TW202304516A - Compounds for degrading alpha-synuclein aggregates and uses thereof - Google Patents

Compounds for degrading alpha-synuclein aggregates and uses thereof Download PDF

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TW202304516A
TW202304516A TW111118050A TW111118050A TW202304516A TW 202304516 A TW202304516 A TW 202304516A TW 111118050 A TW111118050 A TW 111118050A TW 111118050 A TW111118050 A TW 111118050A TW 202304516 A TW202304516 A TW 202304516A
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張明奎
保羅 坦培思特
林易嫻
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香港商新旭生技股份有限公司
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Abstract

The present disclosure provides compounds, compositions and methods useful for the treatment of neurodegenerative diseases, in particular synucleinopathies.

Description

用於降解α-突觸核蛋白聚集體之化合物及其用途Compounds for degrading alpha-synuclein aggregates and uses thereof

估計神經退化性疾病每年影響5千萬美國人，造成難以估量的個人負擔以及每年數千億美元的醫療費用及生產力損失之經濟成本。突觸核蛋白病為特徵在於α-突觸核蛋白(α-Syn)聚集體於神經元及神經膠質細胞中之異常積聚的神經退化性疾病。Neurodegenerative diseases affect an estimated 50 million Americans each year, resulting in an incalculable personal burden and an economic cost of hundreds of billions of dollars in medical costs and lost productivity each year. Synucleinopathies are neurodegenerative diseases characterized by abnormal accumulation of alpha-synuclein (a-Syn) aggregates in neurons and glial cells.

α-突觸核蛋白為較佳在突觸前端處之神經元中表現之140胺基酸，認為其在該神經元中起調節突觸傳輸之作用(Bendor等人，Neuron 2013；79:1044-66)。α-突觸核蛋白可在稱為路易體之神經元中形成病理學聚集體，其為帕金森氏病(Parkinson's Disease；PD)及路易體失智症(dementia with Lewy bodies；DLB)兩者之特徵。病理學聚集體由摺疊異常之α-突觸核蛋白於神經元、神經纖維或神經膠質細胞中聚集的不可溶堆積物組成且為突觸核蛋白病之典型特徵。突觸核蛋白病包括帕金森氏病(PD)、路易體失智症(DLB)及多發性系統萎縮症(MSA)、阿茲海默氏病之路易體變型(LBVAD)、組合之帕金森氏病(PD)及阿茲海默氏病(AD)及伴有腦鐵聚積型1之神經退化(NBIA-1)。在PD及DLB中，α-Syn聚集體在神經元細胞質及軸突過程中分別進入路易體及路易神經突中，而寡樹突神經膠質細胞中之α-Syn內含物為公認的MSA神經病理學標誌。α-synuclein is a 140 amino acid that is preferentially expressed in neurons at the synaptic front where it is thought to play a role in modulating synaptic transmission (Bendor et al., Neuron 2013;79:1044 -66). α-synuclein can form pathological aggregates in neurons called Lewy bodies, which are the cause of both Parkinson's Disease (PD) and dementia with Lewy bodies (DLB) The characteristics. Pathological aggregates consist of insoluble accumulations of abnormally folded α-synuclein aggregated in neurons, nerve fibers, or glial cells and are a typical feature of synucleinopathies. Synucleinopathies include Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple systemic atrophy (MSA), Lewy body variant of Alzheimer's disease (LBVAD), combined parkinsonism Alzheimer's disease (PD) and Alzheimer's disease (AD) and neurodegeneration with brain iron accumulation type 1 (NBIA-1). In PD and DLB, α-Syn aggregates enter Lewy bodies and Lewy neurites in neuronal cytoplasm and axonal processes, respectively, and α-Syn inclusions in oligodendrocytes are well-established in MSA neuropathy Science logo.

自α-突觸核蛋白聚集之視角而言，當前缺乏靶向突觸核蛋白病之治療劑。旨在減少α-突觸核蛋白聚集之策略具有治療患有突觸核蛋白病之患者的治療潛能。There is currently a lack of therapeutics targeting synucleinopathies from the perspective of α-synuclein aggregation. Strategies aimed at reducing alpha-synuclein aggregation have therapeutic potential for treating patients with synucleinopathies.

本發明源自以下認識：包括基於醯亞胺藥物(例如，來那度胺(lenalidomide)、沙立度胺(thalidomide)、VHL配位體)之E3泛蛋白連接酶結合部分且亦包括α-突觸核蛋白之結合劑的雙特異性共軛化合物可誘導α-突觸核蛋白聚集體之蛋白酶體降解。因此，本發明基於此發現提供用於治療多種與α-突觸核蛋白聚集體相關之神經退化性疾病的化合物、組合物及方法。本文所描述之雙特異性共軛物化合物藉由在細胞模型及/或動物模型中移除α-突觸核蛋白聚集體或將α-突觸核蛋白聚集之程度降低至較低水準來降解α-突觸核蛋白聚集體，從而具有治療患有突觸核蛋白病(包括但不限於帕金森氏病(PD)、路易體失智症(DLB)或多發性系統萎縮症(MSA))之患者的治療潛能。The present invention arose from the recognition that E3 ubiquitin ligase binding moieties comprising imide-based drugs (eg, lenalidomide, thalidomide, VHL ligands) and also α- Bispecific conjugated compounds of synuclein-binding agents induce proteasomal degradation of alpha-synuclein aggregates. Accordingly, the present invention is based on this discovery to provide compounds, compositions and methods for the treatment of various neurodegenerative diseases associated with alpha-synuclein aggregates. The bispecific conjugate compounds described herein degrade by removing α-synuclein aggregates or reducing the extent of α-synuclein aggregation to lower levels in cell models and/or animal models Alpha-synuclein aggregates, thereby having therapeutic potential in patients with synucleinopathies (including but not limited to Parkinson's disease (PD), dementia with Lewy bodies (DLB) or multiple systemic atrophy (MSA)) therapeutic potential of the patient.

本發明亦提供用以移除α-突觸核蛋白聚集或減少患有路易體失智症或具有路易體失智症風險之患者的路易體或α-突觸核蛋白聚集體的方法，及用以減少路易體失智症(DLB)或多發性系統萎縮症(MSA)或其他突觸核蛋白病之方法。The present invention also provides methods for removing alpha-synuclein aggregates or reducing Lewy bodies or alpha-synuclein aggregates in a patient suffering from or at risk of Lewy body dementia, and A method for reducing dementia with Lewy bodies (DLB) or multiple system atrophy (MSA) or other synucleinopathies.

本發明之一個態樣為式A化合物， EBM-L-SBM  (式A) 其中 EBM為E3泛蛋白連接酶結合部分； L為共價連接至EBM及SBM之連接子；且 SBM為下式之α-突觸核蛋白結合部分：

Figure 02_image001
或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物、前驅藥， 其中
Figure 02_image003
共價連接至L；且 (i)
Figure 02_image003
為含有至少1個選自O、S及N之環雜原子的經取代或未經取代之雙環稠合芳族環；
Figure 02_image005
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；且
Figure 02_image007
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；或 (ii)
Figure 02_image009
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；
Figure 02_image005
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；且
Figure 02_image007
為含有至少1個選自O、S及N之環雜原子的經取代或未經取代之雙環稠合芳族環。 One aspect of the invention is a compound of formula A, EBM-L-SBM (Formula A) wherein EBM is an E3 ubiquitin ligase binding moiety; L is a linker covalently linked to EBM and SBM; and SBM is of the formula Alpha-synuclein binding moiety:
Figure 02_image001
or pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, racemates, solvates, metabolic precursors, and prodrugs thereof, wherein
Figure 02_image003
covalently attached to L; and (i)
Figure 02_image003
is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N;
Figure 02_image005
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; and
Figure 02_image007
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; or (ii)
Figure 02_image009
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;
Figure 02_image005
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; and
Figure 02_image007
is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N.

本發明之另一態樣為式(I)至(VI)中任一者之化合物：

Figure 02_image013
Figure 02_image015
或其醫藥學上可接受之鹽、溶劑合物、水合物、多晶型物、共結晶體、互變異構物、立體異構物、經同位素標記之衍生物或前驅藥，其中L 1、L 2、L3、X、Y、J、Q、K、T、U、V、Z、Y 1、R'、R''、R'''、R 2'、R 3'、n、m、k及m6如本文所定義。 Another aspect of the invention is a compound of any one of formulas (I) to (VI):
Figure 02_image013
Figure 02_image015
Or its pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotope-labeled derivative or prodrug, wherein L 1 , L 2 , L3, X, Y, J, Q, K, T, U, V, Z, Y 1 , R', R'', R''', R 2' , R 3' , n, m, k and m6 are as defined herein.

本發明之另一態樣為一種組合物，其包含本發明之化合物及醫藥學上可接受之賦形劑。Another aspect of the present invention is a composition comprising a compound of the present invention and a pharmaceutically acceptable excipient.

本發明之另一態樣為一種治療、減輕疾病之嚴重程度、延緩其進展、降低罹患其之風險及/或延緩其發作的方法，該疾病之特徵在於存在α-突觸核蛋白之路易體或病理學聚集體，該方法包含向有需要之個體投與有效量之本發明之化合物或組合物。Another aspect of the invention is a method of treating, lessening the severity, delaying the progression, reducing the risk of having it, and/or delaying the onset of a disease characterized by the presence of alpha-synuclein Lewy bodies or a pathological aggregate, the method comprising administering to an individual in need thereof an effective amount of a compound or composition of the invention.

本發明之另一態樣為一種用於合成本發明之化合物的方法。Another aspect of the invention is a method for the synthesis of the compounds of the invention.

前述發明內容僅具說明性，而非旨在以任何方式進行限制。除了本文所描述之說明性實施例及特徵之外，本發明之其他態樣、實施例、目標及特徵將自圖式及具體實施方式及申請專利範圍變得完全顯而易見。The foregoing summary is illustrative only and not intended to be limiting in any way. In addition to the illustrative embodiments and features described herein, other aspects, embodiments, objects and features of the invention will become fully apparent from the drawings and detailed description and claims.

本發明提供適用於移除α-突觸核蛋白聚集體或將α-突觸核蛋白聚集之程度降低至低水準，從而具有治療患有突觸核蛋白病之患者的治療潛能的化合物、組合物及方法。The present invention provides compounds, combinations useful for removing α-synuclein aggregates or reducing the extent of α-synuclein aggregation to low levels, thereby having therapeutic potential for treating patients suffering from synucleinopathies Things and methods.

本文提供可同時結合目標蛋白(亦即，聚集之α-突觸核蛋白)及E3泛蛋白連接酶之雙特異性共軛物化合物。雙特異性共軛物化合物展現所需的功能特性，包括較佳結合至α-突觸核蛋白聚集體，且允許α-突觸核蛋白接近E3泛蛋白連接酶，從而促進對α-突觸核蛋白聚集體之選擇性泛素化及最終蛋白酶體介導之降解。Provided herein are bispecific conjugate compounds that can simultaneously bind a protein of interest (ie, aggregated α-synuclein) and an E3 ubiquitin ligase. The bispecific conjugate compound exhibits desirable functional properties, including better binding to α-synuclein aggregates, and allows α-synuclein access to E3 ubiquitin ligase, thereby facilitating recognition of α-synuclein Selective ubiquitination and eventual proteasome-mediated degradation of nucleoprotein aggregates.

本文所描述之方法包括向個體投與本發明之化合物或組合物以治療、減緩或預防特徵在於存在α-突觸核蛋白之路易體或病理學聚集體的神經退化性疾病或病症。 化合物 The methods described herein include administering to an individual a compound or composition of the invention to treat, slow or prevent a neurodegenerative disease or disorder characterized by the presence of α-synuclein Lewy bodies or pathological aggregates. compound

本發明之一個態樣為式A化合物， EBM-L-SBM  (式A) 其中 EBM為E3泛蛋白連接酶結合部分； L為共價連接至EBM及SBM之連接子；且 SBM為下式之α-突觸核蛋白結合部分：

Figure 02_image017
或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物、前驅藥， 其中
Figure 02_image019
共價連接至L；且 (i)
Figure 02_image019
為含有至少1個選自O、S及N之環雜原子的經取代或未經取代之雙環稠合芳族環；
Figure 02_image022
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；且
Figure 02_image024
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；或 (ii)
Figure 02_image019
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；
Figure 02_image022
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；且
Figure 02_image024
為含有至少1個選自O、S及N之環雜原子的經取代或未經取代之雙環稠合芳族環。 One aspect of the invention is a compound of formula A, EBM-L-SBM (Formula A) wherein EBM is an E3 ubiquitin ligase binding moiety; L is a linker covalently linked to EBM and SBM; and SBM is of the formula Alpha-synuclein binding moiety:
Figure 02_image017
or pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, racemates, solvates, metabolic precursors, and prodrugs thereof, wherein
Figure 02_image019
covalently attached to L; and (i)
Figure 02_image019
is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N;
Figure 02_image022
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; and
Figure 02_image024
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; or (ii)
Figure 02_image019
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;
Figure 02_image022
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; and
Figure 02_image024
is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N.

在一些實施例中，經取代或未經取代之雙環稠合芳族環為經取代或未經取代之雙環5至6系統。非限制性實例包括

Figure 02_image029
Figure 02_image031
。 In some embodiments, the substituted or unsubstituted bicyclic fused aromatic ring is a substituted or unsubstituted bicyclic 5-6 system. Non-limiting examples include
Figure 02_image029
Figure 02_image031
.

在一些實施例中，SBM具有式B或式C

Figure 02_image033
； 其中 Z為C或N；U為O、S或CH；V為N或NH； K為CH或N；Q為CH或N；其中K及Q不同時為N； R'''在每次出現時獨立地選自由以下組成之群：H、OH、NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基及鹵素；k為0、1、2或3； R'在每次出現時獨立地選自由以下組成之群：H、鹵素、OH、C 1-6烷基、C 1-6鹵烷基及C 1-6烷氧基；m為0、1、2、3或4； R''在每次出現時獨立地選自由以下組成之群：H、鹵基、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6鹵烷基、C 1-6烷胺基、C 3-6環烷胺基、C 3-6環烷基及C 3-6雜環烷基；n為0、1或2； J為CR 6或N；X為CR 6或N；Y為CR 6或N；其中J、X及Y中之至少一者為N，但J及Y不同時為N，X及Y不同時為N； R 6獨立地選自由以下組成之群：H、NH 2、C 1-6烷基及C 1-6烷氧基，其中NH 2、C 1-6烷基或C 1-6烷氧基視情況經C 1-3烷基、C 3-6環烷基及/或鹵基中之1至3者取代；且 在式B中，V為N，其中Z及U不同時為雜原子；且 在式C中，V為N或NH；T為CH或N；其中U、Z、V及T中之至多兩者含有雜原子。 In some embodiments, the SBM has Formula B or Formula C
Figure 02_image033
; wherein Z is C or N; U is O, S or CH; V is N or NH; K is CH or N; Q is CH or N; wherein K and Q are not N at the same time; When present, independently selected from the group consisting of H, OH, NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy and halogen; k is 0, 1, 2 or 3; R', at each occurrence, is independently selected from the group consisting of H, halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy; m is 0, 1, 2, 3 or 4; R'' at each occurrence is independently selected from the group consisting of H, halo, OH, NH2 , C1-6 alkyl, C1-6 alkoxy group, C 1-6 haloalkyl group, C 1-6 alkylamino group, C 3-6 cycloalkylamino group, C 3-6 cycloalkyl group and C 3-6 heterocycloalkyl group; n is 0, 1 or 2; J is CR 6 or N; X is CR 6 or N; Y is CR 6 or N; wherein at least one of J, X and Y is N, but J and Y are not N at the same time, and X and Y are different is N; R 6 is independently selected from the group consisting of H, NH 2 , C 1-6 alkyl and C 1-6 alkoxy, wherein NH 2 , C 1-6 alkyl or C 1-6 Alkoxy is optionally substituted by 1 to 3 of C 1-3 alkyl, C 3-6 cycloalkyl and/or halo; and in formula B, V is N, wherein Z and U are not at the same time and in formula C, V is N or NH; T is CH or N; wherein at most two of U, Z, V and T contain heteroatoms.

在一些實施例中，EBM為

Figure 02_image035
Figure 02_image037
； 其中 R 3'為H或C 1-6烷基； R 2'在每次出現時獨立地選自由以下組成之群：H、OH、C 1-6烷基、C 1-6烷氧基、C 1-6烷胺基及NH 2； m6為0、1、2、3或4；且 Y 1為CH 2或
Figure 02_image039
。 In some embodiments, the EBM is
Figure 02_image035
Figure 02_image037
; wherein R 3' is H or C 1-6 alkyl; R 2' is at each occurrence independently selected from the group consisting of: H, OH, C 1-6 alkyl, C 1-6 alkoxy , C 1-6 alkylamino and NH 2 ; m6 is 0, 1, 2, 3 or 4; and Y 1 is CH 2 or
Figure 02_image039
.

在一些實施例中，化合物具有式(I)至(VI)中之任一者：

Figure 02_image041
Figure 02_image043
其中在式I中，R 3'為H或C 1-6烷基；Y 1為CH 2或
Figure 02_image045
；L 1為一鍵、-C(=O)-、-NR-、-O-或-S-，其中R為氫、視情況經取代之醯基、視情況經取代之烷基或氮保護基；L 3為一鍵、-NR-、-O-或-S-，其中R為氫、視情況經取代之醯基、視情況經取代之烷基或氮保護基。L 2為經取代或未經取代之C 1-50烴鏈；Z為C或N；U為O、S或CH；V為N，其中Z及U不同時為雜原子；K為CH或N；Q為CH或N；其中K及Q不同時為N；R'''在每次出現時獨立地選自由以下組成之群：H、OH、NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基及鹵素；k為0、1、2或3；R'在每次出現時獨立地選自由以下組成之群：H、鹵素、OH、C 1-6烷基、C 1-6鹵烷基及C 1-6烷氧基；m為0、1、2、3或4；R''在每次出現時獨立地選自由以下組成之群：H、鹵基、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6鹵烷基、C 1-6烷胺基、C 3-6環烷胺基、C 3-6環烷基及C 3-6雜環烷基；n為0、1或2；J為CR 6或N；X為CR 6或N；Y為CR 6或N；其中J、X及Y中之至少一者為N，但J及Y不同時為N，X及Y不同時為N；R 6獨立地選自由以下組成之群：H、NH 2、C 1-6烷基及C 1-6烷氧基，其中NH 2、C 1-6烷基或C 1-6烷氧基視情況經C 1-3烷基、C 3-6環烷基及/或鹵基中之1至3者取代； 在式II中，R 2'在每次出現時獨立地選自由以下組成之群：H、OH、C 1-6烷基、C 1-6烷氧基、C 1-6烷基胺基及NH 2；m6為0、1、2、3或4；Y 1為CH 2或
Figure 02_image045
；L 1為一鍵、-C(=O)-、-NR-、-O-或-S-，其中R為氫、視情況經取代之醯基、視情況經取代之烷基或氮保護基；L 2為經取代或未經取代之C 1-50烴鏈；Z為C或N；U為O、S或CH；V為N，其中Z及U不同時為雜原子；K為CH或N；Q為CH或N；其中K及Q不同時為N；R'''在每次出現時獨立地選自由以下組成之群：H、OH、NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基及鹵素；k為0、1、2或3；R'在每次出現時獨立地選自由以下組成之群：H、鹵素、OH、C 1-6烷基、C 1-6鹵烷基及C 1-6烷氧基；m為0、1、2、3或4；R''在每次出現時獨立地選自由以下組成之群：H、鹵基、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6鹵烷基、C 1-6烷胺基、C 3-6環烷基及C 3-6雜環烷基；n為0、1或2；J為CR 6或N；X為CR 6或N；Y為CR 6或N；其中J、X及Y中之至少一者為N，但J及Y不同時為N，X及Y不同時為N；R 6獨立地選自由以下組成之群：H、NH 2、C 1-6烷基及C 1-6烷氧基，其中NH 2、C 1-6烷基或C 1-6烷氧基視情況經C 1-3烷基、C 3-6環烷基及/或鹵基中之1至3者取代； 在式III中，L 1為一鍵、-C(=O)-、-NR-、-O-或-S-，其中R為氫、視情況經取代之醯基、視情況經取代之烷基或氮保護基；L 2為經取代或未經取代之C 1-50烴鏈；Z為C或N；U為O、S或CH；V為N，其中Z及U不同時為雜原子；K為CH或N；Q為CH或N；其中K及Q不同時為N；R'''在每次出現時獨立地選自由以下組成之群：H、OH、NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基及鹵素；k為0、1、2或3；R'在每次出現時獨立地選自由以下組成之群：H、鹵素、OH、C 1-6烷基、C 1-6鹵烷基及C 1-6烷氧基；m為0、1、2、3或4；R''在每次出現時獨立地選自由以下組成之群：H、鹵基、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6鹵烷基、C 1-6烷胺基、C 3-6環烷基、C 3-6環烷胺基及C 3-6雜環烷基；n為0、1或2；J為CR 6或N；X為CR 6或N；Y為CR 6或N；其中J、X及Y中之至少一者為N，但J及Y不同時為N，X及Y不同時為N；R 6獨立地選自由以下組成之群：H、NH 2、C 1-6烷基及C 1-6烷氧基，其中NH 2、C 1-6烷基或C 1-6烷氧基視情況經C 1-3烷基、C 3-6環烷基及/或鹵基中之1至3者取代； 在式IV中，R 3'為H或C 1-6烷基；Y 1為CH 2或
Figure 02_image045
；L 1為一鍵、-C(=O)-、-NR-、-O-或-S-，其中R為氫、視情況經取代之醯基、視情況經取代之烷基或氮保護基；L 3為一鍵、-NR-、-O-或-S-，其中R為氫、視情況經取代之醯基、視情況經取代之烷基或氮保護基；L 2為經取代或未經取代之C 1-50烴鏈；Z為C或N；U為O、S或CH；V為N或NH；T為CH或N；其中U、Z、V及T中之至多兩者含有雜原子；K為CH或N；Q為CH或N；其中K及Q不同時為N；R'''在每次出現時獨立地選自由以下組成之群：H、OH、NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基及鹵素；k為0、1、2或3；R'在每次出現時獨立地選自由以下組成之群：H、鹵素、OH、C 1-6烷基、C 1-6鹵烷基及C 1-6烷氧基；m為0、1、2、3或4；R''在每次出現時獨立地選自由以下組成之群：H、鹵基、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6鹵烷基、C 1-6烷胺基、C 3-6環烷基、C 3-6環烷胺基及C 3-6雜環烷基；n為0、1或2；J為CR 6或N；X為CR 6或N；Y為CR 6或N；其中J、X及Y中之至少一者為N，但J及Y不同時為N，X及Y不同時為N；R 6獨立地選自由以下組成之群：H、NH 2、C 1-6烷基及C 1-6烷氧基，其中NH 2、C 1-6烷基或C 1-6烷氧基視情況經C 1-3烷基、C 3-6環烷基及/或鹵基中之1至3者取代； 在式V中，R 2'在每次出現時獨立地選自由以下組成之群：H、OH、C 1-6烷基、C 1-6烷氧基、C 1-6烷胺基及NH 2；m6為0、1、2、3或4；Y 1為CH 2或
Figure 02_image045
；L 1為一鍵、-C(=O)-、-NR-、-O-或-S-，其中R為氫、視情況經取代之醯基、視情況經取代之烷基或氮保護基；L 2為經取代或未經取代之C 1-50烴鏈；Z為C或N；U為O、S或CH；V為N或NH；T為CH或N；其中U、Z、V及T中之至多兩者含有雜原子；K為CH或N；Q為CH或N；其中K及Q不同時為N；R'''在每次出現時獨立地選自由以下組成之群：H、OH、NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基及鹵素；k為0、1、2或3；R'在每次出現時獨立地選自由以下組成之群：H、鹵素、OH、C 1-6烷基、C 1-6鹵烷基及C 1-6烷氧基；m為0、1、2、3或4；R''在每次出現時獨立地選自由以下組成之群：H、鹵基、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6鹵烷基、C 1-6烷胺基、C 3-6環烷基、C 3-6環烷胺基及C 3-6雜環烷基；n為0、1或2；J為CR 6或N；X為CR 6或N；Y為CR 6或N；其中J、X及Y中之至少一者為N，但J及Y不同時為N，X及Y不同時為N；R 6獨立地選自由以下組成之群：H、NH 2、C 1-6烷基及C 1-6烷氧基，其中NH 2、C 1-6烷基或C 1-6烷氧基視情況經C 1-3烷基、C 3-6環烷基及/或鹵基中之1至3者取代； 在式VI中，L 1為一鍵、-C(=O)-、-NR-、-O-或-S-，其中R為氫、視情況經取代之醯基、視情況經取代之烷基或氮保護基；L 2為經取代或未經取代之C 1-50烴鏈；Z為C或N；U為O、S或CH；V為N；T為CH或N；其中U、Z、V及T中之至多兩者含有雜原子；K為CH或N；Q為CH或N；其中K及Q不同時為N；R'''在每次出現時獨立地選自由以下組成之群：H、OH、NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基及鹵素；k為0、1、2或3；R'在每次出現時獨立地選自由以下組成之群：H、鹵素、OH、C 1-6烷基、C 1-6鹵烷基及C 1-6烷氧基；m為0、1、2、3或4；R''在每次出現時獨立地選自由以下組成之群：H、鹵基、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6鹵烷基、C 1-6烷胺基、C 3-6環烷基、C 3-6環烷胺基及C 3-6雜環烷基；n為0、1或2；J為CR 6或N；X為CR 6或N；Y為CR 6或N；其中J、X及Y中之至少一者為N，但J及Y不同時為N，X及Y不同時為N；R 6獨立地選自由以下組成之群：H、NH 2、C 1-6烷基及C 1-6烷氧基，其中NH 2、C 1-6烷基或C 1-6烷氧基視情況經C 1-3烷基、C 3-6環烷基及/或鹵基中之1至3者取代。視情況，經取代或未經取代之C 1-50烴鏈之一或多個鏈原子獨立地經-C(=O)-、-O-、-NR a1-、-S-或環狀部分置換，其中R a1獨立地為氫、經取代或未經取代之C 1-6烷基(例如，經取代或未經取代之甲基或乙基)、或氮保護基(例如，苯甲基(Bn)、碳酸三級丁酯(BOC或Boc)、胺基甲酸苯甲酯(Cbz)、9-碳酸茀基甲酯(Fmoc)、三氟乙醯基、三苯基甲基、乙醯基或對甲苯磺醯胺(Ts))。 In some embodiments, the compound has any one of Formulas (I)-(VI):
Figure 02_image041
Figure 02_image043
Wherein in formula I, R 3' is H or C 1-6 alkyl; Y 1 is CH 2 or
Figure 02_image045
; L is a bond, -C(=O)-, -NR-, -O- or -S-, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or nitrogen protection group; L3 is a bond, -NR-, -O- or -S-, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group. L2 is a substituted or unsubstituted C 1-50 hydrocarbon chain; Z is C or N; U is O, S or CH; V is N, wherein Z and U are not heteroatoms at the same time; K is CH or N ; Q is CH or N; wherein K and Q are not N at the same time; R''' at each occurrence is independently selected from the group consisting of: H, OH, NH 2 , C 1-6 alkyl, C 1 -6 alkylamino, C 1-6 alkoxy and halogen; k is 0, 1, 2 or 3; R' is independently selected at each occurrence from the group consisting of: H, halogen, OH, C 1 -6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy; m is 0, 1, 2, 3 or 4; R'' at each occurrence is independently selected from the group consisting of: H, halo, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkylamino, C 3-6 cycloalkylamino, C 3-6 cycloalkyl and C 3-6 heterocycloalkyl; n is 0, 1 or 2; J is CR 6 or N; X is CR 6 or N; Y is CR 6 or N; where J, X and at least one of Y is N, but J and Y are not N at the same time, and X and Y are not N at the same time; R 6 is independently selected from the group consisting of H, NH 2 , C 1-6 alkyl and C 1-6 alkoxy, wherein NH 2 , C 1-6 alkyl or C 1-6 alkoxy is optionally modified by one of C 1-3 alkyl, C 3-6 cycloalkyl and/or halo 1 to 3 are substituted; In formula II, R 2' is independently selected at each occurrence from the group consisting of H, OH, C 1-6 alkyl, C 1-6 alkoxy, C 1- 6 alkylamino groups and NH 2 ; m6 is 0, 1, 2, 3 or 4; Y 1 is CH 2 or
Figure 02_image045
; L is a bond, -C(=O)-, -NR-, -O- or -S-, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or nitrogen protection L is a substituted or unsubstituted C 1-50 hydrocarbon chain; Z is C or N; U is O, S or CH; V is N, wherein Z and U are not heteroatoms at the same time; K is CH or N; Q is CH or N; wherein K and Q are not N at the same time; R''' at each occurrence is independently selected from the group consisting of: H, OH, NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy and halogen; k is 0, 1, 2 or 3; R' is independently selected at each occurrence from the group consisting of: H, halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy; m is 0, 1, 2, 3 or 4; R'' is independently selected from the group consisting of Group: H, halo, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkylamino , C 3-6 cycloalkyl and C 3-6 heterocycloalkyl; n is 0, 1 or 2; J is CR 6 or N; X is CR 6 or N; Y is CR 6 or N; wherein at least one of J, X and Y is N, but J and Y are not N at the same time, and X and Y are not N at the same time; R6 is independently selected from the group consisting of H, NH2 , C 1-6 alkyl and C 1-6 alkoxy , wherein NH 2 , C 1-6 alkyl or C 1-6 alkoxy is optionally substituted by 1 to 3 of C 1-3 alkyl, C 3-6 cycloalkyl and/or halo; In formula III, L is a bond, -C(=O)-, -NR-, -O- or -S-, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L 2 is a substituted or unsubstituted C 1-50 hydrocarbon chain; Z is C or N; U is O, S or CH; V is N, wherein Z and U are not heteroatoms at the same time; K is CH or N; Q is CH or N; wherein K and Q are not N at the same time; R''' at each occurrence is independently selected from the group consisting of: H, OH, NH 2 , C 1-6 Alkyl, C 1-6 alkylamino, C 1-6 alkoxy and halogen; k is 0, 1, 2 or 3; R' at each occurrence is independently selected from the group consisting of H, halogen , OH, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy; m is 0, 1, 2, 3 or 4; R'' is independently selected from at each occurrence The following groups: H, halo, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkylamino, C 3-6 Cycloalkyl, C 3-6 cycloalkylamino and C 3-6 heterocycloalkyl; n is 0, 1 or 2; J is CR 6 or N; X is CR 6 or N; Y is CR 6 or N wherein at least one of J, X and Y is N, but J and Y are not N at the same time, and X and Y are not N at the same time; R independently selected from the group consisting of H, NH 2 , C 1-6 alkyl and C 1-6 alkoxy, wherein NH 2 , C 1-6 alkyl or C 1-6 alkoxy is optionally modified by C 1 1 to 3 of -3 alkyl, C 3-6 cycloalkyl and/or halogen are substituted; in formula IV, R 3' is H or C 1-6 alkyl; Y 1 is CH 2 or
Figure 02_image045
; L is a bond, -C(=O)-, -NR-, -O- or -S-, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or nitrogen protection Base; L 3 is a bond, -NR-, -O- or -S-, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or nitrogen protecting group; L 2 is substituted Or unsubstituted C 1-50 hydrocarbon chain; Z is C or N; U is O, S or CH; V is N or NH; T is CH or N; or contain a heteroatom; K is CH or N; Q is CH or N; wherein K and Q are not N at the same time; R''', at each occurrence, is independently selected from the group consisting of: H, OH, NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy and halogen; k is 0, 1, 2 or 3; R' is independently selected from the group consisting of Group: H, halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy; m is 0, 1, 2, 3 or 4; R'' appears in each occurrence is independently selected from the group consisting of H, halo, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkylamino , C 3-6 cycloalkyl, C 3-6 cycloalkylamino and C 3-6 heterocycloalkyl; n is 0, 1 or 2; J is CR 6 or N; X is CR 6 or N; Y is CR 6 or N; wherein at least one of J, X and Y is N, but J and Y are not N at the same time, and X and Y are not N at the same time; R 6 is independently selected from the group consisting of H, NH 2 , C 1-6 alkyl and C 1-6 alkoxy, wherein NH 2 , C 1-6 alkyl or C 1-6 alkoxy can be modified by C 1-3 alkyl, C 3-6 1 to 3 of cycloalkyl and/or halo are substituted; In formula V, R 2' is independently selected from the group consisting of H, OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and NH 2 ; m6 is 0, 1, 2, 3 or 4; Y 1 is CH 2 or
Figure 02_image045
; L is a bond, -C(=O)-, -NR-, -O- or -S-, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or nitrogen protection L 2 is a substituted or unsubstituted C 1-50 hydrocarbon chain; Z is C or N; U is O, S or CH; V is N or NH; T is CH or N; At most two of V and T contain heteroatoms; K is CH or N; Q is CH or N; wherein K and Q are not both N; R''' at each occurrence is independently selected from the group consisting of : H, OH, NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy and halogen; k is 0, 1, 2 or 3; R' in each occurrence independently selected from the group consisting of H, halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy; m is 0, 1, 2, 3 or 4; R'' at each occurrence is independently selected from the group consisting of H, halo, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkylamino and C 3-6 heterocycloalkyl; n is 0, 1 or 2; J is CR 6 or N; X is CR 6 or N; Y is CR 6 or N; wherein at least one of J, X and Y is N, but J and Y are not N at the same time, and X and Y are not N at the same time; R 6 is independently selected from The group consisting of H, NH 2 , C 1-6 alkyl and C 1-6 alkoxy, wherein NH 2 , C 1-6 alkyl or C 1-6 alkoxy is optionally modified by C 1-3 1 to 3 of alkyl, C 3-6 cycloalkyl and/or halogen are substituted; In formula VI, L 1 is a bond, -C(=O)-, -NR-, -O- or -S-, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or nitrogen protecting group; L is substituted or unsubstituted C 1-50 hydrocarbon chain; Z is C or N; U is O, S, or CH; V is N; T is CH or N; wherein up to two of U, Z, V, and T contain heteroatoms; K is CH or N; Q is CH or N; K and Q are not N at the same time; R''' is independently selected from the group consisting of H, OH, NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1 -6 alkoxy and halogen; k is 0, 1, 2 or 3; R' at each occurrence is independently selected from the group consisting of: H, halogen, OH, C 1-6 alkyl, C 1- 6 haloalkyl and C 1-6 alkoxy; m is 0, 1, 2, 3 or 4; R'' is independently selected at each occurrence from the group consisting of: H, halo, OH, NH 2. C 1-6 alkyl, C 1-6 alkoxy , C 1-6 haloalkyl, C 1-6 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkylamino and C 3-6 heterocycloalkyl; n is 0, 1 or 2; J is CR 6 or N; X is CR 6 or N; Y is CR 6 or N wherein at least one of J, X and Y is N, but J and Y are not N at the same time, and X and Y are not N at the same time; R 6 is independently selected from the group consisting of: H, NH 2 , C 1 -6 alkyl and C 1-6 alkoxy, wherein NH 2 , C 1-6 alkyl or C 1-6 alkoxy is optionally modified by C 1-3 alkyl, C 3-6 cycloalkyl and/ Or 1 to 3 of the halo groups are substituted. Optionally, one or more chain atoms of substituted or unsubstituted C 1-50 hydrocarbon chains are independently -C(=O)-, -O-, -NR a1 -, -S- or ring moieties Replacement, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl (for example, substituted or unsubstituted methyl or ethyl), or nitrogen protecting group (for example, benzyl (Bn), tertiary butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl base or p-toluenesulfonamide (Ts)).

在某些實施例中，化合物具有式I之結構。In certain embodiments, compounds have the structure of Formula I.

在某些實施例中，化合物具有式II之結構。In certain embodiments, the compound has the structure of Formula II.

在某些實施例中，化合物具有式III之結構。In certain embodiments, the compound has the structure of Formula III.

在某些實施例中，化合物具有式IV之結構。In certain embodiments, the compound has the structure of Formula IV.

在某些實施例中，化合物具有式V之結構。In certain embodiments, the compound has the structure of Formula V.

在某些實施例中，化合物具有式VI之結構。In certain embodiments, the compound has the structure of Formula VI.

在某些實施例中，式(I)、(II)及(III)中之部分

Figure 02_image050
為
Figure 02_image052
Figure 02_image054
。 In certain embodiments, the moieties in formulas (I), (II) and (III)
Figure 02_image050
for
Figure 02_image052
Figure 02_image054
.

在某些實施例中，式(IV)、(V)及(VI)中之部分

Figure 02_image056
為
Figure 02_image058
Figure 02_image060
。 In certain embodiments, the moieties in formulas (IV), (V) and (VI)
Figure 02_image056
for
Figure 02_image058
Figure 02_image060
.

在某些實施例中，式(I)至(VI)中之部分

Figure 02_image062
為
Figure 02_image064
Figure 02_image066
。 In certain embodiments, the moieties in formulas (I) to (VI)
Figure 02_image062
for
Figure 02_image064
Figure 02_image066
.

在某些實施例中，式(I)及(IV)中之部分

Figure 02_image068
為
Figure 02_image070
。 In certain embodiments, the moieties in formulas (I) and (IV)
Figure 02_image068
for
Figure 02_image070
.

在某些實施例中，式(II)及(V)中之部分

Figure 02_image072
為
Figure 02_image074
。 In certain embodiments, the moieties in formulas (II) and (V)
Figure 02_image072
for
Figure 02_image074
.

在本發明之一個實施例中，L1為一鍵。In one embodiment of the present invention, L1 is a key.

在本發明之一個實施例中，L1為-C(=O)-、-NH-、-O-或-S-。In one embodiment of the present invention, L1 is -C(=O)-, -NH-, -O- or -S-.

在本發明之一個實施例中，L3為一鍵。In one embodiment of the present invention, L3 is a key.

在本發明之一個實施例中，L3為-NH-、-O-或-S-。In one embodiment of the present invention, L3 is -NH-, -O- or -S-.

在本發明之一個實施例中，L2為經取代或未經取代之C 1-30烴鏈，視情況其中烴鏈之一或多個鏈原子獨立地經-C(=O)-、-O-、-NR a1-、-S-或環狀部分置換，其中R a1獨立地為氫、經取代或未經取代之C 1-6烷基或氮保護基。 In one embodiment of the present invention, L2 is a substituted or unsubstituted C 1-30 hydrocarbon chain, where one or more chain atoms of the hydrocarbon chain are independently replaced by -C(=O)-, -O -, -NR a1 -, -S- or cyclic moiety replacement, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or nitrogen protecting group.

在某些實施例中，L2為未經取代之C 1-30烴鏈，視情況其中烴鏈之一或多個鏈原子獨立地經-C(=O)-、-O-、-NR a1-、-S-或環狀部分置換，其中R a1獨立地為氫、經取代或未經取代之C 1-6烷基或氮保護基。 In certain embodiments, L2 is an unsubstituted C 1-30 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently -C(=O)-, -O-, -NR a1 -, -S- or cyclic moiety replacement, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or nitrogen protecting group.

在某些實施例中，L2為經取代或未經取代之C 1-24烴鏈，視情況其中烴鏈之一或多個鏈原子獨立地經-C(=O)-、-O-、-NR a1-、-S-或環狀部分置換，其中R a1獨立地為氫、經取代或未經取代之C 1-6烷基或氮保護基。 In certain embodiments, L2 is a substituted or unsubstituted C 1-24 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently modified by -C(=O)-, -O-, -NR a1 -, -S- or cyclic moiety replacement, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or nitrogen protecting group.

在某些實施例中，L2為未經取代之C 1-24烴鏈，視情況其中烴鏈之一或多個鏈原子獨立地經-C(=O)-、-O-、-NR a1-、-S-或環狀部分置換，其中R a1獨立地為氫、經取代或未經取代之C 1-6烷基或氮保護基。 In certain embodiments, L2 is an unsubstituted C 1-24 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently -C(=O)-, -O-, -NR a1 -, -S- or cyclic moiety replacement, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or nitrogen protecting group.

在某些實施例中，L2為經取代或未經取代之C 1-20烴鏈，視情況其中烴鏈之一或多個鏈原子獨立地經-C(=O)-、-O-、-NR a1-、-S-或環狀部分置換，其中R a1獨立地為氫、經取代或未經取代之C 1-6烷基或氮保護基。 In certain embodiments, L2 is a substituted or unsubstituted C 1-20 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently modified by -C(=O)-, -O-, -NR a1 -, -S- or cyclic moiety replacement, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or nitrogen protecting group.

在某些實施例中，L2為未經取代之C 1-20烴鏈，視情況其中烴鏈之一或多個鏈原子獨立地經-C(=O)-、-O-、-NR a1-、-S-或環狀部分置換，其中R a1獨立地為氫、經取代或未經取代之C 1-6烷基或氮保護基。 In certain embodiments, L2 is an unsubstituted C 1-20 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently modified by -C(=O)-, -O-, -NR a1 -, -S- or cyclic moiety replacement, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or nitrogen protecting group.

在某些實施例中，L2之烴鏈之至少一個鏈原子獨立地經-O-置換。In certain embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently replaced by -O-.

在某些實施例中，L2之鏈的長度包含至多50個連續共價鍵結原子，不包括氫原子及取代基。In certain embodiments, the length of the chain of L2 comprises up to 50 consecutive covalently bonded atoms, excluding hydrogen atoms and substituents.

在某些實施例中，L2的長度包含至多例如46、45、40、35、32、30、25、23、20、15、14、12、11、10、9、8、7、6、5、3個連續共價鍵結原子，不包括氫原子及取代基。In certain embodiments, the length of L2 comprises up to, for example, 46, 45, 40, 35, 32, 30, 25, 23, 20, 15, 14, 12, 11, 10, 9, 8, 7, 6, 5 , 3 consecutive covalently bonded atoms, excluding hydrogen atoms and substituents.

在某些實施例中，L2中之原子中之任一者可經取代。在某些實施例中，連接子L2中之原子中無一者經取代。在某些實施例中，連接子中之碳原子中無一者經取代。In certain embodiments, any of the atoms in L2 can be substituted. In certain embodiments, none of the atoms in linker L2 are substituted. In certain embodiments, none of the carbon atoms in the linker are substituted.

在某些實施例中，L2為含有不對稱碳/立構中心之連接子，亦即，攜帶4個連接至其上之不同基團之sp3雜化碳原子。在某些實施例中，包含此類L2基團之化合物經鏡像異構性增濃或實質上鏡像異構性增濃。在某些實施例中，包含此類L2基團之化合物為鏡像異構性純的。在某些實施例中，包含此類L2基團之化合物為外消旋的。In certain embodiments, L2 is a linker containing an asymmetric carbon/stereocenter, ie, an sp3 hybridized carbon atom that carries 4 different groups attached thereto. In certain embodiments, compounds comprising such L2 groups are enantiomerically enriched or substantially enantiomerically enriched. In certain embodiments, compounds comprising such L2 groups are enantiomerically pure. In certain embodiments, compounds comprising such L2 groups are racemic.

在某些實施例中，L2包含經取代或未經取代之伸碳環基、經取代或未經取代之伸雜環基、經取代或未經取代之伸芳基、經取代或未經取代之伸雜芳基、或經取代或未經取代之伸雜烷基，及其組合。在某些實施例中，L2為經取代或未經取代之伸碳環基、經取代或未經取代之伸雜環基、經取代或未經取代之伸芳基、經取代或未經取代之伸雜芳基或經取代或未經取代之伸雜烷基。在某些實施例中，L2為選自由以下組成之群的連接子：經取代及未經取代之伸烷基、經取代及未經取代之伸烯基、經取代及未經取代之伸炔基、經取代及未經取代之伸雜烷基、經取代及未經取代之伸雜烯基、經取代及未經取代之伸雜炔基、經取代及未經取代之伸雜環基、經取代及未經取代之伸碳環基、經取代及未經取代之伸芳基、經取代及未經取代之伸雜芳基，及其組合。In certain embodiments, L2 comprises substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylylene, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroalkylene, and combinations thereof. In certain embodiments, L2 is substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylylene, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroalkylene. In certain embodiments, L2 is a linker selected from the group consisting of substituted and unsubstituted alkylene, substituted and unsubstituted alkenylene, substituted and unsubstituted alkyne substituted and unsubstituted heteroalkylene, substituted and unsubstituted heteroalkenyl, substituted and unsubstituted heteroalkynyl, substituted and unsubstituted heterocyclyl, Substituted and unsubstituted carbocyclylenes, substituted and unsubstituted arylylenes, substituted and unsubstituted heteroarylylenes, and combinations thereof.

提及L2為本文所描述之二價部分之至少兩個實例之組合係指由第一二價部分之至少一個實例及第二二價部分之至少一個實例組成，其中第一及第二二價部分為相同或不同的且在本文所描述之二價部分之範疇內，且第一及第二二價部分之實例彼此連續共價連接。舉例而言，當L2為伸烷基及伸雜烷基連接子之組合時，-伸烷基-伸雜烷基-、-伸烷基-(伸雜烷基) 2-及-伸雜烷基、-伸烷基-伸雜烷基-皆在L2之範疇內，其中連接子中之任一者中伸烷基的各實例可相同或不同，且連接子中之任一者中伸雜烷基的各實例可相同或不同。 Reference to L2 as a combination of at least two instances of a divalent moiety described herein means consisting of at least one instance of a first divalent moiety and at least one instance of a second divalent moiety, wherein the first and second divalent moieties The moieties are the same or different and are within the scope of the bivalent moieties described herein, and instances of the first and second bivalent moieties are consecutively covalently linked to each other. For example, when L2 is a combination of alkylene and heteroalkylene linkers, -alkylene-heteroalkylene-, -alkylene-(heteroalkylene) 2- and -heteroalkylene The group, -alkylene-heteroalkylene-are all within the scope of L2, wherein each instance of the alkylene in any of the linkers can be the same or different, and any of the linkers in the heteroalkylene Examples of the alkyl group may be the same or different.

在某些實施例中，L2包含經取代或未經取代之伸烷基之至少一個實例，例如經取代或未經取代之C 1-6伸烷基、經取代或未經取代之C 1-2伸烷基、經取代或未經取代之C 1-3伸烷基、經取代或未經取代之C 3-4伸烷基、經取代或未經取代之C 4-5伸烷基、經取代或未經取代之C 5-6伸烷基、經取代或未經取代之C 3-6伸烷基或經取代或未經取代之C 4-6伸烷基。例示性伸烷基包括未經取代之伸烷基，諸如亞甲基(-CH 2-)、伸乙基(-(CH 2) 2-)、伸正丙基(-(CH 2) 3-)、伸正丁基(-(CH 2) 4-)、伸正戊基(-(CH 2) 5-)及伸正己基(-(CH 2) 6-)。 In certain embodiments, L2 comprises at least one instance of substituted or unsubstituted alkylene, such as substituted or unsubstituted C 1-6 alkylene, substituted or unsubstituted C 1- 2 alkylene, substituted or unsubstituted C 1-3 alkylene, substituted or unsubstituted C 3-4 alkylene, substituted or unsubstituted C 4-5 alkylene, A substituted or unsubstituted C 5-6 alkylene group, a substituted or unsubstituted C 3-6 alkylene group or a substituted or unsubstituted C 4-6 alkylene group. Exemplary alkylene groups include unsubstituted alkylene groups such as methylene ( -CH2- ), ethylidene (-( CH2 ) 2- ), n-propylidene (-( CH2 ) 3- ) , n-butyl (-(CH 2 ) 4 -), n-pentyl (-(CH 2 ) 5 -) and n-hexyl (-(CH 2 ) 6 -).

在某些實施例中，L2包含經取代或未經取代之伸烯基之至少一個實例，例如經取代或未經取代之C 2-6伸烯基、經取代或未經取代之C 1-3伸烯基、經取代或未經取代之C 3-4伸烯基、經取代或未經取代之C 4-5伸烯基或經取代或未經取代之C 5-6伸烯基。 In certain embodiments, L2 comprises at least one instance of substituted or unsubstituted alkenylene, such as substituted or unsubstituted C 2-6 alkenylene, substituted or unsubstituted C 1- 3 alkenyl, substituted or unsubstituted C 3-4 alkenyl, substituted or unsubstituted C 4-5 alkenyl or substituted or unsubstituted C 5-6 alkenyl.

在某些實施例中，L2包含經取代或未經取代之伸炔基之至少一個實例，例如經取代或未經取代之C 2-6伸炔基、經取代或未經取代之C 2-3伸炔基、經取代或未經取代之C 3-4伸炔基、經取代或未經取代之C 4-5伸炔基或經取代或未經取代之C 5-6伸炔基。 In certain embodiments, L2 comprises at least one instance of substituted or unsubstituted alkynyl, such as substituted or unsubstituted C2-6alkynyl , substituted or unsubstituted C2- 3 alkynyl, substituted or unsubstituted C 3-4 alkynyl, substituted or unsubstituted C 4-5 alkynyl or substituted or unsubstituted C 5-6 alkynyl.

在某些實施例中，L2包含經取代或未經取代之伸雜烷基之至少一個實例，例如經取代或未經取代之雜C 1-6伸烷基、經取代或未經取代之雜C 1-2伸烷基、經取代或未經取代之雜C 2-3伸烷基、經取代或未經取代之雜C 3-4伸烷基、經取代或未經取代之雜C 4- 5伸烷基或經取代或未經取代之雜C 5-6伸烷基。例示性伸雜烷基包括未經取代之伸雜烷基，諸如-(CH 2) 2-O(CH 2) 2-、-OCH 2-、-CH 2O-、-O(CH 2) 2-、-(CH 2) 2O-、-O(CH 2) 3-、-(CH 2) 3O-、-O(CH 2) 4-、-(CH 2) 4O-、-O(CH 2) 5-、-(CH 2) 5O-、-O(CH 2) 6-及-O(CH 2) 6O-及醯胺基(例如-NH-C(=O)-及-C(=O)NH-)。 In certain embodiments, L2 comprises at least one instance of substituted or unsubstituted heteroalkylene, such as substituted or unsubstituted heteroC 1-6 alkylene, substituted or unsubstituted hetero C 1-2 alkylene, substituted or unsubstituted hetero C 2-3 alkylene, substituted or unsubstituted hetero C 3-4 alkylene, substituted or unsubstituted hetero C 4 - 5 alkylene or substituted or unsubstituted hetero C 5-6 alkylene. Exemplary heteroalkylene groups include unsubstituted heteroalkylene groups such as -(CH 2 ) 2 -O(CH 2 ) 2 -, -OCH 2 -, -CH 2 O-, -O(CH 2 ) 2 -, -(CH 2 ) 2 O-, -O(CH 2 ) 3 -, -(CH 2 ) 3 O-, -O(CH 2 ) 4 -, -(CH 2 ) 4 O-, -O( CH 2 ) 5 -, -(CH 2 ) 5 O-, -O(CH 2 ) 6 - and -O(CH 2 ) 6 O- and amido groups (eg -NH-C(=O)- and - C(=O)NH-).

在某些實施例中，L2包含經取代或未經取代之伸雜烯基之至少一個實例，例如經取代或未經取代之雜C 2-6伸烯基、經取代或未經取代之雜C 1-3伸烯基、經取代或未經取代之雜C 3-4伸烯基、經取代或未經取代之雜C 4-5伸烯基或經取代或未經取代之雜C 5-6伸烯基。 In certain embodiments, L2 comprises at least one instance of substituted or unsubstituted heteroalkenyl, such as substituted or unsubstituted heteroC2-6alkenyl , substituted or unsubstituted hetero C1-3alkenyl , substituted or unsubstituted heteroC3-4alkenyl, substituted or unsubstituted heteroC4-5alkenyl, or substituted or unsubstituted heteroC5 -6 alkenylene.

在某些實施例中，L2包含經取代或未經取代之伸雜炔基之至少一個實例，例如經取代或未經取代之雜C 2-6伸炔基、經取代或未經取代之雜C 2-3伸炔基、經取代或未經取代之雜C 3-4伸炔基、經取代或未經取代之雜C 4-5伸炔基或經取代或未經取代之雜C 5-6伸炔基。 In certain embodiments, L2 comprises at least one instance of substituted or unsubstituted heteroalkynyl, such as substituted or unsubstituted heteroC alkynyl, substituted or unsubstituted hetero C2-3alkynyl , substituted or unsubstituted heteroC3-4alkynyl, substituted or unsubstituted heteroC4-5alkynyl, or substituted or unsubstituted heteroC5 -6 alkynyl.

在某些實施例中，L2包含經取代或未經取代之伸碳環基之至少一個實例，例如經取代或未經取代之C 3-6伸碳環基、經取代或未經取代之C 3-4伸碳環基、經取代或未經取代之C 4-5伸碳環基或經取代或未經取代C 5 -6伸碳環基。 In certain embodiments, L2 comprises at least one instance of a substituted or unsubstituted carbocyclylene, such as a substituted or unsubstituted C 3-6 carbocyclylene, a substituted or unsubstituted C 3-4 carbocyclyl, substituted or unsubstituted C 4-5 carbocyclyl or substituted or unsubstituted C 5-6 carbocyclyl.

在某些實施例中，L2包含經取代或未經取代之伸雜環基之至少一個實例，例如經取代或未經取代之3至6員伸雜環基、經取代或未經取代之3至4員伸雜環基、經取代或未經取代之4至5員伸雜環基或經取代或未經取代之5至6員伸雜環基。在某些實施例中，L2之烴鏈之至少一個鏈原子獨立地經具有1至4個選自由氮、氧及硫組成之群的環雜原子的5至8員雜環基置換。在某些實施例中，L2之烴鏈之至少一個鏈原子獨立地經具有1至3個選自由氮及氧組成之群的環雜原子的6員雜環基置換。在某些實施例中，L2之烴鏈之至少一個鏈原子獨立地經哌啶、哌𠯤或𠰌啉置換。In certain embodiments, L2 comprises at least one instance of a substituted or unsubstituted heterocyclyl, such as a substituted or unsubstituted 3-6 membered heterocyclyl, a substituted or unsubstituted 3 to 4-membered heterocyclic group, substituted or unsubstituted 4-5 membered heterocyclic group or substituted or unsubstituted 5-6 membered heterocyclic group. In certain embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently replaced by a 5-8 membered heterocyclyl having 1-4 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently replaced with a 6-membered heterocyclyl having 1 to 3 ring heteroatoms selected from the group consisting of nitrogen and oxygen. In certain embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently replaced by piperidine, piperidine, or phenoline.

在某些實施例中，L2包含經取代或未經取代之伸芳基之至少一個實例，例如經取代或未經取代之伸苯基。在某些實施例中，L2之烴鏈之至少一個鏈原子獨立地經視情況經取代之苯基置換。In certain embodiments, L2 comprises at least one instance of a substituted or unsubstituted arylylene, such as a substituted or unsubstituted phenylene. In certain embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently replaced with an optionally substituted phenyl group.

在某些實施例中，L2包含經取代或未經取代之伸雜芳基之至少一個實例，例如經取代或未經取代之5員至6員伸雜芳基。In certain embodiments, L2 comprises at least one instance of a substituted or unsubstituted heteroaryl, such as a substituted or unsubstituted 5-6 membered heteroaryl.

在某些實施例中，L2為未經取代之烴鏈，視情況其中烴鏈之一或多個鏈原子獨立地經-NR a1-置換，且R a1之各實例獨立地為氫、經取代或未經取代之C 1-6烷基或氮保護基，或視情況R a1之兩個實例與其插入原子一起形成經取代或未經取代之雜環或經取代或未經取代之雜芳基環。在某些實施例中，R a1之至少一個實例為氫。在某些實施例中，R a1之至少一個實例為經取代或未經取代之C 1-6烷基(例如，經取代或未經取代之甲基或乙基)。在某些實施例中，R a1之至少一個實例為氮保護基(例如苯甲基(Bn)、碳酸三級丁酯(BOC或Boc)、胺基甲酸苯甲酯(Cbz)、碳酸9-茀基甲基酯(Fmoc)、三氟乙醯基、三苯基甲基、乙醯基或對甲苯磺醯胺(Ts))。 In certain embodiments, L2 is an unsubstituted hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced by -NR a1 -, and each instance of R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or nitrogen protecting group, or as the case may be, two instances of R a1 form a substituted or unsubstituted heterocycle or a substituted or unsubstituted heteroaryl together with its intervening atom ring. In certain embodiments, at least one instance of R a1 is hydrogen. In certain embodiments, at least one instance of R a1 is substituted or unsubstituted C 1-6 alkyl (eg, substituted or unsubstituted methyl or ethyl). In certain embodiments, at least one example of R a1 is a nitrogen protecting group such as benzyl (Bn), tertiary butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9- Fenylmethyl ester (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl or p-toluenesulfonamide (Ts)).

在某些實施例中，L2為視情況經取代之C 1-45烴鏈，視情況其中烴鏈之一或多個鏈原子獨立地經-C(=O)-、-O-、-NR a1-、-S-或環狀部分置換，其中R a1獨立地為氫、經取代或未經取代之C 1-6烷基或氮保護基。在某些實施例中，L2為未經取代之C 1-45烴鏈，視情況其中烴鏈之一或多個鏈原子獨立地經-C(=O)-、-O-、-NR a1-、-S-或環狀部分置換，其中R a1獨立地為氫、經取代或未經取代之C 1-6烷基或氮保護基。在某些實施例中，L2為視情況經取代之C 1-24烴鏈，視情況其中烴鏈之一或多個鏈原子獨立地經-C(=O)-、-O-、-NR a1-、-S-或環狀部分置換，其中R a1獨立地為氫、經取代或未經取代之C 1-6烷基或氮保護基。在某些實施例中，L2為未經取代之C 1-24烴鏈，視情況其中烴鏈之一或多個鏈原子獨立地經-C(=O)-、-O-、-NR a1-、-S-或環狀部分置換，其中R a1獨立地為氫、經取代或未經取代之C 1-6烷基或氮保護基。在某些實施例中，L2為視情況經取代之C 1-20烴鏈，視情況其中烴鏈之一或多個鏈原子獨立地經-C(=O)-、-O-、-NR a1-、-S-或環狀部分置換，其中R a1獨立地為氫、經取代或未經取代之C 1-6烷基或氮保護基。在某些實施例中，L2為未經取代之C 1-20烴鏈，視情況其中烴鏈之一或多個鏈原子獨立地經-C(=O)-、-O-、-NR a1-、-S-或環狀部分置換，其中R a1獨立地為氫、經取代或未經取代之C 1-6烷基或氮保護基。在某些實施例中，L2為視情況經取代之C 1-30烴鏈，其中烴鏈之一或多個鏈原子獨立地經-O-或-NR a1-置換。在某些實施例中，L2為未經取代之C 1-30烴鏈，其中烴鏈之一或多個鏈原子獨立地經-O-或-NR a1-置換。在某些實施例中，L2為未經取代之C 1-30烴鏈，其中烴鏈之至少一個鏈原子獨立地經-O-置換。在某些實施例中，L2為未經取代之C 1-26烴鏈，其中烴鏈之一或多個鏈原子獨立地經-C(=O)-、-O-或-NR a1-置換。在某些實施例中，L2為未經取代之C 1-20烴鏈，其中烴鏈之一或多個鏈原子獨立地經-O-置換。在某些實施例中，L2為未經取代之C 5-26烴鏈，其中烴鏈之一或多個鏈原子獨立地經-C(=O)-、-O-或-NR a1-置換。在某些實施例中，L2為未經取代之C 5-26烴鏈，其中烴鏈之一或多個鏈原子獨立地經-O-置換。在某些實施例中，L2為未經取代之C 5-20烴鏈，其中烴鏈之一或多個鏈原子獨立地經-C(=O)-、-O-或-NR a1-置換。在某些實施例中，L2為未經取代之C 5-20烴鏈，其中烴鏈之一或多個鏈原子獨立地經-O-或-NR a1-置換。在某些實施例中，L2為未經取代之C 5-15烴鏈，其中烴鏈之一或多個鏈原子獨立地經-C(=O)-、-O-或-NR a1-置換。在某些實施例中，L2為未經取代之C 15-20烴鏈，其中烴鏈之一或多個鏈原子獨立地經-C(=O)-、-O-或-NR a1-置換。在某些實施例中，L2為未經取代之C 20-25烴鏈，其中烴鏈之一或多個鏈原子獨立地經-C(=O)-、-O-或-NR a1-置換。在某些實施例中，L2為經取代或未經取代之C 1-45烴鏈。在某些實施例中，L2為經取代或未經取代之C 5-40烴鏈。在某些實施例中，L2之烴鏈之一或多個鏈原子獨立地經-C(=O)-、-O-、-S-、-NR a1-、-N=或=N-置換。在某些實施例中，L2之烴鏈之一或多個鏈原子獨立地經-C(=O)-、-O-或-NR a1-置換，其中R a1獨立地為氫、經取代或未經取代之C 1-6烷基或氮保護基。在某些實施例中，L2為未經取代之C 1-26烴鏈，其中烴鏈之至少一個鏈原子獨立地經-O-置換。本文中之環狀部分係指伸環烷基或伸雜環烷基，諸如

Figure 02_image076
Figure 02_image078
或其組合。 In certain embodiments, L2 is an optionally substituted C 1-45 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently -C(=O)-, -O-, -NR a1 -, -S- or cyclic moiety replacement, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or nitrogen protecting group. In certain embodiments, L2 is an unsubstituted C 1-45 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently -C(=O)-, -O-, -NR a1 -, -S- or cyclic moiety replacement, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or nitrogen protecting group. In certain embodiments, L2 is an optionally substituted C 1-24 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently -C(=O)-, -O-, -NR a1 -, -S- or cyclic moiety replacement, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or nitrogen protecting group. In certain embodiments, L2 is an unsubstituted C 1-24 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently -C(=O)-, -O-, -NR a1 -, -S- or cyclic moiety replacement, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or nitrogen protecting group. In certain embodiments, L2 is an optionally substituted C 1-20 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently -C(=O)-, -O-, -NR a1 -, -S- or cyclic moiety replacement, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or nitrogen protecting group. In certain embodiments, L2 is an unsubstituted C 1-20 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently modified by -C(=O)-, -O-, -NR a1 -, -S- or cyclic moiety replacement, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or nitrogen protecting group. In certain embodiments, L2 is an optionally substituted C 1-30 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced by -O- or -NR a1 -. In certain embodiments, L2 is an unsubstituted C 1-30 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced by -O- or -NR a1 -. In certain embodiments, L2 is an unsubstituted C 1-30 hydrocarbon chain, wherein at least one chain atom of the hydrocarbon chain is independently replaced by -O-. In certain embodiments, L2 is an unsubstituted C 1-26 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced by -C(=O)-, -O- or -NR a1 - . In certain embodiments, L2 is an unsubstituted C 1-20 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced by -O-. In certain embodiments, L2 is an unsubstituted C 5-26 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced by -C(=O)-, -O- or -NR a1 - . In certain embodiments, L2 is an unsubstituted C 5-26 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced by -O-. In certain embodiments, L2 is an unsubstituted C 5-20 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced by -C(=O)-, -O- or -NR a1 - . In certain embodiments, L2 is an unsubstituted C 5-20 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced by -O- or -NR a1 -. In certain embodiments, L2 is an unsubstituted C 5-15 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced by -C(=O)-, -O- or -NR a1 - . In certain embodiments, L2 is an unsubstituted C 15-20 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced by -C(=O)-, -O- or -NR a1 - . In certain embodiments, L2 is an unsubstituted C20-25 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced by -C(=O)-, -O- or -NR a1 - . In certain embodiments, L2 is a substituted or unsubstituted C 1-45 hydrocarbon chain. In certain embodiments, L2 is a substituted or unsubstituted C5-40 hydrocarbon chain. In certain embodiments, one or more chain atoms of the hydrocarbon chain of L2 are independently replaced by -C(=O)-, -O-, -S-, -NR a1 -, -N= or =N- . In certain embodiments, one or more chain atoms of the hydrocarbon chain of L2 are independently replaced by -C(=O)-, -O-, or -NR a1 -, wherein R a1 is independently hydrogen, substituted or Unsubstituted C 1-6 alkyl or nitrogen protecting group. In certain embodiments, L2 is an unsubstituted C 1-26 hydrocarbon chain, wherein at least one chain atom of the hydrocarbon chain is independently replaced by -O-. A cyclic moiety herein refers to a cycloalkylene or a heterocycloalkylene, such as
Figure 02_image076
Figure 02_image078
or a combination thereof.

在某些實施例中，L2為全碳、經取代或未經取代之C 1-45烴鏈。在某些實施例中，L2為全碳、經取代或未經取代之C 1-30烴鏈。在某些實施例中，L2為全碳、經取代或未經取代之C 1-26烴鏈。在某些實施例中，L2為全碳、經取代或未經取代之C 1-24烴鏈。在某些實施例中，L2為全碳、經取代或未經取代之C 1-20烴鏈。在某些實施例中，L2為全碳、經取代或未經取代之C 1-20烴鏈。 In certain embodiments, L2 is an all-carbon, substituted or unsubstituted C 1-45 hydrocarbon chain. In certain embodiments, L2 is an all carbon, substituted or unsubstituted C 1-30 hydrocarbon chain. In certain embodiments, L2 is an all carbon, substituted or unsubstituted C 1-26 hydrocarbon chain. In certain embodiments, L2 is an all-carbon, substituted or unsubstituted C 1-24 hydrocarbon chain. In certain embodiments, L2 is an all carbon, substituted or unsubstituted C 1-20 hydrocarbon chain. In certain embodiments, L2 is an all carbon, substituted or unsubstituted C 1-20 hydrocarbon chain.

在某些實施例中，L2為

Figure 02_image080
，其中g為1、2、3、4、5或6。在某些實施例中，g為1。在某些實施例中，g為2。在某些實施例中，g為3。在某些實施例中，g為4。在某些實施例中，g為5。在某些實施例中，g為6。 In some embodiments, L2 is
Figure 02_image080
, wherein g is 1, 2, 3, 4, 5 or 6. In certain embodiments, g is 1. In certain embodiments, g is 2. In certain embodiments, g is 3. In certain embodiments, g is 4. In certain embodiments, g is 5. In certain embodiments, g is 6.

在某些實施例中，L2包含至少一個選自由以下組成之群的實例：經取代或未經取代之亞甲基、伸乙基、伸正丙基、伸正丁基、伸正戊基、伸正己基、-(CH 2) 2-O(CH 2) 2-、-OCH 2-、-CH 2O-、-O(CH 2) 2-、-(CH 2) 2O-、-O(CH 2) 3-、-(CH 2) 3O-、-O(CH 2) 4-、-(CH 2) 4O-、-O(CH 2) 5-、-(CH 2) 5O-、-O(CH 2) 6-、-O(CH 2) 6O-、-C(=O)O-、-O-C(=O)-、-NH-C(=O)-及-C(=O)NH-。 In certain embodiments, L2 comprises at least one instance selected from the group consisting of substituted or unsubstituted methylene, ethylidene, n-propyl, n-butyl, n-pentyl, n-hexyl , -(CH 2 ) 2 -O(CH 2 ) 2 -, -OCH 2 -, -CH 2 O-, -O(CH 2 ) 2 -, -(CH 2 ) 2 O-, -O(CH 2 ) 3 -, -(CH 2 ) 3 O-, -O(CH 2 ) 4 -, -(CH 2 ) 4 O-, -O(CH 2 ) 5 -, -(CH 2 ) 5 O-, - O(CH 2 ) 6 -, -O(CH 2 ) 6 O-, -C(=O)O-, -OC(=O)-, -NH-C(=O)- and -C(=O ) NH-.

在某些實施例中，L2包含至少一個選自由以下組成之群的實例：經取代或未經取代之亞甲基、伸乙基、伸正丙基、伸正丁基、伸正戊基、伸正己基、-(CH 2) 2-O(CH 2) 2-、-OCH 2-、-CH 2O-、-O(CH 2) 2-、-(CH 2) 2O-、-O(CH 2) 3-、-(CH 2) 3O-、-O(CH 2) 4-、-(CH 2) 4O-、-O(CH 2) 5-、-(CH 2) 5O-、-O(CH 2) 6-、-O(CH 2) 6O-、-NH-C(=O)-及-C(=O)NH-。 In certain embodiments, L2 comprises at least one instance selected from the group consisting of substituted or unsubstituted methylene, ethylidene, n-propyl, n-butyl, n-pentyl, n-hexyl , -(CH 2 ) 2- O(CH 2 ) 2- , -OCH 2 -, -CH 2 O-, -O(CH 2 ) 2 -, -(CH 2 ) 2 O-, -O(CH 2 ) 3 -, -(CH 2 ) 3 O-, -O(CH 2 ) 4 -, -(CH 2 ) 4 O-, -O(CH 2 ) 5 -, -(CH 2 ) 5 O-, - O(CH 2 ) 6 -, -O(CH 2 ) 6 O-, -NH-C(=O)- and -C(=O)NH-.

在某些實施例中，L2包括部分-NHC(=O)-。In certain embodiments, L2 includes the moiety -NHC(=0)-.

在某些實施例中，L2包括部分-NH-。In certain embodiments, L2 includes the moiety -NH-.

本發明之L2之實例包括但不限於：

Figure 02_image082
Figure 02_image084
、
Figure 02_image086
，其中各g獨立地為1、2、3、4、5或6；f為1、2、3、4、5或6，且h為1、2、3、4、5或6。 Examples of L2 of the present invention include, but are not limited to:
Figure 02_image082
Figure 02_image084
,
Figure 02_image086
, wherein each g is independently 1, 2, 3, 4, 5 or 6; f is 1, 2, 3, 4, 5 or 6, and h is 1, 2, 3, 4, 5 or 6.

在某些實施例中，L2具有下式：

Figure 02_image088
Figure 02_image090
。 In certain embodiments, L2 has the formula:
Figure 02_image088
Figure 02_image090
.

在某些實施例中，L2具有下式：

Figure 02_image092
Figure 02_image094
。 In certain embodiments, L2 has the formula:
Figure 02_image092
Figure 02_image094
.

