TW201835041A - Compounds with Beta-Adrenergic Agonist and Antimuscarinic Activity - Google Patents

Compounds with Beta-Adrenergic Agonist and Antimuscarinic Activity Download PDF

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TW201835041A
TW201835041A TW107105292A TW107105292A TW201835041A TW 201835041 A TW201835041 A TW 201835041A TW 107105292 A TW107105292 A TW 107105292A TW 107105292 A TW107105292 A TW 107105292A TW 201835041 A TW201835041 A TW 201835041A
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hydroxy
dihydro
amino
methyl
ylhydroxy
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珊傑 斯里瓦斯塔瓦
普帝里克 欣德
阿帕吉 曼德哈爾
拉梅許‧錢德拉 古波塔
阿妮塔 巧德哈利
拉姆 古波塔
沙爾雷許 德許番德
基藍 巧德哈利
加亞 亞伯拉罕
迪帕 約希
柴坦亞 達特
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印度商托仁特生技有限公司
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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Abstract

The present invention relates to novel compounds of formula (I), its pharmaceutically acceptable salts, and isomers, stereoisomers, atropisomers, conformers, tautomers, atropisomers, polymorphs, hydrates, solvates, N-oxide or S-oxide thereof. The present invention also relates to pharmaceutically acceptable compositions and process for preparing said compounds. The invention further relates to the use of the above-mentioned compounds for the preparation of medicament for use as pharmaceuticals.

Description

具β-腎上腺素促效劑及抗蕈毒活性化合物With β-adrenergic agonist and anti-venom active compound

本發明與分子式（I）的創新化合物、其藥學上可接受的鹽類以及它們的異構物、立體異構物、阻轉異構物、構形異構物、互變異構物、阻轉異構物、同素異形體、水合物、溶劑化物，其N-氧化物或S-氧化物有關。本發明還包括藥學上可接受的組合物以及製備該化合物的方法。本發明進一步與上述化合物在製備用以作為藥物的藥劑中的用途有關。Inventive compounds of the formula (I), pharmaceutically acceptable salts thereof, and their isomers, stereoisomers, atropisomers, conformational isomers, tautomers, hindrance Isomers, allotropes, hydrates, solvates, N-oxides or S-oxides. The invention also includes pharmaceutically acceptable compositions and methods of making the compounds. The invention is further related to the use of the above compounds in the preparation of a medicament for use as a medicament.

在儘管有治療進展，但近幾十年來氣道疾病的盛行率有所增加。氣道疾病是阻塞性肺病，包括氣喘、支氣管擴張症、囊腫纖維化以及慢性阻塞性肺病（COPD）。COPD意指特徵為干擾正常呼吸的氣流阻塞的一大群肺部疾病的用語。肺氣腫以及慢性支氣管炎是構成COPD的最重要的病症。（澳大利亞肺基金會， 2006 年）。 此外，氣喘急性加重以及慢性阻塞性肺病（COPD）是住院的主要原因。慢性阻塞性肺病(COPD）是一個正變得普遍的全球主要健康問題，特別是在開發中國家。它是世界上最常見的疾病之一，終身風險估計高達25％，現在同樣影響男性以及女性（ Nature Reviews. 2013;12: 543-559 ）。 In spite of the progress in treatment, the prevalence of airway diseases has increased in recent decades. Airway diseases are obstructive pulmonary diseases, including asthma, bronchiectasis, cystic fibrosis, and chronic obstructive pulmonary disease (COPD). COPD is a term used to describe a large group of lung diseases that interfere with airflow obstructing normal breathing. Emphysema and chronic bronchitis are the most important conditions that constitute COPD. (Australian Lung Foundation, 2006 ). In addition, acute exacerbation of asthma and chronic obstructive pulmonary disease (COPD) are the main causes of hospitalization. Chronic obstructive pulmonary disease (COPD) is a major global health problem that is becoming commonplace, especially in developing countries. It is one of the most common diseases in the world, with an estimated lifetime risk of up to 25%, and now affects both men and women ( Nature Reviews. 2013;12: 543-559 ).

COPD治療的目前形式包括支氣管擴張劑、磷酸二酯酶-4抑制劑、皮質類固醇以及如甲基黃嘌呤之類的其他藥物，然而，支氣管擴張劑仍然是用於具有例如氣喘以及慢性阻塞性肺病之類的肺病症患者的症狀藥理治療的重要方法之一（ J Allergy Clin Immunol. 2007 Nov;120(5): S94-138 ； Curr Opin Pharmacol. 2008 Jun;8(3):300-7 ） 。Current forms of COPD therapy include bronchodilators, phosphodiesterase-4 inhibitors, corticosteroids, and other drugs such as methylxanthin, however, bronchodilators are still used to have, for example, asthma and chronic obstructive pulmonary disease. One of the important methods for symptomatic pharmacological treatment of patients with pulmonary disorders ( J Allergy Clin Immunol. 2007 Nov; 120(5): S94-138 ; Curr Opin Pharmacol. 2008 Jun; 8(3): 300-7 ) .

兩種類型的支氣管擴張劑，β2腎上腺素受體促效劑以及毒蕈鹼受體拮抗劑，目前是可得的並在臨床中廣泛應用。這些化合物通常以吸入給藥。短效b2腎上腺素受體促效劑，如沙丁胺醇以及特布他林，用於緩解呼吸困難的發作，而長效b2腎上腺素受體促效劑，如福莫特羅以及沙美特羅，用於控制更持久的症狀。目前使用的吸入毒蕈鹼拮抗劑包括短效的異丙托溴銨或氧托溴銨以及長效噻托溴銨。Two types of bronchodilators, beta 2 adrenergic receptor agonists and muscarinic receptor antagonists are currently available and widely used in the clinic. These compounds are usually administered by inhalation. Short-acting b2 adrenergic receptor agonists, such as salbutamol and terbutaline, are used to relieve the onset of dyspnea, while long-acting b2 adrenergic receptor agonists, such as formoterol and salmeterol, are used. To control more persistent symptoms. Inhaled muscarinic antagonists currently in use include short-acting ipratropium bromide or oxitropium bromide and long-acting tiotropium bromide.

從幾個臨床前以及臨床研究的結果清楚地展示，來自b2腎上腺素受體促效劑以及毒蕈鹼受體拮抗劑這兩類的支氣管擴張劑的組合的確在氣喘以及COPD的患者中比單獨的任一機制產生較大的功效（ J Pharmacol Exp Ther. 2014 Feb;348(2):303-10 ； Ther Clin Risk Manag. 2015 Mar 25 ； 11481-7; Pulm Pharmacol Ther. 2011 Feb;24(1):147-52 ） 。這導致這些支氣管擴張劑的臨床使用，經由單獨的吸入器或經由單一吸入器遞送的這些支氣管擴張劑固定劑量組合已被共同給藥。在專利申請案WO0238154以及WO03000241中也已揭露了b2腎上腺素受體促效劑以及毒蕈鹼性受體拮抗劑的組合的使用。The results from several preclinical and clinical studies clearly show that the combination of bronchodilators from b2 adrenergic receptor agonists and muscarinic receptor antagonists does indeed differ from asthmatic and COPD patients alone. Either mechanism produces greater efficacy ( J Pharmacol Exp Ther. 2014 Feb; 348(2): 303-10 ; Ther Clin Risk Manag. 2015 Mar 25 ; 11481-7; Pulm Pharmacol Ther. 2011 Feb; 24(1 ):147-52 ) . This results in the clinical use of these bronchodilators, which have been co-administered via a separate inhaler or a fixed dose combination of these bronchodilators delivered via a single inhaler. The use of a combination of a b2 adrenergic receptor agonist and a muscarinic receptor antagonist has also been disclosed in the patent applications WO 0238154 and WO 03000241.

然而對於b2-腎上腺素受體促效劑以及毒蕈鹼性受體拮抗劑正在探索的另一種方法為具有b2腎上腺素受體促效劑以及毒蕈鹼受體拮抗劑兩者活性的單分子的發展。這樣的方法將具有易於配製、兩種藥理學活性的單一藥物動力學特徵的優點，從而最大化兩個機制之間的潛在協同效益，否則這將難以經由具有不同藥物動力學-藥效學特徵的兩種單獨化合物的共同給藥來實現，且在達到與在臨床上與例如吸入性皮質類固醇或其他吸入性消炎藥組合使用的支氣管擴張劑其他潛在藥物的組合有更好的前景（ J Allergy Clin Immunol. 2007 Nov;120(5): S94-138; Am Fam Physician. 2013 Nov 15;88(10):655-63 ） 。However, another approach being explored for b2-adrenergic receptor agonists and muscarinic receptor antagonists is the single molecule with both b2 adrenergic receptor agonists and muscarinic receptor antagonists. development of. Such an approach would have the advantage of a single pharmacokinetic profile that is easy to formulate and have two pharmacological activities, thereby maximizing the potential synergy between the two mechanisms that would otherwise be difficult to achieve via different pharmacokinetic-pharmacodynamic characteristics. Co-administration of two separate compounds is achieved, and there is a better prospect in achieving a combination with other potential drugs for bronchodilators that are clinically used in combination with, for example, inhaled corticosteroids or other inhaled anti-inflammatory drugs ( J Allergy) Clin Immunol. 2007 Nov;120(5): S94-138; Am Fam Physician. 2013 Nov 15;88(10):655-63 ) .

然而，先前技術中揭露的化合物沒有一種是商業可得或已被批准用於市場銷售。因此，存在具有b2腎上腺素受體促效劑以及毒蕈鹼受體拮抗劑兩者活性的化合物的需要，這在COPD以及氣喘患者中將比任一單獨機制產生更大的功效。However, none of the compounds disclosed in the prior art are commercially available or have been approved for marketing. Thus, there is a need for compounds having both b2 adrenergic receptor agonists and muscarinic receptor antagonists, which will produce greater efficacy than any of the individual mechanisms in COPD as well as in asthmatic patients.

在一個實施方式中，本發明提供了一種分子式（I）的創新化合物、其藥學上可接受鹽類以及異構物、立體異構物、阻轉異構物、構形異構物、互變異構物、同素異形體、水合物、溶劑化物、N-氧化物或S-氧化物；I 其中， R1 以及R2 獨立地選自(C3 -C7 )環烷基、芳基以及雜芳基，該(C3 -C7 )環烷基、芳基以及雜芳基可選地被一或更多個(C1 -C6 )烷基、芳基、(C3 -C7 )環烷基、鹵素、O-R14 、SH、CN、(CH2 )p -芳基、(CH2 )p -雜芳基、CH2 OH、CH2 -鹵素、CH2 O-(C1 -C6 )烷基、CH2 O-芳基、COOR12 、CONR16 R17 或NHCOR12 取代； R3 選自氫、羥基、(C1 -C4 )烷氧基、CH2 OH以及(C1 -C6 )烷基； R4 選自氫、(C1 -C6 )烷基、芳基、(CH2 )p -芳基、(CH2 )p -雜芳基以及(C3 -C7 )環烷基； m是1或2； R5 以及R6 獨立地選自氫、(C1 -C6 )烷基、鹵素、(C3 -C7 )環烷基、雜環烷基、(CH2 )P -芳基以及(CH2 )P -雜芳基、或在同一碳上的R5 以及R6 以螺旋方式形成3-7元環烷基或雜環烷基環、或為偕二甲基； n選自0-4； R7 以及R8 獨立地選自氫、(C1 -C6 )烷基以及雜環烷基、或在同一碳上的R7 以及R8 以螺旋方式形成3-7元環烷基或雜環烷基環、或為偕二甲基； p是1或2； R9 以及R10 獨立地選自氫、(C1 -C6 )烷基、(C3 -C7 )環烷基、雜環烷基以及側氧基，或在同一碳上的R9 以及R10 以螺旋方式形成3-7元的環烷基或雜環烷基環或為偕二甲基； R11 選自氫、(C1 -C6 )烷基、芳基、CH2 OH、CH2 -鹵素、鹵素、(C3 -C7 )環烷基、雜芳基、雜環烷基、O-R14 、SH、CN、(CH2 )p -芳基、(CH2 )p -雜芳基、CH2 O-(C1 -C6 )烷基、CH2 O-芳基、COOR12 、CONR16 R17 以及NHCOR12 ； Q是N(A)R12 或O-A； R12 選自氫、(C1 -C6 )烷基、芳基、(CH2 )P -芳基、(CH2 )P -雜芳基、(C3 -C7 )環烷基以及雜環烷基； R13 選自氫、O-R14 以及； R14 獨立地選自氫、(C1 -C6 )烷基、芳基、雜芳基、(CH2 )P -芳基、(CH2 )P -雜芳基、(C3 -C7 )環烷基、Si(C1 -C6 )烷基以及； R15 選自(C1 -C6 )烷基、(C3 -C7 )環烷基、芳基、雜芳基、(CH2 )P -芳基以及(CH2 )P -雜芳基； R16 以及R17 獨立地選自氫、(C1 -C6 )烷基、(C3 -C7 )環烷基以及雜環烷基，或R16 以及R17 與氮原子一起形成3-10元雜環烷基環； A選自：「/」表示附接點。In one embodiment, the invention provides an inventive compound of formula (I), a pharmaceutically acceptable salt thereof, and isomers, stereoisomers, atropisomers, conformational isomers, tautomers a conformation, an allotrope, a hydrate, a solvate, an N-oxide or an S-oxide; Wherein R 1 and R 2 are independently selected from (C 3 -C 7 )cycloalkyl, aryl and heteroaryl, and the (C 3 -C 7 )cycloalkyl, aryl and heteroaryl are optional One or more (C 1 -C 6 )alkyl, aryl, (C 3 -C 7 )cycloalkyl, halogen, OR 14 , SH, CN, (CH 2 ) p -aryl, ( CH 2 ) p -heteroaryl, CH 2 OH, CH 2 -halogen, CH 2 O-(C 1 -C 6 )alkyl, CH 2 O-aryl, COOR 12 , CONR 16 R 17 or NHCOR 12 ; R 3 is selected from the group consisting of hydrogen, hydroxy, (C 1 -C 4 ) alkoxy, CH 2 OH, and (C 1 -C 6 )alkyl; R 4 is selected from hydrogen, (C 1 -C 6 )alkyl, Aryl, (CH 2 ) p -aryl, (CH 2 ) p -heteroaryl, and (C 3 -C 7 )cycloalkyl; m is 1 or 2; R 5 and R 6 are independently selected from hydrogen, (C 1 -C 6 )alkyl, halogen, (C 3 -C 7 )cycloalkyl, heterocycloalkyl, (CH 2 ) P -aryl and (CH 2 ) P -heteroaryl, or in the same R 5 and R 6 on the carbon form a 3-7 membered cycloalkyl or heterocycloalkyl ring in a helical manner, or a fluorenyl dimethyl group; n is selected from 0-4; R 7 and R 8 are independently selected from hydrogen , (C 1 -C 6 )alkyl and heterocycloalkyl, or R 7 and R 8 on the same carbon are formed in a helical manner a 3-7 membered cycloalkyl or heterocycloalkyl ring, or geminal dimethyl; p is 1 or 2; R 9 and R 10 are independently selected from hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 7 ) cycloalkyl, heterocycloalkyl and pendant oxy, or R 9 and R 10 on the same carbon form a 3-7 membered cycloalkyl or heterocycloalkyl ring in a helical manner or Dimethyl; R 11 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, aryl, CH 2 OH, CH 2 -halogen, halogen, (C 3 -C 7 )cycloalkyl, heteroaryl, hetero Cycloalkyl, OR 14 , SH, CN, (CH 2 ) p -aryl, (CH 2 ) p -heteroaryl, CH 2 O-(C 1 -C 6 )alkyl, CH 2 O-aryl , COOR 12 , CONR 16 R 17 and NHCOR 12 ; Q is N(A)R 12 or OA; R 12 is selected from hydrogen, (C 1 -C 6 )alkyl, aryl, (CH 2 ) P -aryl , (CH 2 ) P -heteroaryl, (C 3 -C 7 )cycloalkyl and heterocycloalkyl; R 13 is selected from hydrogen, OR 14 and R 14 is independently selected from hydrogen, (C 1 -C 6 )alkyl, aryl, heteroaryl, (CH 2 ) P -aryl, (CH 2 ) P -heteroaryl, (C 3 -C 7 ) cycloalkyl, Si(C 1 -C 6 )alkyl and ; R 15 is selected from (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, aryl, heteroaryl, (CH 2 ) P -aryl and (CH 2 ) P -heteroaryl R 16 and R 17 are independently selected from hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, and heterocycloalkyl, or R 16 and R 17 are taken together with a nitrogen atom. a 3-10 membered heterocycloalkyl ring; A is selected from the group consisting of "/" indicates the attachment point.

