TW201200516A

TW201200516A - Phenylimidazole derivatives comprising an ethynylene linker as PDE10A enzyme inhibitors

Info

Publication number: TW201200516A
Application number: TW099143188A
Authority: TW
Inventors: Ask Pueschl; Jacob Nielsen; Jan Kehler; John Paul Kilburn; Mauro Marigo; Morten Langgaard
Original assignee: Lundbeck & Co As H
Priority date: 2009-12-17
Filing date: 2010-12-10
Publication date: 2012-01-01
Also published as: WO2011072695A1; AR079497A1

Abstract

This invention is directed to compounds, which are PDE10A enzyme inhibitors. The invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. The present invention also provides processes for the preparation of the compounds of formula I. The present invention further provides a method of treating a subject suffering from a neurodegenerative disorder comprising administering to the subject a therapeutically effective amount of a compound of formula I. The present invention also provides a method of treating a subject suffering from a drug addiction comprising administering to the subject a therapeutically effective amount of a compound of formula I. The present invention further provides a method of treating a subject suffering from a psychiatric disorder comprising administering to the subject a therapeutically effective amount of a compound of formula I.

Description

201200516 六、發明說明：【發明所屬之技術領域】本發明提供為PDE1 0A酵素抑制劑’且因此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之化合物之醫藥組成物及使用本發明之化合物來治療病症之方法。【先前技術】在整個本申請案中，完整地參考各個公開案。此等公開案之揭示内容係以引用的方式併入本申請案中以更為充分地描述本發明所屬之目前技術狀態。環核苷酸環單磷酸腺苷（cAMP )及環單磷酸鳥苷 (cGMP )用作調節神經元中多個過程之細胞内第二信使。細胞内cAMP及cGMP係由腺苷酸及鳥苷酸環化酶產生，且由環核芽酸磷酸一醋酶（PDE )降解。cAMP及cGMP之細胞内含量係由細胞内信號傳導控制，且回應於GPCr活化來刺激/抑制腺苷酸及鳥苷酸環化酶為控制環核苷酸濃度之充为特性化方式（Antoni，F.A. Frcmi. 2000, 2Λ 103-132 )。cAMP 及 cGMP 含量又控制 cAMp 及 cGMp 依賴性激酶以及具有環核苷酸反應元件之其他蛋白質的活性，其經由隨後之蛋白質磷酸化及其他過程來調節關鍵神經元功能’諸如突觸傳輪（Synaptic transmissi〇n)'神經元分化及存活。存在21種磷酸二酯酶基因，其可分為u個基因家族。 201200516 存在1 〇個腺苷醯環化酶家族， 2個鳥苷醯環化酶家族，及201200516 VI. Description of the Invention: [Technical Field of the Invention] The present invention provides a compound which is a PDE10A enzyme inhibitor' and is therefore suitable for treating neurodegenerative disorders and psychiatric disorders. The invention also provides pharmaceutical compositions comprising a compound of the invention and methods of using the compounds of the invention to treat a condition. [Prior Art] Throughout this application, the respective publications are fully referred to. The disclosure of these publications is hereby incorporated by reference in its entirety in its entirety in its entirety in its entirety in the extent of the disclosure of The cyclic nucleotide cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are used as intracellular second messengers that regulate multiple processes in neurons. Intracellular cAMP and cGMP are produced by adenylate and guanylate cyclase and are degraded by cyclic ribo-phospho-monoacetate (PDE). The intracellular content of cAMP and cGMP is controlled by intracellular signaling and stimulates/inhibits adenosine and guanylate cyclase in response to GPCr activation as a means of characterizing the control loop nucleotide concentration (Antoni, FA Frcmi. 2000, 2Λ 103-132). cAMP and cGMP content in turn controls 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 Transmissi〇n) 'neuron differentiation and survival. There are 21 phosphodiesterase genes which can be divided into u gene families. 201200516 There are 1 adenosine cyclase family, 2 guanosine cyclase family, and

者。大多數PDE在許多組織中具有廣泛表現且具有作用而一些更具組織特異性。磷酸二酯酶10Α (PDE10A)為雙特異性磷酸二酯酶，其可將cAMP轉化為AMP且將cGMP轉化為GMP( Loughney， K.4 人，1999, 23( 109-117 ; Fujishige，K.等人，/· 1999, 2紙 1118-1127 及 Soderling，S.等人，尸 iVai/. Jcfli/. iScz·. 1999, 96, 7071-7076)。PDE10A 主要表現於紋狀體（striatum )、依核（n. accumbens )及嗅結節（〇ifactory tubercle)中之神經元中（K〇tera，J·等人，价By. Most PDEs are widely performed and have a role in many tissues and some are more tissue specific. Phosphodiesterase 10Α (PDE10A) is a bispecific phosphodiesterase that converts cAMP to AMP and converts cGMP to GMP (Loughney, K. 4, 1999, 23 (109-117; Fujishige, K.). Et al, /· 1999, 2 paper 1118-1127 and Soderling, S. et al., corpse iVai/. Jcfli/. iScz.. 1999, 96, 7071-7076). PDE10A is mainly expressed in striatum, In the nuclei (n. accumbens) and in the olfactory tubercle (K〇tera, J. et al., price

Comw. 1999，267，55 1-557 及 Seeger，T.F.等人， /^searcA，2003, 955，113-126)。小鼠PDE 10A為磷酸二酯酶之PDE 1 0家族中首先鑑別出的成員（Fujishige，K_等人，《/· 5b/· C/zew. 1999，274, 18438-18445 及 Loughney，K_ 等人，Geize 1999，234, 109-117)且已鑑別出大鼠與人類基因之N端拼接變異體 (Κο\χΐ2ί，3.等 k，Biochem. Biophys. Res. Comm. 1999, 261, 551-557 及 Fujishige，K.等人，^wr. «/. 1999，2(5(5, 111 8-1127 )。跨物種存在高程度之同源性。相對於其他PDE 家族，PDE10A獨特地定位於哺乳動物體内。PDE10之mRNA 高度表現於睾丸及腦中（Fujishige，Κ·等人，五 201200516 1999，266，1118-1127 ; Soderling，S. #A，_Proc.A^ai/.yici^· •Sci. 1999，9(5，7071-7076 及 Loughney，K.等人，1999, 23(109-117)。此等研究表明在腦内，PDE10在紋狀體（尾狀核（caudate )及外核（putamen ))、依核及嗅結節中的表現最高。最近，已對 PDE10A mRNA( Seeger，T.F·等人，Comw. 1999, 267, 55 1-557 and Seeger, T.F. et al., /^searcA, 2003, 955, 113-126). Mouse PDE 10A is the first member identified in the PDE 1 0 family of phosphodiesterases (Fujishige, K_ et al., "·· 5b/· C/zew. 1999, 274, 18438-18445 and Loughney, K_, etc. Human, Geize 1999, 234, 109-117) and has identified N-terminal splicing variants of rat and human genes (Κο\χΐ2ί, 3. et al, Biochem. Biophys. Res. Comm. 1999, 261, 551- 557 and Fujishige, K. et al., ^wr. «/. 1999, 2(5(5, 111 8-1127). There is a high degree of homology across species. PDE10A is uniquely located relative to other PDE families. In mammals, the mRNA of PDE10 is highly expressed in the testis and brain (Fujishige, Κ· et al., 5201 200516 1999, 266, 1118-1127; Soderling, S. #A, _Proc.A^ai/.yici^· • Sci. 1999, 9 (5, 7071-7076 and Loughney, K. et al., 1999, 23 (109-117). These studies show that in the brain, PDE10 is in the striatum (caudate) The highest performance in the putamen, nucleus and olfactory nodules. Recently, PDE10A mRNA has been applied (Seeger, TF et al.,

Soc. Neurosci. 2000, ％，345.10)及 PDE10A 蛋白（Menniti， F.S·等人，William Harvey Research Conference 'Phosphodiesterase in Health and Disease1, Porto， Portugal， 2001年12月5-7曰）在齧齒動物腦中之表現模式進行分析。尾狀核、伏核（accumbens nucleus)之中型多棘神經元 (medium spiny neuron/MSN )，及嗅結節之相應神經元高程度表現PDE10A。其構成基底神經節系統之核心。MSN在皮質-基底神經節-丘腦皮質迴路中具有關鍵作用，其整合彙集皮質/丘腦輸入’且將整合之資訊發送回皮質。MSN表現兩個功能類別之神經元：表現D ι多巴胺受體之D1類別及表現Dz多巴胺受體之類別。D丨類別之神經元為‘直接，紋狀體輸出路徑之一部分，其廣泛用以促進行為反應。〇2 類別之神經元為‘間接’紋狀體輸出路徑之一部分，其用以抑制與受助於‘直接，路徑之行為反應競爭的行為反應。此等競爭路徑如同汽車中之制動器及加速器來起作用。以最簡單之觀點來看，帕金森氏病（Parkins〇n，sdisease) 中之運動缺乏係由‘間接，路徑之過度活性引起，而諸如予丁頓氏病（Huntington's disease )之病症中的運動過量表丁直接路徑之過度活性。此等神經元之樹突狀隔間中 201200516 及/或cGMP信號傳導之PDE10A調節可涉及過濾皮質/丘腦輸入至MSN中。此外，PDE10A可涉及對黑質（substantia nigra)及蒼白球（globus pallidus)中GABA釋放之調節 (Seeger，T.F.等人，2003，P55，113-126)。在精神***症之治療中已公認多巴胺DZ受體拮抗作用。自20世紀50年代以來，精神病治療主要依賴於多巴胺D2受體拮抗作用且所有有效抗精神病藥均拮抗d2受體。Ds之作用可能主要經由紋狀體、依核及嗅結節中之神經元介導’因為此等區域接收最密集之多巴胺激導性投射 (dopaminergic projection )且具有較強之D2受體表現 (Konradi, C.^ Heckers, S. Society of Biological Psychiatry, 2001，50，729-742)。多巴胺D2受體促效作用使得細胞中 cAMP含量降低’在該等細胞中其經由腺苷酸環化酶抑制來表現’且此為Da信號傳導之組分（St00f，j. c·; Kebabian j W. 1981，別，366_368 及 Neve，κ A 等人，〇/ 及and «Signa/ 2004, 24, 165-205 )。相反地’ D2受體拮抗作用有效提高cAMP含量，且此作用可藉由抑制cAMP降解性磷酸二酯酶來模擬。匕21種磷酸二酯酶基因中大多數經廣泛表現；因此抑制可能具有副作用。因為PDE1〇A在此情形中具有特徵（紋狀體、依核及嗅結節中神經元中之表現較高且相對具有特異性），所以PDE10A抑制可能具有類似於匕受體抬抗作用之作用且因此具有抗精神病作用。儘管預期PDE1〇A抑制部分地模擬h受體拮抗作用， 201200516 但可預期其具有不同特徵。〇2受體具有除cAMp外之信號傳導纨分A.等人，J0urnai ofRecepi0rs and Signal 7>mM„c^„ 2004,以，165-2〇5)，因此經由 pDEi〇A 抑制干擾cAMP可負面調節而非直接拮抗經由A受體之多巴胺信號傳導。此可降低由強A拮抗作用所見到之錐體外副作用之風險。相反地，PDE10A抑制可具有一些由〇2受體拮抗作用未見到之作用。pDE10a亦表現於表現Di受體之紋狀體神經元中（Seeger，T. F.等人，如，卯5,Soc. Neurosci. 2000, %, 345.10) and PDE10A protein (Menniti, FS et al., William Harvey Research Conference 'Phosphodiesterase in Health and Disease 1, Porto, Portugal, December 5-7, 2001) in rodent brains The performance pattern is analyzed. The caudate nucleus, the accumbens nucleus medium spiny neuron/MSN, and the corresponding neurons of the olfactory nodule express PDE10A. It forms the core of the basal ganglia system. MSN plays a key role in the cortical-basal ganglia-thalamic cortical circuit, which integrates the collection of cortical/thalamic inputs and sends integrated information back to the cortex. MSN exhibits two functional categories of neurons: the D1 class that exhibits D dopamine receptors and the class of Dz dopamine receptors. Neurons in the D丨 category are part of the 'direct, striatum output pathway, which is widely used to promote behavioral responses. Neurons in the 〇2 category are part of the ‘indirect’ striatum output pathway, which is used to suppress behavioral responses that compete with ‘direct, path-like behavioral responses. These competitive paths act like brakes and accelerators in cars. From the simplest point of view, the lack of exercise in Parkinsin's disease (sdisease) is caused by 'indirect, excessive path activity, and movements in conditions such as Huntington's disease. Excessive activity of the excess path of the excess. PDE10A regulation of 201200516 and/or cGMP signaling in the dendritic compartment of such neurons may involve filtering the cortical/thalatin input into the MSN. In addition, PDE10A may be involved in the regulation of GABA release in substantia nigra and globus pallidus (Seeger, T. F. et al., 2003, P55, 113-126). Dopamine DZ receptor antagonism has been recognized in the treatment of schizophrenia. Since the 1950s, psychiatric treatment has relied mainly on dopamine D2 receptor antagonism and all effective antipsychotics have antagonized d2 receptors. The role of Ds may be mediated primarily by neurons in the striatum, nucleus and olfactory nodules 'because these regions receive the most dense dopaminergic projection and have strong D2 receptor expression (Konradi , C.^ Heckers, S. Society of Biological Psychiatry, 2001, 50, 729-742). Dopamine D2 receptor agonism causes a decrease in cAMP content in cells 'in these cells it is expressed by adenylate cyclase inhibition' and this is a component of Da signaling (St00f, j. c.; Kebabian j W. 1981, 别, 366_368 and Neve, κ A et al., 〇/ and and//Signature/Signature/2004, 24, 165-205). Conversely, D2 receptor antagonism effectively increases cAMP content, and this effect can be mimicked by inhibition of cAMP-degrading phosphodiesterase. Most of the 21 phosphodiesterase genes are widely expressed; therefore, inhibition may have side effects. Because PDE1〇A is characterized in this context (higher and relatively specific in neurons in the striatum, nucleus and olfactory nodules), PDE10A inhibition may have a similar effect as sputum receptor uplift And therefore has an antipsychotic effect. Although PDE1〇A inhibition is expected to partially mimic h receptor antagonism, 201200516 is expected to have different characteristics. The 〇2 receptor has a signaling moiety other than cAMp. A. et al., J0urnai of Recepi0rs and Signal 7> mM „c^„ 2004, 165-2〇5), so inhibition of cAMP via pDEi〇A can be negative. Modulation rather than direct antagonism of dopamine signaling via the A receptor. This reduces the risk of extrapyramidal side effects seen by strong A antagonism. Conversely, PDE10A inhibition may have some effect not seen by the 〇2 receptor antagonism. pDE10a is also expressed in striatum neurons that exhibit Di receptors (Seeger, T. F. et al., eg, 卯5,

113-126)。因為D,受體促效作用引起腺苷酸環化酶刺激，由此提高cAMP含量，所以PDE1〇A抑制可能亦具有模擬 h受體促效作用之作用。最終，pDE1〇A抑制將不僅增加細胞中之cAMP’而且可預期提高cGMp含量，因為pDEi〇A 為雙特異性磷酸二酯酶。cGMp活化細胞中之許多目標蛋白質（如cAMP)，且亦與cAMp信號傳導路徑相互作用。總而言之，PDE10A #制可能部分模擬&受體抬抗作用且因此具有抗精神病作用，但該特徵可不同於用經典A受體拮抗劑觀所察到之特徵。 P D E i 0 A抑制劑馨粟鹼顯示在若干抗精神病模型中具有活性。擧粟鹼加強〇2受體拮抗劑氟哌啶醇於大鼠中之強直作用，但其皁獨不會引起強直症（w〇〇3/〇93499 )。罌粟鹼減釭由PCP誘導之大鼠高活動性，而*** (amPhetamine )誘導之高活動性的減輕可忽略（w〇 03/093499 )。此等模型表明PDE1 〇A抑制具有典型的抗精神病可能性，自理論上考慮可以得出此預期。w〇〇3/〇93499 201200516 進-步揭示選擇性PDE10抑制劑用於治療相關神經及精神病症之用it此外’ PDE1G A抑制逆轉大鼠之注意^勢轉移 (attentional set shifting)之亞慢性pcp誘導型缺陷（心心〜等人，心r. J. 2005,（ 1070_1076 )。此模型表明 PDE1〇A抑制可緩解與精神***症相關之認知缺陷。 PDE10A之組織分佈表明pDE1〇A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中的 cAMP及/或CGMP含量，且本發明之pDE1〇A抑制劑因此將適用於治療涉及基底神經節之各種相關神經精神病學病狀，諸如神經及精神病症、精神***症、雙極性情感性精神障礙、強迫症及其類似病狀，且其益處為不具有與目前市售療法相關之不期望之副作用。此外，最近公開案（W〇 2〇〇5/12〇514、W〇 2〇〇5〇12485, Cantin 等人，Bioorganic & Medicinal Chemistry Letters (2007) 2869-2873 )表明PDE1〇A抑制劑可適用於治療肥胖症及非騰島素依賴型糖尿病。. 關於PDE10A之抑制劑，EP 125〇923揭示一般地選擇 f生PDE10抑制劑及尤其罌粟鹼用於治療某些神經及精神病症之用途。 WO 05/1 13517揭示作為尤其2及4型磷酸二酯酶抑制劑的苯并二氮呼立體特異性化合物，及預防及治療涉及中樞及 /或外圍失調（peripheral dis〇rder )之病理。w〇揭示苯并二氮呼衍生物及其在治療領域作為尤其4型磷酸二酯酶抑制劑的用途。w〇〇4/41258揭示苯并二氮呼衍生物 201200516 及其在治療領域作為尤其2型磷酸二酯酶抑制劑的用途。 WO 05/03129及WO 05/02579中揭示吡咯并二氫異啥啉及其變異體作為PDE10之抑制劑^ WO 05/82883中揭示充當PDE1 0抑制劑之哌啶基-經取代喹唑琳及異喹琳^ w〇 06/1 1 040揭示充當PDE 1 0抑制劑之經取代喹唑啉及異喹啭化合物。US 200501 82079揭示充當有效填酸二酯酶（pj)E ) 抑制劑之喹唑啉及異喹啉之經取代四氫異喹啉基衍生物。特定言之，US 20050丨82079係關於作為PDE10之選擇性抑制劑之化合物。類似地，US 20060019975揭示充當有效磷酸一醋趣（PDE )抑制劑之唾坐琳及異啥琳之„底。定衍生物。 US 20060019975亦關於作為PDE10之選擇性抑制劑的化合物。WO 06/028957揭示用於治療精神病及神經症候群之作為10型填酸二酯酶抑制劑的ο辛啉衍生物。然而’此等揭示案與本發明之化合物不相干，本發明之化合物在結構上與任何已知PDE10抑制劑均無關（Kehler, J.等人，Oph. Γ/jer·尸如⑼以 2007, J7，147-158 及 Kehler，J.等人，五;77ier.尸aiewii 2009，7P， 1715-1725 )且現已由本發明者發現作為高度活性及選擇性 PDE10A酵素抑制劑。本發明之化合物可提供並非在所有患者中均有效的神經退化性及/或精神病症之目前市售治療的替代物。因此，對替代性治療方法仍存在需要。【發明内容】 10 201200516 本&月之目的在於提供為選擇性pdei()a _素抑制劑之化合物。㈣之另一目的在於提供具有此活性且較之先前技術化口物具有改善的溶解性、代謝穩定性及/或生物可用性之化合物本發明之另-目的在於提供不引起典型地與神經及精神病症之目、則療法相關之副作用的對人類患者之有效治療，尤其是長期治療。在閱讀本發明之說明書後，本發明之其他目顯而易知。的將變得因此，在一個態樣中，本發明係關於式j化合物： R3 R2、人 /R4113-126). Because D, receptor agonism causes adenylate cyclase stimulation, thereby increasing cAMP content, so PDE1〇A inhibition may also have a role in mimicking h receptor agonism. Ultimately, pDE1〇A inhibition will not only increase cAMP' in the cell but can also be expected to increase cGMp content since pDEi〇A is a bispecific phosphodiesterase. cGMp activates many of the target proteins (such as cAMP) in cells and also interacts with the cAMp signaling pathway. In conclusion, PDE10A# may partially mimic & receptor upregulation and therefore have an antipsychotic effect, but this feature may differ from that observed with the classical A receptor antagonist. The P D E i 0 A inhibitor, cinnamicin, has been shown to be active in several antipsychotic models. Tilmidine potentiates the tonic effect of the 〇2 receptor antagonist haloperidol in rats, but its soap does not cause tonicity (w〇〇3/〇93499). Papaverine reduced the high activity of rats induced by PCP, while the reduction of high activity induced by amPhetamine was negligible (w〇 03/093499). These models suggest that PDE1 〇A inhibition has a typical antipsychotic likelihood, which can be reached theoretically. W〇〇3/〇93499 201200516 Further reveals the use of selective PDE10 inhibitors for the treatment of related neurological and psychiatric disorders. In addition, 'PDE1G A inhibits the subchronic pcp of attentional set shifting in rats. Inducible Defects (Heart Heart ~ et al, Heart r. J. 2005, (1070_1076). This model demonstrates that PDE1〇A inhibition can alleviate cognitive deficits associated with schizophrenia. The tissue distribution of PDE10A indicates that pDE1〇A inhibitors are available Increasing the level of cAMP and/or CGMP in cells expressing PDE10 enzymes, particularly neurons containing basal ganglia, and the pDE1〇A inhibitors of the invention will therefore be useful in the treatment of various related neuropsychiatric conditions involving the basal ganglia Such as neurological and psychiatric disorders, schizophrenia, bipolar affective disorder, obsessive-compulsive disorder and the like, and the benefit is that they do not have undesirable side effects associated with current marketed therapies. W〇2〇〇5/12〇514, W〇2〇〇5〇12485, Cantin et al., Bioorganic & Medicinal Chemistry Letters (2007) 2869-2873) indicate PDE1〇A Inhibitors are indicated for the treatment of obesity and non-Tengol-dependent diabetes mellitus. For inhibitors of PDE10A, EP 125〇923 reveals the general selection of f-pro-PDE10 inhibitors and especially papaverine for the treatment of certain neurological and psychiatric disorders Uses WO 05/1 13517 discloses benzodiazepine stereospecific compounds as in particular 2 and 4 phosphodiesterase inhibitors, and the prevention and treatment of central and/or peripheral disorders (peripheral dis〇rders) Pathology. 〇 reveals benzodiazepine derivatives and their use as inhibitors of type 4 phosphodiesterase in the therapeutic field. w〇〇4/41258 discloses benzodiazepine derivatives 201200516 and its therapeutic field The use of pyro-dihydroisoindoline and its variants as inhibitors of PDE 10 is disclosed in WO 05/03129 and WO 05/02579. WO 05/82883 discloses the use as PDE1 0 The piperidinyl-substituted quinazoline and isoquinoline oxime 06/1 1 040 of the inhibitors disclose substituted quinazoline and isoquinoline compounds which act as PDE 10 inhibitors. US 200501 82079 discloses acting as an effective fill Acid diesterase (pj)E) Quinazoline and isoquinoline by agents of the substituted tetrahydroisoquinoline derivatives. In particular, US 20050 to 82079 relates to compounds which are selective inhibitors of PDE10. Similarly, US 20060019975 discloses a compound which acts as a potent inhibitor of PDE and is a derivative of PDE 10. WO 06/ 028957 discloses octyl morphine derivatives as a type 10 acid-filled diesterase inhibitor for the treatment of psychosis and neurosis. However, 'the disclosures are not related to the compounds of the invention, the compounds of the invention are structurally and It is known that PDE10 inhibitors are irrelevant (Kehler, J. et al., Oph. Γ/jer corp. (9) 2007, J7, 147-158 and Kehler, J. et al., V; 77 ier. corpus aiewii 2009, 7P, 1715-1725) and has been discovered by the present inventors as a highly active and selective PDE10A enzyme inhibitor. The compounds of the present invention provide current marketed treatments for neurodegenerative and/or psychiatric disorders that are not effective in all patients. Alternatives. Therefore, there is still a need for alternative treatment methods. [Summary of the Invention] 10 201200516 The purpose of this & month is to provide a compound which is a selective pdei()a-inhibitor. (iv) Another purpose is Providing a compound having such activity and having improved solubility, metabolic stability and/or bioavailability over prior art mouths of the present invention is another object of the present invention to provide a therapy that does not cause a typical neurological and psychiatric condition. Effective treatment of human patients with related side effects, especially long-term treatment. After reading the description of the present invention, other aspects of the present invention will become apparent, and thus, in one aspect, the present invention relates to Compound of formula j: R3 R2, human / R4