在某些實施例中，L2具有下式：

Figure 02_image096
Figure 02_image098
，其中g為1、2、3、4或5；h為0、1、2、3、4或5；且f為1、2、3、4、5、6、7或8。 In certain embodiments, L2 has the formula:
Figure 02_image096
Figure 02_image098
, wherein g is 1, 2, 3, 4, or 5; h is 0, 1, 2, 3, 4, or 5; and f is 1, 2, 3, 4, 5, 6, 7, or 8.

在某些實施例中，L2具有下式：

Figure 02_image100
Figure 02_image102
，其中g為1、2、3、4、5、6、7或8；且f為1、2、3、4、5、6、7或8。 In certain embodiments, L2 has the formula:
Figure 02_image100
Figure 02_image102
, wherein g is 1, 2, 3, 4, 5, 6, 7 or 8; and f is 1, 2, 3, 4, 5, 6, 7 or 8.

在某些實施例中，L2具有下式：

Figure 02_image104
，其中g為1、2、3、4、5、6、7或8。 In certain embodiments, L2 has the formula:
Figure 02_image104
, wherein g is 1, 2, 3, 4, 5, 6, 7 or 8.

在某些實施例中，L2具有下式：

Figure 02_image106
，其中g為1、2、3、4、5、6、7或8；且f為1、2、3、4、5、6、7或8。 In certain embodiments, L2 has the formula:
Figure 02_image106
, wherein g is 1, 2, 3, 4, 5, 6, 7 or 8; and f is 1, 2, 3, 4, 5, 6, 7 or 8.

在某些實施例中，L2具有下式：

Figure 02_image108
，其中g為1、2、3、4、5、6、7或8；且f為1、2、3、4、5、6、7或8。 In certain embodiments, L2 has the formula:
Figure 02_image108
, wherein g is 1, 2, 3, 4, 5, 6, 7 or 8; and f is 1, 2, 3, 4, 5, 6, 7 or 8.

在某些實施例中，L2具有下式：

Figure 02_image110
，其中g為1、2、3、4、5、6、7或8。 In certain embodiments, L2 has the formula:
Figure 02_image110
, wherein g is 1, 2, 3, 4, 5, 6, 7 or 8.

在某些實施例中，本發明之化合物具有如下結構中之任一者：

Figure 02_image112
Figure 02_image114
其中在式I-1中，R 3'為H或C 1-6烷基；Y 1為CH 2或
Figure 02_image116
；L 1為一鍵、-C(=O)-、-NR-、-O-或-S-，其中R為氫、視情況經取代之醯基、視情況經取代之烷基或氮保護基；L 3為一鍵、-NR-、-O-或-S-，其中R為氫、視情況經取代之醯基、視情況經取代之烷基或氮保護基；L 2為經取代或未經取代之C 1-50烴鏈；Z為C或N；U為O、S或CH；其中Z及U不同時為雜原子；Q為CH或N；K為CH或N；其中Q及K不同時為N；R'''在每次出現時獨立地選自由以下組成之群：H、OH、NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基及鹵素；k為0、1、2或3；R'在每次出現時獨立地選自由以下組成之群：H、鹵素、OH、C 1-6烷基、C 1-6鹵烷基及C 1-6烷氧基；m為0、1、2、3或4；R''在每次出現時獨立地選自由以下組成之群：H、鹵基、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6鹵烷基、C 1-6烷胺基、C 3-6環烷基、C 3-6環烷胺基及C 3-6雜環烷基；n為0、1或2； 在式II-1中，R 2'在每次出現時獨立地選自由以下組成之群：H、OH、C 1-6烷基、C 1-6烷氧基、C 1-6烷胺基及NH 2；m6為0、1、2、3或4；Y 1為CH 2或
Figure 02_image116
；L 1為一鍵、-C(=O)-、-NR-、-O-或-S-，其中R為氫、視情況經取代之醯基、視情況經取代之烷基或氮保護基；L 3為一鍵、-NR-、-O-或-S-，其中R為氫、視情況經取代之醯基、視情況經取代之烷基或氮保護基；L 2為經取代或未經取代之C 1-50烴鏈；Z為C或N；U為O、S或CH；其中Z及U不同時為雜原子；Q為CH或N；K為CH或N；其中Q及K不同時為N；R'''在每次出現時獨立地選自由以下組成之群：H、OH、NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基及鹵素；k為0、1、2或3；R'在每次出現時獨立地選自由以下組成之群：H、鹵素、OH、C 1-6烷基、C 1-6鹵烷基及C 1-6烷氧基；m為0、1、2、3或4；R''在每次出現時獨立地選自由以下組成之群：H、鹵基、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6鹵烷基、C 1-6烷胺基、C 3-6環烷基、C 3-6環烷胺基及C 3-6雜環烷基；n為0、1或2； 在式III-1中，L 1為一鍵、-C(=O)-、-NR-、-O-或-S-，其中R為氫、視情況經取代之醯基、視情況經取代之烷基或氮保護基；L 3為一鍵、-NR-、-O-或-S-，其中R為氫、視情況經取代之醯基、視情況經取代之烷基或氮保護基；L 2為經取代或未經取代之C 1-50烴鏈；Z為C或N；U為O、S或CH；其中Z及U不同時為雜原子；Q為CH或N；K為CH或N；其中Q及K不同時為N；R'''在每次出現時獨立地選自由以下組成之群：H、OH、NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基及鹵素；k為0、1、2或3；R'在每次出現時獨立地選自由以下組成之群：H、鹵素、OH、C 1-6烷基、C 1-6鹵烷基及C 1-6烷氧基；m為0、1、2、3或4；R''在每次出現時獨立地選自由以下組成之群：H、鹵基、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6鹵烷基、C 1-6烷胺基、C 3-6環烷基、C 3-6環烷胺基及C 3-6雜環烷基；n為0、1或2； 在式IV-1中，R 3'為H或C 1-6烷基；Y 1為CH 2或
Figure 02_image116
；L 1為一鍵、-C(=O)-、-NR-、-O-或-S-，其中R為氫、視情況經取代之醯基、視情況經取代之烷基或氮保護基；L 3為一鍵、-NR-、-O-或-S-，其中R為氫、視情況經取代之醯基、視情況經取代之烷基或氮保護基；L 2為經取代或未經取代之C 1-50烴鏈；Z為C或N；U為O、S或CH；T為CH或N；其中U、Z及T中之僅一者為雜原子；Q為CH或N；K為CH或N；其中Q及K不同時為N；R'''在每次出現時獨立地選自由以下組成之群：H、OH、NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基及鹵素；k為0、1、2或3；R'在每次出現時獨立地選自由以下組成之群：H、鹵素、OH、C 1-6烷基、C 1-6鹵烷基及C 1-6烷氧基；m為0、1、2、3或4；R''在每次出現時獨立地選自由以下組成之群：H、鹵基、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6鹵烷基、C 1-6烷胺基、C 3-6環烷基、C 3-6環烷胺基及C 3-6雜環烷基；n為0、1或2；X為CR 6或N；Y為CR 6或N；其中X及Y中之一者為N，而另一者為CR 6；R 6獨立地選自由以下組成之群：H、NH 2、C 1-6烷基及C 1-6烷氧基，其中NH 2、C 1-6烷基或C 1-6烷氧基視情況經C 1-3烷基、C 3-6環烷基及/或鹵基中之1至3者取代； 在式V-1中，R 2'在每次出現時獨立地選自由以下組成之群：H、OH、C 1-6烷基、C 1-6烷氧基、C 1-6烷胺基及NH 2；m6為0、1、2、3或4；Y 1為CH 2或
Figure 02_image116
；L 1為一鍵、-C(=O)-、-NR-、-O-或-S-，其中R為氫、視情況經取代之醯基、視情況經取代之烷基或氮保護基；L 3為一鍵、-NR-、-O-或-S-，其中R為氫、視情況經取代之醯基、視情況經取代之烷基或氮保護基；L 2為經取代或未經取代之C 1-50烴鏈；Z為C或N；U為O、S或CH；T為CH或N；其中U、Z及T中之僅一者為雜原子；Q為CH或N；K為CH或N；其中Q及K不同時為N；R'''在每次出現時獨立地選自由以下組成之群：H、OH、NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基及鹵素；k為0、1、2或3；R'在每次出現時獨立地選自由以下組成之群：H、鹵素、OH、C 1-6烷基、C 1-6鹵烷基及C 1-6烷氧基；m為0、1、2、3或4；R''在每次出現時獨立地選自由以下組成之群：H、鹵基、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6鹵烷基、C 1-6烷胺基、C 3-6環烷基、C 3-6環烷胺基及C 3-6雜環烷基；n為0、1或2；X為CR 6或N；Y為CR 6或N；其中X及Y中之一者為N，而另一者為CR 6；R 6獨立地選自由以下組成之群：H、NH 2、C 1-6烷基及C 1-6烷氧基，其中NH 2、C 1-6烷基或C 1-6烷氧基視情況經C 1-3烷基、C 3-6環烷基及/或鹵基中之1至3者取代； 在式VI-1中，L 1為一鍵、-C(=O)-、-NR-、-O-或-S-，其中R為氫、視情況經取代之醯基、視情況經取代之烷基或氮保護基；L 3為一鍵、-NR-、-O-或-S-，其中R為氫、視情況經取代之醯基、視情況經取代之烷基或氮保護基；L 2為經取代或未經取代之C 1-50烴鏈；Z為C或N；U為O、S或CH；T為CH或N；其中U、Z及T中之僅一者為雜原子；Q為CH或N；K為CH或N；其中Q及K不同時為N；R'''在每次出現時獨立地選自由以下組成之群：H、OH、NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基及鹵素；k為0、1、2或3；R'在每次出現時獨立地選自由以下組成之群：H、鹵素、OH、C 1-6烷基、C 1-6鹵烷基及C 1-6烷氧基；m為0、1、2、3或4；R''在每次出現時獨立地選自由以下組成之群：H、鹵基、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6鹵烷基、C 1-6烷胺基、C 3-6環烷基、C 3-6環烷胺基及C 3-6雜環烷基；n為0、1或2；X為CR 6或N；Y為CR 6或N；其中X及Y中之一者為N，而另一者為CR 6；R 6獨立地選自由以下組成之群：H、NH 2、C 1-6烷基及C 1-6烷氧基，其中NH 2、C 1-6烷基或C 1-6烷氧基視情況經C 1-3烷基、C 3-6環烷基及/或鹵基中之1至3者取代。 In certain embodiments, compounds of the present invention have any of the following structures:
Figure 02_image112
Figure 02_image114
Wherein in formula I-1, R 3' is H or C 1-6 alkyl; Y 1 is CH 2 or
Figure 02_image116
; L is a bond, -C(=O)-, -NR-, -O- or -S-, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or nitrogen protection Base; L 3 is a bond, -NR-, -O- or -S-, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or nitrogen protecting group; L 2 is substituted Or unsubstituted C 1-50 hydrocarbon chain; Z is C or N; U is O, S or CH; wherein Z and U are not heteroatoms at the same time; Q is CH or N; K is CH or N; and K are not N at the same time; R''' at each occurrence is independently selected from the group consisting of H, OH, NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1- 6 alkoxy and halogen; k is 0, 1, 2 or 3; R' at each occurrence is independently selected from the group consisting of: H, halogen, OH, C 1-6 alkyl, C 1-6 Haloalkyl and C 1-6 alkoxy; m is 0, 1, 2, 3 or 4; R'' at each occurrence is independently selected from the group consisting of: H, halo, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy , C 1-6 haloalkyl, C 1-6 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkylamino and C 3-6 heterocycloalkyl; n is 0, 1 or 2; In formula II-1, R 2' is independently selected at each occurrence from the group consisting of H, OH, C 1-6 alkyl , C 1-6 alkoxy, C 1-6 alkylamino and NH 2 ; m6 is 0, 1, 2, 3 or 4; Y 1 is CH 2 or
Figure 02_image116
; L is a bond, -C(=O)-, -NR-, -O- or -S-, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or nitrogen protection Base; L 3 is a bond, -NR-, -O- or -S-, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or nitrogen protecting group; L 2 is substituted Or unsubstituted C 1-50 hydrocarbon chain; Z is C or N; U is O, S or CH; wherein Z and U are not heteroatoms at the same time; Q is CH or N; K is CH or N; and K are not N at the same time; R''' at each occurrence is independently selected from the group consisting of H, OH, NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1- 6 alkoxy and halogen; k is 0, 1, 2 or 3; R' at each occurrence is independently selected from the group consisting of: H, halogen, OH, C 1-6 alkyl, C 1-6 Haloalkyl and C 1-6 alkoxy; m is 0, 1, 2, 3 or 4; R'' at each occurrence is independently selected from the group consisting of: H, halo, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy , C 1-6 haloalkyl, C 1-6 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkylamino and C 3-6 heterocycloalkyl; n is 0, 1 or 2; In formula III-1, L is a bond, -C(=O)-, -NR-, -O- or -S-, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl, or nitrogen protecting group; L is a bond, -NR-, -O- or -S-, wherein R is hydrogen, optionally substituted A substituted acyl group, an optionally substituted alkyl or nitrogen protecting group; L is a substituted or unsubstituted C 1-50 hydrocarbon chain; Z is C or N; U is O, S or CH; wherein Z and U are not both heteroatoms; Q is CH or N; K is CH or N; wherein Q and K are not both N; R''' at each occurrence is independently selected from the group consisting of: H, OH , NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy and halogen; k is 0, 1, 2 or 3; R' is independently selected from at each occurrence The following groups: H, halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy; m is 0, 1, 2, 3 or 4; R'' is in Each occurrence is independently selected from the group consisting of H, halo, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 Alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkylamino and C 3-6 heterocycloalkyl; n is 0, 1 or 2; In formula IV-1, R 3' is H Or C 1-6 alkyl; Y 1 is CH 2 or
Figure 02_image116
; L is a bond, -C(=O)-, -NR-, -O- or -S-, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or nitrogen protection Base; L 3 is a bond, -NR-, -O- or -S-, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or nitrogen protecting group; L 2 is substituted or unsubstituted C 1-50 hydrocarbon chain; Z is C or N; U is O, S or CH; T is CH or N; wherein only one of U, Z and T is a heteroatom; Q is CH or N; K is CH or N; wherein Q and K are not N at the same time; R''' at each occurrence is independently selected from the group consisting of: H, OH, NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy and halogen; k is 0, 1, 2 or 3; R' is independently selected at each occurrence from the group consisting of: H, halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy; m is 0, 1, 2, 3 or 4; R'' is independently selected from the group consisting of Group: H, halo, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkylamino , C 3-6 cycloalkyl , C 3-6 cycloalkylamino and C 3-6 heterocycloalkyl; n is 0, 1 or 2; X is CR 6 or N; Y is CR 6 or N; wherein one of X and Y is N, and the other is CR 6 ; R 6 is independently selected from the group consisting of H, NH 2 , C 1-6 alkyl and C 1-6 alkoxy, wherein NH 2 , C 1-6 alk C 1-6 alkoxy group or C 1-6 alkoxy group is optionally substituted by 1 to 3 of C 1-3 alkyl, C 3-6 cycloalkyl and/or halo; In formula V-1, R 2' is Each occurrence is independently selected from the group consisting of H, OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and NH 2 ; m6 is 0, 1, 2 , 3 or 4; Y 1 is CH 2 or
Figure 02_image116
; L is a bond, -C(=O)-, -NR-, -O- or -S-, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or nitrogen protection Base; L 3 is a bond, -NR-, -O- or -S-, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or nitrogen protecting group; L 2 is substituted or unsubstituted C 1-50 hydrocarbon chain; Z is C or N; U is O, S or CH; T is CH or N; wherein only one of U, Z and T is a heteroatom; Q is CH or N; K is CH or N; wherein Q and K are not N at the same time; R''' at each occurrence is independently selected from the group consisting of: H, OH, NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy and halogen; k is 0, 1, 2 or 3; R' is independently selected at each occurrence from the group consisting of: H, halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy; m is 0, 1, 2, 3 or 4; R'' is independently selected from the group consisting of Group: H, halo, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkylamino , C 3-6 cycloalkyl , C 3-6 cycloalkylamino and C 3-6 heterocycloalkyl; n is 0, 1 or 2; X is CR 6 or N; Y is CR 6 or N; wherein one of X and Y is N, and the other is CR 6 ; R 6 is independently selected from the group consisting of H, NH 2 , C 1-6 alkyl and C 1-6 alkoxy, wherein NH 2 , C 1-6 alk C 1-6 alkoxy group or C 1-6 alkoxy group is optionally substituted by 1 to 3 of C 1-3 alkyl group, C 3-6 cycloalkyl group and/or halo group; In formula VI-1, L 1 is one Bond, -C(=O)-, -NR-, -O- or -S-, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or nitrogen protecting group; L3 is A bond, -NR-, -O- or -S-, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or nitrogen protecting group; L is substituted or unsubstituted C 1-50 hydrocarbon chain; Z is C or N; U is O, S or CH; T is CH or N; wherein only one of U, Z and T is a heteroatom; Q is CH or N; K is CH or N; wherein Q and K are not N at the same time; R''' at each occurrence is independently selected from the group consisting of: H, OH, NH 2 , C 1-6 alkyl, C 1-6 alkane Amino, C 1-6 alkoxy and halogen; k is 0, 1, 2 or 3; R' at each occurrence is independently selected from the group consisting of: H, halogen, OH, C 1-6 alkane radical, C 1-6 haloalkyl and C 1-6 alkoxy; m is 0, 1, 2, 3 or 4; R'' is independently selected at each occurrence from the group consisting of H, halo group, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkylamino , C 3-6 cycloalkyl, C 3-6 cycloalkylamino and C 3-6 heterocycloalkyl; n is 0, 1 or 2; X is CR 6 or N; Y is CR 6 or N; where One of X and Y is N, and the other is CR 6 ; R 6 is independently selected from the group consisting of H, NH 2 , C 1-6 alkyl and C 1-6 alkoxy, wherein NH 2 , C 1-6 alkyl or C 1-6 alkoxy is optionally substituted by 1 to 3 of C 1-3 alkyl, C 3-6 cycloalkyl and/or halo.

在某些實施例中，式I-1化合物具有下式1、5、6、8、10或13，

Figure 02_image120
Figure 02_image122
其中 各A獨立地為O、NH、
Figure 02_image124
； m2為1、2、3、4、5、6或7； m3為1、2、3、4、5或6； m4為0、1、2或3； m5為0、1、2或3；且 R 1'為O、NH、
Figure 02_image126
。 In certain embodiments, the compound of formula I-1 has the following formula 1, 5, 6, 8, 10 or 13,
Figure 02_image120
Figure 02_image122
Wherein each A is independently O, NH,
Figure 02_image124
; m2 is 1, 2, 3, 4, 5, 6, or 7; m3 is 1, 2, 3, 4, 5, or 6; m4 is 0, 1, 2, or 3; m5 is 0, 1, 2, or 3 ; and R 1' is O, NH,
Figure 02_image126
.

本發明之一實施例為式1化合物，其中R'為H、C 1-3鹵烷基或C 1-3烷氧基，較佳地H、CF 3、CCl 3、甲氧基或乙氧基，更佳地H、CF 3或甲氧基。 One embodiment of the present invention is a compound of formula 1, wherein R' is H, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, CF 3 , CCl 3 , methoxy or ethoxy group, more preferably H, CF 3 or methoxy.

本發明之一實施例為式1化合物，其中m為0、1、2、3或4，較佳地0或1。One embodiment of the present invention is the compound of formula 1, wherein m is 0, 1, 2, 3 or 4, preferably 0 or 1.

本發明之一實施例為式1化合物，其中R''為H、鹵基、OH、NH 2、C 1-3烷氧基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基及C 3-5雜環烷基，較佳地H、F、Cl、NH 2、甲氧基、乙氧基、甲胺基、二甲胺基、乙胺基、二乙胺基、環丙基、環丁基或環戊基，更佳地H、F、二甲胺基或環丙基。 One embodiment of the present invention is a compound of formula 1, wherein R'' is H, halo, OH, NH 2 , C 1-3 alkoxy, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino and C 3-5 heterocycloalkyl, preferably H, F, Cl, NH 2 , methoxy, ethoxy, methylamino, dimethylamino, ethylamino , diethylamino, cyclopropyl, cyclobutyl or cyclopentyl, more preferably H, F, dimethylamino or cyclopropyl.

本發明之一實施例為式1化合物，其中n為0、1或2，較佳地0或1。One embodiment of the present invention is the compound of formula 1, wherein n is 0, 1 or 2, preferably 0 or 1.

本發明之一實施例為式1化合物，其中R'''為H、OH或鹵素，較佳地H、OH、F或Cl，更佳地H。One embodiment of the present invention is the compound of formula 1, wherein R''' is H, OH or halogen, preferably H, OH, F or Cl, more preferably H.

本發明之一實施例為式1化合物，其中k為0、1、2或3，較佳地0或1。One embodiment of the present invention is the compound of formula 1, wherein k is 0, 1, 2 or 3, preferably 0 or 1.

本發明之一實施例為式1化合物，其中R 1'為O、NH、

Figure 02_image128
。本發明之一實施例為式1化合物，其中R 1'為O、NH、
Figure 02_image130
。 One embodiment of the present invention is a compound of formula 1, wherein R 1' is O, NH,
Figure 02_image128
. One embodiment of the present invention is a compound of formula 1, wherein R 1' is O, NH,
Figure 02_image130
.

本發明之一實施例為式1化合物，其中A為O、NH、

Figure 02_image132
，較佳地O或
Figure 02_image134
。 One embodiment of the present invention is a compound of formula 1, wherein A is O, NH,
Figure 02_image132
, preferably O or
Figure 02_image134
.

本發明之一實施例為式1化合物，其中m2為2、3、4或6，較佳地2或6。One embodiment of the present invention is the compound of formula 1, wherein m2 is 2, 3, 4 or 6, preferably 2 or 6.

本發明之一實施例為式1化合物，其中R 3'為H或C 1-3烷基，較佳地H或甲基，更佳地H。 One embodiment of the present invention is the compound of formula 1, wherein R 3' is H or C 1-3 alkyl, preferably H or methyl, more preferably H.

本發明之一實施例為式1化合物，其具有如式1-1中所示之結構，

Figure 02_image136
。 One embodiment of the present invention is a compound of formula 1, which has a structure as shown in formula 1-1,
Figure 02_image136
.

在式1-1中，R 3'為H或C 1-3烷基；Y 1為CH 2或

Figure 02_image138
；A為O、NH、
Figure 02_image140
；m2為1、2、3、4、5、6及7；R 1'為O、NH、
Figure 02_image142
；U為O、S或CH；Z為C或N；其中U及Z不同時為雜原子；R'為H、C 1-3鹵烷基或C 1-3烷氧基；R''為H、F、Cl、OH、NH 2、C 1-3烷氧基、甲胺基、二甲胺基、二乙胺基或環丙胺基；n為0、1或2。 In formula 1-1, R 3' is H or C 1-3 alkyl; Y 1 is CH 2 or
Figure 02_image138
; A is O, NH,
Figure 02_image140
; m2 is 1, 2, 3, 4, 5, 6 and 7; R 1' is O, NH,
Figure 02_image142
; U is O, S or CH; Z is C or N; where U and Z are not heteroatoms at the same time; R' is H, C 1-3 haloalkyl or C 1-3 alkoxy; R'' is H, F, Cl, OH, NH 2 , C 1-3 alkoxy, methylamino, dimethylamino, diethylamino or cyclopropylamino; n is 0, 1 or 2.

本發明之一實施例為式1-1化合物，其中m2為2、3、4或6，較佳地2或6。One embodiment of the present invention is the compound of formula 1-1, wherein m2 is 2, 3, 4 or 6, preferably 2 or 6.

本發明之一實施例為式1-1化合物，其中R 3'為H或甲基。 One embodiment of the present invention is the compound of formula 1-1, wherein R 3' is H or methyl.

本發明之一實施例為式1-1化合物，其中A為O或

Figure 02_image144
。 One embodiment of the present invention is a compound of formula 1-1, wherein A is O or
Figure 02_image144
.

本發明之一實施例為式1-1化合物，其中R 1'為O、NH或

Figure 02_image146
。本發明之一實施例為式1-1化合物，其中R 1'為O、NH、
Figure 02_image148
。 One embodiment of the present invention is a compound of formula 1-1, wherein R 1' is O, NH or
Figure 02_image146
. One embodiment of the present invention is a compound of formula 1-1, wherein R 1' is O, NH,
Figure 02_image148
.

本發明之一實施例為式1-1化合物，其中Z為N，U為CH。One embodiment of the present invention is the compound of formula 1-1, wherein Z is N and U is CH.

本發明之一實施例為式1-1化合物，其中Z為C，U為S或O。One embodiment of the present invention is the compound of formula 1-1, wherein Z is C, and U is S or O.

本發明之一實施例為式1-1化合物，其中R''為H、F、Cl、OH、NH 2、甲氧基、甲胺基、二甲胺基、二乙胺基、環丙基或環丙胺基，較佳地H、F、甲胺基、二甲胺基或環丙胺基。 One embodiment of the present invention is a compound of formula 1-1, wherein R'' is H, F, Cl, OH, NH 2 , methoxy, methylamino, dimethylamino, diethylamino, cyclopropyl Or cyclopropylamino, preferably H, F, methylamino, dimethylamino or cyclopropylamino.

本發明之一實施例為式1-1化合物，其中R'為H、C 1-3氟烷基、甲氧基或乙氧基，較佳地R'為H、甲氧基或CF 3。 One embodiment of the present invention is the compound of formula 1-1, wherein R' is H, C 1-3 fluoroalkyl, methoxy or ethoxy, preferably R' is H, methoxy or CF 3 .

本發明之一實施例為式5化合物，其中R 3'為H或C 1-3烷基，較佳地H或甲基。 One embodiment of the present invention is the compound of formula 5, wherein R 3' is H or C 1-3 alkyl, preferably H or methyl.

本發明之一實施例為式5化合物，其中A為O、NH或

Figure 02_image150
，較佳地O本發明之一實施例為式5化合物，其中各A獨立地為O、NH、
Figure 02_image152
。 One embodiment of the present invention is a compound of formula 5, wherein A is O, NH or
Figure 02_image150
, preferably O An embodiment of the present invention is a compound of formula 5, wherein each A is independently O, NH,
Figure 02_image152
.

本發明之一實施例為式5化合物，其中m4為0、1、2或3，較佳地0或3。One embodiment of the present invention is the compound of formula 5, wherein m4 is 0, 1, 2 or 3, preferably 0 or 3.

本發明之一實施例為式5化合物，其中m5為0、1、2或3，較佳地0或1。One embodiment of the present invention is the compound of formula 5, wherein m5 is 0, 1, 2 or 3, preferably 0 or 1.

本發明之一實施例為式5化合物，其中m3為1、2、3、4、5或6，較佳地3或5。One embodiment of the present invention is the compound of formula 5, wherein m3 is 1, 2, 3, 4, 5 or 6, preferably 3 or 5.

本發明之一實施例為式5化合物，其中R 1'為O、NH或

Figure 02_image154
。 One embodiment of the present invention is a compound of formula 5, wherein R 1' is O, NH or
Figure 02_image154
.

本發明之一實施例為式5化合物，其中R'''為H、OH、C 1-3烷基、C 1-3烷氧基或鹵素，較佳地H、甲基、甲氧基或F，更佳地H。 One embodiment of the present invention is a compound of formula 5, wherein R''' is H, OH, C 1-3 alkyl, C 1-3 alkoxy or halogen, preferably H, methyl, methoxy or F, more preferably H.

本發明之一實施例為式5化合物，其中k為0、1、2或3，較佳地0或1。One embodiment of the present invention is the compound of formula 5, wherein k is 0, 1, 2 or 3, preferably 0 or 1.

本發明之一實施例為式5化合物，其中Z為C，U為O或S。One embodiment of the present invention is the compound of formula 5, wherein Z is C, and U is O or S.

本發明之一實施例為式5化合物，其中Z為N，U為CH。One embodiment of the present invention is the compound of formula 5, wherein Z is N and U is CH.

本發明之一實施例為式5化合物，其中R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基，較佳地H、F、CF 3、CCl 3、甲基或甲氧基，更佳地H或CF 3。 One embodiment of the present invention is a compound of formula 5, wherein R' is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, F , CF 3 , CCl 3 , methyl or methoxy, more preferably H or CF 3 .

本發明之一實施例為式5化合物，其中m為0、1、2或3，較佳地0或1。One embodiment of the present invention is the compound of formula 5, wherein m is 0, 1, 2 or 3, preferably 0 or 1.

本發明之一實施例為式5化合物，其中R''為H、鹵基、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基或C 3-5雜環烷基，較佳地H、F、OH、NH 2、甲基、甲氧基、CF 3、CCl 3、甲胺基、環丙基或二甲胺基，更佳地H、F、CF 3、環丙基、環丙胺基或二甲胺基。 One embodiment of the present invention is a compound of formula 5, wherein R'' is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl, preferably H, F, OH, NH 2 , methyl, methoxy group, CF 3 , CCl 3 , methylamino, cyclopropyl or dimethylamino, more preferably H, F, CF 3 , cyclopropyl, cyclopropylamino or dimethylamino.

本發明之一實施例為式5化合物，其中n為0、1或2，較佳地0或1。One embodiment of the present invention is the compound of formula 5, wherein n is 0, 1 or 2, preferably 0 or 1.

本發明之一實施例為式5化合物，其具有如式5-1中所示之結構，

Figure 02_image156
。 One embodiment of the present invention is a compound of formula 5, which has a structure as shown in formula 5-1,
Figure 02_image156
.

在式5-1中，R 3'為H或C 1-3烷基；Y 1為CH 2或

Figure 02_image158
；A為O、NH、
Figure 02_image160
Figure 02_image162
；m5為0或1；m4為0、1、2、3或4；m3為1、2、3、4、5或6；R 1'為O、NH、
Figure 02_image164
；Z為C或N；U為O、S或CH；其中Z及U不同時為雜原子；R'''為H、OH、C 1-3烷基、C 1-3烷氧基或鹵素；R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基；R''為H、鹵基、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基及C 3-5雜環烷基；n為0、1或2。 In formula 5-1, R 3' is H or C 1-3 alkyl; Y 1 is CH 2 or
Figure 02_image158
; A is O, NH,
Figure 02_image160
Figure 02_image162
; m5 is 0 or 1; m4 is 0, 1, 2, 3 or 4; m3 is 1, 2, 3, 4, 5 or 6; R 1' is O, NH,
Figure 02_image164
; Z is C or N; U is O, S or CH; where Z and U are not heteroatoms at the same time; R''' is H, OH, C 1-3 alkyl, C 1-3 alkoxy or halogen ; R' is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy; R'' is H, halo, OH, NH 2 , C 1- 3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino and C 3-5 hetero Cycloalkyl; n is 0, 1 or 2.

本發明之一實施例為式5-1化合物，其中A為O。One embodiment of the present invention is the compound of formula 5-1, wherein A is O.

本發明之一實施例為式5-1化合物，其中m5為0或1。One embodiment of the present invention is the compound of formula 5-1, wherein m5 is 0 or 1.

本發明之一實施例為式5-1化合物，其中m4為0或3。One embodiment of the present invention is the compound of formula 5-1, wherein m4 is 0 or 3.

本發明之一實施例為式5-1化合物，其中m3為3、5。One embodiment of the present invention is the compound of formula 5-1, wherein m3 is 3,5.

本發明之一實施例為式5-1化合物，其中R 1'為O、NH或

Figure 02_image166
。 One embodiment of the present invention is a compound of formula 5-1, wherein R 1' is O, NH or
Figure 02_image166
.

本發明之一實施例為式5-1化合物，其中Z為C，U為O或S。One embodiment of the present invention is the compound of formula 5-1, wherein Z is C, and U is O or S.

本發明之一實施例為式5-1化合物，其中Z為N，U為CH。One embodiment of the present invention is the compound of formula 5-1, wherein Z is N and U is CH.

本發明之一實施例為式5-1化合物，其中R'為H、鹵素、C 1-3烷基、C 1-3氟烷基或C 1-3烷氧基，較佳地H、甲基、CF 3或甲氧基，更佳地H或CF 3。 One embodiment of the present invention is a compound of formula 5-1, wherein R' is H, halogen, C 1-3 alkyl, C 1-3 fluoroalkyl or C 1-3 alkoxy, preferably H, methyl group, CF 3 or methoxy group, more preferably H or CF 3 .

本發明之一實施例為式5-1化合物，其中R''為H、鹵基、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基或C 3-5雜環烷基，較佳地H、F、CF 3、胺基、甲胺基、二甲胺基、環丙基或環丙胺基，更佳地H、F、CF 3、二甲胺基、環丙胺基或環丙基。 One embodiment of the present invention is a compound of formula 5-1, wherein R'' is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl , C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl, preferably H, F, CF 3 , amino, methylamine , dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, CF 3 , dimethylamino, cyclopropylamino or cyclopropyl.

本發明之一實施例為式6化合物，其中R 3'為H或C 1-3烷基，較佳地H或甲基。 One embodiment of the present invention is the compound of formula 6, wherein R 3' is H or C 1-3 alkyl, preferably H or methyl.

本發明之一實施例為式6化合物，其中A為O、NH或

Figure 02_image168
，較佳地O或NH。 One embodiment of the present invention is a compound of formula 6, wherein A is O, NH or
Figure 02_image168
, preferably O or NH.

本發明之一實施例為式6化合物，其中m2為1、2、3、4、5、6或7，較佳地2或6。One embodiment of the present invention is the compound of formula 6, wherein m2 is 1, 2, 3, 4, 5, 6 or 7, preferably 2 or 6.

本發明之一實施例為式6化合物，其中R 1'為O、NH或

Figure 02_image166
，較佳地O或NH。 One embodiment of the present invention is a compound of formula 6, wherein R 1' is O, NH or
Figure 02_image166
, preferably O or NH.

本發明之一實施例為式6化合物，其中Z為C或N，且U為O、S或CH，其中Z及U不同時為雜原子；較佳地Z為C且U為S。One embodiment of the present invention is a compound of formula 6, wherein Z is C or N, and U is O, S or CH, wherein Z and U are not heteroatoms at the same time; preferably Z is C and U is S.

本發明之一實施例為式6化合物，其中R'''為H、OH、C 1-3烷基、C 1-3烷氧基或鹵素，較佳地H、甲基、甲氧基或F，更佳地H。 One embodiment of the present invention is a compound of formula 6, wherein R''' is H, OH, C 1-3 alkyl, C 1-3 alkoxy or halogen, preferably H, methyl, methoxy or F, more preferably H.

本發明之一實施例為式6化合物，其中R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基，較佳地H、F、CF 3、CCl 3、甲基或甲氧基，更佳地H或CF 3。 One embodiment of the present invention is a compound of formula 6, wherein R' is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, F , CF 3 , CCl 3 , methyl or methoxy, more preferably H or CF 3 .

本發明之一實施例為式6化合物，其中m為0、1、2或3，較佳地0或1。One embodiment of the present invention is the compound of formula 6, wherein m is 0, 1, 2 or 3, preferably 0 or 1.

本發明之一實施例為式6化合物，其中R''為H、鹵基、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基或C 3-5雜環烷基，較佳地H、F、OH、NH 2、甲基、甲氧基、CF 3、CCl 3、甲胺基、環丙基、環丙胺基或二甲胺基，更佳地H、F、CF 3、二甲胺基、環丙基或環丙胺基。 One embodiment of the present invention is a compound of formula 6, wherein R'' is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl, preferably H, F, OH, NH 2 , methyl, methoxy , CF 3 , CCl 3 , methylamino, cyclopropyl, cyclopropylamino or dimethylamino, more preferably H, F, CF 3 , dimethylamino, cyclopropyl or cyclopropylamino.

本發明之一實施例為式6化合物，其中n為0或1。One embodiment of the present invention is the compound of formula 6, wherein n is 0 or 1.

本發明之一實施例為式6化合物，其具有如式6-1中所示之結構，

Figure 02_image171
。 One embodiment of the present invention is a compound of formula 6, which has a structure as shown in formula 6-1,
Figure 02_image171
.

在式6-1中，R 3'為H或C 1-3烷基；Y 1為CH 2或

Figure 02_image173
；A為O、NH、
Figure 02_image175
Figure 02_image177
；m2為1、2、3、4、5、6及7；R 1'為O、NH、
Figure 02_image179
Figure 02_image181
；R'''為H、OH、C 1-3烷基、C 1-3烷氧基或鹵素；k為0、1、2或3；Z為C或N；U為O、S或CH；其中Z及U不同時為雜原子；R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基；m為0、1、2或3；R''為H、鹵基、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基及C 3-5雜環烷基；n為0、1或2。 In formula 6-1, R 3' is H or C 1-3 alkyl; Y 1 is CH 2 or
Figure 02_image173
; A is O, NH,
Figure 02_image175
Figure 02_image177
; m2 is 1, 2, 3, 4, 5, 6 and 7; R 1' is O, NH,
Figure 02_image179
Figure 02_image181
; R''' is H, OH, C 1-3 alkyl, C 1-3 alkoxy or halogen; k is 0, 1, 2 or 3; Z is C or N; U is O, S or CH ; wherein Z and U are not heteroatoms at the same time; R' is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy; m is 0, 1, 2 or 3; R'' is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3 -5 cycloalkyl, C 3-5 cycloalkylamino and C 3-5 heterocycloalkyl; n is 0, 1 or 2.

在式6-1之一些實施例中，R 3'為H或C 1-3烷基；Y 1為CH 2或

Figure 02_image183
；A為O、NH、
Figure 02_image185
；m2為1、2、3、4、5、6或7；R 1'為O、NH、
Figure 02_image187
Figure 02_image189
；R'''為H、OH、C 1-3烷基、C 1-3烷氧基或鹵素；k為0、1、2或3；Z為C或N；U為O、S或CH；其中Z及U不同時為雜原子；R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基；m為0、1、2或3；R''為H、鹵基、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基及C 3-5雜環烷基；n為0、1或2。 In some embodiments of formula 6-1, R 3' is H or C 1-3 alkyl; Y 1 is CH 2 or
Figure 02_image183
; A is O, NH,
Figure 02_image185
; m2 is 1, 2, 3, 4, 5, 6 or 7; R 1' is O, NH,
Figure 02_image187
Figure 02_image189
; R''' is H, OH, C 1-3 alkyl, C 1-3 alkoxy or halogen; k is 0, 1, 2 or 3; Z is C or N; U is O, S or CH ; wherein Z and U are not heteroatoms at the same time; R' is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy; m is 0, 1, 2 or 3; R'' is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3 -5 cycloalkyl, C 3-5 cycloalkylamino and C 3-5 heterocycloalkyl; n is 0, 1 or 2.

本發明之一實施例為式6-1化合物，其中R 3'為H或甲基。 One embodiment of the present invention is the compound of formula 6-1, wherein R 3' is H or methyl.

本發明之一實施例為式6-1化合物，其中A為O或NH。One embodiment of the present invention is the compound of formula 6-1, wherein A is O or NH.

本發明之一實施例為式6-1化合物，其中m2為2或6。One embodiment of the present invention is the compound of formula 6-1, wherein m2 is 2 or 6.

本發明之一實施例為式6-1化合物，其中R 1'為O或NH。 One embodiment of the present invention is the compound of formula 6-1, wherein R 1' is O or NH.

本發明之一實施例為式6-1化合物，其中R'為H或CF 3。 One embodiment of the present invention is the compound of formula 6-1, wherein R' is H or CF 3 .

本發明之一實施例為式6-1化合物，其中m為0、1、2或3，較佳地0或1。One embodiment of the present invention is the compound of formula 6-1, wherein m is 0, 1, 2 or 3, preferably 0 or 1.

本發明之一實施例為式6-1化合物，其中R''為H、鹵基、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基或C 3-5雜環烷基，較佳地H、F、CF 3、甲氧基、甲基、二甲胺基、環丙基、環丙胺基或甲胺基，更佳地H、CF 3、F、二甲胺基、環丙基或環丙胺基，最佳地H、二甲胺基、環丙基或環丙胺基。 One embodiment of the present invention is a compound of formula 6-1, wherein R'' is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl , C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl, preferably H, F, CF 3 , methoxy, methyl Dimethylamino, cyclopropyl, cyclopropylamino or methylamino, more preferably H, CF 3 , F, dimethylamino, cyclopropyl or cyclopropylamino, most preferably H, dimethylamine group, cyclopropyl or cyclopropylamino group.

本發明之一實施例為式6-1化合物，其中n為0或1。One embodiment of the present invention is the compound of formula 6-1, wherein n is 0 or 1.

本發明之一實施例為式6-1化合物，其中R''取代N原子之相鄰位置。One embodiment of the present invention is the compound of formula 6-1, wherein R'' replaces the adjacent position of N atom.

本發明之一實施例為式8化合物，其中R 3'為H或C 1-3烷基，較佳地H或甲基。 One embodiment of the present invention is the compound of formula 8, wherein R 3' is H or C 1-3 alkyl, preferably H or methyl.

本發明之一實施例為式8化合物，其中Y 1為CH 2或

Figure 02_image191
，較佳地CH 2。 One embodiment of the present invention is a compound of formula 8, wherein Y 1 is CH 2 or
Figure 02_image191
, preferably CH 2 .

本發明之一實施例為式8化合物，其中A為O、NH、

Figure 02_image193
，較佳地O。 One embodiment of the present invention is a compound of formula 8, wherein A is O, NH,
Figure 02_image193
, preferably O.

本發明之一實施例為式8化合物，其中m2為1、2、3或4，較佳為2。One embodiment of the present invention is the compound of formula 8, wherein m2 is 1, 2, 3 or 4, preferably 2.

本發明之一實施例為式8化合物，其中R 1'為O、NH、

Figure 02_image195
，較佳地O。 One embodiment of the present invention is a compound of formula 8, wherein R 1' is O, NH,
Figure 02_image195
, preferably O.

本發明之一實施例為式8化合物，其中R'''為H、OH、C 1-3烷基、C 1-3烷氧基或鹵素，較佳地H、甲基、甲氧基或F，更佳地H。 One embodiment of the present invention is a compound of formula 8, wherein R''' is H, OH, C 1-3 alkyl, C 1-3 alkoxy or halogen, preferably H, methyl, methoxy or F, more preferably H.

本發明之一實施例為式8化合物，其中k為0或1。An embodiment of the present invention is a compound of formula 8, wherein k is 0 or 1 .

本發明之一實施例為式8化合物，其中Z為C或N；U為O、S或CH；其中Z及U不同時為雜原子；較佳地Z為N且U為CH；較佳地Z為C且U為S。One embodiment of the present invention is a compound of formula 8, wherein Z is C or N; U is O, S or CH; wherein Z and U are not heteroatoms at the same time; preferably Z is N and U is CH; preferably Z is C and U is S.

本發明之一實施例為式8化合物，其中R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基，較佳地H、F、CF 3、CCl 3、甲基或甲氧基，更佳地H或CF 3。 One embodiment of the present invention is a compound of formula 8, wherein R' is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, F , CF 3 , CCl 3 , methyl or methoxy, more preferably H or CF 3 .

本發明之一實施例為式8化合物，其中m為0、1或2。An embodiment of the present invention is a compound of formula 8, wherein m is 0, 1 or 2.

本發明之一實施例為式8化合物，其中R''為H、鹵基、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基或C 3-5雜環烷基，較佳地H、F、OH、NH 2、甲基、甲氧基、CF 3、CCl 3、甲胺基、二甲胺基、環丙基或環丙胺基，更佳地H、F、CF 3、環丙基或環丙胺基。 One embodiment of the present invention is a compound of formula 8, wherein R'' is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl, preferably H, F, OH, NH 2 , methyl, methoxy , CF 3 , CCl 3 , methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, CF 3 , cyclopropyl or cyclopropylamino.

本發明之一實施例為式8化合物，其中n為0、1或2。An embodiment of the present invention is a compound of formula 8, wherein n is 0, 1 or 2.

本發明之一實施例為式10化合物，其中R 3'為H或C 1-3烷基，較佳地H或甲基。 One embodiment of the present invention is the compound of formula 10, wherein R 3' is H or C 1-3 alkyl, preferably H or methyl.

本發明之一實施例為式10化合物，其中Y 1為CH 2或

Figure 02_image197
，較佳地CH 2。 One embodiment of the present invention is a compound of formula 10, wherein Y 1 is CH 2 or
Figure 02_image197
, preferably CH 2 .

本發明之一實施例為式10化合物，其中各A獨立地為O、NH、

Figure 02_image199
，本發明之一實施例為式10化合物，其中A為O、NH、
Figure 02_image201
，較佳地
Figure 02_image203
。 One embodiment of the present invention is a compound of formula 10, wherein each A is independently O, NH,
Figure 02_image199
, an embodiment of the present invention is a compound of formula 10, wherein A is O, NH,
Figure 02_image201
, preferably
Figure 02_image203
.

本發明之一實施例為式10化合物，其中m5為0或1。One embodiment of the present invention is the compound of formula 10, wherein m5 is 0 or 1.

本發明之一實施例為式10化合物，其中m4為0或1。One embodiment of the present invention is the compound of formula 10, wherein m4 is 0 or 1.

本發明之一實施例為式10化合物，其中m3為1、2、3、4或5，較佳地4。One embodiment of the present invention is the compound of formula 10, wherein m3 is 1, 2, 3, 4 or 5, preferably 4.

本發明之一實施例為式10化合物，其中R 1'為O、NH、

Figure 02_image205
，較佳地O。 One embodiment of the present invention is a compound of formula 10, wherein R 1' is O, NH,
Figure 02_image205
, preferably O.

本發明之一實施例為式10化合物，其中R'''為H、OH、C 1-3烷基、C 1-3烷氧基或鹵素，較佳地H、甲基、甲氧基或F，更佳地H。 One embodiment of the present invention is a compound of formula 10, wherein R''' is H, OH, C 1-3 alkyl, C 1-3 alkoxy or halogen, preferably H, methyl, methoxy or F, more preferably H.

本發明之一實施例為式10化合物，其中k為0或1。An embodiment of the invention is a compound of formula 10, wherein k is 0 or 1 .

本發明之一實施例為式10化合物，其中Z為C，U為S或O。One embodiment of the present invention is the compound of formula 10, wherein Z is C and U is S or O.

本發明之一實施例為式10化合物，其中Z為N，U為CH。One embodiment of the invention is the compound of formula 10, wherein Z is N and U is CH.

本發明之一實施例為式10化合物，其中R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基，較佳地H、F、CF 3、CCl 3、甲基或甲氧基，更佳地H或CF 3。 One embodiment of the present invention is a compound of formula 10, wherein R' is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, F , CF 3 , CCl 3 , methyl or methoxy, more preferably H or CF 3 .

本發明之一實施例為式10化合物，其中m為0或1。An embodiment of the invention is a compound of formula 10, wherein m is 0 or 1 .

本發明之一實施例為式10化合物，其中R''為H、鹵基、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基或C 3-5雜環烷基，較佳地H、F、OH、NH 2、甲基、甲氧基、CF 3、CCl 3、甲胺基、環丙基、環丙胺基或二甲胺基，更佳地H、F或CF 3。 One embodiment of the present invention is a compound of formula 10, wherein R'' is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl, preferably H, F, OH, NH 2 , methyl, methoxy , CF 3 , CCl 3 , methylamino, cyclopropyl, cyclopropylamino or dimethylamino, more preferably H, F or CF 3 .

本發明之一實施例為式10化合物，其中n為0或1。One embodiment of the invention is a compound of formula 10, wherein n is 0 or 1 .

本發明之一實施例為式13化合物，其中R 3'為H或C 1-3烷基，較佳地H或甲基。 One embodiment of the present invention is the compound of formula 13, wherein R 3' is H or C 1-3 alkyl, preferably H or methyl.

本發明之一實施例為式13化合物，其中Y 1為CH 2或

Figure 02_image207
，較佳地CH 2。 One embodiment of the present invention is a compound of formula 13, wherein Y 1 is CH 2 or
Figure 02_image207
, preferably CH 2 .

本發明之一實施例為式13化合物，其中A為O、NH、

Figure 02_image209
，較佳地
Figure 02_image211
。 One embodiment of the present invention is a compound of formula 13, wherein A is O, NH,
Figure 02_image209
, preferably
Figure 02_image211
.

本發明之一實施例為式13化合物，其中m2為1、2、3或4，較佳為1。One embodiment of the present invention is the compound of formula 13, wherein m2 is 1, 2, 3 or 4, preferably 1.

本發明之一實施例為式13化合物，其中R 1'為O、NH、

Figure 02_image213
，較佳地NH。 One embodiment of the present invention is a compound of formula 13, wherein R 1' is O, NH,
Figure 02_image213
, preferably NH.

本發明之一實施例為式13化合物，其中R'''為H、OH、C 1-3烷基、C 1-3烷氧基或鹵素，較佳地H、甲基、甲氧基或F，更佳地H。 One embodiment of the present invention is a compound of formula 13, wherein R''' is H, OH, C 1-3 alkyl, C 1-3 alkoxy or halogen, preferably H, methyl, methoxy or F, more preferably H.

本發明之一實施例為式13化合物，其中k為0、1、2或3，較佳地0或1。One embodiment of the present invention is the compound of formula 13, wherein k is 0, 1, 2 or 3, preferably 0 or 1.

本發明之一實施例為式13化合物，其中Z為C，U為S或O。One embodiment of the invention is the compound of formula 13, wherein Z is C and U is S or O.

本發明之一實施例為式13化合物，其中Z為N，U為CH。One embodiment of the invention is the compound of formula 13, wherein Z is N and U is CH.

本發明之一實施例為式13化合物，其中R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基，較佳地H、F、CF 3、CCl 3、甲基或甲氧基，更佳地H或CF 3。 One embodiment of the present invention is a compound of formula 13, wherein R' is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, F , CF 3 , CCl 3 , methyl or methoxy, more preferably H or CF 3 .

本發明之一實施例為式13化合物，其中m為0、1、2或3，較佳地0或1。One embodiment of the present invention is the compound of formula 13, wherein m is 0, 1, 2 or 3, preferably 0 or 1.

本發明之一實施例為式13化合物，其中R''為H、鹵基、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基或C 3-5雜環烷基，較佳地H、F、OH、NH 2、甲基、甲氧基、CF 3、CCl 3、甲胺基、環丙基、環丙胺基或二甲胺基，更佳地H、F、CF 3、二甲胺基、環丙基或環丙胺基，最佳地二甲胺基。 One embodiment of the present invention is a compound of formula 13, wherein R'' is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl, preferably H, F, OH, NH 2 , methyl, methoxy , CF 3 , CCl 3 , methylamino, cyclopropyl, cyclopropylamino or dimethylamino, more preferably H, F, CF 3 , dimethylamino, cyclopropyl or cyclopropylamino, most preferably Dimethylamino.

本發明之一實施例為式13化合物，其中n為0、1或2，較佳地0或1。One embodiment of the present invention is the compound of formula 13, wherein n is 0, 1 or 2, preferably 0 or 1.

式II-1化合物之一實施例具有下式3，

Figure 02_image215
其中R 1'為O、NH、
Figure 02_image217
。 One embodiment of the compound of formula II-1 has the following formula 3,
Figure 02_image215
Where R 1' is O, NH,
Figure 02_image217
.

本發明之一實施例為式3化合物，其中R 2'為H、OH、C 1-3烷基、C 1-3烷氧基、C 1-3烷胺基或NH 2，較佳地H、OH或NH 2。 One embodiment of the present invention is a compound of formula 3, wherein R 2' is H, OH, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino or NH 2 , preferably H , OH or NH 2 .

本發明之一實施例為式3化合物，其中m6為0、1、2或3，較佳地0或1。One embodiment of the present invention is the compound of formula 3, wherein m6 is 0, 1, 2 or 3, preferably 0 or 1.

本發明之一實施例為式3化合物，其中R 1'為O或NH。 One embodiment of the present invention is the compound of formula 3, wherein R 1' is O or NH.

本發明之一實施例為式3化合物，其中R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基，較佳地H、鹵素或C 1-3氟烷基，更佳地H或F。 One embodiment of the present invention is a compound of formula 3, wherein R' is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, halogen Or C 1-3 fluoroalkyl, more preferably H or F.

本發明之一實施例為式3化合物，其中m為0、1、2、3或4，較佳地0或1。One embodiment of the present invention is the compound of formula 3, wherein m is 0, 1, 2, 3 or 4, preferably 0 or 1.

本發明之一實施例為式3化合物，其中R''為H、鹵基、OH、NH 2、C 1-3烷氧基、C 3-5環烷基、C 3-5環烷胺基或C 1-3烷胺基，較佳地H、鹵基、甲胺基、二甲胺基、環丙胺基或環丙基，更佳地H、F或二甲胺基。 One embodiment of the present invention is a compound of formula 3, wherein R'' is H, halo, OH, NH 2 , C 1-3 alkoxy, C 3-5 cycloalkyl, C 3-5 cycloalkylamino Or C 1-3 alkylamino, preferably H, halo, methylamino, dimethylamino, cyclopropylamino or cyclopropyl, more preferably H, F or dimethylamino.

本發明之一實施例為式3化合物，其中n為0、1、2或3，較佳地0、1或2。One embodiment of the present invention is the compound of formula 3, wherein n is 0, 1, 2 or 3, preferably 0, 1 or 2.

本發明之一實施例為式3化合物，其中Z為C，U為O或S。One embodiment of the present invention is the compound of formula 3, wherein Z is C, and U is O or S.

本發明之一實施例為式3化合物，其中Z為N，U為CH。One embodiment of the present invention is the compound of formula 3, wherein Z is N and U is CH.

本發明之一實施例為式3化合物，其中R'''為H、OH、C 1-3烷基、C 1-3烷氧基或鹵素，較佳地H、F、甲基或甲氧基，更佳地H。 One embodiment of the present invention is a compound of formula 3, wherein R''' is H, OH, C 1-3 alkyl, C 1-3 alkoxy or halogen, preferably H, F, methyl or methoxy base, more preferably H.

本發明之一實施例為式3化合物，其具有如式3-1中所示之結構，

Figure 02_image219
其中R 2'為H、OH、C 1-3烷基、C 1-3烷氧基、C 1-3烷胺基或NH 2；m6為0、1、2或3；Y 1為CH 2
Figure 02_image221
；R 1'為O、NH、
Figure 02_image223
；Z為C或N；U為O、S或CH；其中Z及U不同時為雜原子；R''為H、鹵基、OH、NH 2、C 1-3烷氧基、C 1-3鹵烷基、C 3-5環烷基、C 3-5環烷胺基或C 1-3烷胺基；n為0、1或2。 One embodiment of the present invention is a compound of formula 3, which has a structure as shown in formula 3-1,
Figure 02_image219
Wherein R 2' is H, OH, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino or NH 2 ; m6 is 0, 1, 2 or 3; Y 1 is CH 2
Figure 02_image221
; R 1' is O, NH,
Figure 02_image223
; Z is C or N; U is O, S or CH; where Z and U are not heteroatoms at the same time; R'' is H, halo, OH, NH 2 , C 1-3 alkoxy, C 1- 3 haloalkyl, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 1-3 alkylamino; n is 0, 1 or 2.

本發明之一實施例為式3-1化合物，其中R 2'為H、NH 2或OH。 One embodiment of the present invention is the compound of formula 3-1, wherein R 2' is H, NH 2 or OH.

本發明之一實施例為式3-1化合物，其中m6為0或1。One embodiment of the present invention is the compound of formula 3-1, wherein m6 is 0 or 1.

本發明之一實施例為式3-1化合物，其中當m6為1時，R 2'在苯基中之以下位置經取代：

Figure 02_image225
Figure 02_image227
。 One embodiment of the present invention is a compound of formula 3-1, wherein when m6 is 1, R 2' is substituted in the following positions in the phenyl group:
Figure 02_image225
Figure 02_image227
.

本發明之一實施例為式3-1化合物，其中R 1'為O或NH。 One embodiment of the present invention is the compound of formula 3-1, wherein R 1' is O or NH.

本發明之一實施例為式3-1化合物，其中R''為F、二甲胺基、甲胺基、環丙基或環丙胺基。One embodiment of the present invention is the compound of formula 3-1, wherein R'' is F, dimethylamino, methylamino, cyclopropyl or cyclopropylamino.

本發明之一實施例為式3-1化合物，其中n為0、1或2。One embodiment of the present invention is a compound of formula 3-1, wherein n is 0, 1 or 2.

式III-1化合物之一實施例具有下式15，

Figure 02_image229
其中m2為1、2、3、4、5、6或7；且R 1'為O、NH、
Figure 02_image231
。 One embodiment of the compound of formula III-1 has the following formula 15,
Figure 02_image229
wherein m2 is 1, 2, 3, 4, 5, 6 or 7; and R1 ' is O, NH,
Figure 02_image231
.

本發明之一實施例為式15化合物，其中m2為1、2、3、4、5、6或7，較佳地1、2、3、4、5或6，更佳地2或5。One embodiment of the present invention is the compound of formula 15, wherein m2 is 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2, 3, 4, 5 or 6, more preferably 2 or 5.

本發明之一實施例為式15化合物，其中R 1'為O、NH、

Figure 02_image233
，較佳地O或NH。 One embodiment of the present invention is a compound of formula 15, wherein R 1' is O, NH,
Figure 02_image233
, preferably O or NH.

本發明之一實施例為式15化合物，其中R'''為H、OH、C 1-3烷基、C 1-3烷氧基或鹵素，較佳地H、F、甲基或甲氧基，更佳地H。 One embodiment of the present invention is a compound of formula 15, wherein R''' is H, OH, C 1-3 alkyl, C 1-3 alkoxy or halogen, preferably H, F, methyl or methoxy base, more preferably H.

本發明之一實施例為式15化合物，其中Z為C，U為O或S。One embodiment of the invention is the compound of formula 15, wherein Z is C and U is O or S.

本發明之一實施例為式15化合物，其中Z為N，U為CH。One embodiment of the invention is the compound of formula 15, wherein Z is N and U is CH.

本發明之一實施例為式15化合物，其中R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基，較佳地H、鹵素或C 1-3氟烷基，更佳地H、CF 3或F。 One embodiment of the present invention is a compound of formula 15, wherein R' is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, halogen Or C 1-3 fluoroalkyl, more preferably H, CF 3 or F.

本發明之一實施例為式15化合物，其中m為0、1、2或3，較佳地0、1或2，更佳地0或1。One embodiment of the present invention is the compound of formula 15, wherein m is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

本發明之一實施例為式15化合物，其中R''為H、鹵基、OH、NH 2、C 1-3烷氧基、C 3-5環烷基、C 3-5環烷胺基或C 1-3烷胺基，較佳地H、鹵基、甲胺基、二甲胺基、環丙胺基或環丙基，更佳地H、F、甲胺基、環丙胺基或二甲胺基，最佳地H或二甲胺基。 One embodiment of the present invention is a compound of formula 15, wherein R'' is H, halo, OH, NH 2 , C 1-3 alkoxy, C 3-5 cycloalkyl, C 3-5 cycloalkylamino Or C 1-3 alkylamino, preferably H, halo, methylamino, dimethylamino, cyclopropylamino or cyclopropyl, more preferably H, F, methylamino, cyclopropylamino or di Methylamino, most preferably H or dimethylamino.

本發明之一實施例為式15化合物，其中n為0、1或2，較佳地0或1。One embodiment of the present invention is the compound of formula 15, wherein n is 0, 1 or 2, preferably 0 or 1.

式IV-1化合物之一實施例具有下式2、7、9、11、12或14，

Figure 02_image235
Figure 02_image237
其中 各A獨立地為O、NH、
Figure 02_image239
； m2為2、3、4、5或6； m3為1、2、3、4、5或6； m4為0、1、2、3或4； m5為0、1、2或3；且 R 1'為O、NH、
Figure 02_image241
。 One embodiment of the compound of formula IV-1 has the following formula 2, 7, 9, 11, 12 or 14,
Figure 02_image235
Figure 02_image237
Wherein each A is independently O, NH,
Figure 02_image239
; m2 is 2, 3, 4, 5, or 6; m3 is 1, 2, 3, 4, 5, or 6; m4 is 0, 1, 2, 3, or 4; m5 is 0, 1, 2, or 3; and R 1' is O, NH,
Figure 02_image241
.

本發明之一實施例為式2化合物，其中R 3'為H或C 1-3烷基，較佳地H或甲基。 One embodiment of the present invention is the compound of formula 2, wherein R 3' is H or C 1-3 alkyl, preferably H or methyl.

本發明之一實施例為式2化合物，其中Y 1為CH 2或

Figure 02_image243
。 One embodiment of the present invention is a compound of formula 2, wherein Y 1 is CH 2 or
Figure 02_image243
.

本發明之一實施例為式2化合物，其中A為O、NH、

Figure 02_image245
，較佳地O。 One embodiment of the present invention is a compound of formula 2, wherein A is O, NH,
Figure 02_image245
, preferably O.

本發明之一實施例為式2化合物，其中m2為2、3、4、5或6，較佳地2或6。One embodiment of the present invention is the compound of formula 2, wherein m2 is 2, 3, 4, 5 or 6, preferably 2 or 6.

本發明之一實施例為式2化合物，其中R 1'為O、NH、

Figure 02_image247
，較佳地NH。 One embodiment of the present invention is a compound of formula 2, wherein R 1' is O, NH,
Figure 02_image247
, preferably NH.

本發明之一實施例為式2化合物，其中R''為H、鹵基、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基或C 3-5雜環烷基，較佳地H、F、OH、NH 2、甲基、甲氧基、CF 3、CCl 3、甲胺基、二甲胺基、環丙基或環丙胺基，更佳地H、F、CF 3、環丙基或環丙胺基。 One embodiment of the present invention is a compound of formula 2, wherein R'' is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl, preferably H, F, OH, NH 2 , methyl, methoxy , CF 3 , CCl 3 , methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, CF 3 , cyclopropyl or cyclopropylamino.

本發明之一實施例為式2化合物，其中n為0、1或2，較佳地0或1。One embodiment of the present invention is the compound of formula 2, wherein n is 0, 1 or 2, preferably 0 or 1.

本發明之一實施例為式2化合物，其中R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基，較佳地H、F、CF 3、CCl 3、甲基或甲氧基，更佳地H或CF 3。 One embodiment of the present invention is a compound of formula 2, wherein R' is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, F , CF 3 , CCl 3 , methyl or methoxy, more preferably H or CF 3 .

本發明之一實施例為式2化合物，其中m為0、1、2或3，較佳地0、1或2。One embodiment of the present invention is the compound of formula 2, wherein m is 0, 1, 2 or 3, preferably 0, 1 or 2.

本發明之一實施例為式2化合物，其中Z為C，U為O或S，W為CH。One embodiment of the present invention is a compound of formula 2, wherein Z is C, U is O or S, and W is CH.

本發明之一實施例為式2化合物，其中Z為N，U為CH，W為CH。One embodiment of the present invention is a compound of formula 2, wherein Z is N, U is CH, and W is CH.

本發明之一實施例為式2化合物，其中Z為C，W為N，U為CH。One embodiment of the present invention is a compound of formula 2, wherein Z is C, W is N, and U is CH.

本發明之一實施例為式2化合物，其中R'''為H、OH、NH 2、C 1-3烷基、C 1-3烷胺基、C 1-3烷氧基或鹵素，較佳地H、F、甲氧基、甲胺基或二甲胺基。 One embodiment of the present invention is a compound of formula 2, wherein R''' is H, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylamino, C 1-3 alkoxy or halogen, more Preferably H, F, methoxy, methylamino or dimethylamino.

本發明之一實施例為式2化合物，其中k為0、1、2或3，較佳地0、1或2，更佳地0或1。One embodiment of the present invention is the compound of formula 2, wherein k is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

本發明之一實施例為式7化合物，其中R 3'為H或C 1-3烷基，較佳地H或甲基。 One embodiment of the present invention is the compound of formula 7, wherein R 3' is H or C 1-3 alkyl, preferably H or methyl.

本發明之一實施例為式7化合物，其中Y 1為CH 2或

Figure 02_image243
。 One embodiment of the present invention is a compound of formula 7, wherein Y 1 is CH 2 or
Figure 02_image243
.

本發明之一實施例為式7化合物，其中A為O、NH、

Figure 02_image250
，較佳地O。 One embodiment of the present invention is a compound of formula 7, wherein A is O, NH,
Figure 02_image250
, preferably O.

本發明之一實施例為式7化合物，其中m2為2、3、4、5或6，較佳地2或3。One embodiment of the present invention is the compound of formula 7, wherein m2 is 2, 3, 4, 5 or 6, preferably 2 or 3.

本發明之一實施例為式7化合物，其中R 1'為O、NH、

Figure 02_image252
，較佳地NH。 One embodiment of the present invention is a compound of formula 7, wherein R 1' is O, NH,
Figure 02_image252
, preferably NH.

本發明之一實施例為式7化合物，其中R''為H、鹵基、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基或C 3-5雜環烷基，較佳地H、F、OH、NH 2、甲基、甲氧基、CF 3、CCl 3、甲胺基、二甲胺基、環丙基或環丙胺基，更佳地H、F、CF 3、環丙基或環丙胺基。 One embodiment of the present invention is the compound of formula 7, wherein R'' is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl, preferably H, F, OH, NH 2 , methyl, methoxy , CF 3 , CCl 3 , methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, CF 3 , cyclopropyl or cyclopropylamino.

本發明之一實施例為式7化合物，其中n為0、1或2，較佳地0或1。One embodiment of the present invention is the compound of formula 7, wherein n is 0, 1 or 2, preferably 0 or 1.

本發明之一實施例為式7化合物，其中R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基，較佳地H、F、CF 3、CCl 3、甲基或甲氧基，更佳地H或CF 3。 One embodiment of the present invention is a compound of formula 7, wherein R' is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, F , CF 3 , CCl 3 , methyl or methoxy, more preferably H or CF 3 .

本發明之一實施例為式7化合物，其中m為0、1、2或3，較佳地0、1或2。One embodiment of the present invention is the compound of formula 7, wherein m is 0, 1, 2 or 3, preferably 0, 1 or 2.

本發明之一實施例為式7化合物，其中Z為C，U為O或S，W為CH。One embodiment of the present invention is the compound of formula 7, wherein Z is C, U is O or S, and W is CH.

本發明之一實施例為式7化合物，其中Z為N，U為CH，W為CH。One embodiment of the present invention is the compound of formula 7, wherein Z is N, U is CH, and W is CH.

本發明之一實施例為式7化合物，其中Z為C，W為N，U為CH。One embodiment of the present invention is the compound of formula 7, wherein Z is C, W is N, and U is CH.

本發明之一實施例為式7化合物，其中R'''為H、OH、NH 2、C 1-3烷基、C 1-3烷胺基、C 1-3烷氧基或鹵素，較佳地H、F、甲氧基、甲胺基或二甲胺基。 One embodiment of the present invention is a compound of formula 7, wherein R''' is H, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylamino, C 1-3 alkoxy or halogen, more Preferably H, F, methoxy, methylamino or dimethylamino.

本發明之一實施例為式7化合物，其中k為0、1、2或3，較佳地0、1或2，更佳地0或1。One embodiment of the present invention is the compound of formula 7, wherein k is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

本發明之一實施例為式9化合物，其中R 3'為H或C 1-3烷基，較佳地H或甲基。 One embodiment of the present invention is the compound of formula 9, wherein R 3' is H or C 1-3 alkyl, preferably H or methyl.

本發明之一實施例為式9化合物，其中Y 1為CH 2或

Figure 02_image243
。 One embodiment of the present invention is a compound of formula 9, wherein Y 1 is CH 2 or
Figure 02_image243
.

本發明之一實施例為式9化合物，其中A為O、NH、

Figure 02_image254
，較佳地O。 One embodiment of the present invention is a compound of formula 9, wherein A is O, NH,
Figure 02_image254
, preferably O.

本發明之一實施例為式9化合物，其中m2為2、3、4、5或6，較佳地2或3。One embodiment of the present invention is the compound of formula 9, wherein m2 is 2, 3, 4, 5 or 6, preferably 2 or 3.

本發明之一實施例為式9化合物，其中R 1'為O、NH、

Figure 02_image256
，較佳地NH。 One embodiment of the present invention is a compound of formula 9, wherein R 1' is O, NH,
Figure 02_image256
, preferably NH.

本發明之一實施例為式9化合物，其中R''為H、鹵基、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基或C 3-5雜環烷基，較佳地H、F、OH、NH 2、甲基、甲氧基、CF 3、CCl 3、甲胺基、二甲胺基、環丙基或環丙胺基，更佳地H、F、CF 3、環丙基或環丙胺基。 One embodiment of the present invention is the compound of formula 9, wherein R'' is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl, preferably H, F, OH, NH 2 , methyl, methoxy , CF 3 , CCl 3 , methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, CF 3 , cyclopropyl or cyclopropylamino.

本發明之一實施例為式9化合物，其中n為0、1或2，較佳地0或1。One embodiment of the present invention is the compound of formula 9, wherein n is 0, 1 or 2, preferably 0 or 1.

本發明之一實施例為式9化合物，其中R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基，較佳地H、F、CF 3、CCl 3、甲基或甲氧基，更佳地H或CF 3。 One embodiment of the present invention is a compound of formula 9, wherein R' is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, F , CF 3 , CCl 3 , methyl or methoxy, more preferably H or CF 3 .

本發明之一實施例為式9化合物，其中m為0、1、2或3，較佳地0、1或2。One embodiment of the present invention is the compound of formula 9, wherein m is 0, 1, 2 or 3, preferably 0, 1 or 2.

本發明之一實施例為式9化合物，其中Z為C，U為O或S，W為CH。One embodiment of the present invention is the compound of formula 9, wherein Z is C, U is O or S, and W is CH.

本發明之一實施例為式9化合物，其中Z為N，U為CH，W為CH。One embodiment of the present invention is the compound of formula 9, wherein Z is N, U is CH, and W is CH.

本發明之一實施例為式9化合物，其中Z為C，W為N，U為CH。One embodiment of the present invention is the compound of formula 9, wherein Z is C, W is N, and U is CH.

