和鹽水清洗，以及以無水硫酸鈉乾燥，以及使溶劑於減壓下蒸發。殘質經由矽膠管柱層析術(己烷/乙酸乙酯)純化，以產生標題化合物(1.54g)。 Carbon tetrachloride (2.92 mL) was added to a solution of triphenylphosphine (8.14 g) in 1,2-dichloroethane (80.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes under nitrogen, and a solution of 5-hydroxy-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid tert-butyl ester (1.5 g) was added at room temperature. A suspension of 1,2-dichloroethane (70 mL). The reaction mixture was stirred at 75 ° C to 85 ° C for 4.5 hours under nitrogen and concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified with EtOAc EtOAc EtOAc EtOAc

E)6-甲基-5-(3-甲基-1H-1,2,4-***-1-基)吡唑并 [1,5-a]嘧啶-3-羧酸第三丁酯 E) 6-Methyl-5-(3-methyl-1H-1,2,4-triazol-1-yl)pyrazole [1,5-a]pyrimidine-3-carboxylic acid tert-butyl ester

於室溫，在5-氯-6-甲基吡唑并[1,5-a]嘧啶-3-羧酸第三丁酯(1.08g)於N,N-二甲基甲醯胺(20.2mL)之溶液中添加3-甲基-1H-1,2,4-***(469mg)和碳酸鉀(781mg)。將反應混合物於以氯化鈣乾燥之氣氛下於室溫攪拌，攪拌隔夜且接著於60℃攪拌2小時。反應混合物冷卻至室溫，以及添加水。產生之固體藉由過濾而收集，以水清洗，以及於減壓下乾燥以產生含有位向異構物之標題化合物(870mg)。 At room temperature, tributyl butyl 5-chloro-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (1.08 g) in N,N-dimethylformamide (20.2 To the solution of mL), 3-methyl-1H-1,2,4-triazole (469 mg) and potassium carbonate (781 mg) were added. The reaction mixture was stirred at room temperature under an atmosphere dried with calcium chloride, stirred overnight and then stirred at 60 ° C for 2 hr. The reaction mixture was cooled to room temperature and water was added. The resulting solid was collected by filtration, washed with water and dried under reduced pressure to give the title compound (870 mg).

MS(API+)：[M+H]⁺315.2。 MS (API+): [M+H] ⁺ 315.2.

F)6-甲基-5-(3-甲基-1H-1,2,4-***-1-基)吡唑并[1,5-a]嘧啶-3-羧酸 F) 6-Methyl-5-(3-methyl-1H-1,2,4-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

於0℃，在6-甲基-5-(3-甲基-1H-1,2,4-***-1-基)吡唑并[1,5-a]嘧啶-3-羧酸第三丁酯(870mg)於乙腈(13.8mL)之懸浮液中添加甲磺酸(1.26mL)。反應混合物於室溫攪拌5小時，而且於60℃攪拌30分鐘。於0℃添加1M氫氧化鈉水溶液(19.4mL)，而且使乙腈於減壓下蒸發。產生之固體藉由過濾而收集，以水清洗，以及於減壓下乾燥以產生標題化合物(606mg)。 At 0 ° C in 6-methyl-5-(3-methyl-1H-1,2,4-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid To a suspension of tributyl ester (870 mg) in acetonitrile (13.8 mL) was added methanesulfonic acid (1.26 mL). The reaction mixture was stirred at room temperature for 5 hours and at 60 ° C for 30 minutes. A 1 M aqueous sodium hydroxide solution (19.4 mL) was added at 0 ° C, and acetonitrile was evaporated under reduced pressure. The resulting solid was collected by filtration, washed with water and dried then evaporated

MS(API+)：[M+H]⁺259.1。 MS (API+): [M+H] ⁺ 259.1.

