TW201215607A - Aryl-and heteroarylamid derivatives as PDE10A enzyme inhibitor - Google Patents

Aryl-and heteroarylamid derivatives as PDE10A enzyme inhibitor Download PDF

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TW201215607A
TW201215607A TW100122538A TW100122538A TW201215607A TW 201215607 A TW201215607 A TW 201215607A TW 100122538 A TW100122538 A TW 100122538A TW 100122538 A TW100122538 A TW 100122538A TW 201215607 A TW201215607 A TW 201215607A
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Jan Kehler
Mogens Larsen
Mette Norman Erichsen
Sebastian Leth-Petersen
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Abstract

The invention relates to compounds of the formula and their use as pharmaceutical ingredients, in particular for the treatment of CNS related diseases.

Description

201215607 六、發明說明： 【發明所屬之技術領域】 本發明提供作為PDE1〇A酵素抑制劑且因而適用於治 療神經退化性病症及精神病症之化合物。本發明亦提供包 含本發明化合物之醫藥組成物及使用本發明化合物治療病 症之方法。 【先前技術】 本申請案通篇參考多個公開案全文。此等公開案之揭 示内容以引用的方式併入本申請案中以更充分地描述本發 明所屬之技術現狀。 %狀核苦酸環單鱗酸腺苷（cAMP )及環單磷酸鳥普 (cGMP )充當調節神經元中眾多過程之細胞内第二信使。 細胞内cAMP及cGMP由腺苷及鳥苷環化酶產生，且由環狀 核苦酸磷酸二酯酶（PDE)降解。CAMP及cGMP之細胞内 含量藉由細胞内信號傳導來控制，且響應於GpCR活化刺 激/抑制腺苷及鳥苷環化酶為控制環狀核苷酸濃度之充分特 f·生化之方式（Antoni，F.A. Frowi. jfno/· 2000，2/， 103-132 )。cAMP及cGMP含量又控制cAMP及cGMp依賴 性激酶以及具有環狀核苷酸反應元件之其他蛋白質的活 性’其經由後續蛋白質磷酸化及其他過程調節關鍵神經元 功能，諸如突觸傳遞、神經元分化及存活。 填酸二酯酶10A ( PDE10A )為可使CAMP轉化為AMP 且使cGMP轉化為GMP之雙重特異性磷酸二酯酶 201215607 (Loughney，Κ·等人，1999, 234, 109-117 ; Fujishige，Κ. 等人，五wr. ·/· 1999, 2M，1118_1127 及 s〇derling，s. 專人，Proc. Natl. Acad. Sci. 1999，96, 〇 PDE10A主要表現於紋狀體、伏隔核（n. accumbens) 及嗅結節中之神經元中。 PDE 1 0A藉由尾狀核、伏隔核之棘神經元介質（me(jium spiny neurons，MSN )及嗅結節之相應神經元以高含量神經 元表現於紋狀體中（Kotera, J.201215607 VI. Description of the Invention: [Technical Field of the Invention] The present invention provides a compound which is a PDE1A enzyme inhibitor and thus is suitable for treating a neurodegenerative disorder and a psychiatric disorder. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compounds of the invention to treat a condition. [Prior Art] The entire disclosure of the present application is incorporated by reference in its entirety. The disclosure of these publications is hereby incorporated by reference in its entirety in its entirety in its entirety in the extent of the disclosure of the disclosure. The nucleus accumbens ring cAMP and cGMP act as intracellular second messengers that regulate numerous processes in neurons. Intracellular cAMP and cGMP are produced by adenosine and guanosine cyclase and are degraded by cyclic nucleotide picurate phosphodiesterase (PDE). The intracellular content of CAMP and cGMP is controlled by intracellular signaling, and stimulation/inhibition of adenosine and guanosine cyclase in response to GpCR activation is a sufficient means of controlling the concentration of cyclic nucleotides (Antoni) , FA Frowi. jfno/· 2000, 2/, 103-132). cAMP and cGMP levels in turn control the activity of cAMP and cGMp-dependent kinases and other proteins with cyclic nucleotide response elements', which regulate key neuronal functions via subsequent protein phosphorylation and other processes, such as synaptic transmission, neuronal differentiation And survive. Diesterase 10A (PDE10A) is a dual-specific phosphodiesterase 201215607 that converts CAMP to AMP and converts cGMP to GMP (Loughney, Κ· et al, 1999, 234, 109-117; Fujishige, Κ Etc., five wr. ·/· 1999, 2M, 1118_1127 and s〇derling, s. Specialist, Proc. Natl. Acad. Sci. 1999,96, 〇PDE10A mainly in the striatum, nucleus accumbens (n . accumbens) and neurons in the olfactory nodules. PDE 1 0A uses high-level neurons in the caudate nucleus, the mesenchymal neurons of the nucleus accumbens (MSN) and the corresponding neurons of the olfactory tubercle Expressed in the striatum (Kotera, J.

Comw. 1999，267，55 1 -557 及 Seeger，T.F.事乂，心ak Μ，2003，衫5, 113-126)。此等部分構成基底神經節系 統之核心。MSN在皮層_基底神經節-丘腦皮層循環中起關 鍵作用’整合收斂性皮層/丘腦輸入且將此整合資訊發送回 皮層。MSN表現兩個功能類別之神經元：表現多巴胺受 體之D〗類及表現A多巴胺受體之〇2類。a類神經元為『直 接』紋狀體輸出路徑之一部分，其廣泛用以促進行為反應。 類神經元辱『間接』紋狀體輸出路徑之一部分，其用以 抑止與藉由『直接』路徑促進之彼等行為反應競爭的行為 反應。此等競爭路徑作用類似汽車中之制動器及加速器。 就最簡單之觀點而言，帕金森氏病（parkinson，s disease) 中之運動缺乏由『間接』路徑過度活躍所致，而諸如亨丁 頓氏病（Huntington’s disease )之病症中的過量運動表示直 接路徑過度活躍。在此等神經元之樹突狀區中camp及/或 cGMP信號傳導之PDE1〇A調節可能與將皮層/丘腦輸入過 濾至MSN中有關。此外，pDE1〇A可與調節黑質及蒼白球 4 201215607 中之 GABA 釋放有關（Seeger，T.F.等人， 2003, 985, 113-126)〇 在精神分裂症之治療中充分確定多巴胺D2受體拮抗作 用。自1950年代開始’多巴胺〇2受體拮抗作用為精神病治 療之主要依靠且所有有效抗精神病藥均拮抗d2受體，〇2之 效應可能主要經由紋狀體、伏隔核及嗅結節中之神經元介 導’此係由於此等區域接受緻密多巴胺激導性投射且強烈 表現 1>2 受體（Konradi，C.及 Heckers，S. o/5z〇/〇g/Ca/ h_yc/n·如π，2001，M，729-742)。多巴胺d2受體促效作用會 引起細胞中之cAMP含量降低，其經由腺苷酸環化酶抑制 表現，且此情況為D2信號傳導之組分（St〇〇f，j. c ; KebaMan J· W. iV⑽1981，2 以，366-368 及 Neve，K. A.等人， of Receptors and Signal Transduction 2004, 24, 165-205 ) 〇 相反，d2党體拮抗作用有效增加eAMp含量且此效應可藉 由cAMP降解磷酸二酯酶之抑制作用模擬。 21個磷酸二酯酶基因中之大多數已廣泛表現；因此抑 制作用可能具有副作用。因為PDE1〇A就此而言在紋狀體、 伏隔核及嗅結節之神經元中具有較高且相對特異性表現之 所要表現特徵，所以PDE10A抑制作用可能具有與A受體 拮抗作用類似之效應且因此具有抗精神病作用。 儘管PDE10A抑制作用預期會部分模擬D2受體拮抗^ 用，但預期可能具有不同特徵。〇2受體具有除。屢外戈 信號傳導組分（NeVe，K. A.等人，^⑽/。/細中 沿忘加/ 7>⑽如⑽2004，以，165_2〇5 )，由於此原因，經佳 201215607 PDE10A抑制作用干擾cAMp可經由〇2受體消極地調節而 非直接拮抗多巴胺信號傳導。此舉可降低在強D2拮抗作用 下觀察到之錐體外副作用之風險。相反，pDE丨〇 A抑制作用 可具有一些未在D2受體拮抗作用下觀察到之效應^ Pde丨〇 a 亦表現於表現D,受體之紋狀體神經元中（Seeger，τ· F•等 人，β削>2 /^⑽以，2003, P55, 113-126)。因為D丨受體促效Comw. 1999, 267, 55 1 -557 and Seeger, T. F. Business, Heart ak Μ, 2003, pp. 5, 113-126). These parts form the core of the basal ganglia system. MSN plays a key role in the cortical-basal ganglia-thalamic cortical cycle' integration of astringent cortical/thalamic inputs and sends this integration information back to the cortex. MSN exhibits two functional categories of neurons: a class D that exhibits dopamine receptors and a class 2 that exhibits A dopamine receptors. Class a neurons are part of the "direct" striatum output pathway and are widely used to promote behavioral responses. Neuron-like elements are part of the indirect striatum output pathway, which is used to suppress behavioral responses that compete with their behavioral responses promoted by the "direct" path. These competitive paths act like brakes and accelerators in cars. In the simplest terms, the lack of exercise in Parkinson's disease is caused by an overactive path, and excessive exercise in conditions such as Huntington's disease indicates The direct path is overactive. PDE1〇A regulation of camp and/or cGMP signaling in the dendritic regions of these neurons may be associated with transdermal/thalamic input filtration into MSN. In addition, pDE1〇A is involved in the regulation of GABA release in substantia nigra and globus pallidus 4 201215607 (Seeger, TF et al., 2003, 985, 113-126). Dopamine D2 receptor antagonism is well established in the treatment of schizophrenia. effect. Since the 1950s, 'dopamine 〇2 receptor antagonism has been the mainstay of psychiatric treatment and all effective antipsychotics have antagonized the d2 receptor. The effect of 〇2 may be mainly through the striatum, nucleus accumbens and nerves in the olfactory tubercle. Meta-mediated 'this line receives dense dopamine-induced projections from these regions and strongly expresses 1>2 receptors (Konradi, C. and Heckers, S. o/5z〇/〇g/Ca/h_yc/n· π, 2001, M, 729-742). Dopamine d2 receptor agonism causes a decrease in cAMP levels in cells, which is inhibited by adenylate cyclase, and this is a component of D2 signaling (St〇〇f, j. c; KebaMan J· W. iV (10) 1981, 2, 366-368 and Neve, KA et al, of Receptors and Signal Transduction 2004, 24, 165-205) In contrast, d2 parting antagonism effectively increases eAMp content and this effect can be degraded by cAMP Simulation of inhibition by phosphodiesterase. Most of the 21 phosphodiesterase genes have been widely exhibited; therefore, inhibition may have side effects. Because PDE1〇A has high and relatively specific expression characteristics in the striatum, nucleus accumbens, and olfactory tuberculosis neurons, PDE10A inhibition may have similar effects to A receptor antagonism. And therefore has an antipsychotic effect. Although PDE10A inhibition is expected to partially mimic D2 receptor antagonism, it is expected to have different characteristics. The 〇2 receptor has a division. Repeated-go signal transduction components (NeVe, KA et al., ^(10)/./ 细中沿忘加/7>(10)如(10)2004,以,165_2〇5), for this reason, the interference of good 201215607 PDE10A interferes with cAMp Dopamine signaling can be negatively regulated via the 〇2 receptor rather than directly antagonizing. This reduces the risk of extrapyramidal side effects observed under strong D2 antagonism. In contrast, pDE丨〇A inhibition may have some effects not observed under D2 receptor antagonism. Pde丨〇a is also expressed in expression D, receptor striatum neurons (Seeger, τ· F• Et al., β-cut > 2 / ^ (10) to, 2003, P55, 113-126). Because D丨 receptors act

作用導致刺激腺苷酸環化酶且使camp含量增加，所以 PDE10A抑制作用亦可能具有模擬Di受體促效作用之效 應。最終，PDE1 0A抑制作用不僅使細胞中之eAMp增加， 且預期亦可使cGMP含量增加，此係因為pDE丨〇 a為雙重特 異性磷酸二酯酶。cGMp活化如cAMp之細胞中許多目標蛋 白質且亦與cAMP信號傳導路徑相互作用。總之，pDEl〇A 抑制作用可能部分模擬A受體拮抗作用且因此具有抗精神 病作用，但該特徵與在經典A受體拮抗劑下所觀測到之特 徵可能不同。 ^ PDE10A抑制劑罌粟鹼顯示在若干抗精神病模型中具 有活性。罌粟鹼增強大鼠中A受體拮抗劑氟哌啶醇之強直 症效應，但不會使其自身患強直症（WO 03/093499 )。罌粟 鹼減輕藉由PCP誘導之大鼠之過動症，而安非他命 (amphetamine )誘導之過動症的減輕不明顯（w〇 03/093499 )。此等模型表明pDE1〇A抑制作用具有理論研究 所預期之典型抗精神病潛能。w〇 〇3/〇93499進一步揭示選 擇性PDE10抑制劑之用途，其係用於治療相關神經及精神 病症。此外，在大鼠中pDE1〇A抑制作用逆轉注意力定勢 201215607 轉換中之亞慢性PCp誘發之缺乏（R〇defer等人，j 2005, 4, 1070-1076 )。此模型表明 PDE10A 抑制作 用可能緩解與精神分裂症相關之認知能力缺乏。 PDE10A之組織分佈顯示PDE10A抑制劑可用以提高表 現PDE10酵素之細胞，尤其包含基底神經節之神經元内的 cAMP及/或cGMP之含量，且因此，本發明之pDEi〇A抑 制劑適用於治療多種牽涉基底神經節之相關神經精神病 狀，諸如神經及精神病症、精神分裂症、躁鬱症、強迫症 及其類似病狀，且益處可為不具有與當前市售療法相關之 有害副作用。 此外，近期公開案（WO 2005/1205 14; WO 2005012485 ;The effect is to stimulate adenylate cyclase and increase the camp content, so PDE10A inhibition may also have the effect of mimicking the Di receptor agonistic effect. Finally, PDE10A inhibition not only increases eAMp in cells, but is also expected to increase cGMP levels, since pDE丨〇a is a dual-specific phosphodiesterase. cGMp activates many of the target proteins in cells such as cAMp and also interacts with the cAMP signaling pathway. In conclusion, pDEl〇A inhibition may partially mimic A receptor antagonism and therefore have an antipsychotic effect, but this feature may differ from that observed under classical A receptor antagonists. ^ The PDE10A inhibitor papaverine has been shown to be active in several antipsychotic models. Papaverine enhances the tonic effect of the A receptor antagonist haloperidol in rats, but does not cause it to develop tonicity (WO 03/093499). Papaverine alleviates hyperactivity in rats induced by PCP, whereas amphetamine-induced hyperactivity is less pronounced (w〇 03/093499). These models demonstrate that pDE1〇A inhibition has the typical antipsychotic potential expected from theoretical studies. W〇 〇3/〇93499 further discloses the use of a selective PDE10 inhibitor for the treatment of related neurological and psychiatric disorders. In addition, pDE1〇A inhibition reverses attention in rats in 201215607. The lack of subchronic PCp induction in the transformation (R〇defer et al, j 2005, 4, 1070-1076). This model suggests that PDE10A inhibition may attenuate cognitive abilities associated with schizophrenia. The tissue distribution of PDE10A shows that PDE10A inhibitors can be used to increase the content of cAMP and/or cGMP in cells expressing PDE10 enzyme, especially in neurons containing basal ganglia, and therefore, the pDEi〇A inhibitor of the present invention is suitable for treating various kinds Related neuropsychiatric conditions involving the basal ganglia, such as neurological and psychiatric disorders, schizophrenia, bipolar disorder, obsessive-compulsive disorder, and the like, and the benefit may be that there are no deleterious side effects associated with current marketed therapies. In addition, the recent publication (WO 2005/1205 14; WO 2005012485;

