TWI880167B - Polycyclic pyridotriazine derivative - Google Patents

Abstract

The present inventon provides the compound represented by the following formula (I).

wherein

ring A is a substituted or unsubstituted heterocycle; ring B is a benzene ring or a pyridine ring; Q is -NHC(O)- or a 5-membered aromatic heterocycle; R¹ is each independently halogen, alkyl, haloalkyl, alkyloxy, cyano or haloalkyloxy; R^2a and R^2b are each independently a hydrogen atom, alkyl or haloalkyl; R³ is alkyl or haloalkyl; R⁴ is a hydrogen atom or alkyl; and n is an integer of 1 to 3.

Description

Translated fromChinese

多環性吡啶并三衍生物Polycyclic pyridotriazole derivatives

本發明係關於一種具有抗病毒作用的新穎化合物，更詳細而言，係具有HIV整合酶(integrase)抑制活性的多環吡啶并三

衍生物及含有該衍生物的醫藥，特別是抗HIV藥物。The present invention relates to a novel compound having antiviral activity, more specifically, a polycyclic pyridine tris(III) compound having HIV integrase inhibitory activity.

Derivatives and medicines containing the derivatives, especially anti-HIV drugs.

在病毒中，屬於反轉錄病毒之一的人類免疫缺乏病毒(Human Immunodeficiency Virus，以下縮寫為HIV)已知為後天性免疫缺乏症候群(Acquired immunodeficiency syndrome，以下縮寫為AIDS)的原因。作為該AIDS的治療劑者，目前，是以各種指南向初發患者(Naive patient)推薦以整合酶抑制劑(例如，杜魯特韋(Dolutegravir)等)作為主要藥劑而具有不同抗藥性譜(Resistance profile)的兩劑核酸系逆轉錄酶抑制劑(例如，ABC+3TC、FTC+TAF等)組合而成的合劑。相較於初期的治療藥，由於藥效強且安全性亦高而提高滿意度。另一方面，由於安全的藥物的出現及良好的預後故建議一旦知道HIV感染就開始治療，並且HIV感染者的平均餘命亦接近於健康人因此引起服藥期間的長期化。由於長期服藥，當核酸系反轉錄酶抑制劑的副作用出現或一旦抗藥性病毒出現時，則之後沒有簡單的治療方法，因此有不使用核酸系反轉錄酶抑制劑的措施。因此，期望著確立由兩劑主要藥劑的雙劑治療，並且期望開發可與整合酶抑制劑組合的主要藥劑。再者，為了改善由長期服藥導致的服藥疲累的、更佳享受日常生活等改善患者的生活品質(Quality of Life，QOL)而期望開發出服藥間隔更長的治療藥，亦即，例如每間隔一個月以上的時間注射一次即可完成治療的持續性注射劑。Among viruses, human immunodeficiency virus (HIV), which is one of the retroviruses, is known to be the cause of acquired immunodeficiency syndrome (AIDS). As a therapeutic agent for AIDS, various guidelines currently recommend a combination of an integrase inhibitor (e.g., Dolutegravir, etc.) as the main drug for naive patients and a two-drug nucleic acid reverse transcriptase inhibitor (e.g., ABC+3TC, FTC+TAF, etc.) with different resistance profiles. Compared with the initial treatment drugs, the drug satisfaction is improved due to its strong efficacy and high safety. On the other hand, due to the emergence of safe drugs and good prognosis, it is recommended to start treatment as soon as HIV infection is known, and the average life expectancy of HIV-infected people is close to that of healthy people, which leads to a longer medication period. Due to long-term medication, when the side effects of nucleic acid reverse transcriptase inhibitors appear or once drug-resistant viruses appear, there is no simple treatment method, so there are measures not to use nucleic acid reverse transcriptase inhibitors. Therefore, it is expected to establish a dual-dose treatment with two main drugs, and it is expected to develop a main drug that can be combined with an integrase inhibitor. Furthermore, in order to improve the patient's quality of life (QOL) by improving medication fatigue caused by long-term medication and enjoying daily life better, it is hoped that therapeutic drugs with longer medication intervals will be developed, that is, continuous injections that can complete treatment with a single injection every month or more.

為了滿足此種需要，整合酶抑制劑Cabotegravir作為連續性注射劑正在Ph3(Phase 3)開發中。再者，亦進行著非核酸系反轉錄酶抑制劑Rilpivirin作為連續性注射劑的開法，旨在確立利用該2劑的治療法。然而，此等藥物必須每一到兩個月注射一次，並且伴隨疼痛注射3至4處。因此，為了進一步改善患者的QOL，期望開發出更低用量且較少疼痛，並且可每三個月注射一次即完成的藥劑。To meet this need, the integrase inhibitor Cabotegravir is being developed as a continuous injection in Phase 3. In addition, the non-nucleic acid reverse transcriptase inhibitor Rilpivirin is also being prescribed as a continuous injection to establish a two-dose treatment method. However, these drugs must be injected once every one to two months, and injected into 3 to 4 places with pain. Therefore, in order to further improve the patient's QOL, it is hoped that a drug with a lower dosage and less pain, which can be injected once every three months, can be developed.

整合酶抑制劑已上市有作為第一代口服劑的拉替拉韋(Raltegravir)、埃替格韋(Elvitegravir)；及作為第二代的杜魯特韋。初發患者使用杜魯特韋時，不會出現耐藥變異，惟，在感染了對第一代整合酶抑制劑有抗藥性的病毒之患者的治療中使用杜魯特韋時，則有追增進一步的抗藥性突變而使杜魯特韋失效之情形。因此，期望開發出具有比杜魯特韋更高抗藥性屏障的抑制劑。Integrase inhibitors that are already on the market include Raltegravir and Elvitegravir as first-generation oral agents, and Dolutegravir as the second-generation. When Dolutegravir is used in patients with initial onset of the disease, drug resistance mutations will not occur. However, when Dolutegravir is used in the treatment of patients infected with a virus that is resistant to first-generation integrase inhibitors, further drug resistance mutations may occur, rendering Dolutegravir ineffective. Therefore, it is desirable to develop an inhibitor with a higher resistance barrier than Dolutegravir.

再者，具有整合酶抑制作用的抗HIV藥物之一，已知有雙環性或雙環以上的胺甲醯基吡啶酮衍生物(專利文獻1至29)。該等文獻中，專利文獻3中記載了胺甲醯基三

衍生物。Furthermore, as one of the anti-HIV drugs with integrase inhibitory activity, bicyclic or more bicyclic aminoformylpyridone derivatives are known (Patent Documents 1 to 29). Among these documents, Patent Document 3 describes aminoformyltripyridone derivatives.

derivative.

進一步，具有整合酶抑制作用的抗HIV藥物之一，已知有側鏈為雜環的吡啶酮衍生物(專利文獻5、8、9、12、13、19、23、24、27、30至33)。該等文獻中，專利文獻9記載了縮合三環性的吡啶并吡

衍生物。再者，專利文獻5記載了縮合三環性的吡啶并吡

衍生物和縮合三環性的吡啶并三

衍生物。Furthermore, as one of the anti-HIV drugs with integrase inhibitory effects, there are known pyridone derivatives with heterocyclic side chains (patent documents 5, 8, 9, 12, 13, 19, 23, 24, 27, 30 to 33). Among these documents, patent document 9 describes a condensed tricyclic pyridopyridine derivative.

Derivatives. Furthermore, Patent Document 5 describes a condensed tricyclic pyridine and pyridine derivative.

Derivatives and condensed tricyclic pyridotriazine

derivative.

[先前技術文獻][Prior Art Literature]

[專利文獻][Patent Literature]

專利文獻1：國際公開第WO2006/088173號公報Patent document 1: International Publication No. WO2006/088173

專利文獻2：國際公開第WO2006/116764號公報Patent document 2: International Publication No. WO2006/116764

專利文獻3：國際公開第WO2007/049675號公報Patent document 3: International Publication No. WO2007/049675

專利文獻4：國際公開第WO2011/129095號公報Patent document 4: International Publication No. WO2011/129095

專利文獻5：國際公開第WO2014/099586號公報Patent document 5: International Publication No. WO2014/099586

專利文獻6：國際公開第WO2014/100323號公報Patent document 6: International Publication No. WO2014/100323

專利文獻7：國際公開第WO2014/104279號公報Patent document 7: International Publication No. WO2014/104279

專利文獻8：國際公開第WO2014/183532號公報Patent document 8: International Publication No. WO2014/183532

專利文獻9：國際公開第WO2014/200880號公報Patent document 9: International Publication No. WO2014/200880

專利文獻10：國際公開第WO2015/039348號公報Patent document 10: International Publication No. WO2015/039348

專利文獻11：國際公開第WO2015/048363號公報Patent document 11: International Publication No. WO2015/048363

專利文獻12：國際公開第WO2015/089847號公報Patent document 12: International Publication No. WO2015/089847

專利文獻13：國際公開第WO2015/095258號公報Patent document 13: International Publication No. WO2015/095258

專利文獻14：國際公開第WO2015/006731號公報Patent document 14: International Publication No. WO2015/006731

專利文獻15：國際公開第WO2015/006733號公報Patent document 15: International Publication No. WO2015/006733

專利文獻16：國際公開第WO2015/19967號公報Patent document 16: International Publication No. WO2015/19967

專利文獻17：國際公開第WO2016/090545號公報Patent document 17: International Publication No. WO2016/090545

專利文獻18：國際公開第WO2016/094198號公報Patent document 18: International Publication No. WO2016/094198

專利文獻19：國際公開第WO2016/094197號公報Patent document 19: International Publication No. WO2016/094197

專利文獻20：國際公開第WO2016/106237號公報Patent document 20: International Publication No. WO2016/106237

專利文獻21：國際公開第WO2016/154527號公報Patent document 21: International Publication No. WO2016/154527

專利文獻22：國際公開第WO2016/161382號公報Patent document 22: International Publication No. WO2016/161382

專利文獻23：國際公開第WO2016/187788號公報Patent document 23: International Publication No. WO2016/187788

專利文獻24：國際公開第WO2016/191239號公報Patent document 24: International Publication No. WO2016/191239

專利文獻25：國際公開第WO2017/087256號公報Patent document 25: International Publication No. WO2017/087256

專利文獻26：國際公開第WO2017/087257號公報Patent document 26: International Publication No. WO2017/087257

專利文獻27：國際公開第WO2017/106071號公報Patent document 27: International Publication No. WO2017/106071

專利文獻28：國際公開第WO2017/113288號公報Patent document 28: International Publication No. WO2017/113288

專利文獻29：國際公開第WO2017/116928號公報Patent document 29: International Publication No. WO2017/116928

專利文獻30：國際公開第WO2005/016927號公報Patent document 30: International Publication No. WO2005/016927

專利文獻31：國際公開第WO2011/105590號公報Patent document 31: International Publication No. WO2011/105590

專利文獻32：國際公開第WO2013/054862號公報Patent document 32: International Publication No. WO2013/054862

專利文獻33：國際公開第WO2016/027879號公報Patent document 33: International Publication No. WO2016/027879

本發明之目的係提供一種高抗藥性屏障之新穎的具有持續性整合酶抑制活性之化合物。The purpose of the present invention is to provide a novel compound with a high barrier to drug resistance and sustained integrase inhibitory activity.

本發明者們深入檢討的結果，發現一種新穎的吡啶并三

衍生物，該衍生物具有高抗藥性屏障的整合酶抑制作用。進一步發現本發明化合物及含有該等的醫藥係可用作為抗病毒藥(例如，抗反轉錄病毒藥、抗HIV藥、抗HTLV-1(Human T cell leukemia virus type 1：人類T細胞白血病病毒1型)藥、抗FIV(Feline immunodeficiency virus：貓AIDS病毒)藥、抗SIV(Simian immunodeficiency virus：猿AIDS病毒)藥)，特別是抗HIV藥、抗AIDS藥或與其相關疾病的治療藥等，遂而完成如下所示之本發明。As a result of in-depth research, the inventors discovered a novel pyridotriazine

Derivatives having an integrase inhibitory effect with a high drug resistance barrier. It has been further discovered that the compounds of the present invention and pharmaceuticals containing the same can be used as antiviral drugs (e.g., antiretroviral drugs, anti-HIV drugs, anti-HTLV-1 (Human T cell leukemia virus type 1) drugs, anti-FIV (Feline immunodeficiency virus: Feline AIDS virus) drugs, anti-SIV (Simian immunodeficiency virus: Simian AIDS virus) drugs), especially anti-HIV drugs, anti-AIDS drugs or therapeutic drugs for diseases related thereto, thereby completing the present invention as shown below.

本發明係提供下列所示之發明。This invention provides the invention shown below.

[1]一種式(I)所示之化合物或其製藥上容許的鹽。[1] A compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

(式中，(Where,

A環為下列環：Ring A is the following ring:

X1為CR^9aR^9b或O；X1 is CR^9a R^9b or O;

R^5a、R^5b、R^6a、R^6b、R^7a及R^7b各自獨立地為氫、烷基、烷氧基或烷氧基烷基；R^5a , R^5b , R^6a , R^6b , R^7a and R^7b are each independently hydrogen, alkyl, alkoxy or alkoxyalkyl;

R^5a及R^6a、或R^6a及R^7a可與相鄰的原子一起形成可經鹵素取代的芳香族碳環、可經鹵素取代的3至6員的非芳香族碳環或者可經鹵素取代的4至6員的非芳香族雜環(惟，形成芳香族碳環時，R^5b及R^6b、或R^6b及R^7b一起形成鍵)；R^5a and R^6a , or R^6a and R^7a , together with adjacent atoms, may form an aromatic carbocyclic ring which may be substituted with halogen, a 3- to 6-membered non-aromatic carbocyclic ring which may be substituted with halogen, or a 4- to 6-membered non-aromatic heterocyclic ring which may be substituted with halogen (however, when forming an aromatic carbocyclic ring, R^5b and R^6b , or R^6b and R^7b , together form a bond);

R^5b及R^6b可一起形成鍵；R^5b and R^6b may form a bond together;

R^8a、R^8b、R^9a、R^9b、R^10a、R^10b、R^11a及R^11b各自獨立地為氫、烷基、烷氧基或烷氧基烷基；R^8a , R^8b , R^9a , R^9b , R^10a , R^10b , R^11a and R^11b are each independently hydrogen, alkyl, alkoxy or alkoxyalkyl;

R^8a及R^10a可一起形成C1-C3交聯；R^8a and R^10a may together form a C1-C3 crosslink;

R^10a及R^11a可與相鄰的原子一起形成5員的非芳香族碳環；R^10a and R^11a may form a 5-membered non-aromatic carbon ring together with adjacent atoms;

R^9a及R^9b可與相鄰的原子一起形成4員的非芳香族碳環或5員的非芳香族雜環；R^9a and R^9b may form a 4-membered non-aromatic carbon ring or a 5-membered non-aromatic heterocyclic ring together with adjacent atoms;

R^8a及R^9a可一起形成鍵；R^8a and R^9a may form a bond together;

B環為苯環或吡啶環；Ring B is a benzene ring or a pyridine ring;

Q為-NHC(O)-或5員的芳香族雜環；Q is -NHC(O)- or a 5-membered aromatic heterocyclic ring;

R1各自獨立地為鹵素、烷基、鹵烷基、烷氧基、氰基或鹵烷氧基；R1 is independently halogen, alkyl, halogenalkyl, alkoxy, cyano or halogenalkoxy;

R^2a及R^2b各自獨立地為氫、烷基或鹵烷基；R^2a and R^2b are each independently hydrogen, alkyl or halogenalkyl;

R³為烷基或鹵烷基；^R3 is an alkyl group or a halogenated alkyl group;

R⁴為氫或烷基；及^R4 is hydrogen or alkyl; and

n為1至3的整數)n is an integer from 1 to 3)

[2]如[1]所述之化合物或其製藥上容許的鹽，其中，R³為烷基。[2] The compound according to [1] or a pharmaceutically acceptable salt thereof, wherein R³ is an alkyl group.

[3]如[1]或[2]所述之化合物或其製藥上容許的鹽，其中，R¹各自獨立地為鹵素。[3] The compound according to [1] or [2] or a pharmaceutically acceptable salt thereof, wherein R¹ is independently a halogen.

[4]如[1]至[3]中任一項所述之化合物或其製藥上容許的鹽，其中，R^2a為氫，R^2b為氫或烷基。[4] The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [3], wherein R^2a is hydrogen and R^2b is hydrogen or alkyl.

[5]如[1]至[4]中任一項所述之化合物或其製藥上容許的鹽，其中，Q為-NHC(O)-。[5] A compound as described in any one of [1] to [4] or a pharmaceutically acceptable salt thereof, wherein Q is -NHC(O)-.

[6]如[1]至[4]中任一項所述之化合物或其製藥上容許的鹽，其中，Q為5員的芳香族雜環。[6] A compound as described in any one of [1] to [4] or a pharmaceutically acceptable salt thereof, wherein Q is a 5-membered aromatic heterocyclic ring.

[7]如[1]所述之化合物或其製藥上容許的鹽，該化合物係選自由化合物I-3、I-7、I-11、I-16、I-23、I-24及I-32所組成的群組。[7] The compound as described in [1] or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of compounds I-3, I-7, I-11, I-16, I-23, I-24 and I-32.

[8]如[1]所述之化合物或其製藥上容許的鹽，該化合物係選自由化合物II-1、II-4、II-5、II-13、II-14、II-16、II-19、II-21、II-23、II-26、II-31、II-34、II-36、II-38、II-41、II-43、II-45、II-47、II-49、II-52、II-56、II-58、II-62、II-63、II-64、II-68、II-89、II-92、II-93、II-95、II-96、II-98、II-106、II-109、II-110、II-112、II-113、II-117、II-118、II-125、II-127、II-128、II-129、II-130、II-131、II-132、II-136、II-138、II-139、II-142、II-143、II-144、II-147、II-148、II-149、II-150、II-151、II-155、II-156及II-157所組成的群組。[8] The compound as described in [1] or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of compounds II-1, II-4, II-5, II-13, II-14, II-16, II-19, II-21, II-23, II-26, II-31, II-34, II-36, II-38, II-41, II-43, II-45, II-47, II-49, II-52, II-56, II-58, II-62, II-63, II-64, II-68, II-89, II-92, II-93, II-95, II-1 I-96, II-98, II-106, II-109, II-110, II-112, II-113, II-117, II-118, II-125, II-127, II-128, II-129, II-130, II-131, II-1 32. The group consisting of II-136, II-138, II-139, II-142, II-143, II-144, II-147, II-148, II-149, II-150, II-151, II-155, II-156 and II-157.

[9]一種醫藥組成物，該醫藥組成物含有[1]至[8]中任一項所述之化合物或其製藥上容許的鹽。[9] A pharmaceutical composition comprising a compound described in any one of [1] to [8] or a pharmaceutically acceptable salt thereof.

[10]如[9]所述之醫藥組成物，該醫藥組成物係抗HIV劑。[10] The pharmaceutical composition as described in [9], which is an anti-HIV agent.

[11]如[9]所述之一種醫藥組成物，該醫藥組成物係HIV整合酶抑制劑。[11] A pharmaceutical composition as described in [9], which is an HIV integrase inhibitor.

[12]一種抗HIV劑，該抗HIV劑含有[1]至[8]中任一項所述之化合物或其製藥上容許的鹽。[12] An anti-HIV agent, which contains the compound described in any one of [1] to [8] or a pharmaceutically acceptable salt thereof.

[13]一種[1]至[8]中任一項所述之化合物或其製藥上容許的鹽之用途，該用途係用以製造HIV感染症的治療劑及/或預防劑。[13] A use of a compound described in any one of [1] to [8] or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent and/or preventive agent for HIV infection.

[14]如[1]至[8]中任一項所述之化合物或其製藥上容許的鹽，該化合物係為了使用於HIV感染症的治療及/或預防。[14] A compound as described in any one of [1] to [8] or a pharmaceutically acceptable salt thereof, which is used for the treatment and/or prevention of HIV infection.

本發明進一步提供一種HIV感染症的預防或治療方法，該方法包括對人投予有效量的上述化合物。The present invention further provides a method for preventing or treating HIV infection, which comprises administering an effective amount of the above-mentioned compound to a human.

本發明進一步提供用以使用為抗HIV藥劑的上述化合物。The present invention further provides the above-mentioned compound for use as an anti-HIV agent.

本發明化合物係對病毒，特別是HIV或其抗藥性病毒具有整合酶抑制活性及/或細胞增殖抑制活性。因此，對於整合酶相關的各種疾病或病毒感染症(例如，AIDS)等的預防或治療有用。較佳的是，本發明化合物可用作為持續性整合酶抑制劑。再者，在不容易產生新HIV抗藥性病毒等的抗藥性譜方面亦優異。更佳的是，本發明化合物對於HIV藥劑抗藥性病毒也具有預防或治療效果。又更佳的是，本發明化合物係清除率(clearance)小、體內半衰期長、溶解性或代謝穩定性等優異，並且可用作為細胞毒性或副作用(例如，CYP抑制、致突變性、心電圖QT間隔延長、心律不整)的疑慮少之醫藥品。The compounds of the present invention have integrase inhibitory activity and/or cell proliferation inhibitory activity against viruses, especially HIV or its drug-resistant viruses. Therefore, they are useful for the prevention or treatment of various integrase-related diseases or viral infections (e.g., AIDS). Preferably, the compounds of the present invention can be used as persistent integrase inhibitors. Furthermore, they are also excellent in terms of drug resistance profiles that are not prone to the generation of new HIV drug-resistant viruses. More preferably, the compounds of the present invention also have a preventive or therapeutic effect on HIV drug-resistant viruses. Even better, the compounds of the present invention have low clearance, long half-life in vivo, excellent solubility or metabolic stability, and can be used as pharmaceuticals with little concern about cytotoxicity or side effects (e.g., CYP inhibition, mutagenicity, prolonged QT interval of electrocardiogram, arrhythmia).

以下，說明本說明書中所使用的各用語之意義。各用語若無特別說明，於單獨使用時、或與其他用語組合使用時皆指相同的意思。The following is an explanation of the meaning of each term used in this manual. Unless otherwise specified, each term has the same meaning when used alone or in combination with other terms.

用語「由…所組成」意指僅具有構成要件。The term "consisting of..." means that only the constituent elements are present.

用語「含有」意指不限定構成要件，且不排除未記載之要素。The term "including" does not limit the constituent elements and does not exclude elements not listed.

「鹵素」係包括氟原子、氯原子、溴原子及碘原子。特佳為氟原子及氯原子。"Halogen" includes fluorine atom, chlorine atom, bromine atom and iodine atom. Fluorine atom and chlorine atom are particularly preferred.

「烷基」係包含碳數1至15，較佳為碳數1至10，再佳碳數1至6，更佳為碳數1至4的直鏈或支鏈狀的烴基。可舉例如：甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基、正戊基、異戊基、新戊基、正己基、異己基、正庚基、異庚基、正辛基、異辛基、正壬基、正癸基等。"Alkyl" refers to a straight or branched chain alkyl group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, iso-octyl, n-nonyl, n-decyl, etc.

「烷基」之較佳態樣可舉例如：甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基、正戊基。再佳的實施態樣可舉例如：甲基、乙基、正丙基、異丙基、第三丁基。Preferred embodiments of "alkyl" include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl. More preferred embodiments include: methyl, ethyl, n-propyl, isopropyl, tert-butyl.

「芳族碳環式基」意指單環的環狀芳香族烴基。可舉例如苯基。"Aromatic carbocyclic group" means a monocyclic aromatic hydrocarbon group. An example is phenyl.