G)2-((第三丁氧基羰基)胺基)-2-(4-(三氟甲氧基)苯基)乙酸甲酯 G) Methyl 2-((t-butoxycarbonyl)amino)-2-(4-(trifluoromethoxy)phenyl)acetate

於50℃，於4-(三氟甲氧基)苯甲醛(19.0g)和碳酸銨(25.9g)於乙醇(114mL)和水(45.6mL)之混合溶劑之混合物中緩慢地添加氰化鉀(8.14g)之水溶液(71.1mL)。將反應混合物於60℃攪拌3小時，冷卻至室溫，以及使乙醇於減壓下蒸發。殘質之pH於0℃以濃硫酸調整至1，濾除產生之固體，以及以水清洗。於室溫在氫氧化鉀(23.6g)之水溶液(100mL)中添加上述操作獲得之固體，以及將反應混合物於90℃攪拌3天。反應混合物冷卻至室溫，以及以濃硫酸中和。濾除產生之固體，而且將其以水清洗以產生2-胺基-2-(4-(三氟甲氧基)苯基)乙酸之粗產物(13.3g)。於室溫，在所得之粗產物(13.3g)於四氫呋喃(113mL)之溶液中添加二碳酸二第三丁酯(19.7mL)和2M氫氧化鈉水溶液(85mL)。將反應混合物於室溫攪拌隔夜，倒入水，以及將混合物以二乙基醚清洗。水層之pH於0℃以1M鹽酸調整至3，以及將混合物以乙酸乙酯萃取。萃取物以飽和鹽水清洗，以及以無水硫酸鎂乾燥，以及使溶劑於減壓下蒸發以產生2-((第三丁氧基羰基)胺基)-2-(4-(三氟甲氧基)苯基)乙酸之粗產物(11.3g)。於室溫，於所得之粗產物(11.3g)於N,N-二甲基甲醯胺(84mL)之溶液中添加碘甲烷(2.53mL)和碳酸鉀(5.59g)。反應混合物於室溫攪拌2小時，倒入水，以及將混合物以乙酸乙酯萃取。萃取物以飽和鹽水清洗，以及以無水硫酸鎂乾燥，以及使溶劑於減壓下蒸發。殘質經由矽膠管柱層析術(己烷/乙酸乙酯)純化，以產生標題化合物(8.20g)。 Slowly adding potassium cyanide to a mixture of 4-(trifluoromethoxy)benzaldehyde (19.0 g) and ammonium carbonate (25.9 g) in a mixed solvent of ethanol (114 mL) and water (45.6 mL) at 50 °C (8.14 g) of an aqueous solution (71.1 mL). Mix the reaction The mixture was stirred at 60 ° C for 3 hours, cooled to room temperature, and ethanol was evaporated under reduced pressure. The pH of the residue was adjusted to 1 with concentrated sulfuric acid at 0 ° C, the resulting solid was filtered off and washed with water. The solid obtained by the above operation was added to an aqueous solution (100 mL) of potassium hydroxide (23.6 g) at room temperature, and the reaction mixture was stirred at 90 ° C for 3 days. The reaction mixture was cooled to room temperature and neutralized with concentrated sulfuric acid. The resulting solid was filtered off and washed with water to give a crude product (13.3 g) of 2-amino-2-(4-(trifluoromethoxy)phenyl)acetic acid. Di-tert-butyl dicarbonate (19.7 mL) and a 2 M aqueous sodium hydroxide solution (85 mL) were added to a solution of the obtained crude product (13.3 g) in tetrahydrofuran (113 mL). The reaction mixture was stirred at room temperature overnight, poured water, and the mixture was washed with diethyl ether. The pH of the aqueous layer was adjusted to 3 with 1M hydrochloric acid at 0 ° C, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and evaporated, and evaporated under vacuo to give 2-((t-butoxycarbonyl)amino)-2-(4-(trifluoromethoxy) Crude product (11.3 g) of phenyl)acetic acid. Methyl iodide (2.53 mL) and potassium carbonate (5.59 g) were added to a solution of the obtained crude product (11.3 g) in N,N-dimethylformamide (84 mL). The reaction mixture was stirred at room temperature for 2 hr, water was poured, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc)

MS(API-)：[M-H]^- 348.1。 MS (API-): [MH] ^- 348.1.

