TW201524972A - Imidazole derivatives - Google Patents
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- TW201524972A TW201524972A TW103141261A TW103141261A TW201524972A TW 201524972 A TW201524972 A TW 201524972A TW 103141261 A TW103141261 A TW 103141261A TW 103141261 A TW103141261 A TW 103141261A TW 201524972 A TW201524972 A TW 201524972A
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本發明係關於式(I)化合物
其中A係選自由以下組成之群：
B係C1-C4-伸烷基、C2-C4-伸烯基、C2-C4-伸炔基，R1係選自氫、C1-C7-烷基、C1-C7-烷氧基烷基、C1-C7-鹵烷基、-(CH2)0,1,2-C3-C5-環烷基、視情況經鹵素、C1-C7-烷基或C1-C7烷氧基取代之-(CH2)0,1,2-(雜-)芳基，R2係選自視情況經1至3個選自以下各項之取代基取代之雜芳基：鹵素、羥基、C1-C7-烷基、C1-C7-羥基烷基、C1-C7-鹵烷氧基、C1-C7-鹵烷基、C3-C5-環烷基、氰基、胺基、硝基、-O-R6-C(O)-R7、雜芳基、雜環烷基、-SO2R12-C(O)NR’R”、NR’R”，其中R’及R”係獨立地選自氫、C1-C7-烷基或R’及R”與其所附接之氮原子一起形成雜環烷基，或R2係選自視情況經鹵素取代之C1-C2-烷氧基，R6及R12係獨立地選自C1-C7-烷基， R7係選自雜環烷基，X係NR3或CR3，Y係(CH2)n，n係1、2、3、4，R3係選自氫、C1-C7-烷基。 B is a C 1 -C 4 -alkylene group, a C 2 -C 4 -alkenyl group, a C 2 -C 4 -exetylene group, and the R 1 group is selected from the group consisting of hydrogen, C 1 -C 7 -alkyl, C 1 -C 7 -alkoxyalkyl, C 1 -C 7 -haloalkyl, -(CH 2 ) 0,1,2- C 3 -C 5 -cycloalkyl, optionally halogen, C 1 -C 7 -alkyl or C 1 -C 7 alkoxy substituted -(CH 2 ) 0,1,2- (hetero-)aryl, R 2 is selected from 1 to 3, optionally selected from the following Heteroaryl substituted by a substituent: halogen, hydroxy, C 1 -C 7 -alkyl, C 1 -C 7 -hydroxyalkyl, C 1 -C 7 -haloalkoxy, C 1 -C 7 -halide Alkyl, C 3 -C 5 -cycloalkyl, cyano, amine, nitro, -OR 6 -C(O)-R 7 , heteroaryl, heterocycloalkyl, -SO 2 R 12 -C (O) NR'R ", NR'R" , wherein R 'and R "are independently selected hydrogen, C 1 -C 7 - alkyl or R' and R" appended thereto together form a hetero nitrogen atom of contact a cycloalkyl group, or R 2 is selected from C 1 -C 2 -alkoxy optionally substituted by halogen, R 6 and R 12 are independently selected from C 1 -C 7 -alkyl, and R 7 is selected from Heterocycloalkyl, X-based NR 3 or CR 3 , Y-based (CH 2 ) n , n-system 1, 2, 3 , 4, and R 3 is selected from hydrogen and C 1 -C 7 -alkyl.
另外，本發明係關於製造上述化合物、含有該等化合物之醫藥製劑之製程以及該等化合物於製造醫藥製劑之用途。 Further, the present invention relates to a process for producing the above-mentioned compounds, a pharmaceutical preparation containing the same, and the use of the compounds in the manufacture of a pharmaceutical preparation.
精神***症係進行性及破壞性神經疾病，其特徵在於陣發性正性症狀(例如妄想、幻覺、思維病症及精神病)及持續性負性症狀(例如冷漠感情、注意力受損及社交退縮以及認知損害)(Lewis DA及Lieberman JA,Neuron,28：325-33,2000)。數十年來，人們一直致力於研究會導致涉及多巴胺能系統阻斷之治療性干預的「多巴胺能亢進(dopaminergic hyperactivity)」假說(Vandenberg RJ及Aubrey KR.,Exp.Opin.Ther.Targets,5(4)：507-518,2001；Nakazato A及Okuyama S等人，Exp.Opin.Ther.Patents,10(1)：75-98,2000)。除改善精神***症患者之正性症狀外，此藥理學方法不能很好地解決負性及認知症狀，該等症狀係功能結果之最佳預報器(Sharma T.,Br.J.Psychiatry,174(增刊28)：44-51,1999)。另外，當前抗精神病治療會引起諸如體重增加、錐體束外症狀或影響葡萄糖及脂質代謝等不利作用，此等不利作用與其非特異性藥理學相關。 Schizophrenia is a progressive and destructive neurological disorder characterized by paroxysmal positive symptoms (such as delusions, hallucinations, thought disorders, and psychosis) and persistent negative symptoms (such as indifference, impaired attention, and social withdrawal). And cognitive impairment) (Lewis DA and Lieberman JA, Neuron, 28:325-33, 2000 ). For decades, people have been working on the hypothesis of dopaminergic hyperactivity that leads to therapeutic interventions involving dopaminergic system blockade (Vandenberg RJ and Aubrey KR., Exp . Opin . Ther . Targets , 5 ( 4): 507-518, 2001 ; Nakazato A and Okuyama S et al, Exp . Opin . Ther . Patents , 10(1): 75-98, 2000 ). In addition to improving the positive symptoms of patients with schizophrenia, this pharmacological approach does not adequately address negative and cognitive symptoms, which are the best predictors of functional outcomes (Sharma T., Br . J. Psychiatry , 174) (Supplement 28): 44-51, 1999 ). In addition, current antipsychotic treatments can cause adverse effects such as weight gain, extrapyramidal symptoms or effects of glucose and lipid metabolism, which are associated with their non-specific pharmacology.
總之，仍需要研發具有改良功效及安全性質的新穎抗精神病藥物。在1960年代中期，人們根據因麩胺酸鹽系統受到諸如苯環利定(phencyclidine，PCP)等化合物及作為非競爭性NMDA受體拮抗劑之相關藥劑(***(ketamine))阻斷而引發的擬精神病行為提出了精神***症之互補模型。令人感興趣的是，在健康志願者中，PCP誘發之擬 精神病行為包含正性及負性症狀及認知功能障礙，因而非常類似於患者的精神***症(Javitt DC等人，Biol.Psychiatry,45：668-679,1999)。 In summary, there is still a need to develop novel antipsychotic drugs with improved efficacy and safety properties. In the mid-1960s, it was triggered by a compound such as phencyclidine (PCP) and a related agent (ketamine) that is a non-competitive NMDA receptor antagonist due to the glutamate system. Psychotic behavior proposes a complementary model of schizophrenia. Interestingly, in healthy volunteers, PCP induced Psychotic behaviors include positive and negative symptoms and cognitive dysfunction and are therefore very similar to patients with schizophrenia (Javitt DC et al, Biol. Psychiatry, 45: 668-679, 1999).
環狀核苷酸環單磷酸腺苷(cAMP)及環單磷酸鳥苷(cGMP)係普遍存在的第二信使，其負責調節多種細胞外信號(包括神經遞質、光及激素)之生物反應。cAPM及cGMP藉由激活cAMP-及cGMP-依賴性激酶、隨後該等激酶磷酸化參與調控突觸傳遞、神經元分化及存活之蛋白質來調控多種細胞內過程(尤其在中樞神經系統之神經元中)。 Cyclic Nucleotide Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are ubiquitous second messengers that regulate the biological responses of a variety of extracellular signals, including neurotransmitters, light and hormones. . cAPM and cGMP regulate a variety of intracellular processes by activating cAMP- and cGMP-dependent kinases, followed by phosphorylation of these kinases involved in the regulation of synaptic transmission, neuronal differentiation and survival (especially in neurons of the central nervous system) ).
控制細胞內環狀核苷酸含量及因此環狀核苷酸信號傳導之重要機制係經由藉由磷酸二酯酶使3’,5’-磷酸二酯鍵水解。磷酸二酯酶(PDE)係廣泛表現之酶家族，其在人類中係由21種不同基因編碼，其中每一種基因編碼若干種剪接變體(Beavo,J.,Physiol.Rev.1995,75,725-748；Conti,M.、Jin,S.L.,Prog.Nucleic Acid Res.Mol.Biol.1999,63,1-38；Soderling,S.H.、Beavo,J.A.,Curr.Opin.Cell Biol.2000,12,174-179；Manallack,D.T.等人，J.Med.Chem.2005,48(10),3449-3462)。 An important mechanism for controlling the intracellular cyclic nucleotide content and thus the circular nucleotide signaling is by hydrolysis of the 3',5'-phosphodiester linkage by phosphodiesterase. Phosphodiesterase (PDE) is a family of enzymes that are widely expressed in humans and are encoded by 21 different genes, each of which encodes several splice variants (Beavo, J., Physiol. Rev. 1995, 75, 725- 748; Conti, M., Jin, SL, Prog. Nucleic Acid Res. Mol. Biol. 1999, 63, 1-38; Soderling, SH, Beavo, JA, Curr. Opin. Cell Biol. 2000, 12, 174-179; Manallack, DT et al, J. Med. Chem. 2005, 48(10), 3449-3462).
PDE家族在對環狀核苷酸之受質特異性、調控機制及對抑制劑之敏感性方面有所不同。另外，其在生物體中、器官細胞之間且甚至細胞內之分佈具有差異。該等差異導致PDE家族有區別地參與各種生理學功能。 The PDE family differs in the nature of the cyclic nucleotides, the regulatory mechanisms, and the sensitivity to inhibitors. In addition, there are differences in the distribution in organisms, between organ cells and even within cells. These differences lead to a distinct involvement of the PDE family in various physiological functions.
如1999年三個單獨的研究組所報導，PDE10A係由單一基因編碼之雙重受質PDE(Fujishige K.等人，Eur J Biochem(1999)266(3)：1118-1127；Soderling S.H.等人，ProcNatl Acad Sci USA(1999)96(12)：7071-7076；Loughney K.等人，Gene(1999)234(1)：109-117)。PDE10A在以下方面與其他多基因家族成員不同：胺基酸序列(779 aa)、組織特異性表現模式、對cAMP及cGMP之親和性以及特異 及一般抑制劑對PDE活性之影響。 As reported by three separate research groups in 1999, PDE10A is a dual-enhanced PDE encoded by a single gene (Fujishige K. et al., Eur J Biochem (1999) 266(3): 1118-1127; Soderling SH et al. ProcNatl Acad Sci USA (1999) 96(12): 7071-7076; Loughney K. et al., Gene (1999) 234(1): 109-117). PDE10A differs from other multigene family members in the following aspects: amino acid sequence (779 aa), tissue-specific expression pattern, affinity for cAMP and cGMP, and specificity And the effect of general inhibitors on PDE activity.
PDE10A係任何PDE家族中分佈最為受限之家族之一，其主要表現於腦中，尤其表現於伏核及尾狀殼核中。另外，丘腦、嗅球、海馬及額皮質顯示中等PDE10A表現量。已表明，所有該等腦區皆與精神***症及精神病之病理生理異常相關，此表明PDE10A在此破壞性精神疾病中具有重要作用。除中樞神經系統以外，亦在諸如甲狀腺、垂體、胰島素分泌胰臟細胞及睪丸等外周組織中觀察到PDE10A轉錄物之表現(Fujishige,K.等人，J.Biol.Chem.1999,274,18438-18445；Sweet,L.(2005)WO 2005/012485)。另一方面，僅在腸神經節、睪丸及附睪***中觀察到PDE10A蛋白之表現(Coskran T.M等人，J.Histochem.Cytochem.2006,54(11),1205-1213)。 PDE10A is one of the most restricted families of any PDE family, which is mainly expressed in the brain, especially in the nucleus accumbens and caudate putamen. In addition, the thalamus, olfactory bulb, hippocampus, and frontal cortex showed moderate PDE10A performance. It has been shown that all of these brain regions are associated with pathophysiological abnormalities of schizophrenia and psychosis, suggesting that PDE10A plays an important role in this devastating mental disorder. In addition to the central nervous system, PDE10A transcripts were also observed in peripheral tissues such as thyroid, pituitary, insulin-secreting pancreatic cells, and testis (Fujishige, K. et al., J. Biol. Chem. 1999, 274, 18438). -18445; Sweet, L. (2005) WO 2005/012485). On the other hand, the expression of the PDE10A protein was observed only in the intestinal ganglion, the testis and the spermatozoa (Coskran T. M et al., J. Histochem. Cytochem. 2006, 54(11), 1205-1213).
在紋狀體中，mRNA及蛋白質二者皆僅表現於含有GABA(γ-胺基丁酸)之中型多棘投射神經元中，此使其成為治療中樞神經系統疾病之引人興趣的靶(Fujishige,K.等人，Eur.J.Biochem.1999,266,1118-1127；Seeger,T.F.等人，Brain Res.2003,985,113-126)。紋狀體中型多棘神經元係哺乳動物腦之基底神經節迴路中的主要輸入位點及用於資訊整合的首要位點。基底神經節係一系列相互連接之皮質下核，其將廣泛分佈之皮質輸入與多巴胺能信號傳導整合在一起以部署及執行相關活動及認知模式，同時阻抑不期望或不相關之模式(Graybiel,A.M.Curr.Biol.2000,10,R509-R511(2000)。 In the striatum, both mRNA and protein are only expressed in medium-sized spiny projection neurons containing GABA (γ-aminobutyric acid), making it an attractive target for the treatment of central nervous system diseases ( Fujishige, K. et al., Eur. J. Biochem. 1999, 266, 1118-1127; Seeger, TF et al., Brain Res. 2003, 985, 113-126). The striatum medium spine neuron is the main input site in the basal ganglion circuit of the mammalian brain and the primary site for information integration. Basal ganglia A series of interconnected subcortical nucleus that integrates widely distributed cortical inputs with dopaminergic signaling to deploy and perform related activities and cognitive patterns while suppressing undesired or unrelated patterns (Graybiel , AM Curr. Biol. 2000, 10, R509-R511 (2000).
已使用罌粟鹼(papaverine，一種相對特異性PDE10A抑制劑)及PDE10A基因敲除小鼠來探究此酶之生理學功能及PDE10A抑制之可能治療用途。以藥理學方式或經由基因破壞來抑制此酶使得活動性減弱且對精神性運動興奮劑之反應降低。抑制亦減少條件躲避反應，該反應係一種預測臨床抗精神病活性之行為反應(Siuciak,J.A.等人，Neuropharmacology 2006,51(2),386-396；Siuciak,J.A.等人， Neuropharmacology 2006,51(2),374-385)。 Papaverine (a relatively specific PDE10A inhibitor) and PDE10A knockout mice have been used to explore the physiological functions of this enzyme and the possible therapeutic uses of PDE10A inhibition. Inhibition of this enzyme in a pharmacological manner or via genetic disruption results in reduced activity and reduced response to psychomotor stimulants. Inhibition also reduces the conditional avoidance response, a behavioral response that predicts clinical antipsychotic activity (Siuciak, J.A. et al., Neuropharmacology 2006, 51(2), 386-396; Siuciak, J.A., et al. Neuropharmacology 2006, 51(2), 374-385).
另外，PDE10A抑制具有改良與精神***症相關之負性及認知症狀的潛能。實際上，已顯示罌粟鹼可減弱由使用PCP亞慢性治療誘發之大鼠外維度轉換學習(extra-dimensional shift learning)缺陷(NMDA受體功能減退之動物範例)(Rodefer,J,S.等人，Eur.J.Neuroscience 2005,2,：1070-1076)。另外，已觀察到PDE10A2缺失小鼠之社會互動增加(Sano,H.J.Neurochem.2008,105,546-556)。 In addition, PDE10A inhibits the potential to improve negative and cognitive symptoms associated with schizophrenia. In fact, papaverine has been shown to attenuate the extra-dimensional shift learning deficit in rats induced by PCP subchronic therapy (An animal paradigm of NMDA receptor dysfunction) (Rodefer, J, S. et al. , Eur. J. Neuroscience 2005, 2,: 1070-1076). In addition, an increase in social interaction in PDE10A2-deficient mice has been observed (Sano, H.J. Neurochem. 2008, 105, 546-556).
可使用PDE10A抑制劑治療之疾病包括(但不限於)認為部分由基底神經節、中樞神經系統之其他部分及其他PDE10A表現組織之功能障礙介導之疾病。具體而言，可治療抑制PDE10A可具有治療效果之疾病。 Diseases that can be treated with a PDE10A inhibitor include, but are not limited to, diseases that are believed to be mediated, in part, by dysfunction of the basal ganglia, other parts of the central nervous system, and other PDE10A-expressing tissues. Specifically, a disease which inhibits the therapeutic effect of PDE10A can be treated.
該等疾病包括(但不限於)某些精神病症，例如精神***症、與精神***症相關之正性、負性及/或認知症狀、妄想症或物質誘發之精神病症；焦慮症，例如驚恐症、強迫症(obsessive-compulsive disorder)、急性應激病症或廣泛性焦慮症；強迫性病症(obsessive/compulsive disorder)；藥物成癮；運動病症，例如帕金森氏症(Parkinson’s disease)或不寧腿症候群；認知缺陷病症，例如阿茲海默氏症(Alzheimer’s disease)或多發性梗塞性癡呆；情緒病症，例如抑鬱症或雙向情感病症；或神經精神病況，例如精神病、注意力缺陷/多動症(ADHD)或相關注意力病症。 Such diseases include, but are not limited to, certain psychiatric conditions such as schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, delusions or substance-induced psychiatric disorders; anxiety disorders such as panic , obsessive-compulsive disorder, acute stress disorder or generalized anxiety disorder; obsessive/compulsive disorder; drug addiction; motor disorder, such as Parkinson's disease or restlessness Leg syndrome; cognitive deficit disorders such as Alzheimer's disease or multiple infarct dementia; mood disorders such as depression or two-way affective disorders; or neuropsychiatric conditions such as psychosis, attention deficit/hyperactivity disorder ( ADHD) or related attention disorders.
本發明化合物亦適於藉由調控cAMP信號傳導系統來治療糖尿病及相關病症(例如肥胖症)。 The compounds of the invention are also suitable for the treatment of diabetes and related conditions (e.g., obesity) by modulating the cAMP signaling system.
PDE10A抑制劑亦可藉由提高cAMP及cGMP含量用於防止神經元經歷凋亡，且因此可能具有抗發炎性質。可使用PDE10A抑制劑治療之神經變性病症包括(但不限於)阿茲海默氏病、亨廷頓氏病、帕金森氏病、多發性硬化、中風或脊髓損傷。 PDE10A inhibitors can also be used to prevent neuronals from undergoing apoptosis by increasing cAMP and cGMP levels, and thus may have anti-inflammatory properties. Neurodegenerative disorders treatable with PDE10A inhibitors include, but are not limited to, Alzheimer's disease, Huntington's disease, Parkinson's disease, multiple sclerosis, stroke, or spinal cord injury.
cAMP及cGMP抑制癌細胞之生長。因此，藉由增加cAMP及cGMP，PDE10A抑制劑亦可用於治療不同實體腫瘤及血液惡性腫瘤，例如腎細胞癌或乳癌。 cAMP and cGMP inhibit the growth of cancer cells. Therefore, by increasing cAMP and cGMP, PDE10A inhibitors can also be used to treat different solid tumors and hematological malignancies, such as renal cell carcinoma or breast cancer.
除非另有說明，否則在本文中列示以下定義來說明並定義用於闡述本發明之各術語的含義及範疇。 Unless otherwise stated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention.
術語「式(I)化合物」、「式(I)之化合物」、「本發明化合物」或「本發明之化合物」係指選自如由式(I)定義之化合物之群之任一化合物，包括其立體異構物、互變異構物、溶劑合物及鹽(例如醫藥上可接受之鹽)。 The term "compound of formula (I)", "compound of formula (I)", "compound of the invention" or "compound of the invention" means any compound selected from the group consisting of compounds as defined by formula (I), including Stereoisomers, tautomers, solvates and salts thereof (e.g., pharmaceutically acceptable salts).
必須注意，除非上下文另外明確說明，否則如說明書及申請專利範圍中所使用，單數形式「一(a、an)」及「該」皆包括複數個指示物。 It must be noted that the singular forms "a", "an", "the"
當指示取代基之數量時，術語「一或多個」意指一個取代基至最高可能取代數量，即經取代基替代一個氫至高達替代所有氫。 When indicating the number of substituents, the term "one or more" means one substituent to the highest possible substitution number, i.e., replacing one hydrogen with a substituent up to all hydrogens.
術語「可選」或「視情況」表示隨後闡述之事件或情況可能但未必發生，且該描述包括該事件或情況發生之情形以及該事件或情況未發生之情形。 The term "optional" or "as appropriate" means that the subsequently described event or circumstance may, but does not necessarily, occur, and that the description includes the circumstances in which the event or circumstance occurred and the circumstances in which the event or circumstance did not occur.
術語「取代基」表示替代母體分子上之氫原子的原子或原子之群。 The term "substituent" means a group of atoms or atoms that replace a hydrogen atom on a parent molecule.
術語「烯基」表示具有至少一個雙鍵之2至7個碳原子之單價直鏈或具支鏈烴基團。在具體實施例中，烯基具有2至4個碳原子與至少一個雙鍵。烯基之實例包括乙烯基、丙烯基、丙-2-烯基、異丙烯 基、正丁烯基、異丁烯基及第三丁烯基。 The term "alkenyl" denotes a monovalent straight or branched hydrocarbon group having from 2 to 7 carbon atoms of at least one double bond. In a particular embodiment, an alkenyl group has 2 to 4 carbon atoms and at least one double bond. Examples of alkenyl groups include ethenyl, propenyl, prop-2-enyl, isopropene Base, n-butenyl, isobutenyl and third butenyl.
術語「伸烯基」表示具有至少一個雙鍵之2至7個碳原子之直鏈二價烴鏈或3至7個碳原子之具支鏈二價烴鏈。實例性伸烯基包括伸乙烯基、2,2-二甲基伸乙烯基、丙伸烯基、2-甲基丙伸烯基、丁伸烯基及伸戊烯基。 The term "alkenyl group" means a linear divalent hydrocarbon chain of 2 to 7 carbon atoms having at least one double bond or a branched divalent hydrocarbon chain of 3 to 7 carbon atoms. Exemplary alkenyl groups include vinyl, 2,2-dimethylvinyl, propenyl, 2-methylpropenyl, butenyl and pentenyl.
術語「烷氧基」表示式-O-R’之基團，其中R’係烷基。烷氧基部分之實例包括甲氧基、乙氧基、異丙氧基及第三丁氧基。 The term "alkoxy" denotes a radical of the formula -O-R' wherein R' is alkyl. Examples of the alkoxy moiety include a methoxy group, an ethoxy group, an isopropoxy group, and a third butoxy group.
術語「烷基」表示1至12個碳原子之單價直鏈或具支鏈飽和烴基團。在具體實施例中，烷基具有1至7個碳原子，且在更具體實施例中具有1至4個碳原子。烷基之實例包括甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基。 The term "alkyl" denotes a monovalent straight or branched saturated hydrocarbon group of 1 to 12 carbon atoms. In a particular embodiment, the alkyl group has from 1 to 7 carbon atoms, and in more specific embodiments from 1 to 4 carbon atoms. Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a second butyl group or a tert-butyl group.
術語「伸烷基」表示1至7個碳原子之直鏈飽和二價烴基團或3至7個碳原子之二價具支鏈飽和二價烴基團。伸烷基之實例包括亞甲基、伸乙基、伸丙基、2-甲基伸丙基、伸丁基、2-乙基伸丁基、伸戊基、伸己基。 The term "alkylene" means a linear saturated divalent hydrocarbon group of 1 to 7 carbon atoms or a divalent branched saturated divalent hydrocarbon group of 3 to 7 carbon atoms. Examples of alkylene groups include methylene, ethyl, propyl, 2-methylpropyl, butyl, 2-ethylbutyl, pentyl, and hexyl.
術語「伸炔基」表示具有至少一個三鍵之2-6個碳原子之直鏈二價烴鏈或3-6個碳原子之具支鏈二價烴鏈。實例性伸炔基包括伸乙炔基、2,2-二甲基伸乙炔基、伸丙炔基、2-甲基伸丙炔基、伸丁炔基及伸戊炔基。 The term "extended alkynyl" means a straight-chain divalent hydrocarbon chain of 2 to 6 carbon atoms having at least one triple bond or a branched divalent hydrocarbon chain of 3 to 6 carbon atoms. Exemplary alkynyl groups include ethynyl, 2,2-dimethylexetylene, propynyl, 2-methylpropynyl, butynyl and pentynyl.
術語「芳香族」表示芳香度之習用概念，如文獻、具體而言IUPAC-Compendium of Chemical Terminology，第2版，A.D.McNaught及A.Wilkinson(編輯).Blackwell Scientific Publications,Oxford(1997)中所定義。 The term "aromatic" refers to the conventional concept of aroma, as defined in the literature, specifically IUPAC-Compendium of Chemical Terminology, 2nd ed., ADMcNaught and A. Wilkinson (ed.), Blackwell Scientific Publications, Oxford (1997). .
術語「芳基」表示包含6至10個碳環原子之單價芳香族碳環單環或二環系統。芳基部分之實例包括苯基及萘基。 The term "aryl" means a monovalent aromatic carbocyclic monocyclic or bicyclic ring system containing from 6 to 10 carbon ring atoms. Examples of the aryl moiety include a phenyl group and a naphthyl group.
術語「二環系統」表示經由共用單鍵或雙鍵(增環二環系統)、經 由三個或更多個共用原子之序列(橋接二環系統)或經由共用單一原子(螺二環系統)彼此稠合之兩個環。二環系統可為飽和、部分不飽和、不飽和或芳香族系統。二環系統可包含選自N、O及S之雜原子。 The term "bicyclic system" means via a shared single or double bond (additional ring system) Two rings fused to each other by a sequence of three or more shared atoms (bridged bicyclic system) or via a shared single atom (spirobicyclic system). The bicyclic system can be a saturated, partially unsaturated, unsaturated or aromatic system. The bicyclic system may comprise a heteroatom selected from the group consisting of N, O and S.
