TW201307300A - Metabotropic glutamate receptor modulators - Google Patents

Abstract

The invention relates to heterocyclic derivatives as well as their pharmaceutically acceptable salts. The invention further relates to a process for the preparation of such compounds. The compounds of the invention are mGluR5 modulators and are therefore useful for the control and prevention of acute and/or chronic neurological disorders.

Description

趨代謝性麩胺酸受體調節劑 Metabotropic glutamine receptor modulator

本發明係關於雜環衍生物，其可充作新穎之趨代謝性麩胺酸受體(mGluR)調節劑，其合成方法及藉投服此衍生物以治療及/或預防各種不同之疾病及病症(包括神經學病症)。 The present invention relates to a heterocyclic derivative which can be used as a novel metabotropic glutamate receptor (mGluR) modulator, a synthetic method thereof, and a derivative thereof for treating and/or preventing various diseases and A condition (including a neurological condition).

神經元刺激係藉中樞神經系統(CNS)經由神經元所釋出之神經傳導質之交互作用所傳導，此神經傳導質對另一神經元之神經受體具有特定之效應。L-麩胺酸被視為是哺乳動物中樞神經系統中的主要興奮性神經傳導質，因此在大量的生理學過程中扮演關鍵性角色。麩胺酸-依賴性刺激受體分成兩個主要群體。第一群包含配體-控制性離子通道，而另一群包含趨代謝性麩胺酸受體(mGluR)。趨代謝性麩胺酸受體為G蛋白偶合受體(GPCR)之亞族。有漸增之證據顯示趨離子性及趨代謝性麩胺酸受體在(例如慢性疼痛狀態中)中樞神經系統外部的周邊角色。 Neuronal stimulation is transmitted by the central nervous system (CNS) via the interaction of neurotransmitters released by neurons, which have a specific effect on the neuroreceptors of another neuron. L-glutamic acid is considered to be the major excitatory neurotransmitter in the mammalian central nervous system and therefore plays a key role in a number of physiological processes. The glutamate-dependent stimulating receptors are divided into two major groups. The first group contains ligand-controlled ion channels, while the other group contains a metabotropic glutamate receptor (mGluR). The metabotropic glutamate receptor is a subfamily of G protein coupled receptors (GPCRs). There is increasing evidence of ionic and ubiquitous glutamate receptors in peripheral roles outside the central nervous system (eg, in chronic pain states).

目前，這些趨代謝性麩胺酸受體(mGluR)己知有八種不同成員。以結構參數諸如序列相同性、被這些受體利用之第二信使系統及其對低分子量化合物之不同親和力等為基礎，這八種受體可分成三群。mGluR1及mGluR5隸屬於第I群，其正向地偶合至磷脂酶C上且其活性導致分子內鈣離子之流動。mGluR2及mGluR3隸屬於第II群，且 mGluR4、mGluR6、mGluR7及mGluR8隸屬於第III群，此二群均負向地偶合至腺苷醯環化酶上，亦即彼等之活化導致第二信使cAMP之降低，因而抑制神經元活性。 Currently, these metabotropic glutamate receptors (mGluR) are known to have eight different members. These eight receptors can be divided into three groups based on structural parameters such as sequence identity, second messenger systems utilized by these receptors, and their different affinities for low molecular weight compounds. mGluR1 and mGluR5 belong to Group I, which is coupled positively to phospholipase C and whose activity results in the flow of intramolecular calcium ions. mGluR2 and mGluR3 belong to Group II, and mGluR4, mGluR6, mGluR7, and mGluR8 belong to Group III, both of which are negatively coupled to adenosine cyclase, that is, their activation results in a decrease in second messenger cAMP, thereby inhibiting neuronal activity.

mGluR5調節劑已顯示可經由突觸後機轉(受體)調節突觸前釋出之神經傳導質麩胺酸之效應。而且，因為這些調節劑可均為正向及/或負向mGluR5調節劑，故此些調節劑可增加或抑制經由這些趨代謝性麩胺酸受體所媒介之效應。 mGluR5 modulators have been shown to modulate the effects of presynaptic released neurotransmitter glutamate via postsynaptic transduction (receptors). Moreover, because these modulators can be both positive and/or negative mGluR5 modulators, such modulators can increase or inhibit the effects mediated by these metabotropic glutamate receptors.

調節劑為負向mGluR5調節劑，則可降低經由趨代謝性麩胺酸受體所媒介之效應。既然影響中樞神經系統之種種病理生理學過程及疾病狀態被認為與異常麩胺酸神經傳導有關，且mGluR5受體已顯示於中樞神經系統及周邊神經系統之許多區域表現，故這些受體之調節劑可醫療有利地治療涉及中樞神經系統及周邊神經系統之疾病。 The modulator is a negative mGluR5 modulator that reduces the effect of mediation via the metabotropic glutamate receptor. Since the various pathophysiological processes and disease states affecting the central nervous system are thought to be involved in abnormal glutamate nerve conduction, and the mGluR5 receptor has been shown in many regions of the central nervous system and peripheral nervous system, regulation of these receptors The agent can medically treat diseases involving the central nervous system and the peripheral nervous system.

因此，mGluR5正向或負向調節劑可予投服以提供下列急性或慢性病理學病況中之神經保護及/或疾病改善或提供對下列病況之症狀學效應：阿滋海默氏症、庫賈氏症候群/庫賈氏症、狂牛症(BSE)、普恩蛋白相關性感染、涉及粒線體功能障礙之疾病、涉及β-澱粉樣蛋白之疾病及/或tau蛋白病、唐氏症、肝性腦病、亨丁頓氏症、運動神經元病、肌萎縮性側索硬化症(ALS)、橄欖體橋腦小腦萎縮、手術後認知不足(POCD)、系統性紅斑性狼瘡、系統性硬化、修格蘭氏症候群、神經元蠟樣脂褐質沉著症、神經退化性小腦運動失調、帕金森氏症、帕金森氏癡呆症、 輕度知能障礙、各種不同形式之輕度認知障礙中之認知不足、各種不同形式之癡呆症中之認知不足、拳擊手癡呆症、血管及額葉型癡呆症、認知障礙、學習障礙、眼部損傷、眼症、眼疾、青光眼、視網膜病變、黃斑部病變、頭或腦或脊髓損傷、頭或腦或脊髓外傷、外傷、低血糖症、缺氧、週產期缺氧、缺血、因心跳停止或中風或繞道手術或移植所致之缺血、痙攣、癲癇性痙攣、癲癇、顳葉癲癇、陣攣性癲癇、內耳損傷、耳鳴之內耳損傷、耳鳴、聲音-或藥物-誘發性內耳損傷、聲音-或藥物-誘發性耳鳴、聽覺過敏、L-多巴-誘發性運動障礙、帕金森氏症療法中之L-多巴-誘發性運動障礙、運動障礙、亨丁頓氏症之運動障礙、藥物誘發性運動障礙、抗精神病藥物-誘發性運動障礙、氟哌啶醇(haloperidol)-誘發性運動障礙、多巴胺模擬藥-誘發性運動障礙、舞蹈症、亨丁頓氏舞蹈症、指痙症、肌張力不全症、刻板症、顫搐、遲發性運動障礙、抗精神病藥物-誘發性運動障礙、抽動症、痙攣性斜頸、眼瞼痙攣、局部及全身性肌張力不全、眼球震顫、遺傳性小腦運動失調、皮質基底核退化症、顫抖症、原發性顫抖症、濫用、成癮症、尼古丁成癮症、尼古丁濫用、酒精成癮症、酒精濫用、鴉片成癮症、鴉片濫用、古柯鹼成癮症、古柯鹼濫用、***成癮症、***濫用、焦慮症、恐慌症、焦慮及恐慌症、社交焦慮症(SAD)、注意力不足過動症(ADHD)、注意力不足症候群(ADS)、不寧腿症候群(RLS)、孩童過動症、自閉症、癡呆症、阿滋海默氏 症之癡呆症、科爾薩科夫(Korsakoff)症候群之癡呆症、科爾薩科夫(Korsakoff)症候群、血管型癡呆症、與HIV感染相關之癡呆症、HIV-1腦病變、愛滋病腦病變、愛滋病癡呆綜合症、愛滋病相關性癡呆症、重鬱症、重度憂鬱、憂鬱症、因博爾納(Borna)病毒感染所致之憂鬱症、因博爾納(Borna)病毒感染所致之重鬱症、雙極性躁鬱症、藥物耐受性、對鴉片類藥物之藥物耐受性、運動障礙、易脆X症候群、腸躁症(IBS)、偏頭痛、多發性硬化症(MS)、肌肉痙攣、疼痛、慢性疼痛、急性疼痛、炎性疼痛、神經痛、糖尿病性神經痛(DNP)、與風濕性關節炎相關之疼痛、痛覺異常、痛覺過敏、感覺接受性疼痛、癌症疼痛、創傷後壓力症候群(PTSD)、精神***症、精神***症之陽性或認知或陰性症狀、痙攣狀態、妥瑞氏症、尿失禁、嘔吐、搔癢病況、搔癢症、睡眠症、頻尿症、下尿道之神經肌肉疾病、胃食道逆流症(GERD)、胃腸功能障礙、下食道括約肌(LES)病症、功能性胃腸病、消化不良、反胃、呼吸道感染、神經性暴食症、慢性喉炎、氣喘、逆流相關性氣喘、肺病、飲食失調症、肥胖症、肥胖相關病症、肥胖***、食物成癮症、暴食症、廣場恐懼症、廣泛性焦慮症、強迫症、恐慌症、創傷後壓力症候群、社交恐懼症、恐懼症、物質-誘發性焦慮症、妄想症、情感***型病症、類精神***症、物質-誘發性精神病、或譫妄，糖尿病、高氨血症及肝衰竭及睡眠障礙。 Thus, mGluR5 positive or negative modulators can be administered to provide neuroprotective and/or disease amelioration in the following acute or chronic pathological conditions or to provide symptomatic effects on the following conditions: Alzheimer's disease, Cuija Syndrome/Cuija's disease, mad cow disease (BSE), Purin-associated infection, diseases involving mitochondrial dysfunction, diseases involving β -amyloid and/or tauopathy, Down's syndrome, liver Encephalopathy, Huntington's disease, motor neuron disease, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, postoperative cognitive deficit (POCD), systemic lupus erythematosus, systemic sclerosis, repair Gram-negative syndrome, neuronal waxy lipofacia, neurodegenerative cerebellar dysmotility, Parkinson's disease, Parkinson's dementia, mild dysfunction, cognitive deficits in various forms of mild cognitive impairment Cognitive deficit in various forms of dementia, boxer dementia, vascular and frontal dementia, cognitive impairment, learning disabilities, eye damage, eye disease, eye disease, glaucoma, retinopathy, yellow Lesions, head or brain or spinal cord injury, head or brain or spinal cord trauma, trauma, hypoglycemia, hypoxia, hypoxia during perinatal period, ischemia, cardiac arrest or stroke or bypass surgery or transplantation , sputum, epilepsy, epilepsy, temporal lobe epilepsy, clonic epilepsy, inner ear injury, inner ear injury of tinnitus, tinnitus, sound- or drug-induced inner ear injury, sound- or drug-induced tinnitus, hearing hypersensitivity, L-dopa-induced dyskinesia, L-dopa-induced dyskinesia in Parkinson's disease therapy, dyskinesia, dyskinesia in Huntington's disease, drug-induced dyskinesia, antipsychotic-induced Sexual dyskinesia, haloperidol-induced dyskinesia, dopamine mimetic-induced dyskinesia, chorea, Huntington's disease, finger dysfunction, dystonia, stereotype, twitch , tardive dyskinesia, antipsychotics - induced dyskinesia, tic disorder, spastic torticollis, eyelids, local and systemic dystonia, nystagmus, hereditary cerebellar atasia, cortex Degeneration, tremor, primary tremor, abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opium addiction, opium abuse, ***e addiction , ***e abuse, amphetamine addiction, amphetamine abuse, anxiety, panic disorder, anxiety and panic disorder, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit disorder syndrome (ADS), Restless Leg Syndrome (RLS), Childhood Hyperactivity, Autism, Dementia, Alzheimer's Dementia, Korsakoff Syndrome Dementia, Korsakoff Syndrome, vascular dementia, dementia associated with HIV infection, HIV-1 brain disease, AIDS brain disease, AIDS dementia syndrome, AIDS-related dementia, severe depression, severe depression, depression, Inborn (Borna) depression caused by viral infection, severe depression caused by Borna virus infection, bipolar bipolar disorder, drug tolerance, drug tolerance to opioids, dyskinesia, easy Fragile X syndrome, intestinal fistula (IB S), migraine, multiple sclerosis (MS), muscle spasm, pain, chronic pain, acute pain, inflammatory pain, neuralgia, diabetic neuropathic pain (DNP), pain associated with rheumatoid arthritis, pain Abnormal, hyperalgesia, sensory pain, cancer pain, post-traumatic stress syndrome (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, spasticity, dysplasia, urinary incontinence, vomiting, itching Conditions, pruritus, sleep disorder, frequent urination, neuromuscular disease of the lower urinary tract, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disease, indigestion, nausea, respiratory tract Infection, neurological bulimia, chronic laryngitis, asthma, reflux-associated asthma, lung disease, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorder, square phobia, generalized anxiety disorder , obsessive-compulsive disorder, panic disorder, post-traumatic stress syndrome, social phobia, phobia, substance-induced anxiety, paranoia, emotional schizophrenia, Schizophrenia, substance - induced psychosis or delirium, diabetes, hyperammonemia and hepatic failure and sleep disorders.

mGluR5負向或正向調節劑亦可予投服以提供抑制周 邊組織、周邊神經系統及中樞神經系統之腫瘤細胞生長、遷移、侵襲、黏附及毒性。mGluR5調節劑亦可予投服以提供醫療介入於腫瘤形成、增生、發育不良、癌症、癌瘤、肉瘤、口腔癌、鱗狀上皮細胞癌(SCC)、口腔鱗狀上皮細胞癌(SCC)、肺癌、肺腺癌、乳癌、攝護腺癌、胃癌、肝癌、結腸癌、結腸直腸癌、橫紋肌肉瘤、腦腫瘤、神經組織的腫瘤、膠質瘤、惡性膠質瘤、星型膠質瘤、神經膠質瘤、神經母細胞瘤、膠質母細胞瘤、髓母細胞瘤、皮膚細胞的癌症、黑色素瘤、惡性黑色素瘤、上皮腫瘤、淋巴瘤、骨髓瘤、何杰金氏病、伯基特氏(Burkitt’s)淋巴瘤、白血病、胸腺瘤、及其他腫瘤中。 mGluR5 negative or positive regulators can also be administered to provide inhibition weeks Tumor cell growth, migration, invasion, adhesion, and toxicity of the lateral tissues, peripheral nervous system, and central nervous system. mGluR5 modulators can also be administered to provide medical intervention in tumor formation, hyperplasia, dysplasia, cancer, carcinoma, sarcoma, oral cancer, squamous cell carcinoma (SCC), oral squamous cell carcinoma (SCC), Lung cancer, lung adenocarcinoma, breast cancer, prostate cancer, gastric cancer, liver cancer, colon cancer, colorectal cancer, rhabdomyosarcoma, brain tumor, nerve tissue tumor, glioma, malignant glioma, astroglioma, glioma , neuroblastoma, glioblastoma, medulloblastoma, cancer of skin cells, melanoma, malignant melanoma, epithelial tumor, lymphoma, myeloma, Hodgkin's disease, Burkitt's Lymphoma, leukemia, thymoma, and other tumors.

mGluR5正向或負向調節劑亦可予投服以提供對下列病況之疾病改善及/或提供症狀學效應：糖尿病、高氨血症及肝衰竭。 mGluR5 positive or negative modulators can also be administered to provide improved disease and/or provide symptomatic effects on the following conditions: diabetes, hyperammonemia, and liver failure.

mGluR5負向或正向調節劑之進一步適應症包括彼些適應症，其中特定病況未必存在，但其中特定生理學參數可經由投服本化合物而改善，包括認知功能之增強、學習障礙及/或神經保護。 Further indications for mGluR5 negative or positive modulators include those indications in which a particular condition does not necessarily exist, but wherein certain physiological parameters may be improved by administration of the compound, including cognitive enhancement, learning disabilities, and/or Neuroprotection.

正向調節劑可特別用於治療精神***症之陽性及陰性症狀，及各種不同形式之癡呆症及輕度認知障礙中之認知不足。 Positive modulators are particularly useful for the treatment of positive and negative symptoms of schizophrenia, as well as cognitive impairment in various forms of dementia and mild cognitive impairment.

再者，mGluR調節劑當與其它經由不同機轉顯現神經學效應之物質組合投服時，可具有活性。 Furthermore, the mGluR modulator can be active when administered in combination with other substances that exhibit neurological effects via different machines.

第I群mGluR調節劑與NMDA受體拮抗劑之同步投 服亦已顯示可提供動物模型之神經保護(Zieminska et al.Acta Neurobiol.Exp.,2006,66,301-309；Zieminska et al.Neurochemistry International,2003,43,481-492；and Zieminska et al.Neurochemistry International,2006,48,491-497)。 Simultaneous administration of Group I mGluR modulators with NMDA receptor antagonists has also been shown to provide neuroprotection in animal models (Zieminska et al. Acta Neurobiol . Exp., 2006 , 66 , 301-309; Zieminska et al. Neurochemistry International , 2003 , 43 , 481-492; and Zieminska et al. Neurochemistry International , 2006 , 48, 491-497).

第I群mGluR調節劑與化合物諸如L-DOPA、多巴胺模擬藥、及/或抗精神病藥物之同步投服可用於治療各種不同病況包括運動障礙、抗精神病藥物-誘發性運動障礙、氟哌啶醇(haloperidol)-誘發性運動障礙、多巴胺模擬藥-誘發性運動障礙。 Simultaneous administration of Group I mGluR modulators with compounds such as L-DOPA, dopamine mimetic, and/or antipsychotics can be used to treat a variety of conditions including dyskinesia, antipsychotic-induced dyskinesia, haloperidol (haloperidol)-induced dyskinesia, dopamine mimetic-induced dyskinesia.

文獻中已說明一些型式之mGluR5調節劑。 Some types of mGluR5 modulators have been described in the literature.

如今已發現，某些雜環衍生物為有效之mGluR5調節劑。因此，這些物質可醫療有利於治療涉及異常麩胺酸神經傳導之病況或其中mGluR5受體之調節可導致醫療利益之病況。這些物質可以藥學組成物之形式投服，其中彼等係連同一或多種藥學上可接受之稀釋劑、載體、或賦形劑一起存在。 It has now been discovered that certain heterocyclic derivatives are potent mGluR5 modulators. Thus, these materials are medically advantageous for the treatment of conditions involving abnormal glutamate neurotransmission or where modulation of the mGluR5 receptor can lead to medical benefits. These materials may be administered in the form of a pharmaceutical composition in which they are present together with one or more pharmaceutically acceptable diluents, carriers, or excipients.

本發明之目的Purpose of the invention

本發明之目的係提供新穎之藥學化合物(其為mGluR5調節劑)及其藥學組成物。本發明進一步之目的係藉使用本發明化合物或含彼之藥學組成物以提供治療、消除、減 輕、緩和、改善、或改良涉及異常麩胺酸神經傳導之不期望中樞神經系統病症，及/或提供症狀學效應。 The object of the present invention is to provide a novel pharmaceutical compound which is a mGluR5 modulator and a pharmaceutical composition thereof. A further object of the present invention is to provide a treatment, elimination, and subtraction by using a compound of the present invention or a pharmaceutical composition containing the same Light, alleviate, improve, or ameliorate undesirable central nervous system disorders involving abnormal glutamate nerve conduction, and/or provide symptomatic effects.

本發明之另加目的係提供製造雜環衍生物之方法。 A further object of the invention is to provide a process for the manufacture of heterocyclic derivatives.

發明概述Summary of invention

因此吾人咸信吾發明所包含者尤其可以下列敘述概述：一種化合物，其選自式I Therefore, the inclusion of the invention can be summarized in the following description: a compound selected from the formula I

其中X代表CR⁶(C=O)R⁷或NR⁸；R¹代表H、C_1-6烷基、或F；R²代表H、C_1-6烷基、或F；或者R¹及R²與彼等所連接之碳原子共同形成羰基團；或者R¹及R²與彼等所連接之碳原子共同形成3-7員環，其可為飽和或不飽和，其中該環可隨意地含有一或二個選自硫、氧、及氮之雜原子且其中該環可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷基、C_1-6烷氧基、胺基、羥基、氰基、醯基、C_1-6烷胺基、二-(C_1-6烷基)胺基、C_1-6烷基羰基胺基、及側氧基之取代基取代； R³代表H、C_1-6烷基、或F；R⁴代表H、C_1-6烷基、或F；或者R³及R⁴與彼等所連接之碳原子共同形成3-7員環，其可為飽和或不飽和，其中該環可隨意地含有一或二個選自硫、氧、及氮之雜原子且其中該環可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷基、C_1-6烷氧基、胺基、羥基、氰基、醯基、C_1-6烷胺基、二-(C_1-6烷基)胺基、C_1-6烷基羰基胺基、及側氧基之取代基取代；R⁵代表選自芳基、雜芳基、環C_3-6烷基、及雜環基之單環部分；R⁶代表H、C_1-6烷基(其可隨意地被一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、或F；R⁷代表C_1-6烷基(其可隨意地被一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、環C_3-6烷基、雜環基、或NR¹¹R¹²；或者R⁶及R⁷與彼等所連接之碳原子共同形成3-7員環，其可為飽和或不飽和，其中該環可隨意地含有一或二個選自硫、氧、及氮之雜原子且其中該環可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷基、C_1-6烷氧基、胺基、羥基、氰基、醯基、C_1-6烷胺基、二- (C_1-6烷基)胺基、C_1-6烷基羰基胺基、及側氧基之取代基取代；R⁸代表C_1-6烷基(其可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、環C_3-6烷基、雜環基、芳基、雜芳基、C_1-6烷基羰基(其可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、環C_3-6烷基羰基、雜環基羰基、芳基羰基、雜芳基羰基、C_1-6烷氧羰基(其可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、胺基羰基、N-C_1-6烷基胺基羰基(其中該烷基部分可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、N,N-二-(C_1-6烷基)胺基羰基(其中該烷基部分可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、C_1-6烷氧羰基、氰基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、N-C_1-6烷基-N-環C_3-6烷基胺基羰基、N-C_1-6烷基-N-環C_3-6烷基-C_1-6烷基胺基羰基、胺基硫羰基、N-C_1-6烷基胺基硫羰基(其中該烷基部分可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、N,N- 二-(C_1-6烷基)胺基硫羰基(其中該烷基部分可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、C_1-6烷磺醯基(其中該烷基部分可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、環C_3-6烷磺醯基、胺磺醯基、N-C_1-6烷基胺磺醯基(其中該烷基部分可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、或N,N-二-(C_1-6烷基)胺磺醯基(其中該烷基部分可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)；R⁹代表H、C_1-6烷基、或F；R¹⁰代表H、C_1-6烷基、或F；或者R⁹及R¹⁰與彼等所連接之碳原子共同形成3-7員環，其可為飽和或不飽和，其中該環可隨意地含有一或二個選自硫、氧、及氮之雜原子且其中該環可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷基、C_1-6烷氧基、胺基、羥基、氰基、醯基、C_1-6烷胺基、二-(C_1-6烷基)胺基、C_1-6烷基羰基胺基、及側氧基之取代基取代；R¹¹代表H、C_1-6烷基、或環C_3-6烷基； R¹²代表H、C_1-6烷基、或環C_3-6烷基；或者R¹¹及R¹²與彼等所連接之氮原子共同形成3-7員環，其可為飽和或不飽和，其中該環可隨意地含有一或二個選自硫、氧、及氮之雜原子且其中該環可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷基、C_1-6烷氧基、胺基、羥基、氰基、醯基、C_1-6烷胺基、二-(C_1-6烷基)胺基、C_1-6烷基羰基胺基、及側氧基之取代基取代；及其光學異構體、前藥、藥學上可接受之鹽類、水合物、溶劑化物、及多形體；其中：如果R¹及R²與彼等所連接之碳原子共同形成羰基團時，則R⁸亦可代表H；R⁵不可代表隨意經取代之噻唑基；如果R⁸代表未經取代之C_1-6烷基時，則R⁵不代表隨意經取代之苯基；且式(I)化合物不可代表：N-(2,4-二氟苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺，N-(2,4-二甲氧基苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺，N-(2-氟苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺，N-(3,5-二甲氧基苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺， N-(3-甲氧基苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺，N-(4-氟苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺，N-(4-甲氧基苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺，N-苯基-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺，2-((2,4-二氟苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯，2-((2,4-二甲氧基苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯，2-((2,5-二甲氧基苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯，2-((2-甲氧基苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯，2-((3,5-二甲氧基苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯，2-((3-甲氧基苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯，2-((4-氟苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯，2-((4-甲氧基苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯，1-(4-(5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基胺基)苯基)乙酮，或 N-(4-苯氧基苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺。 Wherein X represents CR ⁶ (C=O)R ⁷ or NR ⁸ ; R ¹ represents H, C _1-6 alkyl, or F; R ² represents H, C _1-6 alkyl, or F; or R ¹ and R ² together with the carbon atom to which they are attached form a carbonyl group; or R ¹ and R ² together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may be optionally Containing one or two heteroatoms selected from the group consisting of sulfur, oxygen, and nitrogen, and wherein the ring is optionally optionally subjected to one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl , C _1-6 alkoxy, amine, hydroxy, cyano, decyl, C _1-6 alkylamino, bis-(C _1-6 alkyl)amino, C _1-6 alkylcarbonylamino And substituted with a pendant oxy group; R ³ represents H, C _1-6 alkyl, or F; R ⁴ represents H, C _1-6 alkyl, or F; or R ³ and R ⁴ and their The linked carbon atoms together form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from the group consisting of sulfur, oxygen, and nitrogen and wherein the ring is optionally one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _1-6 alkoxy, amino, hydroxy, cyano , Acyl, C _1-6 alkylamino, di - (C _1-6 alkyl) amino, C _1-6 alkylcarbonyl group, and the oxo substituent; R ⁵ is selected from aryl representatives a monocyclic moiety of a heteroaryl group, a heterocyclic C _3-6 alkyl group, and a heterocyclic group; R ⁶ represents an H, C _1-6 alkyl group (which may optionally be selected from one or more selected from the group consisting of halogen and trifluoro) a substituent of a methyl group, a trifluoromethoxy group, a C _1-6 alkoxy group, an amine group, a hydroxyl group, a C _1-6 alkylamino group, and a bis-(C _1-6 alkyl)amino group), or F; R ⁷ represents a C _1-6 alkyl group (which may optionally be selected from one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxy, amine, hydroxy, C _{a 1-6} alkylamino group, and a substituent of a bis-(C _1-6 alkyl)amino group, a ring C _3-6 alkyl group, a heterocyclic group, or NR ¹¹ R ¹² ; or R ⁶ and R ⁷ Together with the carbon atoms to which they are attached, a 3-7 membered ring may be formed which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from the group consisting of sulfur, oxygen, and nitrogen and wherein the ring Optionally, one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _1-6 alkoxy, amine, hydroxy, cyano, decyl, C _1-6 alkylamine , Di - (C _1-6 alkyl) amino, C _1-6 alkylcarbonyl group, and the oxo substituent; R ⁸ represents a C _1-6 alkyl group (which may be optionally substituted by one or a plurality of selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxy, amine, hydroxy, C _1-6 alkylamino, and bis-(C _1-6 alkyl)amine Substituent substituent), cyclo C _3-6 alkyl, heterocyclyl, aryl, heteroaryl, C _1-6 alkylcarbonyl (which may optionally be selected from one or more selected from halogen, trifluoromethyl a substituent of a substituent such as a trifluoromethoxy group, a C _1-6 alkoxy group, an amine group, a hydroxyl group, a C _1-6 alkylamino group, and a bis-(C _1-6 alkyl)amino group, and a ring C _3-6 alkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, heteroarylcarbonyl, _C1-6 alkoxycarbonyl (which may optionally be selected from one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethyl) An oxy group, a C _1-6 alkoxy group, an amine group, a hydroxyl group, a C _1-6 alkylamino group, and a substituent of a bis-(C _1-6 alkyl)amino group, an amine carbonyl group, an N- C group _{a 1-6} alkylaminocarbonyl group (wherein the alkyl moiety is optionally optionally subjected to one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxy, amine, hydroxy, a C _1-6 alkoxy group, and - (C _1-6 alkyl) amino group substituted with the substituent), N, N - two - (C _1-6 alkyl) aminocarbonyl group (wherein the alkyl moiety may be optionally substituted by one or more substituents selected from Halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxy, C _1-6 alkoxycarbonyl, cyano, amine, hydroxy, C _1-6 alkylamino, and di-(C Substituted by a substituent of a _1-6 alkyl) group, N- C _1-6 alkyl- N -cyclo C _3-6 alkylaminocarbonyl, N- C _1-6 alkyl- N -cyclo C _{3 a -6} alkyl-C _1-6 alkylaminocarbonyl group, an aminothiocarbonyl group, an N- C _1-6 alkylaminothiocarbonyl group (wherein the alkyl moiety is optionally optionally subjected to one or more halogens, a substituent of a trifluoromethyl group, a trifluoromethoxy group, a C _1-6 alkoxy group, an amine group, a hydroxyl group, a C _1-6 alkylamino group, and a bis-(C _1-6 alkyl)amino group) , N,N -di-(C _1-6 alkyl)aminothiocarbonyl (wherein the alkyl moiety is optionally optionally one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _{1 a -6} alkoxy group, an amine group, a hydroxyl group, a C _1-6 alkylamino group, and a substituent of a bis-(C _1-6 alkyl)amino group, and a C _1-6 alkanesulfonyl group (wherein the alkane) The base moiety is optionally optionally one or more selected from the group consisting of halogen, trifluoromethyl, trifluoro Group, C _1-6 alkoxy, amino, hydroxy, C _1-6 alkoxy group, and two - (C _1-6 alkyl) amino group substituted with the substituents), cycloalkyl C _3-6 alkylsulfonyl An anthracenyl, an amine sulfonyl group, an N- C _1-6 alkylamine sulfonyl group (wherein the alkyl moiety is optionally optionally one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _{a 1-6} alkoxy group, an amine group, a hydroxyl group, a C _1-6 alkylamino group, and a substituent of a bis-(C _1-6 alkyl)amino group, or N,N -di-(C _{1- a 6} alkyl)amine sulfonyl group (wherein the alkyl moiety is optionally optionally subjected to one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxy, amine, hydroxy, a C _1-6 alkylamino group, and a substituent of the bis-(C _1-6 alkyl)amino group are substituted; R ⁹ represents H, C _1-6 alkyl, or F; R ¹⁰ represents H, C _{1- 6} alkyl, or F; or R ⁹ and R ¹⁰ together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two selected from a hetero atom of sulfur, oxygen, and nitrogen, and wherein the ring is optionally, optionally, one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, _C1-6 alkyl, _C1-6 alkoxy Amine, hydroxyl, cyano Acyl, C _1-6 alkylamino, di - (C _1-6 alkyl) amino, C _1-6 alkylcarbonyl amino, oxo, and the substituents; R ¹¹ on behalf of H, C _{1 -6} alkyl, or cyclic C _3-6 alkyl; R ¹² represents H, C _1-6 alkyl, or cyclic C _3-6 alkyl; or R ¹¹ and R ¹² are bonded to the nitrogen atom to which they are attached Forming a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from the group consisting of sulfur, oxygen, and nitrogen and wherein the ring is optionally subjected to one or more From halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _1-6 alkoxy, amine, hydroxy, cyano, decyl, C _1-6 alkylamino, di- Substituted with a (C _1-6 alkyl)amino group, a C _1-6 alkylcarbonylamino group, and a pendant oxy group; and optical isomers, prodrugs, pharmaceutically acceptable salts thereof, hydrates , solvate, and polymorph; wherein: if R ¹ and R ² together with the carbon atom to which they are attached form a carbonyl group, then R ⁸ may also represent H; R ⁵ may not represent a randomly substituted thiazolyl; when R ⁸ represents a non-substituted C _1-6 alkyl, then R ⁵ does not represent the freely substituted phenyl; and of formula (I) Representative compounds not: N - (2,4- difluorophenyl) -5,6,7,8-tetrahydro-pyrido [4,3-d] pyrimidin-2-amine, N - (2,4- Dimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, N- (2-fluorophenyl)-5,6,7,8 -tetrahydropyrido[4,3-d]pyrimidin-2-amine, N- (3,5-dimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2-amine, N- (3-methoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, N- (4- Fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, N- (4-methoxyphenyl)-5,6,7,8- Tetrahydropyrido[4,3-d]pyrimidin-2-amine, N -phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, 2-( (2,4-difluorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxylic acid tert-butyl ester, 2-((2, 4-Dimethoxyphenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxylic acid tert-butyl ester, 2-((2,5) -dimethoxyphenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6( 5H )-carboxylic acid tert-butyl ester, 2-((2-methoxy) Phenylphenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6( 5H )-carboxylic acid tert-butyl ester, 2-((3,5-dimethoxy) Phenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine -6 (5 H) - carboxylic acid tert-butyl ester, 2 - ((3-methoxyphenyl) amino) -7,8-dihydro-pyrido [4,3-d] pyrimidine-6 (5 H )-carboxylic acid tert-butyl ester, 2-((4-fluorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxylic acid Tributyl ester, 2-((4-methoxyphenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxylic acid tert-butyl ester, 1-(4-(5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-ylamino)phenyl)ethanone, or N- (4-phenoxyphenyl) -5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine.

本發明進一步方面係關於式I化合物，其中R⁸代表C_1-6烷基(其可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、環C_3-6烷基、雜環基、芳基、雜芳基、C_1-6烷基羰基(其可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、環C_3-6烷基羰基、芳基羰基、雜芳基羰基、C_1-6烷氧羰基(其可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、胺基羰基、N-C_1-6烷基胺基羰基(其中該烷基部分可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、N,N-二-(C_1-6烷基)胺基羰基(其中該烷基部分可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、C_1-6烷磺醯基(其中該烷基部分可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、環C_3-6烷磺醯基、胺磺醯基、N-C_1-6烷基胺磺醯基(其中該烷基部分可隨意地經一或多個選自鹵素、三氟 甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、或N,N-二-(C_1-6烷基)胺磺醯基(其中該烷基部分可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)。 A further aspect of the invention relates to a compound of formula I , wherein R ⁸ represents C _1-6 alkyl (which may optionally be selected from one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkane An oxy group, an amine group, a hydroxyl group, a C _1-6 alkylamino group, and a substituent of a bis-(C _1-6 alkyl)amino group, a ring C _3-6 alkyl group, a heterocyclic group, an aryl group, Heteroaryl, C _1-6 alkylcarbonyl (which may optionally be selected from one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxy, amine, hydroxy, C _{a 1-6} alkylamino group, and a substituent of a bis-(C _1-6 alkyl)amino group, a ring C _3-6 alkylcarbonyl group, an arylcarbonyl group, a heteroarylcarbonyl group, a C _1-6 alkoxy group a carbonyl group (which may optionally be selected from one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxy, amine, hydroxy, C _1-6 alkylamino, and a substituent of a (C _1-6 alkyl)amino group), an aminocarbonyl group, an N- C _1-6 alkylaminocarbonyl group (wherein the alkyl moiety is optionally optionally one or more selected from the group consisting of halogen, three a fluoromethyl group, a trifluoromethoxy group, a C _1-6 alkoxy group, an amine group, a hydroxyl group, a C _1-6 alkylamino group, and a substituent of a bis-(C _1-6 alkyl)amino group), N, N - two a -(C _1-6 alkyl)aminocarbonyl group (wherein the alkyl moiety is optionally optionally subjected to one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxy, amine a hydroxy group, a hydroxy group, a C _1-6 alkylamino group, and a substituent of a bis-(C _1-6 alkyl)amino group, a C _1-6 alkane sulfonyl group (wherein the alkyl moiety is optionally passed through a Or a plurality selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxy, amine, hydroxy, C _1-6 alkylamino, and di-(C _1-6 alkyl) a substituent substituted with an amine group), a ring C _3-6 alkanesulfonyl group, an amine sulfonyl group, an N -C _1-6 alkylamine sulfonyl group (wherein the alkyl moiety is optionally subjected to one or more Substitution from halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxy, amine, hydroxy, C _1-6 alkylamino, and di-(C _1-6 alkyl)amine a substituted or N,N -di-(C _1-6 alkyl)amine sulfonyl group (wherein the alkyl moiety is optionally optionally subjected to one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy a substituent of a C _1-6 alkoxy group, an amine group, a hydroxyl group, a C _1-6 alkylamino group, and a bis-(C _1-6 alkyl)amino group).

本發明進一步方面係關於式I化合物，其中R¹及R²與彼等所連接之碳原子共同形成羰基團，且X代表NR⁸，其中R⁸代表H。 A further aspect of the present invention relates to a compound of formula I, wherein R ¹ and R ² carbons and their atoms are attached together form a carbonyl group of the group, and X represents NR ^8, wherein R ⁸ represents H.

本發明進一步方面係關於式I化合物，其中R¹及R²代表H，且X代表CR⁶(C=O)R⁷，其中R⁶代表H且R⁷代表C_1-6烷基或雜環基。 A further aspect of the invention relates to a compound of formula I , wherein R ¹ and R ² represent H, and X represents CR ⁶ (C=O)R ⁷ , wherein R ⁶ represents H and R ⁷ represents C _1-6 alkyl or heterocycle base.

該式I化合物，其中R⁶代表H且R⁷代表雜環基。 The compound of formula I , wherein R ⁶ represents H and R ⁷ represents a heterocyclic group.

該式I化合物，其中R⁷代表哌啶基。 The compound of formula I , wherein R ⁷ represents piperidinyl.

本發明進一步方面係關於式I化合物，其中R¹及R²代表H，且X代表NR⁸，其中R⁸代表C_1-6烷基羰基、環C_3-6烷基羰基、雜環基羰基、芳基羰基、C_1-6烷氧羰基、N-C_1-6烷基胺基羰基、N,N-二-(C_1-6烷基)胺基羰基、N,N-二-(C_1-6烷基)胺基硫羰基、N-C_1-6烷基-N-環C_3-6烷基胺基羰基、N-C_1-6烷基-N-環C_3-6烷基-C_1-6烷基胺基羰基、C_1-6烷磺醯基、環C_3-6烷磺醯基、N,N-二-(C_1-6烷基)胺磺醯基、或雜芳基。 A further aspect of the invention relates to a compound of formula I , wherein R ¹ and R ² represent H, and X represents NR ⁸ , wherein R ⁸ represents C _1-6 alkylcarbonyl, cyclo C _3-6 alkylcarbonyl, heterocyclylcarbonyl , arylcarbonyl, C _1-6 alkoxycarbonyl, N- C _1-6 alkylaminocarbonyl, N,N -di-(C _1-6 alkyl)aminocarbonyl, N,N -di-( C _1-6 alkyl)aminothiocarbonyl, N- C _1-6 alkyl- N -cyclo C _3-6 alkylaminocarbonyl, N- C _1-6 alkyl- N -cyclo C _3-6 Alkyl-C _1-6 alkylaminocarbonyl, C _1-6 alkanesulfonyl, ring C _3-6 alkanesulfonyl, N,N -di-(C _1-6 alkyl)amine sulfonyl Or a heteroaryl group.

該式I化合物，其中R⁸代表C_1-6烷基羰基、環C_3-6烷基羰基、芳基羰基、C_1-6烷氧羰基、N-C_1-6烷基胺基羰 基、N,N-二-(C_1-6烷基)胺基羰基、C_1-6烷磺醯基、環C_3-6烷磺醯基、N,N-二-(C_1-6烷基)胺磺醯基、或雜芳基。 A compound of formula I , wherein R ⁸ represents C _1-6 alkylcarbonyl, cyclo C _3-6 alkylcarbonyl, arylcarbonyl, C _1-6 alkoxycarbonyl, N- C _1-6 alkylaminocarbonyl, N,N -di-(C _1-6 alkyl)aminocarbonyl, C _1-6 alkanesulfonyl, ring C _3-6 alkanesulfonyl, N,N -di-(C _1-6 alkyl Aminesulfonyl, or heteroaryl.

該式I化合物，其中R⁸代表隨意經取代之吡啶基、四唑基、嘧啶基、呋喃基、噻唑基、或咪唑基。 The compound of formula I , wherein R ⁸ represents an optionally substituted pyridyl, tetrazolyl, pyrimidinyl, furyl, thiazolyl, or imidazolyl group.

該式I化合物，其中R⁸代表隨意經取代之吡啶基或四唑基。 The compound of formula I , wherein R ⁸ represents a randomly substituted pyridyl or tetrazolyl group.

本發明進一步方面係關於式I化合物，其中R⁵代表隨意經一或多個選自鹵素、C_1-6烷基、及氰基之取代基取代之苯基。 A further aspect of the present invention relates to a compound of formula I, wherein R ⁵ represents one or more substituents selected arbitrarily by halo, C _1-6 alkyl, and a cyano substituent of a substituted phenyl group.

本發明進一步方面係關於式I化合物，其選自式IA A further aspect of the invention relates to a compound of formula I selected from formula IA

其中R³-R⁵及R⁸-R¹⁰為如以上式I所定義者，及其光學異構體、前藥、藥學上可接受之鹽類、水合物、溶劑化物、及多形體。 Wherein R ³ -R ⁵ and R ⁸ -R ¹⁰ are as defined in the above formula I , and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

該式IA化合物，其中R⁵代表選自芳基及雜芳基之單環部分。 The compound of formula IA , wherein R ⁵ represents a monocyclic moiety selected from the group consisting of aryl and heteroaryl.

該式IA化合物，其中R³、R⁴、R⁸、R⁹、及R¹⁰各自代表H且R⁵代表選自芳基及雜芳基之單環部分。 The compound of formula IA , wherein R ³ , R ⁴ , R ⁸ , R ⁹ , and R ¹⁰ each represent H and R ⁵ represents a monocyclic moiety selected from the group consisting of aryl and heteroaryl.

該式IA化合物，其中R³、R⁴、R⁸、R⁹、及R¹⁰各自代表H且R⁵代表隨意經一或多個鹵素原子取代之苯基。 The compound of formula IA , wherein R ³ , R ⁴ , R ⁸ , R ⁹ , and R ¹⁰ each represent H and R ⁵ represents a phenyl group optionally substituted with one or more halogen atoms.

本發明進一步方面係關於式I化合物，其選自式IB A further aspect of the invention relates to a compound of formula I selected from formula IB

其中R¹-R⁴、R⁹-R¹²為如以上式I所定義者，及其光學異構體、前藥、藥學上可接受之鹽類、水合物、溶劑化物、及多形體。 Wherein R ¹ -R ⁴ and R ⁹ -R ¹² are as defined in the above formula I , and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

該式IB化合物，其中R⁵代表選自芳基及雜芳基之單環部分。 The compound of formula IB , wherein R ⁵ represents a monocyclic moiety selected from the group consisting of aryl and heteroaryl.

該式IB化合物，其中R³、R⁴、R⁹、及R¹⁰各自代表H，R¹¹及R¹²代表C_1-6烷基(例如甲基或乙基)或者R¹¹及R¹²與彼等所連接之氮原子共同形成3-7員飽和環，且R⁵代表選自芳基及雜芳基之單環部分。 A compound of the formula IB , wherein R ³ , R ⁴ , R ⁹ and R ¹⁰ each represent H, R ¹¹ and R ¹² represent a C _1-6 alkyl group (e.g., methyl or ethyl) or R ¹¹ and R ¹² and The nitrogen atoms to be joined together form a 3-7 membered saturated ring, and R ⁵ represents a monocyclic moiety selected from the group consisting of an aryl group and a heteroaryl group.

該式IB化合物，其中R³、R⁴、R⁹、及R¹⁰各自代表H，R¹¹及R¹²與彼等所連接之氮原子共同形成哌啶基，且R⁵代表隨意經一或多個鹵素原子取代之苯基。 A compound of the formula IB , wherein R ³ , R ⁴ , R ⁹ and R ¹⁰ each represent H, R ¹¹ and R ¹² together with the nitrogen atom to which they are attached form a piperidinyl group, and R ⁵ represents optionally one or more A phenyl group substituted with a halogen atom.

本發明進一步方面係關於式I化合物，其選自式IC A further aspect of the invention relates to a compound of formula I selected from formula IC

其中R¹-R⁵、R⁸-R¹⁰為如以上式I所定義者，及其光學異構體、前藥、藥學上可接受之鹽類、水合物、溶劑化物、及多形體。 Wherein R ¹ -R ⁵ , R ⁸ -R ¹⁰ are as defined in the above formula I , and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

該式IC化合物，其中R⁵代表選自芳基及雜芳基之單環部分。 A compound of the formula IC wherein R ⁵ represents a monocyclic moiety selected from the group consisting of aryl and heteroaryl.

該式IC化合物，其中R¹-R⁴、R⁹、及R¹⁰各自代表H，R⁵代表選自芳基及雜芳基之單環部分，且R⁸代表C_1-6烷基羰基、環C_3-6烷基羰基、雜環基羰基、芳基羰基、C_1-6烷氧羰基、N-C_1-6烷基胺基羰基、N,N-二-(C_1-6烷基)胺基羰基、N,N-二-(C_1-6烷基)胺基硫羰基、N-C_1-6烷基-N-環C_3-6烷基胺基羰基、N-C_1-6烷基-N-環C_3-6烷基-C_1-6烷基胺基羰基、C_1-6烷磺醯基、環C_3-6烷磺醯基、N,N-二-(C_1-6烷基)胺磺醯基、或雜芳基。 A compound of the formula IC , wherein R ^{1 -} R ⁴ , R ⁹ and R ¹⁰ each represent H, R ⁵ represents a monocyclic moiety selected from aryl and heteroaryl, and R ⁸ represents a C _1-6 alkylcarbonyl group, Ring C _3-6 alkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, C _1-6 alkoxycarbonyl, N- C _1-6 alkylaminocarbonyl, N,N -di-(C _1-6 alkane Aminocarbonyl, N,N -di-(C _1-6 alkyl)aminothiocarbonyl, N- C _1-6 alkyl- N -cyclo C _3-6 alkylaminocarbonyl, N -C _1-6 alkyl- N - _{cycloC 3-6} alkyl-C _1-6 alkylaminocarbonyl, C _1-6 alkanesulfonyl, ring C _3-6 alkanesulfonyl, N,N - II -(C _1-6 alkyl)aminesulfonyl, or heteroaryl.

該式IC化合物，其中R⁸代表C_1-6烷基羰基、環C_3-6烷基羰基、芳基羰基、C_1-6烷氧羰基、N-C_1-6烷基胺基羰基、N,N-二-(C_1-6烷基)胺基羰基、C_1-6烷磺醯基、環C_3-6烷磺醯基、N,N-二-(C_1-6烷基)胺磺醯基、或雜芳基。 A compound of the formula IC , wherein R ⁸ represents C _1-6 alkylcarbonyl, cyclo C _3-6 alkylcarbonyl, arylcarbonyl, C _1-6 alkoxycarbonyl, N- C _1-6 alkylaminocarbonyl, N,N -di-(C _1-6 alkyl)aminocarbonyl, C _1-6 alkanesulfonyl, ring C _3-6 alkanesulfonyl, N,N -di-(C _1-6 alkyl Aminesulfonyl, or heteroaryl.

該式IC化合物，其中R¹-R⁴、R⁹、及R¹⁰各自代表H，R⁵代表隨意經一或多個選自鹵素、C_1-6烷基、及氰基之取代基取代之苯基，且R⁸代表C_1-6烷基羰基、環C_3-6烷基羰基、雜環基羰基、芳基羰基、C_1-6烷氧羰基、N-C_1-6烷基胺基羰基、N,N-二-(C_1-6烷基)胺基羰基、N,N-二-(C_1-6烷基)胺基硫羰基、N-C_1-6烷基-N-環C_3-6烷基胺基羰基、N-C_1-6烷基-N-環C_3-6烷基-C_1-6烷基胺基羰基、C_1-6烷磺醯基、環C_3-6烷磺醯基、N,N-二-(C_1-6烷基)胺磺醯基、或雜芳基。 A compound of the formula IC , wherein R ¹ -R ⁴ , R ⁹ and R ¹⁰ each represent H, and R ⁵ represents optionally substituted by one or more substituents selected from the group consisting of halogen, C _1-6 alkyl, and cyano. Phenyl, and R ⁸ represents C _1-6 alkylcarbonyl, cyclo C _3-6 alkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, C _1-6 alkoxycarbonyl, N -C _1-6 alkylamine Carbonyl, N,N -di-(C _1-6 alkyl)aminocarbonyl, N,N -di-(C _1-6 alkyl)aminothiocarbonyl, N- C _1-6 alkyl- N a ring C _3-6 alkylaminocarbonyl, N- C _1-6 alkyl- N -cyclo C _3-6 alkyl-C _1-6 alkylaminocarbonyl, C _1-6 alkanesulfonyl, Ring C _3-6 alkanesulfonyl, N,N -di-(C _1-6 alkyl)aminesulfonyl, or heteroaryl.

