TW202200563A

TW202200563A - Quinoxalinone derivative as irreversible inhibitor of kras g12c mutant protein

Info

Publication number: TW202200563A
Application number: TW110115542A
Authority: TW
Inventors: 趙焰平; 王紅軍; 張道廣; 肖緒枝; 葉佳; 冒莉; 姜媛媛; 祿立彥; 黃淮; 牛海濤; 黃建寶; 劉森; 劉雪蓮; 周麗瑩; 劉亞男
Original assignee: 中國商北京泰德製藥股份有限公司
Priority date: 2020-04-29
Filing date: 2021-04-29
Publication date: 2022-01-01
Also published as: CN115151532A; CN115135636A; TW202200562A; WO2021219091A3; WO2021219091A2; WO2021219090A1; CN115151532B

Abstract

The present invention relates to a novel quinoxalinone derivative, which can be used as an irreversible inhibitor of the KRAS G12C mutant protein. The present invention also relates to a pharmaceutical composition containing the quinoxalinone derivative, and a preparation method and use thereof.

Description

喹喔啉酮衍生物作為KRAS　G12C突變蛋白的不可逆抑制劑Quinoxalinone derivatives as irreversible inhibitors of KRAS G12C muteins

本發明涉及醫藥領域，具體地，本發明提供了能夠不可逆抑制KRAS G12C突變蛋白的化合物及其製備方法和應用。The present invention relates to the field of medicine, in particular, the present invention provides a compound capable of irreversibly inhibiting KRAS G12C mutein and a preparation method and application thereof.

RAS是突變頻率最高的原癌基因之一。RAS突變發生在大約30%的人類癌症中，其中KRAS是最常發生突變的RAS亞型，占RAS突變的80%左右。RAS is one of the most frequently mutated proto-oncogenes. RAS mutations occur in about 30% of human cancers, with KRAS being the most frequently mutated RAS subtype, accounting for about 80% of RAS mutations.

KARS遺傳密碼的蛋白是一種小GTP酶（GTPase），屬於RAS蛋白超家族。在細胞內，KRAS蛋白在非活化和活化狀態之間轉變，當KRAS與GDP（鳥苷二磷酸）結合時，處於非活化狀態，當與GTP（鳥苷三磷酸）結合時，處於活化狀態，並且可以活化下游訊號路徑。KRAS在非活化與活化狀態之間的轉換受到兩類因子的調節。一類是鳥嘌呤核苷酸交換因子（GEF），這類蛋白催化KRAS與GTP的結合，從而促進KRAS的活化，其中包括SOS蛋白。另一類是GTP酶活化蛋白（GAP），這類蛋白能夠促進與KRAS結合的GTP水解成為GDP，從而抑制KRAS的活性。The protein of the KARS genetic code is a small GTPase (GTPase) belonging to the RAS protein superfamily. In the cell, the KRAS protein transitions between inactive and active states. When KRAS binds to GDP (guanosine diphosphate), it is in an inactive state, and when it binds to GTP (guanosine triphosphate), it is in an active state, And can activate the downstream signal path. The transition of KRAS between inactive and activated states is regulated by two types of factors. One is the guanine nucleotide exchange factor (GEF), which catalyzes the binding of KRAS to GTP, thereby promoting the activation of KRAS, including the SOS protein. Another type is GTPase activating protein (GAP), which can promote the hydrolysis of KRAS-bound GTP into GDP, thereby inhibiting the activity of KRAS.

大部分細胞中的KRAS處於非活化狀態，當它被活化後，可以活化多條下游訊號路徑，其中包括MAPK訊號路徑(RAS-RAF-MEK-ERK)，PI3K訊號路徑(PI3K-AKT-mTOR)，和Ral-GEFs訊號路徑等，這些訊號路徑在細胞生長、分化、凋亡和轉移等方面具有重要作用。KRAS in most cells is in an inactive state. When it is activated, it can activate multiple downstream signaling pathways, including MAPK signaling pathway (RAS-RAF-MEK-ERK), PI3K signaling pathway (PI3K-AKT-mTOR) , and Ral-GEFs signaling pathways, which play important roles in cell growth, differentiation, apoptosis and metastasis.

KRAS突變在胰腺癌、非小細胞肺癌和結直腸癌中最為常見,特別是在胰腺癌中高達90%。KRAS突變主要發生在12、13位甘胺酸和61位麩醯胺酸3個位點，突變後的KRAS會影響其與GAP蛋白的結合能力，從而抑制GAP誘導的GTP水解，進而使KRAS維持在活化狀態，最終導致其下游的多條訊號路徑被活化，誘發惡性腫瘤的發生與發展。KRAS G12C突變是12位甘胺酸被半胱胺酸替代的單點突變，流行病學研究顯示，KRAS G12C突變發生於約13%的肺腺癌患者、3%的結直腸癌患者、以及1-3%的其他實體瘤患者中。KRAS mutations are most common in pancreatic cancer, non-small cell lung cancer and colorectal cancer, especially in pancreatic cancer up to 90%. KRAS mutations mainly occur at 3 sites of 12, 13 glycine and 61 glutamic acid. The mutated KRAS will affect its binding ability to GAP protein, thereby inhibiting GAP-induced GTP hydrolysis, thereby maintaining KRAS. In the activated state, multiple downstream signaling pathways are finally activated, which induces the occurrence and development of malignant tumors. KRAS G12C mutation is a single point mutation in which 12 glycines are replaced by cysteine. Epidemiological studies have shown that KRAS G12C mutation occurs in about 13% of lung adenocarcinoma patients, 3% of colorectal cancer patients, and 1 -3% of patients with other solid tumors.

為了解決癌症患者的臨床需求，本領域迫切需要安全有效的KRAS G12C突變蛋白的抑制劑，尤其是不可逆抑制劑。To address the clinical needs of cancer patients, there is an urgent need in the art for safe and effective KRAS G12C mutant protein inhibitors, especially irreversible inhibitors.

在一個方面，本發明提供了式(I)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物：

(I) 其中，環A為C_6-10 芳基或5-14員雜芳基，優選為萘基或9-10員雜芳基，優選萘基、苯並5員雜芳基或苯並6員雜芳基； R₆ 獨立地為H、D、C_0-6 亞烷基-鹵素、C_0-6 亞烷基-CN、C_0-6 亞烷基-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、C_0-6 亞烷基-O-R_1a 、C_0-6 亞烷基-S-R_1a 、C_0-6 亞烷基-N(R_1a )₂ 、C_0-6 亞烷基-C(O)R_1a 、C_0-6 亞烷基-C(O)OR_1a 、C_0-6 亞烷基-C(O)N(R_1a )₂ 或C_0-6 亞烷基-S(O)_m R_1a ；優選地，其中至少一個R₆ 為-O-R_1a ； m=1或2； n=0、1、2、3、4、5、6或7； L₁ 為-H₁ -H₂ -H₃ -H₄ -；In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or a pharmaceutically acceptable salt thereof , precursors or isotopic variants, and mixtures thereof:

(1) wherein, ring A is C _6-10 -membered aryl or 5-14-membered heteroaryl, preferably naphthyl or 9-10-membered heteroaryl, preferably naphthyl, benzo 5-membered heteroaryl or benzo 6-membered heteroaryl; R ₆ is independently H, D, C _0-6 alkylene-halogen, C _0-6 alkylene-CN, C _0-6 alkylene-NO ₂ , C _1-6 Alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _0-6 alkylene-OR _1a , C _0-6 alkylene-SR _1a , C _0-6 Alkylene-N(R _1a ) ₂ , C _0-6 alkylene-C(O)R _1a , C _0-6 alkylene-C(O)OR _1a , C _0-6 alkylene-C (O)N(R _1a ) ₂ or C _0-6 alkylene-S(O) _m R _1a ; preferably, at least one of R ₆ is -OR _1a ; m=1 or 2; n=0, 1 , 2, 3, 4, 5, 6 or 7; L ₁ is -H ₁ -H ₂ -H ₃ -H ₄ -;

其中H₁ 選自-O-、-S-、-N(R_H’ )-、-C(R_H )(R_H )-、-C(R_H )(R_H )-C(R_H )(R_H )-或-C(R_H )(R_H )-C(R_H )(R_H )-C(R_H )(R_H )-，H₂ 、H₃ 和H₄ 獨立地選自-O-、-S-、-N(R_H’ )-或-C(R_H )(R_H )-；wherein H ₁ is selected from -O-, -S-, -N( _RH' )-, -C( _RH )( _RH )-, -C( _RH )( _RH )-C( _RH ) ( _RH )- or -C( _RH )( _RH )-C( _RH )( _RH )-C( _RH )( _RH ) _- , _H2 , _H3 and H4 are independently selected from -O-, -S-, -N( _RH' )- or -C( _RH )( _RH )-;

並且，H₁ 和H₃ 上的R_H /R_H’ 取代基、H₁ 和H₄ 上的R_H /R_H’ 取代基、和H₂ 和H₄ 上的R_H /R_H’ 取代基中的一對或兩對R_H /R_H’ 取代基可以結合形成C_1-3 亞烷基； R_H 為H、D、C_0-6 亞烷基-鹵素、C_0-6 亞烷基-CN、C_0-6 亞烷基-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、C_0-6 亞烷基-O-R_1a 、C_0-6 亞烷基-S-R_1a 或C_0-6 亞烷基-N(R_1a )₂ ； R_H’ 為H、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基或C_2-6 炔基； R₁ 為C_1-6 鹵代烷基或

；Also, _RH / _RH' _substituents _on H1 and _H3 , _RH /RH' substituents _on H1 and H4, and _RH / _RH _' substituents _on _H2 and H4 One or two pairs of _RH / _RH' substituents can be combined to form C _1-3 alkylene; _RH is H, D, C _0-6 alkylene-halogen, C _0-6 alkylene -CN, C _0-6 alkylene-NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _0-6 alkylene- OR _1a , C _0-6 alkylene-SR _1a or C _0-6 alkylene-N(R _1a ) ₂ ; _RH' is H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl; R ₁ is C _1-6 haloalkyl or

;

其中R_a 、R_b 和R_c 獨立地選自H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ；其任選被R’取代；並且R_a 和R_b 可以形成化學鍵從而使得雙鍵變為三鍵；wherein R _a , R _b and R _c are independently selected from H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; it is optionally substituted by R'; and R _a and R _b can form a chemical bond such that a double bond becomes a triple bond;

其中R’為H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； L₂ 為化學鍵、-O-(C(R_L2 )(R_L2 ))_p -、-S-(C(R_L2 )(R_L2 ))_p -、-N(R_L2’ )-(C(R_L2 )(R_L2 ))_p -或-(C(R_L2 )(R_L2 ))_p -；Wherein R' is H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; L ₂ is a chemical bond, -O -(C(R _L2 )(R _L2 )) _p -, -S-(C(R _L2 )(R _L2 )) _p -, -N(R _L2' )-(C(R _L2 )(R _L2 ) ) _p - or - (C(R _L2 )(R _L2 )) _p -;

其中p=0、1、2、3或4； R_L2 為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； R_L2’ 為H、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基或C_2-6 炔基；wherein p=0, 1, 2, 3 or 4; R _L2 is H, D, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; R _L2' is H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl;

並且，相鄰原子上的R_L2 /R_L2’ 可以結合形成C_3-10 環烷基或3-10員雜環基； R₂ 為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-N(R_1a )₂ 、C_3-10 環烷基、3-10員雜環基、C_6-10 芳基或5-14員雜芳基；其任選被r個R取代； L₃ 為化學鍵或-(C(R_L3 )(R_L3 ))_p -；And, R _L2 /R _L2' on adjacent atoms can combine to form C _3-10 cycloalkyl or 3-10 membered heterocyclic group; R ₂ is H, D, halogen, -CN, -NO ₂ , C _{1 -6} alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -N(R _1a ) ₂ , C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl; it is optionally substituted by r R; L ₃ is a chemical bond or -(C(R _L3 )(R _L3 )) _p -;

其中R_L3 為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ；wherein R _L3 is H, D, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , - SR _1a or -N(R _1a ) ₂ ;

並且，相鄰原子上的R_L3 可以結合形成C_3-10 環烷基或3-10員雜環基； R₃ 為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-N(R_1a )₂ 、C_3-10 環烷基、3-10員雜環基、C_6-10 芳基或5-14員雜芳基；其任選被r個R取代；And, R _L3 on adjacent atoms can combine to form C _3-10 cycloalkyl or 3-10 membered heterocyclic group; R ₃ is H, D, halogen, -CN, -NO ₂ , C _1-6 alkyl , C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -N(R _1a ) ₂ , C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl; optionally substituted with r Rs;

其中R為H、D、C_0-6 亞烷基-鹵素、C_0-6 亞烷基-CN、C_0-6 亞烷基-SF₅ 、C_0-6 亞烷基-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、C_0-6 亞烷基-O-R_1a 、C_0-6 亞烷基-S-R_1a 、C_0-6 亞烷基-N(R_1a )₂ 、C_0-6 亞烷基-C(O)R_1a 、C_0-6 亞烷基-C(O)OR_1a 、C_0-6 亞烷基-C(O)N(R_1a )₂ 、C_0-6 亞烷基-S(O)_m R_1a 、C_0-6 亞烷基-C_3-10 環烷基、C_0-6 亞烷基-3-10員雜環基、C_0-6 亞烷基-C_6-10 芳基或C_0-6 亞烷基-5-14員雜芳基； r=0、1、2、3、4、5、6或7； R₄ 為H、D、鹵素、-CN、-SF₅ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 、-N(R_1a )₂ 、C_3-10 環烷基、C_3-10 鹵代環烷基、3-10員雜環基、3-10員鹵代雜環基、C_6-10 芳基或5-14員雜芳基； Z₁ 為CR₅ 或N； Z₂ 為CR₅ 或N； R₅ 獨立地為H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； R₇ 為H，或者R₇ 與-L₃ -R₃ 形成雙鍵，或R₇ 與-L₂ -R₂ 形成=Z； Z為O或S； R_1a 為H、-C(O)H、-C(O)OH、-C(O)C_1-6 烷基、-C(O)OC_1-6 烷基、-S(O)_m C_1-6 烷基、C_1-6 烷基、C_1-6 鹵代烷基、C_3-10 環烷基、C_3-10 鹵代環烷基、3-10員雜環基、3-10員鹵代雜環基、C_6-10 芳基或5-14員雜芳基；Wherein R is H, D, C _0-6 alkylene-halogen, C _0-6 alkylene-CN, C _0-6 alkylene-SF ₅ , C _0-6 alkylene-NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _0-6 alkylene-OR _1a , C _0-6 alkylene-SR _1a , C _0-6 alkylene-N(R _1a ) ₂ , C _0-6 alkylene-C(O)R _1a , C _0-6 alkylene-C(O)OR _1a , C _0-6 alkylene base-C(O)N(R _1a ) ₂ , C _0-6 alkylene-S(O) _m R _1a , C _0-6 alkylene-C _3-10 cycloalkyl, C _0-6 alkylene Alkyl-3-10-membered heterocyclyl, C _0-6 alkylene-C _6-10 aryl or C _0-6 alkylene-5-14-membered heteroaryl; r=0, 1, 2, 3, 4, 5, 6 or 7; R ₄ is H, D, halogen, -CN, -SF ₅ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _{2- 6} alkynyl, -OR _1a , -SR _1a , -N(R _1a ) ₂ , C _3-10 cycloalkyl, C _3-10 halogenated cycloalkyl, 3-10-membered heterocyclyl, 3-10-membered Halogenated heterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl; Z ₁ is CR ₅ or N; Z ₂ is CR ₅ or N; R ₅ is independently H, D, halogen, -CN , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; R ₇ is H, Or R ₇ and -L ₃ -R ₃ form a double bond, or R ₇ and -L ₂ -R ₂ form =Z; Z is O or S; R _1a is H, -C(O)H, -C(O )OH, -C(O)C _1-6 alkyl, -C(O)OC _1-6 alkyl, -S(O) _m C _1-6 alkyl, C _1-6 alkyl, C _{1- 6} haloalkyl, C _3-10 cycloalkyl, C _3-10 halocycloalkyl, 3-10 membered heterocyclyl, 3-10 membered haloheterocyclyl, C _6-10 aryl or 5-14 Member heteroaryl;

上述各基團中含有的OH、NH、NH₂ 、CH、CH₂ 、CH₃ 基團在每次出現時各自任選地被1、2、3或更多個R^s 及其同位素變體取代，其中所述R^s 在每次出現時獨立地選自：鹵素、羥基、胺基、氰基、硝基、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烷基、C_3-10 鹵代環烷基、3-10員雜環基、C_6-10 芳基、5-14員雜芳基、C_6-12 芳烷基、-OR^a’ 、-OC(O)R^a’ 、-C(O)R^a’ 、-C(O)OR^a’ 、-C(O)NR^a’ R^b’ 、-S(O)_q R^a’ 、-S(O)_q OR^a’ 、-S(O)_q NR^a’ R^b’ 、-NR^a’ R^b’ 、-NR^a’ C(O)R^b’ 、-NR^a’ -C(O)OR^b’ 、-NR^a’ -S(O)_q -R^b’ 、-NR^a’ C(O)NR^a’ R^b’ 、-C_1-6 亞烷基-R^a’ 、-C_1-6 亞烷基-OR^a’ 、-C_1-6 亞烷基-OC(O)R^a’ 、-C_1-6 亞烷基-C(O)OR^a’ 、-C_1-6 亞烷基-S(O)_q R^a’ 、-C_1-6 亞烷基-S(O)_q OR^a’ 、-C_1-6 亞烷基-OC(O)NR^a’ R^b’ 、-C_1-6 亞烷基-C(O)NR^a’ R^b’ 、-C_1-6 亞烷基-NR^a’ -C(O)NR^a’ R^b’ 、-C_1-6 亞烷基-OS(O)_q R^a’ 、-C_1-6 亞烷基-S(O)_q NR^a’ R^b’ 、-C_1-6 亞烷基-NR^a’ -S(O)_q NR^a’ R^b’ 、-C_1-6 亞烷基-NR^a’ R^b’ 和-O-C_1-6 亞烷基-NR^a’ R^b’ ，並且其中關於取代基R^s 所述的羥基、胺基、烷基、亞烷基、環烷基、雜環基、芳基、雜芳基和芳烷基進一步任選地被1、2、3或更多個獨立地選自下列的取代基及其同位素變體取代：鹵素、OH、胺基、氰基、硝基、C_1-6 烷基、C_1-6 鹵代烷基、C_1-6 烷基羥基、C_3-6 環烷基、3-10員雜環基、C_6-10 芳基、5-14員雜芳基和C_6-12 芳烷基； q每次出現時各自獨立地為1或2； R^a’ 和R^b’ 在每次出現時各自獨立地選自H、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_1-6 烷基-O-、C_1-6 烷基-S-、C_3-10 環烷基、3-10員雜環基、C_6-10 芳基、5-14員雜芳基和C_6-12 芳烷基。The OH, NH, _NH2 , CH, _CH2 , _CH3 groups contained in each of the above groups are each optionally substituted at each occurrence with 1, 2, 3 or more ^Rs and isotopic variants thereof , wherein said ^Rs at each occurrence is independently selected from: halogen, hydroxyl, amino, cyano, nitro, _C1-6 alkyl, _C1-6 haloalkyl, _C2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _3-10 halocycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-14 membered heteroaryl, C _{6 -12} Aralkyl, -OR ^a' , -OC(O)R ^a' , -C(O)R ^a' , -C(O)OR ^a' , -C(O)NR ^a' R ^b' , -S(O) _q R ^a' , -S(O) _q OR ^a' , -S(O) _q NR ^a' R ^b' , -NR ^a' R ^b' , -NR ^a' C(O)R ^b' , -NR ^a' -C(O)OR ^b' , -NR ^a' -S(O) _q -R ^b' , -NR ^a' C(O)NR ^a' R ^b' , -C _{1- 6} alkylene-R ^a' , -C _1-6 alkylene-OR ^a' , -C _1-6 alkylene-OC(O)R ^a' , -C _1-6 alkylene-C( O)OR ^a' , -C _1-6 alkylene-S(O) _q R ^a' , -C _1-6 alkylene-S(O) _q OR ^a' , -C _1-6 alkylene -OC(O)NR ^a' R ^b' , -C _1-6 alkylene-C(O)NR ^a' R ^b' , -C _1-6 alkylene-NR ^a' -C(O)NR ^a' R ^b' , -C _1-6 alkylene-OS(O) _q R ^a' , -C _1-6 alkylene-S(O) _q NR ^a' R ^b' , -C _1-6 Alkylene-NR ^a' -S(O) _q NR ^a' R ^b' , -C _1-6 alkylene-NR ^a' R ^b' and -OC _1-6 alkylene-NR ^a' R ^{b '} , and wherein the hydroxyl, amine, alkyl, alkylene, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups described with respect to the substituent ^Rs are further optionally replaced by 1, 2 , 3 or more substituents independently selected from the group consisting of halogen, OH, amino, cyano, nitro, C _1-6 alkyl, C _1-6 haloalkyl, C _{1 -6} alkyl hydroxy, C _3-6 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 membered aryl, 5-14 membered heteroaryl and C _6-12 aralkyl; each occurrence of q each independently 1 or 2; R ^a' and R ^b' are each independently selected at each occurrence from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1 -6} alkyl-O-, C _1-6 alkyl-S- , C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-14 membered heteroaryl and C _6-12 membered aralkyl.

在另一個方面，本發明提供了一種藥物組合物，所述藥物組合物含有本發明化合物，和任選地藥學上可接受的賦形劑。In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, and optionally a pharmaceutically acceptable excipient.

在另一個方面，本發明提供了含有本發明化合物和藥學上可接受的賦形劑的藥物組合物，其還含有其它治療劑。In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable excipient, which also contain other therapeutic agents.

在另一個方面，本發明提供了本發明化合物在製備用於治療和/或預防KRAS或其G12C突變蛋白介導的疾病的藥物中的用途。In another aspect, the present invention provides the use of a compound of the present invention in the manufacture of a medicament for the treatment and/or prevention of a disease mediated by KRAS or its G12C mutein.

在另一個方面，本發明提供了在受試者中治療和/或預防KRAS或其G12C突變蛋白介導的疾病的方法，包括向所述受試者給藥本發明化合物或本發明組合物。In another aspect, the present invention provides a method of treating and/or preventing a disease mediated by KRAS or its G12C mutein in a subject, comprising administering to the subject a compound of the present invention or a composition of the present invention.

在另一個方面，本發明提供了本發明化合物或本發明組合物，其用於治療和/或預防KRAS或其G12C突變蛋白介導的疾病。In another aspect, the present invention provides compounds of the present invention or compositions of the present invention for use in the treatment and/or prevention of diseases mediated by KRAS or its G12C mutein.

在具體實施方案中，本發明治療的疾病包括選自以下的癌症：急性骨髓性白血病、青少年癌症、兒童腎上腺皮質癌、AIDS相關的癌症(例如淋巴瘤和卡波西氏肉瘤）、肛門癌、闌尾癌、星形細胞瘤、非典型畸胎樣、基底細胞癌、膽管癌、膀胱癌、骨癌、腦幹膠質細胞瘤、腦瘤、乳腺癌、支氣管腫瘤、布凱特氏淋巴瘤、類癌瘤、非典型畸胎樣、胚胎腫瘤、生殖細胞腫瘤、原發性淋巴瘤、子宮頸癌、兒童癌症、脊索瘤、心臟腫瘤、慢性淋巴性白血病(CLL)、慢性骨髓性白血病(CML)、慢性骨髓增生疾病、結腸癌、結腸直腸癌、顱咽管瘤、皮膚T細胞淋巴瘤、肝外導管原位癌(DCIS)、胚胎腫瘤、CNS癌症、子宮內膜癌、室管膜瘤、食道癌、嗅神經膠母細胞瘤、尤文氏肉瘤、顱外生殖細胞腫瘤、性腺外生殖細胞腫瘤、眼癌、骨骼的纖維組織細胞瘤、膽囊癌、胃癌、胃腸道類癌瘤、胃腸道間質瘤(GIST)、生殖細胞腫瘤、妊娠滋養細胞腫瘤、毛細胞白血病、頭頸癌、心臟癌、肝癌、何杰金氏淋巴瘤、下咽癌、眼內黑色素瘤、胰島細胞瘤、胰腺神經內分泌瘤、腎癌、喉癌、唇和口腔癌、肝癌、小葉原位癌(LCIS)、肺癌、淋巴瘤、轉移性鱗狀頸癌伴隱匿原發灶、中線道癌、口腔癌、多發性內分泌瘤綜合征、多發性骨髓瘤/漿細胞瘤、蕈樣真菌病、骨髓發育不良綜合征、骨髓發育不良/骨髓增殖性瘤、多發性骨髓瘤、梅克爾細胞癌、惡性間皮瘤、骨骼的惡性纖維組織細胞瘤和骨肉瘤、鼻腔和鼻竇癌、鼻咽癌、神經膠母細胞瘤、何杰金氏淋巴瘤、非小細胞肺癌(NSCLC)、口腔癌、唇和口腔癌、口咽癌、卵巢癌、胰腺癌、乳頭瘤、副神經節瘤、鼻竇和鼻腔癌、甲狀旁腺癌、陰莖癌、咽癌、胸膜肺母細胞瘤、原發性中樞神經系統(CNS)淋巴瘤、***癌、直腸癌、移行性細胞癌、視網膜母細胞瘤、橫紋肌肉瘤、唾液腺癌、皮膚癌、胃癌、小細胞肺癌、小腸癌、軟組織肉瘤、細胞淋巴瘤、睾丸癌、喉癌、胸腺瘤和胸腺癌、甲狀腺癌、腎盂和輸尿管的移行性細胞癌、滋養細胞腫瘤、兒童罕見的癌症、尿道癌、子宮肉瘤、***癌、外陰癌或病毒誘導的癌症。In specific embodiments, diseases treated by the present invention include cancers selected from the group consisting of acute myeloid leukemia, juvenile cancer, childhood adrenal cortical cancer, AIDS-related cancers (eg, lymphoma and Kaposi's sarcoma), anal cancer, Appendiceal cancer, astrocytoma, atypical teratoid, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brain stem glioblastoma, brain tumor, breast cancer, bronchial tumor, Bukett's lymphoma, carcinoid tumor, atypical teratoid, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), Chronic myeloproliferative disease, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumor, CNS cancer, endometrial cancer, ependymoma, esophagus Carcinoma, olfactory glioblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, cardiac cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor , kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary tumor, midline tract cancer, oral cancer, multiple endocrine tumor syndrome, multiple myeloma/plasmacytoma, mycosis fungoides, myelodysplastic syndrome, myelodysplasia/myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, skeletal Malignant fibrous histiocytoma and osteosarcoma, nasal cavity and sinus cancer, nasopharyngeal cancer, glioblastoma, Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer , ovarian cancer, pancreatic cancer, papilloma, paraganglioma, sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, Prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach cancer, small cell lung cancer, small bowel cancer, soft tissue sarcoma, cell lymphoma, testicular cancer, laryngeal cancer, thymoma and Thymic, thyroid, transitional cell carcinomas of the renal pelvis and ureter, trophoblastic tumors, rare childhood cancers, urethral cancers, uterine sarcomas, vaginal cancers, vulvar cancers, or virus-induced cancers.

由隨後的具體實施方案、實施例和請求項，本發明的其它目的和優點將對於所屬技術領域中具有通常知識者顯而易見。定義化學定義Other objects and advantages of the present invention will be apparent to those of ordinary skill in the art from the ensuing specific embodiments, examples, and claims. definition chemical definition

下面更詳細地描述具體官能基和化學術語的定義。Definitions of specific functional groups and chemical terms are described in more detail below.

當列出數值範圍時，既定包括每個值和在所述範圍內的子範圍。例如“C_1-6 烷基”包括C₁ 、C₂ 、C₃ 、C₄ 、C₅ 、C₆ 、C_1-6 、C_1-5 、C_1-4 、C_1-3 、C_1-2 、C_2-6 、C_2-5 、C_2-4 、C_2-3 、C_3-6 、C_3-5 、C_3-4 、C_4-6 、C_4-5 和C_5-6 烷基。When numerical ranges are listed, each value and subranges within the range are intended to be included. For example, "C _1-6 alkyl" includes C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C _1-6 , C _1-5 , C _1-4 , C _1-3 , C _{1 -2} , _C2-6 , _C2-5 , _C2-4 , _C2-3 , _C3-6 , _C3-5 , _C3-4 , _C4-6 , _C4-5 , and _{C5 -6} alkyl.

“C_1-6 烷基”是指具有1至6個碳原子的直鏈或支鏈飽和烴基團。在一些實施方案中，C_1-4 烷基是優選的。C_1-6 烷基的例子包括：甲基(C₁ )、乙基(C₂ )、正丙基(C₃ )、異丙基(C₃ )、正丁基(C₄ )、叔丁基(C₄ )、仲丁基(C₄ )、異丁基(C₄ )、正戊基(C₅ )、3-戊基(C₅ )、戊基(C₅ )、新戊基(C₅ )、3-甲基-2-丁基(C₅ )、叔戊基(C₅ )和正己基(C₆ )。術語“C_1-6 烷基”還包括雜烷基，其中一或多個(例如，1、2、3或4個)碳原子被雜原子(例如，氧、硫、氮、硼、矽、磷)替代。烷基基團可以被一或多個取代基任選取代，例如，被1至5個取代基、1至3個取代基或1個取代基取代。常規烷基縮寫包括：Me(-CH₃ )、Et(-CH₂ CH₃ )、iPr(-CH(CH₃ )₂ )、nPr(-CH₂ CH₂ CH₃ )、n-Bu(-CH₂ CH₂ CH₂ CH₃ )或i-Bu(-CH₂ CH(CH₃ )₂ )。"C _1-6 alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C _1-4 alkyl groups are preferred. Examples of C _1-6 alkyl groups include: methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl (C ₄ ), tert-butyl base (C ₄ ), sec-butyl (C ₄ ), isobutyl (C ₄ ), n-pentyl (C ₅ ), 3-pentyl (C ₅ ), pentyl (C ₅ ), neopentyl ( C ₅ ), 3-methyl-2-butyl (C ₅ ), tert-amyl (C ₅ ) and n-hexyl (C ₆ ). The term "C _1-6 alkyl" also includes heteroalkyl groups in which one or more (eg, 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (eg, oxygen, sulfur, nitrogen, boron, silicon, phosphorus) instead. An alkyl group can be optionally substituted with one or more substituents, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional alkyl abbreviations include: Me( _-CH3 ), Et(-CH2CH3), iPr(-CH( _CH3 ₎ ₂ ), _nPr ( _-CH2CH2CH3 ₎ , n _- Bu(-CH _2CH2CH2CH3 ) or i _- Bu(-CH2CH ₍ _CH3 ₎ ₂ ₎ .

“C_2-6 烯基”是指具有2至6個碳原子和至少一個碳碳雙鍵的直鏈或支鏈烴基團。在一些實施方案中，C_2-4 烯基是優選的。C_2-6 烯基的例子包括：乙烯基(C₂ )、1-丙烯基(C₃ )、2-丙烯基(C₃ )、1-丁烯基(C₄ )、2-丁烯基(C₄ )、丁二烯基(C₄ )、戊烯基(C₅ )、戊二烯基(C₅ )、己烯基(C₆ )，等等。術語“C_2-6 烯基”還包括雜烯基，其中一或多個(例如，1、2、3或4個)碳原子被雜原子(例如，氧、硫、氮、硼、矽、磷)替代。烯基基團可以被一或多個取代基任選取代，例如，被1至5個取代基、1至3個取代基或1個取代基取代。"C _2-6 alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C _2-4 alkenyl groups are preferred. Examples of C _2-6 alkenyl groups include: vinyl (C ₂ ), 1-propenyl (C ₃ ), 2-propenyl (C ₃ ), 1-butenyl (C ₄ ), 2-butenyl (C ₄ ), butadienyl (C ₄ ), pentenyl (C ₅ ), pentadienyl (C ₅ ), hexenyl (C ₆ ), and the like. The term "C _2-6 alkenyl" also includes heteroalkenyl groups in which one or more (eg, 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (eg, oxygen, sulfur, nitrogen, boron, silicon, phosphorus) instead. An alkenyl group can be optionally substituted with one or more substituents, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

“C_2-6 炔基”是指具有2至6個碳原子、至少一個碳-碳三鍵以及任選地一個或多個碳-碳雙鍵的直鏈或支鏈烴基團。在一些實施方案中，C_2-4 炔基是優選的。C_2-6 炔基的例子包括但不限於：乙炔基(C₂ )、1-丙炔基(C₃ )、2-丙炔基(C₃ )、1-丁炔基(C₄ )、2-丁炔基(C₄ )，戊炔基(C₅ )、己炔基(C₆ )，等等。術語“C_2-6 炔基”還包括雜炔基，其中一或多個(例如，1、2、3或4個)碳原子被雜原子(例如，氧、硫、氮、硼、矽、磷)替代。炔基基團可以被一或多個取代基任選取代，例如，被1至5個取代基、1至3個取代基或1個取代基取代。"C _2-6 alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, _C2-4alkynyl is preferred. Examples of C _2-6 alkynyl groups include, but are not limited to: ethynyl (C ₂ ), 1-propynyl (C ₃ ), 2-propynyl (C ₃ ), 1-butynyl (C ₄ ), 2-butynyl (C ₄ ), pentynyl (C ₅ ), hexynyl (C ₆ ), and the like. The term "C _2-6 alkynyl" also includes heteroalkynyl groups in which one or more (eg, 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (eg, oxygen, sulfur, nitrogen, boron, silicon, phosphorus) instead. An alkynyl group can be optionally substituted with one or more substituents, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

“C_1-6 亞烷基、C_2-6 亞烯基或C_2-6 亞炔基”指的是上述定義的“C_1-6 烷基、C_2-6 烯基或C_2-6 炔基”的二價基團。"C _1-6 alkylene, C _2-6 alkenylene or C _2-6 alkynylene" means "C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkenyl" as defined above alkynyl" divalent group.

“C_1-6 亞烷基”是指除去C_1-6 烷基的另一個氫而形成的二價基團，並且可以是取代或未取代的。在一些實施方案中，C_1-4 亞烷基、C_2-4 亞烷基和C_1-3 亞烷基是優選的。未取代的所述亞烷基包括但不限於：亞甲基(-CH₂ -)、亞乙基(-CH₂ CH₂ -)、亞丙基(-CH₂ CH₂ CH₂ -)、亞丁基(-CH₂ CH₂ CH₂ CH₂ -)、亞戊基(-CH₂ CH₂ CH₂ CH₂ CH₂ -)、亞己基(-CH₂ CH₂ CH₂ CH₂ CH₂ CH₂ -)，等等。示例性的取代的所述亞烷基，例如，被一個或多個烷基(甲基)取代的所述亞烷基，包括但不限於：取代的亞甲基(-CH(CH₃ )-、-C(CH₃ )₂ -)、取代的亞乙基(-CH(CH₃ )CH₂ -、-CH₂ CH(CH₃ )-、-C(CH₃ )₂ CH₂ -、-CH₂ C(CH₃ )_2- )、取代的亞丙基(-CH(CH₃ )CH₂ CH₂ -、-CH₂ CH(CH₃ )CH₂ -、-CH₂ CH₂ CH(CH₃ )-、-C(CH₃ )₂ CH₂ CH₂ -、-CH₂ C(CH₃ )₂ CH₂ -、-CH₂ CH₂ C(CH₃ )₂ -)，等等。"C _1-6 alkylene group" refers to a divalent group formed by removing another hydrogen of a C _1-6 alkyl group, and may be substituted or unsubstituted. In some embodiments, C _1-4 alkylene, C _2-4 alkylene, and C _1-3 alkylene are preferred. The unsubstituted alkylene groups include, but are not limited to: methylene ( _-CH2- ), ethylene ( _-CH2CH2- ₎ , propylene ₍ _-CH2CH2CH2- ₎ , butylene base (-CH ₂ CH ₂ CH ₂ CH ₂ -), pentylene (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -), hexylene (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -) ,etc. Exemplary substituted such alkylene groups, eg, such alkylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene groups (-CH( _CH3 )- , -C(CH ₃ ) ₂ -), substituted ethylene (-CH(CH ₃ )CH ₂ -, -CH ₂ CH(CH ₃ )-, -C(CH ₃ ) ₂ CH ₂ -, -CH ₂ C(CH ₃ ) _2- ), substituted propylene (-CH(CH ₃ )CH ₂ CH ₂ -, -CH ₂ CH(CH ₃ )CH ₂ -, -CH ₂ CH ₂ CH(CH ₃ ) -, _-C ( _CH3 ) _2CH2CH2- , _-CH2C ( _CH3 ) _2CH2- , _-CH2CH2C ₍ _CH3 ₎ _2- ₎ , etc.

“C_0-6 亞烷基”是指化學鍵以及上述“C_1-6 亞烷基”。The "C _0-6 alkylene group" refers to the chemical bond as well as the above-mentioned "C _1-6 alkylene group".

“C_2-6 亞烯基”是指除去C_2-6 烯基的另一個氫而形成的二價基團，並且可以是取代或未取代的。在一些實施方案中，C_2-4 亞烯基是特別優選的。示例性的未取代的所述亞烯基包括但不限於：亞乙烯基(-CH=CH-)和亞丙烯基(例如，-CH=CHCH₂ -、-CH₂ -CH=CH-)。示例性的取代的所述亞烯基，例如，被一個或多個烷基(甲基)取代的亞烯基，包括但不限於：取代的亞乙基(-C(CH₃ )=CH-、-CH=C(CH₃ )-)、取代的亞丙烯基(-C(CH₃ )=CHCH₂ -、-CH=C(CH₃ )CH₂ -、-CH=CHCH(CH₃ )-、-CH=CHC(CH₃ )₂ -、-CH(CH₃ )-CH=CH-、-C(CH₃ )₂ -CH=CH-、-CH₂ -C(CH₃ )=CH-、-CH₂ -CH=C(CH₃ )-)，等等。"C _2-6 alkenylene" refers to a divalent group formed by removing another hydrogen of a C _2-6 alkenyl, and may be substituted or unsubstituted. In some embodiments, C _2-4 alkenylene groups are particularly preferred. Exemplary unsubstituted such alkenylene groups include, but are not limited to, vinylene (-CH=CH-) and propenylene (eg, -CH=CHCH2-, _-CH2 - _CH =CH-). Exemplary substituted such alkenylene groups, eg, alkenylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted ethylene groups (-C( _CH3 )=CH- , -CH=C(CH ₃ )-), substituted propenylene (-C(CH ₃ )=CHCH ₂ -, -CH=C(CH ₃ )CH ₂ -, -CH=CHCH(CH ₃ )- , -CH=CHC(CH ₃ ) ₂ -, -CH(CH ₃ )-CH=CH-, -C(CH ₃ ) ₂ -CH=CH-, -CH ₂ -C(CH ₃ )=CH-, -CH ₂ -CH=C(CH ₃ )-), etc.

“C_2-6 亞炔基”是指除去C_2-6 炔基的另一個氫而形成的二價基團，並且可以是取代或未取代的。在一些實施方案中，C_2-4 亞炔基是特別優選的。示例性的所述亞炔基包括但不限於：亞乙炔基(-C≡C-)、取代或未取代的亞丙炔基(-C≡CCH₂ -)，等等。"C _2-6 alkynylene" refers to a divalent group formed by removing another hydrogen of a C _2-6 alkynyl group, and may be substituted or unsubstituted. In some embodiments, C _2-4 alkynylene groups are particularly preferred. Exemplary such alkynylene groups include, but are not limited to: ethynylene (-C≡C-), substituted or unsubstituted propynylene ( _-C≡CCH2- ), and the like.

“C_1-6 雜烷基”是指本文所定義的C_1-6 烷基，並且在主鏈內，它進一步含有一或多個(例如，1、2、3或4個)雜原子(例如，氧、硫、氮、硼、矽、磷)，其中，一個或多個雜原子在所述主碳鏈內的相鄰碳原子之間，和/或，一個或多個雜原子在碳原子和母分子之間，即，在連接點之間。C_1-6 雜烷基與母分子的連接點可為碳原子，也可為雜原子。"C _1-6 heteroalkyl" refers to a C _1-6 alkyl group as defined herein, and which further contains one or more (eg, 1, 2, 3, or 4) heteroatoms ( For example, oxygen, sulfur, nitrogen, boron, silicon, phosphorus), wherein one or more heteroatoms are between adjacent carbon atoms within the main carbon chain, and/or one or more heteroatoms are in carbon between the atom and the parent molecule, that is, between the junctions. The point of attachment of the C _1-6 heteroalkyl to the parent molecule can be either a carbon atom or a heteroatom.

“C_2-6 亞雜烷基”是指除去C_1-6 雜烷基的另一個氫而形成的二價基團，並且可以是取代或未取代的。C_1-6 亞雜烷基與母分子其他部分的連接點可為兩個碳原子，也可為兩個雜原子，還可為一個碳原子和一個雜原子。"C _2-6 heteroalkylene" refers to a divalent group formed by removing another hydrogen of a C _1-6 heteroalkyl, and may be substituted or unsubstituted. The point of attachment of the C _1-6 heteroalkylene group to the rest of the parent molecule can be two carbon atoms, two heteroatoms, or one carbon atom and one heteroatom.

“鹵代”或“鹵素”是指氟(F)、氯(Cl)、溴(Br)和碘(I)。"Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

因此，“C_1-6 鹵代烷基”是指上述“C_1-6 烷基”，其被一個或多個鹵素基團取代。在一些實施方案中，C_1-4 鹵代烷基是特別優選的，更優選C_1-2 鹵代烷基。示例性的所述鹵代烷基包括但不限於：-CF₃ 、-CH₂ F、-CHF₂ 、-CHFCH₂ F、-CH₂ CHF₂ 、-CF₂ CF₃ 、-CCl₃ 、-CH₂ Cl、-CHCl₂ 、2,2,2-三氟-1,1-二甲基-乙基，等等。鹵代烷基基團可以在任何可用的連接點上被取代，例如，1至5個取代基、1至3個取代基或1個取代基。Thus, "C _1-6 haloalkyl" refers to the aforementioned "C _1-6 alkyl" substituted with one or more halogen groups. In some embodiments, C _1-4 haloalkyl is particularly preferred, more preferably C _1-2 haloalkyl. Exemplary such _haloalkyl groups include, but are not limited to _: _-CF3 , _-CH2F , _-CHF2 , _-CHFCH2F , _-CH2CHF2 , _-CF2CF3 , _-CCl3 , _-CH2Cl , -CHCl ₂ , 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. A haloalkyl group can be substituted at any available point of attachment, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

“C_3-10 環烷基”是指具有3至10個環碳原子和零個雜原子的非芳香環烴基團。在一些實施方案中，C_4-7 環烷基和C_3-6 環烷基是特別優選的，更優選C_5-6 環烷基。環烷基還包括其中上述環烷基環與一個或多個芳基或雜芳基稠合的環狀系統，其中連接點在環烷基環上，且在這樣的情況中，碳的數目繼續表示環烷基系統中的碳的數目。示例性的所述環烷基包括但不限於：環丙基(C₃ )、環丙烯基(C₃ )、環丁基(C₄ )、環丁烯基(C₄ )、環戊基(C₅ )、環戊烯基(C₅ )、環己基(C₆ )、環己烯基(C₆ )、環已二烯基(C₆ )、環庚基(C₇ )、環庚烯基(C₇ )、環庚二烯基(C₇ )、環庚三烯基(C₇ )，等等。環烷基基團可以被一或多個取代基任選取代，例如，被1至5個取代基、1至3個取代基或1個取代基取代。"C _3-10 cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C _4-7 cycloalkyl and C _3-6 cycloalkyl are particularly preferred, with C _5-6 cycloalkyl being more preferred. Cycloalkyl also includes ring systems in which the aforementioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons continues represents the number of carbons in the cycloalkyl system. Exemplary such cycloalkyl groups include, but are not limited to: cyclopropyl (C ₃ ), cyclopropenyl (C ₃ ), cyclobutyl (C ₄ ), cyclobutenyl (C ₄ ), cyclopentyl ( C ₅ ), cyclopentenyl (C ₅ ), cyclohexyl (C ₆ ), cyclohexenyl (C ₆ ), cyclohexadienyl (C ₆ ), cycloheptyl (C ₇ ), cycloheptene (C ₇ ), cycloheptadienyl (C ₇ ), cycloheptatrienyl (C ₇ ), and the like. Cycloalkyl groups can be optionally substituted with one or more substituents, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

“C_3-10 鹵代環烷基”是指上述“C_3-10 環烷基”，其被一個或多個鹵素基團取代。"C _3-10 halocycloalkyl" refers to the above-mentioned "C _3-10 cycloalkyl", which is substituted with one or more halogen groups.

“3-12員雜環基”是指具有環碳原子和1至5個環雜原子的3至12員非芳香環系的基團，其中，每個雜原子獨立地選自氮、氧、硫、硼、磷和矽。在包含一個或多個氮原子的雜環基中，只要化合價允許，連接點可為碳或氮原子。在一些實施方案中，優選4-12員雜環基，其為具有環碳原子和1至5個環雜原子的4至12員非芳香環系；在一些實施方案中，優選3-10員雜環基，其為具有環碳原子和1至5個環雜原子的3至10員非芳香環系；在一些實施方案中，優選3-8員雜環基，其為具有環碳原子和1至4個環雜原子的3至8員非芳香環系；優選3-6員雜環基，其為具有環碳原子和1至3個環雜原子的3至6員非芳香環系；優選4-7員雜環基，其為具有環碳原子和1至3個環雜原子的4至7員非芳香環系；更優選5-6員雜環基，其為具有環碳原子和1至3個環雜原子的5至6員非芳香環系。雜環基還包括其中上述雜環基環與一個或多個環烷基稠合的環狀系統，其中連接點在環烷基環上，或其中上述雜環基環與一個或多個芳基或雜芳基稠合的環狀系統，其中連接點在雜環基環上；且在這樣的情況下，環成員的數目繼續表示在雜環基環狀系統中環成員的數目。示例性的包含一個雜原子的3員雜環基包括但不限於：氮雜環丙烷基、氧雜環丙烷基、硫雜環丙烷基(thiorenyl)。示例性的含有一個雜原子的4員雜環基包括但不限於：氮雜環丁烷基、氧雜環丁烷基和硫雜環丁烷基。示例性的含有一個雜原子的5員雜環基包括但不限於：四氫呋喃基、二氫呋喃基、四氫噻吩基、二氫噻吩基、吡咯烷基、二氫吡咯基和吡咯基-2,5-二酮。示例性的包含兩個雜原子的5員雜環基包括但不限於：二氧雜環戊烷基、氧硫雜環戊烷基(oxasulfuranyl)、二硫雜環戊烷基(disulfuranyl)和噁唑烷-2-酮。示例性的包含三個雜原子的5員雜環基包括但不限於：***啉基、噁二唑啉基和噻二唑啉基。示例性的包含一個雜原子的6員雜環基包括但不限於：呱啶基、四氫吡喃基、二氫吡啶基和硫雜環己烷基(thianyl)。示例性的包含兩個雜原子的6員雜環基包括但不限於：呱嗪基、嗎啉基、二硫雜環己烷基、二噁烷基。示例性的包含三個雜原子的6員雜環基包括但不限於：六氫三嗪基(triazinanyl)。示例性的含有一個雜原子的7員雜環基包括但不限於：氮雜環庚烷基、氧雜環庚烷基和硫雜環庚烷基。示例性的與C₆ 芳基環稠合的5員雜環基(在本文中也稱作5,6-雙環雜環基)包括但不限於：二氫吲哚基、異二氫吲哚基、二氫苯並呋喃基、二氫苯並噻吩基、苯並噁唑啉酮基，等等。示例性的與C₆ 芳基環稠合的6員雜環基(本文還指的是6,6-雙環雜環基)包括但不限於：四氫喹啉基、四氫異喹啉基，等等。雜環基基團可以被一或多個取代基任選取代，例如，被1至5個取代基、1至3個取代基或1個取代基取代。"3-12 membered heterocyclyl" refers to a group of 3 to 12 membered non-aromatic ring systems having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, Sulfur, Boron, Phosphorus and Silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as valence allows. In some embodiments, 4-12 membered heterocyclyl, which is a 4- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, is preferred; in some embodiments, 3-10 membered Heterocyclyl, which is a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, a 3-8 membered heterocyclyl, which is a ring carbon atom and 3- to 8-membered non-aromatic ring systems of 1 to 4 ring heteroatoms; preferably 3- to 6-membered heterocyclic groups, which are 3- to 6-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms; Preferred is a 4-7 membered heterocyclyl, which is a 4- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably a 5-6 membered heterocyclyl, which is a ring carbon atom and 5- to 6-membered non-aromatic ring systems of 1 to 3 ring heteroatoms. Heterocyclyl also includes ring systems wherein the aforementioned heterocyclyl ring is fused with one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or wherein the aforementioned heterocyclyl ring is fused with one or more aryl groups or a heteroaryl fused ring system where the point of attachment is on the heterocyclyl ring; and in such cases the number of ring members continues to mean the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to: aziridine, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-diketone. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: dioxolane, oxasulfuranyl, disulfuranyl, and oxa oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, pyridyl, tetrahydropyranyl, dihydropyridyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: oxazinyl, morpholinyl, dithiahexyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as _5,6 -bicyclic heterocyclyl groups) fused to a C aryl ring include, but are not limited to: indoline, isoindolyl , dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary ₆ -membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclyl groups) fused to a C aryl ring include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc. A heterocyclyl group can be optionally substituted with one or more substituents, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

“3-12員鹵代雜環基”是指上述“3-12員雜環基”，其被一個或多個鹵素基團取代。類似地，“3-10員鹵代雜環基”是指上述“3-10員雜環基”，其被一個或多個鹵素基團取代。"3-12-membered haloheterocyclyl" refers to the above-mentioned "3-12-membered heterocyclyl", which is substituted with one or more halogen groups. Similarly, "3-10 membered haloheterocyclyl" refers to the aforementioned "3-10 membered heterocyclyl" substituted with one or more halogen groups.

“4-12員亞雜環基”和“5-6員亞雜環基”分別表示上述“4-12員雜環基”和“5-6員雜環基”，其中另一個氫被除去而形成的二價基團，並且可以是取代或未取代的。"4-12-membered heterocyclylene" and "5-6-membered heterocyclylene" respectively represent the above-mentioned "4-12-membered heterocyclyl" and "5-6-membered heterocyclyl" in which another hydrogen is removed and formed divalent groups, and can be substituted or unsubstituted.

“C_6-10 芳基”是指具有6-10個環碳原子和零個雜原子的單環或多環的(例如，雙環) 4n+2芳族環狀系統(例如，具有以環狀排列共用的6或10個π電子)的基團。在一些實施方案中，芳基具有六個環碳原子(“C₆ 芳基”；例如，苯基)。在一些實施方案中，芳基具有十個環碳原子(“C₁₀ 芳基”；例如，萘基，例如，1-萘基和2-萘基)。芳基還包括其中上述芳基環與一個或多個環烷基或雜環基稠合的環系統，而且連接點在所述芳基環上，在這種情況下，碳原子的數目繼續表示所述芳基環系統中的碳原子數目。芳基基團可以被一或多個取代基任選取代，例如，被1至5個取代基、1至3個取代基或1個取代基取代。"C _6-10 aryl" refers to a monocyclic or polycyclic (eg, bicyclic) 4n+2 aromatic ring system (eg, having cyclic carbon atoms and zero heteroatoms) having 6-10 ring carbon atoms and zero heteroatoms groups of 6 or 10 pi electrons in common). In some embodiments, an aryl group has six ring carbon atoms (" _C6 aryl"; eg, phenyl). In some embodiments, aryl groups have ten ring carbon atoms (" _Cio aryl"; eg, naphthyl, eg, 1-naphthyl and 2-naphthyl). Aryl also includes ring systems in which the aforementioned aryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on said aryl ring, in which case the number of carbon atoms continues to indicate The number of carbon atoms in the aryl ring system. The aryl group can be optionally substituted with one or more substituents, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

“C_6-12 芳烷基”表示基團-R-R’，其中R為烷基部分，R’為芳基部分，並且烷基和芳基總共具有6-12個碳原子。"C _6-12 aralkyl" means the group -R-R', where R is an alkyl moiety, R' is an aryl moiety, and the alkyl and aryl groups have a total of 6-12 carbon atoms.

“5-14員雜芳基”是指具有環碳原子和1-4個環雜原子的5-14員單環或雙環的4n+2芳族環狀系統(例如，具有以環狀排列共用的6、10或14個π電子)的基團，其中每個雜原子獨立地選自氮、氧和硫。在含有一個或多個氮原子的雜芳基中，只要化合價允許，連接點可以是碳或氮原子。雜芳基雙環系統在一個或兩個環中可以包括一個或多個雜原子。雜芳基還包括其中上述雜芳基環與一個或多個環烷基或雜環基稠合的環系統，而且連接點在所述雜芳基環上，在這種情況下，碳原子的數目繼續表示所述雜芳基環系統中的碳原子數目。在一些實施方案中，5-10員雜芳基是優選的，其為具有環碳原子和1-4個環雜原子的5-10員單環或雙環的4n+2芳族環狀系統。在另一些實施方案中，5-6員雜芳基是特別優選的，其為具有環碳原子和1-4個環雜原子的5-6員單環或雙環的4n+2芳族環狀系統。示例性的含有一個雜原子的5員雜芳基包括但不限於：吡咯基、呋喃基和噻吩基。示例性的含有兩個雜原子的5員雜芳基包括但不限於：咪唑基、吡唑基、噁唑基、異噁唑基、噻唑基和異噻唑基。示例性的含有三個雜原子的5員雜芳基包括但不限於：***基、噁二唑基(例如，1,2,4-噁二唑基)和噻二唑基。示例性的含有四個雜原子的5員雜芳基包括但不限於：四唑基。示例性的含有一個雜原子的6員雜芳基包括但不限於：吡啶基。示例性的含有兩個雜原子的6員雜芳基包括但不限於：噠嗪基、嘧啶基和吡嗪基。示例性的含有三個或四個雜原子的6員雜芳基分別包括但不限於：三嗪基和四嗪基。示例性的含有一個雜原子的7員雜芳基包括但不限於：氮雜環庚三烯基、氧雜環庚三烯基和硫雜環庚三烯基。示例性的5,6-雙環雜芳基包括但不限於：吲哚基、異吲哚基、吲唑基、苯並***基、苯並噻吩基、異苯並噻吩基、苯並呋喃基、苯並異呋喃基、苯並咪唑基、苯並噁唑基、苯並異噁唑基、苯並噁二唑基、苯並噻唑基、苯並異噻唑基、苯並噻二唑基、茚嗪基和嘌呤基。示例性的6,6-雙環雜芳基包括但不限於：萘啶基、喋啶基、喹啉基、異喹啉基、噌琳基、喹喔啉基、酞嗪基和喹唑啉基。雜芳基基團可以被一或多個取代基任選取代，例如，被1至5個取代基、1至3個取代基或1個取代基取代。"5-14 membered heteroaryl" refers to a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (eg, having a common 6, 10 or 14 pi electrons), wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as valence allows. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the carbon atom is The numbers continue to indicate the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-10 membered heteroaryl groups are preferred, which are 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 5-6 membered heteroaryl groups are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic cyclic rings having ring carbon atoms and 1-4 ring heteroatoms system. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (eg, 1,2,4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azacyclotrienyl, oxepatrienyl, and thiacyclotrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl , benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, Indanyl and purine groups. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to: naphthyridinyl, pteridyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl . Heteroaryl groups can be optionally substituted with one or more substituents, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

“氧代”表示=O。"Oxo" means =O.

本文定義的烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基等為任選取代的基團。Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and the like, as defined herein, are optionally substituted groups.

示例性的碳原子上的取代基包括但不侷限於：鹵素、-CN、-NO₂ 、-N₃ 、-SO₂ H、-SO₃ H、-OH、-OR^aa 、-ON(R^bb )₂ 、-N(R^bb )₂ 、-N(R^bb )₃ ⁺ X^- 、-N(OR^cc )R^bb 、-SH、-SR^aa 、-SSR^cc 、-C(=O)R^aa 、-CO₂ H、-CHO、-C(OR^cc )₂ 、-CO₂ R^aa 、-OC(=O)R^aa 、-OCO₂ R^aa 、-C(=O)N(R^bb )₂ 、-OC(=O)N(R^bb )₂ 、-NR^bb C(=O)R^aa 、-NR^bb CO₂ R^aa 、-NR^bb C(=O)N(R^bb )₂ 、-C(=NR^bb )R^aa 、-C(=NR^bb )OR^aa 、-OC(=NR^bb )R^aa 、-OC(=NR^bb )OR^aa 、-C(=NR^bb )N(R^bb )₂ 、-OC(=NR^bb )N(R^bb )₂ 、-NR^bb C(=NR^bb )N(R^bb )₂ 、-C(=O)NR^bb SO₂ R^aa 、-NR^bb SO₂ R^aa 、-SO₂ N(R^bb )₂ 、-SO₂ R^aa 、-SO₂ OR^aa 、-OSO₂ R^aa 、-S(=O)R^aa 、-OS(=O)R^aa 、-Si(R^aa )₃ 、-OSi(R^aa )₃ 、-C(=S)N(R^bb )₂ 、-C(=O)SR^aa 、-C(=S)SR^aa 、-SC(=S)SR^aa 、-SC(=O)SR^aa 、-OC(=O)SR^aa 、-SC(=O)OR^aa 、-SC(=O)R^aa 、-P(=O)₂ R^aa 、-OP(=O)₂ R^aa 、-P(=O)(R^aa )₂ 、-OP(=O)(R^aa )₂ 、-OP(=O)(OR^cc )₂ 、-P(=O)₂ N(R^bb )₂ 、-OP(=O)₂ N(R^bb )₂ 、-P(=O)(NR^bb )₂ 、-OP(=O)(NR^bb )₂ 、-NR^bb P(=O)(OR^cc )₂ 、-NR^bb P(=O)(NR^bb )₂ 、-P(R^cc )₂ 、-P(R^cc )₃ 、-OP(R^cc )₂ 、-OP(R^cc )₃ 、-B(R^aa )₂ 、-B(OR^cc )₂ 、-BR^aa (OR^cc )、烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基，其中，每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基獨立地被0、1、2、3、4或5個R^dd 基團取代；Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, _-NO2 , _-N3 , _-SO2H , _-SO3H , -OH, ^-ORaa , -ON( ^Rbb ) ₂ , -N(R ^bb ) ₂ , -N(R ^bb ) ₃ ⁺ X ^- , -N(OR ^cc )R ^bb , -SH, -SR ^aa , -SSR ^cc , -C(=O)R ^aa , -CO ₂ H, -CHO, -C(OR ^cc ) ₂ , -CO ₂ R ^aa , -OC(=O)R ^aa , -OCO ₂ R ^aa , -C(=O)N(R ^bb ) ₂ , -OC(=O)N(R ^bb ) ₂ , -NR ^bb C(=O)R ^aa , -NR ^bb CO ₂ R ^aa , -NR ^bb C(=O)N(R ^bb ) ₂ , -C (=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -OC(=NR ^bb )R ^aa , -OC(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , -OC(=NR ^bb )N(R ^bb ) ₂ , -NR ^bb C(=NR ^bb )N(R ^bb ) ₂ , -C(=O)NR ^bb SO ₂ R ^aa , -NR ^bb SO ₂ R ^aa , -SO ₂ N(R ^bb ) ₂ , -SO ₂ R ^aa , -SO ₂ OR ^aa , -OSO ₂ R ^aa , -S(=O)R ^aa , -OS(=O)R ^aa , - Si(R ^aa ) ₃ , -OSi(R ^aa ) ₃ , -C(=S)N(R ^bb ) ₂ , -C(=O)SR ^aa , -C(=S)SR ^aa , -SC(= S)SR ^aa , -SC(=O)SR ^aa , -OC(=O)SR ^aa , -SC(=O)OR ^aa , -SC(=O)R ^aa , -P(=O) ₂ R ^aa , -OP(=O) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -OP(=O)(R ^aa ) ₂ , -OP(=O)(OR ^cc ) ₂ , -P( =O) ₂ N(R ^bb ) ₂ , -OP(=O) ₂ N(R ^bb ) ₂ , -P(=O)(NR ^bb ) ₂ , -OP(=O)(NR ^bb ) ₂ , - NR ^bb P(=O)(OR ^cc ) ₂ , -NR ^bb P(=O)(NR ^bb ) ₂ , -P(R ^cc ) ₂ , -P(R ^cc ) ₃ , -OP(R ^cc ) ₂ , -OP(R ^cc ) ₃ , -B(R ^aa ) ₂ , -B(OR ^cc ) ₂ , -BR ^aa (OR ^cc ), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heterocyclyl Aryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups ;

或者在碳原子上的兩個偕氫被基團=O、=S、=NN(R^bb )₂ 、=NNR^bb C(=O)R^aa 、=NNR^bb C(=O)OR^aa 、=NNR^bb S(=O)₂ R^aa 、=NR^bb 或=NOR^cc 取代；Or two geminal hydrogens on carbon atoms are grouped =O, =S, =NN( ^Rbb ) ₂ , = ^NNRbbC (=O) ^Raa , = ^NNRbbC (=O) ^ORaa , = NNR ^bb S(=O) ₂ R ^aa , =NR ^bb or =NOR ^cc substitution;

R^aa 的每個獨立地選自烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基，或者兩個R^aa 基團結合以形成雜環基或雜芳基環，其中，每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基獨立地被0、1、2、3、4或5個R^dd 基團取代；Each of R ^aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R ^aa groups are combined to form a heterocyclyl or Heteroaryl rings in which each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently replaced by 0, 1, 2, 3, 4, or 5 R ^dd groups group replacement;

R^bb 的每個獨立地選自：氫、-OH、-OR^aa 、-N(R^cc )₂ 、-CN、-C(=O)R^aa 、-C(=O)N(R^cc )₂ 、-CO₂ R^aa 、-SO₂ R^aa 、-C(=NR^cc )OR^aa 、-C(=NR^cc )N(R^cc )₂ 、-SO₂ N(R^cc )₂ 、-SO₂ R^cc 、-SO₂ OR^cc 、-SOR^aa 、-C(=S)N(R^cc )₂ 、-C(=O)SR^cc 、-C(=S)SR^cc 、-P(=O)₂ R^aa 、-P(=O)(R^aa )₂ 、-P(=O)₂ N(R^cc )₂ 、-P(=O)(NR^cc )₂ 、烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基，或者兩個R^bb 基團結合以形成雜環基或雜芳基環，其中，每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基獨立地被0、1、2、3、4或5個R^dd 基團取代；Each of R ^bb is independently selected from: hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -CN, -C(=O)R ^aa , -C(=O)N(R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc ) ₂ , -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=O)SR ^cc , -C(=S)SR ^cc , -P(=O ) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -P(=O) ₂ N(R ^cc ) ₂ , -P(=O)(NR ^cc ) ₂ , alkyl, haloalkyl, alkene radical, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R ^bb groups combined to form a heterocyclyl or heteroaryl ring, where each alkyl, alkenyl, alkyne , cycloalkyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups;

R^cc 的每個獨立地選自氫、烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基，或者兩個R^cc 基團結合以形成雜環基或雜芳基環，其中，每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基獨立地被0、1、2、3、4或5個R^dd 基團取代；Each of ^Rcc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two ^Rcc groups are combined to form a heterocycle aryl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently replaced by 0, 1, 2, 3, 4, or 5 R ^dd group substitution;

R^dd 的每個獨立地選自：鹵素、-CN、-NO₂ 、-N₃ 、-SO₂ H、-SO₃ H、-OH、-OR^ee 、-ON(R^ff )₂ 、-N(R^ff )₂ , 、-N(R^ff )₃ ⁺ X^- 、-N(OR^ee )R^ff 、-SH、-SR^ee 、-SSR^ee 、-C(=O)R^ee 、-CO₂ H、-CO₂ R^ee 、-OC(=O)R^ee 、-OCO₂ R^ee 、-C(=O)N(R^ff )₂ 、-OC(=O)N(R^ff )₂ 、-NR^ff C(=O)R^ee 、-NR^ff CO₂ R^ee 、-NR^ff C(=O)N(R^ff )₂ 、-C(=NR^ff )OR^ee 、-OC(=NR^ff )R^ee 、-OC(=NR^ff )OR^ee 、-C(=NR^ff )N(R^ff )₂ 、-OC(=NR^ff )N(R^ff )₂ 、-NR^ff C(=NR^ff )N(R^ff )₂ 、-NR^ff SO₂ R^ee 、-SO₂ N(R^ff )₂ 、-SO₂ R^ee 、-SO₂ OR^ee 、-OSO₂ R^ee 、-S(=O)R^ee 、-Si(R^ee )₃ 、-OSi(R^ee )₃ 、-C(=S)N(R^ff )₂ 、-C(=O)SR^ee 、-C(=S)SR^ee 、-SC(=S)SR^ee 、-P(=O)₂ R^ee 、-P(=O)(R^ee )₂ 、-OP(=O)(R^ee )₂ 、-OP(=O)(OR^ee )₂ 、烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基、雜芳基，其中，每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基獨立地被0、1、2、3、4或5個R^gg 基團取代，或者兩個偕R^dd 取代基可結合以形成=O或=S；Each of ^Rdd is independently selected from: halogen, -CN, _-NO2 , _-N3 , -SO2H, _-SO3H , -OH, ^-ORee , -ON( ^Rff ₎₂ _, -N (R ^ff ) ₂ , , -N(R ^ff ) ₃ ⁺ X ^- , -N(OR ^ee )R ^ff , -SH, -SR ^ee , -SSR ^ee , -C(=O)R ^ee , -CO ₂ H, -CO ₂ ^Ree , -OC(=O) ^Ree , -OCO ₂ ^Ree , -C(=O)N(R ^ff ) ₂ , -OC(=O)N(R ^ff ) ₂ , - NR ^ff C(=O) ^Ree , -NR ^ff CO ₂ Re , -NR ^ff C(=O)N(R ^ff ) ₂ , -C(=NR ^ff )OR ^ee ^, -OC(=NR ^ff ) ^Ree , -OC(=NR ^ff )OR ^ee , -C(=NR ^ff )N(R ^ff ) ₂ , -OC(=NR ^ff )N(R ^ff ) ₂ , -NR ^ff C(=NR ^ff ) N(R ^ff ) ₂ , -NR ^ff SO ₂ ^Ree , -SO ₂ N(R ^ff ) ₂ , -SO ₂ ^Ree , -SO ₂ OR ^ee , -OSO ₂ ^Ree , -S(=O)R ^ee , -Si(R ^ee ) ₃ , -OSi(R ^ee ) ₃ , -C(=S)N(R ^ff ) ₂ , -C(=O)SR ^ee , -C(=S)SR ^ee , - SC(=S)SR ^ee , -P(=O) ₂ Re ^ee , -P(=O)(R ^ee ) ₂ , -OP(=O)(R ^ee ) ₂ , -OP(=O)(OR ^ee ) ₂ , alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle aryl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups, or two gem R ^dd substituents may combine to form =0 or =S;

R^ee 的每個獨立地選自烷基、鹵代烷基、烯基、炔基、環烷基、芳基、雜環基和雜芳基，其中，每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基獨立地被0、1、2、3、4或5個R^gg 基團取代；Each of R ^ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, ring Alkyl, heterocyclyl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups;

R^ff 的每個獨立地選自氫、烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基，或者兩個R^ff 基團結合形成雜環基或雜芳基環，其中，每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基獨立地被0、1、2、3、4或5個R^gg 基團取代；Each of ^Rff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two ^Rff groups are combined to form a heterocyclyl group or a heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently separated by 0, 1, 2, 3, 4, or 5 R ^gg group substitution;

R^gg 的每個獨立地是：鹵素、-CN、-NO₂ 、-N₃ 、-SO₂ H、-SO₃ H、-OH、-OC_1-6 烷基、-ON(C_1-6 烷基)₂ 、-N(C_1-6 烷基)₂ 、-N(C_1-6 烷基)₃ ⁺ X^- 、-NH(C_1-6 烷基)₂ ⁺ X^- 、-NH₂ (C_1-6 烷基)⁺ X^- 、-NH₃ ⁺ X^- 、-N(OC_1-6 烷基)(C_1-6 烷基)、-N(OH)(C_1-6 烷基)、-NH(OH)、-SH、-SC_1-6 烷基、-SS(C_1-6 烷基)、-C(=O)(C_1-6 烷基)、-CO₂ H、-CO₂ (C_1-6 烷基)、-OC(=O)(C_1-6 烷基)、-OCO₂ (C_1-6 烷基)、-C(=O)NH₂ 、-C(=O)N(C_1-6 烷基)₂ 、-OC(=O)NH(C_1-6 烷基)、-NHC(=O)(C_1-6 烷基)、-N(C_1-6 烷基)C(=O)(C_1-6 烷基)、-NHCO₂ (C_1-6 烷基)、-NHC(=O)N(C_1-6 烷基)₂ 、-NHC(=O)NH(C_1-6 烷基)、-NHC(=O)NH₂ 、-C(=NH)O(C_1-6 烷基)、-OC(=NH)(C_1-6 烷基)、-OC(=NH)OC_1-6 烷基、-C(=NH)N(C_1-6 烷基)₂ 、-C(=NH)NH(C_1-6 烷基)、-C(=NH)NH₂ 、-OC(=NH)N(C_1-6 烷基)₂ 、-OC(NH)NH(C_1-6 烷基)、-OC(NH)NH₂ 、-NHC(NH)N(C_1-6 烷基)₂ 、-NHC(=NH)NH₂ 、-NHSO₂ (C_1-6 烷基)、-SO₂ N(C_1-6 烷基)₂ 、-SO₂ NH(C_1-6 烷基)、-SO₂ NH₂ 、-SO₂ C_1-6 烷基、-SO₂ OC_1-6 烷基、-OSO₂ C_1-6 烷基、-SOC_1-6 烷基、-Si(C_1-6 烷基)₃ 、-OSi(C_1-6 烷基)₃ 、-C(=S)N(C_1-6 烷基)₂ 、C(=S)NH(C_1-6 烷基)、C(=S)NH₂ 、-C(=O)S(C_1-6 烷基)、-C(=S)SC_1-6 烷基、-SC(=S)SC_1-6 烷基、-P(=O)₂ (C_1-6 烷基)、-P(=O)(C_1-6 烷基)₂ 、-OP(=O)(C_1-6 烷基)₂ 、-OP(=O)(OC_1-6 烷基)₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C₂ -C₆ 烯基、C₂ -C₆ 炔基、C₃ -C₇ 環烷基、C₆ -C₁₀ 芳基、C₃ -C₇ 雜環基、C₅ -C₁₀ 雜芳基；或者兩個偕R^gg 取代基可結合形成=O或=S；其中，X^- 為相對離子。Each of Rgg is independently: halogen, -CN, _-NO2 , _-N3 , ^-SO2H , _-SO3H , _-OH , _-OC1-6 alkyl, -ON( _C1-6 alkyl) ₂ , -N(C _1-6 alkyl) ₂ , -N(C _1-6 alkyl) ₃ ⁺ X ^- , -NH(C _1-6 alkyl) ₂ ⁺ X ^- , -NH ₂ (C _1-6 alkyl) ⁺ X ^- , -NH ₃ ⁺ X ^- , -N(OC _1-6 alkyl)(C _1-6 alkyl), -N(OH)(C _1-6 alkyl ), -NH(OH), -SH, -SC _1-6 alkyl, -SS(C _1-6 alkyl), -C(=O)(C _1-6 alkyl), -CO ₂ H, -CO ₂ (C _1-6 alkyl), -OC(=O)(C _1-6 alkyl), -OCO ₂ (C _1-6 alkyl), -C(=O)NH ₂ , -C (=O)N(C _1-6 alkyl) ₂ , -OC(=O)NH(C _1-6 alkyl), -NHC(=O)(C _1-6 alkyl), -N(C _1-6 alkyl)C(=O)(C _1-6 alkyl), -NHCO ₂ (C _1-6 alkyl), -NHC(=O)N(C _1-6 alkyl) ₂ , - NHC(=O)NH(C _1-6 alkyl), -NHC(=O)NH ₂ , -C(=NH)O(C _1-6 alkyl), -OC(=NH)(C _{1- 6} alkyl), -OC(=NH)OC _1-6 alkyl, -C(=NH)N(C _1-6 alkyl) ₂ , -C(=NH)NH(C _1-6 alkyl) , -C(=NH)NH ₂ , -OC(=NH)N(C _1-6 alkyl) ₂ , -OC(NH)NH(C _1-6 alkyl), -OC(NH)NH ₂ , -NHC(NH)N(C _1-6 alkyl) ₂ , -NHC(=NH)NH ₂ , -NHSO ₂ (C _1-6 alkyl), -SO ₂ N(C _1-6 alkyl) ₂ , -SO ₂ NH(C _1-6 alkyl), -SO ₂ NH ₂ , -SO ₂ C _1-6 alkyl, -SO ₂ OC _1-6 alkyl, -OSO ₂ C _1-6 alkyl, -SOC _1-6 alkyl, -Si(C _1-6 alkyl) ₃ , -OSi(C _1-6 alkyl) ₃ , -C(=S)N(C _1-6 alkyl) ₂ , C (=S)NH(C _1-6 alkyl), C(=S)NH ₂ , -C(=O)S(C _1-6 alkyl), -C(=S)SC _1-6 alkyl , -SC(=S)SC _1-6 alkyl, -P(=O) ₂ (C _1-6 alkyl), -P(=O)(C _1-6 alkyl) ₂ , -OP(= O)(C _1-6 alkyl) ₂ , -OP(= O)(OC _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₇ cycloalkyl , C ₆ -C ₁₀ aryl, C ₃ -C ₇ heterocyclyl, C ₅ -C ₁₀ heteroaryl; or two gem R ^gg substituents can be combined to form =O or =S; wherein, X ^- is relative ion.