R6 ΗΕΤ—L—^ N， R1 其中ΗΕΤ為含有2至4個It原子之式II雜芳香族基團R6 ΗΕΤ—L—^ N, R1 wherein ΗΕΤ is a heteroaromatic group of formula II containing 2 to 4 It atoms

ΎΎ

Zi0> Z、NZi0> Z, N

II 其中Y可為N或CH，Z可為N或C，且其中HET可視情 201200516 況經至多三個個別地選自以下者之取代基R7、R8&以取代：H; C,-C6烷基，諸如Me; _素，諸如氣及溴；氰基；齒基（CrCd烷基，諸如三氟甲基；芳基，諸如苯基；烷氧基，較佳為CrC6烷氧基，諸如甲氧基、二甲氧基、乙氧基、甲氧基-乙氧基及乙氧基-曱氧基、及Ci_c6羥烷基，諸如 ch2ch2oh，且其中*表示連接點， -L-為連接子-CEC-， R1係選自η ; Ci-C6烷基，諸如甲基、乙基1丙基、2·丙基、異丁基；CrC6烷基（c^C8)環烷基，諸如環丙基甲基；Wherein Y may be N or CH, and Z may be N or C, and wherein HET may be substituted by up to three substituents R7, R8 & independently selected from: H; C, -C6 alkane; Base, such as Me; _, such as gas and bromine; cyano; dentate (CrCd alkyl, such as trifluoromethyl; aryl, such as phenyl; alkoxy, preferably CrC6 alkoxy, such as A An oxy group, a dimethoxy group, an ethoxy group, a methoxy-ethoxy group, and an ethoxy-methoxy group, and a Ci_c6 hydroxyalkyl group such as ch2ch2oh, wherein * represents a point of attachment, and -L- is a linker -CEC-, R1 is selected from η; Ci-C6 alkyl, such as methyl, ethyl 1-propyl, 2-propyl, isobutyl; CrC6 alkyl (c^C8) cycloalkyl, such as cyclopropyl Methyl group

CrCe羥烷基，諸如羥乙基；CH2Cn ; cH2c⑴）NR: ; c丨G 芳基烷基，諸如苯甲基及4_氣笨曱基；及Ci_C6烷基·雜環烷基，諸如四氫哌喃-4·基-甲基及2_嗎啉_4-基·乙基； M-R6各自獨立地選自H; Ci_C6烧氧基，諸如甲氧基；及南素，諸如氣或氟；及其互變異構體及醫藥學上可接受之鹽、及其多晶型物。在本發明之個別具體實例中，式I化合物係選自本文實驗章節中揭示之特定化合物。 —本發明進—步提供用作為醫藥品之式丨化合物、或其醫藥學上可接受之鹽。 “在另一態樣中，本發明提供一種醫藥組成物，其包含療有效量之式I化合物及醫藥學上可接受之載劑、稀釋劑或賦形劑。發月進步提供式1化合物或其醫藥學上可接受之鹽的用途其用於製備治療神經退化性病症或精神病症之醫藥 12 201200516 品° 此外，在又一態樣中，本發明挺月k供一種治療罹患神經退化性病症之個體的方法，其句合奶& — 7 八巴3投予該個體治療有效量之式I化合物》在又一態樣中，太絡B日坦μ 奉發明提供一種治療罹患精神病症之個體的方法，其包含扮早兮加遍、，CrCe hydroxyalkyl group, such as hydroxyethyl; CH2Cn; cH2c(1))NR: ; c丨G arylalkyl, such as benzyl and 4 oxalin; and Ci_C6 alkyl. heterocycloalkyl, such as tetrahydrogen Piper-4-yl-methyl and 2-morpholine-4-yl-ethyl; M-R6 are each independently selected from H; Ci_C6 alkoxy, such as methoxy; and sulfonamide, such as gas or fluorine And its tautomers and pharmaceutically acceptable salts, and polymorphs thereof. In a particular embodiment of the invention, the compound of formula I is selected from the particular compounds disclosed in the experimental section herein. - The present invention further provides a hydrazine compound, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical. "In another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier, diluent or excipient. Use of a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a neurodegenerative disorder or a psychiatric disorder. 12 201200516 In addition, in another aspect, the present invention provides a treatment for a neurodegenerative disorder The method of the individual, the sentence of the milk & - 7 octa 3 is administered to the individual in a therapeutically effective amount of the compound of formula I. In yet another aspect, the method of providing a treatment for a psychiatric disorder is provided by the invention. Individual method, which involves prematurely adding,

匕3仅予該個體治療有效量之式I 化合物。在另一具體實例中，太路日日组糾尽發明提供一種治療罹患藥物成癮（諸如酒精、***'可4 M u r***或鴉片劑成瘾）之個體的方法。【實施方式】取代基之定義如本發明上下文中所用’術語「齒基」及「函素」可互換使用且係指氟、氣、溴或碘。術π C1-C6烷基」係指具有包括一個至包括六個碳原子之直鏈或分支鏈飽和烴。此等基團之實例包括（但不限於）甲基、乙基、1-丙基、2-丙基、H基、2_τ基、2甲基-2-丙基、2-曱基小丁基及正己基。表述「^心羥烷基」係指經一個羥基取代之如上定義之Ci_Ce烷基。術語「函基 (C]-C6)烷基」係指經至多三個鹵素原子取代的如上定義之 Cl-C6烷基’諸如三氟曱基c 表it Ci Ce院氧基」係指具有包括一個至包括六個碳原子、開環價態（open valency)在氧上之直鏈或分支鏈飽和烷氧基。此等基團之實例包括（但不限於）甲氧基、乙氧基、正丁氧基、2-甲基-戊氧基及正己氧基。 13 201200516 術s吾「C3 - C s環烧基」典型地係指環丙基、環丁基、产戊基、環己基、環庚基或環辛基。表述r C「c：6烧基（c3_c ) 環烷基」係指經直鏈或分支鏈Cl_C：6烷基取代的如上定義之 C3_CS環烧基。此等基團之實例包括（但不限於）環丙基甲基0 術語「雜環烷基」係指含有碳原子及至多三個N、〇或 S原子之四至八員環，限制條件為四至八員環不含有相鄰〇或相鄰S原子。開環價態係在雜原子或者碳原子上。此等基團之實例包括（但不限於）氮雜環丁基 '氧雜環丁基、娘啡基、嗎#基、硫代嗎琳基及[M]二氮雜環庚烧基。術 3吾I基雜蜋烷基」係指經一個羥基取代之如上定義的雜環烷基。術語「Cl-C6烷基-雜環烷基」係指經G-C6烷基取代之如上定義的雜環烷基。此等基團之實例包括（但不限於）四氫哌喃_4·基-甲基及2·嗎啉_4_基-乙基。術语「芳基」係指視情況經如上定義之齒素、^-匕烷基—1 6燒氧基或函基AO烧基取代之苯環。此等基團之實例包括（但不限於）苯基及4-氣苯基。術語「CpC； ^ 6方基烷基」係指經直鏈或分支鏈c丨_Ce烷基取代之如上定萬w 於)另苯:基及此等基團之實例包·(但不限例。另外’本發明進-步提供下述之本發明之某些具體實任本發明夕 t 之式Π雜Η Μ _具體實例中，H E T為含有2個氮原子 '基團。在本發明之另一具體實例t，ΗΕΤ 14 201200516 柳万管族基團。在本發具體實例中，HET為含有4個乃之又一個氮原子之式η雜芳香 ΗΕΤ較佳選自以下雜芳香族基團，盆中「*知基團。 .¾ ：八」表示連接匕3 is administered to the individual only a therapeutically effective amount of a compound of formula I. In another embodiment, the Taiji Daily Group rectifies the invention to provide a method of treating an individual suffering from drug addiction such as alcohol, amphetamine, 4Mu r ***e or opiate addiction. [Embodiment] Definition of Substituents As used in the context of the present invention, the terms "dental group" and "fun" are used interchangeably and mean fluorine, gas, bromine or iodine. The "π C1-C6 alkyl group" means a linear or branched chain saturated hydrocarbon having one to including six carbon atoms. Examples of such groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, H-based, 2-hydrazino, 2-methyl-2-propyl, 2-indenyl butyl And is the base. The expression "heterohydroxyalkyl" refers to a Ci_Ce alkyl group as defined above which is substituted by a hydroxy group. The term "donyl (C]-C6)alkyl" means a Cl-C6 alkyl group as defined above substituted with up to three halogen atoms, such as trifluoromethyl c. A linear or branched chain saturated alkoxy group having up to six carbon atoms and an open valency on oxygen. Examples of such groups include, but are not limited to, methoxy, ethoxy, n-butoxy, 2-methyl-pentyloxy, and n-hexyloxy. 13 201200516 The "C3 - C s cycloalkyl" group typically refers to cyclopropyl, cyclobutyl, pentyl, cyclohexyl, cycloheptyl or cyclooctyl. The expression r C "c: 6 alkyl (c3_c) cycloalkyl" means a C3_CS cycloalkyl group as defined above which is substituted by a straight or branched chain Cl_C:6 alkyl group. Examples of such groups include, but are not limited to, cyclopropylmethyl 0. The term "heterocycloalkyl" refers to a four to eight membered ring containing carbon atoms and up to three N, hydrazine or S atoms, with a limit of four to The eight-membered ring does not contain adjacent or adjacent S atoms. The open-loop valence state is on a hetero atom or a carbon atom. Examples of such groups include, but are not limited to, azetidinyl oxetanyl, niephanyl, oxime, thiomorphinyl, and [M]diazepine. "3" is a heterocycloalkyl group as defined above which is substituted by a hydroxy group. The term "Cl-C6 alkyl-heterocycloalkyl" refers to a heterocycloalkyl group as defined above which is substituted by a G-C6 alkyl group. Examples of such groups include, but are not limited to, tetrahydropyran-4-yl-methyl and 2 morpholin-4-yl-ethyl. The term "aryl" refers to a benzene ring which is optionally substituted with dentate, ^-decane- 16 alkoxy or a aryl group as defined above. Examples of such groups include, but are not limited to, phenyl and 4-phenylphenyl. The term "CpC; ^ 6-terminated alkyl" refers to an example package of a group substituted with a linear or branched c丨-Ce alkyl group as described above, and (but not limited to) In addition, the present invention further provides the following specific examples of the present invention. In the specific example, HET is a group containing two nitrogen atoms. Another specific example t, ΗΕΤ 14 201200516 柳万管族组. In the specific example of the present invention, HET is a formula containing 1,4-heteroaromatic enthalpy of four or more nitrogen atoms, preferably selected from the following heteroaromatic groups. Mission, "* know the group. .3⁄4: eight" means the connection

在另一具體實例中，雜芳香族基團HET係經一個選自以下者之取代基R7取代：H; C丨-Ce烷基，諸如甲基；函素，诸如鼠或溴，亂基’鹵基（Ci-C6)烧基，諸如三i甲基.芳基’諸如苯基；及（VC6羥烷基，諸如CH2CH20H。在另一具體實例中，HET係經兩個個別地選自以下者之取代基R7 及R8取代：Η ; Ci-C6烧基，諸如曱基；鹵素，諸如氯或漠·, 氰基；鹵基（Ci-Ce)烧基，諸如三氟曱基；芳基，諸如笨基；及Ci-Cg經院基’諸如CH2CH2OH。在另一具體實例中，JJET 係經三個個別地選自以下者之取代基R7、R8及R9取代： Η ; C]-C6烷基’諸如曱基；鹵素’諸如氣或溴；氰基；鹵基（Ci-C6)烧基’諸如三氟曱基；芳基，諸如苯基；及 •經烷基，諸如CH2CH2OH。在一個特定具體實例中，R7、Rs及R9均為氫。在一個 15 201200516 不同具體實例中’ R?、Rs及R9中至少一者 a苟L丨-C6燒基，In another embodiment, the heteroaromatic group HET is substituted with a substituent R7 selected from the group consisting of: H; C丨-Ce alkyl, such as methyl; a element, such as murine or bromine, chaotic a halo (Ci-C6) alkyl group such as a tri-i-methyl.aryl group such as phenyl; and a (VC6 hydroxyalkyl group such as CH2CH20H. In another embodiment, the HET system is selected from two individually selected from Substituents R7 and R8 are substituted: Η; Ci-C6 alkyl group, such as fluorenyl; halogen, such as chlorine or molybdenum, cyano; halo (Ci-Ce) alkyl group, such as trifluoromethyl; aryl , such as a stupid base; and a Ci-Cg via a hospital base such as CH2CH2OH. In another embodiment, the JJET is substituted with three substituents R7, R8 and R9 individually selected from the group consisting of: Η; C]-C6 alkane a base such as a fluorenyl group; a halogen such as a gas or a bromine; a cyano group; a halogen (Ci-C6) alkyl group such as a trifluoromethyl group; an aryl group such as a phenyl group; and an alkyl group such as CH2CH2OH. In a specific embodiment, R7, Rs, and R9 are all hydrogen. In a specific example of 15 201200516, at least one of 'R?, Rs, and R9 is a 苟L丨-C6 alkyl group,

諸如甲基。在另一具體實例中，R?、心及R 、 8久R9中至少一者為函素，諸如氣或》臭° 下文給出經衍生HET基團之化合物的特定具體實例。在一個特定具體實例中’爾為味唾并Π，2·定。在第二特定具體實例中，ΗΕΤ為[1，2,4]三4M c 王升[1，5-a]。比咬。在第三特定具體實例中，ΗΕΤ為咪唑林η， Ί 开U，2-a]吡啶。在第四特定具體實例中，HET為咪唑并队％…嘧啶。在第五特定具體實例中，HET為吡唑并。比、疋在第六特定具體實例中，HET為[1，2,4]***并[u-a]嘧啶。、你乐七特定且體實例中，HET為[1，2,4]***并[^-^嘧啶。、你乐八特定具體實例中’ HET為[1，2,4]***并[LSa]吡啡。、在另一特定具體實例中，HET為[1，2,4]***并[丨5丑嘧啶。在另一特定具體實例中，HET為[1，2 41 = k ^ ] ，」二唑并[l，5-a]Such as methyl. In another embodiment, at least one of R?, core, and R, 8 is R9, such as gas or "odor". Specific examples of compounds derived from the HET group are given below. In a specific specific example, the taste is sputum and sputum, 2. In a second specific embodiment, ΗΕΤ is [1, 2, 4] three 4M c Wang Sheng [1, 5-a]. Than bite. In a third specific embodiment, hydrazine is imidazolin η, and U,2-a]pyridine is opened. In a fourth specific embodiment, HET is an imidazolium group ... pyrimidine. In a fifth specific embodiment, HET is pyrazolo. In the sixth specific embodiment, HET is [1,2,4]triazolo[u-a]pyrimidine. HET is [1,2,4]triazolo[^-^pyrimidine in a specific and physical example. In your specific example, HET is [1,2,4]triazolo[LSa]pyridin. In another specific embodiment, HET is [1,2,4]triazolo[丨5 ugly pyrimidine. In another specific embodiment, HET is [1, 2 41 = k ^ ] , "diazolo[l,5-a]

吡啶_6_甲腈。在另一特定具體實例中，HET ’ 甲基-1H- 苯并咪唑。在另一特定具體實例中，HET為 , 本基-1H-苯并味唾。在另一特定具體實例中，HET為2-(心翕〜w 札-本并π米唾Pyridine_6-carbonitrile. In another specific embodiment, HET 'methyl-1H-benzimidazole. In another specific embodiment, HET is , a base-1H-benzene flavored saliva. In another specific embodiment, HET is 2-(heart 翕~w za-ben and π m saliva

-1-基）-乙醇。在另一特定具體實例中，HET ^ 5 5 7 -二甲基 -[1，2,4]***并[^^吡啶。在另一特定具體-1-yl)-ethanol. In another specific embodiment, HET^5 5 7 -dimethyl-[1,2,4]triazolo[^^pyridine. In another specific

