TW202506673A

TW202506673A - An aminopyridine compound, a preparation method thereof, a pharmaceutical composition containing the same and its application

Info

Publication number: TW202506673A
Application number: TW113122045A
Authority: TW
Inventors: 陳旭星; 李京; 陳豔紅; 鄧文佳
Original assignee: 大陸商中山優理生物醫藥有限公司
Priority date: 2023-06-16
Filing date: 2024-06-14
Publication date: 2025-02-16

Abstract

本發明提供了一種胺基吡啶類化合物、其製備方法、包含其藥物組合物及其應用，具體地，所述化合物具有式I所示結構，其可與MTA協同抑制PRMT5，可用於製備治療與MTAP ^-/-相關的癌症的藥物。 The present invention provides an aminopyridine compound, a preparation method thereof, a pharmaceutical composition comprising the same and an application thereof. Specifically, the compound has a structure shown in Formula I, can synergistically inhibit PRMT5 with MTA, and can be used to prepare a drug for treating cancers associated with MTAP ^-/- .

Description

An aminopyridine compound, a preparation method thereof, a pharmaceutical composition containing the same and its application

本發明涉及藥物化學領域，更具體而言，本發明涉及一種胺基吡啶類化合物，其可以作為MTA協同的PRMT5抑制劑，製備用於治療MTAP ^-/-相關的癌症的藥物。 The present invention relates to the field of medicinal chemistry. More specifically, the present invention relates to an aminopyridine compound, which can be used as an MTA-synergistic PRMT5 inhibitor to prepare a drug for treating MTAP ^-/- related cancers.

蛋白質精胺酸N-甲基轉移酶（PRMT）根據產生的甲基精胺酸的種類分為I型、II型和III型。I型主要催化甲基從S-腺苷-L-甲硫胺酸（SAM）轉移到蛋白質L-精胺酸的胍基的ω胺氮上生成單甲基精胺酸（MMA）以及將第二個甲基轉移到胍基的同一個ω胺氮上產生不對稱二甲基精胺酸（aDMA）；II型主要催化生成MMA以及將第二個甲基轉移到另一個ω胺氮上產生對稱二甲基精胺酸（sDMA）；III型僅催化生成MMA。其中，PRMT5是一種II型蛋白精胺酸甲基轉移酶，在調節細胞進程中起著重要作用，包括DNA修復、細胞週期進展、轉錄調控和RNA剪接等。PRMT5的向上調控可導致多種癌症，包括肝癌、乳腺癌、皮膚癌、胰腺癌、頭頸癌、腸癌、肺癌、胃癌、食管癌、腎癌、膀胱癌、尿道癌、前列腺癌、睾丸癌、子宮癌、卵巢癌、陰道癌、輸卵管癌症、膽管癌、多發性骨髓瘤、脊髓神經纖維瘤、星形細胞瘤、神經膠質瘤、急性淋巴細胞白血病、慢性淋巴細胞白血病、霍奇金淋巴瘤、非霍奇金淋巴瘤、肉瘤。Protein arginine N-methyltransferases (PRMTs) are divided into type I, type II, and type III according to the type of methylarginine produced. Type I mainly catalyzes the transfer of methyl groups from S-adenosyl-L-methionine (SAM) to the ω-amine nitrogen of the guanidine group of protein L-arginine to generate monomethylarginine (MMA) and transfers the second methyl group to the same ω-amine nitrogen of the guanidine group to generate asymmetric dimethylarginine (aDMA); type II mainly catalyzes the production of MMA and transfers the second methyl group to another ω-amine nitrogen to generate symmetric dimethylarginine (sDMA); type III only catalyzes the production of MMA. Among them, PRMT5 is a type II protein arginine methyltransferase that plays an important role in regulating cell processes, including DNA repair, cell cycle progression, transcriptional regulation, and RNA splicing. Upregulation of PRMT5 can lead to a variety of cancers, including liver cancer, breast cancer, skin cancer, pancreatic cancer, head and neck cancer, intestinal cancer, lung cancer, stomach cancer, esophageal cancer, kidney cancer, bladder cancer, urethral cancer, prostate cancer, testicular cancer, uterine cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, bile duct cancer, multiple myeloma, spinal neurofibroma, astrocytoma, neuroglioma, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, and sarcoma.

甲硫腺苷磷酸化酶（MTAP）位於p16/CDKN2a基因附近，並在大約15%的人類癌症中與p16/CDKN2a共缺失。這種共缺失導致惡性腫瘤的預後差，缺乏有效的分子標靶治療。MTAP是甲硫腺苷（MTA）的代謝酶，催化MTA轉化為腺苷和5-甲硫基核糖-1-磷酸。在腫瘤細胞中，MTAP缺失導致MTA的積聚，由於MTA結構上和SAM類似，可競爭性抑制PRMT5，形成PRMT5-MTA複合物。基於這一複合物設計的小分子抑制劑，可以選擇性地殺死腫瘤細胞，對正常細胞影響小，提高藥物安全性。Methylthioadenosine phosphorylase (MTAP) is located near the p16/CDKN2a gene and is co-deleted with p16/CDKN2a in approximately 15% of human cancers. This co-deletion leads to poor prognosis in malignant tumors and a lack of effective molecular targeted therapy. MTAP is a metabolite of methylthioadenosine (MTA), catalyzing the conversion of MTA to adenosine and 5-methylthioribose-1-phosphate. In tumor cells, MTAP deficiency leads to the accumulation of MTA. Since MTA is structurally similar to SAM, it can competitively inhibit PRMT5 to form a PRMT5-MTA complex. Small molecule inhibitors designed based on this complex can selectively kill tumor cells, have little effect on normal cells, and improve drug safety.

我們相信在MTAP缺失的癌症中，MTA協同抑制PRMT5活性將為多種癌症提供治療益處。目前缺乏有效的分子標靶治療，因此有必要開發新的MTA協同的PRMT5抑制劑，其能夠在MTA濃度升高的情況下抑制PRMT5活性，用於治療MTAP缺失的相關癌症。We believe that in MTAP-deficient cancers, MTA-synergistic inhibition of PRMT5 activity will provide therapeutic benefits in a variety of cancers. The current lack of effective molecular targeted therapies makes it necessary to develop new MTA-synergistic PRMT5 inhibitors that can inhibit PRMT5 activity in the presence of elevated MTA concentrations for the treatment of MTAP-deficient cancers.

本發明目的是提供一種更加高效、成藥性更好的MTA協同的PRMT5抑制劑。The purpose of the present invention is to provide a more efficient and druggable MTA-synergistic PRMT5 inhibitor.

本發明的第一方面，提供了一種式I所示的化合物、或其藥學上可接受的鹽、對掌異構體、非對掌異構體、互變異構體、順反異構體、溶劑化物、多晶型物、氘代物或其組合，其中， R ¹、R ²各自獨立地為氫、鹵素、氰基、羥基、C1-C3烷基、C1-C3鹵代烷基、C2-C4烯基、C2-C4鹵代烯基、C2-C4炔基、C2-C4鹵代炔基、3-6元環烷基、3-6元鹵代環烷基、3-6元雜環基、C1-C3烷氧基、-NH ₂、-NH(C1-C3烷基)、-N(C1-C3烷基) ₂、C1-C6烷基-S-、-S(O) ₂-C1-C6烷基、-S(O)- C1-C6烷基、-S(O) ₂NH ₂、S(O) ₂NH(C1-C6烷基)、-NHS(O) ₂(C1-C6烷基)、-C(O)H、-C(O)-C1-C6烷基、-C(O)-3-6環烷基、-C(O)-3-6元雜環基、-C(O)O-C1-C6烷基、-CONR ^1aR ^1b(其中R ^1a和R ^1b是H、D、C1-C3烷基、3-6元環烷基、3-6元雜環基)、-SF ₅、-P(O)(C1-C3烷基) ₂；其中所述的烷基、環烷基和雜環基可任選地被一個或多個選自以下的取代基進一步取代：氫、氘、鹵素、C1-C3烷基； A環為任選取代的5-7元雜環基、任選取代的苯環或任選取代的5-7元雜芳環；所述取代是指被一個或多個R ^A取代；各個R ^A獨立地選自氫、氘、C1-C4烷基、鹵代C1-C4烷基、C3-C6環烷基、3-8元雜環基、氧代、鹵素、C1-C4烷氧基、羥基和胺基； R ³為； L ¹為不存在、C1-C3伸烷基或C1-C3鹵代伸烷基； n為伸甲基的個數，n選自0、1、2、3、4； R ⁴為任選取代的C1-C6烷基、C2-C6烯基、C2-C6炔基、任選取代的C3-C12碳環基、任選取代的C3-C12雜環基、任選取代的6-10元芳環基或任選取代的5-10元芳雜環基；所述取代是指被一個或多個R取代； R ⁵為任選取代的C1-C6烷基、任選取代的C3-C12碳環基、任選取代的C3-C12雜環基、任選取代的6-10芳環、任選取代的5-10元雜芳環、-NR ^aR ^b、-OR ^a或-SR ^a；每個R ^a和R ^b各自獨立的為氫、任選取代的C1-C6烷基、任選取代的C3-C6碳環基、任選取代的C3-C6雜環基、任選取代的6-10芳環或任選取代的5-10元芳雜環；所述取代是指被一個或多個R取代；每個R ⁶各自獨立的為氫、鹵素、羥基、C1-C3烷基、C1-C3鹵代烷基、C3-C4環烷基、C3-C4鹵代環烷基、C1-C3烷氧基、-NH ₂、-NH(C1-C3烷基)或-N(C1-C3烷基) ₂； m為R ⁶的個數，m選自0、1、2、3、4； R ⁷、R ⁸各自獨立地為氫、氘、C1-C3烷基、C1-C3鹵代烷基、3-4元環烷基或3-4元鹵代環烷基；或者R ⁷、R ⁸與相連的碳原子形成3-5元碳環；每一個R各自獨立地選自：H、氘、鹵素、氰基、胺基、羥基、硝基、氧代基( )、硫代(=S)、-SF ₅、任選取代的C1-C6烷基、任選取代的C2-C6烯基、任選取代的C2-C6炔基、任選取代的C1-C6烷氧基、-OC2-C6烯基、O環烷基、O雜環基、O-芳基、O-雜芳基、-N(任選取代的C ₁-C ₆烷基) ₂、NH(任選取代的C ₁-C ₆烷基)、N(任選取代的C ₁-C ₆烷基)(任選取代的C ₁-C ₆烷基苯基)、NH(任選取代的C ₁-C ₆烷基苯基)、N(C1-C6烷基)(芳基)、N(C1-C6烷基)(雜芳基)、NH(芳基)、-NH(雜芳基)、-P(O)(C1-C3烷基) ₂、任選取代的C1-C6烷基-S-、-S(O) ₂-任選取代的C1-C6烷基、-S(O)-任選取代的C1-C6烷基、-S(O) ₂-任選取代的苯基、-S(O) ₂NH ₂、S(O) ₂NH(任選取代的C1-C6烷基)、S(O) ₂NH(任選取代的苯基)、-NHS(O) ₂(任選取代的C1-C6烷基)、-NHS(O) ₂(任選取代的苯基)、任選取代的C3-C16碳環基、任選取代的4-16元雜環基、任選取代的C6-C16芳基或任選取代的5-16元雜芳基；或任意相鄰的2個R和與其相連的原子形成任選取代的4-8元雜環基或任選取代的C3-C8元碳環基；其中，R中所述取代是指被選自下組的一個或多個基團取代：H、氘、鹵素、氰基、胺基、羥基、硝基、氧代基( )、硫代(=S)、-SF ₅、-P(O)(C1-C3烷基) ₂、R’取代或未取代的C1-C6烷基、R’取代或未取代的C1-C6烷氧基、R’取代或未取代的C1-C6烷基碸基、R’取代或未取代的C3-C16碳環基、R’取代或未取代的4-16元雜環基、R’取代或未取代的C6-C16芳基、R’取代或未取代的5-16元雜芳基、NH(R’取代或未取代的C1-C6烷基)、N(R’取代或未取代的C1-C6烷基) ₂、CH ₂-NH(R’取代或未取代的C1-C6烷基)和CH ₂-N(R’取代或未取代的C1-C6烷基) ₂，其中，R’選自下組的一個或多個基團：H、鹵素、氘(D)、鹵素、OH、硝基、胺基、氧代(=O)、巰基、氰基、-CD ₃、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8環烷基和4-8元雜環基，其中，所述的烷基、烯基、炔基、環烷基和雜環基中的每一個任選被一個或多個選自以下的取代基進一步取代：H、氘、C1-C6烷基、C1-C6烷氧基、鹵素、-OH、氧代(=O)、-NH ₂、N(R’’取代或未取代的C1-C6烷基) ₂、NH(C1-C6烷基)、N(C1-C6烷基)(C1-C6烷基苯基)、NH(C1-C6烷基苯基)、N(C1-C6烷基)(芳基)、NH(芳基)、C3-C8環烷基、4-8元雜環基、C1-C4鹵代烷基-、-C1-C4烷基OH、-C1-C4烷基O-C1-C4烷基、OC1-C4鹵代烷基、氰基、硝基、-C(O)-OH、C(O)OC1-C6烷基、CON(C1-C6烷基) ₂、CONH(C1-C6烷基)、CONH ₂、NHC(O)(C1-C6烷基)、NH(C1-C6烷基)C(O)(C1-C6烷基)、-SO ₂(C1-C6烷基)、-SO ₂(苯基)、-SO ₂(C1-C6鹵代烷基)、-SO ₂NH ₂、SO ₂NH(C1-C6烷基)、SO ₂NH(苯基)、-NHSO ₂(C1-C6烷基)、-NHSO ₂(苯基)、NHSO ₂(C1-C6鹵代烷基)或C1-C6烷基NH ₂，其中，R’’選自下組的一個或多個基團：H、鹵素、氰基、胺基、羥基、氧代基( )、C1-C6烷基和C1-C6烷氧基；表示基團的連接位置。 The first aspect of the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, a chiral isomer, a non-chiral isomer, a tautomer, a cis-trans isomer, a solvate, a polymorph, a deuterated compound or a combination thereof, wherein R ¹ and R ² are each independently hydrogen, halogen, cyano, hydroxyl, C1-C3 alkyl, C1-C3 halogenated alkyl, C2-C4 alkenyl, C2-C4 halogenated alkenyl, C2-C4 alkynyl, C2-C4 halogenated alkynyl, 3-6 membered cycloalkyl, 3-6 membered halogenated cycloalkyl, 3-6 membered heterocyclic group, C1-C3 alkoxy, -NH ₂ , -NH(C1-C3 alkyl), -N(C1-C3 alkyl) ₂ , C1-C6 alkyl-S-, -S(O) ₂ -C1-C6 alkyl, -S(O)- C1-C6 alkyl, -S(O) ₂ NH ₂ , S(O) ₂ NH(C1-C6 alkyl), -NHS(O) ₂ (C1-C6 alkyl), -C(O)H, -C(O)-C1-C6 alkyl, -C(O)-3-6 cycloalkyl, -C(O)-3-6 membered heterocyclic group, -C(O)O-C1-C6 alkyl, -CONR ^1a R ^1b (wherein R ^1a and R ^1b are H, D, C1-C3 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group), -SF ₅ , -P(O)(C1-C3 alkyl) ₂ ; wherein said alkyl, cycloalkyl and heterocyclic group may be optionally further substituted by one or more substituents selected from the following: hydrogen, deuterium, halogen, C1-C3 alkyl; Ring A is an optionally substituted 5-7 membered heterocyclic group, an optionally substituted benzene ring or an optionally substituted 5-7 membered heteroaromatic ring; the substitution refers to substitution by one or more ^RA ; each ^RA is independently selected from hydrogen, deuterium, C1-C4 alkyl, halogenated C1-C4 alkyl, C3-C6 cycloalkyl, 3-8 membered heterocyclic group, oxo, halogen, C1-C4 alkoxy, hydroxyl and amino; ^R3 is ; ^L1 is absent, C1-C3 alkylene or C1-C3 halogenated alkylene; n is the number of methylene groups, and n is selected from 0, 1, 2, 3, and 4; ^R4 is an optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, an optionally substituted C3-C12 carbocyclic group, an optionally substituted C3-C12 heterocyclic group, an optionally substituted 6-10 membered aromatic ring group, or an optionally substituted 5-10 membered heteroaromatic ring group; the substitution means substitution by one or more R; ^R5 is an optionally substituted C1-C6 alkyl, an optionally substituted C3-C12 carbocyclic group, an optionally substituted C3-C12 heterocyclic group, an optionally substituted 6-10 aromatic ring, an optionally substituted 5-10 membered heteroaromatic ^ring , ^-NRaRb , -OR ^a or -SR ^a ; each ^Ra and R ^b are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 carbocyclic group, optionally substituted C3-C6 heterocyclic group, optionally substituted 6-10 aromatic ring or optionally substituted 5-10 aromatic heterocyclic ring; the substitution means substitution by one or more R; each R ⁶ is independently hydrogen, halogen, hydroxyl, C1-C3 alkyl, C1-C3 halogenated alkyl, C3-C4 cycloalkyl, C3-C4 halogenated cycloalkyl, C1-C3 alkoxy, -NH ₂ , -NH(C1-C3 alkyl) or -N(C1-C3 alkyl) ₂ ; m is the number of R ⁶ , m is selected from 0, 1, 2, 3, 4; R ⁷ , R ^{R 8} is independently hydrogen, deuterium, C1-C3 alkyl, C1-C3 halogenated alkyl, 3-4-membered cycloalkyl or 3-4-membered halogenated cycloalkyl; or R ⁷ , R ⁸ and the carbon atom to which they are connected form a 3-5-membered carbocyclic ring; each R is independently selected from: H, deuterium, halogen, cyano, amine, hydroxyl, nitro, oxo ( ), thio (=S), -SF ₅ , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, -OC2-C6 alkenyl, O-cycloalkyl, O-heterocyclo, O-aryl, O-heteroaryl, -N(optionally substituted C ₁ -C ₆ alkyl) ₂ , NH(optionally substituted C ₁ -C ₆ alkyl), N(optionally substituted C ₁ -C ₆ alkyl)(optionally substituted C ₁ -C ₆ alkylphenyl), NH(optionally substituted C ₁ -C ₆ alkylphenyl), N(C1-C6 alkyl)(aryl), N(C1-C6 alkyl)(heteroaryl), NH(aryl), -NH(heteroaryl), -P(O)(C1-C3 alkyl) ₂ , optionally substituted C1-C6 alkyl-S-, -S(O) ₂ -optionally substituted C1-C6 alkyl, -S(O)-optionally substituted C1-C6 alkyl, -S(O) ₂ -optionally substituted phenyl, -S(O) ₂ NH ₂ , S(O) ₂ NH(optionally substituted C1-C6 alkyl), S(O) ₂ NH(optionally substituted phenyl), -NHS(O) ₂ (optionally substituted C1-C6 alkyl), -NHS(O) ₂ (optionally substituted phenyl), optionally substituted C3-C16 carbocyclic group, optionally substituted 4-16 membered heterocyclic group, optionally substituted C6-C16 aryl group or optionally substituted 5-16 membered heteroaryl group; or any two adjacent R and the atoms connected thereto form an optionally substituted 4-8 membered heterocyclic group or an optionally substituted C3-C8 membered carbocyclic group; wherein the substitution in R refers to substitution by one or more groups selected from the following group: H, deuterium, halogen, cyano, amine, hydroxyl, nitro, oxo ( ), thio (=S), -SF ₅ , -P(O)(C1-C3 alkyl) ₂ , R' substituted or unsubstituted C1-C6 alkyl, R' substituted or unsubstituted C1-C6 alkoxy, R' substituted or unsubstituted C1-C6 alkylsulfonyl, R' substituted or unsubstituted C3-C16 carbocyclic group, R' substituted or unsubstituted 4-16 membered heterocyclic group, R' substituted or unsubstituted C6-C16 aryl, R' substituted or unsubstituted 5-16 membered heteroaryl, NH(R' substituted or unsubstituted C1-C6 alkyl), N(R' substituted or unsubstituted C1-C6 alkyl) ₂ , CH ₂ -NH(R' substituted or unsubstituted C1-C6 alkyl) and CH ₂ -N(R' substituted or unsubstituted C1-C6 alkyl) ₂ , wherein R' is selected from one or more groups of the following groups: H, halogen, deuterium (D), halogen, OH, nitro, amine, oxo (=O), alkynyl, cyano, -CD ₃ , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl and 4-8 membered heterocyclic groups, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclic groups is optionally further substituted with one or more substituents selected from the following groups: H, deuterium, C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, oxo (=O), -NH ₂ , N(R'' substituted or unsubstituted C1-C6 alkyl) ₂ , NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkylphenyl), NH(C1-C6 alkylphenyl), N(C1-C6 alkyl)(aryl), NH(aryl), C3-C8 cycloalkyl, 4-8 membered heterocyclic group, C1-C4 halogenated alkyl-, -C1-C4 alkylOH, -C1-C4 alkylO-C1-C4 alkyl, OC1-C4 halogenated alkyl, cyano, nitro, -C(O)-OH, C(O)OC1-C6 alkyl, CON(C1-C6 alkyl) ₂ , CONH(C1-C6 alkyl), CONH ₂ , NHC(O)(C1-C6 alkyl), NH(C1-C6 alkyl)C(O)(C1-C6 alkyl), -SO ₂ (C1-C6 alkyl), -SO ₂ (phenyl), -SO ₂ (C1-C6 halogenated alkyl), -SO ₂ NH ₂ , SO ₂ NH(C1-C6 alkyl), SO ₂ NH(phenyl), -NHSO ₂ (C1-C6 alkyl), -NHSO ₂ (phenyl), NHSO ₂ (C1-C6 halogenated alkyl) or C1-C6 alkylNH ₂ , wherein R '' is one or more groups selected from the following group: H, halogen, cyano, amine, hydroxyl, oxo ( ), C1-C6 alkyl and C1-C6 alkoxy; Indicates the attachment position of the group.

在部分實施方式中， A環選自：任選取代的苯環、任選取代的吡啶、任選取代的噻吩、任選取代的吡咯、任選取代的呋喃、任選取代的咪唑、任選取代的吡唑和任選取代的噻唑；優選地，A環為任選取代的吡咯；所述取代是指被一個或多個R ^A取代；各個R ^A獨立地選自氫、氘、C1-C4烷基、鹵代C1-C4烷基、C3-C6環烷基、3-8元雜環基、氧代、鹵素、C1-C4烷氧基、羥基和胺基。 In some embodiments, ring A is selected from: optionally substituted benzene ring, optionally substituted pyridine, optionally substituted thiophene, optionally substituted pyrrole, optionally substituted furan, optionally substituted imidazole, optionally substituted pyrazole and optionally substituted thiazole; preferably, ring A is optionally substituted pyrrole; the substitution refers to substitution by one or more ^RA ; each ^RA is independently selected from hydrogen, deuterium, C1-C4 alkyl, halogenated C1-C4 alkyl, C3-C6 cycloalkyl, 3-8 membered heterocyclic group, oxo, halogen, C1-C4 alkoxy, hydroxyl and amine.

在部分實施方式中， R ¹為氫、鹵素、氰基、C1-C3烷基、C1-C3鹵代烷基、3-4元環烷基、-C(O)NH ₂、-C(O)NH(C1-C3烷基)、-C(O)N(C1-C3烷基) ₂； R ²為氫、鹵素、氰基、C1-C3烷基。 In some embodiments, R ¹ is hydrogen, halogen, cyano, C1-C3 alkyl, C1-C3 halogenated alkyl, 3-4-membered cycloalkyl, -C(O)NH ₂ , -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl) ₂ ; R ² is hydrogen, halogen, cyano, C1-C3 alkyl.

在部分實施方式中， L ¹為不存在或伸甲基； n選自1、2； R ⁴為任選取代的C1-C6烷基、C2-C6烯基、C2-C6炔基、任選取代的C3-C8碳環基、任選取代的C3-C8雜環基、任選取代的苯環或任選取代的5-7元芳雜環基；所述取代是指被一個或多個R取代； R ⁵為任選取代的C1-C6烷基、任選取代的C3-C8碳環基、任選取代的C3-C8雜環基或-NR ^aR ^b；每個R ^a和R ^b各自獨立的為氫、任選取代的C1-C6烷基、任選取代的C3-C6碳環基、任選取代的C3-C6雜環基、任選取代的6-10芳環或任選取代的5-10元芳雜環；所述取代是指被一個或多個R取代； R的定義如上所述。 In some embodiments, ^L1 is absent or is a methyl group; n is selected from 1 and 2; ^R4 is an optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, an optionally substituted C3-C8 carbocyclic group, an optionally substituted C3-C8 heterocyclic group, an optionally substituted benzene ring, or an optionally substituted 5-7 membered aromatic heterocyclic group; the substitution means substitution by one or more R; ^R5 is an optionally substituted C1-C6 alkyl, an optionally substituted C3-C8 carbocyclic group, an optionally substituted C3-C8 heterocyclic group, or ^-NRaRb ; each of ^Ra and ^R ^b are each independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 carbocyclic group, optionally substituted C3-C6 heterocyclic group, optionally substituted 6-10 membered aromatic ring or optionally substituted 5-10 membered aromatic heterocyclic ring; the substitution refers to substitution by one or more R; R is defined as above.

在部分實施方式中，所述化合物選自下組：、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、。、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、。、、、、。 In some embodiments, the compound is selected from the following group: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , . , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , . , , , , .

在本發明的第二方面，提供了一種藥物組合物，所述藥物組合物包括：（1）治療有效量的如本發明第一方面所述的化合物、其藥學上可接受的鹽、對掌異構體、非對掌異構體、互變異構體、順反異構體、溶劑化物、多晶型物和氘代物中的一種或多種作為活性成分；和（2）任選的藥學上可接受的載體。 In the second aspect of the present invention, a pharmaceutical composition is provided, comprising: (1) a therapeutically effective amount of one or more of the compounds described in the first aspect of the present invention, their pharmaceutically acceptable salts, chiral isomers, non-chiral isomers, tautomers, cis-trans isomers, solvates, polymorphs and deuterated compounds as active ingredients; and (2) an optional pharmaceutically acceptable carrier.

在本發明的第三方面，提供了如本發明第一方面所述的化合物，其藥學上可接受的鹽、對掌異構體、非對掌異構體、互變異構體、順反異構體、溶劑化物、多晶型物或氘代物或如本發明第二方面所述的藥物組合物在製備用於預防或治療MTAP ^-/-相關的癌症的藥物中的用途。 In the third aspect of the present invention, provided is the use of the compound as described in the first aspect of the present invention, its pharmaceutically acceptable salt, chiral isomer, non-chiral isomer, tautomer, cis-trans isomer, solvate, polymorph or deuterated product or the drug composition as described in the second aspect of the present invention in the preparation of a drug for preventing or treating MTAP ^-/- related cancers.

在部分實施方式中，所述癌症選自：肝癌、乳腺癌、皮膚癌、胰腺癌、頭頸癌、腸癌、肺癌、胃癌、食管癌、腎癌、膀胱癌、尿道癌、前列腺癌、睾丸癌、子宮癌、卵巢癌、陰道癌、輸卵管癌症、膽管癌、多發性骨髓瘤、脊髓神經纖維瘤、星形細胞瘤、神經膠質瘤、急性淋巴細胞白血病、慢性淋巴細胞白血病、霍奇金淋巴瘤、非霍奇金淋巴瘤、肉瘤。In some embodiments, the cancer is selected from: liver cancer, breast cancer, skin cancer, pancreatic cancer, head and neck cancer, intestinal cancer, lung cancer, stomach cancer, esophageal cancer, kidney cancer, bladder cancer, urethral cancer, prostate cancer, testicular cancer, uterine cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, bile duct cancer, multiple myeloma, spinal neurofibroma, astrocytoma, neuroglioma, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, sarcoma.

應理解，在本發明範圍內中，本發明的上述各技術特徵和在下文(如實施例)中具體描述的各技術特徵之間都可以互相組合，從而構成新的或優選的技術方案。限於篇幅，在此不再一一累述。It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described one by one here.

本發明人經過廣泛而深入地研究，首次意外地開發了一種可有效抑制MTA協同的PRMT5的胺基吡啶類化合物，可用於製備治療與MTAP ^-/-相關的癌症的藥物。在此基礎上，完成了本發明。 After extensive and in-depth research, the inventors unexpectedly developed an aminopyridine compound that can effectively inhibit PRMT5 synergistic with MTA for the first time, which can be used to prepare drugs for treating cancers associated with MTAP ^-/- . On this basis, the present invention was completed.

術語說明Terminology

除非另外定義，否則本文中所用的全部技術與科學術語均具有如本發明所屬領域的普通技術人員通常理解的相同含義。Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

如本文所用，術語“含有”或“包括(包含)”可以是開放式、半封閉式和封閉式的。換言之，所述術語也包括“基本上由…構成”、或“由…構成”。As used herein, the term "comprising" or "including (comprising)" may be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of" or "consisting of.

下面結合具體實施例，進一步闡述本發明。應理解，這些實施例僅用於說明本發明而不用於限制本發明的範圍。下列實施例中未註明具體條件的實驗方法，通常按照常規條件，或按照製造廠商所建議的條件。除非另外說明，否則百分比和份數按重量計算。The present invention is further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

基團定義Group Definition

可在參考文獻(包括Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York)中找到對標準化學術語的定義。除非另有說明，否則採用本領域技術範圍內的常規方法，如質譜、NMR、IR和UV/VIS光譜法和藥理學方法。除非提出具體定義，否則本文在分析化學、有機合成化學以及藥物和藥物化學的有關描述中採用的術語是本領域已知的。可在化學合成、化學分析、藥物製備、製劑和遞送，以及對患者的治療中使用標準技術。例如，可利用廠商對套組的使用說明，或者按照本領域公知的方式或本發明的說明來實施反應和進行純化。通常可根據本說明書中引用和討論的多個概要性和較具體的文獻中的描述，按照本領域熟知的常規方法實施上述技術和方法。在本說明書中，可由本領域技術人員選擇基團及其取代基以提供穩定的結構部分和化合物。Definitions of standard chemical terms can be found in the reference literature, including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy, and pharmacological methods, are employed. Unless specific definitions are provided, the terms employed herein in the description of analytical chemistry, organic synthetic chemistry, and drugs and medicinal chemistry are known in the art. Standard techniques may be used in chemical syntheses, chemical analyses, drug preparation, formulation and delivery, and treatment of patients. For example, reactions and purifications may be performed using the manufacturer's instructions for use of the kit, or in a manner known in the art or as described herein. The above techniques and methods can generally be implemented according to the description in the various general and more specific literature cited and discussed in this specification, according to conventional methods well known in the art. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural parts and compounds.

當通過從左向右書寫的常規化學式描述取代基時，該取代基也同樣包括從右向左書寫結構式時所得到的在化學上等同的取代基。舉例而言，-CH ₂O-等同於-OCH ₂-。 When substituents are described by a conventional chemical formula written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, _-CH2O- is equivalent to _-OCH2- .

本文所用的章節標題僅用於組織文章的目的，而不應被解釋為對所述主題的限制。本申請中引用的所有文獻或文獻部分包括但不限於專利、專利申請、文章、書籍、操作手冊和論文，均通過引用方式整體併入本文。The section headings used herein are for the purpose of organizing the article only and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and theses, are incorporated herein by reference in their entirety.

在本文中定義的某些化學基團前面通過簡化符號來表示該基團中存在的碳原子總數。例如，C1-C6烷基是指具有總共1至6個碳原子的如下文所定義的烷基。簡化符號中的碳原子總數不包括可能存在於所述基團的取代基中的碳。Certain chemical groups defined herein are preceded by a simplified notation to indicate the total number of carbon atoms present in the group. For example, C1-C6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the simplified notation does not include carbons that may be present in substituents of the group.

除前述以外，當用於本申請的說明書及申請專利範圍中時，除非另外特別指明，否則以下術語具有如下所示的含義。In addition to the foregoing, when used in the specification and scope of the patent application of this application, unless otherwise specifically indicated, the following terms have the meanings as shown below.

在本申請中，術語“鹵素”是指氟、氯、溴或碘。In this application, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

“羥基”是指-OH基團。"Hydroxy" refers to an -OH group.

“羥基烷基”是指被羥基(-OH)取代的如下文所定義的烷基。"Hydroxyalkyl" refers to an alkyl group, as defined below, substituted with a hydroxy (-OH) group.

“羰基”是指-C(=O)-基團。"Carbonyl" refers to a -C(=O)- group.

“硝基”是指-NO ₂。 "Nitro" refers to _-NO2 .

“氰基”是指-CN。"Cyano" refers to -CN.

“胺基”是指-NH ₂。 "Amine" refers to _-NH2 .

“取代的胺基”是指被一個或兩個如下文所定義的烷基、烷基羰基、芳基烷基、雜芳基烷基取代的胺基，例如，單烷基胺基、二烷基胺基、烷基醯胺基、芳基烷基胺基、雜芳基烷基胺基。"Substituted amino" refers to an amino group substituted with one or two alkyl groups, alkylcarbonyl groups, arylalkyl groups, heteroarylalkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkylamide, arylalkylamide, heteroarylalkylamide.

“羧基”是指-COOH。"Carboxyl" refers to -COOH.

在本申請中，作為基團或是其它基團的一部分(例如用在鹵素取代的烷基等基團中)，術語“烷基”是指完全飽和的直鏈或支鏈的烴鏈基，僅由碳原子和氫原子組成、具有例如1至12個(優選為1至8個，更優選為1至6個)碳原子，且通過1個或多個單鍵與分子的其餘部分連接，例如包括但不限於甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。就本發明而言，術語“烷基”優選指含有1至6個碳原子的烷基。In the present application, as a group or as part of other groups (e.g., in groups such as halogen-substituted alkyl), the term "alkyl" refers to a fully saturated straight or branched hydrocarbon chain consisting only of carbon atoms and hydrogen atoms, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and connected to the rest of the molecule by one or more single bonds, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, and decyl, etc. For the purposes of the present invention, the term "alkyl" preferably refers to an alkyl group containing 1 to 6 carbon atoms.

在本申請中，作為基團或是其它基團的一部分，術語“烯基”意指僅由碳原子和氫原子組成、含有至少一個雙鍵、具有例如2至14個(優選為2至10個，更優選為2至6個)碳原子且通過1個或多個單鍵與分子的其餘部分連接的直鏈或支鏈的烴鏈基團，例如但不限於乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-1,4-二烯基等。In the present application, the term "alkenyl", as a group or part of other groups, means a straight or branched hydrocarbon chain group consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and connected to the rest of the molecule through one or more single bonds, such as but not limited to ethenyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl, etc.

本文中作為基團或是其它基團的一部分，術語“炔基”意指僅由碳原子和氫原子組成、含有至少一個碳-碳三鍵、具有例如2至14個(優選為2至10個，更優選為2至6個)碳原子且通過1個或多個單鍵與分子的其餘部分連接的直鏈或支鏈的烴鏈基團，例如但不限於乙炔基、1-丙炔基、1-丁炔基、庚炔基、辛炔基等。As used herein, the term "alkynyl" as a group or as part of another group refers to a straight or branched hydrocarbon chain group consisting only of carbon atoms and hydrogen atoms, containing at least one carbon-carbon triple bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and connected to the rest of the molecule by one or more single bonds, such as, but not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, etc.

在本申請中，作為基團或是其它基團的一部分，術語“碳環（基）”意指僅由碳原子和氫原子組成的穩定的非芳香族單環或多環烴基，其可包括稠合環體系、橋環體系或螺環體系，具有3至15個碳原子，優選具有3至10個碳原子，更優選具有3至8個碳原子，更優選3至6個碳原子（即C3-C6），且其為飽和或不飽和環（即環烷基、環烯基等）並可經由任何適宜的碳原子通過1個或多個單鍵與分子的其餘部分連接。除非本說明書中另外特別指明，碳環基中的碳原子可以任選地被氧化。碳環基的實例包括但不限於環丙基、環丁基、環戊基、環己基、環庚基、環辛基、金剛烷基、2,3-二氫化茚基、八氫-4,7-亞甲基-1H-茚基、1,2,3,4-四氫-萘基、5,6,7,8-四氫-萘基、環戊烯基、環己烯基、環己二烯基、1H-茚基、8,9-二氫-7H-苯并環庚烯-6-基、6,7,8,9-四氫-5H-苯并環庚烯基、5,6,7,8,9,10-六氫-苯并環辛烯基、芴基、二環[1.1.1]戊烷、二環[2.2.1]庚基、7,7-二甲基-二環[2.2.1]庚基、二環[2.2.1]庚烯基、二環[2.2.2]辛基、二環[3.1.1]庚基、二環[3.2.1]辛基、二環[2.2.2]辛烯基、二環[3.2.1]辛烯基和八氫-2,5-亞甲基-并環戊二烯基等。In the present application, as a group or part of other groups, the term "carbocyclic (base)" means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon atoms and hydrogen atoms, which may include a fused ring system, a bridged ring system or a spirocyclic system, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms (i.e. C3-C6), and which is a saturated or unsaturated ring (i.e. cycloalkyl, cycloalkenyl, etc.) and can be connected to the rest of the molecule through one or more single bonds via any suitable carbon atom. Unless otherwise specifically indicated in this specification, the carbon atoms in the carbocyclic group can be optionally oxidized. Examples of carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, 2,3-dihydroindenyl, octahydro-4,7-methylene-1H-indenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, 1H-indenyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocyclohepten-5 ... 6,7,8,9,10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl and octahydro-2,5-methylene-cyclopentadienyl, etc.

在本申請中，作為基團或是其它基團的一部分，術語“環烷基”是指上述完全飽和的碳環（基），典型的環烷基包括但不限於環丙基、環丁基、環戊基、環己基、環庚基、環辛基、金剛烷基等。In the present application, the term "cycloalkyl" as a group or part of other groups refers to the above-mentioned fully saturated carbon ring (group), and typical cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, etc.

在本申請中，作為基團或是其它基團的一部分，術語“環烯基”是指部分不飽和的碳環（基），典型的環烯基包括但不限於環丁烯基、環戊烯基、環己烯基等。In the present application, as a group or part of other groups, the term "cycloalkenyl" refers to a partially unsaturated carbon ring (group). Typical cycloalkenyl groups include but are not limited to cyclobutenyl, cyclopentenyl, cyclohexenyl, etc.

在本申請中，作為基團或是其它基團的一部分，術語“雜環（基）”意指由2至14個碳原子以及1至6個選自氮、磷、氧和硫的雜原子組成的穩定的3元至20元非芳香族環狀基團。除非本說明書中另外特別指明，否則雜環基可以為單環、雙環、三環或更多環的環體系，其可包括稠合環體系、橋環體系或螺環體系；其雜環基中的氮、碳或硫原子可任選地被氧化；氮原子可任選地被季銨化；且雜環基可為部分或完全飽和。雜環基可以經由碳原子或者雜原子並通過1個或多個單鍵與分子其餘部分連接。在包含稠環的雜環基中，一個或多個環可以是下文所定義的芳基或雜芳基，條件是與分子其餘部分的連接點為非芳香族環原子。就本發明的目的而言，雜環基優選為包含1至3個選自氮、氧和硫的雜原子的穩定的4元至11元非芳香性單環、雙環、橋環或螺環基團，更優選為包含1至3個選自氮、氧和硫的雜原子的穩定的4元至8元非芳香性單環、雙環、橋環或螺環基團。雜環基的實例包括但不限於：吡咯烷基、嗎啉基、哌嗪基、高哌嗪基、哌啶基、硫代嗎啉基、2-氮雜雙環[2.2.2]辛烷基、2,7-二氮雜-螺[3.5]壬烷-7-基、2-氧雜-6-氮雜-螺[3.3]庚烷-6-基、2,5-二氮雜-雙環[2.2.1]庚烷-2-基、氮雜環丁烷基、吡喃基、四氫吡喃基、噻喃基、四氫呋喃基、噁嗪基、二氧環戊基、四氫異喹啉基、十氫異喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、異噻唑烷基、異噁唑烷基、二氫吲哚基、八氫吲哚基、八氫異吲哚基、吡咯烷基、吡唑烷基、鄰苯二甲醯亞胺基等。In the present application, as a group or part of other groups, the term "heterocyclic (base)" means a stable 3- to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. Unless otherwise specifically indicated in the specification, the heterocyclic group can be a monocyclic, bicyclic, tricyclic or more ring system, which can include a fused ring system, a bridged ring system or a spirocyclic system; the nitrogen, carbon or sulfur atom in the heterocyclic group can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclic group can be partially or completely saturated. The heterocyclic radical may be attached to the rest of the molecule via a carbon atom or a heteroatom and via one or more single bonds. In heterocyclic radicals comprising fused rings, one or more rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, the heterocyclic radical is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic radical containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic radical containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclic groups include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2-azabicyclo[2.2.2]octanyl, 2,7-diaza-spiro[3.5]nonan-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptane-2 In some embodiments, the present invention comprises a cyclopentyl group, azocyclobutyl group, a pyranyl group, a tetrahydropyranyl group, a thiopyranyl group, a tetrahydrofuranyl group, an oxazinyl group, a dioxolanyl group, a tetrahydroisoquinolyl group, a decahydroisoquinolyl group, an imidazolinyl group, an imidazolidinyl group, a quinolizinyl group, a thiazolidinyl group, an isothiazolidinyl group, an isoxazolidinyl group, a dihydroindolyl group, an octahydroindolyl group, an octahydroisoindolyl group, a pyrrolidinyl group, a pyrazolidinyl group, a phthalimide group, and the like.

在本申請中，作為基團或是其它基團的一部分，術語“芳基”意指具有6至18個碳原子(優選具有6至10個碳原子，即C6-C10芳基)的共軛烴環體系基團。就本發明的目的而言，芳基可以為單環、雙環、三環或更多環的環體系，還可以與上文所定義的碳環基或雜環基稠合，條件是芳基經由芳香環上的原子通過1個或多個單鍵與分子的其餘部分連接。芳基的實例包括但不限於苯基、萘基、蒽基、菲基、芴基、2,3-二氫-1H-異吲哚基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等。In the present application, the term "aryl" as a radical or part of another radical means a conjugated hydrocarbon ring system radical having 6 to 18 carbon atoms (preferably 6 to 10 carbon atoms, i.e. C6-C10 aryl). For the purposes of the present invention, the aryl group can be a monocyclic, bicyclic, tricyclic or higher ring system, and can also be fused with a carbocyclic or heterocyclic group as defined above, provided that the aryl group is connected to the rest of the molecule through one or more single bonds via atoms on the aromatic ring. Examples of aryl include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-on-7-yl, and the like.

在本申請中，術語“芳基烷基”是指被上文所定義的芳基所取代的上文所定義的烷基。In this application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.

在本申請中，作為基團或是其它基團的一部分，術語“雜芳基”意指環內具有1至15個碳原子(優選具有1至10個碳原子)和1至6個選自氮、氧和硫的雜原子的5元至16元共軛環系基團。除非本說明書中另外特別指明，否則雜芳基可為單環、雙環、三環或更多環的環體系，還可以與上文所定義的碳環基或雜環基稠合，條件是雜芳基經由雜芳香環上的原子通過1個或多個單鍵與分子的其餘部分連接。雜芳基中的氮、碳或硫原子可任選地被氧化；氮原子可任選地被季銨化。就本發明的目的而言，雜芳基優選為包含1至5個選自氮、氧和硫的雜原子的穩定的5元至12元芳香性基團，更優選為包含1至4個選自氮、氧和硫的雜原子的穩定的5元至10元芳香性基團或者包含1至3個選自氮、氧和硫的雜原子的5元至6元芳香性基團。雜芳基的實例包括但不限於噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、異噁唑基、吡啶基、嘧啶基、吡嗪基、噠嗪基、苯并咪唑基、苯并吡唑基、吲哚基、呋喃基、吡咯基、三唑基、四唑基、三嗪基、吲嗪基、異吲哚基、吲唑基、異吲唑基、嘌呤基、喹啉基、異喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、異噻唑基、苯并噻唑基、苯并噻吩基、噁三唑基、噌啉基、喹唑啉基、苯硫基、中氮茚基、鄰二氮雜菲基、異噁唑基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氫苯并[b]噻吩基、萘并吡啶基、[1,2,4]三唑并[4,3-b]噠嗪、[1,2,4]三唑并[4,3-a]吡嗪、[1,2,4]三唑并[4,3-c]嘧啶、[1,2,4]三唑并[4,3-a]吡啶、咪唑并[1,2-a]吡啶、咪唑并[1,2-b]噠嗪、咪唑并[1,2-a]吡嗪等。In the present application, as a group or part of other groups, the term "heteroaryl" means a 5- to 16-membered concentric ring system group having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Unless otherwise specifically indicated in the specification, the heteroaryl group can be a monocyclic, bicyclic, tricyclic or more ring system, and can also be fused with a carbocyclic group or a heterocyclic group defined above, provided that the heteroaryl group is connected to the rest of the molecule through one or more single bonds via atoms on the heteroaromatic ring. The nitrogen, carbon or sulfur atoms in the heteroaryl group can be optionally oxidized; the nitrogen atom can be optionally quaternized. For the purpose of the present invention, heteroaryl is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 5- to 10-membered aromatic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, or a 5- to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, oxazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolyl, isoquinolyl, naphthazinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothiophenyl, oxatriol, oxazolyl, cinnolinyl, quinazolinyl, phenylthio, indolizinyl, o-phenanthroline, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridinyl, [1,2,4]triazolo[4,3-b]oxazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1,2,4]triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]oxazine, imidazo[1,2-a]pyrazine, etc.

在本申請中，術語“雜芳基烷基”是指被上文所定義的雜芳基所取代的上文所定義的烷基。In this application, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above.

