TW201302730A - Pyrazole compounds - Google Patents
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Abstract
Description
本發明係關於醫藥組成物,例如有關作為與磷酸二酯酶10A(PDE10A)關聯的疾病之預防及/或治療用醫藥組成物的有效成分為有用之吡唑化合物。 The present invention relates to a pharmaceutical composition, for example, a pyrazole compound which is useful as an active ingredient of a pharmaceutical composition for prevention and/or treatment of a disease associated with phosphodiesterase 10A (PDE10A).
磷酸二酯酶(Phosphodiesterase(PDE))為分解作為細胞內第二訊息使者的cyclic AMP(cAMP)及cyclic GMP(cGMP)的酵素。PDE以酵素化學的性質(將cAMP作為特異性基質,將cGMP作為特異性基質,或將兩方作為基質)、觸媒部位的胺基酸序列相同性、及結構模體(鈣調蛋白結合區域、GAF區域、PAS區域等)為準,分類為11種類之家族。上述PDE家族會再組織特異性上表現或細胞內局部地與特定蛋白質相互作用,故被認為與特定臟器‧組織內細胞內訊息相關(Folia Pharmacologica Japonica.、2005年、第126卷、p.121)。 Phosphodiesterase (PDE) is an enzyme that breaks down cyclic AMP (cAMP) and cyclic GMP (cGMP), which are the second messengers in cells. PDE is based on the nature of enzyme chemistry (using cAMP as a specific matrix, cGMP as a specific matrix, or both as a matrix), amino acid sequence identity of the catalytic site, and structural motif (calmodulin binding region) , GAF area, PAS area, etc., which are classified into 11 types of families. The above-mentioned PDE family will be associated with specific tissue expression or intracellular local interaction with specific proteins, and is therefore thought to be associated with intracellular messages in specific organs and tissues (Folia Pharmacologica Japonica., 2005, Vol. 126, p. 121).
已有報告PDE家族中,特別以PDE10A在哺乳類中不管任何種皆以遺傳學的方式被保存下來,其表現在腦內,特別在線條體及側坐核之中型有棘神經細胞上以特異性且高度地表現,將cAMP及cGMP之雙方作為基質(Neuropharmacology、2010年、第59卷、p.367)。將PDE10A以特異性缺失的小老鼠在使用誘發人體中精神分裂症病樣之障礙的苯環利定(Phencyclidine)之行動試驗 中,可降低對該誘發藥之感受性(Neuropharmacology、2006年、第51卷、p.374)。且,社會性行動比野生群更高(Journal of Neurochemistry.、2008年、第105卷、p.546),亦不會誘發出錐體外疾障礙(Neuropharmacology、2008年、第54卷、p.417)。對於使用PDE10A選擇的阻礙藥之研究,該阻礙藥可促進線條體中使出力神經細胞內之cAMP及cGMP上昇的各種細胞內傳達。該結果已有苯環利定(Phencyclidine)誘發之過活動、及精神分裂症患者中之特異性中所觀察到之auditory sensory gating障礙受到改善之報告(Journal of Pharmacology and Experimental Therapeutics、2008年、第325卷、p.681)。另外,對應精神分裂症的主症狀之陽性症狀、陰性症狀、及認知功能障礙的任意動物模型中亦顯示PDE10A選擇性阻礙藥之有效性。另一方面,已有報告藉由已有的抗精神病藥之錐體外疾障礙誘發風險較為低(Journal of Pharmacology and Experimental Therapeutics、2009年、第331卷、p.574)。由上述得知,PDE10A選擇的阻礙藥為錐體外疾障礙誘發之風險較低,對於精神分裂症的任意主症狀亦期待成為有效之抗精神病藥。 It has been reported that in the PDE family, in particular, PDE10A is preserved genetically in any type of mammal, which is manifested in the brain, especially on the linear and lateral nucleus of the spine. Highly expressed, both cAMP and cGMP are used as a matrix (Neuropharmacology, 2010, Vol. 59, p. 367). PDE10A is specifically tested for the use of Phencyclidine, a disorder in which schizophrenia-like disorders are induced in humans. In this case, the sensitivity to the induced drug can be reduced (Neuropharmacology, 2006, Vol. 51, p. 374). Moreover, social actions are higher than wild populations (Journal of Neurochemistry., 2008, Vol. 105, p. 546), and no extrapyramidal disorders are induced (Neuropharmacology, 2008, Vol. 54, p. 417). ). For the study of the inhibitory drug selected using PDE10A, the inhibitory drug can promote various intracellular communication in the line body to increase the cAMP and cGMP in the nerve cells. This result has been reported to have improved the auditory sensory gating disorder observed in Phencyclidine-induced activity and specificity in schizophrenia patients (Journal of Pharmacology and Experimental Therapeutics, 2008, pp. 325 volumes, p.681). In addition, the effectiveness of the PDE10A selective inhibitory drug is also shown in any animal model corresponding to the positive symptoms, negative symptoms, and cognitive dysfunction of the main symptoms of schizophrenia. On the other hand, it has been reported that the risk of induction of extrapyramidal disorders by existing antipsychotic drugs is relatively low (Journal of Pharmacology and Experimental Therapeutics, 2009, Vol. 331, p. 574). From the above, it is known that the obstruction drug selected by PDE10A is low in the risk of induction of extrapyramidal disorders, and it is expected to be an effective antipsychotic for any main symptom of schizophrenia.
已知使PDE10A為遺傳性缺失的小老鼠顯示社會性提升,或對於亨丁頓舞蹈症之動物模型,PDE10A阻礙藥可抑制該藥劑誘發神經變性(Neurobiology of disease、2009年、第34卷、p.450)。又亦已知使用於精神分裂症 的陽性症狀動物模型的興奮劑(非那明(Phenamine))及麻藥(苯環利定(Phencyclidine))誘發之行動變化,PDE10A阻礙藥顯示改善作用(Journal of Pharmacology and Experimental Therapeutics、2008年、第325卷、p.681)、N-甲基-D-天冬醯胺酸(NMDA)拮抗藥誘發顯示對於認知障礙之改善效果(European Journal of Neuroscience、2005年、第21卷、p.1070)。由上述得知,PDE10A阻礙不僅可作為精神分裂症的藥物治療標的,亦可期待作為焦慮症、亨丁頓舞蹈症、藥物依存或阿茲海默病的認知障礙及其周邊症狀之藥物治療的標的。 It is known that PDE10A is a genetically deficient small mouse showing a social improvement, or for an animal model of Huntington's disease, PDE10A inhibitors can inhibit the drug-induced neurodegeneration (Neurobiology of disease, 2009, Vol. 34, p .450). Also known for use in schizophrenia Positive symptoms of animal models of stimulants (Phenamine) and anesthetic (Phencyclidine)-induced changes in action, PDE10A inhibitors show improvement (Journal of Pharmacology and Experimental Therapeutics, 2008, 325 volumes, p.681), N-methyl-D-aspartate (NMDA) antagonist induction showed improvement in cognitive impairment (European Journal of Neuroscience, 2005, Vol. 21, p. 1070) . It is known from the above that PDE10A can be used not only as a drug treatment target for schizophrenia, but also as a drug treatment for anxiety disorders, Huntington's disease, drug dependence or cognitive impairment of Alzheimer's disease and its peripheral symptoms. Subject.
作為顯示PDE10阻礙作用的化合物,已有報告出下述式之化合物A(專利文獻1)、化合物B(專利文獻2)、化合物C(專利文獻3)、及化合物D(先行技術4及5)。 Compounds A (Patent Document 1), Compound B (Patent Document 2), Compound C (Patent Document 3), and Compound D (Previous Techniques 4 and 5) of the following formula have been reported as compounds exhibiting an inhibitory action on PDE10. .
又,作為顯示PDE10A阻礙作用的化合物,已有報告下述式之化合物E(專利文獻6)、化合物F(專利文獻7)及化合物G(專利文獻8)。 Further, as a compound exhibiting a PDE10A inhibitory action, a compound E (Patent Document 6), a compound F (Patent Document 7), and a compound G (Patent Document 8) of the following formula have been reported.
然而,對於本發明中之式(I)的化合物或其鹽的揭示或記載並非上述任一文獻。 However, the disclosure or description of the compound of the formula (I) or a salt thereof in the present invention is not one of the above documents.
[專利文獻1]國際公開第WO2006/072828號手冊 [Patent Document 1] International Publication No. WO2006/072828
[專利文獻2]國際公開第WO2007/077490號手冊 [Patent Document 2] International Publication No. WO2007/077490
[專利文獻3]國際公開第WO2007/129183號手冊 [Patent Document 3] International Publication No. WO2007/129183
[專利文獻4]國際公開第WO2009/158393號手冊 [Patent Document 4] International Publication No. WO2009/158393
[專利文獻5]國際公開第WO2009/158473號手冊 [Patent Document 5] International Publication No. WO2009/158473
[專利文獻6]國際公開第WO2004/002484號手冊 [Patent Document 6] International Publication No. WO2004/002484
[專利文獻7]國際公開第WO2006/034491號手冊 [Patent Document 7] International Publication No. WO2006/034491
[專利文獻8]國際公開第WO2008/084299號手冊 [Patent Document 8] International Publication No. WO2008/084299
本發明提供一種醫藥組成物,例如作為精神分裂症治療用醫藥組成物之有效成分為有用的化合物。 The present invention provides a pharmaceutical composition which is useful as an active ingredient of a pharmaceutical composition for treating schizophrenia, for example.
本發明者們對於具有PDE10A阻礙作用之化合物進行詳細檢討結果,發現本發明的吡唑化合物具有PDE10A阻礙作用而完成本發明。 The inventors of the present invention conducted a detailed review of the compound having a PDE10A inhibitory effect, and found that the pyrazole compound of the present invention has a PDE10A inhibitory action to complete the present invention.
即,本發明係關於式(I)的化合物或其鹽、以及含有式(I)的化合物或其鹽、及賦形劑之醫藥組成物。 That is, the present invention relates to a compound of the formula (I) or a salt thereof, and a pharmaceutical composition comprising the compound of the formula (I) or a salt thereof and an excipient.
且,若無特別記載,本說明書中的化學式中之符號使用於其他化學式時,表示相同符號或相同意義。 Further, unless otherwise stated, the symbols in the chemical formulae in the present specification are used in the other chemical formulas to indicate the same symbols or the same meanings.
又,本發明係關於含有式(I)的化合物或其鹽之精神分裂症、焦慮症、亨丁頓舞蹈症、藥物依存及/或阿茲海默病的預防及/或治療用醫藥組成物。且,該醫藥組成物為包含含有式(I)之化合物或其鹽的精神分裂症、焦慮症、亨丁頓舞蹈症、藥物依存、及/或阿茲海默病之預防及/或治療劑。 Further, the present invention relates to a pharmaceutical composition for preventing and/or treating schizophrenia, anxiety, Huntington's disease, drug dependence and/or Alzheimer's disease containing a compound of the formula (I) or a salt thereof . Further, the pharmaceutical composition is a prophylactic and/or therapeutic agent comprising schizophrenia, anxiety, Huntington's disease, drug dependence, and/or Alzheimer's disease containing the compound of the formula (I) or a salt thereof .
又,本發明係關於對製造精神分裂症、焦慮症、亨丁頓舞蹈症、藥物依存、及/或阿茲海默病之預防及/或治療用醫藥組成物的式(I)之化合物或其鹽的使用,對精神分裂症、焦慮症、亨丁頓舞蹈症、藥物依存、及/或阿茲海默病的預防及/或治療之式(I)的化合物或其鹽的使用、對精神分裂症、焦慮症、亨丁頓舞蹈症、藥物依存、及/或阿茲海默病的預防及/或治療之式(I)的化合物或其鹽、以及對式(I)的化合物或其鹽之有效量投與於對象所成的精神分裂症、焦慮症、亨丁頓舞蹈症、藥物依存、及 /或阿茲海默病之預防及/或治療方法。且,所謂「對象」為必須該預防或治療的人體或其他動物,作為該態樣為必要該預防或治療之人體。 Further, the present invention relates to a compound of the formula (I) for the manufacture of a pharmaceutical composition for the prevention and/or treatment of schizophrenia, anxiety, Huntington's disease, drug dependence, and/or Alzheimer's disease or Use of a salt thereof, use of a compound of the formula (I) or a salt thereof for the prevention and/or treatment of schizophrenia, anxiety, Huntington's disease, drug dependence, and/or Alzheimer's disease, a compound of the formula (I) or a salt thereof for the prevention and/or treatment of schizophrenia, anxiety, Huntington's disease, drug dependence, and/or Alzheimer's disease, and a compound of the formula (I) or The effective amount of salt is administered to the subject of schizophrenia, anxiety, Huntington's disease, drug dependence, and / or prevention and / or treatment of Alzheimer's disease. Further, the "subject" is a human body or other animal that must be prevented or treated, and this aspect is a human body that is necessary for prevention or treatment.
式(I)的化合物或其鹽具有PDE10A阻礙作用,可作為精神分裂症、焦慮症、亨丁頓舞蹈症、藥物依存、及/或阿茲海默病之預防及/或治療劑使用。 The compound of the formula (I) or a salt thereof has a PDE10A inhibitory action and can be used as a prophylactic and/or therapeutic agent for schizophrenia, anxiety, Huntington's disease, drug dependence, and/or Alzheimer's disease.
以下詳細說明本發明。 The invention is described in detail below.
本說明書中,所謂「烷基」為含有直鏈狀烷基及分支狀烷基。因此,所謂「C1-6烷基」為直鏈或分支狀碳數1~6的烷基,例如為甲基、乙基、丙基、異丙基、丁基、tert-丁基、戊基、己基等,作為其他態樣可為甲基、乙基、丙基、異丙基,進一步作為其他態樣可為甲基、乙基、異丙基。 In the present specification, the "alkyl group" is a linear alkyl group and a branched alkyl group. Therefore, the "C 1-6 alkyl group" is a linear or branched alkyl group having 1 to 6 carbon atoms, and is, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group, or a pentyl group. The group, the hexyl group and the like may be a methyl group, an ethyl group, a propyl group or an isopropyl group as another aspect, and may further be a methyl group, an ethyl group or an isopropyl group as another aspect.
所謂「伸烷基」為除去上述「烷基」之任意1個氫原子所成的二價基。因此,所謂「C1-6伸烷基」為直鏈或分支狀碳數為1~6的伸烷基,例如為伸甲基、伸乙基、三伸甲基、四伸甲基、五伸甲基、六伸甲基、甲基伸甲基、二甲基伸甲基、乙基伸甲基、甲基伸乙基、二甲基伸乙基、乙基伸乙基等,作為其他態樣伸甲基、伸乙基。 The "alkylene group" is a divalent group formed by removing any one of the hydrogen atoms of the above "alkyl group". Therefore, the "C 1-6 alkylene group" is a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, trimethyl, tetramethyl, and Methyl, hexamethyl, methyl methyl, dimethyl methyl, ethyl methyl, methyl ethyl, dimethyl ethyl, ethyl ethyl, etc., as other aspects Methyl, ethylene.
所謂「環烷基」為環員數3~8的飽和烴基環基,該 環烷基可具有交聯,可與苯環進行縮合,一部份的結合可為不飽和。例如為環丙基、環丁基、環戊基、環己基、環庚基、環辛基等,作為其他態樣有C3-6環烷基。 The "cycloalkyl group" is a saturated hydrocarbon group ring group having a ring number of 3 to 8, and the cycloalkyl group may have a crosslinkage and may be condensed with a benzene ring, and a part of the bond may be unsaturated. For example, it is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, etc., and has C 3-6 cycloalkyl group as another aspect.
所謂「芳基」為、碳數6~14的單環至三環式芳香族烴基環基。具體為例苯基、萘基等。 The "aryl group" is a monocyclic to tricyclic aromatic hydrocarbon ring group having 6 to 14 carbon atoms. Specific examples are phenyl, naphthyl and the like.
所謂「芳香族雜環」為含有選自O、N及、S的1個以上的雜原子作為環構成原子,其為環員數5至6的單環芳香族雜環基,該單環芳香族雜環可與選自環己烷、苯,或噻吩、咪唑、吡唑、吡啶、三唑、及吡嗪所成群的環進行縮合。又,環構成原子的氮可被氧化。具體例如為吡啶基、吡咯基、吡嗪基、嘧啶基、噠嗪基、咪唑基、三唑基、三嗪基、四唑基、噻唑基、吡唑基、異噻唑基、噁唑基、異噁唑基、噻二唑基、異二噁基、噻吩基、呋喃基、吲哚基、異吲哚基、苯並咪唑基、吲唑基、喹啉基、異喹啉基、喹唑啉基、喹喔啉基、酞嗪基、苯並噻唑基、苯並異噻唑基、苯並噻二唑基、苯並噁唑基、苯並異噁唑基、苯並呋喃基、苯並噻吩基、苯並三唑基、噻吩並吡啶基、噻吩並嘧啶基、噻吩並吡嗪、5,6,7,8-四氫喹啉基、咪唑並〔1,2-a〕吡啶基、咪唑並〔1,2-a〕嘧啶基、咪唑並〔1,2-b〕噠嗪基、吡唑〔1,5-a〕嘧啶基、咪唑並〔4,5-b〕吡啶基、1,8-萘啶基、咪唑並〔2,1-b〕〔1,3〕噻唑基、〔1,2,4〕三唑並〔1,5-a〕吡啶基、吡啶並〔2,3-b〕吡嗪基、N-氧化物吡啶基等。 The "aromatic heterocyclic ring" is a ring-constituting atom containing one or more hetero atoms selected from O, N and S, and is a monocyclic aromatic heterocyclic group having a ring member number of 5 to 6, and the monocyclic aromatic group The heterocyclic ring may be condensed with a ring selected from the group consisting of cyclohexane, benzene, or thiophene, imidazole, pyrazole, pyridine, triazole, and pyrazine. Further, the nitrogen constituting the atom of the ring can be oxidized. Specifically, for example, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, triazolyl, triazinyl, tetrazolyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, Isoxazolyl, thiadiazolyl, isodoxyl, thienyl, furyl, decyl, isodecyl, benzimidazolyl, oxazolyl, quinolyl, isoquinolyl, quinazoline Polinyl, quinoxalinyl, pyridazinyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, benzo Thienyl, benzotriazolyl, thienopyridyl, thienopyrimidinyl, thienopyrazine, 5,6,7,8-tetrahydroquinolyl, imidazo[1,2-a]pyridinyl, Imidazo[1,2-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, pyrazol[1,5-a]pyrimidinyl, imidazo[4,5-b]pyridinyl, 1 , 8-naphthyridinyl, imidazo[2,1-b][1,3]thiazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, pyrido[2,3 -b] pyrazinyl, N-oxide pyridyl and the like.
所謂「非芳香族雜環」為含有選自O、N及、S的1 至4個雜原子作為環構成原子,其為環員數4至8的單環非芳香族雜環基。該單環非芳香族雜環可與苯環進行縮合。又,環構成原子之硫原子可被氧化,環的一部份鍵結可為不飽和。具體例如可舉出氮雜環丁烷基、吡咯烷基、哌啶基、哌嗪基、氮雜環庚烷基、二氮雜環庚烷基、嗎啉基、環丁碸、噻嗎啉基、1,1-二氧化物噻嗎啉基、四氫吡啶基、四氫嘧啶基、氧環丁烷基、四氫呋喃基、四氫吡喃基、二環氧乙烷基、二噁烷基、四氫噻吡喃、吲哚啉基、1,2-二氫吡啶基、1,2-二氫嘧啶基、1,2-二氫吡嗪基、1,2-二氫噠嗪基等。 The "non-aromatic heterocyclic ring" contains 1 selected from O, N, and S. To four hetero atoms as a ring-constituting atom, which is a monocyclic non-aromatic heterocyclic group having a ring number of 4 to 8. The monocyclic non-aromatic heterocyclic ring can be condensed with a benzene ring. Further, the sulfur atom constituting the ring may be oxidized, and a part of the ring may be unsaturated. Specific examples thereof include azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, azepanyl group, diazepanyl group, morpholinyl group, cyclobutytidine, and thiamorpholine. 1,1,1-dioxythiamorpholinyl, tetrahydropyridyl, tetrahydropyrimidinyl, oxycyclobutane, tetrahydrofuranyl, tetrahydropyranyl, dioxiranyl, dioxoalkyl , tetrahydrothiapyran, porphyrin, 1,2-dihydropyridyl, 1,2-dihydropyrimidinyl, 1,2-dihydropyrazinyl, 1,2-dihydropyridazinyl, etc. .
所謂「鹵素」為F、Cl、Br、I。 The "halogen" is F, Cl, Br, and I.
作為「伸苯基」之態樣為1,4-伸苯基,作為「吡啶二基」之態樣為吡啶-2,5-二基,作為「噻吩二基」的態樣為噻吩-2,5-二基。 The aspect of "stretching phenyl" is 1,4-phenylene, and the aspect of "pyridinediyl" is pyridine-2,5-diyl, and the aspect of "thiophenediyl" is thiophene-2. , 5-diyl.
本說明書中所謂「可被取代的」為無取代,或具有取代基1~5個之意思。且,具有複數個取代基時,這些取代基可為相同或相異。 In the present specification, the term "may be substituted" means unsubstituted or has 1 to 5 substituents. Also, when there are a plurality of substituents, these substituents may be the same or different.
作為式(I)的環A中之「可被取代的芳香族雜環」中可被許可的取代基,可舉出(1)可由選自鹵素、-OH、-O-C1-6烷基、及-N(C1-6烷基)2所成群的相同或相異的1個以上之基所取代的C1-6烷基、(2)鹵素、(3)-O-(由相同或相異的1個以上之鹵素所取代的 C1-6烷基)、(4)-NH2、(5)-NH(C1-6烷基)、(6)-N(C1-6烷基)2、(7)-CN、(8)環烷基、(9)-C(O)O-C1-6烷基、(10)-C(O)H。 The substituent which may be permitted in the "aromatic heterocyclic ring which may be substituted" in the ring A of the formula (I) may, for example, be selected from the group consisting of halogen, -OH, -OC 1-6 alkyl group, and -N (C 1-6 alkyl) 2 identical or different groups of one or more of the groups substituted C 1-6 alkyl, (2) halo, (3) -O- (by the same Or a C 1 alkyl group substituted by one or more halogens, (4)-NH 2 , (5)-NH(C 1-6 alkyl), (6)-N (C 1- 6 alkyl) 2 , (7)-CN, (8) cycloalkyl, (9)-C(O)OC 1-6 alkyl, (10)-C(O)H.
作為式(I)之B中可被取代的伸苯基、吡啶二基,或噻吩二基之取代基可被許可的「可被取代的環烷基」、「可被取代的非芳香族雜環」中可被許可的取代基,可舉出C1-6烷基、鹵素、及-OH。 As a substituent of a pendant phenyl group, a pyridyldiyl group or a thiophenediyl group which may be substituted in the formula (I), a "cycloalkyl group which may be substituted" or a non-aromatic group which may be substituted may be permitted. Examples of the substituent which may be permitted in the ring include a C 1-6 alkyl group, a halogen, and -OH.
作為對於式(I)的環E中「可被取代的環烷基」之可被許可的取代基,可舉出C1-6烷基、-OH、-C(O)NH2、-C(O)NH(C1-6烷基)、-C(O)N(C1-6烷基)2、-CN、=N-O-C1-6烷基、及側氧。 As a permissible substituent of the "cycloalkyl group which may be substituted" in the ring E of the formula (I), a C 1-6 alkyl group, -OH, -C(O)NH 2 , -C may be mentioned. (O) NH(C 1-6 alkyl), -C(O)N(C 1-6 alkyl) 2 , -CN, =NOC 1-6 alkyl, and pendant oxygen.
作為式(I)之環E中「可被取代的芳基」中之可被許可的取代基,可舉出C1-6烷基、鹵素、及-OH。 Examples of the permissible substituent in the "aryl group which may be substituted" in the ring E of the formula (I) include a C 1-6 alkyl group, a halogen, and -OH.
作為對於式(I)之環E中的「可被取代的芳香族雜環」之可被許可的取代基,可舉出可由選自i)鹵素、-OH、-O-C1-6烷基、-O-tert-丁基二甲基矽(以下-O-TBS)、及-N(C1-6烷基)2所成群的相同或相異的1個以上之基所取代的C1-6烷基、ii)鹵素、iii)-O-C1-6烷基、iv)-OH、以及v)環烷基。 As a pharmaceutically acceptable substituent for the "aromatic heterocyclic ring which may be substituted" in the ring E of the formula (I), it may be selected from the group consisting of i) halogen, -OH, -OC 1-6 alkyl group, C 1 substituted by the same or different one or more groups of -O-tert-butyldimethylhydrazine (hereinafter -O-TBS) and -N(C 1-6 alkyl) 2 -6 alkyl, ii) halogen, iii) -OC 1-6 alkyl, iv)-OH, and v) cycloalkyl.
作為對於式(I)的環E的「可被取代的非芳香族雜環」之可被許可的取代基,可舉出(1)可由選自鹵素、-OH、-O-C1-6烷基、及-N(C1-6烷基)2所成群的相同或相異的1個以上之基所取代的C1-6烷基、(2)鹵素、(3)-OH、(4)-S(O)2-C1-6烷基、(5)-C(O)-(-O-C1-6烷基所取代的C1-6烷基)、(6)-C(O)-N(C1-6烷基)2、(7)-C(O)O-C1-6烷基、(8)側氧。 As a permissible substituent of the "non-aromatic heterocyclic ring which may be substituted" for the ring E of the formula (I), (1) may be selected from a halogen, -OH, -OC 1-6 alkyl group. And C- 1-6 alkyl, (2) halogen, (3)-OH, (4) substituted with the same or different one or more groups of -N(C 1-6 alkyl) 2 ) -S (O) 2 -C 1-6 alkyl, (5) -C (O) - (- OC 1-6 alkyl substituted C 1-6 alkyl group), (6) -C (O -N(C 1-6 alkyl) 2 , (7)-C(O)OC 1-6 alkyl, (8) side oxygen.
式(I)的化合物或其鹽之態樣如以下所示。 The aspect of the compound of the formula (I) or a salt thereof is shown below.
(1)環A為可由選自i)可由選自鹵素、-OH、-O-C1-6烷基、及-N(C1-6烷基)2所成群的相同或相異的1個以上之基所取代的C1-6烷基、ii)鹵素、iii)-O-(由相同或相異的1個以上之鹵素所取代的C1-6烷基)、iv)-N(C1-6烷基)2、v)-CN、以及vi)環烷基所成群的相同或相異的1個以上之基所取代的芳香族雜環之式(I)的化合物或其鹽。 (1) Ring A is the same or different one selected from the group consisting of i) selected from the group consisting of halogen, -OH, -OC 1-6 alkyl, and -N(C 1-6 alkyl) 2 the above groups substituted with C 1-6 alkyl, ii) halogen, iii) -O- (by the same or different one or more substituted with halogen or C 1-6 alkyl), iv) -N ( a compound of the formula (I) wherein C 1-6 alkyl) 2 , v)-CN, and vi) an aromatic heterocyclic ring substituted with the same or different one or more groups of cycloalkyl groups; salt.
作為其他態樣,環A可由選自i)可由選自鹵素、-OH、-O-C1-6烷基、及-N(C1-6烷基)2所成群的相同或相異的1個以上之基所取代的C1-6烷基、ii)鹵素、iii)-O-(由相同或相異的1個以上之鹵素所取代的C1-6烷基)、iv )-N(C1-6烷基)2、v)-CN、以及vi)環烷基所成群的相同或相異的1個以上之基各所取代的苯並咪唑基、吡啶基、喹啉基、咪唑並〔1,2-a〕吡啶基、咪唑並〔4,5-b〕吡啶基、1,8-萘啶基,或咪唑並〔1,2-b〕噠嗪基之式(I)的化合物或其鹽。 As a further aspect, Ring A may be the same or different 1 selected from i) selected from the group consisting of halogen, -OH, -OC 1-6 alkyl, and -N(C 1-6 alkyl) 2 one of the above groups substituted with C 1-6 alkyl, ii) halogen, iii) -O- (by the same or different one or more substituted with halogen or C 1-6 alkyl), iv) -N (C 1-6 alkyl) 2 , v)-CN, and vi) a benzimidazolyl group, a pyridyl group, a quinolyl group substituted with the same or different one or more groups of a cycloalkyl group. Formula (I) of imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl, 1,8-naphthyridinyl, or imidazo[1,2-b]pyridazinyl a compound or a salt thereof.
進一步作為其他態樣,環A為由C1-6烷基所取代的苯並咪唑基之式(I)的化合物或其鹽。 Further, as another aspect, the ring A is a compound of the formula (I) or a salt thereof of the benzimidazolyl group substituted by a C 1-6 alkyl group.
進一步作為其他態樣,環A為由C1-6烷基所取代的苯並咪唑-4-基之式(I)的化合物或其鹽。 Further, as another aspect, the ring A is a compound of the formula (I) or a salt thereof of the benzimidazol-4-yl group substituted by a C 1-6 alkyl group.
進一步作為其他態樣,環A為由甲基或乙基所取代的苯並咪唑-4-基的式(I)之化合物或其鹽。 Further, as another aspect, the ring A is a compound of the formula (I) or a salt thereof of the benzimidazol-4-yl group substituted by a methyl group or an ethyl group.
進一步作為其他態樣,環A為可由選自C1-6烷基、-O-C1-6烷基、-N(C1-6烷基)2、及環烷基所成群的相同或相異的1個以上之基所取代的吡啶基的式(I)之化合物或其鹽。 Further, as another aspect, ring A is the same or a group which may be grouped by a group selected from a C 1-6 alkyl group, a —OC 1-6 alkyl group, a —N(C 1-6 alkyl) 2 group, and a cycloalkyl group. A compound of the formula (I) or a salt thereof, which has a pyridyl group substituted with one or more substituents.
進一步作為其他態樣,環A為可由選自C1-6烷基及-O-C1-6烷基所成群的相同或相異的1個以上之基所取代的吡啶-2-基的式(I)之化合物或其鹽。 Further, as another aspect, the ring A is a pyridin-2-yl group which may be substituted by the same or different one or more groups selected from the group consisting of a C 1-6 alkyl group and a -OC 1-6 alkyl group. a compound of (I) or a salt thereof.
進一步作為其他態樣,環A為由甲基所取代的吡啶-2-基的式(I)之化合物或其鹽。 Further, as another aspect, the ring A is a pyridin-2-yl group-substituted compound of the formula (I) or a salt thereof.
進一步作為其他態樣,環A為可由選自i)可由選自鹵素、-OH、-O-C1-6烷基、及-N(C1-6烷基)2所成群的相同相異的1個以上之基所取代的C1-6烷基、ii)鹵素、iii)-O-(由相同或相異的1個以上之鹵素所取代的C1-6烷基 )、iv)-N(C1-6烷基)2、v)-CN、以及vi)環烷基所成群的相同或相異的1個以上之基所取代的喹啉基的式(I)之化合物或其鹽。 Further as another aspect, Ring A is the same dissimilarly groupable from the group consisting of: i) may be selected from the group consisting of halogen, -OH, -OC 1-6 alkyl, and -N(C 1-6 alkyl) 2 one or more of the groups substituted with C 1-6 alkyl, ii) halogen, iii) -O- (by the same or different one or more substituted with halogen or C 1-6 alkyl), iv) - a compound of formula (I) wherein N(C 1-6 alkyl) 2 , v)-CN, and vi) a quinolyl group substituted by the same or different one or more groups of cycloalkyl groups or Its salt.
進一步作為其他態樣,環A為可由選自i)為可由選自鹵素及-N(C1-6烷基)2所成群的相同或相異的1個以上之基所取代的C1-6烷基、ii)鹵素、以及iii)-O-C1-6烷基所成群的相同或相異的1個以上之基所取代的喹啉基的式(I)之化合物或其鹽。 Further, as another aspect, the ring A is a C 1 which may be substituted by the same or different one or more groups selected from the group consisting of halogen and -N(C 1-6 alkyl) 2 selected from i). A compound of the formula (I) or a salt thereof, wherein the -6 alkyl group, the ii) halogen group, and the iii)-OC 1-6 alkyl group are substituted by the same or different one or more substituents.
進一步作為其他態樣,環A為可由選自甲基、乙基、二氟甲基、二甲基胺基甲基、F、及-O-甲基所成群的相同或相異的1個以上之基所取代的喹啉基的式(I)之化合物或其鹽。 Further, as another aspect, Ring A is the same or different one group which may be grouped by a group selected from methyl, ethyl, difluoromethyl, dimethylaminomethyl, F, and -O-methyl. A compound of the formula (I) or a salt thereof of the quinolyl group substituted by the above group.
進一步作為其他態樣,環A為可由選自甲基、乙基、二氟甲基、二甲基胺基甲基、F、及-O-甲基所成群之相同或相異的1個以上之基所取代之的喹啉-2-基的式(I)之化合物或其鹽。 Further, as another aspect, Ring A is the same or different one group selected from the group consisting of methyl, ethyl, difluoromethyl, dimethylaminomethyl, F, and -O-methyl. A compound of the formula (I) or a salt thereof, which is substituted with the above quinolin-2-yl group.
進一步作為其他態樣,環A為可由選自甲基、乙基、F、及-O-甲基所成群的相同或相異的1個以上之基所取代之喹啉-2-基的式(I)之化合物或其鹽。 Further, as another aspect, the ring A is a quinoline-2-yl group which may be substituted by the same or different one or more groups selected from the group consisting of methyl, ethyl, F, and -O-methyl groups. a compound of the formula (I) or a salt thereof.
進一步作為其他態樣,環A為可由選自甲基、乙基、二氟甲基、二甲基胺基甲基、F、及-O-甲基所成群的相同或相異的1個以上之基所取代的喹啉-8-基的式(I)之化合物或其鹽。 Further, as another aspect, Ring A is the same or different one group which may be grouped by a group selected from methyl, ethyl, difluoromethyl, dimethylaminomethyl, F, and -O-methyl. A compound of the formula (I) or a salt thereof of the quinoline-8-yl group substituted by the above group.
又,進一步作為其他態樣,環A為可由選自甲基、乙 基、F、及-O-甲基所成群的相同或相異的1個以上之基所取代的喹啉-8-基的式(I)之化合物或其鹽。 Further, as another aspect, the ring A is selected from the group consisting of methyl and B. A compound of the formula (I) or a salt thereof, wherein the group, the F, and the -O-methyl group are substituted by the same or different one or more substituents of the quinoline-8-yl group.
(2)B為可由選自C1-6烷基、鹵素、-O-C1-6烷基、可被取代的環烷基、及可被取代之非芳香族雜環所成群的相同或相異的1個以上之基各所取代之伸苯基或吡啶二基的式(I)之化合物或其鹽。 (2) B is the same or a group which may be grouped by a C 1-6 alkyl group, a halogen, a -OC 1-6 alkyl group, a cycloalkyl group which may be substituted, and a non-aromatic heterocyclic ring which may be substituted A compound of the formula (I) or a salt thereof, which is substituted with a phenyl or pyridyl group, each of which is substituted by one or more substituents.
作為其他態樣,B為-C≡C-的式(I)之化合物或其鹽。 As another aspect, B is a compound of the formula (I) wherein -C≡C- or a salt thereof.
進一步作為其他態樣,B為可由選自C1-6烷基、鹵素、-O-C1-6烷基、可被取代的環烷基、及可被取代之非芳香族雜環所成群的相同或相異的1個以上之基所取代的伸苯基的式(I)之化合物或其鹽。 Further, as another aspect, B is a group which may be grouped by a C 1-6 alkyl group, a halogen, a -OC 1-6 alkyl group, a cycloalkyl group which may be substituted, and a non-aromatic heterocyclic ring which may be substituted. A compound of the formula (I) or a salt thereof, which is substituted with a phenyl group substituted by the same or different one or more groups.
進一步作為其他態樣,B為可由選自C1-6烷基、鹵素、及-O-C1-6烷基所成群的相同或相異的1個以上之基所取代之伸苯基的式(I)之化合物或其鹽。 Further, as another aspect, B is a phenyl group substituted by the same or different one or more groups selected from the group consisting of a C 1-6 alkyl group, a halogen group, and a —OC 1-6 alkyl group. a compound of (I) or a salt thereof.
進一步作為其他態樣,B為可由選自甲基、F、及-O-甲基所成群的相同或相異的1個以上之基所取代的伸苯基的式(I)之化合物或其鹽。 Further, as another aspect, B is a compound of the formula (I) which may be substituted with a phenyl group which is substituted by the same or different one or more groups selected from the group consisting of methyl, F, and -O-methyl or Its salt.
進一步作為其他態樣,B為可由選自甲基、F、及-O-甲基所成群的相同或相異的1個以上之基所取代的1,4-伸苯基的式(I)之化合物或其鹽。 Further, as another aspect, B is a formula (I) of 1,4-phenylene group which may be substituted by the same or different one or more groups selected from the group consisting of methyl, F, and -O-methyl groups. a compound or a salt thereof.
進一步作為其他態樣,B為1,4-伸苯基的式(I)之化合物或其鹽。 Further, as another aspect, B is a compound of the formula (I) or a salt thereof which is a 1,4-phenylene group.
進一步作為其他態樣,B為可由選自C1-6烷基、鹵素 、及-O-C1-6烷基所成群的相同或相異的1個以上之基所取代的吡啶二基的式(I)之化合物或其鹽。 Further, as another aspect, B is a formula of a pyridyl group which may be substituted by the same or different one or more groups selected from the group consisting of a C 1-6 alkyl group, a halogen group, and a —OC 1-6 alkyl group. a compound of (I) or a salt thereof.
進一步作為其他態樣,B為可由選自C1-6烷基、鹵素、及-O-C1-6烷基所成群的相同或相異的1個以上之基所取代的吡啶-2,5-二基的式(I)之化合物或其鹽。 Further, as another aspect, B is pyridine-2,5 which may be substituted by the same or different one or more groups selected from the group consisting of C 1-6 alkyl, halogen, and -OC 1-6 alkyl. a dibasic compound of the formula (I) or a salt thereof.
又,進一步作為其他態樣,B為吡啶-2,5-二基的式(I)之化合物或其鹽。 Further, as another aspect, B is a pyridine-2,5-diyl compound of the formula (I) or a salt thereof.
(3)n為1的式(I)之化合物或其鹽。 (3) A compound of the formula (I) wherein n is 1 or a salt thereof.
(4)L1為-C1-6伸烷基-T-或-T-C1-6伸烷基的式(I)之化合物或其鹽。 (4) A compound of the formula (I) wherein L 1 is -C 1-6 alkyl-T- or -TC 1-6 alkylene or a salt thereof.
作為其他態樣,L1為-C1-6伸烷基-的式(I)之化合物或其鹽。 As another aspect, the compound of the formula (I) wherein L 1 is -C 1-6 alkylene- or a salt thereof.
進一步作為其他態樣,L1為-C1-6伸烷基-O-或-O-C1-6伸烷基的式(I)之化合物或其鹽。 Further, as another aspect, the compound of the formula (I) wherein L 1 is -C 1-6 alkyl-O- or -OC 1-6 alkylene or a salt thereof.
進一步作為其他態樣,L1為-C1-6伸烷基-NH-或-NH-C1-6伸烷基的式(I)之化合物或其鹽。 Further, as another aspect, the compound of the formula (I) wherein L 1 is -C 1-6 alkyl-NH- or -NH-C 1-6 alkylene or a salt thereof.
進一步作為其他態樣,L1為-CH2-O-或-O-CH2-的式(I)之化合物或其鹽。 Further, as another aspect, the compound of the formula (I) wherein L 1 is -CH 2 -O- or -O-CH 2 - or a salt thereof.
進一步作為其他態樣,L1為-CH2-O-的式(I)之化合物或其鹽。進一步作為其他態樣,L1為-O-CH2-的式(I)之化合物或其鹽。 Further, as another aspect, the compound of the formula (I) wherein L 1 is -CH 2 -O- or a salt thereof. Further, as another aspect, the compound of the formula (I) wherein L 1 is -O-CH 2 - or a salt thereof.
又進一步作為其他態樣,L1為伸乙基的式(I)之化合物或其鹽。 Still further, as another aspect, L 1 is a compound of the formula (I) or a salt thereof which is an ethyl group.
(5)X為CH或N的式(I)之化合物或其鹽。 (5) A compound of the formula (I) wherein X is CH or N or a salt thereof.
作為其他態樣,X為CH的式(I)之化合物或其鹽。 As another aspect, the compound of the formula (I) wherein X is CH or a salt thereof.
進一步作為其他態樣,X為N的式(I)之化合物或其鹽。 Further, as another aspect, X is a compound of the formula (I) or a salt thereof.
(6)R1為可由選自鹵素、-OH、-O-C1-6烷基、-CN、-C(O)OH、及-C(O)O-C1-6烷基所成群之相同或相異的1個以上的基所取代的C1-6烷基的式(I)之化合物或其鹽。 (6) R 1 is the same or may be grouped from halogen, -OH, -OC 1-6 alkyl, -CN, -C(O)OH, and -C(O)OC 1-6 alkyl A compound of the formula (I) or a salt thereof of a C 1-6 alkyl group substituted with one or more different groups.
作為其他態樣,R1為可由選自F、-OH、-O-甲基、-CN、-C(O)OH、及-C(O)O-乙基所成群之相同或相異的1個以上的基所取代的C1-6烷基的式(I)之化合物或其鹽。 As a further aspect, R 1 is the same or different from a group selected from the group consisting of F, -OH, -O-methyl, -CN, -C(O)OH, and -C(O)O-ethyl. A compound of the formula (I) or a salt thereof of the C 1-6 alkyl group substituted with one or more substituents.
進一步作為其他態樣,R1為由F所取代的C1-6烷基的式(I)之化合物或其鹽。 Further, as another aspect, R 1 is a C 1-6 alkyl group-substituted compound of the formula (I) or a salt thereof.
進一步作為其他態樣,R1為三氟甲基的式(I)之化合物或其鹽。 Further, as another aspect, the compound of the formula (I) wherein R 1 is a trifluoromethyl group or a salt thereof.
進一步作為其他態樣,R1為由-OH所取代的C1-6烷基的式(I)之化合物或其鹽。 Further, as another aspect, R 1 is a C 1-6 alkyl group-substituted compound of the formula (I) or a salt thereof.