汽例中，H£T ^ 5,7-二甲基♦坐并[以外…在另_特定具體實例中’ HET為5_氣十坐并比啶。在另—特定中，hem 5_甲基米唾并π，定。在 :立貫例符定具體管：例中’ ΗΕΤ為5_三氟曱基-味唑并[l,2_a]。比啶。在—三具體實例中’ HET為6_溴·5,7_二甲基_π，2,4 特疋 !开 L!，5-a] 16 201200516 吡啶。在另一特定具體實例中，HET為6_溴_7_曱基 ***并[l，5-a]吡啶。在另—特定具體實例中’ HET為6’氣 -8-甲基-[1，2,4]二唾并[1，5_叫吡啶。在另一特定具體實例中，HET為6-氣米唑并⑴之-小比。定。在另一特定具體實例中’ HET為7-曱基-[1，2,4]***并[l，5_a]。比啶。在另-特定具體實例中，HET為8·甲基-咪唑并^化比咬。在另—特定具體實例中，HET為咪唑并^^^吡啶_7_甲腈。在另— 特定具體實例巾’ HET為5,7_二甲基…，以]***并[Ha] 痛咬。典型地’ HET為5,7-二甲基_咪唑并[y-a]嘧啶或 ***并[l，5-c]嘧啶或[I，2,4]***并[丨，5々]吡畊。在本發明之另一具體實例中，心為H。在另一具體實例中，1為Ct-C6直鏈或分支鏈烧基。在另一具體實例中， R丨為tVC6羥烷基。在另一具體實例中，R丨為c丨烷基 (Cs-C8)環烷基。在另一具體實例中，&為烷基-雜環烷基。在另一具體實例中，心為Ci_Ce芳基烷基。在另一具體實例中，Rl為CHAN。在又一具體實例中，R丨為 CH2C(〇)nh2 〇 —在-個特定具❹例中，R1為甲基。在另一特定具體實例中’ R,為乙基。在另-特定具體實例中，Ri為卜丙基。在另一特定具體實例中，R1為2·丙基。在另一特定具體實例中’ R!為異丁基。在另一特定具體實例中，&為經乙基。在特定具體實例中，&為環丙基甲基。在另-特定具體貫例中’ R,為四氫哌喃-4-基·曱基。在另一特定具體實例 17 201200516 中鳴A 2·嗎琳_4_基.乙基。在另—敎具體實例中& 為苯曱基。在另一特定具體實例中，Ri & 4氯苯甲基。在另-特定具體實例中，Rl4 CH2CN。在另一特定具體實例中 ’ Ri 為 CH2C(0)NH2。在本發明之一個具體實例中，1、Rj、I、h及以均為氫。在另一具體實例中，m 115及116中至少一者為CrC6烷氧基，諸如甲氧基。在本發明之另一具體實例中’ R2、R3、r4、r5a r6中至少一者為齒素，諸如氣或氟。在本發明之一個具體實例中，I為氫。在另一具體實例中，R2為（：】-(：6烷氧基，諸如曱氧基。在另一具體實例中， I為鹵素’諸如氣或氟。在本發明之一個具體實例中，I為氫。在另一具體實例中，R3為CrC：6烷氧基，諸如曱氧基。在另一具體實例中， 1為鹵素，諸如氯或氟。 ,在本發明之一個具體實例中，R4為氫。在另一具體實 =中，尺4為C,-C6烷氧基，諸如甲氧基。在另一具體實例中，歹在本發明之一個具體實例中，Rs為氫。在另一具體實反中尺5為Ci-C：6烷氧基，諸如曱氧基。在另一具體實例中， 5為函素’諸如氯或氟。你在本發明之一個具體實例中，R6為氫。在另一具體實 =中，以為CrC6烷氧基，諸如甲氧基。在另一具體實例中， 6為齒素’諸如氣或氟。應瞭解，本文所提及之本發明之各態樣、具體實例、 18 201200516 實施及特徵可分別主張，或以任何組合來主張，如以下非限制性實例所說明：在一個特定具體實例中，HET為5,7-二甲基-咪唑并 [l，2-a]嘧啶；-L-為-C=C-，Ri係選自氫、曱基、1-丙基、異丁基、環丙基曱基、苯曱基及2-嗎啉-4-基-乙基；且R2-R6 均為氮。在另一特定具體實例中，HET係選自5,7-二曱基-咪唑并[1，2-3]嘧啶、5,7-二曱基-[1,2,4]***并[1，5-&]吡啶、5,7-二甲基-[1,2,4]***并[l，5-a]嘧啶、5-三氟曱基-咪唑并[l，2-a] °比啶、[1,2,4]***并[1,5-&]。比啶及6-氣-8-曱基-[1，2,4]*** 并[1，5 a ]0比0定，-L -為—C=C_，R1係選自鼠、甲基、乙基、 2-丙基、CH2CN及四氫哌喃-4-基-甲基；且R2-R6均為氫。在另一具體實例中，一或多個氫原子已經氘取代。特定言之，氫已被氘置換，其中取代基Ri至R6中任一者為曱基或曱氧基。在本發明之個別具體實例中，式I化合物係選自以下特定化合物，呈自由鹼、其一或多種互變異構體或其醫藥學上可接受之鹽的形式。表1列出本發明之化合物。各化合物構成本發明之個別具體實例：表1 :本發明之化合物化合物 5,7-二曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-咪唑并 [l，2-a]°i。定 8-甲基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]*** 19 201200516 并[1，5-a]°比啶 5 -甲基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]*** 并[1,5-a]°比啶 2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并 [1,5-巳]0比。定 2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-5-(三氟曱基）咪唑并[l，2-a]吼啶 5.7- 二曱基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4] 三σ坐并[1，5-a]B* °定 6.8- 二曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4] 三嗤并[l，5-a]°比0定 5.7- 二曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4] 三。坐并[1，5-a]°密。定 5.8- 二曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4] 三。坐并[1，5-a]<nt °定 5-甲基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1,2,4]*** 并[1,5-a]°密啶-7-醇 5 -曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]*** 并[l，5-a]嘧啶 5 -甲基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-7-嗎啉-4-基-[1，2,4]***并[l，5-a]嘧啶 5,6,7-三甲基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[l，5-a]嘧啶 5-甲基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-7-苯基 201200516 -[1，2,4]***并[1，5-3]嘧啶 2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-5,6,7,8-四氫-[1，2,4] 三。坐并[1，5 - a] °比啡 2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-1Η-咪唑并[4,5-b] D比口定 2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-5-三氟曱基-[1，2,4] 三唾并[l，5-a]°密。定-7-醇 8-甲氧基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]三 D坐并[l，5-a]D比。定 7- 甲氧基-5-曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[l，5-a]嘧啶 8- 曱氧基-5-曱基-2-(卜曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[l，5-ap比啶 8-氟-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并 [1,5-a]β比。定 5-乙基-2-(1-曱基-4-苯基-1Η-咪唑-2-基乙炔基）-[1,2,4]*** 并[1,5-a]。比啶 7- 氣-8-乙基-5-曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[l，5-c]嘧啶 8- 乙基-5-曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1,2,4]***并[l，5-c]嘧啶 5-二氟曱基-7-曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[l，5-a]嘧啶 5 -曱基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-7-丙基 21 201200516 -[1，2,4]***并[l，5-a]嘧啶 5.8- 二曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[l,2,4] 三。坐并[1,5 - a] °比啡 7-曱氧基-5-曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1,2,4]***并[l，5-c]嘧啶 7-異丙基-5-甲基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[1,5-a]嘧啶 7-環丙基-5-甲基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1,2,4]***并[l，5-a]嘧啶 7-曱氧基-5，8-二甲基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1,2,4]***并[l，5-c]嘧啶 5-甲氧基-7-曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[l，5-a]嘧啶 5.8- 二甲基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4] 三。坐并[1，5 - c ] °密0定 7-曱氧基甲基-5-曱基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1,2,4]***并[l，5-a]嘧啶 5,7-二曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4] 三。坐并[l，5-a]°密咬-6-醇 5 -甲基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-咪唑并 [1,2-a]°tb ^ {5-曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]三唑并[1,5-a]嘧啶-7-基}-甲醇 2-(8-甲基-咪唑并[l，2-a]吡啶-2-基）-1-(1-曱基-4-苯基-1H- 22 201200516 咪唑-2-基）-乙醇 2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-5-吡啶-4-基-[1，2,4] 三σ坐并[1，5-3]°比。定 2-(1-曱基-4-苯基-1Η-咪唑-2-基乙炔基）-8-吡啶-4-基-[1,2,4] 三。坐并[1，5-a]。比σ定 5 -環丙基-8-曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1,2,4]***并[l，5-c]嘧啶 8-曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1,2,4]*** 并[l，5-c]嘧啶 8-乙基-5-曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1,2,4]***并[l，5-a]。比啶 5.8- 二甲氧基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[l，5-a]吼啶 8-曱氧基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-5-吡啶 -4-基-[1，2,4]***并[l，5-a]。比啶 2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并 [l，5-a]吡啶-8-醇 5.8- 二曱基-3-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4] ***并[4,3-a]吡啡 5-曱基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]*** 并[1，5-a]°比σ定-8-醇 5-曱氧基-2-(1-甲基-4-苯基-1Η-咪唑-2-基乙炔基）-[1,2,4]三 0坐并[1，5-a]°比。定 5.8- 二曱基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-咪唑并 23 201200516 [l，2-a]。比明： N-{2-(l -甲基-4-苯基-1H-咪唑-2-基乙炔基）-[l，2,4]***并 [1，5 - a ] °比°定-8 -基}-乙酿胺 8-曱氧基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1,2,4]三 α坐并[1，5_a]D比啡 8-乙炔基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]三 °坐并[1,5-a]*nt °定 N-{5-曱基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4] ***并[1,5-3]吡啶-8-基}-乙醯胺 8-甲氧基-5,6-二曱基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[l，5-a]吼明： 5.8- 二曱基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4] ***并[l，5_a]吡啡7_氧化物 {5 -甲基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]三唑并[l,5_a]。比啡-8-基}-曱醇 5 -曱基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1,2,4]*** 并[1，5-a]0比。定-8-甲腈 8-氰基-5-曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[l，5-a]。比啡-6-曱酸乙酯 5.8- 二甲基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1,2,4] 三峻并[1，5-c]°密。定 7-甲氧基曱基-5-甲基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[l，5-a]嘧啶 5,7-二曱基-2-(1-甲基-4-苯基-111-咪唑-2-基乙炔基）-[1，2,4] 24 201200516 三。坐并[l，5-a]嘴。定-6-醇 5 -甲基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-咪唑并 [1，2-a]0比咬 {5 -曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]三唑并[l，5-a]嘧啶-7-基}-曱醇 2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-5-°比啶-4-基-[1，2,4] 三σ坐并[1，5 - a] °比〇定 2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-8-吡啶-4-基-[1，2,4] 三0坐并[1,5- a]σ比α定 5 -環丙基-8 -曱基-2 - (1 -曱基-4 -苯基-1Η - σ米σ坐-2 -基乙快基）-[1，2,4]***并[l，5-c]嘧啶In the case of steam, H£T^5,7-dimethyl ♦ sits and [external... in another _specific example] HET is 5_gas ten-seat and pyridine. In another specific, hem 5_methyl rice is sputum and π, fixed. In the example: the specific tube: In the case, 'ΗΕΤ is 5_trifluoromethyl-isoxazole [l, 2_a]. Bisidine. In the three specific examples, HET is 6_bromo·5,7-dimethyl-π, 2,4 疋! Open L!,5-a] 16 201200516 pyridine. In another specific embodiment, HET is 6-bromo-7-mercaptotriazolo[l,5-a]pyridine. In another specific embodiment, the HET is 6' gas -8-methyl-[1,2,4]disindol [1,5-called pyridine. In another specific embodiment, HET is a 6-gas azole and a small ratio of (1). set. In another specific embodiment, the HET is 7-mercapto-[1,2,4]triazolo[l,5-a]. Bisidine. In another specific embodiment, HET is 8-methyl-imidazole and the ratio is bitten. In another specific embodiment, HET is imidazolium pyridine _7-carbonitrile. In another - specific specific case towel 'HET is 5,7-dimethyl..., to triazolo[Ha] bite. Typically 'HET is 5,7-dimethyl-imidazo[ya]pyrimidine or triazolo[l,5-c]pyrimidine or [I,2,4]triazolo[丨,5々]pyrazine . In another embodiment of the invention, the heart is H. In another specific embodiment, 1 is a Ct-C6 straight or branched chain alkyl group. In another embodiment, R丨 is tVC6 hydroxyalkyl. In another embodiment, R is c丨 alkyl (Cs-C8) cycloalkyl. In another embodiment, & is an alkyl-heterocycloalkyl group. In another embodiment, the core is Ci_Ce arylalkyl. In another specific example, Rl is CHAN. In yet another embodiment, R is CH2C(〇)nh2 〇 - in a particular example, R1 is methyl. In another specific embodiment, 'R, is ethyl. In another specific embodiment, Ri is a propyl group. In another specific embodiment, R1 is 2·propyl. In another specific embodiment, 'R! is an isobutyl group. In another specific embodiment, & is ethyl. In a particular embodiment, & is cyclopropylmethyl. In another specific embodiment, 'R, is tetrahydropyran-4-yl-indenyl. In another specific example 17 201200516, A 2 · holly _4_ yl. ethyl. In another example, & is benzoquinone. In another specific embodiment, Ri & 4 chlorobenzyl. In another specific embodiment, Rl4 CH2CN. In another specific embodiment, ' Ri is CH2C(0)NH2. In one embodiment of the invention, 1, Rj, I, h and both are hydrogen. In another embodiment, at least one of m 115 and 116 is a CrC6 alkoxy group, such as a methoxy group. In another embodiment of the invention at least one of 'R2, R3, r4, r5a r6 is a dentate such as gas or fluorine. In one embodiment of the invention, I is hydrogen. In another embodiment, R2 is (:]-(:6 alkoxy, such as a decyloxy group. In another embodiment, I is a halogen such as gas or fluorine. In one embodiment of the invention, I is hydrogen. In another embodiment, R3 is CrC: 6 alkoxy, such as a decyloxy group. In another embodiment, 1 is a halogen, such as chloro or fluoro. In one embodiment of the invention R4 is hydrogen. In another embodiment, the rule 4 is C,-C6 alkoxy, such as methoxy. In another embodiment, in one embodiment of the invention, Rs is hydrogen. In another specific embodiment, the rule 5 is Ci-C: 6 alkoxy, such as a decyloxy group. In another embodiment, 5 is a peptidin such as chlorine or fluorine. In one embodiment of the invention R6 is hydrogen. In another specific =, it is considered to be a CrC6 alkoxy group, such as a methoxy group. In another specific example, 6 is a dentate 'such as gas or fluorine. It should be understood that the text mentioned herein Various aspects, specific examples, 18 201200516 implementations and features of the invention may be claimed separately or in any combination, such as the following non-limiting examples Description: In a specific embodiment, HET is 5,7-dimethyl-imidazo[l,2-a]pyrimidine; -L- is -C=C-, and Ri is selected from hydrogen, sulfhydryl, 1-propyl, isobutyl, cyclopropylindenyl, benzoinyl and 2-morpholin-4-yl-ethyl; and R2-R6 are all nitrogen. In another specific embodiment, HET is selected From 5,7-dimercapto-imidazo[1,2-3]pyrimidine, 5,7-dimercapto-[1,2,4]triazolo[1,5-&]pyridine, 5, 7-Dimethyl-[1,2,4]triazolo[l,5-a]pyrimidine, 5-trifluorodecyl-imidazo[1,2-a] ° than pyridine, [1, 2, 4] Triazolo[1,5-&]. Bis-pyridine and 6-gas-8-mercapto-[1,2,4]triazolo[1,5 a ]0 are 0-, -L- Is -C=C_, R1 is selected from the group consisting of murine, methyl, ethyl, 2-propyl, CH2CN and tetrahydropyran-4-yl-methyl; and R2-R6 are all hydrogen. Wherein one or more hydrogen atoms have been substituted by deuterium. In particular, hydrogen has been replaced by deuterium, wherein any of the substituents Ri to R6 is a mercapto or a decyloxy group. In some specific embodiments of the invention, The compound I is selected from the group consisting of a free base, one or more tautomers thereof, or a pharmaceutically acceptable In the form of the salt. Table 1 lists the compounds of the present invention. Each compound constitutes an individual specific example of the present invention: Table 1: Compound of the present invention Compound 5,7-dimercapto-2-(1-indolyl-4 -phenyl-1H-imidazol-2-ylethynyl)-imidazo[1,2-a]°i. 8-methyl-2-(1-indolyl-4-phenyl-1H-imidazole- 2-ylethynyl)-[1,2,4]triazole 19 201200516 and [1,5-a]° pyridine 5-methyl-2-(1-indolyl-4-phenyl-1H-imidazole -2-ylethynyl)-[1,2,4]triazolo[1,5-a]° pyridine 2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl )-[1,2,4]triazolo[1,5-巳]0 ratio. 2-(1-Mercapto-4-phenyl-1H-imidazol-2-ylethynyl)-5-(trifluoromethyl)imidazo[1,2-a]acridine 5.7-didecyl- 2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4] tris-sigma[1,5-a]B* ° 6.8-di 2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4] triazino[l,5-a]° ratio 0 5.7- Mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4] III. Sit and [1,5-a]° dense. 5.8-Dimercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4] III. Sit and [1,5-a]<nt ° to 5-methyl-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4] Triazolo[1,5-a]°Midine-7-ol 5-nonyl-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2 , 4] Triazolo[l,5-a]pyrimidine 5-methyl-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-7-morpholin-4- -[1,2,4]triazolo[l,5-a]pyrimidine 5,6,7-trimethyl-2-(1-methyl-4-phenyl-1H-imidazol-2-yl Ethynyl)-[1,2,4]triazolo[l,5-a]pyrimidine 5-methyl-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl) -7-phenyl201200516-[1,2,4]triazolo[1,5-3]pyrimidine 2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-5 , 6,7,8-tetrahydro-[1,2,4] III. Sit and [1,5 - a] ° than the ratio of 2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-1Η-imidazo[4,5-b] D 2-(1-Mercapto-4-phenyl-1H-imidazol-2-ylethynyl)-5-trifluoromethyl-[1,2,4]tris-[1,5-a]° dense. D--7-alcohol 8-methoxy-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]tridentate and [l,5 -a]D ratio. 7-Methoxy-5-mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[l,5 -a]pyrimidine 8-methoxy-4-indenyl-2-(d-decyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[l,5 -ap-pyridyl 8-fluoro-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[1,5-a]β ratio. 5-Ethyl-2-(1-indolyl-4-phenyl-1Η-imidazol-2-ylethynyl)-[1,2,4]triazolo[1,5-a]. Pyridinium 7-gas-8-ethyl-5-mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazole [l,5-c]pyrimidine 8-ethyl-5-mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4] Zizo[1,5-c]pyrimidine 5-difluoroindolyl-7-mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2 , 4] Triazolo[l,5-a]pyrimidine 5-indenyl-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-7-propyl 21 201200516 - [1,2,4]triazolo[l,5-a]pyrimidine 5.8-dimercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[l , 2, 4] III. Sit and [1,5 - a] ° than 7-decyloxy-5-mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1, 2,4]triazolo[l,5-c]pyrimidine 7-isopropyl-5-methyl-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)- [1,2,4]triazolo[1,5-a]pyrimidine 7-cyclopropyl-5-methyl-2-(1-methyl-4-phenyl-1H-imidazol-2-ylacetylene ))-[1,2,4]triazolo[l,5-a]pyrimidine 7-decyloxy-5,8-dimethyl-2-(1-indolyl-4-phenyl-1H- Imidazolyl-2-ylethynyl)-[1,2,4]triazolo[l,5-c]pyrimidine 5-methoxy-7-mercapto-2-(1-indolyl-4-phenyl -1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[l,5-a]pyrimidine 5.8-dimethyl-2-(1-indolyl-4-phenyl-1H -Imidazolyl-2-ylethynyl)-[1,2,4] III. Sit and [1,5 - c ] ° 密 0 7-methoxymethyl-5-mercapto-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)- [1,2,4]triazolo[l,5-a]pyrimidine 5,7-dimercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)- [1,2,4] III. Sit and [l,5-a]° sessile-6-alcohol 5-methyl-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-imidazo[1, 2-a]°tb ^ {5-mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[1, 5-a]pyrimidin-7-yl}-methanol 2-(8-methyl-imidazo[l,2-a]pyridin-2-yl)-1-(1-indolyl-4-phenyl-1H - 22 201200516 imidazol-2-yl)-ethanol 2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-5-pyridin-4-yl-[1,2,4] Three σ sit and [1,5-3] ° ratio. 2-(1-Mercapto-4-phenyl-1Η-imidazol-2-ylethynyl)-8-pyridin-4-yl-[1,2,4] III. Sit and [1,5-a]. Σσ 5-cyclopropyl-8-mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[l ,5-c]pyrimidine 8-mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[l,5- c]pyrimidine 8-ethyl-5-mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[l, 5-a]. Bisidine 5.8-dimethoxy-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[l,5-a] Acridine 8-methoxy-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-5-pyridin-4-yl-[1,2,4]triazole [l,5-a]. Bisidine 2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[l,5-a]pyridin-8-ol 5.8- Dimercapto-3-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[4,3-a]pyridin-5-indole 2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[1,5-a]° ratio σ-8 Alcohol 5-methoxy-2-(1-methyl-4-phenyl-1Η-imidazol-2-ylethynyl)-[1,2,4]trim[1,5-a]° ratio. 5.8-Dimercapto-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-imidazo 23 201200516 [l,2-a]. Illustrative: N-{2-(l-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-[l,2,4]triazolo[1,5 - a ] ° ratio Dine-8-yl}-ethanoamine 8-methoxy-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]three alpha And [1,5_a]D is more than morphine 8-ethynyl-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4] 1,5-a]*nt °N-{5-mercapto-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4] Zoxao[1,5-3]pyridin-8-yl}-acetamide 8-methoxy-5,6-dimercapto-2-(1-methyl-4-phenyl-1H-imidazole- 2-(2-ethynyl)-[1,2,4]triazolo[l,5-a] oxime: 5.8-dimercapto-2-(1-methyl-4-phenyl-1H-imidazole- 2-ylethynyl)-[1,2,4]triazolo[l,5_a]pyridin 7-oxide {5-methyl-2-(1-indolyl-4-phenyl-1H-imidazole -2-ylethynyl)-[1,2,4]triazolo[l,5-a]. Pentano-8-yl}-nonanol 5-mercapto-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[ 1,5-a]0 ratio. -8-carbonitrile 8-cyano-5-mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazole [l,5-a]. Bisino-6-capric acid ethyl ester 5.8-dimethyl-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4] 1,5-c] ° dense. 7-methoxyindolyl-5-methyl-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[l , 5-a] pyrimidine 5,7-dimercapto-2-(1-methyl-4-phenyl-111-imidazol-2-ylethynyl)-[1,2,4] 24 201200516 III. Sit and [l,5-a] mouth. Ding-6-ol 5-methyl-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-imidazo[1,2-a]0 ratio bite {5 -曱2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[l,5-a]pyrimidin-7-yl}- Sterol 2-(1-mercapto-4-phenyl-1H-imidazol-2-ylethynyl)-5-°pyridin-4-yl-[1,2,4] tris-sigma[1, 5 - a] ° ratio 2-(1-mercapto-4-phenyl-1H-imidazol-2-ylethynyl)-8-pyridin-4-yl-[1,2,4] And [1,5- a]σ ratio α is determined to be 5-cyclopropyl-8-fluorenyl-2 -(1-indolyl-4-phenyl-1Η-σ米σ sit-2-ylethyl fast radical) -[1,2,4]triazolo[l,5-c]pyrimidine