術語「氰基烷基」表示其中烷基之至少一個氫原子經氰基替代之烷基。氰基烷基之實例包括氰基甲基、氰基乙基、氰基丙基、氰基-異丙基、氰基-異丁基、氰基-第二丁基、氰基-第三丁基、氰基戊基或氰基己基。 The term "cyanoalkyl" denotes an alkyl group wherein at least one hydrogen atom of the alkyl group is replaced by a cyano group. Examples of the cyanoalkyl group include a cyanomethyl group, a cyanoethyl group, a cyanopropyl group, a cyano-isopropyl group, a cyano-isobutyl group, a cyano-second butyl group, and a cyano-third butyl group. Base, cyanopentyl or cyanohexyl.
術語「環烷基」表示3至10個環碳原子之單價飽和單環或二環烴基團。在具體實施例中，環烷基表示3至8個環碳原子之單價飽和單環烴基團。二環意指由兩個具有一或多個共用碳原子之飽和碳環組成。具體環烷基係單環。單環環烷基之實例係環丙基、環丁基、環戊基、環己基或環庚基。二環環烷基之實例係二環[2.2.1]庚基或二環[2.2.2]辛基。 The term "cycloalkyl" means a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms. In a particular embodiment, a cycloalkyl group represents a monovalent saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. Bicyclic means consisting of two saturated carbon rings having one or more shared carbon atoms. The specific cycloalkyl group is a single ring. Examples of monocyclic cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples of bicyclic cycloalkyl groups are bicyclo [2.2.1] heptyl or bicyclo [2.2.2] octyl.
術語「鹵烷氧基」表示其中烷氧基之至少一個氫原子經相同或不同的鹵素原子(尤其氟原子)替代之烷氧基。鹵烷氧基之實例包括單氟-、二氟-或三氟-甲氧基、-乙氧基或-丙氧基，例如3,3,3-三氟丙氧基、2-氟乙氧基、2,2,2-三氟乙氧基、氟甲氧基或三氟甲氧基。術語「全鹵烷氧基」表示其中烷氧基之所有氫原子皆經相同或不同的鹵素原子替代之烷氧基。 The term "haloalkoxy" denotes an alkoxy group in which at least one hydrogen atom of the alkoxy group is replaced by the same or different halogen atom, especially a fluorine atom. Examples of haloalkoxy groups include monofluoro-, difluoro- or trifluoro-methoxy, -ethoxy or -propoxy, such as 3,3,3-trifluoropropoxy, 2-fluoroethoxy Base, 2,2,2-trifluoroethoxy, fluoromethoxy or trifluoromethoxy. The term "perhaloalkoxy" denotes an alkoxy group wherein all of the hydrogen atoms of the alkoxy group are replaced by the same or different halogen atoms.
術語「鹵烷基」表示其中烷基之至少一個氫原子經相同或不同的鹵素原子(尤其氟原子)替代之烷基。鹵烷基之實例包括單氟-、二氟-或三氟-甲基、-乙基或-丙基，例如3,3,3-三氟丙基、2-氟乙基、2,2,2-三氟乙基、氟甲基或三氟甲基。術語「全鹵烷基」表示其中烷基之所有氫原子皆經相同或不同的鹵素原子替代之烷基。 The term "haloalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is replaced by the same or a different halogen atom, especially a fluorine atom. Examples of haloalkyl groups include monofluoro-, difluoro- or trifluoro-methyl, -ethyl or -propyl, such as 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2, 2-Trifluoroethyl, fluoromethyl or trifluoromethyl. The term "perhaloalkyl" means an alkyl group wherein all of the hydrogen atoms of the alkyl group are replaced by the same or different halogen atoms.
術語「雜芳基」表示具有5至12個環原子、包含1個、2個、3個或4個選自N、O及S之雜原子、其餘環原子皆為碳之單價芳香族雜環 單環或二環環系統。雜芳基部分之實例包括吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、噻唑基、***基、噁二唑基、噻二唑基、四唑基、吡啶基、吡基、吡唑基、嗒基、嘧啶基、三基、氮呯基、二氮呯基、異噁唑基、苯并呋喃基、異噻唑基、苯并噻吩基、吲哚基、異吲哚基、異苯并呋喃基、苯并咪唑基、苯并噁唑基、苯并異噁唑基、苯并噻唑基、苯并異噻唑基、苯并噁二唑基、苯并噻二唑基、苯并***基、嘌呤基、喹啉基、異喹啉基、喹唑啉基或喹喔啉基。 The term "heteroaryl" means a monovalent aromatic heterocyclic ring having 5 to 12 ring atoms, containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Single or two ring system. Examples of heteroaryl moieties include pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridyl Base, pyrazolyl, anthracene Base, pyrimidinyl, three Base, aziridine, diazenium, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, fluorenyl, isodecyl, isobenzofuranyl, benzimidazolyl, Benzooxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, fluorenyl, quinolyl , isoquinolyl, quinazolinyl or quinoxalinyl.
術語「雜環烷基」表示具有3個至9個環原子、包含1個、2個或3個選自N、O及S之環雜原子、其餘環原子皆為碳之單價飽和或部分不飽和單環或二環環系統。在具體實施例中，雜環烷基係具有4至7個環原子、包含1個、2個或3個選自N、O及S之環雜原子、其餘環原子皆為碳之單價飽和單環環系統。單環飽和雜環烷基之實例係氮丙啶基、環氧乙烷基、氮雜環丁基、氧雜環丁基、吡咯啶基、四氫呋喃基、四氫-噻吩基、吡唑啶基、咪唑啶基、噁唑啶基、異噁唑啶基、噻唑啶基、六氫吡啶基、四氫吡喃基、四氫噻喃基、六氫吡基、嗎啉基、硫嗎啉基、1,1-二側氧基-硫嗎啉-4-基、氮雜環庚基、二氮雜環庚基、高六氫吡基或氧氮雜環庚基。二環飽和雜環烷基之實例係8-氮雜-二環[3.2.1]辛基、奎寧環基、8-氧雜-3-氮雜-二環[3.2.1]辛基、9-氮雜-二環[3.3.1]壬基、3-氧雜-9-氮雜-二環[3.3.1]壬基或3-硫雜-9-氮雜-二環[3.3.1]壬基。部分不飽和雜環烷基之實例係二氫呋喃基、咪唑啉基、二氫-噁唑基、四氫-吡啶基或二氫吡喃基。 The term "heterocycloalkyl" denotes a monovalent or partial moiety having from 3 to 9 ring atoms, containing 1, 2 or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Saturated monocyclic or bicyclic ring systems. In a particular embodiment, the heterocycloalkyl group has from 4 to 7 ring atoms, contains one, two or three ring heteroatoms selected from N, O and S, and the remaining ring atoms are all monovalent saturated carbons. Ring system. Examples of monocyclic saturated heterocycloalkyl groups are aziridine, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl. , imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, hexahydropyridyl, tetrahydropyranyl, tetrahydrothiopyranyl, hexahydropyridyl , morpholinyl, thiomorpholinyl, 1,1-di-oxy-thiomorpholin-4-yl, azepanyl, diazepine, homohexahydropyridyl Or oxazepanyl. Examples of bicyclic saturated heterocycloalkyl groups are 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]fluorenyl, 3-oxa-9-aza-bicyclo[3.3.1]fluorenyl or 3-thia-9-aza-bicyclo[3.3. 1] 壬基. Examples of partially unsaturated heterocycloalkyl groups are dihydrofuranyl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridyl or dihydropyranyl.
術語「羥基烷基」表示其中烷基之至少一個氫原子經羥基替代之烷基。羥基烷基之實例包括羥基甲基、2-羥基乙基、2-羥基丙基、3-羥基丙基、1-(羥基甲基)-2-甲基丙基、2-羥基丁基、3-羥基丁基、4-羥基丁基、2,3-二羥基丙基、2-羥基-1-羥基甲基乙基、2,3-二羥基丁基、3,4-二羥基丁基或2-(羥基甲基)-3-羥基丙基。 The term "hydroxyalkyl" denotes an alkyl group wherein at least one hydrogen atom of the alkyl group is replaced by a hydroxy group. Examples of the hydroxyalkyl group include a hydroxymethyl group, a 2-hydroxyethyl group, a 2-hydroxypropyl group, a 3-hydroxypropyl group, a 1-(hydroxymethyl)-2-methylpropyl group, a 2-hydroxybutyl group, and 3 -hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl or 2-(hydroxymethyl)-3-hydroxypropyl.
術語「醫藥上可接受」表示可用於製備醫藥組合物之材料之屬性，其通常安全、無毒性且既不在生物上亦不在其他方面不合意且為獸醫以及人類醫藥用途可接受。 The term "pharmaceutically acceptable" means an attribute of a material that can be used in the preparation of a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and acceptable for veterinary and human medical use.
術語「醫藥上可接受之賦形劑」及「治療惰性賦形劑」可互換使用，且表示醫藥組合物中不具治療活性且對所投與個體無毒性之任何醫藥上可接受之成份，例如用於調配醫藥產品之崩解劑、黏合劑、填充劑、溶劑、緩衝劑、張度劑、穩定劑、抗氧化劑、表面活性劑、載劑、稀釋劑或潤滑劑。 The terms "pharmaceutically acceptable excipient" and "therapeutic inert excipient" are used interchangeably and mean any pharmaceutically acceptable ingredient in a pharmaceutical composition that is not therapeutically active and non-toxic to the individual to whom it is administered, for example A disintegrant, a binder, a filler, a solvent, a buffer, a tonicity agent, a stabilizer, an antioxidant, a surfactant, a carrier, a diluent or a lubricant for formulating a pharmaceutical product.
術語「緩衝劑」表示穩定醫藥製劑之pH的醫藥上可接受之賦形劑。適宜緩衝劑為業內所熟知且可參見文獻。醫藥上可接受之具體緩衝劑包含組胺酸緩衝劑、精胺酸緩衝劑、檸檬酸鹽緩衝劑、琥珀酸鹽緩衝劑、乙酸鹽緩衝劑及磷酸鹽緩衝劑。獨立於所使用之緩衝劑，可使用業內已知之酸或鹼來調節pH，該等酸或鹼係例如鹽酸、乙酸、磷酸、硫酸及檸檬酸、氫氧化鈉及氫氧化鉀。 The term "buffer" means a pharmaceutically acceptable excipient that stabilizes the pH of a pharmaceutical preparation. Suitable buffers are well known in the art and can be found in the literature. Particular pharmaceutically acceptable buffers include histidine buffers, arginine buffers, citrate buffers, succinate buffers, acetate buffers, and phosphate buffers. Independent of the buffer used, the pH can be adjusted using acids or bases known in the art such as hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid and citric acid, sodium hydroxide and potassium hydroxide.
本文所述定義不管所討論之術語單獨抑或組合出現皆適用。預期可附加本文所述定義以形成化學上相關之組合，例如「雜環烷基芳基」、「鹵烷基雜芳基」、「芳基烷基雜環烷基」或「烷氧基烷基」。組合之最後一個成員係與分子之其他部分結合之基團。組合之其他成員以與文字序列相反之順序附接至結合基團，例如組合芳基烷基雜環烷基係指藉由經芳基取代之烷基取代的雜環烷基。 The definitions described herein apply regardless of whether the terms in question are used alone or in combination. It is contemplated that the definitions described herein may be appended to form chemically relevant combinations, such as "heterocycloalkylaryl", "haloalkylheteroaryl", "arylalkylheterocycloalkyl" or "alkoxyalkyl" base". The last member of the combination is the group that binds to the rest of the molecule. Other members of the combination are attached to the binding group in the reverse order of the literal sequence, for example, a combined arylalkylheterocycloalkyl group refers to a heterocycloalkyl group substituted by an aryl group-substituted alkyl group.
本發明係關於式(I)化合物
其中A係選自由以下組成之群：
B係C1-C4-伸烷基、C2-C4-伸烯基、C2-C4-伸炔基，R1係選自氫、C1-C7-烷基、C1-C7-烷氧基烷基、C1-C7-鹵烷基、-(CH2)0,1,2-C3-C5-環烷基、視情況經鹵素、C1-C7-烷基或C1-C7烷氧基取代之-(CH2)0,1,2-(雜-)芳基，R2係選自視情況經1至3個選自以下各項之取代基取代之雜芳基：鹵素、羥基、C1-C7-烷基、C1-C7-羥基烷基、C1-C7-鹵烷氧基、C1-C7-鹵烷基、C3-C5-環烷基、氰基、胺基、硝基、-O-R6-C(O)-R7、雜芳基、雜環烷基、-SO2R12-C(O)NR’R”、NR’R”，其中R’及R”係獨立地選自氫、C1-C7-烷基或R’及R”與其所附接之氮原子一起形成雜環烷基，或R2係選自視情況經鹵素取代之C1-C2-烷氧基，R6及R12係獨立地選自C1-C7-烷基，R7係選自雜環烷基，X係NR3或CR3，Y係(CH2)n，n係1、2、3、4，R3係選自氫、C1-C7-烷基。 B is a C 1 -C 4 -alkylene group, a C 2 -C 4 -alkenyl group, a C 2 -C 4 -exetylene group, and the R 1 group is selected from the group consisting of hydrogen, C 1 -C 7 -alkyl, C 1 -C 7 -alkoxyalkyl, C 1 -C 7 -haloalkyl, -(CH 2 ) 0,1,2- C 3 -C 5 -cycloalkyl, optionally halogen, C 1 -C 7 -alkyl or C 1 -C 7 alkoxy substituted -(CH 2 ) 0,1,2- (hetero-)aryl, R 2 is selected from 1 to 3, optionally selected from the following Heteroaryl substituted by a substituent: halogen, hydroxy, C 1 -C 7 -alkyl, C 1 -C 7 -hydroxyalkyl, C 1 -C 7 -haloalkoxy, C 1 -C 7 -halide Alkyl, C 3 -C 5 -cycloalkyl, cyano, amine, nitro, -OR 6 -C(O)-R 7 , heteroaryl, heterocycloalkyl, -SO 2 R 12 -C (O) NR'R ", NR'R" , wherein R 'and R "are independently selected hydrogen, C 1 -C 7 - alkyl or R' and R" appended thereto together form a hetero nitrogen atom of contact a cycloalkyl group, or R 2 is selected from C 1 -C 2 -alkoxy optionally substituted by halogen, R 6 and R 12 are independently selected from C 1 -C 7 -alkyl, and R 7 is selected from Heterocycloalkyl, X-based NR 3 or CR 3 , Y-based (CH 2 ) n , n-system 1, 2, 3 , 4, and R 3 is selected from hydrogen and C 1 -C 7 -alkyl.
在具體實施例中，本發明係關於式(I)化合物，其中R2係選自視情況經1至3個選自以下各項之取代基取代之雜芳基：鹵素、C1-C7-烷基、C1-C7-鹵烷基、視情況經鹵素取代之C1-C2-烷氧基、C3-C5-環烷基、氰基；在具體實施例中，本發明係關於式(I)化合物，其中A係
在具體實施例中，本發明係關於式(I)化合物，其中A係
在具體實施例中，本發明係關於式(I)化合物，其中R2係選自由以下組成之群：
其中一或多個R5係選自氫、鹵素、C1-C7-烷基、C1-C7-羥基烷基、C1-C7-鹵烷氧基、C1-C7-鹵烷基、C3-C5-環烷基、氰基、胺基、硝基、-O-R6-C(O)-R7、-SO2R8、視情況經鹵素取代之C1-C2-烷氧基、C1-C2-烷氧基或雜環烷基，R6及R8係獨立地選自C1-C7-烷基，R7係選自雜環烷基。 One or more of R 5 are selected from the group consisting of hydrogen, halogen, C 1 -C 7 -alkyl, C 1 -C 7 -hydroxyalkyl, C 1 -C 7 -haloalkoxy, C 1 -C 7 - haloalkyl, C 3 -C 5 - cycloalkyl, cyano, amino, nitro, -OR 6 -C (O) -R 7, -SO 2 R 8, optionally substituted by halogen of C 1 - C 2 -alkoxy, C 1 -C 2 -alkoxy or heterocycloalkyl, R 6 and R 8 are independently selected from C 1 -C 7 -alkyl, and R 7 is selected from heterocycloalkyl .
R8及R9係獨立地選自氫、鹵素、C1-C7-烷基、C1-C7-鹵烷基、C1-C7-羥基烷基、氰基，或R8與R9一起形成C3-C8環烷基；R10係選自氫、C1-C7-鹵烷氧基、C3-C8環烷基、C1-C7烷氧基、羥基、鹵素、S(O)2-C1-C7-烷基、-C(O)NR’R”、NR’R”，其中R’及R”係獨立地選自氫、C1-C7-烷基或R’及R”與其所附接之氮原子一起形成雜環烷基，或R10與R4一起形成C3-C8環烷基，R11係選自雜芳基或雜環烷基，較佳5員或6員雜芳基或5員或6員雜環烷基， X1係N或C-R4，其中R4係選自氫、C1-C7-烷基、C1-C7烷氧基、C1-C7-鹵烷基、C3-C8環烷基；-C(O)NR’R”，其中R’及R”係獨立地選自氫及C1-C7-烷基。 R 8 and R 9 are independently selected from the group consisting of hydrogen, halogen, C 1 -C 7 -alkyl, C 1 -C 7 -haloalkyl, C 1 -C 7 -hydroxyalkyl, cyano, or R 8 R 9 together form a C 3 -C 8 cycloalkyl group; R 10 is selected from the group consisting of hydrogen, C 1 -C 7 -haloalkoxy, C 3 -C 8 cycloalkyl, C 1 -C 7 alkoxy, hydroxy Halogen, S(O) 2 -C 1 -C 7 -alkyl, -C(O)NR'R", NR'R", wherein R' and R" are independently selected from hydrogen, C 1 -C 7 -alkyl or R' and R" together with the nitrogen atom to which they are attached form a heterocycloalkyl group, or R 10 and R 4 together form a C 3 -C 8 cycloalkyl group, R 11 is selected from heteroaryl or Heterocycloalkyl, preferably 5 or 6 membered heteroaryl or 5 or 6 membered heterocycloalkyl, X 1 is N or CR 4 wherein R 4 is selected from hydrogen, C 1 -C 7 -alkyl , C 1 -C 7 alkoxy, C 1 -C 7 -haloalkyl, C 3 -C 8 cycloalkyl; -C(O)NR'R", wherein R' and R" are independently selected from Hydrogen and C 1 -C 7 -alkyl.
在具體實施例中，本發明係關於式(I)化合物，其中R2係選自由以下組成之群：
其中R5係獨立地選自氫、鹵素、C1-7烷基、C1-C7-鹵烷基，R8及R9係獨立地選自C1-7烷基、C1-C7-鹵烷基，且R10係選自氫及-C(O)NR’R”，其中R’及R”係獨立地選自氫及C1-C7-烷基。 Wherein R 5 is independently selected from the group consisting of hydrogen, halogen, C 1-7 alkyl, C 1 -C 7 -haloalkyl, and R 8 and R 9 are independently selected from C 1-7 alkyl, C 1 -C 7-- haloalkyl, and R 10 is selected from hydrogen and -C (O) NR'R ", wherein R 'and R" are independently selected hydrogen and C 1 -C 7 - alkyl.
在具體實施例中，本發明係關於式(I)化合物，其中B係選自伸乙基、伸乙烯基及伸乙炔基。 In a particular embodiment, the invention is directed to a compound of formula (I) wherein B is selected from the group consisting of exoethyl, vinyl and ethynyl.
在具體實施例中，本發明係關於式(I)化合物，其中X係CR3且Y係CH2，其中R3係氫。 In a particular embodiment, the invention relates to a compound of formula (I), wherein X is CR 3 and Y is CH 2 , wherein R 3 is hydrogen.
在具體實施例中，本發明係關於式(I)化合物，其中X係NR3且Y係CH2，其中R3係C1-7烷基。 In a particular embodiment, the invention relates to compounds of formula (I), wherein X is NR 3 and Y is CH 2 , wherein R 3 is C 1-7 alkyl.
在具體實施例中，本發明係關於式(I)化合物，其中R1係選自C1-C7-烷基、C1-C7-鹵烷基、-(CH2)0,1,2-C3-C5-環烷基、苯基。 In a particular embodiment, the invention relates to a compound of formula (I), wherein R 1 is selected from the group consisting of C 1 -C 7 -alkyl, C 1 -C 7 -haloalkyl, -(CH 2 ) 0,1, 2 -C 3 -C 5 -cycloalkyl, phenyl.
在具體實施例中，本發明係關於選自由以下組成之群之式(I)化合物： In a particular embodiment, the invention relates to a compound of formula (I) selected from the group consisting of:
1-(2-(2-(5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基)乙基)-1-甲基-1H-咪唑-4-基)吡咯啶-2-酮 1-(2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)ethyl)-1-methyl-1H -imidazol-4-yl)pyrrolidin-2-one
1-(2-(2-(5,8-二甲基-[1,2,4]***并[1,5-a]吡-2-基)乙基)-1-苯基-1H-咪唑-4-基)吡咯啶-2-酮 1-(2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl) -2-yl)ethyl)-1-phenyl-1H-imidazol-4-yl)pyrrolidin-2-one
1-[2-[(E)-2-(5,8-二甲基-[1,2,4]***并[1,5-a]吡-2-基)乙烯基]-1-苯基咪唑-4-基]吡咯啶-2-酮 1-[2-[(E)-2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)vinyl]-1-phenylimidazol-4-yl]pyrrolidin-2-one
1-(1-(環丙基甲基)-2-(2-(5,8-二甲基-[1,2,4]***并[1,5-a]吡-2-基)乙基)-1H-咪唑-4-基)吡啶-2(1H)-酮 1-(1-(cyclopropylmethyl)-2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl) -2-yl)ethyl)-1H-imidazol-4-yl)pyridine-2(1H)-one
1-(2-(2-(5,8-二甲基-[1,2,4]***并[1,5-a]吡-2-基)乙基)-1-甲基-1H-咪唑-4-基)吡啶-2(1H)-酮 1-(2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl) -2-yl)ethyl)-1-methyl-1H-imidazol-4-yl)pyridine-2(1H)-one
1-[1-環丙基-2-[(E)-2-(5,8-二甲基-[1,2,4]***并[1,5-a]吡-2-基)乙烯基]咪唑-4-基]吡咯啶-2-酮 1-[1-cyclopropyl-2-[(E)-2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)vinyl]imidazol-4-yl]pyrrolidin-2-one
1-(1-環丙基-2-(2-(5,8-二甲基-[1,2,4]***并[1,5-a]吡-2-基)乙基)-1H-咪唑-4-基)吡咯啶-2-酮 1-(1-cyclopropyl-2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl) -2-yl)ethyl)-1H-imidazol-4-yl)pyrrolidin-2-one
1-[2-[(E)-2-(5,8-二甲基-[1,2,4]***并[1,5-a]吡-2-基)乙烯基]-1-甲基-咪唑-4-基]-3-甲基-咪唑啶-2-酮 1-[2-[(E)-2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)vinyl]-1-methyl-imidazol-4-yl]-3-methyl-imidazolidin-2-one
1-(2-((4,8-二甲基喹唑啉-2-基)乙炔基)-1-甲基-1H-咪唑-4-基)吡咯啶-2-酮 1-(2-((4,8-dimethylquinazolin-2-yl)ethynyl)-1-methyl-1H-imidazol-4-yl)pyrrolidin-2-one
1-{2-[(E)-2-{4,7-二甲基-[1,2,4]***并[1,5-a]吡-2-基}乙烯基]-1-甲基-1H-咪唑-4-基}吡咯啶-2-酮 1-{2-[(E)-2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}vinyl]-1-methyl-1H-imidazol-4-yl}pyrrolidin-2-one
1-[2-(2-{4,7-二甲基-[1,2,4]***并[1,5-a]吡-2-基}乙基)-1-甲基-1H-咪唑-4-基]吡咯啶-2-酮 1-[2-(2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}ethyl)-1-methyl-1H-imidazol-4-yl]pyrrolidin-2-one
1-[1-(環丙基甲基)-2-(2-{4,7-二甲基-[1,2,4]***并[1,5-a]吡-2-基}乙基)-1H-咪唑-4-基]吡咯啶-2-酮 1-[1-(cyclopropylmethyl)-2-(2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}ethyl)-1H-imidazol-4-yl]pyrrolidin-2-one
1-[2-(2-{4,7-二甲基-[1,2,4]***并[1,5-a]吡-2-基}乙基)-1-(2,2,2-三氟乙基)-1H-咪唑-4-基]吡咯啶-2-酮 1-[2-(2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}ethyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl]pyrrolidin-2-one
1-[1-(2,2-二氟乙基)-2-(2-{4,7-二甲基-[1,2,4]***并[1,5-a]吡-2-基}乙基)-1H-咪唑-4-基]吡咯啶-2-酮 1-[1-(2,2-difluoroethyl)-2-(2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}ethyl)-1H-imidazol-4-yl]pyrrolidin-2-one
1-[2-(2-{4,7-二甲基-[1,2,4]***并[1,5-a]吡-2-基}乙炔基)-1-甲基-1H-咪唑-4-基]吡咯啶-2-酮 1-[2-(2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}ethynyl)-1-methyl-1H-imidazol-4-yl]pyrrolidin-2-one
1-[1-(環丙基甲基)-2-(2-{5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基}乙基)-1H-咪唑-4-基]吡咯啶-2-酮 1-[1-(cyclopropylmethyl)-2-(2-{5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl} Ethyl)-1H-imidazol-4-yl]pyrrolidin-2-one
1-[2-[2-(5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基)乙基]-1-苯基-咪唑-4-基]吡咯啶-2-酮 1-[2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)ethyl]-1-phenyl-imidazole -4-yl]pyrrolidin-2-one
1-[2-(2-{5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基}乙基)-1-(2,2,2-三氟乙基)-1H-咪唑-4-基]吡咯啶-2-酮 1-[2-(2-{5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl}ethyl)-1-(2,2 ,2-trifluoroethyl)-1H-imidazol-4-yl]pyrrolidin-2-one
1-[1-(2,2-二氟乙基)-2-(2-{5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基}乙基)-1H-咪唑-4-基]吡咯啶-2-酮 1-[1-(2,2-difluoroethyl)-2-(2-{5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidine-2 -yl}ethyl)-1H-imidazol-4-yl]pyrrolidin-2-one
1-{2-[(E)-2-{4,7-二甲基-[1,2,4]***并[1,5-a]吡-2-基}乙烯基]-1-苯基-1H-咪唑-4-基}吡咯啶-2-酮 1-{2-[(E)-2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}vinyl]-1-phenyl-1H-imidazol-4-yl}pyrrolidin-2-one
1-[2-(2-{5,7-二甲基-[1,2,4]***并[1,5-a]嘧啶-2-基}乙基)-1-甲基-1H-咪唑-4-基]吡咯啶-2-酮 1-[2-(2-{5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}ethyl)-1-methyl-1H -imidazol-4-yl]pyrrolidin-2-one
1-(2-{2-[3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-6-基]乙基}-1-苯基-1H-咪唑-4基)吡咯啶-2-酮 1-(2-{2-[3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]ethyl}-1-phenyl-1H-imidazol-4-yl)pyrrolidin-2-one
1-(1-甲基-2-{2-[3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-6-基]乙炔基}-1H-咪唑-4-基)吡咯啶-2-酮 1-(1-methyl-2-{2-[3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]ethynyl}-1H-imidazol-4-yl)pyrrolidin-2-one
1-(2-{2-[3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-6-基]乙炔基}-1-苯基-1H-咪唑-4-基)吡咯啶-2-酮 1-(2-{2-[3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]ethynyl}-1-phenyl-1H-imidazol-4-yl)pyrrolidin-2-one
N,3-二甲基-6-{2-[1-甲基-4-(2-側氧基吡咯啶-1-基)-1H-咪唑-2-基]乙基}-2-三氟甲基)咪唑并[1,2-b]嗒-8-甲醯胺 N,3-Dimethyl-6-{2-[1-methyl-4-(2-o-oxypyrrolidin-1-yl)-1H-imidazol-2-yl]ethyl}-2-tri Fluoromethyl)imidazo[1,2-b]indole -8-carbamamine
N,3-二甲基-6-{2-[4-(2-側氧基吡咯啶-1-基)-1-苯基-1H-咪唑-2-基]乙基}-2-(三氟甲基)咪唑并[1,2-b]嗒-8-甲醯胺 N,3-Dimethyl-6-{2-[4-(2-o-oxypyrrolidin-1-yl)-1-phenyl-1H-imidazol-2-yl]ethyl}-2-( Trifluoromethyl)imidazo[1,2-b]indole -8-carbamamine
本發明係關於製造式(I)化合物之製程，其包含： The present invention relates to a process for the manufacture of a compound of formula (I) comprising:
a)使式(II)化合物
b)與式(III)或(IV)化合物反應(III)或(IV) b) reacting with a compound of formula (III) or (IV) (III) or (IV)
成為式(I)化合物並視情況氫化，其中R1、R2、X及Y係如前文所定義。 The compound of formula (I) is hydrogenated as appropriate, wherein R 1 , R 2 , X and Y are as defined above.