「芳香族碳環式基」的較佳態樣可舉出苯基。A preferred example of the "aromatic carbocyclic group" is phenyl.

「非芳香族碳環式基」意指單環的環狀飽和烴基或環狀非芳香族不飽和烴基。"Non-aromatic carbocyclic group" means a monocyclic cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group.

單環的非芳香族碳環式基較佳為碳數3至16，再佳為碳數3至6。可舉例如：環丙基、環丁基、環戊基、環己基、環庚基、環辛基、環壬基、環癸基、環丙烯基、環丁烯基、環戊烯基、環己烯基、環庚烯基、環己二烯基等。The monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, and more preferably has 3 to 6 carbon atoms. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, etc.

「芳香族雜環式基」意指在環中具有一個以上任意地選自O、S及N的相同或相異的雜原子之5員的芳香族環式基。"Aromatic heterocyclic group" means an aromatic cyclic group having 5 members in the ring, one or more heteroatoms arbitrarily selected from O, S and N, which are the same or different.

5員芳香族雜環式基可舉例如：吡咯基、咪唑基、吡唑基、三唑基、四唑基、呋喃基、噻吩基、異噁唑基、

唑基、

二唑基、異噻唑基、噻唑基、噻二唑基等。Examples of the 5-membered aromatic heterocyclic group include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl,

Azolyl,

oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl and the like.

「非芳香族雜環式基」意指在環中具有一個以上任意選自O、S和N的相同或相異的雜原子之單環非芳族環式基。"Non-aromatic heterocyclic group" means a monocyclic non-aromatic cyclic group having one or more heteroatoms arbitrarily selected from O, S and N which are the same or different in the ring.

單環的非芳香族雜環式基較佳為3至8員，再佳為4至6員。The monocyclic non-aromatic heterocyclic group preferably has 3 to 8 members, more preferably 4 to 6 members.

3員非芳香族雜環基可舉例如：環硫乙烷基、環氧乙烷基和吖丙啶基。4員非芳香族雜環基可舉例如：氧雜環丁烷基和氮雜環丁烷基。5員非芳香族雜環基可舉例如：氧雜環硫丙烷基、四氫噻唑基、吡咯啶基、吡咯啉基、咪唑啶基、咪唑啉基、吡唑啶基、吡唑啉基、四氫呋喃基、二氫噻唑基、四氫異喹啉噻唑基、二氧雜環戊烷基、二氧雜環戊烯基、四氫噻吩基等。6員非芳香族雜環基可舉例如：二氧雜環己基、噻烷基(thianyl)、哌啶基、哌

基、

啉基(morpholinyl)、N-

啉基(morpholino)、硫代

啉基(thiomorpholinyl)、硫代N-

啉基(thiomorpholino)、二氫吡啶基、四氫吡啶基、四氫吡喃基、二氫

基(dihydroxazinyl)、四氫嗒

基(tetrahydropyridazinyl)、六氫嘧啶基、二

基、噻吩基(thienyl)、噻

基等。7員非芳芳族雜環基可舉例如：六氫氮呯基(azepinyl)、四氫二氮呯基、氧雜環庚烷基。Examples of the 3-membered non-aromatic heterocyclic group include thioethanethiol, oxirane and aziridinyl. Examples of the 4-membered non-aromatic heterocyclic group include oxathiobutyl and azidebutyl. Examples of the 5-membered non-aromatic heterocyclic group include oxathiobutyl, tetrahydrothiazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, tetrahydrofuranyl, dihydrothiazolyl, tetrahydroisoquinolinothiazolyl, dioxathiocyclopentanyl, dioxathiocyclopentenyl, tetrahydrothienyl, and the like. Examples of the 6-membered non-aromatic heterocyclic group include dioxane, thianyl, piperidinyl, piperidinyl,

base,

Morpholinyl, N-

Morpholino, thio

thiomorpholinyl, thio N-

thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydropyranyl, dihydro

dihydroxazinyl, tetrahydroxazinyl

Tetrahydropyridazinyl, hexahydropyridinyl, dihydropyridazinyl

Thienyl, thienyl

Examples of the 7-membered non-aromatic heterocyclic group include hexahydroazepinyl, tetrahydrodiazepinyl, and oxacycloheptanyl.

「芳香族碳環」、「非芳香族碳環」、「芳香族雜環」及「非芳香族雜環」各別意指衍生自上述「芳香族碳環式基」、「非芳香族碳環式基」、「芳族雜環式基」及「非芳香族雜環式基團」的環。"Aromatic carbocyclic ring", "non-aromatic carbocyclic ring", "aromatic heterocyclic ring" and "non-aromatic heterocyclic ring" respectively refer to rings derived from the above-mentioned "aromatic carbocyclic group", "non-aromatic carbocyclic group", "aromatic heterocyclic group" and "non-aromatic heterocyclic group".

式(I)表示的化合物中各記號的較佳態樣如下所示。式(I)所示的化合物可例示如下所示的具體例的所有組合態樣。The preferred aspects of each symbol in the compound represented by formula (I) are shown below. The compound represented by formula (I) can be exemplified by all the combination aspects of the specific examples shown below.

A環可列舉下列環：Ring A can include the following rings:

A環較佳的態樣之一係下列環：One of the better forms of A ring is the following ring:

A環再佳的態樣係上述(a)或(b-1)。The best state of A ring is the above (a) or (b-1).

B環可舉例如苯環或吡啶環。Ring B may be, for example, a benzene ring or a pyridine ring.

B環的較佳的態樣係苯環。The preferred form of the B ring is a benzene ring.

R¹各自獨立地可列舉：鹵素、烷基、鹵烷基、烷氧基、氰基或鹵烷氧基。R¹ can be independently exemplified by halogen, alkyl, halogenalkyl, alkoxy, cyano or halogenalkoxy.

R¹的較佳態樣之一係鹵素、烷基或鹵烷基。One of the preferred embodiments of R¹ is halogen, alkyl or halogenalkyl.

R¹的再佳態樣係鹵素。The best example of R¹ is halogen.

R^2a及R^2b各自獨立地可列舉：氫、烷基或鹵烷基。R^2a and R^2b can each independently be exemplified by hydrogen, alkyl or halogenalkyl.

R^2a及R^2b的較佳態樣之一係氫。One of the preferred embodiments of R^2a and R^2b is hydrogen.

R^2a的較佳態樣之一係氫。One of the preferred forms of R^2a is hydrogen.

R^2b的較佳態樣之一係氫或甲基，再佳態樣係氫。One of the more preferred embodiments of R^2b is hydrogen or methyl, and a further preferred embodiment is hydrogen.

R³可列舉例：烷基或鹵烷基。Examples of R³ include alkyl and halogenalkyl groups.

R³的較佳態樣之一係烷基。One of the preferred embodiments of R³ is an alkyl group.

R⁴可舉例如：氫或烷基。R⁴ can be exemplified by hydrogen or alkyl.

R⁴的較佳態樣之一係氫或甲基，再佳態樣係氫。One of the more preferred embodiments of R⁴ is hydrogen or methyl, and a further preferred embodiment is hydrogen.

R^5a、R^5b、R^6a、R^6b、R^7a及R^7b各自獨立地可以列舉：氫、烷基、烷氧基或烷氧基烷基。R^5a , R^5b , R^6a , R^6b , R^7a and R^7b can each independently be hydrogen, alkyl, alkoxy or alkoxyalkyl.

R^5a的較佳態樣之一係氫或烷基，再佳態樣係氫。One of the more preferred embodiments of R^5a is hydrogen or alkyl, and a further preferred embodiment is hydrogen.

R^5b的較佳態樣之一係氫或烷基，再佳態樣係氫。One of the more preferred embodiments of R^5b is hydrogen or alkyl, and a further preferred embodiment is hydrogen.

R^6a的較佳態樣之一係氫、烷基或烷氧基烷基，再佳態樣係氫。One of the more preferred embodiments of R^6a is hydrogen, alkyl or alkoxyalkyl, and a further preferred embodiment is hydrogen.

R^6b的較佳態樣之一係氫。One of the better forms of R^6b is hydrogen.

R^7a的較佳態樣之一係氫、烷基或烷氧基烷基，再佳態樣係烷氧基烷基。One of the more preferred embodiments of R^7a is hydrogen, alkyl or alkoxyalkyl, and a further preferred embodiment is alkoxyalkyl.

R^7b的較佳態樣之一係氫。One of the better forms of R^7b is hydrogen.

R^5a及R^6a、或R^6a及R^7a可與相鄰的原子一起形成可經鹵素取代的芳香族碳環、可經鹵素取代的3至6員非芳香族碳環或可經鹵素取代的4至6員非芳香族雜環(惟，形成芳香族碳環時，R^5b及R^6b、或R^6b及R^7b一起形成鍵)。R^5a and R^6a , or R^6a and R^7a , together with adjacent atoms, may form an aromatic carbocyclic ring which may be substituted with halogen, a 3- to 6-membered non-aromatic carbocyclic ring which may be substituted with halogen, or a 4- to 6-membered non-aromatic heterocyclic ring which may be substituted with halogen (however, when forming an aromatic carbocyclic ring, R^5b and R^6b , or R^6b and R^7b , together form a bond).

R^5b及R^6b可一起形成鍵。R^5b and R^6b may form a bond together.

R^8a、R^8b、R^9a、R^9b、R^10a、R^10b、R^11a和R^11b各自獨立地可列舉：氫、烷基、烷氧基或烷氧基烷基。R^8a , R^8b , R^9a , R^9b , R^10a , R^10b , R^11a and R^11b may each independently be hydrogen, alkyl, alkoxy or alkoxyalkyl.

R^8a的較佳態樣之一係氫或烷基，再佳態樣係氫。One of the more preferred embodiments of R^8a is hydrogen or alkyl, and a further preferred embodiment is hydrogen.

R^8b的較佳態樣之一係氫或烷基，再佳態樣係氫。One of the more preferred embodiments of R^8b is hydrogen or alkyl, and a further preferred embodiment is hydrogen.

R^9a的較佳態樣之一係氫、烷基或烷氧基烷基。One of the preferred embodiments of R^9a is hydrogen, alkyl or alkoxyalkyl.

R^9b的較佳態樣之一係氫或烷基，再佳態樣係氫。One of the more preferred embodiments of R^9b is hydrogen or alkyl, and a further preferred embodiment is hydrogen.

R¹⁰的較佳態樣之一係氫、烷基或烷氧基，再佳態樣係氫。One of the more preferred embodiments of R¹⁰ is hydrogen, alkyl or alkoxy, and a further preferred embodiment is hydrogen.

R^10b的較佳態樣之一係氫。One of the better forms of R^10b is hydrogen.

R^11a的較佳態樣之一係氫或烷基，再佳態樣係氫。One of the more preferred embodiments of R^11a is hydrogen or alkyl, and a further preferred embodiment is hydrogen.

R^11b的較佳態樣之一係氫。One of the better forms of R^11b is hydrogen.

R^8a及R^10a可一起形成C1-C3交聯，較佳為C1-C2交聯。R^8a and R^10a may form a C1-C3 crosslink, preferably a C1-C2 crosslink.

R^10a及R^11a可與相鄰的原子一起形成5員的非芳香族碳環。R^10a and R^11a may form a 5-membered non-aromatic carbon ring together with adjacent atoms.

R^9a及R^9b可與相鄰的原子一起形成4員的非芳香族碳環或5員的非芳香族雜環。R^9a and R^9b may form a 4-membered non-aromatic carbon ring or a 5-membered non-aromatic heterocyclic ring together with adjacent atoms.

R^8a及R^9a可一起形成鍵。R^8a and R^9a may form a bond together.

n可舉出1至3的整數。n can be an integer from 1 to 3.

n的較佳態樣之一係2至3的整數。One of the better examples of n is an integer between 2 and 3.

n的再佳態樣之一係1至2的整數。Another good example of n is an integer between 1 and 2.

Q可舉出-NHC(O)-或5員的芳香族雜環。Q can be -NHC(O)- or a 5-membered aromatic heterocyclic ring.

Q的較佳態樣之一係-NHC(O)-(左側的鍵結鍵與CR^2aR^2b鍵結)。One of the better forms of Q is -NHC(O)- (the left bond is bonded to CR^2a R^2b ).

Q的其他較佳態樣之一係5員芳香族雜環。One of the other better forms of Q is a 5-membered aromatic heterocyclic ring.

Q的其他較佳態樣之一係下列環(左側的鍵結鍵與CR^2aR^2b鍵結)；One of the other better forms of Q is the following ring (the left key is keyed with CR^2a R^2b );

Q的再佳態樣之一係上述(1)所示之環。One of the best forms of Q is the ring shown in (1) above.

本發明化合物的特徵為藉由在式(I)中使A環固定在特定的立體結構中，而具有優異的抗藥性譜、體內動態及安全性優異的特點。再者，本發明化合物的特徵為在式(I)中，成為光學活性的三環性以上的吡啶并三

衍生物，而具有優異的抗藥性譜、體內動態及安全性優異的特點。The compound of the present invention is characterized in that the A ring in formula (I) is fixed in a specific stereostructure, thereby having excellent drug resistance spectrum, in vivo dynamics and safety. Furthermore, the compound of the present invention is characterized in that in formula (I), the A ring is an optically active tricyclic or higher pyridotriazine.

derivatives, and have excellent drug resistance profile, in vivo dynamics and excellent safety characteristics.

本發明的化合物除非另有說明，否則不限於特定的異構物，並且包含所有可能的異構物(例如，酮-烯醇異構物、亞胺-烯胺異構物、非鏡像異構物、光學異構物、旋轉異構物等)、外消旋體或該等的混合物。Unless otherwise specified, the compounds of the present invention are not limited to specific isomers and include all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, non-mirror isomers, optical isomers, rotational isomers, etc.), racemates, or mixtures thereof.

本發明化合物之製藥上容許的鹽可列舉例如：本發明化合物與鹼金屬(例如，鋰、鈉、鉀等)、鹼土類金屬(例如，鈣、鋇等)、鎂、過渡金屬(例如，鋅、鐵等)、氨、有機鹼(例如，三甲胺、三乙胺、二環己胺、乙醇胺、二乙醇胺、三乙醇胺、葡甲胺(Meglumine)、乙二胺、吡啶、甲基吡啶、喹啉等)及胺基酸的鹽；或與無機酸(例如，鹽酸、硫酸、硝酸、碳酸、氫溴酸、磷酸、氫碘酸等)、及有機酸(例如，甲酸、乙酸、丙酸、三氟乙酸、檸檬酸、乳酸、酒石酸、草酸、順丁烯二酸、反丁烯二酸、苦杏仁酸、戊二酸、蘋果酸、苯甲酸、鄰苯二甲酸、抗壞血酸、苯磺酸、對甲苯磺酸、甲磺酸、乙磺酸等)的鹽等。該等鹽可以藉由通常進行的方法形成。The pharmaceutically acceptable salts of the compounds of the present invention include, for example, the compounds of the present invention and alkali metals (e.g., lithium, sodium, potassium, etc.), alkali earth metals (e.g., calcium, barium, etc.), magnesium, transition metals (e.g., zinc, iron, etc.), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, quinoline, etc.) and amino acid salts; or salts with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.), and organic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, citric acid, fumaric acid, mandelic acid, glutaric acid, apple acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc.). Such salts can be formed by commonly performed methods.

本發明化合物或其製藥上容許的鹽有形成溶劑合物(例如，水合物等)、共晶體及/或晶體多晶型物的情形，本發明也包含如此之各種溶劑合物、共晶體及晶體多形。「溶劑合物」係相對於本發明的化合物，可以與任意數量的溶劑分子(例如，水分子等)配位。將本發明化合物或其製藥上容許的鹽在空氣中靜置，藉此，有吸收水份而附著有吸附水之情形或形成水合物之情形。再者，有將本發明化合物或其製藥上容許的鹽藉由再結晶形成晶體多形的情形。「共晶體」係指本發明之化合物或鹽與配位分子(Counter molecule)存在於同一晶體格子內，並且可與任意數量的配位分子一起形成。The compound of the present invention or its pharmaceutically acceptable salt may form a solvate (e.g., hydrate), cocrystal and/or crystal polymorph, and the present invention also includes such various solvates, cocrystals and crystal polymorphs. "Solvent" means that the compound of the present invention can coordinate with any number of solvent molecules (e.g., water molecules). The compound of the present invention or its pharmaceutically acceptable salt is left in the air, whereby it absorbs water and attaches adsorbed water or forms a hydrate. Furthermore, the compound of the present invention or its pharmaceutically acceptable salt may form a crystal polymorph by recrystallization. "Cocrystal" means that the compound or salt of the present invention and the counter molecule exist in the same crystal lattice, and can be formed with any number of counter molecules.

本發明化合物或其製藥上容許的鹽有形成前驅藥之情形，本發明也包含如此之各種前驅藥。前驅藥係具有可化學性或代謝性分解的基之本發明化合物的衍生物，並且是藉由溶劑分解或在生理條件下於生體內(in vivo)成為具有藥學活性的本發明化合物之化合物。前驅藥包含在生體內之生理條件下受到酵素氧化、還原、水解等而變換為式(I)所示之化合物的化合物、及藉由胃酸水解等而變換為式(I)所示之化合物的化合物等。選擇適當的前驅藥衍生物的方法及製造方法已記載於例如「Design of Prodrugs,Elsevier,Amsterdam,1985」。前驅藥有其本身具有活性的情形。The compounds of the present invention or their pharmaceutically acceptable salts may form prodrugs, and the present invention also includes various prodrugs. Prodrugs are derivatives of the compounds of the present invention that have a chemically or metabolically decomposable base, and are compounds that are converted into pharmaceutically active compounds of the present invention by solvent decomposition or in vivo under physiological conditions. Prodrugs include compounds that are converted into compounds represented by formula (I) by enzyme oxidation, reduction, hydrolysis, etc. under physiological conditions in the body, and compounds that are converted into compounds represented by formula (I) by gastric acid hydrolysis, etc. Methods for selecting appropriate prodrug derivatives and methods for producing them are described in, for example, "Design of Prodrugs, Elsevier, Amsterdam, 1985". Prodrugs may be active themselves.

式(I)所示之化合物或其製藥上容許的鹽具有羥基時，可例示如醯氧基衍生物、磺醯氧基衍生物之前驅藥，該前驅藥係藉由具有羥基的化合物予適當的醯基鹵化物、適當的酸酐、適當的磺醯氯、適當的磺酸酐及混合酐反應或者是使用縮合劑進行反應而製造。可列舉例如：CH₃COO-、C₂H₅COO-、tert-BuCOO-、C₁₅H₃₁COO-、PhCOO-、(m-NaOOCPh)COO-、NaOOCCH₂CH₂COO-、CH₃CH(NH₂)COO-、CH₂N(CH₃)₂COO-、CH₃SO₃-、CH₃CH₂SO₃-、CF₃SO₃-、CH₂FSO₃-、CF₃CH₂SO₃-、p-CH₃O-PhSO₃-、PhSO₃-、p-CH₃PhSO₃-。When the compound represented by formula (I) or its pharmaceutically acceptable salt has a hydroxyl group, examples thereof include acyloxy derivatives and sulfonyloxy derivatives as prodrugs, which are prepared by reacting a compound having a hydroxyl group with a suitable acyl halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable sulfonic acid anhydride or a mixed anhydride, or by reacting the compound using a condensation agent. Examples include: CH₃ COO-, C₂ H₅ COO-, tert-BuCOO-, C₁₅ H₃₁ COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH₂ CH₂ COO-, CH₃ CH(NH₂ )COO-, CH₂ N(CH₃ )₂ COO-, CH₃ SO₃ -, CH₃ CH₂ SO₃ -, CF₃ SO₃ -, CH₂ FSO₃ -, CF₃ CH₂ SO₃ -, p-CH₃ O-PhSO₃ -, PhSO₃ -, p-CH₃ PhSO₃ -.

(本發明化合物的製造方法)(Method for producing the compound of the present invention)

本發明化合物可以藉由例如下述所示之一般的合成法製造。萃取、純化等只要是可進行以藉由普通的有機化學實驗進行之處理即可。The compound of the present invention can be produced by a general synthesis method such as the one shown below. Extraction, purification, etc. can be carried out as long as they can be carried out by ordinary organic chemical experiments.

本發明之化合物係可以參考所屬技術領域中已知的方法合成。The compounds of the present invention can be synthesized by referring to methods known in the relevant technical field.

(製法1)Q為-NHC(O)-時(Preparation Method 1) When Q is -NHC(O)-

(式中，P¹係羥基保護基；P²係胺基保護基；R及R'係羧基保護基；Z¹係CR^5aR^5b或CR^8aR^8b；m係2至3的整數，m為2時，-(Z)₂-係-(CR^7aR^7b-CR^6aR^6b)-，m為3時，-(Z)₃-係-(CR^11aR^11b-CR^10aR^10b-CR^9aR^9b)-、或-(CR^11aR^11b-CR^10aR^10b-O)-；Hal係鹵素；P¹、P²、R及R'係只要是可利用記載於Protective Groups in Organic Synthesis、Theodora W Greene(John Wiley & Sons)等中的方法而保護及/或去保護的基即可，例如，P¹係芳香族碳環烷基等，P²係烷氧基羰基等，R及R'係烷基等；其它的記號與前述相同意義)(wherein,^P1 is a hydroxyl protecting group;^P2 is an amine protecting group; R^and R' are carboxyl protecting groups;^Z1 is^CR5aR5b or^CR8aR8b ; m is an integer from 2 to³ , when m is 2, -(Z)_2- is -(^CR7aR7b -^CR6aR6b )-, when m is³ , -(Z)^3-_is -(^CR11aR11b -^CR10aR10b -^CR9aR9b )-, or -(^{CR11aR11b-CR10aR10b-O} )-; Hal is^a halogen;^P1 ,^P2 , R and R' are any of the following as long as they are available and recorded in Protective Groups in Organic Synthesis, Theodora W Greene (John Wiley & Sons)^, Sons) etc., for example,^P1 is an aromatic carbocyclic alkyl group,^P2 is an alkoxycarbonyl group, R and R' are alkyl groups, and other symbols have the same meanings as above.)

步驟1Step 1

將市售或可藉由已知的方法調製的化合物a添附於羧基保護基的一般去保護反應中，藉此，可以獲得化合物a1。Compound a1 can be obtained by attaching a commercially available compound a or a compound a prepared by a known method to a general deprotection reaction of a carboxyl protecting group.

步驟2Step 2

在DMF、DMA、NMP、THF、氯仿、二氯甲烷等溶劑存在下，於化合物a1中添加HATU、WSC‧HCl、PyBOP等縮合劑，再添加市售或可藉由已知的方法調製的化合物a2及三乙胺、N-甲基

啉、吡啶、DIEA等3級胺，在10℃至60℃，較佳為在20℃至40℃，反應0.1小時至24小時，較佳為1小時至12小時，藉此，可以獲得化合物a3。In the presence of a solvent such as DMF, DMA, NMP, THF, chloroform, or dichloromethane, a condensing agent such as HATU, WSC‧HCl, or PyBOP is added to compound a1, and then a commercially available compound a2 or a compound prepared by a known method and triethylamine, N-methyl

A tertiary amine such as phenoxyethylene, pyridine, or DIEA is reacted at 10 to 60°C, preferably 20 to 40°C, for 0.1 to 24 hours, preferably 1 to 12 hours, thereby obtaining compound a3.

