TW202120510A - Novel tetracyclic heterocyclic compounds and pharmaceutical use thereof - Google Patents

Abstract

The disclosure relates to novel tetracyclic heterocyclic compounds and pharmaceutical thereof Specifically, the disclosure provides a compound of formula I or a pharmaceutical salt thereof, the medicinal salt or its stereoisomer, rotational isomer or tautomer thereof, which can be used for the treatment or prevention of human immunodeficiency virus (HIV) infection. The substituents of general formula (I) is the same as those defined in the description.

Description

新型四環雜環化合物及其藥物用途 Novel tetracyclic heterocyclic compound and its pharmaceutical use

本公開屬於醫藥領域，涉及四環雜環化合物及其藥物用途。 The present disclosure belongs to the field of medicine, and relates to tetracyclic heterocyclic compounds and their pharmaceutical uses.

人類免疫缺陷病毒(HIV)的逆轉錄病毒，特別是已知為HIV1型(HIV-1)病毒和HIV2型(HIV-2)病毒的毒株，是複雜疾病的病原體，所述複雜疾病包括免疫系統的進行性地破壞(獲得性免疫缺陷綜合征；艾滋病)以及中樞和周圍神經系統的退化。人類免疫缺陷性病毒感染((HIV)是全世界的主要公共衛生問題。 Human immunodeficiency virus (HIV) retroviruses, particularly strains known as HIV type 1 (HIV-1) virus and HIV type 2 (HIV-2) virus, are pathogens of complex diseases including immunity Progressive destruction of the system (acquired immunodeficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. Human immunodeficiency virus infection ((HIV) is a major public health problem worldwide.

已知一些HIV抑制劑用於治療與AIDS或其類似疾病，如逆轉錄酶抑制劑如疊氮胸苷(AZT)和依法韋侖以及蛋白酶抑制劑如茚地那韋和奈非那韋。但是毒性和抗性株的發展限制了它們的有用性(Richman,D.D.Nature，(2001)410：995-1001)。因此，需要開發新的HIV抑制劑。 Some HIV inhibitors are known for the treatment of AIDS or similar diseases, such as reverse transcriptase inhibitors such as azidothymidine (AZT) and efavirenz and protease inhibitors such as indinavir and nelfinavir. However, the development of virulent and resistant strains limits their usefulness (Richman, DD Nature , (2001) 410:995-1001). Therefore, there is a need to develop new HIV inhibitors.

本公開(The disclosure)提供了式I所示化合物， The disclosure provides a compound represented by formula I,

或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體，

Or its pharmaceutically acceptable salt or its stereoisomers, rotamers or tautomers,

其中，環A、環C各自獨立地5至8員單環環烷基或雜環基、8至11員雙環環烷基或雙環雜環烷基，該環A或環C任選被側氧基，或者任選被選自鹵素(如氟、氯、溴)、羥基、烷基(如甲基、乙基、丙基、異丙基)、烷氧基(如甲氧基、乙氧基、丙氧基、異丙氧基)、環烷基(如環丙基、環戊基、環己基)、雜環基、-COR'、-S(O)₂R'、-CON(R')₂、芳基或雜芳基所取代，該烷基、烷氧基、環烷基、雜環基、芳基或雜芳基任選被一個或多個選自鹵素、烷基、環烷基、烷氧基、烯基、炔基、氧基、羥基、芳基、雜芳基、硝基、腈基、鹵烷基、鹵烷氧基、鹵環烷基、鹵雜環基、鹵芳基、鹵雜芳基、SR'、NR'(R")、OCOR'、OCOOR'、COOR'、CONR'(R")或OCONR'(R")所取代； Wherein, ring A and ring C are each independently a 5- to 8-membered monocyclic cycloalkyl or heterocyclic group, 8- to 11-membered bicyclic cycloalkyl or bicyclic heterocycloalkyl, the ring A or ring C is optionally pendant oxygen Group, or optionally selected from halogen (such as fluorine, chlorine, bromine), hydroxy, alkyl (such as methyl, ethyl, propyl, isopropyl), alkoxy (such as methoxy, ethoxy) , Propoxy, isopropoxy), cycloalkyl (such as cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl, -COR', -S(O) ₂ R', -CON(R' ) _2. Substituted by aryl or heteroaryl, the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted by one or more selected from halogen, alkyl, cycloalkane Group, alkoxy, alkenyl, alkynyl, oxy, hydroxyl, aryl, heteroaryl, nitro, nitrile, haloalkyl, haloalkoxy, halocycloalkyl, haloheterocyclyl, halo Substituted by aryl, haloheteroaryl, SR', NR'(R"), OCOR', OCOOR', COOR', CONR'(R") or OCONR'(R");

R¹或R²各自獨立地選自氫、鹵素(如氟、氯、溴)、羥基、烷基(如甲基、乙基、丙基、異丙基)、烷氧基(如甲氧基、乙氧基、丙氧基、異丙氧基)、環烷基(如環丙基、環戊基、環己基)、雜環基、芳基、雜芳基、SR'、NR'(R")、COOR'或CONR'(R")，該烷基、烷氧基、環烷基、雜環基、芳基或雜芳基任選被一個或多個選自烷基、烷氧基、環烷基、雜環基、烷氧基、烯基、炔基、芳基、雜芳基、硝基、腈基、羥基、鹵素、鹵烷基、鹵烷氧基、鹵環烷基、鹵雜環基、鹵芳基、鹵雜芳基、SR'、NR'(R")、COOR'或CONR'(R")所取代，或者，R¹、R²與其相鄰碳原子一起形成5員至12員碳環、雜環、芳環或雜芳環，較佳6員至8員碳環、雜環、芳環或雜芳環，該碳環、雜環、芳環或雜芳環 任選被選自烷基、鹵素、羥基、胺基、氧基、羧基、硝基、氰基、烷氧基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； R ¹ or R ² are each independently selected from hydrogen, halogen (such as fluorine, chlorine, bromine), hydroxyl, alkyl (such as methyl, ethyl, propyl, isopropyl), alkoxy (such as methoxy , Ethoxy, propoxy, isopropoxy), cycloalkyl (such as cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl, aryl, heteroaryl, SR', NR'(R "), COOR' or CONR'(R"), the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally selected from one or more alkyl groups, alkoxy groups , Cycloalkyl, heterocyclyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxyl, halogen, haloalkyl, haloalkoxy, halocycloalkyl, Substituted by haloheterocyclyl, haloaryl, haloheteroaryl, SR', NR'(R"), COOR' or CONR'(R"), or, R ¹ , R ² and its adjacent carbon atoms together form 5-membered to 12-membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, preferably 6 to 8-membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, the carbocyclic, heterocyclic, aromatic or heteroaromatic ring The ring is optionally selected from one or more of alkyl, halogen, hydroxyl, amino, oxy, carboxy, nitro, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl. Substituted by a substituent;

X、Y各自獨立地選自CH或N； X and Y are each independently selected from CH or N;

R'或R"獨立地選自氫、羥基、烷基、烷氧基、烯基、醯基、芳基或雜芳基，該烷基、烷氧基、芳基或雜芳基任選被一個或多個選自鹵素、烷基、環烷基、烷氧基、烯基、炔基、氧基、羥基、硝基、腈基或-R^a所取代，該R^a選自芳基或雜芳基，該芳基或雜芳基任選被一個或多個選自鹵素、烷基、環烷基、烷氧基、烯基、炔基、氧基、羥基、芳基、雜芳基、硝基、腈基、鹵烷基、鹵烷氧基、鹵環烷基、鹵雜環基、鹵芳基或鹵雜芳基所取代。 R'or R" is independently selected from hydrogen, hydroxy, alkyl, alkoxy, alkenyl, aryl, aryl or heteroaryl, and the alkyl, alkoxy, aryl or heteroaryl is optionally selected by one or more substituents selected from halo, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, alkoxy, hydroxy, nitro, nitrile, or substituted with -R ^a, R ^a is selected from the aryl group or Heteroaryl, the aryl or heteroaryl is optionally selected by one or more selected from halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxy, aryl, heteroaryl , Nitro, nitrile, haloalkyl, haloalkoxy, halocycloalkyl, haloheterocyclyl, haloaryl or haloheteroaryl.

在一個實施方案中，本公開提供式I化合物中環A或環C獨立選自雜環烷基是5員單環雜環烷基。在另一個實施方案中，雜環烷基是6-員單環雜環烷基。在另一個實施方案中，雜環烷基是8-員單環雜環烷基。 In one embodiment, the present disclosure provides that ring A or ring C in the compound of formula I independently selected from heterocycloalkyl is a 5-membered monocyclic heterocycloalkyl. In another embodiment, the heterocycloalkyl group is a 6-membered monocyclic heterocycloalkyl group. In another embodiment, the heterocycloalkyl group is an 8-membered monocyclic heterocycloalkyl group.

另一方面，在一個實施方案中，本公開提供式I化合物中環A或環C獨立選自環烷基是5員單環環烷基。在另一個實施方案中，雜環烷基是6員單環環烷基。在另一個實施方案中，雜環烷基是8員單環環烷基。 On the other hand, in one embodiment, the present disclosure provides that ring A or ring C in the compound of formula I independently selected from cycloalkyl is a 5-membered monocyclic cycloalkyl. In another embodiment, the heterocycloalkyl group is a 6-membered monocyclic cycloalkyl group. In another embodiment, the heterocycloalkyl group is an 8-membered monocyclic cycloalkyl group.

在一些可選實施方案中，式I所示的化合物為： In some alternative embodiments, the compound represented by Formula I is:

其中，環A、環C、R¹、X、Y如式I化合物中所定義；B選自-CONR^b-、-COO-，或五員至六員雜環； Wherein, ring A, ring C, R ¹ , X, Y are as defined in the compound of formula I; B is selected from -CONR ^b -, -COO-, or a five-member to six-member heterocycle;

R^b選自氫、羥基、烷基、烷氧基、烯基、醯基、芳基或雜芳基，該烷基、烷氧基、芳基或雜芳基任選被一個或多個選自鹵素、烷基、環烷基、烷氧基、烯基、炔基、氧基、羥基、硝基、腈基或-R^a所取代，該R^a選自芳基或雜芳基，該芳基或雜芳基任選被一個或多個選自鹵素、烷基、環烷基、烷氧基、烯基、炔基、氧基、羥基、芳基、雜芳基、硝基、腈基、鹵烷基、鹵烷氧基、鹵環烷基、鹵雜環基、鹵芳基或鹵雜芳基所取代； R ^{b is} selected from hydrogen, hydroxy, alkyl, alkoxy, alkenyl, acyl, aryl or heteroaryl, and the alkyl, alkoxy, aryl or heteroaryl is optionally selected from one or more from halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, alkoxy, hydroxy, nitro, nitrile, or substituted with -R ^a, R ^a is selected from the aryl group or heteroaryl group, which Aryl or heteroaryl is optionally selected by one or more selected from halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxy, aryl, heteroaryl, nitro, nitrile Group, haloalkyl, haloalkoxy, halocycloalkyl, haloheterocyclyl, haloaryl or haloheteroaryl;

R³選自氫、C_1-6烷基、C_3-8環烷基、3至8員雜環基、C_6-12芳基或6至12員雜芳基，該C_1-6烷基、C_3-8環烷基、3至8員雜環基、C_6-12芳基或6至12員雜芳基任選被一個或多個鹵素、烷基、環烷基、烷氧基、烯基、炔基、氧基、羥基、硝基、腈基、芳基或雜芳基所取代，該烷基、環烷基、烷氧基、芳基或雜芳基任選被一個或多個選自鹵素、烷基、環烷基、烷氧基、烯基、炔基、氧基、羥基、硝基、腈基或-R^a所取代。 R ^{3 is} selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, 3 to 8-membered heterocyclic group, C _6-12 aryl or 6 to 12 membered heteroaryl, the C _1-6 alkane Group, C _3-8 cycloalkyl, 3 to 8 membered heterocyclic group, C _6-12 aryl group or 6 to 12 membered heteroaryl group is optionally substituted by one or more halogen, alkyl, cycloalkyl, alkoxy Group, alkenyl, alkynyl, oxy, hydroxy, nitro, nitrile, aryl or heteroaryl, the alkyl, cycloalkyl, alkoxy, aryl or heteroaryl group is optionally substituted by one or more substituents selected from halo, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, alkoxy, hydroxy, nitro, nitrile, or substituted with -R ^a.

在另一些實施方案中，式I所示的化合物為： In other embodiments, the compound represented by Formula I is:

其中，R^c或R^d各自獨立地選自氫、鹵素、烷基、環烷基、烷氧基、烯基、炔基、氧基、羥基、芳基、雜芳基、硝基、腈基、鹵烷基、鹵烷氧基、鹵環烷基、鹵雜環基、鹵芳基或鹵雜芳基，或者R^c、R^d與其相鄰碳原子一起形成3員至12員碳環、雜環、芳環或雜芳環，較佳3員至8員碳環、雜環、芳環或雜芳環，該碳環、雜環、芳環或雜芳環任選被選自烷基、鹵素、羥基、胺 基、氧基、羧基、硝基、氰基、烷氧基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； Wherein, R ^c or R ^d are each independently selected from hydrogen, halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxy, aryl, heteroaryl, nitro, nitrile group , Haloalkyl, haloalkoxy, halocycloalkyl, haloheterocyclyl, haloaryl or haloheteroaryl, or R ^c , R ^d and their adjacent carbon atoms together form a 3-member to 12-member carbocyclic ring, Heterocyclic ring, aromatic ring or heteroaromatic ring, preferably 3-membered to 8-membered carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring, the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring is optionally selected from alkyl , Halogen, hydroxy, amino, oxy, carboxy, nitro, cyano, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl substituted by one or more substituents;

R⁴選自鹵素、烷基、環烷基、烷氧基、烯基、炔基、氧基、羥基、硝基、腈基、芳基或雜芳基，該芳基或雜芳基任選被一個或多個選自鹵素、烷基、環烷基、烷氧基、烯基、炔基、氧基、羥基、芳基、雜芳基、硝基、腈基，進一步地，R⁴較佳芳基或雜芳基。 R ^{4 is} selected from halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxyl, nitro, nitrile, aryl or heteroaryl, the aryl or heteroaryl optionally By one or more selected from halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxy, aryl, heteroaryl, nitro, nitrile, further, R ⁴ is more Best aryl or heteroaryl.