I 8-曱基-2-(1-曱基-4-笨基-1H-咪唑-2-基乙炔基）-[1，2,4]*** 并[1，5-c]°密。定 8-乙基-5-曱基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[l，5-a]吼啶 5.8- 二曱氧基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[l，5-a]吼啶 5.8- 二曱氧基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[l，5-a]。比啶 8-曱氧基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-5-吡啶 -4-基-[1,2,4]***并[1，5-&]。比啶 2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并 [1，5 - a ]π比 α定-8 -醉 5.8- 二曱基-3-(1-甲基-4-苯基-1Η-咪唑-2-基乙炔基）-[1，2,4] 25 201200516 ***并[4,3-a]吡啡 5-甲基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]*** 并[1，5- a]°比°定-8-醇 5 -甲基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1,2,4]*** 并[l，5-a]吼啶-8-醇 5-曱基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]*** 并[l，5-a]吡啶-8-醇 5-甲氧基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1,2,4]三。坐并[1，5-a]0比0定 5,8-二甲基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-咪唑并 [l，2-a]吡畊 Ν-{2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并 [1，5 - a ]D比。定-8-基}-乙酿胺 8-甲氧基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]三唑并[l,5-a]°比畊 8-乙炔基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]三 0坐并[l，5-a]。比咬 N-{5-曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1,2,4] ***并[l，5-a]吡啶-8-基}-乙醯胺 8-甲氧基-5,6-二甲基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[l，5_a]吡畊 {5-曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]三唑并[l，5-a]吡啡_8_基}-曱醇 5-曱基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]*** 26 201200516 并[l，5-a]»比啶-8-甲腈在本發明之一個特定具體實例中，本發明之化合物之 IC50值小於50 nM，諸如在0.2-20 nM之範圍内，尤其在 0.2-10 nM之範圍内，諸如在0.2-5 nM之範圍内或在0.2-1 nM之範圍内。IC5〇值可根據本發明之章節「PDE10抑制檢定」中揭示之方法測定。醫藥學上可接受之鹽本發明亦包含化合物之鹽，典型地醫藥學上可接受之鹽。此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。適合無機酸之代表性實例包括鹽酸、氫溴酸、氫碘酸、磷酸、硫酸、胺基磺酸、硝酸及其類似物。適合有機酸之代表性實例包括曱酸、乙酸、三氣乙酸、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 (itaconic)、乳酸、曱烷磺酸、順丁烯二酸、蘋果酸、丙二酸、杏仁酸、乙二酸、苦味酸、丙酮酸、水楊酸、丁二酸、 '曱烷磺酸、乙烷磺酸、酒石酸、抗壞血酸、雙羥萘酸、雙亞曱基水楊酸、乙烷二磺酸、葡萄糖酸、檸康酸 (citraconic )、天冬胺酸、硬脂酸、棕櫚酸、EDTA、乙醇酸、對胺基苯曱酸、麩胺酸、苯磺酸、對曱笨磺酸、茶鹼乙酸，以及8-齒茶鹼，例如8-溴茶鹼及其類似物。醫藥學上可接受之無機酸或有機酸加成鹽之其他實例包括Berge，S.Μ·等人，/. PAarm. 1977, 66, 2 (其内容係以引用的方式併入 27 201200516 本文中）中所列之醫藥學上可接受之鹽。此外’本發明之化合物可以非溶劑化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）形成之溶劑化形式存在。一般而言’為了本發明之目的，將溶劑化形式視為等效於非溶劑化形式。治療有效量在本發明之上下文中，術語化合物之「治療有效量」意謂在包含投予該化合物之治療性介入中足以治癒、緩解或部分停滞既定疾病及其併發症之臨床表現的量。足以實現此舉之量係定義為「治療有效量」。用於各目的之有效量將視疾病或損傷之嚴重度以及個體之體重及一般狀況而疋應瞭解，可使用常規貫驗，藉由構造值矩陣及測試矩陣中之不同點來確定適當劑量，其所有均在經過訓練之醫師之一般技能内。在本發明之上下文中，術語「治療」意謂管理及照料患者以達成對抗病狀（諸如疾病或病症）之目的。該術語思瓜包括患者所罹患之既定病狀之完整治療範圍，諸如投予活性化合物以緩解症狀或併發症、延緩疾病、病症或病狀之進展、緩解或減輕症狀及併發症，及/或治癒或消除疾病、病症或病狀，以及預防病狀，其中預防係視為管理及照料患者以達成對抗疾病、病狀或病症之目的且包括投予活性化合物以預防症狀或併發症之發作。然而預防性及治療性（治癒性）處理為本發明之兩個個別態樣。欲治療 28 201200516 之患者較佳為哺乳動物，尤其為人類醫藥組成物本發明進一步提供一種醫藥 « . τ . 、、，·成物，其包含治療有效量之式I化合物及醫藥學上可接 ^•之载劑或稀釋劑。本發明亦提供一種醫藥組成物，其包含 … 療有效量之一種在本文實驗章節中揭示之特定化合物請糸學上可接受之載劑或稀釋劑。本發明之化合物可以單次或多次劑量單獨投予或與醫藥學上可接受之載劑、稀釋劑或賦形劑組合投予。本發明之醫藥組成物可用醫藥學上可接受之載劑或稀釋劑以及根據習知技術（諸如Remington: The Science —〇fI 8-mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[1,5-c]° dense. 8-Ethyl-5-mercapto-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[l,5- a] acridine 5.8-dimethoxy-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[l,5- a] acridine 5.8-dimethoxy-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[l,5- a]. Bis-8-methoxy-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-5-pyridin-4-yl-[1,2,4]triazole [1,5-&]. Bisidine 2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[1,5 - a ]π ratio α--8 Drunk 5.8-dimercapto-3-(1-methyl-4-phenyl-1Η-imidazol-2-ylethynyl)-[1,2,4] 25 201200516 Triazolo[4,3-a] Pyridin 5-methyl-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[1,5-a]° ratio ̄-8-alcohol 5-methyl-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[l,5- a] acridine-8-ol 5-mercapto-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[l, 5-a]pyridine-8-ol 5-methoxy-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]tri. Sit and [1,5-a] 0 to 0 to determine 5,8-dimethyl-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-imidazo[1, 2-a]pyrazine-{2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[1,5 - a ] D ratio. -8-yl}-ethanoamine 8-methoxy-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazole [l,5-a]° is more than argon 8-ethynyl-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4] [l,5-a]. N-{5-mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[l,5-a Pyridine-8-yl}-acetamide 8-methoxy-5,6-dimethyl-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[ 1,2,4]triazolo[l,5_a]pyrazine {5-mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2 , 4] Triazolo[l,5-a]pyrimidin-8-yl}-nonanol 5-mercapto-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl -[1,2,4]triazole 26 201200516 and [l,5-a]»bipyridin-8-carbonitrile In a particular embodiment of the invention, the compound of the invention has an IC50 value of less than 50 nM, Such as in the range of 0.2-20 nM, especially in the range of 0.2-10 nM, such as in the range of 0.2-5 nM or in the range of 0.2-1 nM. The IC5 threshold can be determined according to the method disclosed in the section "PDE10 inhibition assay" of the present invention. Pharmaceutically Acceptable Salts The present invention also encompasses salts of the compounds, typically pharmaceutically acceptable salts. Such salts include pharmaceutically acceptable acid addition salts. Acid addition salts include inorganic acids and salts of organic acids. Representative examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, aminosulfonic acid, nitric acid, and the like. Representative examples of suitable organic acids include citric acid, acetic acid, tri-gas acetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, itaconic acid, itaconic acid, Lactic acid, decane sulfonic acid, maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, 'decane sulfonic acid, ethane sulfonate Acid, tartaric acid, ascorbic acid, pamoic acid, bis-indenyl salicylic acid, ethane disulfonic acid, gluconic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, EDTA, ethanol Acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, p-dosamine sulfonic acid, theophylline acetic acid, and 8-toophylline, such as 8-bromophylline and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include Berge, S., et al., /. PAarm. 1977, 66, 2 (the contents of which are hereby incorporated by reference in The pharmaceutically acceptable salts listed in the ). Further, the compounds of the present invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. Generally, for the purposes of the present invention, a solvated form is considered equivalent to an unsolvated form. Therapeutically Effective Amount In the context of the present invention, the term "therapeutically effective amount" of a compound means an amount sufficient to cure, alleviate or partially arrest a clinical manifestation of a given disease and its complications in a therapeutic intervention involving administration of the compound. A quantity sufficient to achieve this is defined as a "therapeutically effective amount." The effective amount for each purpose will be understood depending on the severity of the disease or injury and the weight and general condition of the individual. Conventional tests can be used to determine the appropriate dose by constructing a matrix of values and different points in the test matrix. All of them are within the general skills of a trained physician. In the context of the present invention, the term "treatment" means the management and care of a patient for the purpose of combating a condition, such as a disease or condition. The term includes the complete therapeutic range of a given condition in which the patient is suffering, such as administration of the active compound to relieve symptoms or complications, delaying the progression of the disease, disorder or condition, alleviating or alleviating symptoms and complications, and/or Curing or eliminating a disease, disorder or condition, and preventing a condition, wherein prevention is considered to manage and care for the patient for the purpose of combating the disease, condition or condition and includes administering the active compound to prevent the onset of symptoms or complications. However, prophylactic and therapeutic (curative) treatments are two distinct aspects of the invention. The patient to be treated 28 201200516 is preferably a mammal, especially a human pharmaceutical composition. The invention further provides a pharmaceutical «. τ.,,,, a composition comprising a therapeutically effective amount of a compound of formula I and pharmaceutically acceptable ^• Carrier or thinner. The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a particular compound disclosed in the experimental section herein, a drop-off carrier or diluent. The compounds of the invention may be administered alone or in combination with a pharmaceutically acceptable carrier, diluent or excipient, in single or multiple doses. The pharmaceutical composition of the present invention may be used as a pharmaceutically acceptable carrier or diluent and according to conventional techniques (such as Remington: The Science - 〇f)

Pharmacy，第 19 版，Gennar〇編，pubHshing 公司，Pharmacy, 19th edition, Gennar〇, pubHshing,

Easton’ PA，1995中所揭示者）之任何其他已知佐劑及賦形劑來調配。可特定調配醫藥組成物以便藉由任何適合途徑來投予，諸如經口、直腸、經鼻、肺部、局部（包括頰内及舌下）、經皮、腦池内、腹膜内、經***及非經腸（包括皮下、肌肉内、鞘内、靜脈内及皮内）途徑。應瞭解，途徑將視待治療個體之一般狀況及年齡、待治療病狀及活性成分之性質而定。供經口投予之醫藥組成物包括固體劑型，諸如膠囊、錠劑、糖衣藥丸、丸劑、***錠、散劑及顆粒劑。適當時，根據此項技術中熟知之方法，組成物可製備為具有包衣， 29 201200516 諸如腸溶衣’或其可經調配以提供活性成分之控制釋放，諸如持續或長期釋放。供經口投予之液體劑型包括溶液、乳液、懸浮液、糖漿及酏劑。供非經腸投予之醫藥組成物包括無菌水性及非水性可注射溶液、分散液、懸浮液或乳液以及在使用前在無菌可注射溶液或分散液中復原之無菌散劑。其他適合之投予形式包括（但不限於）拴劑、喷霧劑、軟膏劑、乳膏劑、凝膠'吸入劑' 真皮貼片及植入物。典型經口劑量介於每日每公斤體重約〇 00丨至約1 毫克之範圍内。典型經口劑量亦介於每日每公斤體重約0.01 至約50毫克之範圍内。典型經口劑量進一步介於每曰每公斤體重約0.05至約10毫克之範圍内。經口劑量通常以每日 ^多次劑量，典型地一至三次劑量投予。精確劑量將視投藥頻率及模式、所治療個體之性別、年齡、體重及一般狀況、所治療病狀及任何欲治療伴隨疾病之性質及嚴重度及熟習此項技術者顯而易知之其他因素而定。，調配物亦可藉由熟習此項技術者已知之方法以單位劑型呈現。& 了進行說明，供經口投予之典型單位劑型可含有約〇·(Η mg至約1000 mg、約〇〇5叫至約5〇〇呵，或約〇·5 mg 至約 200 mg。鞘内、肌肉内及類似對於非經腸途徑，諸如靜脈内投予途徑，典型劑量為經口投予所用劑量之一半的等級本發明亦提供—種製造醫藥組成物之方法，其包含混合治療有效量之式；!化合物與至少一種醫藥學上可接受之 30 201200516 載劑或稀釋劑。&女I a日+ „ 在本發明之一個具體實例中，上述方法中所用之化合物為—種在本文實驗章節中揭示之特定化合物0 本發明之化合物一般以自由物質或其醫藥學上可接受的开〆式利用。一個貫例為利用自由驗之化合物的酸加成鹽。當式I化合物含有自由鹼時，此等鹽係以習知方式藉由以莫耳當量之醫藥學上可接受之酸處理式I自由鹼之溶液或U液來製備。上文描述適合之有機酸及無機酸的代表性實例。對於非經腸投予，可採用式！化合物於無菌水溶液、丙二醇水溶液、維生素W溶液或芝麻油或花生油中之溶液。必要時宜緩衝此等水溶液且首先使液體稀釋液與足夠鹽水或葡萄糖等渗。水溶液尤其適用於靜脈内、肌肉内、皮下及腹膜内投予。可使用4習此項技術者已知之標準技術將式I化合物輕易併入已知無菌水性介質中。適合之醫藥載劑包括惰性固體稀釋劑或填料、無菌水溶液及各種有機溶劑。㈣載劑之㈣包括乳糖、白土（（咖 alba)、嚴糖、環糊精、滑石、明膠、瓊脂、果膠、*** 膠（acaeia)、硬脂酸鎂、硬脂酸及纖維素之低碳液體載劑之實例包括（但不限於）糖漿、花生油、橄欖油、鱗脂、脂肪酸、脂肪酸胺、聚氧化乙烯及水。類似地，載劑或稀釋劑可包括此項技術中已知之任何持續釋放物質，诸如單獨或與壞混合之單硬脂酸甘、士砂+ 卞又如θ夂甘油酯或二硬脂酸甘油酯。藉由組合式I化合物與醫荦擧Η 窗樂予上可接受之載劑形成的醫 31 201200516 藥組成物接著㈣以各種適用於所揭示投藥途徑之劑型來投予。藉由藥劑學技術中已知之方法’調配物宜型呈現。 w 適用於經口投予之本發明調配物可以個別單位呈現，諸=各自含有預定量活性成分及視情況選用之適合賦形劑的膠囊或旋劑。此外，經σ可得調配物可呈散劑或顆粒劑、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的形式。若將固體載劑用於經口投予，則製劑可經壓錠，以散劑或顆粒形式置於硬明膠膠囊中，或其可呈糖衣錠或*** 錠形式。固體載劑之量將廣泛變化，但將介於每劑量單位約25 mg至約1 g之範圍内。若使用液體載劑，則製劑可呈糖漿、乳液、軟明膠膠囊或無菌可注射液體（諸如水性或非水性液體懸浮液或溶液）之形式。本發明之醫藥組成物可藉由此項技術中之習知方法製備。舉例而言，錠劑可如下製備：混合活性成分與一般佐劑及/或稀釋劑，隨後在習知壓錠機中壓縮混合物，製備出錠劑。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、膠及其類似物.可使用通吊用於此等目的之任何其他佐劑或添加劑，諸如著色劑、調味劑、防腐劑等’限制條件為其與活性成分相容。治療病症如上所述，式Ϊ化合物為PDE10A酵素抑制劑且因此適 32 201200516 用於治療相關神經及精神病症。提供式1化合物或其醫藥學上可接受之 :二含有此化合物之醫藥組成物，其適用於治療哺乳動才（匕括人類）之神經退化性病症筚 , 病症係選自由以下者所組成之雜 ==兹海默氏症（AIzheimer,s Disease)、多梗塞性癌呆、相呆或其他藥物相關癡呆、與顱内腫瘤或腦創傷 Ατης '丙或ψ金森氏病相關之癡呆，咬 Α⑽相關癡呆；譫妄（delidum);失憶症·創傷後虔力症，智力遲純；學習障礙，例如閱讀障礙Any other known adjuvants and excipients as disclosed by Easton' PA, 1995 are formulated. The pharmaceutical composition can be specifically formulated for administration by any suitable route, such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, transvaginal and Parenteral (including subcutaneous, intramuscular, intrathecal, intravenous, and intradermal) routes. It will be appreciated that the route will depend on the general condition and age of the individual to be treated, the condition to be treated, and the nature of the active ingredient. Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, lozenges, dragees, pills, buccal tablets, powders, and granules. Where appropriate, the compositions may be prepared to have a coating according to methods well known in the art, 29 201200516 such as enteric coatings' or they may be formulated to provide controlled release of the active ingredient, such as sustained or prolonged release. Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs. The pharmaceutical compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions, and sterile powders which are reconstituted in sterile injectable solutions or dispersions before use. Other suitable dosage forms include, but are not limited to, elixirs, sprays, ointments, creams, gels, inhalants, dermal patches, and implants. Typical oral doses range from about 00 丨 to about 1 mg per kilogram of body weight per day. Typical oral doses are also in the range of from about 0.01 to about 50 mg per kilogram of body weight per day. Typical oral doses are further in the range of from about 0.05 to about 10 mg per kilogram of body weight per kilogram. Oral doses are usually administered in multiple doses per day, typically one to three doses. The precise dose will depend on the frequency and mode of administration, the sex, age, weight and general condition of the individual being treated, the condition being treated and any other factors which are intended to be treated with the nature and severity of the concomitant disease and which are readily apparent to those skilled in the art. set. Formulations may also be presented in unit dosage form by methods known to those skilled in the art. & It is stated that a typical unit dosage form for oral administration may contain about 〇·(Η mg to about 1000 mg, about 5 to about 5 ,, or about 〇·5 mg to about 200 mg. Intrathecal, intramuscular, and the like for parenteral routes, such as intravenous routes of administration, typical dosages are one-half of the doses administered orally. The present invention also provides a method of making a pharmaceutical composition comprising mixing A therapeutically effective amount of a compound and at least one pharmaceutically acceptable 30 201200516 carrier or diluent. & Female I a day + „ In one embodiment of the invention, the compound used in the above method is - Specific Compounds Revealed in the Experimental Sections herein The compounds of the present invention are generally utilized as free substances or in their pharmaceutically acceptable open form. One example is an acid addition salt utilizing a freely detectable compound. When the compound contains a free base, these salts are prepared in a conventional manner by treatment of a solution of the free base or a liquid of the formula I in a molar equivalent of a pharmaceutically acceptable acid. Suitable organic acids and inorganics are described above. acid A representative example of a parenteral administration can be a solution of a compound in a sterile aqueous solution, an aqueous solution of propylene glycol, a vitamin W solution or sesame oil or peanut oil. If necessary, buffer the aqueous solution and firstly dilute the liquid with sufficient saline. Or isotonic in water. The aqueous solution is especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The compounds of formula I can be readily incorporated into known sterile aqueous media using standard techniques known to those skilled in the art. Pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. (iv) Carriers (IV) include lactose, white clay ((alba), sucrose, cyclodextrin, talc, gelatin, agar, pectin, arab Examples of low carbon liquid carriers of acaeia, magnesium stearate, stearic acid and cellulose include, but are not limited to, syrup, peanut oil, olive oil, squamos, fatty acids, fatty acid amines, polyethylene oxide, and water. Similarly, the carrier or diluent can include any sustained release material known in the art, such as alone or in combination with bad脂甘、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、 Administration is carried out in a variety of dosage forms suitable for the disclosed routes of administration. Formulations are suitably formulated by methods known in the art of pharmacy. w Formulations of the invention suitable for oral administration can be presented in individual units, A capsule or a syringe containing a predetermined amount of the active ingredient and optionally a suitable excipient. In addition, the sigma may be obtained as a powder or granule, a solution or suspension in an aqueous or non-aqueous liquid, or a water-in-pack. In the form of an oily or water-in-oil liquid emulsion. If a solid carrier is used for oral administration, the preparation may be placed in a hard gelatin capsule in the form of a powder or granules, or it may be in the form of a sugar-coated or ingot. . The amount of solid carrier will vary widely, but will range from about 25 mg to about 1 g per dosage unit. If a liquid carrier is employed, the preparation may be in the form of a syrup, an emulsion, a soft gelatin capsule or a sterile injectable liquid such as an aqueous or nonaqueous liquid suspension or solution. The pharmaceutical composition of the present invention can be prepared by a conventional method in the art. For example, a tablet may be prepared by mixing the active ingredient with a conventional adjuvant and/or diluent, and then compressing the mixture in a conventional tablet press to prepare a tablet. Examples of adjuvants or diluents include: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums and the like. Any other adjuvant or additive may be used for such purposes, such as Colorants, flavoring agents, preservatives, and the like are limited in their ability to be compatible with the active ingredient. Treating Disorders As noted above, the guanidine compound is a PDE10A enzyme inhibitor and is therefore suitable for treating related neurological and psychiatric disorders. Provided is a compound of formula 1 or a pharmaceutically acceptable composition thereof; a pharmaceutical composition comprising the compound, which is suitable for use in the treatment of a neurodegenerative disorder of a mammalian (including human), the disorder being selected from the group consisting of Miscellaneous == AIzheimer, s Disease, multi-infarct cancer, dementia or other drug-related dementia, dementia associated with intracranial tumor or brain trauma 丙 ς ς 丙 or ψ金森氏病, bite Α (10) Related dementia; delidum; amnesia, post-traumatic stress disorder, mental retardation; learning disabilities, such as dyslexia