示例性的氮原子上取代基包括但不侷限於：氫、-OH、-OR^aa 、-N(R^cc )₂ 、-CN、-C(=O)R^aa 、-C(=O)N(R^cc )₂ 、-CO₂ R^aa 、-SO₂ R^aa 、-C(=NR^bb )R^aa 、-C(=NR^cc )OR^aa 、-C(=NR^cc )N(R^cc )₂ 、-SO₂ N(R^cc )₂ 、-SO₂ R^cc 、-SO₂ OR^cc 、-SOR^aa 、-C(=S)N(R^cc )₂ 、-C(=O)SR^cc 、-C(=S)SR^cc 、-P(=O)₂ R^aa 、-P(=O)(R^aa )₂ 、-P(=O)₂ N(R^cc )₂ 、-P(=O)(NR^cc )₂ 、烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基，或者連接至氮原子的兩個R^cc 基團結合形成雜環基或雜芳基環，其中，每個烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基獨立地被0、1、2、3、4或5個R^dd 基團取代，且其中R^aa 、R^bb 、R^cc 和R^dd 如上所述。其它定義Exemplary substituents on nitrogen include, but are not limited to: hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -CN, -C(=O)R ^aa , -C(=O)N (R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C(=NR ^bb )R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc ) ₂ , -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=O)SR ^cc , -C(=S)SR ^cc , -P(=O) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -P(=O) ₂ N(R ^cc ) ₂ , -P(=O )( ^NRcc ) ₂ , alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two ^Rcc groups attached to a nitrogen atom combine to form a heterocycle aryl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently replaced by 0, 1, 2, 3, 4, or 5 R The ^dd group is substituted and wherein R ^aa , R ^bb , R ^cc and R ^dd are as described above. Other definitions

術語“KRAS G12C”是指哺乳動物KRAS蛋白的突變形式，其在12位胺基酸處含有半胱氨胺酸對甘胺酸的胺基酸取代。人KRAS的胺基酸密碼子和殘基位置的定位是基於由UniProtKB/Swiss-Prot Ρ01116:Variant ρ.Glyl2Cys鑒定的胺基酸序列。The term "KRAS G12C" refers to a mutant form of mammalian KRAS protein that contains an amino acid substitution of cysteine to glycine at amino acid position 12. The mapping of amino acid codons and residue positions of human KRAS is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116:Variant p.Glyl2Cys.

術語“KRAS G12C抑制劑”是指本發明化合物，這些化合物能夠負性調控或抑制KRAS G12C的全部或部分酶活性。本發明的KRAS G12C抑制劑透過與12處於半胱氨胺酸殘基的巰基側鏈形成共價加成物而與KRAS G12C相互作用和不可逆地結合，導致抑制KRAS G12C的酶活性。The term "KRAS G12C inhibitor" refers to compounds of the present invention which are capable of negatively modulating or inhibiting all or part of the enzymatic activity of KRAS G12C. The KRAS G12C inhibitors of the present invention interact and irreversibly bind to KRAS G12C through the formation of covalent adducts with the sulfhydryl side chain of 12 cysteine residues, resulting in inhibition of the enzymatic activity of KRAS G12C.

術語“癌症”包括但不限於下列癌症：乳腺、卵巢、子宮頸、***、睾丸、食道、胃、皮膚、肺、骨、結腸、胰腺、甲狀腺、膽道、頰腔與咽(口)、唇、舌、口腔、咽、小腸、結腸直腸、大腸、直腸、腦與中樞神經系統的癌症、成膠質細胞瘤、神經膠母細胞瘤、角質棘皮瘤、表皮樣癌、大細胞癌、腺癌、腺瘤、濾泡癌、未分化的癌、乳突癌、精原細胞瘤、黑色素瘤、肉瘤、膀胱癌、肝癌、腎癌、骨髓病症、淋巴病症、何杰金氏病、毛細胞癌和白血病。The term "cancer" includes, but is not limited to, the following cancers: breast, ovary, cervix, prostate, testis, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, biliary tract, buccal cavity and pharynx (mouth), lips , cancer of tongue, oral cavity, pharynx, small intestine, colorectum, large intestine, rectum, brain and central nervous system, glioblastoma, glioblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, Adenoma, follicular carcinoma, undifferentiated carcinoma, mastoid carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, kidney cancer, bone marrow disorders, lymphatic disorders, Hodgkin's disease, hair cell carcinoma and leukemia.

本文所用的術語“治療”涉及逆轉、減輕、抑制該術語適用的病症或病況的進展或者預防之，或者這類病症或病況的一種或多種症狀。本文所用的名詞“治療”涉及動詞治療的動作，後者是如剛才所定義的。The term "treating" as used herein refers to reversing, alleviating, inhibiting the progression or preventing the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition. The term "treatment" as used herein refers to the action of the verb treat, as just defined.

本文所用的術語“藥學上可接受的鹽”表示本發明化合物的那些羧酸鹽、胺基酸加成鹽，它們在可靠的醫學判斷範圍內適用于與患者組織接觸，不會產生不恰當的毒性、刺激作用、變態反應等，與合理的益處/風險比相稱，就它們的預期應用而言是有效的，包括(可能的話)本發明化合物的兩性離子形式。As used herein, the term "pharmaceutically acceptable salts" refers to those carboxylates, amino acid addition salts of the compounds of the present invention, which are suitable, within the scope of sound medical judgment, for use in contact with patient tissue without causing inappropriate Toxicity, irritation, allergy, etc., commensurate with a reasonable benefit/risk ratio, are effective for their intended use, including (where possible) the zwitterionic forms of the compounds of the present invention.

藥學上可接受的鹼加成鹽是與金屬或胺生成的，例如鹼金屬與鹼土金屬氫氧化物或有機胺。用作陽離子的金屬的實例有鈉、鉀、鎂、鈣等。適合的胺的實例有N,N'-二苄基乙二胺、氯普魯卡因、膽鹼、二乙醇胺、乙二胺、N-甲基葡萄糖胺和普魯卡因。Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine.

酸性化合物的鹼加成鹽可以這樣製備，按照常規方式使游離酸形式與足量所需的鹼接觸，生成鹽。按照常規方式使鹽形式與酸接觸，再分離游離酸，可以使游離酸再生。游離酸形式在某些物理性質上多少不同於它們各自的鹽形式，例如在極性溶劑中的溶解度，但是出於本發明的目的，鹽還是等價於它們各自的游離酸。Base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the desired base in a conventional manner to form the salt. The free acid can be regenerated by contacting the salt form with the acid in a conventional manner and isolating the free acid. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the present invention, the salts are nevertheless equivalent to their respective free acids.

鹽可以是從無機酸製備的硫酸鹽、焦硫酸鹽、硫酸氫鹽、亞硫酸鹽、亞硫酸氫鹽、硝酸鹽、磷酸鹽、磷酸一氫鹽、磷酸二氫鹽、偏磷酸鹽、焦磷酸鹽、氯化物、溴化物、碘化物，酸例如鹽酸、硝酸、硫酸、氫溴酸、氫碘酸、磷酸等。代表性鹽包括：氫溴酸鹽、鹽酸鹽、硫酸鹽、硫酸氫鹽、硝酸鹽、乙酸鹽、草酸鹽、戊酸鹽、油酸鹽、棕櫚酸鹽、硬脂酸鹽、月桂酸鹽、硼酸鹽、苯甲酸鹽、乳酸鹽、磷酸鹽、甲苯磺酸鹽、檸檬酸鹽、馬來酸鹽、延胡索酸鹽、琥珀酸鹽、酒石酸鹽、萘甲酸鹽、甲磺酸鹽、葡庚糖酸鹽、乳糖酸鹽、月桂基磺酸鹽和羥乙磺酸鹽等。鹽也可以是從有機酸製備的，例如脂肪族一員與二員羧酸、苯基取代的烷酸、羥基烷酸、烷二酸、芳香族酸、脂肪族與芳香族磺酸等。代表性鹽包括乙酸鹽、丙酸鹽、辛酸鹽、異丁酸鹽、草酸鹽、丙二酸鹽、琥珀酸鹽、辛二酸鹽、癸二酸鹽、延胡索酸鹽、馬來酸鹽、扁桃酸鹽、苯甲酸鹽、氯苯甲酸盆、甲基苯甲酸鹽、二硝基苯甲酸鹽、萘甲酸鹽、苯磺酸鹽、甲苯磺酸鹽、苯乙酸鹽、檸檬酸鹽、乳酸鹽、馬來酸鹽、酒石酸鹽、甲磺酸鹽等。藥學上可接受的鹽可以包括基於鹼金屬與鹼土金屬的陽離子，例如鈉、鋰、鉀、鈣、鎂等，以及無毒的銨、季銨和胺陽離子，包括但不限於銨、四甲基銨、四乙基銨、甲胺、二甲胺、三甲胺、三乙胺、乙胺等。還涵蓋胺基酸的鹽，例如精胺酸鹽、葡萄糖酸鹽、半乳糖醛酸鹽等(例如參見Berge S. M. et al.，"Pharmaceutical Salts,”J. Pharm. Sci.，1977; 66: 1-19，引入此作為參考)。Salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates prepared from inorganic acids Salts, chlorides, bromides, iodides, acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like. Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, lauric acid salt, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, Glucoheptonate, lactobionate, lauryl sulfonate and isethionate, etc. Salts can also be prepared from organic acids such as aliphatic one- and two-membered carboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Representative salts include acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, Mandelate, Benzoate, Chlorobenzoate, Methylbenzoate, Dinitrobenzoate, Naphthoate, Besylate, Tosylate, Phenylacetate, Citric Acid Salt, lactate, maleate, tartrate, mesylate, etc. Pharmaceutically acceptable salts may include alkali metal and alkaline earth metal based cations such as sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium and amine cations, including but not limited to ammonium, tetramethylammonium , tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. Also encompassed are salts of amino acids, such as arginine, gluconate, galacturonate, etc. (see, eg, Berge SM et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1 -19, incorporated herein by reference).

給藥的“受試者”包括但不限於：人(即，任何年齡組的男性或女性，例如，兒科受試者(例如，嬰兒、兒童、青少年)或成人受試者(例如，年輕的成人、中年的成人或年長的成人))和/或非人的動物，例如，哺乳動物，例如，靈長類(例如，食蟹猴、恆河猴)、牛、豬、馬、綿羊、山羊、齧齒動物、貓和/或狗。在一些實施方案中，受試者是人。在一些實施方案中，受試者是非人動物。本文可互換使用術語“人”、“患者”和“受試者”。"Subjects" for administration include, but are not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and/or non-human animals, eg, mammals, eg, primates (eg, cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep , goats, rodents, cats and/or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human", "patient" and "subject" are used interchangeably herein.

“疾病”、“病症”和“病況”在本文中可互換地使用。"Disease," "disorder," and "condition" are used interchangeably herein.

除非另作說明，否則，本文使用的術語“治療”包括受試者患有具體疾病、病症或病況時所發生的作用，它降低疾病、病症或病況的嚴重程度，或延遲或減緩疾病、病症或病況的發展(“治療性治療”)，還包括在受試者開始患有具體疾病、病症或病況之前發生的作用(“預防性治療”)。Unless otherwise specified, the term "treatment" as used herein includes the effect that occurs when a subject has a particular disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or delays or slows down the disease, disorder or condition or development of a condition ("therapeutic treatment"), also includes effects that occur before a subject begins to suffer from a particular disease, disorder or condition ("prophylactic treatment").

通常，化合物的“有效量”是指足以引起目標生物反應的數量。正如所屬領域通常知識者所理解的那樣，本發明化合物的有效量可以根據下列因素而改變：例如，生物學目標、化合物的藥物動力學、所治療的疾病、給藥模式以及受試者的年齡健康情況和症狀。有效量包括治療有效量和預防有效量。Generally, an "effective amount" of a compound refers to an amount sufficient to elicit a target biological response. As understood by those of ordinary skill in the art, the effective amount of a compound of the present invention may vary depending on factors such as, for example, the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age of the subject health conditions and symptoms. An effective amount includes a therapeutically effective amount and a prophylactically effective amount.

除非另作說明，否則，本文使用的化合物的“治療有效量”是在治療疾病、病症或病況的過程中足以提供治療益處的量，或使與疾病、病症或病況有關的一或多種症狀延遲或最小化的量。化合物的治療有效量是指單獨使用或與其它療法聯用時，治療劑的量，它在治療疾病、病症或病況的過程中提供治療益處。術語“治療有效量”可以包括改善總體治療、降低或避免疾病或病況的症狀或病因、或增強其它治療劑的治療效果的量。Unless otherwise specified, a "therapeutically effective amount" of a compound as used herein is an amount sufficient to provide a therapeutic benefit during the treatment of a disease, disorder or condition, or to delay one or more symptoms associated with the disease, disorder or condition or minimized amount. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic effect of other therapeutic agents.

除非另作說明，否則，本文使用的化合物的“預防有效量”是足以預防疾病、病症或病況的量，或足以預防與疾病、病症或病況有關的一或多種症狀的量，或防止疾病、病症或病況復發的量。化合物的預防有效量是指單獨使用或與其它藥劑聯用時，治療劑的量，它在預防疾病、病症或病況的過程中提供預防益處。術語“預防有效量”可以包括改善總體預防的量，或增強其它預防藥劑的預防效果的量。 “組合”以及相關術語是指同時或依次給藥本發明化合物和其它治療劑。例如，本發明化合物可以與其它治療劑以分開的單位劑量同時或依次給藥，或與其它治療劑一起在單一單位劑量中同時給藥。Unless otherwise specified, a "prophylactically effective amount" of a compound as used herein is an amount sufficient to prevent a disease, disorder or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder or condition, or to prevent a disease, disorder or condition. The amount of recurrence of a disorder or condition. A prophylactically effective amount of a compound refers to that amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of a disease, disorder or condition. The term "prophylactically effective amount" can include an amount that improves overall prophylaxis, or an amount that enhances the prophylactic effect of other prophylactic agents. "Combination" and related terms refer to the simultaneous or sequential administration of a compound of the present invention and another therapeutic agent. For example, the compounds of the present invention may be administered concurrently or sequentially with other therapeutic agents in separate unit doses, or concurrently with other therapeutic agents in a single unit dose.

本文中，“本發明化合物”指的是以下的式(I)化合物(包括子通式，例如式(I-1)、式(II)等)、其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物。Herein, "compounds of the present invention" refers to the following compounds of formula (I) (including sub-formulae such as formula (I-1), formula (II), etc.), pharmaceutically acceptable salts thereof, enantiomers compounds, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof.

本文中，化合物使用標準的命名法命名。具有非對稱中心的化合物，應該明白(除非另有說明)所有的光學異構物及其混合物均包含在內。此外，除非另有規定，本發明所包括的所有異構化合物與碳碳雙鍵可能以Z和E的形式出現。在不同的互變異構形式存在的化合物，一個所述化合物並不侷限於任何特定的互變異構物，而是旨在涵蓋所有的互變異構形式。Herein, compounds are named using standard nomenclature. For compounds having asymmetric centers, it should be understood that (unless otherwise stated) all optical isomers and mixtures thereof are included. Furthermore, all isomeric compounds and carbon-carbon double bonds encompassed by this invention may occur in the Z and E forms unless otherwise specified. Compounds exist in different tautomeric forms, and one such compound is not limited to any particular tautomer, but is intended to encompass all tautomeric forms.

在一個實施方案中，本發明涉及式(I)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物：

(I) 其中，環A為C_6-10 芳基或5-14員雜芳基，優選為萘基或9-10員雜芳基，優選萘基、苯並5員雜芳基或苯並6員雜芳基； R₆ 獨立地為H、D、C_0-6 亞烷基-鹵素、C_0-6 亞烷基-CN、C_0-6 亞烷基-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、C_0-6 亞烷基-O-R_1a 、C_0-6 亞烷基-S-R_1a 、C_0-6 亞烷基-N(R_1a )₂ 、C_0-6 亞烷基-C(O)R_1a 、C_0-6 亞烷基-C(O)OR_1a 、C_0-6 亞烷基-C(O)N(R_1a )₂ 或C_0-6 亞烷基-S(O)_m R_1a ；優選地，其中至少一個R₆ 為-O-R_1a ； m=1或2； n=0、1、2、3、4、5、6或7； L₁ 為-H₁ -H₂ -H₃ -H₄ -；In one embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorphism thereof, or a pharmaceutically acceptable salt thereof drugs, precursors or isotopic variants, and mixtures thereof:

(I) wherein, ring A is C _6-10 aryl or 5-14 membered heteroaryl, preferably naphthyl or 9-10 membered heteroaryl, preferably naphthyl, benzo 5-membered heteroaryl or benzo 6-membered heteroaryl; R ₆ is independently H, D, C _0-6 alkylene-halogen, C _0-6 alkylene-CN, C _0-6 alkylene-NO ₂ , C _1-6 Alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _0-6 alkylene-OR _1a , C _0-6 alkylene-SR _1a , C _0-6 Alkylene-N(R _1a ) ₂ , C _0-6 alkylene-C(O)R _1a , C _0-6 alkylene-C(O)OR _1a , C _0-6 alkylene-C (O)N(R _1a ) ₂ or C _0-6 alkylene-S(O) _m R _1a ; preferably, at least one of R ₆ is -OR _1a ; m=1 or 2; n=0, 1 , 2, 3, 4, 5, 6 or 7; L ₁ is -H ₁ -H ₂ -H ₃ -H ₄ -;

;

並且，相鄰原子上的R_L2 /R_L2’ 可以結合形成C_3-10 環烷基或3-10員雜環基； R₂ 為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-N(R_1a )₂ 、C_3-10 環烷基、3-10員雜環基、C_6-10 芳基或5-14員雜芳基；其任選被r個R取代； L₃ 為化學鍵或-(C(R_L3 )(R_L3 ))_p -；And, R _L2 /R _L2' on adjacent atoms can combine to form C _3-10 cycloalkyl or 3-10 membered heterocyclic group; R ₂ is H, D, halogen, -CN, -NO ₂ , C _{1 -6} alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -N(R _1a ) ₂ , C _3-10 cycloalkyl, 3-10 members Heterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl; it is optionally substituted by r R; L ₃ is a chemical bond or -(C(R _L3 )(R _L3 )) _p -;

上述各基團中含有的OH、NH、NH₂ 、CH、CH₂ 、CH₃ 基團在每次出現時各自任選地被1、2、3或更多個R^s 及其同位素變體取代，其中所述R^s 在每次出現時獨立地選自：鹵素、羥基、胺基、氰基、硝基、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烷基、C_3-10 鹵代環烷基、3-10員雜環基、C_6-10 芳基、5-14員雜芳基、C_6-12 芳烷基、-OR^a’ 、-OC(O)R^a’ 、-C(O)R^a’ 、-C(O)OR^a’ 、-C(O)NR^a’ R^b’ 、-S(O)_q R^a’ 、-S(O)_q OR^a’ 、-S(O)_q NR^a’ R^b’ 、-NR^a’ R^b’ 、-NR^a’ C(O)R^b’ 、-NR^a’ -C(O)OR^b’ 、-NR^a’ -S(O)_q -R^b’ 、-NR^a’ C(O)NR^a’ R^b’ 、-C_1-6 亞烷基-R^a’ 、-C_1-6 亞烷基-OR^a’ 、-C_1-6 亞烷基-OC(O)R^a’ 、-C_1-6 亞烷基-C(O)OR^a’ 、-C_1-6 亞烷基-S(O)_q R^a’ 、-C_1-6 亞烷基-S(O)_q OR^a’ 、-C_1-6 亞烷基-OC(O)NR^a’ R^b’ 、-C_1-6 亞烷基-C(O)NR^a’ R^b’ 、-C_1-6 亞烷基-NR^a’ -C(O)NR^a’ R^b’ 、-C_1-6 亞烷基-OS(O)_q R^a’ 、-C_1-6 亞烷基-S(O)_q NR^a’ R^b’ 、-C_1-6 亞烷基-NR^a’ -S(O)_q NR^a’ R^b’ 、-C_1-6 亞烷基-NR^a’ R^b’ 和-O-C_1-6 亞烷基-NR^a’ R^b’ ，並且其中關於取代基R^s 所述的羥基、胺基、烷基、亞烷基、環烷基、雜環基、芳基、雜芳基和芳烷基進一步任選地被1、2、3或更多個獨立地選自下列的取代基及其同位素變體取代：鹵素、OH、胺基、氰基、硝基、C_1-6 烷基、C_1-6 鹵代烷基、C_1-6 烷基羥基、C_3-6 環烷基、3-10員雜環基、C_6-10 芳基、5-14員雜芳基和C_6-12 芳烷基； q每次出現時各自獨立地為1或2； R^a’ 和R^b’ 在每次出現時各自獨立地選自H、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_1-6 烷基-O-、C_1-6 烷基-S-、C_3-10 環烷基、3-10員雜環基、C_6-10 芳基、5-14員雜芳基和C_6-12 芳烷基。The OH, NH, _NH2 , CH, _CH2 , _CH3 groups contained in each of the above groups are each optionally substituted at each occurrence with 1, 2, 3 or more ^Rs and isotopic variants thereof , wherein said ^Rs at each occurrence is independently selected from: halogen, hydroxyl, amino, cyano, nitro, _C1-6 alkyl, _C1-6 haloalkyl, _C2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _3-10 halocycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-14 membered heteroaryl, C _{6 -12} Aralkyl, -OR ^a' , -OC(O)R ^a' , -C(O)R ^a' , -C(O)OR ^a' , -C(O)NR ^a' R ^b' , -S(O) _q R ^a' , -S(O) _q OR ^a' , -S(O) _q NR ^a' R ^b' , -NR ^a' R ^b' , -NR ^a' C(O)R ^b' , -NR ^a' -C(O)OR ^b' , -NR ^a' -S(O) _q -R ^b' , -NR ^a' C(O)NR ^a' R ^b' , -C _{1- 6} alkylene-R ^a' , -C _1-6 alkylene-OR ^a' , -C _1-6 alkylene-OC(O)R ^a' , -C _1-6 alkylene-C( O)OR ^a' , -C _1-6 alkylene-S(O) _q R ^a' , -C _1-6 alkylene-S(O) _q OR ^a' , -C _1-6 alkylene -OC(O)NR ^a' R ^b' , -C _1-6 alkylene-C(O)NR ^a' R ^b' , -C _1-6 alkylene-NR ^a' -C(O)NR ^a' R ^b' , -C _1-6 alkylene-OS(O) _q R ^a' , -C _1-6 alkylene-S(O) _q NR ^a' R ^b' , -C _1-6 Alkylene-NR ^a' -S(O) _q NR ^a' R ^b' , -C _1-6 alkylene-NR ^a' R ^b' and -OC _1-6 alkylene-NR ^a' R ^{b '} , and wherein the hydroxyl, amine, alkyl, alkylene, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups described with respect to the substituent ^Rs are further optionally replaced by 1, 2 , 3 or more substituents independently selected from the group consisting of halogen, OH, amino, cyano, nitro, C _1-6 alkyl, C _1-6 haloalkyl, C _{1 -6} alkylhydroxy, _C3-6 cycloalkyl, 3-10 membered heterocyclyl, _C6-10 membered aryl, 5-14 membered heteroaryl and _C6-12 membered aralkyl; each occurrence of q each independently 1 or 2; R ^a' and R ^b' at each occurrence are each independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1 -6} alkyl-O-, C _1-6 alkyl-S- , C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-14 membered heteroaryl and C _6-12 membered aralkyl.

環A 在一個具體實施方案中，環A為C_6-10 芳基；在另一個具體實施方案中，環A為5-14員雜芳基；在另一個具體實施方案中，環A為萘基；在另一個具體實施方案中，環A為9-10員雜芳基；在另一個具體實施方案中，環A為苯並5員雜芳基，例如苯並吡咯基、苯並吡唑基、苯並噻唑基、吲唑基、苯並噻吩基或苯並呋喃基，優選苯並噻唑基和吲唑基；在另一個具體實施方案中，環A為苯並6員雜芳基，例如苯並吡啶基、苯並噠嗪基、苯並吡嗪基、苯並嘧啶基或苯並三嗪基。Ring A In one embodiment, Ring A is C _6-10 aryl; in another embodiment, Ring A is 5-14 membered heteroaryl; in another embodiment, Ring A is naphthalene In another specific embodiment, Ring A is a 9-10 membered heteroaryl; in another specific embodiment, Ring A is a benzo 5-membered heteroaryl, such as benzopyrrolyl, benzopyrazole indazolyl, benzothiazolyl, indazolyl, benzothienyl or benzofuranyl, preferably benzothiazolyl and indazolyl; in another specific embodiment, ring A is benzo 6-membered heteroaryl, For example benzopyridyl, benzopyridazinyl, benzopyrazinyl, benzopyrimidinyl or benzotriazinyl.

R₆ 在一個具體實施方案中，R₆ 獨立地為H；在另一個具體實施方案中，R₆ 獨立地為D；在另一個具體實施方案中，R₆ 獨立地為C_0-6 亞烷基-鹵素；在另一個具體實施方案中，R₆ 獨立地為C_0-6 亞烷基-CN；在另一個具體實施方案中，R₆ 獨立地為C_0-6 亞烷基-NO₂ ；在另一個具體實施方案中，R₆ 獨立地為C_1-6 烷基；在另一個具體實施方案中，R₆ 獨立地為C_1-6 鹵代烷基；在另一個具體實施方案中，R₆ 獨立地為C_2-6 烯基；在另一個具體實施方案中，R₆ 獨立地為C_2-6 炔基；在另一個具體實施方案中，R₆ 獨立地為C_0-6 亞烷基-O-R_1a ，優選-OH；在另一個具體實施方案中，R₆ 獨立地為C_0-6 亞烷基-S-R_1a ；在另一個具體實施方案中，R₆ 獨立地為C_0-6 亞烷基-N(R_1a )₂ ；在另一個具體實施方案中，R₆ 獨立地為C_0-6 亞烷基-C(O)R_1a ；在另一個具體實施方案中，R₆ 獨立地為C_0-6 亞烷基-C(O)OR_1a ；在另一個具體實施方案中，R₆ 獨立地為C_0-6 亞烷基-C(O)N(R_1a )₂ ；在另一個具體實施方案中，R₆ 獨立地為C_0-6 亞烷基-S(O)_m R_1a ；在另一個具體實施方案中，R₆ 為非H基團；在另一個具體實施方案中，其中至少一個R₆ 為-O-R_1a 。R ₆ In one specific embodiment, R ₆ is independently H; in another specific embodiment, R ₆ is independently D; in another specific embodiment, R ₆ is independently C _0-6 alkylene In another specific embodiment, R ₆ is independently C _0-6 alkylene-CN; in another specific embodiment, R ₆ is independently C _0-6 alkylene-NO ₂ In another specific embodiment, R ₆ is independently C _1-6 alkyl; In another specific embodiment, R ₆ is independently C _1-6 haloalkyl; In another specific embodiment, R ₆ is independently C _2-6 alkenyl; in another specific embodiment, R ₆ is independently C _2-6 alkynyl; in another specific embodiment, R ₆ is independently C _0-6 alkylene group-OR _1a , preferably -OH; in another specific embodiment, R ₆ is independently _{Co 0-6} alkylene-SR _1a ; in another specific embodiment, R ₆ is independently C _0-6 Alkylene-N(R _1a ) ₂ ; in another specific embodiment, R ₆ is independently C _0-6 alkylene-C(O)R _1a ; in another specific embodiment, R ₆ is independently In another specific embodiment, R ₆ is independently _{Co-6 alkylene-C(O)N(R 1a} ₎ ₂ _; _in In another specific embodiment, R ₆ is independently C _0-6 alkylene-S(O) _m R _1a ; in another specific embodiment, R ₆ is a non-H group; in another specific embodiment , wherein at least one R ₆ is -OR _1a .

m 在一個具體實施方案中，m=1；在另一個具體實施方案中，m=2。m In one specific embodiment, m=1; in another specific embodiment, m=2.

n 在一個具體實施方案中，n=0；在另一個具體實施方案中，n=1；在另一個具體實施方案中，n=2；在另一個具體實施方案中，n=3；在另一個具體實施方案中，n=4；在另一個具體實施方案中，n=5；在另一個具體實施方案中，n=6；在另一個具體實施方案中，n=7。n In one specific embodiment, n=0; in another specific embodiment, n=1; in another specific embodiment, n=2; in another specific embodiment, n=3; In a specific embodiment, n=4; in another specific embodiment, n=5; in another specific embodiment, n=6; in another specific embodiment, n=7.

在一個具體實施方案中，

為

，其中Z₃ 、Z₄ 和Z₅ 獨立地為CR₆ 或N；環B為苯基或5-6員雜芳基；在另一個具體實施方案中，

為

；在另一個具體實施方案中，

為

；在另一個具體實施方案中，

為

；在另一個具體實施方案中，

為

；在另一個具體實施方案中，

為

；在另一個具體實施方案中，

為

；在另一個具體實施方案中，

為

；在另一個具體實施方案中，

為

；在另一個具體實施方案中，

為

；在另一個具體實施方案中，

為

；在另一個具體實施方案中，

為

；在另一個具體實施方案中，

為

；在另一個具體實施方案中，

為

。在另一個具體實施方案中，

為

、

、

或

；在另一個具體實施方案中，

為

或

。In a specific embodiment,

for

, wherein Z ₃ , Z ₄ and Z ₅ are independently CR ₆ or N; Ring B is phenyl or 5-6 membered heteroaryl; In another specific embodiment,

for

; In another specific embodiment,

for

; In another specific embodiment,

for

; In another specific embodiment,

for

; In another specific embodiment,

for

; In another specific embodiment,

for

; In another specific embodiment,

for

; In another specific embodiment,

for

; In another specific embodiment,

for

; In another specific embodiment,

for

; In another specific embodiment,

for

; In another specific embodiment,

for

; In another specific embodiment,

for

. In another specific embodiment,

for

,

or

; In another specific embodiment,

for

or

.

L₁ L₁ 為-H₁ -H₂ -H₃ -H₄ -，其中H₁ 選自-O-、-S-、-N(R_H’ )-、-C(R_H )(R_H )-、-C(R_H )(R_H )-C(R_H )(R_H )-或-C(R_H )(R_H )-C(R_H )(R_H )-C(R_H )(R_H )-，H₂ 、H₃ 和H₄ 獨立地選自-O-、-S-、-N(R_H’ )-或-C(R_H )(R_H )-。在一個具體實施方案中，L₁ 為-C-C-C-N-骨架；在另一個具體實施方案中，L₁ 為-N-C-C-N-骨架；在另一個具體實施方案中，L₁ 為-O-C-C-N-骨架；在另一個具體實施方案中，L₁ 為-S-C-C-N-骨架；在另一個具體實施方案中，L₁ 為-N-C-C-O-骨架；在另一個具體實施方案中，L₁ 為-N-C-C-S-骨架；在另一個具體實施方案中，L₁ 為-C-C-C-C-N-骨架；在另一個具體實施方案中，L₁ 為-C-C-C-C-C-N-骨架。L ₁ L ₁ is -H ₁ -H ₂ -H ₃ -H ₄ -, wherein H ₁ is selected from -O-, -S-, -N( _RH' )-, -C( _RH )( _RH )-, -C( _RH )( _RH )-C( _RH )( _RH )- or -C( _RH )( _RH )-C( _RH )( _RH )-C( _RH ) )( _RH ) _- , _H2 , _H3 and H4 are independently selected from -O-, -S-, -N( _RH' )- or -C( _RH )( _RH )-. In one specific embodiment, L ₁ is -CCCN-skeleton; in another specific embodiment, L ₁ is -NCCN-skeleton; in another specific embodiment, L ₁ is -OCCN-skeleton; In a specific embodiment, L ₁ is -SCCN-framework; in another embodiment, L ₁ is -NCCO-framework; in another embodiment, L ₁ is -NCCS-framework; in another embodiment In the scheme, L ₁ is -CCCCN-framework; in another specific embodiment, L1 is _-CCCCCN -framework.

在另一個具體實施方案中，H₁ 為-O-；在另一個具體實施方案中，H₁ 為-S-；在另一個具體實施方案中，H₁ 為-N(R_H’ )-；在另一個具體實施方案中，H₁ 為-C(R_H )(R_H )-；在另一個具體實施方案中，H₁ 為-C(R_H )(R_H )-C(R_H )(R_H )-；在另一個具體實施方案中，H₁ 為-C(R_H )(R_H )-C(R_H )(R_H )-C(R_H )(R_H )-；In another specific embodiment, H ₁ is -O-; in another specific embodiment, H ₁ is -S-; in another specific embodiment, H ₁ is -N( _RH' )-; In another specific embodiment, H ₁ is -C( _RH )( _RH )-; in another specific embodiment, H ₁ is -C( _RH )( _RH )-C( _RH ) ( _RH )-; _In another specific embodiment, H1 is -C( _RH )( _RH )-C( _RH )( _RH )-C( _RH )( _RH )-;

在另一個具體實施方案中，H₂ 為-O-；在另一個具體實施方案中，H₂ 為-S-；在另一個具體實施方案中，H₂ 為-N(R_H’ )-；在另一個具體實施方案中，H₂ 為-C(R_H )(R_H )-；In another specific embodiment, _H2 is -O-; in another specific embodiment, _H2 is -S-; in another specific embodiment, _H2 is -N( _RH' )-; In another specific embodiment, _H2 is -C( _RH )( _RH )-;

在另一個具體實施方案中，H₃ 為-O-；在另一個具體實施方案中，H₃ 為-S-；在另一個具體實施方案中，H₃ 為-N(R_H’ )-；在另一個具體實施方案中，H₃ 為-C(R_H )(R_H )-；In another specific embodiment, _H3 is -O-; in another specific embodiment, _H3 is -S-; in another specific embodiment, _H3 is -N( _RH' )-; In another specific embodiment, _H3 is -C( _RH )( _RH )-;

在另一個具體實施方案中，H₄ 為-O-；在另一個具體實施方案中，H₄ 為-S-；在另一個具體實施方案中，H₄ 為-N(R_H’ )-；在另一個具體實施方案中，H₄ 為-C(R_H )(R_H )-。 _In another specific embodiment, H4 is -O-; in another specific embodiment, H4 is -S-; in another specific embodiment, _H4 is -N( _RH' ) _- ; _In another specific embodiment, H4 is -C( _RH )( _RH )-.

在另一個具體實施方案中，H₁ 和H₃ 上的一對R_H /R_H’ 取代基可以結合形成C_1-3 亞烷基；在另一個具體實施方案中，H₁ 和H₄ 上的一對R_H /R_H’ 取代基可以結合形成C_1-3 亞烷基；在另一個具體實施方案中，H₂ 和H₄ 上的一對R_H /R_H’ 取代基可以結合形成C_1-3 亞烷基。In another specific embodiment, a pair of _RH / _RH' substituents on H ₁ and H ₃ can combine to form a C _1-3 alkylene group; in another specific embodiment, on H ₁ and H ₄ A pair of _RH / _RH' substituents can be combined to form C _1-3 alkylene; in another specific embodiment, a pair of _RH / _RH' substituents on H ₂ and H ₄ can be combined to form C _1-3 alkylene.

在另一個具體實施方案中，L₁ 為

；在另一個具體實施方案中，L₁ 為

；在另一個具體實施方案中，L₁ 為

；在另一個具體實施方案中，L₁ 為

；在另一個具體實施方案中，L₁ 為

；在另一個具體實施方案中，L₁ 為

；在另一個具體實施方案中，L₁ 為

；在另一個具體實施方案中，L₁ 為

；在另一個具體實施方案中，L₁ 為

；在另一個具體實施方案中，L₁ 為

；在另一個具體實施方案中，L₁ 為

；在另一個具體實施方案中，L₁ 為

；在另一個具體實施方案中，L₁ 為

；在另一個具體實施方案中，L₁ 為

。In another specific embodiment, L ₁ is

; In another specific embodiment, L ₁ is

.

R₁ 在一個具體實施方案中，R₁ 為C_1-6 鹵代烷基；在另一個具體實施方案中，R₁ 為鹵代甲基，優選氯甲基；在另一個具體實施方案中，R₁ 為

，其中R_a 、R_b 和R_c 獨立地選自H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ；其任選被R’取代；並且R_a 和R_b 可以形成化學鍵從而使得雙鍵變為三鍵。R ₁ In one specific embodiment, R ₁ is C _1-6 haloalkyl; in another specific embodiment, R ₁ is halomethyl, preferably chloromethyl; in another specific embodiment, R ₁ for

, wherein R _a , R _b and R _c are independently selected from H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; it is optionally substituted with R'; and R _a and R _b can form a chemical bond such that a double bond becomes a triple bond.

在一個具體實施方案中，R₁ 為

；在另一個具體實施方案中，R₁ 為

；在另一個具體實施方案中，R₁ 為

；在另一個具體實施方案中，R₁ 為

。In a specific embodiment, R ₁ is

; In another specific embodiment, R ₁ is

.

L₂ 在一個具體實施方案中，L₂ 為化學鍵；在另一個具體實施方案中，L₂ 為-O-(C(R_L2 )(R_L2 ))_p -；在另一個具體實施方案中，L₂ 為-S-(C(R_L2 )(R_L2 ))_p -；在另一個具體實施方案中，L₂ 為-N(R_L2’ )-(C(R_L2 )(R_L2 ))_p -；在另一個具體實施方案中，L₂ 為-(C(R_L2 )(R_L2 ))_p -；在另一個具體實施方案中，L₂ 為-O-；在另一個具體實施方案中，L₂ 為-OCH₂ -；在另一個具體實施方案中，L₂ 為-OCH₂ CH₂ -；在另一個具體實施方案中，L₂ 為-OCH₂ CH₂ CH₂ -；在另一個具體實施方案中，L₂ 為-NH-；在另一個具體實施方案中，L₂ 為-NHCH₂ -；在另一個具體實施方案中，L₂ 為-NHCH₂ CH₂ -；在另一個具體實施方案中，L₂ 為-NHCH₂ CH₂ CH₂ -；在另一個具體實施方案中，L₂ 為-NMeCH₂ CH₂ -；在另一個具體實施方案中，L₂ 為-CH₂ CH₂ -；在另一個具體實施方案中，L₂ 為-O-、-OCH₂ -、-OCH₂ CH₂ -、-OCH₂ CH₂ CH₂ -、-NH-、-NHCH₂ -、-NHCH₂ CH₂ -或-NHCH₂ CH₂ CH₂ -。L ₂ In one specific embodiment, L ₂ is a chemical bond; in another specific embodiment, L ₂ is -O-(C(R _L2 )(R _L2 )) _p -; in another specific embodiment, L ₂ is -S-(C(R _L2 )(R _L2 )) _p -; in another specific embodiment, L ₂ is -N(R _L2' )-(C(R _L2 )(R _L2 )) _p- ; in another specific embodiment, L ₂ is -(C(R _L2 )(R _L2 )) _p -; in another specific embodiment, L ₂ is -O-; in another specific embodiment In another specific embodiment, L ₂ is -OCH ₂ CH ₂ -; in another specific embodiment, L ₂ is -OCH ₂ CH ₂ CH ₂ -; in another specific embodiment, L ₂ is -OCH 2 CH 2 CH ₂ -; In one specific embodiment, L ₂ is -NH-; in another specific embodiment, L ₂ is -NHCH ₂ -; in another specific embodiment, L ₂ is -NHCH ₂ CH ₂ -; in another specific embodiment In a specific embodiment, L ₂ is -NHCH ₂ CH ₂ CH ₂ -; in another specific embodiment, L ₂ is -NMeCH ₂ CH ₂ -; in another specific embodiment, L ₂ is -CH ₂ CH _2- ; in another specific embodiment, _L2 is _-O- , _-OCH2- , _-OCH2CH2- , _-OCH2CH2CH2- , _-NH- , _-NHCH2- , _-NHCH _2CH2- _or _{-NHCH2CH2CH2-} _. _{_}

在一個更具體的實施方案中，p=0；在另一個更具體的實施方案中，p=1；在另一個更具體的實施方案中，p=2；在另一個更具體的實施方案中，p=3；在另一個更具體的實施方案中，p=4。In a more specific embodiment, p=0; in another more specific embodiment, p=1; in another more specific embodiment, p=2; in another more specific embodiment , p=3; in another more specific embodiment, p=4.

R₂ 在一個具體實施方案中，R₂ 為H；在另一個具體實施方案中，R₂ 為D；在另一個具體實施方案中，R₂ 為鹵素；在另一個具體實施方案中，R₂ 為-CN；在另一個具體實施方案中，R₂ 為-NO₂ ；在另一個具體實施方案中，R₂ 為C_1-6 烷基；在另一個具體實施方案中，R₂ 為C_1-6 鹵代烷基；在另一個具體實施方案中，R₂ 為C_2-6 烯基；在另一個具體實施方案中，R₂ 為C_2-6 炔基；在另一個具體實施方案中，R₂ 為-O-R_1a ；在另一個具體實施方案中，R₂ 為-N(R_1a )₂ ；在另一個具體實施方案中，R₂ 為C_3-10 環烷基；在另一個具體實施方案中，R₂ 為3-10員雜環基；在另一個具體實施方案中，R₂ 為C_6-10 芳基；在另一個具體實施方案中，R₂ 為5-14員雜芳基；；在另一個具體實施方案中，R₂ 被r個R取代。R ₂ In one specific embodiment, R ₂ is H; in another specific embodiment, R ₂ is D; in another specific embodiment, R ₂ is halogen; in another specific embodiment, R ₂ is -CN; in another specific embodiment, R ₂ is -NO ₂ ; in another specific embodiment, R ₂ is C _1-6 alkyl; in another specific embodiment, R ₂ is C _{1 -6} haloalkyl; in another specific embodiment, R ₂ is C _2-6 alkenyl; in another specific embodiment, R ₂ is C _2-6 alkynyl; in another specific embodiment, R ₂ is -OR _1a ; in another specific embodiment, R ₂ is -N(R _1a ) ₂ ; in another specific embodiment, R ₂ is C _3-10 cycloalkyl; in another specific embodiment In, R ₂ is a 3-10-membered heterocyclic group; in another specific embodiment, R ₂ is a C _6-10 aryl group; in another specific embodiment, R ₂ is a 5-14-membered heteroaryl group; ; In another specific embodiment, R ₂ is substituted with r Rs.

在另一個具體實施方案中，R₂ 為

；在另一個具體實施方案中，R₂ 為

。In another specific embodiment, R ₂ is

; In another specific embodiment, R ₂ is

.

在另一個具體實施方案中，-L₂ -R₂ 為

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

或

。In another specific embodiment, -L ₂ -R ₂ is

,

or

.

L₃ 在一個具體實施方案中，L₃ 為化學鍵；在另一個具體實施方案中，L₃ 為-(C(R_L3 )(R_L3 ))_p -；在另一個具體實施方案中，L₃ 為-CH₂ -；在另一個具體實施方案中，L₃ 為-CH₂ CH₂ -。L ₃ In one specific embodiment, L ₃ is a chemical bond; in another specific embodiment, L ₃ is -(C(R _L3 )(R _L3 )) _p -; in another specific embodiment, L ₃ is _-CH2- _; in another specific embodiment, _L3 is _-CH2CH2- .

R₃ 在一個具體實施方案中，R₃ 為H；在另一個具體實施方案中，R₃ 為D；在另一個具體實施方案中，R₃ 為鹵素；在另一個具體實施方案中，R₃ 為-CN；在另一個具體實施方案中，R₃ 為-NO₂ ；在另一個具體實施方案中，R₃ 為C_1-6 烷基；在另一個具體實施方案中，R₃ 為C_1-6 鹵代烷基；在另一個具體實施方案中，R₃ 為C_2-6 烯基；在另一個具體實施方案中，R₃ 為C_2-6 炔基；在另一個具體實施方案中，R₃ 為-N(R_1a )₂ ；在另一個具體實施方案中，R₃ 為C_3-10 環烷基；在另一個具體實施方案中，R₃ 為3-10員雜環基；在另一個具體實施方案中，R₃ 為C_6-10 芳基；在另一個具體實施方案中，R₃ 為5-14員雜芳基；在另一個具體實施方案中，R₃ 被r個R取代。R ₃ In one specific embodiment, R ₃ is H; in another specific embodiment, R ₃ is D; in another specific embodiment, R ₃ is halogen; in another specific embodiment, R ₃ is -CN; in another specific embodiment, R ₃ is -NO ₂ ; in another specific embodiment, R ₃ is C _1-6 alkyl; in another specific embodiment, R ₃ is C _{1 -6} haloalkyl; in another specific embodiment, R ₃ is C _2-6 alkenyl; in another specific embodiment, R ₃ is C _2-6 alkynyl; in another specific embodiment, R ₃ is -N(R _1a ) ₂ ; in another specific embodiment, R ₃ is C _3-10 cycloalkyl; in another specific embodiment, R ₃ is 3-10 membered heterocyclyl; In one specific embodiment, R ₃ is C _6-10 aryl; in another specific embodiment, R ₃ is 5-14 membered heteroaryl; in another specific embodiment, R ₃ is substituted with r Rs .

在另一個具體實施方案中，R₃ 為

；在另一個具體實施方案中，R₃ 為

。In another specific embodiment, _R3 is

; In another specific embodiment, R ₃ is

.

R 在一個具體實施方案中，R為H；在另一個具體實施方案中，R為D；在另一個具體實施方案中，R為C_0-6 亞烷基-鹵素；在另一個具體實施方案中，R為C_0-6 亞烷基-CN；在另一個具體實施方案中，R為C_0-6 亞烷基-SF₅ ；在另一個具體實施方案中，R為C_0-6 亞烷基-NO₂ ；在另一個具體實施方案中，R為C_1-6 烷基；在另一個具體實施方案中，R為C_1-6 鹵代烷基；在另一個具體實施方案中，R為C_2-6 烯基；在另一個具體實施方案中，R為C_2-6 炔基；在另一個具體實施方案中，R為C_0-6 亞烷基-O-R_1a ；在另一個具體實施方案中，R為C_0-6 亞烷基-S-R_1a ；在另一個具體實施方案中，R為C_0-6 亞烷基-N(R_1a )₂ ；在另一個具體實施方案中，R為C_0-6 亞烷基-C(O)R_1a ；在另一個具體實施方案中，R為C_0-6 亞烷基-C(O)OR_1a ；在另一個具體實施方案中，R為C_0-6 亞烷基-C(O)N(R_1a )₂ ；在另一個具體實施方案中，R為C_0-6 亞烷基-S(O)_m R_1a ；在另一個具體實施方案中，R為C_0-6 亞烷基-C_3-10 環烷基；在另一個具體實施方案中，R為C_0-6 亞烷基-3-10員雜環基；在另一個具體實施方案中，R為C_0-6 亞烷基-C_6-10 芳基；在另一個具體實施方案中，R為C_0-6 亞烷基-5-14員雜芳基。R In one specific embodiment, R is H; in another specific embodiment, R is D; in another specific embodiment, R is C _0-6 alkylene-halogen; in another specific embodiment In, R is C _0-6 alkylene-CN; In another specific embodiment, R is C _0-6 alkylene-SF ₅ ; In another specific embodiment, R is C _0-6 alkylene Alkyl-NO ₂ ; in another specific embodiment, R is C _1-6 alkyl; in another specific embodiment, R is C _1-6 haloalkyl; in another specific embodiment, R is C _2-6 alkenyl; in another specific embodiment, R is C _2-6 alkynyl; in another specific embodiment, R is C _0-6 alkylene-OR _1a ; in another specific embodiment In the scheme, R is C _0-6 alkylene-SR _1a ; in another specific embodiment, R is C _0-6 alkylene-N(R _1a ) ₂ ; in another specific embodiment, R is C _0-6 alkylene-C(O)R _1a ; in another specific embodiment, R is C _0-6 alkylene-C(O)OR _1a ; in another specific embodiment, R is C _0-6 alkylene-C(O)N(R _1a ) ₂ ; in another specific embodiment, R is C _0-6 alkylene-S(O) _m R _1a ; in another specific embodiment In an embodiment, R is C _0-6 alkylene-C _3-10 cycloalkyl; in another specific embodiment, R is C _0-6 alkylene-3-10 membered heterocyclyl; In one specific embodiment, R is C _0-6 alkylene-C _6-10 aryl; in another specific embodiment, R is C _0-6 alkylene-5-14 membered heteroaryl.

r 在一個具體實施方案中，r=0；在另一個具體實施方案中，r=1；在另一個具體實施方案中，r=2；在另一個具體實施方案中，r=3；在另一個具體實施方案中，r=4；在另一個具體實施方案中，r=5；在另一個具體實施方案中，r=6；在另一個具體實施方案中，r=7。r In one specific embodiment, r=0; in another specific embodiment, r=1; in another specific embodiment, r=2; in another specific embodiment, r=3; In a specific embodiment, r=4; in another specific embodiment, r=5; in another specific embodiment, r=6; in another specific embodiment, r=7.

R₄ 在一個具體實施方案中，R₄ 為H；在另一個具體實施方案中，R₄ 為D；在另一個具體實施方案中，R₄ 為鹵素，優選Cl和F，更優選Cl；在另一個具體實施方案中，R₄ 為-CN；在另一個具體實施方案中，R₄ 為-SF₅ ；在另一個具體實施方案中，R₄ 為C_1-6 烷基；在另一個具體實施方案中，R₄ 為C_1-6 鹵代烷基；在另一個具體實施方案中，R₄ 為C_2-6 烯基；在另一個具體實施方案中，R₄ 為C_2-6 炔基；在另一個具體實施方案中，R₄ 為-O-R_1a ；在另一個具體實施方案中，R₄ 為-S-R_1a ；在另一個具體實施方案中，R₄ 為-N(R_1a )₂ ；在另一個具體實施方案中，R₄ 為C_3-10 環烷基；在另一個具體實施方案中，R₄ 為C_3-10 鹵代環烷基；在另一個具體實施方案中，R₄ 為3-10員雜環基；在另一個具體實施方案中，R₄ 為3-10員鹵代雜環基；在另一個具體實施方案中，R₄ 為C_6-10 芳基；在另一個具體實施方案中，R₄ 為5-14員雜芳基。R ₄ In one specific embodiment, R ₄ is H; in another specific embodiment, R ₄ is D; in another specific embodiment, R ₄ is halogen, preferably Cl and F, more preferably Cl; in In another specific embodiment, R ₄ is -CN; in another specific embodiment, R ₄ is -SF ₅ ; in another specific embodiment, R ₄ is C _1-6 alkyl; in another specific embodiment In an embodiment, R ₄ is C _1-6 haloalkyl; in another specific embodiment, R ₄ is C _2-6 alkenyl; in another specific embodiment, R ₄ is C _2-6 alkynyl; In another specific embodiment, R ₄ is -OR _1a ; In another specific embodiment, R ₄ is -SR _1a ; In another specific embodiment, R ₄ is -N(R _1a ) ₂ ; in In another specific embodiment, R ₄ is C _3-10 cycloalkyl; in another specific embodiment, R ₄ is C _3-10 halocycloalkyl; in another specific embodiment, R ₄ is 3-10 membered heterocyclyl; in another specific embodiment, R4 is 3-10 _membered haloheterocyclyl; in another specific embodiment, R4 is _C6-10 aryl _; in another In specific embodiments, R4 is a 5-14 _membered heteroaryl.

Z₁ 和Z₂ 在一個具體實施方案中，Z₁ 為CR₅ ；在另一個具體實施方案中，Z₁ 為N。在一個具體實施方案中，Z₂ 為CR₅ ；在另一個具體實施方案中，Z₂ 為N。Z ₁ and Z ₂ In one specific embodiment, Z ₁ is CR ₅ ; in another specific embodiment, Z ₁ is N. In one specific embodiment, Z ₂ is CR ₅ ; in another specific embodiment, Z ₂ is N.

R₅ 在一個具體實施方案中，R₅ 獨立地為H；在另一個具體實施方案中，R₅ 獨立地為D；在另一個具體實施方案中，R₅ 獨立地為鹵素；在另一個具體實施方案中，R₅ 獨立地為-CN；在另一個具體實施方案中，R₅ 獨立地為C_1-6 烷基；在另一個具體實施方案中，R₅ 獨立地為C_1-6 鹵代烷基；在另一個具體實施方案中，R₅ 獨立地為C_2-6 烯基；在另一個具體實施方案中，R₅ 獨立地為C_2-6 炔基；在另一個具體實施方案中，R₅ 獨立地為-O-R_1a ；在另一個具體實施方案中，R₅ 獨立地為-S-R_1a ；在另一個具體實施方案中，R₅ 獨立地為-N(R_1a )₂ 。In one specific embodiment, R ₅ is independently H; in another specific embodiment, R ₅ is independently D; in another specific embodiment, R ₅ is independently halogen; in another specific embodiment, R ₅ is independently halogen; In an embodiment, R ₅ is independently -CN; in another specific embodiment, R ₅ is independently C _1-6 alkyl; in another specific embodiment, R ₅ is independently C _1-6 haloalkane In another specific embodiment, R ₅ is independently C _2-6 alkenyl; in another specific embodiment, R ₅ is independently C _2-6 alkynyl; In another specific embodiment, R ₅ is independently -OR _1a ; in another specific embodiment, R ₅ is independently -SR _1a ; in another specific embodiment, R ₅ is independently -N(R _1a ) ₂ .

R₇ 在一個具體實施方案中，R₇ 為H；在另一個具體實施方案中，R₇ 與-L₃ -R₃ 形成雙鍵；在另一個具體實施方案中，R₇ 與-L₂ -R₂ 形成=Z；在另一個具體實施方案中，R₇ 與-L₂ -R₂ 形成=O；在另一個具體實施方案中，R₇ 與-L₂ -R₂ 形成=S。R ₇ In one specific embodiment, R ₇ is H; in another specific embodiment, R ₇ forms a double bond with -L ₃ -R ₃ ; In another specific embodiment, R ₇ and -L ₂ - R ₂ forms =Z; in another specific embodiment, R ₇ forms =O with -L ₂ -R ₂ ; in another specific embodiment, R ₇ forms =S with -L ₂ -R ₂ .

以上任一具體實施方案中的任一技術方案或其任意組合，可以與其它具體實施方案中的任一技術方案或其任意組合進行組合。例如，R₁ 的任一技術方案或其任意組合，可以與L₁ 、L₂ 、L₃ 、R₂ 、R₃ 、R₄ 、R₅ 、R₆ 、R₇ 、m和n等的任一技術方案或其任意組合進行組合。本發明旨在包括所有這些技術方案的組合，限於篇幅，不再一一列出。Any technical solution in any of the above specific embodiments or any combination thereof may be combined with any technical solution in other specific embodiments or any combination thereof. For example, any technical solution of R ₁ or any combination thereof can be combined with any one of L ₁ , L ₂ , L ₃ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , m and n, etc. technical solutions or any combination thereof. The present invention is intended to include all the combinations of these technical solutions, and is not listed one by one due to space limitations.

在更具體的實施方案中，本發明提供了上述(I)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物，其中，R₆ 獨立地為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基或-O-R_1a ；優選地，R₆ 獨立地為-O-R_1a 、優選-OH；優選地，至少一個R₆ 為非H基團。In a more specific embodiment, the present invention provides the above-mentioned compound (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, Homogeneous polymorphs, precursors or isotopic variants, and mixtures thereof, wherein R ₆ is independently H, D, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl or -OR _1a ; preferably, R ₆ is independently -OR _1a , preferably -OH; preferably, at least one R ₆ is a non-H group.

在更具體的實施方案中，本發明提供了上述(I)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物，In a more specific embodiment, the present invention provides the above-mentioned compound (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, Homogeneous polymorphs, precursors or isotopic variants, and mixtures thereof,

其中，

為

，其中Z₃ 、Z₄ 和Z₅ 獨立地為CR₆ 或N；環B為苯基或5-6員雜芳基；優選地，

為

，優選地為：

、

或

，優選

、

或

，更優選

。in,

for

, wherein Z ₃ , Z ₄ and Z ₅ are independently CR ₆ or N; Ring B is phenyl or 5-6 membered heteroaryl; preferably,

for

, preferably:

,

or

, preferably

,

or

, more preferably

.

其中，L₁ 為：

、

或

；優選地，L₁ 為

。where L1 is _:

,

or

; preferably, L ₁ is

.