該式IC化合物，其中R⁸代表C_1-6烷基羰基、環C_3-6烷基羰基、芳基羰基、C_1-6烷氧羰基、N-C_1-6烷基胺基羰基、N,N-二-(C_1-6烷基)胺基羰基、C_1-6烷磺醯基、環C_3-6 烷磺醯基、N,N-二-(C_1-6烷基)胺磺醯基、或雜芳基。 A compound of the formula IC , wherein R ⁸ represents C _1-6 alkylcarbonyl, cyclo C _3-6 alkylcarbonyl, arylcarbonyl, C _1-6 alkoxycarbonyl, N- C _1-6 alkylaminocarbonyl, N,N -di-(C _1-6 alkyl)aminocarbonyl, C _1-6 alkanesulfonyl, ring C _3-6 alkanesulfonyl, N,N -di-(C _1-6 alkyl Aminesulfonyl, or heteroaryl.

該式IC化合物，其中R¹-R⁴、R⁹、及R¹⁰各自代表H，R⁵代表隨意經一或多個選自鹵素、C_1-6烷基、及氰基之取代基取代之苯基，且R⁸代表隨意經取代之吡啶基、四唑基、嘧啶基、呋喃基、噻唑基、或咪唑基。 A compound of the formula IC , wherein R ¹ -R ⁴ , R ⁹ and R ¹⁰ each represent H, and R ⁵ represents optionally substituted by one or more substituents selected from the group consisting of halogen, C _1-6 alkyl, and cyano. Phenyl, and R ⁸ represents optionally substituted pyridyl, tetrazolyl, pyrimidinyl, furyl, thiazolyl, or imidazolyl.

該式IC化合物，其中R⁸代表隨意經取代之吡啶基或四唑基。 A compound of the formula IC wherein R ⁸ represents a randomly substituted pyridyl or tetrazolyl group.

本發明進一步方面係關於式I化合物，其選自式ID A further aspect of the invention relates to a compound of formula I selected from formula ID

其中R¹-R⁵及R⁹-R¹⁰為如以上式I所定義者且R¹³代表C_1-6烷基(其可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、環C_3-6烷基、雜環基、芳基、雜芳基、C_1-6烷氧基(其可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、胺基羰基、N-C_1-6烷胺基(其中該烷基部分可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、N,N-二-(C_1-6烷基)胺基(其中該烷基部分可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、C_1-6烷氧羰基、氰基、胺基、羥基、 C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、N-C_1-6烷基-N-環C_3-6烷基胺基、或N-C_1-6烷基-N-環C_3-6烷基-C_1-6烷基胺基，及其光學異構體、前藥、藥學上可接受之鹽類、水合物、溶劑化物、及多形體。 Wherein R ¹ -R ⁵ and R ⁹ -R ¹⁰ are as defined above for formula I and R ¹³ represents C _1-6 alkyl (which may optionally be selected from halo, trifluoromethyl, tri a fluoromethoxy group, a C _1-6 alkoxy group, an amine group, a hydroxyl group, a C _1-6 alkylamino group, and a substituent of a bis-(C _1-6 alkyl)amino group, and a ring C _3-6 An alkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a C _1-6 alkoxy group (which may optionally be selected from one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _1-6 Alkoxy group, amine group, hydroxyl group, C _1-6 alkylamino group, and substituent of bis-(C _1-6 alkyl)amino group), aminocarbonyl group, N- C _1-6 alkylamino group ( Wherein the alkyl moiety is optionally optionally one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, _C1-6 alkoxy, amine, hydroxy, _C1-6 alkylamino, and a substituent of a bis-(C _1-6 alkyl)amino group, an N,N -di-(C _1-6 alkyl)amino group (wherein the alkyl moiety is optionally exemplified by one or more Halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxy, C _1-6 alkoxycarbonyl, cyano, amine, hydroxy, C _1-6 alkylamino, and di-(C _C1-6 alkyl) amino group substituted with the substituents), N -C _1-6 alkyl - N - cycloalkyl C _3-6 alkylamino, or N -C _1-6 alkyl - N - C _3-6 cycloalkyl -C _1-6 alkylamino group, its enantiomers, before Medicaments, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs.

該式ID化合物，其中R¹³代表C_1-6烷基、環C_3-6烷基、雜環基、芳基、C_1-6烷氧基、N-C_1-6烷胺基、N,N-二-(C_1-6烷基)胺基、N-C_1-6烷基-N-環C_3-6烷基胺基、或N-C_1-6烷基-N-環C_3-6烷基-C_1-6烷基胺基。 A compound of the formula ID , wherein R ¹³ represents C _1-6 alkyl, cyclo C _3-6 alkyl, heterocyclyl, aryl, C _1-6 alkoxy, N- C _1-6 alkylamino, N , N -di-(C _1-6 alkyl)amino, N- C _1-6 alkyl- N -cyclo C _3-6 alkylamino, or N- C _1-6 alkyl- N -ring C _3-6 alkyl-C _1-6 alkylamino group.

該式ID化合物，其中R⁵代表選自芳基及雜芳基之單環部分。 A compound of the formula ID wherein R ⁵ represents a monocyclic moiety selected from the group consisting of aryl and heteroaryl.

該式ID化合物，其中R¹-R⁴、R⁹、及R¹⁰各自代表H且R⁵代表選自芳基及雜芳基之單環部分。 A compound of the formula ID wherein R ^{1 -} R ⁴ , R ⁹ , and R ¹⁰ each represent H and R ⁵ represents a monocyclic moiety selected from the group consisting of an aryl group and a heteroaryl group.

該式ID化合物，其中R³、R⁴、R⁸、R⁹、及R¹⁰各自代表H且R⁵代表隨意經一或多個選自鹵素、C_1-6烷基、及氰基之取代基取代之苯基。 A compound of the formula ID , wherein R ³ , R ⁴ , R ⁸ , R ⁹ , and R ¹⁰ each represent H and R ⁵ represents optionally substituted by one or more selected from the group consisting of halogen, C _1-6 alkyl, and cyano. Substituted phenyl.

本發明範圍內之特定式I化合物包括(但不限定於)下列化合物：2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-5(6H)-酮，(消旋)-(2-((3-氯苯基)胺基)-5,6,7,8-四氫喹唑啉-6-基)(哌啶-1-基)甲酮，1-(2-((3-氟苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)-2-甲基丙-1-酮， 1-(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)-2-甲基丙-1-酮，2-甲基-1-(2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)丙-1-酮，2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(環丙基)甲酮，1-(2-((4-氟苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)-2,2-二甲基丙-1-酮，1-(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)-2,2-二甲基丙-1-酮，3-((6-特戊醯基-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈，(消旋)-1-(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)-2-甲基丁-1-酮，2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(環丁基)甲酮，1-(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)-2-乙基丁-1-酮，2-((3-氟苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(苯基)甲酮，2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(苯基)甲酮，2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸甲酯， 2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸乙酯，2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸異丙酯，2-((3-氟苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯，2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯，2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯，2-((3-氰苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯，2-((3-氯苯基)胺基)-N-乙基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，2-((3-氯苯基)胺基)-N,N-二甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，N-(3-氯苯基)-6-(異丙磺醯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺，N-(3-氯苯基)-6-(環丙磺醯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺，2-((3-氯苯基)胺基)-N,N-二甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-磺醯胺，N-(3-氯苯基)-6-(吡啶-2-基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺， 6-(1-(第三丁基)-1H-四唑-5-基)-N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺，N-(3-氯苯基)-6-(1-異丙基-1H-四唑-5-基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺，2-((3-氰苯基)胺基)-N,N-二甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，2-((3-氯苯基)胺基)-N,N-二乙基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，2-((3-氰苯基)胺基)-N,N-二乙基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，(消旋)-3-((6-(2-甲基丁醯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈，(消旋)-2-((3-氯苯基)胺基)-N,N-二甲基-5,6,7,8-四氫喹唑啉-6-甲醯胺，(消旋)-2-((3-氯苯基)胺基)-N,N-二乙基-5,6,7,8-四氫喹唑啉-6-甲醯胺，2-((3-氯苯基)胺基)-N,N-二甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-硫代甲醯胺，(消旋)-1-(2-((3-氯苯基)胺基)-5,6,7,8-四氫喹唑啉-6-基)-2-甲基丙-1-酮，2-(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)煙腈，(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(吡咯烷-1-基)甲酮， 2-((3-氰苯基)胺基)-N,N-二異丙基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，3-((6-(2-甲氧基-2-甲基丙醯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈，3-((6-(嗎啉-4-羰基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈，N-(3-氯苯基)-6-(嘧啶-2-基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺，(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(呋喃-2-基)甲酮，(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(噻唑-2-基)甲酮，(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(噻唑-5-基)甲酮，2-((5-氯基吡啶-3-基)胺基)-N,N-二甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，N-(3-氯苯基)-6-(1-甲基-1H-四唑-5-基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺，N-(3-氯苯基)-6-(1-甲基-1H-咪唑-2-基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺，3-((6-(2-乙基丁醯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈，N-丁基-(2-((3-氰苯基)胺基)-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺， 2-((3-氰苯基)胺基)-N-環丙基-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，2-((3-氯苯基)胺基)-N-乙基-N-丙基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，N,N-二甲基-2-((6-甲基吡啶-2-基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，(消旋)-3-((6-(2-乙基吡咯烷-1-羰基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈，N-(氰甲基)-2-((3-氰苯基)胺基)-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，3-((6-(1-甲基環丙烷羰基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈，3-((6-(2-甲基環丙烷羰基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈，2,2,-二甲基-1-(2-((6-甲基吡啶-2-基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)丙-1-酮，3-((6-(2-羥基-2-甲基丙醯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈，N,N-二乙基-2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，2-((3-氰苯基)胺基)-N-異丙基-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，2-((3-氰苯基)胺基)-N-乙基-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺， 2-((3-氯苯基)胺基)-N-(環丙基甲基)-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，N,N-二甲基-2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，2-((3-氯苯基)胺基)-N-環丙基-N-乙基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，吡咯啶-1-基(2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)甲酮，(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(1-甲基環丙基)甲酮，(1-甲基環丙基)(2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)甲酮，N-乙基-N-丙基-2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，(消旋)-3-((6-(3-甲基吡咯烷-1-羰基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈，(消旋)-3-((6-(2-甲基吡咯烷-1-羰基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈，3-((6-(3,3-二甲基吖丁啶-1-羰基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈，2-((3-氰苯基)胺基)-N-乙基-N-丙基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，(消旋)-1-(2-((3-氯苯基)胺基)-5-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)-2,2-二甲基丙-1-酮， (消旋)-1-(2-((3-氯苯基)胺基)-7-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)-2,2-二甲基丙-1-酮，2-((3-氰苯基)胺基)-N,N-雙(2,2,2-三氟乙基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，吖丁啶-1-基(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)甲酮，2-(2-((3-氯苯基)胺基)-N-甲基-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-6-甲醯胺基)乙酸甲酯，N-(2-氰乙基)-2-((3-氰苯基)胺基)-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，2-((3-氰苯基)胺基)-N-(2-甲氧基乙基)-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，2-(2-(對位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)煙腈，2-((3-氰苯基)胺基)-N-甲基-N-丙基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，6-(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)吡啶-2-腈，2-(2-((3-氰苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)異煙腈，2-(2-((3-氰苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)-6-甲基煙腈，吖丁啶-1-基(2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)甲酮， N-乙基-N-甲基-2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，N-甲基-N-丙基-2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，2-((3-氯苯基)胺基)-N-甲基-N-丙基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，2-((3-氯苯基)胺基)-N-乙基-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，3-((6-(1-異丙基-1H-咪唑-2-基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈，3-((6-(3-甲基環氧丙烷-3-羰基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈，(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(3-甲基環氧丙烷-3-基)甲酮，(3-甲基環氧丙烷-3-基)(2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)甲酮，及及其光學異構體、前藥、藥學上可接受之鹽類、水合物、溶劑化物、及多形體。 Specific compounds of formula I within the scope of the invention include, but are not limited to, the following compounds: 2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 5(6 H )-keto, (racemic)-(2-((3-chlorophenyl)amino)-5,6,7,8-tetrahydroquinazolin-6-yl)(piperidine- 1-yl)methanone, 1-(2-((3-fluorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)- 2-methylpropan-1-one, 1-(2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )- 2-methylpropan-1-one, 2-methyl-1-(2-(meta-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5 H )-yl)propan-1-one, 2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H ) -yl)(cyclopropyl)methanone, 1-(2-((4-fluorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6( 5H ) -yl)-2,2-dimethylpropan-1-one, 1-(2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine -6(5 H )-yl)-2,2-dimethylpropan-1-one, 3-((6-pententyl-5,6,7,8-tetrahydropyrido[4,3 -d]pyrimidin-2-yl)amino)benzonitrile, (racemic)-1-(2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3 -d] pyrimidine -6 (5 H) - yl) -2-methylbutan-1-one, 2 - ((3-chloro Yl) amino) -7,8-dihydro-pyrido [4,3-d] pyrimidin -6 (5 H) - yl) (cyclobutyl) methanone, 1- (2 - ((3-Chlorophenyl Amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)-2-ethylbutan-1-one, 2-((3-fluorobenzene) Amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)(phenyl)methanone, 2-((3-chlorophenyl)amino group -7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)(phenyl)methanone, 2-((3-chlorophenyl)amino)-7, 8-Dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxylic acid methyl ester, 2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4 ,3-d]pyrimidine-6( 5H )-carboxylic acid ethyl ester, 2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6 (5 H )-Ionic acid isopropyl ester, 2-((3-fluorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxylic acid Third butyl ester, 2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxylic acid tert-butyl ester, 2 -(meta-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6( 5H )-carboxylic acid tert-butyl ester, 2-((3-cyanophenyl) Amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6( 5H )-carboxylic acid tert-butyl ester, 2-((3-chlorophenyl)amino) -N -ethyl-7,8-dihydropyrido[4,3-d]pyrimidine -6 (5 H) - A Amides, 2 - ((3-chlorophenyl) amino) - N, N - dimethyl-7,8-dihydro-pyrido [4,3-d] pyrimidine - 6(5 H )-carbamide, N- (3-chlorophenyl)-6-(isopropylsulfonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine 2-amine, N- (3-chlorophenyl)-6-(cyclopropanesulfonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, 2-((3-Chlorophenyl)amino) -N,N -dimethyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-sulfonamide, N -(3-chlorophenyl)-6-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, 6-(1-( tert-butyl) -1 H - tetrazol-5-yl) - N - (3- chlorophenyl) -5,6,7,8-tetrahydro-pyrido [4,3-d] pyrimidine-2 Amine, N- (3-chlorophenyl)-6-(1-isopropyl-1 H -tetrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d Pyrimidine-2-amine, 2-((3-cyanophenyl)amino) -N,N -dimethyl-7,8-dihydropyrido[4,3-d]pyrimidine-6 (5 H -Metformamide, 2-((3-chlorophenyl)amino) -N,N -diethyl-7,8-dihydropyrido[4,3-d]pyrimidin-6( 5H ) -Procarbamide, 2-((3-cyanophenyl)amino) -N,N -diethyl-7,8-dihydropyrido[4,3-d]pyrimidin-6( 5H )- Methionamine, (racemic)-3-((6-(2-methylbutylidene))-5,6,7,8-tetrahydropyrido[4,3-d] 2-yl) amino) benzonitrile, (rac) -2 - ((3-chlorophenyl) amino) - N, N - dimethyl-5,6,7,8-tetrahydro Quinazoline-6-carbamide, (racemic)-2-((3-chlorophenyl)amino) -N,N -diethyl-5,6,7,8-tetrahydroquinazoline -6-carbamamine, 2-((3-chlorophenyl)amino) -N,N -dimethyl-7,8-dihydropyrido[4,3-d]pyrimidine-6 (5 H - thioformamide, (racemic)-1-(2-((3-chlorophenyl)amino)-5,6,7,8-tetrahydroquinazolin-6-yl)-2 -methylpropan-1-one, 2-(2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl Nicotinonitrile, (2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)(pyrrolidine-1- Methyl ketone, 2-((3-cyanophenyl)amino) -N , N -diisopropyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H ) -Procarbamide, 3-((6-(2-methoxy-2-methylpropenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2- Benzo)benzonitrile, 3-((6-(morpholin-4-carbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amine Benzocarbonitrile, N- (3-chlorophenyl)-6-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine , (2 - ((3-chlorophenyl) amino) -7,8-dihydro-pyrido [4,3-d] pyrimidin -6 (5 H) - ) (Furan-2-yl) methanone, (2 - ((3-chlorophenyl) amino) -7,8-dihydro-pyrido [4,3-d] pyrimidin -6 (5 H) - yl (thiazol-2-yl)methanone, (2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl (thiazol-5-yl)methanone, 2-((5-chloropyridin-3-yl)amino) -N , N -dimethyl-7,8-dihydropyrido[4,3- d]pyrimidine-6(5 H )-formamide, N -(3-chlorophenyl)-6-(1-methyl-1 H -tetrazol-5-yl)-5,6,7,8 -tetrahydropyrido[4,3-d]pyrimidin-2-amine, N- (3-chlorophenyl)-6-(1-methyl-1 H -imidazol-2-yl)-5,6, 7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, 3-((6-(2-ethylbutylidene)-5,6,7,8-tetrahydropyrido[4, 3-d]pyrimidin-2-yl)amino)benzonitrile, N -butyl-(2-((3-cyanophenyl)amino) -N -methyl-7,8-dihydropyridine [4,3-d]pyrimidine-6(5 H )-formamide, 2-((3-cyanophenyl)amino) -N -cyclopropyl- N -methyl-7,8-dihydro Pyrido[4,3-d]pyrimidin-6(5 H )-formamide, 2-((3-chlorophenyl)amino) -N -ethyl- N -propyl-7,8-di Hydropyrido[4,3-d]pyrimidin-6( 5H )-carbenamide, N , N -dimethyl-2-((6-methylpyridin-2-yl)amino)-7, 8- dihydro-pyrido [4,3-d] pyrimidin -6 (5 H) - A Amides, ( Cyclo)-3-((6-(2-ethylpyrrolidin-1-carbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino) Benzoonitrile, N- (cyanomethyl)-2-((3-cyanophenyl)amino) -N -methyl-7,8-dihydropyrido[4,3-d]pyrimidine-6 ( 5 H )-carbamamine, 3-((6-(1-methylcyclopropanecarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amine Benzocarbonitrile, 3-((6-(2-methylcyclopropanecarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino) Benzoonitrile, 2,2,-dimethyl-1-(2-((6-methylpyridin-2-yl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine -6(5 H )-yl)propan-1-one, 3-((6-(2-hydroxy-2-methylpropenyl)-5,6,7,8-tetrahydropyrido[4, 3-d]pyrimidin-2-yl)amino)benzonitrile, N,N -diethyl-2-(meta-tolylamino)-7,8-dihydropyrido[4,3- d]pyrimidine-6(5 H )-formamide, 2-((3-cyanophenyl)amino) -N -isopropyl- N -methyl-7,8-dihydropyrido[4, 3-d]pyrimidin-6(5 H )-carbenamide, 2-((3-cyanophenyl)amino) -N -ethyl- N -methyl-7,8-dihydropyrido[4 , 3-d] pyrimidin -6 (5 H) - A Amides, 2 - ((3-chlorophenyl) amino) - N - (cyclopropylmethyl) - N - methyl-7,8 Dihydropyrido[4,3-d]pyrimidin-6(5 H )- Indoleamine, N , N -dimethyl-2-(meta-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carbenamide, 2-((3-Chlorophenyl)amino) -N -cyclopropyl- N -ethyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )- formazan Amine, pyrrolidin-1-yl (2-(meta-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)methanone, ( 2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)(1-methylcyclopropyl)methanone ,(1-Methylcyclopropyl)(2-(meta-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)methanone , N -ethyl- N -propyl-2-(meta-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-formamide, (racemic)-3-((6-(3-methylpyrrolidin-1-carbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amine Benzocarbonitrile, (racemic)-3-((6-(2-methylpyrrolidin-1-carbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine 2-yl)amino)benzonitrile, 3-((6-(3,3-dimethylazetidin-1-carbonyl)-5,6,7,8-tetrahydropyrido[4, 3-d]pyrimidin-2-yl)amino)benzonitrile, 2-((3-cyanophenyl)amino) -N -ethyl- N -propyl-7,8-dihydropyridin[ 4,3-d]pyrimidine - 6(5 H )-carbamamine, (racemic)-1-(2-((3-chlorophenyl)amino)-5-methyl-7,8-dihydropyrido[4,3- d]pyrimidin-6(5 H )-yl)-2,2-dimethylpropan-1-one, (racemic)-1-(2-((3-chlorophenyl)amino)-7- Methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)-2,2-dimethylpropan-1-one, 2-((3-cyanobenzene) Amino) -N , N -bis(2,2,2-trifluoroethyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-formamide , azetidin-1-yl (2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)methanone ,2-(2-((3-chlorophenyl)amino) -N -methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-carboxamido Methyl acetate, N- (2-cyanoethyl)-2-((3-cyanophenyl)amino) -N -methyl-7,8-dihydropyrido[4,3-d]pyrimidine -6 (5 H) - A Amides, 2 - ((3-cyanophenyl) amino) - N - (2- methoxyethyl) - N - methyl-7,8-dihydro-pyrido [4,3-d]pyrimidin-6(5 H )-formamide, 2-(2-(p-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidine -6(5 H )-yl)nicotinonitrile, 2-((3-cyanophenyl)amino) -N -methyl- N -propyl-7,8-dihydropyrido[4,3-d ] pyrimidin -6 (5 H) - A Amides, 6- (2 - ((3-chlorophenyl) amino) -7,8-dihydro- Pyrido [4,3-d] pyrimidin -6 (5 H) - yl) pyridine-2-carbonitrile, 2- (2 - ((3-cyanophenyl) amino) -7,8-dihydro-pyrido [4,3-d]pyrimidin-6(5 H )-yl)isonicotinonitrile, 2-(2-((3-cyanophenyl)amino)-7,8-dihydropyrido[4,3 -d]pyrimidine-6(5 H )-yl)-6-methylnicotinonitrile, azetidin-1-yl (2-(meta-tolylamino)-7,8-dihydropyridinium[ 4,3-d]pyrimidin-6(5 H )-yl)methanone, N -ethyl- N -methyl-2-(meta-tolylamino)-7,8-dihydropyridinium[ 4,3-d]pyrimidin-6(5 H )-formamide, N -methyl- N -propyl-2-(meta-tolylamino)-7,8-dihydropyrido[4 , 3-d]pyrimidin-6(5 H )-formamide, 2-((3-chlorophenyl)amino) -N -methyl- N -propyl-7,8-dihydropyridin[ 4,3-d]pyrimidine-6(5 H )-formamide, 2-((3-chlorophenyl)amino) -N -ethyl- N -methyl-7,8-dihydropyridine [4,3-d]pyrimidin-6(5 H )-carbenamide, 3-((6-(1-isopropyl-1 H -imidazol-2-yl)-5,6,7,8- Tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile, 3-((6-(3-methylepoxypropan-3-carbonyl)-5,6,7, 8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile, (2-((3-chlorophenyl)amino)-7,8-dihydropyridin[ 4,3-d] pyrimidin -6 (5 H) - yl) (3- Propylene oxide-3-yl)methanone, (3-methyl propylene oxide-3-yl) (2-(meta-tolylamino)-7,8-dihydropyrido[4,3- d] pyrimidine-6(5 H )-yl)methanone, and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

再者，本發明係關於如上所定義之式I化合物或其光學異構體、藥學上可接受之鹽、水合物、溶劑化物、及多形體，係供治療及/或預防與異常麩胺酸神經傳導有關之病況或疾病，包括受mGluR5受體之調節所影響或幫助之病況或疾病，包括選自稍早說明中所述之病況或疾病。 Furthermore, the present invention relates to a compound of the formula I as defined above, or an optical isomer, a pharmaceutically acceptable salt, a hydrate, a solvate thereof, and a polymorph thereof, for the treatment and/or prophylaxis with abnormal glutamic acid A condition or disease associated with nerve conduction, including a condition or disease affected or aided by modulation of the mGluR5 receptor, including a condition or disease selected from those described earlier.

進一步方面，本發明係關於如上所定義之式I化合物 或其光學異構體、藥學上可接受之鹽、水合物、溶劑化物、及多形體，係供治療及/或預防中樞神經系統病症。再者，本發明係關於如上所定義之式I化合物或其光學異構體、藥學上可接受之鹽、水合物、溶劑化物、及多形體，係供治療及/或預防異常麩胺酸神經傳導。本發明另關於如上所定義之式I化合物或其光學異構體、藥學上可接受之鹽、水合物、溶劑化物、及多形體，係供mGluR5受體之調節。此外，本發明關於此化合物以供治療、預防及或調節選自稍早說明中所述之病況或疾病。本發明尚進一步關於此化合物以供治療、預防或調節生理學參數，諸如認知病症(無論是否存在特定之可識別之病況)。 In a further aspect, the invention relates to a compound of formula I as defined above, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, and polymorph thereof, for use in the treatment and/or prevention of a central nervous system disorder. Furthermore, the present invention relates to a compound of the formula I as defined above, or an optical isomer, a pharmaceutically acceptable salt, a hydrate, a solvate thereof and a polymorph thereof, for the treatment and/or prevention of abnormal glutamate nerves Conduction. The invention further relates to a compound of formula I as defined above, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, and polymorph thereof, for modulation of the mGluR5 receptor. Furthermore, the invention relates to such compounds for the treatment, prevention and or modulation of a condition or disease selected from those described in the earlier description. The invention is further directed to such compounds for the treatment, prevention or modulation of physiological parameters, such as cognitive conditions (whether or not there is a particular identifiable condition).

本發明進一步方面係關於如上所定義之式I化合物或其光學異構體、藥學上可接受之鹽、水合物、溶劑化物、及多形體，係供治療及/或預防與異常麩胺酸神經傳導有關之病況或其中mGluR5受體之調節可導致醫療利益之病況。可予治療之病況已於上述。這些病況及適應症包括： A further aspect of the invention relates to a compound of formula I as defined above, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, and polymorph thereof, for use in the treatment and/or prophylaxis of aberrant glutamate A condition associated with conduction or modulation of the mGluR5 receptor therein may result in a medical benefit. The conditions that can be treated are as described above. These conditions and indications include:

a)mGluR5調節劑方面：慢性疼痛、神經痛、糖尿病性神經痛(DNP)、癌症疼痛、與風濕性關節炎相關之疼痛、炎性疼痛、L-多巴-誘發性運動障礙、多巴胺模擬藥-誘發性運動障礙、帕金森氏症療法中之L-多巴-誘發性運動障礙、帕金森氏症療法中之多巴胺模擬藥-誘發性運動障礙、遲發性運動障礙、帕金森氏症、焦慮症、恐慌症、焦慮及恐慌症、社交焦慮症(SAD)、廣泛性焦慮症、物質-誘發性焦慮症、飲食失調症、肥胖症、暴食症、亨丁頓氏 舞蹈症、癲癇、阿滋海默氏症、精神***症之陽性及陰性症狀、認知障礙、功能性胃腸病、胃食道逆流症(GERD)、偏頭痛、腸躁症(IBS)、或供認知功能增強及/或神經保護。 a) mGluR5 modulator: chronic pain, neuralgia, diabetic neuropathic pain (DNP), cancer pain, pain associated with rheumatoid arthritis, inflammatory pain, L-dopa-induced dyskinesia, dopamine mimetic - induced dyskinesia, L-dopa-induced dyskinesia in Parkinson's disease therapy, dopamine mimetic-induced dyskinesia in Parkinson's disease therapy, tardive dyskinesia, Parkinson's disease, Anxiety disorders, panic disorder, anxiety and panic disorder, social anxiety disorder (SAD), generalized anxiety disorder, substance-induced anxiety disorder, eating disorder, obesity, binge eating disorder, Huntington's disease Chorus, epilepsy, Alzheimer's disease, positive and negative symptoms of schizophrenia, cognitive impairment, functional gastrointestinal disease, gastroesophageal reflux disease (GERD), migraine, intestinal fistula (IBS), or for cognition Functional enhancement and / or neuroprotection.

b)mGluR5之負向調節可特別用於：慢性疼痛、神經痛、糖尿病性神經痛(DNP)、癌症疼痛、與風濕性關節炎相關之疼痛、炎性疼痛、L-多巴-誘發性運動障礙、多巴胺模擬藥-誘發性運動障礙、帕金森氏症療法中之L-多巴-誘發性運動障礙、帕金森氏症療法中之多巴胺模擬藥-誘發性運動障礙、遲發性運動障礙、帕金森氏症、焦慮症、恐慌症、焦慮及恐慌症、社交焦慮症(SAD)、廣泛性焦慮症、物質-誘發性焦慮症、飲食失調症、肥胖症、暴食症、偏頭痛、腸躁症(IBS)、功能性胃腸病、胃食道逆流症(GERD)、亨丁頓氏舞蹈症及/或癲癇。 b) Negative regulation of mGluR5 can be used especially for: chronic pain, neuralgia, diabetic neuropathic pain (DNP), cancer pain, pain associated with rheumatoid arthritis, inflammatory pain, L-dopa-induced exercise Obstruction, dopamine mimetic-induced dyskinesia, L-dopa-induced dyskinesia in Parkinson's disease therapy, dopamine mimetic-induced dyskinesia in Parkinson's disease therapy, tardive dyskinesia, Parkinson's disease, anxiety, panic disorder, anxiety and panic disorder, social anxiety disorder (SAD), generalized anxiety disorder, substance-induced anxiety disorder, eating disorder, obesity, binge eating disorder, migraine, intestinal fistula Syndrome (IBS), functional gastrointestinal disease, gastroesophageal reflux disease (GERD), Huntington's disease and/or epilepsy.

c)mGluR5之正向調節可特別用於：阿滋海默氏症、精神***症之陽性及/或陰性症狀、認知障礙，或供認知功能增強及/或神經保護。 c) Positive regulation of mGluR5 may be particularly useful for: Alzheimer's disease, positive and/or negative symptoms of schizophrenia, cognitive impairment, or for cognitive enhancement and/or neuroprotection.

本發明進一步方面係關於如上所定義之式I化合物或其光學異構體、藥學上可接受之鹽、水合物、溶劑化物、及多形體，係供治療暴食症。 A further aspect of the invention relates to a compound of formula I as defined above, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, and polymorph thereof, for the treatment of bulimia.

本發明進一步係關於如上所定義之式I化合物或其光學異構體、藥學上可接受之鹽、水合物、溶劑化物、及多形體於製備供治療或預防與異常麩胺酸神經傳導有關之病況或疾病之醫藥上之用途。該用途包括該化合物於製備供 預防及/或治療動物包括人類之病況或疾病之醫藥上之用途，此病況或疾病係受mGluR5受體之調節所影響或幫助。 The invention further relates to a compound of formula I as defined above, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, and polymorph thereof, for use in the manufacture or prevention of abnormal glutamate nerve conduction The medical use of a condition or disease. Such uses include the use of the compounds in the manufacture of a medicament for the prevention and/or treatment of a condition or disease in an animal, including a human, which is affected or aided by modulation of the mGluR5 receptor.

再者，本發明係關於治療或預防與異常麩胺酸神經傳導有關之病況或疾病(包括受mGluR5受體之調節所影響或幫助之病況或疾病，包括選自稍早於說明中所述之病況或疾病)之方法。 Furthermore, the present invention relates to the treatment or prevention of a condition or disease associated with abnormal glutamate nerve conduction, including a condition or disease affected or assisted by modulation of the mGluR5 receptor, including from those described earlier in the description. Method of disease or disease).

此外，本發明係關於藥學組成物，其包含作為活性成分之至少一種如上所定義之式I化合物或其光學異構體、藥學上可接受之鹽、水合物、溶劑化物、及多形體，連同一或多種藥學上可接受之賦形劑。 Further, the present invention relates to a pharmaceutical composition comprising, as an active ingredient, at least one compound of the formula I as defined above, or an optical isomer, a pharmaceutically acceptable salt, a hydrate, a solvate thereof, and a polymorph, together with One or more pharmaceutically acceptable excipients.

再者，如上所述之mGluR調節劑當與經由不同機轉顯現神經學效應之其他物質組合使用時，預期具有高活性。 Furthermore, the mGluR modulators as described above are expected to have high activity when used in combination with other substances that exhibit neurological effects via different machines.

再更進一步方面，故本發明係關於如上所定義之式I化合物或其光學異構體、藥學上可接受之鹽、水合物、溶劑化物、及多形體，係與至少一種NMDA受體拮抗劑諸如美金剛胺(Memantine)組合以供神經保護及/或供認知功能增強。 In still a further aspect, the invention relates to a compound of formula I as defined above, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, and polymorph thereof, and at least one NMDA receptor antagonist A combination such as memantine for neuroprotection and/or for cognitive function enhancement.

本發明進一步方面係關於藥學組成物，其包含至少兩種不同之活性成分，包括至少一種選自如上所定義之式I化合物，另外，至少一種NMDA-拮抗劑，連同一或多種藥學上可接受之賦形劑。這些組成物可用於治療中樞神經系統-相關疾病、認知功能增強及供神經保護。故本發明 另提供組成物，其包含至少兩種不同之活性成分，包括至少一種選自如上所定義之式I化合物，另外，至少一種NMDA-拮抗劑，係供治療本文所指出之任何病況，包括中樞神經系統-相關疾病、認知功能增強及供神經保護。 A further aspect of the invention relates to a pharmaceutical composition comprising at least two different active ingredients, comprising at least one compound selected from formula I as defined above, in addition, at least one NMDA-antagonist, one or more pharmaceutically acceptable Excipients. These compositions are useful for the treatment of central nervous system-related diseases, cognitive enhancement, and neuroprotection. The invention further provides a composition comprising at least two different active ingredients, including at least one compound selected from formula I as defined above, in addition, at least one NMDA-antagonist, for the treatment of any of the conditions indicated herein, Including central nervous system-related diseases, cognitive function enhancement and neuroprotection.

本發明亦關於藥學組成物(包含如上所述之式I化合物與NMDA受體拮抗劑之組合)，包括其中NMDA受體拮抗劑為(例如)美金剛胺(Memantine)及其藥學上可接受之鹽類、多形體、水合物及溶劑化物之組成物。 The invention also relates to pharmaceutical compositions comprising a combination of a compound of formula I as described above and an NMDA receptor antagonist, including wherein the NMDA receptor antagonist is, for example, memantine and pharmaceutically acceptable thereof a composition of salts, polymorphs, hydrates, and solvates.

本發明亦關於藥學組成物，其包含至少兩種不同之活性成分，包括至少一種選自如上所定義之式I化合物，另外，至少一種選自L-多巴、其他多巴胺模擬藥(諸如抗巴金森氏症多巴胺模擬藥，包括溴隱亭(bromocriptine)、卡麥角林(cabergolin)、羅匹尼羅(ropinirole)、普拉克索(pramipexole)、培高利特(pergolide)、羅替戈丁(rotigotine))，及抗精神病藥物(諸如傳統抗精神病藥物，包括氟哌啶醇(haloperidol)、奮乃淨(perphenazin)、氯丙嗪(chlorpromazine)、甲氧氯普胺(metoclopramide))之活性成分。 The invention also relates to a pharmaceutical composition comprising at least two different active ingredients, including at least one compound selected from formula I as defined above, and additionally, at least one selected from the group consisting of L-dopa, other dopamine mimetic drugs (such as anti-Bakin Sjogren's dopamine mimetic, including bromocriptine, caberolin, ropinirole, pramipexole, pergolide, rotigotine Rotigotine)), and antipsychotic drugs (such as traditional antipsychotic drugs, including haloperidol (haloperidol), perphenazin (perphenazin), chlorpromazine, metoclopramide) .

本發明亦提供活動物(包括人類)之神經保護之方法，包含將醫療有效量之如上所述之組成物投服予活動物(包括人類)之步驟。 The invention also provides a method of neuroprotection of a living animal, including a human, comprising the step of administering a medically effective amount of a composition as described above to a living animal, including a human.

再者，本發明亦提供如上所述之組成物於製造提供動物(包括人類)神經保護之醫藥上之用途。 Furthermore, the present invention also provides the use of a composition as described above for the manufacture of a medicament for providing neuroprotection in animals, including humans.

本發明亦關於合成或製備式IA’化合物 或其光學異構體、前藥、藥學上可接受之鹽、水合物、溶劑化物、或多形體之方法，其中R⁵為如上式I所定義者，其中將式II之β-丙胺酸酯 The invention also relates to the synthesis or preparation of a compound of formula IA' Or a method of the optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein R ⁵ is as defined above in Formula I , wherein β-alanine of Formula II is

以式III之甲基丙二醯氯處理 Treated with methyl propylene dichloride chloride of formula III

以得式IV之二酯 Diester of formula IV

令其接受環化狀況以得式V之內醯胺 Cyclization conditions to make it accepts the formula V of Amides

令其接受脫羧狀況以得式VI化合物 Allowing it to undergo a decarboxylation condition to give a compound of formula VI

將其以二甲基甲醯胺二甲基縮醛於增溫下處理以得式VII化合物 Treating it with dimethylformamide dimethyl acetal at elevated temperature to give a compound of formula VII

令其與式VIII之胍起反應 Let it react with the formula VIII

即得式IA’化合物，如有需要，可將其轉化成光學異構體、前藥、藥學上可接受之鹽、水合物、溶劑化物、或多形體。 That is, the compound of the formula IA' can be converted into an optical isomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate, or a polymorph, if necessary.

本發明亦關於合成或製備式IB’化合物 The invention also relates to the synthesis or preparation of a compound of the formula IB'

或其光學異構體、前藥、藥學上可接受之鹽、水合物、溶劑化物、或多形體之方法，其中R⁵、R¹¹、及R¹²為如上式I所定義者，其中將式IX之4-側氧基環己烷羧酸甲酯 Or a method of optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof, wherein R ⁵ , R ¹¹ , and R ¹² are as defined above in Formula I , wherein Methyl 4-oxocyclohexanecarboxylate of IX

以二甲基甲醯胺二甲基縮醛於增溫下處理以得式X化合物 Treating the compound of formula X with dimethylformamide dimethyl acetal at elevated temperature

將其與式VIII之胍起反應 Reacts with the formula VIII

以得式XI化合物 Compound of formula XI

將其以(例如)氫氧化鋰水解以形成式XII之羧酸 Hydrolyzing it with, for example, lithium hydroxide to form a carboxylic acid of formula XII

將其與式XIII之胺 Combine it with the amine of formula XIII

於偶合劑(諸如EDC)之存在下偶合，即得式IB’化合物，如有需要，可將其轉化成光學異構體、前藥、藥學上可接受之鹽、水合物、溶劑化物、或多形體。 Coupling in the presence of a coupling agent, such as EDC, to give a compound of formula IB' , which may be converted to an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or Polymorphism.

本發明亦關於合成或製備式IB’化合物 The invention also relates to the synthesis or preparation of a compound of the formula IB'

或其光學異構體、前藥、藥學上可接受之鹽、水合物、溶劑化物、或多形體之方法，其中R⁵、R¹¹、及R¹²為如上式I所定義者，其中將如上所製備之式XI化合物 Or a method of the optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein R ⁵ , R ¹¹ , and R ¹² are as defined above in Formula I , wherein Prepared compound of formula XI

以式XIII之胺處理 Treated with an amine of formula XIII

即得式IB’化合物，如有需要，可將其轉化成光學異構體、前藥、藥學上可接受之鹽、水合物、溶劑化物、或多形體。 That is, the compound of the formula IB' can be converted into an optical isomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate, or a polymorph, if necessary.

本發明亦關於合成或製備式IC’化合物 The invention also relates to the synthesis or preparation of a compound of the formula IC'

或其光學異構體、前藥、藥學上可接受之鹽、水合物、溶劑化物、或多形體之方法，其中R⁵及R⁸為如上式I所定義者，其中將式XIV化合物 Or a method of the optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, wherein R ⁵ and R ⁸ are as defined above in formula I , wherein compound of formula XIV

以二甲基甲醯胺二甲基縮醛於增溫下處理以得式XV化合物 Treatment with dimethylformamide dimethyl acetal at elevated temperature to obtain a compound of formula XV

將其與式VIII之胍起反應 Reacts with the formula VIII

以得式XVI化合物 Formula XVI compound

將其去保護(例如，經由以三氟乙酸處理)，以得式XVII化合物 Deprotection (eg, via treatment with trifluoroacetic acid) to give a compound of formula XVII

將其以適當試劑(例如醯基氯、氯甲酸酯、磺醯氯、胺基甲醯氯、烷基鹵、異氰酸酯、異硫氰酸酯、或芳基化劑)處理，即得式IC’化合物，如有需要，可將其轉化成光學異構體、前藥、藥學上可接受之鹽、水合物、溶劑化物、或多形體。 Which is the appropriate reagents (e.g. acyl chloride, chloroformate, sulfonyl acyl chloride, urethane acyl chloride, alkyl halides, isocyanates, isothiocyanates, or arylating agent) treatment, i.e. formula IC ' Compound, if desired, can be converted to an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph.

本發明亦關於合成或製備式IC’化合物 The invention also relates to the synthesis or preparation of a compound of the formula IC'

或其光學異構體、前藥、藥學上可接受之鹽、水合物、溶劑化物、或多形體之方法，其中R⁵及R⁸為如上式I所定義者，其中將式XIV化合物 Or a method of the optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, wherein R ⁵ and R ⁸ are as defined above in formula I , wherein compound of formula XIV

去保護(例如經由以三氟乙酸處理)以得式XVIII化合物 Deprotection (eg, via treatment with trifluoroacetic acid) to give a compound of formula XVIII

將其與適當之醯化劑或烷基化劑起反應以得式XIX化合物 Reacting with a suitable oximation or alkylating agent to give a compound of formula XIX

將其以二甲基甲醯胺二甲基縮醛於增溫下處理以得式XX化合物 Treating it with dimethylformamide dimethyl acetal at elevated temperature to give a compound of formula XX

將其與式VIII之胍起反應 Reacts with the formula VIII

即得式IC’化合物，如有需要，可將其轉化成光學異構體、前藥、藥學上可接受之鹽、水合物、溶劑化物、或多形體。 That is, the compound of the formula IC' can be converted into an optical isomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate, or a polymorph, if necessary.

本發明亦關於合成或製備式ID’化合物 The invention also relates to the synthesis or preparation of a compound of the formula ID'

或其光學異構體、前藥、藥學上可接受之鹽、水合物、溶劑化物、或多形體之方法，其中R^5’代表芳基或雜芳基且R¹³為如上式ID所定義者，其中將式XIV化合物 Or a method of the optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein R ^{5 '} represents an aryl or heteroaryl group and R ¹³ is as defined in the above formula ID Which compound of formula XIV

以二甲基甲醯胺二甲基縮醛於增溫下處理以得式XV化合物 Treatment with dimethylformamide dimethyl acetal at elevated temperature to obtain a compound of formula XV

將其與式XXI之脒基硫代酸甲酯起反應 It is reacted with methyl thioglycolate of formula XXI

以得式XXII化合物 Compound of formula XXII

將其去保護(例如經由以三氟乙酸處理)，然後以式XXIII之醯化劑處理 Deprotection (for example via treatment with trifluoroacetic acid) followed by treatment with a hydrazide of formula XXIII

以得式XXIV化合物 Compound of formula XXIV

將其以氧化劑(例如mCPBA)處理以得式XXV化合物 Treating it with an oxidizing agent (eg, mCPBA) to give a compound of formula XXV

將其以式XXVI化合物處理R^5'NH₂ XXVI, Which process R ^{5 'NH} ₂ XXVI to a compound of formula XXVI,

即得式ID’化合物，如有需要，可將其轉化成光學異構體、前藥、藥學上可接受之鹽、水合物、溶劑化物、或 多形體。 That is, the compound of the formula ID' can be converted into an optical isomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate, or a polymorph, if necessary.

發明之詳細說明Detailed description of the invention

供本發明之目的方面，式I化合物中，各種不同含-烴部分中之碳原子含量係藉由該部分中於字首所標出之碳原子之最小及最大數目表示，亦即，字首C_i-j意指整數“i”至整數“j”個碳原子之部分(內含)。故，例如，(C_1-3)烷基意指一至三個碳原子(亦即1、2或3個碳原子)之烷基，內含(亦即甲基、乙基、丙基及異丙基)，其直或支鏈形式，(C_1-6)例如意指一至六個碳原子(亦即1、2、3、4、5或6個碳原子)之基團。 For the purposes of the present invention, in the compounds of formula I , the carbon atom content of the various different hydrocarbon-containing moieties is represented by the minimum and maximum number of carbon atoms indicated in the prefix in the moiety, ie, the prefix C _ij means a part (inclusive) of an integer "i" to an integer "j" carbon atoms. Thus, for example, (C _1-3 )alkyl means an alkyl group of one to three carbon atoms (i.e., 1, 2 or 3 carbon atoms), contained (i.e., methyl, ethyl, propyl, and iso-) Propyl), in its straight or branched form, ( _C1-6 ), for example, means a radical of one to six carbon atoms (i.e., 1, 2, 3, 4, 5 or 6 carbon atoms).

本文所用之術語，除非另有說明，否則可應用下列之定義。術語“C_1-6烷基”代表直或支鏈烷基團。此烷基團之實例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、另丁基、及第三丁基。 As used herein, the following definitions apply unless otherwise indicated. The term " _C1-6 alkyl" denotes a straight or branched alkyl group. Examples of such an alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, butyl, and t-butyl groups.

術語“C_2-6烯基”代表直或支鏈烯基團。 The term "C _2-6 alkenyl" represents a straight or branched alkenyl group.

術語“C_1-6烷氧基”代表直或支鏈-O-C_1-6烷基團。此烷氧基團之實例包括甲氧基、乙氧基、正丙氧基、及異丙氧基、另丁氧基、第三丁氧基。 The term " _C1-6 alkoxy" represents a straight or branched -OC _1-6 alkyl group. Examples of the alkoxy group include a methoxy group, an ethoxy group, a n-propoxy group, and an isopropoxy group, a butoxy group, and a third butoxy group.

術語“醯基”代表C_1-6烷基羰基、三氟乙醯基、羥基-C_1-6烷基羰基、C_1-6烷氧羰基、N-C_1-6烷基胺基羰基、N,N-二-(C_1-6烷基)胺基羰基、C_1-6烷氧基-C_1-6烷基羰基、芳基羰基、雜芳基羰基、環-C_3-12烷基羰基、芳基-C_1-6烷基羰基、雜芳基-C_1-6烷基羰基、芳胺基-C_1-6烷基 羰基、雜芳胺基-C_1-6烷基羰基、雜環基羰基及雜環基-C_1-6烷基羰基。 The term "mercapto" denotes C _1-6 alkylcarbonyl, trifluoroethenyl, hydroxy-C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, N- C _1-6 alkylaminocarbonyl, N,N -di-(C _1-6 alkyl)aminocarbonyl, C _1-6 alkoxy-C _1-6 alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, cyclo-C _3-12 alkane Carbocarbonyl, aryl-C _1-6 alkylcarbonyl, heteroaryl-C _1-6 alkylcarbonyl, arylamino-C _1-6 alkylcarbonyl, heteroarylamino-C _1-6 alkylcarbonyl And a heterocyclic carbonyl group and a heterocyclic group -C _1-6 alkylcarbonyl group.

術語“環C_3-12烷基”代表單環或雙環、或三環烷基團，包括環丙基、環丁基、環戊基、環己基、雙環[2.2.1]庚基及金剛烷基，其可隨意地經一或多個(例如1、2、3、4或5個)可相同或互異之獨立地選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷基、C_2-6烯基、C_1-6烷氧基、胺基、羥基、氰基、C_1-6烷氧羰基、C_1-6烷胺基、及二-(C_1-6烷基)胺基、C_1-6烷基羰基胺基、側氧基、C_1-6烷氧基亞胺基、N-C_1-6烷基胺基羰基、N,N-二-(C_1-6烷基)胺基羰基、芳基C_1-6烷氧羰基、及C_1-6亞烷基二氧基之取代基取代。 The term " _{cycloC 3-12} alkyl" represents a monocyclic or bicyclic, or tricycloalkyl group, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl and adamantane. a group optionally substituted by one or more (e.g., 1, 2, 3, 4 or 5), which may be the same or different, independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _{1- 6} alkyl, C _2-6 alkenyl, C _1-6 alkoxy, amine, hydroxy, cyano, C _1-6 alkoxycarbonyl, C _1-6 alkylamino, and di-(C _{1- 6} alkyl)amino, C _1-6 alkylcarbonylamino, pendant oxy, C _1-6 alkoxyimino, N -C _1-6 alkylaminocarbonyl, N,N -di- Substituent substitution of a (C _1-6 alkyl)aminocarbonyl group, an aryl C _1-6 alkoxycarbonyl group, and a C _1-6 alkylenedioxy group.