Si障礙;注意力缺乏，過動症;及年齡相關 ^中該精神病症係選自由以下者所組成之群組：精神分如偏狂型、錯亂型、緊張型、未分化型或殘:；礙症’類精神***症精神障礙；***情感性精神障物質：或抑#型***情感性精神障礙；妄想症；卡因病症’例如由酒精、***、***、可誘導之攻藉幻：、吸入劑、類鴉片或苯環己派咬(phencyclidine) 礙之精神病，·偏狂型人格障礙；及精神***症型人格障成應且其中藥物成癌為酒精、***、***或***劑他華合物或其醫藥學上可接受之鹽可與一或多種其狀發明之化合物具有效用 4 樂物在—起之組合比單獨之藥物更安全或更有另外’本發明之化合物可與-或多種治療、預防、控 33 201200516 =、改善或降低本發明之化合物之副作用或毒性之風 ::藥物組合使用。此等其他藥物可以為此常及 :與本發明之化合物同時或依次投予。因此，本發明二 =組成物包括除本發明之化合物外亦含有一或多種其他活性成分之醫藥組成物。該等組合可呈以下形式投予：、位劑型组合產品之-部分，或套組或治療方案，其中一或夕種其他藥物係以個別劑型、作為治療方案之-部分投予Γ 本發明提供一種治療罹串搜ώ 患選自認知病症或運動病症之神、盈退化性病症之哺乳動物（包 4入& I包括人類）的方法，該方法 13杈予個體治療有效量之式J化合物。本發明進-步提供一種治療哺乳動物（包括人類）之神經退化性病症或病狀之方法，老6亥方法包含投予該哺乳動物有效抑制PDE10之量的式J化合物。本發明亦提供一種治;麻fig $ ，丄縻1患精神病症之個體的方法，該方法包含投予該個體治療有效量之式ς化合物。可根據本發明治療之精神病症的實例包括（但不限於）精神***症，例如偏狂型、錯亂型、势徉』 %張ι、未为化型或殘餘型精神分裂症；類精神***症精神障礙；***情感性精神障礙，例如妄想型或抑鬱型***情感性精神障礙；妄想症；物質誘導之精神病症，例如由酒精、***、***、***、逑幻樂、吸入劑、類聽只赤貝媽片或本環己哌啶誘導之精神病；偏 51人格障礙，及精神***症型人格障礙；且焦慮症係選 U症’ It工曠症，特殊恐懼症；社交恐懼症；強迫症；創傷後壓力力症；及廣泛性焦慮症。 34 201200516 已發現式i化合物或其醫藥學上可接受之鹽宜與至少一種精神抑制劑（其可為典型或非典型抗精神病劑）組合投予以改善精神病症（諸如精神***症）之治療。本發= 之治療的組合、用途及方法亦可在治療不能適當反應於其他已知治療或對其他已知治療具有抗性之患者的治療中提供優勢。因此，本發明提供一種治療，展患精神病症（諸如精神 ***症）m動物的方法，該方法包含單獨投予或以連同至少-種精神抑制劑之組合療法的形式投予哺乳動物治療有效量之式I化合物。如本文所用，術語「精神抑制劑（neur〇leptic ag⑶G」係指減少患有精神病之患者的混亂、妄想、幻覺及心理動作躁動（PSyCh〇motor agitati〇n)之抗精神病劑藥物對認知及行為具有作用的藥⑯。精神抑制劑亦稱為強寧神劑及抗精神病藥’包括（但不限於）：典型抗精神病藥，包括啡㈣，其進-步分為脂肪族化合物、娘。定及娘畊”塞〇山（例如高抗素（eiscmiinGl))、苯丁酮（例如氟㈣醇）、二苯氧氮呼⑽⑶繼叫⑻川朴洛沙平⑷鄉㈣）、二氫^朵酮（例如嗎節鲷（m〇Hnd〇ne))、三苯基丁基派 =例如㈣清（_zide))，及非典型抗精神病藥，包括本并異腭唑（例如利培酮（risperidone ))、舍吲哚 C sertindole olanzapine quetiapine ) ' 奥沙奈坦（°Sanetant)及齊拉西酮（ziprasidone)。適用於本發明之尤其較佳精神抑制劑為舍吲哚、奥氮 35 201200516 平、利培酮、喹硫平、阿立哌唑（aripipraz〇1 / , · 、 J 氟派。定醇、氣氮平（clozapme )、齊拉西酮及奥沙奈坦。本發明進-步提供-種治療羅患認知病症之個體的方法，該方法包含投予該個體治療有效量之式丨化合物。可根據本發明治療之認知病症的實例包括（但不限於）阿:二默氏症、多梗塞性疲呆、酒中卷柯，齒笨十甘u — 甲每14癡呆或其他藥物相關癡呆、與顱内腫瘤或腦創傷相關之癡呆、盥亨 .. β ^ J明R病或帕金森氏病相關之癡呆，或AIDS相關癡呆；譫妄；失憔疒創傷後壓力症；智力遲純；學習障礙，例如閱讀障礙數學障礙或書寫表達障礙；注意力缺乏/過動症；及年齡相關認知衰退。本發明亦提供一種治療運動病症之方法，該方法包含投予個體治療有效量之式丨化合物。可根據本發明治療之運動：症的實例包括（但不限於）肖多巴胺促效劑：法相關之予丁頓氏病及運動困冑。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病症的方法，該方法包3 4又予個體治療有效量之式I化合物。本發明亦提供-種治療情緒病症之方法’該方法包含投予個體治療有效量之式！化合物。可根據本發明治療之情緒病症及情緒發作（_d epis〇de )的實例包括（但不限於）輕型、中型或重型之重度抑鬱發作、躁狂或混合型情緒發作、輕度蹲狂型情緒發作；具有典型特徵之抑營發作；具有沉鬱特徵之抑鬱發作；具有緊張特徵之抑鬱發作；具^ 產後初發之情緒發作；中風後抑鬱症；重度抑營症；低落 36 201200516 性情感障礙（dysthymie dis〇rder);輕度抑營症（ depressivedisorder);經前不悅症；精神***症之精神病後抑鬱症：重度抑鬱病症重疊諸如妄想症或精神***症之精神病症，雙極性情感性精神障礙，例如i型雙極性情感性精神障礙II型雙極性情感性精神障礙及循環情感性精神障礙。應瞭解，情緒病症為精神病症。 “本發明進一步提供一種治療哺乳動物（包括人類）之藥物成瘾（例如酒精、***、***或鶴片劑成應）之方去該方法包含投予該哺乳動物有效治療藥物成癮之量的式I化合物。本發明亦提供-種治療哺乳動物（包括人類）之藥物成癌（例如酒精、***、***或鴻片劑成幻之方法，該方法包含投予該哺乳動物有效抑制PDE10之量的式 I化合物。如本文所用，術語「藥物成癮」意謂對藥物之異常需要且一般特性化為動機干擾（motivational disturban^)，諸如服用所需藥物之強迫性及強烈藥物渴求之發作。普遍認為藥物成瘾是-種病理狀態。成瘾性病症包括急性用藥進展至產生尋藥行為、易復發，及反應於天然有益刺激物（naturally rewarding stimuli)之能力降低、減緩。舉例而言，The Diagnostic and Statistical ManualSi disorder; lack of attention, hyperactivity disorder; and age-related disorders in which the mental disorder is selected from the group consisting of: schizophrenia, disordered, nervous, undifferentiated or disabled; Insufficient schizophrenia mental disorder; schizoaffective mental disorder substance: or depression type schizophrenic psychosis; delusion; cardinal disease 'for example, alcohol, amphetamine, marijuana, inducible illusion: Inhalation, opioid or phencyclidine, mental disorder, mad personality disorder; and schizophrenia-type personality disorder and in which the drug is cancerous, alcohol, amphetamine, ***e or opiate The compound or a pharmaceutically acceptable salt thereof may have utility with one or more of the compounds of the invention. The combination of the music is safer or more in combination with the drug alone - or the compound of the present invention may be - or A variety of treatments, prevention, control 33 201200516 =, improve or reduce the side effects or toxicity of the compounds of the present invention:: combination of drugs. These other drugs may be used for this purpose either simultaneously or sequentially with the compounds of the invention. Accordingly, the present invention includes a pharmaceutical composition comprising one or more other active ingredients in addition to the compound of the present invention. The combinations may be administered in the form of a portion of a combination of dosage forms, or a kit or treatment regimen, wherein one or the other of the other drugs is administered in a separate dosage form as part of a therapeutic regimen. A method for treating a mammal selected from the group consisting of a cognitive or motor disorder, a mammal with a degenerative disorder (including a human), and a method for administering a therapeutically effective amount of a compound of formula J to a subject. . The present invention further provides a method of treating a neurodegenerative disorder or condition in a mammal, including a human, comprising administering a compound of formula J which is effective to inhibit PDE10 by the mammal. The invention also provides a method of treating a subject suffering from a psychiatric disorder, the method comprising administering to the individual a therapeutically effective amount of a compound of the formula. Examples of psychiatric disorders that can be treated in accordance with the present invention include, but are not limited to, schizophrenia, such as madness, disorder, sputum, sputum, unsexual or residual schizophrenia; schizophrenia Mental disorders; schizoaffective disorders, such as delusional or depressive schizoaffective disorders; delusions; substance-induced psychotic disorders, such as alcohol, amphetamines, marijuana, ***e, scorpio, inhalants, Pico-Mama tablets or this cyclohexaphene-induced psychosis; 51 personality disorder, and schizophrenia type personality disorder; and anxiety disorder selected U disease 'It work stagnation, special phobia; social phobia; obsessive-compulsive disorder; Post-traumatic stress disorder; and generalized anxiety disorder. 34 201200516 It has been found that a compound of formula i or a pharmaceutically acceptable salt thereof is preferably administered in combination with at least one psychoactive inhibitor which may be a typical or atypical antipsychotic to ameliorate the treatment of a psychiatric disorder, such as schizophrenia. The combination, use, and method of treatment of the present invention can also provide advantages in the treatment of patients who are not adequately responsive to other known treatments or who are resistant to other known therapies. Accordingly, the present invention provides a method of treating an animal exhibiting a psychiatric disorder (such as schizophrenia), the method comprising administering to the mammal a therapeutically effective amount either alone or in combination with at least one psychotropic inhibitor. A compound of formula I. As used herein, the term "neur〇leptic ag(3)G" refers to the antipsychotic drug for cognitive and behavioral reduction of confusion, delusions, hallucinations and psychomotor agitation (PSyCh〇motor agitati〇n) in patients with psychosis. Acting drugs 16. Psychoactive inhibitors are also known as Qiang Ning Shen and antipsychotic drugs 'including but not limited to: typical antipsychotic drugs, including brown (four), which is further divided into aliphatic compounds, mother. And mother-in-law" Seychelles (such as eiscmiinGl), phenylbutanone (such as fluoro (tetra) alcohol), benzophenone (10) (3) followed by (8) Chuan Puluoping (4) township (four)), dihydro ^ Ketones (eg, m〇Hnd〇ne), triphenylbutylene = (4) clear (_zide), and atypical antipsychotics, including the present isoxazole (eg risperidone) )), ser 吲哚 ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser ser Risperidone, quetiapine, aripiprazole (ari Pipraz〇1 / , · , J Fluorine. Determination of alcohol, clozapme, ziprasidone and oxatanide. The present invention further provides a method for treating a subject suffering from a cognitive disorder, the method A therapeutically effective amount of a guanidine compound is administered to the subject. Examples of cognitive disorders that can be treated in accordance with the present invention include, but are not limited to, A: Ermer's disease, multi-infarct fatigue, alcoholic sputum, tooth stupid Ganu — A dementia per 14 or other drug-related dementia, dementia associated with intracranial tumor or brain trauma, Qiheng.. β ^ J Ming R disease or Parkinson's disease-related dementia, or AIDS-related dementia; Post-traumatic stress disorder; mental retardation; learning disabilities, such as dyslexia mathematics or writing expression disorders; attention deficit/hyperactivity disorder; and age-related cognitive decline. The present invention also provides a method for treating a sports disorder, The method comprises administering to the individual a therapeutically effective amount of a compound of the formula. The exercise that can be treated according to the invention: examples of but not limited to, the dobutamine agonist: the law-related Dytenton's disease and exercise disorders The invention further provides a method of treating a motor condition selected from the group consisting of Parkinson's disease and leg restlessness syndrome, the method further comprising administering to the individual a therapeutically effective amount of a compound of formula I. The invention also provides a method for treating an emotional condition 'This method comprises administering to a subject a therapeutically effective amount! Compounds. Examples of mood disorders and mood episodes (_d epis〇de) that can be treated according to the invention include, but are not limited to, mild, moderate or severe severe depressive episodes, Manic or mixed emotional episodes, mild manic episodes; episodes of depression with typical characteristics; depressive episodes with depression; depressive episodes with stressful characteristics; emotional episodes with postpartum postpartum; post-stroke depression Symptoms; severe depression; depression 36 201200516 Sexual affective disorder (dysthymie dis〇rder); mild depression (depressivedisorder); premenstrual discomfort; post-psychotic depression of schizophrenia: overlap of major depressive disorders such as delusions Mental disorder of schizophrenia or schizophrenia, bipolar affective disorder, such as i-type bipolar affective disorder II Bipolar affective disorder and circulatory affective disorder. It should be understood that an emotional condition is a mental condition. "The present invention further provides a method of treating a drug addiction (e.g., alcohol, amphetamine, ***e, or crane tablet) in a mammal, including a human, to the method comprising administering to the mammal an amount effective to treat the drug addiction. A compound of formula I. The invention also provides a method of treating a cancer of a mammal, including a human, into a cancer (eg, alcohol, amphetamine, ***e, or tablets), the method comprising administering to the mammal an amount effective to inhibit PDE10 A compound of formula I. As used herein, the term "drug addiction" means an abnormal need for a drug and is generally characterized by a motivational disturbance, such as the compulsiveness of taking the desired drug and the onset of a strong drug craving. Drug addiction is generally considered to be a pathological condition. Addictive conditions include the progression of acute medication to the production of drug-seeking behavior, recurrence, and reduced ability to respond to natural rewarding stimuli, for example. The Diagnostic and Statistical Manual

Disorders，第四版（DSM_IV)已將成癮分類為三個階段：先占（preoccupation) /期盼（anticipati〇n)、無節制（心⑷ /中毒，及戒除/負面影響。此等階段在各處經分別特性化為 37 201200516 獲得物質之恆定渴望及先占；使用多於必需之物質而經歷Disorders, Fourth Edition (DSM_IV) has classified addiction into three phases: preoccupation/anticipati〇n, incontinence (heart (4)/poisoning, and abstinence/negative effects. These stages are in each Characterized by 37 201200516 to obtain a constant desire and preoccupation of the substance; experience with more than necessary substances

機降低。The machine is lowered.