本發明之一實施例為式9化合物，其中R'''為H、OH、NH 2、C 1-3烷基、C 1-3烷胺基、C 1-3烷氧基或鹵素，較佳地H，F，甲氧基，甲胺基或二甲胺基。 One embodiment of the present invention is a compound of formula 9, wherein R''' is H, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylamino, C 1-3 alkoxy or halogen, more Preferably H, F, methoxy, methylamino or dimethylamino.

本發明之一實施例為式9化合物，其中k為0、1、2或3，較佳地0、1或2，更佳地0或1。One embodiment of the present invention is the compound of formula 9, wherein k is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

本發明之一實施例為式11化合物，其中R 3'為H或C 1-3烷基，較佳地H或甲基。 One embodiment of the present invention is the compound of formula 11, wherein R 3' is H or C 1-3 alkyl, preferably H or methyl.

本發明之一實施例為式11化合物，其中Y 1為CH 2或

Figure 02_image258
。 One embodiment of the present invention is a compound of formula 11, wherein Y 1 is CH 2 or
Figure 02_image258
.

本發明之一實施例為式11化合物，其中A為O、NH、

Figure 02_image260
，較佳地O。 One embodiment of the present invention is a compound of formula 11, wherein A is O, NH,
Figure 02_image260
, preferably O.

本發明之一實施例為式11化合物，其中m2為2、3、4、5或6，較佳地2或3。One embodiment of the present invention is the compound of formula 11, wherein m2 is 2, 3, 4, 5 or 6, preferably 2 or 3.

本發明之一實施例為式11化合物，其中R 1'為O、NH、

Figure 02_image262
，較佳地NH。 One embodiment of the present invention is a compound of formula 11, wherein R 1' is O, NH,
Figure 02_image262
, preferably NH.

本發明之一實施例為式11化合物，其中R''為H、鹵基、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基或C 3-5雜環烷基，較佳地H、F、OH、NH 2、甲基、甲氧基、CF 3、CCl 3、甲胺基、二甲胺基、環丙基或環丙胺基，更佳地H、F、CF 3、環丙基或環丙胺基。 One embodiment of the present invention is a compound of formula 11, wherein R'' is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl, preferably H, F, OH, NH 2 , methyl, methoxy , CF 3 , CCl 3 , methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, CF 3 , cyclopropyl or cyclopropylamino.

本發明之一實施例為式11化合物，其中n為0、1或2，較佳地0或1。One embodiment of the present invention is the compound of formula 11, wherein n is 0, 1 or 2, preferably 0 or 1.

本發明之一實施例為式11化合物，其中R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基，較佳地H、F、CF 3、CCl 3、甲基或甲氧基，更佳地H或CF 3。 One embodiment of the present invention is a compound of formula 11, wherein R' is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, F , CF 3 , CCl 3 , methyl or methoxy, more preferably H or CF 3 .

本發明之一實施例為式11化合物，其中m為0、1、2或3，較佳地0、1或2。One embodiment of the present invention is the compound of formula 11, wherein m is 0, 1, 2 or 3, preferably 0, 1 or 2.

本發明之一實施例為式11化合物，其中Z為C，U為O或S，W為CH。One embodiment of the present invention is the compound of formula 11, wherein Z is C, U is O or S, and W is CH.

本發明之一實施例為式11化合物，其中Z為N，U為CH，W為CH。One embodiment of the invention is the compound of formula 11, wherein Z is N, U is CH, and W is CH.

本發明之一實施例為式11化合物，其中Z為C，W為N，U為CH。One embodiment of the present invention is the compound of formula 11, wherein Z is C, W is N, and U is CH.

本發明之一實施例為式11化合物，其中R'''為H、OH、NH 2、C 1-3烷基、C 1-3烷胺基、C 1-3烷氧基或鹵素，較佳地H，F，甲氧基，甲胺基或二甲胺基。 One embodiment of the present invention is a compound of formula 11, wherein R''' is H, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylamino, C 1-3 alkoxy or halogen, more Preferably H, F, methoxy, methylamino or dimethylamino.

本發明之一實施例為式11化合物，其中k為0、1、2或3，較佳地0、1或2，更佳地0或1。One embodiment of the present invention is the compound of formula 11, wherein k is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

本發明之一實施例為式12化合物，其中R 3'為H或C 1-3烷基，較佳地H或甲基。 One embodiment of the present invention is the compound of formula 12, wherein R 3' is H or C 1-3 alkyl, preferably H or methyl.

本發明之一實施例為式12化合物，其中Y 1為CH 2或

Figure 02_image264
，較佳地CH 2。 One embodiment of the present invention is a compound of formula 12, wherein Y 1 is CH 2 or
Figure 02_image264
, preferably CH 2 .

本發明之一實施例為式12化合物，其中各A獨立地為O、NH、

Figure 02_image266
。本發明之一實施例為式12化合物，其中A為O、NH、
Figure 02_image268
，較佳地O。 One embodiment of the present invention is a compound of formula 12, wherein each A is independently O, NH,
Figure 02_image266
. One embodiment of the present invention is a compound of formula 12, wherein A is O, NH,
Figure 02_image268
, preferably O.

本發明之一實施例為式12化合物，其中m3為1、2、3、4、5或6，較佳地2或3。One embodiment of the present invention is the compound of formula 12, wherein m3 is 1, 2, 3, 4, 5 or 6, preferably 2 or 3.

本發明之一實施例為式12化合物，其中m4為0或1、2或3，較佳地0或3。One embodiment of the present invention is the compound of formula 12, wherein m4 is 0 or 1, 2 or 3, preferably 0 or 3.

本發明之一實施例為式12化合物，其中m5為0或1、2或3，較佳地0或1。One embodiment of the present invention is the compound of formula 12, wherein m5 is 0 or 1, 2 or 3, preferably 0 or 1.

本發明之一實施例為式12化合物，其中R 1'為O、NH、

Figure 02_image270
，較佳地NH。 One embodiment of the present invention is a compound of formula 12, wherein R 1' is O, NH,
Figure 02_image270
, preferably NH.

本發明之一實施例為式12化合物，其中R''為H、鹵基、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基或C 3-5雜環烷基，較佳地H、F、OH、NH 2、甲基、甲氧基、CF 3、CCl 3、甲胺基、二甲胺基、環丙基或環丙胺基，更佳地H、F、CF 3、環丙基或環丙胺基。 One embodiment of the present invention is a compound of formula 12, wherein R'' is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl, preferably H, F, OH, NH 2 , methyl, methoxy , CF 3 , CCl 3 , methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, CF 3 , cyclopropyl or cyclopropylamino.

本發明之一實施例為式12化合物，其中n為0、1或2，較佳地0或1。One embodiment of the present invention is the compound of formula 12, wherein n is 0, 1 or 2, preferably 0 or 1.

本發明之一實施例為式12化合物，其中R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基，較佳地H、F、CF 3、CCl 3、甲基或甲氧基，更佳地H或CF 3。 One embodiment of the present invention is a compound of formula 12, wherein R' is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, F , CF 3 , CCl 3 , methyl or methoxy, more preferably H or CF 3 .

本發明之一實施例為式12化合物，其中m為0、1、2或3，較佳地0、1或2。One embodiment of the present invention is the compound of formula 12, wherein m is 0, 1, 2 or 3, preferably 0, 1 or 2.

本發明之一實施例為式12化合物，其中Z為C，U為O或S，W為CH。One embodiment of the present invention is the compound of formula 12, wherein Z is C, U is O or S, and W is CH.

本發明之一實施例為式12化合物，其中Z為N，U為CH，W為CH。One embodiment of the invention is the compound of formula 12, wherein Z is N, U is CH, and W is CH.

本發明之一實施例為式12化合物，其中Z為C，W為N，U為CH。One embodiment of the invention is the compound of formula 12, wherein Z is C, W is N, and U is CH.

本發明之一實施例為式12化合物，其中R'''為H、OH、NH 2、C 1-3烷基、C 1-3烷胺基、C 1-3烷氧基或鹵素，較佳地H，F，甲氧基，甲胺基或二甲胺基。 One embodiment of the present invention is a compound of formula 12, wherein R''' is H, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylamino, C 1-3 alkoxy or halogen, more Preferably H, F, methoxy, methylamino or dimethylamino.

本發明之一實施例為式12化合物，其中k為0、1、2或3，較佳地0、1或2，更佳地0或1。One embodiment of the present invention is the compound of formula 12, wherein k is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

本發明之一實施例為式14化合物，其中R 3'為H或C 1-3烷基，較佳地H或甲基。 One embodiment of the present invention is the compound of formula 14, wherein R 3' is H or C 1-3 alkyl, preferably H or methyl.

本發明之一實施例為式14化合物，其中Y 1為CH 2或

Figure 02_image272
，較佳地CH 2。 One embodiment of the present invention is a compound of formula 14, wherein Y 1 is CH 2 or
Figure 02_image272
, preferably CH 2 .

本發明之一實施例為式14化合物，其中各A獨立地為O、NH、

Figure 02_image274
。本發明之一實施例為式14化合物，其中A為O、NH、
Figure 02_image276
，較佳地O。 One embodiment of the present invention is a compound of formula 14, wherein each A is independently O, NH,
Figure 02_image274
. One embodiment of the present invention is a compound of formula 14, wherein A is O, NH,
Figure 02_image276
, preferably O.

本發明之一實施例為式14化合物，其中m3為1、2、3、4、5或6，較佳地2、3或4。One embodiment of the present invention is the compound of formula 14, wherein m3 is 1, 2, 3, 4, 5 or 6, preferably 2, 3 or 4.

本發明之一實施例為式14化合物，其中m4為0、1、2、3或4，較佳地0或3。One embodiment of the present invention is the compound of formula 14, wherein m4 is 0, 1, 2, 3 or 4, preferably 0 or 3.

本發明之一實施例為式14化合物，其中m5為0或1、2或3，較佳地0或1。One embodiment of the present invention is the compound of formula 14, wherein m5 is 0 or 1, 2 or 3, preferably 0 or 1.

本發明之一實施例為式14化合物，其中R 1'為O、NH、

Figure 02_image278
，較佳地
Figure 02_image280
。 One embodiment of the present invention is a compound of formula 14, wherein R 1' is O, NH,
Figure 02_image278
, preferably
Figure 02_image280
.

本發明之一實施例為式14化合物，其中R''為H、鹵基、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基或C 3-5雜環烷基，較佳地H、F、OH、NH 2、甲基、甲氧基、CF 3、CCl 3、甲胺基、二甲胺基、環丙基或環丙胺基，更佳地H、F、CF 3、環丙基或環丙胺基。 One embodiment of the present invention is a compound of formula 14, wherein R'' is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl, preferably H, F, OH, NH 2 , methyl, methoxy , CF 3 , CCl 3 , methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, CF 3 , cyclopropyl or cyclopropylamino.

本發明之一實施例為式14化合物，其中n為0、1或2，較佳地0或1。One embodiment of the present invention is the compound of formula 14, wherein n is 0, 1 or 2, preferably 0 or 1.

本發明之一實施例為式14化合物，其中R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基，較佳地H、F、CF 3、CCl 3、甲基或甲氧基，更佳地H或CF 3。 One embodiment of the present invention is a compound of formula 14, wherein R' is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, F , CF 3 , CCl 3 , methyl or methoxy, more preferably H or CF 3 .

本發明之一實施例為式14化合物，其中m為0、1、2或3，較佳地0、1或2。One embodiment of the present invention is the compound of formula 14, wherein m is 0, 1, 2 or 3, preferably 0, 1 or 2.

本發明之一實施例為式14化合物，其中Z為C，U為O或S，W為CH。One embodiment of the present invention is the compound of formula 14, wherein Z is C, U is O or S, and W is CH.

本發明之一實施例為式14化合物，其中Z為N，U為CH，W為CH。One embodiment of the invention is the compound of formula 14, wherein Z is N, U is CH, and W is CH.

本發明之一實施例為式14化合物，其中Z為C，W為N，U為CH。One embodiment of the invention is the compound of formula 14, wherein Z is C, W is N, and U is CH.

本發明之一實施例為式14化合物，其中R'''為H、OH、NH 2、C 1-3烷基、C 1-3烷胺基、C 1-3烷氧基或鹵素，較佳地H，F，甲氧基，甲胺基或二甲胺基。 One embodiment of the present invention is a compound of formula 14, wherein R''' is H, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylamino, C 1-3 alkoxy or halogen, more Preferably H, F, methoxy, methylamino or dimethylamino.

本發明之一實施例為式14化合物，其中k為0、1、2或3，較佳地0、1或2，更佳地0或1。One embodiment of the present invention is the compound of formula 14, wherein k is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

式V-1化合物之一實施例具有下式4，

Figure 02_image282
其中R 1'為O、NH、
Figure 02_image284
。 One embodiment of the compound of formula V-1 has the following formula 4,
Figure 02_image282
Where R 1' is O, NH,
Figure 02_image284
.

本發明之一實施例為式4化合物，其中R 2'為H、OH、C 1-3烷基、C 1-3烷氧基、C 1-3烷胺基或NH 2，較佳地H、OH或NH 2。 One embodiment of the present invention is a compound of formula 4, wherein R 2' is H, OH, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino or NH 2 , preferably H , OH or NH 2 .

本發明之一實施例為式4化合物，其中m6為0、1、2或3，較佳地0或1。One embodiment of the present invention is the compound of formula 4, wherein m6 is 0, 1, 2 or 3, preferably 0 or 1.

本發明之一實施例為式4化合物，其中R 1'為O、NH、

Figure 02_image286
，較佳地O或NH。 One embodiment of the present invention is a compound of formula 4, wherein R 1' is O, NH,
Figure 02_image286
, preferably O or NH.

本發明之一實施例為式4化合物，其中R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基，較佳地H、鹵素或C 1-3氟烷基，更佳地H或F。 One embodiment of the present invention is a compound of formula 4, wherein R' is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, halogen Or C 1-3 fluoroalkyl, more preferably H or F.

本發明之一實施例為式4化合物，其中m為0、1、2、3或4，較佳地0或1。One embodiment of the present invention is the compound of formula 4, wherein m is 0, 1, 2, 3 or 4, preferably 0 or 1.

本發明之一實施例為式4化合物，其中R''為H、鹵基、OH、NH 2、C 1-3烷氧基、C 3-5環烷基、C 3-5環烷胺基或C 1-3烷胺基，較佳地H、鹵基、甲胺基、二甲胺基、環丙胺基或環丙基，更佳地H、F或二甲胺基。 One embodiment of the present invention is a compound of formula 4, wherein R'' is H, halo, OH, NH 2 , C 1-3 alkoxy, C 3-5 cycloalkyl, C 3-5 cycloalkylamino Or C 1-3 alkylamino, preferably H, halo, methylamino, dimethylamino, cyclopropylamino or cyclopropyl, more preferably H, F or dimethylamino.

本發明之一實施例為式4化合物，其中n為0、1或2，較佳地0或1。One embodiment of the present invention is the compound of formula 4, wherein n is 0, 1 or 2, preferably 0 or 1.

本發明之一實施例為式4化合物，其中Z為C，U為O或S，W為CH。One embodiment of the present invention is the compound of formula 4, wherein Z is C, U is O or S, and W is CH.

本發明之一實施例為式4化合物，其中Z為N，U為CH，W為CH。One embodiment of the present invention is the compound of formula 4, wherein Z is N, U is CH, and W is CH.

本發明之一實施例為式4化合物，其中Z為C，U為CH，W為N。One embodiment of the present invention is the compound of formula 4, wherein Z is C, U is CH, and W is N.

本發明之一實施例為式4化合物，其中R'''為H、OH、NH 2、C 1-3烷基、C 1-3烷胺基、C 1-3烷氧基或鹵素，較佳地H，F，甲氧基，甲胺基或二甲胺基。 One embodiment of the present invention is a compound of formula 4, wherein R''' is H, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylamino, C 1-3 alkoxy or halogen, more Preferably H, F, methoxy, methylamino or dimethylamino.

本發明之一實施例為式4化合物，其中k為0、1、2或3，較佳地0、1或2，更佳地0或1。One embodiment of the present invention is the compound of formula 4, wherein k is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

本發明之一實施例為式4化合物，其具有如式4-1中所示之結構，

Figure 02_image288
。 One embodiment of the present invention is a compound of formula 4, which has a structure as shown in formula 4-1,
Figure 02_image288
.

在式4-1中，R 2'為H、OH、C 1-3烷基、C 1-3烷氧基、C 1-3烷胺基或NH 2；Y 1為CH 2或

Figure 02_image290
；R 1'為O、NH、
Figure 02_image292
；R''為H、鹵基、OH、NH 2、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基或C 3-5雜環烷基；n為0、1或2；R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基；m為0、1或2；U為O或S；R'''為H、OH、NH 2、C 1-3烷基、C 1-3烷胺基、C 1-3烷氧基或鹵素；k為0、1、2、3或4。 In formula 4-1, R 2' is H, OH, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino or NH 2 ; Y 1 is CH 2 or
Figure 02_image290
; R 1' is O, NH,
Figure 02_image292
; R'' is H, halo, OH, NH 2 , C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino or C 3-5 heterocycloalkyl; n is 0, 1 or 2; R' is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy; m is 0, 1 or 2; U is O or S; R''' is H, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylamino, C 1-3 alkoxy or halogen; k is 0, 1, 2, 3 or 4 .

本發明之一實施例為式4-1化合物，其中R 1'為NH。 One embodiment of the present invention is a compound of formula 4-1, wherein R 1 ' is NH.

本發明之一實施例為式4-1化合物，其中R''為H。One embodiment of the present invention is the compound of formula 4-1, wherein R'' is H.

本發明之一實施例為式4-1化合物，其中R'為H。One embodiment of the present invention is the compound of formula 4-1, wherein R' is H.

本發明之一實施例為式4-1化合物，其中R 2'為OH。 An embodiment of the invention is a compound of formula 4-1, wherein R 2' is OH.

本發明之一實施例為式4-1化合物，其中R'''為H、OH、NH 2、C 1-3烷基、C 1-3烷胺基、C 1-3烷氧基或鹵素，較佳地H，F，甲氧基，甲胺基或二甲胺基。 One embodiment of the present invention is a compound of formula 4-1, wherein R''' is H, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylamino, C 1-3 alkoxy or halogen , preferably H, F, methoxy, methylamino or dimethylamino.

本發明之一實施例為式4化合物，其中k為0、1、2或3，較佳地0、1或2，更佳地0或1。One embodiment of the present invention is the compound of formula 4, wherein k is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

本發明之一實施例為式4化合物，其中U為S。An embodiment of the present invention is a compound of formula 4, wherein U is S.

式VI-1化合物之一實施例具有下式16或17，

Figure 02_image294
其中m2為1、2、3、4、5、6或7；且R 1'為O、NH、
Figure 02_image296
。 One embodiment of the compound of formula VI-1 has the following formula 16 or 17,
Figure 02_image294
wherein m2 is 1, 2, 3, 4, 5, 6 or 7; and R1 ' is O, NH,
Figure 02_image296
.

本發明之一實施例為式16化合物，其中m2為1、2、3、4、5或6，較佳地2或5。One embodiment of the present invention is the compound of formula 16, wherein m2 is 1, 2, 3, 4, 5 or 6, preferably 2 or 5.

本發明之一實施例為式16化合物，其中R 1'為O、NH、

Figure 02_image298
，較佳地NH。 One embodiment of the present invention is a compound of formula 16, wherein R 1' is O, NH,
Figure 02_image298
, preferably NH.

本發明之一實施例為式16化合物，其中R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基，較佳地H、鹵素或C 1-3氟烷基，更佳地H或F。 One embodiment of the present invention is a compound of formula 16, wherein R' is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, halogen Or C 1-3 fluoroalkyl, more preferably H or F.

本發明之一實施例為式16化合物，其中m為0、1、2、3或4，較佳地0或1。One embodiment of the present invention is the compound of formula 16, wherein m is 0, 1, 2, 3 or 4, preferably 0 or 1.

本發明之一實施例為式16化合物，其中R''為H、鹵基、OH、NH 2、C 1-3烷氧基、C 3-5環烷基、C 3-5環烷胺基或C 1-3烷胺基，較佳地H、鹵基、甲胺基、二甲胺基、環丙胺基或環丙基，更佳地H、F或二甲胺基。 One embodiment of the present invention is a compound of formula 16, wherein R'' is H, halo, OH, NH 2 , C 1-3 alkoxy, C 3-5 cycloalkyl, C 3-5 cycloalkylamino Or C 1-3 alkylamino, preferably H, halo, methylamino, dimethylamino, cyclopropylamino or cyclopropyl, more preferably H, F or dimethylamino.

本發明之一實施例為式16化合物，其中n為0、1或2，較佳地0或1。One embodiment of the present invention is the compound of formula 16, wherein n is 0, 1 or 2, preferably 0 or 1.

本發明之一實施例為式16化合物，其中Z為C，U為O或S，W為CH。One embodiment of the present invention is the compound of formula 16, wherein Z is C, U is O or S, and W is CH.

本發明之一實施例為式16化合物，其中Z為N，U為CH，W為CH。One embodiment of the invention is the compound of formula 16, wherein Z is N, U is CH, and W is CH.

本發明之一實施例為式16化合物，其中Z為C，U為CH，W為N。One embodiment of the invention is the compound of formula 16, wherein Z is C, U is CH, and W is N.

本發明之一實施例為式16化合物，其中R'''為H、OH、NH 2、C 1-3烷基、C 1-3烷胺基、C 1-3烷氧基或鹵素，較佳地H，F，甲氧基，甲胺基或二甲胺基。 One embodiment of the present invention is a compound of formula 16, wherein R''' is H, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylamino, C 1-3 alkoxy or halogen, more Preferably H, F, methoxy, methylamino or dimethylamino.

本發明之一實施例為式16化合物，其中k為0、1、2或3，較佳地0、1或2，更佳地0或1。One embodiment of the present invention is the compound of formula 16, wherein k is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

本發明之一實施例為式17化合物，其中m2為1、2、3、4、5或6，較佳地2或5。One embodiment of the present invention is the compound of formula 17, wherein m2 is 1, 2, 3, 4, 5 or 6, preferably 2 or 5.

本發明之一實施例為式17化合物，其中R 1'為O、NH、

Figure 02_image298
，較佳地NH。 One embodiment of the present invention is a compound of formula 17, wherein R 1' is O, NH,
Figure 02_image298
, preferably NH.

本發明之一實施例為式17化合物，其中R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基，較佳地H、鹵素或C 1-3氟烷基，更佳地H或F。 One embodiment of the present invention is a compound of formula 17, wherein R' is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, preferably H, halogen Or C 1-3 fluoroalkyl, more preferably H or F.

本發明之一實施例為式17化合物，其中m為0、1、2、3或4，較佳地0或1。One embodiment of the present invention is the compound of formula 17, wherein m is 0, 1, 2, 3 or 4, preferably 0 or 1.

本發明之一實施例為式17化合物，其中R''為H、鹵基、OH、NH 2、C 1-3烷氧基、C 3-5環烷基、C 3-5環烷胺基或C 1-3烷胺基，較佳地H、鹵基、甲胺基、二甲胺基、環丙胺基或環丙基，更佳地H、F或二甲胺基。 One embodiment of the present invention is a compound of formula 17, wherein R'' is H, halo, OH, NH 2 , C 1-3 alkoxy, C 3-5 cycloalkyl, C 3-5 cycloalkylamino Or C 1-3 alkylamino, preferably H, halo, methylamino, dimethylamino, cyclopropylamino or cyclopropyl, more preferably H, F or dimethylamino.

本發明之一實施例為式17化合物，其中n為0、1或2，較佳地0或1。One embodiment of the present invention is the compound of formula 17, wherein n is 0, 1 or 2, preferably 0 or 1.

本發明之一實施例為式17化合物，其中Z為C，U為O或S，W為CH。One embodiment of the invention is the compound of formula 17, wherein Z is C, U is O or S, and W is CH.

本發明之一實施例為式17化合物，其中Z為N，U為CH，W為CH。One embodiment of the invention is the compound of formula 17, wherein Z is N, U is CH, and W is CH.

本發明之一實施例為式17化合物，其中Z為C，U為CH，W為N。One embodiment of the invention is the compound of formula 17, wherein Z is C, U is CH, and W is N.

本發明之一實施例為式17化合物，其中R'''為H、OH、NH 2、C 1-3烷基、C 1-3烷胺基、C 1-3烷氧基或鹵素，較佳地H，F，甲氧基，甲胺基或二甲胺基。 One embodiment of the present invention is a compound of formula 17, wherein R''' is H, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylamino, C 1-3 alkoxy or halogen, more Preferably H, F, methoxy, methylamino or dimethylamino.

本發明之一實施例為式17化合物，其中k為0、1、2或3，較佳地0、1或2，更佳地0或1。One embodiment of the present invention is the compound of formula 17, wherein k is 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1.

本發明之一些實施例為具有表2中描繪之結構的化合物或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物、前驅藥。 表2.

Figure 02_image301
Figure 02_image303
Figure 02_image305
Figure 02_image307
Figure 02_image309
Figure 02_image311
Figure 02_image313
Figure 02_image315
Figure 02_image317
Figure 02_image319
Figure 02_image321
Figure 02_image323
Figure 02_image325
Figure 02_image327
Figure 02_image329
Figure 02_image331
Figure 02_image333
Figure 02_image335
Figure 02_image337
Figure 02_image339
Figure 02_image341
Figure 02_image343
Some embodiments of the invention are compounds having the structures depicted in Table 2, or pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, racemates, solvates thereof , metabolic precursors, prodrugs. Table 2.
Figure 02_image301
Figure 02_image303
Figure 02_image305
Figure 02_image307
Figure 02_image309
Figure 02_image311
Figure 02_image313
Figure 02_image315
Figure 02_image317
Figure 02_image319
Figure 02_image321
Figure 02_image323
Figure 02_image325
Figure 02_image327
Figure 02_image329
Figure 02_image331
Figure 02_image333
Figure 02_image335
Figure 02_image337
Figure 02_image339
Figure 02_image341
Figure 02_image343

在一些實施例中，本文提供本發明之化合物之溶劑合物、水合物、鹽或酯。In some embodiments, provided herein are solvates, hydrates, salts or esters of compounds of the invention.

本發明之某些化合物進一步論述於2020年11月13日申請之國際專利申請案第PCT/US2020/060459號中，其主張2019年11月13日申請之美國臨時申請案第62/935,017號之優先權，該等專利之內容各自以全文引用之方式併入本文中。Certain compounds of the present invention are further discussed in International Patent Application No. PCT/US2020/060459, filed November 13, 2020, which claims the benefits of U.S. Provisional Application No. 62/935,017, filed November 13, 2019. Priority, the contents of each of these patents are incorporated herein by reference in their entirety.

本發明之一態樣為一種組合物，其包含本文所揭示之化合物及至少一種醫藥學上可接受之賦形劑。 定義 One aspect of the invention is a composition comprising a compound disclosed herein and at least one pharmaceutically acceptable excipient. definition

除非另外定義，否則本文所使用之所有技術術語、符號及其他科學術語或術語集意欲具有涉及本申請案之熟習此項技術者通常理解的含義。在一些情況下，出於清楚起見及/或方便參考，在本文中定義具有通常所理解含義之術語，且本文中包括此類定義不應必然解釋為表示與此項技術中一般所理解存在實質性差異。熟習此項技術者充分瞭解且通常使用習知方法採用本文中所描述或提及之多種技術及程序。Unless otherwise defined, all technical terms, symbols and other scientific terms or terminology used herein are intended to have the meanings commonly understood by those skilled in the art to which this application relates. In some instances, terms that have commonly understood meanings are defined herein for clarity and/or ease of reference, and the inclusion of such definitions herein should not necessarily be construed as indicating the existence of substantive difference. Many of the techniques and procedures described or referred to herein are well understood and commonly employed by those skilled in the art using well-known methods.

當提供值範圍時，應理解除非上下文另外明確指示，否則本發明內涵蓋該範圍之上限與下限之間的各中間值(至下限之單位的十分之一)及所述範圍內之任何其他指定值或中間值。此等較小範圍之上限及下限可獨立地包括於較小範圍內且亦涵蓋於本發明內，在所規定範圍內受到任何特定排他性限制。在所述範圍包括界限中之一或兩者時，不包括彼等所包括界限中之任一者或兩者之範圍亦包括於本發明中。When a range of values is provided, it is understood that unless the context clearly dictates otherwise, each intermediate value between the upper and lower limit of that range (to the tenth of the unit of the lower limit) and any other value within said range is encompassed within the invention. Specifies a value or an intermediate value. The upper and lower limits of such smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specific exclusive limitation within that stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

應理解，出於清晰性在個別實施例之上下文中所描述的本發明之某些特徵亦可在單一實施例中組合提供。反之，為簡潔起見而在單一實施例之上下文中描述的本發明之各種特徵亦可分開地或以任何適合之子組合提供。關於本發明之實施例之所有組合特定地由本發明包涵且揭示於本文中，正如同個別地及明確地揭示每一個組合一般。另外，各種實施例及其要素之所有子組合亦特定地由本發明包涵且揭示於本文中，正如同個別地及明確地在本文中揭示每一個此類子組合一般。當列舉值之範圍時，其意欲涵蓋該範圍內之各值及子範圍。舉例而言，「C 1-6」意欲涵蓋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、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及C 5-6。 It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of embodiments of the invention are specifically encompassed by the invention and disclosed herein as if each combination were individually and expressly disclosed. Additionally, all subcombinations of various embodiments and elements thereof are also specifically encompassed by this disclosure and disclosed herein, as if each such subcombination were individually and expressly disclosed herein. When a range of values is recited, it is intended that each value and subranges within that range be encompassed. For example, "C 1-6 " is intended to cover 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 , 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 and C 5-6 .

「烷基」係指具有指定數目個碳原子之直鏈或分支鏈飽和烴基的基團。在一些實施例中，烷基具有1至6個碳原子(「C 1-6烷基」)。在一些實施例中，烷基具有1至5個碳原子(「C 1-5烷基」)。在一些實施例中，烷基具有1至4個碳原子(「C 1-4烷基」)。在一些實施例中，烷基具有1至3個碳原子(「C 1-3烷基」)。在一些實施例中，烷基具有1至2個碳原子(「C 1-2烷基」)。在一些實施例中，烷基具有1個碳原子(「C 1烷基」)。在一些實施例中，烷基具有2至6個碳原子(「C 2-6烷基」)。C 1-6烷基之實例包括甲基(C 1)、乙基(C 2)、正丙基(C 3)、異丙基(C 3)、正丁基(C 4)、三級丁基(C 4)、二級丁基(C 4)、異丁基(C 4)、正戊基(C 5)、3-戊基(C 5)、戊基(C 5)、新戊基(C 5)、3-甲基-2-丁基(C 5)、三級戊基(C 5)及正己基(C 6)。 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having the indicated number of carbon atoms. In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("C alkyl "). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2-6 alkyl”). 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 ), secondary 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 ), tertiary pentyl (C 5 ) and n-hexyl (C 6 ).

「烯基」係指在鏈之任何位置處具有一或多個碳-碳雙鍵之烷基，其可經單取代或多取代，且可為單價、二價或多價的。烯基之實例包括乙烯基、丙烯基、丁烯基、戊烯基、己烯基、丁二烯基、戊二烯基、己二烯基等。"Alkenyl" means an alkyl group having one or more carbon-carbon double bonds anywhere in the chain, which may be mono- or polysubstituted, and which may be monovalent, divalent, or polyvalent. Examples of alkenyl groups include vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, and the like.

「炔基」係指在鏈之任何位置具有一或多個碳-碳參鍵之烷基，其可經單取代或多取代，且可為單價、二價或多價的。炔基之實例包括乙炔基、丙炔基、丁炔基、戊炔基等。"Alkynyl" means an alkyl group having one or more carbon-carbon triple bonds anywhere in the chain, which may be mono- or polysubstituted, and which may be monovalent, divalent, or polyvalent. Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, and the like.

「環烷基」包括任何穩定環狀或多環烴基及飽和之任何碳原子，其可經單取代或多取代，且可為單價、二價或多價的。此類環烷基之實例包括但不限於環丙基、降𦯉基、[2.2.2]二環辛烷、[4.4.0]二環壬烷等。"Cycloalkyl" includes any stable cyclic or polycyclic hydrocarbon group and any saturated carbon atom, which may be monosubstituted or polysubstituted, and which may be monovalent, divalent or polyvalent. Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, northyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, and the like.

「視情況」意謂隨後描述之事件或情形可出現但未必出現，且描述包括上文所提及之事件或情形的存在及其中所描述之事件或情形的不存在。"Conditional" means that the subsequently described event or circumstance can but need not occur, and that the description includes the presence of the above-mentioned event or circumstance and the absence of the event or circumstance described therein.

「經取代」意謂特定原子上之任何一或多個氫原子經包括氘及氫變體之取代基置換，只要特定原子之價數正常且經取代之化合物穩定即可。當取代基為酮基(亦即=O)時，其意謂兩個氫原子經取代。芳族基上不發生酮取代。術語「視情況經取代」意謂其可或可不經取代。除非另外規定，否則取代基之類型及數目可基於化學上可達成而任意。"Substituted" means that any one or more hydrogen atoms on the specified atom are replaced with substituents including deuterium and hydrogen variants, so long as the valency of the specified atom is normal and the substituted compound is stable. When a substituent is keto (ie =0), it means that two hydrogen atoms are substituted. Keto substitution does not occur on the aromatic group. The term "optionally substituted" means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents can be arbitrary based on chemically achievable.

當任何變數(例如R)在化合物之任何組分或式中出現超過一次時，其在每次出現時之定義獨立於其在其他每次出現時之定義。因此，舉例而言，若基團展示為經0至2個R取代，則該基團可視情況經至多兩個R基團取代，且R在每次出現時獨立地選自R之定義。此外，取代基及/或變數之組合僅當此等組合產生穩定化合物時才為容許的。When any variable (eg, R) occurs more than one time in any component or formula of a compound, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0 to 2 R groups, that group may optionally be substituted with up to two R groups, and R at each occurrence is independently selected from the definition of R. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

當鍵結基團之數目為零時，例如-(A) 0-，則此鍵結基團為單鍵。 When the number of bonding groups is zero, such as -(A) 0 -, the bonding group is a single bond.

「烷氧基」係指具有經由氧橋連接之指定數目個碳原子之該烷基。除非另外規定，否則C 1-6烷氧基包括C 1、C 2、C 3、C 4、C 5及C 6烷氧基。烷氧基之實例包括但不限於甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、二級丁氧基、三級丁氧基、正戊氧基及S-戊氧基。 "Alkoxy" means an alkyl group having the indicated number of carbon atoms attached through an oxygen bridge. Unless otherwise specified, C 1-6 alkoxy includes C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, secondary butoxy, tertiary butoxy, n-pentoxy, and S - pentyloxy.

「芳基」係指多不飽和芳族烴取代基，其可經單取代或多取代，且可為單價、二價或多價的，且可為單環或多環的(例如，1至3個環；其中至少一個環為芳族的)。其稠合在一起或共價連接。"Aryl" refers to a polyunsaturated aromatic hydrocarbon substituent, which may be monosubstituted or polysubstituted, and may be monovalent, divalent, or polyvalent, and may be monocyclic or polycyclic (for example, 1 to 3 rings; at least one of which is aromatic). They are fused together or covalently linked.

自身或作為另一取代基之一部分的「鹵基」或「鹵素」係指氟、氯、溴或碘原子。"Halo" or "halogen" by themselves or as part of another substituent refers to a fluorine, chlorine, bromine or iodine atom.

「鹵烷基」包括單鹵烷基及多鹵烷基兩者。舉例而言，術語「鹵基(C 1-4)烷基」包括但不限於三氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基等。除非另外規定，否則鹵烷基之實例包括但不限於三氟甲基、三氯甲基、五氟乙基及五氯乙基。 "Haloalkyl" includes both monohaloalkyl and polyhaloalkyl. For example, the term "halo(C 1-4 )alkyl" includes, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl and the like. Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl, unless otherwise specified.

「雜環」係指具有指定環碳原子(諸如2至6個環碳原子)及1至4個環雜原子之3至10員非芳族環或芳族環系統之基團，其中各雜原子獨立地選自氮、氧及硫(「C 2-6雜環」)。在含有一或多個氮原子之雜環基中，價數允許時，連接點可為碳或氮原子。雜環基可為單環(「單環雜環」)或稠合、橋連或螺環系統，諸如雙環系統(「雙環雜環」)，且可為飽和或部分不飽和的。雜環雙環系統可在一個或兩個環中包括一或多個雜原子。「雜環」亦包括其中如上文所定義之雜環與一或多個碳環基稠合之環系統，其中連接點位於碳環或雜環上，或其中如上文所定義之雜環與一或多個芳基或雜芳基稠合之環系統，其中連接點位於雜環上，且在此類情況下，環成員之數目繼續表示雜環系統中之環成員之數目。 "Heterocyclic ring" means a group of 3 to 10 membered non-aromatic rings or aromatic ring systems having specified ring carbon atoms (such as 2 to 6 ring carbon atoms) and 1 to 4 ring heteroatoms, wherein each heterocycle The atoms are independently selected from nitrogen, oxygen and sulfur (" C2-6 heterocycle"). In a heterocyclic group containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. A heterocyclyl group can be a single ring ("monocyclic heterocycle") or a fused, bridged or spiro ring system, such as a bicyclic ring system ("bicyclic heterocycle"), and can be saturated or partially unsaturated. Heterocyclic bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocycle" also includes ring systems wherein a heterocycle as defined above is fused to one or more carbocyclyls, wherein the point of attachment is on the carbocycle or heterocycle, or wherein a heterocycle as defined above is fused to a or multiple aryl or heteroaryl fused ring systems wherein the point of attachment is on the heterocyclic ring, and in such cases the number of ring members continues to refer to the number of ring members in the heterocyclic ring system.

「氮保護基」係指用於防止胺基氮位置處之副反應的保護基。代表性胺基保護基包括但不限於甲醯基；醯基，諸如烷醯基(例如，乙醯基、三氯乙醯基或三氟乙醯基)；烷氧基羰基，諸如三級丁氧基羰基(Boc)；芳基甲氧基羰基，諸如苯甲氧基羰基(Cbz)及9-茀基甲氧基羰基(Fmoc)；芳基甲基，諸如苯甲基(Bn)、三苯甲基(Tr)、1,1-二(4'-甲氧基苯基)甲基；矽基，諸如三甲基矽烷基(TMS)及三級丁基二甲基矽基(TBS)等。"Nitrogen protecting group" refers to a protecting group used to prevent side reactions at the nitrogen position of an amine group. Representative amine protecting groups include, but are not limited to, formyl; acyl, such as alkyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butyl; Oxycarbonyl (Boc); Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), tris Benzyl (Tr), 1,1-bis(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tertiary butyldimethylsilyl (TBS) wait.

在一些實施例中，雜環基為具有指定環碳原子及1至4個環雜原子之5至10員非芳族環系統或芳族環系統，其中各雜原子獨立地選自氮、氧及硫。在一些實施例中，雜環基為具有指定環碳原子及1至4個環雜原子之5至6員非芳族環系統或芳族環系統，其中各雜原子獨立地選自氮、氧及硫(「5至6員雜環」)。在一些實施例中，5至6員雜環具有1至3個選自氮、氧及硫之環雜原子。在一些實施例中，5至6員雜環具有1至2個選自氮、氧及硫之環雜原子。在一些實施例中，5至6員雜環具有一個選自氮、氧及硫之環雜原子。In some embodiments, heterocyclyl is a 5 to 10 membered non-aromatic or aromatic ring system having a designated ring carbon atom and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, heterocyclyl is a 5 to 6 membered non-aromatic or aromatic ring system having a designated ring carbon atom and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5 to 6 membered heterocycle"). In some embodiments, the 5-6 membered heterocycle has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocycle has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocycle has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

含有一個雜原子之例示性3員雜環基包括但不限於氮丙啶基(azirdinyl)、環氧乙烷基及環硫乙烷基(thiorenyl)。含有一個雜原子之例示性4員雜環基包括但不限於氮雜環丁烷基、氧雜環丁烷基及硫雜環丁烷基。含有一個雜原子之例示性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、吡咯啶基、二氫吡咯基及吡咯基-2,5-二酮。含有兩個雜原子之例示性5員雜環基包括但不限於二氧戊環基(dioxolanyl)、氧硫呋喃基(oxasulfuranyl)、二硫呋喃基(disulfuranyl)及㗁唑啶-2-酮。含有三個雜原子之例示性5員雜環基包括但不限於三唑啉基、㗁二唑啉基及噻二唑啉基。含有一個雜原子之例示性6員雜環基包括但不限於哌啶基、四氫哌喃基、二氫吡啶基以及噻烷基。含有兩個雜原子之例示性6員雜環基包括但不限於哌𠯤基、𠰌啉基、二噻烷基及二㗁烷基。含有兩個雜原子之例示性6員雜環基包括但不限於三氮雜環己烷基。含有一個雜原子之例示性7員雜環基包括但不限於氮雜環庚烷基、氧雜環庚烷基及硫雜環庚烷基。含有一個雜原子之例示性8員雜環基包括但不限於氮雜環辛烷基、氧雜環辛烷基及硫雜環辛烷基。與C 6芳環稠合之例示性5員雜環基(在本文中亦稱為5,6-雙環雜環)包括但不限於吲哚啉基、異吲哚啉基、二氫苯并呋喃基、二氫苯并噻吩基、苯并㗁烷酮基及其類似基團。與芳環稠合之例示性6員雜環基(在本文中亦稱為6,6-雙環雜環)包括但不限於四氫喹啉基、四氫異喹啉基及其類似基團。 Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5- diketone. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and 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, piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperyl, olyl, dithianyl, and diazanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazacyclohexyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azacanyl, oxocanyl, and thiecanyl. Exemplary 5- membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocycles) fused to a C aromatic ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuran group, dihydrobenzothienyl group, benzoalkanonyl group and similar groups. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocycles) fused to an aromatic ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

術語「醫藥學上可接受之鹽」意謂對哺乳動物，尤其人類無害的鹽。醫藥學上可接受之鹽可使用無毒酸或鹼，包括無機酸或無機鹼，或有機酸或有機鹼形成。醫藥學上可接受之鹽的實例包括用鋁、鈣、鋰、鎂、鉀、鈉、鋅等形成之金屬鹽，及用離胺酸、N,N'-二苯甲基乙二胺、氯普魯卡因(chloroprocaine)、膽鹼、二乙醇胺、乙二胺、葡甲胺(N-甲基還原葡糖胺)、普魯卡因等形成之有機鹽。另外，醫藥學上可接受之鹽含有酸加成鹽及鹼加成鹽。The term "pharmaceutically acceptable salt" means a salt that is not harmful to mammals, especially humans. Pharmaceutically acceptable salts can be formed with non-toxic acids or bases, including inorganic acids or bases, or organic acids or bases. Examples of pharmaceutically acceptable salts include metal salts formed with aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, etc., and lysine, N,N'-benzhydrylethylenediamine, chloride Organic salts formed by procaine (chloroprocaine), choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine, etc. In addition, the pharmaceutically acceptable salts include acid addition salts and base addition salts.

術語「溶劑合物」意謂藉由一個或複數個溶劑分子與本發明化合物之結合形成的含溶劑化合物。溶劑合物包括例如單溶劑合物、二溶劑合物、三溶劑合物及四溶劑合物。此外，溶劑合物包括水合物。術語「水合物」意謂進一步含有化學計量或非化學計量之量的藉由非共價鍵結分子間力限制之水的化合物，或其鹽。水合物包括單水合物、二水合物、三水合物、四水合物及其類似物。The term "solvate" means a solvent-containing compound formed by the association of one or more solvent molecules with a compound of the present invention. Solvates include, for example, monosolvates, disolvates, trisolvates and tetrasolvates. Furthermore, solvates include hydrates. The term "hydrate" means a compound, or a salt thereof, which further contains a stoichiometric or non-stoichiometric amount of water bounded by non-covalent bonding intermolecular forces. Hydrates include monohydrates, dihydrates, trihydrates, tetrahydrates and the like.

本文在數值前存在術語「約」之情況下呈現某些範圍。術語「約」在本文中用以提供其後之準確數值以及接近或近似該術語之後之數值之數值的文字支持。在確定數值是否接近或近似特定敍述之數值時，接近或近似未敍述之數值可為在呈現其之上下文中提供特定敍述之數值的實質性等效物的數值。若使用一般熟習此項技術者並不清楚之術語，則給定使用該術語之上下文，「約」將意謂具體術語至多加或減10%。Certain ranges are presented herein where the term "about" precedes the numerical value. The term "about" is used herein to provide literal support for the exact value that it precedes and for a value that is near or approximately the value that the term precedes. In determining whether a value is near or approximately a specifically recited value, a value close to or approximately unrecited may be a value that provides a substantial equivalent of the specifically recited value in the context in which it is presented. Where a term is used that is not clear to one of ordinary skill in the art, "about" will mean up to plus or minus 10% of the particular term, given the context in which the term is used.

預期投與之「個體」包括但不限於人類(亦即，任何年齡組之男性或女性，例如兒科個體(例如，嬰兒、兒童、青少年)或成人個體(例如，年輕人、中年人或老年人))及/或其他非人類動物，例如哺乳動物(例如，靈長類動物(例如，食蟹獼猴、恆河猴)；商業相關的哺乳動物，諸如牛、豬、馬、綿羊、山羊、貓及/或狗)及鳥類(例如，商業相關的鳥類，諸如雞、鴨、鵝及/或火雞)。在某些實施例中，動物為哺乳動物。動物可為雄性或雌性且處於任何發育階段。非人類動物可為轉殖基因動物。"Subjects" to which administration is intended include, but are not limited to, human (i.e., male or female of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young, middle-aged, or elderly humans)) and/or other non-human animals such as mammals (e.g. primates (e.g. cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats and/or dogs) and birds (eg, commercially relevant birds such as chickens, ducks, geese and/or turkeys). In certain embodiments, the animal is a mammal. Animals can be male or female and at any stage of development. A non-human animal can be a transgenic animal.

術語「投與(administer/administering/administration)」係指植入、吸收、攝取、注入、吸入或以其他方式引入本發明化合物或其醫藥組合物。The term "administer/administering/administration" refers to implanting, absorbing, ingesting, infusing, inhaling or otherwise introducing a compound of the present invention or a pharmaceutical composition thereof.

術語「治療(treatment/treat/treating)」係指逆轉、減緩、延遲本文中所描述之「病理性病況」(例如，疾病、病症或病況，或其一或多種病徵或症狀)之發病，或阻止該「病理性病況」之進展。在一些實施例中，在已出現或已觀測到疾病之一或多種病徵或症狀之後可投與治療。在其他實施例中，可在無疾病或病況之病徵或症狀存在下投與治療。舉例而言，治療可在症狀發作之前向易患病個人投與(例如根據症狀病史及/或根據遺傳性或其他敏感性因素)。亦可在症狀已消退之後繼續治療，例如以延遲或預防復發。The term "treatment/treat/treating" means reversing, slowing down, delaying the onset of a "pathological condition" (e.g., a disease, disorder or condition, or one or more signs or symptoms thereof) as described herein, or prevent the progression of the "pathological condition". In some embodiments, treatment is administered after one or more signs or symptoms of a disease have occurred or have been observed. In other embodiments, treatment can be administered in the absence of signs or symptoms of a disease or condition. For example, treatment can be administered to predisposed individuals prior to the onset of symptoms (eg, based on a history of symptoms and/or based on genetic or other susceptibility factors). Treatment can also be continued after symptoms have subsided, eg, to delay or prevent relapse.

術語「病況」、「疾病」及「病症」可互換地使用。The terms "condition", "disease" and "disease" are used interchangeably.

化合物或組合物之「有效量」係指足以引起所需生物反應，亦即治療病況的量。如一般熟習此項技術者將瞭解，化合物或組合物之有效量可視諸如所需生物學終點、化合物之藥物動力學、所治療之病況、投藥模式及個體之年齡及健康的因素而變化。有效量涵蓋治療性及預防性治療。An "effective amount" of a compound or composition is an amount sufficient to elicit the desired biological response, ie, treat the condition. As will be appreciated by those of ordinary skill in the art, an effective amount of a compound or composition may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the individual. Effective amounts encompass both therapeutic and prophylactic treatments.

化合物或組合物之「治療有效量」為足以提供治療病況之治療效益或延遲與病況相關之一或多個症狀或使其降至最低的量。治療有效量之化合物或組合物意謂單獨或與其他療法組合提供治療病況之治療效益的一定量治療劑。術語「治療有效量」可涵蓋改善整個療法、減輕或避免症狀或病況之病因，或增強另一治療劑之治療功效的量。A "therapeutically effective amount" of a compound or composition is an amount sufficient to provide a therapeutic benefit in treating the condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound or composition means an amount of a therapeutic agent that, alone or in combination with other therapies, provides a therapeutic benefit for treating a condition. The term "therapeutically effective amount" can encompass an amount that improves the overall therapy, alleviates or avoids the etiology of a symptom or condition, or enhances the therapeutic efficacy of another therapeutic agent.

術語「α-突觸核蛋白(alpha-synuclein/α-synuclein/α-Syn)」在本文中可互換地使用且係指具有以下胺基酸序列之140胺基酸多肽(野生型人類α-突觸核蛋白)。 表1 GenBank寄存編號P37840 SEQ ID NO: 1 MDVFMKGLSKAKEGVVAAAEKTKQGVAEAAGKTKEGVLYVGSKTKEGVVHGVATVAEKTKEQVTNVGGAV VTGVTAVAQKTVEGAGSIAAATGFVKKDQLGKNEEGAPQEGILEDMPVDPDNEAYEMPSEEGYQDYEPEA The term "α-synuclein (alpha-synuclein/α-synuclein/α-Syn)" is used interchangeably herein and refers to a 140 amino acid polypeptide having the following amino acid sequence (wild-type human α- synuclein). Table 1 GenBank deposit number P37840 SEQ ID NO: 1 MDVFMKGLSKAKEGVVAAAEKTKQGVAEAAGKTKEGVLYVGSKTKEGVVHGVATVAEKTKEQVTNVGGAV VTGVTAVAQKTVEGAGSIAAATGFVKKDQLGKNEEGAPQEGILEDMPVDPDNEAYEMPSEEGYQDYEPEA

術語「聚集之α-突觸核蛋白」、「α-突觸核蛋白聚集體(α-synuclein aggregate/α-synuclein aggregates)」在本文中可互換地使用。The terms "aggregated α-synuclein", "α-synuclein aggregates (α-synuclein aggregates)" are used interchangeably herein.

對於E3泛蛋白連接酶，例示性胺基酸序列展示於表2中。 表2 E3泛蛋白連接酶[智人] GenBank寄存編號AAP47174.1 SEQ ID NO: 2 MEEGNNNEEVIHLNNFHCHRGQEWINLRDGPITISDSSDEERIPMLVTPAPQQHEEEDLDDDVILTEDDS EDDYGEFLDLGPPGISEFTKPSGQTEREPKPGPSHNQAANDIVNPRSEQKVIILEEGSLLYTESDPLETQ NQSSEDSETELLSNLGESAALADDQAIEEDCWLDHPYFQSLNQQPREITNQVVPQERQPEAELGRLLFQH EFPGPAFPRPEPQQGGISGPSSPQPAHPLGEFEDQQLASDDEEPGPAFPMQESQEPNLENIWGQEAAEVD QELVELLVKETEARFPDVANGFIEEIIHFKNYYDLNVLCNFLLENPDYPKREDRIIINPSSSLLASQDET KLPKIDFFDYSKLTPLDQRCFIQAADLLMADFKVLSSQDIKWALHELKGHYAITRKALSDAIKKWQELSP ETSGKRKKRKQMNQYSYIDFKFEQGDIKIEKRMFFLENKRRHCRSYDRRALLPAVQQEQEFYEQKIKEMA EHEDFLLALQMNEEQYQKDGQLIECRCCYGEFPFEELTQCADAHLFCKECLIRYAQEAVFGSGKLELSCM EGSCTCSFPTSELEKVLPQTILYKYYERKAEEEVAAAYADELVRCPSCSFPALLDSDVKRFSCPNPHCRK ETCRKCQGLWKEHNGLTCEELAEKDDIKYRTSIEEKMTAARIRKCHKCGTGLIKSEGCNRMSCRCGAQMC YLCRVSINGYDHFCQHPRSPGAPCQECSRCSLWTDPTEDDEKLIEEIQKEAEEEQKRKNGENTFKRIGPP LEKPVEKVQRVEALPRPVPQNLPQPQMPPYAFAHPPFPLPPVRPVFNNFPLNMGPIPAPYVPPLPNVRVN YDFGPIHMPLEHNLPMHFGPQPRHRF Exemplary amino acid sequences are shown in Table 2 for E3 ubiquitin ligases. Table 2 E3泛蛋白連接酶[智人] GenBank寄存編號AAP47174.1 SEQ ID NO: 2 MEEGNNNEEVIHLNNFHCHRGQEWINLRDGPITISDSSDEERIPMLVTPAPQQHEEEDLDDDVILTEDDS EDDYGEFLDLGPPGISEFTKPSGQTEREPKPGPSHNQAANDIVNPRSEQKVIILEEGSLLYTESDPLETQ NQSSEDSETELLSNLGESAALADDQAIEEDCWLDHPYFQSLNQQPREITNQVVPQERQPEAELGRLLFQH EFPGPAFPRPEPQQGGISGPSSPQPAHPLGEFEDQQLASDDEEPGPAFPMQESQEPNLENIWGQEAAEVD QELVELLVKETEARFPDVANGFIEEIIHFKNYYDLNVLCNFLLENPDYPKREDRIIINPSSSLLASQDET KLPKIDFFDYSKLTPLDQRCFIQAADLLMADFKVLSSQDIKWALHELKGHYAITRKALSDAIKKWQELSP ETSGKRKKRKQMNQYSYIDFKFEQGDIKIEKRMFFLENKRRHCRSYDRRALLPAVQQEQEFYEQKIKEMA EHEDFLLALQMNEEQYQKDGQLIECRCCYGEFPFEELTQCADAHLFCKECLIRYAQEAVFGSGKLELSCM EGSCTCSFPTSELEKVLPQTILYKYYERKAEEEVAAAYADELVRCPSCSFPALLDSDVKRFSCPNPHCRK ETCRKCQGLWKEHNGLTCEELAEKDDIKYRTSIEEKMTAARIRKCHKCGTGLIKSEGCNRMSCRCGAQMC YLCRVSINGYDHFCQHPRSPGAPCQECSRCSLWTDPTEDDEKLIEEIQKEAEEEQKRKNGENTFKRIGPP LEKPVEKVQRVEALPRPVPQNLPQPQMPPYAFAHPPFPLPPVRPVFNNFPLNMGPIPAPYVPPLPNVRVN YDFGPIHMPLEHNLPMHFGPQPRHRF

對於E3泛蛋白連接酶，另一例示性胺基酸序列展示於表3中。 表3 E3泛蛋白連接酶[智人] GenBank寄存編號AAP47175.1 SEQ ID NO: 3 MEEGNNNEEVIHLNNFHCHRGQEWINLRDGPITISDSSDEERIPMLVTPAPQQHEEEDLDDDVILTETNK PQRSRPNLIKPAAQWQDLKRLGEERPKKSRAAFESDKSSYFSVCNNPLFDSGAQDDSEDDYGEFLDLGPP GISEFTKPSGQTEREPKPGPSHNQAANDIVNPRSEQKVIILEEGSLLYTESDPLETQNQSSEDSETELLS NLGESAALADDQAIEEDCWLDHPYFQSLNQQPREITNQVVPQERQPEAELGRLLFQHEFPGPAFPRPEPQ QGGISGPSSPQPAHPLGEFEDQQLASDDEEPGPAFPMQESQEPNLENIWGQEAAEVDQELVELLVKETEA RFPDVANGFIEEIIHFKNYYDLNVLCNFLLENPDYPKREDRIIINPSSSLLASQDETKLPKIDFFDYSKL TPLDQRCFIQAADLLMADFKVLSSQDIKWALHELKGHYAITRKALSDAIKKWQELSPETSGKRKKRKQMN QYSYIDFKFEQGDIKIEKRMFFLENKRRHCRSYDRRALLPAVQQEQEFYEQKIKEMAEHEDFLLALQMNE EQYQKDGQLIECRCCYGEFPFEELTQCADAHLFCKECLIRYAQEAVFGSGKLELSCMEGSCTCSFPTSEL EKVLPQTILYKYYERKAEEEVAAAYADELVRCPSCSFPALLDSDVKRFSCPNPHCRKETCRKCQGLWKEH NGLTCEELAEKDDIKYRTSIEEKMTAARIRKCHKCGTGLIKSEGCNRMSCRCGAQMCYLCRVSINGYDHF CQHPRSPGAPCQECSRCSLWTDPTEDDEKLIEEIQKEAEEEQKRKNGENTFKRIGPPLEKPVEKVQRVEA LPRPVPQNLPQPQMPPYAFAHPPFPLPPVRPVFNNFPLNMGPIPAPYVPPLPNVRVNYDFGPIHMPLEHN LPMHFGPQPRHRF Another exemplary amino acid sequence is shown in Table 3 for the E3 ubiquitin ligase. table 3 E3泛蛋白連接酶[智人] GenBank寄存編號AAP47175.1 SEQ ID NO: 3 MEEGNNNEEVIHLNNFHCHRGQEWINLRDGPITISDSSDEERIPMLVTPAPQQHEEEDLDDDVILTETNK PQRSRPNLIKPAAQWQDLKRLGEERPKKSRAAFESDKSSYFSVCNNPLFDSGAQDDSEDDYGEFLDLGPP GISEFTKPSGQTEREPKPGPSHNQAANDIVNPRSEQKVIILEEGSLLYTESDPLETQNQSSEDSETELLS NLGESAALADDQAIEEDCWLDHPYFQSLNQQPREITNQVVPQERQPEAELGRLLFQHEFPGPAFPRPEPQ QGGISGPSSPQPAHPLGEFEDQQLASDDEEPGPAFPMQESQEPNLENIWGQEAAEVDQELVELLVKETEA RFPDVANGFIEEIIHFKNYYDLNVLCNFLLENPDYPKREDRIIINPSSSLLASQDETKLPKIDFFDYSKL TPLDQRCFIQAADLLMADFKVLSSQDIKWALHELKGHYAITRKALSDAIKKWQELSPETSGKRKKRKQMN QYSYIDFKFEQGDIKIEKRMFFLENKRRHCRSYDRRALLPAVQQEQEFYEQKIKEMAEHEDFLLALQMNE EQYQKDGQLIECRCCYGEFPFEELTQCADAHLFCKECLIRYAQEAVFGSGKLELSCMEGSCTCSFPTSEL EKVLPQTILYKYYERKAEEEVAAAYADELVRCPSCSFPALLDSDVKRFSCPNPHCRKETCRKCQGLWKEH NGLTCEELAEKDDIKYRTSIEEKMTAARIRKCHKCGTGLIKSEGCNRMSCRCGAQMCYLCRVSINGYDHF CQHPRSPGAPCQECSRCSLWTDPTEDDEKLIEEIQKEAEEEQKRKNGENTFKRIGPPLEKPVEKVQRVEA LPRPVPQNLPQPQMPPYAFAHPPFPLPPVRPVFNNFPLNMGPIPAPYVPPLPNVRVNYDFGPIHMPLEHN LPMHFGPQPRHRF

術語「結合劑」係指結合至蛋白質之化合物。結合劑以以下之Kd結合至蛋白質：小於50,000 nM、小於20,000 nM、小於10,000 nM、小於5,000 nM、小於2,500 nM、小於1,000 nM、小於900 nM、小於800 nM、小於700 nM、小於600 nM、小於500 nM、小於400 nM、小於300 nM、小於200 nM、小於100 nM、小於90 nM、小於80 nM、小於70 nM、小於60 nM、小於50 nM、小於40 nM、小於30 nM、小於20 nM、小於10 nM、小於5 nM、小於4 nM、小於3 nM、小於2 nM或小於1 nM。The term "binding agent" refers to a compound that binds to a protein. The binding agent binds to the protein with a Kd of less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, Less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM.

術語「蛋白酶體」係指用於進行蛋白質之降解的蛋白酶複合物。特定言之，蛋白酶體為多次單元酶複合物，其亦可起調節控制細胞週期進程及細胞凋亡之蛋白質的關鍵作用。蛋白酶體導引所選蛋白質之蛋白分解。The term "proteasome" refers to the complex of proteases used to carry out the degradation of proteins. In particular, the proteasome is a multiunit enzyme complex that also plays a key role in regulating proteins that control cell cycle progression and apoptosis. The proteasome directs the proteolysis of selected proteins.

術語「醫藥學上可接受之賦形劑」意謂醫藥學上可接受之材料、組合物或媒劑，諸如生理鹽水溶液、液體或固體填充劑、稀釋劑、溶劑或囊封劑。醫藥學上可接受之賦形劑之實例包括水、鹽水、生理鹽水或磷酸鹽緩衝鹽水(PBS)、氯化鈉注射溶液、林格氏注射溶液(Ringer's injection solution)、等張右旋糖注射溶液、無菌水注射溶液、右旋糖及乳酸林格氏注射溶液。 化合物之合成 The term "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle, such as physiological saline solution, liquid or solid filler, diluent, solvent or encapsulating agent. Examples of pharmaceutically acceptable excipients include water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection solution, Ringer's injection solution, isotonic dextrose injection solution, Sterile Water Injection Solution, Dextrose and Lactated Ringer's Injection Solution. Compound Synthesis

本發明之化合物可藉由熟習此項技術者熟知之多種合成方法製備，包括下文所列之實施例、其與其他化學合成方法之組合及熟習此項技術者已知之等效替代方案。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the examples listed below, their combinations with other chemical synthesis methods and equivalent substitutions known to those skilled in the art.

作為實例提供以下合成程序，一般熟習此項技術者使用其可合成本發明之化合物。The following synthetic procedures are provided as examples, which can be used by one of ordinary skill in the art to synthesize the compounds of the present invention.

式 (I) 化合物

Figure 02_image345
Compound of formula ( I)
Figure 02_image345

通式(I)化合物係如以下流程中所闡述製備：

Figure 02_image347
Compounds of general formula (I) are prepared as illustrated in the following schemes:
Figure 02_image347

式 (II) 化合物

Figure 02_image349
Compound of formula ( II)
Figure 02_image349

通式(II)化合物係如以下流程中所闡述製備：

Figure 02_image351
Compounds of general formula (II) are prepared as illustrated in the following schemes:
Figure 02_image351

式 (III) 化合物

Figure 02_image353
Compound of formula (III)
Figure 02_image353

通式(III)化合物係如以下流程中所闡述製備：

Figure 02_image355
Compounds of general formula (III) are prepared as illustrated in the following schemes:
Figure 02_image355

式 (IV) 化合物

Figure 02_image357
Compound of formula ( IV)
Figure 02_image357

通式(IV)化合物係如以下流程中所闡述製備：

Figure 02_image359
Compounds of general formula (IV) are prepared as illustrated in the following schemes:
Figure 02_image359

式 (V) 化合物

Figure 02_image361
Compound of formula ( V)
Figure 02_image361

通式(V)化合物係如以下流程中所闡述製備：

Figure 02_image363
Compounds of general formula (V) are prepared as illustrated in the following schemes:
Figure 02_image363

式 (VI) 化合物

Figure 02_image365
Compound of formula ( VI)
Figure 02_image365

通式(VI)化合物係如以下流程中所闡述製備：

Figure 02_image367
Compounds of general formula (VI) are prepared as illustrated in the following schemes:
Figure 02_image367

在本發明範疇內之其他化合物藉由如此等之方法，及藉由類似於以下實例中所闡述之方法合成。額外合成方法可見於WO2019214681、WO2018102067及WO2019014429中，其均以全文引用之方式併入本文中。 治療方法 Other compounds within the scope of the present invention were synthesized by such methods, and by methods analogous to those set forth in the Examples below. Additional synthetic methods can be found in WO2019214681, WO2018102067 and WO2019014429, all of which are incorporated herein by reference in their entirety. treatment method

本發明之另一態樣為一種輔助治療個體之突觸核蛋白病的方法，該方法包含以下、基本上以下其組成或由以下組成：向該個體投與有效量之如本文所揭示之化合物或如本文所揭示之組合物。Another aspect of the invention is a method of adjunctively treating a synucleinopathy in a subject, the method comprising, consisting essentially of, or consisting of: administering to the subject an effective amount of a compound as disclosed herein Or a composition as disclosed herein.

本發明之另一態樣為一種治療患有特徵在於存在α-突觸核蛋白之路易體或病理學聚集體之疾病的個體(例如，人類)的方法，該方法包含以下、基本上由以下組成或由以下組成：向該個體投與有效量之如本文所揭示之化合物或如本文所揭示之組合物。Another aspect of the invention is a method of treating an individual (e.g., a human) suffering from a disease characterized by the presence of alpha-synuclein Lewy bodies or pathological aggregates, the method comprising, consisting essentially of Consisting of or consisting of administering to the individual an effective amount of a compound as disclosed herein or a composition as disclosed herein.

本發明之另一態樣為一種用於防治個體之特徵在於存在α-突觸核蛋白之路易體或病理學聚集體之疾病的方法，該方法包含以下、基本上由以下組成或由以下組成：向該個體投與有效量之如本文所揭示之化合物或組合物。Another aspect of the invention is a method for preventing and treating a disease in an individual characterized by the presence of alpha-synuclein Lewy bodies or pathological aggregates, the method comprising, consisting essentially of, or consisting of : administering to the individual an effective amount of a compound or composition as disclosed herein.

在另一態樣中，本文提供治療個體之特徵在於存在α-突觸核蛋白之路易體或病理學聚集體之疾病的方法，該方法包含以下、基本上由以下組成或由以下組成：向該個體投與有效量之本文所描述之化合物或醫藥組合物。In another aspect, provided herein is a method of treating a disease in an individual characterized by the presence of alpha-synuclein Lewy bodies or pathological aggregates, the method comprising, consisting essentially of, or consisting of: The subject is administered an effective amount of a compound or pharmaceutical composition described herein.

在另一態樣中，本文提供用於減輕個體之特徵在於存在α-突觸核蛋白之路易體或病理學聚集體之疾病之嚴重程度的方法，該方法包含以下、基本上由以下組成或由以下組成：向該個體投與有效量之本文所描述之化合物或醫藥組合物。In another aspect, provided herein is a method for lessening the severity of a disease in an individual characterized by the presence of alpha-synuclein Lewy bodies or pathological aggregates comprising, consisting essentially of, or consists of administering to the individual an effective amount of a compound or pharmaceutical composition described herein.

在另一態樣中，本文提供延遲個體之特徵在於存在α-突觸核蛋白之路易體或病理學聚集體之疾病之進展的方法，該方法包含以下、基本上由以下組成或由以下組成：向該個體投與有效量之本文所描述之化合物或醫藥組合物。In another aspect, provided herein is a method of delaying the progression of a disease in an individual characterized by the presence of alpha-synuclein Lewy bodies or pathological aggregates, the method comprising, consisting essentially of, or consisting of : Administering to the individual an effective amount of a compound or pharmaceutical composition described herein.

在另一態樣中，本文提供降低個體罹患特徵在於存在α-突觸核蛋白之路易體或病理學聚集體之疾病之風險的方法，該方法包含以下、基本上以下其組成或由以下組成：向處於罹患該疾病之風險下的該個體投與有效量之本文所描述之化合物或醫藥組合物。In another aspect, provided herein is a method of reducing the risk of an individual suffering from a disease characterized by the presence of alpha-synuclein Lewy bodies or pathological aggregates, the method comprising, consisting essentially of, or consisting of : Administering an effective amount of a compound or pharmaceutical composition described herein to the individual at risk of developing the disease.

在另一態樣中，本文提供延遲處於罹患特徵在於存在α-突觸核蛋白之路易體或病理學聚集體之疾病之風險下的個體之該疾病之發作的方法，該方法包含以下、基本上以下其組成或由以下組成：向該個體投與有效量之本文所描述之化合物或醫藥組合物。In another aspect, provided herein is a method of delaying the onset of a disease in an individual at risk of suffering from a disease characterized by the presence of luwy bodies or pathological aggregates of alpha-synuclein, the method comprising essentially Consisting of or consisting of: administering to the individual an effective amount of a compound or pharmaceutical composition described herein.

在一些實施例中，待治療之個體展現出突觸核蛋白病之一或多種症狀(病徵)，諸如神經精神病學表現(抑鬱、癡呆、幻覺、焦慮、冷漠、失樂症)、自主神經變化(起立性低血壓、膀胱紊亂、便秘、大便失禁、流涎、吞咽困難、性功能障礙、大腦血流變化)、感官變化(嗅覺、疼痛、顏色辨別異常感覺)、睡眠障礙(快速動眼期睡眠行為障礙(RBD)、腿不寧症候群/週期性肢體運動、嗜睡、失眠)或其他病徵及症狀(疲勞、複視、視力模糊、皮脂溢、體重減輕/增加)。In some embodiments, the individual to be treated exhibits one or more symptoms (signs) of a synucleinopathy, such as neuropsychiatric manifestations (depression, dementia, hallucinations, anxiety, apathy, amusia), autonomic changes (orthostatic hypotension, bladder disturbance, constipation, fecal incontinence, salivation, dysphagia, sexual dysfunction, changes in blood flow to the brain), sensory changes (sensation of smell, pain, abnormal color discrimination), sleep disturbance (rapid eye movement sleep behavior (RBD), restless legs syndrome/periodic limb movements, lethargy, insomnia) or other signs and symptoms (fatigue, double vision, blurred vision, seborrhea, weight loss/gain).