又,進一步作為其他態樣,R1為甲基的式(I)之化合物或其鹽。 Further, as another aspect, the compound of the formula (I) wherein R 1 is a methyl group or a salt thereof.
(7)環E為可被取代之芳香族雜環或非芳香族雜環的式(I)之化合物或其鹽。作為其他態樣,環E為可被取代之芳香族雜環的式(I)之化合物或其鹽。 (7) A compound of the formula (I) wherein the ring E is an aromatic heterocyclic ring or a non-aromatic heterocyclic ring which may be substituted, or a salt thereof. As another aspect, the ring E is a compound of the formula (I) or a salt thereof which can be substituted with an aromatic heterocyclic ring.
進一步作為其他態樣,環E為可被取代之非芳香族雜環的式(I)之化合物或其鹽。 Further, as another aspect, the ring E is a compound of the formula (I) or a salt thereof which may be substituted with a non-aromatic heterocyclic ring.
進一步作為其他態樣,環E為可由選自i)可由選自鹵素、-OH、-O-C1-6烷基、-O-TBS、及-N(C1-6烷基)2所成群之相同或相異的1個以上的基所取代的C1-6烷基、ii)鹵素、iii)-O-C1-6烷基、iv)-OH、以及v)環烷基所成群之相同或相異的1個以上的基所取代的芳香族雜環的式(I)之化合物或其鹽。 Further, as another aspect, the ring E may be grouped from the group consisting of halogen, -OH, -OC 1-6 alkyl, -O-TBS, and -N(C 1-6 alkyl) 2 selected from i) Groups of C 1-6 alkyl, ii) halogen, iii) -OC 1-6 alkyl, iv)-OH, and v) cycloalkyl substituted by the same or different one or more groups A compound of the formula (I) or a salt thereof, which is an aromatic heterocyclic ring substituted with one or more substituents which are the same or different.
進一步作為其他態樣,環E為可由選自鹵素、-OH、-O-C1-6烷基、及-N(C1-6烷基)2所成群之相同或相異的1個以上的基所取代的C1-6烷基所取代的芳香族雜環的式(I)之化合物或其鹽。 Further, as another aspect, the ring E is one or more of the same or different ones selected from the group consisting of halogen, -OH, -OC 1-6 alkyl, and -N(C 1-6 alkyl) 2 . A compound of the formula (I) or a salt thereof, which is substituted with an aromatic heterocyclic ring substituted by a C 1-6 alkyl group.
進一步作為其他態樣,環E為可由選自-O-C1-6烷基及-OH所成群之相同或相異的1個以上的基所取代的C1-6烷基所取代的芳香族雜環的式(I)之化合物或其鹽。 Further, as another aspect, the ring E is an aromatic group substituted by a C 1-6 alkyl group substituted by the same or different one or more groups selected from the group consisting of -OC 1-6 alkyl group and -OH group. A heterocyclic compound of formula (I) or a salt thereof.
進一步作為其他態樣,環E為可由選自-O-C1-6烷基及-OH所成群之相同或相異的1個以上的基所取代的C1-6烷基所取代的吡啶基的式(I)之化合物或其鹽。 Further, as another aspect, the ring E is a pyridyl group substituted by a C 1-6 alkyl group substituted by the same or different one or more groups selected from the group consisting of -OC 1-6 alkyl group and -OH group. A compound of the formula (I) or a salt thereof.
進一步作為其他態樣,環E為可由選自-O-C1-6烷基及-OH所成群之相同或相異的1個以上的基所取代的C1-6烷基所取代的N-氧化物吡啶基的式(I)之化合物或其鹽。 Further, as another aspect, the ring E is N-substituted by a C 1-6 alkyl group substituted by the same or different one or more groups selected from the group consisting of -OC 1-6 alkyl and -OH. Oxide pyridyl compound of formula (I) or a salt thereof.
進一步作為其他態樣,環E可由選自-O-C1-6烷基及-OH所成群之相同或相異的1個以上的基所取代的C1-6烷基所取代之噠嗪基的式(I)之化合物或其鹽。 Further, as another aspect, the ring E may be a pyridazine group substituted with a C 1-6 alkyl group substituted with the same or different one or more groups selected from the group consisting of -OC 1-6 alkyl group and -OH group. A compound of the formula (I) or a salt thereof.
進一步作為其他態樣,環E為可由選自-O-C1-6烷基 及-OH所成群之相同或相異的1個以上的基所取代的C1-6烷基所取代的吡唑基的式(I)之化合物或其鹽。 Further, as another aspect, the ring E is a pyrazole substituted with a C 1-6 alkyl group substituted by the same or different one or more groups selected from the group consisting of -OC 1-6 alkyl and -OH. a compound of the formula (I) or a salt thereof.
進一步作為其他態樣,環E為可由選自i)可由選自鹵素、-OH、-O-C1-6烷基、及-N(C1-6烷基)2所成群之相同或相異的1個以上的基所取代的C1-6烷基、ii)鹵素、iii)-OH、iv)-S(O)2-C1-6烷基、v)-C(O)-(-O-C1-6烷基所取代的C1-6烷基)、vi)-C(O)-N(C1-6烷基)2、vii)-C(O)O-C1-6烷基、以及viii)側氧所成群之相同或相異的1個以上之基所取代非芳香族雜環的式(I)之化合物或其鹽。 Further as another aspect, the ring E is the same or different from the group selected from the group consisting of halogen, -OH, -OC 1-6 alkyl, and -N(C 1-6 alkyl) 2 a C 1-6 alkyl group substituted by one or more groups, ii) halogen, iii) -OH, iv)-S(O) 2 -C 1-6 alkyl, v)-C(O)-( -OC 1-6 alkyl substituted with C 1-6 alkyl), vi) -C (O) -N (C 1-6 alkyl) 2, vii) -C (O ) OC 1-6 alkyl And a compound of the formula (I) or a salt thereof in which the non-aromatic heterocyclic ring is substituted with one or more of the same or different groups of side oxygen groups.
進一步作為其他態樣,環E為可由選自,可由選自鹵素、-OH、-O-C1-6烷基、及-N(C1-6烷基)2所成群之相同或相異的1個以上的基所取代的C1-6烷基、以及側氧所成群之相同或相異的1個以上之基,所取代的非芳香族雜環的式(I)之化合物或其鹽。 Further as another aspect, ring E is the same or different selected from the group consisting of halogen, -OH, -OC 1-6 alkyl, and -N(C 1-6 alkyl) 2 a C 1-6 alkyl group substituted with one or more groups, and one or more groups having the same or different groups of side oxygen groups, a substituted non-aromatic heterocyclic compound of the formula (I) or salt.
進一步作為其他態樣,環E為可由選自,可由選自鹵素、-OH、-O-C1-6烷基、及-N(C1-6烷基)2所成群之相同或相異的1個以上的基所取代的C1-6烷基、以及側氧所成群之相同或相異的1個以上之基,所取代的1,2-二氫吡啶基的式(I)之化合物或其鹽。 Further as another aspect, ring E is the same or different selected from the group consisting of halogen, -OH, -OC 1-6 alkyl, and -N(C 1-6 alkyl) 2 a C 1-6 alkyl group substituted with one or more groups, and one or more groups having the same or different groups of side oxygen groups, and a substituted formula of the formula (I) of the 1,2-dihydropyridyl group a compound or a salt thereof.
進一步作為其他態樣,環E為可由選自C1-6烷基及側氧所成群之相同或相異的1個以上之基所取代的1,2-二氫吡啶基的式(I)之化合物或其鹽。 Further, as another aspect, the ring E is a formula (I) of a 1,2-dihydropyridyl group which may be substituted by the same or different one or more groups selected from the group consisting of a C 1-6 alkyl group and a side oxygen group. a compound or a salt thereof.
進一步作為其他態樣,環E為可由選自,可由選自鹵素、-OH、-O-C1-6烷基、及-N(C1-6烷基)2所成群之相同或 相異的1個以上的基所取代的C1-6烷基、以及側氧所成群之相同或相異的1個以上之基,所取代的哌啶基的式(I)之化合物或其鹽。 Further as another aspect, ring E is the same or different selected from the group consisting of halogen, -OH, -OC 1-6 alkyl, and -N(C 1-6 alkyl) 2 A compound of the formula (I) or a salt thereof, wherein the C 1-6 alkyl group substituted with one or more groups and the same or different one or more groups in which the side oxygen groups are the same, the substituted piperidinyl group.
又,進一步作為其他態樣,環E為可由選自C1-6烷基及側氧所成群之相同或相異的1個以上之基所取代的哌啶基的式(I)之化合物或其鹽。 Further, as another aspect, the ring E is a compound of the formula (I) which may be substituted with one or more of the same or different ones selected from the group consisting of a C 1-6 alkyl group and a side oxygen group. Or its salt.
(8)由上述(1)至(7)所記載的基中二個以上組合之式(I)之化合物或其鹽。 (8) A compound of the formula (I) or a salt thereof, which is a combination of two or more of the groups described in the above (1) to (7).
本發明中包含如上述(8)所記載之上述(1)至(7)所記載的基中二個以上組合之化合物或其鹽,但亦可舉出含有該具體例之以下態樣。 In the present invention, the compound or a salt thereof, which is a combination of two or more of the groups described in the above (1) to (7), is contained, and the following aspects of the specific examples are also included.
(9)B為可由選自C1-6烷基、鹵素、-O-C1-6烷基、可被取代的環烷基、及可被取代之非芳香族雜環所成群之相同或相異的1個以上之基所取代的伸苯基,n為1,L1為-C1-6伸烷基-T-或-T-C1-6伸烷基的式(I)之化合物或其鹽。 (9) B is the same or a group which may be grouped by a C 1-6 alkyl group, a halogen group, a -OC 1-6 alkyl group, a cycloalkyl group which may be substituted, and a non-aromatic heterocyclic ring which may be substituted a compound of formula (I) wherein phenyl is substituted with one or more substituents, n is 1, and L 1 is -C 1-6 alkyl-T- or -TC 1-6 alkylene or salt.
(10)B為可由選自C1-6烷基、鹵素、-O-C1-6烷基、可被取代的環烷基、及可被取代之非芳香族雜環所成群之相同或相異的1個以上之基所取代的伸苯基,n為1,L1為-C1-6伸烷基-的式(I)之化合物或其鹽。 (10) B is the same or a group which may be grouped by a C 1-6 alkyl group, a halogen, a -OC 1-6 alkyl group, a cycloalkyl group which may be substituted, and a non-aromatic heterocyclic ring which may be substituted A compound of the formula (I) or a salt thereof, wherein one or more substituents are substituted with a phenyl group, n is 1, and L 1 is a -C 1-6 alkyl group.
(11)B為-C≡C-,n為1,L1為-C1-6伸烷基-T-的式(I)之化合物或其鹽。 (11) A compound of the formula (I) wherein B is -C≡C-, n is 1, and L 1 is -C 1-6 alkyl-T- or a salt thereof.
(12)L1為-C1-6伸烷基-O-或-O-C1-6伸烷基之(9)記載的化合物或其鹽。 (12) The compound of (9) or a salt thereof, wherein L 1 is -C 1-6 alkyl-O- or -OC 1-6 alkylene.
(13)L1為伸乙基的(10)記載的化合物或其鹽。 (13) The compound of (10) wherein L 1 is an ethyl group or a salt thereof.
(14)L1為-C1-6伸烷基-O-之(10)記載的化合物或其鹽。 (14) The compound of (10) wherein L 1 is -C 1-6 alkyl-O- or a salt thereof.
(15)環A為可由選自i)可由選自鹵素、-OH、-O-C1-6烷基、及-N(C1-6烷基)2所成群之相同或相異的1個以上的基所取代的C1-6烷基、ii)鹵素、iii)-O-(由相同或相異的1個以上之鹵素所取代的C1-6烷基)、iv)-N(C1-6烷基)2、v)-CN、以及vi)環烷基所成群之相同或相異的1個以上的基所取代的芳香族雜環之(12)、(13),或(14)記載的化合物或其鹽。 (15) Ring A is the same or different one selected from the group consisting of halogen, -OH, -OC 1-6 alkyl, and -N(C 1-6 alkyl) 2 the above groups substituted with C 1-6 alkyl, ii) halogen, iii) -O- (by the same or different one or more substituted with halogen or C 1-6 alkyl), iv) -N ( (12), (13), an aromatic heterocyclic ring substituted with one or more groups in which the C 1-6 alkyl group 2 , v)-CN, and vi) are the same or different groups of cycloalkyl groups, Or the compound of (14) or a salt thereof.
(16)R1為可由選自鹵素、-OH、-O-C1-6烷基、-CN、-C(O)OH、及-C(O)O-C1-6烷基所成群之相同或相異的1個以上的基所取代的C1-6烷基的(15)記載的化合物或其鹽。 (16) R 1 is the same or may be grouped by halogen, -OH, -OC 1-6 alkyl, -CN, -C(O)OH, and -C(O)OC 1-6 alkyl The compound of the above (15) which is a C 1-6 alkyl group substituted with one or more different groups or a salt thereof.
(17)X為CH或N之(16)記載的化合物或其鹽。 (17) A compound according to (16), wherein X is CH or N, or a salt thereof.
(18)環E為可由選自i)可由選自鹵素、-OH、-O-C1-6烷基、-O-TBS、及-N(C1-6烷基)2所成群之相同或相異的1個以上的基所取代的C1-6烷基、ii)鹵素、iii)-O-C1-6烷基、iv)-OH、以及v)環烷基所成群之相同或相異的1個以上的基所取代的芳香族雜環的(17)記載的化合物或其鹽。 (18) Ring E is the same or may be grouped from i) selected from the group consisting of halogen, -OH, -OC 1-6 alkyl, -O-TBS, and -N(C 1-6 alkyl) 2 The same or phase of a group of C 1-6 alkyl, ii) halogen, iii) -OC 1-6 alkyl, iv)-OH, and v) cycloalkyl substituted with one or more different bases The compound of (17) or a salt thereof, which is an aromatic heterocyclic ring substituted with one or more different groups.
(19)環E為可由選自i)可由選自鹵素、-OH、-O-C1-6烷基、及-N(C1-6烷基)2所成群之相同或相異的1個以上的基所取代的C1-6烷基、ii)鹵素、iii)-OH、iv) -S(O)2-C1-6烷基、v)-C(O)-(-O-C1-6烷基所取代的C1-6烷基)、vi)-C(O)-N(C1-6烷基)2、vii)-C(O)O-C1-6烷基、以及viii)側氧所成群之相同或相異的1個以上之基所取代的非芳香族雜環之(17)記載的化合物或其鹽。 (19) Ring E is an identical or different one selected from the group consisting of halogen, -OH, -OC 1-6 alkyl, and -N(C 1-6 alkyl) 2 selected from i) Substituted C 1-6 alkyl, ii) halogen, iii) -OH, iv) -S(O) 2 -C 1-6 alkyl, v)-C(O)-(-OC 1 1-6 alkyl substituted with C 1-6 alkyl), vi) -C (O) -N (C 1-6 alkyl) 2, vii) -C (O ) OC 1-6 alkyl, and viii A compound of the above (17) or a salt thereof, which is a non-aromatic heterocyclic ring substituted with one or more of the same or different groups of side oxygen.
式(I)之化合物或其鹽的其他態樣如以下所示。 Other aspects of the compound of the formula (I) or a salt thereof are shown below.
(20) (20)
(20-1) (20-1)
環A為可由選自(i)可由選自鹵素、-OH、-O-C1-6烷基、及-N(C1-6烷基)2所成群之相同或相異的1個以上的基所取代的C1-6烷基、(ii)鹵素、(iii)-O-(由相同或相異的1個以上之鹵素所取代的C1-6烷基)、(iv)-N(C1-6烷基)2、(v)-CN、(vi)環烷基、(vii)-C(O)H、所成群之相同或相異的1個以上的基所取代的芳香族雜環的式(I)之化合物或其鹽。 Ring A is one or more selected from the group consisting of (i) the same or different groups selected from the group consisting of halogen, -OH, -OC 1-6 alkyl, and -N(C 1-6 alkyl) 2 Substituted C 1-6 alkyl group, (ii) halogen, (iii)-O- (C 1-6 alkyl group substituted by the same or different one or more halogens), (iv)-N (C 1-6 alkyl) 2 , (v)-CN, (vi) cycloalkyl, (vii)-C(O)H, substituted by one or more groups of the same or different groups An aromatic heterocyclic compound of the formula (I) or a salt thereof.
(20-2) (20-2)
(20-2-1) (20-2-1)
環A為可由選自i)可由選自鹵素、-OH、-O-C1-6烷基、及-N(C1-6烷 基)2所成群之相同或相異的1個以上的基所取代的C1-6烷基、ii)鹵素、iii)-O-(由相同或相異的1個以上之鹵素所取代的C1-6烷基)、iv)-CN、v)環烷基、以及vi)-C(O)H所成群之相同或相異的1個以上之基所取代的喹啉基、i)可由選自-OH及-O-C1-6烷基所成群之相同或相異的1個以上的基所取代的C1-6烷基、ii)-O-(C1-6烷基)、以及iii)可由選自-N(C1-6烷基)2所成群之相同或相異的1個以上的基所取代的吡啶基,或可選自i)可由選自鹵素、及-O-C1-6烷基所成群之相同或相異的1個以上的基所取代的C1-6烷基、ii)環烷基、以及、iii)鹵素所成群之相同或相異的1個以上的基所取代的苯並咪唑基的式(I)之化合物或其鹽。 Ring A is one or more groups which may be the same or different from the group selected from the group consisting of halogen, -OH, -OC 1-6 alkyl, and -N(C 1-6 alkyl) 2 substituted C 1-6 alkyl, ii) halogen, iii) -O- (by the same or different one or more substituted with halogen or C 1-6 alkyl), iv) -CN, v) ring a quinolyl group substituted by an alkyl group and one or more of the same or different groups of vi)-C(O)H, i) may be selected from the group consisting of -OH and -OC 1-6 alkyl The C 1-6 alkyl group, ii)-O-(C 1-6 alkyl), and iii) substituted by the same or different one or more groups may be selected from -N (C 1-6 alkane) yl) two or more identical or different groups of the groups substituted pyridyl, or selected from i) may be selected from halogen, and groups of the same or different alkyl group -OC 1-6 Formula of benzimidazolyl substituted with one or more groups in which one or more of the groups are substituted with a C 1-6 alkyl group, ii) a cycloalkyl group, and iii) a group of the same or different groups of halogens a compound of (I) or a salt thereof.
(20-2-2) (20-2-2)
環A為可由選自鹵素、C1-6烷基及-O-C1-6烷基所成群之相同或相異的1個以上之基所取代的喹啉基、可由相同或相異的1個上之C1-6烷基所取代的吡啶基 ,或可由相同或相異的1個以上之C1-6烷基所取代的苯並咪唑基的式(I)之化合物或其鹽。 Ring A is a quinolyl group which may be substituted by the same or different one or more groups selected from the group consisting of halogen, C 1-6 alkyl and -OC 1-6 alkyl, and may be the same or different a pyridyl group substituted with a C 1-6 alkyl group, or a benzimidazolyl compound of the same or different one or more C 1-6 alkyl groups, or a salt thereof.
(20-3) (20-3)
(20-3-1) (20-3-1)
環A為可由選自i)可由選自鹵素、-OH、-O-C1-6烷基、及-N(C1-6烷基)2所成群之相同或相異的1個以上的基所取代的C1-6烷基、ii)鹵素、iii)-O-(由相同或相異的1個以上之鹵素所取代的C1-6烷基)、iv)-CN、v)環烷基、以及vi)-C(O)H所成群之相同或相異的1個以上之基所取代的喹啉基,或可由選自i)可由選自鹵素、及-O-C1-6烷基所成群之相同或相異的1個以上的基所取代的C1-6烷基、ii)環烷基、以及、iii)鹵素所成群之相同或相異的1個以上的基所取代的苯並咪唑基的式(I)之化合物或其鹽。 Ring A is one or more groups which may be the same or different from the group selected from the group consisting of halogen, -OH, -OC 1-6 alkyl, and -N(C 1-6 alkyl) 2 substituted C 1-6 alkyl, ii) halogen, iii) -O- (by the same or different one or more substituted with halogen or C 1-6 alkyl), iv) -CN, v) ring An alkyl group, and a quinolyl group substituted with the same or different one or more groups of vi)-C(O)H, or may be selected from the group consisting of halogen, and -OC 1-6 One or more of the same or different groups of C 1-6 alkyl groups, ii) cycloalkyl groups substituted with one or more groups in which the alkyl groups are the same or different, and iii) halogen groups A compound of the formula (I) or a salt thereof, substituted with a benzimidazolyl group.
(20-3-2) (20-3-2)
環A為可由選自i)可由選自鹵素、及-O-C1-6烷基所成群之相同或相 異的1個以上的基所取代的C1-6烷基、ii)環烷基、以及、iii)鹵素所成群之相同或相異的1個以上的基所取代的苯並咪唑基的式(I)之化合物或其鹽。 Ring A is a C 1-6 alkyl group, ii) cycloalkyl group which may be substituted by one or more groups selected from i) which may be selected from the group consisting of halogen and -OC 1-6 alkyl group. And iii) a compound of the formula (I) or a salt thereof, wherein the halogen is a group of the same or different one or more substituted benzimidazolyl groups.
(20-3-3) (20-3-3)
環A為可由選自鹵素、及-O-C1-6烷基所成群之相同或相異的1個以上之基所取代的相同或相異的1個以上之C1-6烷基所取代的苯並咪唑基的式(I)之化合物或其鹽。 Ring A is substituted by the same or different one or more C 1-6 alkyl groups which may be substituted by the same or different one or more groups selected from the group consisting of halogen and -OC 1-6 alkyl group. A benzimidazolyl compound of the formula (I) or a salt thereof.
(20-3-4) (20-3-4)
環A為1-甲基苯並咪唑-4-基的式(I)之化合物或其鹽。 Ring A is a 1-methylbenzimidazol-4-yl compound of formula (I) or a salt thereof.
(20-4) (20-4)
(20-4-1) (20-4-1)
環A為可由選自i)可由選自鹵素、-OH、-O-C1-6烷基、及-N(C1-6烷基)2所成群之相同或相異的1個以上的基所取代的C1-6烷基、ii)鹵素、iii)-O-(由相同或相異的1個以上之鹵素所取代的C1-6烷基)、iv)-CN、v)環烷基、以及vi)-C(O)H所成群之相同或相異的1個以上之基所取代的喹啉基的式(I)之化合物或其鹽。 Ring A is one or more groups which may be the same or different from the group selected from the group consisting of halogen, -OH, -OC 1-6 alkyl, and -N(C 1-6 alkyl) 2 substituted C 1-6 alkyl, ii) halogen, iii) -O- (by the same or different one or more substituted with halogen or C 1-6 alkyl), iv) -CN, v) ring A compound of the formula (I) or a salt thereof, wherein the alkyl group and the violinyl group substituted with one or more of the same or different groups of vi)-C(O)H are grouped.
(20-4-2) (20-4-2)
環A可由選自鹵素、C1-6烷基及-O-C1-6烷基所成群之相同或相異的1個以上之基所取代的喹啉基的式(I)之化合物或其鹽。 a compound of the formula (I) wherein ring A may be a quinolinyl group substituted by the same or different one or more groups selected from the group consisting of halogen, C 1-6 alkyl and -OC 1-6 alkyl or salt.
(20-4-3) (20-4-3)
環A為可由選自i)可由選自鹵素、-OH、-O-C1-6烷基、及-N(C1-6烷基)2所成群之相同或相異的1個以上的基所取代的C1-6烷基、ii)鹵素、iii)-O-(由相同或相異的1個以上之鹵素所取代的C1-6烷基)、iv)-CN、v)環烷基、以及vi)-C(O)H所成群之相同或相異的1個以上之基所取代的喹啉-2-基,或可由選自C1-6烷基及-O-C1-6烷基所成群之相同或相異的1個以上之基所取代的喹啉-8-基的式(I)之化合物或其鹽。 Ring A is one or more groups which may be the same or different from the group selected from the group consisting of halogen, -OH, -OC 1-6 alkyl, and -N(C 1-6 alkyl) 2 substituted C 1-6 alkyl, ii) halogen, iii) -O- (by the same or different one or more substituted with halogen or C 1-6 alkyl), iv) -CN, v) ring An alkyl group, and a quinoline-2-yl group substituted with one or more of the same or different groups of vi)-C(O)H, or may be selected from C1-6 alkyl and -OC 1 A compound of the formula (I) or a salt thereof, wherein the -6 alkyl group is substituted by the same or different one or more substituents of the quinoline-8-yl group.
(20-4-4) (20-4-4)
環A為可由選自i)可由選自鹵素、-OH、-O-C1-6烷基、及-N(C1-6烷基)2所成群之相同或相異的1個以上的基所取代的C1-6烷基、ii)鹵素、iii)-O-(由相同或相異的1個以上之鹵素所取代的C1-6烷基)、 iv)-CN、v)環烷基、以及vi)-C(O)H所成群之相同或相異的1個以上之基所取代的喹啉-2-基的式(I)之化合物或其鹽。 Ring A is one or more groups which may be the same or different from the group selected from the group consisting of halogen, -OH, -OC 1-6 alkyl, and -N(C 1-6 alkyl) 2 substituted C 1-6 alkyl, ii) halogen, iii) -O- (by the same or different one or more substituted with halogen or C 1-6 alkyl), iv) -CN, v) ring A compound of the formula (I) or a salt thereof, wherein the alkyl group and the quinoline-2-yl group substituted with one or more of the same or different groups of vi)-C(O)H are present.
(20-4-5) (20-4-5)
環A為可由選自C1-6烷基及-O-C1-6烷基所成群之相同或相異的1個以上之基所取代的喹啉-8-基的式(I)之化合物或其鹽。 Ring A is a compound of formula (I) wherein quinoline-8-yl which may be substituted by the same or different one or more groups selected from the group consisting of C 1-6 alkyl and -OC 1-6 alkyl Or its salt.
(20-4-6) (20-4-6)
環A為喹啉-2-基、3-甲基喹啉-2-基、3-羥基甲基喹啉-2-基、3-甲氧基喹啉-2-基、6-氟喹啉-2-基、6-甲氧基喹啉-2-基、6-甲氧基-3-甲基喹啉-2-基,或喹啉-8-基的式(I)之化合物或其鹽。 Ring A is quinolin-2-yl, 3-methylquinolin-2-yl, 3-hydroxymethylquinolin-2-yl, 3-methoxyquinolin-2-yl, 6-fluoroquinoline a compound of formula (I) wherein 2-yl, 6-methoxyquinolin-2-yl, 6-methoxy-3-methylquinolin-2-yl, or quinoline-8-yl or salt.
(20-4-7) (20-4-7)
環A為喹啉-2-基、3-甲基喹啉-2-基、3-羥基甲基喹啉-2-基、3-甲氧基喹啉-2-基、6-氟喹啉-2-基、6-甲氧基喹啉-2-基,或6-甲氧基-3-甲基喹啉-2-基的式(I)之化合物或其鹽。 Ring A is quinolin-2-yl, 3-methylquinolin-2-yl, 3-hydroxymethylquinolin-2-yl, 3-methoxyquinolin-2-yl, 6-fluoroquinoline a compound of the formula (I) wherein 2-yl, 6-methoxyquinolin-2-yl or 6-methoxy-3-methylquinolin-2-yl or a salt thereof.
(20-4-8) (20-4-8)
環A為喹啉-2-基、3-羥基甲基喹啉-2-基、3-甲氧基喹啉-2-基、6-氟喹啉-2-基、6-甲氧基喹啉-2-基、6-甲氧基-3-甲基喹啉-2-基,或喹啉-8-基的式(I)之化合物或其鹽。 Ring A is quinolin-2-yl, 3-hydroxymethylquinolin-2-yl, 3-methoxyquinolin-2-yl, 6-fluoroquinolin-2-yl, 6-methoxyquin A compound of the formula (I) or a salt thereof, which is oxa-2-yl, 6-methoxy-3-methylquinolin-2-yl, or quinoline-8-yl.
(20-4-9) (20-4-9)
環A為喹啉-2-基、3-羥基甲基喹啉-2-基、3-甲氧基喹啉-2-基、6-氟喹啉-2-基、6-甲氧基喹啉-2-基,或6-甲氧基-3-甲基喹啉-2-基的式(I)之化合物或其鹽。 Ring A is quinolin-2-yl, 3-hydroxymethylquinolin-2-yl, 3-methoxyquinolin-2-yl, 6-fluoroquinolin-2-yl, 6-methoxyquin A compound of the formula (I) or a salt thereof, which is a quinolin-2-yl group or a 6-methoxy-3-methyl quinolin-2-yl group.
(20-4-10) (20-4-10)
環A為喹啉-2-基的式(I)之化合物或其鹽。 Ring A is a quinolin-2-yl compound of formula (I) or a salt thereof.
(20-4-11) (20-4-11)
環A為3-甲基喹啉-2-基的式(I)之化合物或其鹽。 Ring A is a 3-methylquinolin-2-yl compound of the formula (I) or a salt thereof.
(20-4-12) (20-4-12)
環A為3-羥基甲基喹啉-2-基的式(I)之化合物或其鹽。 Ring A is a compound of formula (I) wherein 3-hydroxymethylquinolin-2-yl or a salt thereof.
(20-4-13) (20-4-13)
環A為3-甲氧基喹啉-2-基的式(I)之化合物或其鹽。 The compound of the formula (I) wherein ring A is 3-methoxyquinolin-2-yl or a salt thereof.
(20-4-14) (20-4-14)
環A為6-氟喹啉-2-基的式(I)之化合物或其鹽。 The compound of the formula (I) wherein ring A is 6-fluoroquinolin-2-yl or a salt thereof.
(20-4-15) (20-4-15)
環A為6-甲氧基喹啉-2-基的式(I)之化合物或其鹽。 The compound of the formula (I) wherein ring A is 6-methoxyquinolin-2-yl or a salt thereof.
(20-4-16) (20-4-16)
環A為6-甲氧基-3-甲基喹啉-2-基的式(I)之化合物或其鹽。 The compound of the formula (I) wherein ring A is 6-methoxy-3-methylquinolin-2-yl or a salt thereof.
(20-4-17) (20-4-17)
環A為喹啉-8-基的式(I)之化合物或其鹽。 Ring A is a quinoline-8-yl compound of formula (I) or a salt thereof.
(21) (twenty one)
(21-1) (21-1)
B為可由選自C1-6烷基、鹵素、-O-C1-6烷基、環烷基、及非芳香族雜環所成群之相同或相異的1個以上之基所取代的伸苯基、吡啶二基、或噻吩二基、或-C≡C-的式(I)之化合物或其鹽。 B is a group which may be substituted by the same or different one or more groups selected from the group consisting of a C 1-6 alkyl group, a halogen group, a —OC 1-6 alkyl group, a cycloalkyl group, and a non-aromatic heterocyclic ring. A compound of the formula (I) or a salt thereof, which is a phenyl group, a pyridyldiyl group, or a thiophenediyl group, or -C≡C-.
(21-2) (21-2)
B為可由選自C1-6烷基、鹵素、-O-C1-6烷基、環烷基、及非芳香族雜環所成群之相同或相異的1個以上之基所取代的伸苯基、吡啶二基、或噻吩二基的式(I)之化合物或其鹽。 B is a group which may be substituted by the same or different one or more groups selected from the group consisting of a C 1-6 alkyl group, a halogen group, a —OC 1-6 alkyl group, a cycloalkyl group, and a non-aromatic heterocyclic ring. A compound of formula (I), or a salt thereof, of phenyl, pyridyldiyl or thiophenediyl.
(22) (twenty two)
R1為C1-6烷基的式(I)之化合物或其鹽。 A compound of the formula (I) wherein R 1 is a C 1-6 alkyl group or a salt thereof.
(23) (twenty three)
(23-1) (23-1)
環E為可由選自C1-6烷基、-OH、-C(O)NH2、-C(O)NH(C1-6烷基)、-C(O)N(C1-6烷基)2、-CN、=N-O-C1-6烷基、及側氧所成群之相同或相異的1個以上的基所取代的環烷基、 芳基、i)可由選自鹵素、-OH、-O-C1-6烷基、-O-TBS、及-N(C1-6烷基)2所成群之相同或相異的1個以上的基所取代的C1-6烷基、ii)鹵素、iii)-O-C1-6烷基、iv)-OH、以及v)環烷基所成群之相同或相異的1個以上的基所取代的芳香族雜環,或可由選自i)可由選自鹵素、-OH、-O-C1-6烷基、及-N(C1-6烷基)2所成群之相同或相異的1個以上的基所取代的C1-6烷基、ii)-OH、iii)-S(O)2-C1-6烷基、iv)-C(O)-(由-O-C1-6烷基所取代的C1-6烷基)、v)-C(O)-N(C1-6烷基)2、vi)-C(O)O-C1-6烷基、以及vii)側氧所成群之相同或相異的1個以上之基所取代的非芳香族雜環的式(I)之化合物或其鹽。 Ring E is selected from C 1-6 alkyl, -OH, -C(O)NH 2 , -C(O)NH(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -CN, =NOC 1-6 alkyl, and a cycloalkyl group, an aryl group, i) substituted with the same or different one or more groups of side oxygen groups may be selected from halogens, C 1-6 alkane substituted with one or more groups of the same or different groups of -OH, -OC 1-6 alkyl, -O-TBS, and -N(C 1-6 alkyl) 2 a aryl group, ii) halogen, iii) -OC 1-6 alkyl, iv)-OH, and v) an aromatic heterocyclic ring substituted with the same or different one or more groups of cycloalkyl groups, or It may be substituted by one or more groups selected from i) which may be the same or different groups selected from the group consisting of halogen, -OH, -OC 1-6 alkyl, and -N(C 1-6 alkyl) 2 C 1-6 alkyl, ii)-OH, iii)-S(O) 2 -C 1-6 alkyl, iv)-C(O)- (C 1 substituted by -OC 1-6 alkyl) -6 alkyl), v)-C(O)-N(C 1-6 alkyl) 2 , vi)-C(O)OC 1-6 alkyl, and vii) the same group of side oxygen groups or A compound of the formula (I) or a salt thereof which is a non-aromatic heterocyclic ring substituted with one or more different groups.
(23-2) (23-2)
環E為1-甲基-6-側氧-1,6-二氫吡啶-3-基的式(I)之化合物或其鹽。 The compound of the formula (I) wherein ring E is 1-methyl-6-oxo-oxy-1,6-dihydropyridin-3-yl or a salt thereof.
(23-3) (23-3)
環E為2-甲基吡啶-4-基的式(I)之化合物或其鹽。 The compound of the formula (I) wherein ring E is 2-methylpyridin-4-yl or a salt thereof.
(24)上述(1)至(7)及(20)至(23)所記載的基中二個以上組合的式(I)之化合物或其鹽。 (24) A compound of the formula (I) or a salt thereof in combination of two or more of the groups described in the above (1) to (7) and (20) to (23).
本發明中包含如上述(24)記載之上述(1)至(7)及(20)至(23)所記載的基中二個以上組合之化合物或其鹽,但含有該具體例亦可舉出以下態樣。 In the present invention, the compound or a salt thereof in combination of two or more of the groups (1) to (7) and (20) to (23) described in the above (24) is contained, but the specific example may be included. The following aspects are presented.
(25)環A為(1),或(20)的式(I)之化合物或其鹽。 (25) A compound of the formula (I) wherein the ring A is (1) or (20) or a salt thereof.
(26)B為(2),或(21)之(25)記載的化合物或其鹽。 (26) B is the compound of (2), or (21) (25) or a salt thereof.
(27)n為(3)之(25)~(26)記載的化合物或其鹽。 (27) The compound of (25) to (26) or a salt thereof.
(28)L1為(4)之(25)~(27)記載的化合物或其鹽。 (28) L 1 is (4) of (25) to (27) or a salt thereof described.
(29)X為(5)之(25)~(28)記載的化合物或其鹽。 (29) The compound according to any one of (25) to (28), wherein X is (5) or a salt thereof.
(30)R1為(6),或(22)之(25)~(29)記載的化合物或其鹽。 (30) R 1 is (6), or (22) of (25) to (29) or a salt thereof described.
(31)環E為(7),或(23)之(25)~(30)記載的化合物或其鹽。 (31) The compound of the formula (25), or the compound of (25) to (30), or a salt thereof.
作為包含於式(I)的化合物或其鹽之具體化合物的例子,可舉出以下化合物。 Examples of the specific compound contained in the compound of the formula (I) or a salt thereof include the following compounds.