步驟3Step 3

在THF、甲醇、乙醇、氯仿、二氯甲烷、THF等溶劑存在下，於化合物a3中添加化合物a4，在60℃至120℃，較佳為在80℃至100℃，反應0.5小時至24小時，較佳為1小時至12小時，藉此，可以獲得化合物a5。In the presence of THF, methanol, ethanol, chloroform, dichloromethane, THF and other solvents, compound a4 is added to compound a3, and the reaction is carried out at 60°C to 120°C, preferably 80°C to 100°C, for 0.5 hours to 24 hours, preferably 1 hour to 12 hours, thereby obtaining compound a5.

步驟4Step 4

將化合物a5添附於胺基保護基的一般去保護反應中，藉此，可以獲得化合物a6。Compound a5 is attached to a general deprotection reaction of an amino protecting group, thereby obtaining compound a6.

步驟5Step 5

在二氯甲烷、二氯乙烷、氯仿、甲醇、乙醇、甲苯、DMF、DMA、THF等溶劑存在下，於化合物a6中添加市售或可藉由已知的方法調製的化合物a7及乙酸、對甲苯磺酸、甲磺酸等酸，在20℃至130℃，較佳為在20℃至100℃，反應0.1小時至24小時，較佳為1小時至12小時，藉此，可以獲得化合物a8。In the presence of a solvent such as dichloromethane, dichloroethane, chloroform, methanol, ethanol, toluene, DMF, DMA, THF, etc., add a commercially available compound a7 and an acid such as acetic acid, p-toluenesulfonic acid, methanesulfonic acid, etc. to compound a6, and react at 20°C to 130°C, preferably at 20°C to 100°C, for 0.1 hour to 24 hours, preferably 1 hour to 12 hours, thereby obtaining compound a8.

步驟6Step 6

在DMF、DMA、NMP、THF等溶劑存在下，於化合物a8中添加碳酸銫或碳酸鉀等鹼及碘化鈉或碘化鉀等鹽，在0℃至60℃，較佳為在0℃至40℃，反應0.1小時至24小時，較佳為1小時至12小時，藉此，可以獲得化合物a9。In the presence of solvents such as DMF, DMA, NMP, THF, etc., add a base such as cesium carbonate or potassium carbonate and a salt such as sodium iodide or potassium iodide to compound a8, and react at 0°C to 60°C, preferably at 0°C to 40°C, for 0.1 hour to 24 hours, preferably 1 hour to 12 hours, thereby obtaining compound a9.

步驟7Step 7

化合物a9可以藉由掌性SFC分割成a10。Compound a9 can be split into a10 by chiral SFC.

步驟8Step 8

將化合物a10進行羥基保護基的一般去保護反應，藉此，可以獲得化合物Ia。Compound a10 is subjected to a general deprotection reaction of the hydroxyl protecting group, thereby obtaining compound Ia.

(製法2)(Method 2)

(式中，各記號與前述相同意義)(In the formula, each symbol has the same meaning as above)

步驟1Step 1

在DMF、DMA、NMP、THF等溶劑的存在下，於化合物a5中添加碳酸銫、碳酸鉀、三乙胺等鹼，Hal為氯時添加碘化鈉或碘化鉀等鹽，再添加市售或可藉由已知的方法調製的化合物b1，在0℃至60℃，較佳為在20℃至40℃，反應0.1小時至24小時，較佳為1小時至12小時，藉此，可以獲得化合物b2。In the presence of solvents such as DMF, DMA, NMP, and THF, add alkalis such as cesium carbonate, potassium carbonate, and triethylamine to compound a5. When Hal is chlorine, add salts such as sodium iodide or potassium iodide. Then add compound b1 which is commercially available or can be prepared by known methods. The reaction is carried out at 0°C to 60°C, preferably at 20°C to 40°C, for 0.1 hours to 24 hours, preferably 1 hour to 12 hours. In this way, compound b2 can be obtained.

步驟2Step 2

將化合物b2添附於縮醛的一般去保護反應，藉此，可以獲得化合物b3。Compound b2 is added to the general deprotection reaction of acetal to obtain compound b3.

步驟3Step 3

在二氯甲烷、二氯乙烷、氯仿、乙腈、甲醇、乙醇、甲苯、DMF、DMA、THF等溶劑的存在下，於化合物b3中添加乙酸、對甲苯磺酸、甲磺酸、三氟乙酸等酸，在20℃至130℃，較佳為80℃至120℃，反應0.1至24小時，較佳為1小時至12小時，藉此，可以獲得化合物a9。In the presence of solvents such as dichloromethane, dichloroethane, chloroform, acetonitrile, methanol, ethanol, toluene, DMF, DMA, THF, etc., add acetic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, etc. to compound b3, and react at 20°C to 130°C, preferably 80°C to 120°C, for 0.1 to 24 hours, preferably 1 hour to 12 hours, thereby obtaining compound a9.

步驟4Step 4

化合物Ia可以根據製法1的步驟7及8進行合成。Compound Ia can be synthesized according to steps 7 and 8 of preparation method 1.

(製法3)(Method 3)

(式中，各記號與前述相同意義)(In the formula, each symbol has the same meaning as above)

步驟1Step 1

在THF、甲苯等溶劑的存在下，於化合物a5中添加市售或可藉由已知的方法調製的化合物c1，再添加DEAD/PPh₃、DIAD/PPh₃、DMEAD/PPh₃、ADDP/n-Bu₃P等光延試藥(Mitsunobu)，在0℃至100℃，較佳為在20℃至80℃，反應0.1小時至24小時，較佳為1小時至12小時，藉此，可以獲得化合物c2。In the presence of a solvent such as THF or toluene, a commercially available compound c1 or a compound prepared by a known method is added to compound a5, and then a Mitsunobu reagent such as DEAD/PPh₃ , DIAD/PPh₃ , DMEAD/PPh₃ , ADDP/n-Bu₃ P is added. The reaction is carried out at 0°C to 100°C, preferably 20°C to 80°C, for 0.1 hour to 24 hours, preferably 1 hour to 12 hours, to obtain compound c2.

步驟2Step 2

將化合物c2添附於烯烴的一般氧化裂解反應，藉此，可以獲得化合物c3。例如，使用臭氧分解或K₂O₄O_4/NaIO₄等。Compound c2 can be added to an olefin by a general oxidative cleavage reaction to obtain compound c3, for example, by using ozonolysis or K₂ O₄ O_{4 /} NaIO₄ .

步驟3Step 3

將化合物c3以與製法2的步驟3相同的條件反應，藉此，可以獲得化合物a9。Compound c3 is reacted under the same conditions as step 3 of preparation method 2, thereby obtaining compound a9.

步驟4Step 4

化合物Ia可以根據製法1的步驟7和8進行合成。Compound Ia can be synthesized according to steps 7 and 8 of preparation method 1.

(製法4)(Method 4)

(式中，各記號與前述相同意義)(In the formula, each symbol has the same meaning as above)

步驟1Step 1

將化合物a5及化合物d1以與製法3的步驟1相同的條件反應，藉此，可以獲得化合物d2。Compound a5 and compound d1 are reacted under the same conditions as step 1 of preparation method 3, thereby obtaining compound d2.

步驟2Step 2

將化合物d2添附於羥基保護基的一般去保護反應，藉此，可以獲得化合物d3。Compound d2 is attached to a hydroxyl protecting group through a general deprotection reaction, thereby obtaining compound d3.

步驟3Step 3

將化合物d3進行羥基的一般氧化反應，藉此，可以獲得化合物d4。Compound d3 is subjected to a general oxidation reaction of the hydroxyl group to obtain compound d4.

步驟4Step 4

將化合物d4以與製法2的步驟3相同的條件進行反應，藉此，可以獲得化合物a9。Compound d4 is reacted under the same conditions as step 3 of preparation method 2, thereby obtaining compound a9.

步驟5Step 5

化合物Ia可以根據製法1的步驟7和8進行合成。Compound Ia can be synthesized according to steps 7 and 8 of preparation method 1.

(製法5)(Method 5)

(式中，各記號與前述相同意義)(In the formula, each symbol has the same meaning as above)

步驟1Step 1

將化合物a5和化合物e1以與製法1的步驟5相同的條件反應，藉此，可以獲得化合物e2。Compound a5 and compound e1 are reacted under the same conditions as step 5 of preparation method 1, thereby obtaining compound e2.

步驟2Step 2

在DMF、DMA、NMP、THF等溶劑的存在下，於化合物e2中添加碳酸銫或碳酸鉀等鹼，在0℃至60℃，較佳為在0℃至40℃，反應0.1小時至24小時，較佳為1小時至12小時，藉此，可以獲得化合物e3。In the presence of solvents such as DMF, DMA, NMP, THF, etc., add a base such as cesium carbonate or potassium carbonate to compound e2, and react at 0°C to 60°C, preferably at 0°C to 40°C, for 0.1 hours to 24 hours, preferably 1 hour to 12 hours, thereby obtaining compound e3.

步驟3Step 3

進行羥基保護基的一般去保護反應，藉此，可以獲得化合物e4。A general deprotection reaction of the hydroxyl protecting group is performed to obtain compound e4.

步驟4Step 4

在THF、甲苯等的溶劑存在下，於化合物e4中添加DEAD/PPh₃、DIAD/PPh₃、DMEAD/PPh₃、ADDP/n-Bu₃P等光延試藥(Mitsunobu)，在0℃至100℃，較佳為在0℃至80℃，反應1小時至24小時，較佳為1小時至12小時，藉此，可以獲得化合物a9。In the presence of a solvent such as THF or toluene, a Mitsunobu reagent such as DEAD/PPh₃ , DIAD/PPh₃ , DMEAD/PPh₃ , ADDP/n-Bu₃ P or the like is added to compound e4 and reacted at 0 to 100°C, preferably 0 to 80°C, for 1 to 24 hours, preferably 1 to 12 hours to obtain compound a9.

步驟5Step 5

化合物Ia可以根據製法1的步驟7和8進行合成。Compound Ia can be synthesized according to steps 7 and 8 of preparation method 1.

(製法6)Q為5員的芳香族雜環時(Preparation Method 6) When Q is a 5-membered aromatic heterocyclic ring

(其中，Q為5員芳香雜環；其它的記號與前述相同意義)(Wherein, Q is a 5-membered aromatic heterocyclic ring; other symbols have the same meaning as above)

步驟1Step 1

在DMF、DMA、NMP、THF、氯仿、二氯甲烷等溶劑的存在下，故市售或可藉由已知的方法調製的化合物f中添加HATU、WSC‧HCl、PyBOP等縮合劑，再添加市售或可藉由已知的方法調製的化合物a4及三乙胺、N-甲基

啉、吡啶、二異丙基乙胺等3級胺，在10℃至60℃，較佳為在20℃至40℃，反應0.1小時至24小時，較佳為1小時至12小時，藉此，可以獲得化合物f1。In the presence of a solvent such as DMF, DMA, NMP, THF, chloroform, or dichloromethane, a condensing agent such as HATU, WSC‧HCl, or PyBOP is added to a commercially available or known compound f, and then a commercially available or known compound a4 and triethylamine, N-methyl

A tertiary amine such as quinoline, pyridine, or diisopropylethylamine is reacted at 10 to 60°C, preferably 20 to 40°C, for 0.1 to 24 hours, preferably 1 to 12 hours, thereby obtaining compound f1.

步驟2Step 2

在DMF、DMA、NMP等溶劑的存在下，於化合物f1中添加市售或可藉由已知的方法調製的化合物f2及乙酸、對甲苯磺酸吡啶鎓、對甲苯磺酸、甲磺酸等酸，在20℃至120℃，較佳為在60℃至100℃，反應0.1小時至24小時，較佳為1小時至12小時，藉此，可以獲得化合物f3。In the presence of solvents such as DMF, DMA, and NMP, compound f2, which is commercially available or can be prepared by known methods, and acids such as acetic acid, pyridinium p-toluenesulfonate, p-toluenesulfonic acid, and methanesulfonic acid are added to compound f1, and the reaction is carried out at 20°C to 120°C, preferably at 60°C to 100°C, for 0.1 hour to 24 hours, preferably 1 hour to 12 hours, thereby obtaining compound f3.

步驟3Step 3

將化合物f3添附於胺基保護基的已知的一般去保護反應，藉此，可以獲得化合物f4。Compound f3 is attached to an amino protecting group through a known general deprotection reaction, thereby obtaining compound f4.

步驟4Step 4

將化合物f4以與製法1至5中記載的方法相同的條件進行反應，藉此，可以獲得化合物f5。Compound f4 is reacted under the same conditions as those described in Preparation Methods 1 to 5, thereby obtaining compound f5.

步驟5Step 5

在二氯甲烷、二氯乙烷、乙腈或DMF等溶劑中，於化合物f5中添加溴、NBS、NCS、NIS等鹵化試劑，Hal為溴時，在-30℃至50℃，較佳為在-10℃至20℃，反應0.1小時至10小時，較佳為0.5小時至2小時，藉此，可以獲得化合物f6。Hal為氯或碘時，在10℃至150℃，較佳為在60℃至120℃，反應0.5小時至24小時，較佳為1小時至6小時，藉此，可以獲得化合物f6。In a solvent such as dichloromethane, dichloroethane, acetonitrile or DMF, add bromine, NBS, NCS, NIS and other halogenating reagents to compound f5. When Hal is bromine, the reaction is carried out at -30°C to 50°C, preferably at -10°C to 20°C, for 0.1 to 10 hours, preferably 0.5 to 2 hours, thereby obtaining compound f6. When Hal is chlorine or iodine, the reaction is carried out at 10°C to 150°C, preferably at 60°C to 120°C, for 0.5 to 24 hours, preferably 1 to 6 hours, thereby obtaining compound f6.

步驟7Step 7

在二

、DMF、DME、THF、DMSO等溶劑或混合溶劑中，於化合物f6中添加Pd(PPh₃)₄、Pd(OAc)₂、Pd(PPh₃)₂Cl₂、Pd(dppf)₂Cl₂或Pd(dtbpf)等鈀催化劑；乙酸鉀、乙酸鈉、碳酸鉀或磷酸鉀等鹼；及雙聯(頻哪醇)硼酸酯(Bis(pinacolato)diboron)，在氮環境下，在0℃至150℃，較佳為在60℃至120℃，反應0.5小時至24小時，較佳為1小時至12小時，藉此，可以獲得化合物f7。In the second

A palladium catalyst such as Pd(PPh₃ )₄ , Pd(OAc)₂ , Pd(PPh₃ )₂ Cl₂ , Pd(dppf)₂ Cl₂ or Pd(dtbpf); a base such as potassium acetate, sodium acetate, potassium carbonate or potassium phosphate; and bis(pinacolato)diboron are added to compound f6 in a solvent such as DMF, DME, THF, DMSO or a mixed solvent, and the reaction is carried out at 0° C. to 150° C., preferably at 60° C. to 120° C., for 0.5 to 24 hours, preferably 1 to 12 hours, under a nitrogen environment to obtain compound f7.

步驟8Step 8

在二

、DMF、DME、THF、水等溶劑或混合溶劑中，於化合物f7中添加Pd(PPh₃)₄、Pd(OAc)₂、Pd(PPh₃)₂Cl₂、Pd(dppf)₂或Pd(dtbpf)等鈀催化劑；碳酸鉀、碳酸鈉、碳酸銫或磷酸鉀等鹼；及市售或藉由已知的方法調製的化合物f8，在氮環境中，在0℃至150℃，較佳為在60℃至120℃，反應0.5小時至24小時，較佳為1小時至12小時，藉此，可以獲得化合物f9。In the second

A palladium catalyst such as Pd(PPh₃ )₄ , Pd(OAc)₂ , Pd(PPh₃ )₂ Cl₂ , Pd(dppf)₂ or Pd(dtbpf); a base such as potassium carbonate, sodium carbonate, cesium carbonate or potassium phosphate; and a commercially available compound f8 prepared by a known method are added to compound f7 in a solvent such as DMF, DME, THF, water or a mixed solvent, and the reaction is carried out at 0° C. to 150° C., preferably at 60° C. to 120° C., for 0.5 hour to 24 hours, preferably 1 hour to 12 hours in a nitrogen environment to obtain compound f9.

步驟9Step 9

化合物Ib可以根據製法1的步驟7及8進行合成。Compound Ib can be synthesized according to steps 7 and 8 of preparation method 1.

(製法7)(Method 7)

(式中，各記號與前述相同意義)(In the formula, each symbol has the same meaning as above)

步驟1Step 1

在二氯甲烷、二氯乙烷、氯仿、DMF、DMA、NMP、THF等溶劑的存在下，於化合物g中添加三乙胺或二異丙基乙胺等鹼及氯甲酸乙酯等製成醯氯後，再添加市售或可藉由已知的方法調製的化合物g1，在0℃至60℃，較佳為在0℃至20℃下，反應0.1小時至24小時，較佳為1小時至12小時，藉此，可以獲得化合物g2。In the presence of solvents such as dichloromethane, dichloroethane, chloroform, DMF, DMA, NMP, THF, etc., add a base such as triethylamine or diisopropylethylamine and ethyl chloroformate to compound g to prepare acyl chloride, then add compound g1 which is commercially available or can be prepared by a known method, and react at 0°C to 60°C, preferably at 0°C to 20°C, for 0.1 hour to 24 hours, preferably 1 hour to 12 hours, thereby obtaining compound g2.

步驟2Step 2

在乙酸乙酯、二氯甲烷、二氯乙烷、氯仿、二

、DMF、DMA、THF等溶劑的存在下，使化合物g2與T3P、三氟乙酸、磷酸、鹽酸、硫酸、氫溴酸等酸作用，在20℃至130℃，較佳為60℃至100℃，反應0.1小時至24小時，較佳為1小時至12小時，藉此，可以獲得化合物g3。In ethyl acetate, dichloromethane, dichloroethane, chloroform,

In the presence of a solvent such as DMF, DMA, THF, etc., compound g2 is reacted with an acid such as T3P, trifluoroacetic acid, phosphoric acid, hydrochloric acid, sulfuric acid, hydrobromic acid, etc. at 20°C to 130°C, preferably 60°C to 100°C, for 0.1 hour to 24 hours, preferably 1 hour to 12 hours, thereby obtaining compound g3.

步驟3Step 3

化合物Ic可以根據製法1的步驟7和8進行合成。Compound Ic can be synthesized according to steps 7 and 8 of preparation method 1.

可以進一步化學修飾上述所得的本發明化合物而合成其他化合物。再者，在上反應中，在側鏈部分等中存在反應性官能基(例如，OH、COOH、NH₂)時，可因應所需在反應前保護，也可以在反應後去保護。The compound of the present invention obtained above can be further chemically modified to synthesize other compounds. In the above reaction, when a reactive functional group (e.g., OH, COOH, NH₂ ) exists in the side chain part, it can be protected before the reaction or deprotected after the reaction as required.

保護基(胺基保護基、羥基保護基等)可列舉例如：乙氧基羰基、第三丁氧基羰基、乙醯基、苄基等記載於有機合成中的保護基(Protective Groups in Organic Synthesis)，T.W.Green著，John Wiley & Sons Inc.(1991)等中的保護基。保護基的導入及脫離方法可利用有機合成化學中常用的方法[例如，參見有機合成中的保護基(Protective Groups in Organic Synthesis)，T.W.Greene著，John Wiley & Sons Inc.(1991)]等中記載的方法或依據該等所得。再者，各取代基中包含的官能基的變換可除了上述製法以外亦可藉由已知的方法[例如，綜合有機轉換(Comprehensive Organic Transformations)，R.C.Larock著(1989)等]進行，本發明之化合物中也有將此作為合成中間物而可進一步轉化為新衍生物者。上述各製造法中的中間物及目的化合物可利用有機合成化學中常用的純化法，例如，可添附於中和、過濾、萃取、洗淨、乾燥、濃縮、再結晶、各種層析等而單離精製。再者，中間物亦可以不特別純化而提供於後續反應中。Examples of the protecting group (amino protecting group, hydroxy protecting group, etc.) include ethoxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl, etc., which are described in Protective Groups in Organic Synthesis, written by T.W.Greene, John Wiley & Sons Inc. (1991), etc. The method for introducing and removing the protecting group can be the method commonly used in organic synthetic chemistry [for example, see Protective Groups in Organic Synthesis, written by T.W.Greene, John Wiley & Sons Inc. (1991)] or the method described therein. Furthermore, the transformation of the functional groups contained in each substituent can be carried out by known methods other than the above-mentioned preparation methods [e.g., Comprehensive Organic Transformations, R.C.Larock (1989), etc.], and some of the compounds of the present invention can be further transformed into new derivatives by using them as synthetic intermediates. The intermediates and target compounds in the above-mentioned preparation methods can be purified by commonly used purification methods in organic synthetic chemistry, for example, by neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, etc. for isolation and purification. Furthermore, the intermediates can also be provided in subsequent reactions without special purification.

本發明化合物作為例如抗病毒藥等醫藥有用。本發明化合物對病毒的整合酶具有顯著的抑制作用。因此，可期待本發明化合物對於起因於在動物細胞內感染時至少產生整合酶的病毒所引起的各種疾病具有預防或治療效果，例如，可用作為針對反轉錄病毒(例如，HIV-1、HIV-2、HTLV-1、SIV、FIV等)的整合酶抑制劑，且可用作為抗HIV藥。再佳的化合物，就體內動態而言，具有如血中濃度高、效果的持續時間長、及/或組織轉移性顯著等特徵。再者，較佳的化合物就副作用(例如，對於CYP酵素的抑制、致突變性、心電圖QT間隔延長、心律不整)之觀點而言係安全的。The compounds of the present invention are useful as medicines such as antiviral drugs. The compounds of the present invention have a significant inhibitory effect on viral integrase. Therefore, it is expected that the compounds of the present invention have preventive or therapeutic effects on various diseases caused by viruses that produce at least integrase when infecting animal cells. For example, they can be used as integrase inhibitors against retroviruses (e.g., HIV-1, HIV-2, HTLV-1, SIV, FIV, etc.) and can be used as anti-HIV drugs. More preferred compounds have characteristics such as high blood concentration, long duration of effect, and/or significant tissue metastasis in terms of in vivo dynamics. Furthermore, the preferred compounds are safe from the perspective of side effects (e.g., inhibition of CYP enzymes, mutagenicity, prolonged QT interval of electrocardiogram, arrhythmia).

再者，本發明化合物還可使用於與反轉錄酵素抑制劑、蛋白酶抑制劑、及/或侵入抑制劑等具有不同作用機制的抗HIV藥組合的併用療法中。Furthermore, the compounds of the present invention can also be used in combination therapy with anti-HIV drugs with different mechanisms of action, such as reverse transcriptase inhibitors, protease inhibitors, and/or entry inhibitors.

進一步，就上述用途而言，不僅可作為抗HIV用合劑，還包含作為如雞尾酒療法等使其他抗HIV藥的抗HIV活性上升的併用劑之用途。Furthermore, the above-mentioned uses include not only being used as a combination agent for anti-HIV, but also being used as a concomitant agent to increase the anti-HIV activity of other anti-HIV drugs, such as in cocktail therapy.

再者，本發明化合物在基因治療領域中，使用基於HIV或MLV的反轉錄病毒載體時，也可以為了防止反轉錄病毒載體的感染擴散至標靶組織之外而使用。特別是，在試管中使細胞等感染載體再返回體內時，若事先投予本發明化合物，則可以防止體內不必要的感染。Furthermore, the compounds of the present invention can also be used in the field of gene therapy to prevent the infection of the retroviral vector from spreading outside the target tissue when using retroviral vectors based on HIV or MLV. In particular, when the infection vectors such as cells in a test tube are returned to the body, if the compounds of the present invention are administered in advance, unnecessary infection in the body can be prevented.