其中，R₁ 為

、

或

；優選地，R₁ 為

。where _R1 is

,

or

; preferably, R ₁ is

.

其中，L₂ 為化學鍵、-O-、-OCH₂ -、-OCH₂ CH₂ -、-OCH₂ CH₂ CH₂ -、-NH-、-NHCH₂ -、-NHCH₂ CH₂ -、-NHCH₂ CH₂ CH₂ -、-NMeCH₂ CH₂ -或-CH₂ CH₂ -，優選-OCH₂ -或-OCH₂ CH₂ -；L₃ 為-CH₂ -或-CH₂ CH₂ -。Wherein, L ₂ is a chemical bond, -O-, -OCH ₂ -, -OCH ₂ CH ₂ -, -OCH ₂ CH ₂ CH ₂ -, -NH-, -NHCH ₂ -, -NHCH ₂ CH ₂ -, -NHCH ₂ CH ₂ CH ₂ -, -NMeCH ₂ CH ₂ - or -CH ₂ CH ₂ -, preferably -OCH ₂ - or -OCH ₂ CH ₂ -; L ₃ is -CH ₂ - or -CH ₂ CH ₂ -.

其中，R₂ 或R₃ 為H、-N(R_1a )₂ 、C_3-6 環烷基、4-7員雜環基、苯基或5-6員雜芳基，優選-NMe₂ 、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

或

，優選H、

或

；Wherein, R ₂ or R ₃ is H, -N(R _1a ) ₂ , C _3-6 cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, preferably -NMe ₂ ,

,

or

, preferably H,

or

;

優選地，R₂ 或R₃ 被1-3個R取代，其中R選自C_0-6 亞烷基-鹵素、C_0-6 亞烷基-CN、C_0-6 亞烷基-SF₅ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、C_0-6 亞烷基-O-R_1a 、C_0-6 亞烷基-S-R_1a 、C_0-6 亞烷基-N(R_1a )₂ 、C_0-6 亞烷基-C(O)R_1a 、C_0-6 亞烷基-C(O)OR_1a 、C_0-6 亞烷基-C(O)N(R_1a )₂ 、C_0-6 亞烷基-S(O)_m R_1a 、C_0-6 亞烷基-C_3-10 環烷基、C_0-6 亞烷基-3-10員雜環基、C_0-6 亞烷基-C_6-10 芳基或C_0-6 亞烷基-5-14員雜芳基。Preferably, R ₂ or R ₃ is substituted with 1-3 Rs, wherein R is selected from C _0-6 alkylene-halogen, C _0-6 alkylene-CN, C _0-6 alkylene-SF ₅ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _0-6 alkylene-OR _1a , C _0-6 alkylene-SR _1a , C _0-6 alkylene-N(R _1a ) ₂ , C _0-6 alkylene-C(O)R _1a , C _0-6 alkylene-C(O)OR _1a , C _0-6 Alkylene-C(O)N(R _1a ) ₂ , C _0-6 alkylene-S(O) _m R _1a , C _0-6 alkylene-C _3-10 cycloalkyl, C _{0- 6} -alkylene-3-10-membered heterocyclyl, C _0-6 alkylene-C _6-10 -aryl or C _0-6 alkylene-5-14-membered heteroaryl.

其中，R₄ 為H、鹵素、-CN、-SF₅ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烷基或C_3-10 鹵代環烷基，優選鹵素，更優選Cl。Wherein, R ₄ is H, halogen, -CN, -SF ₅ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkane or C _3-10 halocycloalkyl, preferably halogen, more preferably Cl.

在更具體的實施方案中，本發明提供了上述式(I)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物，其中：

選自

、

或

； L₁ 為-H₁ -H₂ -H₃ -H₄ -；In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof , homogeneous polymorphs, precursors or isotopic variants, and mixtures thereof, wherein:

selected from

,

or

; L ₁ is -H ₁ -H ₂ -H ₃ -H ₄ -;

其中H₁ 為-C(R_H )(R_H )-，H₂ 、H₃ 和H₄ 獨立地選自-O-、-S-、-N(R_H’ )-或-C(R_H )(R_H )-；wherein H ₁ is -C( _RH )( _RH )-, and H ₂ , H ₃ and H ₄ are independently selected from -O-, -S-, -N( _RH' )- or -C( _RH ) )(R _H )-;

並且，H₁ 和H₃ 上的R_H /R_H’ 取代基、H₁ 和H₄ 上的R_H /R_H’ 取代基、和H₂ 和H₄ 上的R_H /R_H’ 取代基中的一對或兩對R_H /R_H’ 取代基可以結合形成C_1-3 亞烷基；Also, _RH / _RH' _substituents _on H1 and _H3 , _RH /RH' substituents _on H1 and H4, and _RH / _RH _' substituents _on _H2 and H4 One or two pairs of _RH / _RH' substituents in can combine to form C _1-3 alkylene;

R_H 為H、D、C_0-6 亞烷基-鹵素、C_0-6 亞烷基-CN、C_0-6 亞烷基-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、C_0-6 亞烷基-O-R_1a 、C_0-6 亞烷基-S-R_1a 或C_0-6 亞烷基-N(R_1a )₂ ； _RH is H, D, C _0-6 alkylene-halogen, C _0-6 alkylene-CN, C _0-6 alkylene-NO ₂ , C _1-6 alkyl, C _1-6 haloalkane group, C _2-6 alkenyl, C _2-6 alkynyl, C _0-6 alkylene-OR _1a , C _0-6 alkylene-SR _1a or C _0-6 alkylene-N(R _1a ) ₂ ;

R_H’ 為H、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基或C_2-6 炔基； R₁ 為

； _RH' is H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl; R ₁ is

;

其中R_a 、R_b 和R_c 獨立地選自H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ；並且R_a 和R_b 可以形成化學鍵從而使得雙鍵變為三鍵；wherein R _a , R _b and R _c are independently selected from H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; and R _a and R _b can form a chemical bond so that the double bond becomes a triple bond;

L₂ 為化學鍵、-O-(C(R_L2 )(R_L2 ))_p -、-S-(C(R_L2 )(R_L2 ))_p -、-N(R_L2’ )-(C(R_L2 )(R_L2 ))_p -或-(C(R_L2 )(R_L2 ))_p -；L ₂ is a chemical bond, -O-(C(R _L2 )(R _L2 )) _p -, -S-(C(R _L2 )(R _L2 )) _p -, -N(R _L2' )-(C( R _L2 )(R _L2 )) _p - or -(C(R _L2 )(R _L2 )) _p -;

其中p=0、1、2、3或4；where p=0, 1, 2, 3 or 4;

R_L2 為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ；R _L2 is H, D, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ;

R_L2’ 為H、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基或C_2-6 炔基；R _L2' is H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl;

並且，R_L2 /R_L2’ 可以結合形成C_3-10 環烷基或3-10員雜環基；And, R _L2 /R _L2' can be combined to form C _3-10 cycloalkyl or 3-10 membered heterocyclyl;

R₂ 為鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-N(R_1a )₂ 、C_3-10 環烷基、3-10員雜環基、C_6-10 芳基或5-14員雜芳基；其任選被r個R取代；R ₂ is halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -N(R _1a ) _2. C _3-10 cycloalkyl, 3-10-membered heterocyclyl, C _6-10 -membered aryl or 5-14-membered heteroaryl; it is optionally substituted by r Rs;

其中R為H、D、C_0-6 亞烷基-鹵素、C_0-6 亞烷基-CN、C_0-6 亞烷基-SF₅ 、C_0-6 亞烷基-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、C_0-6 亞烷基-O-R_1a 、C_0-6 亞烷基-S-R_1a 、C_0-6 亞烷基-N(R_1a )₂ 、C_0-6 亞烷基-C(O)R_1a 、C_0-6 亞烷基-C(O)OR_1a 、C_0-6 亞烷基-C(O)N(R_1a )₂ 、C_0-6 亞烷基-S(O)_m R_1a 、C_0-6 亞烷基-C_3-10 環烷基、C_0-6 亞烷基-3-10員雜環基、C_0-6 亞烷基-C_6-10 芳基或C_0-6 亞烷基-5-14員雜芳基；Wherein R is H, D, C _0-6 alkylene-halogen, C _0-6 alkylene-CN, C _0-6 alkylene-SF ₅ , C _0-6 alkylene-NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _0-6 alkylene-OR _1a , C _0-6 alkylene-SR _1a , C _0-6 alkylene-N(R _1a ) ₂ , C _0-6 alkylene-C(O)R _1a , C _0-6 alkylene-C(O)OR _1a , C _0-6 alkylene base-C(O)N(R _1a ) ₂ , C _0-6 alkylene-S(O) _m R _1a , C _0-6 alkylene-C _3-10 cycloalkyl, C _0-6 alkylene Alkyl-3-10-membered heterocyclyl, C _0-6 alkylene-C _6-10 aryl or C _0-6 alkylene-5-14-membered heteroaryl;

r=0、1、2、3、4、5、6或7；r=0, 1, 2, 3, 4, 5, 6 or 7;

m=1或2；m=1 or 2;

R₄ 為H、D、鹵素、-CN、-SF₅ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 、-N(R_1a )₂ 、C_3-10 環烷基、C_3-10 鹵代環烷基、3-10員雜環基、3-10員鹵代雜環基、C_6-10 芳基或5-14員雜芳基；R ₄ is H, D, halogen, -CN, -SF ₅ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a , -N(R _1a ) ₂ , C _3-10 cycloalkyl, C _3-10 halogenated cycloalkyl, 3-10-membered heterocyclyl, 3-10-membered halogenated heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl;

Z₁ 為CR₅ ；Z ₁ is CR ₅ ;

Z₂ 為CR₅ ；Z ₂ is CR ₅ ;

其中R₅ 獨立地為H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ；wherein R ₅ is independently H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ;

R₇ 與-L₃ -R₃ 形成雙鍵；R ₇ and -L ₃ -R ₃ form a double bond;

R_1a 為H、-C(O)H、-C(O)OH、-C(O)C_1-6 烷基、-C(O)OC_1-6 烷基、-S(O)_m C_1-6 烷基、C_1-6 烷基、C_1-6 鹵代烷基、C_3-10 環烷基、C_3-10 鹵代環烷基、3-10員雜環基、3-10員鹵代雜環基、C_6-10 芳基或5-14員雜芳基。R _1a is H, -C(O)H, -C(O)OH, -C(O)C _1-6 alkyl, -C(O)OC _1-6 alkyl, -S(O) _m C _1-6 alkyl, C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _3-10 halocycloalkyl, 3-10 membered heterocyclyl, 3-10 membered Halogenated heterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl.

在更具體的實施方案中，本發明提供了上述(I)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物，其具有以下結構：

(I-1)、

(I-2)、

(II)、

(III)、

(IV)、

(IV-1)、

(IV-2)、

(IV-3)，In a more specific embodiment, the present invention provides the above-mentioned compound (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, Homogeneous polymorphs, precursors or isotopic variants, and mixtures thereof, having the following structures:

(I-1),

(I-2),

(II),

(III),

(IV),

(IV-1),

(IV-2),

(IV-3),

其中，in,

環B為苯基或5-6員雜芳基；Ring B is phenyl or 5-6 membered heteroaryl;

R_N1 、R_N2 和R_N3 獨立地為H、C_1-6 烷基或C_1-6 鹵代烷基；或者，R_N2 和R_N3 可以結合形成C_2-4 亞烷基；R _N1 , R _N2 and R _N3 are independently H, C _1-6 alkyl or C _1-6 haloalkyl; alternatively, R _N2 and R _N3 may combine to form C _2-4 alkylene;

其他基團如上文所定義。Other groups are as defined above.

在更具體的實施方案中，本發明提供了式(I-1)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物：

(I-1)In a more specific embodiment, the present invention provides a compound of formula (I-1), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrated thereof substances, polymorphs, precursors or isotopic variants, and mixtures thereof:

(I-1)

其中，in,

環B為苯基或5-6員雜芳基；Ring B is phenyl or 5-6 membered heteroaryl;

R₆ 獨立地為H、D、C_0-6 亞烷基-鹵素、C_0-6 亞烷基-CN、C_0-6 亞烷基-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、C_0-6 亞烷基-O-R_1a 、C_0-6 亞烷基-S-R_1a 或C_0-6 亞烷基-N(R_1a )₂ ，並且其中至少一個R₆ 為-OH； n=0、1、2、3、4、5、6或7； L₁ 為-H₁ -H₂ -H₃ -H₄ -；R ₆ is independently H, D, C _0-6 alkylene-halogen, C _0-6 alkylene-CN, C _0-6 alkylene-NO ₂ , C _1-6 alkyl, C _{1- 6} haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _0-6 alkylene-OR _1a , C _0-6 alkylene-SR _1a or C _0-6 alkylene-N ( R _1a ) ₂ , and at least one of R ₆ is -OH; n=0, 1, 2, 3, 4, 5, 6 or 7; L ₁ is -H ₁ -H ₂ -H ₃ -H ₄ -;

並且，H₁ 和H₃ 上的R_H /R_H’ 取代基、H₁ 和H₄ 上的R_H /R_H’ 取代基、和H₂ 和H₄ 上的R_H /R_H’ 取代基中的一對或兩對R_H /R_H’ 取代基可以結合形成C_1-3 亞烷基； R_H 為H、D、C_0-6 亞烷基-鹵素、C_0-6 亞烷基-CN、C_0-6 亞烷基-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、C_0-6 亞烷基-O-R_1a 、C_0-6 亞烷基-S-R_1a 或C_0-6 亞烷基-N(R_1a )₂ ； R_H’ 為H、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基或C_2-6 炔基； R₁ 為

；Also, _RH / _RH' _substituents _on H1 and _H3 , _RH /RH' substituents _on H1 and H4, and _RH / _RH _' substituents _on _H2 and H4 One or two pairs of _RH / _RH' substituents can be combined to form C _1-3 alkylene; _RH is H, D, C _0-6 alkylene-halogen, C _0-6 alkylene -CN, C _0-6 alkylene-NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _0-6 alkylene- OR _1a , C _0-6 alkylene-SR _1a or C _0-6 alkylene-N(R _1a ) ₂ ; _RH' is H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl; R ₁ is

;

其中R_a 、R_b 和R_c 獨立地選自H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ；並且R_a 和R_b 可以形成化學鍵從而使得雙鍵變為三鍵； L₂ 為化學鍵、-O-(C(R_L2 )(R_L2 ))_p -、-S-(C(R_L2 )(R_L2 ))_p -、-N(R_L2’ )-(C(R_L2 )(R_L2 ))_p -或-(C(R_L2 )(R_L2 ))_p -；wherein R _a , R _b and R _c are independently selected from H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; and R _a and R _b can form a chemical bond so that the double bond becomes a triple bond; L ₂ is a chemical bond, -O-(C(R _L2 )(R _L2 )) _p -, -S-(C(R _L2 )(R _L2 )) _p -, -N(R _L2' )-(C(R _L2 )(R _L2 )) _p - or -(C(R _L2 )(R _L2 )) _p -;

並且，R_L2 /R_L2’ 可以結合形成C_3-10 環烷基或3-10員雜環基； R₂ 為鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-N(R_1a )₂ 、C_3-10 環烷基、3-10員雜環基、C_6-10 芳基或5-14員雜芳基；其任選被r個R取代；And, R _L2 /R _L2' can be combined to form C _3-10 cycloalkyl or 3-10 membered heterocyclic group; R ₂ is halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 Haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -N(R _1a ) ₂ , C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl; it is optionally substituted with r R;

其中R為H、D、C_0-6 亞烷基-鹵素、C_0-6 亞烷基-CN、C_0-6 亞烷基-SF₅ 、C_0-6 亞烷基-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、C_0-6 亞烷基-O-R_1a 、C_0-6 亞烷基-S-R_1a 、C_0-6 亞烷基-N(R_1a )₂ 、C_0-6 亞烷基-C(O)R_1a 、C_0-6 亞烷基-C(O)OR_1a 、C_0-6 亞烷基-C(O)N(R_1a )₂ 、C_0-6 亞烷基-S(O)_m R_1a 、C_0-6 亞烷基-C_3-10 環烷基、C_0-6 亞烷基-3-10員雜環基、C_0-6 亞烷基-C_6-10 芳基或C_0-6 亞烷基-5-14員雜芳基； r=0、1、2、3、4、5、6或7； R₄ 為H、D、鹵素、-CN、-SF₅ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 、-N(R_1a )₂ 、C_3-10 環烷基、C_3-10 鹵代環烷基、3-10員雜環基、3-10員鹵代雜環基、C_6-10 芳基或5-14員雜芳基； R₅ 獨立地為H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； m=1或2； R_1a 為H、-C(O)H、-C(O)OH、-C(O)C_1-6 烷基、-C(O)OC_1-6 烷基、-S(O)_m C_1-6 烷基、C_1-6 烷基、C_1-6 鹵代烷基、C_3-10 環烷基、C_3-10 鹵代環烷基、3-10員雜環基、3-10員鹵代雜環基、C_6-10 芳基或5-14員雜芳基。Wherein R is H, D, C _0-6 alkylene-halogen, C _0-6 alkylene-CN, C _0-6 alkylene-SF ₅ , C _0-6 alkylene-NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _0-6 alkylene-OR _1a , C _0-6 alkylene-SR _1a , C _0-6 alkylene-N(R _1a ) ₂ , C _0-6 alkylene-C(O)R _1a , C _0-6 alkylene-C(O)OR _1a , C _0-6 alkylene base-C(O)N(R _1a ) ₂ , C _0-6 alkylene-S(O) _m R _1a , C _0-6 alkylene-C _3-10 cycloalkyl, C _0-6 alkylene Alkyl-3-10-membered heterocyclyl, C _0-6 alkylene-C _6-10 aryl or C _0-6 alkylene-5-14-membered heteroaryl; r=0, 1, 2, 3, 4, 5, 6 or 7; R ₄ is H, D, halogen, -CN, -SF ₅ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _{2- 6} alkynyl, -OR _1a , -SR _1a , -N(R _1a ) ₂ , C _3-10 cycloalkyl, C _3-10 halogenated cycloalkyl, 3-10-membered heterocyclyl, 3-10-membered Halogenated heterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl; R ₅ is independently H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; m=1 or 2; R _1a is H, -C(O)H, -C( O)OH, -C(O)C _1-6 alkyl, -C(O)OC _1-6 alkyl, -S(O) _m C _1-6 alkyl, C _1-6 alkyl, C _{1 -6} haloalkyl, C _3-10 cycloalkyl, C _3-10 halocycloalkyl, 3-10 membered heterocyclyl, 3-10 membered haloheterocyclyl, C _6-10 aryl or 5- 14-membered heteroaryl.

在更具體的實施方案中，本發明提供了上述式(I-1)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物，其中，環B為苯基； R₆ 獨立地為H、D、C_0-6 亞烷基-鹵素、C_0-6 亞烷基-CN、C_0-6 亞烷基-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、C_0-6 亞烷基-O-R_1a 、C_0-6 亞烷基-S-R_1a 或C_0-6 亞烷基-N(R_1a )₂ ，並且其中至少一個R₆ 為-OH； n=0、1、2、3、4、5、6或7； L₁ 為

或

； R₁ 為

；In a more specific embodiment, the present invention provides the above-mentioned compound of formula (I-1), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, Hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein Ring B is phenyl; R ₆ is independently H, D, C _0-6 alkylene-halogen, C _{0- 6} alkylene-CN, C _0-6 alkylene-NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _0-6 alkylene-OR _1a , C _0-6 alkylene-SR _1a or C _0-6 alkylene-N(R _1a ) ₂ , and at least one of R ₆ is -OH; n=0, 1, 2 , 3, 4, 5, 6 or 7; L ₁ is

or

; R ₁ is

;

其中R_a 、R_b 和R_c 獨立地選自H、D、鹵素、-CN、C_1-6 烷基或C_1-6 鹵代烷基；並且R_a 和R_b 可以形成化學鍵從而使得雙鍵變為三鍵； L₂ 為化學鍵、-O-(C(R_L2 )(R_L2 ))_p -、-S-(C(R_L2 )(R_L2 ))_p -或-N(R_L2’ )-(C(R_L2 )(R_L2 ))_p -；wherein R _a , R _b and R _c are independently selected from H, D, halogen, -CN, C _1-6 alkyl or C _1-6 haloalkyl; and R _a and R _b may form a chemical bond such that the double bond changes is a triple bond; L ₂ is a chemical bond, -O-(C(R _L2 )(R _L2 )) _p -, -S-(C(R _L2 )(R _L2 )) _p - or -N(R _L2' ) -(C(R _L2 )(R _L2 )) _p -;

其中R為H、D、C_0-6 亞烷基-鹵素、C_0-6 亞烷基-CN、C_0-6 亞烷基-SF₅ 、C_0-6 亞烷基-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、C_0-6 亞烷基-O-R_1a 、C_0-6 亞烷基-S-R_1a 、C_0-6 亞烷基-N(R_1a )₂ 、C_0-6 亞烷基-C(O)R_1a 、C_0-6 亞烷基-C(O)OR_1a 或C_0-6 亞烷基-C(O)N(R_1a )₂ ； r=0、1、2、3、4、5、6或7； R₄ 為H、D、鹵素、-CN或-SF₅ ； R₅ 獨立地為H、D、鹵素、-CN、C_1-6 烷基或C_1-6 鹵代烷基； m=1或2； R_1a 為H、C_1-6 烷基、C_1-6 鹵代烷基、C_3-10 環烷基、C_3-10 鹵代環烷基、3-10員雜環基、3-10員鹵代雜環基、C_6-10 芳基或5-14員雜芳基。Wherein R is H, D, C _0-6 alkylene-halogen, C _0-6 alkylene-CN, C _0-6 alkylene-SF ₅ , C _0-6 alkylene-NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _0-6 alkylene-OR _1a , C _0-6 alkylene-SR _1a , C _0-6 alkylene-N(R _1a ) ₂ , C _0-6 alkylene-C(O)R _1a , C _0-6 alkylene-C(O)OR _1a or C _0-6 alkylene Base-C(O)N(R _1a ) ₂ ; r=0, 1, 2, 3, 4, 5, 6 or 7; R ₄ is H, D, halogen, -CN or -SF ₅ ; R ₅ is independent is H, D, halogen, -CN, C _1-6 alkyl or C _1-6 haloalkyl; m=1 or 2; R _1a is H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _3-10 halocycloalkyl, 3-10 membered heterocyclyl, 3-10 membered haloheterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl .

在更具體的實施方案中，本發明提供了上述式(I-1)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物，其中，環B為苯基； R₆ 獨立地為H、D、鹵素、-CN、-OH、-SH或-NH₂ ，並且其中至少一個R₆ 為-OH； n=0、1、2或3； L₁ 為

或

； R₁ 為

；In a more specific embodiment, the present invention provides the above-mentioned compound of formula (I-1), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, Hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein Ring B is phenyl _; R is independently H, D, halogen, -CN, -OH, -SH or -NH ₂ , and at least one of R ₆ is -OH; n=0, 1, 2 or 3; L ₁ is

or

; R ₁ is

;

其中R_a 、R_b 和R_c 獨立地選自H、D、鹵素或-CN； L₂ 為化學鍵、-O-(C(R_L2 )(R_L2 ))_p -或-N(R_L2’ )-(C(R_L2 )(R_L2 ))_p -；wherein R _a , R _b and R _c are independently selected from H, D, halogen or -CN; L ₂ is a chemical bond, -O-(C(R _L2 )(R _L2 )) _p - or -N(R _L2' )-(C(R _L2 )(R _L2 )) _p -;

其中p=0、1、2、3或4； R_L2 為H、D、鹵素、C_1-6 烷基或C_1-6 鹵代烷基； R_L2’ 為H；wherein p=0, 1, 2, 3 or 4; R _L2 is H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl; R _L2' is H;

並且，R_L2 /R_L2’ 可以結合形成C_3-6 環烷基或4-7員雜環基； R₂ 為C_1-6 烷基、C_1-6 鹵代烷基、-OH、-N(R_1a )₂ 、C_3-6 環烷基、4-7員雜環基、C_6-10 芳基或5-6員雜芳基；其任選被r個R取代；And, R _L2 /R _L2' can be combined to form C _3-6 cycloalkyl or 4-7 membered heterocyclic group; R ₂ is C _1-6 alkyl, C _1-6 haloalkyl, -OH, -N( R _1a ) ₂ , C _3-6 cycloalkyl, 4-7 membered heterocyclyl, C _6-10 membered heteroaryl, or 5-6 membered heteroaryl; it is optionally substituted with r Rs;

其中R為H、D、鹵素、C_1-6 烷基、C_1-6 鹵代烷基、C_0-6 亞烷基-O-R_1a 、C_0-6 亞烷基-S-R_1a 、C_0-6 亞烷基-N(R_1a )₂ ； r=0、1、2、3、4、5、6或7； R₄ 為鹵素； R₅ 獨立地為H、D或鹵素； m=1或2； R_1a 為H、C_1-6 烷基或C_1-6 鹵代烷基。wherein R is H, D, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _0-6 alkylene-OR _1a , C _0-6 alkylene-SR _1a , C _0-6 alkylene Alkyl-N(R _1a ) ₂ ; r=0, 1, 2, 3, 4, 5, 6 or 7; R ₄ is halogen; R ₅ is independently H, D or halogen; m=1 or 2; R _1a is H, C _1-6 alkyl or C _1-6 haloalkyl.

在更具體的實施方案中，本發明提供了式(II)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物：

(II)In a more specific embodiment, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, Homogeneous polymorphs, precursors or isotopic variants, and mixtures thereof:

(II)

其中，環B為苯基或5-6員雜芳基； R₆ 獨立地為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； n=0、1、2、3、4或5； R₁ 為C_1-6 鹵代烷基或

；Wherein, ring B is phenyl or 5-6 membered heteroaryl; R ₆ is independently H, D, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; n=0, 1, 2, 3, 4 or 5; R ₁ is C _1-6 haloalkane base or

;

其中R_a 、R_b 和R_c 獨立地選自H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ；其任選被R’取代；並且R_a 和R_b 可以形成化學鍵從而使得雙鍵變為三鍵； R’為H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； L₂ 為化學鍵、-O-(C(R_L2 )(R_L2 ))_p -、-S-(C(R_L2 )(R_L2 ))_p -、-N(R_L2’ )-(C(R_L2 )(R_L2 ))_p -或-(C(R_L2 )(R_L2 ))_p -；wherein R _a , R _b and R _c are independently selected from H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; it is optionally substituted by R'; and R _a and R _b can form a chemical bond so that the double bond becomes a triple bond; R' is H, D, halogen, -CN, C _1-6 alkyl, C _{1- 6} haloalkyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; L ₂ is a chemical bond, -O-(C(R _L2 )(R _L2 )) _p -, -S-(C(R _L2 ) )(R _L2 )) _p -, -N(R _L2' )-(C(R _L2 )(R _L2 )) _p - or -(C(R _L2 )(R _L2 )) _p -;

並且，相鄰原子上的R_L2 /R_L2’ 可以結合形成C_3-10 環烷基或3-10員雜環基； R₂ 為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-N(R_1a )₂ 、C_3-10 環烷基、3-10員雜環基、C_6-10 芳基或5-14員雜芳基；其任選被1-7個R取代；And, R _L2 /R _L2' on adjacent atoms can combine to form C _3-10 cycloalkyl or 3-10 membered heterocyclic group; R ₂ is H, D, halogen, -CN, -NO ₂ , C _{1 -6} alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -N(R _1a ) ₂ , C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl; it is optionally substituted by 1-7 R;

其中R為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 、-N(R_1a )₂ 、C_3-10 環烷基、3-10員雜環基、C_6-10 芳基或5-14員雜芳基； R₄ 為H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 、-N(R_1a )₂ 、C_3-10 環烷基或3-10員雜環基； R_1a 為H、C_1-6 烷基或C_1-6 鹵代烷基。wherein R is H, D, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a , -N(R _1a ) ₂ , C _3-10 cycloalkyl, 3-10-membered heterocyclyl, C _6-10 aryl or 5-14-membered heteroaryl; R ₄ is H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a , -N(R _1a ) ₂ , C _{3- 10} -cycloalkyl or 3-10-membered heterocyclyl; R _1a is H, C _1-6 alkyl or C _1-6 haloalkyl.

在更具體的實施方案中，本發明提供了式(III)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物：

(III)In a more specific embodiment, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, Homogeneous polymorphs, precursors or isotopic variants, and mixtures thereof:

(III)

其中， R₁ 為C_1-6 鹵代烷基或

；Wherein, R ₁ is C _1-6 haloalkyl or

;

其中R為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 、-N(R_1a )₂ 、C_3-10 環烷基、3-10員雜環基、C_6-10 芳基或5-14員雜芳基； R₄ 為鹵素、-CN或-NO₂ ； R₆ 為鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； R_1a 為H、C_1-6 烷基或C_1-6 鹵代烷基。wherein R is H, D, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a , -N(R _1a ) ₂ , C _3-10 cycloalkyl, 3-10-membered heterocyclyl, C _6-10 aryl or 5-14-membered heteroaryl; R ₄ is halogen, -CN or - NO ₂ ; R ₆ is halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; R _1a is H, C _1-6 alkyl or C _1-6 haloalkyl.

在更具體的實施方案中，本發明提供了式(III)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物，其中 R₁ 為C_1-6 鹵代烷基或

；In a more specific embodiment, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, Homogeneous polymorphs, precursors or isotopic variants, and mixtures thereof, wherein R ₁ is C _1-6 haloalkyl or

;

其中R_a 、R_b 和R_c 獨立地選自H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ；並且R_a 和R_b 可以形成化學鍵從而使得雙鍵變為三鍵； L₂ 為化學鍵、-O-(C(R_L2 )(R_L2 ))_p -或-N(R_L2’ )-(C(R_L2 )(R_L2 ))_p -；wherein R _a , R _b and R _c are independently selected from H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; and R _a and R _b can form a chemical bond so that the double bond becomes a triple bond; L ₂ is a chemical bond, -O-(C(R _L2 )(R _L2 )) _p - or -N(R _L2' )- (C(R _L2 )(R _L2 )) _p -;

其中p=0、1、2、3或4； R_L2 為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基或C_1-6 鹵代烷基； R_L2’ 為H、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基或C_2-6 炔基； R₂ 為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-N(R_1a )₂ 、C_3-10 環烷基或3-10員雜環基；其任選被1-5個R取代；Wherein p=0, 1, 2, 3 or 4; R _L2 is H, D, halogen, -CN, -NO ₂ , C _1-6 alkyl or C _1-6 haloalkyl; R _L2' is H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl; R ₂ is H, D, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -N(R _1a ) ₂ , C _3-10 cycloalkyl or 3-10 membered heterocyclyl; -5 R substitutions;

其中R為H、-O-R_1a 、-S-R_1a 、-N(R_1a )₂ 、C_1-6 烷基或C_1-6 鹵代烷基； R₄ 為鹵素； R₆ 為鹵素、-CN、-NO₂ 或-O-R_1a ，優選-OH； R_1a 為H、C_1-6 烷基或C_1-6 鹵代烷基。Wherein R is H, -OR _1a , -SR _1a , -N(R _1a ) ₂ , C _1-6 alkyl or C _1-6 haloalkyl; R ₄ is halogen; R ₆ is halogen, -CN, -NO ₂ or -OR _1a , preferably -OH; R _1a is H, C _1-6 alkyl or C _1-6 haloalkyl.

在更具體的實施方案中，本發明提供了式(IV)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物：

(IV)In a more specific embodiment, the present invention provides a compound of formula (IV), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, Homogeneous polymorphs, precursors or isotopic variants, and mixtures thereof:

(IV)

其中， L₂ 為化學鍵、-O-(C(R_L2 )(R_L2 ))_p -、-S-(C(R_L2 )(R_L2 ))_p -、-N(R_L2’ )-(C(R_L2 )(R_L2 ))_p -或-(C(R_L2 )(R_L2 ))_p -；Wherein, L ₂ is a chemical bond, -O-(C(R _L2 )(R _L2 )) _p -, -S-(C(R _L2 )(R _L2 )) _p -, -N(R _L2' )-( C(R _L2 )(R _L2 )) _p - or -(C(R _L2 )(R _L2 )) _p -;

其中p=1、2、3或4； R_L2 為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； R_L2’ 為H、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基或C_2-6 炔基；wherein p=1, 2, 3 or 4; R _L2 is H, D, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; R _L2' is H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _{2 -6} alkynyl;

並且，R_L2 /R_L2’ 可以結合形成C_3-10 環烷基或3-10員雜環基； R₂ 為鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-N(R_1a )₂ 、C_3-10 環烷基、3-10員雜環基、C_6-10 芳基、5-14員雜芳基；其任選被1-5個R取代；And, R _L2 /R _L2' can be combined to form C _3-10 cycloalkyl or 3-10 membered heterocyclic group; R ₂ is halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 Haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -N(R _1a ) ₂ , C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5- 14-membered heteroaryl; optionally substituted with 1-5 Rs;

其中m=1或2； R₄ 為鹵素、-CN或-NO₂ ； R₆ 為鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； R_a 、R_b 和R_c 獨立地選自H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ；並且R_a 和R_b 可以形成化學鍵從而使得雙鍵變為三鍵； R_1a 為H、C_1-6 烷基或C_1-6 鹵代烷基。Wherein m=1 or 2; R ₄ is halogen, -CN or -NO ₂ ; R ₆ is halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkene group, C _2-6 alkynyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; R _a , R _b and R _c are independently selected from H, D, halogen, -CN, C _1-6 Alkyl, C _1-6 haloalkyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; and R _a and R _b can form a chemical bond so that a double bond becomes a triple bond; R _1a is H, C _1-6 alkyl or C _1-6 haloalkyl.

在更具體的實施方案中，本發明提供了上述式(IV)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物，其中， L₂ 為化學鍵、-O-(C(R_L2 )(R_L2 ))_p -、-S-(C(R_L2 )(R_L2 ))_p -或-N(R_L2’ )-(C(R_L2 )(R_L2 ))_p -；In a more specific embodiment, the present invention provides a compound of formula (IV) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof , homogeneous polymorphs, precursors or isotopic variants, and mixtures thereof, wherein L ₂ is a chemical bond, -O-(C(R _L2 )(R _L2 )) _p -, -S-(C(R _L2 )(R _L2 )) _p - or -N(R _L2' )-(C(R _L2 )(R _L2 )) _p -;

其中p=1、2、3或4； R_L2 為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基或C_2-6 炔基； R_L2’ 為H、C_1-6 烷基或C_1-6 鹵代烷基；wherein p=1, 2, 3 or 4; R _L2 is H, D, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _{2 -6} alkynyl; R _L2' is H, C _1-6 alkyl or C _1-6 haloalkyl;

並且，R_L2 /R_L2’ 可以結合形成C_3-10 環烷基或3-10員雜環基； R₂ 為鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-N(R_1a )₂ 、C_3-10 環烷基、3-10員雜環基、C_6-10 芳基或5-14員雜芳基；其任選被1-5個R取代；And, R _L2 /R _L2' can be combined to form C _3-10 cycloalkyl or 3-10 membered heterocyclic group; R ₂ is halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 Haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -N(R _1a ) ₂ , C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl or 5- 14-membered heteroaryl; optionally substituted with 1-5 Rs;

其中R為H、D、C_0-6 亞烷基-鹵素、C_0-6 亞烷基-CN、C_0-6 亞烷基-SF₅ 、C_0-6 亞烷基-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、C_0-6 亞烷基-O-R_1a 、C_0-6 亞烷基-S-R_1a 或C_0-6 亞烷基-N(R_1a )₂ ； R₄ 為鹵素、-CN或-NO₂ ； R₆ 為鹵素、-CN、-NO₂ 、-OH、-SH或-NH₂ ； R_a 、R_b 和R_c 獨立地選自H、D、鹵素、-CN、C_1-6 烷基或C_1-6 鹵代烷基；並且R_a 和R_b 可以形成化學鍵從而使得雙鍵變為三鍵； R_1a 為H、C_1-6 烷基或C_1-6 鹵代烷基。Wherein R is H, D, C _0-6 alkylene-halogen, C _0-6 alkylene-CN, C _0-6 alkylene-SF ₅ , C _0-6 alkylene-NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _0-6 alkylene-OR _1a , C _0-6 alkylene-SR _1a or C _0-6 alkylene-N(R _1a ) ₂ ; R ₄ is halogen, -CN or -NO ₂ ; R ₆ is halogen, -CN, -NO ₂ , -OH, -SH or -NH ₂ ; R _a , R _b and R _c are independently selected from H, D, halogen, -CN, C _1-6 alkyl or C _1-6 haloalkyl; and R _a and R _b can form a chemical bond such that a double bond becomes a triple bond ; R _1a is H, C _1-6 alkyl or C _1-6 haloalkyl.

其中p=1、2、3或4； R_L2 為H、D、鹵素、C_1-6 烷基或C_1-6 鹵代烷基； R_L2’ 為H；wherein p=1, 2, 3 or 4; R _L2 is H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl; R _L2' is H;

並且，R_L2 /R_L2’ 可以結合形成C_3-6 環烷基或4-7員雜環基； R₂ 為C_1-6 烷基、C_1-6 鹵代烷基、-N(R_1a )₂ 、C_3-6 環烷基、4-7員雜環基、C_6-10 芳基、5-6員雜芳基；其任選被1-2個R取代；And, R _L2 /R _L2' can be combined to form C _3-6 cycloalkyl or 4-7 membered heterocyclic group; R ₂ is C _1-6 alkyl, C _1-6 haloalkyl, -N(R _1a ) _2. C _3-6 cycloalkyl, 4-7-membered heterocyclyl, C _6-10 -membered aryl, 5-6-membered heteroaryl; it is optionally substituted by 1-2 R;

其中R為H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基或-N(R_1a )₂ ； R₄ 為鹵素； R₆ 為-OH； R_a 、R_b 和R_c 獨立地選自H、D、鹵素或-CN； R_1a 為H、C_1-6 烷基或C_1-6 鹵代烷基。wherein R is H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl or -N(R _1a ) ₂ ; R ₄ is halogen; R ₆ is -OH; R _a , R _b and R _c is independently selected from H, D, halogen or -CN; R _1a is H, C _1-6 alkyl or C _1-6 haloalkyl.

(IV)

並且，相鄰原子上的R_L2 /R_L2’ 可以結合形成C_3-10 環烷基或3-10員雜環基； R₂ 為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-N(R_1a )₂ 、C_3-10 環烷基、3-10員雜環基、C_6-10 芳基、5-14員雜芳基；其任選被1-5個R取代；And, R _L2 /R _L2' on adjacent atoms can combine to form C _3-10 cycloalkyl or 3-10 membered heterocyclic group; R ₂ is H, D, halogen, -CN, -NO ₂ , C _{1 -6} alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -N(R _1a ) ₂ , C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-14 membered heteroaryl; it is optionally substituted by 1-5 R;

其中R為H、-N(R_1a )₂ 、C_1-6 烷基或C_1-6 鹵代烷基； R₄ 為鹵素、-CN或-NO₂ ； R₆ 為鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； R_a 、R_b 和R_c 獨立地選自H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ；並且R_a 和R_b 可以形成化學鍵從而使得雙鍵變為三鍵； R_1a 為H、C_1-6 烷基或C_1-6 鹵代烷基。Wherein R is H, -N(R _1a ) ₂ , C _1-6 alkyl or C _1-6 haloalkyl; R ₄ is halogen, -CN or -NO ₂ ; R ₆ is halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; R _a , R _b and R _c independently selected from H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; and R _a and R _b can form a chemical bond such that a double bond becomes a triple bond; R _1a is H, C _1-6 alkyl or C _1-6 haloalkyl.

在更具體的實施方案中，本發明提供了式(IV-1)、(IV-2)或(IV-3)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物：

(IV-1)、

(IV-2)或

(IV-3)In a more specific embodiment, the present invention provides a compound of formula (IV-1), (IV-2) or (IV-3), or a pharmaceutically acceptable salt, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof compounds, racemates, solvates, hydrates, polymorphs, precursors or isotopic variants, and mixtures thereof:

(IV-1),

(IV-2) or

(IV-3)

其中， L₂ 為化學鍵、-O-、-S-或-N(R_L2’ )-；Wherein, L ₂ is a chemical bond, -O-, -S- or -N(R _L2' )-;

其中R_L2’ 為H、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基或C_2-6 炔基； R₄ 為鹵素、-CN或-NO₂ ； R₆ 為鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； R_N1 、R_N2 和R_N3 獨立地為H、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基或C_2-6 炔基；或者，R_N2 和R_N3 可以結合形成C_2-4 亞烷基； R_1a 為H、C_1-6 烷基或C_1-6 鹵代烷基。Wherein R _L2' is H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl; R ₄ is halogen, -CN or -NO ₂ ; R ₆ is Halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; R _N1 , R _N2 and R _N3 are independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl; or, R _N2 and R _N3 can combine to form C _2-4 alkylene; R _1a is H, C _1-6 alkyl or C _1-6 haloalkyl.

在更具體的實施方案中，本發明提供了式(IV-1)、(IV-2)或(IV-3)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物，其中 L₂ 為化學鍵、-O-、-S-或-NH-，優選-O-； R₄ 為鹵素，優選Cl； R₆ 為鹵素、-CN、-NO₂ 或-O-R_1a ，優選-OH； R_N1 、R_N2 和R_N3 獨立地為H、C_1-6 烷基或C_1-6 鹵代烷基；或者，R_N2 和R_N3 可以結合形成C_2-4 亞烷基； R_1a 為H、C_1-6 烷基或C_1-6 鹵代烷基。In a more specific embodiment, the present invention provides a compound of formula (IV-1 ), (IV-2) or (IV-3), or a pharmaceutically acceptable salt, enantiomer, diastereoisomer thereof Compounds, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein _L is a chemical bond, -O-, -S- or -NH-, preferably -O-; R ₄ is halogen, preferably Cl; R ₆ is halogen, -CN, -NO ₂ or -OR _1a , preferably -OH; R _N1 , R _N2 and R _N3 are independently H, C _1-6 alkanes or C _1-6 haloalkyl; alternatively, R _N2 and R _N3 may combine to form C _2-4 alkylene; R _1a is H, C _1-6 alkyl or C _1-6 haloalkyl.

在更具體的實施方案中，本發明提供了以下化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物，其中所述化合物選自：

、

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或

。In more specific embodiments, the present invention provides the following compounds, or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs thereof, or pharmaceutically acceptable salts thereof compounds, prodrugs or isotopic variants, and mixtures thereof, wherein the compounds are selected from:

,

or

.

本發明化合物可包括一個或多個不對稱中心，且因此可以存在多種立體異構體形式，例如，鏡像異構物和/或非鏡像異構物形式。例如，本發明化合物可為單獨的鏡像異構物、非鏡像異構物或幾何異構體(例如順式和反式異構體)，或者可為立體異構體的混合物的形式，包括外消旋物混合物和富含一種或多種立體異構體的混合物。異構體可透過所屬技術領域中具有通常知識者已知的方法從混合物中分離，所述方法包括：對掌性高壓液相色譜法(HPLC)以及對掌性鹽的形成和結晶；或者優選的異構體可透過不對稱合成來製備。The compounds of the present invention may contain one or more asymmetric centers, and thus may exist in various stereoisomeric, eg, enantiomer and/or non-enantiomer forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (eg, cis and trans isomers), or may be in the form of mixtures of stereoisomers, including exoisomers. Racemate mixtures and mixtures enriched in one or more stereoisomers. Isomers can be separated from the mixture by methods known to those of ordinary skill in the art, including: para-chiral high pressure liquid chromatography (HPLC) and para-chiral salt formation and crystallization; or preferably Isomers of can be prepared by asymmetric synthesis.

所屬技術領域中具有通常知識者將理解，有機化合物可以與溶劑形成複合物，其在該溶劑中發生反應或從該溶劑中沉澱或結晶出來。這些複合物稱為“溶合物”。當溶劑是水時，複合物稱為“水合物”。本發明涵蓋了本發明化合物的所有溶合物。Those of ordinary skill in the art will understand that organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are called "solvates". When the solvent is water, the complex is called a "hydrate". The present invention encompasses all solvates of the compounds of the present invention.

術語“溶合物”是指通常由溶劑分解反應形成的與溶劑相結合的化合物或其鹽的形式。這個物理締合可包括氫鍵鍵合。常規溶劑包括包括水、甲醇、乙醇、乙酸、DMSO、THF、***等。本文所述的化合物可製備成，例如，結晶形式，且可被溶劑化。合適的溶合物包括藥學上可接受的溶合物且進一步包括化學計量的溶合物和非化學計量的溶合物。在一些情況下，所述溶合物將能夠分離，例如，當一或多個溶劑分子摻入結晶固體的晶格中時。“溶合物”包括溶液狀態的溶合物和可分離的溶合物。代表性的溶合物包括水合物、乙醇合物和甲醇合物。The term "solvate" refers to a solvent-bound compound or salt form thereof, usually formed by a solvolysis reaction. This physical association may include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein can be prepared, eg, in crystalline forms, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solate" includes solvates in solution and isolatable solvates. Representative solvates include hydrates, ethanolates and methanolates.

術語“水合物”是指與水相結合的化合物。通常，包含在化合物的水合物中的水分子數與該水合物中該化合物分子數的比率確定。因此，化合物的水合物可用例如通式R．x H₂ O代表，其中R是該化合物，和x是大於0的數。給定化合物可形成超過一種水合物類型，包括，例如，單水合物(x為1)、低級水合物(x是大於0且小於1的數，例如，半水合物(R．0.5 H₂ O))和多水合物(x為大於1的數，例如，二水合物(R．2 H₂ O)和六水合物(R．6 H₂ O))。The term "hydrate" refers to a compound that is combined with water. Typically, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Therefore, the hydrate of the compound can be used, for example, the general formula R. x H ₂ O represents, wherein R is the compound, and x is a number greater than zero. A given compound can form more than one hydrate type, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1, for example, hemihydrate (R.0.5 _H2O) . )) and polyhydrates (x is a number greater than 1, eg, dihydrate ( _R.2H2O ) and hexahydrate ( _R.6H2O )).

本發明化合物可以是非晶形或結晶形式(同質多晶物)。此外，本發明化合物可以以一種或多種結晶形式存在。因此，本發明在其範圍內包括本發明化合物的所有非晶形或結晶形式。術語“同質多晶物”是指特定晶體堆積排列的化合物的結晶形式(或其鹽、水合物或溶合物)。所有的同質多晶物具有相同的員素組成。不同的結晶形式通常具有不同的X射線衍射圖、紅外光譜、熔點、密度、硬度、晶體形狀、光電性質、穩定性和溶解度。重結晶溶劑、結晶速率、貯存溫度和其他因素可導致一種結晶形式占優。化合物的各種同質多晶物可在不同的條件下透過結晶製備。The compounds of the present invention may be in amorphous or crystalline form (polymorphs). Furthermore, the compounds of the present invention may exist in one or more crystalline forms. Accordingly, the present invention includes within its scope all amorphous or crystalline forms of the compounds of the present invention. The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate or solvate thereof) of a particular crystal packing arrangement. All polymorphs have the same member element composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optoelectronic properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature and other factors can cause one crystalline form to dominate. Various polymorphs of the compounds can be prepared by crystallization under different conditions.

本發明還包括同位素標記的化合物(同位素變體)，它們等同於式(I)所述的那些，但一個或多個原子被原子品質或質量數不同於自然界常見的原子品質或質量數的原子所代替。可以引入本發明化合物中的同位素的實例包括氫、碳、氮、氧、磷、硫、氟和氯的同位素，分別例如² H、³ H、¹³ C、¹¹ C、¹⁴ C、¹⁵ N、¹⁸ O、¹⁷ O、³¹ P、³² P、³⁵ S、¹⁸ F和³⁶ Cl。含有上述同位素和/或其它原子的其它同位素的本發明化合物、其前驅藥物和所述化合物或所述前驅藥物的藥學上可接受的鹽都屬於本發明的範圍。某些同位素標記的本發明化合物、例如引入放射性同位素(例如³ H和¹⁴ C)的那些可用於藥物和/或受質組織分佈測定。氚、即³ H和碳-14、即¹⁴ C同位素是特別優選的，因為它們容易製備和檢測。進而，被更重的同位素取代，例如氘、即² H，由於代謝穩定性更高可以提供治療上的益處，例如延長體內半衰期或減少劑量需求，因而在有些情況下可能是優選的。同位素標記的本發明式(I)化合物及其前驅藥物一般可以這樣製備，在進行下述流程和/或實施例與製備例所揭露的製程時，用容易得到的同位素標記的試劑代替非同位素標記的試劑。The present invention also includes isotopically-labeled compounds (isotopic variants) that are equivalent to those described in formula (I), except that one or more of the atoms is replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature replaced. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of ^hydrogen , carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, ^3H , ^13C , ^11C , ^14C , ^15N , ¹⁸ , respectively O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl. Compounds of the invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or said prodrugs containing the above isotopes and/or other isotopes of other atoms are within the scope of the present invention. Certain isotopically-labeled compounds of the invention, such as those into which radioactive isotopes (eg, ^3H ^and14C ) have been incorporated, are useful in drug and/or substrate tissue distribution assays. Tritium, ie ³ H, and carbon-14, ie ¹⁴ C isotopes are particularly preferred because of their ease of preparation and detection. Furthermore, substitution with heavier isotopes, such as deuterium, ie, 2H, may be preferred in some circumstances because greater metabolic stability may provide therapeutic benefits, such as increased in vivo half ^- life or reduced dosage requirements. Isotopically labeled compounds of the formula (I) of the present invention and their prodrugs can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents when carrying out the processes disclosed in the following schemes and/or examples and preparation examples. reagent.

此外，前驅藥也包括在本發明的上下文內。本文所用的術語“前驅藥”是指在體內透過例如在血液中水解轉變成其具有醫學效應的活性形式的化合物。藥學上可接受的前驅藥描述於T. Higuchi和V. Stella，Prodrugs as Novel Delivery Systems，A.C.S. Symposium Series的Vol. 14，Edward B. Roche，ed.，Bioreversible Carriers in Drug Design，American Pharmaceutical Association and Pergamon Press，1987，以及D. Fleisher、S. Ramon和H. Barbra “Improved oral drug delivery：solubility limitations overcome by the use of prodrugs”，Advanced Drug Delivery Reviews (1996) 19(2) 115-130，每篇引入本文作為參考。Furthermore, prodrugs are also included within the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted in vivo to its active form which has a medical effect by, for example, hydrolysis in blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon, and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, per article introduced This article is for reference.

前驅藥為任何共價鍵合的本發明化合物，當將這種前驅藥給予患者時，其在體內釋放母體化合物。通常透過修飾官能基來製備前驅藥，修飾是以使得該修飾可以透過常規操作或在體內裂解產生母體化合物的方式進行的。前驅藥包括，例如，其中羥基、胺基或巰基與任意基團鍵合的本發明化合物，當將其給予患者時，可以裂解形成羥基、胺基或巰基。因此，前驅藥的代表性實例包括(但不限於)式(I)化合物的羥基、巰基和胺基官能基的乙酸酯/醯胺、甲酸酯/醯胺和苯甲酸酯/醯胺衍生物。另外，在羧酸(-COOH)的情況下，可以使用酯，例如甲酯、乙酯等。酯本身可以是有活性的和/或可以在人體體內條件下水解。合適的藥學上可接受的體內可水解的酯基包括容易在人體中分解而釋放母體酸或其鹽的那些基團。A prodrug is any covalently bonded compound of the invention which, when administered to a patient, releases the parent compound in vivo. Prodrugs are typically prepared by modifying functional groups in such a way that the modification can be cleaved, either by routine manipulation or in vivo, to yield the parent compound. Prodrugs include, for example, compounds of the invention in which a hydroxyl, amine or sulfhydryl group is bonded to any group that, when administered to a patient, can be cleaved to form a hydroxyl, amine or sulfhydryl group. Thus, representative examples of prodrugs include, but are not limited to, acetate/amide, formate/amide and benzoate/amide of the hydroxyl, sulfhydryl and amine functional groups of the compounds of formula (I) derivative. Additionally, in the case of carboxylic acids (-COOH), esters such as methyl esters, ethyl esters, and the like can be used. The esters themselves may be active and/or hydrolyzable under human in vivo conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those groups which are readily cleaved in humans to release the parent acid or salt thereof.

本發明還提供藥物製劑，包含治療有效量的式(I)化合物或其治療學上可接受的鹽和其藥學上可接受的載體、稀釋劑或賦形劑。所有這些形式都屬於本發明。The present invention also provides pharmaceutical formulations comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All of these forms belong to the present invention.

藥物組合物和試劑盒Pharmaceutical compositions and kits

在另一方面，本發明提供了藥物組合物，其包含本發明化合物(還稱為“活性組分”)和藥學上可接受的賦形劑。在一些實施方案中，所述藥物組合物包含有效量的本發明化合物。在一些實施方案中，所述藥物組合物包含治療有效量的本發明化合物。在一些實施方案中，所述藥物組合物包含預防有效量的本發明化合物。In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present invention.

用於本發明的藥學上可接受的賦形劑是指不會破壞一起調配的化合物的藥理學活性的無毒載劑、佐劑或媒劑。可以用於本發明組合物中的藥學上可接受的載劑、佐劑或媒劑包括(但不限於)離子交換劑、氧化鋁、硬脂酸鋁、卵磷脂、血清蛋白(如人類血清白蛋白)、緩衝物質(如磷酸鹽)、甘胺酸、山梨酸、山梨酸鉀、飽和植物脂肪酸的偏甘油酯混合物、水、鹽或電解質(如硫酸魚精蛋白)、磷酸氫二鈉、磷酸氫鉀、氯化鈉、鋅鹽、矽膠、三矽酸鎂、聚乙烯吡咯烷酮、基於纖維素的物質、聚乙二醇、羧甲基纖維素鈉、聚丙烯酸酯、蠟、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇以及羊毛脂。A pharmaceutically acceptable excipient for use in the present invention refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated together. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (eg, human serum albumin). protein), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, phosphoric acid Potassium hydrogen, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxygen Propylene-block polymers, polyethylene glycols and lanolin.

本發明還包括試劑盒(例如，藥物包裝)。所提供的試劑盒可以包括本發明化合物、其它治療劑，以及含有本發明化合物、其它治療劑的第一和第二容器(例如，小瓶、安瓿瓶、瓶、注射器和/或可分散包裝或其它合適的容器)。在一些實施方案中，提供的試劑盒還可以任選包括第三容器，其含有用於稀釋或懸浮本發明化合物和/或其它治療劑的藥用賦形劑。在一些實施方案中，提供在第一容器和第二容器中的本發明化合物和其它治療劑組合形成一個單位劑量。The present invention also includes kits (eg, pharmaceutical packages). Provided kits can include a compound of the present invention, other therapeutic agents, and first and second containers (eg, vials, ampoules, bottles, syringes, and/or dispersible packs or other) containing the compounds of the present invention, other therapeutic agents. suitable container). In some embodiments, provided kits can also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending a compound of the present invention and/or other therapeutic agent. In some embodiments, the compound of the invention and the other therapeutic agent provided in the first container and the second container are combined to form a unit dose.

給藥dosing

本發明提供的藥物組合物可以透過許多途徑給藥，包括但不限於：口服給藥、腸胃外給藥、吸入給藥、局部給藥、直腸給藥、鼻腔給藥、口腔給藥、***給藥、透過植入劑給藥或其它給藥方式。例如，本文使用的腸胃外給藥包括皮下給藥、皮內給藥、靜脈內給藥、肌肉內給藥、關節內給藥、動脈內給藥、滑膜腔內給藥、胸骨內給藥、腦脊髓膜內給藥、病灶內給藥、和顱內的注射或輸藥技術。The pharmaceutical compositions provided by the present invention can be administered by many routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration drug, through implants, or other modes of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration , intrameningeal administration, intralesional administration, and intracranial injection or infusion techniques.

通常，給予有效量的本文所提供的化合物。按照有關情況，包括所治療的病況、選擇的給藥途徑、實際給予的化合物、個體患者的年齡、體重和響應、患者症狀的嚴重程度，等等，可以由醫生確定實際上給予的化合物的量。Typically, an effective amount of a compound provided herein is administered. The amount of compound actually administered can be determined by the physician depending on the circumstances, including the condition being treated, the route of administration chosen, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc. .

當用於預防本發明所述病況時，給予處於形成所述病況危險之中的受試者本文所提供的化合物，典型地基於醫生的建議並在醫生監督下給藥，劑量水準如上所述。處於形成具體病況的危險之中的受試者，通常包括具有所述病況的家族史的受試者，或透過遺傳試驗或篩選確定尤其對形成所述病況敏感的那些受試者。When used to prevent the conditions of the invention, the compounds provided herein are administered to subjects at risk of developing the conditions, typically on the advice and supervision of a physician, at dosage levels as described above. Subjects at risk for developing a particular condition typically include subjects with a family history of the condition, or those determined by genetic testing or screening to be particularly susceptible to developing the condition.

還可以長期給予本文所提供的藥物組合物(“長期給藥”)。長期給藥是指在長時間內給予化合物或其藥物組合物，例如，3個月、6個月、1年、2年、3年、5年等等，或者可無限期地持續給藥，例如，受試者的餘生。在一些實施方案中，長期給藥意欲在長時間內在血液中提供所述化合物的恆定水準，例如，在治療窗內。The pharmaceutical compositions provided herein can also be administered chronically ("chronic administration"). Chronic administration refers to administration of a compound or a pharmaceutical composition thereof over an extended period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue indefinitely, For example, the rest of the subject's life. In some embodiments, chronic administration is intended to provide constant levels of the compound in the blood over an extended period of time, eg, within a therapeutic window.

可以使用各種給藥方法，進一步遞送本發明的藥物組合物。例如，在一些實施方案中，可以推注給藥藥物組合物，例如，為了使化合物在血液中的濃度提高至有效水準。推注劑量取決於透過身體的活性組分的目標全身性水準，例如，肌內或皮下的推注劑量使活性組分緩慢釋放，而直接遞送至靜脈的推注(例如，透過IV靜脈滴注)能夠更加快速地遞送，使得活性組分在血液中的濃度快速升高至有效水準。在其它實施方案中，可以以持續輸藥形式給予藥物組合物，例如，透過IV靜脈滴注，從而在受試者身體中提供穩態濃度的活性組分。此外，在其它實施方案中，可以首先給予推注劑量的藥物組合物，而後持續輸藥。Various methods of administration can be used to further deliver the pharmaceutical compositions of the present invention. For example, in some embodiments, the pharmaceutical composition may be administered as a bolus injection, eg, in order to increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of active ingredient penetration through the body, e.g., intramuscular or subcutaneous bolus doses provide slow release of the active ingredient, while bolus injections delivered directly into the vein (e.g., via IV infusion) ) can be delivered more rapidly, resulting in a rapid increase in the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, eg, by IV infusion, to provide a steady state concentration of the active ingredient in the body of the subject. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by a continuous infusion.

口服組合物可以採用散裝液體溶液或混懸劑或散裝粉劑形式。然而，更通常，為了便於精確地劑量給藥，以單位劑量形式提供所述組合物。術語“單位劑量”是指適合作為人類患者及其它哺乳動物的單元劑量的物理離散單位，每個單位包含預定數量的、適於產生所需要的治療效果的活性物質與合適藥學賦形劑。典型的單位劑量形式包括液體組合物的預裝填的、預先測量的安瓿或注射器，或者在固體組合物情況下的丸劑、片劑、膠囊劑等。在這種組合物中，所述化合物通常為較少的組分(約0.1至約50重量%，或優選約1至約40重量%)，剩餘部分為對於形成所需給藥形式有用的各種載體或賦形劑以及加工助劑。Oral compositions can take the form of bulk liquid solutions or suspensions or bulk powders. More generally, however, the compositions are presented in unit dosage form for ease of precise dosing. The term "unit dose" refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material suitable for producing the desired therapeutic effect in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampoules or syringes of liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, and the like. In such compositions, the compound will generally be the minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various useful in forming the desired administration form Carriers or excipients and processing aids.

對於口服劑量，代表性的方案是，每天一個至五個口服劑量，尤其是兩個至四個口服劑量，典型地是三個口服劑量。使用這些劑量給藥模式，每個劑量提供大約0.01至大約20 mg/kg的本發明化合物，優選的劑量各自提供大約0.1至大約10 mg/kg，尤其是大約1至大約5 mg/kg。For oral doses, a typical regimen is one to five oral doses, especially two to four oral doses, typically three oral doses per day. Using these dosing patterns, each dose provides about 0.01 to about 20 mg/kg of a compound of the invention, with preferred doses each providing about 0.1 to about 10 mg/kg, especially about 1 to about 5 mg/kg.

為了提供與使用注射劑量類似的血液水準，或比使用注射劑量更低的血液水準，通常選擇透皮劑量，數量為大約0.01至大約20%重量，優選大約0.1至大約20%重量，優選大約0.1至大約10%重量，且更優選大約0.5至大約15%重量。In order to provide blood levels similar to, or lower than, the use of injectable doses, transdermal doses are typically selected in amounts of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight.

從大約1至大約120小時，尤其是24至96小時，注射劑量水準在大約0.1 mg/kg/小時至至少10 mg/kg/小時的範圍。為了獲得足夠的穩定狀態水準，還可以給予大約0.1 mg/kg至大約10 mg/kg或更多的預載推注。對於40至80 kg的人類患者來說，最大總劑量不能超過大約2 g/天。From about 1 to about 120 hours, especially 24 to 96 hours, injection dosage levels are in the range of about 0.1 mg/kg/hour to at least 10 mg/kg/hour. To achieve adequate steady state levels, a preloaded bolus of about 0.1 mg/kg to about 10 mg/kg or more may also be administered. For human patients of 40 to 80 kg, the maximum total dose should not exceed approximately 2 g/day.

適於口服給藥的液體形式可包括合適的水性或非水載體以及緩衝劑、懸浮劑和分散劑、著色劑、調味劑，等等。固體形式可包括，例如，任何下列組份，或具有類似性質的化合物：粘合劑，例如，微晶纖維素、黃蓍膠或明膠；賦形劑，例如，澱粉或乳糖，崩解劑，例如，褐藻酸、Primogel或玉米澱粉；潤滑劑，例如，硬脂酸鎂；助流劑，例如，膠體二氧化矽；甜味劑，例如，蔗糖或糖精；或調味劑，例如，薄荷、水楊酸甲酯或橙味調味劑。Liquid forms suitable for oral administration can include suitable aqueous or non-aqueous carriers as well as buffering agents, suspending and dispersing agents, coloring agents, flavoring agents, and the like. Solid forms may include, for example, any of the following components, or compounds of similar properties: binders, such as microcrystalline cellulose, tragacanth, or gelatin; excipients, such as starch or lactose, disintegrants, For example, alginic acid, Primogel, or cornstarch; lubricants, for example, magnesium stearate; glidants, for example, colloidal silica; sweeteners, for example, sucrose or saccharin; or flavoring agents, for example, peppermint, water Methyl cylate or orange flavoring.

可注射的組合物典型地基於可注射用的無菌鹽水或磷酸鹽緩衝鹽水，或本領域中已知的其它可注射的賦形劑。如前所述，在這種組合物中，活性化合物典型地為較少的組分，經常為約0.05至10%重量，剩餘部分為可注射的賦形劑等。Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. In such compositions, as previously mentioned, the active compound is typically the minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.

典型地將透皮組合物配製為含有活性組分的局部軟膏劑或乳膏劑。當配製為軟膏劑時，活性組分典型地與石蠟或可與水混溶的軟膏基質組合。或者，活性組分可與例如水包油型乳膏基質一起配製為乳膏劑。這種透皮製劑是本領域中公知的，且通常包括用於提升活性組分或製劑的穩定的皮膚滲透的其它組份。所有這種已知的透皮製劑和組份包括在本發明提供的範圍內。Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically include other components for enhancing stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and compositions are included within the scope of the present invention.

本發明化合物還可透過經皮裝置給予。因此，經皮給藥可使用貯存器(reservoir)或多孔膜類型、或者多種固體基質的貼劑實現。The compounds of the present invention may also be administered by transdermal devices. Thus, transdermal administration can be accomplished using reservoir or porous membrane types, or patches of various solid matrices.