10.一種製造式I化合物之製程，其中B係伸乙炔基，該製程包含： 10. A process for the manufacture of a compound of formula I, wherein B is an ethynyl group, the process comprising:
a)使式(V)化合物與
b)與式(III)或(IV)化合物反應(III)或(IV) b) reacting with a compound of formula (III) or (IV) (III) or (IV)
成為式(I)化合物，其中R1、R2、X及Y係如前文所定義。 Compounds of formula (I) wherein R 1 , R 2 , X and Y are as defined above.
在另一態樣中，本發明係關於本發明化合物於治療或預防以下疾病之用途：精神病症、精神***症、與精神***症相關之正性、負性及/或認知症狀、妄想症、物質誘發之精神病症、焦慮症、驚恐症、強迫症、急性應激病症、廣泛性焦慮症、藥物上癮、運動病症、帕金森氏病、不寧腿症候群、認知缺陷病症、阿茲海默氏病、多發性梗塞性癡呆、情緒病症、抑鬱、雙向情感病症、神經精神病況、精神病、注意力缺陷/多動症、注意力病症、糖尿病及相關病症、2型糖尿 病、神經變性病症、亨廷頓氏病、多發性硬化、中風、脊髓損傷、實體腫瘤、血液惡性腫瘤、腎細胞癌或乳癌。 In another aspect, the invention relates to the use of a compound of the invention for the treatment or prevention of a psychiatric disorder, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, delusions, Substance-induced psychiatric disorders, anxiety disorders, panic disorder, obsessive-compulsive disorder, acute stress disorder, generalized anxiety disorder, drug addiction, motor disorder, Parkinson's disease, restless leg syndrome, cognitive deficit disorder, Alzheimer's Disease, multiple infarct dementia, mood disorders, depression, two-way affective disorder, neuropsychiatric condition, psychosis, attention deficit/hyperactivity disorder, attention disorder, diabetes and related disorders, type 2 diabetes Disease, neurodegenerative disorder, Huntington's disease, multiple sclerosis, stroke, spinal cord injury, solid tumor, hematological malignancy, renal cell carcinoma or breast cancer.
在另一態樣中，本發明係關於本發明化合物於製備用於治療或預防以下疾病之藥劑之用途：精神病症、精神***症、與精神***症相關之正性、負性及/或認知症狀、妄想症、物質誘發之精神病症、焦慮症、驚恐症、強迫症、急性應激病症、廣泛性焦慮症、藥物上癮、運動病症、帕金森氏病、不寧腿症候群、認知缺陷病症、阿茲海默氏病、多發性梗塞性癡呆、情緒病症、抑鬱、雙向情感病症、神經精神病況、精神病、注意力缺陷/多動症、注意力病症、糖尿病及相關病症、2型糖尿病、神經變性病症、亨廷頓氏病、多發性硬化、中風、脊髓損傷、實體腫瘤、血液惡性腫瘤、腎細胞癌或乳癌。 In another aspect, the invention relates to the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a psychiatric disorder, schizophrenia, positive, negative and/or cognitive related to schizophrenia Symptoms, delusions, substance-induced psychosis, anxiety, panic disorder, obsessive-compulsive disorder, acute stress disorder, generalized anxiety disorder, drug addiction, motor disorder, Parkinson's disease, restless leg syndrome, cognitive deficit disorder, Alzheimer's disease, multiple infarct dementia, mood disorders, depression, two-way affective disorder, neuropsychiatric condition, psychosis, attention deficit/hyperactivity disorder, attention disorder, diabetes and related disorders, type 2 diabetes, neurodegenerative disorders , Huntington's disease, multiple sclerosis, stroke, spinal cord injury, solid tumors, hematological malignancies, renal cell carcinoma or breast cancer.
在另一態樣中，本發明係關於用於治療或預防以下疾病之本發明化合物：精神病症、精神***症、與精神***症相關之正性、負性及/或認知症狀、妄想症、物質誘發之精神病症、焦慮症、驚恐症、強迫症、急性應激病症、廣泛性焦慮症、藥物上癮、運動病症、帕金森氏病、不寧腿症候群、認知缺陷病症、阿茲海默氏病、多發性梗塞性癡呆、情緒病症、抑鬱、雙向情感病症、神經精神病況、精神病、注意力缺陷/多動症、注意力病症、糖尿病及相關病症、2型糖尿病、神經變性病症、亨廷頓氏病、多發性硬化、中風、脊髓損傷、實體腫瘤、血液惡性腫瘤、腎細胞癌或乳癌。 In another aspect, the invention relates to a compound of the invention for use in the treatment or prevention of a psychiatric disorder, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, delusions, Substance-induced psychiatric disorders, anxiety disorders, panic disorder, obsessive-compulsive disorder, acute stress disorder, generalized anxiety disorder, drug addiction, motor disorder, Parkinson's disease, restless leg syndrome, cognitive deficit disorder, Alzheimer's Disease, multiple infarct dementia, mood disorders, depression, two-way affective disorder, neuropsychiatric condition, psychosis, attention deficit/hyperactivity disorder, attention disorder, diabetes and related disorders, type 2 diabetes, neurodegenerative disorders, Huntington's disease, Multiple sclerosis, stroke, spinal cord injury, solid tumor, hematological malignancy, renal cell carcinoma or breast cancer.
在另一態樣中，本發明係關於用於治療或預防以下疾病之方法：精神病症、精神***症、與精神***症相關之正性、負性及/或認知症狀、妄想症、物質誘發之精神病症、焦慮症、驚恐症、強迫症、急性應激病症、廣泛性焦慮症、藥物上癮、運動病症、帕金森氏病、不寧腿症候群、認知缺陷病症、阿茲海默氏病、多發性梗塞性癡呆、情緒病症、抑鬱、雙向情感病症、神經精神病況、精神病、注意 力缺陷/多動症、注意力病症、糖尿病及相關病症、2型糖尿病、神經變性病症、亨廷頓氏病、多發性硬化、中風、脊髓損傷、實體腫瘤、血液惡性腫瘤、腎細胞癌或乳癌，該方法包含向有需要之個體投與有效量之本發明化合物。 In another aspect, the invention relates to methods for treating or preventing: psychotic disorders, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, delusions, substance induction Mental illness, anxiety, panic disorder, obsessive-compulsive disorder, acute stress disorder, generalized anxiety disorder, drug addiction, motor disorder, Parkinson's disease, restless leg syndrome, cognitive deficit disorder, Alzheimer's disease, Multiple infarction dementia, emotional disorders, depression, two-way emotional disorders, neuropsychiatric conditions, mental illness, attention Force defect/hyperactivity disorder, attention disorder, diabetes and related disorders, type 2 diabetes, neurodegenerative disorder, Huntington's disease, multiple sclerosis, stroke, spinal cord injury, solid tumor, hematological malignancy, renal cell carcinoma or breast cancer, the method An effective amount of a compound of the invention is administered to an individual in need thereof.
通式(1a)、(1b)及(1c)化合物可如方案1中所概述來製備。 Compounds of formula (1a), (1b) and (1c) can be prepared as outlined in Scheme 1.
通式(1b)化合物可在適宜鹼(例如DBU)存在下在溶劑(例如THF、EtOH或其混合物)中藉由醛(D)與威悌鹽(E)之間之威悌反應(Wittig reaction)(步驟3)、然後藉由使用銅來源(例如Cu(I)I)、鈀觸媒(例如叁(二亞苄基丙酮)二鈀(0))、鹼(例如碳酸銫)及極性溶劑(例如二噁烷、DMF及水)與醯胺(G)之過渡金屬催化之偶合(步驟4)來製備。式(1a)化合物係藉由在環境壓力(氣球)下在溶劑(例如EtOH或MeOH)中使用觸媒(例如Pd/C、雷尼鎳或林德拉(Lindlar))之後續氫化(步驟5)獲得(方案1)。 The compound of the formula (1b) can be subjected to a detergency reaction between the aldehyde (D) and the deuterium salt (E) in a solvent (for example, THF, EtOH or a mixture thereof) in the presence of a suitable base (for example, DBU) (Wittig reaction) (Step 3), then by using a copper source (such as Cu(I)I), a palladium catalyst (such as hydrazine (dibenzylideneacetone) dipalladium (0)), a base (such as cesium carbonate), and a polar solvent (for example, dioxane, DMF and water) is prepared by coupling with a transition metal catalyzed by guanamine (G) (step 4). The compound of formula (1a) is subsequently hydrogenated by the use of a catalyst (eg Pd/C, Raney nickel or Lindlar) in a solvent (eg EtOH or MeOH) under ambient pressure (balloon) (step 5 ) Obtained (Scheme 1).
另一選擇為，藉由在環境壓力(氣球)下在溶劑(例如EtOH或MeOH)中使用觸媒(例如Pd/C、雷尼鎳或林德拉)氫化式(1c)化合物(步驟8)獲得式(1a)化合物(方案1)。 Alternatively, the compound of formula (1c) can be hydrogenated by the use of a catalyst (eg, Pd/C, Raney nickel or lindra) in a solvent (eg, EtOH or MeOH) under ambient pressure (balloon) (step 8). The compound of formula (1a) is obtained (Scheme 1).
通式(1c)化合物可使用銅來源(例如Cu(I)I)、鈀觸媒(例如雙(三苯基膦)氯化鈀(II))、鹼(例如三乙胺)及極性溶劑(例如DMF)藉由雜芳香族鹵化物(J)與炔烴(H)之間之Sonogashira反應來製備(步驟6)。尤其當使用氯化物作為起始材料時，需要升高溫度及延長反應時間。 The compound of the formula (1c) may be a copper source (for example, Cu(I)I), a palladium catalyst (for example, bis(triphenylphosphine)palladium(II) chloride), a base (for example, triethylamine), and a polar solvent ( For example, DMF) is prepared by a Sonogashira reaction between a heteroaromatic halide (J) and an alkyne (H) (step 6). Especially when using chloride as a starting material, it is necessary to raise the temperature and prolong the reaction time.
式(H)化合物可如方案1及以下實驗部分中所闡述以及藉由文獻已知之方法自化合物(D)製備。 Compounds of formula (H) can be prepared from compound (D) as set forth in Scheme 1 and in the experimental section below and by methods known in the literature.
式(A)、(B)、(C)、(D)、(E)、(G)及(J)化合物為市售或可如以下實驗部分中所闡述或藉由彼等熟習此項技術者熟悉之文獻已知之方法來製備。 Compounds of formula (A), (B), (C), (D), (E), (G) and (J) are commercially available or may be as described in the experimental section below or by familiarizing themselves with the art Prepared by methods known in the literature.
另一選擇為，式(D)化合物可藉由引入保護基團(例如三苯基甲基)(步驟9)、以與方案1、步驟2中所概述類似之方式引入醛官能基(步驟10)、使用適宜試劑(如乙酸)對氮實施去保護(步驟11)及使用鹼(例如碳酸銫)及極性溶劑(例如DMF)與式(B)試劑最終反應(步驟12)自式(A)化合物製備。適用於引入及移除之保護基團及條件為文獻已知或為彼等熟習此項技術者所熟悉。 Alternatively, the compound of formula (D) can be introduced into the aldehyde functional group by introducing a protecting group (e.g., triphenylmethyl) (step 9) in a manner similar to that outlined in Scheme 1, Step 2 (step 10). Deprotection of nitrogen using a suitable reagent (such as acetic acid) (step 11) and final reaction with a reagent of formula (B) using a base (such as cesium carbonate) and a polar solvent (such as DMF) (step 12) from formula (A) Compound preparation. Protecting groups and conditions suitable for introduction and removal are known to the literature or are familiar to those skilled in the art.
製備式(1c)化合物之另一方法包含使用銅來源(例如Cu(I)I)、鈀觸媒(例如雙(三苯基膦)氯化鈀(II))、鹼(例如三乙胺)及極性溶劑(例如DMF)之雜芳香族鹵化物(J)與炔烴(O)之間之Sonogashira反應(步驟 15)。式(O)化合物可藉由使用過渡金屬觸媒(例如叁(二亞苄基丙酮)二鈀(0))、銅來源(例如Cu(I)I)、鹼(例如碳酸銫)及極性溶劑(例如二噁烷、DMF及水)偶合式(D)化合物與式(G)醯胺(步驟13)、然後藉由與(1-重氮-2-側氧基丙基)膦酸二甲基酯反應(步驟14)來製備。 Another method of preparing a compound of formula (1c) involves the use of a copper source (e.g., Cu(I)I), a palladium catalyst (e.g., bis(triphenylphosphine)palladium(II) chloride), a base (e.g., triethylamine). Sonogashira reaction between heteroaromatic halide (J) and alkyne (O) of a polar solvent (such as DMF) (step 15). The compound of the formula (O) can be obtained by using a transition metal catalyst (for example, bis(dibenzylideneacetone) dipalladium (0)), a copper source (for example, Cu(I)I), a base (for example, cesium carbonate), and a polar solvent. (for example, dioxane, DMF and water) coupled with a compound of formula (D) with decylamine of formula (G) (step 13), and then with (1-diazo-2-oxopropyl)phosphonate The base ester reaction (step 14) is prepared.
另一實施例提供含有本發明化合物及治療惰性載劑、稀釋劑或賦形劑之醫藥組合物或藥劑以及使用本發明化合物製備該等組合物及藥劑之方法。 Another embodiment provides a pharmaceutical composition or medicament comprising a compound of the invention and a therapeutically inert carrier, diluent or excipient, and a method of making the compositions and medicaments using the compounds of the invention.
在一實例中，式(I)化合物可藉由在環境溫度下在適當pH下及期望純度下將生理上可接受之載劑(即在所用劑量及濃度下對接受者無毒之載劑)混合成蓋侖氏投與形式來調配。調配物之pH主要取決於化合物之具體用途及濃度，但較佳介於約3至約8之任一範圍內。在一實例中，於pH 5下將式(I)化合物調配於乙酸鹽緩衝液中。在另一實施例中，式(I)化合物無菌。化合物可以(例如)固體或非晶型組合物形式、以凍乾調配物形式或以水溶液形式儲存。 In one example, a compound of formula (I) can be prepared by mixing a physiologically acceptable carrier (i.e., a carrier that is non-toxic to the recipient at the dosages and concentrations employed) at the appropriate pH and the desired purity at ambient temperature. Formed by Galen's cast. The pH of the formulation will depend primarily on the particular use and concentration of the compound, but is preferably in the range of from about 3 to about 8. In one example, the compound of formula (I) is formulated in an acetate buffer at pH 5. In another embodiment, the compound of formula (I) is sterile. The compound can be stored, for example, in the form of a solid or amorphous composition, in the form of a lyophilized formulation or in the form of an aqueous solution.
組合物係以與良好醫療實踐一致之方式調配、投用及投與。在此上下文中需考慮之因素包括所治療之具體病症、所治療之具體哺乳動物、個體患者之臨床病況、病因、藥劑之遞送位點、投與方法、投與時間安排及從業醫師所知之其他因素。欲投與化合物之「有效量」將受該等考慮因素管控，且係抑制PDE10及控制cAMP信號傳導途徑所需之最小量。舉例而言，該量可小於對正常細胞或哺乳動物整體有 毒性之量。 The compositions are formulated, administered, and administered in a manner consistent with good medical practice. Factors to be considered in this context include the particular condition being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause, the delivery site of the agent, the method of administration, the timing of administration, and the knowledge of the practitioner other factors. The "effective amount" of the compound to be administered will be governed by such considerations and is the minimum amount required to inhibit PDE10 and control the cAMP signaling pathway. For example, the amount can be less than that for normal cells or mammals as a whole. The amount of toxicity.
在一實例中，每劑量中非經腸投與之本發明化合物之醫藥有效量介於約0.01-100mg/kg患者體重/日、另一選擇為約0.1-20mg/kg患者體重/日，其中所使用化合物之典型初始範圍為0.3-15mg/kg/日。在另一實施例中，經口單位劑型(例如錠劑及膠囊)較佳含有約25-100mg本發明化合物。 In one embodiment, the pharmaceutically effective amount of the compound of the invention administered parenterally in each dose is between about 0.01-100 mg/kg patient body weight/day, and the other option is about 0.1-20 mg/kg patient body weight/day, wherein A typical initial range for the compounds used is from 0.3 to 15 mg/kg/day. In another embodiment, the oral unit dosage form (e.g., tablets and capsules) preferably contains from about 25 mg to about 100 mg of the compound of the invention.
本發明化合物可藉由任何適宜方式來投與，包括經口、局部(包含經頰及舌下)、經直腸、經***、經真皮、非經腸、皮下、腹膜內、肺內、真皮內、鞘內及硬膜外及鼻內以及(若需要用於局部治療)病灶內投與。非經腸輸注包括肌內、靜脈內、動脈內、腹膜內或皮下投與。 The compounds of the invention may be administered by any suitable means, including orally, topically (including buccal and sublingual), transrectal, transvaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal Intrathecal and epidural and intranasal and (if required for topical treatment) intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.
本發明化合物可依任何方便投與形式投與，例如錠劑、粉劑、膠囊、溶液、分散液、懸浮液、糖漿、噴霧劑、栓劑、凝膠、乳液、貼劑等。該等組合物可含有醫藥製劑中之習用組份，例如稀釋劑、載劑、pH改質劑、甜味劑、增積劑及其他活性劑。 The compounds of the present invention can be administered in any convenient administration form such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, lotions, patches, and the like. Such compositions may contain conventional ingredients in pharmaceutical preparations such as diluents, carriers, pH modifiers, sweeteners, bulking agents, and other active agents.
典型調配物係藉由混合本發明化合物與載劑或賦形劑來製備。適宜載劑及賦形劑為彼等熟習此項技術者所熟知且詳細闡述於例如以下文獻中：Ansel,Howard C.等人，Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia：Lippincott,Williams & Wilkins,2004；Gennaro,Alfonso R.等人，Remington：The Science and Practice of Pharmacy.Philadelphia：Lippincott,Williams & Wilkins,2000；及Rowe,Raymond C.Handbook of Pharmaceutical Excipients.Chicago,Pharmaceutical Press,2005。調配物亦可包括一或多種緩衝劑、穩定劑、表面活性劑、潤濕劑、潤滑劑、乳化劑、懸浮劑、防腐劑、抗氧化劑、遮光劑、助流劑、處理助劑、著色劑、甜味劑、芳香劑、矯味劑、稀釋劑及其他已知添加劑，以提供藥物(即本發明化合 物或其醫藥組合物)之美觀呈現或幫助製造醫藥產品(即藥劑)。 A typical formulation is prepared by mixing a compound of the invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins , 2004; Gennaro, Alfonso R. et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants , sweeteners, flavoring agents, flavoring agents, diluents, and other known additives to provide a drug (ie, the present invention The aesthetic appearance of the article or its pharmaceutical composition) or aid in the manufacture of a pharmaceutical product (ie, a pharmaceutical agent).
適宜經口劑型之實例係含有約25mg、50mg、100mg、250mg或500mg本發明化合物與約90-300mg無水乳糖、約5-40mg交聯羧甲纖維素鈉、約5-30mg聚乙烯基吡咯啶酮(PVP)K30及約1-10mg硬脂酸鎂複合之錠劑。首先將粉末狀成份混合在一起，且然後與PVP溶液混合。可將所得組合物乾燥，粒化，與硬脂酸鎂混合並使用習用設備壓縮成錠劑形式。氣溶膠調配物之實例可藉由將化合物(例如5-400mg)溶解於適宜緩衝溶液(例如磷酸鹽緩衝液)中並視需要添加等張劑(tonicifier)(例如諸如氯化鈉等鹽)來製備。可使用(例如)0.2微米過濾器來過濾溶液以移除雜質及污染物。 Examples of suitable oral dosage forms comprise about 25 mg, 50 mg, 100 mg, 250 mg or 500 mg of a compound of the invention and about 90-300 mg of anhydrous lactose, about 5-40 mg of croscarmellose sodium, about 5-30 mg of polyvinylpyrrolidine. A ketone (PVP) K30 and a complex of about 1-10 mg of magnesium stearate. The powdered ingredients are first mixed together and then mixed with the PVP solution. The resulting composition can be dried, granulated, mixed with magnesium stearate and compressed into a tablet form using conventional equipment. An example of an aerosol formulation can be obtained by dissolving a compound (e.g., 5-400 mg) in a suitable buffer solution (e.g., phosphate buffer) and optionally adding a tonicifier (e.g., a salt such as sodium chloride). preparation. The solution can be filtered using, for example, a 0.2 micron filter to remove impurities and contaminants.
因此，一實施例包括一種醫藥組合物，其包含式(I)化合物或其立體異構物或醫藥上可接受之鹽。在另一實施例中包括一種醫藥組合物，其包含式(I)化合物或其立體異構物或醫藥上可接受之鹽以及醫藥上可接受之載劑或賦形劑。 Accordingly, an embodiment comprises a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof. In another embodiment is a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
在96孔微量滴定板中實施人類PDE10A全長分析。50μl反應混合物含有20mM HEPES(pH=7.5)/10mM MgCl2/0.05mg/ml BSA(Sigma目錄編號A-7906)、50nM cGMP(Sigma，目錄編號G6129)及50nM[3H]-cGMP(GE Healthcare，目錄編號TRK392 S.A.13.2Ci/mmol)、含或不含特定測試化合物之3.75ng/孔PDE10A酶(Enzo Life Science,Lausen,Switzerland目錄編號SE-534)。使用一系列濃度的潛在抑制劑來產生用於計算導致50%效應之抑制劑濃度(例如IC50，即抑制50%之PDE10A活性之競爭者濃度)的數據。於不存在酶下測試非特異性活性。藉由添加受質溶液(cGMP及[3H]-cGMP)起始反應，且容許在室溫下進行20分鐘。藉由於18mM硫酸鋅溶液中添加25μl YSi-SPA閃爍珠粒(GE Healthcare，目錄編號RPNQ0150)(終止試劑)來終止反應。振盪1h後，在170g下將板離心1分鐘以容許珠粒沉降。然後，在Perkin Elmer TopCount閃爍板讀數器上量測放射性計數。 Full length analysis of human PDE10A was performed in 96-well microtiter plates. 50 μl of the reaction mixture contained 20 mM HEPES (pH=7.5)/10 mM MgCl 2 /0.05 mg/ml BSA (Sigma Catalog No. A-7906), 50 nM cGMP (Sigma, Cat. No. G6129) and 50 nM [3H]-cGMP (GE Healthcare, Catalog No. TRK392 SA13.2 Ci/mmol), 3.75 ng/well PDE10A enzyme with or without specific test compound (Enzo Life Science, Lausen, Switzerland Catalog No. SE-534). A range of concentrations of potential inhibitors are used to generate data for calculating the concentration of inhibitor that results in a 50% effect (eg, IC50, a competitor concentration that inhibits 50% of PDE10A activity). Non-specific activity was tested in the absence of enzyme. The reaction was initiated by the addition of a substrate solution (cGMP and [3H]-cGMP) and allowed to proceed at room temperature for 20 minutes. The reaction was terminated by the addition of 25 μl of YSi-SPA scintillation beads (GE Healthcare, Cat. No. RPNQ0150) (terminating reagent) to a 18 mM zinc sulphate solution. After shaking for 1 h, the plate was centrifuged at 170 g for 1 minute to allow the beads to settle. The radioactivity count was then measured on a Perkin Elmer TopCount scintillation plate reader.