在一些實施方案中，本公開提供式III化合物中R⁴選自如下取代的芳基或雜芳基： In some embodiments, the present disclosure provides that R ^{4 in the} compound of formula III is selected from the following substituted aryl or heteroaryl:

在另一方面，本公開提供式I所示的化合物，其中B選自-CONH-或噻二唑基。 In another aspect, the present disclosure provides a compound represented by formula I, wherein B is selected from -CONH- or thiadiazolyl.

另一方面，本公開提供式I所示的化合物，其中環C選自： In another aspect, the present disclosure provides a compound represented by formula I, wherein ring C is selected from:

，其可以在環C碳原子上任選自且獨立地被選自C_1-6烷基(包括甲基、乙基、異丙基等)、C_1-6烷基氧基(包括甲氧基、乙氧基、異丙氧基等)、C_3-7環烷基(包括環丙烷基、環戊烷基、環己烷基等)所取代，可以在環C氮原子上任選自且獨立地被選自C_1-6烷基、-COR'、-S(O)₂R'、-CON(R')₂、C_3-7環烷基所取代，可以在環C硫原子上任選自且獨立地被氧化，R'如式I化合物中所定義。

, Which can be optionally and independently selected from C _1-6 alkyl (including methyl, ethyl, isopropyl, etc.), C _1-6 alkyloxy (including methoxy) on the ring C carbon atom Group, ethoxy group, isopropoxy group, etc.), C _3-7 cycloalkyl (including cyclopropyl, cyclopentyl, cyclohexane, etc.), and can be optionally substituted on the ring C nitrogen atom And are independently substituted by C _1-6 alkyl, -COR', -S(O) ₂ R', -CON(R') ₂ , and C _3-7 cycloalkyl, which can be in the ring C sulfur atom The above is optionally and independently oxidized, and R'is as defined in the compound of formula I.

在一些實施方案中，本公開提供式I所示的化合物中環C選自 In some embodiments, the present disclosure provides that ring C in the compound represented by formula I is selected from

環C結構中標注“*”表示相應官能團具有不同的空間構型，如 The mark "*" in the structure of ring C indicates that the corresponding functional groups have different spatial configurations, such as

另一方面，本公開提供式I所示的化合物，其中環A選自： In another aspect, the present disclosure provides a compound represented by formula I, wherein ring A is selected from:

，其可以在環A碳原子上任選自且獨立地被選自C_1-6烷基、C_1-6烷基氧基、C_3-7環烷基所取代，可以在環A氮原子上任選自且獨立地被選自C_1-6烷基、-COR'、-S(O)₂R'、-CON(R')₂、C_3-7環烷基所取代，可以在環A硫原子上任選自且獨立地被氧化，R'如式I化合物中所定義。

, Which can be optionally and independently substituted on the carbon atom of ring A by C _1-6 alkyl group, C _1-6 alkyloxy group, C _3-7 cycloalkyl group, and can be substituted on the ring A nitrogen atom The above is optionally and independently substituted by C _1-6 alkyl, -COR', -S(O) ₂ R', -CON(R') ₂ , C _3-7 cycloalkyl, and can be The sulfur atom of ring A is optionally and independently oxidized, and R'is as defined in the compound of formula I.

在一些實施方案中，本公開提供式I所示的化合物環A選自： In some embodiments, the present disclosure provides that the compound represented by Formula I, Ring A is selected from:

環A結構中標注“*”表示相應官能團具有不同的空間構型，如 The mark "*" in the structure of ring A means that the corresponding functional groups have different spatial configurations, such as

另一方面，本公開提供式III所示化合物中R^c、R^d選自氫；R⁴為被1至4個鹵素取代的苯基。 On the other hand, the present disclosure provides that R ^c and R ^d in the compound represented by formula III are selected from hydrogen; R ⁴ is a phenyl group substituted with 1 to 4 halogens.

在一些實施方案中，式III所示化合物中R^c、R^d選自氫；R⁵為被1至4個鹵素取代的苯基。 ^{In some embodiments, R c} and R ^d in the compound represented by formula III are selected from hydrogen; R ⁵ is phenyl substituted with 1 to 4 halogens.

在一些實施方案中，式III所示化合物中R⁴為被2個鹵素取代的苯基，較佳2,4-二氟苯基、2-氟-3-氯苯基、4-氟-3-氯苯基、2,3-二氟苯基、2,6-二氟苯基，3,4-二氟苯基、2-氟-4-氯苯基或3,5-二氟苯基。 ^{In some embodiments, R 4} in the compound represented by formula III is phenyl substituted with 2 halogens, preferably 2,4-difluorophenyl, 2-fluoro-3-chlorophenyl, 4-fluoro-3 -Chlorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 2-fluoro-4-chlorophenyl or 3,5-difluorophenyl .

在一些實施方案中，式III所示化合物中R⁴為被3個鹵素取代的苯基，較佳2,4,6-三氟苯基、2,3,4-三氟苯基、2,4,5-三氟苯基或2,4-二氟-3-氯苯基。 ^{In some embodiments, R 4} in the compound represented by formula III is phenyl substituted with 3 halogens, preferably 2,4,6-trifluorophenyl, 2,3,4-trifluorophenyl, 2, 4,5-trifluorophenyl or 2,4-difluoro-3-chlorophenyl.

在一些實施方案中，式III所示化合物中R⁴為被4個鹵素取代的苯基，較佳2,3,4,5-四氟苯基或2,3,4,6-四氟苯基。 ^{In some embodiments, R 4} in the compound of formula III is phenyl substituted with 4 halogens, preferably 2,3,4,5-tetrafluorophenyl or 2,3,4,6-tetrafluorobenzene base.

式I所示典型化合物，包括但不限於： Typical compounds represented by formula I include but are not limited to:

，或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體。

, Or its pharmaceutically acceptable salt or its stereoisomers, rotamers or tautomers.

在一些所示方案中，本公開提供式I所示化合物選自： In some of the shown schemes, the present disclosure provides that the compound of formula I is selected from:

，

或其可藥用的鹽或互變異構體。

,

Or its pharmaceutically acceptable salt or tautomer.

本公開中還提供了一種醫藥組成物，包括至少一種治療有效量的前述式I、II或III所示化合物或其可藥用的鹽以及藥學上可接受的載體、稀釋劑或賦形劑。 The present disclosure also provides a pharmaceutical composition, which includes at least one therapeutically effective amount of the compound represented by Formula I, II, or III or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

在一些實施方案中，該醫藥組成物的單位劑量為0.001mg-1000mg。 In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

在某些實施方案中，基於組合物的總重量，該醫藥組成物含有0.01-99.99%的前述化合物或其可藥用的鹽。在某些實施方案中，該醫藥組成物含有0.1-99.9%的前述化合物或其可藥用的鹽。在某些實施方案中，該醫藥組成物含有0.5%-99.5%的化合物或其可藥用的鹽。在某些實施方案中，該醫藥組成物含有1%-99%的化合物或其可藥用的鹽。在某些實施方案中，該醫藥組成物含有2%-98%的化合物或其可藥用的鹽。 In some embodiments, based on the total weight of the composition, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 1%-99% of the compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 2%-98% of the compound or a pharmaceutically acceptable salt thereof.

在某些實施方案中，基於組合物的總重量，該醫藥組成物含有0.01%-99.99%的藥學上可接受的賦形劑。在某些實施方案中，該醫藥組成物含有0.1%-99.9%的藥學上可接受的賦形劑。在某些實施方案中，該的醫藥組成物含有0.5%-99.5%的藥學上可接受的賦形劑。在某些實施方案中，該醫藥組成物含有1%-99%的藥學上可接受的賦形劑。在某些實施方案中，該醫藥組成物含有2%-98%的藥學上可接受的賦形劑。 In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of pharmaceutically acceptable excipients based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1% to 99.9% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 1%-99% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 2%-98% of pharmaceutically acceptable excipients.

另一方面，本公開中還提供了一種治療患有感染或處於患有感染風險中患者的HIV感染的方法，其藉由向該患者施用治療有效量的前述式I、II或III所示化合物或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體，或前述的醫藥組成物。 On the other hand, the present disclosure also provides a method for treating HIV infection in a patient suffering from infection or at risk of suffering from infection by administering to the patient a therapeutically effective amount of the compound represented by formula I, II or III. Or a pharmaceutically acceptable salt or a stereoisomer, rotamer or tautomer, or the aforementioned pharmaceutical composition.

本公開中還涉及上述方案中所述化合物或其可藥用鹽或其立體異構體、旋轉異構體或互變異構體，或前述的醫藥組成物在製備治療患有感染或處於患有感染風險中患者的HIV感染的藥物中的用途。 The present disclosure also relates to the compounds described in the above schemes or their pharmaceutically acceptable salts or their stereoisomers, rotamers or tautomers, or the aforementioned pharmaceutical compositions in the preparation and treatment of infections or patients suffering from Use in medicines for HIV infection in patients at risk of infection.

另一方面，本公開中所述化合物可藥用鹽選自無機鹽或有機鹽，本公開所述化合物與酸如三氟乙酸反應成相應鹽，該酸選自但不限於乙酸、鹽酸、水楊酸、蘋果酸、抗壞血酸、磷酸、檸檬酸、苯甲酸或富馬酸。本公開所述化合物與鹼如N-甲基-D葡甲胺或二環已胺反應成相應鹽，該鹼選自但不限於鈉、鹼土金屬、胺基酸(如精胺酸、賴胺酸)。 On the other hand, the pharmaceutically acceptable salt of the compound described in the present disclosure is selected from inorganic salts or organic salts, and the compound described in the present disclosure reacts with an acid such as trifluoroacetic acid to form a corresponding salt, and the acid is selected from but not limited to acetic acid, hydrochloric acid, water Salicylic acid, malic acid, ascorbic acid, phosphoric acid, citric acid, benzoic acid or fumaric acid. The compound described in the present disclosure reacts with a base such as N-methyl-D meglumine or dicyclohexylamine to form the corresponding salt, and the base is selected from but not limited to sodium, alkaline earth metals, amino acids (such as arginine, lysine) acid).

另一方面，本公開化合物可以存在特定的幾何或立體異構體形式。本公開設想所有的這類化合物，包括順式和反式異構體、(-)-和(+)-對對映體、(R)-和(S)-對映體、非對映異構體、(D)-異構體、(L)-異構體，及其外消旋混合物和其他混合物，例如對映異構體或非對映體富集的混合物，所有這些混合物都屬於本公開的範圍之內。烷基等取代基中可存在另外的不對稱碳原子。所有這些異構體以及它們的混合物，均包括在本公開的範圍之內。 On the other hand, the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. This disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Conformers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to Within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present disclosure.

另外，本公開的化合物和中間體還可以以不同的互變異構體形式存在，並且所有這樣的形式包含於本公開的範圍內。術語“互變異構體”或“互變異構體形式”是指可經由低能壘互變的不同能量的結構異構體。例如，質子互變異構體(也稱為質子轉移互變異構體)包括經由質子遷移的互變，如酮-烯醇及亞胺-烯胺、內醯胺-內醯亞胺異構化。內醯胺-內醯亞胺平衡實例是在如下所示的A和B之間。 In addition, the compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included in the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine, lactamine-endolimine isomerization. An example of a lactam-endimine balance is between A and B as shown below.

本發明中的所有化合物可以被畫成A型或B型。所有的互變異構形式在本發明的範圍內。化合物的命名不排除任何互變異構體。” All compounds in the present invention can be drawn as type A or type B. All tautomeric forms are within the scope of the invention. The naming of the compounds does not exclude any tautomers. "

本公開化合物可以是不對稱的，例如，具有一個或多個立體異構體。除非另有說明，所有立體異構體都包括，如對映異構體和非對映異構體。本公開的含有不對稱碳原子的化合物可以以光學活性純的形式或外消旋形式被分離出來。光學活性純的形式可以從外消旋混合物拆分，或藉由使用手性原料或手性試劑合成。 The compounds of the present disclosure may be asymmetric, for example, have one or more stereoisomers. Unless otherwise specified, all stereoisomers include, for example, enantiomers and diastereomers. The compounds containing asymmetric carbon atoms of the present disclosure can be isolated in an optically pure form or in a racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by using chiral raw materials or chiral reagents.

可以藉由的手性合成或手性試劑或者其他常規技術製備光學活性的(R)-和(S)-異構體以及D和L異構體。如果想得到本公開某化合物的一種對映體，可以藉由不對稱合成或者具有手性助劑的衍生作用來製備，其中將所得非對映體混合物分離，並且輔助基團裂開以提供純的所需對映異構體。或者，當分子中含有鹼性官能團(如胺基)或酸性官能團(如羧基)時，與適當的光學活性的酸或鹼形成非對映異構體的鹽，然後藉由本領域所公知的常規方法進行非對映異構體拆分，然後回收得到純的對映體。此外，對映異構體和非對映異構體的分離通常是藉由使用色譜法完成的，該色譜法採用手性固定相，並任選地與化學衍生法相結合(例如由胺生成胺基甲酸鹽)。 The optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one wants to obtain an enantiomer of a compound of the present disclosure, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amine group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with a suitable optically active acid or base, and then uses conventional methods known in the art to form diastereomeric salts. The method carries out the resolution of diastereomers, and then recovers the pure enantiomers. In addition, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography, which uses a chiral stationary phase and is optionally combined with chemical derivatization (for example, amine formation from amines). Formate).