包含投予該哺乳動物有效治療該病症之量的式合物。可根據本發明治療之其他病症為強迫症、妥瑞症候群 (Tourette’s syndrome )及其他痙攣病症。如本文所用，且除非另外規定，否則否則「神經退化性病症或病狀」係指由中樞神經系統中神經元之功能異常及/或死亡引起之病症或病狀。投予預防處於此等病症或病狀風險中之神經元之功能異常或死亡及/或增強受損或健康神經元之功能的藥劑可以補償由處於風險中之神經元的功能異常或死亡引起之功能損失的方式促進對此等病症及病狀之治療。如本文所用，術語「神經營養劑（neurotr〇phic agent)」係指具有一些或所有此等特性之物質或藥劑。可根據本發明治療之神經退化性病症及病狀的實例包括（但不限於）帕金森氏病；亨丁頓氏病；癡呆，例如阿茲海默氏症、多梗塞性癡呆、AIDS相關癡呆，及額顳葉型癡呆（Fronto temperal Dementia );與腦創傷相關之神經退化；與中風相關之神經退化、與腦梗塞相關之神經退化；低血糖症誘導之神經退化；與癲、癇發作相關之神經退化；與神經毒素中毒相關之神經退化；及多系統萎縮。在本發明之一個具體實例中，神經退化性病症或病狀 38 201200516 涉及哺乳動物（包括人類）體内紋狀體中型多棘神經元之神經退化。一在本發明之另一具體實例中’神經退化性病症或病狀為予丁頓氏病。在另八體貫例中，本發明提供一種治療個體以減少體脂肪或體重，或治療非胰島素需求性糖尿病（NIDDM)、代謝症候群或葡萄糖不耐之方法，其包含投予有需體治療有效量之式Ϊ化合物。在較佳具體實例中，個體為人類，個體過重或肥胖且經口投予括抗劑。在另一較佳具體實例中，該方法進-步包含投予該個體第二治療劑，較佳為抗肥胖劑，例如利莫納班（rimonabant )、羅氏鮮 (orhstat )、***（sibutramine )、溴麥角環肽 (bromocriptine)、麻黃素（ephedrine)、瘦素（㈣叫、假麻黃素（pseudoephedrine)或肽YY3-36，或其類似物。如本文所用，術語「代謝症候群」係指將人置於高冠狀動脈病風險中之病狀的群集。此等病狀包括2型糖尿病= 肥胖症、高血壓，及具有冑LDL (「不良」）膽固醇、低 HDL (「良好」）膽固醇及高三酸甘油酯之不良脂質特徵。所有此等病狀均與血液胰島素高含量相關。代謝症候群之基本缺陷在於脂肪組織與肌肉之膜島素抗性。本說明書中所引用之所有參考文獻，包括公開案、專利申請案及專利均以全文引用的方式併入本文中，且其引用的程度如同個別且特定地將各參考文獻以全文引用的方式併入及闡述一般（達法律允許之最大程度）β 39 201200516 所有標題及副標題在本文中僅為方便而使用且不應被視為以任何方式限制本發明。 " 除非另外規定，否則在本說明書中使用任何及所有實，，或例示性語言（包括「例如/舉例而言」、「例如」及諸如」）均僅意欲較好地說明本發明，且不對本發明之範鳴造成限制。在本文中僅為了便利而引用及併有專利文件且不反映此等專利文件之有效性、可專利性及/或可執行性的任何觀如適用法律所允許，本發明包括隨附申請專利範圍中所述之標的物的所有修改及等效物。實驗章節製備本發明之化合物Formulations are included which are administered to the mammal in an amount 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 delirium conditions. As used herein, and unless otherwise specified, "neurodegenerative disease or condition" refers to a condition or condition caused by dysfunction and/or death of a neuron in the central nervous system. Administration of an agent that prevents dysfunction or death of a neuron at risk of such a condition or condition and/or enhances the function of an impaired or healthy neuron may compensate for dysfunction or death of a neuron at risk The loss of function promotes the treatment of these conditions and conditions. As used herein, the term "neurotr〇phic agent" 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, AIDS-related dementia , and Fronto temperal Dementia; neurodegeneration associated with brain trauma; neurodegeneration associated with stroke, neurodegeneration associated with cerebral infarction; neurodegeneration induced by hypoglycemia; associated with epileptic seizures Neurodegeneration; neurodegeneration associated with neurotoxin poisoning; and multiple system atrophy. In one embodiment of the invention, a neurodegenerative disorder or condition 38 201200516 relates to neurodegeneration of striatal mid-spine neurons in mammals, including humans. In another embodiment of the invention, the neurodegenerative disorder or condition is Dytenton's disease. In another embodiment, the invention provides a method of treating an individual to reduce body fat or body weight, or treating non-insulin demanding diabetes mellitus (NIDDM), metabolic syndrome or glucose intolerance, comprising administering an active body treatment effective Amount of hydrazine compound. In a preferred embodiment, the individual is a human, the individual is overweight or obese and orally administered. In another preferred embodiment, the method further comprises administering to the individual a second therapeutic agent, preferably an anti-obesity agent, such as rimonabant, orhstat, sibutramine (sibutramine), bromocriptine, ephedrine, leptin (p), pseudoephedrine or peptide YY3-36, or an analogue thereof. As used herein, the term " "Metabolic syndrome" refers to a cluster of conditions that place people at risk of high coronary artery disease. These conditions include type 2 diabetes = obesity, high blood pressure, and sputum LDL ("bad") cholesterol, low HDL ( "Good") Bad lipid characteristics of cholesterol and high triglycerides All of these conditions are associated with high levels of blood insulin. The basic deficiency of metabolic syndrome is the resistance of adipose tissue to muscle membranes. All references, including publications, patent applications, and patents, are hereby incorporated by reference in their entirety in their entirety in the extent the the the the the the Incorporation and elaboration in general (to the maximum extent permitted by law) β 39 201200516 All headings and subheadings are used herein for convenience only and are not to be construed as limiting the invention in any way. " Unless otherwise stated, The use of any and all examples of the invention, such as "such as" In this document, any reference to and convenience of patent documents and without reflecting the validity, patentability and/or enforceability of such patent documents, as permitted by applicable law, includes the scope of the accompanying claims. All modifications and equivalents of the subject matter described herein. Experimental Section Preparation of Compounds of the Invention

本發明之通式I化合物可如以下反應流程中所述來製備。除非另外規定，否則在以下反應流程及討論中，HET、 Ri-R9、-L-、Z及Y係如上所定義。式Ϊ化合物（其中L包含參鍵）可如流程1中所示藉由式1v咪β坐基炔烴與式in雜芳基ii化物之間的偶合反應 201200516 或藉由式v雜芳基炔烴與式VI咪唑基鹵化物之間的逆向偶合(reverse coupling )來製備。The compounds of formula I of the present invention can be prepared as described in the following reaction schemes. Unless otherwise specified, in the following reaction schemes and discussions, HET, Ri-R9, -L-, Z, and Y are as defined above. A hydrazine compound (wherein L comprises a hydrazone bond) can be coupled as described in Scheme 1 by a coupling reaction between a formula 1v of a beta-synthesis alkyne and a compound of a heteroaryl ii compound 201200516 or by a formula v heteroaryl alkyne The reverse coupling between the hydrocarbon and the imidazolium halide of formula VI is prepared.

此反應典型地在適合溶劑（諸如四氫呋喃）中進行且如下進行：混合雜芳基齒化物與雜芳基炔烴以及適合之催化劑’例如蛾化銅（I)，與膦配位體’例如1，丨，-雙（二苯膦基） —茂鐵-二氯化鈀（ii)二氣甲烷錯合物，及有機鹼，如三乙胺接著在密封之小瓶中在！ 2〇。(3下加熱反應液丨5分鐘（微波）。以下非限制性實施例進一步說明本文所揭示之發明。通用方法分析性LC-MS資料可使用一種以下方法獲得。方法A : 41 201200516 使用配備有大氣壓光電離（atmospheric pressure photo ionisation)及 Shimadzu LC-8A/SLC-10A LC 系統之 PE Sciex API 150EX儀器。管柱：具有3.5 // m粒度之4.6x30 mmThis reaction is typically carried out in a suitable solvent such as tetrahydrofuran and is carried out by mixing a heteroaryl dentate with a heteroarylalkyne and a suitable catalyst such as copper molybdenum (I) and a phosphine ligand 'for example 1 , hydrazine, - bis(diphenylphosphino)-ferrocene-palladium dichloride (ii) di-methane methane complex, and an organic base such as triethylamine in a sealed vial! 2〇. (The reaction solution is heated for 5 minutes (microwave). The following non-limiting examples further illustrate the invention disclosed herein. General Methods Analytical LC-MS data can be obtained using one of the following methods. Method A: 41 201200516 Atmospheric pressure photo ionisation and PE Sciex API 150EX instrument from Shimadzu LC-8A/SLC-10A LC system. Column: 4.6x30 mm with a particle size of 3.5 // m

Waters Symmetry C18 管柱；柱溫：60°C ;溶劑系統：A = 水/三氟乙酸（100:0.05 )且 B =水/乙腈/三氟乙酸 (5:95:0.035 ):方法：用 A:B = 90:10 至 0:100 (在 2.4 分鐘内）且流動速率為3.3 mL/min之線性梯度洗提。方法B : 使用具有G1946C或G1946A質量偵測器之Agilent 1100 LCMS系統。管柱：具有5 // m粒度之2.0x50 mm YMC ODS-AQ;柱溫：50°C ;溶劑系統：A =水/三氟乙酸（99.9:0.1 ) 且B=乙腈/三氟乙酸（99.95:0.05 );方法：用A:B = 95:5 至0:100 (在3.5分鐘内）且流動速率為0.8 mL/min之線性梯度洗提。方法C :Waters Symmetry C18 column; column temperature: 60 ° C; solvent system: A = water / trifluoroacetic acid (100: 0.05) and B = water / acetonitrile / trifluoroacetic acid (5: 95: 0.035): Method: with A :B = 90:10 to 0:100 (within 2.4 minutes) and a linear gradient elution with a flow rate of 3.3 mL/min. Method B: An Agilent 1100 LCMS system with a G1946C or G1946A mass detector was used. Column: 2.0x50 mm YMC ODS-AQ with 5 // m particle size; column temperature: 50 ° C; solvent system: A = water / trifluoroacetic acid (99.9: 0.1) and B = acetonitrile / trifluoroacetic acid (99.95 :0.05); Method: eluted with a linear gradient of A:B = 95:5 to 0:100 (within 3.5 minutes) and a flow rate of 0.8 mL/min. Method C:

使用配備有大氣壓光電離及Waters UPLC系統之PEUse PE equipped with atmospheric pressure photoionization and Waters UPLC system

Sciex API 300 儀器。管柱：AcqUity UPLC BEH C18 1.7 μ111 ’ 2.1x5 0 mm ( Waters);柱溫：6(TC ;溶劑系統：Α =水/三敗乙酸（100:0.05 )且B =水/乙腈/三氟乙酸（5:95:〇·〇35 ); 方法：用A:B = 90:10至0:10〇 (在ίο分鐘内）且流動速率為1.2 mL/min之線性梯度洗提。 42 201200516 方法D : 使用具有G1946C或G1946A質量偵測器之Agilent 1100 LCMS系統。管柱：具有5 /zm粒度之2.0x50 mm YMC ODS-AQ;柱溫：5〇°c ;溶劑系統：A =水/三氟乙酸（99.9:0.1 ) 且B=乙腈/三氟乙酸（ 99.95:0.05);方法：用A:B = 90:10 至0:100 (在3.4分鐘内）且流動速率為0.8 mL/min之線性梯度洗提。方法E : 使用配備有大氣壓光電離及Shimadzu LC-8A/SLC-10A LC系統之PE Sciex API 150EX儀器。管柱：具有3.5 μ m 粒度之 4.6x30 mm Waters Symmetry C18 管柱；柱溫：60 °C ; 溶劑系.統：A =水/三氟乙酸（99.95:0.05 )且B =甲醇/三氟乙酸（.99.965:0.035);方法：用 A:B = 83:17 至 0:100(在 2.4分鐘内）且流動速率為3.0 mL/min之線性梯度洗提。在具有大氣壓化學電離之PE Sciex API 150EX儀器上進行製備型LC-MS純化。管柱：具有5 Μ爪粒度之50x20 mm YMC ODS-A ;方法：用 a:B = 80:20 至 0:100 (在 7 分鐘内）且流動速率為22.7毫升/分鐘之線性梯度洗提。藉由分流MS偵測收集洗提份。在 Bruker Avance AV500 儀器上在 500.13 MHz 下或在 Bruker Avance DPX250 儀器上在 250.13 MHz 下記錄 NMR光譜。將TMS用作内部參考標準物。以ppm表示化 43 201200516 學位移值。將以下縮寫用於NMR信號之多重性：s =單峰、 d—雙重峰、t=三重峰、q=四重峰、qUi=五重峰、h =七重峰、dd =兩組雙重峰、dt =兩組三重峰、dq =兩組四重峰、 tt=二組三重峰、^^：：；；多重峰、brs=寬單峰且br=寬信號。縮寫係根據 ACS Style Guide:「The ACS Styleguide - A manual for authors and editors」Janet S. Dodd 編· 1997，ISBN: 0841234620 。藥理學測試 PDE10A酵素以許多適用於PDE檢定之方式製備活性PDE10A酵素 (Loughney，K·等人，Gene 1999, 109-117; Fujishige，K. 等人，i：Mr «/ 1999, 26(5，1118-1127 及 Soderling，S. 等人，Scz. 1999, P(5, 7071-7076 )。PDE 10A 可表現為全長蛋白質或截短蛋白質，前提為其表現催化域。PDE 10A可在不同細胞類型（例如昆蟲細胞或大腸桿菌 (E· coli))中製備。獲得催化活性PDE10A之方法的實施例如下：自全人腦全 rNA ( total human brain total RNA ) 藉由標準RT-PCR擴增人類PDE10A之催化域（具有寄存編號NP 006652之序列的胺基酸440-779 )且將其選殖於 pET28a載體（Novagen)之BamHl及Xhol位點。根據標準方案表現於大腸桿菌中。簡言之，將表現質體轉型至BL21 (DE3 )大腸桿菌株中，且以在蛋白質表現之前允許生長至 44 201200516Sciex API 300 instrument. Column: AcqUity UPLC BEH C18 1.7 μ111 ' 2.1x5 0 mm (Waters); column temperature: 6 (TC; solvent system: Α = water / tri-acetic acid (100:0.05) and B = water / acetonitrile / trifluoroacetic acid (5:95: 〇·〇35); Method: elute with a linear gradient of A:B = 90:10 to 0:10 〇 (within ίο minutes) and a flow rate of 1.2 mL/min. 42 201200516 Method D : Agilent 1100 LCMS system with G1946C or G1946A mass detector. Column: 2.0x50 mm YMC ODS-AQ with 5 /zm particle size; column temperature: 5 〇 °c; solvent system: A = water / trifluoro Acetic acid (99.9:0.1) and B=acetonitrile/trifluoroacetic acid (99.95:0.05); Method: Linearity with A:B = 90:10 to 0:100 (within 3.4 minutes) and a flow rate of 0.8 mL/min Gradient elution Method E: PE Sciex API 150EX instrument equipped with atmospheric pressure photoionization and Shimadzu LC-8A/SLC-10A LC system. Column: 4.6 x 30 mm Waters Symmetry C18 column with 3.5 μm particle size; Temperature: 60 ° C; Solvent system: A = water / trifluoroacetic acid (99.95: 0.05) and B = methanol / trifluoroacetic acid (.99.965: 0.035); Method: with A: B = 83:17 to 0 : 100 (within 2.4 minutes) and flowing Linear gradient elution at a rate of 3.0 mL/min. Preparative LC-MS purification on a PE Sciex API 150EX instrument with atmospheric pressure chemical ionization. Column: 50 x 20 mm YMC ODS-A with 5 paw size; Method: Linear gradient elution with a:B = 80:20 to 0:100 (within 7 minutes) and a flow rate of 22.7 ml/min. The elution fraction was collected by shunt MS detection. On the Bruker Avance AV500 instrument NMR spectra were recorded at 500.13 MHz or at 250.13 MHz on a Bruker Avance DPX250 instrument. TMS was used as an internal reference standard. The value of the displacement was expressed in ppm. The following abbreviations were used for the multiplicity of NMR signals: s = Single peak, d-double peak, t=triple peak, q=quadruple peak, qUi=five peak, h=seven peak, dd=two sets of double peaks, dt=two sets of triplet, dq=two groups of four Peak, tt = two sets of triplet, ^^::;; multiplet, brs = wide single peak and br = wide signal. The abbreviations are based on the ACS Style Guide: "The ACS Styleguide - A manual for authors and editors" by Janet S. Dodd, 1997, ISBN: 0841234620. Pharmacological Testing PDE10A Enzymes Active PDE10A enzymes are prepared in a number of ways suitable for PDE assays (Loughney, K. et al., Gene 1999, 109-117; Fujishige, K. et al., i: Mr «/ 1999, 26(5, 1118-1127 and Soderling, S. et al., Scz. 1999, P(5, 7071-7076). PDE 10A can be expressed as a full-length protein or a truncated protein, provided that it exhibits a catalytic domain. PDE 10A can be in different cell types. Prepared in (for example, insect cells or E. coli). The method for obtaining catalytically active PDE10A is as follows: Amplification of human PDE10A by standard RT-PCR from total human brain total RNA The catalytic domain (amino acid 440-779 with the sequence of accession number NP 006652) was cloned into the BamHl and Xhol sites of the pET28a vector (Novagen) and was expressed in E. coli according to standard protocols. Briefly, Transforming the expression plastid into the BL21 (DE3) E. coli strain and allowing growth to 44 before the protein is expressed 2012 201216

0.4-0.6之OD600的細胞接種50 mL培養物，以0.5 mM IPTG 誘導。誘導之後，在室溫下培育細胞隔夜，之後藉由離心收集細胞。將表現PDE10A之細胞再懸浮於i 2 mL ( 5〇 mM TRIS-HCl-pH8.0、1 mM MgCl2及蛋白酶抑制劑）中。藉由音波處理溶解細胞’且在所有細胞均溶解之後，根據 Novagen方案添加TritonXlOO。在q瓊脂糖凝膠上部分純化PDE1 0 A且彙集大多數活性洗提份。 PDE10A抑制檢定 PDE10A檢定例如可如下進行：在含有固定量之相關 PDE酵素（足以轉化20-25%環核苷酸受質）、緩衝液（5〇 ' 0-1 mg/ml HEPES7.6 ； 10 mM MgCl2 ；〇.〇2〇/0 Tween20) BSA、225 pCi標記3Η之環核芽酸受質、標記氚之cAMp(最終濃度達5 nM)及變化量之抑制劑的6〇 “I樣本中進行檢定。藉由添加環核苷酸受質起始反應，且使反應在室溫下進行1小時，隨後經由與15 〃L8mg/mL石夕酸在乙卯八珠粒（Amersham)混合來終止。使珠粒在黑暗中沈降丨小時，隨後在Wallac 1450 Microbeta計數器中對培養盤進行計數。可將量測到之信號轉化為相對於未受抑制之對照組 (100% )的活性且可使用EXCEL之Xlm擴展（幻出 extension to EXCEL)計算 ic50 值。 20-25% β L檢 0-02% 在本發明上下文中，檢定係在含有足以轉化 10nM3H-cAMP之PDE10A及變化量之抑制劑的定緩衝液（50mMHEPES(pH7.6) ; 1〇mMMgCi2 45 201200516Cells of 0.4-0.6 OD600 were inoculated with 50 mL cultures and induced with 0.5 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 i 2 mL (5 mM mM TRIS-HCl-pH 8.0, 1 mM MgCl2 and protease inhibitor). Triton X100 was added according to the Novagen protocol after sonication of the cells by sonication and after all cells were dissolved. PDE10A was partially purified on a q agarose gel and most of the active fractions were pooled. PDE10A Inhibition Assay The PDE10A assay can be performed, for example, by containing a fixed amount of the relevant PDE enzyme (sufficient to convert 20-25% cyclic nucleotide receptor), buffer (5〇' 0-1 mg/ml HEPES7.6; 10 mM MgCl2 ; 〇.〇2〇/0 Tween20) BSA, 225 pCi labeled 3Η cyclonuclear acid physic acid, labeled 氚 cAMp (final concentration up to 5 nM) and varying amounts of inhibitors in 6〇 “I sample The assay was carried out by adding a cyclic nucleotide to initiate the reaction, and the reaction was allowed to proceed at room temperature for 1 hour, followed by termination by mixing with 15 〃L8 mg/mL of oxalic acid in Ampere. The beads were allowed to settle in the dark for a few hours, then the plates were counted in a Wallac 1450 Microbeta counter. The measured signal was converted to activity relative to the uninhibited control (100%) and used EXCEL's Xlm extension (extension to EXCEL) calculates the ic50 value. 20-25% β L detection 0-02% In the context of the present invention, the assay is contained in an inhibitor containing PDE10A and a varying amount of inhibitor sufficient to convert 10 nM 3H-cAMP Buffer (50mMHEPES (pH7.6); 1〇mMMgCi2 45 201200516