8-〔4-({〔1-甲基-4-(吡啶-4-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕喹啉、 1-甲基-5-(1-甲基-3-{〔4-(3-甲基喹啉-2-基)苯氧基〕甲基}-1H-吡唑-4-基)吡啶-2(1H)-酮、1-甲基-5-(1-甲基-3-{〔4-(1-甲基-1H-苯並咪唑-4-基)苯氧基〕甲基}-1H-吡唑-4-基)吡啶-2(1H)-酮、1-甲基-5-(1-甲基-3-{〔4-(1-甲基-1H-苯並咪唑-4-基)苯甲基〕氧基}-1H-吡唑-4-基)吡啶-2(1H)-酮、2-(3-{〔1-甲基-4-(吡啶-4-基)-1H-吡唑-3-基〕氧基}丙-1-炔-1-基)喹啉、1-甲基-5-(1-甲基-3-{〔4-(3-甲基喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)哌啶-2-酮、4-(3-{〔4-(6-氟-3-甲基喹啉-2-基)苯甲基〕氧基}-1-甲基-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮、5-(3-{〔4-(6-甲氧基-3-甲基喹啉-2-基)苯甲基〕氧基}-1-甲基-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮、1-甲基-4-(4-{〔1-甲基-4-(2-甲基吡啶-4-基)-1H-吡唑-3-基〕甲氧基}苯基)-1H-苯並咪唑、5-(3-{〔4-(3-乙基喹啉-2-基)苯甲基〕氧基}-1-甲基-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮、3-甲基-2-(4-{〔1-甲基-4-(吡啶-4-基)-1H-吡唑-3-基〕甲氧基}苯基)喹啉、3-甲基-2-〔4-({〔1-甲基-4-(噠嗪-4-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕喹啉、2-(4-{〔(1,1'-二甲基-1H,1'H-4,4'-雙吡唑-3-基)氧基〕甲基}苯基)-3-甲基喹啉、 1-甲基-5-(1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)吡啶-2(1H)-酮、1-乙基-5-(1-甲基-3-{〔4-(3-甲基喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)吡啶-2(1H)-酮、5-(1-甲基-3-{〔4-(3-甲基喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)-1-丙基吡啶-2(1H)-酮、5-(3-{〔4-(6-氟-3-甲基喹啉-2-基)苯甲基〕氧基}-1-甲基-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮、1-甲基-5-(2-甲基-5-{〔4-(3-甲基喹啉-2-基)苯氧基〕甲基}-2H-1,2,3-三唑-4-基)吡啶-2(1H)-酮、3-甲基-2-(4-{〔1-甲基-4-(2-甲基吡啶-4-基)-1H-吡唑-3-基〕甲氧基}苯基)喹啉、2-(4-{〔4-(2,6-二甲基吡啶-4-基)-1-甲基-1H-吡唑-3-基〕甲氧基}苯基)-3-甲基喹啉、1-甲基-4-(1-甲基-3-{2-〔4-(3-甲基喹啉-2-基)苯基〕乙基}-1H-吡唑-4-基)吡啶-2(1H)-酮、1-甲基-4-(1-甲基-3-{〔4-(3-甲基喹啉-2-基)苯氧基〕甲基}-1H-吡唑-4-基)吡啶-2(1H)-酮、1-甲基-4-(4-{〔1-甲基-4-(2-甲基-1-氧化物吡啶-4-基)-1H-吡唑-3-基〕甲氧基}苯基)-1H-苯並咪唑、1-甲基-4-(4-{〔1-甲基-4-(噠嗪-4-基)-1H-吡唑-3-基〕甲氧基}苯基)-1H-苯並咪唑、1-甲基-4-(1-甲基-3-{〔4-(1-甲基-1H-苯並咪唑-4-基)苯氧基〕甲基}-1H-吡唑-4-基)吡啶-2(1H)-酮、 1'-乙基-1-甲基-3-{〔4-(1-甲基-1H-苯並咪唑-4-基)苯氧基〕甲基}-1H,1'H-4,4'-雙吡唑、1-甲基-5-(1-甲基-3-{〔4-(喹啉-8-基)苯氧基〕甲基}-1H-吡唑-4-基)吡啶-2(1H)-酮、5-(3-{〔4-(6-甲氧基-3-甲基喹啉-2-基)苯氧基〕甲基}-1-甲基-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮、8-(4-{〔1-甲基-4-(吡嗪-4-基)-1H-吡唑-3-基〕甲氧基}苯基)喹啉、1-甲基-5-(1-甲基-3-{〔4-(喹啉-2-基)苯氧基〕甲基}-1H-吡唑-4-基)吡啶-2(1H)-酮、5-(3-{〔4-(3-甲氧基喹啉-2-基)苯氧基〕甲基}-1-甲基-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮、5-(3-{〔4-(6-氟喹啉-2-基)苯氧基〕甲基}-1-甲基-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮、5-(3-{〔4-(6-甲氧基喹啉-2-基)苯氧基〕甲基}-1-甲基-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮、3-甲基-8-(4-{〔1-甲基-4-(2-甲基吡啶-4-基)-1H-吡唑-3-基〕甲氧基}苯基)咪唑並〔1,2-a〕吡啶、1,1'-二甲基-3-{〔4-(3-甲基咪唑並〔1,2-a〕吡啶-8-基)苯氧基〕甲基}-1H,1'H-4,4'-雙吡唑、2-(4-{〔1-甲基-4-(2-甲基吡啶-4-基)-1H-吡唑-3-基〕甲氧基}苯基)喹啉及彼等之鹽。 8-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)oxy}methyl)phenyl]quinoline, 1-Methyl-5-(1-methyl-3-{[4-(3-methylquinolin-2-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridine- 2(1H)-ketone, 1-methyl-5-(1-methyl-3-{[4-(1-methyl-1H-benzimidazol-4-yl)phenoxy]methyl}- 1H-pyrazol-4-yl)pyridine-2(1H)-one, 1-methyl-5-(1-methyl-3-{[4-(1-methyl-1H-benzimidazole-4) -yl)benzyloxy]-1H-pyrazol-4-yl)pyridine-2(1H)-one, 2-(3-{[1-methyl-4-(pyridin-4-yl) -1H-pyrazol-3-yl]oxy}prop-1-yn-1-yl)quinoline, 1-methyl-5-(1-methyl-3-{[4-(3-methyl) Quinoline-2-yl)benzyloxy]-1H-pyrazol-4-yl)piperidin-2-one, 4-(3-{[4-(6-fluoro-3-methylquin) Phenyl-2-yl)benzyloxy]-1-methyl-1H-pyrazol-4-yl)-1-methylpyridine-2(1H)-one, 5-(3-{[4 -(6-methoxy-3-methylquinolin-2-yl)benzyl}oxy}-1-methyl-1H-pyrazol-4-yl)-1-methylpyridine-2 ( 1H)-keto, 1-methyl-4-(4-{[1-methyl-4-(2-methylpyridin-4-yl)-1H-pyrazol-3-yl]methoxy}benzene -1H-benzimidazole, 5-(3-{[4-(3-ethylquinolin-2-yl)benzyl)oxy}-1-methyl-1H-pyrazole-4- 1-methylpyridin-2(1H)-one, 3-methyl-2-(4-{[1-methyl-4-(pyridyl) Pyridin-4-yl)-1H-pyrazol-3-yl]methoxy}phenyl)quinoline, 3-methyl-2-[4-({[1-methyl-4-(pyridazine)- 4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline, 2-(4-{[(1,1'-dimethyl-1H,1'H-4 , 4'-bispyrazol-3-yl)oxy]methyl}phenyl)-3-methylquinoline, 1-methyl-5-(1-methyl-3-{[4-(quinolin-2-yl)benzyl)oxy}-1H-pyrazol-4-yl)pyridine-2 (1H) -keto, 1-ethyl-5-(1-methyl-3-{[4-(3-methylquinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl Pyridine-2(1H)-one, 5-(1-methyl-3-{[4-(3-methylquinolin-2-yl)benzyl]oxy}-1H-pyrazole-4 -yl)-1-propylpyridine-2(1H)-one, 5-(3-{[4-(6-fluoro-3-methylquinolin-2-yl)benzyl)oxy}- 1-methyl-1H-pyrazol-4-yl)-1-methylpyridine-2(1H)-one, 1-methyl-5-(2-methyl-5-{[4-(3- Methylquinolin-2-yl)phenoxy]methyl}-2H-1,2,3-triazol-4-yl)pyridine-2(1H)-one, 3-methyl-2-(4 -{[1-methyl-4-(2-methylpyridin-4-yl)-1H-pyrazol-3-yl]methoxy}phenyl)quinoline, 2-(4-{[4- (2,6-Dimethylpyridin-4-yl)-1-methyl-1H-pyrazol-3-yl]methoxy}phenyl)-3-methylquinoline, 1-methyl-4 -(1-methyl-3-{2-[4-(3-methylquinolin-2-yl)phenyl]ethyl}-1H-pyrazol-4-yl)pyridine-2(1H)- Ketone, 1-methyl-4-(1-methyl-3-{[4-(3-methylquinolin-2-yl)phenoxy]methyl}-1H-pyrazol-4-yl) Pyridine-2(1H)-one, 1-methyl-4-(4-{[1-methyl-4-(2-methyl-1-oxide pyridine-4) -yl)-1H-pyrazol-3-yl]methoxy}phenyl)-1H-benzimidazole, 1-methyl-4-(4-{[1-methyl-4-(pyridazine)- 4-yl)-1H-pyrazol-3-yl]methoxy}phenyl)-1H-benzimidazole, 1-methyl-4-(1-methyl-3-{[4-(1- Methyl-1H-benzimidazol-4-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridine-2(1H)-one, 1'-Ethyl-1-methyl-3-{[4-(1-methyl-1H-benzimidazol-4-yl)phenoxy]methyl}-1H,1'H-4,4 '-Dipyrazole, 1-methyl-5-(1-methyl-3-{[4-(quinolin-8-yl)phenoxy)methyl}-1H-pyrazol-4-yl) Pyridine-2(1H)-one, 5-(3-{[4-(6-methoxy-3-methylquinolin-2-yl)phenoxy]methyl}-1-methyl-1H -pyrazol-4-yl)-1-methylpyridine-2(1H)-one, 8-(4-{[1-methyl-4-(pyrazin-4-yl)-1H-pyrazole- 3-yl]methoxy}phenyl)quinoline, 1-methyl-5-(1-methyl-3-{[4-(quinolin-2-yl)phenoxy]methyl}-1H -pyrazol-4-yl)pyridine-2(1H)-one, 5-(3-{[4-(3-methoxyquinolin-2-yl)phenoxy]methyl}-1-methyl -1H-pyrazol-4-yl)-1-methylpyridine-2(1H)-one, 5-(3-{[4-(6-fluoroquinolin-2-yl)phenoxy]- -1-methyl-1H-pyrazol-4-yl)-1-methylpyridine-2(1H)-one, 5-(3-{[4-(6-methoxyquinoline-2) -yl)phenoxy]methyl}-1-methyl-1H-pyrazol-4-yl)-1-methylpyridine-2(1H)-one, 3-methyl-8-(4-{ [1-Methyl-4-(2-methylpyridin-4-yl)-1H-pyrazol-3-yl]methoxy}phenyl)imidazo[1,2-a]pyridine, 1,1 '-Dimethyl-3-{[4-(3-methylimidazo[1,2-a]pyridin-8-yl) Oxy]methyl}-1H, 1'H-4,4'-bispyrazole, 2-(4-{[1-methyl-4-(2-methylpyridin-4-yl)-1H- Pyrazol-3-yl]methoxy}phenyl)quinoline and the salts thereof.
L1的結合樣式,例如記載為-C1-6伸烷基-T-時,T結合於含有2個氮原子與X作為環構成原子之5員環雜環, 表示-C1-6伸烷基-與(B)n或環A結合的意思。作為例子為後述表58記載的Ex.1。又,若記載為-T-C1-6伸烷基-時,-C1-6伸烷基-結合於含有2個氮原子與X作為環構成原子之5員環雜環,表示T與(B)n或環A結合的意思。例如為後述表60記載的Ex.12。 When the binding pattern of L 1 is, for example, described as -C 1-6 alkyl-T-, T is bonded to a 5-membered ring heterocyclic ring containing two nitrogen atoms and X as a ring-constituting atom, and represents -C 1-6 The meaning of alkyl-in combination with (B) n or ring A. As an example, Ex. 1 described in Table 58 which will be described later. Further, when it is described as -TC 1-6 alkylene group, -C 1-6 alkylene group-bonds to a 5-membered ring heterocyclic ring containing two nitrogen atoms and X as a ring-constituting atom, indicating T and (B). n or the meaning of ring A binding. For example, it is Ex. 12 described in Table 60 mentioned later.
式(I)的化合物中依據取代基的種類,存在著互變異構物或幾何異構物。本說明書中,雖僅記載式(I)的化合物之一異構物形態,本發明中亦包含此以外之異構物、由異構物分離者,或亦包含這些混合物。 Among the compounds of the formula (I), tautomers or geometric isomers exist depending on the kind of the substituent. In the present specification, only one isomeric form of the compound of the formula (I) is described, and the present invention also includes the other isomers, the isomers are separated, or these mixtures are also included.
又,式(I)的化合物中若具有不對稱碳原子或軸不對稱時,依據此存在著光學異構物。本發明亦包含式(I)的化合物之光學異構物經分離者,或這些混合物。 Further, when the compound of the formula (I) has an asymmetric carbon atom or an asymmetrical axis, an optical isomer is present in accordance therewith. The invention also encompasses optical isomers of the compounds of formula (I), or mixtures thereof.
且,本發明亦包含式(I)的化合物之製藥學上可被許可的前體藥物。所謂製藥學上可被許可的前體藥物為,藉由加溶劑分解或在生理學條件下,具有可轉變為胺基、羥基、羧基等基之化合物。作為形成前體藥物之基,例如可舉出Prog.Med.,5,2157-2161(1985)或「醫藥品之開發」(廣川書店、1990年)第7卷 分子設計163-198所記載的基。 Moreover, the invention also encompasses pharmaceutically acceptable prodrugs of a compound of formula (I). The pharmaceutically acceptable prodrug is a compound which can be converted into an amine group, a hydroxyl group, a carboxyl group or the like by decomposition with a solvent or under physiological conditions. Examples of the base for forming a prodrug include those described in Prog. Med., 5, 2157-2161 (1985) or "Development of Pharmaceutical Products" (Guangchuan Bookstore, 1990), Volume 7, Molecular Designs 163-198. base.
又,式(I)的化合物依取代基的種類有時可形成酸加成鹽或與鹼之鹽類,該鹽若為製藥學上可被許可的鹽即包含於本發明中。具體可舉出鹽酸、氫溴酸、氫碘酸、硫酸、硝酸、磷酸等無機酸,或與甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富馬酸、馬來酸、乳酸、蘋果酸、扁 桃酸、酒石酸、二苯甲醯基酒石酸、甲苯甲酰基酒石酸、檸檬酸、甲烷磺酸、乙烷磺酸、苯磺酸、p-甲苯磺酸、天冬醯胺酸、麩胺酸等有機酸之酸加成鹽、鈉、鉀、鎂、鈣、鋁等無機鹼、與甲基胺、乙基胺、乙醇胺、賴胺酸、鳥胺酸等有機鹼之鹽、與乙醯基亮胺酸等各種胺基酸及胺基酸衍生物之鹽或銨鹽等。 Further, the compound of the formula (I) may form an acid addition salt or a salt with a base depending on the kind of the substituent, and the salt is a pharmaceutically acceptable salt, and is included in the present invention. Specific examples thereof include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, or with formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, and lactic acid. Malic acid, flat Peach acid, tartaric acid, benzoyl tartaric acid, toluyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, etc. Acid acid addition salt, inorganic base such as sodium, potassium, magnesium, calcium, aluminum, salt with organic base such as methylamine, ethylamine, ethanolamine, lysine, ornithic acid, and ethionylamine A salt or an ammonium salt of various amino acids and amino acid derivatives such as an acid.
且,本發明亦包含式(I)的化合物及其製藥學上可被許可的鹽之各種水合物或溶劑合物、及結晶多形之物質。又,本發明亦包含種種放射性或非放射性同位體所標識之化合物。 Further, the present invention also encompasses various hydrates or solvates of the compound of the formula (I) and pharmaceutically acceptable salts thereof, and a crystalline polymorph. Further, the invention also encompasses a variety of compounds identified by radioactive or non-radioactive isomers.
(製造法) (manufacturing method)
式(I)的化合物及其製藥學上可被許可的鹽為利用該基本骨架或依據取代基種類的特徵,使用種種公知合成法而可製造。此時,藉由官能基之種類,將該官能基在由原料至中間體的階段,取代為適當保護基(可容易轉化為該官能基之基)時,在製造技術上有時具有效果。作為如此官能基,例如為胺基、羥基、羧基等,作為這些保護基,例如可舉出Greene及Wuts著之「Protective Groups in Organic Synthesis(第3版、1999年)」所記載的)保護基等,僅配合這些反應條件下適宜選擇使用即可。如此方法中,導入該保護基進行反應後,視必要藉由除去保護基,可得到所望化合物。 The compound of the formula (I) and a pharmaceutically acceptable salt thereof can be produced by using various basic synthetic methods depending on the basic skeleton or depending on the kind of the substituent. In this case, when the functional group is substituted with a suitable protecting group (which can be easily converted into a group of the functional group) from the raw material to the intermediate by the kind of the functional group, it may have an effect in terms of manufacturing technology. Examples of such a functional group include an amine group, a hydroxyl group, and a carboxyl group. Examples of the protective group include a protective group described in "Protective Groups in Organic Synthesis (3rd edition, 1999)" by Greene and Wuts. Etc., it can be selected and used only in accordance with these reaction conditions. In such a method, after the protective group is introduced and reacted, the desired compound can be obtained by removing the protective group as necessary.
又,式(I)的化合物之前體藥物與上述保護基同樣 地,在原料至中間體的階段導入特定基,或使用所得之式(I)的化合物,進一步進行反應後可製造。反應一般使用酯化、醯胺化、脫水等斯業者所公知之方法而進行。 Further, the prodrug of the compound of the formula (I) is the same as the above protecting group The specific group is introduced at the stage of the raw material to the intermediate, or the obtained compound of the formula (I) is used, and further, the reaction can be carried out. The reaction is generally carried out by a method known to those skilled in the art of esterification, guanidation or dehydration.
以下說明式(I)的化合物之代表性製造法。各製法可參照該說明中提及的參考文獻而進行。且各發明的製造法並未限定於以下所示例子。 A representative production method of the compound of the formula (I) is explained below. Each method can be carried out with reference to the references mentioned in the description. Further, the manufacturing method of each invention is not limited to the examples shown below.
(第1製法) (the first method)
本發明化合物(I-1)可由化合物1a與化合物1b之光延反應而得。 The compound (I-1) of the present invention can be obtained by a reaction of the compound 1a with the compound 1b.
本反應中若使用化合物1a與化合物1b之當量或一方過剩量時,在對反應為惰性之溶劑中或無溶劑下,於膦試藥、偶氮二羧酸二乙基(DEAD)存在下,在由冷卻下至加熱迴流下,較佳為0℃至100℃中,一般進行0.1小時至5天之攪拌。作為其中所使用的溶劑例子,雖無特別限定,可舉出苯、甲苯、二甲苯等芳香族烴基類、二乙基醚、 四氫呋喃、二噁烷、二甲氧基乙烷等醚類等。作為膦試藥,雖無特別限定,可舉出三苯基膦或三丁基膦。取代DEAD使用1,1'-(偶氮二羰基)二哌啶時,可使反應順利地進行故有時較為有利。又角田試藥之氰伸甲基三丁基膦對於反應順利進行上有時為有利。 In the present reaction, when the equivalent amount or the excess amount of the compound 1a and the compound 1b is used, in the presence of a phosphine reagent or diethyl azodicarboxylate (DEAD) in a solvent inert to the reaction or in the absence of a solvent, The stirring is generally carried out for 0.1 hour to 5 days under cooling from heating to reflux, preferably from 0 ° C to 100 ° C. Examples of the solvent to be used therein are not particularly limited, and examples thereof include aromatic hydrocarbon groups such as benzene, toluene, and xylene, and diethyl ether. An ether such as tetrahydrofuran, dioxane or dimethoxyethane. The phosphine reagent is not particularly limited, and examples thereof include triphenylphosphine and tributylphosphine. When 1,1'-(azodicarbonyl)dipiperidine is used instead of DEAD, the reaction can be carried out smoothly, which is sometimes advantageous. It is sometimes advantageous for the cyanide methyltributylphosphine to be reacted smoothly.
上述方法以外,使用當量或一方過剩量的將R2A或R2B的-C1-6伸烷基-OH之羥基部分轉換為所定脫離基,例如轉換為鹵素等化合物,在鹼存在下,於對反應為惰性之溶劑中或無溶劑下,在冷卻下至加熱迴流下,較佳為0℃至100℃中,一般進行0.1小時至5天攪拌。作為其中所使用的溶劑的例子,雖無特別限定可舉出N,N-二甲基甲醯胺等。作為鹼可舉出碳酸鉀等無機鹼等。 In addition to the above method, an equivalent or one excess amount of a hydroxyl group of -C 1-6 alkyl-OH of R 2A or R 2B is converted into a predetermined leaving group, for example, converted into a compound such as a halogen, in the presence of a base, The solvent is inert to the reaction or in the absence of a solvent, and is preferably stirred at a temperature of from 0 ° C to 100 ° C under cooling to reflux at from 0.1 ° to 5 ° C. The example of the solvent to be used is not particularly limited, and examples thereof include N,N-dimethylformamide and the like. The base may, for example, be an inorganic base such as potassium carbonate.
(第2製法) (the second method)
本發明化合物(I-2)可藉由化合物1c與化合物1d之還原的胺基化反應而得。 The compound (I-2) of the present invention can be obtained by amination reaction of the compound 1c with the reduction of the compound 1d.
本反應為使用化合物1c與化合物1d之當量或一方過 剩量,將彼等混合物在還原劑存在下,於對反應為惰性之溶劑中,由-45℃至加熱迴流下,一般進行0.1小時至5天攪拌。作為於此所使用的溶劑例子,並無特別限定,可舉出甲醇、乙醇等醇類、二乙基醚、四氫呋喃、二噁烷、二甲氧基乙烷等醚類、及彼等混合物。作為還原劑可舉出氰氫化硼鈉、三乙醯氧基氫化硼鈉、氫化硼鈉等。在分子篩(molecular sieve)等脫水劑,或乙酸、鹽酸、鈦(IV)異丙氧化物錯體等酸存在下進行反應為佳。藉由反應,經化合物1c與化合物1d之縮合生成亞胺,可作為安定中間體而分離。此時,可藉由該亞胺中間體之還原反應而得到化合物(I-2)。又,取代在前述還原劑之處理,在甲醇、乙醇、乙酸乙酯等溶劑中、乙酸、鹽酸等酸之存在下或非存在下,可使用還原觸媒(例如鈀碳、雷尼鎳等)進行反應。此時,將反應在常壓至50氣壓的氫環境下,於冷卻下至加熱下進行為佳。 This reaction uses the equivalent or one of the compound 1c and the compound 1d. The remaining amount is stirred in the presence of a reducing agent in a solvent inert to the reaction from -45 ° C to reflux under heating, usually for 0.1 to 5 days. The solvent to be used herein is not particularly limited, and examples thereof include alcohols such as methanol and ethanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, and mixtures thereof. Examples of the reducing agent include sodium cyanoborohydride, sodium triethoxy hydride borohydride, and sodium borohydride. It is preferred to carry out the reaction in the presence of a dehydrating agent such as a molecular sieve or an acid such as acetic acid, hydrochloric acid or titanium (IV) isopropoxide. By reacting, the compound 1c is condensed with the compound 1d to form an imine, which can be isolated as a stable intermediate. At this time, the compound (I-2) can be obtained by a reduction reaction of the imine intermediate. Further, instead of the treatment with the reducing agent, a reducing catalyst (for example, palladium carbon, Raney nickel, etc.) may be used in a solvent such as methanol, ethanol or ethyl acetate, or in the presence or absence of an acid such as acetic acid or hydrochloric acid. Carry out the reaction. At this time, it is preferred to carry out the reaction under a hydrogen atmosphere at a normal pressure to 50 atmospheres under cooling to heating.
A. R. Katritzky及R. J. K. Taylor著、「Comprehensive Organic Functional Group Transformations II」、第2卷、Elsevier Pergamon、2005年 A. R. Katritzky and R. J. K. Taylor, "Comprehensive Organic Functional Group Transformations II", Volume 2, Elsevier Pergamon, 2005
日本化學會編「實驗化學講座(第5版)」14卷(2005年)(丸善) The Chemical Society of Japan, "Experimental Chemistry Lecture (5th Edition)", Volume 14 (2005) (Maruzen)
(第3製法) (the third method)
本發明化合物(I-3)可藉由化合物1e與化合物1f之Wittig反應,接著氫化反應而得。但B除-C≡C-以外。 The compound (I-3) of the present invention can be obtained by a Wittig reaction of the compound 1e with the compound 1f followed by hydrogenation. But B is other than -C≡C-.
首先,使用化合物1e與化合物1f之當量或一方過剩量,於對反應為惰性之溶劑中或無溶劑下,在鹼的存在下,由冷卻下至加熱迴流下,較佳為0℃至100℃中,一般進行0.1小時至5天攪拌。其中作為所使用的溶劑例子,並無特別限定,可舉出二乙基醚、四氫呋喃、二噁烷、二甲氧基乙烷等醚類等。又作為鹼,並無特別限定,但可舉出二氮雜雙環十一碳烯等有機鹼。 First, using an equivalent amount or a excess amount of the compound 1e and the compound 1f, in a solvent inert to the reaction or in the absence of a solvent, in the presence of a base, from cooling to heating under reflux, preferably from 0 ° C to 100 ° C In general, stirring is carried out for 0.1 hour to 5 days. The solvent to be used is not particularly limited, and examples thereof include ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane. Further, the base is not particularly limited, and examples thereof include an organic base such as diazabicycloundecene.
其次將所得之具有雙鍵的化合物在氫環境下,於對反應為惰性之溶劑中,金屬觸媒存在下,一般進行1小時~5天攪拌。該反應一般自冷卻下至加熱下,較佳為在室溫下進行。作為其中所使用的溶劑例子,並無特別限定,可舉出甲醇、乙醇、2-丙醇等醇類、二乙基醚、四氫呋喃、二噁烷、二甲氧基乙烷等醚類、水、乙酸乙酯、N,N-二甲基甲醯胺、二甲基亞碸及這些混合物。作為金屬觸媒可使用鈀碳、鈀黑、氫氧化鈀等鈀觸媒、鉑板、氧化鉑等鉑觸媒、還原鎳、雷尼鎳等鎳觸媒、肆三苯基膦氯銠等銠觸媒 、還原鐵等鐵觸媒等為佳。取代氫氣,可將對於具有雙鍵的化合物為當量至過剩量之甲酸或甲酸銨作為氫源使用。 Next, the obtained compound having a double bond is stirred in a hydrogen atmosphere in a solvent inert to the reaction in the presence of a metal catalyst for 1 hour to 5 days. The reaction is generally carried out from cooling to heating, preferably at room temperature. Examples of the solvent to be used therein are not particularly limited, and examples thereof include alcohols such as methanol, ethanol, and 2-propanol, and ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane, and water. Ethyl acetate, N,N-dimethylformamide, dimethylhydrazine and mixtures thereof. As the metal catalyst, a palladium catalyst such as palladium carbon, palladium black or palladium hydroxide, a platinum catalyst such as a platinum plate or platinum oxide, a nickel catalyst such as reduced nickel or Raney nickel, or a triphenylphosphine chloride or the like can be used. catalyst It is preferable to reduce iron or the like such as iron. Instead of hydrogen, an equivalent to an excess amount of formic acid or ammonium formate can be used as a hydrogen source for a compound having a double bond.
M. Hudlicky著、「Reductions in Organic Chemistry, 2nd ed(ACS Monograph: 188)」、ACS、1996年 M. Hudlicky, "Reductions in Organic Chemistry, 2nd ed (ACS Monograph: 188)", ACS, 1996
日本化學會編「實驗化學講座(第5版)」19卷(2005年)(丸善) The Chemical Society of Japan, "Experimental Chemistry Lecture (5th Edition)", Vol. 19 (2005) (Maruzen)
(第4製法) (the fourth method)
本發明化合物(I-4)可藉由化合物1g與化合物1h之偶合反應而得。 The compound (I-4) of the present invention can be obtained by a coupling reaction of the compound 1g with the compound 1h.
本反應為使用化合物1g與化合物1h之當量或一方過剩量,於對反應為惰性之溶劑中,在鹼及鈀觸媒的存在下,自室溫至加熱迴流下,一般進行0.1小時至5天攪拌。本反應在惰性氣體環境下進行為佳。作為其中所使用的溶 劑例子,並無特別限定,可舉出苯、甲苯、二甲苯等芳香族烴基類、二乙基醚、四氫呋喃、二噁烷、二甲氧基乙烷等醚類、二氯甲烷、1,2-二氯乙烷或氯仿等鹵化烴基類、甲醇、乙醇、2-丙醇、丁醇等醇類、N,N-二甲基甲醯胺、二甲基亞碸、及這些混合溶劑。作為鹼以Na2CO3、K2CO3、氫氧化鈉等無機鹼為佳。作為鈀觸媒,以肆(三苯基膦)鈀、二氯雙(三苯基膦)鈀、氯化鈀-1,1’-雙(二苯基膦)二茂鐵等為佳。又作為脫離基,可舉出鹵素、三氟甲烷磺酸酯基。 The reaction is carried out by using an equivalent amount or a excess amount of the compound 1g and the compound 1h, and stirring in a solvent inert to the reaction in the presence of a base and a palladium catalyst from room temperature to heating under reflux, generally for 0.1 to 5 days. . The reaction is preferably carried out under an inert gas atmosphere. The solvent to be used is not particularly limited, and examples thereof include an aromatic hydrocarbon group such as benzene, toluene or xylene, and an ether such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane. Halogenated hydrocarbon groups such as methyl chloride, 1,2-dichloroethane or chloroform; alcohols such as methanol, ethanol, 2-propanol and butanol, N,N-dimethylformamide, dimethyl alum, And these mixed solvents. As the base, an inorganic base such as Na 2 CO 3 , K 2 CO 3 or sodium hydroxide is preferred. As the palladium catalyst, palladium (triphenylphosphine) palladium, dichlorobis(triphenylphosphine)palladium, palladium chloride-1,1'-bis(diphenylphosphino)ferrocene or the like is preferred. Further, examples of the leaving group include a halogen and a trifluoromethanesulfonate group.
A. d. Meijere及F. Diederich編、「Metal-Catalyzed Cross-Coupling Reactions」、第1版、VCH Publishers Inc.、1997年 A. d. Edited by Meijere and F. Diederich, "Metal-Catalyzed Cross-Coupling Reactions", 1st edition, VCH Publishers Inc., 1997
日本化學會編「實驗化學講座(第5版)」13卷(2005年)(丸善) The Chemical Society of Japan, "Experimental Chemistry Lecture (5th Edition)", Vol. 13 (2005) (Maruzen)
(第5製法) (the fifth method)
本發明化合物(I-5)可藉由將化合物1i與經鹵化的化合物1j與化合物1k之偶合反應而得。 The compound (I-5) of the present invention can be obtained by a coupling reaction of the compound 1i with the halogenated compound 1j and the compound 1k.
(第1步驟) (Step 1)
本步驟為將化合物1i經鹵化得到化合物1j之步驟。 This step is a step of halogenating compound 1i to give compound 1j.
本步驟為使用化合物1i與所定鹵化劑之當量或一方過剩量,於對反應為惰性之溶劑中,自室溫至加熱迴流下,一般藉由0.1小時至5天的攪拌進行。作為於此所使用的溶劑例子,並無特別限定,可舉出乙腈等。作為鹵化劑可舉出N-溴琥珀醯亞胺、N-碘琥珀醯亞胺、碘等。 This step is carried out by using an equivalent amount or a excess amount of the compound 1i and the halogenating agent, and stirring in a solvent inert to the reaction from room temperature to heating under reflux, generally for 0.1 to 5 days. The solvent used herein is not particularly limited, and examples thereof include acetonitrile and the like. Examples of the halogenating agent include N-bromosuccinimide, N-iodosuccinimide, iodine, and the like.
(第2步驟) (Step 2)
本步驟為藉由化合物1j與化合物1k之偶合反應而得到本發明化合物(I-5)之步驟。 This step is a step of obtaining a compound (I-5) of the present invention by a coupling reaction of the compound 1j with the compound 1k.
反應條件與第4製法相同。 The reaction conditions were the same as in the fourth method.
式(I)的化合物中之R1、環A、環B及環E上的種種取代基為,將式(I)的化合物作為原料,藉由使用後述實施例記載的反應、斯業者為熟知的反應或這些變法,可容易地轉換為其他官能基。例如將O-烷基化、N-烷基化、氧化、還原、還原的烷基化、環化、水解、醯胺化、醯基化、脫保護等斯業者一般採用的步驟做任意組合而進行。 Among the compounds of the formula (I), various substituents on R 1 , ring A, ring B and ring E are known, and the compound of the formula (I) is used as a raw material, and is known by the use of the reaction described in the examples described later. The reaction or these modifications can be easily converted to other functional groups. For example, O-alkylation, N-alkylation, oxidation, reduction, reduction of alkylation, cyclization, hydrolysis, amide, thiolation, deprotection, etc. get on.
(原料化合物的製造) (Manufacture of raw material compounds)
上述製造法中之原料化合物,例如可使用下述方法、後述製造例所記載的方法、公知方法或這些變法而製造。 The raw material compound in the above production method can be produced, for example, by the following method, a method described in the production examples described below, a known method, or a modification thereof.
(原料合成1) (Material synthesis 1)
本製法各製造出第1製法之原料化合物1a中之R2A為-OH、X為CH之化合物、及第2製法之原料化合物1c中之X為CH之化合物2b之方法。 In the present process, each of the raw material compounds 1a of the first production method is a method in which R 2A is -OH, X is a compound of CH, and the raw material compound 1c of the second production method is a compound 2b wherein X is CH.
化合物2b可藉由化合物2a之環化而製造。 Compound 2b can be produced by cyclization of compound 2a.
本反應為使用化合物2a與例如N,N-二甲基甲醯胺二甲基縮醛及R1NH-NH2之當量或一方過剩量,於對反應為惰性之溶劑中,自室溫至加熱迴流下,一般藉由0.1小時至5天的攪拌而進行。作為於此所使用的溶劑之例子,並無特別限定,可舉出N,N-二甲基甲醯胺等。 The reaction is carried out by using the equivalent amount or one excess of the compound 2a and, for example, N,N-dimethylformamide dimethyl acetal and R 1 NH-NH 2 in a solvent inert to the reaction, from room temperature to heating. Under reflux, it is usually carried out by stirring for 0.1 to 5 days. The example of the solvent used herein is not particularly limited, and examples thereof include N,N-dimethylformamide and the like.
(原料合成2) (Material Synthesis 2)
本製法為製造第1製法之原料化合物1a中之R2A為-OH的化合物3d之方法。 This production method is a method for producing the compound 3d wherein R 2A is -OH in the starting material compound 1a of the first production method.
化合物3d可由將化合物3a的鹵素部分經硼化後,藉由所得之化合物3b與化合物3c之偶合反應而得。 The compound 3d can be obtained by subjecting the halogen moiety of the compound 3a to boronization, followed by coupling reaction of the obtained compound 3b with the compound 3c.
(第1步驟) (Step 1)
本步驟為將化合物3a經硼化後得到化合物3b之步驟。 This step is a step of subjecting compound 3a to boronization to obtain compound 3b.
使用化合物3a與所定硼試藥之當量或一方過剩量,於對反應為惰性之溶劑中,在所定鹼及鈀試藥之存在下,自室溫至加熱迴流下,一般藉由0.1小時至5天的攪拌而 進行。作為其中所使用的溶劑例子,並無特別限定可舉出二噁烷等。作為所定硼試藥之例子,可舉出聯硼酸頻那醇酯等。作為所定鹼,可舉出乙酸鉀等。作為鈀試藥之例子,可舉出1,1’-雙(二苯基膦)二茂鐵-鈀(II)二氯化物等。 Using the equivalent or one excess of the compound 3a and the predetermined boron reagent, in a solvent inert to the reaction, in the presence of the determined base and the palladium reagent, from room temperature to heating under reflux, generally from 0.1 to 5 days Stirring get on. The solvent used in the example is not particularly limited, and examples thereof include dioxane and the like. Examples of the predetermined boron reagent include boronic acid pinacol ester and the like. As a predetermined base, potassium acetate etc. are mentioned. Examples of the palladium reagent include 1,1'-bis(diphenylphosphino)ferrocene-palladium (II) dichloride.
(第2步驟) (Step 2)
本步驟為藉由化合物3b與化合物3c之偶合反應而得到化合物3d之步驟。 This step is a step of obtaining a compound 3d by a coupling reaction of the compound 3b and the compound 3c.
反應條件與第4製法相同。 The reaction conditions were the same as in the fourth method.
(原料合成3) (Material Synthesis 3)
本製法為各製造第1製法的原料化合物1a中之R2A為-C1-6伸烷基-OH之化合物4d、及第3製法的原料化合物1e之方法。 This production method is a method of producing the compound 4d wherein R 2A is -C 1-6 alkyl-OH in the raw material compound 1a of the first production method, and the raw material compound 1e of the third production method.
(第1步驟) (Step 1)
本步驟為將化合物4a經鹵化後得到化合物4b之步驟。 This step is a step of obtaining a compound 4b by halogenating the compound 4a.
反應條件與第5製法之第1步驟相同。 The reaction conditions are the same as in the first step of the fifth production method.
(第2步驟) (Step 2)
本步驟為藉由化合物4b與化合物1k之偶合反應而得到化合物4c之步驟。 This step is a step of obtaining a compound 4c by a coupling reaction of the compound 4b with the compound 1k.
反應條件與第4製法相同。 The reaction conditions were the same as in the fourth method.
(第3步驟) (Step 3)
本步驟為將化合物4c經還原得到化合物4d之步驟。 This step is a step of reducing compound 4c to give compound 4d.
使用化合物4c與所定還原劑的當量或一方過剩量,於對反應為惰性之溶劑中,自冰冷下至加熱迴流下,一般藉由0.1小時至5天的攪拌而進行。作為所定還原劑,可舉出氫化鋰鋁、氫化二異丁基鋁、氫化硼鋰、氫化硼鈉等。作為此所使用的溶劑例子,雖無特別限定,可舉出二乙基醚、四氫呋喃、二噁烷、二甲氧基乙烷等醚類等。 The equivalent amount or the excess amount of the compound 4c and the predetermined reducing agent is used, and the solvent which is inert to the reaction is usually stirred from 0.1 to 5 days from ice-cooling to heating under reflux. Examples of the predetermined reducing agent include lithium aluminum hydride, diisobutylaluminum hydride, lithium borohydride, and sodium borohydride. The solvent used herein is not particularly limited, and examples thereof include ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane.
(第4步驟) (Step 4)
本步驟為將化合物4d經氧化後得到化合物1e之步驟。 This step is a step of obtaining a compound 1e by oxidizing the compound 4d.
使用化合物4d與所定氧化劑之當量,或過剩量,於 對反應為惰性之溶劑中,自冰冷下至加熱迴流下,一般藉由0.1小時至5天的攪拌而進行。作為所定氧化劑,可舉出氧化錳等。作為此所使用的溶劑例子,雖無特別限定,可舉出二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳等鹵化烴基類等。 Using the equivalent of compound 4d and the given oxidant, or excess amount, The solvent which is inert to the reaction is usually carried out by stirring from 0.1 to 5 days from ice cooling to heating under reflux. As a predetermined oxidizing agent, manganese oxide etc. are mentioned. The solvent used herein is not particularly limited, and examples thereof include halogenated hydrocarbon groups such as dichloromethane, 1,2-dichloroethane, chloroform, and carbon tetrachloride.
(原料合成4) (Material Synthesis 4)
本製法為製造第一製法的原料化合物1b中n為1之化合物5c的方法。 The present process is a process for producing a compound 5c wherein n is 1 in the starting compound 1b of the first process.
反應條件與第4製法相同。 The reaction conditions were the same as in the fourth method.
(原料合成5) (Material synthesis 5)
本製法為製造第4製法的原料化合物1g中,L1為-C1-6伸烷基-O-或-O-C1-6伸烷基-之化合物6b的方法。 The present process is a process for producing a compound 6b wherein L 1 is -C 1-6 alkyl-O- or -OC 1-6 alkyl-alkyl group in 1 g of the starting material compound of the fourth process.
反應條件與第1製法相同。 The reaction conditions were the same as in the first method.
(原料合成6) (Material synthesis 6)
本製法為製造第5製法的原料化合物1i中L1為-C1-6伸烷基-O-或-O-C1-6伸烷基-、n為1之化合物7c的方法。 The present process is a process for producing a compound 7c in which the L 1 is -C 1-6 alkyl-O- or -OC 1-6 alkyl-, and n is 1 in the starting compound 1i of the fifth process.
反應條件與第1製法相同。 The reaction conditions were the same as in the first method.
式(I)的化合物係以游離化合物、其製藥學上可被許可的鹽、水合物、溶劑合物或結晶多形的物質方式被分離、被純化。式(I)的化合物之製藥學上可被許可的鹽可藉由常法之造鹽反應而製造。 The compound of the formula (I) is isolated and purified as a free compound, a pharmaceutically acceptable salt, hydrate, solvate or crystalline polymorph. The pharmaceutically acceptable salt of the compound of the formula (I) can be produced by a conventional salt-forming reaction.
分離、純化可使用萃取、分別結晶化、各種部分層析法等一般化學操作進行。 The separation and purification can be carried out by a general chemical operation such as extraction, separate crystallization, and various partial chromatography.
各種異構物可藉由選擇適當原料化合物而製造,或利用異構物間之物理化學性質的差異進行分離。例如光學異構物係藉由外消旋體的一般光學分割法(例如使用可導出與光學活性鹼或酸之非對映異構物鹽的分別結晶化,或異構物分離管柱等層析法等)得到,又亦可由適當光學活性原料化合物所製造。 The various isomers can be produced by selecting an appropriate starting compound or by utilizing the difference in physicochemical properties between the isomers. For example, an optical isomer is a general optical splitting method by a racemic body (for example, a separate crystallisation of a diastereomeric salt which can be derived from an optically active base or an acid, or a layer of an isomer separation column) The method of analysis, etc.) can also be produced from a suitable optically active starting material compound.
式(I)的化合物之藥理活性可由以下試驗得到確認。 The pharmacological activity of the compound of formula (I) can be confirmed by the following experiment.
1. PDE10A酵素阻礙活性 1. PDE10A enzyme blocking activity
欲測定被檢藥之PDE10A酵素阻礙活性,選殖人體PDE10A基因,以棒狀病毒表現於Sf9細胞之方式取得酵素。 To determine the PDE10A enzyme blocking activity of the test drug, the human PDE10A gene was selected, and the enzyme was obtained in the form of a baculovirus expressed in Sf9 cells.
測定係使用cAMP測定套組(SCETI公司、cAMP femto 2 kit)及萃取、上述人體PDE10A酵素(參考文獻:Eur.J.Biochem.266,1118-1127(1999))。測定方法依據添付的說明書。以下做概略說明。 The measurement was carried out using a cAMP assay kit (SCETI, cAMP femto 2 kit) and extraction, the above human PDE10A enzyme (Reference: Eur. J. Biochem. 266, 1118-1127 (1999)). The method of measurement is based on the instructions added. The following is a brief description.
將PDE10A酵素及試驗化合物以反應緩衝液(40mM Tris-HCl、5mM MgCl2、pH 7.5)中在384孔盤中混合(total 8μL),在室溫下進行30分鐘恆溫培養。混合基質之cAMP(最終濃度100nM、4μL/well),進一步在室溫下進行1小時恆溫培養。添加cAMP femto 2 kit試藥之cAMP-d2液及anti cAMP-cryptate液各4μL,使反應停止。進行1小時以上之室溫恆溫培養後,使用螢光測定機(PerkinElmer公司製,多重標識‧盤式分析儀:EnVision)進行測定。將酵素未添加時的反應率作為0%,酵素添加而試驗化合物未添加時的反應率作為100%,依據logistic法算出化合物之IC50值(nM)。 The PDE10A enzyme and the test compound were mixed in a reaction buffer (40 mM Tris-HCl, 5 mM MgCl 2 , pH 7.5) in a 384-well plate (total 8 μL), and cultured at room temperature for 30 minutes under constant temperature. The cAMP of the mixed medium (final concentration: 100 nM, 4 μL/well) was further cultured at room temperature for 1 hour at a constant temperature. 4 μL of cAMP-d2 solution and anti cAMP-cryptate solution of cAMP femto 2 kit reagent were added to stop the reaction. After the incubation was carried out at room temperature for 1 hour or more, the measurement was carried out using a fluorescence measuring machine (manufactured by PerkinElmer Co., Ltd., multi-label ‧ disc analyzer: EnVision). The reaction rate when the enzyme was not added was 0%, the reaction rate when the enzyme was added and the test compound was not added was taken as 100%, and the IC 50 value (nM) of the compound was calculated according to the logistic method.
表1表示幾項式(I)的化合物之本試驗結果。表中Ex表示實施例號碼。 Table 1 shows the results of this test for several compounds of the formula (I). Ex in the table indicates the embodiment number.
2.小老鼠‧苯環利定(Phencyclidine)誘發過活動抑制試驗 2. Little mouse ‧ Phencyclidine induced activity inhibition test
實驗中,使用雄性ICR小老鼠(日本SLC股份有限公司)(5週齡,約30g)。將試驗化合物懸浮於0.5%甲基纖維素溶液中,進行10mL/kg之試驗化合物或溶劑的經口投與。投與後快速將動物放入運動量測定裝置(室町機 械股份有限公司製之自發運動量測定系統‧SuperMex)中,開始測定。過活動為測定開始1小時後,對於各動物以苯環利定(Phencyclidine)(2.5mg/10mL/kg)進行皮下投與後誘發,對於該過活動的化合物之抑制作用以1小時測定並評估藥效。將溶劑-溶劑投與群之運動量作為0%,將溶劑-苯環利定(Phencyclidine)投與群之運動量作為100%,藉由直線回歸法算出試驗化合物之ED50值。本發明化合物中作為代表性化合物的試驗結果如以下表所示。且本試驗結果中化合物係以30mg/kg之抑制效果(%)作為其結果。 In the experiment, a male ICR mouse (Japan SLC Co., Ltd.) (5 weeks old, about 30 g) was used. The test compound was suspended in a 0.5% methylcellulose solution, and 10 mL/kg of the test compound or solvent was orally administered. After the administration, the animals were placed in an exercise amount measuring device (spontaneous exercise amount measuring system ‧ SuperMex manufactured by Muromachi Machinery Co., Ltd.), and measurement was started. The activity was measured 1 hour after the start of the measurement, and each animal was induced by subcutaneous administration with Phencyclidine (2.5 mg/10 mL/kg), and the inhibitory effect on the active compound was measured and evaluated in 1 hour. Drug effect. The amount of exercise of the solvent-solvent administration group was taken as 0%, and the amount of exercise of the solvent-Phencyclidine administration group was taken as 100%, and the ED 50 value of the test compound was calculated by linear regression. The test results as representative compounds in the compounds of the present invention are shown in the following table. Further, the results of the test were based on the inhibitory effect (%) of 30 mg/kg.