用於口服給予、注射或局部給予的組合物的上述組份僅僅是代表性的。其它材料以及加工技術等闡述於Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania的第8部分中，本文以引用的方式引入該文獻。The above-described components of compositions for oral administration, injection or topical administration are only representative. Additional materials, processing techniques, etc. are described in Section 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

本發明化合物還可以以持續釋放形式給予，或從持續釋放給藥系統中給予。代表性的持續釋放材料的描述可在Remington's Pharmaceutical Sciences中找到。The compounds of the present invention can also be administered in sustained release form, or from a sustained release drug delivery system. Descriptions of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

本發明還涉及本發明化合物的藥學上可接受的製劑。在一個實施方案中，所述製劑包含水。在另一個實施方案中，所述製劑包含環糊精衍生物。最常見的環糊精為分別由6、7和8個α-1,4-連接的葡萄糖單元組成的α-、β-和γ-環糊精，其在連接的糖部分上任選包括一個或多個取代基，其包括但不限於：甲基化的、羥基烷基化的、醯化的和磺烷基醚取代。在一些實施方案中，所述環糊精為磺烷基醚β-環糊精，例如，磺丁基醚β-環糊精，也稱作Captisol。參見，例如，U.S.5,376,645。在一些實施方案中，所述製劑包括六丙基-β-環糊精(例如，在水中，10-50%)。The present invention also relates to pharmaceutically acceptable formulations of the compounds of the present invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ-cyclodextrins consisting of 6, 7 and 8 α-1,4-linked glucose units, respectively, which optionally include a or multiple substituents including, but not limited to, methylated, hydroxyalkylated, sulfonated, and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether beta-cyclodextrin, eg, a sulfobutyl ether beta-cyclodextrin, also known as Captisol. See, eg, U.S. 5,376,645. In some embodiments, the formulation includes hexapropyl-beta-cyclodextrin (eg, in water, 10-50%).

藥物聯用drug combination

目前本領域中已知的許多化學治療劑可與本發明化合物組合使用。在一些實施方案中，化學治療劑選自有絲***抑制劑、烷化劑、抗代謝物、嵌入抗生素、生長因子抑制劑、細胞週期抑制劑、酶、拓撲異構酶抑制劑、生物反應調節劑、抗激素、血管生成抑制劑和抗雄激素。Many chemotherapeutic agents currently known in the art can be used in combination with the compounds of the present invention. In some embodiments, the chemotherapeutic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, Antihormones, angiogenesis inhibitors and antiandrogens.

實施例Example

本文所用的材料或試劑為可購買到的或由本領域通常已知的合成方法製備。The materials or reagents used herein are either commercially available or prepared by synthetic methods generally known in the art.

實施例1：1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-7-氟-6-(3-羥基萘-1-基)喹喔啉-2(1H)-酮的製備

Example 1: 1-((1-Propenylazetidin-3-yl)methyl)-7-fluoro-6-(3-hydroxynaphthalen-1-yl)quinoxaline-2(1H )-ketone preparation

第一步：將1-溴-2,5-二氟-4-硝基苯(5.0 g，21.0 mmol)溶解在乙腈(ACN)(100 mL)中，加入二異丙基乙基胺(DIEA)(10.8 g, 83.7 mmol)。0℃下，緩慢加入甘胺酸甲酯鹽酸鹽(2.9 g，23.0 mmol)。室溫攪拌16小時。系統直接減壓濃縮，濃縮物經中壓flash矽膠層析法(沖提液：乙酸乙酯:石油醚=0 - 30%)分離純化，得到N-(5-溴-4-氟-2-硝基苯基)甘胺酸甲酯(3.9 g)，為黃色固體，產率53%。ESI-MS: 307, 309 [M+H]⁺ 。Step 1: Dissolve 1-bromo-2,5-difluoro-4-nitrobenzene (5.0 g, 21.0 mmol) in acetonitrile (ACN) (100 mL) and add diisopropylethylamine (DIEA ) (10.8 g, 83.7 mmol). At 0 °C, methyl glycinate hydrochloride (2.9 g, 23.0 mmol) was added slowly. Stir at room temperature for 16 hours. The system was directly concentrated under reduced pressure, and the concentrate was separated and purified by medium pressure flash silica gel chromatography (eluent: ethyl acetate: petroleum ether=0-30%) to obtain N-(5-bromo-4-fluoro-2- Nitrophenyl)glycine methyl ester (3.9 g) as a yellow solid in 53% yield. ESI-MS: 307, 309 [M+H] ⁺ .

第二步：將N-(5-溴-4-氟-2-硝基苯基)甘胺酸甲酯(3.9 g，11.3 mmol)，溶解在乙醇(60 mL)和水（15 mL）中。室溫攪拌狀態下，加入鐵粉(100目，6.3 g，112.5 mmol)，氯化銨(6.1 g，114.0 mmol)，90℃反應2小時。冷卻至室溫後透過矽藻土過濾，濾餅用乙醇(100 mL)和乙酸乙酯(100 mL)洗滌，濾液減壓濃縮，所得水相用乙酸乙酯 (3 x 100 mL)萃取，再用飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，減壓濃縮，濃縮物經中壓flash矽膠層析法(沖提液：甲醇:二氯甲烷=0 - 10%)分離純化，得到6-溴-7-氟-3,4-二氫喹喔啉-2(1H)-酮(2.3 g)，為棕色油狀液體，產率82%。ESI-MS: 245, 247[M+H]⁺ 。Step 2: Methyl N-(5-bromo-4-fluoro-2-nitrophenyl)glycinate (3.9 g, 11.3 mmol) was dissolved in ethanol (60 mL) and water (15 mL) . Under stirring at room temperature, iron powder (100 mesh, 6.3 g, 112.5 mmol) and ammonium chloride (6.1 g, 114.0 mmol) were added, and the mixture was reacted at 90° C. for 2 hours. After cooling to room temperature, it was filtered through celite, the filter cake was washed with ethanol (100 mL) and ethyl acetate (100 mL), the filtrate was concentrated under reduced pressure, the obtained aqueous phase was extracted with ethyl acetate (3 x 100 mL), and then Washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was separated and purified by medium pressure flash silica gel chromatography (eluent: methanol: dichloromethane=0-10%) to obtain 6-bromo -7-Fluoro-3,4-dihydroquinoxalin-2(1H)-one (2.3 g) as a brown oily liquid, 82% yield. ESI-MS: 245, 247[M+H] ⁺ .

第三步：將6-溴-7-氟-3,4-二氫喹喔啉-2(1H)-酮(3.1 g，12.65 mmol)溶解在二氯甲烷(20 mL)和甲醇(20 mL)中。室溫下，緩慢倒入二氧化錳粉末(9.5 g, 109.2 mmol)，攪拌16小時，透過矽藻土過濾，濾餅用甲醇:二氯甲烷(10%，200 mL)洗滌，然後減壓濃縮後的濃縮物經中壓flash矽膠層析法(沖提液：甲醇:二氯甲烷=0 - 10%)分離純化，得到6-溴-7-氟喹喔啉-2(1H)-酮(1.2 g)，為白色固體，產率39%。ESI-MS: 243, 245 [M+H]⁺ 。Step 3: Dissolve 6-bromo-7-fluoro-3,4-dihydroquinoxalin-2(1H)-one (3.1 g, 12.65 mmol) in dichloromethane (20 mL) and methanol (20 mL) )middle. At room temperature, slowly poured manganese dioxide powder (9.5 g, 109.2 mmol), stirred for 16 hours, filtered through celite, the filter cake was washed with methanol: dichloromethane (10%, 200 mL), then concentrated under reduced pressure The resulting concentrate was separated and purified by medium pressure flash silica gel chromatography (eluent: methanol: dichloromethane=0-10%) to obtain 6-bromo-7-fluoroquinoxalin-2(1H)-one ( 1.2 g) as a white solid, 39% yield. ESI-MS: 243, 245 [M+H] ⁺ .

第四步： N2環境下，將6-溴-7-氟喹喔啉-2(1H)-酮(260 mg，1.07 mmol)，3-(溴甲基)氮雜環丁烷-1-羧酸叔丁酯(535 mg，2.14 mmol)，碳酸鉀(590 mg，4.28 mmol)分散在N,N-二甲基甲醯胺(DMF)(8 mL)中。於室溫攪拌16小時。系統用水(10 mL)淬熄後，加入乙酸乙酯(100 mL)，用水(3 x 20 mL)洗滌，最後用飽和食鹽水(10 mL)洗滌，無水硫酸鈉乾燥，過濾並減壓濃縮有機相後用中壓flash矽膠層析法(沖提液：乙酸乙酯:石油醚=0 - 50%)分離純化，得到3-((6-溴-7-氟-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(220 mg)，為淺棕色固體，產率49%。ESI-MS: 412, 414 [M+H]⁺ 。The fourth step: under N2 environment, 6-bromo-7-fluoroquinoxalin-2(1H)-one (260 mg, 1.07 mmol), 3-(bromomethyl)azetidine-1-carboxyl tert-Butyl acid (535 mg, 2.14 mmol), potassium carbonate (590 mg, 4.28 mmol) were dispersed in N,N-dimethylformamide (DMF) (8 mL). Stir at room temperature for 16 hours. After the system was quenched with water (10 mL), ethyl acetate (100 mL) was added, washed with water (3 x 20 mL), and finally washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. After the phase, use medium pressure flash silica gel chromatography (eluent: ethyl acetate: petroleum ether=0-50%) to separate and purify to obtain 3-((6-bromo-7-fluoro-2-oxoquinoxaline -1(2H)-yl)methyl)azetidine-1-carboxylate tert-butyl ester (220 mg) as a light brown solid, 49% yield. ESI-MS: 412, 414 [M+H] ⁺ .

第五步： N2環境下，將3-((6-溴-7-氟-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(120 mg，0.29 mmol)，4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)萘-2-醇(95 mg，0.35 mmol)，[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(Pd(dppf)Cl₂ ，22 mg，0.03 mmol)，碳酸鉀(121 mg，0.88 mmol)分散在1,4-二氧六環/水(5:1，6 mL)中。加熱至100℃，攪拌2小時。系統減壓濃縮後用中壓flash矽膠層析法(沖提液：甲醇:二氯甲烷=0 - 10%)分離純化，得到3-((7-氟-6-(3-羥基萘-1-基)-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(60 mg)，為淺棕色固體，產率43%。ESI-MS: 476 [M+H]⁺ 。The fifth step: under N2 environment, 3-((6-bromo-7-fluoro-2-oxoquinoxalin-1(2H)-yl)methyl)azetidine-1-carboxylic acid tertiary Butyl ester (120 mg, 0.29 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)naphthalen-2-ol ( 95 mg, 0.35 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl2, ₂₂ mg, 0.03 mmol), potassium carbonate (121 mg, 0.88 mmol) in 1,4-dioxane/water (5:1, 6 mL). Heat to 100°C and stir for 2 hours. After the system was concentrated under reduced pressure, it was separated and purified by medium pressure flash silica gel chromatography (eluent: methanol: dichloromethane=0-10%) to obtain 3-((7-fluoro-6-(3-hydroxynaphthalene-1). -yl)-2-oxoquinoxalin-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (60 mg) as a light brown solid, 43% yield. ESI-MS: 476 [M+H] ⁺ .

第六步：將3-((7-氟-6-(3-羥基萘-1-基)-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(60 mg，0.13 mmol)溶解在二氯甲烷(5 mL)中。室溫下，緩慢滴加三氟乙酸(0.3 mL)，攪拌2小時，然後減壓濃縮後得到1-(氮雜環丁烷-3-基甲基)-7-氟-6-(3-羥基萘-1-基)喹喔啉-2(1H)-酮(47 mg)。為棕色固體，產率(100%)。ESI-MS: 376 [M+H]⁺ 。The sixth step: 3-((7-Fluoro-6-(3-hydroxynaphthalen-1-yl)-2-oxoquinoxalin-1(2H)-yl)methyl)azetidine- tert-Butyl 1-carboxylate (60 mg, 0.13 mmol) was dissolved in dichloromethane (5 mL). At room temperature, trifluoroacetic acid (0.3 mL) was slowly added dropwise, stirred for 2 hours, and then concentrated under reduced pressure to obtain 1-(azetidin-3-ylmethyl)-7-fluoro-6-(3- Hydroxynaphthalen-1-yl)quinoxalin-2(1H)-one (47 mg). As a brown solid, yield (100%). ESI-MS: 376 [M+H] ⁺ .

第七步： N₂ 環境下，將1-(氮雜環丁烷-3-基甲基)-7-氟-6-(3-羥基萘-1-基)喹喔啉-2(1H)-酮(47 mg，0.13 mmol)溶解在二氯甲烷(4mL)中，加入三乙胺(128 mg, 1.22 mmol)。冷卻至0℃，將丙烯醯氯(13 mg，0.14 mmol)的二氯甲烷(1mL)溶液緩慢滴加到系統中，並於0℃攪拌0.5 小時。系統用prep-TLC (沖提液：MeOH:DCM=10:1)分離純化，得到的粗產物再用二甲基亞碸(DMSO)(2 mL)溶解，然後用C¹⁸ 逆相管柱進行純化(沖提液：ACN:5 mmol/L NH₄ HCO₃ 水溶液=0 - 40%)。凍乾得到1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-7-氟-6-(3-羥基萘-1-基)喹喔啉-2(1H)-酮(9.96 mg)，為白色固體，產率18%。ESI-MS: 430 [M+H]⁺ 。¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: ppm 10.00 (s, 1H), 8.28 (s, 1H), 8.95~7.90 (m, 2H), 7.82~7.80(m, 1H), 7.47~7.40 (m, 2H), 7.28~7.25 (m, 2H), 7.10 (d, 1H,J = 2.4 Hz), 6.36~6.29(m, 1H), 6.11 (dd, 1H,J = 17.2, 2.4 Hz), 5.68 (dd, 1H,J = 10.4, 2.4 Hz), 4.55~4.60 (m, 2H), 4.32~4.27 (m, 1H), 4.16~4.12 (m, 1H), 4.01~3.97 (m, 1H), 3.89~3.84(m, 1H), 3.22~3.17(m, 1H)。Step 7: Under _N2 environment, 1-(azetidin-3-ylmethyl)-7-fluoro-6-(3-hydroxynaphthalen-1-yl)quinoxaline-2(1H) -ketone (47 mg, 0.13 mmol) was dissolved in dichloromethane (4 mL) and triethylamine (128 mg, 1.22 mmol) was added. After cooling to 0°C, a solution of acrylonitrile chloride (13 mg, 0.14 mmol) in dichloromethane (1 mL) was slowly added dropwise to the system and stirred at 0°C for 0.5 h. The system was separated and purified by prep-TLC (eluent: MeOH:DCM=10:1), and the obtained crude product was dissolved in dimethylsulfite (DMSO) (2 mL), and then carried out with a C ¹⁸ reverse phase column. Purification (eluent: ACN:5 mmol/L aq _{. NH4HCO3} ₌ 0-40%). Lyophilization yields 1-((1-propenylazetidin-3-yl)methyl)-7-fluoro-6-(3-hydroxynaphthalen-1-yl)quinoxaline-2(1H) - Ketone (9.96 mg) as a white solid, 18% yield. ESI-MS: 430 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 10.00 (s, 1H), 8.28 (s, 1H), 8.95~7.90 (m, 2H), 7.82~7.80(m, 1H), 7.47~ 7.40 (m, 2H), 7.28~7.25 (m, 2H), 7.10 (d, 1H, J = 2.4 Hz), 6.36~6.29(m, 1H), 6.11 (dd, 1H, J = 17.2, 2.4 Hz) , 5.68 (dd, 1H, J = 10.4, 2.4 Hz), 4.55~4.60 (m, 2H), 4.32~4.27 (m, 1H), 4.16~4.12 (m, 1H), 4.01~3.97 (m, 1H) , 3.89~3.84(m, 1H), 3.22~3.17(m, 1H).

實施例2：1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-7-氯-6-(3-羥基萘-1-基)喹喔啉-2(1H)-酮的製備

Example 2: 1-((1-Propenylazetidin-3-yl)methyl)-7-chloro-6-(3-hydroxynaphthalen-1-yl)quinoxaline-2(1H )-ketone preparation

第一步：將1-溴-2-氯-5-氟-4-硝基苯(5.0 g，19.7 mmol)溶解在乙腈(ACN)(100 mL)中，加入二異丙基乙基胺(DIEA)(12.7 g, 98.4 mmol)。0 ℃下，緩慢加入甘胺酸甲酯鹽酸鹽(4.91 g，39.4 mmol)。室溫攪拌16小時。系統直接減壓濃縮，將濃縮物經中壓flash矽膠層析法(沖提液：乙酸乙酯:二氯甲烷=0 - 10%)分離純化，得到N-(5-溴-4-氯-2-硝基苯基)甘胺酸甲酯(6.3 g)，為黃色固體，產率99%。ESI-MS: 323, 325 [M+H]⁺ 。Step 1: Dissolve 1-bromo-2-chloro-5-fluoro-4-nitrobenzene (5.0 g, 19.7 mmol) in acetonitrile (ACN) (100 mL), add diisopropylethylamine ( DIEA) (12.7 g, 98.4 mmol). At 0 °C, methyl glycinate hydrochloride (4.91 g, 39.4 mmol) was added slowly. Stir at room temperature for 16 hours. The system was directly concentrated under reduced pressure, and the concentrate was separated and purified by medium pressure flash silica gel chromatography (eluent: ethyl acetate: dichloromethane=0-10%) to obtain N-(5-bromo-4-chloro- 2-Nitrophenyl)glycine methyl ester (6.3 g) as a yellow solid in 99% yield. ESI-MS: 323, 325 [M+H] ⁺ .

第二步：將N-(5-溴-4-氯-2-硝基苯基)甘胺酸甲酯(4.0 g，11.11 mmol)溶解在乙醇(76 mL)和水（20mL）中。室溫攪拌狀態下，加入鐵粉(100目，6.2 g，111.1 mmol)，氯化銨(5.9 g，111.1 mmol)，90℃反應2小時。冷卻至室溫後透過矽藻土過濾，濾餅用乙醇(100 mL)和乙酸乙酯(100 mL)洗滌，濾液減壓濃縮，所得水相用乙酸乙酯(3 x 100 mL)萃取，再用飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，減壓濃縮，將濃縮物經中壓flash矽膠層析法(沖提液：甲醇:二氯甲烷=0 - 10%)分離純化，得到6-溴-7-氯-3,4-二氫喹喔啉-2(1H)-酮(3.0 g)，為棕色油狀液體，產率100%。ESI-MS: 261, 263 [M+H]⁺ 。Second step: Methyl N-(5-bromo-4-chloro-2-nitrophenyl)glycinate (4.0 g, 11.11 mmol) was dissolved in ethanol (76 mL) and water (20 mL). Under stirring at room temperature, iron powder (100 mesh, 6.2 g, 111.1 mmol) and ammonium chloride (5.9 g, 111.1 mmol) were added, and the mixture was reacted at 90° C. for 2 hours. After cooling to room temperature, it was filtered through celite, the filter cake was washed with ethanol (100 mL) and ethyl acetate (100 mL), the filtrate was concentrated under reduced pressure, the obtained aqueous phase was extracted with ethyl acetate (3 x 100 mL), and then Washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was separated and purified by medium pressure flash silica gel chromatography (eluent: methanol: dichloromethane=0-10%) to obtain 6- Bromo-7-chloro-3,4-dihydroquinoxalin-2(1H)-one (3.0 g) as a brown oily liquid, 100% yield. ESI-MS: 261, 263 [M+H] ⁺ .

第三步：將6-溴-7-氯-3,4-二氫喹喔啉-2(1H)-酮(2.8 g，10.7 mmol)溶解在二氯甲烷(50 mL)和甲醇(50 mL)中。室溫下，緩慢倒入二氧化錳粉末(4.6 g, 52.9 mmol)，攪拌16小時，透過矽藻土過濾，濾餅用甲醇:二氯甲烷(50%，400 mL)洗滌，然後減壓濃縮後的濃縮物經中壓flash矽膠層析法(沖提液：甲醇:二氯甲烷=0 - 10%)分離純化，得到6-溴-7-氯喹喔啉-2(1H)-酮(1.8 g)，為白色固體，產率64%。ESI-MS: 259, 261 [M+H]⁺ 。Step 3: Dissolve 6-bromo-7-chloro-3,4-dihydroquinoxalin-2(1H)-one (2.8 g, 10.7 mmol) in dichloromethane (50 mL) and methanol (50 mL) )middle. At room temperature, slowly poured manganese dioxide powder (4.6 g, 52.9 mmol), stirred for 16 hours, filtered through celite, the filter cake was washed with methanol: dichloromethane (50%, 400 mL), then concentrated under reduced pressure The resulting concentrate was separated and purified by medium pressure flash silica gel chromatography (eluent: methanol: dichloromethane=0-10%) to obtain 6-bromo-7-chloroquinoxaline-2(1H)-one (1.8 g) as a white solid in 64% yield. ESI-MS: 259, 261 [M+H] ⁺ .

第四步： N₂ 環境下，將6-溴-7-氯喹喔啉-2(1H)-酮(364 mg，1.41 mmol)，3-(溴甲基)氮雜環丁烷-1-羧酸叔丁酯(527 mg，2.11 mmol)，碳酸鉀(776 mg，5.62 mmol)分散在N,N-二甲基甲醯胺(DMF)(5 mL)中。於室溫攪拌16小時。系統用水(10 mL)淬熄後，加入乙酸乙酯(100 mL)，用水(3 x 20 mL)洗滌，最後用飽和食鹽水(10 mL)洗滌，無水硫酸鈉乾燥，過濾減壓濃縮後用中壓flash矽膠層析法(沖提液：乙酸乙酯:石油醚=0 - 50%)分離純化，得到3-((6-溴-7-氯-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(300 mg)，為淺棕色固體，產率50%。ESI-MS: 428, 430 [M+H]⁺ 。The fourth step: under _N2 environment, 6-bromo-7-chloroquinoxalin-2(1H)-one (364 mg, 1.41 mmol), 3-(bromomethyl)azetidine-1-carboxyl tert-Butyl acid (527 mg, 2.11 mmol), potassium carbonate (776 mg, 5.62 mmol) were dispersed in N,N-dimethylformamide (DMF) (5 mL). Stir at room temperature for 16 hours. After the system was quenched with water (10 mL), ethyl acetate (100 mL) was added, washed with water (3 x 20 mL), and finally washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and used Medium pressure flash silica gel chromatography (eluent: ethyl acetate: petroleum ether=0-50%) was isolated and purified to obtain 3-((6-bromo-7-chloro-2-oxoquinoxaline-1( 2H)-yl)methyl)azetidine-1-carboxylate tert-butyl ester (300 mg) as a light brown solid in 50% yield. ESI-MS: 428, 430 [M+H] ⁺ .

第五步： N₂ 環境下，將3-((6-溴-7-氯-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(140 mg，0.33 mmol)，4-(4,4,5,5-四甲基-1,3,2-二氧雜硼環戊烷-2-基)萘-2-醇(106 mg，0.39 mmol)，[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(Pd(dppf)Cl₂ ，24 mg，0.033 mmol)，碳酸鉀(135 mg，0.98 mmol)分散在1,4-二氧六環/水(5:1，6 mL)中。加熱至100℃，攪拌2小時。系統減壓濃縮後用中壓flash矽膠層析法(沖提液：甲醇:二氯甲烷=0 - 10%)分離純化，得到3-((7-氯-6-(3-羥基萘-1-基)-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(160 mg)，為淺棕色固體，產率99%。ESI-MS: 492 [M+H]⁺ 。The fifth step: under _N2 environment, 3-((6-bromo-7-chloro-2-oxoquinoxalin-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-Butyl ester (140 mg, 0.33 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol ( 106 mg, 0.39 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl2, ₂₄ mg, 0.033 mmol), potassium carbonate (135 mg, 0.98 mmol) in 1,4-dioxane/water (5:1, 6 mL). Heat to 100°C and stir for 2 hours. After the system was concentrated under reduced pressure, it was separated and purified by medium pressure flash silica gel chromatography (eluent: methanol: dichloromethane=0-10%) to obtain 3-((7-chloro-6-(3-hydroxynaphthalene-1 -yl)-2-oxoquinoxalin-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (160 mg) as a light brown solid in 99% yield. ESI-MS: 492 [M+H] ⁺ .

第六步：將3-((7-氯-6-(3-羥基萘-1-基)-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(160 mg，0.33 mmol)溶解在二氯甲烷(4 mL)中。室溫下，緩慢滴加三氟乙酸(0.6 mL)，攪拌2小時，然後減壓濃縮後得到1-(氮雜環丁烷-3-基甲基)-7-氯-6-(3-羥基萘-1-基)喹喔啉-2(1H)-酮(127 mg)，為棕色固體，產率100%。ESI-MS: 392 [M+H]⁺ 。The sixth step: 3-((7-chloro-6-(3-hydroxynaphthalen-1-yl)-2-oxoquinoxalin-1(2H)-yl)methyl)azetidine- 1-Carboxylic acid tert-butyl ester (160 mg, 0.33 mmol) was dissolved in dichloromethane (4 mL). At room temperature, trifluoroacetic acid (0.6 mL) was slowly added dropwise, stirred for 2 hours, and then concentrated under reduced pressure to obtain 1-(azetidin-3-ylmethyl)-7-chloro-6-(3- Hydroxynaphthalen-1-yl)quinoxalin-2(1H)-one (127 mg) as a brown solid in 100% yield. ESI-MS: 392 [M+H] ⁺ .

第七步： N₂ 環境下，將1-(氮雜環丁烷-3-基甲基)-7-氯-6-(3-羥基萘-1-基)喹喔啉-2(1H)-酮(64 mg，0.16 mmol)溶解在二氯甲烷(3mL)中，加入三乙胺(164 mg, 1.6 mmol)。冷卻至0℃，將丙烯醯氯(16 mg，0.18 mmol)的二氯甲烷(2mL)溶液緩慢滴加到系統中，並於0℃攪拌0.5 小時。系統用prep-TLC (沖提液：MeOH:DCM=1:10)分離純化，得到的粗產物再用二甲基亞碸(DMSO)(2 mL)溶解後，用C18逆相管柱進行純化(沖提液：ACN:5 mmol/L NH₄ HCO₃ 水溶液=0 - 40%)。凍乾得到1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-7-氯-6-(3-羥基萘-1-基)喹喔啉-2(1H)-酮(7.84 mg)，為白色固體，產率11%。ESI-MS: 446 [M+H]⁺ 。¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: ppm 9.94 (s, 1H), 8.31 (s, 1H), 8.11 (d, 1H,J = 2.8 Hz), 7.83 (s, 1H), 7.80 (d, 1H,J = 8.0 Hz), 7.44~7.40 (m, 1H), 7.24~7.22 (m, 3H), 7.02 (d, 1H,J = 2.4 Hz), 6.32 (dd, 1H,J = 17.2, 10.4 Hz), 6.11 (dd, 1H,J = 16.8, 2.4 Hz), 5.67 (dd, 1H,J = 10.4, 2.4 Hz), 4.63~4.59 (m, 2H), 4.33~4.28 (m, 1H), 4.16~4.12 (m, 1H), 4.03~3.98 (m, 1H), 3.90~3.84 (m, 1H), 3.24~3.13 (m, 1H)。Step 7: Under _N2 environment, 1-(azetidin-3-ylmethyl)-7-chloro-6-(3-hydroxynaphthalen-1-yl)quinoxaline-2(1H) -ketone (64 mg, 0.16 mmol) was dissolved in dichloromethane (3 mL) and triethylamine (164 mg, 1.6 mmol) was added. After cooling to 0°C, a solution of acrylonitrile chloride (16 mg, 0.18 mmol) in dichloromethane (2 mL) was slowly added dropwise to the system and stirred at 0°C for 0.5 h. The system was separated and purified by prep-TLC (eluent: MeOH:DCM=1:10), the obtained crude product was dissolved in dimethylsulfoxide (DMSO) (2 mL), and purified by C18 reverse phase column (Eluent: ACN:5 mmol/L NH ₄ HCO ₃ aqueous solution = 0 - 40%). Lyophilization yields 1-((1-propenylazetidin-3-yl)methyl)-7-chloro-6-(3-hydroxynaphthalen-1-yl)quinoxaline-2(1H) -ketone (7.84 mg) as a white solid, 11% yield. ESI-MS: 446 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 9.94 (s, 1H), 8.31 (s, 1H), 8.11 (d, 1H, J = 2.8 Hz), 7.83 (s, 1H), 7.80 (d, 1H, J = 8.0 Hz), 7.44~7.40 (m, 1H), 7.24~7.22 (m, 3H), 7.02 (d, 1H, J = 2.4 Hz), 6.32 (dd, 1H, J = 17.2 , 10.4 Hz), 6.11 (dd, 1H, J = 16.8, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 4.63~4.59 (m, 2H), 4.33~4.28 (m, 1H) , 4.16~4.12 (m, 1H), 4.03~3.98 (m, 1H), 3.90~3.84 (m, 1H), 3.24~3.13 (m, 1H).

透過參考以上實施例化合物2的製備方法和使用不同的反應原料，製備了以下實施例化合物15、22和23：實施例結構［M+H］⁺ ¹ HNMR 15

464.3 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 8.30 (s, 1H), 8.15 (dd, 1H, J = 8.4, 1.2 Hz), 8.08 (dd, 1H, J = 8.4, 1.2 Hz), 8.01 (d, 1H, J = 2.0 Hz), 7.84 (s, 1H), 7.70~7.62 (m, 2H), 7.56~7.52 (m, 1H), 7.45 (d, 1H, J = 6.8 Hz), 6.35~6.27 (m, 1H), 6.10 (dd, 1H, J = 17.2, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 4.67~4.52 (m, 2H), 4.33~4.27 (m, 1H), 4.13 (dd, 1H, J = 8.8, 5.6 Hz), 4.03~3.96 (m, 1H), 3.86 (dd, 1H, J = 10.0, 5.6 Hz), 3.20~3.11 (m, 1H)。 22

434.1 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 13.15 (s, 1H), 8.31 (s, 1H), 8.13 (d, 1H, J = 1.6 Hz), 7.80 (s, 1H), 7.55~7.53 (m, 1H), 7.49 (s, 1H), 7.35 (d, 1H, J = 8.8 Hz), 6.36~6.29 (m, 1H), 6.11 (dd, 1H, J = 16.8, 2.4 Hz), 5.69~5.66 (m, 1H), 4.61~4.59 (m, 2H), 4.33~4.28 (m, 1H), 4.16~4.12 (m, 1H), 4.03~3.98 (m, 1H), 3.89~3.85 (m, 1H), 3.21~3.14 (m, 1H), 2.17 (s, 3H)。 23

414.2 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 10.06 (d, 1H, J = 1.6 Hz), 8.27 (s, 1H), 8.03 (s, 1H), 7.75 (s, 1H), 7.31~7.25 (m, 1H), 6.82 (d, 1H, J = 7.6 Hz), 6.78~6.73 (m, 1H), 6.30 (dd, 1H, J = 17.2, 10.8 Hz), 6.10 (dd, 1H, J = 17.6, 2.4 Hz), 5.66 (dd, 1H, J = 10.4, 2.4 Hz), 4.56 (d, 2H, J = 7.6 Hz), 4.28 (t, 1H, J = 8.8 Hz), 4.11 (dd, 1H, J = 9.2, 5.2 Hz), 3.98 (t, 1H, J = 10.0 Hz), 3.84 (dd, 1H, J = 10.4, 5.6 Hz), 3.18~3.10 (m, 1H)。 By referring to the preparation method of Example Compound 2 above and using different reaction starting materials, the following Example Compounds 15, 22 and 23 were prepared:

Example structure [M+H] ⁺ ¹ HNMR 15

464.3 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 8.30 (s, 1H), 8.15 (dd, 1H, J = 8.4, 1.2 Hz), 8.08 (dd, 1H, J = 8.4, 1.2 Hz), 8.01 (d, 1H, J = 2.0 Hz), 7.84 (s, 1H), 7.70~7.62 (m, 2H), 7.56~7.52 (m, 1H), 7.45 (d, 1H, J = 6.8 Hz), 6.35~ 6.27 (m, 1H), 6.10 (dd, 1H, J = 17.2, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 4.67~4.52 (m, 2H), 4.33~4.27 (m, 1H), 4.13 (dd, 1H, J = 8.8, 5.6 Hz), 4.03~3.96 (m, 1H), 3.86 (dd, 1H, J = 10.0, 5.6 Hz), 3.20~3.11 (m, 1H). twenty two

434.1 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 13.15 (s, 1H), 8.31 (s, 1H), 8.13 (d, 1H, J = 1.6 Hz), 7.80 (s, 1H), 7.55~7.53 (m, 1H), 7.49 (s, 1H), 7.35 (d, 1H, J = 8.8 Hz), 6.36~6.29 (m, 1H), 6.11 (dd, 1H, J = 16.8, 2.4 Hz), 5.69~ 5.66 (m, 1H), 4.61~4.59 (m, 2H), 4.33~4.28 (m, 1H), 4.16~4.12 (m, 1H), 4.03~3.98 (m, 1H), 3.89~3.85 (m, 1H) ), 3.21~3.14 (m, 1H), 2.17 (s, 3H). twenty three

414.2 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 10.06 (d, 1H, J = 1.6 Hz), 8.27 (s, 1H), 8.03 (s, 1H), 7.75 (s, 1H), 7.31~7.25 (m, 1H), 6.82 (d, 1H, J = 7.6 Hz), 6.78~6.73 (m, 1H), 6.30 (dd, 1H, J = 17.2, 10.8 Hz), 6.10 (dd, 1H, J = 17.6 , 2.4 Hz), 5.66 (dd, 1H, J = 10.4, 2.4 Hz), 4.56 (d, 2H, J = 7.6 Hz), 4.28 (t, 1H, J = 8.8 Hz), 4.11 (dd, 1H, J = 9.2, 5.2 Hz), 3.98 (t, 1H, J = 10.0 Hz), 3.84 (dd, 1H, J = 10.4, 5.6 Hz), 3.18~3.10 (m, 1H).

實施例3：1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-3-(2-(二甲基胺基)乙氧基)-7-氟-6-(3-羥基萘基-1-基)喹喔啉-2(1H)-酮的製備

Example 3: 1-((1-Propenylazetidine-3-yl)methyl)-3-(2-(dimethylamino)ethoxy)-7-fluoro-6- Preparation of (3-hydroxynaphthyl-1-yl)quinoxalin-2(1H)-one

第一步： N₂ 環境下，將3-((6-溴-7-氟-2,3-二氧代-3,4-二氫喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(230 mg，0.54 mmol)，2-(二甲基胺基)乙醇(96 mg，1.07 mmol)，三苯基膦(280 mg，1.07 mmol)分散在四氫呋喃(THF)(5 mL)中。降至0℃後，將偶氮二甲酸二異丙酯(216 mg，1.07 mmol)的四氫呋喃(THF)(1 mL)溶液緩慢滴加到系統中，緩慢升至室溫，於室溫攪拌16小時。系統減壓濃縮後用中壓flash矽膠層析法(沖提液：甲醇:二氯甲烷=0 – 10%)分離純化，得到3-((6-溴-3-(2-(二甲基胺基)乙氧基)-7-氟-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯和3-((6-溴-4-(2-(二甲基胺基)乙基)-7-氟-2,3-二氧代-3,4-二氫喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯的混合物(187 mg)，為黃色固體，產率70%。ESI-MS: 499, 501 [M+H]⁺ 。The first step: under _N2 environment, 3-((6-bromo-7-fluoro-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)methyl) tert-butyl azetidine-1-carboxylate (230 mg, 0.54 mmol), 2-(dimethylamino)ethanol (96 mg, 1.07 mmol), triphenylphosphine (280 mg, 1.07 mmol) Disperse in tetrahydrofuran (THF) (5 mL). After dropping to 0 °C, a solution of diisopropyl azodicarboxylate (216 mg, 1.07 mmol) in tetrahydrofuran (THF) (1 mL) was slowly added dropwise to the system, slowly warmed to room temperature, and stirred at room temperature for 16 Hour. After the system was concentrated under reduced pressure, it was separated and purified by medium pressure flash silica gel chromatography (eluent: methanol: dichloromethane = 0 – 10%) to obtain 3-((6-bromo-3-(2-(dimethylene) Amino)ethoxy)-7-fluoro-2-oxoquinoxalin-1(2H)-yl)methyl)azetidine-1-carboxylate tert-butyl ester and 3-((6- bromo-4-(2-(dimethylamino)ethyl)-7-fluoro-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)methyl) A mixture of tert-butyl azetidine-1-carboxylate (187 mg) as a yellow solid, 70% yield. ESI-MS: 499, 501 [M+H] ⁺ .

第二步： N₂ 環境下，將3-((6-溴-3-(2-(二甲基胺基)乙氧基)-7-氟-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯和3-((6-溴-4-(2-(二甲基胺基)乙基)-7-氟-2,3-二氧代-3,4-二氫喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯的混合物(187 mg，0.37 mmol)，4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)萘-2-醇(121 mg，0.45 mmol)，[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(Pd(dppf)Cl₂ ，28 mg，0.037 mmol)，碳酸鉀(156 mg，1.12 mmol)分散在1,4-二氧六環/水(5:1，5 mL)中。加熱至100℃，攪拌2小時。系統減壓濃縮後用中壓flash矽膠層析法(沖提液：甲醇:二氯甲烷=0 - 10%)分離純化，得到3-((3-(2-(二甲基胺基)乙氧基)-7-氟-6-(3-羥基萘-1-基)-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(120 mg)，為紫黑色固體，產率57%。ESI-MS: 563 [M+H]⁺ 。The second step: under _N2 environment, 3-((6-bromo-3-(2-(dimethylamino)ethoxy)-7-fluoro-2-oxoquinoxaline-1(2H )-yl)methyl)azetidine-1-carboxylate tert-butyl ester and 3-((6-bromo-4-(2-(dimethylamino)ethyl)-7-fluoro-2 , a mixture of tert-butyl 3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)methyl)azetidine-1-carboxylate (187 mg, 0.37 mmol), 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)naphthalen-2-ol (121 mg, 0.45 mmol), [1, 1'-Bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl ₂ , 28 mg, 0.037 mmol), potassium carbonate (156 mg, 1.12 mmol) dispersed in 1,4-dichloride in oxane/water (5:1, 5 mL). Heat to 100°C and stir for 2 hours. After the system was concentrated under reduced pressure, it was separated and purified by medium pressure flash silica gel chromatography (eluent: methanol: dichloromethane = 0 - 10%) to obtain 3-((3-(2-(dimethylamino)ethyl) oxy)-7-fluoro-6-(3-hydroxynaphthalen-1-yl)-2-oxoquinoxalin-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert. Butyl ester (120 mg) as a purple-black solid, 57% yield. ESI-MS: 563 [M+H] ⁺ .

第三步：將3-((3-(2-(二甲基胺基)乙氧基)-7-氟-6-(3-羥基萘-1-基)-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁酮烷-1-羧酸叔丁酯(143 mg，0.25 mmol)溶解在二氯甲烷(6 mL)中。室溫下，緩慢滴加三氟乙酸(0.6 mL)，攪拌2小時，然後減壓濃縮得到1-(氮雜環丁烷-3-基甲基)-3-(2-(二甲基胺基)乙氧基)-7-氟-6-(3-羥基萘-1-基)喹喔啉-2(1H)-酮(118 mg)，為棕色固體，產率(100%)。ESI-MS: 463 [M+H]⁺ 。The third step: 3-((3-(2-(dimethylamino)ethoxy)-7-fluoro-6-(3-hydroxynaphthalen-1-yl)-2-oxoquinoxaline -1(2H)-yl)methyl)azetidinone-1-carboxylate tert-butyl ester (143 mg, 0.25 mmol) was dissolved in dichloromethane (6 mL). At room temperature, trifluoroacetic acid (0.6 mL) was slowly added dropwise, stirred for 2 hours, and then concentrated under reduced pressure to obtain 1-(azetidin-3-ylmethyl)-3-(2-(dimethylamine) (118 mg) as a brown solid, yield (100%). ESI-MS: 463 [M+H] ⁺ .

第四步： N₂ 環境下，將1-(氮雜環丁烷-3-基甲基)-3-(2-(二甲基胺基)乙氧基)-7-氟-6-(3-羥基萘-1-基)喹喔啉-2(1H)-酮(118 mg，0.25 mmol)溶解在二氯甲烷(4mL)中，加入三乙胺(257 mg, 2.5 mmol)。冷卻至0℃，將丙烯醯氯(23 mg，0.25 mmol)的二氯甲烷(1mL)溶液緩慢滴加到系統中，並於0℃攪拌0.5 小時。系統用prep-TLC (沖提液：MeOH:DCM=1:10)分離純化，得到的粗產物再用二甲基亞碸(DMSO)(2 mL)溶解，然後用C18逆相管柱進行純化(沖提液：ACN:5 mmol/L NH₄ HCO₃ 水溶液=0 - 40%)。凍乾得1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-3-(2-(二甲基胺基)乙氧基)-7-氟-6-(3-羥基萘基-1-基)喹喔啉-2(1H)-酮(12.47 mg)，為白色固體，產率9%。ESI-MS: 517[M+H]⁺ 。¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: ppm 9.99 (s, 1H), 7.81~7.72 (m, 2H), 7.47~7.42 (m, 3H), 7.29~7.25 (m, 2H), 7.10 (d, 1H, J = 2.4 Hz), 6.32 (dd, 1H, J =16.8, 10.0 Hz), 6.11 (dd, 1H, J =16.8, 2.4 Hz), 5.67 (dd, 1H, J =10.4, 2.4 Hz), 4.52~4.50 (m, 2H), 4.32~4.22 (m, 3H), 4.14~4.10 (m, 1H), 4.02~3.97 (m, 1H), 3.86~3.82 (m, 1H), 3.21~3.14 (m, 1H), 2.52~2.51 (m, 2H), 2.10 (s, 6H)。The fourth step: under N environment, 1-(azetidin- ₃ -ylmethyl)-3-(2-(dimethylamino)ethoxy)-7-fluoro-6-( 3-Hydroxynaphthalen-1-yl)quinoxalin-2(1H)-one (118 mg, 0.25 mmol) was dissolved in dichloromethane (4 mL) and triethylamine (257 mg, 2.5 mmol) was added. After cooling to 0°C, a solution of acryl chloride (23 mg, 0.25 mmol) in dichloromethane (1 mL) was slowly added dropwise to the system and stirred at 0°C for 0.5 h. The system was separated and purified by prep-TLC (eluent: MeOH:DCM=1:10), the obtained crude product was dissolved in dimethylsulfite (DMSO) (2 mL), and then purified by C18 reverse phase column (Eluent: ACN:5 mmol/L NH ₄ HCO ₃ aqueous solution = 0 - 40%). Lyophilized to obtain 1-((1-propenyl azetidine-3-yl)methyl)-3-(2-(dimethylamino)ethoxy)-7-fluoro-6-( 3-Hydroxynaphthyl-1-yl)quinoxalin-2(1H)-one (12.47 mg) as a white solid, 9% yield. ESI-MS: 517[M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 9.99 (s, 1H), 7.81~7.72 (m, 2H), 7.47~7.42 (m, 3H), 7.29~7.25 (m, 2H), 7.10 (d, 1H, J = 2.4 Hz), 6.32 (dd, 1H, J =16.8, 10.0 Hz), 6.11 (dd, 1H, J =16.8, 2.4 Hz), 5.67 (dd, 1H, J =10.4, 2.4 Hz), 4.52~4.50 (m, 2H), 4.32~4.22 (m, 3H), 4.14~4.10 (m, 1H), 4.02~3.97 (m, 1H), 3.86~3.82 (m, 1H), 3.21 ~3.14 (m, 1H), 2.52~2.51 (m, 2H), 2.10 (s, 6H).

實施例4：7-氯-1-((1-(2-氯乙醯基)氮雜環丁烷-3-基)甲基)-6-(3-羥基萘-1-基)喹喔啉-2(1H)-酮的製備

Example 4: 7-Chloro-1-((1-(2-chloroacetyl)azetidin-3-yl)methyl)-6-(3-hydroxynaphthalen-1-yl)quinoxa Preparation of olin-2(1H)-ones

N₂ 環境下，將1-(氮雜環丁烷-3-基甲基)-7-氯-6-(3-羥基萘-1-基)喹喔啉-2(1H)-酮(64 mg，0.16 mmol)溶解在二氯甲烷(3mL)中，加入三乙胺(164 mg, 1.6 mmol)。冷卻至0℃，將氯乙醯氯(20 mg，0.18 mmol)的二氯甲烷(2mL)溶液緩慢滴加到系統中，並於0℃攪拌0.5 小時。系統用prep-TLC (沖提液：MeOH:DCM=10:1)分離純化，得到的粗產物再用二甲基亞碸(DMSO)(2 mL)溶解，然後用C18逆相管柱進行純化(沖提液：ACN:5 mmol/L NH₄ HCO₃ 水溶液=0 - 40%)。凍乾得到7-氯-1-((1-(2-氯乙醯基)氮雜環丁烷-3-基)甲基)-6-(3-羥基萘-1-基)喹喔啉-2(1H)-酮(15.16 mg)，為白色固體，產率20%。 ESI-MS: 468 [M+H]⁺ 。¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: ppm 9.94 (s, 1H), 8.31 (s, 1H), 8.09 (d, 1H,J = 2.4 Hz), 7.83 (s, 1H), 7.79 (d, 1H,J = 8.4 Hz), 7.44~7.40 (m, 1H), 7.24~7.22 (m, 3H), 7.01 (d, 1H,J = 2.4 Hz), 4.68~4.61 (m, 1H), 4.60~4.53 (m, 1H), 4.32~4.29 (m, 1H), 4.17~4.15 (m, 1H), 4.13~4.10 (m, 3H), 4.01~3.96 (m, 1H), 3.89~3.84 (m, 1H)。1-(azetidin- ₃ -ylmethyl)-7-chloro-6-(3-hydroxynaphthalen-1-yl)quinoxalin-2(1H)-one (64 mg, 0.16 mmol) was dissolved in dichloromethane (3 mL) and triethylamine (164 mg, 1.6 mmol) was added. After cooling to 0°C, a solution of chloroacetyl chloride (20 mg, 0.18 mmol) in dichloromethane (2 mL) was slowly added dropwise to the system and stirred at 0°C for 0.5 h. The system was separated and purified by prep-TLC (eluent: MeOH:DCM=10:1), the obtained crude product was dissolved in dimethylsulfite (DMSO) (2 mL), and then purified by C18 reverse phase column (Eluent: ACN:5 mmol/L NH ₄ HCO ₃ aqueous solution = 0 - 40%). Lyophilization yields 7-chloro-1-((1-(2-chloroacetyl)azetidin-3-yl)methyl)-6-(3-hydroxynaphthalen-1-yl)quinoxaline -2(1H)-one (15.16 mg) as a white solid, 20% yield. ESI-MS: 468 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 9.94 (s, 1H), 8.31 (s, 1H), 8.09 (d, 1H, J = 2.4 Hz), 7.83 (s, 1H), 7.79 (d, 1H, J = 8.4 Hz), 7.44~7.40 (m, 1H), 7.24~7.22 (m, 3H), 7.01 (d, 1H, J = 2.4 Hz), 4.68~4.61 (m, 1H), 4.60~4.53 (m, 1H), 4.32~4.29 (m, 1H), 4.17~4.15 (m, 1H), 4.13~4.10 (m, 3H), 4.01~3.96 (m, 1H), 3.89~3.84 (m , 1H).

實施例5：1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-7-氯-6-(8-甲基萘-1-基)喹喔啉-2(1H )-酮的合成

Example 5: 1-((1-Propenylazetidine-3-yl)methyl)-7-chloro-6-(8-methylnaphthalen-1-yl)quinoxaline-2( Synthesis of 1 H )-ketone

第一步：將1-溴-8-甲基萘(200 mg，0.9 mmol)溶解在異丙醇(5 mL)中，加入乙酸鉀(260 mg，2.7 mmol)，頻哪醇聯硼酸酯(348 mg，1.35 mmol)和Pd(dppf)Cl₂ (131 mg，0.18 mmol)。氮氣保護下加熱至80℃，攪拌1小時，反應液冷卻後過濾，濾液減壓濃縮，濃縮物經矽膠層析法(沖提液：石油醚:乙酸乙酯=10:1)分離純化，得到(8-甲基萘-1-基)硼酸頻哪醇酯(180 mg)，為白色固體，產率75%。ESI-MS: 269 [M+H]⁺ 。Step 1: Dissolve 1-bromo-8-methylnaphthalene (200 mg, 0.9 mmol) in isopropanol (5 mL), add potassium acetate (260 mg, 2.7 mmol), pinacol biborate (348 mg, 1.35 mmol) and Pd(dppf)Cl2 (131 _mg , 0.18 mmol). Heated to 80°C under nitrogen protection, stirred for 1 hour, the reaction solution was cooled and filtered, the filtrate was concentrated under reduced pressure, and the concentrate was separated and purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to obtain (8-Methylnaphthalen-1-yl)boronic acid pinacol ester (180 mg) as a white solid, 75% yield. ESI-MS: 269 [M+H] ⁺ .

第二步：將3-((6-溴-7-氯-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(150 mg，0.35 mmol)溶解在異丙醇(5 mL)中，加入碳酸鉀(138 mg，1.0 mmol)，(8-甲基萘-1-基)硼酸頻哪醇酯(113 mg，0.42 mmol)和Pd(dppf)Cl₂ (49 mg，0.07 mmol)。氮氣保護下加熱至80℃，攪拌1小時，反應液冷卻後過濾，濾液減壓濃縮，將濃縮物經矽膠層析法(沖提液：石油醚:乙酸乙酯=2:1)分離純化，得到3-((7-氯-6-(8-甲基萘-1-基)-2-氧代喹喔啉-1(2H )-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(80 mg)，為白色固體，產率48%。ESI-MS: 490 [M+H]⁺ 。The second step: tert-butyl 3-((6-bromo-7-chloro-2-oxoquinoxalin-1(2H)-yl)methyl)azetidine-1-carboxylate (150 mg, 0.35 mmol) was dissolved in isopropanol (5 mL), potassium carbonate (138 mg, 1.0 mmol), (8-methylnaphthalen-1-yl)boronic acid pinacol ester (113 mg, 0.42 mmol) was added and Pd(dppf)Cl2 (49 _mg , 0.07 mmol). It was heated to 80°C under nitrogen protection, stirred for 1 hour, the reaction solution was cooled and filtered, the filtrate was concentrated under reduced pressure, and the concentrate was separated and purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 2:1). 3-((7-Chloro-6-(8-methylnaphthalen-1-yl)-2-oxoquinoxalin-1( 2H )-yl)methyl)azetidine-1- tert-Butyl carboxylate (80 mg) as a white solid, 48% yield. ESI-MS: 490 [M+H] ⁺ .

第三步：將3-((7-氯-6-(8-甲基萘-1-基)-2-氧代喹喔啉-1(2H )-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(60 mg, 0.12 mmol)溶於二氯甲烷(2.5 mL)中，加入三氟乙酸(0.5 mL)，在室溫下攪拌1小時，然後減壓濃縮得到1-(氮雜環丁烷-3-基甲基)-7-氯-6-(8-甲基萘-1-基)喹喔啉-2(1H )-酮(40 mg)，為淡黃色固體，產率85%。ESI-MS: 390[M+H]⁺ 。The third step: 3-((7-chloro-6-(8-methylnaphthalene-1-yl)-2-oxoquinoxalin-1( 2H )-yl)methyl)azetidine Alkane-1-carboxylate tert-butyl ester (60 mg, 0.12 mmol) was dissolved in dichloromethane (2.5 mL), trifluoroacetic acid (0.5 mL) was added, stirred at room temperature for 1 hour, and then concentrated under reduced pressure to give 1 -(azetidin-3-ylmethyl)-7-chloro-6-(8-methylnaphthalen-1-yl)quinoxalin-2( 1H )-one (40 mg) as pale Yellow solid, 85% yield. ESI-MS: 390[M+H] ⁺ .

第四步：將1-(氮雜環丁烷-3-基甲基)-7-氯-6-(8-甲基萘-1-基)喹喔啉-2(1H )-酮(40 mg，0.1 mmol)溶解在二氯甲烷(1 mL)中，加入三乙胺(30mg，0.3 mmol)，在氮氣保護和-78℃條件下，緩慢滴加丙烯醯氯(14 mg，0.15 mmol)的二氯甲烷溶液(0.5 mL)，在-78℃攪拌10分鐘後繼續攪拌1小時，將反應液減壓濃縮，殘留物經prep-HPLC純化(沖提液：乙腈:水(5 mmol/L NH₄ HCO₃ ) =25%~45%)分離純化，得到1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-7-氯-6-(8-甲基萘-1-基)喹喔啉-2(1H )-酮(12 mg)，為淡黃色固體，產率26%。ESI-MS: 444.1 [M+H]⁺ 。¹ H NMR (400 MHz, DMSO-d6 ) δ 8.31 (d, J = 5.0 Hz, 1H), 7.97 (dd, J = 10.2, 2.3 Hz, 2H), 7.87 (dd, J = 10.4, 2.5 Hz, 2H), 7.51 (d, J = 2.3 Hz, 1H), 7.35 (dd, J = 10.4, 3.6 Hz, 1H), 7.29 (d, J = 3.5 Hz, 2H), 6.33 – 6.20 (m, 1H), 6.08 (t, J = 7.6 Hz, 1H), 5.70 – 5.56 (m, 1H), 4.58 (m, 2H), 4.28 (m, 1H), 4.11 (m, 1H), 3.97 (m, 1H), 3.82 (m, 1H), 3.11 (m, 1H), 1.97 (s, 3H)。The fourth step: 1-(azetidin-3-ylmethyl)-7-chloro-6-(8-methylnaphthalene-1-yl)quinoxalin-2( 1H )-one ( 40 mg, 0.1 mmol) was dissolved in dichloromethane (1 mL), triethylamine (30 mg, 0.3 mmol) was added, and under nitrogen protection at -78 °C, acrylonitrile chloride (14 mg, 0.15 mmol) was slowly added dropwise. ) in dichloromethane (0.5 mL), stirred at -78°C for 10 minutes and then continued to stir for 1 hour, the reaction solution was concentrated under reduced pressure, and the residue was purified by prep-HPLC (eluent: acetonitrile: water (5 mmol/ L NH ₄ HCO ₃ )=25%~45%) was separated and purified to obtain 1-((1-propenylazetidin-3-yl)methyl)-7-chloro-6-(8-methyl) Naphthalen-1-yl)quinoxalin-2( 1H )-one (12 mg) as a pale yellow solid, 26% yield. ESI-MS: 444.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d6 ) δ 8.31 (d, J = 5.0 Hz, 1H), 7.97 (dd, J = 10.2, 2.3 Hz, 2H), 7.87 (dd, J = 10.4, 2.5 Hz, 2H) ), 7.51 (d, J = 2.3 Hz, 1H), 7.35 (dd, J = 10.4, 3.6 Hz, 1H), 7.29 (d, J = 3.5 Hz, 2H), 6.33 – 6.20 (m, 1H), 6.08 (t, J = 7.6 Hz, 1H), 5.70 – 5.56 (m, 1H), 4.58 (m, 2H), 4.28 (m, 1H), 4.11 (m, 1H), 3.97 (m, 1H), 3.82 ( m, 1H), 3.11 (m, 1H), 1.97 (s, 3H).

實施例6：1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-7-氯-6-(6-氟-1H-吲哚-4-基)喹喔啉-2(1H)-酮的製備

Example 6: 1-((1-Propenylazetidin-3-yl)methyl)-7-chloro-6-(6-fluoro-1H-indol-4-yl)quinoxaline Preparation of -2(1H)-one

將1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-6-溴-7-氯喹喔啉-2(1H )-酮(60 mg，0.16 mmol)溶解在異丙醇(1 mL)中，加入碳酸鉀(66 mg，0.48 mmol)，6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1H-吲哚(46 mg，0.19 mmol)和Pd(dppf)Cl₂ (22 mg，0.03 mmol)。氮氣保護下加熱至80℃，攪拌1小時，反應液冷卻後過濾，濾液減壓濃縮，殘留物經prep-HPLC (沖提液：乙腈:水(5 mmol/L NH₄ HCO₃ )=20%~45%)分離純化，得到1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-7-氯-6-(6-氟-1H-吲哚-4-基)喹喔啉-2(1H )-酮(5.0 mg)，為淡黃色固體，產率7%。ESI-MS: 437.1 [M+H]⁺ 。¹ H NMR (400 MHz, DMSO-d 6) δ 11.34 (s, 1H), 8.26 (s, 1H), 8.06 (s, 1H), 7.83 (s, 1H), 7.36 (s, 1H), 7.24 (d, J = 9.7 Hz, 1H), 6.88 (d, J = 10.4 Hz, 1H), 6.35 – 6.19 (m, 1H), 6.07 (d, J = 18.7 Hz, 2H), 5.63 (d, J = 10.1 Hz, 1H), 4.55 (d, J = 7.6 Hz, 2H), 4.25 (t, J = 8.4 Hz, 1H), 4.08 (d, J = 8.8 Hz, 1H), 3.95 (t, J = 9.2 Hz, 1H), 3.79 (m, 1H), 3.12 (m, 1H)。1-((1-Propenylazetidin-3-yl)methyl)-6-bromo-7-chloroquinoxalin-2( 1H )-one (60 mg, 0.16 mmol) was dissolved in In isopropanol (1 mL), potassium carbonate (66 mg, 0.48 mmol), 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) were added Cyclopentan-2-yl)-lH-indole (46 mg, 0.19 mmol) and Pd(dppf)Cl2 ( ₂₂ mg, 0.03 mmol). It was heated to 80°C under nitrogen protection, stirred for 1 hour, the reaction solution was cooled and filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to prep-HPLC (eluent: acetonitrile: water (5 mmol/L NH ₄ HCO ₃ )=20% ~45%) was isolated and purified to obtain 1-((1-propenylazetidin-3-yl)methyl)-7-chloro-6-(6-fluoro-1H-indol-4-yl) ) quinoxalin-2( 1H )-one (5.0 mg) as a pale yellow solid in 7% yield. ESI-MS: 437.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d 6) δ 11.34 (s, 1H), 8.26 (s, 1H), 8.06 (s, 1H), 7.83 (s, 1H), 7.36 (s, 1H), 7.24 ( d, J = 9.7 Hz, 1H), 6.88 (d, J = 10.4 Hz, 1H), 6.35 – 6.19 (m, 1H), 6.07 (d, J = 18.7 Hz, 2H), 5.63 (d, J = 10.1 Hz, 1H), 4.55 (d, J = 7.6 Hz, 2H), 4.25 (t, J = 8.4 Hz, 1H), 4.08 (d, J = 8.8 Hz, 1H), 3.95 (t, J = 9.2 Hz, 1H), 3.79 (m, 1H), 3.12 (m, 1H).

實施例7：1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-7-氯-6-(1H-吲哚-4-基)喹喔啉-2(1H)-酮的製備

Example 7: 1-((1-Propenylazetidine-3-yl)methyl)-7-chloro-6-(1H-indol-4-yl)quinoxaline-2(1H )-ketone preparation

第一步：將3-((6-溴-7-氯-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(200 mg，0.47 mmol)溶於二氯甲烷(2.5 mL)中, 加入三氟乙酸(0.5 mL)，在室溫下攪拌1小時，然後減壓濃縮後得到1-(氮雜環丁烷-3-基)甲基)-6-溴-7-氯喹喔啉-2(1H )-酮(120 mg)，為淡黃色固體，產率78%。ESI-MS: 328, 330 [M+H]⁺ 。The first step: tert-butyl 3-((6-bromo-7-chloro-2-oxoquinoxalin-1(2H)-yl)methyl)azetidine-1-carboxylate (200 mg, 0.47 mmol) was dissolved in dichloromethane (2.5 mL), trifluoroacetic acid (0.5 mL) was added, stirred at room temperature for 1 hour, and then concentrated under reduced pressure to obtain 1-(azetidine-3- yl)methyl)-6-bromo-7-chloroquinoxalin-2( 1H )-one (120 mg) as a pale yellow solid in 78% yield. ESI-MS: 328, 330 [M+H] ⁺ .

第二步：將1-(氮雜環丁烷-3-基)甲基)-6-溴-7-氯喹喔啉-2(1H )-酮(120 mg，0.37 mmol)溶解在二氯甲烷(2 mL)中，加入三乙胺(112 mg，1.11 mmol)，在氮氣保護，-78℃下，緩慢滴加丙烯醯氯(40 mg，0.45 mmol)的二氯甲烷溶液(0.5 mL)，在-78℃攪拌10分鐘後繼續攪拌1小時，將反應液減壓濃縮，濃縮物經矽膠層析法(沖提液：二氯甲烷:甲醇=15:1)分離純化，得到1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-6-溴-7-氯喹喔啉-2(1H )-酮(120 mg)，為淡黃色固體，產率86%。ESI-MS: 382, 384 [M+H]⁺ 。Second step: 1-(azetidin-3-yl)methyl)-6-bromo-7-chloroquinoxalin-2( 1H )-one (120 mg, 0.37 mmol) was dissolved in dichloro In methane (2 mL), triethylamine (112 mg, 1.11 mmol) was added, and under nitrogen protection, at -78 °C, a dichloromethane solution (0.5 mL) of allyl chloride (40 mg, 0.45 mmol) was slowly added dropwise. , stirred at -78°C for 10 minutes and then continued to stir for 1 hour, the reaction solution was concentrated under reduced pressure, and the concentrate was separated and purified by silica gel chromatography (eluent: dichloromethane: methanol = 15: 1) to obtain 1-( (1-Propenylazetidin-3-yl)methyl)-6-bromo-7-chloroquinoxalin-2( 1H )-one (120 mg) as pale yellow solid, yield 86 %. ESI-MS: 382, 384 [M+H] ⁺ .

第三步：將1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-6-溴-7-氯喹喔啉-2(1H )-酮(60 mg，0.16 mmol)溶解在異丙醇(1 mL)中，加入碳酸鉀(66 mg，0.48 mmol)，4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1H-吲哚(45 mg，0.19 mmol)和Pd(dppf)Cl₂ (22 mg，0.03 mmol)。氮氣保護下加熱至80℃，攪拌1小時，反應液冷卻後過濾，濾液減壓濃縮，殘留物經prep-HPLC (沖提液：乙腈:水(5 mmol/L NH₄ HCO₃ )=20%~45%)分離純化，得到1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-7-氯-6-(1H-吲哚-4-基)喹喔啉-2(1H )-酮(8 mg)，為白色固體，產率12%。ESI-MS: 419.1 [M+H]⁺ 。¹ H NMR (400 MHz, DMSO-d6 ). δ 11.27 (s, 1H), 8.25 (s, 1H), 8.03 (s, 1H), 7.80 (s, 1H), 7.43 (s, 1H), 7.36 (s, 1H), 7.16 (d, J = 12.7 Hz, 1H), 6.97 (s, 1H), 6.26 (d, J = 16.7 Hz, 1H), 6.07 (d, J = 23.0 Hz, 2H), 5.63 (d, J = 12.4 Hz, 1H), 4.55 (s, 2H), 4.26 (m, 1H), 4.09 (d, J = 3.4 Hz, 1H), 3.94 (m, 1H), 3.82 (m, 1H), 3.13 (m, 1H)。The third step: 1-((1-propenylazetidine-3-yl)methyl)-6-bromo-7-chloroquinoxalin-2( 1H )-one (60 mg, 0.16 mmol) was dissolved in isopropanol (1 mL), potassium carbonate (66 mg, 0.48 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) were added Cyclopentan-2-yl)-lH-indole (45 mg, 0.19 mmol) and Pd(dppf)Cl2 ( ₂₂ mg, 0.03 mmol). It was heated to 80°C under nitrogen protection, stirred for 1 hour, the reaction solution was cooled and filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to prep-HPLC (eluent: acetonitrile: water (5 mmol/L NH ₄ HCO ₃ )=20% ~45%) separation and purification to obtain 1-((1-propenylazetidin-3-yl)methyl)-7-chloro-6-(1H-indol-4-yl)quinoxaline -2( 1H )-one (8 mg) as a white solid, 12% yield. ESI-MS: 419.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d6 ). δ 11.27 (s, 1H), 8.25 (s, 1H), 8.03 (s, 1H), 7.80 (s, 1H), 7.43 (s, 1H), 7.36 ( s, 1H), 7.16 (d, J = 12.7 Hz, 1H), 6.97 (s, 1H), 6.26 (d, J = 16.7 Hz, 1H), 6.07 (d, J = 23.0 Hz, 2H), 5.63 ( d, J = 12.4 Hz, 1H), 4.55 (s, 2H), 4.26 (m, 1H), 4.09 (d, J = 3.4 Hz, 1H), 3.94 (m, 1H), 3.82 (m, 1H), 3.13 (m, 1H).

實施例8：1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-6-(3-羥基萘-1-基)喹喔啉-2(1H)-酮的製備

Example 8: Synthesis of 1-((1-propenylazetidin-3-yl)methyl)-6-(3-hydroxynaphthalen-1-yl)quinoxalin-2(1H)-one preparation

第一步將6-溴喹喔啉-2(1H)-酮(600 mg，2.7 mmol)，3-(碘甲基)氮雜環丁烷-1-羧酸叔丁酯(1 g, 3.2 mmol)和碳酸鉀(1.12 g, 8.4 mmol)溶解在DMF(10 mL)中，混合液在50°C攪拌3小時。反應結束後，加入乙酸乙酯(30 mL)稀釋，用飽和食鹽水洗滌三次後，用無水硫酸鈉乾燥，減壓濃縮，濃縮物經矽膠層析法(沖提液：正己烷:乙酸乙酯=1:1)分離純化，得到3-((6-溴-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(0.3 g)，為白色固體，產率28%。ESI-MS: 394[M+H]⁺ 。The first step was 6-bromoquinoxalin-2(1H)-one (600 mg, 2.7 mmol), tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (1 g, 3.2 mmol) and potassium carbonate (1.12 g, 8.4 mmol) were dissolved in DMF (10 mL) and the mixture was stirred at 50°C for 3 hours. After the reaction was completed, ethyl acetate (30 mL) was added to dilute it, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was subjected to silica gel chromatography (eluent: n-hexane:ethyl acetate). =1:1) separation and purification to obtain tert-butyl 3-((6-bromo-2-oxoquinoxalin-1(2H)-yl)methyl)azetidine-1-carboxylate (0.3 g) as a white solid in 28% yield. ESI-MS: 394[M+H] ⁺ .