在本申請中，術語“不存在”是指被上文所定義的基團的兩側直接通過化學鍵相連。例如，“A-B-C中B是不存在”表示“A-C”。In this application, the term "absent" means that the two sides of the groups defined above are directly connected by a chemical bond. For example, "A-B-C where B is absent" means "A-C".

在本申請中，“ ”中的“ ”表示基團R的連接位置。 In this application, “ " ” indicates the attachment position of group R.

在本申請中，除申請專利範圍中特殊說明外，“任選地”、“任選”表示隨後描述的事件或狀況可能發生也可能不發生，且該描述同時包括該事件或狀況發生和不發生的情況。例如，“任選取代的芳基”表示芳基上的氫被取代或未被取代，且該描述同時包括被取代的芳基與未被取代的芳基。例如，在沒有明確列出取代基的情況下，本文所用的術語“任選取代的”、“被取代的”或“被……取代”意指給定的原子或基團上的一個或多個氫原子獨立地被一個或多個、例如1、2、3或4個取代基取代，所述取代基獨立地選自：氘(D)、鹵素、OH、氧代(=O)、巰基、氰基、-CD ₃、-C1-C6烷基(優選-C1-3烷基)、C2-C6烯基、C2-C6炔基、環烷基(優選C3-C8環烷基)、芳基、雜環基(優選3-8元雜環基)、雜芳基、芳基C1-C6烷基、雜芳基C1-C6烷基、C1-C6鹵代烷基-、OC1-C6烷基(優選-OC1-C3烷基)、-OC2-C6烯基、O環烷基、O雜環基、O芳基、O雜芳基、OC1-C6烷基苯基、-C1-C6烷基OH (優選-C1-C4烷基OH)、-C1-C6烷基SH、-C1-C6烷基O-C1-C6烷基、OC1-C6鹵代烷基、NH ₂、C1-C6烷基NH ₂(優選C1-C3烷基NH ₂)、N(C1-C6烷基) ₂[優選N(C1-C3烷基) ₂]、NH(C1-C6烷基)[優選NH(C1-C3烷基)]、N(C1-C6烷基)(C1-C6烷基苯基)、NH(C1-C6烷基苯基)、N(C1-C6烷基)(芳基)、NH(芳基)、硝基、C(O)-OH、C(O)OC1-C6烷基[優選C(O)OC1-C3烷基]、-CONR ⁱR ⁱⁱ(其中R ⁱ和R ⁱⁱ是H、D和C1-6烷基，優選C1-3烷基)、NHC(O)(C1-C6烷基)、NHC(O)(苯基)、N(C1-C6烷基)C(O)(C1-C6烷基)、N(C1-C6烷基)C(O)(苯基)、C(O)C1-C6烷基、C(O)雜芳基(優選C(O)-5-7元雜芳基)、C(O)C1-C6烷基苯基、C(O)C1-C6鹵代烷基、OC(O)C1-C6烷基[優選OC(O)C1-C3烷基]、-S(O) ₂-C1-C6烷基、-S(O)-C1-C6烷基、-S(O) ₂-苯基、-S(O) ₂-C1-C6鹵代烷基、-S(O) ₂NH ₂、S(O) ₂NH(C1-C6烷基)、S(O) ₂NH(苯基)、-NHS(O) ₂(C1-C6烷基)、-NHS(O) ₂(苯基)和NHS(O) ₂(C1-C6鹵代烷基)，其中所述的烷基、烯基、炔基、環烷基、苯基、芳基、雜環基和雜芳基中的每一個任選被一個或多個選自以下的取代基進一步取代：鹵素、-OH、氧代(=O)、-NH ₂、環烷基、3-8元雜環基、C1-C4烷基、C1-C4鹵代烷基-、-OC1-C4烷基、-C1-C4烷基OH、-C1-C4烷基O-C1-C4烷基、OC1-C4鹵代烷基、氰基、硝基、-C(O)-OH、C(O)OC1-C6烷基、CON(C1-C6烷基) ₂、CONH(C1-C6烷基)、CONH ₂、NHC(O)(C1-C6烷基)、NH(C1-C6烷基)C(O)(C1-C6烷基)、-SO ₂(C1-C6烷基)、-SO ₂(苯基)、-SO ₂(C1-C6鹵代烷基)、-SO ₂NH ₂、SO ₂NH(C1-C6烷基)、SO ₂NH(苯基)、-NHSO ₂(C1-C6烷基)、-NHSO ₂(苯基)和NHSO ₂(C1-C6鹵代烷基)。當一個原子或基團被多個取代基取代時，所述取代基可以相同或不同。本文所用術語“部分”、“結構部分”、“化學部分”、“基團”、“化學基團”是指分子中的特定片段或官能團。化學部分通常被認為是嵌入或附加到分子上的化學實體。 In this application, unless otherwise specified in the scope of the application, "optionally" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes both the occurrence and non-occurrence of the event or situation. For example, "optionally substituted aryl" means that the hydrogen on the aryl is substituted or unsubstituted, and the description includes both substituted aryl and unsubstituted aryl. For example, in the absence of explicit listing of substituents, the terms "optionally substituted", "substituted" or "substituted by..." as used herein mean that one or more hydrogen atoms on a given atom or group are independently replaced by one or more, for example, 1, 2, 3 or 4 substituents, and the substituents are independently selected from: deuterium (D), halogen, OH, oxo (=O), hydroxyl, cyano, -CD ₃ , -C1-C6 alkyl (preferably -C1-3 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl (preferably C3-C8 cycloalkyl), aryl, heterocyclic group (preferably 3-8 membered heterocyclic group), heteroaryl, aryl C1-C6 alkyl, heteroaryl C1-C6 alkyl, C1-C6 halogenated alkyl-, OC1-C6 alkyl (preferably -OC1-C3 alkyl), -OC2-C6 alkenyl, O cycloalkyl, O heterocyclic group, O aryl, O heteroaryl, OC1-C6 alkylphenyl, -C1-C6 alkyl OH (preferably -C1-C4 alkyl OH), -C1-C6 alkyl SH, -C1-C6 alkyl O-C1-C6 alkyl, OC1-C6 halogenated alkyl, NH ₂ , C1-C6 alkyl NH ₂ (preferably C1-C3 alkyl NH ₂ ), N(C1-C6 alkyl) ₂ [preferably N(C1-C3 alkyl) ₂ ], NH(C1-C6 alkyl) [preferably NH(C1-C3 alkyl)], N(C1-C6 alkyl)(C1-C6 alkylphenyl), NH(C1-C6 alkylphenyl), N(C1-C6 alkyl)(aryl), NH(aryl), nitro, C(O)-OH, C(O)OC1-C6 alkyl [preferably C(O)OC1-C3 alkyl], -CONR ⁱ R ⁱⁱ (wherein R ⁱ and R ⁱⁱ is H, D and C1-6 alkyl, preferably C1-3 alkyl), NHC(O)(C1-C6 alkyl), NHC(O)(phenyl), N(C1-C6 alkyl)C(O)(C1-C6 alkyl), N(C1-C6 alkyl)C(O)(phenyl), C(O)C1-C6 alkyl, C(O) heteroaryl (preferably C(O)-5-7 membered heteroaryl), C(O)C1-C6 alkylphenyl, C(O)C1-C6 halogenated alkyl, OC(O)C1-C6 alkyl [preferably OC(O)C1-C3 alkyl], -S(O) ₂ -C1-C6 alkyl, -S(O)-C1-C6 alkyl, -S(O) ₂ -phenyl, -S(O) ₂ -C1-C6 halogenated alkyl, _-S (O) _2NH2 , S(O) ₂ NH(C1-C6 alkyl), S(O) ₂ NH(phenyl), -NHS(O) ₂ (C1-C6 alkyl), -NHS(O) ₂ (phenyl) and NHS(O) ₂ (C1-C6 halogenated alkyl), wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, aryl, heterocyclic and heteroaryl groups is optionally further substituted with one or more substituents selected from the group consisting of halogen, -OH, oxo (=O), -NH ₂ , cycloalkyl, 3-8 membered heterocyclic group, C1-C4 alkyl, C1-C4 halogenated alkyl-, -OC1-C4 alkyl, -C1-C4 alkylOH, -C1-C4 alkylO-C1-C4 alkyl, OC1-C4 halogenated alkyl, cyano, nitro, -C(O)-OH, C(O)OC1-C6 alkyl, CON(C1-C6 alkyl) ₂ , CONH(C1-C6 alkyl), CONH ₂ , NHC(O)(C1-C6 alkyl), NH(C1-C6 alkyl)C(O)(C1-C6 alkyl), -SO ₂ (C1-C6 alkyl), -SO ₂ (phenyl), -SO ₂ (C1-C6 halogenated alkyl), -SO ₂ NH ₂ , SO ₂ NH(C1-C6 alkyl), SO ₂ NH(phenyl), -NHSO ₂ (C1-C6 alkyl), -NHSO ₂ (phenyl) and NHSO ₂ (C1-C6 halogenated alkyl). When an atom or group is substituted with multiple substituents, the substituents may be the same or different. As used herein, the terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" refer to a specific fragment or functional group in a molecule. A chemical moiety is generally considered to be a chemical entity embedded in or attached to a molecule.

在本發明中，(C1-C4烷基) ₂胺基，代表2個C1-C4烷基取代的胺，例如可以是、、、或等。 In the present invention, (C1-C4 alkyl) _2- amino represents an amine substituted with two C1-C4 alkyl groups, for example, , , , or wait.

本發明中“多個”是指2、3或4個。In the present invention, "plurality" means 2, 3 or 4.

活性成分Active ingredients

如本文所用，“本發明化合物”或“活性成分”指式I所示的化合物，並且還包含其藥學上可接受的鹽、對掌異構體、非對掌異構體、互變異構體、順反異構體、溶劑化物、多晶型物、氘代物或其組合。As used herein, "compound of the present invention" or "active ingredient" refers to the compound represented by Formula I, and also includes pharmaceutically acceptable salts, chiral isomers, non-chiral isomers, tautomers, cis-trans isomers, solvates, polymorphs, deuterated compounds or combinations thereof.

“立體異構體”是指由相同原子組成，通過相同的鍵鍵合，但具有不同三維結構的化合物。本發明將涵蓋各種立體異構體及其混合物。"Stereoisomers" refer to compounds composed of the same atoms, bonded by the same bonds, but with different three-dimensional structures. The present invention is intended to encompass various stereoisomers and mixtures thereof.

當本發明的化合物中含有烯雙鍵時，除非另有說明，否則本發明的化合物旨在包含E-和Z-幾何異構體。When the compounds of the present invention contain olefinic double bonds, unless otherwise specified, the compounds of the present invention are intended to include both E- and Z-geometric isomers.

“互變異構體”是指質子從分子的一個原子轉移至相同分子的另一個原子而形成的異構體。本發明的化合物的所有互變異構形式也將包含在本發明的範圍內。"Tautomers" refer to isomers formed when a proton is transferred from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the present invention are also intended to be included within the scope of the present invention.

本發明的化合物或其藥學上可接受的鹽可能含有一個或多個掌性碳原子，且因此可產生對掌異構體、非對掌異構體及其它立體異構形式。每個掌性碳原子可以基於立體化學而被定義為(R)-或(S)-。本發明旨在包括所有可能的異構體，以及其外消旋體和光學純形式。本發明的化合物的製備可以選擇外消旋體、非對掌異構體或對掌異構體作為原料或中間體。光學活性的異構體可以使用掌性合成子或掌性試劑來製備，或者使用常規技術進行拆分，例如採用結晶以及掌性色譜等方法。The compounds of the present invention or their pharmaceutically acceptable salts may contain one or more chiral carbon atoms and may therefore produce chiral isomers, non-chiral isomers and other stereoisomeric forms. Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The preparation of the compounds of the present invention may select racemates, non-chiral isomers or chiral isomers as raw materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or separated using conventional techniques, such as crystallization and chiral chromatography.

製備/分離個別異構體的常規技術包括由合適的光學純前體的掌性合成，或者使用例如掌性高效液相色譜法拆分外消旋體(或鹽或衍生物的外消旋體)，例如可參見Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004；A.M. Stalcup, Chiral Separations, Annu. Rev. Anal. Chem.3:341-63, 2010；Fumiss et al. (eds.), VOGEL’S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816；Heller, Acc. Chem. Res. 1990, 23, 128。 Conventional techniques for preparing/isolating individual isomers include chiral synthesis from appropriate optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography, see, for example, Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004 ; AM Stalcup, Chiral Separations, Annu. Rev. Anal. Chem. 3:341-63, 2010 ; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991 , 809-816; Heller, Acc. Chem. Res. 1990 , 23, 128.

在本申請中，術語“藥學上可接受的鹽”包括藥學上可接受的酸加成鹽和藥學上可接受的鹼加成鹽。In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

“藥學上可接受的酸加成鹽”是指能夠保留游離鹼的生物有效性而無其它副作用的，與無機酸或有機酸所形成的鹽。無機酸鹽包括但不限於鹽酸鹽、氫溴酸鹽、硫酸鹽、硝酸鹽、磷酸鹽等；有機酸鹽包括但不限於甲酸鹽、乙酸鹽、2,2-二氯乙酸鹽、三氟乙酸鹽、丙酸鹽、己酸鹽、辛酸鹽、癸酸鹽、十一碳烯酸鹽、乙醇酸鹽、葡糖酸鹽、乳酸鹽、癸二酸鹽、己二酸鹽、戊二酸鹽、丙二酸鹽、草酸鹽、馬來酸鹽、琥珀酸鹽、富馬酸鹽、酒石酸鹽、檸檬酸鹽、棕櫚酸鹽、硬脂酸鹽、油酸鹽、肉桂酸鹽、月桂酸鹽、蘋果酸鹽、麩胺酸鹽、焦麩胺酸鹽、天冬胺酸鹽、苯甲酸鹽、甲磺酸鹽、苯磺酸鹽、對甲苯磺酸鹽、海藻酸鹽、抗壞血酸鹽、水楊酸鹽、4-胺基水楊酸鹽、萘二磺酸鹽等。這些鹽可通過本專業已知的方法製備。"Pharmaceutically acceptable acid addition salt" refers to a salt formed with an inorganic acid or organic acid that can retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include but are not limited to hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, etc.; organic acid salts include but are not limited to formates, acetates, 2,2-dichloroacetates, trifluoroacetates, propionates, caproates, octanoates, decanoates, undecylenates, glycolates, gluconates, lactates, sebacates, adipates, glutarates, malonates, oxalates. , maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, appletate, glutamine, pyroglutamine, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalene disulfonate, etc. These salts can be prepared by methods known in the art.

“藥學上可接受的鹼加成鹽”是指能夠保持游離酸的生物有效性而無其它副作用的、與無機鹼或有機鹼所形成的鹽。衍生自無機鹼的鹽包括但不限於鈉鹽、鉀鹽、鋰鹽、銨鹽、鈣鹽、鎂鹽、鐵鹽、鋅鹽、銅鹽、錳鹽、鋁鹽等。優選的無機鹽為銨鹽、鈉鹽、鉀鹽、鈣鹽及鎂鹽。衍生自有機鹼的鹽包括但不限於以下的鹽：一級胺類、二級胺類及三級胺類，被取代的胺類，包括天然的被取代胺類、環狀胺類及鹼性離子交換樹脂，例如氨、異丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲胺基乙醇、2-二乙胺基乙醇、二環己胺、離胺酸、精胺酸、組胺酸、咖啡因、普魯卡因、膽鹼、甜菜鹼、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可鹼、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺樹脂等。優選的有機鹼包括異丙胺、二乙胺、乙醇胺、三甲胺、二環己基胺、膽鹼及咖啡因。這些鹽可通過本專業已知的方法製備。"Pharmaceutically acceptable base addition salt" refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include but are not limited to sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts and magnesium salts. Salts derived from organic bases include, but are not limited to, the following salts: primary amines, diamines and tertiary amines, substituted amines, including naturally substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.

藥物組合物和施用方法Pharmaceutical compositions and methods of administration

在本申請中，“藥物組合物”是指本發明化合物與本領域通常接受的用於將生物活性化合物輸送至哺乳動物(例如人)的介質的製劑。該介質包括藥學上可接受的載體。藥物組合物的目的是促進生物體的投藥，利於活性成分的吸收進而發揮生物活性。In this application, "pharmaceutical composition" refers to a preparation of the compound of the present invention and a medium generally accepted in the art for delivering biologically active compounds to mammals (such as humans). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of the drug into the organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

通式(I)所述化合物可以與已知的治療或改進相似病狀的其他藥物聯用。聯合投藥時，原來藥物的投藥方式和劑量可以保持不變，而同時或隨後服用式I的化合物。當式I化合物與其它一種或幾種藥物同時服用時，可以優選使用同時含有一種或幾種已知藥物和式I化合物的藥用組合物。藥物聯用也包括在重疊的時間段服用式I化合物與其它一種或幾種已知藥物。當式I化合物與其它一種或幾種藥物進行藥物聯用時，式I化合物或已知藥物的劑量可能比它們單獨用藥的劑量低。The compounds of general formula (I) can be used in combination with other drugs known to treat or improve similar conditions. When administered in combination, the administration method and dosage of the original drug can remain unchanged, while the compound of formula I is taken simultaneously or subsequently. When the compound of formula I is taken simultaneously with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compound of formula I can be preferably used. Drug combination also includes taking the compound of formula I and one or more other known drugs at overlapping time periods. When the compound of formula I is used in combination with one or more other drugs, the dosage of the compound of formula I or the known drug may be lower than the dosage of them taken alone.

可以與通式(I)所述化合物進行藥物聯用的藥物或活性成分包括但不局限為：PD-1抑制劑（如納武單抗、派姆單抗等）、PD-L1抑制劑（如度伐單抗、阿特珠單抗atezolizumab等）、CD47抗體（如Hu5F9-G4，CC-90002等)、CD20抗體（如利妥昔單抗、伊布單抗等）、KRAS抑制劑（如AMG510等）、ALK抑制劑（如色瑞替尼、艾樂替尼、布加替尼、蘿拉替尼、奧卡替尼）、EGFR抑制劑（如阿法替尼、吉非替尼、厄洛替尼、拉帕替尼、達克替尼、艾克替尼、奧希替尼等）、VEGFR抑制劑（如索拉非尼、帕唑帕尼、瑞戈非尼、卡博替尼、舒尼替尼等）、PI3K抑制劑（如Dactolisib、Taselisib等）、BTK抑制劑（如依魯替尼、替拉布替尼、阿卡布替尼、澤布替尼、維卡布替尼等）、HDAC抑制劑（如Vorinostat、Fimepinostat、Givinostat、Tucidinostat等）、CDK抑制劑（如帕博西尼、Ribociclib、Abemaciclib等）、MEK抑制劑（如司美替尼(AZD6244)、Trametinib等）、ERK抑制劑（如BVD523、HH2710等）、mTOR抑制劑（如Vistusertib等）、SHP2抑制劑（如RMC-4630、JAB-3068）、SOS1抑制劑（如BI1701963等）、PRMT1抑制劑、MAT2A抑制劑或其組合。Drugs or active ingredients that can be used in combination with the compound of formula (I) include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, etc.), CD20 antibodies (such as rituximab, ibrutinib, etc.), KRAS inhibitors ( Such as AMG510, etc.), ALK inhibitors (such as ceritinib, alectinib, brigatinib, larvatinib, oclatinib), EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, osimertinib, etc.), VEGFR inhibitors (such as sorafenib, pazopanib, regorafenib, cabozantinib, sunitinib, etc.), PI3K inhibitors (such as dactolisib, Ta selisib, etc.), BTK inhibitors (such as Ibrutinib, Tilabutinib, Acalabrutinib, Zebutinib, Vicabrutinib, etc.), HDAC inhibitors (such as Vorinostat, Fimepinostat, Givinostat, Tucidinostat, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, etc.), MEK inhibitors (such as Selumetinib (AZD6244), Trametinib, etc.), ERK inhibitors (such as BVD523, HH2710, etc.), mTOR inhibitors (such as Visusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068), SOS1 inhibitors (such as BI1701963, etc.), PRMT1 inhibitors, MAT2A inhibitors or their combinations.

本文所用術語“藥學上可接受的”是指不影響本發明化合物的生物活性或性質的物質(如載體或稀釋劑)，並且相對無毒，即該物質可施用於個體而不造成不良的生物反應或以不良方式與組合物中包含的任意組分相互作用。The term "pharmaceutically acceptable" as used herein refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., the substance can be administered to a subject without causing adverse biological reactions or interacting in an adverse manner with any components contained in the composition.

在本申請中，“藥學上可接受的載體”包括但不限於任何被相關的政府管理部門許可為可接受供人類或家畜使用的佐劑、載體、賦形劑、助流劑、增甜劑、稀釋劑、防腐劑、染料/著色劑、矯味劑、表面活性劑、潤濕劑、分散劑、助懸劑、穩定劑、等滲劑、溶劑或乳化劑。In this application, "pharmaceutically acceptable carrier" includes but is not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant governmental regulatory authorities as acceptable for human or livestock use.

本發明化合物或藥物組合物的施用方式沒有特別限制，代表性的施用方式包括(但並不限於)：口服、瘤內、直腸、腸胃外(靜脈內、肌肉內或皮下)、和局部投藥。The administration method of the compound or pharmaceutical composition of the present invention is not particularly limited. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

用於口服投藥的固體劑型包括膠囊劑、片劑、丸劑、散劑和顆粒劑。在這些固體劑型中，活性化合物與至少一種常規惰性賦形劑(或載體)混合，如檸檬酸鈉或磷酸二鈣，或與下述成分混合：(a) 填料或增容劑，例如，澱粉、乳糖、蔗糖、葡萄糖、甘露醇和矽酸；(b) 粘合劑，例如，羥甲基纖維素、藻酸鹽、明膠、聚乙烯基吡咯烷酮、蔗糖和阿拉伯膠；(c) 保濕劑，例如，甘油；(d) 崩解劑，例如，瓊脂、碳酸鈣、馬鈴薯澱粉或木薯澱粉、藻酸、某些複合矽酸鹽、和碳酸鈉；(e) 緩溶劑，例如石蠟；(f) 吸收加速劑，例如，季銨化合物；(g) 潤濕劑，例如鯨蠟醇和單硬脂酸甘油酯；(h) 吸附劑，例如，高嶺土；和(i) 潤滑劑，例如，滑石、硬脂酸鈣、硬脂酸鎂、固體聚乙二醇、十二烷基硫酸鈉，或其混合物。膠囊劑、片劑和丸劑中，劑型也可包含緩衝劑。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) buffers, for example, paraffin; (f) Absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain a buffering agent.

固體劑型如片劑、糖丸、膠囊劑、丸劑和顆粒劑可採用包衣和殼材製備，如腸衣和其它本領域公知的材料。它們可包含不透明劑，並且，這種組合物中活性化合物或化合物的釋放可以延遲的方式在消化道內的某一部分中釋放。可採用的包埋組分的實例是聚合物質和蠟類物質。必要時，活性化合物也可與上述賦形劑中的一種或多種形成微膠囊形式。Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be adopted are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsule form with one or more of the above-mentioned excipients.

用於口服投藥的液體劑型包括藥學上可接受的乳液、溶液、懸浮液、糖漿或酊劑。除了活性化合物外，液體劑型可包含本領域中常規採用的惰性稀釋劑，如水或其它溶劑，增溶劑和乳化劑，例知，乙醇、異丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲醯胺以及油，特別是棉籽油、花生油、玉米胚油、橄欖油、蓖麻油和芝麻油或這些物質的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.

除了這些惰性稀釋劑外，組合物也可包含助劑，如潤濕劑、乳化劑和懸浮劑、甜味劑、矯味劑和香料。Besides these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and flavoring agents.

除了活性化合物外，懸浮液可包含懸浮劑，例如，乙氧基化異十八烷醇、聚氧乙烯山梨醇和脫水山梨醇酯、微晶纖維素、甲醇鋁和瓊脂或這些物質的混合物等。In addition to the active compounds, the suspension may contain a suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar or mixtures of these substances.

用於腸胃外注射的組合物可包含生理上可接受的無菌含水或無水溶液、分散液、懸浮液或乳液，和用於重新溶解成無菌的可注射溶液或分散液的無菌粉末。適宜的含水和非水載體、稀釋劑、溶劑或賦形劑包括水、乙醇、多元醇及其適宜的混合物。Compositions for parenteral injection may include physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

本發明所述“腫瘤”包括但不限於肺癌、胰腺癌、結直腸癌、白血病、尤文氏肉瘤、乳腺癌、前列腺癌、T細胞淋巴瘤、B細胞淋巴瘤、惡性橫紋肌瘤、滑膜肉瘤、子宮內膜瘤、胃癌、肝癌、腎癌、黑色素瘤、卵巢癌、腦膠質瘤、膽管癌、鼻咽癌、宮頸癌、頭頸癌、食管癌、甲狀腺癌和膀胱癌等疾病。本文所用術語“預防的”、“預防”和“防止”包括使病患減少疾病或病症的發生或惡化的可能性。The "tumor" described in the present invention includes but is not limited to lung cancer, pancreatic cancer, colorectal cancer, leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdomyosarcoma, synovial sarcoma, endometrioma, gastric cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, brain glioma, bile duct cancer, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer and bladder cancer. The terms "preventive", "prevention" and "prevention" used herein include reducing the possibility of the occurrence or deterioration of a disease or condition in a patient.

本文所用的術語“治療”和其它類似的同義詞包括以下含義： (i)預防疾病或病症在哺乳動物中出現，特別是當這類哺乳動物易患有該疾病或病症，但尚未被診斷為已患有該疾病或病症時； (ii)抑制疾病或病症，即遏制其發展； (iii)緩解疾病或病症，即，使該疾病或病症的狀態消退；或者 (iv)減輕該疾病或病症所造成的症狀。 As used herein, the term "treat" and other similar synonyms include the following meanings: (i) preventing a disease or condition from occurring in a mammal, particularly when such mammal is susceptible to the disease or condition but has not yet been diagnosed with the disease or condition; (ii) inhibiting the disease or condition, i.e., arresting its development; (iii) relieving the disease or condition, i.e., causing the disease or condition to regress; or (iv) alleviating the symptoms caused by the disease or condition.

本文所使用術語“有效量”、“治療有效量”或“藥學有效量”是指服用後足以在某種程度上緩解所治療的疾病或病症的一個或多個症狀的至少一種藥劑或化合物的量。其結果可以為跡象、症狀或病因的消減和/或緩解，或生物系統的任何其它所需變化。例如，用於治療的“有效量”是在臨床上提供顯著的病症緩解效果所需的包含本文公開化合物的組合物的量。可使用諸如劑量遞增試驗的技術測定適合於任意個體病例中的有效量。As used herein, the term "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" refers to an amount of at least one agent or compound sufficient to relieve to some extent one or more symptoms of the disease or condition being treated after administration. The result can be the elimination and/or alleviation of signs, symptoms or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide a significant symptom-relieving effect clinically. Techniques such as dose escalation trials can be used to determine the effective amount appropriate for any individual case.

本文所用術語“服用”、“施用”、“投藥”等是指能夠將化合物或組合物遞送到進行生物作用的所需位點的方法。這些方法包括但不限於口服途徑、經十二指腸途徑、胃腸外注射(包括靜脈內、皮下、腹膜內、肌內、動脈內注射或輸注)、局部投藥和經直腸投藥。本領域技術人員熟知可用於本文所述化合物和方法的施用技術，例如在Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington’s, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa中討論的那些。在優選的實施方案中，本文討論的化合物和組合物通過口服施用。As used herein, the terms "administering," "applying," "dosing," and the like refer to methods that enable a compound or composition to be delivered to the desired site for biological action. These methods include, but are not limited to, oral routes, transduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used for the compounds and methods described herein, such as those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.

本文所使用術語“藥物組合”、“藥物聯用”、“聯合用藥”、“施用其它治療”、“施用其它治療劑”等是指通過混合或組合不止一種活性成分而獲得的藥物治療，其包括活性成分的固定和不固定組合。術語“固定組合”是指以單個實體或單個劑型的形式向患者同時施用至少一種本文所述的化合物和至少一種協同藥劑。術語“不固定組合”是指以單獨實體的形式向患者同時施用、合用或以可變的間隔時間順次施用至少一種本文所述的化合物和至少一種協同製劑。這些也應用到雞尾酒療法中，例如施用三種或更多種活性成分。As used herein, the terms "drug combination", "drug combination", "combination therapy", "administration of other treatments", "administration of other therapeutic agents" and the like refer to drug treatments obtained by mixing or combining more than one active ingredient, including fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form. The term "non-fixed combination" refers to the simultaneous administration, combined administration or sequential administration with variable intervals of at least one compound described herein and at least one synergistic agent to a patient in the form of separate entities. These also apply to cocktail therapies, such as the administration of three or more active ingredients.

本發明的藥物組合物包含安全有效量範圍內的本發明化合物或其藥理上可接受的鹽及藥理上可以接受的賦形劑或載體。其中“安全有效量”指的是：化合物的量足以明顯改善病情，而不至於產生嚴重的副作用。通常，藥物組合物含有1-2000mg本發明化合物/劑，更佳地，含有10-1000mg本發明化合物/劑。較佳地，所述的“一劑”為一個膠囊或藥片。The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable formulation or carrier. The "safe and effective amount" means that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-1000 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

相對於現有技術，本發明具有以下有益效果：（1）本發明提供了一種結構新穎的如式I所示的化合物或其藥學上可接受的鹽；（2）本發明化合物可與MTA協同抑制PRMT5，其可用於製備治療與MTAP ^-/-相關的癌症的藥物。 Compared with the prior art, the present invention has the following beneficial effects: (1) The present invention provides a novel compound as shown in Formula I or a pharmaceutically acceptable salt thereof; (2) The compound of the present invention can synergistically inhibit PRMT5 with MTA, and can be used to prepare drugs for treating cancers associated with MTAP ^-/- .

下面通過具體實施方式來進一步說明本發明的技術方案。本領域技術人員應該明瞭，所述實施例僅僅是幫助理解本發明，不應視為對本發明的具體限制。The technical solution of the present invention is further described below through specific implementations. Those skilled in the art should understand that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

下列實施例中未註明具體條件的實驗方法，通常按照常規條件，或按照製造廠商所建議的條件。除非另外說明，否則百分比和份數是重量百分比和重量份數。The experimental methods without specifying specific conditions in the following examples are usually carried out under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are percentages by weight and parts by weight.

以下實施例中所用的實驗材料和試劑如無特別說明均可從市售管道獲得。Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial sources.

各實施例中， ¹H NMR由BRUKER AVANCE NEO 400 MHz型核磁共振儀記錄，化學位移以 δ(ppm) 表示；液質聯用(LCMS)由Shimadzu LC-20AD，SIL-20A，CTO-20AC，SPD-M20A，CBM-20A，LCMS-2020型質譜儀記錄；製備HPLC分離使用Gilson-281型號液相色譜儀。 In each example, ¹ H NMR was recorded by a BRUKER AVANCE NEO 400 MHz nuclear magnetic resonance instrument, and the chemical shift was expressed in δ (ppm); liquid chromatography-mass spectrometry (LCMS) was recorded by a Shimadzu LC-20AD, SIL-20A, CTO-20AC, SPD-M20A, CBM-20A, LCMS-2020 mass spectrometer; and preparative HPLC separation was performed using a Gilson-281 liquid chromatograph.

實施例Embodiment

1、中間體A的製備 1. Preparation of intermediate A

中間體A的合成路線如下所示： The synthetic route of intermediate A is as follows:

(1) 向化合物A-1(5.00 g, 22.8 mmol, 鹽酸鹽)的二氯甲烷溶液(50.0mL)中加入三乙胺(2.76 g, 27.3 mmol, 3.80 mL)，硫酸鎂(27.4 g, 228 mmol)。隨後加入苯甲醛(2.42 g, 22.8mmol, 2.30 mL)，反應液在氮氣保護下25液攪拌8小時。反應液過濾，濾液減壓濃縮得到化合物A-2。(1) Add triethylamine (2.76 g, 27.3 mmol, 3.80 mL) and magnesium sulfate (27.4 g, 228 mmol) to a dichloromethane solution (50.0 mL) of compound A-1 (5.00 g, 22.8 mmol, hydrochloride). Then add benzaldehyde (2.42 g, 22.8 mmol, 2.30 mL) and stir the reaction solution at 25 °C for 8 hours under nitrogen protection. Filter the reaction solution and concentrate the filtrate under reduced pressure to obtain compound A-2.

MS-ESI [M+H] ⁺，計算值272，實測值272。 MS-ESI [M+H] ⁺ , calcd. 272, found 272.

(2) 向化合物A-2(6.18 g, 22.8 mmol)的乙腈溶液 (60.0 mL)中加入碳酸鉀(9.45 g, 68.3 mmol)，丙烯酸甲酯(6.31 g, 73.3 mmol, 6.60 mL)。反應液在氮氣保護下25應攪拌5小時。反應液加入水(60.0 mL)，用乙酸乙酯(300 mL × 3)萃取，合併有機相用飽和食鹽水(300 mL)洗滌，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/乙酸乙酯 = 1 ：0 到 20 ：1)分離得到化合物A-3。(2) Potassium carbonate (9.45 g, 68.3 mmol) and methyl acrylate (6.31 g, 73.3 mmol, 6.60 mL) were added to an acetonitrile solution (60.0 mL) of compound A-2 (6.18 g, 22.8 mmol). The reaction solution was stirred for 5 hours at 25°C under nitrogen protection. Water (60.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (300 mL × 3). The combined organic phases were washed with saturated brine (300 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 20:1) to obtain compound A-3.

MS-ESI [M+H] ⁺，計算值358，實測值358。 MS-ESI [M+H] ⁺ , calcd. 358, found 358.

¹H NMR (400 MHz, CDCl ₃) δ8.13 (s, 1H), 7.78 (dd, J= 7.6, 1.6 Hz, 2H), 7.37-7.50 (m, 5H), 6.90-6.99 (m, 2H), 3.68 (s, 3H), 3.50 (s, 3H), 2.50-2.56 (m, 2H), 2.29-2.39 (m, 1H), 2.22 (dd, J= 10, 6.0 Hz, 1H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.13 (s, 1H), 7.78 (dd, J = 7.6, 1.6 Hz, 2H), 7.37-7.50 (m, 5H), 6.90-6.99 (m, 2H), 3.68 (s, 3H), 3.50 (s, 3H), 2.50-2.56 (m, 2H), 2.29-2.39 (m, 1H), 2.22 (dd, J = 10, 6.0 Hz, 1H).

(3) 將化合物A-3(3.39 g, 9.49 mmol)裝入反應瓶中，在氮氣保護下120保攪拌12小時。反應液減壓濃縮，粗品經矽膠柱層析法(石油醚/乙酸乙酯 = 1 ：0 到 30 ：1)分離得到化合物A。(3) Compound A-3 (3.39 g, 9.49 mmol) was placed in a reaction bottle and stirred at 120°C for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 30:1) to obtain compound A.

¹H NMR (400 MHz, CDCl ₃) δ7.37 (td, J= 8.0, 6.0 Hz, 1H), 6.99-7.23 (m, 3H), 3.78 (s, 3H), 3.04 (ddd, J= 12.4, 8.4, 6.4 Hz, 1H), 2.26-2.52 (m, 3H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37 (td, J = 8.0, 6.0 Hz, 1H), 6.99-7.23 (m, 3H), 3.78 (s, 3H), 3.04 (ddd, J = 12.4, 8.4, 6.4 Hz, 1H), 2.26-2.52 (m, 3H).

中間體A的第二種合成路線如下所示。The second synthetic route of intermediate A is shown below.

2、中間體B, C, D, F的製備2. Preparation of intermediates B, C, D, F

中間體B, C, D, D的製備參考中間體A MS-ESI [M+H] ⁺，計算值238，實測值238 MS-ESI [M+H] ⁺，計算值256，實測值256 MS-ESI [M+H] ⁺，計算值256，實測值256 MS-ESI [M+H] ⁺，計算值220，實測值220 The preparation of intermediates B, C, D, D refers to intermediate A MS-ESI [M+H] ⁺ , calcd. 238, found 238 MS-ESI [M+H] ⁺ , calculated 256, found 256 MS-ESI [M+H] ⁺ , calculated 256, found 256 MS-ESI [M+H] ⁺ , calc. 220, found 220

3、中間體G的製備 3. Preparation of intermediate G

(1) 0 下向化合物G-1(12.5 g, 87.6 mmol)的乙腈 (100 mL)溶液中，加入N-溴代丁二醯亞胺(15.6 g, 87.6 mmol)。反應液在氮氣保護下25應攪拌1小時。反應液加入水(200 mL)，用二氯甲烷(500 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/乙酸乙酯 = 1 ：0 到 4 ：1)分離得到化合物G-2。(1) Add N-bromosuccinimide (15.6 g, 87.6 mmol) to a solution of compound G-1 (12.5 g, 87.6 mmol) in acetonitrile (100 mL) at 0 °C. The reaction mixture was stirred for 1 hour at 25 °C under nitrogen. Water (200 mL) was added to the reaction mixture, which was extracted with dichloromethane (500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 4:1) to obtain compound G-2.

(2) 向化合物1-2 (9.00 g, 40.64 mmol)的二氧六環(100 mL)溶液中，加入化合物G-3(10.7 g, 121 mmol, 8.59 mL)，三乙胺(18.1 g, 178 mmol, 24.9 mL)，醋酸鈀(2.01 g, 8.94 mmol)，三苯基膦(2.13 g, 8.13 mmol)。反應液在氮氣保護下100液攪拌12小時。反應液加入氫氧化鈉水溶液(50.0 mL, 2 mol/L)，用甲基第三丁基醚(200 mL)洗滌，有機相用氫氧化鈉水溶液(30.0 mL, 2 mol/L)萃取，合併水相加入稀鹽酸酸化至棕色固體析出，過濾得到化合物G-4。(2) Compound G-3 (10.7 g, 121 mmol, 8.59 mL), triethylamine (18.1 g, 178 mmol, 24.9 mL), palladium acetate (2.01 g, 8.94 mmol), and triphenylphosphine (2.13 g, 8.13 mmol) were added to a solution of compound 1-2 (9.00 g, 40.64 mmol) in dioxane (100 mL). The reaction mixture was stirred at 100% nitrogen for 12 hours. Aqueous sodium hydroxide solution (50.0 mL, 2 mol/L) was added to the reaction solution, and the mixture was washed with methyl tert-butyl ether (200 mL). The organic phase was extracted with aqueous sodium hydroxide solution (30.0 mL, 2 mol/L). The combined aqueous phases were acidified by adding dilute hydrochloric acid until a brown solid precipitated, and the compound G-4 was obtained by filtration.

MS-ESI [M+H] ⁺，計算值211，實測值211。 MS-ESI [M+H] ⁺ , calcd. 211, found 211.

(3) 0 下向化合物G-4(15.0 g, 71.2 mmol)的甲醇(200 mL)溶液中，加入硫酸(6.99 g, 71.22 mmol, 3.80 mL)。反應液在氮氣保護下80應攪拌12小時。反應液加入水(100 mL)，用二氯甲烷(500 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/乙酸乙酯 = 1 ：0 到 4 ：1)分離得到化合物G-5。(3) Sulfuric acid (6.99 g, 71.22 mmol, 3.80 mL) was added to a solution of compound G-4 (15.0 g, 71.2 mmol) in methanol (200 mL) at 0 °C. The reaction solution was stirred at 80 °C for 12 h under nitrogen protection. Water (100 mL) was added to the reaction solution, which was extracted with dichloromethane (500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 4:1) to obtain compound G-5.

MS-ESI [M+H] ⁺，計算值225，實測值225。 MS-ESI [M+H] ⁺ , calcd. 225, found 225.

¹H NMR (400 MHz, CDCl ₃) δ8.85-9.13 (m, 1H), 7.63 (s, 1H), 3.98 (s, 3H), 2.51 (s, 3H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.85-9.13 (m, 1H), 7.63 (s, 1H), 3.98 (s, 3H), 2.51 (s, 3H).

(4) 0 下向化合物G-5(1.00 g, 4.45 mmol)的四氫呋喃(15.0 mL)溶液中，加入雙(三甲基矽烷基)胺基鉀(5.34 mL, 1 mol/L)。反應液在氮氣保護下5反攪拌0.5小時。加入2-(三甲基矽烷基)乙氧甲基氯(890 mg, 5.34 mmol, 945 μL)，繼續在氮氣保護下5氮攪拌1小時。反應液加入氯化銨水溶液(20.0 mL)，用乙酸乙酯(100 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法 (石油醚/乙酸乙酯 = 1 ：0 到 4 ：1) 分離得到化合物G-6。(4) To a solution of compound G-5 (1.00 g, 4.45 mmol) in tetrahydrofuran (15.0 mL) was added potassium bis(trimethylsilyl)amide (5.34 mL, 1 mol/L). The reaction mixture was stirred for 0.5 h under nitrogen protection. 2-(Trimethylsilyl)ethoxymethyl chloride (890 mg, 5.34 mmol, 945 μL) was added and the mixture was stirred for 1 h under nitrogen protection. An aqueous solution of ammonium chloride (20.0 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 4:1) to obtain compound G-6.

MS-ESI [M+H] ⁺，計算值355，實測值355。 MS-ESI [M+H] ⁺ , calcd. 355, found 355.

(5) 0 下向化合物G-6(1.20 g, 3.38 mmol)的二氯甲烷(25.0 mL)溶液中，加入二異丙基氫化鋁(7.44 mL, 1 mol/L)。反應液在氮氣保護下0反攪拌0.5小時。反應液加入氫氧化鈉水溶液(30.0 mL, 2 mol/L)，用二氯甲烷(100 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/乙酸乙酯 = 1 ：0 到 3 ：1)分離得到化合物G。(5) Add diisopropylaluminum hydroxide (7.44 mL, 1 mol/L) to a solution of compound G-6 (1.20 g, 3.38 mmol) in dichloromethane (25.0 mL) at 0 °C. The reaction solution was stirred for 0.5 h under nitrogen protection. Sodium hydroxide aqueous solution (30.0 mL, 2 mol/L) was added to the reaction solution, which was extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 3:1) to obtain compound G.

4、中間體H的製備 4. Preparation of intermediate H

(1) 向化合物H-1(25.0 g, 118 mmol)的二氧六環(200 mL)溶液中，加入胺基甲酸第三丁酯(15.3 g, 130.68 mmol)、碳酸銫(77.4 g, 237 mmol)、三(二亞苄基丙酮)二鈀(4.35 g, 4.75 mmol)、4,5-雙二苯基膦-9,9-二甲基氧雜蒽(4.12 g, 7.13 mmol)。反應液在氮氣保護下80應攪拌12小時，反應液過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/乙酸乙酯 = 1 ：0 到 10 ：1)分離得到化合物H-2。(1) To a solution of compound H-1 (25.0 g, 118 mmol) in dioxane (200 mL), add tert-butyl carbamate (15.3 g, 130.68 mmol), cesium carbonate (77.4 g, 237 mmol), tris(dibenzylideneacetone)dipalladium (4.35 g, 4.75 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (4.12 g, 7.13 mmol). The reaction solution was stirred at 80°C for 12 hours under nitrogen protection, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 10:1) to obtain compound H-2.

MS-ESI [M+H] ⁺，計算值247，實測值247。 MS-ESI [M+H] ⁺ , calcd. 247, found 247.

(2) 向化合物H-2(23.0 g, 93.24 mmol)的二氯甲烷 (10.0 mL)溶液中，加入三氟乙酸(15.3 g, 134 mmol, 10.0 mL)。反應液在氮氣保護下50應攪拌24小時。反應液在0時下加入碳酸鈉水溶液調節pH值到7，用乙酸乙酯(100 mL × 3)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/乙酸乙酯 = 1 ：0 到 3 ：1)分離得到化合物H-3。(2) Add trifluoroacetic acid (15.3 g, 134 mmol, 10.0 mL) to a solution of compound H-2 (23.0 g, 93.24 mmol) in dichloromethane (10.0 mL). The reaction solution was stirred at 50°C for 24 hours under nitrogen protection. At 0:0, sodium carbonate aqueous solution was added to the reaction solution to adjust the pH value to 7, and the solution was extracted with ethyl acetate (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 3:1) to obtain compound H-3.

MS-ESI [M+H] ⁺，計算值147，實測值147。 MS-ESI [M+H] ⁺ , calcd. 147, found 147.

¹H NMR (400 MHz, CDCl ₃) δ7.70 (d, J= 2.4 Hz, 1H), 6.82 (dd, J= 9.6, 2.4 Hz, 1H), 3.09-3.39 (m, 2H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70 (d, J = 2.4 Hz, 1H), 6.82 (dd, J = 9.6, 2.4 Hz, 1H), 3.09-3.39 (m, 2H).

(3) 0 下向化合物H-3(5.80 g, 39.5 mmol)的乙腈 (10.0 mL)溶液中，加入N-溴代丁二醯亞胺(7.04 g, 39.5 mmol)。反應液在氮氣保護下25應攪拌1小時。反應液加入水(20.0 mL)，用乙酸乙酯(50.0 mL × 2)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/乙酸乙酯 = 1 ：0 到 20 ：1)分離得到化合物H-4。(3) N-bromosuccinimide (7.04 g, 39.5 mmol) was added to a solution of compound H-3 (5.80 g, 39.5 mmol) in acetonitrile (10.0 mL) at 0 °C. The reaction mixture was stirred for 1 hour at 25 °C under nitrogen. Water (20.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50.0 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 20:1) to obtain compound H-4.

MS-ESI [M+H] ⁺，計算值227，實測值227。 MS-ESI [M+H] ⁺ , calcd. 227, found 227.