在另一個實施方式中，本發明附屬於如上的化合物，然而僅包括其藥學上可接受鹽類。In another embodiment, the invention is affixed to a compound as above, but only includes pharmaceutically acceptable salts thereof.

在另一個實施方式中，本發明包括在製備分子式（I）化合物中有用的合成中間產物以及製備這樣的中間產物的方法。In another embodiment, the invention includes synthetic intermediates useful in the preparation of compounds of formula (I) and methods of preparing such intermediates.

在另一個實施方式中，本發明包括分子式（I）化合物的代謝物。In another embodiment, the invention includes a metabolite of a compound of formula (I).

本發明的另一個實施方式是用於製備如本文中方案1以及2所述的分子式（I）化合物或中間產物的方法。Another embodiment of the invention is a process for the preparation of a compound of formula (I) or an intermediate as described in Schemes 1 and 2 herein.

本發明的另一個實施方式提供了包括分子式（I）的化合物的藥學組合物，可選地與藥學上可接受賦形劑混合。Another embodiment of the invention provides a pharmaceutical composition comprising a compound of formula (I), optionally in admixture with a pharmaceutically acceptable excipient.

本發明的另一個實施方式提供了藉由將醫療有效量的分子式（I）化合物給予至需要其的哺乳動物（包括人類）以治療呼吸道病症的方法。Another embodiment of the invention provides a method of treating a respiratory condition by administering a therapeutically effective amount of a compound of formula (I) to a mammal, including a human, in need thereof.

本發明的另一個實施方式提供了藉由將醫療有效量的分子式（I）化合物給予至需要其的哺乳動物（包括人類）以治療呼吸道病症的方法，呼吸道病症例如氣喘、慢性阻塞性肺病、慢性支氣管炎、急性呼吸窘迫綜合症（ARDS）、慢性呼吸道阻塞、支氣管亢進、肺纖維化、肺氣腫以及過敏性鼻炎。Another embodiment of the invention provides a method of treating a respiratory condition by administering a therapeutically effective amount of a compound of formula (I) to a mammal, including a human, in need thereof, a respiratory condition such as asthma, chronic obstructive pulmonary disease, chronic Bronchitis, acute respiratory distress syndrome (ARDS), chronic airway obstruction, bronchoconstriction, pulmonary fibrosis, emphysema, and allergic rhinitis.

本發明的另一個實施方式提供了藉由將醫療有效量的分子式（I）化合物給予至需要其的哺乳動物（包括人類）以治療慢性阻塞性肺病或氣喘的方法。Another embodiment of the invention provides a method of treating chronic obstructive pulmonary disease or asthma by administering a therapeutically effective amount of a compound of formula (I) to a mammal, including a human, in need thereof.

本發明的另一個實施方式提供了分子式（I）化合物用於製備治療呼吸道病症的藥物的用途。Another embodiment of the invention provides the use of a compound of formula (I) for the manufacture of a medicament for the treatment of a respiratory disorder.

本發明的另一個實施方式提供了分子式（I）化合物在用於製備治療呼吸道病症的藥物的用途，呼吸道病症例如氣喘、慢性阻塞性肺病、慢性支氣管炎、急性呼吸窘迫綜合症（ARDS）、慢性呼吸阻塞、支氣管亢進、肺纖維化、肺氣腫以及過敏性鼻炎。Another embodiment of the present invention provides the use of a compound of formula (I) for the manufacture of a medicament for the treatment of a respiratory disorder, such as asthma, chronic obstructive pulmonary disease, chronic bronchitis, acute respiratory distress syndrome (ARDS), chronic Respiratory obstruction, bronchospasm, pulmonary fibrosis, emphysema, and allergic rhinitis.

本發明的另一個實施方式提供了分子式（I）化合物在用於製備治療慢性阻塞性肺病或氣喘的藥物的用途。Another embodiment of the invention provides the use of a compound of formula (I) for the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease or asthma.

在一個實施方式中，本發明提供了創新的分子式（I）化合物，（I） 其中R1 、R2 、R3 、R4 、R5 、R6 、R7 、R8 、R9 、R10 、R11 、Q、m、n以及p如上所定義；或其藥學上可接受鹽類、異構物、立體異構物、阻轉異構物、構形異構物、互變異構物、同素異形體、水合物、N-氧化物、S-氧化物以及溶劑化物。In one embodiment, the invention provides an innovative compound of formula (I), (I) wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , Q, m, n and p are as defined above; Pharmaceutically acceptable salts, isomers, stereoisomers, atropisomers, conformational isomers, tautomers, allotropes, hydrates, N-oxides, S-oxides And solvates.

在一個較佳的實施方式中，本發明提供如上所述的創新分子式（I）化合物，其中： R1 以及R2 獨立地選自(C3 -C7 )環烷基、芳基以及雜芳基； R3 選自羥基以及(C1 -C6 )烷基； R4 是氫； m是1或2； R5 以及R6 獨立地為氫、或在同一碳上的R5 以及R6 為偕二​​甲基； n選自0-2； R7 以及R8 獨立地為氫、或在同一碳上的R7 以及R8 為偕二​​甲基； p是1或2； R9 以及R10 是氫； R11 是氫或(C1 -C6 )烷基； Q是N(A)R12 ； R12 是氫或(C1 -C6 )烷基； R13 是氫或O-R14 ； R14 選自氫以及Si(C1 -C6 )烷基； R15 是(C1 -C6 )烷基； A選自：「/」表示附接點。In a preferred embodiment, the invention provides an inventive compound of formula (I) as defined above, wherein: R 1 and R 2 are independently selected from (C 3 -C 7 )cycloalkyl, aryl and heteroaryl group; R. 3 is selected from hydroxy and (C 1 -C 6) alkyl; R is hydrogen. 4; m is 1 or 2; R 5 and R 6 are independently hydrogen, or R 5 on the same carbon and R 6 Is 偕 dimethyl; n is selected from 0 to 2; R 7 and R 8 are independently hydrogen, or R 7 and R 8 on the same carbon are decyl dimethyl; p is 1 or 2; R 9 and R 10 are hydrogen; R 11 is hydrogen or (C 1 -C 6 )alkyl; Q is N(A)R 12 ; R 12 is hydrogen or (C 1 -C 6 )alkyl; R 13 is Hydrogen or OR 14 ; R 14 is selected from hydrogen and Si(C 1 -C 6 )alkyl; R 15 is (C 1 -C 6 )alkyl; A is selected from: "/" indicates the attachment point.

本發明範圍內特別感興趣的特定化合物家族由如下化合物及其藥學上可接受的鹽類組成： 表I： 定義： 除非在特定情況中另外限制，以下定義適用於整個此說明書中使用的用語：A particular family of compounds of particular interest within the scope of the present invention consists of the following compounds and their pharmaceutically acceptable salts: Table I: Definition: Unless otherwise limited in certain circumstances, the following definitions apply to the terms used throughout this specification:

本文中使用的用語「化合物」意指本文中所揭露的一般分子式包含的任何化合物。本文所述的化合物可含有一或更多個雙鍵，且因此可以異構物、例如幾何異構物、E以及Z異構物之類的立體異構物存在，且可具有不對稱碳原子（光學中心），且因此可以鏡像異構物、非鏡像異構物存在。因此，本文所述的化學結構包括所示化合物的所有可能的立體異構物，包括立體異構純形式（例如幾何上純的）以及立體異構混合物（外消旋物）。本文中所述的化合物可以例如椅形式或船形式之類的構形異構物存在。化合物也可以幾種互變異構形式存在，包括烯醇形式、酮形式及其混合物。因此，本文中所述的化學結構包含所示化合物的所有可能的互變異構形式。所描述的化合物也包括同位素標記的化合物，其中一或更多個原子的原子量具有與自然界中傳統發現的原子量不同的分子量。可以併入本發明化合物的同位素的範例包括但不限於2 H、3 H、13 C、14 C、15 N、18 O、17 O等等。化合物可以非溶劑化形式以及溶劑化形式存在，包括水合形式。一般而言，化合物可為水合或溶劑化的。某些化合物可以以多晶或非晶形形式存在。一般而言，所有物理形式對於本文中考慮的用途是均等的，且意欲在本發明的範圍內。The term "compound" as used herein means any compound encompassed by the general formula disclosed herein. The compounds described herein may contain one or more double bonds and may therefore exist as isomers, such as geometric isomers, E and Z isomers, and may have asymmetric carbon atoms (optical center), and thus can be present as an image isomer, a non-image isomer. Thus, the chemical structures described herein include all possible stereoisomers of the indicated compounds, including stereoisomeric pure forms (e.g., geometrically pure) and stereoisomeric mixtures (racemates). The compounds described herein may exist as conformational isomers such as in the form of a chair or a boat. The compounds may also exist in several tautomeric forms, including the enol form, the keto form, and mixtures thereof. Thus, the chemical structures described herein contain all possible tautomeric forms of the compounds shown. The compounds described also include isotopically labeled compounds in which the atomic weight of one or more atoms has a molecular weight that is different from the amount of atoms conventionally found in nature. Examples of isotopes that may be incorporated into the compounds of the invention include, but are not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, and the like. The compounds may exist in unsolvated as well as solvated forms, including hydrated forms. In general, the compound can be hydrated or solvated. Certain compounds may exist in polycrystalline or amorphous form. In general, all physical forms are equally intended for the purposes contemplated herein and are intended to be within the scope of the invention.

除非在本文中另外指出或明顯與上下文矛盾，在描述本發明的上下文中（尤其是在下面的申請專利範圍的上下文中）用語「一（a）」、「一（an）」以及「該」以及類似參照的使用應被解釋為涵蓋單數以及複數兩者。In the context of describing the invention (especially in the context of the scope of the claims below), the terms "a", "an" and "the" are used in the context of the present invention. The use of similar references should be construed to cover both singular and plural.

如本文中指出的本發明化合物的命名是根據ACD/Lab的具有「logD Suite」（版本12.0）的ChemDraw。The nomenclature of the compounds of the invention as indicated herein is according to ACD/Lab's ChemDraw with "logD Suite" (version 12.0).

「藥學上可接受的鹽類」意指具有母化合物的期望藥理學活性的化合物的鹽類。這樣的鹽類包括：（1）與例如氫氯酸、氫溴酸、硫酸、硝酸、碳酸、磷酸等等的無機酸形成的酸加成鹽；或與例如乙酸、三氟乙酸、丙酸、異丁酸、己酸、環戊烷丙酸、草酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、辛二酸、蘋果酸、馬來酸、富馬酸、酒石酸、檸檬酸、苯甲酸、三苯基乙酸、3-(4-羥基苯甲醯基)苯甲酸、鄰苯二甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙烷二磺酸、2-羥基乙磺酸、苯磺酸、4-氯苯磺酸、2-萘磺酸、4-甲苯磺酸、樟腦磺酸、4-甲基雙環[2.2.2]-辛-2-烯-1-羧酸、葡庚糖酸、3-苯基丙酸酸、三甲基乙酸、叔丁基乙酸、月桂基硫酸、葡糖酸、葡醣醛酸、半乳醣醛酸、麩胺酸、羥基萘甲酸、水楊酸、硬脂酸、黏康酸、[(1S,4R)-7,7-二甲基-2-側氧降冰片烷-1-基]甲基磺酸，1,5-萘二磺酸等等的有機酸形成的酸加成鹽；或（2）當母化合物中存在的酸性質子被金屬離子例如鹼金屬離子、鹼土金屬離子或鋁離子置換時形成的鹽類；或與例如乙醇胺，二乙醇胺、三乙醇胺、N-甲基葡糖胺等等之類的有機鹼配位。也包括的是胺基酸的鹽，例如精胺酸鹽等等（見，例如Berge, S.M. 等人， “Pharmaceutical Salts”, Journal of Pharmaceutical Science.1977; 66:1-19 ）。本發明的化合物可以形成半鹽、單鹽、二鹽或三鹽。"Pharmaceutically acceptable salt" means a salt of a compound having the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like; or with, for example, acetic acid, trifluoroacetic acid, propionic acid, Isobutyric acid, caproic acid, cyclopentanepropionic acid, oxalic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, suberic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, Benzoic acid, triphenylacetic acid, 3-(4-hydroxybenzhydryl)benzoic acid, phthalic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid , 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2- Alkene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, t-butyl acetic acid, lauryl sulfate, gluconic acid, glucuronic acid, galacturonic acid, bran Amine acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, [(1S,4R)-7,7-dimethyl-2-oxo-norbornan-1-yl]methanesulfonic acid An acid addition salt formed by an organic acid of 1,5-naphthalenedisulfonic acid or the like; or (2) when a parent compound a salt formed when an acidic proton present is replaced by a metal ion such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion; or with, for example, ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, or the like Organic base coordination. Also included are salts of amino acids such as arginine salts and the like (see, for example, Berge, SM et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science. 1977; 66: 1-19 ). The compounds of the invention may form a half salt, a single salt, a di salt or a tri salt.

如本文中使用的，用語「同素異形體」與具有相同化學式、相同鹽類型且具有相同形式的水合物/溶劑化物但具有不同晶體學性質的化合物有關。As used herein, the term "homologous" relates to a compound having the same chemical formula, the same salt type, and having the same form of hydrate/solvate but having different crystallographic properties.

如本文中使用的，用語「水合物」與具有許多結合至化合物的水分子的化合物有關。As used herein, the term "hydrate" relates to a compound having a plurality of water molecules that bind to a compound.

如本文中使用的，用語「溶劑化物」與具有許多結合至化合物的溶劑分子的化合物有關。As used herein, the term "solvate" relates to a compound having a plurality of solvent molecules that bind to a compound.

如本文中使用的，用語「取代的」包括經由命名取代基的單取代以及多取代到在化學上允許這樣的單一以及多重取代（包括在相同位點的多重取代）的程度，且這意指在指定的原子上的任一或更多個氫被指定基團的選擇取代，條件是不超過指定原子的正常價數，且取代導致穩定的化合物，例如，當取代基是酮時，則在原子上的兩個氫被取代。本文中所描述的所有取代基(R1 、R2 ，…）及它們進一步的取代基可在導致形成穩定化合物的任何雜原子或碳原子上附接至主結構。As used herein, the term "substituted" includes both mono- and poly-substitutions via named substituents to the extent that chemically allows such single and multiple substitutions, including multiple substitutions at the same position, and this means Any one or more hydrogens at a given atom are replaced by a selection of a specified group, provided that the normal valence of the specified atom is not exceeded, and the substitution results in a stable compound, for example, when the substituent is a ketone, then Two hydrogens on the atom are replaced. All of the substituents (R 1 , R 2 , ...) described herein and their further substituents may be attached to the main structure at any heteroatom or carbon atom that results in the formation of a stable compound.

如本文中使用的，「鹵素」取代基是選自氯、溴、碘以及氟的一價鹵素自由基。As used herein, a "halogen" substituent is a monovalent halogen radical selected from the group consisting of chlorine, bromine, iodine, and fluorine.