第二步將3-((6-溴-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(300 mg，0.76mmol)溶解在1,4-二氧六環/水(5mL/1 mL)中，加入碳酸鉀(318 mg，2.28 mmol)，4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)萘-2-醇(240 mg，0.76 mmol)和Pd(dppf)Cl₂ (56 mg，0.076 mmol)。氮氣保護下加熱至100℃，攪拌1小時，反應液冷卻後過濾，濾液減壓濃縮，將殘留物直接濃縮，濃縮物經矽膠層析法(沖提液：正己烷:乙酸乙酯=1:1)分離純化得3-((6-(3-羥基萘-1-基)-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(300 mg)，為白色固體，產率86.2%。ESI-MS: 458[M+H]⁺ 。The second step was tert-butyl 3-((6-bromo-2-oxoquinoxalin-1(2H)-yl)methyl)azetidine-1-carboxylate (300 mg, 0.76 mmol) Dissolve in 1,4-dioxane/water (5mL/1mL), add potassium carbonate (318 mg, 2.28 mmol), 4-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborol-2-yl)naphthalen- ₂ -ol (240 mg, 0.76 mmol) and Pd(dppf)Cl2 (56 mg, 0.076 mmol). It was heated to 100°C under nitrogen protection, stirred for 1 hour, the reaction solution was cooled and filtered, the filtrate was concentrated under reduced pressure, the residue was directly concentrated, and the concentrate was subjected to silica gel chromatography (eluent: n-hexane:ethyl acetate=1: 1) Separation and purification to obtain 3-((6-(3-hydroxynaphthalene-1-yl)-2-oxoquinoxalin-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-Butyl ester (300 mg) as a white solid, 86.2% yield. ESI-MS: 458[M+H] ⁺ .

第三步將3-((6-(3-羥基萘-1-基)-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(300 mg，0.72 mmol)溶於二氯甲烷(3 mL)中，加入三氟乙酸(0.6 mL)，在室溫下攪拌1小時，然後減壓濃縮得到粗產物1-(氮雜環丁烷-3-基甲基)-6-(3-羥基萘-1-基)喹喔啉-2(1H)-酮(250 mg)，為淡黃色固體，產率98%。ESI-MS: 358[M+H]⁺ 。In the third step, 3-((6-(3-hydroxynaphthalen-1-yl)-2-oxoquinoxalin-1(2H)-yl)methyl)azetidine-1-carboxylic acid tertiary Butyl ester (300 mg, 0.72 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (0.6 mL) was added, stirred at room temperature for 1 hour, and then concentrated under reduced pressure to obtain the crude product 1-(azacyclic Butan-3-ylmethyl)-6-(3-hydroxynaphthalen-1-yl)quinoxalin-2(1H)-one (250 mg) as a pale yellow solid, 98% yield. ESI-MS: 358[M+H] ⁺ .

第四步將1-(氮雜環丁烷-3-基甲基)-6-(3-羥基萘-1-基)喹喔啉-2(1H)-酮(250 mg, 0.70 mol)和三乙胺(220 mg, 2.1 mmol)溶於二氯甲烷(5ml)，然後在0°C下將丙烯醯氯(71 mg, 0.8 mmol)的二氯甲烷溶液(0.5 mL)滴加到反應液中。滴加完後在室溫下攪拌10分鐘，然後將反應液倒入到水中，用乙酸乙酯萃取，合併有機相後經無水硫酸鈉乾燥，過濾後減壓濃縮。殘留物經製備的TLC(DCM:CH₃ OH=10:1)純化，得到1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-6-(3-羥基萘-1-基)喹喔啉-2(1H)-酮(27 mg)，為白色固體，產率(10 %)。 ESI-MS: 412[M+H]⁺ 。¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.93(s, 1H), 8.33(s, 1H), 7.91 - 7.89 (m, 2H), 7.80 - 7.76(m, 2H),7.67 -.7.64(m,1 H) 7.45 - 7.42(m, 1H), 7.28 - 7.21 (m, 2H), 7.08 (d,J = 2 Hz, 1H), 6.35 - 6.28 (m, 1H), 6.13 - 6.08 (m, 1H), 5.68 - 5.65 (m, 1H), 4.62(d,J =7.48 Hz, 1H), 4.32 - 4.28 (m, 1H), 4.18 -4.14 (m, 1H), 4.02- 3.98 (m, 1H), 3.90- 3.86(m, 1H), 3.23 - 3.18 (m, 1H)。In the fourth step, 1-(azetidin-3-ylmethyl)-6-(3-hydroxynaphthalen-1-yl)quinoxalin-2(1H)-one (250 mg, 0.70 mol) and Triethylamine (220 mg, 2.1 mmol) was dissolved in dichloromethane (5 ml), then a dichloromethane solution (0.5 mL) of acryl chloride (71 mg, 0.8 mmol) was added dropwise to the reaction solution at 0°C middle. After the dropwise addition, the mixture was stirred at room temperature for 10 minutes, then the reaction solution was poured into water, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:CH3OH ₌ 10:1) to give 1-((1-propenylazetidin-3-yl)methyl)-6-(3-hydroxynaphthalene -1-yl)quinoxalin-2(1H)-one (27 mg) as a white solid, yield (10%). ESI-MS: 412[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.93(s, 1H), 8.33(s, 1H), 7.91 - 7.89 (m, 2H), 7.80 - 7.76(m, 2H), 7.67 -.7.64( m,1 H) 7.45 - 7.42(m, 1H), 7.28 - 7.21 (m, 2H), 7.08 (d, J = 2 Hz, 1H), 6.35 - 6.28 (m, 1H), 6.13 - 6.08 (m, 1H), 5.68 - 5.65 (m, 1H), 4.62(d, J =7.48 Hz, 1H), 4.32 - 4.28 (m, 1H), 4.18 -4.14 (m, 1H), 4.02- 3.98 (m, 1H) , 3.90- 3.86 (m, 1H), 3.23 - 3.18 (m, 1H).

實施例9：1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-7-氯-3-(2-(二甲基胺基)乙氧基)-6-(3-羥基萘-1-基)喹喔啉-2(1H)-酮的製備

Example 9: 1-((1-Propenylazetidine-3-yl)methyl)-7-chloro-3-(2-(dimethylamino)ethoxy)-6- Preparation of (3-hydroxynaphthalen-1-yl)quinoxalin-2(1H)-one

第一步 N₂ 環境下，將3-((6-溴-7-氯-2,3-二氧代-3,4-二氫喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(430 mg，0.97 mmol)，2-(二甲基胺基)乙醇(172 mg，1.93 mmol)，三苯基膦(508 mg，1.94 mmol)分散在四氫呋喃(THF)(8 mL)中。系統溫度降至0℃後，將偶氮二甲酸二異丙酯(392 mg，1.94 mmol)的四氫呋喃(THF)(2 mL)溶液緩慢滴加到系統中，緩慢升至室溫，於室溫攪拌16小時。系統減壓濃縮後用中壓flash矽膠層析法(沖提液：甲醇:二氯甲烷=0 – 10%)分離純化，得到3-((6-溴-7-氯-3-(2-(二甲基胺基)乙氧基)-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(170 mg)，為黃色固體，產率34%。ESI-MS:515、517[M+H]⁺ 。In the first step, under _N2 environment, 3-((6-bromo-7-chloro-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)methyl) nitrogen tert-Butyl tetracyclobutane-1-carboxylate (430 mg, 0.97 mmol), 2-(dimethylamino)ethanol (172 mg, 1.93 mmol), triphenylphosphine (508 mg, 1.94 mmol) were dispersed in tetrahydrofuran (THF) (8 mL). After the temperature of the system dropped to 0 °C, a solution of diisopropyl azodicarboxylate (392 mg, 1.94 mmol) in tetrahydrofuran (THF) (2 mL) was slowly added dropwise to the system, slowly warmed to room temperature, and kept at room temperature. Stir for 16 hours. After the system was concentrated under reduced pressure, it was separated and purified by medium pressure flash silica gel chromatography (eluent: methanol: dichloromethane = 0 – 10%) to obtain 3-((6-bromo-7-chloro-3-(2- (Dimethylamino)ethoxy)-2-oxoquinoxalin-1(2H)-yl)methyl)azetidine-1-carboxylate tert-butyl ester (170 mg) as yellow Solid, 34% yield. ESI-MS: 515, 517 [M+H] ⁺ .

第二步 N₂ 環境下，將3-((6-溴-7-氯-3-(2-(二甲基胺基)乙氧基)-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(170 mg，0.33 mmol)，4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環烷-2-基)萘-2-醇(107 mg，0.40 mmol)，[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(Pd(dppf)Cl₂ ，24 mg，0.033 mmol)，碳酸鉀(137 mg，0.99 mmol)分散在1,4-二氧六環/水(5:1，5 mL)中。加熱至100℃，攪拌2小時。系統減壓濃縮後用中壓flash矽膠層析法(沖提液：甲醇:二氯甲烷=0 - 10%)分離純化，得到3-((7-氯-3-(2-(二甲基胺基)乙氧基)-6-(3-羥基萘-1-基)-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(144 mg)，為黑色固體，產率75%。ESI-MS:579[M+H]⁺ 。In the second step, under _N2 environment, 3-((6-bromo-7-chloro-3-(2-(dimethylamino)ethoxy)-2-oxoquinoxaline-1(2H) -yl)methyl)azetidine-1-carboxylate tert-butyl ester (170 mg, 0.33 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxo Borin-2-yl)naphthalen-2-ol (107 mg, 0.40 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf) Cl2, ₂₄ mg, 0.033 mmol), potassium carbonate (137 mg, 0.99 mmol) were dispersed in 1,4-dioxane/water (5:1, 5 mL). Heat to 100°C and stir for 2 hours. After the system is concentrated under reduced pressure, it is separated and purified by medium pressure flash silica gel chromatography (eluent: methanol: dichloromethane=0-10%) to obtain 3-((7-chloro-3-(2-(dimethyl Amino)ethoxy)-6-(3-hydroxynaphthalen-1-yl)-2-oxoquinoxalin-1(2H)-yl)methyl)azetidine-1-carboxylic acid tertiary Butyl ester (144 mg) as a black solid, 75% yield. ESI-MS: 579[M+H] ⁺ .

第三步將3-((7-氯-3-(2-(二甲基胺基)乙氧基)-6-(3-羥基萘-1-基)-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(144 mg，0.25 mmol)溶解在二氯甲烷(6 mL)中。室溫下，緩慢滴加三氟乙酸(0.6 mL)，攪拌2小時，然後減壓濃縮得到1-(氮雜環丁烷-3-基甲基)-7-氯-3-(2-(二甲基胺基)乙氧基)-6-(3-羥基萘-1-基)喹喔啉-2(1H)-酮(119 mg)，為棕色固體，產率(100%)。ESI-MS:479[M+H]⁺ 。In the third step, 3-((7-chloro-3-(2-(dimethylamino)ethoxy)-6-(3-hydroxynaphthalen-1-yl)-2-oxoquinoxaline- 1(2H)-yl)methyl)azetidine-1-carboxylate tert-butyl ester (144 mg, 0.25 mmol) was dissolved in dichloromethane (6 mL). At room temperature, trifluoroacetic acid (0.6 mL) was slowly added dropwise, stirred for 2 hours, and then concentrated under reduced pressure to obtain 1-(azetidin-3-ylmethyl)-7-chloro-3-(2-( Dimethylamino)ethoxy)-6-(3-hydroxynaphthalen-1-yl)quinoxalin-2(1H)-one (119 mg) as a brown solid, yield (100%). ESI-MS: 479[M+H] ⁺ .

第四步 N₂ 環境下，將1-(氮雜環丁烷-3-基甲基)-7-氯-3-(2-(二甲基胺基)乙氧基)-6-(3-羥基萘-1-基)喹喔啉-2(1H)-酮(119 mg，0.25 mmol)溶解在二氯甲烷(4mL)中，加入三乙胺(252 mg, 2.5 mmol)。冷卻至0℃，將丙烯醯氯(25 mg，0.27 mmol)的二氯甲烷(1mL)溶液緩慢滴加到系統中，並於0℃攪拌0.5 小時。系統用prep-TLC (沖提液：MeOH:DCM=1:10)分離純化，得到的粗產物再用二甲基亞碸(DMSO)(2 mL)溶解後，用C18逆相管柱進行純化(沖提液：ACN:5 mmol/L NH₄ HCO₃ 水溶液=0 - 50%)。凍乾得1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-7-氯-3-(2-(二甲基胺基)乙氧基)-6-(3-羥基萘-1-基)喹喔啉-2(1H)-酮(12.23 mg)，為白色固體，產率9%。 ESI-MS: 533[M+H]⁺ 。¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: ppm 9.90 (s, 1H), 7.98 (d, 1H,J = 3.2 Hz), 7.78 (d, 1H,J = 8.4 Hz), 7.51 (s, 1H), 7.43~7.39 (m, 1H), 7.22~7.21 (m, 3H), 6.99 (d, 1H,J = 2.4 Hz), 6.32 (dd, 1H,J = 16.8, 10.0 Hz), 6.11 (dd, 1H,J = 13.2, 2.4 Hz), 5.67 (dd, 1H,J = 10.4, 2.4 Hz), 4.61 (d, 2H,J = 7.6 Hz), 4.43 (t, 2H,J = 6.0 Hz), 4.32~4.28 (m, 1H), 4.16~4.12 (m, 1H), 4.02~3.98 (m, 1H), 3.88~3.84 (m, 1H), 3.21~3.15 (m, 1H), 2.67 (t, 2H,J = 6.0 Hz), 2.21 (s, 6H)。In the fourth step, under _N2 environment, 1-(azetidin-3-ylmethyl)-7-chloro-3-(2-(dimethylamino)ethoxy)-6-(3 -Hydroxynaphthalen-1-yl)quinoxalin-2(1H)-one (119 mg, 0.25 mmol) was dissolved in dichloromethane (4 mL) and triethylamine (252 mg, 2.5 mmol) was added. After cooling to 0°C, a solution of acrylonitrile chloride (25 mg, 0.27 mmol) in dichloromethane (1 mL) was slowly added dropwise to the system and stirred at 0°C for 0.5 h. The system was separated and purified by prep-TLC (eluent: MeOH:DCM=1:10), the obtained crude product was dissolved in dimethylsulfoxide (DMSO) (2 mL), and purified by C18 reverse phase column (Eluent: ACN:5 mmol/L NH ₄ HCO ₃ aqueous solution = 0 - 50%). Lyophilized to obtain 1-((1-propenyl azetidine-3-yl)methyl)-7-chloro-3-(2-(dimethylamino)ethoxy)-6-( 3-Hydroxynaphthalen-1-yl)quinoxalin-2(1H)-one (12.23 mg) as a white solid, 9% yield. ESI-MS: 533[M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 9.90 (s, 1H), 7.98 (d, 1H, J = 3.2 Hz), 7.78 (d, 1H, J = 8.4 Hz), 7.51 (s , 1H), 7.43~7.39 (m, 1H), 7.22~7.21 (m, 3H), 6.99 (d, 1H, J = 2.4 Hz), 6.32 (dd, 1H, J = 16.8, 10.0 Hz), 6.11 ( dd, 1H, J = 13.2, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 4.61 (d, 2H, J = 7.6 Hz), 4.43 (t, 2H, J = 6.0 Hz), 4.32~4.28 (m, 1H), 4.16~4.12 (m, 1H), 4.02~3.98 (m, 1H), 3.88~3.84 (m, 1H), 3.21~3.15 (m, 1H), 2.67 (t, 2H) , J = 6.0 Hz), 2.21 (s, 6H).

實施例10：(S)-1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-7-氯-6-(3-羥基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)喹喔啉-2(1H)-酮的製備

Example 10: (S)-1-((1-Propenylazetidin-3-yl)methyl)-7-chloro-6-(3-hydroxynaphthalen-1-yl)-3- Preparation of ((1-methylpyrrolidin-2-yl)methoxy)quinoxalin-2(1H)-one

第一步 N₂ 環境下，將3-((6-溴-7-氯-2,3-二氧代-3,4-二氫喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(630 mg，1.42 mmol)，(S)-(1-甲基吡咯烷-2-基)甲醇(327mg，2.84 mmol)，三苯基膦(744 mg，2.84 mmol)分散在四氫呋喃(THF)(18 mL)中。系統溫度降至0℃後，將偶氮二甲酸二異丙酯(574 mg，2.84 mmol)的四氫呋喃(THF)(2 mL)溶液緩慢滴加到系統中，緩慢升至室溫，於室溫攪拌16小時。系統減壓濃縮後用中壓flash矽膠層析法(沖提液：甲醇:二氯甲烷=0 – 10%)分離純化，得到(S)-3-((6-溴-7-氯-3-((1-甲基吡咯烷-2-基)甲氧基)-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯和(S)-3-((6-溴-7-氯-4-((1-甲基吡咯烷-2-基)甲基)-2,3-二氧代-3,4-二氫喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯的混合物(750 mg)，為黃色固體，產率98%。ESI-MS:541, 543[M+H]⁺ 。In the first step, under _N2 environment, 3-((6-bromo-7-chloro-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)methyl) nitrogen tert-butyl tetracyclobutane-1-carboxylate (630 mg, 1.42 mmol), (S)-(1-methylpyrrolidin-2-yl)methanol (327 mg, 2.84 mmol), triphenylphosphine (744 mg, 2.84 mmol) in tetrahydrofuran (THF) (18 mL). After the temperature of the system dropped to 0 °C, a solution of diisopropyl azodicarboxylate (574 mg, 2.84 mmol) in tetrahydrofuran (THF) (2 mL) was slowly added dropwise to the system, slowly warmed to room temperature, and kept at room temperature. Stir for 16 hours. After the system was concentrated under reduced pressure, it was separated and purified by medium pressure flash silica gel chromatography (eluent: methanol: dichloromethane = 0 – 10%) to obtain (S)-3-((6-bromo-7-chloro-3 -((1-Methylpyrrolidin-2-yl)methoxy)-2-oxoquinoxalin-1(2H)-yl)methyl)azetidine-1-carboxylate tert-butyl ester and (S)-3-((6-bromo-7-chloro-4-((1-methylpyrrolidin-2-yl)methyl)-2,3-dioxo-3,4-dihydro A mixture of quinoxalin-1(2H)-yl)methyl)azetidine-1-carboxylate tert-butyl esters (750 mg) as a yellow solid in 98% yield. ESI-MS: 541, 543[M+H] ⁺ .

第二步 N₂ 環境下，將(S)-3-((6-溴-7-氯-3-((1-甲基吡咯烷-2-基)甲氧基)-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯和(S)-3-((6-溴-7-氯-4-((1-甲基吡咯烷-2-基)甲基)-2,3-二氧代-3,4-二氫喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯的混合物(400 mg，0.74 mmol)，4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)萘-2-醇(240 mg，0.89 mmol)，[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(Pd(dppf)Cl₂ ，54 mg，0.074 mmol)，碳酸鉀(306 mg，2.22 mmol)分散在1,4-二氧六環/水(5:1，6 mL)中。加熱至100℃，攪拌2小時。系統減壓濃縮後用中壓flash矽膠層析法(沖提液：甲醇:二氯甲烷=0 - 10%)分離純化，得到(S)-3-((7-氯-6-(3-羥基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(220 mg)，為黑色固體，產率49%。ESI-MS:605[M+H]⁺ 。In the second step _N2 environment, (S)-3-((6-bromo-7-chloro-3-((1-methylpyrrolidin-2-yl)methoxy)-2-oxoquine Oxalin-1(2H)-yl)methyl)azetidine-1-carboxylate tert-butyl ester and (S)-3-((6-bromo-7-chloro-4-((1-methyl) pyrrolidin-2-yl)methyl)-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)methyl)azetidine-1-carboxylic acid A mixture of tert-butyl esters (400 mg, 0.74 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)naphthalene-2 - alcohol (240 mg, 0.89 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (Pd(dppf)Cl2, 54 _mg , 0.074 mmol), potassium carbonate ( 306 mg, 2.22 mmol) dispersed in 1,4-dioxane/water (5:1, 6 mL). Heat to 100°C and stir for 2 hours. After the system is concentrated under reduced pressure, it is separated and purified by medium pressure flash silica gel chromatography (eluent: methanol: dichloromethane=0-10%) to obtain (S)-3-((7-chloro-6-(3- Hydroxynaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-2-oxoquinoxalin-1(2H)-yl)methyl)azetidine tert-Butyl alkane-1-carboxylate (220 mg) as a black solid, 49% yield. ESI-MS: 605[M+H] ⁺ .

第三步將(S)-3-((7-氯-6-(3-羥基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(220 mg，0.36 mmol)溶解在二氯甲烷(6 mL)中。室溫下，緩慢滴加三氟乙酸(0.6 mL)，攪拌2小時，然後減壓濃縮得到(S)-1-(氮雜環丁烷-3-基甲基)-7-氯-6-(3-羥基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)喹喔啉-2(1H)-酮(184 mg)，為棕色固體，產率(100%)。ESI-MS:505[M+H]⁺ 。In the third step, (S)-3-((7-chloro-6-(3-hydroxynaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-2 -Oxoquinoxalin-1(2H)-yl)methyl)azetidine-1-carboxylate tert-butyl ester (220 mg, 0.36 mmol) was dissolved in dichloromethane (6 mL). At room temperature, trifluoroacetic acid (0.6 mL) was slowly added dropwise, stirred for 2 hours, and then concentrated under reduced pressure to obtain (S)-1-(azetidin-3-ylmethyl)-7-chloro-6- (3-Hydroxynaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)quinoxalin-2(1H)-one (184 mg) as a brown solid, yielded rate (100%). ESI-MS: 505[M+H] ⁺ .

第四步 N₂ 環境下，將(S)-1-(氮雜環丁烷-3-基甲基)-7-氯-6-(3-羥基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)喹喔啉-2(1H)-酮(184 mg，0.36 mmol)溶解在二氯甲烷(4mL)中，加入三乙胺(401 mg, 4.0 mmol)。冷卻至0℃，將丙烯醯氯(40 mg，0.44 mmol)的二氯甲烷(2mL)溶液緩慢滴加到系統中，並於0℃攪拌0.5 小時。系統用prep-TLC (沖提液：MeOH:DCM=1:10)分離純化，得到的粗產物再用二甲基亞碸(DMSO)(2 mL)溶解後，用C18逆相管柱進行純化(沖提液：ACN:5 mmol/L NH₄ HCO₃ 水溶液=0 - 50%)。凍乾得到(S)-1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-7-氯-6-(3-羥基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)喹喔啉-2(1H)-酮(2.88 mg)，為白色固體，產率1%。 ESI-MS: 559[M+H]⁺ 。¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: ppm 9.94 (s, 1H), 7.97 (d, 1H,J = 3.2 Hz), 7.78 (d, 1H,J = 8.0 Hz), 7.51 (s, 1H), 7.43~7.39 (m, 1H), 7.22~7.21 (m, 3H), 6.99 (d, 1H,J = 2.0 Hz), 6.33 (dd, 1H,J = 16.8, 10.0 Hz), 6.11 (dd, 1H,J = 16.8, 2.4 Hz), 5.67 (dd, 1H,J = 10.4, 2.4 Hz), 4.61 (d, 2H,J = 7.6 Hz), 4.32~4.24 (m, 3H), 4.16~4.12 (m, 1H), 4.02~3.98 (m, 1H), 3.87~3.83 (m, 1H), 3.21~3.16 (m, 1H), 2.96~2.93 (m, 1H), 2.68~2.66 (m, 1H), 2.37 (d, 3H,J = 1.6 Hz), 2.20~2.16 (m, 2H), 2.02~1.94 (m, 2H), 1.70~1.62 (m, 1H)。 _The fourth step under N environment, (S)-1-(azetidin-3-ylmethyl)-7-chloro-6-(3-hydroxynaphthalene-1-yl)-3-(( 1-Methylpyrrolidin-2-yl)methoxy)quinoxalin-2(1H)-one (184 mg, 0.36 mmol) was dissolved in dichloromethane (4 mL) and triethylamine (401 mg, 0.36 mmol) was added. 4.0 mmol). After cooling to 0°C, a solution of acrylonitrile chloride (40 mg, 0.44 mmol) in dichloromethane (2 mL) was slowly added dropwise to the system and stirred at 0°C for 0.5 h. The system was separated and purified by prep-TLC (eluent: MeOH:DCM=1:10), the obtained crude product was dissolved in dimethylsulfite (DMSO) (2 mL), and purified by C18 reverse phase column (Eluent: ACN:5 mmol/L NH ₄ HCO ₃ aqueous solution = 0 - 50%). Lyophilization to give (S)-1-((1-propenylazetidin-3-yl)methyl)-7-chloro-6-(3-hydroxynaphthalen-1-yl)-3-( (1-Methylpyrrolidin-2-yl)methoxy)quinoxalin-2(1H)-one (2.88 mg) as a white solid, 1% yield. ESI-MS: 559[M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 9.94 (s, 1H), 7.97 (d, 1H, J = 3.2 Hz), 7.78 (d, 1H, J = 8.0 Hz), 7.51 (s , 1H), 7.43~7.39 (m, 1H), 7.22~7.21 (m, 3H), 6.99 (d, 1H, J = 2.0 Hz), 6.33 (dd, 1H, J = 16.8, 10.0 Hz), 6.11 ( dd, 1H, J = 16.8, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 4.61 (d, 2H, J = 7.6 Hz), 4.32~4.24 (m, 3H), 4.16~4.12 (m, 1H), 4.02~3.98 (m, 1H), 3.87~3.83 (m, 1H), 3.21~3.16 (m, 1H), 2.96~2.93 (m, 1H), 2.68~2.66 (m, 1H) , 2.37 (d, 3H, J = 1.6 Hz), 2.20~2.16 (m, 2H), 2.02~1.94 (m, 2H), 1.70~1.62 (m, 1H).

實施例11：(S)-1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-7-氟-6-(3-羥基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)喹喔啉-2(1H)-酮的製備

Example 11: (S)-1-((1-Propenylazetidin-3-yl)methyl)-7-fluoro-6-(3-hydroxynaphthalen-1-yl)-3- Preparation of ((1-methylpyrrolidin-2-yl)methoxy)quinoxalin-2(1H)-one

第一步 N₂ 環境下，將3-((6-溴-7-氟-2,3-二氧代-3,4-二氫喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(300 mg，0.70 mmol)，(S)-(1-甲基吡咯烷-2-基)甲醇(161 mg，1.40 mmol)，三苯基膦(367 mg，1.40 mmol)分散在四氫呋喃(THF)(5 mL)中。系統溫度降至0℃後，將偶氮二甲酸二異丙酯(283 mg，1.40 mmol)的四氫呋喃(THF)(1 mL)溶液緩慢滴加到系統中，緩慢升至室溫，於室溫攪拌16小時。系統減壓濃縮後用中壓flash矽膠層析法(沖提液：甲醇:二氯甲烷=0 – 10%)分離純化，得到(S)-3-((6-溴-7-氟-3-((1-甲基吡咯烷-2-基)甲氧基)-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯和(S)-3-((6-溴-7-氟-4-((1-甲基吡咯烷-2-基)甲基)-2,3-二氧代-3,4-二氫喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯的混合物(350 mg)，為黃色固體。混合物溶於二甲基亞碸(DMSO)(2 mL)後，用C18逆相管柱進行純化(沖提液：ACN:5 mmol/L NH₄ HCO₃ 水溶液=0 - 80%)。凍乾得到(S)-3-((6-溴-7-氟-3-((1-甲基吡咯烷-2-基)甲氧基)-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(110 mg)，為白色固體，產率30%。ESI-MS:525, 527[M+H]⁺ 。In the first step, under _N2 environment, 3-((6-bromo-7-fluoro-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)methyl) nitrogen tert-butyl tetracyclobutane-1-carboxylate (300 mg, 0.70 mmol), (S)-(1-methylpyrrolidin-2-yl)methanol (161 mg, 1.40 mmol), triphenylphosphine ( 367 mg, 1.40 mmol) was dispersed in tetrahydrofuran (THF) (5 mL). After the temperature of the system dropped to 0 °C, a solution of diisopropyl azodicarboxylate (283 mg, 1.40 mmol) in tetrahydrofuran (THF) (1 mL) was slowly added dropwise to the system, slowly warmed to room temperature, and kept at room temperature. Stir for 16 hours. After the system was concentrated under reduced pressure, it was separated and purified by medium pressure flash silica gel chromatography (eluent: methanol: dichloromethane = 0 – 10%) to obtain (S)-3-((6-bromo-7-fluoro-3 -((1-Methylpyrrolidin-2-yl)methoxy)-2-oxoquinoxalin-1(2H)-yl)methyl)azetidine-1-carboxylate tert-butyl ester and (S)-3-((6-bromo-7-fluoro-4-((1-methylpyrrolidin-2-yl)methyl)-2,3-dioxo-3,4-dihydro A mixture of quinoxalin-1(2H)-yl)methyl)azetidine-1-carboxylate tert-butyl esters (350 mg) as a yellow solid. The mixture was dissolved in dimethylsulfoxide (DMSO) (2 mL) and purified with a C18 reverse phase column (eluent: ACN: 5 mmol/L aqueous NH ₄ HCO ₃ = 0 - 80%). Lyophilization to give (S)-3-((6-bromo-7-fluoro-3-((1-methylpyrrolidin-2-yl)methoxy)-2-oxoquinoxaline-1(2H )-yl)methyl)azetidine-1-carboxylate tert-butyl ester (110 mg) as a white solid in 30% yield. ESI-MS: 525, 527[M+H] ⁺ .

第二步 N₂ 環境下，將(S)-3-((6-溴-7-氟-3-((1-甲基吡咯烷-2-基)甲氧基)-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(110 mg，0.21 mmol)，4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)萘-2-醇(68 mg，0.25 mmol)，四(三苯膦)鈀(Pd(PPh₃ )₄ ，24 mg，0.021 mmol)，碳酸鈉(67 mg，0.63 mmol)分散在1,4-二氧六環/水(4:1，5 mL)中。加熱至70℃，攪拌2小時。系統減壓濃縮後用中壓flash矽膠層析法(沖提液：含1%胺水的甲醇:二氯甲烷=0 - 10%)分離純化，得到(S)-3-((7-氟-6-(3-羥基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(100 mg)，為棕黑色固體，產率81%。ESI-MS:589[M+H]⁺ 。In the second step _N2 environment, (S)-3-((6-bromo-7-fluoro-3-((1-methylpyrrolidin-2-yl)methoxy)-2-oxoquine Oxalin-1(2H)-yl)methyl)azetidine-1-carboxylate tert-butyl ester (110 mg, 0.21 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborol-2-yl)naphthalen-2-ol (68 mg, 0.25 mmol), tetrakis(triphenylphosphine)palladium (Pd(PPh ₃ ) ₄ , 24 mg, 0.021 mmol), sodium carbonate (67 mg, 0.63 mmol) was dispersed in 1,4-dioxane/water (4:1, 5 mL). Heat to 70°C and stir for 2 hours. After the system is concentrated under reduced pressure, it is separated and purified by medium pressure flash silica gel chromatography (eluent: methanol containing 1% amine water: dichloromethane=0-10%) to obtain (S)-3-((7-fluoro -6-(3-Hydroxynaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-2-oxoquinoxalin-1(2H)-yl)methane base) tert-butyl azetidine-1-carboxylate (100 mg) as a brown-black solid in 81% yield. ESI-MS: 589[M+H] ⁺ .

第三步將(S)-3-((7-氟-6-(3-羥基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-羧酸叔丁酯(100 mg，0.17 mmol)溶解在二氯甲烷(5 mL)中。室溫下，緩慢滴加三氟乙酸(0.5 mL)，攪拌2小時，然後減壓濃縮得到(S)-1-(氮雜環丁烷-3-基甲基)-7-氟-6-(3-羥基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)喹喔啉-2(1H)-酮(83 mg)，為棕色固體，產率(100%)。ESI-MS:489[M+H]⁺ 。In the third step, (S)-3-((7-fluoro-6-(3-hydroxynaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-2 -Oxoquinoxalin-1(2H)-yl)methyl)azetidine-1-carboxylate tert-butyl ester (100 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL). At room temperature, trifluoroacetic acid (0.5 mL) was slowly added dropwise, stirred for 2 hours, and then concentrated under reduced pressure to obtain (S)-1-(azetidin-3-ylmethyl)-7-fluoro-6- (3-Hydroxynaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)quinoxalin-2(1H)-one (83 mg) as a brown solid, yielded rate (100%). ESI-MS: 489[M+H] ⁺ .

第四步 N₂ 環境下，將(S)-1-(氮雜環丁烷-3-基甲基)-7-氟-6-(3-羥基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)喹喔啉-2(1H)-酮(83 mg，0.17 mmol)溶解在二氯甲烷(4mL)中，加入三乙胺(172 mg, 1.7 mmol)。冷卻至0℃，將丙烯醯氯(17 mg，0.19 mmol)的二氯甲烷(2mL)溶液緩慢滴加到系統中，並於0℃攪拌0.5 小時。系統用prep-TLC (沖提液：NH₃ •H₂ O:MeOH:DCM=0.01:1:10)分離純化，得到的粗產物再用二甲基亞碸(DMSO)(2 mL)溶解後，用C18逆相管柱進行純化(沖提液：ACN:5 mmol/L NH₄ HCO₃ 水溶液=0 - 50%)。凍乾得到(S)-1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-7-氟-6-(3-羥基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)喹喔啉-2(1H)-酮(25.25 mg)，為白色固體，產率27%。 ESI-MS: 543[M+H]⁺ 。¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: ppm 9.96 (s, 1H), 7.83~7.78 (m, 2H), 7.57 (d, 1H,J = 7.6 Hz), 7.45~7.40 (m, 2H), 7.28~7.23 (m, 2H), 7.07 (d, 1H,J = 2.4 Hz), 6.33 (dd, 1H,J = 16.8, 10.0 Hz), 6.11 (dd, 1H,J = 16.8, 2.4 Hz), 5.67 (dd, 1H,J = 10.4, 2.4 Hz), 4.58 (d, 2H,J = 7.2 Hz), 4.32~4.24 (m, 3H), 4.16~4.13 (m, 1H), 4.02~3.97 (m, 1H), 3.88~3.84 (m, 1H), 3.20~3.17 (m, 1H), 2.96~2.93 (m, 1H), 2.66~2.63 (m, 1H), 2.38 (s, 3H), 2.20~2.17 (m, 2H), 2.01~1.94 (m, 2H), 1.71~1.62 (m, 1H)。In the fourth step _N2 environment, (S)-1-(azetidin-3-ylmethyl)-7-fluoro-6-(3-hydroxynaphthalene-1-yl)-3-(( 1-Methylpyrrolidin-2-yl)methoxy)quinoxalin-2(1H)-one (83 mg, 0.17 mmol) was dissolved in dichloromethane (4 mL) and triethylamine (172 mg, 0.17 mmol) was added. 1.7 mmol). After cooling to 0°C, a solution of acrylonitrile chloride (17 mg, 0.19 mmol) in dichloromethane (2 mL) was slowly added dropwise to the system and stirred at 0°C for 0.5 hours. The system was separated and purified by prep-TLC (eluent: NH ₃ ·H ₂ O:MeOH:DCM=0.01:1:10), and the obtained crude product was dissolved in dimethylsulfoxide (DMSO) (2 mL). , and purified by C18 reverse phase column (eluent: ACN: 5 mmol/L NH ₄ HCO ₃ aqueous solution=0-50%). Lyophilization to give (S)-1-((1-propenylazetidin-3-yl)methyl)-7-fluoro-6-(3-hydroxynaphthalen-1-yl)-3-( (1-Methylpyrrolidin-2-yl)methoxy)quinoxalin-2(1H)-one (25.25 mg) as a white solid, 27% yield. ESI-MS: 543[M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 9.96 (s, 1H), 7.83~7.78 (m, 2H), 7.57 (d, 1H, J = 7.6 Hz), 7.45~7.40 (m, 2H), 7.28~7.23 (m, 2H), 7.07 (d, 1H, J = 2.4 Hz), 6.33 (dd, 1H, J = 16.8, 10.0 Hz), 6.11 (dd, 1H, J = 16.8, 2.4 Hz) ), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 4.58 (d, 2H, J = 7.2 Hz), 4.32~4.24 (m, 3H), 4.16~4.13 (m, 1H), 4.02~3.97 ( m, 1H), 3.88~3.84 (m, 1H), 3.20~3.17 (m, 1H), 2.96~2.93 (m, 1H), 2.66~2.63 (m, 1H), 2.38 (s, 3H), 2.20~ 2.17 (m, 2H), 2.01~1.94 (m, 2H), 1.71~1.62 (m, 1H).

實施例12：(2S)-2-(((4-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-6-氯-7-(3-羥基萘-1-基)-3-氧代-3,4-二氫喹喔啉-2-基)胺基)甲基)-1-甲基吡咯烷-1-鎓2,2,2-三氟乙酸鹽的製備

Example 12: (2S)-2-(((4-((1-propenylazetidin-3-yl)methyl)-6-chloro-7-(3-hydroxynaphthalene-1- (yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)amino)methyl)-1-methylpyrrolidine-1-onium 2,2,2-trifluoroacetate preparation

第一步將3-((6-溴-7-氯-2,3-二氧代-3,4-二氫喹喔啉-1(2H )-基)甲基)氮雜環丁烷-1-甲酸叔丁酯(2.0 g，4.51 mmol)溶解在1,2-二氧乙烷(25 mL)中，加入氯化亞碸(5.32 g，45.1 mmol)，緩慢滴加N ,N -二甲基甲醯胺(330 mg，4.51 mmol)，室溫下攪拌直至溶液變為澄清，反應結束將反應液減壓濃縮，粗產物用三乙胺中和殘餘的氯化亞碸後，用矽膠層析法(沖提液：石油醚：乙酸乙酯=5:1)分離純化，得到3-((6-溴-3,7-二氯-2-氧代喹喔啉-1(2H )-基)甲基)氮雜環丁烷-1-甲酸叔丁酯(1.1 g)，為黃色固體。產率53%。ESI-MS: 462,464[M+H]⁺ 。In the first step, 3-((6-bromo-7-chloro-2,3-dioxo-3,4-dihydroquinoxalin-1( 2H )-yl)methyl)azetidine tert-Butyl-1-carboxylate (2.0 g, 4.51 mmol) was dissolved in 1,2-dioxoethane (25 mL), thionite chloride (5.32 g, 45.1 mmol) was added, and N , N- Dimethylformamide (330 mg, 4.51 mmol) was stirred at room temperature until the solution became clear. After the reaction was completed, the reaction solution was concentrated under reduced pressure. Silica gel chromatography (eluent: petroleum ether: ethyl acetate = 5:1) was separated and purified to obtain 3-((6-bromo-3,7-dichloro-2-oxoquinoxaline-1(2). H )-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (1.1 g) as a yellow solid. Yield 53%. ESI-MS: 462,464[M+H] ⁺ .

第二步將3-((6-溴-3,7-二氯-2-氧代喹喔啉-1(2H )-基)甲基)氮雜環丁烷-1-甲酸叔丁酯(150 mg，0.32 mmol)，N ,N -二異丙基乙胺(206 mg，1.6 mmol)和(S )-(1-甲基吡咯烷-2-基)甲胺(74 mg，0.64 mmol)均勻混合在一起，加熱至100℃攪拌1小時，反應液冷卻後，將反應液減壓濃縮，濃縮物經矽膠層析法(沖提液：二氯甲烷:甲醇=15:1)分離純化，得到(S )-3-((6-溴-7-氯-3-(((1-甲基吡咯烷-2-基)甲基)胺基)-2-氧代喹喔啉-1(2H )-基)甲基)氮雜環丁烷-1-甲酸叔丁酯(140 mg)，為淡黃色固體。產率81%。ESI-MS: 540,542[M+H]⁺ 。In the second step, tert-butyl 3-((6-bromo-3,7-dichloro-2-oxoquinoxalin-1( 2H )-yl)methyl)azetidine-1-carboxylate (150 mg, 0.32 mmol), N , N -diisopropylethylamine (206 mg, 1.6 mmol) and ( S )-(1-methylpyrrolidin-2-yl)methanamine (74 mg, 0.64 mmol) ) were evenly mixed together, heated to 100°C and stirred for 1 hour. After the reaction solution was cooled, the reaction solution was concentrated under reduced pressure, and the concentrate was separated and purified by silica gel chromatography (eluent: dichloromethane: methanol = 15:1). , to give ( S )-3-((6-bromo-7-chloro-3-(((1-methylpyrrolidin-2-yl)methyl)amino)-2-oxoquinoxaline-1 ( 2H )-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (140 mg) as a pale yellow solid. Yield 81%. ESI-MS: 540,542[M+H] ⁺ .

第三步將(S )-3-((6-溴-7-氯-3-(((1-甲基吡咯烷)-2-基)甲基)胺基)-2-氧代喹喔啉-1(2H )-基)甲基)氮雜環丁烷-1-甲酸叔丁酯(140 mg，0.26 mmol)溶於二氯甲烷(1 mL)中，加入三氟乙酸(0.2 mL)，在室溫下攪拌1小時，然後減壓濃縮得到(S )-1-(氮雜環丁烷-3-基甲基)-6-溴-7-氯-3-(((1-甲基吡咯烷-2-基)甲基)胺基)喹喔啉-2(1H )-酮(100 mg)，為淡黃色固體。產率83%。ESI-MS:440,442[M+H]⁺ 。The third step will ( S )-3-((6-bromo-7-chloro-3-(((1-methylpyrrolidin)-2-yl)methyl)amino)-2-oxoquinoxa Lin-1( 2H )-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (140 mg, 0.26 mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.2 mL) was added ), stirred at room temperature for 1 hour, and then concentrated under reduced pressure to give ( S )-1-(azetidin-3-ylmethyl)-6-bromo-7-chloro-3-((((1- Methylpyrrolidin-2-yl)methyl)amino)quinoxalin-2( 1H )-one (100 mg) as a pale yellow solid. Yield 83%. ESI-MS: 440,442 [M+H] ⁺ .

第四步將(S )-1-(氮雜環丁烷-3-基甲基)-6-溴-7-氯-3-(((1-甲基吡咯烷-2-基)甲基)胺基)喹喔啉-2(1H )-酮(100 mg，0.23 mmol)溶解在二氯甲烷(2 mL)中，加入三乙胺(70.0 mg，0.70 mmol)，在氮氣保護，-78℃下，緩慢滴加丙烯醯氯(25 mg，0.27 mmol)的二氯甲烷溶液(0.5 mL)，在-78℃下繼續攪拌1小時，將反應液減壓濃縮，濃縮物經矽膠層析法(沖提液：二氯甲烷:甲醇=15:1)分離純化，得到(S )-1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-6-溴-7-氯-3-(((1-甲基吡咯烷-2-基)甲基)胺基)喹喔啉-2(1H )-酮(85 mg)，為淡黃色固體。產率76%。ESI-MS:494,496[M+H]⁺ 。The fourth step will ( S )-1-(azetidin-3-ylmethyl)-6-bromo-7-chloro-3-(((1-methylpyrrolidin-2-yl)methyl )amino)quinoxalin-2( 1H )-one (100 mg, 0.23 mmol) was dissolved in dichloromethane (2 mL), triethylamine (70.0 mg, 0.70 mmol) was added, under nitrogen protection, - At 78°C, a solution of acrylonitrile chloride (25 mg, 0.27 mmol) in dichloromethane (0.5 mL) was slowly added dropwise, and stirring was continued for 1 hour at -78°C. The reaction solution was concentrated under reduced pressure, and the concentrate was subjected to silica gel chromatography method (eluent: dichloromethane: methanol = 15: 1) separation and purification to obtain ( S )-1-((1-propenylazetidine-3-yl)methyl)-6-bromo -7-Chloro-3-(((1-methylpyrrolidin-2-yl)methyl)amino)quinoxalin-2( 1H )-one (85 mg) as a pale yellow solid. Yield 76%. ESI-MS: 494,496[M+H] ⁺ .

第五步將(S )-1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-6-溴-7-氯-3-(((1-甲基吡咯烷-2-基)甲基)胺基)喹喔啉-2(1H )-酮(85 mg，0.17 mmol)溶解在異丙醇(2 mL)中，加入碳酸鉀(71 mg，0.51 mmol)，(3-羥基萘-1-基)硼酸(39 mg，0.2 mmol)和Pd(dppf)Cl₂ (25 mg，0.03 mmol)。氮氣保護下加熱至70℃，攪拌1小時，反應液冷卻後過濾，濾液減壓濃縮，殘留物經prep-HPLC (沖提液：乙腈:水(0.1% TFA)=25%~45%)分離純化，得到(2S)-2-(((4-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-6-氯-7-(3-羥基萘-1-基)-3-氧代-3,4-二氫喹喔啉-2-基)胺基)甲基)-1-甲基吡咯烷-1-鎓2,2,2-三氟乙酸鹽(50 mg)，為白色固體，產率44%。 ESI-MS: 558.2[M+H]⁺ ¹ H NMR (400 MHz, DMSO-d6 ) δ 9.91 (s, 1H), 9.24 (s, 1H), 8.20 (m, 1H), 7.85 (d, 1H), 7.73 (d, 1H), 7.37 (m, 2H), 7.21 (m, 2H), 6.95 (d, J = 16.2 Hz, 1H), 6.35 – 6.20 (m, 1H), 6.08 (d, J = 17.4 Hz, 1H), 5.69 – 5.51 (m, 1H), 4.60 (m, 2H), 4.30 (m, 1H), 4.11 (m, 1H), 3.97 (m, 1H), 3.85 (m, 1H), 3.77 – 3.45 (m, 4H), 3.16 (m, 1H), 3.05 (m, 1H), 2.94 (d, 3H),2.10 (m, 1H), 1.86 (m, 3H)。The fifth step will ( S )-1-((1-propenyl azetidine-3-yl) methyl)-6-bromo-7-chloro-3-((((1-methylpyrrolidine -2-yl)methyl)amino)quinoxalin-2( 1H )-one (85 mg, 0.17 mmol) was dissolved in isopropanol (2 mL) and potassium carbonate (71 mg, 0.51 mmol) was added , (3-hydroxynaphthalen-1-yl)boronic acid (39 mg, 0.2 mmol) and Pd(dppf)Cl2 ( ₂₅ mg, 0.03 mmol). Heated to 70°C under nitrogen protection, stirred for 1 hour, the reaction solution was cooled and filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by prep-HPLC (eluent: acetonitrile: water (0.1% TFA) = 25%~45%) Purification to give (2S)-2-(((4-((1-propenylazetidin-3-yl)methyl)-6-chloro-7-(3-hydroxynaphthalen-1-yl )-3-oxo-3,4-dihydroquinoxalin-2-yl)amino)methyl)-1-methylpyrrolidine-1-onium 2,2,2-trifluoroacetate (50 mg) as a white solid in 44% yield. ESI-MS: 558.2[M+H] ⁺ ¹ H NMR (400 MHz, DMSO- d6 ) δ 9.91 (s, 1H), 9.24 (s, 1H), 8.20 (m, 1H), 7.85 (d, 1H) , 7.73 (d, 1H), 7.37 (m, 2H), 7.21 (m, 2H), 6.95 (d, J = 16.2 Hz, 1H), 6.35 – 6.20 (m, 1H), 6.08 (d, J = 17.4 Hz, 1H), 5.69 – 5.51 (m, 1H), 4.60 (m, 2H), 4.30 (m, 1H), 4.11 (m, 1H), 3.97 (m, 1H), 3.85 (m, 1H), 3.77 – 3.45 (m, 4H), 3.16 (m, 1H), 3.05 (m, 1H), 2.94 (d, 3H), 2.10 (m, 1H), 1.86 (m, 3H).

實施例13：1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-7-氯-3-(3-(二甲基胺基)氮雜環丁烷-1-基)-6-(3-羥基萘-1-基)喹喔啉-2(1H )-酮的製備

Example 13: 1-((1-Propenylazetidine-3-yl)methyl)-7-chloro-3-(3-(dimethylamino)azetidine-1 -yl)-6-(3-hydroxynaphthalen-1-yl)quinoxalin-2( 1H )-one

第一步將3-((6-溴-3,7-二氯-2-氧代喹喔啉-1(2H )-基)甲基)氮雜環丁烷-1-甲酸叔丁酯(120 mg，0.26 mmol)，N ,N -二異丙基乙胺(100 mg，0.78 mmol)和N ,N -二甲基氮雜環丁烷-3-胺(52 mg，0.52 mmol)均勻混合在一起，加熱至100℃攪拌1小時，反應液冷卻後，將反應液減壓濃縮，濃縮物經矽膠層析法(沖提液：二氯甲烷:甲醇=15:1)分離純化，得到3-((6-溴-7-氯-3-(3-(二甲基胺基)氮雜環丁烷-1-基)-2-氧代喹喔啉-1(2H )-基)甲基)氮雜環丁烷-1-甲酸叔丁酯(110 mg)，為白色固體，產率81%。ESI-MS: 526,528[M+H]⁺ 。The first step is tert-butyl 3-((6-bromo-3,7-dichloro-2-oxoquinoxalin-1( 2H )-yl)methyl)azetidine-1-carboxylate (120 mg, 0.26 mmol), N , N -diisopropylethylamine (100 mg, 0.78 mmol) and N , N -dimethylazetidin-3-amine (52 mg, 0.52 mmol) uniformly They were mixed together, heated to 100°C and stirred for 1 hour. After the reaction solution was cooled, the reaction solution was concentrated under reduced pressure. The concentrate was separated and purified by silica gel chromatography (eluent: dichloromethane: methanol = 15:1) to obtain 3-((6-Bromo-7-chloro-3-(3-(dimethylamino)azetidin-1-yl)-2-oxoquinoxalin-1( 2H )-yl )methyl)azetidine-1-carboxylate tert-butyl ester (110 mg) as a white solid in 81% yield. ESI-MS: 526,528[M+H] ⁺ .

第二步將3-((6-溴-7-氯-3-(3-(二甲基胺基)氮雜環丁烷-1-基)-2-氧代喹喔啉-1(2H )-基)甲基)氮雜環丁烷-1-甲酸叔丁酯(110 mg，0.21 mmol)溶解在二氯甲烷(2.5 mL)中，加入三氟乙酸(0.5 mL)，在室溫下攪拌1小時，然後減壓濃縮得到1-(氮雜環丁烷-3-基甲基)-6-溴-7-氯-3-(3-(二甲基胺基)氮雜環丁烷-1-基)喹喔啉-2(1H )-酮(75 mg)，為白色固體, 產率85%。ESI-MS: 426,428[M+H]⁺ 。In the second step, 3-((6-bromo-7-chloro-3-(3-(dimethylamino)azetidin-1-yl)-2-oxoquinoxaline-1(2 H )-yl)methyl) tert-butyl azetidine-1-carboxylate (110 mg, 0.21 mmol) was dissolved in dichloromethane (2.5 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was heated at room temperature was stirred for 1 hour under reduced pressure, and then concentrated under reduced pressure to give 1-(azetidin-3-ylmethyl)-6-bromo-7-chloro-3-(3-(dimethylamino)azetidine) Alk-1-yl)quinoxalin-2( 1H )-one (75 mg) as a white solid, 85% yield. ESI-MS: 426,428[M+H] ⁺ .

第三步將1-(氮雜環丁烷-3-基甲基)-6-溴-7-氯-3-(3-(二甲基胺基)氮雜環丁烷-1-基)喹喔啉-2(1H )-酮(75 mg，0.18 mmol)溶解在二氯甲烷(2 mL)中，加入三乙胺(55.0 mg，0.54 mmol)，在氮氣保護，-78℃下，緩慢滴加丙烯醯氯(20 mg，0.22 mmol)的二氯甲烷溶液(0.5 mL)，在-78℃下繼續攪拌1小時，將反應液減壓濃縮，濃縮物經矽膠層析法(沖提液：二氯甲烷:甲醇=15:1)分離純化，得到1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-6-溴-7-氯-3-(3-(二甲基胺基)氮雜環丁烷-1-基)喹喔啉-2(1H )-酮(80 mg)，為白色固體，產率95%。ESI-MS: 480,482[M+H]⁺ 。The third step will be 1-(azetidin-3-ylmethyl)-6-bromo-7-chloro-3-(3-(dimethylamino)azetidin-1-yl) Quinoxalin-2( 1H )-one (75 mg, 0.18 mmol) was dissolved in dichloromethane (2 mL), triethylamine (55.0 mg, 0.54 mmol) was added, and under nitrogen protection, at -78 °C, A solution of acrylonitrile chloride (20 mg, 0.22 mmol) in dichloromethane (0.5 mL) was slowly added dropwise, and stirring was continued for 1 hour at -78 °C. The reaction solution was concentrated under reduced pressure, and the concentrate was subjected to silica gel chromatography (elution extraction). Liquid: dichloromethane:methanol=15:1) separation and purification to obtain 1-((1-propenylazetidin-3-yl)methyl)-6-bromo-7-chloro-3-( 3-(Dimethylamino)azetidin-1-yl)quinoxalin-2( 1H )-one (80 mg) as a white solid, 95% yield. ESI-MS: 480,482[M+H] ⁺ .

第四步將1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-6-溴-7-氯-3-(3-(二甲基胺基)氮雜環丁烷-1-基)喹喔啉-2(1H )-酮(60mg，0.13 mmol)溶解在異丙醇(2 mL)中，加入碳酸鉀(52 mg，0.38 mmol)，(3-羥基萘-1-基)硼酸(32mg，0.15 mmol)和Pd(dppf)Cl₂ (18mg，0.03 mmol)。氮氣保護下加熱至70℃，攪拌1小時，反應液冷卻後過濾，濾液減壓濃縮，殘留物經prep-HPLC (沖提液：乙腈:水(10 mM NH₄ HCO₃ )=25%~45%)分離純化，得到1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-7-氯-3-(3-(二甲基胺基)氮雜環丁烷-1-基)-6-(3-羥基萘-1-基)喹喔啉-2(1H )-酮(23.0 mg)，為白色固體，產率34%。 ESI-MS: 544.2 [M+H]⁺ 。¹ H NMR (400 MHz, DMSO-d 6) δ 9.85 (s, 1H), 7.72 (m, 2H), 7.42 – 7.30 (m, 1H), 7.21 (s, 1H), 7.20 – 7.13 (m, 3H), 6.92 (s, 1H), 6.29 (dd, J = 16.9, 10.2 Hz, 1H), 6.07 (d, J = 16.7 Hz, 1H), 5.64 (d, J = 10.9 Hz, 1H), 4.50 (m, 3H), 4.27 (t, J = 8.5 Hz, 2H), 4.07 (d, J = 8.0 Hz, 2H), 3.95 (d, J = 9.1 Hz, 1H), 3.80 (d, J = 11.5 Hz, 2H), 3.10 (d, J = 18.3 Hz, 2H), 2.06 (s, 6H)。The fourth step will 1-((1-propenyl azetidine-3-yl) methyl)-6-bromo-7-chloro-3-(3-(dimethylamino) nitrogen heterocycle Butan-1-yl)quinoxalin-2( 1H )-one (60 mg, 0.13 mmol) was dissolved in isopropanol (2 mL), potassium carbonate (52 mg, 0.38 mmol) was added, (3-hydroxy Naphthalen-l-yl)boronic acid (32 mg, 0.15 mmol) and Pd(dppf)Cl2 ( ₁₈ mg, 0.03 mmol). It was heated to 70°C under nitrogen protection, stirred for 1 hour, the reaction solution was cooled and filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to prep-HPLC (eluent: acetonitrile: water (10 mM NH ₄ HCO ₃ ) = 25%~45% %) separation and purification to obtain 1-((1-propenyl azetidine-3-yl) methyl)-7-chloro-3-(3-(dimethylamino) azetidine -1-yl)-6-(3-hydroxynaphthalen-1-yl)quinoxalin-2( 1H )-one (23.0 mg) as a white solid, 34% yield. ESI-MS: 544.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d 6) δ 9.85 (s, 1H), 7.72 (m, 2H), 7.42 – 7.30 (m, 1H), 7.21 (s, 1H), 7.20 – 7.13 (m, 3H) ), 6.92 (s, 1H), 6.29 (dd, J = 16.9, 10.2 Hz, 1H), 6.07 (d, J = 16.7 Hz, 1H), 5.64 (d, J = 10.9 Hz, 1H), 4.50 (m , 3H), 4.27 (t, J = 8.5 Hz, 2H), 4.07 (d, J = 8.0 Hz, 2H), 3.95 (d, J = 9.1 Hz, 1H), 3.80 (d, J = 11.5 Hz, 2H) ), 3.10 (d, J = 18.3 Hz, 2H), 2.06 (s, 6H).