對於上述小老鼠‧苯環利定(Phencvclidine)誘發過活動抑制試驗,式(I)之化合物的幾項化合物可抑制苯 環利定(Phencyclidine)誘發之過活動。 For the above-mentioned small mouse ‧ phencycline induced (Phencvclidine) induced activity inhibition test, several compounds of the compound of formula (I) can inhibit benzene Phencyclidine induced activity.
上述試驗的結果,式(I)的化合物被確認有PDE10A阻礙活性,可使用於精神分裂症之預防及/或治療上。 As a result of the above test, the compound of the formula (I) was confirmed to have PDE10A inhibitory activity and can be used for the prevention and/or treatment of schizophrenia.
對於CytochromeP450(CYP)3A4酵素阻礙試驗,式(I)的化合物或其鹽之幾項,於作為醫藥品可使用之程度下,確認其為CytochromeP450的代謝酵素之阻礙能較小的化合物。 In the Cytochrome P450 (CYP) 3A4 enzyme inhibition test, a compound of the formula (I) or a salt thereof was used as a pharmaceutical product, and it was confirmed that it was a compound having a small inhibitory energy of the metabolic enzyme of Cytochrome P450.
又,對於CytochromeP450(CYP)1A2、2C9、2C19、2D6酵素阻礙試驗,式(I)的化合物或其鹽之幾項,於作為醫藥品可使用之程度下,確認其為CytochromeP450的代謝酵素之阻礙能較小的化合物。其結果(IC50(μM))如以下表所示。 Further, for the Cytochrome P450 (CYP) 1A2, 2C9, 2C19, and 2D6 enzyme inhibition tests, a compound of the formula (I) or a salt thereof was confirmed to be a hindrance to the metabolic enzyme of Cytochrome P450 to the extent that it can be used as a pharmaceutical product. Can be smaller compounds. The results (IC 50 (μM)) are shown in the following table.
含有式(I)之化合物或其鹽的1種或2種以上作為有效成分之醫藥組成物,可使用該領域中一般使用的賦形劑,即藥劑用賦形劑或藥劑用載體等,使用一般方法調製出。 The pharmaceutical composition containing one or two or more kinds of the compound of the formula (I) or a salt thereof as an active ingredient can be used by using an excipient which is generally used in the field, that is, a pharmaceutical excipient or a pharmaceutical carrier. The general method is modulated.
投與為以錠劑、丸劑、膠囊劑、顆粒劑、散劑、液劑等藉由經口投與,或關節內、靜脈內、肌肉內等注射劑、塞劑、點眼劑、眼軟膏、經皮用液劑、軟膏劑、經皮用貼付劑、經黏膜液劑、經黏膜貼劑、吸入劑等非經口投與中 任一形態皆可。 The administration is by oral administration of a tablet, a pill, a capsule, a granule, a powder, a liquid, or the like, or an intra-articular, intravenous, intramuscular injection, a suppository, an eye drop, an ophthalmic ointment, a Liquid preparation for ointment, ointment, percutaneous patch, transmucosal solution, transmucosal patch, inhalant, etc. Any form is acceptable.
作為使用於經口投與之固體組成物,使用錠劑、散劑、顆粒劑等。對於如此固體組成物,將1種或2種以上之有效成分與至少1種惰性賦形劑,例如與乳糖、甘露醇、葡萄糖、羥基丙基纖維素、微結晶纖維素、澱粉、聚乙烯基吡咯烷酮、及/或偏矽酸鋁酸鎂等混合。組成物依據常法,可含有惰性添加劑,例如含有如硬脂酸鎂之滑澤劑或羧基甲基澱粉鈉等崩壞劑、安定化劑、溶解補助劑。錠劑或丸劑視必要可藉由糖衣或胃溶性或腸溶性物質之薄膜包膜。 As a solid composition for oral administration, a tablet, a powder, a granule, or the like is used. For such a solid composition, one or more active ingredients and at least one inert excipient, for example, with lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinyl Pyrrolidone, and/or magnesium metasilicate aluminate are mixed. The composition may contain an inert additive according to a usual method, for example, a slip agent such as a magnesium stearate or a sodium carboxymethyl starch, a stabilizer, a dissolution aid, and a dissolution aid. Tablets or pills may optionally be coated with a film of sugar-coated or gastric-soluble or enteric material.
使用於經口投與之液體組成物,含有藥劑上被許可的乳濁劑、溶液劑、懸浮劑、糖漿劑或酏劑等,含有一般使用的惰性稀釋劑,例如純化水或乙醇。該液體組成物可含有除惰性稀釋劑以外之如可溶化劑、濕潤劑、懸浮劑的補助劑、甜味劑、風味劑、芳香劑、防腐劑。 The liquid composition for oral administration contains a pharmaceutically acceptable emulsion, a solution, a suspension, a syrup or an elixir, and the like, and contains an inert diluent which is generally used, such as purified water or ethanol. The liquid composition may contain, in addition to an inert diluent, a solubilizing agent, a wetting agent, a suspending agent, a sweetener, a flavoring agent, a flavoring agent, and a preservative.
欲使用於非經口投與之注射劑含有無菌水性或非水性的溶劑、懸浮劑或乳濁劑。作為水性溶劑,例如含有注射用蒸餾水或生理食鹽液。作為非水性之溶劑,例如有如丙二醇、聚乙二醇或橄欖油之植物油、如乙醇之醇類,或Polysorbate80(局方名)等。如此組成物可進一步含有等張化劑、防腐劑、濕潤劑、乳化劑、分散劑、安定化劑,或溶解補助劑。這些可藉由例如通過細菌保留濾器之過濾、殺菌劑之配合,或照射而使其無菌化。又,這些亦可製造無菌固體組成物,於使用前溶解或懸浮於無菌水或無菌 之注射用溶劑後使用。 The injection to be used for parenteral administration contains a sterile aqueous or nonaqueous solvent, suspending agent or opacifying agent. The aqueous solvent contains, for example, distilled water for injection or physiological saline. As the nonaqueous solvent, for example, a vegetable oil such as propylene glycol, polyethylene glycol or olive oil, an alcohol such as ethanol, or Polysorbate 80 (the name of the party) may be mentioned. Such a composition may further contain an isotonic agent, a preservative, a wetting agent, an emulsifier, a dispersing agent, a stabilizer, or a dissolution aid. These can be sterilized by, for example, filtration through a bacteria-retaining filter, mixing of a bactericide, or irradiation. Also, these can also be used to make sterile solid compositions which are dissolved or suspended in sterile water or sterile prior to use. It is used after the solvent for injection.
作為外用劑,包含軟膏劑、硬膏劑、乳霜劑、果凍劑、貼劑、噴霧劑、乳液劑、點眼劑、眼軟膏等。含有一般使用的軟膏基劑、乳液基劑、水性或非水性液劑、懸浮劑、乳劑等。例如,作為軟膏或乳液基劑,可舉出聚乙二醇、丙二醇、白色凡士林、蜜蠟、聚環氧乙烯硬化蓖蔴油、單硬脂酸甘油、硬脂醇、十六醇、聚桂醇(Lauromacrogol)、山梨糖醇半油酸脂等。 The external preparation includes an ointment, a plaster, a cream, a jelly, a patch, a spray, an emulsion, an eye drop, an eye ointment, and the like. Contains commonly used ointment bases, emulsion bases, aqueous or non-aqueous liquids, suspensions, emulsions, and the like. For example, as an ointment or emulsion base, polyethylene glycol, propylene glycol, white petrolatum, beeswax, polyepoxy hardened castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, polyglycerol may be mentioned. (Lauromacrogol), sorbitol hemioleate, and the like.
吸入劑或經鼻劑等經黏膜劑使用固體、液體或半固體狀者,可依據過去公知方法製造。例如,可適宜地添加公知賦形劑或進一步添加pH調整劑、防腐劑、界面活性劑、滑澤劑、安定劑或增黏劑等。投與可使用適當吸入或吹送之裝置。例如使用計量投與吸入裝置等公知裝置或噴霧器,作為將化合物單獨或經處方的混合物之粉末,或與醫藥上可被許可的載體組合後作為溶液或懸浮液進行投與。乾燥粉末吸入器等可為單次或多數次之投與用者,亦可利用乾燥粉末或含有粉末之膠囊。或亦可使用適當驅出劑,例如氯氟烷烴、氫氟烷烴或二氧化碳等較佳氣體之加壓氣容膠噴霧等形態。 A solid, liquid or semi-solid form of a transmucosal agent such as an inhalant or a nasal spray can be produced according to a conventionally known method. For example, a known excipient or a pH adjusting agent, a preservative, a surfactant, a slip agent, a stabilizer or a tackifier may be added as appropriate. A device that can be properly inhaled or blown can be used for administration. For example, a known device or a nebulizer such as a metered administration inhalation device is used as a powder or a mixture of a prescribed compound, or a pharmaceutically acceptable carrier, and then administered as a solution or suspension. A dry powder inhaler or the like may be administered to a single or a plurality of times, and a dry powder or a capsule containing a powder may also be used. Alternatively, a suitable expelling agent such as a pressurized gas-capacitor spray of a preferred gas such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide may be used.
一般進行經口投與時,1天投與量以體重為準下約0.001~100 mg/kg,較佳為0.1~30 mg/kg,更佳為0.1~10 mg/kg為適當,此可經1次或分為2次~4次進行投與。進行靜脈內投與時,1天的投與量以體重為準下約0.0001~10 mg/kg為適當,分為1天1次~複數次進行投 與。又,作為經黏膜劑,以體重為準下,約0.001~100 mg/kg分為1天1次~複數次進行投與。投與量可考慮到症狀狀、年齡、性別等配合各別情況下做適宜決定。 Generally, when administered orally, the dosage for one day is about 0.001 to 100 mg/kg, preferably 0.1 to 30 mg/kg, more preferably 0.1 to 10 mg/kg, depending on the body weight. It is administered once or twice to 4 times. For intravenous administration, the daily dose is about 0.0001 to 10 mg/kg, which is appropriate for the body weight, and is divided into 1 day to several times. versus. Further, as a transmucosal agent, about 0.001 to 100 mg/kg is divided into one to several times and administered in a plurality of times. The amount of administration can be determined by taking into account the symptoms, age, gender, etc., in accordance with the individual circumstances.
雖依據投與途徑、劑形、投與部位、賦形劑或添加劑種類有所不同,但本發明的醫藥組成物中含有0.01~100重量%,作為某態樣時含有0.01~50重量%的有效成分之1種或此以上的式(I)之化合物或其鹽。 Although it is different depending on the administration route, the dosage form, the administration site, the excipient or the type of the additive, the pharmaceutical composition of the present invention contains 0.01 to 100% by weight, and as a certain aspect, it contains 0.01 to 50% by weight. One or more of the active ingredients or a salt of the compound of the formula (I).
式(I)的化合物可與前述式(I)的化合物顯示有效性之疾病的種種治療或預防劑並用。該並用可同時投與,或各別連續,或以所望時間間隔進行投與亦可。同時投與製劑可為配合劑或各別製劑化。 The compound of the formula (I) can be used in combination with various therapeutic or prophylactic agents for the disease of the compound of the above formula (I) which exhibits effectiveness. The combined use may be administered simultaneously, or may be continuous, or may be administered at desired intervals. Simultaneous administration of the preparation may be a compounding agent or a separate formulation.
以下依據實施例更詳細說明式(I)的化合物及其原料化合物的製造法。且本發明並未限定於下述實施例所記載的化合物。又,原料化合物之製法以製造例方式表示。又,式(I)之化合物的製造法並非僅限定於以下所示具體實施例之製造法,式(I)的化合物可由這些製造法之組合,或斯業者熟知的方法製造。 Hereinafter, the production method of the compound of the formula (I) and a raw material compound thereof will be explained in more detail based on the examples. Further, the present invention is not limited to the compounds described in the following examples. Further, the production method of the raw material compound is represented by a production example. Further, the production method of the compound of the formula (I) is not limited to the production method of the specific examples shown below, and the compound of the formula (I) can be produced by a combination of these production methods or a method well known to those skilled in the art.
又,製造例、實施例、及後述表中可使用以下簡稱符號。 Further, the following abbreviations may be used in the production examples, the examples, and the tables to be described later.
PEx:製造例號碼、Ex:實施例號碼、Syn:以同樣方法製造之實施例號碼、PSyn:以同樣方法製造之製造例號 碼、Str:結構式、Data:物理化學數據、ESI+:質量分析中之m/z值(離子化法ESI,若無特別狀況(M+H)+)、ESI-:m/z值(離子化法ESI,若無特別狀況表示(M-H)-)、EI+:質量分析中之m/z值(離子化法EI,若無特別狀況表示(M)+)、CI+:質量分析中之m/z值(化學離子化法CI,若無特別狀況表示(M)+)、NMR1:表示二甲基亞碸-d6中之1H NMR中的δ(ppm)、製造例及實施例中之〔M〕:〔mol/L〕,WSC表示1-乙基-3-(3-二甲基胺基丙基)碳二亞胺鹽酸鹽,tBu表示tert-丁基,TIPS表示三異丙基矽,TBS表示tert-丁基二甲基矽。 PEx: manufacturing example number, Ex: example number, Syn: example number manufactured by the same method, PSyn: manufacturing example number manufactured by the same method, Str: structural formula, Data: physicochemical data, ESI+: quality analysis m/z value (ionization method ESI, if no special condition (M+H) + ), ESI-:m/z value (ionization method ESI, if no special condition indicates (MH) - ), EI+: mass The m/z value in the analysis (ionization method EI, if there is no special condition (M)+), CI+: m/z value in mass analysis (chemical ionization method CI, if there is no special condition (M)+ NMR1: δ (ppm) in 1 H NMR in dimethyl sulfonium-d 6 , [M]: [mol/L] in the production example and the examples, and WSC represents 1-ethyl-3 -(3-Dimethylaminopropyl)carbodiimide hydrochloride, tBu represents tert-butyl, TIPS represents triisopropylsulfonium, and TBS represents tert-butyldimethylhydrazine.
又,實施例表中之Syn部分有時記載PEx號碼,該實施例化合物表示與PEx號碼之化合物的同樣方法製造(例如,Ex.131表示與PEx.60之同樣方法製造)。 Further, the PEx number may be described in the Syn portion of the examples, and the compound of this example is produced by the same method as the compound of the PEx number (for example, Ex. 131 indicates the same method as that of PEx. 60).
又,結構式中之HCl表示鹽酸鹽,Oxa表示草酸鹽,Suc表示琥珀酸鹽,TFA表示三氟乙酸鹽,Fum表示富馬酸鹽,Pho表示磷酸鹽,Tar表示L-(+)-酒石酸鹽,Mal表示L-(-)-蘋果酸鹽,HCl的前數字表示莫耳比。例如2HCl表示二鹽酸鹽,0.5Oxa及0.5Suc各表示半草酸鹽、半琥珀酸鹽,1.5Pho表示倍半磷酸鹽。 Further, HCl in the formula represents a hydrochloride, Oxa represents an oxalate, Suc represents a succinate, TFA represents a trifluoroacetate, Fum represents a fumarate, Pho represents a phosphate, and Tar represents L-(+). - Tartrate, Mal stands for L-(-)-malate, and the former number of HCl indicates Morabi. For example, 2HCl means dihydrochloride, 0.5Oxa and 0.5Suc each represent hemi-oxalate, hemisuccinate, and 1.5Pho means sesquiphosphate.
又,結構式中雙鍵部分交差之化合物表示順體與反體之混合物。 Further, the compound in which the double bond partially intersects in the structural formula represents a mixture of an cis and a trans.
且依化合物,例如有時不進行成為鹽酸鹽之步驟,僅以自由體合成法作成最終體的化合物(例如Ex.201等)。 Further, depending on the compound, for example, a compound which is a final form by a free-body synthesis method (for example, Ex. 201 or the like) may be omitted.
製造例1 Manufacturing example 1
於4-吡啶基乙腈鹽酸鹽(2.01g)、四氫呋喃(30mL)與乙醇(30mL)之混合物,在攪拌下加入1M氫氧化鈉水溶液,過濾反應液,將濾液進行減壓濃縮。於殘渣中加入N,N-二甲基甲醯胺二甲基縮醛的N,N-二甲基甲醯胺(10mL)溶液,在80℃進行1小時攪拌後,將反應液減壓濃縮。於殘渣加入甲醇(20mL)、乙酸(780mg)、甲基聯胺(718mg),在60℃進行12小時攪拌。將反應液濃縮後,將殘渣以矽膠管柱層析法(氯仿/甲醇)進行純化後得到1-甲基-4-(吡啶-4-基)-1H-吡唑-3-胺(400mg)。 A mixture of 4-pyridylacetonitrile hydrochloride (2.01 g), tetrahydrofuran (30 mL) and ethanol (30 mL) was evaporated. A solution of N,N-dimethylformamide dimethyl acetal in N,N-dimethylformamide (10 mL) was added to the residue, and the mixture was stirred at 80 ° C for 1 hour, and then the mixture was concentrated under reduced pressure. . Methanol (20 mL), acetic acid (780 mg), and methyl hydrazine (718 mg) were added to the residue, and the mixture was stirred at 60 ° C for 12 hours. After concentrating the reaction mixture, the residue was purified by silica gel column chromatography (chloroform/methanol) to give 1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-amine (400 mg) .
製造例2 Manufacturing Example 2
氬氣流下,於2-氯喹啉(3.0g)的N,N-二甲基甲醯胺(30mL)溶液加入高炔丙醇(1.54g)、三乙基胺(5.1mL)、碘化銅(I)(173mg)、及雙三苯基膦鈀二氯化物(257mg)並在室溫下進行5小時攪拌。將反應液以乙酸乙酯稀釋後,以飽和碳酸氫鈉水溶液洗淨。由水層再次以乙酸乙酯萃取,將合併的有機層以無水硫酸鎂乾燥後,經減壓濃縮後將殘渣以矽膠管柱層析法(乙酸乙酯/氯仿)進行純化後得到4-(喹啉-2-基)丁-3-炔-1-醇(4.2g)。 Add high propargyl alcohol (1.54g), triethylamine (5.1mL), copper iodide in a solution of 2-chloroquinoline (3.0g) in N,N-dimethylformamide (30mL) under argon. (I) (173 mg) and bistriphenylphosphine palladium dichloride (257 mg) were stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen sulfate. The aqueous layer was extracted again with ethyl acetate. EtOAc (EtOAc m.). Quinoline-2-yl)but-3-yn-1-ol (4.2 g).
製造例3 Manufacturing Example 3
氬氣流下,冰冷下於4-碘-1H-吡唑-3-羧酸甲基(980mg)的四氫呋喃(20mL)混合物中加入55%氫化鈉(203mg),進行20分鐘攪拌。加入碘化甲基(830mg),於室溫下進行14小時攪拌。冰冷下加入飽和碳酸氫鈉水溶液及飽和食鹽水,以乙酸乙酯進行萃取。將有機層以無水硫酸鎂進行乾燥後減壓濃縮。將殘渣以矽膠管柱層析法(乙酸乙酯/氯仿)進行純化後得到4-碘-1-甲基-1H-吡唑-3-羧酸甲基(915mg)。 Under a stream of argon, 55% sodium hydride (203 mg) was added to a mixture of 4-iodo-1H-pyrazole-3-carboxylic acid methyl (980 mg) in tetrahydrofuran (20 mL). Methyl iodide (830 mg) was added, and the mixture was stirred at room temperature for 14 hours. Saturated aqueous sodium hydrogencarbonate solution and saturated brine were added under ice-cooling, and ethyl acetate was evaporated. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate / chloroform) to afford 4-iodo-1-methyl-1H-pyrazole-3-carboxylic acid methyl (915 mg).
製造例4 Manufacturing Example 4
於4-(喹啉-2-基)丁-3-炔-1-醇(3.65g)的乙醇(36mL)溶解中加入10%鈀-碳(788mg),氫氣流下在常壓下進行22小時攪拌。矽藻土過濾後,濃縮濾液。將殘渣以矽膠管柱層析法(乙酸乙酯/氯仿)進行純化後得到4-(喹啉-2-基)丁烷-1-醇(2.90g)。 To a solution of 4-(quinolin-2-yl)but-3-yn-1-ol (3.65 g) in ethanol (36 mL) was added 10% palladium-carbon (788 mg), and under a hydrogen atmosphere for 22 hours under normal pressure. Stir. After filtering the diatomaceous earth, the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / chloroform) to afford 4-(quinolin-2-yl)butane-1-ol (2.90 g).
製造例5 Manufacturing Example 5
於1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-羧酸乙基(257mg)、乙醇(2.6mL)、及四氫呋喃(1.3mL)的混合物中加入1M氫氧化鈉水溶液(1.3mL),於70℃進行11小時攪拌。將反應液放冷後,以1M鹽酸中和。過濾取出所生成的沈澱,減壓乾燥後得到1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-羧酸(137mg)。 To 1-methyl-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazole-4-carboxylic acid ethyl (257 mg), ethanol (2.6 mL), A 1 M aqueous sodium hydroxide solution (1.3 mL) was added to a mixture of tetrahydrofuran (1.3 mL), and stirred at 70 ° C for 11 hours. After the reaction solution was allowed to cool, it was neutralized with 1 M hydrochloric acid. The resulting precipitate was filtered off and dried under reduced pressure to give 1-methyl-3-{[4-(quinolin-2-yl)benzyloxy}-1H-pyrazole-4-carboxylic acid (137 mg) ).
製造例6 Manufacturing Example 6
於4-{3-〔(4-溴苯甲基)氧基〕-1-甲基-1H-吡唑-4-基}吡啶(292 mg)、聯硼酸頻那醇酯(259 mg)、乙酸鉀(250 mg)、二噁烷(3 mL)的混合物中加入1,1'-雙(二苯基膦)二茂鐵-鈀(II)二氯化物-二氯甲烷錯體(69 mg),氬環境下在100℃進行3小時攪拌。放冷後以矽藻土過濾,將濾液經減壓濃縮。將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化後得到4-(1-甲基-3-{〔4-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)苯甲基〕氧基}-1H-吡唑-4-基)吡啶(135 mg)。 4-{3-[(4-Bromobenzyl)oxy]-1-methyl-1H-pyrazol-4-yl}pyridine (292 mg), boronic acid pinacol ester (259 mg), Add 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (69 mg) to a mixture of potassium acetate (250 mg) and dioxane (3 mL) The mixture was stirred at 100 ° C for 3 hours under an argon atmosphere. After cooling, it was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform) to give 4-(1-methyl-3-{[4-(4,4,5,5-tetramethyl-1,3,2) -Dioxaborolan-2-yl)benzyloxy]-1H-pyrazol-4-yl)pyridine (135 mg).
製造例7 Manufacturing Example 7
氬氣流下,於氫化鋁鋰(104mg)的四氫呋喃(10mL)混合物下,冰冷下滴入2-氟-4-(喹啉-2-基)安息香酸甲酯(515mg)的四氫呋喃(10mL)混合物,同溫下進行2小時攪拌。同溫下徐徐少量地滴入28%氨水使其至不再發砲,加入甲醇及氯仿(1:9)之混合溶劑(100mL),在室溫下進行2小時攪拌。加入無水硫酸鎂及矽藻土後,將不溶物經矽藻土過濾後,將濾液減壓濃縮。將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化後得到〔2-氟-4-(喹啉-2-基)苯基〕甲醇(460mg)。 A mixture of tetrafluorofuran (10 mL) of methyl 2-fluoro-4-(quinolin-2-yl)benzoate (515 mg) was added dropwise to a mixture of lithium aluminum hydride (104 mg) in tetrahydrofuran (10 mL). Stir at 2 hours with the same temperature. At the same temperature, a small amount of 28% ammonia water was slowly added dropwise so as not to be shot, and a mixed solvent of methanol and chloroform (1:9) (100 mL) was added thereto, and the mixture was stirred at room temperature for 2 hours. After adding anhydrous magnesium sulfate and diatomaceous earth, the insoluble matter was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform) to afford [2-fluoro-4-(quinolin-2-yl)phenyl]methanol (460 mg).
製造例8 Manufacturing Example 8
使4-(溴乙醯基)安息香酸乙基(1.11 g)、2-胺基吡啶(385 mg)的乙醇(10 mL)混合物進行1小時加熱迴流。放冷後將反應液減壓濃縮,於殘渣加入飽和碳酸氫鈉水溶液並攪拌。過濾取出所產生的沈澱,以水洗淨後,將所得之固體以矽膠管柱層析法(乙酸乙酯/己烷)進行純化,得到4-(咪唑並〔1,2-a〕吡啶-2-基)安息香酸乙基(1.09 g)。 A mixture of 4-(bromoethenyl)benzoic acid ethyl (1.11 g) and 2-aminopyridine (385 mg) in ethanol (10 mL) was evaporated. After allowing to cool, the reaction mixture was concentrated under reduced pressure. The resulting precipitate was taken by filtration, washed with water, and then the obtained solid was purified by silica gel column chromatography (ethyl acetate/hexane) to give 4-(imidazo[1,2-a]pyridine- 2-based) benzoic acid ethyl (1.09 g).
製造例9 Manufacturing Example 9
於4-(吡啶-4-基)-1H-吡唑-3-醇(7.84g)的吡啶(78mL)混合物中加入乙酸酐(4.8mL),在100℃進行2小時攪拌。將反應液經減壓濃縮,於殘渣加入水,過濾取出所生成的沈澱。將固體以己烷洗淨,減壓乾燥後得到1-〔3-羥基-4-(吡啶-4-基)-1H-吡唑-1-基〕乙酮(10g)。 Acetic anhydride (4.8 mL) was added to a mixture of 4-(pyridin-4-yl)-1H-pyrazol-3-ol (7.84 g) in pyridine (78 mL), and stirred at 100 ° C for 2 hours. The reaction liquid was concentrated under reduced pressure, water was added to the residue, and the resulting precipitate was filtered. The solid was washed with hexane and dried under reduced pressure to give 1-[3-hydroxy-4-(pyridin-4-yl)-1H-pyrazol-1-yl]ethanone (10 g).
製造例10 Manufacturing Example 10
於4-吡啶基乙酸乙酯(25g)的N,N-二甲基甲醯胺(100mL)溶液中加入N,N-二甲基甲醯胺二甲基縮醛(50mL),在80℃進行2小時攪拌。將反應液放冷後減壓濃縮。冰冷下加入乙醇(250mL)、甲基聯胺(16mL)、及乙酸(60mL),在室溫下進行16小時攪拌。將反應液減壓濃縮後,將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化。將粗純化物以乙酸乙酯及己烷的混合溶劑洗淨後得到1-甲基-4-(吡啶-4-基)-1H-吡唑-3-醇(15.3g)。 Add N,N-dimethylformamide dimethyl acetal (50 mL) to a solution of ethyl 4-pyridylacetate (25 g) in N,N-dimethylformamide (100 mL) at 80 ° C Stir for 2 hours. The reaction solution was allowed to cool and concentrated under reduced pressure. Ethanol (250 mL), methyl hydrazine (16 mL), and acetic acid (60 mL) were added under ice cooling, and stirred at room temperature for 16 hours. After the reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (methanol / chloroform). The crude product was washed with a mixed solvent of ethyl acetate and hexane to give 1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-ol (15.3 g).
製造例11 Manufacturing Example 11
冰冷下於5-(喹啉-2-基)噻吩-2-甲醛(630mg)的乙醇(19mL)混合物中加入氫化硼鈉(100mg),在同溫下進行2小時攪拌。加入水及飽和食鹽水,以乙酸乙酯進行萃取。將有機層以無水硫酸鎂乾燥後減壓濃縮,得到〔5-(喹啉-2-基)-2-噻吩基〕甲醇(504mg)。 Sodium borohydride (100 mg) was added to a mixture of 5-(quinolin-2-yl)thiophene-2-carbaldehyde (630 mg) in ethanol (19 mL), and the mixture was stirred at room temperature for 2 hours. Water and saturated brine were added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate (MgSO4).
製造例12 Manufacturing Example 12
將4-碘安息香酸甲酯(700 mg)、吲哚(376 mg)、碘化銅(I)(254 mg)、DL-脯胺酸(308 mg)、碳酸鉀(1.11 g)的二甲基亞碸(3 mL)混合物,在氬環境下,在100℃進行20小時攪拌。放冷後加入水,以乙酸乙酯萃取。將有機層經減壓濃縮後,將殘渣以矽膠管柱層析法(乙酸乙酯/己烷)進行純化後得到4-(1H-吲哚-1-基)安息香酸甲酯(542 mg)。 Methyl 4-iodobenzoate (700 mg), hydrazine (376 mg), copper (I) iodide (254 mg), DL-proline (308 mg), potassium carbonate (1.11 g) The mixture of guanidine (3 mL) was stirred at 100 ° C for 20 hours under an argon atmosphere. After cooling, water was added and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and then purified to ethylamine (hexane) .
製造例13 Manufacturing Example 13
於4-(3-甲基喹啉-2-基)酚(170mg)、4-溴-5-(溴甲基)-2-甲基-2H-1,2,3-三唑(184mg)、及N,N-二甲基甲醯胺(3.4mL)的混合物中加入碳酸鉀(250mg),在60℃進行4小時攪拌。放冷後加入水及飽和食鹽水,以氯仿進行萃取。將有機層以無水硫酸鎂乾燥後減壓濃縮。將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化後得到、2- {4-〔(5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲氧基〕苯基}-3-甲基喹啉(295mg)。 4-(3-methylquinolin-2-yl)phenol (170 mg), 4-bromo-5-(bromomethyl)-2-methyl-2H-1,2,3-triazole (184 mg) Potassium carbonate (250 mg) was added to a mixture of N,N-dimethylformamide (3.4 mL), and the mixture was stirred at 60 ° C for 4 hours. After cooling, water and saturated brine were added, and extraction was performed with chloroform. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (methanol / chloroform), 2- {4-[(5-Bromo-2-methyl-2H-1,2,3-triazol-4-yl)methoxy]phenyl}-3-methylquinoline (295 mg).
製造例14 Manufacturing Example 14
於{4-〔(3-硝基吡啶-2-基)胺基〕苯基}甲醇(2.13 g)的乙醇(30 mL)及水(7.5 mL)之混合物中加入氯化銨(232 mg)、鐵(2.42 g),經30分鐘加熱迴流。放冷後加入氯仿、水,以矽藻土過濾。將濾液以氯仿進行萃取,將有機層進行減壓濃縮後得到{4-〔(3-胺基吡啶-2-基)胺基〕苯基}甲醇之粗純化物(2.42 g)。於該粗生成物(2.42 g)、鄰甲酸三乙基(3.3 mL)、及四氫呋喃(25 mL)的混合物中加入對甲苯磺酸一水合物(149 mg),在60℃進行15分攪拌。放冷後加入乙酸乙酯,以飽和碳酸氫鈉水溶液、飽和食鹽水洗淨。將有機層經減壓濃縮後,將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化後得到、〔4-(3H-咪唑並〔4,5-b〕吡啶-3-基)苯基〕甲醇(639 mg)。 Add ammonium chloride (232 mg) to a mixture of {4-[(3-nitropyridin-2-yl)amino]phenyl}methanol (2.13 g) in ethanol (30 mL) and water (7.5 mL) Iron (2.42 g), heated to reflux for 30 minutes. After cooling, chloroform and water were added, and the mixture was filtered through Celite. The filtrate was extracted with chloroform, and the organic layer was concentrated under reduced pressure to yield crude crystals of (4-[(3-aminopyridin-2-yl)amino]phenyl}methanol (2.42 g). p-Toluenesulfonic acid monohydrate (149 mg) was added to a mixture of the crude product (2.42 g), triethyl acetate (3.3 mL), and tetrahydrofuran (25 mL), and stirred at 60 ° C for 15 minutes. After cooling, ethyl acetate was added, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and brine. After the organic layer was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (methanol/chloroform) to give [4-(3H-imidazo[4,5-b]pyridin-3-yl)benzene. Methyl methoxide (639 mg).
製造例15 Manufacturing Example 15
將1-甲基-1H-吡唑-3-醇(8.1g)、苯甲基溴化物(16.9g)與碳酸鉀(13.7g)的N,N-二甲基甲醯胺(100mL)混合物在室溫下進行1.5小時,在50℃進行4小時攪拌。加入水與乙酸乙酯,將有機層以飽和食鹽水洗淨後以無水硫酸鎂乾燥並減壓濃縮。將殘渣以矽膠管柱層析法(乙 酸乙酯/己烷)進行純化後得到3-(苯甲氧基)-1-甲基-1H-吡唑(13.0g)。 a mixture of 1-methyl-1H-pyrazol-3-ol (8.1 g), benzyl bromide (16.9 g) and potassium carbonate (13.7 g) in N,N-dimethylformamide (100 mL) The mixture was stirred at room temperature for 1.5 hours and at 50 ° C for 4 hours. After adding water and ethyl acetate, the organic layer was washed with brine, dried over anhydrous magnesium sulfate The residue is subjected to gel column chromatography (B Purification with ethyl acetate/hexanes gave 3-(benzyloxy)-1-methyl-1H-pyrazole (13.0 g).
製造例16 Manufacturing Example 16
於2-(4-甲氧基苯基)咪唑並〔1,2-a〕吡啶(4.89g)之二氯甲烷(120mL)溶液,冰冷下加入1mol之三溴化硼的二氯甲烷溶液(65mL),在室溫下進行18小時攪拌。將反應液加入於飽和碳酸氫鈉水溶液中所產生的沈澱經過濾取出。濾液以10%甲醇-氯仿進行萃取。合併有機層與固體,經減壓濃縮後,殘渣以甲醇及水的順序洗淨後得到4-咪唑並〔1,2-a〕吡啶-2-基酚(3.37g)。 To a solution of 2-(4-methoxyphenyl)imidazo[1,2-a]pyridine (4.89 g) in dichloromethane (120 mL), 1 m. 65 mL) was stirred at room temperature for 18 hours. The precipitate obtained by adding the reaction solution to a saturated aqueous sodium hydrogencarbonate solution was taken out by filtration. The filtrate was extracted with 10% methanol-chloroform. The organic layer and the solid were combined, and the residue was evaporated to ethylamine.
製造例17 Manufacturing Example 17
於2-(4-{〔(4-碘-1-甲基-1H-吡唑-3-基)氧基〕甲基}苯基)喹啉(2.0g)的四氫呋喃(40mL)混合物中,在-10℃以下加入2M異丙基鎂氯化物的四氫呋喃溶液(0.5mL)。在-18℃至-10℃下進行45分攪拌,加入丙氧基-4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷(2.6mL),在室溫下進行1.5小時攪拌。再度冷卻至-15℃,加入2-異丙氧基-4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷(1.0mL),在室溫下進行1小時攪拌。於反應液加入飽和氯化銨水溶液與乙酸乙酯,將有機層以飽和食鹽水洗淨後以無水硫酸鎂乾燥再經減壓濃縮。將殘渣以矽膠管柱層析法(乙酸乙酯/己烷)進行純化後得到2-〔4-({〔1-甲基-4-(4,4,5,5-四甲 基-1,3,2-二氧雜戊硼烷-2-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕喹啉(1.67g)。 In a mixture of 2-(4-{[(4-iodo-1-methyl-1H-pyrazol-3-yl)oxy]methyl}phenyl)quinoline (2.0 g) in tetrahydrofuran (40 mL) A solution of 2M isopropylmagnesium chloride in tetrahydrofuran (0.5 mL) was added below -10 °C. 45 minutes stirring at -18 ° C to -10 ° C, adding propoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.6 mL), in the room Stir for 1.5 hours at a temperature. Cool again to -15 ° C, add 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 mL), at room temperature 1 Stir for hours. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the mixture, and the organic layer was washed with brine, The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 2-[4-({[1-methyl-4-(4,4,5,5- Base-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (1.67 g).
製造例18 Manufacturing Example 18
冰冷下,於4-(咪唑並〔1,2-a〕吡啶-2-基)安息香酸乙基(3.11g)的四氫呋喃(50mL)混合物中加入氫化硼鋰(806mg)、乙醇(2.2mL),進行2小時加熱迴流。將反應液放冷後,加入飽和碳酸氫鈉水溶液。將反應液以乙酸乙酯萃取,將有機層減壓濃縮。將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化後得到〔4-(咪唑並〔1,2-a〕吡啶-2-基)苯基〕甲醇(2.46g)。 Add lithium borohydride (806 mg) and ethanol (2.2 mL) to a mixture of 4-(imidazo[1,2-a]pyridin-2-yl)benzoic acid ethyl (3.11 g) in tetrahydrofuran (50 mL). , heating and refluxing for 2 hours. After the reaction solution was allowed to cool, a saturated aqueous solution of sodium hydrogencarbonate was added. The reaction mixture was extracted with EtOAc. The residue was purified by silica gel column chromatography (methanol / chloroform) to afford [4-(imidazo[1,2-a]pyridin-2-yl)phenyl]methanol (2.46 g).
製造例19 Manufacturing Example 19
於2-氯-3-甲基喹啉(533 mg)、〔4-(羥基甲基)苯基〕亞硼酸(501 mg)的1,2-二甲氧基乙烷(20 mL)懸浮液中加入肆(三苯基膦)鈀(173 mg)、1 M碳酸鈉水溶液(7.5 mL),氬環境下在90℃進行19小時攪拌。放冷後於反應液加入水,並以乙酸乙酯進行萃取後減壓濃縮。將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化後得到〔4-(3-甲基喹啉-2-基)苯基〕甲醇(696 mg)。 a suspension of 2-chloro-3-methylquinoline (533 mg), [4-(hydroxymethyl)phenyl]boronic acid (501 mg) in 1,2-dimethoxyethane (20 mL) A solution of ruthenium (triphenylphosphine)palladium (173 mg) and 1 M aqueous sodium carbonate (7.5 mL) was added thereto, and the mixture was stirred at 90 ° C for 19 hours under an argon atmosphere. After cooling, water was added to the reaction mixture, and extracted with ethyl acetate. The residue was purified by silica gel column chromatography (methanol / chloroform) to afford [4-(3-methylquinolin-2-yl)phenyl]methanol (696 mg).
製造例20 Manufacturing Example 20
於2-(4-{〔(1-甲基-1H-吡唑-3-基)氧基〕甲基}苯基)喹啉(5.32g)的乙腈(140mL)溶液中加入硝酸二銨 鈰(5.55g)、及碘(2.57g),在室溫下進行10分鐘攪拌。於反應液冰冷下加入5%亞硫酸氫鈉水溶液與乙酸乙酯,將有機層以飽和食鹽水洗淨,以無水硫酸鎂乾燥後減壓濃縮。將殘渣以矽膠管柱層析法(乙酸乙酯/己烷)進行純化後得到2-(4-{〔(4-碘-1-甲基-1H-吡唑-3-基)氧基〕甲基}苯基)喹啉(4.94g)。 Add diammonium nitrate to a solution of 2-(4-{[(1-methyl-1H-pyrazol-3-yl)oxy]methyl}phenyl)quinoline (5.32 g) in acetonitrile (140 mL) 铈 (5.55 g) and iodine (2.57 g) were stirred at room temperature for 10 minutes. The reaction mixture was washed with EtOAc EtOAc. The residue was purified by silica gel column chromatography (ethyl acetate /hexane) to give 2-(4-{[(4-iodo-1-methyl-1H-pyrazol-3-yl)oxy] Methyl}phenyl)quinoline (4.94 g).
製造例21 Manufacturing Example 21
於1-〔4-(羥基甲基)苯基〕丙烷-1-酮(710 mg)的四氫呋喃(10 mL)溶液中加入吡啶鎓溴化物過溴化物(1.45 g),在室溫下進行1.5小時攪拌。過濾後減壓濃縮後得到2-溴-1-〔4-(羥基甲基)苯基〕丙烷-1-酮之粗純化物(2.02 g)。 Pyrithion bromide perbromide (1.45 g) was added to a solution of 1-[4-(hydroxymethyl)phenyl]propan-1-one (710 mg) in tetrahydrofuran (10 mL). Stir for hours. After filtration and concentration under reduced pressure, a crude purified material (yield, 2-bromo-1-[4-(hydroxymethyl)phenyl)propan-1-one (2.02 g).
製造例22 Manufacturing Example 22
將1M六甲基二矽胺化鋰的四氫呋喃溶液(30mL)加入於四氫呋喃(45mL),將1,4-二氧螺〔4.5〕癸-8-基乙酸乙酯(6.55g)的四氫呋喃(20mL)溶液在-78℃加入。同溫下進行50分鐘攪拌後,加入甲酸甲酯(3.5mL)。在同溫下進行10分鐘攪拌後,室溫中進行3小時攪拌。冰冷後加入1M鹽酸及飽和食鹽水,以氯仿進行萃取。以無水硫酸鎂進行乾燥後,減壓濃縮後得到2-(1,4-二氧螺〔4.5〕癸-8-基)-3-羥基丙烯酸乙酯。於所得之2-(1,4-二氧螺〔4.5〕癸-8-基)-3-羥基丙烯酸乙酯的乙醇(60mL) 溶液中加入甲基聯胺(3.0mL),在100℃進行3小時攪拌。放冷後減壓濃縮,將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化後得到4-(1,4-二氧螺〔4.5〕癸-8-基)-1-甲基-1H-吡唑-3-醇位置異構物混合物(2.91g)。 A 1 M solution of lithium hexamethyldiguanidinium chloride in tetrahydrofuran (30 mL) was added to tetrahydrofuran (45 mL), 1,4-dioxaspiro[4.5]hydrazin-8-ylacetic acid ethyl ester (6.55 g) in THF (20 mL) The solution was added at -78 °C. After stirring for 50 minutes at the same temperature, methyl formate (3.5 mL) was added. After stirring at the same temperature for 10 minutes, the mixture was stirred at room temperature for 3 hours. After ice-cooling, 1 M hydrochloric acid and saturated brine were added, and the mixture was extracted with chloroform. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to give ethyl 2-(1,4-dioxaspiro[4.5]indole-8-yl)-3-hydroxy acrylate. Ethanol (60 mL) of 2-(1,4-dioxospiro[4.5]癸-8-yl)-3-hydroxyethyl acrylate obtained Methyl hydrazine (3.0 mL) was added to the solution, and the mixture was stirred at 100 ° C for 3 hours. After cooling, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / chloroform) to give 4-(1,4-dioxaspiro[4.5] 癸-8-yl)-1-methyl- 1H-pyrazol-3-ol positional isomer mixture (2.91 g).