(4) 向化合物H-4(8.00 g, 35.4 mmol)的二氧六環(100 mL)溶液中，加入化合物丙酮酸(9.37 g, 106 mmol, 7.50 mL)，三乙胺(10.7 g, 106 mmol, 14.8 mL)，醋酸鈀(796 mg, 3.55 mmol)，三苯基膦(1.86 g, 7.10 mmol)。反應液在氮氣保護下110液攪拌12小時。反應液加入氫氧化鈉水溶液(50.0 mL, 2 mol/L)，用甲基第三丁基醚(200 mL)洗滌，有機相用氫氧化鈉水溶液(30.0 mL, 2 mol/L)萃取，合併水相加入稀鹽酸酸化至棕色固體析出，過濾得到化合物H-5。(4) To a solution of compound H-4 (8.00 g, 35.4 mmol) in dioxane (100 mL), add pyruvic acid (9.37 g, 106 mmol, 7.50 mL), triethylamine (10.7 g, 106 mmol, 14.8 mL), palladium acetate (796 mg, 3.55 mmol), and triphenylphosphine (1.86 g, 7.10 mmol). The reaction mixture was stirred at 1:10 for 12 hours under nitrogen protection. Aqueous sodium hydroxide solution (50.0 mL, 2 mol/L) was added to the reaction solution, and the mixture was washed with methyl tert-butyl ether (200 mL). The organic phase was extracted with aqueous sodium hydroxide solution (30.0 mL, 2 mol/L). The combined aqueous phases were acidified by adding dilute hydrochloric acid until a brown solid precipitated, and the mixture was filtered to obtain compound H-5.

MS-ESI [M+H] ⁺，計算值215，實測值215。 MS-ESI [M+H] ⁺ , calcd. 215, found 215.

(5) 0 下向化合物H-5(9.40 g, 43.8 mmol)的甲醇(100 mL)溶液中，加入硫酸(8.59 g, 87.6 mmol, 4.67 mL)。反應液在氮氣保護下80應攪拌12小時。反應液在0時下加入碳酸鈉水溶液調節pH值到7，隨後加入水(100 mL)，用二氯甲烷(100 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/乙酸乙酯 = 1 ：0 到 6 ：1)分離得到化合物H-6。(5) Sulfuric acid (8.59 g, 87.6 mmol, 4.67 mL) was added to a solution of compound H-5 (9.40 g, 43.8 mmol) in methanol (100 mL) at 0°C. The reaction mixture was stirred at 80°C for 12 hours under nitrogen protection. At 0°C, an aqueous sodium carbonate solution was added to the reaction mixture to adjust the pH value to 7, and then water (100 mL) was added. The mixture was extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 6:1) to obtain compound H-6.

MS-ESI [M+H] ⁺，計算值229，實測值229。 MS-ESI [M+H] ⁺ , calcd. 229, found 229.

(6) 0 下向化合物H-6(3.60 g, 15.75 mmol)的四氫呋喃(30.0 mL)溶液中，加入雙(三甲基矽烷基)胺基鉀(28.3 mL, 1 mol/L)。反應液在氮氣保護下0反攪拌0.5小時。加入2-(三甲基矽烷基)乙氧甲基氯(5.25 g, 31.5 mmol, 5.57 mL)，繼續在氮氣保護下5續攪拌1小時。反應液加入氯化銨水溶液 (50.0 mL)，用乙酸乙酯(500 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/乙酸乙酯 = 1 ：0 到 4 ：1)分離得到化合物H。(6) To a solution of compound H-6 (3.60 g, 15.75 mmol) in tetrahydrofuran (30.0 mL) was added potassium bis(trimethylsilyl)amide (28.3 mL, 1 mol/L). The reaction solution was stirred for 0.5 h under nitrogen protection. 2-(Trimethylsilyl)ethoxymethyl chloride (5.25 g, 31.5 mmol, 5.57 mL) was added and the stirring was continued for 1 h under nitrogen protection. An aqueous solution of ammonium chloride (50.0 mL) was added to the reaction solution and extracted with ethyl acetate (500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 4:1) to obtain compound H.

MS-ESI [M+H] ⁺，計算值359，實測值359。 MS-ESI [M+H] ⁺ , calcd. 359, found 359.

5、中間體I的製備5. Preparation of Intermediate I

中間體I的製備參考中間體H，最後一步使用二異丙基氘代鋁替換二異丙基氫化鋁。 MS-ESI [M+H] ⁺，計算值333，實測值333 The preparation of intermediate I is similar to that of intermediate H, except that diisopropylaluminum deuteride is used in the last step to replace diisopropylaluminum hydroxide. MS-ESI [M+H] ⁺ , calcd. 333, found 333

5、中間體J的製備5. Preparation of intermediate J

中間體J的製備參考中間體G，最後一步使用二異丙基氘代鋁替換二異丙基氫化鋁。 MS-ESI [M+H] ⁺，計算值329，實測值329 The preparation of intermediate J is similar to that of intermediate G, except that diisopropylaluminum deuteride is used in the last step to replace diisopropylaluminum hydroxide. MS-ESI [M+H] ⁺ , calcd. 329, found 329

6、中間體K的製備6. Preparation of intermediate K

中間體K的製備參考中間體G，使用5-胺基-2,3-二氯吡啶作為起始原料。 MS-ESI [M+H] ⁺，計算值347，實測值347 The preparation of intermediate K was similar to that of intermediate G, using 5-amino-2,3-dichloropyridine as the starting material. MS-ESI [M+H] ⁺ , calcd. 347, found 347

7、中間體L的製備7. Preparation of intermediate L

中間體L的製備參考中間體G，使用5-胺基-2,3-二氯吡啶作為起始原料並在最後一步使用二異丙基氘代鋁替換二異丙基氫化鋁。 MS-ESI [M+H] ⁺，計算值349，實測值349 Intermediate L was prepared by referring to Intermediate G, using 5-amino-2,3-dichloropyridine as the starting material and using diisopropylaluminum deuteride instead of diisopropylaluminum hydroxide in the last step. MS-ESI [M+H] ⁺ , calcd. 349, found 349

8、中間體M的製備 8. Preparation of intermediate M

(1) 向化合物M-1(2.00 g, 9.80 mmol)的 N,N-二甲基甲醯胺溶液(20.0 mL)中加入三乙胺(1.98 g, 19.6 mmol, 2.73 mL)，硫代乙酸甲酯(1.27 g, 11.9 mmol, 1.09 mL)。反應液在氮氣保護下100℃攪拌4小時。反應液加入水(200 mL)，過濾得到化合物M-2。 (1) Add triethylamine (1.98 g, 19.6 mmol, 2.73 mL) and methyl thioacetate (1.27 g, 11.9 mmol, 1.09 mL) to a solution of compound M-1 (2.00 g, 9.80 mmol) in N,N -dimethylformamide (20.0 mL). Stir the reaction mixture at 100°C for 4 hours under nitrogen protection. Add water (200 mL) to the reaction mixture and filter to obtain compound M-2.

MS-ESI [M+H] ⁺，計算值274，實測值274。 MS-ESI [M+H] ⁺ , calcd. 274, found 274.

¹H NMR (400 MHz, CDCl ₃) δ8.15 (s, 1H), 8.05 (d, J= 8.4 Hz, 1H), 7.52 (d, J= 8.4 Hz, 1H), 3.99 (s, 3H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.15 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 3.99 (s, 3H).

(2) 0 下向化合物M-2 (1.00 g, 3.67 mmol)的二氯甲烷(10.0 mL)溶液中，加入二異丙基氫化鋁(7.35 mL, 1 mol/L)。反應液在氮氣保護下0反攪拌1小時。反應液加入氫氧化鈉水溶液(0.35 mL, 15%)和水(10.0 mL)，用乙酸乙酯(100 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/乙酸乙酯 = 1 ：0 到 3 ：1)分離得到化合物M。 (2) Add diisopropylaluminum hydroxide (7.35 mL, 1 mol/L) to a solution of compound M-2 ( 1.00 g, 3.67 mmol) in dichloromethane (10.0 mL) at 0 °C. The reaction solution was stirred for 1 hour under nitrogen protection. Sodium hydroxide aqueous solution (0.35 mL, 15%) and water (10.0 mL) were added to the reaction solution, extracted with ethyl acetate (100 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 3:1) to obtain compound M.

MS-ESI [M+H] ⁺，計算值246，實測值246。 MS-ESI [M+H] ⁺ , calcd. 246, found 246.

9、中間體N的製備 9. Preparation of intermediate N

0℃下向化合物N-1(800 mg, 3.74 mmol)的四氫呋喃(15.0 mL)溶液中，加入硼烷四氫呋喃(11.2 mL, 1 mol/L)。反應液在氮氣保護下25℃攪拌12小時。反應液加入甲醇(15 mL)和水(10.0 mL)，用乙酸乙酯(100 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/乙酸乙酯 = 1 ：0 到 5 ：1)分離得到化合物N。Borane tetrahydrofuran (11.2 mL, 1 mol/L) was added to a solution of compound N-1 (800 mg, 3.74 mmol) in tetrahydrofuran (15.0 mL) at 0°C. The reaction solution was stirred at 25°C for 12 hours under nitrogen protection. Methanol (15 mL) and water (10.0 mL) were added to the reaction solution, extracted with ethyl acetate (100 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 5:1) to obtain compound N.

MS-ESI [M+H] ⁺，計算值200，實測值200。 MS-ESI [M+H] ⁺ , calcd. 200, found 200.

實施例1 合成化合物1 Example 1 Synthesis of Compound 1

(1)向化合物G(300 mg, 917 μmol)的二氯甲烷(10.0 mL)溶液中，加入二氯亞碸(327 mg, 2.75 mmol, 199 μL)。反應液在氮氣保護下25應攪拌1小時。反應液加入碳酸氫鈉水溶液(5.0 mL)，用二氯甲烷(50.0 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。得到化合物1-1。(1) To a solution of compound G (300 mg, 917 μmol) in dichloromethane (10.0 mL), add dichlorosulfonyl chloride (327 mg, 2.75 mmol, 199 μL). The reaction solution was stirred for 1 hour at 25 °C under nitrogen protection. A sodium bicarbonate aqueous solution (5.0 mL) was added to the reaction solution, which was extracted with dichloromethane (50.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1-1.

(2)0-下向化合物1-1(300 mg, 868 μmol)的 N,N-二甲基甲醯胺(5.0 mL)溶液中，加入碳酸銫(849 mg, 2.61 mmol)和化合物F(200 mg, 912 μmol)。反應液在氮氣保護下60℃攪拌2小時。反應液加入水(10.0 mL)，用二氯甲烷(50.0 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/乙酸乙酯 = 1 ：0 到 1 ：1)分離得到化合物1-2。 (2) To a solution of compound 1-1 (300 mg, 868 μmol) in N,N -dimethylformamide (5.0 mL) was added cesium carbonate (849 mg, 2.61 mmol) and compound F (200 mg, 912 μmol). The reaction solution was stirred at 60°C for 2 hours under nitrogen protection. Water (10.0 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 1:1) to obtain compound 1-2.

MS-ESI [M+H] ⁺，計算值530，實測值530。 MS-ESI [M+H] ⁺ , calcd. 530, found 530.

¹H NMR (400 MHz, CDCl ₃) δ7.50 (s, 1H), 7.15-7.26 (m, 5H), 6.00 (s, 1H), 5.39 (s, 2H), 4.50-4.89 (m, 2H), 3.61 (s, 3H), 3.44 (t, J= 8.0 Hz, 2H), 2.89 (ddd, J= 13.2, 7.6, 5.6 Hz, 1H), 2.55 (s, 2H), 2.46 (s, 3H), 2.33-2.43 (m, 1H), 0.85 (td, J= 8.0, 2.4 Hz, 2H), 0.06 (s, 9H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.50 (s, 1H), 7.15-7.26 (m, 5H), 6.00 (s, 1H), 5.39 (s, 2H), 4.50-4.89 (m, 2H), 3.61 (s, 3H), 3.44 (t, J = 8.0 Hz, 2H), 2.89 (ddd, J = 13.2, 7.6, 5.6 Hz, 1H), 2.55 (s, 2H), 2.46 (s, 3H), 2.33-2.43 (m, 1H), 0.85 (td, J = 8.0, 2.4 Hz, 2H), 0.06 (s, 9H).

(3) 向化合物1-2(100 mg, 189 μmol)的甲苯(2.0 mL)溶液中，加入二苯甲酮亞胺(68.6 mg, 378 μmol, 63.5 μL)，第三丁醇鈉(36.3 mg, 378 μmol)，三(二亞苄基丙酮)二鈀 (17.3 mg, 18.9 μmol)，1,1'-聯萘-2,2'-雙二苯膦(2.13 g, 8.13 mmol)，碘化鉀(157 mg, 946 μmol)。反應液在氮氣保護下120在攪拌12小時，反應液過濾，減壓濃縮。粗品經製備液相色譜法分離得到化合物1-3。(3) To a toluene (2.0 mL) solution of compound 1-2 (100 mg, 189 μmol), benzophenone imine (68.6 mg, 378 μmol, 63.5 μL), sodium tert-butoxide (36.3 mg, 378 μmol), tri(dibenzylideneacetone)dipalladium (17.3 mg, 18.9 μmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (2.13 g, 8.13 mmol), potassium iodide (157 mg, 946 μmol) were added. The reaction solution was stirred at 120°C for 12 hours under nitrogen protection, and the reaction solution was filtered and concentrated under reduced pressure. The crude product was separated by preparative liquid chromatography to obtain compound 1-3.

MS-ESI [M+H] ⁺，計算值659，實測值659。 MS-ESI [M+H] ⁺ , calcd. 659, found 659.

(4) 向化合物1-3(40.0 mg, 80.8 μmol)的二氯甲烷(3.0 mL)溶液中加入二異丙基乙基胺(31.3 mg, 242 μmol, 42.2 μL)和 N,N,Nmg,-四甲基- O-(7-氮雜苯并三唑-1-基)六氟磷酸脲(46. mg, 121 μmol)，室溫下攪拌25分鐘，隨後加入3,3-二氟氮雜環丁烷鹽酸鹽(12.5 mg, 97.0 μmol)，反應液在氮氣保護下25℃攪拌5小時。反應液加入水(10.0 mL)，用二氯甲烷(30.0 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(二氯甲烷/甲醇 = 1 ：0 到 16 ：1)分離得到化合物1-4。 (4) To a solution of compound 1-3 (40.0 mg, 80.8 μmol) in dichloromethane (3.0 mL) were added diisopropylethylamine (31.3 mg, 242 μmol, 42.2 μL) and N,N,Nmg, -tetramethyl- O- (7-azabenzotriazol-1-yl)uronium hexafluorophosphate (46. mg, 121 μmol). The mixture was stirred at room temperature for 25 min. Subsequently, 3,3-difluoroazacyclobutane hydrochloride (12.5 mg, 97.0 μmol) was added. The reaction mixture was stirred at 25°C for 5 h under nitrogen protection. Water (10.0 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane/methanol = 1:0 to 16:1) to obtain compound 1-4.

MS-ESI [M+H] ⁺，計算值570，實測值570。 MS-ESI [M+H] ⁺ , calcd. 570, found 570.

(5) 05下向化合物1-4(5.00 mg, 8.78 μmol)的二氯甲烷(1.0 mL)溶液中，加入三氟乙酸(200 μL)。反應液在氮氣保護下25應攪拌1小時。反應液加入碳酸鉀並繼續攪拌2小時。過濾，減壓濃縮。粗品經製備高效液相色譜法(Xtimate C18, 150 mm × 40 mm 10 μm, A:水(甲酸)；B:乙腈, 0%-30%：25分鐘) 分離得到化合物1的甲酸鹽。(5) Add trifluoroacetic acid (200 μL) to a solution of compound 1-4 (5.00 mg, 8.78 μmol) in dichloromethane (1.0 mL) at 0.5 °C. Stir the reaction mixture for 1 hour at 25 °C under nitrogen protection. Add potassium carbonate to the reaction mixture and continue stirring for 2 hours. Filter and concentrate under reduced pressure. The crude product was separated by preparative HPLC (Xtimate C18, 150 mm × 40 mm 10 μm, A: water (formic acid); B: acetonitrile, 0%-30%: 25 minutes) to obtain the formate salt of compound 1.

MS-ESI [M+H] ⁺，計算值440，實測值440。 MS-ESI [M+H] ⁺ , calcd. 440, found 440.

¹H NMR (400 MHz, MeOD) δ7.63 (s, 1H), 7.27-7.48 (m, 5H), 5.53 (s, 1H), 4.80 (s, 1H), 4.33-4.63 (m, 3H), 4.28 (d, J= 16.4 Hz, 1H), 3.52-3.71 (m, 1H), 2.85-2.97 (m, 1H), 2.54-2.79 (m, 3H), 2.22 (s, 3H)。 ¹ H NMR (400 MHz, MeOD) δ 7.63 (s, 1H), 7.27-7.48 (m, 5H), 5.53 (s, 1H), 4.80 (s, 1H), 4.33-4.63 (m, 3H), 4.28 (d, J = 16.4 Hz, 1H), 3.52-3.71 (m, 1H), 2.85-2.97 (m, 1H), 2.54-2.79 (m, 3H), 2.22 (s, 3H).

實施例2 合成化合物2 Example 2 Synthesis of Compound 2

合成參考實施例1，使用環丙基胺替換3,3-二氟氮雜環丁烷鹽酸鹽得到化合物2。 MS-ESI [M+H] ⁺, 計算值404, 實測值404。 Synthesize according to Reference Example 1, using cyclopropylamine to replace 3,3-difluoroazanacyclobutane hydrochloride to obtain compound 2. MS-ESI [M+H] ⁺ , calculated value 404, found value 404.

¹H NMR (400 MHz, MeOD) δ7.31-7.34 (m, 6H), 5.58 (s, 1H), 4.38-4.56 (m, 2H), 2.63-2.73 (m, 3H), 2.54-2.56 (m, 2H), 2.20 (s, 3H) , 0.63-0.68 (m, 2H), 0.34-0.38 (m, 2H)。 ¹ H NMR (400 MHz, MeOD) δ 7.31-7.34 (m, 6H), 5.58 (s, 1H), 4.38-4.56 (m, 2H), 2.63-2.73 (m, 3H), 2.54-2.56 (m, 2H), 2.20 (s, 3H) , 0.63-0.68 (m, 2H), 0.34-0.38 (m, 2H).

實施例3 合成化合物3 Example 3 Synthesis of Compound 3

合成參考實施例1，使用中間體A替換化合物1-9得到化合物3。MS-ESI [M+H] ⁺，計算值458，實測值458。 Synthesize Reference Example 1, use Intermediate A to replace Compound 1-9 to obtain Compound 3. MS-ESI [M+H] ⁺ , calculated value 458, found value 458.

¹H NMR (400 MHz, MeOD) δ7.54 (s, 1H), 7.35-7.37 (m, 1H), 7.16-7.24 (m, 2H), 7.03-7.04 (m, 1H), 5.55 (s, 1H), 4.28-4.57 (m, 5H), 3.71-3.72 (m, 1H), 2.59-2.87 (m, 4H), 2.22 (s, 3H)。 ¹ H NMR (400 MHz, MeOD) δ 7.54 (s, 1H), 7.35-7.37 (m, 1H), 7.16-7.24 (m, 2H), 7.03-7.04 (m, 1H), 5.55 (s, 1H), 4.28-4.57 (m, 5H), 3.71-3.72 (m, 1H), 2.59-2.87 (m, 4H), 2.22 (s, 3H).

實施例4 合成化合物4 Example 4 Synthesis of Compound 4

(1)化合物1-1的合成參考實施例1，0 下向化合物1-1(809 mg, 2.11 mmol)的 N,N-二甲基甲醯胺(15.0 mL)溶液中，加入碳酸銫(2.06 g, 6.32 mmol)和化合物A(500 mg, 2.11 mmol)。反應液在氮氣保護下60應攪拌2小時。反應液加入水(10.0 mL)，用乙酸乙酯(30.0 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/乙酸乙酯 = 1 ：0 到 4 ：1)分離得到化合物4-1。 (1) Synthesis of Compound 1-1 Referring to Example 1, 0 Cs carbonate (2.06 g, 6.32 mmol) and Compound A (500 mg, 2.11 mmol) were added to a solution of Compound 1-1 (809 mg, 2.11 mmol) in N,N -dimethylformamide (15.0 mL). The reaction solution was stirred at 60°C for 2 hours under nitrogen protection. Water (10.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30.0 mL). The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 4:1) to obtain Compound 4-1.

MS-ESI [M+H] ⁺，計算值546，實測值546。 MS-ESI [M+H] ⁺ , calcd. 546, found 546.

(2)向化合物4-1(500 mg, 590 μmol)的甲苯(10.0 mL)溶液中，加入對甲氧基苄胺(162 mg, 1.18 mmol)，碳酸銫(384 mg, 1.18 mmol)，三(二亞苄基丙酮)二鈀(54.0 mg, 59.0 μmol)，1,1'-聯萘-2,2'-雙二苯膦(73.4 mg, 118 μmol)。反應液在氮氣保護下120在攪拌12小時，反應液過濾，減壓濃縮。加入水(10.0 mL)，用乙酸乙酯(30.0 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/乙酸乙酯 = 1 ：0 到 3 ：1)分離得到化合物4-2。(2) Add p-methoxybenzylamine (162 mg, 1.18 mmol), cesium carbonate (384 mg, 1.18 mmol), tris(dibenzylideneacetone)dipalladium (54.0 mg, 59.0 μmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (73.4 mg, 118 μmol) to a toluene (10.0 mL) solution of compound 4-1 (500 mg, 590 μmol). Stir the reaction solution at 120°C for 12 hours under nitrogen protection, filter the reaction solution, and concentrate under reduced pressure. Add water (10.0 mL), extract with ethyl acetate (30.0 mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 3:1) to obtain compound 4-2.

MS-ESI [M+H] ⁺，計算值647，實測值647。 MS-ESI [M+H] ⁺ , calcd. 647, found 647.

(3)向化合物4-2(353 mg, 546 μmol)的四氫呋喃(2.00 mL)溶液中加入水(0.5 mL)，甲醇(1.00 mL)和一水合氫氧化鋰(183 mg, 4.37 mmol)，反應液在25液下攪拌8小時。反應液減壓濃縮，加入水(5.0 mL)，用稀鹽酸調節pH值到3-4，用二氯甲烷(30.0 mL)萃取。有機相用無水硫酸鈉乾燥，過濾，減壓濃縮得到化合物4-3。(3) Water (0.5 mL), methanol (1.00 mL) and lithium hydroxide monohydrate (183 mg, 4.37 mmol) were added to a solution of compound 4-2 (353 mg, 546 μmol) in tetrahydrofuran (2.00 mL), and the reaction solution was stirred at 25°C for 8 hours. The reaction solution was concentrated under reduced pressure, water (5.0 mL) was added, the pH value was adjusted to 3-4 with dilute hydrochloric acid, and extracted with dichloromethane (30.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 4-3.

MS-ESI [M+H] ⁺，計算值633，實測值633。 MS-ESI [M+H] ⁺ , calcd. 633, found 633.

(4)向化合物4-4(633 mg, 4.74 mmol, 鹽酸鹽)的吡啶(4.0 mL)溶液中加入化合物4-3(300 mg, 474 μmol)和 N,N,Ng, ′,-四甲基- O-(7-氮雜苯并三唑-1-基)六氟磷酸脲(270 mg, 711 μmol)，反應液在氮氣保護下25液攪拌12小時。反應液加入水(20.0 mL)，用乙酸乙酯(50.0 mL)萃取。有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(二氯甲烷/甲醇 = 1 ：0 到 0 ：1)分離得到化合物4-5。 (4) Compound 4-3 (300 mg, 474 μmol) and N,N,Ng, ′, -tetramethyl- O- (7-azabenzotriazol-1-yl)uronium hexafluorophosphate (270 mg, 711 μmol) were added to a solution of compound 4-4 (633 mg, 4.74 mmol, hydrochloride) in pyridine (4.0 mL), and the reaction solution was stirred at 25 °C for 12 hours under nitrogen protection. Water (20.0 mL) was added to the reaction solution, and it was extracted with ethyl acetate (50.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane/methanol = 1:0 to 0:1) to obtain compound 4-5.

(5)05下向化合物4-5(50.0 mg, 70.2 μmol)中，加入三氟乙酸(1.0 mL)。反應液在氮氣保護下25應攪拌2小時。減壓濃縮後加入甲醇(1.00 mL)和氨水(910 mg, 7.79 mmol, 1.00 mL, 30%)並繼續攪拌4小時。反應液加入水(10.0 mL)，用乙酸乙酯(20.0 mL)萃取。有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經製備高效液相色譜法(Xtimate C18, 150 mm × 40 mm 10 μm, A:水(甲酸)；B:乙腈, 0%-38%：25分鐘)分離得到化合物4的甲酸鹽。(5) Trifluoroacetic acid (1.0 mL) was added to compound 4-5 (50.0 mg, 70.2 μmol) at 0.5 °C. The reaction mixture was stirred for 2 h at 25 °C under nitrogen protection. After concentration under reduced pressure, methanol (1.00 mL) and aqueous ammonia (910 mg, 7.79 mmol, 1.00 mL, 30%) were added and stirring continued for 4 h. Water (10.0 mL) was added to the reaction mixture and extracted with ethyl acetate (20.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative HPLC (Xtimate C18, 150 mm × 40 mm 10 μm, A: water (formic acid); B: acetonitrile, 0%-38%: 25 min) to obtain the formate salt of compound 4.

MS-ESI [M+H] ⁺，計算值462，實測值462。 MS-ESI [M+H] ⁺ , calcd. 462, found 462.

(6) 化合物4的甲酸鹽經掌性超臨界流體色譜法拆分得到化合物4-P1和4-P2。(6) The formate salt of compound 4 was separated by chiral supercritical fluid chromatography to give compounds 4-P1 and 4-P2.

分離條件：色譜柱型號：CHIRALPAK IG；色譜柱規格：250 × 30 mm I.D., 10 μm；進樣量：10.0 μL；流動相：A：二氧化碳, B：乙醇 (0.1% 氨水), B%：50%洗提3.5分鐘；檢測波長：254 nm；柱溫：35℃。Separation conditions: chromatographic column model: CHIRALPAK IG; chromatographic column specifications: 250 × 30 mm I.D., 10 μm; injection volume: 10.0 μL; mobile phase: A: carbon dioxide, B: ethanol (0.1% ammonia water), B%: 50% elution for 3.5 minutes; detection wavelength: 254 nm; column temperature: 35°C.

化合物4-P1滯留時間1.481分鐘，ee值100%。The retention time of compound 4-P1 was 1.481 minutes and the ee value was 100%.

¹H NMR (400 MHz, MeOD) δ7.22-7.42 (m, 1H), 7.32 (td, J= 8.0, 6.0 Hz, 1H), 7.16 (dd, J= 8.0, 0.8 Hz, 1H), 7.10 (dt, J= 10.4, 2.0 Hz, 1H), 7.01 (td, J= 8.0, 2.4 Hz, 1H), 5.51 (s, 1H), 4.78 (br d, J= 16.1 Hz, 1H), 4.29 (d, J= 16.1 Hz, 1H), 4.02 (s, 2H), 3.88 (d, J= 9.6 Hz, 1H), 3.20 (br d, J= 9.6 Hz, 1H), 2.65-2.79 (m, 2H), 2.52-2.63 (m, 2H), 2.20 (s, 3H), 1.97-2.16 (m, 4H), 1.70-1.83 (m, 2H)。 ¹ H NMR (400 MHz, MeOD) δ 7.22-7.42 (m, 1H), 7.32 (td, J = 8.0, 6.0 Hz, 1H), 7.16 (dd, J = 8.0, 0.8 Hz, 1H), 7.10 (dt, J = 10.4, 2.0 Hz, 1H), 7.01 (td, J = 8.0, 2.4 Hz, 1H), 5.51 (s, 1H), 4.78 (br d, J = 16.1 Hz, 1H), 4.29 (d, J = 16.1 Hz, 1H), 4.02 (s, 2H), 3.88 (d, J = 9.6 Hz, 1H), 3.20 (br d, J = 9.6 Hz, 1H), 2.65-2.79 (m, 2H), 2.52-2.63 (m, 2H), 2.20 (s, 3H), 1.97-2.16 (m, 4H), 1.70-1.83 (m, 2H).

化合物4-P2滯留時間2.059分鐘，ee值100%。The retention time of compound 4-P2 was 2.059 minutes and the ee value was 100%.

¹H NMR (400 MHz, MeOD) δ7.28-7.35 (m, 2H), 7.15 (d, J= 8.0 Hz, 1H), 7.09 (dt, J= 10.0, 2.0 Hz, 1H), 6.97-7.04 (m, 1H), 5.45 (s, 1H), 4.74 (s, 1H), 4.29 (d, J= 16.0 Hz, 1H), 4.01 (s, 2H), 3.85 (br d, J= 9.6 Hz, 1H), 3.41 (d, J= 9.6 Hz, 1H), 2.64-2.79 (m, 2H), 2.54-2.62 (m, 2H), 2.18 (s, 3H), 1.99 (br s, 4H), 1.65-1.83 (m, 2H)。 ¹ H NMR (400 MHz, MeOD) δ 7.28-7.35 (m, 2H), 7.15 (d, J = 8.0 Hz, 1H), 7.09 (dt, J = 10.0, 2.0 Hz, 1H), 6.97-7.04 (m, 1H), 5.45 (s, 1H), 4.74 (s, 1H), 4.29 (d, J = 16.0 Hz, 1H), 4.01 (s, 2H), 3.85 (br d, J = 9.6 Hz, 1H), 3.41 (d, J = 9.6 Hz, 1H), 2.64-2.79 (m, 2H), 2.54-2.62 (m, 2H), 2.18 (s, 3H), 1.99 (br s, 4H), 1.65-1.83 (m, 2H).

實施例5-23 合成化合物5-23Example 5-23 Synthesis of Compound 5-23

化合物5-23的製備參考實施例4，使用對應的胺替換4-4，使用化合物1-9替換中間體A，並且不進行掌性拆分。 MS-ESI [M+H] ⁺，計算值447，實測值447。 ¹H NMR (400 MHz, MeOD) δ7.38-7.40 (m, 2H), 7.33-7.34 (m, 3H), 7.32 (s, 1H), 5.36 (d, J= 3.2 Hz, 1H), 4.72-4.74 (m, 1H), 3.85-4.25 (m, 4H), 3.27-3.46 (m, 1H), 3.00-3.03 (m, 1H), 2.81-2.84 (m, 1H), 2.50-2.65 (m, 3H), 2.17 (s, 3H), 2.11 (s, 3H), 2.06 (s, 3H)。 MS-ESI [M+H] ⁺，計算值482，實測值482。 ¹H NMR (400 MHz, MeOD) δ7.65-7.66 (m, 1H), 7.30-7.43 (m, 5H), 5.55 (d, J= 10.8 Hz, 1H), 4.72-4.74 (m, 1H), 4.08-4.38 (m, 5H), 3.66-3.67 (m, 1H), 2.87-2.93 (m, 4H), 2.57-2.70 (m, 3H), 2.22 (s, 3H)。 MS-ESI [M+H] ⁺，計算值418，實測值418。 ¹H NMR (400 MHz, MeOD) δ7.26-7.29 (m, 6H), 5.18 (s, 1H), 4.02-4.06 (m, 1H), 2.86-3.00 (m, 1H), 2.47-2.74 (m, 8H), 2.22 (s, 3H), 0.70-0.88 (m, 4H)。 MS-ESI [M+H] ⁺，計算值472，實測值472。 ¹H NMR (400 MHz, MeOD) δ7.32-7.41 (m, 5H), 7.26 (s, 1H), 5.33-5.39 (m, 1H), 4.73-4.77 (m, 2H), 4.10-4.31 (m, 4H), 3.60-3.72 (m, 1H), 2.54-2.88 (m, 4H), 2.17 (s, 3H)。 MS-ESI [M+H] ⁺，計算值444，實測值444。 ¹H NMR (400 MHz, MeOD) δ7.47 (s, 1H), 7.31-7.35 (m, 5H), 5.46 (s, 1H), 4.73-4.77 (m, 2H), 4.23-4.27 (m, 2H), 4.02 (s, 1H), 3.86-3.89 (m, 1H), 2.55-2.83 (m, 4H), 2.20 (s, 3H), 1.72-2.14 (m, 6H)。 MS-ESI [M+H] ⁺，計算值434，實測值434。 ¹H NMR (400 MHz, MeOD) δ7.65 (s, 1H), 7.30-7.40 (m, 5H), 5.54 (s, 1H), 4.75-4.77 (m, 2H), 4.22-4.27 (m, 2H), 4.09-4.23 (m, 1H), 3.51-3.92 (m, 2H), 3.18-3.22 (m, 3H), 2.58-2.88 (m, 4H), 2.23 (s, 3H)。 MS-ESI [M+H] ⁺，計算值448，實測值448。 ¹H NMR (400 MHz, MeOD) δ7.64 (s, 1H), 7.34-7.40 (m, 5H), 5.54 (s, 1H), 4.75-4.77 (m, 2H), 4.23-4.27 (m, 2H), 4.01-4.03 (m, 1H), 3.68-3.92 (m, 2H), 3.11-3.18 (m, 3H), 2.57-2.89 (m, 4H), 2.22 (s, 3H), 1.31-1.41 (m, 3H)。 MS-ESI [M+H] ⁺，計算值433，實測值433。 ¹H NMR (400 MHz, MeOD) δ7.31-7.41 (m, 5H), 7.26 (s, 1H), 5.32-5.34 (m, 1H), 4.73-4.75 (m, 1H), 4.18-4.23 (m, 1H), 3.70-3.93 (m, 3H), 3.13-3.15 (m, 1H), 2.55-2.67 (m, 4H), 2.23 (s, 3H), 1.32-1.32 (m, 3H)。 MS-ESI [M+H] ⁺，計算值418，實測值418。 ¹H NMR (400 MHz, MeOD) δ7.56 (s, 1H), 7.30-7.34 (m, 5H), 5.66 (s, 1H), 4.31-4.39 (m, 2H), 2.71-2.75 (m, 2H), 2.52-2.59 (m, 2H), 2.20-2.28 (m, 6H), 1.60-1.95 (m, 4H)。 MS-ESI [M+H] ⁺，計算值454，實測值454。 ¹H NMR (400 MHz, MeOD) δ7.43 (s, 1H), 7.31-7.40 (m, 5H), 5.32 (s, 1H), 3.84-4.16 (m, 3H), 3.40-3.62 (m, 2H), 4.01-4.03 (m, 1H), 3.01-3.02 (m, 2H), 2.54-2.74 (m, 3H), 2.12-2.38 (m, 4H) MS-ESI [M+H] ⁺，計算值462，實測值462。 ¹H NMR (400 MHz, MeOD) δ7.29-7.36 (m, 6H), 5.18 (s, 1H), 4.00-4.12 (m, 2H), 3.40-3.44 (m, 2H), 3.00-3.13 (m, 3H), 2.68-2.72 (m, 2H), 2.53-2.55 (m, 2H), 2.17 (s, 3H), 2.04 (m, 3H), 1.94-2.02 (m, 1H), 1.58-1.62 (m, 2H), 1.18-1.29 (m, 1H)。 MS-ESI [M+H] ⁺，計算值461，實測值461。 ¹H NMR (400 MHz, MeOD) δ7.28-7.38 (m, 6H), 5.33-5.37 (m, 1H), 4.73-4.88 (m, 2H), 3.94-4.41 (m, 5H), 3.60-3.74 (m, 1H), 2.55-2.86 (m, 4H), 2.17 (s, 3H), 1.90 (s, 3H)。 MS-ESI [M+H] ⁺，計算值418，實測值418。 ¹H NMR (400 MHz, MeOD) δ7.31-7.38 (m, 5H), 7.27 (s, 1H), 5.33 (s, 1H), 4.50-4.76 (m, 3H), 4.20-4.24 (m, 1H), 3.87-3.93 (m, 1H), 2.52-2.83 (m, 4H), 2.25-2.33 (m, 1H), 2.17 (s, 3H), 1.76-1.79 (m, 1H), 1.49-1.50 (m, 3H)。 MS-ESI [M+H] ⁺，計算值448，實測值448。 ¹H NMR (400 MHz, MeOD) δ7.25-7.37 (m, 6H), 5.20-5.24 (m, 1H), 3.95-4.12 (m, 2H), 3.64-3.83 (m, 3H), 2.90-3.31 (m, 5H), 2.54-2.75 (m, 3H), 2.17 (s, 3H), 1.64-1.89 (m, 2H), 1.44-1.68 (m, 1H)。 MS-ESI [M+H] ⁺，計算值432，實測值432。 ¹H NMR (400 MHz, MeOD) δ7.53 (s, 1H), 7.28-7.30 (m, 5H), 5.32 (s, 1H), 3.95-4.04 (m, 2H), 3.06-3.08 (m, 4H), 2.72-2.82 (m, 1H), 2.48-2.58 (m, 3H), 2.21-2.31 (m, 7H), 1.57-1.77 (m, 2H)。 MS-ESI [M+H] ⁺，計算值468，實測值468。 ¹H NMR (400 MHz, CDCl ₃) δ7.23-7.45 (m, 6H), 5.16 (s, 1H), 4.70-4.74 (m, 2H), 3.77-4.10 (m, 3H), 3.11-3.49 (m, 3H), 2.87-2.90 (m, 1H), 2.61-2.67 (m, 2H), 2.41-2.48 (m, 1H), 2.19 (s, 3H) , 2.07-2.09 (m, 2H)。 MS-ESI [M+H] ⁺，計算值462，實測值462。 ¹H NMR (400 MHz, MeOD) δ7.26-7.44 (m, 6H), 5.15 (s, 1H), 3.97-4.43 (m, 2H), 3.31-3.41 (m, 4H), 3.00-3.13 (m, 3H), 2.53-2.86 (m, 5H), 2.17 (s, 3H), 1.07-1.83 (m, 4H)。 MS-ESI [M+H] ⁺，計算值446，實測值446。 ¹H NMR (400 MHz, MeOD) δ7.50 (s, 1H),7.28-7.43 (m, 5H), 5.31 (s, 1H), 4.03-4.41 (m, 2H), 4.49-4.60 (m, 2H), 2.97-3.02 (m, 2H), 2.72-2.77 (m, 2H), 2.50-2.59 (m, 5H), 2.17 (s, 3H), 1.75-2.00 (m, 6H)。 MS-ESI [M+H] ⁺，計算值468，實測值468。 ¹H NMR (400 MHz, MeOD) δ7.59 (s, 1H), 7.29-7.37 (m, 5H), 5.38 (s, 1H), 4.05-4.27 (m, 2H), 3.66-3.76 (m, 2H), 3.09 (s, 3H), 2.73-2.76 (m, 1H), 2.56-2.58 (m, 2H), 2.17 (s, 3H), 1.96-1.97 (m, 2H), 1.43 (s, 2H)。 The preparation of compound 5-23 was carried out according to Example 4, using the corresponding amine to replace 4-4, using compound 1-9 to replace intermediate A, and not performing chiral resolution. MS-ESI [M+H] ⁺ , calcd. 447, found 447. ¹ H NMR (400 MHz, MeOD) δ 7.38-7.40 (m, 2H), 7.33-7.34 (m, 3H), 7.32 (s, 1H), 5.36 (d, J = 3.2 Hz, 1H), 4.72-4.74 (m, 1H), 3.85-4.25 (m, 4H), 3.27-3.46 (m, 1H), 3.00-3.03 (m, 1H), 2.81-2.84 (m, 1H), 2.50-2.65 (m, 3H), 2.17 (s, 3H), 2.11 (s, 3H), 2.06 (s, 3H). MS-ESI [M+H] ⁺ , calcd. 482, found 482. ¹ H NMR (400 MHz, MeOD) δ 7.65-7.66 (m, 1H), 7.30-7.43 (m, 5H), 5.55 (d, J = 10.8 Hz, 1H), 4.72-4.74 (m, 1H), 4.08-4.38 (m, 5H), 3.66-3.67 (m, 1H), 2.87-2.93 (m, 4H), 2.57-2.70 (m, 3H), 2.22 (s, 3H). MS-ESI [M+H] ⁺ , calcd. 418, found 418. ¹ H NMR (400 MHz, MeOD) δ 7.26-7.29 (m, 6H), 5.18 (s, 1H), 4.02-4.06 (m, 1H), 2.86-3.00 (m, 1H), 2.47-2.74 (m, 8H), 2.22 (s, 3H), 0.70-0.88 (m, 4H). MS-ESI [M+H] ⁺ , calcd. 472, found 472. ¹ H NMR (400 MHz, MeOD) δ 7.32-7.41 (m, 5H), 7.26 (s, 1H), 5.33-5.39 (m, 1H), 4.73-4.77 (m, 2H), 4.10-4.31 (m, 4H), 3.60-3.72 (m, 1H), 2.54-2.88 (m, 4H), 2.17 (s, 3H). MS-ESI [M+H] ⁺ , calcd. 444, found 444. ¹ H NMR (400 MHz, MeOD) δ 7.47 (s, 1H), 7.31-7.35 (m, 5H), 5.46 (s, 1H), 4.73-4.77 (m, 2H), 4.23-4.27 (m, 2H), 4.02 (s, 1H), 3.86-3.89 (m, 1H), 2.55-2.83 (m, 4H), 2.20 (s, 3H), 1.72-2.14 (m, 6H). MS-ESI [M+H] ⁺ , calcd. 434, found 434. ¹ H NMR (400 MHz, MeOD) δ 7.65 (s, 1H), 7.30-7.40 (m, 5H), 5.54 (s, 1H), 4.75-4.77 (m, 2H), 4.22-4.27 (m, 2H), 4.09-4.23 (m, 1H), 3.51-3.92 (m, 2H), 3.18-3.22 (m, 3H), 2.58-2.88 (m, 4H), 2.23 (s, 3H). MS-ESI [M+H] ⁺ , calcd. 448, found 448. ¹ H NMR (400 MHz, MeOD) δ 7.64 (s, 1H), 7.34-7.40 (m, 5H), 5.54 (s, 1H), 4.75-4.77 (m, 2H), 4.23-4.27 (m, 2H), 4.01-4.03 (m, 1H), 3.68-3.92 (m, 2H), 3.11-3.18 (m, 3H), 2.57-2.89 (m, 4H), 2.22 (s, 3H), 1.31-1.41 (m, 3H). MS-ESI [M+H] ⁺ , calcd. 433, found 433. ¹ H NMR (400 MHz, MeOD) δ 7.31-7.41 (m, 5H), 7.26 (s, 1H), 5.32-5.34 (m, 1H), 4.73-4.75 (m, 1H), 4.18-4.23 (m, 1H), 3.70-3.93 (m, 3H), 3.13-3.15 (m, 1H), 2.55-2.67 (m, 4H), 2.23 (s, 3H), 1.32-1.32 (m, 3H). MS-ESI [M+H] ⁺ , calcd. 418, found 418. ¹ H NMR (400 MHz, MeOD) δ 7.56 (s, 1H), 7.30-7.34 (m, 5H), 5.66 (s, 1H), 4.31-4.39 (m, 2H), 2.71-2.75 (m, 2H), 2.52-2.59 (m, 2H), 2.20-2.28 (m, 6H), 1.60-1.95 (m, 4H). MS-ESI [M+H] ⁺ , calcd. 454, found 454. ¹ H NMR (400 MHz, MeOD) δ 7.43 (s, 1H), 7.31-7.40 (m, 5H), 5.32 (s, 1H), 3.84-4.16 (m, 3H), 3.40-3.62 (m, 2H), 4.01-4.03 (m, 1H), 3.01-3.02 (m, 2H), 2.54-2.74 (m, 3H), 2.12-2.38 (m, 4H) MS-ESI [M+H] ⁺ , calcd. 462, found 462. ¹ H NMR (400 MHz, MeOD) δ 7.29-7.36 (m, 6H), 5.18 (s, 1H), 4.00-4.12 (m, 2H), 3.40-3.44 (m, 2H), 3.00-3.13 (m, 3H), 2.68-2.72 (m, 2H), 2.53-2.55 (m, 2H), 2.17 (s, 3H), 2.04 (m, 3H), 1.94-2.02 (m, 1H), 1.58-1.62 (m, 2H), 1.18-1.29 (m, 1H). MS-ESI [M+H] ⁺ , calcd. 461 , found 461 . ¹ H NMR (400 MHz, MeOD) δ 7.28-7.38 (m, 6H), 5.33-5.37 (m, 1H), 4.73-4.88 (m, 2H), 3.94-4.41 (m, 5H), 3.60-3.74 (m, 1H), 2.55-2.86 (m, 4H), 2.17 (s, 3H), 1.90 (s, 3H). MS-ESI [M+H] ⁺ , calcd. 418, found 418. ¹ H NMR (400 MHz, MeOD) δ 7.31-7.38 (m, 5H), 7.27 (s, 1H), 5.33 (s, 1H), 4.50-4.76 (m, 3H), 4.20-4.24 (m, 1H), 3.87-3.93 (m, 1H), 2.52-2.83 (m, 4H), 2.25-2.33 (m, 1H), 2.17 (s, 3H), 1.76-1.79 (m, 1H), 1.49-1.50 (m, 3H). MS-ESI [M+H] ⁺ , calcd. 448, found 448. ¹ H NMR (400 MHz, MeOD) δ 7.25-7.37 (m, 6H), 5.20-5.24 (m, 1H), 3.95-4.12 (m, 2H), 3.64-3.83 (m, 3H), 2.90-3.31 (m, 5H), 2.54-2.75 (m, 3H), 2.17 (s, 3H), 1.64-1.89 (m, 2H), 1.44-1.68 (m, 1H). MS-ESI [M+H] ⁺ , calcd. 432, found 432. ¹ H NMR (400 MHz, MeOD) δ 7.53 (s, 1H), 7.28-7.30 (m, 5H), 5.32 (s, 1H), 3.95-4.04 (m, 2H), 3.06-3.08 (m, 4H), 2.72-2.82 (m, 1H), 2.48-2.58 (m, 3H), 2.21-2.31 (m, 7H), 1.57-1.77 (m, 2H). MS-ESI [M+H] ⁺ , calcd. 468, found 468. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.23-7.45 (m, 6H), 5.16 (s, 1H), 4.70-4.74 (m, 2H), 3.77-4.10 (m, 3H), 3.11-3.49 (m, 3H), 2.87-2.90 (m, 1H), 2.61-2.67 (m, 2H), 2.41-2.48 (m, 1H), 2.19 (s, 3H), 2.07-2.09 (m, 2H). MS-ESI [M+H] ⁺ , calcd. 462, found 462. ¹ H NMR (400 MHz, MeOD) δ 7.26-7.44 (m, 6H), 5.15 (s, 1H), 3.97-4.43 (m, 2H), 3.31-3.41 (m, 4H), 3.00-3.13 (m, 3H), 2.53-2.86 (m, 5H), 2.17 (s, 3H), 1.07-1.83 (m, 4H). MS-ESI [M+H] ⁺ , calcd. 446, found 446. ¹ H NMR (400 MHz, MeOD) δ 7.50 (s, 1H),7.28-7.43 (m, 5H), 5.31 (s, 1H), 4.03-4.41 (m, 2H), 4.49-4.60 (m, 2H), 2.97-3.02 (m, 2H), 2.72-2.77 (m, 2H), 2.50-2.59 (m, 5H), 2.17 (s, 3H), 1.75-2.00 (m, 6H). MS-ESI [M+H] ⁺ , calcd. 468, found 468. ¹ H NMR (400 MHz, MeOD) δ 7.59 (s, 1H), 7.29-7.37 (m, 5H), 5.38 (s, 1H), 4.05-4.27 (m, 2H), 3.66-3.76 (m, 2H), 3.09 (s, 3H), 2.73-2.76 (m, 1H), 2.56-2.58 (m, 2H), 2.17 (s, 3H), 1.96-1.97 (m, 2H), 1.43 (s, 2H).