Cantin 等人，Bi〇organic & Medicinal Chemistry LeUers 17 (2〇07) 2869-2873 )提出PDE10A抑制劑可適用於治療肥胖 症及非胰島素依賴型糖尿病。 關於PDE10A抑制劑，EP 1250923 —般揭示選擇性 PDE10 #制劑，且詳言之f粟驗之用$，其係用於治療某 些神經及精神病症。 WO09/152825揭示作為PDE10A酵素抑制劑之苯基咪 唑衍生物，其適用於治療各種疾病，包括CNS相關疾病， 堵如精神分裂症。 。比咯并二氫異喹啉及其變異體作為pDEl〇抑制劑揭示 於WO 05/03129及WO 05/02579中。充當PDE1〇抑制劑之 經哌啶基取代之喹唑啉及異喹啉揭示於w〇 〇5/82883中。 WO 06/11040揭示充當PDE1〇抑制劑之經取代之喹唑啉及 201215607 異喹啉化合物。US 20050182079揭示充當有效磷酸二酯酶 (PDE )抑制劑之喹唑啉及異喹啉之經取代之四氫異喹啉基 衍生物。詳言之，US 20050182079係關於作為PDE10之選 擇性抑制劑的該等化合物。類似地，US 20060019975揭示 充當有效構酸二酯酶（PDE )抑制劑之喹。坐琳及異啥琳之〇底 。定衍生物。US 20060019975亦係關於作為PDE10之選擇性 抑制劑之化合物。WO 06/028957揭示作為1〇型磷酸二酯酶 之抑制劑之σ辛啉衍生物，其係用於治療精神及神經症候 群°然而’此等揭示案均與本發明化合物無關，其與任何 已知PDE10抑制劑在結構上不相關（Kehler, j等人，五力 Opin. Ther. Patents 2007, 17, 147-158 )» 本發明化合物經證實為有效ppE1〇A酵素抑制劑及活 體内活性化合物，其逆轉pcp誘發之過動症且因此可為神 經退化性病症及/或精神病症之當前市售治療提供替代治 療’其並非在所有患者中均有效。㈣，仍存在對替代治 療方法之需要。 L發明内容】 本發明之目的為提供作為選擇性PDE10A酵素抑制 之化合物。 本發明之另-目的為提供與先前技術化合物相 該活性且具有良奸、紐乂土 ％ A ^ m 肖佳改良之溶解性、代謝穩定性及 生物可用性之化合物。 Γ 本發明之另一目的為提供人類患者之有效治療，詳 201215607 長期，口冑❿不產生典型地與神經及精神病症之當前療 法相關之副作用。 在閱讀本說明書後’本發明之其他目的將變得顯而易知。 因此，在-態#中本發明係關於式j化合物：Cantin et al., Bi〇organic & Medicinal Chemistry LeUers 17 (2〇07) 2869-2873) suggest that PDE10A inhibitors are indicated for the treatment of obesity and non-insulin dependent diabetes. With regard to PDE10A inhibitors, EP 1250923 generally discloses a selective PDE10 # formulation, and in particular, $ for the treatment of certain neurological and psychiatric disorders. WO09/152825 discloses phenylimidazole derivatives as PDE10A enzyme inhibitors which are useful for the treatment of various diseases, including CNS related diseases, such as schizophrenia. . Pirolohydrodihydroisoquinolines and variants thereof are disclosed as pDE1 inhibitors in WO 05/03129 and WO 05/02579. The piperidinyl substituted quinazolines and isoquinolines which act as PDE1 inhibitors are disclosed in w〇 5/82883. WO 06/11040 discloses substituted quinazolines and 201215607 isoquinoline compounds which act as PDE1 inhibitors. US 20050182079 discloses substituted tetrahydroisoquinolinyl derivatives of quinazolines and isoquinolines which act as potent phosphodiesterase (PDE) inhibitors. In particular, US 20050182079 relates to such compounds as selective inhibitors of PDE10. Similarly, US 20060019975 discloses quinquins which act as potent acid diesterase (PDE) inhibitors. Sitting on the bottom of Lin and the different 啥琳. Derivatives. US 20060019975 is also directed to compounds which are selective inhibitors of PDE10. WO 06/028957 discloses sigma octylamine derivatives as inhibitors of phosphonium diesterase, which are used for the treatment of psychotic and neurological syndromes. However, these disclosures are not related to the compounds of the present invention, and any It is known that PDE10 inhibitors are structurally unrelated (Kehler, j et al., Wuli Opin. Ther. Patents 2007, 17, 147-158). The compounds of the present invention have been shown to be effective ppE1〇A enzyme inhibitors and active compounds in vivo. It reverses the pcp-induced hyperactivity disorder and thus can provide an alternative treatment for current marketed treatments of neurodegenerative disorders and/or psychiatric disorders, which are not effective in all patients. (iv) There is still a need for alternative treatments. SUMMARY OF THE INVENTION The object of the present invention is to provide a compound which is a selective PDE10A enzyme inhibitor. Another object of the present invention is to provide a compound which is active with the prior art compounds and which has the solubility, metabolic stability and bioavailability of the rape, mulberry soil % A ^ m Xiao Jia.另一 Another object of the present invention is to provide an effective treatment for human patients, detailed 201215607 For a long time, oral sputum does not produce side effects typically associated with current therapies for neurological and psychiatric disorders. Other objects of the present invention will become apparent after reading this specification. Thus, in the state - the invention relates to the compound of formula j:

式I -本發明化合物 其中het!(亦表示為 het-1 )係選自由以下者所組成之群組Formula I - a compound of the invention wherein het! (also denoted as het-1) is selected from the group consisting of

H/Me 且其中*表示連拯點， 且het2 (亦表不為het 2 )係選自由以下者所組成之群組: 201215607H/Me and where * means Lianzheng, and het2 (also not het 2) is selected from the group consisting of: 201215607

且其中L進一步為選自由以下者所組成之群組的連接基團：And wherein L is further a linking group selected from the group consisting of:

Ο LaΟ La

V * R1 Lb 且其中R1係選自由以下者所組成之群組：H; ci-C6燒基， 諸如甲基、乙基、1_丙基、2_丙基、異丁基、正丁基第二 丁基或第三丁基；C1-C6烷基（C3-C8)環烷基，諸如環丙基 甲基，且其中*表示連接點，以及本發明化合物之互變異構 體及醫藥學上可接受之酸加成鹽。 在一具體實例中，本發明化合物中之HET_2係選自由 以下者所組成之群組： 201215607V * R1 Lb and wherein R1 is selected from the group consisting of: H; ci-C6 alkyl, such as methyl, ethyl, 1-propyl, 2-propyl, isobutyl, n-butyl a second butyl or tert-butyl; a C1-C6 alkyl (C3-C8) cycloalkyl group, such as a cyclopropylmethyl group, and wherein * represents a point of attachment, as well as tautomers and pharmaceutics of the compounds of the invention An acceptable acid addition salt. In a specific embodiment, the HET 2 in the compound of the present invention is selected from the group consisting of: 201215607

在另一具體實例中，R1為CH3，緣4 叶5之若HET-2係選 自由以下者所組成之群組，則R1為Cij3 :In another embodiment, R1 is CH3, and if the HET-2 is selected from the group consisting of the following, R1 is Cij3:

在另-具體實例中，本發明化合物係選自由以下者所 組成之群組u基m4_基_4·(㈣_2•基甲氧基）苯 :醯胺、N-(苯并[d]嗟唾-6-基）-N-曱基-4-(啥琳_2_基甲氧基） 苯甲酿胺、N-(苯并[d]腭唾-6-基）-N-曱基_4-(啥琳_2_基甲氧 基）苯曱醯胺、N-(咪唑并U，2-a]吡啶-6-基）-N-曱基-4-(喹啉 基甲氧基）笨曱醯胺、N-曱基_4-(喹琳-2-基曱氧 基）N [1，2,4]二唑并[ita]吡啶_6基-苯甲醯胺、N-quy 唑并[1，5_a]吡啶-7-基）-N-甲基-4-(喹啉_2-基曱氧基）苯甲 醯胺2-吡啶-3-基-噻唑曱酸甲基-[4-(喹淋-2-基甲氧基）_ 苯基]-醯胺、2-吡啶_4_基_噻唑_4_甲酸甲基-[4_(喹啉_2_基曱 氧基）-笨基]醯胺、2-吡啶-3-基-噻唑-4-甲酸曱基-[4-(喹啉In another embodiment, the compound of the invention is selected from the group consisting of u-based m4_yl-4((tetra)-2-ylmethoxy)benzene: decylamine, N-(benzo[d]pyrene Sal-7-yl)-N-mercapto-4-(啥琳_2_ylmethoxy)benzamide, N-(benzo[d]indole-6-yl)-N-fluorenyl _4-(啥琳_2_ylmethoxy)phenylamine, N-(imidazo-U,2-a]pyridin-6-yl)-N-mercapto-4-(quinolinylmethoxy) Alkylamine, N-fluorenyl_4-(quinolin-2-ylmethoxy)N [1,2,4]diazolo[ita]pyridine-6-benzamide, N -quy oxazo[1,5_a]pyridin-7-yl)-N-methyl-4-(quinolin-2-yloxy)benzamide 2-pyridine-3-yl-thiazolyl -[4-(quinolin-2-ylmethoxy)_phenyl]-decylamine, 2-pyridine-4-yl_thiazole-4-carboxylic acid methyl-[4_(quinoline-2-yl) Oxy)-peptidyl]decylamine, 2-pyridin-3-yl-thiazole-4-carboxylic acid decyl-[4-(quinoline)

V 201215607 -2 -基曱氧基）_苯基]_醯胺、5_n比咬_2 -基-1Η-°比哇-3-曱酸曱基 _[4-(喹啉-2-基甲氧基）_苯基]_醢胺、5-吡啶-3-基-1H-吼唑-3-曱酸甲基-[4-(喹啉-2-基甲氧基）-苯基]-醯胺、5-吡啶-4-基 -1H-吼嗤-3-曱酸曱基-[4-(喹啉-2-基曱氧基）-苯基]-醯胺、苯 并售唾-6-曱酸曱基-[4-(喹啉_2_基曱氧基）-苯基]-醢胺、苯并 嘆唾曱酸甲基-[4-(1-曱基-1H-苯并咪唑-2-基甲氧基）_苯 基]-醯胺及N-曱基-N-[4-(喹啉-2-基甲氧基）_苯基]_異菸鹼 醯胺。 在又一具體實例中，本發明化合物係選自由以下者所 組成之群組：N-(苯并[d]噻唑_6_基）_N_甲基_4 (喹啉_2_基曱 氧基）苯甲醯胺、5-吡啶-3-基-1H-吡唑-3-曱酸甲基-[4_(喹啉 基曱氧基）-本基]-酿胺、5 _ u比咬—4 -基-1 fj - u比唾_ 3 _甲酸甲其 [4 (喧琳-2-基甲氧基）_苯基]_酿胺及苯并n塞唾_6_曱酸甲基 _[4-(啥啉-2-基曱氧基）_苯基]•醯胺。 在連接基團為La之情況下，為便於參考，本發明化合 物稱為化合物la °V 201215607 -2 -yloxy)phenyl]-decylamine, 5_n ratio bite_2-yl-1Η-° than wow-3-decanoic acid _[4-(quinolin-2-yl-methyl) Oxy)-phenyl]-decylamine, 5-pyridin-3-yl-1H-indazole-3-indolemethyl-[4-(quinolin-2-ylmethoxy)-phenyl]- Indoleamine, 5-pyridin-4-yl-1H-indole-3-indole decyl-[4-(quinolin-2-ylindenyloxy)-phenyl]-decylamine, benzo-salt- 6-decanoic acid-[4-(quinolin-2-ylindolyloxy)-phenyl]-decylamine, benzoxanthionylmethyl-[4-(1-mercapto-1H-benzene) And imidazol-2-ylmethoxy)-phenyl]-nonylamine and N-fluorenyl-N-[4-(quinolin-2-ylmethoxy)-phenyl]-isonicotinamide. In yet another embodiment, the compound of the invention is selected from the group consisting of N-(benzo[d]thiazole-6-yl)_N_methyl-4 (quinoline-2-yloxy) Benzobenzamide, 5-pyridin-3-yl-1H-pyrazole-3-furoic acid methyl-[4-(quinolinylmethoxy)-benyl]-bristamine, 5 _ u ratio bite -4 -yl-1 fj - u is more than salivary _ 3 _ formic acid, its [4 (喧琳-2-ylmethoxy)_phenyl]-bristamine and benzon-sodium- 6-decanoic acid methyl _[4-(Porphyrin-2-ylmethoxy)phenyl] decylamine. In the case where the linking group is La, the compound of the present invention is referred to as a compound la ° for ease of reference.

合物1 b 而當連接基團為Lb時，為便於參考，本發明化合物稱為化 12 201215607Compound 1 b and when the linking group is Lb, the compound of the present invention is referred to as a reference for ease of reference 12 201215607