H)(2-羥基-2-甲基-1-(4-(三氟甲氧基)苯基)丙基)胺基甲酸第三丁酯 H) (2-Hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)carbamic acid tert-butyl ester

於0℃，2-((第三丁氧基羰基)胺基)-2-(4-(三氟甲氧基)苯基)乙酸甲酯(5.00g)於四氫呋喃(71.6mL)之溶液中緩慢地添加1M甲基鎂溴化物/四氫呋喃溶液(57.3mL)。將反應混合物於氬氣氛下於0℃攪拌1小時，於0℃在其中添加飽和氯化銨水溶液，以及將混合物以乙酸乙酯萃取。萃取物以飽和鹽水清洗，以及以無水硫酸鎂乾燥，以及使溶劑於減壓下蒸發。殘質經由矽膠管柱層析術(己烷/乙酸乙酯)純化，以產生標題化合物(3.99g)。 Methyl 2-((t-butoxycarbonyl)amino)-2-(4-(trifluoromethoxy)phenyl)acetate (5.00 g) in tetrahydrofuran (71.6 mL) A 1 M methylmagnesium bromide/tetrahydrofuran solution (57.3 mL) was slowly added. The reaction mixture was stirred at 0 ° C for 1 hour under an argon atmosphere, a saturated aqueous solution of ammonium chloride was added thereto at 0 ° C, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified with EtOAc EtOAc (EtOAc)

MS(API-)：[M-H]^- 348.2。 MS (API-): [MH] ^- 348.2.

I)(S)-1-胺基-2-甲基-1-(4-(三氟甲氧基)苯基)丙-2-醇鹽酸鹽 I) (S)-1-Amino-2-methyl-1-(4-(trifluoromethoxy)phenyl)propan-2-ol hydrochloride

(2-羥基-2-甲基-1-(4-(三氟甲氧基)苯基)丙基)胺基甲酸第三丁酯之消旋物(17.9g)經HPLC(管柱：CHIRALPAK AD，50mmID×500mmL，由Daicel Corporation所製造，流動相：己烷/乙醇=950/50)解析，以產生具有較短的保持時間之{(1S)-2-羥基-2-甲基-1-[4-(三氟甲氧基)苯基]丙基}胺基甲酸第三丁酯(8.06g)。在4M氯化氫/乙酸乙酯溶液(115mL)中添加{(1S)-2-羥基-2-甲基-1-[4-(三氟甲氧基)苯基]丙基}胺基甲酸第三丁酯(8.06g)。將反應混合物於室溫攪拌15分鐘，而且使溶劑於減壓下蒸發。在殘質中添加二異丙基醚，而且產生之結晶藉由過濾而收集以產生標題化合物(5.39g)。 Racemate (17.9 g) of (2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)carbamic acid tert-butyl ester by HPLC (column: CHIRALPAK) AD, 50 mm ID × 500 mmL, manufactured by Daicel Corporation, mobile phase: hexane/ethanol = 950/50), to give {(1S)-2-hydroxy-2-methyl-1 with a shorter retention time -[4-(Trifluoromethoxy)phenyl]propyl}carbamic acid tert-butyl ester (8.06 g). Add {(1S)-2-hydroxy-2-methyl-1-[4-(trifluoromethoxy)phenyl]propyl}carbamic acid third in 4M hydrogen chloride / ethyl acetate solution (115 mL) Butyl ester (8.06 g). The reaction mixture was stirred at room temperature for 15 min and the solvent was evaporated evaporated. Diisopropyl ether was added to the residue, and the crystals obtained were collected by filtration to give the title compound (5.39 g).

MS(API+)，實測值：250.1。 MS (API+), found: 250.1.