製造例23 Production Example 23
冰冷下於5,6,7,8-四氫喹啉-2(1H)-酮(1.03 g)、三乙基胺(1.9 mL)之二氯甲烷(20 mL)溶液中加入三氟甲烷磺酸無水物(1.7 mL),同溫下進行1小時攪拌。將反應液以飽和碳酸氫鈉水溶液中和,以氯仿萃取。將有機層經減壓濃縮後得到5,6,7,8-四氫喹啉-2-基 三氟甲烷磺酸酯(2.653 g)。 Adding trifluoromethanesulfonate to a solution of 5,6,7,8-tetrahydroquinolin-2(1H)-one (1.03 g), triethylamine (1.9 mL) in dichloromethane (20 mL) The acid anhydride (1.7 mL) was stirred at the same temperature for 1 hour. The reaction solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was concentrated under reduced pressure to give 5,6,7,8-tetrahydroquinolin-2-yltrifluoromethanesulfonate (2.653 g).
製造例24 Manufacturing Example 24
於〔1-甲基-4-(吡啶-4-基)-1H-吡唑-3-基〕甲醇(1.00g)的氯仿(30mL)溶液中加入二氧化錳(10.0g),在50℃進行12小時攪拌。將反應液以矽藻土過濾後將殘渣減壓濃縮,得到1-甲基-4-(吡啶-4-基)-1H-吡唑-3-甲醛(576mg)。 Add manganese dioxide (10.0 g) to a solution of [1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]methanol (1.00 g) in chloroform (30 mL) at 50 ° C Stir for 12 hours. The reaction mixture was filtered through Celite, and the residue was evaporated.
製造例25 Manufacturing Example 25
於2-〔4-(氯甲基)苯基〕-3-甲基喹啉(1.78g)的乙腈(120mL)溶液加入三苯基膦(2.62g),在70℃進行10小時攪拌。將反應液經減壓濃縮,將殘渣以二乙基醚洗 淨,氯化〔4-(3-甲基喹啉-2-基)苯甲基〕三苯基鏻(2.66g)。 Triphenylphosphine (2.62 g) was added to a solution of 2-[4-(chloromethyl)phenyl]-3-methylquinoline (1.78 g) in EtOAc (EtOAc) The reaction solution was concentrated under reduced pressure and the residue was washed with diethyl ether. Net, [4-(3-methylquinolin-2-yl)benzyl]triphenylphosphonium chloride (2.66 g).
製造例26 Manufacturing Example 26
於1-甲基-4-(吡啶-4-基)-1H-吡唑-3-甲醛(576mg)的四氫呋喃(20mL)溶液中加入氯化〔4-(3-甲基喹啉-2-基)苯甲基〕三苯基鏻(1.63g)、二氮雜雙環十一碳烯(703mg),在室溫下進行48小時攪拌。將反應液經減壓濃縮,將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化後得到3-甲基-2-(4-{2-〔1-甲基-4-(吡啶-4-基)-1H-吡唑-3-基〕乙烯基}苯基)喹啉(967mg)。 Add chlorinated [4-(3-methylquinolin-2-) to a solution of 1-methyl-4-(pyridin-4-yl)-1H-pyrazole-3-carbaldehyde (576 mg) in tetrahydrofuran (20 mL) Benzophenyl]triphenylphosphonium (1.63 g) and diazabicycloundecene (703 mg) were stirred at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure, and then purified and purified, m. m. 4-yl)-1H-pyrazol-3-yl]vinyl}phenyl)quinoline (967 mg).
製造例27 Manufacturing Example 27
於1-溴-3-氟-2-硝苯(1.00 g)、碳酸鉀(942 mg)的N,N-二甲基甲醯胺(3 mL)混合液中加入9.8 M甲基胺之甲醇溶液(2.3 mL),在室溫下進行3小時攪拌。於反應液加入乙酸乙酯,將有機層以飽和碳酸氫鈉水溶液及飽和食鹽水洗淨後減壓濃縮,得到3-溴-N-甲基-2-硝基苯胺(1.05 g)。 Add 9.8 M methylamine methanol to a mixture of 1-bromo-3-fluoro-2-nitrobenzene (1.00 g) and potassium carbonate (942 mg) in N,N-dimethylformamide (3 mL) The solution (2.3 mL) was stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with saturated aqueous sodium hydrogen sulfate and brine, and evaporated.
製造例28 Manufacturing Example 28
於3-溴-N-甲基-2-硝基苯胺(1.05 g)、乙醇(8 mL)、及水(2 mL)的混合物中加入氯化銨(122 mg)、鐵(1.27 g),經2小時加熱迴流。放冷後加入氯仿、水, 以矽藻土過濾。將濾液以氯仿萃取,將有機層經減壓濃縮後得到2-胺基-3-溴-N-甲基苯胺(914 mg)。 Ammonium chloride (122 mg) and iron (1.27 g) were added to a mixture of 3-bromo-N-methyl-2-nitroaniline (1.05 g), ethanol (8 mL), and water (2 mL). It was heated to reflux over 2 hours. After cooling, add chloroform and water. Filter with diatomaceous earth. The filtrate was extracted with chloroform, and the organic layer was concentrated under reduced pressure to give 2-amino-3-bromo-N-methylaniline (914 mg).
製造例29 Manufacturing Example 29
於2-胺基-3-溴-N-甲基苯胺(914 mg)、鄰甲酸三乙基(1.9 mL)的四氫呋喃(10 mL)溶液中加入對甲苯磺酸一水合物(86 mg),經1小時加熱迴流。放冷後於反應液加入乙酸乙酯,以飽和碳酸氫鈉水溶液、飽和食鹽水洗淨。將有機層經減壓濃縮後,將殘渣以矽膠管柱層析法(乙酸乙酯/己烷)進行純化後得到4-溴-1-甲基-1H-苯並咪唑(826 mg)。 To a solution of 2-amino-3-bromo-N-methylaniline (914 mg), triethyl orthoformate (1.9 mL) in tetrahydrofuran (10 mL). It was heated to reflux over 1 hour. After cooling, ethyl acetate was added to the reaction mixture, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and brine. The organic layer was concentrated under reduced pressure, and then purified, mjjjjjjj
製造例30 Manufacturing Example 30
將5-(3-羥基-1-甲基-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮(285mg)、氧化鉑(50mg)、及乙酸(10mL)的混合物在氫環境下,室溫中3氣壓下進行15小時攪拌。將反應液以矽藻土過濾,將濾液經減壓濃縮。將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化後得到5-(3-羥基-1-甲基-1H-吡唑-4-基)-1-甲基哌啶-2(1H)-酮(193mg)。 5-(3-Hydroxy-1-methyl-1H-pyrazol-4-yl)-1-methylpyridine-2(1H)-one (285 mg), platinum oxide (50 mg), and acetic acid (10 mL) The mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours at 3 atmospheres. The reaction solution was filtered through Celite, and the filtrate was evaporated. The residue was purified by silica gel column chromatography (methanol / chloroform) to give 5-(3-hydroxy-1-methyl-1H-pyrazol-4-yl)-1-methylpiperidine-2 (1H )-ketone (193 mg).
製造例31 Manufacturing Example 31
將5-溴-2(1H)-吡啶酮(2.0g)、碳酸銫(11.24g)、2-氯-N,N-二甲基乙烷胺鹽酸鹽(2.06g)、及N,N-二甲 基甲醯胺(40mL)的混合物,在60℃進行20小時攪拌。於反應液加入水與乙酸乙酯,將有機層以飽和食鹽水洗淨,以無水硫酸鎂乾燥後減壓濃縮。將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化後得到5-溴-1-〔2-(二甲基胺基)乙基〕吡啶-2(1H)-酮(1.63g)。 5-Bromo-2(1H)-pyridone (2.0 g), cesium carbonate (11.24 g), 2-chloro-N,N-dimethylethaneamine hydrochloride (2.06 g), and N,N -dimethyl A mixture of carbamide (40 mL) was stirred at 60 ° C for 20 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was washed with brine, dried over anhydrous The residue was purified by silica gel column chromatography (methanol / chloroform) to afford 5-bromo-1-[2-(dimethylamino)ethyl]pyridin-2 (1H)-one (1.63 g).
製造例32 Manufacturing Example 32
將(1-甲基-1H-吡唑-3-基)甲醇(4.00g)、4-(3-甲基喹啉-2-基)酚(8.53g)、氰伸甲基三丁基膦(13.1g)、甲苯(120mL)的混合物在100℃進行8小時攪拌。將反應液減壓濃縮,將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化。於所得之3-甲基-2-{4-〔(1-甲基-1H-吡唑-3-基)甲氧基〕苯基}喹啉中加入乙腈(250mL)、硝酸鈰銨(16.0g)、碘(14.9g),在室溫下進行45分鐘攪拌。將反應液減壓濃縮,於殘渣加入氯仿,以飽和硫代硫酸鈉水溶液洗淨。將有機層經減壓濃縮後,將殘渣以矽膠管柱層析法(乙酸乙酯/己烷)進行純化。將所得之固體以乙酸乙酯-己烷洗淨,得到2-{4-〔(4-碘-1-甲基-1H-吡唑-3-基)甲氧基〕苯基}-3-甲基喹啉(10.63g)。 (1-Methyl-1H-pyrazol-3-yl)methanol (4.00 g), 4-(3-methylquinolin-2-yl)phenol (8.53 g), cyanide methyltributylphosphine A mixture of (13.1 g) and toluene (120 mL) was stirred at 100 ° C for 8 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified to silica gel column chromatography (methanol / chloroform). Add acetonitrile (250 mL) and cerium ammonium nitrate (16.0) to the obtained 3-methyl-2-{4-[(1-methyl-1H-pyrazol-3-yl)methoxy]phenyl}quinoline. g), iodine (14.9 g), stirred at room temperature for 45 minutes. The reaction mixture was concentrated under reduced pressure. EtOAc was evaporated. After the organic layer was concentrated under reduced pressure, the residue was purified, m. The obtained solid was washed with ethyl acetate-hexane to give 2-{4-[(4-iodo-1-methyl-1H-pyrazol-3-yl)methoxy]phenyl}-3- Methylquinoline (10.63 g).
製造例33 Manufacturing Example 33
於氯化銅(II)(795 mg)及水(10 mL)的混合物中加入(2-甲氧基喹啉-3-基)亞硼酸(300 mg)的甲醇(10 mL)溶液,在90℃進行1小時攪拌。放冷後加入乙酸 乙酯與水,將有機層以飽和食鹽水洗淨。將殘渣以矽膠管柱層析法(氯仿/己烷)進行純化後得到3-氯-2-甲氧基喹啉(246 mg)。 Add a solution of (2-methoxyquinolin-3-yl)boronic acid (300 mg) in methanol (10 mL) in a mixture of copper (II) chloride (795 mg) and water (10 mL). The mixture was stirred at ° C for 1 hour. Add acetic acid after cooling Ethyl acetate and water, the organic layer was washed with saturated brine. The residue was purified by silica gel column chromatography (chloroform/hexane) to afford 3-chloro-2-methoxyquinoline (246 mg).
製造例34 Manufacturing Example 34
於6-〔4-(羥基甲基)苯基〕菸酸(2.91g)的甲醇(50mL)混合物中,冰冷下加入硫酸(2.04mL),在60℃進行96小時攪拌。將反應液加入於冰水中,以碳酸氫鈉中和,以乙酸乙酯萃取。將有機層經減壓濃縮,將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化後得到6-〔4-(羥基甲基)苯基〕菸酸甲酯(1.72g)。 To a mixture of 6-[4-(hydroxymethyl)phenyl]nicotinic acid (2.91 g) in methanol (50 mL). The reaction solution was poured into ice water, neutralized with sodium hydrogen sulfate, and ethyl acetate. The organic layer was concentrated under reduced pressure, and then purified, mjjjjjjjj
製造例35 Manufacturing Example 35
於3-氯-2-甲氧基喹啉(804 mg)的乙腈(20 mL)溶液中加入碘化鈉(1.56 g)、三甲基氯矽烷(1.3 mL),在50℃進行1小時攪拌。放冷後加入飽和碳酸氫鈉水溶液,以乙酸乙酯萃取。將有機層以水、飽和食鹽水洗淨,經減壓濃縮。將殘渣以矽膠管柱層析法(乙酸乙酯/己烷)進行純化後得到3-氯喹啉-2-醇(603 mg)。 Add sodium iodide (1.56 g) and trimethylchlorosilane (1.3 mL) to a solution of 3-chloro-2-methoxyquinoline (804 mg) in acetonitrile (20 mL) and stir at 50 ° C for 1 hour. . After cooling, a saturated aqueous solution of sodium hydrogencarbonate was added and ethyl acetate was evaporated. The organic layer was washed with water and saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate /hexane) to afford 3-chloroquinolin-2-ol (603 mg).
製造例36 Manufacturing Example 36
將3-(苯甲氧基)-1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)-1H-吡唑(4.66g)、5-溴-1-甲基吡啶-2(1H)-酮(3.37g)、1,1'-雙(二苯基膦)二茂鐵-鈀二 氯化物-二氯甲烷錯體(723mg)、碳酸鈉(4.72g)、N,N-二甲基甲醯胺(56mL)、及水(11mL)的混合物在氬環境下,在100℃進行1小時攪拌。於反應液加入乙酸乙酯及水,將所生成的不溶物以矽藻土過濾分離。將有機層以飽和食鹽水洗淨,以無水硫酸鎂乾燥後減壓濃縮。將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化後得到5-〔3-(苯甲氧基)-1-甲基-1H-吡唑-4-基〕-1-甲基吡啶-2(1H)-酮(2.57g)。 3-(Benzyloxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridyl Azole (4.66 g), 5-bromo-1-methylpyridine-2(1H)-one (3.37 g), 1,1'-bis(diphenylphosphino)ferrocene-palladium II A mixture of chloride-dichloromethane (723 mg), sodium carbonate (4.72 g), N,N-dimethylformamide (56 mL), and water (11 mL) was taken at 100 ° C under argon. Stir for hours. Ethyl acetate and water were added to the reaction mixture, and the resulting insoluble material was separated by filtration over Celite. The organic layer was washed with brine, dried over anhydrous magnesium sulfate The residue was purified by silica gel column chromatography (methanol / chloroform) to give 5-[3-(benzyloxy)-1-methyl-1H-pyrazol-4-yl]-1-methylpyridine. -2(1H)-one (2.57 g).
製造例37 Manufacturing Example 37
於2-氯喹啉-3-醇(1.27 g)、碳酸鉀(2.44 g)的N,N-二甲基甲醯胺(20 mL)混合液加入碘化甲基(0.485mL),在室溫下進行15分攪拌。加入乙酸乙酯以飽和食鹽水洗淨。將有機層經減壓濃縮後,將殘渣以矽膠管柱層析法(乙酸乙酯/己烷)進行純化後得到2-氯-3-甲氧基喹啉(1.28 g)。 Add methyl iodide (0.485 mL) to a mixture of 2-chloroquinolin-3-ol (1.27 g), potassium carbonate (2.44 g) in N,N-dimethylformamide (20 mL) at room temperature Stir for 15 minutes. Ethyl acetate was added and washed with saturated brine. The organic layer was concentrated under reduced pressure, and then purified, m.j.
製造例38 Manufacturing Example 38
將5-〔3-(苯甲氧基)-1-甲基-1H-吡唑-4-基〕-1-甲基吡啶-2(1H)-酮(2.57g)、20%氫氧化鈀(350mg)、及乙醇(40mL)的混合物在氫環境下,在室溫於3氣壓下進行一夜攪拌。將反應液使用矽藻土進行過濾。將濾液減壓濃縮後得到5-(3-羥基-1-甲基-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮(1.49g)。 5-[3-(Benzyloxy)-1-methyl-1H-pyrazol-4-yl]-1-methylpyridine-2(1H)-one (2.57 g), 20% palladium hydroxide A mixture of (350 mg) and ethanol (40 mL) was stirred overnight under a hydrogen atmosphere at room temperature under 3 atmospheres. The reaction solution was filtered using diatomaceous earth. The filtrate was concentrated under reduced pressure to give 5-(3-hydroxy-1-methyl-1H-pyrazol-4-yl)-1-methylpyridine-2(1H)-one (1.49 g).
製造例39 Manufacturing Example 39
氬環境下,將3-(苯甲氧基)-4-碘-1-甲基-1H-吡唑(7g)、丙烯酸乙酯(7.3mL)、乙酸鈀(250mg)、N,N-二異丙基乙基胺(19mL)、N,N-二甲基甲醯胺(28mL)的混合物,在100℃進行24小時攪拌。將反應液恢復至室溫後以矽藻土過濾,將濾液以水、飽和食鹽水之順序洗淨後,以無水硫酸鈉乾燥後經減壓濃縮。將殘渣以矽膠管柱層析法(己烷/乙酸乙酯)進行純化後得到(2E)-3-〔3-(苯甲氧基)-1-甲基-1H-吡唑-4-基〕丙烯酸乙酯(5.217g)。 3-(Benzyloxy)-4-iodo-1-methyl-1H-pyrazole (7g), ethyl acrylate (7.3mL), palladium acetate (250mg), N,N-di A mixture of isopropylethylamine (19 mL) and N,N-dimethylformamide (28 mL) was stirred at 100 ° C for 24 hours. After the reaction mixture was cooled to room temperature, it was filtered over Celite, and the filtrate was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford (2E)-3-[3-(benzyloxy)-1-methyl-1H-pyrazol-4-yl Ethyl acrylate (5.217 g).
製造例40 Manufacturing Example 40
於〔4-(3-甲基喹啉-2-基)苯基〕甲醇(12g)的二氯甲烷(200mL)懸浮液中加入氯化亞碸(10mL),在室溫下進行1小時攪拌。將反應液減壓濃縮,於殘渣加入飽和碳酸氫鈉並以氯仿萃取。將有機層以飽和碳酸氫鈉水溶液洗淨。以無水硫酸鈉乾燥後減壓濃縮,得到2-〔4-(氯甲基)苯基〕-3-甲基喹啉(13.345g)。 To a suspension of [4-(3-methylquinolin-2-yl)phenyl]methanol (12 g) in dichloromethane (200 mL) was added EtOAc (10 mL) and stirred at room temperature for 1 hour. . The reaction mixture was concentrated under reduced vacuo. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate (MgSO4).
製造例41 Manufacturing Example 41
氬環境下,於(2E)-3-〔3-(苯甲氧基)-1-甲基-1H-吡唑-4-基〕丙烯酸乙酯(2.6g)的四氫呋喃(20mL)溶液中加入硝基甲烷(2.5mL)、二氮雜雙環十一碳烯( 1.7mL),在60℃進行17小時攪拌。追加硝基甲烷(2.5mL)、二氮雜雙環十一碳烯(1.7mL),在70℃進行19小時攪拌。將反應液減壓濃縮,將殘渣以矽膠管柱層析法(己烷/乙酸乙酯)進行純化後得到3-〔3-(苯甲氧基)-1-甲基-1H-吡唑-4-基〕-4-硝基丁烷酸乙基(2.266g)。 Add to a solution of ethyl (2E)-3-[3-(benzyloxy)-1-methyl-1H-pyrazol-4-yl]acrylate (2.6 g) in tetrahydrofuran (20 mL) Nitromethane (2.5 mL), diazabicycloundecene ( 1.7 mL) was stirred at 60 ° C for 17 hours. Nitromethane (2.5 mL) and diazabicycloundecene (1.7 mL) were added, and the mixture was stirred at 70 ° C for 19 hours. The reaction mixture was concentrated under reduced pressure and purified residue purified eluted eluted eluted eluted elut elut 4-[4-]-4-nitrobutanoic acid ethyl (2.266 g).
製造例42 Manufacturing Example 42
將3-〔3-(苯甲氧基)-1-甲基-1H-吡唑-4-基〕-4-硝基丁烷酸乙基(2.246g)、鐵(1.81g)、氯化銨(1.73g)、乙醇(19mL)、及水(7.2mL)的混合物,在90℃進行6小時攪拌。追加鐵(1.81g)、氯化銨(1.73 g),在90℃進行2小時攪拌。以矽藻土過濾後減壓濃縮。於殘渣加入三乙基胺(2.7mL)、甲苯(100mL),進行5小時加熱迴流。將反應液減壓濃縮,將殘渣以矽膠管柱層析法(氯仿/甲醇)進行純化後得到4-〔3-(苯甲氧基)-1-甲基-1H-吡唑-4-基〕吡咯烷-2-酮(1.41g)。 3-[3-(Benzyloxy)-1-methyl-1H-pyrazol-4-yl]-4-nitrobutanoic acid ethyl (2.246 g), iron (1.81 g), chlorinated A mixture of ammonium (1.73 g), ethanol (19 mL), and water (7.2 mL) was stirred at 90 ° C for 6 hours. Iron (1.81 g) and ammonium chloride (1.73 g) were added, and the mixture was stirred at 90 ° C for 2 hours. It was filtered through celite and concentrated under reduced pressure. Triethylamine (2.7 mL) and toluene (100 mL) were added to the residue, and the mixture was heated under reflux for 5 hours. The reaction solution was concentrated under reduced pressure and the residue was purified mjjjjjjjjjjjjj Pyrrolidin-2-one (1.41 g).
製造例43 Manufacturing Example 43
氮氣流下,將四氫呋喃(15mL)冰冷,加入氫化鋰鋁(325mg)。其次加入4-〔3-(苯甲氧基)-1-甲基-1H-吡唑-4-基〕吡咯烷-2-酮(1.161g)之四氫呋喃(8mL)溶液,在50℃進行10小時攪拌。將反應液冰冷後,加入硫酸鈉10水合物並攪拌。以矽藻土過濾後,於濾液中加入二- tert-丁基二碳酸酯(1.12g)之四氫呋喃溶液,在室溫下進行4小時攪拌。將反應液減壓濃縮,將殘渣以矽膠管柱層析法(己烷/乙酸乙酯)進行純化後得到tert-丁基3-〔3-(苯甲氧基)-1-甲基-1H-吡唑-4-基〕吡咯烷-1-羧酸酯(1.08g)。 Tetrahydrofuran (15 mL) was ice-cooled under a nitrogen stream, and lithium aluminum hydride (325 mg) was added. Next, a solution of 4-[3-(benzyloxy)-1-methyl-1H-pyrazol-4-ylpyrrolidin-2-one (1.161 g) in tetrahydrofuran (8 mL) was added and Stir for hours. After the reaction solution was ice-cooled, sodium sulfate 10 hydrate was added and stirred. After filtering with diatomaceous earth, add two to the filtrate. A solution of tert-butyl dicarbonate (1.12 g) in tetrahydrofuran was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and purified residue purified eluted eluted eluted eluted elut elut Pyrazol-4-ylpyrrolidin-1-carboxylate (1.08 g).
製造例44 Manufacturing Example 44
於1-甲基-4-吡啶-4-基-1H-吡唑-3-醇(1.00g)中加入(4-溴苯基)甲醇(1.60g)、四氫呋喃(100mL)、1,1'-(偶氮二羰基)二哌啶(2.88g)、三正丁基膦(2.31g),在室溫下進行12小時攪拌。將反應液減壓濃縮,將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化。將所得之粗純化物以己烷洗淨,得到4-{3-〔(4-溴苯甲基)氧基〕-1-甲基-1H-吡唑-4-基}吡啶(1.26g)。 (4-Bromophenyl)methanol (1.60 g), tetrahydrofuran (100 mL), 1,1' was added to 1-methyl-4-pyridin-4-yl-1H-pyrazol-3-ol (1.00 g). -(Azodicarbonyl)dipiperidine (2.88 g) and tri-n-butylphosphine (2.31 g) were stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified to silica gel column chromatography (methanol / chloroform). The obtained crude product was washed with hexane to give 4-{3-[(4-bromophenylmethyl)oxy]-1-methyl-1H-pyrazol-4-yl}pyridine (1.26 g). .
製造例45 Manufacturing Example 45
於4-溴-2,5-二甲基-2H-1,2,3-三唑(545mg)的四氯化碳(10mL)溶液中,加入N-溴琥珀醯亞胺(606mg)及2,2'-偶氮二(異丁腈)(51mg),在90℃進行19小時攪拌。將沈澱物過濾分離,減壓濃縮後,將殘渣以矽膠管柱層析法(乙酸乙酯/己烷)進行純化後得到4-溴-5-(溴甲基)-2-甲基-2H-1,2,3-三唑(185mg)。 Add N-bromosuccinimide (606 mg) and 2 to a solution of 4-bromo-2,5-dimethyl-2H-1,2,3-triazole (545 mg) in carbon tetrachloride (10 mL) 2'-Azobis(isobutyronitrile) (51 mg) was stirred at 90 ° C for 19 hours. The precipitate was separated by filtration and concentrated under reduced pressure. EtOAc EtOAc EtOAc -1,2,3-triazole (185 mg).
製造例46 Manufacturing Example 46
將2-胺基吡啶(4.82g)、p-甲苯基氰(5.00g)、溴化銅(I)(306mg)、碘化鋅(681mg)、1,10-二氮雜菲(770mg)、及甲苯(100mL)的混合物在110℃進行24小時攪拌。將反應液經減壓濃縮後,將殘渣以乙酸乙酯稀釋並以矽藻土過濾。將濾液經水洗,將有機層減壓濃縮後,將殘渣以矽膠管柱層析法(乙酸乙酯/己烷)進行純化後得到2-(4-甲基苯基)〔1,2,4〕三唑並〔1,5-a〕吡啶(1.00g)。 2-Aminopyridine (4.82 g), p-tolyl cyanide (5.00 g), copper (I) bromide (306 mg), zinc iodide (681 mg), 1,10-diazaphenanthrene (770 mg), The mixture of toluene (100 mL) was stirred at 110 ° C for 24 hours. The reaction mixture was concentrated under reduced pressure. The filtrate was washed with water, and the organic layer was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 2-(4-methylphenyl)[1,2,4 Triazolo[1,5-a]pyridine (1.00 g).
製造例47 Manufacturing Example 47
於2-氟-4-(3-甲基喹啉-2-基)安息香酸甲酯(700mg)的二甲基亞碸(5.0mL)溶液,在室溫滴入嗎啉(0.25mL)、二異丙基乙基胺(0.61mL),在80℃進行15小時攪拌。進一步追加嗎啉(0.5mL)、二異丙基乙基胺(1.2mL),在100℃進行48小時攪拌。加入水並以乙酸乙酯萃取。分離有機層後,以飽和食鹽水洗淨,以無水硫酸鎂乾燥。將溶劑減壓濃縮,將殘渣以矽膠管柱層析法(己烷/乙酸乙酯)進行純化後得到4-(3-甲基喹啉-2-基)-2-(嗎啉-4-基)安息香酸甲酯(467mg)。 To a solution of methyl 2-fluoro-4-(3-methylquinolin-2-yl)benzoate (700 mg) in dimethyl hydrazine (5.0 mL), morpholine (0.25 mL) Diisopropylethylamine (0.61 mL) was stirred at 80 ° C for 15 hours. Further, morpholine (0.5 mL) and diisopropylethylamine (1.2 mL) were added, and the mixture was stirred at 100 ° C for 48 hours. Water was added and extracted with ethyl acetate. The organic layer was separated, washed with brine and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure and the residue was purified mjjjjjjjjjjj Methyl benzoate (467 mg).
製造例48 Manufacturing Example 48
冰冷下於1-甲基-4-(1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-3-羧酸甲基(812mg)的四氫呋喃(20mL)混合物中加入氫化硼鋰(143mg)、乙醇(0.57mL),進 行2小時加熱迴流。將反應液放冷後,加入1M鹽酸(10mL)。將反應以飽和碳酸氫鈉水溶液中和後減壓濃縮。將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化後得到5-〔3-(羥基甲基)-1-甲基-1H-吡唑-4-基〕-1-甲基吡啶-2(1H)-酮(205mg)。 Tetrahydrofuran under 1-cold 1-methyl-4-(1-methyl-6-oxo-oxy-1,6-dihydropyridin-3-yl)-1H-pyrazole-3-carboxylic acid methyl (812 mg) Add lithium borohydride (143 mg) and ethanol (0.57 mL) to the mixture (20 mL). The mixture was heated to reflux for 2 hours. After the reaction mixture was allowed to cool, 1M hydrochloric acid (10 mL) was added. The reaction was neutralized with a saturated aqueous sodium hydrogencarbonate solution and concentrated. The residue was purified by silica gel column chromatography (methanol / chloroform) to give 5-[3-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl]-1-methylpyridine- 2(1H)-one (205 mg).
製造例49 Manufacturing Example 49
於5-(3-甲基喹啉-2-基)吡啶-2-羧酸甲基(182mg)、四氫呋喃(4.0mL)、及甲醇(4.0mL)的混合物,在室溫加入1M氫氧化鈉水溶液(1.5mL),在同溫進行7小時攪拌。冰冷下以1M鹽酸(1.5mL)中和後減壓濃縮。於殘渣加入水並過濾取出析出之固體。於所得之固體中加入四氫呋喃(5.0m),冰冷下加入羰基二咪唑(130mg)並攪拌後,在室溫下進行2小時攪拌。冰冷下滴入氫化硼鈉(60mg)之水溶液(0.5mL),在同溫進行15分攪拌後,在室溫下進行一晚攪拌。於反應溶液加入水並以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨後,以無水硫酸鎂乾燥,將溶劑減壓餾去。將殘渣以矽膠管柱層析法(己烷/乙酸乙酯)進行純化後得到〔5-(3-甲基喹啉-2-基)吡啶-2-基〕甲醇(70mg)。 a mixture of 5-(3-methylquinolin-2-yl)pyridine-2-carboxylic acid methyl (182 mg), tetrahydrofuran (4.0 mL), and methanol (4.0 mL). The aqueous solution (1.5 mL) was stirred at the same temperature for 7 hours. After neutralizing with 1 M hydrochloric acid (1.5 mL), the mixture was evaporated. Water was added to the residue and the precipitated solid was taken out by filtration. Tetrahydrofuran (5.0 m) was added to the obtained solid, and carbonyldiimidazole (130 mg) was added thereto under ice cooling, and the mixture was stirred at room temperature for 2 hours. An aqueous solution (0.5 mL) of sodium borohydride (60 mg) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 15 minutes, and then stirred at room temperature overnight. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford (5-(3-methylquinolin-2-yl)pyridin-2-yl]methanol (70 mg).
製造例50 Manufacturing Example 50
於N,N-二甲基甲醯胺(1.4mL),冰冷下加入氧氯化磷(3.3mL),在同溫進行30分鐘攪拌。於混合物中加入 N-(4-氟苯基)丙烷醯胺(2g)、十六烷基三甲基銨溴化物(436mg)、及乙腈(20mL),在80℃進行8小時攪拌後,在100℃進行4小時攪拌。將反應液減壓濃縮,將殘渣注入於冰中並攪拌,以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨後,以無水硫酸鈉乾燥、過濾,並減壓濃縮。將殘渣以矽膠管柱層析法(己烷/乙酸乙酯)進行純化後得到2-氯-6-氟-3-甲基喹啉(558mg)。 To N,N-dimethylformamide (1.4 mL), phosphorus oxychloride (3.3 mL) was added under ice cooling, and stirred at the same temperature for 30 minutes. Add to the mixture N-(4-fluorophenyl)propane decylamine (2 g), cetyltrimethylammonium bromide (436 mg), and acetonitrile (20 mL) were stirred at 80 ° C for 8 hours and then at 100 ° C. Stir for hours. The reaction mixture was concentrated under reduced pressure. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford 2-chloro-6-fluoro-3-methylquinoline (558 mg).
製造例51 Manufacturing Example 51
冰冷下,於(1,5-二甲基-1H-吡唑-3-基)甲醇(2.0g)加入二氯甲烷(100mL)、氯化亞碸(3.6mL),在室溫下進行2小時攪拌。將反應液減壓濃縮,將殘渣減壓乾燥。加入N,N-二甲基甲醯胺(180mL)、4-(3-甲基喹啉-2-基)酚(3.53g)、及碳酸鉀(5.18g),在70℃進行8小時攪拌。將反應液經減壓濃縮後,於殘渣加入水,以乙酸乙酯萃取。將有機層減壓濃縮,將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化後得到2-{4-〔(1,5-二甲基-1H-吡唑-3-基)甲氧基〕苯基}-3-甲基喹啉(5.05g)。 To a solution of (1,5-dimethyl-1H-pyrazol-3-yl)methanol (2.0 g) in dichloromethane (100 mL) Stir for hours. The reaction solution was concentrated under reduced pressure and the residue was evaporated. N,N-dimethylformamide (180 mL), 4-(3-methylquinolin-2-yl)phenol (3.53 g), and potassium carbonate (5.18 g) were added, and stirred at 70 ° C for 8 hours. . The reaction mixture was concentrated under reduced pressure. The organic layer was concentrated under reduced pressure and the residue was purified to silica gel column chromatography (methanol/chloroform) to afford 2-{4-[(1,5-dimethyl-1H-pyrazol-3-yl). Oxy]phenyl}-3-methylquinoline (5.05 g).
製造例52 Manufacturing Example 52
於3-溴-1-N-甲基苯-1,2-二胺(970mg)的4M鹽酸(3.0mL)混合物中,在室溫加入乙酸(0.35mL),在120℃進行18小時攪拌。冰冷下以飽和碳酸氫鈉水溶液中和,以氯仿萃取。將有機層以無水硫酸鎂乾燥,將溶劑減壓餾 去。將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化後得到4-溴-1,2-二甲基-1H-苯並咪唑(549mg)。 To a mixture of 3-bromo-1-N-methylbenzene-1,2-diamine (970 mg) in 4M hydrochloric acid (3.0 mL), acetic acid (0.35 mL) was added at room temperature and stirred at 120 ° C for 18 hours. It was neutralized with a saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. go with. The residue was purified by silica gel column chromatography (methanol / chloroform) to afford 4-bromo-1,2-dimethyl-1H-benzimidazole (549 mg).
製造例53 Manufacturing Example 53
冰冷下於6-〔4-(羥基甲基)苯基〕菸酸甲酯(1.72g)加入二氯甲烷(60mL)、氯化亞碸(1.56mL),在室溫下進行2小時攪拌。將反應液減壓濃縮,將殘渣經減壓乾燥。於所得之固體中加入N,N-二甲基甲醯胺(50mL)、5-(3-羥基-1-甲基-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮(1.00g)、碳酸鉀(1.68g),在70℃進行8小時攪拌。將反應液經減壓濃縮後,於殘渣加入水,以甲醇及氯仿的混合溶劑(1:10)萃取。將有機層經減壓濃縮後,將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化。將所得之粗純化物以乙酸乙酯及己烷之順序洗淨,得到6-〔4-({〔1-甲基-4-(1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕菸酸甲酯(1.48g)。 Methyl 6-[4-(hydroxymethyl)phenyl]nicotinic acid (1.72 g) was added to dichloromethane (60 mL) and EtOAc (1. The reaction liquid was concentrated under reduced pressure, and the residue was dried under reduced pressure. To the obtained solid was added N,N-dimethylformamide (50 mL), 5-(3-hydroxy-1-methyl-1H-pyrazol-4-yl)-1-methylpyridine-2 ( 1H)-ketone (1.00 g) and potassium carbonate (1.68 g) were stirred at 70 ° C for 8 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with a mixture of methanol and chloroform (1:10). After the organic layer was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude purified product was washed in the order of ethyl acetate and hexane to give 6-[4-({[1-methyl-4-(1-methyl-6- s. Methyl hydropyridine-3-yl)-1H-pyrazol-3-yloxy}methyl)phenyl]nicotinic acid (1.48 g).
製造例54 Manufacturing Example 54
於3,4-二氟苯胺(6.46g)、碳酸鉀(6.91g)、及二氯甲烷(200mL)的混合物,在-15℃加入溴(7.99g)的二氯甲烷(50mL)溶液,在同溫進行15分鐘攪拌。將反應液加入於冰中,以氯仿萃取。將有機層經減壓濃縮,將殘渣以矽膠管柱層析法(乙酸乙酯/己烷)進行純化後得 到2-溴-4,5-二氟苯胺(9.84g)。 A mixture of 3,4-difluoroaniline (6.46 g), potassium carbonate (6.91 g), and dichloromethane (200 mL) was added at -15 ° C to a solution of bromo (7.99 g) in dichloromethane (50 mL) Stir at the same temperature for 15 minutes. The reaction solution was added to ice and extracted with chloroform. The organic layer was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (ethyl acetate /hexane) To 2-bromo-4,5-difluoroaniline (9.84 g).
製造例55 Manufacturing Example 55
於(5-溴吡啶-2-基)甲醇(2.77g)、二甲基吡啶(4.7mL)、及四氫呋喃(30mL)的混合物,加入三異丙基矽三氟甲烷磺酸(2.0mL),在室溫下進行1小時攪拌。於反應液加入水及乙酸乙酯,將有機層以飽和食鹽水洗淨後,以無水硫酸鈉乾燥,並減壓濃縮。將殘渣以鹼性矽膠管柱層析法(乙酸乙酯/己烷)進行純化後得到5-溴-2-{〔(三異丙基矽)氧基〕甲基}吡啶(3.61g)。 To a mixture of (5-bromopyridin-2-yl)methanol (2.77 g), dimethylpyridine (4.7 mL), and tetrahydrofuran (30 mL), triisopropyltrifluoromethanesulfonic acid (2.0 mL), Stirring was carried out for 1 hour at room temperature. Water and ethyl acetate were added to the reaction mixture, and the organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by basic EtOAc EtOAc EtOAc (EtOAc)
製造例56 Manufacturing Example 56
於1-甲基-4-(6-{〔(三異丙基矽)氧基〕甲基}吡啶-3-基)-1H-苯並咪唑(2.37g)的四氫呋喃(20mL)溶液中加入四丁基銨氟化物(9.0mL),在室溫下進行1小時攪拌。將反應液減壓濃縮,將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化後得到〔5-(1-甲基-1H-苯並咪唑-4-基)吡啶-2-基〕甲醇(0.974g)。 Add to a solution of 1-methyl-4-(6-{[(triisopropylsulfonyl)oxy)methyl}pyridin-3-yl)-1H-benzimidazole (2.37 g) in tetrahydrofuran (20 mL) Tetrabutylammonium fluoride (9.0 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and purified residue purified m. Methanol (0.974 g).
製造例57 Manufacturing Example 57
氬環境下,將2-溴-4,5-二甲氧基苯胺(4.73g)、甲基丙烯酸甲基(6.5mL)、乙酸鈀(229mg)、參(2-甲基苯基)膦(620mg)、N,N-二異丙基乙基胺(11mL)、及N,N-二甲基甲醯胺(50mL)的混合物在100℃進行48小 時攪拌。於反應液加入水,並以乙酸乙酯萃取。將有機層以無水硫酸鈉乾燥後減壓濃縮。於殘渣加入6M鹽酸(70mL),在100℃進行1小時攪拌。將反應液冰冷,將析出之固體濾取並減壓乾燥後,得到6,7-二甲氧基-3-甲基喹啉-2(1H)-酮(0.85g)。 2-Bromo-4,5-dimethoxyaniline (4.73 g), methyl methacrylate (6.5 mL), palladium acetate (229 mg), ginseng (2-methylphenyl) phosphine (under argon) a mixture of 620 mg), N,N-diisopropylethylamine (11 mL), and N,N-dimethylformamide (50 mL) at 48 ° C for 48 hours Stir when. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated. 6M Hydrochloric acid (70 mL) was added to the residue, and the mixture was stirred at 100 ° C for 1 hour. The reaction liquid was ice-cooled, and the precipitated solid was filtered and dried under reduced pressure to give 6,7-dimethoxy-3-methylquinoline-2(1H)-one (0.85 g).
製造例58 Manufacturing Example 58
於6,7-二甲氧基-3-甲基喹啉-2(1H)-酮(840mg),冰冷下加入三氯氧磷(4mL),在100℃進行1小時攪拌。將反應液減壓濃縮,將殘渣以氯仿稀釋後,注入冰。加入飽和碳酸氫鈉水溶液,並以氯仿萃取後,將有機層以飽和碳酸氫鈉洗淨。以無水硫酸鈉進行乾燥後減壓濃縮,將殘渣以矽膠管柱層析法(己烷/乙酸乙酯)進行純化後得到2-氯-6,7-二甲氧基-3-甲基喹啉(569mg)。 To 6,7-dimethoxy-3-methylquinolin-2(1H)-one (840 mg), phosphorus oxychloride (4 mL) was added under ice cooling, and the mixture was stirred at 100 ° C for 1 hour. The reaction liquid was concentrated under reduced pressure, and the residue was diluted with chloroform, and then poured into ice. After adding a saturated aqueous solution of sodium hydrogencarbonate and extracting with chloroform, the organic layer was washed with saturated sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified to silica gel column chromatography (hexane/ethyl acetate) to give 2-chloro-6,7-dimethoxy-3-methylquine. Porphyrin (569 mg).
製造例59 Manufacturing Example 59
於1-甲基-4-(吡啶-4-基)-1H-吡唑-3-醇(5g)的甲醇(250mL)溶液中,加入75%之m-氯過安息香酸(8.53g),在室溫下進行24小時攪拌。於反應液中加入溶解於水(25mL)之硫代硫酸鈉(2.25g),在室溫下進行5分鐘攪拌。將反應液減壓濃縮,將殘渣以矽膠管柱層析法(氯仿/甲醇)進行純化後得到1-甲基-4-(1-氧化物吡啶-4-基)-1H-吡唑-3-醇(3.957g)。 To a solution of 1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-ol (5 g) in methanol (250 mL), EtOAc (EtOAc) Stirring was carried out for 24 hours at room temperature. Sodium thiosulfate (2.25 g) dissolved in water (25 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 5 minutes. The reaction solution was concentrated under reduced pressure and the residue was purified to silica gel column chromatography (chloroform/methanol) to give 1-methyl-4-(1-oxide pyridin-4-yl)-1H-pyrazole-3 - Alcohol (3.957 g).