藥學上可接受 本發明進一步提供本發明化合物或其醫 之酸加成鹽，其係用作醫藥品。 在另-態樣中，本發明提供一種醫藥組成物，其包含 本發明化合物及醫藥學上可接受之載劑、稀釋劑或賦形劑。 本發明進-步提供本發明化合物之用途，其係用於製 備用以治療神經退化性病症或精神病症之醫藥品。 本發明進-步提供本發明化合物，其係用作醫藥品。 、本發明進-步提供本發明化合物，其係用於治療選自 由以下者所組成之群組的精神病纟：精神分裂症，例如偏 執型、混亂型、緊張症型、未分型或剩餘類型之精神分裂 症；類精神分裂症精神障礙；分裂情感性精神障礙，例: 妄想型或抑鬱型分裂情感性精神障礙；妄想症；躁蠻症， 例如I型躁鬱症、π型躁鬱症及循環情感性精神障礙；物質 誘發之精神病症，例如酒精、安非他命、大麻（cannabis)、 可卡因（cocaine)、迷幻藥（hallucin〇gen)、吸入劑、類鴉 片（opioids)或苯環利定（phencyclidine)誘發之精神病； 偏執型人格障礙；及精神分裂症型人格障礙。 此外，本發明提供一種治療患有神經退化性病症之患 13 201215607 者的方法，該方法包含向患者投予本發明化合物。在另一 態樣中，本發明提供一種治療患精神病症之患者的方法， 該方法包含向患者投予本發明化合物。在另—具體實例 中，本發明提供一種治療患藥物成癌（諸如酒精、安非他 命、可卡因或牙鳥片劑成瘾症）之患者的方法，該方法包含 向患者投予本發明化合物。 【實施方式】 除非另作說明，否則「本發明化合物（c〇mp〇und〇fthe invention)」係指本發明化合物，亦即式工化合物所涵蓋之 一或多種化合物。 本發明化合物當如PDE1〇A酵素抑制作用檢定部分中 所述測试時，其IC5G值介於約15與400 nM之間，該值使 其成為適用於抑制PDE 1〇A酵素活性之化合物。 此外，已測試化合物逆轉苯環利定（pcp)誘發之過動 症^力Q如「苯環利定（pcp)誘發之過動症」部分中所 述畺、j PCP效應之逆轉。貫驗顯示本發明化合物為逆轉pep 誘發之過動症的活體内活性化合物。 醫藥學上可接受之鹽 本發明亦包含本發明化合物之鹽，典型地包含醫藥學 上可接受之鹽。該等鹽包括醫藥學上可接受之酸加成鹽。 酸加成鹽包括無機酸以及有機酸之鹽。 適。無機酸之代表性實例包括鹽酸、氫溴酸、氫碘酸、 14 201215607 磷酸、硫酸、胺磺酸、硝酸及其類似酸。適合有機酸之代 表性實例包括甲酸、乙酸、三氯乙酸、三氟乙酸、丙酸、 苯曱酸、肉桂酸、檸檬酸、反丁烯二酸、乙醇酸、衣康酸、 乳酸、甲烷磺酸、順丁烯二酸、蘋果酸、丙二酸、杏仁酸、 草酸、苦味酸、丙_酸、柳酸、丁二酸、甲烧石黃酸、乙烧 磺酸、酒石酸、抗壞血酸、雙羥萘酸、雙亞甲基柳酸、乙 二確酸、葡萄糖酸、曱順丁烯二酸、天冬胺酸、硬脂酸、 棕搁酸、EDTA、乙醇酸、對胺基苯曱酸、麩胺酸、苯磺酸、 對甲苯磺酸、茶鹼乙酸以及8-函茶鹼，例如8-溴茶鹼及其 類似物。醫藥學上可接受之無機或有機酸加成鹽之其他實 例包括 Berge，S.M.等人，《/· P/zarw. 1977，66，2 中所列 舉之醫藥學上可接受之鹽，該文獻之内容以引用的方式併 入本文中。 丨此外，本發明化合物可以非溶劑合物形式以及與醫藥 學上可接受之溶劑（諸如水、乙醇及其類似物）形成之溶 J 口物形式存在。一般而言，出於本發明之目#，認為溶 劑合物形式等效於非溶劑合物形式。 醫藥組成物 本發明進一步接供—括6¾ w /、種醫樂組成物，其包含單獨本發 明化合物或與另—活性成八 成刀之組合及醫藥學上可接受之載 wJ或稀釋劑。本發明亦提一 aB .u . ^ 種醫樂組成物，其包含本發 月化&物及醫藥學上可接受 條又之載劑或稀釋劑。 本發明化合物可單獨或盥 蜀次與醫樂學上可接受之载劑、豨 15 201215607 釋劑或賦形劑組合以單次或多次劑量投予。本發明之醫藥 組成物可根據諸如以下文獻中揭示之習知技術與醫藥學上 可接受之載劑或稀釋劑’以及任何其他已知佐劑及賦形劑 一起調配：Remington: The Science and practice of Pharmacy， 第 21 版，Gennaro 編，Mack Publishing 公司，Easton，PA, 2005 ° 醫樂組成物可經特定調配用於藉由諸如口服、直腸、 經鼻、肺部、局部（包括類内及舌下）、經皮、腦池内、腹 膜内、陰道及非經腸（包括皮下、肌肉内、勒内、靜脈内 及皮内）途徑之任何適合途徑投予。應瞭解，途徑將視待 治療患者之一般狀況及年齡、待治療病狀之性質及活性成 分而定。 用於口服投予之醫藥組成物包括諸如膠囊、錠劑、糖 衣藥丸、丸劑、口含錠、散劑及顆粒之固體劑型。適當時， 可製備具有包衣（諸如腸溶包衣）之組成物，或其可根據 此項技術中熟知之方法經調配以便提供活性成分之控制釋 放，諸如持續或延長釋放。用於口服投予之液體劑型包括 溶液、乳液、懸浮液、糖漿及酏劑。 用於非經腸投予之醫藥組成物包括滅菌水性及非水性 可注射溶液、分散液、懸浮液及乳液以及在使用之前方可 復原成滅菌可注射溶液或分散液之滅菌粉末。其他適合投 予形式包括（但不限於）栓劑、喷霧劑、軟膏、乳霜、凝 膠、吸入劑、皮膚貼片及植入物。 本發明化合物之每天典型口服劑量在每公斤體重約 16 201215607 0.001至、約loo毫克之範圍内。每天典型口服劑量亦在每公 斤體重約0_01至約50毫克之範圍内。本發明化合物之每天 典型口服劑量進一步在每公斤體重約0 05至約10毫克之範 圍内。每天通常投予一或多個劑量，典型地i i 3個劑量 之口服劑量。精確劑量將視投予頻率及模式；所治療患者 之J·生別、年齡、體重及一般狀況；所治療病狀之性質及嚴 重程度及待治療之任何併發疾病及熟習此項技術者知曉之 其他因素而定。 糟由熟習此項技術者已知之方法，組成物亦可呈單位 劑型。出於說明性目的，口服投予之典型單位劑型可含有 約0_01至約1_ mg、約0.05至約500 mg、或約〇 5叫 至約200 mg本發明化合物。 對於諸如靜脈内、鞘内、肌肉内及類似投予之非經腸 途徑而言，典型劑量為口服投予所用劑量之大約一半。 本發明亦提供一種製造醫藥組成物之方法，其包含使 本發明化合物單獨电盥s __、.壬w A、 干判名興为活性成分組合與至少一種醫藥 學上可接受之載劑或稀釋劑混合。 ' 本發明化合物一般以自由物質或其醫藥學上可接受之 鹽形式使用。 對於非經腸投藥而言，可㈣本發明化合物於滅菌水 溶液、丙二醇水溶液、維生f E水溶液或芝麻油或花生油 中之溶液。必要時應適當緩衝該等水溶液，且液體稀釋劑 首先使得與足夠生理食鹽水或葡萄糖等張。水溶液尤其適 用於靜脈Θ肌肉内、皮下及腹膜内投予。可使用熟習此 17 201215607 項技術者已知之標準技術將本發明化合物輕易併入已知滅 菌水介質中。 ，々合適醫藥載劑包括惰性固體稀釋劑或填充劑、滅菌水 =液及各種有機溶劑。固體載劑之實例包括乳糖、白土、 篇糖、環糊精、滑石、明膠、瓊脂、果膠、阿拉伯膠、硬 脂酸鎂、硬脂酸及纖維素之低碳烧基_。液體載劑之實例 4 (仁不限於）糖漿、花生油、橄欖油、磷脂、脂肪酸、 :肪酸胺、聚氧乙婦及水。類似地，載劑或稀釋劑可包括 單獨或。躐混合的此項技術中已知之任何持續釋放物質， 諸如單硬脂酸甘油醋或二硬脂酸甘油醋。接著容易投予呈 適用於所揭示投藥途徑之多種㈣㈣由組合本發明化合 物與醫藥學上可接受之載劑形成的醫藥組成物。藉由藥劑 學技術已知之方法’組成物宜呈單位劑型。 適用於口服投予之本發明組成物可呈諸如膠囊或錠劑 之個別單位，各含有預定量之活性成分及視情況選用之適 。賦形劑。此外’可經口使用之組成物可呈散劑或顆粒、 於水性或非水性液體中之溶液或懸浮液或水包油或油包水 液體乳液形式。 、若使用固體載劑進行口服投予，則製劑可經壓片、以 叔末或小球形式置於硬明膠膠囊中或可呈口含鍵或口含劑 形^固體栽劑之量將廣泛變化，但每劑量單位在约25邮 至約1 g之範圍内。若使用液體載劑’可Pharmaceutically Acceptable The present invention further provides a compound of the present invention or a pharmaceutical acid addition salt thereof, which is used as a pharmaceutical. In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient. The invention further provides for the use of a compound of the invention for use in the manufacture of a medicament for the treatment of a neurodegenerative disorder or a psychiatric disorder. The present invention further provides a compound of the invention for use as a pharmaceutical. Further, the present invention provides a compound of the present invention for the treatment of a psychotic disorder selected from the group consisting of: schizophrenia, such as paranoid, disordered, nervous, untyped or residual type Schizophrenia; schizophrenia-like mental disorder; schizoaffective psychosis, for example: delusional or depressive schizoaffective psychosis; delusional disorder; bruises, such as type I bipolar disorder, π-type bipolar disorder and circulation Affective mental disorders; substance-induced mental disorders such as alcohol, amphetamines, cannabis, cocaine, hallucin〇gen, inhalants, opioids, or phencyclidine Induced psychosis; paranoid personality disorder; and schizophrenia-type personality disorder. Furthermore, the invention provides a method of treating a subject suffering from a neurodegenerative disorder 13 201215607 comprising administering to a patient a compound of the invention. In another aspect, the invention provides a method of treating a patient suffering from a psychiatric condition, the method comprising administering to the patient a compound of the invention. In another embodiment, the invention provides a method of treating a patient suffering from a cancerous form of a drug, such as alcohol, amphetamine, cocaine or tooth tablet addiction, comprising administering to a patient a compound of the invention. [Embodiment] Unless otherwise specified, "a compound of the present invention (c〇mp〇und〇fthe invention)" means a compound of the present invention, that is, one or more compounds encompassed by a compound of the formula. The compounds of the present invention have an IC5G value between about 15 and 400 nM when tested as described in the PDE1A enzyme inhibitor assay portion, which makes it a compound suitable for inhibiting PDE 1A enzyme activity. In addition, the tested compounds reversed the reversal of the PC, j PCP effect described in the benzocyclidine (pcp)-induced hyperactivity, such as the "phenididine-induced hyperactivity disorder". The test shows that the compound of the present invention is an in vivo active compound that reverses pep-induced hyperactivity. Pharmaceutically Acceptable Salts The present invention also encompasses salts of the compounds of the invention, typically comprising a pharmaceutically acceptable salt. Such salts include pharmaceutically acceptable acid addition salts. Acid addition salts include inorganic acids as well as salts of organic acids. suitable. Representative examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, 14 201215607 phosphoric acid, sulfuric acid, amine sulfonic acid, nitric acid, and the like. Representative examples of suitable organic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, itaconic acid, lactic acid, methanesulfonate. Acid, maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, propionic acid, salicylic acid, succinic acid, tocopheryl acid, sulphuric acid, tartaric acid, ascorbic acid, double Hydronaphthoic acid, bis-methylene sulphate, oxadicarboxylic acid, gluconic acid, hydrazine maleic acid, aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid , glutamic acid, benzenesulfonic acid, p-toluenesulfonic acid, theophylline acetic acid, and octaphylline, such as 8-bromophylline and the like. Other examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in Berge, SM et al., / P/zarw. 1977, 66, 2. The content is incorporated herein by reference. Further, the compounds of the present invention may exist in the form of unsolvated forms and in the form of a solvate formed with a pharmaceutically acceptable solvent such as water, ethanol and the like. In general, for the purpose of the present invention, the solvate form is considered to be equivalent to the unsolvated form. Pharmaceutical Compositions The present invention is further provided as a composition comprising a compound of the present invention alone or in combination with another active octagonal knife and a pharmaceutically acceptable carrier or diluent. The invention also provides a pharmaceutical composition comprising a carrier or a diluent of the present invention and a pharmaceutically acceptable strip. The compounds of the present invention can be administered in single or multiple doses, either alone or in combination with a pharmaceutically acceptable carrier, 豨 15 201215607 release or excipient. The pharmaceutical compositions of the present invention may be formulated according to conventional techniques such as those disclosed in the literature with pharmaceutically acceptable carriers or diluents, as well as any other known adjuvants and excipients: Remington: The Science and practice of Pharmacy, 21st ed., Gennaro ed., Mack Publishing Company, Easton, PA, 2005 ° PharmaTech composition can be specifically formulated for use by, for example, oral, rectal, nasal, pulmonary, topical (including intra- and sublingual) ), any suitable route of transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intra-, intra-, and intra-cutaneous) routes. It will be appreciated that the route will depend on the general condition and age of the patient to be treated, the nature of the condition to be treated, and the active ingredient. Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, lozenges, dragees, pills, troches, powders and granules. Where appropriate, a composition having a coating such as an enteric coating may be prepared, or it may be formulated according to methods well known in the art to provide controlled release of the active ingredient, such as sustained or extended release. Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs. Pharmaceutical compositions for parenteral administration include sterilized aqueous and non-aqueous injectable solutions, dispersions, suspensions and emulsions, and sterile powders which can be reconstituted into sterile injectable solutions or dispersions before use. Other suitable forms of administration include, but are not limited to, suppositories, sprays, ointments, creams, gels, inhalants, dermal patches, and implants. A typical oral dose per day for a compound of the invention is in the range of about 16 201215607 0.001 to about loo milligrams per kilogram of body weight. Typical oral doses per day are also in the range of from about 0 mg to about 50 mg per kg of body weight. A typical oral dose per day of the compound of the invention is further in the range of from about 0.05 to about 10 mg per kilogram of body weight. One or more doses, typically an oral dose of 3 doses, are typically administered daily. The exact dose will depend on the frequency and mode of administration; the J, the age, weight and general condition of the patient being treated; the nature and severity of the condition being treated and any concurrent disease to be treated and known to those skilled in the art. Depending on other factors. The composition may also be in unit dosage form by methods known to those skilled in the art. For illustrative purposes, a typical unit dosage form for oral administration may contain from about 0. 01 to about 1 mg, from about 0.05 to about 500 mg, or from about 5 to about 200 mg of the compound of the present invention. For parenteral routes such as intravenous, intrathecal, intramuscular, and the like, the typical dose is about one-half of the dose administered orally. The invention also provides a method of making a pharmaceutical composition comprising reacting a compound of the invention with s__, 壬w A, a combination of active ingredients and at least one pharmaceutically acceptable carrier or dilution. Mix the agents. The compound of the present invention is generally used in the form of a free substance or a pharmaceutically acceptable salt thereof. For parenteral administration, a solution of the compound of the present invention in a sterile aqueous solution, an aqueous solution of propylene glycol, an aqueous solution of vitamin E or sesame oil or peanut oil may be used. The aqueous solutions should be suitably buffered if necessary, and the liquid diluent is first rendered as isotonic with sufficient physiological saline or glucose. The aqueous solution is especially suitable for intramuscular, subcutaneous and intraperitoneal administration of intravenous sputum. The compounds of the present invention can be readily incorporated into known sterilized aqueous media using standard techniques known to those skilled in the art. , Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile water = liquid and various organic solvents. Examples of solid carriers include lactose, terra alba, sugar, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and low carbon alkyl of cellulose. Examples of liquid carriers 4 (not limited to) syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxymethylene and water. Similarly, the carrier or diluent can include the individual or. Any sustained release material known in the art, such as glycerol monostearate or glyceryl distearate. It is then easy to administer a plurality of (4) (4) pharmaceutical compositions which are formed by combining the compounds of the present invention with a pharmaceutically acceptable carrier in a manner suitable for the disclosed routes of administration. The composition is known in the art of pharmacy as a unit dosage form. The compositions of the present invention which are suitable for oral administration may be in the form of individual units such as capsules or lozenges, each containing a predetermined amount of the active ingredient, and optionally, as appropriate. excipient. Further, the composition which can be used orally can be in the form of a powder or granule, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion. If the solid carrier is used for oral administration, the preparation may be tableted, placed in a hard gelatin capsule in the form of a tertiary or pellet, or may be in the form of a mouth-containing bond or a buccal form. Changes, but each dosage unit is in the range of about 25 to about 1 g. If a liquid carrier is used, '