本公開還包括一些與本文中記載的那些相同的，但一個或多個原子被原子量或質量數不同於自然中通常發現的原子量或質量數的原子置換的同位素標記的本公開化合物。可結合到本公開化合物的同位素的實例包括氫、碳、氮、氧、磷、硫、氟、碘和氯的同位素，諸如分別為²H、³H、¹¹C、¹³C、¹⁴C、¹³N、¹⁵N、¹⁵O、¹⁷O、¹⁸O、³¹P、³²P、³⁵S、¹⁸F、¹²³I、¹²⁵I和³⁶Cl等。 The present disclosure also includes some compounds of the present disclosure that are the same as those described herein, but have one or more atoms replaced with an isotope-labeled atom having an atomic weight or mass number different from the atomic weight or mass number commonly found in nature. Examples of isotopes that can be bound to the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I, ¹²⁵ I and ³⁶ Cl, etc.

除另有說明，當一個位置被特別地指定為氘(D)時，該位置應理解為具有大於氘的天然豐度(其為0.015%)至少1000倍的豐度的氘(即，至少10%的氘摻入)。示例中化合物的具有大於氘的天然豐度可以是至少1000倍的豐度的 氘、至少2000倍的豐度的氘、至少3000倍的豐度的氘、至少4000倍的豐度的氘、至少5000倍的豐度的氘、至少6000倍的豐度的氘或更高豐度的氘。本公開還包括各種氘化形式的式(I)化合物。與碳原子連接的各個可用的氫原子可獨立地被氘原子替換。本領域技術人員能夠參考相關文獻合成氘化形式的式(I)化合物。在製備氘代形式的式(I)化合物時可使用市售的氘代起始物質，或它們可使用常規技術採用氘代試劑合成，氘代試劑包括但不限於氘代硼烷、三氘代硼烷四氫呋喃溶液、氘代氫化鋰鋁、氘代碘乙烷和氘代碘甲烷等。 Unless otherwise specified, when a position is specifically designated as deuterium (D), the position should be understood as having an abundance of deuterium (ie, at least 10 % Deuterium incorporation). The compound in the example has a natural abundance greater than deuterium can be at least 1000 times the abundance Deuterium, at least 2000 times the abundance of deuterium, at least 3000 times the abundance of deuterium, at least 4000 times the abundance of deuterium, at least 5000 times the abundance of deuterium, at least 6000 times the abundance of deuterium or higher Degrees of deuterium. The present disclosure also includes compounds of formula (I) in various deuterated forms. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the compound of formula (I) in the deuterated form with reference to relevant literature. Commercially available deuterated starting materials can be used when preparing the deuterated form of the compound of formula (I), or they can be synthesized using conventional techniques using deuterated reagents. Deuterated reagents include but are not limited to deuterated borane and tri-deuterated. Borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.

“任選地”或“任選”是指意味著隨後所描述的事件或環境可以但不必發生，該說明包括該事件或環境發生或不發生的場合。例如“任選的被鹵素或者氰基取代的C_1-6烷基”是指鹵素或者氰基可以但不必須存在，該說明包括烷基被鹵素或者氰基取代的情形和烷基不被鹵素和氰基取代的情形。 "Optionally" or "optionally" means that the event or environment described later can but does not have to occur, and the description includes occasions where the event or environment occurs or does not occur. _{For example, "C 1-6} alkyl optionally substituted by halogen or cyano" means that halogen or cyano may but need not be present. The description includes the case where the alkyl is substituted by halogen or cyano and the alkyl is not substituted by halogen. And cyano substitution.

本發明所述化合物的化學結構中，鍵“

”表示未指定構型，即如果化學結構中存在手性異構體，鍵“

”可以為“

”或“

”，或者同時包含“

”和“

”兩種構型。雖然為簡便起見將全部上述結構式畫成某些異構體形式，但是本發明可以包括所有的異構體，如互變異構體、旋轉異構體、幾何異構體、非對映異構體、外消旋體和對映異構體。 In the chemical structure of the compound of the present invention, the bond "

"Indicates that the configuration is not specified, that is, if a chiral isomer exists in the chemical structure, the bond"

"Can be"

"or"

", or both "

"with"

"Two configurations. Although all the above structural formulas are drawn as certain isomer forms for simplicity, the present invention may include all isomers, such as tautomers, rotamers, and geometric isomers. Isomers, diastereomers, racemates and enantiomers.

製備式I所示化合物的方法 Method for preparing compound shown in formula I

根據有機合成領域技術人員已知的方法，由已知或容易製備的起始原料製備式I所示的化合物製備式I所示的化合物的方法如下所示，並概括在下面的方案中。對於有機合成領域的技術人員來說，替代的合成途徑和類似結構是顯而易見。 According to methods known to those skilled in the art of organic synthesis, the method for preparing the compound represented by formula I from known or easily prepared starting materials is as follows and is summarized in the following scheme. For those skilled in the field of organic synthesis, alternative synthetic routes and similar structures are obvious.

方案： Program:

其中，環A、環C、R¹-R³如前所述，PG₁、PG₂、PG₃為保護基。 Wherein, ring A, ring C, and R ¹ -R ^{3 are} as described above, and PG ₁ , PG ₂ , and PG ₃ are protecting groups.

術語解釋： Term explanation:

“可藥用載體、稀釋劑或賦形劑”包括但不限於任何已經被美國食品和藥物管理局批准對於人類或家畜動物使用可接受的任何助劑、載體、賦形劑、助流劑、甜味劑、稀釋劑、防腐劑、染料/著色劑、增香劑、表面活性劑、潤濕劑、分散劑、助懸劑、穩定劑、等滲劑、溶劑或乳化劑。 "Pharmaceutically acceptable carriers, diluents or excipients" include but are not limited to any adjuvants, carriers, excipients, glidants, Sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.

“烷基”指飽和的脂族烴基團，包括1至20個碳原子的直鏈和支鏈基團。較佳含有1至12個碳原子的烷基，更佳含有1至6個碳原子的烷基。非限制性實施例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基，及其各種支鏈異構體等。烷基可以是取代的或未取代的，當被取代時，取代基可以在任何可使用的連接點上被取代，較佳為一個或多個以下基團，獨立地選自鹵素、烷基、環烷基、烷氧基、烯基、炔基、氧基、羥基、硝基、腈基、芳基或雜芳基。 "Alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms. An alkyl group having 1 to 12 carbon atoms is preferred, and an alkyl group having 1 to 6 carbon atoms is more preferred. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, second butyl, n-pentyl, 1,1-dimethylpropyl Group, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, and various branched isomers体等。 Body and so on. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, alkyl, Cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxyl, nitro, nitrile, aryl or heteroaryl.

“烯基”包括具有2至12個碳原子的支鏈和直鏈烯烴或含有脂族烴基團的烯烴。例如“C_2-6烯基”表示具有2、3、4、5或6個碳原子的烯基。烯基的實例包括但不限於，乙烯基、烯丙基、1-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、2-甲基丁-2-烯基、3-甲基丁-1-烯基、1-戊烯基、3-戊烯基及4-己烯基。烯基可以是取代的或未取代的，當被取代時，取代基可以在任何可使用的連接 點上被取代，較佳為一個或多個以下基團，獨立地選自鹵素、烷基、環烷基、烷氧基、烯基、炔基、氧基、羥基、硝基、腈基、芳基或雜芳基。 "Alkenyl" includes branched and straight chain olefins having 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups. For example, "C _2-6 alkenyl" means an alkenyl group having 2, 3, 4, 5, or 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl. The alkenyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, alkyl, Cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxyl, nitro, nitrile, aryl or heteroaryl.

術語“環烷基”指飽和或部分不飽和單環或多環環狀烴取代基，環烷基環包含3至20個碳原子，較佳包含3至12個碳原子，更佳包含3至6個碳原子。單環環烷基的非限制性實例包括環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環己二烯基、環庚基、環庚三烯基、環辛基等；多環環烷基包括螺環、稠環和橋環的環烷基。 The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.

該環烷基環可以稠合於芳基、雜芳基或雜環烷基環上，其中與母體結構連接在一起的環為環烷基，非限制性實例包括茚滿基、四氫萘基、苯并環庚烷基等。環烷基可以是任選取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自鹵素、烷基、環烷基、烷氧基、烯基、炔基、氧基、羥基、硝基、腈基、芳基或雜芳基。 The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected with the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl , Benzocycloheptanyl, etc. Cycloalkyl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from halogen, alkyl, cycloalkyl, alkoxy, Alkenyl, alkynyl, oxy, hydroxy, nitro, nitrile, aryl, or heteroaryl.

術語“雜環基”指飽和或部分不飽和單環或多環環狀烴取代基，其包含3至20個環原子，其中一個或多個環原子為選自氮、氧或S(O)_m(其中m是整數0至2)的雜原子，但不包括-O-O-、-O-S-或-S-S-的環部分，其餘環原子為碳。較佳包含3至12個環原子，其中1~4個是雜原子；更佳包含3至8個環原子。單環雜環基的非限制性實例包括吡咯烷基、咪唑烷基、四氫呋喃基、四氫噻吩基、二氫咪唑基、二氫呋喃基、二氫吡唑基、二氫吡咯基、哌啶基、哌嗪基、嗎啉基、硫代嗎啉基、高哌嗪基等。多環雜環基包括螺環、稠環和橋環的雜環基。“雜環基”非限制性實例包括： The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) _m (where m is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine Group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups. Non-limiting examples of "heterocyclyl" include:

等等。

and many more.

該雜環基環可以稠合於芳基、雜芳基或環烷基環上，其中與母體結構連接在一起的環為雜環基，其非限制性實例包括： The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples of which include:

和

等。

with

Wait.

雜環烷基的環碳原子可以被氧代(官能化為羰基)。這種雜環烷基的示例性實例是： The ring carbon atoms of the heterocycloalkyl group can be oxo (functionalized as a carbonyl group). Illustrative examples of such heterocycloalkyl groups are:

術語“5至8員單環環烷基”是指具有5至8個環原子的單環環烷基，包括5員、6員、7員或8員環原子。術語“5至8員單環雜環烷基”是指具有5至8個環原子的單環雜環烷基，包括5員、6員、7員或8員環原子，至少一個環原子選自除碳原子以外的，如氮、氧或硫。術語“8至12員雙環環烷基”是指具有8至12個環原子的雙環環烷基，包括8員、10員或12員環原子。術語“8至12員雙環雜環烷基”是指具有8至12個環原子的雙環雜環烷基，包括8員、10員或12員 環原子，至少一個環原子選自除碳原子以外的，如氮、氧或硫。除非另有說明，環烷基、雜環烷基可以被取代的。 The term "5- to 8-membered monocyclic cycloalkyl" refers to a monocyclic cycloalkyl having 5 to 8 ring atoms, including 5-membered, 6-membered, 7-membered, or 8-membered ring atoms. The term "5- to 8-membered monocyclic heterocycloalkyl" refers to a monocyclic heterocycloalkyl having 5 to 8 ring atoms, including 5-, 6-, 7-, or 8-membered ring atoms, at least one ring atom is selected From other than carbon atoms, such as nitrogen, oxygen, or sulfur. The term "8 to 12 membered bicyclic cycloalkyl group" refers to a bicyclic cycloalkyl group having 8 to 12 ring atoms, including 8-membered, 10-membered, or 12-membered ring atoms. The term "8 to 12 membered bicyclic heterocycloalkyl group" refers to a bicyclic heterocycloalkyl group having 8 to 12 ring atoms, including 8-membered, 10-membered, or 12-membered The ring atoms, at least one ring atom is selected from other than carbon atoms, such as nitrogen, oxygen or sulfur. Unless otherwise specified, cycloalkyl and heterocycloalkyl may be substituted.

雜環基可以是任選取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自鹵素、烷基、環烷基、烷氧基、烯基、炔基、氧基、羥基、硝基、腈基、芳基或雜芳基。 The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from halogen, alkyl, cycloalkyl, alkoxy, Alkenyl, alkynyl, oxy, hydroxy, nitro, nitrile, aryl, or heteroaryl.

“炔基”包括具有2至12個碳原子的支鏈和直鏈炔基或含有脂族烴基的烯烴，或若規定指定碳原子數，則意指該特定數目。例如乙炔基、丙炔基(例如1-丙炔基、2-丙炔基)、3-丁炔基、戊炔基、己炔基及1-甲基戊-2-炔基。炔基可以是任選取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自鹵素、烷基、環烷基、烷氧基、烯基、炔基、氧基、羥基、硝基、腈基、芳基或雜芳基。 "Alkynyl" includes branched and straight chain alkynyl groups having 2 to 12 carbon atoms or alkene containing aliphatic hydrocarbon groups, or if the number of carbon atoms is specified, it means that specific number. For example, ethynyl, propynyl (e.g., 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl, and 1-methylpent-2-ynyl. The alkynyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from halogen, alkyl, cycloalkyl, alkoxy, alkene Group, alkynyl, oxy, hydroxy, nitro, nitrile, aryl or heteroaryl.

術語“芳基”指具有共軛的π電子體系的6至14員全碳單環或稠合多環(也就是共享毗鄰碳原子對的環)基團，較佳為6至12員，例如苯基和萘基。該芳基環可以稠合於雜芳基、雜環基或環烷基環上，其中與母體結構連接在一起的環為芳基環，其非限制性實例包括： The term "aryl" refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group with a conjugated π-electron system, preferably 6 to 12 members, for example Phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include:

芳基可以是取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自環烷基可以是任選取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自鹵素、烷基、環烷 基、烷氧基、烯基、炔基、氧基、羥基、硝基、腈基、芳基或雜芳基，較佳苯基。 Aryl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from cycloalkyl groups, which may be optionally substituted or unsubstituted, when When substituted, the substituent is preferably one or more of the following groups, which are independently selected from halogen, alkyl, cycloalkane Group, alkoxy, alkenyl, alkynyl, oxy, hydroxyl, nitro, nitrile, aryl or heteroaryl, preferably phenyl.