本發明之醫藥組成物可利用經口的、非經口的任一種方法投予。非經口投予的方法可列舉：經皮、皮下、靜脈內、動脈內、肌肉內、腹腔內、經黏膜、吸入、經鼻、滴眼、滴耳、陰道內投予等。The pharmaceutical composition of the present invention can be administered by any method, oral or non-oral. Non-oral administration methods include: transdermal, subcutaneous, intravenous, intra-arterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drops, ear drops, vaginal administration, etc.

在經口投予時，只要是根據常規方法調製成內用固形製劑(例如，錠劑、粉劑、顆粒劑、膠囊劑、丸劑、膜劑等)、內用液劑(例如，懸浮劑、乳劑、酏劑、糖漿、檸檬劑、酒精劑、芳香水劑、萃取劑、煎劑、酊劑等)等通常使用的任何劑型進行投予即可。錠劑可以是糖衣錠、膜包衣錠、腸溶性包衣錠、緩釋錠、錠劑錠、舌下錠、口含錠、咀嚼錠或口腔內崩解錠，粉劑及顆粒劑可以是乾糖漿，膠囊可以是軟膠囊、微膠囊或緩釋性膠囊。In the case of oral administration, any commonly used dosage form such as solid preparations for internal use (e.g., tablets, powders, granules, capsules, pills, films, etc.) or liquid preparations for internal use (e.g., suspensions, emulsions, elixirs, syrups, lemonades, alcohols, aromatic waters, extracts, decoctions, tinctures, etc.) prepared according to conventional methods may be used for administration. Tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets or orally disintegrating tablets; powders and granules may be dry syrups; capsules may be soft capsules, microcapsules or sustained-release capsules.

在非經口投予時，可適當地投予注射劑、點滴劑、外用劑(例如，滴眼劑、滴鼻劑、滴耳劑、氣溶膠劑、吸入劑、乳液劑、注入劑、塗布劑、含漱劑、洗腸劑、軟膏劑、硬膏劑、果凍劑、乳膏劑、貼附劑、泥罨劑、外用粉劑、栓劑等)等通常使用的任何劑型。注入劑可以是O/W、W/O、O/W/O、W/O/W型等的乳劑。When administered parenterally, any commonly used dosage form such as injection, drip, external preparation (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, emulsions, injections, ointments, gargles, enema, ointments, plasters, jellies, creams, patches, poultices, external powders, suppositories, etc.) can be appropriately administered. Injections can be emulsions of O/W, W/O, O/W/O, W/O/W type, etc.

在本發明化合物的有效量中因應所需混合適合於其劑型的賦形劑、結合劑、崩解劑、潤滑劑等各種醫藥用添加劑，而製成醫藥組成物。再者，藉由適當地變更本發明化合物的有效量、劑型及/或各種醫藥添加劑，而可作為作為兒童用、高齡者用、重症患者用或手術用的醫藥組成物。例如，兒童用醫藥組成物可對新生兒(出生後未滿4週)、嬰兒(出生後4周至未滿1歲)、幼兒(1歲以上且未滿7歲)、兒童(7歲以上且未滿15歲)或15至18歲的患者進行投予。例如，高齡者用醫藥組成物可對65歲以上的患者進行投予。The effective amount of the compound of the present invention is mixed with various pharmaceutical additives such as a formulation, a binder, a disintegrant, a lubricant, etc. suitable for the dosage form as needed to prepare a pharmaceutical composition. Furthermore, by appropriately changing the effective amount, dosage form and/or various pharmaceutical additives of the compound of the present invention, it can be used as a pharmaceutical composition for children, the elderly, critically ill patients or surgery. For example, the pharmaceutical composition for children can be administered to newborns (less than 4 weeks after birth), infants (4 weeks after birth to less than 1 year old), toddlers (over 1 year old and under 7 years old), children (over 7 years old and under 15 years old) or patients aged 15 to 18. For example, a pharmaceutical composition for the elderly can be administered to patients over 65 years of age.

本發明之醫藥組成物投予量係提望考量患者的年齡、體重、疾病的種類或程度、投予途徑而設定，但在經口投予時通常為0.05至100mg/kg/日，較佳為0.1至10mg/kg/日的範圍內。在非經口投予時依據投予途徑有很大的差異，但通常為0.005至10mg/kg/日，較佳為0.01至1mg/kg/日的範圍內。該醫藥組成物可以一日一次至一個月一次或三個月一次進行投予。The dosage of the pharmaceutical composition of the present invention is set in consideration of the patient's age, weight, type or degree of disease, and route of administration, but is usually in the range of 0.05 to 100 mg/kg/day, preferably 0.1 to 10 mg/kg/day when administered orally. There is a great difference in parenteral administration depending on the route of administration, but it is usually in the range of 0.005 to 10 mg/kg/day, preferably 0.01 to 1 mg/kg/day. The pharmaceutical composition can be administered once a day to once a month or once every three months.

[實施例][Implementation example]

實施例係如下所示。The implementation example is as follows.

(縮寫)(Abbreviation)

ADDP：1,1’-(偶氮二羰基)二哌

ADDP: 1,1'-(azodicarbonyl)dipiperidin

Bn：苄基Bn: benzyl

DEAD：偶氮二羧酸二乙酯DEAD: diethyl azodicarboxylate

DIAD：偶氮二羧酸二異丙酯DIAD: diisopropyl azodicarboxylate

DIEA：N,N-二異丙基乙胺DIEA: N,N-diisopropylethylamine

DMA：二甲基乙醯胺DMA: dimethylacetamide

DME：二甲氧基乙烷DME: dimethoxyethane

DMEAD：偶氮二羧酸二-2-甲氧基乙酯DMEAD: di-2-methoxyethyl azodicarboxylate

DMF：二甲基甲醯胺DMF: dimethylformamide

DMSO：二甲基亞碸DMSO: dimethyl sulfoxide

HATU：O-(7-氮雜苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸鹽HATU: O-(7-nitrobenzotriazole-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate

NBS：N-溴琥珀醯亞胺NBS: N-bromosuccinimide

NCS：N-氯琥珀醯亞胺NCS: N-chlorosuccinimide

NIS：N-碘琥珀醯亞胺NIS: N-iodosuccinimide

NMP：N-甲基吡咯烷酮NMP: N-methylpyrrolidone

PyBOP：六氟磷酸(苯并三唑-1-基氧基)三吡咯烷基鏻PyBOP: (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate

TBAF：四丁基氟化銨TBAF: Tetrabutylammonium fluoride

THF：四氫呋喃THF: Tetrahydrofuran

WSC‧HCl：1-乙基-3-(3-二甲基胺基丙基)碳二亞胺鹽酸鹽WSC‧HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

各實施例中所得的NMR分析係以300MHz或400MHz進行，並使用DMSO-d₆和CDCl₃測定。再者，顯示NMR數據時，存在未記載所有測定的測量峰的情形。The NMR analysis obtained in each example was performed at 300 MHz or 400 MHz using DMSO-d₆ and CDCl_3. In addition, when NMR data are shown, not all measured peaks may be shown.

在實施例中，「No.」係表示化合物編號，「Structure」係表示化學結構，「MS」係表示LC/MS(液相層析/質譜)中的分子量。In the examples, "No." refers to the compound number, "Structure" refers to the chemical structure, and "MS" refers to the molecular weight in LC/MS (liquid chromatography/mass spectrometry).

(測量條件)(Measurement conditions)

(A)管柱：ACQUITY UPLC(註冊商標)BEH C18(1.7μm i.d.2.1x 50mm)(waters)(A) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7μm i.d. 2.1x 50mm) (waters)

流速：0.8mL/分鐘；UV檢測波長：254nm；Flow rate: 0.8mL/min; UV detection wavelength: 254nm;

移動相：[A]係含有0.1%甲酸的水溶液，[B]係含有0.1%甲酸的乙腈溶液Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid

進行5%至100%溶劑[B]的線性梯度3.5分鐘後，維持100%溶劑[B]0.5分鐘。A linear gradient from 5% to 100% solvent [B] was performed for 3.5 minutes, and then 100% solvent [B] was maintained for 0.5 minutes.

(B)管柱：Shim-pack XR-ODS(2.2μm,i.d.50 x 3.0mm)(Shimadzu)(B) Column: Shim-pack XR-ODS (2.2μm, i.d.50 x 3.0mm) (Shimadzu)

流速：1.6mL/分鐘；UV檢測波長：254nm；Flow rate: 1.6mL/min; UV detection wavelength: 254nm;

移動相：[A]係含有0.1%甲酸的水溶液，[B]係含有0.1%甲酸的乙腈溶液Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid

梯度：進行10%至100%溶劑[B]的線性梯度3分鐘，維持100%溶劑[B]0.5分鐘。Gradient: Perform a linear gradient from 10% to 100% solvent [B] for 3 minutes, and maintain 100% solvent [B] for 0.5 minutes.

(C)管柱：Shim-pack XR-ODS(2.2μm,i.d.50 x 3.0mm)(Shimadzu)(C) Column: Shim-pack XR-ODS (2.2μm, i.d.50 x 3.0mm) (Shimadzu)

流速：1.6mL/分鐘；UV檢測波長：254nm；Flow rate: 1.6mL/min; UV detection wavelength: 254nm;

移動相：[A]係含有0.1%甲酸的水溶液，[B]係含有0.1%甲酸的乙腈溶液Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid

梯度：進行10%-100%溶劑[B]的線性梯度8分鐘，維持100%溶劑[B]0.5分鐘。Gradient: A linear gradient of 10%-100% solvent [B] was performed for 8 minutes, and 100% solvent [B] was maintained for 0.5 minutes.

實施例1Example 1

步驟1Step 1

於化合物1中(1.50g，3.59mmol)添加2mol/L乙胺的甲醇溶液(17.9ml，35.9mmol)，在微波照射下，以100℃攪拌1小時。將反應液的溶劑減壓餾除後，添加稀鹽酸成為酸性，並用乙酸乙酯萃取。用硫酸鈉乾燥有機層後，餾除溶劑。所得之殘渣藉由矽膠管柱層析(氯仿-甲醇)精製，得到化合物2(1.15g，產率74%)。Add 2 mol/L ethylamine methanol solution (17.9 ml, 35.9 mmol) to compound 1 (1.50 g, 3.59 mmol), and stir at 100 ° C for 1 hour under microwave irradiation. After the solvent in the reaction solution was distilled off under reduced pressure, dilute hydrochloric acid was added to make it acidic, and extracted with ethyl acetate. After drying the organic layer with sodium sulfate, the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound 2 (1.15 g, yield 74%).

1H-NMR(CDCL₃)δ：14.53(s,1H),8.64(brs,1H),8.46(s,1H),7.37(m,5H),6.57(brs,1H),5.38(s,2H),3.24(dt,J=14.0,6.6Hz,2H),1.45(s,9H),1.02(t,J=7.3Hz,4H).1H-NMR (CDCL₃ )δ: 14.53(s,1H),8.64(brs,1H),8.46(s,1H),7.37(m,5H),6.57(brs,1H),5 .38(s,2H),3.24(dt,J=14.0,6.6Hz,2H),1.45(s,9H),1.02(t,J=7.3Hz,4H).

步驟2Step 2

使化合物2(9.59g，22.2mmol)溶解在二氯甲烷(180ml)中，添加(2,4-二氟苯基)甲胺(4.77g，33.3mmol)、PyBOP(13.9g，26.7mmol)及DIEA(11.7ml，66.7mmol)並在室溫攪拌18小時。將反應液用水和飽和食鹽水洗淨，將有機層用硫酸鈉乾燥後，餾除溶劑。所得殘渣藉由矽膠管柱層析(氯仿-甲醇)精製，得到化合物3(11.5g，產率93%)。Compound 2 (9.59 g, 22.2 mmol) was dissolved in dichloromethane (180 ml), (2,4-difluorophenyl)methylamine (4.77 g, 33.3 mmol), PyBOP (13.9 g, 26.7 mmol) and DIEA (11.7 ml, 66.7 mmol) were added and stirred at room temperature for 18 hours. The reaction solution was washed with water and saturated brine, the organic layer was dried with sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound 3 (11.5 g, yield 93%).

1H-NMR(CDCL₃)δ：10.20(t,J=5.8Hz,1H),8.54(brs,1H),8.49(s,1H),7.38(m,5H),6.87-6.79(m,2H),6.61(t,J=5.5Hz,1H),5.28(s,2H),4.64(d,J=5.9Hz,2H),3.18(ddt,J=18.8,10.2,3.8Hz,3H),1.83-1.80(m,1H),1.43(s,9H),0.99(t,J=7.3Hz,3H).1H-NMR (CDCL₃ )δ: 10.20(t,J=5.8Hz,1H),8.54(brs,1H),8.49(s,1H),7.38(m,5H),6.87-6.79(m,2H),6.61(t,J=5.5Hz,1H),5.28(s, 2H),4.64(d,J=5.9Hz,2H),3.18(ddt,J=18.8,10.2,3.8Hz,3H),1.83-1.80(m,1H),1.43(s,9H),0.99(t,J=7.3Hz,3H).

步驟3Step 3

使化合物3(11.5g，9.54mmol)溶解在二

(57.5ml)，添加4mol/L鹽酸/二

溶液(300ml)，並在室溫攪拌4小時。將反應液的溶劑減壓餾除後，添加飽和碳酸鈉水溶液，並用氯仿-甲醇萃取。將有機層用硫酸鈉乾燥後，餾除溶劑所得到的粗產物用二異丙醚固體化，得到化合物4(7.80g，產率83%)。Compound 3 (11.5 g, 9.54 mmol) was dissolved in distilled water.

(57.5 ml), add 4 mol/L hydrochloric acid/dihydrochloric acid

solution (300 ml) and stirred at room temperature for 4 hours. After the solvent in the reaction solution was distilled off under reduced pressure, a saturated sodium carbonate aqueous solution was added and extracted with chloroform-methanol. The organic layer was dried over sodium sulfate and the solvent was distilled off. The crude product obtained was solidified with diisopropyl ether to obtain compound 4 (7.80 g, yield 83%).

1H-NMR(CDCL₃)δ：10.33(s,1H),8.60(s,1H),7.39(m,5H),6.83(m,3H),5.82(s,2H),5.26(s,2H),4.64(d,J=5.8Hz,2H),3.28-3.21(m,2H),1.02(t,J=7.3Hz,3H).1H-NMR (CDCL₃ )δ: 10.33(s,1H),8.60(s,1H),7.39(m,5H),6.83(m,3H),5.82(s,2H),5.2 6(s,2H),4.64(d,J=5.8Hz,2H),3.28-3.21(m,2H),1.02(t,J=7.3Hz,3H).

步驟4Step 4

使化合物4(200mg，0.438mmol)溶解在二氯甲烷(4ml)，添加化合物5(111mg，0.920mmol)和乙酸(觸媒量)，並在室溫攪拌19小時。將反應液減壓濃縮後，藉由矽膠管柱層析(氯仿-甲醇)精製，得到化合物6(265mg，產率100%)。Compound 4 (200 mg, 0.438 mmol) was dissolved in dichloromethane (4 ml), and compound 5 (111 mg, 0.920 mmol) and acetic acid (catalyst amount) were added, and stirred at room temperature for 19 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (chloroform-methanol) to obtain compound 6 (265 mg, yield 100%).

MS：m/z=559[M+H]+MS: m/z=559[M+H]+

步驟5Step 5

使化合物6(245mg，0.438mmol)溶解在DMF(5ml)，在0℃添加碳酸銫(428mg，1.31mmol)並在室溫攪拌18小時。將稀鹽酸添加至反應溶液中，並用乙酸乙酯萃取。將有機層用水洗淨，用硫酸鈉乾燥後，餾除溶劑。所得殘渣藉由矽膠管柱層析(氯仿-甲醇)精製，得到外消旋化合物(139mg，產率60%)。Compound 6 (245 mg, 0.438 mmol) was dissolved in DMF (5 ml), cesium carbonate (428 mg, 1.31 mmol) was added at 0°C and stirred at room temperature for 18 hours. Dilute hydrochloric acid was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water, dried with sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain a racemic compound (139 mg, yield 60%).

將所得之外消旋化合物藉由SFC進行光學分割，得到化合物7。The obtained racemic compound was optically resolved by SFC to obtain compound 7.

管柱：CHIRALPAK IA/SFC(5μm,i.d.250 x 20mm)Column: CHIRALPAK IA/SFC (5μm, i.d. 250 x 20mm)

流速：30mL/分鐘Flow rate: 30mL/min

UV檢測波長：250nmUV detection wavelength: 250nm

製備條件：維持MeOH/CO₂=45/55的組成比，進行送液21分鐘。Preparation conditions: maintaining a composition ratio of MeOH/CO₂ = 45/55, and delivering the solution for 21 minutes.

1H-NMR(CDCL₃)δ：10.46(s,1H),8.51(s,1H),7.58(m,2H),7.34(m,4H),6.81(m,2H),5.41(d,J=10.4Hz,1H),5.26(d,J=10.4Hz,1H),4.91(s,1H),4.64(m,2H),4.39(dd,J=14.3,7.2Hz,1H),3.18-2.88(m,3H),2.24(d,J=14.7Hz,1H),2.00(m,1H),1.85(m,2H),1.72(d,J=13.6Hz,1H),1.38(m,1H),1.16(t,J=7.1Hz,3H).1H-NMR (CDCL₃ )δ: 10.46(s,1H),8.51(s,1H),7.58(m,2H),7.34(m,4H),6.81(m,2H),5.41 (d,J=10.4Hz,1H),5.26(d,J=10.4Hz,1H),4.91(s,1H),4.64(m,2H),4.39(d d,J=14.3,7.2Hz,1H),3.18-2.88(m,3H),2.24(d,J=14.7Hz,1H),2.00(m,1 H),1.85(m,2H),1.72(d,J=13.6Hz,1H),1.38(m,1H),1.16(t,J=7.1Hz,3H).

步驟6Step 6

使化合物7(44.0mg，0.0840mmol)溶解在DMF(0.88ml)，添加氯化鋰(35.7mg，0.842mmol)，在90℃攪拌1.5小時。將水添加至反應液中，利用10%檸檬酸水溶液成為酸性，並用乙酸乙酯萃取。將有機層用水洗淨，用硫酸鈉乾燥後，餾除溶劑。所得到的粗產物用乙醚固體化，得到化合物I-23(19mg，產率52%)。Compound 7 (44.0 mg, 0.0840 mmol) was dissolved in DMF (0.88 ml), lithium chloride (35.7 mg, 0.842 mmol) was added, and the mixture was stirred at 90°C for 1.5 hours. Water was added to the reaction solution, and the solution was acidified with 10% citric acid aqueous solution, and extracted with ethyl acetate. The organic layer was washed with water, dried with sodium sulfate, and the solvent was distilled off. The obtained crude product was solidified with diethyl ether to obtain compound I-23 (19 mg, yield 52%).

1H-NMR(CDCl₃)δ：11.98(s,1H),10.42(s,1H),8.46(s,1H),7.36(dd,J=15.2,8.6Hz,1H),6.83-6.77(m,2H)),5.06(s,1H),4.64(m,2H),4.35(td,J=14.2,6.9Hz,1H),3.20-3.09(m,2H),3.00(d,J=10.8Hz,1H),2.31(d,J=15.4Hz,1H),2.06(m,1H),1.89(m,2H),1.76(m,1H),1.42-1.36(m,1H),1.24(t,J=7.1Hz,4H).1H-NMR (CDCl₃ )δ: 11.98(s,1H),10.42(s,1H),8.46(s,1H),7.36(dd,J=15.2,8.6Hz,1H) ,6.83-6.77(m,2H)),5.06(s,1H),4.64(m,2H),4.35(td,J=14.2,6.9Hz,1H ),3.20-3.09(m,2H),3.00(d,J=10.8Hz,1H),2.31(d,J=15.4Hz,1H),2.06( m,1H),1.89(m,2H),1.76(m,1H),1.42-1.36(m,1H),1.24(t,J=7.1Hz,4H).

實施例2Example 2

步驟1Step 1

在氮環境下，在鎂(322mg，13.3mmol)的THF(3.0mL)溶液中滴入化合物8(1.3mL，11.1mmol)的THF(7.0mL)溶液，在室溫攪拌30分鐘。將反應液冷卻至0℃，添加碘化銅(210mg，1.1mmol)，滴下化合物9(1.2mL，16.6mmol)的THF(6.0mL)溶液，升溫至室溫並攪拌2小時。將飽和氯化銨水溶液添加至反應溶液中，並用乙酸乙酯萃取。將有機層用飽和食鹽水洗淨，用無水硫酸鈉乾燥後，餾除溶劑。所得之殘渣藉由矽膠管柱層析(己烷-乙酸乙酯)精製，得到化合物10(192mg，產率11%)。Under nitrogen atmosphere, a solution of compound 8 (1.3 mL, 11.1 mmol) in THF (7.0 mL) was added dropwise to a solution of magnesium (322 mg, 13.3 mmol) in THF (3.0 mL), and stirred at room temperature for 30 minutes. The reaction solution was cooled to 0°C, copper iodide (210 mg, 1.1 mmol) was added, and a solution of compound 9 (1.2 mL, 16.6 mmol) in THF (6.0 mL) was added dropwise, and the mixture was heated to room temperature and stirred for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 10 (192 mg, yield 11%).

1H-NMR(CDCl₃)δ：4.86(t,J=4.8Hz,1H),3.99-3.96(m,2H),3.90-3.79(m,3H),1.72-1.67(m,2H),1.55-1.48(m,4H),1.36(d,J=4.5Hz,1H),1.20(d,J=6.3Hz,3H).1H-NMR (CDCl₃ )δ: 4.86(t,J=4.8Hz,1H),3.99-3.96(m,2H),3.90-3.79(m,3H),1.72-1.6 7(m,2H),1.55-1.48(m,4H),1.36(d,J=4.5Hz,1H),1.20(d,J=6.3Hz,3H).

步驟2Step 2

在化合物11(334mg，0.60mmol)的THF(2.0mL)溶液中，添加化合物10(192.2mg，1.2mmol)、三苯膦(315mg，1.2mmol)及偶氮二羧酸雙(2-甲氧基乙基酯)(281mg，1.0mmol)並在室溫攪拌1小時。將水添加至反應液中，並用乙酸乙酯萃取。將有機層用飽和食鹽水洗淨，用無水硫酸鈉乾燥後，餾除溶劑。所得之殘渣藉由矽膠管柱層析(己烷-乙酸乙酯)粗精製。Compound 10 (192.2 mg, 1.2 mmol), triphenylphosphine (315 mg, 1.2 mmol) and azodicarboxylic acid bis(2-methoxyethyl ester) (281 mg, 1.0 mmol) were added to a THF (2.0 mL) solution of compound 11 (334 mg, 0.60 mmol) and stirred at room temperature for 1 hour. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was crudely purified by silica gel column chromatography (hexane-ethyl acetate).