製造例60 Manufacturing Example 60
於4-碘-1-甲基-1H-吡唑-3-羧酸甲基(9.00g)、1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)吡啶-2(1H)-酮(11.9g)、N,N-二甲基甲醯胺(240mL)、及水(72mL)加入碳酸銫(22.0g)、肆三苯基膦鈀(3.65g),在80℃進行9小時攪拌。將反應液減壓濃縮,將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化後得到1-甲基-4-(1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-3-羧酸甲基(8.24g)。 4-Iodo-1-methyl-1H-pyrazole-3-carboxylic acid methyl (9.00 g), 1-methyl-5-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)pyridine-2(1H)-one (11.9 g), N,N-dimethylformamide (240 mL), and water (72 mL) were added cesium carbonate (22.0) g), triphenylphosphine palladium (3.65 g), stirred at 80 ° C for 9 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified to silica gel column chromatography (methanol / chloroform) to give 1-methyl-4-(1-methyl-6-s-oxo-1,6-dihydropyridine. 3-yl)-1H-pyrazole-3-carboxylic acid methyl (8.24 g).
製造例61 Manufacturing Example 61
氬環境下,將4-溴-1-甲基-1H-苯並咪唑(920mg)、丙烯酸乙酯(1.4mL)、雙(三-tert-丁基膦)鈀(111mg)、N,N-二環己基甲基胺(936mg)、及二噁烷(4.6mL)的混合物,在100℃進行12小時攪拌。追加雙(三-tert-丁基膦)鈀(111mg),在100℃進行3小時攪拌。減壓濃縮後將殘渣以矽膠管柱層析法(己烷/乙酸乙酯)進行純化後得到(2E)-3-(1-甲基-1H-苯並咪唑-4-基)丙烯酸乙酯(600mg)。 4-Bromo-1-methyl-1H-benzimidazole (920 mg), ethyl acrylate (1.4 mL), bis(tri-tert-butylphosphine)palladium (111 mg), N,N- under argon atmosphere A mixture of dicyclohexylmethylamine (936 mg) and dioxane (4.6 mL) was stirred at 100 ° C for 12 hours. Bis(tri-tert-butylphosphine)palladium (111 mg) was added, and the mixture was stirred at 100 ° C for 3 hours. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford ethyl (2E)-3-(1-methyl-1H-benzimidazol-4-yl) (600mg).
製造例62 Manufacturing Example 62
氬環境下,於(2E)-3-(1-甲基-1H-苯並咪唑-4-基)丙烯酸乙酯(568mg)的四氫呋喃(12mL)溶液中,在-50℃加入1.01M的氫化二異丁基鋁之甲苯溶液(7.4mL )。經3小時升溫至-30℃後,加入飽和洛捷爾鹽水溶液與乙酸乙酯,暫時攪拌。以乙酸乙酯萃取後,將有機層以無水硫酸鈉乾燥並減壓濃縮。將殘渣以矽膠管柱層析法(氯仿/甲醇)進行純化後得到(2E)-3-(1-甲基-1H-苯並咪唑-4-基)丙-2-烯-1-醇(241 mg)。 Addition of 1.01M hydrogenation at -50 ° C in a solution of ethyl (2E)-3-(1-methyl-1H-benzimidazol-4-yl)acrylate (568 mg) in tetrahydrofuran (12 mL) Diisobutyl aluminum toluene solution (7.4mL ). After heating to -30 ° C over 3 hours, a saturated aqueous solution of Lodil brine and ethyl acetate were added and stirred temporarily. After extracting with ethyl acetate, the org. The residue was purified by silica gel column chromatography (chloroform/methanol) to give (2E)-3-(1-methyl-1H-benzimidazol-4-yl)prop-2-en-1-ol ( 241 mg).
製造例63 Manufacturing Example 63
氬環境下,將3-(苯甲氧基)-1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)-1H-吡唑(2g)、4-氯-3-氟吡啶(925mg)、參(二苯亞甲基丙酮)二鈀(290mg)、三環己基膦(215mg)、磷酸鉀(4.06g)、二噁烷(30mL)、及水(15mL)的混合物在100℃進行5小時攪拌。將反應液恢復至室溫後,加入乙酸乙酯,以飽和食鹽水洗淨。將有機層減壓濃縮後,將殘渣以矽膠管柱層析法(己烷/乙酸乙酯)進行純化後得到4-〔3-(苯甲氧基)-1-甲基-1H-吡唑-4-基〕-3-氟吡啶(830 mg)。 3-(Benzyloxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl under argon -1H-pyrazole (2g), 4-chloro-3-fluoropyridine (925mg), ginseng (diphenylmethyleneacetone) dipalladium (290mg), tricyclohexylphosphine (215mg), potassium phosphate (4.06g) The mixture of dioxane (30 mL) and water (15 mL) was stirred at 100 ° C for 5 hours. After the reaction solution was returned to room temperature, ethyl acetate was added and the mixture was washed with brine. After the organic layer was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 4-[3-(benzyloxy)-1-methyl-1H-pyrazole. 4-yl]-3-fluoropyridine (830 mg).
製造例64 Manufacturing Example 64
將4-〔3-(苯甲氧基)-1-甲基-1H-吡唑-4-基〕-3-氟吡啶(820mg)、五甲基苯(858mg)、及三氟乙酸(4.5mL)的混合物在室溫中進行12小時攪拌。加入乙酸乙酯,將固體濾取並減壓乾燥後得到4-(3-氟吡啶-4-基)-1-甲基-1H-吡唑-3-醇 三氟乙酸鹽(713 mg)。 4-[3-(Benzyloxy)-1-methyl-1H-pyrazol-4-yl]-3-fluoropyridine (820 mg), pentamethylbenzene (858 mg), and trifluoroacetic acid (4.5 The mixture of mL) was stirred at room temperature for 12 hours. Ethyl acetate was added, and the solid was filtered and dried under reduced pressure to give 4-(3-fluoropyridin-4-yl)-1-methyl-1H-pyrazol-3-ol trifluoroacetate ( 713 mg).
製造例65 Manufacturing Example 65
於(4-碘-1-甲基-1H-吡唑-3-基)甲醇(1.284g)、咪唑(1.06g)、N,N-二甲基甲醯胺(13mL)的混合物中加入tert-丁基二甲基氯矽烷(1g),在室溫下進行1小時攪拌。加入水並以乙酸乙酯萃取。將有機層以水、飽和食鹽水之順序洗淨後,以無水硫酸鈉乾燥並減壓濃縮。將殘渣以矽膠管柱層析法(己烷/乙酸乙酯)進行純化後得到3-({〔tert-丁基(二甲基)矽基〕氧基}甲基)-4-碘-1-甲基-1H-吡唑(1.564 g)。 Add tert to a mixture of (4-iodo-1-methyl-1H-pyrazol-3-yl)methanol (1.284 g), imidazole (1.06 g), N,N-dimethylformamide (13 mL) Butyldimethylchloromethane (1 g) was stirred at room temperature for 1 hour. Water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 3-({[tert-butyl(dimethyl)methyl)oxy}methyl)-4-io -Methyl-1H-pyrazole (1.564 g).
製造例66 Manufacturing Example 66
於1-甲基-1H-吡唑-3-醇(9.92g)的N,N-二甲基甲醯胺(120mL)溶液中加入碳酸鉀(16.8g)、苯甲基溴化物(20.8g),在50℃進行4小時加熱攪拌。將反應液減壓濃縮,於殘渣加入水並以乙酸乙酯萃取。將有機相減壓濃縮,將殘渣以矽膠管柱層析法(乙酸乙酯-己烷)進營分離純化後得到3-(苯甲氧基)-1-甲基-1H-吡唑(13.8g)。 Potassium carbonate (16.8 g), benzyl bromide (20.8 g) was added to a solution of 1-methyl-1H-pyrazol-3-ol (9.92 g) in N,N-dimethylformamide (120 mL). ), heating and stirring at 50 ° C for 4 hours. The reaction mixture was concentrated under reduced vacuo. The organic phase was concentrated under reduced pressure, and the residue was purified and purified eluted eluted eluted eluting eluting g).
製造例371 Manufacturing Example 371
於1-甲基-1H-苯並三唑-4-胺(333mg)與乙腈(8ml)的混合物中,加入溴化銅(II)(552mg)與亞硝酸異戊酯(319mg),在室溫下進行2小時攪拌。將反應液以矽藻土過濾,以乙酸乙酯洗淨後,將濾液減壓下濃縮。將 殘渣以矽膠管柱層析法(己烷/乙酸乙酯)進行純化後得到4-溴-1-甲基-1H-苯並三唑(181mg)。 In a mixture of 1-methyl-1H-benzotriazol-4-amine (333 mg) and acetonitrile (8 ml), copper (II) bromide (552 mg) and isoamyl nitrite (319 mg) were added to the chamber. Stirring was carried out for 2 hours at a temperature. The reaction mixture was filtered through Celite, washed with ethyl acetate, and evaporated. will The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford 4-bromo-1-methyl-1H-benzotriazole (181 mg).
製造例372 Manufacturing Example 372
將8-〔4-(四氫-2H-吡喃-2-氧基)苯基〕咪唑並〔1,2-a〕吡啶(535mg)、碳酸氫鈉(679mg)、N-溴琥珀酸醯亞胺(324mg)及氯仿(10ml)的混合物,在室溫下進行4小時攪拌。於反應液中加入飽和碳酸氫鈉水溶液,以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨後,乾燥並在減壓下濃縮。將殘渣以矽膠管柱層析法(己烷/乙酸乙酯)進行純化後得到3-溴-8-〔4-(四氫-2H-吡喃-2-氧基)苯基〕咪唑並〔1,2-a〕吡啶(540mg)。 8-[4-(Tetrahydro-2H-pyran-2-oxy)phenyl]imidazo[1,2-a]pyridine (535 mg), sodium hydrogencarbonate (679 mg), N-bromosuccinate A mixture of the imine (324 mg) and chloroform (10 ml) was stirred at room temperature for 4 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and ethyl acetate was evaporated. The organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 3-bromo-8-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]imidazo[ 1,2-a]pyridine (540 mg).
製造例385 Manufacturing Example 385
於4-甲氧基安息香酸(1.52g)、N-甲基-1,2-苯二胺‧鹽酸鹽(2.52g)、1-羥基苯並三唑(1.62g)、三乙基胺(3.48 mL)的N,N-二甲基甲醯胺(50 ml)溶液中加入1-(3-二甲基胺基丙基)-3-乙基碳二亞胺‧鹽酸鹽(2.30 g),在室溫下進行12小時攪拌。於反應液中加入乙酸乙酯,將有機相以水、飽和食鹽水洗淨後減壓濃縮。將所得之粗純化物溶解於乙酸(46 mL),在90℃進行12小時加熱攪拌。放冷後,將反應液減壓濃縮,於殘渣加入飽和碳酸氫鈉水溶液並以氯仿萃取。將有機層經減壓濃縮後,將殘渣以矽膠管柱層析法(甲醇/氯仿)進行分離純化後得 到2-(4-甲氧基苯基)-1-甲基-1H-苯並咪唑(1.98 g)。 4-methoxybenzoic acid (1.52g), N-methyl-1,2-phenylenediamine hydrochloride (2.52g), 1-hydroxybenzotriazole (1.62g), triethylamine (3.48 mL) of N,N-dimethylformamide (50 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide ‧ hydrochloride (2.30) g), stirring was carried out for 12 hours at room temperature. Ethyl acetate was added to the reaction mixture, and the organic phase was washed with water and brine, and evaporated. The obtained crude purified product was dissolved in acetic acid (46 mL), and stirred at 90 ° C for 12 hours. After allowing to cool, the reaction mixture was evaporated to dryness. After the organic layer was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (methanol / chloroform). To 2-(4-methoxyphenyl)-1-methyl-1H-benzimidazole (1.98 g).
製造例387 Manufacturing Example 387
將3-溴-N-1-甲基苯-1,2-二胺二鹽酸鹽(350 mg)溶解於甲苯(5.9 ml),在室溫加入三氟乙酸(2.9 ml),在80℃進行6小時加熱攪拌。將反應溶液放冷,減壓下濃縮,將殘渣以管柱層析法(己烷/乙酸乙酯)進行分離純化後得到4-溴-1-甲基-2-(三氟甲基)-1H-苯並咪唑(388 mg)。 3-Bromo-N-1-methylbenzene-1,2-diamine dihydrochloride (350 mg) was dissolved in toluene (5.9 ml), trifluoroacetic acid (2.9 ml) was added at room temperature at 80 ° C Heat and stir for 6 hours. The reaction solution was cooled, concentrated under reduced pressure, and the residue was purified by column chromatography (hexane/ethyl acetate) to give 4-bromo-1-methyl-2-(trifluoromethyl)- 1H-benzimidazole (388 mg).
製造例389 Manufacturing Example 389
於3-溴-N-1-甲基苯-1,2-二胺二鹽酸鹽(350 mg)的四氫呋喃溶液(5.0 ml)中,冰冷下將吡啶(0.36 ml)與甲氧基乙醯基氯化物(0.12 ml)依順序加入,在室溫下進行1小時攪拌。於反應溶液加入1M鹽酸(2.0 ml),以乙酸乙酯萃取。將分離之有機層以飽和食鹽水洗淨,以無水硫酸鈉乾燥後,經濃縮所得之殘渣中加入乙酸(3.5 ml),在90℃進行15小時攪拌。於室溫放冷後,將反應溶液濃縮,將殘渣以矽膠管柱層析法(鹼性矽膠;以乙酸乙酯-己烷=70:30→50:50)分離純化後得到4-溴-2-(甲氧基甲基)-1-甲基-1H-苯並咪唑(165 mg)。 To a solution of 3-bromo-N-1-methylbenzene-1,2-diamine dihydrochloride (350 mg) in tetrahydrofuran (5.0 ml), pyridine (0.36 ml) The base chloride (0.12 ml) was added in order and stirred at room temperature for 1 hour. 1M Hydrochloric acid (2.0 ml) was added to the reaction solution, and ethyl acetate was evaporated. The separated organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then evaporated to ethyl acetate (3.5 ml), and the mixture was stirred at 90 ° C for 15 hours. After allowing to cool at room temperature, the reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (basic silica gel; ethyl acetate-hexane=70:30→50:50) to give 4-bromo- 2-(Methoxymethyl)-1-methyl-1H-benzimidazole (165 mg).
製造例391 Manufacturing Example 391
於甲醇(1.2 ml)的四氫呋喃溶液(12.0ml)冰冷下 加入60%油性氫化鈉(200 mg),在同溫度下進行15分鐘攪拌後,加入8-溴-4-氯喹啉(600 mg),恢復至室溫後,在80℃進行2小時加熱攪拌。冰冷下於反應液加入乙酸(0.28 ml)並中和後,加入乙酸乙酯與水,分離有機層。將經分離之有機層以無水硫酸鎂乾燥後,濃縮,將殘渣以矽膠管柱層析法(己烷/乙酸乙酯)進行純化後得到8-溴-4-甲氧基喹啉(327mg)。 Under ice cooling in methanol (1.2 ml) in tetrahydrofuran (12.0 ml) 60% of an oily sodium hydride (200 mg) was added, and after stirring at the same temperature for 15 minutes, 8-bromo-4-chloroquinoline (600 mg) was added thereto, and the mixture was returned to room temperature, followed by heating and stirring at 80 ° C for 2 hours. After adding acetic acid (0.28 ml) to the reaction mixture under ice cooling and neutralizing, ethyl acetate and water were added, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and then evaporated. mjjjjjjjj .
製造例398 Manufacturing Example 398
將6-氯-8-〔4-(四氫-2H-吡喃-2-氧基)苯基〕咪唑並〔1,2-b〕噠嗪(304mg)、10%鈀/碳(100mg;55%含水)及乙醇(20ml)的混合物,在常壓之氫環境下,在室溫下進行2小時攪拌。將反應液以矽藻土過濾,減壓下濃縮。將殘渣懸浮於四氫呋喃(10ml)中,加入1M鹽酸(2ml)並在室溫中進行2小時攪拌。於反應液中加入1M氫氧化鈉水溶液(2ml),以氯仿萃取。將有機層乾燥後減壓下濃縮,得到4-(咪唑並〔1,2-b〕噠嗪-8-基)酚(169mg)。 6-Chloro-8-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]imidazo[1,2-b]pyridazine (304 mg), 10% palladium on carbon (100 mg; A mixture of 55% aqueous) and ethanol (20 ml) was stirred at room temperature for 2 hours under a hydrogen atmosphere at normal pressure. The reaction solution was filtered through Celite, and concentrated. The residue was suspended in tetrahydrofuran (10 ml), and 1M hydrochloric acid (2 ml) was added and stirred at room temperature for 2 hours. A 1 M aqueous sodium hydroxide solution (2 ml) was added to the mixture and the mixture was evaporated. The organic layer was dried and concentrated under reduced pressure to give 4-(im[rho]-[l,2-b]pyridazin-8-yl) phenol (169 mg).
製造例409 Manufacturing Example 409
使2-甲基-3-〔4-(四氫-2H-吡喃-2-氧基)苯基〕喹喔啉(1.345g)的四氫呋喃(10mL)溶液冰冷,加入1M鹽酸(9mL)並進行5小時攪拌。將反應液以1mol/l氫氧化鈉水溶液(9mL)中和,以乙酸乙酯萃取。將反應溶液 以無水硫酸鈉乾燥後減壓濃縮。將殘渣以乙酸乙酯-己烷洗淨,得到4-(3-甲基喹喔啉-2-基)酚(960mg)。 A solution of 2-methyl-3-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]quinoxaline (1.345 g) in tetrahydrofuran (10 mL) was evaporated. Stir for 5 hours. The reaction solution was neutralized with a 1 mol/l aqueous sodium hydroxide solution (9 mL) and ethyl acetate. Reaction solution It was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was washed with ethyl acetate-hexane to give 4-(3-methylquinoxalin-2-yl)phenol (960 mg).
製造例432 Manufacturing Example 432
將4-〔4-(四氫-2H-吡喃-2-氧基)苯基-1,3-苯並噁唑(359mg)、吡啶鎓 對甲苯磺酸酯(31mg)及乙醇(12ml)的混合物,在油溫80℃中進行30分加熱攪拌。於室溫冷卻後,加入飽和碳酸氫鈉,以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨後,乾燥、減壓下濃縮,將所得之殘渣以水洗淨,得到4-(1,3-苯並噁唑-4-基)酚(206mg)。 4-[4-(Tetrahydro-2H-pyran-2-oxy)phenyl-1,3-benzoxazole (359 mg), pyridinium p-toluenesulfonate (31 mg) and ethanol (12 ml) The mixture was heated and stirred at an oil temperature of 80 ° C for 30 minutes. After cooling at room temperature, saturated sodium bicarbonate was added and ethyl acetate was evaporated. The organic layer was washed with saturated brine, dried and evaporated, evaporated, evaporated
製造例461 Manufacturing Example 461
將4-溴-1-甲基-1H-苯並咪唑(300mg)、2,6-二氟-4-甲氧基苯基亞硼酸(267mg)、參(二苯亞甲基丙酮)二鈀(0)(65mg)、三-t-丁基鏻四氟硼酸鹽(52mg)、氟化鉀(273mg)、四氫呋喃(4ml)及水(0.4ml)的混合物在油溫65℃中進行1整天加熱攪拌。於室溫冷卻後將反應液以乙酸乙酯稀釋,以水再以飽和食鹽水洗淨後,乾燥並減壓下濃縮。將殘渣以矽膠管柱層析法(氯仿/甲醇)進行純化後得到4-(2,6-二氟-4-甲氧基苯基)-1-甲基-1H-苯並咪唑(31mg)。 4-Bromo-1-methyl-1H-benzimidazole (300 mg), 2,6-difluoro-4-methoxyphenylboronic acid (267 mg), ginseng (diphenylmethyleneacetone) dipalladium A mixture of (0) (65 mg), tri-t-butylhydrazine tetrafluoroborate (52 mg), potassium fluoride (273 mg), tetrahydrofuran (4 ml) and water (0.4 ml) was taken at an oil temperature of 65 ° C. Stir under heating. After cooling at room temperature, the reaction mixture was diluted with EtOAc. The residue was purified by column chromatography (chloroform/methanol) to give 4-(2,6-difluoro-4-methoxyphenyl)-1-methyl-1H-benzimidazole (31 mg) .
製造例462 Manufacturing example 462
於4-氯-8-〔4-(四氫-2H-吡喃-2-氧基)苯基〕喹啉(200 mg)、三甲基環硼氧烷(0.1 ml)的1,2-二甲氧基乙烷(2.0 ml)懸浮液中,加入肆(三苯基膦)鈀(0)(70 mg)、2 M碳酸鈉水溶液(0.4 ml),以微波在120℃下進行1小時反應。放冷後將不溶物以矽藻土過濾,於濾液加入水並以乙酸乙酯萃取,進行減壓濃縮。將殘渣以矽膠管柱層析法(己烷/乙酸乙酯)進行分離純化,得到4-甲基-8-〔4-(四氫-2H-吡喃-2-氧基)苯基〕喹啉(164 mg)。 1,2-O-chloro-8-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]quinoline (200 mg), trimethylboroxine (0.1 ml) To a suspension of dimethoxyethane (2.0 ml), hydrazine (triphenylphosphine) palladium (0) (70 mg), 2 M aqueous sodium carbonate (0.4 ml) was added, and the mixture was stirred at 120 ° C for one hour. reaction. After cooling, the insoluble material was filtered over Celite, and water was added to the filtrate, and ethyl acetate was evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford 4-methyl-8-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl] Porphyrin (164 mg).
製造例463 Manufacturing Example 463
於3-溴-8-〔4-(四氫-2H-吡喃-2-氧基)苯基〕咪唑並〔1,2-a〕吡啶(284mg)與甲苯(6.3ml)的混合物中,加入水(0.43ml)、三甲基環硼氧烷(96mg)、磷酸三鉀(291mg)、乙酸鈀(II)(17mg)及三環己基膦(43mg),在油溫110℃下進行24小時加熱攪拌。於室溫冷卻後加入乙酸乙酯,以水洗淨。將有機層以飽和食鹽水洗淨後,乾燥並在減壓下濃縮。將殘渣以矽膠管柱層析法(己烷/乙酸乙酯)進行純化,再以鹼性矽膠管柱層析法(己烷/乙酸乙酯)進行純化後得到3-甲基-8-〔4-(四氫-2H-吡喃-2-氧基)苯基〕咪唑並〔1,2-a〕吡啶(102mg)。 In a mixture of 3-bromo-8-[4-(tetrahydro-2H-pyran-2-oxy)phenyl]imidazo[1,2-a]pyridine (284 mg) and toluene (6.3 ml), Water (0.43 ml), trimethylboroxine (96 mg), tripotassium phosphate (291 mg), palladium(II) acetate (17 mg) and tricyclohexylphosphine (43 mg) were added at an oil temperature of 110 ° C. Heat and stir for hours. After cooling at room temperature, ethyl acetate was added and washed with water. The organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) 4-(Tetrahydro-2H-pyran-2-yloxy)phenyl]imidazo[1,2-a]pyridine (102 mg).
製造例466 Manufacturing example 466
將2-胺基-4'-甲氧基聯苯基-3-羧酸(975mg)、甲脒 乙酸鹽(1.3g)及乙醇(10ml)的混合物,在油溫75℃中進行16小時加熱攪拌。於室溫冷卻後,過濾取出析出物,得到8-(4-甲氧基苯基)喹唑啉-4-醇(852mg)。 2-Amino-4'-methoxybiphenyl-3-carboxylic acid (975 mg), formazan A mixture of acetate (1.3 g) and ethanol (10 ml) was heated and stirred at an oil temperature of 75 ° C for 16 hours. After cooling at room temperature, the precipitate was filtered off to give 8-(4-methoxyphenyl)quinazolin-4-ol (852 mg).
製造例467 Manufacturing Example 467
將8-(4-甲氧基苯基)喹唑啉-4-醇(300mg)、五氯化磷(500mg)及氧氯化磷(1.8ml)的混合物,在油溫105℃中進行8小時加熱攪拌。於室溫冷卻後減壓下濃縮,於殘渣加入甲苯並在減壓下濃縮。於殘渣加入氯仿,以飽和碳酸氫鈉水溶液,再以飽和食鹽水洗淨後乾燥,過濾並在減壓下濃縮。將殘渣以矽膠管柱層析法(己烷/乙酸乙酯)進行純化後得到4-氯-8-(4-甲氧基苯基)喹唑啉(142mg)。 A mixture of 8-(4-methoxyphenyl)quinazolin-4-ol (300 mg), phosphorus pentachloride (500 mg) and phosphorus oxychloride (1.8 ml) was carried out at an oil temperature of 105 ° C. Heat and stir for hours. After cooling at room temperature, it was concentrated under reduced pressure. After the residue was added to chloroform, the mixture was washed with saturated aqueous sodium hydrogen sulfate and brine and evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford 4-chloro-8-(4-methoxyphenyl) quinazoline (142 mg).
製造例469 Manufacturing Example 469
於4-氯-8-(4-甲氧基苯基)喹唑啉(177mg)的二氯甲烷(5ml)溶液中,加入p-甲苯磺醯醯肼(125mg),在室溫下進行5小時攪拌。將反應液減壓下濃縮,於殘渣加入乙醇(2ml)與1M氫氧化鈉水溶液(2ml),在油溫85℃中進行4小時加熱攪拌。於室溫冷卻後加入水,以二乙基醚進行萃取。將有機層乾燥後過濾,減壓下濃縮,將殘渣以矽膠管柱層析法(己烷/:乙酸乙酯)純化後得到8-(4-甲氧基苯基)喹唑啉(101mg)。 To a solution of 4-chloro-8-(4-methoxyphenyl)quinazoline (177 mg) in dichloromethane (5 ml), p-toluenesulfonate (125 mg) Stir for hours. The reaction mixture was concentrated under reduced pressure. ethyl acetate (2 ml) and 1M aqueous sodium hydroxide (2 ml) was added to the residue, and the mixture was stirred and stirred at an oil temperature of 85 ° C for 4 hours. After cooling at room temperature, water was added and the mixture was extracted with diethyl ether. The organic layer was dried, filtered, evaporated, evaporated, evaporated, mjjjjjjjjjjjjj .
製造例481 Manufacturing Example 481
冰冷下,於5-〔3-(羥基甲基)-1-甲基-1H-吡唑-4-基〕-1-甲基吡啶-2(1H)-酮(33.3g)的二氯甲烷(330mL)混合物中加入氯化亞碸(16.6mL),在室溫下進行5小時攪拌。於反應液加入乙酸乙酯後,將析出之固體經過濾取出,減壓下乾燥後得到5-〔3-(氯甲基)-1-甲基-1H-吡唑-4-基〕-1-甲基吡啶-2(1H)-酮 鹽酸鹽(36.1g)。 Dichloromethane in 5-[3-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl]-1-methylpyridine-2(1H)-one (33.3g) under ice cooling (330 mL) To the mixture was added hydrazine chloride (16.6 mL), and the mixture was stirred at room temperature for 5 hours. After ethyl acetate was added to the reaction mixture, the precipitated solid was filtered and dried under reduced pressure to give 5-[3-(chloromethyl)-1-methyl-1H-pyrazol-4-yl]-1 -methylpyridine-2(1H)-one hydrochloride (36.1 g).
與上述製造例之方法同樣下,製造出後述表所示製造例之化合物。製造例化合物之化學結構式、物理化學性數據及製造法如表6至表57及表148至表166所示。 The compound of the production example shown in the following table was produced in the same manner as in the method of the above production example. The chemical structural formula, physicochemical data and manufacturing method of the compound of the production example are shown in Tables 6 to 57 and Tables 148 to 166.
實施例1 Example 1
於1-甲基-4-(吡啶-4-基)-1H-吡唑-3-胺(177mg)、4-(喹啉-2-基)苯甲醛(284mg)、及1,2-二氯乙烷(1mL)的混合物中,加入鄰鈦酸四異丙基(0.45mL),在85℃進行2小時攪拌。將反應液冰冷後,加入甲醇(5mL)及氫化硼鈉(130mg),在室溫下進行3小時攪拌。追加氫化硼鈉(140mg),再進行2小時攪拌。加入碳酸氫鈉溶液,以氯仿稀釋後,以矽藻土過濾,將濾液之有機層以矽膠管柱層析法(氯仿/甲醇)進行純化後得到1-甲基-4-(吡啶-4-基)-N-〔4-喹啉-2-基)苯甲基〕-1H-吡唑-3-胺(138mg)。 1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-amine (177 mg), 4-(quinolin-2-yl)benzaldehyde (284 mg), and 1,2-di To a mixture of ethyl chloride (1 mL), tetraisopropyl orthotitanate (0.45 mL) was added, and the mixture was stirred at 85 ° C for 2 hours. After the reaction mixture was ice-cooled, methanol (5 mL) and sodium borohydride (130 mg) were added, and the mixture was stirred at room temperature for 3 hours. Sodium borohydride (140 mg) was added, followed by stirring for 2 hours. After adding sodium bicarbonate solution, diluting with chloroform, filtering with diatomaceous earth, the organic layer of the filtrate was purified by column chromatography (chloroform/methanol) to give 1-methyl-4-(pyridine-4- -N-[4-quinolin-2-yl)benzyl]-1H-pyrazol-3-amine (138 mg).
實施例2 Example 2
於1-甲基-4-(吡啶-4-基)-N-〔4-(喹啉-2-基)苯甲基〕-1H-吡唑-3-胺(77mg)、二氯甲烷(4mL)、及乙酸(0.80mL)的混合物中加入甲醛(164mg),進行10分鐘攪拌。加入鈉三乙醯氧基硼氫化物(167mg),在室溫下進行2小時攪拌。追加甲醛(164mg)及鈉三乙醯氧基硼氫化物(167mg),在室溫下進行一夜攪拌。再度加入甲醛(164mg)及鈉三乙醯氧基硼氫化物(167mg),在室溫下進行12小時攪拌。加入碳酸氫鈉溶液,以氯仿萃取。將有機層以矽膠管柱層析法(氯仿/甲醇)進行純化,將所得之殘渣溶解於甲醇中,加入4M氯化氫-乙酸乙酯溶液並減壓濃縮。將殘渣以二異丙基醚/2-丙醇洗淨,得到N,1-二甲基-4-(吡啶-4-基)-N-〔4-(喹啉-2-基)苯甲基〕-1H-吡唑-3-胺 二鹽酸鹽(21mg)。 1-methyl-4-(pyridin-4-yl)-N-[4-(quinolin-2-yl)benzyl]-1H-pyrazol-3-amine (77 mg), methylene chloride Formaldehyde (164 mg) was added to a mixture of 4 mL) and acetic acid (0.80 mL), and stirred for 10 minutes. Sodium triethoxy hydride borohydride (167 mg) was added, and the mixture was stirred at room temperature for 2 hours. Addition of formaldehyde (164 mg) and sodium triethoxyphosphonium hydride (167 mg) was carried out overnight at room temperature. Further, formaldehyde (164 mg) and sodium triethoxyphosphonium hydride (167 mg) were added, and the mixture was stirred at room temperature for 12 hours. A sodium hydrogen carbonate solution was added and extracted with chloroform. The organic layer was purified by EtOAc EtOAc (EtOAc) elute The residue was washed with diisopropyl ether/2-propanol to give N,1-dimethyl-4-(pyridin-4-yl)-N-[4-(quinolin-2-yl)benzene. -1H-pyrazol-3-amine dihydrochloride (21 mg).
實施例3 Example 3
於1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-羧酸(137mg)的二氯甲烷(4mL)溶液中將羰基二咪唑(105mg)在室溫下加入,同溫度下進行15分攪拌。再加入N-羥基乙脒(48mg),在室溫下進行0.5小時攪拌後,將混合物減壓濃縮。於殘渣加入甲苯,在110℃進行12小時攪拌後,加入對甲苯磺酸鹽一水合物(7mg),並進行4小時同溫之攪拌。繼續加入N-甲基吡咯烷酮(2mL),同溫下進一步進行4小時攪拌。放冷後加入水 及飽和食鹽水並以氯仿萃取。將有機層以無水硫酸鎂乾燥後,減壓濃縮,將所得之殘渣懸浮於乙醇及乙酸乙酯之混合溶劑(4:1)中,加入4M氯化氫之乙酸乙酯溶液,在室溫下進行3小時攪拌,得到2-〔4-({〔1-甲基-4-(3-甲基-1,2,4-噁二唑-5-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕喹啉 一鹽酸鹽(70mg)。 In a solution of 1-methyl-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazole-4-carboxylic acid (137 mg) in dichloromethane (4 mL) Carbonyldiimidazole (105 mg) was added at room temperature and stirred at 15 minutes with the same temperature. Further, N-hydroxyacetamidine (48 mg) was added, and the mixture was stirred at room temperature for 0.5 hr. Toluene was added to the residue, and after stirring at 110 ° C for 12 hours, p-toluenesulfonate monohydrate (7 mg) was added, and stirred at the same temperature for 4 hours. Further, N-methylpyrrolidone (2 mL) was added, and the mixture was further stirred at the same temperature for 4 hours. Add water after cooling Saturated brine and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was evaporated from ethyl acetate and ethyl acetate (4:1). After stirring for an hour, 2-[4-({[1-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-pyrazol-3-yl]oxy) was obtained. Methyl)phenyl]quinoline monohydrochloride (70 mg).
實施例4 Example 4
於4-{3-〔(4-溴苯甲基)氧基〕-1-甲基-1H-吡唑-4-基}吡啶(137 mg)、0.5M 2-吡啶基鋅溴化物的四氫呋喃溶液(1.6 mL)、及四氫呋喃(1 mL)的混合物中,加入肆(三苯基膦)鈀(92 mg),封管中於120℃進行1小時之微波照射。放冷後於反應液加入水並使反應停止。將混合物以矽藻土過濾,於殘渣加入乙酸乙酯。將有機層以飽和氯化銨水溶液、飽和食鹽水洗淨。減壓濃縮後將殘渣以矽膠管柱層析法(氯仿/己烷)進行純化。將所得之粗純化物溶解於乙醇中,加入4M氯化氫之乙酸乙酯溶液,在室溫下進行1小時攪拌。加入二乙基醚,過濾取出所生成的沈澱,以二乙基醚洗淨後得到2-〔4-({〔1-甲基-4-(吡啶-4-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕吡啶 二鹽酸鹽(30 mg)。 4-{3-[(4-Bromobenzyl)oxy]-1-methyl-1H-pyrazol-4-yl}pyridine (137 mg), 0.5 M 2-pyridyl zinc bromide in tetrahydrofuran To a mixture of the solution (1.6 mL) and tetrahydrofuran (1 mL), hydrazine (triphenylphosphine)palladium (92 mg) was added, and the mixture was subjected to microwave irradiation at 120 ° C for 1 hour in a sealed tube. After cooling, water was added to the reaction solution and the reaction was stopped. The mixture was filtered over celite, and ethyl acetate was added to the residue. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform/hexane). The obtained crude purified product was dissolved in ethanol, and a 4 M solution of hydrogen chloride in ethyl acetate was added thereto, and the mixture was stirred at room temperature for 1 hour. Diethyl ether was added, and the resulting precipitate was filtered off and washed with diethyl ether to give 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazole)- 3-yl]oxy}methyl)phenyl]pyridine dihydrochloride (30 mg).
實施例5 Example 5
於4-({〔1-甲基-4-(吡啶-4-基)-1H-吡唑-3-基〕氧 基}甲基)安息香酸(400 mg)、1,2-伸苯基二胺(154 mg)、1-羥基苯並三唑(210 mg)、三乙基胺(0.27mL)、及N,N-二甲基甲醯胺(5 mL)混合物中加入WSC鹽酸鹽(296 mg),在室溫下進行1小時攪拌。於反應液中加入乙酸乙酯,將有機層以水、飽和食鹽水洗淨後,並減壓濃縮。將所得之粗純化物溶解於乙酸,在90℃進行12小時攪拌。放冷後將反應液減壓濃縮,於殘渣加入飽和碳酸氫鈉水溶液(40 mL)、水(20 mL)、飽和食鹽水(20 mL)、及氯仿,並進行1小時攪拌。以氯仿萃取後減壓濃縮,將殘渣以矽膠管柱層析法(甲醇/乙酸乙酯)進行純化。將所得之粗純化物溶解於乙醇中,加入4M氯化氫之乙酸乙酯溶液,並在室溫中進行15小時攪拌。於反應液加入二乙基醚,過濾取出所生成的沈澱,以二乙基醚洗淨後得到2-〔4-({〔1-甲基-4-(吡啶-4-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕-1H-苯並咪唑 二鹽酸鹽(148 mg)。 4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy Benzoic acid (400 mg), 1,2-phenylenediamine (154 mg), 1-hydroxybenzotriazole (210 mg), triethylamine (0.27 mL), and N, WSC hydrochloride (296 mg) was added to a mixture of N-dimethylformamide (5 mL), and stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with water and brine, and evaporated. The obtained crude purified product was dissolved in acetic acid, and stirred at 90 ° C for 12 hours. After the reaction mixture was cooled, the reaction mixture was evaporated, evaporated, evaporated,,,,,,,,,,,,,,, After extracting with chloroform, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / ethyl acetate). The obtained crude purified product was dissolved in ethanol, and a 4M solution of hydrogen chloride in ethyl acetate was added and stirred at room temperature for 15 hours. Diethyl ether was added to the reaction mixture, and the resulting precipitate was filtered off and washed with diethyl ether to give 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-) Pyrazol-3-yloxy}methyl)phenyl]-1H-benzimidazole dihydrochloride (148 mg).
實施例6 Example 6
於2-〔4-({〔1-甲基-4-(吡啶-4-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕-1H-苯並咪唑(124 mg)、碳酸鉀(135 mg)、及N,N-二甲基甲醯胺(3 mL)混合物中加入碘化甲基(0.041mL),在室溫下進行2小時攪拌。於反應液中加入乙酸乙酯,將有機層以飽和食鹽水洗淨,並經減壓濃縮。將殘渣以矽膠管柱層析法(氯仿)進行純化。將所得之粗純化物溶解於乙醇中,加入4M氯化氫之乙 酸乙酯溶液,在室溫下進行15小時攪拌。過濾取出所生成的沈澱,以二乙基醚洗淨,得到1-甲基-2-〔4-({〔1-甲基-4-(吡啶-4-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕-1H-苯並咪唑 二鹽酸鹽(76 mg)。 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)oxy}methyl)phenyl]-1H-benzimidazole (124 To a mixture of potassium carbonate (135 mg) and N,N-dimethylformamide (3 mL), methyl iodide (0.041 mL) was added and stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with brine and evaporated. The residue was purified by silica gel column chromatography (chloroform). The obtained crude purified product was dissolved in ethanol, and 4 M of hydrogen chloride was added thereto. The acid ethyl ester solution was stirred at room temperature for 15 hours. The resulting precipitate was filtered off and washed with diethyl ether to give 1-methyl-2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazole-3). -yloxy}methyl)phenyl]-1H-benzimidazole dihydrochloride (76 mg).
實施例7 Example 7
於4-{3-〔(4-溴苯甲基)氧基〕-1-甲基-1H-吡唑-4-基}吡啶(413mg)、喹啉-8-基亞硼酸(311mg)、及1,2-二甲氧基乙烷(30mL)的混合物中,加入肆(三苯基膦)鈀(277mg)及1M碳酸鈉水溶液(3mL),在90℃進行5小時攪拌。將反應液減壓濃縮,將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化。將所得之粗純化物溶解於乙酸乙酯,加入4M氯化氫的乙酸乙酯溶液,並進行30分鐘攪拌。過濾取出所生成的沈澱,以乙酸乙酯洗淨後得到8-〔4-({〔1-甲基-4-(吡啶-4-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕喹啉 二鹽酸鹽(468mg)。 4-{3-[(4-Bromobenzyl)oxy]-1-methyl-1H-pyrazol-4-yl}pyridine (413 mg), quinoline-8-ylboronic acid (311 mg), To a mixture of 1,2-dimethoxyethane (30 mL), hydrazine (triphenylphosphine)palladium (277 mg) and 1 M aqueous sodium carbonate (3 mL) were added, and stirred at 90 ° C for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified to silica gel column chromatography (methanol / chloroform). The obtained crude purified product was dissolved in ethyl acetate, and a 4M solution of hydrogen chloride in ethyl acetate was added and stirred for 30 minutes. The resulting precipitate was filtered off and washed with ethyl acetate to give 8-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)oxy} Methyl)phenyl]quinoline dihydrochloride (468 mg).
實施例8 Example 8
於2-〔4-({〔4-(吡啶-4-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕喹啉(567mg)的N,N-二甲基甲醯胺(20mL)溶液中加入1,1,1-三氟-2-碘乙烷(630mg)、及碳酸銫(1.46g),在60℃進行5小時攪拌。使反應液減壓濃縮後,於殘渣加入水,以乙酸乙酯萃取。將有機層以矽膠管柱層析法(甲醇/氯仿)進行純化。將粗純化物溶解 於乙酸乙酯,加入4M氯化氫之乙酸乙酯溶液,進行30分鐘攪拌。過濾取出所生成的沈澱,以乙酸乙酯洗淨,得到2-〔4-({〔4-(吡啶-4-基)-1-(2,2,2-三氟甲基)-1H-吡唑-3-基〕氧基}甲基)苯基〕喹啉 二鹽酸鹽(650mg)。 N,N-dimethyl at 2-[4-({[4-(pyridin-4-yl)-1H-pyrazol-3-yl)oxy}methyl)phenyl]quinoline (567 mg) To a solution of tolamine (20 mL), 1,1,1-trifluoro-2-iodoethane (630 mg) and cesium carbonate (1.46 g) were added, and the mixture was stirred at 60 ° C for 5 hours. The reaction mixture was concentrated under reduced pressure. The organic layer was purified by column chromatography (methanol / chloroform). Dissolve the crude extract To a solution of ethyl acetate, a 4M solution of hydrogen chloride in ethyl acetate was added and stirred for 30 min. The resulting precipitate was filtered and washed with ethyl acetate to give 2-[4-({[4-(pyridin-4-yl)-1-(2,2,2-trifluoromethyl)-1H- Pyrazol-3-yloxy}methyl)phenyl]quinoline dihydrochloride (650 mg).