術語“雜芳基”指包含1至4個雜原子、5至14個環原子的雜芳族體系，其中雜原子選自氧、硫和氮。雜芳基較佳為6至12員，更佳為5員或6員。例如。其非限制性實例包括：咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、吡嗪，噻二唑

、

、

，等等。 The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group preferably has 6 to 12 members, more preferably 5 or 6 members. E.g. Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazine, thiadiazole

,

,

,and many more.

該雜芳基環可以稠合於芳基、雜環基或環烷基環上，其中與母體結構連接在一起的環為雜芳基環，其非限制性實例包括： The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

雜芳基可以是任選取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自環烷基可以是任選取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自鹵素、烷基、環烷基、烷氧基、烯基、炔基、氧基、羥基、硝基、腈基、芳基或雜芳基。 Heteroaryl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from cycloalkyl groups, which may be optionally substituted or unsubstituted When substituted, the substituent is preferably one or more of the following groups, which are independently selected from halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxyl, nitro , Nitrile, aryl or heteroaryl.

術語“烷氧基”指-O-(烷基)和-O-(非取代的環烷基)，其中烷基的定義如上該。烷氧基的非限制性實例包括：甲氧基、乙氧基、丙氧基、丁氧基、環丙氧基、環丁氧基、環戊氧基、環己氧基。烷氧基可以是任選取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選 自環烷基可以是任選取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自鹵素、烷基、環烷基、烷氧基、烯基、炔基、氧基、羥基、硝基、腈基、芳基或雜芳基。 The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected The self-cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from halogen, alkyl, cycloalkyl, alkoxy , Alkenyl, alkynyl, oxy, hydroxyl, nitro, nitrile, aryl or heteroaryl.

術語“鹵烷基”指被鹵素取代的烷基，其中烷基如上所定義。 The term "haloalkyl" refers to an alkyl substituted by halogen, where alkyl is as defined above.

術語“鹵芳基”指被鹵素取代的芳基，其中芳基如上所定義。 The term "haloaryl" refers to an aryl group substituted by halogen, wherein the aryl group is as defined above.

術語“鹵雜芳基”指被鹵素取代的雜芳基，其中雜芳基如上所定義。 The term "haloheteroaryl" refers to a heteroaryl group substituted by halogen, wherein the heteroaryl group is as defined above.

術語“鹵雜環基”指被鹵素取代的雜環基，其中雜環基如上所定義。 The term "haloheterocyclyl" refers to a heterocyclyl substituted by halogen, wherein the heterocyclyl is as defined above.

術語“鹵環烷基”指被鹵素取代的環基，其中環烷基如上所定義。 The term "halocycloalkyl" refers to a cyclic group substituted by halogen, wherein cycloalkyl is as defined above.

術語“羥基”指-OH基團。 The term "hydroxy" refers to the -OH group.

術語“鹵素”指氟、氯、溴或碘。 The term "halogen" refers to fluorine, chlorine, bromine or iodine.

術語“胺基”指-NH₂。 The term "amino" refers to -NH ₂ .

術語“氰基”指-CN。 The term "cyano" refers to -CN.

術語“硝基”指-NO₂。 The term "nitro" refers to -NO ₂ .

術語“側氧基”指=O取代基。 The term "pendant oxy" refers to the =0 substituent.

“任選”或“任選地”意味著隨後所描述地事件或環境可以但不必發生，該說明包括該事件或環境發生或不發生地場合。例如，“任選被烷基取代的雜環基團”意味著烷基可以但不必須存在，該說明包括雜環基團被烷基取代的情形和雜環基團不被烷基取代的情形。 "Optional" or "optionally" means that the event or environment described later can but does not have to occur, and the description includes the occasion where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may but does not have to be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .

“取代的”指基團中的一個或多個氫原子，較佳為最多5個，更佳為1~3個氫原子彼此獨立地被相應數目的取代基取代。不言而喻，取代基僅處在它們的可能的化學位置，本領域技術人員能夠在不付出過多努力的情況下確定(藉由實驗或理論)可能或不可能的取代。例如，具有游離氫的胺基或羥基與具有不飽和(如烯屬)鍵的碳原子結合時可能是不穩定的。 "Substituted" refers to one or more hydrogen atoms in the group, preferably at most 5, and more preferably 1 to 3 hydrogen atoms are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amine group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

本領域已知其在合成過程期間保護反應基團(包括而不限於羥基和胺基)免於副反應。用保護基保護的羥基和胺基在本文中分別稱為“保護的羥基”和“保護的胺基”。保護基通常選擇性地和/或正交性地使用以在其他反應性位點反應期間保護位點且然後可以被除去而留下無保護的基團保持原狀或參與進一步的反應。如本領域已知的保護基一般描述在Greene and Wuts,Protective Groups in Organic Synthes is,3rd edition,John Wiley&Sons,New York(1999)中。“羥基保護基”的實例包括但不限於第三丁基、第三-丁氧基甲基、甲氧基甲基、四氫吡喃基、1-乙氧基乙基、1-(2-氯乙氧基)乙基、2-三甲基甲矽烷基乙基、對-氯苯基、2,4-二硝基苯基、苄基、2,6-二氯苄基、二苯基-甲基、對-硝基苄基、三苯基甲基、三甲基甲矽烷基、三乙基甲矽烷基、第三丁基二甲基甲矽烷基、第三丁基-二苯基甲矽烷基(TBDPS)、三苯基甲矽烷基、苯甲醯基甲酸酯、乙酸酯、氯乙酸酯、三氯乙酸酯、三氟乙酸酯、特戊酸酯(pivaloate)、苯甲酸酯、對-苯甲酸苯酯、9-芴基甲基碳酸酯、甲磺酸酯和甲苯磺酸酯。 It is known in the art to protect reactive groups (including but not limited to hydroxyl and amine groups) from side reactions during the synthesis process. The hydroxyl group and the amino group protected with a protecting group are referred to herein as "protected hydroxyl group" and "protected amino group", respectively. Protecting groups are usually used selectively and/or orthogonally to protect sites during other reactive site reactions and can then be removed leaving the unprotected group intact or participating in further reactions. Protecting groups as known in the art are generally described in Greene and Wuts, Protective Groups in Organic Synthes is, 3rd edition, John Wiley & Sons, New York (1999). Examples of "hydroxy protecting groups" include, but are not limited to, tertiary butyl, tertiary butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1-(2- (Chloroethoxy) ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl, 2,6-dichlorobenzyl, diphenyl -Methyl, p-nitrobenzyl, triphenylmethyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyl-diphenyl Silyl (TBDPS), triphenylsilyl, benzoyl formate, acetate, chloroacetate, trichloroacetate, trifluoroacetate, pivaloate , Benzoate, phenyl p-benzoate, 9-fluorenyl methyl carbonate, mesylate and tosylate.

“胺基保護基”的實例包括但不限於胺基甲酸酯保護基，比如2-三甲基-甲矽烷基乙氧基羰基(Teoc)、1-甲基-1-(4-聯苯基)-乙氧基-羰基(Bpoc)、第三-丁氧基羰基(BOC)、烯丙氧基羰基(Al loc)、9-芴基甲基氧基羰基(Fmoc)和苄基氧基羰基(Cbz)；醯胺保護基，比如甲醯基、乙醯基、三氯乙醯基、苯甲醯基和 硝基苯基乙醯基；磺醯胺-保護基，比如2-硝基苯磺醯基；和亞胺和環狀亞胺保護基，比如苯二甲醯亞胺基和二硫雜丁二醯基。 Examples of "amino protecting groups" include, but are not limited to, carbamate protecting groups, such as 2-trimethyl-silylethoxycarbonyl (Teoc), 1-methyl-1-(4-biphenyl) Group)-ethoxy-carbonyl (Bpoc), third-butoxycarbonyl (BOC), allyloxycarbonyl (Al loc), 9-fluorenylmethyloxycarbonyl (Fmoc) and benzyloxy Carbonyl (Cbz); amide protecting groups, such as formyl, acetyl, trichloroacetyl, benzyl and Nitrophenylacetonitrile; sulfonamide-protecting groups, such as 2-nitrobenzenesulfonyl; and imine and cyclic imine protecting groups, such as xylylenedimethine imino and dithiabutane醯基.

本公開還考慮了式I化合物的前藥和溶劑化物。“前藥”是指在體內轉化以提供四環雜化合物或該化合物的可藥用鹽的化合物。轉化可藉由各種機制(如藉由代謝過程或化學過程)發生，例如在血液中的水解。四環雜環化合物中含有“--OH”官能團可以藉由用諸如以下的基團代替醇基的一個或多個氫原子來形成前藥：(C_1-6)烷醯氧基甲基、1-((C_1-6)烷醯氧基)乙基、1-甲基-1-((C_1-6)烷醯氧基)乙基、(C_1-6)烷氧基羰氧基甲基、N-(C_1-6)烷氧基羰基胺基甲基、琥珀醯基、(C_1-6)烷醯基、α-胺基(C_1-4)烷基、α-胺基(C_1-4)亞烷基-芳基、芳醯基和α-胺醯基、或α-胺醯基-α-胺醯基，其中每個α-胺醯基獨立地選自天然存在的L-胺基酸或糖基(藉由除去碳水化合物的半縮醛形式的羥基而產生的基團)。 The present disclosure also contemplates prodrugs and solvates of compounds of formula I. "Prodrug" refers to a compound that is transformed in the body to provide a tetracyclic heterocompound or a pharmaceutically acceptable salt of the compound. Transformation can occur through various mechanisms (such as through metabolic or chemical processes), such as hydrolysis in the blood. Tetracyclic heterocyclic compounds containing "--OH" functional groups can form prodrugs by replacing one or more hydrogen atoms of alcohol groups with groups such as the following: (C _1-6 )alkyloxymethyl, 1-((C _1-6 )alkyloxy)ethyl, 1-methyl-1-((C _1-6 )alkyloxy)ethyl, (C _1-6 )alkoxycarbonyloxy Alkylmethyl, N-(C _1-6 )alkoxycarbonylaminomethyl, succinyl, (C _1-6 )alkanoyl, α-amino(C _1-4 )alkyl, α- Amino (C _1-4 ) alkylene-aryl, aryl and α-amino groups, or α-amino groups-α-amino groups, wherein each α-amino group is independently selected from Naturally occurring L-amino acids or sugar groups (groups produced by removing the hydroxyl group in the hemiacetal form of carbohydrates).

另一方面，如果四環雜環化合物包含胺官能團，則可以藉由用諸如以下的基團代替胺基中的氫原子來形成前藥：R^e-羰基-，R^eO-羰基-，NRR^f-羰基，其中R^e和R^f各自獨立地為(C_1-10)烷基、(C_3-7)環烷基、苄基、天然α-胺醯基、-C(OH)C(O)OZ₁(其中Z₁是H、(C_1-6)烷基或苄基)、-C(OZ₂)Z₃(其中Z₂是(C_1-4)烷基，Z₃是(C_1-6)烷基；羧基(C_1-6)烷基；胺基(C_1-4)烷基或單-N-(C_1-6)烷基胺基烷基或二-N,N-(C_1-6)烷基胺基烷基；-C(Z₄)Z₅(其中Z₄是H或甲基，Z₅是單-N-(C_1-6)烷基胺基嗎啉基或二-N,N-(C_1-6)烷基胺基嗎啉基；哌啶-1-基或吡咯烷-1-基等。 On the other hand, if the tetracyclic heterocyclic compound comprises an amine functional group, such as the following may be used by the group in place of a hydrogen atom in the amine group to form a prodrug: R ^e - carbonyl -, R ^e O- carbonyl -, NRR ^f -carbonyl, wherein R ^e and R ^f are each independently (C _1-10 ) alkyl, (C _3-7 ) cycloalkyl, benzyl, natural α-amino acyl, -C(OH)C( O) OZ ₁ (where Z ₁ is H, (C _1-6 )alkyl or benzyl), -C(OZ ₂ )Z ₃ (where Z ₂ is (C _1-4 )alkyl, Z ₃ is ( C _1-6 )alkyl; carboxy(C _1-6 )alkyl; amino(C _1-4 )alkyl or mono-N-(C _1-6 )alkylaminoalkyl or di-N, N-(C _1-6 )alkylaminoalkyl; -C(Z ₄ )Z ₅ (where Z ₄ is H or methyl, and Z ₅ is mono-N-(C _1-6 )alkylamino Morpholinyl or di-N,N-(C _1-6 )alkylaminomorpholinyl; piperidin-1-yl or pyrrolidin-1-yl, etc.

“醫藥組成物”表示含有一種或多種本文所述化合物或其生理學上可藥用的鹽或前體藥物與其他化學組分的混合物，以及其他組分例如生理學可藥用的載體和賦形劑。醫藥組成物的目的是促進對生物體的給藥，利於活性成分的吸收進而發揮生物活性。 "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients. Shape agent. The purpose of the medicinal composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.

以下結合實施例進一步描述本公開中，但這些實施例並非限制本公開中的範圍。 The following further describes the present disclosure in conjunction with embodiments, but these embodiments do not limit the scope of the present disclosure.

本公開中實施例中未註明具體條件的實驗方法，通常按照常規條件，或按照原料或商品製造廠商所建議的條件。未註明具體來源的試劑，為市場購買的常規試劑。 In the embodiments of the present disclosure, the experimental methods without specific conditions are usually in accordance with conventional conditions, or in accordance with the conditions suggested by the raw material or commodity manufacturers. The reagents without specific sources are the conventional reagents purchased on the market.

化合物的結構是藉由核磁共振(NMR)或/和質譜(MS)來確定的。NMR位移(δ)以10^-6(ppm)的單位給出。NMR的測定是用Bruker AVANCE-400核磁儀，測定溶劑為氘代二甲基亞碸(DMSO-d ₆ )，氘代氯仿(CDCl₃)，氘代甲醇(CD₃OD)，內標為四甲基矽烷(TMS)。 The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift (δ) is given in units of ^{10 -6 (ppm).} NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was four Methyl Silane (TMS).