單獨使用或與另一基團連接使用的用語「烷基」意指具有指定碳原子數且未被取代或被取代的脂族碳氫自由基。當關於烷基使用下標時，下標意指那個基團可含有的碳原子數。例如，「C1 -C6 」意指在結構中含有一至六個碳的任何烷基。所述「烷基」可為直鏈（例如甲基、乙基、正丙基、正丁基、正戊基、正己基）或支鏈（例如異丙基、異丁基、仲丁基、叔丁基），且其可含有一個或兩個雙鍵或三鍵以形成相對應的烯烴或炔烴。所述「烷基」也可以螺旋方式含有(C3 -C7 )環烷基環。The term "alkyl", used alone or in connection with another group, means an aliphatic hydrocarbon radical having the specified number of carbon atoms and which is unsubstituted or substituted. When a subscript is used with respect to an alkyl group, the subscript means the number of carbon atoms that that group can contain. For example, "C 1 -C 6 " means any alkyl group containing from one to six carbons in the structure. The "alkyl group" may be a straight chain (eg, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl) or a branched chain (eg, isopropyl, isobutyl, sec-butyl, Tert-butyl), and which may contain one or two double or triple bonds to form the corresponding olefin or alkyne. The "alkyl group" may also contain a (C 3 -C 7 )cycloalkyl ring in a helical manner.

用語「烷氧基」意指如本文中上述定義經由氧橋附接至母分子基元的的任何烷基。The term "alkoxy" means any alkyl group attached to the parent molecular moiety via an oxygen bridge as defined herein above.

如本文使用的用語「羥基」意指-OH基團。The term "hydroxy" as used herein means an -OH group.

單獨使用或與另一基團連接使用的用語「環烷基」意指具有指定數目碳原子且未被取代或被在任何可用原子處附接的基團或取代基取代以產生穩定化合物的環狀環系統。當關於環烷基使用下標時，下標指的是那個基團可含有的碳原子數目。例如，用語「(C3 -C7 )環烷基」意指具有3至7個碳原子且未被取代或被取代的環狀環系統。所述「(C3 -C7 )環烷基」意指在環系統骨架中僅含有碳原子的環狀環系統，例如環丙基、環丁基、環戊基、環己基。環烷基可包括雙環。環烷基可具有任何飽和度，條件是環系統中的至少一個環不是芳香族。The term "cycloalkyl" as used alone or in connection with another group means a ring having the indicated number of carbon atoms and which is unsubstituted or substituted with a group or substituent attached at any available atom to give a stable compound. Ring system. When a subscript is used with respect to a cycloalkyl group, the subscript refers to the number of carbon atoms that that group can contain. For example, the phrase "(C 3 -C 7 )cycloalkyl" means a cyclic ring system having from 3 to 7 carbon atoms which is unsubstituted or substituted. The "(C 3 -C 7 )cycloalkyl group" means a cyclic ring system containing only a carbon atom in the ring system skeleton, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group. A cycloalkyl group can include a bicyclic ring. The cycloalkyl group can have any degree of saturation provided that at least one ring in the ring system is not aromatic.

單獨使用或與另一基團連接使用的用語「芳基」是指芳族基團，例如其是6至10元單環或雙環含碳環系統，其可為未取代的或取代的。芳基包括但不限於苯基、萘基、聯苯基、四氫萘基以及茚烷。較佳地，芳基是苯基。The term "aryl" used alone or in connection with another group refers to an aromatic group, for example, which is a 6 to 10 membered monocyclic or bicyclic carbon containing ring system which may be unsubstituted or substituted. Aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, tetrahydronaphthyl, and decane. Preferably, the aryl group is a phenyl group.

單獨使用或與另一基團連接使用的用語「雜芳基」是指芳族基團，例如其為5至14元單環或雙環系統，其具有至少一個可未被取代或被取代的雜原子。如本文中所使用的用語「雜原子」包括氧、硫以及氮。在雙環環系中，環可以經由橋雜原子稠合。雜芳基包括但不限於吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噁唑基、異噁唑基、噻唑基、***基、噁二唑基、噻二唑基、四唑基、吡啶基、噠嗪基、嘧啶基、吡嗪基、三嗪基、吲哚基、苯並呋喃基、苯並苯硫基、吲唑基、苯並咪唑基、苯並噁唑基、苯並異噁唑基、苯並噻唑基、喹啉基、異喹啉基、噌啉基、喹唑啉基、喹噁啉基、呔嗪基或萘啶基。The term "heteroaryl" used alone or in connection with another group refers to an aromatic group, for example, a 5- to 14-membered monocyclic or bicyclic ring system having at least one impurity which may be unsubstituted or substituted. atom. The term "heteroatom" as used herein includes oxygen, sulfur, and nitrogen. In a bicyclic ring system, the ring can be fused via a bridge heteroatom. Heteroaryl includes, but is not limited to, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetra Azyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, fluorenyl, benzofuranyl, benzophenylthio, oxazolyl, benzimidazolyl, benzoxazolyl , benzoisoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, porphyrinyl, quinazolinyl, quinoxalinyl, pyridazinyl or naphthyridinyl.

用語「雜環烷基」意指完全或部分飽和的環狀基團，例如，其是具有至少一個雜原子的3至14元單環或雙環系統。如本文中所使用的用語「雜原子」包括O、N、S。在雙環雜環系統中，至少一個環不是芳香族，且這些環也可以螺旋方式彼此附接。雜環（heterocyclic）或雜環（heterocycle）基包括但不限於環氧乙烷基、氮丙啶基、氧雜環丁烷基、氮雜環丁烷基、吡咯啶基、二氫吡咯基、四氫呋喃基、二氫呋喃基、四氫噻吩基、二氫噻吩基、吡唑啶基、咪唑啶基、噁唑啶基、異噁唑啶基、噻唑啶基、***啶基、噁二唑啶基、哌啶基、四氫吡啶基、二氫吡啶基、哌嗪基、四氫吡喃基、二噁烷基、嗎啉基、三嗪烷基、氮雜環庚烷基、二氮雜環庚烷基、氧雜環庚烷基、二氧雜環庚烷基、氧氮雜環庚烷基、吲哚啉基、苯並嗎啉基、四氫喹啉基、四氫異喹啉基或硫代嗎啉基。The term "heterocycloalkyl" means a fully or partially saturated cyclic group, for example, a 3 to 14 membered monocyclic or bicyclic ring system having at least one hetero atom. The term "heteroatom" as used herein includes O, N, S. In a bicyclic heterocyclic ring system, at least one ring is not aromatic, and these rings may also be attached to each other in a helical manner. Heterocyclic or heterocyclic groups include, but are not limited to, oxiranyl, aziridine, oxetanyl, azetidinyl, pyrrolidinyl, dihydropyrrolyl, Tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, pyrazolyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, triazolyl, oxadiazole Pyridyl, piperidinyl, tetrahydropyridyl, dihydropyridyl, piperazinyl, tetrahydropyranyl, dioxoalkyl, morpholinyl, triazinyl, azepanyl, dinitrogen Heterocyclic heptyl, oxetanyl, dioxepane, oxazepine, porphyrin, benzomorpholinyl, tetrahydroquinolyl, tetrahydroisoquinoline Orolinyl or thiomorpholinyl.

如本文使用的，「室溫」意指20℃至30℃之間的溫度。As used herein, "room temperature" means a temperature between 20 ° C and 30 ° C.

如本文中使用的，用語「哺乳動物」意指人或動物，例如猴子、靈長類動物、狗、貓、馬、牛等等。As used herein, the term "mammal" means a human or an animal, such as a monkey, a primate, a dog, a cat, a horse, a cow, and the like.

如本文中使用的，任何疾病或病症的用語「治療（treating）」或「治療（treatment）」意指完全或部分地預防或延遲疾病或病症或其症候或症狀的發作；及/或部分或完全治癒或改善疾病或病症及/或可歸因於該病症的不利作用。As used herein, the term "treating" or "treatment" of any disease or condition means completely or partially preventing or delaying the onset of a disease or condition or its symptoms or symptoms; and/or partial or A complete cure or amelioration of a disease or condition and/or an adverse effect attributable to the condition.

措辭「醫療有效量」意指當向患者給藥以治療疾病時足以實現對於疾病的這種治療的化合物量。「醫療有效量」將取決於待治療患者的化合物、給藥模式、疾病及其嚴重程度以及年齡、體重等而不同。The phrase "medically effective amount" means the amount of a compound that is sufficient to effect such treatment for a disease when administered to a patient to treat the disease. The "medical effective amount" will vary depending on the compound to be treated, the mode of administration, the disease and its severity, and the age, weight, and the like.

在整個說明書以及所附申請專利範圍中，要了解的是，除非上下文另外要求，應包含地解譯用字「包括（comprise）」以及「包括（include）」以及例如「包括（comprises）」、「包括（comprising）」、「包括（includes）」、「包括（including）」。也就是說，這些用字的使用可意味著包含未具體列舉的一或多個元素。Throughout the specification and the appended claims, it is to be understood that the words "comprise" and "include" and "comprises", "comprising", "includes", "including". That is, the use of these words may mean the inclusion of one or more elements not specifically recited.

也包括在本發明範圍內的是分子式（I）化合物的代謝物，也就是，在給予藥物之後活體內形成的化合物。依照本發明代謝物的一些範例包括以下化合物。 Also included within the scope of the invention are metabolites of the compound of formula (I), that is, compounds formed in vivo after administration of the drug. Some examples of metabolites in accordance with the invention include the following compounds.

在另一個實施方式中，本發明提供了用於製備分子式（I）化合物的過程。In another embodiment, the invention provides a process for the preparation of a compound of formula (I).

給出了以下反應方案以揭露根據本發明的化合物的合成。The following reaction schemes are given to reveal the synthesis of the compounds according to the invention.

因此，本發明分子式（I）化合物可以如給定方案中所述來製備。方案 -1 Thus, the compounds of formula (I) of the invention can be prepared as described in the given schemes. Scheme -1

分子式I化合物（其中Q是N(A)R12 ；且R12 是氫）的合成顯示在方案1中。可在例如甲苯-甲醇之類的適合溶劑中在升高的溫度下將分子式II化合物與適合的分子式A-NH2 的胺反應，接著以例如硼氫化鈉之類的適合還原劑來還原、並使用三乙胺-氟化氫錯合物在例如二氯甲烷之類的適合溶劑中進一步去保護來獲得分子式I化合物。分子式II化合物是在例如三乙胺之類的適合鹼以及例如四氫呋喃之類的適合溶劑存在下，從分子式VII-A化合物與分子式III或分子式IV化合物或分子式V或分子式VI化合物在回流溫度下處理而合成。在IPA-HCl存在下的分子式VII化合物的去保護產生分子式VII-A化合物。分子式VII化合物是在例如氫化鈉之類的適合的鹼以及例如甲苯之類的溶劑存在下，從分子式VIII以及IX化合物的反應獲得。方案 -2 Formula I compounds (wherein Q is N (A) R 12; and R 12 is hydrogen) the synthesis is shown in Scheme 1. The compound of formula II can be reacted with an appropriate amine of formula A-NH 2 at elevated temperatures in a suitable solvent such as toluene-methanol, followed by reduction with a suitable reducing agent such as sodium borohydride, and The compound of formula I is obtained by further deprotection using a triethylamine-hydrogen fluoride complex in a suitable solvent such as dichloromethane. The compound of formula II is treated from a compound of formula VII-A with a compound of formula III or formula IV or a compound of formula V or formula VI at reflux temperature in the presence of a suitable base such as triethylamine and a suitable solvent such as tetrahydrofuran. And synthesis. Deprotection of a compound of formula VII in the presence of IPA-HCl yields a compound of formula VII-A. The compound of formula VII is obtained from the reaction of a compound of formula VIII and IX in the presence of a suitable base such as sodium hydride and a solvent such as toluene. Scheme -2

於方案2中描述了分子式III、IV、V以及VI化合物的合成。分子式X的N-乙醯基吲哚啉化合物的去乙醯化，其中p = 1，是在高溫下使用氫氧化鈉水溶液進行，並在例如三甲胺之類的適合的鹼以及例如二氯甲烷之類的適合溶劑的存在下分開與分子式VIII或分子式IX的化合物任一進一步反應，以分別完成分子式III或IV的化合物。使用與如同用於合成分子式III以及IV 的類似條件， 進行了分子式XI的N-乙醯基四氫喹啉化合物的N -去乙醯化，其中p = 2中，且在與分子式VIII或分子式IX的化合物任一反應之後分別提供了分子式V以及VI的化合物。在高溫下在三氟乙酸存在下，分子式XII的N-乙醯基吲哚啉化合物或分子式XIII的N-乙醯基四氫喹啉化合物與己胺的甲醯化反應分別提供各自的醛衍生物X或XI。The synthesis of compounds of formula III, IV, V and VI is described in Scheme 2. Deacetylation of an N-acetyl porphyrin compound of formula X, wherein p = 1, is carried out using an aqueous solution of sodium hydroxide at elevated temperatures, and a suitable base such as trimethylamine and, for example, dichloromethane Further, any of the compounds of Formula VIII or Formula IX is further reacted in the presence of a suitable solvent such as to complete the compound of Formula III or IV, respectively. As used for the synthesis of the formula III and IV, similar conditions, were of the formula XI N- acetyl group tetrahydroquinoline compounds the N - acetylated, wherein p = 2, and with the formula VIII or formula Compounds of formula V and VI are provided separately after either reaction of the compound of IX. The acetalization of an N-ethylhydrazine porphyrin compound of formula XII or an N-ethyl sulfhydryl tetrahydroquinoline compound of formula XIII with hexylamine at elevated temperature in the presence of trifluoroacetic acid provides the respective aldehyde derivative X or XI.

分子式VIII的取代的氯乙醯氯以及分子式IX的氯丙醯氯、分子式XII的N-乙醯基吲哚啉化合物、分子式XIII的N-乙醯基四氫喹啉化合物、羥基吡咯啶、分子式VIII的羥基哌啶以及分子式IX的適當酯化合物為商業可得或使用本領域技術人員已知的傳統方法合成。Substituted chloroacetamidine chloride of the formula VIII, chloropropione chloride of the formula IX, N-acetanylporphyrin compound of the formula XII, N-ethylmercaptotetrahydroquinoline compound of the formula XIII, hydroxypyrrolidine, molecular formula The hydroxy piperidine of VIII and the appropriate ester compound of formula IX are either commercially available or synthesized using conventional methods known to those skilled in the art.

方案1以及2提供了製備根據本發明的化合物以及中間產物的一般方法。本領域具一般技藝的技術人員將識別適當修飾的起始材料中的適當取代的各種基團，例如R1 、R2 、R3 、R4 、R5 、R6 、R7 、R8 、R9 、R10 以及R11 ，以製備根據分子式（I）的期望化合物。作為給定方案的替代方案，具一般技藝的技術人員將使用傳統合成有機技術從商業可得或可立即製備的適合起始材料來立即地合成根據本發明的化合物。Schemes 1 and 2 provide general methods for preparing the compounds according to the invention as well as intermediates. Those of ordinary skill in the art will recognize various groups of suitably substituted starting materials in suitably modified starting materials, such as R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 to prepare the desired compound according to formula (I). As an alternative to a given solution, one of ordinary skill in the art will immediately synthesize a compound according to the present invention from a suitable starting material that is commercially available or ready to be prepared using conventional synthetic organic techniques.

對於本領域技術人員顯而易見的是，反應時間、溫度、溶劑及/或試劑的變化可增加產率。It will be apparent to those skilled in the art that changes in reaction time, temperature, solvent and/or reagents can increase the yield.

本發明的化合物可具有掌性中心並作為外消旋物、外消旋混合物以及作為具有包含在本發明中所有異構物形式的個別非鏡像異構物或鏡像異構物存在。因此，在化合物是掌性的情況下，實質上不含另一種的個別鏡像異構物被包括在本發明的範圍內；進一步包括的是兩種鏡像異構物的全部混合物。The compounds of the present invention may have a palmitic center and exist as racemates, racemic mixtures, and as individual non-image or isomers having all of the isomeric forms included in the present invention. Thus, where the compound is palmier, it is within the scope of the invention to be substantially free of another individual mirror image isomer; further included are all mixtures of the two mirror image isomers.

本發明的創新化合物是根據本文中如上所述的方案程序，使用適當的材料來製備，並藉由以下具體範例進一步示範說明。這些範例不應被認為或解釋為限制所闡述的本發明範圍。The inventive compounds of the present invention are prepared using suitable materials in accordance with the protocol procedures described above herein and are further exemplified by the following specific examples. These examples should not be considered or construed as limiting the scope of the invention as set forth.