在一些實施例中，待治療之個體不展現突觸核蛋白病之一或多種症狀，但已知具有罹患特徵在於大腦中存在α-突觸核蛋白之路易體或病理學聚集體之疾病的遺傳性風險。舉例而言，此個體可與疾病具有一或多種關係，或其風險藉由遺傳性或生物化學標記之分析來測定。舉例而言，SNCA (PARK1，編碼α-突觸核蛋白)中之突變，包括A30P、E46K、H50Q、G51D及A53T以及全部SNCA基因之複本及三倍體造成PD之體染色體顯性形式。LRRK2 (PARKS，富含白胺酸之重複激酶2)中之突變及VPS35 (PARK17，液泡蛋白質分選35)中之突變亦引起PD之體染色體顯性形式(Hernandez等人，(2016) Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance. Journal of Neurochemistry 10.1111/jnc.13593)。PINK1(PARK6，PTEN誘導之激酶1)、DJ-1 (PARK7)、帕金蛋白(Parkin) (PARK2)、ATP13A2 (PARK9，ATP酶型13A2)、FBXO7 (PARK15，僅F-box蛋白質7)及PLA2 GB (PARK14，磷脂酶A2，第VI族)中之突變已展示引起體染色體隱性PD/帕金森症(parkinonism)。另外，已鑑別出與PD及相關突觸核蛋白病相關之28種不同遺傳性風險基因位點，包括SNCA、LRRK2、GBA/SYT11、MAPT、HLA-DRB5、GAK、GCH1、NUCKS1/RAB7L1、SLC41A1、BST1、SIPA1L2、ACMSD/TMEM163、STK39、MCCC1、TMEM175/GAK/DGKQ、FAM47E/SCARB2、GPNMB、FGF20、INPP5F、MIR4697、CCDC62、GCH1、VPS13C、BCKDK/STX1B、SREBF/RAI1、RIT2及DDRGK1 (Nails等人. (2014) Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nature Genetics 46(9): 989-993)。因此，在防治性應用中，以有效降低疾病之風險、減輕疾病之嚴重程度或延遲疾病之至少一種病症或症狀發作的方案(劑量、頻率及投藥途徑)向易患疾病或以其他方式處於疾病風險下之患者投與本文所描述之抗體或包含其之醫藥組合物。在一些防治性應用中，該方案有效抑制或延遲大腦中α-突觸核蛋白之聚積，及/或抑制或延遲其毒性影響及/或抑制或延遲患者之行為缺陷的發展。In some embodiments, the individual to be treated does not exhibit one or more symptoms of a synucleinopathy, but is known to have a disorder characterized by the presence of luwy bodies or pathological aggregates of alpha-synuclein in the brain genetic risk. For example, the individual may have one or more relationships with the disease, or whose risk is determined by analysis of genetic or biochemical markers. For example, mutations in SNCA (PARK1, encoding α-synuclein), including A30P, E46K, H50Q, G51D, and A53T, as well as duplication and triploidy of all SNCA genes result in an autosomal dominant form of PD. Mutations in LRRK2 (PARKS, leucine-rich repeat kinase 2) and in VPS35 (PARK17, vacuolar protein sorting 35) also cause autosomal dominant forms of PD (Hernandez et al., (2016) Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance. Journal of Neurochemistry 10.1111/jnc.13593). PINK1 (PARK6, PTEN-induced kinase 1), DJ-1 (PARK7), Parkin (PARK2), ATP13A2 (PARK9, ATPase type 13A2), FBXO7 (PARK15, F-box protein 7 only) and Mutations in PLA2 GB (PARK14, phospholipase A2, family VI) have been shown to cause autosomal recessive PD/parkinonism. In addition, 28 different genetic risk loci have been identified associated with PD and related synucleinopathies, including SNCA, LRRK2, GBA/SYT11, MAPT, HLA-DRB5, GAK, GCH1, NUCKS1/RAB7L1, SLC41A1 , BST1, SIPA1L2, ACMSD/TMEM163, STK39, MCCC1, TMEM175/GAK/DGKQ, FAM47E/SCARB2, GPNMB, FGF20, INPP5F, MIR4697, CCDC62, GCH1, VPS13C, BCKDK/STX1B, SREBF/RAI1, RIT2 and DDRGK1 (Nails et al. (2014) Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nature Genetics 46(9): 989-993). Thus, in prophylactic applications, a regimen (dosage, frequency, and route of administration) effective to reduce the risk of disease, lessen the severity of disease, or delay the onset of at least one symptom or symptom of disease is the A patient at risk is administered an antibody described herein, or a pharmaceutical composition comprising the same. In some prophylactic applications, the regimen is effective in inhibiting or delaying the accumulation of alpha-synuclein in the brain, and/or inhibiting or delaying its toxic effects and/or inhibiting or delaying the development of behavioral deficits in the patient.

在一些實施例中，上文所描述之方法在個體中產生有益的治療反應(例如，減少大腦中之α-突觸核蛋白聚集體、改善認知功能，及/或逆轉、治療或預防認知減退)。因此，在一些實施例中，以有效減輕或至少抑制疾病之至少一種病症或症狀之進一步惡化的方案(劑量、頻率及投藥途徑)向懷疑或已經患有特徵在於存在α-突觸核蛋白之路易體或病理學聚集體之疾病的患者投與本文所描述之化合物或醫藥組合物。在一些治療性應用中，該方案有效降低α-突觸核蛋白、相關毒性及/或行為缺陷之水準或至少抑制其進一步增加。在某些實施例中，相對於開始治療之前或相較於未治療對照患者群，該治療可引起例如大腦中α-突觸核蛋白聚集體減少10%或更多、20%或更多、30%或更多、40%或更多、50%或更多、60%或更多、70%或更多、80%或更多、或90%或更多。In some embodiments, the methods described above result in a beneficial therapeutic response (e.g., reducing alpha-synuclein aggregates in the brain, improving cognitive function, and/or reversing, treating or preventing cognitive decline in an individual) ). Thus, in some embodiments, a regimen (dosage, frequency, and route of administration) effective to alleviate or at least inhibit further exacerbation of at least one sign or symptom of a disease is administered to suspected or already suffering patients characterized by the presence of alpha-synuclein. A patient with a disease of Lewy bodies or pathological aggregates is administered a compound or pharmaceutical composition described herein. In some therapeutic applications, the regimen is effective in reducing the level of alpha-synuclein, associated toxicity and/or behavioral deficits, or at least inhibiting further increases thereof. In certain embodiments, the treatment results in, for example, a 10% or greater, 20% or greater, reduction in alpha-synuclein aggregates in the brain, relative to prior to initiation of treatment, or compared to an untreated control patient population. 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more.

在一些實施例中，特徵在於大腦中存在α-突觸核蛋白之路易體或病理學聚集體的疾病為帕金森氏病(包括特發性帕金森氏病)、DLB、DLBD、LBVAD、單純性自主神經衰竭、路易體吞咽困難、偶發性LBD、遺傳性LBD (例如，SNCA (PARK1)、LRRK2 (PARK8)、VPS35 (PARK17)、PINK1 (PARK6)、DJ-1 (PARK7)、帕金蛋白(PARK2)、ATP13A2 (PARK9)、FBXO7 (PARK15)及PLA2 GB (PARK14)之突變)或多發性系統萎縮症(MSA；例如橄欖體腦橋小腦萎縮、紋狀體黑質退化及Shy-Drageri症候群)。In some embodiments, the disease characterized by the presence of alpha-synuclein Lewy bodies or pathological aggregates in the brain is Parkinson's disease (including idiopathic Parkinson's disease), DLB, DLBD, LBVAD, simplex Autonomic failure, dysphagia with Lewy bodies, sporadic LBD, inherited LBD (eg, SNCA (PARK1), LRRK2 (PARK8), VPS35 (PARK17), PINK1 (PARK6), DJ-1 (PARK7), Parkin (PARK2), ATP13A2 (PARK9), FBXO7 (PARK15), and PLA2 GB (PARK14) mutations) or multiple system atrophy (MSA; eg, olivopontocerebellar atrophy, striatonigral degeneration, and Shy-Drageri syndrome) .

亦提供用於保持或增加突觸密度及/或樹突密度之方法，使用突觸形成之標記(突觸素)及/或樹突(MAP2)所量測。因此，在一些實施例中，相對於開始治療之前或相較於未治療對照患者群，用本文所描述之化合物或組合物治療之個體展現出突觸或樹突密度升高10%或更多、20%或更多、30%或更多、40%或更多、或50%或更多。 A. 投藥 Also provided are methods for maintaining or increasing synapse density and/or dendrite density, as measured using markers of synapse formation (synaptophysin) and/or dendrites (MAP2). Accordingly, in some embodiments, an individual treated with a compound or composition described herein exhibits a 10% or greater increase in synaptic or dendritic density relative to prior to initiation of treatment or compared to an untreated control patient population , 20% or more, 30% or more, 40% or more, or 50% or more. A. Dosing

在以所需劑量用適當醫藥學上可接受之賦形劑調配之後，本發明之醫藥組合物可視所治療之疾病或病狀而經口、非經腸、腦池內、腹膜內、鞘內、腦室內、局部、經頰或其類似方式向人類及其他動物投與。After formulation in the desired dosage with suitable pharmaceutically acceptable excipients, the pharmaceutical composition of the present invention can be administered orally, parenterally, intracisternally, intraperitoneally, intrathecally depending on the disease or condition to be treated. , intracerebroventricularly, topically, bucally, or the like, to humans and other animals.

在某些實施例中，包含本發明之化合物的醫藥組合物以足以遞送約0.001 mg/kg至約200 mg/kg之劑量水準經口或非經腸投與一或多個劑量持續一天或若干天。在一些實施例中，每劑之有效量在以下範圍內變化：約0.001 mg/kg至約200 mg/kg、約0.001 mg/kg至約100 mg/kg、約0.01 mg/kg至約100 mg/kg、約0.01 mg/kg至約50 mg/kg、約0.1 mg/kg至約40 mg/kg、約0.5 mg/kg至約30 mg/kg、約0.01 mg/kg至約10 mg/kg、約0.1 mg/kg至約10 mg/kg個體體重/天，一天一或多次，以獲得所要治療及/或預防功效。在一些實施例中，本文所描述之化合物呈足以遞送約0.001 mg/kg至約200 mg/kg、約0.001 mg/kg至約100 mg/kg、約0.01 mg/kg至約100 mg/kg、約0.01 mg/kg至約50 mg/kg、約0.1 mg/kg至約40 mg/kg、約0.5 mg/kg至約30 mg/kg、約0.01 mg/kg至約10 mg/kg、約0.1 mg/kg至約10 mg/kg或約1 mg/kg至約25 mg/kg個體體重/天之劑量，一天一或多次，以獲得所要治療及/或防治性功效。所需劑量可一天三次、一天兩次、一天一次、每隔一天、每三天、每週、每兩週、每三週或每四週遞送。在一些實施例中，使用多次投與(例如兩次、三次、四次、五次、六次、七次、八次、九次、十次、十一次、十二次、十三次、十四次或更多次投與)遞送劑量。在一些實施例中，本文中所描述之組合物以低於試劑會引起非特異性作用之劑量的劑量投與。 B. 組合物 In certain embodiments, pharmaceutical compositions comprising a compound of the invention are administered orally or parenterally in one or more doses at dosage levels sufficient to deliver from about 0.001 mg/kg to about 200 mg/kg for one or more days. sky. In some embodiments, the effective amount per dose ranges from about 0.001 mg/kg to about 200 mg/kg, from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 100 mg /kg, about 0.01 mg/kg to about 50 mg/kg, about 0.1 mg/kg to about 40 mg/kg, about 0.5 mg/kg to about 30 mg/kg, about 0.01 mg/kg to about 10 mg/kg , about 0.1 mg/kg to about 10 mg/kg individual body weight/day, one or more times a day, to obtain the desired therapeutic and/or prophylactic effect. In some embodiments, the compounds described herein are present in an amount sufficient to deliver about 0.001 mg/kg to about 200 mg/kg, about 0.001 mg/kg to about 100 mg/kg, about 0.01 mg/kg to about 100 mg/kg, About 0.01 mg/kg to about 50 mg/kg, about 0.1 mg/kg to about 40 mg/kg, about 0.5 mg/kg to about 30 mg/kg, about 0.01 mg/kg to about 10 mg/kg, about 0.1 mg/kg to about 10 mg/kg or about 1 mg/kg to about 25 mg/kg of individual body weight per day, one or more times a day to obtain the desired therapeutic and/or preventive effects. The desired dosage may be delivered three times a day, twice a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In some embodiments, multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen) are used , fourteen or more administrations) delivered dose. In some embodiments, a composition described herein is administered at a dose that is lower than the dose at which the agent would cause a non-specific effect. B. Composition

本文所述之醫藥組合物可藉由藥理學技術中通常已知之方法製備。一般而言，此類方法包括以下步驟：組合本發明化合物與載劑及/或一或多種其他附屬成分，且隨後將產物成型及/或封裝成所要單劑量或多劑量單元。The pharmaceutical compositions described herein can be prepared by methods generally known in the art of pharmacology. In general, such methods comprise the steps of combining a compound of the invention with the carrier and/or one or more other accessory ingredients, and subsequently shaping and/or packaging the product into the desired single or multi-dose unit.

醫藥組合物可以批量、作為單一單位劑量及/或作為複數個單一單位劑量製備、封裝及/或出售。如本文中所使用，「單位劑量」為包含預定量之活性成分之醫藥組合物的個別量。活性成分之量通常等於將向個體投與之活性成分之劑量及/或此劑量之適宜分數，諸如此類劑量之一半或三分之一。Pharmaceutical compositions may be prepared, packaged and/or sold in bulk, as a single unit dose and/or as a plurality of single unit doses. As used herein, a "unit dose" is a discrete quantity of pharmaceutical composition containing a predetermined quantity of active ingredient. The amount of active ingredient is usually equal to the dose of active ingredient to be administered to the individual and/or an appropriate fraction of such a dose, such as one-half or one-third of such a dose.

用於製造醫藥組合物之醫藥學上可接受之賦形劑包括惰性稀釋劑、分散劑及/或成粒劑、界面活性劑及/或乳化劑、崩解劑、黏合劑、防腐劑、穩定劑、緩衝液、潤滑劑及/或油。賦形劑，諸如可可脂及栓劑蠟、著色劑、塗佈劑、甜味劑、調味劑及芳香劑亦可存在於組合物中。Pharmaceutically acceptable excipients used in the manufacture of pharmaceutical compositions include inert diluents, dispersants and/or granulating agents, surfactants and/or emulsifiers, disintegrants, binders, preservatives, stabilizers agents, buffers, lubricants and/or oils. Excipients, such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents can also be present in the compositions.

適合的稀釋劑包括碳酸鈣、碳酸鈉、磷酸鈣、磷酸鈣、硫酸鈣、磷酸氫鈣、磷酸鈉乳糖、蔗糖、纖維素、微晶纖維素、高嶺土、甘露糖醇、山梨糖醇、肌醇、氯化鈉、乾澱粉、玉米澱粉、粉糖及其混合物。Suitable diluents include calcium carbonate, sodium carbonate, calcium phosphate, calcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol , sodium chloride, dry starch, corn starch, powdered sugar and mixtures thereof.

適合之成粒劑及/或分散劑包括馬鈴薯澱粉、玉米澱粉、木薯澱粉、羥基乙酸澱粉鈉、黏土、褐藻酸、瓜爾膠、柑桔渣、瓊脂、膨潤土、纖維素及木製品、天然海綿、陽離子交換樹脂、碳酸鈣、矽酸鹽、碳酸鈉、交聯聚(乙烯基吡咯啶酮) (交聯聚維酮)、羧甲基澱粉鈉(羥基乙酸澱粉鈉)、羧甲基纖維素、交聯羧甲基纖維素鈉(交聯羧甲纖維素)、甲基纖維素、預膠凝化澱粉(澱粉1500)、微晶澱粉、水不溶性澱粉、羧甲基纖維素鈣、矽酸鎂鋁。Suitable granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pomace, agar, bentonite, cellulose and wood products, natural sponge, Cation Exchange Resin, Calcium Carbonate, Silicate, Sodium Carbonate, Cross-Linked Poly(vinylpyrrolidone) (Crosspovidone), Sodium Carboxymethyl Starch (Sodium Starch Glycolate), Carboxymethyl Cellulose, Croscarmellose Sodium (Crosscarmellose), Methylcellulose, Pregelatinized Starch (Starch 1500), Microcrystalline Starch, Water Insoluble Starch, Carmellose Calcium, Magnesium Silicate aluminum.

本發明中所提及之所有公開案及專利申請案均以引用方式併入本文中，其引用的程度如同各個別公開案或專利申請案經特定及個別指示以引用方式併入一般。All publications and patent applications mentioned in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

未承認本文所引用之任何參考文獻構成先前技術。參考文獻之論述陳述其作者斷言之內容，且本發明人保留挑戰所引用文獻之準確性及相關性的權利。將清楚地理解，儘管本文中參考多種資訊來源，包括科學雜誌文章、專利文獻及教科書；但此參考不構成承認此等文獻中之任一者形成此項技術中公共常識之部分。No admission is made that any reference cited herein constitutes prior art. The discussion of the references states what their authors assert, and the inventors reserve the right to challenge the accuracy and pertinence of the cited documents. It will be clearly understood that, although reference is made herein to various sources of information, including scientific journal articles, patent documents, and textbooks; this reference does not constitute an admission that any of these documents form part of the common general knowledge in the art.

本文所給出之通用方法之論述僅意欲用於說明之目的。其他替代方法及替代方案對於熟習此項技術者在檢閱本發明後將為顯而易見的，且應包括於本申請案之精神及範疇內。 實例 The discussion of general methods given herein is intended for illustrative purposes only. Other alternatives and alternatives will be apparent to those skilled in the art upon review of this disclosure and are intended to be included within the spirit and scope of this application. example

提供以下實例作為對於一般熟習此項技術者之進一步指導，且並不意欲以任何方式限制所主張之本發明之範疇。The following examples are provided as further guidance to those of ordinary skill in the art and are not intended to limit the scope of the claimed invention in any way.

一般而言，在以下實例中，化學物質係購自Sinopharm Chemical Reagent Co. (SCRC)，Sigma-Aldrich，Alfa或其他供應商。在Bruker AVIII 400或Bruker AVIII 500光譜儀上記錄 1H NMR及 19F NMR光譜。 In general, in the following examples, chemicals were purchased from Sinopharm Chemical Reagent Co. (SCRC), Sigma-Aldrich, Alfa or other suppliers. 1 H NMR and 19 F NMR spectra were recorded on a Bruker AVIII 400 or Bruker AVIII 500 spectrometer.

LCMS量測在Agilent 1200 HPLC/6100 SQ系統上使用以下條件進行：方法A：移動相：A：水(0.01% TFA) B：CAN (0.01% TFA)；梯度階段：在1.4 min內5%B遞增至95%B，在1.6 min內95%B (總運行時間：3 min)；流速：2.3 mL/min；管柱：SunFire C18，4.6×50 mm，3.5 µm；管柱溫度：50℃。偵測器：ADC ELSD，DAD (214 nm及254 nm)，ES-API。方法B：移動相：A：水(10 mM NH 4HCO 3) B：乙腈；梯度階段：在1.5 min內5%至95%B，95%B 1.5 min(總運行時間：3 min)；流速：2.0 mL/min；管柱：XBridge C18，4.6×50 mm，3.5 µm；管柱溫度：40℃。偵測器：ADC ELSD，DAD (214 nm及254 nm)、MSD (ES-API)。方法C：移動相：A：水(10 mM NH 4HCO 3) B：乙腈；梯度階段：在1.5 min內5%至95%B，95%B 1.5 min(總運行時間：3 min)；流速：2.0 mL/min；管柱：XBridge C18，4.6×50mm，3.5 µm；管柱溫度：40℃。偵測器：ADC ELSD，DAD (214 nm及254 nm)，MSD (ES-API)。 LCMS measurements were performed on an Agilent 1200 HPLC/6100 SQ system using the following conditions: Method A: mobile phase: A: water (0.01% TFA) B: CAN (0.01% TFA); gradient phase: 5% B in 1.4 min Incremental to 95%B, 95%B within 1.6 min (total run time: 3 min); flow rate: 2.3 mL/min; column: SunFire C18, 4.6×50 mm, 3.5 µm; column temperature: 50°C. Detectors: ADC ELSD, DAD (214 nm and 254 nm), ES-API. Method B: Mobile phase: A: Water (10 mM NH 4 HCO 3 ) B: Acetonitrile; Gradient phase: 5% to 95% B in 1.5 min, 95% B for 1.5 min (total run time: 3 min); flow rate : 2.0 mL/min; column: XBridge C18, 4.6×50 mm, 3.5 µm; column temperature: 40℃. Detectors: ADC ELSD, DAD (214 nm and 254 nm), MSD (ES-API). Method C: Mobile phase: A: Water (10 mM NH 4 HCO 3 ) B: Acetonitrile; Gradient phase: 5% to 95% B in 1.5 min, 95% B for 1.5 min (total run time: 3 min); flow rate : 2.0 mL/min; column: XBridge C18, 4.6×50mm, 3.5 µm; column temperature: 40℃. Detectors: ADC ELSD, DAD (214 nm and 254 nm), MSD (ES-API).

縮寫：THF-四氫呋喃；DMF- N,N-二甲基甲醯胺；EtOAc-乙酸乙酯；DCM-二氯甲烷；MeOH-甲醇；EtOH-乙醇；TEA-三乙醇胺；TFA-三氟乙酸；RT-室溫。Abbreviations: THF-tetrahydrofuran; DMF-N,N-dimethylformamide; EtOAc-ethyl acetate; DCM-dichloromethane; MeOH-methanol; EtOH-ethanol; TEA-triethanolamine; TFA-trifluoroacetic acid; RT - room temperature.

額外實施例進一步詳細揭示於以下實例中，其以說明方式提供且不意欲以任何方式限制本發明或申請專利範圍之範疇。儘管已揭示本發明之特定替代方案，但應理解，各種修改及組合為可能的且涵蓋在隨附申請專利範圍之真實精神及範疇內。因此，不意圖限制本文中呈現之確切摘要及揭示內容。 實例1：化合物159985之合成

Figure 02_image369
Additional embodiments are disclosed in further detail in the following examples, which are provided by way of illustration and are not intended to limit the scope of the invention or claims in any way. While certain alternatives to the invention have been disclosed, it should be understood that various modifications and combinations are possible and are covered within the true spirit and scope of the appended claims. Accordingly, it is not intended to be limited to the exact abstract and disclosures presented herein. Example 1: Synthesis of Compound 159985
Figure 02_image369

(A) 4- 甲基苯磺酸 2-[2-[2-[2-[2-[2-[[2-[4-[6-( 二甲胺基 ) 吡啶 -3- 基 ] 苯基 ]-1,3- 苯并噻唑 -6- 基 ]-[(2- 甲基丙 -2- 基 ) 氧基羰基 ] 胺基 ] 乙氧基 ] 乙氧基 ] 乙氧基 ] 乙氧基 ] 乙氧基 ] 乙酯 ：在0℃下向N-[2-[4-[6-(二甲胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(500 mg，1.12 mmol)於DMF (10 mL)中之溶液中添加NaH (107.49 mg，4.48 mmol)且在RT下攪拌1 h。將含4-甲基苯磺酸2-[2-[2-[2-[2-[2-(4-甲基苯基)磺醯基氧基乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙酯(2.65 g，4.48 mmol)之DMF (10 mL)添加至反應混合物中，且在RT下攪拌14 h。藉由在0℃下添加水淬滅混合物且接著用EtOAc (200 mL)萃取。有機層用水(100 mL)、鹽水(100 mL)洗滌，經Na 2SO 4乾燥，濃縮且藉由管柱層析(DCM:MeOH=10:1，Rf=0.7)純化，得到呈淡黃色固體狀之4-甲基苯磺酸2-[2-[2-[2-[2-[2-[[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙酯(化合物159835，603 mg，0.70 mmol，產率62%)。 (A) 2- [2-[2-[2-[2-[2-[[[2-[4-[6-( dimethylamino ) pyridin -3- yl ] benzene ) 4-methylbenzenesulfonic acid Base ]-1,3- benzothiazol - 6- yl ]-[(2- methylpropan - 2- yl ) oxycarbonyl ] amino] ethoxy ] ethoxy ] ethoxy ] ethoxy ] Ethoxy ] ethyl ester : at 0°C to N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazole-6- To a solution of tert-butyl]carbamate (500 mg, 1.12 mmol) in DMF (10 mL) was added NaH (107.49 mg, 4.48 mmol) and stirred at RT for 1 h. 4-methylbenzenesulfonic acid 2-[2-[2-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy ]ethoxy]ethoxy]ethyl ester (2.65 g, 4.48 mmol) in DMF (10 mL) was added to the reaction mixture and stirred at RT for 14 h. The mixture was quenched by adding water at 0 °C and then extracted with EtOAc (200 mL). The organic layer was washed with water (100 mL), brine (100 mL), dried over Na 2 SO 4 , concentrated and purified by column chromatography (DCM:MeOH=10:1, Rf=0.7) to give a pale yellow solid 4-methylbenzenesulfonic acid 2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]benzene Base]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy ]ethoxy]ethyl ester (compound 159835, 603 mg, 0.70 mmol, 62% yield).

(B) N-[2-[4-[6-( 二甲基胺基 ) 吡啶 -3- 基 ] 苯基 ]-1,3- 苯并噻唑 -6- 基 ]-N-[2-[2-[2-[2-[2-(2- 碘基乙氧基 ) 乙氧基 ] 乙氧基 ] 乙氧基 ] 乙氧基 ] 乙基 ] 胺基甲酸三級丁酯：將4-甲基苯磺酸2-[2-[2-[2-[2-[2-[[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙酯(200 mg，0.23 mmol)及NaI (42 mg，0.28 mmol)於CH 3CN (5 mL)中之混合物在80℃下加熱20 h。將殘餘物溶解於DCM (50 mL)及水(50 mL)中。有機層用水(50 mL)、鹽水(50 mL)洗滌，經Na 2SO 4乾燥且濃縮，得到呈黃色固體狀之N-[2-[4-[6-(二甲胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]-N-[2-[2-[2-[2-[2-(2-碘基乙氧基)乙氧基]乙氧基]乙氧基]乙氧基]乙基]胺基甲酸三級丁酯(化合物159890，185.1 mg，0.23 mmol，產率98%)。 (B) N-[2-[4-[6-( dimethylamino ) pyridin -3 -yl ] phenyl ]-1,3- benzothiazol -6- yl ]-N-[2-[ 2-[2-[2-[2-(2- Iodoethoxy ) ethoxy ] ethoxy ] ethoxy ] ethoxy ] ethyl ] tertiary butyl carbamate : the 4- Toluenesulfonic acid 2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1 ,3-Benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy ] A mixture of ethyl ester (200 mg, 0.23 mmol) and NaI (42 mg, 0.28 mmol) in CH 3 CN (5 mL) was heated at 80° C. for 20 h. The residue was dissolved in DCM (50 mL) and water (50 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over Na 2 SO 4 and concentrated to give N-[2-[4-[6-(dimethylamino)pyridine-3 as a yellow solid -yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy] tert-butyl ethoxy]ethoxy]ethoxy]ethyl]carbamate (Compound 159890, 185.1 mg, 0.23 mmol, 98% yield).

(C) N-[2-[2-[2-[2-[2-[2-[2-[2,6- 雙 ( 側氧基 ) 哌啶 -3- 基 ]-1,3- 雙 ( 側氧基 ) 異吲哚 -5- 基 ] 氧基乙氧基 ] 乙氧基 ] 乙氧基 ] 乙氧基 ] 乙氧基 ] 乙基 ]-N-[2-[4-[6-( 二甲基胺基 ) 吡啶 -3- 基 ] 苯基 ]-1,3- 苯并噻唑 -6- 基 ] 胺基甲酸三級丁酯：將2-[2,6-雙(側氧基)哌啶-3-基]-5-羥基-異吲哚-1,3-二酮(67 mg，0.24 mmol)、K 2CO 3(51 mg，0.37 mmol)及N-[2-[4-[6-(二甲胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]-N-[2-[2-[2-[2-[2-(2-碘基乙氧基)乙氧基]乙氧基]乙氧基]乙氧基]乙基]胺基甲酸三級丁酯(100 mg，0.12 mmol)於DMF (5 mL)中之混合物在50℃下加熱5 h。混合物用水淬滅，接著用DCM (200 mL)萃取。有機層經Na 2SO 4乾燥，濃縮，且藉由矽膠管柱層析(DCM:MeOH=20:1，Rf=0.52)純化，得到呈淡黃色固體狀之N-[2-[2-[2-[2-[2-[2-[2-[2,6-雙(側氧基)哌啶-3-基]-1,3-雙(側氧基)異吲哚-5-基]氧基乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙基]-N-[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(53 mg，0.05 mmol，產率45%)。 (C) N-[2-[2-[2-[2-[2-[2-[2-[2,6- bis ( side oxy ) piperidin -3- yl ]-1,3- bis ( Oxy ) isoindol -5- yl ] oxyethoxy] ethoxy]ethoxy ] ethoxy ] ethoxy ] ethyl ] -N- [ 2-[4-[ 6- ( Dimethylamino ) pyridin -3- yl ] phenyl ]-1,3- benzothiazol -6- yl ] carbamate tertiary butyl ester : 2-[2,6-bis(side oxy )piperidin-3-yl]-5-hydroxyl-isoindole-1,3-dione (67 mg, 0.24 mmol), K 2 CO 3 (51 mg, 0.37 mmol) and N-[2-[4 -[6-(Dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-[2-[2-[2-[2- (2-Iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (100 mg, 0.12 mmol) in DMF (5 mL) The mixture was heated at 50 °C for 5 h. The mixture was quenched with water and extracted with DCM (200 mL). The organic layer was dried over Na 2 SO 4 , concentrated, and purified by silica gel column chromatography (DCM:MeOH=20:1, Rf=0.52) to give N-[2-[2-[ 2-[2-[2-[2-[2-[2,6-bis(side oxy)piperidin-3-yl]-1,3-bis(side oxy)isoindol-5-yl ]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl ]phenyl]-1,3-benzothiazol-6-yl]carbamate (53 mg, 0.05 mmol, 45% yield).

(D) 2-[2,6- 雙 ( 側氧基 ) 哌啶 -3- 基 ]-5-[2-[2-[2-[2-[2-[2-[[2-[4-[6-( 二甲基胺基 ) 吡啶 -3- 基 ] 苯基 ]-1,3- 苯并噻唑 -6- 基 ] 胺基 ] 乙氧基 ] 乙氧基 ] 乙氧基 ] 乙氧基 ] 乙氧基 ] 乙氧基 ] 異吲哚 -1,3- 二酮：向N-[2-[2-[2-[2-[2-[2-[2-[2,6-雙(側氧基)哌啶-3-基]-1,3-雙(側氧基)異吲哚-5-基]氧基乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙基]-N-[2-[4-[6-(二甲胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(52 mg，0.05 mmol)於DCM (5 mL)中之溶液中添加TFA (0.08 mL，1.08 mmol)且在RT下攪拌20 h。將混合物傾入冰水中且用飽和NaHCO 3溶液中和至pH 8。將殘餘物溶解於DCM (20 mL)及水(10 mL)中。有機層用水(10 mL)、鹽水(10 mL)洗滌，經Na 2SO 4乾燥且濃縮至乾燥，得到呈黃色固體狀之2-[2,6-雙(側氧基)哌啶-3-基]-5-[2-[2-[2-[2-[2-[2-[[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]異吲哚-1,3-二酮(化合物159985，41 mg，0.05 mmol，產率83%)。 1H NMR (400 MHz，DMSO-d 6). MS (ESI) m/z 867 (M+H) +。 實例2：化合物160219之合成

Figure 02_image371
(D) 2-[2,6- bis ( side oxy ) piperidin -3- yl ]-5-[2-[2-[2-[2-[2-[2-[2-[[2-[4 -[6-( Dimethylamino ) pyridin - 3- yl ] phenyl ]-1,3- benzothiazol -6- yl ] amino ] ethoxy ] ethoxy ] ethoxy ] ethoxy Base ] ethoxy ] ethoxy ] isoindole -1,3- dione : to N-[2-[2-[2-[2-[2-[2-[2-[2-[2,6- Bis(side oxy)piperidin-3-yl]-1,3-bis(side oxy)isoindol-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy] Ethoxy]ethyl]-N-[2-[4-[6-(Dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate To a solution of tert-butyl ester (52 mg, 0.05 mmol) in DCM (5 mL) was added TFA (0.08 mL, 1.08 mmol) and stirred at RT for 20 h. The mixture was poured into ice water and neutralized to pH 8 with saturated NaHCO 3 solution. The residue was dissolved in DCM (20 mL) and water (10 mL). The organic layer was washed with water (10 mL), brine (10 mL), dried over Na 2 SO 4 and concentrated to dryness to give 2-[2,6-bis(oxo)piperidine-3- Base]-5-[2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]- 1,3-Benzothiazol-6-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]isoindole-1,3-dione ( Compound 159985, 41 mg, 0.05 mmol, 83% yield). 1 H NMR (400 MHz, DMSO-d 6 ). MS (ESI) m/z 867 (M+H) + . Example 2: Synthesis of Compound 160219
Figure 02_image371

(A) 化合物 160087：在0℃下向N-[2-[4-[6-(二甲胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(500 mg，1.12 mmol)於DMF (10 mL)中之溶液中添加NaH (107 mg，4.48 mmol)且在室溫下攪拌1 h。將含4-甲基苯磺酸2-[2-(4-甲基苯基)磺醯基氧基乙氧基]乙酯(1.86 g，4.48 mmol)之DMF (10 mL)添加至反應混合物中且在室溫下攪拌14 h。將混合物冷卻至0℃且用水淬滅。藉由過濾收集沈澱物，用水洗滌且藉由管柱層析(DCM:MeOH=20:1，Rf=0.68)純化，得到呈黃色固體狀之4-甲基苯磺酸2-[2-[[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙酯(595 mg，0.86 mmol，產率77%)。 (A) Compound 160087 : N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl] at 0°C To a solution of tert-butyl carbamate (500 mg, 1.12 mmol) in DMF (10 mL) was added NaH (107 mg, 4.48 mmol) and stirred at room temperature for 1 h. 2-[2-(4-Methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (1.86 g, 4.48 mmol) in DMF (10 mL) was added to the reaction mixture and stirred at room temperature for 14 h. The mixture was cooled to 0 °C and quenched with water. The precipitate was collected by filtration, washed with water and purified by column chromatography (DCM:MeOH=20:1, Rf=0.68) to give 4-methylbenzenesulfonic acid 2-[2-[ [2-[4-[6-(Dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl )oxycarbonyl]amino]ethoxy]ethyl ester (595 mg, 0.86 mmol, 77% yield).

(B) 化合物 160150 ：將4-甲基苯磺酸2-[2-[[2-[4-[6-(二甲胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙酯(595 mg，0.86 mmol)、NaI (156 mg，1.04 mmol)於MeCN (15 mL)中之混合物在80℃下加熱17 h。將殘餘物溶解於DCM (50 mL)及水(50 mL)中。有機層用水(50 mL)、鹽水(50 mL)洗滌，經Na 2SO 4乾燥且濃縮，得到呈黃色固體狀之N-[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]-N-[2-(2-碘基乙氧基)乙基]胺基甲酸三級丁基酯(449 mg，0.70 mmol，產率81%)。 (B) Compound 160150 : 4-methylbenzenesulfonic acid 2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzene Thiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl ester (595 mg, 0.86 mmol), NaI (156 mg, 1.04 mmol) in The mixture in MeCN (15 mL) was heated at 80 °C for 17 h. The residue was dissolved in DCM (50 mL) and water (50 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over Na 2 SO 4 and concentrated to give N-[2-[4-[6-(dimethylamino)pyridine- 3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-(2-iodoethoxy)ethyl]carbamate (449 mg, 0.70 mmol, yield 81%).

(C) 化合物 160159：將2-[2,6-雙(側氧基)哌啶-3-基]-5-羥基-異吲哚-1,3-二酮(96 mg，0.35 mmol)、K 2CO 3(96 mg，0.70 mmol)、N-[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]-N-[2-(2-碘基乙氧基)乙基]胺基甲酸三級丁酯(150 mg，0.23 mmol)於DMF (5 mL)中之混合物在50℃下加熱5 h。將水(10 mL)添加至混合物中且藉由過濾收集所得沈澱物。殘餘物藉由管柱層析(DCM:EtOAc=5:2，Rf=0.32)純化，得到呈黃色固體狀之N-[2-[2-[2-[2,6-雙(側氧基)哌啶-3-基]-1,3-雙(側氧基)異吲哚-5-基]氧基乙氧基]乙基]-N-[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(121 mg，0.15 mmol，產率66%)。 (C) Compound 160159 : 2-[2,6-bis(side oxy)piperidin-3-yl]-5-hydroxyl-isoindole-1,3-dione (96 mg, 0.35 mmol), K 2 CO 3 (96 mg, 0.70 mmol), N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazole-6- A mixture of tert-butyl]-N-[2-(2-iodoethoxy)ethyl]carbamate (150 mg, 0.23 mmol) in DMF (5 mL) was heated at 50°C for 5 h . Water (10 mL) was added to the mixture and the resulting precipitate was collected by filtration. The residue was purified by column chromatography (DCM:EtOAc=5:2, Rf=0.32) to give N-[2-[2-[2-[2,6-bis(oxo) as a yellow solid )piperidin-3-yl]-1,3-bis(side oxy)isoindol-5-yl]oxyethoxy]ethyl]-N-[2-[4-[6-(two Methylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (121 mg, 0.15 mmol, 66% yield).

(D) 化合物 160219：向N-[2-[2-[2-[2,6-雙(側氧基)哌啶-3-基]-1,3-雙(側氧基)異吲哚-5-基]氧基乙氧基]乙基]-N-[2-[4-[6-(二甲胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(120 mg，0.15 mmol)於DCM (5 mL)中之溶液中添加TFA (0.23 mL，3.03 mmol)，且將混合物在室溫下攪拌20 h。將混合物傾入冰水中且用飽和NaHCO 3中和至pH 8。將殘餘物溶解於DCM (20 mL)及水(10 mL)中。有機層用水(10 mL)、鹽水(10 mL)洗滌，經Na 2SO 4乾燥，且濃縮至乾燥，得到呈黃色固體狀之2-[2,6-雙(側氧基)哌啶-3-基]-5-[2-[2-[[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基]乙氧基]乙氧基]異吲哚-1,3-二酮(21 mg，0.03 mmol，產率18%)。 實例3：化合物160939之合成

Figure 02_image373
(D) Compound 160219 : To N-[2-[2-[2-[2,6-bis(side oxy)piperidin-3-yl]-1,3-bis(side oxy)isoindole -5-yl]oxyethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazole- To a solution of ter-butyl 6-yl]carbamate (120 mg, 0.15 mmol) in DCM (5 mL) was added TFA (0.23 mL, 3.03 mmol), and the mixture was stirred at room temperature for 20 h. The mixture was poured into ice water and neutralized to pH 8 with saturated NaHCO 3 . The residue was dissolved in DCM (20 mL) and water (10 mL). The organic layer was washed with water (10 mL), brine (10 mL), dried over Na2SO4 , and concentrated to dryness to give 2-[2,6-bis(oxo)piperidine-3 as a yellow solid -yl]-5-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl ]amino]ethoxy]ethoxy]isoindole-1,3-dione (21 mg, 0.03 mmol, 18% yield). Example 3: Synthesis of Compound 160939
Figure 02_image373

(A) 化合物 160812： 在0℃下向N-[2-[4-[6-(二甲胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(500 mg，1.12 mmol)於DMF (10 mL)中之溶液中添加NaH (107 mg，4.48 mmol)且在RT下攪拌1 h。將含4-甲基苯磺酸2-[2-[2-[2-(4-甲基苯基)磺醯基氧基乙氧基]乙氧基]乙氧基]乙酯(1125 mg，2.24 mmol)之DMF (5 mL)添加至反應混合物中，且在RT下攪拌22 h。將混合物溶解於水(50 mL)及DCM (50 mL)中。有機層用水(50 mL)、鹽水(50 mL)洗滌，經Na 2SO 4乾燥，濃縮且藉由矽膠管柱層析(EtOAc:DCM=1:5，Rf=0.13)純化，得到呈黃色固體狀之4-甲基苯磺酸2-[2-[2-[2-[[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙氧基]乙氧基]乙酯(733 mg，0.94 mmol，產率84%)。 (A) Compound 160812 : N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl] at 0°C To a solution of tert-butyl carbamate (500 mg, 1.12 mmol) in DMF (10 mL) was added NaH (107 mg, 4.48 mmol) and stirred at RT for 1 h. 2-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (1125 mg , 2.24 mmol) of DMF (5 mL) was added to the reaction mixture and stirred at RT for 22 h. The mixture was dissolved in water (50 mL) and DCM (50 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over Na 2 SO 4 , concentrated and purified by silica gel column chromatography (EtOAc:DCM=1:5, Rf=0.13) to give a yellow solid 4-Methylbenzenesulfonic acid 2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3 -Benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethyl ester (733 mg, 0.94 mmol, Yield 84%).

(B) 化合物 160829：將4-甲基苯磺酸2-[2-[2-[2-[[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙氧基]乙氧基]乙酯(333 mg，0.43 mmol)及NaI (109 mg，0.73 mmol)於CH 3CN (10 mL)中之混合物在80℃下加熱15 h。藉由真空移除溶劑且將殘餘物再溶解於EtOAc中。混合物用水(50 mL)、鹽水(50 mL)洗滌，經MgSO 4乾燥且濃縮，得到呈黃色固體狀之N-[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]-N-[2-[2-[2-(2-碘基乙氧基)乙氧基]乙氧基]乙基]胺基甲酸三級丁酯(112 mg，0.15 mmol，產率36%)。 (B) compound 160829 : 4-methylbenzenesulfonic acid 2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl ]-1,3-benzothiazol-6-yl]-[(2-methylprop-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethyl ester (333 mg, 0.43 mmol) and NaI (109 mg, 0.73 mmol) in CH3CN (10 mL) was heated at 80 °C for 15 h. The solvent was removed by vacuum and the residue was redissolved in EtOAc. The mixture was washed with water (50 mL), brine (50 mL), dried over MgSO4 and concentrated to afford N-[2-[4-[6-(dimethylamino)pyridin-3-yl as a yellow solid ]phenyl]-1,3-benzothiazol-6-yl]-N-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethyl]amine Tertiary butyl carbamate (112 mg, 0.15 mmol, 36% yield).

(C) 化合物 160889：將N-[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-3a,7a-二氫-1,3-苯并噻唑-6-基]-N-[2-[2-[2-(2-碘基乙氧基)乙氧基]乙氧基]乙基]胺基甲酸三級丁基酯(112 mg，0.15 mmol)、Cs 2CO 3(149.09 mg，0.46 mmol)及4-羥基苯-1,2-二甲酸二甲酯(64 mg，0.30 mmol)於DMF (2 mL)中之混合物在50℃下攪拌1 h。將混合物冷卻至室溫且添加水。藉由過濾收集沈澱物，且隨後藉由管柱層析(EtOAc:DCM=1:1，Rf=0.33)純化，得到呈黃色固體狀之4-[2-[2-[2-[2-[[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙氧基]乙氧基]乙氧基]苯-1,2-二甲酸二甲基酯(102 mg，0.13 mmol，產率82%)。 (C) Compound 160889 : N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-3a,7a-dihydro-1,3-benzothiazole- 6-yl]-N-[2-[2-[2-(2-Iodoethoxy)ethoxy]ethoxy]ethyl]carbamate (112 mg, 0.15 mmol ), Cs 2 CO 3 (149.09 mg, 0.46 mmol) and dimethyl 4-hydroxybenzene-1,2-dicarboxylate (64 mg, 0.30 mmol) in DMF (2 mL) were stirred at 50°C for 1 h. The mixture was cooled to room temperature and water was added. The precipitate was collected by filtration and then purified by column chromatography (EtOAc:DCM=1:1, Rf=0.33) to give 4-[2-[2-[2-[2- [[2-[4-[6-(Dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylprop-2- yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]benzene-1,2-dicarboxylic acid dimethyl ester (102 mg, 0.13 mmol, 82% yield).

(D) 化合物 160901：向4-[2-[2-[2-[2-[[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙氧基]乙氧基]乙氧基]苯-1,2-二甲酸二甲酯(102 mg，0.13 mmol)於EtOH (2 mL)中之溶液中添加含NaOH (40 mg，1 mmol)之水(2 mL)。將所得混合物在RT下攪拌40 h。將反應物用EtOAc (10 mL)稀釋且用1N HCl溶液酸化至pH 1。有機層用水(10 mL)、鹽水(10 mL)洗滌，經Na 2SO 4乾燥且濃縮至乾燥，得到呈橙色固體狀之4-[2-[2-[2-[2-[[2-[4-[6-(二甲胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基]乙氧基]乙氧基]乙氧基]乙氧基]鄰苯二甲酸(86 mg，0.13 mmol，產率99.9%)。 (D) Compound 160901 : To 4-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1, 3-Benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]benzene-1, To a solution of dimethyl 2-dicarboxylate (102 mg, 0.13 mmol) in EtOH (2 mL) was added NaOH (40 mg, 1 mmol) in water (2 mL). The resulting mixture was stirred at RT for 40 h. The reaction was diluted with EtOAc (10 mL) and acidified to pH 1 with 1N HCl solution. The organic layer was washed with water (10 mL), brine ( 10 mL), dried over Na2SO4 and concentrated to dryness to give 4-[2-[2-[2-[2-[[2- [4-[6-(Dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]ethoxy]ethyl Oxy]phthalic acid (86 mg, 0.13 mmol, 99.9% yield).

(E) 化合物 160939：將4-[2-[2-[2-[2-[[2-[4-[6-(二甲胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基]乙氧基]乙氧基]乙氧基]乙氧基]鄰苯二甲酸(122 mg，0.18 mmol)及3-胺基哌啶-2,6-二酮鹽酸鹽(32 mg，0.20 mmol)於吡啶(5 mL)中之混合物在120℃下加熱19 h。將混合物冷卻至RT，用DCM (100 mL)稀釋且用水(50 mL)及鹽水(50 mL)洗滌。收集有機層，經Na 2SO 4乾燥，濃縮且藉由管柱層析(MeOH：DCM=1:10，Rf=0.73)純化，得到呈黃色固體狀之2-[2,6-雙(側氧基)哌啶-3-基]-5-[2-[2-[2-[2-[[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基]乙氧基]乙氧基]乙氧基]乙氧基]異吲哚-1,3-二酮(49 mg，0.06 mmol，產率35%)。 實例4：化合物161103之合成

Figure 02_image375
Figure 02_image377
Figure 02_image379
(E) Compound 160939 : 4-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3 -Benzothiazol-6-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]phthalic acid (122 mg, 0.18 mmol) and 3-aminopiperidine-2,6 - A mixture of diketone hydrochloride (32 mg, 0.20 mmol) in pyridine (5 mL) was heated at 120 °C for 19 h. The mixture was cooled to RT, diluted with DCM (100 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was collected, dried over Na 2 SO 4 , concentrated and purified by column chromatography (MeOH:DCM=1:10, Rf=0.73) to give 2-[2,6-bis(side) as a yellow solid Oxy)piperidin-3-yl]-5-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl ]-1,3-Benzothiazol-6-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]isoindole-1,3-dione (49 mg, 0.06 mmol, Yield 35%). Example 4: Synthesis of Compound 161103
Figure 02_image375
Figure 02_image377
Figure 02_image379

(A) 化合物 160891：在0℃下向N-[2-[4-[6-(二甲胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(500 mg，1.12 mmol)於DMF (10 mL)中之溶液中添加NaH (107 mg，4.48 mmol)且在RT下攪拌1 h。將含4-甲基苯磺酸5-(4-甲基苯基)磺醯基氧基戊酯(1.85 g，4.48 mmol)之DMF (10 mL)添加至反應混合物中，且在RT下攪拌17 h。將混合物冷卻至0℃且用水淬滅。所得沈澱物藉由過濾收集且藉由管柱層析(DCM:EtOAc=4:1，Rf=0.7)純化，得到呈黃色固體狀之4-甲基苯磺酸5-[[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]-[(2-甲基丙- 2-基)氧基羰基]胺基]戊酯(604 mg，0.88 mmol，產率79%)。 (A) Compound 160891 : N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl] at 0°C To a solution of tert-butyl carbamate (500 mg, 1.12 mmol) in DMF (10 mL) was added NaH (107 mg, 4.48 mmol) and stirred at RT for 1 h. 5-(4-Methylphenyl)sulfonyloxypentyl 4-methylbenzenesulfonate (1.85 g, 4.48 mmol) in DMF (10 mL) was added to the reaction mixture and stirred at RT 17 h. The mixture was cooled to 0 °C and quenched with water. The resulting precipitate was collected by filtration and purified by column chromatography (DCM:EtOAc=4:1, Rf=0.7) to give 4-methylbenzenesulfonic acid 5-[[2-[4 as a yellow solid -[6-(Dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl] Amino]pentyl ester (604 mg, 0.88 mmol, 79% yield).

(B) 化合物 160938：將4-羥基苯-1,2-二甲酸二甲酯(122 mg，0.58 mmol)、Cs 2CO 3(285 mg，0.87 mmol)、KI (5 mg，0.03 mmol)及4-甲基苯磺酸5-[[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]-[(2-甲基丙-2-基)氧基羰基]胺基]戊酯(200 mg，0.29 mmol)於DMF (2 mL)中之混合物在50℃下加熱2 h。將反應物用水淬滅。所得固體藉由過濾收集且用水洗滌，得到呈黃色固體狀之4-[5-[[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]-[(2-甲基丙-2-基)氧基羰基]胺基]戊氧基]苯-1,2-二甲酸二甲酯(206 mg，0.28 mmol，產率98%)。 (B) Compound 160938 : Dimethyl 4-hydroxybenzene-1,2-dicarboxylate (122 mg, 0.58 mmol), Cs 2 CO 3 (285 mg, 0.87 mmol), KI (5 mg, 0.03 mmol) and 4-Methylbenzenesulfonic acid 5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[ A mixture of (2-methylpropan-2-yl)oxycarbonyl]amino]pentyl ester (200 mg, 0.29 mmol) in DMF (2 mL) was heated at 50 °C for 2 h. The reaction was quenched with water. The resulting solid was collected by filtration and washed with water to afford 4-[5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1 as a yellow solid, 3-Benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentyloxy]benzene-1,2-dicarboxylic acid dimethyl ester (206 mg, 0.28 mmol, yield 98%).

(C) 化合物 160999：向4-[5-[[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]-[(2-甲基丙-2-基)氧基羰基]胺基]戊氧基]苯-1,2-二甲酸二甲酯(100 mg，0.14 mmol)於EtOH (2 mL)中之溶液中添加含NaOH (110 mg，2.76 mmol)之水(2 mL)，且在RT下攪拌40 h。用1 N HCl溶液將反應物中和至pH 1。藉由過濾收集沈澱物且用水洗滌，得到呈黃色固體狀之4-[5-[[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]-[(2-甲基丙-2-基)氧基羰基]胺基]戊氧基]鄰苯二甲酸(93 mg，0.13 mmol，產率97%)。 (C) Compound 160999 : To 4-[5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl Dimethyl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentyloxy]benzene-1,2-dicarboxylate (100 mg, 0.14 mmol) in EtOH (2 mL) To a solution of NaOH (110 mg, 2.76 mmol) in water (2 mL) was added and stirred at RT for 40 h. The reaction was neutralized to pH 1 with 1 N HCl solution. The precipitate was collected by filtration and washed with water to afford 4-[5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1 as a yellow solid, 3-Benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentyloxy]phthalic acid (93 mg, 0.13 mmol, 97% yield) .

(D) 化合物 161054：將4-[5-[[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]-[(2-甲基丙-2-基)氧基羰基]胺基]戊氧基]鄰苯二甲酸(93 mg，0.13 mmol)及3-胺基哌啶-2,6-二酮鹽酸鹽(48 mg，0.29 mmol)於吡啶(3 mL)中之混合物在120℃下加熱40 h。接著將水添加至混合物中。藉由過濾收集沈澱物且藉由管柱層析(DCM:EtOAc=4:1，Rf=0.28)純化，得到呈黃色固體狀之N-[5-[2-[2,6-雙(側氧基)哌啶-3-基]-1,3-雙(側氧基)異吲哚-5-基]氧基戊基]-N-[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(61 mg，0.08 mmol，產率58%)。 (D) Compound 161054 : 4-[5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl ]-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentyloxy]phthalic acid (93 mg, 0.13 mmol) and 3-aminopiperidine-2,6-dione A mixture of hydrochloride (48 mg, 0.29 mmol) in pyridine (3 mL) was heated at 120 °C for 40 h. Water was then added to the mixture. The precipitate was collected by filtration and purified by column chromatography (DCM:EtOAc=4:1, Rf=0.28) to give N-[5-[2-[2,6-bis(side Oxy)piperidin-3-yl]-1,3-bis(side oxy)isoindol-5-yl]oxypentyl]-N-[2-[4-[6-(dimethyl Amino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamic acid tert-butyl ester (61 mg, 0.08 mmol, 58% yield).

(E) 化合物 161103：向N-[5-[2-[2,6-雙(側氧基)哌啶-3-基]-1,3-雙(側氧基)異吲哚-5-基]氧基戊基]-N-[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(61 mg，0.08 mmol)於DCM (5 mL)中之溶液中添加TFA (0.12 mL，1.55 mmol)，且在RT下攪拌6 h。將混合物傾入冰水中且用飽和NaHCO 3溶液中和至pH 8。將殘餘物溶解於DCM (20 mL)及水(10 mL)中。有機層用水(10 mL)、鹽水(10 mL)洗滌，經Na 2SO 4乾燥，且濃縮至乾燥，得到呈黃色固體狀之2-[2,6-雙(側氧基)哌啶-3-基]-5-[5-[[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基]戊氧基]異吲哚-1,3-二酮(44 mg，0.06 mmol，產率80%)。 實例5：化合物160273之合成

Figure 02_image381
(E) Compound 161103 : To N-[5-[2-[2,6-bis(side oxy)piperidin-3-yl]-1,3-bis(side oxy)isoindole-5- Base] oxypentyl] -N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino To a solution of tert-butyl formate (61 mg, 0.08 mmol) in DCM (5 mL) was added TFA (0.12 mL, 1.55 mmol) and stirred at RT for 6 h. The mixture was poured into ice water and neutralized to pH 8 with saturated NaHCO 3 solution. The residue was dissolved in DCM (20 mL) and water (10 mL). The organic layer was washed with water (10 mL), brine (10 mL), dried over Na2SO4 , and concentrated to dryness to give 2-[2,6-bis(oxo)piperidine-3 as a yellow solid -yl]-5-[5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino ]pentyloxy]isoindole-1,3-dione (44 mg, 0.06 mmol, 80% yield). Example 5: Synthesis of Compound 160273
Figure 02_image381

(A) 化合物 160210：將3-(6-羥基-3-側氧基-1H-異吲哚-2-基)哌啶-2,6-二酮(95 mg，0.37 mmol)、K 2CO 3(101 mg，0.73 mmol)、N-[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑- 6-基]-N-[2-[2-[2-[2-[2-(2-碘基乙氧基)乙氧基]乙氧基]乙氧基]乙氧基]乙基]胺基甲酸三級丁酯(200 mg，0.24 mmol)於DMF (5 mL)中之混合物在50℃下加熱5 h。混合物用水淬滅且用DCM (200 mL)萃取。收集有機層，經Na 2SO 4乾燥，濃縮且藉由管柱層析(DCM:MeOH=20:1，Rf=0.48)純化，得到呈淡黃色固體狀之N-[2-[2-[2-[2-[2-[2-[[2-[2,6-雙(側氧基)哌啶-3-基]-1-側氧基-3H-異吲哚-5-基]-氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙基]-N-[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(83 mg，0.09 mmol，產率36%)。 (A) Compound 160210 : 3-(6-hydroxy-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione (95 mg, 0.37 mmol), K 2 CO 3 (101 mg, 0.73 mmol), N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]- N-[2-[2-[2-[2-[2-(2-Iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate A mixture of butyl ester (200 mg, 0.24 mmol) in DMF (5 mL) was heated at 50 °C for 5 h. The mixture was quenched with water and extracted with DCM (200 mL). The organic layer was collected, dried over Na 2 SO 4 , concentrated and purified by column chromatography (DCM:MeOH=20:1, Rf=0.48) to give N-[2-[2-[ 2-[2-[2-[2-[[2-[2,6-bis(oxo)piperidin-3-yl]-1-oxo-3H-isoindol-5-yl] -Oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridine-3- yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (83 mg, 0.09 mmol, yield 36%).

(B) 化合物 160273：向N-[2-[2-[2-[2-[2-[2-[[2-[2,6-雙(側氧基)哌啶-3-基]-1-側氧基-3H-異吲哚-5-基]氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]-乙基]-N-[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(83 mg，0.09 mmol)於DCM (5 mL)中之溶液中添加TFA (0.13 mL，1.74 mmol)，且在RT下攪拌7 h。將混合物傾入冰水中且用飽和NaHCO 3溶液中和至pH 8。將殘餘物溶解於DCM (20 mL)及水(10 mL)中。有機層用水(10 mL)、鹽水(10 mL)洗滌，經Na 2SO 4乾燥且濃縮至乾燥，得到呈黃色固體狀之3-[6-[2-[2-[2-[2-[2-[2-[[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]-3-側氧基-1H-異吲哚-2-基]哌啶-2,6-二酮(73 mg，0.08 mmol，產率92%)。 實例6：化合物160313之合成

Figure 02_image383
(B) Compound 160273 : To N-[2-[2-[2-[2-[2-[2-[[2-[2,6-bis(side oxy)piperidin-3-yl]- 1-oxo-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-ethyl]-N-[2-[ tertiary-butyl 4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (83 mg, 0.09 mmol) in DCM To the solution in (5 mL) was added TFA (0.13 mL, 1.74 mmol) and stirred at RT for 7 h. The mixture was poured into ice water and neutralized to pH 8 with saturated NaHCO 3 solution. The residue was dissolved in DCM (20 mL) and water (10 mL). The organic layer was washed with water (10 mL), brine (10 mL), dried over Na 2 SO 4 and concentrated to dryness to give 3-[6-[2-[2-[2-[2-[ 2-[2-[[2-[4-[6-(Dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy ]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione (73 mg , 0.08 mmol, yield 92%). Example 6: Synthesis of Compound 160313
Figure 02_image383

(A) 化合物 160284：將3-(6-羥基-3-側氧基-1H-異吲哚-2-基)哌啶-2,6-二酮(58 mg，0.22 mmol)、K 2CO 3(61 mg，0.44 mmol)、N-[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]-N-[2-(2-碘基乙氧基)乙基]胺基甲酸三級丁酯(95 mg，0.15 mmol)於DMF (2 mL)中之混合物在50℃下加熱5 h。將水(10 mL)添加至混合物中。所得沈澱物藉由過濾收集且接著藉由管柱層析(DCM:MeOH=20:1，Rf=0.52)純化，得到呈黃色固體狀之N-[2-[2-[[2-[2,6-雙(側氧基)哌啶-3-基]-1-側氧基-3H-異吲哚-5-基]氧基]乙氧基]-乙基]-N-[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(57 mg，0.07 mmol，產率50%)。 (A) Compound 160284 : 3-(6-hydroxy-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione (58 mg, 0.22 mmol), K 2 CO 3 (61 mg, 0.44 mmol), N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]- A mixture of ter-butyl N-[2-(2-iodoethoxy)ethyl]carbamate (95 mg, 0.15 mmol) in DMF (2 mL) was heated at 50 °C for 5 h. Water (10 mL) was added to the mixture. The resulting precipitate was collected by filtration and then purified by column chromatography (DCM:MeOH=20:1, Rf=0.52) to give N-[2-[2-[[2-[2 ,6-bis(side oxy)piperidin-3-yl]-1-side oxy-3H-isoindol-5-yl]oxy]ethoxy]-ethyl]-N-[2- [4-[6-(Dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (57 mg, 0.07 mmol, yield rate 50%).

(B) 化合物 160313：向N-[2-[2-[[2-[2,6-雙(側氧基)哌啶-3-基]-1-側氧基-3H-異吲哚-5-基]氧基]乙氧基]乙基]-N-[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(54 mg，0.07 mmol)於DCM (5 mL)中之溶液中添加TFA (0.11 mL，1.39 mmol)，且將混合物在室溫下攪拌20 h。將混合物傾入冰水中且用飽和NaHCO 3溶液中和至pH 8。將殘餘物溶解於DCM (20 mL)及水(10 mL)中。有機層用水(10 mL)、鹽水(10 mL)洗滌，經Na 2SO 4乾燥且濃縮至乾燥，得到呈黃色固體狀之3-[6-[2-[2-[[2-[4-[6-(二甲胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基]乙氧基]乙氧基]-3-側氧基-1H-異吲哚-2-基]哌啶-2,6-二酮(39 mg，0.05 mmol，產率77%)。 實例7：化合物162640之合成

Figure 02_image385
(B) Compound 160313 : To N-[2-[2-[[2-[2,6-bis(side oxy)piperidin-3-yl]-1-side oxy-3H-isoindole- 5-yl]oxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazole To a solution of ter-butyl-6-yl]carbamate (54 mg, 0.07 mmol) in DCM (5 mL) was added TFA (0.11 mL, 1.39 mmol), and the mixture was stirred at room temperature for 20 h. The mixture was poured into ice water and neutralized to pH 8 with saturated NaHCO 3 solution. The residue was dissolved in DCM (20 mL) and water (10 mL). The organic layer was washed with water (10 mL), brine ( 10 mL), dried over Na2SO4 and concentrated to dryness to give 3-[6-[2-[2-[[2-[4- [6-(Dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]-3-oxo-1H -Isoindol-2-yl]piperidine-2,6-dione (39 mg, 0.05 mmol, 77% yield). Example 7: Synthesis of Compound 162640
Figure 02_image385

化合物162640係根據類似於實例6之方法合成。Compound 162640 was synthesized according to a method similar to Example 6.

1H NMR (600 MHz，DMSO-d6) δ 10.97 (s，1H)，8.36 (s，1H)，8.24 (d， J= 2.3 Hz，1H)，8.01-8.05 (m，4H)，7.72 (d， J= 8.4 Hz，2H)，7.62 (d， J= 8.4 Hz，1H)，7.52 (d， J= 9.7 Hz，1H)，7.17 (d， J= 1.7 Hz，1H)，7.05-7.09 (m，2H)，6.81-6.85 (m，2H)，6.61 (t， J= 5.8 Hz，1H)，5.07 (dd， J= 13.2，5.1 Hz，1H)，4.36 (d， J= 17.2 Hz，1H)，4.19-4.27 (m，4H)，3.79-3.85 (m，7H)，3.66 (t， J= 5.8 Hz，3H)，3.48-3.54 (m，3H)，2.85-2.93 (m，1H)，1.92-1.99 (m，1H)。 實例8：化合物162842之合成

Figure 02_image387
1 H NMR (600 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.36 (s, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.01-8.05 (m, 4H), 7.72 (d , J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 9.7 Hz, 1H), 7.17 (d, J = 1.7 Hz, 1H), 7.05-7.09 (m , 2H), 6.81-6.85 (m, 2H), 6.61 (t, J = 5.8 Hz, 1H), 5.07 (dd, J = 13.2, 5.1 Hz, 1H), 4.36 (d, J = 17.2 Hz, 1H) , 4.19-4.27 (m, 4H), 3.79-3.85 (m, 7H), 3.66 (t, J = 5.8 Hz, 3H), 3.48-3.54 (m, 3H), 2.85-2.93 (m, 1H), 1.92 -1.99 (m, 1H). Example 8: Synthesis of Compound 162842
Figure 02_image387

化合物162842係根據類似於實例6之方法合成。Compound 162842 was synthesized according to a method similar to Example 6.

1H NMR (600 MHz，DMSO-d6) δ 10.96 (s，1H)，8.50 (d， J= 2.5 Hz，1H)，8.40 (s，1H)，8.13 (d， J= 6.6 Hz，1H)，7.99 (d， J= 8.2 Hz，2H)，7.89 (dd， J= 8.9，2.5 Hz，1H)，7.68 (d， J= 8.2 Hz，2H)，7.60 (d， J= 8.4 Hz，1H)，7.19 (s，1H)，7.08 (d， J= 8.4 Hz，1H)，6.79 (t， J= 7.4 Hz，1H)，6.75 (d， J= 8.9 Hz，1H)，6.70 (d， J= 7.4 Hz，1H)，5.06 (dd， J= 13.2，5.1 Hz，1H)，4.35-4.38 (m，2H)，4.32 (d， J= 17.2 Hz，1H)，4.28 (dd， J= 8.2，4.5 Hz，2H)，4.20 (d， J= 17.2 Hz，1H)，3.96-3.99 (m，2H)，3.92-3.95 (m，2H)，3.08 (s，7H)，2.85-2.93 (m，1H)，2.26-2.37 (m，2H)，1.91-1.98 (m，2H)。 實例9：化合物162903之合成

Figure 02_image389
1 H NMR (600 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.50 (d, J = 2.5 Hz, 1H), 8.40 (s, 1H), 8.13 (d, J = 6.6 Hz, 1H), 7.99 (d, J = 8.2 Hz, 2H), 7.89 (dd, J = 8.9, 2.5 Hz, 1H), 7.68 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.19 (s, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.79 (t, J = 7.4 Hz, 1H), 6.75 (d, J = 8.9 Hz, 1H), 6.70 (d, J = 7.4 Hz, 1H), 5.06 (dd, J = 13.2, 5.1 Hz, 1H), 4.35-4.38 (m, 2H), 4.32 (d, J = 17.2 Hz, 1H), 4.28 (dd, J = 8.2, 4.5 Hz , 2H), 4.20 (d, J = 17.2 Hz, 1H), 3.96-3.99 (m, 2H), 3.92-3.95 (m, 2H), 3.08 (s, 7H), 2.85-2.93 (m, 1H), 2.26-2.37 (m, 2H), 1.91-1.98 (m, 2H). Example 9: Synthesis of Compound 162903
Figure 02_image389

化合物162903係根據類似於實例6之方法合成。Compound 162903 was synthesized according to a method similar to Example 6.

1H NMR (600 MHz，DMS-d6) δ 10.97 (s，1H)，8.63 (d， J= 2.4 Hz，1H)，8.12 (s，1H)，8.08 (d， J= 8.0 Hz，1H)，8.03 (dd， J= 8.9，2.6 Hz，1H)，7.99 (d， J= 8.9 Hz，1H)，7.87 (d， J= 8.0 Hz，1H)，7.78 (d， J= 2.4 Hz，1H)，7.63 (d， J= 8.4 Hz，1H)，7.18-7.21 (m，1H)，7.08 (dd， J= 8.4，2.4 Hz，1H)，6.79 (d， J= 8.8 Hz，1H)，5.08 (dd， J= 13.4，5.1 Hz，1H)，4.38 (d， J= 17.2 Hz，1H)，4.22-4.29 (m，4H)，3.89 (dd， J= 9.2，5.0 Hz，3H)，3.11 (s，3H)，2.56-2.63 (m，1H)，2.33-2.40 (m，1H)。 實例10：化合物163123之合成

Figure 02_image391
1 H NMR (600 MHz, DMS-d6) δ 10.97 (s, 1H), 8.63 (d, J = 2.4 Hz, 1H), 8.12 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 8.03 (dd, J = 8.9, 2.6 Hz, 1H), 7.99 (d, J = 8.9 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.18-7.21 (m, 1H), 7.08 (dd, J = 8.4, 2.4 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 5.08 (dd , J = 13.4, 5.1 Hz, 1H), 4.38 (d, J = 17.2 Hz, 1H), 4.22-4.29 (m, 4H), 3.89 (dd, J = 9.2, 5.0 Hz, 3H), 3.11 (s, 3H), 2.56-2.63 (m, 1H), 2.33-2.40 (m, 1H). Example 10: Synthesis of Compound 163123
Figure 02_image391

化合物163123係根據類似於實例6之方法合成。Compound 163123 was synthesized according to a method similar to Example 6.

1H NMR (600 MHz，DMSO-d6) δ 10.97 (s，1H)，8.56 (d， J= 2.5 Hz，1H)，8.06 (d， J= 8.4 Hz，2H)，7.92-7.96 (m，2H)，7.82 (d， J= 8.4 Hz，2H)，7.74 (d， J= 2.5 Hz，1H)，7.62 (d， J= 8.4 Hz，1H)，7.13-7.18 (m，2H)，7.07 (dd， J= 8.4，2.1 Hz，1H)，6.77 (d， J= 9.0 Hz，1H)，5.07 (dd， J= 13.4，5.2 Hz，1H)，4.35 (d， J= 17.1 Hz，1H)，4.22-4.27 (m，6H)，3.85-3.91 (m，5H)，3.10 (s，7H)，2.85-2.96 (m，1H)，2.55-2.63 (m，2H)，2.31-2.42 (m，2H)。 實例11：化合物163365之合成

Figure 02_image393
1 H NMR (600 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.56 (d, J = 2.5 Hz, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.92-7.96 (m, 2H ), 7.82 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 2.5 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.13-7.18 (m, 2H), 7.07 (dd , J = 8.4, 2.1 Hz, 1H), 6.77 (d, J = 9.0 Hz, 1H), 5.07 (dd, J = 13.4, 5.2 Hz, 1H), 4.35 (d, J = 17.1 Hz, 1H), 4.22 -4.27 (m, 6H), 3.85-3.91 (m, 5H), 3.10 (s, 7H), 2.85-2.96 (m, 1H), 2.55-2.63 (m, 2H), 2.31-2.42 (m, 2H) . Example 11: Synthesis of Compound 163365
Figure 02_image393

化合物163365係根據類似於實例6之方法合成。Compound 163365 was synthesized according to a method similar to Example 6.