J)N-((1S)-2-羥基-2-甲基-1-(4-(三氟甲氧基)苯基) 丙基)-6-甲基-5-(3-甲基-1H-1,2,4-***-1-基)吡唑并[1,5-a]嘧啶-3-甲醯胺 J) N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl) Propyl)-6-methyl-5-(3-methyl-1H-1,2,4-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

在6-甲基-5-(3-甲基-1H-1,2,4-***-1-基)吡唑并[1,5-a]嘧啶-3-羧酸(606mg)於N,N-二甲基甲醯胺(11.7mL)之懸浮液中添加(S)-1-胺基-2-甲基-1-(4-(三氟甲氧基)苯基)丙-2-醇鹽酸鹽(805mg)、1-羥基苯并***單水合物(431mg)、1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(540mg)以及三乙胺(392μL)。將反應混合物於室溫攪2小時，倒入水，以及將混合物以乙酸乙酯萃取。萃取物以飽和鹽水清洗，以無水硫酸鎂乾燥，以及使溶劑於減壓下蒸發。殘質經由矽膠管柱層析術(NH、己烷/乙酸乙酯)純化，而且從乙酸乙酯和二異丙基醚再結晶以產生標題化合物(858mg)。 In 6-methyl-5-(3-methyl-1H-1,2,4-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (606 mg) in N (S)-1-Amino-2-methyl-1-(4-(trifluoromethoxy)phenyl)propane-2 was added to a suspension of N-dimethylformamide (11.7 mL) - alkoxide hydrochloride (805 mg), 1-hydroxybenzotriazole monohydrate (431 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (540 mg) ) and triethylamine (392 μL). The reaction mixture was stirred at room temperature for 2 hr, water was poured, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by EtOAc EtOAc (EtOAc) elute

MS(API+)：[M+H]⁺490.3. MS (API+): [M+H] ⁺ 490.3.

¹H NMR(300MHz,DMSO-d₆)δ 1.00(3H,s),1.31(3H,s),2.46(3H,s),2.64(3H,d,J=0.8Hz),4.87(1H,d,J=8.0Hz),5.32(1H,s),7.27(2H,d,J=8.0Hz),7.51(2H,d,J=8.7Hz),8.49(1H,s),8.85(1H,d,J=8.3Hz),9.46-9.53(2H,m)。 ^{1 H NMR (300MHz, DMSO-} d 6) δ 1.00 (3H, s), 1.31 (3H, s), 2.46 (3H, s), 2.64 (3H, d, J = 0.8Hz), 4.87 (1H, d , J = 8.0 Hz), 5.32 (1H, s), 7.27 (2H, d, J = 8.0 Hz), 7.51 (2H, d, J = 8.7 Hz), 8.49 (1H, s), 8.85 (1H, d , J = 8.3 Hz), 9.46 - 9.53 (2H, m).

以下表中顯示根據上述方法或與其類似之方法製備之實施例之化合物。表中之質量以所測之值表示。 The compounds of the examples prepared according to the above methods or methods analogous thereto are shown in the following tables. The mass in the table is expressed as the measured value.

實驗例1 Experimental example 1 PDE酶抑制測定法 PDE enzyme inhibition assay

將人類PDE2A3全長基因轉導入Sf9，而且將人類PDE2A3酶經His標籤親和性管柱純化和凝膠過濾。將酶於-70℃儲存，直到使用。PDE活性係用SPA(鄰近閃爍測定法)(GE Healthcare)測量。將10μl之連續稀釋化合物與20μl之PDE酶於測定緩衝劑(50mM HEPES-NaOH、8.3mM MgCl₂、1.7mM EGTA、0.1% BSA(pH 7.4))於室溫反應30分鐘，以評估化合物之抑制活性。反應溶液中之DMSO之最終濃度為1百分率。化合物係於96孔半區域盤(Corning)或384孔OptiPlate(PerkinElmer)中以二重複測試。反應開始時，添加10μl之基質[³H]cGMP(最終濃度77nM、PerkinElmer)以達總體積為40μl。於室溫反應60分鐘之後，添加20μl之含有硫酸鋅之20mg/mL釔SPA珠以終止PDE反應。進一步沈降1小時之後，於閃爍計數器(PerkinElmer)中計數測定法盤以允許抑制速率之計算。抑制率係在具有酶和DMSO之0%對照孔和不具有酶之100%對照孔之基準上計算。表2中顯示結果。 The human PDE2A3 full-length gene was transduced into Sf9, and the human PDE2A3 enzyme was purified by His-tag affinity column and gel-filtered. The enzyme was stored at -70 ° C until use. PDE activity was measured using SPA (near scintillation assay) (GE Healthcare). 10 μl of serially diluted compound was reacted with 20 μl of PDE enzyme in assay buffer (50 mM HEPES-NaOH, 8.3 mM MgCl ₂ , 1.7 mM EGTA, 0.1% BSA (pH 7.4)) for 30 minutes at room temperature to evaluate inhibition of the compound. active. The final concentration of DMSO in the reaction solution was 1%. Compounds were tested in duplicate in 96-well half-region plates (Corning) or 384-well OptiPlate (PerkinElmer). At the beginning of the reaction, 10 μl of matrix [ ³ H]cGMP (final concentration 77 nM, PerkinElmer) was added to a total volume of 40 μl. After reacting at room temperature for 60 minutes, 20 μl of 20 mg/mL 钇 SPA beads containing zinc sulfate was added to terminate the PDE reaction. After further sedimentation for 1 hour, the assay disk was counted in a scintillation counter (PerkinElmer) to allow calculation of the inhibition rate. The inhibition rate was calculated on the basis of 0% control wells with enzyme and DMSO and 100% control wells without enzyme. The results are shown in Table 2.