MS：m/z=699[M+H]+MS: m/z=699[M+H]+

步驟3Step 3

在步驟2所得的粗精製物(100mg)的乙腈(1.0mL)溶液中，添加對甲苯磺酸水合物(45.1mg，0.242mmol)，並加熱回流210分鐘。將反應液冷卻至室溫，添加飽和碳酸氫鈉水溶液，並用乙酸乙酯萃取。將有機層用飽和食鹽水洗淨，用無水硫酸鈉乾燥後，餾除溶劑。使所得殘渣溶解在DMF(1.0mL)中，添加碳酸銫(140mg，0.43mmol)及苄基溴(34.1μL，0.29mmol)並在室溫攪拌3小時。將水添加至反應液中，並用乙酸乙酯萃取。將有機層用飽和食鹽水洗淨，用無水硫酸鈉乾燥後，餾除溶劑。所得之殘渣藉由矽膠管柱層析(氯仿-甲醇)精製，得到化合物13(65.1mg)。To a solution of the crude product (100 mg) obtained in step 2 in acetonitrile (1.0 mL), p-toluenesulfonic acid hydrate (45.1 mg, 0.242 mmol) was added, and the mixture was heated to reflux for 210 minutes. The reaction solution was cooled to room temperature, a saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by distillation. The resulting residue was dissolved in DMF (1.0 mL), cesium carbonate (140 mg, 0.43 mmol) and benzyl bromide (34.1 μL, 0.29 mmol) were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound 13 (65.1 mg).

MS：m/z=537[M+H]+MS: m/z=537[M+H]+

步驟4Step 4

進行與實施例1的步驟6相同的反應，得到化合物I-31(31mg，產率57%)。The same reaction as step 6 of Example 1 was carried out to obtain compound I-31 (31 mg, yield 57%).

1H-NMR(CDCl₃)δ：11.93(s,1H),10.40(s,1H),8.39(s,1H),7.40-7.34(m,1H),6.84-6.77(m,2H),511-5.09(m,1H),4.64(d,J=5.8Hz,2H),4.40-4.31(m,1H),3.27-3.21(m,1H),3.13-3.06(m,1H),2.32-2.28(m,1H),2.12-2.04(m,1H),1.86-1.83(m,1H),1.79-1.75(m,1H),1.63-1,48(m,2H),1.21(t,J=7.2Hz,3H),0.89(d,J=6.3Hz,3H).1H-NMR (CDCl₃ )δ: 11.93(s,1H),10.40(s,1H),8.39(s,1H),7.40-7.34(m,1H),6.84-6.77(m,2 H),511-5.09(m,1H),4.64(d,J=5.8Hz,2H),4.40-4.31(m,1H),3.27-3.21(m,1H) ,3.13-3.06(m,1H),2.32-2.28(m,1H),2.12-2.04(m,1H),1.86-1.83(m,1H),1. 79-1.75(m,1H),1.63-1,48(m,2H),1.21(t,J=7.2Hz,3H),0.89(d,J=6.3Hz,3H).

實施例3Implementation Example 3

步驟1Step 1

在化合物11(352mg，0.629mmol)的DMF(3.5ml)溶液中添加碳酸鉀(261mg，1.89mmol)和4-溴丁烯(147mg，0.943mmol)，並在室溫反應整晚。將水添加至反應液中，並用乙酸乙酯萃取。將有機層用水、飽和食鹽水洗淨，用無水硫酸鈉乾燥後，餾除溶劑。Potassium carbonate (261 mg, 1.89 mmol) and 4-bromobutene (147 mg, 0.943 mmol) were added to a DMF (3.5 ml) solution of compound 11 (352 mg, 0.629 mmol) and reacted at room temperature overnight. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with anhydrous sodium sulfate, and the solvent was distilled off.

MS：m/z=611[M+H]+MS: m/z=611[M+H]+

步驟2Step 2

在步驟1中所得的粗產物中添加4mol/L鹽酸/二

溶液(3.15ml)，並在室溫攪拌2小時。將飽和碳酸氫鈉水添加至反應液中，並用乙酸乙酯萃取。將有機層用飽和食鹽水洗淨，用無水硫酸鈉乾燥後，餾除溶劑。Add 4 mol/L hydrochloric acid/dihydrochloric acid to the crude product obtained in step 1.

solution (3.15 ml) and stirred at room temperature for 2 hours. Saturated sodium bicarbonate water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off.

MS：m/z=511[M+H]+MS: m/z=511[M+H]+

步驟3Step 3

使步驟2中所得的粗產物、丙烯醛(102mg，1.83mmol)、對甲苯磺酸水合物(11.6mg，0.061mmol)溶解在二氯乙烷(9.6mL)，在100℃攪拌6小時。將反應液冷卻至室溫後，添加水及飽和碳酸氫鈉水，並用乙酸乙酯萃取。將有機層用飽和食鹽水洗淨，用無水硫酸鈉乾燥後，餾除溶劑。所得之殘渣藉由矽膠管柱層析(己烷-乙酸乙酯)精製，得到化合物16(115mg)。The crude product obtained in step 2, acrolein (102 mg, 1.83 mmol), and p-toluenesulfonic acid hydrate (11.6 mg, 0.061 mmol) were dissolved in dichloroethane (9.6 mL) and stirred at 100°C for 6 hours. After the reaction solution was cooled to room temperature, water and saturated sodium bicarbonate were added, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 16 (115 mg).

MS：m/z=549[M+H]+MS: m/z=549[M+H]+

步驟4Step 4

使化合物16(66.4mg，0.121mmol)、Hoveyda-Grubbs第二代催化劑(60mg，0.139mmol)溶解在二氯甲烷(10mL)，並加熱回流6小時。餾除反應液的溶劑，所得之殘渣藉由矽膠管柱層析(乙酸乙酯-甲醇)粗精製。Compound 16 (66.4 mg, 0.121 mmol) and Hoveyda-Grubbs second generation catalyst (60 mg, 0.139 mmol) were dissolved in dichloromethane (10 mL) and heated to reflux for 6 hours. The solvent in the reaction solution was distilled off, and the resulting residue was crudely purified by silica gel column chromatography (ethyl acetate-methanol).

MS：m/z=521[M+H]+MS: m/z=521[M+H]+

步驟5Step 5

將步驟4中所得的化合物17藉由SFC進行光學分割，得到化合物18。The compound 17 obtained in step 4 was optically fragmented by SFC to obtain compound 18.

管柱：CHIRALPAK IC/SFC(5μm,i.d.250 x 20mm)Column: CHIRALPAK IC/SFC (5μm, i.d. 250 x 20mm)

流速：20mL/分鐘Flow rate: 20mL/min

UV檢測波長：220nmUV detection wavelength: 220nm

製備條件：維持MeOH/CO₂=70/30的組成比，送液21分鐘。Preparation conditions: maintain a composition ratio of MeOH/CO₂ = 70/30 and deliver the solution for 21 minutes.

步驟6Step 6

進行與實施例1的步驟6相同的反應，得到化合物II-65(11mg，產率74%)。The same reaction as step 6 of Example 1 was carried out to obtain compound II-65 (11 mg, yield 74%).

1H-NMR(CDCl₃)δ：11.93(s,1H),10.42(t,J=5.6Hz,1H),8.50(s,1H),7.40-7.33(m,1H),6.84-6.77(m,2H),6.28-6.24(m,1 H),5.96-5.91(m,1H),5.32(d,J=5.2Hz,1H),4.68(dd,J=15.2,6.0Hz,1H),4.61(dd,J=15.6,6.0Hz,1H),3.83(dt,J=21.2,7.2Hz,1H),3.53(dt,J=20.8,6.8Hz,1H),3.39(td,J=11.2,4.4Hz,1H),3.04(dd,J=10.8,6.8Hz,1H),2.77-2.68(m,1H),2.35(dt,J=18.8,4.8Hz,1H),1.23(t,J=7.2Hz,3H).1H-NMR(CDCl₃ )δ: 11.93(s,1H),10.42(t,J=5.6Hz,1H),8.50(s,1H),7.40-7.33(m,1H),6.84-6.77(m,2H),6.28-6.24(m,1 H),5.96-5.91(m,1H),5.32(d,J=5.2Hz,1H),4.68(dd,J=15.2,6.0Hz,1H),4.61(dd,J=15.6,6.0Hz,1H),3.83(dt,J=21.2,7.2Hz,1H),3.53(dt,J =20.8,6.8Hz,1H),3.39(td,J=11.2,4.4Hz,1H),3.04(dd,J=10.8,6.8Hz,1 H),2.77-2.68(m,1H),2.35(dt,J=18.8,4.8Hz,1H),1.23(t,J=7.2Hz,3H).

實施例4Example 4

步驟1Step 1

在化合物11(326mg，0.59mmol)、化合物19(87mg，0.77mmol)及三苯膦(307mg，1.18mmol)的THF(3.5mL)溶液中，在0℃添加偶氮二羧酸雙-2-甲氧基乙基酯(274mg，1.18mmol)，在室溫下靜置12小時。將水添加至反應液中，並用乙酸乙酯萃取。將有機層用水、飽和食鹽水洗淨，用無水硫酸鈉乾燥後，餾除溶劑。所得之殘渣藉由矽膠管柱層析(己烷-乙酸乙酯)精製，得到化合物20(293mg，產率77%)。Azodicarboxylic acid bis-2-methoxyethyl ester (274 mg, 1.18 mmol) was added to a THF (3.5 mL) solution of compound 11 (326 mg, 0.59 mmol), compound 19 (87 mg, 0.77 mmol) and triphenylphosphine (307 mg, 1.18 mmol) at 0°C and allowed to stand at room temperature for 12 hours. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 20 (293 mg, yield 77%).

MS：m/z=653[M+H]+MS: m/z=653[M+H]+

步驟2Step 2

使化合物20(287mg，0.44mmol)懸浮於二

(3.4mL)、水(2.3mL)，並在0℃添加2,6-二甲吡啶(0.10mL)、過碘酸氫鈉(282mg，1.32mmol)、鋨酸鉀(VI)二水合物(8.0mg，0.02mmol)，並花費5小時由0℃升溫至室溫。將反應液用矽藻土(Celite)(註冊商標)過濾，添加10%硫代硫酸鈉水溶液，並用乙酸乙酯萃取。將有機層用水、飽和食鹽水洗淨，用無水硫酸鈉乾燥後，餾除溶劑。所得之殘渣藉由矽膠管柱層析(己烷-乙酸乙酯)精製，得到化合物21(223mg，產率78%)。Compound 20 (287 mg, 0.44 mmol) was suspended in di

(3.4 mL), water (2.3 mL), and at 0°C, 2,6-dimethylpyridine (0.10 mL), sodium hydrogen periodate (282 mg, 1.32 mmol), potassium diatomate (VI) dihydrate (8.0 mg, 0.02 mmol) were added, and the temperature was raised from 0°C to room temperature over 5 hours. The reaction solution was filtered through diatomaceous earth (Celite) (registered trademark), 10% sodium thiosulfate aqueous solution was added, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 21 (223 mg, yield 78%).

MS：m/z=655[M+H]+MS: m/z=655[M+H]+

步驟3Step 3

使化合物21(192mg，0.29mmol)溶解在4mol/L鹽酸/二

溶液(1.47ml)，並在室溫攪拌2小時。餾除溶劑，將所得之粗產物溶解在甲苯(2.0ml)中，添加觸媒量的乙酸，在90℃攪拌2小時。將飽和碳酸氫鈉水添加反應溶液，並用乙酸乙酯萃取。將有機層用水、飽和食鹽水洗淨，用硫酸鈉乾燥後，餾除溶劑。所得之殘渣藉由矽膠管柱層析精製，得到非鏡像異構物混合物。將所得之非鏡像異構物混合物藉由SFC進行光學分割，得到化合物22(69mg，產率44%)。Compound 21 (192 mg, 0.29 mmol) was dissolved in 4 mol/L hydrochloric acid/distilled water.

solution (1.47 ml) and stirred at room temperature for 2 hours. The solvent was distilled off, and the obtained crude product was dissolved in toluene (2.0 ml), and a catalytic amount of acetic acid was added, and stirred at 90°C for 2 hours. Saturated sodium bicarbonate was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to obtain a non-mirror isomer mixture. The obtained non-mirror isomer mixture was optically segmented by SFC to obtain compound 22 (69 mg, yield 44%).

管柱：CHIRALPAK IC/SFC(5μm，i.d.250 x 20mm)兩個串聯使用Column: CHIRALPAK IC/SFC (5μm, i.d. 250 x 20mm) two in series

流速：20mL/分鐘Flow rate: 20mL/min

UV檢測波長：220nmUV detection wavelength: 220nm

製備條件：維持MeOH/CO₂=65/35的組成比，送液35分鐘。Preparation conditions: maintain a composition ratio of MeOH/CO₂ = 65/35 and deliver the solution for 35 minutes.

MS：m/z=537[M+H]+MS: m/z=537[M+H]+

步驟4Step 4

進行與實施例1的步驟6相同的反應，得到化合物II-34。Carry out the same reaction as step 6 of Example 1 to obtain compound II-34.

MS：m/z=447[M+H]+MS: m/z=447[M+H]+

實施例5Example 5

步驟1Step 1

在化合物23(1.59g，12.2mmol)的DMF(16.0mL)溶液中，在0℃添加咪唑(0.998g，14.66mmol)、第三丁基二甲基矽基氯(1.84g，12.21mmol)，在室溫攪拌3小時。將飽和氯化銨水溶液添加至反應液中，並用乙酸乙酯萃取。將有機層用水、飽和食鹽水洗淨，用無水硫酸鈉乾燥後，餾除溶劑。所得之殘渣藉由矽膠管柱層析(己烷-乙酸乙酯)精製，得到化合物24(1.39g，產率47%)。In a DMF (16.0 mL) solution of compound 23 (1.59 g, 12.2 mmol), imidazole (0.998 g, 14.66 mmol) and tert-butyldimethylsilyl chloride (1.84 g, 12.21 mmol) were added at 0°C and stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 24 (1.39 g, yield 47%).

1 H-NMR(CDCl₃)δ：3.47-3.55(m,4H),2.09-2.15(m,2H),1.88-1.95(s,1H),1.65-1.79(m,2H),1.32-1.42(m,2H),0.88-0.89(m,1H),0.85(s,9H),0.039(s,6H).1 H-NMR (CDCl₃ )δ: 3.47-3.55(m,4H),2.09-2.15(m,2H),1.88-1.95(s,1H),1.65-1.79( m,2H),1.32-1.42(m,2H),0.88-0.89(m,1H),0.85(s,9H),0.039(s,6H).

步驟2Step 2

在化合物24(400mg，0.164mmol)、化合物11(700mg，1.26mmol)及三苯膦(660mg，2.52mmol)的THF(7mL)溶液中，在0℃添加偶氮二羧酸雙-2-甲氧基乙基酯(589mg，2.52mmol)，並在室溫靜置12小時。將水添加至反應液中，並用乙酸乙酯萃取。將有機層用水洗淨，用無水硫酸鈉乾燥後，餾除溶劑。所得之殘渣藉由矽膠管柱層析(己烷-乙酸乙酯)粗精製。Azodicarboxylic acid bis-2-methoxyethyl ester (589 mg, 2.52 mmol) was added to a THF (7 mL) solution of compound 24 (400 mg, 0.164 mmol), compound 11 (700 mg, 1.26 mmol) and triphenylphosphine (660 mg, 2.52 mmol) at 0°C and allowed to stand at room temperature for 12 hours. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water, dried with anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was crudely purified by silica gel column chromatography (hexane-ethyl acetate).

步驟3Step 3

在化合物25(1.06g，1.35mmol)的THF(10.0mL)溶液中，添加1mol/L TBAF/THF溶液(1.63ml，1.63mmol)，在室溫攪拌12小時。將飽和氯化銨水溶液添加至反應液中，並用乙酸乙酯萃取。將有機層用水、飽和食鹽水洗淨，用無水硫酸鈉乾燥後，餾除溶劑。所得之殘渣藉由矽膠管柱層析(己烷-乙酸乙酯)精製，得到化合物26(720mg，產率80%)。1 mol/L TBAF/THF solution (1.63 ml, 1.63 mmol) was added to a THF (10.0 mL) solution of compound 25 (1.06 g, 1.35 mmol) and stirred at room temperature for 12 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 26 (720 mg, yield 80%).

MS：m/z=669[M+H]+MS: m/z=669[M+H]+

步驟4Step 4

在化合物26(720mg，1.08mmol)的二氯甲烷(8.0mL)溶液中，在0℃添加戴斯-馬丁氧化劑(Dess-Martin periodinane)，並在室溫攪拌1小時。將10%硫代硫酸鈉水溶液、飽和碳酸氫鈉水溶液添加至反應液中，並用氯仿萃取。將有機層用水和飽和食鹽水洗淨，用無水硫酸鈉乾燥後，餾除溶劑。所得之殘渣藉由矽膠管柱層析(己烷-乙酸乙酯)精製，得到化合物27(393mg，產率55%)。Dess-Martin periodinane was added to a solution of compound 26 (720 mg, 1.08 mmol) in dichloromethane (8.0 mL) at 0°C and stirred at room temperature for 1 hour. A 10% aqueous sodium thiosulfate solution and a saturated aqueous sodium bicarbonate solution were added to the reaction solution and extracted with chloroform. The organic layer was washed with water and saturated brine, dried with anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 27 (393 mg, yield 55%).

MS：m/z=667[M+H]+MS: m/z=667[M+H]+

步驟5Step 5

將化合物27(393mg，0.59mmol)的乙腈(8.0mL)溶液在60℃加熱並攪拌80分鐘。將飽和碳酸氫鈉水溶液添加至反應液中，並用乙酸乙酯萃取。將有機層用水和飽和食鹽水洗淨，用無水硫酸鈉乾燥後，餾除溶劑。使所得之粗產物溶解在DMF(4.0mL)，在0℃下添加碳酸銫(576mg，1.77mmol)、溴甲苯(0.21mL，1.77mmol)，並在室溫攪拌過夜。將水添加至反應液中，並用乙酸乙酯萃取。將有機層用水、飽和食鹽水洗淨，用無水硫酸鈉乾燥後，餾除溶劑。所得之殘渣藉由矽膠管柱層析(己烷-乙酸乙酯)精製，藉由SFC進行光學分割，得到化合物28(89mg，產率28%)。A solution of compound 27 (393 mg, 0.59 mmol) in acetonitrile (8.0 mL) was heated at 60°C and stirred for 80 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained crude product was dissolved in DMF (4.0 mL), and cesium carbonate (576 mg, 1.77 mmol) and bromotoluene (0.21 mL, 1.77 mmol) were added at 0°C, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) and optically segmented by SFC to obtain compound 28 (89 mg, yield 28%).

管柱：CHIRALPAK IC/SFC(5μm,i.d.250 x 20mm)兩個串聯使用Column: CHIRALPAK IC/SFC (5μm, i.d. 250 x 20mm) two in series

流速：20mL/分鐘Flow rate: 20mL/min

UV檢測波長：220nmUV detection wavelength: 220nm

製備條件：維持MeOH/CO₂=75/25的組成比，送液45分鐘。Preparation conditions: maintain a composition ratio of MeOH/CO₂ = 75/25 and deliver the solution for 45 minutes.

MS：m/z=549[M+H]+MS: m/z=549[M+H]+

步驟6Step 6

進行與實施例1的步驟6相同的反應，得到化合物II-1(11mg，產率74%)。The same reaction as step 6 of Example 1 was carried out to obtain compound II-1 (11 mg, yield 74%).

MS：m/z=459[M+H]+MS: m/z=459[M+H]+

實施例6Example 6

步驟1Step 1

在化合物2(3g，6.95mmol)的DMF(60ml)溶液中添加碳酸鉀(2.02g，14.6mmol)和2-(4-溴丁基)-1,3-二氧環戊烷(2.53ml，16.7mmol)，並在室溫反應過夜。將反應液用1mol/L鹽酸中和並用乙酸乙酯萃取。將有機層用水、飽和食鹽水洗淨，用硫酸鈉乾燥後，餾除溶劑，得到化合物29。Potassium carbonate (2.02 g, 14.6 mmol) and 2-(4-bromobutyl)-1,3-dioxolane (2.53 ml, 16.7 mmol) were added to a DMF (60 ml) solution of compound 2 (3 g, 6.95 mmol) and reacted at room temperature overnight. The reaction solution was neutralized with 1 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with sodium sulfate, and the solvent was distilled off to obtain compound 29.

MS：m/z=688[M+H]+MS: m/z=688[M+H]+

步驟2Step 2

在化合物29的THF(47.8mL)溶液中添加2mol/L氫氧化鈉水溶液(17.38ml，139mmol)，在室溫攪拌2小時。將反應液逐次少量地添加2mol/L鹽酸中和，並用乙酸乙酯萃取。將有機層用飽和食鹽水洗淨，用硫酸鈉乾燥後，餾除溶劑，得到化合物30。Add 2 mol/L sodium hydroxide aqueous solution (17.38 ml, 139 mmol) to the THF (47.8 mL) solution of compound 29 and stir at room temperature for 2 hours. Add 2 mol/L hydrochloric acid in small amounts to the reaction solution for neutralization and extract with ethyl acetate. Wash the organic layer with saturated brine, dry with sodium sulfate, and distill off the solvent to obtain compound 30.

MS：m/z=560[M+H]+MS: m/z=560[M+H]+

步驟3Step 3

在化合物30的1,4-二

(5mL)溶液中添加4mol/L氯化氫(1,4-二

溶液，34.8ml，139mmol)，在室溫攪拌1小時。餾除反應液的溶劑，添加甲苯再次餾除，得到化合物31。In compound 30, 1,4-di

4 mol/L hydrogen chloride (1,4-dichlorobenzene) was added to the solution (5 mL)

The reaction mixture was stirred at room temperature for 1 hour. The solvent in the reaction solution was distilled off, and toluene was added and distilled off again to obtain compound 31.

MS：m/z=416[M+H]+MS: m/z=416[M+H]+

步驟4Step 4

在化合物31的甲苯(50mL)溶液中添加數滴乙酸，在110℃攪拌30分鐘。餾除反應液的溶劑，所得之殘渣用乙醇/異丙醚固體化，得到化合物32(2.44g，4步驟產率88%)。Add a few drops of acetic acid to a toluene (50 mL) solution of compound 31 and stir at 110°C for 30 minutes. Distill off the solvent from the reaction solution, and solidify the resulting residue with ethanol/isopropyl ether to obtain compound 32 (2.44 g, 88% yield over 4 steps).

¹H-NMR(CDCl₃)δ：15.1(s,1H),8.48(s,1H),7.57-7.55(m,2H),7.36-7.29(m,3H),5.53(d,J=10.4Hz,1H),5.36(d,J=10.4Hz,1H),4.93-4.91(m,1H),4.20(td,J=21.6,7.2Hz,1H),3.24-3.02(m,3H),2.28-1.73(m,5H),1.41-1.31(m,1H),1.18(t,J=7.2Hz,3H).¹ H-NMR (CDCl₃ )δ: 15.1(s,1H),8.48(s,1H),7.57-7.55(m,2H),7.36-7.29(m,3H),5.53(d,J=10.4Hz,1H),5.36(d,J=10.4Hz,1H),4.93- 4.91(m,1H),4.20(td,J=21.6,7.2Hz,1H),3.24-3.02(m,3H),2.28-1.73(m,5H),1.41-1.31(m,1H),1.18(t,J=7.2Hz,3H).

步驟5Step 5

在化合物32(300mg，0.755mmol)的二氯甲烷(3ml)溶液中，在0℃添加三乙胺(0.419ml，3.02mmol)和氯甲酸乙酯(90.0mg，0.830mmol)，在室溫攪拌30分鐘。將化合物33(216mg，0.906mmol)添加至反應液中，在室溫攪拌1小時。濃縮反應液，並將所得之殘渣藉由矽膠管柱層析(氯仿-甲醇)精製，得到化合物34(466mg，產率100%)。Triethylamine (0.419 ml, 3.02 mmol) and ethyl chloroformate (90.0 mg, 0.830 mmol) were added to a dichloromethane (3 ml) solution of compound 32 (300 mg, 0.755 mmol) at 0°C and stirred at room temperature for 30 minutes. Compound 33 (216 mg, 0.906 mmol) was added to the reaction solution and stirred at room temperature for 1 hour. The reaction solution was concentrated and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound 34 (466 mg, yield 100%).