在本說明書中，一些通用用語是以其已知的意欲含義使用，其在下文中定義： In this specification, some general terms are used in their intended meanings, which are defined below:

使用下列來測量根據本發明製備的化合物的質量：使用APCI電離技術（電噴灑化學電離探針）的單四極質譜儀（Water ZQ 2000儀器）、或使用ESI或APCI的熱儀器技術的Finnigan LXQ。藉由使用Bruker TopSpin400MHz NMR光譜儀來記錄所有化合物的1 HNMR光譜。範例： The quality of the compounds prepared according to the present invention was measured using the following: a single quadrupole mass spectrometer (Water ZQ 2000 instrument) using APCI ionization technique (electrospray chemical ionization probe), or Finnigan LXQ using thermal instrument technology of ESI or APCI. The 1 H NMR spectrum of all the compounds was recorded by using a Bruker TopSpin 400 MHz NMR spectrometer. example:

範例 1 ： 製備哌啶-4-基羥基(二噻吩-2-基)乙酸酯鹽酸在裝備有機械攪拌器以及迪安斯達克（Dean Stark）裝置的3公升四頸圓底燒瓶中，在氮氣下加入60％氫化鈉（5.9 gm，0.147 mol）懸浮液，然後加入甲苯（1200 ml），接著加入1-Boc-4-羥基哌啶（59.35 gm，0.295 mol）以及羥基[二(噻吩-2-基)]乙酸甲酯（75 gm，0.295 mol）。將反應混合物回流3至4小時，並冷卻至室溫。將甲苯層分離並經由硫酸鈉乾燥並在真空下蒸發，獲得109.0 gm為棕色半固體的1-Boc-哌啶-4-基羥基(二噻吩-2-基)乙酸酯粗產物，其本身用於進一步反應。 將上述棕色半固體溶於異丙醇（400 ml）並加入7％異丙醇-HCl（650 ml）。將反應混合物在室溫下攪拌22至24小時，並進一步以乙酸乙酯（600 ml）稀釋。將分離的固體過濾並以乙酸乙酯洗滌並在50±5℃下真空下乾燥10至12小時，以獲得62.0 gm為淺黃色固體的期望化合物。1 HNMR (DMSO-d 6 ) δ 7.47(2H, d), 7.08 (2H, s), 6.99-6.97 (2H, m), 4.90-4.86 (1H, m), 2.81-2.77 (2H, m), 2.57-2.52 (2H，部分與溶劑峰（solvent signal）合併), 1.77-1.74 (2H, bs), 1.49-1.44 (2H, m) ESMS: 323.85/324.92 [MH]+1 Example 1 : Preparation of piperidin-4-ylhydroxy (dithiophen-2-yl) acetate hydrochloride In a 3 liter four-necked round bottom flask equipped with a mechanical stirrer and a Dean Stark apparatus, 60% sodium hydride (5.9 gm, 0.147 mol) suspension was added under nitrogen, then toluene (1200) was added. Ml) followed by 1-Boc-4-hydroxypiperidine (59.35 gm, 0.295 mol) and methyl hydroxy [bis(thiophen-2-yl)]acetate (75 gm, 0.295 mol). The reaction mixture was refluxed for 3 to 4 hours and cooled to room temperature. The toluene layer was separated and dried over sodium sulfate and evaporated in vacuo to give 10 <RTI ID=0.0>#</RTI></RTI><RTIgt; Used for further reactions. The above brown semisolid was dissolved in isopropanol (400 ml) and 7% isopropanol-HCl (650 ml) was added. The reaction mixture was stirred at room temperature for 22 to 24 hours and further diluted with ethyl acetate (600 ml). The isolated solid was filtered and washed with ethyl acetate and dried at 50 <RTI ID=0.0></RTI><RTIgt; 1 H NMR (DMSO-d 6 ) δ 7.47 (2H, d), 7.08 (2H, s), 6.99-6.97 (2H, m), 4.90-4.86 (1H, m), 2.81-2.77 (2H, m), 2.57-2.52 (2H, partially combined with solvent signal), 1.77-1.74 (2H, bs), 1.49-1.44 (2H, m) ESMS: 323.85/324.92 [MH] +1

範例 2 ： 哌啶-4-基羥基(二苯基)乙酸酯鹽酸鹽的製備使用如範例1中對於哌啶-4-基羥基(二噻吩-2-基)乙酸酯鹽酸鹽描述的類似程序，從羥基(二苯基)乙酸甲酯合成上述化合物。 Example 2 : Preparation of piperidin-4-ylhydroxy (diphenyl) acetate hydrochloride The above compound was synthesized from methyl hydroxy(diphenyl)acetate using a similar procedure as described for the piperidin-4-ylhydroxy (dithien-2-yl)acetate hydrochloride in Example 1.

範例 3 ： 製備1-[2-(5-甲醯基-2,3-二氫-1H-吲哚-1-基)-2-側氧乙基]哌啶-4-基羥基(二噻吩-2-基)乙酸酯 對在四氫呋喃（750 ml）中的哌啶-4-基羥基(二噻吩-2-基)乙酸酯鹽酸鹽（100g，0.278mol）的經攪拌的懸浮液中加入1-(氯乙醯基)-2,3-二氫-1H-吲哚-5-甲醛（68.3 gm，0.306）以及三乙胺（116毫升，0.83 mol），並將反應混合物回流12小時。將反應混合物冷卻至室溫，並以乙酸乙酯（750 ml）以及水（750 ml）稀釋。將有機層分離、以木炭處理、過濾並蒸發至乾燥。將殘餘物懸浮在乙酸乙酯（1000 ml）中並攪拌2小時，並將因此獲得的固體過濾、以乙酸乙酯洗滌並在真空下於55±5℃乾燥8至12小時，以獲得108.0 gm為有色固體的期望化合物。1 HNMR (DMSO-d 6 ) δ 9.86 (1H, s), 8.21-8.19 (1H, m), 7.76-7.73 (2H, m), 7.48-7.47 (2H, m), 7.28 (1H, s), 7.12-7.11 (2H, m), 7.00-6.98(2H, m), 4.87-4.85 (1H, m), 4.26-4.22 (2H, m), 3.21 (2H, s), 3.19-3.17 (2H, m), 2.55-2.50 (2H，部分與溶劑峰合併), 2.46-2.43 (2H，部分與溶劑峰合併), 1.86-1.85 (2H, bs), 1.82-1.75 (2H, bs) ESMS: 510.80/511.87 [MH]+ Example 3 : Preparation of 1-[2-(5-methylindolyl-2,3-dihydro-1H-indol-1-yl)-2-yloxyethyl]piperidin-4-ylhydroxy (dithiophene-2- To a stirred suspension of piperidin-4-ylhydroxy (dithiophen-2-yl)acetate hydrochloride (100 g, 0.278 mol) in tetrahydrofuran (750 ml) -(Chlorobenzyl)-2,3-dihydro-1H-indole-5-carbaldehyde (68.3 gm, 0.306) and triethylamine (116 ml, 0.83 mol), and the reaction mixture was refluxed for 12 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (EtOAc) The organic layer was separated, treated with charcoal, filtered and evaporated to dryness. The residue was suspended in ethyl acetate (1000 ml) and stirred for 2 hr, and the solid thus obtained was filtered, washed with ethyl acetate and dried under vacuum at 55 ± 5 ° C for 8 to 12 hours to obtain 108.0 gm. The desired compound is a colored solid. 1 H NMR (DMSO-d 6 ) δ 9.86 (1H, s), 8.21-8.19 (1H, m), 7.76-7.73 (2H, m), 7.48-7.47 (2H, m), 7.28 (1H, s), 7.12-7.11 (2H, m), 7.00-6.98(2H, m), 4.87-4.85 (1H, m), 4.26-4.22 (2H, m), 3.21 (2H, s), 3.19-3.17 (2H, m ), 2.55-2.50 (2H, partially combined with solvent peak), 2.46-2.43 (2H, partially combined with solvent peak), 1.86-1.85 (2H, bs), 1.82-1.75 (2H, bs) ESMS: 510.80/511.87 [MH] +

範例 4 ： 1-[3-(5-甲醯基-2,3-二氫-1H-吲哚-1-基)-3-側氧丙基]哌啶-4-基羥基(二噻吩-2-基)乙酸酯 Example 4 : 1-[3-(5-Mercapto-2,3-dihydro-1H-indol-1-yl)-3-oxopropyl]piperidin-4-ylhydroxy (dithiophene- 2-based) acetate

範例 5 ： 1-[3-(5-甲醯基-2,3-二氫-1H-吲哚-1-基)-3-側氧丙基]哌啶-4-基羥基(二苯基)乙酸酯 Example 5 : 1-[3-(5-Mercapto-2,3-dihydro-1H-indol-1-yl)-3-oxopropyl]piperidin-4-ylhydroxy (diphenyl) Acetate

範例 6 ： 1-[3-(5-甲醯基-2,3-二氫-1H-吲哚-1-基)-3-側氧丁基]哌啶-4-基羥基(二噻吩-2-基)乙酸酯 Example 6 : 1-[3-(5-Mercapto-2,3-dihydro-1H-indol-1-yl)-3-oxooxybutyl]piperidin-4-ylhydroxy (dithiophene- 2-based) acetate

範例 7 ： 1-[3-(5-甲醯基-2,3-二氫-1H-吲哚-1-基)-3-側氧乙基]哌啶-4-基羥基(二苯基)乙酸酯 Example 7 : 1-[3-(5-Mercapto-2,3-dihydro-1H-indol-1-yl)-3-oxooxyethyl]piperidin-4-ylhydroxy (diphenyl) Acetate

範例 8 ： 1-[3-(6-甲醯基-3,4-二氫喹啉-1(2H)-基)-3-側氧丙基]哌啶-4-基羥基(二噻吩-2-基)乙酸酯 以適當的起始材料、使用如範例3中所提及的相同實驗條件合成如範例4-8中所述的化合物。 Example 8 : 1-[3-(6-Mercapto-3,4-dihydroquinolin-1(2H)-yl)-3-oxopropyl]piperidin-4-ylhydroxy (dithiophene- 2-Base) Acetate The compounds as described in Examples 4-8 were synthesized using the appropriate starting materials, using the same experimental conditions as described in Example 3.

範例 9 ： 1-乙醯基-2,3-二氫-1H- 吲哚-5-甲醛的製備在8±5℃下，在攪拌下對三氟乙酸（900毫升）中的1-乙醯基吲哚啉（177 gm，1.09 mol）的經攪拌的溶液中分批地加入己胺（170 gm，1.20 mol），並在大約80±5℃下攪拌RM 8至10小時。將反應混合物冷卻至RT，以水淬熄並以MDC萃取，經由硫酸鈉乾燥有機層並蒸發至乾燥以獲得粗產物。使用矽膠作為固定相以及在己烷溶液中的40％EtOAc作為洗提液以藉由管柱層析純化粗化合物而獲得147.0 gm為固體的期望化合物。1 HNMR (DMSO-d6 ) δ 9.85 (1H, s), 8.19-8.16 (1H, m), 7.75-7.72 (2H, m), 4.18-4.03 (2H, m), 3.19-3.17 (2H, m), 2.20 (3H, s) Example 9 : Preparation of 1-ethenyl-2,3-dihydro- 1H- indole-5-formaldehyde Add hexylamine (170 gm) in portions to a stirred solution of 1-ethylhydrazinoporphyrin (177 gm, 1.09 mol) in trifluoroacetic acid (900 ml) at 8 ± 5 °C with stirring. , 1.20 mol), and stirred at about 80 ± 5 ° C for RM 8 to 10 hours. The reaction mixture was cooled to RT, quenched with water and extracted with EtOAc. The crude compound was purified by column chromatography using silica gel as the stationary phase and 40% EtOAc in hexanes to afford 147.0 gm as the desired compound. 1 H NMR (DMSO-d 6 ) δ 9.85 (1H, s), 8.19-8.16 (1H, m), 7.75-7.72 (2H, m), 4.18-4.03 (2H, m), 3.19-3.17 (2H, m ), 2.20 (3H, s)

範例 10 ： 1-(氯乙醯基)-2,3-二氫-1H-吲哚-5-甲醛的製備在75±5℃下進行在NaOH水溶液（20.31 gm，0.507 mol）（500 ml）中的1-乙醯基-2,3-二氫-1H- 吲哚-5-甲醛（48 gm，0.253 mol）的去乙醯化反應1至2小時。反應混合物冷卻至RT、以MDC萃取、並將有機層通過硫酸鈉乾燥、過濾，且本身用於進一步反應。對經攪拌的MDC層加入三乙胺（70 ml，1.04 mol），並將反應混合物冷卻至0-5℃，並在30分鐘的期間逐滴加入氯乙醯氯（22.5 ml，0.55 mol）。將反應混合物在RT下攪拌1小時。將反應混合物以水淬熄並以MDC萃取，將有機層通過硫酸鈉乾燥並蒸發至乾燥以獲得50.0 gm為固體的期望化合物。1 HNMR (DMSO-d6 ) δ 10.09 (1H, s), 8.20-8.18 (1H, m), 7.80-7.76 (2H, m), 4.79 (2H, s), 4.23-4.18 (2H, m), 3.26-3.22 (2H, m)。 Example 10 : Preparation of 1-(chloroethinyl)-2,3-dihydro-1H-indole-5-carboxaldehyde 1-Ethyl-2,3-dihydro- 1H- indole-5-carbaldehyde (48 gm, 0.253 mol) in aqueous NaOH (20.31 gm, 0.507 mol) (500 ml) at 75 ± 5 °C The deacetylation reaction is carried out for 1 to 2 hours. The reaction mixture was cooled to RT, extracted with M.sub.2, and organic layer dried over sodium sulfate, filtered and used for further reaction. Triethylamine (70 ml, 1.04 mol) was added to the stirred MDC layer, and the reaction mixture was cooled to 0-5 ° C, and chloroethyl chloride (22.5 ml, 0.55 mol) was added dropwise over 30 minutes. The reaction mixture was stirred at RT for 1 hour. The reaction mixture was quenched with water and extracted with EtOAc (EtOAc)EtOAc 1 H NMR (DMSO-d 6 ) δ 10.09 (1H, s), 8.20-8.18 (1H, m), 7.80-7.76 (2H, m), 4.79 (2H, s), 4.23-4.18 (2H, m), 3.26-3.22 (2H, m).

範例 11 ： 1-(3-氯丙醯基)-2,3-二氫-1H-吲哚-5-甲醛 Example 11 : 1-(3-Chloropropionyl)-2,3-dihydro-1H-indole-5-formaldehyde

範例 12 ： 1-(4-氯丁醯基)-2,3-二氫-1H-吲哚-5-甲醛 Example 12 : 1-(4-Chlorobutyryl)-2,3-dihydro-1H-indole-5-formaldehyde

範例 13 ： 1-(3-氯丙醯基)-1,2,3,4-四氫喹啉-6-甲醛 以適當的起始材料、使用與範例10中所提及的類似條件製備範例11-13中所述的化合物。 Example 13 : 1-(3-Chloropropionyl)-1,2,3,4-tetrahydroquinolin-6-carboxaldehyde was prepared using appropriate starting materials, using similar conditions as those mentioned in Example 10. The compound described in 11-13.