實施例24 化合物24的合成 Example 24 Synthesis of Compound 24

合成參考實施例4，使用中間體C替換化合物A得到化合物24。MS-ESI [M+H] ⁺，計算值476，實測值476。 Synthesize Reference Example 4, use Intermediate C to replace Compound A to obtain Compound 24. MS-ESI [M+H] ⁺ , calculated value 476, found value 476.

¹H NMR (400 MHz, MeOD) δ7.61 (s, 1H), 7.33-7.38 (m, 1H), 7.19-7.24 (m, 2H), 5.61 (s, 1H), 4.44-4.48 (m, 4H), 4.27 (d, J= 16.4 Hz, 1H), 3.66 (s, 1H), 2.59-2.81 (m, 4H), 2.24 (s, 3H)。 ¹ H NMR (400 MHz, MeOD) δ 7.61 (s, 1H), 7.33-7.38 (m, 1H), 7.19-7.24 (m, 2H), 5.61 (s, 1H), 4.44-4.48 (m, 4H), 4.27 (d, J = 16.4 Hz, 1H), 3.66 (s, 1H), 2.59-2.81 (m, 4H), 2.24 (s, 3H).

實施例25 化合物25的合成 Example 25 Synthesis of Compound 25

合成參考實施例4，使用中間體B替換化合物A得到化合物25。 MS-ESI [M+H] ⁺，計算值458，實測值458。 Synthesize Reference Example 4, use intermediate B to replace compound A to obtain compound 25. MS-ESI [M+H] ⁺ , calculated value 458, found value 458.

¹H NMR (400 MHz, MeOD) δ7.34-7.37 (m, 2H), 7.28 (s, 1H), 7.18-7.20 (m, 1H), 7.00-7.03 (m, 1H), 5.57 (s, 1H), 4.55-4.79 (m, 2H), 4.23-4.29 (m, 3H), 3.80-3.90 (m, 1H), 2.61-2.77 (m, 4H), 2.17 (s, 3H)。 ¹ H NMR (400 MHz, MeOD) δ 7.34-7.37 (m, 2H), 7.28 (s, 1H), 7.18-7.20 (m, 1H), 7.00-7.03 (m, 1H), 5.57 (s, 1H), 4.55-4.79 (m, 2H), 4.23-4.29 (m, 3H), 3.80-3.90 (m, 1H), 2.61-2.77 (m, 4H), 2.17 (s, 3H).

實施例26 化合物26的合成 Example 26 Synthesis of Compound 26

合成參考實施例4，使用中間體D替換化合物A得到化合物25。MS-ESI [M+H] ⁺，計算值476，實測值476。 Synthesize Reference Example 4, use Intermediate D to replace Compound A to obtain Compound 25. MS-ESI [M+H] ⁺ , calculated value: 476, found value: 476.

¹H NMR (400 MHz, MeOD) δ7.61 (s, 1H), 7.05-7.08 (m, 2H), 6.85-6.89 (m, 1H), 5.68 (s, 1H), 4.86-4.93 (m, 1H), 4.2-4.48 (m, 4H), 3.81-3.84 (s, 1H), 2.60-2.81 (m, 4H), 2.17 (s, 3H)。 ¹ H NMR (400 MHz, MeOD) δ 7.61 (s, 1H), 7.05-7.08 (m, 2H), 6.85-6.89 (m, 1H), 5.68 (s, 1H), 4.86-4.93 (m, 1H), 4.2-4.48 (m, 4H), 3.81-3.84 (s, 1H), 2.60-2.81 (m, 4H), 2.17 (s, 3H).

實施例27 合成化合物1-P1和化合物1-P2 Example 27 Synthesis of Compound 1-P1 and Compound 1-P2

化合物1經掌性超臨界流體色譜法拆分得到化合物1-P1和1-P2。Compound 1 was separated by chiral supercritical fluid chromatography to give compounds 1-P1 and 1-P2.

分離條件：色譜柱型號：Chiralpak IH-3；色譜柱規格：50 × 4.6mm I.D.，3 μm；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇 (0.05% 二乙胺)，B%：20%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，20%固定濃度洗提1分鐘；檢測波長：254 nm；柱溫：40℃。Separation conditions: chromatographic column model: Chiralpak IH-3; chromatographic column specifications: 50 × 4.6mm I.D., 3 μm; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 20%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 20% fixed concentration elution for 1 minute; detection wavelength: 254 nm; column temperature: 40°C.

化合物1-P1滯留時間0.934分鐘，ee值99.628%。The retention time of compound 1-P1 was 0.934 min and the ee value was 99.628%.

¹H NMR (400 MHz, MeOD) δ7.40-7.42 (m, 2H), 7.34-7.36 (m, 3H), 7.27 (s, 1H), 5.35 (s, 1H), 4.58-4.67 (m, 2H), 4.41-4.44 (m, 2H), 4.26 (d, J= 8.0 Hz, 1H), 3.66 (s, 1H), 2.57-2.89 (m, 4H), 2.17 (s, 3H)。 ¹ H NMR (400 MHz, MeOD) δ 7.40-7.42 (m, 2H), 7.34-7.36 (m, 3H), 7.27 (s, 1H), 5.35 (s, 1H), 4.58-4.67 (m, 2H), 4.41-4.44 (m, 2H), 4.26 (d, J = 8.0 Hz, 1H), 3.66 (s, 1H), 2.57-2.89 (m, 4H), 2.17 (s, 3H).

化合物1-P2滯留時間1.335分鐘，ee值98.29%。The retention time of compound 1-P2 was 1.335 minutes and the ee value was 98.29%.

¹H NMR (400 MHz, MeOD) δ7.34-7.43 (m, 6H), 5.43 (s, 1H), 4.60 (s, 2H), 4.39 (s, 2H), 4.30 (d, J= 8.0 Hz, 1H), 3.66 (s, 1H), 2.58-2.90 (m, 4H), 2.20 (s, 3H)。 ¹ H NMR (400 MHz, MeOD) δ 7.34-7.43 (m, 6H), 5.43 (s, 1H), 4.60 (s, 2H), 4.39 (s, 2H), 4.30 (d, J = 8.0 Hz, 1H), 3.66 (s, 1H), 2.58-2.90 (m, 4H), 2.20 (s, 3H).

實施例28 合成化合物3-P1和化合物3-P2 Example 28 Synthesis of Compound 3-P1 and Compound 3-P2

化合物3經掌性超臨界流體色譜法拆分得到化合物3-P1和3-P2。Compound 3 was separated by chiral supercritical fluid chromatography to give compounds 3-P1 and 3-P2.

分離條件：色譜柱型號：Chiralpak IC-3；色譜柱規格：50 × 4.6mm I.D.，3 μm；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇 (0.05% 二乙胺)，B%：40%固定濃度洗提7分鐘；檢測波長：254 nm；柱溫：40℃。Separation conditions: chromatographic column model: Chiralpak IC-3; chromatographic column specifications: 50 × 4.6mm I.D., 3 μm; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 40% fixed concentration elution for 7 minutes; detection wavelength: 254 nm; column temperature: 40°C.

化合物3-P1滯留時間2.888分鐘，ee值99.80%。The retention time of compound 3-P1 was 2.888 minutes and the ee value was 99.80%.

MS-ESI [M+H] ⁺，計算值458，實測值458。 MS-ESI [M+H] ⁺ , calcd. 458, found 458.

¹H NMR (400 MHz, MeOD) δ7.30-7.35 (m, 2H), 7.02-7.23 (m, 3H), 5.44 (s, 1H), 4.27-4.44 (m, 5H), 3.67-3.79 (m, 1H), 2.57-2.81 (m, 4H), 2.17 (s, 3H)。 ¹ H NMR (400 MHz, MeOD) δ 7.30-7.35 (m, 2H), 7.02-7.23 (m, 3H), 5.44 (s, 1H), 4.27-4.44 (m, 5H), 3.67-3.79 (m, 1H), 2.57-2.81 (m, 4H), 2.17 (s, 3H).

化合物3-P2滯留時間4.069分鐘，ee值99.46%。The retention time of compound 3-P2 was 4.069 minutes and the ee value was 99.46%.

¹H NMR (400 MHz, MeOD) δ7.29-7.35 (m, 2H), 7.02-7.22 (m, 3H), 5.43 (s, 1H), 4.27-4.47 (m, 5H), 3.67-3.79 (m, 1H), 2.59-2.81 (m, 4H), 2.18 (s, 3H)。 ¹ H NMR (400 MHz, MeOD) δ 7.29-7.35 (m, 2H), 7.02-7.22 (m, 3H), 5.43 (s, 1H), 4.27-4.47 (m, 5H), 3.67-3.79 (m, 1H), 2.59-2.81 (m, 4H), 2.18 (s, 3H).

實施例29 合成化合物7-P1和化合物7-P2 Example 29 Synthesis of Compound 7-P1 and Compound 7-P2

化合物7經掌性超臨界流體色譜法拆分得到化合物7-P1和7-P2。Compound 7 was separated by chiral supercritical fluid chromatography to give compounds 7-P1 and 7-P2.

分離條件：色譜柱型號：Chiralpak AS-3；色譜柱規格：50 × 4.6mm I.D.，3 μm；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇 (0.05% 二乙胺)，B%：5%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，5%固定濃度洗提0.5分鐘；檢測波長：254 nm；柱溫：40℃。Separation conditions: chromatographic column model: Chiralpak AS-3; chromatographic column specifications: 50 × 4.6mm I.D., 3 μm; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 5%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 5% fixed concentration elution for 0.5 minutes; detection wavelength: 254 nm; column temperature: 40°C.

化合物7-P1滯留時間1.530分鐘，ee值99.82%。The retention time of compound 7-P1 was 1.530 min and the ee value was 99.82%.

MS-ESI [M+H] ⁺，計算值418，實測值418。 MS-ESI [M+H] ⁺ , calcd. 418, found 418.

¹H NMR (400 MHz, MeOD) δ7.27-7.28 (m, 6H), 5.18 (s, 1H), 4.79-4.80 (m, 1H), 4.02-4.06 (m, 1H), 2.50-3.03 (m, 8H), 2.17 (s, 3H), 0.71-0.88 (m, 4H)。 ¹ H NMR (400 MHz, MeOD) δ 7.27-7.28 (m, 6H), 5.18 (s, 1H), 4.79-4.80 (m, 1H), 4.02-4.06 (m, 1H), 2.50-3.03 (m, 8H), 2.17 (s, 3H), 0.71-0.88 (m, 4H).

化合物7-P2滯留時間1.968分鐘，ee值99.20%。The retention time of compound 7-P2 was 1.968 minutes and the ee value was 99.20%.

MS-ESI [M+H] ⁺, 計算值418, 實測值418。 MS-ESI [M+H] ⁺ , calcd. 418, found 418.

¹H NMR (400 MHz, MeOD) δ7.27-7.28 (m, 6H), 5.18 (s, 1H), 4.81-4.82 (m, 1H), 4.02-4.06 (m, 1H), 2.51-2.97 (m, 8H), 2.17 (s, 3H), 0.71-0.88 (m, 4H)。 ¹ H NMR (400 MHz, MeOD) δ 7.27-7.28 (m, 6H), 5.18 (s, 1H), 4.81-4.82 (m, 1H), 4.02-4.06 (m, 1H), 2.51-2.97 (m, 8H), 2.17 (s, 3H), 0.71-0.88 (m, 4H).

實施例30 合成化合物8-P1和化合物8-P2 Example 30 Synthesis of Compound 8-P1 and Compound 8-P2

化合物8經掌性超臨界流體色譜法拆分得到化合物8-P1和8-P2。Compound 8 was separated by chiral supercritical fluid chromatography to give compounds 8-P1 and 8-P2.

分離條件：色譜柱型號：Chiralpak AD-3；色譜柱規格：50 × 4.6mm I.D.，3 μm；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇 (0.05% 二乙胺)，B%：5%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，5%固定濃度洗提0.5分鐘；檢測波長：254 nm；柱溫：40℃。Separation conditions: chromatographic column model: Chiralpak AD-3; chromatographic column specifications: 50 × 4.6mm I.D., 3 μm; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 5%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 5% fixed concentration elution for 0.5 minutes; detection wavelength: 254 nm; column temperature: 40°C.

化合物8-P1滯留時間1.695分鐘，ee值100%。The retention time of compound 8-P1 was 1.695 minutes, and the ee value was 100%.

MS-ESI [M+H] ⁺, 計算值472, 實測值472。 MS-ESI [M+H] ⁺ , calcd. 472, found 472.

¹H NMR (400 MHz, MeOD) δ7.27-7.41 (m, 6H), 5.33-5.40 (m, 1H), 4.74-4.80 (m, 2H), 4.01-4.30 (m, 4H), 3.65-3.83 (m, 1H), 2.54-2.88 (m, 4H), 2.17 (s, 3H)。 ¹ H NMR (400 MHz, MeOD) δ 7.27-7.41 (m, 6H), 5.33-5.40 (m, 1H), 4.74-4.80 (m, 2H), 4.01-4.30 (m, 4H), 3.65-3.83 (m, 1H), 2.54-2.88 (m, 4H), 2.17 (s, 3H).

化合物8-P2滯留時間2.366分鐘，ee值99.32%。The retention time of compound 8-P2 was 2.366 minutes and the ee value was 99.32%.

¹H NMR (400 MHz, MeOD) δ7.29-7.41 (m, 6H), 5.34-5.40 (m, 1H), 4.74-4.81 (m, 2H), 4.01-4.30 (m, 4H), 3.62-3.83 (m, 1H), 2.52-2.88 (m, 4H), 2.17 (s, 3H)。 ¹ H NMR (400 MHz, MeOD) δ 7.29-7.41 (m, 6H), 5.34-5.40 (m, 1H), 4.74-4.81 (m, 2H), 4.01-4.30 (m, 4H), 3.62-3.83 (m, 1H), 2.52-2.88 (m, 4H), 2.17 (s, 3H).

實施例31-35 合成化合物31-P1, 31-P2至35-P1, 35-P2Examples 31-35 Synthesis of Compounds 31-P1, 31-P2 to 35-P1, 35-P2

化合物31-P1, 31-P2至35-P1, 35-P2的製備參考實施例4，使用對應的胺替換4-4。分離條件：色譜柱型號：Chiralpak AD-3；色譜柱規格：50 × 4.6mm I.D.，3 μm；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇 (0.05% 二乙胺)，B%：5%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，5%固定濃度洗提0.5分鐘；檢測波長：254 nm；柱溫：40℃。 31-P1 滯留時間1.532分鐘，ee值100%。 MS-ESI [M+H] ⁺，計算值490，實測值490。 ¹H NMR (400 MHz, MeOD) δ7.28-7.32 (m, 2H), 7.16-7.21 (m, 2H), 7.01-7.04 (m, 1H), 5.41-5.44 (m, 1H), 4.13-4.31 (m, 4H), 3.65 -3.94 (m, 1H), 3.37-3.41 (m, 2H), 2.56-2.83 (m, 4H), 2.17 (s, 3H)。 31-P2 滯留時間2.062分鐘，ee值99.92%。 MS-ESI [M+H] ⁺，計算值490，實測值490。 ¹H NMR (400 MHz, MeOD) δ7.30-7.33 (m, 2H), 7.14-7.22 (m, 2H), 7.01-7.02 (m, 1H), 5.42-5.45 (m, 1H), 4.13-4.32 (m, 4H), 3.65 -3.94 (m, 1H), 3.37-3.40 (m, 2H), 2.55-2.82 (m, 4H), 2.18 (s, 3H)。分離條件：色譜柱型號：Chiralpak AD-3；色譜柱規格：50 × 4.6mm I.D.，3 μm；進樣量：10 μL；流動相：A：二氧化碳，B：異丙醇 (0.05% 二乙胺)，B%：40%梯度固定濃度洗提4分鐘；檢測波長：254 nm；柱溫：40℃。 32-P1 滯留時間0.690分鐘，ee值100%。 MS-ESI [M+H] ⁺，計算值472，實測值472。 ¹H NMR (400 MHz, MeOD) δ7.29-7.32 (m, 2H), 7.14-7.20 (m, 2H), 7.00-7.08 (m, 1H), 5.31 (s, 1H), 3.84-4.16 (m, 3H), 3.40-3.62 (m, 2H), 2.95-3.12 (m, 2H), 2.34-2.78 (m, 5H), 2.18 (s, 3H)。 32-P2 滯留時間1.521分鐘，ee值98.88%。 MS-ESI [M+H] ⁺，計算值472，實測值472。 ¹H NMR (400 MHz, MeOD) δ7.29-7.32 (m, 2H), 7.12-7.20 (m, 2H), 6.97-7.02 (m, 1H), 5.31 (s, 1H), 3.84-4.16 (m, 3H), 3.42-3.62 (m, 2H), 2.95-3.02 (m, 2H), 2.34-2.78 (m, 5H), 2.18 (s, 3H)。分離條件：色譜柱型號：Chiralpak AD-3；色譜柱規格：50 × 4.6mm I.D.，3 μm；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇 (0.05% 二乙胺)，B%：40%固定濃度洗提4分鐘；檢測波長：254 nm；柱溫：40℃。 33-P1 滯留時間0.714分鐘，ee值98.96%。 MS-ESI [M+H] ⁺，計算值436，實測值436。 ¹H NMR (400 MHz, MeOD) δ7.25-7.28 (m, 2H), 7.04-7.12 (m, 2H), 6.96-6.99 (m, 1H), 5.26-5.27 (m, 1H), 4.05-4.12 (m, 1H), 2.69-2.95 (m, 4H), 2.49-2.61 (m, 5H), 2.17 (s, 3H), 0.71-0.90 (m, 4H)。 33-P2 滯留時間2.050分鐘，ee值97.28%。 MS-ESI [M+H] ⁺，計算值436，實測值436。 ¹H NMR (400 MHz, MeOD) δ7.25-7.32 (m, 2H), 7.07-7.12 (m, 2H), 6.96-6.99 (m, 1H), 5.27-5.28 (m, 1H), 4.05-4.09 (m, 1H), 2.70-2.97 (m, 4H), 2.52-2.61 (m, 5H), 2.18 (s, 3H), 0.70-0.93 (m, 4H)。分離條件：色譜柱型號：Chiralpak AS-3；色譜柱規格：50 × 4.6mm I.D.，3 μm；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇 (0.05% 二乙胺)，B%：5%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，5%固定濃度洗提0.5分鐘；檢測波長：254 nm；柱溫：40℃。 34-P1 滯留時間1.401分鐘，ee值100%。 MS-ESI [M+H] ⁺，計算值464，實測值464。 ¹H NMR (400 MHz, MeOD) δ7.26-7.28 (m, 2H), 6.96-7.14 (m, 3H), 5.25 (s, 1H), 4.02-4.06 (m, 1H), 3.48-3.62 (m, 2H), 2.75-2.97 (m, 4H), 2.60 (s, 3H), 2.52-2.56 (m, 2H), 2.17 (s, 3H), 1.86-2.12 (m, 6H)。 34-P2 滯留時間1.821分鐘，ee值99.56%。 MS-ESI [M+H] ⁺，計算值464，實測值464。 ¹H NMR (400 MHz, MeOD) δ7.26-7.28 (m, 2H), 6.96-7.14 (m, 3H), 5.25 (s, 1H), 4.02-4.06 (m, 1H), 3.48-3.62 (m, 2H), 2.75-2.97 (m, 4H), 2.60 (s, 3H), 2.52-2.55 (m, 2H), 2.17 (s, 3H), 1.86-2.12 (m, 6H)。分離條件：色譜柱型號：Chiralpak AD-3；色譜柱規格：50 × 4.6mm I.D.，3 μm；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇 (0.05% 二乙胺)，B%：40%固定濃度洗提4.0分鐘；檢測波長：254 nm；柱溫：40℃。 35-P1 滯留時間0.894分鐘，ee值100%。 MS-ESI [M+H] ⁺，計算值450，實測值450。 ¹H NMR (400 MHz, MeOD) δ7.27-7.34 (m, 2H), 6.97-7.08 (m, 3H), 5.27 (s, 1H), 3.89-4.06 (m, 2H), 3.06 (s, 3H), 2.23-2.72 (m, 6H), 2.17 (s, 3H), 2.06-2.12 (m, 1H) , 1.59-1.75 (m, 2H) , 1.29-1.36 (m, 2H)。 35-P2 滯留時間1.821分鐘，ee值99.56%。 MS-ESI [M+H] ⁺，計算值450，實測值450。 ¹H NMR (400 MHz, MeOD) δ7.26-7.32 (m, 2H), 6.96-7.08 (m, 3H), 5.27 (s, 1H), 3.89-4.06 (m, 2H), 3.07 (s, 3H), 2.23-2.72 (m, 6H), 2.18 (s, 3H), 2.06-2.12 (m, 1H) , 1.59-1.75 (m, 2H) , 1.29-1.33 (m, 2H)。 The preparation of compounds 31-P1, 31-P2 to 35-P1, 35-P2 was carried out according to Example 4, using the corresponding amines to replace 4-4. Separation conditions: chromatographic column model: Chiralpak AD-3; chromatographic column specifications: 50 × 4.6mm ID, 3 μm; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 5%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 5% fixed concentration elution for 0.5 minutes; detection wavelength: 254 nm; column temperature: 40°C. 31-P1 Retention time 1.532 min, ee 100%. MS-ESI [M+H] ⁺ , calculated 490, found 490. ¹ H NMR (400 MHz, MeOD) δ 7.28-7.32 (m, 2H), 7.16-7.21 (m, 2H), 7.01-7.04 (m, 1H), 5.41-5.44 (m, 1H), 4.13-4.31 (m, 4H), 3.65 -3.94 (m, 1H), 3.37-3.41 (m, 2H), 2.56-2.83 (m, 4H), 2.17 (s, 3H). 31-P2 Retention time 2.062 min, ee 99.92%. MS-ESI [M+H] ⁺ , calculated 490, found 490. ¹ H NMR (400 MHz, MeOD) δ 7.30-7.33 (m, 2H), 7.14-7.22 (m, 2H), 7.01-7.02 (m, 1H), 5.42-5.45 (m, 1H), 4.13-4.32 (m, 4H), 3.65 -3.94 (m, 1H), 3.37-3.40 (m, 2H), 2.55-2.82 (m, 4H), 2.18 (s, 3H). Separation conditions: chromatographic column model: Chiralpak AD-3; chromatographic column specifications: 50 × 4.6mm ID, 3 μm; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: isopropanol (0.05% diethylamine), B%: 40% gradient fixed concentration elution for 4 minutes; detection wavelength: 254 nm; column temperature: 40°C. 32-P1 Retention time 0.690 min, ee 100%. MS-ESI [M+H] ⁺ , calculated 472, found 472. ¹ H NMR (400 MHz, MeOD) δ 7.29-7.32 (m, 2H), 7.14-7.20 (m, 2H), 7.00-7.08 (m, 1H), 5.31 (s, 1H), 3.84-4.16 (m, 3H), 3.40-3.62 (m, 2H), 2.95-3.12 (m, 2H), 2.34-2.78 (m, 5H), 2.18 (s, 3H). 32-P2 Retention time 1.521 min, ee 98.88%. MS-ESI [M+H] ⁺ , calculated 472, found 472. ¹ H NMR (400 MHz, MeOD) δ 7.29-7.32 (m, 2H), 7.12-7.20 (m, 2H), 6.97-7.02 (m, 1H), 5.31 (s, 1H), 3.84-4.16 (m, 3H), 3.42-3.62 (m, 2H), 2.95-3.02 (m, 2H), 2.34-2.78 (m, 5H), 2.18 (s, 3H). Separation conditions: chromatographic column model: Chiralpak AD-3; chromatographic column specifications: 50 × 4.6mm ID, 3 μm; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 40% fixed concentration elution for 4 minutes; detection wavelength: 254 nm; column temperature: 40°C. 33-P1 Retention time 0.714 min, ee 98.96%. MS-ESI [M+H] ⁺ , calculated 436, found 436. ¹ H NMR (400 MHz, MeOD) δ 7.25-7.28 (m, 2H), 7.04-7.12 (m, 2H), 6.96-6.99 (m, 1H), 5.26-5.27 (m, 1H), 4.05-4.12 (m, 1H), 2.69-2.95 (m, 4H), 2.49-2.61 (m, 5H), 2.17 (s, 3H), 0.71-0.90 (m, 4H). 33-P2 Retention time 2.050 min, ee 97.28%. MS-ESI [M+H] ⁺ , calculated 436, found 436. ¹ H NMR (400 MHz, MeOD) δ 7.25-7.32 (m, 2H), 7.07-7.12 (m, 2H), 6.96-6.99 (m, 1H), 5.27-5.28 (m, 1H), 4.05-4.09 (m, 1H), 2.70-2.97 (m, 4H), 2.52-2.61 (m, 5H), 2.18 (s, 3H), 0.70-0.93 (m, 4H). Separation conditions: chromatographic column model: Chiralpak AS-3; chromatographic column specifications: 50 × 4.6mm ID, 3 μm; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 5%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 5% fixed concentration elution for 0.5 minutes; detection wavelength: 254 nm; column temperature: 40°C. 34-P1 Retention time 1.401 min, ee 100%. MS-ESI [M+H] ⁺ , calculated 464, found 464. ¹ H NMR (400 MHz, MeOD) δ 7.26-7.28 (m, 2H), 6.96-7.14 (m, 3H), 5.25 (s, 1H), 4.02-4.06 (m, 1H), 3.48-3.62 (m, 2H), 2.75-2.97 (m, 4H), 2.60 (s, 3H), 2.52-2.56 (m, 2H), 2.17 (s, 3H), 1.86-2.12 (m, 6H). 34-P2 Retention time 1.821 min, ee 99.56%. MS-ESI [M+H] ⁺ , calculated 464, found 464. ¹ H NMR (400 MHz, MeOD) δ 7.26-7.28 (m, 2H), 6.96-7.14 (m, 3H), 5.25 (s, 1H), 4.02-4.06 (m, 1H), 3.48-3.62 (m, 2H), 2.75-2.97 (m, 4H), 2.60 (s, 3H), 2.52-2.55 (m, 2H), 2.17 (s, 3H), 1.86-2.12 (m, 6H). Separation conditions: chromatographic column model: Chiralpak AD-3; chromatographic column specifications: 50 × 4.6mm ID, 3 μm; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 40% fixed concentration elution for 4.0 minutes; detection wavelength: 254 nm; column temperature: 40°C. 35-P1 Retention time 0.894 min, ee 100%. MS-ESI [M+H] ⁺ , calculated 450, found 450. ¹ H NMR (400 MHz, MeOD) δ 7.27-7.34 (m, 2H), 6.97-7.08 (m, 3H), 5.27 (s, 1H), 3.89-4.06 (m, 2H), 3.06 (s, 3H), 2.23-2.72 (m, 6H), 2.17 (s, 3H), 2.06-2.12 (m, 1H), 1.59-1.75 (m, 2H), 1.29-1.36 (m, 2H). 35-P2 Retention time 1.821 min, ee 99.56%. MS-ESI [M+H] ⁺ , calculated 450, found 450. ¹ H NMR (400 MHz, MeOD) δ 7.26-7.32 (m, 2H), 6.96-7.08 (m, 3H), 5.27 (s, 1H), 3.89-4.06 (m, 2H), 3.07 (s, 3H), 2.23-2.72 (m, 6H), 2.18 (s, 3H), 2.06-2.12 (m, 1H), 1.59-1.75 (m, 2H), 1.29-1.33 (m, 2H).

實施例36 合成化合物9-P1和化合物9-P2 Example 36 Synthesis of Compound 9-P1 and Compound 9-P2

化合物9經掌性高效液相色譜法拆分得到化合物9-P1和9-P2。Compound 9 was separated by chiral HPLC to give compounds 9-P1 and 9-P2.

分離條件：色譜柱型號：ChiralPAK IE-3；色譜柱規格：100 × 4.6mm I.D.，3 μm；進樣量：10 μL；流動相：A：環己烷，B：乙醇和乙腈 (0.1% 二乙胺)，B%：70%固定濃度洗提10分鐘；檢測波長：254 nm；柱溫：40℃。Separation conditions: chromatographic column model: ChiralPAK IE-3; chromatographic column specifications: 100 × 4.6mm I.D., 3 μm; injection volume: 10 μL; mobile phase: A: cyclohexane, B: ethanol and acetonitrile (0.1% diethylamine), B%: 70% fixed concentration elution for 10 minutes; detection wavelength: 254 nm; column temperature: 40°C.

化合物9-P1滯留時間3.804分鐘，ee值99.88%。The retention time of compound 9-P1 was 3.804 minutes and the ee value was 99.88%.

MS-ESI [M+H] ⁺，計算值444，實測值444。 MS-ESI [M+H] ⁺ , calcd. 444, found 444.

¹H NMR (400 MHz, CDCl ₃) δ9.20 (br s, 1H), 7.31-7.39 (m, 3H), 7.21-7.24 (m, 3H), 5.45 (s, 1H), 4.59 (d, J= 15.6 Hz, 1H), 4.19-4.36 (m, 3H), 4.06 (br d, J= 6.0 Hz, 2H), 3.69 (br d, J= 9.2 Hz, 1H), 3.47 (br d, J= 9.2 Hz, 1H), 2.55-2.59 (m, 4H), 2.20 (s, 3H), 2.01-2.15 (m, 5H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 (br s, 1H), 7.31-7.39 (m, 3H), 7.21-7.24 (m, 3H), 5.45 (s, 1H), 4.59 (d, J = 15.6 Hz, 1H), 4.19-4.36 (m, 3H), 4.06 (br d, J = 6.0 Hz, 2H), 3.69 (br d, J = 9.2 Hz, 1H), 3.47 (br d, J = 9.2 Hz, 1H), 2.55-2.59 (m, 4H), 2.20 (s, 3H), 2.01-2.15 (m, 5H).

化合物9-P2滯留時間4.625分鐘，ee值95.20%。The retention time of compound 9-P2 was 4.625 minutes and the ee value was 95.20%.

¹H NMR (400 MHz, CDCl ₃) δ9.20 (br s, 1H), 7.33-7.39 (m, 3H), 7.21-7.25 (m, 3H), 5.45 (s, 1H), 4.59 (d, J= 15.6 Hz, 1H), 4.20-4.34 (m, 3H), 4.01-4.11 (m, 2H), 3.69 (br d, J= 9.2 Hz, 1H), 3.43-3.51 (m, 1H), 2.55-2.60 (m, 4H), 2.19-2.21 (m, 3H), 2.05-2.15 (m, 2H), 2.03 (s, 3H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.20 (br s, 1H), 7.33-7.39 (m, 3H), 7.21-7.25 (m, 3H), 5.45 (s, 1H), 4.59 (d, J = 15.6 Hz, 1H), 4.20-4.34 (m, 3H), 4.01-4.11 (m, 2H), 3.69 (br d, J = 9.2 Hz, 1H), 3.43-3.51 (m, 1H), 2.55-2.60 (m, 4H), 2.19-2.21 (m, 3H), 2.05-2.15 (m, 2H), 2.03 (s, 3H).

實施例37 合成化合物14-P1和化合物14-P2 Example 37 Synthesis of Compound 14-P1 and Compound 14-P2

化合物14經掌性超臨界流體色譜法拆分得到化合物14-P1和14-P2。Compound 14 was separated by chiral supercritical fluid chromatography to give compounds 14-P1 and 14-P2.

分離條件：色譜柱型號：Chiralpak AD-3；色譜柱規格：50 × 4.6mm I.D.，3 μm；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇(0.05% 二乙胺)，B%：40%固定濃度洗提3分鐘；檢測波長：254 nm；柱溫：40℃。Separation conditions: chromatographic column model: Chiralpak AD-3; chromatographic column specifications: 50 × 4.6mm I.D., 3 μm; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 40% fixed concentration elution for 3 minutes; detection wavelength: 254 nm; column temperature: 40°C.

化合物14-P1滯留時間0.768分鐘，ee值99.64%。The retention time of compound 14-P1 was 0.768 min and the ee value was 99.64%.

MS-ESI [M+H] ⁺，計算值454，實測值454。 MS-ESI [M+H] ⁺ , calcd. 454, found 454.

¹H NMR (400 MHz, CDCl ₃) δ9.11 (br s, 1H), 7.34-7.45 (m, 3H), 7.23 (br d, J= 4.0 Hz, 3H), 5.21 (br d, J= 14.2 Hz, 1H), 4.69 (br d, J= 5.6 Hz, 1H), 4.43-4.62 (m, 2H), 4.03-4.09 (m, 1H), 3.87-3.94 (m, 1H), 3.29-3.44 (m, 1H), 3.06-3.21 (m, 1H), 2.77-2.88 (m, 1H), 2.59-2.71 (m, 2H), 2.44-2.56 (m, 1H), 2.31-2.40 (m, 1H), 2.18 (s, 4H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.11 (br s, 1H), 7.34-7.45 (m, 3H), 7.23 (br d, J = 4.0 Hz, 3H), 5.21 (br d, J = 14.2 Hz, 1H), 4.69 (br d, J = 5.6 Hz, 1H), 4.43-4.62 (m, 2H), 4.03-4.09 (m, 1H), 3.87-3.94 (m, 1H), 3.29-3.44 (m, 1H), 3.06-3.21 (m, 1H), 2.77-2.88 (m, 1H), 2.59-2.71 (m, 2H), 2.44-2.56 (m, 1H), 2.31-2.40 (m, 1H), 2.18 (s, 4H).

化合物14-P2滯留時間1.345分鐘，ee值97.98%。The retention time of compound 14-P2 was 1.345 minutes and the ee value was 97.98%.

¹H NMR (400 MHz, CDCl ₃) δ9.14 (br s, 1H), 7.35-7.43 (m, 3H), 7.21-7.24 (m, 3H), 5.22 (br d, J= 14.4 Hz, 1H), 4.51-4.73 (m, 3H), 4.02-4.08 (m, 1H), 3.87-3.93 (m, 1H), 3.29-3.45 (m, 1H), 3.09-3.21 (m, 1H), 2.77-2.89 (m, 1H), 2.60-2.69 (m, 2H), 2.41-2.58 (m, 3H), 2.18 (s, 3H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.14 (br s, 1H), 7.35-7.43 (m, 3H), 7.21-7.24 (m, 3H), 5.22 (br d, J = 14.4 Hz, 1H), 4.51-4.73 (m, 3H), 4.02-4.08 (m, 1H), 3.87-3.93 (m, 1H), 3.29-3.45 (m, 1H), 3.09-3.21 (m, 1H), 2.77-2.89 (m, 1H), 2.60-2.69 (m, 2H), 2.41-2.58 (m, 3H), 2.18 (s, 3H).

實施例38 合成化合物19-P1和化合物19-P2 Example 38 Synthesis of Compound 19-P1 and Compound 19-P2

化合物19經掌性超臨界流體色譜法拆分得到化合物19-P1和19-P2。Compound 19 was separated by chiral supercritical fluid chromatography to give compounds 19-P1 and 19-P2.

化合物19-P1滯留時間1.054分鐘，ee值100%。The retention time of compound 19-P1 was 1.054 minutes and the ee value was 100%.

MS-ESI [M+H] ⁺，計算值432，實測值432。 MS-ESI [M+H] ⁺ , calcd. 432, found 432.

¹H NMR (400 MHz, CDCl ₃) δ9.13 (br s, 1H), 7.29-7.40 (m, 3H), 7.11-7.22 (m, 3H), 5.01-5.11 (m, 1H), 4.75 (d, J= 15.6 Hz, 1H), 4.29 (br s, 2H), 3.91 (br d, J= 15.6 Hz, 2H), 3.07 (s, 2H), 2.77-2.93 (m, 1H), 2.54-2.65 (m, 3H), 2.35-2.47 (m, 1H), 2.25 (br d, J= 10.4 Hz, 1H), 2.18 (s, 3H), 2.09-2.15 (m, 1H), 1.96-2.05 (m, 2H), 1.56-1.67 (m, 1H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.13 (br s, 1H), 7.29-7.40 (m, 3H), 7.11-7.22 (m, 3H), 5.01-5.11 (m, 1H), 4.75 (d, J = 15.6 Hz, 1H), 4.29 (br s, 2H), 3.91 (br d, J = 15.6 Hz, 2H), 3.07 (s, 2H), 2.77-2.93 (m, 1H), 2.54-2.65 (m, 3H), 2.35-2.47 (m, 1H), 2.25 (br d, J = 10.4 Hz, 1H), 2.18 (s, 3H), 2.09-2.15 (m, 1H), 1.96-2.05 (m, 2H), 1.56-1.67 (m, 1H).

化合物19-P2滯留時間2.077分鐘，ee值98.96%。The retention time of compound 19-P2 was 2.077 minutes and the ee value was 98.96%.

¹H NMR (400 MHz, CDCl ₃) δ9.16 (br s, 1H), 7.29-7.40 (m, 3H), 7.12-7.23 (m, 3H), 5.04-5.11 (m, 1H), 4.74 (d, J= 15.6 Hz, 1H), 4.41 (br s, 2H), 3.85-3.99 (m, 2H), 3.07 (s, 2H), 2.78-2.91 (m, 1H), 2.54-2.65 (m, 3H), 2.41 (ddd, J= 12.8, 8.8, 4.0 Hz, 1H), 2.25 (br d, J= 10.4 Hz, 1H), 2.18 (s, 3H), 2.09-2.14 (m, 3H), 1.97-2.04 (m, 1H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.16 (br s, 1H), 7.29-7.40 (m, 3H), 7.12-7.23 (m, 3H), 5.04-5.11 (m, 1H), 4.74 (d, J = 15.6 Hz, 1H), 4.41 (br s, 2H), 3.85-3.99 (m, 2H), 3.07 (s, 2H), 2.78-2.91 (m, 1H), 2.54-2.65 (m, 3H), 2.41 (ddd, J = 12.8, 8.8, 4.0 Hz, 1H), 2.25 (br d, J = 10.4 Hz, 1H), 2.18 (s, 3H), 2.09-2.14 (m, 3H), 1.97-2.04 (m, 1H).

實施例39 合成化合物22-P1和化合物22-P2 Example 39 Synthesis of Compound 22-P1 and Compound 22-P2

化合物22經掌性超臨界流體色譜法拆分得到化合物22-P1和22-P2。Compound 22 was separated by chiral supercritical fluid chromatography to give compounds 22-P1 and 22-P2.

分離條件：色譜柱型號：Chiralpak IH-3；色譜柱規格：50 × 4.6mm I.D.，3 μm；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇(0.05% 二乙胺)，B%：5%-40%梯度洗提1.5分鐘，40%固定濃度洗提1.5分鐘，5%固定濃度洗提1分鐘；檢測波長：254 nm；柱溫：40℃。Separation conditions: chromatographic column model: Chiralpak IH-3; chromatographic column specifications: 50 × 4.6mm I.D., 3 μm; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 5%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1.5 minutes, 5% fixed concentration elution for 1 minute; detection wavelength: 254 nm; column temperature: 40°C.

化合物22-P1滯留時間1.551分鐘，ee值100%。The retention time of compound 22-P1 was 1.551 minutes, and the ee value was 100%.

MS-ESI [M+H] ⁺，計算值446，實測值446。 MS-ESI [M+H] ⁺ , calcd. 446, found 446.

¹H NMR (400 MHz, CDCl ₃) δ9.26 (br s, 1H), 7.31-7.40 (m, 3H), 7.19-7.25 (m, 3H), 5.13 (s, 1H), 4.48-4.78 (m, 3H), 3.96 (d, J= 15.6 Hz, 1H), 3.46-3.66 (m, 2H), 2.99 (s, 1H), 2.71-2.86 (m, 2H), 2.57-2.65 (m, 5H), 2.45-2.55 (m, 1H), 2.07-2.20 (m, 7H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.26 (br s, 1H), 7.31-7.40 (m, 3H), 7.19-7.25 (m, 3H), 5.13 (s, 1H), 4.48-4.78 (m, 3H), 3.96 (d, J = 15.6 Hz, 1H), 3.46-3.66 (m, 2H), 2.99 (s, 1H), 2.71-2.86 (m, 2H), 2.57-2.65 (m, 5H), 2.45-2.55 (m, 1H), 2.07-2.20 (m, 7H).

化合物22-P2滯留時間1.944分鐘，ee值98.00%。The retention time of compound 22-P2 was 1.944 minutes and the ee value was 98.00%.

實施例40 合成化合物40 Example 40 Synthesis of Compound 40

(1)01下向化合物H(1.40 g, 4.23 mmol)的二氯甲烷(20.0 mL)溶液中，加入二氯亞碸(1.51 g, 12.7 mmol, 922 μL)。反應液在氮氣保護下25應攪拌1小時。反應液加入碳酸氫鈉水溶液(50.0 mL)，用二氯甲烷(100 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。得到化合物40-1。(1) To a solution of compound H (1.40 g, 4.23 mmol) in dichloromethane (20.0 mL) was added dichlorosulfoxide (1.51 g, 12.7 mmol, 922 μL) at 0.1 °C. The reaction mixture was stirred for 1 hour at 25 °C under nitrogen protection. Aqueous sodium bicarbonate solution (50.0 mL) was added to the reaction mixture, which was extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 40-1.

(2)02下向化合物40-1(1.47 g, 4.22 mmol)的 N,N-二甲基甲醯胺(30.0 mL)溶液中，加入碳酸銫(2.75 g, 8.43 mmol)和中間體A(1.00 g, 4.22 mmol)。反應液在氮氣保護下60應攪拌1小時。反應液加入水(50.0 mL)，用乙酸乙酯(200 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/乙酸乙酯 = 1 ：0 到 4 ：1)分離得到化合物40-2。 (2) To a solution of compound 40-1 (1.47 g, 4.22 mmol) in N,N -dimethylformamide (30.0 mL) was added cesium carbonate (2.75 g, 8.43 mmol) and intermediate A (1.00 g, 4.22 mmol) at 0.2 °C. The reaction solution was stirred at 60 °C for 1 hour under nitrogen protection. Water (50.0 mL) was added to the reaction solution, which was extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 4:1) to obtain compound 40-2.

MS-ESI [M+H] ⁺，計算值550，實測值550。 MS-ESI [M+H] ⁺ , calcd. 550, found 550.

¹H NMR (400 MHz, CDCl ₃) δ7.48 (d, J= 8.8 Hz, 1H), 7.19-7.26 (m, 1H), 6.88-7.01 (m, 3H), 6.03 (s, 1H), 5.35-5.49 (m, 2H), 4.61-4.84 (m, 2H), 3.65 (s, 3H), 3.49 (t, J= 8.0 Hz, 2H), 2.86-2.93 (m, 2H), 2.51-2.60 (m, 2H), 0.86-0.96 (m, 2H), 0.03 (s, 9H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.48 (d, J = 8.8 Hz, 1H), 7.19-7.26 (m, 1H), 6.88-7.01 (m, 3H), 6.03 (s, 1H), 5.35-5.49 (m, 2H), 4.61-4.84 (m, 2H), 3.65 (s, 3H), 3.49 (t, J = 8.0 Hz, 2H), 2.86-2.93 (m, 2H), 2.51-2.60 (m, 2H), 0.86-0.96 (m, 2H), 0.03 (s, 9H).