軟明膠膠囊或滅菌可注射液體(諸如水性或= 體懸浮液或溶液）形式。 F J 18 201215607 本發明之醫藥組成物可藉由此項技術中習知之方法來 製備。舉例而言，錠劑可藉由以下操作來製備：使活性成 分與普通佐齊m/或稀釋劑混合且隨後用習知屋片機將《昆合 物塵在-起來製備銘劑。佐劑或稀釋劑之實例包含：玉米 澱粉、馬鈴薯澱粉、滑石、硬脂酸鎂、明膠、乳糖'樹膠 及其類似物。亦可使用諸如著色劑、調味劑、防腐劑等: 通常用於該等目的之任何其他佐劑或添加劑，其限制條件 為該等佐劑或添加劑與活性成分相容。 治療病症 如上文所提及，本發明化合物4 PDE10A酵素抑制劑 且因而適用於治療相關神經及精神病症。 —因此，本發明提供本發明化合物以及含有該化合物之 醫藥、，且成物，其係用於治療患者之神經退化性病症、精神 病症或樂物成瘾；其中該神經退化性病症係選自由以下者 所組成之群組：阿兹海默氏病（Alzheimer's disease )、多梗 塞性癡呆、酒精性癡呆或其他藥物相關 瘤或腦創傷相關之命一 -願内腫 费相關之廢呆、與予丁頓氏病或帕金森氏病相關 知If t或AIDS相關之癡呆；譫妄；失憶症；創傷後壓力症； 曰:P平礙’學習障礙，例如閱讀障礙、數學障礙或寫作表 t礙，注意力不足/過動症；及年齡相關之認知能力下降； 2其中精神病症係選自由以下者所組成之群組：精神分裂 =浐？ t偏執型、混亂型、緊張症型、未分型或剩餘類型 "刀裂症，類精神分裂症精神障礙；分裂情感性精神 19 201215607 障礙，例如妄想型或抑鬱型分 物冑a + χ清感性精神障礙；妄想症； 物質誘發之精神病症，例如酒 m . 女非他命、大麻、可卡 & ^本％利定誘發之精神病； 偏執型人格障礙；及精神分 成.廄A、，两社 ^ μ , ^'人格障礙；且其中藥物 成癮為酒精、安非他命、可 及鴉片劑成瘾。 本务明化合物可與一或多種 治療本發明化合物適用之疾病=樂：組合使用，用於 物相比藥物組合在一起更安全：、中與任-單獨藥 合物可與-或多種治療、預防=效二外，本發明化 儿人& 徑制、改善或降低本發明 化〇物之副作用風險或毒性 ^ ^ ^ 他樂物組合使用。因此， 該4其他樂物可藉由一種途徑 ^ π + , 仏且U㊉用之量與本發明化合 物同時或相繼投予。因此，本發 nn A , 、請梁組成物包括除本 心明化合物外亦含有一或多 .> Μ 卉他，舌性成分之彼等組成 物。該4組合可作為單位劑型組 座。σ之一部分或作為套 組或治療方法投予，豆中一 Λ炙絲廿 八 或多種其他藥物以各別劑型作 為>〇療方案之一部分投予。’ 本發明提供一種治療患選自認知障礙或運動障礙之神 經退化性病症之患者的方法，該方法包含向患者 明化合物。 s 本發明亦提供-種治療患精神病症之患者的方法1 方法包含向患者投予本發明化合物。可根據本發明治療Z 精神病症之實例包括（但不限於）精神分裂症，例如偏執 型、混亂型、緊張症型、未分型剩餘類型之精神分裂症； 類精神分裂症精神障礙；分裂情感性精神障礙，例^妄想 20 201215607 型或抑鬱型分裂情感性精神障礙；妄想 神病症，例如酒精、安非他命、大麻、可卡因質=精 吸入劑、_片或苯環利定誘發之精神病；偏執型之人格 障礙，及精神分裂症型人格障礙；焦慮症係選自恐慌症. 畏_症mm社交恐懼症；強迫症；創傷後壓力 症；急性壓力症；及廣泛性焦慮症。 本發月化。物可與至少一種精神安定劑（可為典型或 非典型抗精神病藥劑）植合投予以改良諸如精神分裂症之 精神病症的治療。本發明之組合、用途及治療方法亦可在 治療對其他已知治療未能充分反應或對其他已知治療抵抗 之患者中提供優勢。 因此，本發明提供一種治療患諸如精神分裂症之精神 病症之患者的方法，該方法包含向患者單獨投予本發明化 5物或以連同至少一種精神安定劑一起之組合療法投予。 士本文所用，術語「精神安定劑（neur〇leptic ）」 係指具有抗精神病藥之認知及行為作用的藥物，其能減輕 患精神病患者之精神混亂、妄想、幻覺及心理動作激動。 亦稱為強安神劑及抗精神病藥之精神安定劑包括（但不限 於）.典型抗精神病藥，包括啡噻啡，進一步分.成脂肪族化 口物 °底°定及α辰啡、嘆卩山（例如氣售嘲（cisordinol )、苯丁 嗣（例如氟略咬醇）、二苯氧氮呼（例如洛沙平（l〇xapine ))、 二氮叫丨"朵_ (例如嗎茚酮）、二苯基丁基哌啶（例如哌迷清 (pimozide ));及非典型抗精神病藥，包括苯并異聘唑（例 如利培酮（risperidone ))、舍引嗓（sertindole )、奥氮平 21 201215607 (〇lanZapine)、喹硫平（quetiaPine)、奥沙奈坦（osanetant) 及齊拉西酮（Ziprasid〇ne)。 用於本發明之尤佳精神安定劑為舍叫丨D朵、奥氮平、利 培酮、喹硫平、阿立哌唑（aripipraz〇le )、氟哌啶醇、氣氮 平、齊拉西酮及奥沙奈坦。 本發明進一步提供一種治療患認知障礙之患者的方 法，該方法包含向患者投予本發明化合物。可根據本發明 治療之認知障礙之實例包括（但不限於）阿茲海默氏病、 多梗塞性癡呆、酒精性癡呆或其他藥物相關性癡呆、與顱 内腫瘤或腦創傷相關之癡呆、與亨丁頓氏病或帕金森氏病 相關之癡呆或AIDS相關之癡呆；譫妄；失憶症；創傷後壓 力症，智能障礙；學習障礙，例如閱讀障礙、數學障礙或 寫作表達障礙；注意力不足/過動症；及年齡相關之認知能 力下降。 本發明亦提供一種治療患者之運動障礙的方法，該方 法包含向患者投予本發明化合物。可根據本發明治療之運 動障礙之實例包括（但不限於）亨丁頓氏病及與多巴胺促 效劑療法相關之運動困難。本發明進一步提供一種治療選 自帕金森氏病及腿不寧症候群之運動障礙之方法，該方法 包含向患者投予本發明化合物。 本發明亦提供一種治療情緒降礙之方法，該方法包含 向患者投予本發明化合物。可根據本發明治療之情緒障礙 及情緒發作（mood episode)之實例包括（但不限於）輕型、 中型或重型主要抑蕾發作（major depressive episode )、躁 22 201215607 狂或混合型情緒發作、輕 之抑鬱發作；具有憂#特之、'月緒發作；具有典型特性 之抑鬱發作；產後發病之# 行儂 抑鬱症，·於袖太心·_ 作；中風後抑誉症；嚴重 R之：、：卩’正，輕型抑鬱症；經前不悅症；精神分 裂症之精神病後抑鬱症； 歹刀 神分f症之掊嚴重抑鬱症疊加諸如妄想症或精 症躁營症，例如1型躁臀症、11型躁鬱 ㈣神障礙。應瞭解情緒障礙為精神病症。 =進一步提供一種治療患者之藥物成癌，例如酒 精、女非他命、可卡因或鴆片劑成瘾的方法，該方法包含 向该患者投予有效治療藥物成瘾之量的本發明化合物。 如本文所用’術語「藥物成瘾（drUgaddiction)j音謂 對藥物之異常需求且-般特性在於動機干擾，諸如獲㈣ 需藥物之強迫性衝動及強烈藥物渴望之發作。 一/藥物成癮被廣泛視為病理狀態。成瘾病症涉及產生見 藥行為之短期藥物使用過程、易復發及對天然報償性刺激 反應之能力降低、減緩。舉例而言，精神疾病診斷與統計 手冊（The Diagnostic and Statistical Manual 〇f MentalSoft gelatin capsules or sterile injectable liquids (such as aqueous or body suspensions or solutions). F J 18 201215607 The pharmaceutical composition of the present invention can be prepared by a method known in the art. For example, a lozenge can be prepared by mixing the active ingredient with a conventional accompaniment m/or a diluent and then using the conventional roofing machine to prepare the granules. Examples of adjuvants or diluents include: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose' gum and the like. It is also possible to use, for example, coloring agents, flavoring agents, preservatives and the like: any other adjuvant or additive commonly used for such purposes, with the proviso that such adjuvants or additives are compatible with the active ingredient. Therapeutic Conditions As mentioned above, the Compound 4 PDE10A enzyme inhibitor of the present invention is thus suitable for the treatment of related neurological and psychiatric disorders. - Accordingly, the present invention provides a compound of the present invention, and a medicament, and a composition thereof, for use in treating a neurodegenerative disorder, a psychiatric disorder or a addiction to a patient; wherein the neurodegenerative disorder is selected from A group consisting of Alzheimer's disease, multi-infarct dementia, alcoholic dementia, or other drug-related tumors or brain trauma-related life-related insufficiency Dementia related to Dyton's disease or Parkinson's disease or AIDS-related dementia; sputum; amnesia; post-traumatic stress disorder; 曰: P punish' learning disabilities, such as dyslexia, mathematics disorder or writing Insufficient attention/hyperactivity disorder; and age-related cognitive decline; 2 wherein the mental illness is selected from the group consisting of: schizophrenia = 浐? t paranoid, chaotic, stress disorder, untyped or residual type &" cleavage, schizophrenia-like mental disorder; schizophrenic spirit 19 201215607 Disorders, such as delusional or depressive 胄a + χ Clear mental disorder; delusional disorder; substance-induced mental illness, such as alcohol m. Female non-life, marijuana, cocaine & ^% glibenclamide-induced psychosis; paranoid personality disorder; and mental division. 廄A, , two communities ^ μ, ^ 'personality disorder; and drug addiction is alcohol, amphetamine, and opiate addiction. The compound of the present invention can be used in combination with one or more diseases for the treatment of the compound of the present invention, which is safer than the combination of the drug: the intermediate-administered compound can be combined with - or a plurality of treatments, In addition to the second effect, the present invention reduces the risk or toxicity of the side effects of the phlegm of the present invention. Therefore, the other musical substances can be administered simultaneously or sequentially with the compound of the present invention by a route ^ π + , and U. Therefore, the present invention includes the composition of the beam including one or more of the compounds of the present invention. > This combination of 4 can be used as a unit dosage form. One part of σ is administered as a kit or treatment, and one or more of the other drugs are administered as a part of the > treatment regimen. The present invention provides a method of treating a patient suffering from a degenerative disorder selected from a cognitive or dyskinesia, the method comprising administering a compound to the patient. s The invention also provides a method of treating a patient suffering from a psychiatric condition. The method comprises administering to a patient a compound of the invention. Examples of treatments for Z mental disorders according to the present invention include, but are not limited to, schizophrenia, such as paranoid, chaotic, stress-type, untyped residual types of schizophrenia; schizophrenia-like mental disorders; Sexual distress disorder, case^妄想20 201215607 or depression-type schizoaffective disorder; delusional illness, such as alcohol, amphetamine, marijuana, cocaine = refined inhaler, _ tablets or phencyclidine-induced psychosis; paranoid type Personality disorder, and schizophrenia-type personality disorder; anxiety disorder is selected from panic disorder. Aphobia _ mm social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; acute stress disorder; and generalized anxiety disorder. This month is monthly. The treatment may be combined with at least one neuroleptic (which may be a typical or atypical antipsychotic) to improve the treatment of a psychiatric disorder such as schizophrenia. The combinations, uses, and treatments of the present invention may also provide advantages in treating patients who have not responded adequately to other known treatments or to other known treatments. Accordingly, the present invention provides a method of treating a patient suffering from a psychiatric disorder such as schizophrenia, the method comprising administering to the patient a separate agent of the invention or administering a combination therapy together with at least one neuroleptic. As used herein, the term "neur〇leptic" refers to a drug that has the cognitive and behavioral effects of antipsychotic drugs, which can alleviate mental confusion, delusions, hallucinations and psychomotor agitation in mentally ill patients. Also known as strong antipsychotic and antipsychotic spirit stabilizers include (but not limited to). Typical antipsychotic drugs, including morphine, further divided into fatty mouthparts ° bottom and α □ 啡 、, sigh Lushan (such as gas singer (cisordinol), benzopyrene (such as fluoctanol), diphenoxyxine (such as loxapine (l〇xapine)), diazonium 丨 朵 朵 朵 ( ( ( ( ( ( ( Anthrone), diphenylbutylpiperidine (eg, pimozide); and atypical antipsychotics, including benzoisoxazole (eg, risperidone), sertindole Olanzapine 21 201215607 (〇lanZapine), quetiapine, osanetant and ziprasidone. The superior neuroleptic used in the present invention is called 丨D , olanzapine, risperidone, quetiapine, aripiprazole (aripipraz〇le), haloperidol, nitrozapine, ziprasidone and oxatanide. The invention further provides a treatment for cognitive A method of treating a patient of a disorder, the method comprising administering to the patient a compound of the invention. Therapeutic according to the invention Examples of cognitive impairment include, but are not limited to, Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial or brain trauma, and Huntington's disease Or Parkinson's disease-related dementia or AIDS-related dementia; sputum; amnesia; post-traumatic stress disorder, mental retardation; learning disabilities such as dyslexia, mathematical disorders or writing expression disorders; attention deficit/hyperactivity disorder; Age-related cognitive decline. The invention also provides a method of treating a dyskinesia in a patient, the method comprising administering to a patient a compound of the invention. Examples of dyskinesia treatable according to the invention include, but are not limited to, Huntington The disease and the difficulty associated with dopamine agonist therapy. The present invention further provides a method of treating a dyskinesia selected from the group consisting of Parkinson's disease and leg restlessness syndrome, the method comprising administering a compound of the invention to a patient. Also provided is a method of treating mood disorders, the method comprising administering to a patient a compound of the invention. Examples of mood disorders and mood episodes for treatment include, but are not limited to, mild, moderate or severe major depressive episodes, 躁22 201215607 mad or mixed emotional episodes, mild depressive episodes; Have worries #特之, '月绪袭; Depression episodes with typical characteristics; Postpartum onset# Depression of depression, · Sleeve too hearty _ work; Post-stroke syndrome; Severe R:, 卩' Positive, mild depression; premenstrual discomfort; post-psychotic depression of schizophrenia; sputum sputum f-sickness, severe depression, such as paranoia or dysentery, such as type 1 licking, Type 11 depression (four) God obstacles. It should be understood that emotional disorders are psychiatric disorders. Further, a method of treating a patient's drug into cancer, such as alcohol, a female, cocaine or sputum tablet, is provided, the method comprising administering to the patient an amount of the compound of the present invention in an amount effective to treat the drug. As used herein, the term 'drUgaddiction' refers to the abnormal demand for drugs and the general characteristic is the motivational disturbance, such as the (4) compulsive urge to take drugs and the onset of strong drug cravings. Widely regarded as a pathological condition. Addictive conditions involve short-term drug use, drug-producing behavior, and ability to respond to natural compensatory stimuli, such as the Diagnostic and Statistical Manual. Manual 〇f Mental

Disorders)第四版（DSM_IV)已將成瘾症分為三個階段： 全神貫注/期望、狂歡/興奮及戒斷/負性情緒。此等階段之特 性分別為隨處持續渴望及全神貫注於獲得物質；使用比經 歷酒精效應（intoxicating effect)所需更多之物質；及經歷 耐受、戒斷症狀及對正常生命活動之動機降低。 本發明進一步提供一種治療患者中包含注意力及/或認 知能力缺乏作為症狀之病症的方法，該方法包含向該患者 23 201215607 技予有效治療該病症之量的本發明化合物。 可根據本發明治療之其他病症為強迫症、妥瑞氏症候 群（Tourette’s syndrome )及其他抽動障礙。 如本文所用，且除非另外指出，否則「神經退化性病 症或病狀（neur〇degenerative dis〇rder 〇r c〇nditi〇n)」係指 由中枢神經系統中神經元之功能障礙及/或死亡所引起之病 症或病狀。此等病症及病狀之治療可藉由投予如下藥劑來 促進’該藥劑預防處於此等病症或病狀之風險中的神經元 之功能障礙或死亡及/或增強損傷或健康神經元之功能，以 便補償由風时之神經元之功能障礙或死亡所引起之功能 損失。如本文所用，術語「神經營養藥齊！（親她〇他 咖)」係指具有一些或所有此等性質之物質或藥劑。 可根據本發明治療之神經退化性病症及病狀之實例包 括（但不限於）帕金森氏病；亨丁頓氏病；癡呆’例如阿 兹海默氏病、多梗塞性癡呆、細S相關之癡呆及額顳療呆. 與腦創傷相關之神經退化；肖中風相關之神經退化、與腦 =::之！經退化；低血糖症誘發之神經退化；與痛癇 神經退化；與神經毒素中毒相關之神經退化； 及多糸統萎縮。 及串'ίίίΓ之—具體實例中’神經退化性病症或病狀涉 〜'者之、、文狀體棘神經元介質之神經退化。 二::r—具體㈣’神經一或病狀 在另-具雜實例令，本發明提供，種治療患者以減少 24 201215607 體脂肪或體重或治療非需胰島素性糖尿病（NIDDM)、代謝 症候群或葡萄糖不耐之方法，該方法包含向有需要之患者 投予本發明化合物。在一些具體實例中，患者超重或肥胖， 且經口投予本發明化合物。在另一較佳具體實例中，該方 法進一步包含向患者投予第二治療劑，較佳抗肥胖藥，例 如利莫納班（rimonabant )、羅氏鮮（〇rHstat )、諾美婷 (SibUtramine )、溴麥角環肽（br〇m〇criptine )、麻黃素 (ephedrine)、瘦素（leptin)、假麻黃素（pseud〇ephedrine) 或肽YY3-36或其類似物。 如本文所用，術語「代謝症候群（metab〇lic syndr〇me )」 係指使人處於冠狀動脈病之高風險下的病狀群。此等病狀 包括2型舖屈；戌、hp _古/ π ——.The fourth edition of Disorders (DSM_IV) has divided addiction into three phases: preoccupation/expectation, carnival/excitement, and withdrawal/negative emotions. The characteristics of these stages are continuous cravings and concentrating on the acquisition of substances; use of more substances than necessary to experience the intoxicating effect; and experience of tolerance, withdrawal symptoms and reduced motivation for normal life activities. The invention further provides a method of treating a condition in a patient comprising a lack of attention and/or a lack of cognitive ability as a condition, the method comprising administering to the patient 23 201215607 an amount of a compound of the invention effective to treat the condition. Other conditions that may be treated in accordance with the present invention are obsessive-compulsive disorder, Tourette's syndrome, and other tic disorder. As used herein, and unless otherwise indicated, "neur degenerative disorder or condition (neur〇degenerative dis〇rder 〇rc〇nditi〇n)" refers to dysfunction and/or death of neurons in the central nervous system. The condition or condition caused. The treatment of such conditions and conditions can be facilitated by the administration of an agent that prevents dysfunction or death of neurons in the risk of such conditions or conditions and/or enhances the function of the injury or healthy neurons. In order to compensate for the loss of function caused by dysfunction or death of neurons in the wind. As used herein, the term "neurotrophic drug!" (affinity) refers to a substance or agent that has some or all of these properties. Examples of neurodegenerative disorders and conditions that may be treated in accordance with the present invention include, but are not limited to, Parkinson's disease; Huntington's disease; dementia such as Alzheimer's disease, multi-infarct dementia, fine S correlation Dementia and frontotemporal therapy. Neurodegeneration associated with brain trauma; Xiao Defeng related neurodegeneration, and brain =::! Degenerative; hypoglycemia-induced neurodegeneration; neurodegeneration with painful epilepsy; neurodegeneration associated with neurotoxin poisoning; and polydipsia atrophy. And the string 'ίίίΓ—in the specific example, the neurodegenerative disorder of the neurodegenerative disorder or the condition of the sinusoidal neuron. Two:: r - specific (four) 'neural one or condition in another - with examples, the present invention provides a treatment for patients to reduce 24 201215607 body fat or body weight or treatment of non-insulinemia diabetes (NIDDM), metabolic syndrome or A method of glucose intolerance comprising administering a compound of the invention to a patient in need thereof. In some embodiments, the patient is overweight or obese and orally administered a compound of the invention. In another preferred embodiment, the method further comprises administering to the patient a second therapeutic agent, preferably an anti-obesity agent, such as rimonabant, 〇rHstat, and SibUtramine. , bromocriptine (br〇m〇criptine), ephedrine, leptin, pseudoephedrine or peptide YY3-36 or an analogue thereof. As used herein, the term "metab〇lic syndr〇me" refers to a group of conditions that place a person at a high risk of coronary artery disease. These conditions include type 2 paving; 戌, hp _ ancient / π ——.