術語“環C_3-6烷基”代表單環烷基團，包括環丙基、環丁基、環戊基及環己基，其可隨意地經一或多個(例如1、2、3、4或5個)可相同或互異之獨立地選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷基、C_2-6烯基、C_1-6烷氧基、胺基、羥基、氰基、C_1-6烷氧羰基、C_1-6烷胺基、及二-(C_1-6烷基)胺基、C_1-6烷基羰基胺基、側氧基、C_1-6烷氧基亞胺基、N-C_1-6烷基胺基羰基、N,N-二-(C_1-6烷基)胺基羰基、芳基C_1-6烷氧羰基、及C_1-6亞烷基二氧基之取代基取代。 The term "cyclo C _3-6 alkyl" represents a monocyclic alkyl group, including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, optionally at one or more (eg 1, 2, 3, 4 or 5) independently or differently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _2-6 alkenyl, C _1-6 alkoxy, Amine, hydroxy, cyano, C _1-6 alkoxycarbonyl, C _1-6 alkylamino, and bis-(C _1-6 alkyl)amine, C _1-6 alkylcarbonylamino, side oxygen , C _1-6 alkoxyimino, N -C _1-6 alkylaminocarbonyl, N,N -di-(C _1-6 alkyl)aminocarbonyl, aryl C _1-6 alkane Substituted by an oxycarbonyl group and a substituent of a C _1-6 alkylenedioxy group.

術語“芳基”代表苯基或萘基，其中該苯基或萘基團乃隨意地經一或多個(例如1、2、3、4或5個)可相同或互異之獨立地選自鹵素、氟甲基、二氟甲基、三氟甲基、 氟甲氧基、二氟甲氧基、三氟甲氧基、C_1-6烷基、羥基C_1-6烷基、C_2-6烯基、C_1-6烷氧基、C_1-6烷氧基C_1-6烷基、胺基、羥基、硝基、氰基、甲醯基、C_1-6烷基羰基、C_1-6烷氧羰基、C_1-6烷基羰氧基、C_1-6烷基羰氧基C_1-6烷基、C_1-6烷胺基、二-(C_1-6烷基)胺基、環C_3-12烷胺基、C_1-6烷基羰基胺基、苯基羰基胺基、胺基羰基、N-C_1-6烷基胺基羰基、N,N-二-(C_1-6烷基)胺基羰基、吡咯烷基、哌啶基、嗎啉基、哌嗪基、環C_3-12烷基、吡啶基、及C_1-6亞烷基二氧基之取代基取代。 The term "aryl" denotes phenyl or naphthyl, wherein the phenyl or naphthyl group is optionally independently selected by one or more (eg 1, 2, 3, 4 or 5) which may be the same or different From halogen, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, C _1-6 alkyl, hydroxy C _1-6 alkyl, C _2-6 alkenyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl, amine, hydroxy, nitro, cyano, formyl, C _1-6 alkylcarbonyl , C _1-6 alkoxycarbonyl, C _1-6 alkylcarbonyloxy, C _1-6 alkylcarbonyloxy C _1-6 alkyl, C _1-6 alkylamino, di-(C _1-6 Alkyl)amino, cyclo C _3-12 alkylamino, C _1-6 alkylcarbonylamino, phenylcarbonylamino, aminocarbonyl, N- C _1-6 alkylaminocarbonyl, N, N -di-(C _1-6 alkyl)aminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, cyclo C _3-12 alkyl, pyridyl, and C _1-6 alkylene Substituted by a substituent of a dioxy group.

術語“雜芳基”代表含有一至四個選自氧、硫及氮之雜原子之芳族5-6員環，或包含含有一至四個選自氧、硫及氮之雜原子之5-6員環且與含有一至四個選自氧、硫及氮之雜原子之苯環或5-6員環稠合之雙環基團，其中該雜芳基團可隨意地經一或多個(例如1、2、3、4或5個)可相同或互異之獨立地選自鹵素、氟甲基、二氟甲基、三氟甲基、氟甲氧基、二氟甲氧基、三氟甲氧基、C_1-6烷基、羥基C_1-6烷基、C_2-6烯基、C_1-6烷氧基、胺基、羥基、硝基、氰基、C_1-6烷基羰基、C_1-6烷氧羰基、C_1-6烷氧基羰氧基、C_1-6烷胺基、及二-(C_1-6烷基)胺基、環C_3-12烷胺基、C_1-6烷基羰基胺基、胺基羰基、N-C_1-6烷基胺基羰基、N,N-二-C_1-6烷基胺基羰基、吡咯烷基、哌啶基、嗎啉基、環C_3-12烷基、C_1-6亞烷基二氧基、芳基、及吡啶基之取代基取代。代表性雜芳基團包括呋喃基、噻吩基、吡咯基、唑基、異唑基、異噻唑基、二唑基、吡唑 基、***基、噻二唑基、噻唑基、咪唑基、二唑基、四唑基、吡啶基、嘧啶基、噠嗪基、吡嗪基、三嗪基、嘌呤基、苯並呋喃基、苯並噻吩基、吲哚基、吲哚嗪基、異吲哚基、二氫吲哚基、吲唑基、苯並咪唑基、苯並唑基、苯並噻唑基、喹啉基、喹唑啉基、喹啉基、噌啉基、萘啶基、異喹啉基、喹嗪基、酞嗪基、及蝶啶基。 The term "heteroaryl" denotes an aromatic 5-6 membered ring containing one to four heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, or 5-6 containing one to four heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen. And a bicyclic group fused to a benzene ring or a 5-6 membered ring containing one to four heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, wherein the heteroaryl group is optionally subjected to one or more (eg, 1, 2, 3, 4 or 5) may be the same or different independently selected from the group consisting of halogen, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoro Methoxy, C _1-6 alkyl, hydroxy C _1-6 alkyl, C _2-6 alkenyl, C _1-6 alkoxy, amine, hydroxy, nitro, cyano, C _1-6 alkane Carbonyl group, C _1-6 alkoxycarbonyl group, C _1-6 alkoxycarbonyloxy group, C _1-6 alkylamino group, and di-(C _1-6 alkyl)amino group, ring C _3-12 alkane Amino, C _1-6 alkylcarbonylamino, aminocarbonyl, N- C _1-6 alkylaminocarbonyl, N,N -di-C _1-6 alkylaminocarbonyl, pyrrolidinyl, piperidine Substituents of pyridine, morpholinyl, cyclo C _3-12 alkyl, C _1-6 alkylenedioxy, aryl, and pyridyl are substituted. Representative heteroaryl groups include furyl, thienyl, pyrrolyl, Azolyl, different Azyl, isothiazolyl, Diazolyl, pyrazolyl, triazolyl, thiadiazolyl, thiazolyl, imidazolyl, Diazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, fluorenyl, benzofuranyl, benzothienyl, fluorenyl, pyridazinyl, isoindole Mercapto, dihydroindenyl, carbazolyl, benzimidazolyl, benzo Azolyl, benzothiazolyl, quinolyl, quinazolinyl, quin Alkyl, porphyrin, naphthyridyl, isoquinolyl, quinazolyl, pyridazinyl, and pteridinyl.

術語“雜環基”代表包含一至四個選自氧、硫及氮之雜原子之飽和或不飽和非芳族3至12員環，及包含一至六個選自氧、硫及氮之雜原子之具有3至12員之飽和或不飽和非芳族雙環系統，其中該雜環或環系統可隨意地經一或多個(例如1、2、3、4或5個)可相同或互異之獨立地選自鹵素、三氟甲基、氟甲氧基、二氟甲氧基、三氟甲氧基、C_1-6烷基、C_2-6烯基、C_1-6烷氧基、胺基、羥基、硝基、氰基、C_1-6烷氧羰基、C_1-6烷胺基、及二-(C_1-6烷基)胺基、C_1-6烷基羰基胺基、側氧基、C_1-6烷氧基亞胺基、N-C_1-6烷基胺基羰基、N,N-二-(C_1-6烷基)胺基羰基、芳基C_1-6烷氧羰基、及C_1-6亞烷基二氧基之取代基取代；此雜環基團之實例包括哌啶基、嗎啉基、硫代嗎啉基、咪唑啉基、咪唑烷基、吡唑啉基、吡唑烷基、吡咯啉基、吡咯烷基或哌嗪基，其中該雜環或環系統乃隨意地經由氮或碳原子連接至其所連接之基團上。 The term "heterocyclyl" denotes a saturated or unsaturated, non-aromatic 3 to 12 membered ring containing one to four heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, and one to six heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen. a saturated or unsaturated non-aromatic bicyclic ring system having from 3 to 12 members, wherein the heterocyclic ring or ring system may optionally be the same or different via one or more (eg 1, 2, 3, 4 or 5) Independently selected from the group consisting of halogen, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, C _1-6 alkyl, C _2-6 alkenyl, C _1-6 alkoxy , amine, hydroxy, nitro, cyano, C _1-6 alkoxycarbonyl, C _1-6 alkylamino, and bis-(C _1-6 alkyl)amino, C _1-6 alkylcarbonylamine Base, pendant oxy group, C _1-6 alkoxyimino group, N -C _1-6 alkylaminocarbonyl, N,N -di-(C _1-6 alkyl)aminocarbonyl, aryl C Substituted with a substituent of _1-6 alkoxycarbonyl and a C _1-6 alkylenedioxy group; examples of the heterocyclic group include piperidinyl, morpholinyl, thiomorpholinyl, imidazolinyl, imidazole An alkyl group, a pyrazolinyl group, a pyrazolidinyl group, a pyrrolinyl group, a pyrrolidinyl group or a piperazinyl group, wherein the heterocyclic ring or ring system is optionally Connected to the group of which it is attached by a nitrogen or carbon atom.

術語“鹵素”代表氟、氯、溴及碘。 The term "halogen" stands for fluorine, chlorine, bromine and iodine.

本發明化合物通常係根據IUPAC或CAS命名系統命名。熟諳此藝者詳知之縮寫可予使用(例如”Ph”為苯基， “Me”為甲基，“Et”為乙基，“min”為分鐘，“h”為小時，且“rt”為室溫)。 The compounds of the invention are generally named according to the IUPAC or CAS nomenclature system. Abbreviations that are well known to those skilled in the art can be used (for example, "Ph" is a phenyl group, "Me" is a methyl group, "Et" is an ethyl group, "min" is a minute, "h" is an hour, and "rt" is a room temperature).

美金剛胺(Memantine)，又名為1-胺基-3,5-二甲基金剛烷，乃揭露於美國專利號4,122,193；4,273,774；及5,061,703中，這些專利之主旨均併入本文中以供參考。 Memantine, also known as 1-amino-3,5-dimethyladamantane, is disclosed in U.S. Patent Nos. 4,122,193, 4,273,774, and 5,061,703, the disclosures of each of reference.

美金剛胺(Memantine)為對受體具有中等親和力之系統活性之非競爭型NMDA受體拮抗劑。其顯現強電壓依賴性特性及快速之封閉及解封閉動力(例如參見Görtelmeyer et al.,Arzneim-Forsch/Drug Res.,1992,42：904-913；Winblad et al.,Int.J.Geriat.Psychiatry,1999,14：135-146；Rogawski,Amino Acids,2000,19：133-49；Danysz et al.,Curr.Pharm.Des.,2002,8：835-43；Jirgensons et.al.Eur.J.Med.Chem.,2000,35：555-565)。 Memantine is a non-competitive NMDA receptor antagonist with a systemic activity of moderate affinity for the receptor. It exhibits strong voltage-dependent properties and rapid closure and deblocking dynamics (see, for example, Görtelmeyer et al., Arzneim-Forsch/Drug Res., 1992, 42: 904-913; Winblad et al., Int. J. Geriat. Psychiatry, 1999, 14: 135-146; Rogawski, Amino Acids, 2000, 19: 133-49; Danysz et al., Curr. Pharm. Des., 2002, 8: 835-43; Jirgensons et. al. Eur. J. Med. Chem., 2000, 35: 555-565).

術語“類似物”或“衍生物”在本文中係以慣常之藥學概念使用，意指結構類似於參考分子之分子，但以靶向性及控制性方式修飾以將參考分子中之一或多個特定取代基以替代之取代基替代，因而產生結構類似於參考分子之分子。類似物之合成及篩選(例如使用結構及/或生化分析)，以鑑定可能具有改善或偏差特點之已知化合物之略修飾版(諸如於特定靶向性受體型式下具較高效力及/或選擇性，具較大之穿透血-腦障壁之能力，較少副作用等)為藥學化學中詳知之藥物設計方法。 The term "analog" or "derivative" is used herein in the conventional pharmaceutical concept to mean a molecule that is structurally similar to a reference molecule, but modified in a targeted and controlled manner to one or more of the reference molecules. The particular substituent is replaced with an alternate substituent, thereby producing a molecule that is structurally similar to the reference molecule. Synthesis and screening of analogs (eg, using structural and/or biochemical assays) to identify slightly modified versions of known compounds that may have improved or biased characteristics (such as higher potency under specific targeted receptor formats and/or Or selective, with a greater ability to penetrate the blood-brain barrier, less side effects, etc.) is a detailed drug design method in pharmaceutical chemistry.

此外，使用熟諳此藝者已知之方法，亦可創造出具有 改善醫療效力(亦即於特定靶向性受體型式下具較高效力及/或選擇性，具較大或較低之穿透哺乳動物血-腦障壁之能力(例如較高或較低之血腦障壁穿透率)，較少副作用等)之本發明化合物之類似物及衍生物。 In addition, using methods known to those skilled in the art, it is also possible to create Improves medical efficacy (ie, higher potency and/or selectivity in specific targeted receptor formats, with greater or lower ability to penetrate mammalian blood-brain barriers (eg higher or lower) Analogs and derivatives of the compounds of the invention with blood-brain barrier penetration, less side effects, and the like.

術語“前藥”在本文中係以慣常之藥學概念使用，意指可於活體內經歷轉變(例如酵素或化學轉變)以釋出活性母藥之分子。本發明式I化合物之前藥可藉將式I化合物中存在之官能基團進行化學修飾而製得，因而該經過化學修飾之化合物可於活體內經歷轉變(例如酵素水解)而提供式I化合物。可予修飾以製得前藥之式I化合物中存在之官能基團之實例包括羧基、羥基、胺基、及硫基團。本發明式I化合物之前藥可根據已於技藝中說明之慣用技術(例如Stella V.,et al.,Prodrugs：Challenges and Rewards,AAPS Press/Springer,New York,2007)製得。 The term "prodrug" is used herein in the conventional pharmaceutical concept to mean a molecule that undergoes a transformation (eg, an enzyme or chemical transformation) in vivo to release the active parent drug. The prodrugs of the compounds of formula I of the present invention can be prepared by chemical modification of functional groups present in the compounds of formula I , whereby the chemically modified compounds can undergo transformation (e.g., enzymatic hydrolysis) in vivo to provide compounds of formula I. Examples of functional groups present in the compounds of formula I which may be modified to produce prodrugs include carboxyl groups, hydroxyl groups, amine groups, and sulfur groups. The prodrugs of the compounds of the formula I according to the invention can be prepared according to conventional techniques which have been described in the art (for example Stella V., et al., Prodrugs: Challenges and Rewards, AAPS Press/Springer, New York, 2007 ).

所用之與本發用組成物有關之詞組“藥學上可接受”意指此組成物之分子整體及其他成分為生理學上可耐受的且當投服予哺乳動物(例如人類)時，不會典型地產生不利反應。術語“藥學上可接受”亦可意指由聯邦政府或州政府之管理機構所批准或列於美國藥典或其他供哺乳動物，尤其人類使用之公認藥典中所列者。 The phrase "pharmaceutically acceptable" in relation to the present hair composition means that the molecular entity and other components of the composition are physiologically tolerable and when administered to a mammal (eg, a human), Unfavorable reactions typically occur. The term "pharmaceutically acceptable" may also mean approved by the regulatory agency of the federal or state government or listed in the United States Pharmacopoeia or other recognized pharmacopoeia for mammals, particularly humans.

本發明化合物可為藥學上可接受之鹽類形式。“藥學上可接受之鹽類”意指彼些鹽類，其具有母化合物之生物學效用及性質且不為生物學或其他方面不期望者。鹽之特性並未苛定，前提是其為無毒性且實質上不干擾期望之藥 理學活性。 The compounds of the invention may be in the form of a pharmaceutically acceptable salt. "Pharmaceutically acceptable salt" means a salt thereof which has the biological utility and properties of the parent compound and which is not biologically or otherwise undesirable. The nature of the salt is not critical, provided that it is non-toxic and does not substantially interfere with the desired drug Scientific activity.

熟諳此藝者應了解，具有手性中心之本發明化合物可以旋光及消旋形式存在及受解析。一些化合物可顯現多形性。應該理解的是，本發明涵蓋本發明化合物之任何消旋、旋光、多形體、互變體或立體異構體形式，或其混合物，其具有本文所述之有用性質。 Those skilled in the art will appreciate that the compounds of the invention having a chiral center may exist and be resolved in optically active and racemic forms. Some compounds can exhibit polymorphism. It is to be understood that the invention encompasses any racemic, optically active, polymorphic, tautomeric or stereoisomeric forms of the compounds of the invention, or mixtures thereof, having the useful properties described herein.

下列反應圖1-4說明本發明式I化合物之製備。所有原材料均可藉這些反應圖中所述之步驟、藉熟諳有機化學者詳知之步驟製備，或可由市面獲得。本發明之所有終化合物均可藉這些圖表中所述之步驟或藉其類似而為熟諳有機化學者詳知之步驟製得。反應圖1-4中所用之所有變數均為如下所定義或如申請專利範圍中所定義者。含有一或多個手性中心之化合物可製成消旋物或各種立體異構體之混合物形式，然後再分離。然而，彼等亦可藉特別之對映選擇合成法製得。某些手性化合物方面，對映體之藥理學活性不同。 The following reactions Figures 1-4 illustrate the preparation of the compounds of formula I of the present invention. All raw materials can be prepared by the steps described in these reaction diagrams, by well-known steps of organic chemists, or commercially available. All of the final compounds of the present invention can be prepared by the procedures described in the figures or by analogous procedures known to those skilled in the art of organic chemistry. All variables used in Reaction Schemes 1-4 are as defined below or as defined in the scope of the patent application. Compounds containing one or more chiral centers can be prepared as racemates or mixtures of various stereoisomers and then isolated. However, they may also be prepared by a special enantioselective synthesis method. In some chiral compounds, the pharmacological activity of the enantiomers is different.

反應圖1-製備式IA’化合物之一般步驟。 Reaction Scheme 1 - General procedure for the preparation of a compound of formula IA' .

將β-丙胺酸酯1以甲基丙二醯氯(2)醯化。將所得二酯3環化成內醯胺4，繼而脫羧成哌啶-2,4-二酮(5)。將中間體5以二甲基甲醯胺二甲基縮醛(DMF-DMA)於增溫下處理以形成二甲胺基亞甲基衍生物6，再將其與適當之胍7起反應，即得式IA’化合物。 The β-alaninate 1 was deuterated with methyl propylene dichloride ( 2 ). The resulting diester 3 is cyclized to the indoleamine 4 , which is then decarboxylated to piperidine-2,4-dione ( 5 ). Intermediate 5 is treated with dimethylformamide dimethyl acetal (DMF-DMA) at elevated temperature to form dimethylaminomethylene derivative 6 , which is then reacted with a suitable hydrazine 7 That is, the compound of formula IA' is obtained.

反應圖2-製備式IB’化合物之一般步驟。 Reaction Scheme 2 - General procedure for the preparation of a compound of formula IB' .

將4-側氧基環己烷羧酸甲酯8以二甲基甲醯胺二甲基縮醛(DMF-DMA)於增溫下處理以形成二甲胺基亞甲基衍生物9，再將其與經取代胍7起反應以得四氫喹唑啉-6-羧酸甲酯10。使用氫氧化鋰將該酯基團水解成羧酸，且該羧酸11可用以於標準條件下(例如胺12，EDC)製備式IB’化合物。另外，酯10可直接轉化成式IB’化合物(例如經由使用催化劑諸如KCN而與過量之胺12起反應)。 Methyl 4-oxocyclohexanecarboxylate 8 is treated with dimethylformamide dimethyl acetal (DMF-DMA) under temperature to form dimethylaminomethylene derivative 9 , This is reacted with substituted hydrazine 7 to give methyl tetrahydroquinazoline-6-carboxylate 10 . The ester group is hydrolyzed to a carboxylic acid using lithium hydroxide, and the carboxylic acid 11 can be used to prepare a compound of formula IB' under standard conditions (e.g., amine 12 , EDC). Additionally, ester 10 can be directly converted to a compound of formula IB' (e.g., by reaction with an excess of amine 12 via the use of a catalyst such as KCN).

反應圖3-製備式IC’化合物之一般步驟。 Reaction Scheme 3 - General procedure for the preparation of compounds of the formula IC' .

將Boc-保護之哌啶酮13以二甲基甲醯胺二甲基縮醛(DMF-DMA)於增溫下處理以形成二甲胺基亞甲基衍生物14，再將其與經取代胍7起反應以得中間體15。將Boc基團以三氟乙酸(TFA)裂解以得胺16，再使用醯基氯、氯甲酸酯、磺醯氯或胺基甲醯氯予以醯化，或以烷基鹵予以 烷基化即得式IC’化合物。胺16亦可與異氰酸酯或異硫氰酸酯起反應以得脲或硫脲，或者可將其芳基化以得相應之N-芳基衍生物。 Boc-protected piperidone 13 is treated with dimethylformamide dimethyl acetal (DMF-DMA) at elevated temperature to form dimethylaminomethylene derivative 14 , which is then substituted胍7 reacted to obtain intermediate 15 . The Boc group is cleaved with trifluoroacetic acid (TFA) to give the amine 16 , which is then deuterated using mercapto chloride, chloroformate, sulfonium chloride or aminomethyl chloride, or alkylated with an alkyl halide. That is, the compound IC' compound. The amine 16 can also be reacted with an isocyanate or isothiocyanate to give a urea or thiourea, or it can be arylated to give the corresponding N -aryl derivative.

另外，可將去保護之哌啶酮17直接與適當之醯化或烷基化試劑起反應以得酮18，繼而藉由二甲基甲醯胺二甲基縮醛(DMF-DMA)將其轉化成二甲胺基亞甲基衍生物19。終化合物IC’係以類似於上述之方法，使用經取代之胍於三乙胺或另一種適當鹼之存在下形成。 Alternatively, the deprotected piperidone 17 can be reacted directly with a suitable deuteration or alkylation reagent to yield the ketone 18 , which is then dimethylformamide dimethyl acetal (DMF-DMA). Conversion to the dimethylaminomethylene derivative 19 . The final compound IC ' is formed in a manner similar to that described above using the substituted hydrazine in the presence of triethylamine or another suitable base.

反應圖4-製備二氫吡啶並[4,3-d]嘧啶類之另一合成路徑。 Reaction Figure 4 - Preparation of another synthetic route for dihydropyrido[4,3-d]pyrimidines.

將Boc-保護之中間體14與脒基硫代酸甲酯(20)於酸性條件下、於增溫下起反應以形成中間體21，將其去保護，再轉化成相應之醯化化合物23。藉由氧化劑像mCPBA予以氧化成甲磺醯基衍生物24後，將甲磺酸鹽基 團以芳基胺25取代，即得式ID’化合物。 Boc-protected intermediate 14 is reacted with methyl mercaptothioester ( 20 ) under acidic conditions at elevated temperature to form intermediate 21 , which is deprotected and converted to the corresponding deuterated compound 23 . After oxidation to the methanesulfonyl derivative 24 by an oxidizing agent like mCPBA, the mesylate salt group is substituted with an arylamine 25 to obtain a compound of the formula ID '.

應了解，上述之轉變中，可能必需或期望保護化合物分子中之任何敏感基團以求避免不期望之副反應。 It will be appreciated that in the above transformations, it may be necessary or desirable to protect any sensitive groups in the molecule of the compound in order to avoid undesirable side reactions.

本發明化合物及中間體之純立體異構體形式(包括光學異構體)可藉技藝已知步驟之應用獲得。非對映異構體可藉物理分離法諸如選擇性結晶法及層析技術(例如使用手性固定相進行液態層析)分離。對映體(旋光異構體)可藉將其非對映異構體鹽類以旋光酸進行選擇性結晶而彼此分離。另外，對映體可藉使用手性固定相進行層析技術而分離。 The pure stereoisomeric forms (including optical isomers) of the compounds and intermediates of the invention can be obtained by the application of procedures known in the art. Diastereomers can be separated by physical separation methods such as selective crystallization and chromatographic techniques (e.g., liquid chromatography using a chiral stationary phase). Enantiomers (optical isomers) can be separated from one another by selective crystallization of their diastereomeric salts with optically active acids. Alternatively, the enantiomers can be separated by chromatographic techniques using a chiral stationary phase.

純立體異構體形式亦可由適當原材料之相應純立體異構體形式中衍出，條件是反應係立體選擇性地發生。式I之立體異構體形式乃包括於本發明之範圍內。 Pure stereoisomeric forms can also be derived from the corresponding pure stereoisomeric forms of the appropriate starting materials, provided that the reaction occurs stereoselectively. Stereoisomer forms of formula I are included within the scope of the invention.

標記放射活性原子之式I化合物可使用技藝已知之步驟獲得。典型之化合物包括彼些其中一或多個氫被氚取代，其中一或多個¹²C被¹⁴C取代，其中一或多個氟原子被¹⁸F或其他同位素取代者。這些可用以治療疾病(例如癌症)但亦供診斷之目的。分子中被交換之放射活性原子通常為碳、氫、鹵素、硫或磷之同位素。標記放射活性原子之式I化合物乃包括於本發明之範圍內。 Compounds of formula I which are labeled with a radioactive atom can be obtained using procedures known in the art. Typical compounds include one or more of which are replaced by deuterium wherein one or more of ¹² C are substituted by ¹⁴ C wherein one or more of the fluorine atoms are replaced by ¹⁸ F or other isotopes. These can be used to treat diseases such as cancer but are also for diagnostic purposes. The radioactive atoms exchanged in the molecule are typically isotopes of carbon, hydrogen, halogen, sulfur or phosphorus. Compounds of formula I which are labeled with a radioactive atom are included within the scope of the invention.

加成鹽類Addition salt

供醫療之用途方面，式I化合物之鹽類為彼些其中抗衡離子為藥學上可接受者。然而，非藥學上可接受之酸及 鹼之鹽類亦可發現(例如)在藥學上可接受之化合物之製備及純化中之用途。所有鹽類(無論是否為藥學上可接受者)均在本發明之範圍內。如上所述之藥學上可接受之鹽類意味著包含醫療上活性之無毒性鹽形式，此為式I化合物可形成者。後者可便利地藉將鹼形式以適當之酸諸如無機酸，例如氫鹵酸諸如氫氯酸、氫溴酸等；硫酸；硝酸；磷酸等；或有機酸諸如乙酸、丙酸、羥基乙酸、2-羥基丙酸、側氧基丙酸、草酸、丙二酸、琥珀酸、馬來酸、富馬酸、蘋果酸、酒石酸、2-羥基-1,2,3-丙烷三羧酸、甲磺酸、乙磺酸、苯磺酸、4-甲苯磺酸、環己磺酸、2-羥基苯甲酸、4-胺基-2-羥基苯甲酸等酸類處理而得。反之，鹽形式可藉以鹼處理而轉化成游離鹼形式。 For medical use, the salts of the compounds of formula I are those in which the counterion is pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable acids and bases are also found, for example, for use in the preparation and purification of pharmaceutically acceptable compounds. All salts, whether pharmaceutically acceptable or not, are within the scope of the invention. A pharmaceutically acceptable salt as defined above is meant to comprise a medically active, non-toxic salt form, which is a formable compound of formula I. The latter may conveniently be in the form of a base with a suitable acid such as a mineral acid such as a hydrohalic acid such as hydrochloric acid, hydrobromic acid or the like; sulfuric acid; nitric acid; phosphoric acid or the like; or an organic acid such as acetic acid, propionic acid, glycolic acid, 2 -hydroxypropionic acid, oxopropionic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, methanesulfonic acid It is obtained by treating an acid such as acid, ethanesulfonic acid, benzenesulfonic acid, 4-toluenesulfonic acid, cyclohexanesulfonic acid, 2-hydroxybenzoic acid or 4-amino-2-hydroxybenzoic acid. Conversely, the salt form can be converted to the free base form by treatment with a base.

藥學組成物Pharmaceutical composition

本發明化合物之活性成分，連同一或多種賦形劑諸如輔劑、載體、或稀釋劑，可置入藥學組成物、單位劑量或劑型之形式中。藥學組成物可以固態劑型，諸如粉末、顆粒、丸劑、包衣或未包衣片劑或填充膠囊等，或液態劑型，諸如溶液、懸浮液、乳膠、或填充彼之膠囊等，或半固態劑型，諸如凝膠、乳油及軟膏等形式使用。藥學劑型之活性成分溶出及釋放廓線可在數秒至數月間變化。 The active ingredient of the compound of the present invention may be placed in the form of a pharmaceutical composition, unit dose or dosage form together with one or more excipients such as adjuvants, carriers, or diluents. The pharmaceutical composition may be in a solid dosage form such as a powder, granule, pill, coated or uncoated tablet or filled capsule, or a liquid dosage form such as a solution, suspension, latex, or a capsule filled with it, or a semi-solid dosage form. Used in the form of gels, creams and ointments. The dissolution and release profiles of the active ingredients of the pharmaceutical dosage form can vary from seconds to months.

藥學組成物經設計供動物及人類使用且可經由應用路徑應用。理想之應用路徑為經口路徑、皮膚路徑、肺部路徑、鼻部路徑、直腸部路徑、非經腸部路徑。此藥學組成 物及其單位劑型可包含慣用或特殊比例之慣用或新穎成分，含或不含另加之活性化合物或成分，且此單位劑型可含有任何適當有效量之與待使用之所欲每日劑量範圍相稱之活性成分。每粒片劑中含有一(1)至一百(100)毫克活性成分或者(更廣泛地)零點五(0.5)至五百(500)毫克活性成分之片劑為適當代表性單位劑型。 Pharmaceutical compositions are designed for use by animals and humans and can be applied via application routes. The ideal application path is the oral path, the skin path, the lung path, the nasal path, the rectal path, and the parenteral path. This pharmaceutical composition And unit dosage forms thereof may contain conventional or novel ingredients in conventional or specific proportions, with or without additional active compounds or ingredients, and the unit dosage form may contain any suitable effective amount of the desired daily dosage range to be used. Proportionate active ingredient. Tablets containing from one (1) to one hundred (100) milligrams of active ingredient or (more broadly) from five (0.5) to five hundred (500) milligrams of active ingredient per tablet are suitably representative unit dosage forms.

應用至本發明藥學組成物中之術語“載體”意指隨活性化合物投服之稀釋劑、賦形劑、或載劑。此藥學載體可為無菌液體，諸如水、鹽水溶液、水性右旋糖溶液、水性甘油溶液、及油類，包括石油、動物、植物或合成來源者，諸如花生油、大豆油、礦油、芝麻油等。A.R.Gennaro(20版)於“Remington：The Science and Practice of Pharmacy”中說明適當之藥學載體。 The term "carrier" as used in the pharmaceutical compositions of the invention means a diluent, excipient, or carrier with which the active compound is administered. The pharmaceutical carrier can be a sterile liquid such as water, a saline solution, an aqueous dextrose solution, an aqueous glycerin solution, and an oil, including petroleum, animal, plant or synthetic sources such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. . A. R. Gennaro (20 version) describes suitable pharmaceutical carriers in "Remington: The Science and Practice of Pharmacy".

治療方法treatment method

由於其高度之活性及其低毒性，同時展現最有利之醫療指數，故本發明活性成分可投服予有此需求的病患，例如活動物(包括人)體，以治療、減輕、或改良、緩和、或消除易受其影響之適應症或病況，或本申請案之其他處所提出之代表性適應症或病況，較佳係同時、同步，連同一或多種藥學上可接受之賦形劑、載體、或稀釋劑，尤其且較佳為其藥學組成物之形式，無論是經口、直腸部、或非經腸部(包括靜脈內及皮下)或者在某些情況下甚至局部地以有效量投服。適當劑量範圍為每日1-1000毫克，隨意 地每日10-500毫克，及隨意地每日50-500毫克，照例地依確切之投服模式、所投服之形式、投服所針對之適應症、所涉及之病患及所涉及病患之體重，以及負責醫師或獸醫師之偏好及經驗而定。 Due to its high activity and low toxicity, and exhibiting the most favorable medical index, the active ingredient of the present invention can be administered to patients with such needs, such as living animals (including humans), for treatment, alleviation, or improvement. , mitigating, or eliminating the indications or conditions that are susceptible to it, or representative indications or conditions presented elsewhere in this application, preferably simultaneously, simultaneously, with one or more pharmaceutically acceptable excipients , a carrier, or a diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether orally, orally, or parenterally (including intravenously and subcutaneously) or, in some cases, even partially effective The amount of investment. The appropriate dosage range is 1-1000 mg per day, free 10-500 mg daily, and 50-500 mg daily, as usual, according to the exact mode of administration, the form of administration, the indications for the application, the patients involved and the diseases involved The weight of the person affected, as well as the preferences and experience of the physician or veterinarian.

本文所用之術語“治療”意指免除或減輕病患疾病之至少一種症狀。在本發明之定義中，術語“治療”亦意指遏止、延緩發作(亦即疾病之臨床表現之前的時間)及/或降低疾病發展或惡化之危險。 The term "treating" as used herein means to relieve or alleviate at least one symptom of a disease in a patient. In the definition of the invention, the term "treatment" also means to arrest, delay the onset (i.e., the time prior to the clinical manifestation of the disease) and/or reduce the risk of developing or worsening the disease.

本文所用之術語“組合”定義為單一藥學組成物(配方)，其包含本發明化合物及第二種活性成分(例如NMDA受體拮抗劑、L-DOPA、多巴胺模擬藥、或抗精神病藥物)於技藝中已知之配方中；或兩種個別之藥學組成物(配方)，一種包含如上所調配之本發明化合物且一種包含第二種活性成分(例如NMDA受體拮抗劑、L-DOPA、多巴胺模擬藥、或抗精神病藥物)於技藝中已知之配方中，以待相連投服。 The term "combination" as used herein is defined as a single pharmaceutical composition (formulation) comprising a compound of the invention and a second active ingredient (eg, an NMDA receptor antagonist, L-DOPA, a dopamine mimetic, or an antipsychotic). In a formulation known in the art; or two individual pharmaceutical compositions (formulations), one comprising a compound of the invention as formulated above and one comprising a second active ingredient (eg NMDA receptor antagonist, L-DOPA, dopamine mimetic) The drug, or antipsychotic drug, is formulated in a formulation known in the art to be administered in succession.

本發明定義中之術語“相連投服”乃用以意指本發明化合物與第二種活性成分(例如NMDA受體拮抗劑、L-DOPA、多巴胺模擬藥、或抗精神病藥物)於一種組成物中投服，或於不同組成物中同步投服，或者接續投服。接續投服被視為是“相連”，然而，本發明化合物與NMDA受體拮抗劑必需間隔一段時間分開投服仍能允許使哺乳動物達到有利之效應結果。例如，本發明化合物與NMDA受體拮抗劑必需於同一天投服(例如各自-每日一次或兩 次)，包括彼此於一小時內，且包括同步。 The term "consistently administered" in the definition of the present invention is used to mean a compound of the present invention and a second active ingredient (for example, an NMDA receptor antagonist, L-DOPA, a dopamine mimetic, or an antipsychotic) in a composition. In the middle of the investment, or in different compositions to simultaneously vote, or continue to vote. Successive administration is considered to be "linked", however, the fact that the compound of the invention and the NMDA receptor antagonist must be administered separately at intervals may still allow the mammal to achieve a beneficial effect. For example, a compound of the invention and an NMDA receptor antagonist must be administered on the same day (eg, each - once or twice daily) Times), including each other within an hour, and including synchronization.

應用至劑量或量上之術語“醫療有效量”意指化合物或藥學組成物在投服予有此需求之動物體之後，足以導致期望之活性之量。 The term "medically effective amount" as applied to a dose or amount means the amount of the compound or pharmaceutical composition sufficient to result in the desired activity after administration to an animal in need thereof.

本發明化合物可經口、局部、非經腸部、或黏膜部(例如頰部、藉吸入法、或直腸部)於含有慣用無毒性藥學上可接受載體之劑量單位配方中投服。通常期望使用經口路徑。活性劑可以膠囊、片劑等形式經口投服(參見Remington：The Science and Practice of Pharmacy,20^th Edition”。經口投服之藥學組成物可以時間-控釋型載劑之形式，包括擴散-控制系統，滲透裝置，溶出-控制基質，及可沖蝕/可降解性基質之形式投服。 The compounds of the invention may be administered orally, topically, parenterally, or mucosally (e.g., buccally, by inhalation, or rectal) in a dosage unit formulation containing a conventional non-toxic pharmaceutically acceptable carrier. It is often desirable to use an oral path. Active agents in the form of capsules, tablets and other orally administered service (see, Remington:. The Science and Practice of Pharmacy, 20 th Edition " pharmaceutical composition via the mouth may hurl the time - in the form of controlled-release carriers, including diffusion - Control system, osmotic device, dissolution-control matrix, and erosive/degradable matrix.

片劑或膠囊形式之經口投服方面，式I活性藥物組份可與無毒性、藥學上可接受之賦形劑諸如黏結劑(例如預凝膠玉米澱粉、聚乙烯基吡咯烷酮或羥丙基甲基纖維素)；填料(例如乳糖、蔗糖、葡萄糖、甘露糖醇、山梨糖醇及其他還原糖及非還原糖、微晶纖維素、硫酸鈣、或磷酸氫鈣)；潤滑劑(例如硬脂酸鎂、滑石、或矽石、硬脂酸、硬脂富馬酸鈉、山嵛酸甘油酸酯、硬脂酸鈣，等等)；崩解劑(例如馬鈴薯澱粉或羧甲基澱粉鈉)；及/或濕化劑(例如月桂基硫酸鈉)，著色及芳香劑、明膠、甜味劑、天然及合成膠(諸如金合歡膠、黃蓍膠或藻酸鹽)，緩衝鹽類，羧甲基纖維素、聚乙二醇、蠟，等等組合。供液態形式之經口投服方面，藥物組份可與無毒性、藥學上可 接受之惰性載體(例如乙醇、甘油、水)，懸浮劑(例如山梨糖醇糖漿、纖維素衍生物或氫化食用脂肪)，乳化劑(例如卵磷脂或金合歡膠)，非水性載劑(例如杏仁油、油性酯、乙醇或分餾植物油)，防腐劑(例如對位-羥基苯甲酸甲酯或丙酯或山梨酸)，等等組合。安定劑諸如抗氧化劑(BHA、BHT、沒食子酸丙酯、抗壞血酸鈉、檸檬酸)亦可加入以使劑型安定。 In the case of oral administration in the form of a tablet or capsule, the active pharmaceutical ingredient of the formula I can be combined with non-toxic, pharmaceutically acceptable excipients such as binders (for example pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl). Methylcellulose); fillers (eg lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen phosphate); lubricants (eg hard Magnesium oleate, talc, or vermiculite, stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, etc.); disintegrant (eg potato starch or sodium carboxymethyl starch) And/or wetting agents (such as sodium lauryl sulfate), coloring and fragrances, gelatin, sweeteners, natural and synthetic gums (such as acacia, tragacanth or alginate), buffer salts, A combination of carboxymethyl cellulose, polyethylene glycol, wax, and the like. For oral administration in liquid form, the pharmaceutical component can be combined with a non-toxic, pharmaceutically acceptable inert carrier (eg, ethanol, glycerol, water), a suspending agent (eg, sorbitol syrup, cellulose derivative or hydrogenated food). Fat), emulsifier (such as lecithin or acacia), non-aqueous carrier (such as almond oil, oily ester, ethanol or fractionated vegetable oil), preservative (such as methyl or propyl paraben or sorbate) Acid), and so on. Stabilizers such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) may also be added to stabilize the dosage form.

片劑可藉技藝中詳知之方法予以包衣。含有作為活性化合物之式I化合物之本發明組成物亦可置入(例如由聚乙醇酸/乳酸(PGLA)所製)珠粒、微球或微膠囊中。供口服之液態製劑可採用(例如)溶液、糖漿、乳膠或懸浮液之形式，或者彼等可以乾燥產物之形式呈現以供於使用前以水或其他適當載劑再構成。口服製劑可予適當調配以控制或延緩活性化合物之釋出。 Tablets can be coated by methods well known in the art. The compositions of the invention containing a compound of formula I as an active compound can also be incorporated (for example, from polyglycolic acid/lactic acid (PGLA)) in beads, microspheres or microcapsules. Liquid preparations for oral administration can be in the form of, for example, solutions, syrups, emulsions or suspensions, or they can be presented in the form of a dry product for reconstitution with water or other suitable vehicle before use. Oral formulations can be formulated to control or delay the release of the active compound.

本發明化合物亦可以微脂粒遞送系統之形式，諸如單層小微脂粒、單層大微脂粒及多層微脂粒等形式遞送。微脂粒可由各種詳知之磷脂類，諸如膽固醇、硬脂酸胺或磷醯膽鹼中形成。 The compounds of the invention may also be delivered in the form of a liposome delivery system, such as a single layer of small vesicles, a single layer of large vesicles, and multiple layers of vesicles. The vesicles can be formed from a variety of well-known phospholipids, such as cholesterol, stearic acid amine or choline.

本發明化合物亦可藉使用作為個別載體之單株抗體(化合物分子偶合至其上)遞送。活性藥物亦可與作為可靶向型藥物載體之可溶性聚合物偶合。此些聚合物包括聚乙烯基吡咯烷酮、吡喃共聚物、聚羥基-丙基甲基丙烯醯胺-苯酚、聚羥基-乙基-天冬醯胺-苯酚、或以棕櫚醯基殘基取代之聚氧化乙烯-聚賴胺酸。再者，活性成分可偶合至 一種用以達到藥物控制性釋出目的之可生物降解性聚合物，例如聚乳酸、聚乙醇酸、聚乳酸與聚乙醇酸之共聚物、聚ε己內酯、聚羥基丁酸、聚原酸酯、聚縮醛、聚氫吡喃、聚氰基丙烯酸酯、及水凝膠之交聯性或兩親嵌段共聚物上。 The compounds of the invention may also be delivered by the use of monoclonal antibodies (on which the compound molecules are coupled) as individual carriers. The active drug can also be coupled to a soluble polymer that is a targetable drug carrier. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propylmethacrylamide-phenol, polyhydroxy-ethyl-aspartamide-phenol, or substituted with palmitoyl residues Polyethylene oxide-polylysine. Furthermore, the active ingredient can be coupled to A biodegradable polymer for achieving controlled release of a drug, such as polylactic acid, polyglycolic acid, a copolymer of polylactic acid and polyglycolic acid, poly-ε-caprolactone, polyhydroxybutyric acid, poly-orthoacid Crosslinking or amphiphilic block copolymers of esters, polyacetals, polyhydropyrans, polycyanoacrylates, and hydrogels.

藉吸入法投服方面，含有作為活性化合物之式I化合物之根據本發明之醫療劑可便利地以由加壓包裝或噴霧器中，使用適當推進劑例如二氯二氟甲烷、三氯氟甲烷、二氯四-氟乙烷、二氧化碳、或其他適當氣體而表現之氣溶膠噴霧形式遞送。如為加壓氣溶膠，則劑量單位可藉提供一個可遞送定量之量之閥而決定。供吸入器或吹入器用之(例如)明膠之膠囊及藥筒可調配成含有化合物與適當粉末藥基諸如乳糖或澱粉之粉末混合物。 In the case of administration by inhalation, the medical agent according to the invention containing the compound of the formula I as the active compound can be conveniently employed in a pressurized pack or spray, using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, Delivery in the form of an aerosol spray of dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve that delivers a quantitative amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch.

含有本發明化合物之配方可由非經腸部，亦即藉靜脈內(i.v.)、腦室內(i.c.v.)、皮下(s.c.)、腹膜內(i.p.)、肌內(i.m.)、真皮下(s.d.)、或皮內(i.d.)投服法，藉直接注射，經由(例如)彈丸注射或連續輸注而遞送。注射配方可以單位劑型，例如於安瓶中或於多劑量容器中(加入防腐劑)呈現。組成物可採用諸如於油性或水性載劑中之賦形劑、懸浮液、溶液或乳膠形式，且可含有調配劑諸如懸浮劑、安定劑及/或分散劑。另外，活性劑可為粉末形式以供於使用前以適當之載劑例如無菌無熱原之水予以再構成。 The formulation containing the compound of the present invention may be parenteral, that is, intravenous (iv), intraventricular (icv), subcutaneous (sc), intraperitoneal (ip), intramuscular (im), subdermal (sd), Or intradermal (id) administration, by direct injection, delivered via, for example, bolus injection or continuous infusion. The injectable formulation can be presented in unit dosage form, for example in an ampoule or in a multi-dose container (with a preservative added). The composition may take the form of an excipient, suspension, solution or emulsion, such as in an oily or aqueous vehicle, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active agent can be in powder form for reconstitution with a suitable carrier, such as sterile pyrogen-free water, before use.

本發明化合物亦可調配成(例如)坐藥或保留灌腸之形式(例如含有慣用之坐藥藥基諸如可可油或其他甘油酯)以 供直腸部投服。 The compounds of the invention may also be formulated, for example, in the form of a medicated or retained enema (for example, containing a conventional medicinal base such as cocoa butter or other glycerides). For the rectum to take.

如有需要，含有式I化合物之組成物可於包裝或分配器裝置中呈現，其可含有一或多種含活性成分之單位劑型及/或可含有不同之劑量水準以幫助劑量之滴定。包裝可(例如)包含金屬箔或塑膠薄膜，諸如罩板包裝。包裝或分配器裝置可藉投服教示而完成。調配於可相容性藥學載體中之本發明組成物亦可予製備，放置於適當容器中，再標記以供適應病況之治療。 If desired, compositions containing a compound of formula I can be presented in a package or dispenser device which may contain one or more unit dosage forms containing the active ingredient and/or may contain various dosage levels to aid in the titration of the dosage. The package may, for example, comprise a metal foil or a plastic film, such as a blister pack. The packaging or dispenser device can be completed by a service instruction. The compositions of the invention formulated in a compatible pharmaceutical carrier can also be prepared, placed in a suitable container, and labeled for treatment in a condition.

如本文中所揭露，本發明組成物中之組份之劑量係經決定以確保所連續或間歇投服之劑量不會超過考量測試動物及病患個別狀況之結果後所決定之量。特定劑量自然地依劑量步驟、病患或動物病患之狀況諸如年齡、體重、性別、敏感度、餐食、給藥期間、組合中所用的藥物、疾病嚴重性而變化。於某些狀況下之適當劑量及投藥時間可藉以上述索引為基礎進行之試驗決定，但可再琢磨，且最終係根據醫師之判斷及各個病患之情況(年齡、一般狀況、症狀嚴性、性別等)根據標準臨床技術決定。 As disclosed herein, the dosage of the components of the compositions of the present invention is determined to ensure that the continuous or intermittent dose will not exceed the amount determined after considering the results of the test animal and the individual condition of the patient. The particular dose will naturally vary depending on the dosage step, the condition of the patient or animal patient such as age, weight, sex, sensitivity, meal, period of administration, the drug used in the combination, the severity of the disease. The appropriate dosage and timing of administration under certain conditions may be determined on the basis of the above index, but may be further honed, and ultimately based on the judgment of the physician and the condition of each patient (age, general condition, symptom severity, Gender, etc.) is determined according to standard clinical techniques.

本發明組成物之毒性及療效可藉於實驗動物中進行標準之藥學步驟，例如藉測定LD₅₀(使50%族群致死之劑量)及ED₅₀(於50%族群中具有療效之劑量)而得知。醫療效應與毒性效應間之劑量比率為醫療指數且其可以LD₅₀/ED₅₀比表示。以顯現大醫療指數之組成物較佳。 Toxicity and efficacy of the compositions of the present invention may by the standard experimental animal in pharmaceutical procedures, e.g., by measuring LD ₅₀ (lethal to 50% of the dose groups) and the ED ₅₀ (the dose therapeutically effective in having 50% of the group) to give know. The dose ratio between the medical effect and the toxic effect is the medical index and it can be expressed as the LD ₅₀ /ED ₅₀ ratio. It is preferred to present a composition of a large medical index.

由本文下列所述之實例中顯見，本發明提供本發明化合物之新穎及有用之應用及用途，此化合物包含根據本發 明之活性成分，以及其新穎藥學組成物及其製備方法及以其治療之方法。 The invention provides novel and useful applications and uses of the compounds of the invention, as exemplified by the examples described herein below, which The active ingredient of the invention, as well as the novel pharmaceutical composition thereof, the preparation method thereof and the method for treating the same.

本發明活性劑及其組成物之高階活性(藉由所報告之試驗證明)顯示以其於人類以及於低等動物之有用活性為基準之功用。人類之臨床評估尚未完全。吾人應清楚地了解，落入本發明範圍內之供人類用之任何化合物或組成物之分佈及銷售當然必需以負責及授權裁定該案之政府機關之預先核准為依據。 The higher order activity of the active agents and compositions thereof (as evidenced by the reported assays) is shown to be based on their usefulness in humans and in lower animals. The clinical assessment of humans is not yet complete. It is expressly understood that the distribution and sale of any compound or composition for human use within the scope of the invention must of course be based on the prior approval of the government agency responsible for and authorizing the case.

本式I化合物代表一種新穎的mGluR5調節劑。有鑑於其效力，彼等將為廣泛範圍之涉及過度麩胺酸誘導性刺激之病症，尤其是中樞神經系統病症之有用療法。 The compound of formula I represents a novel mGluR5 modulator. In view of their efficacy, they will be a useful treatment for a wide range of conditions involving excessive glutamate-induced stimuli, especially central nervous system disorders.