實施例9 Example 9
於〔4-(吡啶-4-基)-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-1-基〕乙酸乙酯(380mg)的乙醇(15mL)溶液加入1M氫氧化鈉水溶液(2.5mL),在60℃進行5小時攪拌。將反應液減壓濃縮,以1N鹽酸中和。將過濾取出所生成的沈澱、濾液以乙酸乙酯萃取。合併有機層與沈澱,以矽膠管柱層析法(甲醇/氯仿)進行純化。將所得之粗純化物以乙酸乙酯-己烷洗淨,得到〔4-(吡啶-4-基)-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-1-基〕乙酸(57mg)。 Ethyl [4-(pyridin-4-yl)-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazol-1-yl]acetate (380 mg) A solution of ethanol (15 mL) was added to a 1M aqueous sodium hydroxide solution (2.5 mL), and stirred at 60 ° C for 5 hours. The reaction solution was concentrated under reduced pressure and neutralized with 1N hydrochloric acid. The resulting precipitate was taken out by filtration, and the filtrate was extracted with ethyl acetate. The organic layer and the precipitate were combined and purified by silica gel column chromatography (methanol / chloroform). The obtained crude product was washed with ethyl acetate-hexane to give [4-(pyridin-4-yl)-3-{[4-(quinolin-2-yl)phenylmethyl]oxy}- 1H-pyrazol-1-yl]acetic acid (57 mg).
實施例10 Example 10
將2-〔4-({〔1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕喹啉(300mg)、3-氯噠嗪鹽酸鹽(228mg)、1,1'-雙(二苯基膦)二茂鐵-鈀(II)二氯化物-二氯甲烷錯體(33mg)、碳酸鈉(288mg)、N,N-二甲基甲醯胺(3mL)、及水(1mL)的混合物在氬環境下,在100℃進行12小時攪拌。加入乙酸乙酯及水,將所生成的不溶物以矽藻土過濾分離。將 有機層以飽和食鹽水洗淨後以無水硫酸鎂乾燥後減壓濃縮。將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化。將所得之粗純化物溶解於乙醇-乙酸乙酯,加入4M氯化氫之乙酸乙酯溶液,將溶液減壓濃縮。將所生成的固體以乙醇-醚洗淨並濾取後得到2-〔4-({〔1-甲基-4-(噠嗪-3-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕喹啉 二鹽酸鹽(56mg)。 2-[4-({[1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole) 3-yl]oxy}methyl)phenyl]quinoline (300 mg), 3-chloropyridazine hydrochloride (228 mg), 1,1'-bis(diphenylphosphino)ferrocene-palladium ( II) a mixture of dichloride-dichloromethane (33 mg), sodium carbonate (288 mg), N,N-dimethylformamide (3 mL), and water (1 mL) under argon at 100 ° C Stir for 12 hours. Ethyl acetate and water were added, and the resulting insoluble material was separated by filtration from celite. will The organic layer was washed with brine, dried over anhydrous magnesium The residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude purified product was dissolved in ethyl acetate-ethyl acetate. The resulting solid was washed with ethanol-ether and filtered to give 2-[4-({[1-methyl-4-(pyridazin-3-yl)-1H-pyrazol-3-yl)oxy Methyl)phenyl]quinoline dihydrochloride (56 mg).
實施例11 Example 11
冰冷下於〔4-(吡啶-4-基)-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-1-基〕乙酸乙酯(600mg)的四氫呋喃(40mL)混合物中加入1M氫化二異丁基鋁之甲苯溶液(3.9mL),在室溫下進行1小時攪拌。將反應液冰冷,加入甲醇使反應停止。將所生成的凝膠以矽藻土過濾,將濾液減壓濃縮。將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化。將所得之粗純化物溶解於乙醇中,加入4M氯化氫之乙酸乙酯溶液並減壓濃縮。將殘渣以乙酸乙酯洗淨後得到〔4-(吡啶-4-基)-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-1-基〕乙醇二鹽酸鹽(189mg)。 Ethyl acetate [4-(pyridin-4-yl)-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazol-1-yl] (600 mg) A 1 M solution of diisobutylaluminum hydride in toluene (3.9 mL) was added to a mixture of tetrahydrofuran (40 mL), and stirred at room temperature for 1 hour. The reaction solution was ice-cooled, and methanol was added to stop the reaction. The resulting gel was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude purified product was dissolved in ethanol, and then ethylamine sulfate The residue was washed with ethyl acetate to give [4-(pyridin-4-yl)-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazole-1- Ethyl alcohol dihydrochloride (189 mg).
實施例12 Example 12
於4-(咪唑並〔1,2-a〕吡啶-2-基)酚(330mg)、〔1-甲基-4-(吡啶-4-基)-1H-吡唑-3-基〕甲醇(330mg)的甲苯(10mL)混合物中,加入氰伸甲基三丁基膦( 570mg),在100℃進行8小時攪拌。將反應液減壓濃縮,將殘渣以矽膠管柱層析法(甲醇/氯仿),繼續以鹼性矽膠管柱層析法(乙酸乙酯-己烷)進行純化。於所得之粗純化物中加入乙醇、4M氯化氫的乙酸乙酯溶液,在室溫下進行30分鐘攪拌。將反應液經減壓濃縮後,將殘渣以乙酸乙酯洗淨,得到2-(4-{〔1-甲基-4-(吡啶-4-基)-1H-吡唑-3-基〕甲氧基}苯基)咪唑並〔1,2-a〕吡啶 二鹽酸鹽(459mg)。 4-(Imidazo[1,2-a]pyridin-2-yl)phenol (330 mg), [1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]methanol (330 mg) of a mixture of toluene (10 mL) was added with cyanide methyltributylphosphine ( 570 mg), stirred at 100 ° C for 8 hours. The reaction mixture was concentrated under reduced pressure and purified residue purified eluting eluting eluting eluting Ethyl alcohol and 4 M hydrogen chloride in ethyl acetate solution were added to the obtained crude purified product, and the mixture was stirred at room temperature for 30 minutes. After the reaction mixture was concentrated under reduced pressure, the residue was purified eluting ethyl acetate to afford 2-(4-{[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl] Methoxy}phenyl)imidazo[1,2-a]pyridine dihydrochloride (459 mg).
實施例13 Example 13
於1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-羧酸(246mg)的N,N-二甲基甲醯胺(7mL)溶液中加入羰基二咪唑(166mg),在室溫下進行15小時攪拌。加入乙醯基醯肼(0.40mL),在60℃進行18小時攪拌。冰冷下加入飽和碳酸氫鈉水溶液及飽和食鹽水,以氯仿進行萃取。將有機層以無水硫酸鎂乾燥後減壓下濃縮,將所得之殘渣以矽膠管柱層析法(乙酸乙酯/氯仿)進行純化後得到N'-乙醯基-1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-碳醯肼(198mg)。將所得之N'-乙醯基-1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-碳醯肼(267mg)、Burgess試藥(459mg)、及二氯乙烷(8mL)混合物在封管中,進行130℃ 20分鐘之微波照射。放冷後加入飽和碳酸氫鈉水溶液及飽和食鹽水,以氯仿萃取。將有機層以無水硫酸鎂乾燥後減壓濃縮,將所得 之殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化。將所得之固體懸浮於乙醇後,加入4M氯化氫的乙酸乙酯溶液,並進行30分鐘攪拌,過濾取出所生成的固體,得到2-〔4-({〔1-甲基-4-(5-甲基-1,3,4-噁二唑-2-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕喹啉 一鹽酸鹽(219mg)。 N,N-dimethylformamidine of 1-methyl-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazole-4-carboxylic acid (246 mg) To the amine (7 mL) solution was added carbonyldiimidazole (166 mg), and the mixture was stirred at room temperature for 15 hours. Ethyl hydrazide (0.40 mL) was added and stirred at 60 ° C for 18 hours. Saturated aqueous sodium hydrogencarbonate solution and saturated brine were added under ice-cooling, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and evaporated, evaporated, evaporated,,,,,,,,,, {[4-(Quinolin-2-yl)benzyl)oxy}-1H-pyrazole-4-carboindole (198 mg). The resulting N'-ethinyl-1-methyl-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazole-4-carboquinone (267 mg) A mixture of Burgess test (459 mg) and dichloroethane (8 mL) was placed in a sealed tube and subjected to microwave irradiation at 130 ° C for 20 minutes. After cooling, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine were added, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform). After the obtained solid was suspended in ethanol, a 4 M solution of hydrogen chloride in ethyl acetate was added, and the mixture was stirred for 30 minutes, and the resulting solid was collected by filtration to give 2-[4-({[1-methyl-4-(5- Methyl-1,3,4-oxadiazol-2-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline monohydrochloride (219 mg).
實施例14 Example 14
於1-甲基-4-吡啶-4-基-1H-吡唑-3-醇(200 mg)、〔4-(咪唑並〔1,2-a〕吡啶-3-基)苯基〕甲醇(300 mg)、及甲苯(15 mL)的混合物中,加入氰伸甲基三丁基膦(413 mg),在100℃進行24小時攪拌。放冷後將反應液減壓濃縮,將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化。將所得之粗純化物溶解於乙醇中,加入4M氯化氫之乙酸乙酯溶液,在室溫下進行2小時攪拌。於反應液加入二乙基醚,過濾取出所生成的沈澱,以二乙基醚洗淨,得到3-〔4-({〔1-甲基-4-(吡啶-4-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕咪唑並〔1,2-a〕吡啶 二鹽酸鹽(117 mg)。 1-methyl-4-pyridin-4-yl-1H-pyrazol-3-ol (200 mg), [4-(imidazo[1,2-a]pyridin-3-yl)phenyl]methanol To a mixture of (300 mg) and toluene (15 mL), cyanide methyltributylphosphine (413 mg) was added, and the mixture was stirred at 100 ° C for 24 hours. After allowing to cool, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude purified product was dissolved in ethanol, and a 4 M solution of hydrogen chloride in ethyl acetate was added thereto, and the mixture was stirred at room temperature for 2 hours. Diethyl ether was added to the reaction mixture, and the resulting precipitate was filtered and washed with diethyl ether to give 3-[4-({[1-methyl-4-(pyridin-4-yl)-1H-) Pyrazol-3-yloxy}methyl)phenyl]imidazo[1,2-a]pyridine dihydrochloride (117 mg).
實施例15 Example 15
於2-〔4-(氯甲基)苯基〕喹啉鹽酸鹽(950mg)、4-(1,4-二氧螺〔4.5〕癸-8-基)-1-甲基-1H-吡唑-3-醇(819mg)、及N,N-二甲基甲醯胺(9.5mL)的混合物加入碳酸鉀(1.13g),在60℃進行1小時攪拌。放冷後加入 水及飽和食鹽水,以甲醇及氯仿之混合溶劑進行萃取,以無水硫酸鎂乾燥後減壓濃縮。將殘渣以矽膠管柱層析法(甲醇/氯仿→乙酸乙酯/己烷)進行純化後得到2-〔4-({〔4-(1,4-二氧螺〔4.5〕癸-8-基)-1-甲基-1H-吡唑-3-基〕氧基}甲基)苯基〕喹啉(738mg)。於所得之2-〔4-({〔4-(1,4-二氧螺〔4.5〕癸-8-基)-1-甲基-1H-吡唑-3-基〕氧基}甲基)苯基〕喹啉(1.095g)、四氫呋喃(11mL)、及水(11mL)的混合物,加入對甲苯磺酸鹽(229mg),在室溫下進行3天攪拌。於反應液加入飽和碳酸氫鈉水溶液及飽和食鹽水,並以氯仿萃取。以無水硫酸鎂乾燥後減壓濃縮。將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化。將所得之粗純化物溶解於乙酸乙酯,加入4M氯化氫之乙酸乙酯溶液,在同溫下進行15分鐘攪拌。過濾取出所生成的固體,得到4-(1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)環己酮 一鹽酸鹽(105mg)。 2-[4-(Chloromethyl)phenyl]quinoline hydrochloride (950 mg), 4-(1,4-dioxo[4.5]癸-8-yl)-1-methyl-1H- A mixture of pyrazole-3-ol (819 mg) and N,N-dimethylformamide (9.5 mL) was added to potassium carbonate (1.13 g), and stirred at 60 ° C for 1 hour. Join after cooling Water and saturated brine were extracted with a mixed solvent of methanol and chloroform, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (methanol / chloroform - ethyl acetate /hexane) to give 2-[4-({[4-(1,4-dioxos[4.5]]-8- ))-1-methyl-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (738 mg). 2-[4-({[4-(1,4-Dioxaspiro[4.5]癸-8-yl)-1-methyl-1H-pyrazol-3-yl)oxy}methyl) A mixture of phenyl]quinoline (1.095 g), tetrahydrofuran (11 mL) and water (11 mL) was added to p-toluenesulfonate (229 mg), and stirred at room temperature for 3 days. Saturated aqueous sodium hydrogencarbonate solution and saturated brine were added to the mixture, and the mixture was evaporated. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude purified product was dissolved in ethyl acetate, and a 4M aqueous solution of hydrogen chloride was added, and the mixture was stirred at the same temperature for 15 minutes. The resulting solid was removed by filtration to give 4-(1-methyl-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)cyclohexanone. Monohydrochloride (105 mg).
實施例16 Example 16
氬氣流下,於碘化三甲基氧化鋶(94mg)的二甲基亞碸(1.3mL)混合物中加入鉀tert-丁氧化物,在室溫下進行1.5小時攪拌。於反應混合物中加入4-(1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)環己酮(160mg)的甲苯(3mL)溶液,在室溫下進行9小時攪拌。加入水,以氯仿萃取。將有機層以水、飽和食鹽水洗淨 後,以無水硫酸鎂乾燥,並減壓濃縮後得到2-〔4-({〔1-甲基-4-(1-氧雜螺〔2.5〕辛-6-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕喹啉(150mg)。氬氣流下,於氫化鋰鋁(40mg)的四氫呋喃(3mL)混合物,冰冷下加入2-〔4-({〔1-甲基-4-(1-氧雜螺〔2.5〕辛-6-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕喹啉(150mg)的四氫呋喃(4.5mL)溶液,在同溫進行1小時攪拌。將氨水在冰冷下加入,以甲醇及氯仿之混合溶劑(1:9)稀釋後,在室溫下進行1小時攪拌。將所生成的固體以矽藻土過濾分離,將濾液減壓濃縮後所得之殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化後得到1-甲基-4-(1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)環己醇(97mg)。於所得之1-甲基-4-(1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)環己醇(56mg)之N,N-二甲基甲醯胺(2mL)溶液中加入咪唑(45mg)及tert-丁基二甲基氯矽烷(49mg),在室溫下進行15小時攪拌,其次在50℃下進行24小時攪拌。反應液直接以矽膠管柱層析法(甲醇/氯仿)進行純化,溶解於乙酸乙酯後,加入4M氯化氫之乙酸乙酯溶液,在室溫下進行1小時攪拌。過濾取出所生成的固體,得到1-甲基-4-(1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)環己醇 二鹽酸鹽(25mg)。 Under a stream of argon, potassium tert-butoxide was added to a mixture of dimethylidene iodide (94 mg) in dimethyl hydrazine (1.3 mL) and stirred at room temperature for 1.5 hours. 4-(1-Methyl-3-{[4-(quinolin-2-yl)benzyl)oxy}-1H-pyrazol-4-yl)cyclohexanone (160 mg) was added to the reaction mixture. A solution of toluene (3 mL) was stirred at room temperature for 9 hours. Water was added and extracted with chloroform. Wash the organic layer with water and saturated brine. After drying over anhydrous magnesium sulfate and concentration under reduced pressure afforded 2-[4-({[1-methyl-4-(1-oxaspiro[2.5]oct-6-yl)-1H-pyrazole- 3-yl]oxy}methyl)phenyl]quinoline (150 mg). Under a stream of argon, a mixture of lithium aluminum hydride (40 mg) in tetrahydrofuran (3 mL) was added with 2-[4-({[1-methyl-4-(1-oxaspiro[2.5]oct-6-yl) A solution of -1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (150 mg) in tetrahydrofuran (4.5 mL) was stirred at room temperature for 1 hour. Ammonia water was added under ice cooling, diluted with a mixed solvent of methanol and chloroform (1:9), and stirred at room temperature for 1 hour. The resulting solid was separated by filtration through celite, and the residue was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform) to give 1-methyl-4-(1-methyl- 3-{[4-(Quinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)cyclohexanol (97 mg). 1-Methyl-4-(1-methyl-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)cyclohexanol obtained (56 mg) of N,N-dimethylformamide (2 mL) was added with imidazole (45 mg) and tert-butyldimethylchloromethane (49 mg), stirred at room temperature for 15 hours, followed by 50 Stirring was carried out for 24 hours at °C. The reaction solution was directly purified by silica gel column chromatography (methanol / chloroform), and ethyl acetate was dissolved in ethyl acetate. The resulting solid was removed by filtration to give 1-methyl-4-(1-methyl-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazole-4- Cyclohexanol dihydrochloride (25 mg).
實施例17 Example 17
於4-(1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)環己酮(300mg)、乙醇(6mL)、及水(1.2mL)的混合物中加入羥基胺鹽酸鹽(61mg)及乙酸鈉(78mg),在室溫下進行1小時攪拌。加入飽和食鹽水,以氯仿萃取。以無水硫酸鎂乾燥後減壓濃縮,得到N-羥基-4-(1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)環己烷亞胺(310mg)。於N-羥基-4-(1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)環己烷亞胺(310mg)的四氫呋喃(3mL)溶液中加入3M氫氧化鈉水溶液(606μL),加入氯化4-甲基苯磺醯(166mg)的四氫呋喃(3.2mL)溶液。在50℃進行6小時攪拌後,加入飽和食鹽水並以氯仿萃取。將有機層以無水硫酸鎂乾燥,減壓濃縮後將所得之殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化後得到5-(1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)氮雜環庚烷-2-酮(288mg)。於所得之5-(1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)氮雜環庚烷-2-酮(116mg)的乙酸乙酯(4.6mL)溶液中加入4M氯化氫之二噁烷溶液,在室溫下進行2小時攪拌。過濾取出所生成的固體,得到5-(1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)氮雜環庚烷-2-酮 二鹽酸鹽(102mg)。 4-(1-methyl-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)cyclohexanone (300 mg), ethanol (6 mL) Hydroxylamine hydrochloride (61 mg) and sodium acetate (78 mg) were added to a mixture of water and water (1.2 mL), and stirred at room temperature for 1 hour. Saturated brine was added and extracted with chloroform. After drying over anhydrous magnesium sulfate and concentration under reduced pressure to give N-hydroxy-4-(1-methyl-3-{[4-(quinolin-2-yl)phenylmethyl]oxy}-1H-pyrazole- 4-yl)cyclohexaneimine (310 mg). N-Hydroxy-4-(1-methyl-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)cyclohexaneimine ( A solution of 310 mg of tetrahydrofuran (3 mL) was added 3M aqueous sodium hydroxide (606 μL), and a solution of 4-methylbenzenesulfonium chloride (166 mg) in tetrahydrofuran (3.2 mL) was added. After stirring at 50 ° C for 6 hours, saturated brine was added and extracted with chloroform. The organic layer was dried over anhydrous MgSO.sub.sub.sub.sub.sub.sub.sub.sub.sub. -2-yl)benzyloxy]-1H-pyrazol-4-yl)azepane-2-one (288 mg). 5-(1-methyl-3-{[4-(quinolin-2-yl)benzyl}oxy}-1H-pyrazol-4-yl)azepane-2- A solution of the ketone (116 mg) in ethyl acetate (4.6 mL) was then evaporated. The resulting solid was removed by filtration to give 5-(1-methyl-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)azacyclohexane. Heptan-2-one dihydrochloride (102 mg).
實施例18 Example 18
氬氣流下,於4-(1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)環己酮(462mg)、1,2-二甲氧基乙烷(7mL)、及tert-丁醇(2.8mL)的混合物中,冰冷下加入p-甲苯磺醯甲基異腈(329mg)及鉀tert-丁氧化物(227mg),在同溫進行30分鐘攪拌。且在室溫中進行7小時攪拌。加入水及飽和食鹽水,以乙酸乙酯萃取。以無水硫酸鎂乾燥後減壓濃縮。將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化後得到4-(1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)環己烷腈(167mg)。 4-(1-methyl-3-{[4-(quinolin-2-yl)benzyl)oxy}-1H-pyrazol-4-yl)cyclohexanone (462 mg) under argon In a mixture of 1,2-dimethoxyethane (7 mL) and tert-butanol (2.8 mL), p-toluenesulfonylmethyl isocyanide (329 mg) and potassium tert-butoxide were added under ice cooling. (227 mg), stirred at the same temperature for 30 minutes. And stirring was carried out for 7 hours at room temperature. Water and saturated brine were added, and the mixture was extracted with ethyl acetate. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform) to give 4-(1-methyl-3-{[4-(quinolin-2-yl)phenylmethyl)oxy}-1H- Pyrazol-4-yl)cyclohexanecarbonitrile (167 mg).
實施例19 Example 19
於4-(1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)環己烷腈(166mg、反體及順體的混合物)的乙醇(8.3mL)溶液中,冰冷下加入1M氫氧化鈉水溶液(1.38mL)及30%過氧化氫水(0.28mL),在室溫下進行4天攪拌。加入水並以乙酸乙酯萃取,將有機層以稀亞硫酸鈉水溶液、飽和食鹽水之順序洗淨。將水層以乙酸乙酯萃取,以無水硫酸鎂乾燥後減壓濃縮。將殘渣以矽膠管柱層析法(甲醇/乙酸乙酯)進行純化。將所得之反體溶解於乙酸乙酯中,加入4M氯化氫之乙酸乙酯溶液,在室溫中進行攪拌後,過濾取出所生成的固體,得到反式-4-(1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)環己烷胺甲醯 二鹽酸鹽(26mg、Ex.19)。順體亦 進行同樣處理得到順-4-(1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)環己烷胺甲醯 二鹽酸鹽(58mg、Ex.149)。 4-(1-methyl-3-{[4-(quinolin-2-yl)benzyl}oxy}-1H-pyrazol-4-yl)cyclohexanecarbonitrile (166 mg, anti-body and A solution of the cis-mixed mixture in ethanol (8.3 mL) was added 1M aqueous sodium hydroxide (1. 38 mL) and 30% aqueous hydrogen peroxide (0.28 mL) under ice cooling, and stirred at room temperature for 4 days. Water was added and the mixture was extracted with ethyl acetate, and the organic layer was washed with aqueous sodium sulfate aqueous solution and brine. The aqueous layer was extracted with EtOAc. The residue was purified by column chromatography (methanol / ethyl acetate). The obtained transester was dissolved in ethyl acetate, and a 4 M solution of hydrogen chloride in ethyl acetate was added thereto, and the mixture was stirred at room temperature, and the resulting solid was removed by filtration to give trans-4-(1-methyl-3- {[4-(Quinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)cyclohexaneamine formazan dihydrochloride (26 mg, mp. Shun The same treatment was carried out to give cis-4-(1-methyl-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)cyclohexaneamine A Bismuth hydrochloride (58 mg, Ex. 149).
實施例20 Example 20
於3-甲基-2-(4-{2-〔1-甲基-4-(吡啶-4-基)-1H-吡唑-3-基〕乙烯基}苯基)喹啉(950mg)的乙醇(10mL)溶液中加入10%氫氧化鈀-碳(200mg),氫環境下加壓,在室溫下進行5天攪拌。以矽藻土過濾後減壓濃縮。將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化。將所得之粗純化物溶解於乙酸乙酯,加入4M氯化氫之乙酸乙酯溶液,在室溫下進行15分鐘攪拌。將溶劑減壓濃縮,於殘渣加入2-丙醇-二異丙基醚並固體化後得到3-甲基-2-(4-{2-〔1-甲基-4-(吡啶-4-基)-1H-吡唑-3-基〕乙基}苯基)喹啉 二鹽酸鹽(27mg)。 3-methyl-2-(4-{2-[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]vinyl}phenyl)quinoline (950mg) To a solution of ethanol (10 mL), 10% palladium hydroxide-carbon (200 mg) was added, and the mixture was pressurized under a hydrogen atmosphere, and stirred at room temperature for 5 days. It was filtered through celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude purified product was dissolved in ethyl acetate, and then a solution of 4M hydrogen chloride in ethyl acetate was added, and the mixture was stirred at room temperature for 15 minutes. The solvent was concentrated under reduced pressure, and the residue was added 2-propanol-diisopropyl ether and solidified to give 3-methyl-2-(4-{2-[1-methyl-4-(pyridine-4- -1H-pyrazol-3-yl]ethyl}phenyl)quinoline dihydrochloride (27 mg).
實施例21 Example 21
於4-(1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)環己酮(183mg)、乙醇(3.7mL)、及水(0.7mL)的混合物加入胺氧基甲烷鹽酸鹽(45mg)及乙酸鈉(47mg),在室溫下進行2小時攪拌。加入飽和食鹽水,以氯仿萃取。以無水硫酸鎂乾燥後減壓濃縮。將所得之殘渣以矽膠管柱層析法(乙醇/己烷)進行純化,將殘渣溶解於乙酸乙酯(5mL),加入4M氯化氫之乙酸乙酯 溶液,在室溫下進行1小時攪拌後,將所生成的固體過濾取出,得到N-甲氧基-4-(1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)環己烷亞胺 二鹽酸鹽(157mg)。 4-(1-methyl-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)cyclohexanone (183 mg), ethanol (3.7 A mixture of mL) and water (0.7 mL) was added with aminooxymethane hydrochloride (45 mg) and sodium acetate (47 mg), and stirred at room temperature for 2 hours. Saturated brine was added and extracted with chloroform. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc/hexane). The solution was stirred at room temperature for 1 hour, and the resulting solid was filtered off to give N-methoxy-4-(1-methyl-3-{[4-(quinolin-2-yl)benzene. Methyl]oxy}-1H-pyrazol-4-yl)cyclohexaneimine dihydrochloride (157 mg).
實施例22 Example 22
冰冷下於4-(1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)環己酮(203mg)的乙醇(4mL)溶液,加入氫化硼鈉(22mg),進行1小時攪拌。加入水及飽和食鹽水,以氯仿萃取。以無水硫酸鎂乾燥後減壓濃縮,將殘渣以矽膠管柱層析法(乙酸乙酯/己烷)進行純化後得到反式-4-(1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)環己醇(150mg)之無色油狀物,進一步得到順-4-(1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)環己醇(25mg)的白色固體。將反體溶解於乙醇(4mL),加入草酸(22mg),進行30分鐘攪拌。減壓濃縮後,以乙醇及乙酸乙酯之混合溶劑固體化,得到反式-4-(1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)環己醇 草酸鹽(74mg、Ex.22)。順體為溶解於乙酸乙酯(6mL)中,加入4M氯化氫之乙酸乙酯溶液,在室溫下進行1小時攪拌後得到順-4-(1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)環己醇 二鹽酸鹽(28mg、Ex.154)。 Ethanol in 4-(1-methyl-3-{[4-(quinolin-2-yl)benzyl)oxy}-1H-pyrazol-4-yl)cyclohexanone (203 mg) under ice cooling (4 mL) solution, sodium borohydride (22 mg) was added, and the mixture was stirred for 1 hour. Water and saturated brine were added, and the mixture was extracted with chloroform. After drying over anhydrous magnesium sulfate and concentrating under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give trans-4-(1-methyl-3-{[4- a colorless oil of oxa-4-yl)benzyloxy]-1H-pyrazol-4-yl)cyclohexanol (150 mg), further cis-4-(1-methyl-3-{ [4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)cyclohexanol (25 mg) as a white solid. The trans-body was dissolved in ethanol (4 mL), and oxalic acid (22 mg) was added and stirred for 30 minutes. After concentration under reduced pressure, the solid was combined with ethyl acetate and ethyl acetate to give trans-4-(1-methyl-3-{[4-(quinolin-2-yl)benzyl)oxy} -1H-pyrazol-4-yl)cyclohexanol oxalate (74 mg, Ex. 22). The solution was dissolved in ethyl acetate (6 mL), and then 4M hydrogen chloride in ethyl acetate was added and stirred at room temperature for 1 hour to give cis-4-(1-methyl-3-{[4-( Phenyl-2-yl)benzyloxy]-1H-pyrazol-4-yl)cyclohexanol dihydrochloride (28 mg, Ex. 154).
實施例23 Example 23
於1-(2-{〔tert-丁基(二甲基)矽基〕氧基}乙基)-5-(1-甲基-3-{〔4-(3-甲基喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)吡啶-2(1H)-酮(143mg)的四氫呋喃(3mL)溶液中加入四丁基銨氟化物(0.4mL),在室溫下進行3小時攪拌。將反應液減壓濃縮,將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化。將所得之粗純化物溶解於乙酸乙酯,加入4M氯化氫之乙酸乙酯溶液。過濾取出所生成的沈澱,以乙酸乙酯洗淨後得到1-(2-羥基乙基)-5-(1-甲基-3-{〔4-(3-甲基喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)吡啶-2(1H)-酮 二鹽酸鹽(80mg)。 1-(2-{[tert-butyl(dimethyl)indolyl)oxy}ethyl)-5-(1-methyl-3-{[4-(3-methylquinoline-2) To a solution of 4-benzyloxy]-1H-pyrazol-4-yl)pyridine-2(1H)-one (143 mg) in tetrahydrofuran (3 mL) was added tetrabutylammonium fluoride (0.4 mL). Stirring was carried out for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified to silica gel column chromatography (methanol / chloroform). The obtained crude purified product was dissolved in ethyl acetate, and then 4M hydrogen chloride ethyl acetate was added. The resulting precipitate was filtered off and washed with ethyl acetate to give 1-(2-hydroxyethyl)-5-(1-methyl-3-{[4-(3-methylquinolin-2-yl) Benzyl]oxy}-1H-pyrazol-4-yl)pyridine-2(1H)-one dihydrochloride (80 mg).
實施例24 Example 24
於2-〔4-({〔1-甲基-4-(吡啶-4-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕喹啉-3-甲醛(175 mg)、二甲基胺鹽酸鹽(68 mg)、及二氯甲烷(5 mL)混合物中加入三乙基胺(116μL)及三乙醯氧基氫化硼鈉(264 mg),在室溫下進行22小時攪拌。將反應液以飽和碳酸氫鈉水溶液中和,以氯仿萃取。將有機層經減壓濃縮,將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化。將所得之粗純化物溶解於乙醇中,加入4M氯化氫之乙酸乙酯溶液,在室溫下進行13小時攪拌。於反應液加入二乙基醚,過濾取出所生成的沈澱,進一步以二乙基醚洗淨,得到N,N-二甲基-1-{2-〔4-({〔1-甲基-4-(吡啶-4-基)-1H-吡唑-3-基 〕氧基}甲基)苯基〕喹啉-3-基}甲烷胺 三鹽酸鹽(118 mg)。 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)oxy}methyl)phenyl]quinolin-3-carbaldehyde (175) To a mixture of mg), dimethylamine hydrochloride (68 mg), and dichloromethane (5 mL), triethylamine (116 μL) and sodium triethyloxyborohydride (264 mg) at room temperature The mixture was stirred for 22 hours. The reaction solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was concentrated under reduced pressure and the residue was purified mjjjjjd The obtained crude purified product was dissolved in ethanol, and a 4M solution of hydrogen chloride in ethyl acetate was added, and the mixture was stirred at room temperature for 13 hours. Diethyl ether was added to the reaction mixture, and the resulting precipitate was filtered off and further washed with diethyl ether to give N,N-dimethyl-1-{2-[4-({[1-methyl- 4-(pyridin-4-yl)-1H-pyrazol-3-yl Oxy]methyl)phenyl]quinolin-3-yl}methaneamine trihydrochloride (118 mg).
實施例25 Example 25
冰冷下,於{2-〔4-({〔1-甲基-4-(吡啶-4-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕喹啉-3-基}甲醇(270 mg)之N,N-二甲基甲醯胺(5 mL)溶液中,加入55%氫化鈉(42 mg),在同溫下進行15分鐘攪拌。加入碘化甲基(60μL)後升溫至室溫,進行12小時攪拌。將反應液冰冷加入55%氫化鈉(42 mg)、碘化甲基(60μL),升溫至室溫後進行1小時攪拌。於反應液中加入水使反應停止,加入乙酸乙酯,將有機層以飽和食鹽水洗淨。進行減壓濃縮後,將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化。將所得之粗純化物溶解於乙醇中,加入4M氯化氫之乙酸乙酯溶液,在室溫下進行1小時攪拌。於反應液加入二乙基醚,過濾取出所生成的沈澱,以二乙基醚洗淨後得到3-(甲氧基甲基)-2-〔4-({〔1-甲基-4-(吡啶-4-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕喹啉 二鹽酸鹽(84 mg)。 Under ice cooling, {2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)oxy}methyl)phenyl]quinoline-3 To a solution of methanol (270 mg) in N,N-dimethylformamide (5 mL), 55% sodium hydride (42 mg) was added and stirred at the same temperature for 15 min. After adding methyl iodide (60 μL), the temperature was raised to room temperature, and the mixture was stirred for 12 hours. The reaction solution was ice-cooled, and 55% sodium hydride (42 mg) and methyl iodide (60 μL) were added, and the mixture was warmed to room temperature, and then stirred for 1 hour. Water was added to the reaction mixture to stop the reaction, and ethyl acetate was added thereto, and the organic layer was washed with saturated brine. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude purified product was dissolved in ethanol, and a 4 M solution of hydrogen chloride in ethyl acetate was added thereto, and the mixture was stirred at room temperature for 1 hour. Diethyl ether was added to the reaction mixture, and the resulting precipitate was filtered off and washed with diethyl ether to give 3-(methoxymethyl)-2-[4-({[1-methyl-4-) (Pyridin-4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline dihydrochloride (84 mg).
實施例26 Example 26
將2-(4-{〔(4-碘-1-甲基-1H-吡唑-3-基)氧基〕甲基}苯基)-3-甲基喹啉(338mg)、嗎啉(2.7mL)、銅(142mg)、磷酸三鉀(473mg)、2-(二甲基胺基)乙醇( 2.7mL)的混合物在110℃進行15小時攪拌。於反應液中加入水,以乙酸乙酯萃取。將有機層經減壓濃縮,將殘渣以矽膠管柱層析法(己烷/乙酸乙酯)進行純化。於粗純化物加入乙酸乙酯、乙醇、4M氯化氫之乙酸乙酯溶液,並在室溫下進行30分鐘攪拌。過濾取出所生成的固體,以乙酸乙酯洗淨後得到3-甲基-2-〔4-({〔1-甲基-4-(嗎啉-4-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕喹啉 二鹽酸鹽(164mg)。 2-(4-{[(4-Iodo-1-methyl-1H-pyrazol-3-yl)oxy]methyl}phenyl)-3-methylquinoline (338 mg), morpholine ( 2.7 mL), copper (142 mg), tripotassium phosphate (473 mg), 2-(dimethylamino)ethanol ( The mixture of 2.7 mL) was stirred at 110 ° C for 15 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. Ethyl acetate, ethanol, 4M hydrogen chloride in ethyl acetate solution was added to the crude material, and stirred at room temperature for 30 minutes. The resulting solid was taken by filtration and washed with ethyl acetate to give 3-methyl-2-[4-({[1-methyl-4-(morpholin-4-yl)-1H-pyrazole-3 -yloxy}methyl)phenyl]quinoline dihydrochloride (164 mg).
實施例27 Example 27
冷卻2-{4-〔(4-碘-1-甲基-1H-吡唑-3-基)甲氧基〕苯基}-3-甲基喹啉(6.00g)的四氫呋喃(120mL)溶液,加入2M氯化異丙基鎂之四氫呋喃溶液(16.5mL)。在同溫下進行45分鐘攪拌,加入2-異丙氧基-4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷(4.30mL)。在室溫下進行2小時攪拌後,加入氯化銨水溶液,以乙酸乙酯萃取。將有機層經減壓濃縮後,將殘渣以矽膠管柱層析法(乙酸乙酯/己烷)進行純化後得到3-甲基-2-(4-{〔1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)-1H-吡唑-3-基〕甲氧基}苯基)喹啉(2.32g)。 Cooling solution of 2-{4-[(4-iodo-1-methyl-1H-pyrazol-3-yl)methoxy]phenyl}-3-methylquinoline (6.00 g) in tetrahydrofuran (120 mL) A 2M solution of isopropylmagnesium chloride in tetrahydrofuran (16.5 mL) was added. Stirring was carried out for 45 minutes at the same temperature, and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.30 mL) was added. After stirring at room temperature for 2 hours, an aqueous solution of ammonium chloride was added and the mixture was extracted with ethyl acetate. After the organic layer was concentrated under reduced pressure, the residue was purified to silica gel column chromatography (ethyl acetate/hexane) to give 3-methyl-2-(4-{[1-methyl-4-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-3-yl]methoxy}phenyl)quinoline (2.32 g).
於3-甲基-2-(4-{〔1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)-1H-吡唑-3-基〕甲氧基}苯基)喹啉(500mg)、5-溴-1-甲基吡啶-2(1H)-酮(413mg)、N,N-二甲基甲醯胺(5mL)、及水(1mL)的混合物中加 入〔1,1'-雙(二苯基膦)二茂鐵〕二氯鈀(II)之二氯甲烷加成體(54mg)及碳酸鈉(349mg),在100℃進行1小時攪拌。於反應液加入水,並以乙酸乙酯萃取。將有機層經減壓濃縮後,將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化。將所得之粗純化物溶解於乙醇中,加入4M氯化氫之乙酸乙酯溶液,在室溫下進行30分鐘攪拌。將反應液減壓濃縮後,將殘渣以乙酸乙酯洗淨,得到1-甲基-5-(1-甲基-3-{〔4-(3-甲基喹啉-2-基)苯氧基〕甲基}-1H-吡唑-4-基)吡啶-2(1H)-酮 二鹽酸鹽(80mg)。 3-methyl-2-(4-{[1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-3-yl]methoxy}phenyl)quinoline (500 mg), 5-bromo-1-methylpyridine-2(1H)-one (413 mg), N,N-dimethyl a mixture of methotrexate (5 mL) and water (1 mL) A dichloromethane adduct (54 mg) of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) and sodium carbonate (349 mg) were added, and the mixture was stirred at 100 ° C for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. After the organic layer was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude purified product was dissolved in ethanol, and a 4M solution of hydrogen chloride in ethyl acetate was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. Oxy]methyl}-1H-pyrazol-4-yl)pyridine-2(1H)-one dihydrochloride (80 mg).
實施例28 Example 28
冰冷下,於1-〔4-(羥基甲基)苯基〕-2-甲基-1H-苯並咪唑(1.19g)的二氯甲烷(50mL)混合物中加入氯化亞碸(1.1mL),在室溫下進行2小時攪拌。將反應液減壓濃縮,將殘渣減壓乾燥。於所得之固體(483mg)中加入1-甲基-4-吡啶-4-基-1H-吡唑-3-醇(263mg)、碳酸鉀(520mg)、N,N-二甲基甲醯胺(15mL),在70℃進行8小時攪拌。將反應液減壓濃縮後,於殘渣加入水,以乙酸乙酯萃取。將有機層經減壓濃縮,將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化。將所得之粗純化物溶解於乙醇中,加入4M氯化氫之乙酸乙酯溶液,在室溫中進行15分鐘攪拌。過濾取出所生成的沈澱,以乙酸乙酯洗淨後得到2-甲基-1-〔4-({〔1-甲基-4-(吡啶-4-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕-1H-苯並咪唑 二鹽酸鹽( 445mg)。 Addition of thallium chloride (1.1 mL) to a mixture of 1-[4-(hydroxymethyl)phenyl]-2-methyl-1H-benzimidazole (1.19 g) in dichloromethane (50 mL) Stir at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and the residue was evaporated. To the obtained solid (483 mg) was added 1-methyl-4-pyridin-4-yl-1H-pyrazol-3-ol (263 mg), potassium carbonate (520 mg), N,N-dimethylformamide (15 mL) was stirred at 70 ° C for 8 hours. The reaction mixture was concentrated under reduced pressure. The organic layer was concentrated under reduced pressure and the residue was purified mjjjjjd The obtained crude purified product was dissolved in ethanol, and a 4M solution of hydrogen chloride in ethyl acetate was added, and the mixture was stirred at room temperature for 15 minutes. The resulting precipitate was filtered off and washed with ethyl acetate to give 2-methyl-1-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazole-3- Alkyloxy}methyl)phenyl]-1H-benzimidazole dihydrochloride ( 445 mg).