1H NMR (600 MHz，DMSO-d6) δ 10.96 (s，1H)，8.57 (d， J= 2.5 Hz，1H)，8.16 (d， J= 8.4 Hz，2H)，8.09 (s，1H)，7.96 (dd， J= 8.9，2.4 Hz，1H)，7.86 (d， J= 8.4 Hz，2H)，7.68 (d， J= 8.7 Hz，1H)，7.62 (d， J= 8.4 Hz，1H)，7.45 (d， J= 2.1 Hz，1H)，7.18 (s，1H)，7.08 (d， J= 8.3 Hz，1H)，7.02 (dd， J= 8.7，2.2 Hz，1H)，6.77 (d， J= 8.9 Hz，1H)，5.07 (dd， J= 13.3，5.2 Hz，1H)，4.36 (d， J= 17.2 Hz，1H)，4.22-4.28 (m，5H)，3.86-3.91 (m，3H)，3.10 (s，5H)，2.84-2.94 (m，2H)。 實例12：化合物161247之合成

Figure 02_image395
1 H NMR (600 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.57 (d, J = 2.5 Hz, 1H), 8.16 (d, J = 8.4 Hz, 2H), 8.09 (s, 1H), 7.96 (dd, J = 8.9, 2.4 Hz, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.7 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 2.1 Hz, 1H), 7.18 (s, 1H), 7.08 (d, J = 8.3 Hz, 1H), 7.02 (dd, J = 8.7, 2.2 Hz, 1H), 6.77 (d, J = 8.9 Hz, 1H), 5.07 (dd, J = 13.3, 5.2 Hz, 1H), 4.36 (d, J = 17.2 Hz, 1H), 4.22-4.28 (m, 5H), 3.86-3.91 (m, 3H) , 3.10 (s, 5H), 2.84-2.94 (m, 2H). Example 12: Synthesis of Compound 161247
Figure 02_image395

(A) 化合物 161084：在0℃下向N-[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(200 mg，0.45 mmol)於DMF (3 mL)中之溶液中添加NaH (32 mg，1.34 mmol)。將所得混合物在RT下攪拌1 h。將4-甲基苯磺酸2-[2-[2-[2-[2-[三級丁基(二甲基)矽基]氧基乙氧基]乙氧基]乙氧基]乙氧基]乙酯(454 mg，0.90 mmol)添加至反應混合物中且在RT下攪拌22 h。混合物用水淬滅。藉由過濾收集沈澱物且藉由管柱層析(EtOAC:DCM=2:3，Rf=0.48)純化，得到呈黃色固體狀之N-[2-[2-[2-[2-[2-[三級丁基(二甲基)矽基]氧基乙氧基]乙氧基]乙氧基]乙氧基]乙基]-N-[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(235 mg，0.30 mmol，產率67%)。 (A) Compound 161084 : N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl at 0°C ] To a solution of tert-butyl carbamate (200 mg, 0.45 mmol) in DMF (3 mL) was added NaH (32 mg, 1.34 mmol). The resulting mixture was stirred at RT for 1 h. 2-[2-[2-[2-[2-[tertiary butyl(dimethyl)silyl]oxyethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonic acid Oxy]ethyl ester (454 mg, 0.90 mmol) was added to the reaction mixture and stirred at RT for 22 h. The mixture was quenched with water. The precipitate was collected by filtration and purified by column chromatography (EtOAC:DCM=2:3, Rf=0.48) to give N-[2-[2-[2-[2-[2 as a yellow solid -[tertiary butyl(dimethyl)silyl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethyl ylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (235 mg, 0.30 mmol, yield 67%).

(B) 化合物 161112：向N-[2-[2-[2-[2-[2-[三級丁基-(二甲基)矽基]氧基乙氧基]乙氧基]乙氧基]乙氧基]乙基]-N-[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(235 mg，0.30 mmol)於THF (5 mL)中之溶液中逐滴添加1 M TBAF於THF中的溶液(1.81 mL，1.81 mmol)。將反應混合物在RT下攪拌7 h。將反應混合物濃縮至乾燥且將殘餘物溶解於EtOAc (100 mL)中。混合物用水(100 mL)及鹽水(100 mL)洗滌。收集有機層，經Na 2SO 4乾燥且濃縮，得到呈黃色固體狀之N-[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]-N-[2-[2-[2-[2-(2-羥基乙基氧基)乙氧基]乙氧基]乙氧基]乙基]胺基甲酸三級丁酯(200 mg，0.30 mmol，產率99.7%)。 (B) Compound 161112 : To N-[2-[2-[2-[2-[2-[tertiary butyl-(dimethyl)silyl]oxyethoxy]ethoxy]ethoxy base] ethoxy] ethyl] -N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl] To a solution of tert-butyl carbamate (235 mg, 0.30 mmol) in THF (5 mL) was added dropwise a solution of 1 M TBAF in THF (1.81 mL, 1.81 mmol). The reaction mixture was stirred at RT for 7 h. The reaction mixture was concentrated to dryness and the residue was dissolved in EtOAc (100 mL). The mixture was washed with water (100 mL) and brine (100 mL). The organic layer was collected, dried over Na2SO4 and concentrated to give N-[2-[4-[6-(dimethylamino)pyridin-3 - yl]phenyl]-1,3 as a yellow solid -Benzothiazol-6-yl]-N-[2-[2-[2-[2-(2-Hydroxyethyloxy)ethoxy]ethoxy]ethoxy]ethyl]amino Tertiary butyl formate (200 mg, 0.30 mmol, 99.7% yield).

(C) 化合物 161181：在0℃下向N-[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]-N-[2-[2-[2-[2-(2-羥基乙基氧基)乙氧基]乙氧基]乙氧基]乙基]胺基甲酸三級丁酯(120 mg，0.18 mmol)於THF (3 mL)中之溶液中添加NaH (9 mg，0.36 mmol)且攪拌30 min。接著添加2-溴乙酸三級丁酯(0.08 mL，0.54 mmol)且將混合物在50℃下加熱8 h。藉由真空移除溶劑。殘餘物藉由管柱層析(EtOAc:DCM=2:3，Rf=0.35)純化，得到呈黃色固體狀之2-[2-[2-[2-[2-[2-[[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙酸三級丁酯(84 mg，0.11 mmol，產率60%)。 (C) Compound 161181 : N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl at 0°C tertiary butyl]-N-[2-[2-[2-[2-(2-hydroxyethyloxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate (120 mg , 0.18 mmol) in THF (3 mL) was added NaH (9 mg, 0.36 mmol) and stirred for 30 min. Then tert-butyl 2-bromoacetate (0.08 mL, 0.54 mmol) was added and the mixture was heated at 50 °C for 8 h. Solvent was removed by vacuum. The residue was purified by column chromatography (EtOAc:DCM=2:3, Rf=0.35) to give 2-[2-[2-[2-[2-[2-[[2- [4-[6-(Dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxy Carbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetate tert-butyl ester (84 mg, 0.11 mmol, 60% yield).

(D) 化合物 161218：將2-[2-[2-[2-[2-[2-[[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙酸三級丁酯(84 mg，0.11 mmol)及TFA (0.12 mL，1.61 mmol)於DCM (2 mL)中之混合物在RT下攪拌23 h。用1 N HCl溶液將混合物酸化至pH 1。混合物用DCM萃取。有機層用鹽水洗滌，經Na 2SO 4乾燥且濃縮至乾燥，得到呈黃色固體狀之2-[2-[2-[2-[2-[2-[[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙酸(60 mg，0.10 mmol，產率89%)。 (D) Compound 161218 : 2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl] -1,3-Benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethyl A mixture of tert-butyloxy]acetate (84 mg, 0.11 mmol) and TFA (0.12 mL, 1.61 mmol) in DCM (2 mL) was stirred at RT for 23 h. The mixture was acidified to pH 1 with 1 N HCl solution. The mixture was extracted with DCM. The organic layer was washed with brine, dried over Na2SO4 and concentrated to dryness to give 2-[2-[2-[2-[2-[2-[[2-[4-[6- (Dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy base] acetic acid (60 mg, 0.10 mmol, 89% yield).

(E) 化合物 161247：將(2S,4R)-1-[(2S)-2-胺基-3,3-二甲基-丁醯基]-N-[[4-(4-甲基-1,3-噻唑-5-基)苯基]甲基]-4-羥基-吡咯啶-2-甲醯胺(45 mg，0.11 mmol)、2-[2-[2-[2-[2-[2-[[2-[4-[6-(二甲胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙酸(60 mg，0.10 mmol)、DIPEA (0.03 mL，0.14 mmol)及HATU (73 mg，0.19 mmol)於無水DMF (3 mL)中之混合物在RT下攪拌18 h。混合物用DCM稀釋，用水及鹽水洗滌，經Na 2SO 4乾燥，濃縮且藉由NH矽膠管柱層析(MeOH:DCM=97:3，Rf=0.48)純化，得到呈黃色固體狀之外消旋-(2R,4S)-N-[[4-(4-甲基-1,3-噻唑-5-基)苯基]甲基]-4-羥基-1-[外消旋-(2R)-2-[2-[2-[2-[2-[2-[2-[[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙醯基胺基]-3,3-二甲基-丁醯基]吡咯啶-2-甲醯胺(16 mg，0.01 mmol，產率14%)。 實例13：化合物160275之合成

Figure 02_image397
Figure 02_image399
(E) Compound 161247 : (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butyryl]-N-[[4-(4-methyl-1, 3-thiazol-5-yl)phenyl]methyl]-4-hydroxy-pyrrolidine-2-carboxamide (45 mg, 0.11 mmol), 2-[2-[2-[2-[2-[ 2-[[2-[4-[6-(Dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy A mixture of ]ethoxy]ethoxy]ethoxy]acetic acid (60 mg, 0.10 mmol), DIPEA (0.03 mL, 0.14 mmol) and HATU (73 mg, 0.19 mmol) in anhydrous DMF (3 mL) was Stir at RT for 18 h. The mixture was diluted with DCM, washed with water and brine, dried over Na 2 SO 4 , concentrated and purified by NH silica gel column chromatography (MeOH:DCM = 97:3, Rf = 0.48) to give thioxan as yellow solid. Cyclo-(2R,4S)-N-[[4-(4-Methyl-1,3-thiazol-5-yl)phenyl]methyl]-4-hydroxyl-1-[rac-(2R )-2-[2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1 ,3-Benzothiazol-6-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetylamino]-3,3-dimethyl-butyryl ] Pyrrolidine-2-carboxamide (16 mg, 0.01 mmol, 14% yield). Example 13: Synthesis of Compound 160275
Figure 02_image397
Figure 02_image399

(A) 化合物 160161：在0℃下向NaH (81 mg，2.02 mmol)於DMF (1 mL)中之溶液中添加N-[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]胺基甲酸三級丁酯(300 mg，0.67 mmol)於DMF (6 mL)中之溶液，且在25℃下攪拌30 min。將4-甲基苯磺酸2-[2-[2-[2-[2-[2-(4-甲基苯基)磺醯基氧基乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙酯(794 mg，1.34 mmol)於DMF (3 mL)中之溶液添加至反應混合物中且在50℃下加熱2 h。混合物用飽和NH 4Cl溶液淬滅且用DCM萃取。有機層用鹽水洗滌，經MgSO 4乾燥，濃縮且藉由管柱層析(MeOH:DCM=3:97，Rf=0.3)純化，得到呈黃色油狀之4-甲基苯磺酸2-[2-[2-[2-[2-[2-[[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙酯(273 mg，0.32 mmol，產率47%)。 (A) Compound 160161 : To a solution of NaH (81 mg, 2.02 mmol) in DMF (1 mL) was added N-[5-[4-[6-(dimethylamino)-1 at 0°C , A solution of 3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate (300 mg, 0.67 mmol) in DMF (6 mL) was stirred at 25°C 30 min. 4-methylbenzenesulfonic acid 2-[2-[2-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy] A solution of ethoxy]ethoxy]ethyl ester (794 mg, 1.34 mmol) in DMF (3 mL) was added to the reaction mixture and heated at 50 °C for 2 h. The mixture was quenched with saturated NH4Cl solution and extracted with DCM. The organic layer was washed with brine, dried over MgSO 4 , concentrated and purified by column chromatography (MeOH:DCM=3:97, Rf=0.3) to give 4-methylbenzenesulfonic acid 2-[ 2-[2-[2-[2-[2-[[5-[4-[6-(Dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridine-2 -yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl ester (273 mg, 0.32 mmol, yield 47%).

(B) 化合物 160244：將4-甲基苯磺酸2-[2-[2-[2-[2-[2-[[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙酯(270 mg，0.31 mmol)及NaI (56.18 mg，0.37 mmol)於CH 3CN (5 mL)中之混合物在80℃下加熱19 h。混合物用DCM稀釋且用水(50 mL)及鹽水(50 mL)萃取。有機層經MgSO4乾燥且濃縮至乾燥，得到呈橙色油狀之N-[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]-N-[2-[2-[2-[2-[2-(2-碘基乙氧基)乙氧基]乙氧基]乙氧基]乙氧基]乙基]胺基甲酸三級丁酯(256 mg，0.31 mmol，產率99.9%)。 (B) Compound 160244 : 2-[2-[2-[2-[2-[2-[2-[[[5-[4-[6-(dimethylamino)-1 ,3-Benzothiazol-2-yl]phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy A mixture of ethoxy]ethoxy]ethyl ester (270 mg, 0.31 mmol) and NaI (56.18 mg, 0.37 mmol) in CH3CN (5 mL) was heated at 80 °C for 19 h. The mixture was diluted with DCM and extracted with water (50 mL) and brine (50 mL). The organic layer was dried over MgSO4 and concentrated to dryness to give N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl] as an orange oil Pyridin-2-yl]-N-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy Base] tertiary butyl carbamate (256 mg, 0.31 mmol, yield 99.9%).

(C) 化合物 160252：將2-[2,6-雙(側氧基)哌啶-3-基]-5-羥基-異吲哚-1,3-二酮(102 mg，0.37 mmol)、K 2CO 3(77 mg，0.56 mmol)及N-[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]-N-[2-[2-[2-[2-[2-(2-碘基乙氧基)乙氧基]乙氧基]乙氧基]乙氧基]乙基]胺基甲酸三級丁酯(153 mg，0.19 mmol)於DMF (4 mL)中之混合物在50℃下加熱18 h。混合物用DCM (200 mL)稀釋且用水萃取。收集有機層，經MgSO4乾燥，濃縮且藉由管柱層析(MeOH:DCM=5:95，Rf=0.3)純化，得到呈黃色固體狀之N-[2-[2-[2-[2-[2-[2-[2-[2,6-雙(側氧基)哌啶-3-基]-1,3-雙(側氧基)異吲哚-5-基]氧基乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙基]-N-[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]胺基甲酸三級丁酯(61 mg，0.06 mmol，產率34%)。 (C) Compound 160252 : 2-[2,6-bis(side oxy)piperidin-3-yl]-5-hydroxyl-isoindole-1,3-dione (102 mg, 0.37 mmol), K 2 CO 3 (77 mg, 0.56 mmol) and N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridine-2- Base]-N-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]amino A mixture of tert-butyl formate (153 mg, 0.19 mmol) in DMF (4 mL) was heated at 50 °C for 18 h. The mixture was diluted with DCM (200 mL) and extracted with water. The organic layer was collected, dried over MgSO4, concentrated and purified by column chromatography (MeOH:DCM=5:95, Rf=0.3) to give N-[2-[2-[2-[2 as a yellow solid -[2-[2-[2-[2,6-bis(side oxy)piperidin-3-yl]-1,3-bis(side oxy)isoindol-5-yl]oxyethyl Oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazole- tert-butyl 2-yl]phenyl]pyridin-2-yl]carbamate (61 mg, 0.06 mmol, 34% yield).

(D) 化合物 160275：在0℃下向N-[2-[2-[2-[2-[2-[2-[2-[2,6-雙(側氧基)哌啶-3-基]-1,3-雙(側氧基)異吲哚-5-基]氧基乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙基]-N-[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]胺基甲酸三級丁酯(61 mg，0.06 mmol)於DCM (1 mL)中之溶液中添加TFA (0.5 mL，6.53 mmol)。將所得混合物在RT下攪拌5 h。溶液在0℃下用飽和NaHCO 3溶液中和且用DCM萃取。有機層用鹽水洗滌，經MgSO 4乾燥，濃縮且藉由NH矽膠管柱層析(MeOH:DCM=99:1，Rf=0.3)純化，得到呈黃色固體狀之2-[2,6-雙(側氧基)哌啶-3-基]-5-[2-[2-[2-[2-[2-[2-[[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]胺基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]異吲哚-1,3-二酮(51 mg，0.05 mmol，產率86%)。 實例14：化合物161177之合成

Figure 02_image401
(D) Compound 160275 : N-[2-[2-[2-[2-[2-[2-[2-[2,6-bis(side oxy))piperidine-3- Base]-1,3-bis(side oxy)isoindol-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[ tertiary-butyl 5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate (61 mg, 0.06 mmol ) in DCM (1 mL) was added TFA (0.5 mL, 6.53 mmol). The resulting mixture was stirred at RT for 5 h. The solution was neutralized with saturated NaHCO 3 solution at 0 °C and extracted with DCM. The organic layer was washed with brine, dried over MgSO 4 , concentrated and purified by NH silica gel column chromatography (MeOH:DCM=99:1, Rf=0.3) to give 2-[2,6-bis (Oxy)piperidin-3-yl]-5-[2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino) -1,3-Benzothiazol-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]iso Indole-1,3-dione (51 mg, 0.05 mmol, 86% yield). Example 14: Synthesis of Compound 161177
Figure 02_image401

(A) 化合物 161026：將4-羥基鄰苯二甲酸二甲酯(139 mg，0.62 mmol)、Cs 2CO 3(303 mg，0.93 mmol)、N-[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]-N-[2-(2-碘基乙氧基)乙基]胺基甲酸三級丁酯(200 mg，0.31 mmol)於DMF (5 mL)中之混合物在50℃下加熱1 h。混合物用水淬滅且用DCM萃取。有機層經MgSO 4乾燥，濃縮且藉由管柱層析(EtOAc:Hex=1:1，Rf=0.4)純化，得到呈黃色固體狀之4-[2-[2-[[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙氧基]苯-1,2-二甲酸二甲酯(148 mg，0.20 mmol，產率66%)。 (A) Compound 161026 : Dimethyl 4-hydroxyphthalate (139 mg, 0.62 mmol), Cs 2 CO 3 (303 mg, 0.93 mmol), N-[5-[4-[6-(di Methylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-N-[2-(2-iodoethoxy)ethyl]carbamate A mixture of butyl ester (200 mg, 0.31 mmol) in DMF (5 mL) was heated at 50 °C for 1 h. The mixture was quenched with water and extracted with DCM. The organic layer was dried over MgSO 4 , concentrated and purified by column chromatography (EtOAc:Hex=1:1, Rf=0.4) to give 4-[2-[2-[[5-[4 as a yellow solid -[6-(Dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl] Dimethyl amino]ethoxy]ethoxy]benzene-1,2-dicarboxylate (148 mg, 0.20 mmol, 66% yield).

(B) 化合物 161083：向4-[2-[2-[[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙氧基]苯-1,2-二甲酸二甲酯(148 mg，0.20 mmol)於MeOH (1 mL)及水(1 mL)中之溶液中添加LiOH (39 mg，1.63 mmol)。將反應混合物在RT下攪拌5天。用1 N HCl將溶液酸化至pH 4至5。所得沈澱物藉由過濾收集，用水洗滌且經真空乾燥，得到呈黃色固體狀之4-[2-[2-[[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙氧基]鄰苯二甲酸(119 mg，0.17 mmol，產率84%)。 (B) Compound 161083 : To 4-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridine- 2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]benzene-1,2-dicarboxylic acid dimethyl ester (148 mg, 0.20 mmol) To a solution in MeOH (1 mL) and water (1 mL) was added LiOH (39 mg, 1.63 mmol). The reaction mixture was stirred at RT for 5 days. The solution was acidified to pH 4-5 with 1 N HCl. The resulting precipitate was collected by filtration, washed with water and dried in vacuo to afford 4-[2-[2-[[5-[4-[6-(dimethylamino)-1,3) as a yellow solid -Benzothiazol-2-yl]phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]phthalic acid (119 mg, 0.17 mmol, 84% yield).

(C) 化合物 161115：將4-[2-[2-[[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙氧基]鄰苯二甲酸(119 mg，0.17 mmol)及3-胺基哌啶-2,6-二酮鹽酸鹽(31 mg，0.19 mmol)於吡啶(2 mL)中之混合物在120℃下加熱2天。將混合物濃縮至乾燥且藉由管柱層析(MeOH:DCM=5:95，Rf=0.3)純化，得到呈黃色固體狀之N-[2-[2-[2-[2,6-雙(側氧基)哌啶-3-基]-1,3-雙(側氧基)異吲哚-5-基]氧基乙氧基]乙基]-N-[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]胺基甲酸三級丁酯(39 mg，0.05 mmol，產率29%)。 (C) Compound 161115 : 4-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridine- 2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]phthalic acid (119 mg, 0.17 mmol) and 3-aminopiperidine - A mixture of 2,6-dione hydrochloride (31 mg, 0.19 mmol) in pyridine (2 mL) was heated at 120°C for 2 days. The mixture was concentrated to dryness and purified by column chromatography (MeOH:DCM=5:95, Rf=0.3) to give N-[2-[2-[2-[2,6-bis (Oxy)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethyl]-N-[5-[4-[ tertiary-butyl 6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate (39 mg, 0.05 mmol, 29% yield) .

(D) 化合物 161177：在0℃下向N-[2-[2-[2-[2,6-雙(側氧基)哌啶-3-基]-1,3-雙(側氧基)異吲哚-5-基]氧基乙氧基]乙基]-N-[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]胺基甲酸三級丁酯(39 mg，0.05 mmol)於DCM (1 mL)中之溶液中添加TFA (1 mL，13.06 mmol)。將所得混合物在RT下攪拌2 h。溶液用飽和NaHCO 3溶液中和且用DCM萃取。有機層用鹽水洗滌，經MgSO4乾燥，濃縮且藉由層析(MeOH:DCM=1:99，Rf=0.1)純化，得到呈黃色固體狀之2-[2,6-雙(側氧基)哌啶-3-基]-5-[2-[2-[[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]胺基]乙氧基]乙氧基]異吲哚-1,3-二酮(11 mg，0.02 mmol，產率31%)。 實例15：化合物160383之合成

Figure 02_image403
Figure 02_image405
(D) Compound 161177 : N-[2-[2-[2-[2,6-bis(side oxy)piperidin-3-yl]-1,3-bis(side oxy )isoindol-5-yl]oxyethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl] To a solution of tert-butyl phenyl]pyridin-2-yl]carbamate (39 mg, 0.05 mmol) in DCM (1 mL) was added TFA (1 mL, 13.06 mmol). The resulting mixture was stirred at RT for 2 h. The solution was neutralized with saturated NaHCO 3 solution and extracted with DCM. The organic layer was washed with brine, dried over MgSO4, concentrated and purified by chromatography (MeOH:DCM=1:99, Rf=0.1) to give 2-[2,6-bis(oxo) as a yellow solid Piperidin-3-yl]-5-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridine -2-yl]amino]ethoxy]ethoxy]isoindole-1,3-dione (11 mg, 0.02 mmol, 31% yield). Example 15: Synthesis of Compound 160383
Figure 02_image403
Figure 02_image405

(A) 化合物 160366：將3-(6-羥基-3-側氧基-1H-異吲哚-2-基)哌啶-2,6-二酮(63 mg，0.24 mmol)、K 2CO 3(51 mg，0.37 mmol)、N-[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]-N-[2-[2-[2-[2-[2-(2-碘基乙氧基)乙氧基]乙氧基]乙氧基]乙氧基]乙基]胺基甲酸三級丁酯(100 mg，0.12 mmol)於DMF (2 mL)中之混合物在50℃下加熱3 h。混合物用水淬滅，用DCM (200 mL)萃取，經MgSO 4乾燥，濃縮且藉由層析(MeOH:DCM=5:95，Rf=0.3)純化，得到呈黃色固體狀之N-[2-[2-[2-[2-[2-[2-[[2-[2,6-雙(側氧基)哌啶-3-基]-1-側氧基-3H-異吲哚-5-基]氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙基]-N-[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]胺基甲酸三級丁酯(26 mg，0.03 mmol，產率22%)。 (A) Compound 160366 : 3-(6-hydroxy-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione (63 mg, 0.24 mmol), K 2 CO 3 (51 mg, 0.37 mmol), N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]- N-[2-[2-[2-[2-[2-(2-Iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate A mixture of butyl ester (100 mg, 0.12 mmol) in DMF (2 mL) was heated at 50 °C for 3 h. The mixture was quenched with water, extracted with DCM (200 mL), dried over MgSO 4 , concentrated and purified by chromatography (MeOH:DCM=5:95, Rf=0.3) to give N-[2- [2-[2-[2-[2-[2-[[2-[2,6-bis(oxo)piperidin-3-yl]-1-oxo-3H-isoindole- 5-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)- tert-butyl 1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate (26 mg, 0.03 mmol, 22% yield).

(B) 化合物 160383：在0℃下向N-[2-[2-[2-[2-[2-[2-[[2-[2,6-雙(側氧基)哌啶-3-基]-1-側氧基-3H-異吲哚-5-基]氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙基]-N-[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]胺基甲酸三級丁基酯(26 mg，0.03 mmol)於DCM (1 mL)中之溶液中添加TFA (0.5 mL，6.53 mmol)，且將混合物在RT下攪拌3 h。溶液在0℃下用飽和NaHCO 3溶液中和且隨後用DCM萃取。有機層用鹽水洗滌，經MgSO 4乾燥，濃縮且藉由NH矽膠管柱層析(MeOH:DCM=5:95，Rf=0.2)純化，得到呈黃色固體狀之3-[6-[2-[2-[2-[2-[2-[2-[[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]胺基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]-3-側氧基-1H-異吲哚-2-基]哌啶-2,6-二酮(9 mg，0.01 mmol，產率33%)。 實例16：化合物160744之合成

Figure 02_image407
(B) Compound 160383 : N-[2-[2-[2-[2-[2-[2-[2-[[2-[2,6-bis(side oxy))piperidine-3 at 0°C -yl]-1-oxo-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[ tertiary butyl 5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate (26 mg, 0.03 mmol) in DCM (1 mL) was added TFA (0.5 mL, 6.53 mmol) and the mixture was stirred at RT for 3 h. The solution was neutralized with saturated NaHCO 3 solution at 0 °C and then extracted with DCM. The organic layer was washed with brine, dried over MgSO 4 , concentrated and purified by NH silica gel column chromatography (MeOH:DCM=5:95, Rf=0.2) to give 3-[6-[2- [2-[2-[2-[2-[2-[[5-[4-[6-(Dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridine- 2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-3-oxo-1H-isoindol-2-yl]piperidine -2,6-dione (9 mg, 0.01 mmol, 33% yield). Example 16: Synthesis of Compound 160744
Figure 02_image407

(A) 化合物 160690：在0℃下向2-[4-[6-(二甲胺基)-2-氟-吡啶-3-基]苯基]咪唑并[1,2-a]吡啶-6-醇(400 mg，1.15 mmol)於DMF (10 mL)中之溶液中添加NaH (184 mg，4.59 mmol)且在RT下攪拌1 h。將4-甲基苯磺酸2-[2-[2-[2-[2-[2-(4-甲基苯基)磺醯基氧基乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙酯(2 mL，4.13 mmol)添加至混合物中且在氬氣下在RT下攪拌14 h。混合物用DCM (10 mL)稀釋，用水(10 mL)及鹽水(10 mL)洗滌。收集有機層，經Na 2SO 4乾燥，濃縮且藉由管柱層析(DCM:MeOH=50:1，Rf=0.29)純化，得到呈淡黃色固體狀之4-甲基苯磺酸2-[2-[2-[2-[2-[2-[2-[4-[6-(二甲基胺基)-2-氟-吡啶-3-基]苯基]咪唑并[1,2-a]吡啶-6-基]氧基乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙酯(520 mg，0.68 mmol，產率59%)。 (A) Compound 160690 : 2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridine- To a solution of 6-alcohol (400 mg, 1.15 mmol) in DMF (10 mL) was added NaH (184 mg, 4.59 mmol) and stirred at RT for 1 h. 4-methylbenzenesulfonic acid 2-[2-[2-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy] Ethoxy]ethoxy]ethyl ester (2 mL, 4.13 mmol) was added to the mixture and stirred at RT under argon for 14 h. The mixture was diluted with DCM (10 mL), washed with water (10 mL) and brine (10 mL). The organic layer was collected, dried over Na 2 SO 4 , concentrated and purified by column chromatography (DCM:MeOH=50:1, Rf=0.29) to give 4-methylbenzenesulfonic acid 2- [2-[2-[2-[2-[2-[2-[4-[6-(Dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1, 2-a]pyridin-6-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl ester (520 mg, 0.68 mmol, 59% yield).

(B) 化合物 160707：將4-甲基苯磺酸2-[2-[2-[2-[2-[2-[2-[4-[6-(二甲胺基)-2-氟-吡啶-3-基]苯基]咪唑并[1,2-a]吡啶-6-基]氧基乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙酯(520 mg，0.68 mmol)及NaI (122 mg，0.81 mmol)於CH 3CN (6 mL)中之混合物在80℃下加熱5 h。向混合物中添加水且用DCM萃取。有機層用水(20 mL)、鹽水(20 mL)洗滌，經Na 2SO 4乾燥，濃縮且藉由層析(MeOH:DCM=1:50，Rf=0.39)純化，得到呈淡黃色固體狀之6-氟-5-[4-[6-[2-[2-[2-[2-[2-(2-碘基乙氧基)乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]咪唑并[1,2-a]吡啶-2-基]苯基]-N,N-二甲基-吡啶-2-胺(427 mg，0.59 mmol，產率87%)。 (B) compound 160707 : 4-methylbenzenesulfonic acid 2-[2-[2-[2-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoro -pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl ester ( A mixture of 520 mg, 0.68 mmol) and NaI (122 mg, 0.81 mmol) in CH3CN (6 mL) was heated at 80 °C for 5 h. Water was added to the mixture and extracted with DCM. The organic layer was washed with water (20 mL), brine (20 mL), dried over Na 2 SO 4 , concentrated and purified by chromatography (MeOH:DCM = 1:50, Rf = 0.39) to give the compound as a light yellow solid. 6-fluoro-5-[4-[6-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy yl]ethoxy]imidazo[1,2-a]pyridin-2-yl]phenyl]-N,N-dimethyl-pyridin-2-amine (427 mg, 0.59 mmol, 87% yield) .

(C) 化合物 160744：將2-[2,6-雙(側氧基)哌啶-3-基]-5-羥基-異吲哚-1,3-二酮(114 mg，0.41 mmol)、Cs 2CO 3(202 mg，0.62 mmol)及6-氟-5-[4-[6-[2-[2-[2-[2-[2-(2-碘基乙氧基)乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]-3,8a-二氫咪唑并[1,2-a]吡啶-2-基]苯基]-N,N-二甲基-吡啶-2-胺(150 mg，0.21 mmol)於DMF (3 mL)中之混合物在50℃下加熱20 h。混合物用水淬滅且藉由過濾收集所得沈澱物。殘餘物藉由管柱層析(MeOH:DCM=1:20，Rf=0.34)純化，得到呈棕色固體狀之2-[2,6-雙(側氧基)哌啶-3-基]-5-[2-[2-[2-[2-[2-[2-[2-[4-[6-(二甲基胺基)-2-氟-吡啶-3-基]苯基]咪唑并[1,2-a]吡啶-6-基]氧基乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]異吲哚-1,3-二酮(28 mg，0.03 mmol，產率15%)。 (C) Compound 160744 : 2-[2,6-bis(side oxy)piperidin-3-yl]-5-hydroxyl-isoindole-1,3-dione (114 mg, 0.41 mmol), Cs 2 CO 3 (202 mg, 0.62 mmol) and 6-fluoro-5-[4-[6-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy Base]ethoxy]ethoxy]ethoxy]ethoxy]-3,8a-dihydroimidazo[1,2-a]pyridin-2-yl]phenyl]-N,N-dimethyl A mixture of yl-pyridin-2-amine (150 mg, 0.21 mmol) in DMF (3 mL) was heated at 50 °C for 20 h. The mixture was quenched with water and the resulting precipitate was collected by filtration. The residue was purified by column chromatography (MeOH:DCM=1:20, Rf=0.34) to give 2-[2,6-bis(sideoxy)piperidin-3-yl]- 5-[2-[2-[2-[2-[2-[2-[2-[4-[6-(Dimethylamino)-2-fluoro-pyridin-3-yl]phenyl] Imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]isoindole-1,3-di Ketone (28 mg, 0.03 mmol, 15% yield).

1H NMR (400 MHz，DMSO-d6) δ 11.09 (s，1H)，8.28 (s，1H)，8.23 (d， J= 2.3Hz，1H)，7.97 (d， J= 7.8，2H)，7.87 (dd， J= 10.8，8.4Hz，1H)，7.81 (d， J= 8.4Hz，1H)，7.57 (d， J= 7.8Hz，2H)，7.50 (d， J= 9.7 Hz，1H)，7.43 (d， J= 2.3Hz，1H)，7.34 (dd， J= 8.4，2.3 Hz，1H)，7.05 (dd， J= 9.7，2.3 Hz，1H)，6.63 (dd， J= 8.4，2.0 Hz，1H)，5.11 (dd， J= 12.9，5.5 Hz，1H)，4.25-4.32 (m，2H)，4.06-4.14 (m，2H)，3.74-3.79 (m，4H)，3.47-3.63 (m，18H)，3.06 (s，6H)，2.80-2.96 (m，2H)。 實例17：化合物161111之合成

Figure 02_image409
Figure 02_image411
1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.28 (s, 1H), 8.23 (d, J = 2.3Hz, 1H), 7.97 (d, J = 7.8, 2H), 7.87 (dd, J = 10.8, 8.4Hz, 1H), 7.81 (d, J = 8.4Hz, 1H), 7.57 (d, J = 7.8Hz, 2H), 7.50 (d, J = 9.7Hz, 1H), 7.43 (d, J = 2.3Hz, 1H), 7.34 (dd, J = 8.4, 2.3 Hz, 1H), 7.05 (dd, J = 9.7, 2.3 Hz, 1H), 6.63 (dd, J = 8.4, 2.0 Hz, 1H), 5.11 (dd, J = 12.9, 5.5 Hz, 1H), 4.25-4.32 (m, 2H), 4.06-4.14 (m, 2H), 3.74-3.79 (m, 4H), 3.47-3.63 (m, 18H), 3.06 (s, 6H), 2.80-2.96 (m, 2H). Example 17: Synthesis of Compound 161111
Figure 02_image409
Figure 02_image411

(A) 化合物 160947：在0℃下向2-[4-[6-(二甲胺基)-2-氟-吡啶-3-基]苯基]咪唑并[1,2-a]吡啶-6-醇(400 mg，1.15 mmol)於無水DMF(8 mL)中之溶液中添加NaH (0.14 g，3.44 mmol)且在RT下攪拌1 h。將4-甲基苯磺酸2-[2-(4-甲基苯基)磺醯基氧基乙氧基]乙酯(1.43 g，3.44 mmol)添加至混合物中且在同一溫度下攪拌16 h。反應物用水淬滅且用DCM萃取。有機層用水、鹽水洗滌，經Na 2SO 4乾燥，濃縮且藉由矽膠管柱層析(EtOAc:DCM=1:5，Rf=0.33)純化，得到呈橙色固體狀之4-甲基苯磺酸2-[2-[2-[4-[6-(二甲胺基)-2-氟-吡啶-3-基]苯基]咪唑并[1,2-a]吡啶-6-基]氧基乙氧基]乙酯(227 mg，0.38 mmol，產率33%)。 (A) Compound 160947 : 2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridine- To a solution of 6-alcohol (400 mg, 1.15 mmol) in anhydrous DMF (8 mL) was added NaH (0.14 g, 3.44 mmol) and stirred at RT for 1 h. 2-[2-(4-Methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (1.43 g, 3.44 mmol) was added to the mixture and stirred at the same temperature for 16 h. The reaction was quenched with water and extracted with DCM. The organic layer was washed with water, brine, dried over Na2SO4 , concentrated and purified by silica gel column chromatography (EtOAc:DCM=1:5, Rf=0.33) to give 4 - methylbenzenesulfonate as an orange solid Acid 2-[2-[2-[4-[6-(Dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl] Oxyethoxy] ethyl ester (227 mg, 0.38 mmol, 33% yield).

(B) 化合物 160997：將4-羥基苯-1,2-二甲酸二甲酯(161 mg，0.77 mmol)、Cs 2CO 3(374.2 mg，1.15 mmol)、KI (6 mg，0.04 mmol)及4-甲基苯磺酸2-[2-[2-[4-[6-(二甲基胺基)-2-氟-吡啶-3-基]苯基]咪唑并[1,2-a]吡啶-6-基]氧基乙氧基]乙酯(226 mg，0.38 mmol)於DMF (4 mL)中之混合物在50℃下加熱4 h。混合物用水淬滅且所得沈澱物藉由過濾收集且用水洗滌，得到呈橙色固體狀之4-[2-[2-[2-[4-[6-(二甲基胺基)-2-氟-吡啶-3-基]苯基]咪唑并[1,2-a]吡啶-6-基]氧基乙氧基]乙氧基]苯-1,2-二甲酸二甲酯(212 mg，0.34 mmol，產率88%)。 (B) Compound 160997 : Dimethyl 4-hydroxybenzene-1,2-dicarboxylate (161 mg, 0.77 mmol), Cs 2 CO 3 (374.2 mg, 1.15 mmol), KI (6 mg, 0.04 mmol) and 4-Methylbenzenesulfonic acid 2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a A mixture of ]pyridin-6-yl]oxyethoxy]ethyl ester (226 mg, 0.38 mmol) in DMF (4 mL) was heated at 50 °C for 4 h. The mixture was quenched with water and the resulting precipitate was collected by filtration and washed with water to give 4-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoro) as an orange solid -pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethoxy]benzene-1,2-dicarboxylic acid dimethyl ester (212 mg, 0.34 mmol, yield 88%).

(C) 化合物 161006：向4-[2-[2-[2-[4-[6-(二甲基胺基)-2-氟-吡啶-3-基]苯基]咪唑并[1,2-a]吡啶-6-基]氧基乙氧基]乙氧基]苯-1,2-二甲酸二甲酯(211 mg，0.34 mmol)於MeOH (2 mL)中之溶液中添加含NaOH (443 mg，11.08 mmol)之水(2 mL)，且在RT下攪拌5天。反應物用EtOAc (50 mL)稀釋且用1 N HCl溶液酸化至pH 1。有機層用水(50 mL)、鹽水(50 mL)洗滌，經Na 2SO 4乾燥且濃縮，得到呈黃色固體狀之4-[2-[2-[2-[4-[6-(二甲基胺基)-2-氟-吡啶-3-基]苯基]咪唑并[1,2-a]吡啶-6-基]氧基乙氧基]乙氧基]鄰苯二甲酸(185 mg，0.31 mmol，產率92%)。 (C) Compound 161006 : To 4-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1, To a solution of dimethyl 2-a]pyridin-6-yl]oxyethoxy]ethoxy]benzene-1,2-dicarboxylate (211 mg, 0.34 mmol) in MeOH (2 mL) was added containing NaOH (443 mg, 11.08 mmol) in water (2 mL) and stirred at RT for 5 days. The reaction was diluted with EtOAc (50 mL) and acidified to pH 1 with 1 N HCl solution. The organic layer was washed with water (50 mL), brine (50 mL), dried over Na 2 SO 4 and concentrated to give 4-[2-[2-[2-[4-[6-(dimethyl Amino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethoxy]phthalic acid (185 mg , 0.31 mmol, yield 92%).

(D) 化合物 161111：將4-[2-[2-[2-[4-[6-(二甲基胺基)-2-氟-吡啶-3-基]苯基]咪唑并[1,2-a]吡啶-6-基]氧基乙氧基]乙氧基]鄰苯二甲酸(67 mg，0.11 mmol)及3-胺基哌啶-2,6-二酮鹽酸鹽(20 mg，0.15 mmol)於吡啶(3 mL)中之混合物在120℃下加熱14 h。藉由真空移除溶劑。將殘餘物再溶解於DCM中且添加水。所得沈澱物藉由過濾收集且藉由管柱層析(MeOH:DCM=1:100，Rf=0.19)純化，得到呈黃色固體狀之2-[2,6-雙(側氧基)哌啶-3-基]-5-[2-[2-[2-[4-[6-(二甲基胺基)-2-氟-吡啶-3-基]苯基]咪唑并[1,2-a]吡啶-6-基]氧基乙氧基]乙氧基]異吲哚-1,3-二酮(18 mg，0.02 mmol，產率22%)。 實例18：化合物161215之合成

Figure 02_image413
Figure 02_image415
(D) Compound 161111 : 4-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1, 2-a]pyridin-6-yl]oxyethoxy]ethoxy]phthalic acid (67 mg, 0.11 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (20 mg, 0.15 mmol) in pyridine (3 mL) was heated at 120 °C for 14 h. Solvent was removed by vacuum. The residue was redissolved in DCM and water was added. The resulting precipitate was collected by filtration and purified by column chromatography (MeOH:DCM=1:100, Rf=0.19) to give 2-[2,6-bis(oxo)piperidine as a yellow solid -3-yl]-5-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2 -a]pyridin-6-yl]oxyethoxy]ethoxy]isoindole-1,3-dione (18 mg, 0.02 mmol, 22% yield). Example 18: Synthesis of Compound 161215
Figure 02_image413
Figure 02_image415

(A) 化合物 160806：在0℃下向NaH (138 mg，3.45 mmol)於DMF (2 mL)中之溶液中添加N-[6-氟-5-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]胺基甲酸三級丁酯(500 mg，1.15 mmol)於DMF (10 mL)中之溶液。將所得混合物在室溫下攪拌30 min。將含4-甲基苯磺酸2-[2-(4-甲基苯基)磺醯基氧基乙氧基]乙酯(954 mg，2.30 mmol)之DMF (3 mL)添加至反應混合物中且在室溫下攪拌21 h。混合物用飽和NH 4Cl溶液淬滅且用EtOAc萃取。有機層用鹽水洗滌，經MgSO 4乾燥，濃縮且藉由管柱層析(MeOH:DCM=3:17，Rf=0.3)純化，得到呈黃色固體狀之4-甲基苯磺酸2-[2-[[6-氟-5-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙酯(339 mg，0.50 mmol，產率44%)。 (A) Compound 160806 : To a solution of NaH (138 mg, 3.45 mmol) in DMF (2 mL) was added N-[6-fluoro-5-[4-(6-methoxyimidazolo) at 0°C A solution of tert-butyl [1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate (500 mg, 1.15 mmol) in DMF (10 mL). The resulting mixture was stirred at room temperature for 30 min. 2-[2-(4-Methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (954 mg, 2.30 mmol) in DMF (3 mL) was added to the reaction mixture and stirred at room temperature for 21 h. The mixture was quenched with saturated NH4Cl solution and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO 4 , concentrated and purified by column chromatography (MeOH:DCM=3:17, Rf=0.3) to give 4-methylbenzenesulfonic acid 2-[ 2-[[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methyl Propan-2-yl)oxycarbonyl]amino]ethoxy]ethyl ester (339 mg, 0.50 mmol, 44% yield).

(B) 化合物 160814：將4-甲基苯磺酸2-[2-[[6-氟-5-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙酯(339 mg，0.50 mmol)及NaI (90 mg，0.60 mmol)於MeCN (10 mL)中之混合物在80℃下加熱19 h。將混合物添加至水中且用EtOAc萃取。有機層用水(50 mL)、鹽水(50 mL)洗滌，經MgSO 4乾燥，濃縮，且藉由管柱層析(EtOAc:DCM=1:9，Rf=0.3)純化，得到呈黃色固體狀之N-[6-氟-5-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]-N-[2-(2-碘基乙氧基)乙基]胺基甲酸三級丁酯(197 mg，0.31 mmol，產率62%)。 (B) Compound 160814 : 4-methylbenzenesulfonic acid 2-[2-[[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl )phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl ester (339 mg, 0.50 mmol) and NaI (90 mg, 0.60 mmol) in MeCN (10 mL) was heated at 80 °C for 19 h. The mixture was added to water and extracted with EtOAc. The organic layer was washed with water (50 mL), brine (50 mL), dried over MgSO 4 , concentrated, and purified by column chromatography (EtOAc:DCM = 1:9, Rf = 0.3) to give the compound as a yellow solid. N-[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-N-[2-(2 - Iodoethoxy)ethyl]carbamate (197 mg, 0.31 mmol, 62% yield).

(C) 化合物 161091：將4-側氧基苯-1,2-二甲酸二甲酯(131 mg，0.62 mmol)、Cs 2CO 3(305 mg，0.93 mmol)、N-[6-氟-5-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]-N-[2-(2-碘基乙氧基)乙基]胺基甲酸三級丁酯(197 mg，0.31 mmol)於DMF (5 mL)中之混合物在50℃下加熱1 h。混合物用水淬滅，用DCM萃取，經MgSO 4乾燥，濃縮，且藉由管柱層析(EtOAc:己烷=1:1，Rf=0.3)純化，得到呈黃色固體狀之4-[2-[2-[[6-氟-5-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙氧基]苯-1,2-二甲酸二甲酯(147 mg，0.21 mmol，產率66%)。 (C) Compound 161091 : Dimethyl 4-oxobenzene-1,2-dicarboxylate (131 mg, 0.62 mmol), Cs 2 CO 3 (305 mg, 0.93 mmol), N-[6-fluoro- 5-[4-(6-Methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-N-[2-(2-iodoethoxy) A mixture of tert-butyl ethyl]carbamate (197 mg, 0.31 mmol) in DMF (5 mL) was heated at 50 °C for 1 h. The mixture was quenched with water, extracted with DCM, dried over MgSO 4 , concentrated, and purified by column chromatography (EtOAc:hexane=1:1, Rf=0.3) to give 4-[2- [2-[[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methyl Dimethylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]benzene-1,2-dicarboxylate (147 mg, 0.21 mmol, 66% yield).

(D) 化合物 161105：向4-[2-[2-[[6-氟-5-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙氧基]苯-1,2-二甲酸二甲酯(147 mg，0.21 mmol)於MeOH (2 mL)中之溶液中添加含NaOH (66 mg，1.65 mmol)之水(2 mL)，且將混合物在室溫下攪拌3天。反應物用1 N HCl溶液中和至pH 1。沈澱物藉由過濾收集且用水洗滌，得到呈白色固體狀之4-[2-[2-[[6-氟-5-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙氧基]鄰苯二甲酸(135 mg，0.20 mmol，產率96%)。 (D) Compound 161105 : To 4-[2-[2-[[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl] Pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]benzene-1,2-dicarboxylic acid dimethyl ester (147 mg, 0.21 To a solution of mmol) in MeOH (2 mL) was added NaOH (66 mg, 1.65 mmol) in water (2 mL), and the mixture was stirred at room temperature for 3 days. The reaction was neutralized to pH 1 with 1 N HCl solution. The precipitate was collected by filtration and washed with water to give 4-[2-[2-[[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a] as a white solid Pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]phthalic acid (135 mg , 0.20 mmol, yield 96%).

(E) 化合物 161183：將4-[2-[2-[[6-氟-5-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙氧基]鄰苯二甲酸(135 mg，0.20 mmol)及3-胺基哌啶-2,6-二酮鹽酸鹽(49 mg，0.29 mmol)於吡啶(2 mL)中之混合物在120℃下加熱20 h。將混合物濃縮至乾燥，且藉由NH矽膠管柱層析(MeOH:DCM=1:99，Rf=0.1)純化，得到呈黃色固體狀之N-[2-[2-[2-[2,6-雙(側氧基)哌啶-3-基]-1,3-雙(側氧基)異吲哚-5-基]氧基乙氧基]乙基]-N-[6-氟-5-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]胺基甲酸三級丁酯(47 mg，0.06 mmol，產率30%)。 (F) 化合物 161215：在0℃下向N-[2-[2-[2-[2,6-雙(側氧基)哌啶-3-基]-1,3-雙(側氧基)異吲哚-5-基]氧基乙氧基]乙基]-N-[6-氟-5-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]胺基甲酸三級丁酯(47 mg，0.06 mmol)於DCM (1 mL)中之溶液中添加TFA (1 mL，13 mmol)，且將混合物在室溫下攪拌2 h。溶液用飽和NaHCO 3溶液中和且用DCM萃取。有機層用鹽水洗滌，經MgSO 4乾燥，濃縮且藉由NH矽膠管柱層析(MeOH:DCM=1:99，Rf=0.1)純化，得到呈黃色固體狀之2-[2,6-雙(側氧基)哌啶-3-基]-5-[2-[2-[[6-氟-5-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]胺基]乙氧基]乙氧基]異吲哚-1,3-二酮(17 mg，0.02 mmol，產率38%)。 1H NMR (400 MHz，DMSO-d6) δ 11.07 (s，1H)，8.28 (s，1H)，8.19 (d， J= 2.3 Hz，1H)，7.92 (d， J= 8.3 Hz，2H)，7.79 (d， J= 8.3 Hz，1H)，7.70 (dd， J= 10.3，8.2 Hz，1H)，7.46-7.52 (m，3H)，7.43 (d， J= 2.2 Hz，1H)，7.34 (dd， J= 8.2，2.3 Hz，1H)，7.14 (t， J= 5.7 Hz，1H)，7.01 (dd， J= 10.3，2.2 Hz，1H)，6.49 (d， J= 8.5 Hz，1H)，5.08 (dd， J= 13.1，5.3 Hz，1H)，4.34-4.28 (m，2H)，3.75-3.83 (m，5H)，3.62 (t， J= 5.5 Hz，2H)，3.39-3.44 (m，2H)，2.77-2.91 (m，1H)，2.49-2.66 (m，2)。 實例19：化合物161409之合成

Figure 02_image417
化合物161409可藉由類似於實例19之方法合成。 1H NMR (400 MHz，DMSO-d6) δ 11.09 (s，1H)，8.27 (s，1H)，8.19 (d， J= 2.5 Hz，1H)，7.92 (d， J= 8.0 Hz，2H)，7.78 (d， J= 8.4 Hz，1H)，7.71 (dd， J= 10.2，8.6 Hz，1H)，7.45-7.53 (m，3H)，7.41 (d， J= 2.0 Hz，1H)，7.32 (dd， J= 8.6，2.1 Hz，1H)，7.13 (t， J= 5.3 Hz，1H)，7.00 (dd， J= 9.7，1.6 Hz，1H)，6.49 (d， J= 9.2 Hz，1H)，5.07 (dd， J= 12.8，5.3 Hz，1H)，4.24-4.29 (m，2H)，3.77 (s，3H)，3.72-3.76 (m，2H)，3.44-3.58 (m，20H)，3.34-3.41 (m，3H)，2.77-2.91 (m，2H)。 實例20：化合物161104之合成
Figure 02_image419
(E) Compound 161183 : 4-[2-[2-[[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl] Pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]phthalic acid (135 mg, 0.20 mmol) and 3-amino A mixture of piperidine-2,6-dione hydrochloride (49 mg, 0.29 mmol) in pyridine (2 mL) was heated at 120 °C for 20 h. The mixture was concentrated to dryness and purified by NH silica gel column chromatography (MeOH:DCM=1:99, Rf=0.1) to obtain N-[2-[2-[2-[2, 6-bis(side oxy)piperidin-3-yl]-1,3-bis(side oxy)isoindol-5-yl]oxyethoxy]ethyl]-N-[6-fluoro -5-[4-(6-Methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate (47 mg, 0.06 mmol, Yield 30%). (F) Compound 161215 : N-[2-[2-[2-[2,6-bis(side oxy)piperidin-3-yl]-1,3-bis(side oxy ) isoindol-5-yl]oxyethoxy]ethyl]-N-[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridine-2- To a solution of tert-butyl)phenyl]pyridin-2-yl]carbamate (47 mg, 0.06 mmol) in DCM (1 mL) was added TFA (1 mL, 13 mmol), and the mixture was incubated at room temperature. Stir at room temperature for 2 h. The solution was neutralized with saturated NaHCO 3 solution and extracted with DCM. The organic layer was washed with brine, dried over MgSO 4 , concentrated and purified by NH silica gel column chromatography (MeOH:DCM=1:99, Rf=0.1) to give 2-[2,6-bis (Oxy)piperidin-3-yl]-5-[2-[2-[[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridine-2 -yl)phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]isoindole-1,3-dione (17 mg, 0.02 mmol, 38% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.28 (s, 1H), 8.19 (d, J = 2.3 Hz, 1H), 7.92 (d, J = 8.3 Hz, 2H), 7.79 (d, J = 8.3 Hz, 1H), 7.70 (dd, J = 10.3, 8.2 Hz, 1H), 7.46-7.52 (m, 3H), 7.43 (d, J = 2.2 Hz, 1H), 7.34 (dd , J = 8.2, 2.3 Hz, 1H), 7.14 (t, J = 5.7 Hz, 1H), 7.01 (dd, J = 10.3, 2.2 Hz, 1H), 6.49 (d, J = 8.5 Hz, 1H), 5.08 (dd, J = 13.1, 5.3 Hz, 1H), 4.34-4.28 (m, 2H), 3.75-3.83 (m, 5H), 3.62 (t, J = 5.5 Hz, 2H), 3.39-3.44 (m, 2H ), 2.77-2.91 (m, 1H), 2.49-2.66 (m, 2). Example 19: Synthesis of Compound 161409
Figure 02_image417
Compound 161409 can be synthesized by a method similar to Example 19. 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.27 (s, 1H), 8.19 (d, J = 2.5 Hz, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.4 Hz, 1H), 7.71 (dd, J = 10.2, 8.6 Hz, 1H), 7.45-7.53 (m, 3H), 7.41 (d, J = 2.0 Hz, 1H), 7.32 (dd , J = 8.6, 2.1 Hz, 1H), 7.13 (t, J = 5.3 Hz, 1H), 7.00 (dd, J = 9.7, 1.6 Hz, 1H), 6.49 (d, J = 9.2 Hz, 1H), 5.07 (dd, J = 12.8, 5.3 Hz, 1H), 4.24-4.29 (m, 2H), 3.77 (s, 3H), 3.72-3.76 (m, 2H), 3.44-3.58 (m, 20H), 3.34-3.41 (m, 3H), 2.77-2.91 (m, 2H). Example 20: Synthesis of Compound 161104
Figure 02_image419

(A) 化合物 160937：在0℃下向2-[4-[6-[(2-甲基丙-2-基)氧基羰基胺基]吡啶-3-基]苯基]吡咯并[2,3-c]-吡啶-1-甲酸三級丁酯(500 mg，1.03 mmol)於DMF (10 mL)中之溶液中添加NaH (49 mg，1.23 mmol)，且在RT下攪拌30 min。將4-甲基苯磺酸2-[2-[2-[2-[2-[2-(4-甲基苯基)磺醯基氧基乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙酯(789 mg，1.34 mmol)添加至反應混合物中，且在RT下攪拌6 h。混合物用飽和NH 4Cl溶液淬滅且用DCM萃取。有機層用鹽水洗滌，經MgSO 4乾燥，濃縮且藉由管柱層析(EtOAc:DCM=1:4，Rf=0.33)純化，得到呈淡黃色油狀之2-[4-[6-[2-[2-[2-[2-[2-[2-(4-甲基苯基)磺醯基氧基乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙基-[(2-甲基丙-2-基)氧基羰基]胺基]吡啶-3-基]苯基]吡咯并[2,3-c]吡啶-1-甲酸三級丁酯(280 mg，0.31 mmol，產率30%)。 (A) Compound 160937 : 2-[4-[6-[(2-methylprop-2-yl)oxycarbonylamino]pyridin-3-yl]phenyl]pyrrolo[2 ,3-c]-Pyridine-1-carboxylic acid tert-butyl ester (500 mg, 1.03 mmol) in DMF (10 mL) was added NaH (49 mg, 1.23 mmol) and stirred at RT for 30 min. 4-methylbenzenesulfonic acid 2-[2-[2-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy] Ethoxy]ethoxy]ethyl ester (789 mg, 1.34 mmol) was added to the reaction mixture and stirred at RT for 6 h. The mixture was quenched with saturated NH4Cl solution and extracted with DCM. The organic layer was washed with brine, dried over MgSO 4 , concentrated and purified by column chromatography (EtOAc:DCM=1:4, Rf=0.33) to give 2-[4-[6-[ 2-[2-[2-[2-[2-[2-(4-Methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy] Ethyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]pyridin-3-yl]phenyl]pyrrolo[2,3-c]pyridine-1-carboxylic acid tertiary butyl ester ( 280 mg, 0.31 mmol, yield 30%).

(B) 化合物 160987：將4-羥基苯-1,2-二甲酸二甲酯(130.05 mg，0.62 mmol)、Cs 2CO 3(303 mg，0.93 mmol)及2-[4-[6-[2-[2-[2-[2-[2-[2-(4-甲基苯基)磺醯基氧基乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙基-[(2-甲基丙-2-基)氧基羰基]胺基]吡啶-3-基]苯基]吡咯并[2,3-c]吡啶-1-甲酸三級丁酯(280 mg，0.31 mmol)於DMF (3 mL)中之溶液在50℃下加熱3 h。混合物用水淬滅且藉由過濾收集所得沈澱物。固體隨後藉由管柱層析(EtOAc:DCM=4:1，Rf=0.32)純化，得到呈淡黃色油狀之4-[2-[2-[2-[2-[2-[2-[(2-甲基丙-2-基)氧基羰基-[5-[4-[1-[(2-甲基丙-2-基)氧基羰基]吡咯并[2,3-c]吡啶-2-基]苯基]吡啶-2-基]胺基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]苯-1,2-二甲酸二甲酯(98 mg，0.10 mmol，產率34%)。 (B) Compound 160987 : Dimethyl 4-hydroxybenzene-1,2-dicarboxylate (130.05 mg, 0.62 mmol), Cs 2 CO 3 (303 mg, 0.93 mmol) and 2-[4-[6-[ 2-[2-[2-[2-[2-[2-(4-Methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy] Ethyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]pyridin-3-yl]phenyl]pyrrolo[2,3-c]pyridine-1-carboxylic acid tertiary butyl ester ( A solution of 280 mg, 0.31 mmol) in DMF (3 mL) was heated at 50 °C for 3 h. The mixture was quenched with water and the resulting precipitate was collected by filtration. The solid was then purified by column chromatography (EtOAc:DCM=4:1, Rf=0.32) to give 4-[2-[2-[2-[2-[2-[2- [(2-methylprop-2-yl)oxycarbonyl-[5-[4-[1-[(2-methylprop-2-yl)oxycarbonyl]pyrrolo[2,3-c] Pyridin-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]benzene-1,2-dicarboxylic acid Dimethyl ester (98 mg, 0.10 mmol, 34% yield).

(C) 化合物 161004：向4-[2-[2-[2-[2-[2-[2-[(2-甲基丙-2-基)氧基羰基-[5-[4-[1-[(2-甲基丙-2-基)氧基羰基]吡咯并[2,3-c]吡啶-2-基]苯基]吡啶-2-基]胺基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]苯-1,2-二甲酸二甲酯(98 mg，0.10 mmol)於EtOH (5 mL)中之溶液中添加含NaOH (33 mg，0.83 mmol)之水(5 mL)，且在RT下攪拌4天。反應物用DCM (10 mL)稀釋且用1 N HCl溶液酸化至pH 1。有機層用水(10 mL)、鹽水(10 mL)洗滌，經Na 2SO 4乾燥且濃縮至乾燥，得到呈淡黃色固體狀之4-[2-[2-[2-[2-[2-[2-[[5-[4-[1-[(2-甲基丙-2-基)氧基羰基]吡咯并[2,3-c]吡啶-2-基]苯基]吡啶-2-基]胺基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]鄰苯二甲酸(79 mg，0.10 mmol，產率93%)。 (C) Compound 161004 : To 4-[2-[2-[2-[2-[2-[2-[(2-methylprop-2-yl)oxycarbonyl-[5-[4-[ 1-[(2-Methylprop-2-yl)oxycarbonyl]pyrrolo[2,3-c]pyridin-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethyl To a solution of dimethyloxy]ethoxy]ethoxy]ethoxy]ethoxy]benzene-1,2-dicarboxylate (98 mg, 0.10 mmol) in EtOH (5 mL) was added NaOH containing (33 mg, 0.83 mmol) in water (5 mL), and stirred at RT for 4 days. The reaction was diluted with DCM (10 mL) and acidified to pH 1 with 1 N HCl solution. The organic layer was washed with water (10 mL), brine (10 mL), dried over Na2SO4 and concentrated to dryness to give 4-[2-[2-[2-[2-[2- [2-[[5-[4-[1-[(2-Methylprop-2-yl)oxycarbonyl]pyrrolo[2,3-c]pyridin-2-yl]phenyl]pyridine-2 -yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]phthalic acid (79 mg, 0.10 mmol, 93% yield).

(D) 化合物 161045：將4-[2-[2-[2-[2-[2-[2-[[5-[4-[1-[(2-甲基丙-2-基)氧基羰基]吡咯并[2,3-c]吡啶-2-基]苯基]吡啶-2-基]胺基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]鄰苯二甲酸(79 mg，0.10 mmol)及3-胺基哌啶-2,6-二酮HCl (18 mg，0.11 mmol)於吡啶(3 mL)中之混合物在120℃下加熱42 h。真空移除溶劑。將殘餘物再溶解於DCM (10 mL)中，用鹽水洗滌，經Na 2SO 4乾燥，濃縮且藉由管柱層析(MeOH：DCM=1:19，Rf=0.3)純化，得到呈黃色固體狀之2-[4-[6-[2-[2-[2-[2-[2-[2-[2-[2,6-雙(側氧基)哌啶-3-基]-1,3-雙(側氧基)異吲哚-5-基]氧基乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙基胺基]吡啶-3-基]苯基]吡咯并[2,3-c]吡啶-1-甲酸三級丁酯(22 mg，0.02 mmol，產率25%)。 (D) Compound 161045 : 4-[2-[2-[2-[2-[2-[2-[[5-[4-[1-[(2-methylprop-2-yl) oxygen ylcarbonyl]pyrrolo[2,3-c]pyridin-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy] A mixture of ethoxy]phthalic acid (79 mg, 0.10 mmol) and 3-aminopiperidine-2,6-dione HCl (18 mg, 0.11 mmol) in pyridine (3 mL) at 120°C Heat for 42 h. Solvent was removed in vacuo. The residue was redissolved in DCM (10 mL), washed with brine, dried over Na 2 SO 4 , concentrated and purified by column chromatography (MeOH:DCM=1:19, Rf=0.3) to give a yellow 2-[4-[6-[2-[2-[2-[2-[2-[2-[2-[2,6-bis(endoxy)piperidin-3-yl] in solid form -1,3-bis(side oxy)isoindol-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]pyridine-3- yl]phenyl]pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (22 mg, 0.02 mmol, 25% yield).

(E) 化合物 161104：向2-[4-[6-[2-[2-[2-[2-[2-[2-[2-[2,6-雙(側氧基)哌啶-3-基]-1,3-雙(側氧基)異吲哚-5-基]氧基乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙基胺基]吡啶-3-基]苯基]吡咯并[2,3-c]吡啶-1-甲酸三級丁酯(22 mg，0.02 mmol)於DCM (3 mL)中之溶液中添加TFA (0.03 mL，0.36 mmol)，且將混合物在RT下攪拌42 h。混合物隨後用飽和NaHCO 3中和至pH 8且用DCM (10 mL)萃取。有機層用鹽水洗滌，經Na 2SO 4乾燥且濃縮至乾燥，得到呈黃色固體狀之2-[2,6-雙(側氧基)哌啶-3-基]-5-[2-[2-[2-[2-[2-[2-[[5-[4-(1H-吡咯并[2,3-c]吡啶-2-基)苯基]吡啶-2-基]胺基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]異吲哚-1,3-二酮(15 mg，0.02 mmol，產率73%)。 實例21：化合物160624之合成

Figure 02_image421
(E) Compound 161104 : to 2-[4-[6-[2-[2-[2-[2-[2-[2-[2-[2,6-bis(side oxy)piperidine- 3-yl]-1,3-bis(side oxy)isoindol-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino] To a solution of pyridin-3-yl]phenyl]pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (22 mg, 0.02 mmol) in DCM (3 mL) was added TFA (0.03 mL, 0.36 mmol), and the mixture was stirred at RT for 42 h. The mixture was then neutralized to pH 8 with saturated NaHCO 3 and extracted with DCM (10 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated to dryness to give 2-[2,6-bis(oxo)piperidin-3-yl ] -5-[2-[ 2-[2-[2-[2-[2-[[5-[4-(1H-pyrrolo[2,3-c]pyridin-2-yl)phenyl]pyridin-2-yl]amino ]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]isoindole-1,3-dione (15 mg, 0.02 mmol, 73% yield). Example 21: Synthesis of Compound 160624
Figure 02_image421

化合物 160557：將3-(6-氧烷基-3-亞氧烷基-1H-異吲哚-2-基)哌啶-2,6-二酮(169 mg，0.65 mmol)、Cs 2CO 3(317 mg，0.97 mmol)、N-[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]-N-[2-(2-碘烷基乙氧基)乙基]胺基甲酸三級丁酯(209 mg，0.32 mmol)於DMF (5 mL)中之混合物在50℃下加熱1 h。混合物用水淬滅，用DCM萃取，經MgSO 4乾燥，濃縮且藉由管柱層析(溶劑梯度0%至3% MeOH/DCM，Rf=0.2)純化，得到呈黃色固體狀之(5-(4-(6-(二甲胺基)苯并[d]噻唑-2-基)苯基)吡啶-2-基)(2-(2-(3-(5-羥基-1-側氧基異吲哚啉-2-基)-2,6-二側氧基哌啶-1-基)乙氧基)乙基)胺基甲酸三級丁酯(68 mg，0.09 mmol，產率27%)。 Compound 160557 : 3-(6-oxoalkyl-3-oxyalkylene-1H-isoindol-2-yl)piperidine-2,6-dione (169 mg, 0.65 mmol), Cs 2 CO 3 (317 mg, 0.97 mmol), N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]- A mixture of ter-butyl N-[2-(2-iodoalkylethoxy)ethyl]carbamate (209 mg, 0.32 mmol) in DMF (5 mL) was heated at 50 °C for 1 h. The mixture was quenched with water, extracted with DCM, dried over MgSO 4 , concentrated and purified by column chromatography (solvent gradient 0% to 3% MeOH/DCM, Rf=0.2) to afford (5-( 4-(6-(Dimethylamino)benzo[d]thiazol-2-yl)phenyl)pyridin-2-yl)(2-(2-(3-(5-hydroxyl-1-side oxy Isoindolin-2-yl)-2,6-dioxopiperidin-1-yl)ethoxy)ethyl)carbamate (68 mg, 0.09 mmol, 27% yield ).

化合物 160624：在0℃下向(5-(4-(6-(二甲胺基)苯并[d]噻唑-2-基)苯基)吡啶-2-基)(2-(2-(3-(5-羥基-1-側氧基異吲哚啉-2-基)-2,6-二側氧基哌啶-1-基)乙氧基)乙基)胺基甲酸三級丁酯(68 mg，0.09 mmol)於DCM (2 mL)中之溶液中添加TFA (1 mL，13.06 mmol)且在室溫下攪拌6 h。溶液在0℃下用飽和NaHCO 3溶液中和且用DCM萃取溶液。有機層用鹽水洗滌，經MgSO 4乾燥且濃縮至乾燥，得到呈黃色固體狀之1-(2-(2-((5-(4-(6-(二甲胺基)苯并[d]噻唑-2-基)苯基)吡啶-2-基)胺基)乙氧基)乙基)-3-(5-羥基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(51 mg，0.07 mmol，產率85%)。 實例22：化合物162641之合成

Figure 02_image423
Compound 160624 : To (5-(4-(6-(dimethylamino)benzo[d]thiazol-2-yl)phenyl)pyridin-2-yl)(2-(2-( 3-(5-Hydroxy-1-oxoisoindoline-2-yl)-2,6-dioxopiperidin-1-yl)ethoxy)ethyl)carbamate To a solution of the ester (68 mg, 0.09 mmol) in DCM (2 mL) was added TFA (1 mL, 13.06 mmol) and stirred at room temperature for 6 h. The solution was neutralized with saturated NaHCO 3 solution at 0 °C and the solution was extracted with DCM. The organic layer was washed with brine, dried over MgSO and concentrated to dryness to give 1-(2-( 2 -((5-(4-(6-(dimethylamino)benzo[d] Thiazol-2-yl)phenyl)pyridin-2-yl)amino)ethoxy)ethyl)-3-(5-hydroxy-1-oxoisoindoline-2-yl)piperidine- 2,6-Diketone (51 mg, 0.07 mmol, 85% yield). Example 22: Synthesis of Compound 162641
Figure 02_image423

化合物 162586：向N-[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]-N-[2-(2-碘烷基乙氧基)乙基]胺基甲酸三級丁酯(100 mg，0.16 mmol)於DMF (5 mL)中之溶液中添加3-(7-氮烷基-3-亞氧烷基-1H-異吲哚-2-基)哌啶-2,6-二酮(48 mg，0.19 mmol)及K 2CO 3(101 mg，0.31 mmol)，且在80℃下加熱3 h。混合物用DCM稀釋，用水及鹽水洗滌，經Na 2SO 4乾燥，濃縮且藉由管柱層析(MeOH:DCM=1:20，Rf=0.3)純化，得到呈黃色固體狀之N-[2-[2-[3-(7-氮烷基-3-亞氧烷基-1H-異吲哚-2-基)-2,6-雙(亞氧烷基)哌啶-1-基]乙氧基]乙基]-N-[2-[4-[6-(二甲胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(70 mg，0.09 mmol，產率58%)。 Compound 162586 : To N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2- To a solution of tert-butyl (2-iodoalkylethoxy)ethyl]carbamate (100 mg, 0.16 mmol) in DMF (5 mL) was added 3-(7-azanyl-3-ylidene Oxyalkyl-1H-isoindol-2-yl)piperidine-2,6-dione (48 mg, 0.19 mmol) and K 2 CO 3 (101 mg, 0.31 mmol), and heated at 80°C for 3 h. The mixture was diluted with DCM, washed with water and brine , dried over Na2SO4 , concentrated and purified by column chromatography (MeOH:DCM=1:20, Rf=0.3) to give N-[2 as a yellow solid -[2-[3-(7-Azaalkyl-3-oxyalkylene-1H-isoindol-2-yl)-2,6-bis(oxyalkylene)piperidin-1-yl] Ethoxy]ethyl]-N-[2-[4-[6-(Dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate Tertiary butyl ester (70 mg, 0.09 mmol, 58% yield).