實驗例2 Experimental example 2

對恐懼情境條件測試中之MK-801((5S,10R)-5-甲基-10,11-二氫-5H-5,10-環亞胺基二苯并[a,d][7]環輪烯)-誘發之異常之改善效果。 MK-801 ((5S,10R)-5-methyl-10,11-dihydro-5H-5,10-cycloimidodibenzo[a,d][7] in the fear condition test Ring olefin)-induced improvement effect of abnormality.

實驗動物 Experimental animal

從CLEA Japan,Inc.購買雄性C57BL/6小鼠。牠們是在被承載於動物實驗設施中之後之至少一週之習慣期後用於實驗。牠們在動物實驗設施中培育，該動物實驗設施具有其中進行12小時之光暗循環，控制濕度和溫度，以及允許自由飲用水和餵食之環境。武田製藥股份有限公司之實驗動物規範委員會(Experimental Animal Ethics Committee of Takeda Pharmaceutical Company Limited)核准這研究之實驗動物之處理和實驗程序。 Male C57BL/6 mice were purchased from CLEA Japan, Inc. They were used for experiments after a habit period of at least one week after being carried in an animal experimental facility. They are bred in an animal laboratory facility with an environment in which 12 hours of light and dark cycles are controlled, humidity and temperature are controlled, and free drinking water and feeding are allowed. The Experimental Animal Ethics Committee of Takeda Pharmaceutical Company Limited approved the processing and experimental procedures for the experimental animals of this study.

使用之藥物 Drug used

將受試化合物以30mg/kg之劑量懸浮於0.5%甲基纖維素溶液，並且口服投藥。將MK-801(馬來酸酯)(Sigma-AldricH,st Louis,MO)以0.08mg/kg之劑量溶解於鹽水，並且皮下投藥。對小鼠以10mL/kg之劑量投藥所有藥物。 The test compound was suspended in a 0.5% methylcellulose solution at a dose of 30 mg/kg and administered orally. MK-801 (maleate) (Sigma-Aldric H, st Louis, MO) was dissolved in saline at a dose of 0.08 mg/kg and administered subcutaneously. All drugs were administered to mice at a dose of 10 mL/kg.

對恐懼情境條件測試中之MK-801誘發之不足之改善效果。 The improvement effect of the MK-801 induced deficiency in the fear situation test.