式(I)化合物具有小於10μM、更特定而言小於5μM、更特定而言小於1μM之IC50值。下表顯示一些實例之數據。 The compound of formula (I) has an IC50 value of less than 10 [mu]M, more specifically less than 5 [mu]M, more specifically less than 1 [mu]M. The table below shows data for some examples.
在氬氣氛下，將2-(氯甲基)-5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶(如US2012/178748中所闡述製備)(2.254g,11.5mmol，當量：1.00)及三苯基膦(3.01g,11.5mmol，當量：1.00)於乙腈(143ml)中之混合物回流23.5h。蒸發溶劑且將固體與醚一起研磨，過濾掉固體，用醚洗滌並在高真空下乾燥，提供淺棕色粉末狀(5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基甲基)-三苯基氯化鏻(3.959g,75.3%)。MS-Cl：m/z=423.6(M+H+) 2-(Chloromethyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidine (prepared as described in US 2012/178748) under an argon atmosphere (2.254 g, 11.5 mmol, eq. 1.00) and a mixture of triphenylphosphine (3.01 g, 11.5 mmol, eq. The solvent was evaporated and the solid was triturated with ether. EtOAc was filtered, washed with ether and dried under high vacuum to afford pale brown powder (5,8-dimethyl-[1,2,4]triazolo[1] , 5-c]pyrimidin-2-ylmethyl)-triphenylphosphonium chloride (3.959 g, 75.3%). MS-Cl: m/z = 423.6 (M+H+)
將1.6M正丁基鋰之己烷溶液(1.83ml,2.93mmol，當量：1.05)攪拌於二***(2.5ml)中，且在乾冰浴中冷卻至-78℃。經20min經由注射器分約4-5份添加溶於二***(0.75ml)中之4-溴-1-甲基-1H-咪唑(450mg,2.8mmol，當量：1.00)。在-78℃下攪拌約60min後，經約15min經由注射器逐份添加二***(0.5ml)中之DMF(215mg,226μl,2.93mmol，當量：1.05)。在-78℃下將反應混合物攪拌2.5h。添加水且用乙酸乙酯萃取三次，經硫酸鎂乾燥，過濾並蒸發。藉由管柱層析使用庚烷/乙酸乙酯(0-100%乙酸乙酯)作為溶析劑純化粗材料，提供淺黃色固體狀4-溴-1-甲基-1H-咪唑-2-甲醛(326mg,61.7%)。MS：m/z=191.3(M+H+) A 1.6 M solution of n-butyllithium in hexane (1.83 mL, 2.93 mmol, eq. 1.05) was stirred in diethyl ether (2.5 mL) and cooled to -78 ° C in dry ice bath. 4-Bromo-1-methyl-1H-imidazole (450 mg, 2.8 mmol, eq.: 1.00) dissolved in diethyl ether (0.75 ml) was added over a period of 20 min. After stirring at -78 ° C for about 60 min, DMF (215 mg, 226 μl, 2.93 mmol, eq.: 1.05) in diethyl ether (0.5 ml) was added portionwise via syringe over 15 min. The reaction mixture was stirred at -78 °C for 2.5 h. Water was added and extracted three times with ethyl acetate dried over magnesium sulfate, filtered and evaporated. The crude material was purified by column chromatography eluting EtOAc EtOAc EtOAc Formaldehyde (326 mg, 61.7%). MS: m/z = 191.3 (M+H+)
向4-溴-1-甲基-1H-咪唑-2-甲醛(50mg,265μmol，當量：1.00)於四氫呋喃(5ml)中之溶液添加((5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基)甲基)三苯基氯化鏻(121mg,265μmol，當量：1)及DBU(44.3mg,43.9μl,291μmol，當量：1.1)。在25℃下將反應混合物攪拌18小時。將粗材料施加於矽膠上且藉由矽膠管柱上之急驟層析使用乙酸乙酯/甲醇0-10%作為溶析劑來純化，提供白色固體狀2-[(E)-2-(4-溴-1-甲基-1H-咪唑-2-基)-乙烯基]-5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶(73mg,82.8%)。MS：m/z=333.1(M+H+) To a solution of 4-bromo-1-methyl-1H-imidazol-2-carbaldehyde (50 mg, 265 μmol, equivalent: 1.00) in tetrahydrofuran (5 ml) ((5,8-dimethyl-[1,2, 4] Triazolo[1,5-c]pyrimidin-2-yl)methyl)triphenylphosphonium chloride (121 mg, 265 μmol, equivalent: 1) and DBU (44.3 mg, 43.9 μl, 291 μmol, equivalent: 1.1 ). The reaction mixture was stirred at 25 ° C for 18 hours. The crude material was applied to a silica gel and purified by flash chromatography on a silica gel column using ethyl acetate/methanol 0-10% as a solvent to afford 2-[(E)-2-(4) as a white solid. -bromo-1-methyl-1H-imidazol-2-yl)-vinyl]-5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidine (73 mg, 82.8%). MS: m/z = 333.1 (M+H+)
在閉合容器中，將(E)-2-(2-(4-溴-1-甲基-1H-咪唑-2-基)乙烯基)-5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶(70mg,210μmol，當量：1.00)、吡咯啶-2-酮(35.8mg,32.2μl,420μmol，當量：2)、碳酸銫(137mg,420μmol，當量：2)、叁(二亞苄基丙酮)二鈀(0)/Pd2(dba)3(3.85mg,4.2μmol，當量：0.02)及4,5-雙(二苯基膦基)-9,9-二甲基呫噸(xant-phos)(4.86mg,8.4μmol，當量：0.04)於二噁烷(3.5ml)中之混合物加熱至140℃。再添加叁(二亞苄基丙酮)二鈀(0)/Pd2(dba)3(3.85mg,4.2μmol，當量：0.02)及4,5-雙(二苯基膦基)-9,9-二甲基口呫噸(xant-phos)(4.86mg,8.4μmol，當量：0.04)，並持續攪拌4h。將粗材料施加於矽膠上且藉由管柱層析使用乙酸乙酯/甲醇(0-10%甲醇)作為溶析 劑來純化，提供淺黃色固體狀1-{2-[(E)-2-(5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基)-乙烯基]-1-甲基-1H-咪唑-4-基}-吡咯啶-2-酮(24mg,33.9%)。MS：m/z=337(M+) In a closed vessel, (E)-2-(2-(4-bromo-1-methyl-1H-imidazol-2-yl)vinyl)-5,8-dimethyl-[1,2, 4] Triazolo[1,5-c]pyrimidine (70 mg, 210 μmol, equivalent: 1.00), pyrrolidin-2-one (35.8 mg, 32.2 μl, 420 μmol, equivalent: 2), cesium carbonate (137 mg, 420 μmol, Equivalent: 2), hydrazine (dibenzylideneacetone) dipalladium (0) / Pd 2 (dba) 3 (3.85 mg, 4.2 μmol, equivalent: 0.02) and 4,5-bis(diphenylphosphino)- A mixture of 9,9-dimethylxanthene (xant-phos) (4.86 mg, 8.4 μmol, equivalent: 0.04) in dioxane (3.5 ml) was heated to 140 °C. Further added hydrazine (dibenzylideneacetone) dipalladium(0)/Pd 2 (dba) 3 (3.85 mg, 4.2 μmol, equivalent: 0.02) and 4,5-bis(diphenylphosphino)-9,9 - xant-phos (4.86 mg, 8.4 μmol, equivalent: 0.04) and stirring was continued for 4 h. The crude material was applied to a silica gel and purified by column chromatography using ethyl acetate/methanol (0-10% methanol) as a solvent to afford 1-{2-[(E)-2 -(5,8-Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)-vinyl]-1-methyl-1H-imidazol-4-yl }-pyrrolidin-2-one (24 mg, 33.9%). MS: m/z = 337 (M+)
在氫氣氛下在室溫下，將(E)-1-(2-(2-(5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基)乙烯基)-1-甲基-1H-咪唑-4-基)吡咯啶-2-酮(20mg,59.3μmol，當量：1.00)與10%碳載鈀(6.31mg,5.93μmol，當量：0.1)一起於甲醇(2ml)中攪拌過夜。將粗材料施加於矽膠上且藉由管柱層析使用乙酸乙酯/甲醇(0-10%)甲醇作為溶析劑來純化，提供白色固體狀1-{2-[2-(5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基)-乙基]-1-甲基-1H-咪唑-4-基}-吡咯啶-2-酮(7.7mg,38.3%)。MS：m/z=340.5(M+H+) (E)-1-(2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidine- under a hydrogen atmosphere at room temperature 2-yl)vinyl)-1-methyl-1H-imidazol-4-yl)pyrrolidin-2-one (20 mg, 59.3 μmol, equivalent: 1.00) and 10% palladium on carbon (6.31 mg, 5.93 μmol, Equivalent: 0.1) stirred together in methanol (2 ml) overnight. The crude material was applied to a silica gel and purified by column chromatography using ethyl acetate/methanol (0-10%) methanol as a solvent to afford 1-{2-[2-(5,8 -Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)-ethyl]-1-methyl-1H-imidazol-4-yl}-pyrrolidine- 2-ketone (7.7 mg, 38.3%). MS: m/z = 340.5 (M+H+)
其係以與實例1a)中所闡述類似之方式使用2-(氯甲基)-5,8-二甲基-[1,2,4]***并[1,5-a]吡(如US2012/178748中所闡述製備)(3.259g,16.6mmol，當量：1.00)來製備，提供淺棕色固體狀((5,8-二甲基-[1,2,4]***并[1,5-a]吡-2-基甲基)-三苯基-鏻(11.5g,98.5%)。MS-Cl：m/z=423.4(M+H+) It was used in a similar manner to that described in Example 1a) using 2-(chloromethyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin. Prepared (as prepared as described in US 2012/178748) (3.259 g, 16.6 mmol, eq: 1.00) to provide a light brown solid ((5,8-dimethyl-[1,2,4]triazolo[ 1,5-a]pyridyl -2-ylmethyl)-triphenyl-indole (11.5 g, 98.5%). MS-Cl: m/z = 423.4 (M+H+)
將4-溴-1H-咪唑(3000mg,20.4mmol，當量：1.00)、碘苯(3.75g,2.05ml,18.4mmol，當量：0.9)、碘化銅(I)(194mg,1.02mmol，當量：0.05)、8-羥基喹啉(148mg,1.02mmol，當量：0.05)及碳酸銫(8.85g,27.1mmol，當量：1.33)之混合物溶解於DMF(45.0ml)及水(4.5ml)中。在130℃下將混合物攪拌2.5天。用乙酸乙酯稀釋殘餘物，且用水、飽和氯化銨溶液及飽和碳酸氫鈉洗滌。分離有機層，經硫酸鎂乾燥，過濾並蒸發。將粗材料施加於矽膠上且藉由70g矽膠管柱上之急驟層析使用庚烷/乙酸乙酯10%-30%作為溶析劑來純化，提供灰白色固體狀4-溴-1-苯基-1H-咪唑(2.345g,51.5%)。MS：m/z=222.98(M+) 4-Bromo-1H-imidazole (3000 mg, 20.4 mmol, equivalent: 1.00), iodobenzene (3.75 g, 2.05 ml, 18.4 mmol, equivalent: 0.9), copper (I) iodide (194 mg, 1.02 mmol, equivalent: A mixture of 0.05), 8-hydroxyquinoline (148 mg, 1.02 mmol, equivalent: 0.05) and cesium carbonate (8.85 g, 27.1 mmol, eq.: 1.33) was dissolved in DMF (45.0 ml) and water (4.5 ml). The mixture was stirred at 130 ° C for 2.5 days. The residue was diluted with ethyl acetate and washed with EtOAc EtOAc. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated. The crude material was applied to a silica gel and purified by flash chromatography on a 70 g silica gel column using heptane / ethyl acetate 10% to 30% as a solvent. -1H-imidazole (2.345 g, 51.5%). MS: m/z = 222.98 (M+)
將1.6M正丁基鋰之己烷溶液(6.9ml,11.0mmol，當量：1.05)攪拌於THF(12.0ml)中，且在乾冰浴中冷卻至-78℃。經20min經由注射器分約4-5份添加溶於THF(3.59ml)中之4-溴-1-苯基-1H-咪唑/RO7016494-000-002(2.345g,10.5mmol，當量：1.00)。在-78℃下攪拌約60min後，經約15min經由注射器逐份添加THF(2.39ml)中之DMF(807mg,849μl,11.0mmol，當量：1.05)。在-78℃下將反應混合物攪拌2.5h。添加水且用乙酸乙酯萃取三次，經硫酸鎂乾燥，過濾並蒸發。將粗材料施加於矽膠上且藉由急驟層析使用庚烷/乙酸乙酯10%-30%作為溶析劑來純化，提供淺黃色固體狀4-溴-1-苯基-1H-咪唑-2-甲醛(1.461g,55.4%)。MS：m/z=251.1(M+H+) A 1.6 M solution of n-butyllithium in hexane (6.9 mL, 11.0 mmol, eq. 1.05) was stirred in THF (12.0 mL) and cooled to -78. 4-Bromo-1-phenyl-1H-imidazole/RO7016494-000-002 (2.345 g, 10.5 mmol, equivalent: 1.00) dissolved in THF (3.59 ml) was added over a period of 20 min. After stirring at -78 ° C for about 60 min, DMF (807 mg, 849 μl, 11.0 mmol, eq.: 1.05) in THF (2.39 ml) was added portionwise via syringe over 15 min. The reaction mixture was stirred at -78 °C for 2.5 h. Water was added and extracted three times with ethyl acetate dried over magnesium sulfate, filtered and evaporated. The crude material was applied to a silica gel and purified by flash chromatography using heptane / ethyl acetate 10% to 30% as elutant to afford 4-bromo-1-phenyl-1H-imidazole as a pale yellow solid. 2-formaldehyde (1.461 g, 55.4%). MS: m/z = 251.1 (M+H+)
其係以與實例1c)中所闡述類似之方式使用((5,8-二甲基-[1,2,4]***并[1,5-a]吡-2-基)甲基)三苯基氯化鏻(1.16g,2.53mmol，當量：1.00)及4-溴-1-苯基-1H-咪唑-2-甲醛(635mg,2.53mmol，當量：1.00)作為起始材料來製備，提供白色固體狀2-[(E)-2-(4-溴-1-苯基-1H-咪唑-2-基)-乙烯基]-5,8-二甲基-[1,2,4]***并[1,5-a]吡(278mg,27.8%)。MS：m/z=395.2(M+H+) It was used in a similar manner as described in Example 1c) ((5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl) 2-yl)methyl)triphenylphosphonium chloride (1.16 g, 2.53 mmol, equivalent: 1.00) and 4-bromo-1-phenyl-1H-imidazol-2-carbaldehyde (635 mg, 2.53 mmol, eq.: 1.00) Prepared as starting material to give 2-[(E)-2-(4-bromo-1-phenyl-1H-imidazol-2-yl)-vinyl]-5,8- Methyl-[1,2,4]triazolo[1,5-a]pyridyl (278 mg, 27.8%). MS: m/z = 395.2 (M+H+)
其係以與實例1d)中所闡述類似之方式使用(E)-2-(2-(4-溴-1-苯基-1H-咪唑-2-基)乙烯基)-5,8-二甲基-[1,2,4]***并[1,5-a]吡(80mg,202μmol，當量：1.00)及吡咯啶-2-酮(34.5mg,31.0μl,405μmol，當量：2)、碳酸銫(198mg,607μmol，當量：3)作為起始材料來製備，提供淺黃色固體狀1-{2-[(E)-2-(5,8-二甲基-[1,2,4]***并[1,5-a]吡-2-基)-乙烯基]-1-苯基-1H-咪唑-4-基}-吡咯啶-2-酮(80.8mg,18.8%)。MS：m/z=400.3(M+H+) Using (E)-2-(2-(4-bromo-1-phenyl-1H-imidazol-2-yl)vinyl)-5,8-di in a similar manner as described in Example 1d) Methyl-[1,2,4]triazolo[1,5-a]pyridyl (80 mg, 202 μmol, equivalent: 1.00) and pyrrolidin-2-one (34.5 mg, 31.0 μl, 405 μmol, equivalent: 2), cesium carbonate (198 mg, 607 μmol, equivalent: 3) as a starting material, provided shallow 1-{2-[(E)-2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridine 2-yl)-vinyl]-1-phenyl-1H-imidazol-4-yl}-pyrrolidin-2-one (80.8 mg, 18.8%). MS: m/z = 400.3 (M+H+)
其係以與實例1e)中所闡述類似之方式使用(E)-1-(2-(2-(5,8-二甲基-[1,2,4]***并[1,5-a]吡-2-基)乙烯基)-1-苯基-1H-咪唑-4-基)吡咯啶-2-酮(13mg,32.5μmol，當量：1.00)作為起始材料來製備，提供白色固體狀1-{2-[2-(5,8-二甲基-[1,2,4]***并[1,5-a]吡-2-基)-乙基]-1-苯基-1H-咪唑-4-基}-吡咯啶-2-酮(7mg,53.6%)。MS：m/z=402.4(M+H+) It was used in a similar manner to that described in Example 1e) using (E)-1-(2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5- a]pyridyl 2-yl)vinyl)-1-phenyl-1H-imidazol-4-yl)pyrrolidin-2-one (13 mg, 32.5 μmol, equivalent: 1.00) was prepared as a starting material to afford a white solid. -{2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl 2-yl)-ethyl]-1-phenyl-1H-imidazol-4-yl}-pyrrolidin-2-one (7 mg, 53.6%). MS: m/z = 402.4 (M+H+)
其係如實例2e)中所闡述來製備。MS：m/z=400.3(M+H+) It was prepared as described in Example 2e). MS: m/z = 400.3 (M+H + )
其係以與實例2b)中所闡述類似之方式使用4-溴-1H-咪唑(2.38g,16.2mmol，當量：1.00)及(碘甲基)環丙烷(4.91g,16.2mmol，當量：1)作為起始材料來製備，提供橙色油狀4-溴-1-(環丙基甲基)-1H-咪唑(980mg,24.1%)。MS：m/z=201(M+H+) 4-bromo-1H-imidazole (2.38 g, 16.2 mmol, equivalent: 1.00) and (iodomethyl)cyclopropane (4.91 g, 16.2 mmol, equivalent: 1) were used in a similar manner as described in Example 2b). Prepared as starting material afforded 4-bromo-1-(cyclopropylmethyl)-1H-imidazole (980 mg, 24.1%). MS: m/z = 201 (M+H+)
其係以與實例2c)中所闡述類似之方式使用4-溴-1-(環丙基甲基)-1H-咪唑(258mg,1.28mmol，當量：1.00)作為起始材料來製備，提供淺黃色油狀4-溴-1-(環丙基甲基)-1H-咪唑-2-甲醛(114mg,38.8%)。 MS：m/z=229.0(M+H+) It was prepared in a similar manner to that described in Example 2c) using 4-bromo-1-(cyclopropylmethyl)-1H-imidazole (258 mg, 1.28 mmol, eq.: 1.00) as starting material. 4-Bromo-1-(cyclopropylmethyl)-1H-imidazole-2-carbaldehyde (114 mg, 38.8%) as a yellow oil. MS: m/z = 229.0 (M+H+)
其係以與實例1c)中所闡述類似之方式使用((5,8-二甲基-[1,2,4]***并[1,5-a]吡-2-基)甲基)三苯基氯化鏻(228mg,497μmol，當量：1.00)及4-溴-1-(環丙基甲基)-1H-咪唑-2-甲醛(114mg,498μmol，當量：1.00)作為起始材料來製備，提供黃色固體狀2-[(E)-2-(4-溴-1-環丙基甲基-1H-咪唑-2-基)-乙烯基]-5,8-二甲基-[1,2,4]***并[1,5-a]吡(479mg,58.9%)。MS：m/z=375.2(M+H+) It was used in a similar manner as described in Example 1c) ((5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl) 2-yl)methyl)triphenylphosphonium chloride (228 mg, 497 μmol, equivalent: 1.00) and 4-bromo-1-(cyclopropylmethyl)-1H-imidazole-2-carbaldehyde (114 mg, 498 μmol, Equivalent: 1.00) Prepared as starting material afforded 2-[(E)-2-(4-bromo-1-cyclopropylmethyl-1H-imidazol-2-yl)-vinyl]- 5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl (479 mg, 58.9%). MS: m/z = 375.2 (M+H+)
在140℃下在閉合容器中，將(E)-2-(2-(4-溴-1-(環丙基甲基)-1H-咪唑-2-基)乙烯基)-5,8-二甲基-[1,2,4]***并[1,5-a]吡(50mg,134μmol，當量：1.00)、吡啶-2(3H)-酮(25.5mg,268μmol，當量：2)、碳酸銫(87.3mg,268μmol，當量：2)、碘化銅(I)(6.13mg,6.7μmol，當量：0.05)及8-羥基喹啉(3.88mg,6.7μmol，當量：0.05)於DMF(350 μl)及水(35.0μl)中之混合物加熱1h。將粗材料施加於矽膠上且藉由管柱層析使用乙酸乙酯/甲醇(0-10%甲醇)來純化。仍不純。藉由製備型HPLC純化該材料，提供淺黃色固體狀1-{1-環丙基甲基-2-[(E)-2-(5,8-二甲基-[1,2,4]***并[1,5-a]吡-2-基)-乙烯基]-1H-咪唑-4-基}-1H-吡啶-2-酮(15mg,28.9%)。MS：m/z=388.2(M+H+) (E)-2-(2-(4-Bromo-1-(cyclopropylmethyl)-1H-imidazol-2-yl)vinyl)-5,8- in a closed vessel at 140 °C Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl (50 mg, 134 μmol, equivalent: 1.00), pyridine-2(3H)-one (25.5 mg, 268 μmol, equivalent: 2), cesium carbonate (87.3 mg, 268 μmol, equivalent: 2), copper (I) iodide (6.13) Mg, 6.7 μmol, equivalent: 0.05) and a mixture of 8-hydroxyquinoline (3.88 mg, 6.7 μmol, equivalent: 0.05) in DMF (350 μl) and water (35.0 μl). The crude material was applied to silica gel and purified by column chromatography using ethyl acetate / methanol (0-10% methanol). Still not pure. The material was purified by preparative HPLC to afford 1-{1-cyclopropylmethyl-2-[(E)-2-(5,8-dimethyl-[1,2,4] Triazolo[1,5-a]pyridyl 2-yl)-vinyl]-1H-imidazol-4-yl}-1H-pyridin-2-one (15 mg, 28.9%). MS: m/z = 388.2 (M+H+)
其係以與實例1e)中所闡述類似之方式使用(E)-1-(1-(環丙基甲基)-2-(2-(5,8-二甲基-[1,2,4]***并[1,5-a]吡-2-基)乙烯基)-1H-咪唑-4-基)吡啶-2(1H)-酮(13mg,33.6μmol，當量：1.00)作為起始材料來製備，提供灰白色固體狀1-{1-環丙基甲基-2-[2-(5,8-二甲基-[1,2,4]***并[1,5-a]吡-2-基)-乙基]-1H-咪唑-4-基}-1H-吡啶-2-酮(4.06mg,31.1%)。MS：m/z=390.3(M+H+) It was used in a similar manner to that described in Example 1e) using (E)-1-(1-(cyclopropylmethyl)-2-(2-(5,8-dimethyl-[1,2, 4] Triazolo[1,5-a]pyridin 2-Benzyl)vinyl)-1H-imidazol-4-yl)pyridine-2(1H)-one (13 mg, 33.6 μmol, eq.: 1.00) was obtained as starting material to afford white solids 1-{1 -cyclopropylmethyl-2-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl 2-yl)-ethyl]-1H-imidazol-4-yl}-1H-pyridin-2-one (4.06 mg, 31.1%). MS: m/z = 390.3 (M+H+)
其係以與實例1c)中所闡述類似之方式使用4-溴-1-甲基-1H-咪唑-2-甲醛(350mg,1.85mmol，當量：1.00)及((5,8-二甲基-[1,2,4]***并[1,5-a]吡-2-基)甲基)三苯基氯化鏻(850mg,1.85mmol，當量：1)作為起始材料來製備，提供白色固體狀2-[(E)-2-(4-溴-1-甲基-1H-咪唑-2-基)-乙烯基]-5,8-二甲基-[1,2,4]***并[1,5-a]吡(480mg,77.8%)。 MS：m/z=333.3(M+H+) 4-bromo-1-methyl-1H-imidazol-2-carbaldehyde (350 mg, 1.85 mmol, eq: 1.00) and ((5,8-dimethyl) was used in a similar manner as described in Example 1c). -[1,2,4]triazolo[1,5-a]pyridyl 2-Benzyl)methyl)triphenylphosphonium chloride (850 mg, 1.85 mmol, eq: 1) was obtained as starting material to afford 2-[(E)-2-(4-bromo-1) as a white solid. -methyl-1H-imidazol-2-yl)-vinyl]-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl (480 mg, 77.8%). MS: m/z = 333.3 (M+H+)
其係以與實例4d)中所闡述類似之方式使用(E)-2-(2-(4-溴-1-甲基-1H-咪唑-2-基)乙烯基)-5,8-二甲基-[1,2,4]***并[1,5-a]吡(50mg,150μmol，當量：1.00)及吡啶-2(3H)-酮(28.5mg,300μmol，當量：2)作為起始材料來製備，提供淺黃色固體狀1-{2-[(E)-2-(5,8-二甲基-[1,2,4]***并[1,5-a]吡-2-基)-乙烯基]-1-甲基-1H-咪唑-4-基}-1H-吡啶-2-酮(22.3mg,42.8%)。MS：m/z=348.16(M+H+) It was used in a similar manner to that described in Example 4d) using (E)-2-(2-(4-bromo-1-methyl-1H-imidazol-2-yl)vinyl)-5,8-di Methyl-[1,2,4]triazolo[1,5-a]pyridyl (50 mg, 150 μmol, equivalent: 1.00) and pyridine-2(3H)-one (28.5 mg, 300 μmol, equivalent: 2) were prepared as starting materials to afford 1-{2-[(E)- 2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl 2-yl)-vinyl]-1-methyl-1H-imidazol-4-yl}-1H-pyridin-2-one (22.3 mg, 42.8%). MS: m/z = 348.16 (M+H+)