MS：m/z=582[M+H]+MS: m/z=582[M+H]+

步驟6Step 6

在化合物34(439mg，0.755mmol)的乙酸乙酯(6ml)溶液中添加50%T3P/乙酸乙酯溶液(2.25ml，7,55mmol)，並在100℃攪拌1小時。將飽和碳酸氫鈉水溶液添加反應液，並用乙酸乙酯萃取。將有機層用水洗淨，用硫酸鈉乾燥後，餾除溶劑，所得殘渣藉由矽膠管柱層析法(氯仿-甲醇)精製，得到外消旋化合物。將所得外消旋化合物藉由SFC進行光學分割，得到化合物35。50% T3P/ethyl acetate solution (2.25 ml, 7.55 mmol) was added to a solution of compound 34 (439 mg, 0.755 mmol) in ethyl acetate (6 ml), and stirred at 100°C for 1 hour. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with water, dried with sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain a racemic compound. The obtained racemic compound was optically resolved by SFC to obtain compound 35.

管柱：CHIRALPAK IA/SFC(5μm,i.d.250 x 20mm)Column: CHIRALPAK IA/SFC (5μm, i.d. 250 x 20mm)

流速：20mL/分鐘Flow rate: 20mL/min

UV檢測波長：220nmUV detection wavelength: 220nm

製備條件：維持MeOH/CO 2=65/35的組成比，送液25分鐘。Preparation conditions: Maintain a composition ratio of MeOH/CO 2 = 65/35 and deliver the solution for 25 minutes.

1H-NMR(CDCl3)δ：8.80(s,1H),7.60(m,2H),7.34-7.27(m,4H),6.85(t,J=8.9Hz,2H),5.55(d,J=10.3Hz,1H),5.33(d,J=10.4Hz,1H),4.97(m,1H),4.46(s,2H),4.40(m,1H),3.23(m,1H),3.10-3.03(m,2H),2.24(m,1H),2.02(m,1H),1.89(m,2H),1.72(m,1H),1.42(m,1H),1.17(t,J=7.2Hz,3H).1H-NMR(CDCl3)δ: 8.80(s,1H),7.60(m,2H),7.34-7.27(m,4H),6.85(t,J =8.9Hz,2H),5.55(d,J=10.3Hz,1H),5.33(d,J=10.4Hz,1H),4.97(m,1H), 4.46(s,2H),4.40(m,1H),3.23(m,1H),3.10-3.03(m,2H),2.24(m,1H),2 .02(m,1H),1.89(m,2H),1.72(m,1H),1.42(m,1H),1.17(t,J=7.2Hz,3H).

步驟7Step 7

藉由與實施例1的步驟6相同的方法，得到化合物I-11(63mg，產率68%)。Compound I-11 (63 mg, yield 68%) was obtained by the same method as step 6 of Example 1.

1H-NMR(CDCl3)δ：12.04(s,1H),8.73(s,1H),7.31(m,1H),6.84(t,J=8.6Hz,2H),5.14(s,1H),4.45(s,2H),4.36(m,1H),3.26-3.04(m,3H),2.33(d,J=14.9Hz,1H),2.08(t,J=14.7Hz,1H),1.91(m,3H),1.42(m,1H),1.24(t,J=7.2Hz,3H).1H-NMR(CDCl3)δ: 12.04(s,1H),8.73(s,1H),7.31(m,1H),6.84(t,J=8.6Hz,2H),5.14(s,1H),4.45(s,2H),4.36(m,1H ),3.26-3.04(m,3H),2.33(d,J=14.9Hz,1H),2.08(t,J=14.7Hz,1H),1.91(m,3H),1.42(m,1H),1.24(t,J=7.2Hz,3H).

實施例7Example 7

步驟1Step 1

將以與實施例1相同的方式合成的化合物36(1.0g，2.8mmol)的二氯甲烷(10mL)溶液冷卻至0℃，添加NBS(0.56g，3.1mmol)，在室溫攪拌整晚。餾除反應液的溶劑，將所得之殘渣藉由矽膠管柱層析法(氯仿-甲醇)精製，得到外消旋化合物。將所得之外消旋化合物藉由SFC進行光學分割，得到化合物37。A dichloromethane (10 mL) solution of compound 36 (1.0 g, 2.8 mmol) synthesized in the same manner as in Example 1 was cooled to 0°C, NBS (0.56 g, 3.1 mmol) was added, and stirred at room temperature overnight. The solvent of the reaction solution was distilled off, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain a racemic compound. The resulting racemic compound was optically segmented by SFC to obtain compound 37.

管柱：CHIRALPAK IB/SFC(5μm,i.d.250 x 20mm)Column: CHIRALPAK IB/SFC (5μm, i.d. 250 x 20mm)

流速：30mL/分鐘Flow rate: 30mL/min

UV檢測波長：220nmUV detection wavelength: 220nm

製備條件：維持MeOH/CO₂=35/65的組成比，送液21分鐘。Preparation conditions: maintain a composition ratio of MeOH/CO₂ = 35/65 and deliver the solution for 21 minutes.

1H-NMR(CDCl₃)δ：7.83(s,1H),7.64(d,J=7.0Hz,2H),7.34-7.27(m,3H),5.48(d,J=10.3Hz,1H),5.26(d,J=10.3Hz,1H),4.92-4.90(m,1H),4.43-4.39(m,1H),3.20-3.14(m,1H),3.05-2.98(m,2H),2.26-2.22(m,1H),1.97-1.94(m,1H),1.84-1.82(m,2H),1.73-1.69(m,1H),1.41-1.39(m,1H),1.16(t,J=7.2Hz,3H).1H-NMR (CDCl₃ )δ: 7.83(s,1H),7.64(d,J=7.0Hz,2H),7.34-7.27(m,3H),5.48(d,J=10.3H z,1H),5.26(d,J=10.3Hz,1H),4.92-4.90(m,1H),4.43-4.39(m,1H),3.20- 3.14(m,1H),3.05-2.98(m,2H),2.26-2.22(m,1H),1.97-1.94(m,1H),1.84 -1.82(m,2H),1.73-1.69(m,1H),1.41-1.39(m,1H),1.16(t,J=7.2Hz,3H).

步驟2Step 2

使化合物37(250mg，0.58mmol)溶解在甲苯，添加化合物38(183mg，0.87mmol)、Pd(OAc)₂(13.0mg，0.06mmol)、2-二環己基膦基-2'-(N，N-二胺基)聯苯(46mg，0.12mmol)及碳酸銫(565mg，1.7mmol)並密封，在140℃攪拌2小時。冷卻至室溫，用矽藻土過濾去除不溶物，餾除溶劑。所得之殘渣藉由矽膠管柱層析法(己烷-乙酸乙酯)粗精製，並利用逆相精製得到化合物39(40mg，產率12%)。Compound 37 (250 mg, 0.58 mmol) was dissolved in toluene, and compound 38 (183 mg, 0.87 mmol), Pd(OAc)₂ (13.0 mg, 0.06 mmol), 2-dicyclohexylphosphino-2'-(N,N-diamino)biphenyl (46 mg, 0.12 mmol) and cesium carbonate (565 mg, 1.7 mmol) were added and sealed, and stirred at 140°C for 2 hours. The mixture was cooled to room temperature, filtered through diatomaceous earth to remove insoluble matter, and the solvent was distilled off. The resulting residue was crudely purified by silica gel column chromatography (hexane-ethyl acetate), and then purified by reverse phase to obtain compound 39 (40 mg, yield 12%).

1H-NMR(CDCl3)δ：8.63(s,1H),7.64-7.61(m,3H),7.34-7.19(m,4H),6.83-6.79(m,2H),5.58(d,J=10.3Hz,1H),5.33(d,J=10.3Hz,1H),4.96-4.94(m,1H),4.44-4.40(m,1H),4.19(s,2H),3.22-3.18(m,1H),3.09-3.02(m,2H),2.27-2.23(m,1H),2.01-1.97(m,1H),1.86-1.84(m,2H),1.74-1.70(m,1H),1.43-1.40(m,1H),1.17(t,J=7.0Hz,3H).1H-NMR(CDCl3)δ: 8.63(s,1H),7.64-7.61(m,3H),7.34-7.19(m,4H),6.83-6.79(m,2H ),5.58(d,J=10.3Hz,1H),5.33(d,J=10.3Hz,1H),4.96-4.94(m,1H),4.44-4.40(m,1H ),4.19(s,2H),3.22-3.18(m,1H),3.09-3.02(m,2H),2.27-2.23(m,1H),2.01-1.97(m ,1H),1.86-1.84(m,2H),1.74-1.70(m,1H),1.43-1.40(m,1H),1.17(t,J=7.0Hz,3H).

步驟3Step 3

藉由與實施例1的步驟6相同的方法，得到化合物I-2(22mg，產率67%)。Compound I-2 (22 mg, yield 67%) was obtained by the same method as step 6 of Example 1.

1H-NMR(CDCl₃)δ：11.81(brs,1H),8.59(s,1H),7.54(s,1H),7.20-7.18(m,1H),6.83-6.78(m,2H),5.11-5.09(m,1H),4.40-4.31(m,1H),4.18(s,2H),3.24-3.02(m,3H),2.34-2.29(m,1H),2.09-2.01(m,1H),1.90-1.85(m,2H),1.78-1.74(m,1H),1.46-1.36(m,1H),1.23(t,J=7.0Hz,3H).1H-NMR (CDCl₃ )δ: 11.81(brs,1H),8.59(s,1H),7.54(s,1H),7.20-7.18(m,1H),6.83-6.78(m,2H),5.11-5.09(m,1H),4.40-4.31(m,1H),4.18(s,2H), 3.24-3.02(m,3H),2.34-2.29(m,1H),2.09-2.01(m,1H),1.90-1.85(m,2H),1.78-1.74(m,1H),1.46-1.36(m,1H),1.23(t,J=7.0Hz,3H).

實施例8Example 8

步驟1Step 1

在化合物40(528mg，2.10mmol)的THF(5.0mL)溶液中，在0℃添加氫化鈉(60wt%，135mg，3.38mmol)，並在0℃攪拌10分鐘。將化合物41(500mg，2.415mmol)添加至反應液中，並升溫至室溫使其反應整晚。將水添加至反應液中，並用乙酸乙酯萃取。將有機層用飽和食鹽水洗淨，用無水硫酸鈉乾燥後，餾除溶劑。所得之殘渣藉由矽膠管柱層析(己烷-乙酸乙酯)精製，得到化合物42(517mg，產率67%)。Sodium hydride (60wt%, 135mg, 3.38mmol) was added to a THF (5.0mL) solution of compound 40 (528mg, 2.10mmol) at 0°C and stirred at 0°C for 10 minutes. Compound 41 (500mg, 2.415mmol) was added to the reaction solution and the temperature was raised to room temperature to react overnight. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 42 (517mg, yield 67%).

MS：m/z=321[M+H]+MS: m/z=321[M+H]+

步驟2Step 2

使化合物42(89mg，0.278mmol)、化合物37(60mg，0.139mmol)、碳酸銫(68mg，0.208mmol)、四(三苯基膦)鈀(16mg，0.014mmol)溶解在二

溶液(1.8mL)，在90℃反應7小時。將水添加至反應液中，並用乙酸乙酯萃取。將有機層用飽和食鹽水洗淨，用無水硫酸鈉乾燥後，餾除溶劑。所得之殘渣透過矽膠柱層析(乙酸乙酯-甲醇)粗精製。Compound 42 (89 mg, 0.278 mmol), compound 37 (60 mg, 0.139 mmol), cesium carbonate (68 mg, 0.208 mmol), tetrakis(triphenylphosphine)palladium (16 mg, 0.014 mmol) were dissolved in distilled water.

The solution (1.8 mL) was reacted at 90°C for 7 hours. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was crudely purified by silica gel column chromatography (ethyl acetate-methanol).

MS：m/z=546[M+H]+MS: m/z=546[M+H]+

步驟3Step 3

藉由與實施例1的步驟6相同的方法，得到化合物II-100。Compound II-100 was obtained by the same method as step 6 of Example 1.

1H-NMR(CDCl₃)δ：8.66(s,1H),7.77(s,1H),7.72(s,1H),7.20-7.15(m,1H),6.86-6.80(m,2H),5.35(s,2H),5.08(s,1H),4.40-4.30(m,1H),3.20-2.95(m,3H),2.35-2.25(m,1H),2.01-1.40(m,6H),1.22(t,J=7.2Hz,3H).1H-NMR (CDCl₃ )δ: 8.66(s,1H),7.77(s,1H),7.72(s,1H),7.20-7.15(m,1H),6.86-6.80(m,2H),5.35(s,2H),5.08(s, 1H),4.40-4.30(m,1H),3.20-2.95(m,3H),2.35-2.25(m,1H),2.01-1.40(m,6H),1.22(t,J=7.2Hz,3H).

使用上述一般的合成法或實施例中記載的合成法，同樣地施作而合成出下列化合物。The following compounds were synthesized by using the above general synthesis method or the synthesis method described in the examples in the same manner.

[表1]

[Table 1]

[表2]

[Table 2]

[表3]

[Table 3]

[表4]

[Table 4]

[表5]

[Table 5]

[表6]

[Table 6]

[表7]

[Table 7]

[表8]

[Table 8]

[表9]

[Table 9]

[表10]

[Table 10]

[表11]

[Table 11]

各化合物的物理數據如下所示。The physical data of each compound are shown below.

[表12]

[Table 12]

以下，記載本發明化合物的生物試驗例。The following are biological test examples of the compounds of the present invention.

試驗例1：抗HIV活性Test Example 1: Anti-HIV activity

在96孔微量盤(50μL/孔)中製作出測試試料的階段稀釋系列。將2.5×10⁵個/mL的MT-4細胞懸浮液以各100μL/孔分注到注入有測試試料的盤後，以各50μL/孔分注HIV病毒液。用盤混合器混合，並在CO₂培養箱中培養4天。將MTT(溴化3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑)溶液各30μL分注到各孔。在CO₂培養箱中反應1小時。從各個孔中以不吸取細胞之方式去除150μL上清液。添加150μL的細胞溶解液並用盤混合器充分地混合直至所有細胞溶解。混合後的盤用微量盤檢測儀以560nm/690nm兩個波長測定吸光度。使用下述所示的四參數邏輯曲線擬合模型，由濃度依存曲線決定50%HIV抑制濃度(EC 50)。A stepwise dilution series of the test sample was prepared in a 96-well microplate (50 μL/well). 2.5×10⁵ /mL MT-4 cell suspension was dispensed into the plate injected with the test sample at 100 μL/well, and then 50 μL/well of HIV virus solution was dispensed. Mix with a plate mixer and incubate in a CO₂ incubator for 4 days. 30 μL of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) solution was dispensed into each well. Reacted in a CO₂ incubator for 1 hour. 150 μL of supernatant was removed from each well without aspirating the cells. 150 μL of cell lysis solution was added and mixed thoroughly with a plate mixer until all cells were lysed. The mixed plate was then measured for absorbance at two wavelengths, 560nm/690nm, using a microplate detector. The 50% HIV inhibition concentration (EC 50) was determined from the concentration dependence curve using the four-parameter logical curve fitting model shown below.

y=A+((B-A)/(1+(C/x)^D))y=A+((BA)/(1+(C/x)^D ))

A=抑制率的最小值(陰性對照，0%)A=minimum inhibition rate (negative control, 0%)

B=抑制率的最大值(陽性對照，100%)B = Maximum inhibition rate (positive control, 100%)

C=轉折點處的化合物濃度C = Compound concentration at the turning point

D=斜率係數D = slope coefficient

x=化合物濃度x=compound concentration

y=抑制率(%)y=inhibition rate (%)

(結果)(result)

[表13]

[Table 13]

由以上的試驗結果可知，由於本發明化合物顯示出高抗HIV活性，故具有作為HIV藥物之有用性。From the above test results, it can be seen that since the compound of the present invention exhibits high anti-HIV activity, it is useful as an HIV drug.

試驗例2：抗藥性評估試驗Test Example 2: Drug resistance assessment test

在96孔微微量盤(50μL/孔)中製作出測試試料的階段稀釋系列。將2.5×10⁵個/mL的HeLa-CD4細胞懸浮液以各100μL/孔分注到含有測試試料的盤後，以各50μL/孔分注HIV病毒液(野生株及突變株)。用盤混合器混合，並在CO₂培養箱中培養3天。將各孔的培養上清液吸引去除，分注100μL報導測定套組中的細胞溶解緩衝液，接著在冷凍庫(-80℃)中凍結。將在冷凍庫凍結的盤於室溫解凍後，用盤混合器混合，以1,200rpm離心5分鐘。將各孔的上清液以各20μL紛取至96孔微量盤(BLACK)中，再分注各100μl報導測定套組中的化學發光試藥，在室溫反應約1小時後，用MicroBeta TRILUX測定發光量。使用下述所示的四參數邏輯曲線擬合模型，從濃度依存曲線決定50%HIV抑制濃度(EC 50)。A stepwise dilution series of the test sample was prepared in a 96-well microplate (50 μL/well). After 2.5×10⁵ cells/mL of HeLa-CD4 cell suspension was dispensed into the plate containing the test sample at 100 μL/well, HIV virus solution (wild strain and mutant strain) was dispensed at 50 μL/well. Mix with a plate mixer and culture in a CO₂ incubator for 3 days. The culture supernatant of each well was removed by aspiration, and 100 μL of the cell lysis buffer in the reporter assay kit was dispensed, followed by freezing in a freezer (-80°C). After thawing the plate frozen in the freezer at room temperature, mix with a plate mixer, and centrifuge at 1,200 rpm for 5 minutes. 20 μL of the supernatant from each well was aliquoted into a 96-well microplate (BLACK), and 100 μL of the chemiluminescent reagent in the reporter assay kit was dispensed. After reacting at room temperature for about 1 hour, the luminescence was measured using MicroBeta TRILUX. The 50% HIV inhibition concentration (EC 50) was determined from the concentration dependence curve using the four-parameter logical curve fitting model shown below.

y=A+((B-A)/(1+(C/x)^D))y=A+((BA)/(1+(C/x)^D ))

A=抑制率的最小值(陰性對照，0%)A=minimum inhibition rate (negative control, 0%)

B=抑制率的最大值(陽性對照，100%)B = Maximum inhibition rate (positive control, 100%)

C=轉折點處的化合物濃度C = Compound concentration at the turning point

D=斜率係數D = slope coefficient

x=化合物濃度x=compound concentration

y=抑制率(%)y=inhibition rate (%)

再者，依據下列計算式計算出各突變株的抗藥性度(差異倍數(FC))。Furthermore, the drug resistance of each mutant strain (fold difference (FC)) was calculated according to the following formula.

FC=突變株的EC50/野生株的EC50FC=EC50 of mutant strain/EC50 of wild strain

(結果)(result)

於表中顯示相對於突變株1(E138K/G140S/Q148H/N155H)的FC及相對於突變株2的FC(E92Q/E138T/G140S/Q148H)。The table shows the FC relative to mutant 1 (E138K/G140S/Q148H/N155H) and the FC relative to mutant 2 (E92Q/E138T/G140S/Q148H).

[表14]

[Table 14]

相對於突變株3(E92Q/E138K/G140S/Q148H)的FCRelative to the FC of mutant 3 (E92Q/E138K/G140S/Q148H)

化合物I-032：7.7Compound I-032: 7.7

化合物I-011：7.7Compound I-011: 7.7

相對於突變菌株4(T97A/E138T/G140S/Q148H)的FCFC relative to mutant strain 4 (T97A/E138T/G140S/Q148H)

化合物I-032：10Compound I-032: 10

化合物I-011：3.2Compound I-011: 3.2

由以上的試驗結果可知，本發明化合物抗藥性屏障高，並且使HIV抗藥性病毒不容易產生。From the above test results, it can be seen that the drug resistance barrier of the compound of the present invention is high and it is not easy for HIV drug-resistant viruses to be produced.

試驗例3：CYP抑制試驗Test Example 3: CYP inhibition test

使用市售的混合人類肝微粒體(Pooled human liver microsomes)，以屬於人類主要CYP5分子種(CYP1A2、2C9、2C19、2D6、3A4)的典型基質代謝反應之7-乙氧基試鹵靈的鄰-脫乙基化(CYP1A2)、甲苯磺丁脲的甲基-羥基化(CYP2C9)、美芬妥英(Mephenytoin)的4'-羥基化(CYP2C19)、右美沙芬(Dextromethorphan)的鄰-脫甲基化(CYP2D6)、特芬那定(Terfenadine)的羥基化(CYP3A4)作為指標，評估各種代謝物生成量受到本發明化合物抑制的程度。Using commercially available pooled human liver microsomes, the typical matrix metabolic reactions of the main human CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) were used as indicators, including o-deethylation of 7-ethoxytesthalol (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4'-hydroxylation of mephenytoin (CYP2C19), o-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4), to evaluate the degree to which the production of various metabolites is inhibited by the compounds of the present invention.

反應條件如下所述，基質：乙氧基試鹵靈(CYP1A2)0.5μmol/L、甲苯磺丁脲(CYP2C9)100μmol/L、S-美芬妥英(CYP2C19)50μmol/L、右美沙芬(CYP2D6)5μmol/L、特芬那定(CYP3A4)1μmol/L；反應時間：15分鐘；反應溫度：37℃；酵素：混合人類肝微粒體0.2mg蛋白質/mL；本發明化合物濃度：1、5、10、20μmol/L(4點)。The reaction conditions are as follows: substrate: ethoxysilane (CYP1A2) 0.5μmol/L, tolbutamide (CYP2C9) 100μmol/L, S-mephenytoin (CYP2C19) 50μmol/L, dextromethorphan (CYP2D6) 5μmol/L, terfenadine (CYP3A4) 1μmol/L; reaction time: 15 minutes; reaction temperature: 37°C; enzyme: mixed human liver microsomes 0.2mg protein/mL; concentration of the compound of the present invention: 1, 5, 10, 20μmol/L (4 points).

在96孔盤中的50mmol/L Hepes緩衝液中依上述組成添加各五種基質、人類肝微粒體和本發明化合物，並添加輔酶NADPH使作為指標的代謝反應開始進行。在37℃反應15分鐘後，藉由添加甲醇/乙腈=1/1(V/V)溶液終止反應。3000rpm離心15分鐘後，用螢光多標記計數器或LC/MS/MS定量離心上清液中的試鹵靈(CYP1A2代謝物)，用LC/MS/MS定量甲苯磺丁脲氫氧化物(CYP2C9代謝物)、美芬妥英4'-氫氧化物(CYP2C19代謝物)、右美沙芬(CYP2D6代謝物)、特芬那定酒精體(CYP3A4代謝物)。Five substrates, human liver microsomes and the compound of the present invention were added to the 50 mmol/L Hepes buffer in a 96-well plate according to the above composition, and the coenzyme NADPH was added to start the metabolic reaction as an indicator. After reacting at 37°C for 15 minutes, the reaction was terminated by adding a methanol/acetonitrile = 1/1 (V/V) solution. After centrifugation at 3000 rpm for 15 minutes, the supernatant was quantified by fluorescent multilabel counter or LC/MS/MS for quantification of testachlor (CYP1A2 metabolite), and LC/MS/MS was used to quantify tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4'-hydroxide (CYP2C19 metabolite), dextromethorphan (CYP2D6 metabolite), and terfenadine alcohol (CYP3A4 metabolite).