HPLC的測定使用Waters ACQUITY ultra high performance LC、Shimadzu LC-20A systems、Shimadzu LC-2010HT series或安捷倫Agilent 1200 LC高壓液相色譜儀(ACQUITY UPLC BEH C18 1.7UM 2.1X50MM色譜管柱、Ultimate XB-C18 3.0*150mm色譜管柱或Xtimate C18 2.1*30mm色譜管柱)。 HPLC determination uses Waters ACQUITY ultra high performance LC, Shimadzu LC-20A systems, Shimadzu LC-2010HT series or Agilent 1200 LC high pressure liquid chromatograph (ACQUITY UPLC BEH C18 1.7UM 2.1X50MM chromatographic column, Ultimate XB-C18 3.0 *150mm chromatographic column or Xtimate C18 2.1*30mm chromatographic column).

MS的測定用Waters SQD2質譜儀，以正/負離子模式掃描，質量掃描範圍為100~1200。 The MS determination uses Waters SQD2 mass spectrometer, scanning in positive/negative ion mode, and the mass scanning range is 100~1200.

手性HPLC分析測定使用Chiralpak IC-3 100×4.6mm I.D.，3um、Chiralpak AD-3 150×4.6mm I.D.，3um、Chiralpak AD-3 50×4.6mm I.D.，3um、Chiralpak AS-3 150×4.6mm I.D.，3um、Chiralpak AS-3 100×4.6mm I.D.，3μm、ChiralCel OD-3 150×4.6mm I.D.，3um、Chiralcel OD-3 100×4.6mm I.D.，3μm、 ChiralCel OJ-H 150×4.6mm I.D.，5um、Chiralcel OJ-3 150×4.6mm I.D.，3um色譜管柱； Chiralpak IC-3 100×4.6mm ID, 3um, Chiralpak AD-3 150×4.6mm ID, 3um, Chiralpak AD-3 50×4.6mm ID, 3um, Chiralpak AS-3 150×4.6mm ID, 3um, Chiralpak AS-3 100×4.6mm ID, 3 μm , ChiralCel OD-3 150×4.6mm ID, 3um, Chiralcel OD-3 100×4.6mm ID, 3 μm , ChiralCel OJ-H 150× 4.6mm ID, 5um, Chiralcel OJ-3 150×4.6mm ID, 3um chromatographic column;

薄層層析矽膠板使用煙臺黃海HSGF254或青島GF254矽膠板，薄層色譜法(TLC)使用的矽膠板採用的規格是0.15mm~0.2mm，薄層層析分離純化產品採用的規格是0.4mm~0.5mm。 The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the size of thin layer chromatography separation and purification products is 0.4mm. ~0.5mm.

快速管柱純化系統使用Combiflash Rf150(TELEDYNE ISCO)或者Isolara one(Biotage)。 The fast column purification system uses Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).

正向管柱層析一般使用煙臺黃海矽膠100~200目、200~300目或300~400目矽膠為載體，或者使用常州三泰預填預填超純正相矽膠管柱(40-63μm，60，12g,，25g，40g，80g或其他規格)。 Forward column chromatography generally uses Yantai Huanghai silicone gel 100~200 mesh, 200~300 mesh or 300~400 mesh silica gel as the carrier, or use Changzhou Santai pre-filled and pre-filled ultra-pure normal phase silica gel column (40-63 μ m , 60, 12g,, 25g, 40g, 80g or other specifications).

反相管柱層析一般使用常州三泰預填超純C18矽膠管柱(20-45μm，100□，40g，80g，120g，220g或其他規格)。 Reversed-phase column chromatography generally uses Changzhou Santai pre-packed ultra-pure C18 silica gel column (20-45 μm , 100□, 40g, 80g, 120g, 220g or other specifications).

高壓管柱純化系統使用Waters AutoP，配合使用Waters XBridge BEH C18 OBD Prep Column，130Å，5μm，19mm X 150mm或者Atlantis T3 OBD Prep Column，100Å，5μm，19mm X 150mm。 The high-pressure column purification system uses Waters AutoP, with Waters XBridge BEH C18 OBD Prep Column, 130Å, 5μm, 19mm X 150mm or Atlantis T3 OBD Prep Column, 100Å, 5μm, 19mm X 150mm.

手性製備管柱使用DAICEL CHIRALCEL AD(250mm*30mm,10um)或Phenomenex-Amylose-1(250mm*30mm,5um)。 The chiral preparation column uses DAICEL CHIRALCEL AD (250mm*30mm, 10um) or Phenomenex-Amylose-1 (250mm*30mm, 5um).

本公開中的已知的起始原料可以採用或按照本領域已知的方法來合成，或可購買自上海泰坦科技，ABCR GmbH & Co.KG，Acros Organics，Aldrich Chemical Company，韶遠化學科技(Accela ChemBio Inc)、達瑞化學品等公司。 The known starting materials in the present disclosure can be synthesized by or according to methods known in the art, or can be purchased from Shanghai Titan Technology, ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology ( Accela ChemBio Inc), Darui Chemicals and other companies.

實施例中無特殊說明，反應能夠均在氬氣氛或氮氣氛下進行。 There is no special description in the examples, and the reaction can all be carried out under an argon atmosphere or a nitrogen atmosphere.

氬氣氛或氮氣氛是指反應瓶連接一個約1L容積的氬氣或氮氣氣球。 The argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.

氫氣氛是指反應瓶連接一個約1L容積的氫氣氣球。 The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.

加壓氫化反應使用Parr 3916EKX型氫化儀和清藍QL-500型氫氣發生器或HC2-SS型氫化儀。 The pressure hydrogenation reaction uses Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.

氫化反應通常抽真空，充入氫氣，重複操作3次。 The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.

微波反應使用CEM Discover-S 908860型微波反應器。 The microwave reaction uses a CEM Discover-S 908860 microwave reactor.

實施例中無特殊說明，溶液是指水溶液。 No special instructions in the examples, the solution refers to an aqueous solution.

實施例中無特殊說明，反應的溫度為室溫，為20℃~30℃。 There are no special instructions in the examples, and the reaction temperature is room temperature, which is 20°C to 30°C.

實施例中的反應進程的監測採用薄層色譜法(TLC)，反應所使用的展開劑，純化化合物採用的管柱層析的沖提劑的體系和薄層色譜法的展開劑體系，溶劑的體積比根據化合物的極性不同而進行調節，也可以加入少量的三乙胺和醋酸等鹼性或酸性試劑進行調節。 The monitoring of the reaction progress in the examples adopts thin-layer chromatography (TLC), the developing reagent used in the reaction, the eluent system of column chromatography used to purify the compound, and the developing reagent system of thin-layer chromatography. The volume ratio is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.

實施例1 Example 1

N-(2,4-二氟苯甲基)-6-羥基-5,7-二羰基-2,2a,2a1,3,4,5,7,9b-八氫-1H-4a,9a-二氮雜戊搭烯并[1,6-ab]萘-8-甲醯胺異構體(A)化合物1 N -(2,4-Difluorobenzyl)-6-hydroxy-5,7-dicarbonyl-2,2a,2a1,3,4,5,7,9b-octahydro-1 H -4a,9a -Diazapenteno[1,6-ab]naphthalene-8-formamide isomer (A) compound 1

第一步 first step

(Z)-2-((二甲胺基)亞甲基)-4-甲氧基-3-羰基丁酸甲基酯1c (Z)-2-((Dimethylamino)methylene)-4-methoxy-3-carbonylbutyric acid methyl ester 1c

將4-甲氧基乙醯乙酸甲酯(26.57mL,205.28mmol)和N,N-二甲基甲醯胺二甲縮醛(27.48mL,205.28mmol)的混合物在85℃加熱攪拌30分鐘。反應液冷卻至室溫，減壓濃縮，得到標題化合物1c(40.4g，產率98%)。 A mixture of methyl 4-methoxyacetate (26.57 mL, 205.28 mmol) and N,N-dimethylformamide dimethyl acetal (27.48 mL, 205.28 mmol) was heated and stirred at 85°C for 30 minutes. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the title compound 1c (40.4 g, yield 98%).

MS(ESI)m/z 224.1[M+H]⁺ MS(ESI)m/z 224.1[M+H] ⁺

第二步 Second step

3-甲氧基-4-羰基-4H-吡喃-2,5-二羧酸2-乙基酯5-甲基酯1d 3-Methoxy-4-carbonyl-4H-pyran-2,5-dicarboxylic acid 2-ethyl ester 5-methyl ester 1d

將第三丁醇鈉(13.37g,139.15mmol)加到化合物1c(10g,139.1512mmol)與草酸二乙酯(20mL)的混合物中。所得反應液在室溫下反應12小時後，加入醋酸(20mL)。所得混合物直接用C18反相管柱以乙腈、水沖提純化，凍乾後得到標題化合物1d(4g，產率11%)。 Sodium tertiary butoxide (13.37 g, 139.15 mmol) was added to a mixture of compound 1c (10 g, 139.1512 mmol) and diethyl oxalate (20 mL). After reacting the resulting reaction solution at room temperature for 12 hours, acetic acid (20 mL) was added. The obtained mixture was directly purified by C18 reversed-phase column with acetonitrile and water, and lyophilized to obtain the title compound 1d (4g, yield 11%).

MS(ESI)m/z 257.1[M+H]⁺ MS(ESI)m/z 257.1[M+H] ⁺

第三步 third step

順式-6R-6-羥基六氫環戊二烯并[b]吡咯-1(2H)-羧酸第三-丁基酯1f Cis-6R-6-Hydroxyhexahydrocyclopenta[b]pyrrole-1(2H)-carboxylic acid tert-butyl ester 1f

將順式-6R-八氫環戊二烯并[b]吡咯-6-酚鹽酸(250mg,1.53mmol)溶解於5毫升二氯甲烷中，依次加入三乙胺(0.42mL,3.05mmol)二碳酸二第三丁酯(400.09mg，1.83mmol)，室溫攪拌5小時。將反應液藉由減壓濃縮，濃縮完後用乙酸乙酯(20mL)稀釋。有機相經過20毫升水洗兩次，並用無水硫酸鈉乾燥，再經過減壓濃縮得到標題化合物1f(300mg，產率86%)。 Dissolve cis-6R-octahydrocyclopenta[b]pyrrole-6-phenol hydrochloric acid (250mg, 1.53mmol) in 5ml of dichloromethane, and add triethylamine (0.42mL, 3.05mmol) in turn. Di-tert-butyl carbonate (400.09 mg, 1.83 mmol) was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and then diluted with ethyl acetate (20 mL) after concentration. The organic phase was washed twice with 20 ml of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound 1f (300 mg, yield 86%).

MS(ESI)m/z 250.2[M+Na]⁺ MS(ESI)m/z 250.2[M+Na] ⁺

第四步 the fourth step

順式-6-羰基六氫環戊二烯并[b]吡咯-1(2H)-羧酸第三-丁基酯1g Cis-6-carbonyl hexahydrocyclopenta[b]pyrrole-1(2H)-carboxylic acid tertiary-butyl ester 1g

將化合物1f(300mg,1.32mmol)溶於3毫升二氯甲烷中，再加入戴斯-馬丁氧化劑(840mg,1.98mmol)，反應在25℃攪拌12h。反應完後，將反應液進行濃縮得到粗品化合物，粗品化合物再經過反相C18純化得到標題化合物1g(250mg，產率84%)。 Compound 1f (300mg, 1.32mmol) was dissolved in 3ml of dichloromethane, and Dess-Martin oxidant (840mg, 1.98mmol) was added, and the reaction was stirred at 25°C for 12h. After the reaction, the reaction solution was concentrated to obtain the crude compound. The crude compound was purified by reversed-phase C18 to obtain the title compound 1g (250 mg, yield 84%).

MS(ESI)m/z 248.2[M+Na]⁺ MS(ESI)m/z 248.2[M+Na] ⁺

第五步 the fifth step

順式-6-胺基六氫環戊二烯并[b]吡咯-1(2H)-羧酸第三-丁基酯1h Cis-6-aminohexahydrocyclopenta[b]pyrrole-1(2H)-carboxylic acid tert-butyl ester 1h

將化合物1g(250mg,1.11mmol)溶於5mL甲醇中，並依次加入乙酸銨(854mg,11.10mmol)和氰基硼氫化鈉(335mg，5.55mmol)，室溫反應24小時。反應完後濃縮得到粗品，藉由C18反相純化，得到標題化合物1h(130mg,產率51.76%)。 Compound 1g (250mg, 1.11mmol) was dissolved in 5mL methanol, and ammonium acetate (854mg, 11.10mmol) and sodium cyanoborohydride (335mg, 5.55mmol) were added in sequence, and reacted at room temperature for 24 hours. After the reaction was completed, it was concentrated to obtain the crude product, which was purified by C18 reverse phase to obtain the title compound 1h (130 mg, yield 51.76%).

MS(ESI)m/z 171.1[M-55]⁺ MS(ESI)m/z 171.1[M-55] ⁺

第六步 Sixth step

1-((順式)-1-(第三-丁氧基羰基)八氫環戊二烯并[b]吡咯-6-基)-3-甲氧基-4-羰基-1,4-二氫吡啶-2,5-二羧酸2-乙基酯5-甲基酯1i 1-((cis)-1-(third-butoxycarbonyl)octahydrocyclopenta[b]pyrrol-6-yl)-3-methoxy-4-carbonyl-1,4- Dihydropyridine-2,5-dicarboxylic acid 2-ethyl ester 5-methyl ester 1i

將化合物1h(50mg,0.22mmol)溶於2毫升乙醇中，將3-甲氧基-4-羰基-4H-吡喃-2,5-二羧酸2-乙基酯5-甲基酯(56mg,0.22mmol)和三乙胺(22mg,0.22mmol)加入到反應，在80℃反應5小時。反應液藉由濃縮直接得到粗品標題化合物1i(110mg)，粗品直接用於下一步。 Compound 1h (50mg, 0.22mmol) was dissolved in 2 ml of ethanol, and 3-methoxy-4-carbonyl-4H-pyran-2,5-dicarboxylic acid 2-ethyl ester 5-methyl ester ( 56mg, 0.22mmol) and triethylamine (22mg, 0.22mmol) were added to the reaction and reacted at 80°C for 5 hours. The reaction solution was concentrated to directly obtain the crude title compound 1i (110 mg), and the crude product was directly used in the next step.