範例 14 ： 1-{2-[5-({[(2R)-2-羥基-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}哌啶-4-基羥基(二噻吩-2-基)乙酸酯（第2號化合物）的製備對在甲苯（1000 ml）以及甲醇（500 ml）中的1-[2-(5-甲醯基-2,3-二氫-1H-吲哚-1-基)-2-側氧乙基]哌啶-4-基羥基(二噻吩-2-基)乙酸酯（100 gm，0.196 mol）的經攪拌的溶液加入5-[(1R)-2-胺基-1-{[叔丁基(二甲基)矽基]氧基}乙基]-8-羥基喹啉-2(1H)-酮二乙酸酯（97.9 gm，0.215 mol），並將反應混合物在60±5℃下加熱直到獲得澄清溶液。將反應混合物冷卻至室溫，以及在0-5℃下分批加入硼氫化鈉（3.62 gm，0.097 mol）30到45分鐘，並將反應混合物攪拌30分鐘。在室溫下，以飽和碳酸氫鈉水溶液（750 ml）淬熄反應混合物，以MDC（1000 ml）萃取，將有機層分離、經由硫酸鈉乾燥並過濾以獲得在MDC層中的1-{2-[5-({[(2R)-2-{[叔丁基(二甲基)矽基]氧基}-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}哌啶-4-基羥基(二噻吩-2-基)乙酸酯。 對此，在RT下，加入氫氟酸三乙胺（96.2ml，0.587mol），並將反應混合物在RT下攪拌10至12小時。過濾所獲得的固體並以MDC洗滌。將固體懸浮於水中並以飽和碳酸氫鈉中和、並在RT下攪拌8至10小時。將所獲得的固體過濾、以大量的水洗滌並在50±5℃下在真空下乾燥。此外，將此固體懸浮在乙酸乙酯（1000 ml）中並攪拌2至3小時、過濾並在大約50±5℃下在真空下乾燥以獲得116.0 gm為固體的期望化合物。 使用如US2006/0035931以及2015,19,315-319 Organic Process Research＆Development中提及的類似程序製備5-[(1R)-2-胺基-1-{[叔丁基(二甲基)矽基]氧基}乙基]-8-羥基喹啉-2(1H)-酮二乙酸酯的合成。 Example 14 : 1-{2-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2-yloxy-1,2-dihydroquinolin-5-yl)ethyl) Amino}methyl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}piperidin-4-ylhydroxy(dithien-2-yl)acetate Preparation of (No. 2 compound) 1-[2-(5-Methylcarbonyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl in toluene (1000 ml) and methanol (500 ml) a stirred solution of piperidin-4-ylhydroxy (dithiophen-2-yl)acetate (100 gm, 0.196 mol) was added to 5-[(1R)-2-amino-1-{[t-butyl (dimethyl)indolyl]oxy}ethyl]-8-hydroxyquinolin-2(1H)-one diacetate (97.9 gm, 0.215 mol), and the reaction mixture is at 60 ± 5 ° C Heat until a clear solution is obtained. The reaction mixture was cooled to room temperature, and sodium borohydride (3.62 gm, 0.097 mol) was added portionwise at 0-5 ° C for 30 to 45 minutes, and the reaction mixture was stirred for 30 minutes. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (750 mL), EtOAc (EtOAc) (EtOAcjjjjjjjj -[5-({[(2R)-2-{[tert-butyl(dimethyl)indolyl]oxy}-2-(8-hydroxy-2-oxoyl-1,2-dihydroquine啉-5-yl)ethyl]amino}methyl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}piperidin-4-ylhydroxy (dithiophene) -2-yl) acetate. For this, triethylamine hydrofluoride (96.2 ml, 0.587 mol) was added at RT and the reaction mixture was stirred at RT for 10 to 12 hours. The solid obtained was filtered and washed with MDC. The solid was suspended in water and neutralized with saturated sodium bicarbonate and stirred at RT for 8 to 10 hours. The solid obtained was filtered, washed with a large amount of water and dried under vacuum at 50 ± 5 °C. Further, this solid was suspended in ethyl acetate (1000 ml) and stirred for 2 to 3 hours, filtered and dried under vacuum at about 50 ± 5 ° C to obtain a desired compound of 116.0 gm as a solid. Preparation of 5-[(1R)-2-amino-1-{[tert-butyl(dimethyl)decyl]oxy group using a similar procedure as mentioned in US 2006/0035931 and 2015, 19, 315-319 Organic Process Research & Development Synthesis of ethyl]-8-hydroxyquinoline-2(1H)-one diacetate.

範例 15 ： 1-{2-[5-({[(2R)-2-羥基-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-2，3-二氫-1H-吲哚-1-基]-2-側氧乙基}哌啶-4-基羥基(二苯基)乙酸酯（第11號化合物）的製備對在甲醇（15 ml）中的1-[3-(5-甲醯基-2,3-二氫-1H-吲哚-1-基)-3-側氧乙基]哌啶-4-基羥基(二苯基)乙酸乙酯（0.8 gm，0.0016 mol）的經攪拌的溶液加入催化量的乙酸以及5-[(1R)-2-胺基-1-{[叔丁基(二甲基)矽基]氧基}乙基]-8-羥基喹啉-2(1H)酮二乙酸酯（0.8 gm，0.00176 mol），並將反應混合物在60±5℃下加熱直到獲得澄清溶液。將RM冷卻至室溫，並在0-5℃下分批加入硼氫化鈉（43 mg，0.00112 mol）5分鐘，並將RM攪拌30分鐘。RM在RT下以飽和碳酸氫鈉水溶液（20 ml）淬熄、並以乙酸乙酯（100 ml×3）萃取。將有機層分離、經由硫酸鈉乾燥並蒸發至乾燥以獲得1-{2-[5-({[(2R)-2-{[叔丁基(二甲基)矽基]氧基}-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}哌啶-4-基羥基(二苯基)乙酸酯。 將所獲得的化合物置於甲醇（10 ml）中，在RT下加入三乙胺氫氟酸（788mg，0.00489mol），並在RT下攪拌反應混合物10至12小時。將固體過濾並以MDC洗滌。以飽和碳酸氫鈉水溶液中和固體，並在RT下攪拌6至8小時。將固體過濾、以水洗滌、並在50±5℃下在真空下乾燥。將固體懸浮在乙酸乙酯（15ml）中，並在RT下攪拌2小時，過濾並在50±5℃下在真空下乾燥以獲得150mg為白色固體的期望化合物。 Example 15 : 1-{2-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2-yloxy-1,2-dihydroquinolin-5-yl)ethyl) Amino}methyl}-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}piperidin-4-ylhydroxy(diphenyl)acetate (11th Preparation of compound 1-[3-(5-Methylcarbonyl-2,3-dihydro-1H-indol-1-yl)-3-oxoethylethylpiperidine-4- in methanol (15 ml) A stirred solution of ethyl hydroxy(diphenyl)acetate (0.8 gm, 0.0016 mol) was added to a catalytic amount of acetic acid and 5-[(1R)-2-amino-1-{[tert-butyl (dimethyl) Base thiol]oxy}ethyl]-8-hydroxyquinoline-2(1H)one diacetate (0.8 gm, 0.00176 mol), and the reaction mixture is heated at 60 ± 5 ° C until a clear solution is obtained . The RM was cooled to room temperature and sodium borohydride (43 mg, 0.00112 mol) was added portionwise at 0-5 °C for 5 min and RM was stirred for 30 min. The RM was quenched with saturated aqueous sodium bicarbonate (20 mL) andEtOAcEtOAc The organic layer was separated, dried over sodium sulfate and evaporated to dryness to afford 1-{2-[5-({[(2R)-2-{[tert-butyl(dimethyl) decyl)oxy}-2 -(8-hydroxy-2-oxooxy-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-2,3-dihydro-1H-indol-1-yl ]-2-Sideoxyethyl}piperidin-4-ylhydroxy (diphenyl) acetate. The obtained compound was placed in methanol (10 ml), triethylamine hydrofluoric acid (788 mg, 0.00489 mol) was added at RT, and the reaction mixture was stirred at RT for 10 to 12 hours. The solid was filtered and washed with MDC. The solid was neutralized with a saturated aqueous solution of sodium hydrogencarbonate and stirred at RT for 6 to 8 hours. The solid was filtered, washed with water and dried under vacuum at 50 ± 5 °C. The solid was suspended in ethyl acetate (15 mL) and EtOAc (EtOAc)EtOAc.

範例 16 ： 1-{2-[5-({[(2R)-2-羥基-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}哌啶-4-基羥基(二噻吩-2-基)乙酸酯半富馬酸鹽（第8號化合物）的製備對在MeCN：THF：EtOH（1：2：1）（4000 ml）中的1-{2-[5-({[(2R)-2-羥基-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}哌啶-4-基羥基(二噻吩-2-基)乙酸酯（100g，0.140mol）的經攪拌的溶液在5-10分鐘內加入在EtOH（1000 ml）以及MeCN（1000 ml）中製備的富馬酸（16.22 gm，0.139mol）溶液，並在RT下攪拌反應混合物20至24小時。將所獲得的固體過濾、以乙醇（100 ml）洗滌、並在50±5℃下在真空下乾燥6至8小時。此外，將固體懸浮於EtOH（1600 ml）中以及在攪拌下回流12至16小時、並經熱過濾以獲得72.0 gm為白色固體的期望化合物。 Example 16 : 1-{2-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2-yloxy-1,2-dihydroquinolin-5-yl)ethyl) Amino}methyl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}piperidin-4-ylhydroxy(dithien-2-yl)acetate Preparation of hemifumarate (Compound No. 8) 1-{2-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2-)-oxo in MeCN:THF:EtOH(1:2:1) (4000 ml) 1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethylethylper A stirred solution of pyridine-4-ylhydroxy (dithien-2-yl)acetate (100 g, 0.140 mol) was added over 5-10 minutes in EtOH (1000 ml) and MeCN (1000 ml). A solution of fumaric acid (16.22 gm, 0.139 mol) was added and the reaction mixture was stirred at RT for 20 to 24 hours. The solid obtained was filtered, washed with ethanol (100 ml) and dried under vacuum at 50 ± 5 °C for 6 to 8 hours. Further, the solid was suspended in EtOH (1600 ml) and refluxed for 12 to 16 hours with stirring, and filtered to obtain 72.0 gm of the desired compound as a white solid.

藉由使用如上所述的合成方案以類似方式製備本發明的其他代表性化合物，且製備的化合物的特徵數據在下表II中給出：表二： 組合療法 Other representative compounds of the invention were prepared in a similar manner by using the synthetic schemes described above, and the characterization data for the prepared compounds are given in Table II below: Table 2: Combination therapy

本發明化合物可與用於治療/預防/抑制或改善分子式（I）化合物對其有用的疾病或病症的其它藥物組合給藥。這樣的其他藥物可與分子式（I）的化合物同時或相繼給藥。當分子式（I）化合物與一或更多個其它藥物同時使用時，除了分子式（I）化合物之外，含有這樣的其它藥物的藥學組合物是較佳的。因此，除了分子式（I）的化合物之外，本發明的藥學組合物還包括也含有一或更多個其它活性成分的那些藥學組合物。藥學組合物 The compounds of the present invention can be administered in combination with other drugs for treating/preventing/inhibiting or ameliorating a disease or condition for which the compound of formula (I) is useful. Such other drugs may be administered simultaneously or sequentially with the compound of formula (I). When a compound of the formula (I) is used together with one or more other drugs, a pharmaceutical composition containing such a drug other than the compound of the formula (I) is preferred. Thus, in addition to the compounds of formula (I), the pharmaceutical compositions of the present invention also include those pharmaceutical compositions which also contain one or more additional active ingredients. Pharmaceutical composition

在本發明的另一個實施方式中，有提供了包括醫療有效量的一或更多個分子式（I）化合物的藥學組合物。雖然可能直接地單獨或組合給予醫療有效量的分子式（I）化合物而不需要任何配方，通常的做法是以包括藥學上可接受的賦形劑以及至少一活性成分的藥物劑型的形式來給予化合物。這些劑型可藉由各種途徑給藥，包括鼻內、經肺、口服、局部、穿皮、皮下、肌肉內、靜脈內、腹膜內等等。In another embodiment of the invention, there is provided a pharmaceutical composition comprising a medically effective amount of one or more compounds of formula (I). While it is possible to administer a therapeutically effective amount of a compound of formula (I), either alone or in combination, without the need for any formulation, it is common practice to administer the compound in the form of a pharmaceutical dosage form comprising a pharmaceutically acceptable excipient and at least one active ingredient. . These dosage forms can be administered by a variety of routes including intranasal, pulmonary, oral, topical, transdermal, subcutaneous, intramuscular, intravenous, intraperitoneal, and the like.

口服組合物可為固體或液體劑型的形式。固體劑型可包括丸劑、小袋、小藥囊或例如片劑、多顆粒單位、膠囊（軟以及硬明膠）等等的離散單元。液體劑型可為酏劑、混懸劑、乳劑、溶液、糖漿等等。意欲用於口服使用的組合物可根據本領域已知用於製造組合物的任何方法來製備，且除了活性成分外，這樣的藥學組合物是含有賦形劑，例如稀釋劑、崩解劑、黏合劑、增溶劑、潤滑劑、助流劑、表面活性劑、懸浮液、乳化液、螯合劑、穩定劑、調味劑、甜味劑、著色劑等等。適合的賦形劑的一些範例包括乳糖、纖維素及其衍生物，該衍生物例如微晶纖維素、甲基纖維素、羥丙基甲基纖維素以及乙基纖維素、磷酸二鈣、甘露糖醇、澱粉、明膠、聚乙烯吡咯啶酮、各種樹膠，例如***膠、黃蓍膠、黃原膠、藻酸鹽及其衍生物，山梨醇、右旋葡萄糖、木糖醇、硬脂酸鎂、滑石粉、膠體二氧化矽、礦物油、單硬脂酸甘油酯、扁油酸甘油酯、乙醇酸澱粉鈉、交聯聚維酮、交聯羧甲基纖維素、各種乳化液，例如聚乙二醇、山梨糖醇、脂肪酸酯、聚乙二醇烷基醚、糖酯、聚氧乙烯聚氧丙基嵌段共聚物、聚乙氧基化脂肪酸單酯、二酯及其混合物。Oral compositions can be in the form of a solid or liquid dosage form. Solid dosage forms can include pills, sachets, sachets or discrete units such as tablets, multiparticulate units, capsules (soft and hard gelatin), and the like. Liquid dosage forms can be in the form of elixirs, suspensions, emulsions, solutions, syrups and the like. Compositions intended for oral use can be prepared according to any method known in the art for making compositions, and in addition to the active ingredients, such pharmaceutical compositions contain excipients such as diluents, disintegrating agents, Binders, solubilizers, lubricants, glidants, surfactants, suspensions, emulsions, chelating agents, stabilizers, flavoring agents, sweeteners, colorants, and the like. Some examples of suitable excipients include lactose, cellulose and derivatives thereof such as microcrystalline cellulose, methylcellulose, hydroxypropylmethylcellulose, and ethylcellulose, dicalcium phosphate, mannose Sugar alcohol, starch, gelatin, polyvinylpyrrolidone, various gums such as acacia, tragacanth, xanthan gum, alginate and its derivatives, sorbitol, dextrose, xylitol, stearic acid Magnesium, talc, colloidal cerium oxide, mineral oil, glyceryl monostearate, glyceryl linoleate, sodium starch glycolate, crospovidone, croscarmellose, various emulsions, for example Polyethylene glycol, sorbitol, fatty acid esters, polyethylene glycol alkyl ethers, sugar esters, polyoxyethylene polyoxypropyl block copolymers, polyethoxylated fatty acid monoesters, diesters and mixtures thereof .

根據本發明的鼻內或肺部組合物可為適合用於鼻腔給藥的液體或固體或半固體組合物的形式。液體組合物可為水性、非水性組合物、懸浮液或乳化液，固體組合物可為粉末等形式，且半固體組合物可為凝膠等形式。鼻/肺組合物也可形成原位凝膠。所述鼻或肺組合物包括分子式（I）的化合物，可選地具有一或更多種賦形劑，該賦形劑選自原位膠凝劑、黏膜黏附劑、聚合物、濕潤劑、緩衝劑、穩定劑、表面活性劑、防腐劑、增稠劑、溶劑、共溶劑、滲透促進劑、螯合劑、黏度調節劑、甜味劑、掩味劑、增溶劑、調味劑以及等滲劑。The intranasal or pulmonary composition according to the invention may be in the form of a liquid or solid or semi-solid composition suitable for nasal administration. The liquid composition may be in the form of an aqueous, non-aqueous composition, suspension or emulsion, the solid composition may be in the form of a powder or the like, and the semi-solid composition may be in the form of a gel or the like. The nasal/lung composition can also form an in situ gel. The nasal or pulmonary composition comprises a compound of formula (I), optionally having one or more excipients selected from the group consisting of in situ gelling agents, mucoadhesives, polymers, humectants, Buffers, stabilizers, surfactants, preservatives, thickeners, solvents, cosolvents, penetration enhancers, chelating agents, viscosity modifiers, sweeteners, taste masking agents, solubilizers, flavoring agents, and isotonic agents .