實施例29 Example 29
冰冷下,於4-(1-甲基-3-{〔4-(喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)環己酮(213mg)的乙醇溶液(8.5mL)加入氫化硼鈉(23mg)後進行1小時攪拌。加入水及飽和食鹽水,以氯仿萃取。以無水硫酸鎂乾燥後減壓濃縮,將所得之殘渣以矽膠管柱層析法(乙酸乙酯/己烷)進行純化後得到4-(1-甲基-3-{〔4-(3-甲基喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)環己醇(214mg)。於所得之4-(1-甲基-3-{〔4-(3-甲基喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)環己醇(214mg)之N,N-二甲基甲醯胺(3.2mL)溶液中加入咪唑(136mg)、tert-丁基二甲基氯矽烷(151mg)及N,N-二甲基-4-胺基吡啶(18mg),在室溫下進行14小時攪拌。加入水後,以乙酸乙酯萃取。有機層以飽和食鹽水洗淨後以無水硫酸鎂乾燥,並進行減壓濃縮。將所得之殘渣以矽膠管柱層析法(乙酸乙酯/己烷)進行純化後得到2-〔4-({〔4-(反式-4-{〔tert-丁基(二甲基)矽基〕氧基}環己基)-1-甲基-1H-吡唑-3-基〕氧基}甲基)苯基〕-3-甲基喹啉(160mg)。於所得之2-〔4-({〔4-(反式-4-{〔tert-丁基(二甲基)矽基〕氧基}環己基)-1-甲基-1H-吡唑-3-基〕氧基}甲基)苯基〕-3-甲基喹啉(160mg)的四氫呋喃(3.2mL)溶液中,加入氟化四-N-丁基銨(886μL),在室溫下進行7小 時攪拌。濃縮後將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化,將殘渣溶解於乙酸乙酯(6.4mL)後,加入4M氯化氫之乙酸乙酯溶液(295μL),在室溫下進行1小時攪拌。過濾取出所生成的固體,得到反式-4-(1-甲基-3-{〔4-(3-甲基喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)環己醇 二鹽酸鹽(104mg)。 Under ice cooling, 4-(1-methyl-3-{[4-(quinolin-2-yl)benzyl)oxy}-1H-pyrazol-4-yl)cyclohexanone (213 mg) To the ethanol solution (8.5 mL), sodium borohydride (23 mg) was added, followed by stirring for 1 hour. Water and saturated brine were added, and the mixture was extracted with chloroform. After drying over anhydrous magnesium sulfate, the residue was evaporated. mjjjjjjjj Methylquinolin-2-yl)benzyloxy]-1H-pyrazol-4-yl)cyclohexanol (214 mg). 4-(1-methyl-3-{[4-(3-methylquinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)cyclohexanol obtained ( 214 mg) of N,N-dimethylformamide (3.2 mL) was added with imidazole (136 mg), tert-butyldimethylchloromethane (151 mg) and N,N-dimethyl-4-amino group. Pyridine (18 mg) was stirred at room temperature for 14 hours. After adding water, it was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (ethyl acetate /hexane) to give 2-[4-({[4-(trans)-4-{[tert-butyl(dimethyl)) Mercapto]oxy}cyclohexyl)-1-methyl-1H-pyrazol-3-yl]oxy}methyl)phenyl]-3-methylquinoline (160 mg). 2-[4-({[4-(trans-4-{[tert-butyl(dimethyl)indenyl)oxy}cyclohexyl)-1-methyl-1H-pyrazole) To a solution of 3-methyl]oxy}methyl)phenyl]-3-methylquinoline (160 mg) in tetrahydrofuran (3.2 mL), tetra-N-butylammonium fluoride (886 μL) was added at room temperature Carry out 7 small Stir when. After concentrating, the residue was purified by silica gel column chromatography (methanol / chloroform), and the residue was dissolved in ethyl acetate (6.4 mL). Stir for hours. The resulting solid was removed by filtration to give trans-4-(1-methyl-3-{[4-(3-methylquinolin-2-yl)benzyl]oxy}-1H-pyrazole- 4-yl)cyclohexanol dihydrochloride (104 mg).
實施例30 Example 30
將3-甲基-2-〔4-({〔1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-yl)-1H-吡唑-3-基〕氧基}甲基)苯基〕喹啉(507mg)、5-溴-2-(tert-丁氧基)吡啶(384mg)、1,1'-雙(二苯基膦)二茂鐵-鈀(II)二氯化物-二氯甲烷錯體(54mg)、碳酸鈉(354mg)、N,N-二甲基甲醯胺(7.5mL)、及水(1.5mL)的混合物在氬環境下,於100℃進行1小時攪拌。加入乙酸乙酯及水,將所生成的不溶物以矽藻土過濾。將有機層以飽和食鹽水洗淨,以無水硫酸鎂乾燥後減壓濃縮。將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化。將所得之化合物溶解於二氯甲烷(2mL)後,加入三氟乙酸(2mL),在室溫下進行2小時攪拌。將反應液減壓濃縮,加入飽和碳酸氫鈉溶液及乙酸乙酯。將有機層以飽和食鹽水洗淨後,以無水硫酸鎂乾燥,並進行減壓濃縮。將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化。將所得之粗純化物溶解於乙醇中,入4M氯化氫之乙酸乙酯溶液。將溶液進行減壓濃縮。過濾 取出所生成的沈澱,以醚洗淨後得到6-(1-甲基-3-{〔4-(3-甲基喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)吡啶-2(1H)-酮 二鹽酸鹽(160mg)。 3-methyl-2-[4-({[1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-3-yloxy}methyl)phenyl]quinoline (507 mg), 5-bromo-2-(tert-butoxy)pyridine (384 mg), 1,1'-double (diphenylphosphine)ferrocene-palladium(II) dichloride-dichloromethane (54 mg), sodium carbonate (354 mg), N,N-dimethylformamide (7.5 mL), and water The mixture (1.5 mL) was stirred at 100 ° C for 1 hour under an argon atmosphere. Ethyl acetate and water were added, and the resulting insoluble material was filtered over Celite. The organic layer was washed with brine, dried over anhydrous magnesium sulfate The residue was purified by silica gel column chromatography (methanol / chloroform). After dissolving the obtained compound in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and saturated aqueous sodium hydrogen sulfate and ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude purified product was dissolved in ethanol, and then a solution of 4 M hydrogen chloride in ethyl acetate. The solution was concentrated under reduced pressure. filter The resulting precipitate was taken out and washed with ether to give 6-(1-methyl-3-{[4-(3-methylquinolin-2-yl)benzyl]oxy}-1H-pyrazole. 4-yl)pyridine-2(1H)-one dihydrochloride (160 mg).
實施例31 Example 31
於2-{4-〔(5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲氧基〕苯基}-3-甲基喹啉(290mg)、4-(4,4,5,5-四甲基-1,3,2-二氧雜戊硼烷-2-基)吡啶(436mg)、N,N-二甲基甲醯胺(2.9mL)、及水(1.2mL)的混合物中,加入碳酸銫(462mg)及肆三苯基膦鈀(123mg),在80℃進行18小時攪拌。放冷後加入水,並以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨,以無水硫酸鎂乾燥後減壓濃縮。將所得之殘渣以矽膠管柱層析法(乙酸乙酯/己烷)進行純化,將殘渣溶解於乙酸乙酯(12mL),加入4M氯化氫之二噁烷溶液,在室溫下進行1小時攪拌。過濾取出所生成的固體,得到3-甲基-2-(4-{〔2-甲基-5-(吡啶-4-基)-2H-1,2,3-三唑-4-基〕甲氧基}苯基)喹啉 二鹽酸鹽(99mg)。 2-{4-[(5-Bromo-2-methyl-2H-1,2,3-triazol-4-yl)methoxy]phenyl}-3-methylquinoline (290 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (436 mg), N,N-dimethylformamide (2.9 mL) To a mixture of water and water (1.2 mL), cesium carbonate (462 mg) and triphenylphosphine palladium (123 mg) were added, and the mixture was stirred at 80 ° C for 18 hours. After cooling, water was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate The residue was purified by silica gel column chromatography (ethyl acetate / hexane), and the residue was dissolved in ethyl acetate (12 mL), and 4M hydrogen chloride in dioxane was added and stirred at room temperature for 1 hour. . The resulting solid was removed by filtration to give 3-methyl-2-(4-{[2-methyl-5-(pyridin-4-yl)-2H-1,2,3-triazol-4-yl] Methoxy}phenyl)quinoline dihydrochloride (99 mg).
實施例32 Example 32
冰冷下,於5-〔3-(羥基甲基)-1-甲基-1H-吡唑-4-基〕-1-甲基吡啶-2(1H)-酮(394mg)的二氯甲烷(20mL)混合物中加入氯化亞碸(0.4mL),在室溫下進行2小時攪拌。將反應液減壓濃縮,將殘渣減壓乾燥。加入 N,N-二甲基甲醯胺(16mL)、4-(1-甲基-1H-苯並咪唑-4-基)酚(270mg)、及碳酸鉀(414mg),在70℃進行8小時攪拌。將反應液減壓濃縮後,於殘渣中加入水,以乙酸乙酯萃取。經減壓濃縮後將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化。將所得之粗純化物溶解於乙酸乙酯,加入4M氯化氫之乙酸乙酯溶液,在室溫下進行10分鐘攪拌。將溶劑減壓濃縮後,將殘渣以乙酸乙酯洗淨,得到1-甲基-5-(1-甲基-3-{〔4-(1-甲基-1H-苯並咪唑-4-基)苯氧基〕甲基}-1H-吡唑-4-基)吡啶-2(1H)-酮 二鹽酸鹽(206mg)。 Under ice-cooling, dichloromethane in 5-[3-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl]-1-methylpyridine-2(1H)-one (394 mg) To a mixture of 20 mL), hydrazine chloride (0.4 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and the residue was evaporated. Join N,N-dimethylformamide (16 mL), 4-(1-methyl-1H-benzimidazol-4-yl)phenol (270 mg), and potassium carbonate (414 mg) at 80 ° C for 8 hours Stir. After the reaction mixture was concentrated under reduced pressure, water was evaporated and evaporated. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude purified product was dissolved in ethyl acetate, and then a 4M aqueous solution of hydrogen chloride was added, and the mixture was stirred at room temperature for 10 minutes. After the solvent was concentrated under reduced pressure, the residue was purified ethyl ethyl acetate ethyldiethyldiethylethylethylethylethylethylethylethylethylethylethylethylethylethylethylethylethylethyldiethylethyl Phenyloxy]methyl}-1H-pyrazol-4-yl)pyridine-2(1H)-one dihydrochloride (206 mg).
實施例33 Example 33
於3-(1-甲基-3-{〔4-(3-甲基喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)吡咯烷-1-羧酸tert-丁基(152mg)的二氯甲烷(0.3mL)溶液中加入三氟乙酸(0.3mL),在室溫下進行2小時攪拌。將反應液冰冷後,加入飽和碳酸氫鈉水溶液,以氯仿萃取。將有機層以無水硫酸鈉乾燥、過濾、減壓濃縮。將殘渣溶解於二氯甲烷(3mL)後冰冷,加入三乙基胺(51μL)、乙醯基氯化物(24μL)後,在室溫下進行30分攪拌。於反應液中加入飽和碳酸氫鈉水溶液,以氯仿萃取。將有機層以無水硫酸鈉乾燥後減壓濃縮,將殘渣以矽膠管柱層析法(氯仿/甲醇)進行純化。將所得之粗純化物溶解於乙酸乙酯,加入4M氯化氫之乙酸乙酯溶液,在室溫下進行30分鐘攪拌。過濾取出所生 成的固體,以乙酸乙酯洗淨後得到1-〔3-(1-甲基-3-{〔4-(3-甲基喹啉-2-基)苯甲基〕氧基}-1H-吡唑-4-基)吡咯烷-1-基〕乙酮 二鹽酸鹽(125mg)。 3-(1-methyl-3-{[4-(3-methylquinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)pyrrolidine-1-carboxyl To a solution of the acid tert-butyl (152 mg) in dichloromethane (0.3 mL) was added trifluoroacetic acid (0.3 mL), and the mixture was stirred at room temperature for 2 hours. After the reaction mixture was ice-cooled, a saturated aqueous The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was dissolved in dichloromethane (3 mL), and then ice-cooled. Triethylamine (51 μL) and ethyl acetate (24 μL) were added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was evaporated. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol). The obtained crude purified product was dissolved in ethyl acetate, and a 4M aqueous solution of hydrogen chloride was added, and the mixture was stirred at room temperature for 30 minutes. Filter out and take out The solid was washed with ethyl acetate to give 1-[3-(1-methyl-3-{[4-(3-methylquinolin-2-yl)benzyl]oxy}-1H. Pyrazol-4-yl)pyrrolidin-1-yl]ethanone dihydrochloride (125 mg).
實施例34 Example 34
於2-〔4-({〔1-甲基-4-(1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕喹啉-3-甲醛(569mg)、甲醇(5mL)、及四氫呋喃(5mL)混合物中加入氫化硼鈉(96mg),在室溫下進行22小時攪拌。於反應液加入水,以氯仿萃取。將有機層以無水硫酸鎂乾燥,並進行減壓濃縮。將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化。將所得之粗純化物溶解於甲醇中,加入4M氯化氫之二噁烷溶液,將溶液進行減壓濃縮。將所生成的固體以甲醇-醚洗淨後並濾取,得到5-〔3-({4-〔3-(羥基甲基)喹啉-2-基〕苯甲基}氧基)-1-甲基-1H-吡唑-4-基〕-1-甲基吡啶-2(1H)-酮 一鹽酸鹽(74mg)。 2-[4-({[1-methyl-4-(1-methyl-6-oxo-oxy-1,6-dihydropyridin-3-yl)-1H-pyrazol-3-yl]oxy) Sodium borohydride (96 mg) was added to a mixture of benzyl]methyl]phenyl]quinoline-3-carbaldehyde (569 mg), methanol (5 mL) and THF (5 mL), and the mixture was stirred at room temperature for 22 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude purified product was dissolved in methanol, 4M hydrogen chloride in dioxane solution was added, and the solution was concentrated under reduced pressure. The resulting solid was washed with methanol-ether and filtered to give 5-[3-({4-[3-(hydroxymethyl)quinolin-2-yl]phenylmethyl}oxy)-1 -Methyl-1H-pyrazol-4-yl]-1-methylpyridine-2(1H)-one monohydrochloride (74 mg).
實施例35 Example 35
於2-〔4-({〔1-甲基-4-(1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕喹啉-3-甲醛(150mg)的二氯甲烷(3mL)溶液中加入雙(2-甲氧基乙基)胺基硫三氟化物(0.1mL),在室溫下進行一夜攪拌。加入水並以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨後,以無水硫酸鈉乾燥,並進行減壓濃縮。將殘渣以鹼 性矽膠管柱層析法(氯仿/己烷)進行純化。將所得之粗純化物溶解於乙酸乙酯,加入4M氯化氫之乙酸乙酯溶液。過濾取出所生成的沈澱,以乙酸乙酯洗淨後得到5-〔3-({4-〔3-(二氟甲基)喹啉-2-基〕苯甲基}氧基)-1-甲基-1H-吡唑-4-基〕-1-甲基吡啶-2(1H)-酮 二鹽酸鹽(83mg)。 2-[4-({[1-methyl-4-(1-methyl-6-oxo-oxy-1,6-dihydropyridin-3-yl)-1H-pyrazol-3-yl]oxy) Add bis(2-methoxyethyl)aminosulfur trifluoride (0.1 mL) to a solution of methylene (methyl)phenyl]quinolin-3-carbaldehyde (150 mg) in dichloromethane (3 mL) Stir for one night under warm conditions. Water was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. Residue as alkali Purification by column chromatography (chloroform/hexane). The obtained crude purified product was dissolved in ethyl acetate, and then 4M hydrogen chloride ethyl acetate was added. The resulting precipitate was filtered off and washed with ethyl acetate to give 5-[3-({4-[3-(difluoromethyl)quinolin-2-yl]benzyl}oxy)-1- Methyl-1H-pyrazol-4-yl]-1-methylpyridine-2(1H)-one dihydrochloride (83 mg).
實施例36 Example 36
於2-〔4-({〔1-甲基-4-(1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕喹啉-3-甲醛(155mg)、四氫呋喃(3.5mL)、及甲醇(0.4mL)混合物中加入羥基胺鹽酸鹽(48mg)及粉末碳酸鉀(143mg),於室溫中進行0.5小時攪拌。減壓濃縮後加入水,並以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨後,以無水硫酸鎂乾燥,並進行減壓濃縮。於所得之化合物的二氯甲烷(3mL)溶液中加入三乙基胺(0.056mL)、三氟乙酸酐(0.052mL),在室溫下進行2小時攪拌。追加三乙基胺(0.216mL)及三氟乙酸酐(0.219mL),並在室溫下進行5小時攪拌。於反應液加入水,以氯仿萃取。將有機層以無水硫酸鎂乾燥,並進行減壓濃縮。將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化。將所得之固體以乙醇洗淨後濾取,得到2-〔4-({〔1-甲基-4-(1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕喹啉-3-腈(83mg)。 2-[4-({[1-methyl-4-(1-methyl-6-oxo-oxy-1,6-dihydropyridin-3-yl)-1H-pyrazol-3-yl]oxy) Hydroxyamine hydrochloride (48 mg) and powdered potassium carbonate (143 mg) were added to a mixture of methyl}methyl)phenyl]quinolin-3-carbaldehyde (155 mg), tetrahydrofuran (3.5 mL), and methanol (0.4 mL). Stirring was carried out for 0.5 hour at room temperature. After concentration under reduced pressure, water was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. Triethylamine (0.056 mL) and trifluoroacetic anhydride (0.052 mL) were added to a solution of the obtained compound in dichloromethane (3 mL), and the mixture was stirred at room temperature for 2 hours. Triethylamine (0.216 mL) and trifluoroacetic anhydride (0.219 mL) were added, and stirred at room temperature for 5 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (methanol / chloroform). The obtained solid was washed with ethanol, and then filtered to give 2-[4-({[1-methyl-4-(1-methyl-6-oxooxy-1,6-dihydropyridin-3-yl). -1H-pyrazol-3-yloxy}methyl)phenyl]quinolin-3-carbonitrile (83 mg).
實施例37 Example 37
冰冷下,於6-〔4-({〔1-甲基-4-(1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕菸酸甲酯(1.47g)的四氫呋喃(50mL)混合物中加入氫化硼鋰(148mg)、乙醇(0.60mL),進行2小時加熱迴流。將反應液放冷,加入飽和碳酸氫鈉水溶液,以乙酸乙酯萃取。將有機層進行減壓濃縮。將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化。將所得之粗純化物以乙酸乙酯及己烷之順去洗淨,得到5-〔3-({4-〔5-(羥基甲基)吡啶-2-基〕苯甲基}氧基)-1-甲基-1H-吡唑-4-基〕-1-甲基吡啶-2(1H)-酮(770mg)。 Under ice cooling, 6-[4-({[1-methyl-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrazole-3- To a mixture of methyl oxy)methyl)phenyl]nicotinic acid methyl ester (1.47 g) in tetrahydrofuran (50 mL) was added lithium borohydride (148 mg) and ethanol (0.60 mL). The reaction solution was cooled, and a saturated aqueous The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform). The obtained crude purified product was washed with ethyl acetate and hexane to give 5-[3-({4-[5-(hydroxymethyl)pyridin-2-yl]phenylmethyl}oxy) 1-Methyl-1H-pyrazol-4-yl]-1-methylpyridine-2(1H)-one (770 mg).
實施例38 Example 38
將4-〔4-(氯甲基)苯基〕-1-甲基-1H-苯並咪唑鹽酸鹽(143mg)、5-(3-羥基-1-甲基-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮(100mg)、碳酸鉀(168mg)、及N,N-二甲基甲醯胺(2mL)的混合物在60℃進行5小時攪拌。加入水,過濾取出所生成的固體,以矽膠管柱層析法(甲醇/氯仿)進行純化。將所得之粗純化物溶解於乙酸乙酯,過濾取出所生成的沈澱,得到1-甲基-5-(1-甲基-3-{〔4-(1-甲基-1H-苯並咪唑-4-基)苯甲基〕氧基}-1H-吡唑-4-基)吡啶-2(1H)-酮(75mg)。 4-[4-(Chloromethyl)phenyl]-1-methyl-1H-benzimidazole hydrochloride (143 mg), 5-(3-hydroxy-1-methyl-1H-pyrazole-4 A mixture of 1-methylpyridin-2(1H)-one (100 mg), potassium carbonate (168 mg), and N,N-dimethylformamide (2 mL) was stirred at 60 ° C for 5 hours. Water was added, and the resulting solid was taken out by filtration and purified by silica gel column chromatography (methanol / chloroform). The obtained crude purified product was dissolved in ethyl acetate, and the resulting precipitate was filtered to give 1-methyl-5-(1-methyl-3-{[4-(1-methyl-1H-benzimidazole). 4-yl)benzylmethyloxy}-1H-pyrazol-4-yl)pyridine-2(1H)-one (75 mg).
實施例39 Example 39
於1-甲基-4-吡啶-4-基-1H-吡唑-3-醇(90mg)、〔4-(咪唑並〔1,2-a〕吡啶-2-基)苯基〕甲醇(174mg)的四氫呋喃(9mL)混合物中加入1,1'-(偶氮二羰基)二哌啶(259mg)、三正丁基膦(208mg),在室溫下進行12小時攪拌。將反應液減壓濃縮,將殘渣以矽膠管柱層析法(甲醇/氯仿),繼續以鹼性矽膠管柱層析法(乙酸乙酯-己烷)進行純化。於所得之粗純化物加入乙醇、4M氯化氫之乙酸乙酯溶液,在室溫下進行30分鐘攪拌。將反應液進行減壓濃縮後,將殘渣以乙醇-乙酸乙酯洗淨,得到2-〔4-({〔1-甲基-4-(吡啶-4-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕咪唑並〔1,2-a〕吡啶 二鹽酸鹽(122mg)。 1-methyl-4-pyridin-4-yl-1H-pyrazol-3-ol (90 mg), [4-(imidazo[1,2-a]pyridin-2-yl)phenyl]methanol ( 1,1'-(Azodicarbonyl)dipiperidine (259 mg) and tri-n-butylphosphine (208 mg) were added to a mixture of 174 mg of tetrahydrofuran (9 mL), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and purified residue purified eluting eluting eluting eluting The obtained crude purified product was added with ethanol, 4M aqueous solution of hydrogen chloride, and stirred at room temperature for 30 minutes. After the reaction mixture was concentrated under reduced pressure, the residue was purified ethyl ether ethyl acetate to afford 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazole-3 -yloxy}methyl)phenyl]imidazo[1,2-a]pyridine dihydrochloride (122 mg).
實施例40 Example 40
於1-甲基-4-(四氫-2H-吡喃-4-基)-1H-吡唑-3-醇(250mg)及4-(喹啉-2-基)丁烷-1-醇(360mg)的甲苯(18ml)溶液中加入氰伸甲基三丁基膦(497mg),在100℃進行2.5小時加熱攪拌。將反應液減壓濃縮,將殘渣以矽膠管柱層析法(甲醇/氯仿)及鹼性矽膠管柱層析法(甲醇/乙酸乙酯)進行純化。將此溶解於乙酸乙酯中,並加入草酸(62mg),在室溫進行攪拌。對減壓下濃縮後所得之固體進行濾取後得到2-(4-{〔1-甲基-4-(四氫-2H-吡喃-4-基)-1H-吡唑-3-基〕氧基}丁基)喹啉 草酸鹽 (250mg)。 1-methyl-4-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-ol (250 mg) and 4-(quinolin-2-yl)butan-1-ol Cyanide methyltributylphosphine (497 mg) was added to a solution of (360 mg) in toluene (18 ml), and the mixture was stirred under heating at 100 ° C for 2.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified mjjjjjlilililililililili This was dissolved in ethyl acetate, and oxalic acid (62 mg) was added and stirred at room temperature. The solid obtained after concentration under reduced pressure was filtered to give 2-(4-{[1-methyl-4-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl. Oxyoxy}butyl)quinoline oxalate (250mg).
實施例41 Example 41
於〔5-(喹啉-2-基)-2-噻吩基〕甲醇(320mg)的二氯甲烷(6mL)溶液加入氯化亞碸(290μL),在室溫進行3小時攪拌。加入甲苯,過濾取出所生成的固體。於所得之2-〔5-(氯甲基)-2-噻吩基〕喹啉 鹽酸鹽(302mg)及1-甲基-4-(吡啶-4-基)-1H-吡唑-3-醇(179mg)之N,N-二甲基甲醯胺(6mL)懸浮液中加入碳酸鉀(352mg),在室溫下進行20分鐘攪拌後,升溫至60℃並進行7小時攪拌。放冷後加入水及飽和食鹽水,以乙酸乙酯萃取,以硫酸鎂乾燥後減壓下濃縮。將所得之殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化。將此溶解於乙酸乙酯後,加入琥珀酸(35mg)並在室溫下進行1小時攪拌。過濾取出所生成的固體,得到2-〔5-({〔1-甲基-4-(吡啶-4-基)-1H-吡唑-3-基〕氧基}甲基)-2-噻吩基〕喹啉 0.5琥珀酸鹽(205mg)。 To a solution of [5-(quinolin-2-yl)-2-thienyl]methanol (320 mg) in dichloromethane (6 mL) was then evaporated. Toluene was added, and the resulting solid was taken out by filtration. 2-[5-(Chloromethyl)-2-thienyl]quinoline hydrochloride (302 mg) and 1-methyl-4-(pyridin-4-yl)-1H-pyrazole-3- Potassium carbonate (352 mg) was added to a suspension of alcohol (179 mg) in N,N-dimethylformamide (6 mL), and the mixture was stirred at room temperature for 20 minutes, and then the mixture was heated to 60 ° C and stirred for 7 hours. After cooling, water and a saturated brine were added, and ethyl acetate was evaporated. The residue thus obtained was purified by silica gel column chromatography (methanol / chloroform). After dissolving this in ethyl acetate, succinic acid (35 mg) was added and stirred at room temperature for 1 hour. The resulting solid was removed by filtration to give 2-[5-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)oxy}methyl)-2-thiophene Quinoline 0.5 succinate (205 mg).
實施例42 Example 42
於1-甲基-4-吡啶-4-基-1H-吡唑-3-醇(550mg)及3-(喹啉-2-基)丙-2-炔-1-醇(603mg)的甲苯(55mL)溶液中加入氰伸甲基三丁基膦(953mg),在100℃進行2.5小時加熱攪拌。將反應液減壓濃縮,將殘渣以鹼性矽膠管柱層析法(乙酸乙酯-氯仿)進行純化。將此溶解於乙醇 (3mL),加入琥珀酸(13mg),進行5分鐘加熱攪拌。放冷後減壓下濃縮,將殘渣以乙酸乙酯固體化後得到2-(3-{〔1-甲基-4-(吡啶-4-基)-1H-吡唑-3-基〕氧基}丙-1-炔-1-基)喹啉 琥珀酸鹽(59mg)。 Toluene of 1-methyl-4-pyridin-4-yl-1H-pyrazol-3-ol (550 mg) and 3-(quinolin-2-yl)prop-2-yn-1-ol (603 mg) Cyanide methyltributylphosphine (953 mg) was added to the solution (55 mL), and the mixture was stirred under heating at 100 ° C for 2.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified mjjjd Dissolve this in ethanol (3 mL), succinic acid (13 mg) was added, and the mixture was stirred under heating for 5 minutes. After cooling, it was concentrated under reduced pressure and the residue was solidified ethyl acetate to give 2-(3-{[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy }}prop-1-yn-1-yl)quinoline succinate (59 mg).
實施例43 Example 43
將1-〔3-羥基-4-(吡啶-4-基)-1H-吡唑-1-基〕乙酮(3.19g)、2-〔4-(氯甲基)苯基〕喹啉鹽酸鹽(4.15g)、碳酸鉀的N,N-二甲基甲醯胺(80mL)混合物在60℃進行3小時攪拌。將反應液減壓濃縮後,於殘渣加入甲醇(80mL)及水(20mL),並在60℃下進行3小時攪拌。將反應液減壓濃縮,將所生成的沈澱過濾取出後水洗。將固體以矽膠管柱層析法(甲醇/氯仿)進行純化後得到2-〔4-({〔4-(吡啶-4-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕喹啉(1.52g)。 1-[3-Hydroxy-4-(pyridin-4-yl)-1H-pyrazol-1-yl]ethanone (3.19 g), 2-[4-(chloromethyl)phenyl]quinoline salt A mixture of the acid salt (4.15 g) and potassium carbonate in N,N-dimethylformamide (80 mL) was stirred at 60 ° C for 3 hours. After the reaction mixture was concentrated under reduced pressure, methanol (80 mL) and water (20 mL) were added to the residue, and the mixture was stirred at 60 ° C for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting precipitate was filtered and evaporated. The solid was purified by column chromatography (methanol / chloroform) to give 2-[4-({[4-(pyridin-4-yl)-1H-pyrazol-3-yl)oxy}methyl Phenyl]quinoline (1.52 g).
實施例44 Example 44
於3-(1-甲基-3-{〔4-(3-甲基喹啉-2-基)苯甲氧基}-1H-吡唑-4-基)吡咯烷-1-羧酸tert-丁基(916mg)的二氯甲烷(1.8mL)溶液中,加入三氟乙酸(1.8mL),在室溫下進行2小時攪拌。將反應液冰冷後,加入飽和碳酸氫鈉水溶液,以氯仿萃取。將有機層以無水硫酸鈉乾燥後減壓濃縮後得到3-甲基-2-〔4-({〔1-甲基-4-(吡咯烷-3-基)-1H-吡唑-3-基〕氧基}甲基)苯基〕喹啉(806 mg)。 3-(1-methyl-3-{[4-(3-methylquinolin-2-yl)benzyloxy}-1H-pyrazol-4-yl)pyrrolidine-1-carboxylic acid tert To a solution of butyl (916 mg) in dichloromethane (1.8 mL), trifluoroacetic acid (1.8 mL) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction mixture was ice-cooled, a saturated aqueous The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3-methyl-2-[4-({[1-methyl-4-(pyrrolidin-3-yl)-1H-pyrazole-3- Ethyloxy}methyl)phenyl]quinoline (806 mg).
實施例45 Example 45
冰冷下,於1-甲基-4-(4-{〔1-甲基-4-(2-甲基吡啶-4-基)-1H-吡唑-3-基〕甲氧基}苯基)-1H-苯並咪唑(731mg)的氯仿(30mL)溶液中,加入75%之m-氯過安息香酸(534mg),在室溫下進行24小時攪拌。於反應液中,加入溶解於水(5 mL)之硫代硫酸鈉(570mg),進行5分鐘攪拌。將反應液減壓濃縮,將殘渣以矽膠管柱層析法(甲醇/氯仿)進行純化後得到1-甲基-4-(4-{〔1-甲基-4-(2-甲基-1-氧化物吡啶-4-基)-1H-吡唑-3-基〕甲氧基}苯基)-1H-苯並咪唑(503mg)。 Under ice cooling, 1-methyl-4-(4-{[1-methyl-4-(2-methylpyridin-4-yl)-1H-pyrazol-3-yl]methoxy}phenyl To a solution of -1H-benzimidazole (731 mg) in chloroform (30 mL), 75% of m-chloro-benzoic acid (534 mg) was added and stirred at room temperature for 24 hours. To the reaction mixture, sodium thiosulfate (570 mg) dissolved in water (5 mL) was added and stirred for 5 minutes. The reaction solution was concentrated under reduced pressure and purified residue purified eluted eluted eluted eluted eluted eluted eluted eluted eluted 1-Oxylpyridin-4-yl)-1H-pyrazol-3-yl]methoxy}phenyl)-1H-benzimidazole (503 mg).
實施例46 Example 46
將3-(1-甲基-1H-苯並咪唑-4-基)丙烷-1-醇(62mg)的二氯甲烷(1.5mL)混合物冰冷下,加入三乙基胺(82μL)及甲磺醯氯(38μL),在同溫下進行30分攪拌。加入飽和碳酸氫鈉水溶液,以氯仿萃取後,將有機層以無水硫酸鈉乾燥並過濾、減壓濃縮。於殘渣加入5-(3-羥基-1-甲基-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮 三氟乙酸鹽(115mg)、碳酸鉀(135mg)、N,N-二甲基甲醯胺(1.5mL),在60℃進行12小時攪拌。加入飽和氯化鈉水溶液,以氯仿進行萃取。將有機層以無水硫酸鈉乾燥、過濾、減壓濃縮。將殘渣以矽膠管柱層析法(氯仿/甲醇)進行純化。將所得之粗純化物溶解於乙酸乙酯,加入 4M氯化氫之乙酸乙酯溶液,並在室溫下進行30分鐘攪拌。將析出之固體進行濾取、減壓乾燥後得到1-甲基-5-{1-甲基-3-〔3-(1-甲基-1H-苯並咪唑-4-基)丙氧基〕-1H-吡唑-4-基}吡啶-2(1H)-酮 三鹽酸鹽(16 mg)。 A mixture of 3-(1-methyl-1H-benzimidazol-4-yl)propan-1-ol (62 mg) in dichloromethane (1.5 mL) was iced cold, and triethylamine (82 μL) and methane. Chlorohydrazine (38 μL) was stirred at the same temperature for 30 minutes. After adding a saturated aqueous solution of sodium hydrogencarbonate and EtOAc (EtOAc) Add 5-(3-hydroxy-1-methyl-1H-pyrazol-4-yl)-1-methylpyridine-2(1H)-one trifluoroacetate (115 mg) and potassium carbonate (135 mg) to the residue. N,N-dimethylformamide (1.5 mL) was stirred at 60 ° C for 12 hours. A saturated aqueous solution of sodium chloride was added and the mixture was extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography (chloroform / methanol). The obtained crude purified product was dissolved in ethyl acetate and added A 4 M solution of hydrogen chloride in ethyl acetate was stirred at room temperature for 30 minutes. The precipitated solid was filtered and dried under reduced pressure to give 1-methyl-5-{1-methyl-3-[3-(1-methyl-1H-benzimidazol-4-yl)propoxy. -1H-pyrazol-4-yl}pyridine-2(1H)-one trihydrochloride (16 mg).
實施例47 Example 47
於1-甲基-5-(1-甲基-3-{〔4-(1-三苯甲基-1H-苯並咪唑-4-基)苯氧基〕甲基}-1H-吡唑-4-基)吡啶-2(1H)-酮(311mg)的二噁烷(8mL)溶液中,加入4M氯化氫之二噁烷溶液(0.6mL),在70℃進行1.5小時攪拌。將反應液減壓濃縮,於殘渣加入飽和碳酸氫鈉水溶液。加入飽和氯化鈉,以氯仿萃取。將有機層以無水硫酸鈉乾燥、過濾、減壓濃縮。將殘渣以矽膠管柱層析法(氯仿/甲醇)進行純化。將所得之粗純化物溶解於乙醇,加入4M氯化氫之乙酸乙酯溶液,在室溫下進行30分攪拌。加入乙酸乙酯,將析出之固體經濾取、減壓乾燥後得到5-(3-{〔4-(1H-苯並咪唑-4-基)苯氧基〕甲基}-1-甲基-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮 三鹽酸鹽(160 mg)。 1-methyl-5-(1-methyl-3-{[4-(1-trityl-1H-benzimidazol-4-yl)phenoxy]methyl}-1H-pyrazole To a solution of -4-yl)pyridine-2(1H)-one (311 mg) in dioxane (8 mL) was added 4M hydrogen chloride in dioxane (0.6 mL) and stirred at 70 ° C for 1.5 hours. The reaction solution was concentrated under reduced pressure. Saturated sodium chloride was added and extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography (chloroform / methanol). The obtained crude purified product was dissolved in ethanol, and a 4 M solution of hydrogen chloride in ethyl acetate was added thereto, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate was added, and the precipitated solid was filtered and dried under reduced pressure to give 5-(3-{[4-(1H-benzimidazol-4-yl)phenoxy]methyl}-1-methyl -1H-pyrazol-4-yl)-1-methylpyridine-2(1H)-one trihydrochloride (160 mg).
實施例338 Example 338
氬環境下,於2-{4-〔(4-碘-1-甲基-1H-吡唑-3-基)甲氧基〕苯基}-3-甲基喹啉(500 mg)的甲苯(10 mL)溶液中加入4-(三丁基甲錫烷基)噠嗪(500 mg)、參( 二苯亞甲基丙酮)二鈀(0)(50 mg)、2-二環己基膦-2',4',6'-三異丙基聯苯基(52 mg),在110℃進行12小時加熱攪拌。將反應液減壓濃縮,將殘渣以矽膠管柱層析法(甲醇/氯仿)進行分離純化。將所得之粗純化物以乙酸乙酯-己烷洗淨後得到3-甲基-2-(4-{〔1-甲基-4-(噠嗪-4-基)-1H-吡唑-3-基〕甲氧基}苯基)喹啉(255 mg)。 Toluene in 2-{4-[(4-iodo-1-methyl-1H-pyrazol-3-yl)methoxy]phenyl}-3-methylquinoline (500 mg) under argon (10 mL) solution was added 4-(tributylstannyl)pyridazine (500 mg), ginseng ( Diphenylmethyleneacetone) dipalladium (0) (50 mg), 2-dicyclohexylphosphine-2', 4',6'-triisopropylbiphenyl (52 mg), 12 at 110 ° C Heat and stir for hours. The reaction solution was concentrated under reduced pressure, and the residue was purified and purified by silica gel column chromatography (methanol / chloroform). The obtained crude purified product was washed with ethyl acetate-hexane to give 3-methyl-2-(4-{[1-methyl-4-(pyridazin-4-yl)-1H-pyrazole- 3-yl]methoxy}phenyl)quinoline (255 mg).
實施例397 Example 397
將2-{4-〔(4-碘-1-甲基-1H-吡唑-3-基)甲氧基〕苯基}-3-甲基喹啉(200mg)、5-甲基噠嗪-3-亞硼酸頻哪醇酯(116mg)、三-t-丁基鏻四氟硼酸鹽(16mg)、參(二苯亞甲基丙酮)二鈀(0)(20mg)、磷酸三鉀(308mg)、乙腈(3ml)的混合物,在油溫80℃下進行4小時加熱攪拌後,加入N,N-二甲基甲醯胺(2ml),在油溫90℃下再進行18小時加熱攪拌。在室溫冷卻後,將反應液以乙酸乙酯稀釋,以飽和食鹽水洗淨後乾燥,減壓下濃縮,將殘渣以矽膠管柱層析法(氯仿/甲醇)進行純化後得到3-甲基-2-(4-{〔1-甲基-4-(6-甲基噠嗪-4-基)-1H-吡唑-3-基〕甲氧基}苯基)喹啉(9mg)。 2-{4-[(4-Iodo-1-methyl-1H-pyrazol-3-yl)methoxy]phenyl}-3-methylquinoline (200 mg), 5-methylpyridazine -3-boronic acid pinacol ester (116 mg), tri-t-butyl phosphonium tetrafluoroborate (16 mg), ginseng (diphenylmethyleneacetone) dipalladium (0) (20 mg), tripotassium phosphate ( A mixture of 308 mg) and acetonitrile (3 ml) was heated and stirred at an oil temperature of 80 ° C for 4 hours, then N,N-dimethylformamide (2 ml) was added, and the mixture was heated and stirred at an oil temperature of 90 ° C for an additional 18 hours. . After cooling at room temperature, the reaction mixture was diluted with ethyl acetate, washed with brine, dried, evaporated, evaporated, evaporated. Benzyl-2-(4-{[1-methyl-4-(6-methylpyridazin-4-yl)-1H-pyrazol-3-yl]methoxy}phenyl)quinoline (9mg) .
實施例404 Example 404
將5-〔3-(氯甲基)-1-甲基-1H-吡唑-4-基〕-1-甲基吡啶-2(1H)-酮 鹽酸鹽(180mg)、4-(喹啉-2-基)酚(120mg)、碳酸鉀(205mg)及N,N-二甲基甲醯胺( 13mL)的混合物在70℃進行8小時攪拌。於反應液中加入水,以乙酸乙酯萃取。將有機層經減壓濃縮,將殘渣以矽膠管柱層析法(甲醇/氯仿)、鹼性矽膠管柱層析法(甲醇/氯仿)進行純化後得到1-甲基-5-(1-甲基-3-{〔4-(喹啉-2-基)苯氧基〕甲基}-1H-吡唑-4-基)吡啶-2(1H)-酮(90mg)。 5-[3-(Chloromethyl)-1-methyl-1H-pyrazol-4-yl]-1-methylpyridine-2(1H)-one hydrochloride (180 mg), 4-(quin Oxalin-2-yl)phenol (120 mg), potassium carbonate (205 mg) and N,N-dimethylformamide ( The mixture of 13 mL) was stirred at 70 ° C for 8 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / chloroform) and basic hexanes column chromatography (methanol / chloroform) to give 1-methyl-5-(1- Methyl-3-{[4-(quinolin-2-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridine-2(1H)-one (90 mg).
實施例412 Example 412
將1-甲基-5-(1-甲基-3-{〔4-(1-甲基-1H-苯並咪唑-4-基)苯氧基〕甲基}-1H-吡唑-4-基)吡啶-2(1H)-酮(2.5g)的甲醇(30mL)懸浮液在水浴溫60℃中加熱並溶解。在該溫度下,加入0.1M磷酸-乙醇溶液118mL,相同溫度下進行30分鐘攪拌。將反應液恢復至室溫後,減壓濃縮。於殘渣中加入乙醇(500mL)與水(50mL),於水浴溫90℃中進行2小時攪拌。恢復至室溫後進行1小時攪拌後,過濾取出固體,以乙醇洗淨。在50℃進行一夜減壓乾燥後得到1-甲基-5-(1-甲基-3-{〔4-(1-甲基-1H-苯並咪唑-4-基)苯氧基〕甲基}-1H-吡唑-4-基)吡啶-2(1H)-酮‧磷酸鹽2.96g。 1-Methyl-5-(1-methyl-3-{[4-(1-methyl-1H-benzimidazol-4-yl)phenoxy]methyl}-1H-pyrazole-4 A suspension of -pyridine)-2(1H)-one (2.5 g) in methanol (30 mL) was heated and dissolved in a water bath at 60 °C. At this temperature, 118 mL of a 0.1 M phosphoric acid-ethanol solution was added, and the mixture was stirred at the same temperature for 30 minutes. After returning the reaction mixture to room temperature, it was concentrated under reduced pressure. Ethanol (500 mL) and water (50 mL) were added to the residue, and the mixture was stirred at a water bath temperature of 90 ° C for 2 hours. After returning to room temperature and stirring for 1 hour, the solid was taken out by filtration and washed with ethanol. After drying under reduced pressure at 50 ° C overnight, 1-methyl-5-(1-methyl-3-{[4-(1-methyl-1H-benzimidazol-4-yl)phenoxy]- Base}-1H-pyrazol-4-yl)pyridine-2(1H)-one ‧ phosphate 2.96 g.
與上述實施例之方法同樣下,製造出後述表所示實施例之化合物。實施例化合物之化學結構式如表58至表125及表167至表182所示,物理化學性數據及製造法各如表126至表147及表183至表188所示。 The compound of the examples shown in the following Table was produced in the same manner as in the above examples. The chemical structural formulas of the example compounds are shown in Tables 58 to 125 and Tables 167 to 182, and the physicochemical data and the manufacturing methods are shown in Tables 126 to 147 and Tables 183 to 188, respectively.
式(I)之化合物或其鹽具有PDE10A阻礙作用,可作為精神分裂症、焦慮症、亨丁頓舞蹈症、藥物依存及/或阿茲海默病之預防及/或治療劑使用。 The compound of the formula (I) or a salt thereof has a PDE10A inhibitory action and can be used as a prophylactic and/or therapeutic agent for schizophrenia, anxiety, Huntington's disease, drug dependence and/or Alzheimer's disease.
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