MS(ESI)m/z 465.4[M+H]⁺ MS(ESI)m/z 465.4[M+H] ⁺

第七步 Seventh step

N-(2,4-二氟苯甲基)-順式-6-甲氧基-5,7-二羰基-2,2a,2a1,3,4,5,7,9b-八氫-1H-4a,9a-二氮雜戊搭烯并[1,6-ab]萘-8-甲醯胺1k N-(2,4-Difluorobenzyl)-cis-6-methoxy-5,7-dicarbonyl-2,2a,2a1,3,4,5,7,9b-octahydro-1H -4a,9a-Diazapentano[1,6-ab]naphthalene-8-formamide 1k

將化合物1i粗品(697mg，1.24mmol)溶於毫升二甲苯中，然後依次加入醋酸(372mg,6.2mmol)和2,4-二氟苄胺(195mg,1.36mmol)，反應在200℃加熱回流3小時。然後將一水對甲苯磺酸(520mg,2.72mmol)加入反應液中，繼續200℃加熱回流2小時。反應液藉由濃縮直接得到粗品標題化合物，藉由C18反相純化，得到標題化合物1k(125mg，產率23.1%)。 The crude compound 1i (697mg, 1.24mmol) was dissolved in ml of xylene, and then acetic acid (372mg, 6.2mmol) and 2,4-difluorobenzylamine (195mg, 1.36mmol) were added in sequence. The reaction was heated to reflux at 200°C. hour. Then p-toluenesulfonic acid monohydrate (520 mg, 2.72 mmol) was added to the reaction solution, and heating at 200° C. under reflux was continued for 2 hours. The reaction solution was concentrated to directly obtain the crude title compound, and purified by C18 reverse phase to obtain the title compound 1k (125 mg, yield 23.1%).

MS(ESI)m/z 430.4[M+H]⁺ MS(ESI)m/z 430.4[M+H] ⁺

第八步 Eighth step

N-(2,4-二氟苯甲基)-6-甲氧基-5,7-二羰基-2,2a,2a1,3,4,5,7,9b-八氫-1H-4a,9a-二氮雜戊搭烯并[1,6-ab]萘-8-甲醯胺異構體(A)1l N-(2,4-Difluorobenzyl)-6-methoxy-5,7-dicarbonyl-2,2a,2a1,3,4,5,7,9b-octahydro-1H-4a, 9a-Diazapenteno[1,6-ab]naphthalene-8-formamide isomer (A) 1l

N-(2,4-二氟苯甲基)-6-甲氧基-5,7-二羰基-2,2a,2a1,3,4,5,7,9b-八氫-1H-4a,9a-二氮雜戊搭烯并[1,6-ab]萘-8-甲醯胺異構體(B)1m N-(2,4-Difluorobenzyl)-6-methoxy-5,7-dicarbonyl-2,2a,2a1,3,4,5,7,9b-octahydro-1H-4a, 9a-Diazapenteno[1,6-ab]naphthalene-8-formamide isomer (B) 1m

N-(2,4-二氟苯甲基)-6-羥基-5,7-二羰基-2,2a,2a1,3,4,5,7,9b-八氫-1H-4a,9a-二氮雜戊搭烯并[1,6-ab]萘-8-甲醯胺異構體(C)1n N-(2,4-Difluorobenzyl)-6-hydroxy-5,7-dicarbonyl-2,2a,2a1,3,4,5,7,9b-octahydro-1H-4a,9a- Diazapenteno[1,6-ab]naphthalene-8-carboxamide isomer (C) 1n

N-(2,4-二氟苯甲基)-6-羥基-5,7-二羰基-2,2a,2a1,3,4,5,7,9b-八氫-1H-4a,9a-二氮雜戊搭烯并[1,6-ab]萘-8-甲醯胺異構體(D)1o N-(2,4-Difluorobenzyl)-6-hydroxy-5,7-dicarbonyl-2,2a,2a1,3,4,5,7,9b-octahydro-1H-4a,9a- Diazapenteno[1,6-ab]naphthalene-8-formamide isomer (D) 1o

將化合物1k(125mg)進行手性拆分，得到標題化合物1l(34.1mg,產率27%)，標題化合物1m(33.4mg，產率27%)，標題化合物1n(19.5mg，產率16%)和標題化合物1o(19.7mg，產率16%)。 The compound 1k (125mg) was subjected to chiral resolution to obtain title compound 1l (34.1mg, yield 27%), title compound 1m (33.4mg, yield 27%), title compound 1n (19.5mg, yield 16%) ) And the title compound 1o (19.7mg, yield 16%).

拆分方法 Split method

SFC(Column：DAICEL CHIRALCEL AD(250mm*30mm,10um)；Condition：55-55% B(A：CO₂,B：0.1%NH₃H₂O/EtOH)；Flow Rate：80ml/min). SFC (Column: DAICEL CHIRALCEL AD (250mm*30mm, 10um); Condition: 55-55% B (A: CO ₂ , B: 0.1% NH ₃ H ₂ O/EtOH); Flow Rate: 80ml/min).

第九步 Step 9

N-(2,4-二氟苯甲基)-6-羥基-5,7-二羰基-2,2a,2a1,3,4,5,7,9b-八氫-1H-4a,9a-二氮雜戊搭烯并[1,6-ab]萘-8-甲醯胺異構體(A)化合物1 N -(2,4-Difluorobenzyl)-6-hydroxy-5,7-dicarbonyl-2,2a,2a1,3,4,5,7,9b-octahydro-1 H -4a,9a -Diazapenteno[1,6-ab]naphthalene-8-formamide isomer (A) compound 1

於化合物1l(34.1mg，0.08mmol)的乙腈(4mL)溶液中加入二溴化鎂(30mg,0.16mmol)。所得混合物於40℃下反應0.5小時。反應液冷卻後直接使用C18反相管柱以乙腈、水沖提純化，得到標題化合物1(20mg，產率60%)。 Magnesium dibromide (30 mg, 0.16 mmol) was added to a solution of compound 11 (34.1 mg, 0.08 mmol) in acetonitrile (4 mL). The resulting mixture was reacted at 40°C for 0.5 hour. After the reaction solution was cooled, it was directly extracted and purified using a C18 reversed-phase column with acetonitrile and water to obtain the title compound 1 (20 mg, yield 60%).

MS(ESI)m/z 416.1[M+H]⁺ MS(ESI)m/z 416.1[M+H] ⁺

¹H NMR(400MHz,DMSO-d6)：12.32(br s,1H),10.41(t,J=6.0Hz,1H),8.51(s,1H),7.48-7.32(m,1H),7.31-7.17(m,1H),7.14-6.97(m,1H),5.02-4.90(m,1H),4.62-4.46(m,2H),4.24(t,J=5.6Hz,1H),3.99-3.91(m,1H),3.36-3.33(m,1H),2.97-2.85(m,1H),2.29-2.11(m,2H),1.98-1.86(m,1H),1.82-1.63(m,2H),1.56-1.42(m,1H)。 ¹ H NMR (400MHz, DMSO-d6): 12.32 (br s, 1H), 10.41 (t, J=6.0Hz, 1H), 8.51 (s, 1H), 7.48-7.32 (m, 1H), 7.31-7.17 (m,1H),7.14-6.97(m,1H),5.02-4.90(m,1H),4.62-4.46(m,2H), 4.24(t,J=5.6Hz,1H),3.99-3.91(m ,1H),3.36-3.33(m,1H),2.97-2.85(m,1H),2.29-2.11(m,2H),1.98-1.86(m,1H),1.82-1.63(m,2H),1.56 -1.42(m,1H).

實施例2 Example 2

N-(2,4-二氟苯甲基)-6-羥基-5,7-二羰基-2,2a,2a1,3,4,5,7,9b-八氫-1H-4a,9a-二氮雜戊搭烯并[1,6-ab]萘-8-甲醯胺異構體(B)化合物2 N -(2,4-Difluorobenzyl)-6-hydroxy-5,7-dicarbonyl-2,2a,2a1,3,4,5,7,9b-octahydro-1 H -4a,9a -Diazapentano[1,6-ab]naphthalene-8-formamide isomer (B) compound 2

於化合物1m(33.4mg，0.08mmol)的乙腈(4mL)溶液中加入二溴化鎂(30mg,0.16mmol)。所得混合物於40℃下反應0.5小時。反應液冷卻後直接使用C18反相管柱以乙腈、水沖提純化，得到標題化合物2(20mg，產率60%)。 Magnesium dibromide (30 mg, 0.16 mmol) was added to a solution of compound 1m (33.4 mg, 0.08 mmol) in acetonitrile (4 mL). The resulting mixture was reacted at 40°C for 0.5 hour. After the reaction solution was cooled, it was directly extracted and purified with acetonitrile and water using a C18 reversed-phase column to obtain the title compound 2 (20 mg, yield 60%).

MS(ESI)m/z 416.1[M+H]⁺ MS(ESI)m/z 416.1[M+H] ⁺

¹H NMR(400MHz,DMSO-d6)：12.32(br s,1H),10.41(t,J=6.0Hz,1H),8.51(s,1H),7.40(q,J=8.0Hz,1H),7.24(t,J=9.2Hz,1H),7.06(t,J=8.0Hz,1H),5.03-4.89(m,1H),4.59-4.49(m,2H),4.24(t,J=5.2Hz,1H),3.99-3.91(m,1H),3.36-3.31(m,1H),2.97-2.85(m,1H),2.30-2.10(m,2H),1.98-1.86(m,1H),1.82-1.65(m,2H),1.54-1.44(m,1H). ¹ H NMR(400MHz,DMSO-d6): 12.32(br s,1H), 10.41(t,J=6.0Hz,1H), 8.51(s,1H),7.40(q,J=8.0Hz,1H), 7.24(t,J=9.2Hz,1H),7.06(t,J=8.0Hz,1H),5.03-4.89(m,1H),4.59-4.49(m,2H),4.24(t,J=5.2Hz ,1H),3.99-3.91(m,1H),3.36-3.31(m,1H),2.97-2.85(m,1H),2.30-2.10(m,2H),1.98-1.86(m,1H),1.82 -1.65 (m, 2H), 1.54-1.44 (m, 1H).

實施例3 Example 3

N-(2,4-二氟苯甲基)-6-羥基-5,7-二羰基-2,2a,2a1,3,4,5,7,9b-八氫-1H-4a,9a-二氮雜戊搭烯并[1,6-ab]萘-8-甲醯胺異構體(C)化合物3 N -(2,4-Difluorobenzyl)-6-hydroxy-5,7-dicarbonyl-2,2a,2a1,3,4,5,7,9b-octahydro-1 H -4a,9a -Diazapentano[1,6-ab]naphthalene-8-formamide isomer (C) compound 3

於化合物1n(19.5mg，0.045mmol)的乙腈(2mL)溶液中加入二溴化鎂(17mg,0.09mmol)。所得混合物於40℃下反應0.5小時。反應液冷卻後直接使用C18反相管柱以乙腈、水沖提純化，得到標題化合物3(11mg，產率58%)。 Magnesium dibromide (17 mg, 0.09 mmol) was added to a solution of compound 1n (19.5 mg, 0.045 mmol) in acetonitrile (2 mL). The resulting mixture was reacted at 40°C for 0.5 hour. After the reaction solution was cooled, it was directly extracted and purified with acetonitrile and water using a C18 reversed-phase column to obtain the title compound 3 (11 mg, yield 58%).

MS(ESI)m/z 416.1[M+H]⁺ MS(ESI)m/z 416.1[M+H] ⁺

¹H NMR(400MHz,DMSO-d6)：10.69(br s,1H),10.34(t,J=5.6Hz,1H),8.00(s,1H),7.48-7.32(m,1H),7.30-7.17(m,1H),7.13-6.98(m,1H),4.62-4.44(m,2H),4.32-4.20(m,1H),4.15(dd,J=7.6,11.2Hz,1H),4.03(t,J=10.0Hz,1H),3.46-3.40(m,1H),2.89-2.75(m,1H),2.46-2.41(m,1H),2.30-2.21(m,1H),2.16-2.02(m,2H),1.84-1.65(m,2H). ¹ H NMR (400MHz, DMSO-d6): 10.69 (br s, 1H), 10.34 (t, J=5.6Hz, 1H), 8.00 (s, 1H), 7.48-7.32 (m, 1H), 7.30-7.17 (m,1H),7.13-6.98(m,1H),4.62-4.44(m,2H),4.32-4.20(m,1H),4.15(dd,J=7.6,11.2Hz,1H),4.03(t ,J=10.0Hz,1H),3.46-3.40(m,1H),2.89-2.75(m,1H),2.46-2.41(m,1H),2.30-2.21(m,1H),2.16-2.02(m ,2H),1.84-1.65(m,2H).