(3)向化合物40-2(1.70 g, 3.09 mmo)的甲苯(30.0 mL)溶液中，加入2,4-二甲氧基苄胺(1.03 g, 6.18 mmol, 928 μL)，碳酸銫(2.01 g, 6.18 mmol)，三(二亞苄基丙酮)二鈀(283 mg, 309 μmol)，1,1'-聯萘-2,2'-雙二苯膦(384 mg, 618 μmol)。反應液在氮氣保護下120液攪拌12小時，反應液加入水(50.0 mL)，用乙酸乙酯(200 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/乙酸乙酯 = 1 ：0 到 3 ：1)分離得到化合物40-3。(3) To a toluene (30.0 mL) solution of compound 40-2 (1.70 g, 3.09 mmol), 2,4-dimethoxybenzylamine (1.03 g, 6.18 mmol, 928 μL), cesium carbonate (2.01 g, 6.18 mmol), tris(dibenzylideneacetone)dipalladium (283 mg, 309 μmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (384 mg, 618 μmol) were added. The reaction solution was stirred at 120 °C for 12 hours under nitrogen protection, water (50.0 mL) was added to the reaction solution, and the solution was extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 3:1) to give compound 40-3.

MS-ESI [M+H] ⁺，計算值681，實測值681。 MS-ESI [M+H] ⁺ , calcd. 681 , found 681 .

(4)向化合物40-3(1.90 g, 2.79 mmol)的四氫呋喃(30.0 mL)溶液中，加入一水合氫氧化鋰(10.0 mL, 2 mol/L)。反應液在氮氣保護下25℃攪拌12小時。反應液在0℃下加入鹽酸水溶液調節pH值到7，用二氯甲烷(100 mL × 2)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。得到化合物40-4。(4) To a solution of compound 40-3 (1.90 g, 2.79 mmol) in tetrahydrofuran (30.0 mL), lithium hydroxide monohydrate (10.0 mL, 2 mol/L) was added. The reaction solution was stirred at 25°C for 12 hours under nitrogen protection. Aqueous hydrochloric acid solution was added to the reaction solution at 0°C to adjust the pH value to 7, and the solution was extracted with dichloromethane (100 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 40-4.

MS-ESI [M+H] ⁺，計算值667，實測值667。 MS-ESI [M+H] ⁺ , calcd. 667, found 667.

(5)向化合物40-4(300 mg, 449 μmol)的二氯甲烷(8.0 mL)溶液中加入二異丙基乙基胺(407 mg, 3.15 mmol, 548 μL)和 N,N,Nmg, ′,-四甲基- O-(7-氮雜苯并三唑-1-基)六氟磷酸脲(256 mg, 674 μmol)，室溫下攪拌25分鐘，隨後加入甲基環丙基胺鹽酸鹽(242 mg, 2.25 mmol)，反應液在氮氣保護下25液攪拌24小時。反應液加入水(30.0 mL)，用乙酸乙酯(100 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法 (二氯甲烷/甲醇 = 1 ：0 到 10 ：1) 分離得到化合物40-5。 (5) Diisopropylethylamine (407 mg, 3.15 mmol, 548 μL) and N,N,Nmg, ′, -tetramethyl- O -(7-azabenzotriazol-1-yl) uronium hexafluorophosphate (256 mg, 674 μmol) were added to a solution of compound 40-4 (300 mg, 449 μmol) in dichloromethane (8.0 mL), and the mixture was stirred at room temperature for 25 minutes. Methylcyclopropylamine hydrochloride (242 mg, 2.25 mmol) was then added, and the reaction mixture was stirred for 24 hours under nitrogen protection. Water (30.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane/methanol = 1:0 to 10:1) to give compound 40-5.

MS-ESI [M+H] ⁺，計算值720，實測值720。 MS-ESI [M+H] ⁺ , calcd. 720, found 720.

(6) 06下將化合物40-5(100 mg, 138 μmol)的二氯甲烷(1.0 mL)溶液中，加入三氟乙酸(10 μL)。反應液在氮氣保護下25應攪拌1小時。反應液加入甲醇(1.0 mL)和氨水(1.37 g, 11.6 mmol, 1.50 mL)並在氮氣保護下40℃攪拌0.5小時。反應液加入水(50.0 mL)，用乙酸乙酯(50.0 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經製備高效液相色譜法 (Xtimate C18, 200 mm × 40 mm 7 μm, A:水(甲酸)；B:乙腈, 0%-32%：25分鐘) 分離得到化合物40的甲酸鹽。(6) Trifluoroacetic acid (10 μL) was added to a solution of compound 40-5 (100 mg, 138 μmol) in dichloromethane (1.0 mL) at 0.6 °C. The reaction mixture was stirred at 25 °C for 1 hour under nitrogen protection. Methanol (1.0 mL) and aqueous ammonia (1.37 g, 11.6 mmol, 1.50 mL) were added to the reaction mixture and stirred at 40 °C for 0.5 hour under nitrogen protection. Water (50.0 mL) was added to the reaction mixture and extracted with ethyl acetate (50.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative HPLC (Xtimate C18, 200 mm × 40 mm 7 μm, A: water (formic acid); B: acetonitrile, 0%-32%: 25 min) to give the formate salt of compound 40.

(7) 化合物40的甲酸鹽經掌性超臨界流體色譜法拆分得到化合物40-P1和40-P2。(7) The formate salt of compound 40 was separated by chiral supercritical fluid chromatography to give compounds 40-P1 and 40-P2.

分離條件：色譜柱型號：CHIRALPAK AS；色譜柱規格：250 × 30 mm I.D.，10 μm；進樣量：10.0 μL；流動相：A：二氧化碳，B：乙醇 (0.1% 氨水)，B%：50%洗提3.0分鐘；檢測波長：254 nm；柱溫：35℃。Separation conditions: chromatographic column model: CHIRALPAK AS; chromatographic column specifications: 250 × 30 mm I.D., 10 μm; injection volume: 10.0 μL; mobile phase: A: carbon dioxide, B: ethanol (0.1% ammonia water), B%: 50% elution for 3.0 minutes; detection wavelength: 254 nm; column temperature: 35°C.

化合物40-P1滯留時間1.157分鐘，ee值99.30%。The retention time of compound 40-P1 was 1.157 minutes and the ee value was 99.30%.

¹H NMR (400 MHz, MeOD) δ7.24-7.32 (m, 2H), 7.01-7.17 (m, 2H), 6.90-7.00 (m, 1H), 5.28 (s, 1H), 4.92 (s, 1H), 4.06 (br d, J= 15.6 Hz, 1H), 2.83-2.98 (m, 2H), 2.68-2.77 (m, 1H), 2.58 (s, 3H), 2.51-2.55 (m, 1H), 1.27-1.34 (m, 1H), 0.78-0.93 (m, 3H), 0.64-0.75 (m, 1H)。 ¹ H NMR (400 MHz, MeOD) δ 7.24-7.32 (m, 2H), 7.01-7.17 (m, 2H), 6.90-7.00 (m, 1H), 5.28 (s, 1H), 4.92 (s, 1H), 4.06 (br d, J = 15.6 Hz, 1H), 2.83-2.98 (m, 2H), 2.68-2.77 (m, 1H), 2.58 (s, 3H), 2.51-2.55 (m, 1H), 1.27-1.34 (m, 1H), 0.78-0.93 (m, 3H), 0.64-0.75 (m, 1H).

化合物40-P2滯留時間1.731分鐘，ee值98.58%。The retention time of compound 40-P2 was 1.731 min and the ee value was 98.58%.

MS-ESI [M+H] ⁺, 計算值440, 實測值440。 MS-ESI [M+H] ⁺ , calcd. 440, found 440.

¹H NMR (400 MHz, MeOD) δ7.22-7.34 (m, 2H), 7.01-7.16 (m, 2H), 6.92-7.00 (m, 1H), 5.28 (s, 1H), 4.92 (s, 1H), 3.98-4.17 (m, 1H), 2.82-3.00 (m, 2H), 2.68-2.78 (m, 1H), 2.58 (s, 3H), 2.47-2.55 (m, 1H), 1.27-1.35 (m, 1H), 0.74-0.94 (m, 3H), 0.65-0.74 (m, 1H)。 ¹ H NMR (400 MHz, MeOD) δ 7.22-7.34 (m, 2H), 7.01-7.16 (m, 2H), 6.92-7.00 (m, 1H), 5.28 (s, 1H), 4.92 (s, 1H), 3.98-4.17 (m, 1H), 2.82-3.00 (m, 2H), 2.68-2.78 (m, 1H), 2.58 (s, 3H), 2.47-2.55 (m, 1H), 1.27-1.35 (m, 1H), 0.74-0.94 (m, 3H), 0.65-0.74 (m, 1H).

實施例41-47 合成化合物41-P1, 41-P2至47-P1, 47-P2Examples 41-47 Synthesis of Compounds 41-P1, 41-P2 to 47-P1, 47-P2

化合物41-P1, 41-P2至47-P1, 47-P2的製備參考實施例40，使用對應的胺替換甲基環丙基胺。分離條件：色譜柱型號：Chiralpak AD；色譜柱規格：50 × 4.6mm I.D.，3 μm；進樣量：10 μL；流動相：A：二氧化碳，B：異丙醇 (0.1% 氨水)，B%：5%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，5%固定濃度洗提0.5分鐘；檢測波長：254 nm；柱溫：40℃。 41-P1 滯留時間1.711分鐘，ee值100%。 MS-ESI [M+H] ⁺，計算值466，實測值466。 ¹H NMR (400 MHz, MeOD) δ7.23-7.40 (m, 2H), 7.15 (d, J= 8.0 Hz, 1H), 7.09 (d, J= 10.4 Hz, 1H), 6.97-7.05 (m, 1H), 5.47 (s, 1H), 4.76-4.81 (m, 2H), 4.28 (d, J= 16.0 Hz, 1H), 4.02 (s, 2H), 3.87 (d, J= 9.6 Hz, 1H), 2.49-2.82 (m, 4H), 1.91-2.19 (m, 4H), 1.64-1.86 (m, 2H)。 41-P2 滯留時間1.937分鐘，ee值98.26%。 MS-ESI [M+H] ⁺，計算值466，實測值466。 ¹H NMR (400 MHz, MeOD) δ7.26-7.39 (m, 2H), 7.15 (d, J= 7.2 Hz, 1H), 7.06-7.12 (m, 1H), 6.97-7.05 (m, 1H), 5.46 (s, 1H), 4.78 (d, J= 15.6 Hz, 2H), 4.27 (d, J= 16.4 Hz, 1H), 4.02 (s, 2H), 3.86 (d, J= 9.2 Hz, 1H), 2.50-2.82 (m, 4H), 1.95-2.18 (m, 4H), 1.68-1.84 (m, 2H)。分離條件：色譜柱型號：Chiralpak AS-3；色譜柱規格：50 × 4.6mm I.D.，10 μm；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇 (0.05% 二乙胺)，B%：5%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，5%固定濃度洗提0.5分鐘；檢測波長：254 nm；柱溫：40℃。 42-P1 滯留時間1.087分鐘，ee值100%。 MS-ESI [M+H] ⁺，計算值476，實測值476。 ¹H NMR (400 MHz, MeOD) δ7.24-7.36 (m, 2H), 7.08-7.22 (m, 2H), 7.00 (br t, J= 8.4 Hz, 1H), 5.33 (s, 1H), 4.88 (br s, 2H), 4.13 (dd, J= 16.0, 4.4 Hz, 1H), 3.78-4.07 (m, 2H), 3.41-3.65 (m, 1H), 2.92-3.02 (m, 1H), 2.75 (s, 1H), 2.51-2.65 (m, 2H), 2.14-2.44 (m, 2H)。 42-P2 滯留時間1.413分鐘，ee值99.80%。 MS-ESI [M+H] ⁺，計算值476，實測值476。 ¹H NMR (400 MHz, MeOD) δ7.23-7.35 (m, 2H), 7.09-7.21 (m, 2H), 6.94-7.05 (m, 1H), 5.33 (s, 1H), 4.92 (br d, J= 4.4 Hz, 2H), 4.08-4.19 (m, 1H), 3.79-4.06 (m, 2H), 3.39-3.67 (m, 1H), 2.93-3.02 (m, 1H), 2.69-2.80 (m, 1H), 2.51-2.66 (m, 2H), 2.15-2.42 (m, 2H)。分離條件：色譜柱型號：Chiralcel OJ-3；色譜柱規格：100 × 4.6mm I.D.，3 μm；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇 (0.05% 二乙胺)，B%：5%-50%梯度洗提1.4分鐘，50%固定濃度洗提1分鐘，5%固定濃度洗提0.6分鐘；檢測波長：254 nm；柱溫：40℃。 43-P1 滯留時間1.374分鐘，ee值99.74%。 MS-ESI [M+H] ⁺，計算值494，實測值494。 ¹H NMR (400 MHz, MeOD) δ7.25-7.39 (m, 2H), 7.18-7.24 (m, 1H), 7.14 (d, J= 10.4 Hz, 1H), 7.02 (td, J= 8.4, 2.0 Hz, 1H), 5.39-5.51 (m, 1H), 4.00-4.37 (m, 4H), 3.60-3.96 (m, 1H), 3.38 (d, J= 6.4 Hz, 2H), 2.67-2.88 (m, 2H), 2.51-2.62 (m, 2H)。 43-P2 滯留時間1.510分鐘，ee值98.30%。 MS-ESI [M+H] ⁺，計算值494，實測值494。 ¹H NMR (400 MHz, MeOD) δ7.25-7.38 (m, 2H), 7.20 (d, J= 6.8 Hz, 1H), 7.14 (d, J= 11.2 Hz, 1H), 7.02 (td, J= 8.4, 2.4 Hz, 1H), 5.40-5.50 (m, 1H), 4.02-4.36 (m, 4H), 3.65-3.94 (m, 1H), 3.35-3.41 (m, 2H), 2.67-2.89 (m, 2H), 2.52-2.62 (m, 2H)。分離條件：色譜柱型號：Chiralcel IC-3；色譜柱規格：50 × 4.6mm I.D.，3 μm；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇 (0.05% 二乙胺)，B%：40%固定濃度洗提4分鐘；檢測波長：254 nm；柱溫：40℃。 44-P1 滯留時間1.002分鐘，ee值99.62%。 MS-ESI [M+H] ⁺，計算值468，實測值468。 ¹H NMR (400 MHz, MeOD) δ7.24-7.30 (m, 2H), 7.12-7.15 (m, 1H), 7.04-7.08 (m, 1H), 6.94-6.99 (m, 1H), 5.28 (s, 1H), 4.03 (d, J= 16.0 Hz, 1H), 3.59-3.67 (m, 1H), 3.45-3.50 (m, 1H), 2.88-3.03 (m, 2H), 2.70-2.82 (m, 2H), 2.60 (s, 3H), 2.48-2.58 (m, 2H), 2.05-2.18 (m, 2H), 1.80-2.02 (m, 4H)。 44-P2 滯留時間1.868分鐘，ee值99.78%。 MS-ESI [M+H] ⁺，計算值468，實測值468。 ¹H NMR (400 MHz, MeOD) δ7.24-7.30 (m, 2H), 7.13 (d, J= 7.2 Hz, 1H), 7.03-7.08 (m, 1H), 6.94-6.99 (m, 1H), 5.28 (s, 1H), 4.03 (d, J= 16.0 Hz, 1H), 3.55-3.68 (m, 1H), 3.44-3.53 (m, 1H), 2.87-3.06 (m, 2H), 2.67-2.81 (m, 2H), 2.60 (s, 3H), 2.46-2.57 (m, 2H), 2.05-2.19 (m, 2H), 1.81-2.03 (m, 4H)。分離條件：色譜柱型號：Chiralcel AS-3；色譜柱規格：50 × 4.6mm I.D.，3 μm；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇 (0.05% 二乙胺)，B%：5%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，5%固定濃度洗提0.5分鐘；檢測波長：254 nm；柱溫：40℃。 45-P1 滯留時間1.134分鐘，ee值100%。 MS-ESI [M+H] ⁺，計算值454，實測值454。 ¹H NMR (400 MHz, MeOD) δ7.22-7.34 (m, 2H), 6.92-7.15 (m, 3H), 5.26 (s, 1H), 3.83-4.10 (m, 2H), 3.00-3.10 (m, 3H), 2.68-2.79 (m, 1H), 2.39-2.62 (m, 3H), 2.15-2.36 (m, 3H), 1.99-2.12 (m, 1H), 1.60 (q, J= 9.6 Hz, 1H), 1.31-1.41 (m, 2H)。 45-P2 滯留時間1.856分鐘，ee值99.42%。 MS-ESI [M+H] ⁺，計算值454，實測值454。 ¹H NMR (400 MHz, MeOD) δ7.23-7.32 (m, 2H), 6.93-7.14 (m, 3H), 5.26 (s, 1H), 3.84-4.09 (m, 2H), 2.98-3.09 (m, 3H), 2.68-2.78 (m, 1H), 2.40-2.63 (m, 3H), 2.13-2.38 (m, 3H), 1.99-2.12 (m, 1H), 1.54-1.66 (m, 1H), 1.31-1.44 (m, 2H)。分離條件：色譜柱型號：Chiralpak AS-3；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇 (0.05% 二乙胺)，B%：5%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，5%固定濃度洗提0.5分鐘；檢測波長：254 nm；柱溫：35℃。 46-P1 滯留時間1.107分鐘，ee值100.00%。 MS-ESI [M+H] ⁺，計算值454，實測值454。 ¹H NMR: (400 MHz, CD ₃OD) δ(ppm) 7.23-7.34 (m, 2H), 7.07-7.22 (m, 2H), 6.98-6.98 (m, 1H), 6.97 (br s, 1H), 5.28 (br s, 1H), 4.04 (br dd, J= 16.0, 4.3 Hz, 1H), 3.42-3.61 (m, 1H), 3.27 (br s, 1H), 3.15 (br d, J= 3.6 Hz, 1H), 2.91-3.04 (m, 1H), 2.73-2.82 (m, 1H), 2.66-2.72 (m, 3H), 2.48-2.64 (m, 2H), 1.07-1.25 (m, 1H), 0.53-0.75 (m, 2H), 0.22-0.48 (m, 2H)。 46-P2 滯留時間1.646分鐘，ee值99.44%。 MS-ESI [M+H] ⁺，計算值454，實測值454。 ¹H NMR: (400 MHz, CD ₃OD) δ(ppm) 7.23-7.32 (m, 2H), 7.07-7.21 (m, 2H), 6.93-7.02 (m, 1H), 5.28 (s, 1H), 4.04 (d, J= 16.0 Hz, 1H), 3.51 (dd, J= 13.6, 7.2 Hz, 1H), 3.27 (br d, J= 7.2 Hz, 1H), 3.15 (s, 1H), 2.92-3.03 (m, 1H), 2.72-2.79 (m, 1H), 2.70 (s, 3H), 2.50-2.64 (m, 2H), 1.09-1.23 (m, 1H), 0.60 (br d, J= 8.0 Hz, 2H), 0.35 (br dd, J= 10.4, 4.8 Hz, 2H)。分離條件：色譜柱型號：Chiralpak IH-3；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇(0.05% 二乙胺)，B%：20%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，20%固定濃度洗提0.5分鐘；檢測波長：254 nm；柱溫：35℃。 47-P1 滯留時間0.704分鐘，ee值98.78%。 MS-ESI [M+H] ⁺，計算值457，實測值457。 ¹H NMR: (CDCl ₃, 400 MHz) δ(ppm) 9.29 (br s, 1H), 7.28-7.35 (m, 1H), 7.18 (d, J= 10.8 Hz, 1H), 7.04-7.12 (m, 1H), 6.92-7.02 (m, 1H), 6.84-6.92 (m, 1H), 5.16-5.30 (m, 1H), 4.76 (br d, J= 16.0 Hz, 1H), 4.24-4.48 (m, 2H), 3.79-4.05 (m, 2H), 2.72-2.88 (m, 1H), 2.53-2.70 (m, 2H), 2.36-2.51 (m, 1H), 2.10-2.34 (m, 3H), 1.99-2.07 (m, 1H), 1.26-1.38 (m, 2H)。 47-P2 滯留時間1.732分鐘，ee值99.70%。 MS-ESI [M+H] ⁺，計算值457，實測值457。 ¹H NMR: (CDCl ₃, 400 MHz) δ(ppm) 9.14-9.35 (m, 1H), 7.29-7.33 (m, 1H), 7.17 (d, J= 12.0 Hz, 1H), 7.04-7.11 (m, 1H), 6.93-7.00 (m, 1H), 6.84-6.92 (m, 1H), 5.17-5.26 (m, 1H), 4.77 (d, J= 16.0 Hz, 1H), 4.30 (br s, 2H), 3.79-4.04 (m, 2H), 2.74-2.85 (m, 1H), 2.57-2.67 (m, 2H), 2.45 (dt, J= 8.4, 4.5 Hz, 1H), 2.11-2.33 (m, 3H), 1.95-2.09 (m, 1H), 1.26-1.38 (m, 2H)。 The preparation of compounds 41-P1, 41-P2 to 47-P1, 47-P2 was carried out according to Example 40, using corresponding amines instead of methylcyclopropylamine. Separation conditions: chromatographic column model: Chiralpak AD; chromatographic column specifications: 50 × 4.6mm ID, 3 μm; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: isopropanol (0.1% ammonia water), B%: 5%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 5% fixed concentration elution for 0.5 minutes; detection wavelength: 254 nm; column temperature: 40°C. 41-P1 Retention time 1.711 min, ee 100%. MS-ESI [M+H] ⁺ , calculated 466, found 466. ¹ H NMR (400 MHz, MeOD) δ 7.23-7.40 (m, 2H), 7.15 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 10.4 Hz, 1H), 6.97-7.05 (m, 1H), 5.47 (s, 1H), 4.76-4.81 (m, 2H), 4.28 (d, J = 16.0 Hz, 1H), 4.02 (s, 2H), 3.87 (d, J = 9.6 Hz, 1H), 2.49-2.82 (m, 4H), 1.91-2.19 (m, 4H), 1.64-1.86 (m, 2H). 41-P2 Retention time 1.937 min, ee 98.26%. MS-ESI [M+H] ⁺ , calculated 466, found 466. ¹ H NMR (400 MHz, MeOD) δ 7.26-7.39 (m, 2H), 7.15 (d, J = 7.2 Hz, 1H), 7.06-7.12 (m, 1H), 6.97-7.05 (m, 1H), 5.46 (s, 1H), 4.78 (d, J = 15.6 Hz, 2H), 4.27 (d, J = 16.4 Hz, 1H), 4.02 (s, 2H), 3.86 (d, J = 9.2 Hz, 1H), 2.50-2.82 (m, 4H), 1.95-2.18 (m, 4H), 1.68-1.84 (m, 2H). Separation conditions: chromatographic column model: Chiralpak AS-3; chromatographic column specifications: 50 × 4.6mm ID, 10 μm; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 5%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 5% fixed concentration elution for 0.5 minutes; detection wavelength: 254 nm; column temperature: 40°C. 42-P1 Retention time 1.087 min, ee 100%. MS-ESI [M+H] ⁺ , calculated 476, found 476. ¹ H NMR (400 MHz, MeOD) δ 7.24-7.36 (m, 2H), 7.08-7.22 (m, 2H), 7.00 (br t, J = 8.4 Hz, 1H), 5.33 (s, 1H), 4.88 (br s, 2H), 4.13 (dd, J = 16.0, 4.4 Hz, 1H), 3.78-4.07 (m, 2H), 3.41-3.65 (m, 1H), 2.92-3.02 (m, 1H), 2.75 (s, 1H), 2.51-2.65 (m, 2H), 2.14-2.44 (m, 2H). 42-P2 Retention time 1.413 min, ee 99.80%. MS-ESI [M+H] ⁺ , calculated 476, found 476. ¹ H NMR (400 MHz, MeOD) δ 7.23-7.35 (m, 2H), 7.09-7.21 (m, 2H), 6.94-7.05 (m, 1H), 5.33 (s, 1H), 4.92 (br d, J = 4.4 Hz, 2H), 4.08-4.19 (m, 1H), 3.79-4.06 (m, 2H), 3.39-3.67 (m, 1H), 2.93-3.02 (m, 1H), 2.69-2.80 (m, 1H), 2.51-2.66 (m, 2H), 2.15-2.42 (m, 2H). Separation conditions: chromatographic column model: Chiralcel OJ-3; chromatographic column specifications: 100 × 4.6mm ID, 3 μm; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 5%-50% gradient elution for 1.4 minutes, 50% fixed concentration elution for 1 minute, 5% fixed concentration elution for 0.6 minutes; detection wavelength: 254 nm; column temperature: 40°C. 43-P1 Retention time 1.374 min, ee 99.74%. MS-ESI [M+H] ⁺ , calculated 494, found 494. ¹ H NMR (400 MHz, MeOD) δ 7.25-7.39 (m, 2H), 7.18-7.24 (m, 1H), 7.14 (d, J = 10.4 Hz, 1H), 7.02 (td, J = 8.4, 2.0 Hz, 1H), 5.39-5.51 (m, 1H), 4.00-4.37 (m, 4H), 3.60-3.96 (m, 1H), 3.38 (d, J = 6.4 Hz, 2H), 2.67-2.88 (m, 2H), 2.51-2.62 (m, 2H). 43-P2 Retention time 1.510 min, ee 98.30%. MS-ESI [M+H] ⁺ , calculated 494, found 494. ¹ H NMR (400 MHz, MeOD) δ 7.25-7.38 (m, 2H), 7.20 (d, J = 6.8 Hz, 1H), 7.14 (d, J = 11.2 Hz, 1H), 7.02 (td, J = 8.4, 2.4 Hz, 1H), 5.40-5.50 (m, 1H), 4.02-4.36 (m, 4H), 3.65-3.94 (m, 1H), 3.35-3.41 (m, 2H), 2.67-2.89 (m, 2H), 2.52-2.62 (m, 2H). Separation conditions: chromatographic column model: Chiralcel IC-3; chromatographic column specifications: 50 × 4.6mm ID, 3 μm; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 40% fixed concentration elution for 4 minutes; detection wavelength: 254 nm; column temperature: 40°C. 44-P1 Retention time 1.002 min, ee 99.62%. MS-ESI [M+H] ⁺ , calculated 468, found 468. ¹ H NMR (400 MHz, MeOD) δ 7.24-7.30 (m, 2H), 7.12-7.15 (m, 1H), 7.04-7.08 (m, 1H), 6.94-6.99 (m, 1H), 5.28 (s, 1H), 4.03 (d, J = 16.0 Hz, 1H), 3.59-3.67 (m, 1H), 3.45-3.50 (m, 1H), 2.88-3.03 (m, 2H), 2.70-2.82 (m, 2H), 2.60 (s, 3H), 2.48-2.58 (m, 2H), 2.05-2.18 (m, 2H), 1.80-2.02 (m, 4H). 44-P2 Retention time 1.868 min, ee 99.78%. MS-ESI [M+H] ⁺ , calculated 468, found 468. ¹ H NMR (400 MHz, MeOD) δ 7.24-7.30 (m, 2H), 7.13 (d, J = 7.2 Hz, 1H), 7.03-7.08 (m, 1H), 6.94-6.99 (m, 1H), 5.28 (s, 1H), 4.03 (d, J = 16.0 Hz, 1H), 3.55-3.68 (m, 1H), 3.44-3.53 (m, 1H), 2.87-3.06 (m, 2H), 2.67-2.81 (m, 2H), 2.60 (s, 3H), 2.46-2.57 (m, 2H), 2.05-2.19 (m, 2H), 1.81-2.03 (m, 4H). Separation conditions: chromatographic column model: Chiralcel AS-3; chromatographic column specifications: 50 × 4.6mm ID, 3 μm; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 5%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 5% fixed concentration elution for 0.5 minutes; detection wavelength: 254 nm; column temperature: 40°C. 45-P1 Retention time 1.134 min, ee 100%. MS-ESI [M+H] ⁺ , calculated 454, found 454. ¹ H NMR (400 MHz, MeOD) δ 7.22-7.34 (m, 2H), 6.92-7.15 (m, 3H), 5.26 (s, 1H), 3.83-4.10 (m, 2H), 3.00-3.10 (m, 3H), 2.68-2.79 (m, 1H), 2.39-2.62 (m, 3H), 2.15-2.36 (m, 3H), 1.99-2.12 (m, 1H), 1.60 (q, J = 9.6 Hz, 1H), 1.31-1.41 (m, 2H). 45-P2 Retention time 1.856 min, ee 99.42%. MS-ESI [M+H] ⁺ , calculated 454, found 454. ¹ H NMR (400 MHz, MeOD) δ 7.23-7.32 (m, 2H), 6.93-7.14 (m, 3H), 5.26 (s, 1H), 3.84-4.09 (m, 2H), 2.98-3.09 (m, 3H), 2.68-2.78 (m, 1H), 2.40-2.63 (m, 3H), 2.13-2.38 (m, 3H), 1.99-2.12 (m, 1H), 1.54-1.66 (m, 1H), 1.31-1.44 (m, 2H). Separation conditions: chromatographic column model: Chiralpak AS-3; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 5%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 5% fixed concentration elution for 0.5 minutes; detection wavelength: 254 nm; column temperature: 35°C. 46-P1 Retention time 1.107 min, ee 100.00%. MS-ESI [M+H] ⁺ , calculated 454, found 454. ¹ H NMR: (400 MHz, CD ₃ OD) δ (ppm) 7.23-7.34 (m, 2H), 7.07-7.22 (m, 2H), 6.98-6.98 (m, 1H), 6.97 (br s, 1H), 5.28 (br s, 1H), 4.04 (br dd, J = 16.0, 4.3 Hz, 1H), 3.42-3.61 (m, 1H), 3.27 (br s, 1H), 3.15 (br d, J = 3.6 Hz, 1H), 2.91-3.04 (m, 1H), 2.73-2.82 (m, 1H), 2.66-2.72 (m, 3H), 2.48-2.64 (m, 2H), 1.07-1.25 (m, 1H), 0.53-0.75 (m, 2H), 0.22-0.48 (m, 2H). 46-P2 Retention time 1.646 min, ee 99.44%. MS-ESI [M+H] ⁺ , calculated 454, found 454. ¹ H NMR: (400 MHz, CD ₃ OD) δ (ppm) 7.23-7.32 (m, 2H), 7.07-7.21 (m, 2H), 6.93-7.02 (m, 1H), 5.28 (s, 1H), 4.04 (d, J = 16.0 Hz, 1H), 3.51 (dd, J = 13.6, 7.2 Hz, 1H), 3.27 (br d, J = 7.2 Hz, 1H), 3.15 (s, 1H), 2.92-3.03 (m, 1H), 2.72-2.79 (m, 1H), 2.70 (s, 3H), 2.50-2.64 (m, 2H), 1.09-1.23 (m, 1H), 0.60 (br d, J = 8.0 Hz, 2H), 0.35 (br dd, J = 10.4, 4.8 Hz, 2H). Separation conditions: chromatographic column model: Chiralpak IH-3; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 20%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 20% fixed concentration elution for 0.5 minutes; detection wavelength: 254 nm; column temperature: 35°C. 47-P1 Retention time 0.704 min, ee 98.78%. MS-ESI [M+H] ⁺ , calculated 457, found 457. ¹ H NMR: (CDCl ₃ , 400 MHz) δ (ppm) 9.29 (br s, 1H), 7.28-7.35 (m, 1H), 7.18 (d, J = 10.8 Hz, 1H), 7.04-7.12 (m, 1H), 6.92-7.02 (m, 1H), 6.84-6.92 (m, 1H), 5.16-5.30 (m, 1H), 4.76 (br d, J = 16.0 Hz, 1H), 4.24-4.48 (m, 2H), 3.79-4.05 (m, 2H), 2.72-2.88 (m, 1H), 2.53-2.70 (m, 2H), 2.36-2.51 (m, 1H), 2.10-2.34 (m, 3H), 1.99-2.07 (m, 1H), 1.26-1.38 (m, 2H). 47-P2 Retention time 1.732 min, ee 99.70%. MS-ESI [M+H] ⁺ , calculated 457, found 457. ¹ H NMR: (CDCl ₃ , 400 MHz) δ (ppm) 9.14-9.35 (m, 1H), 7.29-7.33 (m, 1H), 7.17 (d, J = 12.0 Hz, 1H), 7.04-7.11 (m, 1H), 6.93-7.00 (m, 1H), 6.84-6.92 (m, 1H), 5.17-5.26 (m, 1H), 4.77 (d, J = 16.0 Hz, 1H), 4.30 (br s, 2H), 3.79-4.04 (m, 2H), 2.74-2.85 (m, 1H), 2.57-2.67 (m, 2H), 2.45 (dt, J = 8.4, 4.5 Hz, 1H), 2.11-2.33 (m, 3H), 1.95-2.09 (m, 1H), 1.26-1.38 (m, 2H).

實施例48 合成化合物48 Example 48 Synthesis of Compound 48

(1)化合物40-9的合成參考實施例40。00下向化合物40-9(660 mg, 1.89 mmol)的 N,N-二甲基甲醯胺(10.0 mL)溶液中，加入碳酸銫(1.54 g, 4.72 mmol)和中間體F(414 mg, 1.89 mmol)。反應液在氮氣保護下60應攪拌3小時。反應液加入水(50.0 mL)，用乙酸乙酯(200 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/乙酸乙酯 = 1 ：0 到 1 ：1) 分離得到化合物48-1。 (1) Synthesis of Compound 40-9 Refer to Example 40. Cs (2-(4-(6-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-

MS-ESI [M+H] ⁺，計算值532，實測值532。 MS-ESI [M+H] ⁺ , calcd. 532, found 532.

(2)向化合物48-1(750 mg, 1.41 mmol)的甲苯 (10.0 mL)溶液中，加入2,4-二甲氧基苄胺(471 mg, 2.82 mmol, 423 μL)，碳酸銫(918 mg, 2.82 mmol)，三(二亞苄基丙酮)二鈀(129 mg, 140 μmol)，1,1'-聯萘-2,2'-雙二苯膦(175 mg, 281 μmol)。反應液在氮氣保護下120℃攪拌12小時，反應液加入水(50.0 mL)，用乙酸乙酯(200 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/乙酸乙酯 = 1 ：0 到 3 ：1)分離得到化合物48-2。(2) To a toluene (10.0 mL) solution of compound 48-1 (750 mg, 1.41 mmol), 2,4-dimethoxybenzylamine (471 mg, 2.82 mmol, 423 μL), cesium carbonate (918 mg, 2.82 mmol), tri(dibenzylideneacetone)dipalladium (129 mg, 140 μmol), and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (175 mg, 281 μmol) were added. The reaction solution was stirred at 120°C for 12 hours under nitrogen protection, water (50.0 mL) was added to the reaction solution, and the solution was extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 3:1) to obtain compound 48-2.

MS-ESI [M+H] ⁺，計算值663，實測值663。 MS-ESI [M+H] ⁺ , calcd. 663, found 663.

(3)向化合物48-2(900 mg, 1.36 mmol)的四氫呋喃(9.0 mL)溶液中，加入一水合氫氧化鋰(3.0 mL, 2 mol/L)。反應液在氮氣保護下30℃攪拌12小時。反應液在0℃下加入鹽酸水溶液調節pH值到7，用乙酸乙酯(100 mL × 2)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。得到化合物48-3。(3) To a solution of compound 48-2 (900 mg, 1.36 mmol) in tetrahydrofuran (9.0 mL), lithium hydroxide monohydrate (3.0 mL, 2 mol/L) was added. The reaction solution was stirred at 30°C for 12 hours under nitrogen protection. Aqueous hydrochloric acid solution was added to the reaction solution at 0°C to adjust the pH value to 7, and the solution was extracted with ethyl acetate (100 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 48-3.

MS-ESI [M+H] ⁺，計算值650，實測值650。 MS-ESI [M+H] ⁺ , calcd. 650, found 650.

(4)向化合物48-3(300 mg, 462 μmol)的 N,N-二甲基甲醯胺(5.0 mL)溶液中加入二異丙基乙基胺(298 mg, 2.31 mmol, 402 μL)和 N,N,Nmg,-四甲基- O-(7-氮雜苯并三唑-1-基)六氟磷酸脲(263 mg, 693 μmol)，室溫下攪拌25分鐘，隨後加入甲基環丁基胺鹽酸鹽(281 mg, 2.31 mmol)，反應液在氮氣保護下25液攪拌2小時。反應液加入水(30.0 mL)，用乙酸乙酯(100 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/四氫呋喃 = 1 ：0 到 2 ：1)分離得到化合物48-4。 (4) Diisopropylethylamine (298 mg, 2.31 mmol, 402 μL) and N,N, N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (263 mg, 693 μmol) were added to a solution of compound 48-3 (300 mg, 462 μmol) in N,N- dimethylformamide (5.0 mL), and the mixture was stirred at room temperature for 25 minutes. Methylcyclobutylamine hydrochloride (281 mg, 2.31 mmol) was then added, and the reaction mixture was stirred for 2 hours under nitrogen protection. Water (30.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/tetrahydrofuran = 1:0 to 2:1) to obtain compound 48-4.

MS-ESI [M+H] ⁺，計算值716，實測值716。 MS-ESI [M+H] ⁺ , calcd. 716, found 716.

(5)05下將化合物48-4(220 mg, 307 μmol)的二氯甲烷(3.0 mL)溶液中，加入三氟乙酸(1.0 mL)。反應液在氮氣保護下25應攪拌1小時。反應液加入甲醇(1.0 mL)和氨水 (0.91 g, 7.78 mmol, 1.0 mL)並在氮氣保護下30℃攪拌2小時。反應液加入水(50.0 mL)，用乙酸乙酯(50.0 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經製備高效液相色譜法 (Xtimate C18, 200 mm × 40 mm 7 μm, A:水(甲酸)；B:乙腈, 0%-38%：25分鐘)分離得到化合物48的甲酸鹽。(5) Trifluoroacetic acid (1.0 mL) was added to a solution of compound 48-4 (220 mg, 307 μmol) in dichloromethane (3.0 mL) at 0.5 °C. The reaction solution was stirred at 25 °C for 1 hour under nitrogen protection. Methanol (1.0 mL) and aqueous ammonia (0.91 g, 7.78 mmol, 1.0 mL) were added to the reaction solution and stirred at 30 °C for 2 hours under nitrogen protection. Water (50.0 mL) was added to the reaction solution, and the solution was extracted with ethyl acetate (50.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative HPLC (Xtimate C18, 200 mm × 40 mm 7 μm, A: water (formic acid); B: acetonitrile, 0%-38%: 25 min) to give the formate salt of compound 48.

MS-ESI [M+H] ⁺，計算值436，實測值436。 MS-ESI [M+H] ⁺ , calcd. 436, found 436.

(6) 化合物48的甲酸鹽經掌性超臨界流體色譜法拆分得到化合物48-P1和48-P2。(6) The formate salt of compound 48 was separated by chiral supercritical fluid chromatography to give compounds 48-P1 and 48-P2.

分離條件：色譜柱型號：CHIRALPAK AS-3；色譜柱規格：50 × 4.6 mm I.D.，3 μm；進樣量：10.0 μL；流動相：A：二氧化碳，B：乙醇 (0.05% 二乙胺)，B%：20%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，20%固定濃度洗提0.5分鐘；檢測波長：254 nm；柱溫：35℃。Separation conditions: chromatographic column model: CHIRALPAK AS-3; chromatographic column specifications: 50 × 4.6 mm I.D., 3 μm; injection volume: 10.0 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 20%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 20% fixed concentration elution for 0.5 minutes; detection wavelength: 254 nm; column temperature: 35°C.

化合物48-P1滯留時間0.765分鐘，ee值99.10%。The retention time of compound 48-P1 was 0.765 min and the ee value was 99.10%.

¹H NMR (400 MHz, CDCl ₃) δ9.35 (br s, 1H), 7.32-7.38 (m, 3H), 7.15-7.21 (m, 3H), 5.12-5.20 (m, 1H), 4.71 (d, J= 15.6 Hz, 1H), 4.45 (br d, J= 2.4 Hz, 2H), 3.88-3.92 (m, 1H), 3.08 (s, 3H), 2.84-2.92 (m, 1H), 2.62 (br s, 1H), 2.58 (s, 1H), 2.43 (ddd, J= 13.2, 9.2, 4.0 Hz, 1H), 2.26 (br d, J= 10.0 Hz, 1H), 2.16 (br d, J= 10.4 Hz, 1H), 2.02 (br d, J= 6.8 Hz, 1H), 1.74-1.81 (m, 1H), 1.61 (br d, J= 11.2 Hz, 1H), 1.43-1.53 (m, 1H), 1.28 (br d, J= 13.2 Hz, 1H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.35 (br s, 1H), 7.32-7.38 (m, 3H), 7.15-7.21 (m, 3H), 5.12-5.20 (m, 1H), 4.71 (d, J = 15.6 Hz, 1H), 4.45 (br d, J = 2.4 Hz, 2H), 3.88-3.92 (m, 1H), 3.08 (s, 3H), 2.84-2.92 (m, 1H), 2.62 (br s, 1H), 2.58 (s, 1H), 2.43 (ddd, J = 13.2, 9.2, 4.0 Hz, 1H), 2.26 (br d, J = 10.0 Hz, 1H), 2.16 (br d, J = 10.4 Hz, 1H), 2.02 (br d, J = 6.8 Hz, 1H), 1.74-1.81 (m, 1H), 1.61 (br d, J = 11.2 Hz, 1H), 1.43-1.53 (m, 1H), 1.28 (br d, J = 13.2 Hz, 1H).

化合物48-P2滯留時間1.548分鐘，ee值99.74%。The retention time of compound 48-P2 was 1.548 minutes and the ee value was 99.74%.

MS-ESI [M+H] ⁺, 計算值436, 實測值436。 MS-ESI [M+H] ⁺ , calcd. 436, found 436.

¹H NMR (400 MHz, CDCl ₃) δ9.31 (br s, 1H), 7.24-7.30 (m, 3H), 7.07-7.14 (m, 3H), 5.08 (s, 1H), 4.62 (d, J= 15.6 Hz, 1H), 4.45 (br s, 2H), 3.83 (br s, 1H), 3.00 (s, 3H), 2.75-2.84 (m, 1H), 2.55 (br d, J= 5.2 Hz, 1H), 2.51 (s, 1H), 2.32-2.38 (m, 1H), 2.13-2.19 (m, 1H), 2.07 (s, 1H), 1.92-1.96 (m, 1H), 1.66-1.74 (m, 1H), 1.53 (br d, J= 10.0 Hz, 1H), 1.37-1.44 (m, 1H), 1.22-1.27 (m, 1H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.31 (br s, 1H), 7.24-7.30 (m, 3H), 7.07-7.14 (m, 3H), 5.08 (s, 1H), 4.62 (d, J = 15.6 Hz, 1H), 4.45 (br s, 2H), 3.83 (br s, 1H), 3.00 (s, 3H), 2.75-2.84 (m, 1H), 2.55 (br d, J = 5.2 Hz, 1H), 2.51 (s, 1H), 2.32-2.38 (m, 1H), 2.13-2.19 (m, 1H), 2.07 (s, 1H), 1.92-1.96 (m, 1H), 1.66-1.74 (m, 1H), 1.53 (br d, J = 10.0 Hz, 1H), 1.37-1.44 (m, 1H), 1.22-1.27 (m, 1H).