化合物 162641：向N-[2-[2-[3-(7-氮烷基-3-亞氧烷基-1H-異吲哚-2-基)-2,6-雙(亞氧烷基)哌啶-1-基]乙氧基]乙基]-N-[2-[4-[6-(二甲基胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(70 mg，0.09 mmol)於DCM (2 mL)中之溶液中添加TFA (0.1 mL，1.35 mmol)，且在室溫下攪拌20 h。混合物用飽和NaHCO 3溶液中和至pH 8。將殘餘物溶解於DCM (20 mL)及水(10 mL)中。有機層用水(10 mL)及鹽水(10 mL)洗滌，經Na 2SO 4乾燥且濃縮，得到呈黃色固體狀之3-(7-氮烷基-3-亞氧烷基-1H-異吲哚-2-基)-1-[2-[2-[[2-[4-[6-(二甲胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]胺基]乙氧基]乙基]哌啶-2,6-二酮(30 mg，0.04 mmol，產率46%)。 實例23：化合物161598之合成

Figure 02_image425
Figure 02_image427
Compound 162641 : To N-[2-[2-[3-(7-azanyl-3-oxyalkylene-1H-isoindol-2-yl)-2,6-bis(oxyalkylene )piperidin-1-yl]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzo To a solution of tert-butylthiazol-6-yl]carbamate (70 mg, 0.09 mmol) in DCM (2 mL) was added TFA (0.1 mL, 1.35 mmol) and stirred at room temperature for 20 h. The mixture was neutralized to pH 8 with saturated NaHCO 3 solution. The residue was dissolved in DCM (20 mL) and water (10 mL). The organic layer was washed with water (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated to give 3-(7-azanyl-3-oxyalkylene-1H-isoind as a yellow solid Indol-2-yl)-1-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazole-6 -yl]amino]ethoxy]ethyl]piperidine-2,6-dione (30 mg, 0.04 mmol, 46% yield). Example 23: Synthesis of Compound 161598
Figure 02_image425
Figure 02_image427

化合物 161444：在0℃下向N-[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]胺基甲酸三級丁酯(200 mg，0.45 mmol)於DMF (5 mL)中之溶液中添加NaH (43 mg，1.79 mmol)且在室溫下攪拌1 h。向混合物中添加4-甲基苯磺酸2-[2-[2-[2-[2-[三級丁基(二甲基)矽基]氧基乙氧基]乙氧基]乙氧基]乙氧基]乙酯(681 mg，1.34 mmol)且在同一溫度下攪拌24 h。藉由添加水來淬滅反應物。所得固體藉由過濾收集且藉由管柱層析(EtOAc:DCM=7:3，Rf=0.4)純化，得到呈黃色油狀之N-[2-[2-[2-[2-[2-[三級丁基(二甲基)矽基]氧基乙氧基]乙氧基]乙氧基]乙氧基]乙基]-N-[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]胺基甲酸三級丁酯(252 mg，0.32 mmol，產率72%)。 Compound 161444 : N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]amino at 0°C To a solution of tert-butyl formate (200 mg, 0.45 mmol) in DMF (5 mL) was added NaH (43 mg, 1.79 mmol) and stirred at room temperature for 1 h. To the mixture was added 4-methylbenzenesulfonic acid 2-[2-[2-[2-[2-[tertiary butyl(dimethyl)silyl]oxyethoxy]ethoxy]ethoxy [Ethoxy]ethyl ester (681 mg, 1.34 mmol) and stirred at the same temperature for 24 h. The reaction was quenched by adding water. The resulting solid was collected by filtration and purified by column chromatography (EtOAc:DCM=7:3, Rf=0.4) to afford N-[2-[2-[2-[2-[2 -[tertiary butyl(dimethyl)silyl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[5-[4-[6-(dimethyl tert-butylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate (252 mg, 0.32 mmol, 72% yield).

化合物 161467：向N-[2-[2-[2-[2-[2-[三級丁基(二甲基)矽基]氧基乙氧基]乙氧基]乙氧基]乙氧基]乙基]-N-[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]胺基甲酸三級丁酯(252 mg，0.32 mmol)於THF (5 mL)中之溶液中逐滴添加TBAF (1M於THF中，1.94 mL，1.94 mmol)且在室溫下攪拌19 h。將反應混合物濃縮至乾燥且使殘餘物溶解於EtOAc (50 mL)中。混合物用水(50 mL)及鹽水(50 mL)洗滌，經Na 2SO 4乾燥。且濃縮至乾燥，得到呈黃色油狀之N-[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]-N-[2-[2-[2-[2-(2-羥基乙基氧基)乙氧基]乙氧基]乙氧基]乙基]胺基甲酸三級丁酯(214 mg，0.32 mmol，產率99%)。 Compound 161467 : To N-[2-[2-[2-[2-[2-[tertiary butyl(dimethyl)silyl]oxyethoxy]ethoxy]ethoxy]ethoxy Base] ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamic acid tri To a solution of butyl ester (252 mg, 0.32 mmol) in THF (5 mL) was added TBAF (IM in THF, 1.94 mL, 1.94 mmol) dropwise and stirred at room temperature for 19 h. The reaction mixture was concentrated to dryness and the residue was dissolved in EtOAc (50 mL). The mixture was washed with water (50 mL) and brine (50 mL), dried over Na 2 SO 4 . and concentrated to dryness to give N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl as a yellow oil tertiary butyl]-N-[2-[2-[2-[2-(2-hydroxyethyloxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate (214 mg , 0.32 mmol, yield 99%).

化合物 161530：在0℃下向N-[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]-N-[2-[2-[2-[2-(2-羥基乙基氧基)乙氧基]乙氧基]乙氧基]乙基]胺基甲酸三級丁酯(214 mg，0.32 mmol)及2-溴烷基乙酸三級丁酯(0.14 mL，0.96 mmol)於THF (3 mL)中之混合物中添加NaH (19 mg，0.80 mmol)且在室溫下攪拌42 h。藉由添加水來淬滅反應物。混合物用DCM (50 mL)稀釋，用水(50 mL)及鹽水(50 mL)洗滌，經Na 2SO 4乾燥，濃縮至乾燥且藉由管柱層析(EtOAc:Hex=1:1，Rf=0.35)純化，得到呈黃色油狀之2-[2-[2-[2-[2-[2-[[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙酸三級丁酯(130 mg，0.17 mmol，產率52%)。 Compound 161530 : N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-N at 0°C -[2-[2-[2-[2-(2-Hydroxyethyloxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate (214 mg, 0.32 mmol ) and tert-butyl 2-bromoalkylacetate (0.14 mL, 0.96 mmol) in THF (3 mL) were added NaH (19 mg, 0.80 mmol) and stirred at room temperature for 42 h. The reaction was quenched by adding water. The mixture was diluted with DCM (50 mL), washed with water (50 mL) and brine (50 mL), dried over Na 2 SO 4 , concentrated to dryness and analyzed by column chromatography (EtOAc:Hex=1:1, Rf= 0.35) purification to give 2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzene) as a yellow oil Andthiazol-2-yl]phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy tert-butyl]ethoxy]acetate (130 mg, 0.17 mmol, 52% yield).

化合物 161586：向2-[2-[2-[2-[2-[2-[[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙酸三級丁酯(130 mg，0.17 mmol)於DCM (2mL)中之溶液中添加TFA (0.38 mL，4.99 mmol)，且在室溫下攪拌22 h。將混合物濃縮至乾燥，得到呈橙色油狀之2-[2-[2-[2-[2-[2-[[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]胺基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙酸TFA鹽(179 mg，0.29 mmol，產率＞99%)。 Compound 161586 : To 2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl ]phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy] To a solution of tert-butyl acetate (130 mg, 0.17 mmol) in DCM (2 mL) was added TFA (0.38 mL, 4.99 mmol) and stirred at room temperature for 22 h. The mixture was concentrated to dryness to afford 2-[2-[2-[2-[2-[2-[[[5-[4-[6-(dimethylamino)-1,3 -Benzothiazol-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetic acid TFA salt (179 mg, 0.29 mmol , yield > 99%).

化合物 161598：將(2S,4R)-1-[(2S)-2-氮烷基-3,3-二甲基-丁醯基]-N-[[4-(4-甲基-1,3-噻唑-5-基)苯基]甲基]-4-氧烷基-吡咯啶-2-甲醯胺(79 mg，0.18 mmol)、2-[2-[2-[2-[2-[2-[[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]胺基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙酸(104 mg，0.17 mmol)、DIPEA (0.04 mL，0.25 mmol)及HATU (127 mg，0.33 mmol)於無水DMF (3 mL)中之混合物在室溫下攪拌18 h。將混合物溶解於DCM中，用水及鹽水洗滌，經無水Na 2SO 4乾燥，濃縮且藉由矽膠管柱層析(MeOH:DCM=3:100，Rf=0.32)純化，得到呈黃色固體狀之外消旋-(2R,4S)-N-[[4-(4-甲基-1,3-噻唑-5-基)苯基]甲基]-4-氧烷基-1-[外消旋-(2R)-2-[2-[2-[2-[2-[2-[2-[[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]胺基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙醯基胺基]-3,3-二甲基-丁醯基]吡咯啶-2-甲醯胺(16 mg，0.01 mmol，產率8%)。 實例24：化合物160570之合成

Figure 02_image429
Compound 161598 : (2S,4R)-1-[(2S)-2-azanyl-3,3-dimethyl-butyryl]-N-[[4-(4-methyl-1,3- Thiazol-5-yl)phenyl]methyl]-4-oxoalkyl-pyrrolidine-2-carboxamide (79 mg, 0.18 mmol), 2-[2-[2-[2-[2-[ 2-[[5-[4-[6-(Dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy A mixture of ethoxy]ethoxy]ethoxy]acetic acid (104 mg, 0.17 mmol), DIPEA (0.04 mL, 0.25 mmol) and HATU (127 mg, 0.33 mmol) in anhydrous DMF (3 mL) Stir at room temperature for 18 h. The mixture was dissolved in DCM, washed with water and brine, dried over anhydrous Na 2 SO 4 , concentrated and purified by silica gel column chromatography (MeOH:DCM = 3:100, Rf = 0.32) to obtain the rac-(2R,4S)-N-[[4-(4-Methyl-1,3-thiazol-5-yl)phenyl]methyl]-4-oxoalkyl-1-[racemic Spin-(2R)-2-[2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzo Thiazol-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetylamino]-3,3-di Methyl-butyryl]pyrrolidine-2-carboxamide (16 mg, 0.01 mmol, 8% yield). Example 24: Synthesis of Compound 160570
Figure 02_image429

化合物 160491：在0℃下向2-[4-[6-(二甲胺基)-2-氟烷基-吡啶-3-基]苯基]咪唑并[1,2-a]吡啶-6-醇(0.43 g，1.24 mmol)於無水DMF (4 mL)中之溶液中添加NaH (0.10 g，2.48 mmol)且在室溫下攪拌1 h。將含4-甲基苯磺酸2-[2-(4-甲基苯基)磺醯基氧基乙氧基]乙酯(1.54 g，3.72 mmol)之無水DMF (4 mL)添加至反應混合物中且在同一溫度下攪拌14 h。將混合物冷卻至0℃，用水(30 mL)淬滅且用DCM (30 mL)萃取。有機層用水(30 mL)及鹽水(30 mL)洗滌，經無水Na 2SO 4乾燥，濃縮且藉由管柱層析(EtOAc:DCM=1:5，Rf=0.33)純化，得到呈橙色固體狀之4-甲基苯磺酸2-[2-[2-[4-[6-(二甲胺基)-2-氟烷基-吡啶-3-基]苯基]咪唑并[1,2-a]吡啶-6-基]氧基乙氧基]乙酯(234 mg，0.40 mmol，產率32%)。 Compound 160491 : 2-[4-[6-(dimethylamino)-2-fluoroalkyl-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridine-6 at 0°C - To a solution of alcohol (0.43 g, 1.24 mmol) in anhydrous DMF (4 mL) was added NaH (0.10 g, 2.48 mmol) and stirred at room temperature for 1 h. 2-[2-(4-Methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (1.54 g, 3.72 mmol) in anhydrous DMF (4 mL) was added to the reaction The mixture was stirred at the same temperature for 14 h. The mixture was cooled to 0 °C, quenched with water (30 mL) and extracted with DCM (30 mL). The organic layer was washed with water (30 mL) and brine (30 mL), dried over anhydrous Na 2 SO 4 , concentrated and purified by column chromatography (EtOAc:DCM=1:5, Rf=0.33) to give an orange solid 2-[2-[2-[4-[6-(dimethylamino)-2-fluoroalkyl-pyridin-3-yl]phenyl]imidazo[1, 2-a]pyridin-6-yl]oxyethoxy]ethyl ester (234 mg, 0.40 mmol, 32% yield).

化合物 160508：將4-甲基苯磺酸2-[2-[[2-[4-[6-(二甲胺基)-2-氟烷基-吡啶-3-基]苯基]-3,8a-二氫咪唑并[1,2-a]吡啶-6-基]氧基]乙氧基]乙酯(232 mg，0.39 mmol)及NaI (70 mg，0.47 mmol)於ACN (2 mL)中之混合物在80℃下加熱14 h。向混合物中添加水且用DCM萃取。有機層用水(20 mL)及鹽水(20 mL)洗滌，經Na 2SO 4乾燥，濃縮且藉由層析(EtOAc:DCM=1:10，Rf=0.20)純化，得到呈淡黃色固體狀之6-氟烷基-5-[4-[6-[2-(2-碘烷基乙氧基)乙氧基]-3,8a-二氫咪唑并[1,2-a]吡啶-2-基]苯基]-N,N-二甲基-吡啶-2-胺(204 mg，0.37 mmol，產率95%)。 Compound 160508 : 4-methylbenzenesulfonic acid 2-[2-[[2-[4-[6-(dimethylamino)-2-fluoroalkyl-pyridin-3-yl]phenyl]-3 ,8a-dihydroimidazo[1,2-a]pyridin-6-yl]oxy]ethoxy]ethyl ester (232 mg, 0.39 mmol) and NaI (70 mg, 0.47 mmol) in ACN (2 mL ) was heated at 80°C for 14 h. Water was added to the mixture and extracted with DCM. The organic layer was washed with water (20 mL) and brine (20 mL), dried over Na 2 SO 4 , concentrated and purified by chromatography (EtOAc:DCM = 1:10, Rf = 0.20) to give the compound as a pale yellow solid. 6-fluoroalkyl-5-[4-[6-[2-(2-iodoalkylethoxy)ethoxy]-3,8a-dihydroimidazo[1,2-a]pyridine-2 -yl]phenyl]-N,N-dimethyl-pyridin-2-amine (204 mg, 0.37 mmol, 95% yield).

化合物 160570：將2-[2,6-雙(亞氧烷基)哌啶-3-基]-5-氧烷基-異吲哚-1,3-二酮(101 mg，0.37 mmol)、Cs 2CO 3(180 mg，0.55 mmol)及6-氟烷基-5-[4-[6-[2-(2-碘烷基乙氧基)乙氧基]-3,8a-二氫咪唑并[1,2-a]吡啶-2-基]苯基]-N,N-二甲基-吡啶-2-胺(101 mg，0.18 mmol)於DMF (3 mL)中之混合物在50℃下加熱4 h，且隨後在室溫下攪拌3天。混合物用水濕磨且收集所得沈澱物且藉由管柱層析(EtOAc:DCM=1:4，Rf=0.05)純化，得到呈棕色固體狀之2-[1-[2-[2-[2-[4-[6-(二甲胺基)-2-氟烷基-吡啶-3-基]苯基]咪唑并[1,2-a]吡啶-6-基]氧基乙氧基]乙基]-2,6-雙(亞氧烷基)哌啶-3-基]-5-氧烷基-異吲哚-1,3-二酮(15 mg，0.02 mmol，產率11%)。 實例25：化合物160703之合成

Figure 02_image431
Compound 160570 : 2-[2,6-bis(oxyalkylene)piperidin-3-yl]-5-oxoalkyl-isoindole-1,3-dione (101 mg, 0.37 mmol), Cs 2 CO 3 (180 mg, 0.55 mmol) and 6-fluoroalkyl-5-[4-[6-[2-(2-iodoalkylethoxy)ethoxy]-3,8a-dihydro A mixture of imidazo[1,2-a]pyridin-2-yl]phenyl]-N,N-dimethyl-pyridin-2-amine (101 mg, 0.18 mmol) in DMF (3 mL) at 50 It was heated at °C for 4 h and then stirred at room temperature for 3 days. The mixture was triturated with water and the resulting precipitate was collected and purified by column chromatography (EtOAc:DCM=1:4, Rf=0.05) to give 2-[1-[2-[2-[2 as a brown solid -[4-[6-(Dimethylamino)-2-fluoroalkyl-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy] Ethyl]-2,6-bis(oxyalkylene)piperidin-3-yl]-5-oxoalkyl-isoindole-1,3-dione (15 mg, 0.02 mmol, 11% yield ). Example 25: Synthesis of Compound 160703
Figure 02_image431

化合物 160686：將2-[2,6-雙(亞氧烷基)哌啶-3-基]-5-氧烷基-異吲哚-1,3-二酮(68 mg，0.25 mmol)、Cs 2CO 3(121 mg，0.37 mmol)及N-[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]-N-[2-(2-碘烷基乙氧基)乙基]胺基甲酸三級丁酯(80 mg，0.12 mmol)於DMF (5 mL)中之混合物在50℃下加熱3 h。混合物用DCM稀釋，用水萃取，經MgSO 4乾燥，濃縮且藉由NH矽膠管柱層析(MeOH:DCM=1:20，Rf=0.2)純化，得到呈黃色固體狀之N-[2-[2-[2-[2,6-雙(亞氧烷基)哌啶-3-基]-1,3-雙(亞氧烷基)異吲哚-5-基]氧基乙氧基]乙基]-N-[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]胺基甲酸三級丁酯(25 mg，0.03 mmol，產率25%)。 Compound 160686 : 2-[2,6-bis(oxyalkylene)piperidin-3-yl]-5-oxoalkyl-isoindole-1,3-dione (68 mg, 0.25 mmol), Cs 2 CO 3 (121 mg, 0.37 mmol) and N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridine-2- A mixture of tert-butyl]-N-[2-(2-iodoalkylethoxy)ethyl]carbamate (80 mg, 0.12 mmol) in DMF (5 mL) was heated at 50°C for 3 h. The mixture was diluted with DCM, extracted with water, dried over MgSO 4 , concentrated and purified by NH silica gel column chromatography (MeOH:DCM=1:20, Rf=0.2) to give N-[2-[ 2-[2-[2,6-bis(oxyalkylene)piperidin-3-yl]-1,3-bis(oxyalkylene)isoindol-5-yl]oxyethoxy] Ethyl]-N-[5-[4-[6-(Dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamic acid tertiary butyl Ester (25 mg, 0.03 mmol, 25% yield).

化合物 160703：在0℃下向N-[2-[2-[2-[2,6-雙(亞氧烷基)哌啶-3-基]-1,3-雙(亞氧烷基)異吲哚-5-基]氧基乙氧基]乙基]-N-[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]胺基甲酸三級丁酯(42 mg，0.05 mmol)於DCM (5 mL)中之溶液中添加TFA (0.04 mL，0.53 mmol)，且在室溫下攪拌23 h。混合物用飽和NaHCO 3溶液中和至pH 8且用DCM萃取。有機層經Na 2SO 4乾燥且濃縮至乾燥，得到呈黃色固體狀之2-[1-[2-[2-[[5-[4-[6-(二甲基胺基)-1,3-苯并噻唑-2-基]苯基]吡啶-2-基]胺基]乙氧基]乙基]-2,6-雙(亞氧烷基)哌啶-3-基]-5-氧烷基-異吲哚-1,3-二酮(34 mg，0.05 mmol，產率88%)。 實例26：化合物161262之合成

Figure 02_image433
Figure 02_image435
Compound 160703 : N-[2-[2-[2-[2,6-bis(oxyalkylene)piperidin-3-yl]-1,3-bis(oxyalkylene) at 0°C Isoindol-5-yl]oxyethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]benzene To a solution of tert-butyl]pyridin-2-yl]carbamate (42 mg, 0.05 mmol) in DCM (5 mL) was added TFA (0.04 mL, 0.53 mmol) and stirred at room temperature for 23 h . The mixture was neutralized to pH 8 with saturated NaHCO 3 solution and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated to dryness to afford 2-[1-[2-[2-[[5-[4-[6-(dimethylamino)-1, 3-Benzothiazol-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethyl]-2,6-bis(oxyalkylene)piperidin-3-yl]-5 -Oxyalkyl-isoindole-1,3-dione (34 mg, 0.05 mmol, 88% yield). Example 26: Synthesis of Compound 161262
Figure 02_image433
Figure 02_image435

化合物 161176：間2-[4-[6-[(2-甲基丙-2-基)氧基羰基胺基]吡啶-3-基]苯基]吡咯并[2,3-c]吡啶-1-甲酸三級丁酯(250 mg，0.51 mmol)於DMF (5 mL)中之溶液冷卻至0℃，添加NaH (37 mg，0.92 mmol)且在同一溫度下攪拌30 min。將4-[2-[2-(4-甲基苯基)磺醯基氧基乙氧基]乙氧基]苯-1,2-二甲酸二甲酯(302 mg，0.67 mmol)添加至反應混合物中且在室溫下攪拌20 h且加熱至50℃持續20 h。混合物用水淬滅且用DCM萃取。有機層用鹽水洗滌，經MgSO 4乾燥，濃縮且藉由矽膠管柱層析(EtOAc:DCM=1:2.3，Rf=0.375)純化，得到呈黃色油狀之4-[2-[2-[(2-甲基丙-2-基)氧基羰基-[5-[4-[1-[(2-甲基丙-2-基)氧基羰基]吡咯并[2,3-c]吡啶-2-基]苯基]吡啶-2-基]胺基]乙氧基]乙氧基]苯-1,2-二甲酸二甲酯(183 mg，0.24 mmol，產率46%)。 Compound 161176 : Between 2-[4-[6-[(2-methylprop-2-yl)oxycarbonylamino]pyridin-3-yl]phenyl]pyrrolo[2,3-c]pyridine- A solution of tert-butyl-1-carboxylate (250 mg, 0.51 mmol) in DMF (5 mL) was cooled to 0°C, NaH (37 mg, 0.92 mmol) was added and stirred at the same temperature for 30 min. Dimethyl 4-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]benzene-1,2-dicarboxylate (302 mg, 0.67 mmol) was added to The reaction mixture was stirred at room temperature for 20 h and heated to 50 °C for 20 h. The mixture was quenched with water and extracted with DCM. The organic layer was washed with brine, dried over MgSO 4 , concentrated and purified by silica gel column chromatography (EtOAc:DCM=1:2.3, Rf=0.375) to give 4-[2-[2-[ (2-Methylprop-2-yl)oxycarbonyl-[5-[4-[1-[(2-methylprop-2-yl)oxycarbonyl]pyrrolo[2,3-c]pyridine -2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]benzene-1,2-dicarboxylic acid dimethyl ester (183 mg, 0.24 mmol, 46% yield).

化合物 161217：向4-[2-[2-[(2-甲基丙-2-基)氧基羰基-[5-[4-[1-[(2-甲基丙-2-基)氧基羰基]吡咯并[2,3-c]吡啶-2-基]苯基]吡啶-2-基]胺基]乙氧基]乙氧基]苯-1,2-二甲酸二甲酯(273 mg，0.36 mmol)於EtOH (3 mL)中之溶液中添加含NaOH (228 mg，5.70 mmol)之水(3 mL)，且在室溫下攪拌4天。反應物用1 N HCl溶液中和至pH 1。所得沈澱物經收集，用水(10 mL)洗滌且真空乾燥，得到呈白色固體狀之4-[2-[2-[[5-[4-[1-[(2-甲基丙-2-基)氧基羰基]吡咯并[2,3-c]吡啶-2-基]苯基]吡啶-2-基]胺基]乙氧基]乙氧基]鄰苯二甲酸(201 mg，0.31 mmol，產率88%)。 Compound 161217 : To 4-[2-[2-[(2-methylprop-2-yl)oxycarbonyl-[5-[4-[1-[(2-methylpropan-2-yl)oxy ylcarbonyl]pyrrolo[2,3-c]pyridin-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]benzene-1,2-dicarboxylic acid dimethyl ester ( To a solution of 273 mg, 0.36 mmol) in EtOH (3 mL) was added NaOH (228 mg, 5.70 mmol) in water (3 mL) and stirred at room temperature for 4 days. The reaction was neutralized to pH 1 with 1 N HCl solution. The resulting precipitate was collected, washed with water (10 mL) and dried in vacuo to give 4-[2-[2-[[5-[4-[1-[(2-methylpropane-2- yl)oxycarbonyl]pyrrolo[2,3-c]pyridin-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]phthalic acid (201 mg, 0.31 mmol, yield 88%).

化合物 161230：將將4-[2-[2-[[5-[4-[1-[(2-甲基丙-2-基)氧基羰基]吡咯并[2,3-c]吡啶-2-基]苯基]吡啶-2-基]胺基]乙氧基]乙氧基]鄰苯二甲酸(201 mg，0.31 mmol)及3-氮烷基哌啶-2,6-二酮鹽酸鹽(78 mg，0.47 mmol)於吡啶(3 mL)中之混合物在120℃下加熱19 h。藉由真空移除溶劑且所得殘餘物用水濕磨。沈澱物經收集且藉由NH矽膠管柱層析(MeOH:DCM=3:100，Rf=0.25)純化，得到呈黃色固體狀之2-[4-[6-[2-[2-[2-[2,6-雙(亞氧烷基)哌啶-3-基]-1,3-雙(亞氧烷基)異吲哚-5-基]氧基乙氧基]乙基胺基]吡啶-3-基]苯基]吡咯并[2,3-c]吡啶-1-甲酸三級丁酯(47 mg，0.06 mmol，產率20%)。 Compound 161230 : 4-[2-[2-[[[5-[4-[1-[(2-methylprop-2-yl)oxycarbonyl]pyrrolo[2,3-c]pyridine- 2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]phthalic acid (201 mg, 0.31 mmol) and 3-azanylpiperidine-2,6-dione A mixture of hydrochloride (78 mg, 0.47 mmol) in pyridine (3 mL) was heated at 120 °C for 19 h. The solvent was removed by vacuum and the resulting residue was triturated with water. The precipitate was collected and purified by NH silica gel column chromatography (MeOH:DCM=3:100, Rf=0.25) to give 2-[4-[6-[2-[2-[2-[2-[4-[6-[2-[2-[2 -[2,6-bis(oxyalkylene)piperidin-3-yl]-1,3-bis(oxyalkylene)isoindol-5-yl]oxyethoxy]ethylamino ]pyridin-3-yl]phenyl]pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (47 mg, 0.06 mmol, 20% yield).

化合物 161262：向2-[4-[6-[2-[2-[2-[2,6-雙(亞氧烷基)哌啶-3-基]-1,3-雙(亞氧烷基)異吲哚-5-基]氧基乙氧基]乙基胺基]吡啶-3-基]苯基]吡咯并[2,3-c]吡啶-1-甲酸三級丁酯(47 mg，0.06 mmol)於DCM (3 mL)中之溶液中添加TFA (0.07 mL，0.96 mmol)，且在室溫下攪拌23 h。混合物用飽和NaHCO 3溶液中和至pH 8。所得沈澱物經收集，用水洗滌且經真空乾燥，得到呈黃色固體狀之2-[2,6-雙(亞氧烷基)哌啶-3-基]-5-[2-[2-[[5-[4-(1H-吡咯并[2,3-c]吡啶-2-基)苯基]吡啶-2-基]胺基]乙氧基]乙氧基]異吲哚-1,3-二酮(36 mg，0.05 mmol，產率82%)。 實例27：化合物164625之合成

Figure 02_image437
Compound 161262 : To 2-[4-[6-[2-[2-[2-[2,6-bis(oxyalkylene) piperidin-3-yl]-1,3-bis(oxyalkylene Base) isoindol-5-yl]oxyethoxy]ethylamino]pyridin-3-yl]phenyl]pyrrolo[2,3-c]pyridine-1-carboxylic acid tertiary butyl ester (47 mg, 0.06 mmol) in DCM (3 mL) was added TFA (0.07 mL, 0.96 mmol) and stirred at room temperature for 23 h. The mixture was neutralized to pH 8 with saturated NaHCO 3 solution. The resulting precipitate was collected, washed with water and dried in vacuo to give 2-[2,6-bis(oxyalkylene)piperidin-3-yl]-5-[2-[2-[ [5-[4-(1H-pyrrolo[2,3-c]pyridin-2-yl)phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]isoindole-1, 3-Diketone (36 mg, 0.05 mmol, 82% yield). Example 27: Synthesis of Compound 164625
Figure 02_image437

化合物 164581：將3-[2-(2-碘烷基乙氧基)乙氧基]丙酸三級丁酯(500 mg，1.45 mmol)、K 2CO 3(602 mg，4.36 mmol)及5-氮烷基-5-亞氧烷基-4-(6-氧烷基-3-亞氧烷基-1H-異吲哚-2-基)戊酸甲酯(467 mg，1.60 mmol)於DMF (15 mL)中之混合物在80℃下加熱7 h。混合物用EtOAc稀釋，用鹽水萃取，經MgSO 4乾燥，濃縮且藉由管柱層析(MeOH:DCM=1:20，Rf=0.48)純化，得到呈白色固體狀之3-[2-[2-[[2-[2,6-雙(亞氧烷基)哌啶-3-基]-1-亞氧烷基-3H-異吲哚-5-基]氧基]乙氧基]乙氧基]丙酸三級丁酯(387 mg，0.81 mmol，產率56%)。 Compound 164581 : tertiary butyl 3-[2-(2-iodoalkylethoxy)ethoxy]propionate (500 mg, 1.45 mmol), K 2 CO 3 (602 mg, 4.36 mmol) and 5 -Azaalkyl-5-oxyalkylene-4-(6-oxoalkyl-3-oxyalkylene-1H-isoindol-2-yl)pentanoic acid methyl ester (467 mg, 1.60 mmol) in The mixture in DMF (15 mL) was heated at 80 °C for 7 h. The mixture was diluted with EtOAc, extracted with brine, dried over MgSO 4 , concentrated and purified by column chromatography (MeOH:DCM=1:20, Rf=0.48) to give 3-[2-[2 as a white solid -[[2-[2,6-bis(oxyalkylene)piperidin-3-yl]-1-oxyalkylene-3H-isoindol-5-yl]oxy]ethoxy]ethyl Oxy]propionate tert-butyl (387 mg, 0.81 mmol, 56% yield).

化合物 164617：向3-[2-[2-[[2-[2,6-雙(亞氧烷基)哌啶-3-基]-1-亞氧烷基-3H-異吲哚-5-基]氧基]乙氧基]乙氧基]丙酸三級丁酯(387 mg，0.81 mmol)於DCM (10 mL)中之溶液中添加TFA (0.62 mL，8.12 mmol)且在室溫下攪拌15 h。混合物經濃縮至乾燥，得到成白色油狀之3-[2-[2-[[2-[2,6-雙(亞氧烷基)哌啶-3-基]-1-亞氧烷基-3H-異吲哚-5-基]氧基]乙氧基]乙氧基]丙酸TFA鹽(494 mg，1.18 mmol)。 Compound 164617 : To 3-[2-[2-[[2-[2,6-bis(oxyalkylene)piperidin-3-yl]-1-oxyalkylene-3H-isoindole-5 To a solution of tert-butyl]-oxy]ethoxy]ethoxy]propionate (387 mg, 0.81 mmol) in DCM (10 mL) was added TFA (0.62 mL, 8.12 mmol) and incubated at room temperature Stir for 15 h. The mixture was concentrated to dryness to afford 3-[2-[2-[[2-[2,6-bis(oxyalkylene)piperidin-3-yl]-1-oxyalkylene as a white oil -3H-isoindol-5-yl]oxy]ethoxy]ethoxy]propanoic acid TFA salt (494 mg, 1.18 mmol).

化合物 164625：將3-[2-[2-[[2-[2,6-雙(亞氧烷基)哌啶-3-基]-1-亞氧烷基-3H-異吲哚-5-基]氧基]乙氧基]乙氧基]丙酸(346 mg，0.82 mmol)、TBTU (352 mg，1.10 mmol)及2-[4-[6-(二甲胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-胺(190 mg，0.55 mmol)於吡啶(3 mL)中之混合物在室溫下攪拌17 h。向混合物中添加水且所得沈澱物藉由過濾收集且藉由管柱層析(MeOH:DCM=1:19，Rf=0.3)純化，得到呈黃色固體狀之3-[2-[2-[[2-[2,6-雙(亞氧烷基)哌啶-3-基]-1-亞氧烷基-3H-異吲哚-5-基]氧基]乙氧基]乙氧基]-N-[2-[4-[6-(二甲胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]丙醯胺(285 mg，0.36 mmol，產率66%)。 實例28：化合物164657之合成

Figure 02_image439
Compound 164625 : 3-[2-[2-[[2-[2,6-bis(oxyalkylene)piperidin-3-yl]-1-oxyalkylene-3H-isoindole-5 -yl]oxy]ethoxy]ethoxy]propionic acid (346 mg, 0.82 mmol), TBTU (352 mg, 1.10 mmol) and 2-[4-[6-(dimethylamino)pyridine-3 A mixture of -yl]phenyl]-1,3-benzothiazol-6-amine (190 mg, 0.55 mmol) in pyridine (3 mL) was stirred at room temperature for 17 h. Water was added to the mixture and the resulting precipitate was collected by filtration and purified by column chromatography (MeOH:DCM=1:19, Rf=0.3) to give 3-[2-[2-[ [2-[2,6-bis(oxyalkylene)piperidin-3-yl]-1-oxyalkylene-3H-isoindol-5-yl]oxy]ethoxy]ethoxy ]-N-[2-[4-[6-(Dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]propionamide (285 mg, 0.36 mmol , yield 66%). Example 28: Synthesis of Compound 164657
Figure 02_image439

化合物 164263：將N-(2-溴烷基-1,3-苯并噻唑-6-基)胺基甲酸三級丁酯(1100 mg，3.34 mmol)、N,N-二甲基-5-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)-3-(三氟甲基)苯基]吡啶-2-胺(1704 mg，4.34 mmol)、Pd(dppf)Cl 2(247 mg，0.33 mmol)及2M Na 2CO 3(水性)溶液(5 mL，10.02 mmol)於二㗁烷(35 mL)中之混合物在氬氣下在80℃下加熱16 h。混合物經由矽藻土墊過濾且將殘餘物溶解於EtOAc (100 mL)及水(50 mL)中。有機層用水(50 mL)、鹽水(50 mL)洗滌，經Na 2SO 4乾燥且濃縮至乾燥。殘餘物藉由管柱層析(EtOAc:Hex=1:4，Rf=0.15)純化，得到呈黃色油狀之N-[2-[4-[6-(二甲胺基)吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(1.06 g，2.05 mmol，產率61%)。 Compound 164263 : tertiary butyl N-(2-bromoalkyl-1,3-benzothiazol-6-yl)carbamate (1100 mg, 3.34 mmol), N,N-dimethyl-5- [4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)phenyl]pyridin-2-amine (1704 mg, 4.34 mmol), a mixture of Pd(dppf)Cl 2 (247 mg, 0.33 mmol) and 2M Na 2 CO 3 (aqueous) solution (5 mL, 10.02 mmol) in dioxane (35 mL) was Heated at 80 °C for 16 h under argon. The mixture was filtered through a pad of celite and the residue was dissolved in EtOAc (100 mL) and water (50 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over Na 2 SO 4 and concentrated to dryness. The residue was purified by column chromatography (EtOAc:Hex=1:4, Rf=0.15) to give N-[2-[4-[6-(dimethylamino)pyridine-3- tert-butyl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate (1.06 g, 2.05 mmol, 61% yield).

化合物 164346：在0℃下向N-[2-[4-[6-(二甲胺基)吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(1056 mg，2.05 mmol)於DMF (20 mL)中之溶液中添加NaH (148 mg，6.16 mmol)且在25℃下攪拌1 h。將含4-甲基苯磺酸2-[2-(4-甲基苯基)磺醯基氧基乙氧基]乙酯(2.55 g，6.16 mmol)之DMF (20 mL)添加至反應混合物中且在室溫下攪拌14 h。混合物在0℃下用水淬滅。將殘餘物溶解於EtOAc (50 mL)及水(50 mL)中。有機層用水(50 mL)、鹽水(50 mL)洗滌，經Na 2SO 4乾燥且濃縮至乾燥。殘餘物藉由管柱層析(EtOAc:Hex=1:1，Rf=0.4)純化，得到呈黃色油狀之4-甲基苯磺酸2-[2-[[2-[4-[6-(二甲胺基)吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙酯(955 mg，1.26 mmol，產率61%)。 Compound 164346 : N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzo To a solution of tert-butylthiazol-6-yl]carbamate (1056 mg, 2.05 mmol) in DMF (20 mL) was added NaH (148 mg, 6.16 mmol) and stirred at 25 °C for 1 h. 2-[2-(4-Methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (2.55 g, 6.16 mmol) in DMF (20 mL) was added to the reaction mixture and stirred at room temperature for 14 h. The mixture was quenched with water at 0 °C. The residue was dissolved in EtOAc (50 mL) and water (50 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over Na 2 SO 4 and concentrated to dryness. The residue was purified by column chromatography (EtOAc:Hex=1:1, Rf=0.4) to give 4-methylbenzenesulfonic acid 2-[2-[[2-[4-[6 -(Dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl )oxycarbonyl]amino]ethoxy]ethyl ester (955 mg, 1.26 mmol, 61% yield).

化合物 164398：將4-甲基苯磺酸2-[2-[[2-[4-[6-(二甲胺基)吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙酯(955 mg，1.26 mmol)、NaI (378 mg，2.52 mmol)於MeCN (20 mL)中之混合物在80℃下加熱17 h。將殘餘物溶解於EtOAc (50 mL)及水(50 mL)中。有機層用水(50 mL)、鹽水(50 mL)洗滌，經Na 2SO 4乾燥且濃縮。殘餘物藉由管柱層析(EtOAc:Hex=1:1，Rf=0.7)純化，得到呈黃色油狀之N-[2-[4-[6-(二甲胺基)吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]-N-[2-(2-碘烷基乙氧基)乙基]胺基甲酸三級丁酯(805 mg，1.13 mmol，產率90%)。 Compound 164398 : 4-methylbenzenesulfonic acid 2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl] -1,3-Benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl ester (955 mg, 1.26 mmol), NaI (378 mg, 2.52 mmol) in MeCN (20 mL) was heated at 80 °C for 17 h. The residue was dissolved in EtOAc (50 mL) and water (50 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over Na 2 SO 4 and concentrated. The residue was purified by column chromatography (EtOAc:Hex=1:1, Rf=0.7) to give N-[2-[4-[6-(dimethylamino)pyridine-3- Base]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]-N-[2-(2-iodoalkylethoxy)ethyl]carbamate tri Grade butyl ester (805 mg, 1.13 mmol, 90% yield).

化合物 164350：將N-[2-[4-[6-(二甲胺基)吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]-N-[2-(2-碘烷基乙氧基)乙基]胺基甲酸三級丁酯(110 mg，0.15 mmol)、K 2CO 3(64 mg，0.46 mmol)及5-氮烷基-5-亞氧烷基-4-(6-氧烷基-3-亞氧烷基-1H-異吲哚-2-基)戊酸甲酯(50 mg，0.17 mmol)於DMF (2.5 mL)中之混合物在80℃下加熱8 h。向混合物中添加水，用DCM萃取，經MgSO 4乾燥且濃縮至乾燥。殘餘物藉由管柱層析(MeOH:DCM= 1:20，Rf = 0.4)純化，得到呈黃色固體狀之N-[2-[2-[[2-[2,6-雙(亞氧烷基)哌啶-3-基]-1-亞氧烷基-3H-異吲哚-5-基]氧基]乙氧基]乙基]-N-[2-[4-[6-(二甲胺基)吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(110 mg，0.13 mmol，產率84%)。 Compound 164350 : N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazole-6- Base]-N-[2-(2-iodoalkylethoxy)ethyl]carbamate tertiary butyl ester (110 mg, 0.15 mmol), K 2 CO 3 (64 mg, 0.46 mmol) and 5- Azaalkyl-5-oxyalkylene-4-(6-oxoalkyl-3-oxyalkylene-1H-isoindol-2-yl)pentanoic acid methyl ester (50 mg, 0.17 mmol) in DMF (2.5 mL) was heated at 80 °C for 8 h. Water was added to the mixture, extracted with DCM, dried over MgSO 4 and concentrated to dryness. The residue was purified by column chromatography (MeOH:DCM = 1:20, Rf = 0.4) to give N-[2-[2-[[2-[2,6-bis(oxygen Alkyl)piperidin-3-yl]-1-oxyalkylene-3H-isoindol-5-yl]oxy]ethoxy]ethyl]-N-[2-[4-[6- (Dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate (110 mg, 0.13 mmol , yield 84%).

化合物 164657：在25℃下向N-[2-[2-[[2-[2,6-雙(亞氧烷基)哌啶-3-基]-1-亞氧烷基-3H-異吲哚-5-基]氧基]乙氧基]乙基]-N-[2-[4-[6-(二甲胺基)吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(550 mg，0.65 mmol)於DCM (10 mL)中之溶液中添加TFA (0.75 mL，9.76 mmol)且攪拌15 h。將混合物傾入冰水中且用飽和NaHCO 3溶液中和至pH 8。將殘餘物溶解於DCM (20 mL)及水(10 mL)中。有機層用水(10 mL)、鹽水(10 mL)洗滌，經Na 2SO 4乾燥且濃縮至乾燥。殘餘物藉由管柱層析(DCM:MeOH= 10:1，Rf = 0.58)純化，得到呈黃色固體狀之3-[6-[2-[2-[[2-[4-[6-(二甲胺基)吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]胺基]乙氧基]乙氧基]-3-亞氧烷基-1H-異吲哚-2-基]哌啶-2,6-二酮(254 mg，0.34 mmol，產率52%)。 實例29：化合物162640之合成

Figure 02_image441
Compound 164657 : N-[2-[2-[[2-[2,6-bis(oxyalkylene)piperidin-3-yl]-1-oxyalkylene-3H-iso Indol-5-yl]oxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl) To a solution of tert-butyl phenyl]-1,3-benzothiazol-6-yl]carbamate (550 mg, 0.65 mmol) in DCM (10 mL) was added TFA (0.75 mL, 9.76 mmol) and Stir for 15 h. The mixture was poured into ice water and neutralized to pH 8 with saturated NaHCO 3 solution. The residue was dissolved in DCM (20 mL) and water (10 mL). The organic layer was washed with water (10 mL), brine (10 mL), dried over Na 2 SO 4 and concentrated to dryness. The residue was purified by column chromatography (DCM:MeOH=10:1, Rf=0.58) to give 3-[6-[2-[2-[[2-[4-[6- (Dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]-3 -Oxyalkylene-1H-isoindol-2-yl]piperidine-2,6-dione (254 mg, 0.34 mmol, 52% yield). Example 29: Synthesis of Compound 162640
Figure 02_image441

化合物 162534：將N-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶-2-基]胺基甲酸三級丁酯(1.52 g，4.75 mmol)、2-(4-溴苯基)-6-甲氧基-咪唑并[1,2-a]吡啶(1.2 g，3.96 mmol)及三苯膦(34.6 mg，0.13 mmol)於EtOH (4 mL)及甲苯(2.8 mL)中之溶液用氬氣淨化，且隨後逐滴添加K 2CO 3溶液(1.75M，7.92 mL，13.85 mmol)。在氬氣下向混合物中添加Pd(OAc) 2(87 mg，0.40 mmol)且在90℃下加熱4 h。混合物經由矽藻土墊過濾，傾入飽和NaHCO 3溶液中且用EtOAc萃取。有機層經MgSO 4乾燥，濃縮且藉由管柱層析(EtOAc:DCM = 1:4，Rf = 0.3)純化，得到呈淡棕色固體狀之N-[4-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]胺基甲酸三級丁酯(987 mg，2.37 mmol，產率60%)。 Compound 162534 : N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamic acid Butyl ester (1.52 g, 4.75 mmol), 2-(4-bromophenyl)-6-methoxy-imidazo[1,2-a]pyridine (1.2 g, 3.96 mmol) and triphenylphosphine (34.6 mg , 0.13 mmol) in EtOH (4 mL) and toluene (2.8 mL) was purged with argon, and then K 2 CO 3 solution (1.75M, 7.92 mL, 13.85 mmol) was added dropwise. To the mixture was added Pd(OAc) 2 (87 mg, 0.40 mmol) under argon and heated at 90 °C for 4 h. The mixture was filtered through a pad of celite, poured into saturated NaHCO 3 solution and extracted with EtOAc. The organic layer was dried over MgSO 4 , concentrated and purified by column chromatography (EtOAc:DCM = 1:4, Rf = 0.3) to give N-[4-[4-(6-methoxyl) as a light brown solid tert-butyl imidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate (987 mg, 2.37 mmol, 60% yield).

化合物 162547：在0℃下向4-甲基苯磺酸2-[2-(4-甲基苯基)磺醯基氧基乙氧基]乙酯(2.86 g，6.90 mmol)於DMF (10 mL)中之溶液中添加NaH (368 mg，9.20 mmol)且在室溫下攪拌1 h。向混合物中添加含4-甲基苯磺酸2-[2-(4-甲基苯基)磺醯基氧基乙氧基]乙酯(2.86 g，6.90 mmol)之DMF (10 mL)且在室溫下攪拌19 h。將混合物冷卻至0℃，藉由添加水淬滅且用DCM稀釋。所得混合物用水及鹽水洗滌，經Na 2SO 4乾燥，濃縮且藉由管柱層析(EtOAc:DCM= 4:1，Rf = 0.4)純化，得到呈橙色油狀之4-甲基苯磺酸2-[2-[[4-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙酯(924 mg，1.40 mmol，產率61%)。 Compound 162547 : 2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (2.86 g, 6.90 mmol) in DMF (10 mL) was added NaH (368 mg, 9.20 mmol) and stirred at room temperature for 1 h. To the mixture was added 2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (2.86 g, 6.90 mmol) in DMF (10 mL) and Stir at room temperature for 19 h. The mixture was cooled to 0 °C, quenched by adding water and diluted with DCM. The resulting mixture was washed with water and brine, dried over Na2SO4 , concentrated and purified by column chromatography (EtOAc:DCM=4:1, Rf = 0.4) to give 4-methylbenzenesulfonic acid as orange oil 2-[2-[[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropane -2-yl)oxycarbonyl]amino]ethoxy]ethyl ester (924 mg, 1.40 mmol, 61% yield).

化合物 162568：將4-甲基苯磺酸2-[2-[[4-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙酯(924 mg，1.40 mmol)及NaI (421 mg，2.81 mmol)於CH 3CN (20 mL)中之混合物在80℃下加熱17 h。混合物用DCM稀釋，用水(50 mL)及鹽水(50 mL)洗滌，經Na 2SO 4乾燥，濃縮且藉由管柱層析(MeOH:DCM = 1:100，Rf = 0.19)純化，得到呈橙色固體狀之N-[2-(2-碘烷基乙氧基)乙基]-N-[4-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]胺基甲酸三級丁酯(585 mg，0.95 mmol，產率68%)。 Compound 162568 : 2-[2-[[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridine-2 -yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl ester (924 mg, 1.40 mmol) and NaI (421 mg, 2.81 mmol) in CH 3 CN ( 20 mL) was heated at 80 °C for 17 h. The mixture was diluted with DCM, washed with water (50 mL) and brine (50 mL), dried over Na 2 SO 4 , concentrated and purified by column chromatography (MeOH:DCM = 1:100, Rf = 0.19) to give N-[2-(2-iodoalkylethoxy)ethyl]-N-[4-[4-(6-methoxyimidazo[1,2-a]pyridine-2- yl)phenyl]pyridin-2-yl]carbamate (585 mg, 0.95 mmol, 68% yield).

化合物 162599：將N-[2-(2-碘烷基乙氧基)乙基]-N-[4-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]胺基甲酸三級丁酯(250 mg，0.41 mmol)、3-(6-氧烷基-3-亞氧烷基-1H-異吲哚-2-基)哌啶-2,6-二酮(212 mg，0.81 mmol)及K 2CO 3(169 mg，1.22 mmol)於DMF (4 mL)中之溶液在50℃下加熱3 h。混合物用水淬滅，且藉由過濾收集所得固體。固體用水洗滌且殘餘物藉由NH凝膠管柱層析(MeOH:DCM = 3:100，Rf = 0.33)純化，得到呈白色固體狀之N-[2-[2-[[2-[2,6-雙(亞氧烷基)哌啶-3-基]-1-亞氧烷基-3H-異吲哚-5-基]氧基]乙氧基]乙基]-N-[4-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]胺基甲酸三級丁酯(76 mg，0.10 mmol，產率25%)。 Compound 162599 : N-[2-(2-iodoalkylethoxy) ethyl]-N-[4-[4-(6-methoxyimidazo[1,2-a]pyridine-2- yl)phenyl]pyridin-2-yl]tert-butylcarbamate (250 mg, 0.41 mmol), 3-(6-oxoalkyl-3-oxyalkylene-1H-isoindole-2- A solution of piperidine-2,6-dione (212 mg, 0.81 mmol) and K 2 CO 3 (169 mg, 1.22 mmol) in DMF (4 mL) was heated at 50° C. for 3 h. The mixture was quenched with water, and the resulting solid was collected by filtration. The solid was washed with water and the residue was purified by NH gel column chromatography (MeOH:DCM = 3:100, Rf = 0.33) to give N-[2-[2-[[2-[2 as a white solid ,6-bis(oxyalkylene)piperidin-3-yl]-1-oxyalkylene-3H-isoindol-5-yl]oxy]ethoxy]ethyl]-N-[4 -[4-(6-Methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamic acid tertiary butyl ester (76 mg, 0.10 mmol, yield 25%).

化合物 162640向N-[2-[2-[[2-[2,6-雙(亞氧烷基)哌啶-3-基]-1-亞氧烷基-3H-異吲哚-5-基]氧基]乙氧基]乙基]-N-[4-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]胺基甲酸三級丁酯(76 mg，0.10 mmol)於DCM (2 mL)中之溶液中添加TFA (0.12 mL，1.53 mmol)，且攪拌38 h。將混合物傾入冰水中且用飽和NaHCO 3溶液中和至pH 8。將殘餘物溶解於DCM (20 mL)及水(10 mL)中。有機層用水(10 mL)、鹽水(10 mL)洗滌，經Na 2SO 4乾燥，濃縮且藉由管柱層析(DCM:MeOH = 100:3，Rf =0.35)純化，得到呈淺棕色固體狀之3-[6-[2-[2-[[4-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]胺基]乙氧基]乙氧基]-3-亞氧烷基-1H-異吲哚-2-基]哌啶-2,6-二酮(22 mg，0.03 mmol，產率33%)。 實例30：化合物162843之合成

Figure 02_image443
Compound 162640 to N-[2-[2-[[2-[2,6-bis(oxyalkylene)piperidin-3-yl]-1-oxyalkylene-3H-isoindole-5- Base]oxy]ethoxy]ethyl]-N-[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl ] To a solution of tert-butyl carbamate (76 mg, 0.10 mmol) in DCM (2 mL) was added TFA (0.12 mL, 1.53 mmol) and stirred for 38 h. The mixture was poured into ice water and neutralized to pH 8 with saturated NaHCO 3 solution. The residue was dissolved in DCM (20 mL) and water (10 mL). The organic layer was washed with water (10 mL), brine (10 mL), dried over Na 2 SO 4 , concentrated and purified by column chromatography (DCM:MeOH=100:3, Rf=0.35) to give a light brown solid 3-[6-[2-[2-[[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl] Amino]ethoxy]ethoxy]-3-oxyalkylene-1H-isoindol-2-yl]piperidine-2,6-dione (22 mg, 0.03 mmol, 33% yield) . Example 30: Synthesis of Compound 162843
Figure 02_image443

化合物 162723：在0℃下向4-甲基苯磺酸2-[2-(4-甲基苯基)磺醯基氧基乙氧基]乙酯(4.72 g，11.38 mmol)於DMF (30 mL)中之溶液中添加NaH (455 mg，11.38 mmol)且在室溫下攪拌1 h。將含4-甲基苯磺酸2-[2-(4-甲基苯基)磺醯基氧基乙氧基]乙酯(4.72 g，11.38 mmol)之DMF (30 mL)添加至反應混合物中且在室溫下再攪拌16 h。將混合物冷卻至0℃且用水淬滅。混合物用DCM稀釋，用水及鹽水洗滌，經Na 2SO 4乾燥，濃縮且藉由管柱層析(EtOAc:Hex = 1:1，Rf = 0.23)純化，得到呈橙色固體狀之4-甲基苯磺酸2-[2-[[5-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙酯(1.3 g，1.97 mmol，產率69%)。 Compound 162723 : 2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (4.72 g, 11.38 mmol) in DMF (30 mL) was added NaH (455 mg, 11.38 mmol) and stirred at room temperature for 1 h. 2-[2-(4-Methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (4.72 g, 11.38 mmol) in DMF (30 mL) was added to the reaction mixture and stirred at room temperature for another 16 h. The mixture was cooled to 0 °C and quenched with water. The mixture was diluted with DCM, washed with water and brine , dried over Na2SO4 , concentrated and purified by column chromatography (EtOAc:Hex = 1:1, Rf = 0.23) to give 4-methyl as an orange solid Benzenesulfonic acid 2-[2-[[5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2- Methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl ester (1.3 g, 1.97 mmol, 69% yield).

化合物 162762：將4-甲基苯磺酸2-[2-[[5-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙酯(1.3 g，1.97 mmol)及NaI (592 mg，3.95 mmol)於ACN (10 mL)中之混合物在80℃下加熱15 h。向混合物中添加水且用DCM萃取。有機層用水(50 mL)、鹽水(50 mL)洗滌，經Na 2SO 4乾燥，濃縮至乾且藉由層析(MeOH:DCM = 1:100，Rf = 0.19)純化，得到呈黃色固體狀之N-[2-(2-碘烷基乙氧基)乙基]-N-[5-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]胺基甲酸三級丁酯(920 mg，1.50 mmol，產率76%)。 Compound 162762 : 4-methylbenzenesulfonic acid 2-[2-[[5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridine-2 -yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl ester (1.3 g, 1.97 mmol) and NaI (592 mg, 3.95 mmol) in ACN (10 mL ) was heated at 80°C for 15 h. Water was added to the mixture and extracted with DCM. The organic layer was washed with water (50 mL), brine (50 mL), dried over Na2SO4 , concentrated to dryness and purified by chromatography (MeOH:DCM = 1:100, Rf = 0.19) to give a yellow solid N-[2-(2-iodoalkylethoxy)ethyl]-N-[5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)benzene yl]pyridin-2-yl]carbamate tert-butyl ester (920 mg, 1.50 mmol, yield 76%).

化合物 162798：將N-[2-(2-碘烷基乙氧基)乙基]-N-[5-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]胺基甲酸三級丁酯(200 mg，0.33 mmol)、3-(6-氧烷基-3-亞氧烷基-1H-異吲哚-2-基)哌啶-2,6-二酮(169 mg，0.65 mmol)及Na 2CO 3(103 mg，0.98 mmol)於DMF (4 mL)中之混合物在50℃下加熱37 h。向混合物中添加水且所得沈澱物藉由過濾收集，用水洗滌且藉由NH凝膠管柱層析(MeOH:DCM = 1:100，Rf=0.21)純化，得到呈黃色固體狀之N-[2-[2-[[2-[2,6-雙(亞氧烷基)哌啶-3-基]-1-亞氧烷基-3H-異吲哚-5-基]氧基]乙氧基]乙基]-N-[5-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]胺基甲酸三級丁酯(68 mg，0.09 mmol，產率28%)。 Compound 162798 : N-[2-(2-iodoalkylethoxy) ethyl]-N-[5-[4-(6-methoxyimidazo[1,2-a]pyridine-2- yl)phenyl]pyridin-2-yl]tert-butyl carbamate (200 mg, 0.33 mmol), 3-(6-oxoalkyl-3-oxyalkylene-1H-isoindole-2- A mixture of piperidine-2,6-dione (169 mg, 0.65 mmol) and Na 2 CO 3 (103 mg, 0.98 mmol) in DMF (4 mL) was heated at 50° C. for 37 h. Water was added to the mixture and the resulting precipitate was collected by filtration, washed with water and purified by NH gel column chromatography (MeOH:DCM = 1:100, Rf = 0.21) to give N-[ 2-[2-[[2-[2,6-bis(oxyalkylene)piperidin-3-yl]-1-oxyalkylene-3H-isoindol-5-yl]oxy]ethyl Oxy]ethyl]-N-[5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamic acid tertiary Butyl ester (68 mg, 0.09 mmol, 28% yield).

化合物 162843：向N-[2-[2-[[2-[2,6-雙(亞氧烷基)哌啶-3-基]-1-亞氧烷基-3H-異吲哚-5-基]氧基]乙氧基]乙基]-N-[5-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]胺基甲酸三級丁酯(68 mg，0.09 mmol)於DCM (2 mL)中之溶液中添加TFA (0.07 mL，0.9100 mmol)，且在室溫下攪拌48 h。混合物用DCM (3 mL)稀釋且用飽和NaHCO 3(水性)溶液中和至pH 8。沈澱物經收集且用DCM洗滌，得到呈黃色固體狀之3-[6-[2-[2-[[5-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]胺基]乙氧基]乙氧基]-3-亞氧烷基-1H-異吲哚-2-基]哌啶-2,6-二酮(38 mg，0.05 mmol，產率59%)。 實例31：化合物165559之合成

Figure 02_image445
Compound 162843 : To N-[2-[2-[[2-[2,6-bis(oxyalkylene)piperidin-3-yl]-1-oxyalkylene-3H-isoindole-5 -yl]oxy]ethoxy]ethyl]-N-[5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridine-2- To a solution of tert-butyl]carbamate (68 mg, 0.09 mmol) in DCM (2 mL) was added TFA (0.07 mL, 0.9100 mmol) and stirred at room temperature for 48 h. The mixture was diluted with DCM (3 mL) and neutralized to pH 8 with saturated NaHCO 3 (aq) solution. The precipitate was collected and washed with DCM to give 3-[6-[2-[2-[[5-[4-(6-methoxyimidazo[1,2-a]pyridine- 2-yl)phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]-3-oxyalkylene-1H-isoindol-2-yl]piperidine-2,6-di Ketone (38 mg, 0.05 mmol, 59% yield). Example 31: Synthesis of Compound 165559
Figure 02_image445

化合物 165511：將4-甲基苯磺酸2-[2-(4-甲基苯基)磺醯基氧基乙氧基]乙酯(2567 mg，6.19 mmol)於DMF (10 mL)這種溶液冷卻至0℃，添加NaH (248 mg，6.19 mmol)，且隨後在室溫下攪拌1 h。將4-甲基苯磺酸2-[2-(4-甲基苯基)磺醯基氧基乙氧基]乙酯(2567 mg，6.19 mmol)添加至反應混合物中且在室溫下攪拌17 h。將反應物冷卻至0℃且藉由添加水淬滅。混合物用DCM稀釋，用水及鹽水洗滌，經Na 2SO 4乾燥，濃縮且藉由管柱層析(DCM:EtOAc = 10:1，Rf = 0.3)純化，得到呈白色固體狀之4-甲基苯磺酸2-[2-[[4-[4-(6-氟烷基-1,3-苯并噻唑-2-基)苯基]吡啶-2-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙酯(455 mg，0.68 mmol，產率33%)。 Compound 165511 : 2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (2567 mg, 6.19 mmol) in DMF (10 mL) The solution was cooled to 0 °C, NaH (248 mg, 6.19 mmol) was added, and then stirred at room temperature for 1 h. 2-[2-(4-Methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (2567 mg, 6.19 mmol) was added to the reaction mixture and stirred at room temperature 17 h. The reaction was cooled to 0 °C and quenched by adding water. The mixture was diluted with DCM, washed with water and brine , dried over Na2SO4 , concentrated and purified by column chromatography (DCM:EtOAc = 10:1, Rf = 0.3) to give 4-methyl as a white solid Benzenesulfonic acid 2-[2-[[4-[4-(6-fluoroalkyl-1,3-benzothiazol-2-yl)phenyl]pyridin-2-yl]-[(2-methyl Propan-2-yl)oxycarbonyl]amino]ethoxy]ethyl ester (455 mg, 0.68 mmol, 33% yield).

化合物 165547：將5-氮烷基-5-亞氧烷基-4-(6-氧烷基-3-亞氧烷基-1H-異吲哚-2-基)戊酸甲酯(220 mg，0.75 mmol)、K 2CO 3(284 mg，2.06 mmol)、KI (11 mg，0.07 mmol)及4-甲基苯磺酸2-[2-[[4-[4-(6-氟烷基-1,3-苯并噻唑-2-基)苯基]吡啶-2-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙酯(455 mg，0.69 mmol)於DMF (6 mL)中之混合物在80℃下加熱7 h。混合物用EtOAc (20 mL)稀釋，用水(10 mL)及鹽水(10 mL)萃取，經Na 2SO 4乾燥，濃縮且藉由管柱層析(MeOH:DCM= 1:20，Rf = 0.4)純化，得到呈白色固體之N-[2-[2-[[2-2,6-雙(亞氧烷基)哌啶-3-基]-1-亞氧烷基-3H-異吲哚-5-基]氧基]乙氧基]乙基]-N-[4-[4-(6-氟烷基-1,3-苯并噻唑-2-基)苯基]吡啶-2-基]胺基甲酸三級丁酯(245 mg，0.33 mmol，產率48%)。 Compound 165547 : methyl 5-azanyl-5-oxyalkylene-4-(6-oxoalkyl-3-oxyalkylene-1H-isoindol-2-yl)pentanoate (220 mg , 0.75 mmol), K 2 CO 3 (284 mg, 2.06 mmol), KI (11 mg, 0.07 mmol) and 4-methylbenzenesulfonic acid 2-[2-[[4-[4-(6-fluoroalkane Base-1,3-benzothiazol-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl ester ( A mixture of 455 mg, 0.69 mmol) in DMF (6 mL) was heated at 80 °C for 7 h. The mixture was diluted with EtOAc (20 mL), extracted with water (10 mL) and brine (10 mL), dried over Na 2 SO 4 , concentrated and purified by column chromatography (MeOH:DCM=1:20, Rf=0.4) Purification afforded N-[2-[2-[[2-2,6-bis(oxyalkylene)piperidin-3-yl]-1-oxyalkylene-3H-isoindole as a white solid -5-yl]oxy]ethoxy]ethyl]-N-[4-[4-(6-fluoroalkyl-1,3-benzothiazol-2-yl)phenyl]pyridine-2- base] tertiary butyl carbamate (245 mg, 0.33 mmol, 48% yield).

化合物 165559：向N-[2-[2-[[2-[2,6-雙(亞氧烷基)哌啶-3-基]-1-亞氧烷基-3H-異吲哚-5-基]氧基]乙氧基]乙基]-N-[4-[4-(6-氟烷基-1,3-苯并噻唑-2-基)苯基]吡啶-2-基]胺基甲酸三級丁酯(245 mg，0.33 mmol)於DCM (5 mL)中之溶液中添加TFA (0.38 mL，4.89 mmol)，且在室溫下攪拌20 h。混合物用DCM (20 mL)稀釋且用飽和NaHCO 3溶液中和至pH 8。混合物用水萃取，經MgSO 4乾燥，濃縮且藉由管柱層析(DCM:MeOH = 20:1，Rf = 0.3)純化，得到呈白色固體狀之3-[6-[2-[2-[[4-[4-(6-氟烷基-1,3-苯并噻唑-2-基)苯基]吡啶-2-基]胺基]乙氧基]乙氧基]-3-亞氧烷基-1H-異吲哚-2-基]哌啶-2,6-二酮(160 mg，0.24 mmol，產率75%)。 實例32：化合物163685之合成

Figure 02_image447
Compound 165559 : To N-[2-[2-[[2-[2,6-bis(oxyalkylene) piperidin-3-yl]-1-oxyalkylene-3H-isoindole-5 -yl]oxy]ethoxy]ethyl]-N-[4-[4-(6-fluoroalkyl-1,3-benzothiazol-2-yl)phenyl]pyridin-2-yl] To a solution of tert-butyl carbamate (245 mg, 0.33 mmol) in DCM (5 mL) was added TFA (0.38 mL, 4.89 mmol) and stirred at room temperature for 20 h. The mixture was diluted with DCM (20 mL) and neutralized to pH 8 with saturated NaHCO 3 solution. The mixture was extracted with water, dried over MgSO 4 , concentrated and purified by column chromatography (DCM:MeOH=20:1, Rf=0.3) to give 3-[6-[2-[2-[ [4-[4-(6-fluoroalkyl-1,3-benzothiazol-2-yl)phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]-3-oxygen Alkyl-1H-isoindol-2-yl]piperidine-2,6-dione (160 mg, 0.24 mmol, 75% yield). Example 32: Synthesis of Compound 163685
Figure 02_image447

化合物 162862：在0℃下向2-[4-[6-(二甲胺基)吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-醇(516 mg，1.24 mmol)於無水DMF (12 mL)中之溶液中添加NaH (149 mg，3.72 mmol)且在室溫下攪拌1 h。將含4-甲基苯磺酸2-[2-(4-甲基苯基)磺醯基氧基乙氧基]乙酯(1543 mg，3.72 mmol)之無水DMF (12 mL)添加至反應混合物中且在同一溫度下攪拌18 h。將混合物傾入水(50 mL)中且用DCM (50 mL)萃取。有機層用水(50 mL)及鹽水(50 mL)洗滌，經無水Na 2SO 4乾燥，濃縮且藉由管柱層析(Rf = 0.51，EtOAc:DCM = 1:9)純化，得到呈淡黃色固體狀之4-甲基苯磺酸2-[2-[[2-[4-[6-(二甲胺基)吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]氧基]乙氧基]乙酯(627 mg，0.95 mmol，產率77%)。 Compound 162862 : 2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazole-6 at 0°C - To a solution of alcohol (516 mg, 1.24 mmol) in anhydrous DMF (12 mL) was added NaH (149 mg, 3.72 mmol) and stirred at room temperature for 1 h. 2-[2-(4-Methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (1543 mg, 3.72 mmol) in anhydrous DMF (12 mL) was added to the reaction The mixture was stirred at the same temperature for 18 h. The mixture was poured into water (50 mL) and extracted with DCM (50 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 , concentrated and purified by column chromatography (Rf = 0.51, EtOAc:DCM = 1:9) to give pale yellow 4-Methylbenzenesulfonic acid 2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]- 1,3-Benzothiazol-6-yl]oxy]ethoxy]ethyl ester (627 mg, 0.95 mmol, 77% yield).

化合物 162891：將4-甲基苯磺酸2-[2-[[2-[4-[6-(二甲胺基)吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]氧基]乙氧基]乙酯(627 mg，0.95 mmol)及NaI (286 mg，1.91 mmol)於ACN (10 mL)中之混合物在80℃下加熱17 h。向混合物中添加水(20 mL)且用EtOAc萃取。有機層用鹽水洗滌，經MgSO 4乾燥且濃縮至乾燥，得到呈黃色固體狀之5-[4-[6-[2-(2-碘烷基乙氧基)乙氧基]-1,3-苯并噻唑-2-基]-3-(三氟甲基)苯基]-N,N-二甲基-吡啶-2-胺(540 mg，0.88 mmol，產率92%)。 Compound 162891 : 4-methylbenzenesulfonic acid 2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl] A mixture of -1,3-benzothiazol-6-yl]oxy]ethoxy]ethyl ester (627 mg, 0.95 mmol) and NaI (286 mg, 1.91 mmol) in ACN (10 mL) at 80°C Under heating for 17 h. Water (20 mL) was added to the mixture and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated to dryness to give 5-[4-[6-[2-(2-iodoalkylethoxy)ethoxy]-1,3 as a yellow solid -Benzothiazol-2-yl]-3-(trifluoromethyl)phenyl]-N,N-dimethyl-pyridin-2-amine (540 mg, 0.88 mmol, 92% yield).