可藉由將活性物質溶解或懸浮於載體中，根據傳統藥物實施來配製用於注射的無菌組合物，載體例如用於注射的水、N-甲基-2-吡咯啶酮、丙二醇以及其它二醇、醇類、天然存在的植物油（例如芝麻油、椰子油、花生油、棉花籽油）、或像是油酸乙酯之類的合成脂肪載體等等。可依需要而併入緩衝劑、抗氧化劑、防腐劑、像是纖維素衍生物的錯合劑、胜肽、多肽以及環糊精等等。A sterile composition for injection can be formulated according to conventional pharmaceutical practice by dissolving or suspending the active substance in a carrier, such as water for injection, N-methyl-2-pyrrolidone, propylene glycol, and the like. Alcohols, alcohols, naturally occurring vegetable oils (such as sesame oil, coconut oil, peanut oil, cottonseed oil), or synthetic fat carriers such as ethyl oleate, and the like. Buffers, antioxidants, preservatives, complexing agents such as cellulose derivatives, peptides, polypeptides, and cyclodextrins, and the like, may be incorporated as needed.

除了立即釋放劑型之外，劑型可具有緩慢、延遲或控制的活性成分釋放。In addition to the immediate release dosage form, the dosage form can have a slow, delayed or controlled release of the active ingredient.

達到醫療效果所需的活性成分量當然將隨著特定的化合物、給藥途徑、治療中的受試者以及所治療的特定病症或疾病而變化。The amount of active ingredient required to achieve a therapeutic effect will of course vary with the particular compound, the route of administration, the subject being treated, and the particular condition or condition being treated.

本發明化合物可藉由口服、吸入或胃腸外途徑，以每天0.0005至100mg / kg，較佳為每天0.0005至50 mg/kg，更佳為每天0.001至20 mg/kg，最佳為每天0.001至10 mg/kg的劑量給藥。成人的劑量範圍通常為每天5 μg至5 g，且較佳為每天10 μg至2 g。The compound of the present invention can be administered orally, inhaled or parenterally at a daily dose of 0.0005 to 100 mg / kg, preferably 0.0005 to 50 mg / kg per day, more preferably 0.001 to 20 mg / kg per day, most preferably 0.001 to 0.001 per day. Dosage at 10 mg/kg. The dosage range for adults is usually from 5 μg to 5 g per day, and preferably from 10 μg to 2 g per day.

以離散單位提供的劑量呈現形式可方便地含有一量的本發明化合物，此化合物在這樣的劑量或作為多個這樣的劑量下有效，例如含有5 μg至1000 mg的單位。Dosage forms provided in discrete units may conveniently contain an amount of a compound of the invention effective at such a dose or as a plurality of such doses, for example, containing from 5 μg to 1000 mg.

在另一個實施方式中，本發明提供了藉由將醫療有效量的分子式（I）化合物給藥至需要其的哺乳動物（包括人類）以治療例如氣喘以及慢性阻塞性肺病、慢性支氣管炎、成人/急性呼吸窘迫綜合症（ARDS）、慢性呼吸道阻塞、支氣管亢進、肺纖維化、肺氣腫以及過敏性鼻炎之類的呼吸道病症的方法。In another embodiment, the invention provides for the treatment of, for example, asthma and chronic obstructive pulmonary disease, chronic bronchitis, adults by administering a therapeutically effective amount of a compound of formula (I) to a mammal, including a human, in need thereof. /Methods of respiratory disorders such as acute respiratory distress syndrome (ARDS), chronic airway obstruction, bronchoconstriction, pulmonary fibrosis, emphysema, and allergic rhinitis.

本發明的較佳實施方式是藉由將醫療有效量的分子式（I）化合物給藥至需要其的哺乳動物（包括人類）以治療慢性阻塞性肺病或氣喘的方法。生物測試： 活體外測試： 測量腎上腺素 β2 受體媒介的 cAMP 產生以確認促效劑活性的分析法： A preferred embodiment of the invention is a method of treating chronic obstructive pulmonary disease or asthma by administering a therapeutically effective amount of a compound of formula (I) to a mammal, including a human, in need thereof. Biological Testing: In Vitro Testing: An assay to measure cAMP production by the adrenergic beta 2 receptor mediator to confirm agonist activity:

使用了表現人類β（b2）腎上腺素受體的CHOK1細胞株系（PerkinElmer，Es-033-C）。使用了LANCE® Ultra cAMP測量套組（Perkin Elmer® ），設計用以測量cAMP的均質時間解析螢光共振能量轉移（TR-FRET）分析法。根據套組說明書，將所有試劑加入384孔光學盤中。以分析緩衝液將測試化合物稀釋為2X濃度。將細胞與指定的促效劑濃度培養30分鐘。在多模式盤式讀取器上測量時間解析螢光（EnVision® ,PerkinElmer® ）。A CHOK1 cell line (PerkinElmer, Es-033-C) expressing human β(b2) adrenergic receptor was used. The LANCE ® Ultra cAMP measurement kit (Perkin Elmer ® ) was designed to measure the homogenization time-resolved fluorescence resonance energy transfer (TR-FRET) analysis of cAMP. All reagents were added to a 384-well optical disk according to the kit instructions. The test compound was diluted to a 2X concentration with assay buffer. Cells were incubated with the indicated agonist concentrations for 30 minutes. Measuring the time-resolved fluorescence (EnVision ®, PerkinElmer ®) on the multi-mode disk reader.

展現β2腎上腺素受體促效劑活性的本發明化合物顯示出細胞內cAMP水準的增加。結果表示為與載體處理的控制組相比的cAMP的增加百分比。用以測量抑制毒蕈鹼（ M3 ）受體媒介的鈣產生的抑制以確認拮抗劑活性的分析法： Compounds of the invention exhibiting beta 2 adrenergic receptor agonist activity exhibit an increase in intracellular cAMP levels. Results are expressed as a percentage increase in cAMP compared to the vehicle treated control group. Analytical method for measuring inhibition of calcium production by inhibition of muscarinic ( M3 ) receptor mediators to confirm antagonist activity:

使用了表現人類毒蕈鹼（M3）受體的CHO細胞（Perkin Elmer®ES-212-C）。根據用於測量細胞內鈣水準的製造商說明書來使用fluo-4 NW指示劑（Invitrogen）。在37℃下將細胞加入fluo-4 NW達30分鐘，接著與載體或化合物培養30分鐘。然後用促效劑碳醯膽鹼（Sigma）刺激細胞 。在促效劑處理之後在多模式盤式讀取器（EnVision® ,PerkinElmer® ）上監測細胞內鈣水準上至90秒。CHO cells (Perkin Elmer® ES-212-C) expressing the human muscarinic (M3) receptor were used. The fluo-4 NW indicator (Invitrogen) was used according to the manufacturer's instructions for measuring intracellular calcium levels. The cells were added to fluo-4 NW for 30 minutes at 37 ° C, followed by incubation with the vehicle or compound for 30 minutes. The cells were then stimulated with the agonist, carbon choline (Sigma). After agonist treatment on the monitoring of intracellular calcium level to 90 seconds in a multi-mode disk reader (EnVision ®, PerkinElmer ®).

展現出毒蕈鹼M3受體拮抗活性的本發明化合物顯示出抑制了碳醯膽鹼誘導的細胞內鈣水準增加。結果表示為與載體處理的控制組相比的鈣增加的抑制百分比。 表三： 標準：+ = ＜30​​％；++ = 40-70％；+++ = 70-80％；++++ = 80-90％；+++++ =＞ 90-100％；相對於控制組The compounds of the present invention exhibiting muscarinic M3 receptor antagonistic activity have been shown to inhibit carbachol-induced increase in intracellular calcium levels. Results are expressed as percent inhibition of calcium increase compared to vehicle treated control groups. Table 3: Standard: + = <30%; ++ = 40-70%; +++ = 70-80%; ++++ = 80-90%; +++++ =>90-100%; Control group

觀察：體外數據顯示本發明化合物具有抗毒蕈鹼以及β腎上腺素促效劑活性。活體內支氣管保護研究： Observation: In vitro data show that the compounds of the invention have antimuscarinic and beta adrenergic agonist activities. In vivo bronchial protection studies:

使用通氣壓力作為氣道阻力的替代量度來評估在麻醉的天竺鼠模型中第1號化合物的支氣管保護活性（J Pharmacol Toxicol Methods. 2011 Jan-Feb;63(1):89-95 ）。在此模型中，藉由確定第1號化合物在吸入給藥後1.5小時以及24小時的對抗乙醯甲膽鹼誘導的支氣管收縮的保護效用來評估效果的功效以及持續時間。Ventilation pressure was used as an alternative measure of airway resistance to assess the bronchial protective activity of Compound No. 1 in an anesthetized guinea pig model ( J Pharmacol Toxicol Methods. 2011 Jan-Feb; 63(1): 89-95 ). In this model, the efficacy and duration of the effect was assessed by determining the protective effect of Compound No. 1 against methotrexate-induced bronchoconstriction 1.5 hours and 24 hours after inhalation administration.

使用了體重在250至400克之間雄性Duncan-Hartley天竺鼠。使用5 ml給藥溶液，在全身曝露的給藥室中在15分鐘的期間內藉由吸入來給予載體或第1號化合物的溶液（300 μg/ml）。使用Omron, NE-C29霧化器以產生用於給藥的氣霧劑。給藥45分鐘後，以胺甲酸乙酯（1 g/kg）以及戊巴比妥鈉（20 mg/kg）的腹膜內注射來麻醉天竺鼠。在動物達到麻醉的手術面後，分離頸靜脈並使用肝素鹽水填充的聚乙烯導管進行插管以允許乙醯甲膽鹼的靜脈內注射。然後經由中線鈍切口接近氣管、解剖游離並插管。插管完成後，使用小動物呼吸器（Columbus，美國）以1 ml/100g體重但不超過2.5 ml體積的脈動體積、並以每分鐘100次脈動的速率對動物進行通氣。使用耦合至Powerlab-quad橋式電腦組件的MTL844生理壓力轉換器（ADInstruments，澳大利亞）以在呼吸器的呼氣管中測量通氣壓力。在整個實驗中，使用加熱墊將動物保持在37℃。在開始收集數據之前，腹腔地給予戊巴比妥（10 mg/kg）以抑制自主呼吸，並獲得穩定的基線。在穩定期以及收集基線通氣壓力值之後，以非累積增量劑量的支氣管收縮劑乙醯甲膽鹼來靜脈內地刺激天竺鼠。使用LabChart軟體（ADInstruments，澳大利亞）記錄通氣壓力的變化。完成研究後，將動物安樂死。Male Duncan-Hartley guinea pigs weighing between 250 and 400 grams were used. A vehicle or a solution of the No. 1 compound (300 μg/ml) was administered by inhalation in a systemic exposed administration chamber using a 5 ml administration solution over a period of 15 minutes. An Omron, NE-C29 nebulizer was used to create an aerosol for administration. After 45 minutes of administration, guinea pigs were anesthetized by intraperitoneal injection of ethyl urethane (1 g/kg) and sodium pentobarbital (20 mg/kg). After the animal reached the anesthetized surgical surface, the jugular vein was isolated and cannulated with a heparin saline filled polyethylene catheter to allow intravenous injection of methotrexate. The trachea is then accessed via a midline blunt incision, dissected free and cannulated. After the cannula was completed, the animals were ventilated using a small animal respirator (Columbus, USA) at a pulsating volume of 1 ml/100 g body weight but not exceeding 2.5 ml volume and at a rate of 100 pulsations per minute. Ventilation pressure was measured in the expiratory tube of the respirator using a MTL844 physiological pressure transducer (ADInstruments, Australia) coupled to a Powerlab-quad bridge computer assembly. The animals were kept at 37 °C using a heating pad throughout the experiment. Before starting to collect data, pentobarbital (10 mg/kg) was given intraperitoneally to suppress spontaneous breathing and a stable baseline was obtained. After the stationary phase and the baseline ventilation pressure value were collected, the guinea pig was intravenously stimulated with a non-cumulative incremental dose of the bronchoconstrictor, methotrexate. Changes in ventilation pressure were recorded using LabChart software (ADInstruments, Australia). After completing the study, the animals were euthanized.

以代表支氣管收縮劑刺激之後的峰值壓力以及基線壓力的差異的「cm的水」來測量通氣壓力的改變。計算出與載體處理相比，對8 μg/kg的乙醯甲膽鹼刺激的支氣管收縮反應的處理誘導抑制百分比。The change in ventilation pressure was measured in "cm of water" representing the peak pressure after the bronchoconstrictor stimulation and the difference in baseline pressure. The percent inhibition of treatment-induced bronchoconstriction response to 8 μg/kg of methotrexate was calculated as compared to vehicle treatment.

已在第1圖中藉由圖表呈現出在給藥1.5以及24小時之後，由以300 µg/ml的第1號化合物造成的乙醯甲膽鹼誘導支氣管收縮的抑制％結果。（數據表示為平均值±平均值的標準差，n = 6 /組）。***表示相對於載體控制組的p ＜0.001；使用Student's檢驗進行統計分析。 觀察：The results of the % inhibition of inducing bronchoconstriction induced by methotrexate caused by the first compound at 300 μg/ml after 1.5 and 24 hours of administration have been shown in Fig. 1 by the graph. (Data are expressed as mean ± standard deviation of the mean, n = 6 / group). *** indicates p < 0.001 vs. vehicle control group; statistical analysis was performed using Student's test. Observed:

觀察到的是，第1號化合物產生了有效以及持續的支氣管保護作用。第1號化合物的單次給藥在給藥後1.5小時完全消除了乙醯甲膽鹼誘導的支氣管收縮。在給藥後24小時，測試化合物引起乙醯甲膽鹼誘導的支氣管收縮的87％抑制。It was observed that Compound No. 1 produced potent and sustained bronchial protection. A single administration of Compound No. 1 completely eliminated methotrexate-induced bronchoconstriction 1.5 hours after administration. At 24 hours post dose, the test compound caused 87% inhibition of methotrexate-induced bronchoconstriction.

無。no.

第1圖 為編號1化合物在天竺鼠中的支氣管保護作用。Figure 1 shows the bronchial protection of No. 1 compound in guinea pigs.