因此這些化合物發現在治療活動物體(特別是人類)之如同稍早於說明中陳列之病症方面之應用。 These compounds are therefore found to be useful in the treatment of active objects, particularly humans, as well as those exhibited earlier in the description.

這些化合物亦發現在治療活動物體(特別是人類)之適應症方面之應用，其中特定之病況並不必要存在，但其中特定生理學參數可經由投服本化合物而改善，包括認知功能之增強。 These compounds have also been found to be useful in the treatment of indications for active objects, particularly humans, where specific conditions are not necessarily present, but where specific physiological parameters can be improved by administration of the present compound, including enhancement of cognitive function.

神經保護作用及認知功能增強亦可藉投服本化合物與NMDA受體拮抗劑像美金剛胺(Memantine)之組合而達成。 Neuroprotective effects and cognitive enhancement can also be achieved by administering a combination of the present compound and an NMDA receptor antagonist such as memantine.

以本發明化合物治療活動物體以抑制所選擇輕病之進展或減輕該輕病之方法係如前所述地藉任何一般公認之藥學路徑，使用選定之有效以減輕期望被減輕之特定輕病之劑量達成。本發明化合物於製造供治療活動物以抑制所選 擇輕病或病況之進展或減輕該輕病或病況，尤其是易受第I群mGluR5調節劑之治療所影響之輕病或病況之醫藥上之用途係以常用之方法進行，包含將有效之本發明化合物與藥學上可接受之稀釋劑、賦形劑、或載體混合之步驟，治療方法，藥學組成物，及本發明化合物於製造醫藥上之用途。 The method of treating a moving subject with a compound of the invention to inhibit the progression of the selected mild disease or alleviating the mild disease is by any generally accepted pharmaceutical route, as described above, using a selected effective agent to alleviate the particular mild disease desired to be alleviated. The dose is reached. The compounds of the invention are formulated for the treatment of active animals to inhibit selection The use of a mild disease or condition, or a palliative use of a mild disease or condition, particularly a mild disease or condition susceptible to treatment with a Group I mGluR5 modulator, is carried out in a conventional manner and includes The step of mixing a compound of the present invention with a pharmaceutically acceptable diluent, excipient, or carrier, a method of treatment, a pharmaceutical composition, and a compound of the present invention for use in the manufacture of a medicament.

藉將活性成分與適當之藥學上可接受之賦形劑、稀釋劑、或載體混合所製得之代表性藥學組成物包括片劑、膠囊、注射溶液、液態口服配方、氣溶膠配方、TDS配方、及奈米微粒配方，故製得供口服、注射、或皮膚使用、亦根據前述者使用之醫藥。 Representative pharmaceutical compositions prepared by combining the active ingredient with suitable pharmaceutically acceptable excipients, diluents, or carriers include tablets, capsules, injection solutions, liquid oral formulations, aerosol formulations, TDS formulations And nanoparticle formula, so that it can be used for oral, injection, or skin use, and also according to the aforementioned medicine.

實驗部分Experimental part

本發明化合物及其製備將藉由下列實例而更加明瞭，這些實例意欲作為說明而非限制本發明之範圍。 The compounds of the present invention and their preparation will be more apparent from the following examples, which are intended to be illustrative, not limiting.

下文中，“ACN”定義為乙腈，“Boc”為第三丁氧羰基，“DCM”為二氯甲烷，“DEE”為***，“DMAP”為4-二甲胺基吡啶(N,N-二甲基吡啶-4-胺)，“DIPEA”為N,N-二異丙基乙胺(N-乙基-N-異丙基丙-2-胺)，“DMF”為N,N-二甲基甲醯胺，“DMF-DMA”為N,N-二甲基甲醯胺二甲基縮醛，“EDC”為1-乙基-3-(3-二甲胺基丙基)碳化二亞胺(N ¹-((乙亞胺基)亞甲基-N ³,N ³-二甲基丙-1,3-二胺)，“EtOAc”為乙酸乙酯，“EtOH”為乙醇，“HOBt”為羥基苯並***(1H-苯並[d][1,2,3]***-4-醇)，“mCPBA”為間 位-氯基過苯甲酸，“MeOH”為甲醇，“TBTU”為O-(苯並***-1-基)-N,N,N',N’-四甲基脲四氟硼酸酯，“TEA”為三乙胺，且“THF”為四氫呋喃。 Hereinafter, "ACN" is defined as acetonitrile, "Boc" is a third butoxycarbonyl group, "DCM" is dichloromethane, "DEE" is diethyl ether, and "DMAP" is 4-dimethylaminopyridine ( N, N - Lutidine-4-amine), "DIPEA" is N,N -diisopropylethylamine ( N -ethyl-N-isopropylpropan-2-amine), and "DMF" is N,N- Dimethylformamide, "DMF-DMA" is N,N -dimethylformamide dimethyl acetal, "EDC" is 1-ethyl-3-(3-dimethylaminopropyl) Carbodiimide ( N ¹ -((ethylimino)methylene- N ³ , N ³ -dimethylpropyl-1,3-diamine), "EtOAc" is ethyl acetate, "EtOH" is Ethanol, "HOBt" is hydroxybenzotriazole (1 H -benzo[d][1,2,3]triazol-4-ol), "mCPBA" is meta-chloroperbenzoic acid, "MeOH "Methanol", "TBTU" is O- (benzotriazol-1-yl) -N,N,N',N' -tetramethyluronium tetrafluoroborate, "TEA" is triethylamine, and "THF" is tetrahydrofuran.

一般步驟1-經取代胍類之製備General procedure 1 - Preparation of substituted steroids

將水性硝酸溶液(67%，d=1.4)其後氰胺加至於20℃下之已攪拌之適當胺之乙醇溶液中。將所得溶液於迴流下攪拌4-8小時。然後將混合物冷卻至15℃，再將***加入以誘使產物結晶。將所形成之懸浮液於20℃下攪拌15分鐘或過夜。將沈澱物濾出，以***與乙醇之混合液(3：1)清洗，再風乾，即得標題化合物。 An aqueous nitric acid solution (67%, d = 1.4) was then added to the stirred solution of the appropriate amine in ethanol at 20 °C. The resulting solution was stirred at reflux for 4-8 hours. The mixture was then cooled to 15 ° C and diethyl ether was added to induce the product to crystallize. The resulting suspension was stirred at 20 ° C for 15 minutes or overnight. The precipitate was filtered, washed with a mixture of diethyl ether and ethyl ether (3:1).

製備1 Preparation 1 2-((3-氯苯基)胺基)-5,6,7,8-四氫喹唑啉-6-羧酸乙酯Ethyl 2-((3-chlorophenyl)amino)-5,6,7,8-tetrahydroquinazoline-6-carboxylate

將DMF-DMA(2.10克，17.63毫莫耳)加至4-側氧基環己烷羧酸乙酯(2.00克，11.75毫莫耳)之無水苯(7毫升)懸浮液中，再將所得混合物於100℃下加熱2天。而後將反應混合物冷卻，以水稀釋及以乙酸乙酯萃取。將有機相於無水硫酸鈉上乾燥，再蒸發以得1.5克(57%)棕色油狀之3-((二甲胺基)亞甲基)-4-側氧基環己基羧酸乙酯。令此中間體溶於無水乙醇(7毫升)中，再將1-(3-氯苯基)胍(1.13克，6.66毫莫耳)加入。將混合物於密封管瓶中加熱至100℃ 24小時。冷卻後，將反應混合物蒸發，再將餘留物藉急驟柱式層析予以純化，即得1.03克(47%)黃色固 狀之標題化合物。 DMF-DMA (2.10 g, 17.63 mmol) was added to a suspension of 4-ethyloxycyclohexanecarboxylate (2.00 g, 11.75 mmol) in anhydrous benzene (7 mL). The mixture was heated at 100 ° C for 2 days. The reaction mixture was then cooled, diluted with water and extracted with EtOAc. The organic phase was dried over anhydrous sodium sulfate and evaporated tolululululululululululululululu This intermediate was dissolved in absolute ethanol (7 mL) and then 1-(3-chlorophenyl)indole (1.13 g, 6.66 mmol). The mixture was heated to 100 ° C for 24 hours in a sealed vial. After cooling, the reaction mixture was evaporated, and the residue was purified by flash column chromatography to yield 1.03 g (47%) of yellow solid. The title compound.

一般步驟2a-N-取代之5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺類之醯化General procedure 2a- N -substituted 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amines

令N-取代之5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺(1當量)溶於無水二氯甲烷中，再將粉狀碳酸鉀(5當量)加入，其後將醯化劑(醯基氯、氯甲酸酯、胺基甲醯基氯或磺醯氯)(1.05當量)加入。將混合物於室溫下攪拌過夜，過濾及蒸發。再將餘留物藉急驟柱式層析或製備HPLC予以純化，即得N-醯化之產物。 Let N -substituted 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (1 equivalent) be dissolved in anhydrous dichloromethane, and then powdered potassium carbonate (5 equivalents) After the addition, a deuterating agent (hydrazinyl chloride, chloroformate, aminomethylguanidinyl chloride or sulfonium chloride) (1.05 equivalent) was added. The mixture was stirred at room temperature overnight, filtered and evaporated. The residue is purified by flash column chromatography or preparative HPLC to obtain the N -deuterated product.

一般步驟2b-另一醯化步驟General Step 2b - Another Deuteration Step

令經取代之5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與相應之醯化劑(1.2當量)於TBTU(1.3當量)及三乙胺(2.7當量)之存在下，於乙腈中，於室溫下起反應22小時。然後將反應混合物以水稀釋及以二氯甲烷萃取。將結合之有機相於硫酸鈉上乾燥及於減壓下濃縮。再將所得餘留物藉柱式層析(矽膠，二氯甲烷/乙醇或二氯甲烷/乙酸乙酯)予以純化，即得終產物。 Substituting 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine with the corresponding oximation agent (1.2 equivalents) in TBTU (1.3 equivalents) and triethylamine (2.7 In the presence of equivalents, the reaction was carried out in acetonitrile at room temperature for 22 hours. The reaction mixture was then diluted with water and extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated under reduced vacuum. The residue obtained is purified by column chromatography (silica gel, methylene chloride/ethanol or dichloromethane/ethyl acetate) to give the final product.

製備2 Preparation 2 N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺 N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine

令4-側氧基哌啶-1-羧酸第三丁酯(2.0克，10.04毫莫耳)溶於N,N-二甲基甲醯胺(2.5毫升)中，再將N,N-二甲基 甲醯胺二甲基縮醛(1.67克，14.05毫莫耳)加入。將混合物於100℃下加熱60小時，然後冷卻及蒸發至乾以得3-((二甲胺基)亞甲基)-4-側氧基哌啶-1-羧酸第三丁酯。令此中間體(1.0克，3.93毫莫耳)溶於無水乙醇(20毫升)中，再將3-氯苯基胍(0.444克，2.62毫莫耳)加入。將混合物於100℃下加熱16小時，然後冷卻及蒸發至乾。將餘留物藉急驟柱式層析予以純化以得黃色固狀之2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯(0.54克，57%)。令此中間體(0.085克，0.23毫莫耳)溶於二氯甲烷(5毫升)中，將三氟乙酸(1毫升)加入，再將混合物於室溫下攪拌6小時。將混合物蒸發，再分配於二氯甲烷與飽和水性碳酸氫鈉溶液之間。將有機相分離出，於無水硫酸鈉上乾燥及蒸發，即得棕色固狀之標題化合物(60毫克，98%)。 4-tertyloxypiperidine-1-carboxylic acid tert-butyl ester (2.0 g, 10.04 mmol) was dissolved in N,N -dimethylformamide (2.5 ml), then N,N - Dimethylformamide dimethyl acetal (1.67 g, 14.05 mmol) was added. The mixture was heated at 100 ° C for 60 hours, then cooled and evaporated to dryness to give 3-((dimethylamino)methylene)-4-oxoxypiperidine-1-carboxylic acid tert-butyl ester. This intermediate (1.0 g, 3.93 mmol) was dissolved in dry ethanol (20 mL) and then 3-chlorophenylindole (0.444 g, 2.62 mmol). The mixture was heated at 100 ° C for 16 hours, then cooled and evaporated to dryness. The residue was purified by flash column chromatography to give 2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6 as a yellow solid. ( 5H )-Dicarboxylic acid tert-butyl ester (0.54 g, 57%). This intermediate (0.085 g, 0.23 mmol) was dissolved in dichloromethane (5 ml), trifluoroacetic acid (1 ml) was added and the mixture was stirred at room temperature for 6 hr. The mixture was evaporated and redistributed between dichloromethane and saturated aqueous sodium bicarbonate. The title compound (60 mg, 98%) eluted elute

N-(3-氟苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺、N-(3-甲苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺、及3-((5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈均依密切類似於上述之步驟製得。 N- (3-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, N- (3-tolyl)-5,6,7, 8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, and 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amine The benzonitrile is prepared in close proximity to the above procedure.

一般步驟3-經由2-(甲磺醯基)-5,6,7,8-四氫喹唑啉衍生物以形成二芳基胺General Step 3 - Formation of a diarylamine via a 2-(methylsulfonyl)-5,6,7,8-tetrahydroquinazoline derivative

將六甲基二矽基胺基鋰之四氫呋喃溶液(1M，3當量)加至隨意經取代之苯胺或胺基吡啶(3當量)之無水甲苯溶液中，再將混合物於室溫下於氮氣氛下拌15分鐘。然 後，將2-(甲磺醯基)-5,6,7,8-四氫喹唑啉衍生物(1當量)之四氫呋喃懸浮液加入，再將混合物於90℃下加熱1小時。冷卻至室溫後，以數滴水令混合物之反應中止，再於真空中濃縮。繼而藉急驟柱式層析或製備HPLC予以純化，即得終化合物。 A solution of hexamethyldidecylamino lithium in tetrahydrofuran (1 M, 3 eq.) was added to a solution of the optionally substituted aniline or aminopyridine (3 eq.) in anhydrous toluene. Mix for 15 minutes. Of course Thereafter, a suspension of 2-(methylsulfonyl)-5,6,7,8-tetrahydroquinazoline derivative (1 equivalent) in tetrahydrofuran was added, and the mixture was heated at 90 ° C for 1 hour. After cooling to room temperature, the mixture was quenched with a few drops of water and concentrated in vacuo. It is then purified by flash column chromatography or preparative HPLC to give the final compound.

製備3Preparation 3 2,2-二甲基-1-(2-(甲磺醯基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)丙-1-酮2,2-Dimethyl-1-(2-(methylsulfonyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)propan-1-one

將4M鹽酸之二唍溶液(1.1毫升，4.2毫莫耳，0.1當量)加至粗製3-((二甲胺基)亞甲基)-4-側氧基哌啶-1-羧酸第三丁酯(參見製備2)(10.70克，42.1毫莫耳)及脒基硫代酸甲酯半硫酸鹽(14.05克，50.5毫莫耳，1.2當量)之二甲亞碸(200毫升)溶液中。將混合物於130℃下加熱過夜。冷卻至室溫後，將乙酸乙酯(330毫升)及***(660毫升)加入，再將有機層以水(1升)、鹽水(3次，每次1升)清洗，於硫酸鈉上乾燥，及於真空中濃縮。再藉急驟柱式層析(矽膠，梯度100%庚烷至40%乙酸乙酯/庚烷)予以純化，即得4.6克(35%，純度90%)中間產物2-(甲硫基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯。 Will 4M hydrochloric acid two A solution of hydrazine (1.1 mL, 4.2 mmol, 0.1 eq) was added to the crude 3-((dimethylamino)methylene)-4-oxoxypiperidine-1-carboxylic acid tert-butyl ester (see Preparation) 2 ) (10.70 g, 42.1 mmol) and methyl mercapto thioate hemisulfate (14.05 g, 50.5 mmol, 1.2 eq.) in dimethyl hydrazine (200 mL). The mixture was heated at 130 ° C overnight. After cooling to room temperature, ethyl acetate (330 ml) and diethyl ether (660 ml) were added and the organic layer was washed with water (1 liter), brine (3 times, 1 liter each time) and dried over sodium sulfate And concentrated in a vacuum. Purification by flash column chromatography (gelatin, gradient 100% heptane to 40% ethyl acetate / heptane) afforded 4.6 g (35%, purity 90%) of intermediate 2-(methylthio)- 7,8-Dihydropyrido[4,3-d]pyrimidin-6( 5H )-carboxylic acid tert-butyl ester.

將三氟乙酸(25.7毫升，334毫莫耳，40當量)加至2-(甲硫基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯(2.35克，8.4毫莫耳)之二氯甲烷(50毫升)溶液中，再將混合物於室溫下攪拌45分鐘。將混合物於真空中濃縮， 再與二氯甲烷共蒸發2次以得橙色油狀之2-(甲硫基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶之三氟乙酸鹽，其係用於下一步驟中而不必進一步純化。 Trifluoroacetic acid (25.7 ml, 334 mmol, 40 equivalents) was added to 2-(methylthio)-7,8-dihydropyrido[4,3-d]pyrimidin-6( 5H )-carboxylate A solution of the acid tert-butyl ester (2.35 g, 8.4 mmol) in dichloromethane (50 mL). The mixture was concentrated in vacuo and evaporated twice with dichloromethane to give 2-(methylthio)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine as an orange oil. Trifluoroacetate salt was used in the next step without further purification.

將三乙胺(5.8毫升，41.8毫莫耳，5當量)及特戊醯氯(1.2毫升，10.0毫莫耳，1.2當量)加至2-(甲硫基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶(三氟乙酸鹽，1.51克，8.4毫莫耳)之二氯甲烷(50毫升)溶液中，再將混合物於室溫下攪拌過夜。將溶液以另外之二氯甲烷(100毫升)稀釋，再將有機層以飽和水性碳酸氫鈉溶液(150毫升)、鹽水(150毫升)清洗，於硫酸鈉上乾燥及於真空中濃縮。再藉急驟柱式層析(吸附至hydromatrix上，矽膠，梯度7%至60%乙酸乙酯/庚烷)予以純化，即得1.64克(於2步驟得74%，純度80%)黃色油狀之2-(甲硫基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)丙-1-酮，其於靜置後固化。 Add triethylamine (5.8 ml, 41.8 mmol, 5 equivalents) and pentyl chloride (1.2 ml, 10.0 mmol, 1.2 equivalents) to 2-(methylthio)-5,6,7,8 To a solution of tetrahydropyrido[4,3-d]pyrimidine (trifluoroacetate, 1.51 g, 8.4 mmol) in dichloromethane (50 mL) The solution was diluted with EtOAc (EtOAc)EtOAc. Purification by flash column chromatography (adsorption onto hydromatrix, hydrazine, gradient 7% to 60% ethyl acetate / heptane) gave 1.64 g (74% in 2 steps, purity 80%). 2-(Methylthio)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)propan-1-one which solidifies upon standing.

將間位-氯基過苯甲酸(3.13克，13.6毫莫耳，2.2當量)加至2,2-二甲基-1-(2-(甲硫基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)丙-1-酮(1.64克，6.2毫莫耳)之二氯甲烷(100毫升)溶液中。於室溫下攪拌45分鐘後，將混合物以另外之二氯甲烷(100毫升)稀釋，再將有機層以半飽和水性碳酸鉀(2次，每次200毫升)清洗。將結合之水性層以另外之二氯甲烷(200毫升)萃取，然後以鹽水(200毫升)清洗，於硫酸鈉上乾燥及於真空中濃縮，即得黃色油狀之標題化合物(1.60克，87%)，其於靜置後固化。 The m-chloroperbenzoic acid (3.13 g, 13.6 mmol, 2.2 eq.) was added to 2,2-dimethyl-1-(2-(methylthio)-7,8-dihydropyridine. [4,3-d]pyrimidine-6( 5H )-yl)propan-1-one (1.64 g, 6.2 mmol) in dichloromethane (100 mL). After stirring at room temperature for 45 minutes, the mixture was diluted with additional dichloromethane (100 mL) and the organic layer was washed with a half-saturated aqueous potassium carbonate (2 times, 200 ml each). The combined aqueous layer was extracted with EtOAc (EtOAc m. %), which solidifies after standing.

N,N-二甲基-2-(甲磺醯基)-7,8-二氫吡啶並[4,3-d]嘧 啶-6(5H)-甲醯胺係以密切類似於上述之步驟，使用二甲基胺基甲醯基氯取代特戊醯氯製得。 N,N -dimethyl-2-(methylsulfonyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carbamimid is closely related to the above The step is carried out by using dimethylaminomethylmethyl chloride instead of pentylene chloride.

實例1 Example 1 2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-5(6H)-酮2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6 H )-one

將1,3-((二甲胺基)亞甲基)哌啶-2,4-二酮(3.79克，33.5毫莫耳)及N,N-二甲基甲醯胺二甲基縮醛(8.00克，67.0毫莫耳)之乙腈(35毫升)混合液於室溫下攪拌過夜，再於真空中濃縮。將混合物以***碾磨，過濾，以***清洗，再於真空下乾燥以得棕色固狀之3-((二甲胺基)亞甲基)哌啶-2,4-二酮(3.84克，68%)。 1,3-((Dimethylamino)methylene)piperidine-2,4-dione (3.79 g, 33.5 mmol) and N,N -dimethylformamide dimethyl acetal (8.00 g, 67.0 mmol) of acetonitrile (35 mL) was stirred at room temperature overnight and concentrated in vacuo. The mixture was triturated with diethyl ether, filtered, washed with diethyl ether and then evaporated to dryness to give 3-((dimethylamino)methylene)piperidine-2,4-dione (3.84 g, 68%).

將所得中間體(0.168克，1.00毫莫耳)連同1-(3-氯苯基)胍硝酸鹽(233毫克，1.00毫莫耳)及三乙胺(0.3毫升)於乙醇(6毫升)中迴流4小時，再冷卻至室溫。將所形成之沈澱物藉過濾法收集，以甲醇、水、***清洗，再乾燥，即得米黃色固狀之標題化合物(220毫克，80%)。 The obtained intermediate (0.168 g, 1.00 mmol) was combined with 1-(3-chlorophenyl)indole nitrate (233 mg, 1.00 mmol) and triethylamine (0.3 mL) in ethanol (6 mL) It was refluxed for 4 hours and then cooled to room temperature. The resulting precipitate was collected by EtOAc (EtOAc)EtOAc.

¹H NMR(CDCl₃),δ_H,2.93(t,2H),3.40-3.50(m,2H),7.03,(d,1H),7.32(t,1H),7.72(d,1H),7.74(br s,1H),7.97(s,1H),8.76(s,1H),10.15(br s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 2.93 (t, 2H), 3.40-3.50 (m, 2H), 7.03, (d, 1H), 7.32 (t, 1H), 7.72 (d, 1H), 7.74 (br s, 1H), 7.97 (s, 1H), 8.76 (s, 1H), 10.15 (br s, 1H).

LC/MS(M+H)⁺=275,277 LC/MS (M+H) ⁺ =275,277

實例2Example 2 (2-((3-氯苯基)胺基)-5,6,7,8-四氫喹唑啉-6-基)(哌啶-(2-((3-Chlorophenyl)amino)-5,6,7,8-tetrahydroquinazolin-6-yl)(piperidine- 1-基)甲酮1-yl)methanone

令2-((3-氯苯基)胺基)-5,6,7,8-四氫喹唑啉-6-羧酸乙酯(100毫克，0.30毫莫耳)及4-二甲胺基吡啶(4毫克，0.03毫莫耳)溶於哌啶(3.0毫升)中，再將混合物於密封管瓶中加熱至100℃ 3天。冷卻後，將反應混合物蒸發，再將餘留物藉急驟柱式層析予以純化，即得8毫克(7%)無色固狀之標題化合物。 Ethyl 2-((3-chlorophenyl)amino)-5,6,7,8-tetrahydroquinazoline-6-carboxylate (100 mg, 0.30 mmol) and 4-dimethylamine The pyridine (4 mg, 0.03 mmol) was dissolved in piperidine (3.0 mL) and the mixture was heated to 100 ° C for 3 days in a sealed vial. After chilling, the reaction mixture was evaporated and purified mjjjjjjjjj

¹H NMR(CDCl₃),δ_H,1.50-1.75(m,6H),1.85-2.12(m,2H),2.61-3.05(m,5H),3.49(m,2H),3.61(m,2H),6.95(d,1H),7.11-7.39(m,3H),7.85(s,1H),8.16(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.50-1.75 (m, 6H), 1.85-2.12 (m, 2H), 2.61-3.05 (m, 5H), 3.49 (m, 2H), 3.61 (m, 2H) ), 6.95 (d, 1H), 7.11-7.39 (m, 3H), 7.85 (s, 1H), 8.16 (s, 1H).

LC/MS(M+H)⁺=371 LC/MS (M+H) ⁺ =371

實例3 Example 3 1-(2-((3-氟苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)-2-甲基丙-1-酮1-(2-((3-fluorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)-2-methylpropan-1 -ketone

根據一般步驟2a，令N-(3-氟苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺(75毫克，0.21毫莫耳)與異丁醯氯起反應，即得黃色固狀之標題化合物(15毫克，23%)。 According to general procedure 2a, let N- (3-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (75 mg, 0.21 mmol) and The title compound (15 mg, 23%) was obtained as a yellow solid.

¹H NMR(CDCl₃),δ_H,1.15-1.17(重疊的d,6H),2.86-2.92(m,3H),3.79和3.90(各為m,2H),4.58和4.65(各為s,2H),6.69(t,1H),7.15(d,1H),7.20-7.25(m,1H),7.68-7.73(m,2H),8.20(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.15-1.17 (overlapping d, 6H), 2.86-2.92 (m, 3H), 3.79 and 3.90 (m, 2H), 4.58 and 4.65 (each s, 2H), 6.69 (t, 1H), 7.15 (d, 1H), 7.20-7.25 (m, 1H), 7.68-7.73 (m, 2H), 8.20 (s, 1H).

LC/MS(M+H)⁺=315 LC/MS (M+H) ⁺ =315

實例4 Example 4 1-(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)-2-甲基丙-1-酮1-(2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)-2-methylpropan-1 -ketone

根據一般步驟2a，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺(50毫克，0.19毫莫耳)與異丁醯氯起反應，即得黃色固狀之標題化合物(15毫克，24%)。 According to general procedure 2a, let N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (50 mg, 0.19 mmol) and The title compound (15 mg, 24%) was obtained as a yellow solid.

¹H NMR(CDCl₃),δ_H,1.16-1.19(重疊的d,6H),2.85-2.95(m,3H),3.82-3.91(m,2H),4.60和4.66(各為s,2H),6.98(d,1H),7.22(t,1H),7.42(d,1H),7.86(s,1H),7.98(s,1H),8.21(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.16-1.19 (overlapping d, 6H), 2.85-2.95 (m, 3H), 3.82-3.91 (m, 2H), 4.60 and 4.66 (each s, 2H) , 6.98 (d, 1H), 7.22 (t, 1H), 7.42 (d, 1H), 7.86 (s, 1H), 7.98 (s, 1H), 8.21 (s, 1H).

LC/MS(M+H)⁺=331 LC/MS(M+H) ⁺ =331

實例5 Example 5 2-甲基-1-(2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)丙-1-酮2-methyl-1-(2-(meta-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)propan-1-one

根據一般步驟2a，令N-(間位-甲苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺(51毫克，0.15毫莫耳)與異丁醯氯起反應，即得黃色固狀之標題化合物(10毫克，22%)。 According to general procedure 2a, let N- (meta-tolyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (51 mg, 0.15 mmol) and The title compound (10 mg, 22%) was obtained as a yellow solid.

¹H NMR(CDCl₃),δ_H,1.15-1.17(重疊的d,6H),2.33(s,3H),2.83-2.89(m,3H),3.79和3.89(各為m,2H),4.56和4.63(各為s,2H),6.84(d,1H),7.19(t,1H),7.29(s,1H),7.37(s,2H),7.43(d,1H),8.17(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.15-1.17 (overlapping d, 6H), 2.33 (s, 3H), 2.83-2.89 (m, 3H), 3.79 and 3.89 (m, 2H), 4.56 And 4.63 (each s, 2H), 6.84 (d, 1H), 7.19 (t, 1H), 7.29 (s, 1H), 7.37 (s, 2H), 7.43 (d, 1H), 8.17 (s, 1H) ).

LC/MS(M+H)⁺=311 LC/MS(M+H) ⁺ =311

實例6 Example 6 2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(環丙基)甲酮2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)(cyclopropyl)methanone

根據一般步驟2a，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺(70毫克，0.27毫莫耳)與環丙烷羰基氯起反應，即得黃色固狀之標題化合物(30毫克，34%)。 According to general procedure 2a, N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (70 mg, 0.27 mmol) The title compound (30 mg, 34%) was obtained as a yellow solid.

¹H NMR(CDCl₃),δ_H,0.76(m,2H),0.98(m,2H),1.76(m,1H),2.81和9.92(各為m,2H),3.86和3.92(各為m,2H),4.61和4.72(各為s,2H),6.93(d,1H),7.06(s,1H),7.16(t,1H),7.31(d,1H),7.78(s,1H),8.16(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 0.76 (m, 2H), 0.98 (m, 2H), 1.76 (m, 1H), 2.81 and 9.92 (m, 2H), 3.86 and 3.92 (each m , 2H), 4.61 and 4.72 (each s, 2H), 6.93 (d, 1H), 7.06 (s, 1H), 7.16 (t, 1H), 7.31 (d, 1H), 7.78 (s, 1H), 8.16 (s, 1H).

LC/MS(M+H)⁺=329 LC/MS (M+H) ⁺ =329

實例7 Example 7 1-(2-((4-氟苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)-2,2-二甲基丙-1-酮1-(2-((4-fluorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)-2,2-dimethyl Propan-1-one

根據一般步驟2a，令N-(4-氟苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺(50毫克，0.2毫莫耳)與特戊醯氯起反應，即得白色固狀之標題化合物(20毫克，30%)。 According to general procedure 2a, let N- (4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (50 mg, 0.2 mmol) and The title compound (20 mg, 30%) was obtained as a white solid.

¹H NMR(CDCl₃),δ_H,1.31(s,9H),2.86(t,2H),3.91(t,2H),4.65(s,2H),7.01(t,2H),7.23(s,1H),7.51-7.58(m,2H),8.16(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.31 (s, 9H), 2.86 (t, 2H), 3.91 (t, 2H), 4.65 (s, 2H), 7.01 (t, 2H), 7.23 (s, 1H), 7.51 - 7.58 (m, 2H), 8.16 (s, 1H).

LC/MS(M+H)⁺=329 LC/MS (M+H) ⁺ =329

實例8 Example 8 1-(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)-2,2-二甲基丙-1-酮1-(2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)-2,2-dimethyl Propan-1-one

根據一般步驟2a，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺(50毫克，0.19毫莫耳)與特戊醯氯起反應，即得白色固狀之標題化合物(27毫克，41%)。 According to general procedure 2a, let N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (50 mg, 0.19 mmol) and The title compound (27 mg, 41%) was obtained as a white solid.

¹H NMR(CDCl₃),δ_H,1.32(s,9H),2.89(t,2H),3.92(t,2H),4.66(s,2H),6.98(d,2H),7.21(t,1H),7.36-7.40(m,2H),7.84(m,1H),8.20(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.32 (s, 9H), 2.89 (t, 2H), 3.92 (t, 2H), 4.66 (s, 2H), 6.98 (d, 2H), 7.21. 1H), 7.36-7.40 (m, 2H), 7.84 (m, 1H), 8.20 (s, 1H).

LC/MS(M+H)⁺=345 LC/MS (M+H) ⁺ =345

實例9 Example 9 3-((6-特戊醯基-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈3-((6-Pententyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile

根據一般步驟2a，令3-((5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈(97毫克，0.40毫莫耳)與特戊醯氯起反應，即得白色固狀之標題化合物(30毫克，21%)。 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile (97 mg, 0.40 mmol) according to general procedure 2a The title compound (30 mg, 21%) was obtained as a white solid.

¹H NMR(CDCl₃),δ_H,1.33(s,6H),2.91(t,2H),3.96(t,2H),4.69(s,2H),7.30-7.42(m,2H),7.64(d,1H),8.23(s,1H),8.24(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.33 (s, 6H), 2.91 (t, 2H), 3.96 (t, 2H), 4.69 (s, 2H), 7.30-7.42 (m, 2H), 7.64 ( d, 1H), 8.23 (s, 1H), 8.24 (s, 1H).

LC/MS(M+H)⁺=336 LC/MS (M+H) ⁺ =336

實例10 Example 10 1-(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)-2-甲基丁-1-酮1-(2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)-2-methylbut-1 -ketone

根據一般步驟2a，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺(70毫克，0.27毫莫耳)與2-甲基丁醯氯起反應，即得白色固狀之標題化合物(40毫克，43%)。 According to general procedure 2a, N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (70 mg, 0.27 mmol) The title compound (40 mg, 43%) was obtained as a white solid.

¹H NMR(CDCl₃),δ_H,0.90(m,3H),1.16(m,3H),1.46(m,1H),1.75(m,1H),2.71(m,1H),2.90(m,2H),3.79-3.95(m,2H),4.60和4.67(各為s,2H),6.98(d,1H),7.22(t,1H),7.25(s,1H),7.38(d,2H),7.84(s,1H),8.23(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 0.90 (m, 3H), 1.16 (m, 3H), 1.46 (m, 1H), 1.75 (m, 1H), 2.71 (m, 1H), 2.90 (m, 2H), 3.79-3.95 (m, 2H), 4.60 and 4.67 (each s, 2H), 6.98 (d, 1H), 7.22 (t, 1H), 7.25 (s, 1H), 7.38 (d, 2H) , 7.84 (s, 1H), 8.23 (s, 1H).

LC/MS(M+H)⁺=345 LC/MS (M+H) ⁺ =345

實例11 Example 11 2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(環丁基)甲酮2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)(cyclobutyl)methanone

根據一般步驟2a，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺(70毫克，0.27毫莫耳)與環丁烷羰基氯起反應，即得黃色固狀之標題化合物(60毫克，65%)。 According to general procedure 2a, N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (70 mg, 0.27 mmol) The title compound (60 mg, 65%) was obtained as a yellow solid.

¹H NMR(CDCl₃),δ_H,1.85-2.44(m,6H),2.84(t,2H),3.34(m,1H),3.64和3.89(各為t,2H),4.41和4.64(各為s,2H),6.97(d,1H),7.21(t,1H),7.26-7.37(m,2H),7.83(s,1H),8.16和8.21(各為s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.85-2.44 (m, 6H), 2.84 (t, 2H), 3.34 (m, 1H), 3.64 and 3.89 (each t, 2H), 4.41 and 4.64 (each s, 2H), 6.97 (d, 1H), 7.21 (t, 1H), 7.26-7.37 (m, 2H), 7.83 (s, 1H), 8.16 and 8.21 (each s, 1H).

LC/MS(M+H)⁺=343 LC/MS (M+H) ⁺ =343

實例12 Example 12 1-(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)-2-乙基丁-1-酮1-(2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)-2-ethylbutan-1 -ketone

根據一般步驟2a，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺(70毫克，0.27毫莫耳)與2-乙基丁醯氯起反應，即得白色固狀之標題化合物(45毫克，47%)。 According to general procedure 2a, N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (70 mg, 0.27 mmol) The title compound (45 mg, 47%) was obtained as a white solid.

¹H NMR(CDCl₃),δ_H,0.84(m,6H),1.51(m,2H),1.68(m,2H),2.57(m,1H),2.84和2.88(各為t,2H),3.83和3.93(各為t,2H),4.62和4.69(各為s,2H),6.96(d,1H),7.20(t,1H),7.28(s,1H),7.36(d,1H),7.82(s,1H),8.18和8.21(各為s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 0.84 (m, 6H), 1.51 (m, 2H), 1.68 (m, 2H), 2.57 (m, 1H), 2.84 and 2.88 (t, 2H) 3.83 and 3.93 (each t, 2H), 4.62 and 4.69 (each s, 2H), 6.96 (d, 1H), 7.20 (t, 1H), 7.28 (s, 1H), 7.36 (d, 1H), 7.82 (s, 1H), 8.18 and 8.21 (each s, 1H).

LC/MS(M+H)⁺=359 LC/MS(M+H) ⁺ =359

實例13 Example 13 2-((3-氟苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(苯基)甲酮2-((3-fluorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)(phenyl)methanone

根據一般步驟2a，令N-(3-氟苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺(75毫克，0.21毫莫耳)與苯甲醯氯起反應，即得黃色固狀之標題化合物(9毫克，12%)。 According to general procedure 2a, let N- (3-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (75 mg, 0.21 mmol) and The reaction of the benzamidine chloride gave the title compound (9 mg, 12%).

¹H NMR(CDCl₃),δ_H,2.95-3.00(m,2H),3.78-3.99(m,2H),4.67和4.72(各為s,2H),6.72(m,1H),7.25(m,1H),7.46-7.56(m,5H),7.76(d,1H),8.11-8.24(m,2H),8.44和8.58(各為s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 2.95-3.00 (m, 2H), 3.78-3.99 (m, 2H), 4.67 and 4.72 (each s, 2H), 6.72 (m, 1H), 7.25 (m) , 1H), 7.46-7.56 (m, 5H), 7.76 (d, 1H), 8.11-8.24 (m, 2H), 8.44 and 8.58 (each s, 1H).

LC/MS(M+H)⁺=349 LC/MS(M+H) ⁺ =349

實例14 Example 14 2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(苯基)甲酮2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)(phenyl)methanone

根據一般步驟2a，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺(50毫克，0.19毫莫耳)與苯甲醯氯起反應，即得黃色固狀之標題化合物(60毫克，86%)。 According to general procedure 2a, let N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (50 mg, 0.19 mmol) and The title compound (60 mg, 86%) was obtained as a yellow solid.

¹H NMR(CDCl₃),δ_H,2.90(m,2H),3.75(m,2H),4.73(m,2H),6.97(d,1H),7.20(t,1H),7.35-7.47(m,7H),7.82(s,1H),8.22(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 2.90 (m, 2H), 3.75 (m, 2H), 4.73 (m, 2H), 6.97 (d, 1H), 7.20 (t, 1H), 7.35-7.47 ( m, 7H), 7.82 (s, 1H), 8.22 (s, 1H).

LC/MS(M+H)⁺=365 LC/MS(M+H) ⁺ =365

實例15 Example 15 2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸甲酯Methyl 2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxylate

根據一般步驟2a，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺(70毫克，0.27毫莫耳)與氯甲酸甲酯起反應，即得黃色固狀之標題化合物(30毫克，35%)。 According to general procedure 2a, N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (70 mg, 0.27 mmol) The title compound (30 mg, 35%) was obtained as a yellow solid.

¹H NMR(CDCl₃),δ_H,2.86(t,2H),3.76(s,3H),3.78(t,2H),4.55(s,2H),6.98(d,1H),7.15(s,1H),7.22(t,1H),7.38(d,1H),7.83(m,1H),8.19(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 2.86 (t, 2H), 3.76 (s, 3H), 3.78 (t, 2H), 4.55 (s, 2H), 6.98 (d, 1H), 7.15 (s, 1H), 7.22 (t, 1H), 7.38 (d, 1H), 7.83 (m, 1H), 8.19 (s, 1H).

LC/MS(M+H)⁺=319 LC/MS (M+H) ⁺ =319

實例16 Example 16 2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸乙酯Ethyl 2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6( 5H )-carboxylate

根據一般步驟2a，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺(70毫克，0.27毫莫耳)與氯甲酸乙酯起反應，即得黃色固狀之標題化合物(25毫克，28%)。 According to general procedure 2a, N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (70 mg, 0.27 mmol) The title compound (25 mg, 28%) was obtained as a yellow solid.

¹H NMR(CDCl₃),δ_H,1.30(t,3H),2.86(t,2H),3.77(s,3H),4.20(q,2H),4.55(s,2H),698(d,1H),7.18-7.22(m,2H),7.38(d,1H),7.82(m,1H),8.19(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.30 (t, 3H), 2.86 (t, 2H), 3.77 (s, 3H), 4.20 (q, 2H), 4.55 (s, 2H), 698 (d, 1H), 7.18-7.22 (m, 2H), 7.38 (d, 1H), 7.82 (m, 1H), 8.19 (s, 1H).

LC/MS(M+H)⁺=333 LC/MS(M+H) ⁺ =333

實例17 Example 17 2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸異丙酯2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxylic acid isopropyl ester

根據一般步驟2a，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺(70毫克，0.27毫莫耳)與氯甲酸異丙酯起反應，即得黃色固狀之標題化合物(30毫克，32%)。 According to general procedure 2a, N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (70 mg, 0.27 mmol) The title compound (30 mg, 32%) was obtained as a yellow solid.

¹H NMR(CDCl₃),δ_H,1.28(d,6H),2.86(t,2H),3.76(s,3H),3.76(t,2H),4.53(s,2H),4.98(m,1H),6.98(d,1H),7.17-7.22(m,2H),7.38(d,1H),7.84(m,1H),8.20(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.28 (d, 6H), 2.86 (t, 2H), 3.76 (s, 3H), 3.76 (t, 2H), 4.53 (s, 2H), 4.98 (m, 1H), 6.98 (d, 1H), 7.17-7.22 (m, 2H), 7.38 (d, 1H), 7.84 (m, 1H), 8.20 (s, 1H).

LC/MS(M+H)⁺=347 LC/MS (M+H) ⁺ =347

實例18 Example 18 2-((3-氟苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-2-((3-fluorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5H)-羧酸第三丁酯6(5 H )-carboxylic acid tert-butyl ester

令3-((二甲胺基)亞甲基)-4-側氧基哌啶-1-羧酸第三丁酯(1.0克，3.93毫莫耳)溶於無水乙醇(20毫升)中，再將1-(3-氟苯基)胍(0.401毫克，2.62毫莫耳)加入。將混合物於100℃下加熱20小時，然後冷卻，再蒸發至乾。繼而將餘留物藉急驟柱式層析予以純化，即得黃色固狀之標題化合物(0.50克，56%)。 3-((Dimethylamino)methylene)-4-oxoxypiperidine-1-carboxylic acid tert-butyl ester (1.0 g, 3.93 mmol) was dissolved in anhydrous ethanol (20 mL). 1-(3-Fluorophenyl)anthracene (0.401 mg, 2.62 mmol) was added. The mixture was heated at 100 ° C for 20 hours, then cooled and evaporated to dryness. The title compound (0.50 g, 56%)

¹H NMR(CDCl₃),δ_H,1.49(s,6H),2.85(t,2H),3.72(t,2H),4.95(s,2H),6.72(t,1H),7.11-7.23(m,2H),7.73(m,1H),8.18(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.49 (s, 6H), 2.85 (t, 2H), 3.72 (t, 2H), 4.95 (s, 2H), 6.72 (t, 1H), 7.11 - 7.23 ( m, 2H), 7.73 (m, 1H), 8.18 (s, 1H).

LC/MS(M+H)⁺=345 LC/MS (M+H) ⁺ =345

實例19 Example 19 2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxylic acid tert-butyl ester

令3-((二甲胺基)亞甲基)-4-側氧基哌啶-1-羧酸第三丁酯(1.0克，3.93毫莫耳)溶於無水乙醇(20毫升)中，再將1-(3-氯苯基)胍(0.444克，2.62毫莫耳)加入。將混合物於100℃下加熱16小時，然後冷卻，再蒸發至乾。繼而將餘留物藉急驟柱式層析予以純化，即得黃色固狀之標題化合物(0.54克，57%)。 3-((Dimethylamino)methylene)-4-oxoxypiperidine-1-carboxylic acid tert-butyl ester (1.0 g, 3.93 mmol) was dissolved in anhydrous ethanol (20 mL). 1-(3-Chlorophenyl)indole (0.444 g, 2.62 mmol) was added. The mixture was heated at 100 ° C for 16 hours, then cooled and evaporated to dryness. The title compound (0.54 g, 57%)

¹H NMR(CDCl₃),δ_H,1.50(s,6H),2.85(t,2H),3.73(t,2H),4.50(s,2H),6.97(d,1H),7.15(s,1H),7.22(t,1H),7.38(d,1H),7.84(m,1H),8.19(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.50 (s, 6H), 2.85 (t, 2H), 3.73 (t, 2H), 4.50 (s, 2H), 6.97 (d, 1H), 7.15 (s, 1H), 7.22 (t, 1H), 7.38 (d, 1H), 7.84 (m, 1H), 8.19 (s, 1H).

LC/MS(M+H)⁺=361 LC/MS(M+H) ⁺ =361

實例20 Example 20 2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯2-(meta-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxylic acid tert-butyl ester

令3-((二甲胺基)亞甲基)-4-側氧基哌啶-1-羧酸第三丁酯(0.51克，2.01毫莫耳)溶於無水乙醇(20毫升)中，再將1-(間位-甲苯基)胍(0.20克，1.34毫莫耳)加入。將混合物於100℃下加熱16小時，然後冷卻，再蒸發至乾。繼而將餘留物藉急驟柱式層析予以純化，即得黃色固狀之標題化合物(0.25克，55%)。 3-((Dimethylamino)methylene)-4-oxoxypiperidine-1-carboxylic acid tert-butyl ester (0.51 g, 2.01 mmol) was dissolved in anhydrous ethanol (20 mL). Further, 1-(meta-methylphenyl)phosphonium (0.20 g, 1.34 mmol) was added. The mixture was heated at 100 ° C for 16 hours, then cooled and evaporated to dryness. The title compound (0.25 g, 55%) was obtained as a yellow solid.

¹H NMR(CDCl₃),δ_H,1.49(s,6H),2.35(s,3H),2.83(t,2H),3.72(t,2H),4.48(s,2H),6.84(d,1H),7.10(s,1H),7.21(t,1H),7.38(s,1H),7.45(d,1H),8.16(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.49 (s, 6H), 2.35 (s, 3H), 2.83 (t, 2H), 3.72 (t, 2H), 4.48 (s, 2H), 6.84 (d, 1H), 7.10 (s, 1H), 7.21 (t, 1H), 7.38 (s, 1H), 7.45 (d, 1H), 8.16 (s, 1H).

LC/MS(M+H)⁺=341 LC/MS(M+H) ⁺ =341

實例21 Example 21 2-((3-氰苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯2-((3-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxylic acid tert-butyl ester

令3-((二甲胺基)亞甲基)-4-側氧基哌啶-1-羧酸第三丁酯(1.1克，4.33毫莫耳)溶於無水乙醇(20毫升)中，再將1-(3-氰苯基)胍(0.46克，2.90毫莫耳)加入。將混合物於100℃下加熱16小時，然後冷卻，再蒸發至乾。繼而將 餘留物藉急驟柱式層析予以純化，即得黃色固狀之標題化合物(0.62克，60%)。 3-((Dimethylamino)methylene)-4-oxoxypiperidine-1-carboxylic acid tert-butyl ester (1.1 g, 4.33 mmol) was dissolved in anhydrous ethanol (20 mL). Further, 1-(3-cyanophenyl)anthracene (0.46 g, 2.90 mmol) was added. The mixture was heated at 100 ° C for 16 hours, then cooled and evaporated to dryness. Then will The residue was purified by flash column chromatography eluting elut elut elut elut

¹H NMR(CDCl₃),δ_H,1.49(s,9H),2.85(t,2H),3.73(t,2H),4.51(s,2H),7.24-7.41(m,3H),7.62-7.66(m,1H),8.20(s,1H),8.24(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.49 (s, 9H), 2.85 (t, 2H), 3.73 (t, 2H), 4.51 (s, 2H), 7.24-7.41 (m, 3H), 7.62 7.66 (m, 1H), 8.20 (s, 1H), 8.24 (s, 1H).

LC/MS(M+H)⁺=352 LC/MS(M+H) ⁺ =352

實例22 Example 22 2-((3-氯苯基)胺基)-N-乙基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺2-((3-Chlorophenyl)amino) -N -ethyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxamide

令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺(70毫克，0.27毫莫耳)溶於二氯甲烷(0.5毫升)中，再將異氰酸正丙酯(20毫克，0.28毫莫耳)加入。將混合物於室溫下攪拌過夜，然後蒸發。再將餘留物由乙醇中再結晶，即得黃色固狀之標題化合物(50毫克，56%)。 N- (3-Chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (70 mg, 0.27 mmol) was dissolved in dichloromethane ( In 0.5 ml), n-propyl isocyanate (20 mg, 0.28 mmol) was added. The mixture was stirred at room temperature overnight and then evaporated. The residue was recrystallized from EtOAc (EtOAc:EtOAc)

¹H NMR(CDCl₃),δ_H,1.19(t,3H),2.89(t,2H),3.32(q,2H),3.69(t,2H),4.76(s,2H),6.98(d,1H),7.13(s,1H),7.22(t,1H),7.40(d,1H),7.85(m,1H),8.21(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.19 (t, 3H), 2.89 (t, 2H), 3.32 (q, 2H), 3.69 (t, 2H), 4.76 (s, 2H), 6.98 (d, 1H), 7.13 (s, 1H), 7.22 (t, 1H), 7.40 (d, 1H), 7.85 (m, 1H), 8.21 (s, 1H).

LC/MS(M+H)⁺=332 LC/MS (M+H) ⁺ =332

實例23Example 23 2-((3-氯苯基)胺基)-N,N-二甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺 2-((3-Chlorophenyl)amino) -N , N -dimethyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxamide

根據一般步驟2a，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺(70毫克，0.27毫莫耳)與二甲基胺基甲醯氯起反應，即得黃色固狀之標題化合物(50毫克，56%)。 According to general procedure 2a, N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (70 mg, 0.27 mmol) The title compound (50 mg, 56%) was obtained as a yellow solid.