恐懼情境條件測試係廣泛用作依賴海馬迴和杏仁核之記憶和學習測試系統。恐懼情境條件測試調查受試化合物對MK-801誘發之不足之改善效果。測試之前，分別投藥60分鐘和30分鐘之受試化合物和MK-801(馬來酸酯)。測試之前，對對照組分別投藥60分鐘和30分鐘之0.5%甲基纖維素和鹽水。測試之前，對載劑組分別投藥60分鐘和30分鐘之0.5%甲基纖維素和MK-801(馬來酸酯)。實驗中，使用具有用於電擊之板網之小室和靜止測量裝置(O'Hara & Co.,Ltd.)。將小室放在隔音盒中以阻隔才自外面的噪音，並且進行試驗。實驗第1天之訓練中，習慣小室3分鐘之後，以1分鐘間隔對小鼠給予兩次足底電擊。實驗第2天之測試中，將小鼠放置於相同小室中7分鐘，並且在那期間測量靜止。靜止係以由O'Hara & Co.,Ltd.所製造之自動分析軟體，而計算為測量期間之靜止率之百分率。所有數據顯示為平均數+標準差(n=10)。兩個群組之間之比較以學生t檢驗(^*p0.05，與對照組比較。^#p0.05，與單獨經MK-801處理之組比較。)進行。第1圖中顯示結果。化合物A為實施例1-II中獲得之化合物(30mg/kg,p.o.)，化合物B為實施例2-II中獲得之化合物(30mg/kg,p.o.)，以及化合物C為實施例3中獲得之化合物(30mg/kg,p.o.)。 The Fear Situation Condition Test is widely used as a memory and learning test system that relies on the hippocampus and the amygdala. The Fear Situation Condition Test investigates the improvement effect of the test compound on the deficiency induced by MK-801. Test compounds and MK-801 (maleate) were administered for 60 minutes and 30 minutes, respectively, before the test. Prior to the test, 0.5% methylcellulose and saline were administered to the control group for 60 minutes and 30 minutes, respectively. Prior to testing, 0.5% methylcellulose and MK-801 (maleate) were administered to the vehicle group for 60 minutes and 30 minutes, respectively. In the experiment, a chamber having a plate for electric shock and a stationary measuring device (O'Hara & Co., Ltd.) were used. The chamber was placed in a soundproof box to block the noise from the outside and the test was conducted. During the first day of the experiment, the mice were given two foot shocks at 1 minute intervals after 3 minutes of accustomed to the chamber. In the test on day 2 of the experiment, the mice were placed in the same chamber for 7 minutes, and during that time the rest was measured. The stationary system was calculated as an automatic analysis software manufactured by O'Hara & Co., Ltd., and was calculated as a percentage of the static rate during the measurement. All data are shown as mean + standard deviation (n = 10). Comparison between the two groups by Student's t test ( ^* p 0.05, compared with the control group. ^# p 0.05, compared to the group treated with MK-801 alone. )get on. The results are shown in Figure 1. Compound A is the compound obtained in Example 1-II (30 mg/kg, po), Compound B is the compound obtained in Example 2-II (30 mg/kg, po), and Compound C is obtained in Example 3. Compound (30 mg/kg, po).

對MK-801誘發之不足之改善效果係在測試前之60分鐘，對小鼠口服投藥各受試化合物(A、B、C)所示。 The improvement effect on the deficiency induced by MK-801 was 60 minutes before the test, and the test compounds (A, B, and C) were orally administered to mice.

實施例1式之調配物 Formulation of the formula of Example 1

實施例1之化合物(10.0g)和硬脂酸鎂(3.0g)於可溶性澱粉(7.0g as可溶性澱粉)之水溶液(70mL)中造粒，接著乾燥，將產生之混合物與乳糖(70.0g)和玉米澱粉(50.0g)(乳糖、玉米澱粉、可溶性澱粉以及硬脂酸鎂為符合日本藥典第14版之所有產物)混合。混合物經壓縮以產生錠劑。 The compound of Example 1 (10.0 g) and magnesium stearate (3.0 g) were granulated in an aqueous solution (70 mL) of soluble starch (7.0 g as soluble starch), followed by drying, and the resulting mixture was combined with lactose (70.0 g). And corn starch (50.0g) (lactose, corn starch, soluble starch and magnesium stearate in line with Japanese medicine) All products of the 14th edition of the Code are mixed. The mixture is compressed to produce a tablet.

產業可利用性 Industrial availability

由於第1圖為實驗例結果圖，並非本案的代表圖。 Since Fig. 1 is a result chart of an experimental example, it is not a representative figure of the present case.

故本案無指定代表圖。 Therefore, there is no designated representative map in this case.