其係以與實例1e)中所闡述類似之方式使用(E)-1-(2-(2-(5,8-二甲基-[1,2,4]***并[1,5-a]吡-2-基)乙烯基)-1-甲基-1H-咪唑-4-基)吡啶-2(1H)-酮(22mg,63.3μmol，當量：1.00)作為起始材料來製備，提供白色固體狀1-{2-[2-(5,8-二甲基-[1,2,4]***并[1,5-a]吡-2-基)-乙基]-1-甲基-1H-咪唑-4-基}-1H-吡啶-2-酮(1.6mg,7.23%)。MS：m/z=350.3(M+H+) It was used in a similar manner to that described in Example 1e) using (E)-1-(2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5- a]pyridyl 2-yl)vinyl)-1-methyl-1H-imidazol-4-yl)pyridine-2(1H)-one (22 mg, 63.3 μmol, eq: 1.00) was obtained as starting material to afford white solid 1-{2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl 2-yl)-ethyl]-1-methyl-1H-imidazol-4-yl}-1H-pyridin-2-one (1.6 mg, 7.23%). MS: m/z = 350.3 (M+H+)
在70℃下在氬氣下，將4-溴-1H-咪唑(1g,6.8mmol，當量：1.00)、環丙基酸(1.17g,13.6mmol，當量：2)、乙酸銅(II)(1.24g,6.8mmol，當量：1.00)、2,2'-聯吡啶(1.06g,6.8mmol，當量：1)及碳酸鉀(1.88g,13.6mmol，當量：2)於1,2-二氯乙烷(52.3ml)中之混合物加熱4小時。用50ml二氯甲烷稀釋反應物，用水、HCl(1mol)及 飽和Na2CO3洗滌。分離有機層，經硫酸鎂乾燥，過濾並蒸發。使水層呈鹼性且用1,2-二氯甲烷萃取三次，經硫酸鎂乾燥，過濾並與第一有機相合併。在真空下蒸發溶劑。將粗材料施加於矽膠上且藉由矽膠管柱上之急驟層析、使用二氯甲烷/甲醇0-5%作為溶析劑純化，提供棕色油狀4-溴-1-環丙基-1H-咪唑(452mg,28.4%)。MS：m/z=186.98(M+H+) 4-bromo-1H-imidazole (1 g, 6.8 mmol, equivalent: 1.00), cyclopropyl at 70 ° C under argon Acid (1.17 g, 13.6 mmol, equivalent: 2), copper (II) acetate (1.24 g, 6.8 mmol, equivalent: 1.00), 2,2'-bipyridine (1.06 g, 6.8 mmol, equivalent: 1) and carbonic acid A mixture of potassium (1.88 g, 13.6 mmol, equivalent: 2) in 1,2-dichloroethane (52.3 ml) was heated for 4 h. Washed with HCl (1mol) with saturated Na 2 CO 3 and the reaction was diluted with 50ml of dichloromethane, washed with water,. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated. The aqueous layer was made basic and extracted three times with dichloromethane, dried over magnesium sulfate, filtered and combined with the first organic phase. The solvent was evaporated under vacuum. The crude material was applied to a silica gel and purified by flash chromatography on a silica gel column using dichloromethane/methanol 0-5% as a solvent to afford 4-bromo-1-cyclopropyl-1H as a brown oil. - Imidazole (452 mg, 28.4%). MS: m/z = 186.98 (M+H+)
其係以與實例1b)中所闡述類似之方式使用4-溴-1-環丙基-1H-咪唑(452mg,2.42mmol，當量：1.00)作為起始材料來製備，提供灰白色固體狀4-溴-1-環丙基-1H-咪唑-2-甲醛(257mg,49.5%)。MS：m/z=215.1(M+H+) Prepared in a similar manner to that described in Example 1b) using 4-bromo-1-cyclopropyl-1H-imidazole (452 mg, 2.42 mmol, eq.: 1.00) as starting material to afford an off-white solid 4- Bromo-1-cyclopropyl-1H-imidazole-2-carbaldehyde (257 mg, 49.5%). MS: m/z = 215.1 (M+H+)
其係以與實例1c)中所闡述類似之方式使用((5,8-二甲基-[1,2,4]***并[1,5-a]吡-2-基)甲基)三苯基氯化鏻(523mg,1.14mmol，當量：1.00)及4-溴-1-環丙基-1H-咪唑-2-甲醛(245mg,1.14mmol，當量：1.00)作為起始材料來製備，提供白色固體狀4-溴-1-環丙基-1H-咪唑-2-甲醛(340mg,83.1%)。MS：m/z=361.2(M+H+) It was used in a similar manner as described in Example 1c) ((5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl) 2-yl)methyl)triphenylphosphonium chloride (523 mg, 1.14 mmol, eq: 1.00) and 4-bromo-1-cyclopropyl-1H-imidazol-2-carbaldehyde (245 mg, 1.14 mmol, eq. 1.00) Prepared as starting material afforded 4-bromo-1-cyclopropyl-1H-imidazole-2-carbaldehyde (340 mg, 83.1%) as a white solid. MS: m/z = 361.2 (M+H+)
其係以與實例1d)中所闡述類似之方式使用(E)-2-(2-(4-溴-1-環丙基-1H-咪唑-2-基)乙烯基)-5,8-二甲基-[1,2,4]***并[1,5-a]吡(110mg,306μmol，當量：1.00)及吡咯啶-2-酮(52.1mg,47.0μl,612μmol，當量：2)作為起始材料來製備，提供黃色黏性油狀1-{2-[(E)-2-(5,8-二甲基-[1,2,4]***并[1,5-a]吡-2-基)-乙烯基]-1-苯基-1H-咪唑-4-基}-吡咯啶-2-酮(39mg,35%)。MS：m/z=364.3(M+H+) It was used in a similar manner to that described in Example 1d) using (E)-2-(2-(4-bromo-1-cyclopropyl-1H-imidazol-2-yl)vinyl)-5,8- Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl (110 mg, 306 μmol, equivalent: 1.00) and pyrrolidin-2-one (52.1 mg, 47.0 μl, 612 μmol, equivalent: 2) were prepared as starting materials to provide a yellow viscous oil 1-{2-[(E )-2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin 2-yl)-vinyl]-1-phenyl-1H-imidazol-4-yl}-pyrrolidin-2-one (39 mg, 35%). MS: m/z = 364.3 (M+H+)
其係以與實例1e)中所闡述類似之方式使用(E)-1-(1-環丙基-2-(2-(5,8-二甲基-[1,2,4]***并[1,5-a]吡-2-基)乙烯基)-1H-咪唑-4-基)吡咯啶-2-酮(35mg,96.3μmol，當量：1.00)作為起始材料來製備，提供白色固體狀1-{1-環丙基-2-[2-(5,8-二甲基-[1,2,4]***并[1,5-a]吡-2-基)-乙基]-1H-咪唑-4-基}-吡咯啶-2-酮(23.8mg,67.6%)。MS：m/z=366.3(M+H+) Using (E)-1-(1-cyclopropyl-2-(2-(5,8-dimethyl-[1,2,4]triazole) in a similar manner as described in Example 1e) And [1,5-a]pyridyl 2-yl)vinyl)-1H-imidazol-4-yl)pyrrolidin-2-one (35 mg, 96.3 μmol, equivalent: 1.00) was prepared as starting material to afford 1-{1-ring as a white solid Propyl-2-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl 2-yl)-ethyl]-1H-imidazol-4-yl}-pyrrolidin-2-one (23.8 mg, 67.6%). MS: m/z = 366.3 (M+H+)
其係以與實例1d)中所闡述類似之方式使用(E)-2-(2-(4-溴-1-甲基-1H-咪唑-2-基)乙烯基)-5,8-二甲基-[1,2,4]***并[1,5-a]吡(50mg,150μmol，當量：1.00)及1-甲基咪唑啶-2-酮(30.0mg,300μmol，當量：2)作為起始材料來製備，提供黃色固體狀2'-[(E)-2-(5,8-二甲基-[1,2,4]***并[1,5-a]吡-2-基)-乙烯基]-3,1'-二甲基-4,5-二氫-3H,1'H-[1,4']二咪唑基-2-酮(6mg,11.3%)。MS：m/z=353.3(M+H+) Using (E)-2-(2-(4-bromo-1-methyl-1H-imidazol-2-yl)vinyl)-5,8-di in a similar manner as described in Example 1d) Methyl-[1,2,4]triazolo[1,5-a]pyridyl (50 mg, 150 μmol, equivalent: 1.00) and 1-methylimidazolidin-2-one (30.0 mg, 300 μmol, equivalent: 2) were prepared as starting materials to afford 2'-[(E)-2 as a yellow solid. -(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl)-vinyl]-3,1'-dimethyl-4,5-dihydro-3H,1'H-[1,4']diimidazolyl-2-one (6 mg, 11.3%) ). MS: m/z = 353.3 (M+H+)
在室溫下在氬氣氛下，向4-溴-1-甲基-1H-咪唑-2-甲醛(400mg,2.12mmol，當量：1.00)及碳酸鉀(585mg,4.23mmol，當量：2)於甲醇(30.0ml)中之攪拌混合物一次添加全量1-重氮-2-側氧基丙基膦酸二甲基酯(488mg,381μl,2.54mmol，當量：1.2)。然後在室溫下持續攪拌過夜。用Et2O稀釋混合物並用5% KHCO3水溶液洗滌。用Et2O反 萃取水相且經硫酸鎂乾燥，過濾並濃縮以留下淺棕色油狀粗產物。將粗材料施加於矽膠上且藉由管柱層析使用庚烷/乙酸乙酯(0-50%乙酸乙酯)作為溶析劑來純化，提供棕色固體狀4-溴-2-乙炔基-1-甲基-1H-咪唑(319mg,81.5%)。MS：m/z=185.0(M+H+) To 4-bromo-1-methyl-1H-imidazol-2-carbaldehyde (400 mg, 2.12 mmol, eq: 1.00) and potassium carbonate (585 mg, 4.23 mmol, eq: 2) at room temperature under argon A stirred mixture of methanol (30.0 ml) was added in one portion to a full amount of 1-dimethyldiamine-2-oxopropylphosphonic acid dimethyl ester (488 mg, 381 μl, 2.54 mmol, equivalent: 1.2). Stirring was then continued overnight at room temperature. The mixture was diluted with Et 2 O and washed with aqueous 5% KHCO 3. With Et 2 O and the aqueous phase was back extracted dried over magnesium sulfate, filtered and concentrated to leave a pale brown oily crude product. The crude material was applied to a silica gel and purified by column chromatography using heptane/ethyl acetate (0-50% ethyl acetate) as a solvent to afford 4-bromo-2-ethynyl as a brown solid. 1-Methyl-1H-imidazole (319 mg, 81.5%). MS: m/z = 185.0 (M+H+)
在室溫下在氬氣氛下，向2-氯-4,8-二甲基喹唑啉(如WO2013/50527中所闡述製備)(100mg,519μmol，當量：1.00)及4-溴-2-乙炔基-1-甲基-1H-咪唑(106mg,571μmol，當量：1.1)於DMF(8.00ml)中之攪拌溶液添加三乙胺(105mg,144μl,1.04mmol，當量：2)、碘化銅(I)(4.94mg,26.0μmol，當量：0.05)及雙(三苯基膦)氯化鈀(II)(18.2mg,26.0μmol，當量：0.05)。將混合物脫氣且用氬氣回填，然後將其加熱至80℃。在此溫度下持續攪拌整個週末(深色溶液)。LCMS顯示產物峰。將粗材料施加於矽膠上且藉由管柱層析使用庚烷/乙酸乙酯(0-100%乙酸乙酯)作為溶析劑來純化，提供淺棕色固體狀4,8-二甲基-2-(2-甲基-5-吡咯啶-1-基-2H-[1,2,4]***-3-基乙炔基)-喹唑啉(55mg,31.1%)。MS：m/z=341.1(M+H+) To 2-chloro-4,8-dimethylquinazoline (prepared as described in WO 2013/50527) under an argon atmosphere at room temperature (100 mg, 519 μmol, equivalent: 1.00) and 4-bromo-2- Add a solution of ethynyl-1-methyl-1H-imidazole (106 mg, 571 μmol, equivalent: 1.1) in DMF (8.00 ml), triethylamine (105 mg, 144 μl, 1.04 mmol, equivalent: 2), copper iodide (I) (4.94 mg, 26.0 μmol, equivalent: 0.05) and bis(triphenylphosphine)palladium(II) chloride (18.2 mg, 26.0 μmol, equivalent: 0.05). The mixture was degassed and backfilled with argon and then heated to 80 °C. Stirring was continued throughout the weekend at this temperature (dark solution). LCMS showed the product peak. The crude material was applied to a silica gel and purified by column chromatography using heptane/ethyl acetate (0-100% ethyl acetate) as a solvent to afford 4,8-dimethyl- 2-(2-Methyl-5-pyrrolidin-1-yl-2H-[1,2,4]triazol-3-ylethynyl)-quinazoline (55 mg, 31.1%). MS: m/z = 341.1 (M+H+)
其係以與實例1d)中所闡述類似之方式使用2-((4-溴-1-甲基-1H-咪唑-2-基)乙炔基)-4,8-二甲基喹唑啉(80mg,234μmol，當量：1.00)及吡咯啶-2-酮(39.9mg,36.0μl,469μmol，當量：2)作為起始材料來製備，提供淺黃色固體狀1-[2-(4,8-二甲基-喹唑啉-2-基乙炔基)-1-甲基-1H-咪唑-4-基]-吡咯啶-2-酮(2.42mg,2.99%)。MS：m/z=346.2(M+H+)。 2-((4-bromo-1-methyl-1H-imidazol-2-yl)ethynyl)-4,8-dimethylquinazoline was used in a similar manner as described in Example 1d) 80 mg, 234 μmol, equivalent: 1.00) and pyrrolidin-2-one (39.9 mg, 36.0 μl, 469 μmol, equivalent: 2) were prepared as starting materials to provide 1-[2-(4,8-) as a pale yellow solid. Dimethyl-quinazolin-2-ylethynyl)-1-methyl-1H-imidazol-4-yl]-pyrrolidin-2-one (2.42 mg, 2.99%). MS: m/z = 346.2 (M + H +).
在25℃下在密封管中，向4-溴-2-[(E)-2-{4,7-二甲基-[1,2,4]***并[1,5-a]吡-2-基}乙烯基]-1-甲基-1H-咪唑(200mg,0.60mmol)於1,4-二噁烷(10ml)中之溶液添加吡咯啶-2-酮(0.07ml,0.90mmol)、Brettphos環鈀(71.9mg,0.09mmol)及Ruphos(56mg,0.12mmol)，且用氬氣將混合物吹掃10min。此後添加NaOtBu(173mg,1.80mmol)並用氬氣再吹掃10min。然後將反應混合物加熱至110℃且在此溫度下攪拌6h。將反應混合物升溫至25℃，經由矽藻土床過濾，用EtOAc(30ml)洗滌。用水(30ml)稀釋濾液且用EtOAc(2×50ml)萃取，並用水(50ml)、鹽水(50ml)洗滌合併之有機層，經Na2SO4乾燥且在真空 中濃縮。藉由管柱層析經由胺矽膠純化粗製物，使用40%乙酸乙酯之己烷溶液溶析，以獲得黃色固體狀1-{2-[(E)-2-{4,7-二甲基-[1,2,4]***并[1,5-a]吡-2-基}乙烯基]-1-甲基-1H-咪唑-4-基}吡咯啶-2-酮(60mg,29%)。MS：M/Z=338.2(M+H+)。 To 4-bromo-2-[(E)-2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrene in a sealed tube at 25 °C Add pyrrrolidin-2-one (0.07 ml, 0.90 mmol) to a solution of 2-yl}vinyl]-1-methyl-1H-imidazole (200 mg, 0.60 mmol) in 1,4-dioxane (10 mL) , Brettphos cyclopalladium (71.9 mg, 0.09 mmol) and Ruphos (56 mg, 0.12 mmol), and the mixture was purged with argon for 10 min. Thereafter NaOtBu (173 mg, 1.80 mmol) was added and spurt with argon for 10 min. The reaction mixture was then heated to 110 ° C and stirred at this temperature for 6 h. The reaction mixture was warmed to EtOAc (30 mL). Washed with water (30ml) and extracted filtrate was diluted with EtOAc (2 × 50ml), and washed with water (50ml), brine (50ml) the organic layers were washed, 2 SO 4 and concentrated in vacuo dried over Na. The crude material was purified by column chromatography eluting with EtOAc EtOAc (EtOAc) elut -[1,2,4]triazolo[1,5-a]pyridyl -2-yl}vinyl]-1-methyl-1H-imidazol-4-yl}pyrrolidin-2-one (60 mg, 29%). MS: M/Z = 338.2 (M + H +).
然後向1-{2-[(E)-2-{4,7-二甲基-[1,2,4]***并[1,5-a]吡-2-基}乙烯基]-1-甲基-1H-咪唑-4-基}吡咯啶-2-酮(60mg,0.18mmol)於甲醇(5ml)中之溶液添加雷尼鎳(30mg)。在氫氣球壓力下將反應團塊攪拌16h。完成反應後，經由矽藻土床過濾反應混合物，用甲醇(15ml)洗滌且在減壓下濃縮濾液。藉由二氧化矽管柱使用二氯甲烷中之4%甲醇純化粗製物，以獲得白色固體狀1-[2-(2-{4,7-二甲基-[1,2,4]***并[1,5-a]吡-2-基}乙基)-1-甲基-1H-咪唑-4-基]吡咯啶-2-酮(16mg,26%)。MS：M/Z=340.2(M+H+)。 Then to 1-{2-[(E)-2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl Raney nickel (30 mg) was added to a solution of 2-yl}vinyl]-1-methyl-1H-imidazol-4-yl}pyrrolidin-2-one (60 mg, 0.18 mmol) in MeOH (5 mL). The reaction mass was stirred under a hydrogen balloon pressure for 16 h. After completion of the reaction, the reaction mixture was filtered and evaporated. The crude material was purified by a ruthenium dioxide column using 4% methanol in dichloromethane to afford 1-[2-(2-{4,7-dimethyl-[1,2,4] Oxazo[1,5-a]pyridin -2-yl}ethyl)-1-methyl-1H-imidazol-4-yl]pyrrolidin-2-one (16 mg, 26%). MS: M/Z = 340.2 (M + H +).
其係以與實例10中所闡述類似之方式使用4-溴-1-(環丙基甲基)-2-[(E)-2-{4,7-二甲基-[1,2,4]***并[1,5-a]吡-2-基}乙烯基]-1H-咪唑(170mg,0.45mmol)及吡咯啶-2-酮(0.07ml,0.91mmol)作為起始材料來製備，提供黃色固體狀1-[1-(環丙基甲基)-2-[(E)-2-{4,7-二甲基-[1,2,4]***并[1,5-a]吡-2-基}乙烯基]-1H-咪唑-4-基]吡咯啶-2-酮(70mg,40%)；MS：M/Z=378(M+H+)。 It was used in a similar manner to that described in Example 10 using 4-bromo-1-(cyclopropylmethyl)-2-[(E)-2-{4,7-dimethyl-[1,2, 4] Triazolo[1,5-a]pyridin 2-Benzyl}vinyl]-1H-imidazole (170 mg, 0.45 mmol) and pyrrolidin-2-one (0.07 ml, 0.91 mmol) were obtained as starting material to afford 1-[1-[ Propylmethyl)-2-[(E)-2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}vinyl]-1H-imidazol-4-yl]pyrrolidin-2-one (70 mg, 40%); MS: M/Z = 378 (M+H+).
其係以與實例11中所闡述類似之方式使用1-[1-(環丙基甲基)-2-[(E)-2-{4,7-二甲基-[1,2,4]***并[1,5-a]吡-2-基}乙烯基]-1H-咪唑-4-基]吡咯啶-2-酮(70mg,0.186mmol)作為起始材料來製備，提供白色固體狀1-[1-(環丙基甲基)-2-(2-{4,7-二甲基-[1,2,4]***并[1,5-a]吡-2-基}乙基)-1H-咪唑-4-基]吡咯啶-2-酮(7mg,11%)；MS：M/Z=380.1(M+H+)。 It was used in a similar manner to that described in Example 11 using 1-[1-(cyclopropylmethyl)-2-[(E)-2-{4,7-dimethyl-[1,2,4 Triazolo[1,5-a]pyridyl 2-Benzyl}vinyl]-1H-imidazol-4-yl]pyrrolidin-2-one (70 mg, 0.186 mmol) was obtained as a starting material to afford 1-[1-(cyclopropylmethyl) as a white solid 2-(2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}ethyl)-1H-imidazol-4-ylpyrrolidin-2-one (7 mg, 11%); MS: M/Z = 380.1 (M+H+).
將4-溴-1H-咪唑(10g,68.04mmol)於THF(330ml)中之溶液冷卻至0℃。在0℃下緩慢添加K2CO3(18.77g,136.08mmol)。在0℃下攪拌1h後，在0℃下逐滴添加碘甲烷(8.50ml,136.08mmol)。將混合物升溫至25℃且在25℃下攪拌16h。用水(100ml)稀釋反應物並用乙酸乙酯(3×250ml)萃取。用水(2×100ml)、鹽水(100ml)洗滌有機層，且經硫酸鈉乾燥，過濾並蒸發。藉由二氧化矽管柱層析純化粗製物，使用10%乙酸乙酯之己烷溶液溶析，以獲得無色液體狀4-溴-1-(三苯基甲基)-1H-咪唑(12g,50%)。 A solution of 4-bromo-1H-imidazole (10 g, 68.04 mmol) in THF (330 mL) was cooled to 0. K 2 CO 3 (18.77 g, 136.08 mmol) was slowly added at 0 °C. After stirring at 0 ° C for 1 h, iodomethane (8.50 ml, 136.08 mmol) was added dropwise at 0 °C. The mixture was warmed to 25 ° C and stirred at 25 ° C for 16 h. The reaction was diluted with water (100 mL) The organic layer was washed with EtOAc (EtOAc)EtOAc. The crude material was purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane to afford 4-bromo-1-(triphenylmethyl)-1H-imidazole as a colorless liquid (12 g , 50%).
在-78℃下在氬氣下，向4-溴-1-(三苯基甲基)-1H-咪唑(6g,15.42mmol)於四氫呋喃(250ml)中之溶液逐滴添加正丁基鋰(1.6M於己烷 中，12.44ml,18.55mmol)。在-78℃下將所得混合物攪拌30分鐘。然後在-78℃下逐滴添加溶於45ml THF中之二甲基甲醯胺(2.49ml,30.89mmol)且將混合物緩慢升溫至25℃。在25℃下用飽和氯化銨溶液(500ml)驟冷混合物且用乙酸乙酯(2×500ml)萃取，用水(2×400ml)及鹽水(400ml)洗滌分離之有機層，經硫酸鈉乾燥，過濾並蒸發。藉由正相矽膠管柱純化粗製物，用30%乙酸乙酯之己烷溶液溶析，以獲得白色固體狀4-溴-1-(三苯基甲基)-1H-咪唑-2-甲醛(2g,31%)。 n-Butyllithium was added dropwise to a solution of 4-bromo-1-(triphenylmethyl)-1H-imidazole (6 g, 15.42 mmol) in tetrahydrofuran (250 ml) under argon at -78 °C. 1.6M in hexane Medium, 12.44 ml, 18.55 mmol). The resulting mixture was stirred at -78 °C for 30 minutes. Then dimethylformamide (2.49 ml, 30.89 mmol) dissolved in 45 ml of THF was added dropwise at -78 °C and the mixture was slowly warmed to 25 °C. The mixture was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) Filter and evaporate. The crude material was purified by a normal phase column chromatography eluting with 30% ethyl acetate in hexane to afford 4-bromo-1-(triphenylmethyl)-1H-imidazole-2-carbaldehyde as a white solid. (2g, 31%).
向4-溴-1-(三苯基甲基)-1H-咪唑-2-甲醛(5.5g,13.18mmol)於甲醇(100ml)中之溶液添加AcOH(1.5ml,26.4mmol)，然後將其升溫至60℃且在此溫度下攪拌2h。完成反應後，將反應混合物升溫至25℃並在減壓下濃縮。用水(150ml)稀釋粗殘餘物，用碳酸氫鹽溶液中和，調節至pH約7，並用乙酸乙酯(2×300ml)萃取，分離有機層且用鹽水(100ml)洗滌，並經硫酸鈉乾燥，過濾且濃縮以獲得粗製物。藉由combiflash管柱使用30%乙酸乙酯之己烷溶液純化粗製物，以獲得棕色固體狀4-溴-1H-咪唑-2-甲醛(700mg,31%)。 Add AcOH (1.5 ml, 26.4 mmol) to a solution of 4-bromo-1-(triphenylmethyl)-1H-imidazol-2-carbaldehyde (5.5 g, 13.18 mmol) in methanol (100 mL) The temperature was raised to 60 ° C and stirred at this temperature for 2 h. After completion of the reaction, the reaction mixture was warmed to 25 ° C and concentrated under reduced pressure. The crude residue was diluted with EtOAc (EtOAc) (EtOAc (EtOAc) Filtered and concentrated to obtain a crude material. The crude material was purified using a EtOAc EtOAc EtOAc EtOAc (EtOAc)
將4-溴-1H-咪唑-2-甲醛(350mg,2mmol)於DMF(10ml)中之溶液冷卻至0℃。在0℃下緩慢添加Cs2CO3(1.71g,2mmol)。在0℃下攪拌10min後，在0℃下逐滴添加三氟甲烷磺酸2,2-二氟乙基酯(928ng,2mmol)。將混合物升溫至25℃且在相同溫度下攪拌2h。用水(50ml)稀 釋反應物且用乙酸乙酯(3×100ml)萃取。用水(2×100ml)、鹽水(50ml)洗滌有機層，且經硫酸鈉乾燥，過濾並蒸發。藉由combiflash管柱層析純化粗製物，用20%乙酸乙酯之己烷溶液溶析，以獲得白色固體狀4-溴-1-(2,2,2-三氟乙基)-1H-咪唑-2-甲醛(350mg,68%)。MS：M/Z=257(M+H+)。 A solution of 4-bromo-1H-imidazole-2-carbaldehyde (350 mg, 2 mmol) in DMF (10 mL) was cooled to 0. Cs 2 CO 3 (1.71 g, 2 mmol) was slowly added at 0 °C. After stirring at 0 ° C for 10 min, 2,2-difluoroethyl trifluoromethanesulfonate (928 ng, 2 mmol) was added dropwise at 0 °C. The mixture was warmed to 25 ° C and stirred at the same temperature for 2 h. The reaction was diluted with water (50 mL) The organic layer was washed with EtOAc (EtOAc)EtOAc. The crude material was purified by EtOAc EtOAc (EtOAc) eluting Imidazole-2-carbaldehyde (350 mg, 68%). MS: M/Z = 257 (M + H +).