Claims (12)

一種分子式（I）的化合物（I） 其藥學上可接受鹽類以及異構物、立體異構物、阻轉異構物、構形異構物、互變異構物、同素異形體、水合物、溶劑化物、N-氧化物或S-氧化物； 其中， R1 以及R2 獨立地選自(C3 -C7 )環烷基、芳基以及雜芳基，該(C3 -C7 )環烷基、芳基以及雜芳基可選地由一或更多個(C1 -C6 )烷基、芳基、(C3 -C7 )環烷基、鹵素、O-R14 、SH、CN、(CH2 )p -芳基、(CH2 )p -雜芳基、CH2 OH、CH2 -鹵素、CH2 O-(C1 -C6 )烷基、CH2 O-芳基、COOR12 、CONR16 R17 或NHCOR12 ； R3 選自氫、羥基、(C1 -C4 )烷氧基、CH2 OH以及(C1 -C6 )烷基； R4 選自氫、(C1 -C6 )烷基、芳基、(CH2 )p -芳基、(CH2 )p -雜芳基以及(C3 -C7 )環烷基； m是1或2； R5 以及R6 獨立地選自氫、(C1 -C6 )烷基、鹵素、(C3 -C7 )環烷基、雜環烷基、(CH2 )P -芳基以及(CH2 )P -雜芳基、或在同一個碳上的R5 以及R6 以一螺旋方式形成3-7元環烷基或雜環烷基環、或為偕二甲基； n選自0-4； R7 以及R8 獨立地選自氫、(C1 -C6 )烷基以及雜環烷基、或在同一碳上的R7 以及R8 以一螺旋方式形成3-7元環烷基或雜環烷基環、或為偕二甲基； p是1或2； R9 以及R10 獨立地選自氫、(C1 -C6 )烷基、(C3 -C7 )環烷基、雜環烷基以及側氧基、或在同一碳上的R9 以及R10 以一螺旋方式形成3-7元環烷基或雜環烷基環、或為偕二甲基； R11 選自氫、(C1 -C6 )烷基、芳基、CH2 OH、CH2 -鹵素、鹵素、(C3 -C7 )環烷基、雜芳基、雜環烷基、O-R14 、SH、CN、(CH2 )p -芳基、(CH2 )p -雜芳基、CH2 O-(C1 -C6 )烷基、CH2 O-芳基、COOR12 、CONR16 R17 以及NHCOR12 ； Q是N(A)R12 或O-A； R12 選自氫、(C1 -C6 )烷基、芳基、(CH2 )P -芳基、(CH2 )P -雜芳基、(C3 -C7 )環烷基以及雜環烷基； R13 選自氫、O-R14 以及； R14 獨立地選自氫、(C1 -C6 )烷基、芳基、雜芳基、(CH2 )P -芳基、(CH2 )P -雜芳基、(C3 -C7 )環烷基、Si(C1 -C6 )烷基以及； R15 選自(C1 -C6 )烷基、(C3 -C7 )環烷基、芳基、雜芳基、(CH2 )P -芳基以及(CH2 )P -雜芳基； R16 以及R17 獨立地選自氫、(C1 -C6 )烷基、(C3 -C7 )環烷基以及雜環烷基，或R16 以及R17 與氮原子一起形成3-10元雜環烷基環； A選自「/」表示附接點。a compound of formula (I) (I) pharmaceutically acceptable salts thereof and isomers, stereoisomers, atropisomers, conformational isomers, tautomers, allotropes, hydrates, solvates, N- Oxide or S-oxide; wherein R 1 and R 2 are independently selected from (C 3 -C 7 )cycloalkyl, aryl and heteroaryl, the (C 3 -C 7 )cycloalkyl, aryl And heteroaryl optionally consisting of one or more (C 1 -C 6 )alkyl, aryl, (C 3 -C 7 )cycloalkyl, halogen, OR 14 , SH, CN, (CH 2 P -aryl, (CH 2 ) p -heteroaryl, CH 2 OH, CH 2 -halogen, CH 2 O-(C 1 -C 6 )alkyl, CH 2 O-aryl, COOR 12 , CONR 16 R 17 or NHCOR 12 ; R 3 is selected from the group consisting of hydrogen, hydroxy, (C 1 -C 4 ) alkoxy, CH 2 OH and (C 1 -C 6 )alkyl; R 4 is selected from hydrogen, (C 1 - C 6 )alkyl, aryl, (CH 2 ) p -aryl, (CH 2 ) p -heteroaryl and (C 3 -C 7 )cycloalkyl; m is 1 or 2; R 5 and R 6 Independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, halogen, (C 3 -C 7 )cycloalkyl, heterocycloalkyl, (CH 2 ) P -aryl, and (CH 2 ) P - an aryl group, or R 5 and R on the same carbon 6 in a spiral-shaped manner 3-7 membered cycloalkyl or heterocycloalkyl ring, or is a gem-dimethyl; n-is selected from 0-4; R 7 and R 8 are independently selected from hydrogen, (C 1 -C 6) alkyl and heteroaryl a cycloalkyl group, or R 7 and R 8 on the same carbon, form a 3-7 membered cycloalkyl or heterocycloalkyl ring in a helical manner, or a geminal dimethyl group; p is 1 or 2; R 9 and R 10 is independently selected from hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, heterocycloalkyl, and pendant oxy, or R 9 and R 10 on the same carbon A helix is formed into a 3-7 membered cycloalkyl or heterocycloalkyl ring, or is fluorenyl dimethyl; R 11 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, aryl, CH 2 OH, CH 2 - halogen, halogen, (C 3 -C 7 )cycloalkyl, heteroaryl, heterocycloalkyl, OR 14 , SH, CN, (CH 2 ) p -aryl, (CH 2 ) p -heteroaryl , CH 2 O-(C 1 -C 6 )alkyl, CH 2 O-aryl, COOR 12 , CONR 16 R 17 and NHCOR 12 ; Q is N(A)R 12 or OA; R 12 is selected from hydrogen, (C 1 -C 6 )alkyl, aryl, (CH 2 ) P -aryl, (CH 2 ) P -heteroaryl, (C 3 -C 7 )cycloalkyl and heterocycloalkyl; R 13 Selected from hydrogen, OR 14 and R 14 is independently selected from hydrogen, (C 1 -C 6 )alkyl, aryl, heteroaryl, (CH 2 ) P -aryl, (CH 2 ) P -heteroaryl, (C 3 -C 7 ) cycloalkyl, Si(C 1 -C 6 )alkyl and ; R 15 is selected from (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, aryl, heteroaryl, (CH 2 ) P -aryl and (CH 2 ) P -heteroaryl R 16 and R 17 are independently selected from hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, and heterocycloalkyl, or R 16 and R 17 are taken together with a nitrogen atom. 3-10 membered heterocycloalkyl ring; A selected from "/" indicates the attachment point. 如申請專利範圍第1項所述的分子式（I）化合物，其中 R1 以及R2 獨立地選自(C3 -C7 )環烷基、芳基以及雜芳基； R3 選自羥基以及(C1 -C6 )烷基； R4 是氫； m是1或2； R5 以及R6 獨立地為氫、或在同一碳上的R5 以及R6 為偕二​​甲基； n選自0-2； R7 以及R8 獨立地為氫、或在同一碳上的R7 以及R8 為偕二​​甲基；p是1或2； R9 以及R10 是氫； R11 是氫或(C1 -C6 )烷基； Q是N(A)R12 ； R12 是氫或(C1 -C6 )烷基； R13 是氫或O-R14 ； R14 選自氫以及Si(C1 -C6 )烷基； R15 是(C1 -C6 )烷基； A選自「/」表示附接點。The compound of formula (I) according to claim 1, wherein R 1 and R 2 are independently selected from (C 3 -C 7 )cycloalkyl, aryl and heteroaryl; R 3 is selected from hydroxy and (C 1 -C 6) alkyl; R is hydrogen. 4; m is 1 or 2; R 5 and R 6 are independently hydrogen, or R 5 on the same carbon and R 6 is gem-dimethyl; n is selected from 0-2; R 7 and R 8 are independently hydrogen, or R 7 and R 8 on the same carbon are decyl dimethyl; p is 1 or 2; R 9 and R 10 are hydrogen; R 11 is hydrogen or (C 1 -C 6) alkyl; Q is N (A) R 12; R 12 is hydrogen or (C 1 -C 6) alkyl; R 13 is hydrogen or oR 14; R 14 is selected from From hydrogen and Si(C 1 -C 6 )alkyl; R 15 is (C 1 -C 6 )alkyl; A is selected from "/" indicates the attachment point. 如申請專利範圍第1項所述的分子式（I）化合物，其選自由以下組成的群組： 1-{3-[5-({[(2R)-2-羥基-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-3-側氧丙基}哌啶-4-基羥基(二噻吩-2-基)乙酸酯； 1-{2-[5-({[(2R)-2-羥基-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}哌啶-4-基羥基(二噻吩-2-基)乙酸酯； 1-{3-[6-({[(2R)-2-羥基-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-3,4-二氫喹啉-1(2H)-基]-3-側氧丙基}哌啶-4-基羥基(二噻吩-2-基)乙酸酯； 1-{4-[5-({[(2R)-2-羥基-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-4-側氧丁基}哌啶-4-基羥基(二噻吩-2-基)乙酸酯； 1-{2-[5-({[(2R)-2-羥基-2-{4-羥基-3-[(甲磺醯基)胺基]苯基}乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}哌啶-4-基羥基(二噻吩-2-基)乙酸酯； 1-{2-[5-({[(RS)-2-羥基-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}哌啶-4-基羥基(二噻吩-2-基)乙酸酯； 1-{3-[5-({[(2R)-2-羥基-2-{4-羥基-3-[(甲磺醯基)胺基]苯基}乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-3-側氧丙基}哌啶-4-基羥基(二噻吩-2-基)乙酸酯； 1-{2-[5-({[(2R)-2-羥基-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}哌啶-4-基羥基(二噻吩-2-基)乙酸酯半富馬酸鹽； 1-{2-[5-({[(2R)-2-羥基-2-(8-羥基-2-側氧基-1,2,3,4-四氫喹啉-5-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}哌啶-4-基羥基(二噻吩-2-基)乙酸酯； 1-{3-[5-({[(2R)-2-羥基-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-3-側氧丙基}哌啶-4-基羥基(二苯基)乙酸酯； 1-{2-[5-({[(2R)-2-羥基-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}哌啶-4-基羥基(二苯基)乙酸酯； 1-{3-[5-({[(2R)-2-羥基-2-{4-羥基-3-[(甲磺醯基)胺基]苯基}乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-3-側氧丙基}哌啶-4-基羥基(二苯基)乙酸酯； 1-{2-[5-({[(2R)-2-羥基-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}吡咯啶-3-基羥基(二噻吩-2-基)乙酸酯； 1-(2-{5-[({(2R)-2-羥基-2-[4-羥基-3-(羥基甲基)苯基]乙基}胺基)甲基]-2,3-二氫-1H-吲哚-1-基}-2-側氧乙基)哌啶-4-基羥基(二噻吩-2-基)乙酸酯； 1-{2-[5-({乙基[(2R)-2-羥基-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}哌啶-4-基羥基(二噻吩-2-基)乙酸酯； 1-{2-[5-({[(2R)-2-羥基-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-6-甲基-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}哌啶-4-基羥基(二噻吩-2-基)乙酸酯； 1-{2-[5-({[(2R)-2-羥基-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}-3,3-二甲基哌啶-4-基羥基(二噻吩-2-基)乙酸酯； 1-{2-[5-({[(2R)-2-羥基-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}-2,2-二甲基哌啶-4-基羥基(二噻吩-2-基)乙酸酯； 1-{2-[5-({[(2R)-2-羥基-2-(5-羥基-3-側氧基-3,4-二氫-2H-1,4-苯并噁嗪-8-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}哌啶-4-基羥基(二噻吩-2-基)乙酸酯； 1-(2-{5-[({(2R)-2-[3-(甲醯胺基)-4-羥基苯基]-2-羥基乙基}胺基)甲基]-2,3-二氫-1H-吲哚-1-基}-2-側氧乙基)哌啶-4-基羥基(二噻吩-2-基)乙酸酯； 1-{2-[5-({[(2R)-2-羥基-2-(4-羥基-2-側氧基-2,3-二氫-1,3-苯並噻唑-7-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}哌啶-4-基羥基(二噻吩-2-基)乙酸酯； 1-{2-[5-({[(2R)-2-羥基-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}哌啶-4-基環戊基(羥基)苯基乙酸酯； 1-{3-[5-({[(2R)-2-羥基-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2,2-二甲基-3-側氧丙基}哌啶-4-基羥基(二噻吩-2-基)乙酸酯； 1-{2-[5-({[2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}哌啶-4-基羥基(二噻吩-2-基)乙酸酯； 1-{2-[5-({[(2R)-2-羥基-2-{4-羥基-3-[(甲磺醯基)胺基]苯基}乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}哌啶-4-基羥基(二苯基)乙酸酯； 1-{2-[5-({[(2S)-2-羥基-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}哌啶-4-基羥基(二噻吩-2-基)乙酸酯； 1-{2-[5-({[(2R)-2-羥基-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}哌啶-4-基羥基(二噻吩-2-基)乙酸酯乙酸酯； 1-{2-[5-({[(2R)-2-羥基-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}哌啶-4-基羥基(二噻吩-2-基)乙酸酯丁二酸酯(半琥珀酸鹽)； 1-{2-[5-({[(2R)-2-羥基-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}哌啶-4-基羥基(二噻吩-2-基)乙酸酯2,3-二羥基丁二酸酯（1：1）； 1-{2-[5-({[(2R)-2-羥基-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}哌啶-4-基羥基(二噻吩-2-基)乙酸酯半乙烷-1,2-二磺酸； 1-{2-[5-({[2-羥基-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}哌啶-4-基羥基(二噻吩-2-基)乙酸酯氫氟酸（1：1）； 1-{3-[6-({[(2R)-2-羥基-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-3,4-二氫喹啉-1(2H)-基]-3-側氧丙基}哌啶-4-基羥基(二苯基)乙酸酯； 1-{3-[6-({[(2R)-2-羥基-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-3,4-二氫喹啉-1(2H)-基]-3-側氧丙基}-2,2-二甲基哌啶-4-基羥基(二苯基)乙酸酯； 1-{3-[6-({[(2R)-2-羥基-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基](2-甲基丙基)胺基}甲基)-3,4-二氫喹啉-1(2H)-基]-3-側氧丙基}哌啶-4-基羥基(二苯基)乙酸酯； 1-(2-{6-[({(2R)-2-羥基-2-[4-羥基-3-(羥基甲基)苯基]乙基}胺基)甲基]-3,4-二氫喹啉-1(2H)-基}-2-側氧乙基)哌啶-4-基羥基(二苯基)乙酸酯； 1-{2-[6-({[(2R)-2-羥基-2-{4-羥基-3-[(甲磺醯基)胺基]苯基}乙基]胺基}甲基)-3,4-二氫喹啉-1(2H)-基]-2-側氧乙基}哌啶-4-基羥基(二苯基)乙酸酯； 1-{2-[6-({[(2R)-2-羥基-2-(6-羥基-3-側氧基-3,4-二氫-2H-1,4-苯并噁嗪-8-基)乙基]胺基}甲基)-3,4-二氫喹啉-1(2H)-基]-2-側氧乙基}哌啶-4-基羥基(二苯基)乙酸酯； 1-{3-[6-({[(2R)-2-羥基-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-3,4-二氫喹啉-1(2H)-基]-3-側氧丙基}哌啶-4-基環戊基(羥基)苯基乙酸酯； 1-{3-[6-({[(2R)-2-羥基-2-(6-羥基-3-側氧基-3,4-二氫-2H-1,4-苯并噁嗪-8-基)乙基]胺基}甲基)-3,4-二氫喹啉-1(2H)-基]-2,2-二甲基-3-側氧丙基}哌啶-4-基羥基(二噻吩-2-基)乙酸酯； 1-{2-[7-({[(2R)-2-羥基-2-(4-羥基-2-側氧基-2,3-二氫-1,3-苯並噻唑-7-基)乙基]胺基}甲基)-3,4-二氫喹啉-1(2H)-基]-2-側氧乙基}哌啶-4-基2,2-二(噻吩-2-基)丙酸酯； 1-{2-[6-({[(2R)-2-羥基-2-(6-羥基-3-側氧基-3,4-二氫-2H-1,4-苯并噁嗪-8-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}哌啶-4-基2,2-二(噻吩-2-基)丙酸酯； 1-{2-[5-({[(2R)-2-{[叔丁基(二甲基)矽基]氧基}-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}哌啶-4-基羥基(二噻吩-2-基)乙酸酯； 1-{2-[5-({[(2R)-2-{[叔丁基(二甲基)矽基]氧基}-2-(8-羥基-2-側氧基-1,2-二氫喹啉-5-基)乙基]胺基}甲基)-2,3-二氫-1H-吲哚-1-基]-2-側氧乙基}哌啶-4-基羥基(二苯基)乙酸酯； 及其藥學上可接受的鹽類。