¹H NMR(CDCl₃),δ_H,2.83(s,6H),2.86(t,2H),3.46(t,2H),4.23(s,2H),6.90(d,1H),7.10(s,1H),7.15(t,1H),7.31(d,1H),7.77(m,1H),8.12(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 2.83 (s, 6H), 2.86 (t, 2H), 3.46 (t, 2H), 4.23 (s, 2H), 6.90 (d, 1H), 7.10 (s, 1H), 7.15 (t, 1H), 7.31 (d, 1H), 7.77 (m, 1H), 8.12 (s, 1H).

LC/MS(M+H)⁺=332 LC/MS (M+H) ⁺ =332

實例24 Example 24 N-(3-氯苯基)-6-(異丙磺醯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺 N- (3-chlorophenyl)-6-(isopropylsulfonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine

根據一般步驟2a，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺(70毫克，0.27毫莫耳)與異丙磺醯氯起反應，即得黃色固狀之標題化合物(45毫克，46%)。 According to general procedure 2a, N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (70 mg, 0.27 mmol) The title compound (45 mg, 46%) was obtained as a yellow solid.

¹H NMR(CDCl₃),δ_H,1.36(d,6H),2.93(t,2H),3.24(m,1H),3.68(t,2H),4.44(s,2H),6.97(d,1H),7.14(s,1H),7.21(t,1H),7.37(d,1H),7.82(m,1H),8.16(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.36 (d, 6H), 2.93 (t, 2H), 3.24 (m, 1H), 3.68 (t, 2H), 4.44 (s, 2H), 6.97 (d, 1H), 7.14 (s, 1H), 7.21 (t, 1H), 7.37 (d, 1H), 7.82 (m, 1H), 8.16 (s, 1H).

LC/MS(M+H)⁺=367 LC/MS(M+H) ⁺ =367

實例25 Example 25 N-(3-氯苯基)-6-(環丙磺醯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺 N- (3-chlorophenyl)-6-(cyclopropanesulfonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine

根據一般步驟2a，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺(70毫克，0.27毫莫耳)與環丙磺醯氯起反應，即得黃色固狀之標題化合物(30毫克，31%)。 According to general procedure 2a, N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (70 mg, 0.27 mmol) The title compound (30 mg, 31%) was obtained as a yellow solid.

¹H NMR(CDCl₃),δ_H,1.01(m,2H),1.24(m,2H),2.31(m,1H),2.99(t,2H),3.68(t,2H),4.44(s,2H),7.00(d,1H),7.15(s,1H),7.23(t,1H),7.37(d,1H),7.84(m,1H),8.20(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.01 (m, 2H), 1.24 (m, 2H), 2.31 (m, 1H), 2.99 (t, 2H), 3.68 (t, 2H), 4.44 (s, 2H), 7.00 (d, 1H), 7.15 (s, 1H), 7.23 (t, 1H), 7.37 (d, 1H), 7.84 (m, 1H), 8.20 (s, 1H).

LC/MS(M+H)⁺=365 LC/MS(M+H) ⁺ =365

實例26 Example 26 2-((3-氯苯基)胺基)-N,N-二甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-磺醯胺2-((3-Chlorophenyl)amino) -N , N -dimethyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-sulfonamide

根據一般步驟2a，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺(70毫克，0.27毫莫耳)與二甲基胺磺醯氯起反應，即得黃色固狀之標題化合物(50毫克，51%)。 According to general procedure 2a, N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (70 mg, 0.27 mmol) The title compound (50 mg, 51%) was obtained as a yellow solid.

¹H NMR(CDCl₃),δ_H,2.79(s,6H),2.89(t,2H),3.53(t,2H),4.27(s,2H),6.92(d,1H),7.05(s,1H),7.16(t,1H),7.31(d,1H),7.77(s,1H),8.12(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 2.79 (s, 6H), 2.89 (t, 2H), 3.53 (t, 2H), 4.27 (s, 2H), 6.92 (d, 1H), 7.05 (s, 1H), 7.16 (t, 1H), 7.31 (d, 1H), 7.77 (s, 1H), 8.12 (s, 1H).

LC/MS(M+H)⁺=368 LC/MS(M+H) ⁺ =368

實例27 Example 27 N-(3-氯苯基)-6-(吡啶-2-基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺 N- (3-chlorophenyl)-6-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine

令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺(77毫克，0.30毫莫耳)、N,N-二異丙基乙胺(114毫克，0.89毫莫耳)、及2-溴基吡啶(93毫克，0.59毫莫耳)溶於二烷(0.5毫升)中，再將混合物於密封管瓶中、於150℃下加熱14小時。冷卻後，將混合物蒸發，再將餘留物藉製備HPLC予以純化，即得10毫克(10%)黃色固狀之標題化合物。 Let N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (77 mg, 0.30 mmol), N,N - II Isopropylethylamine (114 mg, 0.89 mmol) and 2-bromopyridine (93 mg, 0.59 mmol) are dissolved in two The mixture was heated in a sealed vial and heated at 150 ° C for 14 hours. After chilling, the mixture was evaporated and purified title crystall

¹H NMR(CDCl₃),δ_H,2.99(t,2H),3.93(t,2H),4.63(s,2H),6.61-6.75(m,2H),6.98(dd,1H),7.19(d,1H),7.39-7.57(m,2H),7.72(s,1H),7.87(t,1H),8.82-8.27(m,2H)。 ¹ H NMR (CDCl ₃ ), δ _H , 2.99 (t, 2H), 3.93 (t, 2H), 4.63 (s, 2H), 6.61-6.75 (m, 2H), 6.98 (dd, 1H), 7.19 ( d, 1H), 7.39-7.57 (m, 2H), 7.72 (s, 1H), 7.87 (t, 1H), 8.82-8.27 (m, 2H).

LC/MS(M+H)⁺=338 LC/MS (M+H) ⁺ =338

實例28 Example 28 6-(1-(第三丁基)-1H-四唑-5-基)-N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺6- (l- (tert-butyl) -1 H - tetrazol-5-yl) - N - (3- chlorophenyl) -5,6,7,8-tetrahydro-pyrido [4,3 d]pyrimidine-2-amine

令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺(100毫克，0.38毫莫耳)溶於1毫升無水四氫呋喃中，再將異硫氰酸第三丁酯(44毫克，0.38毫莫耳)加入。將混合物於室溫下攪拌40小時，然後蒸發至乾以得黃色固狀之中間體硫脲(120毫克，84%)，令其溶於N,N-二甲基甲醯胺(10毫升)中。將疊氮化鈉(62毫克，0.96毫莫耳)、氯化汞(95毫克，0.35毫莫耳)及三乙胺(96毫克，0.96毫莫耳)加入，再將混合物於室溫下攪拌12小時，然後分配於二 氯甲烷與飽和水性碳酸氫鈉溶液之間。將有機相分離出，於無水硫酸鈉上乾燥，再蒸發。繼而將餘留物藉急驟柱式層析予以純化，即得黃色固狀之標題化合物(45毫克，37%)。 N- (3-Chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (100 mg, 0.38 mmol) was dissolved in 1 mL of anhydrous tetrahydrofuran Further, tributyl isothiocyanate (44 mg, 0.38 mmol) was added. The mixture was stirred at room temperature for 40 hours and then evaporated to dryness to give a yellow solid of the intermediate thiourea (120 mg, 84%), so that it was dissolved in N, N - dimethylformamide (10 mL) in. Sodium azide (62 mg, 0.96 mmol), mercuric chloride (95 mg, 0.35 mmol) and triethylamine (96 mg, 0.96 mmol) were added and the mixture was stirred at room temperature After 12 hours, it was then partitioned between dichloromethane and a saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate and evaporated. The title compound (45 mg, 37%)

¹H NMR(CDCl₃),δ_H,1.74(s,9H),3.07(t,2H),3.44(t,2H),4.21(s,2H),7.00(dd,1H),7.15(s,1H),7.25(t,1H),7.38(dd,1H),7.87(s,1H),8.18(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.74 (s, 9H), 3.07 (t, 2H), 3.44 (t, 2H), 4.21 (s, 2H), 7.00 (dd, 1H), 7.15 (s, 1H), 7.25 (t, 1H), 7.38 (dd, 1H), 7.87 (s, 1H), 8.18 (s, 1H).

LC/MS(M+H)⁺=385 LC/MS (M+H) ⁺ =385

實例29 Example 29 N-(3-氯苯基)-6-(1-異丙基-1H-四唑-5-基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺 N- (3-chlorophenyl)-6-(1-isopropyl-1 H -tetrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine 2-amine

令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺(100毫克，0.38毫莫耳)溶於1毫升無水四氫呋喃中，再將異硫氰酸異丙酯(39毫克，0.38毫莫耳)加入。將混合物於室溫下攪拌40小時，然後蒸發至乾以得黃色固狀之中間體硫脲(130毫克，93%)，令其溶於N,N-二甲基甲醯胺(5毫升)中。將疊氮化鈉(70毫克，1.08毫莫耳)、氯化汞(107毫克，0.40毫莫耳)及三乙胺(109毫克，1.08毫莫耳)加入，再將混合物於室溫下攪拌12小時，然後分配於二氯甲烷與飽和水性碳酸氫鈉溶液之間。將有機相分離出，於無水硫酸鈉上乾燥，再蒸發。繼而將餘留物藉急驟柱式層析予以純化，即得黃色固狀之標題化合物(60毫克，45%)。 N- (3-Chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (100 mg, 0.38 mmol) was dissolved in 1 mL of anhydrous tetrahydrofuran Isopropyl isothiocyanate (39 mg, 0.38 mmol) was added. The mixture was stirred at room temperature for 40 hours and then evaporated to dryness to give a yellow solid of the intermediate thiourea (130 mg, 93%), so that it was dissolved in N, N - dimethylformamide (5 ml) in. Sodium azide (70 mg, 1.08 mmol), mercuric chloride (107 mg, 0.40 mmol) and triethylamine (109 mg, 1.08 mmol) were added and the mixture was stirred at room temperature After 12 hours, it was then partitioned between dichloromethane and a saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate and evaporated. The title compound (60 mg, 45%) was obtained eluted eluted elute

¹H NMR(CDCl₃),δ_H,1.62(d,6H),3.07(t,2H),3.57(t,2H),4.38(s,2H),4.53(m,1H),7.00(dd,1H),7.22(t,1H),7.29(s,1H),7.37-7.40(m,2H),7.86(s,1H),8.24(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.62 (d, 6H), 3.07 (t, 2H), 3.57 (t, 2H), 4.38 (s, 2H), 4.53 (m, 1H), 7.00 (dd, 1H), 7.22 (t, 1H), 7.29 (s, 1H), 7.37-7.40 (m, 2H), 7.86 (s, 1H), 8.24 (s, 1H).

LC/MS(M+H)⁺=371 LC/MS (M+H) ⁺ =371

實例30 Example 30 2-((3-氰苯基)胺基)-N,N-二甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺2-((3-cyanophenyl)amino) -N , N -dimethyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxamide

根據一般步驟2a，令N-(3-氰苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺(67毫克，0.27毫莫耳)與二甲基胺基甲醯氯起反應，即得黃色固狀之標題化合物(71毫克，82%)。 According to general procedure 2a, N- (3-cyanophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (67 mg, 0.27 mmol) The title compound (71 mg, 82%) was obtained as a yellow solid.

¹H NMR(CDCl₃),δ_H,2.90(s,6H),2.95(t,2H),3.54(t,2H),4.32(s,2H),7.19(s,1H),7.28(d,1H),7.38(t,1H),7.64(d,1H),8.21(s,1H),8.26(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 2.90 (s, 6H), 2.95 (t, 2H), 3.54 (t, 2H), 4.32 (s, 2H), 7.19 (s, 1H), 7.28 (d, 1H), 7.38 (t, 1H), 7.64 (d, 1H), 8.21 (s, 1H), 8.26 (s, 1H).

LC/MS(M+H)⁺=323 LC/MS (M+H) ⁺ = 323

實例31 Example 31 2-((3-氯苯基)胺基)-N,N-二乙基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺2-((3-Chlorophenyl)amino) -N , N -diethyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxamide

根據一般步驟2a，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺(50毫克，0.19毫莫耳)與二乙基胺基甲醯氯起反應，即得黃色固狀之標題化合物(60毫克， 87%)。 According to general procedure 2a, let N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (50 mg, 0.19 mmol) and The title compound (60 mg, 87%) was obtained as a yellow solid.

¹H NMR(CDCl₃),δ_H,1.15(t,6H),2.92(t,2H),3.26(q,4H),3.50(t,2H),4.27(s,2H),6.97(d,1H),7.21(t,1H),7.23(s,1H),7.37(d,1H),7.84(m,1H),8.18(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.15 (t, 6H), 2.92 (t, 2H), 3.26 (q, 4H), 3.50 (t, 2H), 4.27 (s, 2H), 6.97 (d, 1H), 7.21 (t, 1H), 7.23 (s, 1H), 7.37 (d, 1H), 7.84 (m, 1H), 8.18 (s, 1H).

LC/MS(M+H)⁺=360 LC/MS(M+H) ⁺ =360

實例32 Example 32 2-((3-氰苯基)胺基)-N,N-二乙基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺2-((3-cyanophenyl)amino) -N , N -diethyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxamide

根據一般步驟2a，令N-(3-氰苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺(50毫克，0.20毫莫耳)與二乙基胺基甲醯氯起反應，即得黃色固狀之標題化合物(60毫克，87%)。 According to the general procedure 2a, N- (3-cyanophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (50 mg, 0.20 mmol) and The title compound (60 mg, 87%) was obtained as a yellow solid.

¹H NMR(CDCl₃),δ_H,1.16(t,6H),2.94(t,2H),3.27(q,4H),3.52(t,2H),4.28(s,2H),7.28(d,1H),7.32-7.42(m,3H),7.65(d,2H),8.20(s,1H),8.26(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.16 (t, 6H), 2.94 (t, 2H), 3.27 (q, 4H), 3.52 (t, 2H), 4.28 (s, 2H), 7.28 (d, 1H), 7.32-7.42 (m, 3H), 7.65 (d, 2H), 8.20 (s, 1H), 8.26 (s, 1H).

LC/MS(M+H)⁺=351 LC/MS(M+H) ⁺ =351

實例33 Example 33 3-((6-(2-甲基丁醯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈3-((6-(2-methylbutylidene)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile

根據一般步驟2a，令N-(3-氰苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺(79毫克，0.31毫莫耳)與2-甲基丁醯 氯起反應，即得黃色固狀之標題化合物(50毫克，48%)。 According to general procedure 2a, N- (3-cyanophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (79 mg, 0.31 mmol) The title compound (50 mg, 48%) was obtained as a yellow solid.

¹H NMR(CDCl₃),δ_H,0.91和1.19(各為m,6H),1.50和1.75(各為m,2H),2.47和2.71(各為q,1H),2.91(m,2H),3.84和3.93(各為t,2H),4.63和4.69(各為s,2H),7.28(d,1H),7.39(t,1H),7.52(s,1H),7.65(d,1H),8.26(s,2H)。 ¹ H NMR (CDCl ₃ ), δ _H , 0.91 and 1.19 (m, 6H), 1.50 and 1.75 (m, 2H), 2.47 and 2.71 (q, 1H), 2.91 (m, 2H) , 3.84 and 3.93 (each t, 2H), 4.63 and 4.69 (each s, 2H), 7.28 (d, 1H), 7.39 (t, 1H), 7.52 (s, 1H), 7.65 (d, 1H) , 8.26 (s, 2H).

LC/MS(M+H)⁺=351 LC/MS(M+H) ⁺ =351

實例34 Example 34 2-((3-氯苯基)胺基)-N,N-二甲基-5,6,7,8-四氫喹唑啉-6-甲醯胺2-((3-Chlorophenyl)amino) -N , N -dimethyl-5,6,7,8-tetrahydroquinazolin-6-carboxamide

將2-((3-氯苯基)胺基)-5,6,7,8-四氫喹唑啉-6-羧酸(100毫克，0.33毫莫耳)、HOBt(66毫克，0.43毫莫耳)、EDC(82毫克，0.43毫莫耳)、DIPEA(140毫克，1.09毫莫耳)、及二甲胺鹽酸鹽(35毫克，0.43毫莫耳)之無水N,N-二甲基甲醯胺(1毫升)溶液於室溫下攪拌24小時。將混合物以水稀釋，再以乙酸乙酯萃取。將有機相於無水硫酸鈉上乾燥，再蒸發至乾。繼而將餘留物藉急驟柱式層析予以純化，即得黃色固狀之標題化合物(64毫克，59%)。 2-((3-Chlorophenyl)amino)-5,6,7,8-tetrahydroquinazolin-6-carboxylic acid (100 mg, 0.33 mmol), HOBt (66 mg, 0.43 m Mohr), EDC (82 mg, 0.43 mmol), DIPEA (140 mg, 1.09 mmol), and dimethylamine hydrochloride (35 mg, 0.43 mmol) of anhydrous N,N -dimethyl The solution of carbamide (1 ml) was stirred at room temperature for 24 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The title compound (64 mg, 59%)

¹H NMR(CDCl₃),δ_H,1.94-2.12(m,2H),2.17-3.01(m,4H),3.12(s,6H),3.72(m,1H),7.19(s,1H),6.96(d,1H),7.11(s,1H),7.20(t,1H),7.37(d,1H),7.85(s,1H),8.16(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.94-2.12 (m, 2H), 2.17-3.01 (m, 4H), 3.12 (s, 6H), 3.72 (m, 1H), 7.19 (s, 1H), 6.96 (d, 1H), 7.11 (s, 1H), 7.20 (t, 1H), 7.37 (d, 1H), 7.85 (s, 1H), 8.16 (s, 1H).

LC/MS(M+H)⁺=331 LC/MS(M+H) ⁺ =331

實例35 Example 35 2-((3-氯苯基)胺基)-N,N-二乙基-5,6,7,8-四氫喹唑啉-6-甲醯胺2-((3-Chlorophenyl)amino) -N , N -diethyl-5,6,7,8-tetrahydroquinazolin-6-carboxamide

將2-((3-氯苯基)胺基)-5,6,7,8-四氫喹唑啉-6-羧酸(80毫克，0.26毫莫耳)、HOBt(52毫克，0.34毫莫耳)、EDC(66毫克，0.34毫莫耳)、DIPEA(75毫克，0.58毫莫耳)、及二乙胺(25毫克，0.34毫莫耳)之無水N,N-二甲基甲醯胺(1毫升)溶液於室溫下攪拌24小時。將混合物以水稀釋，再以乙酸乙酯萃取。將有機相於無水硫酸鈉上乾燥，再蒸發至乾。繼而將餘留物藉急驟柱式層析予以純化，即得黃色固狀之標題化合物(50毫克，53%)。 2-((3-Chlorophenyl)amino)-5,6,7,8-tetrahydroquinazolin-6-carboxylic acid (80 mg, 0.26 mmol), HOBt (52 mg, 0.34 m Mohr), EDC (66 mg, 0.34 mmol), DIPEA (75 mg, 0.58 mmol), and diethylamine (25 mg, 0.34 mmol) of anhydrous N,N -dimethylformamidine The amine (1 ml) solution was stirred at room temperature for 24 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The title compound (50 mg, 53%)

¹H NMR(CDCl₃),δ_H,1.07-1.29(m,6H),1.97-2.12(m,2H),2.65-3.07(m,5H),3.27-3.51(m,4H),6.95(d,1H),7.13(s,1H),7.20(t,1H),7.37,7.85(s,1H),8.16(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.07-1.29 (m, 6H), 1.97-2.12 (m, 2H), 2.65-3.07 (m, 5H), 3.27-3.51 (m, 4H), 6.95 (d) , 1H), 7.13 (s, 1H), 7.20 (t, 1H), 7.37, 7.85 (s, 1H), 8.16 (s, 1H).

LC/MS(M+H)⁺=359 LC/MS(M+H) ⁺ =359

實例36 Example 36 2-((3-氯苯基)胺基)-N,N-二甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-硫代甲醯胺2-((3-Chlorophenyl)amino) -N , N -dimethyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-thiocarbamidine

根據一般步驟2a，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與二甲基胺基硫代甲醯氯起反應，即得米黃色固狀之標題化合物(37%)。 According to general procedure 2a, N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and dimethylaminothiocarbamidine The title compound (37%) was obtained as a beige solid.

¹H NMR(CDCl₃),δ_H,3.05(t,2H),3.21(s,6H),3.72(t,2H),4.52(s,2H),6.98(d,1H),7.19-7.22(m,2H),7.37(d,1H),7.84(s,1H),8.20(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 3.05 (t, 2H), 3.21 (s, 6H), 3.72 (t, 2H), 4.52 (s, 2H), 6.98 (d, 1H), 7.19-7.22 ( m, 2H), 7.37 (d, 1H), 7.84 (s, 1H), 8.20 (s, 1H).

LC/MS(M+H)⁺=347,349 LC/MS(M+H) ⁺ =347,349

實例37Example 37 (消旋)-1-(2-((3-氯苯基)胺基)-5,6,7,8-四氫喹唑啉-6-基)-2-甲基丙-1-酮(racemic)-1-(2-((3-chlorophenyl)amino)-5,6,7,8-tetrahydroquinazolin-6-yl)-2-methylpropan-1-one

將N,O-二甲基羥胺鹽酸鹽(0.13克，1.28毫莫耳)加至2-((3-氯苯基)胺基)-5,6,7,8-四氫喹唑啉-6-羧酸(0.30克，0.98毫莫耳)、HOBt水合物(0.20克，1.28毫莫耳)、EDC(0.25克，1.28毫莫耳)、及DIPEA(0.56毫升，3.26毫莫耳)之無水N,N-二甲基甲醯胺(3毫升)溶液中，再將所得混合物於室溫下攪拌24小時。將反應混合物以水稀釋，以乙酸乙酯萃取，於無水硫酸鈉上乾燥，再蒸發。繼而將餘留物藉急驟柱式層析予以純化，以得154毫克(45%)黃色粉狀之2-((3-氯苯基)胺基)-N-(甲氧基甲基)-5,6,7,8-四氫喹唑啉-6-甲醯胺。 Add N,O -dimethylhydroxylamine hydrochloride (0.13 g, 1.28 mmol) to 2-((3-chlorophenyl)amino)-5,6,7,8-tetrahydroquinazoline -6-carboxylic acid (0.30 g, 0.98 mmol), HOBt hydrate (0.20 g, 1.28 mmol), EDC (0.25 g, 1.28 mmol), and DIPEA (0.56 mL, 3.26 mmol) In a solution of anhydrous N,N -dimethylformamide (3 ml), the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The then remaining was purified by flash column chromatography to to give 154 mg (45%) of a yellow powder of 2 - ((3-chlorophenyl) amino) - N - (methoxymethyl) - 5,6,7,8-Tetrahydroquinazoline-6-carboxamide.

將2-((3-氯苯基)胺基)-N-(甲氧基甲基)-5,6,7,8-四氫喹唑啉-6-甲醯胺(0.08克，0.23毫莫耳)之四氫呋喃(2毫升)溶液逐滴加至異丙基氯化鎂(1.0毫莫耳)溶液中，再將所得混合物於室溫下攪拌12小時。以飽和氯化銨溶液令反應混合物之反應中止，以乙酸乙酯萃取，再將有機相於無水硫酸鈉上乾燥，再蒸發。繼而將餘留物藉急驟柱式層 析予以純化，即得無色固狀之標題化合物(4毫克，5%)。 2 - ((3-chlorophenyl) amino) - N - (methoxymethyl) -5,6,7,8-tetrahydro quinazoline-6-acyl-amine (0.08 g, 0.23 mmol A solution of the THF in THF (2 mL) was added dropwise to a solution of isopropylmagnesium chloride (1.0 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The title compound (4 mg, 5%) was obtained as a colorless solid.

¹H NMR(CDCl₃),δ_H,1.15(d,6H),1.72-1.93(m,1H),2.07-2.24(m,1H),2.67-3.05(m,6H),6.96(d,1H),7.21(t,1H),7.37(d,1H),7.85(s,1H),8.17(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.15 (d, 6H), 1.72-1.93 (m, 1H), 2.07-2.24 (m, 1H), 2.67-3.05 (m, 6H), 6.96 (d, 1H) ), 7.21 (t, 1H), 7.37 (d, 1H), 7.85 (s, 1H), 8.17 (s, 1H).

LC/MS(M+H)⁺=329,331 LC/MS(M+H) ⁺ =329,331

實例38 Example 38 2-(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)煙腈2-(2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)nicotinonitrile

根據密切類似於實例27中所述之步驟，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與2-溴基煙腈起反應，即得米黃色固狀之標題化合物(39%)。 According to the procedure closely described in Example 27 , N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and 2- The brominated nicotinonitrile was reacted to give the title compound (39%).

¹H NMR(CDCl₃),δ_H,3.04(t,2H),3.99(t,2H),4.68(s,2H),6.74(dd,1H),6.91(dd,1H),7.10(s,1H),7.15(t,1H),7.32(dd,1H),7.74-7.78(m,2H),8.20(s,1H),8.31(dd,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 3.04 (t, 2H), 3.99 (t, 2H), 4.68 (s, 2H), 6.74 (dd, 1H), 6.91 (dd, 1H), 7.10 (s, 1H), 7.15 (t, 1H), 7.32 (dd, 1H), 7.74-7.78 (m, 2H), 8.20 (s, 1H), 8.31 (dd, 1H).

LC/MS(M+H)⁺=363,365 LC/MS(M+H) ⁺ =363,365

實例39Example 39 (2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(吡咯烷-1-基)甲酮(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)(pyrrolidin-1-yl)methanone

根據一般步驟2a，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與吡咯烷-1-羰基氯起反應，即得固狀之標題化合物(22%)。 According to general procedure 2a, N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine is reacted with pyrrolidine-1-carbonyl chloride The title compound (22%) was obtained as a solid.

¹H NMR(CDCl₃),δ_H,1.83-1.90(m,4H),2.92(t,2H),3.93-3.46(m,4H),3.57(t,2H),4.35(s,2H),6.97(d,1H),7.08-7.28(m,2H),7.38(d,1H),7.85(s,1H),8.19(s1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.83-1.90 (m, 4H), 2.92 (t, 2H), 3.93-3.46 (m, 4H), 3.57 (t, 2H), 4.35 (s, 2H), 6.97 (d, 1H), 7.08-7.28 (m, 2H), 7.38 (d, 1H), 7.85 (s, 1H), 8.19 (s1H).

LC/MS(M+H)⁺=357,359 LC/MS(M+H) ⁺ =357,359

實例40 Example 40 2-((3-氰苯基)胺基)-N,N-二異丙基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺2-((3-Cyanophenyl)amino) -N , N -diisopropyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxamide

根據一般步驟2a，令3-((5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈與二異丙基胺基甲醯氯起反應，即得無色固狀之標題化合物(37%)。 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile and diisopropylaminocarbamidine according to general procedure 2a The title compound (37%) was obtained as a colorless solid.

¹H NMR(CDCl₃),δ_H,1.30(d,12H),2.92(t,2H),3.41(t,2H),3.69(m,2H),4.17(s,2H),7.28-7.41(m,3H),7.63(d,1H),8.17(s,1H),8.26(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.30 (d, 12H), 2.92 (t, 2H), 3.41 (t, 2H), 3.69 (m, 2H), 4.17 (s, 2H), 7.28-7.41 ( m, 3H), 7.63 (d, 1H), 8.17 (s, 1H), 8.26 (s, 1H).

LC/MS(M+H)⁺=379 LC/MS (M+H) ⁺ =379

實例41 Example 41 3-((6-(2-甲氧基-2-甲基丙醯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈3-((6-(2-Methoxy-2-methylpropenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino) Benzoonitrile

根據一般步驟2b，令3-((5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈與2-甲氧基-2-甲基丙酸起反應，即得淡黃色固狀之標題化合物(42毫克，8%)。 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile and 2-methoxy-2-, according to general procedure 2b The title compound (42 mg, 8%) was obtained as a pale yellow solid.

¹H NMR(CDCl₃),δ_H,1.48(s,6H),2.93(t,2H),3.23 (s,3H),3.86-4.39(br d,2H),4.60-5.15(br d,2H),7.16(s,1H),7.28(d,1H),7.39(dd,1H),7.65-7.70(m,1H),8.22(s,1H),8.25(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.48 (s, 6H), 2.93 (t, 2H), 3.23 (s, 3H), 3.86-4.39 (brd, 2H), 4.60-5.15 (brd, 2H) ), 7.16 (s, 1H), 7.28 (d, 1H), 7.39 (dd, 1H), 7.65-7.70 (m, 1H), 8.22 (s, 1H), 8.25 (s, 1H).

LC/MS(M+H)⁺=352,248 LC/MS(M+H) ⁺ =352,248

實例42 Example 42 3-((6-(嗎啉-4-羰基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈3-((6-(morpholine-4-carbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile

根據一般步驟2a，令3-((5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈與嗎啉-4-羰基氯起反應，即得無色固狀之標題化合物(4%)。 According to general procedure 2a, 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile and morpholine-4-carbonyl chloride The title compound (4%) was obtained.

¹H NMR(CDCl₃),δ_H,2.96(t,2H),3.19-3.34(m,4H),3.55(t,2H),3.72(m,4H),4.36(s,2H),7.19-7.43(m,3H),7.63(d,1H),8.22-8.26(m,2H)。 ¹ H NMR (CDCl ₃ ), δ _H , 2.96 (t, 2H), 3.19-3.34 (m, 4H), 3.55 (t, 2H), 3.72 (m, 4H), 4.36 (s, 2H), 7.19- 7.43 (m, 3H), 7.63 (d, 1H), 8.22-8.26 (m, 2H).

LC/MS(M+H)⁺=365 LC/MS(M+H) ⁺ =365

實例43 Example 43 N-(3-氯苯基)-6-(嘧啶-2-基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺 N- (3-chlorophenyl)-6-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine

根據密切類似於實例27中所述之步驟，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與2-溴基嘧啶起反應，即得固狀之標題化合物(62%)。 According to the procedure closely described in Example 27 , N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and 2- The bromopyrimidine reacted to give the title compound (62%).

¹H NMR(CDCl₃),δ_H,2.96(t,2H),4.17(t,2H),4.86(s,2H),6.57(t,1H),6.97(dd,1H),7.07(s,1H),7.23 9t, 1H),7.40(dd,1H),7.85(t,1H),8.28(s,1H),8.37(d,2H)。 _{^{1 H NMR (CDCl 3),}} δ H, 2.96 (t, 2H), 4.17 (t, 2H), 4.86 (s, 2H), 6.57 (t, 1H), 6.97 (dd, 1H), 7.07 (s, 1H), 7.23 9t, 1H), 7.40 (dd, 1H), 7.85 (t, 1H), 8.28 (s, 1H), 8.37 (d, 2H).

LC/MS(M+H)⁺=338,340 LC/MS(M+H) ⁺ =338,340

實例44Example 44 (2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(呋喃-2-基)甲酮(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)(furan-2-yl)methanone

根據一般步驟2a，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與呋喃-2-羰基氯起反應，即得固狀之標題化合物(43%)。 According to the general procedure 2a, N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine is reacted with furan-2-carbonyl chloride. The title compound (43%) was obtained as a solid.

¹H NMR(CDCl₃),δ_H,2.99(t,2H),4.07(t,2H),4.83(s,2H),6.52(dd,1H),6.98(d,1H),7.10(d,1H),7.22(t,1H),7.39(dd,1H),7.54(s,1H),7.84(dd,1H),8.23(s,1H)。 _{^{1 H NMR (CDCl 3),}} δ H, 2.99 (t, 2H), 4.07 (t, 2H), 4.83 (s, 2H), 6.52 (dd, 1H), 6.98 (d, 1H), 7.10 (d, 1H), 7.22 (t, 1H), 7.39 (dd, 1H), 7.54 (s, 1H), 7.84 (dd, 1H), 8.23 (s, 1H).

LC/MS(M+H)⁺=354,356 LC/MS(M+H) ⁺ =354,356

實例45Example 45 (2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(噻唑-2-基)甲酮(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)(thiazol-2-yl)methanone

根據一般步驟2a，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與噻唑-2-羰基氯起反應，即得固狀之標題化合物(41%)。 According to the general procedure 2a, N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine is reacted with thiazole-2-carbonyl chloride. The title compound (41%) was obtained as a solid.

¹H NMR(CDCl₃),δ_H,3.02(t,2H),4.10(t,2H),4.84(s,2H),6.98(d,1H),7.18-7.23(m,2H),7.39(d,1H), 7.58(d,1H),7.85(s,1H),7.94(d,1H),8.26(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 3.02 (t, 2H), 4.10 (t, 2H), 4.84 (s, 2H), 6.98 (d, 1H), 7.18-7.23 (m, 2H), 7.39 ( d, 1H), 7.58 (d, 1H), 7.85 (s, 1H), 7.94 (d, 1H), 8.26 (s, 1H).

LC/MS(M+H)⁺=371,373 LC/MS (M+H) ⁺ = 371,373

實例46Example 46 (2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(噻唑-5-基)甲酮(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)(thiazol-5-yl)methanone

根據一般步驟2a，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與噻唑-5-羰基氯起反應，即得固狀之標題化合物(55%)。 According to the general procedure 2a, N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine is reacted with thiazole-5-carbonyl chloride. The title compound (55%) was obtained as a solid.

¹H NMR(CDCl₃),δ_H,3.00(t,2H),4.01(t,2H),4.80(s,2H),6.99(d,1H),7.21-7.23(m,2H),7.40(d,1H),7.83(s,1H),8.16(s,1H),8.23(s,1H),8.93(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 3.00 (t, 2H), 4.01 (t, 2H), 4.80 (s, 2H), 6.99 (d, 1H), 7.21 - 7.23 (m, 2H), 7.40 ( d, 1H), 7.83 (s, 1H), 8.16 (s, 1H), 8.23 (s, 1H), 8.93 (s, 1H).

LC/MS(M+H)⁺=371,373 LC/MS (M+H) ⁺ = 371,373

實例47 Example 47 2-((5-氯基吡啶-3-基)胺基)-N,N-二甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺2-((5-Chloropyridin-3-yl)amino) -N , N -dimethyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )- Guanamine

根據一般步驟3，令N,N-二甲基-2-(甲磺醯基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺與3-胺基-5-氯基吡啶起反應，以甲苯/甲醇碾磨後，即得棕色油狀之標題化合物(96毫克，81%)。 According to general procedure 3, let N,N -dimethyl-2-(methylsulfonyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxamide and The title compound (96 mg, 81%) was obtained as a brown oil.

¹H NMR(CDCl₃),δ_H,2.93(s,6H),3.09(t,2H),3.58(t,2H),4.36(s,2H),8.30(s,1H),8.33-8.36(m,1H),9.02(d,1H),10.39(br s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 2.93 (s, 6H), 3.09 (t, 2H), 3.58 (t, 2H), 4.36 (s, 2H), 8.30 (s, 1H), 8.33 - 8.36 ( m, 1H), 9.02 (d, 1H), 10.39 (br s, 1H).

LC/MS(M+H)⁺=333,335 LC/MS(M+H) ⁺ =333,335

實例48 Example 48 N-(3-氯苯基)-6-(1-甲基-1H-四唑-5-基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺 N- (3-chlorophenyl)-6-(1-methyl-1 H -tetrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine- 2-amine

根據密切類似於實例28中所提供之步驟，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與異硫氰酸甲酯起反應以得中間體硫脲，將其以疊氮化鈉及氯化汞處理，即得固狀之標題化合物(43%) According to the procedure closely provided in Example 28 , N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and isosulfur Methyl cyanate is reacted to give the intermediate thiourea, which is treated with sodium azide and mercuric chloride to give the title compound (43%).

¹H NMR(DMSO-d₆),δ_H,2.96(t,2H),3.66(t,2H),3.95(s,3H),4.51(s,2H),6.93(d,1H),7.26(t,1H),7.62(d,1H),7.97(s,1H),8.38(s,1H),9.81(s,1H)。 ¹ H NMR (DMSO-d ₆ ), δ _H , 2.96 (t, 2H), 3.66 (t, 2H), 3.95 (s, 3H), 4.51 (s, 2H), 6.93 (d, 1H), 7.26 ( t, 1H), 7.62 (d, 1H), 7.97 (s, 1H), 8.38 (s, 1H), 9.81 (s, 1H).

LC/MS(M+H)⁺=342,344 LC/MS(M+H) ⁺ =342,344

實例49 Example 49 N-(3-氯苯基)-6-(1-甲基-1H-咪唑-2-基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺 N- (3-chlorophenyl)-6-(1-methyl-1 H -imidazol-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2 -amine

根據密切類似於實例28中所提供之步驟，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與異硫氰酸甲酯起反應以得中間體2-((3-氯苯基)胺基)-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-硫代甲醯胺。令此中間體(0.38毫莫耳，128毫克)溶於2.5毫升無水N,N-二甲基甲醯胺中，再將甲基碘(0.96毫莫耳，136毫克)之0.8毫升無水N,N-二甲基甲醯胺溶液加入。將混合物於室溫下攪 拌過夜，然後將溶劑蒸發，以得2-((3-氯苯基)胺基)-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-硫代甲亞胺酸甲酯，其係用於下一步驟中而不必進一步純化。 According to the procedure closely provided in Example 28 , N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and isosulfur Methyl cyanate is reacted to give the intermediate 2-((3-chlorophenyl)amino) -N -methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6 (5 H ) - thioformamide. This intermediate (0.38 mmol, 128 mg) was dissolved in 2.5 mL of anhydrous N,N -dimethylformamide, then methyl iodide (0.96 mmol, 136 mg) . A solution of N -dimethylformamide was added. The mixture was stirred at room temperature overnight, then the solvent was evaporated to give 2-((3-chlorophenyl)amino) -N -methyl-7,8-dihydropyrido[4,3-d] Pyrimidine-6( 5H )-thiomethylimidate methyl ester was used in the next step without further purification.

令2-((3-氯苯基)胺基)-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-硫代甲亞胺酸甲酯(0.30毫莫耳，104毫克)溶於2毫升吡啶中，再將2,2-二甲氧基乙胺(0.33毫莫耳，34毫克)加入。將混合物加熱至100℃ 3小時，然後於室溫下攪拌過夜。將溶劑蒸發，將2毫升2N水性鹽酸加入，再將溶液迴流2小時。然後將反應混合物以碳酸鉀鹼化，再以二氯甲烷萃取。將有機相於硫酸鈉上乾燥，再將溶劑於減壓下移除。繼而將餘留物藉急驟柱式層析予以純化，即得黃色固狀之標題化合物(55毫克，54%)。 2-((3-Chlorophenyl)amino) -N -methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-thiomethionine The ester (0.30 mmol, 104 mg) was dissolved in 2 mL of pyridine and then 2,2-dimethoxyethylamine (0.33 mmol, 34 mg). The mixture was heated to 100 ° C for 3 hours and then stirred at room temperature overnight. The solvent was evaporated, 2 mL of 2N aqueous hydrochloric acid was added and the solution was refluxed for 2 hr. The reaction mixture was then basified with potassium carbonate and extracted with dichloromethane. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. The title compound (55 mg, 54%)

¹H NMR(CDCl₃),δ_H,3.00(t,2H),3.37(t,2H),3.53(s,3H),4.21(s,2H),6.71(d,1H),6.81(d,1H),6.96(d,1H),7.20(t,1H),7.36-7.40(m,2H),7.85(s,1H),8.17(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 3.00 (t, 2H), 3.37 (t, 2H), 3.53 (s, 3H), 4.21 (s, 2H), 6.71 (d, 1H), 6.81 (d, 1H), 6.96 (d, 1H), 7.20 (t, 1H), 7.36-7.40 (m, 2H), 7.85 (s, 1H), 8.17 (s, 1H).

LC/MS(M+H)⁺=340,342 LC/MS(M+H) ⁺ =340,342

實例50 Example 50 3-((6-(2-乙基丁醯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈3-((6-(2-ethylbutylidene)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile

根據一般步驟2a，令3-((5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈與2-乙基丁醯氯起反應，即得無色固狀之標題化合物(43%)。 According to general procedure 2a, 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile and 2-ethylbutylphosphonium chloride The title compound (43%) was obtained.

¹H NMR(CDCl₃),δ_H,0.77-1.00(m,6H),1.46-1.78(m,4H),2.60(m,1H),2.84-2.95(m,2H),3.84-3.99(m,2H),4.66和4.73(both s,2H),7.29(s,1H),7.38(t,1H),7.66(d,1H),7.79(s,1H),8.24(s,1H),8.25(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 0.77-1.00 (m, 6H), 1.46-1.78 (m, 4H), 2.60 (m, 1H), 2.84-2.95 (m, 2H), 3.84-3.99 (m , 2H), 4.66 and 4.73 (both s, 2H), 7.29 (s, 1H), 7.38 (t, 1H), 7.66 (d, 1H), 7.79 (s, 1H), 8.24 (s, 1H), 8.25 (s, 1H).

LC/MS(M+H)⁺=350 LC/MS (M+H) ⁺ =350

實例51 Example 51 N-丁基-(2-((3-氰苯基)胺基)-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺 N -butyl-(2-((3-cyanophenyl)amino) -N -methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )- formazan amine

根據一般步驟2a，令3-((5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈與丁基(甲基)胺基甲醯氯起反應，即得無色固狀之標題化合物(14%)。 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile and butyl(methyl)amine group according to general procedure 2a The reaction of formazan chloride gave the title compound (14%) as a colorless solid.

¹H NMR(CDCl₃),δ_H,0.92(t,3H),1.30(m,2H),1.54(m,2H),2.89(s,3H),2.94(t,2H),3.22(t,2H),3.51(t,2H),4.29(s,2H),7.29(s,1H),7.38(t,1H),7.66(d,1H),8.21(s,1H),8.25(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 0.92 (t, 3H), 1.30 (m, 2H), 1.54 (m, 2H), 2.89 (s, 3H), 2.94 (t, 2H), 3.22 (t, 2H), 3.51 (t, 2H), 4.29 (s, 2H), 7.29 (s, 1H), 7.38 (t, 1H), 7.66 (d, 1H), 8.21 (s, 1H), 8.25 (s, 1H) ).

LC/MS(M+H)⁺=365 LC/MS(M+H) ⁺ =365

實例52 Example 52 2-((3-氰苯基)胺基)-N-環丙基-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺2-((3-Cyanophenyl)amino) -N -cyclopropyl- N -methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )- formazan amine

根據一般步驟2a，令3-((5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈與環丙基(甲基)胺基甲醯氯起反 應，即得無色固狀之標題化合物(12%)。 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile and cyclopropyl(methyl)amine according to general procedure 2a Base methyl chloride The title compound (12%) was obtained as a colorless solid.

¹H NMR(CDCl₃),δ_H,0.64(m,2H),0.76(m,2H),2.70(m,1H),2.89(s,3H),2.94(t,2H)3.64(t,2H),4.42(s,2H),7.29-7.42(m,3H),7.64(d,1H),8.21(s,1H),8.26(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 0.64 (m, 2H), 0.76 (m, 2H), 2.70 (m, 1H), 2.89 (s, 3H), 2.94 (t, 2H) 3.64 (t, 2H) ), 4.42 (s, 2H), 7.29-7.42 (m, 3H), 7.64 (d, 1H), 8.21 (s, 1H), 8.26 (s, 1H).

LC/MS(M+H)⁺=349 LC/MS(M+H) ⁺ =349

實例53 Example 53 2-((3-氯苯基)胺基)-N-乙基-N-丙基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺2-((3-Chlorophenyl)amino) -N -ethyl- N -propyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxamide

根據一般步驟2a，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與丙基(乙基)胺基甲醯氯起反應，即得固狀之標題化合物(22%)。 According to general procedure 2a, N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and propyl(ethyl)aminol The title compound (22%) was obtained as a solid.

¹H NMR(CDCl₃),δ_H,0.89(t,3H),1.14(t,3H),1.57(m,2H),2.92(t,2H),3.12-3.32(m,4H),3.50(t,2H),4.26(s,2H),6.97(d,1H),7.05-7.22(m,2H),7.38(d,1H),7.85(s,1H),8.19(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 0.89 (t, 3H), 1.14 (t, 3H), 1.57 (m, 2H), 2.92 (t, 2H), 3.12-3.32 (m, 4H), 3.50 ( t, 2H), 4.26 (s, 2H), 6.97 (d, 1H), 7.05-7.22 (m, 2H), 7.38 (d, 1H), 7.85 (s, 1H), 8.19 (s, 1H).

LC/MS(M+H)⁺=373,375 LC/MS (M+H) ⁺ = 373,375

實例54 Example 54 N,N-二甲基-2-((6-甲基吡啶-2-基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺 N , N -Dimethyl-2-((6-methylpyridin-2-yl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )- Guanamine

根據一般步驟3，令N,N二甲基-2-(甲磺醯基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺與6-甲基吡啶-2-胺起 反應，即得黃色固狀之標題化合物(35毫克，21%)。 According to general procedure 3, let N,N dimethyl-2-(methylsulfonyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxamide and 6 The title compound (35 mg, 21%) was obtained as a yellow solid.

¹H NMR(CDCl₃),δ_H,2.46(s,3H),2.90(s,6H),2.95(t,2H),3.54(t,2H),4.32(s,2H),6.78(d,1H),7.75(t,1H),7.75(br s,1H),8.19(d,1H),8.22(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 2.46 (s, 3H), 2.90 (s, 6H), 2.95 (t, 2H), 3.54 (t, 2H), 4.32 (s, 2H), 6.78 (d, 1H), 7.75 (t, 1H), 7.75 (br s, 1H), 8.19 (d, 1H), 8.22 (s, 1H).

LC/MS(M+H)⁺=313 LC/MS (M+H) ⁺ =313

實例55Example 55 (消旋)-3-((6-(2-乙基吡咯烷-1-羰基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈(racemic)-3-((6-(2-ethylpyrrolidin-1-carbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amine Benzocarbonitrile

根據一般步驟2a，令3-((5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈與2-乙基吡咯烷-1-羰基氯起反應，即得無色固狀之標題化合物(45%)。 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile and 2-ethylpyrrolidine-1 according to general procedure 2a - The carbonyl chloride was reacted to give the title compound (45%).

¹H NMR(CDCl₃),δ_H,0.85(t,3H),1.25-1.85(m,5H),2.10(m,1H),2.74-3.11(m,2H),3.38-3.43(m,3H),3.76-3.85(m,2H),4.35(s,2H),7.29-7.42(m,3H),7.64(d,1H),8.21(s,1H),8.26(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 0.85 (t, 3H), 1.25-1.85 (m, 5H), 2.10 (m, 1H), 2.74-3.11 (m, 2H), 3.38-3.43 (m, 3H) ), 3.76-3.85 (m, 2H), 4.35 (s, 2H), 7.29-7.42 (m, 3H), 7.64 (d, 1H), 8.21 (s, 1H), 8.26 (s, 1H).

LC/MS(M+H)⁺=377 LC/MS (M+H) ⁺ =377

實例56 Example 56 N-(氰甲基)-2-((3-氰苯基)胺基)-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺 N- (cyanomethyl)-2-((3-cyanophenyl)amino) -N -methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6( 5H )- Formamide

根據一般步驟2a，令3-((5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈與(氰甲基)(甲基)胺基甲醯氯起反應，即得無色固狀之標題化合物(6%)。 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile and (cyanomethyl)(methyl) according to general procedure 2a The aminoguanidinium chloride is reacted to give the title compound (6%) as a colorless solid.

¹H NMR(CDCl₃),δ_H,2.96(t,2H),3.06(s,3H),3.63(t,2H),4.07(s,2H),4.41(s,2H),7.23-7.35(m,2H),7.40(t,1H),7.62(d,1H),8.22(s,1H),8.25(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 2.96 (t, 2H), 3.06 (s, 3H), 3.63 (t, 2H), 4.07 (s, 2H), 4.41 (s, 2H), 7.23-7.35 ( m, 2H), 7.40 (t, 1H), 7.62 (d, 1H), 8.22 (s, 1H), 8.25 (s, 1H).

LC/MS(M+H)⁺=348 LC/MS (M+H) ⁺ =348

實例57 Example 57 3-((6-(1-甲基環丙烷羰基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈3-((6-(1-methylcyclopropanecarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile

根據一般步驟2b，令3-((5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈與1-甲基環丙烷羧酸起反應，即得米黃色固狀之標題化合物(162毫克，32%)。 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile and 1-methylcyclopropanecarboxylic acid according to general procedure 2b The title compound (162 mg, 32%) was obtained.

¹H NMR(CDCl₃),δ_H,0.63-0.68(m,2H),0.97-1.02(m,2H),1.37(s,3H),2.93(t,2H),3.98(t,2H),4.70(s,2H),7.19(s,1H),7.29(d,1H),7.39(dd,1H),7.64-7.69(m,1H),8.23(s,1H),8.25(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 0.63-0.68 (m, 2H), 0.97-1.02 (m, 2H), 1.37 (s, 3H), 2.93 (t, 2H), 3.98 (t, 2H), 4.70 (s, 2H), 7.19 (s, 1H), 7.29 (d, 1H), 7.39 (dd, 1H), 7.64-7.69 (m, 1H), 8.23 (s, 1H), 8.25 (s, 1H) .