其係以與實例1c)中所闡述類似之方式使用4-溴-1-(2,2,2-三氟乙基)-1H-咪唑-2-甲醛(4d)(250mg,0.97mmol)及{4,7-二甲基-[1,2,4]***并[1,5-a]吡-2-基}甲基)三苯基氯化鏻(5)(412mg,0.97mmol)作為起始材料來製備，提供白色固體狀4-溴-2-[(E)-2-{4,7-二甲基-[1,2,4]***并[1,5-a]吡-2-基}乙烯基]-1-(2,2,2-三氟乙基)-1H-咪唑(180mg,46%)；MS：M/Z=401(M+H+)。 4-bromo-1-(2,2,2-trifluoroethyl)-1H-imidazol-2-carbaldehyde (4d) (250 mg, 0.97 mmol) was used in a similar manner as described in Example 1c) {4,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl 4-Benzyl}methyl)triphenylphosphonium chloride (5) (412 mg, 0.97 mmol) was obtained as starting material to afford 4-bromo-2-[(E)-2-{4 as a white solid. 7-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl 2-yl}vinyl]-1-(2,2,2-trifluoroethyl)-1H-imidazole (180 mg, 46%); MS: M/Z = 401 (M+H+).
在25℃下在密封管中，向4-溴-2-[(E)-2-{4,7-二甲基-[1,2,4]***并[1,5-a]吡-2-基}乙烯基]-1-(2,2,2-三氟乙基)-1H-咪唑(6a)(160mg,0.4mmol)於1,4-二噁烷(6ml)中之溶液添加吡咯啶-2-酮(0.06ml,0.8 mmol)、Brettphos環鈀(47.93mg,0.06mmol)及Ruphos(37.3mg,0.08mmol)，且用氬氣將混合物吹掃10min。此後添加NaOtBu(115.3mg,1.2mmol)並用氬氣再吹掃10min。然後將反應混合物加熱至110℃且在此溫度下攪拌6h。將反應混合物升溫至25℃，經由矽藻土床過濾，用EtOAc(30ml)洗滌。用水(30ml)稀釋濾液且用EtOAc(2×50ml)萃取，並用水(50ml)、鹽水(50ml)洗滌合併之有機層，經Na2SO4乾燥且在真空中濃縮。藉由管柱層析經由胺矽膠純化粗製物，用40%乙酸乙酯之己烷溶液溶析，以獲得黃色固體狀1-{2-[(E)-2-{4,7-二甲基-[1,2,4]***并[1,5-a]吡-2-基}乙烯基]-1-(2,2,2-三氟乙基)-1H-咪唑-4-基}吡咯啶-2-酮(60mg,37%)；MS：M/Z=406(M+H+)。 To 4-bromo-2-[(E)-2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrene in a sealed tube at 25 °C a solution of 2-yl}vinyl]-1-(2,2,2-trifluoroethyl)-1H-imidazole (6a) (160 mg, 0.4 mmol) in 1,4-dioxane (6 mL) Pyrrolidin-2-one (0.06 ml, 0.8 mmol), Brettphos cyclopalladium (47.93 mg, 0.06 mmol) and Ruphos (37.3 mg, 0.08 mmol) were added and the mixture was purged with argon for 10 min. Thereafter NaOtBu (115.3 mg, 1.2 mmol) was added and the mixture was purged with argon for 10 min. The reaction mixture was then heated to 110 ° C and stirred at this temperature for 6 h. The reaction mixture was warmed to EtOAc (30 mL). Washed with water (30ml) and extracted filtrate was diluted with EtOAc (2 × 50ml), and washed with water (50ml), brine (50ml) the organic layers were washed, 2 SO 4 and concentrated in vacuo dried over Na. The crude material was purified by column chromatography eluting with EtOAc EtOAc (EtOAc) elut -[1,2,4]triazolo[1,5-a]pyridyl -2-yl}vinyl]-1-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl}pyrrolidin-2-one (60 mg, 37%); MS: M/Z =406 (M+H+).
然後向1-{2-[(E)-2-{4,7-二甲基-[1,2,4]***并[1,5-a]吡-2-基}乙烯基]-1-(2,2,2-三氟乙基)-1H-咪唑-4-基}吡咯啶-2-酮(8d)(70mg,0.17mmol)於甲醇(5ml)中之溶液添加雷尼鎳(30mg)。在氫氣球壓力下將反應團塊攪拌16h。完成反應後，經由矽藻土床過濾反應混合物，用甲醇(15ml)洗滌且在減壓下濃縮濾液。藉由二氧化矽管柱使用二氯甲烷中之4%甲醇純化粗製物，以獲得白色固體狀1-[2-(2-{4,7-二甲基-[1,2,4]***并[1,5-a]吡-2-基}乙基)-1-(2,2,2-三氟乙基)-1H-咪唑-4-基]吡咯啶-2-酮(20mg,28%)；MS：M/Z=408.2(M+H+)。 Then to 1-{2-[(E)-2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}vinyl]-1-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl}pyrrolidin-2-one (8d) (70 mg, 0.17 mmol) in methanol ( Raney nickel (30 mg) was added to the solution in 5 ml). The reaction mass was stirred under a hydrogen balloon pressure for 16 h. After completion of the reaction, the reaction mixture was filtered and evaporated. The crude material was purified by a ruthenium dioxide column using 4% methanol in dichloromethane to afford 1-[2-(2-{4,7-dimethyl-[1,2,4] Oxazo[1,5-a]pyridin -2-yl}ethyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl]pyrrolidin-2-one (20 mg, 28%); MS: M/Z =408.2 (M+H+).
將4-溴-1H-咪唑-2-甲醛(450mg,2.57mmol)於DMF(12ml)中之溶液冷卻至0℃。在0℃下緩慢添加Cs2CO3(1.71g,5.14mmol)。在0℃下攪拌10min後，在0℃下逐滴添加三氟甲烷磺酸2,2-二氟乙基酯(825.5mg,3.87mmol)。將混合物升溫至25℃且在相同溫度下攪拌2h。用水(50ml)稀釋反應物且用乙酸乙酯(3×100ml)萃取。用水(2×100ml)、鹽水(50ml)洗滌有機層，且經硫酸鈉乾燥，過濾並蒸發。藉由combiflash管柱層析純化粗製物，用20%乙酸乙酯之己烷溶液溶析，以獲得無色液體狀4-溴-1-(2,2-二氟乙基)-1H-咪唑-2-甲醛(220mg,36%)；MS：M/Z=239(M+H+)。 A solution of 4-bromo-1H-imidazole-2-carbaldehyde (450 mg, 2.57 mmol) in DMF (12 mL) was cooled to 0. Cs 2 CO 3 (1.71 g, 5.14 mmol) was slowly added at 0 °C. After stirring at 0 ° C for 10 min, 2,2-difluoroethyl trifluoromethanesulfonate (825.5 mg, 3.87 mmol) was added dropwise at 0 °C. The mixture was warmed to 25 ° C and stirred at the same temperature for 2 h. The reaction was diluted with water (50 mL) The organic layer was washed with EtOAc (EtOAc)EtOAc. The crude material was purified by combiflash column chromatography eluting with 20% ethyl acetate in hexane to afford 4-bromo-1-(2,2-difluoroethyl)-1H-imidazole as colorless liquid. 2-Formaldehyde (220 mg, 36%); MS: M/Z = 239 (M+H+).
其係以與實例5a中所闡述類似之方式使用4-溴-1-(2,2-二氟乙基)-1H-咪唑-2-甲醛(200mg,0.84mmol)及{4,7-二甲基-[1,2,4]***并[1,5- a]吡-2-基}甲基)三苯基氯化鏻(354mg,0.84mmol)作為起始材料來製備，提供白色固體狀4-溴-1-(2,2-二氟乙基)-2-[(E)-2-{4,7-二甲基-[1,2,4]***并[1,5-a]吡-2-基}乙烯基]-1H-咪唑(120mg,38%)；MS：M/Z=383(M+H+)。 4-bromo-1-(2,2-difluoroethyl)-1H-imidazol-2-carbaldehyde (200 mg, 0.84 mmol) and {4,7-di, in a similar manner as described in Example 5a. Methyl-[1,2,4]triazolo[1,5- a]pyridyl 4-Benzyl}methyl)triphenylphosphonium chloride (354 mg, 0.84 mmol) was obtained as starting material afforded 4-bromo-1-(2,2-difluoroethyl)-2- [(E)-2-{4,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl 2-yl}vinyl]-1H-imidazole (120 mg, 38%); MS: M/Z = 383 (M+H+).
其係以與實例10中所闡述類似之方式使用4-溴-1-(2,2-二氟乙基)-2-[(E)-2-{4,7-二甲基-[1,2,4]***并[1,5-a]吡-2-基}乙烯基]-1H-咪唑(100mg,0.26mmol)及吡咯啶-2-酮(0.04ml,0.91mmol)作為起始材料來製備，提供白色固體狀1-[1-(2,2-二氟乙基)-2-[(E)-2-{4,7-二甲基-[1,2,4]***并[1,5-a]吡-2-基}乙烯基]-1H-咪唑-4-基]吡咯啶-2-酮(13mg,12%)；MS：M/Z=388.2(M+H+)。 4-bromo-1-(2,2-difluoroethyl)-2-[(E)-2-{4,7-dimethyl-[1] was used in a similar manner as described in Example 10. , 2,4]triazolo[1,5-a]pyridyl 2-yl}vinyl]-1H-imidazole (100 mg, 0.26 mmol) and pyrrolidin-2-one (0.04 ml, 0.91 mmol) were obtained as starting material to afford 1-[1-(2) as a white solid. ,2-difluoroethyl)-2-[(E)-2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}vinyl]-1H-imidazol-4-yl]pyrrolidin-2-one (13 mg, 12%); MS: M/Z = 388.2 (M+H+).
其係以與實例11中所闡述類似之方式使用1-[1-(2,2-二氟乙基)-2-[(E)-2-{4,7-二甲基-[1,2,4]***并[1,5-a]吡-2-基}乙烯基]-1H-咪唑-4-基]吡咯啶-2-酮(23mg,0.06mmol)作為起始材料來製備，提供白色固 體狀1-[1-(2,2-二氟乙基)-2-(2-{4,7-二甲基-[1,2,4]***并[1,5-a]吡-2-基}乙基)-1H-咪唑-4-基]吡咯啶-2-酮(6mg,25%)；MS：M/Z=390.4(M+H+)。 It was used in a similar manner to that described in Example 11 using 1-[1-(2,2-difluoroethyl)-2-[(E)-2-{4,7-dimethyl-[1, 2,4]triazolo[1,5-a]pyridyl 2-Benzyl}vinyl]-1H-imidazol-4-yl]pyrrolidin-2-one (23 mg, 0.06 mmol) was obtained as a starting material to afford 1-[1-(2,2- Difluoroethyl)-2-(2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridyl -2-yl}ethyl)-1H-imidazol-4-ylpyrrolidin-2-one (6 mg, 25%); MS: M/Z = 390.4 (M+H+).
向4-溴-1-甲基-1H-咪唑-2-甲醛(400mg,5.8mmol)及吡咯啶-2-酮(0.35ml,2.11mmol)於甲苯(20ml)中之溶液添加Cs2CO3(3.7g,11.6mmol)、xantphos(335mg,0.58mmol)，且用氬氣將混合物吹掃10min。添加Pd2(dba)3(1.03g,3.17mmol)並用氬氣再吹掃10min。然後將反應混合物加熱至50℃且在此溫度下在氬氣下攪拌16h。此後檢查TLC且存在起始材料，故再添加0.5當量xantphos及0.5當量Pd2(dba)3及1當量Cs2CO3，在90℃下再持續3h。將反應混合物升溫至25℃，經由矽藻土床過濾，在真空中濃縮。藉由管柱層析經由二氧化矽(100-200目)純化粗製物，用20%乙酸乙酯之己烷溶液溶析，以獲得黃色固體狀1-甲基-4-(2-側氧基吡咯啶-1-基)-1H-咪唑-2-甲醛(60mg,15%)。MS：M/Z=194(M+H+)。 Add Cs 2 CO 3 to a solution of 4-bromo-1-methyl-1H-imidazol-2-carbaldehyde (400 mg, 5.8 mmol) and pyrrolidine-2-one (0.35 ml, 2.11 mmol) in toluene (20 ml) (3.7 g, 11.6 mmol), xantphos (335 mg, 0.58 mmol), and the mixture was purged with argon for 10 min. Pd 2 (dba) 3 (1.03 g, 3.17 mmol) was added and rinsed with argon for 10 min. The reaction mixture was then heated to 50 ° C and stirred at this temperature under argon for 16 h. Thereafter TLC was checked and the starting material was present, so an additional 0.5 equivalents of xantphos and 0.5 equivalents of Pd 2 (dba) 3 and 1 equivalent of Cs 2 CO 3 were added and continued at 90 ° C for an additional 3 h. The reaction mixture was warmed to 25 <0>C, filtered over a pad of celite and concentrated in vacuo. The crude material was purified by column chromatography eluting with EtOAc (EtOAc:EtOAc) Pyrrolidin-1-yl)-1H-imidazole-2-carbaldehyde (60 mg, 15%). MS: M/Z = 194 (M + H +).
在氬氣下在25℃下，向1-甲基-4-(2-側氧基吡咯啶-1-基)-1H-咪唑-2-甲醛(60mg,0.311mmol)於甲醇(6ml)中之溶液添加Bestmann ohira試劑(72mg,0.373mmol)及K2CO3(85g,0.622mmol)且在25℃下將混合物攪拌2h。此後檢查TLC且經由矽藻土床過濾並在真空中濃縮。藉由combiflash管柱層析純化粗製物，用20%乙酸乙酯之己烷溶液溶析，以獲得白色固體狀1-(2-乙炔基-1-甲基-1H-咪唑-4-基)吡咯啶-2-酮(30mg,51%)。MS：M/Z=190(M+H+)。 To 1-methyl-4-(2-o-oxypyrrolidin-1-yl)-1H-imidazole-2-carboxaldehyde (60 mg, 0.311 mmol) in MeOH (6 mL) A solution of Bestmann ohira reagent (72 mg, 0.373 mmol) and K 2 CO 3 (85 g, 0.622 mmol) was added and the mixture was stirred at 25 ° C for 2 h. Thereafter TLC was checked and filtered through a bed of diatomaceous earth and concentrated in vacuo. The crude material was purified by EtOAc EtOAc (EtOAc) elute Pyrrolidin-2-one (30 mg, 51%). MS: M/Z = 190 (M + H +).
向1-(2-乙炔基-1-甲基-1H-咪唑-4-基)吡咯啶-2-酮(55mg,0.291mmol)及2-溴-4,7-二甲基-[1,2,4]***并[1,5-a]吡(73mg,0.32mmol)於DMF(3ml)中之溶液添加TEA(0.08ml,0.58mmol)，然後添加CuI，且用氬氣將混合物吹掃10min。此後添加Pd(PPh3)2Cl2(11mg,0.015mmol)，並用氬氣再吹掃5min。然後將反應混合物加熱至75℃且在此溫度下在氬氣下攪拌2h。此後經由矽藻土床過濾反應混合物，用水(30ml)稀釋，用EtOAc(2×50ml)萃取，且用水(50ml)、鹽水(50ml)洗滌合併之有機層，經Na2SO4乾燥並在真空中濃縮。藉由製備型TLC純化粗製物，以獲得白色黏性固體狀1-[2-(2-{4,7-二甲基-[1,2,4]***并[1,5-a]吡-2-基}乙炔基)-1-甲基-1H-咪唑-4-基]吡咯啶-2-酮(21)(4mg,4%)。MS：M/Z=336(M+H+)。 To 1-(2-ethynyl-1-methyl-1H-imidazol-4-yl)pyrrolidin-2-one (55 mg, 0.291 mmol) and 2-bromo-4,7-dimethyl-[1, 2,4]triazolo[1,5-a]pyridyl (73 mg, 0.32 mmol) <RTI ID=0.0></RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt; Thereafter Pd(PPh 3 ) 2 Cl 2 (11 mg, 0.015 mmol) was added and then purged with argon for 5 min. The reaction mixture was then heated to 75 ° C and stirred at argon for 2 h under argon. After the reaction mixture was filtered, diluted with water (30ml) via diatomaceous earth bed, and extracted with EtOAc (2 × 50ml), and washed with water (50ml), the organic layer with brine (50ml) of washed, dried over Na 2 SO 4 and in vacuo Concentrated in. The crude material was purified by preparative TLC to afford 1-[2-(2-{4,7-dimethyl-[1,2,4]triazolo[1,5-a] as a white viscous solid. Pyridine 2-yl}ethynyl)-1-methyl-1H-imidazol-4-yl]pyrrolidin-2-one (21) (4 mg, 4%). MS: M/Z = 336 (M + H +).
其係以與實例1c中所闡述類似之方式使用4-溴-1-(環丙基甲基)-1H-咪唑-2-甲醛(400mg,1.74mmol)及{5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基}甲基)三苯基氯化鏻(740mg,1.74mmol)作為起始材料來製備，提供灰白色固體狀4-溴-1-(環丙基甲基)-2-[(E)-2-{5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基}乙烯基]-1H-咪唑(360mg,55%)。MS：M/Z=372.8(M+H+)。 4-bromo-1-(cyclopropylmethyl)-1H-imidazol-2-carbaldehyde (400 mg, 1.74 mmol) and {5,8-dimethyl-- was used in a similar manner as described in Example 1c. [1,2,4]Triazolo[1,5-c]pyrimidin-2-yl}methyl)triphenylphosphonium chloride (740 mg, 1.74 mmol) was prepared as a starting material to afford a white solid. -Bromo-1-(cyclopropylmethyl)-2-[(E)-2-{5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidine- 2-yl}vinyl]-1H-imidazole (360 mg, 55%). MS: M/Z = 372.8 (M + H +).
其係以與實例1d中所闡述類似之方式使用4-溴-1-(環丙基甲基)-2- [(E)-2-{5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基}乙烯基]-1H-咪唑(200mg,0.54mmol)及吡咯啶-2-酮(0.08ml,0.90mmol)作為起始材料來製備，提供灰白色固體狀1-[1-(環丙基甲基)-2-[(E)-2-{5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基}乙烯基]-1H-咪唑-4-基]吡咯啶-2-酮(90mg,45%)。MS：M/Z=378.0(M+H+)。 It was used in a similar manner to that described in Example 1d using 4-bromo-1-(cyclopropylmethyl)-2- [(E)-2-{5,8-Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl}vinyl]-1H-imidazole (200 mg, 0.54 Methyl) and pyrrolidin-2-one (0.08 ml, 0.90 mmol) were obtained as starting material to afford 1-[1-(cyclopropylmethyl)-2-[(E)-2-{ 5,8-Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl}vinyl]-1H-imidazol-4-yl]pyrrolidin-2-one ( 90mg, 45%). MS: M/Z = 378.0 (M + H +).
其係以與實例11中所闡述類似之方式使用1-[1-(環丙基甲基)-2-[(E)-2-{5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基}乙烯基]-1H-咪唑-4-基]吡咯啶-2-酮(90mg,0.239mmol)作為起始材料來製備，提供白色固體狀1-[1-(環丙基甲基)-2-(2-{5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基}乙基)-1H-咪唑-4-基]吡咯啶-2-酮(26mg,29%)。MS：M/Z=380.2(M+H+)。 It was used in a similar manner to that described in Example 11 using 1-[1-(cyclopropylmethyl)-2-[(E)-2-{5,8-dimethyl-[1,2,4 Triazolo[1,5-c]pyrimidin-2-yl}vinyl]-1H-imidazol-4-yl]pyrrolidin-2-one (90 mg, 0.239 mmol) as a starting material, white Solid 1-[1-(cyclopropylmethyl)-2-(2-{5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2- Base ethyl)-1H-imidazol-4-yl]pyrrolidin-2-one (26 mg, 29%). MS: M/Z = 380.2 (M + H +).
其係以與實例1c中所闡述類似之方式使用4-溴-1-苯基-1H-咪唑(200mg,0.80mmol)及{5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基}甲基)三苯基氯化鏻(338mg,0.80mmol)作為起始材料來製備，提供灰白色固體狀2-[(E)-2-(4-溴-1-苯基-咪唑-2-基)乙烯基]-5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶(180mg,58%)；MS：M/Z=395(M+H+)。 4-bromo-1-phenyl-1H-imidazole (200 mg, 0.80 mmol) and {5,8-dimethyl-[1,2,4]triazole were used in a similar manner as described in Example 1c. And [1,5-c]pyrimidin-2-yl}methyl)triphenylphosphonium chloride (338 mg, 0.80 mmol) was obtained as a starting material to afford 2-[(E)-2- 4-bromo-1-phenyl-imidazol-2-yl)vinyl]-5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidine (180 mg, 58% MS: M/Z = 395 (M+H+).
其係以與實例1d中所闡述類似之方式使用2-[(E)-2-(4-溴-1-苯基-咪唑-2-基)乙烯基]-5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶(110mg,0.28mmol)及吡咯啶-2-酮(0.045ml,0.91mmol)作為起始材料來製備，提供白色固體狀2-[(E)-2-(4-溴-1-苯基-咪唑-2-基)乙烯基]-5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶(55mg,50%)；MS：M/Z=399(M+H+)。 It was used in a similar manner to that described in Example 1d using 2-[(E)-2-(4-bromo-1-phenyl-imidazol-2-yl)vinyl]-5,8-dimethyl- [1,2,4]Triazolo[1,5-c]pyrimidine (110 mg, 0.28 mmol) and pyrrolidin-2-one (0.045 ml, 0.91 mmol) were prepared as starting material to afford a white solid. -[(E)-2-(4-bromo-1-phenyl-imidazol-2-yl)vinyl]-5,8-dimethyl-[1,2,4]triazolo[1,5 -c]pyrimidine (55 mg, 50%); MS: M/Z = 399 (M+H+).
其係以與實例11中所闡述類似之方式使用2-[(E)-2-(4-溴-1-苯基-咪唑-2-基)乙烯基]-5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶(15mg,0.04 mmol)作為起始材料來製備，提供灰白色固體狀1-[2-[2-(5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基)乙基]-1-苯基-咪唑-4-基]吡咯啶-2-酮(4mg,25%)；MS：M/Z=402(M+H+)。 It was used in a similar manner to that described in Example 11 using 2-[(E)-2-(4-bromo-1-phenyl-imidazol-2-yl)vinyl]-5,8-dimethyl- [1,2,4]triazolo[1,5-c]pyrimidine (15 mg, 0.04 Prepared as starting material to provide 1-[2-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidine-2 as an off-white solid. -yl)ethyl]-1-phenyl-imidazol-4-yl]pyrrolidin-2-one (4 mg, 25%); MS: M/Z = 402 (M+H+).
其係以與實例1c中所闡述類似之方式使用4-溴-1-(2,2,2-三氟乙基)-1H-咪唑-2-甲醛(250mg,0.97mmol)及{5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基}甲基)三苯基氯化鏻(412mg,0.97mmol)作為起始材料來製備，提供白色固體狀4-溴-2-[(E)-2-{5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基}乙烯基]-1-(2,2,2-三氟乙基)-1H-咪唑(170mg,43%)；MS：M/Z=401(M+H+)。 4-bromo-1-(2,2,2-trifluoroethyl)-1H-imidazol-2-carbaldehyde (250 mg, 0.97 mmol) and {5,8 were used in a similar manner as described in Example 1c. -Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl}methyl)triphenylphosphonium chloride (412 mg, 0.97 mmol) as a starting material, Provided 4-bromo-2-[(E)-2-{5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl}ethylene as a white solid 1-(2,2,2-trifluoroethyl)-1H-imidazole (170 mg, 43%); MS: M/Z = 401 (M+H+).
其係以與實例1d中所闡述類似之方式使用4-溴-2-[(E)-2-{5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基}乙烯基]-1-(2,2,2-三氟乙基)-1H-咪唑(170mg,0.42mmol)及吡咯啶-2-酮(0.065ml,0.85mmol)作為起始材料來製備，提供黃色固體狀1-{2-[(E)-2-{5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基}乙烯基]-1-(2,2,2-三氟乙基)-1H-咪唑-4-基}吡咯啶-2-酮(70mg,41%)；MS：M/Z=406(M+H+)。 It was used in a similar manner to that described in Example 1d using 4-bromo-2-[(E)-2-{5,8-dimethyl-[1,2,4]triazolo[1,5- c]pyrimidin-2-yl}vinyl]-1-(2,2,2-trifluoroethyl)-1H-imidazole (170 mg, 0.42 mmol) and pyrrolidine-2-one (0.065 ml, 0.85 mmol) Prepared as starting material to provide 1-{2-[(E)-2-{5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidine as a yellow solid. -2-yl}vinyl]-1-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl}pyrrolidin-2-one (70 mg, 41%); MS: M/Z =406 (M+H+).
其係以與實例11中所闡述類似之方式使用1-{2-[(E)-2-{5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基}乙烯基]-1-(2,2,2-三氟乙基)-1H-咪唑-4-基}吡咯啶-2-酮(8d)(70mg,0.17mmol)作為起始材料來製備，提供灰白色固體狀1-[2-(2-{5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基}乙基)-1-(2,2,2-三氟乙基)-1H-咪唑-4-基]吡咯啶-2-酮(15mg,21%)；MS：M/Z=408.2(M+H+)。 It was used in a similar manner to that described in Example 11 using 1-{2-[(E)-2-{5,8-dimethyl-[1,2,4]triazolo[1,5-c Pyrimidine-2-yl}vinyl]-1-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl}pyrrolidin-2-one (8d) (70 mg, 0.17 mmol) as The starting material was prepared to give 1-[2-(2-{5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl} as an off-white solid. Ethyl)-1-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl]pyrrolidin-2-one (15 mg, 21%); MS: M/Z = 408.2 (M+ H+).