併入一般（以達法律所允許之最大程度）。Incorporate in general (to the maximum extent permitted by law).

例如（for instance/for 25 201215607 example/e.g)」及「因而（assuch)」）僅意欲更好地說明本 發明，且不會對本發明之範疇造成限制。 為方便起見僅將專利文獻引用及併入本文中，且不反 映該等專利文獻之有效性、專利性及/或執行性之任何觀點。 本發明包括如適用法律所允許之隨附申請專利範圍中 所述之容許物質（patient-matter )的所有修改及等效物。 實驗部分 製備本發明化合物 本發明之通式la及lb之化合物可如以下反應流程中所 述製備。除非另外指出，否則在以下反應流程及討論中， Ri至R5如上文所定義。 以下流程1描述式2之烷基_[4_(雜芳基甲氧基）_苯基 胺與式3之雜環羧酸之衍生物之間的偶合反應，產生式la 之雜環4 -烧氧基醯苯胺。For example, (for instance/for 25 201215607 example/e.g) and "as" are intended to be illustrative only and not to limit the scope of the invention. For the sake of convenience, only the patent documents are cited and incorporated herein by reference. The present invention includes all modifications and equivalents of the patient-matter described in the accompanying claims, as permitted by applicable law. Experimental Section Preparation of Compounds of the Invention The compounds of the formula la and lb of the present invention can be prepared as described in the following reaction schemes. Unless otherwise indicated, in the following reaction schemes and discussion, Ri to R5 are as defined above. Scheme 1 below illustrates the coupling reaction between an alkyl group of formula 2, [4-(heteroarylmethoxy)-phenylamine, and a derivative of a heterocyclic carboxylic acid of formula 3, to give a heterocyclic 4-burner of formula la Oxalaniline.

地^中X可為羥基或適合離去基，例如氣。此反應典型 t在諸如二氯甲燒之溶劑中，視情況在碳酸鹽驗或胺驗存 、勺〇 C至約2 0 0 C之溫度範圍内進行。其他適合溶 26 201215607 劑包括甲苯、苯、氯仿、二曝烧、乙腈、乙酸乙酷、2-丙醇 及二曱苯。較佳視情況使用微波烘箱，在回流下在甲苯與 2_丙醇之溶劑混合物中加熱反應物約2小時至約24小時。 X為羥基時，流程丨中所述之反應亦宜藉由使用例如二 環己基碳化二亞胺（DCC )之偶合劑來進行。典型地，在室 溫下搜拌式2化合物、式3化合物與適合偶合劑之混合物 24小時，之後藉由製備型HpLC純化產物以獲得所需產物。 式2之起始物質可藉由例如DE 3 6073 82及US 5 157039 中所述之方法來製備。式3之起始物質可購得或可藉由此 項技術中已知之方法來製備。 以下流程2描述式4之烷基-[4-(雜芳基甲氧基）_苯基]_ 致酸與式5之雜環胺之衍生物之間的偶合反應，產生式lb 之雜環4-烧氧基苯甲醯胺化合物。 流程2 hetX may be a hydroxyl group or a suitable leaving group such as a gas. This reaction is typically carried out in a solvent such as dichloromethane, optionally in the range of carbonate or amine storage, scoop C to about 20,000 C. Other suitable solvents 26 201215607 agents include toluene, benzene, chloroform, two exposure, acetonitrile, ethyl acetate, 2-propanol and diphenylbenzene. Preferably, the reactant is heated in a solvent mixture of toluene and 2-propanol under reflux for about 2 hours to about 24 hours using a microwave oven. When X is a hydroxyl group, the reaction described in the scheme is also preferably carried out by using a coupling agent such as dicyclohexylcarbodiimide (DCC). Typically, a mixture of a compound of formula 2, a compound of formula 3 and a suitable coupling agent is admixed at room temperature for 24 hours, after which the product is purified by preparative HpLC to obtain the desired product. The starting materials of the formula 2 can be prepared by the methods described in, for example, DE 3 6073 82 and US Pat. No. 5,157,039. The starting materials of formula 3 are either commercially available or can be prepared by methods known in the art. Scheme 2 below illustrates the coupling reaction between an alkyl-[4-(heteroarylmethoxy)-phenyl]-acid of formula 4 and a derivative of a heterocyclic amine of formula 5 to yield a heterocyclic ring of formula lb 4-alkoxybenzamide compound. Process 2 het

HN—het2 R1 Ο I R1 oHN—het2 R1 Ο I R1 o

lb ”中X可為經基或適合離去基，例士口 t。此反應典型 地在諸如二氯甲烧之溶劑中，視情況在碳酸鹽驗或胺驗存 在下二在約(TC約200。。溫度範圍内進行。其他適合溶劑包 括甲本、本、氣仿、二曝燒、乙腈、乙酸乙醋、2-丙醇及二 27 201215607 甲苯。較佳視情況使用微波烘箱，在回流下在曱苯與2_丙 醇之溶劑混合物中加熱反應物約2小時至約24小時。 X為羥基時，流程2中所述之反應亦宜藉由使用例如二 環己基碳化二亞胺（DCC )之偶合劑來進行。典型地，在室 溫下攪拌式4化合物、式5化合物與適合偶合劑之混合物 24小時，之後藉由製備型HPLC純化產物獲得所需產物。 式4之起始物質可藉由例如US 2007155779, AlexandriaX in lb" may be a transradical or a suitable leaving group, such as t. This reaction is typically carried out in a solvent such as dichloromethane, optionally in the presence of a carbonate or amine test. 200. The temperature range is carried out. Other suitable solvents include A, Ben, V, II, acetonitrile, ethyl acetate, 2-propanol and II 27 201215607 toluene. It is preferred to use a microwave oven at reflux The reaction is heated in a solvent mixture of toluene and 2-propanol for about 2 hours to about 24 hours. When X is a hydroxyl group, the reaction described in Scheme 2 is also preferably carried out by using, for example, dicyclohexylcarbodiimide ( The coupling of the compound of formula 4, the compound of formula 5 and a suitable coupling agent is stirred at room temperature for 24 hours, after which the product is purified by preparative HPLC to obtain the desired product. Substances can be made, for example, by US 2007155779, Alexandria

Journal of Pharmaceutical Sciences (1991), 5(1), 16-20 ；Journal of Pharmaceutical Sciences (1991), 5(1), 16-20;

Journal of Medicinal Chemistry (2009)，52(16)，5188-5196 ; 及 Journal of Medicinal Chemistry (1991)，34(5)，17〇4_7 中 所述方法來製備。式5之起始物質可購得或可藉由此項技 術中已知之方法來製備。 本文所揭示之本發明進一步藉由以下非限制性實施例 說明。 製備中間物 一般方法 使用以下方法中之一者獲得分析型LC-MS資料。 使用裝備有大氣壓光電離及Shimadzu LC-SA/iSLCUOA LC 系統之 PE Sciex API 150EX 儀器。管柱：4 6x3〇 mmPrepared by the method described in Journal of Medicinal Chemistry (2009), 52(16), 5188-5196; and Journal of Medicinal Chemistry (1991), 34(5), 17〇4-7. The starting materials of Formula 5 are either commercially available or can be prepared by methods known in the art. The invention disclosed herein is further illustrated by the following non-limiting examples. Preparation of Intermediates General Methods Analytical LC-MS data were obtained using one of the following methods. A PE Sciex API 150EX instrument equipped with an atmospheric pressure photoionization and Shimadzu LC-SA/iSLCUOA LC system was used. String: 4 6x3〇 mm

Waters Symmetry C18 管柱，粒度為 3.5 μηι;管柱溫度：6〇°c ; 溶劑系統·· A=水/三氟乙酸（100:0.05)且B =水/乙猜/三氟乙 酸（5:95:0.035 );方法：線性梯度溶離，其中2.4分鐘内 A:B = 90:10 至 〇:!〇〇，且流動速率為 3.3 mL/min。 28 201215607 用具有大氣壓化學電離之PE Sciex API 150EX儀器執 行製備型LC-MS純化。管柱：50x20 mm YMC ODS-A，粒 度為5 μιη ;方法：線性梯度溶離，7分鐘内A:B = 80:2〇至 0:1 00且流動速率為22.7 mL/min。藉由分流MS偵測執行溶 離份收集。 經 Bruker Avance AV500 儀器在 500.13 MHz 下或經Waters Symmetry C18 column, particle size 3.5 μηι; column temperature: 6 ° ° C; solvent system · A = water / trifluoroacetic acid (100: 0.05) and B = water / B guess / trifluoroacetic acid (5: 95:0.035); Method: Linear gradient elution with A:B = 90:10 to 〇:!〇〇 in 2.4 minutes and a flow rate of 3.3 mL/min. 28 201215607 Preparative LC-MS purification was performed using a PE Sciex API 150EX instrument with atmospheric pressure chemical ionization. Column: 50x20 mm YMC ODS-A, particle size 5 μιη; Method: Linear gradient elution, A:B = 80:2 〇 to 0:1 00 and flow rate 22.7 mL/min in 7 minutes. The fraction collection was performed by shunt MS detection. Via Bruker Avance AV500 instrument at 500.13 MHz or via

Bruker Avance DPX250 儀器在 250.13 MHz 下記錄丨H NMR 光譜。TMS用作内部參考標準。化學位移值以ppm表示。 以下縮寫用於表示NMR信號之多重性：S =單峰、d =二重峰、 二重峰、q=四重♦、qui =五重峰、h=七重峰、dd=雙二重 峰、dt=雙三重峰、dq=雙四重峰、tt=三個三重峰、多重 峰、br s=寬單峰且br=寬信號。 縮寫係根據 the ACS Style Guide: 「The ACS Styleguide-A manual for authors and editors」Janet S. D〇dd 編，1997, ISBN: 0841234620 得到。 N-(4-經基-苯基）_曱醢胺The Bruker Avance DPX250 instrument recorded 丨H NMR spectra at 250.13 MHz. TMS is used as an internal reference standard. Chemical shift values are expressed in ppm. The following abbreviations are used to indicate the multiplicity of NMR signals: S = singlet, d = doublet, doublet, q = quadruple ♦, qui = quintuple, h = sigmoid, dd = doublet, Dt = double triplet, dq = double quartet, tt = three triplet, multiplet, br s = broad singlet and br = wide signal. The abbreviations are obtained according to the ACS Style Guide: "The ACS Styleguide-A manual for authors and editors", Janet S. D〇dd, 1997, ISBN: 0841234620. N-(4-carbyl-phenyl)-decylamine

向 HCO〇H( 72 g，1·37 mol)與 ZnO( 18.3 g，0.229 mol) 之混合物中添加4_胺基苯酚（5〇 g，0.458 m〇l )，接著在7〇〇c 下用磁性授拌器授拌反應混合物。反應進程藉由TLC (石Add 4-aminophenol (5〇g, 0.458 m〇l) to a mixture of HCO〇H (72 g, 1.37 mol) and ZnO ( 18.3 g, 0.229 mol), followed by 7 〇〇c The magnetic stirrer is used to mix the reaction mixture. Reaction process by TLC (stone

29 S 201215607 油鍵：EtOAc=l:l)監測。反應完成之後，將500 mL EtOAc 添加至反應混合物中’且藉由過濾移除ZnO。用h20 ( 250 mL><4 )、飽和NaHC03( 25 0 mL )洗務有機層，經無水Na2S〇4 乾燥且真空濃縮，得到2 1 g呈暗紅色固體狀之n_(4_經基_ 苯基）-曱醯胺。 Ν·[4-(喹啉-2-基甲氧基）-苯基】_甲醯胺29 S 201215607 Oil key: EtOAc = l: l) Monitoring. After the reaction was completed, 500 mL of EtOAc was added to the reaction mixture' and ZnO was removed by filtration. The organic layer was washed with h20 (250 mL) <4>, sat. NaHC.sub.3 (250 mL), dried over anhydrous Na? Phenyl)-guanamine. Ν·[4-(quinolin-2-ylmethoxy)-phenyl]-carboxamide

在回流下撥拌Ν-(4-經基-苯基）·曱醯胺（1 mmol )、2-氯甲基-啥淋（1.3 g，7.3 mmol )與 K2CO3(4.0g， 14.9 mmol)於無水CH3CN ( 1〇 mL)中之混合物隔夜。過 慮反應混合物且真空濃縮波液’得到2· 1 g粗產物N- [4-(σ奎 琳-2-基甲氧基）_苯基]-曱醯胺’其未經進一步純化即用於下 一 步。 甲基-[4-(喹啉-2-基甲氧基）-苯基卜胺Under reflux, mix Ν-(4-carbyl-phenyl)-guanamine (1 mmol), 2-chloromethyl-phosphonium (1.3 g, 7.3 mmol) and K2CO3 (4.0 g, 14.9 mmol) The mixture in anhydrous CH3CN (1 mL) was taken overnight. The reaction mixture was taken care of and the mixture was concentrated in vacuo to give 2·1 g of crude product N-[4-(σ quinolin-2-ylmethoxy)-phenyl]-indoleamine, which was used without further purification. Next step. Methyl-[4-(quinolin-2-ylmethoxy)-phenylethylamine

30 201215607 在冰浴中，向粗產物n_[4_(喹啉_2_基曱氧基）苯基]_甲 醯胺（2.1 g，7.5 mmol )於15〇 無水THF中之溶液中緩 It 添加 LiAlH4 ( 0.86 g ’ 22.5 mmol)。1〇 小時之後，藉由 15 mL 1〇〇/0 NH4C1 及 1〇 mL 4〇% K2C〇3 中止反應。經 Na2S〇4 乾燥有機層且真空濃縮。藉由矽膠管柱層析（石油 醚：Et〇Ac=5:1)純化殘餘物，得到0.6 g甲基-[4-(喹啉-2-基曱乳基）-苯基]-胺。 ‘（喹啉-2-基甲氧基）_苯甲酸30 201215607 In the ice bath, add the crude product n_[4_(quinoline-2-yloxy)phenyl]-formamide (2.1 g, 7.5 mmol) in 15 〇 anhydrous THF. LiAlH4 (0.86 g '22.5 mmol). After 1 hour, the reaction was stopped by 15 mL of 1 〇〇/0 NH4C1 and 1 〇 mL 4〇% K2C〇3. The organic layer was dried with EtOAc (EtOAc m. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc ‘(Quinolin-2-ylmethoxy)-benzoic acid

在回流下攪拌化合物N_甲氧基_N甲基_4(喹啉_2_基曱 氧基）-苯甲醯胺（5.0 g，〇 〇15 於3〇 mL 2 N Na〇H中 之/¾。物直至TLC(石油鍵：Et〇Ac=1:1)顯示化合物4完全 耗盡。冷部混合物至室溫且藉由濃酸化至pH=3。藉由 過慮收集白色固體且真空乾燥得到2 2 g (嗜淋_2_基曱氧 基）-苯曱酸。 實施例1 w甲基-iV-[4-(喹琳-2-基甲氧基）_笨基]異於驗酿胺 31 201215607The compound N_methoxy_Nmethyl-4 (quinolin-2-yloxy)-benzamide (5.0 g, 〇〇15 in 3〇mL 2 N Na〇H was stirred under reflux) The product until TLC (petroleum bond: Et 〇Ac = 1:1) showed that compound 4 was completely consumed. The mixture was cooled to room temperature and concentrated to pH = 3. The white solid was collected by vacuum and dried in vacuo. 2 2 g (menosin-2-yloxy)-benzoic acid was obtained. Example 1 w-methyl-iV-[4-(quinolin-2-ylmethoxy)-styl] Amine amine 31 201215607

在室溫下攪拌甲基-[4-(喹啉-2-基曱氧基）-苯基]-胺 (〇_3 g，1.14 mmol)、異於驗醯氯（〇·3 g’ 2.13 mmol)與 Et3N (0.516 g，5.1 mmol)於 20 mL CH2CI2 中之混合物 6 小時，直至TLC (石油醚：EtOAc =1:1)指示起始物質幾乎Stir the methyl-[4-(quinolin-2-ylindolyl)-phenyl]-amine (〇_3 g, 1.14 mmol) at room temperature, different from the test chlorine (〇·3 g' 2.13 Mixture of Et3N (0.516 g, 5.1 mmol) in 20 mL CH2CI2 for 6 h until TLC (petrole ether:EtOAc = 1:1)

iNajnLUV-/3 T 耗盡。藉由20 mL飽和 稀釋。分離所得有機層，用鹽水（20 mL)洗滌，細無水iNajnLUV-/3 T is exhausted. Dilute with 20 mL of saturation. The resulting organic layer was separated and washed with brine (20 mL)