透過參考以上實施例化合物13的製備方法和使用不同的反應原料，製備了以下實施例化合物：實施例結構［M+H］⁺ ¹ HNMR 14

557.2 ¹ H NMR (400 MHz, DMSO-d6 ) δ7.96 (d, J = 12.1 Hz, 1H), 7.85 (m, 2H), 7.50 (m, 2H), 7.39 (t, J = 8.0 Hz 1H), 7.25 (m, 2H), 6.26 (m, 1H), 6.07 (m, 1H), 5.64 (dd, J = 12.5 2.0 Hz, 1H), 4.55 (m, 3H), 4.24 (m, 3H), 4.10 (m, 1H), 3.96 (m, 1H), 3.82 (m, 1H), 3.11 (m, 1H), 2.90 (m, 1H), 2.63 (m, 1H), 2.33 (s, 3H), 2.14 (m, 1H), 1.97 (s, 3H), 1.92 (m, 1H), 1.63 (m, 3H). 16

550.2 ¹ H NMR (600 MHz, DMSO-d6 ) δ 11.36 (s, 1H), 7.94 (d, 1H), 7.67(s, 1H), 7.39 (d, J = 4.8 Hz, 1H), 7.27 (dd, J = 11.8, 1.2 Hz, 1H), 6.89 (dd, J = 12.7, 4.2 Hz, 1H), 6.32 (dd, J = 20.4, 10.8 Hz,1H), 6.17– 6.03 (m, 2H), 5.66 – 5.67 (dd, J = 5.4, 3.6 Hz,1H), 4.59 (d, J = 8.2 Hz, 2H), 4.32 – 4.22 (m, 3H), 4.13 (m, 1H), 3.99 (t, J = 13.8 Hz,1H), 3.85 (dd, J = 10.2, 2.4 Hz, 1H), 3.16 (m, 1H), 2.96 (m, 2H), 2.68– 2.61 (m, 1H), 2.38 (s, 3H), 2.19 (m, 1H), 2.04 – 1.91 (m, 1H), 1.73 – 1.67 (m, 3H). 17

532.1 ¹ H NMR (600 MHz, DMSO-d6 ) δ 11.28 (s, 1H), 7.92 (s, 1H), 7.54 (s, 1H), 7.48 – 7.45 (m, 1H), 7.38 (d,J = 3.1 Hz, 1H), 7.19 (t,J = 7.7 Hz, 1H), 6.99 (m, 1H), 6.32 (dd, J = 16.9, 10.2 Hz, 1H), 6.16 – 6.08 (m, 2H), 5.67 (dd,J = 10.2, 2.3 Hz, 1H), 4.59 (d, J = 7.5 Hz, 2H), 4.33 – 4.22 (m, 3H), 4.16 – 4.10 (m, 1H), 3.99 (t, J = 9.4 Hz, 1H), 3.88 – 3.82 (m, 1H), 3.21 – 3.12 (m, 1H), 2.98 – 2.92 (m, 1H), 2.68 – 2.60 (m, 1H), 2.38 (s, 3H), 2.23 – 2.16 (m, 1H), 2.01 – 1.90 (m, 2H), 1.73 – 1.57 (m, 3H). 20

526.2 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 10.00 (s, 1H), 7.88 (s, 1H), 7.44 (s, 1H), 7.29~7.23 (m, 1H), 6.81 (d, 1H, J = 8.4 Hz), 6.76~6.71 (m, 1H), 6.31 (dd, 1H, J = 16.8, 10.0 Hz), 6.10 (dd, 1H, J = 16.8, 2.4 Hz), 5.66 (dd, 1H, J = 14.4, 2.4 Hz), 4.56 (d, 2H, J = 7.6 Hz), 4.30~4.26 (m, 3H), 4.13~4.09 (m, 1H), 4.00~3.96 (m, 1H), 3.85~3.81 (m, 1H), 3.16~3.09 (m, 1H), 2.98~2.93 (m, 1H), 2.68~2.63 (m, 1H), 2.39 (s, 3H), 1.99~1.96 (m, 2H), 1.70~1.66 (m, 3H)。 21

559.3 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 9.93 (s, 1H), 7.98 (d, 1H, J = 2.0 Hz), 7.78 (d, 1H, J = 8.4 Hz), 7.52 (s, 1H), 7.44~7.39 (m, 1H), 7.23~7.21 (m, 3H), 6.99 (d, 1H, J = 2.0 Hz), 6.33 (dd, 1H, J = 16.4, 10.0 Hz), 6.11 (dd, 1H, J = 16.8, 1.6 Hz), 5.67 (dd, 1H, J = 14.4, 2.4 Hz), 4.62 (d, 2H, J = 7.6 Hz), 4.33~4.29 (m, 3H), 4.16~4.12 (m, 1H), 4.03~3.98 (m, 1H), 3.88~3.84 (m, 1H), 3.23~3.15 (m, 1H), 3.04 (brs, 1H), 2.54~2.52 (m, 1H), 2.50~2.44 (m, 4 H), 2.03~1.98 (m, 1H), 1.75~1.63 (m, 3H)。 24

547.1 ¹ H NMR (400 MHz, DMSO-d6 ) δ 9.91 (s, 1H), 7.93 (d,J = 3.3 Hz, 1H), 7.74 (d,J = 8.3 Hz, 1H), 7.46 (s, 1H), 7.37 (m, 1H), 7.18 (m, 3H), 6.95 (d,J = 2.4 Hz, 1H), 6.26 (m, 1H), 6.07 (m, 1H), 5.64 (m, 1H), 4.57 (d,J = 7.5 Hz, 2H), 4.33 (t,J = 6.7 Hz, 2H), 4.26 (t,J = 8.5 Hz, 1H), 4.13 – 4.06 (m, 1H), 3.96 (t,J = 9.3 Hz, 1H), 3.82 (m, 1H), 3.08 (m, 1H), 2.30 (m, 2H), 2.09 (s, 6H), 1.94 – 1.80 (m, 2H). 25

575.3 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 9.93 (s, 1H), 7.98 (d, 1H, J = 3.2 Hz), 7.78 (d, 1H, J = 8.4 Hz), 7.51 (s, 1H), 7.44~7.39 (m, 1H), 7.22~7.21 (m, 3H), 6.99 (d, 1H, J = 2.4 Hz), 6.32 (dd, 1H, J = 17.2, 10.4 Hz), 6.11 (dd, 1H, J = 17.2, 2.4 Hz), 5.67 (dd, 1H, J = 10.0, 2.4 Hz), 4.61 (d, 2H, J = 7.6 Hz), 4.45 (t, 2H, J = 6.0 Hz), 4.30 (t, 1H, J = 8.8 Hz), 4.15~4.12 (m, 1H), 4.00 (t, 1H, J = 9.2 Hz), 3.85 (dd, 1H, J = 14.4, 5.6 Hz), 3.55 (t, 8H, J = 4.8 Hz), 3.21~3.15 (m, 1H), 2.74 (t, 2H, J = 6.0 Hz)。 26

532.2 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.87 (s, 1H), 7.81 (d,J = 2.2 Hz, 1H), 7.73 (d,J = 11.4 Hz, 1H), 7.37 (m, 1H), 7.29 (s, 1H), 7.18 (m, 3H), 6.93 (d,J = 2.4 Hz, 1H), 6.29 (m, 1H), 6.11 – 6.04 (m, 1H), 5.64 (m, 1H), 4.59 (m, 2H), 4.28 (m, 1H), 4.10 (m, 1H), 3.98 (m, 1H), 3.83 (m, 1H), 3.48 (m, 2H), 3.18 (m, 1H), 2.40 (m, 6H), 1.96 (m, 2H). 27

546.3 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.86 (s, 1H), 7.77 – 7.70 (m, 2H), 7.36 (m, 1H), 7.27 – 7.14 (m, 4H), 6.94 (d,J = 2.4 Hz, 1H), 6.28 (m, 1H), 6.07 (m, 1H), 5.63 (dd,J = 10.2, 2.4 Hz, 1H), 4.55 (m, 2H), 4.28 (t,J = 8.5 Hz, 1H), 4.15 – 4.06 (m, 1H), 4.01 – 3.79 (m, 4H), 3.17 (m, 4H), 2.42 (m, 2H), 2.11 (s, 6H). 28

558.3 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.90 (s, 1H), 7.76 (m, 2H), 7.40 (t,J = 7.8 Hz, 1H), 7.25 (s, 1H), 7.21 (m, 3H), 6.99 – 6.93 (m, 1H), 6.32 (m, 1H), 6.11 (m, 1H), 5.67 (d,J = 11.8 Hz, 1H), 4.67 (m, 1H), 4.59 – 4.47 (m, 2H), 4.31 (t,J = 9.4 Hz, 1H), 4.23 (m, 1H), 4.11 (m, 2H), 4.05 – 3.95 (m, 1H), 3.85 (m, 1H), 3.71 (m, 1H), 3.21 – 3.11 (m, 1H), 2.88 – 2.78 (m, 1H), 2.46 (m, 2H), 2.13 (s, 6H). 29

517.2 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 9.89 (s, 1H), 7.78~7.75 (m, 2H), 7.42~7.38 (m, 1H), 7.26 (s, 1H), 7.22~7.19 (m, 2H), 6.96 (d, 1H, J = 2.4 Hz), 6.33 (dd, 1H, J = 16.8, 10.0 Hz), 6.11 (dd, 1H, J = 17.2, 2.4 Hz), 5.71 (d, 1H, J = 6.0 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 5.32 (brs, 1H), 4.56~4.50 (m, 3H), 4.33~4.28 (m, 2H), 4.13~4.09 (m, 1H), 4.02~3.98 (m, 1H), 3.87~3.82 (m, 1H), 3.31~3.29 (m, 2H), 3.19~3.11 (m, 1H), 2.03~1.95 (m, 1H)。 30

544.2 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.78 (d,J = 2.9 Hz, 1H), 7.72 (d,J = 8.2 Hz, 1H), 7.52 (d,J = 7.3 Hz, 1H), 7.36 (m, 1H), 7.27 (s, 1H), 7.24 – 7.11 (m, 3H), 6.94 (m, 1H), 6.28 (m, 1H), 6.07 (m, 1H), 5.63 (dd,J = 10.3, 2.4 Hz, 1H), 4.58 (d,J = 7.5 Hz, 2H), 4.36 (m, 1H), 4.28 (t,J = 8.5 Hz, 1H), 4.13 – 4.04 (m, 1H), 3.97 (t,J = 9.3 Hz, 1H), 3.83 (m, 1H), 3.14 (m, 1H), 2.69 (m, 1H), 2.64 – 2.52 (m, 1H), 2.38 – 2.24 (m, 1H), 2.20 (d,J = 3.6 Hz, 3H), 2.12 (m, 1H), 1.97 – 1.88 (m, 1H), 1.83 (m, 1H). 31

558.3 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.84 (s, 1H), 7.82 – 7.68 (m, 2H), 7.51 (d,J = 8.2 Hz, 1H), 7.36 (m, 1H), 7.26 – 7.09 (m, 4H), 6.93 (d,J = 2.4 Hz, 1H), 6.28 (m, 1H), 6.07 (m, 1H), 5.63 (dd,J = 10.3, 2.4 Hz, 1H), 4.57 (d,J = 7.5 Hz, 2H), 4.28 (t,J = 8.5 Hz, 1H), 4.15 – 4.04 (m, 1H), 3.98 (t,J = 9.3 Hz, 1H), 3.83 (m, 2H), 3.14 (m, 1H), 2.71 – 2.61 (m, 2H), 2.10 (s, 3H), 1.95 – 1.81 (m, 2H), 1.75 (m, 2H), 1.63 (m, 2H). 32

586.2 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.88 (s, 1H), 7.82 (d,J = 2.7 Hz, 1H), 7.77 (d,J = 8.4 Hz, 1H), 7.67 (d,J = 8.1 Hz, 1H), 7.40 (m, 1H), 7.31 (s, 1H), 7.27 – 7.18 (m, 3H), 6.98 (m, 1H), 6.32 (m, 1H), 6.11 (m, 1H), 5.67 (dd,J = 10.3, 2.3 Hz, 1H), 4.62 (d,J = 7.5 Hz, 2H), 4.39 – 4.30 (m, 2H), 4.15 (m, 2H), 4.02 (t,J = 9.4 Hz, 1H), 3.92 – 3.78 (m, 2H), 3.24 – 3.05 (m, 2H), 2.65 (m, 1H), 1.99 (s, 3H), 1.93 – 1.82 (m, 2H), 1.62 (m, 1H), 1.51 – 1.44 (m, 1H). 33

558.3 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.86 (s, 1H), 7.78 (d,J = 2.9 Hz, 1H), 7.72 (m, 1H), 7.59 (t,J = 5.7 Hz, 1H), 7.36 (m, 1H), 7.26 (s, 1H), 7.23 – 7.09 (m, 3H), 6.94 (d,J = 2.4 Hz, 1H), 6.28 (m, 1H), 6.07 (m, 1H), 5.63 (dd,J = 10.3, 2.4 Hz, 1H), 4.58 (d,J = 7.5 Hz, 2H), 4.27 (t,J = 8.5 Hz, 1H), 4.13 – 4.06 (m, 1H), 3.97 (t,J = 9.3 Hz, 1H), 3.83 (m, 1H), 3.45 (m, 2H), 3.15 (m, 1H), 2.61 (m, 2H), 2.43 (m, 4H), 1.62 (m, 4H). 34

572.3 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.88 (s, 1H), 7.82 (d,J = 2.96 Hz, 1H), 7.79 - 7.74 (m, 1H), 7.61 - 7.50(m, 1H), 7.43 - 7.38 (m, 1H), 7.30 (s, 1H), 7.27 - 7.23 (m, 1H), 7.22 - 7.18 (m, 2H), 7.00 - 6.96 (m, 1H), 6.38 - 6.25 (m, 1H),6.15 - 6.06 (m, 1H), 5.88 - 5.63 (m, 1H), 4.61(d,J = 7.64 Hz, 2H), 4.32 (t,J = 8.44 Hz,1H), 4.16 -4.10 (m, 1H), 4.05 - 3.93 (m, 1H), 3.90 - 3.80 (m, 1H), 3.50- 3.44 (m, 2H), 3.25 -3.12 (m, 1H), 2.49 - 2.47 (m, 2H), 2.40 - 2.30 (m, 4H), 1.50 - 1.40(m, 4H), 1.39- 1.30 (m, 2H). 35

547.2 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 13.12 (s, 1H), 7.98 (d, 1H, J = 2.4 Hz), 7.52~7.46 (m, 3H), 7.33 (d, 1H, J = 8.4 Hz), 6.36~6.29 (m, 1H), 6.11 (dd, 1H, J = 16.8, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 4.60 (d, 2H, J = 7.6 Hz), 4.33~4.22 (m, 4H), 4.16~4.12 (m, 1H), 4.03~3.96 (m, 1H), 3.90~3.83 (m, 1H), 3.22~3.14 (m, 1H), 2.98~2.90 (m, 1H), 2.67~2.59 (m, 1H), 2.42~2.32 (m, 1H), 2.37 (s, 3H), 2.22~2.12 (m, 1H), 2.16 (s, 3H), 1.97~1.90 (m, 1H), 1.71~1.60 (m, 1H)。 36

556.2 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 9.93 (s, 1H), 7.98 (d, 1H, J = 3.2 Hz), 7.78 (d, 1H, J = 8.4 Hz), 7.69 (t, 1H, J = 1.2 Hz), 7.53 (s, 1H), 7.43~7.39 (m, 1H), 7.26 (t, 1H, J = 1.2 Hz), 7.23~7.21 (m, 3H), 6.99 (d, 1H, J = 2.4 Hz), 6.88 (t, 1H, J = 1.2 Hz), 6.32 (dd, 1H, J = 17.2, 10.4 Hz), 6.11 (dd, 1H, J = 16.8, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 4.62~4.60 (m, 4H), 4.43 (t, 2H, J = 5.2 Hz), 4.30 (t, 1H, J = 8.4 Hz), 4.14 (dd, 1H, J = 8.8, 5.6 Hz), 4.02~3.98 (m, 1H), 3.86 (dd, 1H, J = 10.4, 5.6 Hz), 3.21~3.14 (m, 1H)。 37

577.2 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 8.14 (dd, 1H, J = 8.4, 1.2 Hz), 8.07 (dd, 1H, J = 8.0, 1.2 Hz), 7.87 (d, 1H, J = 2.8 Hz), 7.68~7.61 (m, 2H), 7.55~7.51 (m, 2H), 7.41 (d, 1H, J = 7.2 Hz), 6.35~6.27 (m, 1H), 6.10 (dd, 1H, J = 16.8, 2.4 Hz), 5.67 (dd, 1H, J = 10.0, 2.4 Hz), 4.66~4.53 (m, 3H), 4.33~4.21 (m, 4H), 4.15~4.11 (m, 1H), 4.03~3.95 (m, 1H), 3.87~3.83 (m, 1H), 3.17~3.10 (m, 1H), 2.97~2.92 (m, 1H), 2.68~2.62 (m, 1H), 2.37 (s, 3H), 2.22~2.16 (m, 1H), 2.02~1.91 (m, 1H), 1.71~1.59 (m, 1H)。 38

558.3 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 9.89 (s, 1H), 7.83 (d, 1H, J = 3.2 Hz), 7.76 (d, 1H, J = 8.4 Hz), 7.42~7.38 (m, 2H), 7.31 (s, 1H), 7.26~7.22 (m, 1H), 7.20~7.19 (m, 1H), 6.97 (d, 1H, J = 2.4 Hz), 6.32 (ddd, 1H, J = 16.8, 10.4, 1.6 Hz), 6.11 (dd, 1H, J = 17.2, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 4.62 (d, 2H, J = 7.6 Hz), 4.32 (t, 1H, J = 8.8 Hz), 4.16~4.10 (m, 2H), 4.02 (t, 1H, J = 9.2 Hz), 3.89~3.85 (m, 1H), 3.22~3.15 (m, 1H), 2.68~2.62 (m, 1H), 2.48~2.33 (m, 3H), 2.17 (d, 3H, J = 5.2 Hz), 2.13~2.08 (m, 1H), 1.66~1.58 (m, 2H), 1.55~1.46 (m, 2H)。 39

544.2 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 9.89 (s, 1H), 7.85 (d, 1H, J = 2.8 Hz), 7.77 (d, 1H, J = 8.0 Hz), 7.42~7.38 (m, 1H), 7.36 (s, 1H), 7.25~7.20 (m, 3H), 6.98 (d, 1H, J = 2.4 Hz), 6.33 (dd, 1H, J = 17.2, 10.8 Hz), 6.11 (dd, 1H, J = 16.8, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4Hz), 4.63~4.53 (m, 2H), 4.31 (t, 1H, J = 8.4 Hz), 4.14 (dd, 1H, J = 8.8, 5.6 Hz), 4.03~3.98 (m, 1H), 3.89~3.85 (m, 5H), 3.20~3.11 (m, 1H), 2.43 (t, 4H, J = 4.8 Hz), 2.20 (s, 3H)。 40

572.3 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.88 (s, 1H), 7.82 (d,J = 2.84 Hz, 1H), 7.80 - 7.70 (m, 1H), 7.45 - 7.37(m, 1H), 7.34 (s, 1H), 7.25 - 7.18 (m, 4H), 6.98 (d,J = 2.4 Hz, 1H), 6.38 - 6.29(m, 1H), 6.13 - 6.08(m, 1H), 5.68 - 5.55 (m, 1H), 4.85 - 4.75(m, 2H), 4.62 - 4.50 (m, 1H), 4.35 - 4.28 (m, 1H), 4.20 -4.10 (m, 1H), 4.05 - 3.90 (m, 1H), 3.88 - 3.85 (m, 1H), 3.20 - 3.10 (m, 1H), 2.99 - 2.90 (m, 2H), 2.17 (s, 6H), 1.85 - 1.80(m, 2H), 1.50 - 1.39(m, 3H) 41

559.2 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 9.95 (brs, 1H), 7.95 (d, 1H, J = 3.2 Hz), 7.77 (d, 1H, J = 8.4 Hz),7.49 (s, 1H), 7.43~7.39 (m, 1H), 7.24~7.19 (m, 3H), 6.99 (d, 1H, J = 2.0 Hz), 6.33 (dd, 1H, J = 16.8, 10.4 Hz), 6.11 (dd, 1H, J = 16.8, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 5.09~5.02 (m, 1H), 4.65~4.55 (m, 2H), 4.30 (t, 1H, J = 8.8 Hz), 4.15 (dd, 1H, J = 8.8, 5.2 Hz), 4.01 (t, 1H, J = 10.0 Hz), 3.86 (dd, 1H, J = 10.8, 5.6 Hz), 3.21~3.14 (m, 1H), 2.68~2.63 (m, 2H), 2.18~2.11 (m, 2H), 2.17 (s, 3H), 2.04~1.97 (m, 2H), 1.78~1.70 (m, 2H)。 43

543.2 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 9.90 (s, 1H), 8.31 (t, 1H, J = 6.4 Hz), 7.90 (d, 1H, J = 3.2 Hz), 7.77 (d, 1H, J = 8.0 Hz), 7.43~7.39 (m, 1H), 7.38 (s, 1H), 7.25~7.19 (m, 3H), 6.98 (d, 1H, J = 2.4 Hz), 6.33 (dd, 1H, J = 16.8, 10.4 Hz), 6.11 (dd, 1H, J = 17.2, 2.4 Hz), 5.68 (dd, 1H, J = 10.0, 2.4 Hz), 4.64 (d, 2H, J = 7.6 Hz), 4.33 (t, 1H, J = 8.4 Hz), 4.25~4.13 (m, 3H), 4.04~4.00 (m, 1H), 3.88 (dd, 1H, J = 10.4, 5.6 Hz), 3.26~3.15 (m, 1H)。 44

543.2 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 9.89 (s, 1H), 7.78~7.75 (m, 2H), 7.42~7.38 (m, 1H), 7.27 (s, 1H), 7.23~7.17 (m, 3H), 6.96 (d, 1H, J = 2.4 Hz), 6.32 (dd, 1H, J = 16.8, 10.4 Hz), 6.11 (dd, 1H, J = 16.8, 2.4 Hz), 5.68 (dd, 1H, J = 10.4, 2.4 Hz), 4.77~4.68 (m, 6H), 4.60~4.48 (m, 3H), 4.30 (t, 1H, J = 8.4 Hz), 4.26~4.20 (m, 1H), 4.13~4.09 (m, 1H), 4.01~3.96 (m, 1H), 3.86~3.82 (m, 1H), 3.18~3.11 (m, 1H)。 45

505.2 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.86 (s, 1H), 7.79 (d,J = 3.0 Hz, 1H), 7.73 (d,J = 8.3 Hz, 1H), 7.62 (t,J = 5.8 Hz, 1H), 7.37 (m, 1H), 7.29 – 7.11 (m, 4H), 6.94 (d,J = 2.4 Hz, 1H), 6.28 (m, 1H), 6.07 (m, 1H), 5.64 (dd,J = 10.3, 2.3 Hz, 1H), 4.78 (t,J = 5.5 Hz, 1H), 4.59 (d,J = 7.6 Hz, 2H), 4.28 (t,J = 8.5 Hz, 1H), 4.10 (m, 1H), 3.98 (t,J = 9.3 Hz, 1H), 3.83 (m, 1H), 3.55 (m, 2H), 3.42 (m, 2H), 3.22 – 3.06 (m, 1H). 46

558.2 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 9.88 (s, 1H), 7.77~7.75 (m, 2H), 7.42~7.38 (m, 1H), 7.26~7.18 (m, 4H), 6.97 (d, 1H, J = 2.4 Hz), 6.33 (dd, 1H, J = 16.8, 10.4 Hz), 6.11 (dd, 1H, J = 16.8, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 4.62~4.49 (m, 2H), 4.33~4.29 (m, 1H), 4.15~4.12 (m, 1H), 4.00 (t, 1H, J = 9.2 Hz), 3.89~3.85 (m, 1H), 3.32~3.29 (m, 2H), 3.20~3.15 (m, 1H), 2.72~2.63 (m, 1H), 2.19 (s, 6H), 2.12~1.97 (m, 2H), 1.79~1.65 (m, 2H)。 47

558.2 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 9.88 (s, 1H), 7.77~7.75 (m, 2H), 7.42~7.38 (m, 1H), 7.26~7.18 (m, 4H), 6.97 (d, 1H, J = 2.4 Hz), 6.33 (dd, 1H, J = 16.8, 10.4 Hz), 6.11 (dd, 1H, J = 16.8, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 4.62~4.49 (m, 2H), 4.31 (t, 1H, J = 8.4 Hz), 4.15~4.12 (m, 1H), 4.00 (t, 1H, J = 9.2 Hz), 3.89~3.85 (m, 1H), 3.32~3.29 (m, 2H), 3.20~3.15 (m, 1H), 2.74~2.65 (m, 1H), 2.19 (s, 6H), 2.12~1.97 (m, 2H), 1.79~1.65 (m, 2H)。 48

572.3 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 9.89 (s, 1H), 7.82 (d, 1H, J = 2.8 Hz), 7.77 (d, 1H, J = 8.4 Hz), 7.42~7.38 (m, 1H), 7.33 (s, 1H), 7.26~7.19 (m, 3H), 6.98~6.97 (m, 1H), 6.36~6.29 (m, 1H), 6.11 (dd, 1H, J = 16.8, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 4.85 ( m, 1H), 4.66~4.59 (m, 3H), 4.34~4.29 (m, 1H), 4.16~4.12 (m, 1H), 4.03~3.98 (m, 1H), 3.90~3.85 (m, 1H), 3.21~3.13 (m, 1H), 3.03~2.89 (m, 2H), 2.33~2.26 (m, 1H), 2.21 (d, 6H, J = 2.4 Hz), 1.90~1.87 (m, 1H), 1.79~1.75 (m, 1H), 1.52~1.45 (m, 2H)。 49

574.2 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 9.90 (s, 1H), 7.83 (d, 1H, J = 2.8 Hz), 7.77 (d, 1H, J = 8.4 Hz), 7.69~7.64 (m, 1H), 7.42~7.38 (m, 1H), 7.31 (s, 1H), 7.26~7.22 (m, 2H), 7.21~7.18 (m, 1H), 6.98 (d, 1H, J = 2.4 Hz), 6.32 (dd, 1H, J = 16.8, 10.4 Hz), 6.11 (dd, 1H, J = 17.2, 2.4 Hz), 5.68 (dd, 1H, J = 10.4, 2.4 Hz), 4.62 (d, 2H, J = 7.6 Hz), 4.32 (t, 1H, J = 8.4 Hz), 4.16~4.12 (m, 1H), 4.01 (t, 1H, J = 9.2 Hz), 3.87 (dd, 1H, J = 10.4, 5.6 Hz), 3.56~3.54 (m, 4H), 3.51~3.48 (m, 2H), 3.22~3.17 (m, 1H), 2.53~2.51 (m, 2H), 2.45~2.39 (m, 4H)。 50

546.3 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 9.90 (s, 1H), 7.99 (t, 1H, J = 6.0 Hz), 7.81 (d, 1H, J = 2.8 Hz), 7.76 (d, 1H, J = 8.4 Hz), 7.42~7.38 (m, 1H), 7.30~7.28 (m, 1H), 7.26~7.24 (m, 1H), 7.22~7.18 (m, 2H), 6.98 (d, 1H, J = 2.0 Hz), 6.32 (dd, 1H, J = 17.2, 10.0 Hz), 6.11 (dd, 1H, J = 16.8, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 4.62 (d, 2H, J = 7.6 Hz), 4.32 (t, 1H, J = 8.4 Hz), 4.15~4.11 (m, 1H), 4.01 (t, 1H, J = 9.2 Hz), 3.89~3.85 (m, 1H), 3.40 (dd, 2H, J = 13.2, 6.8 Hz), 3.22~3.15 (m, 1H), 2.26 (t, 2H, J = 6.8 Hz), 2.12 (s, 6H), 1.76~1.69 (m, 2H)。 51

572.3 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 9.90 (s, 1H), 7.88 (t, 1H, J = 6.0 Hz), 7.81 (d, 1H, J = 2.8 Hz), 7.76 (d, 1H, J = 8.4 Hz), 7.42~7.38 (m, 1H), 7.29 (s, 1H), 7.27~7.18 (m, 3H), 6.98 (d, 1H, J = 2.4 Hz), 6.32 (dd, 1H, J = 16.8, 10.4 Hz), 6.11 (dd, 1H, J = 17.2, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 4.62 (d, 2H, J = 7.6 Hz), 4.32 (t, 1H, J = 8.4 Hz), 4.16~4.12 (m, 1H), 4.04~3.99 (m, 1H), 3.89~3.86 (m, 1H), 3.31~3.26 (m, 2H), 3.24~3.17 (m, 2H), 2.68~2.64 (m, 1H), 2.57~2.52 (m, 2H), 2.09 (d, 3H, J = 1.6 Hz), 2.03~1.94 (m, 1H), 1.85~1.79 (m, 1H), 1.66~1.57 (m, 2H), 1.40~1.37 (m, 1H). 52

558.3 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 9.90 (s, 1H), 7.97 (t, 1H, J = 5.6 Hz), 7.82 (d, 1H, J = 2.8 Hz), 7.76 (d, 1H, J = 8.8 Hz), 7.42~7.38 (m, 1H), 7.30 (s, 1H), 7.26~7.19 (m, 3H), 6.97 (d, 1H, J = 2.4 Hz), 6.32 (dd, 1H, J = 16.8, 10.4 Hz), 6.11 (dd, 1H, J = 17.2, 2.4 Hz), 5.68 (dd, 1H, J = 10.4, 2.4 Hz), 4.62 (d, 2H, J = 7.6 Hz), 4.32 (t, 1H, J = 8.4 Hz), 4.14 (t, 1H, J = 7.2 Hz), 4.04~3.99 (m, 1H), 3.89~3.85 (m, 1H), 3.30~3.25 (m, 1H), 2.64~2.56 (m, 2H), 2.46~2.39 (m, 2H), 2.28 (s, 3H), 1.93~1.84 (m, 2H), 1.55~1.43 (m, 3H). 53

572.2 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 9.90 (s, 1H), 7.98 (t, 1H, J = 6.0 Hz), 7.81 (d, 1H, J = 2.8 Hz), 7.77 (d, 1H, J = 8.4 Hz), 7.42~7.39 (m, 1H), 7.28 (s, 1H), 7.27~7.25 (m, 1H), 7.23~7.18 (m, 2H), 6.98 (d, 1H, J = 2.4 Hz), 6.32 (dd, 1H, J = 17.2, 10.4 Hz), 6.11 (dd, 1H, J = 16.8, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 4.62 (d, 2H, J = 7.6 Hz), 4.32 (t, 1H, J = 8.4 Hz), 4.15~4.11 (m, 1H), 4.01 (t, 1H, J = 9.2 Hz), 3.89~3.85 (m, 1H), 3.41 (dd, 2H, J = 13.6, 6.8 Hz), 3.22~3.15 (m, 1H), 2.93~2.89 (m, 1H), 2.20 (s, 3H), 2.09~2.06 (m, 1H), 2.04~1.97 (m, 1H), 1.91~1.84 (m, 2H), 1.61~1.55 (m, 3H), 1.52~1.43 (m, 1H)。 54

552.2 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 9.87 (s, 1H), 8.52~8.50 (m, 1H), 8.37 (t, 1H, J = 6.0 Hz), 7.85 (d, 1H, J = 2.8 Hz), 7.76~7.71 (m, 2H), 7.41~7.37 (m, 2H), 7.27~7.17 (m, 5H), 6.95 (d, 1H, J = 2.4 Hz), 6.34 (dd, 1H, J = 16.8, 10.4 Hz), 6.12 (dd, 1H, J = 17.2, 2.4 Hz), 5.68 (dd, 1H, J = 10.4, 2.4 Hz), 4.70 (d, 2H, J = 6.0 Hz), 4.66 (d, 2H, J = 7.6 Hz), 4.34 (t, 1H, J = 8.4 Hz), 4.19~4.15 (m, 1H), 4.06~4.01 (m, 1H), 3.92~3.87 (m, 1H), 3.25~3.18 (m, 1H)。 55

580.3 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 9.89 (s, 1H), 7.83 (d, 1H, J = 3.2 Hz), 7.78~7.74 (m, 2H), 7.43~7.38 (m, 1H), 7.33 (s, 1H), 7.26~7.24 (m, 1H), 7.22~7.18 (m, 2H), 6.98 (d, 1H, J = 2.4 Hz), 6.32 (dd, 1H, J = 16.8, 10.4 Hz), 6.11 (dd, 1H, J = 16.8, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 4.62 (d, 2H, J = 7.6 Hz), 4.32 (t, 1H, J = 8.4 Hz), 4.16~4.12 (m, 1H), 4.04~3.99 (m, 1H), 3.89~3.85 (m, 1H), 3.61 (t, 4H, J = 12.4 Hz), 3.40~3.36 (m, 2H), 3.23~3.15 (m, 1H), 2.76 (t, 2H, J = 6.4 Hz). 56

553.2 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 9.87 (s, 1H), 8.78 (d, 2H, J = 4.8 Hz), 8.18 (t, 1H, J = 5.6 Hz), 7.85 (d, 1H, J = 2.8 Hz), 7.75 (d, 1H, J = 8.4 Hz), 7.41~7.37 (m, 2H), 7.24~7.17 (m, 4H), 6.95 (d, 1H, J = 2.4 Hz), 6.34 (dd, 1H, J = 16.8, 10.4 Hz), 6.12 (dd, 1H, J = 16.8, 2.4 Hz), 5.68 (dd, 1H, J = 10.4, 2.4 Hz), 4.80 (d, 2H, J = 5.6 Hz), 4.66 (d, 2H, J = 7.6 Hz), 4.34 (t, 1H, J = 8.4 Hz), 4.19~4.15 (m, 1H), 4.06~4.01 (m, 1H), 3.92~3.88 (m, 1H), 3.25~3.18 (m, 1H)。 57

572.3 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 9.92 (s, 1H), 8.24 (t, 1H, J = 6.0 Hz), 7.91 (d, 1H, J = 5.2 Hz), 7.77 (d, 1H, J = 8.4 Hz), 7.43~7.39 (m, 2H), 7.25~7.19 (m, 3H), 7.00~6.97 (m, 1H), 6.29 (dd, 1H, J = 16.8, 10.4 Hz), 6.08 (dd, 1H, J = 16.8, 2.4 Hz), 5.65 (dd, 1H, J = 10.0, 2.4 Hz), 4.58~4.47 (m, 2H), 4.33 (d, 1H, J = 8.8 Hz), 4.05 (d, 1H, J = 10.0 Hz), 3.92~3.89 (m, 1H), 3.82~3.78 (m, 1H), 3.76~3.72 (m, 1H), 3.64~3.53 (m, 3H), 3.10~3.02 (m, 1H), 2.94 (d, 3H, J = 4.8 Hz), 2.19~2.13 (m, 1H), 2.03~1.93 (m, 1H), 1.86~1.82 (m, 2H), 1.36 (s, 3H)。 60

620.3 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 10.15 (s, 1H), 8.26 (t, 1H, J = 6.4 Hz), 8.19~8.16 (m, 2H), 7.81 (s, 1H), 7.69 (d, 1H, J = 9.2 Hz), 7.65 (d, 1H, J = 7.6 Hz), 7.49 (s, 1H), 7.46 (d, 1H, J = 7.2 Hz), 6.35~6.27 (m, 1H), 6.11 (dd, 1H, J = 16.8, 2.4 Hz), 5.68 (dd, 1H, J = 10.4, 2.4 Hz), 4.73~4.54 (m, 2H), 4.33 (q, 1H, J = 8.4 Hz), 4.14 (dd, 1H, J = 8.8, 5.6 Hz), 4.01 (q, 1H, J = 8.8 Hz), 3.88 (dd, 1H, J = 10.0, 5.6 Hz), 3.83~3.68 (m, 2H), 3.58~3.50 (m, 2H), 3.21~3.13 (m, 3H), 2.18~2.11 (m, 2H), 2.08~1.97 (m, 2H), 1.94~1.85 (m, 4H)。 61

541.2 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 7.73 (s, 1H), 7.45 (brs, 1H), 7.17 (s, 1H), 7.14 (d, 1H, J = 8.4 Hz), 6.60 (dd, 1H, J = 8.8, 2.8 Hz), 6.48 (d, 1H, J = 2.8 Hz), 6.31 (dd, 1H, J = 16.8, 10.4 Hz), 6.10 (dd, 1H, J = 16.8, 2.4 Hz), 5.66 (dd, 1H, J = 10.0, 2.4 Hz), 5.34~5.32 (m, 2H), 4.57 (d, 2H, J = 7.6 Hz), 4.32~4.27 (m, 1H), 4.12~4.10 (m, 1H), 4.01~3.96 (m, 1H), 3.86~3.81 (m, 1H), 3.62~3.58 (m, 1H), 3.32~3.30 (m, 1H), 3.27~3.23 (m, 1H), 3.16~3.09 (m, 1H), 2.98~2.95 (m, 1H), 2.31 (s, 3H), 2.17~2.10 (m, 1H), 1.86~1.79 (m, 1H), 1.66~1.56 (m, 3H)。 62

542.2 ¹ H NMR (400 MHz, DMSO-d6 ) δ: ppm 9.85 (brs, 1H), 7.75 (s, 1H), 7.47~7.42 (m, 1H), 7.33 (d, 1H, J = 8.8 Hz), 7.21 (s, 1H), 6.84 (dd, 1H, J = 8.8, 2.8 Hz), 6.70 (d, 1H, J = 2.8 Hz), 6.31 (dd, 1H, J = 16.8, 10.4 Hz), 6.10 (dd, 1H, J = 16.8, 2.4 Hz), 5.66 (dd, 1H, J = 10.4, 2.4 Hz), 4.58~4.57 (m, 2H), 4.32~4.27 (m, 1H), 4.13~4.09 (m, 1H), 4.01~3.97 (m, 1H), 3.86~3.83 (m, 1H), 3.63~3.57 (m, 1H), 3.30~3.23 (m, 2H), 3.17~3.11 (m, 1H), 2.99~2.95 (m, 1H), 2.31 (s, 3H), 2.17~2.11 (m, 1H), 1.85~1.79 (m, 1H), 1.66~1.54 (m, 3H)。 By referring to the preparation method of Example Compound 13 above and using different reaction starting materials, the following example compounds were prepared:

Example structure [M+H] ⁺ ¹ HNMR 14

557.2 ¹ H NMR (400 MHz, DMSO- d6 ) δ7.96 (d, J = 12.1 Hz, 1H), 7.85 (m, 2H), 7.50 (m, 2H), 7.39 (t, J = 8.0 Hz 1H), 7.25 (m, 2H), 6.26 (m, 1H), 6.07 (m, 1H), 5.64 (dd, J = 12.5 2.0 Hz, 1H), 4.55 (m, 3H), 4.24 (m, 3H), 4.10 ( m, 1H), 3.96 (m, 1H), 3.82 (m, 1H), 3.11 (m, 1H), 2.90 (m, 1H), 2.63 (m, 1H), 2.33 (s, 3H), 2.14 (m , 1H), 1.97 (s, 3H), 1.92 (m, 1H), 1.63 (m, 3H). 16

550.2 ¹ H NMR (600 MHz, DMSO- d6 ) δ 11.36 (s, 1H), 7.94 (d, 1H), 7.67 (s, 1H), 7.39 (d, J = 4.8 Hz, 1H), 7.27 (dd, J = 11.8, 1.2 Hz, 1H), 6.89 (dd, J = 12.7, 4.2 Hz, 1H), 6.32 (dd, J = 20.4, 10.8 Hz, 1H), 6.17– 6.03 (m, 2H), 5.66 – 5.67 ( dd, J = 5.4, 3.6 Hz, 1H), 4.59 (d, J = 8.2 Hz, 2H), 4.32 – 4.22 (m, 3H), 4.13 (m, 1H), 3.99 (t, J = 13.8 Hz, 1H) ), 3.85 (dd, J = 10.2, 2.4 Hz, 1H), 3.16 (m, 1H), 2.96 (m, 2H), 2.68– 2.61 (m, 1H), 2.38 (s, 3H), 2.19 (m, 1H), 2.04 – 1.91 (m, 1H), 1.73 – 1.67 (m, 3H). 17

532.1 ¹ H NMR (600 MHz, DMSO- d6 ) δ 11.28 (s, 1H), 7.92 (s, 1H), 7.54 (s, 1H), 7.48 – 7.45 (m, 1H), 7.38 (d, J = 3.1 Hz , 1H), 7.19 (t, J = 7.7 Hz, 1H), 6.99 (m, 1H), 6.32 (dd, J = 16.9, 10.2 Hz, 1H), 6.16 – 6.08 (m, 2H), 5.67 (dd, J = 10.2, 2.3 Hz, 1H), 4.59 (d, J = 7.5 Hz, 2H), 4.33 – 4.22 (m, 3H), 4.16 – 4.10 (m, 1H), 3.99 (t, J = 9.4 Hz, 1H) ), 3.88 – 3.82 (m, 1H), 3.21 – 3.12 (m, 1H), 2.98 – 2.92 (m, 1H), 2.68 – 2.60 (m, 1H), 2.38 (s, 3H), 2.23 – 2.16 (m , 1H), 2.01 – 1.90 (m, 2H), 1.73 – 1.57 (m, 3H). 20

526.2 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 10.00 (s, 1H), 7.88 (s, 1H), 7.44 (s, 1H), 7.29~7.23 (m, 1H), 6.81 (d, 1H, J = 8.4 Hz), 6.76~6.71 (m, 1H), 6.31 (dd, 1H, J = 16.8, 10.0 Hz), 6.10 (dd, 1H, J = 16.8, 2.4 Hz), 5.66 (dd, 1H, J = 14.4, 2.4 Hz), 4.56 (d, 2H, J = 7.6 Hz), 4.30~4.26 (m, 3H), 4.13~4.09 (m, 1H), 4.00~3.96 (m, 1H), 3.85~3.81 ( m, 1H), 3.16~3.09 (m, 1H), 2.98~2.93 (m, 1H), 2.68~2.63 (m, 1H), 2.39 (s, 3H), 1.99~1.96 (m, 2H), 1.70~ 1.66 (m, 3H). twenty one

559.3 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 9.93 (s, 1H), 7.98 (d, 1H, J = 2.0 Hz), 7.78 (d, 1H, J = 8.4 Hz), 7.52 (s, 1H ), 7.44~7.39 (m, 1H), 7.23~7.21 (m, 3H), 6.99 (d, 1H, J = 2.0 Hz), 6.33 (dd, 1H, J = 16.4, 10.0 Hz), 6.11 (dd, 1H, J = 16.8, 1.6 Hz), 5.67 (dd, 1H, J = 14.4, 2.4 Hz), 4.62 (d, 2H, J = 7.6 Hz), 4.33~4.29 (m, 3H), 4.16~4.12 (m , 1H), 4.03~3.98 (m, 1H), 3.88~3.84 (m, 1H), 3.23~3.15 (m, 1H), 3.04 (brs, 1H), 2.54~2.52 (m, 1H), 2.50~2.44 (m, 4H), 2.03~1.98 (m, 1H), 1.75~1.63 (m, 3H). twenty four

547.1 ¹ H NMR (400 MHz, DMSO- d6 ) δ 9.91 (s, 1H), 7.93 (d, J = 3.3 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.46 (s, 1H), 7.37 (m, 1H), 7.18 (m, 3H), 6.95 (d, J = 2.4 Hz, 1H), 6.26 (m, 1H), 6.07 (m, 1H), 5.64 (m, 1H), 4.57 (d , J = 7.5 Hz, 2H), 4.33 (t, J = 6.7 Hz, 2H), 4.26 (t, J = 8.5 Hz, 1H), 4.13 – 4.06 (m, 1H), 3.96 (t, J = 9.3 Hz , 1H), 3.82 (m, 1H), 3.08 (m, 1H), 2.30 (m, 2H), 2.09 (s, 6H), 1.94 – 1.80 (m, 2H). 25

575.3 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 9.93 (s, 1H), 7.98 (d, 1H, J = 3.2 Hz), 7.78 (d, 1H, J = 8.4 Hz), 7.51 (s, 1H ), 7.44~7.39 (m, 1H), 7.22~7.21 (m, 3H), 6.99 (d, 1H, J = 2.4 Hz), 6.32 (dd, 1H, J = 17.2, 10.4 Hz), 6.11 (dd, 1H, J = 17.2, 2.4 Hz), 5.67 (dd, 1H, J = 10.0, 2.4 Hz), 4.61 (d, 2H, J = 7.6 Hz), 4.45 (t, 2H, J = 6.0 Hz), 4.30 ( t, 1H, J = 8.8 Hz), 4.15~4.12 (m, 1H), 4.00 (t, 1H, J = 9.2 Hz), 3.85 (dd, 1H, J = 14.4, 5.6 Hz), 3.55 (t, 8H , J = 4.8 Hz), 3.21~3.15 (m, 1H), 2.74 (t, 2H, J = 6.0 Hz). 26

532.2 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.87 (s, 1H), 7.81 (d, J = 2.2 Hz, 1H), 7.73 (d, J = 11.4 Hz, 1H), 7.37 (m, 1H) , 7.29 (s, 1H), 7.18 (m, 3H), 6.93 (d, J = 2.4 Hz, 1H), 6.29 (m, 1H), 6.11 – 6.04 (m, 1H), 5.64 (m, 1H), 4.59 (m, 2H), 4.28 (m, 1H), 4.10 (m, 1H), 3.98 (m, 1H), 3.83 (m, 1H), 3.48 (m, 2H), 3.18 (m, 1H), 2.40 (m, 6H), 1.96 (m, 2H). 27

546.3 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.86 (s, 1H), 7.77 – 7.70 (m, 2H), 7.36 (m, 1H), 7.27 – 7.14 (m, 4H), 6.94 (d, J = 2.4 Hz, 1H), 6.28 (m, 1H), 6.07 (m, 1H), 5.63 (dd, J = 10.2, 2.4 Hz, 1H), 4.55 (m, 2H), 4.28 (t, J = 8.5 Hz , 1H), 4.15 – 4.06 (m, 1H), 4.01 – 3.79 (m, 4H), 3.17 (m, 4H), 2.42 (m, 2H), 2.11 (s, 6H). 28

558.3 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.90 (s, 1H), 7.76 (m, 2H), 7.40 (t, J = 7.8 Hz, 1H), 7.25 (s, 1H), 7.21 (m, 3H), 6.99 – 6.93 (m, 1H), 6.32 (m, 1H), 6.11 (m, 1H), 5.67 (d, J = 11.8 Hz, 1H), 4.67 (m, 1H), 4.59 – 4.47 (m , 2H), 4.31 (t, J = 9.4 Hz, 1H), 4.23 (m, 1H), 4.11 (m, 2H), 4.05 – 3.95 (m, 1H), 3.85 (m, 1H), 3.71 (m, 1H), 3.21 – 3.11 (m, 1H), 2.88 – 2.78 (m, 1H), 2.46 (m, 2H), 2.13 (s, 6H). 29

517.2 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 9.89 (s, 1H), 7.78~7.75 (m, 2H), 7.42~7.38 (m, 1H), 7.26 (s, 1H), 7.22~7.19 ( m, 2H), 6.96 (d, 1H, J = 2.4 Hz), 6.33 (dd, 1H, J = 16.8, 10.0 Hz), 6.11 (dd, 1H, J = 17.2, 2.4 Hz), 5.71 (d, 1H , J = 6.0 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 5.32 (brs, 1H), 4.56~4.50 (m, 3H), 4.33~4.28 (m, 2H), 4.13~4.09 ( m, 1H), 4.02~3.98 (m, 1H), 3.87~3.82 (m, 1H), 3.31~3.29 (m, 2H), 3.19~3.11 (m, 1H), 2.03~1.95 (m, 1H). 30

544.2 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.78 (d, J = 2.9 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.36 (m, 1H), 7.27 (s, 1H), 7.24 – 7.11 (m, 3H), 6.94 (m, 1H), 6.28 (m, 1H), 6.07 (m, 1H), 5.63 (dd, J = 10.3 , 2.4 Hz, 1H), 4.58 (d, J = 7.5 Hz, 2H), 4.36 (m, 1H), 4.28 (t, J = 8.5 Hz, 1H), 4.13 – 4.04 (m, 1H), 3.97 (t , J = 9.3 Hz, 1H), 3.83 (m, 1H), 3.14 (m, 1H), 2.69 (m, 1H), 2.64 – 2.52 (m, 1H), 2.38 – 2.24 (m, 1H), 2.20 ( d, J = 3.6 Hz, 3H), 2.12 (m, 1H), 1.97 – 1.88 (m, 1H), 1.83 (m, 1H). 31

558.3 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.84 (s, 1H), 7.82 – 7.68 (m, 2H), 7.51 (d, J = 8.2 Hz, 1H), 7.36 (m, 1H), 7.26 – 7.09 (m, 4H), 6.93 (d, J = 2.4 Hz, 1H), 6.28 (m, 1H), 6.07 (m, 1H), 5.63 (dd, J = 10.3, 2.4 Hz, 1H), 4.57 (d , J = 7.5 Hz, 2H), 4.28 (t, J = 8.5 Hz, 1H), 4.15 – 4.04 (m, 1H), 3.98 (t, J = 9.3 Hz, 1H), 3.83 (m, 2H), 3.14 (m, 1H), 2.71 – 2.61 (m, 2H), 2.10 (s, 3H), 1.95 – 1.81 (m, 2H), 1.75 (m, 2H), 1.63 (m, 2H). 32

586.2 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.88 (s, 1H), 7.82 (d, J = 2.7 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.40 (m, 1H), 7.31 (s, 1H), 7.27 – 7.18 (m, 3H), 6.98 (m, 1H), 6.32 (m, 1H), 6.11 (m, 1H), 5.67 (dd, J = 10.3, 2.3 Hz, 1H), 4.62 (d, J = 7.5 Hz, 2H), 4.39 – 4.30 (m, 2H), 4.15 (m, 2H), 4.02 (t, J = 9.4 Hz) , 1H), 3.92 – 3.78 (m, 2H), 3.24 – 3.05 (m, 2H), 2.65 (m, 1H), 1.99 (s, 3H), 1.93 – 1.82 (m, 2H), 1.62 (m, 1H) ), 1.51 – 1.44 (m, 1H). 33

558.3 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.86 (s, 1H), 7.78 (d, J = 2.9 Hz, 1H), 7.72 (m, 1H), 7.59 (t, J = 5.7 Hz, 1H) , 7.36 (m, 1H), 7.26 (s, 1H), 7.23 – 7.09 (m, 3H), 6.94 (d, J = 2.4 Hz, 1H), 6.28 (m, 1H), 6.07 (m, 1H), 5.63 (dd, J = 10.3, 2.4 Hz, 1H), 4.58 (d, J = 7.5 Hz, 2H), 4.27 (t, J = 8.5 Hz, 1H), 4.13 – 4.06 (m, 1H), 3.97 (t , J = 9.3 Hz, 1H), 3.83 (m, 1H), 3.45 (m, 2H), 3.15 (m, 1H), 2.61 (m, 2H), 2.43 (m, 4H), 1.62 (m, 4H) . 34

572.3 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.88 (s, 1H), 7.82 (d, J = 2.96 Hz, 1H), 7.79 - 7.74 (m, 1H), 7.61 - 7.50 (m, 1H), 7.43 - 7.38 (m, 1H), 7.30 (s, 1H), 7.27 - 7.23 (m, 1H), 7.22 - 7.18 (m, 2H), 7.00 - 6.96 (m, 1H), 6.38 - 6.25 (m, 1H) ), 6.15 - 6.06 (m, 1H), 5.88 - 5.63 (m, 1H), 4.61(d, J = 7.64 Hz, 2H), 4.32 (t, J = 8.44 Hz, 1H), 4.16 -4.10 (m, 1H), 4.05 - 3.93 (m, 1H), 3.90 - 3.80 (m, 1H), 3.50- 3.44 (m, 2H), 3.25 -3.12 (m, 1H), 2.49 - 2.47 (m, 2H), 2.40 - 2.30 (m, 4H), 1.50 - 1.40(m, 4H), 1.39- 1.30 (m, 2H). 35

547.2 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 13.12 (s, 1H), 7.98 (d, 1H, J = 2.4 Hz), 7.52~7.46 (m, 3H), 7.33 (d, 1H, J = 8.4 Hz), 6.36~6.29 (m, 1H), 6.11 (dd, 1H, J = 16.8, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 4.60 (d, 2H, J = 7.6 Hz), 4.33~4.22 (m, 4H), 4.16~4.12 (m, 1H), 4.03~3.96 (m, 1H), 3.90~3.83 (m, 1H), 3.22~3.14 (m, 1H), 2.98~ 2.90 (m, 1H), 2.67~2.59 (m, 1H), 2.42~2.32 (m, 1H), 2.37 (s, 3H), 2.22~2.12 (m, 1H), 2.16 (s, 3H), 1.97~ 1.90 (m, 1H), 1.71~1.60 (m, 1H). 36

556.2 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 9.93 (s, 1H), 7.98 (d, 1H, J = 3.2 Hz), 7.78 (d, 1H, J = 8.4 Hz), 7.69 (t, 1H) , J = 1.2 Hz), 7.53 (s, 1H), 7.43~7.39 (m, 1H), 7.26 (t, 1H, J = 1.2 Hz), 7.23~7.21 (m, 3H), 6.99 (d, 1H, J = 2.4 Hz), 6.88 (t, 1H, J = 1.2 Hz), 6.32 (dd, 1H, J = 17.2, 10.4 Hz), 6.11 (dd, 1H, J = 16.8, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 4.62~4.60 (m, 4H), 4.43 (t, 2H, J = 5.2 Hz), 4.30 (t, 1H, J = 8.4 Hz), 4.14 (dd, 1H, J = 8.8, 5.6 Hz), 4.02~3.98 (m, 1H), 3.86 (dd, 1H, J = 10.4, 5.6 Hz), 3.21~3.14 (m, 1H). 37

577.2 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 8.14 (dd, 1H, J = 8.4, 1.2 Hz), 8.07 (dd, 1H, J = 8.0, 1.2 Hz), 7.87 (d, 1H, J = 2.8 Hz), 7.68~7.61 (m, 2H), 7.55~7.51 (m, 2H), 7.41 (d, 1H, J = 7.2 Hz), 6.35~6.27 (m, 1H), 6.10 (dd, 1H, J = 16.8, 2.4 Hz), 5.67 (dd, 1H, J = 10.0, 2.4 Hz), 4.66~4.53 (m, 3H), 4.33~4.21 (m, 4H), 4.15~4.11 (m, 1H), 4.03~ 3.95 (m, 1H), 3.87~3.83 (m, 1H), 3.17~3.10 (m, 1H), 2.97~2.92 (m, 1H), 2.68~2.62 (m, 1H), 2.37 (s, 3H), 2.22~2.16 (m, 1H), 2.02~1.91 (m, 1H), 1.71~1.59 (m, 1H). 38

558.3 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 9.89 (s, 1H), 7.83 (d, 1H, J = 3.2 Hz), 7.76 (d, 1H, J = 8.4 Hz), 7.42~7.38 (m , 2H), 7.31 (s, 1H), 7.26~7.22 (m, 1H), 7.20~7.19 (m, 1H), 6.97 (d, 1H, J = 2.4 Hz), 6.32 (ddd, 1H, J = 16.8 , 10.4, 1.6 Hz), 6.11 (dd, 1H, J = 17.2, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 4.62 (d, 2H, J = 7.6 Hz), 4.32 (t , 1H, J = 8.8 Hz), 4.16~4.10 (m, 2H), 4.02 (t, 1H, J = 9.2 Hz), 3.89~3.85 (m, 1H), 3.22~3.15 (m, 1H), 2.68~ 2.62 (m, 1H), 2.48~2.33 (m, 3H), 2.17 (d, 3H, J = 5.2 Hz), 2.13~2.08 (m, 1H), 1.66~1.58 (m, 2H), 1.55~1.46 ( m, 2H). 39

544.2 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 9.89 (s, 1H), 7.85 (d, 1H, J = 2.8 Hz), 7.77 (d, 1H, J = 8.0 Hz), 7.42~7.38 (m , 1H), 7.36 (s, 1H), 7.25~7.20 (m, 3H), 6.98 (d, 1H, J = 2.4 Hz), 6.33 (dd, 1H, J = 17.2, 10.8 Hz), 6.11 (dd, 1H, J = 16.8, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4Hz), 4.63~4.53 (m, 2H), 4.31 (t, 1H, J = 8.4 Hz), 4.14 (dd, 1H , J = 8.8, 5.6 Hz), 4.03~3.98 (m, 1H), 3.89~3.85 (m, 5H), 3.20~3.11 (m, 1H), 2.43 (t, 4H, J = 4.8 Hz), 2.20 ( s, 3H). 40

572.3 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.88 (s, 1H), 7.82 (d, J = 2.84 Hz, 1H), 7.80 - 7.70 (m, 1H), 7.45 - 7.37 (m, 1H), 7.34 (s, 1H), 7.25 - 7.18 (m, 4H), 6.98 (d, J = 2.4 Hz, 1H), 6.38 - 6.29(m, 1H), 6.13 - 6.08(m, 1H), 5.68 - 5.55 ( m, 1H), 4.85 - 4.75(m, 2H), 4.62 - 4.50 (m, 1H), 4.35 - 4.28 (m, 1H), 4.20 -4.10 (m, 1H), 4.05 - 3.90 (m, 1H), 3.88 - 3.85 (m, 1H), 3.20 - 3.10 (m, 1H), 2.99 - 2.90 (m, 2H), 2.17 (s, 6H), 1.85 - 1.80(m, 2H), 1.50 - 1.39(m, 3H) ) 41

559.2 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 9.95 (brs, 1H), 7.95 (d, 1H, J = 3.2 Hz), 7.77 (d, 1H, J = 8.4 Hz), 7.49 (s, 1H ), 7.43~7.39 (m, 1H), 7.24~7.19 (m, 3H), 6.99 (d, 1H, J = 2.0 Hz), 6.33 (dd, 1H, J = 16.8, 10.4 Hz), 6.11 (dd, 1H, J = 16.8, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 5.09~5.02 (m, 1H), 4.65~4.55 (m, 2H), 4.30 (t, 1H, J = 8.8 Hz), 4.15 (dd, 1H, J = 8.8, 5.2 Hz), 4.01 (t, 1H, J = 10.0 Hz), 3.86 (dd, 1H, J = 10.8, 5.6 Hz), 3.21~3.14 (m, 1H), 2.68~2.63 (m, 2H), 2.18~2.11 (m, 2H), 2.17 (s, 3H), 2.04~1.97 (m, 2H), 1.78~1.70 (m, 2H). 43

543.2 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 9.90 (s, 1H), 8.31 (t, 1H, J = 6.4 Hz), 7.90 (d, 1H, J = 3.2 Hz), 7.77 (d, 1H) , J = 8.0 Hz), 7.43~7.39 (m, 1H), 7.38 (s, 1H), 7.25~7.19 (m, 3H), 6.98 (d, 1H, J = 2.4 Hz), 6.33 (dd, 1H, J = 16.8, 10.4 Hz), 6.11 (dd, 1H, J = 17.2, 2.4 Hz), 5.68 (dd, 1H, J = 10.0, 2.4 Hz), 4.64 (d, 2H, J = 7.6 Hz), 4.33 ( t, 1H, J = 8.4 Hz), 4.25~4.13 (m, 3H), 4.04~4.00 (m, 1H), 3.88 (dd, 1H, J = 10.4, 5.6 Hz), 3.26~3.15 (m, 1H) . 44

543.2 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 9.89 (s, 1H), 7.78~7.75 (m, 2H), 7.42~7.38 (m, 1H), 7.27 (s, 1H), 7.23~7.17 ( m, 3H), 6.96 (d, 1H, J = 2.4 Hz), 6.32 (dd, 1H, J = 16.8, 10.4 Hz), 6.11 (dd, 1H, J = 16.8, 2.4 Hz), 5.68 (dd, 1H , J = 10.4, 2.4 Hz), 4.77~4.68 (m, 6H), 4.60~4.48 (m, 3H), 4.30 (t, 1H, J = 8.4 Hz), 4.26~4.20 (m, 1H), 4.13~ 4.09 (m, 1H), 4.01~3.96 (m, 1H), 3.86~3.82 (m, 1H), 3.18~3.11 (m, 1H). 45

505.2 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.86 (s, 1H), 7.79 (d, J = 3.0 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.62 (t, J = 5.8 Hz, 1H), 7.37 (m, 1H), 7.29 – 7.11 (m, 4H), 6.94 (d, J = 2.4 Hz, 1H), 6.28 (m, 1H), 6.07 (m, 1H), 5.64 ( dd, J = 10.3, 2.3 Hz, 1H), 4.78 (t, J = 5.5 Hz, 1H), 4.59 (d, J = 7.6 Hz, 2H), 4.28 (t, J = 8.5 Hz, 1H), 4.10 ( m, 1H), 3.98 (t, J = 9.3 Hz, 1H), 3.83 (m, 1H), 3.55 (m, 2H), 3.42 (m, 2H), 3.22 – 3.06 (m, 1H). 46

558.2 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 9.88 (s, 1H), 7.77~7.75 (m, 2H), 7.42~7.38 (m, 1H), 7.26~7.18 (m, 4H), 6.97 ( d, 1H, J = 2.4 Hz), 6.33 (dd, 1H, J = 16.8, 10.4 Hz), 6.11 (dd, 1H, J = 16.8, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz) ), 4.62~4.49 (m, 2H), 4.33~4.29 (m, 1H), 4.15~4.12 (m, 1H), 4.00 (t, 1H, J = 9.2 Hz), 3.89~3.85 (m, 1H), 3.32~3.29 (m, 2H), 3.20~3.15 (m, 1H), 2.72~2.63 (m, 1H), 2.19 (s, 6H), 2.12~1.97 (m, 2H), 1.79~1.65 (m, 2H) ). 47

558.2 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 9.88 (s, 1H), 7.77~7.75 (m, 2H), 7.42~7.38 (m, 1H), 7.26~7.18 (m, 4H), 6.97 ( d, 1H, J = 2.4 Hz), 6.33 (dd, 1H, J = 16.8, 10.4 Hz), 6.11 (dd, 1H, J = 16.8, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz) ), 4.62~4.49 (m, 2H), 4.31 (t, 1H, J = 8.4 Hz), 4.15~4.12 (m, 1H), 4.00 (t, 1H, J = 9.2 Hz), 3.89~3.85 (m, 1H), 3.32~3.29 (m, 2H), 3.20~3.15 (m, 1H), 2.74~2.65 (m, 1H), 2.19 (s, 6H), 2.12~1.97 (m, 2H), 1.79~1.65 ( m, 2H). 48

572.3 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 9.89 (s, 1H), 7.82 (d, 1H, J = 2.8 Hz), 7.77 (d, 1H, J = 8.4 Hz), 7.42~7.38 (m , 1H), 7.33 (s, 1H), 7.26~7.19 (m, 3H), 6.98~6.97 (m, 1H), 6.36~6.29 (m, 1H), 6.11 (dd, 1H, J = 16.8, 2.4 Hz ), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 4.85 (m, 1H), 4.66~4.59 (m, 3H), 4.34~4.29 (m, 1H), 4.16~4.12 (m, 1H), 4.03~3.98 (m, 1H), 3.90~3.85 (m, 1H), 3.21~3.13 (m, 1H), 3.03~2.89 (m, 2H), 2.33~2.26 (m, 1H), 2.21 (d, 6H) , J = 2.4 Hz), 1.90~1.87 (m, 1H), 1.79~1.75 (m, 1H), 1.52~1.45 (m, 2H). 49

574.2 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 9.90 (s, 1H), 7.83 (d, 1H, J = 2.8 Hz), 7.77 (d, 1H, J = 8.4 Hz), 7.69~7.64 (m , 1H), 7.42~7.38 (m, 1H), 7.31 (s, 1H), 7.26~7.22 (m, 2H), 7.21~7.18 (m, 1H), 6.98 (d, 1H, J = 2.4 Hz), 6.32 (dd, 1H, J = 16.8, 10.4 Hz), 6.11 (dd, 1H, J = 17.2, 2.4 Hz), 5.68 (dd, 1H, J = 10.4, 2.4 Hz), 4.62 (d, 2H, J = 7.6 Hz), 4.32 (t, 1H, J = 8.4 Hz), 4.16~4.12 (m, 1H), 4.01 (t, 1H, J = 9.2 Hz), 3.87 (dd, 1H, J = 10.4, 5.6 Hz) , 3.56~3.54 (m, 4H), 3.51~3.48 (m, 2H), 3.22~3.17 (m, 1H), 2.53~2.51 (m, 2H), 2.45~2.39 (m, 4H). 50

546.3 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 9.90 (s, 1H), 7.99 (t, 1H, J = 6.0 Hz), 7.81 (d, 1H, J = 2.8 Hz), 7.76 (d, 1H) , J = 8.4 Hz), 7.42~7.38 (m, 1H), 7.30~7.28 (m, 1H), 7.26~7.24 (m, 1H), 7.22~7.18 (m, 2H), 6.98 (d, 1H, J = 2.0 Hz), 6.32 (dd, 1H, J = 17.2, 10.0 Hz), 6.11 (dd, 1H, J = 16.8, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 4.62 (d , 2H, J = 7.6 Hz), 4.32 (t, 1H, J = 8.4 Hz), 4.15~4.11 (m, 1H), 4.01 (t, 1H, J = 9.2 Hz), 3.89~3.85 (m, 1H) , 3.40 (dd, 2H, J = 13.2, 6.8 Hz), 3.22~3.15 (m, 1H), 2.26 (t, 2H, J = 6.8 Hz), 2.12 (s, 6H), 1.76~1.69 (m, 2H ). 51

572.3 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 9.90 (s, 1H), 7.88 (t, 1H, J = 6.0 Hz), 7.81 (d, 1H, J = 2.8 Hz), 7.76 (d, 1H) , J = 8.4 Hz), 7.42~7.38 (m, 1H), 7.29 (s, 1H), 7.27~7.18 (m, 3H), 6.98 (d, 1H, J = 2.4 Hz), 6.32 (dd, 1H, J = 16.8, 10.4 Hz), 6.11 (dd, 1H, J = 17.2, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 4.62 (d, 2H, J = 7.6 Hz), 4.32 ( t, 1H, J = 8.4 Hz), 4.16~4.12 (m, 1H), 4.04~3.99 (m, 1H), 3.89~3.86 (m, 1H), 3.31~3.26 (m, 2H), 3.24~3.17 ( m, 2H), 2.68~2.64 (m, 1H), 2.57~2.52 (m, 2H), 2.09 (d, 3H, J = 1.6 Hz), 2.03~1.94 (m, 1H), 1.85~1.79 (m, 1H), 1.66~1.57 (m, 2H), 1.40~1.37 (m, 1H). 52

558.3 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 9.90 (s, 1H), 7.97 (t, 1H, J = 5.6 Hz), 7.82 (d, 1H, J = 2.8 Hz), 7.76 (d, 1H) , J = 8.8 Hz), 7.42~7.38 (m, 1H), 7.30 (s, 1H), 7.26~7.19 (m, 3H), 6.97 (d, 1H, J = 2.4 Hz), 6.32 (dd, 1H, J = 16.8, 10.4 Hz), 6.11 (dd, 1H, J = 17.2, 2.4 Hz), 5.68 (dd, 1H, J = 10.4, 2.4 Hz), 4.62 (d, 2H, J = 7.6 Hz), 4.32 ( t, 1H, J = 8.4 Hz), 4.14 (t, 1H, J = 7.2 Hz), 4.04~3.99 (m, 1H), 3.89~3.85 (m, 1H), 3.30~3.25 (m, 1H), 2.64 ~2.56 (m, 2H), 2.46~2.39 (m, 2H), 2.28 (s, 3H), 1.93~1.84 (m, 2H), 1.55~1.43 (m, 3H). 53

572.2 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 9.90 (s, 1H), 7.98 (t, 1H, J = 6.0 Hz), 7.81 (d, 1H, J = 2.8 Hz), 7.77 (d, 1H) , J = 8.4 Hz), 7.42~7.39 (m, 1H), 7.28 (s, 1H), 7.27~7.25 (m, 1H), 7.23~7.18 (m, 2H), 6.98 (d, 1H, J = 2.4 Hz), 6.32 (dd, 1H, J = 17.2, 10.4 Hz), 6.11 (dd, 1H, J = 16.8, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 4.62 (d, 2H , J = 7.6 Hz), 4.32 (t, 1H, J = 8.4 Hz), 4.15~4.11 (m, 1H), 4.01 (t, 1H, J = 9.2 Hz), 3.89~3.85 (m, 1H), 3.41 (dd, 2H, J = 13.6, 6.8 Hz), 3.22~3.15 (m, 1H), 2.93~2.89 (m, 1H), 2.20 (s, 3H), 2.09~2.06 (m, 1H), 2.04~1.97 (m, 1H), 1.91~1.84 (m, 2H), 1.61~1.55 (m, 3H), 1.52~1.43 (m, 1H). 54

552.2 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 9.87 (s, 1H), 8.52~8.50 (m, 1H), 8.37 (t, 1H, J = 6.0 Hz), 7.85 (d, 1H, J = 2.8 Hz), 7.76~7.71 (m, 2H), 7.41~7.37 (m, 2H), 7.27~7.17 (m, 5H), 6.95 (d, 1H, J = 2.4 Hz), 6.34 (dd, 1H, J = 16.8, 10.4 Hz), 6.12 (dd, 1H, J = 17.2, 2.4 Hz), 5.68 (dd, 1H, J = 10.4, 2.4 Hz), 4.70 (d, 2H, J = 6.0 Hz), 4.66 (d , 2H, J = 7.6 Hz), 4.34 (t, 1H, J = 8.4 Hz), 4.19~4.15 (m, 1H), 4.06~4.01 (m, 1H), 3.92~3.87 (m, 1H), 3.25~ 3.18 (m, 1H). 55

580.3 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 9.89 (s, 1H), 7.83 (d, 1H, J = 3.2 Hz), 7.78~7.74 (m, 2H), 7.43~7.38 (m, 1H) , 7.33 (s, 1H), 7.26~7.24 (m, 1H), 7.22~7.18 (m, 2H), 6.98 (d, 1H, J = 2.4 Hz), 6.32 (dd, 1H, J = 16.8, 10.4 Hz) ), 6.11 (dd, 1H, J = 16.8, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 4.62 (d, 2H, J = 7.6 Hz), 4.32 (t, 1H, J = 8.4 Hz), 4.16~4.12 (m, 1H), 4.04~3.99 (m, 1H), 3.89~3.85 (m, 1H), 3.61 (t, 4H, J = 12.4 Hz), 3.40~3.36 (m, 2H) ), 3.23~3.15 (m, 1H), 2.76 (t, 2H, J = 6.4 Hz). 56

553.2 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 9.87 (s, 1H), 8.78 (d, 2H, J = 4.8 Hz), 8.18 (t, 1H, J = 5.6 Hz), 7.85 (d, 1H) , J = 2.8 Hz), 7.75 (d, 1H, J = 8.4 Hz), 7.41~7.37 (m, 2H), 7.24~7.17 (m, 4H), 6.95 (d, 1H, J = 2.4 Hz), 6.34 (dd, 1H, J = 16.8, 10.4 Hz), 6.12 (dd, 1H, J = 16.8, 2.4 Hz), 5.68 (dd, 1H, J = 10.4, 2.4 Hz), 4.80 (d, 2H, J = 5.6 Hz), 4.66 (d, 2H, J = 7.6 Hz), 4.34 (t, 1H, J = 8.4 Hz), 4.19~4.15 (m, 1H), 4.06~4.01 (m, 1H), 3.92~3.88 (m , 1H), 3.25~3.18 (m, 1H). 57

572.3 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 9.92 (s, 1H), 8.24 (t, 1H, J = 6.0 Hz), 7.91 (d, 1H, J = 5.2 Hz), 7.77 (d, 1H , J = 8.4 Hz), 7.43~7.39 (m, 2H), 7.25~7.19 (m, 3H), 7.00~6.97 (m, 1H), 6.29 (dd, 1H, J = 16.8, 10.4 Hz), 6.08 ( dd, 1H, J = 16.8, 2.4 Hz), 5.65 (dd, 1H, J = 10.0, 2.4 Hz), 4.58~4.47 (m, 2H), 4.33 (d, 1H, J = 8.8 Hz), 4.05 (d , 1H, J = 10.0 Hz), 3.92~3.89 (m, 1H), 3.82~3.78 (m, 1H), 3.76~3.72 (m, 1H), 3.64~3.53 (m, 3H), 3.10~3.02 (m , 1H), 2.94 (d, 3H, J = 4.8 Hz), 2.19~2.13 (m, 1H), 2.03~1.93 (m, 1H), 1.86~1.82 (m, 2H), 1.36 (s, 3H). 60

620.3 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 10.15 (s, 1H), 8.26 (t, 1H, J = 6.4 Hz), 8.19~8.16 (m, 2H), 7.81 (s, 1H), 7.69 (d, 1H, J = 9.2 Hz), 7.65 (d, 1H, J = 7.6 Hz), 7.49 (s, 1H), 7.46 (d, 1H, J = 7.2 Hz), 6.35~6.27 (m, 1H) , 6.11 (dd, 1H, J = 16.8, 2.4 Hz), 5.68 (dd, 1H, J = 10.4, 2.4 Hz), 4.73~4.54 (m, 2H), 4.33 (q, 1H, J = 8.4 Hz), 4.14 (dd, 1H, J = 8.8, 5.6 Hz), 4.01 (q, 1H, J = 8.8 Hz), 3.88 (dd, 1H, J = 10.0, 5.6 Hz), 3.83~3.68 (m, 2H), 3.58 ~3.50 (m, 2H), 3.21~3.13 (m, 3H), 2.18~2.11 (m, 2H), 2.08~1.97 (m, 2H), 1.94~1.85 (m, 4H). 61

541.2 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 7.73 (s, 1H), 7.45 (brs, 1H), 7.17 (s, 1H), 7.14 (d, 1H, J = 8.4 Hz), 6.60 (dd , 1H, J = 8.8, 2.8 Hz), 6.48 (d, 1H, J = 2.8 Hz), 6.31 (dd, 1H, J = 16.8, 10.4 Hz), 6.10 (dd, 1H, J = 16.8, 2.4 Hz) , 5.66 (dd, 1H, J = 10.0, 2.4 Hz), 5.34~5.32 (m, 2H), 4.57 (d, 2H, J = 7.6 Hz), 4.32~4.27 (m, 1H), 4.12~4.10 (m , 1H), 4.01~3.96 (m, 1H), 3.86~3.81 (m, 1H), 3.62~3.58 (m, 1H), 3.32~3.30 (m, 1H), 3.27~3.23 (m, 1H), 3.16 ~3.09 (m, 1H), 2.98~2.95 (m, 1H), 2.31 (s, 3H), 2.17~2.10 (m, 1H), 1.86~1.79 (m, 1H), 1.66~1.56 (m, 3H) . 62

542.2 ¹ H NMR (400 MHz, DMSO- d6 ) δ: ppm 9.85 (brs, 1H), 7.75 (s, 1H), 7.47~7.42 (m, 1H), 7.33 (d, 1H, J = 8.8 Hz), 7.21 (s, 1H), 6.84 (dd, 1H, J = 8.8, 2.8 Hz), 6.70 (d, 1H, J = 2.8 Hz), 6.31 (dd, 1H, J = 16.8, 10.4 Hz), 6.10 (dd, 1H, J = 16.8, 2.4 Hz), 5.66 (dd, 1H, J = 10.4, 2.4 Hz), 4.58~4.57 (m, 2H), 4.32~4.27 (m, 1H), 4.13~4.09 (m, 1H) , 4.01~3.97 (m, 1H), 3.86~3.83 (m, 1H), 3.63~3.57 (m, 1H), 3.30~3.23 (m, 2H), 3.17~3.11 (m, 1H), 2.99~2.95 ( m, 1H), 2.31 (s, 3H), 2.17~2.11 (m, 1H), 1.85~1.79 (m, 1H), 1.66~1.54 (m, 3H).