將在反應溶液中取代本發明的化合物僅添加有屬於溶解化合物的溶劑之DMSO者作為對照組(100%)，算出殘留活性(%)，使用濃度與抑制率，藉由以對數模式進行之逆推定算出IC₅₀。A control group (100%) was prepared by adding only DMSO, a solvent for dissolving the compound, to the reaction solution instead of the compound of the present invention. The residual activity (%) was calculated, and IC₅₀ was calculated by reverse estimation in a logarithmic model using the concentration and inhibition rate.

試驗例4：CYP3A4(MDZ)MBI試驗Test example 4: CYP3A4 (MDZ) MBI test

此係針對本發明化合物的CYP3A4抑制，由起因於本發明化合物的代謝反應所致之抑制作用增強，評估機制型抑制(mechanism based inhibition，MBI)能力的試驗。使用混合人類肝微粒體，並以咪達唑侖(Midazolam，MDZ)的1-羥基化反應作為指標，評估CYP3A4抑制。This is a test to evaluate the mechanism based inhibition (MBI) ability of the CYP3A4 inhibition of the compounds of the present invention by enhancing the inhibitory effect caused by the metabolic reactions of the compounds of the present invention. CYP3A4 inhibition was evaluated using mixed human liver microsomes and the 1-hydroxylation reaction of midazolam (MDZ) as an indicator.

反應條件如下所述，基質：MDZ 10μmol/L；預反應時間：0或30分鐘；基質代謝反應時間：2分鐘；反應溫度：37℃；混合人類肝微粒體：預反應時為0.5mg/mL，反應時為0.05mg/mL(10倍稀釋時)；本發明化合物預反應時的濃度：1、5、10、20μmol/L(4點)或0.83、5、10、20μmol/L(4點)。The reaction conditions are as follows: substrate: MDZ 10μmol/L; pre-reaction time: 0 or 30 minutes; substrate metabolic reaction time: 2 minutes; reaction temperature: 37°C; mixed human liver microsomes: 0.5mg/mL during pre-reaction, 0.05mg/mL during reaction (10-fold dilution); concentration of the compound of the present invention during pre-reaction: 1, 5, 10, 20μmol/L (4 points) or 0.83, 5, 10, 20μmol/L (4 points).

在96孔盤中的作為預反應液的K-Pi緩衝液(pH7.4)中依上述的預反應組成添加混合人類肝微粒體、及本發明化合物溶液，接著，將其一部分移行至另一個96孔盤並利用含有基質的K-Pi緩衝液稀釋為1/10，添加屬於輔酶之NADPH，使作為指標的反應開始進行(無預反應：預培養0分鐘)，反應預定時間後，藉由添加甲醇/乙腈=1/1(V/V)溶液終止反應。再者，將NADPH添加至剩餘的預反應液中開始預反應(有預反應：預培養30分鐘)，並且在預反應預定時間後，將其一部分移行至另一個盤中，並利用含有基質的K-Pi緩衝液稀釋為1/10，並開始作為指標的反應。反應預定時間後，藉由添加甲醇/乙腈=1/1(V/V)溶液終止反應。將各個進行指標反應的盤以3000rpm離心15分鐘後，用LC/MS/MS定量上清液中的1-咪達唑侖氫氧化物。In a 96-well plate, a mixture of human liver microsomes and a solution of the compound of the present invention was added according to the above-mentioned pre-reaction composition to a K-Pi buffer (pH 7.4) as a pre-reaction solution. Then, a portion of the mixture was transferred to another 96-well plate and diluted to 1/10 using a K-Pi buffer containing a matrix. NADPH, a coenzyme, was added to start a reaction as an indicator (no pre-reaction: pre-incubation for 0 minutes). After the predetermined reaction time, the reaction was terminated by adding a methanol/acetonitrile = 1/1 (V/V) solution. Furthermore, NADPH was added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction: pre-incubation for 30 minutes), and after the pre-reaction predetermined time, a portion of it was transferred to another plate and diluted to 1/10 with K-Pi buffer containing the matrix, and the reaction as an index was started. After the predetermined reaction time, the reaction was terminated by adding a methanol/acetonitrile = 1/1 (V/V) solution. After each plate for the index reaction was centrifuged at 3000 rpm for 15 minutes, 1-midazolum hydroxide in the supernatant was quantified by LC/MS/MS.

將在反應溶液中取代本發明的化合物僅添加有屬於溶解化合物的溶劑之DMSO者作為對照組(100%)，算出添加有各個濃度的本發明化合物時的殘留活性(%)，並使用濃度與抑制率，藉由以對數模式進行之逆推定算出IC。將預培養0分鐘之IC/預培養30分鐘之IC作為移位(shifted)IC值，若移位IC為1.5以上，則為陽性(+)，若移位IC為1.0以下，則為陰性(-)。The control group (100%) was set to add only DMSO, a solvent for dissolving the compound, instead of the compound of the present invention in the reaction solution. The residual activity (%) when each concentration of the compound of the present invention was added was calculated, and the IC was calculated by reverse estimation in a logarithmic model using the concentration and inhibition rate. The IC at 0 minutes of pre-incubation/the IC at 30 minutes of pre-incubation was taken as the shifted IC value. If the shifted IC is 1.5 or more, it is positive (+), and if the shifted IC is less than 1.0, it is negative (-).

(結果)(result)

化合物I-032：(-)Compound I-032: (-)

化合物II-058：(-)Compound II-058: (-)

化合物II-117：(-)Compound II-117: (-)

化合物II-130：(-)Compound II-130: (-)

試驗例5：BA試驗Test example 5: BA test

經口吸收性的檢討實驗材料和方法Experimental materials and methods for evaluating oral absorbability

(1)使用動物：使用大鼠。(1) Animals used: Rats were used.

(2)飼育條件：使大鼠自由地攝取固形飼料及滅菌自來水。(2) Rearing conditions: Rats were allowed to freely ingest solid feed and sterilized tap water.

(3)投予量、分組設定：以預定投予量經口投予及靜脈內投予。如下述般設定分組。(有依各化合物變更投予量)(3) Dosage and group setting: Oral and intravenous administration at a predetermined dose. Grouping is set as follows. (The dosage may vary depending on the compound)

經口投予2至60μmol/kg或1至30mg/kg(n=2至3)Oral administration: 2 to 60 μmol/kg or 1 to 30 mg/kg (n=2 to 3)

靜脈內投予1至30μmol/kg或0.5至10mg/kg(n=2至3)Intravenous administration of 1 to 30 μmol/kg or 0.5 to 10 mg/kg (n=2 to 3)

(4)投予液的調製：經口投予係作成溶液或懸浮液投予。靜脈內投予係進行可溶化後投予。(4) Preparation of the dosing solution: Oral administration is made into a solution or suspension. Intravenous administration is made into a solubilized solution before administration.

(5)投予方法：經口投予係藉由經口探測器強制地投予至胃內。靜脈內投予係藉由附注射針的注射器由尾靜脈投予。(5) Administration method: Oral administration is forced into the stomach through an oral probe. Intravenous administration is administered through the coccygeal vein using a syringe with an injection needle.

(6)評估項目：隨時間採集血液，並使用LC/MS/MS測定血漿中本發明化合物濃度。(6) Evaluation items: Collect blood at different times and use LC/MS/MS to measure the concentration of the compound of the present invention in plasma.

(7)統計分析：針對血漿中本發明化合物濃度推移，藉由動量分析法(moment analysis method)算出血漿中濃度-時間曲線下面積(AUC)，並由經口投予組和靜脈內投予組之投予量比及AUC比算出本發明化合物的生體可用率(bioavailability)(BA)。(7) Statistical analysis: The concentration of the compound of the present invention in plasma was analyzed by the moment analysis method to calculate the area under the plasma concentration-time curve (AUC), and the bioavailability (BA) of the compound of the present invention was calculated from the dosage ratio and AUC ratio of the oral administration group and the intravenous administration group.

試驗例6：清除率評估試驗Test Example 6: Clearance Evaluation Test

實驗材料和方法Experimental materials and methods

(1)使用動物：使用大鼠。(1) Animals used: Rats were used.

(2)飼育條件：使大鼠自由地攝取固形飼料及無菌自來水。(2) Rearing conditions: Rats were allowed to freely ingest solid feed and sterile tap water.

(3)劑量、分組設定：以預定投予量投予靜脈內投予。如下述般設定分組。(3) Dose and group setting: Administer intravenously at a predetermined dose. Set the group as follows.

靜脈內投予1μmol/kg(n=2)Intravenous administration of 1μmol/kg (n=2)

(4)投予液的調製：使用二甲基亞碸/丙二醇=1/1溶劑進行可溶化後投予。(4) Preparation of the dosing solution: Use a solvent of dimethyl sulfoxide/propylene glycol = 1/1 to dissolve the solution and then administer.

(5)投予方法：藉由附注射針的注射器由尾靜脈投予。(5) Administration method: Injection through the coccygeal vein using a syringe with an injection needle.

(6)評估項目：隨時間採集血液，並使用LC/MS/MS測定血漿中本發明化合物濃度。(6) Evaluation items: Collect blood at different times and use LC/MS/MS to measure the concentration of the compound of the present invention in plasma.

(7)統計分析：關於血漿中本發明化合物濃度推移，藉由動量分析法算出全身清除率(CLtot)及消失半衰期(t1/2)。(7) Statistical analysis: Regarding the concentration transition of the compound of the present invention in plasma, the systemic clearance (CLtot) and the disappearance half-life (t1/2) were calculated by kinetic analysis.

(結果)(result)

化合物I-032：0.111mL/min/kg，12.3hrCompound I-032: 0.111mL/min/kg, 12.3hr

化合物II-023：0.102mL/min/kg，26.7hrCompound II-023: 0.102mL/min/kg, 26.7hr

化合物II-104：0.0226mL/min/kg，35.4hrCompound II-104: 0.0226mL/min/kg, 35.4hr

化合物II-110：0.0364mL/min/kg，23.6hrCompound II-110: 0.0364mL/min/kg, 23.6hr

由以上試驗結果可知，本發明化合物由於清除率小且消失半衰期長，因此可用作為持續性整合酶抑制劑。From the above test results, it can be seen that the compound of the present invention can be used as a persistent integrase inhibitor due to its low clearance rate and long disappearance half-life.

試驗例7：代謝穩定性試驗Test Example 7: Metabolic stability test

使市售的混合人類肝微粒體與本發明化合物反應一定時間，藉由反應試料和未反應試料的比較計算出殘留率，並評估本發明化合物在肝臟中被代謝的程度。Commercially available mixed human liver microsomes were reacted with the compound of the present invention for a certain period of time, and the residual rate was calculated by comparing the reaction sample with the unreacted sample, and the degree of metabolism of the compound of the present invention in the liver was evaluated.

含有人類肝微粒體0.5mg蛋白/mL的緩衝液(Tris-HCl 50mmol/L、pH 7.4，氯化鉀150mmol/L，氯化鎂10mmol/L)0.2mL中，在1mmol/L的NADPH存在下，在37℃進行0或30分鐘反應(氧化反應)。反應後，將反應液50μL添加至甲醇/乙腈=1/1(v/v)溶液100μL中，混合，並以3000rpm離心15分鐘。用LC/MS/MS或固相萃取(SPE)/MS定量該離心上清液中的本發明化合物，將反應0分鐘時的化合物量作為100%計算反應後本發明化合物的殘留量。In 0.2 mL of buffer (Tris-HCl 50 mmol/L, pH 7.4, potassium chloride 150 mmol/L, magnesium chloride 10 mmol/L) containing 0.5 mg protein/mL of human liver microsomes, the reaction (oxidation reaction) was carried out at 37°C for 0 or 30 minutes in the presence of 1 mmol/L NADPH. After the reaction, 50 μL of the reaction solution was added to 100 μL of a methanol/acetonitrile = 1/1 (v/v) solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the supernatant of the centrifugation was quantified by LC/MS/MS or solid phase extraction (SPE)/MS, and the amount of the compound at 0 minutes of the reaction was taken as 100% to calculate the residual amount of the compound of the present invention after the reaction.

(結果)化合物濃度為0.5μmol/L的殘留率如下表所示。(Results) The residual rate of the compound at a concentration of 0.5 μmol/L is shown in the following table.

[表15]

[Table 15]

試驗例8：彷徨變異(Fluctuation)安氏(Ames)試驗Test Example 8: Fluctuation Ames test

評估本發明化合物的致突變性。Evaluate the mutagenicity of the compounds of the present invention.

將凍結保存的鼠傷寒沙門桿菌(Salmonella typhimurium TA98株、TA100株)20μL接種在10mL液體營養培養基(2.5%Oxoid nutrient broth No.2)，於37℃，震盪前培養10小時。將TA98株的菌液7.70至8.00mL離心(2000×g，10分鐘)後去除培養液。將菌懸浮在與離心所用的菌液同容量的Micro F緩衝液(K₂HPO₄：3.5g/L、KH₂PO₄：1g/L、(NH₄)₂SO₄：1g/L、檸檬酸三鈉二水合物：0.25g/L、MgSO₄．7H₂O：0.1g/L)中，並添加至120mL的暴露培養基(Exposure medium)(含有生物素：8μg/mL、組胺酸：0.2μg/mL、葡萄糖：8mg/mL的MicroF緩衝液)。TA100株係將3.10至3.42mL的菌液添加至120至130mL的暴露培養基中而調製試驗菌液。將分別12μL之本發明化合物DMSO溶液(從最高用量50mg/mL以2至3倍公比進行數階段稀釋)、作為陰性對照組之DMSO、及作為陽性對照組係於非代謝活性化條件下，針對TA98株係50μg/mL的4-硝基喹啉-1-氧化物DMSO溶液，針對TA100株係0.25μg/mL的2-(2-呋喃基)-3-(5-硝基-2-呋喃基)丙烯醯胺DMSO溶液，於代謝活性化條件下針對TA98株係40μg/mL的2-胺基蒽DMSO溶液，針對TA 100株係20μg/mL的2-胺基蒽DMSO溶液，，與試驗菌液588μL混合(於代謝活性化條件下，試驗菌液為498μL和S9 mix 90μL的混合液)，並在37℃震盪培養90分鐘。將暴露有本發明化合物的菌液460μL與指示(indicator)培養基(含有生物素：8μg/mL、組胺酸：0.2μg/mL、葡萄糖：8mg/mL、溴甲酚紫：37.5μg/mL的MicroF緩衝液)2300μL混合，以各50μl分注到微量盤48孔/用量，並在37℃靜置培養3天。含有藉由胺基酸(組胺酸)合成酵素基因的突變而獲得增殖能力的菌之孔，係由於pH變化而從紫色變為黃色，因此計數每1用量48個孔中變色為黃色的菌增殖孔，與陰性對照組比較並評估。致突變性係陰性者表示為(-)，係陽性者表示為(+)。20 μL of frozen Salmonella typhimurium (Salmonella typhimurium TA98 strain, TA100 strain) was inoculated into 10 mL of liquid nutrient medium (2.5% Oxoid nutrient broth No. 2) and incubated at 37°C for 10 hours before shaking. 7.70 to 8.00 mL of the TA98 strain bacterial suspension was centrifuged (2000×g, 10 minutes) and the culture medium was removed. The bacteria were suspended in the same volume of Micro F buffer (K₂ HPO₄ : 3.5 g/L, KH₂ PO₄ : 1 g/L, (NH₄ )₂ SO₄ : 1 g/L, trisodium citrate dihydrate: 0.25 g/L, MgSO₄ .7H₂ O: 0.1 g/L) as the bacterial solution used for centrifugation, and added to 120 mL of exposure medium (Micro F buffer containing biotin: 8 μg/mL, histidine: 0.2 μg/mL, glucose: 8 mg/mL). For the TA100 strain, 3.10 to 3.42 mL of bacterial solution was added to 120 to 130 mL of exposure medium to prepare the test bacterial solution. 12 μL of the DMSO solution of the compound of the present invention (diluted in 2- to 3-fold ratios from the highest dose of 50 mg/mL), DMSO as a negative control group, and 50 μg/mL 4-nitroquinoline-1-oxide DMSO solution for TA98 strain, 0.25 μg/mL 2-(2-furanyl)-3-(5-nitro-2-furanyl)acrylamide DMSO solution for TA100 strain under non-metabolism activation conditions, 40 μg/mL 2-aminoanthracene DMSO solution for TA98 strain under metabolism activation conditions, and 0.25 μg/mL 2-aminoanthracene DMSO solution for TA100 strain under metabolism activation conditions were added to the positive control group. 100 strains of 20μg/mL 2-aminoanthracene DMSO solution were mixed with 588μL of test bacterial solution (498μL of test bacterial solution and 90μL of S9 mix under metabolic activation conditions) and cultured with shaking at 37°C for 90 minutes. 460μL of bacterial solution exposed to the compound of the present invention was mixed with 2300μL of indicator medium (MicroF buffer containing biotin: 8μg/mL, histidine: 0.2μg/mL, glucose: 8mg/mL, bromocresol purple: 37.5μg/mL), and 50μL was dispensed into 48 wells/dosage of a microtiter plate and cultured statically at 37°C for 3 days. The wells containing bacteria that have acquired the ability to proliferate due to mutations in the amino acid (histidine) synthase gene will change from purple to yellow due to pH changes. Therefore, count the wells with yellow bacterial proliferation among 48 wells per dose and compare with the negative control group for evaluation. Mutagenicity is indicated as (-) for negative and (+) for positive.

試驗例9：hERG試驗Test Example 9: hERG test

以本發明化合物的心電圖QT間隔風險評估作為目的，使用表現human ether-a-go-go related基因(hERG)通道的CHO細胞，檢討本發明化合物對於心室再極化過程中擔任重要功能的延遲整流K⁺電流(I_Kr)的作用。For the purpose of evaluating the electrocardiographic QT interval risk of the compounds of the present invention, CHO cells expressing human ether-a-go-go related gene (hERG) channels were used to examine the effects of the compounds of the present invention on delayed rectifier K⁺ current (I_Kr ) which plays an important role in the process of ventricular repolarization.

使用全自動膜片箝制系統(QPatch；Sophion Bioscience A/S)透過全細胞膜片箝制法將細胞保持在-80mV的膜電位，並施予-50mV的滲漏電位後，再施予+20mV的去極化刺激2秒，接著記錄施予-50mV的再極化刺激2秒時所誘發的I_Kr。將二甲基亞碸調整為0.1%的細胞外液(NaCl：145mmol/L、KCl：4mmol/L、CaCl2：2mmol/L、MgCl 2：1mmol/L、葡萄糖：10mmol/L、HEPES(4-(2-羥乙基)-1-哌

乙磺酸、4-(2-羥乙基)-1-哌

乙磺酸)：10mmol/L，pH=7.4)作為媒介，將媒介及溶解有目標濃度的本發明化合物溶解之細胞外液分別在室溫條件下適用於細胞7分鐘以上。由所得的I_Kr使用解析軟體(QPatch Assay軟體；Sophion Bioscience A/S)，將保持膜電位中的電流值作為基準計測最大尾電流的絕對值。進一步，將本發明化合物適用後的最大尾電流相對於媒介適用後的最大尾電流作為抑制率算出，評估本發明化合物對I_Kr的影響。The cells were held at a membrane potential of -80 mV by whole-cell patch clamping using a fully automated patch clamp system (QPatch; Sophion Bioscience A/S). After applying a leak potential of -50 mV, a depolarizing stimulus of +20 mV was applied for 2 seconds, and then the I_Kr induced by a repolarizing stimulus of -50 mV for 2 seconds was recorded. The extracellular solution (NaCl: 145 mmol/L, KCl: 4 mmol/L, CaCl2: 2 mmol/L, MgCl2: 1 mmol/L, glucose: 10 mmol/L, HEPES (4-(2-hydroxyethyl)-1-piperidinol) was adjusted to 0.1% dimethyl sulfoxide.

Ethylenesulfonic acid, 4-(2-hydroxyethyl)-1-piperidin

ethanesulfonic acid): 10mmol/L, pH=7.4) as a medium, and the medium and the extracellular solution in which the target concentration of the compound of the present invention is dissolved are applied to the cells at room temperature for more than 7 minutes. The obtained I_Kr is analyzed using analysis software (QPatch Assay software; Sophion Bioscience A/S), and the absolute value of the maximum tail current is measured using the current value in the membrane potential as a benchmark. Furthermore, the maximum tail current after the application of the compound of the present invention relative to the maximum tail current after the application of the medium is calculated as the inhibition rate to evaluate the effect of the compound of the present invention on I_Kr .

試驗例10：溶解度試驗Test Example 10: Solubility test

本發明化合物的溶解度係在添加1%DMSO的條件下測定。用DMSO調製成10mmol/L化合物溶液。將本發明的化合物溶液2μL分別添加至198μL的JP-1溶液、JP-2溶液。在室溫震盪1小時後，吸引過濾混合液。將濾液用甲醇/水=1/1(V/V)或乙腈/甲醇/水=1/1/2(V/V/V)進行10或100倍稀釋，並藉由絕對校準曲線法用LC/MS或固相萃取(SPE)/MS測定濾液中的濃度。The solubility of the compound of the present invention is measured under the condition of adding 1% DMSO. DMSO is used to prepare a 10mmol/L compound solution. 2μL of the compound solution of the present invention is added to 198μL of JP-1 solution and JP-2 solution respectively. After shaking at room temperature for 1 hour, the mixed solution is filtered by suction. The filtrate is diluted 10 or 100 times with methanol/water = 1/1 (V/V) or acetonitrile/methanol/water = 1/1/2 (V/V/V), and the concentration in the filtrate is measured by LC/MS or solid phase extraction (SPE)/MS by the absolute calibration curve method.

JP-1液的組成如下所述。The composition of JP-1 liquid is as follows.

於氯化鈉2.0g、鹽酸7.0mL中加水至1000mL。Add water to 2.0g sodium chloride and 7.0mL hydrochloric acid to make 1000mL.

JP-2的組成如下所述。The composition of JP-2 is as follows.

將磷酸二氫鉀3.40g及無水磷酸氫二鈉3.55g溶於水並製成1000mL者，並於其1容量中加水1容量。Dissolve 3.40g of potassium dihydrogen phosphate and 3.55g of anhydrous sodium dihydrogen phosphate in water to make 1000mL, and add 1 volume of water to 1 volume of the solution.

試驗例11：粉末溶解度試驗Test Example 11: Powder solubility test

將適量的本發明化合物放入適當的容器中，並在各容器中各添加200μL的JP-1液(氯化鈉2.0g、鹽酸7.0mL中加水製成1000mL)、JP-2液(將磷酸二氫鉀3.40g及無水磷酸氫二鈉3.55g溶於水並製成1000mL，並以其1容量加水1容量)、牛磺膽酸鈉(TCA)/JP-2液(在TCA 1.08g中添加JP-2液並製成100mL)20mmol/L。試驗液添加後並全量溶解時，適當地追加本發明化合物。密封並在37℃震盪1小時後過濾，各濾液100μL中添加甲醇100μL以進行2倍稀釋。稀釋倍率係因應需要而變更。確認沒有氣泡和析出物後密封並搖晃。藉由絕對校準曲線法用HPLC定量本發明化合物。Place an appropriate amount of the compound of the present invention in an appropriate container, and add 200 μL of JP-1 solution (2.0 g of sodium chloride, 7.0 mL of hydrochloric acid, add water to make 1000 mL), JP-2 solution (3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous sodium dihydrogen phosphate are dissolved in water to make 1000 mL, and 1 volume of water is added to 1 volume of the solution), sodium taurocholate (TCA)/JP-2 solution (1.08 g of TCA is added to JP-2 solution to make 100 mL) 20 mmol/L to each container. When the test solution is added and the entire amount is dissolved, add the compound of the present invention as appropriate. Seal and shake at 37°C for 1 hour, then filter, and add 100 μL of methanol to 100 μL of each filtrate to dilute it 2-fold. The dilution ratio is changed as needed. After confirming that there are no bubbles or precipitates, seal and shake. The compound of the present invention is quantified by HPLC using the absolute calibration curve method.