LC/MS(M+H)⁺=334,248 LC/MS(M+H) ⁺ =334,248

實例58 Example 58 3-((6-(2-甲基環丙烷羰基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈3-((6-(2-methylcyclopropanecarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile

根據一般步驟2b，令3-((5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈與2-甲基環丙烷羧酸起反應，即得白色固狀之標題化合物(57毫克，11%)(順式與反式異構體之混合物，約1：3)。 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile and 2-methylcyclopropanecarboxylic acid according to general procedure 2b The title compound (57 mg, 11%) (yield of cis and trans isomers, about 1:3) was obtained as a white solid.

¹H NMR(CDCl₃),δ_H,0.63-1.85(m,4H),1.17(d,3H),2.94(s,2H)3.85-4.24(m,2H),4.61-4.87(m,2H),7.18(s,1H),7.29(d,1H),7.39(dd,1H),7.66(d,1H),8.23(s,1H),8.25(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 0.63-1.85 (m, 4H), 1.17 (d, 3H), 2.94 (s, 2H) 3.85-4.24 (m, 2H), 4.61-4.87 (m, 2H) , 7.18 (s, 1H), 7.29 (d, 1H), 7.39 (dd, 1H), 7.66 (d, 1H), 8.23 (s, 1H), 8.25 (s, 1H).

LC/MS(M+H)⁺=334,248 LC/MS(M+H) ⁺ =334,248

實例59 Example 59 2,2,-二甲基-1-(2-((6-甲基吡啶-2-基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)丙-1-酮2,2,-Dimethyl-1-(2-((6-methylpyridin-2-yl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6 (5 H )-yl)propan-1-one

根據一般步驟3，令2,2-二甲基-1-(2-(甲磺醯基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)丙-1-酮與6-甲基吡啶-2-胺起反應，即得標題化合物(15毫克，9%)。 According to general procedure 3, 2,2-dimethyl-1-(2-(methylsulfonyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl The propan-1-one was reacted with 6-methylpyridin-2-amine to give the title compound (15 mg, 9%).

¹H NMR(CDCl₃),δ_H,1.33(s,9H),2.46(s,3H),2.92(t,2H),3.94(t,2H),4.68(s,2H),6.79(d,1H),7.58(t,1H),7.73(br s,1H),8.18(d,1H),8.24(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.33 (s, 9H), 2.46 (s, 3H), 2.92 (t, 2H), 3.94 (t, 2H), 4.68 (s, 2H), 6.79 (d, 1H), 7.58 (t, 1H), 7.73 (br s, 1H), 8.18 (d, 1H), 8.24 (s, 1H).

LC/MS(M+H)⁺=326 LC/MS (M+H) ⁺ =326

實例60 Example 60 3-((6-(2-羥基-2-甲基丙醯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈3-((6-(2-hydroxy-2-methylpropenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzamide Nitrile

根據一般步驟2b，令3-((5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈與2-羥基-2-甲基丙酸起反應，即得米黃色固狀之標題化合物(32毫克，3%)。 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile and 2-hydroxy-2-methyl according to general procedure 2b The title compound (32 mg, 3%) was obtained as a beige solid.

¹H NMR(CDCl₃),δ_H,1.55(s,6H),2.94(t,2H),3.61 (s,1H),4.02(t,2H),4.78(s,2H),7.19(s,1H),7.29(d,1H),7.39(dd,1H),7.64-7.69(m,1H),8.21(s,1H),8.24(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.55 (s, 6H), 2.94 (t, 2H), 3.61 (s, 1H), 4.02 (t, 2H), 4.78 (s, 2H), 7.19 (s, 1H), 7.29 (d, 1H), 7.39 (dd, 1H), 7.64-7.69 (m, 1H), 8.21 (s, 1H), 8.24 (s, 1H).

LC/MS(M+H)⁺=338 LC/MS (M+H) ⁺ =338

實例61 Example 61 N,N-二乙基-2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺 N , N -diethyl-2-(meta-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-formamide

根據一般步驟2a，令N-(間位-甲苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與二乙基胺基甲醯氯起反應，即得無色固狀之標題化合物(66%)。 According to general procedure 2a, let N- (meta-tolyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and diethylaminocarbazine The title compound (66%) was obtained.

¹H NMR(CDCl₃),δ_H,1.15(t,6H),2.34(s,3H),2.89(t,2H),3.25(q,4H),3.48(t,2H),4.25(s,2H),6.83(d,1H),7.16-7.25(m,2H),7.38(s,1H),7.44(d,1H),8.15(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.15 (t, 6H), 2.34 (s, 3H), 2.89 (t, 2H), 3.25 (q, 4H), 3.48 (t, 2H), 4.25 (s, 2H), 6.83 (d, 1H), 7.16-7.25 (m, 2H), 7.38 (s, 1H), 7.44 (d, 1H), 8.15 (s, 1H).

LC/MS(M+H)⁺=340 LC/MS (M+H) ⁺ =340

實例62 Example 62 2-((3-氰苯基)胺基)-N-異丙基-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺2-((3-Cyanophenyl)amino) -N -isopropyl- N -methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )- formazan amine

根據一般步驟2a，令3-((5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈與異丙基(甲基)胺基甲醯氯起反應，即得無色固狀之標題化合物(50%)。 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile and isopropyl(methyl)amine according to general procedure 2a The title compound (50%) was obtained as a colorless solid.

¹H NMR(CDCl₃),δ_H,1.17(d,6H),2.77(s,3H),2.95 (t,2H),3.51(t,2H),4.12(m,1H),4.28(s,2H),7.18(s,1H),7.28(d,1H),7.38(t,1H),7.63(d,1H),8.21(s,1H),8.26(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.17 (d, 6H), 2.77 (s, 3H), 2.95 (t, 2H), 3.51 (t, 2H), 4.12 (m, 1H), 4.28 (s, 2H), 7.18 (s, 1H), 7.28 (d, 1H), 7.38 (t, 1H), 7.63 (d, 1H), 8.21 (s, 1H), 8.26 (s, 1H).

LC/MS(M+H)⁺=351 LC/MS(M+H) ⁺ =351

實例63 Example 63 2-((3-氰苯基)胺基)-N-乙基-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺2-((3-Cyanophenyl)amino) -N -ethyl- N -methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxamide

根據一般步驟2a，令3-((5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈與乙基(甲基)胺基甲醯氯起反應，即得無色固狀之標題化合物(28%)。 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile and ethyl(methyl)amino group according to general procedure 2a The reaction of formazan chloride gave the title compound (28%) as a colorless solid.

¹H NMR(CDCl₃),δ_H,1.18(t,3H),2.94(s,3H),2.97(t,2H),3.27(q,2H),3.52(t,2H),4.30(s,2H),7.20(s,1H),7.32(d,1H),7.40(t,1H),7.63(d,1H),8.21(s,1H),8.26(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.18 (t, 3H), 2.94 (s, 3H), 2.97 (t, 2H), 3.27 (q, 2H), 3.52 (t, 2H), 4.30 (s, 2H), 7.20 (s, 1H), 7.32 (d, 1H), 7.40 (t, 1H), 7.63 (d, 1H), 8.21 (s, 1H), 8.26 (s, 1H).

LC/MS(M+H)⁺=337 LC/MS (M+H) ⁺ =337

實例64 Example 64 2-((3-氯苯基)胺基)-N-(環丙基甲基)-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺2 - ((3-chlorophenyl) amino) - N - (cyclopropylmethyl) - N - methyl-7,8-dihydro-pyrido [4,3-d] pyrimidin -6 (5 H )-Metamine

根據一般步驟2a，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與環丙基甲基(甲基)胺基甲醯氯起反應，即得固狀之標題化合物(8%)。 According to general procedure 2a, N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and cyclopropylmethyl(methyl) The aminoguanidinium chloride is reacted to give the title compound (8%) as a solid.

¹H NMR(CDCl₃),δ_H,0.21(m,2H),0.54(m,2H), 0.97(m,1H),2.94(t,2H),2.97(s,3H),3.11(d,2H),3.53(t,2H),4.29(s,2H),6.98(d,1H),7.05(s,1H),7.22(t,1H),7.38(d,1H),7.84(s,1H),8.19(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 0.21 (m, 2H), 0.54 (m, 2H), 0.97 (m, 1H), 2.94 (t, 2H), 2.97 (s, 3H), 3.11 (d, 2H), 3.53 (t, 2H), 4.29 (s, 2H), 6.98 (d, 1H), 7.05 (s, 1H), 7.22 (t, 1H), 7.38 (d, 1H), 7.84 (s, 1H) ), 8.19 (s, 1H).

LC/MS(M+H)⁺=371,373 LC/MS (M+H) ⁺ = 371,373

實例65 Example 65 N,N-二甲基-2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺 N , N -Dimethyl-2-(meta-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxamide

根據一般步驟2a，令N-(間位-甲苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與二甲基胺基甲醯氯起反應，即得無色固狀之標題化合物(54%)。 According to general procedure 2a, let N- (meta-tolyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and dimethylaminoformamidine The title compound (54%) was obtained.

¹H NMR(CDCl₃),δ_H,2.34(s,3H),2.89(s,6H),2.90(t,3H),3.52(t,2H),4.29(s,2H),6.83(d,1H),7.11(s,1H),7.20(t,1H),7.38(s,1H),7.44(d,1H),8.16(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 2.34 (s, 3H), 2.89 (s, 6H), 2.90 (t, 3H), 3.52 (t, 2H), 4.29 (s, 2H), 6.83 (d, 1H), 7.11 (s, 1H), 7.20 (t, 1H), 7.38 (s, 1H), 7.44 (d, 1H), 8.16 (s, 1H).

LC/MS(M+H)⁺=312 LC/MS (M+H) ⁺ =312

實例66 Example 66 2-((3-氯苯基)胺基)-N-環丙基-N-乙基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺2-((3-Chlorophenyl)amino) -N -cyclopropyl- N -ethyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )- formazan amine

根據一般步驟2a，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與環丙基(乙基)胺基甲醯氯起反應，即得固狀之標題化合物(7%)。 According to general procedure 2a, N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and cyclopropyl(ethyl)amino group The reaction of formazan chloride gives the title compound (7%) as a solid.

¹H NMR(CDCl₃),δ_H,0.64(m,2H),0.77(m,2H), 1.19(t,3H),2.93(m,1H),3.15(t,2H)3.34(t,2H),3.64(t,2H),4.42(s,2H),6.98(d,1H),7.08(s,1H),7.22(t,1H),7.38(d,1H),7.85(s,1H),8.23(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 0.64 (m, 2H), 0.77 (m, 2H), 1.19 (t, 3H), 2.93 (m, 1H), 3.15 (t, 2H) 3.34 (t, 2H) ), 3.64 (t, 2H), 4.42 (s, 2H), 6.98 (d, 1H), 7.08 (s, 1H), 7.22 (t, 1H), 7.38 (d, 1H), 7.85 (s, 1H) , 8.23 (s, 1H).

LC/MS(M+H)⁺=371,373 LC/MS (M+H) ⁺ = 371,373

實例67Example 67 吡咯烷-1-基(2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)甲酮Pyrrolidin-1-yl (2-(meta-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)methanone

根據一般步驟2a，令N-(間位-甲苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與吡咯烷-1-羰基氯起反應，即得無色固狀之標題化合物(53%)。 According to general procedure 2a, N- (meta-tolyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine is reacted with pyrrolidine-1-carbonyl chloride The title compound (53%) was obtained as a colorless solid.

¹H NMR(CDCl₃),δ_H,1.85(m,4H),2.34(s,3H),2.89(t,2H),3.43(m,4H),3.56(t,2H),4.33(s,2H),6.83(d,1H),7.16-7.24(m,2H),7.37(s,1H),7.44(d,1H),8.15(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.85 (m, 4H), 2.34 (s, 3H), 2.89 (t, 2H), 3.43 (m, 4H), 3.56 (t, 2H), 4.33 (s, 2H), 6.83 (d, 1H), 7.16-7.24 (m, 2H), 7.37 (s, 1H), 7.44 (d, 1H), 8.15 (s, 1H).

LC/MS(M+H)⁺=338 LC/MS (M+H) ⁺ =338

實例68Example 68 (2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(1-甲基環丙基)甲酮(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)(1-methylcyclopropyl) A ketone

根據一般步驟2b，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與1-甲基環丙烷羧酸起反應，即得米黃色固狀之標題化合物(243毫克，16%)。 According to general procedure 2b, let N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and 1-methylcyclopropanecarboxylic acid The title compound (243 mg, 16%) was obtained.

¹H NMR(CDCl₃),δ_H,0.64(t,2H),0.99(t,2H),1.37 (s,3H),2.91(t,2H),3.96(t,2H),4.68(s,2H),6.99(d,1H),7.08(s,1H),7.22(dd,1H),7.39(d,1H),7.84(s,1H),8.23(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 0.64 (t, 2H), 0.99 (t, 2H), 1.37 (s, 3H), 2.91 (t, 2H), 3.96 (t, 2H), 4.68 (s, 2H), 6.99 (d, 1H), 7.08 (s, 1H), 7.22 (dd, 1H), 7.39 (d, 1H), 7.84 (s, 1H), 8.23 (s, 1H).

LC/MS(M+H)⁺=345,343,259,257 LC/MS (M+H) ⁺ =345,343,259,257

實例69Example 69 (1-甲基環丙基)(2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)甲酮(1-methylcyclopropyl)(2-(meta-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)methanone

根據一般步驟2b，令N-(間位-甲苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與1-甲基環丙烷羧酸起反應，即得米黃色固狀之標題化合物(72毫克，15%)。 According to general procedure 2b, let N- (meta-tolyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and 1-methylcyclopropanecarboxylic acid The title compound (72 mg, 15%) was obtained.

¹H NMR(CDCl₃),δ_H,0.64(t,2H),0.99(t,2H),1.36(s,3H),2.36(s,3H),2.89(t,2H),3.95(t,2H),4.66(s,2H),6.86(d,1H),7.02(s,1H),7.21(dd,1H),7.39(s,1H),7.45(d,1H),8.20(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 0.64 (t, 2H), 0.99 (t, 2H), 1.36 (s, 3H), 2.36 (s, 3H), 2.89 (t, 2H), 3.95 (t, 2H), 4.66 (s, 2H), 6.86 (d, 1H), 7.02 (s, 1H), 7.21 (dd, 1H), 7.39 (s, 1H), 7.45 (d, 1H), 8.20 (s, 1H) ).

LC/MS(M+H)⁺=323,237 LC/MS(M+H) ⁺ =323,237

實例70 Example 70 N-乙基-N-丙基-2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺 N -ethyl- N -propyl-2-(meta-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-formamide

根據一般步驟2a，令N-(間位-甲苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與丙基(乙基)胺基甲醯氯起反應，即得無色固狀之標題化合物(51%)。 According to general procedure 2a, let N- (meta-tolyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and propyl(ethyl)amino group A The title compound (51%) was obtained as a colorless solid.

¹H NMR(CDCl₃),δ_H,0.88(t,3H),1.14(t,3H),1.57 (m,2H),2.35(s,3H),2.91(t,2H),3.12-3.32(m,4H),3.50(t,2H),4.25(s,2H),6.84(d,1H),7.00(s,1H),7.21(t,1H),7.38(s,1H),7.45(d,1H),8.16(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 0.88 (t, 3H), 1.14 (t, 3H), 1.57 (m, 2H), 2.35 (s, 3H), 2.91 (t, 2H), 3.12-3.32 ( m,4H), 3.50 (t, 2H), 4.25 (s, 2H), 6.84 (d, 1H), 7.00 (s, 1H), 7.21 (t, 1H), 7.38 (s, 1H), 7.45 (d) , 1H), 8.16 (s, 1H).

LC/MS(M+H)⁺=354 LC/MS (M+H) ⁺ =354

實例71Example 71 (消旋)-3-((6-(3-甲基吡咯烷-1-羰基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈(racemic)-3-((6-(3-methylpyrrolidin-1-carbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amine Benzocarbonitrile

根據一般步驟2a，令3-((5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈與3-甲基吡咯烷-1-羰基氯起反應，即得無色固狀之標題化合物(10%)。 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile and 3-methylpyrrolidine-1 according to general procedure 2a - The carbonyl chloride was reacted to give the title compound (10%).

¹H NMR(CDCl₃),δ_H,1.07(d,3H),1.20(m,1H),1.95-2.03(m,1H),2.17-2.30(m,1H),2.88-3.07(m,3H),3.38-3.75(m,5H),4.35(s,2H),7.28(d,1H),7.33(t,1H),7.42(s,1H),7.65(d,1H),8.20(s,1H),8.26(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.07 (d, 3H), 1.20 (m, 1H), 1.95-2.03 (m, 1H), 2.17-2.30 (m, 1H), 2.88-3.07 (m, 3H) ), 3.38-3.75 (m, 5H), 4.35 (s, 2H), 7.28 (d, 1H), 7.33 (t, 1H), 7.42 (s, 1H), 7.65 (d, 1H), 8.20 (s, 1H), 8.26 (s, 1H).

LC/MS(M+H)⁺=363 LC/MS (M+H) ⁺ =363

實例72Example 72 (消旋)-3-((6-(2-甲基吡咯烷-1-羰基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈(racemic)-3-((6-(2-methylpyrrolidin-1-carbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amine Benzocarbonitrile

根據一般步驟2a，令3-((5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈與2-甲基吡咯烷-1-羰基氯起反應，即得無色固狀之標題化合物(18%)。 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile and 2-methylpyrrolidine-1 according to general procedure 2a - The carbonyl chloride was reacted to give the title compound (18%).

¹H NMR(CDCl₃),δ_H,1.20(d,3H),1.42(m,1H), 1.62-1.95(m,2H),2.11(m,1H),2.71-3.13(m,2H),3.30-3.51(m,3H),3.83(m,1H),4.05(m,1H),4.35(s,2H),7.24-7.47(m,3H),7.64(d,1H),8.20(s,1H),8.25(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.20 (d, 3H), 1.42 (m, 1H), 1.62-1.95 (m, 2H), 2.11 (m, 1H), 2.71-3.13 (m, 2H), 3.30-3.51 (m, 3H), 3.83 (m, 1H), 4.05 (m, 1H), 4.35 (s, 2H), 7.24-7.47 (m, 3H), 7.64 (d, 1H), 8.20 (s, 1H), 8.25 (s, 1H).

LC/MS(M+H)⁺=363 LC/MS (M+H) ⁺ =363

實例73 Example 73 3-((6-(3,3-二甲基吖丁啶-1-羰基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈3-((6-(3,3-Dimethylazetidin-1-carbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino Benzoonitrile

根據一般步驟2a，令3-((5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈與3,3-二甲基吖丁啶-1-羰基氯起反應，即得無色固狀之標題化合物(10%)。 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile and 3,3-dimethylhydrazine according to general procedure 2a The title compound (10%) was obtained as a colorless solid.

¹H NMR(CDCl₃),δ_H,1.28(s,6H),2.87(t,2H),3.61(t,2H),3.74(s,4H),4.42(s,2H),7.29-7.42(m,3H),7.64(d,1H),8.20(s,1H),8.25(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.28 (s, 6H), 2.87 (t, 2H), 3.61 (t, 2H), 3.74 (s, 4H), 4.42 (s, 2H), 7.29-7.42 ( m, 3H), 7.64 (d, 1H), 8.20 (s, 1H), 8.25 (s, 1H).

LC/MS(M+H)⁺=363 LC/MS (M+H) ⁺ =363

實例74 Example 74 2-((3-氰苯基)胺基)-N-乙基-N-丙基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺2-((3-Cyanophenyl)amino) -N -ethyl- N -propyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxamide

根據一般步驟2a，令3-((5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈與丙基(乙基)胺基甲醯氯起反應，即得無色固狀之標題化合物(44%)。 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile and propyl(ethyl)amino group according to general procedure 2a The reaction of formazan chloride gave the title compound (44%) as a colorless solid.

¹H NMR(CDCl₃),δ_H,0.89(t,3H),1.15(t,3H),1.57 (m,2H),2.93(t,2H),3.13-3.32(m,4H),3.51(t,2H),4.28(s,2H),7.22-7.42(m,3H),7.63(d,1H),8.20(s,1H),8.26(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 0.89 (t, 3H), 1.15 (t, 3H), 1.57 (m, 2H), 2.93 (t, 2H), 3.13 - 3.32 (m, 4H), 3.51 ( t, 2H), 4.28 (s, 2H), 7.22-7.42 (m, 3H), 7.63 (d, 1H), 8.20 (s, 1H), 8.26 (s, 1H).

LC/MS(M+H)⁺=365 LC/MS(M+H) ⁺ =365

實例75Example 75 (消旋)-1-(2-((3-氯苯基)胺基)-5-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)-2,2-二甲基丙-1-酮(racemic)-1-(2-((3-chlorophenyl)amino)-5-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6( 5H )- Base-2,2-dimethylpropan-1-one

將2-甲基-4-側氧基哌啶-1-羧酸第三丁酯(1.965克，9.21毫莫耳)及N,N-二甲基甲醯胺二甲基縮醛(4.93毫升，4.391克，36.85毫莫耳)之混合物於120℃下攪拌8小時，冷卻至室溫，再於減壓下濃縮。將餘留物以水(10毫升)稀釋，再以乙酸乙酯(40毫升)萃取。將有機相以鹽水清洗，於硫酸鈉上乾燥，於減壓下濃縮，再乾燥以得油狀之3-((二甲胺基)亞甲基)-2-甲基-4-側氧基哌啶-1-羧酸第三丁酯與其區域異構體5-((二甲胺基)亞甲基)-2-甲基-4-側氧基哌啶-1-羧酸第三丁酯之混合物(2.404克，97%)，其係用於下一階段中而不必分離及進一步純化。 2-Methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (1.965 g, 9.21 mmol) and N,N -dimethylformamide dimethyl acetal (4.93 ml) A mixture of 4.391 g, 36.85 mmol was stirred at 120 ° C for 8 hours, cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (10 mL) andEtOAc. The organic phase was washed with brine, dried over sodium sulfate and evaporated. Piperacidine-1-carboxylic acid tert-butyl ester and its regioisomeric 5-((dimethylamino)methylene)-2-methyl-4-oxooxypiperidine-1-carboxylic acid tert-butyl A mixture of esters (2.404 g, 97%) was used in the next stage without isolation and further purification.

令所得混合物(1.320克，4.91毫莫耳)與1-(3-氯苯基)胍硝酸鹽(953毫克，4.10毫莫耳)於碳酸氫鈉(1.032克，12.29毫莫耳)之存在下、於N,N-二甲基甲醯胺中、於120℃下反應3小時，冷卻至室溫，再以水(10毫升)稀釋。將水層傾析，令所得油狀物溶於二氯甲烷中。將所得溶液於硫酸鈉上乾燥，再於減壓下濃縮。繼而將所得餘留 物藉柱式層析(矽膠，乙酸乙酯/己烷，1：5)予以純化，再以***/己烷混合液(1：1)清洗以得不純之2-((3-氯苯基)胺基)-5-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯與2-((3-氯苯基)胺基)-7-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯之混合物(共369毫克)。將母液藉將溶劑蒸發，繼而進行柱式層析(矽膠，乙酸乙酯/己烷，1：5)予以純化後，以得另一批(263毫克)。將該二批結合，再藉製備HPLC(C18，乙腈/水)予以純化，以得白色固狀之不可分離之2-((3-氯苯基)胺基)-5-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯與2-((3-氯苯基)胺基)-7-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯之混合物(595毫克，39%，根據NMR及HPLC測得為1.3：1比)。 The resulting mixture (1.320 g, 4.91 mmol) and 1-(3-chlorophenyl)phosphonium nitrate (953 mg, 4.10 mmol) in the presence of sodium bicarbonate (1.032 g, 12.29 mmol) The reaction was carried out in N,N -dimethylformamide at 120 ° C for 3 hours, cooled to room temperature and diluted with water (10 mL). The aqueous layer was decanted and the obtained oil was dissolved in dichloromethane. The resulting solution was dried over sodium sulfate and evaporated. The residue obtained was purified by column chromatography (silica gel, ethyl acetate/hexane, 1:5), and then washed with diethyl ether/hexane mixture (1:1) to obtain impure 2-(( 3-chlorophenyl)amino)-5-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxylic acid tert-butyl ester with 2-((3) -Chlorophenyl)amino)-7-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6( 5H )-carboxylic acid tert-butyl ester mixture (369 mg total) . The mother liquor was evaporated by evaporation of the solvent, followed by column chromatography (EtOAc, ethyl acetate/hexanes, 1:5) to afford another crop (263 mg). The two batches were combined and purified by preparative HPLC (C18, acetonitrile / water) to afford 2-((3-chlorophenyl)amino)-5-methyl-7 as a white solid. 8-Dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxylic acid tert-butyl ester and 2-((3-chlorophenyl)amino)-7-methyl-7,8 a mixture of dihydropyrido[4,3-d]pyrimidin-6( 5H )-carboxylic acid tert-butyl ester (595 mg, 39%, 1.3:1 ratio, as determined by NMR and HPLC).

將所得混合物(553毫克，1.48毫莫耳)及二烷(2毫升)於鹽酸之二烷溶液(18%，3.0毫升，14.75毫莫耳)中、於迴流下攪拌1小時，冷卻至室溫，再以***(20毫升)稀釋。將所形成之固狀物藉過濾法收集，以丙酮/***(1：1)清洗，再風乾以得白色固狀之N-(3-氯苯基)-5-甲基-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與N-(3-氯苯基)-7-甲基-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺之混合物(496毫克，97%)。 The resulting mixture (553 mg, 1.48 mmol) and two Alkane (2 ml) in hydrochloric acid The mixture was stirred with EtOAc (EtOAc)EtOAc. The solid formed was collected by filtration, washed with acetone/diethyl ether (1:1), and then air dried to give N- (3-chlorophenyl)-5-methyl-5,6 as a white solid. 7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and N- (3-chlorophenyl)-7-methyl-5,6,7,8-tetrahydropyrido[4 , a mixture of 3-d]pyrimidin-2-amine (496 mg, 97%).

將特戊醯氯(0.21毫升，204毫克，1.69毫莫耳)逐滴加至於室溫下之所得混合物(489毫克，1.41毫莫耳)及三乙胺(0.79毫升，569毫克，5.63毫莫耳)之二氯甲烷(10 毫升)溶液中。將反應混合物於室溫下攪拌30分鐘，以二氯甲烷(40毫升)稀釋，以水清洗，於硫酸鈉上乾燥，再於減壓下濃縮。繼而將所得餘留物藉柱式層析(矽膠，乙酸乙酯/己烷，1：2)予以純化，即得標題化合物與其區域異構體1-(2-((3-氯苯基)胺基)-7-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)-2,2-二甲基丙-1-酮(參見實例76)之混合物。 Pentylene chloride (0.21 ml, 204 mg, 1.69 mmol) was added dropwise to the resulting mixture (489 mg, 1.41 mmol) and triethylamine (0.79 mL, 569 mg, 5.63 mmol). Ear) in a solution of dichloromethane (10 ml). The reaction mixture was stirred with EtOAc EtOAc. The residue obtained was purified by column chromatography (EtOAc, EtOAc/hexanes: 1:2) to give the title compound and its res. 1-(2-((3-chlorophenyl) Amino)-7-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)-2,2-dimethylpropan-1-one (see example) 76 ) a mixture.

異構體之分離係藉柱式層析(矽膠，乙酸乙酯/己烷)進行。將每種異構體之組合樣品以***/己烷(1：1)碾磨，以己烷清洗，再風乾，即得白色固狀之標題化合物(207毫克，35%)。 The separation of the isomers was carried out by column chromatography (silica gel, ethyl acetate /hexane). The combined sample of each isomer was triturated with diethyl ether / hexane (1:1).

¹H NMR(CDCl₃),δ_H,1.33(s,9H),1.45(d,3H),2.74-2.82(m,1H),2.90-3.01(m,1H),3.38(t,1H),4.38-4.50(m,1H),5.53-5.63(m,1H),6.99(d,1H),7.08(d,1H),7.23(dd,1H),7.39(d,1H),7.84(s,1H),8.23(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.33 (s, 9H), 1.45 (d, 3H), 2.74-2.82 (m, 1H), 2.90-3.01 (m, 1H), 3.38 (t, 1H), 4.38-4.50 (m, 1H), 5.53-5.63 (m, 1H), 6.99 (d, 1H), 7.08 (d, 1H), 7.23 (dd, 1H), 7.39 (d, 1H), 7.84 (s, 1H), 8.23 (s, 1H).

LC/MS(M+H)⁺=359,361 LC/MS(M+H) ⁺ =359,361

實例76Example 76 (消旋)-1-(2-((3-氯苯基)胺基)-7-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)-2,2-二甲基丙-1-酮(racemic)-1-(2-((3-chlorophenyl)amino)-7-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6( 5H )- Base-2,2-dimethylpropan-1-one

將實例75之合成期間所得之產物混合物純化後，即分離出白色固狀之標題化合物(78毫克，13%)。 The obtained during the synthesis of Example 75 the product was purified mixture, i.e., isolated as a white solid of the title compound (78 mg, 13%).

¹H NMR(CDCl₃),δ_H,1.24(d,3H),1.34(s,9H), 2.63-2.68(two s,1H),3.10-3.15(two d,1H),4.11-4.15(two s,1H),4.98(m,1H),5.16-5.20(two s,1H),6.99(d,1H),7.09(s,1H),7.22(dd,1H),7.39(d,1H),7.85(s,1H),8.23(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.24 (d, 3H), 1.34 (s, 9H), 2.63-2.68 (two s, 1H), 3.10-3.15 (two d, 1H), 4.11-4.15 (two s, 1H), 4.98 (m, 1H), 5.16-5.20 (two s, 1H), 6.99 (d, 1H), 7.09 (s, 1H), 7.22 (dd, 1H), 7.39 (d, 1H), 7.85 (s, 1H), 8.23 (s, 1H).

LC/MS(M+H)⁺=359,361 LC/MS(M+H) ⁺ =359,361

實例77 Example 77 2-((3-氰苯基)胺基)-N,N-雙(2,2,2-三氟乙基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺2-((3-cyanophenyl)amino) -N , N -bis(2,2,2-trifluoroethyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6 (5 H )-methylamine

根據一般步驟2a，令3-((5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈與雙(2,2,2-三氟乙基)胺基甲醯氯起反應，即得無色固狀之標題化合物(6%)。 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile and bis(2,2,2- according to general procedure 2a The title compound (6%) is obtained as a colorless solid.

¹H NMR(CDCl₃),δ_H,2.97(t,2H),3.64(t,2H),3.98(q,4H),4.41(s,2H),7.21(s,1H),7.29(d,1H),7.40(t,1H),7.64(d,1H),8.24(s,2H)。 ¹ H NMR (CDCl ₃ ), δ _H , 2.97 (t, 2H), 3.64 (t, 2H), 3.98 (q, 4H), 4.41 (s, 2H), 7.21. (s, 1H), 7.29 (d, 1H), 7.40 (t, 1H), 7.64 (d, 1H), 8.24 (s, 2H).

LC/MS(M+H)⁺=505 LC/MS (M+H) ⁺ =505

實例78Example 78 吖丁啶-1-基(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)甲酮Azetidin-1-yl (2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)methanone

根據一般步驟2a，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與吖丁啶-1-羰基氯起反應，即得固狀之標題化合物(54%)。 According to general procedure 2a, N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and azetidin-1-carbonyl chloride The title compound (54%) was obtained.

¹H NMR(CDCl₃),δ_H,2.28(m,2H),2.87(t,2H),3.61 (t,2H),4.06(t,2H),4.40(s,2H),6.98(d,1H),7.00(s,1H),718(t,1H),7.39(d,1H),7.84(s,1H),8.19(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 2.28 (m, 2H), 2.87 (t, 2H), 3.61 (t, 2H), 4.06 (t, 2H), 4.40 (s, 2H), 6.98 (d, 1H), 7.00 (s, 1H), 718 (t, 1H), 7.39 (d, 1H), 7.84 (s, 1H), 8.19 (s, 1H).

LC/MS(M+H)⁺=343,345 LC/MS(M+H) ⁺ =343,345

實例79 Example 79 2-(2-((3-氯苯基)胺基)-N-甲基-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-6-甲醯胺基)乙酸甲酯2-(2-((3-chlorophenyl)amino) -N -methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-carboxamido) Methyl acetate

根據一般步驟2a，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與2-((氯羰基)(甲基)胺基)乙酸甲酯起反應，即得固狀之標題化合物(10%)。 According to general procedure 2a, let N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and 2-((chlorocarbonyl)(A) The title compound (10%) was obtained as a solid.

¹H NMR(CDCl₃),δ_H,2.94(t,2H),3.03(s,3H),3.57(t,2H),3.75(s,3H),3.97(s,2H),4.33(s,2H),6.97(d,1H),7.17-7.21(m,2H),7.38(d,1H),7.83(s,1H),8.18(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 2.94 (t, 2H), 3.03 (s, 3H), 3.57 (t, 2H), 3.75 (s, 3H), 3.97 (s, 2H), 4.33 (s, 2H), 6.97 (d, 1H), 7.17-7.21 (m, 2H), 7.38 (d, 1H), 7.83 (s, 1H), 8.18 (s, 1H).

LC/MS(M+H)⁺=389,391 LC/MS(M+H) ⁺ =389,391

實例80 Example 80 N-(2-氰乙基)-2-((3-氰苯基)胺基)-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺 N- (2-cyanoethyl)-2-((3-cyanophenyl)amino) -N -methyl-7,8-dihydropyrido[4,3-d]pyrimidine-6 (5 H )-Metamine

根據一般步驟2a，令3-((5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈與(2-氰乙基)(甲基)胺基甲醯氯起反應，即得無色固狀之標題化合物(28%)。 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile and (2-cyanoethyl) according to general procedure 2a The title compound (28%) was obtained as a colorless solid.

¹H NMR(CDCl₃),δ_H,2.67(m,3H),2.97-3.06(m, 4H),3.43-3.60(m,4H),4.34(s,2H),7.21-7.30(m,2H),7.39(t,1H),7.64(d,1H),8.22(s,2H)。 ¹ H NMR (CDCl ₃ ), δ _H , 2.67 (m, 3H), 2.97-3.06 (m, 4H), 3.43-3.60 (m, 4H), 4.34 (s, 2H), 7.21-7.30 (m, 2H) ), 7.39 (t, 1H), 7.64 (d, 1H), 8.22 (s, 2H).

LC/MS(M+H)⁺=362 LC/MS (M+H) ⁺ =362

實例81 Example 81 2-((3-氰苯基)胺基)-N-(2-甲氧基乙基)-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺2 - ((3-cyanophenyl) amino) - N - (2- methoxyethyl) - N - methyl-7,8-dihydro-pyrido [4,3-d] pyrimidine-6 ( 5 H )-carbamamine

根據一般步驟2a，令3-((5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈與(2-甲氧基乙基)(甲基)胺基甲醯氯起反應，即得無色固狀之標題化合物(53%)。 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile and (2-methoxyethyl) according to general procedure 2a The title compound (53%) was obtained as a colorless solid.

¹H NMR(CDCl₃),δ_H,2.94(t,2H),2.98(s,3H),3.35(s,3H),3.43(t,2H),3.51-3.57(m,4H),4.32(s,2H),7.23(d,1H),7.29(s,1H),7.38(t,1H),7.63(d,1H),8.20(s,1H),8.25(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 2.94 (t, 2H), 2.98 (s, 3H), 3.35 (s, 3H), 3.43 (t, 2H), 3.51-3.57 (m, 4H), 4.32 ( s, 2H), 7.23 (d, 1H), 7.29 (s, 1H), 7.38 (t, 1H), 7.63 (d, 1H), 8.20 (s, 1H), 8.25 (s, 1H).

LC/MS(M+H)⁺=367 LC/MS(M+H) ⁺ =367

實例82 Example 82 2-(2-(對位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)煙腈2-(2-(p-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)nicotinonitrile

根據密切類似於實例27中所述之步驟，令N-(對位-甲苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與2-溴基煙腈起反應，即得無色固狀之標題化合物(24%)。 According to the procedure closely described in Example 27 , N- (p-tolyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and 2- The brominated nicotinonitrile was reacted to give the title compound (24%).

¹H NMR(CDCl₃),δ_H,2.36(s,3H),3.09(t,2H),4.05(t,2H),4.73(s,2H),6.77-6.87(m,2H),7.17-7.28(m, 2H),7.41-7.48(m,2H),7.82(dd,1H),8.24(s,1H),8.37(m,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 2.36 (s, 3H), 3.09 (t, 2H), 4.05 (t, 2H), 4.73 (s, 2H), 6.77-6.87 (m, 2H), 7.17- 7.28 (m, 2H), 7.41-7.48 (m, 2H), 7.82 (dd, 1H), 8.24 (s, 1H), 8.37 (m, 1H).

LC/MS(M+H)⁺=343 LC/MS (M+H) ⁺ =343

實例83 Example 83 2-((3-氰苯基)胺基)-N-甲基-N-丙基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺2-((3-Cyanophenyl)amino) -N -methyl- N -propyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxamide

根據一般步驟2a，令3-((5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈與(丙基)(甲基)胺基甲醯氯起反應，即得無色固狀之標題化合物(79%)。 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile and (propyl)(methyl) according to general procedure 2a The title compound (79%) was obtained as a colorless solid.

¹H NMR(CDCl₃),δ_H,0.89(t,3H),1.60(m,2H),2.89(s,3H),2.94(t,2H),3.19(t,2H),3.52(t,2H),4.29(s,2H),7.25-7.29(m,2H),7.38(t,1H),7.64(d,1H),8.21(s,1H),8.25(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 0.89 (t, 3H), 1.60 (m, 2H), 2.89 (s, 3H), 2.94 (t, 2H), 3.19 (t, 2H), 3.52 (t, 2H), 4.29 (s, 2H), 7.25-7.29 (m, 2H), 7.38 (t, 1H), 7.64 (d, 1H), 8.21 (s, 1H), 8.25 (s, 1H).

LC/MS(M+H)⁺=351 LC/MS(M+H) ⁺ =351

實例84 Example 84 6-(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)吡啶-2-腈6-(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)pyridine-2-carbonitrile

根據密切類似於實例27中所述之步驟，令3-((5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈與6-溴基吡啶-2-腈起反應，即得無色固狀之標題化合物(13%)。 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile was prepared according to the procedure closely analogous to Example 27 The bromopyridine-2-carbonitrile was reacted to give the title compound (13%).

¹H NMR(CDCl₃),δ_H,3.00(t,2H),3.96(t,2H),4.69 (s,2H),6.92(d,1H),7.04(d,1H),7.30(s,1H),7.40(t,1H),7.56-7.68(m,3H),8.28(s,1H),8.31(m,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 3.00 (t, 2H), 3.96 (t, 2H), 4.69 (s, 2H), 6.92 (d, 1H), 7.04 (d, 1H), 7.30 (s, 1H), 7.40 (t, 1H), 7.56-7.68 (m, 3H), 8.28 (s, 1H), 8.31 (m, 1H).

LC/MS(M+H)⁺=354 LC/MS (M+H) ⁺ =354

實例85 Example 85 2-(2-((3-氰苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)異煙腈2-(2-((3-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)isonicotinonitrile

根據密切類似於實例27中所述之步驟，令3-((5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈與2-溴基異煙腈起反應，即得無色固狀之標題化合物(7%)。 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile was obtained according to the procedure closely analogous to Example 27 - The bromo-isonicotinonitrile is reacted to give the title compound (7%) as a colorless solid.

¹H NMR(CDCl₃),δ_H,3.02(t,2H),3.97(t,2H),4.68(s,2H),6.82(d,1H),6.90(s,1H),7.23(s,1H),7.29(d,1H),7.40(t,1H),7.65(d,1H),8.26(s,1H),8.32(m,2H)。 ¹ H NMR (CDCl ₃ ), δ _H , 3.02 (t, 2H), 3.97 (t, 2H), 4.68 (s, 2H), 6.82 (d, 1H), 6.90 (s, 1H), 7.23 (s, 1H), 7.29 (d, 1H), 7.40 (t, 1H), 7.65 (d, 1H), 8.26 (s, 1H), 8.32 (m, 2H).

LC/MS(M+H)⁺=354 LC/MS (M+H) ⁺ =354

實例86 Example 86 2-(2-((3-氰苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)-6-甲基煙腈2-(2-((3-Cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)-6-methylnicotinonitrile

根據密切類似於實例27中所述之步驟，令3-((5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈與2-溴基-6-甲基煙腈起反應，即得無色固狀之標題化合物(43%)。 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile was obtained according to the procedure closely analogous to Example 27 -Bromo-6-methylnicotinonitrile afforded the title compound (43%).

¹H NMR(CDCl₃),δ_H,2.46(s,3H),3.09(t,2H),4.03 (t,2H),4.74(s,2H),6.65(d,1H),7.26(d,1H),7.35(t,1H),7.40(s,1H),7.67(m,2H),8.21(s,1H),8.27(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 2.46 (s, 3H), 3.09 (t, 2H), 4.03 (t, 2H), 4.74 (s, 2H), 6.65 (d, 1H), 7.26 (d, 1H), 7.35 (t, 1H), 7.40 (s, 1H), 7.67 (m, 2H), 8.21 (s, 1H), 8.27 (s, 1H).

LC/MS(M+H)⁺=368 LC/MS(M+H) ⁺ =368

實例87Example 87 吖丁啶-1-基(2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)甲酮Azetidin-1-yl (2-(meta-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)methanone

根據一般步驟2a，令N-(間位-甲苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與吖丁啶-1-羰基氯起反應，即得無色固狀之標題化合物(30%)。 According to general procedure 2a, let N- (meta-tolyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and azetidin-1-carbonyl chloride The title compound (30%) was obtained as a colorless solid.

¹H NMR(CDCl₃),δ_H,2.27(m,2H),2.35(s,3H),2.85(t,2H),3.60(t,2H),4.06(t,4H),4.39(s,2H),6.84(d,1H),6.99(s,1H),7.21(t,1H),7.37(s,1H),7.44(d,1H),8.16(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 2.27 (m, 2H), 2.35 (s, 3H), 2.85 (t, 2H), 3.60 (t, 2H), 4.06 (t, 4H), 4.39 (s, 2H), 6.84 (d, 1H), 6.99 (s, 1H), 7.21 (t, 1H), 7.37 (s, 1H), 7.44 (d, 1H), 8.16 (s, 1H).

LC/MS(M+H)⁺=324 LC/MS (M+H) ⁺ =324

實例88 Example 88 N-乙基-N-甲基-2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺 N -ethyl- N -methyl-2-(meta-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-formamide

根據一般步驟2a，令N-(間位-甲苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與乙基(甲基)胺基甲醯氯起反應，即得無色固狀之標題化合物(25%)。 According to general procedure 2a, let N- (meta-tolyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and ethyl(methyl)amino group A The title compound (25%) was obtained as a colorless solid.

¹H NMR(CDCl₃),δ_H,1.17(t,3H),2.35(s,3H),2.87 (s,3H),2.91(t,2H),3.26(q,2H),3.51(t,2H),4.27(s,2H),6.84(d,1H),7.00(s,1H),7.21(t,1H),7.38(s,1H),7.45(d,1H),8.16(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.17 (t, 3H), 2.35 (s, 3H), 2.87 (s, 3H), 2.91 (t, 2H), 3.26 (q, 2H), 3.51 (t, 2H), 4.27 (s, 2H), 6.84 (d, 1H), 7.00 (s, 1H), 7.21 (t, 1H), 7.38 (s, 1H), 7.45 (d, 1H), 8.16 (s, 1H) ).

LC/MS(M+H)⁺=326 LC/MS (M+H) ⁺ =326

實例89 Example 89 N-甲基-N-丙基-2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺 N -methyl- N -propyl-2-(meta-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-formamide

根據一般步驟2a，令N-(間位-甲苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與丙基(甲基)胺基甲醯氯起反應，即得無色固狀之標題化合物(26%)。 According to general procedure 2a, let N- (meta-tolyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and propyl(methyl)amino group A The title compound (26%) was obtained as a colorless solid.

¹H NMR(CDCl₃),δ_H,0.89(t,3H),1.59(m,2H),2.35(s,3H),2.88(s,3H),2.91(t,2H),3.18(t,2H),3.50(t,2H),4.26(s,2H),6.84(d,1H),7.16(s,1H),7.20(t,1H),7.38(s,1H),7.45(d,1H),8.16(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 0.89 (t, 3H), 1.59 (m, 2H), 2.35 (s, 3H), 2.88 (s, 3H), 2.91 (t, 2H), 3.18 (t, 2H), 3.50 (t, 2H), 4.26 (s, 2H), 6.84 (d, 1H), 7.16 (s, 1H), 7.20 (t, 1H), 7.38 (s, 1H), 7.45 (d, 1H) ), 8.16 (s, 1H).

LC/MS(M+H)⁺=340 LC/MS (M+H) ⁺ =340

實例90 Example 90 2-((3-氯苯基)胺基)-N-甲基-N-丙基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺2-((3-Chlorophenyl)amino) -N -methyl- N -propyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxamide

根據一般步驟2a，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與丙基(甲基)胺基甲醯氯起反應，即得固狀之標題化合物(62%)。 According to general procedure 2a, N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and propyl(methyl)aminol The title compound (62%) was obtained as a solid.

¹H NMR(CDCl₃),δ_H,1.16(t,3H),1.60(m,2H),2.89 (s,3H),2.93(t,2H),3.26(t,2H)3.51(t,2H),4.27(s,2H),6.96(d,1H),7.11(s,1H),7.22(t,1H),7.37(d,1H),7.85(s,1H),8.19(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.16 (t, 3H), 1.60 (m, 2H), 2.89 (s, 3H), 2.93 (t, 2H), 3.26 (t, 2H) 3.51 (t, 2H) ), 4.27 (s, 2H), 6.96 (d, 1H), 7.11 (s, 1H), 7.22 (t, 1H), 7.37 (d, 1H), 7.85 (s, 1H), 8.19 (s, 1H) .

LC/MS(M+H)⁺=359,361 LC/MS(M+H) ⁺ =359,361

實例91 Example 91 2-((3-氯苯基)胺基)-N-乙基-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺2-((3-Chlorophenyl)amino) -N -ethyl- N -methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxamide

根據一般步驟2a，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與乙基(甲基)胺基甲醯氯起反應，即得固狀之標題化合物(52%)。 According to general procedure 2a, N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and ethyl(methyl)aminol The title compound (52%) was obtained as a solid.

¹H NMR(CDCl₃),δ_H,1.16(t,3H),2.86(s,3H),2.91(t,2H),3.24(q,2H)3.52(t,2H),4.28(s,2H),6.96(d,1H),7.11(s,1H),7.21(t,1H),7.37(d,1H),7.84(s,1H),8.18(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.16 (t, 3H), 2.86 (s, 3H), 2.91 (t, 2H), 3.24 (q, 2H) 3.52 (t, 2H), 4.28 (s, 2H) ), 6.96 (d, 1H), 7.11 (s, 1H), 7.21 (t, 1H), 7.37 (d, 1H), 7.84 (s, 1H), 8.18 (s, 1H).

LC/MS(M+H)⁺=345,347 LC/MS(M+H) ⁺ =345,347

實例92 Example 92 3-((6-(1-異丙基-1H-咪唑-2-基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈3-((6-(1-isopropyl-1 H -imidazol-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino Benzoonitrile

根據密切類似於實例49中所述之步驟，令3-((5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈與異硫氰酸異丙酯起反應，再進一步轉化成19%總產率之標題化合物。 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile was differentiated according to the procedure closely described in Example 49 Isopropyl thiocyanate was reacted and further converted to the title compound in 19% overall yield.

¹H NMR(CDCl₃),δ_H,1.40(d,6H),3.02(t,2H),3.36(t,2H),4.20(s,2H),4.48(m,1H),6.79(s,1H),6.87(s,1H),7.27-7.40(m,3H),7.64(d,1H),8.18(s,1H),8.26(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.40 (d, 6H), 3.02 (t, 2H), 3.36 (t, 2H), 4.20 (s, 2H), 4.48 (m, 1H), 6.79 (s, 1H), 6.87 (s, 1H), 7.27-7.40 (m, 3H), 7.64 (d, 1H), 8.18 (s, 1H), 8.26 (s, 1H).

LC/MS(M+H)⁺=360 LC/MS(M+H) ⁺ =360

實例93 Example 93 3-((6-(3-甲基氧雜環丁烷-3-羰基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈3-((6-(3-methyloxetan-3-carbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino) Benzoonitrile

根據一般步驟2a，令3-((5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈與3-甲基氧雜環丁烷-3-羰基氯起反應，即得無色固狀之標題化合物(16%)。 3-((5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile and 3-methyloxetane according to general procedure 2a The title compound (16%) was obtained as a colorless solid.

¹H NMR(CDCl₃),δ_H,1.65和1.73(both s,3H),2.92(t,2H),3.35(t,1H),3.93和4.11(both m,1H),4.42(d,2H),4.68(s,1H),5.03(d,2H),7.21-7.44(m,3H),7.62(d,1H),8.18(s,1H),8.26(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.65 and 1.73 (both s, 3H), 2.92 (t, 2H), 3.35 (t, 1H), 3.93 and 4.11 (both m, 1H), 4.42 (d, 2H) ), 4.68 (s, 1H), 5.03 (d, 2H), 7.21 - 7.44 (m, 3H), 7.62 (d, 1H), 8.18 (s, 1H), 8.26 (s, 1H).