實施例49-51 合成化合物49-P1, 49-P2至51-P1, 51-P2Example 49-51 Synthesis of Compounds 49-P1, 49-P2 to 51-P1, 51-P2

化合物49-P1, 49-P2至51-P1, 51-P2的製備參考實施例48，使用對應的胺替換甲基環丁基胺。分離條件：色譜柱型號：Chiralpak AS-3；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇(0.05% 二乙胺)，B%：20%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，20%固定濃度洗提0.5分鐘；檢測波長：254 nm；柱溫：35℃。 49-P1 滯留時間0.725分鐘，ee值99.60%。 MS-ESI [M+H] ⁺，計算值439，實測值439。 ¹H NMR: (CDCl ₃, 400 MHz) δ9.29 (br d, J= 1.2 Hz, 1H), 7.30-7.42 (m, 3H), 7.11-7.22 (m, 3H), 5.07-5.18 (m, 1H), 4.73 (br d, J= 15.2 Hz, 1H), 4.30 (br s, 2H), 3.85-3.98 (m, 2H), 2.78-3.00 (m, 1H), 2.55-2.69 (m, 2H), 2.37-2.49 (m, 1H), 2.10-2.30 (m, 3H), 1.97-2.07 (m, 1H), 1.65-1.82 (m, 1H), 1.25-1.37 (m, 1H)。 49-P2 滯留時間1.533分鐘，ee值98.42%。 MS-ESI [M+H] ⁺，計算值439，實測值439。 ¹H NMR: (CDCl ₃, 400 MHz) δ9.33 (br d, J= 2.0 Hz, 1H), 7.30-7.37 (m, 4H), 7.10-7.24 (m, 2H), 5.08-5.25 (m, 1H), 4.66-4.82 (m, 1H), 4.29-4.59 (m, 2H), 3.83-4.05 (m, 2H), 2.88 (br dd, J= 9.2, 4.4 Hz, 1H), 2.59-2.70 (m, 2H), 2.38-2.49 (m, 1H), 2.11-2.34 (m, 3H), 2.02 (br s, 1H), 1.78-1.90 (m, 1H), 1.25-1.39 (m, 1H)。分離條件：色譜柱型號：Chiralpak AS-3；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇(0.05% 二乙胺)，B%：20%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，20%固定濃度洗提0.5分鐘；檢測波長：254 nm；柱溫：352。 50-P1 滯留時間0.788分鐘，ee值99.90%。 MS-ESI [M+H] ⁺，計算值422，實測值422。 ¹H NMR: (400 MHz, CD ₃OD) δ(ppm) 7.20-7.40 (m, 6H), 5.20 (s, 1H), 4.86-4.87 (m, 1H), 4.04 (br d, J= 16.0 Hz, 1H), 2.64-3.19 (m, 4H), 2.57 (br s, 3H), 2.46-2.54 (m, 1H), 0.63-0.97 (m, 4H)。 50-P2 滯留時間1.346分鐘，ee值98.80%。 MS-ESI [M+H] ⁺，計算值422，實測值422。 ¹H NMR：(400 MHz, CD ₃OD) δ(ppm) 7.21-7.36 (m, 6H), 5.20 (s, 1H), 4.89 (br s, 1H), 4.04 (br d, J= 16.0 Hz, 1H), 2.62-3.10 (m, 4H), 2.57 (br s, 3H), 2.47-2.54 (m, 1H), 0.56-1.05 (m, 4H)。分離條件：色譜柱型號：Chiralpak AS-3；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇(0.05% 二乙胺)，B%：5%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，5%固定濃度洗提0.5分鐘；檢測波長：254 nm；柱溫：35℃。 51-P1 滯留時間1.321分鐘，ee值99.06%。 MS-ESI [M+H] ⁺，計算值448，實測值448。 ¹H NMR: (CDCl ₃, 400 MHz) δ(ppm) 9.39 (br s, 1H), 7.34-7.40 (m, 3H), 7.18-7.25 (m, 3H), 5.49 (s, 1H), 4.57 (d, J= 16.0 Hz, 1H), 4.32 (br s, 2H), 4.21 (d, J= 16.0 Hz, 1H), 4.03-4.12 (m, 2H), 3.73 (br d, J= 10.0 Hz, 1H), 3.47 (br d, J= 8.80 Hz, 1H), 2.53-2.64 (m, 4H), 2.07-2.21 (m, 2H), 1.92-2.04 (m, 2H), 1.78-1.87 (m, 1H), 1.68-1.77 (m, 1H)。 51-P2 滯留時間1.456分鐘，ee值97.82%。 MS-ESI [M+H] ⁺，計算值448，實測值448。 ¹H NMR: (CDCl ₃, 400 MHz) δ(ppm) 9.42 (br s, 1H), 7.34-7.40 (m, 3H), 7.19-7.25 (m, 3H), 5.50 (s, 1H), 4.56 (d, J= 15.6 Hz, 1H), 4.24-4.52 (m, 2H), 4.20 (d, J= 15.6 Hz, 1H), 4.04-4.11 (m, 2H), 3.73 (br d, J= 9.2 Hz, 1H), 3.43-3.49 (m, 1H), 2.54-2.65 (m, 4H), 2.11-2.20 (m, 2H), 1.93-2.02 (m, 2H), 1.78-1.85 (m, 1H), 1.72 (br dd, J= 9.6, 1.1 Hz, 1H)。 The preparation of compounds 49-P1, 49-P2 to 51-P1, 51-P2 was carried out according to Example 48, using corresponding amines instead of methylcyclobutylamine. Separation conditions: chromatographic column model: Chiralpak AS-3; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 20%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 20% fixed concentration elution for 0.5 minutes; detection wavelength: 254 nm; column temperature: 35°C. 49-P1 Retention time 0.725 min, ee 99.60%. MS-ESI [M+H] ⁺ , calculated 439, found 439. ¹ H NMR: (CDCl ₃ , 400 MHz) δ 9.29 (br d, J = 1.2 Hz, 1H), 7.30-7.42 (m, 3H), 7.11-7.22 (m, 3H), 5.07-5.18 (m, 1H), 4.73 (br d, J = 15.2 Hz, 1H), 4.30 (br s, 2H), 3.85-3.98 (m, 2H), 2.78-3.00 (m, 1H), 2.55-2.69 (m, 2H), 2.37-2.49 (m, 1H), 2.10-2.30 (m, 3H), 1.97-2.07 (m, 1H), 1.65-1.82 (m, 1H), 1.25-1.37 (m, 1H). 49-P2 Retention time 1.533 min, ee 98.42%. MS-ESI [M+H] ⁺ , calculated 439, found 439. ¹ H NMR: (CDCl ₃ , 400 MHz) δ 9.33 (br d, J = 2.0 Hz, 1H), 7.30-7.37 (m, 4H), 7.10-7.24 (m, 2H), 5.08-5.25 (m, 1H), 4.66-4.82 (m, 1H), 4.29-4.59 (m, 2H), 3.83-4.05 (m, 2H), 2.88 (br dd, J = 9.2, 4.4 Hz, 1H), 2.59-2.70 (m, 2H), 2.38-2.49 (m, 1H), 2.11-2.34 (m, 3H), 2.02 (br s, 1H), 1.78-1.90 (m, 1H), 1.25-1.39 (m, 1H). Separation conditions: chromatographic column model: Chiralpak AS-3; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 20%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 20% fixed concentration elution for 0.5 minutes; detection wavelength: 254 nm; column temperature: 352. 50-P1 Retention time 0.788 min, ee 99.90%. MS-ESI [M+H] ⁺ , calculated 422, found 422. ¹ H NMR: (400 MHz, CD ₃ OD) δ (ppm) 7.20-7.40 (m, 6H), 5.20 (s, 1H), 4.86-4.87 (m, 1H), 4.04 (br d, J = 16.0 Hz, 1H), 2.64-3.19 (m, 4H), 2.57 (br s, 3H), 2.46-2.54 (m, 1H), 0.63-0.97 (m, 4H). 50-P2 Retention time 1.346 min, ee 98.80%. MS-ESI [M+H] ⁺ , calculated 422, found 422. ¹ H NMR: (400 MHz, CD ₃ OD) δ (ppm) 7.21-7.36 (m, 6H), 5.20 (s, 1H), 4.89 (br s, 1H), 4.04 (br d, J = 16.0 Hz, 1H), 2.62-3.10 (m, 4H), 2.57 (br s, 3H), 2.47-2.54 (m, 1H), 0.56-1.05 (m, 4H). Separation conditions: chromatographic column model: Chiralpak AS-3; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 5%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 5% fixed concentration elution for 0.5 minutes; detection wavelength: 254 nm; column temperature: 35°C. 51-P1 Retention time 1.321 min, ee 99.06%. MS-ESI [M+H] ⁺ , calculated 448, found 448. ¹ H NMR: (CDCl ₃ , 400 MHz) δ (ppm) 9.39 (br s, 1H), 7.34-7.40 (m, 3H), 7.18-7.25 (m, 3H), 5.49 (s, 1H), 4.57 (d, J = 16.0 Hz, 1H), 4.32 (br s, 2H), 4.21 (d, J = 16.0 Hz, 1H), 4.03-4.12 (m, 2H), 3.73 (br d, J = 10.0 Hz, 1H), 3.47 (br d, J = 8.80 Hz, 1H), 2.53-2.64 (m, 4H), 2.07-2.21 (m, 2H), 1.92-2.04 (m, 2H), 1.78-1.87 (m, 1H), 1.68-1.77 (m, 1H). 51-P2 Retention time 1.456 min, ee 97.82%. MS-ESI [M+H] ⁺ , calculated 448, found 448. ¹ H NMR: (CDCl ₃ , 400 MHz) δ (ppm) 9.42 (br s, 1H), 7.34-7.40 (m, 3H), 7.19-7.25 (m, 3H), 5.50 (s, 1H), 4.56 (d, J = 15.6 Hz, 1H), 4.24-4.52 (m, 2H), 4.20 (d, J = 15.6 Hz, 1H), 4.04-4.11 (m, 2H), 3.73 (br d, J = 9.2 Hz, 1H), 3.43-3.49 (m, 1H), 2.54-2.65 (m, 4H), 2.11-2.20 (m, 2H), 1.93-2.02 (m, 2H), 1.78-1.85 (m, 1H), 1.72 (br dd, J = 9.6, 1.1 Hz, 1H).

實施例52 化合物52的合成Example 52 Synthesis of Compound 52

合成參考實施例48，使用中間體I替換中間體H，得到化合物52-P1和52-P2。分離條件：色譜柱型號：Chiralpak AS-3；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇(0.05% 二乙胺)，B%：20%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，20%固定濃度洗提0.5分鐘；檢測波長：254 nm；柱溫：35℃。 52-P1 滯留時間0.679分鐘，ee值99.92%。 MS-ESI [M+H] ⁺，計算值438，實測值438。 ¹H NMR: (400 MHz, CD ₃OD) δ(ppm) 7.28 (s, 6H), 5.18 (s, 1H), 3.87-4.03 (m, 1H), 3.01-3.12 (m, 3H), 2.64-2.76 (m, 1H), 2.39-2.60 (m, 3H), 2.09-2.34 (m, 3H), 2.04 (br d, J= 5.6 Hz, 1H), 1.68-1.86 (m, 1H), 1.52-1.64 (m, 1H)。 52-P2 滯留時間1.443分鐘，ee值99.62%。 MS-ESI [M+H] ⁺，計算值438，實測值438。 ¹H NMR: (400 MHz, CD ₃OD) δ(ppm) 7.61 (d, J= 10.4 Hz, 1H), 7.29 (s, 5H), 5.36 (s, 1H), 3.95 (br t, J= 8.4 Hz, 1H), 3.03-3.15 (m, 3H), 2.66-2.80 (m, 1H), 2.38-2.65 (m, 3H), 1.95-2.38 (m, 4H), 1.65-1.91 (m, 1H), 1.44-1.64 (m, 1H)。 Reference Example 48 was synthesized by using Intermediate I to replace Intermediate H to obtain Compounds 52-P1 and 52-P2. Separation conditions: chromatographic column model: Chiralpak AS-3; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 20%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 20% fixed concentration elution for 0.5 minutes; detection wavelength: 254 nm; column temperature: 35°C. 52-P1 Retention time 0.679 min, ee value 99.92%. MS-ESI [M+H] ⁺ , calculated value 438, found value 438. ¹ H NMR: (400 MHz, CD ₃ OD) δ (ppm) 7.28 (s, 6H), 5.18 (s, 1H), 3.87-4.03 (m, 1H), 3.01-3.12 (m, 3H), 2.64-2.76 (m, 1H), 2.39-2.60 (m, 3H), 2.09-2.34 (m, 3H), 2.04 (br d, J = 5.6 Hz, 1H), 1.68-1.86 (m, 1H), 1.52-1.64 (m, 1H). 52-P2 Retention time 1.443 min, ee 99.62%. MS-ESI [M+H] ⁺ , calculated 438, found 438. ¹ H NMR: (400 MHz, CD ₃ OD) δ (ppm) 7.61 (d, J = 10.4 Hz, 1H), 7.29 (s, 5H), 5.36 (s, 1H), 3.95 (br t, J = 8.4 Hz, 1H), 3.03-3.15 (m, 3H), 2.66-2.80 (m, 1H), 2.38-2.65 (m, 3H), 1.95-2.38 (m, 4H), 1.65-1.91 (m, 1H), 1.44-1.64 (m, 1H).

實施例53 化合物53的合成Example 53 Synthesis of Compound 53

合成參考實施例52，使用氘代甲基環丁基胺替換甲基環丁基胺，得到化合物53-P1和53-P2。分離條件：色譜柱型號：Chiralpak AS-3；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇(0.05% 二乙胺)，B%：20%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，20%固定濃度洗提0.5分鐘；檢測波長：254 nm；柱溫：35℃。 53-P1 滯留時間0.692分鐘，ee值98.24%。 MS-ESI [M+H] ⁺，計算值441，實測值441。 ¹H NMR: (400 MHz, CD ₃OD) δ(ppm) 9.28 (s, 1H), 7.25-7.43 (m, 4H), 7.15-7.18 (m, 2H),5.08-5.13(m, 1H), 4.30 (s, 2H), 3.96-3.92(m, 1H), 2.82-2.92(m, 1H), 2.57-2.60(m, 2H), 2.36-2.49(m, 1H), 2.26-2.33(m, 1H), 2.12-2.17(m, 1H), 1.96-2.05(m, 1H), 1.65-1.8(m, 1H), 1.45-1.52(m, 1H), 1.26-1.35(m, 1H)。 53-P2 滯留時間1.447分鐘，ee值99.54%。 MS-ESI [M+H] ⁺，計算值441，實測值441。 ¹H NMR: (400 MHz, CD ₃OD) δ(ppm) 9.28 (s, 1H), 7.26-7.43 (m, 4H), 7.14-7.18 (m, 2H),5.08-5.17(m, 1H), 4.29 (s, 2H), 3.96-3.92(m, 1H), 2.82-2.92(m, 1H), 2.57-2.60(m, 2H), 2.36-2.49(m, 1H), 2.26-2.33(m, 1H), 2.12-2.17(m, 1H), 1.96-2.05(m, 1H), 1.65-1.8(m, 1H), 1.45-1.52(m, 1H), 1.26-1.34(m, 1H)。 Reference Example 52 was synthesized by using deuterated methylcyclobutylamine in place of methylcyclobutylamine to obtain compounds 53-P1 and 53-P2. Separation conditions: chromatographic column model: Chiralpak AS-3; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 20%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 20% fixed concentration elution for 0.5 minutes; detection wavelength: 254 nm; column temperature: 35°C. 53-P1 Retention time 0.692 min, ee value 98.24%. MS-ESI [M+H] ⁺ , calculated value 441, found value 441. ¹ H NMR: (400 MHz, CD ₃ OD) δ (ppm) 9.28 (s, 1H), 7.25-7.43 (m, 4H), 7.15-7.18 (m, 2H), 5.08-5.13(m, 1H), 4.30 (s, 2H), 3.96-3.92(m, 1H), 2.82-2.92(m, 1H), 2.57-2.60(m, 2H), 2.36-2.49(m, 1H), 2.26-2.33(m, 1H), 2.12-2.17(m, 1H), 1.96-2.05(m, 1H), 1.65-1.8(m, 1H), 1.45-1.52(m, 1H), 1.26-1.35(m, 1H). 53-P2 Retention time 1.447 min, ee 99.54%. MS-ESI [M+H] ⁺ , calculated 441, found 441. ¹ H NMR: (400 MHz, CD ₃ OD) δ (ppm) 9.28 (s, 1H), 7.26-7.43 (m, 4H), 7.14-7.18 (m, 2H), 5.08-5.17(m, 1H), 4.29 (s, 2H), 3.96-3.92(m, 1H), 2.82-2.92(m, 1H), 2.57-2.60(m, 2H), 2.36-2.49(m, 1H), 2.26-2.33(m, 1H), 2.12-2.17(m, 1H), 1.96-2.05(m, 1H), 1.65-1.8(m, 1H), 1.45-1.52(m, 1H), 1.26-1.34 (m, 1H).

實施例54 化合物54的合成Example 54 Synthesis of Compound 54

合成參考實施例40，使用中間體I替換中間體H，得到化合物54-P1和54-P2。分離條件：色譜柱型號：Chiralpak AS-3；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇(0.05% 二乙胺)，B%：5%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，5%固定濃度洗提0.5分鐘；檢測波長：254 nm；柱溫：35℃。 54-P1 滯留時間1.093分鐘，ee值98.54%。 MS-ESI [M+H] ⁺，計算值456，實測值456。 ¹H NMR: (CDCl ₃, 400 MHz) δ(ppm) 9.27 (br s, 1H), 7.29-7.33 (m, 1H), 7.18 (d, J= 10.8 Hz, 1H), 7.07 (br t, J= 7.6 Hz, 1H), 6.93-6.99 (m, 1H), 6.85-6.91 (m, 1H), 5.18-5.27 (m, 1H), 4.35 (br s, 2H), 3.83-3.93 (m, 1H), 3.08 (s, 3H), 2.78-2.86 (m, 1H), 2.59-2.66 (m, 2H), 2.39-2.49 (m, 1H), 2.16-2.29 (m, 2H), 2.01-2.05 (m, 1H), 1.64 (br d, J= 10.8 Hz, 1H), 1.51 (br s, 1H), 1.31-1.38 (m, 1H)。 54-P2 滯留時間1.739分鐘，ee值99.76%。 MS-ESI [M+H] ⁺，計算值456，實測值456。 ¹H NMR: (CDCl ₃, 400 MHz) δ(ppm) 9.27 (br s, 1H), 7.29-7.33 (m, 1H), 7.18 (d, J= 11.2 Hz, 1H), 7.08 (td, J= 8.4, 1.9 Hz, 1H), 6.95 (br d, J= 8.0 Hz, 1H), 6.87 (br d, J= 10.0 Hz, 1H), 5.19-5.25 (m, 1H), 4.33 (br s, 2H), 3.84-3.92 (m, 1H), 3.08 (s, 3H), 2.77-2.86 (m, 1H), 2.59-2.66 (m, 2H), 2.44 (ddd, J= 12.8, 8.9, 3.9 Hz, 1H), 2.23-2.29 (m, 1H), 2.16-2.21 (m, 1H), 2.00-2.06 (m, 1H), 1.67-1.79 (m, 1H), 1.62-1.66 (m, 1H), 1.35 (br d, J= 10.0 Hz, 1H)。 Reference Example 40 was synthesized by using Intermediate I in place of Intermediate H to obtain Compounds 54-P1 and 54-P2. Separation conditions: chromatographic column model: Chiralpak AS-3; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 5%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 5% fixed concentration elution for 0.5 minutes; detection wavelength: 254 nm; column temperature: 35°C. 54-P1 Retention time 1.093 min, ee 98.54%. MS-ESI [M+H] ⁺ , calculated 456, found 456. ¹ H NMR: (CDCl ₃ , 400 MHz) δ (ppm) 9.27 (br s, 1H), 7.29-7.33 (m, 1H), 7.18 (d, J = 10.8 Hz, 1H), 7.07 (br t, J = 7.6 Hz, 1H), 6.93-6.99 (m, 1H), 6.85-6.91 (m, 1H), 5.18-5.27 (m, 1H), 4.35 (br s, 2H), 3.83-3.93 (m, 1H), 3.08 (s, 3H), 2.78-2.86 (m, 1H), 2.59-2.66 (m, 2H), 2.39-2.49 (m, 1H), 2.16-2.29 (m, 2H), 2.01-2.05 (m, 1H), 1.64 (br d, J = 10.8 Hz, 1H), 1.51 (br s, 1H), 1.31-1.38 (m, 1H). 54-P2 Retention time 1.739 min, ee 99.76%. MS-ESI [M+H] ⁺ , calculated 456, found 456. ¹ H NMR: (CDCl ₃ , 400 MHz) δ (ppm) 9.27 (br s, 1H), 7.29-7.33 (m, 1H), 7.18 (d, J = 11.2 Hz, 1H), 7.08 (td, J = 8.4, 1.9 Hz, 1H), 6.95 (br d, J = 8.0 Hz, 1H), 6.87 (br d, J = 10.0 Hz, 1H), 5.19-5.25 (m, 1H), 4.33 (br s, 2H), 3.84-3.92 (m, 1H), 3.08 (s, 3H), 2.77-2.86 (m, 1H), 2.59-2.66 (m, 2H), 2.44 (ddd, J = 12.8, 8.9, 3.9 Hz, 1H), 2.23-2.29 (m, 1H), 2.16-2.21 (m, 1H), 2.00-2.06 (m, 1H), 1.67-1.79 (m, 1H), 1.62-1.66 (m, 1H), 1.35 (br d, J = 10.0 Hz, 1H).

實施例55 化合物55的合成 Example 55 Synthesis of Compound 55

合成參考實施例54，使用氘代甲基環丁基胺替換甲基環丁基胺，得到化合物55。Reference Example 54 was synthesized by using deuterated methylcyclobutylamine to replace methylcyclobutylamine to obtain Compound 55.

MS-ESI [M+H] ⁺, 計算值459, 實測值459。 MS-ESI [M+H] ⁺ , calcd. 459, found 459.

¹H NMR：(CDCl ₃, 400 MHz) δ8.41 (s, 1H), 7.29-7.37 (m, 2H), 7.06-7.14 (m, 1H), 6.91-7.01 (m, 1H), 6.85 (br d, J= 9.6 Hz, 1H), 5.26-5.38 (m, 1H), 3.77-3.99 (m, 1H), 2.78-2.86 (m, 1H), 2.61-2.67 (m, 2H), 2.37-2.51 (m, 1H), 2.12-2.29 (m, 3H), 1.98-2.08 (m, 1H), 1.57-1.89 (m, 2H), 1.52 (br d, J= 4.0 Hz, 1H), 1.30-1.42 (m, 1H)。 ¹ H NMR: (CDCl ₃ , 400 MHz) δ 8.41 (s, 1H), 7.29-7.37 (m, 2H), 7.06-7.14 (m, 1H), 6.91-7.01 (m, 1H), 6.85 (br d, J = 9.6 Hz, 1H), 5.26-5.38 (m, 1H), 3.77-3.99 (m, 1H), 2.78-2.86 (m, 1H), 2.61-2.67 (m, 2H), 2.37-2.51 (m, 1H), 2.12-2.29 (m, 3H), 1.98-2.08 (m, 1H), 1.57-1.89 (m, 2H), 1.52 (br d, J = 4.0 Hz, 1H), 1.30-1.42 (m, 1H).

實施例56-59 合成化合物56至59Examples 56-59 Synthesis of Compounds 56 to 59

化合物56至59的製備參考實施例4，使用對應的胺替換4-4。 MS-ESI [M+H] ⁺，計算值464，實測值464。 ¹H NMR (400 MHz, MeOD) δ8.50 (s, 1H), 7.68 (s, 1H), 7.34 (td, J= 8.0, 6.4 Hz, 1H), 7.09-7.23 (m, 2H), 7.02 (td, J= 8.4, 2.4 Hz, 1H), 5.63 (s, 1H), 4.82 (br d, J= 16.4 Hz, 1H), 4.72 (br t, J= 6.8 Hz, 2H), 4.61-4.68 (m, 1H), 4.55 (br d, J= 6.8 Hz, 1H), 4.28 (d, J= 16.4 Hz, 1H), 4.24 (s, 1H), 4.13 (br d, J= 10.0 Hz, 1H), 3.58 (br d, J= 10.0 Hz, 1H), 2.48-2.90 (m, 4H), 2.23 (s, 3H)。 MS-ESI [M+H] ⁺，計算值452，實測值452。 ¹H NMR (400 MHz, MeOD) δ7.27-7.34 (m, 1H), 7.26 (s, 1H), 7.19-7.23 (m, 1H), 7.15 (dt, J= 10.4, 2.0 Hz, 1H), 6.92-7.01 (m, 1H), 5.24 (s, 1H), 4.90 (d, J= 16.0 Hz, 1H), 4.06 (d, J= 16.0 Hz, 1H), 3.65-3.84 (m, 4H), 3.41-3.50 (m, 1H), 3.32-3.36 (m, 1H), 3.11-3.22 (m, 1H), 2.89-3.04 (m, 2H), 2.66-2.80 (m, 1H), 2.49-2.63 (m, 2H), 2.17 (s, 3H)。 MS-ESI [M+H] ⁺，計算值478，實測值478。 ¹H NMR (400 MHz, CDCl ₃) δ9.11 (br s, 1H), 7.32-7.41 (m, 1H), 7.26 (br s, 1H), 7.02-7.12 (m, 2H), 6.97 (br d, J= 9.2 Hz, 1H), 5.61 (s, 1H), 4.57 (d, J= 15.2 Hz, 1H), 4.34-4.44 (m, 1H), 4.17-4.28 (m, 2H), 4.01-4.09 (m, 2H), 3.61-3.81 (m, 5H), 3.50-3.56 (m, 1H), 2.57-2.63 (m, 3H), 2.47-2.54 (m, 1H), 2.21 (s, 3H), 1.90-2.05 (m, 1H), 1.69-1.79 (m, 1H)。 MS-ESI [M+H] ⁺，計算值488，實測值488。 ¹H NMR (400 MHz, MeOD) δ7.37-7.53 (m, 1H), 7.03-7.37 (m, 4H), 6.84-7.03 (m, 1H), 5.70-6.27 (m, 1H), 5.25 (br d, J= 7.2 Hz, 1H), 4.87-5.04 (m, 2H), 4.42 (br d, J= 16.8 Hz, 1H), 4.04-4.35 (m, 3H), 3.74-4.04 (m, 1H), 3.41-3.68 (m, 1H), 2.96-3.19 (m, 1H), 2.48-2.83 (m, 3H), 2.17 (s, 3H)。 Compounds 56 to 59 were prepared according to Example 4, using the corresponding amines in place of 4-4. MS-ESI [M+H] ⁺ , calcd. 464, found 464. ¹ H NMR (400 MHz, MeOD) δ 8.50 (s, 1H), 7.68 (s, 1H), 7.34 (td, J = 8.0, 6.4 Hz, 1H), 7.09-7.23 (m, 2H), 7.02 (td, J = 8.4, 2.4 Hz, 1H), 5.63 (s, 1H), 4.82 (br d, J = 16.4 Hz, 1H), 4.72 (br t, J = 6.8 Hz, 2H), 4.61-4.68 (m, 1H), 4.55 (br d, J = 6.8 Hz, 1H), 4.28 (d, J = 16.4 Hz, 1H), 4.24 (s, 1H), 4.13 (br d, J = 10.0 Hz, 1H), 3.58 (br d, J = 10.0 Hz, 1H), 2.48-2.90 (m, 4H), 2.23 (s, 3H). MS-ESI [M+H] ⁺ , calcd. 452, found 452. ¹ H NMR (400 MHz, MeOD) δ 7.27-7.34 (m, 1H), 7.26 (s, 1H), 7.19-7.23 (m, 1H), 7.15 (dt, J = 10.4, 2.0 Hz, 1H), 6.92-7.01 (m, 1H), 5.24 (s, 1H), 4.90 (d, J = 16.0 Hz, 1H), 4.06 (d, J = 16.0 Hz, 1H), 3.65-3.84 (m, 4H), 3.41-3.50 (m, 1H), 3.32-3.36 (m, 1H), 3.11-3.22 (m, 1H), 2.89-3.04 (m, 2H), 2.66-2.80 (m, 1H), 2.49-2.63 (m, 2H), 2.17 (s, 3H). MS-ESI [M+H] ⁺ , calcd. 478, found 478. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.11 (br s, 1H), 7.32-7.41 (m, 1H), 7.26 (br s, 1H), 7.02-7.12 (m, 2H), 6.97 (br d, J = 9.2 Hz, 1H), 5.61 (s, 1H), 4.57 (d, J = 15.2 Hz, 1H), 4.34-4.44 (m, 1H), 4.17-4.28 (m, 2H), 4.01-4.09 (m, 2H), 3.61-3.81 (m, 5H), 3.50-3.56 (m, 1H), 2.57-2.63 (m, 3H), 2.47-2.54 (m, 1H), 2.21 (s, 3H), 1.90-2.05 (m, 1H), 1.69-1.79 (m, 1H). MS-ESI [M+H] ⁺ , calcd. 488, found 488. ¹ H NMR (400 MHz, MeOD) δ 7.37-7.53 (m, 1H), 7.03-7.37 (m, 4H), 6.84-7.03 (m, 1H), 5.70-6.27 (m, 1H), 5.25 (br d, J = 7.2 Hz, 1H), 4.87-5.04 (m, 2H), 4.42 (br d, J = 16.8 Hz, 1H), 4.04-4.35 (m, 3H), 3.74-4.04 (m, 1H), 3.41-3.68 (m, 1H), 2.96-3.19 (m, 1H), 2.48-2.83 (m, 3H), 2.17 (s, 3H).

實施例60-62 合成化合物60至62Examples 60-62 Synthesis of Compounds 60 to 62

化合物60-至62的製備參考實施例4，使用對應的第三丁氧羰基保護的胺替換4-4。 MS-ESI [M+H] ⁺，計算值463，實測值463。 ¹H NMR (400 MHz, MeOD) δ7.29-7.38 (m, 2H), 7.07-7.17 (m, 2H), 6.99-7.06 (m, 1H), 5.48-5.63 (m, 1H), 4.56-4.73 (m, 2H), 4.37-4.53 (m, 1H), 4.02-4.15 (m, 2H), 3.76-3.98 (m, 2H), 3.61-3.71 (m, 2H), 3.48-3.60 (m, 1H), 2.53-2.68 (m, 4H), 2.19 (s, 3H)。 MS-ESI [M+H] ⁺，計算值451，實測值451。 ¹H NMR (400 MHz, CDCl ₃) δ9.06 (br s, 1H), 7.28-7.36 (m, 1H), 7.20 (s, 1H), 7.03-7.13 (m, 2H), 6.97 (dd, J= 9.6, 1.6 Hz, 1H), 5.17 (s, 1H), 4.81 (d, J= 15.6 Hz, 1H), 4.16 (br s, 2H), 3.99 (d, J= 15.6 Hz, 1H), 3.66-3.88 (m, 2H), 3.05 (br d, J= 6.0 Hz, 1H), 2.90-3.00 (m, 3H), 2.73-2.83 (m, 1H), 2.64 (dt, J= 8.8, 4.4 Hz, 4H), 2.49-2.57 (m, 1H), 2.19 (s, 3H)。 MS-ESI [M+H] ⁺，計算值477，實測值477。 ¹H NMR (400 MHz, CDCl ₃) δ9.14 (br s, 1H), 7.31-7.37 (m, 1H), 7.24 (s, 1H), 7.03-7.10 (m, 2H), 6.97 (br d, J= 10.0 Hz, 1H), 5.57 (br d, J= 2.00 Hz, 1H), 4.60 (d, J= 15.6 Hz, 1H), 4.32-4.40 (m, 2H), 4.13-4.18 (m, 2H), 4.01 (br s, 2H), 3.61-3.67 (m, 1H), 3.48 (br d, J= 8.80 Hz, 1H), 3.01 (br d, J= 6.80 Hz, 4H), 2.83-2.94 (m,3H), 2.57-2.60 (m, 2H), 2.48-2.54 (m, 1H), 2.20 (s, 3H)。 The preparation of compounds 60- to 62 was carried out according to Example 4, using the corresponding tert-butyloxycarbonyl-protected amine to replace 4-4. MS-ESI [M+H] ⁺ , calcd. 463, found 463. ¹ H NMR (400 MHz, MeOD) δ 7.29-7.38 (m, 2H), 7.07-7.17 (m, 2H), 6.99-7.06 (m, 1H), 5.48-5.63 (m, 1H), 4.56-4.73 (m, 2H), 4.37-4.53 (m, 1H), 4.02-4.15 (m, 2H), 3.76-3.98 (m, 2H), 3.61-3.71 (m, 2H), 3.48-3.60 (m, 1H), 2.53-2.68 (m, 4H), 2.19 (s, 3H). MS-ESI [M+H] ⁺ , calcd. 451 , found 451 . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.06 (br s, 1H), 7.28-7.36 (m, 1H), 7.20 (s, 1H), 7.03-7.13 (m, 2H), 6.97 (dd, J = 9.6, 1.6 Hz, 1H), 5.17 (s, 1H), 4.81 (d, J = 15.6 Hz, 1H), 4.16 (br s, 2H), 3.99 (d, J = 15.6 Hz, 1H), 3.66-3.88 (m, 2H), 3.05 (br d, J = 6.0 Hz, 1H), 2.90-3.00 (m, 3H), 2.73-2.83 (m, 1H), 2.64 (dt, J = 8.8, 4.4 Hz, 4H), 2.49-2.57 (m, 1H), 2.19 (s, 3H). MS-ESI [M+H] ⁺ , calcd. 477, found 477. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.14 (br s, 1H), 7.31-7.37 (m, 1H), 7.24 (s, 1H), 7.03-7.10 (m, 2H), 6.97 (br d, J = 10.0 Hz, 1H), 5.57 (br d, J = 2.00 Hz, 1H), 4.60 (d, J = 15.6 Hz, 1H), 4.32-4.40 (m, 2H), 4.13-4.18 (m, 2H), 4.01 (br s, 2H), 3.61-3.67 (m, 1H), 3.48 (br d, J = 8.80 Hz, 1H), 3.01 (br d, J = 6.80 Hz, 4H), 2.83-2.94 (m,3H), 2.57-2.60 (m, 2H), 2.48-2.54 (m, 1H), 2.20 (s, 3H).

實施例63 化合物63的合成 Example 63 Synthesis of Compound 63

合成參考實施例4，使用中間體J替換中間體G，得到化合物63-P1和63-P2。分離條件：色譜柱型號：Chiralcel OX-3；色譜柱規格：50×4.6mm I.D., 3um；進樣量：10 μL；流動相：A：二氧化碳, B：乙醇+乙腈 (0.1% 二乙胺), B%：40%固定濃度洗提；檢測波長：254 nm；柱溫：35℃。 63-P1 滯留時間1.705分鐘，ee值99.30%。 MS-ESI [M+H] ⁺，計算值464，實測值464。 ¹H NMR: (400 MHz, MeOD) δ7.28-7.36 (m, 2H), 7.13-7.18 (m, 1H), 7.10 (dt, J= 10.4, 2.0 Hz, 1H), 7.01 (td, J= 8.4, 2.0 Hz, 1H), 5.45 (s, 1H), 3.97-4.05 (m, 2H), 3.85 (d, J= 9.6 Hz, 1H), 3.42 (d, J= 9.6 Hz, 1H), 2.49-2.78 (m, 4H), 1.93-2.20 (m, 7H), 1.65-1.85 (m, 2H)。 63-P2 滯留時間2.316分鐘，ee值99.32%。 MS-ESI [M+H] ⁺，計算值464，實測值464。 ¹H NMR: (400 MHz, MeOD) δ7.27-7.36 (m, 2H), 7.15 (d, J= 8.0 Hz, 1H), 7.10 (dt, J= 10.4, 2.0 Hz, 1H), 7.01 (td, J= 8.4, 2.0 Hz, 1H), 5.45 (s, 1H), 3.97-4.05 (m, 2H), 3.85 (d, J= 9.6 Hz, 1H), 3.42 (d, J= 9.6 Hz, 1H), 2.48-2.80 (m, 4H), 1.94-2.23 (m, 7H), 1.64-1.86 (m, 2H)。 The synthesis of Reference Example 4 was carried out by using Intermediate J to replace Intermediate G to obtain Compounds 63-P1 and 63-P2. Separation conditions: chromatographic column model: Chiralcel OX-3; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol + acetonitrile (0.1% diethylamine), B%: 40% fixed concentration elution; detection wavelength: 254 nm; column temperature: 35℃. 63-P1 Retention time 1.705 min, ee 99.30%. MS-ESI [M+H] ⁺ , calculated 464, found 464. ¹ H NMR: (400 MHz, MeOD) δ 7.28-7.36 (m, 2H), 7.13-7.18 (m, 1H), 7.10 (dt, J = 10.4, 2.0 Hz, 1H), 7.01 (td, J = 8.4, 2.0 Hz, 1H), 5.45 (s, 1H), 3.97-4.05 (m, 2H), 3.85 (d, J = 9.6 Hz, 1H), 3.42 (d, J = 9.6 Hz, 1H), 2.49-2.78 (m, 4H), 1.93-2.20 (m, 7H), 1.65-1.85 (m, 2H). 63-P2 Retention time 2.316 min, ee 99.32%. MS-ESI [M+H] ⁺ , calculated 464, found 464. ¹ H NMR: (400 MHz, MeOD) δ 7.27-7.36 (m, 2H), 7.15 (d, J = 8.0 Hz, 1H), 7.10 (dt, J = 10.4, 2.0 Hz, 1H), 7.01 (td, J = 8.4, 2.0 Hz, 1H), 5.45 (s, 1H), 3.97-4.05 (m, 2H), 3.85 (d, J = 9.6 Hz, 1H), 3.42 (d, J = 9.6 Hz, 1H), 2.48-2.80 (m, 4H), 1.94-2.23 (m, 7H), 1.64-1.86 (m, 2H).

實施例64 化合物64的合成 Example 64 Synthesis of Compound 64

(1)01下向化合物K(200 mg, 579 μmol)的二氯甲烷(4.0 mL)溶液中，加入二氯亞碸(343 mg, 2.88 mmol)。反應液在氮氣保護下25應攪拌0.5小時。反應液加入碳酸氫鈉水溶液(50.0 mL)，用二氯甲烷(100 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。得到化合物64-1。(1) To a solution of compound K (200 mg, 579 μmol) in dichloromethane (4.0 mL) was added dichlorosulfonyl chloride (343 mg, 2.88 mmol) at 0.1 °C. The reaction mixture was stirred for 0.5 h at 25 °C under nitrogen protection. A sodium bicarbonate aqueous solution (50.0 mL) was added to the reaction mixture, which was extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 64-1.

MS-ESI [M+H] ⁺，計算值367，實測值367。 MS-ESI [M+H] ⁺ , calcd. 367, found 367.

(2)02下向化合物64-1(200 mg, 547 μmol)的 N,N-二甲基甲醯胺(2.0 mL)溶液中，加入碳酸銫(534 mg, 1.64 mmol)和中間體A(130 mg, 547 μmol)。反應液在氮氣保護下50反攪拌2小時。反應液加入水(10.0 mL)，用乙酸乙酯(100 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/乙酸乙酯 = 1 ：0 到 2 ：1)分離得到化合物64-2。 (2) To a solution of compound 64-1 (200 mg, 547 μmol) in N,N -dimethylformamide (2.0 mL) at 0.2 °C, cesium carbonate (534 mg, 1.64 mmol) and intermediate A (130 mg, 547 μmol) were added. The reaction solution was stirred at 50 °C for 2 hours under nitrogen protection. Water (10.0 mL) was added to the reaction solution, which was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 2:1) to obtain compound 64-2.

MS-ESI [M+H] ⁺，計算值566，實測值566。 MS-ESI [M+H] ⁺ , calcd. 566, found 566.

(3)向化合物64-2(130 mg, 229 μmol)的甲苯(5.0 mL)溶液中，加入2,4-二甲氧基苄胺(95.9 mg, 574 μmol)，碳酸銫(150 mg, 459 μmol)，三(二亞苄基丙酮)二鈀(21.0 mg, 22.9 μmol)，1,1'-聯萘-2,2'-雙二苯膦(28.6 mg, 45.9 μmol)。反應液在氮氣保護下120℃攪拌3小時，反應液加入水(50.0 mL)，用乙酸乙酯(200 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/乙酸乙酯 = 1 ：0 到 3 ：1) 分離得到化合物64-3。(3) To a toluene (5.0 mL) solution of compound 64-2 (130 mg, 229 μmol), 2,4-dimethoxybenzylamine (95.9 mg, 574 μmol), cesium carbonate (150 mg, 459 μmol), tri(dibenzylideneacetone)dipalladium (21.0 mg, 22.9 μmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (28.6 mg, 45.9 μmol) were added. The reaction solution was stirred at 120°C for 3 hours under nitrogen protection, water (50.0 mL) was added to the reaction solution, and the solution was extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 3:1) to obtain compound 64-3.

MS-ESI [M+H] ⁺，計算值697，實測值697。 MS-ESI [M+H] ⁺ , calcd. 697, found 697.

(4)向化合物64-3(130 mg, 186 μmol)的四氫呋喃(2.0 mL)溶液中，加入一水合氫氧化鋰(39.1 mg, 932 μmol)。反應液在氮氣保護下25應攪拌12小時。反應液在0℃下加入鹽酸水溶液調節pH值到7，用二氯甲烷(100 mL × 2)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。得到化合物64-4。(4) To a solution of compound 64-3 (130 mg, 186 μmol) in tetrahydrofuran (2.0 mL), lithium hydroxide monohydrate (39.1 mg, 932 μmol) was added. The reaction solution was stirred for 12 hours at 25°C under nitrogen protection. Aqueous hydrochloric acid solution was added to the reaction solution at 0°C to adjust the pH value to 7, and the solution was extracted with dichloromethane (100 mL × 2). The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 64-4.

(5)向化合物64-4(100 mg, 146 μmol)的 N,N-二甲基甲醯胺(2.0 mL)溶液中加入二異丙基乙基胺(75.7 mg, 585 μmol)和 N,N,N mg,-四甲基- O-(7-氮雜苯并三唑-1-基)六氟磷酸脲(83.5 mg, 220 μmol)，室溫下攪拌25分鐘，隨後加入化合物64-5(47.3 mg, 293 μmol)，反應液在氮氣保護下25液攪拌3小時。反應液加入水 (30.0 mL)，用乙酸乙酯(100 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經製備高效液相色譜法(Xtimate C18, 200 mm × 40 mm 7 μm, A:水(甲酸)；B:乙腈, 0%-18%：25分鐘)分離得到化合物64-6。 (5) Diisopropylethylamine (75.7 mg, 585 μmol) and N,N, N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (83.5 mg, 220 μmol) were added to a solution of compound 64-4 (100 mg, 146 μmol ) in N,N- dimethylformamide (2.0 mL), and the mixture was stirred at room temperature for 25 minutes. Compound 64-5 (47.3 mg, 293 μmol) was then added, and the reaction mixture was stirred for 3 hours under nitrogen protection. Water (30.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative HPLC (Xtimate C18, 200 mm × 40 mm 7 μm, A: water (formic acid); B: acetonitrile, 0%-18%: 25 minutes) to obtain compound 64-6.

MS-ESI [M+H] ⁺，計算值790，實測值790。 MS-ESI [M+H] ⁺ , calcd. 790, found 790.

(5)05下將化合物64-6(28.0 mg, 35.4 μmol)的二氯甲烷(1.0 mL)溶液中，加入三氟乙酸(500 μL)。反應液在氮氣保護下25應攪拌1小時。反應液加入甲醇(1.0 mL)和氨水(1.0 mL)並在氮氣保護下25℃攪拌8小時。反應液加入水(50.0 mL)，用乙酸乙酯(50.0 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經製備高效液相色譜法(Xtimate C18, 200 mm × 40 mm 7 μm, A:水(甲酸)；B:乙腈, 40%-50%：25分鐘)分離得到化合物64的甲酸鹽。(5) Trifluoroacetic acid (500 μL) was added to a solution of compound 64-6 (28.0 mg, 35.4 μmol) in dichloromethane (1.0 mL) at 0.5 °C. The reaction solution was stirred at 25 °C for 1 hour under nitrogen protection. Methanol (1.0 mL) and aqueous ammonia (1.0 mL) were added to the reaction solution and stirred at 25 °C for 8 hours under nitrogen protection. Water (50.0 mL) was added to the reaction solution, and the solution was extracted with ethyl acetate (50.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative HPLC (Xtimate C18, 200 mm × 40 mm 7 μm, A: water (formic acid); B: acetonitrile, 40%-50%: 25 min) to obtain the formate salt of compound 64.

MS-ESI [M+H] ⁺，計算值510，實測值510。 MS-ESI [M+H] ⁺ , calcd. 510, found 510.

¹H NMR (400 MHz, CDCl ₃) δ9.11-9.31 (m, 1H), 7.47 (br s, 1H), 7.33-7.43 (m, 1H), 7.03-7.18 (m, 2H), 6.93-7.02 (m, 1H), 5.49-5.58 (m, 1H), 4.58-4.62 (m, 2H), 4.22-4.31 (m, 2H), 3.77-3.97 (m, 1H), 3.57-3.72 (m, 1H), 3.03-3.32 (m, 1H), 2.51-2.69 (m, 4H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.11-9.31 (m, 1H), 7.47 (br s, 1H), 7.33-7.43 (m, 1H), 7.03-7.18 (m, 2H), 6.93-7.02 (m, 1H), 5.49-5.58 (m, 1H), 4.58-4.62 (m, 2H), 4.22-4.31 (m, 2H), 3.77-3.97 (m, 1H), 3.57-3.72 (m, 1H), 3.03-3.32 (m, 1H), 2.51-2.69 (m, 4H).

實施例65 合成化合物65，93，94Example 65 Synthesis of Compounds 65, 93, and 94

化合物65，93，94的製備參考實施例64，使用對應的胺替換64-5。 MS-ESI [M+H] ⁺，計算值484，實測值484。 ¹H NMR (400 MHz, CDCl ₃) δ9.19-9.37 (m, 1H), 7.47-7.56 (m, 1H), 7.32-7.43 (m, 1H), 7.08-7.14 (m, 1H), 7.00 (br d, J= 8.0 Hz, 1H), 6.89-6.96 (m, 1H), 5.69 (s, 1H), 4.65-4.79 (m, 2H), 4.49-4.62 (m, 2H), 4.38-4.49 (m, 2H), 4.16-4.23 (m, 2H), 3.73-3.85 (m, 2H), 2.44-2.69 (m, 4H), 1.26-1.32 (m, 2H)。 MS-ESI [M+H] ⁺，計算值489，實測值489。 ¹H NMR (400 MHz, CDCl ₃) δ9.25 (s, 1H), 7.44 (s, 1H), 7.33-7.35 (m, 1H), 7.10-7.13 (m, 1H), 6.89-7.02 (m, 2H), 5.24-5.26 (m, 1H), 4.71-4.78 (m, 1H), 4.61 (s, 2H), 4.00-4.05 (m, 2H), 3.76-3.89 (m, 3H), 3.07-3.50 (m, 1H), 2.80-2.86 (m, 1H), 2.30-2.72 (m, 4H) , 1.89-1.95 (m, 1H)。 MS-ESI [M+H] ⁺，計算值489，實測值489。 ¹H NMR (400 MHz, CDCl3) δ 9.24 (s, 1H), 7.44 (s, 1H), 7.31-7.34 (m, 1H), 7.09-7.11 (m, 1H), 6.89-7.01 (m, 2H), 5.39-5.41 (m, 1H), 4.74-4.78 (m, 1H), 4.58 (s, 2H), 4.00-4.06 (m, 2H), 3.74-3.89 (m, 3H), 3.35-3.50 (m, 1H), 2.80-2.84 (m, 1H), 2.54-2.69 (m, 4H) , 1.79-1.94 (m,1H)。 The preparation of compounds 65, 93, and 94 was carried out according to Example 64, using the corresponding amines to replace 64-5. MS-ESI [M+H] ⁺ , calcd. 484, found 484. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.19-9.37 (m, 1H), 7.47-7.56 (m, 1H), 7.32-7.43 (m, 1H), 7.08-7.14 (m, 1H), 7.00 (br d, J = 8.0 Hz, 1H), 6.89-6.96 (m, 1H), 5.69 (s, 1H), 4.65-4.79 (m, 2H), 4.49-4.62 (m, 2H), 4.38-4.49 (m, 2H), 4.16-4.23 (m, 2H), 3.73-3.85 (m, 2H), 2.44-2.69 (m, 4H), 1.26-1.32 (m, 2H). MS-ESI [M+H] ⁺ , calcd. 489, found 489. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.25 (s, 1H), 7.44 (s, 1H), 7.33-7.35 (m, 1H), 7.10-7.13 (m, 1H), 6.89-7.02 (m, 2H), 5.24-5.26 (m, 1H), 4.71-4.78 (m, 1H), 4.61 (s, 2H), 4.00-4.05 (m, 2H), 3.76-3.89 (m, 3H), 3.07-3.50 (m, 1H), 2.80-2.86 (m, 1H), 2.30-2.72 (m, 4H), 1.89-1.95 (m, 1H). MS-ESI [M+H] ⁺ , calcd. 489, found 489. ¹ H NMR (400 MHz, CDCl3) δ 9.24 (s, 1H), 7.44 (s, 1H), 7.31-7.34 (m, 1H), 7.09-7.11 (m, 1H), 6.89-7.01 (m, 2H), 5.39-5.41 (m, 1H), 4.74-4.78 (m, 1H), 4.58 (s, 2H), 4.00-4.06 (m, 2H), 3.74-3.89 (m, 3H), 3.35-3.50 (m, 1H), 2.80-2.84 (m, 1H), 2.54-2.69 (m, 4H), 1.79-1.94 (m,1H).