實施例4 Example 4

N-(2,4-二氟苯甲基)-6-羥基-5,7-二羰基-2,2a,2a1,3,4,5,7,9b-八氫-1H-4a,9a-二氮雜戊搭烯并[1,6-ab]萘-8-甲醯胺異構體(D)立體異構體4 N-(2,4-Difluorobenzyl)-6-hydroxy-5,7-dicarbonyl-2,2a,2a1,3,4,5,7,9b-octahydro-1H-4a,9a- Diazapenteno[1,6-ab]naphthalene-8-carboxamide isomer (D) stereoisomer 4

於化合物1o(19.7mg，0.045mmol)的乙腈(2mL)溶液中加入二溴化鎂(17mg,0.09mmol)。所得混合物於40℃下反應0.5小時。反應液冷卻後直接使用C18反相管柱以乙腈、水沖提純化，得到標題化合物4(11mg，產率58%)。 Magnesium dibromide (17 mg, 0.09 mmol) was added to a solution of compound 1o (19.7 mg, 0.045 mmol) in acetonitrile (2 mL). The resulting mixture was reacted at 40°C for 0.5 hour. After the reaction solution was cooled, it was directly extracted and purified using a C18 reversed-phase column with acetonitrile and water to obtain the title compound 4 (11 mg, yield 58%).

MS(ESI)m/z 416.1[M+H]⁺ MS(ESI)m/z 416.1[M+H] ⁺

¹H NMR(400MHz,DMSO-d6)：10.70(br s,1H),10.34(t,J=6.0Hz,1H),8.00(s,1H),7.46-7.35(m,1H),7.29-7.19(m,1H),7.06(dt,J=2.0,8.4Hz,1H),4.60-4.47(m,2H),4.31-4.20(m,1H),4.15(dd,J=7.6,11.6Hz,1H),4.03(t,J=10.0Hz,1H),3.44-3.39(m,1H),2.90-2.75(m,1H),2.47-2.41(m,1H),2.26(td,J=8.8,13.6Hz,1H),2.17-2.01(m,2H),1.84-1.66(m,2H)。 ¹ H NMR (400MHz, DMSO-d6): 10.70 (br s, 1H), 10.34 (t, J=6.0 Hz, 1H), 8.00 (s, 1H), 7.46-7.35 (m, 1H), 7.29-7.19 (m,1H),7.06(dt,J=2.0,8.4Hz,1H),4.60-4.47(m,2H),4.31-4.20(m,1H),4.15(dd,J=7.6,11.6Hz,1H ),4.03(t,J=10.0Hz,1H),3.44-3.39(m,1H),2.90-2.75(m,1H),2.47-2.41(m,1H),2.26(td,J=8.8,13.6 Hz, 1H), 2.17-2.01 (m, 2H), 1.84-1.66 (m, 2H).

生物學評價Biological evaluation

以下結合測試例進一步描述解釋本公開中，但這些實施例並非意味著限制本公開中的範圍。 The following further describes and explains the present disclosure in conjunction with test examples, but these examples are not meant to limit the scope of the present disclosure.

測試例1、Intergrase酶體外活性檢測實驗：基於時間分辨螢光的鏈轉移實驗(HTRF based strand transfer assay) Test Example 1. Intergrase enzyme in vitro activity detection experiment: HTRF based strand transfer assay based on time-resolved fluorescence

1、實驗儀器及材料 1. Experimental equipment and materials

將N端帶有6個HIS-tag的HIV整合酶(IN F185K/C280S)蛋白用大腸桿菌BL21(DE3)表達系統表達。用基於鎳管柱的親和層析的方法純化得到，純度為85%，濃度為3.85mg/ml的重組HIS-IN蛋白(南京金斯瑞生物科技有限公司)。分裝後-80℃保存。 The N-terminal HIV integrase (IN F185K/C280S ) protein with 6 HIS-tags was expressed in E. coli BL21 (DE3) expression system. Recombinant HIS-IN protein with a purity of 85% and a concentration of 3.85mg/ml (Nanjing GenScript Biotechnology Co., Ltd.) was purified by affinity chromatography based on a nickel column. Store at -80°C after aliquoting.

N155H突變體HIV整合酶(IN F185K/C280S/N155H)表達方法與野生型類似均有由南京金斯瑞生物科技有限公司生產，純度為85%，濃度為1.95mg/ml。 The N155H mutant HIV integrase (IN F185K/C280S/N155H ) expression method is similar to that of the wild type. Both are produced by Nanjing GenScript Biotechnology Co., Ltd. The purity is 85% and the concentration is 1.95mg/ml.

實驗所需脫氧核苷酸序列信息如下，由南京金斯瑞生物科技有限公司生產 The deoxynucleotide sequence information required for the experiment is as follows, produced by Nanjing GenScript Biotechnology Co., Ltd.

實驗所需其它試劑信息如下 The other reagent information required for the experiment is as follows

2、實驗步驟 2. Experimental steps

將50mM Cy-5標記的(donor)兩條序列互補的DNA序列以及生物素(biotin)標記的DNA(acceptor)互補序列分別加入退火溶液中(50mM Tris[pH 7.6]，10mM MgCl₂)加熱至95℃ 20分鐘，然後緩慢冷卻至室溫，使用前儲存在-20℃。 Add 50mM Cy-5 labeled (donor) two complementary DNA sequences and biotin (biotin) labeled DNA (acceptor) complementary sequences to the annealing solution (50mM Tris[pH 7.6], 10mM MgCl ₂ ) and heat to 95°C for 20 minutes, then slowly cool to room temperature, and store at -20°C before use.

待測化合物用DMSO溶解至10mM。用反應液(20mM Hepes[pH 7.5]，7.5mM MgCl₂，1mM DTT，10% glycerol[w/v]，0.1mg/ml bovine serum albumin[BSA]，0.05% Brij-35，10mM ZnSO₄，5mM NaCl)稀釋至不同濃度。基於時間分辨螢光的鏈轉移實驗在384孔板中進行，將終濃度為50nM donor DNA和200nM 6HIS-IN以1：1體積比混合在反應液中，冰上孵育10分鐘。將12.5μl酶和受質的混合液與同體積的待測濃度化合物同比例混合，冰上孵育10分鐘後加入12.5μl的10nM acceptor DNA 37℃震盪混勻2個小時.反正終止後每孔加入25μl 2nM LANCE Eu-W8044-labeled streptavidin的檢測試劑。在室溫孵育3個小時。時間分辨螢光信號使用Envision讀板儀(PerkinElmer激發光波長330nm，發射光波長665/620nm)測量每個孔中的螢光信號。化合物對酶活的抑制活性IC₅₀值用四參數logit方法計算。下列公式中x代表化合物濃度的對數形式；F(x)代表效應值(該濃度條件下對酶活的抑制率)：F(x)=((A-D)/(1+((x/C)^B)))+D。A,B,C和D為四個參數。用Primer premier 6.0將IC₅₀值進一步計算為最佳擬合曲線中50%酶活抑制所需的化合物濃度。 The test compound was dissolved to 10 mM with DMSO. Use the reaction solution (20mM Hepes[pH 7.5], 7.5mM MgCl ₂ , 1mM DTT, 10% glycerol[w/v], 0.1mg/ml bovine serum albumin[BSA], 0.05% Brij-35, 10mM ZnSO ₄ , 5mM NaCl) was diluted to different concentrations. The chain transfer experiment based on time-resolved fluorescence was performed in a 384-well plate. The final concentration of 50nM donor DNA and 200nM 6HIS-IN were mixed in the reaction solution at a volume ratio of 1:1, and incubated on ice for 10 minutes. Mix 12.5μl of the enzyme and substrate mixture with the same volume of the compound to be tested in the same proportion, incubate on ice for 10 minutes, add 12.5μl of 10nM acceptor DNA and shake at 37°C for 2 hours. Add to each well after termination anyway 25μl 2nM LANCE Eu-W8044-labeled streptavidin detection reagent. Incubate for 3 hours at room temperature. Time-resolved fluorescence signal The fluorescence signal in each well was measured using an Envision plate reader (PerkinElmer excitation light wavelength 330nm, emission light wavelength 665/620nm). _{The IC 50} value of the inhibitory activity of the compound on the enzyme activity was calculated by the four-parameter logit method. In the following formula, x represents the logarithmic form of the compound concentration; F(x) represents the effect value (inhibition rate of enzyme activity under this concentration condition): F(x)=((AD)/(1+((x/C)) ^B)))+D. A, B, C and D are four parameters. Using Primer premier 6.0 to _{further calculate the IC 50} value as the compound concentration required for 50% enzyme activity inhibition in the best-fit curve.

本公開中化合物對HIV Intergrase酶體外活性藉由以上的試驗進行測定，測得的IC₅₀值見表1。 The in vitro activity of the compounds in the present disclosure on HIV Intergrase enzyme was determined by the above test, and the measured IC ₅₀ values are shown in Table 1.

本公開中化合物對N155H突變型HIV Integrase酶體外活性藉由以上的試驗進行測定，測得的IC₅₀值見表2。 The in vitro activity of the compounds in the present disclosure on the N155H mutant HIV Integrase enzyme was determined by the above test, and the measured IC ₅₀ values are shown in Table 2.

測試例2、抗HIV病毒及細胞毒性實驗 Test Example 2: Anti-HIV virus and cytotoxicity test

1、實驗儀器及材料 1. Experimental equipment and materials

實驗所需其它試劑信息如下 The other reagent information required for the experiment is as follows

將HIV-1 IIIB和MT-4(NIH AIDS項目)細胞於37℃、5% CO₂培養箱中共培養1小時。同時稀釋受試化合物和參照化合物(AZT，sigma)用DMSO倍比稀釋好後加入細胞培養板中。隨後將感染細胞以每孔10,000個細胞的密度接種於細胞培養板中。細胞培養液中DMSO終濃度為0.5%。將細胞置於37℃、5% CO₂培養箱中培養5天。細胞毒性測試和抗病毒實驗平行進行，實驗的細胞為未感染的MT-4細胞。細胞活力由CellTiter-Glo(Promega)測定。 The HIV-1 IIIB and MT-4 (NIH AIDS project) cells were _{co-cultured in a 37°C, 5% CO 2} incubator for 1 hour. At the same time, the test compound and the reference compound (AZT, sigma) were diluted with DMSO times and then added to the cell culture plate. The infected cells were then seeded in a cell culture plate at a density of 10,000 cells per well. The final concentration of DMSO in the cell culture medium is 0.5%. The cells were cultured in a 37°C, 5% CO ₂ incubator for 5 days. The cytotoxicity test and the antiviral test were carried out in parallel, and the tested cells were uninfected MT-4 cells. Cell viability was determined by CellTiter-Glo (Promega).

化合物的抗病毒活性和細胞毒性分別由化合物對病毒引起的抑制率(%)和細胞活率(%)表示。計算公式如下： The antiviral activity and cytotoxicity of the compound are represented by the inhibition rate (%) and cell viability (%) of the compound against the virus, respectively. Calculated as follows:

抑制率(%)=(測試孔讀值-病毒對照平均值)/(細胞對照平均值-病毒對照平均值)x 100 Inhibition rate (%) = (test hole reading value-virus control average value) / (cell control average value-virus control average value) x 100

細胞活率(%)=(測試孔讀值-培養液對照平均值)/(細胞對照平均值-培養液對照平均值)x 100Cell viability (%) = (reading value of test well-average value of culture medium control) / (average value of cell control-average value of culture medium control) x 100

應用GraphPad Prism軟體(Version 5)計算化合物的EC₅₀和CC₅₀值。EC₅₀和CC₅₀值用四參數logit方法.下列公式中x代表化合物濃度的對數形式；F(x)代表效應值(抑制率或細胞活率)：F(x)=((A-D)/(1+((x/C)^B))+D。A,B,C和D為四個參數。不同的濃度對應不同的抑制率，做出一條反曲線，從曲線上算出待測化合物的EC₅₀和CC₅₀(Primer premier 6.0)。 GraphPad Prism software (Version 5) was used to calculate the EC ₅₀ and CC ₅₀ values of the compound. The EC ₅₀ and CC ₅₀ values use the four-parameter logit method. In the following formula, x represents the logarithmic form of the compound concentration; F(x) represents the effect value (inhibition rate or cell viability): F(x)=((AD)/( 1+((x/C)^B))+D. A, B, C and D are the four parameters. Different concentrations correspond to different inhibition rates, make a reverse curve, and calculate the compound EC ₅₀ and CC ₅₀ (Primer premier 6.0).

本公開中化合物在MT4細胞中的抗病毒活性和細胞毒性藉由以上的試驗進行測定，測得的IC₅₀值見表3。 The antiviral activity and cytotoxicity of the compounds in the present disclosure in MT4 cells were determined by the above test, and the measured IC ₅₀ values are shown in Table 3.

結論：本公開中化合物的抗病毒活性高，細胞毒性小，安全窗口較大。 Conclusion: The compounds in the present disclosure have high antiviral activity, low cytotoxicity, and a large safety window.