Tween2〇)中進行。培育1小時之後，藉由添加15 " L 8 mg/mL石夕西夂紀SP A珠粒（Amersham )來終止反應。使珠粒在黑暗中沈降一小時，隨後在WaUac 145〇 Micr〇beta計數器中對培養盤進行計數。使用XLfit ( IDBS )藉由非直線回歸來計算IC5C值。苯環己哌啶（PCP)誘導之高活動性使用重 20-25 g 之雄性小鼠（NMRI，Charles River)。接收測試化合物（5 mg/kg)加pcp( 2 3 mg/kg)之各組（包括接收測試化合物之媒劑加PCP或僅媒劑注射液之平行對照組）使用八隻小鼠。注射體積為1〇 mL/kg ^在不受干擾之房間中以正常光條件進行實驗。在注射PCP之前每60分鐘庄射測試物質，其為皮下投予。在注射PCP之後立即將小鼠個別地置於特定設計之測试龍(200111)(32(:111) 肖 ns /1 ；ψ藉由間隔4 cm之5x8紅外線光源及光電池量測活性。弁击尤滋& u 士，。 . 尤采在籠底上方1.8 cm穿過籠。記錄活動性計數需要中斷相鄰先爽 I仰州尤禾，因此避免由小鼠之固定運動（stationary movement)誘導之計數。 :5分鐘間隔記錄活動性歷時i小時。用以下方式以【小時行為測試週期期間之總計數計算藥效：由…PCP存在下之媒劑治療誘導之平均活動性用作基線。因此，，總活動性計數減去基線即計為PCP^ 100%作用。接收測試化合物之組的反應因此藉由總活動性計數減去基線（以平行PCP對照組中記錄之類似結果之百分比表 46 201200516 示）來測定。將反應百分比轉化為抑制百分比。【圖式簡單說明】無【主要元件符號說明】無 47In Tween2〇). After 1 hour of incubation, the reaction was stopped by the addition of 15 " L 8 mg/mL Shixi Xiji SP A beads (Amersham). The beads were allowed to settle in the dark for one hour and then the plates were counted in a WaUac 145 〇 Micr〇beta counter. IC5C values were calculated by non-linear regression using XLfit (IDBS). High Activity Induced by Phenylcyclohexyl Piperidine (PCP) Male mice weighing 20-25 g (NMRI, Charles River) were used. Eight mice were used to receive each of the test compound (5 mg/kg) plus pcc (23 mg/kg) (including the vehicle receiving the test compound plus the PCP or the vehicle-only injection). The injection volume was 1 〇 mL/kg ^ and the experiment was performed under normal light conditions in an undisturbed room. The test substance was smeared every 60 minutes prior to injection of PCP, which was administered subcutaneously. Immediately after the injection of PCP, the mice were individually placed in a specific design test dragon (200111) (32 (: 111) Xiao ns /1; ψ by 5 x 8 infrared light source and photocell measurement activity at intervals of 4 cm. Sniper Yuzi & u, yucai passes through the cage at 1.8 cm above the bottom of the cage. Recording the activity count needs to interrupt the adjacent first cool I Yangzhou Youhe, thus avoiding the induction of the stationary movement of the mouse Counting: 5 minutes interval recording activity duration i hours. Calculate the efficacy in the following way with the total count during the hourly behavior test period: The average activity induced by the vehicle treatment in the presence of ... PCP is used as the baseline. , the total activity count minus the baseline is counted as PCP^100% effect. The response of the group receiving the test compound is therefore subtracted from the baseline by the total activity count (as a percentage of similar results recorded in the parallel PCP control group). 201200516 shows) to convert the percentage of reaction into percent inhibition. [Simple description of the diagram] No [Main component symbol description] No 47

Claims

201200516 七、申請專利範圍： 1 · 一種具有結構I之化合物201200516 VII. Patent application scope: 1 · A compound with structure I