實施例18：1-(1-丙烯醯基呱啶-4-基)-7-氯-3-(2-(二甲基胺基)乙氧基)-6-(3-羥基萘-1-基)喹喔啉-2(1H)-酮的製備

Example 18: 1-(1-Propenylpyridin-4-yl)-7-chloro-3-(2-(dimethylamino)ethoxy)-6-(3-hydroxynaphthalene-1 Preparation of -yl)quinoxalin-2(1H)-one

第一步將1-溴-2-氯-4-氟-5-硝基苯(2 g, 7.9 mmol)、4-胺基呱啶-1-羧酸叔丁酯(1.8g, 8.3 mmol)和三乙胺(2.4 g, 23.8 mmol)溶解於乙腈(20 mL)中，於60℃溫度下攪拌2h。待反應完畢後將反應液濃縮幹，加入水(20 mL)攪拌20分鐘,過濾棄濾液，固體烘乾得到4-((4-溴-5-氯-2-硝基苯基)胺基)呱啶-1-甲酸叔丁酯2.8克，為白色固體，產率為81.8%。ESI-MS: 434 [M+H]⁺ 。The first step was 1-bromo-2-chloro-4-fluoro-5-nitrobenzene (2 g, 7.9 mmol), tert-butyl 4-aminopyridine-1-carboxylate (1.8 g, 8.3 mmol) and triethylamine (2.4 g, 23.8 mmol) were dissolved in acetonitrile (20 mL) and stirred at 60 °C for 2 h. After the reaction was completed, the reaction solution was concentrated to dryness, water (20 mL) was added and stirred for 20 minutes, the filtrate was discarded by filtration, and the solid was dried to obtain 4-((4-bromo-5-chloro-2-nitrophenyl)amino) 2.8 g of tert-butyl pyridine-1-carboxylate as a white solid with a yield of 81.8%. ESI-MS: 434 [M+H] ⁺ .

第二步將4-((4-溴-5-氯-2-硝基苯基)胺基)呱啶-1-甲酸叔丁酯(2g, 4mmol)、氯化銨(647 mg, 11.5 mmol)及鐵粉(618 mg, 11.5 mmol)分散於乙醇(8 mL)和水(2 mL)的混合溶液中，反應於90℃攪拌2h。反應完畢後，將反應液冷卻到室溫後，用矽藻土層過濾，以乙醇洗滌固體三次。有機相濃縮，濃縮物經柱層析(DCM:EA=10:1)分離純化得4-((2-胺基-4-溴-5-氯苯基)胺基)呱啶-1-甲酸叔丁酯(0.6 g)，為白色固體，產率為64.5%。ESI-MS: 404 [M+H]⁺ 。In the second step, tert-butyl 4-((4-bromo-5-chloro-2-nitrophenyl) amino) pyridine-1-carboxylate (2 g, 4 mmol), ammonium chloride (647 mg, 11.5 mmol) ) and iron powder (618 mg, 11.5 mmol) were dispersed in a mixed solution of ethanol (8 mL) and water (2 mL), and the reaction was stirred at 90 °C for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through a celite layer, and the solid was washed three times with ethanol. The organic phase was concentrated, and the concentrate was separated and purified by column chromatography (DCM:EA=10:1) to obtain 4-((2-amino-4-bromo-5-chlorophenyl)amino)pyridine-1-carboxylic acid tert-Butyl ester (0.6 g) as a white solid in 64.5% yield. ESI-MS: 404 [M+H] ⁺ .

第三步將4-((2-胺基-4-溴-5-氯苯基)胺基)呱啶-1-甲酸叔丁酯(1.2 g, 3 mmol)、2-氯-2-氧代乙酸甲酯(1.5 g, 12 mmol)和三乙胺(2.4 g, 24 mmol)溶解於四氫呋喃(10 mL)中，於90℃反應2h，經液質檢測反應完畢，將反應液直接濃縮，濃縮物經柱層析(PE:EA=2:1)分離純化得4-(6-溴-7-氯-2,3-二氧代-3,4-二氫喹喔啉-1(2H)-基)呱啶-1-甲酸叔丁酯(1g),為白色固體，產率(72.7%)，ESI-MS: 458 [M+H]⁺ 。The third step was 4-((2-amino-4-bromo-5-chlorophenyl)amino) pyridine-1-carboxylic acid tert-butyl ester (1.2 g, 3 mmol), 2-chloro-2-oxygen Methyl acetate (1.5 g, 12 mmol) and triethylamine (2.4 g, 24 mmol) were dissolved in tetrahydrofuran (10 mL), and reacted at 90 ° C for 2 h. The reaction was completed by liquid quality detection, and the reaction solution was directly concentrated, The concentrate was separated and purified by column chromatography (PE:EA=2:1) to obtain 4-(6-bromo-7-chloro-2,3-dioxo-3,4-dihydroquinoxaline-1(2H )-yl)pyridine-1-carboxylate tert-butyl ester (1 g) as a white solid, yield (72.7%), ESI-MS: 458 [M+H] ⁺ .

第四步將4-(6-溴-7-氯-2,3-二氧代-3,4-二氫-1(2H )-喹喔啉)呱啶-1-甲酸叔丁酯(500 mg，1.1 mmol)溶解在四氫呋喃(10 mL)中，向其中加入2-(二甲基胺基)乙醇(120 mg，1.3 mmol)和三苯基膦(580 mg，2.2 mmol)。反應液冷卻至0℃，在氮氣環境下，將偶氮二甲酸二異丙酯(450 mg，2.2 mmol)緩慢滴加到系統中，滴加完後升至室溫攪拌1小時。反應完成後將反應液減壓濃縮，殘留物經prep-HPLC (沖提液：乙腈:水(10 mM NH₄ HCO₃ )=50%~85%)分離純化，得到4-(6-溴-7-氯-3-(2-(二甲基胺基)乙氧基)-2-氧代喹喔啉-1(2H )-基)呱啶-1-甲酸叔丁酯(230 mg)，為白色固體，產率35%。ESI-MS: 529,531 [M+H]⁺ 。In the fourth step, tert-butyl 4-(6-bromo-7-chloro-2,3-dioxo-3,4-dihydro-1( 2H )-quinoxaline)pyridine-1-carboxylate ( 500 mg, 1.1 mmol) was dissolved in tetrahydrofuran (10 mL), to which were added 2-(dimethylamino)ethanol (120 mg, 1.3 mmol) and triphenylphosphine (580 mg, 2.2 mmol). The reaction solution was cooled to 0°C, and under nitrogen atmosphere, diisopropyl azodicarboxylate (450 mg, 2.2 mmol) was slowly added dropwise to the system, and after the dropwise addition, the mixture was warmed to room temperature and stirred for 1 hour. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by prep-HPLC (eluent: acetonitrile: water (10 mM NH ₄ HCO ₃ )=50%~85%) to obtain 4-(6-bromo- 7-Chloro-3-(2-(dimethylamino)ethoxy)-2-oxoquinoxalin-1( 2H )-yl)ciridine-1-carboxylic acid tert-butyl ester (230 mg) , as a white solid in 35% yield. ESI-MS: 529,531 [M+H] ⁺ .

第五步將4-(6-溴-7-氯-3-(2-(二甲基胺基)乙氧基)-2-氧代喹喔啉-1(2H )-基)呱啶-1-甲酸叔丁酯(230 mg，0.43 mmol)溶解在二氯甲烷(10.0 mL)中，加入三氟乙酸(2.0 mL)，在室溫下攪拌1小時，然後減壓濃縮得到6-溴-7-氯-3-(2-(二甲基胺基)乙氧基)-1-(呱啶-4-基)喹喔啉-2(1H )-酮(150 mg)，為淡黃色固體。產率81%。ESI-MS: 429,431 [M+H]⁺ 。In the fifth step, 4-(6-bromo-7-chloro-3-(2-(dimethylamino)ethoxy)-2-oxoquinoxalin-1( 2H )-yl)pyridine tert-Butyl-1-carboxylate (230 mg, 0.43 mmol) was dissolved in dichloromethane (10.0 mL), trifluoroacetic acid (2.0 mL) was added, stirred at room temperature for 1 hour, and then concentrated under reduced pressure to obtain 6-bromo -7-Chloro-3-(2-(dimethylamino)ethoxy)-1-(guaidin-4-yl)quinoxalin-2( 1H )-one (150 mg) as pale Yellow solid. Yield 81%. ESI-MS: 429,431 [M+H] ⁺ .

第六步將6-溴-7-氯-3-(2-(二甲基胺基)乙氧基)-1-(呱啶-4-基)喹喔啉-2(1H )-酮(150 mg，0.35 mmol)溶解在二氯甲烷(2.0 mL)中，加入三乙胺(106 mg，1.05 mmol)，在氮氣保護，降溫至-78℃，在此溫度下緩慢滴加丙烯醯氯(118 mg，1.32 mmol)的二氯甲烷溶液(0.5 mL)，並維持溫度攪拌反應1小時，反應完成後將反應液減壓濃縮，濃縮物經矽膠層析法(沖提液：二氯甲烷:甲醇=15:1)分離純化，得到1-(1-丙烯醯基呱啶-4-基)-6-溴-7-氯-3-(2-(二甲基胺基)乙氧基)喹喔啉-2(1H)-酮(140 mg)，為淡黃色固體。產率83%。ESI-MS: 483,485 [M+H]⁺ 。The sixth step will be 6-bromo-7-chloro-3-(2-(dimethylamino)ethoxy)-1-(quaridin-4-yl)quinoxalin-2( 1H )-one (150 mg, 0.35 mmol) was dissolved in dichloromethane (2.0 mL), triethylamine (106 mg, 1.05 mmol) was added, and under nitrogen protection, the temperature was lowered to -78 °C, and acrylonitrile chloride was slowly added dropwise at this temperature. (118 mg, 1.32 mmol) in dichloromethane solution (0.5 mL), and the temperature was maintained for stirring for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrate was subjected to silica gel chromatography (eluent: dichloromethane). : methanol=15:1) separation and purification to obtain 1-(1-propenylpyridin-4-yl)-6-bromo-7-chloro-3-(2-(dimethylamino)ethoxy ) quinoxalin-2(1H)-one (140 mg) as a pale yellow solid. Yield 83%. ESI-MS: 483,485 [M+H] ⁺ .

第七步將1-(1-丙烯醯基呱啶-4-基)-6-溴-7-氯-3-(2-(二甲基胺基)乙氧基)喹喔啉-2(1H)-酮(80 mg，0.17 mmol)溶解在異丙醇(1 mL)中，加入碳酸鉀(71mg，0.51 mmol)，(3-羥基萘-1-基)硼酸(39 mg，0.20 mmol)和Pd(dppf)Cl₂ (25 mg，0.03 mmol)。在氮氣保護下加熱至70℃，攪拌1小時，反應液冷卻後過濾，濾液減壓濃縮，殘留物經prep-HPLC(沖提液：乙腈:水(10 mM NH₄ HCO₃ )=25%~45%)分離純化，得1-(1-丙烯醯基呱啶-4-基)-7-氯-3-(2-(二甲基胺基)乙氧基)-6-(3-羥基-1-萘)喹喔啉-2(1H )-酮(10 mg)，為白色固體，產率11%。 ESI-MS:[M+H]⁺ = 547.2¹ H NMR (400 MHz, DMSO-d6 ) δ 8.18 (s, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.50 (s, 1H), 7.41 (m, 1H), 7.26 – 7.18 (m, 3H), 6.99 (d,J = 2.4 Hz, 1H), 6.90 (dd,J = 16.7, 10.5 Hz, 1H), 6.16 (dd,J = 16.7, 2.5 Hz, 1H), 5.71 (dd,J = 10.4, 2.5 Hz, 1H), 4.98 (s, 1H), 4.59 (d, J = 12.8 Hz, 1H), 4.40 (t,J = 5.8 Hz, 2H), 4.21 (d, J = 13.6 Hz, 1H), 3.37 (m, 1H), 2.94 (t, J = 12.8 Hz, 1H), 2.67 – 2.55 (m, 3H), 2.48 (m, 1H), 2.20 (s, 6H), 1.75 (m, 2H).In the seventh step, 1-(1-propenylpyridin-4-yl)-6-bromo-7-chloro-3-(2-(dimethylamino)ethoxy)quinoxaline-2( 1H)-ketone (80 mg, 0.17 mmol) was dissolved in isopropanol (1 mL), potassium carbonate (71 mg, 0.51 mmol), (3-hydroxynaphthalen-1-yl)boronic acid (39 mg, 0.20 mmol) was added and Pd(dppf)Cl2 ( ₂₅ mg, 0.03 mmol). It was heated to 70 °C under nitrogen protection, stirred for 1 hour, the reaction solution was cooled and filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to prep-HPLC (eluent: acetonitrile: water (10 mM NH ₄ HCO ₃ ) = 25%~ 45%) was separated and purified to obtain 1-(1-propenylpyridin-4-yl)-7-chloro-3-(2-(dimethylamino)ethoxy)-6-(3-hydroxyl) -1-Naphthalene)quinoxalin-2( 1H )-one (10 mg) as a white solid, 11% yield. ESI-MS: [M+H] ⁺ = 547.2 ¹ H NMR (400 MHz, DMSO- d6 ) δ 8.18 (s, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.50 (s, 1H), 7.41 (m, 1H), 7.26 – 7.18 (m, 3H), 6.99 (d, J = 2.4 Hz, 1H), 6.90 (dd, J = 16.7, 10.5 Hz, 1H), 6.16 (dd, J = 16.7, 2.5 Hz, 1H), 5.71 (dd, J = 10.4, 2.5 Hz, 1H), 4.98 (s, 1H), 4.59 (d, J = 12.8 Hz, 1H), 4.40 (t, J = 5.8 Hz, 2H) , 4.21 (d, J = 13.6 Hz, 1H), 3.37 (m, 1H), 2.94 (t, J = 12.8 Hz, 1H), 2.67 – 2.55 (m, 3H), 2.48 (m, 1H), 2.20 ( s, 6H), 1.75 (m, 2H).

透過參考以上實施例18化合物的製備方法和使用不同的反應原料，製備了以下實施例化合物19和42：實施例結構［M+H］⁺ ¹ HNMR 19

573.1 ¹ H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.18 (s, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.51 (s, 1H), 7.41 (t, J = 7.3 Hz, 1H), 7.27 - 7.18 (m, 3H), 6.99 (s, 1H), 6.95 - 6.85 (m, 1H), 6.20 - 6.12 (m, 1H), 5.74 - 5.65 (m, 1H), 5.15 - 4.90 (m, 1H), 4.65 - 4.55 (m, 1H), 4.26 - 4.18 (m, 2H), 3.45 - 3.35 (m, 1H), 2.98 - 2.82 (m, 2H), 2.65 - 2.55 (m, 2H), 2.38 - 2.34 (m, 2H), 2.23 - 2.13 (m, 2H), 2.00 - 1.89 (m, 1H), 1.88 - 1.76 (m, 2H), 1.74 -1.40 (m, 4H). 42

572.3 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.88 (s, 1H), 8.06 (s, 1H), 7.77 (d,J = 8.24 Hz, 1H), 7.50 - 7.40 (m, 2H), 7.38 (s, 1H), 7.30 - 7.18 (m, 3H), 6.98 (s, 1H), 6.93 - 6.88(m, 1H), 6.18 - 6.10(m, 1H), 5.76 - 5.60(m, 1H), 5.20 - 4.80 (m, 1H), 4.58(d,J = 12.8 Hz, 1H), 4.20 (d,J = 13 Hz, 1H), 3.53 - 3.50 (m, 1H), 3.37 - 3.25 (m, 3H), 3.97 - 2.90(m, 2H), 2.70 - 2.60 (m, 2H), 2.30 (s, 3H), 2.15 - 2.10 (m, 1H), 2.00 - 1.80 (m, 3H), 1.62 - 1.50 (m, 3H). By referring to the preparation method of the compound of Example 18 above and using different reaction starting materials, the following Example Compounds 19 and 42 were prepared:

Example structure [M+H] ⁺ ¹ HNMR 19

573.1 ¹ H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.18 (s, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.51 (s, 1H), 7.41 (t, J = 7.3 Hz, 1H), 7.27 - 7.18 (m, 3H), 6.99 (s, 1H), 6.95 - 6.85 (m, 1H), 6.20 - 6.12 (m, 1H), 5.74 - 5.65 (m, 1H), 5.15 - 4.90 (m, 1H), 4.65 - 4.55 (m, 1H), 4.26 - 4.18 (m, 2H), 3.45 - 3.35 (m, 1H), 2.98 - 2.82 (m, 2H), 2.65 - 2.55 (m , 2H), 2.38 - 2.34 (m, 2H), 2.23 - 2.13 (m, 2H), 2.00 - 1.89 (m, 1H), 1.88 - 1.76 (m, 2H), 1.74 -1.40 (m, 4H). 42

572.3 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.88 (s, 1H), 8.06 (s, 1H), 7.77 (d, J = 8.24 Hz, 1H), 7.50 - 7.40 (m, 2H), 7.38 ( s, 1H), 7.30 - 7.18 (m, 3H), 6.98 (s, 1H), 6.93 - 6.88(m, 1H), 6.18 - 6.10(m, 1H), 5.76 - 5.60(m, 1H), 5.20 - 4.80 (m, 1H), 4.58(d, J = 12.8 Hz, 1H), 4.20 (d, J = 13 Hz, 1H), 3.53 - 3.50 (m, 1H), 3.37 - 3.25 (m, 3H), 3.97 - 2.90(m, 2H), 2.70 - 2.60 (m, 2H), 2.30 (s, 3H), 2.15 - 2.10 (m, 1H), 2.00 - 1.80 (m, 3H), 1.62 - 1.50 (m, 3H) .

實施例58：(S)-1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-6-(2-胺基苯並[d]噻唑-4-基)-7-氯-3-(((1-甲基吡咯烷-2-基)甲基)胺基)喹喔啉-2(1H)-酮的製備

Example 58: (S)-1-((1-Propenylazetidin-3-yl)methyl)-6-(2-aminobenzo[d]thiazol-4-yl)- Preparation of 7-chloro-3-(((1-methylpyrrolidin-2-yl)methyl)amino)quinoxalin-2(1H)-one

第一步在氮氣保護下，將DMAP(214 mg, 1.75 mmol)和DIEA(6.8 g, 52.5 mmol)加入到2-胺基-4-溴苯並噻唑(4 g, 17.5 mmol)的四氫呋喃(50 ml)溶液中，然後將BOC₂ O(4.6 g, 21 mmol)加入到上述反應系統中，在室溫攪拌2.5小時。反應結束後，繼續在室溫攪拌1小時，然後加飽和碳酸氫鈉溶液(5 mL)淬熄，用乙酸乙酯(20mL)萃取三次，有機相以無水硫酸鈉乾燥，減壓濃縮有機相，濃縮殘留物經矽膠層析法(沖提液：正己烷:乙酸乙酯=5:1)分離純化，得到產品(4-溴苯並[d]噻唑-2-基)胺基甲酸叔丁酯4克，為白色固體，產率(70%)。ESI-MS: 330 [M+H]+。In the first step, DMAP (214 mg, 1.75 mmol) and DIEA (6.8 g, 52.5 mmol) were added to 2-amino-4-bromobenzothiazole (4 g, 17.5 mmol) in tetrahydrofuran (50 under nitrogen protection) ml) solution, then BOC ₂ O (4.6 g, 21 mmol) was added to the above reaction system and stirred at room temperature for 2.5 hours. After the reaction was completed, continue stirring at room temperature for 1 hour, then add saturated sodium bicarbonate solution (5 mL) to quench, extract three times with ethyl acetate (20 mL), dry the organic phase with anhydrous sodium sulfate, and concentrate the organic phase under reduced pressure, The concentrated residue was separated and purified by silica gel chromatography (eluent: n-hexane:ethyl acetate=5:1) to obtain the product (4-bromobenzo[d]thiazol-2-yl)carbamate tert-butyl ester 4 g as a white solid, yield (70%). ESI-MS: 330 [M+H]+.

第二步在氮氣保護下，將(4-溴苯並[d]噻唑-2-基)胺基甲酸叔丁酯(2 g, 6.0 mmol)和硼酸三異丙酯(2.3 g，12 mmol)溶於乾燥四氫呋喃(27 mL)中，將系統溫度降至-78°C，然後將n-BuLi(7.2 mL, 18 mmol, 2.5mol/L正己烷溶液)緩慢滴入到上述反應中，滴加過程中溫度控制在-60°C以下，滴完後升溫至-30°C反應30 min。反應完畢後，反應液用飽和氯化銨淬熄，以二氯甲烷萃取，有機相用飽和食鹽水洗滌，無水硫酸鈉乾燥，將有機相減壓濃縮，殘留物經C18逆相管柱層析(沖提液：CH₃ CN:H₂ O=6:4)分離純化，得到(2-((叔丁氧基羰基)胺基)苯並[d]噻唑-4-基)硼酸400mg，產率(22.6%)，為白色固體。ESI-MS: 295 [M+H]⁺ 。In the second step, under nitrogen protection, tert-butyl (4-bromobenzo[d]thiazol-2-yl)carbamate (2 g, 6.0 mmol) and triisopropyl borate (2.3 g, 12 mmol) were combined Dissolved in dry tetrahydrofuran (27 mL), the system temperature was lowered to -78 ° C, then n-BuLi (7.2 mL, 18 mmol, 2.5 mol/L n-hexane solution) was slowly added dropwise into the above reaction, dropwise added In the process, temperature is controlled below-60 ℃, after dripping, be warming up to-30 ℃ of reaction 30 min. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure, and the residue was subjected to C18 reverse-phase column chromatography. (Eluent: CH ₃ CN:H ₂ O=6:4) was isolated and purified to obtain (2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)boronic acid 400mg, the product yield (22.6%) as a white solid. ESI-MS: 295 [M+H] ⁺ .

第三步在N₂ 保護下，將(2-((叔丁氧基羰基)胺基)苯並[d]噻唑-4-基)硼酸(98 mg，0.33 mmol)、(S)-3-((6-溴-7-氯-3-(((1-甲基吡咯烷-2-基)甲基)胺基)-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-甲酸叔丁酯(150 mg，0.28 mmol)、Pd(dppf)Cl₂ (41 mg, 0.055 mmol)和碳酸鉀(115 mg，0.83 mmol)分散在異丙醇/水(4:1，5 mL)中，加熱至80℃並在此溫度下攪拌反應16小時。反應完成後，將反應液減壓濃縮，得到的殘留物用中壓flash矽膠層析法(沖提液：甲醇(含1%胺水): 二氯甲烷=0 - 10%)分離純化，得到(S)-3-((6-(2-((叔丁氧羰基)胺基)苯並[d]噻唑-4-基)-7-氯-3-(((1-甲基吡咯烷-2-基)甲基)胺基)-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-甲酸叔丁酯(133 mg)，為棕色固體，產率68%。ESI-MS: 710、712 [M+H]⁺ 。In the third step, under _N2 protection, (2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)boronic acid (98 mg, 0.33 mmol), (S)-3- ((6-Bromo-7-chloro-3-(((1-methylpyrrolidin-2-yl)methyl)amino)-2-oxoquinoxalin-1(2H)-yl)methyl ) tert-butyl azetidine-1-carboxylate (150 mg, 0.28 mmol), Pd(dppf)Cl ₂ (41 mg, 0.055 mmol) and potassium carbonate (115 mg, 0.83 mmol) were dispersed in isopropanol/ In water (4:1, 5 mL), heat to 80 °C and stir the reaction at this temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by medium pressure flash silica gel chromatography (eluent: methanol (containing 1% amine water): dichloromethane=0-10%) to obtain (S)-3-((6-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-7-chloro-3-((((1-methylpyrrolidine) -2-yl)methyl)amino)-2-oxoquinoxalin-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (133 mg) as a brown solid , the yield is 68%. ESI-MS: 710, 712 [M+H] ⁺ .

第四步將

(S)-3-((6-(2-((叔丁氧羰基)胺基)苯並[d]噻唑-4-基)-7-氯-3-(((1-甲基吡咯烷-2-基)甲基)胺基)-2-氧代喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-甲酸叔丁酯(133 mg，0.19 mmol)溶解在二氯甲烷(5 mL)中。在室溫下，緩慢滴加三氟乙酸(1 mL)，滴加完畢後在室溫下攪拌反應2小時。反應完成後減壓濃縮得到(S)-6-(2-胺基苯並[d]噻唑-4-基)-1-(氮雜環丁烷-3-基甲基)-7-氯-3-(((1-甲基吡咯烷-2-基)甲基)胺基)喹喔啉-2(1H)-酮(114 mg)，為棕色固體，產率(100%)。ESI-MS: 510、512 [M+H]⁺ 。The fourth step will be

(S)-3-((6-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-7-chloro-3-((((1-methylpyrrolidine) -2-yl)methyl)amino)-2-oxoquinoxalin-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (133 mg, 0.19 mmol) was dissolved in dichloromethane (5 mL). At room temperature, trifluoroacetic acid (1 mL) was slowly added dropwise, and the reaction was stirred at room temperature for 2 hours after the dropwise addition. After the completion of the reaction, it was concentrated under reduced pressure to obtain (S)-6-(2-aminobenzo[d]thiazol-4-yl)-1-(azetidin-3-ylmethyl)-7-chloro- 3-(((1-Methylpyrrolidin-2-yl)methyl)amino)quinoxalin-2(1H)-one (114 mg) as a brown solid, yield (100%). ESI-MS: 510, 512 [M+H] ⁺ .

第五步在N₂ 保護下，將(S)-6-(2-胺基苯並[d]噻唑-4-基)-1-(氮雜環丁烷-3-基甲基)-7-氯-3-(((1-甲基吡咯烷-2-基)甲基)胺基)喹喔啉-2(1H)-酮(114 mg，0.19 mmol)溶解在二氯甲烷(4 mL)中，加入三乙胺(189 mg, 1.87 mmol)，讓反應系統冷卻至-78℃，將丙烯醯氯(18 mg，0.20 mmol)的二氯甲烷(2 mL)溶液緩慢滴加到系統中，並於-78℃攪拌反應1小時。反應完成後減壓濃縮反應液，殘留物用prep-TLC (沖提液：NH₃ •H₂ O:MeOH:DCM=0.01:1:10)初步分離，得到的粗產物再以二甲基亞碸(DMSO)(2 mL)溶解，用高壓製備反相色譜分離純化，收集餾分並冷凍乾燥得到(S)-1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-6-(2-胺基苯並[d]噻唑-4-基)-7-氯-3-(((1-甲基吡咯烷-2-基)甲基)胺基)喹喔啉-2(1H)-酮(21.57 mg)，為白色固體，產率20%。 ESI-MS: 564、566 [M+H]⁺ 。¹ H-NMR (400 MHz, DMSO-d6) δ: ppm 7.71~7.69 (m, 2H), 7.56 (s, 2H), 7.40 (brs, 1H), 7.31 (s, 1H), 7.14~7.06 (m, 2H), 6.31 (dd, 1H, J = 16.8, 10.4 Hz), 6.10 (dd, 1H, J = 16.8, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 4.64~4.53 (m, 2H), 4.33~4.28 (m, 1H), 4.13~4.10 (m, 1H), 4.02~3.96 (m, 1H), 3.86~3.82 (m, 1H), 3.63~3.56 (m, 2H), 3.30~3.24 (m, 2H), 3.18~3.11 (m, 1H), 3.00~2.96 (m, 1H), 2.31 (s, 3H), 2.18~2.12 (m, 1H), 1.85~1.80 (m, 1H), 1.66~1.56 (m, 2H)。The fifth step under the protection of _N2 , (S)-6-(2-aminobenzo[d]thiazol-4-yl)-1-(azetidin-3-ylmethyl)-7 -Chloro-3-(((1-methylpyrrolidin-2-yl)methyl)amino)quinoxalin-2(1H)-one (114 mg, 0.19 mmol) was dissolved in dichloromethane (4 mL) ), triethylamine (189 mg, 1.87 mmol) was added, the reaction system was cooled to -78 °C, and a solution of acryloyl chloride (18 mg, 0.20 mmol) in dichloromethane (2 mL) was slowly added dropwise to the system , and the reaction was stirred at -78°C for 1 hour. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was preliminarily separated by prep-TLC (eluent: NH ₃ ·H ₂ O:MeOH:DCM=0.01:1:10), and the obtained crude product was separated with dimethylmethylene Di (DMSO) (2 mL) was dissolved, separated and purified by high pressure preparative reversed-phase chromatography, fractions were collected and lyophilized to obtain (S)-1-((1-propenylazetidin-3-yl)methyl )-6-(2-aminobenzo[d]thiazol-4-yl)-7-chloro-3-(((1-methylpyrrolidin-2-yl)methyl)amino)quinoxaline -2(1H)-one (21.57 mg) as a white solid, 20% yield. ESI-MS: 564, 566 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d6) δ: ppm 7.71~7.69 (m, 2H), 7.56 (s, 2H), 7.40 (brs, 1H), 7.31 (s, 1H), 7.14~7.06 (m , 2H), 6.31 (dd, 1H, J = 16.8, 10.4 Hz), 6.10 (dd, 1H, J = 16.8, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 4.64~4.53 ( m, 2H), 4.33~4.28 (m, 1H), 4.13~4.10 (m, 1H), 4.02~3.96 (m, 1H), 3.86~3.82 (m, 1H), 3.63~3.56 (m, 2H), 3.30~3.24 (m, 2H), 3.18~3.11 (m, 1H), 3.00~2.96 (m, 1H), 2.31 (s, 3H), 2.18~2.12 (m, 1H), 1.85~1.80 (m, 1H) ), 1.66~1.56 (m, 2H).

實施例59：(S )-1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-7-氯-5-氟-6-(3-羥基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)喹喔啉-2(1H)-酮的製備

Example 59: ( S )-1-((1-propenylazetidin-3-yl)methyl)-7-chloro-5-fluoro-6-(3-hydroxynaphthalen-1-yl Preparation of )-3-((1-methylpyrrolidin-2-yl)methoxy)quinoxalin-2(1H)-one

第一步將5-氯-1,3-二氟-2-硝基苯(6.0 g，31.0 mmol) 溶解在乙腈(100 mL)中，向其中加入3-(胺基甲基)氮雜環丁烷-1-羧酸叔丁酯(5.78 g，31.0 mmol)和無水碳酸鉀(12.8 g，93.0 mmol)。反應在室溫下攪拌16小時。反應液過濾，濾液減壓濃縮，得到3-(((5-氯-3-氟-2-硝基苯基)胺基)甲基)氮雜環丁烷-1-羧酸叔丁酯(10.0 g)，為橙紅色固體，產率90%，粗產物直接用於下一步反應。ESI-MS: 360 [M+H]⁺ Step 1 5-Chloro-1,3-difluoro-2-nitrobenzene (6.0 g, 31.0 mmol) was dissolved in acetonitrile (100 mL), to which was added 3-(aminomethyl)azacycle Butane-1-carboxylate tert-butyl ester (5.78 g, 31.0 mmol) and anhydrous potassium carbonate (12.8 g, 93.0 mmol). The reaction was stirred at room temperature for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 3-(((5-chloro-3-fluoro-2-nitrophenyl)amino)methyl)azetidine-1-carboxylate ( 10.0 g) as an orange-red solid with a yield of 90%, the crude product was directly used in the next reaction. ESI-MS: 360 [M+H] ⁺

第二步將3-(((5-氯-3-氟-2-硝基苯基)胺基)甲基)氮雜環丁烷-1-羧酸叔丁酯(10.0 g，27.8 mmol)溶解在乙醇(100 mL)和水(20 mL)中，加入氯化銨(14.9 g，278 mmol)和鐵粉(7.8 g，139 mmol)。反應在90℃下攪拌1小時，反應液冷卻後過濾，濾液減壓濃縮除去乙醇，混合液用二氯甲烷(3 x 100 mL)萃取，合併有機相，有機相經飽和食鹽水洗滌(100 mL)，無水硫酸鈉乾燥，過濾。濾液濃縮得殘留物，殘留物經矽膠層析法(沖提液：石油醚：乙酸乙酯=2:1)分離純化，得到3-(((2-胺基-5-氯-3-氟苯基)胺基)甲基)氮雜環丁烷-1-羧酸叔丁酯(8.0 g)，為白色固體。產率88 %。ESI-MS: 330 [M+H]⁺ The second step was tert-butyl 3-(((5-chloro-3-fluoro-2-nitrophenyl)amino)methyl)azetidine-1-carboxylate (10.0 g, 27.8 mmol) Dissolve in ethanol (100 mL) and water (20 mL), add ammonium chloride (14.9 g, 278 mmol) and iron powder (7.8 g, 139 mmol). The reaction was stirred at 90 °C for 1 hour, the reaction solution was cooled and filtered, the filtrate was concentrated under reduced pressure to remove ethanol, the mixture was extracted with dichloromethane (3 x 100 mL), the organic phases were combined, and the organic phases were washed with saturated brine (100 mL). ), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a residue, which was separated and purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 2:1) to obtain 3-(((2-amino-5-chloro-3-fluoro. Phenyl)amino)methyl)azetidine-1-carboxylate tert-butyl ester (8.0 g) as a white solid. Yield 88%. ESI-MS: 330 [M+H] ⁺

第三步將3-(((2-胺基-5-氯-3-氟苯基)胺基)甲基)氮雜環丁烷-1-羧酸叔丁酯(1.5 g, 4.56 mmol)溶於四氫呋喃(30 mL)中，加入三乙胺(4.60 g，45.56 mmol)，在冰浴條件下，緩慢滴加草醯氯單甲酯(2.78 g，22.8 mmol)溶液，在室溫下攪拌反應1小時，然後升溫至90℃並攪拌3小時，反應液冷卻後減壓濃縮，濃縮物經矽膠層析法(沖提液：石油醚：乙酸乙酯=1:1)分離純化，得到3-((7-氯-5-氟-2,3-二氧代-3,4-二氫喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-甲酸叔丁酯(1.0g)，為白色固體。產率58%。ESI-MS: 384 [M+H]⁺ 。The third step was tert-butyl 3-(((2-amino-5-chloro-3-fluorophenyl)amino)methyl)azetidine-1-carboxylate (1.5 g, 4.56 mmol) Dissolve in tetrahydrofuran (30 mL), add triethylamine (4.60 g, 45.56 mmol), under ice bath condition, slowly add oxalyl chloride monomethyl ester (2.78 g, 22.8 mmol) solution dropwise, stir at room temperature The reaction was carried out for 1 hour, then heated to 90°C and stirred for 3 hours. The reaction solution was cooled and concentrated under reduced pressure. The concentrate was separated and purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to obtain 3 -((7-Chloro-5-fluoro-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl Ester (1.0 g) as a white solid. Yield 58%. ESI-MS: 384 [M+H] ⁺ .

第四步將3-((7-氯-5-氟-2,3-二氧代-3,4-二氫喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-甲酸叔丁酯(1.0 g，2.08 mmol)溶解在N,N -二甲基甲醯胺(10 mL)中，加入乙酸(125 mg，2.08 mmol)，緩慢滴加溴素(986 mg，6.24 mmol)，在室溫下攪拌1 h，反應結束後加飽和碳酸氫鈉溶液(20 mL)淬熄，用二氯甲烷(20 mL)萃取三次，有機相經無水硫酸鈉乾燥後減壓濃縮，濃縮殘留物經矽膠層析法(沖提液：石油醚：乙酸乙酯=1:1)分離純化，得到3-((6-溴-7-氯-5-氟-2,3-二氧代-3,4-二氫喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-甲酸叔丁酯(700 mg)，為白色固體。產率73%。ESI-MS: 462,464 [M+H]⁺ 。In the fourth step, 3-((7-chloro-5-fluoro-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)methyl)azetidine- tert-Butyl 1-carboxylate (1.0 g, 2.08 mmol) was dissolved in N,N -dimethylformamide (10 mL), acetic acid (125 mg, 2.08 mmol) was added, and bromine (986 mg, 986 mg, 2.08 mmol) was added dropwise slowly 6.24 mmol), stirred for 1 h at room temperature, quenched by adding saturated sodium bicarbonate solution (20 mL) after the reaction, extracted three times with dichloromethane (20 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure , the concentrated residue was separated and purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to obtain 3-((6-bromo-7-chloro-5-fluoro-2,3-di Oxo-3,4-dihydroquinoxalin-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (700 mg) as a white solid. Yield 73%. ESI-MS: 462,464 [M+H] ⁺ .

第五步將3-((6-溴-7-氯-5-氟-2,3-二氧代-3,4-二氫喹喔啉-1(2H)-基)甲基)氮雜環丁烷-1-甲酸叔丁酯(700 mg，1.5 mmol)溶解在四氫呋喃(10 mL)中，向其中加入(S )-(1-甲基吡咯烷-2-基)甲醇(207 mg，1.8 mmol)和三苯基膦(789 mg，3.0 mmol)。將反應液冷卻至0℃，在氮氣環境下，將偶氮二甲酸二異丙酯(606 mg，3.0 mmol)緩慢滴加到系統中，滴加完後升至室溫攪拌1小時。然後將反應液減壓濃縮，濃縮殘留物經矽膠層析法(沖提液：二氯甲烷:甲醇=20:1)分離純化，得到(S )-3-((6-溴-7-氯-5-氟-3-((1-甲基吡咯烷-2-基)甲氧基)-2-氧代-3,4-二氫喹喔啉-1(2H )-基)甲基)氮雜環丁烷-1-甲酸叔丁酯(200 mg)，為白色固體。產率24%。ESI-MS: 561,563 [M+H]⁺ 。The fifth step will 3-((6-bromo-7-chloro-5-fluoro-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)methyl)aza tert-Butyl cyclobutane-1-carboxylate (700 mg, 1.5 mmol) was dissolved in tetrahydrofuran (10 mL), to which was added ( S )-(1-methylpyrrolidin-2-yl)methanol (207 mg, 1.8 mmol) and triphenylphosphine (789 mg, 3.0 mmol). The reaction solution was cooled to 0°C, and under nitrogen atmosphere, diisopropyl azodicarboxylate (606 mg, 3.0 mmol) was slowly added dropwise to the system, and after the dropwise addition, the mixture was warmed to room temperature and stirred for 1 hour. Then the reaction solution was concentrated under reduced pressure, and the concentrated residue was separated and purified by silica gel chromatography (eluent: dichloromethane: methanol = 20: 1) to obtain ( S )-3-((6-bromo-7-chloro- -5-Fluoro-3-((1-methylpyrrolidin-2-yl)methoxy)-2-oxo-3,4-dihydroquinoxalin-1( 2H )-yl)methyl ) tert-butyl azetidine-1-carboxylate (200 mg) as a white solid. Yield 24%. ESI-MS: 561,563 [M+H] ⁺ .

第六步將(S )-3-((6-溴-7-氯-5-氟-3-((1-甲基吡咯烷-2-基)甲氧基)-2-氧代-3,4-二氫喹喔啉-1(2H )-基)甲基)氮雜環丁烷-1-甲酸叔丁酯(200 mg，0.36 mmol)溶解在1,4-二氧六環(5 mL)和水(1 mL)中，加入碳酸鈉(115 mg，1.08 mmol)，4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)萘-2-醇(116 mg，0.43 mmol)和RuPhos Pd G3(58 mg，0.07 mmol)。氮氣保護下加熱至80℃，攪拌1小時，反應液冷卻後過濾，濾液減壓濃縮，濃縮物經矽膠層析法(沖提液：二氯甲烷:甲醇=15:1)分離純化，得到(S )-3-((7-氯-5-氟-6-(3-羥基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)-2-氧代喹喔啉-1(2H )-基)甲基)氮雜環丁烷-1-甲酸叔丁酯(120 mg)，為白色固體。產率54%。ESI-MS: 623 [M+H]⁺ 。The sixth step will ( S )-3-((6-bromo-7-chloro-5-fluoro-3-((1-methylpyrrolidin-2-yl)methoxy)-2-oxo-3 ,4-Dihydroquinoxalin-1( 2H )-yl)methyl)azetidine-1-carboxylate tert-butyl ester (200 mg, 0.36 mmol) was dissolved in 1,4-dioxane ( 5 mL) and water (1 mL), sodium carbonate (115 mg, 1.08 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) were added Alk-2-yl)naphthalen-2-ol (116 mg, 0.43 mmol) and RuPhos Pd G3 (58 mg, 0.07 mmol). Heated to 80°C under nitrogen protection, stirred for 1 hour, the reaction solution was cooled and filtered, the filtrate was concentrated under reduced pressure, and the concentrate was separated and purified by silica gel chromatography (eluent: dichloromethane:methanol=15:1) to obtain ( S )-3-((7-Chloro-5-fluoro-6-(3-hydroxynaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-2- Oxoquinoxalin-1( 2H )-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (120 mg) as a white solid. Yield 54%. ESI-MS: 623 [M+H] ⁺ .

第七步將(S )-3-((7-氯-5-氟-6-(3-羥基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)-2-氧代喹喔啉-1(2H )-基)甲基)氮雜環丁烷-1-甲酸叔丁酯(120 mg, 0.19 mmol)溶於二氯甲烷(5 mL)中，加入三氟乙酸(1 mL)，在室溫下攪拌1小時，然後減壓濃縮得到1-(氮雜環丁烷-3-基甲基)-7-氯-5-氟-6-(3-羥基萘-1-基)-3-(((S)-1-甲基吡咯烷基-2-基)甲氧基)喹喔啉-2(1H)-酮(80 mg)，為白色固體。產率80%。ESI-MS: 523 [M+H]⁺ 。The seventh step will ( S )-3-((7-chloro-5-fluoro-6-(3-hydroxynaphthalene-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy (120 mg, 0.19 mmol) in dichloromethane (5 mL ) , trifluoroacetic acid (1 mL) was added, stirred at room temperature for 1 hour, and then concentrated under reduced pressure to obtain 1-(azetidin-3-ylmethyl)-7-chloro-5-fluoro-6- (3-Hydroxynaphthalen-1-yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinoxalin-2(1H)-one (80 mg), For white solid. Yield 80%. ESI-MS: 523 [M+H] ⁺ .

第八步 1-(氮雜環丁烷-3-基甲基)-7-氯-5-氟-6-(3-羥基萘-1-基)-3-(((S)-1-甲基吡咯烷基-2-基)甲氧基)喹喔啉-2(1H)-酮(80 mg，0.15 mmol)溶解在二氯甲烷(1 mL)中，加入三乙胺(46 mg，0.45 mmol)，在氮氣保護下，降溫至-78℃，在-78℃下，緩慢滴加丙烯醯氯(16 mg，0.18 mmol)的二氯甲烷溶液(0.5 mL)，在此溫度下繼續攪拌1小時，將反應液減壓濃縮，殘留物經prep-HPLC (沖提液：乙腈:水(10 mM NH₄ HCO₃ ) =35%~60%)分離純化，得到(S )-1-((1-丙烯醯基氮雜環丁烷-3-基)甲基)-7-氯-5-氟-6-(3-羥基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)喹喔啉-2(1H)-酮(14 mg)，為白色固體，產率17%。 ESI-MS: 577 [M+H]⁺ ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.98 (s, 1H), 7.88 (s, 1H), 7.80 (d,J = 8.3 Hz, 1H), 7.44 (ddd,J = 8.1, 6.4, 1.6 Hz, 1H), 7.30 – 7.17 (m, 3H), 7.04 (d,J = 2.4 Hz, 1H), 6.32 (dd,J = 16.9, 10.2 Hz, 1H), 6.11 (dd,J = 17.0, 2.3 Hz, 1H), 5.67 (dd,J = 10.2, 2.4 Hz, 1H), 4.60 (d,J = 7.4 Hz, 2H), 4.32 (ddd,J = 17.6, 11.6, 6.8 Hz, 3H), 4.13 (t,J = 7.2 Hz, 1H), 3.99 (t,J = 9.4 Hz, 1H), 3.89 – 3.81 (m, 1H), 3.21 – 3.11 (m, 1H), 2.95 (s, 1H), 2.67 (s, 1H), 2.39 – 2.36 (m, 3H), 2.19 (d,J = 17.0 Hz, 1H), 1.97 (td,J = 11.7, 10.3, 6.9 Hz, 2H), 1.73 – 1.64 (m, 2H).The eighth step 1-(azetidin-3-ylmethyl)-7-chloro-5-fluoro-6-(3-hydroxynaphthalen-1-yl)-3-(((S)-1- Methylpyrrolidin-2-yl)methoxy)quinoxalin-2(1H)-one (80 mg, 0.15 mmol) was dissolved in dichloromethane (1 mL), triethylamine (46 mg, 0.45 mmol), under nitrogen protection, the temperature was lowered to -78 °C, at -78 °C, a dichloromethane solution (0.5 mL) of propenyl chloride (16 mg, 0.18 mmol) was slowly added dropwise, and stirring was continued at this temperature. After 1 hour, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by prep-HPLC (eluent: acetonitrile: water (10 mM NH ₄ HCO ₃ ) = 35%~60%) to obtain ( S )-1-( (1-Propenylazetidine-3-yl)methyl)-7-chloro-5-fluoro-6-(3-hydroxynaphthalen-1-yl)-3-((1-methylpyrrole Alk-2-yl)methoxy)quinoxalin-2(1H)-one (14 mg) as a white solid, 17% yield. ESI-MS: 577 [M+H] ⁺ ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.98 (s, 1H), 7.88 (s, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.44 (ddd, J = 8.1, 6.4, 1.6 Hz, 1H), 7.30 – 7.17 (m, 3H), 7.04 (d, J = 2.4 Hz, 1H), 6.32 (dd, J = 16.9, 10.2 Hz, 1H) , 6.11 (dd, J = 17.0, 2.3 Hz, 1H), 5.67 (dd, J = 10.2, 2.4 Hz, 1H), 4.60 (d, J = 7.4 Hz, 2H), 4.32 (ddd, J = 17.6, 11.6 , 6.8 Hz, 3H), 4.13 (t, J = 7.2 Hz, 1H), 3.99 (t, J = 9.4 Hz, 1H), 3.89 – 3.81 (m, 1H), 3.21 – 3.11 (m, 1H), 2.95 (s, 1H), 2.67 (s, 1H), 2.39 – 2.36 (m, 3H), 2.19 (d, J = 17.0 Hz, 1H), 1.97 (td, J = 11.7, 10.3, 6.9 Hz, 2H), 1.73 – 1.64 (m, 2H).

生物測試測試例1：細胞磷酸化抑制試驗biological test Test Example 1: Cell Phosphorylation Inhibition Test

實驗目的：對本發明化合物進行細胞磷酸化抑制試驗，以驗證本發明化合物對KRAS G12C突變的NCI-H358人類非小細胞肺癌的磷酸化抑制效果。Purpose: The cell phosphorylation inhibition test was performed on the compounds of the present invention to verify the phosphorylation inhibition effect of the compounds of the present invention on KRAS G12C mutant NCI-H358 human non-small cell lung cancer.

主要試劑：細胞株NCI-H358，Advanced Phosphor-ERK1/2(THR202/TYR204) KITS，RPMI1640培養基，胎牛血清，0.25%胰蛋白酶-EDTA消化液，PBS，細胞培養級DMSO，青鏈黴素。Main reagents: Cell line NCI-H358, Advanced Phosphor-ERK1/2 (THR202/TYR204) KITS, RPMI1640 medium, fetal bovine serum, 0.25% trypsin-EDTA digestion solution, PBS, cell culture grade DMSO, penicillin.

主要儀器： BioTek微盤分析儀，細胞培養瓶，96孔細胞培養盤，384孔分析盤，CO2恆溫培養箱，10 μL 12吸量管，100 μL 12吸量管，200 μL 12吸量管。Main instruments: BioTek Microplate Analyzer, cell culture flask, 96-well cell culture dish, 384-well assay dish, CO2 incubator, 10 μL 12 pipettes, 100 μL 12 pipettes, 200 μL 12 pipettes.

試驗方法：在96孔細胞培養盤中加入NCI-H358細胞懸浮液，其中包含25000個細胞，放入二氧化碳培養箱過夜培養。將待測化合物3倍稀釋，9個濃度點(從10000 nM到1.52 nM)，分別加入到細胞培養盤對應的孔中，然後放入培養箱培養3小時。然後根據Advanced Phosphor-ERK1/2 (THR202/TYR204)試劑盒的操作說明，進行細胞裂解30分鐘，抗體孵育4小時，用BioTek讀板。experiment method: The NCI-H358 cell suspension containing 25,000 cells was added to a 96-well cell culture dish and cultured overnight in a carbon dioxide incubator. The compounds to be tested were diluted 3 times, and 9 concentration points (from 10000 nM to 1.52 nM) were added to the corresponding wells of the cell culture plate, and then placed in an incubator for 3 hours. Then, according to the operating instructions of the Advanced Phosphor-ERK1/2 (THR202/TYR204) kit, the cells were lysed for 30 minutes, the antibody was incubated for 4 hours, and the plate was read with BioTek.

資料分析： IC₅₀ 結果由IDBS公司的GraphPad Prism 6.0軟體分析獲得。Data analysis: IC ₅₀ results were obtained by GraphPad Prism 6.0 software analysis from IDBS Corporation.

試驗結果：本發明化合物對於NCI-H358(G12C突變)細胞的磷酸化抑制率IC50的資料為：受試化合物 NCI-H358 IC₅₀ (nM) 實施例2 367.7 實施例3 1923 實施例9 365.6 實施例10 215.3 實施例11 340.6 實施例12 75.69 實施例13 108.5 實施例14 3750 實施例18 1213 實施例19 201.1 實施例20 2876 實施例21 191.7 實施例22 4230 實施例23 ＞10000 實施例24 621.4 實施例25 359.9 實施例26 113.9 實施例27 474.9 實施例28 249.5 實施例29 938.6 實施例30 110.8 實施例31 151.0 實施例32 492.1 實施例33 122.9 實施例34 132.4 實施例35 1469 實施例36 ＞10000 實施例37 2203 實施例38 206.2 實施例39 184.4 實施例40 178.6 實施例41 367.4 實施例42 464.1 實施例44 552.3 實施例45 1221 實施例46 328.3 實施例47 390.9 實施例48 335.9 實施例49 277.3 實施例50 375.2 實施例51 204.6 實施例52 451.5 實施例53 163.5 實施例54 189.1 實施例55 174.4 實施例56 125.2 實施例57 ＞10000 實施例58 398.2 實施例59 291.6 實施例60 ＞10000 實施例62 ＞1000 Test results: The data of the phosphorylation inhibition rate IC50 of the compounds of the present invention to NCI-H358 (G12C mutation) cells are: test compound NCI-H358 IC ₅₀ (nM) Example 2 367.7 Example 3 1923 Example 9 365.6 Example 10 215.3 Example 11 340.6 Example 12 75.69 Example 13 108.5 Example 14 3750 Example 18 1213 Example 19 201.1 Example 20 2876 Example 21 191.7 Example 22 4230 Example 23 >10000 Example 24 621.4 Example 25 359.9 Example 26 113.9 Example 27 474.9 Example 28 249.5 Example 29 938.6 Example 30 110.8 Example 31 151.0 Example 32 492.1 Example 33 122.9 Example 34 132.4 Example 35 1469 Example 36 >10000 Example 37 2203 Example 38 206.2 Example 39 184.4 Example 40 178.6 Example 41 367.4 Example 42 464.1 Example 44 552.3 Example 45 1221 Example 46 328.3 Example 47 390.9 Example 48 335.9 Example 49 277.3 Example 50 375.2 Example 51 204.6 Example 52 451.5 Example 53 163.5 Example 54 189.1 Example 55 174.4 Example 56 125.2 Example 57 >10000 Example 58 398.2 Example 59 291.6 Example 60 >10000 Example 62 >1000

測試例2：蛋白結合試驗Test Example 2: Protein Binding Assay

試驗目的：對本發明化合物進行蛋白結合試驗，以驗證本發明化合物是否結合在KRAS G12C突變的蛋白結構中。Test purposes: The compounds of the present invention are subjected to protein binding assays to verify whether the compounds of the present invention bind to the KRAS G12C mutant protein structure.

主要試劑： Hepes，NaCl，MgCl₂ ，EDTA，DTT，GDP，KRAS-4B-G12C，DMSO，MilliQ H2O，ACN，甲酸。Main reagents: Hepes, NaCl, _MgCl2 , EDTA, DTT, GDP, KRAS-4B-G12C, DMSO, MilliQ H2O, ACN, formic acid.

主要儀器： Waters Acquity I Class UPLC-Xevo G2-XS QTOF，Sepax Bio-C4，2.1 X 50 mm，3 μmMain instruments: Waters Acquity Class I UPLC-Xevo G2-XS QTOF, Sepax Bio-C4, 2.1 X 50 mm, 3 μm

試驗方法： KRAS-4B-G12C蛋白與20倍蛋白濃度的GDP1:1混合，室溫孵育1.5小時，然後將GDP-loaded KRAS-4B-G12C蛋白稀釋至20 μM，5 μL的蛋白，5 μL 30 μM的化合物在12.5 mM Hepes，75 mM NaCl，1 mM MgCl₂ 反應系統中孵育5分鐘或30分鐘；加入5 μL 5%的甲酸，終止反應。樣品以15000 rpm離心10分鐘，上樣檢測。Test method: KRAS-4B-G12C protein was mixed with 20 times protein concentration of GDP 1:1, incubated at room temperature for 1.5 hours, then GDP-loaded KRAS-4B-G12C protein was diluted to 20 μM, 5 μL protein, 5 μL 30 Compounds in μM were incubated in a 12.5 mM Hepes, 75 mM NaCl, 1 mM MgCl ₂ reaction system for 5 minutes or 30 minutes; the reaction was stopped by adding 5 μL of 5% formic acid. Samples were centrifuged at 15,000 rpm for 10 minutes and loaded for detection.

UPLC條件：項目條件儀器: Waters Acquity I Class 柱: Sepax Bio-C4, 2.1 x 50 mm, 3 μm 流速: 0.6 ml/min 上樣量： 10 μL 流動相: A: 0.1%甲酸水溶液 B: 0.1%甲酸的ACN溶液溫度: 65℃ 檢測: TOF MS UPLC condition: project condition instrument: Waters Acquity I Class column: Sepax Bio-C4, 2.1 x 50 mm, 3 μm Flow rate: 0.6 ml/min Loading volume: 10 μL Mobile phase: A: 0.1% formic acid aqueous solution B: 0.1% formic acid in ACN temperature: 65℃ Detection: TOF MS

LC的梯度時間表時間(min) A (%) B (%) 0 95 5 0.75 95 5 1 75 25 6 50 50 6.25 0 100 7.5 0 100 7.75 95 5 9 95 5 Gradient schedule for LC time (min) A (%) B (%) 0 95 5 0.75 95 5 1 75 25 6 50 50 6.25 0 100 7.5 0 100 7.75 95 5 9 95 5

TOF MS參數 Item 條件儀器 Xevo G2-XS Qtof 毛細管電壓(kV) 4 取樣孔電壓(V) 60 源溫度(℃) 120 孔氣流(L/h) 50 去溶劑氣體(L/h) 1000 介面類別型 ES, 正分析器模式敏感掃描範圍 500-2000 m/z TOF MS parameters Item condition instrument Xevo G2-XS Qtof Capillary voltage (kV) 4 Sampling hole voltage (V) 60 Source temperature (℃) 120 Hole airflow (L/h) 50 Desolvation gas (L/h) 1000 interface type ES, positive Analyzer mode sensitive Scan range 500-2000 m/z

資料分析： %結合至KRAS(G12C) = 複合物的峰高/ [複合物的峰高 + 未結合的KRAS G12C的峰高] X 100.ANALYSE information: % bound to KRAS(G12C) = peak height of complex / [peak height of complex + peak height of unbound KRAS G12C] X 100.

試驗結果：測試結果如下表所示：實施例號 POC(%，5 min) POC(%，30 min) 實施例1 7.9 69.2 實施例2 22.4 90.6 實施例4 9.8 74.0 實施例3 54.2 92.1 實施例9 73.7 94.8 實施例10 67.5 93.2 實施例11 60.1 93.4 實施例12 76.8 92.7 實施例13 57.9 90.1 實施例14 13.0 52.4 實施例15 3.3 16.4 實施例16 2.2 12.5 實施例17 1.8 8.3 實施例18 21.7 69.2 實施例19 59.6 90.7 實施例20 9.5 45.5 實施例21 71.6 92.4 實施例22 3.2 18.8 實施例23 5.2 29.0 實施例24 75.9 92.4 實施例25 58.8 85.3 實施例26 62.6 86.9 實施例27 35.9 75.5 實施例28 50.2 84.0 實施例29 26.7 73.1 實施例30 59.9 89.3 實施例31 82.5 92.9 實施例32 54.4 89.9 實施例33 87.4 93.1 實施例34 57.1 87.9 實施例35 14.8 47.6 實施例36 62.8 80.7 實施例37 11.9 39.0 實施例38 60.1 90.3 實施例39 62.7 89.5 實施例40 55.9 84.4 實施例41 80.6 93.3 實施例42 53.3 88.0 實施例43 31.7 68.6 實施例44 38.0 78.5 實施例45 34.5 81.3 實施例46 50.9 81.2 實施例47 55.7 84.6 實施例48 47.1 85.9 實施例49 53.8 85.9 實施例50 67.1 92.6 實施例51 80.9 92.7 實施例52 75.0 92.7 實施例53 81.9 94.5 實施例54 77.0 94.5 實施例55 57.7 91.5 實施例56 64.6 91.9 實施例57 48.9 77.9 實施例58 20.4 64.2 實施例59 54.8 78.6 實施例60 5.8 13.2 實施例61 15.2 65.0 實施例62 29.3 82.3 Test results: The test results are shown in the following table: Example number POC(%, 5 min) POC(%, 30 min) Example 1 7.9 69.2 Example 2 22.4 90.6 Example 4 9.8 74.0 Example 3 54.2 92.1 Example 9 73.7 94.8 Example 10 67.5 93.2 Example 11 60.1 93.4 Example 12 76.8 92.7 Example 13 57.9 90.1 Example 14 13.0 52.4 Example 15 3.3 16.4 Example 16 2.2 12.5 Example 17 1.8 8.3 Example 18 21.7 69.2 Example 19 59.6 90.7 Example 20 9.5 45.5 Example 21 71.6 92.4 Example 22 3.2 18.8 Example 23 5.2 29.0 Example 24 75.9 92.4 Example 25 58.8 85.3 Example 26 62.6 86.9 Example 27 35.9 75.5 Example 28 50.2 84.0 Example 29 26.7 73.1 Example 30 59.9 89.3 Example 31 82.5 92.9 Example 32 54.4 89.9 Example 33 87.4 93.1 Example 34 57.1 87.9 Example 35 14.8 47.6 Example 36 62.8 80.7 Example 37 11.9 39.0 Example 38 60.1 90.3 Example 39 62.7 89.5 Example 40 55.9 84.4 Example 41 80.6 93.3 Example 42 53.3 88.0 Example 43 31.7 68.6 Example 44 38.0 78.5 Example 45 34.5 81.3 Example 46 50.9 81.2 Example 47 55.7 84.6 Example 48 47.1 85.9 Example 49 53.8 85.9 Example 50 67.1 92.6 Example 51 80.9 92.7 Example 52 75.0 92.7 Example 53 81.9 94.5 Example 54 77.0 94.5 Example 55 57.7 91.5 Example 56 64.6 91.9 Example 57 48.9 77.9 Example 58 20.4 64.2 Example 59 54.8 78.6 Example 60 5.8 13.2 Example 61 15.2 65.0 Example 62 29.3 82.3

以上內容是結合具體的最佳實施方式對本發明所作的進一步詳細說明，不能認定本發明的具體實施只侷限於這些說明。對於本發明所屬技術領域的通常知識者來說，在不脫離本發明構思的前提下，還可以做出若干簡單推演或替換，都應當視為屬於本發明的保護範圍。The above content is a further detailed description of the present invention in conjunction with the specific best embodiments, and it cannot be considered that the specific implementation of the present invention is limited to these descriptions. For those skilled in the art to which the present invention pertains, some simple deductions or substitutions can be made without departing from the concept of the present invention, which should be regarded as belonging to the protection scope of the present invention.

無。none.