LC/MS(M+H)⁺=350 LC/MS (M+H) ⁺ =350

實例94Example 94 (2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(3-甲基氧雜環丁烷-3-基)甲酮(2-((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)(3-methyloxetane -3-yl)methanone

根據一般步驟2a，令N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與3-甲基氧雜環丁烷-3-羰基氯起反應，即得固狀之標題化合物(19%)。 According to general procedure 2a, N- (3-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and 3-methyloxetane The title compound (19%) was obtained as a solid crystals.

¹H NMR(CDCl₃),δ_H,1.56和1.65(both s,3H),2.90(t,2H),3.34(t,1H),4.09和4.41(both m,1H),4.67(d,2H),4.67(s,1H),5.03(d,2H),7.00(d,1H),7.09(s,1H),7.21(t,1H),7.37(d,1H),7,85(s,1H),8.26(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.56 and 1.65 (both s, 3H), 2.90 (t, 2H), 3.34 (t, 1H), 4.09 and 4.41 (both m, 1H), 4.67 (d, 2H) ), 4.67 (s, 1H), 5.03 (d, 2H), 7.00 (d, 1H), 7.09 (s, 1H), 7.21 (t, 1H), 7.37 (d, 1H), 7, 85 (s, 1H), 8.26 (s, 1H).

LC/MS(M+H)⁺=358,360 LC/MS(M+H) ⁺ =358,360

實例95Example 95 (3-甲基氧雜環丁烷-3-基)(2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)甲酮(3-methyloxetan-3-yl)(2-(meta-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H ) Ketone

根據一般步驟2a，令N-(間位-甲苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺與3-甲基氧雜環丁烷-3-羰基氯起反應，即得無色固狀之標題化合物(59%)。 According to general procedure 2a, let N- (meta-tolyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and 3-methyloxetane The title compound (59%) was obtained as a colorless solid.

¹H NMR(CDCl₃),δ_H,1.63和1.71(both s,3H),2.34(s,3H),2.83(t,2H),3.29(t,1H),3.89和4.05(both m,1H),4.39(d,2H),4.63(s,1H),5.01(d,2H)6.85(d,1H),7.20(t,1H),7.36(s,2H),7.44(d,1H),8.20(s,1H)。 ¹ H NMR (CDCl ₃ ), δ _H , 1.63 and 1.71 (both s, 3H), 2.34 (s, 3H), 2.83 (t, 2H), 3.29 (t, 1H), 3.89 and 4.05 (both m, 1H) ), 4.39 (d, 2H), 4.63 (s, 1H), 5.01 (d, 2H) 6.85 (d, 1H), 7.20 (t, 1H), 7.36 (s, 2H), 7.44 (d, 1H), 8.20 (s, 1H).

LC/MS(M+H)⁺=339 LC/MS (M+H) ⁺ =339

代表性藥學組成物之實例Examples of representative pharmaceutical compositions

與常用之溶劑、賦形劑、輔助劑及載體組合，本化合物可製成片劑、包衣片劑、膠囊、滴液、坐藥、注射及輸注製劑、等等，且可藉口服、直腸部、非經腸部、及其他路徑進行醫療應用。根據本發明之代表性藥學組成物如下： In combination with commonly used solvents, excipients, adjuvants and carriers, the present compounds can be formulated into tablets, coated tablets, capsules, drops, medicines, injections and infusion preparations, etc., and can be taken orally, rectal Medical, non-enteral, and other routes for medical applications. Representative pharmaceutical compositions according to the invention are as follows:

(a)適於經口投服之含有活性成分之片劑可藉慣用之壓片技術製得。 (a) Tablets containing the active ingredient suitable for oral administration can be prepared by conventional tableting techniques.

(b)坐藥方面，可使用任何常用之坐藥藥基藉由活性成分之常用步驟併入其中，諸如聚乙二醇，其於室溫下為固狀，但於體溫下或體溫附近則熔化。 (b) In terms of medicine, any commonly used drug base may be incorporated by a usual step of the active ingredient, such as polyethylene glycol, which is solid at room temperature, but at or near body temperature. melt.

(c)非經腸部(包括靜脈內及皮下)無菌溶液方面，活性成分係連同常用量之慣用成分一起使用，諸如適量氯化鈉及二次蒸餾水(根據慣用步驟諸如過濾法，無菌填入安瓶或IV-滴瓶中，再高壓滅菌)。 (c) For parenteral (including intravenous and subcutaneous) sterile solutions, the active ingredient is used together with conventional amounts of conventional ingredients, such as appropriate amounts of sodium chloride and double distilled water (according to conventional procedures such as filtration, aseptic filling) Ampoule or IV-dropper bottle, autoclaved).

其他適當藥學組成物對熟諳此藝者而言將是立即理解的。 Other suitable pharmaceutical compositions will be immediately understood by those skilled in the art.

配方實例Recipe example

再次地，下列提供之實例僅供闡述而非將其解釋為限制。 Again, the examples provided below are for illustrative purposes only and are not to be construed as limiting.

實例1Example 1

片劑配方 Tablet formula

含10毫克活性成分之片劑之適當配方如下： The appropriate formulation of a tablet containing 10 mg of the active ingredient is as follows:

實例2Example 2

片劑配方 Tablet formula

另一含100毫克之片劑之適當配方如下： Another suitable formula for tablets containing 100 mg is as follows:

實例3Example 3

膠囊配方 Capsule formula

含50毫克活性成分之膠囊之適當配方如下： The appropriate formulation of capsules containing 50 mg of active ingredient is as follows:

填入明膠膠囊中。 Fill in gelatin capsules.

實例4Example 4

注射溶液 Injection solution

供注射溶液用之適當配方如下： The appropriate formulation for the injection solution is as follows:

實例5Example 5

液態口服配方 Liquid oral formula

含2毫克活性成分於一毫升混合液中之1升口服溶液之適當配方如下： A suitable formulation of 1 liter of oral solution containing 2 mg of the active ingredient in one ml of the mixture is as follows:

實例6Example 6

液態口服配方 Liquid oral formula

另一種含20毫克活性成分於一毫升混合液中之1升液態混合液之適當配方如下： Another suitable formulation of a 1 liter liquid mixture containing 20 mg of the active ingredient in one ml of the mixture is as follows:

實例7Example 7

液態口服配方 Liquid oral formula

另一種含2毫克活性成分於一毫升混合液中之1升液態混合液之適當配方如下： Another suitable formulation of a 1 liter liquid mixture containing 2 mg of the active ingredient in one ml of the mixture is as follows:

實例8Example 8

氣溶膠配方 Aerosol formula

180克氣溶膠溶液含有： 180 grams of aerosol solution contains:

將15毫升該溶液填入鋁質氣溶膠罐中，蓋上定量閥，以3.0巴吹洗。 15 ml of this solution was filled into an aluminum aerosol can, covered with a dosing valve, and purged at 3.0 bar.

實例9Example 9

TDS(經皮給藥系統)配方 TDS (transdermal drug delivery system) formula

100克溶液含有： 100 grams of solution contains:

將1.8毫升該溶液置於被襯背黏箔所覆蓋之絨頭織物上。將該系統藉保護襯墊密封，而於使用前將保護襯墊移除。 1.8 ml of this solution was placed on the pile fabric covered by the backing adhesive foil. The system is sealed with a protective liner and the protective liner is removed prior to use.

實例10Example 10

奈米微粒配方 Nanoparticle formula

10克聚氰基丙烯酸丁酯奈米微粒含有： 10 g of polybutyl cyanoacrylate nanoparticles contain:

聚氰基丙烯酸丁酯奈米微粒係藉於作為聚合介質之水/0.1N鹽酸/乙醇混合液中進行乳膠聚合反應而製得。最終再將於懸浮液中之奈米微粒於真空下低壓凍乾。 The polybutylcyanoacrylate nanoparticles are obtained by performing a latex polymerization reaction in a water/0.1N hydrochloric acid/ethanol mixture as a polymerization medium. Finally, the nanoparticles in the suspension are lyophilized under vacuum.

實例11Example 11

懸浮液配方 Suspension formula

1.0克懸浮液含有： 1.0 g suspension contains:

以高速混合器/摻合器將羥丙基甲基纖維素均勻地分散於水中。羥丙基甲基纖維素進行約一小時之水合時間後，將活性成分均勻地摻合至羥丙基甲基纖維素溶液中。懸浮液之黏度可藉由羥丙基甲基纖維素之量來調整，因而 得到具有極緩慢之微粒沈澱及微粒結塊趨勢之極安定懸浮液。 The hydroxypropyl methylcellulose was uniformly dispersed in water with a high speed mixer/blender. After the hydroxypropyl methylcellulose was subjected to a hydration time of about one hour, the active ingredient was uniformly blended into a hydroxypropylmethylcellulose solution. The viscosity of the suspension can be adjusted by the amount of hydroxypropyl methylcellulose, thus A very stable suspension with very slow particle precipitation and microparticle agglomeration tendency is obtained.

實例12Example 12

注射溶液 Injection solution

1.0毫升溶液含有： The 1.0 ml solution contains:

藉攪拌及加熱令活性成分溶於二甲亞碸中(溶液1)。令甘露糖醇溶於注射用水中(溶液2)。冷卻至室溫後，將溶液1與溶液2藉連續攪拌而混合。再將溶液藉過濾法或藉壓熱法滅菌。 The active ingredient was dissolved in dimethyl hydrazine by stirring and heating (solution 1). The mannitol was dissolved in water for injection (solution 2). After cooling to room temperature, solution 1 and solution 2 were mixed by continuous stirring. The solution is then sterilized by filtration or by means of thermal compression.

藥理學Pharmacology

本發明之活性成分，及含彼之藥學組成物及以彼治療之方法係藉由獨特且有利之性質予以特徵化。化合物及其藥學組成物顯現(於標準之公認可靠之測試步驟中)下列有用之性質及特徵。 The active ingredients of the present invention, as well as the pharmaceutical compositions containing them, and the methods of treatment thereof, are characterized by unique and advantageous properties. The compounds and their pharmaceutical compositions exhibit (in the standard accepted and reliable test procedure) the following useful properties and characteristics.

方法method 供mGluR5拮抗性質之特徵化用之結合分析法Combined analysis method for characterization of mGluR5 antagonistic properties [[ ³³ H]MPEP(2-甲基-6-(苯基乙炔基)吡啶)結合至皮質膜內之mGluR5受體之透膜異位性調節位上H]MPEP (2-methyl-6-(phenylethynyl)pyridine) binds to the transmembrane atopic regulation of the mGluR5 receptor in the cortex 大鼠之皮質膜之製備Preparation of rat cortical membrane

將雄斯普拉格-杜勒(Sprague-Dawley)鼠(200-250克)斬首，再將其腦部快速移出。將皮質解剖，再使用玻璃-鐵氟龍均質器將其於20倍體積之冰-冷0.32M蔗糖中均質化。將該均漿以1,000×g之速離心10分鐘。將沈澱物丟棄，再將上層液以20,000×g之速離心20分鐘。令所得沈澱物再懸浮於20倍體之蒸餾水中，再以8,000×g之速離心20分鐘。然後將上層液及血沈棕黃層於50mM Tris-HCl，pH 8.0之存在下以48,000×g之速離心20分鐘。繼而將沈澱物於50mM Tris-HCl，pH 8.0之存在下再懸浮及以48,000×g之速離心20分鐘另二至三次。所有離心步驟均於4℃下進行。再懸浮於5倍體積之50mM Tris-HCl，pH 8.0中後，將膜懸浮液於-80℃下快速冰凍。 Sprague-Dawley rats (200-250 g) were decapitated and their brains were quickly removed. The cortex was dissected and homogenized in 20 volumes of ice-cold 0.32 M sucrose using a glass-Teflon homogenizer. The homogenate was centrifuged at 1,000 x g for 10 minutes. The precipitate was discarded, and the supernatant was centrifuged at 20,000 x g for 20 minutes. The resulting precipitate was resuspended in 20 volumes of distilled water and centrifuged at 8,000 x g for 20 minutes. The supernatant and buffy coat were then centrifuged at 48,000 x g for 20 minutes in the presence of 50 mM Tris-HCl, pH 8.0. The pellet was then resuspended in the presence of 50 mM Tris-HCl, pH 8.0 and centrifuged at 48,000 x g for another two to three times. All centrifugation steps were carried out at 4 °C. After resuspending in 5 volumes of 50 mM Tris-HCl, pH 8.0, the membrane suspension was rapidly frozen at -80 °C.

分析當日，將膜懸浮液解凍，藉再懸浮於50mM Tris-HCl，pH 8.0中再以48,000×g之速離心20分鐘予以清洗四次，且最終再懸浮於50mM Tris-HCl，pH 7.4中。最終膜製劑(500-700微克/毫升)中之蛋白質量係根據Lowry法(Lowry O.H.et al.1951.J.Biol.Chem.193,256-275)測定。 On the day of analysis, the membrane suspension was thawed, washed four times by resuspending in 50 mM Tris-HCl, pH 8.0, and then centrifuged at 48,000 x g for 20 minutes, and finally resuspended in 50 mM Tris-HCl, pH 7.4. The amount of protein in the final membrane preparation (500-700 μg/ml) was determined according to the Lowry method (Lowry O. H. et al. 1951. J. Biol. Chem. 193, 256-275).

[[ ³³ H]MPEP分析法H]MPEP analysis

培育係藉將[³H]MPEP(50.2居里/毫莫耳，5 nM，Tocris，GB)加至含125-250微克蛋白質(總量0.25毫升)及各種不同濃度藥劑之管瓶中而開始。另外，分析以[³H]MMPEP(2-(3-甲氧基苯基乙炔基)-6-甲基吡啶鹽酸鹽)作為放射性配體來進行。令該培育於室溫下持續60分鐘(於所用條件下達到均衡)。非專一性結合係藉加入未標記.之MPEP(10 μM)來定義。使用微孔(Millipore)濾器系統令培育終止。將樣品於玻璃纖維濾器(Schleicher & Schuell，Germany)上、於恆定真空下以4毫升冰-冷分析緩衝液潤洗兩次。分離及潤洗後，將濾器置於閃爍液體(5毫升Ultima Gold,Perkin Elmer,Germany)中，再使用慣用之液體閃爍計數器(Canberra Packard,Germany)測定濾器上保留之放射活性。 The cultivating department started by adding [ ³ H]MPEP (50.2 Curie/mole, 5 nM, Tocris, GB) to a vial containing 125-250 micrograms of protein (total amount 0.25 ml) and various concentrations of the drug. . Further, the analysis was carried out using [ ³ H]MMPEP (2-(3-methoxyphenylethynyl)-6-methylpyridine hydrochloride) as a radioactive ligand. The incubation was allowed to continue at room temperature for 60 minutes (equalization was achieved under the conditions used). Non-specific binding was defined by the addition of unlabeled MPEP (10 μM). The incubation was terminated using a Millipore filter system. The samples were rinsed twice on a glass fiber filter (Schleicher & Schuell, Germany) under constant vacuum with 4 ml ice-cold assay buffer. After separation and rinsing, the filter was placed in a scintillation liquid (5 ml Ultima Gold, Perkin Elmer, Germany) and the retained radioactivity retained on the filter was measured using a conventional liquid scintillation counter (Canberra Packard, Germany).

特徵化Characterization

專一性結合率極高，亦即>85%且實質上與緩衝液(Tris或HEPES均為50 mM)及pH(6.8-8.9)無關。明顯有可飽和蛋白質依賴性且所選擇之用以供接續分析用之蛋白質濃度(500-700微克/毫升)乃在此依賴性之線性部分範圍內。冷MPEP置換熱配體之IC₅₀為11.2±0.64nM。[³H]MPEP之K_d為13.6 nM係藉斯卡查德(Scatchard)分析法測知且將其根據Cheng Prusoff關聯性用於計算置換劑 之以K_d值表示之親和力(冷MPEP之IC₅₀等同於8.2nM之K_i)。B_max為0.56 pm/毫克蛋白質。 The specificity of binding is extremely high, ie >85% and is essentially independent of buffer (50 mM for Tris or HEPES) and pH (6.8-8.9). The apparently saturable protein dependence and the protein concentration (500-700 [mu]g/ml) selected for subsequent analysis is within the linear portion of this dependence. Cold MPEP replacement IC heat Ligand ₅₀ 11.2 ± 0.64nM. The K _d of [ ³ H]MPEP is 13.6 nM and is measured by the Scatchard analysis method and used to calculate the affinity of the displacer according to the K _d value according to the Cheng Prusoff correlation (IC of cold MPEP) _{50 is} equivalent to 8.2 nM of K _i ). _Bmax is 0.56 pm/mg protein.

mGluR5受體之功能分析Functional analysis of mGluR5 receptor 以經安定轉染之細胞進行之細胞溶質內之鈣之研究Study on calcium in cytosol of cells transfected with stable cells

將中國倉鼠卵巢細胞(CHO-K1細胞)(經安定轉染以供人類趨代謝性麩胺酸受體mGluR5之可誘導性表現)以每孔35000個細胞之密度種至黑色透明底之96孔式盤中。所用之標準生長培養基(達爾伯克改良伊格爾培養基(Dulbecco's modified Eagle Medium)，DMEM加上L-脯胺酸)含有適當誘導劑異丙基-β-D-硫代吡喃半乳糖苷(IPTG)以達到最理想之受體表現。接種後一天，將生長培養基換成Ca-Kit(Molecular Devices,USA)，再培育一小時。Ca-Kit係於含有20 mM HEPES pH 7.4、麩胺酸-丙酮酸轉胺酶、磷酸吡哆醛及丙酮酸鈉於漢克氏(Hank，s)平衡鹽溶液(HBBS)中之分析緩衝液中再構成。對受體為激動性之化合物可引發細胞溶質內之鈣之增加，其可藉使用螢光成像讀盤儀(Molecular Devices)測得螢光信號之增加而得知。欲分析彼等調節鈣-反應之效力，乃將測試化合物(溶於0.5%之最終二甲亞碸濃度中)於受體激動劑(於可提供約80%最大信號之濃度下之L-使君子胺酸)之前5分鐘連線加入。 Chinese hamster ovary cells (CHO-K1 cells) (transfected with diazepam for inducible expression of the human metabotropic glutamate receptor mGluR5) were seeded at a density of 35,000 cells per well to a 96-well black clear bottom. In the tray. The standard growth medium used (Dulbecco's modified Eagle Medium, DMEM plus L-proline) contains the appropriate inducer isopropyl-β-D-thiogalactopyranoside ( IPTG) to achieve optimal receptor performance. One day after the inoculation, the growth medium was changed to Ca-Kit (Molecular Devices, USA) and incubated for an additional hour. Ca-Kit is an assay buffer containing 20 mM HEPES pH 7.4, glutamate-pyruvate transaminase, pyridoxal phosphate and sodium pyruvate in Hank's balanced salt solution (HBBS) Reconstituted. Compounds that are agonistic to the receptor can trigger an increase in calcium in the cytosol, which can be seen by an increase in the fluorescence signal measured using a fluorescent imaging reader (Molecular Devices). To analyze the potency of their regulation of calcium-reaction, the test compound (dissolved in 0.5% of the final dimethyl hydrazine concentration) at the receptor agonist (at a concentration that provides about 80% of the maximum signal) Gentamic acid was added in 5 minutes before the connection.

星狀細胞培養Stellate cell culture

原代星狀細胞培養乃依Booher and Sensenbrenner(1972,Neurobiology 2(3)：97-105)所述，由新生大鼠之皮質中製得。簡言之，將斯普拉格-杜勒(Sprague-Dawley)幼鼠(2-4天大)斬首，再將新皮質解剖，以尼龍濾器(孔徑80微米)裂解，再小心碾磨。將細胞懸浮液塗佈至已預塗附聚-D-賴胺酸之燒瓶(Costar,Netherlands)上，再於添加10%胎牛血清(FCS，Sigma，Germany)、4mM麩醯胺及50微克/毫升健他黴素(均為Biochrom,Germany)之達爾伯克改良伊格爾培養基(Dulbecco's Modified Eagle’s Medium，DMEM，Invitrogen，Germany)中、於37℃下、於5%二氧化碳/95%空氣之濕化氣氛中培養7天，且於第2及6天更換培養基。 Primary stellate cell culture was prepared from the cortex of neonatal rats as described by Booher and Sensenbrenner (1972, Neurobiology 2(3): 97-105). Briefly, Sprague-Dawley pups (2-4 days old) were decapitated and the new cortex was dissected, lysed with a nylon filter (pore size 80 microns) and carefully milled. The cell suspension was applied to a pre-coated poly-D-lysine flask (Costar, Netherlands), followed by the addition of 10% fetal bovine serum (FCS, Sigma, Germany), 4 mM branamide and 50 micrograms. /ml statin (both Biochrom, Germany) in Dulbecco's Modified Eagle's Medium (DMEM, Invitrogen, Germany) at 37 ° C in 5% carbon dioxide / 95% air The culture was carried out for 7 days in a humidified atmosphere, and the medium was changed on the 2nd and 6th days.

體外培養7天(7DIV)後，將細胞以250rpm之速搖動過夜以移除寡突細胞及微膠細胞。隔天，將星狀細胞以CMF-PBS(不含鈣及鎂之磷酸鹽緩衝鹽水，Biochrom,Germany)潤洗兩次，以胰蛋白酶處理，再以40,000個細胞/孔之密度次塗佈至已預塗附聚-D-賴胺酸之96孔式盤(Greiner,Netherlands)上。確立傳代培養後之24小時，將星狀細胞以PBS⁺⁺(磷酸鹽緩衝鹽水，Biochrom,Germany)潤洗，再投入由含有1×G5-添加劑(Invitrogen，Germany)、0.5微克/毫升硫酸乙醯肝素、及1.5微克/毫升纖維連接蛋白(均為Sigma，Germany)之DMEM所組成之星狀細胞-確定成分培養基(Miller et al.,(1993)Brain Res.618(1)：175-8)。3天後，將培養基替 換，再將細胞培育另2-3天，以使得實驗之時之星狀細胞為14-15DIV。 After 7 days of in vitro culture (7 DIV), the cells were shaken overnight at 250 rpm to remove oligodendrocytes and microglial cells. On the next day, the stellate cells were washed twice with CMF-PBS (phosphate buffered saline without calcium and magnesium, Biochrom, Germany), trypsinized, and coated at a density of 40,000 cells/well. It has been precoated with a poly-D-lysine 96-well plate (Greiner, Netherlands). 24 hours after the establishment of the subculture, the stellate cells were rinsed with PBS ⁺⁺ (phosphate buffered saline, Biochrom, Germany), and then put into the sulfuric acid containing 1 × G5-additive (Invitrogen, Germany), 0.5 μg / ml A stellate cell-determined medium consisting of acetaminophen and 1.5 mg/ml fibronectin (all Sigma, Germany) DMEM (Miller et al., (1993) Brain Res. 618(1): 175- 8). After 3 days, the medium was replaced and the cells were incubated for another 2-3 days so that the stellate cells at the time of the experiment were 14-15 DIV.

免疫細胞化學Immunocytochemistry

免疫染色法係進行以求證實星狀細胞標記諸如膠質纖維酸性蛋白(GFAP)之存在，以及用於監測mGluR5受體之表現。 Immunostaining is performed to confirm the presence of stellate cell markers such as glial fibrillary acidic protein (GFAP) and to monitor the performance of the mGluR5 receptor.

以星狀細胞進行之細胞溶質內之鈣之研究Study on calcium in cytosol of stellate cells

以mGluR5激動劑L-使君子胺酸鹽刺激後所致之細胞溶質內之鈣之增加係使用螢光成像讀盤儀(FLIPR)及Ca-Kit(均為Molecular Devices)測量。在加入激動劑或拮抗劑之前，將培養基吸出，再將細胞於室溫下裝載含有於氯化鈉(123 mM)、氯化鉀(5.4 mM)、氯化鎂(0.8 mM)、氯化鈣(1.8 mM)、D-葡萄糖(15 mM)、及HEPES(20 mM)，pH 7.3中再構成之鈣-敏感性染料之150微升裝載緩衝液2小時。繼而將盤轉移至FLIPR以隨著L-使君子胺酸鹽(100 nM)之添加而檢測鈣之增加(測量相對螢光單位(RFU))。如係檢測拮抗劑，則將這些化合物在加入個別激動劑之前於室溫下預培育10分鐘。 The increase in calcium in the cytosol caused by mGluR5 agonist L-suppressed with succinate was measured using a fluorescence imaging plate reader (FLIPR) and Ca-Kit (both Molecular Devices). The medium was aspirated prior to the addition of the agonist or antagonist, and the cells were loaded at room temperature with sodium chloride (123 mM), potassium chloride (5.4 mM), magnesium chloride (0.8 mM), calcium chloride (1.8). 150 μl of loading buffer of calcium-sensitive dye reconstituted in mM), D-glucose (15 mM), and HEPES (20 mM) in pH 7.3 for 2 hours. The disk was then transferred to FLIPR to detect an increase in calcium (measured relative to fluorescent units (RFU)) with the addition of L-telluronate (100 nM). If an antagonist is detected, these compounds are pre-incubated for 10 minutes at room temperature prior to addition to the individual agonist.

在正向調節劑方面，使君子胺酸鹽之濃度-反應曲線係於10 μM調節劑之存在及缺乏下進行以測定增效/激動劑效力增加之程度。其後，正向調節劑之濃度-反應曲線係於展現最大增效窗口之固定濃度(一般為10-30 nM)之使 君子胺酸鹽之存在下進行。 In the case of a positive modulator, the concentration-response curve of the gentisylamine was performed in the presence and absence of a 10 μM modulator to determine the extent of potentiation/agonist potency increase. Thereafter, the concentration-response curve of the positive regulator is at a fixed concentration (typically 10-30 nM) that exhibits the maximum synergistic window. It is carried out in the presence of a gentamic acid salt.

數據分析data analysis

加入激動劑後之螢光信號之增加反映溶胞溶質內鈣之增加。每孔中細胞量之不一致則使用FLIPR操作軟體Screenworks之空間均勻性校正而常態化。計算已複製時間數據之平均值(n=3-5)，再用以供圖形表示。欲評估藥理學，因應不同濃度之激動劑或拮抗劑所致之鈣之改變則使用最大減最小(MaxMin)計算結果測知。 The increase in fluorescence signal after the addition of the agonist reflects an increase in calcium in the lysate. The inconsistency in the amount of cells in each well was normalized using the spatial uniformity correction of the FLIPR operating software Screenworks. Calculate the average of the replicated time data (n=3-5) and use it for graphical representation. To assess pharmacology, changes in calcium due to different concentrations of agonist or antagonist are measured using MaxMin calculations.

所有反應(RFU-值)均以佔對照組(=最大反應)之百分比表示。EC₅₀及IC₅₀係根據邏輯斯諦方程式使用GraFit 5.0(Erithacus軟體，GB)或Prism 4.0(GraphPad軟體，USA)計算。本發明化合物具有在約0.5 nM至100 μM範圍內之效力(IC₅₀)。 All reactions (RFU-values) are expressed as a percentage of the control (=maximum response). EC ₅₀ and IC ₅₀ were calculated according to the Logistic equation using GraFit 5.0 (Erithacus software, GB) or Prism 4.0 (GraphPad software, USA). Compounds of the invention have a potency (IC ₅₀₎ range from about 0.5 nM to 100 μM range.

本發明代表性化合物之結果示於表A1中。 The results of representative compounds of the invention are shown in Table A1.

人類mGluR5值係以安定地表現人類mGluR5之CHO-細胞獲得。低於500 nM之IC50值係以至少獨立之一式三份測出。估計值(est.)則依賴以一式四份進行之一單點實驗。rpA數據係以大鼠之原代星狀細胞產生。 Human mGluR5 values were obtained from CHO-cells that stably expressed human mGluR5. IC50 values below 500 nM are measured in at least three independent samples. The estimate (est.) relies on a single point experiment in quadruplicate. The rpA data was generated from primary stellate cells of rats.

總言之，由前述者明顯可知，本發明提供本發明化合物之新穎及有用之應用以及用途，此化合物包含根據本發明之活性成分，以及其新穎藥學組成物及其製備方法及以其治療之方法。 In summary, it will be apparent from the foregoing that the present invention provides novel and useful applications and uses of the compounds of the present invention, the compounds comprising the active ingredients according to the present invention, as well as novel pharmaceutical compositions thereof, and methods for their preparation and treatment thereof method.

本發明活性劑及其組成物之高階活性(藉由所報告之試驗證明)顯示以其於人類以及於低等動物之有用活性為基準之功用。人類之臨床評估尚未完全。吾人應清楚地了解，落入本發明範圍內之供人類用之任何化合物或組成物之分佈及銷售當然必需以負責及授權裁定該案之政府機關之預先核准為依據。 The higher order activity of the active agents and compositions thereof (as evidenced by the reported assays) is shown to be based on their usefulness in humans and in lower animals. The clinical assessment of humans is not yet complete. It is expressly understood that the distribution and sale of any compound or composition for human use within the scope of the invention must of course be based on the prior approval of the government agency responsible for and authorizing the case.

本式I化合物代表一種新穎的mGluR5調節劑。有鑑於其效力，彼等將為廣泛範圍之涉及過度麩胺酸誘導性刺 激之病症，尤其是中樞神經系統病症之有用療法。 The compound of formula I represents a novel mGluR5 modulator. In view of their efficacy, they will be a useful treatment for a wide range of conditions involving excessive glutamate-induced stimuli, especially central nervous system disorders.

因此這些化合物發現在治療活動物體(特別是人類)之如同稍早於說明中陳列之病症方面之應用。 These compounds are therefore found to be useful in the treatment of active objects, particularly humans, as well as those exhibited earlier in the description.

這些化合物亦發現在治療活動物體(特別是人類)之適應症方面之應用，其中特定之病況並不必要存在，但其中特定生理學參數可經由投服本化合物而改善，包括認知功能之增強。 These compounds have also been found to be useful in the treatment of indications for active objects, particularly humans, where specific conditions are not necessarily present, but where specific physiological parameters can be improved by administration of the present compound, including enhancement of cognitive function.

神經保護作用及認知功能增強亦可藉投服本化合物與NMDA受體拮抗劑像美金剛胺(Memantine)之組合而達成。 Neuroprotective effects and cognitive enhancement can also be achieved by administering a combination of the present compound and an NMDA receptor antagonist such as memantine.

以本發明化合物治療活動物體以抑制所選擇輕病之進展或減輕該輕病之方法係如前所述地藉任何一般公認之藥學路徑，使用選定之有效以減輕期望被減輕之特定輕病之劑量達成。本發明化合物於製造供治療活動物以抑制所選擇輕病或病況之進展或減輕該輕病或病況，尤其是易受第I群mGluR5調節劑之治療所影響之輕病或病況之醫藥上之用途係以常用之方法進行，包含將有效之本發明化合物與藥學上可接受之稀釋劑、賦形劑、或載體混合之步驟，治療方法，藥學組成物，及本發明化合物於製造醫藥上之用途。 The method of treating a moving subject with a compound of the invention to inhibit the progression of the selected mild disease or alleviating the mild disease is by any generally accepted pharmaceutical route, as described above, using a selected effective agent to alleviate the particular mild disease desired to be alleviated. The dose is reached. The compounds of the present invention are useful in the manufacture of a medicament for the treatment of a living animal to inhibit the progression of a selected mild disease or condition or to alleviate the mild disease or condition, particularly a mild disease or condition susceptible to treatment with a Group I mGluR5 modulator. The use is carried out in a conventional manner, comprising the steps of mixing an effective compound of the present invention with a pharmaceutically acceptable diluent, excipient, or carrier, a method of treatment, a pharmaceutical composition, and a compound of the present invention for the manufacture of a medicament. use.

藉將活性成分與適當之藥學上可接受之賦形劑、稀釋劑、或載體混合所製得之代表性藥學組成物包括片劑、膠囊、注射溶液、液態口服配方、氣溶膠配方、TDS配方、及奈米微粒配方，故製得供口服、注射、或皮膚使用、亦 根據前述者使用之醫藥。 Representative pharmaceutical compositions prepared by combining the active ingredient with suitable pharmaceutically acceptable excipients, diluents, or carriers include tablets, capsules, injection solutions, liquid oral formulations, aerosol formulations, TDS formulations And nanoparticle formula, so it can be prepared for oral, injection, or skin use. According to the medicine used by the aforementioned.

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本發明之範圍不被本文中所述之具體實施例所限制。實際上，除了本文所述者之外，本發明之各種不同之修飾將由熟諳此藝者根據前述之說明而理解。 The scope of the invention is not limited by the specific embodiments described herein. In fact, various modifications of the invention in addition to those described herein will be understood by those skilled in the art.

本文中所引用之所有專利、申請案、公開、測試方法、文獻、及其他材料均併入本文中以供參考。 All patents, applications, publications, test methods, documents, and other materials cited herein are hereby incorporated by reference.

Claims (14)