其係以與實例1c中所闡述類似之方式使用4-溴-1-(2,2-二氟乙基)-1H-咪唑-2-甲醛(200mg,0.84mmol)及{5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基}甲基)三苯基氯化鏻(354mg,0.84mmol)作為起始材料來製備，提供灰白色固體狀4-溴-1-(2,2-二氟乙基)-2-[(E)-2-{5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基}乙烯基]-1H-咪唑(125mg,38%)；MS：M/Z=385(M+H+)。 It was used in a similar manner to that described in Example 1c using 4-bromo-1-(2,2-difluoroethyl)-1H-imidazol-2-carbaldehyde (200 mg, 0.84 mmol) and {5,8- Methyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl}methyl)triphenylphosphonium chloride (354 mg, 0.84 mmol) was prepared as a starting material to provide an off-white 4-Bromo-1-(2,2-difluoroethyl)-2-[(E)-2-{5,8-dimethyl-[1,2,4]triazolo[1, 5-c]pyrimidin-2-yl}vinyl]-1H-imidazole (125 mg, 38%); MS: M/Z = 385 (M+H+).
其係以與實例10中所闡述類似之方式使用4-溴-1-(2,2-二氟乙基)-2-[(E)-2-{5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基}乙烯基]-1H-咪唑(150mg,0.40mmol)及吡咯啶-2-酮(0.06ml,0.80mmol)作為起始 材料來製備，提供黃色固體狀1-[1-(2,2-二氟乙基)-2-[(E)-2-{5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基}乙烯基]-1H-咪唑-4-基]吡咯啶-2-酮(70mg,41%)；MS：M/Z=406(M+H+)。 4-bromo-1-(2,2-difluoroethyl)-2-[(E)-2-{5,8-dimethyl-[1] was used in a similar manner to that described in Example 10. , 2,4]triazolo[1,5-c]pyrimidin-2-yl}vinyl]-1H-imidazole (150 mg, 0.40 mmol) and pyrrolidin-2-one (0.06 ml, 0.80 mmol) beginning Material prepared to provide 1-[1-(2,2-difluoroethyl)-2-[(E)-2-{5,8-dimethyl-[1,2,4]3 as a yellow solid Zoxa[1,5-c]pyrimidin-2-yl}vinyl]-1H-imidazol-4-yl]pyrrolidin-2-one (70 mg, 41%); MS: M/Z = 406 (M+ H+).
其係以與實例11中所闡述類似之方式使用1-[1-(2,2-二氟乙基)-2-[(E)-2-{5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基}乙烯基]-1H-咪唑-4-基]吡咯啶-2-酮(30mg,0.08mmol)作為起始材料來製備，提供白色固體狀1-[1-(2,2-二氟乙基)-2-(2-{5,8-二甲基-[1,2,4]***并[1,5-c]嘧啶-2-基}乙基)-1H-咪唑-4-基]吡咯啶-2-酮(11mg,37%)；MS：M/Z=390.0(M+H+)。 It was used in a similar manner to that described in Example 11 using 1-[1-(2,2-difluoroethyl)-2-[(E)-2-{5,8-dimethyl-[1, 2,4] Triazolo[1,5-c]pyrimidin-2-yl}vinyl]-1H-imidazol-4-yl]pyrrolidin-2-one (30 mg, 0.08 mmol) as starting material , 1-[1-(2,2-difluoroethyl)-2-(2-{5,8-dimethyl-[1,2,4]triazolo[1,5- c]pyrimidin-2-yl}ethyl)-1H-imidazol-4-yl]pyrrolidin-2-one (11 mg, 37%); MS: M/Z=390.0 (M+H+).
其係以與實例1d中所闡述類似之方式使用4-溴-2-[(E)-2-{4,7-二甲基-[1,2,4]***并[1,5-a]吡-2-基}乙烯基]-1-苯基-1H-咪唑(110mg,0.28mmol)及吡咯啶-2-酮(0.045ml,0.91mmol)作為起始材料來製備， 提供白色固體狀1-{2-[(E)-2-{4,7-二甲基-[1,2,4]***并[1,5-a]吡-2-基}乙烯基]-1-苯基-1H-咪唑-4-基}吡咯啶-2-酮(55mg,50%)；MS：M/Z=399(M+H+)。 It was used in a similar manner to that described in Example 1d using 4-bromo-2-[(E)-2-{4,7-dimethyl-[1,2,4]triazolo[1,5- a]pyridyl 2-yl}vinyl]-1-phenyl-1H-imidazole (110 mg, 0.28 mmol) and pyrrolidin-2-one (0.045 ml, 0.91 mmol) were prepared as starting materials to afford white solids 1- {2-[(E)-2-{4,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyridyl 2-yl}vinyl]-1-phenyl-1H-imidazol-4-yl}pyrrolidin-2-one (55 mg, 50%); MS: M/Z = 399 (M+H+).
在25℃下在氬氣下，向5,7-二甲基-[1,2,4]***并[1,5-a]嘧啶-2-甲酸(750mg,4.05mmol)於甲醇(100ml)中之攪拌溶液添加H2SO4(0.05ml)。然後在60℃下將混合物攪拌16h。TLC顯示起始材料反應完全。然後將反應混合物冷卻且移除所蒸餾溶劑。此後，將水(50ml)添加至反應混合物中，且用碳酸氫鈉中和。用乙酸乙酯萃取水相。用鹽水(50ml)洗滌合併之有機物，經硫酸鈉乾燥，過濾，並濃縮以獲得粗製物。藉由管柱層析經由胺矽膠純化粗製物，用40%乙酸乙酯之己烷溶液溶析，以獲得灰白色固體狀5,7-二甲基-[1,2,4]***并[1,5-a]嘧啶-2-甲酸甲酯(500mg,60%)。MS：M/Z=207(M+H+)。 To 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylic acid (750 mg, 4.05 mmol) in methanol (100 ml) at 25 ° C under argon H 2 SO 4 (0.05 ml) was added to the stirred solution. The mixture was then stirred at 60 ° C for 16 h. TLC showed the starting material to react completely. The reaction mixture was then cooled and the distilled solvent was removed. Thereafter, water (50 ml) was added to the reaction mixture, and neutralized with sodium hydrogencarbonate. The aqueous phase was extracted with ethyl acetate. The combined organics were washed with brine (50 mL) dried over sodium sulfate The crude material was purified by column chromatography eluting with EtOAc EtOAc (EtOAc) Methyl 1,5-a]pyrimidine-2-carboxylate (500 mg, 60%). MS: M/Z = 207 (M + H +).
在25℃下在氬氣下經5min，向5,7-二甲基-[1,2,4]***并[1,5-a]嘧啶-2-甲酸甲酯(300mg,1.45mmol)於甲醇(100ml)中之攪拌溶液逐份添加硼氫化鈉(117mg,2.91mmol)。然後在25℃下將混合物攪拌16h。TLC顯示起始材料反應完全。此後將水(25ml)添加至反應混合物中，在25℃下攪拌30min且用DCM(50ml)稀釋。用DCM中之10%甲醇(3×50ml)萃取水相。用鹽水(30ml)洗滌合併之有機物，經硫酸鈉乾燥，過濾並濃縮，以獲得粗製物，藉由管柱層析二胺矽膠純化該粗製物，用40%乙酸乙酯之己烷溶液溶析，以獲得灰白色固體狀{5,7-二甲基-[1,2,4]***并[1,5-a]嘧啶-2-基}甲醇(115mg,44%)。MS：M/Z=179(M+H+)。 Methyl 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylate (300 mg, 1.45 mmol) at 25 ° C under argon for 5 min Sodium borohydride (117 mg, 2.91 mmol) was added portionwise over a stirred solution of methanol (100 mL). The mixture was then stirred at 25 ° C for 16 h. TLC showed the starting material to react completely. Water (25 ml) was then added to the reaction mixture, which was stirred at 25 ° C for 30 min and diluted with DCM (50 mL). The aqueous phase was extracted with 10% methanol (3 x 50 mL) in DCM. The combined organics were washed with brine (30 mL), dried over sodium sulfatessssssssssssssssssssssssssssss To give {5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}methanol (115 mg, 44%). MS: M/Z = 179 (M + H +).
在0℃下在氬氣下，向{5,7-二甲基-[1,2,4]***并[1,5-a]嘧啶-2-基}甲醇(200mg,02.52mmol)於二氯甲烷(100ml)中之攪拌溶液逐滴添加吡啶(0.4ml,5.06mmol)，且然後添加亞硫醯氯(0.25ml,3.03mmol)。此後，將混合物升溫至25℃且在25℃下攪拌16h。用水(50ml)稀釋反應混合物。用乙酸乙酯(3×50ml)萃取水相。用鹽水(30ml)及碳酸氫鈉溶液洗滌合併之有機物，經硫酸鈉乾燥，過濾並濃縮，以獲得粗製物。藉由管柱層析矽膠純化粗製物，用DCM中之2%甲醇溶析，以獲得灰白色固體狀2-(氯甲基)-5,7-二甲基-[1,2,4]***并[1,5-a]嘧啶(200mg,40%)。MS：M/Z=197(M+H+)。 To {5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}methanol (200 mg, 02.52 mmol) at 0 ° C under argon Pyridine (0.4 ml, 5.06 mmol) was added dropwise to a stirred solution of dichloromethane (100 ml), and then sulphur sulphite (0.25 ml, 3.03 mmol) was added. Thereafter, the mixture was warmed to 25 ° C and stirred at 25 ° C for 16 h. The reaction mixture was diluted with water (50 ml). The aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined organics were washed with brine (30 mL) EtOAc. The crude material was purified by column chromatography chromatography eluting with 2% methanol in DCM to afford 2-(chloromethyl)-5,7-dimethyl-[1,2,4] Zoxao[1,5-a]pyrimidine (200 mg, 40%). MS: M/Z = 197 (M + H +).
其係以與實例1a中所闡述類似之方式使用2-(氯甲基)-5,7-二甲基-[1,2,4]***并[1,5-a]嘧啶(200mg,0.102mmol)作為起始材料來製備，提供黃色固體狀({5,7-二甲基-[1,2,4]***并[1,5-a]嘧啶-2-基}甲基)三苯基氯化鏻(270mg，粗製物)；MS：M/Z=423(M+H+)。 2-(Chloromethyl)-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (200 mg, in a similar manner as described in Example 1a) Prepared as a starting material to provide a yellow solid ({5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}methyl) Triphenylphosphonium chloride (270 mg, crude); MS: M/Z = 423 (M+H+).
其係以與實例1c中所闡述類似之方式使用4-溴-1-甲基-1H-咪唑-2-甲醛(150mg,0.80mmol)及({5,7-二甲基-[1,2,4]***并[1,5-a]嘧啶-2-基}甲基)三苯基鏻(336mg,0.80mmol)作為起始材料來製備，提供灰白色固體狀4-溴-2-[(E)-2-{5,7-二甲基-[1,2,4]***并[1,5-a]嘧啶-2-基}乙烯基]-1-甲基-1H-咪唑(75mg,28%)；MS：M/Z=335(M+H+)。 4-bromo-1-methyl-1H-imidazol-2-carbaldehyde (150 mg, 0.80 mmol) and ({5,7-dimethyl-[1,2) were used in a similar manner as described in Example 1c. , 4] Triazolo[1,5-a]pyrimidin-2-yl}methyl)triphenylphosphonium (336 mg, 0.80 mmol) was obtained as a starting material to afford 4-bromo-2-[ (E)-2-{5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}vinyl]-1-methyl-1H-imidazole (75 mg, 28%); MS: M/Z = 335 (M+H+).
其係以與實例10中所闡述類似之方式使用4-溴-2-[(E)-2-{5,7-二甲基-[1,2,4]***并[1,5-a]嘧啶-2-基}乙烯基]-1-甲基-1H-咪唑(60mg, 0.18mmol)及吡咯啶-2-酮(0.016ml,0.216mmol)作為起始材料來製備，提供1-{2-[(E)-2-{5,7-二甲基-[1,2,4]***并[1,5-a]嘧啶-2-基}乙烯基]-1-甲基-1H-咪唑-4-基}吡咯啶-2-酮(60mg，粗製物)；MS：M/Z=338.1(M+H+)。 It was used in a similar manner to that described in Example 10 using 4-bromo-2-[(E)-2-{5,7-dimethyl-[1,2,4]triazolo[1,5- a]pyrimidin-2-yl}vinyl]-1-methyl-1H-imidazole (60 mg, Prepared by using 0.18 mmol) and pyrrolidin-2-one (0.016 ml, 0.216 mmol) as starting material to provide 1-{2-[(E)-2-{5,7-dimethyl-[1,2 , 4] Triazolo[1,5-a]pyrimidin-2-yl}vinyl]-1-methyl-1H-imidazol-4-yl}pyrrolidin-2-one (60 mg, crude); MS :M/Z = 338.1 (M+H+).
其係以與實例11中所闡述類似之方式使用41-{2-[(E)-2-{5,7-二甲基-[1,2,4]***并[1,5-a]嘧啶-2-基}乙烯基]-1-甲基-1H-咪唑-4-基}吡咯啶-2-酮(60mg,0.18mmol)作為起始材料來製備，提供黃色固體狀1-[2-(2-{5,7-二甲基-[1,2,4]***并[1,5-a]嘧啶-2-基}乙基)-1-甲基-1H-咪唑-4-基]吡咯啶-2-酮(6mg,10%)；MS：M/Z=340(M+H+)。 It was used in a similar manner to that described in Example 11 using 41-{2-[(E)-2-{5,7-dimethyl-[1,2,4]triazolo[1,5-a Pyrimidin-2-yl}ethenyl]-1-methyl-1H-imidazol-4-yl}pyrrolidin-2-one (60 mg, 0.18 mmol) was obtained as a starting material to afford a yellow solid. 2-(2-{5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}ethyl)-1-methyl-1H-imidazole- 4-yl]pyrrolidin-2-one (6 mg, 10%); MS: M/Z = 340 (M+H+).
在120℃下，將3,6-二氯嗒(10.0g,67.5mmol)於取自密封管之 28%氫氧化銨水溶液(100ml)中之溶液加熱17h。將混合物冷卻至0℃，沈澱析出。此後過濾所得沈澱，且用己烷洗滌殘餘物並乾燥，以獲得白色固體狀6-氯嗒-3-胺(5.0g,57%)。MS：M/Z=129.9(M+H+)。 3,6-Dichloropurine at 120 ° C (10.0 g, 67.5 mmol) was heated in a solution of 28% aqueous ammonium hydroxide (100 mL). The mixture was cooled to 0 ° C and precipitated. Thereafter, the resulting precipitate was filtered, and the residue was washed with hexane and dried to give 6-chloroindole as a white solid. 3-Amine (5.0 g, 57%). MS: M/Z = 129.9 (M + H +).
在60℃下在氬氣下，將6-氯嗒-3-胺(1.0g,7.75mmol)及3-溴-1,1,1-三氟丁-2-酮(1.75g,37.02mmol)於二甲氧基甲烷(10ml)中之溶液加熱18h。完成反應後，冷卻至25℃，然後在減壓下蒸發掉揮發物。藉由正相矽膠上之管柱層析純化由此獲得之粗殘餘物，用5% EtOAc之己烷溶液溶析，以獲得淺棕色固體狀6-氯-3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒(400mg,22%)。MS：M/Z=236(M+H+)。 6-Chloropurine at 60 ° C under argon A solution of 3-amine (1.0 g, 7.75 mmol) and 3-bromo-1,1,1-trifluorobutan-2-one (1.75 g, 37.02 mmol) in dimethoxymethane (10 mL) . After completion of the reaction, it was cooled to 25 ° C, and then the volatiles were evaporated under reduced pressure. The crude residue obtained was purified by column chromatography eluting EtOAc EtOAc EtOAc EtOAc Fluoromethyl)imidazo[1,2-b]indole (400 mg, 22%). MS: M/Z = 236 (M + H +).
用氬氣將6-氯-3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒(1.6g,6.8mmol)於DMF(50ml)中之溶液脫氣10min。然後在25℃下向此混合物添加三丁基(乙烯基)錫烷(2.3g,7.48mmol)及四(三苯基膦)鈀(0)(394mg,0.34mmol)。用氬氣將混合物再脫氣10min且然後加熱至80℃並保持5h。將混合物冷卻至25℃，用水(100ml)稀釋且用EtOAc(2×300ml)萃取水層。用冰冷水(3×50ml)及鹽水(100ml)洗滌合併之有機物，經無水Na2SO4乾燥，過濾並在真空中濃縮。藉由正相矽膠上之管柱層析純化所得粗團塊，用10% EtOAc之己烷溶液溶析，以獲得黃色固體狀6-乙烯基-3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒(1.1g,71%)。MS： M/Z=228(M+H+)。 6-Chloro-3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole with argon A solution of (1.6 g, 6.8 mmol) in DMF (50 mL) was evaporated. To the mixture was then added tributyl(vinyl)stannane (2.3 g, 7.48 mmol) and tetrakis(triphenylphosphine)palladium(0) (394 mg, 0.34 mmol) at 25 °C. The mixture was again degassed with argon for 10 min and then heated to 80 ° C for 5 h. The mixture was cooled to 25 <0>C, diluted with EtOAc (EtOAc < With ice cold water (3 × 50ml) and brine (100ml) The organics were washed, dried over anhydrous Na 2 SO 4, filtered and concentrated in vacuo. The resulting crude mass was purified by column chromatography eluting EtOAc EtOAc (EtOAc) Imidazo[1,2-b]嗒 (1.1g, 71%). MS: M/Z = 228 (M + H +).
在120℃下，將6-乙烯基-3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒(1.1g,4.86mmol)、四氧化鋨(4%水溶液，37mg,0.95ml,0.14mmol)、過碘酸鈉(4.14g,19.38mmol)及苄基三乙基氯化銨(441mg,1.93mmol)於二噁烷(20ml)及水(4ml)中之溶液加熱90分鐘。冷卻後，蒸發溶劑；用乙酸乙酯(2×200ml)稀釋殘餘物且用水及鹽水(2×150ml)洗滌。分離有機層，經硫酸鈉乾燥，過濾並蒸發以獲得粗製物。藉由正相矽膠上之管柱層析純化所得粗團塊，用20% EtOAc之己烷溶液溶析，以獲得白色固體狀3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-6-甲醛(700mg,63%)。MS：M/Z=230(M+H+)。 6-vinyl-3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole at 120 °C (1.1 g, 4.86 mmol), osmium tetroxide (4% aqueous solution, 37 mg, 0.95 ml, 0.14 mmol), sodium periodate (4.14 g, 19.38 mmol) and benzyltriethylammonium chloride (441 mg, 1.93 mmol) The solution in dioxane (20 ml) and water (4 ml) was heated for 90 minutes. After cooling, the solvent was evaporated. EtOAc m. The organic layer was separated, dried over sodium sulfate, filtered and evaporated The resulting crude mass was purified by column chromatography eluting with EtOAc EtOAc (EtOAc) ,2-b]嗒 -6-formaldehyde (700 mg, 63%). MS: M/Z = 230 (M+H+).
在25℃下在氬氣下，向3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-6-甲醛(700mg,3.05mmol)於MeOH(5ml)及DCM(5ml)中之溶液，然後一次添加全量硼氫化鈉(251mg,6.11mmol)。在25℃下將混合物攪拌2h。完成反應後，用冰水驟冷混合物且蒸餾掉甲醇，用DCM(100ml)稀釋，並用洗滌水(50ml)洗滌。用DCM(2×100ml)萃取水相。經無水Na2SO4乾燥合併之有機物，過濾並在真空中濃縮。將所得粗材料與己烷一起研磨且過濾成淡黃色固體狀[3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-6-基]甲醇(500mg,70%)。MS：M/Z=232(M+H+)。 To 3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole at 25 ° C under argon A solution of -6-formaldehyde (700 mg, 3.05 mmol) in MeOH (5 mL) The mixture was stirred at 25 ° C for 2 h. After completion of the reaction, the mixture was quenched with EtOAc (EtOAc)EtOAc. The aqueous phase was extracted with DCM (2 x 100 mL). Dried over anhydrous Na 2 SO 4 the combined organics were dried, filtered and concentrated in vacuo. The resulting crude material was triturated with hexanes and filtered to give crystals of [3-methyl-2-(trifluoromethyl)imidazo[1,2-b] -6-yl]methanol (500 mg, 70%). MS: M/Z = 232 (M+H+).
在0℃下在氮下，向(3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-6-基]甲醇(500mg,2.16mmol)於DCM(10ml)中之溶液逐滴添加亞硫醯氯(0.32ml,4.32mmol)。在25℃下將混合物攪拌15min，且然後加熱至40℃並保持2h。完成反應後，在真空中移除揮發物。藉由combiflash管柱層析使用20%乙酸乙酯之己烷溶液純化所得粗團塊，以獲得黃色固體狀6-(氯甲基)-3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒(450mg,83%)。MS：M/Z=250(M+H+)。 To (3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole at 0 ° C under nitrogen A solution of -6-yl]methanol (500 mg, 2.16 mmol) in DCM (10 mL). The mixture was stirred at 25 ° C for 15 min and then heated to 40 ° C for 2 h. After the reaction was completed, the volatiles were removed in vacuo. The obtained crude mass was purified by combiflash column chromatography using 20% ethyl acetate in hexane to afford 6-(chloromethyl)-3-methyl-2-(trifluoromethyl)imidazole as a yellow solid. And [1,2-b]嗒 (450 mg, 83%). MS: M/Z = 250 (M+H+).
其係以與實例1a中所闡述類似之方式使用6-(氯甲基)-3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒(45mg,1.80mmol)及三苯基膦(521mg,1.98mmol)作為起始材料來製備，提供灰色固體狀{[3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-6-基]甲基}三苯基氯化鏻(800mg，粗製物)。 It was used in a similar manner to that described in Example 1a using 6-(chloromethyl)-3-methyl-2-(trifluoromethyl)imidazo[1,2-b]fluorene. (45 mg, 1.80 mmol) and triphenylphosphine (521 mg, 1.98 mmol) were prepared as starting material to afford {[3-methyl-2-(trifluoromethyl)imidazo[1,2- b]嗒 -6-yl]methyl}triphenylphosphonium chloride (800 mg, crude).
其係以與實例1c中所闡述類似之方式使用4-溴-1-甲基-1H-咪唑-2-甲醛(200mg,1.05mmol)及{[3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒 -6-基]甲基}三苯基氯化鏻(504mg,1.05mmol)作為起始材料來製備，提供棕色固體狀4-溴-1-甲基-2-[(E)-2-[3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-6-基]乙烯基]-1H-咪唑(210mg,52%)。MS：M/Z=386.0(M+H+)。 4-bromo-1-methyl-1H-imidazol-2-carbaldehyde (200 mg, 1.05 mmol) and {[3-methyl-2-(trifluoromethyl) were used in a similar manner as described in Example 1c. Imidazo[1,2-b]嗒 -6-yl]methyl}triphenylphosphonium chloride (504 mg, 1.05 mmol) was obtained as starting material to afford 4-bromo-1-methyl-2-[(E)-2-[ 3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]vinyl]-1H-imidazole (210 mg, 52%). MS: M/Z = 386.0 (M + H +).
其係以與實例10中所闡述類似之方式使用4-溴-1-甲基-2-[(E)-2-[3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-6-基]乙烯基]-1H-咪唑(150mg,0.39mmol)及吡咯啶-2-酮(0.06ml,0.78mmol)作為起始材料來製備，提供黃色固體狀1-{1-甲基-2-[(E)-2-[3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-6-基]乙烯基]-1H-咪唑-4-基}吡咯啶-2-酮(80mg,52%)。MS：M/Z=391.0(M+H+)。 It was used in a similar manner to that described in Example 10 using 4-bromo-1-methyl-2-[(E)-2-[3-methyl-2-(trifluoromethyl)imidazo[1, 2-b]嗒 -6-yl]vinyl]-1H-imidazole (150 mg, 0.39 mmol) and pyrrolidin-2-one (0.06 ml, 0.78 mmol) were obtained as starting material to afford 1-{1-methyl as a yellow solid. -2-[(E)-2-[3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]vinyl]-1H-imidazol-4-yl}pyrrolidin-2-one (80 mg, 52%). MS: M/Z = 391.0 (M + H +).
其係以與實例11中所闡述類似之方式使用1-{1-甲基-2-[(E)-2-[3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-6-基]乙烯基]-1H-咪唑-4-基}吡咯啶-2-酮(80mg,0.21mmol)作為起始材料來製備，提供灰白色固體狀1-(1-甲基-2-{2-[3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-6-基]乙基}- 1H-咪唑-4-基)吡咯啶-2-酮(14mg,18%)。MS：M/Z=393.0(M+H+)。 It was used in a similar manner to that described in Example 11 using 1-{1-methyl-2-[(E)-2-[3-methyl-2-(trifluoromethyl)imidazo[1,2 -b]嗒 -6-yl]vinyl]-1H-imidazol-4-yl}pyrrolidin-2-one (80 mg, 0.21 mmol) was obtained as a starting material to afford 1-(1-methyl-2- {2-[3-Methyl-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]ethyl}- 1H-imidazol-4-yl)pyrrolidin-2-one (14 mg, 18%). MS: M/Z = 393.0 (M + H +).
其係以與實例1c中所闡述類似之方式使用4-溴-1-苯基-1H-咪唑-2-甲醛(200mg,0.79mmol)及{[3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-6-基]甲基}三苯基氯化鏻(380mg,0.79mmol)作為起始材料來製備，提供白色固體狀4-溴-2-[(E)-2-[3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-6-基]乙烯基]-1-苯基-1H-咪唑(180mg,50%)；MS：M/Z=450(M+H+)。 4-bromo-1-phenyl-1H-imidazole-2-carboxaldehyde (200 mg, 0.79 mmol) and {[3-methyl-2-(trifluoromethyl) were used in a similar manner as described in Example 1c. Imidazo[1,2-b]嗒 -6-yl]methyl}triphenylphosphonium chloride (380 mg, 0.79 mmol) was obtained as starting material afforded 4-bromo-2-[(E)-2-[3-methyl- as a white solid. 2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]vinyl]-1-phenyl-1H-imidazole (180 mg, 50%); MS: M/Z = 450 (M+H+).