A compound of formula (I) according to claim 1, which is selected from the group consisting of: 1-{3-[5-({[(2R)-2-hydroxy-2-(8-hydroxyl)) -2-Sideoxy-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-2,3-dihydro-1H-indol-1-yl]-3- side Oxypropyl}piperidin-4-ylhydroxy(dithien-2-yl)acetate; 1-{2-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2) -Sideoxy-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethoxy }}piperidin-4-ylhydroxy (dithien-2-yl)acetate; 1-{3-[6-({[(2R)-2-hydroxy-2-(8-hydroxy-2- side) Oxy-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-3,4-dihydroquinolin-1(2H)-yl]-3-sideoxypropyl} Piperidin-4-ylhydroxy (dithien-2-yl)acetate; 1-{4-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2-yloxy) -1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-2,3-dihydro-1H-indol-1-yl]-4-xyloxybutyl}piperidine 4-ylhydroxy (dithien-2-yl)acetate; 1-{2-[5-({[(2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonate) Amino]phenyl]ethyl]amino}methyl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}piperidin-4-ylhydroxy ( Dithiazide Phen-2-yl)acetate; 1-{2-[5-({[(RS)-2-hydroxy-2-(8-hydroxy-2-yloxy-1,2-dihydroquinoline) -5-yl)ethyl]amino}methyl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}piperidin-4-ylhydroxy (dithiophene- 2-yl)acetate; 1-{3-[5-({[(2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}) Amino]methyl}methyl)-2,3-dihydro-1H-indol-1-yl]-3-oxopropyl}piperidin-4-ylhydroxy (dithien-2-yl)acetic acid Ester; 1-{2-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2-yloxy-1,2-dihydroquinolin-5-yl)ethyl]] Amino}methyl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}piperidin-4-ylhydroxy (dithien-2-yl)acetate Fumarate; 1-{2-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2-yloxy-1,2,3,4-tetrahydroquinoline- 5-yl)ethyl]amino}methyl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}piperidin-4-ylhydroxy (dithiophene-2) -yl)acetate; 1-{3-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2-yloxy-1,2-dihydroquinolin-5-) Ethyl]amino]methyl}methyl)-2,3-dihydro-1H-indol-1-yl]-3-oxopropyl}piperidin-4-ylhydroxy(diphenyl)acetic acid Ester; 1-{2-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2- side) 1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethylethylper Pyridin-4-ylhydroxy (diphenyl) acetate; 1-{3-[5-({[(2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)) Amino]phenyl}ethyl]amino}methyl)-2,3-dihydro-1H-indol-1-yl]-3-oxopropyl}piperidin-4-ylhydroxy (diphenyl) Acetate; 1-{2-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2-yloxy-1,2-dihydroquinolin-5-yl) Ethyl]amino}methyl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}pyrrolidin-3-ylhydroxy (dithien-2-yl) Acetate; 1-(2-{5-[({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl)ethyl]amino)amino)methyl]- 2,3-Dihydro-1H-indol-1-yl}-2-oxoethyl)piperidin-4-ylhydroxy (dithien-2-yl)acetate; 1-{2-[5 -({Ethyl[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)- 2,3-Dihydro-1H-indol-1-yl]-2-oxoethyl}piperidin-4-ylhydroxy (dithien-2-yl)acetate; 1-{2-[5 -({[(2R)-2-hydroxy-2-(8-hydroxy-2-yloxy-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-6- Methyl-2,3-dihydro-1H-indol-1-yl]-2-side Ethyl}piperidin-4-ylhydroxy (dithien-2-yl)acetate; 1-{2-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2-) Oxyoxy-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl }-3,3-Dimethylpiperidin-4-ylhydroxy (dithien-2-yl)acetate; 1-{2-[5-({[(2R)-2-hydroxy-2-() 8-Hydroxy-2-oxooxy-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-2,3-dihydro-1H-indol-1-yl]- 2-sided oxyethyl}-2,2-dimethylpiperidin-4-ylhydroxy (dithien-2-yl)acetate; 1-{2-[5-({[(2R)-2) -hydroxy-2-(5-hydroxy-3-o-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl)ethyl]amino}methyl)-2, 3-dihydro-1H-indol-1-yl]-2-oxoethyl}piperidin-4-ylhydroxy (dithien-2-yl)acetate; 1-(2-{5-[ ({(2R)-2-[3-(Methylamino)-4-hydroxyphenyl]-2-hydroxyethyl}amino)methyl]-2,3-dihydro-1H-indole- 1-yl}-2-oxoethyl)piperidin-4-ylhydroxy (dithien-2-yl)acetate; 1-{2-[5-({[(2R)-2-hydroxy-) 2-(4-Hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}methyl)-2,3-dihydro-1H -吲哚-1-yl]-2-oxoethyl}piperidin-4-ylhydroxy (dithia) Phen-2-yl)acetate; 1-{2-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2-yloxy-1,2-dihydroquinoline) -5-yl)ethyl]amino}methyl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}piperidin-4-ylcyclopentyl (hydroxyl Phenylacetate; 1-{3-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2-yloxy-1,2-dihydroquinolin-5-) Ethyl]amino]methyl}methyl)-2,3-dihydro-1H-indol-1-yl]-2,2-dimethyl-3-oxopropyl}piperidin-4-yl Hydroxy (dithien-2-yl) acetate; 1-{2-[5-({[2-(8-hydroxy-2-yloxy-1,2-dihydroquinolin-5-yl)) Ethyl]amino}methyl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}piperidin-4-ylhydroxy (dithiophen-2-yl) Acid ester; 1-{2-[5-({[(2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl]amino} Methyl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}piperidin-4-ylhydroxy (diphenyl) acetate; 1-{2-[ 5-({[(2S)-2-hydroxy-2-(8-hydroxy-2-yloxy-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-2 , 3-dihydro-1H-indol-1-yl]-2-oxoethyl}piperidin-4-ylhydroxy (dithien-2-yl)acetate; 1-{2-[5- ({[(2R)-2-hydroxy-2-(8-hydroxy-2-yloxy-1,2-dihydroquine)啉-5-yl)ethyl]amino}methyl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}piperidin-4-ylhydroxy (dithiophene) -2-yl)acetate acetate; 1-{2-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2-yloxy-1,2-dihydro) Quinoline-5-yl)ethyl]amino}methyl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}piperidin-4-ylhydroxy (second Thiophen-2-yl)acetate succinate (semisuccinate); 1-{2-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2-)oxy 1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethylethylper Pyridin-4-ylhydroxy (dithien-2-yl)acetate 2,3-dihydroxysuccinate (1:1); 1-{2-[5-({[(2R)-2-) Hydroxy-2-(8-hydroxy-2-oxooxy-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-2,3-dihydro-1H-indole- 1-yl]-2-oxoethyl}piperidin-4-ylhydroxy (dithien-2-yl)acetate hemiethane-1,2-disulfonic acid; 1-{2-[5- ({[2-hydroxy-2-(8-hydroxy-2-oxooxy-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-2,3-dihydro- 1H-indol-1-yl]-2-oxoethyl}piperidin-4-ylhydroxy (dithien-2-yl)acetate hydrofluoric acid (1:1); 1-{3-[ 6-({[(2R)-2-hydroxy-) 2-(8-Hydroxy-2-oxooxy-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-3,4-dihydroquinolin-1(2H)- 3-yloxypropyl}piperidin-4-ylhydroxy (diphenyl) acetate; 1-{3-[6-({[(2R)-2-hydroxy-2-(8-) Hydroxy-2-oxooxy-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-3,4-dihydroquinolin-1(2H)-yl]-3- Sideoxypropyl}-2,2-dimethylpiperidin-4-ylhydroxy(diphenyl)acetate; 1-{3-[6-({[(2R)-2-hydroxy-2-) (8-Hydroxy-2-oxooxy-1,2-dihydroquinolin-5-yl)ethyl](2-methylpropyl)amino}methyl)-3,4-dihydroquinoline -1(2H)-yl]-3-oxopropyl}piperidin-4-ylhydroxy(diphenyl)acetate; 1-(2-{6-[({(2R)-2-hydroxyl) -2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)methyl]-3,4-dihydroquinolin-1(2H)-yl}-2-oxoethoxy Piperidin-4-ylhydroxy (diphenyl) acetate; 1-{2-[6-({[(2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonate) Mercapto)amino]phenyl}ethyl]amino}methyl)-3,4-dihydroquinolin-1(2H)-yl]-2-oxoethyl}piperidin-4-ylhydroxy (diphenyl)acetate; 1-{2-[6-({[(2R)-2-hydroxy-2-(6-hydroxy-3-yloxy-3,4-dihydro-2H-) 1,4-benzoxazine-8-yl)ethyl]amino}methyl)-3,4-di Quinoline-1(2H)-yl]-2-oxoethyl}piperidin-4-ylhydroxy(diphenyl)acetate; 1-{3-[6-({[(2R)-2) -hydroxy-2-(8-hydroxy-2-epoxy-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-3,4-dihydroquinolin-1 ( 2H)-yl]-3-oxopropyl}piperidin-4-ylcyclopentyl(hydroxy)phenyl acetate; 1-{3-[6-({[(2R)-2-hydroxy-) 2-(6-Hydroxy-3-oxooxy-3,4-dihydro-2H-1,4-benzoxazin-8-yl)ethyl]amino}methyl)-3,4-di Hydroquinolin-1(2H)-yl]-2,2-dimethyl-3-oxopropyl}piperidin-4-ylhydroxy (dithien-2-yl)acetate; 1-{2 -[7-({[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]] Amino}methyl)-3,4-dihydroquinolin-1(2H)-yl]-2-oxoethyl}piperidin-4-yl 2,2-di(thiophen-2-yl)propane Acid ester; 1-{2-[6-({[(2R)-2-hydroxy-2-(6-hydroxy-3-yloxy-3,4-dihydro-2H-1,4-benzo) Oxazin-8-yl)ethyl]amino}methyl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}piperidin-4-yl 2,2 - bis(thiophen-2-yl)propionate; 1-{2-[5-({[(2R)-2-{[tert-butyl(dimethyl)indenyl]oxy}-2-( 8-hydroxy-2-oxooxy-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-2,3-dihydro -1H-indol-1-yl]-2-oxoethyl}piperidin-4-ylhydroxy (dithien-2-yl)acetate; 1-{2-[5-({[(2R) -2-{[tert-butyl(dimethyl)indenyl]oxy}-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl] Amino}methyl}-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}piperidin-4-ylhydroxy (diphenyl) acetate; and pharmacy thereof Acceptable salts. 一種化合物，選自以下組成的群組： 1-[3-(5-甲醯基-2,3-二氫-1H-吲哚-1-基)-3-側氧丙基]哌啶-4-基羥基(二噻吩-2-基)乙酸酯； 1-[3-(5-甲醯基-2,3-二氫-1H-吲哚-1-基)-3-側氧丙基]哌啶-4-基羥基(二苯基)乙酸酯； 1-[3-(5-甲醯基-2,3-二氫-1H-吲哚-1-基)-3-側氧丁基]哌啶-4-基羥基(二噻吩-2-基)乙酸酯； 1-[3-(5-甲醯基-2,3-二氫-1H-吲哚-1-基)-3-側氧乙基l]哌啶-4-基羥基(二苯基)乙酸酯； 1-[3-(6-甲醯基-3,4-二氫喹啉-1(2H)-基)-3-側氧丙基]哌啶-4-基羥基(二噻吩-2-基)乙酸酯； 1-(3-氯丙醯基)-2,3-二氫-1H-吲哚-5-甲醛； 1-(4-氯丁醯基)-2,3-二氫-1H-吲哚-5-甲醛； 1-(3-氯丙醯基)-1,2,3,4-四氫喹啉-6-甲醛； 1-(氯乙醯基)-2,3-二氫-1H-吲哚-5-甲醛； 1-[2-(5-甲醯基-2,3-二氫-1H-吲哚-1-基)-2-側氧乙基]哌啶-4-基羥基(二噻吩-2-基)乙酸酯； 以及其藥學上可接受的鹽類。A compound selected from the group consisting of: 1-[3-(5-methylindolyl-2,3-dihydro-1H-indol-1-yl)-3-oxopropyl]piperidine- 4-ylhydroxy(dithien-2-yl)acetate; 1-[3-(5-methylindolyl-2,3-dihydro-1H-indol-1-yl)-3-oxopropane Benzylpiperidin-4-ylhydroxy(diphenyl)acetate; 1-[3-(5-methylindolyl-2,3-dihydro-1H-indol-1-yl)-3- side Oxybutyl]piperidin-4-ylhydroxy (dithien-2-yl)acetate; 1-[3-(5-methylindenyl-2,3-dihydro-1H-inden-1-yl) -3-oxoethylethyl]piperidin-4-ylhydroxy (diphenyl)acetate; 1-[3-(6-carbamimido-3,4-dihydroquinolin-1 (2H) )-yl)-3-oxopropyl]piperidin-4-ylhydroxy (dithien-2-yl)acetate; 1-(3-chloropropionyl)-2,3-dihydro-1H -吲哚-5-formaldehyde; 1-(4-chlorobutylidene)-2,3-dihydro-1H-indole-5-carbaldehyde; 1-(3-chloropropionyl)-1,2,3, 4-tetrahydroquinolin-6-carboxaldehyde; 1-(chloroethenyl)-2,3-dihydro-1H-indole-5-carbaldehyde; 1-[2-(5-methylindenyl-2, 3-Dihydro-1H-indol-1-yl)-2-oxoethyl]piperidin-4-ylhydroxy (dithien-2-yl)acetate; and pharmaceutically acceptable salts thereof . 一種藥學組合物，其包含一醫療有效量的如申請專利範圍第1項至第3項中任一項所述的一或更多化合物，其與一藥學上可接受的賦形劑混合。A pharmaceutical composition comprising a medically effective amount of one or more compounds as described in any one of claims 1 to 3, which is admixed with a pharmaceutically acceptable excipient. 一種在包括人類的一哺乳動物中治療呼吸道病症的方法，該方法包括將一醫療有效量的如申請專利範圍第1項至第3項中任一項所述的化合物給予至需要其的一哺乳動物。A method of treating a respiratory condition in a mammal comprising a human, the method comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 3 to a mammal in need thereof animal. 如申請專利範圍第6項所述的方法，其中該呼吸道病症選自氣喘、慢性阻塞性肺病、慢性支氣管炎、急性呼吸窘迫綜合症（ARDS）、慢性呼吸道阻塞、支氣管亢進、肺纖維化、肺氣腫以及過敏性鼻炎組成的群組。The method of claim 6, wherein the respiratory condition is selected from the group consisting of asthma, chronic obstructive pulmonary disease, chronic bronchitis, acute respiratory distress syndrome (ARDS), chronic airway obstruction, bronchoconstriction, pulmonary fibrosis, lung A group of emphysema and allergic rhinitis. 如申請專利範圍第7項所述的方法，其中該呼吸道病症是慢性阻塞性肺病或氣喘。The method of claim 7, wherein the respiratory condition is chronic obstructive pulmonary disease or asthma. 一種如申請專利範圍第1項至第3項中任一項所述的化合物用於製備治療呼吸道病症的藥物的的用途。Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment of a respiratory disorder. 如申請專利範圍第9項所述的化合物的用途，其中該呼吸道病症選自氣喘、慢性阻塞性肺病、慢性支氣管炎、急性呼吸窘迫綜合症（ARDS）、慢性呼吸道阻塞、支氣管亢進、肺纖維化、肺氣腫以及過敏性鼻炎組成的群組。The use of a compound according to claim 9 wherein the respiratory condition is selected from the group consisting of asthma, chronic obstructive pulmonary disease, chronic bronchitis, acute respiratory distress syndrome (ARDS), chronic airway obstruction, bronchospasm, pulmonary fibrosis , a group of emphysema and allergic rhinitis. 如申請專利範圍第10項所述的化合物的用途，其中該呼吸道病症是慢性阻塞性肺病或氣喘。The use of a compound according to claim 10, wherein the respiratory condition is chronic obstructive pulmonary disease or asthma. 一種如本文中參考說明書的所附範例所述的分子式（I）化合物、其製備方法以及藥學組合物。A compound of formula (I), a process for its preparation, and a pharmaceutical composition as described herein with reference to the accompanying examples of the specification.
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