MgS〇4乾燥有機層且過據。真空濃縮滤液得到；色 餘物。m：«殘餘物得 g、色隻 基甲氧基）·苯基]•異終驗酿胺。.g Ψ基暴[4·(㈣-2- 類似地製備以下化合物： • 2 -0比咬-4 -基-售唾-4 _田 哩4甲醆甲基_[4(啥琳- 基]-醯胺 丞Τ乳基）-本 • 2 - °比咬-3 -基-» 塞。坐_ 4 基]-醯胺 甲酸·甲基-[4-(啥琳 2~基甲氧基）-苯 •5-吡啶-2-基-1Η-吡哇 苯基]-酼胺 甲酸甲基-[4-(喹琳 '2-基甲 氧基 • 5 -D比咬-3 -基-1Η -。比。坐_ 3 苯基]-酿胺 -甲酸曱基-[4-(喹嘴 •2-基甲 氧基）- • 5- η比。定-4-基-1Η- »比。坐 苯基]-醯胺 甲酸甲基-[4-(喹琳 '2-基甲氧基）_ 32 201215607 •苯并噻唑-6-甲酸甲基_[4_(喹啉_2_基甲氧基）_苯基卜醯胺 實施例2 N-甲基-N-啦啶·4_基_4_(喹啉_2_基甲氧基）_苯曱醯胺The organic layer was dried by MgS〇4 and passed through. The filtrate was concentrated in vacuo to give a residue. m: «residues get g, color only methoxy) · phenyl] • different final amines. .g ΨBased violence [4·((四)-2- Similarly prepared the following compounds: • 2 -0 than bite -4 - base - sold saliva-4 _ 哩 哩 4 醆 methyl _ [4 (啥琳-基]-Amidoxime-based milk base)-Ben•2-° than bite-3-yl-» plug. Sit_4 base]-protonic acid methyl-[4-(啥琳2~基methoxy) - Benzene 5-pyridin-2-yl-1 Η-pyridylphenyl]-guanidinoic acid methyl-[4-(quinolin'2-ylmethoxy•5-D ratio bit-3-yl- 1Η -. ratio. sit _ 3 phenyl]-bristamine-formic acid thiol-[4-(quinoin-2-ylmethoxy)- • 5- η ratio. -4-yl-1Η- » ratio Phenyl]-guanidinecarboxylic acid methyl-[4-(quinolin'2-ylmethoxy)_ 32 201215607 • Benzothiazole-6-carboxylic acid methyl _[4_(quinoline_2_yl group) Oxy) phenyl phenyl hydrazide Example 2 N-methyl-N-p-pyridyl 4-yl-4-(quinoline-2-ylmethoxy)-benzoguanamine

在室溫下攪拌4_(喹啉_2_基甲氧基）_苯甲酸（〇.465 g， 1 mmol)、甲基·〇比咬 _4_基-胺（0108 g，1 ^πιοί )、HBTU( 0.76 g’ 2mmol)、DIPEA ( 0.684 g，5.3 mmol)於無水 DMF ( 5 mL )中之混合物隔夜。真空濃縮混合物且藉由矽膠管柱層 析（石油醚：EtOAc=l:l )預先純化殘餘物，在合併由i 5 g 4-(喹啉-2-基曱氧基）-苯曱酸製備之另一批之後得到總計 12 g N-曱基-N-吡啶-4-基-4-(喹啉-2_基甲氧基）·苯曱醢胺。 類似地製備以下化合物： •N-(苯并[d]噻唑-6-基）-N-甲基-4_(喹啉_2_基甲氧基）苯甲醯 胺 •N-(苯并[d]聘唑-6-基）-N-甲基-4-(喹啉-2-基曱氧基）苯曱醯 胺 •N-(咪唑并[ij-a]吡啶_6_基）甲基_4_(喹啉_2_基曱氧基） 苯曱醯胺 •N-甲基_4_(喹啉_2_基甲氧基三唑并比啶 •6-基-苯甲醯胺 33 201215607 N-([l，2,4]二嗤并[154]吡咬_7_基）_N_甲基4-(喹琳_2基曱 氧基）苯曱醯胺 實施例3 N-甲基_Ν·(4-((1_甲基_1H-苯并【d]咪唑_2基）甲氧基）苯基） 笨并[d]養唾-6-甲醯胺 於丙酮（30 mL，400 mmol )中攪拌N-(4-羥苯基）-N-甲基苯并[d]°塞唑-6-甲醯胺（ 200 mg，〇·7 _〇1)、2_(氣曱 基）-1-曱基-1Η-苯并[d]咪唑（160 mg ’ 0.77 mmol )、碳酸鉋 (460 mg ’ 1.4 mmol)及碘化鉀（23 0 mg，1_4 mmol)且在 回流下加熱21小時《使冷卻的反應物與丨〇〇 mL H20混合 且用 1x100 mL EtOAc、2x5 0 mL EtOAc 萃取，且經 MgS04 乾燥合併之有機相’過濾且真空移除溶劑。藉由急驟層析 經24 g二氧化矽管柱（溶離劑：1 〇〇%正庚烷至1 〇〇%Et〇Ac ) 純化萃取物，得到呈白色固體狀之產物（289 mg，96% )。 HRMS: (M+H+: C24H21N402S)計算值：429.1379，實 驗值.429.1380，偏差：0.001 ppm。 *H NMR: (500 MHz, DMSO) δ 9.41 (s, 1H), 8.15 (s, 1H), 7.88 (d, J= 8.2 Hz, 1H), 7.63 (d, J= 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.37 (d, 7 = 8.1 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H)} 7.22 (t, 7.6 Hz, 1H), 7.17 (d, J = 8.5 Hz, 2H), 6.99 (d, / = 8.5 Hz，2H)，5.33 (s，2H)，3.79 (s，3H)，3.36 (s，3H) 〇Stir 4_(quinolin-2-ylmethoxy)-benzoic acid (〇.465 g, 1 mmol) at room temperature, methyl 〇 咬 _4_ yl-amine (0108 g, 1 ^ πιοί ) A mixture of HBTU (0.76 g' 2 mmol), DIPEA (0.684 g, 5.3 mmol) in dry DMF (5 mL) overnight. The mixture was concentrated in vacuo and purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc A further batch was obtained after a total of 12 g of N-mercapto-N-pyridin-4-yl-4-(quinolin-2-ylmethoxy)benzophenone. The following compounds were prepared analogously: • N-(benzo[d]thiazol-6-yl)-N-methyl-4_(quinolin-2-ylmethoxy)benzamide® N-(benzo[ d] oxazol-6-yl)-N-methyl-4-(quinolin-2-yloxy)benzamide•N-(imidazo[ij-a]pyridine_6_yl) A Base_4_(quinolin-2-yloxy) benzoguanamine•N-methyl_4_(quinoline-2-ylmethoxytriazolopyridinyl-6-yl-benzamide 33 201215607 N-([l,2,4]diindolo[154]pyridyl-7_yl)_N_methyl 4-(quinolin-2-yloxy)benzamide Example 3 N-A Base_Ν·(4-((1_methyl_1H-benzo[d]imidazolyl-2-yl)methoxy)phenyl) benzo[d]salt-6-carboxamide in acetone (30 N-(4-hydroxyphenyl)-N-methylbenzo[d]°-pyrazole-6-carboxamide (200 mg, 〇·7 _〇1), 2_ (gas) in mL, 400 mmol) Mercapto)-1-indolyl-1Η-benzo[d]imidazole (160 mg '0.77 mmol), carbonic acid planing (460 mg '1.4 mmol) and potassium iodide (23 0 mg, 1-4 mmol) and heated under reflux 21 Hour "The cooled reaction was mixed with 丨〇〇mL H20 and extracted with 1 x 100 mL EtOAc, 2 x 50 mL EtOAc and dried with EtOAc. Filtration and removal of the solvent in vacuo. Purification of the extract by flash chromatography on a 24 g s[pi] s s s s s s s s s s s s s s s s s s s Product (289 mg, 96%). HRMS: (M+H+: C24H21N402S) Calculated: 429.1379, Calculated: 429.1380, Deviation: 0.001 ppm. *H NMR: (500 MHz, DMSO) δ 9.41 (s, 1H) , 8.15 (s, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.37 (d, 7 = 8.1 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H)} 7.22 (t, 7.6 Hz, 1H), 7.17 (d, J = 8.5 Hz, 2H), 6.99 (d, / = 8.5 Hz, 2H ), 5.33 (s, 2H), 3.79 (s, 3H), 3.36 (s, 3H) 〇

化學名稱 滞留時間 UV ELSD MS 純度 純度 （M+H+) N-甲基-N-。比啶-4-基-4-(喹啉-2-基曱氧基)-0.66 100 100 370.15 34 201215607 苯曱醯胺 N-(苯并[d]噻唑-6-基)-N-曱基-4-(喹啉-2- 2.77 基甲氧基)苯甲醯胺 99.48 100 426.12 N-(苯并[d]聘唑-6-基)-N-曱基-4-(喹啉-2- 2.78 基曱氧基)苯甲醯胺 95.71 93.3 410.14 N-(咪唑并[1，2-a]吡啶-6-基)-N-曱基-4-(喹2.11 啉-2-基甲氧基)苯甲醯胺 96.68 100 409.16 N-曱基-4-(喹啉-2-基曱氧基)-N-[l，2,4]三1.03 唑并[1,5-a]吡啶-6-基-苯甲醯胺 99.3 100 410.15 N-([l，2,4]三唑并[l，5-a]吡啶-7-基)-N-甲基 2.55 -4-(喹啉-2-基曱氧基)苯甲醯胺 97.78 100 410.15 2-吡啶-3-基-噻唑-4-甲酸曱基-[4-(喹啉-2- 0.89 基曱氧基)-苯基]-醯胺 88.98 100 453.13 2-吡啶-4-基-噻唑-4-曱酸甲基-[4-(喹啉-2- 0.77 基甲氧基)_苯基]-酿胺 100 100 453.13 2-吡啶-3-基-噻唑-4-甲酸甲基-[4-(喹啉-2- 0.87 基甲氧基)-苯基]-醯胺 96 100 453.13 5-吡啶-2-基-1H-吡唑-3-曱酸甲基-[4-(喹啉0.8 -2-基曱氧基)-苯基]-酿胺 93.26 100 436.17 5-吡啶-3-基-1H-吡唑-3-甲酸甲基-[4-(喹啉0.73 -2-基甲氧基)-苯基]-醯胺 93.98 100 436.17 5-吡啶-4-基-1H-吡唑-3-曱酸曱基-[4-(喹啉0.7 -2-基甲氧基)-苯基]-酿胺 99.36 100 436.17 苯并噻唑-6-曱酸曱基-[4-(喹啉-2-基甲氧0.6 基)-苯基]-醯胺 97.7 99.7 426.12 苯并噻唑-6-甲酸甲基-[4-(1-甲基-1H-苯并0.96 咪唑-2-基甲氧基)-苯基]-醯胺 99.5 100 429.13 N-曱基-N-[4-(喹啉-2-基甲氧基)-苯基]-異0.69 於驗醯胺 96 100 370.15 表1.例示性化合物之分析型化學特性 藥理學測試 PDE10A酵素Chemical name Residence time UV ELSD MS Purity Purity (M+H+) N-methyl-N-. Bispin-4-yl-4-(quinolin-2-ylmethoxy)-0.66 100 100 370.15 34 201215607 Phenylamine N-(benzo[d]thiazol-6-yl)-N-fluorenyl -4-(quinoline-2-2.77-methoxy)benzamide 99.48 100 426.12 N-(benzo[d]oxazol-6-yl)-N-mercapto-4-(quinoline-2 - 2.78 methoxyl)benzamide 95.71 93.3 410.14 N-(imidazo[1,2-a]pyridin-6-yl)-N-indolyl-4-(quino 2.11 oxa-2-ylmethoxy) Benzomethane 96.68 100 409.16 N-mercapto-4-(quinolin-2-yloximeoxy)-N-[l,2,4]tri-1.03 oxazo[1,5-a]pyridine- 6-yl-benzamide 99.3 100 410.15 N-([l,2,4]triazolo[l,5-a]pyridin-7-yl)-N-methyl 2.55 -4-(quinoline- 2-ylmethoxyoxy)benzamide 97.78 100 410.15 2-pyridin-3-yl-thiazole-4-carboxylic acid decyl-[4-(quinolin-2-0.89 decyloxy)-phenyl]- Guanamine 88.98 100 453.13 2-Pyridin-4-yl-thiazole-4-furoic acid methyl-[4-(quinoline-2-0.77-ylmethoxy)-phenyl]-bristamine 100 100 453.13 2-pyridine -3-yl-thiazole-4-carboxylic acid methyl-[4-(quinoline-2-0.87-ylmethoxy)-phenyl]-decylamine 96 100 453.13 5-pyridin-2-yl-1H-pyrazole -3-decanoic acid methyl-[4-(quinoline 0.8 -2-yloxy)-phenyl]- Amine 93.26 100 436.17 5-Pyridin-3-yl-1H-pyrazole-3-carboxylic acid methyl-[4-(quinoline 0.73 -2-ylmethoxy)-phenyl]-decylamine 93.98 100 436.17 5- Pyridin-4-yl-1H-pyrazole-3-decanoate-yl-[4-(quinoline0.7-2-ylmethoxy)-phenyl]-bristamine 99.36 100 436.17 Benzothiazole-6-oxime Acid thiol-[4-(quinolin-2-ylmethoxy0.6-yl)-phenyl]-decylamine 97.7 99.7 426.12 Benzothiazole-6-carboxylic acid methyl-[4-(1-methyl-1H- Benzo-0.96 imidazol-2-ylmethoxy)-phenyl]-nonylamine 99.5 100 429.13 N-mercapto-N-[4-(quinolin-2-ylmethoxy)-phenyl]-iso-0.69醯 醯 96 96 96 370.15 Table 1. Analytical chemical properties of exemplary compounds Pharmacological test PDE10A enzyme