化合物 163685：將5-[4-[6-[2-(2-碘烷基乙氧基)乙氧基]-1,3-苯并噻唑-2-基]-3-(三氟甲基)苯基]-N,N-二甲基-吡啶-2-胺(100 mg，0.16 mmol)、3-(7-氧烷基-3-亞氧烷基-1H-異吲哚-2-基)哌啶-2,6-二酮(85 mg，0.33 mmol)及K 2CO 3(68 mg，0.49 mmol)於DMF (5 mL)中之混合物在50℃下加熱18 h。向混合物中添加水且用DCM萃取。有機層用鹽水洗滌，經MgSO 4乾燥，濃縮且藉由管柱層析(MeOH:DCM= 1:20，Rf= 0.45)純化，得到呈黃色固體狀之3-[7-[2-[2-[[2-[4-[6-(二甲胺基)吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]氧基]乙氧基]乙氧基]-3-亞氧烷基-1H-異吲哚-2-基]哌啶-2,6-二酮(33 mg，0.04 mmol，產率25%)。 實例33：化合物163863之合成

Figure 02_image449
Compound 163685 : 5-[4-[6-[2-(2-iodoalkylethoxy)ethoxy]-1,3-benzothiazol-2-yl]-3-(trifluoromethyl )phenyl]-N,N-dimethyl-pyridin-2-amine (100 mg, 0.16 mmol), 3-(7-oxoalkyl-3-oxyalkylene-1H-isoindole-2- A mixture of piperidine-2,6-dione (85 mg, 0.33 mmol) and K 2 CO 3 (68 mg, 0.49 mmol) in DMF (5 mL) was heated at 50° C. for 18 h. Water was added to the mixture and extracted with DCM. The organic layer was washed with brine, dried over MgSO 4 , concentrated and purified by column chromatography (MeOH:DCM=1:20, Rf=0.45) to give 3-[7-[2-[2 as a yellow solid -[[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]oxy ]ethoxy]ethoxy]-3-oxyalkylene-1H-isoindol-2-yl]piperidine-2,6-dione (33 mg, 0.04 mmol, 25% yield). Example 33: Synthesis of Compound 163863
Figure 02_image449

化合物 163863：將2-[4-[6-(二甲胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-醇(166 mg，0.48 mmol)、3-[2-[[2-[2,6-雙(亞氧烷基)哌啶-3-基]-1-亞氧烷基-3H-異吲哚-5-基]氧基]乙氧基]丙酸(90 mg，0.24 mmol)、DMAP (3 mg，0.02 mmol)及DCC (52 mg，0.25 mmol)於吡啶(2 mL)中之混合物在室溫下攪拌15 h。藉由減壓移除溶劑。將殘餘物再溶解於DCM (10 mL)中，用水(5 mL)及鹽水(5 mL)洗滌，經MgSO 4乾燥，濃縮且藉由管柱層析(MeOH:DCM = 5:100，Rf = 0.14)純化，得到呈黃色固體狀之3-[2-[[2-[2,6-雙(亞氧烷基)哌啶-3-基]-1-亞氧烷基-3H-異吲哚-5-基]氧基]乙氧基]丙酸[2-[4-[6-(二甲胺基)吡啶-3-基]苯基]-1,3-苯并噻唑-6-基]酯(14 mg，0.02 mmol，產率8%)。 實例34：化合物164484之合成

Figure 02_image451
Compound 163863 : 2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-alcohol (166 mg, 0.48 mmol), 3-[ 2-[[2-[2,6-bis(oxyalkylene)piperidin-3-yl]-1-oxyalkylene-3H-isoindol-5-yl]oxy]ethoxy] A mixture of propionic acid (90 mg, 0.24 mmol), DMAP (3 mg, 0.02 mmol) and DCC (52 mg, 0.25 mmol) in pyridine (2 mL) was stirred at room temperature for 15 h. Solvent was removed by reduced pressure. The residue was redissolved in DCM (10 mL), washed with water (5 mL) and brine (5 mL), dried over MgSO 4 , concentrated and purified by column chromatography (MeOH:DCM=5:100, Rf= 0.14) Purification afforded 3-[2-[[2-[2,6-bis(oxyalkylene)piperidin-3-yl]-1-oxyalkylene-3H-isoindyl as a yellow solid Indol-5-yl]oxy]ethoxy]propanoic acid [2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazole-6- base] ester (14 mg, 0.02 mmol, 8% yield). Example 34: Synthesis of Compound 164484
Figure 02_image451

化合物 164431：將N-[4-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]胺基甲酸三級丁酯(400 mg，0.96 mmol)於無水DMF(10 mL)中之溶液冷卻至0℃且添加NaH (115 mg，2.88 mmol)。將所得混合物在室溫下攪拌1 h。將含4-甲基苯磺酸2-[2-[2-(4-甲基苯基)磺醯基氧基乙氧基]乙氧基]乙酯(1321 mg，2.88 mmol)之無水DMF(10 mL)添加至反應混合物中且在同一溫度下攪拌17 h。混合物用水(30 mL)淬滅且用DCM (30 mL)萃取。有機層用鹽水(30 mL)洗滌，經無水Na 2SO 4乾燥，濃縮且藉由管柱層析(EtOAc:DCM = 1:4，Rf = 0.4)純化，得到呈黃色固體狀之4-甲基苯磺酸2-[2-[2-[[4-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙氧基]乙酯(350 mg，0.50 mmol，產率52%)。 Compound 164431 : N-[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamic acid tertiary butyl ester ( A solution of 400 mg, 0.96 mmol) in anhydrous DMF (10 mL) was cooled to 0 °C and NaH (115 mg, 2.88 mmol) was added. The resulting mixture was stirred at room temperature for 1 h. 2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (1321 mg, 2.88 mmol) in dry DMF (10 mL) was added to the reaction mixture and stirred at the same temperature for 17 h. The mixture was quenched with water (30 mL) and extracted with DCM (30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 , concentrated and purified by column chromatography (EtOAc:DCM = 1:4, Rf = 0.4) to give 4-formazan as a yellow solid 2-[2-[2-[[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]- [(2-Methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethyl ester (350 mg, 0.50 mmol, 52% yield).

化合物 164438：將4-甲基苯磺酸2-[2-[2-[[4-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙氧基]乙酯(350 mg，0.50 mmol)及NaI (149 mg，1.00 mmol)於ACN (10 mL)中之混合物在80℃下加熱6 h。向混合物中添加水且用DCM萃取。有機層用水(50 mL)及鹽水(50 mL)洗滌，經Na 2SO 4乾燥且濃縮至乾燥，得到呈黃色固體狀之N-[2-[2-(2-碘烷基乙氧基)乙氧基]乙基]-N-[4-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]胺基甲酸三級丁酯(317 mg，0.48 mmol，產率97%)。 Compound 164438 : 4-methylbenzenesulfonic acid 2-[2-[2-[[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl] Pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethyl ester (350 mg, 0.50 mmol) and NaI (149 mg, 1.00 mmol) in ACN (10 mL) was heated at 80 °C for 6 h. Water was added to the mixture and extracted with DCM. The organic layer was washed with water (50 mL) and brine (50 mL), dried over Na 2 SO 4 and concentrated to dryness to give N-[2-[2-(2-iodoalkylethoxy) as a yellow solid Ethoxy]ethyl]-N-[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamic acid tris Grade butyl ester (317 mg, 0.48 mmol, 97% yield).

化合物 164465：將N-[2-[2-(2-碘烷基乙氧基)乙氧基]乙基]-N-[4-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]胺基甲酸三級丁酯(100 mg，0.15 mmol)、K 2CO 3(63 mg，0.46 mmol)及5-氮烷基-5-亞氧烷基-4-(6-氧烷基-3-亞氧烷基-1H-異吲哚-2-基)戊酸甲酯(49 mg，0.17 mmol)於DMF (5 mL)中之混合物在80℃下加熱6 h。向混合物中添加水且用DCM萃取。有機層經MgSO 4乾燥，濃縮且藉由管柱層析(MeOH:DCM = 3:100，Rf = 0.3)純化，得到呈白色固體狀之N-[2-[2-[2-[[2-[2,6-雙(亞氧烷基)哌啶-3-基]-1-亞氧烷基-3H-異吲哚-5-基]氧基]乙氧基]乙氧基]乙基]-N-[4-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]胺基甲酸三級丁酯(63 mg，0.08 mmol，產率52%)。 Compound 164465 : N-[2-[2-(2-iodoalkylethoxy)ethoxy]ethyl]-N-[4-[4-(6-methoxyimidazo[1,2 -a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate tertiary butyl ester (100 mg, 0.15 mmol), K 2 CO 3 (63 mg, 0.46 mmol) and 5-azanyl -5-oxyalkylene-4-(6-oxoalkylene-3-oxyalkylene-1H-isoindol-2-yl)pentanoic acid methyl ester (49 mg, 0.17 mmol) in DMF (5 mL ) in the mixture was heated at 80 ° C for 6 h. Water was added to the mixture and extracted with DCM. The organic layer was dried over MgSO 4 , concentrated and purified by column chromatography (MeOH:DCM = 3:100, Rf = 0.3) to give N-[2-[2-[2-[[2 as a white solid -[2,6-bis(oxyalkylene)piperidin-3-yl]-1-oxyalkylene-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]ethyl Base]-N-[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamic acid tertiary butyl ester (63 mg, 0.08 mmol, yield 52%).

化合物 164484：向N-[2-[2-[2-[[2-[2,6-雙(亞氧烷基)哌啶-3-基]-1-亞氧烷基-3H-異吲哚-5-基]氧基]乙氧基]乙氧基]乙基]-N-[4-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]胺基甲酸三級丁酯(63 mg，0.08 mmol)於DCM (5 mL)中之溶液中添加TFA (0.09 mL，1.19 mmol)，且在室溫下攪拌14 h。將混合物傾入冰水中且用飽和NaHCO 3溶液中和至pH 8。混合物用DCM (20 mL)稀釋且用水(10 mL)及鹽水(10 mL)萃取，經Na 2SO 4乾燥且濃縮至乾燥，得到呈淺棕色固體狀之3-[6-[2-[2-[2-[[4-[4-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)苯基]吡啶-2-基]胺基]乙氧基]乙氧基]乙氧基]-3-亞氧烷基-1H-異吲哚-2-基]哌啶-2,6-二酮(52 mg，0.07 mmol，產率89%)。 實例35：化合物165013之合成

Figure 02_image453
Compound 164484 : To N-[2-[2-[2-[[2-[2,6-bis(oxyalkylene) piperidin-3-yl]-1-oxyalkylene-3H-isoind Indol-5-yl]oxy]ethoxy]ethoxy]ethyl]-N-[4-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl) To a solution of tert-butyl phenyl]pyridin-2-yl]carbamate (63 mg, 0.08 mmol) in DCM (5 mL) was added TFA (0.09 mL, 1.19 mmol) and stirred at room temperature for 14 h. The mixture was poured into ice water and neutralized to pH 8 with saturated NaHCO 3 solution. The mixture was diluted with DCM (20 mL) and extracted with water (10 mL) and brine (10 mL), dried over Na 2 SO 4 and concentrated to dryness to give 3-[6-[2-[2 as a light brown solid. -[2-[[4-[4-(6-Methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]amino]ethoxy]ethoxy yl]ethoxy]-3-oxyalkylene-1H-isoindol-2-yl]piperidine-2,6-dione (52 mg, 0.07 mmol, 89% yield). Example 35: Synthesis of Compound 165013
Figure 02_image453

化合物 164953：在0℃下向N-甲基-N-[5-[4-[6-[(2-甲基丙-2-基)氧基羰基胺基]-1,3-苯并噻唑-2-基]-3-(三氟甲基)苯基]吡啶-2-基]胺基甲酸三級丁酯(200 mg，0.33 mmol)於無水DMF(5 mL)中之溶液中添加NaH (40 mg，1.00 mmol)且在室溫下攪拌1 h。將含4-甲基苯磺酸2-[2-(4-甲基苯基)磺醯基氧基乙氧基]乙酯(414 mg，1.00 mmol)之無水DMF(5 mL)添加至反應混合物中且在同一溫度下攪拌14 h。混合物用水(30 mL)淬滅且用DCM (30 mL)萃取。有機層用水(30 mL)及鹽水(30 mL)洗滌，經無水Na 2SO 4乾燥，濃縮且藉由管柱層析(EtOAc:DCM = 1:9，Rf = 0.4)純化，得到呈黃色固體狀之4-甲基苯磺酸2-[2-[[2-[4-[6-[甲基-[(2-甲基丙-2-基)氧基羰基]胺基]吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙酯(130 mg，0.15 mmol，產率46%)。 Compound 164953 : N-methyl-N-[5-[4-[6-[(2-methylprop-2-yl)oxycarbonylamino]-1,3-benzothiazole at 0°C To a solution of tert-butyl-2-yl]-3-(trifluoromethyl)phenyl]pyridin-2-yl]carbamate (200 mg, 0.33 mmol) in dry DMF (5 mL) was added NaH (40 mg, 1.00 mmol) and stirred at room temperature for 1 h. 2-[2-(4-Methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (414 mg, 1.00 mmol) in anhydrous DMF (5 mL) was added to the reaction The mixture was stirred at the same temperature for 14 h. The mixture was quenched with water (30 mL) and extracted with DCM (30 mL). The organic layer was washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4 , concentrated and purified by column chromatography (EtOAc:DCM = 1:9, Rf = 0.4) to give a yellow solid 4-methylbenzenesulfonic acid 2-[2-[[2-[4-[6-[methyl-[(2-methylprop-2-yl)oxycarbonyl]amino]pyridine-3 -yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy Base] ethyl ester (130 mg, 0.15 mmol, 46% yield).

化合物 164984：將5-氮烷基-5-亞氧烷基-4-(6-氧烷基-3-亞氧烷基-1H-異吲哚-2-基)戊酸甲酯(50 mg，0.17 mmol)、K 2CO 3(64 mg，0.46 mmol)、KI (2.56 mg，0.02 mmol)及4-甲基苯磺酸2-[2-[[2-[4-[6-[甲基-[(2-甲基丙-2-基)氧基羰基]胺基]吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]-[(2-甲基丙-2-基)氧基羰基]胺基]乙氧基]乙酯(130 mg，0.15 mmol)於DMF (5 mL)中之混合物在80℃下加熱6 h。混合物用DCM (5 mL)稀釋，冷卻至0℃且逐滴添加水(5 mL)。混合物用水(10 mL)及鹽水(10 mL)萃取，經Na 2SO 4乾燥，濃縮且藉由管柱層析(MeOH:DCM= 3:100，Rf = 0.3)純化，得到呈無色油狀之N-[2-[2-[[2-[2,6-雙(亞氧烷基)哌啶-3-基]-1-亞氧烷基-3H-異吲哚-5-基]氧基]乙氧基]乙基]-N-[2-[4-[6-[甲基-[(2-甲基丙-2-基)氧基羰基]胺基]吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(79 mg，0.08 mmol，產率55%)。 Compound 164984 : methyl 5-azanyl-5-oxyalkylene-4-(6-oxoalkyl-3-oxyalkylene-1H-isoindol-2-yl)pentanoate (50 mg , 0.17 mmol), K 2 CO 3 (64 mg, 0.46 mmol), KI (2.56 mg, 0.02 mmol) and 4-methylbenzenesulfonic acid 2-[2-[[2-[4-[6-[methyl Base-[(2-methylprop-2-yl)oxycarbonyl]amino]pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazole-6- A mixture of ]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl ester (130 mg, 0.15 mmol) in DMF (5 mL) was heated at 80°C for 6 h. The mixture was diluted with DCM (5 mL), cooled to 0 °C and water (5 mL) was added dropwise. The mixture was extracted with water (10 mL) and brine (10 mL), dried over Na 2 SO 4 , concentrated and purified by column chromatography (MeOH:DCM = 3:100, Rf = 0.3) to give the product as a colorless oil. N-[2-[2-[[2-[2,6-bis(oxyalkylene)piperidin-3-yl]-1-oxyalkylene-3H-isoindol-5-yl]oxy base] ethoxy] ethyl] -N-[2-[4-[6-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]pyridin-3-yl] -Ter-butyl-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate (79 mg, 0.08 mmol, 55% yield).

化合物 165013：向N-[2-[2-[[2-[2,6-雙(亞氧烷基)哌啶-3-基]-1-亞氧烷基-3H-異吲哚-5-基]氧基]乙氧基]乙基]-N-[2-[4-[6-[甲基-[(2-甲基丙-2-基)氧基羰基]胺基]吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(79 mg，0.08 mmol)於DCM (3 mL)中之溶液中添加TFA (0.1 mL，1.27 mmol)，且在室溫下攪拌14 h。將混合物傾入冰水中且用飽和NaHCO 3溶液中和至pH 8。混合物用DCM (20 mL)稀釋且用水(10 mL)及鹽水(10 mL)萃取。有機層經收集，經Na 2SO 4乾燥，濃縮且藉由矽膠管柱層析(MeOH:DCM= 3:100，Rf= 0.2)純化，得到呈黃色固體狀之3-[6-[2-[2-[[2-[4-[6-(甲胺基)吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]胺基]乙氧基]乙氧基]-3-亞氧烷基-1H-異吲哚-2-基]哌啶-2,6-二酮(29 mg，0.04 mmol，產率45%)。 實例36：化合物166288之合成

Figure 02_image455
Figure 02_image457
Compound 165013 : To N-[2-[2-[[2-[2,6-bis(oxyalkylene) piperidin-3-yl]-1-oxyalkylene-3H-isoindole-5 -yl]oxy]ethoxy]ethyl]-N-[2-[4-[6-[methyl-[(2-methylprop-2-yl)oxycarbonyl]amino]pyridine- 3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate (79 mg, 0.08 mmol) in DCM (3 mL) To the solution was added TFA (0.1 mL, 1.27 mmol) and stirred at room temperature for 14 h. The mixture was poured into ice water and neutralized to pH 8 with saturated NaHCO 3 solution. The mixture was diluted with DCM (20 mL) and extracted with water (10 mL) and brine (10 mL). The organic layers were collected, dried over Na 2 SO 4 , concentrated and purified by silica gel column chromatography (MeOH:DCM=3:100, Rf=0.2) to give 3-[6-[2- [2-[[2-[4-[6-(methylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]amine yl]ethoxy]ethoxy]-3-oxyalkylene-1H-isoindol-2-yl]piperidine-2,6-dione (29 mg, 0.04 mmol, 45% yield). Example 36: Synthesis of Compound 166288
Figure 02_image455
Figure 02_image457

化合物 166191：在0℃下向N-[2-[4-[6-(二甲胺基)吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(447 mg，0.87 mmol)於DMF (8 mL)中之溶液中添加NaH (63 mg，2.61 mmol)，在室溫下攪拌1 h，且隨後添加含4-甲基苯磺酸5-(4-甲基苯基)磺醯基氧基戊酯(1075 mg，2.61 mmol)之DMF (8 mL)。將所得混合物在室溫下再攪拌16 h，冷卻至0℃且藉由添加水淬滅。將殘餘物溶解於DCM (50 mL)及水(50 mL)中。有機層用水(50 mL)、鹽水(50 mL)洗滌，經Na 2SO 4乾燥且藉由矽膠管柱層析(DCM:EtOAc = 9:1，Rf = 0.52)純化，得到呈黃色固體狀之4-甲基苯磺酸5-[[2-[4-[6-(二甲胺基)吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]-[(2-甲基丙-2-基)氧基羰基]胺基]戊酯(515 mg，0.68 mmol，產率79%)。 Compound 166191 : N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzo To a solution of tert-butyl thiazol-6-yl]carbamate (447 mg, 0.87 mmol) in DMF (8 mL) was added NaH (63 mg, 2.61 mmol), stirred at room temperature for 1 h, and then 5-(4-methylphenyl)sulfonyloxypentyl 4-methylbenzenesulfonate (1075 mg, 2.61 mmol) in DMF (8 mL) was added. The resulting mixture was stirred at room temperature for another 16 h, cooled to 0 °C and quenched by adding water. The residue was dissolved in DCM (50 mL) and water (50 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over Na 2 SO 4 and purified by silica gel column chromatography (DCM:EtOAc = 9:1, Rf = 0.52) to give the compound as a yellow solid. 4-Methylbenzenesulfonic acid 5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzo Thiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentyl ester (515 mg, 0.68 mmol, 79% yield).

化合物 166226：將4-甲基苯磺酸5-[[2-[4-[6-(二甲胺基)吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]-[(2-甲基丙-2-基)氧基羰基]胺基]戊酯(514 mg，0.68 mmol)、K 2CO 3(282 mg，2.04 mmol)、KI (11 mg，0.07 mmol)及5-氮烷基-5-亞氧烷基-4-(6-氧烷基-3-亞氧烷基-1H-異吲哚-2-基)戊酸甲酯(219 mg，0.75 mmol)於DMF (8 mL)中之混合物在室溫下攪拌22 h，且隨後加熱至80℃持續6 h。混合物用DCM (5 mL)稀釋，冷卻至0℃且逐滴添加水(5 mL)。混合物用水(10 mL)及鹽水(10 mL)洗滌，經Na 2SO 4乾燥，濃縮且藉由矽膠管柱層析(MeOH:DCM = 1:20，Rf = 0.55)純化，得到呈黃色固體狀之N-[5-[[2-[2,6-雙(亞氧烷基)哌啶-3-基]-1-亞氧烷基-3H-異吲哚-5-基]氧基]戊基]-N-[2-[4-[6-(二甲胺基)吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(205 mg，0.24 mmol，產率36%)。 Compound 166226 : 4-methylbenzenesulfonic acid 5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1, 3-Benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentyl ester (514 mg, 0.68 mmol), K 2 CO 3 (282 mg, 2.04 mmol ), KI (11 mg, 0.07 mmol) and 5-azanyl-5-oxyalkylene-4-(6-oxoalkyl-3-oxyalkylene-1H-isoindol-2-yl) A mixture of methyl valerate (219 mg, 0.75 mmol) in DMF (8 mL) was stirred at room temperature for 22 h, and then heated to 80 °C for 6 h. The mixture was diluted with DCM (5 mL), cooled to 0 °C and water (5 mL) was added dropwise. The mixture was washed with water (10 mL) and brine (10 mL), dried over Na 2 SO 4 , concentrated and purified by silica gel column chromatography (MeOH:DCM = 1:20, Rf = 0.55) to give a yellow solid N-[5-[[2-[2,6-bis(oxyalkylene)piperidin-3-yl]-1-oxyalkylene-3H-isoindol-5-yl]oxy] Pentyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazole-6- base] tertiary butyl carbamate (205 mg, 0.24 mmol, 36% yield).

化合物 166288：向N-[5-[[2-[2,6-雙(亞氧烷基)哌啶-3-基]-1-亞氧烷基-3H-異吲哚-5-基]氧基]戊基]-N-[2-[4-[6-(二甲胺基)吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(205 mg，0.24 mmol)於DCM (3 mL)中之溶液中添加TFA (0.28 mL，3.65 mmol)且在室溫下攪拌16 h。將混合物傾入冰水中且用飽和NaHCO 3溶液中和至pH 8。將殘餘物溶解於DCM (20 mL)及水(10 mL)中。有機層用水(10 mL)及鹽水(10 mL)洗滌，經Na 2SO 4乾燥且濃縮至乾燥，得到呈黃色固體狀之3-[6-[5-[[2-[4-[6-(二甲胺基)吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]胺基]戊氧基]-3-亞氧烷基-1H-異吲哚-2-基]哌啶-2,6-二酮(132 mg，0.17 mmol，產率71%)。 實例37：化合物166399之合成

Figure 02_image459
Compound 166288 : To N-[5-[[2-[2,6-bis(oxyalkylene) piperidin-3-yl]-1-oxyalkylene-3H-isoindol-5-yl] Oxygen]pentyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazole To a solution of ter-butyl-6-yl]carbamate (205 mg, 0.24 mmol) in DCM (3 mL) was added TFA (0.28 mL, 3.65 mmol) and stirred at room temperature for 16 h. The mixture was poured into ice water and neutralized to pH 8 with saturated NaHCO 3 solution. The residue was dissolved in DCM (20 mL) and water (10 mL). The organic layer was washed with water (10 mL ) and brine (10 mL), dried over Na2SO4 and concentrated to dryness to give 3-[6-[5-[[2-[4-[6- (Dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]amino]pentyloxy]-3-oxoalkylene yl-1H-isoindol-2-yl]piperidine-2,6-dione (132 mg, 0.17 mmol, yield 71%). Example 37: Synthesis of Compound 166399
Figure 02_image459

化合物 166196：將N-[2-[4-[6-(二甲胺基)吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(300 mg，0.58 mmol)於DMF (5 mL)中之溶液冷卻至0℃且添加NaH (56 mg，2.33 mmol)。將混合物在室溫下攪拌1 h，添加含4-甲基苯磺酸2-疊氮基乙酯(281 mg，1.17 mmol)之DMF (5 mL)且在50℃下加熱20 h。將混合物冷卻至0℃且添加水(5 mL)。將所得沈澱物藉由過濾收集，用水洗滌且經真空乾燥。殘餘物藉由矽膠管柱層析(EtOAc:DCM = 1:20, Rf = 0.6)純化，得到呈黃色固體狀之N-(2-疊氮基乙基)-N-[2-[4-[6-(二甲胺基)吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(320 mg，0.55 mmol，94%產率)。 Compound 166196 : N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazole-6- A solution of tert-butyl]carbamate (300 mg, 0.58 mmol) in DMF (5 mL) was cooled to 0 °C and NaH (56 mg, 2.33 mmol) was added. The mixture was stirred at room temperature for 1 h, 2-azidoethyl 4-methylbenzenesulfonate (281 mg, 1.17 mmol) in DMF (5 mL) was added and heated at 50 °C for 20 h. The mixture was cooled to 0 °C and water (5 mL) was added. The resulting precipitate was collected by filtration, washed with water and dried under vacuum. The residue was purified by silica gel column chromatography (EtOAc:DCM = 1:20, Rf = 0.6) to give N-(2-azidoethyl)-N-[2-[4- [6-(Dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate (320 mg , 0.55 mmol, 94% yield).

化合物 166264 ：向N-(2-疊氮基乙基)-N-[2-[4-[6-(二甲胺基)吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(341 mg，0.58 mmol)於THF (5mL)/EtOH (5 mL)中之溶液中添加Pd(OH) 2(1701 mg，1.61 mmol)且在1個H 2大氣壓下攪拌4 h。混合物經由矽藻土墊過濾，且使濾液濃縮至乾燥。殘餘物藉由管柱層析(DCM:EtOAc = 20:1，Rf = 0.15)純化，得到呈淺黃色固體狀之N-(2-氮烷基乙基)-N-[2-[4-[6-(二甲胺基)吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(226 mg，0.41 mmol，產率69%)。 Compound 166264 : To N-(2-azidoethyl)-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl To a solution of tert-butyl]-1,3-benzothiazol-6-yl]carbamate (341 mg, 0.58 mmol) in THF (5 mL)/EtOH (5 mL) was added Pd(OH) 2 ( 1701 mg, 1.61 mmol) and stirred under 1 atmosphere of H 2 for 4 h. The mixture was filtered through a pad of celite, and the filtrate was concentrated to dryness. The residue was purified by column chromatography (DCM:EtOAc = 20:1, Rf = 0.15) to give N-(2-azanylethyl)-N-[2-[4- [6-(Dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]carbamate (226 mg , 0.41 mmol, yield 69%).

化合物 166306：將N-(2-氮烷基乙基)-N-[2-[4-[6-(二甲胺基)吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(326 mg，0.59 mmol)、2-[[2-[2,6-雙(亞氧烷基)哌啶-3-基]-1-亞氧烷基-3H-異吲哚-5-基]氧基]乙酸(372 mg，1.17 mmol)、EDC (280 mg，1.46 mmol)及HOBt (198 mg，1.46 mmol)於吡啶(6 mL)中之混合物在室溫下攪拌16 h。藉由真空移除溶劑且將所得殘餘物再溶解於EtOAc (100 mL)中且用水(50 mL)及鹽水(50 mL)洗滌。有機層經Na 2SO 4乾燥，濃縮且藉由矽膠管柱層析(MeOH:DCM = 1:20，Rf = 0.3)純化，得到呈黃色固體狀之N-[2-[2-[[2-[2,6-雙(亞氧烷基)哌啶-3-基]-1-亞氧烷基-3H-異吲哚-5-基]氧基]乙醯基胺基]乙基]-N-[2-[4-[6-(二甲胺基)吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(277 mg，0.32 mmol，產率55%)。 Compound 166306 : N-(2-azanylethyl)-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl ]-1,3-Benzothiazol-6-yl]carbamate tertiary butyl ester (326 mg, 0.59 mmol), 2-[[2-[2,6-bis(oxyalkylene)piperidine- 3-yl]-1-oxyalkylene-3H-isoindol-5-yl]oxy]acetic acid (372 mg, 1.17 mmol), EDC (280 mg, 1.46 mmol) and HOBt (198 mg, 1.46 mmol ) in pyridine (6 mL) was stirred at room temperature for 16 h. The solvent was removed by vacuum and the resulting residue was redissolved in EtOAc (100 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4 , concentrated and purified by silica gel column chromatography (MeOH:DCM = 1:20, Rf = 0.3) to give N-[2-[2-[[2 as a yellow solid -[2,6-bis(oxyalkylene)piperidin-3-yl]-1-oxyalkylene-3H-isoindol-5-yl]oxy]acetylamino]ethyl] -N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]amine Tertiary butyl carbamate (277 mg, 0.32 mmol, 55% yield).

化合物 166399：向N-[2-[2-[[2-[2,6-雙(亞氧烷基)哌啶-3-基]-1-亞氧烷基-3H-異吲哚-5-基]氧基]乙醯基胺基]乙基]-N-[2-[4-[6-(二甲胺基)吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]胺基甲酸三級丁酯(277 mg，0.32 mmol)於DCM (3 mL)中之溶液中添加TFA (0.37 mL，4.85 mmol)且在室溫下攪拌23 h。將混合物傾入冰水中且用飽和NaHCO 3溶液中和至pH 8。將殘餘物溶解於DCM (20 mL)及水(10 mL)中。有機層用水(10 mL)及鹽水(10 mL)洗滌，經Na 2SO 4乾燥且濃縮，得到呈黃色固體狀之2-[[2-[2,6-雙(亞氧烷基)哌啶-3-基]-1-亞氧烷基-3H-異吲哚-5-基]氧基]-N-[2-[[2-[4-[6-(二甲胺基)吡啶-3-基]-2-(三氟甲基)苯基]-1,3-苯并噻唑-6-基]胺基]乙基]乙醯胺(239 mg，0.30 mmol，產率93%)。 實例38：α-突觸核蛋白競爭性結合分析 Compound 166399 : To N-[2-[2-[[2-[2,6-bis(oxyalkylene)piperidin-3-yl]-1-oxyalkylene-3H-isoindole-5 -yl]oxy]acetylamino]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]-2-(trifluoromethyl)phenyl To a solution of tert-butyl]-1,3-benzothiazol-6-yl]carbamate (277 mg, 0.32 mmol) in DCM (3 mL) was added TFA (0.37 mL, 4.85 mmol) and incubated at room temperature. Stir at room temperature for 23 h. The mixture was poured into ice water and neutralized to pH 8 with saturated NaHCO 3 solution. The residue was dissolved in DCM (20 mL) and water (10 mL). The organic layer was washed with water ( 10 mL) and brine (10 mL), dried over Na2SO4 and concentrated to give 2-[[2-[2,6-bis(oxyalkylene)piperidine as a yellow solid -3-yl]-1-oxyalkylene-3H-isoindol-5-yl]oxyl]-N-[2-[[2-[4-[6-(dimethylamino)pyridine- 3-yl]-2-(trifluoromethyl)phenyl]-1,3-benzothiazol-6-yl]amino]ethyl]acetamide (239 mg, 0.30 mmol, 93% yield) . Example 38: Alpha-Synuclein Competitive Binding Assay

(A)重組野生型人類α-突觸核蛋白之表現及純化：使用0.5 mM IPTG誘導藉由用全長α-突觸核蛋白表現質體轉化之細菌產生野生型人類α-突觸核蛋白。在16℃下振盪20小時之後，將細胞沈澱物再懸浮於溶解緩衝液(10 mM Tris、1 mM EGTA、0.75 mM NaCl、1 mM PMSF，pH 7.5)中且藉由音波處理接著離心(6000 g，30 min，4℃)來溶解。接著將上清液在95℃下在手動攪拌每5分鐘下沸騰15 min，接著離心(6000g，30 min，4℃)。上清液用(10 mM Tris、1 mM EGTA、50 mM NaCl，pH 7.5)緩衝液透析且用濃縮器濃縮。將收集之樣本負載於Superdex200管柱上，隨後將流通部分負載於Q-HP管柱上。將收集之具有α-突觸核蛋白溶離液之級分合併、濃縮且儲存於-80℃下。(A) Expression and purification of recombinant wild-type human α-synuclein: 0.5 mM IPTG was used to induce the production of wild-type human α-synuclein in bacteria transformed with expression plastids of full-length α-synuclein. After shaking at 16°C for 20 hours, the cell pellet was resuspended in lysis buffer (10 mM Tris, 1 mM EGTA, 0.75 mM NaCl, 1 mM PMSF, pH 7.5) and centrifuged by sonication followed by centrifugation (6000 g , 30 min, 4°C) to dissolve. The supernatant was then boiled at 95°C for 15 min with manual stirring every 5 min, followed by centrifugation (6000 g, 30 min, 4°C). The supernatant was dialyzed against (10 mM Tris, 1 mM EGTA, 50 mM NaCl, pH 7.5) buffer and concentrated with a concentrator. The collected samples were loaded on a Superdex200 column, and then the flow-through portion was loaded on a Q-HP column. The collected fractions with α-synuclein lysate were pooled, concentrated and stored at -80°C.

(B)製備聚集之α-突觸核蛋白：將含5 mg/mL α-突觸核蛋白之PBS緩衝液(pH 7.4)於管中在37℃下在振盪(700 rpm)之情況下培育5至10天。(B) Preparation of aggregated α-synuclein: Incubate 5 mg/mL α-synuclein in PBS buffer (pH 7.4) in a tube at 37°C with shaking (700 rpm) 5 to 10 days.

(C)活體外螢光α-突觸核蛋白結合分析：將2 µM α-突觸核蛋白與連續稀釋之化合物(三倍連續稀釋液，10至0.001 µM)在96孔盤中在37℃下培育1小時。藉由微量盤光譜儀讀取螢光強度。化合物Kd值使用以下等式計算：Y = B max×X/(Kd+X)，其中X為化合物濃度；Y為(化合物+α-突觸核蛋白)-(化合物+DMSO)之螢光信號；且B max為最大信號。 (C) In vitro fluorescent α-synuclein binding assay: 2 µM α-synuclein was mixed with serially diluted compounds (3-fold serial dilutions, 10 to 0.001 µM) in 96-well plates at 37°C Incubate for 1 hour. Fluorescence intensity was read by microplate spectrometer. Compound Kd values were calculated using the following equation: Y = B max ×X/(Kd+X), where X is the compound concentration; Y is the fluorescence signal of (compound + α-synuclein) - (compound + DMSO) ; and B max is the maximum signal.

(D)PBB5競爭分析：將2 µM α-突觸核蛋白與0.26 µM 2-(4-(2-(甲胺基)吡啶-5-基)-1,3-丁二烯-1-基)苯并噻唑-6-醇(PBB5)及連續稀釋之化合物(三倍連續稀釋液，10至0.001 µM)在96孔盤中在37℃下培育1小時。PBB5之螢光強度(激發/發射=530/690 nm)藉由微量盤光譜儀讀取。競爭百分比使用以下等式計算：(Max-僅化合物孔)/(Max-Min)×100%，其中Max=(α-突觸核蛋白+PBB5)信號-(緩衝液+PBB5)信號；且Min=(緩衝液+PBB5)信號-(緩衝液+PBB5)信號。各化合物之IC 50值使用GraphPad Prism軟體使用「4參數邏輯模型或S形劑量-反應模型」計算：Y=底部值+(頂部值-底部值)/(1+(IC50/X)^希爾斜率) 表2：與PBB5之競爭分析 化合物 Ex/Em (nm) Kd (µM) PBB5 (µM) 165825 340/480 ND ＞10 166099 350/500 5.63 0.04 165802 335/435 2.44 ＞10 166124 345/545 0.34 0.03 166330 370/500 0.59 2.6 177032 350/480 0.06 ND 177033 350/480 0.65 0.63 180944 345/475 0.43 0.61 163123 340/480 0.26 ＞10 166965 305/485 0.22 10 166123 340/480 0.48 0.41 實例39：用於降解α-突觸核蛋白聚集體之活體外分析 (D) PBB5 competition assay: 2 µM α-synuclein was mixed with 0.26 µM 2-(4-(2-(methylamino)pyridin-5-yl)-1,3-butadien-1-yl ) benzothiazol-6-ol (PBB5) and serially diluted compounds (3-fold serial dilutions, 10 to 0.001 µM) were incubated in 96-well plates at 37°C for 1 hour. The fluorescence intensity (excitation/emission = 530/690 nm) of PBB5 was read by a microplate spectrometer. Percent competition was calculated using the following equation: (Max - compound only wells)/(Max - Min) x 100%, where Max = (α-synuclein + PBB5) signal - (buffer + PBB5) signal; and Min =(buffer+PBB5)signal-(buffer+PBB5)signal. The IC 50 value of each compound was calculated using GraphPad Prism software using "4-parameter logistic model or sigmoid dose-response model": Y=bottom value+(top value-bottom value)/(1+(IC50/X)^Hill slope) Table 2: Competition analysis with PBB5 compound Ex/Em (nm) Kd (µM) PBB5 (µM) 165825 340/480 ND >10 166099 350/500 5.63 0.04 165802 335/435 2.44 >10 166124 345/545 0.34 0.03 166330 370/500 0.59 2.6 177032 350/480 0.06 ND 177033 350/480 0.65 0.63 180944 345/475 0.43 0.61 163123 340/480 0.26 >10 166965 305/485 0.22 10 166123 340/480 0.48 0.41 Example 39: In vitro assay for degradation of α-synuclein aggregates

ReNcell VM α-突觸核蛋白聚集分析係在Charles River Laboratories (CRL)進行。ReNcell VM為源自大腦之腹側中腦區域的永生化人類神經先驅細胞株。ReNcell VM細胞基於其生長特徵、分化成末端分化神經元之潛能及對腺病毒轉導之順應能力而選擇為用於α-突觸核蛋白聚集分析之活體外細胞模型。聚集之人類野生型α-突觸核蛋白經由腺病毒遞送而過度表現。聚集之α-突觸核蛋白使用免疫細胞化學用聚集體選擇性抗α-突觸核蛋白抗體MJFR14偵測；總α-突觸核蛋白含量用Syn205 (α/β-突觸核蛋白特異性抗體)偵測。The ReNcell VM α-synuclein aggregation assay was performed at Charles River Laboratories (CRL). ReNcell VM is an immortalized human neural pioneer cell line derived from the ventral midbrain region of the brain. ReNcell VM cells were chosen as an in vitro cell model for the analysis of α-synuclein aggregation based on their growth characteristics, potential to differentiate into terminally differentiated neurons, and compliance to adenoviral transduction. Aggregated human wild-type α-synuclein is overexpressed via adenoviral delivery. Aggregated α-synuclein was detected using immunocytochemistry with aggregate-selective anti-α-synuclein antibody MJFR14; total α-synuclein content was detected with Syn205 (α/β-synuclein specific Antibody) detection.

ReNcell VM α-突觸核蛋白聚集分析應用於化合物篩選以鑑別能夠降解α-突觸核蛋白聚集體之化合物。特定言之，經腺病毒轉導之ReNcell VM細胞用測試化合物(連續稀釋)處理24小時，接著固定，且隨後藉由用Syn205及MJFR14染色進行處理以用於ReNcell免疫細胞化學。針對聚集(MJFR14)及總α-突觸核蛋白(Syn205)之免疫反應性使用免疫細胞化學影像(用IN Cell 2200(GE Healthcare)執行)中基於高含量之免疫活性區域分段來定量，接著進行免疫螢光強度之定量(藉由CRL研發之演算法使用IN Cell Developer Toolbox軟體執行)。The ReNcell VM α-Synuclein Aggregation Assay was applied to compound screening to identify compounds capable of degrading α-synuclein aggregates. Specifically, adenovirus-transduced ReNcell VM cells were treated with test compounds (serial dilutions) for 24 hours, then fixed, and subsequently processed for ReNcell immunocytochemistry by staining with Syn205 and MJFR14. Immunoreactivity against aggregated (MJFR14) and total α-synuclein (Syn205) was quantified using immunocytochemical imaging (performed with IN Cell 2200 (GE Healthcare)) based on segmentation of high-abundance immunoreactive regions, followed by Quantification of immunofluorescence intensity (executed by the algorithm developed by CRL using IN Cell Developer Toolbox software).

測試一組超過100種化合物對MJFR14免疫反應性之抑制。圖1展示聚集之α-突觸核蛋白物種之基於高含量之定量以及測定分化ReNcell VM細胞中之細胞核計數(剩餘細胞%)。結果顯示分別用測試化合物166362、170357、162640及180948處理24小時誘導MJFR14免疫反應性之濃度依賴性抑制，從而指示α-突觸核蛋白聚集減少。各組圖顯示百分比效應(PE)及剩餘細胞(%)之標準化資料。A panel of over 100 compounds was tested for inhibition of MJFR14 immunoreactivity. Figure 1 shows high level based quantification of aggregated α-synuclein species and determination of nuclei counts (% cells remaining) in differentiated ReNcell VM cells. The results show that treatment with test compounds 166362, 170357, 162640 and 180948, respectively, for 24 hours induces a concentration-dependent inhibition of MJFR14 immunoreactivity, indicating a reduction in α-synuclein aggregation. Each panel shows normalized data for percent effect (PE) and remaining cells (%).

百分比效應(PE)：相較於空白組(0.1% DMSO)之抑制。Percent effect (PE): Inhibition compared to blank (0.1% DMSO).

PE = 100-(化合物之信號/空白組之平均信號)×100PE = 100-(compound signal/average signal of blank group)×100

化合物誘導之細胞毒性(剩餘細胞%)Compound-induced cytotoxicity (% of remaining cells)

剩餘細胞% = (化合物之細胞核計數/空白組之平均細胞核計數)×100Remaining cell % = (nuclei count of compound/average nuclei count of blank group)×100

圖2A至圖2D展示用媒劑(0.1% DMSO)及測試化合物132168、166362及170357處理且用MJFR14進行免疫染色的細胞之代表性免疫細胞化學影像，其示出在用化合物132168及166362處理之後α-突觸核蛋白表現減少。結果顯示分別用化合物132168及166362處理6天誘導對MJFR14免疫反應性之明顯抑制，從而指示化合物132168及166362有效地減少α-突觸核蛋白聚集。Figures 2A-2D show representative immunocytochemical images of cells treated with vehicle (0.1% DMSO) and test compounds 132168, 166362 and 170357 and immunostained with MJFR14, shown after treatment with compounds 132168 and 166362 Alpha-synuclein expression decreased. The results showed that treatment with compounds 132168 and 166362, respectively, for 6 days induced a significant inhibition of MJFR14 immunoreactivity, indicating that compounds 132168 and 166362 were effective in reducing α-synuclein aggregation.

在ReNcell VM α-突觸核蛋白聚集分析中評估化合物之一些實施例。結果彙總於下表3中。 表3. 化合物 活性 159985 A 160273 C 160313 A 170350 B 161177 A 160219 A 170351 B 170352 A 161103 A 161111 A 170353 A 170354 C 170355 A 170356 A 170357 C 160624 A 170358 A 170450 A 170451 A 162641 A 162640 C 177031 A 177032 A 177033 A 177036 A 177037 B 177038 A 177039 A 170742 A 163123 A 184605 A 163365 C 180948 D 189149 A 180950 A 174251 A 175552 A 190753 A 137955 A 132560 A 185563 A 133065 A 138266 A 132168 C 129071 A 127973 C 123374 A 129975 A 138876 B 130177 A 133678 A 161247 A 161598 A 178884 A 177685 A 180187 A 165554 A 165802 A 165824 A 165810 A 165950 A 165954 A 165952 A 166099 A 166330 A 166362 B 註釋： A指示DC 50＞ 10 μM B指示DC 50在0.9與10 μM之間 C指示DC 50在0.01與0.9 μM之間 D指示DC 50＜ 0.01 μM DC 50指示已降解50% α-突觸核蛋白聚集體時之濃度。 實例40：用於降解α-突觸核蛋白聚集體之活體內分析 Some examples of compounds were evaluated in the ReNcell VM α-synuclein aggregation assay. The results are summarized in Table 3 below. table 3. compound active 159985 A 160273 C 160313 A 170350 B 161177 A 160219 A 170351 B 170352 A 161103 A 161111 A 170353 A 170354 C 170355 A 170356 A 170357 C 160624 A 170358 A 170450 A 170451 A 162641 A 162640 C 177031 A 177032 A 177033 A 177036 A 177037 B 177038 A 177039 A 170742 A 163123 A 184605 A 163365 C 180948 D. 189149 A 180950 A 174251 A 175552 A 190753 A 137955 A 132560 A 185563 A 133065 A 138266 A 132168 C 129071 A 127973 C 123374 A 129975 A 138876 B 130177 A 133678 A 161247 A 161598 A 178884 A 177685 A 180187 A 165554 A 165802 A 165824 A 165810 A 165950 A 165954 A 165952 A 166099 A 166330 A 166362 B Notes: A indicates DC 50 > 10 μM B indicates DC 50 between 0.9 and 10 μM C indicates DC 50 between 0.01 and 0.9 μM D indicates DC 50 < 0.01 μM DC 50 indicates that 50% of α-synucleus has been degraded The concentration of protein aggregates. Example 40: In vivo analysis for degradation of α-synuclein aggregates

將三月齡之雄性轉殖基因Line61小鼠用於研究。小鼠經由靜脈內注射化合物132168 (25 mpk)處理一次。在處理後0.25、0.5、1、2、4、8及24 h收集血漿及大腦樣本。經由心臟穿刺將血液樣本收集在MiniCollect® 0.5 mL K2EDTA (乙二胺四乙酸鉀)試管中。將血液樣本在室溫(22℃)下在3000×g下離心10分鐘。將血漿轉移至預先標記之1.5 ml LoBind埃彭道夫管(2個等分試樣，各約75 μl)中，冷凍於乾冰上且儲存於-80℃下直至分析。對於腦樣本，在收集之前進行0.9%鹽水之灌注。將大腦稱重，在冷卻表面上切成對半，稱重且速凍。將半腦用於對可溶及不可溶級分中之人類α-突觸核蛋白進行WES系統分析。在化合物132168處理之後，不可溶α-突觸核蛋白級分相較於DMSO媒劑對照減小30%，從而反映不可溶α-突觸核蛋白聚集體減少。結果展示於圖3中。 實例41：活體內藥物動力學研究 Three-month-old male transgenic Line61 mice were used for the study. Mice were treated once via intravenous injection of compound 132168 (25 mpk). Plasma and brain samples were collected at 0.25, 0.5, 1, 2, 4, 8 and 24 h after treatment. Blood samples were collected via cardiac puncture in MiniCollect® 0.5 mL K2EDTA (potassium ethylenediaminetetraacetic acid) tubes. Blood samples were centrifuged at 3000 xg for 10 minutes at room temperature (22°C). Plasma was transferred to pre-labeled 1.5 ml LoBind Eppendorf tubes (2 aliquots, approximately 75 μl each), frozen on dry ice and stored at -80°C until analysis. For brain samples, perfusion with 0.9% saline was performed prior to collection. Brains were weighed, cut in half on a cooling surface, weighed and snap frozen. Hemibrains were used for WES system analysis of human α-synuclein in soluble and insoluble fractions. Following compound 132168 treatment, the insoluble α-synuclein fraction was reduced by 30% compared to the DMSO vehicle control, reflecting a reduction in insoluble α-synuclein aggregates. The results are shown in Figure 3. Example 41: In vivo pharmacokinetic studies

為確定本發明化合物是否能夠跨越血腦屏障(BBB)，在藥物動力學研究中向小鼠投與實例化合物132168 (10及25 mg/kg，靜脈內)。To determine whether compounds of the present invention are capable of crossing the blood-brain barrier (BBB), example compound 132168 (10 and 25 mg/kg, iv) was administered to mice in a pharmacokinetic study.

動物飼養：小鼠在動物房環境下圈養，通風15次/小時，照明12小時/天，溫度20℃至24℃且濕度40%至70%。研究房間在開始研究之前經殺菌及清潔，且在研究進行期間各給藥或取樣之後清潔操作區域。所有動物在研究期間能夠自由獲取食物及水。動物能夠任意獲取經認證嚙齒動物飼料(Certified Rodent Diet)及水。由第三方組織監測飼料之營養組成及污染物含量以及水之雜質及污染物。根據公認動物飼養程序評價動物之健康狀況且認為適合於實驗用途。Animal breeding: Mice were housed in an animal room with ventilation 15 times/hour, lighting 12 hours/day, temperature 20°C to 24°C and humidity 40% to 70%. The study room was sterilized and cleaned prior to the start of the study, and the operating area was cleaned after each dosing or sampling during the study. All animals had free access to food and water during the study. Animals had ad libitum access to Certified Rodent Diet and water. A third-party organization monitors the nutritional composition and pollutant content of the feed, as well as the impurities and pollutants in the water. The health status of animals was evaluated according to accepted animal husbandry procedures and deemed suitable for experimental use.

樣本收集及處理：在給藥後0.25、0.5、1、2、4、8及24小時，在異氟醚麻醉下經由面部或心臟穿刺，自所有動物收集大約110 µL全血至含有乙二胺四乙酸鉀(K 2EDTA)之試管中。給藥後0.25、0.5、1、2、4、8及24小時收集腦樣本。將在腦收集之前經由心臟穿刺進行預冷鹽水之灌注。將血液樣本在2000 g下在4℃下離心5分鐘以藉由將上清液轉移至新管中來獲得血漿樣本。所有血漿及腦樣本均儲存於大約-70℃下直至分析。 Sample collection and processing: At 0.25, 0.5, 1, 2, 4, 8, and 24 hours after dosing, approximately 110 µL of whole blood was collected from all animals via facial or cardiac puncture under isoflurane anesthesia to contain ethylenediamine Potassium tetraacetate (K 2 EDTA) in a test tube. Brain samples were collected at 0.25, 0.5, 1, 2, 4, 8 and 24 hours post-dose. Perfusion with pre-cooled saline will be performed via cardiac puncture prior to brain collection. Blood samples were centrifuged at 2000 g for 5 minutes at 4°C to obtain plasma samples by transferring the supernatant to fresh tubes. All plasma and brain samples were stored at approximately -70°C until analysis.

生物分析方法建立：使用基於液相層析以及聯合質譜分析(LC-MS/MS)之方法測定血漿及腦樣本中化合物之濃度。 結果：PK參數彙總於表4中。化合物132168能夠在短時間段內穿透BBB。 表4.化合物132168之活體內藥物動力學概況    血漿 大腦 劑量(mg/kg) 10 25 10 25 AUC last(hr*ng/mL) 17780 48660 1330 4069 T 1/2(h) 2.87 2.12 5.88 NA C max(ng/mL) - - 319 581 T max(h) - - 0.5 4 Bioanalytical method development: The concentration of compounds in plasma and brain samples was determined using a method based on liquid chromatography combined with mass spectrometry (LC-MS/MS). Results: PK parameters are summarized in Table 4. Compound 132168 was able to penetrate the BBB in a short period of time. Table 4. In vivo pharmacokinetic profile of compound 132168 plasma brain Dose (mg/kg) 10 25 10 25 AUC last (hr*ng/mL) 17780 48660 1330 4069 T 1/2 (h) 2.87 2.12 5.88 NA C max (ng/mL) - - 319 581 T max (h) - - 0.5 4

某些實施例如下：Some examples are as follows:

實施例1.一種治療有需要個體之突觸核蛋白病的方法，該方法包含向該個體投與有效量之式A化合物， EBM-L-SBM  (式A) 其中 EBM為E3泛蛋白連接酶結合部分； L為共價連接至EBM及SBM之連接子；且 SBM為下式之α-突觸核蛋白結合部分：

Figure 02_image461
或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物、前驅藥， 其中
Figure 02_image463
共價連接至L；且 (i)
Figure 02_image463
為含有至少1個選自O、S及N之環雜原子的經取代或未經取代之雙環稠合芳族環；
Figure 02_image466
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；且
Figure 02_image468
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；或 (ii)
Figure 02_image463
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；
Figure 02_image466
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；且
Figure 02_image468
為含有至少1個選自O、S及N之環雜原子的經取代或未經取代之雙環稠合芳族環。 Embodiment 1. A method of treating a synucleinopathy in an individual in need thereof, the method comprising administering to the individual an effective amount of a compound of formula A, EBM-L-SBM (Formula A) wherein EBM is E3 ubiquitin ligase A binding moiety; L is a linker covalently linked to EBM and SBM; and SBM is an α-synuclein binding moiety of the formula:
Figure 02_image461
or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvate, metabolic precursor, prodrug thereof, wherein
Figure 02_image463
covalently attached to L; and (i)
Figure 02_image463
is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N;
Figure 02_image466
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; and
Figure 02_image468
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; or (ii)
Figure 02_image463
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;
Figure 02_image466
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; and
Figure 02_image468
is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N.

實施例2.一種減少有需要個體之α-突觸核蛋白聚集的方法，該方法包含向該個體投與有效量之式A化合物， EBM-L-SBM  (式A) 其中 EBM為E3泛蛋白連接酶結合部分； L為共價連接至EBM及SBM之連接子；且 SBM為下式之α-突觸核蛋白結合部分：

Figure 02_image472
或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物、前驅藥， 其中
Figure 02_image463
共價連接至L；且 (i)
Figure 02_image463
為含有至少1個選自O、S及N之環雜原子的經取代或未經取代之雙環稠合芳族環；
Figure 02_image466
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；且
Figure 02_image468
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；或 (ii)
Figure 02_image463
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；
Figure 02_image466
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；且
Figure 02_image468
為含有至少1個選自O、S及N之環雜原子的經取代或未經取代之雙環稠合芳族環。 Embodiment 2. A method of reducing alpha-synuclein aggregation in an individual in need thereof, the method comprising administering to the individual an effective amount of a compound of formula A, EBM-L-SBM (Formula A) wherein EBM is E3 ubiquitin a ligase binding moiety; L is a linker covalently linked to EBM and SBM; and SBM is an α-synuclein binding moiety of the formula:
Figure 02_image472
or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvate, metabolic precursor, prodrug thereof, wherein
Figure 02_image463
covalently attached to L; and (i)
Figure 02_image463
is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N;
Figure 02_image466
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; and
Figure 02_image468
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; or (ii)
Figure 02_image463
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;
Figure 02_image466
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; and
Figure 02_image468
is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N.

實施例3.一種減少有需要個體之路易體的方法，該方法包含向該個體投與有效量之式A化合物， EBM-L-SBM  (式A) 其中 EBM為E3泛蛋白連接酶結合部分； L為共價連接至EBM及SBM之連接子；且 SBM為下式之α-突觸核蛋白結合部分：

Figure 02_image472
或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物、前驅藥， 其中
Figure 02_image463
共價連接至L；且 (i)
Figure 02_image463
為含有至少1個選自O、S及N之環雜原子的經取代或未經取代之雙環稠合芳族環；
Figure 02_image466
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；且
Figure 02_image468
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；或 (ii)
Figure 02_image463
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；
Figure 02_image466
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；且
Figure 02_image468
為含有至少1個選自O、S及N之環雜原子的經取代或未經取代之雙環稠合芳族環。 Embodiment 3. A method of reducing Lewy bodies in an individual in need thereof, the method comprising administering to the individual an effective amount of a compound of formula A, EBM-L-SBM (Formula A) wherein EBM is an E3 ubiquitin ligase binding moiety; L is a linker covalently linked to EBM and SBM; and SBM is an α-synuclein binding moiety of the formula:
Figure 02_image472
or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvate, metabolic precursor, prodrug thereof, wherein
Figure 02_image463
covalently attached to L; and (i)
Figure 02_image463
is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N;
Figure 02_image466
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; and
Figure 02_image468
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; or (ii)
Figure 02_image463
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;
Figure 02_image466
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; and
Figure 02_image468
is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N.

實施例4.一種式A化合物： EBM-L-SBM  (式A) 或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥之用途，其用於製造用於治療突觸核蛋白病之藥劑，其中 EBM為E3泛蛋白連接酶結合部分； L為共價連接至EBM及SBM之連接子；且 SBM為下式之α-突觸核蛋白結合部分：

Figure 02_image472
其中
Figure 02_image463
共價連接至L；且 (i)
Figure 02_image463
為含有至少1個選自O、S及N之環雜原子的經取代或未經取代之雙環稠合芳族環；
Figure 02_image466
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；且
Figure 02_image468
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；或 (ii)
Figure 02_image463
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；
Figure 02_image466
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；且
Figure 02_image468
為含有至少1個選自O、S及N之環雜原子的經取代或未經取代之雙環稠合芳族環。 Embodiment 4. A compound of formula A: EBM-L-SBM (Formula A) or its pharmaceutically acceptable salt, mirror image isomer, diastereomer, tautomer, racemate, solvent Compounds, metabolic precursors or prodrugs for the manufacture of a medicament for the treatment of synucleinopathies, wherein EBM is an E3 ubiquitin ligase binding moiety; L is a linker covalently linked to EBM and SBM and SBM is the alpha-synuclein binding moiety of the formula:
Figure 02_image472
in
Figure 02_image463
covalently attached to L; and (i)
Figure 02_image463
is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N;
Figure 02_image466
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; and
Figure 02_image468
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; or (ii)
Figure 02_image463
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;
Figure 02_image466
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; and
Figure 02_image468
is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N.

實施例5.一種式A化合物： EBM-L-SBM  (式A) 或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥之用途，其用於製造用於減少α-突觸核蛋白聚集之藥劑，其中 EBM為E3泛蛋白連接酶結合部分； L為共價連接至EBM及SBM之連接子；且 SBM為下式之α-突觸核蛋白結合部分：

Figure 02_image472
其中
Figure 02_image463
共價連接至L；且 (i)
Figure 02_image463
為含有至少1個選自O、S及N之環雜原子的經取代或未經取代之雙環稠合芳族環；
Figure 02_image466
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；且
Figure 02_image468
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；或 (ii)
Figure 02_image463
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；
Figure 02_image466
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；且
Figure 02_image468
為含有至少1個選自O、S及N之環雜原子的經取代或未經取代之雙環稠合芳族環。 Embodiment 5. A compound of formula A: EBM-L-SBM (Formula A) or its pharmaceutically acceptable salt, mirror image isomer, diastereomer, tautomer, racemate, solvent Compounds, metabolic precursors or prodrugs for the manufacture of a medicament for reducing aggregation of α-synuclein, wherein EBM is an E3 ubiquitin ligase binding moiety; L is covalently linked to EBM and SBM a linker; and the SBM is an α-synuclein binding moiety of the formula:
Figure 02_image472
in
Figure 02_image463
covalently attached to L; and (i)
Figure 02_image463
is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N;
Figure 02_image466
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; and
Figure 02_image468
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; or (ii)
Figure 02_image463
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;
Figure 02_image466
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; and
Figure 02_image468
is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N.

實施例6.一種式A化合物： EBM-L-SBM  (式A) 或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥之用途，其用於製造用於減少路易體之藥劑，其中 EBM為E3泛蛋白連接酶結合部分； L為共價連接至EBM及SBM之連接子；且 SBM為下式之α-突觸核蛋白結合部分：

Figure 02_image472
其中
Figure 02_image463
共價連接至L；且 (i)
Figure 02_image463
為含有至少1個選自O、S及N之環雜原子的經取代或未經取代之雙環稠合芳族環；
Figure 02_image466
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；且
Figure 02_image468
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；或 (ii)
Figure 02_image463
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；
Figure 02_image466
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；且
Figure 02_image468
為含有至少1個選自O、S及N之環雜原子的經取代或未經取代之雙環稠合芳族環。 Embodiment 6. A compound of formula A: EBM-L-SBM (Formula A) or its pharmaceutically acceptable salt, mirror-image isomer, diastereomer, tautomer, racemate, solvent Use of a compound, metabolic precursor or prodrug for the manufacture of a medicament for reducing Lewy bodies, wherein EBM is an E3 ubiquitin ligase binding moiety; L is a linker covalently linked to EBM and SBM; and SBM is the α-synuclein binding moiety of the formula:
Figure 02_image472
in
Figure 02_image463
covalently attached to L; and (i)
Figure 02_image463
is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N;
Figure 02_image466
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; and
Figure 02_image468
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; or (ii)
Figure 02_image463
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;
Figure 02_image466
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; and
Figure 02_image468
is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N.

實施例7.如實施例1之方法或如實施例4之用途，其中該突觸核蛋白病為帕金森氏病(PD)、路易體失智症(DLB)、多發性系統萎縮症(MSA)或其兩者或更多者之組合。Embodiment 7. The method as in embodiment 1 or the purposes as in embodiment 4, wherein the synuclein disease is Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple systemic atrophy (MSA ) or a combination of two or more thereof.

實施例8.如實施例1至7中任一項之方法或用途，其中該經取代或未經取代之雙環稠合芳族環為經取代或未經取代之雙環5至6系統。Embodiment 8. The method or use according to any one of embodiments 1 to 7, wherein the substituted or unsubstituted bicyclic fused aromatic ring is a substituted or unsubstituted bicyclic 5-6 system.

實施例9.如實施例1至8中任一項之方法或用途，其中SBM具有式B或式C

Figure 02_image496
； 其中 Z為C或N；U為O、S或CH；V為N或NH； K為CH或N；Q為CH或N；其中K及Q不同時為N； R'''在每次出現時獨立地選自由以下組成之群：H、OH、NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基及鹵素；k為0、1、2或3； R'在每次出現時獨立地選自由以下組成之群：H、鹵素、OH、C 1-6烷基、C 1-6鹵烷基及C 1-6烷氧基；m為0、1、2、3或4； R''在每次出現時獨立地選自由以下組成之群：H、鹵基、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6鹵烷基、C 1-6烷胺基、C 3-6環烷胺基、C 3-6環烷基及C 3-6雜環烷基；n為0、1或2； J為CR 6或N；X為CR 6或N；Y為CR 6或N；其中J、X及Y中之至少一者為N，但J及Y不同時為N，X及Y不同時為N； R 6獨立地選自由以下組成之群：H、NH 2、C 1-6烷基及C 1-6烷氧基，其中NH 2、C 1-6烷基或C 1-6烷氧基視情況經C 1-3烷基、C 3-6環烷基及/或鹵基中之1至3者取代；且 在式B中，V為N，其中Z及U不同時為雜原子；且 在式C中，V為N或NH；T為CH或N；其中U、Z、V及T中之至多兩者含有雜原子。 Embodiment 9. The method or use of any one of embodiments 1 to 8, wherein the SBM has formula B or formula C
Figure 02_image496
; wherein Z is C or N; U is O, S or CH; V is N or NH; K is CH or N; Q is CH or N; wherein K and Q are not N at the same time; When present, independently selected from the group consisting of H, OH, NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy and halogen; k is 0, 1, 2 or 3; R', at each occurrence, is independently selected from the group consisting of H, halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy; m is 0, 1, 2, 3 or 4; R'' at each occurrence is independently selected from the group consisting of H, halo, OH, NH2 , C1-6 alkyl, C1-6 alkoxy group, C 1-6 haloalkyl group, C 1-6 alkylamino group, C 3-6 cycloalkylamino group, C 3-6 cycloalkyl group and C 3-6 heterocycloalkyl group; n is 0, 1 or 2; J is CR 6 or N; X is CR 6 or N; Y is CR 6 or N; wherein at least one of J, X and Y is N, but J and Y are not N at the same time, and X and Y are different is N; R 6 is independently selected from the group consisting of H, NH 2 , C 1-6 alkyl and C 1-6 alkoxy, wherein NH 2 , C 1-6 alkyl or C 1-6 Alkoxy is optionally substituted by 1 to 3 of C 1-3 alkyl, C 3-6 cycloalkyl and/or halo; and in formula B, V is N, wherein Z and U are not at the same time and in formula C, V is N or NH; T is CH or N; wherein at most two of U, Z, V and T contain heteroatoms.

實施例10.如實施例1至9中任一項之方法或用途，其中EBM為

Figure 02_image498
Figure 02_image500
； 其中 R 3'為H或C 1-6烷基； R 2'在每次出現時獨立地選自由以下組成之群：H、OH、C 1-6烷基、C 1-6烷氧基、C 1-6烷胺基及NH 2； m6為0、1、2、3或4；且 Y 1為CH 2或
Figure 02_image502
。 Embodiment 10. The method or use of any one of embodiments 1 to 9, wherein the EBM is
Figure 02_image498
Figure 02_image500
; wherein R 3' is H or C 1-6 alkyl; R 2' is at each occurrence independently selected from the group consisting of: H, OH, C 1-6 alkyl, C 1-6 alkoxy , C 1-6 alkylamino and NH 2 ; m6 is 0, 1, 2, 3 or 4; and Y 1 is CH 2 or
Figure 02_image502
.

實施例11.如實施例1至10中任一項之方法或用途，其中該化合物具有式I至式VI中之任一者，

Figure 02_image504
Figure 02_image506
或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥； 其中 L 1為一鍵、-C(=O)-、-NR-、-O-或-S-，其中R為氫、視情況經取代之醯基、視情況經取代之烷基或氮保護基； L 2為經取代或未經取代之C 1-50烴鏈，視情況其中該烴鏈之一或多個鏈原子獨立地經-C(=O)-、-O-、-NR a1-、-S-或環狀部分置換，其中R a1獨立地為氫、經取代或未經取代之C 1-6烷基或氮保護基；及 Z為C或N；U為O、S或CH； K為CH或N；Q為CH或N；其中K及Q不同時為N； R'''在每次出現時獨立地選自由以下組成之群：H、OH、NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基及鹵素；k為0、1、2或3； R'在每次出現時獨立地選自由以下組成之群：H、鹵素、OH、C 1-6烷基、C 1-6鹵烷基及C 1-6烷氧基；m為0、1、2、3或4； R''在每次出現時獨立地選自由以下組成之群：H、鹵基、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6鹵烷基、C 1-6烷胺基、C 3-6環烷胺基、C 3-6環烷基及C 3-6雜環烷基；n為0、1或2； J為CR 6或N；X為CR 6或N；Y為CR 6或N；其中J、X及Y中之至少一者為N，但J及Y不同時為N，X及Y不同時為N； R 6獨立地選自由以下組成之群：H、NH 2、C 1-6烷基及C 1-6烷氧基，其中NH 2、C 1-6烷基或C 1-6烷氧基視情況經C 1-3烷基、C 3-6環烷基及/或鹵基中之1至3者取代； 在式I中，L 3為鍵、-NR-、-O-或-S-，其中R為氫、視情況經取代之醯基、視情況經取代之烷基或氮保護基；R 3'為H或C 1-6烷基；Y 1為CH 2或
Figure 02_image508
；V為N，其中Z及U不同時為雜原子； 在式II中，R 2'在每次出現時獨立地選自由以下組成之群：H、OH、C 1-6烷基、C 1-6烷氧基、C 1-6烷胺基及NH 2；m6為0、1、2、3或4；Y 1為CH 2或
Figure 02_image508
；V為N，其中Z及U不同時為雜原子； 在式III中，V為N，其中Z及U不同時為雜原子； 在式IV中，L 3為鍵、-NR-、-O-或-S-，其中R為氫、視情況經取代之醯基、視情況經取代之烷基或氮保護基；R 3'為H或C 1-6烷基；Y 1為CH 2或
Figure 02_image508
；V為N或NH；T為CH或N；其中U、Z、V及T中之至多兩者含有雜原子； 在式V中，R 2'在每次出現時獨立地選自由以下組成之群：H、OH、C 1-6烷基、C 1-6烷氧基、C 1-6烷胺基及NH 2；m6為0、1、2、3或4；Y 1為CH 2或
Figure 02_image508
；V為N或NH；T為CH或N；其中U、Z、V及T中之至多兩者含有雜原子； 在式VI中，V為N；T為CH或N；其中U、Z、V及T中之至多兩者含有雜原子。 Embodiment 11. The method or use of any one of embodiments 1 to 10, wherein the compound has any of formulas I to VI,
Figure 02_image504
Figure 02_image506
Or its pharmaceutically acceptable salt, mirror image isomer, diastereomer, tautomer, racemate, solvate, metabolic precursor or prodrug; wherein L is a bond, - C(=O)-, -NR-, -O- or -S-, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl, or nitrogen protecting group; L is substituted or Unsubstituted C 1-50 hydrocarbon chain, where one or more chain atoms of the hydrocarbon chain are independently -C(=O)-, -O-, -NR a1 -, -S- or cyclic Partial replacement, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or nitrogen protecting group; and Z is C or N; U is O, S or CH; K is CH or N; Q is CH or N; wherein K and Q are not N at the same time; R''' is independently selected from the group consisting of H, OH, NH 2 , C 1-6 alkyl, C 1- 6 alkylamino, C 1-6 alkoxy and halogen; k is 0, 1, 2 or 3; R' is independently selected in each occurrence from the group consisting of: H, halogen, OH, C 1- 6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy; m is 0, 1, 2, 3 or 4; R'' is independently selected at each occurrence from the group consisting of: H , halo, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkylamino, C 3-6 cycloalkylamino, C 3-6 cycloalkyl and C 3-6 heterocycloalkyl; n is 0, 1 or 2; J is CR 6 or N; X is CR 6 or N; Y is CR 6 or N; wherein J, X and At least one of Y is N, but J and Y are not N at the same time, and X and Y are not N at the same time; R 6 is independently selected from the group consisting of H, NH 2 , C 1-6 alkyl and C 1-6 alkoxy, where NH 2 , C 1-6 alkyl or C 1-6 alkoxy is optionally modified by one of C 1-3 alkyl, C 3-6 cycloalkyl and/or halogen Substitution to 3; In formula I, L 3 is a bond, -NR-, -O- or -S-, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or nitrogen protection base; R 3' is H or C 1-6 alkyl; Y 1 is CH 2 or
Figure 02_image508
; V is N, wherein Z and U are not heteroatoms at the same time; In formula II, R 2' is independently selected from the group consisting of H , OH, C 1-6 alkyl, C -6 alkoxy, C 1-6 alkylamino and NH 2 ; m6 is 0, 1, 2, 3 or 4; Y 1 is CH 2 or
Figure 02_image508
V is N, wherein Z and U are not heteroatoms at the same time; In formula III, V is N, and Z and U are not heteroatoms at the same time; In formula IV, L 3 is a bond, -NR-, -O -or-S-, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or nitrogen protecting group; R 3' is H or C 1-6 alkyl; Y 1 is CH 2 or
Figure 02_image508
; V is N or NH; T is CH or N; wherein at most two of U, Z, V, and T contain heteroatoms; In formula V, R 2' at each occurrence is independently selected from the group consisting of Group: H, OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and NH 2 ; m6 is 0, 1, 2, 3 or 4; Y 1 is CH 2 or
Figure 02_image508
; V is N or NH; T is CH or N; wherein at most two of U, Z, V and T contain heteroatoms; In formula VI, V is N; T is CH or N; At most two of V and T contain heteroatoms.