Claims

式(I)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物：

(I) 其中，環A為C_6-10 芳基或5-14員雜芳基，優選為萘基或9-10員雜芳基，優選萘基、苯並5員雜芳基或苯並6員雜芳基； R₆ 獨立地為H、D、C_0-6 亞烷基-鹵素、C_0-6 亞烷基-CN、C_0-6 亞烷基-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、C_0-6 亞烷基-O-R_1a 、C_0-6 亞烷基-S-R_1a 、C_0-6 亞烷基-N(R_1a )₂ 、C_0-6 亞烷基-C(O)R_1a 、C_0-6 亞烷基-C(O)OR_1a 、C_0-6 亞烷基-C(O)N(R_1a )₂ 或C_0-6 亞烷基-S(O)_m R_1a ；優選地，其中至少一個R₆ 為-O-R_1a ； m=1或2； n=0、1、2、3、4、5、6或7； L₁ 為-H₁ -H₂ -H₃ -H₄ -；其中H₁ 選自-O-、-S-、-N(R_H’ )-、-C(R_H )(R_H )-、-C(R_H )(R_H )-C(R_H )(R_H )-或-C(R_H )(R_H )-C(R_H )(R_H )-C(R_H )(R_H )-，H₂ 、H₃ 和H₄ 獨立地選自-O-、-S-、-N(R_H’ )-或-C(R_H )(R_H )-；並且，H₁ 和H₃ 上的R_H /R_H’ 取代基、H₁ 和H₄ 上的R_H /R_H’ 取代基、和H₂ 和H₄ 上的R_H /R_H’ 取代基中的一對或兩對R_H /R_H’ 取代基可以結合形成C_1-3 亞烷基； R_H 為H、D、C_0-6 亞烷基-鹵素、C_0-6 亞烷基-CN、C_0-6 亞烷基-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、C_0-6 亞烷基-O-R_1a 、C_0-6 亞烷基-S-R_1a 或C_0-6 亞烷基-N(R_1a )₂ ； R_H’ 為H、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基或C_2-6 炔基； R₁ 為C_1-6 鹵代烷基或

；其中R_a 、R_b 和R_c 獨立地選自H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ；其任選被R’取代；並且R_a 和R_b 可以形成化學鍵從而使得雙鍵變為三鍵；其中R’為H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； L₂ 為化學鍵、-O-(C(R_L2 )(R_L2 ))_p -、-S-(C(R_L2 )(R_L2 ))_p -、-N(R_L2’ )-(C(R_L2 )(R_L2 ))_p -或-(C(R_L2 )(R_L2 ))_p -；其中p=0、1、2、3或4； R_L2 為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； R_L2’ 為H、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基或C_2-6 炔基；並且，相鄰原子上的R_L2 /R_L2’ 可以結合形成C_3-10 環烷基或3-10員雜環基； R₂ 為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-N(R_1a )₂ 、C_3-10 環烷基、3-10員雜環基、C_6-10 芳基或5-14員雜芳基；其任選被r個R取代； L₃ 為化學鍵或-(C(R_L3 )(R_L3 ))_p -；其中R_L3 為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ；並且，相鄰原子上的R_L3 可以結合形成C_3-10 環烷基或3-10員雜環基； R₃ 為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-N(R_1a )₂ 、C_3-10 環烷基、3-10員雜環基、C_6-10 芳基或5-14員雜芳基；其任選被r個R取代；其中R為H、D、C_0-6 亞烷基-鹵素、C_0-6 亞烷基-CN、C_0-6 亞烷基-SF₅ 、C_0-6 亞烷基-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、C_0-6 亞烷基-O-R_1a 、C_0-6 亞烷基-S-R_1a 、C_0-6 亞烷基-N(R_1a )₂ 、C_0-6 亞烷基-C(O)R_1a 、C_0-6 亞烷基-C(O)OR_1a 、C_0-6 亞烷基-C(O)N(R_1a )₂ 、C_0-6 亞烷基-S(O)_m R_1a 、C_0-6 亞烷基-C_3-10 環烷基、C_0-6 亞烷基-3-10員雜環基、C_0-6 亞烷基-C_6-10 芳基或C_0-6 亞烷基-5-14員雜芳基； r=0、1、2、3、4、5、6或7； R₄ 為H、D、鹵素、-CN、-SF₅ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 、-N(R_1a )₂ 、C_3-10 環烷基、C_3-10 鹵代環烷基、3-10員雜環基、3-10員鹵代雜環基、C_6-10 芳基或5-14員雜芳基； Z₁ 為CR₅ 或N； Z₂ 為CR₅ 或N； R₅ 獨立地為H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； R₇ 為H，或者R₇ 與-L₃ -R₃ 形成雙鍵，或R₇ 與-L₂ -R₂ 形成=Z； Z為O或S； R_1a 為H、-C(O)H、-C(O)OH、-C(O)C_1-6 烷基、-C(O)OC_1-6 烷基、-S(O)_m C_1-6 烷基、C_1-6 烷基、C_1-6 鹵代烷基、C_3-10 環烷基、C_3-10 鹵代環烷基、3-10員雜環基、3-10員鹵代雜環基、C_6-10 芳基或5-14員雜芳基；上述各基團中含有的OH、NH、NH₂ 、CH、CH₂ 、CH₃ 基團在每次出現時各自任選地被1、2、3或更多個R^s 及其同位素變體取代，其中所述R^s 在每次出現時獨立地選自：鹵素、羥基、胺基、氰基、硝基、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、C_3-10 環烷基、C_3-10 鹵代環烷基、3-10員雜環基、C_6-10 芳基、5-14員雜芳基、C_6-12 芳烷基、-OR^a’ 、-OC(O)R^a’ 、-C(O)R^a’ 、-C(O)OR^a’ 、-C(O)NR^a’ R^b’ 、-S(O)_q R^a’ 、-S(O)_q OR^a’ 、-S(O)_q NR^a’ R^b’ 、-NR^a’ R^b’ 、-NR^a’ C(O)R^b’ 、-NR^a’ -C(O)OR^b’ 、-NR^a’ -S(O)_q -R^b’ 、-NR^a’ C(O)NR^a’ R^b’ 、-C_1-6 亞烷基-R^a’ 、-C_1-6 亞烷基-OR^a’ 、-C_1-6 亞烷基-OC(O)R^a’ 、-C_1-6 亞烷基-C(O)OR^a’ 、-C_1-6 亞烷基-S(O)_q R^a’ 、-C_1-6 亞烷基-S(O)_q OR^a’ 、-C_1-6 亞烷基-OC(O)NR^a’ R^b’ 、-C_1-6 亞烷基-C(O)NR^a’ R^b’ 、-C_1-6 亞烷基-NR^a’ -C(O)NR^a’ R^b’ 、-C_1-6 亞烷基-OS(O)_q R^a’ 、-C_1-6 亞烷基-S(O)_q NR^a’ R^b’ 、-C_1-6 亞烷基-NR^a’ -S(O)_q NR^a’ R^b’ 、-C_1-6 亞烷基-NR^a’ R^b’ 和-O-C_1-6 亞烷基-NR^a’ R^b’ ，並且其中關於取代基R^s 所述的羥基、胺基、烷基、亞烷基、環烷基、雜環基、芳基、雜芳基和芳烷基進一步任選地被1、2、3或更多個獨立地選自下列的取代基及其同位素變體取代：鹵素、OH、胺基、氰基、硝基、C_1-6 烷基、C_1-6 鹵代烷基、C_1-6 烷基羥基、C_3-6 環烷基、3-10員雜環基、C_6-10 芳基、5-14員雜芳基和C_6-12 芳烷基； q每次出現時各自獨立地為1或2； R^a’ 和R^b’ 在每次出現時各自獨立地選自H、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_1-6 烷基-O-、C_1-6 烷基-S-、C_3-10 環烷基、3-10員雜環基、C_6-10 芳基、5-14員雜芳基和C_6-12 芳烷基。A compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and their mixtures:

(1) wherein, ring A is C _6-10 -membered aryl or 5-14-membered heteroaryl, preferably naphthyl or 9-10-membered heteroaryl, preferably naphthyl, benzo 5-membered heteroaryl or benzo 6-membered heteroaryl; R ₆ is independently H, D, C _0-6 alkylene-halogen, C _0-6 alkylene-CN, C _0-6 alkylene-NO ₂ , C _1-6 Alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _0-6 alkylene-OR _1a , C _0-6 alkylene-SR _1a , C _0-6 Alkylene-N(R _1a ) ₂ , C _0-6 alkylene-C(O)R _1a , C _0-6 alkylene-C(O)OR _1a , C _0-6 alkylene-C (O)N(R _1a ) ₂ or C _0-6 alkylene-S(O) _m R _1a ; preferably, at least one of R ₆ is -OR _1a ; m=1 or 2; n=0, 1 , 2, 3, 4, 5, 6 or 7; L ₁ is -H ₁ -H ₂ -H ₃ -H ₄ -; wherein H ₁ is selected from -O-, -S-, -N( _RH' ) -, -C( _RH )( _RH )-, -C( _RH )( _RH )-C( _RH )( _RH )- or -C( _RH )( _RH )-C(R _H )( _RH )-C( _RH )( _RH ) _- , _H2 , _H3 and H4 are independently selected from -O-, -S-, -N( _RH' )- or -C( _RH )( _RH )-; and, the RH/ _RH' _substituent _on H1 and _H3 , the _RH /RH' substituent _on H1 and H4, and the _RH / _RH' substituent _on H1 and _H4 One or two pairs of _RH /RH _' substituents in the _RH / _RH' substituents can be combined to form C _1-3 alkylene; _RH is H, D, C _0-6 alkylene- Halogen, C _0-6 alkylene-CN, C _0-6 alkylene-NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _0-6 alkylene-OR _1a , C _0-6 alkylene-SR _1a or C _0-6 alkylene-N(R _1a ) ₂ ; _RH' is H, C _1-6 alkyl , C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl; R ₁ is C _1-6 haloalkyl or

; wherein R _a , R _b and R _c are independently selected from H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; it is optionally substituted by R'; and R _a and R _b can form a chemical bond so that the double bond becomes a triple bond; wherein R' is H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; L ₂ is a chemical bond, -O-(C(R _L2 )(R _L2 )) _p -, -S-(C( R _L2 )(R _L2 )) _p -, -N(R _L2' )-(C(R _L2 )(R _L2 )) _p - or -(C(R _L2 )(R _L2 )) _p -; where p =0, 1, 2, 3 or 4; R _L2 is H, D, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; R _L2' is H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _{2 -6} alkynyl; and, R _L2 /R _L2' on adjacent atoms can combine to form C _3-10 cycloalkyl or 3-10 membered heterocyclic group; R ₂ is H, D, halogen, -CN, - NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -N(R _1a ) ₂ , C _3-10 cycloalkyl, 3-10 Member heterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl; it is optionally substituted by r R; L ₃ is a chemical bond or -(C(R _L3 )(R _L3 )) _p -; wherein R _L3 is H, D, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; and R _L3 on adjacent atoms can combine to form C _3-10 cycloalkyl or 3-10 membered heterocyclic group; R ₃ is H, D, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -N(R _1a ) ₂ , C _3-10 cycloalkyl, 3- 10-membered heterocyclyl, C _6-10 -membered aryl or 5-14-membered heteroaryl; it is optionally substituted by r R; wherein R is H, D, C _0-6 alkylene-halogen, C _{0- 6} alkylene-CN, C _0-6 alkylene-SF ₅ , C _0-6 alkylene-NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _0-6 alkylene-OR _1a , C _0-6 alkylene-SR _1a , C _0-6 alkylene-N(R _1a ) ₂ , C _0-6 alkylene-C(O)R _1a , C _0-6 alkylene-C(O)OR _1a , C _{0- 6} alkylene-C(O)N(R _1a ) ₂ , C _0-6 alkylene-S(O) _m R _1a , C _0-6 alkylene-C _3-10 cycloalkyl, C _{0 -6} alkylene-3-10 membered heterocyclyl, C _0-6 alkylene-C _6-10 aryl or C _0-6 alkylene-5-14 membered heteroaryl; r=0, 1 , 2, 3, 4, 5, 6 or 7; R ₄ is H, D, halogen, -CN, -SF ₅ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a , -N(R _1a ) ₂ , C _3-10 cycloalkyl, C _3-10 halocycloalkyl, 3-10 membered heterocyclyl, 3 -10-membered halogenated heterocyclic group, C _6-10 -membered aryl group or 5-14-membered heteroaryl group; Z ₁ is CR ₅ or N; Z ₂ is CR ₅ or N; R ₅ is independently H, D, halogen , -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; R ₇ It is H, or R ₇ and -L ₃ -R ₃ form a double bond, or R ₇ and -L ₂ -R ₂ form =Z; Z is O or S; R _1a is H, -C(O)H, - C(O)OH, -C(O)C _1-6 alkyl, -C(O)OC _1-6 alkyl, -S(O) _m C _1-6 alkyl, C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _3-10 halocycloalkyl, 3-10 membered heterocyclyl, 3-10 membered haloheterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl; the OH, NH, NH ₂ , CH, CH ₂ , CH ₃ groups contained in each of the above groups are each optionally replaced by 1, 2, 3 or more at each occurrence R ^s and isotopic variants thereof are substituted, wherein said R ^s at each occurrence is independently selected from: halogen, hydroxy, amine, cyano, nitro, C _1-6 alkyl, C _1-6 haloalkyl , C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _3-10 halocycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5- 14-membered heteroaryl, C _6-12 aralkyl, -OR ^a' , -OC(O)R ^a' , -C(O)R ^a' , -C(O)OR ^a' , -C(O )NR ^a' R ^b' , -S(O) _q R ^a' , -S(O) _q OR ^a' , -S(O) _q NR ^a' R ^b' , -NR ^a' R ^b' , - NR ^a' C(O)R ^b' , -NR ^a' -C(O) OR ^b' , -NR ^a' -S(O) _q -R ^b' , -NR ^a' C(O)NR ^a' R ^b' , -C _1-6 alkylene-R ^a' , -C _{1 -6} alkylene-OR ^a' , -C _1-6 alkylene-OC(O)R ^a' , -C _1-6 alkylene-C(O)OR ^a' , -C _1-6 alkylene Alkyl-S(O) _q R ^a' , -C _1-6 alkylene-S(O) _q OR ^a' , -C _1-6 alkylene-OC(O)NR ^a' R ^b' , -C _1-6 alkylene-C(O)NR ^a' R ^b' , -C _1-6 alkylene-NR ^a' -C(O)NR ^a' R ^b' , -C _1-6 alkylene Alkyl-OS(O) _q R ^a' , -C _1-6 alkylene-S(O) _q NR ^a' R ^b' , -C _1-6 alkylene-NR ^a' -S(O) _q NR ^a' R ^b' , -C _1-6 alkylene-NR ^a' R ^b' and -OC _1-6 alkylene-NR ^a' R ^b' , and wherein the substituents R ^s are described Hydroxy, amino, alkyl, alkylene, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are further optionally 1, 2, 3 or more independently selected from the following Substituents and their isotopic variants Substitution: halogen, OH, amino, cyano, nitro, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkyl hydroxyl, C _3-6 cycloalkane group, 3-10 membered heterocyclyl, _C6-10 aryl, 5-14 membered heteroaryl and _C6-12 aralkyl; each occurrence of q is independently 1 or 2; R ^a' and R ^b' at each occurrence is independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl-O-, C _1-6 Alkyl-S-, _C3-10 cycloalkyl, 3-10 membered heterocyclyl, _C6-10 membered aryl, 5-14 membered heteroaryl and _C6-12 membered aralkyl.

請求項1的式(I)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物，其具有以下結構：

(I-1)、

(II)、

(III)、

(IV)、

(IV-1)、

(IV-2)、

(IV-3)，其中，環B為苯基或5-6員雜芳基； R_N1 、R_N2 和R_N3 獨立地為H、C_1-6 烷基或C_1-6 鹵代烷基；或者，R_N2 和R_N3 可以結合形成C_2-4 亞烷基；其他基團如請求項1中所定義。A compound of formula (I) of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or Isotopic variants, and mixtures thereof, having the following structures:

(I-1),

(II),

(III),

(IV),

(IV-1),

(IV-2),

(IV-3), wherein Ring B is phenyl or 5-6 membered heteroaryl; R _N1 , R _N2 and R _N3 are independently H, C _1-6 alkyl or C _1-6 haloalkyl; or , R _N2 and R _N3 can combine to form a C _2-4 alkylene group; other groups are as defined in claim 1.

(I) 其中：

選自

、

、

、

、

、

或

； L₁ 為-H₁ -H₂ -H₃ -H₄ -；其中H₁ 為-C(R_H )(R_H )-，H₂ 、H₃ 和H₄ 獨立地選自-O-、-S-、-N(R_H’ )-或-C(R_H )(R_H )-；並且，H₁ 和H₃ 上的R_H /R_H’ 取代基、H₁ 和H₄ 上的R_H /R_H’ 取代基、和H₂ 和H₄ 上的R_H /R_H’ 取代基中的一對或兩對R_H /R_H’ 取代基可以結合形成C_1-3 亞烷基； R_H 為H、D、C_0-6 亞烷基-鹵素、C_0-6 亞烷基-CN、C_0-6 亞烷基-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、C_0-6 亞烷基-O-R_1a 、C_0-6 亞烷基-S-R_1a 或C_0-6 亞烷基-N(R_1a )₂ ； R_H’ 為H、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基或C_2-6 炔基； R₁ 為

；其中R_a 、R_b 和R_c 獨立地選自H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ；並且R_a 和R_b 可以形成化學鍵從而使得雙鍵變為三鍵； L₂ 為化學鍵、-O-(C(R_L2 )(R_L2 ))_p -、-S-(C(R_L2 )(R_L2 ))_p -、-N(R_L2’ )-(C(R_L2 )(R_L2 ))_p -或-(C(R_L2 )(R_L2 ))_p -；其中p=0、1、2、3或4； R_L2 為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； R_L2’ 為H、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基或C_2-6 炔基；並且，R_L2 /R_L2’ 可以結合形成C_3-10 環烷基或3-10員雜環基； R₂ 為鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-N(R_1a )₂ 、C_3-10 環烷基、3-10員雜環基、C_6-10 芳基或5-14員雜芳基；其任選被r個R取代；其中R為H、D、C_0-6 亞烷基-鹵素、C_0-6 亞烷基-CN、C_0-6 亞烷基-SF₅ 、C_0-6 亞烷基-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、C_0-6 亞烷基-O-R_1a 、C_0-6 亞烷基-S-R_1a 、C_0-6 亞烷基-N(R_1a )₂ 、C_0-6 亞烷基-C(O)R_1a 、C_0-6 亞烷基-C(O)OR_1a 、C_0-6 亞烷基-C(O)N(R_1a )₂ 、C_0-6 亞烷基-S(O)_m R_1a 、C_0-6 亞烷基-C_3-10 環烷基、C_0-6 亞烷基-3-10員雜環基、C_0-6 亞烷基-C_6-10 芳基或C_0-6 亞烷基-5-14員雜芳基； r=0、1、2、3、4、5、6或7； m=1或2； R₄ 為H、D、鹵素、-CN、-SF₅ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 、-N(R_1a )₂ 、C_3-10 環烷基、C_3-10 鹵代環烷基、3-10員雜環基、3-10員鹵代雜環基、C_6-10 芳基或5-14員雜芳基； Z₁ 為CR₅ ； Z₂ 為CR₅ ；其中R₅ 獨立地為H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； R₇ 與-L₃ -R₃ 形成雙鍵； R_1a 為H、-C(O)H、-C(O)OH、-C(O)C_1-6 烷基、-C(O)OC_1-6 烷基、-S(O)_m C_1-6 烷基、C_1-6 烷基、C_1-6 鹵代烷基、C_3-10 環烷基、C_3-10 鹵代環烷基、3-10員雜環基、3-10員鹵代雜環基、C_6-10 芳基或5-14員雜芳基。A compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and their mixtures:

(I) of which:

selected from

,

or

; L ₁ is -H ₁ -H ₂ -H ₃ -H ₄ -; wherein H ₁ is -C( _RH )( _RH )-, and H ₂ , H ₃ and H ₄ are independently selected from -O-, -S-, -N( _RH' )- or -C( _RH )( _RH )-; and, RH/ _RH' substituents on _H ₁ and H ₃ , H ₁ and H ₄ on One or two pairs of the _RH /RH _' substituents, and the _RH / _RH' substituents _on _H and _H may combine to form _{a C1-3} _alkylene group ; _RH is H, D, C _0-6 alkylene-halogen, C _0-6 alkylene-CN, C _0-6 alkylene-NO ₂ , C _1-6 alkyl, C _1-6 Haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _0-6 alkylene-OR _1a , C _0-6 alkylene-SR _1a or C _0-6 alkylene-N(R _1a ) ₂ ; _RH' is H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl; R ₁ is

; wherein R _a , R _b and R _c are independently selected from H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; and R _a and R _b can form a chemical bond so that the double bond becomes a triple bond; L ₂ is a chemical bond, -O-(C(R _L2 )(R _L2 )) _p -, -S-(C(R _L2 )(R _L2 )) _p -, -N(R _L2' )-(C(R _L2 )(R _L2 )) _p - or -(C(R _L2 )(R _L2 )) _p -; where p= 0, 1, 2, 3 or 4; R _L2 is H, D, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _{2- 6alkynyl} , -OR _1a , -SR _1a or -N(R _1a ) ₂ ; R _L2' is H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _{2- 6} alkynyl; and, R _L2 /R _L2' can be combined to form C _3-10 cycloalkyl or 3-10 membered heterocyclic group; R ₂ is halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -N(R _1a ) ₂ , C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 -membered aryl or 5-14-membered heteroaryl; it is optionally substituted by r R; wherein R is H, D, C _0-6 alkylene-halogen, C _0-6 alkylene-CN, C _0-6 alkylene-SF ₅ , C _0-6 alkylene-NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _0-6 alkylene-OR _1a , C _0-6 alkylene-SR _1a , C _0-6 alkylene-N(R _1a ) ₂ , C _0-6 alkylene-C(O)R _1a , C _0-6 alkylene-C(O)OR _1a , C _0-6 alkylene-C(O)N(R _1a ) ₂ , C _0-6 alkylene-S(O) _m R _1a , C _0-6 alkylene-C _3-10 cycloalkyl, C _0-6 alkylene-3-10-membered heterocyclic group, C _0-6 alkylene-C _6-10 aryl or C _0-6 alkylene-5-14 membered heteroaryl; r=0, 1, 2, 3, 4, 5, 6 or 7; m=1 or 2; R ₄ is H, D, halogen, -CN , -SF ₅ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a , -N(R _1a ) ₂ , C _3-10 cycloalkyl, C _3-10 halocycloalkyl, 3-10 membered heterocyclyl, 3-10 membered haloheterocyclyl, C _6-10 aryl or 5-1 4-membered heteroaryl; Z ₁ is CR ₅ ; Z ₂ is CR ₅ ; wherein R ₅ is independently H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; R ₇ and -L ₃ -R ₃ form a double bond; R _1a is H, -C(O) H, -C(O)OH, -C(O)C _1-6 alkyl, -C(O)OC _1-6 alkyl, -S(O) _m C _1-6 alkyl, C _1-6 Alkyl, C _1-6 halogenated alkyl, C _3-10 cycloalkyl, C _3-10 halogenated cycloalkyl, 3-10 membered heterocyclyl, 3-10 membered halogenated heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl.

式(I-1)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物：

(I-1) 其中，環B為苯基或5-6員雜芳基； R₆ 獨立地為H、D、C_0-6 亞烷基-鹵素、C_0-6 亞烷基-CN、C_0-6 亞烷基-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、C_0-6 亞烷基-O-R_1a 、C_0-6 亞烷基-S-R_1a 或C_0-6 亞烷基-N(R_1a )₂ ，並且其中至少一個R₆ 為-OH； n=0、1、2、3、4、5、6或7； L₁ 為-H₁ -H₂ -H₃ -H₄ -；其中H₁ 為-C(R_H )(R_H )-，H₂ 、H₃ 和H₄ 獨立地選自-O-、-S-、-N(R_H’ )-或-C(R_H )(R_H )-；並且，H₁ 和H₃ 上的R_H /R_H’ 取代基、H₁ 和H₄ 上的R_H /R_H’ 取代基、和H₂ 和H₄ 上的R_H /R_H’ 取代基中的一對或兩對R_H /R_H’ 取代基可以結合形成C_1-3 亞烷基； R_H 為H、D、C_0-6 亞烷基-鹵素、C_0-6 亞烷基-CN、C_0-6 亞烷基-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、C_0-6 亞烷基-O-R_1a 、C_0-6 亞烷基-S-R_1a 或C_0-6 亞烷基-N(R_1a )₂ ； R_H’ 為H、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基或C_2-6 炔基； R₁ 為

；其中R_a 、R_b 和R_c 獨立地選自H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ；並且R_a 和R_b 可以形成化學鍵從而使得雙鍵變為三鍵； L₂ 為化學鍵、-O-(C(R_L2 )(R_L2 ))_p -、-S-(C(R_L2 )(R_L2 ))_p -、-N(R_L2’ )-(C(R_L2 )(R_L2 ))_p -或-(C(R_L2 )(R_L2 ))_p -；其中p=0、1、2、3或4； R_L2 為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； R_L2’ 為H、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基或C_2-6 炔基；並且，R_L2 /R_L2’ 可以結合形成C_3-10 環烷基或3-10員雜環基； R₂ 為鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-N(R_1a )₂ 、C_3-10 環烷基、3-10員雜環基、C_6-10 芳基或5-14員雜芳基；其任選被r個R取代；其中R為H、D、C_0-6 亞烷基-鹵素、C_0-6 亞烷基-CN、C_0-6 亞烷基-SF₅ 、C_0-6 亞烷基-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、C_0-6 亞烷基-O-R_1a 、C_0-6 亞烷基-S-R_1a 、C_0-6 亞烷基-N(R_1a )₂ 、C_0-6 亞烷基-C(O)R_1a 、C_0-6 亞烷基-C(O)OR_1a 、C_0-6 亞烷基-C(O)N(R_1a )₂ 、C_0-6 亞烷基-S(O)_m R_1a 、C_0-6 亞烷基-C_3-10 環烷基、C_0-6 亞烷基-3-10員雜環基、C_0-6 亞烷基-C_6-10 芳基或C_0-6 亞烷基-5-14員雜芳基； r=0、1、2、3、4、5、6或7； R₄ 為H、D、鹵素、-CN、-SF₅ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 、-N(R_1a )₂ 、C_3-10 環烷基、C_3-10 鹵代環烷基、3-10員雜環基、3-10員鹵代雜環基、C_6-10 芳基或5-14員雜芳基； R₅ 獨立地為H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； m=1或2； R_1a 為H、-C(O)H、-C(O)OH、-C(O)C_1-6 烷基、-C(O)OC_1-6 烷基、-S(O)_m C_1-6 烷基、C_1-6 烷基、C_1-6 鹵代烷基、C_3-10 環烷基、C_3-10 鹵代環烷基、3-10員雜環基、3-10員鹵代雜環基、C_6-10 芳基或5-14員雜芳基。A compound of formula (I-1), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variation thereof body, and their mixtures:

(I-1) wherein, ring B is phenyl or 5-6 membered heteroaryl; R ₆ is independently H, D, C _0-6 alkylene-halogen, C _0-6 alkylene-CN, C _0-6 alkylene-NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _0-6 alkylene-OR _1a , C _0-6 alkylene-SR _1a or C _0-6 alkylene-N(R _1a ) ₂ , and wherein at least one R ₆ is -OH; n=0, 1, 2, 3, 4, 5, 6 or 7; L ₁ is -H ₁ -H ₂ -H ₃ -H ₄ -; wherein H ₁ is -C( _RH )( _RH )-, and H ₂ , H ₃ and H ₄ are independently selected from - O-, -S-, -N( _RH' )- or -C( _RH )( _RH )-; and, _RH / _RH' _substituents _on H1 and _H3 , H1 and H The _RH / _RH' substituent on ₄ , and one or _two pairs of _RH / _RH' _substituent _on _H and H4 can combine to form _C1-3 Alkylene; R _H is H, D, C _0-6 alkylene-halogen, C _0-6 alkylene-CN, C _0-6 alkylene-NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _0-6 alkylene-OR _1a , C _0-6 alkylene-SR _1a or C _0-6 alkylene- N(R _1a ) ₂ ; _RH' is H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl; R ₁ is

; wherein R _a , R _b and R _c are independently selected from H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; and R _a and R _b can form a chemical bond so that the double bond becomes a triple bond; L ₂ is a chemical bond, -O-(C(R _L2 )(R _L2 )) _p -, -S-(C(R _L2 )(R _L2 )) _p -, -N(R _L2' )-(C(R _L2 )(R _L2 )) _p - or -(C(R _L2 )(R _L2 )) _p -; where p= 0, 1, 2, 3 or 4; R _L2 is H, D, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _{2- 6alkynyl} , -OR _1a , -SR _1a or -N(R _1a ) ₂ ; R _L2' is H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _{2- 6} alkynyl; and, R _L2 /R _L2' can be combined to form C _3-10 cycloalkyl or 3-10 membered heterocyclic group; R ₂ is halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -N(R _1a ) ₂ , C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 -membered aryl or 5-14-membered heteroaryl; it is optionally substituted by r R; wherein R is H, D, C _0-6 alkylene-halogen, C _0-6 alkylene-CN, C _0-6 alkylene-SF ₅ , C _0-6 alkylene-NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _0-6 alkylene-OR _1a , C _0-6 alkylene-SR _1a , C _0-6 alkylene-N(R _1a ) ₂ , C _0-6 alkylene-C(O)R _1a , C _0-6 alkylene-C(O)OR _1a , C _0-6 alkylene-C(O)N(R _1a ) ₂ , C _0-6 alkylene-S(O) _m R _1a , C _0-6 alkylene-C _3-10 cycloalkyl, C _0-6 alkylene-3-10-membered heterocyclic group, C _0-6 alkylene-C _6-10 aryl or C _0-6 alkylene-5-14 membered heteroaryl; r=0, 1, 2, 3, 4, 5, 6 or 7; R ₄ is H, D, halogen, -CN, -SF ₅ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a , -N(R _1a ) ₂ , C _3-10 cycloalkyl , C _3-10 halogenated cycloalkyl, 3-10 membered heterocyclyl, 3-10 membered halogenated heterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl; R ₅ is independently H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; m=1 or 2; R _1a is H, -C(O)H, -C(O)OH, -C(O)C _1-6 alkyl, -C(O) OC _1-6 alkyl, -S(O) _m C _1-6 alkyl, C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _3-10 halocycloalkane group, 3-10-membered heterocyclyl, 3-10-membered halogenated heterocyclyl, C _6-10 -membered aryl or 5-14-membered heteroaryl.

請求項4的式(I-1)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物，其中，環B為苯基； R₆ 獨立地為H、D、C_0-6 亞烷基-鹵素、C_0-6 亞烷基-CN、C_0-6 亞烷基-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、C_0-6 亞烷基-O-R_1a 、C_0-6 亞烷基-S-R_1a 或C_0-6 亞烷基-N(R_1a )₂ ，並且其中至少一個R₆ 為-OH； n=0、1、2、3、4、5、6或7； L₁ 為

或

； R₁ 為

；其中R_a 、R_b 和R_c 獨立地選自H、D、鹵素、-CN、C_1-6 烷基或C_1-6 鹵代烷基；並且R_a 和R_b 可以形成化學鍵從而使得雙鍵變為三鍵； L₂ 為化學鍵、-O-(C(R_L2 )(R_L2 ))_p -、-S-(C(R_L2 )(R_L2 ))_p -或-N(R_L2’ )-(C(R_L2 )(R_L2 ))_p -；其中p=0、1、2、3或4； R_L2 為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； R_L2’ 為H、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基或C_2-6 炔基；並且，R_L2 /R_L2’ 可以結合形成C_3-10 環烷基或3-10員雜環基； R₂ 為鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-N(R_1a )₂ 、C_3-10 環烷基、3-10員雜環基、C_6-10 芳基或5-14員雜芳基；其任選被r個R取代；其中R為H、D、C_0-6 亞烷基-鹵素、C_0-6 亞烷基-CN、C_0-6 亞烷基-SF₅ 、C_0-6 亞烷基-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、C_0-6 亞烷基-O-R_1a 、C_0-6 亞烷基-S-R_1a 、C_0-6 亞烷基-N(R_1a )₂ 、C_0-6 亞烷基-C(O)R_1a 、C_0-6 亞烷基-C(O)OR_1a 或C_0-6 亞烷基-C(O)N(R_1a )₂ ； r=0、1、2、3、4、5、6或7； R₄ 為H、D、鹵素、-CN或-SF₅ ； R₅ 獨立地為H、D、鹵素、-CN、C_1-6 烷基或C_1-6 鹵代烷基； m=1或2； R_1a 為H、C_1-6 烷基、C_1-6 鹵代烷基、C_3-10 環烷基、C_3-10 鹵代環烷基、3-10員雜環基、3-10員鹵代雜環基、C_6-10 芳基或5-14員雜芳基。The compound of formula (I-1) of claim 4, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or precursor thereof Drugs or isotopic variants, and mixtures thereof, wherein Ring B is phenyl; R ₆ is independently H, D, C _0-6 alkylene-halogen, C _0-6 alkylene-CN, C _{0 -6} alkylene-NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _0-6 alkylene-OR _1a , C _{0 -6} alkylene-SR _1a or C _0-6 alkylene-N(R _1a ) ₂ , and wherein at least one R ₆ is -OH; n=0, 1, 2, 3, 4, 5, 6 or ₇ ; L1 is

or

; R ₁ is

wherein R _a , R _b and R _c are independently selected from H, D, halogen, -CN, C _1-6 alkyl or C _1-6 haloalkyl; and R _a and R _b can form a chemical bond such that a double bond Become a triple bond; L ₂ is a chemical bond, -O-(C(R _L2 )(R _L2 )) _p -, -S-(C(R _L2 )(R _L2 )) _p - or -N(R _L2' )-(C(R _L2 )(R _L2 )) _p -; wherein p=0, 1, 2, 3 or 4; R _L2 is H, D, halogen, -CN, -NO ₂ , C _1-6 alkane base, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; R _L2' is H, C _1-6 alkane base, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl; and, R _L2 /R _L2' can be combined to form C _3-10 cycloalkyl or 3-10 membered heterocyclyl; R ₂ is halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -N(R _1a ) _2. C _3-10 cycloalkyl, 3-10-membered heterocyclyl, C _6-10 -membered aryl or 5-14-membered heteroaryl; it is optionally substituted by r Rs; wherein R is H, D, C _0-6 alkylene-halogen, C _0-6 alkylene-CN, C _0-6 alkylene-SF ₅ , C _0-6 alkylene-NO ₂ , C _1-6 alkyl, C _{1 -6} haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _0-6 alkylene-OR _1a , C _0-6 alkylene-SR _1a , C _0-6 alkylene-N (R _1a ) ₂ , C _0-6 alkylene-C(O)R _1a , C _0-6 alkylene-C(O)OR _1a or C _0-6 alkylene-C(O)N( R _1a ) ₂ ; r=0, 1, 2, 3, 4, 5, 6 or 7; R ₄ is H, D, halogen, -CN or -SF ₅ ; R ₅ is independently H, D, halogen, -CN, C _1-6 alkyl or C _1-6 haloalkyl; m=1 or 2; R _1a is H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _3-10 halogenated cycloalkyl, 3-10 membered heterocyclyl, 3-10 membered halogenated heterocyclyl, C _6-10 membered aryl or 5-14 membered heteroaryl.

請求項4的式(I-1)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物，其中，環B為苯基； R₆ 獨立地為H、D、鹵素、-CN、-OH、-SH或-NH₂ ，並且其中至少一個R₆ 為-OH； n=0、1、2或3； L₁ 為

或

； R₁ 為

；其中R_a 、R_b 和R_c 獨立地選自H、D、鹵素或-CN； L₂ 為化學鍵、-O-(C(R_L2 )(R_L2 ))_p -或-N(R_L2’ )-(C(R_L2 )(R_L2 ))_p -；其中p=0、1、2、3或4； R_L2 為H、D、鹵素、C_1-6 烷基或C_1-6 鹵代烷基； R_L2’ 為H；並且，R_L2 /R_L2’ 可以結合形成C_3-6 環烷基或4-7員雜環基； R₂ 為C_1-6 烷基、C_1-6 鹵代烷基、-OH、-N(R_1a )₂ 、C_3-6 環烷基、4-7員雜環基、C_6-10 芳基或5-6員雜芳基；其任選被r個R取代；其中R為H、D、鹵素、C_1-6 烷基、C_1-6 鹵代烷基、C_0-6 亞烷基-O-R_1a 、C_0-6 亞烷基-S-R_1a 、C_0-6 亞烷基-N(R_1a )₂ ； r=0、1、2、3、4、5、6或7； R₄ 為鹵素； R₅ 獨立地為H、D或鹵素； m=1或2； R_1a 為H、C_1-6 烷基或C_1-6 鹵代烷基。The compound of formula (I-1) of claim 4, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or precursor thereof Drugs or isotopic variants, and mixtures thereof, wherein Ring B is phenyl; R ₆ is independently H, D, halogen, -CN, -OH, -SH or -NH ₂ , and wherein at least one R ₆ is -OH; n=0, 1, 2 or 3; L ₁ is

or

; R ₁ is

wherein R _a , R _b and R _c are independently selected from H, D, halogen or -CN; L ₂ is a chemical bond, -O-(C(R _L2 )(R _L2 )) _p - or -N(R _{L2 '} )-(C(R _L2 )(R _L2 )) _p -; wherein p=0, 1, 2, 3 or 4; R _L2 is H, D, halogen, C _1-6 alkyl or C _1-6 Haloalkyl; R _L2' is H; and R _L2 /R _L2' can be combined to form C _3-6 cycloalkyl or 4-7 membered heterocyclic group; R ₂ is C _1-6 alkyl, C _1-6 haloalkyl, -OH, -N(R _1a ) ₂ , C _3-6 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 membered heterocyclyl, C _6-10 membered heteroaryl, or 5-6 membered heteroaryl; R is substituted; wherein R is H, D, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _0-6 alkylene-OR _1a , C _0-6 alkylene-SR _1a , C _0-6 alkylene-N(R _1a ) ₂ ; r=0, 1, 2, 3, 4, 5, 6 or 7; R ₄ is halogen; R ₅ is independently H, D or halogen; m= 1 or 2; R _1a is H, C _1-6 alkyl or C _1-6 haloalkyl.

請求項2的式(I)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物，其為式(II)化合物：

(II) 其中，環B為苯基或5-6員雜芳基； R₆ 獨立地為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； n=0、1、2、3、4或5； R₁ 為C_1-6 鹵代烷基或

；其中R_a 、R_b 和R_c 獨立地選自H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ；其任選被R’取代；並且R_a 和R_b 可以形成化學鍵從而使得雙鍵變為三鍵； R’為H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； L₂ 為化學鍵、-O-(C(R_L2 )(R_L2 ))_p -、-S-(C(R_L2 )(R_L2 ))_p -、-N(R_L2’ )-(C(R_L2 )(R_L2 ))_p -或-(C(R_L2 )(R_L2 ))_p -；其中p=0、1、2、3或4； R_L2 為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； R_L2’ 為H、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基或C_2-6 炔基；並且，相鄰原子上的R_L2 /R_L2’ 可以結合形成C_3-10 環烷基或3-10員雜環基； R₂ 為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-N(R_1a )₂ 、C_3-10 環烷基、3-10員雜環基、C_6-10 芳基或5-14員雜芳基；其任選被1-7個R取代；其中R為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 、-N(R_1a )₂ 、C_3-10 環烷基、3-10員雜環基、C_6-10 芳基或5-14員雜芳基； R₄ 為H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 、-N(R_1a )₂ 、C_3-10 環烷基或3-10員雜環基； R_1a 為H、C_1-6 烷基或C_1-6 鹵代烷基。The compound of formula (I) of claim 2, or a pharmaceutically acceptable salt, enantiomer, non-spiroisomer, racemate, solvate, hydrate, polymorph, prodrug or Isotopic variants, and mixtures thereof, which are compounds of formula (II):

(II) wherein, ring B is phenyl or 5-6 membered heteroaryl; R ₆ is independently H, D, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl , C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; n=0, 1, 2, 3, 4 or 5; R ₁ is C _{1 -6} haloalkyl or

; wherein R _a , R _b and R _c are independently selected from H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; it is optionally substituted by R'; and R _a and R _b can form a chemical bond so that the double bond becomes a triple bond; R' is H, D, halogen, -CN, C _1-6 alkyl, C _{1 -6} haloalkyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; L ₂ is a chemical bond, -O-(C(R _L2 )(R _L2 )) _p -, -S-(C(R _L2 )(R _L2 )) _p -, -N(R _L2' )-(C(R _L2 )(R _L2 )) _p - or -(C(R _L2 )(R _L2 )) _p -; where p= 0, 1, 2, 3 or 4; R _L2 is H, D, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _{2- 6alkynyl} , -OR _1a , -SR _1a or -N(R _1a ) ₂ ; R _L2' is H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _{2- 6} alkynyl; and, R _L2 /R _L2' on adjacent atoms can combine to form C _3-10 cycloalkyl or 3-10 membered heterocyclic group; R ₂ is H, D, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -N(R _1a ) ₂ , C _3-10 cycloalkyl, 3-10 member Heterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl; it is optionally substituted with 1-7 R; wherein R is H, D, halogen, -CN, -NO ₂ , C _1-6 Alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a , -N(R _1a ) ₂ , C _3-10 cycloalkyl, 3- 10-membered heterocyclyl, C _6-10 -membered aryl or 5-14-membered heteroaryl; R ₄ is H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a , -N(R _1a ) ₂ , C _3-10 cycloalkyl or 3-10 membered heterocyclyl; R _1a is H, C _{1 -6} alkyl or C _1-6 haloalkyl.

請求項2的式(I)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物，其為式(III)化合物：

(III) 其中， R₁ 為C_1-6 鹵代烷基或

；其中R_a 、R_b 和R_c 獨立地選自H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ；其任選被R’取代；並且R_a 和R_b 可以形成化學鍵從而使得雙鍵變為三鍵； R’為H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； L₂ 為化學鍵、-O-(C(R_L2 )(R_L2 ))_p -、-S-(C(R_L2 )(R_L2 ))_p -、-N(R_L2’ )-(C(R_L2 )(R_L2 ))_p -或-(C(R_L2 )(R_L2 ))_p -；其中p=0、1、2、3或4； R_L2 為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； R_L2’ 為H、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基或C_2-6 炔基；並且，相鄰原子上的R_L2 /R_L2’ 可以結合形成C_3-10 環烷基或3-10員雜環基； R₂ 為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-N(R_1a )₂ 、C_3-10 環烷基、3-10員雜環基、C_6-10 芳基或5-14員雜芳基；其任選被1-7個R取代；其中R為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 、-N(R_1a )₂ 、C_3-10 環烷基、3-10員雜環基、C_6-10 芳基或5-14員雜芳基； R₄ 為鹵素、-CN或-NO₂ ； R₆ 為鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； R_1a 為H、C_1-6 烷基或C_1-6 鹵代烷基。The compound of formula (I) of claim 2, or a pharmaceutically acceptable salt, enantiomer, non-spiroisomer, racemate, solvate, hydrate, polymorph, prodrug or Isotopic variants, and mixtures thereof, which are compounds of formula (III):

(III) wherein, R ₁ is C _1-6 haloalkyl or

; wherein R _a , R _b and R _c are independently selected from H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; it is optionally substituted by R'; and R _a and R _b can form a chemical bond so that the double bond becomes a triple bond; R' is H, D, halogen, -CN, C _1-6 alkyl, C _{1 -6} haloalkyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; L ₂ is a chemical bond, -O-(C(R _L2 )(R _L2 )) _p -, -S-(C(R _L2 )(R _L2 )) _p -, -N(R _L2' )-(C(R _L2 )(R _L2 )) _p - or -(C(R _L2 )(R _L2 )) _p -; where p= 0, 1, 2, 3 or 4; R _L2 is H, D, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _{2- 6alkynyl} , -OR _1a , -SR _1a or -N(R _1a ) ₂ ; R _L2' is H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _{2- 6} alkynyl; and, R _L2 /R _L2' on adjacent atoms can combine to form C _3-10 cycloalkyl or 3-10 membered heterocyclic group; R ₂ is H, D, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -N(R _1a ) ₂ , C _3-10 cycloalkyl, 3-10 member Heterocyclyl, C _6-10 aryl or 5-14 membered heteroaryl; it is optionally substituted with 1-7 R; wherein R is H, D, halogen, -CN, -NO ₂ , C _1-6 Alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a , -N(R _1a ) ₂ , C _3-10 cycloalkyl, 3- 10-membered heterocyclic group, C _6-10 -membered aryl group or 5-14-membered heteroaryl group; R ₄ is halogen, -CN or -NO ₂ ; R ₆ is halogen, -CN, -NO ₂ , C _1-6 alkane group, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; R _1a is H, C _1-6 alkyl or C _1-6 haloalkyl.

請求項8的式(III)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物，其中 R₁ 為C_1-6 鹵代烷基或

；其中R_a 、R_b 和R_c 獨立地選自H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ；並且R_a 和R_b 可以形成化學鍵從而使得雙鍵變為三鍵； L₂ 為化學鍵、-O-(C(R_L2 )(R_L2 ))_p -或-N(R_L2’ )-(C(R_L2 )(R_L2 ))_p -；其中p=0、1、2、3或4； R_L2 為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基或C_1-6 鹵代烷基； R_L2’ 為H、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基或C_2-6 炔基； R₂ 為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-N(R_1a )₂ 、C_3-10 環烷基或3-10員雜環基；其任選被1-5個R取代；其中R為H、-O-R_1a 、-S-R_1a 、-N(R_1a )₂ 、C_1-6 烷基或C_1-6 鹵代烷基； R₄ 為鹵素； R₆ 為鹵素、-CN、-NO₂ 或-O-R_1a ，優選-OH； R_1a 為H、C_1-6 烷基或C_1-6 鹵代烷基。A compound of formula (III) according to claim 8, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or Isotopic variants, and mixtures thereof, wherein R ₁ is C _1-6 haloalkyl or

; wherein R _a , R _b and R _c are independently selected from H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; and R _a and R _b can form a chemical bond so that the double bond becomes a triple bond; L ₂ is a chemical bond, -O-(C(R _L2 )(R _L2 )) _p - or -N(R _L2' ) -(C(R _L2 )(R _L2 )) _p -; wherein p=0, 1, 2, 3 or 4; R _L2 is H, D, halogen, -CN, -NO ₂ , C _1-6 alkyl or C _1-6 haloalkyl; R _L2' is H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl; R ₂ is H, D, halogen , -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -N(R _1a ) ₂ , C _3-10 cycloalkane It is optionally substituted with 1-5 Rs; wherein R is H, -OR _1a , -SR _1a , -N(R _1a ) ₂ , C _1-6 alkyl or C _1-6 haloalkyl; R ₄ is halogen; R ₆ is halogen, -CN, -NO ₂ or -OR _1a , preferably -OH; R _1a is H, C _1-6 alkyl or C _1-6 haloalkyl.

請求項2的式(I)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物，其為式(IV)化合物：

(IV) 其中， L₂ 為化學鍵、-O-(C(R_L2 )(R_L2 ))_p -、-S-(C(R_L2 )(R_L2 ))_p -、-N(R_L2’ )-(C(R_L2 )(R_L2 ))_p -或-(C(R_L2 )(R_L2 ))_p -；其中p=1、2、3或4； R_L2 為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； R_L2’ 為H、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基或C_2-6 炔基；並且，R_L2 /R_L2’ 可以結合形成C_3-10 環烷基或3-10員雜環基； R₂ 為鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-N(R_1a )₂ 、C_3-10 環烷基、3-10員雜環基、C_6-10 芳基、5-14員雜芳基；其任選被1-5個R取代；其中R為H、D、C_0-6 亞烷基-鹵素、C_0-6 亞烷基-CN、C_0-6 亞烷基-SF₅ 、C_0-6 亞烷基-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、C_0-6 亞烷基-O-R_1a 、C_0-6 亞烷基-S-R_1a 、C_0-6 亞烷基-N(R_1a )₂ 、C_0-6 亞烷基-C(O)R_1a 、C_0-6 亞烷基-C(O)OR_1a 、C_0-6 亞烷基-C(O)N(R_1a )₂ 、C_0-6 亞烷基-S(O)_m R_1a 、C_0-6 亞烷基-C_3-10 環烷基、C_0-6 亞烷基-3-10員雜環基、C_0-6 亞烷基-C_6-10 芳基或C_0-6 亞烷基-5-14員雜芳基；其中m=1或2； R₄ 為鹵素、-CN或-NO₂ ； R₆ 為鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； R_a 、R_b 和R_c 獨立地選自H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ；並且R_a 和R_b 可以形成化學鍵從而使得雙鍵變為三鍵； R_1a 為H、C_1-6 烷基或C_1-6 鹵代烷基。The compound of formula (I) of claim 2, or a pharmaceutically acceptable salt, enantiomer, non-spiroisomer, racemate, solvate, hydrate, polymorph, prodrug or Isotopic variants, and mixtures thereof, which are compounds of formula (IV):

(IV) wherein, L ₂ is a chemical bond, -O-(C(R _L2 )(R _L2 )) _p -, -S-(C(R _L2 )(R _L2 )) _p -, -N(R _L2' )-(C(R _L2 )(R _L2 )) _p - or -(C(R _L2 )(R _L2 )) _p -; where p=1, 2, 3 or 4; R _L2 is H, D, halogen , -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; R _L2' is H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl; and R _L2 /R _L2' can be combined to form C _{3- 10} -cycloalkyl or 3-10-membered heterocyclyl; R ₂ is halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 Alkynyl, -N(R _1a ) ₂ , C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 membered aryl, 5-14 membered heteroaryl; R is substituted; wherein R is H, D, C _0-6 alkylene-halogen, C _0-6 alkylene-CN, C _0-6 alkylene-SF ₅ , C _0-6 alkylene-NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _0-6 alkylene-OR _1a , C _0-6 alkylene-SR _1a , C _0-6 alkylene-N(R _1a ) ₂ , C _0-6 alkylene-C(O)R _1a , C _0-6 alkylene-C(O)OR _1a , C _{0- 6} alkylene-C(O)N(R _1a ) ₂ , C _0-6 alkylene-S(O) _m R _1a , C _0-6 alkylene-C _3-10 cycloalkyl, C _{0 -6} alkylene-3-10 membered heterocyclyl, C _0-6 alkylene-C _6-10 aryl or C _0-6 alkylene-5-14 membered heteroaryl; wherein m=1 or 2; R ₄ is halogen, -CN or -NO ₂ ; R ₆ is halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _{2- 6alkynyl} , -OR _1a , -SR _1a or -N(R _1a ) ₂ ; R _a , R _b and R _c are independently selected from H, D, halogen, -CN, C _1-6 alkyl, C _{1 -6} haloalkyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; and R _a and R _b can form a chemical bond so that the double bond becomes a triple bond; R _1a is H, C _1-6 alkyl or C _1-6 haloalkyl.

請求項10的式(IV)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物，其中， L₂ 為化學鍵、-O-(C(R_L2 )(R_L2 ))_p -、-S-(C(R_L2 )(R_L2 ))_p -或-N(R_L2’ )-(C(R_L2 )(R_L2 ))_p -；其中p=1、2、3或4； R_L2 為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基或C_2-6 炔基； R_L2’ 為H、C_1-6 烷基或C_1-6 鹵代烷基；並且，R_L2 /R_L2’ 可以結合形成C_3-10 環烷基或3-10員雜環基； R₂ 為鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-N(R_1a )₂ 、C_3-10 環烷基、3-10員雜環基、C_6-10 芳基或5-14員雜芳基；其任選被1-5個R取代；其中R為H、D、C_0-6 亞烷基-鹵素、C_0-6 亞烷基-CN、C_0-6 亞烷基-SF₅ 、C_0-6 亞烷基-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、C_0-6 亞烷基-O-R_1a 、C_0-6 亞烷基-S-R_1a 或C_0-6 亞烷基-N(R_1a )₂ ； R₄ 為鹵素、-CN或-NO₂ ； R₆ 為鹵素、-CN、-NO₂ 、-OH、-SH或-NH₂ ； R_a 、R_b 和R_c 獨立地選自H、D、鹵素、-CN、C_1-6 烷基或C_1-6 鹵代烷基；並且R_a 和R_b 可以形成化學鍵從而使得雙鍵變為三鍵； R_1a 為H、C_1-6 烷基或C_1-6 鹵代烷基。A compound of formula (IV) according to claim 10, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or Isotopic variants, and mixtures thereof, wherein L ₂ is a bond, -O-(C(R _L2 )(R _L2 )) _p -, -S-(C(R _L2 )(R _L2 )) _p - or -N(R _L2' )-(C(R _L2 )(R _L2 )) _p -; where p=1, 2, 3 or 4; R _L2 is H, D, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl; R _L2' is H, C _1-6 alkyl or C _1-6 haloalkyl; and, R _L2 /R _L2' can be combined to form C _3-10 cycloalkyl or 3-10 membered heterocyclic group; R ₂ is halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -N(R _1a ) ₂ , C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 membered aryl or 5-14 membered heterocyclyl Aryl; it is optionally substituted with 1-5 R; wherein R is H, D, C _0-6 alkylene-halogen, C _0-6 alkylene-CN, C _0-6 alkylene-SF ₅ , C _0-6 alkylene-NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _0-6 alkylene-OR _1a , C _0-6 alkylene-SR _1a or C _0-6 alkylene-N(R _1a ) ₂ ; R ₄ is halogen, -CN or -NO ₂ ; R ₆ is halogen, -CN, -NO ₂ , -OH, -SH, or _-NH2 ; _Ra , _Rb , and _Rc are independently selected from H, D, halogen, -CN, _{Ci_6alkyl} , or _{Ci_6haloalkyl} ; and _Ra and R _b can form a chemical bond so that the double bond becomes a triple bond; R _1a is H, C _1-6 alkyl or C _1-6 haloalkyl.

請求項10的式(IV)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物，其中， L₂ 為化學鍵、-O-(C(R_L2 )(R_L2 ))_p -、-S-(C(R_L2 )(R_L2 ))_p -或-N(R_L2’ )-(C(R_L2 )(R_L2 ))_p -；其中p=1、2、3或4； R_L2 為H、D、鹵素、C_1-6 烷基或C_1-6 鹵代烷基； R_L2’ 為H；並且，R_L2 /R_L2’ 可以結合形成C_3-6 環烷基或4-7員雜環基； R₂ 為C_1-6 烷基、C_1-6 鹵代烷基、-N(R_1a )₂ 、C_3-6 環烷基、4-7員雜環基、C_6-10 芳基、5-6員雜芳基；其任選被1-2個R取代；其中R為H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基或-N(R_1a )₂ ； R₄ 為鹵素； R₆ 為-OH； R_a 、R_b 和R_c 獨立地選自H、D、鹵素或-CN； R_1a 為H、C_1-6 烷基或C_1-6 鹵代烷基。A compound of formula (IV) according to claim 10, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or Isotopic variants, and mixtures thereof, wherein L ₂ is a bond, -O-(C(R _L2 )(R _L2 )) _p -, -S-(C(R _L2 )(R _L2 )) _p - or -N(R _L2' )-(C(R _L2 )(R _L2 )) _p -; wherein p=1, 2, 3 or 4; R _L2 is H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl; R _L2' is H; and R _L2 /R _L2' can be combined to form C _3-6 cycloalkyl or 4-7 membered heterocyclic group; R ₂ is C _1-6 alkyl, C _1-6 haloalkyl, -N(R _1a ) ₂ , C _3-6 cycloalkyl, 4-7 membered heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl; -2 R substitutions; wherein R is H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, or -N(R _1a ) ₂ ; R ₄ is halogen; R ₆ is -OH ; R _a , R _b and R _c are independently selected from H, D, halogen or -CN; R _1a is H, C _1-6 alkyl or C _1-6 haloalkyl.

(IV) 其中， L₂ 為化學鍵、-O-(C(R_L2 )(R_L2 ))_p -、-S-(C(R_L2 )(R_L2 ))_p -、-N(R_L2’ )-(C(R_L2 )(R_L2 ))_p -或-(C(R_L2 )(R_L2 ))_p -；其中p=1、2、3或4； R_L2 為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； R_L2’ 為H、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基或C_2-6 炔基；並且，相鄰原子上的R_L2 /R_L2’ 可以結合形成C_3-10 環烷基或3-10員雜環基； R₂ 為H、D、鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-N(R_1a )₂ 、C_3-10 環烷基、3-10員雜環基、C_6-10 芳基、5-14員雜芳基；其任選被1-5個R取代；其中R為H、-N(R_1a )₂ 、C_1-6 烷基或C_1-6 鹵代烷基； R₄ 為鹵素、-CN或-NO₂ ； R₆ 為鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； R_a 、R_b 和R_c 獨立地選自H、D、鹵素、-CN、C_1-6 烷基、C_1-6 鹵代烷基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ；並且R_a 和R_b 可以形成化學鍵從而使得雙鍵變為三鍵； R_1a 為H、C_1-6 烷基或C_1-6 鹵代烷基。The compound of formula (I) of claim 2, or a pharmaceutically acceptable salt, enantiomer, non-spiroisomer, racemate, solvate, hydrate, polymorph, prodrug or Isotopic variants, and mixtures thereof, which are compounds of formula (IV):

(IV) wherein, L ₂ is a chemical bond, -O-(C(R _L2 )(R _L2 )) _p -, -S-(C(R _L2 )(R _L2 )) _p -, -N(R _L2' )-(C(R _L2 )(R _L2 )) _p - or -(C(R _L2 )(R _L2 )) _p -; where p=1, 2, 3 or 4; R _L2 is H, D, halogen , -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; R _L2' is H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl; and, R _L2 /R _L2' on adjacent atoms can be Combined to form C _3-10 cycloalkyl or 3-10 membered heterocyclyl; R ₂ is H, D, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, -N(R _1a ) ₂ , C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 membered aryl, 5-14 membered heteroaryl It is optionally substituted by 1-5 R; wherein R is H, -N(R _1a ) ₂ , C _1-6 alkyl or C _1-6 haloalkyl; R ₄ is halogen, -CN or -NO ₂ ; R ₆ is halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a or - N(R _1a ) ₂ ; R _a , R _b and R _c are independently selected from H, D, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; and R _a and R _b may form a chemical bond such that a double bond becomes a triple bond; R _1a is H, C _1-6 alkyl or C _1-6 haloalkyl.

請求項2的式(I)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物，其為式(IV-1)、(IV-2)或(IV-3)化合物：

(IV-1)、

(IV-2)或

(IV-3) 其中， L₂ 為化學鍵、-O-、-S-或-N(R_L2’ )-；其中R_L2’ 為H、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基或C_2-6 炔基； R₄ 為鹵素、-CN或-NO₂ ； R₆ 為鹵素、-CN、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 炔基、-O-R_1a 、-S-R_1a 或-N(R_1a )₂ ； R_N1 、R_N2 和R_N3 獨立地為H、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基或C_2-6 炔基；或者，R_N2 和R_N3 可以結合形成C_2-4 亞烷基； R_1a 為H、C_1-6 烷基或C_1-6 鹵代烷基。The compound of formula (I) of claim 2, or a pharmaceutically acceptable salt, enantiomer, non-spiroisomer, racemate, solvate, hydrate, polymorph, prodrug or Isotopic variants, and mixtures thereof, which are compounds of formula (IV-1), (IV-2) or (IV-3):

(IV-1),

(IV-2) or

(IV-3) wherein, L ₂ is a chemical bond, -O-, -S- or -N(R _L2' )-; wherein R _L2' is H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl; R ₄ is halogen, -CN or -NO ₂ ; R ₆ is halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkane group, C _2-6 alkenyl, C _2-6 alkynyl, -OR _1a , -SR _1a or -N(R _1a ) ₂ ; R _N1 , R _N2 and R _N3 are independently H, C _1-6 alkane group, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl; alternatively, R _N2 and R _N3 can combine to form C _2-4 alkylene; R _1a is H, C _1-6 Alkyl or C _1-6 haloalkyl.

請求項14的式(IV-1)、(IV-2)或(IV-3)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物，其中 L₂ 為化學鍵、-O-、-S-或-NH-，優選-O-； R₄ 為鹵素，優選Cl； R₆ 為鹵素、-CN、-NO₂ 或-O-R_1a ，優選-OH； R_N1 、R_N2 和R_N3 獨立地為H、C_1-6 烷基或C_1-6 鹵代烷基；或者，R_N2 和R_N3 可以結合形成C_2-4 亞烷基； R_1a 為H、C_1-6 烷基或C_1-6 鹵代烷基。A compound of formula (IV-1), (IV-2) or (IV-3) of claim 14, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvent Compounds, hydrates, homogeneous polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein L ₂ is a chemical bond, -O-, -S- or -NH-, preferably -O-; R ₄ is halogen , preferably Cl; R ₆ is halogen, -CN, -NO ₂ or -OR _1a , preferably -OH; R _N1 , R _N2 and R _N3 are independently H, C _1-6 alkyl or C _1-6 haloalkyl or, R _N2 and R _N3 can combine to form C _2-4 alkylene; R _1a is H, C _1-6 alkyl or C _1-6 haloalkyl.

請求項1的式(I)化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，以及它們的混合物，其中所述化合物選自：

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或

。A compound of formula (I) of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or Isotopic variants, and mixtures thereof, wherein the compound is selected from:

,

or

.

藥物組合物，其含有請求項1-16中任一項的化合物，或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體，和藥學上可接受的賦形劑；優選地，其還含有其它治療劑。A pharmaceutical composition comprising the compound of any one of claims 1-16, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, A polymorph, a prodrug or isotopic variant, and a pharmaceutically acceptable excipient; preferably, it also contains other therapeutic agents.

請求項1-16中任一項的化合物或其藥學上可接受的鹽、鏡像異構物、非鏡像異構物、外消旋物、溶合物、水合物、同質多晶物、前驅藥或同位素變體在製備用於治療和/或預防KRAS或其G12C突變蛋白介導的疾病的藥物中的用途。The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug thereof or the use of an isotopic variant in the manufacture of a medicament for the treatment and/or prevention of a disease mediated by KRAS or its G12C mutant protein.

請求項18的用途，其中所述KRAS或其G12C突變蛋白介導的疾病包括選自以下的癌症：急性骨髓性白血病、青少年癌症、兒童腎上腺皮質癌、AIDS相關的癌症(例如淋巴瘤和卡波西氏肉瘤）、肛門癌、闌尾癌、星形細胞瘤、非典型畸胎樣、基底細胞癌、膽管癌、膀胱癌、骨癌、腦幹神經膠質瘤、腦瘤、乳腺癌、支氣管腫瘤、伯基特淋巴瘤、類癌瘤、非典型畸胎樣、胚胎腫瘤、生殖細胞腫瘤、原發性淋巴瘤、宮頸癌、兒童癌症、脊索瘤、心臟腫瘤、慢性淋巴細胞性白血病(CLL)、慢性髓細胞性白血病(CML)、慢性骨髓增殖性病況、結腸癌、結腸直腸癌、顱咽管瘤、皮膚T細胞淋巴瘤、肝外導管原位癌(DCIS)、胚胎腫瘤、CNS癌症、子宮內膜癌、室管膜瘤、食道癌、嗅神經膠母細胞瘤、尤文氏肉瘤、顱外生殖細胞腫瘤、性腺外生殖細胞腫瘤、眼癌、骨骼的纖維組織細胞瘤、膽囊癌、胃癌、胃腸道類癌瘤、胃腸道間質瘤(GIST)、生殖細胞腫瘤、妊娠滋養細胞腫瘤、毛細胞白血病、頭頸癌、心臟癌、肝癌、霍奇金氏淋巴瘤、下嚥癌、眼內黑色素瘤、胰島細胞瘤、胰腺神經內分泌瘤、腎癌、喉癌、唇和口腔癌、肝癌、小葉原位癌(LCIS)、肺癌、淋巴瘤、轉移性鱗狀頸癌伴隱匿原發灶、中線道癌、口腔癌、多發性內分泌瘤綜合征、多發性骨髓瘤/漿細胞瘤、蕈樣真菌病、骨髓發育不良綜合征、骨髓發育不良/骨髓增殖性瘤、多發性骨髓瘤、梅克爾細胞癌、惡性間皮瘤、骨骼的惡性纖維組織細胞瘤和骨肉瘤、鼻腔和鼻竇癌、鼻咽癌、神經膠母細胞瘤、非霍奇金氏淋巴瘤、非小細胞肺癌(NSCLC)、口腔癌、唇和口腔癌、口咽癌、卵巢癌、胰腺癌、乳頭瘤、副神經節瘤、鼻竇和鼻腔癌、甲狀旁腺癌、陰莖癌、咽癌、胸膜肺母細胞瘤、原發性中樞神經系統(CNS)淋巴瘤、***癌、直腸癌、移行性細胞癌、視網膜母細胞瘤、橫紋肌肉瘤、唾液腺癌、皮膚癌、胃癌、小細胞肺癌、小腸癌、軟組織肉瘤、細胞淋巴瘤、睾丸癌、喉癌、胸腺瘤和胸腺癌、甲狀腺癌、腎盂和輸尿管的移行性細胞癌、滋養細胞腫瘤、兒童罕見的癌症、尿道癌、子宮肉瘤、***癌、外陰癌或病毒誘導的癌症。The use of claim 18, wherein the disease mediated by KRAS or its G12C mutein comprises a cancer selected from the group consisting of acute myeloid leukemia, juvenile cancer, childhood adrenocortical cancer, AIDS-related cancers such as lymphoma and Kapo West sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoid, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), Chronic myeloid leukemia (CML), chronic myeloproliferative conditions, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, uterus Endometrial cancer, ependymoma, esophageal cancer, olfactory glioblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, Gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, cardiac cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma tumor, islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary Line cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma/plasmacytoma, mycosis fungoides, myelodysplastic syndrome, myelodysplasia/myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and sinus cancer, nasopharyngeal cancer, glioblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), Oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary Primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric cancer, small cell lung cancer, small bowel cancer, soft tissue sarcoma, cellular lymphoma tumor, testicular cancer, laryngeal cancer, thymoma and thymic cancer, thyroid cancer, transitional cell carcinoma of renal pelvis and ureter, trophoblastic tumor, rare childhood cancer, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virally induced cancer.