其中HET為含有2至4個氮原子之式11雜芳香族基團：鱗 II 其中Y可為N或CH，Z可為N或C’且其中JJET可視情況經至多三個個別地選自以下者之取代基R7_R9取代：氫、 Ci-C：6燒基；鹵素；氰基、鹵基（c「C6)烧基；芳基、烧氧基及Ci-C：6羥烷基，且其中*表示連接點， -L-為連接子-cec-， h係選自Η、CVC6烷基；（^-(：6烷基（(：3-(：8)環烷基；Cl_C6 經统基、ch2cn、ch2c(o)nh2、c〗-c6 芳基燒基、及 Cl_c6 烷基-雜環烷基，尺2-116係個別地選自Η、Cl-c6烷氧基及素，及其互變異構體及醫藥學上可接受之鹽'及其多晶型物，限制條件為该化合物不為2_(5_苯基_1H-咪唑·2·基甲基硫烷基）-1Η•笨并咪唑或2-(5-苯基-1Η-咪唑-2-基-硫烷基·曱基）-1Η-苯并咪唑。 2.如申凊專利範圍第丨項之化合物，其中hEt係選自 48 201200516 由以下者所組成之群組：[1，2,4]***并n s L，5'a]D比阱、咪唑并 [l，2-a]嘧啶、咪唑并[4,5-b]嘧啶、[丨2 41 _ ，叫二唑并[l，5-a]嘧啶、[1，2,4]***并[l，5-c]嘧啶、5,7-二甲其Γι Τ泰-U，2,4]***并 [l，5-a]嘧啶及5,7-二甲基-咪唑并[l，2-a]喷嘴。 3.如申請專利範圍第1項之化合物，复再中HET係選自由以下者所組成之群組：[1，2，4 ]三唾并「1 s π Li，ya]吡啶、咪唑并 [l，2-a]吡啶、吡唑并n，5_a]吡啶、5,7_二曱基[^，叫***并 [l，5-a]吡啶、5,7_二甲基-咪唑并[以外比。定、5_氣·咪唑并 [1，2-&]吡啶、5_曱基_咪唑并[l，2-a]吡啶、5_三并[l，2-a]。比咬、6_漠_5,7·二甲基-⑴以]***并[仏二比啶、 6-漠-7-甲基·Π，2,4]三唾并[l，5-a]咬咬、6_氣_8_甲基_[12,4] ***并[l，5-a]吡啶、6·氯·咪唑并[l，2-a]吡啶、7_曱基-[^，划三唾并[l，5-ap比啶及8_曱基-咪唑并[i，2_a]吡咬。 4·如申請專利範圍第1項之化合物，其中HET係選自由以下者所組成之群組：1 -甲基_ 1笨并咪唑及1 _苯基_ 1H- 本并σ米嗤。 5. 如申請專利範圍第1項之化合物，其中ΗΕΤ為[1，2,4] 二唑并[1，5-&]吡啶_6_曱腈或咪唑并[1，2-&]吡啶_7_曱腈。 6. 如申請專利範圍第1項之化合物，其中ΗΕΤ為2-(6-氣-苯并咪唑-1-基）-乙醇。 7. 如申請專利範圍第1至6項中任一項之化合物，其中 Rl為氫。 8·如申請專利範圍第1至6項中任一項之化合物，其中不為氫。 49 201200516 士申-月專利I巳圍第i至8項中任一項之化合物，其中 R2、R3 ' r4、r5 及 R6 均為氫。士中μ專利範圍第1至8項中任一項之化合物，其中R2 r3 r4、r5&r6中至少一者為C】_C6烧氧基，諸如甲氧基。 Π·如申請專利範圍第1至8項中任一項之化合物，其中2 R3 R4 R5及r6中至少一者為南素諸如氣或氣。 12_如申請專利範圍第4 "項中任一項之化合物其中R7、Rs及R9均為氫。 13_如申請專利範圍第！至n項中任一項之化合物，其中Κ·7 R8及R9中至少一者為Ci_c6烷基，諸如曱基。 Μ·如申請專利範圍第^ n項中任—項之化合物，其中l、R8及I中至少一者為。<6烷氧基。 15_如申請專利範圍第1至Η項中任-項之化合物，其中R? Rs及Rg中至少一者為齒素，諸如氣或溴。 16·如申請專利範圍第丨項之化合物，其中該化合物係選自由以下者所組成之群組： 5,7-二甲基-2-(1-甲基·4-苯基·ιη-咪唑-2-基乙;^基）_咪唑并 [l，2-a]嘧咬 8-曱基-2·(1-曱基-4-苯基-1H-咪唑-2-基乙炔基*** 并[1，5-a]。比咬 5-甲基-2-(1-曱基-4-苯基-1H-咪唑·2-基乙炔*Hi，2,4]*** 并[1，5-a]吡啶 2-(1-甲基-4-笨基-1H-咪β坐-2 -基乙炔基）_[ι，2,4]三嗤并 50 201200516 [1，5- a]°比。定 2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-5-(三氟曱基）咪唑并[1，2-a]°比口定 5.7- 二曱基-2-(1-曱基-4-苯基-111-咪唑-2-基乙炔基）-[1,2,4] 三唾并[1，5- a]。比σ定 6.8- 二甲基-2-(1-曱基-4-苯基-1Η-咪唑-2-基乙炔基）-[1，2,4] 三σ圭并[1,5- a]°比。定 5.7- 二曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4] 三。坐并[1，5-a]D密。定 5.8- 二甲基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4] 三峻并[1,5-a] °比。定 5 -甲基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]*** 并[1,5-a]嘧啶-7-醇 5-曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]*** 并[l，5-a]嘧啶 5 -曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-7-嗎啉-4-基-[1，2,4]***并[1,5-a]嘧啶 5,6,7-三甲基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[l，5-a]嘧啶 5-甲基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-7-苯基 -[1，2,4]***并[1,5-a]嘧啶 2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-5,6,7,8-四氫-[1，2,4] ***并[l,5_a]吡啡 2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-1Η-咪唑并[4,5-b] 51 201200516 〇比。定 2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-5-三氟曱基-[1，2,4] 三。坐并[1，5-a]°密。定-7-醇 8-甲氧基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1,2,4]三 σ坐并[1，5-a]0比0定 7- 甲氧基-5-曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[l，5-a]嘧啶 8- 甲氧基-5-曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[l，5-a]。比啶 8-氟-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1,2,4]***并 [1,5-a]。比口定 5-乙基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]*** 并[1，5-a]°比啶 7- 氣-8-乙基-5-曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[l，5-c]嘧啶 8- 乙基-5-甲基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[l，5-c]嘧啶 5-二氟甲基-7-甲基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[l，5-a]嘧啶 5-甲基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-7-丙基 -[1，2,4]***并[l，5-a]嘧啶 5,8-二曱基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1,2,4] ***并[l，5_a]吡啡 7-甲氧基-5-甲基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔 52 201200516 基）-[1，2,4]***并[1,5-c]嘧啶 7-異丙基-5-甲基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[l，5-a]嘧啶 7-環丙基-5-曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1,2,4]***并[l，5-a]嘧啶 7-曱氧基-5,8-二曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[l，5-c]嘧啶 5-甲氧基-7-曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1,2,4]***并[l，5-a]嘧啶 5,8-二甲基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4] 三。坐并[1，5 - c ]σ密0定 7-曱氧基曱基-5-曱基-2-(卜曱基-4-苯基-1Η-咪唑-2-基乙炔基）-[1，2,4]***并[l，5-a]嘧啶 5,7-二曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4] 三σ坐并[1，5-3]°密°定-6-醇 5-甲基-2-(1-甲基-4-苯基-1Η-咪唑-2-基乙炔基）-咪唑并 [1，2-a]D比 σ定 {5-甲基-2-(1-曱基-4-苯基-1Η-咪唑-2-基乙炔基）-[1，2,4]三唑并[l，5-a]嘧啶-7-基}-曱醇 2-(8-曱基-咪唑并[1,2-a]。比啶-2-基）-1-(1-曱基-4-苯基-1H-咪唑-2-基）-乙醇 2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-5-吡啶-4-基-[1，2,4] 三。坐并[1，5-a]π比0定 2-(1-曱基-4-苯基-1Η-咪唑-2-基乙炔基）-8-。比啶-4-基-[1，2,4] 53 201200516 三。坐并[1，5- a]°比〇定 5-環丙基-8-甲基-2-(1-甲基-4-苯基-1Η-°米。坐-2 -基乙快基）-[1，2,4]***并[l，5-c]嘧啶 8-甲基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]*** 并[l，5-c]嘧啶 8-乙基-5-曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[1,5-a]吼啶 5.8- 二甲氧基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[l，5-a]吼啶 8-甲氧基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-5-吡啶 -4-基-[1,2,4]***并[1，5-a]吼啶 2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并 [1，5 - a ] °比 °定-8 -醉 5.8- 二曱基-3-(1-曱基-4-苯基-111-咪唑-2-基乙炔基）-[1，2,4] ***并[4,3_a]吡啡 5-曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1,2,4]*** 并[1，5-a]。比。定-8-醇 5-甲氧基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]三。坐并[1，5-a]。比0定 5.8- 二曱基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-咪唑并 [l，2-a]吡啡 Ν-{2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并 [1，5 - a ] °比°定-8 -基}-乙酿胺 8-曱氧基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]三 54 201200516 σ坐并[1，5-a]°比啡 8-乙炔基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]三。坐并[1，5-3]。比口定 N-{5-甲基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4] ***并[l，5-a]吡啶-8-基}-乙醯胺 8-曱氧基-5，6-二曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1,2,4]***并[l，5_a]吡啡 5.8- 二曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4] ***并[l，5_a]吡畊7·氧化物 {5-曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]三唑并[l，5_a]吡畊-8-基}-甲醇 5 -曱基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1,2,4]*** 并[l，5-a]吡啶-8-曱腈 8-氰基-5-曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[1,5-a]吡啡-6-曱酸乙酯 5.8- 二曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4] 三。坐并[1，5 - c ] °密。定 7-曱氧基曱基-5-甲基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[l，5-a]嘧啶 5,7-二f基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1,2,4] ***并[l，5-a]嘧啶-6-醇 5 -甲基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-咪唑并 [1，2-a]°fc 咬 {5 -曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]三 55 201200516 唑并[l，5-a]嘧啶-7-基}-曱醇 2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-5-吡啶-4-基-[1，2,4] 三。坐并[1，5 - a ] °比。定 2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-8-。比啶-4-基-[1，2,4] 三。坐并[l，5-a]。比。定 5-環丙基-8-曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[l，5-c]嘧啶 8-曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]*** 并[l，5-c]嘧啶 8-乙基-5-甲基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[l，5-ap比啶 5.8- 二甲氧基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[l，5-a]吼啶 5.8- 二甲氧基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[l，5-a]。比啶 8 -曱氧基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-5-吡啶 -4-基-[1，2,4]***并[l，5-a]°比啶 2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并 [1，5 - a ]11 比。定-8 -醉 5.8- 二曱基-3-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4] ***并[4,3-a]°比啡 5-曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1,2,4]*** 并[1,5-a]。比啶-8-醇 5 -曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]*** 56 201200516 并[1，5 - a ] °比σ定-8 -酉事 5 -曱基-2-(1-甲基-4-苯基-1Η-咪唑-2-基乙炔基）-[1，2,4]*** 弁[1，5 - a ] °比 °定-8 -酉f· 5 -曱氧基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-[1,2,4]三唑并[1，5-a]°比啶 5,8-二甲基-2-(1-甲基-4-苯基-1H-咪唑-2-基乙炔基）-咪唑并 [l，2-a]吡啡 Ν-{2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并 [1，5 - a ]α比。定-8 -基}-乙酿胺 8-曱氧基-2-(1-曱基-4-苯基-1Η-咪唑-2-基乙炔基）-[1，2,4]三 0坐并[1，5-a]。比啡 8-乙炔基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]三。坐并[1，5-a]。比〇定 N-{5-曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4] ***并[1,5-a]。比啶-8-基}-乙醯胺 8-曱氧基-5,6-二曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]***并[l，5-a]。比畊 {5-曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]三唑并[l，5_a]吡畊-δ-基}-曱醇 5 -曱基-2-(1-曱基-4-苯基-1H-咪唑-2-基乙炔基）-[1，2,4]*** 并[l，5-a]吼啶-8-曱腈及其醫藥學上可接受之鹽。 17.—種用作為醫藥品的如申請專利範圍第1至16項中任一項之化合物。 57 201200516 1 8. —種單獨或與一或多種精神抑制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至16項中任一項之化合物，其中該精神抑制劑為諸如以下者：舍吲 0木（sertindole)、奥氮平（olanzapine)、利培嗣（risperidone)、喹硫平（quetiapine)、阿立哌唑（aripipraz〇ie)、氟哌啶醇 (haloperidol)、氯氮平（cl〇zapine)、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：阿茲海默氏症（Alzheimer,s Disease )、多梗塞性癡呆、酒中毒性癡呆或其他藥物相關癡呆、與顱内腫瘤或腦創傷相關之癡呆、與亨丁頓氏病 (Huntingt〇nis disease )或帕金森氏病（Parkins〇nis 以似“）相關之癡呆、或AIDS相關癡呆；譫妄；失憶症；創傷後壓力症’冬力遲純，學習障礙，例如閱讀障礙、數學障礙、或書寫表達障礙；；：主意力缺乏/過動症；及年齡相關認知衰退，且該精神病症係選自由以下者所組成之群組：精神分裂症’例如偏狂型、錯亂型、緊張型、未分化型、或殘餘型精神***症；類精神***症精神障礙；***情感性精神障礙，例如妄想型或抑鬱型***情感性精神障礙；妄想症；雙極性情感性精神障礙，例如Ϊ型雙極性情感性精神障礙、 Η型雙極性情感性精神障礙及循環情感性精神障礙；物質誘導之精神病症’例如由酒精、***（ampheta_小 2、***（coca—、***、吸入劑、類鴻片或苯環 °、啶（Phencyclidine)誘導之精神病；偏狂型人袼及精神***症型人格障礙。 ’ 58 201200516 種用於治療哺乳動 m ^ 1 Σ ν π τ β月号；^ 乾 16射任―項之化合物，該哺乳動物包括人類， "樂物成癮為諸如酒精、***、***或鴉片劑成癮。 ιΓ:種用於製備用於治療哺乳動物之藥物成癮之醫藥。口的如中請專利範圍第！至16項中任_項之化合物，該哺動物包括人類’該藥物成瘾為諸如酒精、***、可卡因或***劑成瘾。之醫由於製備用於治療神經退化性病症或精神病症物t 專利㈣第1至16射任-項之化合物’其中該神經退化性病组：性扃症係4自由以下者所組成之群、·· 可絲海默氏症、多梗塞性癍早, 華物相計2 更隸'廢呆、、酒中毒性癡呆或其他相關癡呆、與顧内腫瘤或腦創傷相關頓氏病或帕金森氏病相m α 了丁妄；失憶症；創傷後壓力症.知/I s相㈣呆；擔閱讀障礙'數學障礙：心：純;學習障礙，例如 .广.Β & 次曰寫表達障礙；注意力缺乏/過動症’及年齡相關認知衰退所組成之群組：精神***症，例二=係'自由以下者型、未分化型、或殘# $ 錯亂型、緊張障礙；***情感性精神症，類精神***症精神感性精神障礙，·妄趨症.雜極^妄想型或抑營型***情型雙極性情感性精神障礙:感性精神障礙，例如J 循環情感性精神障礙；物質誘導ζ 性情感性精神障礙及 ***、***、***：神病症’例如由酒精、環己.定誘導之精神病；偏=、吸入劑、類***或苯 i人袼障礙；及精神***症 59 201200516 型人格障礙。 =種用於製備用於如中請專利範㈣η項之治療神“;：的化合物’其中該精神病症之治療包含共投予精二:舍啊、奥氮平、利培一平：亂底。疋醇、氣氮平、齊拉西嗣及奥沙夺坦。方广:Γ㈣患神經退化性病症或精神病症之個體的森氏病相關之癡呆’或AIDS相關癡呆；譫，失憶症’創傷後壓力症；智力遲鈍閱讀障礙、數學障礙m “ 千為障礙’例如症;及年齡相關It衰意力缺乏/過動衣l且°亥精神病症係選自由以下去，、且 '之群組：精神***症，例如偏狂型、錯亂型 =、未：化型：或殘餘型精神***症；類精神***症精神礙，***情感性精神障礙，例如妄想型或抑感性精神障礙；妄想症；雙極性情感性精神障礙 = 型雙極性情感性精神障礙、Η型雙極性情感性精神障礙及循％情感性精神障礙；物質誘導之精神病症，例如由㈣ =非他命、***、***、***、吸入劑、類***心 %己哌啶誘導之精神病·’偏狂型人格障礙；及精神型人格障礙；該方法包含單獨或與一或多種諸如以下者: 精神抑制劑組合投予有效量之如巾請專利範圍第^ 中任一項之化合物··舍十朵、奥氮平、利培酮、啥硫平、、 60 201200516 阿立娘。坐、氟哌啶醇、氣氮 24, 種在包.括人類之、背拉西_及奧沙奈垣。個體的方法’該藥物成癮例：物中治療罹患藥物成癮之或***劑«，該方法包含/;"精、***、***、之量的式!化合物。…該個體有效治療藥物成癃 25. -種在包括人類之哺乳動物中治療罹，的方法’該藥物成瘾例如為酒精、***、可:因、或鵠片劑成癮，該方法包含投予之量的式工化合物。 ^亥個胆有政抑帝4 PDE1〇A 26_ 一種醫藥組成物，其包含治療有效量之如申請專利已第1至16項中任一項之化合物、及一或多種醫藥學上 Γ接受之載劑、稀釋劑及賦形劑。八、圖式： (無） 61Wherein HET is a heteroaromatic group of formula 11 containing from 2 to 4 nitrogen atoms: scale II wherein Y can be N or CH, Z can be N or C' and wherein JJET can optionally be selected from up to three individually selected from Substituent R7_R9 substituted: hydrogen, Ci-C: 6 alkyl; halogen; cyano, halo (c "C6) alkyl; aryl, alkoxy and Ci-C: 6 hydroxyalkyl, and wherein * indicates a point of attachment, -L- is a linker-cec-, h is selected from a fluorene, CVC6 alkyl group; (^-(:6 alkyl ((:3-(:8) cycloalkyl; Cl_C6) Ch 2 2 2 2 2 2 2 2 2 2 2 2 2 2 Tautomers and pharmaceutically acceptable salts 'and polymorphs thereof, with the proviso that the compound is not 2_(5-phenyl_1H-imidazolyl-2methylsulfanyl)-1Η Stupid imidazole or 2-(5-phenyl-1 Η-imidazol-2-yl-sulfanyl fluorenyl)-1 Η-benzimidazole. 2. A compound of the ninth aspect of the patent application, wherein the hEt system From 48 201200516 A group consisting of: [1,2,4]triazolo ns L,5'a]D than well, microphone Zizo[1,2-a]pyrimidine, imidazo[4,5-b]pyrimidine, [丨2 41 _ , called diazolo[l,5-a]pyrimidine, [1,2,4]triazole And [l,5-c]pyrimidine, 5,7-dimethylpyridinium Τ-U, 2,4]triazolo[l,5-a]pyrimidine and 5,7-dimethyl-imidazo[ l,2-a] Nozzle 3. As in the compound of claim 1, the HET is selected from the group consisting of: [1, 2, 4] three saliva and "1 s π Li , ya]pyridine, imidazo[l,2-a]pyridine, pyrazolo n,5_a]pyridine, 5,7-diindolyl[^, called triazolo[l,5-a]pyridine, 5, 7-Dimethyl-imidazo[external ratio, 5, gas, imidazo[1,2-&]pyridine, 5-mercapto-imidazo[l,2-a]pyridine, 5_three [l,2-a]. Specific bite, 6_ desert_5,7·dimethyl-(1) to] triazolo[indenylpyridine, 6-indol-7-methyl·Π, 2,4] Trisporin [l,5-a] bite, 6_gas_8_methyl_[12,4] triazolo[l,5-a]pyridine, 6·chloro·imidazo[1,2- a] pyridine, 7-fluorenyl-[^, trichosting [l,5-ap-pyridyl and 8-hydrazino-imidazo[i,2_a] pyridine. 4. As claimed in claim 1 a compound wherein the HET is selected from the group consisting of The Groups: 1 - methyl - 1 _ 1 _ and Ben-phenyl imidazole and lH-_ present laugh and σ m. 5. A compound according to claim 1 wherein hydrazine is [1,2,4] oxazolo[1,5-&]pyridine _6_phthalonitrile or imidazo[1,2-&] Pyridine_7_phthalonitrile. 6. The compound of claim 1, wherein the hydrazine is 2-(6-gas-benzimidazol-1-yl)-ethanol. 7. The compound of any one of claims 1 to 6 wherein R1 is hydrogen. 8. A compound according to any one of claims 1 to 6 wherein it is not hydrogen. 49 201200516 The compound of any one of items i to 8 wherein the R2, R3 'r4, r5 and R6 are all hydrogen. The compound of any one of items 1 to 8, wherein at least one of R2 r3 r4, r5 & r6 is C]_C6 alkoxy, such as methoxy. The compound of any one of claims 1 to 8, wherein at least one of 2 R3 R4 R5 and r6 is a sulphur such as gas or gas. The compound of any one of claims 4, wherein R7, Rs and R9 are all hydrogen. 13_If you apply for a patent range! A compound according to any one of the items n, wherein at least one of Κ7 R8 and R9 is a Ci_c6 alkyl group such as an anthracenyl group. Μ· For example, the compound of any one of the items in the scope of the patent application, wherein at least one of l, R8 and I is. <6 alkoxy group. The compound of any one of clauses 1 to 2, wherein at least one of R? Rs and Rg is a dentate such as gas or bromine. The compound of claim 3, wherein the compound is selected from the group consisting of 5,7-dimethyl-2-(1-methyl-4-phenyl·ιη-imidazole -2-ylethyl; ^yl)-imidazo[l,2-a]pyrimidine 8-mercapto-2((1-mercapto-4-phenyl-1H-imidazol-2-ylethynyltriazole) And [1,5-a]. Bite 5-methyl-2-(1-indolyl-4-phenyl-1H-imidazole-2-ylacetylene*Hi, 2,4]triazolo[1, 5-a]pyridine 2-(1-methyl-4-indolyl-1H-m-β-iso-2-ylethynyl)_[ι,2,4]三嗤和50 201200516 [1,5- a] ° ratio of 2-(1-mercapto-4-phenyl-1H-imidazol-2-ylethynyl)-5-(trifluoromethyl)imidazo[1,2-a]° ratio 5.7 - Dimercapto-2-(1-indolyl-4-phenyl-111-imidazol-2-ylethynyl)-[1,2,4]tris-[1,5-a]. 6.8-Dimethyl-2-(1-indolyl-4-phenyl-1Η-imidazol-2-ylethynyl)-[1,2,4] 三σ圭[1,5- a]° ratio 5.7-Dimercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4] III. Sit and [1,5-a] D dense. 5.8-dimethyl-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4] ternary [1,5-a ] Ratio of 5-methyl-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[1,5-a] Pyrimidine-7-ol 5-mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[l,5-a Pyrimidine 5-mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-7-morpholin-4-yl-[1,2,4]triazole [1,5-a]pyrimidine 5,6,7-trimethyl-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4] Azolo[l,5-a]pyrimidine 5-methyl-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-7-phenyl-[1,2,4 Triazolo[1,5-a]pyrimidine 2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-5,6,7,8-tetrahydro-[1, 2,4] Triazolo[l,5_a]pyridin 2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-1Η-imidazo[4,5-b] 51 201200516 〇.. 2-(1-Mercapto-4-phenyl-1H-imidazol-2-ylethynyl)-5-trifluorodecyl-[1,2,4] III. Sit and [1,5-a]° dense. D--7-alcohol 8-methoxy-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]tris-sigma[1,5 -a] 0 to 0 to 7-methoxy-5-mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4] Oxazo[l,5-a]pyrimidine 8-methoxy-5-mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2, 4] Triazolo[l,5-a]. Bisyl 8-fluoro-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[1,5-a]. Specificity of 5-ethyl-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[1,5-a]° Pyridinium 7-gas-8-ethyl-5-mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazole [l,5-c]pyrimidine 8-ethyl-5-methyl-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4] Zydro[l,5-c]pyrimidine 5-difluoromethyl-7-methyl-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2 , 4] Triazolo[l,5-a]pyrimidine 5-methyl-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-7-propyl-[1 , 2,4]triazolo[l,5-a]pyrimidine 5,8-dimercapto-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1 ,2,4] Triazolo[l,5_a]pyridin 7-methoxy-5-methyl-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylacetylene 52 201200516 )-[1,2,4]triazolo[1,5-c]pyrimidine 7-isopropyl-5-methyl-2-(1-methyl-4-phenyl-1H-imidazole-2- Ethynyl)-[1,2,4]triazolo[l,5-a]pyrimidine 7-cyclopropyl-5-mercapto-2-(1-indolyl-4-phenyl-1H-imidazole -2-ylethynyl)-[1,2,4]triazolo[l,5-a]pyrimidine 7-decyloxy-5,8-dimercapto-2-(1-indolyl-4- Phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[l,5-c]pyrimidine 5-methoxy-7-mercapto-2-(1-indenyl) -4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[l,5-a]pyrimidine 5,8-dimethyl-2-(1-indenyl) 4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4] III. Sit and [1,5 - c ] σ 密 0 7-methoxy fluorenyl-5-mercapto-2-(diphenyl-4-phenyl-1 Η-imidazol-2-ylethynyl)-[1, 2,4]triazolo[l,5-a]pyrimidine 5,7-dimercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1, 2,4] Tris-sigma and [1,5-3]°-den-6-alcohol 5-methyl-2-(1-methyl-4-phenyl-1Η-imidazol-2-ylethynyl )-Imidazo[1,2-a]D ratio σ determinate {5-methyl-2-(1-indolyl-4-phenyl-1Η-imidazol-2-ylethynyl)-[1,2, 4] Triazolo[l,5-a]pyrimidin-7-yl}-nonanol 2-(8-fluorenyl-imidazo[1,2-a].pyridin-2-yl)-1-( 1-mercapto-4-phenyl-1H-imidazol-2-yl)-ethanol 2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-5-pyridine-4- Base - [1, 2, 4] III. Sit and [1,5-a]π is 0 to 2-(1-indolyl-4-phenyl-1Η-imidazol-2-ylethynyl)-8-. Bipyridin-4-yl-[1,2,4] 53 201200516 III. Sit and [1,5-a] ° ratio of 5-cyclopropyl-8-methyl-2-(1-methyl-4-phenyl-1Η-° m. sit-2 -ylethyl fast )-[1,2,4]triazolo[l,5-c]pyrimidine 8-methyl-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[ 1,2,4]triazolo[l,5-c]pyrimidine 8-ethyl-5-mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl) -[1,2,4]triazolo[1,5-a]acridine 5.8-dimethoxy-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl) -[1,2,4]triazolo[l,5-a]acridine 8-methoxy-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)- 5-pyridin-4-yl-[1,2,4]triazolo[1,5-a]acridine 2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl) -[1,2,4]triazolo[1,5 - a ] ° ratio °-8 - drunk 5.8-dimercapto-3-(1-mercapto-4-phenyl-111-imidazole-2 -ylethynyl)-[1,2,4]triazolo[4,3_a]pyridin-5-mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl )-[1,2,4]triazolo[1,5-a]. ratio. D--8-alcohol 5-methoxy-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]tri. Sit and [1,5-a]. 5.8-dimercapto-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-imidazo[l,2-a]pyridinium-{2-( 1-mercapto-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[1,5 - a ] ° ratio °-8 -yl}-ethyl Amine 8-methoxy-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]III 54 201200516 σ sit and [1,5-a More than the morphine 8-ethynyl-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]tri. Sit and [1,5-3]. Specific N-{5-methyl-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[l,5- a]pyridin-8-yl}-acetamide 8-decyloxy-5,6-dimercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)- [1,2,4]triazolo[l,5_a]pyridin 5.8-dimercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1, 2,4] Triazolo[l,5_a]pyrazine 7·oxide {5-mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1 , 2,4]triazolo[l,5_a]pyrazine-8-yl}-methanol 5-mercapto-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl) -[1,2,4]triazolo[l,5-a]pyridine-8-indolecarbonitrile 8-cyano-5-mercapto-2-(1-indolyl-4-phenyl-1H-imidazole -2-ylethynyl)-[1,2,4]triazolo[1,5-a]pyridin-6-decanoate ethyl ester 5.8-dimercapto-2-(1-indolyl-4- Phenyl-1H-imidazol-2-ylethynyl)-[1,2,4] III. Sit and [1,5 - c ] ° dense. 7-decyloxyindolyl-5-methyl-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[l ,5-a]pyrimidine 5,7-dif-yl-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[l ,5-a]pyrimidin-6-ol 5-methyl-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-imidazo[1,2-a]°fc Biting {5-mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]tri 55 201200516 oxazo[l,5-a] Pyrimidin-7-yl}-nonanol 2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-5-pyridin-4-yl-[1,2,4] III. Sit and [1,5 - a ] ° ratio. 2-(1-Methyl-4-phenyl-1H-imidazol-2-ylethynyl)-8-. Bipyridin-4-yl-[1,2,4] III. Sit and [l,5-a]. ratio. 5-cyclopropyl-8-mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[l,5 -c]pyrimidine 8-mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[l,5-c] Pyrimidine 8-ethyl-5-methyl-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[l,5- Ap to pyridine 5.8-dimethoxy-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[l,5-a Acridine 5.8-dimethoxy-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[l,5-a ]. Bis-8-methoxy-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-5-pyridin-4-yl-[1,2,4]triazole [l,5-a]° pyridine 2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[1,5 - a ]11 ratio. Ding-8 - drunk 5.8-dimercapto-3-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[4,3- a]°Pentyl 5-mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[1,5-a ]. Bipyridin-8-ol 5-mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazole 56 201200516 and [1, 5 - a ] ° ratio σ -8 - anthraquinone 5 - mercapto-2-(1-methyl-4-phenyl-1 Η-imidazol-2-ylethynyl)-[1,2,4] Azathioprine [1,5 - a ] ° ratio °-8 -酉f· 5 -nonyloxy-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl)-[ 1,2,4]triazolo[1,5-a]° pyridine 5,8-dimethyl-2-(1-methyl-4-phenyl-1H-imidazol-2-ylethynyl) -imidazo[l,2-a]pyridinium-{2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[ 1,5 - a ]α ratio. Dine-8-yl}-ethanoamine 8-methoxy-2-(1-indolyl-4-phenyl-1-indole-2-imidyl-2-ylethynyl)-[1,2,4] And [1,5-a]. Birphin 8-ethynyl-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4] III. Sit and [1,5-a]. Comparatively, N-{5-mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[1,5- a]. Bispin-8-yl}-acetamide 8-decyloxy-5,6-dimercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[ 1,2,4]triazolo[l,5-a]. Specific tillage {5-mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[l,5_a]pyrazine- Δ-yl}-nonanol 5-mercapto-2-(1-indolyl-4-phenyl-1H-imidazol-2-ylethynyl)-[1,2,4]triazolo[l,5 -a] acridine-8-phthalonitrile and its pharmaceutically acceptable salts. A compound for use as a pharmaceutical product according to any one of claims 1 to 16. 57 201200516 1 8. A compound according to any one of claims 1 to 16 wherein the neuroleptic agent is used alone or in combination with one or more psychoactive agents for the treatment of a neurodegenerative disorder or a psychiatric disorder, wherein the psychoactive inhibitor is Such as the following: sertindole, olanzapine, risperidone, quetiapine, aripiprazole (aripipraz〇ie), haloperidol (haloperidol) , clozapine, ziprasidone, and osanetant, wherein the neurodegenerative disorder is selected from the group consisting of: Alzheimer's disease (Alzheimer, s Disease), multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial or brain trauma, Huntingt〇nis disease or Parkinson's disease (Parkins〇nis is associated with ") dementia, or AIDS-related dementia; sputum; amnesia; post-traumatic stress disorder 'winter fatigue, learning disabilities, such as dyslexia, mathematical disorders, or writing expression disorders; Deficit/hyperactivity disorder; and age-related cognitive decline, and the mental disorder is selected from the group consisting of schizophrenia such as madness, disorder, tension, undifferentiation, or residual Schizophrenia; schizophrenia-like mental disorder; schizoaffective disorder, such as delusional or depressive schizoaffective disorder; paranoia; bipolar affective disorder, such as sputum bipolar affective disorder, Η-type bipolar affective disorder and circulatory affective disorder; substance-induced mental illness' such as alcohol, amphetamine (ampheta_small 2, ***e (coca-, ecstasy, inhalant, phlegm or benzene ring) °, Phencyclidine-induced psychosis; mad-type apes and schizophrenia-type personality disorder. '58 201200516 for the treatment of mammals m ^ 1 Σ ν π τ β month number; ^ 16 shots a compound, the mammal including a human, "music addiction is addiction such as alcohol, amphetamine, ***e or opiate. ιΓ: species used for preparation for Medicinal drug addiction medicine for mammals. The patent scope of the mouth is as follows: to the compound of item 1-6, the animal includes humans. The drug addiction is such as alcohol, amphetamine, ***e or opiate. Addiction. The doctor prepares a compound for the treatment of a neurodegenerative disorder or a psychiatric disorder. The patent (4) the compounds of the first to the 16th-those-terms, wherein the neurodegenerative disease group: the group of sexually transmitted diseases is 4 free ,··········································································································· Jinsen's disease phase m α 妄妄; amnesia; post-traumatic stress disorder. Know / I s phase (four) stay; dyslexia 'mathematical obstacles: heart: pure; learning disabilities, such as. Guang. Β & Groups of expression disorders; attention deficit/hyperactivity disorder' and age-related cognitive decline: schizophrenia, case 2 = 'freedom of the following type, undifferentiated, or disabled # $ disorder, tension disorder; Split emotional psychosis, class Divine schizophrenia, psychotic disorder, phlegm and blood stasis. Hybrid 妄妄或抑抑抑抑或或或或 : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : Mental disorders and amphetamines, marijuana, ***e: God's illnesses such as psychosis induced by alcohol, cycloheximide; partial =, inhalation, opioid or benzene i dysfunction; and schizophrenia 59 201200516 personality disorder. = a compound used to prepare a therapeutic "for:" in the case of the patent (4) η, wherein the treatment of the psychiatric condition comprises co-administering the second: 舍, olanzapine, and 培培一平: 乱底. Sterols, nitrozapine, zipraspiride, and oxacitabine. Fang Guang: 四 (4) Sjogren's disease-related dementia or AIDS-related dementia in individuals with neurodegenerative or psychiatric disorders; sputum, amnesia Post-stress syndrome; mental retardation dyslexia, mathematical disorders m "Thousands of obstacles" such as symptoms; and age-related It dysfunction lack / over-the-spot l and ° Hai mental illness is selected from the following, and 'group : schizophrenia, such as madness, confusion =, no: type: or residual schizophrenia; schizophrenia, schizophrenic psychosis, such as delusional or inflammatory psychosis; paranoia Bipolar affective disorder = type bipolar affective disorder, spastic bipolar affective disorder and % affective disorder; substance-induced mental disorder, for example, (4) = non-life, marijuana, ***e Ecstasy, inhalation, opioid heart % piperidine-induced psychosis · 'frequent personality disorder; and psychiatric personality disorder; the method comprises administering alone or in combination with one or more of the following: a psychotropic inhibitor For an effective amount, please refer to the compound of the patent range No.1, olanzapine, risperidone, sulforaphane, 60 201200516 A Li Niang. Sitting, haloperidol, gas nitrogen 24, planted in the package. including human, back pull _ and oxadanone. Individual method 'The drug addiction case: treatment of drug addiction or opiate«, the method contains /; " fine, amphetamine, ***e, amount of formula! Compound. ...the effective treatment of the individual into a sputum. - a method of treating sputum in a mammal including a human. 'The drug addiction is, for example, alcohol, amphetamine, can cause, or lick tablet addiction, the method includes A given amount of a compound of the formula. ^海胆胆政帝4 PDE1〇A 26_ A pharmaceutical composition comprising a therapeutically effective amount of a compound as claimed in any one of claims 1 to 16, and one or more medically acceptable Carriers, diluents and excipients. Eight, schema: (none) 61