實施例12.如實施例11之方法或用途，其中L 2為視情況經取代之C 1-45烴鏈，視情況其中烴鏈之一或多個鏈原子獨立地經-C(=O)-、-O-、-NR a1-、-S-或環狀部分置換，其中R a1獨立地為氫、經取代或未經取代之C 1-6烷基或氮保護基； 較佳地，L 2為經取代或未經取代之C 5-40烴鏈； 較佳地，L 2為經取代或未經取代之C 1-30、C 1-24或C 1-20烴鏈，視情況其中烴鏈之一或多個鏈原子獨立地經-C(=O)-、-O-、-NR a1-、-S-或環狀部分置換，其中R a1獨立地為氫、經取代或未經取代之C 1-6烷基或氮保護基； 較佳地，L 2為未經取代之C 1-26、C 5-26、C 5-20、C 5-15、C 15-20或C 20-25烴鏈，其中烴鏈之一或多個鏈原子獨立地經-C(=O)-、-O-或-NR a1-置換，其中R a1獨立地為氫、經取代或未經取代之C 1-6烷基或氮保護基。 Embodiment 12. The method or use as in embodiment 11, wherein L is an optionally substituted C 1-45 hydrocarbon chain, where one or more chain atoms of the hydrocarbon chain are independently replaced by -C(=O) -, -O-, -NR a1 -, -S- or cyclic partial replacement, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or nitrogen protecting group; preferably, L 2 is a substituted or unsubstituted C 5-40 hydrocarbon chain; preferably, L 2 is a substituted or unsubstituted C 1-30 , C 1-24 or C 1-20 hydrocarbon chain, as appropriate wherein one or more chain atoms of the hydrocarbon chain are independently replaced by -C(=O)-, -O-, -NR a1 -, -S- or a ring moiety, wherein R a1 is independently hydrogen, substituted or Unsubstituted C 1-6 alkyl or nitrogen protecting group; preferably, L 2 is unsubstituted C 1-26 , C 5-26 , C 5-20 , C 5-15 , C 15-20 or C 20-25 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced by -C(=O)-, -O- or -NR a1 -, wherein R a1 is independently hydrogen, substituted or Unsubstituted C 1-6 alkyl or nitrogen protecting group.

實施例13.如實施例11之方法或用途，其中L 2為視情況經取代之C 1-30烴鏈，其中烴鏈之一或多個鏈原子獨立地經-O-或-NR a1-置換，其中R a1獨立地為氫、經取代或未經取代之C 1-6烷基或氮保護基； 較佳地，L 2之烴鏈之至少一個鏈原子獨立地經-C(=O)-、-O-、-S-、-NR a1-、-N=或=N-置換，其中R a1獨立地為氫、經取代或未經取代之C 1-6烷基或氮保護基；較佳經-O-置換。 Embodiment 13. The method or use as in embodiment 11, wherein L 2 is an optionally substituted C 1-30 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently -O- or -NR a1 - Replacement, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or nitrogen protecting group; preferably, at least one chain atom of the hydrocarbon chain of L is independently -C(=O )-, -O-, -S-, -NR a1 -, -N= or =N-replacement, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or nitrogen protecting group ; preferably substituted by -O-.

實施例14.如實施例11之方法或用途，其中L 2係選自由以下組成之群：經取代或未經取代之伸碳環基、經取代或未經取代之伸雜環基、經取代或未經取代之伸芳基、經取代或未經取代之伸雜芳基、或經取代或未經取代之伸雜烷基，及其組合； 較佳地，L 2係選自由以下組成之群：經取代及未經取代之伸烷基、經取代及未經取代之伸烯基、經取代及未經取代之伸炔基、經取代及未經取代之伸雜烷基、經取代及未經取代之伸雜烯基、經取代及未經取代之伸雜炔基、經取代及未經取代之伸雜環基、經取代及未經取代之伸碳環基、經取代及未經取代之伸芳基、經取代及未經取代之伸雜芳基，及其組合。 Embodiment 14. The method or use as in embodiment 11, wherein L is selected from the group consisting of substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted Or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroalkyl, and combinations thereof; Preferably, L is selected from the group consisting of Groups: substituted and unsubstituted alkylene, substituted and unsubstituted alkenylene, substituted and unsubstituted alkynylene, substituted and unsubstituted heteroalkylene, substituted and Unsubstituted heteroalkenyl, substituted and unsubstituted heteroalkynyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted carbocyclylene, substituted and unsubstituted Substituted arylylene, substituted and unsubstituted heteroaryl, and combinations thereof.

實施例15.如實施例14之方法或用途，其中該伸碳環基或該伸雜環基為

Figure 02_image513
。 Embodiment 15. The method or use as in embodiment 14, wherein the carbocyclyl or the heterocyclyl is
Figure 02_image513
.

實施例16.如實施例14之方法或用途，其中L 2包含至少一個選自由以下組成之群的實例：經取代或未經取代之C 1-6伸烷基、經取代或未經取代之C 2-6伸烯基、經取代或未經取代之C 2-6伸炔基、經取代或未經取代之雜C 1-6伸烷基、經取代或未經取代之雜C 2-6伸烯基、經取代或未經取代之雜C 2-6伸炔基、經取代或未經取代之C 3-6伸碳環基、經取代或未經取代之3至6員伸雜環基、經取代或未經取代之伸苯基及經取代或未經取代之5至6員伸雜芳基。 Embodiment 16. The method or use as in embodiment 14, wherein L 2 comprises at least one instance selected from the group consisting of: substituted or unsubstituted C 1-6 alkylene, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted hetero C 1-6 alkylene, substituted or unsubstituted hetero C 2- 6 alkenyl, substituted or unsubstituted hetero C 2-6 alkynyl, substituted or unsubstituted C 3-6 carbocyclyl, substituted or unsubstituted 3 to 6 membered hetero Cyclic group, substituted or unsubstituted phenylene and substituted or unsubstituted 5-6 membered heteroaryl.

實施例17.如實施例14之方法或用途，其中 L2包含至少一個選自由以下組成之群的實例：經取代或未經取代之亞甲基、伸乙基、伸正丙基、伸正丁基、伸正戊基、伸正己基、-(CH 2) 2-O(CH 2) 2-、-OCH 2-、-CH 2O-、-O(CH 2) 2-、-(CH 2) 2O-、-O(CH 2) 3-、-(CH 2) 3O-、-O(CH 2) 4-、-(CH 2) 4O-、-O(CH 2) 5-、-(CH 2) 5O-、-O(CH 2) 6-、-O(CH 2) 6O-、-C(=O)O-、-O-C(=O)-、-NH-C(=O)-及-C(=O)NH-。 Embodiment 17. The method or use as in embodiment 14, wherein L2 comprises at least one instance selected from the group consisting of substituted or unsubstituted methylene, ethylenyl, n-propylenyl, n-butylene, N-pentyl, n-hexyl, -(CH 2 ) 2 -O(CH 2 ) 2 -, -OCH 2 -, -CH 2 O-, -O(CH 2 ) 2 -, -(CH 2 ) 2 O -, -O(CH 2 ) 3 -, -(CH 2 ) 3 O-, -O(CH 2 ) 4 -, -(CH 2 ) 4 O-, -O(CH 2 ) 5 -, -(CH 2 ) 5 O-, -O(CH 2 ) 6 -, -O(CH 2 ) 6 O-, -C(=O)O-, -OC(=O)-, -NH-C(=O) - and -C(=O)NH-.

實施例18.如實施例14之方法或用途，其中L 2之烴鏈之至少一個鏈原子獨立地經具有1至3個選自由氮及氧組成之群之環雜原子的6員雜環基置換； 較佳地，L 2之烴鏈之至少一個鏈原子獨立地經哌啶、哌𠯤或𠰌啉置換； 較佳地，L 2之烴鏈之至少一個鏈原子獨立地經視情況經取代之苯基置換。 Embodiment 18. The method or use as in Embodiment 14, wherein at least one chain atom of the hydrocarbon chain of L is independently a 6-membered heterocyclic group having 1 to 3 ring heteroatoms selected from the group consisting of nitrogen and oxygen Replacement; Preferably, at least one chain atom of the hydrocarbon chain of L is independently replaced by piperidine, piperidine or thioline; preferably, at least one chain atom of the hydrocarbon chain of L is independently substituted as appropriate The phenyl substitution.

實施例19.如實施例14之方法或用途，其中L 2為未經取代之烴鏈，視情況其中烴鏈之一或多個鏈原子獨立地經-NR a1-置換，且R a1之各實例獨立地為氫、經取代或未經取代之C 1-6烷基或氮保護基；或視情況R a1之兩個實例與其插入原子一起形成經取代或未經取代之雜環或經取代或未經取代之雜芳基環。 Embodiment 19. The method or use as in embodiment 14, wherein L 2 is an unsubstituted hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced by -NR a1 -, and each of R a1 Examples are independently hydrogen, substituted or unsubstituted C 1-6 alkyl or nitrogen protecting group; or as the case may be, two instances of R a1 together with its intervening atom form a substituted or unsubstituted heterocyclic ring or substituted Or an unsubstituted heteroaryl ring.

實施例20.如實施例19之方法或用途，其中R a1之至少一個實例為氫、經取代或未經取代之C 1-6烷基(例如，經取代或未經取代之甲基或乙基)或氮保護基(例如，苯甲基、碳酸三級丁酯、胺基甲酸苯甲酯、碳酸9-茀基甲酯、三氟乙醯基、三苯基甲基、乙醯基或對甲苯磺醯胺)。 Embodiment 20. The method or use as in embodiment 19, wherein at least one instance of R a1 is hydrogen, substituted or unsubstituted C 1-6 alkyl (for example, substituted or unsubstituted methyl or ethyl group) or a nitrogen protecting group (for example, benzyl, tert-butyl carbonate, benzyl carbamate, 9-fenylmethyl carbonate, trifluoroacetyl, triphenylmethyl, acetyl or p-toluenesulfonamide).

實施例21. 如實施例11之方法或用途，其中L 2為

Figure 02_image515
，其中g為1、2、3、4、5或6。 Embodiment 21. The method or use as in embodiment 11, wherein L 2 is
Figure 02_image515
, wherein g is 1, 2, 3, 4, 5 or 6.

實施例22. 如實施例11之方法或用途，其中L 2包括部分-O-、

Figure 02_image517
、-NHC(=O)-或-NH-。 Embodiment 22. The method or use as in embodiment 11, wherein L 2 includes moieties -O-,
Figure 02_image517
, -NHC(=O)- or -NH-.

實施例23. 如實施例11之方法或用途，其中L 2係選自由以下組成之群：

Figure 02_image519
Figure 02_image521
Figure 02_image523
，其中各g獨立地為1、2、3、4、5或6；f為1、2、3、4、5或6，且h為1、2、3、4、5或6。 Embodiment 23. The method or use as in embodiment 11, wherein L is selected from the group consisting of:
Figure 02_image519
Figure 02_image521
Figure 02_image523
, wherein each g is independently 1, 2, 3, 4, 5 or 6; f is 1, 2, 3, 4, 5 or 6, and h is 1, 2, 3, 4, 5 or 6.

實施例24.如實施例11之方法或用途，其中該式I化合物具有式I-1；

Figure 02_image525
或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。 Embodiment 24. The method or use of embodiment 11, wherein the compound of formula I has formula I-1;
Figure 02_image525
or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

實施例25.如實施例11之方法或用途，其中該式II化合物具有式II-1；

Figure 02_image527
或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。 Embodiment 25. The method or use of embodiment 11, wherein the compound of formula II has formula II-1;
Figure 02_image527
or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

實施例26.如實施例11之方法或用途，其中該式III化合物具有式III-1；

Figure 02_image529
或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。 Embodiment 26. The method or use of embodiment 11, wherein the compound of formula III has formula III-1;
Figure 02_image529
or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

實施例27.如實施例11之方法或用途，其中該式IV化合物具有式IV-1；

Figure 02_image531
或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。 Embodiment 27. The method or use of embodiment 11, wherein the compound of formula IV has formula IV-1;
Figure 02_image531
or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

實施例28.如實施例11之方法或用途，其中該式V化合物具有式V-1；

Figure 02_image533
或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。 Embodiment 28. The method or use of embodiment 11, wherein the compound of formula V has formula V-1;
Figure 02_image533
or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

實施例29.如實施例11之方法或用途，其中該式VI化合物具有式VI-1；

Figure 02_image535
或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。 Embodiment 29. The method or use of embodiment 11, wherein the compound of formula VI has formula VI-1;
Figure 02_image535
or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

實施例30.如實施例24之方法或用途，其中該式I-1化合物具有式1、5、6、8、10或13；

Figure 02_image537
Figure 02_image539
或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥； 其中 各A獨立地為O、NH、
Figure 02_image541
； m2為1、2、3、4、5、6或7； m3為1、2、3、4、5或6； m4為0、1、2或3； m5為0、1、2或3；且 R 1'為O、NH、
Figure 02_image543
。 Embodiment 30. The method or use of embodiment 24, wherein the compound of formula I-1 has formula 1, 5, 6, 8, 10 or 13;
Figure 02_image537
Figure 02_image539
or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof; wherein each A is independently O, NH,
Figure 02_image541
; m2 is 1, 2, 3, 4, 5, 6, or 7; m3 is 1, 2, 3, 4, 5, or 6; m4 is 0, 1, 2, or 3; m5 is 0, 1, 2, or 3 ; and R 1' is O, NH,
Figure 02_image543
.

實施例31.如實施例30之方法或用途，其中該化合物具有式1，且其中R'為H、C 1-3鹵烷基或C 1-3烷氧基；及/或R''為H、鹵基、OH、NH 2、C 1-3烷氧基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基及C 3-5雜環烷基；及/或R'''為H、OH或鹵素；及/或R 1'為O、NH、

Figure 02_image545
Figure 02_image547
；及/或，A為O、NH、
Figure 02_image549
；及/或，m2為2、3、4或6；及/或R 3'為H或C 1-3烷基；或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。 Embodiment 31. The method or use as in embodiment 30, wherein the compound has formula 1, and wherein R' is H, C 1-3 haloalkyl or C 1-3 alkoxy; and/or R'' is H, halogen, OH, NH 2 , C 1-3 alkoxy, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino and C 3-5 heterocycloalkane and/or R''' is H, OH or halogen; and/or R 1' is O, NH,
Figure 02_image545
Figure 02_image547
and/or, A is O, NH,
Figure 02_image549
; and/or, m2 is 2, 3, 4 or 6; and/or R 3' is H or C 1-3 alkyl; or a pharmaceutically acceptable salt, mirror isomer, diastereomer tautomers, racemates, solvates, metabolic precursors or prodrugs.

實施例32.如實施例30之方法或用途，其中該化合物具有式5，且其中R 3'為H或C 1-3烷基；及/或各A獨立地為O、NH、

Figure 02_image551
；及/或，m4為0、1、2或3；及/或，m5為0、1、2或3；及/或，m3為1、2、3、4、5或6；及/或，R 1'為O、NH或
Figure 02_image553
；及/或，R'''為H、OH、C 1-3烷基、C 1-3烷氧基或鹵素；及/或，R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基；及/或，m為0、1、2或3；及/或，R''為H、鹵基、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基或C 3-5雜環烷基；或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。 Embodiment 32. The method or use as in embodiment 30, wherein the compound has formula 5, and wherein R 3' is H or C 1-3 alkyl; and/or each A is independently O, NH,
Figure 02_image551
and/or, m4 is 0, 1, 2 or 3; and/or, m5 is 0, 1, 2 or 3; and/or, m3 is 1, 2, 3, 4, 5 or 6; and/or , R 1' is O, NH or
Figure 02_image553
and/or, R''' is H, OH, C 1-3 alkyl, C 1-3 alkoxy or halogen; and/or, R' is H, halogen, OH, C 1-3 alkyl , C 1-3 haloalkyl or C 1-3 alkoxy; and/or, m is 0, 1, 2 or 3; and/or, R'' is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3- 5. Heterocycloalkyl; or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

實施例33.如實施例30之方法或用途，其中該化合物具有式6，且其中R 3'為H或C 1-3烷基；及/或各A獨立地為O、NH或

Figure 02_image553
；及/或，m2為1、2、3、4、5、6或7；及/或，R 1'為O、NH或
Figure 02_image553
；及/或，R'''為H、OH、C 1-3烷基、C 1-3烷氧基或鹵素；及/或，R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基；及/或，m為0、1、2或3；及/或，R''為H、鹵基、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基或C 3-5雜環烷基；及/或，n為0或1；或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。 Embodiment 33. The method or use as in embodiment 30, wherein the compound has formula 6, and wherein R 3' is H or C 1-3 alkyl; and/or each A is independently O, NH or
Figure 02_image553
; and/or, m2 is 1, 2, 3, 4, 5, 6 or 7; and/or, R 1' is O, NH or
Figure 02_image553
and/or, R''' is H, OH, C 1-3 alkyl, C 1-3 alkoxy or halogen; and/or, R' is H, halogen, OH, C 1-3 alkyl , C 1-3 haloalkyl or C 1-3 alkoxy; and/or, m is 0, 1, 2 or 3; and/or, R'' is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3- 5 heterocycloalkyl groups; and/or, n is 0 or 1; or pharmaceutically acceptable salts, mirror-image isomers, diastereomers, tautomers, racemates, solvates , metabolic precursors or prodrugs.

實施例34.如實施例30之方法或用途，其中該化合物具有式8，且其中R 3'為H或C 1-3烷基；及/或，各A獨立地為O、NH、

Figure 02_image556
；及/或，m2為1、2、3或4；及/或，R 1'為O、NH、
Figure 02_image558
；及/或，R'''為H、OH、C 1-3烷基、C 1-3烷氧基或鹵素；及/或，k為0或1；及/或，R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基；及/或，m為0、1或2；及/或，R''為H、鹵基、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基或C 3-5雜環烷基；及/或，n為0、1或2；或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。 Embodiment 34. The method or use as in embodiment 30, wherein the compound has formula 8, and wherein R 3' is H or C 1-3 alkyl; and/or, each A is independently O, NH,
Figure 02_image556
; and/or, m2 is 1, 2, 3 or 4; and/or, R 1' is O, NH,
Figure 02_image558
and/or, R''' is H, OH, C 1-3 alkyl, C 1-3 alkoxy or halogen; and/or, k is 0 or 1; and/or, R' is H, Halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy; and/or, m is 0, 1 or 2; and/or, R'' is H, halogen radical, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 Cycloalkylamino or C 3-5 heterocycloalkyl; and/or, n is 0, 1 or 2; or a pharmaceutically acceptable salt, mirror image isomer, diastereomer, tautomer racemate, solvate, metabolic precursor or prodrug.

實施例35.如實施例30之方法或用途，其中該化合物具有式10，且其中R 3'為H或C 1-3烷基；及/或，各A獨立地為O、NH、

Figure 02_image560
；及/或，m5為0或1；及/或，m4為0或1；及/或，m3為1、2、3、4或5；及/或R 1'為O、NH、
Figure 02_image562
；及/或，R'''為H、OH、C 1-3烷基、C 1-3烷氧基或鹵素；及/或，k為0或1；及/或，R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基；及/或，m為0或1；及/或，R''為H、鹵基、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基或C 3-5雜環烷基；及/或，n為0或1；或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。 Embodiment 35. The method or use as in embodiment 30, wherein the compound has formula 10, and wherein R 3' is H or C 1-3 alkyl; and/or, each A is independently O, NH,
Figure 02_image560
and/or, m5 is 0 or 1; and/or, m4 is 0 or 1; and/or, m3 is 1, 2, 3, 4 or 5; and/or R 1' is O, NH,
Figure 02_image562
and/or, R''' is H, OH, C 1-3 alkyl, C 1-3 alkoxy or halogen; and/or, k is 0 or 1; and/or, R' is H, Halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy; and/or, m is 0 or 1; and/or, R'' is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkane Amino or C 3-5 heterocycloalkyl; and/or, n is 0 or 1; or pharmaceutically acceptable salts, mirror-image isomers, diastereomers, tautomers, racemic Rotates, solvates, metabolic precursors or prodrugs.

實施例36.如實施例30之方法或用途，其中該化合物具有式13，且其中R 3'為H或C 1-3烷基；及/或，各A獨立地為O、NH、

Figure 02_image564
；及/或，m2為1、2、3或4；及/或，R 1'為O、NH、
Figure 02_image566
；及/或，R'''為H、OH、C 1-3烷基、C 1-3烷氧基或鹵素；及/或，R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基；及/或，m為0、1、2或3；及/或，R''為H、鹵基、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基或C 3-5雜環烷基；或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。 Embodiment 36. The method or use as in embodiment 30, wherein the compound has formula 13, and wherein R 3' is H or C 1-3 alkyl; and/or, each A is independently O, NH,
Figure 02_image564
; and/or, m2 is 1, 2, 3 or 4; and/or, R 1' is O, NH,
Figure 02_image566
and/or, R''' is H, OH, C 1-3 alkyl, C 1-3 alkoxy or halogen; and/or, R' is H, halogen, OH, C 1-3 alkyl , C 1-3 haloalkyl or C 1-3 alkoxy; and/or, m is 0, 1, 2 or 3; and/or, R'' is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3- 5. Heterocycloalkyl; or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

實施例37.如實施例30之方法或用途，其中該式1化合物具有式1-1；

Figure 02_image568
或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。 Embodiment 37. The method or use of embodiment 30, wherein the compound of formula 1 has formula 1-1;
Figure 02_image568
or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

實施例38.如實施例30之方法或用途，其中該式5化合物具有式5-1；

Figure 02_image570
或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。 Embodiment 38. The method or use according to embodiment 30, wherein the compound of formula 5 has formula 5-1;
Figure 02_image570
or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

實施例39.如實施例30之方法或用途，其中該式6化合物具有式6-1；

Figure 02_image572
或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。 Embodiment 39. The method or use of embodiment 30, wherein the compound of formula 6 has formula 6-1;
Figure 02_image572
or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

實施例40.如實施例37之方法或用途，其中R 3'為H或C 1-3烷基；A為O、NH、

Figure 02_image574
；m2為1、2、3、4、5、6及7；R 1'為O、NH、
Figure 02_image576
；R'為H、C 1-3鹵烷基或C 1-3烷氧基；R''為H、F、Cl、OH、NH 2、C 1-3烷氧基、甲胺基、二甲胺基、二乙胺基或環丙胺基。 Embodiment 40. The method or use as in embodiment 37, wherein R 3' is H or C 1-3 alkyl; A is O, NH,
Figure 02_image574
; m2 is 1, 2, 3, 4, 5, 6 and 7; R 1' is O, NH,
Figure 02_image576
; R' is H, C 1-3 haloalkyl or C 1-3 alkoxy; R'' is H, F, Cl, OH, NH 2 , C 1-3 alkoxy, methylamino, di Methylamino, diethylamino or cyclopropylamino.

實施例41.如實施例38之方法或用途，其中R 3'為H或C 1-3烷基；A為O、NH、

Figure 02_image578
；m5為0或1；m4為0、1、2、3或4；m3為1、2、3、4、5或6；R 1'為O、NH、
Figure 02_image580
；R'''為H、OH、C 1-3烷基、C 1-3烷氧基或鹵素；R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基；R''為H、鹵基、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基及C 3-5雜環烷基。 Embodiment 41. The method or use as in embodiment 38, wherein R 3' is H or C 1-3 alkyl; A is O, NH,
Figure 02_image578
; m5 is 0 or 1; m4 is 0, 1, 2, 3 or 4; m3 is 1, 2, 3, 4, 5 or 6; R 1' is O, NH,
Figure 02_image580
; R''' is H, OH, C 1-3 alkyl, C 1-3 alkoxy or halogen; R' is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl Or C 1-3 alkoxy; R'' is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 Alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino and C 3-5 heterocycloalkyl.

實施例42.如實施例39之方法或用途，其中R 3'為H或C 1-3烷基；A為O、NH、

Figure 02_image582
；m2為1、2、3、4、5、6或7；R 1'為O、NH、
Figure 02_image584
；R'''為H、OH、C 1-3烷基、C 1-3烷氧基或鹵素；R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基；m為0、1、2或3；R''為H、鹵基、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基或C 3-5雜環烷基。 Embodiment 42. The method or use as in embodiment 39, wherein R 3' is H or C 1-3 alkyl; A is O, NH,
Figure 02_image582
; m2 is 1, 2, 3, 4, 5, 6 or 7; R 1' is O, NH,
Figure 02_image584
; R''' is H, OH, C 1-3 alkyl, C 1-3 alkoxy or halogen; R' is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl Or C 1-3 alkoxy; m is 0, 1, 2 or 3; R'' is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1 -3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl.

實施例43.如實施例30之方法或用途，其中該化合物具有式1、5、6、8、10或13，且其中K為CH且Q為N，或K為N且Q為CH，或K及Q之兩者均為CH；或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。Embodiment 43. The method or use of embodiment 30, wherein the compound has formula 1, 5, 6, 8, 10 or 13, and wherein K is CH and Q is N, or K is N and Q is CH, or Both of K and Q are CH; or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvate, metabolic precursor or precursor thereof medicine.

實施例44.如實施例25之方法或用途，其中該化合物具有式3；

Figure 02_image586
其中R 1'為O、NH、
Figure 02_image588
； 或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。 Embodiment 44. The method or use of embodiment 25, wherein the compound has formula 3;
Figure 02_image586
Where R 1' is O, NH,
Figure 02_image588
; or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

實施例45.如實施例44之方法或用途，其中R 2'為H、OH、C 1-3烷基、C 1-3烷氧基、C 1-3烷胺基或NH 2；及/或，m6為0、1、2或3；及/或，R 1'為O或NH；及/或，R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基；及/或，R''為H、鹵基、OH、NH 2、C 1-3烷氧基、C 3-5環烷基、C 3-5環烷胺基或C 1-3烷胺基；及/或，R'''為H、OH、C 1-3烷基、C 1-3烷氧基或鹵素。 Embodiment 45. The method or use as in embodiment 44, wherein R 2' is H, OH, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino or NH 2 ; and/ Or, m6 is 0, 1, 2 or 3; and/or, R 1' is O or NH; and/or, R' is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkane or C 1-3 alkoxy; and/or, R'' is H, halo, OH, NH 2 , C 1-3 alkoxy, C 3-5 cycloalkyl, C 3-5 cycloalkane Amino or C 1-3 alkylamino; and/or, R''' is H, OH, C 1-3 alkyl, C 1-3 alkoxy or halogen.

實施例46.如實施例44之方法或用途，其中Z為C且U為O或S；或Z為N且U為CH； 及/或，K為CH且Q為N，或K為N且Q為CH，或K及Q之兩者均為CH。 Embodiment 46. The method or use according to embodiment 44, wherein Z is C and U is O or S; or Z is N and U is CH; And/or, K is CH and Q is N, or K is N and Q is CH, or both K and Q are CH.

實施例47.如實施例44之方法或用途，其中該化合物具有式3-1：

Figure 02_image590
或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。 Embodiment 47. The method or use of embodiment 44, wherein the compound has formula 3-1:
Figure 02_image590
or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

實施例48.如實施例47之方法或用途，其中R 2'為H、OH、C 1-3烷基、C 1-3烷氧基、C 1-3烷胺基或NH 2；m6為0、1、2或3；R 1'為O、NH、

Figure 02_image592
Figure 02_image594
；R''為H、鹵基、OH、NH 2、C 1-3烷氧基、C 1-3鹵烷基、C 3-5環烷基、C 3-5環烷胺基或C 1-3烷胺基。 Embodiment 48. The method or use as in embodiment 47, wherein R 2' is H, OH, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino or NH 2 ; m6 is 0, 1, 2 or 3; R 1' is O, NH,
Figure 02_image592
Figure 02_image594
; R'' is H, halo, OH, NH 2 , C 1-3 alkoxy, C 1-3 haloalkyl, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 1 -3 alkylamino.

實施例49.如實施例26之方法或用途，其中該化合物具有式15；

Figure 02_image596
其中m2為1、2、3、4、5、6或7；且R 1'為O、NH、
Figure 02_image598
； 或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。 Embodiment 49. The method or use of embodiment 26, wherein the compound has formula 15;
Figure 02_image596
wherein m2 is 1, 2, 3, 4, 5, 6 or 7; and R1 ' is O, NH,
Figure 02_image598
; or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

實施例50.如實施例49之方法或用途，其中m2為1、2、3、4、5、6或7；及/或，R 1'為O、NH、

Figure 02_image598
；及/或，R'''為H、OH、C 1-3烷基、C 1-3烷氧基或鹵素；及/或，R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基；m為0、1、2或3；及/或，R''為H、鹵基、OH、NH 2、C 1-3烷氧基、C 3-5環烷基、C 3-5環烷胺基或C 1-3烷胺基。 Embodiment 50. The method or use according to embodiment 49, wherein m2 is 1, 2, 3, 4, 5, 6 or 7; and/or, R 1' is O, NH,
Figure 02_image598
and/or, R''' is H, OH, C 1-3 alkyl, C 1-3 alkoxy or halogen; and/or, R' is H, halogen, OH, C 1-3 alkyl , C 1-3 haloalkyl or C 1-3 alkoxy; m is 0, 1, 2 or 3; and/or, R'' is H, halo, OH, NH 2 , C 1-3 alkane Oxygen, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 1-3 alkylamino.

實施例51.如實施例27之方法或用途，其中該化合物具有式2、7、9、11、12或14；

Figure 02_image601
Figure 02_image603
或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥； 其中 各A獨立地為O、NH、
Figure 02_image605
； m2為2、3、4、5或6； m3為1、2、3、4、5或6； m4為0、1、2、3或4； m5為0、1、2或3；且 R 1'為O、NH、
Figure 02_image607
。 Embodiment 51. The method or use of embodiment 27, wherein the compound has formula 2, 7, 9, 11, 12 or 14;
Figure 02_image601
Figure 02_image603
or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof; wherein each A is independently O, NH,
Figure 02_image605
; m2 is 2, 3, 4, 5, or 6; m3 is 1, 2, 3, 4, 5, or 6; m4 is 0, 1, 2, 3, or 4; m5 is 0, 1, 2, or 3; and R 1' is O, NH,
Figure 02_image607
.

實施例52.如實施例51之方法或用途，其中該化合物具有式2，且其中R 3'為H或C 1-3烷基；及/或，A為O、NH、

Figure 02_image609
；及/或，m2為2、3、4、5或6；及/或，R 1'為O、NH、
Figure 02_image611
；及/或，R''為H、鹵基、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基或C 3-5雜環烷基；及/或，R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基；及/或，m為0、1、2或3；及/或，R'''為H、OH、NH 2、C 1-3烷基、C 1-3烷胺基、C 1-3烷氧基或鹵素；或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。 Embodiment 52. The method or use according to embodiment 51, wherein the compound has formula 2, and wherein R 3' is H or C 1-3 alkyl; and/or, A is O, NH,
Figure 02_image609
and/or, m2 is 2, 3, 4, 5 or 6; and/or, R 1' is O, NH,
Figure 02_image611
and/or, R'' is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl; and/or, R' is H, halogen, OH, C 1-3 alkyl, C 1-3 Haloalkyl or C 1-3 alkoxy; and/or, m is 0, 1, 2 or 3; and/or, R''' is H, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylamino group, C 1-3 alkoxy group or halogen; or its pharmaceutically acceptable salt, mirror image isomer, diastereomer, tautomer, racemate, solvate substances, metabolic precursors, or prodrugs.

實施例53.如實施例51之方法或用途，其中該化合物具有式7，且其中R 3'為H或C 1-3烷基；及/或A為O、NH、

Figure 02_image613
；及/或，m2為2、3、4、5或6；及/或，R 1'為O、NH、
Figure 02_image615
；及/或，R''為H、鹵基、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基或C 3-5雜環烷基；及/或，R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基；及/或，m為0、1、2或3；或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。 Embodiment 53. The method or use according to embodiment 51, wherein the compound has formula 7, and wherein R 3' is H or C 1-3 alkyl; and/or A is O, NH,
Figure 02_image613
and/or, m2 is 2, 3, 4, 5 or 6; and/or, R 1' is O, NH,
Figure 02_image615
and/or, R'' is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl; and/or, R' is H, halogen, OH, C 1-3 alkyl, C 1-3 Haloalkyl or C 1-3 alkoxy; and/or, m is 0, 1, 2 or 3; or a pharmaceutically acceptable salt, mirror image isomer, diastereomer, tautomer racemate, solvate, metabolic precursor or prodrug.

實施例54.如實施例51之方法或用途，其中該化合物具有式9，且其中R 3'為H或C 1-3烷基；及/或A為O、NH、

Figure 02_image617
；及/或，m2為2、3、4、5或6；及/或，R 1'為O、NH、
Figure 02_image619
；及/或，R''為H、鹵基、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基或C 3-5雜環烷基；及/或，R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基；及/或，m為0、1、2或3；及/或，R'''為H、OH、NH 2、C 1-3烷基、C 1-3烷胺基、C 1-3烷氧基或鹵素；或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。 Embodiment 54. The method or use as in embodiment 51, wherein the compound has formula 9, and wherein R 3' is H or C 1-3 alkyl; and/or A is O, NH,
Figure 02_image617
and/or, m2 is 2, 3, 4, 5 or 6; and/or, R 1' is O, NH,
Figure 02_image619
and/or, R'' is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl; and/or, R' is H, halogen, OH, C 1-3 alkyl, C 1-3 Haloalkyl or C 1-3 alkoxy; and/or, m is 0, 1, 2 or 3; and/or, R''' is H, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylamino, C 1-3 alkoxy or halogen; or pharmaceutically acceptable salts, mirror-image isomers, diastereomers, tautomers, racemates, solvates substances, metabolic precursors, or prodrugs.

實施例55.如實施例51之方法或用途，其中該化合物具有式11，且其中R 3'為H或C 1-3烷基；及/或A為O、NH、

Figure 02_image621
；及/或，m2為2、3、4、5或6；及/或，R 1'為O、NH、
Figure 02_image623
；及/或，R''為H、鹵基、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基或C 3-5雜環烷基；及/或，R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基；及/或，m為0、1、2或3；及/或，R'''為H、OH、NH 2、C 1-3烷基、C 1-3烷胺基、C 1-3烷氧基或鹵素；或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。 Embodiment 55. The method or use as in embodiment 51, wherein the compound has formula 11, and wherein R 3' is H or C 1-3 alkyl; and/or A is O, NH,
Figure 02_image621
and/or, m2 is 2, 3, 4, 5 or 6; and/or, R 1' is O, NH,
Figure 02_image623
and/or, R'' is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl; and/or, R' is H, halogen, OH, C 1-3 alkyl, C 1-3 Haloalkyl or C 1-3 alkoxy; and/or, m is 0, 1, 2 or 3; and/or, R''' is H, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylamino, C 1-3 alkoxy or halogen; or pharmaceutically acceptable salts, mirror-image isomers, diastereomers, tautomers, racemates, solvates substances, metabolic precursors, or prodrugs.

實施例56.如實施例51之方法或用途，其中該化合物具有式12，且其中R 3'為H或C 1-3烷基；各A獨立地為O、NH、

Figure 02_image625
；m3為1、2、3、4、5或6；m4為0或1、2或3；m5為0或1、2或3；R 1'為O、NH、
Figure 02_image627
；R''為H、鹵基、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基或C 3-5雜環烷基；R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基；m為0、1、2或3；R'''為H、OH、NH 2、C 1-3烷基、C 1-3烷胺基、C 1-3烷氧基或鹵素；或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。 Embodiment 56. The method or use of embodiment 51, wherein the compound has formula 12, and wherein R 3' is H or C 1-3 alkyl; each A is independently O, NH,
Figure 02_image625
; m3 is 1, 2, 3, 4, 5 or 6; m4 is 0 or 1, 2 or 3; m5 is 0 or 1, 2 or 3; R 1' is O, NH,
Figure 02_image627
; R'' is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 Cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl; R' is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 Alkoxy; m is 0, 1, 2 or 3; R''' is H, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylamino, C 1-3 alkoxy or halogen ; or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

實施例57.如實施例51之方法或用途，其中該化合物具有式14，且其中R 3'為H或C 1-3烷基；及/或，各A獨立地為O、NH、

Figure 02_image629
；及/或，m3為1、2、3、4、5或6；及/或，m4為0、1、2、3或4；及/或，m5為0或1、2或3；及/或，R 1'為O、NH、
Figure 02_image627
；及/或，R''為H、鹵基、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3鹵烷基、C 1-3烷胺基、C 3-5環烷基、C 3-5環烷胺基或C 3-5雜環烷基；及/或，R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基；m為0、1、2或3；及/或，R'''為H、OH、NH 2、C 1-3烷基、C 1-3烷胺基、C 1-3烷氧基或鹵素；或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。 Embodiment 57. The method or use as in embodiment 51, wherein the compound has formula 14, and wherein R 3' is H or C 1-3 alkyl; and/or, each A is independently O, NH,
Figure 02_image629
and/or, m3 is 1, 2, 3, 4, 5 or 6; and/or, m4 is 0, 1, 2, 3 or 4; and/or, m5 is 0 or 1, 2 or 3; and /or, R 1' is O, NH,
Figure 02_image627
and/or, R'' is H, halo, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 alkylamino, C 3-5 cycloalkyl, C 3-5 cycloalkylamino or C 3-5 heterocycloalkyl; and/or, R' is H, halogen, OH, C 1-3 alkyl, C 1-3 Haloalkyl or C 1-3 alkoxy; m is 0, 1, 2 or 3; and/or, R''' is H, OH, NH 2 , C 1-3 alkyl, C 1-3 alkane Amino group, C 1-3 alkoxy group or halogen; or its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvate, metabolic precursor drug or prodrug.

實施例58.如實施例28之方法或用途，其中該化合物具有式4；

Figure 02_image632
其中R 1'為O、NH、
Figure 02_image634
； 或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。 Embodiment 58. The method or use of embodiment 28, wherein the compound has formula 4;
Figure 02_image632
Where R 1' is O, NH,
Figure 02_image634
; or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

實施例59.如實施例58之方法或用途，其中R 2'為H、OH、C 1-3烷基、C 1-3烷氧基、C 1-3烷胺基或NH 2；及/或，m6為0、1、2或3；及/或，R 1'為O、NH、

Figure 02_image636
；及/或，R'為H、鹵素、OH、C 1-3烷基、C 1-3鹵烷基或C 1-3烷氧基；R''為H、鹵基、OH、NH 2、C 1-3烷氧基、C 3-5環烷基、C 3-5環烷胺基及C 1-3烷胺基；及/或，R'''為H、OH、NH 2、C 1-3烷基、C 1-3烷胺基、C 1-3烷氧基或鹵素。 Embodiment 59. The method or use according to embodiment 58, wherein R 2' is H, OH, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino or NH 2 ; and/ Or, m6 is 0, 1, 2 or 3; and/or, R 1' is O, NH,
Figure 02_image636
and/or, R' is H, halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy; R'' is H, halo, OH, NH 2 , C 1-3 alkoxy, C 3-5 cycloalkyl, C 3-5 cycloalkylamino and C 1-3 alkylamino; and/or, R''' is H, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylamino, C 1-3 alkoxy or halogen.

實施例60.如實施例58之方法或用途，其中該化合物具有式4-1；

Figure 02_image638
或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。 Embodiment 60. The method or use of embodiment 58, wherein the compound has formula 4-1;
Figure 02_image638
or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

實施例61.如實施例29之方法或用途，其中該化合物具有式16或17；

Figure 02_image640
其中m2為1、2、3、4、5、6或7；且R 1'為O、NH、
Figure 02_image642
； 或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。 Embodiment 61. The method or use of embodiment 29, wherein the compound has formula 16 or 17;
Figure 02_image640
wherein m2 is 1, 2, 3, 4, 5, 6 or 7; and R1 ' is O, NH,
Figure 02_image642
; or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvate, metabolic precursor or prodrug thereof.

實施例62.如實施例61之方法或用途，其中該化合物具有式16，且其中Z為C，U為O或S且T為CH；或Z為N，U為CH且T為CH；Z為C，T為N且U為CH；或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。Embodiment 62. The method or use of embodiment 61, wherein the compound has formula 16, and wherein Z is C, U is O or S and T is CH; or Z is N, U is CH and T is CH; Z is C, T is N and U is CH; or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvate, metabolic precursor or prodrug.

實施例63.如實施例61之方法或用途，其中該化合物具有式17，且其中Z為C，U為O或S且T為CH；或，Z為N，U為CH且T為CH；Z為C，T為N且U為CH；或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。Embodiment 63. The method or use of embodiment 61, wherein the compound has formula 17, and wherein Z is C, U is O or S and T is CH; or, Z is N, U is CH and T is CH; Z is C, T is N and U is CH; or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvate, metabolic precursor thereof or prodrugs.

實施例64.如實施例1至7中任一項之方法或用途，其中該化合物係選自表2中所列出之化合物，或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥。Embodiment 64. The method or use according to any one of embodiments 1 to 7, wherein the compound is selected from the compounds listed in Table 2, or pharmaceutically acceptable salts, enantiomers, non- Enantiomers, tautomers, racemates, solvates, metabolic precursors or prodrugs.

實施例65.一種式A化合物： EBM-L-SBM  (式A) 或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥，其用於治療突觸核蛋白病，其中 EBM為E3泛蛋白連接酶結合部分； L為共價連接至EBM及SBM之連接子；且 SBM為下式之α-突觸核蛋白結合部分：

Figure 02_image644
或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物、前驅藥， 其中
Figure 02_image646
共價連接至L；且 (i)
Figure 02_image646
為含有至少1個選自O、S及N之環雜原子的經取代或未經取代之雙環稠合芳族環；
Figure 02_image649
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；且
Figure 02_image651
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；或 (ii)
Figure 02_image646
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；
Figure 02_image649
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；且
Figure 02_image651
為含有至少1個選自O、S及N之環雜原子的經取代或未經取代之雙環稠合芳族環。 Example 65. A compound of formula A: EBM-L-SBM (Formula A) or a pharmaceutically acceptable salt, mirror image, diastereomer, tautomer, racemate, solvent Compounds, metabolic precursors or prodrugs for the treatment of synucleinopathies, wherein EBM is an E3 ubiquitin ligase binding moiety; L is a linker covalently linked to EBM and SBM; and SBM is of the formula Alpha-synuclein binding moiety:
Figure 02_image644
or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvate, metabolic precursor, prodrug thereof, wherein
Figure 02_image646
covalently attached to L; and (i)
Figure 02_image646
is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N;
Figure 02_image649
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; and
Figure 02_image651
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; or (ii)
Figure 02_image646
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;
Figure 02_image649
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; and
Figure 02_image651
is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N.

實施例66.一種式A化合物： EBM-L-SBM  (式A) 或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥，其用於減少α-突觸核蛋白聚集，其中 EBM為E3泛蛋白連接酶結合部分； L為共價連接至EBM及SBM之連接子；且 SBM為下式之α-突觸核蛋白結合部分：

Figure 02_image656
或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物、前驅藥， 其中
Figure 02_image646
共價連接至L；且 (i)
Figure 02_image646
為含有至少1個選自O、S及N之環雜原子的經取代或未經取代之雙環稠合芳族環；
Figure 02_image649
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；且
Figure 02_image651
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；或 (ii)
Figure 02_image646
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；
Figure 02_image649
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；且
Figure 02_image651
為含有至少1個選自O、S及N之環雜原子的經取代或未經取代之雙環稠合芳族環。 Example 66. A compound of formula A: EBM-L-SBM (Formula A) or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvent Compounds, metabolic precursors or prodrugs for reducing α-synuclein aggregation, wherein EBM is an E3 ubiquitin ligase binding moiety; L is a linker covalently attached to EBM and SBM; and SBM is the following The alpha-synuclein binding moiety of the formula:
Figure 02_image656
or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvate, metabolic precursor, prodrug thereof, wherein
Figure 02_image646
covalently attached to L; and (i)
Figure 02_image646
is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N;
Figure 02_image649
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; and
Figure 02_image651
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; or (ii)
Figure 02_image646
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;
Figure 02_image649
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; and
Figure 02_image651
is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N.

實施例67.一種式A化合物： EBM-L-SBM  (式A) 或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物或前驅藥，其用於減少路易體，其中 EBM為E3泛蛋白連接酶結合部分； L為共價連接至EBM及SBM之連接子；且 SBM為下式之α-突觸核蛋白結合部分：

Figure 02_image656
或其醫藥學上可接受之鹽、鏡像異構物、非鏡像異構物、互變異構物、外消旋物、溶劑合物、代謝前驅物、前驅藥， 其中
Figure 02_image646
共價連接至L；且 (i)
Figure 02_image646
為含有至少1個選自O、S及N之環雜原子的經取代或未經取代之雙環稠合芳族環；
Figure 02_image649
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；且
Figure 02_image651
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；或 (ii)
Figure 02_image646
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；
Figure 02_image649
為含有0至2個選自O、S及N之環雜原子的經取代或未經取代之單環芳族環；且
Figure 02_image651
為含有至少1個選自O、S及N之環雜原子的經取代或未經取代之雙環稠合芳族環。 Example 67. A compound of formula A: EBM-L-SBM (Formula A) or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, racemate, solvent A compound, metabolic precursor or prodrug for reducing Lewy bodies, wherein EBM is an E3 ubiquitin ligase binding moiety; L is a linker covalently attached to EBM and SBM; and SBM is an α-mutation of the formula Synuclein-binding moiety:
Figure 02_image656
or pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, racemates, solvates, metabolic precursors, and prodrugs thereof, wherein
Figure 02_image646
covalently attached to L; and (i)
Figure 02_image646
is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N;
Figure 02_image649
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; and
Figure 02_image651
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; or (ii)
Figure 02_image646
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N;
Figure 02_image649
is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S and N; and
Figure 02_image651
is a substituted or unsubstituted bicyclic fused aromatic ring containing at least one ring heteroatom selected from O, S and N.

圖1展示聚集之α-突觸核蛋白物種之基於高含量之定量以及測定分化ReNcell VM細胞中之細胞核計數(剩餘細胞%)。結果顯示分別用測試化合物166362、170357、162640及180948處理24小時誘導MJFR14免疫反應性之濃度依賴性抑制，從而指示α-突觸核蛋白聚集減少。Figure 1 shows high level based quantification of aggregated α-synuclein species and determination of nuclei counts (% cells remaining) in differentiated ReNcell VM cells. The results show that treatment with test compounds 166362, 170357, 162640 and 180948, respectively, for 24 hours induces a concentration-dependent inhibition of MJFR14 immunoreactivity, indicating a reduction in α-synuclein aggregation.

圖2A至圖2D展示用媒劑(0.1% DMSO)及測試化合物132168、166362及170357處理且用MJFR14進行免疫染色的細胞之免疫細胞化學影像，其示出在用化合物132168及166362處理之後α-突觸核蛋白表現減少。圖2A：DMSO (0.1%)；圖2B：化合物132168 (3μM)；圖2C：化合物166362 (3μM)；及圖2D：化合物170357 (10μM)。Figures 2A to 2D show immunocytochemical images of cells treated with vehicle (0.1% DMSO) and test compounds 132168, 166362 and 170357 and immunostained with MJFR14 showing α- Synuclein expression decreased. Figure 2A: DMSO (0.1%); Figure 2B: Compound 132168 (3 μΜ); Figure 2C: Compound 166362 (3 μΜ); and Figure 2D: Compound 170357 (10 μΜ).

圖3展示活體內α-突觸核蛋白降解研究之結果。在化合物132168處理之後，不可溶α-突觸核蛋白級分相較於DMSO媒劑對照減小30%，從而指示不可溶α-突觸核蛋白聚集體減少。Figure 3 shows the results of an in vivo α-synuclein degradation study. Following Compound 132168 treatment, the insoluble α-synuclein fraction was reduced by 30% compared to the DMSO vehicle control, indicating a reduction in insoluble α-synuclein aggregates.

Claims (24)

一種式A化合物 EBM-L-SBM  (式A) 或其醫藥學上可接受之鹽、鏡像異構物、互變異構物、外消旋物、溶劑合物之用途，其用於製造用於治療突觸核蛋白病之藥劑， 其中 EBM為具有以下化學結構之E3泛蛋白連接酶結合部分：
Figure 03_image668
； 其中 R 3'為H或C 1-6烷基； R 2'在每次出現時獨立地選自由以下組成之群：H、OH、C 1-6烷基、C 1-6烷氧基、C 1-6烷胺基及NH 2； m6為0、1、2、3或4；且 Y 1為CH 2或
Figure 03_image670
； L為共價連接至EBM及SBM之連接子；且 SBM為式B或式C之α-突觸核蛋白結合部分：
Figure 03_image672
Figure 03_image674
； 其中 Z為C或N；U為O、S或CH；V為N；T為CH；Z及U不同時為雜原子； K為CH或N；Q為CH或N；其中K及Q不同時為N； R'''在每次出現時獨立地選自由以下組成之群：H、OH、NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基及鹵素；k為0、1、2或3； R'在每次出現時獨立地選自由以下組成之群：H、鹵素、OH、C 1-6烷基、C 1-6鹵烷基及C 1-6烷氧基；m為0、1、2、3或4； R''在每次出現時獨立地選自由以下組成之群：H、鹵基、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6鹵烷基、C 1-6烷胺基、C 3-6環烷胺基、C 3-6環烷基及C 3-6雜環烷基；n為0、1或2； J為CR 6或N；X為CR 6或N；Y為CR 6或N；其中J、X及Y中之至少一者為N，但J及Y不同時為N，X及Y不同時為N；且 R 6獨立地選自由以下組成之群：H、NH 2、C 1-6烷基及C 1-6烷氧基，其中NH 2、C 1-6烷基或C 1-6烷氧基視情況經C 1-3烷基、C 3-6環烷基及/或鹵基中之1至3者取代。 A compound of formula A EBM-L-SBM (formula A) or its pharmaceutically acceptable salt, mirror image isomer, tautomer, racemate, solvate, which is used for the manufacture of An agent for treating synucleinopathies, wherein EBM is an E3 ubiquitin ligase binding moiety having the following chemical structure:
Figure 03_image668
; wherein R 3' is H or C 1-6 alkyl; R 2' is at each occurrence independently selected from the group consisting of: H, OH, C 1-6 alkyl, C 1-6 alkoxy , C 1-6 alkylamino and NH 2 ; m6 is 0, 1, 2, 3 or 4; and Y 1 is CH 2 or
Figure 03_image670
; L is a linker covalently linked to EBM and SBM; and SBM is the α-synuclein binding moiety of formula B or formula C:
Figure 03_image672
Figure 03_image674
wherein Z is C or N; U is O, S or CH; V is N; T is CH; Z and U are not heteroatoms at the same time; K is CH or N; Q is CH or N; wherein K and Q are different is N; R''' at each occurrence is independently selected from the group consisting of H, OH, NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy group and halogen; k is 0, 1, 2 or 3; R' is independently selected at each occurrence from the group consisting of: H, halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy; m is 0, 1, 2, 3 or 4; R'' at each occurrence is independently selected from the group consisting of: H, halo, OH, NH 2 , C 1 -6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkylamino, C 3-6 cycloalkylamino, C 3-6 cycloalkyl and C 3-6 Heterocycloalkyl; n is 0, 1 or 2; J is CR 6 or N; X is CR 6 or N; Y is CR 6 or N; wherein at least one of J, X and Y is N, but J and Y are not N at the same time, X and Y are not N at the same time; and R 6 is independently selected from the group consisting of H, NH 2 , C 1-6 alkyl and C 1-6 alkoxy, wherein NH 2 , C 1-6 alkyl or C 1-6 alkoxy are optionally substituted by 1 to 3 of C 1-3 alkyl, C 3-6 cycloalkyl and/or halo. 如請求項1之用途，其中該突觸核蛋白病為帕金森氏病(Parkinson's Disease；PD)、路易體失智症(dementia with Lewy bodies；DLB)、多發性系統萎縮症(MSA)或其兩者或更多者之組合。As the purposes of claim 1, wherein the synuclein disease is Parkinson's Disease (Parkinson's Disease; PD), Lewy body dementia (dementia with Lewy bodies; DLB), multiple systemic atrophy (MSA) or A combination of two or more. 如請求項1之用途，其中該化合物具有式I至式VI中之任一者，
Figure 03_image676
Figure 03_image678
或其醫藥學上可接受之鹽、鏡像異構物、互變異構物、外消旋物或溶劑合物； 其中 L 1為一鍵、-C(=O)-、-NR-、-O-或-S-，其中R為氫、視情況經取代之醯基、視情況經取代之烷基或氮保護基； L 2為經取代或未經取代之C 1-50烴鏈，視情況其中該烴鏈之一或多個鏈原子獨立地經-C(=O)-、-O-、-NR a1-、-S-或環狀部分置換，其中R a1獨立地為氫、經取代或未經取代之C 1-6烷基或氮保護基；且 L 3為一鍵、-NR-、-O-或-S-，其中R為氫、視情況經取代之醯基、視情況經取代之烷基或氮保護基。 As the purposes of claim 1, wherein the compound has any one of formula I to formula VI,
Figure 03_image676
Figure 03_image678
Or its pharmaceutically acceptable salt, mirror image isomer, tautomer, racemate or solvate; wherein L is a bond, -C(=O)-, -NR-, -O -or-S-, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or nitrogen protecting group; L is substituted or unsubstituted C 1-50 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced by -C(=O)-, -O-, -NR a1 -, -S- or a ring moiety, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or nitrogen protecting group; and L 3 is a bond, -NR-, -O- or -S-, wherein R is hydrogen, optionally substituted acyl, optionally Substituted alkyl or nitrogen protecting group. 如請求項3之用途，其中L 2為視情況經取代之C 1-45烴鏈，視情況其中該烴鏈之一或多個鏈原子獨立地經-C(=O)-、-O-、-NR a1-、-S-或環狀部分置換，其中R a1獨立地為氫、經取代或未經取代之C 1-6烷基或氮保護基。 Such as the use of claim 3, wherein L is an optionally substituted C 1-45 hydrocarbon chain, where one or more chain atoms of the hydrocarbon chain are independently -C(=O)-, -O- , -NR a1 -, -S- or cyclic moiety replacement, wherein R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl or nitrogen protecting group. 如請求項3之用途，其中L 2係選自由以下組成之群：經取代或未經取代之伸碳環基、經取代或未經取代之伸雜環基、經取代或未經取代之伸芳基、經取代或未經取代之伸雜芳基、或經取代或未經取代之伸雜烷基，及其組合。 Such as the use of claim 3 , wherein L is selected from the group consisting of substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted Aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroalkylene, and combinations thereof. 如請求項5之用途，其中該伸碳環基或該伸雜環基為
Figure 03_image680
或其組合。 As the use of claim 5, wherein the carbocyclyl or the heterocyclyl is
Figure 03_image680
or a combination thereof. 如請求項4之用途，其中L 2包含至少一個選自由以下組成之群的實例：經取代或未經取代之亞甲基、伸乙基、伸正丙基、伸正丁基、伸正戊基、伸正己基、 -(CH 2) 2-O(CH 2) 2-、-OCH 2-、-CH 2O-、-O(CH 2) 2-、-(CH 2) 2O-、-O(CH 2) 3-、-(CH 2) 3O-、-O(CH 2) 4-、-(CH 2) 4O-、-O(CH 2) 5-、-(CH 2) 5O-、-O(CH 2) 6-、-O(CH 2) 6O-、-C(=O)O-、-O-C(=O)-、-NH-C(=O)-及-C(=O)NH-。 As the purposes of claim 4, wherein L 2 comprises at least one instance selected from the group consisting of: substituted or unsubstituted methylene, ethylenyl, n-propyl, n-butyl, n-pentyl, n-hexyl, -(CH 2 ) 2 -O(CH 2 ) 2 -, -OCH 2 -, -CH 2 O-, -O(CH 2 ) 2 -, -(CH 2 ) 2 O-, -O( CH 2 ) 3 -, -(CH 2 ) 3 O-, -O(CH 2 ) 4 -, -(CH 2 ) 4 O-, -O(CH 2 ) 5 -, -(CH 2 ) 5 O- , -O(CH 2 ) 6 -, -O(CH 2 ) 6 O-, -C(=O)O-, -OC(=O)-, -NH-C(=O)- and -C( =O)NH-. 如請求項4之用途，其中L 2之該烴鏈之至少一個鏈原子獨立地經具有1至3個選自由氮及氧組成之群的環雜原子的6員雜環基置換。 As the use of claim 4, wherein at least one chain atom of the hydrocarbon chain of L2 is independently replaced by a 6-membered heterocyclic group having 1 to 3 ring heteroatoms selected from the group consisting of nitrogen and oxygen. 如請求項4之用途，其中L 2為未經取代之烴鏈，視情況其中該烴鏈之一或多個鏈原子獨立地經-NR a1-置換，且R a1之各實例獨立地為氫、經取代或未經取代之C 1-6烷基或氮保護基，或視情況R a1中之兩個實例與其插入原子一起形成經取代或未經取代之雜環或經取代或未經取代之雜芳基環。 The use of claim 4, wherein L is an unsubstituted hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced by -NR a1 -, and each instance of R a1 is independently hydrogen , substituted or unsubstituted C 1-6 alkyl or nitrogen protecting group, or as the case may be, two instances of R a1 form a substituted or unsubstituted heterocyclic ring or substituted or unsubstituted The heteroaryl ring. 如請求項3之用途，其中L 2為
Figure 03_image682
，其中g為1、2、3、4、5或6。 Such as the use of claim 3, wherein L 2 is
Figure 03_image682
, wherein g is 1, 2, 3, 4, 5 or 6. 如請求項3之用途，其中L 2包括部分-O-、
Figure 03_image684
、-NHC(=O)-或-NH-。 Such as the use of claim 3, wherein L 2 includes part -O-,
Figure 03_image684
, -NHC(=O)- or -NH-. 如請求項3之用途，其中L 2係選自由以下組成之群：
Figure 03_image686
Figure 03_image688
Figure 03_image690
，其中各g獨立地為1、2、3、4、5或6；f為1、2、3、4、5或6，且h為1、2、3、4、5或6。 Such as the use of claim 3, wherein L 2 is selected from the group consisting of:
Figure 03_image686
Figure 03_image688
Figure 03_image690
, wherein each g is independently 1, 2, 3, 4, 5 or 6; f is 1, 2, 3, 4, 5 or 6, and h is 1, 2, 3, 4, 5 or 6. 如請求項3之用途，其中該式I化合物具有式I-1；
Figure 03_image692
或其醫藥學上可接受之鹽、鏡像異構物、互變異構物、外消旋物或溶劑合物。 As the purposes of claim 3, wherein the compound of formula I has formula I-1;
Figure 03_image692
Or a pharmaceutically acceptable salt, enantiomer, tautomer, racemate or solvate thereof. 如請求項3之用途，其中該式II化合物具有式II-1；
Figure 03_image694
或其醫藥學上可接受之鹽、鏡像異構物、互變異構物、外消旋物或溶劑合物。 As the use of claim 3, wherein the compound of formula II has formula II-1;
Figure 03_image694
Or a pharmaceutically acceptable salt, enantiomer, tautomer, racemate or solvate thereof. 如請求項3之用途，其中該式III化合物具有式III-1；
Figure 03_image696
或其醫藥學上可接受之鹽、鏡像異構物、互變異構物、外消旋物或溶劑合物。 As the use of claim 3, wherein the compound of formula III has formula III-1;
Figure 03_image696
Or a pharmaceutically acceptable salt, enantiomer, tautomer, racemate or solvate thereof. 如請求項3之用途，其中該式IV化合物具有式IV-1；
Figure 03_image698
或其醫藥學上可接受之鹽、鏡像異構物、互變異構物、外消旋物或溶劑合物。 As the use of claim 3, wherein the compound of formula IV has formula IV-1;
Figure 03_image698
Or a pharmaceutically acceptable salt, enantiomer, tautomer, racemate or solvate thereof. 如請求項3之用途，其中該式V化合物具有式V-1；
Figure 03_image700
或其醫藥學上可接受之鹽、鏡像異構物、互變異構物、外消旋物或溶劑合物。 As the use of claim 3, wherein the compound of formula V has formula V-1;
Figure 03_image700
Or a pharmaceutically acceptable salt, enantiomer, tautomer, racemate or solvate thereof. 如請求項3之用途，其中該式VI化合物具有式VI-1；
Figure 03_image702
或其醫藥學上可接受之鹽、鏡像異構物、互變異構物、外消旋物或溶劑合物。 As the use of claim 3, wherein the compound of formula VI has formula VI-1;
Figure 03_image702
Or a pharmaceutically acceptable salt, enantiomer, tautomer, racemate or solvate thereof. 如請求項1之用途，其中該化合物係選自：
Figure 03_image704
Figure 03_image706
Figure 03_image708
Figure 03_image710
Figure 03_image712
Figure 03_image714
Figure 03_image716
Figure 03_image718
Figure 03_image720
Figure 03_image722
Figure 03_image724
Figure 03_image726
Figure 03_image728
Figure 03_image730
Figure 03_image732
Figure 03_image734
Figure 03_image736
Figure 03_image738
Figure 03_image740
Figure 03_image742
Figure 03_image744
Figure 03_image746
， 或其醫藥學上可接受之鹽、鏡像異構物、互變異構物、外消旋物或溶劑合物。 As the purposes of claim 1, wherein the compound is selected from:
Figure 03_image704
Figure 03_image706
Figure 03_image708
Figure 03_image710
Figure 03_image712
Figure 03_image714
Figure 03_image716
Figure 03_image718
Figure 03_image720
Figure 03_image722
Figure 03_image724
Figure 03_image726
Figure 03_image728
Figure 03_image730
Figure 03_image732
Figure 03_image734
Figure 03_image736
Figure 03_image738
Figure 03_image740
Figure 03_image742
Figure 03_image744
Figure 03_image746
, or a pharmaceutically acceptable salt, enantiomer, tautomer, racemate or solvate thereof. 一種式A化合物 EBM-L-SBM  (式A) 或其醫藥學上可接受之鹽、鏡像異構物、互變異構物、外消旋物、溶劑合物之用途，其用於製造用於減少α-突觸核蛋白聚集之藥劑， 其中 EBM為具有以下化學結構之E3泛蛋白連接酶結合部分：
Figure 03_image748
； 其中 R 3'為H或C 1-6烷基； R 2'在每次出現時獨立地選自由以下組成之群：H、OH、C 1-6烷基、C 1-6烷氧基、C 1-6烷胺基及NH 2； m6為0、1、2、3或4；且 Y 1為CH 2或
Figure 03_image750
； L為共價連接至EBM及SBM之連接子；且 SBM為式B或式C之α-突觸核蛋白結合部分：
Figure 03_image752
； 其中 Z為C或N；U為O、S或CH；V為N；T為CH；Z及U不同時為雜原子； K為CH或N；Q為CH或N；其中K及Q不同時為N； R'''在每次出現時獨立地選自由以下組成之群：H、OH、NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基及鹵素；k為0、1、2或3； R'在每次出現時獨立地選自由以下組成之群：H、鹵素、OH、C 1-6烷基、C 1-6鹵烷基及C 1-6烷氧基；m為0、1、2、3或4； R''在每次出現時獨立地選自由以下組成之群：H、鹵基、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6鹵烷基、C 1-6烷胺基、C 3-6環烷胺基、C 3-6環烷基及C 3-6雜環烷基；n為0、1或2； J為CR 6或N；X為CR 6或N；Y為CR 6或N；其中J、X及Y中之至少一者為N，但J及Y不同時為N，X及Y不同時為N；且 R 6獨立地選自由以下組成之群：H、NH 2、C 1-6烷基及C 1-6烷氧基，其中NH 2、C 1-6烷基或C 1-6烷氧基視情況經C 1-3烷基、C 3-6環烷基及/或鹵基中之1至3者取代。 A compound of formula A EBM-L-SBM (formula A) or its pharmaceutically acceptable salt, mirror image isomer, tautomer, racemate, solvate, which is used for the manufacture of An agent that reduces alpha-synuclein aggregation, wherein EBM is an E3 ubiquitin ligase binding moiety having the following chemical structure:
Figure 03_image748
; wherein R 3' is H or C 1-6 alkyl; R 2' is at each occurrence independently selected from the group consisting of: H, OH, C 1-6 alkyl, C 1-6 alkoxy , C 1-6 alkylamino and NH 2 ; m6 is 0, 1, 2, 3 or 4; and Y 1 is CH 2 or
Figure 03_image750
; L is a linker covalently linked to EBM and SBM; and SBM is the α-synuclein binding moiety of formula B or formula C:
Figure 03_image752
wherein Z is C or N; U is O, S or CH; V is N; T is CH; Z and U are not heteroatoms at the same time; K is CH or N; Q is CH or N; wherein K and Q are different is N; R''' at each occurrence is independently selected from the group consisting of H, OH, NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy group and halogen; k is 0, 1, 2 or 3; R' is independently selected at each occurrence from the group consisting of: H, halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy; m is 0, 1, 2, 3 or 4; R'' at each occurrence is independently selected from the group consisting of: H, halo, OH, NH 2 , C 1 -6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkylamino, C 3-6 cycloalkylamino, C 3-6 cycloalkyl and C 3-6 Heterocycloalkyl; n is 0, 1 or 2; J is CR 6 or N; X is CR 6 or N; Y is CR 6 or N; wherein at least one of J, X and Y is N, but J and Y are not N at the same time, X and Y are not N at the same time; and R 6 is independently selected from the group consisting of H, NH 2 , C 1-6 alkyl and C 1-6 alkoxy, wherein NH 2 , C 1-6 alkyl or C 1-6 alkoxy are optionally substituted by 1 to 3 of C 1-3 alkyl, C 3-6 cycloalkyl and/or halo. 一種式A化合物 EBM-L-SBM  (式A) 或其醫藥學上可接受之鹽、鏡像異構物、互變異構物、外消旋物、溶劑合物之用途，其用於製造用於減少路易體之藥劑， 其中 EBM為具有以下化學結構之E3泛蛋白連接酶結合部分：
Figure 03_image754
； 其中 R 3'為H或C 1-6烷基； R 2'在每次出現時獨立地選自由以下組成之群：H、OH、C 1-6烷基、C 1-6烷氧基、C 1-6烷胺基及NH 2； m6為0、1、2、3或4；且 Y 1為CH 2或
Figure 03_image756
； L為共價連接至EBM及SBM之連接子；且 SBM為式B或式C之α-突觸核蛋白結合部分：
Figure 03_image758
； 其中 Z為C或N；U為O、S或CH；V為N；T為CH；Z及U不同時為雜原子； K為CH或N；Q為CH或N；其中K及Q不同時為N； R'''在每次出現時獨立地選自由以下組成之群：H、OH、NH 2、C 1-6烷基、C 1-6烷胺基、C 1-6烷氧基及鹵素；k為0、1、2或3； R'在每次出現時獨立地選自由以下組成之群：H、鹵素、OH、C 1-6烷基、C 1-6鹵烷基及C 1-6烷氧基；m為0、1、2、3或4； R''在每次出現時獨立地選自由以下組成之群：H、鹵基、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6鹵烷基、C 1-6烷胺基、C 3-6環烷胺基、C 3-6環烷基及C 3-6雜環烷基；n為0、1或2； J為CR 6或N；X為CR 6或N；Y為CR 6或N；其中J、X及Y中之至少一者為N，但J及Y不同時為N，X及Y不同時為N；且 R 6獨立地選自由以下組成之群：H、NH 2、C 1-6烷基及C 1-6烷氧基，其中NH 2、C 1-6烷基或C 1-6烷氧基視情況經C 1-3烷基、C 3-6環烷基及/或鹵基中之1至3者取代。 A compound of formula A EBM-L-SBM (formula A) or its pharmaceutically acceptable salt, mirror image isomer, tautomer, racemate, solvate, which is used for the manufacture of An agent that reduces Lewy bodies, wherein EBM is an E3 ubiquitin ligase binding moiety having the following chemical structure:
Figure 03_image754
; wherein R 3' is H or C 1-6 alkyl; R 2' is at each occurrence independently selected from the group consisting of: H, OH, C 1-6 alkyl, C 1-6 alkoxy , C 1-6 alkylamino and NH 2 ; m6 is 0, 1, 2, 3 or 4; and Y 1 is CH 2 or
Figure 03_image756
; L is a linker covalently linked to EBM and SBM; and SBM is the α-synuclein binding moiety of formula B or formula C:
Figure 03_image758
wherein Z is C or N; U is O, S or CH; V is N; T is CH; Z and U are not heteroatoms at the same time; K is CH or N; Q is CH or N; wherein K and Q are different is N; R''' at each occurrence is independently selected from the group consisting of H, OH, NH 2 , C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy group and halogen; k is 0, 1, 2 or 3; R' is independently selected at each occurrence from the group consisting of: H, halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy; m is 0, 1, 2, 3 or 4; R'' at each occurrence is independently selected from the group consisting of: H, halo, OH, NH 2 , C 1 -6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkylamino, C 3-6 cycloalkylamino, C 3-6 cycloalkyl and C 3-6 Heterocycloalkyl; n is 0, 1 or 2; J is CR 6 or N; X is CR 6 or N; Y is CR 6 or N; wherein at least one of J, X and Y is N, but J and Y are not N at the same time, X and Y are not N at the same time; and R 6 is independently selected from the group consisting of H, NH 2 , C 1-6 alkyl and C 1-6 alkoxy, wherein NH 2 , C 1-6 alkyl or C 1-6 alkoxy are optionally substituted by 1 to 3 of C 1-3 alkyl, C 3-6 cycloalkyl and/or halo. 如請求項1之用途，其中EBM為具有以下化學結構之E3泛蛋白連接酶結合部分：
Figure 03_image760
； 其中 R 3'為H或C 1-6烷基；且Y 1為CH 2或
Figure 03_image762
。 As the use of claim 1, wherein EBM is an E3 ubiquitin ligase binding part having the following chemical structure:
Figure 03_image760
; wherein R 3' is H or C 1-6 alkyl; and Y 1 is CH 2 or
Figure 03_image762
. 如請求項1之用途，其中SBM為該式B之α-突觸核蛋白結合部分。The use according to claim 1, wherein SBM is the α-synuclein binding moiety of the formula B. 如請求項1之用途，其中SBM為該式C之α-突觸核蛋白結合部分。The use according to claim 1, wherein SBM is the α-synuclein binding moiety of the formula C.
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