Claims (15)

一種式I所示的化合物或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體， A compound represented by formula I or a pharmaceutically acceptable salt or stereoisomer, rotamer or tautomer thereof,

其中，環A、環C各自獨立地5至8員單環環烷基或雜環基、8至11員雙環環烷基或雙環雜環烷基，該環A或環C任選被側氧基，或者任選被選自鹵素、羥基、烷基、烷氧基、環烷基、雜環基、-COR'、-S(O)₂R'、-CON(R')₂、芳基或雜芳基所取代，該烷基、烷氧基、環烷基、雜環基、芳基或雜芳基任選被一個或多個選自鹵素、烷基、環烷基、烷氧基、烯基、炔基、氧基、羥基、芳基、雜芳基、硝基、腈基、鹵烷基、鹵烷氧基、鹵環烷基、鹵雜環基、鹵芳基、鹵雜芳基、SR'、NR'(R")、OCOR'、OCOOR'、COOR'、CONR'(R")或OCONR'(R")所取代； Wherein, ring A and ring C are each independently a 5- to 8-membered monocyclic cycloalkyl or heterocyclic group, 8- to 11-membered bicyclic cycloalkyl or bicyclic heterocycloalkyl, and the ring A or ring C is optionally pendant oxygen Group, or optionally selected from halogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, -COR', -S(O) ₂ R', -CON(R') ₂ , aryl Or substituted by a heteroaryl group, the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally substituted by one or more selected from halogen, alkyl, cycloalkyl, alkoxy , Alkenyl, alkynyl, oxy, hydroxy, aryl, heteroaryl, nitro, nitrile, haloalkyl, haloalkoxy, halocycloalkyl, haloheterocyclyl, haloaryl, halo Replaced by aryl, SR', NR'(R"), OCOR', OCOOR', COOR', CONR'(R") or OCONR'(R"); R¹或R²各自獨立地選自氫、鹵素、羥基、烷基、烷氧基、環烷基、雜環基、芳基、雜芳基、SR'、NR'(R")、COOR'或CONR'(R")，該烷基、烷氧基、環烷基、雜環基、芳基或雜芳基任選被一個或多個選自烷基、烷氧基、環烷基、雜環基、烷氧基、烯基、炔基、芳基、雜芳基、硝基、腈基、羥基、鹵素、鹵烷基、鹵烷氧基、鹵環烷基、鹵雜環基、鹵芳基、鹵雜芳基、SR'、NR'(R")、COOR'或CONR'(R")所取代，或者，R¹、R²與其相鄰碳原子一起形成5員至12員碳環、雜環、芳環或雜芳環，較佳6員至8員碳環、雜環、芳環或雜芳環，該碳環、雜環、芳環或雜芳環任選被選自烷基、鹵素、羥基、胺基、氧基、羧基、硝基、氰基、烷氧基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； R ¹ or R ² are each independently selected from hydrogen, halogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, SR', NR'(R"), COOR' Or CONR'(R"), the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally selected from one or more alkyl groups, alkoxy groups, cycloalkyl groups, Heterocyclyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxyl, halogen, haloalkyl, haloalkoxy, halocycloalkyl, haloheterocyclyl, Substituted by haloaryl, haloheteroaryl, SR', NR'(R"), COOR' or CONR'(R"), or, R ¹ , R ² and their adjacent carbon atoms together form 5 to 12 members Carbocyclic, heterocyclic, aromatic or heteroaromatic ring, preferably 6 to 8-membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, the carbocyclic, heterocyclic, aromatic or heteroaromatic ring is optionally selected Substituted by one or more substituents among alkyl, halogen, hydroxyl, amine, oxy, carboxy, nitro, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl ； X、Y各自獨立地選自CH或N； X and Y are each independently selected from CH or N; R'或R"獨立地選自氫、羥基、烷基、烷氧基、烯基、醯基、芳基或雜芳基，該烷基、烷氧基、芳基或雜芳基任選被一個或多個選自鹵素、烷基、環烷基、烷氧基、烯基、炔基、氧基、羥基、硝基、腈基或-R^a所取代，該R^a選自芳基或雜芳基，該芳基或雜芳基任選被一個或多個選自鹵素、烷基、環烷基、烷氧基、烯基、炔基、氧基、羥基、芳基、雜芳基、硝基、腈基、鹵烷基、鹵烷氧基、鹵環烷基、鹵雜環基、鹵芳基或鹵雜芳基所取代。 R'or R" are independently selected from hydrogen, hydroxy, alkyl, alkoxy, alkenyl, aryl, aryl or heteroaryl, and the alkyl, alkoxy, aryl or heteroaryl group is optionally selected by one or more substituents selected from halo, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, alkoxy, hydroxy, nitro, nitrile, or substituted with -R ^a, R ^a is selected from the aryl group or Heteroaryl, the aryl or heteroaryl is optionally selected by one or more selected from halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxy, aryl, heteroaryl , Nitro, nitrile, haloalkyl, haloalkoxy, halocycloalkyl, haloheterocyclyl, haloaryl or haloheteroaryl. 如請求項1所述的化合物或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體，其中式I所示化合物為， The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer, wherein the compound represented by formula I is:

其中，B選自-CONR^b-、-COO-，或五員至六員雜環； Wherein, B is selected from -CONR ^b -, -COO-, or a five-member to six-member heterocyclic ring; R^b選自氫、羥基、烷基、烷氧基、烯基、醯基、芳基或雜芳基，該烷基、烷氧基、芳基或雜芳基任選被一個或多個選自鹵素、烷基、環烷基、烷氧基、烯基、炔基、氧基、羥基、硝基、腈基或-R^a所取代，該R^a選自芳基或雜芳基，該芳基或雜芳基任選被一個或多個選自鹵素、烷基、環烷基、烷氧基、烯基、炔基、氧基、羥基、芳基、雜芳基、硝基、腈基、鹵烷基、鹵烷氧基、鹵環烷基、鹵雜環基、鹵芳基或鹵雜芳基所取代； R ^{b is} selected from hydrogen, hydroxy, alkyl, alkoxy, alkenyl, acyl, aryl or heteroaryl, and the alkyl, alkoxy, aryl or heteroaryl is optionally selected from one or more from halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, alkoxy, hydroxy, nitro, nitrile, or substituted with -R ^a, R ^a is selected from the aryl group or heteroaryl group, which Aryl or heteroaryl is optionally selected by one or more selected from halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxy, aryl, heteroaryl, nitro, nitrile Group, haloalkyl, haloalkoxy, halocycloalkyl, haloheterocyclyl, haloaryl or haloheteroaryl; R³選自氫、C_1-6烷基、C_3-8環烷基、3至8員雜環基、C_6-12芳基或6至12員雜芳基，該C_1-6烷基、C_3-8環烷基、3至8員雜環基、C_6-12芳基或6至12員雜芳基任選被一個或多個鹵素、烷基、環烷基、烷氧基、烯基、炔基、氧基、羥基、硝基、腈基、芳基或雜芳基所取代，該烷基、環烷基、烷氧基、芳基或雜 芳基任選被一個或多個選自鹵素、烷基、環烷基、烷氧基、烯基、炔基、氧基、羥基、硝基、腈基或-R^a所取代。 R ^{3 is} selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, 3 to 8-membered heterocyclic group, C _6-12 aryl or 6 to 12 membered heteroaryl, the C _1-6 alkane Group, C _3-8 cycloalkyl, 3 to 8 membered heterocyclic group, C _6-12 aryl group or 6 to 12 membered heteroaryl group is optionally substituted by one or more halogen, alkyl, cycloalkyl, alkoxy Group, alkenyl, alkynyl, oxy, hydroxy, nitro, nitrile, aryl or heteroaryl, the alkyl, cycloalkyl, alkoxy, aryl or heteroaryl group is optionally substituted by one or more substituents selected from halo, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, alkoxy, hydroxy, nitro, nitrile, or substituted with -R ^a. 如請求項1或2所述的化合物或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體，其中式I所示化合物為， The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer, wherein the compound represented by formula I is:

其中，R^c或R^d各自獨立地選自氫、鹵素、烷基、環烷基、烷氧基、烯基、炔基、氧基、羥基、芳基、雜芳基、硝基、腈基、鹵烷基、鹵烷氧基、鹵環烷基、鹵雜環基、鹵芳基或鹵雜芳基，或者R^c、R^d與其相鄰碳原子一起形成3員至12員碳環、雜環、芳環或雜芳環，較佳3員至8員碳環、雜環、芳環或雜芳環，所述碳環、雜環、芳環或雜芳環任選被選自烷基、鹵素、羥基、胺基、氧基、羧基、硝基、氰基、烷氧基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； Wherein, R ^c or R ^d are each independently selected from hydrogen, halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxy, aryl, heteroaryl, nitro, nitrile group , Haloalkyl, haloalkoxy, halocycloalkyl, haloheterocyclyl, haloaryl or haloheteroaryl, or R ^c , R ^d and their adjacent carbon atoms together form a 3-member to 12-member carbocyclic ring, Heterocyclic ring, aromatic ring or heteroaromatic ring, preferably 3-membered to 8-membered carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring, the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring is optionally selected from alkane Substituted by one or more substituents in the group, halogen, hydroxy, amino, oxy, carboxy, nitro, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; R⁴選自鹵素、烷基、環烷基、烷氧基、烯基、炔基、氧基、羥基、硝基、腈基、芳基或雜芳基，該芳基或雜芳基任選被一個或多個選自鹵素、烷基、環烷基、烷氧基、烯基、炔基、氧基、羥基、芳基、雜芳基、硝基、腈基。 R ^{4 is} selected from halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxyl, nitro, nitrile, aryl or heteroaryl, the aryl or heteroaryl optionally One or more are selected from halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxy, aryl, heteroaryl, nitro, nitrile. 如請求項1至3中任一項所述的化合物或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體，其中B選自-CONH-或噻二唑基。 The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer, wherein B is selected from -CONH- or thiadiazolyl . 如請求項1至4中任一項所述的化合物或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體，其中環C選自： The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer, wherein ring C is selected from:

，其可以在環C碳原子上任選自且獨立地被選自C_1-6烷基、C_1-6烷基氧基、C_3-7環烷基所取代，可以在環C氮原子上任選自且獨立地被選自C_1-6烷基、-COR'、-S(O)₂R'、-CON(R')₂、C_3-7環烷基所取代，可以在環C硫原子上任選自且獨立地被氧化，R'如請求項1中所定義。

, Which can be optionally and independently substituted by C _1-6 alkyl, C _1-6 alkyloxy, C _3-7 cycloalkyl on the ring C carbon atom, and can be substituted on the ring C nitrogen atom The above is optionally and independently substituted by C _1-6 alkyl, -COR', -S(O) ₂ R', -CON(R') ₂ , C _3-7 cycloalkyl, and can be The ring C sulfur atom is optionally and independently oxidized, and R'is as defined in claim 1. 如請求項1至5中任一項所述的化合物或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體，其中環A選自： The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer, wherein ring A is selected from:

，其可以在環A碳原子上任選自且獨立地被選自C_1-6烷基、C_1-6烷基氧基、C_3-7環烷基所取代，可以在環A氮原子上任選自且獨立地被選自C_1-6烷基、-COR'、-S(O)₂R'、-CON(R')₂、C_3-7環烷基所取代，可以在環A硫原子上任選自且獨立地被氧化，R'如請求項1中所定義。

, Which can be optionally and independently substituted by C _1-6 alkyl, C _1-6 alkyloxy, C _3-7 cycloalkyl on the carbon atom of ring A, and can be substituted on the ring A nitrogen atom The above is optionally and independently substituted by C _1-6 alkyl, -COR', -S(O) ₂ R', -CON(R') ₂ , C _3-7 cycloalkyl, and can be The sulfur atom of ring A is optionally and independently oxidized, and R'is as defined in claim 1. 如請求項3至6中任一項所述的化合物或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體，其中R^c、R^d選自氫；R⁴為被1至4個鹵素取代的苯基。 The compound according to any one of claims 3 to 6, or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer, wherein R ^c and R ^{d are} selected from hydrogen; R ⁴ Is a phenyl substituted with 1 to 4 halogens. 如請求項7所述的化合物或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體，其中R⁴為被2個鹵素取代的苯基，較佳2,4-二氟苯基、2-氟-3-氯苯基、4-氟-3-氯苯基、2,3-二氟苯基、2,6-二氟苯基、3,4-二氟苯基、2-氟-4-氯苯基或3,5-二氟苯基。 The compound according to claim 7, or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer, wherein R ⁴ is a phenyl substituted with 2 halogens, preferably 2,4 -Difluorophenyl, 2-fluoro-3-chlorophenyl, 4-fluoro-3-chlorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 3,4-difluoro Phenyl, 2-fluoro-4-chlorophenyl or 3,5-difluorophenyl. 如請求項7所述的化合物或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體，其中R⁴為被3個鹵素取代的苯基，較佳2,4,6-三氟苯基、2,3,4-三氟苯基、2,4,5-三氟苯基或2,4-二氟-3-氯苯基。 The compound according to claim 7, or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer or tautomer, wherein R ⁴ is a phenyl substituted with 3 halogens, preferably 2,4 ,6-Trifluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl or 2,4-difluoro-3-chlorophenyl. 如請求項7所述的化合物或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體，其中R⁴為被4個鹵素取代的苯基，較佳2,3,4,5-四氟苯基或2,3,4,6-四氟苯基。 The compound according to claim 7, or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer or tautomer, wherein R ⁴ is a phenyl substituted with 4 halogens, preferably 2,3 ,4,5-tetrafluorophenyl or 2,3,4,6-tetrafluorophenyl. 如請求項1所述的化合物或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體，其選自： The compound according to claim 1 or its pharmaceutically acceptable salt or its stereoisomers, rotamers or tautomers, which are selected from:

或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體。

Or a pharmaceutically acceptable salt or stereoisomer, rotamer or tautomer thereof. 如請求項1所述的化合物或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體，其選自： The compound according to claim 1 or its pharmaceutically acceptable salt or its stereoisomers, rotamers or tautomers, which are selected from:

，

或其可藥用的鹽或互變異構體。

,

Or its pharmaceutically acceptable salt or tautomer. 一種醫藥組成物，包括至少一種治療有效量的如請求項1至12中任一項所述的化合物或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體或其可藥用的鹽以及藥學上可接受的載體、稀釋劑或賦形劑。 A pharmaceutical composition comprising at least one therapeutically effective amount of the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt or stereoisomer, rotamer or tautomer or Its pharmaceutically acceptable salts and pharmaceutically acceptable carriers, diluents or excipients. 一種治療患有感染或處於患有感染風險中患者的HIV感染的方法，其藉由向該患者施用治療有效量的如請求項1至12中任一項所述的化合物或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體或請求項13所述的醫藥組成物。 A method for treating HIV infection in a patient suffering from infection or at risk of suffering from infection, by administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable compound thereof A salt or its stereoisomer, rotamer or tautomer or the pharmaceutical composition according to claim 13. 一種如請求項1至12中任一項所述的化合物或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體或如請求項13所述的醫藥組成物在製備治療患有感染或處於患有感染風險中患者的HIV感染的藥物中的用途。 A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt or stereoisomer, rotamer or tautomer thereof, or the pharmaceutical composition according to claim 13 Use for preparing medicine for treating HIV infection of patients suffering from infection or at risk of suffering from infection.