實施例66-74 合成化合物66-P1，66-P2至74-P1，74-P2Examples 66-74 Synthesis of Compounds 66-P1, 66-P2 to 74-P1, 74-P2

化合物66-P1，66-P2至74-P1，74-P2的製備參考實施例64，使用對應的胺替換化合物64-5，並進行掌性拆分。分離條件：色譜柱型號：Chiralcel AS-3；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇 (0.05% 二乙胺)，B%：5%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，5%固定濃度洗提0.5分鐘；檢測波長：254 nm；柱溫：35℃。 66-P1 滯留時間1.232分鐘，ee值99.74%。 MS-ESI [M+H] ⁺，計算值492，實測值492。 ¹H NMR: (400 MHz, MeOD) δ7.50 (s, 1H), 7.27-7.35 (m, 1H), 7.10-7.22 (m, 2H), 6.94-7.04 (m, 1H), 5.34 (s, 1H), 4.93-4.94 (m, 2H), 4.15 (dd, J= 16.0, 4.8 Hz, 1H), 3.81-3.94 (m, 1H), 3.44-3.51 (m, 1H), 3.04-3.16 (m, 1H), 2.94-3.01 (m, 1H), 2.69-2.83 (m, 1H), 2.51-2.67 (m, 2H), 2.18-2.42 (m, 2H)。 66-P2 滯留時間1.637分鐘，ee值99.16%。 MS-ESI [M+H] ⁺，計算值492，實測值492。 ¹H NMR: (400 MHz, MeOD) δ7.50 (s, 1H), 7.26-7.39 (m, 1H), 7.09-7.23 (m, 2H), 6.96-7.04 (m, 1H), 5.34 (d, J= 2.0Hz, 1H), 4.93 (br d, J= 4.4 Hz, 2H), 4.15 (dd, J= 16.0, 5.1 Hz, 1H), 3.86-3.93 (m, 1H), 3.42-3.50 (m, 1H), 3.03-3.15 (m, 1H), 2.95-3.01 (m, 1H), 2.72-2.80 (m, 1H), 2.52-2.63 (m, 2H), 2.14-2.40 (m, 2H)。分離條件：色譜柱型號：Chiralcel IB N-3；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇 (0.05% 二乙胺)，B%：20%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，20%固定濃度洗提0.5分鐘；檢測波長：254 nm；柱溫：35℃。 67-P1 滯留時間1.046分鐘，ee值98.18%。 MS-ESI [M+H] ⁺，計算值456，實測值456。 ¹H NMR: (400 MHz, MeOD) δ7.51 (s, 1H), 7.27 (td, J= 8.0, 6.0 Hz, 1H), 7.03-7.15 (m, 2H), 6.96 (td, J= 8.4, 2.4 Hz, 1H), 5.30 (s, 1H), 4.93 (s, 2H), 4.08 (br d, J= 16.0 Hz, 1H), 2.92-3.00 (m, 1H), 2.85 (br d, J= 6.0 Hz, 1H), 2.73 (br dd, J= 14.0, 10.6 Hz, 1H), 2.51-2.62 (m, 4H), 0.78-0.92 (m, 3H), 0.66-0.74 (m, 1H)。 67-P2 滯留時間1.210分鐘，ee值95.18%。 MS-ESI [M+H] ⁺，計算值456，實測值456。 ¹H NMR: (400 MHz, MeOD) δ7.50 (s, 1H), 7.22-7.31 (m, 1H), 7.02-7.17 (m, 2H), 6.95 (td, J= 8.4, 2.4 Hz, 1H), 5.30 (s, 1H), 4.92-4.98 (m, 2H), 4.08 (br d, J= 16.4 Hz, 1H), 2.91-3.03 (m, 1H), 2.86 (br s, 1H), 2.68-2.79 (m, 1H), 2.51-2.63 (m, 4H), 0.78-0.94 (m, 3H), 0.65-0.75 (m, 1H)。分離條件：色譜柱型號：Chiralcel AD-3；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇 (0.05% 二乙胺)，B%：40%固定濃度洗提4分鐘；檢測波長：254 nm；柱溫：35℃。 68-P1 滯留時間1.880分鐘，ee值99.60%。 MS-ESI [M+H] ⁺，計算值482，實測值482。 ¹H NMR: (400 MHz, MeOD) δ7.53 (s, 1H), 7.27-7.37 (m, 1H), 7.08-7.18 (m, 2H), 7.00 (td, J= 8.4, 2.0 Hz, 1H), 5.48 (s, 1H), 4.02 (s, 2H), 3.88 (br d, J= 9.6 Hz, 1H), 3.35-3.43 (m, 1H), 2.49-2.85 (m, 5H), 1.93-2.21 (m, 5H), 1.67-1.83 (m, 2H)。 68-P2 滯留時間2.702分鐘，ee值98.04%。 MS-ESI [M+H] ⁺，計算值482，實測值482。 ¹H NMR: (400 MHz, MeOD) δ7.52 (s, 1H), 7.31 (td, J= 8.0, 6.0 Hz, 1H), 7.08-7.18 (m, 2H), 7.00 (td, J= 8.4, 2.4 Hz, 1H), 5.47 (s, 1H), 4.02 (s, 2H), 3.88 (br d, J= 9.6 Hz, 1H), 3.39 (br d, J= 9.6 Hz, 1H), 2.49-2.82 (m, 5H), 1.94-2.20 (m, 5H), 1.67-1.83 (m, 2H)。分離條件：色譜柱型號：Chiralpak AS-3；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇(0.05% 二乙胺)，B%：20%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，20%固定濃度洗提0.5分鐘；檢測波長：254 nm；柱溫：352。 69-P1 滯留時間0.721分鐘，ee值97.68%。 MS-ESI [M+H] ⁺，計算值470，實測值470。 ¹H NMR: (400 MHz, CDCl ₃) δ9.53-9.82 (m, 1H), 7.52-7.61 (m, 1H), 7.31-7.38 (m, 1H), 7.09-7.13 (m, 1H), 6.94 (br d, J= 7.2 Hz, 1H), 6.86 (br d, J= 10.0 Hz, 1H), 5.33-5.39 (m, 1H), 4.64 (br d, J= 15.6 Hz, 1H), 3.96 (d, J= 15.6 Hz, 1H), 3.86 (br t, J= 8.4 Hz, 1H), 3.08 (s, 3H), 2.79-2.86 (m, 1H), 2.65 (br d, J= 4.8 Hz, 1H), 2.58-2.61 (m, 1H), 2.46 (td, J= 8.8, 4.8 Hz, 1H), 2.23-2.31 (m, 1H), 2.17-2.21 (m, 1H), 2.03 (br dd, J= 6.8, 4.4 Hz, 1H), 1.73-1.83 (m, 1H), 1.60-1.71 (m, 1H), 1.36 (br dd, J = 18.8, 8.8 Hz, 1H)。 69-P2 滯留時間1.781分鐘，ee值99.40%。 MS-ESI [M+H] ⁺，計算值470，實測值470。 ¹H NMR: (400 MHz, CDCl ₃) δ9.27 (br s, 1H), 7.44 (s, 1H), 7.28-7.34 (m, 1H), 7.08 (td, J= 8.0, 2.0 Hz, 1H), 6.84-7.01 (m, 2H), 5.16-5.31 (m, 1H), 4.74 (d, J= 15.6 Hz, 1H), 4.57 (br s, 2H), 3.95 (d, J= 15.6 Hz, 1H), 3.82-3.90 (m, 1H), 3.08 (s, 3H), 2.81 (br dd, J= 13.2, 9.6 Hz, 1H), 2.65 (br dd, J= 6.0, 3.2 Hz, 1H), 2.59 (s, 1H), 2.40-2.51 (m, 1H), 2.23-2.30 (m, 1H), 2.16-2.21 (m, 1H), 2.00-2.10 (m, 1H), 1.72-1.85 (m, 1H), 1.64 (br d, J= 10.8 Hz, 1H), 1.32-1.40 (m, 1H)。分離條件：色譜柱型號：Chiralpak AD-3；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳，B：異丙醇(0.05% 二乙胺)，B%：40%固定濃度洗提；檢測波長：254 nm；柱溫：35℃。 70-P1 滯留時間0.627分鐘，ee值99.34%。 MS-ESI [M+H] ⁺，計算值498，實測值498。 ¹H NMR: (400 MHz, CD ₃OD) δ(ppm) 7.53 (s, 1H), 7.34 (td, J= 8.0, 6.0 Hz, 1H), 7.13-7.24 (m, 2H), 7.02 (td, J= 8.4, 2.0 Hz, 1H), 5.48 (s, 1H), 4.30 (dd, J= 16.0, 2.4 Hz, 1H), 4.06 (s, 2H), 3.93 (d, J= 9.6 Hz, 1H), 3.74-3.80 (m, 2H), 3.68-3.72 (m, 1H), 2.74-2.85 (m, 1H), 2.55-2.72 (m, 3H), 1.90-2.22 (m, 3H), 1.28-1.36 (m, 3H)。 70-P2 滯留時間0.933分鐘，ee值97.12%。 MS-ESI [M+H] ⁺，計算值498，實測值498。 ¹H NMR: (400 MHz, CD ₃OD) δ(ppm) 7.78 (s, 1H), 7.32-7.40 (m, 1H), 7.14-7.25 (m, 2H), 7.03 (td, J= 8.4, 2.0 Hz, 1H), 5.60 (s, 1H), 4.30 (d, J= 16.4 Hz, 1H), 4.07 (s, 2H), 3.96 (d, J= 9.6 Hz, 1H), 3.74-3.79 (m, 2H), 3.67-3.74 (m, 1H), 2.80-2.87 (m, 1H), 2.68-2.76 (m, 1H), 2.56-2.66 (m, 2H), 2.00-2.17 (m, 2H), 1.29-1.34 (m, 4H)。分離條件：色譜柱型號：Chiralpak IB N-3；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇(0.05% 二乙胺)，B%：20%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，20%固定濃度洗提0.5分鐘；檢測波長：254 nm；柱溫：35℃。 71-P1 滯留時間0.911分鐘，ee值99.54%。 MS-ESI [M+H] ⁺，計算值459，實測值459。 ¹H NMR: (400 MHz, CD ₃OD) δ(ppm) 7.50 (s, 1H), 7.22-7.32 (m, 1H), 7.04-7.19 (m, 2H), 6.95 (td, J= 8.4, 2.4 Hz, 1H), 5.30 (s, 1H), 4.93 (s, 1H), 4.08 (br d, J= 16.4 Hz, 1H), 2.81-3.03 (m, 2H), 2.67-2.78 (m, 1H), 2.44-2.60 (m, 2H), 0.78-0.94 (m, 3H), 0.64-0.73 (m, 1H)。 71-P2 滯留時間1.065分鐘，ee值97.44%。 MS-ESI [M+H] ⁺，計算值459，實測值459。 ¹H NMR: (400 MHz, CD ₃OD) δ(ppm) 7.50 (s, 1H), 7.22-7.33 (m, 1H), 7.02-7.21 (m, 2H), 6.95 (td, J= 8.4, 2.4 Hz, 1H), 5.30 (s, 1H), 4.93 (s, 1H), 4.08 (br d, J= 16.4 Hz, 1H), 2.83-3.09 (m, 2H), 2.66-2.79 (m, 1H), 2.45-2.61 (m, 2H), 0.65-0.94 (m, 4H)。分離條件：色譜柱型號：Chiralpak AD-3；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳，B：異丙醇(0.05% 二乙胺)，B%：40%固定濃度洗提；檢測波長：254 nm；柱溫：35℃。 72-P1 滯留時間0.855分鐘，ee值98.90%。 MS-ESI [M+H] ⁺，計算值496，實測值496。 ¹H NMR: (CDCl ₃, 400 MHz) δ(ppm) 7.61-7.81 (m, 1H), 7.39-7.50 (m, 1H), 7.13-7.20 (m, 1H), 7.09 (br d, J= 7.2 Hz, 1H), 6.99 (br d, J= 10.8 Hz, 1H), 5.78-5.97 (m, 1H), 4.33-4.61 (m, 1H), 4.20-4.28 (m, 1H), 3.98 (q, J= 8.8 Hz, 2H), 3.68-3.76 (m, 1H), 3.30 (br d, J= 8.4 Hz, 1H), 2.54-2.70 (m, 4H), 1.74-1.81 (m, 2H), 1.62 (br d, J= 4.4 Hz, 6H), 1.20-1.43 (m, 2H)。 72-P2 滯留時間1.102分鐘，ee值96.94%。 MS-ESI [M+H] ⁺，計算值496，實測值496。 ¹H NMR: (CDCl ₃, 400 MHz) δ(ppm) 7.63 (s, 1H), 7.37-7.44 (m, 1H), 7.11-7.17 (m, 1H), 7.07 (br d, J= 8.0 Hz, 1H), 6.99 (dd, J= 9.6, 2.0 Hz, 1H), 5.70-5.85 (m, 1H), 4.40-4.56 (m, 1H), 4.17-4.29 (m, 1H), 3.89-4.04 (m, 2H), 3.69 (br d, J= 9.2 Hz, 1H), 3.24-3.41 (m, 1H), 2.53-2.68 (m, 4H), 1.73-1.79 (m, 2H), 1.61 (br d, J= 13.6 Hz, 6H), 1.18-1.40 (m, 2H)。分離條件：色譜柱型號：Chiralpak AS-3；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇(0.05% 二乙胺)，B%：20%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，20%固定濃度洗提0.5分鐘；檢測波長：254 nm；柱溫：35℃。 73-P1 滯留時間0.667分鐘，ee值99.26%。 MS-ESI [M+H] ⁺，計算值473，實測值473。 ¹H NMR: (400 MHz, MeOD) δ7.50 (s, 1H), 7.21-7.31 (m, 1H), 7.01-7.13 (m, 2H), 6.91-7.00 (m, 1H), 5.28 (s, 1H), 3.84-4.10 (m, 2H), 2.93-3.09 (m, 1H), 2.67-2.80 (m, 1H), 2.40-2.62 (m, 2H), 2.12-2.38 (m, 3H), 2.00-2.11 (m, 1H), 1.55-1.81 (m, 1H), 1.27-1.34 (m, 2H)。 73-P2 滯留時間1.741分鐘，ee值98.70%。 MS-ESI [M+H] ⁺，計算值473，實測值473。 ¹H NMR: (400 MHz, MeOD) δ7.50 (s, 1H), 7.22-7.31 (m, 1H), 7.01-7.14 (m, 2H), 6.96 (td, J= 8.4, 2.0 Hz, 1H), 5.28 (s, 1H), 3.83-4.11 (m, 2H), 2.93-3.10 (m, 1H), 2.69-2.79 (m, 1H), 2.40-2.62 (m, 2H), 2.14-2.37 (m, 3H), 2.00-2.12 (m, 1H), 1.54-1.82 (m, 1H), 1.25-1.35 (m, 2H)。分離條件：色譜柱型號：Chiralpak AD；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳，B：異丙醇 (0.05% 二乙胺)，B%：20%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，20%固定濃度洗提0.5分鐘；檢測波長：254 nm；柱溫：35℃。 74-P1 滯留時間1.348分鐘，ee值99.48%。 MS-ESI [M+H] ⁺，計算值511，實測值511。 ¹H NMR: (400 MHz, MeOD) δ7.53 (d, J= 7.6 Hz, 1H), 7.27-7.39 (m, 1H), 7.08-7.25 (m, 2H), 6.95-7.07 (m, 1H), 5.42-5.57 (m, 1H), 4.75 (d, J= 16.4 Hz, 1H), 4.26-4.41 (m, 1H), 3.94-4.08 (m, 2H), 3.80-3.88 (m, 1H), 3.39 (dd, J= 13.2, 9.2 Hz, 1H), 2.62-2.78 (m, 3H), 2.49-2.61 (m, 5H), 2.28 (d, J= 4.0 Hz, 3H), 1.82-2.13 (m, 2H)。 74-P2 滯留時間1.692分鐘，ee值98.32%。 MS-ESI [M+H] ⁺，計算值511，實測值511。 ¹H NMR: (400 MHz, MeOD) δ7.53 (d, J= 7.6 Hz, 1H), 7.27-7.38 (m, 1H), 7.08-7.24 (m, 2H), 7.01 (t, J= 8.0 Hz, 1H), 5.43-5.57 (m, 1H), 4.72-4.80 (m, 1H), 4.27-4.41 (m, 1H), 3.95-4.08 (m, 2H), 3.85 (dd, J= 9.2, 6.0 Hz, 1H), 3.39 (dd, J= 12.4, 9.2 Hz, 1H), 2.63-2.82 (m, 3H), 2.53-2.63 (m, 5H), 2.31 (s, 3H), 1.85-2.15 (m, 2H)。 The preparation of compounds 66-P1, 66-P2 to 74-P1, 74-P2 was carried out according to Example 64, using corresponding amines to replace compound 64-5 and performing chiral resolution. Separation conditions: chromatographic column model: Chiralcel AS-3; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 5%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 5% fixed concentration elution for 0.5 minutes; detection wavelength: 254 nm; column temperature: 35°C. 66-P1 Retention time 1.232 min, ee 99.74%. MS-ESI [M+H] ⁺ , calculated 492, found 492. ¹ H NMR: (400 MHz, MeOD) δ 7.50 (s, 1H), 7.27-7.35 (m, 1H), 7.10-7.22 (m, 2H), 6.94-7.04 (m, 1H), 5.34 (s, 1H), 4.93-4.94 (m, 2H), 4.15 (dd, J = 16.0, 4.8 Hz, 1H), 3.81-3.94 (m, 1H), 3.44-3.51 (m, 1H), 3.04-3.16 (m, 1H), 2.94-3.01 (m, 1H), 2.69-2.83 (m, 1H), 2.51-2.67 (m, 2H), 2.18-2.42 (m, 2H). 66-P2 Retention time 1.637 min, ee 99.16%. MS-ESI [M+H] ⁺ , calculated 492, found 492. ¹ H NMR: (400 MHz, MeOD) δ 7.50 (s, 1H), 7.26-7.39 (m, 1H), 7.09-7.23 (m, 2H), 6.96-7.04 (m, 1H), 5.34 (d, J = 2.0Hz, 1H), 4.93 (br d, J = 4.4 Hz, 2H), 4.15 (dd, J = 16.0, 5.1 Hz, 1H), 3.86-3.93 (m, 1H), 3.42-3.50 (m, 1H), 3.03-3.15 (m, 1H), 2.95-3.01 (m, 1H), 2.72-2.80 (m, 1H), 2.52-2.63 (m, 2H), 2.14-2.40 (m, 2H). Separation conditions: chromatographic column model: Chiralcel IB N-3; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 20%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 20% fixed concentration elution for 0.5 minutes; detection wavelength: 254 nm; column temperature: 35°C. 67-P1 Retention time 1.046 min, ee 98.18%. MS-ESI [M+H] ⁺ , calculated 456, found 456. ¹ H NMR: (400 MHz, MeOD) δ 7.51 (s, 1H), 7.27 (td, J = 8.0, 6.0 Hz, 1H), 7.03-7.15 (m, 2H), 6.96 (td, J = 8.4, 2.4 Hz, 1H), 5.30 (s, 1H), 4.93 (s, 2H), 4.08 (br d, J = 16.0 Hz, 1H), 2.92-3.00 (m, 1H), 2.85 (br d, J = 6.0 Hz, 1H), 2.73 (br dd, J = 14.0, 10.6 Hz, 1H), 2.51-2.62 (m, 4H), 0.78-0.92 (m, 3H), 0.66-0.74 (m, 1H). 67-P2 Retention time 1.210 min, ee 95.18%. MS-ESI [M+H] ⁺ , calculated 456, found 456. ¹ H NMR: (400 MHz, MeOD) δ 7.50 (s, 1H), 7.22-7.31 (m, 1H), 7.02-7.17 (m, 2H), 6.95 (td, J = 8.4, 2.4 Hz, 1H), 5.30 (s, 1H), 4.92-4.98 (m, 2H), 4.08 (br d, J = 16.4 Hz, 1H), 2.91-3.03 (m, 1H), 2.86 (br s, 1H), 2.68-2.79 (m, 1H), 2.51-2.63 (m, 4H), 0.78-0.94 (m, 3H), 0.65-0.75 (m, 1H). Separation conditions: chromatographic column model: Chiralcel AD-3; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 40% fixed concentration elution for 4 minutes; detection wavelength: 254 nm; column temperature: 35℃. 68-P1 Retention time 1.880 min, ee 99.60%. MS-ESI [M+H] ⁺ , calculated 482, found 482. ¹ H NMR: (400 MHz, MeOD) δ 7.53 (s, 1H), 7.27-7.37 (m, 1H), 7.08-7.18 (m, 2H), 7.00 (td, J = 8.4, 2.0 Hz, 1H), 5.48 (s, 1H), 4.02 (s, 2H), 3.88 (br d, J = 9.6 Hz, 1H), 3.35-3.43 (m, 1H), 2.49-2.85 (m, 5H), 1.93-2.21 (m, 5H), 1.67-1.83 (m, 2H). 68-P2 Retention time 2.702 min, ee 98.04%. MS-ESI [M+H] ⁺ , calculated 482, found 482. ¹ H NMR: (400 MHz, MeOD) δ 7.52 (s, 1H), 7.31 (td, J = 8.0, 6.0 Hz, 1H), 7.08-7.18 (m, 2H), 7.00 (td, J = 8.4, 2.4 Hz, 1H), 5.47 (s, 1H), 4.02 (s, 2H), 3.88 (br d, J = 9.6 Hz, 1H), 3.39 (br d, J = 9.6 Hz, 1H), 2.49-2.82 (m, 5H), 1.94-2.20 (m, 5H), 1.67-1.83 (m, 2H). Separation conditions: chromatographic column model: Chiralpak AS-3; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 20%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 20% fixed concentration elution for 0.5 minutes; detection wavelength: 254 nm; column temperature: 352. 69-P1 Retention time 0.721 min, ee 97.68%. MS-ESI [M+H] ⁺ , calculated 470, found 470. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 9.53-9.82 (m, 1H), 7.52-7.61 (m, 1H), 7.31-7.38 (m, 1H), 7.09-7.13 (m, 1H), 6.94 (br d, J = 7.2 Hz, 1H), 6.86 (br d, J = 10.0 Hz, 1H), 5.33-5.39 (m, 1H), 4.64 (br d, J = 15.6 Hz, 1H), 3.96 (d, J = 15.6 Hz, 1H), 3.86 (br t, J = 8.4 Hz, 1H), 3.08 (s, 3H), 2.79-2.86 (m, 1H), 2.65 (br d, J = 4.8 Hz, 1H), 2.58-2.61 (m, 1H), 2.46 (td, J = 8.8, 4.8 Hz, 1H), 2.23-2.31 (m, 1H), 2.17-2.21 (m, 1H), 2.03 (br dd, J = 6.8, 4.4 Hz, 1H), 1.73-1.83 (m, 1H), 1.60-1.71 (m, 1H), 1.36 (br dd, J = 18.8, 8.8 Hz, 1H). 69-P2 Retention time 1.781 min, ee 99.40%. MS-ESI [M+H] ⁺ , calculated 470, found 470. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 9.27 (br s, 1H), 7.44 (s, 1H), 7.28-7.34 (m, 1H), 7.08 (td, J = 8.0, 2.0 Hz, 1H), 6.84-7.01 (m, 2H), 5.16-5.31 (m, 1H), 4.74 (d, J = 15.6 Hz, 1H), 4.57 (br s, 2H), 3.95 (d, J = 15.6 Hz, 1H), 3.82-3.90 (m, 1H), 3.08 (s, 3H), 2.81 (br dd, J = 13.2, 9.6 Hz, 1H), 2.65 (br dd, J = 6.0, 3.2 Hz, 1H), 2.59 (s, 1H), 2.40-2.51 (m, 1H), 2.23-2.30 (m, 1H), 2.16-2.21 (m, 1H), 2.00-2.10 (m, 1H), 1.72-1.85 (m, 1H), 1.64 (br d, J = 10.8 Hz, 1H), 1.32-1.40 (m, 1H). Separation conditions: chromatographic column model: Chiralpak AD-3; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: isopropanol (0.05% diethylamine), B%: 40% fixed concentration elution; detection wavelength: 254 nm; column temperature: 35°C. 70-P1 Retention time 0.627 min, ee 99.34%. MS-ESI [M+H] ⁺ , calculated 498, found 498. ¹ H NMR: (400 MHz, CD ₃ OD) δ (ppm) 7.53 (s, 1H), 7.34 (td, J = 8.0, 6.0 Hz, 1H), 7.13-7.24 (m, 2H), 7.02 (td, J = 8.4, 2.0 Hz, 1H), 5.48 (s, 1H), 4.30 (dd, J = 16.0, 2.4 Hz, 1H), 4.06 (s, 2H), 3.93 (d, J = 9.6 Hz, 1H), 3.74-3.80 (m, 2H), 3.68-3.72 (m, 1H), 2.74-2.85 (m, 1H), 2.55-2.72 (m, 3H), 1.90-2.22 (m, 3H), 1.28-1.36 (m, 3H). 70-P2 Retention time 0.933 min, ee 97.12%. MS-ESI [M+H] ⁺ , calculated 498, found 498. ¹ H NMR: (400 MHz, CD ₃ OD) δ (ppm) 7.78 (s, 1H), 7.32-7.40 (m, 1H), 7.14-7.25 (m, 2H), 7.03 (td, J = 8.4, 2.0 Hz, 1H), 5.60 (s, 1H), 4.30 (d, J = 16.4 Hz, 1H), 4.07 (s, 2H), 3.96 (d, J = 9.6 Hz, 1H), 3.74-3.79 (m, 2H), 3.67-3.74 (m, 1H), 2.80-2.87 (m, 1H), 2.68-2.76 (m, 1H), 2.56-2.66 (m, 2H), 2.00-2.17 (m, 2H), 1.29-1.34 (m, 4H). Separation conditions: chromatographic column model: Chiralpak IB N-3; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 20%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 20% fixed concentration elution for 0.5 minutes; detection wavelength: 254 nm; column temperature: 35°C. 71-P1 Retention time 0.911 min, ee 99.54%. MS-ESI [M+H] ⁺ , calculated 459, found 459. ¹ H NMR: (400 MHz, CD ₃ OD) δ (ppm) 7.50 (s, 1H), 7.22-7.32 (m, 1H), 7.04-7.19 (m, 2H), 6.95 (td, J = 8.4, 2.4 Hz, 1H), 5.30 (s, 1H), 4.93 (s, 1H), 4.08 (br d, J = 16.4 Hz, 1H), 2.81-3.03 (m, 2H), 2.67-2.78 (m, 1H), 2.44-2.60 (m, 2H), 0.78-0.94 (m, 3H), 0.64-0.73 (m, 1H). 71-P2 Retention time 1.065 min, ee 97.44%. MS-ESI [M+H] ⁺ , calculated 459, found 459. ¹ H NMR: (400 MHz, CD ₃ OD) δ (ppm) 7.50 (s, 1H), 7.22-7.33 (m, 1H), 7.02-7.21 (m, 2H), 6.95 (td, J = 8.4, 2.4 Hz, 1H), 5.30 (s, 1H), 4.93 (s, 1H), 4.08 (br d, J = 16.4 Hz, 1H), 2.83-3.09 (m, 2H), 2.66-2.79 (m, 1H), 2.45-2.61 (m, 2H), 0.65-0.94 (m, 4H). Separation conditions: chromatographic column model: Chiralpak AD-3; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: isopropanol (0.05% diethylamine), B%: 40% fixed concentration elution; detection wavelength: 254 nm; column temperature: 35°C. 72-P1 Retention time 0.855 min, ee 98.90%. MS-ESI [M+H] ⁺ , calculated 496, found 496. ¹ H NMR: (CDCl ₃ , 400 MHz) δ (ppm) 7.61-7.81 (m, 1H), 7.39-7.50 (m, 1H), 7.13-7.20 (m, 1H), 7.09 (br d, J = 7.2 Hz, 1H), 6.99 (br d, J = 10.8 Hz, 1H), 5.78-5.97 (m, 1H), 4.33-4.61 (m, 1H), 4.20-4.28 (m, 1H), 3.98 (q, J = 8.8 Hz, 2H), 3.68-3.76 (m, 1H), 3.30 (br d, J = 8.4 Hz, 1H), 2.54-2.70 (m, 4H), 1.74-1.81 (m, 2H), 1.62 (br d, J = 4.4 Hz, 6H), 1.20-1.43 (m, 2H). 72-P2 Retention time 1.102 min, ee 96.94%. MS-ESI [M+H] ⁺ , calculated 496, found 496. ¹ H NMR: (CDCl ₃ , 400 MHz) δ (ppm) 7.63 (s, 1H), 7.37-7.44 (m, 1H), 7.11-7.17 (m, 1H), 7.07 (br d, J = 8.0 Hz, 1H), 6.99 (dd, J = 9.6, 2.0 Hz, 1H), 5.70-5.85 (m, 1H), 4.40-4.56 (m, 1H), 4.17-4.29 (m, 1H), 3.89-4.04 (m, 2H), 3.69 (br d, J = 9.2 Hz, 1H), 3.24-3.41 (m, 1H), 2.53-2.68 (m, 4H), 1.73-1.79 (m, 2H), 1.61 (br d, J = 13.6 Hz, 6H), 1.18-1.40 (m, 2H). Separation conditions: chromatographic column model: Chiralpak AS-3; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 20%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 20% fixed concentration elution for 0.5 minutes; detection wavelength: 254 nm; column temperature: 35°C. 73-P1 Retention time 0.667 min, ee 99.26%. MS-ESI [M+H] ⁺ , calculated 473, found 473. ¹ H NMR: (400 MHz, MeOD) δ 7.50 (s, 1H), 7.21-7.31 (m, 1H), 7.01-7.13 (m, 2H), 6.91-7.00 (m, 1H), 5.28 (s, 1H), 3.84-4.10 (m, 2H), 2.93-3.09 (m, 1H), 2.67-2.80 (m, 1H), 2.40-2.62 (m, 2H), 2.12-2.38 (m, 3H), 2.00-2.11 (m, 1H), 1.55-1.81 (m, 1H), 1.27-1.34 (m, 2H). 73-P2 Retention time 1.741 min, ee 98.70%. MS-ESI [M+H] ⁺ , calculated 473, found 473. ¹ H NMR: (400 MHz, MeOD) δ 7.50 (s, 1H), 7.22-7.31 (m, 1H), 7.01-7.14 (m, 2H), 6.96 (td, J = 8.4, 2.0 Hz, 1H), 5.28 (s, 1H), 3.83-4.11 (m, 2H), 2.93-3.10 (m, 1H), 2.69-2.79 (m, 1H), 2.40-2.62 (m, 2H), 2.14-2.37 (m, 3H), 2.00-2.12 (m, 1H), 1.54-1.82 (m, 1H), 1.25-1.35 (m, 2H). Separation conditions: chromatographic column model: Chiralpak AD; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: isopropanol (0.05% diethylamine), B%: 20%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 20% fixed concentration elution for 0.5 minutes; detection wavelength: 254 nm; column temperature: 35°C. 74-P1 Retention time 1.348 min, ee 99.48%. MS-ESI [M+H] ⁺ , calculated 511, found 511. ¹ H NMR: (400 MHz, MeOD) δ 7.53 (d, J = 7.6 Hz, 1H), 7.27-7.39 (m, 1H), 7.08-7.25 (m, 2H), 6.95-7.07 (m, 1H), 5.42-5.57 (m, 1H), 4.75 (d, J = 16.4 Hz, 1H), 4.26-4.41 (m, 1H), 3.94-4.08 (m, 2H), 3.80-3.88 (m, 1H), 3.39 (dd, J = 13.2, 9.2 Hz, 1H), 2.62-2.78 (m, 3H), 2.49-2.61 (m, 5H), 2.28 (d, J = 4.0 Hz, 3H), 1.82-2.13 (m, 2H). 74-P2 Retention time 1.692 min, ee value 98.32%. MS-ESI [M+H] ⁺ , calculated value 511, found value 511. ¹ H NMR: (400 MHz, MeOD) δ 7.53 (d, J = 7.6 Hz, 1H), 7.27-7.38 (m, 1H), 7.08-7.24 (m, 2H), 7.01 (t, J = 8.0 Hz, 1H), 5.43-5.57 (m, 1H), 4.72-4.80 (m, 1H), 4.27-4.41 (m, 1H), 3.95-4.08 (m, 2H), 3.85 (dd, J = 9.2, 6.0 Hz, 1H), 3.39 (dd, J = 12.4, 9.2 Hz, 1H), 2.63-2.82 (m, 3H), 2.53-2.63 (m, 5H), 2.31 (s, 3H), 1.85-2.15 (m, 2H).

實施例75-76 合成化合物75-P1，75-P2至76-P1，76-P2Examples 75-76 Synthesis of Compounds 75-P1, 75-P2 to 76-P1, 76-P2

化合物75-P1，75-P2至76-P1，76-P2的製備參考實施例64，使用對應的第三丁基氧羰基保護的胺替換化合物64-5，並進行掌性拆分。分離條件：色譜柱型號：Chiralpak IB N-3；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳, B：乙醇(0.1% 乙醇胺), B%：20%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，20%固定濃度洗提0.5分鐘；檢測波長：254 nm；柱溫：35℃。 75-P1 滯留時間1.628分鐘，ee值91.42%。 MS-ESI [M+H] ⁺，計算值483，實測值483。 ¹H NMR: (400 MHz, CD ₃OD) δ(ppm) 7.50-7.60 (m, 1H), 7.30-7.49 (m, 1H), 7.25-7.49 (m, 1H), 7.07-7.20 (m, 2H), 6.97-7.06 (m, 1H), 5.28-5.58 (m, 2H), 4.75 (br d, J= 16.4 Hz, 1H), 4.32-4.44 (m, 1H), 4.04-4.17 (m, 2H), 3.79-4.02 (m, 2H), 3.57-3.70 (m, 2H), 2.53-2.74 (m, 4H)。 75-P2 滯留時間2.040分鐘，ee值91.10%。 MS-ESI [M+H] ⁺，計算值483，實測值483。 ¹H NMR: (400 MHz, CD ₃OD) δ(ppm) 7.54 (s, 1H), 7.30-7.50 (m, 2H), 7.07-7.18 (m, 2H), 6.98-7.06 (m, 1H), 5.11-5.74 (m, 2H), 4.75 (br d, J = 16.1 Hz, 1H), 4.32-4.43 (m, 1H), 4.06-4.17 (m, 2H), 3.95-4.04 (m, 1H), 3.89-3.95 (m, 1H), 3.73-3.80 (m, 1H), 3.59-3.67 (m, 1H), 2.54-2.72 (m, 4H)。分離條件：色譜柱型號：Chiralcel OX-3；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇+乙腈(0.1% 二乙胺)，B%：50%固定濃度洗提；檢測波長：254 nm；柱溫：35℃。 76-P1 滯留時間1.221分鐘，ee值92.98%。 MS-ESI [M+H] ⁺，計算值497，實測值497。 ¹H NMR: (400 MHz, MeOD) δ7.49-7.55 (m, 1H), 7.28-7.37 (m, 1H), 7.12-7.24 (m, 2H), 7.01 (t, J= 8.4 Hz, 1H), 5.46 (s, 1H), 4.29 (d, J= 16.0 Hz, 1H), 3.95-4.07 (m, 2H), 3.82-3.92 (m, 1H), 3.34-3.40 (m, 1H), 2.56-3.04 (m, 8H), 1.75-2.12 (m, 3H)。 76-P2 滯留時間1.687分鐘，ee值95.34%。 MS-ESI [M+H] ⁺，計算值497，實測值497。 ¹H NMR: (400 MHz, MeOD) δ7.48-7.56 (m, 1H), 7.29-7.37 (m, 1H), 7.12-7.24 (m, 2H), 6.97-7.05 (m, 1H), 5.46 (s, 1H), 4.29 (d, J= 16.0 Hz, 1H), 3.95-4.07 (m, 2H), 3.79-3.91 (m, 1H), 3.36 (dd, J= 9.6, 5.2 Hz, 1H), 2.53-3.02 (m, 8H), 1.77-2.09 (m, 3H)。 The preparation of compounds 75-P1, 75-P2 to 76-P1, 76-P2 was carried out according to Example 64, using the corresponding tert-butyloxycarbonyl-protected amine to replace compound 64-5, and performing chiral resolution. Separation conditions: chromatographic column model: Chiralpak IB N-3; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.1% ethanolamine), B%: 20%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 20% fixed concentration elution for 0.5 minutes; detection wavelength: 254 nm; column temperature: 35°C. 75-P1 Retention time 1.628 min, ee 91.42%. MS-ESI [M+H] ⁺ , calculated 483, found 483. ¹ H NMR: (400 MHz, CD ₃ OD) δ (ppm) 7.50-7.60 (m, 1H), 7.30-7.49 (m, 1H), 7.25-7.49 (m, 1H), 7.07-7.20 (m, 2H), 6.97-7.06 (m, 1H), 5.28-5.58 (m, 2H), 4.75 (br d, J = 16.4 Hz, 1H), 4.32-4.44 (m, 1H), 4.04-4.17 (m, 2H), 3.79-4.02 (m, 2H), 3.57-3.70 (m, 2H), 2.53-2.74 (m, 4H). 75-P2 Retention time 2.040 min, ee 91.10%. MS-ESI [M+H] ⁺ , calculated 483, found 483. ¹ H NMR: (400 MHz, CD ₃ OD) δ (ppm) 7.54 (s, 1H), 7.30-7.50 (m, 2H), 7.07-7.18 (m, 2H), 6.98-7.06 (m, 1H), 5.11-5.74 (m, 2H), 4.75 (br d, J = 16.1 Hz, 1H), 4.32-4.43 (m, 1H), 4.06-4.17 (m, 2H), 3.95-4.04 (m, 1H), 3.89-3.95 (m, 1H), 3.73-3.80 (m, 1H), 3.59-3.67 (m, 1H), 2.54-2.72 (m, 4H). Separation conditions: chromatographic column model: Chiralcel OX-3; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol + acetonitrile (0.1% diethylamine), B%: 50% fixed concentration elution; detection wavelength: 254 nm; column temperature: 35°C. 76-P1 Retention time 1.221 min, ee 92.98%. MS-ESI [M+H] ⁺ , calculated 497, found 497. ¹ H NMR: (400 MHz, MeOD) δ 7.49-7.55 (m, 1H), 7.28-7.37 (m, 1H), 7.12-7.24 (m, 2H), 7.01 (t, J = 8.4 Hz, 1H), 5.46 (s, 1H), 4.29 (d, J = 16.0 Hz, 1H), 3.95-4.07 (m, 2H), 3.82-3.92 (m, 1H), 3.34-3.40 (m, 1H), 2.56-3.04 (m, 8H), 1.75-2.12 (m, 3H). 76-P2 Retention time 1.687 min, ee 95.34%. MS-ESI [M+H] ⁺ , calculated 497, found 497. ¹ H NMR: (400 MHz, MeOD) δ 7.48-7.56 (m, 1H), 7.29-7.37 (m, 1H), 7.12-7.24 (m, 2H), 6.97-7.05 (m, 1H), 5.46 (s, 1H), 4.29 (d, J = 16.0 Hz, 1H), 3.95-4.07 (m, 2H), 3.79-3.91 (m, 1H), 3.36 (dd, J = 9.6, 5.2 Hz, 1H), 2.53-3.02 (m, 8H), 1.77-2.09 (m, 3H).

實施例77 合成化合物77 Example 77 Synthesis of Compound 77

(1)化合物64-1的合成參考實施例64。04下向化合物64-1(1.14 g, 5.19 mmol)的 N,N-二甲基甲醯胺(25.0 mL)溶液中，加入碳酸銫(1.54 g, 4.72 mmol)和中間體F(1.90 g, 5.19 mmol)。反應液在氮氣保護下60應攪拌2小時。反應液加入水(50.0 mL)，用乙酸乙酯(200 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/乙酸乙酯 = 1 ：0 到 3 ：1)分離得到化合物77-1。 (1) Synthesis of Compound 64-1 Refer to Example 64. To a solution of Compound 64-1 (1.14 g, 5.19 mmol) in N,N -dimethylformamide (25.0 mL) at 0.4 °C, cesium carbonate (1.54 g, 4.72 mmol) and intermediate F (1.90 g, 5.19 mmol) were added. The reaction solution was stirred for 2 hours under nitrogen protection. Water (50.0 mL) was added to the reaction solution, and it was extracted with ethyl acetate (200 mL). The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 3:1) to obtain Compound 77-1.

MS-ESI [M+H] ⁺，計算值548，實測值548。 MS-ESI [M+H] ⁺ , calcd. 548, found 548.

¹H NMR (400 MHz, CDCl ₃) δ7.75 (s, 1H), 7.27-7.30 (m, 1H), 7.23-7.27 (m, 2H), 7.16-7.21 (m, 2H), 6.01 (s, 1H), 5.38 (s, 2H), 4.71-4.82 (m, 1H), 4.54-4.66 (m, 1H), 3.66 (s, 3H), 3.45 (t, J= 8.4 Hz, 2H), 2.90 (ddd, J= 12.8, 8.0, 4.8 Hz, 1H), 2.51-2.59 (m, 2H), 2.36-2.48 (m, 1H), 0.85-0.88 (m, 2H), -0.04 (s, 9H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.75 (s, 1H), 7.27-7.30 (m, 1H), 7.23-7.27 (m, 2H), 7.16-7.21 (m, 2H), 6.01 (s, 1H), 5.38 (s, 2H), 4.71-4.82 (m, 1H), 4.54-4.66 (m, 1H), 3.66 (s, 3H), 3.45 (t, J = 8.4 Hz, 2H), 2.90 (ddd, J = 12.8, 8.0, 4.8 Hz, 1H), 2.51-2.59 (m, 2H), 2.36-2.48 (m, 1H), 0.85-0.88 (m, 2H), -0.04 (s, 9H).

(2)向化合物77-1(1.98 g, 3.61 mmol)的甲苯(20.0 mL)溶液中，加入2,4-二甲氧基苄胺(1.51 g, 9.02 mmol)，碳酸銫(2.35 g, 7.22 mmol)，三(二亞苄基丙酮)二鈀(331 mg, 361 μmol)，1,1'-聯萘-2,2'-雙二苯膦(450 mg, 722 μmol)。反應液在氮氣保護下120℃攪拌3小時，反應液加入水(50.0 mL)，用乙酸乙酯(200 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法 (石油醚/乙酸乙酯 = 1 ：0 到 3 ：1) 分離得到化合物77-2。(2) To a toluene (20.0 mL) solution of compound 77-1 (1.98 g, 3.61 mmol), 2,4-dimethoxybenzylamine (1.51 g, 9.02 mmol), cesium carbonate (2.35 g, 7.22 mmol), tri(dibenzylideneacetone)dipalladium (331 mg, 361 μmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (450 mg, 722 μmol) were added. The reaction solution was stirred at 120°C for 3 hours under nitrogen protection, water (50.0 mL) was added to the reaction solution, and the solution was extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 3:1) to give compound 77-2.

MS-ESI [M+H] ⁺, 計算值679, 實測值679。 MS-ESI [M+H] ⁺ , calcd. 679, found 679.

¹H NMR (400 MHz, CDCl ₃) δ7.43-7.53 (m, 1H), 7.28-7.33 (m, 3H), 7.16-7.23 (m, 2H), 6.49 (d, J= 2.4 Hz, 1H), 6.42-6.47 (m, 1H), 6.05 (s, 1H), 5.31 (s, 2H), 5.23 (br t, J= 5.6 Hz, 1H), 5.19 (s, 1H), 4.80 (d, J= 16.0 Hz, 1H), 4.62 (dd, J= 5.6, 2.0 Hz, 2H), 4.53 (d, J= 16.0 Hz, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 3.57 (s, 3H), 3.39 (t, J= 8.0 Hz, 2H), 2.92 (dt, J= 13.2, 6.4 Hz, 1H), 2.49-2.60 (m, 2H), 2.29-2.37 (m, 1H), 0.78-0.88 (m, 2H), -0.11--0.01 (m, 9H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43-7.53 (m, 1H), 7.28-7.33 (m, 3H), 7.16-7.23 (m, 2H), 6.49 (d, J = 2.4 Hz, 1H), 6.42-6.47 (m, 1H), 6.05 (s, 1H), 5.31 (s, 2H), 5.23 (br t, J = 5.6 Hz, 1H), 5.19 (s, 1H), 4.80 (d, J = 16.0 Hz, 1H), 4.62 (dd, J = 5.6, 2.0 Hz, 2H), 4.53 (d, J = 16.0 Hz, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 3.57 (s, 3H), 3.39 (t, J = 8.0 Hz, 2H), 2.92 (dt, J = 13.2, 6.4 Hz, 1H), 2.49-2.60 (m, 2H), 2.29-2.37 (m, 1H), 0.78-0.88 (m, 2H), -0.11--0.01 (m, 9H).