Claims

一種式(I)所示之化合物或其鹽：其中，環A為吡唑環；環B為嘧啶環，其係經1至3個選自下列之取代基取代：(1)C_1-6烷基，(2)視需要經1至3個C_1-6烷基取代之***基，以及(3)視需要經1至3個C_1-6烷基取代之吡啶基；環D為經C_1-6烷氧基取代之苯環，該C_1-6烷氧基視需要經1至3個鹵素原子取代；X為碳原子；L為鍵結；以及Y為下式所表示之基團：環R²為氫原子； R³為C_1-6烷基；以及R⁴為C_1-6烷基。 A compound of the formula (I) or a salt thereof: Wherein ring A is a pyrazole ring; ring B is a pyrimidine ring substituted by 1 to 3 substituents selected from the group consisting of: (1) C _1-6 alkyl, (2) 1 to 3 as needed a C _1-6 alkyl-substituted triazolyl group; and (3) a pyridyl group substituted with 1 to 3 C _1-6 alkyl groups as required; and ring D is a benzene ring substituted with a C _1-6 alkoxy group, The C _1-6 alkoxy group is optionally substituted by 1 to 3 halogen atoms; X is a carbon atom; L is a bond; and Y is a group represented by the following formula: Ring R ² is a hydrogen atom; R ³ is a C _1-6 alkyl group; and R ⁴ is a C _1-6 alkyl group.

一種化合物或其鹽，該化合物係N-((1S)-2-羥基-2-甲基-1-(4-(三氟甲氧基)苯基)丙基)-5-(6-甲基吡啶-3-基)吡唑并[1,5-a]嘧啶-3-甲醯胺。 A compound or a salt thereof, which is N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-5-(6-A Pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.

一種化合物或其鹽，該化合物係N-((1S)-2-羥基-2-甲基-1-(4-(三氟甲氧基)苯基)丙基)-6-甲基-5-(4-甲基-1H-1,2,3-***-1-基)吡唑并[1,5-a]嘧啶-3-甲醯胺。 A compound or a salt thereof, which is N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-6-methyl-5 -(4-Methyl-1H-1,2,3-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.

一種化合物或其鹽，該化合物係N-((1S)-2-羥基-2-甲基-1-(4-(三氟甲氧基)苯基)丙基)-6-甲基-5-(3-甲基-1H-1,2,4-***-1-基)吡唑并[1,5-a]嘧啶-3-甲醯胺。 A compound or a salt thereof, which is N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-6-methyl-5 -(3-Methyl-1H-1,2,4-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.

一種藥劑，包括如申請專利範圍第1至4項中任一項所述之化合物或其鹽。 An agent, which comprises a compound according to any one of claims 1 to 4, or a salt thereof.

如申請專利範圍第5項所述之藥劑，其係磷酸雙酯酶2A抑制劑。 The agent of claim 5, which is a phosphodiesterase 2A inhibitor.

如申請專利範圍第5項所述之藥劑，其係精神***症之預防性或治療性藥物。 The agent according to claim 5, which is a prophylactic or therapeutic drug for schizophrenia.

如申請專利範圍第1至4項中任一項所述之化合物或其鹽，係用於預防或治療精神***症。 The compound of any one of claims 1 to 4, or a salt thereof, for use in the prevention or treatment of schizophrenia.

一種抑制哺乳動物中之磷酸雙酯酶2A之方法，包括對該哺乳動物投藥有效量之如申請專利範圍第1至4項中任一項所述之化合物或其鹽。 A method of inhibiting phosphodiesterase 2A in a mammal, comprising administering to the mammal an effective amount of a compound of any one of claims 1 to 4, or a salt thereof.

一種預防或治療哺乳動物之精神***症之方法，包括對該哺乳動物投藥有效量之如申請專利範圍第1至4項中任一項所述之化合物或其鹽。 A method for preventing or treating schizophrenia in a mammal, comprising administering an effective amount to the mammal as in claim 1 to 4 A compound according to any one of the compounds or a salt thereof.

一種如申請專利範圍第1至4項中任一項所述之化合物或其鹽之用途，其係用於製造精神***症之預防性或治療性藥物。 A use of a compound according to any one of claims 1 to 4, or a salt thereof, for the manufacture of a prophylactic or therapeutic drug for schizophrenia.