一種化合物，其選自式I 其中X代表CR⁶(C=O)R⁷或NR⁸；R¹代表H、C_1-6烷基、或F；R²代表H、C_1-6烷基、或F；或者R¹及R²與彼等所連接之碳原子共同形成羰基團；或者R¹及R²與彼等所連接之碳原子共同形成3-7員環，其可為飽和或不飽和，其中該環可隨意地含有一或二個選自硫、氧、及氮之雜原子且其中該環可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷基、C_1-6烷氧基、胺基、羥基、氰基、醯基、C_1-6烷胺基、二-(C_1-6烷基)胺基、C_1-6烷基羰基胺基、及側氧基之取代基取代；R³代表H、C_1-6烷基、或F；R⁴代表H、C_1-6烷基、或F；或者R³及R⁴與彼等所連接之碳原子共同形成3-7員環，其可為飽和或不飽和，其中該環可隨意地含有一或二個選自硫、氧、及氮之雜原子且其中該環可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷基、C_1-6 烷氧基、胺基、羥基、氰基、醯基、C_1-6烷胺基、二-(C_1-6烷基)胺基、C_1-6烷基羰基胺基、及側氧基之取代基取代；R⁵代表選自芳基、雜芳基、環C_3-6烷基、及雜環基之單環部分；R⁶代表H、C_1-6烷基(其可隨意地被一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、或F；R⁷代表C_1-6烷基(其可隨意地被一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、環C_3-6烷基、雜環基、或NR¹¹R¹²；或者R⁶及R⁷與彼等所連接之碳原子共同形成3-7員環，其可為飽和或不飽和，其中該環可隨意地含有一或二個選自硫、氧、及氮之雜原子且其中該環可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷基、C_1-6烷氧基、胺基、羥基、氰基、醯基、C_1-6烷胺基、二-(C_1-6烷基)胺基、C_1-6烷基羰基胺基、及側氧基之取代基取代；R⁸代表C_1-6烷基(其可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、環C_3-6烷基、雜環基、芳基、雜芳基、C_1-6烷基羰基(其可隨意地 經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、環C_3-6烷基羰基、雜環基羰基、芳基羰基、雜芳基羰基、C_1-6烷氧羰基(其可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、胺基羰基、N-C_1-6烷基胺基羰基(其中該烷基部分可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、N,N-二-(C_1-6烷基)胺基羰基(其中該烷基部分可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、C_1-6烷氧羰基、氰基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、N-C_1-6烷基-N-環C_3-6烷基胺基羰基、N-C_1-6烷基-N-環C_3-6烷基-C_1-6烷基胺基羰基、胺基硫羰基、N-C_1-6烷基胺基硫羰基(其中該烷基部分可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、N,N-二-(C_1-6烷基)胺基硫羰基(其中該烷基部分可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、C_1-6烷磺醯基(其中該烷基部分可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基 取代)、環C_3-6烷磺醯基、胺磺醯基、N-C_1-6烷基胺磺醯基(其中該烷基部分可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)、或N,N-二-(C_1-6烷基)胺磺醯基(其中該烷基部分可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷氧基、胺基、羥基、C_1-6烷胺基、及二-(C_1-6烷基)胺基之取代基取代)；R⁹代表H、C_1-6烷基、或F；R¹⁰代表H、C_1-6烷基、或F；或者R⁹及R¹⁰與彼等所連接之碳原子共同形成3-7員環，其可為飽和或不飽和，其中該環可隨意地含有一或二個選自硫、氧、及氮之雜原子且其中該環可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷基、C_1-6烷氧基、胺基、羥基、氰基、醯基、C_1-6烷胺基、二-(C_1-6烷基)胺基、C_1-6烷基羰基胺基、及側氧基之取代基取代；R¹¹代表H、C_1-6烷基、或環C_3-6烷基；R¹²代表H、C_1-6烷基、或環C_3-6烷基；或者R¹¹及R¹²與彼等所連接之氮原子共同形成3-7員環，其可為飽和或不飽和，其中該環可隨意地含有一或二個選自硫、氧、及氮之雜原子且其中該環可隨意地經一或多個選自鹵素、三氟甲基、三氟甲氧基、C_1-6烷基、C_1-6烷氧基、胺基、羥基、氰基、醯基、C_1-6烷胺基、 二-(C_1-6烷基)胺基、C_1-6烷基羰基胺基、及側氧基之取代基取代；及其光學異構體、前藥、藥學上可接受之鹽類、水合物、溶劑化物、及多形體；其中：如果R¹及R²與彼等所連接之碳原子共同形成羰基團時，則R⁸亦可代表H；R⁵不可代表隨意經取代之噻唑基；如果R⁸代表未經取代之C_1-6烷基時，則R⁵不代表隨意經取代之苯基；且式(I)化合物不可代表：N-(2,4-二氟苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺，N-(2,4-二甲氧基苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺，N-(2-氟苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺，N-(3,5-二甲氧基苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺，N-(3-甲氧基苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺，N-(4-氟苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺，N-(4-甲氧基苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺，N-苯基-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺， 2-((2,4-二氟苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯，2-((2,4-二甲氧基苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯，2-((2,5-二甲氧基苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯，2-((2-甲氧基苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯，2-((3,5-二甲氧基苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯，2-((3-甲氧基苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯，2-((4-氟苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯，2-((4-甲氧基苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯，1-(4-(5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基胺基)苯基)乙酮，或N-(4-苯氧基苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺。 a compound selected from Formula I Wherein X represents CR ⁶ (C=O)R ⁷ or NR ⁸ ; R ¹ represents H, C _1-6 alkyl, or F; R ² represents H, C _1-6 alkyl, or F; or R ¹ and R ² together with the carbon atom to which they are attached form a carbonyl group; or R ¹ and R ² together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may be optionally Containing one or two heteroatoms selected from the group consisting of sulfur, oxygen, and nitrogen, and wherein the ring is optionally optionally subjected to one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl , C _1-6 alkoxy, amine, hydroxy, cyano, decyl, C _1-6 alkylamino, bis-(C _1-6 alkyl)amino, C _1-6 alkylcarbonylamino And substituted with a pendant oxy group; R ³ represents H, C _1-6 alkyl, or F; R ⁴ represents H, C _1-6 alkyl, or F; or R ³ and R ⁴ and their The linked carbon atoms together form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from the group consisting of sulfur, oxygen, and nitrogen and wherein the ring is optionally One or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _1-6 alkoxy, amine, hydroxy, cyano , Acyl, C _1-6 alkylamino, di - (C _1-6 alkyl) amino, C _1-6 alkylcarbonyl group, and the oxo substituent; R ⁵ is selected from aryl representatives a monocyclic moiety of a heteroaryl group, a heterocyclic C _3-6 alkyl group, and a heterocyclic group; R ⁶ represents an H, C _1-6 alkyl group (which may optionally be selected from one or more selected from the group consisting of halogen and trifluoro) a substituent of a methyl group, a trifluoromethoxy group, a C _1-6 alkoxy group, an amine group, a hydroxyl group, a C _1-6 alkylamino group, and a bis-(C _1-6 alkyl)amino group), or F; R ⁷ represents a C _1-6 alkyl group (which may optionally be selected from one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxy, amine, hydroxy, C _{a 1-6} alkylamino group, and a substituent of a bis-(C _1-6 alkyl)amino group, a ring C _3-6 alkyl group, a heterocyclic group, or NR ¹¹ R ¹² ; or R ⁶ and R ⁷ Together with the carbon atoms to which they are attached, a 3-7 membered ring may be formed which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from the group consisting of sulfur, oxygen, and nitrogen and wherein the ring Optionally, one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _1-6 alkoxy, amine, hydroxy, cyano, decyl, C _1-6 alkylamino group Substituted with a substituent of a di-(C _1-6 alkyl)amino group, a C _1-6 alkylcarbonylamino group, and a pendant oxy group; R ⁸ represents a C _1-6 alkyl group (which may optionally be subjected to one or a plurality of selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxy, amine, hydroxy, C _1-6 alkylamino, and bis-(C _1-6 alkyl)amine Substituent substituent), cyclo C _3-6 alkyl, heterocyclyl, aryl, heteroaryl, C _1-6 alkylcarbonyl (which may optionally be selected from one or more selected from halogen, trifluoromethyl a substituent of a substituent such as a trifluoromethoxy group, a C _1-6 alkoxy group, an amine group, a hydroxyl group, a C _1-6 alkylamino group, and a bis-(C _1-6 alkyl)amino group, and a ring C _3-6 alkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, heteroarylcarbonyl, _C1-6 alkoxycarbonyl (which may optionally be selected from one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethyl) An oxy group, a C _1-6 alkoxy group, an amine group, a hydroxyl group, a C _1-6 alkylamino group, and a substituent of a bis-(C _1-6 alkyl)amino group, an amine carbonyl group, an N- C group _{a 1-6} alkylaminocarbonyl group (wherein the alkyl moiety is optionally optionally subjected to one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxy, amine, hydroxy, C _1-6 alkylamino group, and two a substituent substituted with a -(C _1-6 alkyl)amino group), N,N -di-(C _1-6 alkyl)aminocarbonyl (wherein the alkyl moiety is optionally optionally selected from one or more Halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkoxy, C _1-6 alkoxycarbonyl, cyano, amine, hydroxy, C _1-6 alkylamino, and di-(C Substituted by a substituent of a _1-6 alkyl) group, N- C _1-6 alkyl- N -cyclo C _3-6 alkylaminocarbonyl, N- C _1-6 alkyl- N -cyclo C _{3 a -6} alkyl-C _1-6 alkylaminocarbonyl group, an aminothiocarbonyl group, an N- C _1-6 alkylaminothiocarbonyl group (wherein the alkyl moiety is optionally optionally subjected to one or more halogens, a substituent of a trifluoromethyl group, a trifluoromethoxy group, a C _1-6 alkoxy group, an amine group, a hydroxyl group, a C _1-6 alkylamino group, and a bis-(C _1-6 alkyl)amino group) , N,N -di-(C _1-6 alkyl)aminothiocarbonyl (wherein the alkyl moiety is optionally optionally subjected to one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _{1 a -6} alkoxy group, an amine group, a hydroxyl group, a C _1-6 alkylamino group, and a substituent of a bis-(C _1-6 alkyl)amino group, and a C _1-6 alkanesulfonyl group (wherein the alkane) The base moiety may optionally be one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethyl Group, C _1-6 alkoxy, amino, hydroxy, C _1-6 alkoxy group, and two - (C _1-6 alkyl) amino group substituted with the substituents), cycloalkyl C _3-6 alkyl sulfonylurea a sulfonyl group, an N- C _1-6 alkylamine sulfonyl group (wherein the alkyl moiety is optionally optionally one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C _{1 a 6} -alkoxy group, an amine group, a hydroxyl group, a C _1-6 alkylamino group, and a substituent of a bis-(C _1-6 alkyl)amino group, or N,N -di-(C _1-6) Alkyl)sulfonyl (wherein the alkyl moiety is optionally optionally one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, _C1-6 alkoxy, amine, hydroxy, C _a substituent of a _1-6 alkylamino group and a bis-(C _1-6 alkyl)amino group; R ⁹ represents H, C _1-6 alkyl, or F; R ¹⁰ represents H, C _1-6 An alkyl group, or F; or R ⁹ and R ¹⁰ together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two selected from sulfur a hetero atom of oxygen, and nitrogen, and wherein the ring is optionally, optionally, one or more selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, _C1-6 alkyl, _C1-6 alkoxy, Amine, hydroxyl, cyano, Group, C _1-6 alkylamino, di - (C _1-6 alkyl) amino, C _1-6 alkylcarbonyl amino, oxo, and the substituents; R ¹¹ on behalf of H, C _{1- a 6} alkyl group, or a cyclic C _3-6 alkyl group; R ¹² represents H, C _1-6 alkyl, or a cyclic C _3-6 alkyl group; or R ¹¹ and R ¹² are formed together with the nitrogen atom to which they are attached a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from the group consisting of sulfur, oxygen, and nitrogen, and wherein the ring is optionally arbitrarily selected from one or more Halogen, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _1-6 alkoxy, amine, hydroxy, cyano, decyl, C _1-6 alkylamino, di-( a C _1-6 alkyl)amino group, a C _1-6 alkylcarbonylamino group, and a substituent of a pendant oxy group; and optical isomers, prodrugs, pharmaceutically acceptable salts thereof, hydrates, a solvate, and a polymorph; wherein: if R ¹ and R ² together with the carbon atom to which they are attached form a carbonyl group, then R ⁸ may also represent H; R ⁵ may not represent a randomly substituted thiazolyl; when the ⁸ represents unsubstituted C _1-6 alkyl, then R ⁵ does not represent the phenyl group substituted arbitrarily; (the I) and of formula It was not representative of: N - (2,4- difluorophenyl) -5,6,7,8-tetrahydro-pyrido [4,3-d] pyrimidin-2-amine, N - (2,4- two Methoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, N- (2-fluorophenyl)-5,6,7,8- Tetrahydropyrido[4,3-d]pyrimidin-2-amine, N- (3,5-dimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d Pyrimidine-2-amine, N- (3-methoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, N- (4-fluoro Phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, N- (4-methoxyphenyl)-5,6,7,8-tetra Hydropyrido[4,3-d]pyrimidin-2-amine, N -phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, 2-(( 2,4-difluorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxylic acid tert-butyl ester, 2-((2,4 -dimethoxyphenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxylic acid tert-butyl ester, 2-((2,5- Dimethoxyphenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxylic acid tert-butyl ester, 2-((2-methoxy) Phenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxylic acid tert-butyl ester, 2-((3,5-dimethoxybenzene) Amino)-7,8-dihydropyrido[4,3-d]pyrimidine -6(5 H )-carboxylic acid tert-butyl ester, 2-((3-methoxyphenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6 (5 H )-carboxylic acid tert-butyl ester, 2-((4-fluorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxylic acid Tributyl ester, 2-((4-methoxyphenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxylic acid tert-butyl ester, 1-(4-(5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-ylamino)phenyl)ethanone, or N- (4-phenoxyphenyl) -5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine. 如申請專利範圍第1項之化合物，其中R¹及R²與彼等所連接之碳原子共同形成羰基團，且X代表NR⁸，其中R⁸代表H。 A compound according to claim 1, wherein R ¹ and R ² together with the carbon atom to which they are attached form a carbonyl group, and X represents NR ⁸ , wherein R ⁸ represents H. 如申請專利範圍第1項之化合物，其中R¹及R² 代表H，且X代表CR⁶(C=O)R⁷，其中R⁶代表H且R⁷代表C_1-6烷基、雜環基或NR¹¹R¹²，其中R¹¹及R¹²代表C_1-6烷基。 The compound of claim 1, wherein R ¹ and R ² represent H, and X represents CR ⁶ (C=O)R ⁷ , wherein R ⁶ represents H and R ⁷ represents C _1-6 alkyl, heterocyclic ring Or NR ¹¹ R ¹² , wherein R ¹¹ and R ¹² represent C _1-6 alkyl. 如申請專利範圍第1項之化合物，其中R¹及R²代表H，且X代表NR⁸，其中R⁸代表C_1-6烷基羰基、環C_3-6烷基羰基、雜環基羰基、芳基羰基、C_1-6烷氧羰基、N-C_1-6烷基胺基羰基、N,N-二-(C_1-6烷基)胺基羰基、N,N-二-(C_1-6烷基)胺基硫羰基、N-C_1-6烷基-N-環C_3-6烷基胺基羰基、N-C_1-6烷基-N-環C_3-6烷基-N-C_1-6烷基胺基羰基、C_1-6烷磺醯基、環C_3-6烷磺醯基、N,N-二-(C_1-6烷基)胺磺醯基、或雜芳基。 The compound of claim 1, wherein R ¹ and R ² represent H, and X represents NR ⁸ , wherein R ⁸ represents C _1-6 alkylcarbonyl, cyclo C _3-6 alkylcarbonyl, heterocyclylcarbonyl , arylcarbonyl, C _1-6 alkoxycarbonyl, N- C _1-6 alkylaminocarbonyl, N,N -di-(C _1-6 alkyl)aminocarbonyl, N,N -di-( C _1-6 alkyl)aminothiocarbonyl, N- C _1-6 alkyl- N -cyclo C _3-6 alkylaminocarbonyl, N- C _1-6 alkyl- N -cyclo C _3-6 Alkyl- N- C _1-6 alkylaminocarbonyl, C _1-6 alkanesulfonyl, cyclo C _3-6 alkanesulfonyl, N,N -di-(C _1-6 alkyl)amine sulfonate Mercapto, or heteroaryl. 如申請專利範圍第4項之化合物，其中R⁸代表隨意經取代之吡啶基、四唑基、嘧啶基、呋喃基、噻唑基、或咪唑基。 A compound according to claim 4, wherein R ⁸ represents an optionally substituted pyridyl, tetrazolyl, pyrimidinyl, furyl, thiazolyl, or imidazolyl group. 如申請專利範圍第1至5項中任一項之化合物，其中R⁵代表隨意經一或多個選自鹵素、C_1-6烷基、及氰基之取代基取代之苯基。 The compound of any one of claims 1 to 5, wherein R ⁵ represents a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen, C _1-6 alkyl, and cyano. 如申請專利範圍第1項之化合物，其選自：2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-5(6H)-酮，(消旋)-(2-((3-氯苯基)胺基)-5,6,7,8-四氫喹唑啉-6-基)(哌啶-1-基)甲酮，1-(2-((3-氟苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)-2-甲基丙-1-酮， 1-(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)-2-甲基丙-1-酮，2-甲基-1-(2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)丙-1-酮，(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(環丙基)甲酮，1-(2-((4-氟苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)-2,2-二甲基丙-1-酮，1-(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)-2,2-二甲基丙-1-酮，3-((6-特戊醯基-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈，(消旋)-1-(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)-2-甲基丁-1-酮，(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(環丁基)甲酮，1-(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)-2-乙基丁-1-酮，(2-((3-氟苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(苯基)甲酮，(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(苯基)甲酮，2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸甲酯， 2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸乙酯，2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸異丙酯，2-((3-氟苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯，2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯，2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯，2-((3-氰苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-羧酸第三丁酯，2-((3-氯苯基)胺基)-N-乙基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，2-((3-氯苯基)胺基)-N,N-二甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，N-(3-氯苯基)-6-(異丙磺醯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺，N-(3-氯苯基)-6-(環丙磺醯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺，2-((3-氯苯基)胺基)-N,N-二甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-磺醯胺，N-(3-氯苯基)-6-(吡啶-2-基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺， 6-(1-(第三丁基)-1H-四唑-5-基)-N-(3-氯苯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺，N-(3-氯苯基)-6-(1-異丙基-1H-四唑-5-基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺，2-((3-氰苯基)胺基)-N,N-二甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，2-((3-氯苯基)胺基)-N,N-二乙基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，2-((3-氰苯基)胺基)-N,N-二乙基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，(消旋)-3-((6-(2-甲基丁醯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈，(消旋)-2-((3-氯苯基)胺基)-N,N-二甲基-5,6,7,8-四氫喹唑啉-6-甲醯胺，(消旋)-2-((3-氯苯基)胺基)-N,N-二乙基-5,6,7,8-四氫喹唑啉-6-甲醯胺，2-((3-氯苯基)胺基)-N,N-二甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-硫代甲醯胺，(消旋)-1-(2-((3-氯苯基)胺基)-5,6,7,8-四氫喹唑啉-6-基)-2-甲基丙-1-酮，2-(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)煙腈，(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(吡咯烷-1-基)甲酮， 2-((3-氰苯基)胺基)-N,N-二異丙基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，3-((6-(2-甲氧基-2-甲基丙醯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈，3-((6-(嗎啉-4-羰基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈，N-(3-氯苯基)-6-(嘧啶-2-基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺，(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(呋喃-2-基)甲酮，(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(噻唑-2-基)甲酮，(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(噻唑-5-基)甲酮，2-((5-氯基吡啶-3-基)胺基)-N,N-二甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，N-(3-氯苯基)-6-(1-甲基-1H-四唑-5-基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺，N-(3-氯苯基)-6-(1-甲基-1H-咪唑-2-基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-胺，3-((6-(2-乙基丁醯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈，N-丁基-(2-((3-氰苯基)胺基)-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺， 2-((3-氰苯基)胺基)-N-環丙基-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，2-((3-氯苯基)胺基)-N-乙基-N-丙基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，N,N-二甲基-2-((6-甲基吡啶-2-基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，(消旋)-3-((6-(2-乙基吡咯烷-1-羰基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈，N-(氰甲基)-2-((3-氰苯基)胺基)-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，3-((6-(1-甲基環丙烷羰基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈，3-((6-(2-甲基環丙烷羰基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈，2,2,-二甲基-1-(2-((6-甲基吡啶-2-基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)丙-1-酮，3-((6-(2-羥基-2-甲基丙醯基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈，N,N-二乙基-2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，2-((3-氰苯基)胺基)-N-異丙基-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，2-((3-氰苯基)胺基)-N-乙基-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺， 2-((3-氯苯基)胺基)-N-(環丙基甲基)-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，N,N-二甲基-2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，2-((3-氯苯基)胺基)-N-環丙基-N-乙基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，吡咯啶-1-基(2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)甲酮，(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(1-甲基環丙基)甲酮，(1-甲基環丙基)(2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)甲酮，N-乙基-N-丙基-2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，(消旋)-3-((6-(3-甲基吡咯烷-1-羰基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈，(消旋)-3-((6-(2-甲基吡咯烷-1-羰基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈，3-((6-(3,3-二甲基吖丁啶-1-羰基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈，2-((3-氰苯基)胺基)-N-乙基-N-丙基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，(消旋)-1-(2-((3-氯苯基)胺基)-5-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)-2,2-二甲基丙-1-酮， (消旋)-1-(2-((3-氯苯基)胺基)-7-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)-2,2-二甲基丙-1-酮，2-((3-氰苯基)胺基)-N,N-雙(2,2,2-三氟乙基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，吖丁啶-1-基(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)甲酮，2-(2-((3-氯苯基)胺基)-N-甲基-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-6-甲醯胺基)乙酸甲酯，N-(2-氰乙基)-2-((3-氰苯基)胺基)-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，2-((3-氰苯基)胺基)-N-(2-甲氧基乙基)-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，2-(2-(對位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)煙腈，2-((3-氰苯基)胺基)-N-甲基-N-丙基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，6-(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)吡啶-2-腈，2-(2-((3-氰苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)異煙腈，2-(2-((3-氰苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)-6-甲基煙腈，吖丁啶-1-基(2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)甲酮， N-乙基-N-甲基-2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，N-甲基-N-丙基-2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，2-((3-氯苯基)胺基)-N-甲基-N-丙基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，2-((3-氯苯基)胺基)-N-乙基-N-甲基-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-甲醯胺，3-((6-(1-異丙基-1H-咪唑-2-基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈，3-((6-(3-甲基環氧丙烷-3-羰基)-5,6,7,8-四氫吡啶並[4,3-d]嘧啶-2-基)胺基)苯甲腈，(2-((3-氯苯基)胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)(3-甲基環氧丙烷-3-基)甲酮，(3-甲基環氧丙烷-3-基)(2-(間位-甲苯基胺基)-7,8-二氫吡啶並[4,3-d]嘧啶-6(5H)-基)甲酮，及及其光學異構體、前藥、藥學上可接受之鹽類、水合物、溶劑化物、及多形體。 A compound according to claim 1 which is selected from the group consisting of: 2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-5( 6H ) -ketone, (racemic)-(2-((3-chlorophenyl)amino)-5,6,7,8-tetrahydroquinazolin-6-yl)(piperidin-1-yl)- Ketone, 1-(2-((3-fluorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)-2-methylpropane 1-ketone, 1-(2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)-2- Methyl propan-1-one, 2-methyl-1-(2-(meta-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H ) -yl)propan-1-one, (2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl) Cyclopropyl)methanone, 1-(2-((4-fluorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)- 2,2-Dimethylpropan-1-one, 1-(2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6 (5 H )-yl)-2,2-dimethylpropan-1-one, 3-((6-pententyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine -2-yl)amino)benzonitrile, (racemic)-1-(2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine -6(5 H )-yl)-2-methylbutan-1-one, (2-((3-chlorophenyl)amino)-7,8-dihydro Pyrido[4,3-d]pyrimidin-6(5 H )-yl)(cyclobutyl)methanone, 1-(2-((3-chlorophenyl)amino)-7,8-dihydro Pyrido[4,3-d]pyrimidin-6(5 H )-yl)-2-ethylbutan-1-one, (2-((3-fluorophenyl)amino)-7,8-di Hydropyrido[4,3-d]pyrimidin-6(5 H )-yl)(phenyl)methanone, (2-((3-chlorophenyl)amino)-7,8-dihydropyridyl) [4,3-d]pyrimidin-6(5 H )-yl)(phenyl)methanone, 2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3 -d]pyrimidine-6( 5H )-carboxylic acid methyl ester, 2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6 (5 H )-Carboxylic acid ethyl ester, 2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxylic acid isopropyl ester , 2-((3-fluorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxylic acid tert-butyl ester, 2-((3 -Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxylic acid tert-butyl ester, 2-(meta-tolylamino) -7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxylic acid tert-butyl ester, 2-((3-cyanophenyl)amino)-7,8-di Hydrogen pyrido[4,3-d]pyrimidin-6(5 H )-carboxylic acid tert-butyl ester, 2-((3-chlorophenyl)amino) -N -ethyl-7,8-dihydro pyrido [4,3-d] pyrimidin -6 (5 H) - A Amides 2 - ((3-chlorophenyl) amino) - N, N - dimethyl-7,8-dihydro-pyrido [4,3-d] pyrimidin -6 (5 H) - carboxylic acyl amine, N -(3-chlorophenyl)-6-(isopropylsulfonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, N- (3-chloro Phenyl)-6-(cyclopropanesulfonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, 2-((3-chlorophenyl)amine -N , N -Dimethyl-7,8-dihydropyrido[4,3-d]pyrimidin-6( 5H )-sulfonamide, N- (3-chlorophenyl)-6- (pyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, 6-(1-(t-butyl)-1 H -tetrazole 5-yl) - N - (3- chlorophenyl) -5,6,7,8-tetrahydro-pyrido [4,3-d] pyrimidin-2-amine, N - (3- chlorophenyl) -6-(1-isopropyl-1 H -tetrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, 2-(( 3-cyanophenyl)amino) -N , N -dimethyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carbenamide, 2-((3 -Chlorophenyl)amino) -N , N -diethyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carbenamide, 2-((3- Cyanophenyl)amino) -N , N -diethyl-7,8-dihydropyrido[4,3-d]pyrimidin-6( 5H )-carbenamide, (racemic)-3- ((6-(2-methylbutylidene)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl) Yl) benzonitrile, (rac) -2 - ((3-chlorophenyl) amino) - N, N - dimethyl-5,6,7,8-tetrahydro-6-quinazoline Indoleamine, (racemic)-2-((3-chlorophenyl)amino) -N , N -diethyl-5,6,7,8-tetrahydroquinazolin-6-carboxamide, 2-((3-Chlorophenyl)amino) -N , N -dimethyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-thiocarbamidine , (racemic)-1-(2-((3-chlorophenyl)amino)-5,6,7,8-tetrahydroquinazolin-6-yl)-2-methylpropan-1- Ketone, 2-(2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)nicotinonitrile, (2- ((3-Chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)(pyrrolidin-1-yl)methanone, 2- ((3-Cyanophenyl)amino) -N , N -diisopropyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carbenamide, 3- ((6-(2-Methoxy-2-methylpropenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzamide Nitrile, 3-((6-(morpholin-4-carbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile, N -(3-chlorophenyl)-6-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, (2-((3) - chlorophenyl) amino) -7,8-dihydro-pyrido [4,3-d] pyrimidin -6 (5 H) - yl) (furosemide 2-yl) methanone, (2 - ((3-chlorophenyl) amino) -7,8-dihydro-pyrido [4,3-d] pyrimidin -6 (5 H) - yl) (thiazole 2-yl)methanone, (2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl) (thiazole) -5-yl)methanone, 2-((5-chloropyridin-3-yl)amino) -N , N -dimethyl-7,8-dihydropyrido[4,3-d]pyrimidine -6(5 H )-carbamamine, N -(3-chlorophenyl)-6-(1-methyl-1 H -tetrazol-5-yl)-5,6,7,8-tetrahydro Pyrido[4,3-d]pyrimidin-2-amine, N- (3-chlorophenyl)-6-(1-methyl-1 H -imidazol-2-yl)-5,6,7,8 -tetrahydropyrido[4,3-d]pyrimidin-2-amine, 3-((6-(2-ethylbutylidene)-5,6,7,8-tetrahydropyrido[4,3-d Pyrimidin-2-yl)amino)benzonitrile, N -butyl-(2-((3-cyanophenyl)amino) -N -methyl-7,8-dihydropyrido[4, 3-d]pyrimidine-6(5 H )-formamide, 2-((3-cyanophenyl)amino) -N -cyclopropyl- N -methyl-7,8-dihydropyridin[ 4,3-d]pyrimidine-6(5 H )-formamide, 2-((3-chlorophenyl)amino) -N -ethyl- N -propyl-7,8-dihydropyridine [4,3-d]pyrimidine-6(5 H )-formamide, N , N -dimethyl-2-((6-methylpyridin-2-yl)amino)-7,8-di Hydropyrido[4,3-d]pyrimidin-6(5 H )-formamide, (racemic)-3 -((6-(2-ethylpyrrolidin-1-carbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile, N- (cyanomethyl)-2-((3-cyanophenyl)amino) -N -methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6( 5H )- Formamide, 3-((6-(1-methylcyclopropanecarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzamide Nitrile, 3-((6-(2-methylcyclopropanecarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile, 2,2,-Dimethyl-1-(2-((6-methylpyridin-2-yl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6 (5 H )-yl)propan-1-one, 3-((6-(2-hydroxy-2-methylpropenyl)-5,6,7,8-tetrahydropyrido[4,3-d] Pyrimidin-2-yl)amino)benzonitrile, N , N -diethyl-2-(meta-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5 H )-carbamide, 2-((3-cyanophenyl)amino) -N -isopropyl- N -methyl-7,8-dihydropyrido[4,3-d] Pyrimidine-6(5 H )-formamide, 2-((3-cyanophenyl)amino) -N -ethyl- N -methyl-7,8-dihydropyrido[4,3-d ] pyrimidin -6 (5 H) - A Amides, 2 - ((3-chlorophenyl) amino) - N - (cyclopropylmethyl) - N - methyl-7,8-dihydro-pyrido [4,3-d]pyrimidine-6(5 H )-formamide , N , N -Dimethyl-2-(meta-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carbenamide, 2- ((3-chlorophenyl)amino) -N -cyclopropyl- N -ethyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carboxamide, Pyrrolidin-1-yl (2-(meta-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)methanone, (2- ((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)(1-methylcyclopropyl)methanone, ( 1-methylcyclopropyl)(2-(meta-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)methanone, N -ethyl- N -propyl-2-(meta-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-carbamide, Cyclo)-3-((6-(3-methylpyrrolidin-1-carbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino) Benzonitrile, (racemic)-3-((6-(2-methylpyrrolidin-1-carbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2 -yl)amino)benzonitrile, 3-((6-(3,3-dimethylazetidin-1-carbonyl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-2-yl)amino)benzonitrile, 2-((3-cyanophenyl)amino) -N -ethyl- N -propyl-7,8-dihydropyrido[4, 3-d]pyrimidine-6 (5 H -Metformamide, (racemic)-1-(2-((3-chlorophenyl)amino)-5-methyl-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5 H )-yl)-2,2-dimethylpropan-1-one, (racemic)-1-(2-((3-chlorophenyl)amino)-7-methyl-7 , 8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)-2,2-dimethylpropan-1-one, 2-((3-cyanophenyl)amino group ) -N , N -bis(2,2,2-trifluoroethyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-formamide, azetidine 1-yl (2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 H )-yl)methanone, 2-( Methyl 2-((3-chlorophenyl)amino) -N -methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-carboxamido)acetate , N- (2-cyanoethyl)-2-((3-cyanophenyl)amino) -N -methyl-7,8-dihydropyrido[4,3-d]pyrimidine-6 (5 H) - A Amides, 2 - ((3-cyanophenyl) amino) - N - (2- methoxyethyl) - N - methyl-7,8-dihydro-pyrido [4,3- -d]pyrimidine-6(5 H )-formamide, 2-(2-(p-tolylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6 (5 H )-yl)nicotinonitrile, 2-((3-cyanophenyl)amino) -N -methyl- N -propyl-7,8-dihydropyrido[4,3-d]pyrimidine-6 (5 H) - A Amides, 6- (2 - ((3-chlorophenyl) amino) -7,8-dihydro-pyridine [4,3-d] pyrimidin -6 (5 H) - yl) pyridine-2-carbonitrile, 2- (2 - ((3-cyanophenyl) amino) -7,8-dihydro-pyrido [4 ,3-d]pyrimidin-6(5 H )-yl)isonicotinonitrile, 2-(2-((3-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d Pyrimidine-6(5 H )-yl)-6-methylnicotinonitrile, azetidin-1-yl (2-(meta-tolylamino)-7,8-dihydropyrido[4, 3-d]pyrimidin-6(5 H )-yl)methanone, N -ethyl- N -methyl-2-(meta-tolylamino)-7,8-dihydropyrido[4, 3-d]pyrimidin-6(5 H )-formamide, N -methyl- N -propyl-2-(meta-tolylamino)-7,8-dihydropyrido[4,3 -d]pyrimidin-6(5 H )-formamide, 2-((3-chlorophenyl)amino) -N -methyl- N -propyl-7,8-dihydropyrido[4, 3-d]pyrimidin-6(5 H )-formamide, 2-((3-chlorophenyl)amino) -N -ethyl- N -methyl-7,8-dihydropyrido[4 ,3-d]pyrimidine-6(5 H )-formamide, 3-((6-(1-isopropyl-1 H -imidazol-2-yl)-5,6,7,8-tetrahydrol Pyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile, 3-((6-(3-methylepoxypropan-3-carbonyl)-5,6,7,8- Tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile, (2-((3-chlorophenyl)amino)-7,8-dihydropyrido[4, 3-d] pyrimidin -6 (5 H) - yl) (3-methylcyclohexyl Propane-3-yl)methanone, (3-methylepoxypropan-3-yl)(2-(meta-tolylamino)-7,8-dihydropyrido[4,3-d] Pyrimidine-6(5 H )-yl)methanone, and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof. 一種藥學組成物，其包含如先前任一申請專利範圍所主張之化合物，連同一或多種藥學上可接受之賦形劑。 A pharmaceutical composition comprising a compound as claimed in any of the preceding claims, together with one or more pharmaceutically acceptable excipients. 一種如申請專利範圍第1至7項中任一項之化合物，係用於治療及/或預防異常麩胺酸神經傳導。 A compound according to any one of claims 1 to 7 for use in the treatment and/or prevention of abnormal glutamate nerve conduction. 一種如申請專利範圍第1至7項中任一項之化合 物，係用於治療及/或預防選自阿滋海默氏症、庫賈氏症候群/庫賈氏症、狂牛症(BSE)、普恩蛋白相關性感染、涉及粒線體功能障礙之疾病、涉及β-澱粉樣蛋白之疾病及/或tau蛋白病、唐氏症、肝性腦病、亨丁頓氏症、運動神經元病、肌萎縮性側索硬化症(ALS)、橄欖體橋腦小腦萎縮、手術後認知不足(POCD)、系統性紅斑性狼瘡、系統性硬化、修格蘭氏症候群、神經元蠟樣脂褐質沉著症、神經退化性小腦運動失調、帕金森氏症、帕金森氏癡呆症、輕度知能障礙、各種不同形式之輕度認知障礙中之認知不足、各種不同形式之癡呆症中之認知不足、拳擊手癡呆症、血管及額葉型癡呆症、認知障礙、學習障礙、眼部損傷、眼症、眼疾、青光眼、視網膜病變、黃斑部病變、頭或腦或脊髓損傷、頭或腦或脊髓外傷、外傷、低血糖症、缺氧、週產期缺氧、缺血、因心跳停止或中風或繞道手術或移植所致之缺血、痙攣、癲癇性痙攣、癲癇、顳葉癲癇、陣攣性癲癇、內耳損傷、耳鳴之內耳損傷、耳鳴、聲音-或藥物-誘發性內耳損傷、聲音-或藥物-誘發性耳鳴、L-多巴-誘發性運動障礙、帕金森氏症療法中之L-多巴-誘發性運動障礙、運動障礙、亨丁頓氏症之運動障礙、藥物誘發性運動障礙、抗精神病藥物-誘發性運動障礙、氟哌啶醇(haloperidol)-誘發性運動障礙、多巴胺模擬藥-誘發性運動障礙、舞蹈症、亨丁頓氏舞蹈症、指痙症、肌張力不全症、刻板症、顫搐、遲發性運動障礙、抽動症、痙攣性斜頸、眼瞼痙攣、局部及全身性肌張力不全、眼球震 顫、遺傳性小腦運動失調、皮質基底核退化症、顫抖症、原發性顫抖症、濫用、成癮症、尼古丁成癮症、尼古丁濫用、酒精成癮症、酒精濫用、鴉片成癮症、鴉片濫用、古柯鹼成癮症、古柯鹼濫用、***成癮症、***濫用、焦慮症、恐慌症、焦慮及恐慌症、社交焦慮症(SAD)、注意力不足過動症(ADHD)、注意力不足症候群(ADS)、不寧腿症候群(RLS)、孩童過動症、自閉症、癡呆症、阿滋海默氏症之癡呆症、科爾薩科夫(Korsakoff)症候群之癡呆症、科爾薩科夫(Korsakoff)症候群、血管型癡呆症、與HIV感染相關之癡呆症、HIV-1腦病變、愛滋病腦病變、愛滋病癡呆綜合症、愛滋病相關性癡呆症、重鬱症、重度憂鬱、憂鬱症、因博爾納(Borna)病毒感染所致之憂鬱症、因博爾納(Borna)病毒感染所致之重鬱症、雙極性躁鬱症、藥物耐受性、對鴉片類藥物之藥物耐受性、運動障礙、易脆X症候群、腸躁症(IBS)、偏頭痛、多發性硬化症(MS)、肌肉痙攣、疼痛、慢性疼痛、急性疼痛、炎性疼痛、神經痛、糖尿病性神經痛(DNP)、與風濕性關節炎相關之疼痛、痛覺異常、痛覺過敏、感覺接受性疼痛、癌症疼痛、創傷後壓力症候群(PTSD)、精神***症、精神***症之陽性或認知或陰性症狀、痙攣狀態、妥瑞氏症、尿失禁、嘔吐、搔癢病況、搔癢症、睡眠症、頻尿症、下尿道之神經肌肉疾病、胃食道逆流症(GERD)、胃腸功能障礙、下食道括約肌(LES)病症、功能性胃腸病、消化不良、反胃、呼吸道感染、神經性暴食症、慢性喉 炎、氣喘、逆流相關性氣喘、肺病、飲食失調症、肥胖症、肥胖相關病症、肥胖***、食物成癮症、暴食症、廣場恐懼症、廣泛性焦慮症、強迫症、恐慌症、創傷後壓力症候群、社交恐懼症、恐懼症、物質-誘發性焦慮症、妄想症、情感***型病症、類精神***症、物質-誘發性精神病、或譫妄之疾病或病況；抑制周邊組織、周邊神經系統及中樞神經系統之腫瘤細胞生長、遷移、侵襲、黏附及毒性；腫瘤形成、增生、發育不良、癌症、癌瘤、肉瘤、口腔癌、鱗狀上皮細胞癌(SCC)、口腔鱗狀上皮細胞癌(SCC)、肺癌、肺腺癌、乳癌、攝護腺癌、胃癌、肝癌、結腸癌、結腸直腸癌、橫紋肌肉瘤、腦腫瘤、神經組織的腫瘤、膠質瘤、惡性膠質瘤、星型膠質瘤、神經膠質瘤、神經母細胞瘤、膠質母細胞瘤、髓母細胞瘤、皮膚細胞的癌症、黑色素瘤、惡性黑色素瘤、上皮腫瘤、淋巴瘤、骨髓瘤、何杰金氏病、伯基特氏(Burkitt’s)淋巴瘤、白血病、胸腺瘤、腫瘤、糖尿病、高氨血症及肝衰竭及睡眠障礙。 A compound according to any one of claims 1 to 7 for use in the treatment and/or prevention of a disease selected from the group consisting of Alzheimer's disease, CJ's syndrome, CJD, BSE, and Protein-associated infections, diseases involving mitochondrial dysfunction, diseases involving beta -amyloid and/or tauopathy, Down's disease, hepatic encephalopathy, Huntington's disease, motor neuron disease, muscle Atrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, postoperative cognitive deficit (POCD), systemic lupus erythematosus, systemic sclerosis, repairing granule syndrome, neuronal waxy lipofacia , neurodegenerative cerebellar dysmotility, Parkinson's disease, Parkinson's disease, mild dysfunction, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, boxers Dementia, vascular and frontal dementia, cognitive impairment, learning disabilities, eye damage, eye disease, eye disease, glaucoma, retinopathy, macular degeneration, head or brain or spinal cord injury, head or brain or spinal cord trauma, trauma ,low Hypoglycemia, hypoxia, hypoxia during perinatal period, ischemia, ischemia due to cardiac arrest or stroke or bypass surgery or transplantation, epilepsy, epilepsy, temporal lobe epilepsy, clonic epilepsy, inner ear injury Inner ear injury, tinnitus, sound- or drug-induced inner ear injury, sound- or drug-induced tinnitus, L-dopa-induced dyskinesia, L-dopa-induced in Parkinson's disease therapy Sexual dyskinesia, dyskinesia, dyskinesia in Huntington's disease, drug-induced dyskinesia, antipsychotic-induced dyskinesia, haloperidol-induced dyskinesia, dopamine mimetic-induced Dyskinesia, chorea, Huntington's disease, dysthymia, dystonia, stereotypic, twitching, tardive dyskinesia, tic disorder, spastic torticollis, eyelids, local and systemic muscles Insufficient tension, nystagmus, hereditary cerebellar dysmotility, cortical basal ganglia degeneration, trembling, primary tremor, abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol Use, opium addiction, opium abuse, ***e addiction, ***e abuse, amphetamine addiction, amphetamine abuse, anxiety, panic disorder, anxiety and panic disorder, social anxiety disorder (SAD), attention Insufficient Hyperactivity Disorder (ADHD), Attention Deficit Syndrome (ADS), Restless Leg Syndrome (RLS), Childhood Hyperactivity, Autism, Dementia, Alzheimer's Dementia, Corsac Korsakoff syndrome dementia, Korsakoff syndrome, vascular dementia, dementia associated with HIV infection, HIV-1 brain disease, AIDS brain disease, AIDS dementia syndrome, AIDS-related Dementia, severe depression, severe depression, depression, depression due to Borna virus infection, severe depression due to Borna virus infection, bipolar bipolar disorder, drug tolerance Sex, tolerance to opioids, dyskinesia, fragile X syndrome, intestinal tract (IBS), migraine, multiple sclerosis (MS), muscle cramps, pain, chronic pain, acute pain, inflammation Sexual pain, neuralgia, diabetic god Menstrual pain (DNP), pain associated with rheumatoid arthritis, pain abnormalities, hyperalgesia, sensory pain, cancer pain, post-traumatic stress syndrome (PTSD), schizophrenia, schizophrenia, positive or cognitive or negative symptoms , sputum status, turdy disease, urinary incontinence, vomiting, pruritus, pruritus, sleep disorder, frequent urination, neuromuscular disease of the lower urinary tract, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter ( LES) Disorders, functional gastrointestinal disorders, dyspepsia, nausea, respiratory infections, bulimia nervosa, chronic laryngitis, asthma, reflux-associated asthma, lung disease, eating disorders, obesity, obesity-related disorders, obesity abuse, food Addiction, binge eating disorder, square phobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress syndrome, social phobia, phobia, substance-induced anxiety disorder, delusional disorder, emotional schizophrenic disorder, class Schizophrenia, substance-induced psychosis, or disease or condition of sputum; inhibition of peripheral tissues, peripheral nervous system, and central nervous system Tumor cell growth, migration, invasion, adhesion and toxicity; tumor formation, proliferation, dysplasia, cancer, carcinoma, sarcoma, oral cancer, squamous cell carcinoma (SCC), oral squamous cell carcinoma (SCC), lung cancer , lung adenocarcinoma, breast cancer, prostate cancer, gastric cancer, liver cancer, colon cancer, colorectal cancer, rhabdomyosarcoma, brain tumor, nerve tissue tumor, glioma, malignant glioma, astroglioma, glioma, Neuroblastoma, glioblastoma, medulloblastoma, cancer of skin cells, melanoma, malignant melanoma, epithelial tumor, lymphoma, myeloma, Hodgkin's disease, Burkitt's lymph Tumor, leukemia, thymoma, tumor, diabetes, hyperammonemia and liver failure and sleep disorders. 一種如申請專利範圍第1至7項中任一項之化合物之用途，係用於製造供治療及/或預防選自阿滋海默氏症、庫賈氏症候群/庫賈氏症、狂牛症(BSE)、普恩蛋白相關性感染、涉及粒線體功能障礙之疾病、涉及β-澱粉樣蛋白之疾病及/或tau蛋白病、唐氏症、肝性腦病、亨丁頓氏症、運動神經元病、肌萎縮性側索硬化症(ALS)、橄欖體橋腦小腦萎縮、手術後認知不足(POCD)、系統性紅 斑性狼瘡、系統性硬化、修格蘭氏症候群、神經元蠟樣脂褐質沉著症、神經退化性小腦運動失調、帕金森氏症、帕金森氏癡呆症、輕度知能障礙、各種不同形式之輕度認知障礙中之認知不足、各種不同形式之癡呆症中之認知不足、拳擊手癡呆症、血管及額葉型癡呆症、認知障礙、學習障礙、眼部損傷、眼症、眼疾、青光眼、視網膜病變、黃斑部病變、頭或腦或脊髓損傷、頭或腦或脊髓外傷、外傷、低血糖症、缺氧、週產期缺氧、缺血、因心跳停止或中風或繞道手術或移植所致之缺血、痙攣、癲癇性痙攣、癲癇、顳葉癲癇、陣攣性癲癇、內耳損傷、耳鳴之內耳損傷、耳鳴、聲音-或藥物-誘發性內耳損傷、聲音-或藥物-誘發性耳鳴、L-多巴-誘發性運動障礙、帕金森氏症療法中之L-多巴-誘發性運動障礙、運動障礙、亨丁頓氏症之運動障礙、藥物誘發性運動障礙、抗精神病藥物-誘發性運動障礙、氟哌啶醇(haloperidol)-誘發性運動障礙、多巴胺模擬藥-誘發性運動障礙、舞蹈症、亨丁頓氏舞蹈症、指痙症、肌張力不全症、刻板症、顫搐、遲發性運動障礙、抽動症、痙攣性斜頸、眼瞼痙攣、局部及全身性肌張力不全、眼球震顫、遺傳性小腦運動失調、皮質基底核退化症、顫抖症、原發性顫抖症、濫用、成癮症、尼古丁成癮症、尼古丁濫用、酒精成癮症、酒精濫用、鴉片成癮症、鴉片濫用、古柯鹼成癮症、古柯鹼濫用、***成癮症、***濫用、焦慮症、恐慌症、焦慮及恐慌症、社交焦慮症(SAD)、注意力不足過動症(ADHD)、注意力不 足症候群(ADS)、不寧腿症候群(RLS)、孩童過動症、自閉症、癡呆症、阿滋海默氏症之癡呆症、科爾薩科夫(Korsakoff)症候群之癡呆症、科爾薩科夫(Korsakoff)症候群、血管型癡呆症、與HIV感染相關之癡呆症、HIV-1腦病變、愛滋病腦病變、愛滋病癡呆綜合症、愛滋病相關性癡呆症、重鬱症、重度憂鬱、憂鬱症、因博爾納(Borna)病毒感染所致之憂鬱症、因博爾納(Borna)病毒感染所致之重鬱症、雙極性躁鬱症、藥物耐受性、對鴉片類藥物之藥物耐受性、運動障礙、易脆X症候群、腸躁症(IBS)、偏頭痛、多發性硬化症(MS)、肌肉痙攣、疼痛、慢性疼痛、急性疼痛、炎性疼痛、神經痛、糖尿病性神經痛(DNP)、與風濕性關節炎相關之疼痛、痛覺異常、痛覺過敏、感覺接受性疼痛、癌症疼痛、創傷後壓力症候群(PTSD)、精神***症、精神***症之陽性或認知或陰性症狀、痙攣狀態、妥瑞氏症、尿失禁、嘔吐、搔癢病況、搔癢症、睡眠症、頻尿症、下尿道之神經肌肉疾病、胃食道逆流症(GERD)、胃腸功能障礙、下食道括約肌(LES)病症、功能性胃腸病、消化不良、反胃、呼吸道感染、神經性暴食症、慢性喉炎、氣喘、逆流相關性氣喘、肺病、飲食失調症、肥胖症、肥胖相關病症、肥胖***、食物成癮症、暴食症、廣場恐懼症、廣泛性焦慮症、強迫症、恐慌症、創傷後壓力症候群、社交恐懼症、恐懼症、物質-誘發性焦慮症、妄想症、情感***型病症、類精神***症、物質-誘發性精神病、或譫妄之疾病或病況；抑制周邊組 織、周邊神經系統及中樞神經系統之腫瘤細胞生長、遷移、侵襲、黏附及毒性；腫瘤形成、增生、發育不良、癌症、癌瘤、肉瘤、口腔癌、鱗狀上皮細胞癌(SCC)、口腔鱗狀上皮細胞癌(SCC)、肺癌、肺腺癌、乳癌、攝護腺癌、胃癌、肝癌、結腸癌、結腸直腸癌、橫紋肌肉瘤、腦腫瘤、神經組織的腫瘤、膠質瘤、惡性膠質瘤、星型膠質瘤、神經膠質瘤、神經母細胞瘤、膠質母細胞瘤、髓母細胞瘤、皮膚細胞的癌症、黑色素瘤、惡性黑色素瘤、上皮腫瘤、淋巴瘤、骨髓瘤、何杰金氏病、伯基特氏(Burkitt’s)淋巴瘤、白血病、胸腺瘤、腫瘤、糖尿病、高氨血症及肝衰竭及睡眠障礙之醫藥。 Use of a compound according to any one of claims 1 to 7 for the manufacture and/or prevention of a disease selected from the group consisting of Alzheimer's disease, CJ's syndrome/CJ's disease, mad cow disease ( BSE), Purin-associated infection, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/or tau protein disease, Down's disease, hepatic encephalopathy, Huntington's disease, motor nerve Meta-disease, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, postoperative cognitive deficit (POCD), systemic red Lupus erythematosus, systemic sclerosis, granulosus syndrome, neuronal waxy lipofacia, neurodegenerative cerebellar dysmotility, Parkinson's disease, Parkinson's dementia, mild dysfunction, various forms Cognitive deficits in mild cognitive impairment, cognitive deficits in various forms of dementia, boxer dementia, vascular and frontal dementia, cognitive impairment, learning disabilities, eye injuries, eye disorders, eye disorders, glaucoma , retinopathy, macular degeneration, head or brain or spinal cord injury, head or brain or spinal cord trauma, trauma, hypoglycemia, hypoxia, hypoxia during perinatal period, ischemia, cardiac arrest or stroke or bypass surgery or transplantation Ischemia, convulsions, epilepsy, epilepsy, temporal lobe epilepsy, clonic epilepsy, inner ear injury, inner ear injury of tinnitus, tinnitus, sound- or drug-induced inner ear injury, sound- or drug-induced Tinnitus, L-dopa-induced dyskinesia, L-dopa-induced dyskinesia in Parkinson's disease therapy, dyskinesia, dyskinesia in Huntington's disease, drug-induced movement Obstacle, antipsychotic-induced dyskinesia, haloperidol-induced dyskinesia, dopamine mimetic-induced dyskinesia, chorea, Huntington's disease, dysthymia, dystonia Symptoms, stereotypes, twitching, tardive dyskinesia, tic disorder, spastic torticollis, eyelids, local and systemic dystonia, nystagmus, hereditary cerebellar dysmotility, cortical basal ganglia degeneration, tremor , primary tremor, abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opium addiction, opium abuse, ***e addiction, ***e abuse, amphetamine Addiction, amphetamine abuse, anxiety, panic disorder, anxiety and panic disorder, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit Foot Syndrome (ADS), Restless Leg Syndrome (RLS), Childhood Hyperactivity, Autism, Dementia, Alzheimer's Dementia, Korsakoff Syndrome Dementia, Section Korsakoff syndrome, vascular dementia, dementia associated with HIV infection, HIV-1 brain disease, AIDS brain disease, AIDS dementia syndrome, AIDS-related dementia, severe depression, severe depression, depression Symptoms, depression due to Borna virus infection, severe depression due to Borna virus infection, bipolar bipolar disorder, drug tolerance, drug tolerance to opioids Sex, dyskinesia, fragile X syndrome, intestinal fistula (IBS), migraine, multiple sclerosis (MS), muscle cramps, pain, chronic pain, acute pain, inflammatory pain, neuralgia, diabetic neuralgia (DNP), pain associated with rheumatoid arthritis, hyperalgesia, hyperalgesia, sensory pain, cancer pain, post-traumatic stress syndrome (PTSD), schizophrenia, schizophrenia, positive or cognitive or negative symptoms, State Toray's disease, urinary incontinence, vomiting, pruritus, pruritus, sleep disorder, frequent urination, neuromuscular disease of the lower urinary tract, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, Functional gastrointestinal disorders, dyspepsia, nausea, respiratory infections, bulimia nervosa, chronic laryngitis, asthma, reflux-associated asthma, lung disease, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, Bulimia, square phobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress syndrome, social phobia, phobia, substance-induced anxiety, paranoia, schizophrenia, schizophrenia, Substance-induced psychosis, or disease or condition of sputum; inhibition of peripheral groups Tumor cell growth, migration, invasion, adhesion and toxicity of the woven, peripheral nervous system and central nervous system; tumor formation, proliferation, dysplasia, cancer, carcinoma, sarcoma, oral cancer, squamous cell carcinoma (SCC), oral cavity Squamous cell carcinoma (SCC), lung cancer, lung adenocarcinoma, breast cancer, prostate cancer, gastric cancer, liver cancer, colon cancer, colorectal cancer, rhabdomyosarcoma, brain tumor, nerve tissue tumor, glioma, malignant glioma , astroglia, glioma, neuroblastoma, glioblastoma, medulloblastoma, cancer of skin cells, melanoma, malignant melanoma, epithelial tumor, lymphoma, myeloma, Hodgkin's Medicine, Burkitt's lymphoma, leukemia, thymoma, tumor, diabetes, hyperammonemia and liver failure and sleep disorders. 一種如申請專利範圍第8項之藥學組成物，係用於治療或預防與異常麩胺酸神經傳導有關之病況或疾病，或用於調節mGluR5受體以達治療效益。 A pharmaceutical composition according to item 8 of the patent application for use in the treatment or prevention of a condition or disease associated with abnormal glutamate nerve conduction, or for modulating the mGluR5 receptor for therapeutic benefit. 如申請專利範圍第12項之藥學組成物，其中該與異常麩胺酸神經傳導有關之病況，或其中該mGluR5受體之調節以達治療效益係選自：阿滋海默氏症、庫賈氏症候群/庫賈氏症、狂牛症(BSE)、普恩蛋白相關性感染、涉及粒線體功能障礙之疾病、涉及β-澱粉樣蛋白之疾病及/或tau蛋白病、唐氏症、肝性腦病、亨丁頓氏症、運動神經元病、肌萎縮性側索硬化症(ALS)、橄欖體橋腦小腦萎縮、手術後認知不足(POCD)、系統性紅斑性狼瘡、系統性硬化、修格蘭氏症候群、神經元蠟樣脂褐質沉著症、神經退化性小腦運動失調、帕金森氏症、帕金森氏癡呆症、 輕度知能障礙、各種不同形式之輕度認知障礙中之認知不足、各種不同形式之癡呆症中之認知不足、拳擊手癡呆症、血管及額葉型癡呆症、認知障礙、學習障礙、眼部損傷、眼症、眼疾、青光眼、視網膜病變、黃斑部病變、頭或腦或脊髓損傷、頭或腦或脊髓外傷、外傷、低血糖症、缺氧、週產期缺氧、缺血、因心跳停止或中風或繞道手術或移植所致之缺血、痙攣、癲癇性痙攣、癲癇、顳葉癲癇、陣攣性癲癇、內耳損傷、耳鳴之內耳損傷、耳鳴、聲音-或藥物-誘發性內耳損傷、聲音-或藥物-誘發性耳鳴、L-多巴-誘發性運動障礙、帕金森氏症療法中之L-多巴-誘發性運動障礙、運動障礙、亨丁頓氏症之運動障礙、藥物誘發性運動障礙、抗精神病藥物-誘發性運動障礙、氟哌啶醇(haloperidol)-誘發性運動障礙、多巴胺模擬藥-誘發性運動障礙、舞蹈症、亨丁頓氏舞蹈症、指痙症、肌張力不全症、刻板症、顫搐、遲發性運動障礙、抽動症、痙攣性斜頸、眼瞼痙攣、局部及全身性肌張力不全、眼球震顫、遺傳性小腦運動失調、皮質基底核退化症、顫抖症、原發性顫抖症、濫用、成癮症、尼古丁成癮症、尼古丁濫用、酒精成癮症、酒精濫用、鴉片成癮症、鴉片濫用、古柯鹼成癮症、古柯鹼濫用、***成癮症、***濫用、焦慮症、恐慌症、焦慮及恐慌症、社交焦慮症(SAD)、注意力不足過動症(ADHD)、注意力不足症候群(ADS)、不寧腿症候群(RLS)、孩童過動症、自閉症、癡呆症、阿滋海默氏症之癡呆症、科爾薩科夫(Korsakoff)症候 群之癡呆症、科爾薩科夫(Korsakoff)症候群、血管型癡呆症、與HIV感染相關之癡呆症、HIV-1腦病變、愛滋病腦病變、愛滋病癡呆綜合症、愛滋病相關性癡呆症、重鬱症、重度憂鬱、憂鬱症、因博爾納(Borna)病毒感染所致之憂鬱症、因博爾納(Borna)病毒感染所致之重鬱症、雙極性躁鬱症、藥物耐受性、對鴉片類藥物之藥物耐受性、運動障礙、易脆X症候群、腸躁症(IBS)、偏頭痛、多發性硬化症(MS)、肌肉痙攣、疼痛、慢性疼痛、急性疼痛、炎性疼痛、神經痛、糖尿病性神經痛(DNP)、與風濕性關節炎相關之疼痛、痛覺異常、痛覺過敏、感覺接受性疼痛、癌症疼痛、創傷後壓力症候群(PTSD)、精神***症、精神***症之陽性或認知或陰性症狀、痙攣狀態、妥瑞氏症、尿失禁、嘔吐、搔癢病況、搔癢症、睡眠症、頻尿症、下尿道之神經肌肉疾病、胃食道逆流症(GERD)、胃腸功能障礙、下食道括約肌(LES)病症、功能性胃腸病、消化不良、反胃、呼吸道感染、神經性暴食症、慢性喉炎、氣喘、逆流相關性氣喘、肺病、飲食失調症、肥胖症、肥胖相關病症、肥胖***、食物成癮症、暴食症、廣場恐懼症、廣泛性焦慮症、強迫症、恐慌症、創傷後壓力症候群、社交恐懼症、恐懼症、物質-誘發性焦慮症、妄想症、情感***型病症、類精神***症、物質-誘發性精神病、或譫妄；抑制周邊組織、周邊神經系統及中樞神經系統之腫瘤細胞生長、遷移、侵襲、黏附及毒性；腫瘤形成、增生、發育不良、癌症、癌瘤、肉瘤、口腔癌、鱗狀 上皮細胞癌(SCC)、口腔鱗狀上皮細胞癌(SCC)、肺癌、肺腺癌、乳癌、攝護腺癌、胃癌、肝癌、結腸癌、結腸直腸癌、橫紋肌肉瘤、腦腫瘤、神經組織的腫瘤、膠質瘤、惡性膠質瘤、星型膠質瘤、神經膠質瘤、神經母細胞瘤、膠質母細胞瘤、髓母細胞瘤、皮膚細胞的癌症、黑色素瘤、惡性黑色素瘤、上皮腫瘤、淋巴瘤、骨髓瘤、何杰金氏病、伯基特氏(Burkitt’s)淋巴瘤、白血病、胸腺瘤、腫瘤、糖尿病、高氨血症及肝衰竭及睡眠障礙。 The pharmaceutical composition of claim 12, wherein the condition associated with abnormal glutamate nerve conduction, or wherein the mGluR5 receptor is modulated to achieve therapeutic benefit, is selected from the group consisting of: Alzheimer's disease, Cuija Syndrome/Cuija's disease, mad cow disease (BSE), Purkinin-related infection, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/or tau protein disease, Down's syndrome, liver Encephalopathy, Huntington's disease, motor neuron disease, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, postoperative cognitive deficit (POCD), systemic lupus erythematosus, systemic sclerosis, repair Gram's syndrome, neuronal waxy lipofacia, neurodegenerative cerebellar dysmotility, Parkinson's disease, Parkinson's dementia, Mild dysfunction, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, boxer dementia, vascular and frontal dementia, cognitive impairment, learning disabilities, eye Injury, eye, eye disease, glaucoma, retinopathy, macular degeneration, head or brain or spinal cord injury, head or brain or spinal cord trauma, trauma, hypoglycemia, hypoxia, hypoxia during perinatal period, ischemia, heartbeat Ischemia, convulsions, epilepsy, epilepsy, temporal lobe epilepsy, clonic epilepsy, inner ear injury, tinnitus inner ear injury, tinnitus, sound- or drug-induced inner ear injury caused by cessation or stroke or bypass surgery or transplantation , sound- or drug-induced tinnitus, L-dopa-induced dyskinesia, L-dopa-induced dyskinesia in Parkinson's disease therapy, dyskinesia, dyskinesia in Huntington's disease, drugs Induced dyskinesia, antipsychotic-induced dyskinesia, haloperidol-induced dyskinesia, dopamine mimetic-induced dyskinesia, chorea, Huntington's Mind, dysthymia, dystonia, stereotypic, twitching, tardive dyskinesia, tic disorder, spastic torticollis, eyelids, local and systemic dystonia, nystagmus, hereditary cerebellar movement Dysfunction, cortical basal ganglia degeneration, trembling, primary tremor, abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opium addiction, opium abuse, ***e Addiction, ***e abuse, amphetamine addiction, amphetamine abuse, anxiety, panic disorder, anxiety and panic disorder, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit disorder ( ADS), Restless Leg Syndrome (RLS), Childhood Hyperactivity, Autism, Dementia, Alzheimer's Dementia, Korsakoff Symptoms Group dementia, Korsakoff syndrome, vascular dementia, dementia associated with HIV infection, HIV-1 brain disease, AIDS brain disease, AIDS dementia syndrome, AIDS-related dementia, weight Depression, severe depression, depression, depression caused by Borna virus infection, severe depression caused by Borna virus infection, bipolar bipolar disorder, drug tolerance, opium Drug-tolerance, dyskinesia, fragile X syndrome, intestinal fistula (IBS), migraine, multiple sclerosis (MS), muscle cramps, pain, chronic pain, acute pain, inflammatory pain, nerves Pain, diabetic neuropathic pain (DNP), pain associated with rheumatoid arthritis, analgesia, hyperalgesia, sensory pain, cancer pain, post-traumatic stress syndrome (PTSD), schizophrenia, schizophrenia Or cognitive or negative symptoms, spasticity, dysplasia, urinary incontinence, vomiting, pruritus, pruritus, sleep disorder, frequent urination, neuromuscular disease of the lower urinary tract, gastroesophageal reflux disease (GERD), stomach Dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disease, dyspepsia, nausea, respiratory infection, bulimia nervosa, chronic laryngitis, asthma, reflux-associated asthma, lung disease, eating disorders, obesity, obesity Related conditions, obesity abuse, food addiction, binge eating disorder, square phobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress syndrome, social phobia, phobia, substance-induced anxiety, paranoia , schizophrenia, schizophrenia, substance-induced psychosis, or sputum; inhibition of tumor growth, migration, invasion, adhesion and toxicity of peripheral tissues, peripheral nervous system and central nervous system; tumor formation, proliferation, development Adverse, cancer, cancer, sarcoma, oral cancer, squamous Epithelial cell carcinoma (SCC), oral squamous cell carcinoma (SCC), lung cancer, lung adenocarcinoma, breast cancer, prostate cancer, gastric cancer, liver cancer, colon cancer, colorectal cancer, rhabdomyosarcoma, brain tumor, nerve tissue Tumor, glioma, malignant glioma, astroglia, glioma, neuroblastoma, glioblastoma, medulloblastoma, cancer of skin cells, melanoma, malignant melanoma, epithelial tumor, lymphoma , myeloma, Hodgkin's disease, Burkitt's lymphoma, leukemia, thymoma, tumor, diabetes, hyperammonemia and liver failure and sleep disorders. 一種藥學組成物，其包含至少一種如申請專利範圍第1至7項中任一項之化合物及至少一種NMDA受體拮抗劑之組合，連同一或多種藥學上可接受之賦形劑。 A pharmaceutical composition comprising at least one combination of a compound according to any one of claims 1 to 7 and at least one NMDA receptor antagonist, together with one or more pharmaceutically acceptable excipients.