活性PDE10A酵素以用於PDE檢定之許多方式來製備 (Loughney，K·等人，Gene 1999, 234, 109-117 ; Fujishige，K. 等人，Eur J Biochem. 1999，266，1118-1127 及 Soderling，S. 等人，Proc. Natl. Acad. Sci. 1999, 96, 7071-7076 )。PDE10A 可表現為全長蛋白質或截短蛋白質，只要其表現催化結構 35 201215607 域即可。PDE10A可在不同細胞類型，例如昆蟲細胞或大腸 桿菌（E. coli.)中製備。 在本發明之上下文中，催化活性之PDE1 0 A酵素由以 下方式製備：藉由標準RT-PCR使人類PDE1 0 A之催化結構 域（寄存編號NP 006652之序列之胺基酸440至779)自全 部人類腦總RNA擴增且選殖至pET28a載體（Novagen)之 BamHl及Xhol位點中。根據標準方案執行於大腸菌中之表 現。簡言之’將表現質體轉型至BL21(DE3)大腸桿菌菌株 中，且使50 mL用細胞接種之培養物生長至〇D600為〇.4 至0_6’之後用〇·5 mM IPTG誘導蛋白質表現。在誘導之後， 在室溫下培育細胞隔夜，此後藉由離心收集細胞。使表現 PDE10A 之細胞再懸浮於 12 mL ( 50 mM TRIS-HCl-pH 8.0、 1 mM MgCh及蛋白酶抑制劑）中。藉由音波處理溶解細胞， 且在所有細胞溶解之後’根據Novagen方案添加 TritonXIOO。經Q瓊脂糖部分純化PDE10A且彙集最具活性 之溶離份。 PDE10A抑制作用檢定 在本發明之上下文中，於60 μΕ含有足以使20%至25% 10 nM 3H-cAMP轉化之PDE10A及不同量之抑制劑的檢定 緩衝液（50 mM HEPES pH 7.6 ; 10 mM MgCl2 ; 0.02% Tween20 )中執行檢定。藉由添加環狀核苷酸受質起始反 應。在室溫下培育1小時之後，藉由添加1 5 pL 8 mg/mL矽 酸釔SPA珠粒（Amersham )終止反應。使珠粒在黑暗中沈 36 201215607 澱一小時，之後用WalUc 145〇 Micr〇beta計數器計數培養 盤。使用XLfit (IDBS)藉由非線性回歸計算iCs〇值。 實驗結果顯示測試之本發明化合物抑制pdei〇a酵 素’〗c50值介於約ι5ηΜ至400 nM之間，參見表2: 化合物 N-甲基-N-吡啶-4-基-4-(喹啉-2-基甲氧基)-苯甲醯胺 PDE10A ICs〇 (nM) 180 15 93 130 240 400 170 88 87 30 31 100 31 61 250 N-(苯并[d]噻唑-6-基)-N-曱基_4_(啥啉冬基甲氧基)笨甲酿 Ν-(苯并[d]腭唑-6-基)-Ν-甲基斗(喧啉I基曱氧基)笨甲醯胺 Ν-(_唑并[l，2-a]吡啶-6-基)-Ν-甲基·4_(喹啉冬基甲氧基)苯甲 Ν-曱基-4-(喹啉-2-基甲氧基)-N-[l，2,4]三唑并[l，5-a]»比啶_6-基_装甲赫脸 N-([l，2,4]三唑并[l，5-a]吡啶-7-基)-N-曱基斗(啥啉-2·基曱氧基) 2-吡啶-3-基-噻唑-4-曱酸曱基-[4-(喹咐-2-基甲氧基)_苯基]_醯胺T ^ 2-吡啶-4-基-噻唑-4-甲酸甲基-[4-(喹琳-2-基甲氧基)_苯基]_醯胺 2-吡啶-3-基-»塞唑-4-曱酸甲基-[4-(喹琳-2-基曱氧基)苯基醯胺 5-吡啶-2-基-1H-吡唑-3-甲酸甲基-[4-(喧啦·2·基甲氧基)_苯基]_酿胺 5-吡啶-3-基-1Η-0比0坐_3_曱酸甲基-[4-(喹琳-2-基甲氧基)-苯基]-醯胺 5_吡啶-4-基-1Η-吡唑各甲酸曱基-[4-(喹琳-2-基甲氧基)-苯基]-醯胺 苯并噻唑-6-甲酸甲基-[4-(喹啉-2-基甲氧基)-笨基]-醯胺 苯并噻唑-6-甲酸甲基-[4-(1-曱基-1Η-苯并咪唑-2-基甲氧基)-苯基]-醯胺 N-甲基」N-[4-(喧啉-2-基甲氧基)-苯基]-異菸鹼醯胺 表2 :例示性本發明化合物之IC50值 苯環利定（PCP)誘發之過動症 使用稱重為20至25 g之雄性小鼠（NMRI，Charles River )。在接受測試化合物（5 mg/kg )加 PCP ( 2.3 mg/kg ) 之各組中，包括僅接受測試化合物之媒劑加PCP或媒劑注 射劑之平行對照組中使用8隻小鼠。注射體積為10 ml/kg。 在未受干擾房間中在正常光條件下進行實驗。在注射PCP 之前60分鐘經口（ per oss)注入測試物質，PCP經皮下投 予0 37 201215607 試籠（20 cmx32 cm)中。由間隔4 cm之^寺別設計之測 光電池量測活性。光束越過籠底之上丨8 〇 8紅外光源及 之記錄需要令斷鄰近光束，由此避免由二豸動性計數 起之計數。 小鼠之穩定運動引 以5分鐘時間間隔記錄運動性歷暗 小時。在1小時 行為測S式期間由以下方式基於總計數計算藥效 將無PCP存在下媒劑處理所引起 十岣運動性用作基 線。因此PCP之100。/❶效應經計算為總運動性計數減基線。 因此，藉由總運動性計數減基線測定接受測試化合物i之植 中之反應’以平行PCP對照組中所記錄之類似結果之百分 數表示。將反應百分數轉化為PCP讀狢々、a 4 一 發之過動症的逆轉百 分數。 實驗結果顯示本發明化合物為逆轉PCP誘發之過動症 之活體内活性化合物，例如N-曱基_N_吡啶_4_基_4 —(喹啉-2_ 基甲氧基）-笨曱醯胺之ED5〇為10 mg/kg且化合物N曱基 -N-[4-(喹啉-2-基曱氧基）-苯基]-異菸鹼醯胺之]&〇5〇為6ι mg/kg。 【圖式簡單說明】 益 【主要元件符號說明】 無 38Active PDE10A enzymes are prepared in a number of ways for PDE assays (Loughney, K. et al., Gene 1999, 234, 109-117; Fujishige, K. et al., Eur J Biochem. 1999, 266, 1118-1127 and Soderling). , S. et al., Proc. Natl. Acad. Sci. 1999, 96, 7071-7076). PDE10A can be expressed as a full-length protein or a truncated protein, as long as it exhibits a catalytic structure 35 201215607 domain. PDE10A can be prepared in different cell types, such as insect cells or E. coli. In the context of the present invention, the catalytically active PDE10A enzyme is prepared by standard catalytic RT-PCR of the catalytic domain of human PDE10A (amino acid 440 to 779 of the sequence numbering NP 006652). All human brain total RNA was amplified and cloned into the BamHl and Xhol sites of the pET28a vector (Novagen). Performed in coliforms according to standard protocols. Briefly, 'transform the plastid into the BL21(DE3) E. coli strain, and grow 50 mL of the cell-inoculated culture to 〇D600 to 〇.4 to 0_6' and induce protein expression with 〇·5 mM IPTG. . After the induction, the cells were incubated overnight at room temperature, after which the cells were collected by centrifugation. The cells expressing PDE10A were resuspended in 12 mL (50 mM TRIS-HCl-pH 8.0, 1 mM MgCh and protease inhibitor). The cells were lysed by sonication and after all the cells were lysed, Triton XIOO was added according to the Novagen protocol. PDE10A was partially purified via Q Sepharose and the most active fractions were pooled. PDE10A Inhibition Assay In the context of the present invention, assay buffer (50 mM HEPES pH 7.6; 10 mM MgCl2) containing 60% to 25% PDE10A and a different amount of inhibitor for conversion of 20% to 25% 10 nM 3H-cAMP in the context of the present invention ; 0.02% Tween20) performs the check. The reaction is initiated by the addition of a cyclic nucleotide. After incubation for 1 hour at room temperature, the reaction was stopped by the addition of 15 pL of 8 mg/mL bismuth citrate SPA beads (Amersham). The beads were allowed to sink in the dark 36 201215607 After one hour, the plates were counted using a WalUc 145〇 Micr〇beta counter. The iCs 〇 value was calculated by nonlinear regression using XLfit (IDBS). The experimental results show that the tested compounds of the invention inhibit the pdei〇a enzyme's c50 value between about ι5ηΜ and 400 nM, see Table 2: Compound N-methyl-N-pyridin-4-yl-4-(quinoline) -2-ylmethoxy)-benzimidamide PDE10A ICs〇(nM) 180 15 93 130 240 400 170 88 87 30 31 100 31 61 250 N-(Benzo[d]thiazole-6-yl)-N - mercapto _4_(porphyrin winter methoxy) stupid Ν-(benzo[d]carbazol-6-yl)-indole-methyl ketone (porphyrin I methoxyl) Amidoxime-(-oxazolo[l,2-a]pyridin-6-yl)-indole-methyl·4_(quinolinylmethoxy)benzhydryl-mercapto-4-(quinoline-2) -ylmethoxy)-N-[l,2,4]triazolo[l,5-a]»pyridyl-6-yl-armored-face N-([l,2,4]triazole [l,5-a]pyridin-7-yl)-N-indolyl (porphyrin-2·yloxy) 2-pyridin-3-yl-thiazole-4-decanoic acid-based-[4- (quinacridin-2-ylmethoxy)-phenyl]-nonylamine T^2-pyridin-4-yl-thiazole-4-carboxylic acid methyl-[4-(quinolin-2-ylmethoxy) _Phenyl]-nonylamine 2-pyridin-3-yl-»setazole-4-furoic acid methyl-[4-(quinolin-2-yloxy)phenyl decylamine 5-pyridine-2- -1H-pyrazole-3-carboxylic acid methyl-[4-(喧啦·2·ylmethoxy)_phenyl]-bristamine 5-pyridin-3-yl-1 Η-0 to 0 sitting _3_ decanoic acid methyl-[4-(quinolin-2-ylmethoxy)-phenyl]-decylamine 5_pyridin-4-yl-1 Η-pyrazole -[4-(Quinolin-2-ylmethoxy)-phenyl]-nonylamine benzothiazole-6-carboxylic acid methyl-[4-(quinolin-2-ylmethoxy)-phenyl ]-Protonamine benzothiazole-6-carboxylic acid methyl-[4-(1-indolyl-1Η-benzoimidazol-2-ylmethoxy)-phenyl]-nonylamine N-methyl"N- [4-(Porphyrin-2-ylmethoxy)-phenyl]-isonicotinamide decylamine Table 2: Exemplary IC50 values of the compounds of the invention Benzaliride (PCP) induced hyperactivity using weighing Male mice (NMRI, Charles River) of 20 to 25 g. Eight mice were used in each of the groups receiving the test compound (5 mg/kg) plus PCP (2.3 mg/kg), including the vehicle containing only the test compound plus PCP or vehicle injection. The injection volume is 10 ml/kg. Experiments were performed under normal light conditions in undisturbed rooms. Test substances were injected orally (per oss) 60 minutes before the injection of PCP, and PCP was subcutaneously administered to 0 37 201215607 test cages (20 cm x 32 cm). The photometric battery was measured by a 4 cm interval. The beam passes over the bottom of the cage. 8 〇 8 The infrared source and its recordings need to interrupt the adjacent beam, thereby avoiding counting by the two turbulence counts. The stable movement of the mice was recorded at 5 minute intervals to record the dark hours of exercise. The efficacy was calculated based on the total count during the 1-hour behavioral test period. The tenth motility was used as the baseline due to the absence of PCP in the presence of the vehicle treatment. Therefore 100 of the PCP. The /❶ effect is calculated as the total exercise count minus the baseline. Therefore, the reaction in the plant receiving test compound i was determined by total motility count minus baseline, as expressed as a percentage of similar results recorded in the parallel PCP control group. The percentage of response was converted to a reversal percentage of PCP reading a, a 4 hyperactivity disorder. The results of the experiment show that the compound of the present invention is an in vivo active compound which reverses PCP-induced hyperactivity, such as N-mercapto_N_pyridine-4-yl-4-(quinolin-2-ylmethoxy)-crack The ED5 oxime of the amine is 10 mg/kg and the compound N-yl-N-[4-(quinolin-2-ylmethoxy)-phenyl]-isonicotin decylamine]&〇5〇 is 6ι Mg/kg. [Simple description of the diagram] Benefits [Main component symbol description] None 38

Claims (1)