試驗例12：安氏試驗Test Example 12: Angle's test

將鼠傷寒沙門桿菌(Salmonella typhimurium)TA98株、TA100株、TA1535株、TA1537株及大腸桿菌(Escherichia coli)WP2uvrA株作為試驗菌株，藉由安氏試驗評估本發明化合物的致突變性。本發明化合物的DMSO溶液0.1mL中，在代謝活性化條件下混合S9 mix 0.5mL，在非代謝活性化條件下混合磷酸鹽緩衝液0.5mL及試驗菌液0.1mL，再與含有組胺酸及生物素或色胺酸的多層用軟瓊脂2mL一起覆蓋在最少葡萄糖瓊脂平板上。同時，對於陰性對照物質(DMSO)及陽性對照物質(2-(2-呋喃基)-3-(5-硝基-2-呋喃基)丙烯醯胺、疊氮化鈉、9-胺基吖啶或2-胺基蒽)亦同樣地實施。在37℃培養48小時後，計數出現的回復突變菌落並與陰性對照組比較評估。回復突變菌落數係以濃度依存地增加，並且將菌落數為陰性對照組的兩倍以上時判定為陽性(+)。The mutagenicity of the compounds of the present invention was evaluated by the Andrzej Klein test using Salmonella typhimurium TA98, TA100, TA1535, TA1537 and Escherichia coli WP2uvrA as test strains. 0.1 mL of the DMSO solution of the compounds of the present invention was mixed with 0.5 mL of S9 mix under metabolic activation conditions, 0.5 mL of phosphate buffer and 0.1 mL of test bacterial solution under non-metabolism activation conditions, and then covered on a minimal glucose agar plate together with 2 mL of multilayer soft agar containing histidine and biotin or tryptophan. At the same time, the negative control substance (DMSO) and the positive control substance (2-(2-furanyl)-3-(5-nitro-2-furanyl) acrylamide, sodium azide, 9-aminoacridine or 2-aminoanthracene) were also implemented in the same way. After 48 hours of incubation at 37°C, the reverted mutant colonies were counted and compared with the negative control group for evaluation. The number of reverted mutant colonies increased in a concentration-dependent manner, and when the number of colonies was more than twice that of the negative control group, it was judged to be positive (+).

測試例13：Nav測試Test Example 13: Nav Test

以本發明化合物的致心律不整風險評估作為目的，使用表達編碼SCN5A基因的電位閘控鈉離子通道(Voltage gated sodium channel，Nav1.5通道)的HEK細胞，檢討本發明化合物對於在心肌去極化過程中擔任重要功能的Na⁺電流(I_Na)的作用。For the purpose of evaluating the arrhythmogenic risk of the compounds of the present invention, HEK cells expressing the voltage-gated sodium channel (Nav1.5 channel) encoding the SCN5A gene were used to examine the effects of the compounds of the present invention on Na⁺ current (I_Na ) which plays an important role in the myocardial depolarization process.

使用全自動膜片箝制系統(QPatch；Sophion Bioscience A/S)透過全細胞膜片箝制法將細胞保持在-100mV的膜電位，記錄在施予-10mV的去極化刺激20ms時所誘發的I_Na。將二甲基亞碸調整至0.3%的細胞外液(NaCl：145mmol/L、KCl：4mmol/L、CaCl₂：2mmol/L、MgCl₂：1mmol/L、葡萄糖：10mmol/L、HEPES(4-(2-羥乙基)-1-哌

乙磺酸、4-(2-羥乙基)-1-哌

乙磺酸)：10mmol/L、TEA(四乙基氫氧化銨)：10mmol/L，pH=7.4)作為媒介，將媒介及溶解有目標濃度的本發明化合物的細胞外液分別在室溫條件下適用於細胞5分鐘以上。由所得的I_Na使用分析軟體(QPatch Assay軟體；Sophion Bioscience A/S)，以保持膜電位中的電流值作為基準計測最大峰值電流的絕對值。進一步，算出本發明化合物適用時的最大峰值電流相對於媒介適用時的最大峰值電流的比率，以評估本發明化合物對I_Na的影響。The cells were held at a membrane potential of -100 mV by whole-cell patch clamping using a fully automated patch clamp system (QPatch; Sophion Bioscience A/S), and the I_Na induced by a -10 mV depolarizing stimulus for 20 ms was recorded. The extracellular solution (NaCl: 145 mmol/L, KCl: 4 mmol/L, CaCl₂ : 2 mmol/L, MgCl₂ : 1 mmol/L, glucose: 10 mmol/L, HEPES (4-(2-hydroxyethyl)-1-piperidin-2-yl)-1-hydroxy ...

Ethylenesulfonic acid, 4-(2-hydroxyethyl)-1-piperidin

The medium and the extracellular solution containing the target concentration of the compound of the present invention were applied to the cells at room temperature for more than 5 minutes. The absolute value of the maximum peak current was measured using the analysis software (QPatch Assay software; Sophion Bioscience A/S) from the obtained I_Na , with the current value in the membrane potential maintained as the reference. Furthermore, the ratio of the maximum peak current when the compound of the present invention was applied to the maximum peak current when the medium was applied was calculated to evaluate the effect of the compound of the present invention on I_Na .

(結果)(result)

化合物I-007 103%Compound I-007 103%

化合物I-011 102%Compound I-011 102%

化合物I-022 97.1%Compound I-022 97.1%

化合物I-023 101%Compound I-023 101%

化合物I-032 92.1%Compound I-032 92.1%

化合物II-026 79%Compound II-026 79%

化合物II-098 96.7%Compound II-098 96.7%

化合物II-106 109%Compound II-106 109%

化合物II-109 93.3%Compound II-109 93.3%

化合物II-110 89.3%Compound II-110 89.3%

化合物II-117 88.8%Compound II-117 88.8%

化合物II-118 86.2%Compound II-118 86.2%

化合物II-120 78.8%Compound II-120 78.8%

化合物II-158 90.7%Compound II-158 90.7%

由以上的結果可知，未觀察到明顯的電流增加，本發明化合物係由Na電流的增加所引發的心律不整之疑慮低。From the above results, it can be seen that no obvious increase in current was observed, and the possibility of the compound of the present invention causing arrhythmia due to the increase in Na current is low.

試驗實施例14：使用健康人的末梢血單核球(Peripheral Blood Mononuclear Cell(PBMC))的抗HIV活性評估試驗Experimental Example 14: Anti-HIV activity evaluation test using peripheral blood mononuclear cells (PBMC) from healthy subjects

在96孔微量盤(50μL/孔)中製作測試試料的階段稀釋系列。將2.5×10⁵個/孔經過植物血凝素(Phytohemagglutinin(PHA))刺激後的PBMC和HIV病毒液，依所需孔數量份混和，並在37℃反應1小時。反應後，離心細胞懸浮液並廢棄上清液，將感染細胞以150μL/孔分散至所需孔數量份的培養液，並在含有測試試料的96孔微量盤中各分注150μL/孔。用盤混合器混合，並在CO₂培養箱中培養4天。測定培養液中的反轉錄酶活性。使用下述所示的四參數邏輯曲線擬合模型，由濃度依存曲線決定90%HIV抑制濃度(EC 90)。Prepare a series of step dilutions of the test sample in a 96-well microplate (50 μL/well). Mix 2.5×10⁵ cells/well of PBMCs stimulated with phytohemagglutinin (PHA) and HIV virus solution according to the number of wells required, and react at 37°C for 1 hour. After the reaction, centrifuge the cell suspension and discard the supernatant. Distribute the infected cells into the required number of wells at 150 μL/well of the culture medium, and dispense 150 μL/well into each of the 96-well microplates containing the test sample. Mix with a plate mixer and culture in a CO₂ incubator for 4 days. Determine the reverse transcriptase activity in the culture medium. The 90% HIV inhibition concentration (EC 90 ) was determined from the concentration dependence curve using the four-parameter logistic curve fitting model shown below.

y=A+((B-A)/(1+(C/x)^D))y=A+((BA)/(1+(C/x)^D ))

A=抑制率的最小值(陰性對照，0%)A=minimum inhibition rate (negative control, 0%)

B=抑制率的最大值(陽性對照，100%)B = Maximum inhibition rate (positive control, 100%)

C=轉折點處的化合物濃度C = Compound concentration at the turning point

D=斜率係數D = slope coefficient

x=化合物濃度x=compound concentration

y=抑制率(%)y=inhibition rate (%)

(結果)(result)

化合物I-007 1.0nMCompound I-007 1.0nM

化合物II-026 0.73nMCompound II-026 0.73nM

化合物II-045 3.3nMCompound II-045 3.3nM

化合物II-109 1.7nMCompound II-109 1.7nM

試驗例15：在人類血清蛋白存在下的抗HIV活性評估試驗Test Example 15: Anti-HIV activity evaluation test in the presence of human serum proteins

在96孔微量盤(50μL/孔)中製作測試試料的階段稀釋系列。將人類血清蛋白溶液(人類血清蛋白濃度：50%)以各100μL/孔分注到含有測試試料的盤，在室溫靜置1小時。血清非存在用的盤係以各100μL/孔分注培養液。將3.0×10⁵個細胞/孔的MT-4細胞和3μL/孔的HIV病毒溶液，依所需孔數量份混合，並在37℃反應1小時。反應後，離心細胞懸浮液並廢棄上清液，將感染細胞以50μL/孔分散至所需孔數量份的培養液，並在含有測試試料、人類血清蛋白的96孔微量盤中各分注50μL/孔(人類血清蛋白最終濃度：25%)。用盤混合器混合，並在CO₂培養箱中培養4天。將MTT(溴化3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑)溶液各30μL分注到各孔。在CO₂培養箱中反應1小時。從各個孔中以不吸除細胞之方式去除150μL上清液。添加150μL的細胞溶解液並用盤混合器充分地混合至所有細胞溶解。混合後的盤用微量盤檢測儀以560nm/690nm兩個波長測定吸光度。使用下述所示的四參數邏輯曲線擬合模型，由濃度依存曲線決定50%HIV抑制濃度(EC 50)。Prepare a series of step dilutions of the test sample in a 96-well microplate (50 μL/well). Pipette 100 μL/well of human serum protein solution (human serum protein concentration: 50%) into the plate containing the test sample and leave it at room temperature for 1 hour. Pipette 100 μL/well of culture medium into the plate without serum. Mix 3.0×10⁵ cells/well of MT-4 cells and 3 μL/well of HIV virus solution according to the required number of wells and react at 37°C for 1 hour. After the reaction, centrifuge the cell suspension and discard the supernatant. Distribute the infected cells into the required number of wells at 50 μL/well of the culture medium and dispense 50 μL/well into each well of a 96-well microtiter plate containing the test sample and human serum albumin (final concentration of human serum albumin: 25%). Mix with a plate mixer and incubate in a CO₂ incubator for 4 days. Dispense 30 μL of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) solution into each well. Incubate in a CO₂ incubator for 1 hour. Remove 150 μL of supernatant from each well without aspirating the cells. Add 150 μL of cell lysis solution and mix thoroughly with a plate mixer until all cells are dissolved. The mixed plate is measured for absorbance at two wavelengths of 560nm/690nm using a microplate detector. Using the four-parameter logical curve fitting model shown below, the 50% HIV inhibition concentration (EC 50) is determined from the concentration dependence curve.

y=A+((B-A)/(1+(C/x)^D))y=A+((BA)/(1+(C/x)^D ))

A=抑制率的最小值(陰性對照，0%)A=minimum inhibition rate (negative control, 0%)

B=抑制率的最大值(陽性對照，100%)B = Maximum inhibition rate (positive control, 100%)

C=轉折點處的化合物濃度C = Compound concentration at the turning point

D=斜率係數D = slope coefficient

x=化合物濃度x=compound concentration

y=抑制率(%)y=inhibition rate (%)

又，依據下述計算式算出效價轉移(potency shift(PS))。此外，PS係作為人類血清蛋白濃度外推值100%。In addition, the potency shift (PS) was calculated according to the following formula. In addition, PS is an extrapolated value of 100% of the human serum protein concentration.

PS=4×(人類血清蛋白25%存在下之EC50/人類血清蛋白非存在下之EC50)PS=4×(EC50 in the presence of 25% human serum protein/EC50 in the absence of human serum protein)

(結果)(result)

將人類血清蛋白存在下的PS示於表中(100%外推值)。The PS in the presence of human serum proteins is shown in the table (100% extrapolated value).

化合物I-007 116Compound I-007 116

化合物II-026 364Compound II-026 364

化合物II-045 236Compound II-045 236

化合物II-109 56Compound II-109 56

製劑例Preparation examples

本發明之化合物可以藉由以往的任意途徑，特別是經腸，例如經口例如以錠劑或膠囊劑的形態；或非經口例如以注射液劑或懸浮劑的形態；局部例如以乳液劑、凝膠、軟膏劑或乳膏劑的形態；經鼻形態或栓劑形態作成醫藥組成物投予。含有游離形態或藥學上可容許的鹽形態的本發明化合物及至少一種藥學上可容許的載體或稀釋劑之醫藥組成物，係可利用以往的方法藉由混合、造粒或塗膜法製造。例如，經口用組成物可製成含有賦形劑、崩解劑、結合劑、潤滑劑等及有效成分等的錠劑、顆粒劑、膠囊劑。又，注射用組成物可製成溶液劑或懸浮劑，也可為經滅菌者，亦可含有防腐劑、穩定劑、緩衝劑等。The compounds of the present invention can be administered as pharmaceutical compositions by any conventional route, particularly enteral, for example, oral, for example, in the form of tablets or capsules; or parenteral, for example, in the form of injection solutions or suspensions; topically, for example, in the form of emulsions, gels, ointments or creams; nasal, or suppositories. Pharmaceutical compositions containing the compounds of the present invention in free form or in the form of pharmaceutically acceptable salts and at least one pharmaceutically acceptable carrier or diluent can be prepared by conventional methods by mixing, granulating, or coating. For example, oral compositions can be prepared into tablets, granules, and capsules containing excipients, disintegrants, binders, lubricants, etc. and active ingredients. In addition, injectable compositions can be prepared into solutions or suspensions, can be sterilized, and can also contain preservatives, stabilizers, buffers, etc.

[產業上之可利用性][Industrial availability]

本發明化合物係對病毒，特別是針對HIV具有整合酶抑制活性及/或細胞增殖抑制活性。因此，可用於整合酶所參予的各種疾病或病毒感染症(例如AIDS)等的預防或治療。The compound of the present invention has integrase inhibitory activity and/or cell proliferation inhibitory activity against viruses, especially HIV. Therefore, it can be used to prevent or treat various diseases or viral infections (such as AIDS) involved in integrase.

Claims (11)

Translated fromChinese

一種式(I)所示之化合物或其製藥上容許的鹽，

式中，A環為下列環之任一者，

X1為CR^9aR^9b或O；R^5a、R^5b、R^6a、R^6b、R^7a及R^7b各自獨立地為氫、C1-C4烷基、C1-C4烷氧基或C1-C4烷氧基C1-C4烷基；以及R^5a及R^6a、或R^6a及R^7a可與相鄰的原子一起形成為可經鹵素取代的芳香族碳環、可經鹵素取代的3至6員的非芳香族碳環或者可經鹵素取代的4至6員的非芳香族雜環，惟，形成芳香族碳環時，R^5b及R^6b、或R^6b及R^7b一起形成鍵；或R^5b及R^6b可一起形成鍵；R^8a、R^8b、R^9a、R^9b、R^10a、R^10b、R^11a及R^11b各自獨立地為氫、C1-C4烷基、C1-C4烷氧基或C1-C4烷氧基C1-C4烷基；以及R^8a及R^10a可一起形成C1-C3交聯；或R^10a及R^11a可與相鄰的原子一起形成5員的非芳香族碳環；或R^9a及R^9b可與相鄰的原子一起形成4員的非芳香族碳環或5員的非芳香族雜環；R^8a及R^9a可一起形成鍵；B環為苯環；Q為下列環之任一者；

R¹各自獨立地為鹵素、C1-C4烷基、鹵C1-C4烷基、C1-C4烷氧基、氰基或鹵C1-C4烷氧基；R^2a及R^2b各自獨立地為氫、C1-C4烷基或鹵C1-C4烷基；R³為C1-C4烷基或鹵C1-C4烷基；R⁴為氫或C1-C4烷基；及n為1至3的整數。A compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

Wherein, ring A is any one of the following rings,

X1 is^CR9aR9b or O;^R5a, R5b,^R6a ,^R6b ,^R7a and^R7b are each independently hydrogen, C1-C4 alkyl, C1-C4 alkoxy or C1-C4 alkoxy^- C1-C4 alkyl; and^R5a and^R6a , or^R6a and^R7a may form together with adjacent atoms an aromatic carbocyclic ring which may be substituted by a halogen, a 3-6-membered non-aromatic carbocyclic ring which may be substituted by a halogen, or a 4-6-membered non-aromatic heterocyclic ring which may be substituted by a halogen, but when forming an aromatic carbocyclic ring,^R5b and^R6b , or^R6b and^R7b may form a bond together; or^R5b and^R6b may form a bond together;^R8a ,^R8b ,^R9a R , R^9b , R^10a , R^10b , R^11a and R^11b are each independently hydrogen, C1-C4 alkyl, C1-C4 alkoxy or C1-C4 alkoxy C1-C4 alkyl; and R^8a and R^10a may form a C1-C3 crosslink together; or R^10a and R^11a may form a 5-membered non-aromatic carbocyclic ring together with adjacent atoms; or R^9a and R^9b may form a 4-membered non-aromatic carbocyclic ring or a 5-membered non-aromatic heterocyclic ring together with adjacent atoms; R^8a and R^9a may form a bond together; Ring B is a benzene ring; Q is any one of the following rings;

^R1 is each independently halogen, C1-C4 alkyl, halogen C1-C4 alkyl, C1-C4 alkoxy, cyano or halogen C1-C4 alkoxy;^R2a and^R2b are each independently hydrogen, C1-C4 alkyl or halogen C1-C4 alkyl;^R3 is C1-C4 alkyl or halogen C1-C4 alkyl;^R4 is hydrogen or C1-C4 alkyl; and n is an integer from 1 to 3.如申請專利範圍第1項所述之化合物或其製藥上容許的鹽，其中，R³為C1-C4烷基。The compound or a pharmaceutically acceptable salt thereof as described in claim 1, wherein R³ is a C1-C4 alkyl group.如申請專利範圍第1項所述之化合物或其製藥上容許的鹽，其中，R¹各自獨立地為鹵素。The compound or a pharmaceutically acceptable salt thereof as described in claim 1, wherein each R¹ is independently a halogen.如申請專利範圍第1項所述之化合物或其製藥上容許的鹽，其中，R^2a為氫，R^2b為氫或C1-C4烷基。The compound or its pharmaceutically acceptable salt as described in Item 1 of the patent application, wherein R^2a is hydrogen and R^2b is hydrogen or C1-C4 alkyl.如申請專利範圍第1項所述之化合物或其製藥上容許的鹽，其中，Q為下式所示之環

The compound as described in item 1 of the patent application or its pharmaceutically acceptable salt, wherein Q is a ring represented by the following formula:

如申請專利範圍第1項所述之化合物或其製藥上容許的鹽，其中，R^5a、R^5b、R^6a、R^6b、R^7a及R^7b各自獨立地為氫、C1-C4烷基、C1-C4烷氧基或C1-C4烷氧基C1-C4烷基；以及R^8a、R^8b、R^9a、R^9b、R^10a、R^10b、R^11a及R^11b各自獨立地為氫、C1-C4烷基、C1-C4烷氧基或C1-C4烷氧基C1-C4烷基。The compound as described in claim 1 or a pharmaceutically acceptable salt thereof, wherein R^5a , R 5b , R^6a , R^6b , R^7a and R^7b are each independently hydrogen, C1-C4 alkyl, C1-C4 alkoxy or C1-C4 alkoxy-C1-C4 alkyl; and^R8a , R^8b , R 9a , R^9b , R^10a , R^10b , R^11a and R^11b are each independently hydrogen, C1-C4 alkyl, C1-C4 alkoxy or C1-C4 alkoxy^- C1-C4 alkyl.如申請專利範圍第1項所述之化合物或其製藥上容許的鹽，其中，R^5a、R^5b、R^6a、R^6b、R^7a及R^7b各自獨立地為氫、C1-C4烷基、C1-C4烷氧基或C1-C4烷氧基C1-C4烷基；R^8a、R^8b、R^9a、R^9b、R^10a、R^10b、R^11a及R^11b各自獨立地為氫、C1-C4烷基、C1-C4烷氧基或C1-C4烷氧基C1-C4烷基；R¹各自獨立地為鹵素；R^2a為氫，及R^2b為氫或烷基；以及R³為C1-C4烷基。The compound as described in claim 1 or a pharmaceutically acceptable salt thereof, wherein R^5a , R 5b , R^6a , R^6b , R^7a and R^7b are each independently hydrogen, C1-C4 alkyl, C1-C4 alkoxy or C1-C4 alkoxy-C1-C4 alkyl;^R8a , R^8b , R 9a , R^9b , R^10a , R^10b , R^11a and R^11b are each independently hydrogen, C1-C4 alkyl, C1-C4 alkoxy or C1-C4 alkoxy^- C1-C4 alkyl; R¹ is each independently halogen; R^2a is hydrogen, and R^2b is hydrogen or alkyl; and R³ is C1-C4 alkyl.如申請專利範圍第1項所述之化合物或其製藥上容許的鹽，該化合物係選自由下列化合物所組成的群組：

The compound or its pharmaceutically acceptable salt as described in item 1 of the patent application is selected from the group consisting of the following compounds:

如申請專利範圍第1項所述之化合物或其製藥上容許的鹽，該化合物係選自由化合物I-007、I-011、II-098、II-099、II-102、II-103、II-105、II-106、II-109、II-110、II-112、II-117、II-126、II-127及II-151所組成的群組：

The compound or its pharmaceutically acceptable salt as described in item 1 of the patent application is selected from the group consisting of compounds I-007, I-011, II-098, II-099, II-102, II-103, II-105, II-106, II-109, II-110, II-112, II-117, II-126, II-127 and II-151:

一種醫藥組成物，該醫藥組成物含有申請專利範圍第1至9項中任一項所述之化合物或其製藥上容許的鹽以及至少一種製藥上容許的載體及稀釋劑。A pharmaceutical composition, which contains a compound described in any one of items 1 to 9 of the patent application or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier and diluent.一種申請專利範圍第1至9項中任一項所述之化合物或其製藥上容許的鹽之用途，該用途係用以製造HIV感染症的治療劑及/或預防劑。A use of a compound described in any one of items 1 to 9 of the patent application scope or a pharmaceutically acceptable salt thereof, which is used to manufacture a therapeutic agent and/or preventive agent for HIV infection.