其係以與實例10中所闡述類似之方式使用4-溴-2-[(E)-2-[3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-6-基]乙烯基]-1-苯基-1H-咪唑(150mg,0.335mmol)及吡咯啶-2-酮(0.05ml,0.67mmol)作為起始材料來製備，提供黃色固體狀1-{2-[(E)-2-[3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-6-基]乙烯基]-1-苯基-1H-咪唑-4-基}吡咯啶-2-酮(70mg,46%)；MS：M/Z=452(M+H+)。 It was used in a similar manner to that described in Example 10 using 4-bromo-2-[(E)-2-[3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]vinyl]-1-phenyl-1H-imidazole (150 mg, 0.335 mmol) and pyrrolidin-2-one (0.05 ml, 0.67 mmol) were prepared as starting materials to afford yellow solids 1- {2-[(E)-2-[3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole 6-yl]vinyl]-1-phenyl-1H-imidazol-4-yl}pyrrolidin-2-one (70 mg, 46%); MS: M/Z = 452 (M+H+).
其係以與實例11中所闡述類似之方式使用1-{2-[(E)-2-[3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-6-基]乙烯基]-1-苯基-1H-咪唑-4-基}吡咯啶-2-酮(70mg,0.155mmol)作為起始材料來製備，提供黃色固體狀1-(2-{2-[3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-6-基]乙基}-1-苯基-1H-咪唑-4基)吡咯啶-2-酮(12mg,17%)；MS：M/Z=455(M+H+)。 Using 1-{2-[(E)-2-[3-methyl-2-(trifluoromethyl)imidazo[1,2-b]fluorene in a similar manner as described in Example 11. -6-yl]vinyl]-1-phenyl-1H-imidazol-4-yl}pyrrolidin-2-one (70 mg, 0.155 mmol) was obtained as a starting material to afford 1-(2- {2-[3-Methyl-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]ethyl}-1-phenyl-1H-imidazol-4-yl)pyrrolidin-2-one (12 mg, 17%); MS: M/Z = 455 (M+H+).
將6-氯嗒-3-胺(2.5g,19.38mmol)於水中之57%鹽酸(11.601ml,155.04mmol)中之溶液加熱至100℃且保持18h。將反應物冷卻至室溫並添加乙酸乙酯(5ml)。在25℃下將懸浮液再劇烈攪拌5分鐘。藉由過濾收集固體，用乙酸乙酯洗滌且在真空下乾燥，以獲得黃色固體晶體。將固體溶解於甲醇(60ml)中，且添加氫氧化鈉(0.93g,23.256mmol)。在100℃下將懸浮液加熱5min且再冷卻至25℃。在減壓下濃縮反應團塊且用水洗滌，以獲得白色固體狀純6-碘嗒-3-胺(2g,43%)。LC-MS(ESI)：222(M+1)。 6-chloropurine A solution of 3-amine (2.5 g, 19.38 mmol) in 57% EtOAc (1. The reaction was cooled to room temperature and ethyl acetate (5 mL) was evaporated. The suspension was stirred vigorously for 5 minutes at 25 °C. The solid was collected by filtration, washed with ethyl acetate and dried under vacuum to afford crystals of yellow solid. The solid was dissolved in methanol (60 mL) and sodium hydroxide (0.93 g, 23.. The suspension was heated at 100 °C for 5 min and cooled to 25 °C. The reaction mass was concentrated under reduced pressure and washed with water to give pure 6-iodonium as a white solid. 3-Amine (2 g, 43%). LC-MS (ESI): 422 (21.
其係以與實例22b中所闡述類似之方式使用6-碘嗒-3-胺(500mg,2.26mmol)及3-溴-1,1,1-三氟丁-2-酮(555mg,2.7mmol)作為起始材料來製備，提供棕色黏性固體狀6-碘-3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒(200mg,27%)。MS：M/Z=328(M+H+)。 It uses 6-iodoquinone in a similar manner to that described in Example 22b. 3-Amine (500mg, 2.26mmol) and 3-bromo-1,1,1-trifluorobutan-2-one (555mg, 2.7mmol) were prepared as starting materials to provide 6-iodine as a brown viscous solid. -3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole (200 mg, 27%). MS: M/Z = 328 (M + H +).
其係以與實例15c中所闡述類似之方式使用1-(2-乙炔基-1-甲基-1H-咪唑-4-基)吡咯啶-2-酮(30mg,0.16mmol)及6-碘-3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒(57mg,0.17mmol)作為起始材料來製備，提供黃色固體狀1-(1-甲基-2-{2-[3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-6-基]乙炔基}-1H-咪唑-4-基)吡咯啶-2-酮(4mg,6%)。MS：M/Z=389(M+H+)。 1-(2-ethynyl-1-methyl-1H-imidazol-4-yl)pyrrolidin-2-one (30 mg, 0.16 mmol) and 6-iodine were used in a similar manner as described in Example 15c. -3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole (57 mg, 0.17 mmol) was obtained as starting material afforded 1-(1-methyl-2-{2-[3-methyl-2-(trifluoromethyl)imidazo[1,2 -b]嗒 -6-yl]ethynyl}-1H-imidazol-4-yl)pyrrolidin-2-one (4 mg, 6%). MS: M/Z = 389 (M + H +).
其係以與實例15a中所闡述類似之方式使用4-溴-1-苯基-1H-咪唑-2-甲醛(800mg,3.18mmol)及吡咯啶-2-酮(0.54ml,6.35mmol)作為起始材料來製備，提供白色黏性固體狀4-(2-側氧基吡咯啶-1-基)-1-苯基 -1H-咪唑-2-甲醛(50mg,7%)；MS：M/Z=256(M+H+)。 4-bromo-1-phenyl-1H-imidazol-2-carbaldehyde (800 mg, 3.18 mmol) and pyrrolidin-2-one (0.54 ml, 6.35 mmol) were used in a similar manner as described in Example 15a. Prepared from the starting material to provide 4-(2-oxopyrrolidin-1-yl)-1-phenyl as a white viscous solid -1H-imidazole-2-carbaldehyde (50 mg, 7%); MS: M/Z = 256 (M+H+).
其係以與實例15b中所闡述類似之方式使用4-(2-側氧基吡咯啶-1-基)-1-苯基-1H-咪唑-2-甲醛(90mg,0.35mmol)作為起始材料來製備，提供棕色黏性固體狀1-(2-乙炔基-1-苯基-1H-咪唑-4-基)吡咯啶-2-酮(18mg,20%)；MS：M/Z=252.2(M+H+)。 Starting with 4-(2-oxopyrrolidin-1-yl)-1-phenyl-1H-imidazol-2-carbaldehyde (90 mg, 0.35 mmol) in a similar manner as described in Example 15b Prepared to give 1-(2-ethynyl-1-phenyl-1H-imidazol-4-yl)pyrrolidin-2-one as a brown viscous solid (18 mg, 20%); MS: M/Z = 252.2 (M+H+).
其係以與實例15c中所闡述類似之方式使用1-(2-乙炔基-1-苯基-1H-咪唑-4-基)吡咯啶-2-酮(18mg,0.07mmol)及(6-碘-3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒(26mg,0.08mmol)作為起始材料來製備，提供棕色黏性固體狀1-(2-{2-[3-甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-6-基]乙炔基}-1-苯基-1H-咪唑-4-基)吡咯啶-2-酮(5mg,15%)；MS：M/Z=451(M+H+)。 1-(2-ethynyl-1-phenyl-1H-imidazol-4-yl)pyrrolidin-2-one (18 mg, 0.07 mmol) and (6-) were used in a similar manner as described in Example 15c. Iodo-3-methyl-2-(trifluoromethyl)imidazo[1,2-b]indole (26 mg, 0.08 mmol) was prepared as starting material to afford 1-(2-{2-[3-methyl-2-(trifluoromethyl)imidazo[1,2-b] as a brown solid. despair -6-yl]ethynyl}-1-phenyl-1H-imidazol-4-yl)pyrrolidin-2-one (5 mg, 15%); MS: M/Z = 451 (M+H+).
在0℃下在氬氣下，向3,6-二氯嗒-4-甲酸(5g,26.04mmol)於DCM(50ml)中之溶液添加草醯氯(2.5ml,28.64mmol)，然後添加催化量之DMF(0.1ml)。在25℃下將反應團塊攪拌5h。完成反應後，在減壓下在氮下移除溶劑以移除揮發物並蒸發，以獲得白色液體狀3,6-二氯嗒-4-羰醯氯(5.5g，粗製物)。將此粗製物用於下一步驟中。 3,6-Dichloropurine at 0 ° C under argon A solution of 4-carboxylic acid (5 g, 26.04 mmol) in EtOAc (EtOAc) The reaction mass was stirred at 25 ° C for 5 h. After completion of the reaction, the solvent was removed under reduced pressure under nitrogen to remove the volatiles and evaporated to give 3,6-dichloroindole as a white liquid. 4-carbonylcarbonyl chloride (5.5 g, crude). This crude material was used in the next step.
在0℃下在氬氣下，向3,6-二氯嗒-4-羰醯氯(5.5g,26.6mmol)於DCM(50ml)中之溶液添加甲胺(2M於THF中，26ml)，然後添加TEA(7.4ml,52.13mmol)。在25℃下將反應團塊攪拌1h。完成反應後，用水稀釋反應混合物且用DCM(2×300ml)萃取，用水(2×100ml)及鹽水(100ml)洗滌分離之有機層，經硫酸鈉乾燥，過濾並蒸發，以獲得粗製物。藉由combi急驟層析使用20%乙酸乙酯之己烷溶液純化粗製 物，以獲得白色固體狀3,6-二氯-N-甲基嗒-4-甲醯胺(3.2g,60%)。 3,6-Dichloropurine at 0 ° C under argon To a solution of -4-carbonylindole chloride (5.5 g, 26.6 mmol) in EtOAc (EtOAc) The reaction mass was stirred at 25 ° C for 1 h. After completion of the reaction, the reaction mixture was diluted with H~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The crude material was purified by combi flash chromatography using 20% ethyl acetate in hexane to afford 3,6-dichloro-N-methylindole as a white solid. 4-Metformamide (3.2 g, 60%).
在120℃下，將3,6-二氯-N-甲基嗒-4-甲醯胺(6.6g,32.19mmol)於取自密封管之28%氫氧化銨水溶液(100ml)中之溶液加熱16h。將混合物冷卻至0℃，沈澱析出。此後過濾所得沈澱，且用己烷洗滌殘餘物並乾燥，以獲得白色固體狀3-胺基-6-氯-N-甲基嗒-4-甲醯胺(2.2g,50%)。MS：M/Z=187(M+H+)。 3,6-Dichloro-N-methylindole at 120 ° C 4-Methylguanamine (6.6 g, 32.19 mmol) was heated in a solution of 28% aqueous ammonium hydroxide (100 mL). The mixture was cooled to 0 ° C and precipitated. Thereafter, the obtained precipitate was filtered, and the residue was washed with hexane and dried to afford 3-amino-6-chloro-N-methylindole as a white solid. 4-Metformamide (2.2 g, 50%). MS: M/Z = 187 (M + H +).
在60℃下在氬氣下，將3-胺基-6-氯-N-甲基嗒-4-甲醯胺(6.7g,36.02mmol)及3-溴-1,1,1-三氟丁-2-酮(4.3ml,36.02mmol)於二甲氧基甲烷(100ml)中之溶液加熱18h。完成反應後，冷卻至25℃，然後在減壓下蒸發掉揮發物。藉由正相矽膠上之管柱層析純化由此獲得之粗殘餘物，用5% EtOAc之己烷溶液溶析，以獲得灰白色固體狀6-氯-N,3-二甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-8-甲醯胺(3g,28%)。MS：M/Z=293(M+H+)。 3-Amino-6-chloro-N-methylindole at 60 ° C under argon a solution of 4-carbamoylamine (6.7 g, 36.02 mmol) and 3-bromo-1,1,1-trifluorobutan-2-one (4.3 ml, 36.02 mmol) in dimethoxymethane (100 ml) Heat for 18h. After completion of the reaction, it was cooled to 25 ° C, and then the volatiles were evaporated under reduced pressure. The crude residue was purified by EtOAc EtOAc EtOAc elut elut elut elut (trifluoromethyl)imidazo[1,2-b]indole -8-carbamamine (3 g, 28%). MS: M/Z = 293 (M + H +).
用氬氣將6-氯-N,3-二甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-8-甲醯胺(3g,10.27mmol)於DMF(10ml)中之溶液脫氣10min。然後在25℃下向此混合物添加三丁基(乙烯基)錫烷(3.9g,12.32mmol)及四(三苯基膦)鈀(0)(594mg,0.514mmol)。用氬氣將混合物再脫氣10min且然後加熱至80℃並保持5h。將混合物冷卻至25℃，用水(100ml)稀釋且用EtOAc(2×300ml)萃取水層。用冰冷水(3×50ml)及鹽水(100ml)洗滌合併之有機物，經無水Na2SO4乾燥，過濾並在真空中濃縮。藉由正相矽膠上之管柱層析純化所得粗團塊，用10% EtOAc之己烷溶液溶析，以獲得灰白色固體狀6-乙烯基-N,3-二甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-8-甲醯胺(1.1g,38%)。MS：M/Z=285(M+H+)。 6-Chloro-N,3-dimethyl-2-(trifluoromethyl)imidazo[1,2-b]indole with argon A solution of -8-mercaptoamine (3 g, 10.27 mmol) in DMF (10 mL) was degassed for 10 min. To the mixture was then added tributyl(vinyl)stannane (3.9 g, 12.32 mmol) and tetrakis(triphenylphosphine)palladium(0) (594 mg, 0.514 mmol) at 25 °C. The mixture was again degassed with argon for 10 min and then heated to 80 ° C for 5 h. The mixture was cooled to 25 <0>C, diluted with EtOAc (EtOAc < With ice cold water (3 × 50ml) and brine (100ml) The organics were washed, dried over anhydrous Na 2 SO 4, filtered and concentrated in vacuo. The resulting crude mass was purified by column chromatography eluting EtOAc EtOAc (EtOAc) elute Fluoromethyl)imidazo[1,2-b]indole -8-carbamamine (1.1 g, 38%). MS: M/Z = 285 (M + H +).
在120℃下，將6-乙烯基-N,3-二甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-8-甲醯胺(1.1g,3.87mmol)、四氧化鋨(4%水溶液，30mg,0.90ml,0.12mmol)、過碘酸鈉(3.3g,15.4mmol)及苄基三乙基氯化銨(370mg,1.63mmol)於二噁烷(44ml)及水(11ml)中之溶液加熱5h。冷卻後，蒸發溶劑；用乙酸乙酯(2×200ml)稀釋殘餘物且用水及鹽水(2×150ml)洗滌。分離有機層，經硫酸鈉乾燥，過濾並蒸發以獲得粗製物。藉由正相矽膠上之管柱層析純化所得粗團塊，用20% EtOAc之己烷溶液溶析，以獲得淺黃色固體狀6-甲醯基-N,3-二甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-8-甲醯胺(800mg，粗製物)。MS：M/Z=286(M+H+)。 6-vinyl-N,3-dimethyl-2-(trifluoromethyl)imidazo[1,2-b]fluorene at 120 °C -8-carbamamine (1.1 g, 3.87 mmol), osmium tetroxide (4% aqueous solution, 30 mg, 0.90 ml, 0.12 mmol), sodium periodate (3.3 g, 15.4 mmol) and benzyltriethyl chloride A solution of ammonium (370 mg, 1.63 mmol) in dioxane (44 ml) After cooling, the solvent was evaporated. EtOAc m. The organic layer was separated, dried over sodium sulfate, filtered and evaporated The resulting crude mass was purified by column chromatography eluting EtOAc EtOAc (EtOAc) (trifluoromethyl)imidazo[1,2-b]indole -8-carbamamine (800 mg, crude). MS: M/Z = 286 (M + H +).
其係以與實例22e中所闡述類似之方式使用6-甲醯基-N,3-二甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-8-甲醯胺(800mg,2.79mmol)作為起始材料來製備，提供6-(羥基甲基)-N,3-二甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-8-甲醯胺(240mg,30%)。MS：M/Z=289(M+H+)。 It was used in a similar manner to that described in Example 22e using 6-mercapto-N,3-dimethyl-2-(trifluoromethyl)imidazo[1,2-b]fluorene. -8-Protonamine (800 mg, 2.79 mmol) was prepared as starting material to provide 6-(hydroxymethyl)-N,3-dimethyl-2-(trifluoromethyl)imidazo[1,2 -b]嗒 -8-carbamamine (240 mg, 30%). MS: M/Z = 289 (M + H +).
其係以與實例22f中所闡述類似之方式使用6-(羥基甲基)-N,3-二甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-8-甲醯胺(240mg,0.84mmol)作為起始材料來製備，提供灰白色固體狀6-(氯甲基)-N,3-二甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-8-甲醯胺(150mg,59%)。MS：M/Z=307(M+H+)。 It was used in a similar manner to that described in Example 22f using 6-(hydroxymethyl)-N,3-dimethyl-2-(trifluoromethyl)imidazo[1,2-b]fluorene. -8-Protonamine (240 mg, 0.84 mmol) was obtained as a starting material to afford 6-(chloromethyl)-N,3-dimethyl-2-(trifluoromethyl)imidazole as a white solid. 1,2-b]嗒 -8-carbamamine (150 mg, 59%). MS: M/Z = 307 (M + H +).
其係以與實例1a中所闡述類似之方式使用6-(氯甲基)-N,3-二甲基 -2-(三氟甲基)咪唑并[1,2-b]嗒-8-甲醯胺(150mg,0.50mmol)及三苯基膦(192mg,0.58mmol)作為起始材料來製備，提供灰白色固體狀{[3-甲基-8-(甲基胺甲醯基)-2-(三氟甲基)咪唑并[1,2-b]嗒-6-基]甲基}三苯基氯化鏻(320mg，粗製物)。MS：M/Z=533(M+H+)。 It was used in a similar manner to that described in Example 1a using 6-(chloromethyl)-N,3-dimethyl-2-(trifluoromethyl)imidazo[1,2-b]fluorene. -8-Mergamine (150 mg, 0.50 mmol) and triphenylphosphine (192 mg, 0.58 mmol) were obtained as starting material to afford as a white solid. )-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]methyl}triphenylphosphonium chloride (320 mg, crude). MS: M/Z = 533 (M + H +).
其係以與實例5a中所闡述類似之方式使用4-溴-1-甲基-1H-咪唑-2-甲醛(85mg,0.45mmol)及{[3-甲基-8-(甲基胺甲醯基)-2-(三氟甲基)咪唑并[1,2-b]嗒-6-基]甲基}三苯基氯化鏻(240mg,0.45mmol)作為起始材料來製備，提供黃色固體狀6-[(E)-2-(4-溴-1-甲基-1H-咪唑-2-基)乙烯基]-N,3-二甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-8-甲醯胺)(90mg,45%)。MS：M/Z=445.0(M+H+)。 4-bromo-1-methyl-1H-imidazol-2-carbaldehyde (85 mg, 0.45 mmol) and {[3-methyl-8-(methylamine A) were used in a similar manner as described in Example 5a. Mercapto)-2-(trifluoromethyl)imidazo[1,2-b]indole -6-yl]methyl}triphenylphosphonium chloride (240 mg, 0.45 mmol) was obtained as a starting material to afford 6-[(E)-2-(4-bromo-1-methyl- 1H-imidazol-2-yl)vinyl]-N,3-dimethyl-2-(trifluoromethyl)imidazo[1,2-b]indole -8-carbamamine) (90 mg, 45%). MS: M/Z = 445.0 (M + H +).
其係以與實例10中所闡述類似之方式使用6-[(E)-2-(4-溴-1-甲基-1H-咪唑-2-基)乙烯基]-N,3-二甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-8- 甲醯胺(60mg,0.14mmol)作為起始材料來製備，提供白色固體狀N,3-二甲基-6-[(E)-2-[1-甲基-4-(2-側氧基吡咯啶-1-基)-1H-咪唑-2-基]乙烯基]-2-(三氟甲基)咪唑并[1,2-b]嗒-8-甲醯胺(20mg,33%)。MS：M/Z=448.0(M+H+)。 6-[(E)-2-(4-bromo-1-methyl-1H-imidazol-2-yl)vinyl]-N,3-dimethyl was used in a similar manner to that described in Example 10. 2-(trifluoromethyl)imidazo[1,2-b]indole -8-Mergamine (60 mg, 0.14 mmol) was obtained as starting material to afford N,3-dimethyl-6-[(E)-2-[1-methyl-4-(2) -Sideoxypyrrolidin-1-yl)-1H-imidazol-2-yl]vinyl]-2-(trifluoromethyl)imidazo[1,2-b]indole -8-carbamamine (20 mg, 33%). MS: M/Z = 448.0 (M + H +).
其係以與實例11中所闡述類似之方式使用N,3-二甲基-6-[(E)-2-[1-甲基-4-(2-側氧基吡咯啶-1-基)-1H-咪唑-2-基]乙烯基]-2-(三氟甲基)咪唑并[1,2-b]嗒-8-甲醯胺(20mg,0.05mmol)作為起始材料來製備，提供灰白色固體狀N,3-二甲基-6-{2-[1-甲基-4-(2-側氧基吡咯啶-1-基)-1H-咪唑-2-基]乙基}-2-三氟甲基)咪唑并[1,2-b]嗒-8-甲醯胺(14mg,69%)。MS：M/Z=450.0(M+H+)。 Using N,3-dimethyl-6-[(E)-2-[1-methyl-4-(2-o-oxypyrrolidin-1-yl) in a similar manner to that described in Example 11 -1H-imidazol-2-yl]vinyl]-2-(trifluoromethyl)imidazo[1,2-b]indole -8-Protonamine (20 mg, 0.05 mmol) was prepared as a starting material to afford N,3-dimethyl-6-{2-[1-methyl-4-(2- </RTI> Pyrrrolidin-1-yl)-1H-imidazol-2-yl]ethyl}-2-trifluoromethyl)imidazo[1,2-b]indole -8-carbamamine (14 mg, 69%). MS: M/Z = 450.0 (M + H +).
其係以與實例5a中所闡述類似之方式使用4-溴-1-苯基-1H-咪唑-2-甲醛(150mg,0.6mmol)及{[3-甲基-8-(甲基胺甲醯基)-2-(三氟甲基)咪唑并[1,2-b]嗒-6-基]甲基}三苯基氯化鏻(318mg,0.6mmol)作為起始材料來製備，提供白色固體狀6-[(E)-2-(4-溴-1-苯基-1H-咪唑-2-基)乙烯基]-N,3-二甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-8-甲醯胺(150mg，粗製物)；MS：M/Z=506(M+H+)。 4-bromo-1-phenyl-1H-imidazol-2-carbaldehyde (150 mg, 0.6 mmol) and {[3-methyl-8-(methylamine A) were used in a similar manner as described in Example 5a. Mercapto)-2-(trifluoromethyl)imidazo[1,2-b]indole 6-yl]methyl}triphenylphosphonium chloride (318 mg, 0.6 mmol) was obtained as a starting material to afford 6-[(E)-2-(4-bromo-1-phenyl- 1H-imidazol-2-yl)vinyl]-N,3-dimethyl-2-(trifluoromethyl)imidazo[1,2-b]indole -8-Mergamine (150 mg, crude); MS: M/Z = 506 (M+H+).
其係以與實例10中所闡述類似之方式使用6-[(E)-2-(4-溴-1-苯基-1H-咪唑-2-基)乙烯基]-N,3-二甲基-2-(三氟甲基)咪唑并[1,2-b]嗒-8-甲醯胺(110mg,0.22mmol)及吡咯啶-2-酮(0.04ml,0.44mmol)作為起始材料來製備，提供灰白色固體狀N,3-二甲基-6-[(E)-2-[4-(2-側氧基吡咯啶-1-基)-1-苯基-1H-咪唑-2-基]乙烯基]-2-(三氟甲基)咪唑并[1,2-b]嗒-8-甲醯胺(70mg，粗製物)；MS：M/Z=510(M+H+)。 6-[(E)-2-(4-bromo-1-phenyl-1H-imidazol-2-yl)vinyl]-N,3-dimethyl was used in a similar manner to that described in Example 10. 2-(trifluoromethyl)imidazo[1,2-b]indole -8-Protonamine (110 mg, 0.22 mmol) and pyrrolidin-2-one (0.04 mL, 0.44 mmol) were obtained as starting material to afford N,3-dimethyl-6-[(E) -2-[4-(2-Sideoxypyrrolidin-1-yl)-1-phenyl-1H-imidazol-2-yl]vinyl]-2-(trifluoromethyl)imidazo[1] ,2-b]嗒 -8-Mergamine (70 mg, crude); MS: M/Z = 510 (M+H+).
其係以與實例11中所闡述類似之方式使用N,3-二甲基-6-[(E)-2-[4-(2-側氧基吡咯啶-1-基)-1-苯基-1H-咪唑-2-基]乙烯基]-2-(三氟甲基)咪唑并[1,2-b]嗒-8-甲醯胺(70mg,0.14mmol)作為起始材料來製備，提供黃色固體狀N,3-二甲基-6-{2-[4-(2-側氧基吡咯啶-1-基)-1-苯基-1H-咪唑-2-基]乙基}-2-(三氟甲基)咪唑并[1,2-b]嗒-8-甲醯胺(12mg,17%)；MS：M/Z=512(M+H+)。 N,3-dimethyl-6-[(E)-2-[4-(2-o-oxypyrrolidin-1-yl)-1-benzene was used in a similar manner to that described in Example 11. -1H-imidazol-2-yl]vinyl]-2-(trifluoromethyl)imidazo[1,2-b]indole -8-Mergamine (70 mg, 0.14 mmol) was obtained as a starting material to afford N,3-dimethyl-6-{2-[4-(2- s. 1-phenyl-1H-imidazol-2-yl]ethyl}-2-(trifluoromethyl)imidazo[1,2-b]indole -8-Mergamine (12 mg, 17%); MS: M/Z = 512 (M+H+).
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