201215607 七、申請專利範圍： 1. 一種化合物201215607 VII. Patent application scope: 1. A compound hetj 其中het!係選自由以下者所組成之群組 H/MeHetj where het! is selected from the group consisting of: H/Me 且其中*表示連接點，及 het2係選自由以下者所組成之群組：And wherein * indicates a connection point, and het2 is selected from the group consisting of: 且其中*表示連接點， 且其中L進一步為選自由以下者所組成之群組的連接基團：And wherein * represents a point of attachment, and wherein L is further a linking group selected from the group consisting of: 且其中R1係選自由以下者所組成之群組：C1-C6烷基，諸 39 201215607 如甲基、乙基、1-丙基、2_岛茸.田 A -U ^ . 土、，、丁基、正 丁基、第二丁 卷或第二丁基；C1-C6拉…、 土（ 3-C8)環烷基，諸如環丙基曱 基’且其中*表示連接點， 以及其互變異構體及醫藥學上可接受之酸加成鹽。 2.如申請專利範圍第！項之化合物，其巾脆_2係選自 由以下者所組成之群組：And wherein R1 is selected from the group consisting of C1-C6 alkyl, 39.201215607, such as methyl, ethyl, 1-propyl, 2_shimarong, Tian A-U ^. soil,,, Butyl, n-butyl, second butyl or second butyl; C1-C6-..., tert-(3-C8)cycloalkyl, such as cyclopropyl fluorenyl' and wherein * represents a point of attachment, and Isomers and pharmaceutically acceptable acid addition salts. 2. If you apply for a patent scope! The compound of the item, the crispy _2 is selected from the group consisting of: 3.如申請專利範圍第丨項或第2項中任一項之化合物， 其中該連接基團中之R1為CH3。 4 ·如申請專利範圍第1項之化合物，其選自由以下者所 、、且成之群組.N-甲基-N-°比唆-4-基-4-(噎淋-2-基曱氧基）-苯 甲酿胺、N-(苯并[d]噻唑_6_基）_N_曱基_4_(喹啉_2_基曱氧基） 苯曱醯胺、N-(苯并[d]腭唑-6-基）-N-甲基-4-(喹啉·2_基甲氧 基）苯甲醯胺、Ν-(咪唑并[l，2-a]吡啶-6-基）-Ν-曱基-4-(喹啉 -2-基曱氧基）苯曱醢胺、N-曱基_4-(啥琳-2-基甲氧 基）-N-[l，2,4]三唑并[i，5-a]吡啶-6-基-苯曱醯胺、n_([1，2,4] 二唑并[l，5-a]吡啶-7_基）_n-曱基-4-(喹啉-2-基甲氧基）苯曱 醯胺、2-吡啶_3-基-噻唑-4-甲酸甲基-[4-(喹啉-2-基甲氧基）_ 苯基]-醯胺、2-吡啶-4-基-噻唑-4-甲酸甲基-[4-(喹啉-2-基曱 氧基）-苯基]-醯胺、2-吡啶-3-基-噻唑-4-曱酸曱基-[4-(喹啉 -2-基甲氧基）_苯基]_醢胺、5-吡啶-2-基-1H-吡唑-3-曱酸曱基 -[4-(喹啉_2-基曱氧基）_苯基]-醯胺、5-吡啶-3-基-1士吡唑-3- 201215607 甲隨曱基-[4-(啥啉_2_基甲氧基）_苯基]_醯胺、5_吡啶_4_基 -1H-吡唑-3-甲酸甲基_[4_(喹啉_2_基甲氧基）苯基卜醯胺、苯 并噻唑_6-曱酸甲基_[4_(喹啉_2_基曱氧基苯基]_醯胺、苯并 喔。坐-6-甲酸甲基-[4_(1_甲基―丨仏苯并咪唑基甲氧基）_苯 基]-醯胺及N-甲基-N_[4_(喹啉_2_基甲氧基）苯基]•異菸鹼 醯胺。 5.如申請專利範圍第1項之化合物，其選自由以下者所 組成之群組：N-(苯并噻唑_6_基）_N_甲基_4_(喹啉_2_基甲 氧基）苯曱醯胺、5-吡啶·3_*_1Η_吡唑_3_曱酸曱基-[4·(喹啉 -2-基曱氧基）-苯基]_醯胺、5吡啶_4_基_1Η-吡唑_3_甲酸曱基 -[4-(喹啉-2-基甲氧基）_苯基]_醯胺及苯并噻唑_6_甲酸曱基 -[4-'(喹啉-2-基曱氧基）_苯基]_醯胺。 6· —種用作醫藥品的如申請專利範圍第1項至第5項中 任一項之化合物。 7 · —種單獨或與一或多種精神安定劑組合用於治療神 經退化性病症或精神病症的如申請專利範圍第1項至第5 項中任一項之化合物，該或該等精神安定劑係選自由以下 者所組成之群組：舍吲哚（sertind〇le )、奥氮平 (olanzapine )、利培酮（risperid〇ne )、喹硫平（quetiapine )、 阿立哌唑（aripiprazole)、氟哌啶醇（hal〇perid〇1)、氣氮平 (clozapine )、齊拉西酮（ziprasid〇ne )及奥沙奈坦 (osanetant) ’其中該神經退化性病症係選自由以下者所組成 之群組.阿茲海默氏病（Alzheimer,sdisease)、多梗塞性癡 呆、酒精性癡呆或其他藥物相關之癡呆、與顱内腫瘤或腦 201215607 創傷相關之#呆、與亨丁頓氏病（HUntington，s disease )或 帕金森氏病（Parkins〇nisdisease)或Aids相關之癌呆；擔 妄，失憶症；創傷後壓力症；智能障礙；學習障礙，例如 閱讀障礙、數學障礙或寫作表達障礙；注意力不足/過動症，· 及年齡相關之認知能力下降，且該精神病症係選自由以下 者所組成之群組：精神分裂症，例如偏執型m緊 張症型、未分型或剩餘類型之精神分裂症；類精神分裂症 精神障礙；分裂情感性精神障礙，例如妄想型或抑鬱型分 裂情感性精神障礙；妄想症；躁#症，例如丨型躁鬱症、η 型躁鬱症及循環情感性精神障礙；物質誘發之精神病症， 例如酒精、安非他命（卿⑻一）、大麻（c咖咖）、 可卡因（cocaine )、迷幻藥、吸入劑、.類鴻片或苯環利定 (、phenCyelidine)料之精神鲁；偏執型人格障礙；及精神 分裂症型人格障礙。 8.-種如申請專利範圍第J項至第5項中任一項之化人 ㈣用途’其係用於製備用以治療神經退化性病症或精； ’症之醫樂品，其中該神經退化性病症係選自由以下者所 組成之群組：阿茲海默氏病 多梗塞性癡呆、酒精性癡呆 ^、樂目關之癡呆、與顱内腫瘤或腦創傷相關之 呆、與予丁頓氏病或帕金森氏 疋 森氏病相關之癡呆或aids相關之 2呆，擔妄；失憶症；創傷後壓,力症;智能障礙；學習障 礙，例如閱讀障礙、數學障礙或寫作表達障礙；注音 ==年齡相關之認知能力下降，且該_症係 選自由以下者所組成之群組.：精神分裂症，例如偏執型、 42 201215607 混亂型、緊張症型、未分型或剩餘類型之精神分裂症·類 或抑鬱型分裂情二;：精神障礙，例如妄想型 型躁鬱症、π型跸鬱二及％ ’妄想症，躁鬱症，例如1 之产神症广營症及循環情感性精神障礙；物質誘發 精神病症’例如酒精、安非他命、大麻、 樂、吸入劑、類戒y + θ 4幻 ."片或本％利定誘發之精神病；偏執型人 格障礙；及精神分裂症型人格障礙。 9·=治療患有神經退化性病症或精神病症 :法二Γ神經退化性病症係選自由以下者所組成之群 二一每默氏病、多梗塞性療呆、酒精性 “目關之癌呆、與顧内腫瘤或腦創傷相關之癌呆； 帕金森氏病相關之癌呆或AIDS相關之療； 二=„傷後壓力症；智能障礙；學習障礙，例： =二數學障礙或寫作表達障礙;注意力不足/過動症; “目關之認知能力τ降’且該精神病症係選自由以下 2、、且成之群組：精神分裂症，例如偏執型、混亂型、緊 料Ίί礙未分型或剩餘類型之精神分裂症；類精神分裂症 二中：礙；分裂情感性精神障礙，例如妄想 =性精神障礙；妄想症；躁營症，例如1型躁费症、π 2鬱症及循環情感性精神障礙；物質誘發之 =精、安非他命、大麻、可卡因、迷幻藥、吸入劑、 =或苯環利定誘發之精神病；偏執型人格_; 貝及第2項中任一項之化合物或與 43 201215607 醇、氣氮平、齊拉西明及奥沙奈坦。 一或多種精神安定劑組合投予 自舍吲哚、奥氮平、利培_、 ，該或該等精神安定劑係選 喹硫平、阿立哌唑、氟哌啶 10.-種醫藥組成物，其包含如申請專利範圍第i項至 第5項中任一項之化合物及一或多種醫藥學上可接受之載 劑、稀釋劑及賦形劑。 1 1 · 一種如申請專利範 合物及選自由舍㈣、奥氮平 '利㈣ '切平、阿立痕 唑、氣0底咬醇'氣氮平、齊拉西酮及奥沙奈坦所組成之群 組的另-化合物之用途’其係用於製備用以治療神經退化 ‘生：症或精神病症之醫藥品，其中該神經退化性病症係選 自由以下者所組成之群組：阿兹海默氏病、多梗塞性癌呆、 或其他藥物相關之蠢呆、與顧内腫 :之癌呆、與亨丁頓氏病或帕金森氏病相 务 她S相關之癡呆；譫妄；失憶症；創傷後壓力症；智= :意=礙、例如閲讀障礙、數學障礙或寫作表達障礙; 二 /過動症：及年齡相關之認知能力下降，且該料 係選自由以下者所組成之群組：精神分裂： ， 、張症1、未勿型或剩餘類型之精神八 ::’類精神分裂症精神障礙；分裂情感性精神障: 型分裂.情感性精神障礙;妄想症;躁繫症： 誘發之::11型躁鬱症及猶環情感性精神障礙;物質 = 如酒精、安非他命、大麻、可卡因 貝鴉片或苯環利定誘發之精神病；偏執 44 201215607 5L人格障礙；及精神分裂症型人格障礙。 種么、同時、各別或連續用於治療神經退化性病症 或精神病症的呈組合製劑的如中請專利範圍第1項至第$ η:令任—項之化合物及選自由舍吲哚、奥氮平、利培酮、 瓜平阿立0底°坐、氣D底咬醇、氯氮平、齊拉西酮及奥沙 奈坦所組成之群組的另—化合物’其中該神經退化性病症 係選自由以下者所組成之群組：㈣海默氏病、多梗塞性 癡呆、酒精性療呆或其他藥物相關之癡呆、與顱内腫瘤或 ::傷相關之癡呆、與亨丁頓氏病或帕金森氏病相關之癡 ::p DS相關之癡呆；譫妄；失憶症；創傷後壓力症，·智 =早礙，學習障礙，例如閱讀障礙、數學障礙或寫作表達 注意力不足/過動症；及年齡相關之認知能力下降， 且該精神病症係選自由以下者所組成之群組：精神分裂 ί揞71偏執型，、混亂型、緊張症型、未分型或剩餘類型 障礙’二裂症’類精神分裂症精神障礙；分裂情感性精神 二二例::妄想型或抑誉型分裂情感性精神障礙；妄想症： :鬱：：…型躁繁症'„型螺營症及循環情 ;二：發：精神病症，例如酒精、安非他命、大麻、 病m幻樂 ' 吸入劑 '類鸦片或苯環利定誘發之精神 偏執型人格障礙；及精神分裂症型人格障礙。 13 · 一種用於治療神經很札 專利範圍第！項至第5項中任’病§症或精神病症的如申請 退化性病症係選自由以下者所二之化合物，其中該神經 病、多梗塞性癡呆、酒精早且成之群組：阿兹海默氏 ’疑呆或其他藥物相關之癡呆、 45 201215607 與顱内腫瘤或腦創傷相關之癌呆、 氏病相關之癡呆或她相關之癡平、氏病或帕金森 後麼力症；智能障礙；學習障礙詹妄；失憶症；創傷 于S阼礙，例如閲讀障礙、數學障 礙或寫作表達障礙；注意力 ^數千障 知能力下降，且該精神病症传選自：，及年齡相關之認 植.夢純八划 神病症係選自由以下者所組成之群 ，、’精神刀裂症，例如偏執型、混亂型 型或剩餘類型之精神分 ’、;正尘、未刀 裂情感性精神_ 症㈣障礙；分 障礙.妄_ r. 妄想型或抑鬱型分裂情感性精神 =妄想症，躁鬱症，例如I型躁替症、Π型躁鬱症及循 裱情感性精神障礙.& # 玉卞鬱症及循 非他命、大麻二卡Γ:發ΐ精神病症，例如酒精、安 利定誘發之精n偏/、幻樂、吸人劑、_片或苯環 格障礙。申病，偏執型人格障礙， ·及精神分裂症型人 八、圖式： (無） 463. The compound according to any one of the preceding claims, wherein R1 in the linking group is CH3. 4. A compound as claimed in claim 1 which is selected from the group consisting of: N-methyl-N-° than 唆-4-yl-4-(anthene-2-yl)曱oxy)-benzamide, N-(benzo[d]thiazole-6-yl)_N_indenyl_4_(quinolin-2-yloxy)benzamide, N-(benzene And [d] carbazol-6-yl)-N-methyl-4-(quinoline-2-ylmethoxy)benzamide, hydrazine-(imidazo[l,2-a]pyridine-6 -yl)-fluorenyl-mercapto-4-(quinolin-2-ylmethoxy)phenylamine, N-fluorenyl-4-(indolyl-2-ylmethoxy)-N-[l , 2,4]triazolo[i,5-a]pyridin-6-yl-benzoguanamine, n_([1,2,4] oxazolo[l,5-a]pyridine-7-yl )_n-mercapto-4-(quinolin-2-ylmethoxy)phenylamine, 2-pyridine-3-yl-thiazole-4-carboxylic acid methyl-[4-(quinolin-2-yl) Methoxy)-phenyl]-nonylamine, 2-pyridin-4-yl-thiazole-4-carboxylic acid methyl-[4-(quinolin-2-ylmethoxy)-phenyl]-decylamine, 2-pyridin-3-yl-thiazol-4-indole decyl-[4-(quinolin-2-ylmethoxy)-phenyl]-decylamine, 5-pyridin-2-yl-1H-pyridyl Oxazol-3-indole decyl-[4-(quinolin-2-yloxy)phenyl]-decylamine, 5-pyridin-3-yl-1 syrazole-3-201215607 -[4-(porphyrin-2-ylmethoxy)phenyl]-decylamine, 5-pyridine-4-yl-1H-pyrazole-3-carboxylic acid methyl-[4_(quinoline_2_ Methoxy)phenyl hydrazide, benzothiazole -6-decanoic acid methyl _[4_(quinolin-2-yloxyphenyl)-decylamine, benzopyrene. Methyl-[4_(1_methyl-indolezimidazolylmethoxy)phenyl]-nonylamine and N-methyl-N_[4_(quinolin-2-ylmethoxy)phenyl An isonicotinium amide. 5. A compound according to claim 1 which is selected from the group consisting of N-(benzothiazole-6-yl)_N_methyl_4_(quinine啉_2_ylmethoxy)phenylamine, 5-pyridine·3_*_1Η_pyrazole_3_decanoic acid-[4·(quinolin-2-ylmethoxy)-phenyl] _ guanamine, 5 pyridine _4_ yl 1 Η-pyrazole _3 carboxylic acid decyl-[4-(quinolin-2-ylmethoxy) phenyl] decylamine and benzothiazole _6_ Mercaptocarboxylic acid-[4-'(quinolin-2-ylindoleoxy)-phenyl]-decylamine. 6-- for use as a pharmaceutical product, as in any of claims 1 to 5 a compound of the formula 7 - alone or in combination with one or more neuroleptics for the treatment of neurodegenerative or psychiatric disorders The compound of any one of claims 1 to 5, wherein the neuroleptic is selected from the group consisting of: sertind〇le, olanzapine ), risperid〇ne, quetiapine, aripiprazole, haloperidol (hal〇perid〇1), clozapine, ziprasidone Ziprasid〇ne and osanetant 'where the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, multiple infarct dementia, alcoholic dementia or Other drug-related dementia, cancer associated with intracranial tumor or brain 201215607 trauma, cancer with Huntington's disease (Parking〇nisdisease) or Aids; , amnesia; post-traumatic stress disorder; mental retardation; learning disabilities such as dyslexia, mathematical disorders or writing expression disorders; attention deficit/hyperactivity disorder, and age-related cognitive decline, and the mental disorder is selected from Following Group consisting of: schizophrenia, such as paranoid m-type, untyped or residual type of schizophrenia; schizophrenia-like mental disorder; schizoaffective disorder, such as delusional or depressive dissociative emotions Sexual disorders; paranoia; 躁#, such as sputum type depression, η type bipolar disorder and circulatory affective disorder; substance-induced mental illness, such as alcohol, amphetamine (Qing (8) one), marijuana (c café) , cocaine, ecstasy, inhalation, phlegm or phencyclidine (, phenCyelidine) material spirit; paranoid personality disorder; and schizophrenia personality disorder. 8. The use of a human (IV) use as claimed in any one of claims J to 5, which is for the preparation of a medical treatment for treating a neurodegenerative disorder or a disease; The degenerative disorder is selected from the group consisting of Alzheimer's disease, multiple infarct dementia, alcoholic dementia, dementia of Lemuguan, and dementia associated with intracranial or brain trauma. Dementia or Aids-related dementia or Parkinson's disease-related dementia; amnesia; post-traumatic stress, stress disorder; mental retardation; learning disabilities such as dyslexia, mathematics or writing disorder ; phonetic == age-related cognitive decline, and the _ syndrome is selected from the group consisting of: schizophrenia, such as paranoid, 42 201215607 confusion, stress disorder, untyped or residual type Schizophrenia class or depression type II;: mental disorders, such as delusional type bipolar disorder, π type sputum stagnation and % ' delusion, bipolar disorder, such as 1 Sexual mental disorder Induced psychiatric disorders' such as alcohol, amphetamine, cannabis, music, inhalants, y + θ 4 ring type magic ".% Of the present sheet or the induced psychosis vinzolidine; paranoid-type human cell disorder; and schizotypal personality disorder. 9·=Treatment of a neurodegenerative or psychiatric disorder: A neurodegenerative disorder is selected from the group consisting of the following: Every Mohs disease, multi-infarct therapy, alcoholic Staying, cancer associated with intracranial tumor or brain trauma; Parkinson's disease-related cancer or AIDS-related treatment; II = „ post-traumatic stress disorder; mental retardation; learning disabilities, for example: = two mathematics disorders or writing Expression disorder; attention deficit/hyperactivity disorder; "the cognitive ability of the target is reduced" and the mental disorder is selected from the group consisting of the following 2: schizophrenia, such as paranoid, chaotic, tight Ί 碍 未 未 未 或 ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; 2 depression and circulatory affective disorder; substance-induced = fine, amphetamine, marijuana, cocaine, ecstasy, inhalation, = or phencyclidine-induced psychosis; paranoid personality _; Bay and the second item a compound or with 4 3 201215607 Alcohol, nitrozapine, ziprasamine and oxatanide. Combination of one or more neuroleptics administered from sputum, olanzapine, risper, _, or the neuroleptics A pharmaceutical composition comprising thiophene, aripiprazole, and droperidol, comprising a compound according to any one of claims 1 to 5 and one or more pharmaceutically acceptable carriers , diluent and excipients 1 1 · A patent application formula and selected from the group (4), olanzapine 'Li (4) 'cut flat, a pilazole, gas 0 bottom bite 'gas nitrogen flat, Qi Use of a further compound of a group consisting of rasidone and oxatanide for the preparation of a medicament for the treatment of a neurodegenerative disease or a psychiatric disorder, wherein the neurodegenerative disorder is selected from the following Group of people: Alzheimer's disease, multi-infarct cancer, or other drug-related stupid, with cancer: cancer, with Huntington's disease or Parkinson's disease Her S-related dementia; sputum; amnesia; post-traumatic stress disorder; intelligence =: meaning = hindrance, such as dyslexia Mathematical disorder or writing expression disorder; II/hyperactivity disorder: and age-related cognitive decline, and the material is selected from the group consisting of: schizophrenia: , , Zhang Zhang 1, no type or residual type Spirit 8:: 'Psychiatric disorders of schizophrenia; schizoaffective mental disorder: type division. Affective mental disorder; delusional disorder; sputum syndrome: induced:: type 11 bipolar disorder and auspicious emotional disorder; Substance = psychosis such as alcohol, amphetamines, marijuana, cocaine opiates or phencyclidine; paranoid 44 201215607 5L personality disorder; and schizophrenia type personality disorder. What, simultaneous, individual or continuous treatment of neurodegeneration A combination preparation of a sexual or psychiatric condition, such as a compound of the scope of the patent range 1 to # η: order - and a compound selected from the group consisting of sputum, olanzapine, risperidone, and melon ° Another compound of the group consisting of sputum, clozapine, ziprasidone and oxatanide. The neurodegenerative disorder is selected from the group consisting of: (4) the sea Mohs disease, Infarct dementia, alcoholic therapy or other drug-related dementia, dementia associated with intracranial neoplasms or:: injury, dementia associated with Huntington's disease or Parkinson's disease: pDS-related dementia; Amnesia; post-traumatic stress disorder, mental retardation, learning disabilities, such as dyslexia, mathematics or writing, lack of attention/hyperactivity; and age-related cognitive decline, and the mental disorder is selected from Group of the following: schizophrenia 揞 揞 71 paranoid type, chaotic type, stress disorder type, untyped or residual type disorder 'diploid disease' schizophrenia mental disorder; split emotional spirit 22 cases :: delusional or suspicious schizophrenic psychosis; paranoia: : Yu:: type 躁 症 ' '„ 螺 营 及 及 循环 „ „ „ ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; 精神 精神 精神 精神 精神 精神 精神 精神 精神 精神 精神 精神 精神Disease m illusion 'inhalation' opioid or phencyclidine-induced mental paranoid personality disorder; and schizophrenia type personality disorder. 13 · One kind of treatment for nerves is very popular Patent scope! The application to the degenerative condition of any of the diseases to the disease or the mental condition is selected from the group consisting of a compound in which the neuropathy, multi-infarct dementia, alcohol is early and a group: Azhai Mohs' suspected or other drug-related dementia, 45 201215607 Dementia associated with intracranial or brain trauma, dementia associated with her's disease, or her related obsessive-compulsive disorder, Parker's disease or Parkinson's disease; mental retardation Learning Disability Zhan Yi; Amnesia; Trauma in S, such as dyslexia, mathematics or writing expression disorder; Attention; Thousands of impaired ability, and the mental illness is selected from: and age-related recognition植.梦纯八划神病 is selected from the group consisting of: 'spiritual knife disease, such as paranoid, chaotic type or residual type of spiritual points';; dust, unscrewed emotional spirit _ 症 (4) disorders; sub-disorders. 妄 _ r. delusional or depressive schizophrenic psychosis = paranoia, bipolar disorder, such as type I dysentery, sputum type depression and circulatory affective disorder. &# Jade stagnation Not his life cycle, cannabidiol card Γ: Hair ΐ psychiatric disorders, such as an alcohol, Ann vinzolidine induce partial essence n /, phantom music, inhalation agents, or a benzene ring frame _ sheet disorder. Sickness, paranoid personality disorder, and schizophrenia type VIII. Schema: (none) 46
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