(3) 向化合物77-2 (2.50 g, 3.68 mmol) 的四氫呋喃 (16.0 mL) 溶液中, 加入一水合氫氧化鋰 (1.08 g, 25.8 mmol)。反應液在氮氣保護下25℃攪拌4小時。反應液在0℃下加入鹽酸水溶液調節pH值到7, 用乙酸乙酯 (100 mL × 2) 萃取, 有機相用無水硫酸鈉乾燥, 過濾, 減壓濃縮。得到化合物77-3。(3) To a solution of compound 77-2 (2.50 g, 3.68 mmol) in tetrahydrofuran (16.0 mL) was added lithium hydroxide monohydrate (1.08 g, 25.8 mmol). The reaction solution was stirred at 25°C for 4 hours under nitrogen protection. The reaction solution was adjusted to pH 7 by adding hydrochloric acid aqueous solution at 0°C, extracted with ethyl acetate (100 mL × 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 77-3.

MS-ESI [M+H] ⁺，計算值665，實測值665。 MS-ESI [M+H] ⁺ , calcd. 665, found 665.

¹H NMR (400 MHz, CDCl ₃) δ7.46 (s, 1H), 7.34 (d, J= 7.2 Hz, 2H), 7.16-7.27 (m, 4H), 6.47 (d, J= 2.4 Hz, 1H), 6.35-6.40 (m, 2H), 5.31-5.33 (m, 2H), 5.15 (d, J= 12.0 Hz, 1H), 4.93 (d, J= 16.0 Hz, 1H), 4.55 (s, 3H), 3.83 (s, 3H), 3.79 (s, 3H), 3.37 (t, J= 8.0 Hz, 2H), 2.96-3.06 (m, 1H), 2.44-2.71 (m, 2H), 2.22-2.35 (m, 1H), 0.77-0.85 (m, 2H), -0.08 (s, 9H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46 (s, 1H), 7.34 (d, J = 7.2 Hz, 2H), 7.16-7.27 (m, 4H), 6.47 (d, J = 2.4 Hz, 1H), 6.35-6.40 (m, 2H), 5.31-5.33 (m, 2H), 5.15 (d, J = 12.0 Hz, 1H), 4.93 (d, J = 16.0 Hz, 1H), 4.55 (s, 3H), 3.83 (s, 3H), 3.79 (s, 3H), 3.37 (t, J = 8.0 Hz, 2H), 2.96-3.06 (m, 1H), 2.44-2.71 (m, 2H), 2.22-2.35 (m, 1H), 0.77-0.85 (m, 2H), -0.08 (s, 9H).

(4)向化合物77-3(160 mg, 241 μmol)的 N,N-二甲基甲醯胺(4.0 mL)溶液中加入二異丙基乙基胺(218 mg, 1.68 mmol)和 N,N,Nm,N,-四甲基- O-(7-氮雜苯并三唑-1-基)六氟磷酸脲(137 mg, 361 μmol)，室溫下攪拌25分鐘，隨後加入甲基環丁基胺鹽酸鹽(146 mg, 1.20 mmol)，反應液在氮氣保護下25液攪拌2小時。反應液加入水(30.0 mL)，用二氯甲烷(100 mL)萃取有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(二氯甲烷/甲醇 = 1 ：0 到 30 ：1)分離得到化合物77-4。 (4) Diisopropylethylamine (218 mg, 1.68 mmol) and N ,N,Nm,N,-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (137 mg, 361 μmol) were added to a solution of compound 77-3 (160 mg, 241 μmol) in N,N- dimethylformamide (4.0 mL), and the mixture was stirred at room temperature for 25 minutes. Methylcyclobutylamine hydrochloride (146 mg, 1.20 mmol) was then added, and the reaction mixture was stirred for 2 hours under nitrogen protection. Water (30.0 mL) was added to the reaction mixture, and the organic phase was extracted with dichloromethane (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane/methanol = 1:0 to 30:1) to give compound 77-4.

MS-ESI [M+H] ⁺，計算值732，實測值732。 MS-ESI [M+H] ⁺ , calcd. 732, found 732.

(5)05下將化合物77-4(190 mg, 259 μmol)的二氯甲烷(1.0 mL)溶液中，加入三氟乙酸(1.0 mL)。反應液在氮氣保護下25應攪拌1小時。反應液加入甲醇(1.0 mL)和氨水 (0.91 g, 7.78 mmol, 1.00 mL)並在氮氣保護下30氮攪拌8小時。反應液加入水(50.0 mL)，用乙酸乙酯(50.0 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經製備高效液相色譜法 (Xtimate C18, 200 mm × 40 mm 7 μm, A:水(氨水)；B:乙腈, 18%-58%：25分鐘)分離得到化合物77。(5) Trifluoroacetic acid (1.0 mL) was added to a solution of compound 77-4 (190 mg, 259 μmol) in dichloromethane (1.0 mL) at 0.5 °C. The reaction solution was stirred at 25 °C for 1 hour under nitrogen protection. Methanol (1.0 mL) and aqueous ammonia (0.91 g, 7.78 mmol, 1.00 mL) were added to the reaction solution and stirred at 30 °C for 8 hours under nitrogen protection. Water (50.0 mL) was added to the reaction solution, and the solution was extracted with ethyl acetate (50.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative HPLC (Xtimate C18, 200 mm × 40 mm 7 μm, A: water (ammonia water); B: acetonitrile, 18%-58%: 25 min) to give compound 77.

MS-ESI [M+H] ⁺，計算值452，實測值452。 MS-ESI [M+H] ⁺ , calcd. 452, found 452.

(7)化合物77經掌性超臨界流體色譜法拆分得到化合物77-P1和77-P2。分離條件：色譜柱型號：Chiralpak AS-3；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇(0.05% 二乙胺)，B%：40%固定濃度洗提；檢測波長：254 nm；柱溫：35℃。 77-P1 滯留時間0.366分鐘，ee值100.00%。 MS-ESI [M+H] ⁺，計算值452，實測值452。 ¹H NMR: (400 MHz, CDCl ₃) δ(ppm) 9.28 (br s, 1H), 7.42 (s, 1H), 7.30-7.38 (m, 3H), 7.13-7.20 (m, 2H), 5.10-5.15 (m, 1H), 4.71 (d, J= 15.6 Hz, 1H), 4.55 (br s, 2H), 3.82-4.04 (m, 2H), 3.08 (s, 2H), 2.79-2.93 (m, 1H), 2.55-2.67 (m, 3H), 2.36-2.47 (m, 1H), 2.12-2.30 (m, 3H), 1.97-2.07 (m, 1H)。 77-P2 滯留時間1.124分鐘，ee值99.80%。 MS-ESI [M+H] ⁺，計算值452，實測值452。 ¹H NMR: (400 MHz, CDCl ₃) δ(ppm) 9.28 (br s, 1H), 7.42 (s, 1H), 7.29-7.39 (m, 3H), 7.12-7.20 (m, 2H), 5.10-5.15 (m, 1H), 4.71 (d, J= 15.2 Hz, 1H), 4.55 (br s, 2H), 3.85-4.00 (m, 2H), 3.08 (s, 2H), 2.81-2.94 (m, 1H), 2.56-2.68 (m, 3H), 2.37-2.47 (m, 1H), 2.10-2.31 (m, 3H), 1.96-2.08 (m, 1H)。 (7) Compound 77 was separated by chiral supercritical fluid chromatography to give compounds 77-P1 and 77-P2. Separation conditions: chromatographic column model: Chiralpak AS-3; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 40% fixed concentration elution; detection wavelength: 254 nm; column temperature: 35℃. 77-P1 Retention time 0.366 min, ee value 100.00%. MS-ESI [M+H] ⁺ , calculated value 452, found value 452. ¹ H NMR: (400 MHz, CDCl ₃ ) δ (ppm) 9.28 (br s, 1H), 7.42 (s, 1H), 7.30-7.38 (m, 3H), 7.13-7.20 (m, 2H), 5.10-5.15 (m, 1H), 4.71 (d, J = 15.6 Hz, 1H), 4.55 (br s, 2H), 3.82-4.04 (m, 2H), 3.08 (s, 2H), 2.79-2.93 (m, 1H), 2.55-2.67 (m, 3H), 2.36-2.47 (m, 1H), 2.12-2.30 (m, 3H), 1.97-2.07 (m, 1H). 77-P2 Retention time 1.124 min, ee 99.80%. MS-ESI [M+H] ⁺ , calculated 452, found 452. ¹ H NMR: (400 MHz, CDCl ₃ ) δ (ppm) 9.28 (br s, 1H), 7.42 (s, 1H), 7.29-7.39 (m, 3H), 7.12-7.20 (m, 2H), 5.10-5.15 (m, 1H), 4.71 (d, J = 15.2 Hz, 1H), 4.55 (br s, 2H), 3.85-4.00 (m, 2H), 3.08 (s, 2H), 2.81-2.94 (m, 1H), 2.56-2.68 (m, 3H), 2.37-2.47 (m, 1H), 2.10-2.31 (m, 3H), 1.96-2.08 (m, 1H).

實施例78-81 合成化合物78-P1，78-P2至81-P1，81-P2Examples 78-81 Synthesis of Compounds 78-P1, 78-P2 to 81-P1, 81-P2

化合物78-P1，78-P2至81-P1，81-P2的製備參考實施例77，使用對應的胺替換甲基環丁基胺。分離條件：色譜柱型號：Chiralpak IH-3；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇(0.05% 二乙胺)，B%：20%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，20%固定濃度洗提0.5分鐘；檢測波長：254 nm；柱溫：35℃。 78-P1 滯留時間1.114分鐘，ee值100.00%。 MS-ESI [M+H] ⁺，計算值455，實測值455。 ¹H NMR: (400 MHz, MeOD) δ7.49 (s, 1H), 7.27 (s, 5H), 5.21 (s, 1H), 3.88-4.08 (m, 2H), 3.04-3.15 (m, 1H), 2.67-2.77 (m, 1H), 2.40-2.59 (m, 2H), 2.14-2.33 (m, 3H), 2.09 (d, J= 2.0 Hz, 1H), 1.52-1.82 (m, 2H), 1.20-1.28 (m, 1H)。 78-P2 滯留時間2.376分鐘，ee值99.32%。 MS-ESI [M+H] ⁺，計算值455，實測值455。 ¹H NMR: (400 MHz, MeOD) δ7.49 (s, 1H), 7.27 (s, 5H), 5.20 (s, 1H), 3.87-4.08 (m, 2H), 3.04-3.15 (m, 1H), 2.67-2.77 (m, 1H), 2.40-2.59 (m, 2H), 2.14-2.34 (m, 3H), 2.00-2.10 (m, 1H), 1.53-1.82 (m, 2H), 1.19-1.28 (m, 1H)。分離條件：色譜柱型號：Chiralpak AD-3；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳，B：異丙醇(0.05% 二乙胺)，B%：40%固定濃度洗提；檢測波長：254 nm；柱溫：35℃。 79-P1 滯留時間0.900分鐘，ee值99.06%。 MS-ESI [M+H] ⁺，計算值464，實測值464。 ¹H NMR: (400 MHz, CD ₃OD) δ(ppm) 7.50 (s, 1H), 7.26-7.37 (m, 5H), 5.39 (s, 1H), 4.75 (d, J= 16.0 Hz, 1H), 4.24 (d, J= 16.0 Hz, 1H), 4.02 (s, 2H), 3.86 (d, J= 9.6 Hz, 1H), 3.35 (s, 1H), 2.77-2.89 (m, 1H), 2.62-2.72 (m, 1H), 2.50-2.61 (m, 2H), 2.03-2.17 (m, 3H), 1.89-1.98 (m, 1H), 1.67-1.84 (m, 2H)。 79-P2 滯留時間1.395分鐘，ee值99.80%。 MS-ESI [M+H] ⁺，計算值464，實測值464。 ¹H NMR: (400 MHz, CD ₃OD) δ(ppm) 7.50 (s, 1H), 7.28-7.37 (m, 5H), 5.39 (s, 1H), 4.75 (d, J= 16.0 Hz, 1H), 4.24 (d, J= 16.0 Hz, 1H), 4.02 (s, 2H), 3.86 (d, J= 9.6 Hz, 1H), 3.35 (s, 1H), 2.77-2.89 (m, 1H), 2.62-2.72 (m, 1H), 2.50-2.61 (m, 2H), 2.02-2.18 (m, 3H), 1.94 (td, J= 9.2, 6.6 Hz, 1H), 1.65-1.84 (m, 2H)。分離條件：色譜柱型號：Chiralpak AS-3；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇(0.05% 二乙胺)，B%：20%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，20%固定濃度洗提0.5分鐘；檢測波長：254 nm；柱溫：35℃。 80-P1 滯留時間0.935分鐘，ee值99.20%。 MS-ESI [M+H] ⁺，計算值438，實測值438。 ¹H NMR: (400 MHz, CDCl ₃) δ(ppm) 9.19-9.36 (m, 1H), 7.43 (s, 1H), 7.31-7.39 (m, 3H), 7.14-7.23 (m, 2H), 5.15 (br d, J = 3.6 Hz, 1H), 4.74 (d, J = 15.6 Hz, 1H), 4.55-4.70 (m, 2H), 4.01 (br d, J = 15.4 Hz, 1H), 2.45-2.96 (m, 8H), 0.70-0.98 (m, 4H)。 80-P2 滯留時間1.654分鐘，ee值99.04%。 MS-ESI [M+H] ⁺，計算值438，實測值438。 ¹H NMR: (400 MHz, CDCl ₃) δ(ppm) 9.27 (br s, 1H), 7.43 (s, 1H), 7.31-7.39 (m, 3H), 7.19 (br s, 2H), 5.14 (br s, 1H), 4.74 (d, J= 15.6 Hz, 1H), 4.57 (br s, 2H), 4.01 (br d, J= 15.6 Hz, 1H), 2.71-2.98 (m, 3H), 2.52-2.66 (m, 5H), 0.67-0.99 (m, 4H)。分離條件：色譜柱型號：(S,S)-Whelk-0-1.8；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇+乙腈(0.1% 二乙胺)，B%：50%固定濃度洗提；檢測波長：254 nm；柱溫：35℃。 81-P1 滯留時間1.581分鐘，ee值99.52%。 MS-ESI [M+H] ⁺，計算值480，實測值480。 ¹H NMR: (400 MHz, CDCl ₃) δ(ppm) 9.36 (br dd, J= 2.8, 1.6 Hz, 1H), 7.45-7.50 (m, 1H), 7.32-7.44 (m, 4H), 7.30 (br s, 1H), 5.47 (s, 1H), 4.54-4.72 (m, 3H), 4.17-4.29 (m, 1H), 4.04-4.15 (m, 2H), 3.68-3.83 (m, 5H), 3.36-3.54 (m, 1H), 2.60-2.69 (m, 3H), 2.49-2.58 (m, 1H), 2.08-2.15 (m, 1H), 1.92-2.01 (m, 1H)。 81-P2 滯留時間1.998分鐘，ee值81.38%。 MS-ESI [M+H] ⁺，計算值480，實測值480。 ¹H NMR: (400 MHz, CDCl ₃) δ(ppm) 9.39 (br s, 1H), 7.50-7.63 (m, 1H), 7.46-7.50 (m, 1H), 7.34-7.45 (m, 4H), 5.48 (s, 1H), 4.55-4.77 (m, 3H), 4.17-4.30 (m, 1H), 4.06-4.14 (m, 2H), 3.68 (br s, 5H), 3.44 (br t, J= 8.4 Hz, 1H), 2.60-2.67 (m, 3H), 2.49-2.57 (m, 1H), 2.07-2.14 (m, 1H), 1.93-2.00 (m, 1H)。 The preparation of compounds 78-P1, 78-P2 to 81-P1, 81-P2 refers to Example 77, using corresponding amines instead of methylcyclobutylamine. Separation conditions: chromatographic column model: Chiralpak IH-3; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 20%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 20% fixed concentration elution for 0.5 minutes; detection wavelength: 254 nm; column temperature: 35°C. 78-P1 Retention time 1.114 min, ee 100.00%. MS-ESI [M+H] ⁺ , calculated 455, found 455. ¹ H NMR: (400 MHz, MeOD) δ 7.49 (s, 1H), 7.27 (s, 5H), 5.21 (s, 1H), 3.88-4.08 (m, 2H), 3.04-3.15 (m, 1H), 2.67-2.77 (m, 1H), 2.40-2.59 (m, 2H), 2.14-2.33 (m, 3H), 2.09 (d, J = 2.0 Hz, 1H), 1.52-1.82 (m, 2H), 1.20-1.28 (m, 1H). 78-P2 Retention time 2.376 min, ee 99.32%. MS-ESI [M+H] ⁺ , calculated 455, found 455. ¹ H NMR: (400 MHz, MeOD) δ 7.49 (s, 1H), 7.27 (s, 5H), 5.20 (s, 1H), 3.87-4.08 (m, 2H), 3.04-3.15 (m, 1H), 2.67-2.77 (m, 1H), 2.40-2.59 (m, 2H), 2.14-2.34 (m, 3H), 2.00-2.10 (m, 1H), 1.53-1.82 (m, 2H), 1.19-1.28 (m, 1H). Separation conditions: chromatographic column model: Chiralpak AD-3; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: isopropanol (0.05% diethylamine), B%: 40% fixed concentration elution; detection wavelength: 254 nm; column temperature: 35°C. 79-P1 Retention time 0.900 min, ee 99.06%. MS-ESI [M+H] ⁺ , calculated 464, found 464. ¹ H NMR: (400 MHz, CD ₃ OD) δ (ppm) 7.50 (s, 1H), 7.26-7.37 (m, 5H), 5.39 (s, 1H), 4.75 (d, J = 16.0 Hz, 1H), 4.24 (d, J = 16.0 Hz, 1H), 4.02 (s, 2H), 3.86 (d, J = 9.6 Hz, 1H), 3.35 (s, 1H), 2.77-2.89 (m, 1H), 2.62-2.72 (m, 1H), 2.50-2.61 (m, 2H), 2.03-2.17 (m, 3H), 1.89-1.98 (m, 1H), 1.67-1.84 (m, 2H). 79-P2 Retention time 1.395 min, ee 99.80%. MS-ESI [M+H] ⁺ , calculated 464, found 464. ¹ H NMR: (400 MHz, CD ₃ OD) δ (ppm) 7.50 (s, 1H), 7.28-7.37 (m, 5H), 5.39 (s, 1H), 4.75 (d, J = 16.0 Hz, 1H), 4.24 (d, J = 16.0 Hz, 1H), 4.02 (s, 2H), 3.86 (d, J = 9.6 Hz, 1H), 3.35 (s, 1H), 2.77-2.89 (m, 1H), 2.62-2.72 (m, 1H), 2.50-2.61 (m, 2H), 2.02-2.18 (m, 3H), 1.94 (td, J = 9.2, 6.6 Hz, 1H), 1.65-1.84 (m, 2H). Separation conditions: chromatographic column model: Chiralpak AS-3; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 20%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 20% fixed concentration elution for 0.5 minutes; detection wavelength: 254 nm; column temperature: 35°C. 80-P1 Retention time 0.935 min, ee 99.20%. MS-ESI [M+H] ⁺ , calculated 438, found 438. ¹ H NMR: (400 MHz, CDCl ₃ ) δ (ppm) 9.19-9.36 (m, 1H), 7.43 (s, 1H), 7.31-7.39 (m, 3H), 7.14-7.23 (m, 2H), 5.15 (br d, J = 3.6 Hz, 1H), 4.74 (d, J = 15.6 Hz, 1H), 4.55-4.70 (m, 2H), 4.01 (br d, J = 15.4 Hz, 1H), 2.45-2.96 (m, 8H), 0.70-0.98 (m, 4H). 80-P2 Retention time 1.654 min, ee 99.04%. MS-ESI [M+H] ⁺ , calculated 438, found 438. ¹ H NMR: (400 MHz, CDCl ₃ ) δ (ppm) 9.27 (br s, 1H), 7.43 (s, 1H), 7.31-7.39 (m, 3H), 7.19 (br s, 2H), 5.14 (br s, 1H), 4.74 (d, J = 15.6 Hz, 1H), 4.57 (br s, 2H), 4.01 (br d, J = 15.6 Hz, 1H), 2.71-2.98 (m, 3H), 2.52-2.66 (m, 5H), 0.67-0.99 (m, 4H). Separation conditions: chromatographic column model: (S,S)-Whelk-0-1.8; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol + acetonitrile (0.1% diethylamine), B%: 50% fixed concentration elution; detection wavelength: 254 nm; column temperature: 35°C. 81-P1 Retention time 1.581 min, ee 99.52%. MS-ESI [M+H] ⁺ , calculated 480, found 480. ¹ H NMR: (400 MHz, CDCl ₃ ) δ (ppm) 9.36 (br dd, J = 2.8, 1.6 Hz, 1H), 7.45-7.50 (m, 1H), 7.32-7.44 (m, 4H), 7.30 (br s, 1H), 5.47 (s, 1H), 4.54-4.72 (m, 3H), 4.17-4.29 (m, 1H), 4.04-4.15 (m, 2H), 3.68-3.83 (m, 5H), 3.36-3.54 (m, 1H), 2.60-2.69 (m, 3H), 2.49-2.58 (m, 1H), 2.08-2.15 (m, 1H), 1.92-2.01 (m, 1H). 81-P2 Retention time 1.998 min, ee value 81.38%. MS-ESI [M+H] ⁺ , calculated value 480, found value 480. ¹ H NMR: (400 MHz, CDCl ₃ ) δ (ppm) 9.39 (br s, 1H), 7.50-7.63 (m, 1H), 7.46-7.50 (m, 1H), 7.34-7.45 (m, 4H), 5.48 (s, 1H), 4.55-4.77 (m, 3H), 4.17-4.30 (m, 1H), 4.06-4.14 (m, 2H), 3.68 (br s, 5H), 3.44 (br t, J = 8.4 Hz, 1H), 2.60-2.67 (m, 3H), 2.49-2.57 (m, 1H), 2.07-2.14 (m, 1H), 1.93-2.00 (m, 1H).

實施例82 合成化合物82Example 82 Synthesis of Compound 82

化合物82的製備參考實施例77，使用對應的第三丁基氧羰基保護的胺替換甲基環丁基胺。 MS-ESI [M+H] ⁺，計算值453，實測值453。 ¹H NMR (400 MHz, MeOD) δ7.95-8.05 (m, 1H), 7.16-7.48 (m, 4H), 5.35-5.42 (m, 1H), 5.12-5.22 (m, 1H), 4.38-4.52 (m, 1H), 3.86-4.31 (m, 5H), 3.60-3.79 (m, 1H), 2.59-2.91 (m, 7H)。 Compound 82 was prepared according to Example 77, using the corresponding tert-butyloxycarbonyl-protected amine in place of methylcyclobutylamine. MS-ESI [M+H] ⁺ , calcd. 453, found 453. ¹ H NMR (400 MHz, MeOD) δ 7.95-8.05 (m, 1H), 7.16-7.48 (m, 4H), 5.35-5.42 (m, 1H), 5.12-5.22 (m, 1H), 4.38-4.52 (m, 1H), 3.86-4.31 (m, 5H), 3.60-3.79 (m, 1H), 2.59-2.91 (m, 7H).

實施例83 化合物83的合成Example 83 Synthesis of Compound 83

合成參考實施例77，使用中間體I替換中間體H，得到化合物83-P1和83-P2。分離條件：色譜柱型號：Chiralpak AS-3；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇(0.05% 二乙胺)，B%：20%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，20%固定濃度洗提0.5分鐘；檢測波長：254 nm；柱溫：35℃。 83-P1 滯留時間0.898分鐘，ee值100.00%。 MS-ESI [M+H] ⁺，計算值454，實測值454。 ¹H NMR: (400 MHz, MeOD) δ7.49 (s, 1H), 7.22-7.35 (m, 5H), 5.20 (s, 1H), 3.91-4.02 (m, 1H), 3.03-3.11 (m, 3H), 2.67-2.76 (m, 1H), 2.37-2.64 (m, 3H), 2.10-2.37 (m, 3H), 1.98-2.10 (m, 1H), 1.53-1.81 (m, 1H), 1.18-1.29 (m, 1H)。 83-P2 滯留時間1.888分鐘，ee值99.86%。 MS-ESI [M+H] ⁺，計算值454，實測值454。 ¹H NMR: (400 MHz, MeOD) δ7.49 (s, 1H), 7.27 (s, 5H), 5.20 (s, 1H), 3.89-4.05 (m, 1H), 3.04-3.14 (m, 3H), 2.66-2.76 (m, 1H), 2.38-2.64 (m, 3H), 2.11-2.37 (m, 3H), 1.99-2.10 (m, 1H), 1.53-1.81 (m, 1H), 1.18-1.29 (m, 1H)。 Reference Example 77 was synthesized by using Intermediate I to replace Intermediate H to obtain Compounds 83-P1 and 83-P2. Separation conditions: chromatographic column model: Chiralpak AS-3; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 20%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 20% fixed concentration elution for 0.5 minutes; detection wavelength: 254 nm; column temperature: 35°C. 83-P1 Retention time 0.898 min, ee 100.00%. MS-ESI [M+H] ⁺ , calculated 454, found 454. ¹ H NMR: (400 MHz, MeOD) δ 7.49 (s, 1H), 7.22-7.35 (m, 5H), 5.20 (s, 1H), 3.91-4.02 (m, 1H), 3.03-3.11 (m, 3H), 2.67-2.76 (m, 1H), 2.37-2.64 (m, 3H), 2.10-2.37 (m, 3H), 1.98-2.10 (m, 1H), 1.53-1.81 (m, 1H), 1.18-1.29 (m, 1H). 83-P2 Retention time 1.888 min, ee 99.86%. MS-ESI [M+H] ⁺ , calculated 454, found 454. ¹ H NMR: (400 MHz, MeOD) δ 7.49 (s, 1H), 7.27 (s, 5H), 5.20 (s, 1H), 3.89-4.05 (m, 1H), 3.04-3.14 (m, 3H), 2.66-2.76 (m, 1H), 2.38-2.64 (m, 3H), 2.11-2.37 (m, 3H), 1.99-2.10 (m, 1H), 1.53-1.81 (m, 1H), 1.18-1.29 (m, 1H).

實施例84 化合物84的合成Example 84 Synthesis of Compound 84

合成參考實施例83，使用氘代甲基環丁基胺替換甲基環丁基胺，得到化合物84-P1和84-P2。分離條件：色譜柱型號：Chiralpak AS-3；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇(0.05% 二乙胺)，B%：20%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，20%固定濃度洗提0.5分鐘；檢測波長：254 nm；柱溫：35℃。 84-P1 滯留時間0.925分鐘，ee值99.78%。 MS-ESI [M+H] ⁺，計算值457，實測值457。 ¹H NMR: (400 MHz, CD ₃OD) δ(ppm) 7.49 (s, 1H), 7.27 (s, 6H), 5.20 (s, 1H), 3.89-4.02 (m, 1H), 2.97-3.12 (m, 1H), 2.67-2.78 (m, 1H), 2.40-2.57 (m, 2H), 2.12-2.32 (m, 3H), 1.45-1.85 (m, 2H)。 84-P2 滯留時間1.878分鐘，ee值99.12%。 MS-ESI [M+H] ⁺，計算值457，實測值457。 ¹H NMR：(400 MHz, CD ₃OD) δ(ppm) 7.53 (s, 1H), 7.23-7.38 (m, 6H), 5.23 (d, J= 1.32 Hz, 1H), 3.96 (br dd, J= 16.8, 8.8 Hz, 1H), 2.97-3.15 (m, 1H), 2.68-2.76 (m, 1H), 2.43-2.58 (m, 2H), 2.14-2.32 (m, 3H), 1.51-1.84 (m, 2H)。 Reference Example 83 was synthesized by using deuterated methylcyclobutylamine in place of methylcyclobutylamine to obtain compounds 84-P1 and 84-P2. Separation conditions: chromatographic column model: Chiralpak AS-3; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 20%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 20% fixed concentration elution for 0.5 minutes; detection wavelength: 254 nm; column temperature: 35°C. 84-P1 Retention time 0.925 min, ee 99.78%. MS-ESI [M+H] ⁺ , calculated 457, found 457. ¹ H NMR: (400 MHz, CD ₃ OD) δ (ppm) 7.49 (s, 1H), 7.27 (s, 6H), 5.20 (s, 1H), 3.89-4.02 (m, 1H), 2.97-3.12 (m, 1H), 2.67-2.78 (m, 1H), 2.40-2.57 (m, 2H), 2.12-2.32 (m, 3H), 1.45-1.85 (m, 2H). 84-P2 Retention time 1.878 min, ee 99.12%. MS-ESI [M+H] ⁺ , calculated 457, found 457. ¹ H NMR: (400 MHz, CD ₃ OD) δ (ppm) 7.53 (s, 1H), 7.23-7.38 (m, 6H), 5.23 (d, J = 1.32 Hz, 1H), 3.96 (br dd, J = 16.8, 8.8 Hz, 1H), 2.97-3.15 (m, 1H), 2.68-2.76 (m, 1H), 2.43-2.58 (m, 2H), 2.14-2.32 (m, 3H), 1.51-1.84 (m, 2H).

實施例85 化合物85的合成Example 85 Synthesis of Compound 85

合成參考實施例85，使用2-氮雜螺[3.3]庚烷替換甲基環丁基胺，得到化合物85-P1和85-P2。分離條件：色譜柱型號：Chiralpak AD-3；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳，B：異丙醇(0.05% 二乙胺)，B%：40%固定濃度洗提；檢測波長：254 nm；柱溫：35℃。 85-P1 滯留時間0.876分鐘，ee值97.78%。 MS-ESI [M+H] ⁺，計算值466，實測值466。 ¹H NMR: (400 MHz, CD ₃OD) δ(ppm) 7.52 (s, 1H), 7.24-7.43 (m, 5H), 5.30-5.46 (m, 1H), 4.02 (s, 2H), 3.86 (br d, J= 9.2 Hz, 1H), 3.35 (s, 1H), 2.75-2.87 (m, 1H), 2.43-2.72 (m, 3H), 1.90-2.21 (m, 4H), 1.61-1.88 (m, 2H)。 85-P2 滯留時間1.356分鐘，ee值98.32%。 MS-ESI [M+H] ⁺，計算值466，實測值466。 ¹H NMR: (400 MHz, CD ₃OD) δ(ppm) 7.51 (s, 1H), 7.20-7.41 (m, 5H), 5.29-5.48 (m, 1H), 4.02 (s, 2H), 3.86 (br d, J= 9.2 Hz, 1H), 3.35 (s, 1H), 2.75-2.90 (m, 1H), 2.43-2.74 (m, 3H), 1.91-2.23 (m, 4H), 1.63-1.87 (m, 2H)。 Reference Example 85 was synthesized by using 2-azaspiro[3.3]heptane to replace methylcyclobutylamine to give compounds 85-P1 and 85-P2. Separation conditions: chromatographic column model: Chiralpak AD-3; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: isopropanol (0.05% diethylamine), B%: 40% fixed concentration elution; detection wavelength: 254 nm; column temperature: 35°C. 85-P1 Retention time 0.876 min, ee 97.78%. MS-ESI [M+H] ⁺ , calculated 466, found 466. ¹ H NMR: (400 MHz, CD ₃ OD) δ (ppm) 7.52 (s, 1H), 7.24-7.43 (m, 5H), 5.30-5.46 (m, 1H), 4.02 (s, 2H), 3.86 (br d, J = 9.2 Hz, 1H), 3.35 (s, 1H), 2.75-2.87 (m, 1H), 2.43-2.72 (m, 3H), 1.90-2.21 (m, 4H), 1.61-1.88 (m, 2H). 85-P2 Retention time 1.356 min, ee 98.32%. MS-ESI [M+H] ⁺ , calculated 466, found 466. ¹ H NMR: (400 MHz, CD ₃ OD) δ (ppm) 7.51 (s, 1H), 7.20-7.41 (m, 5H), 5.29-5.48 (m, 1H), 4.02 (s, 2H), 3.86 (br d, J = 9.2 Hz, 1H), 3.35 (s, 1H), 2.75-2.90 (m, 1H), 2.43-2.74 (m, 3H), 1.91-2.23 (m, 4H), 1.63-1.87 (m, 2H).

實施例86 化合物86的合成Example 86 Synthesis of Compound 86

合成參考實施例85，使用中間體I替換中間體H，得到化合物86-P1和86-P2。分離條件：色譜柱型號：Chiralpak AD-3；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇(0.05% 二乙胺)，B%：40%固定濃度洗提；檢測波長：254 nm；柱溫：35℃。 86-P1 滯留時間1.698分鐘，ee值96.12%。 MS-ESI [M+H] ⁺，計算值484，實測值484。 ¹H NMR: (400 MHz, MeOD) δ7.52 (s, 1H), 7.26-7.37 (m, 1H), 7.06-7.19 (m, 2H), 7.00 (td, J= 8.4, 2.4 Hz, 1H), 5.47 (s, 1H), 3.97-4.06 (m, 2H), 3.88 (br d, J= 9.2 Hz, 1H), 3.39 (d, J= 9.6 Hz, 1H), 2.48-2.82 (m, 4H), 1.92-2.20 (m, 4H), 1.65-1.85 (m, 2H)。 86-P2 滯留時間2.496分鐘，ee值96.30%。 MS-ESI [M+H] ⁺，計算值484，實測值484。 ¹H NMR: (400 MHz, MeOD) δ7.52 (s, 1H), 7.27-7.36 (m, 1H), 7.06-7.19 (m, 2H), 6.96-7.05 (m, 1H), 5.47 (s, 1H), 3.98-4.06 (m, 2H), 3.88 (d, J= 9.2 Hz, 1H), 3.39 (d, J= 9.2 Hz, 1H), 2.50-2.81 (m, 4H), 1.93-2.20 (m, 4H), 1.67-1.85 (m, 2H)。 Reference Example 85 was synthesized by using Intermediate I to replace Intermediate H to obtain Compounds 86-P1 and 86-P2. Separation conditions: chromatographic column model: Chiralpak AD-3; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 40% fixed concentration elution; detection wavelength: 254 nm; column temperature: 35°C. 86-P1 Retention time 1.698 min, ee 96.12%. MS-ESI [M+H] ⁺ , calculated 484, found 484. ¹ H NMR: (400 MHz, MeOD) δ 7.52 (s, 1H), 7.26-7.37 (m, 1H), 7.06-7.19 (m, 2H), 7.00 (td, J = 8.4, 2.4 Hz, 1H), 5.47 (s, 1H), 3.97-4.06 (m, 2H), 3.88 (br d, J = 9.2 Hz, 1H), 3.39 (d, J = 9.6 Hz, 1H), 2.48-2.82 (m, 4H), 1.92-2.20 (m, 4H), 1.65-1.85 (m, 2H). 86-P2 Retention time 2.496 min, ee 96.30%. MS-ESI [M+H] ⁺ , calculated 484, found 484. ¹ H NMR: (400 MHz, MeOD) δ 7.52 (s, 1H), 7.27-7.36 (m, 1H), 7.06-7.19 (m, 2H), 6.96-7.05 (m, 1H), 5.47 (s, 1H), 3.98-4.06 (m, 2H), 3.88 (d, J = 9.2 Hz, 1H), 3.39 (d, J = 9.2 Hz, 1H), 2.50-2.81 (m, 4H), 1.93-2.20 (m, 4H), 1.67-1.85 (m, 2H).

實施例87-89 合成化合物87-P1，87-P2至89-P1，89-P2Examples 87-89 Synthesis of Compounds 87-P1, 87-P2 to 89-P1, 89-P2

化合物87-P1，87-P2至89-P1，89-P2的製備參考實施例86，使用對應的胺替換2-氮雜螺[3.3]庚烷。分離條件：色譜柱型號：Chiralpak IB N-3；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇(0.05% 二乙胺)，B%：20%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，20%固定濃度洗提0.5分鐘；檢測波長：254 nm；柱溫：35℃。 87-P1 滯留時間0.926分鐘，ee值93.68%。 MS-ESI [M+H] ⁺，計算值458，實測值458。 ¹H NMR: (400 MHz, MeOD) δ7.50 (s, 1H), 7.23-7.33 (m, 1H), 7.01-7.21 (m, 2H), 6.96 (td, J= 8.4, 2.4 Hz, 1H), 5.30 (s, 1H), 2.61-3.11 (m, 4H), 2.46-2.61 (m, 4H), 0.63-0.97 (m, 4H)。 87-P2 滯留時間1.079分鐘，ee值95.18%。 MS-ESI [M+H] ⁺，計算值458，實測值458。 ¹H NMR: (400 MHz, MeOD) δ7.50 (s, 1H), 7.22-7.33 (m, 1H), 7.01-7.21 (m, 2H), 6.96 (td, J= 8.4, 2.4 Hz, 1H), 5.23-5.39 (m, 1H), 2.62-3.08 (m, 4H), 2.45-2.61 (m, 4H), 0.63-0.98 (m, 4H)。分離條件：色譜柱型號：Chiralpak IB N-3；色譜柱規格：50×4.6mm I.D.，um；進樣量：10 μL；流動相：A：二氧化碳，B：乙醇(0.05% 二乙胺)，B%：20%-40%梯度洗提1.5分鐘，40%固定濃度洗提1分鐘，20%固定濃度洗提0.5分鐘；檢測波長：254 nm；柱溫：35℃。 88-P1 滯留時間0.926分鐘，ee值97.16%。 MS-ESI [M+H] ⁺，計算值461，實測值461。 ¹H NMR: (400 MHz, MeOD) δ7.50 (s, 1H), 7.23-7.32 (m, 1H), 7.01-7.22 (m, 2H), 6.96 (td, J= 8.4, 2.4 Hz, 1H), 5.25-5.39 (m, 1H), 2.80-3.08 (m, 2H), 2.67-2.80 (m, 1H), 2.45-2.63 (m, 2H), 0.63-0.98 (m, 4H)。 88-P2 滯留時間1.082分鐘，ee值97.10%。 MS-ESI [M+H] ⁺，計算值461，實測值461。 ¹H NMR: (400 MHz, MeOD) δ7.50 (s, 1H), 7.23-7.31 (m, 1H), 7.01-7.22 (m, 2H), 6.96 (td, J= 8.4, 2.4 Hz, 1H), 5.25-5.40 (m, 1H), 2.82-3.08 (m, 2H), 2.67-2.81 (m, 1H), 2.43-2.64 (m, 2H), 0.63-0.97 (m, 4H)。分離條件：色譜柱型號：Chiralpak AD-3；色譜柱規格：50×4.6mm I.D.，3um；進樣量：10 μL；流動相：A：二氧化碳，B：異丙醇 (0.05% 二乙胺)，B%：40%固定濃度洗提；檢測波長：254 nm；柱溫：35℃。 89-P1 滯留時間0.624分鐘，ee值98.88%。 MS-ESI [M+H] ⁺，計算值500，實測值500。 ¹H NMR: (CDCl ₃, 400 MHz) δ(ppm) 9.23-9.38 (m, 1H), 7.48 (s, 1H), 7.33-7.41 (m, 1H), 7.11 (br t, J= 8.4 Hz, 1H), 7.05 (br d, J= 8.0 Hz, 1H), 6.95-7.01 (m, 1H), 5.58 (br s, 1H), 4.54-4.64 (m, 2H), 4.09 (br s, 2H), 3.47-3.84 (m, 6H), 2.55-2.66 (m, 4H), 1.85-2.18 (m, 2H)。 89-P2 滯留時間0.938分鐘，ee值98.22%。 MS-ESI [M+H] ⁺，計算值500，實測值500。 ¹H NMR: (CDCl ₃, 400 MHz) δ(ppm) 9.32 (br s, 1H), 7.48 (s, 1H), 7.33-7.41 (m, 1H), 7.08-7.14 (m, 1H), 7.05 (br d, J= 8.0 Hz, 1H), 6.94-7.01 (m, 1H), 5.58 (br s, 1H), 4.55-4.70 (m, 2H), 4.05-4.12 (m, 2H), 3.47-3.84 (m, 6H), 2.55-2.66 (m, 4H), 1.85-2.17 (m, 2H)。 The preparation of compounds 87-P1, 87-P2 to 89-P1, 89-P2 was carried out according to Example 86, using the corresponding amines instead of 2-azaspiro[3.3]heptane. Separation conditions: chromatographic column model: Chiralpak IB N-3; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 20%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 20% fixed concentration elution for 0.5 minutes; detection wavelength: 254 nm; column temperature: 35°C. 87-P1 Retention time 0.926 min, ee 93.68%. MS-ESI [M+H] ⁺ , calculated 458, found 458. ¹ H NMR: (400 MHz, MeOD) δ 7.50 (s, 1H), 7.23-7.33 (m, 1H), 7.01-7.21 (m, 2H), 6.96 (td, J = 8.4, 2.4 Hz, 1H), 5.30 (s, 1H), 2.61-3.11 (m, 4H), 2.46-2.61 (m, 4H), 0.63-0.97 (m, 4H). 87-P2 Retention time 1.079 min, ee 95.18%. MS-ESI [M+H] ⁺ , calculated 458, found 458. ¹ H NMR: (400 MHz, MeOD) δ 7.50 (s, 1H), 7.22-7.33 (m, 1H), 7.01-7.21 (m, 2H), 6.96 (td, J = 8.4, 2.4 Hz, 1H), 5.23-5.39 (m, 1H), 2.62-3.08 (m, 4H), 2.45-2.61 (m, 4H), 0.63-0.98 (m, 4H). Separation conditions: chromatographic column model: Chiralpak IB N-3; chromatographic column specifications: 50×4.6mm ID, um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 20%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 20% fixed concentration elution for 0.5 minutes; detection wavelength: 254 nm; column temperature: 35°C. 88-P1 Retention time 0.926 min, ee 97.16%. MS-ESI [M+H] ⁺ , calculated 461, found 461. ¹ H NMR: (400 MHz, MeOD) δ 7.50 (s, 1H), 7.23-7.32 (m, 1H), 7.01-7.22 (m, 2H), 6.96 (td, J = 8.4, 2.4 Hz, 1H), 5.25-5.39 (m, 1H), 2.80-3.08 (m, 2H), 2.67-2.80 (m, 1H), 2.45-2.63 (m, 2H), 0.63-0.98 (m, 4H). 88-P2 Retention time 1.082 min, ee 97.10%. MS-ESI [M+H] ⁺ , calculated 461, found 461. ¹ H NMR: (400 MHz, MeOD) δ 7.50 (s, 1H), 7.23-7.31 (m, 1H), 7.01-7.22 (m, 2H), 6.96 (td, J = 8.4, 2.4 Hz, 1H), 5.25-5.40 (m, 1H), 2.82-3.08 (m, 2H), 2.67-2.81 (m, 1H), 2.43-2.64 (m, 2H), 0.63-0.97 (m, 4H). Separation conditions: chromatographic column model: Chiralpak AD-3; chromatographic column specifications: 50×4.6mm ID, 3um; injection volume: 10 μL; mobile phase: A: carbon dioxide, B: isopropanol (0.05% diethylamine), B%: 40% fixed concentration elution; detection wavelength: 254 nm; column temperature: 35°C. 89-P1 Retention time 0.624 min, ee 98.88%. MS-ESI [M+H] ⁺ , calculated 500, found 500. ¹ H NMR: (CDCl ₃ , 400 MHz) δ (ppm) 9.23-9.38 (m, 1H), 7.48 (s, 1H), 7.33-7.41 (m, 1H), 7.11 (br t, J = 8.4 Hz, 1H), 7.05 (br d, J = 8.0 Hz, 1H), 6.95-7.01 (m, 1H), 5.58 (br s, 1H), 4.54-4.64 (m, 2H), 4.09 (br s, 2H), 3.47-3.84 (m, 6H), 2.55-2.66 (m, 4H), 1.85-2.18 (m, 2H). 89-P2 Retention time 0.938 min, ee 98.22%. MS-ESI [M+H] ⁺ , calculated 500, found 500. ¹ H NMR: (CDCl ₃ , 400 MHz) δ (ppm) 9.32 (br s, 1H), 7.48 (s, 1H), 7.33-7.41 (m, 1H), 7.08-7.14 (m, 1H), 7.05 (br d, J = 8.0 Hz, 1H), 6.94-7.01 (m, 1H), 5.58 (br s, 1H), 4.55-4.70 (m, 2H), 4.05-4.12 (m, 2H), 3.47-3.84 (m, 6H), 2.55-2.66 (m, 4H), 1.85-2.17 (m, 2H).

實施例90 化合物90的合成 Example 90 Synthesis of Compound 90

(1)向化合物90-1(1.00 g, 4.82 mmol)的甲苯(15 mL)溶液中，加入化合物90-2(538 mg, 6.27 mmol)、磷酸鉀(2.56 g, 12.1 mmol)、醋酸鈀(108 mg, 482 μmol)、三環己基膦(946 mg, 3.37 mmol, 1.09 mL)。反應液在氮氣保護下120℃攪拌12小時，反應液加入水(200 mL)，用乙酸乙酯(500 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/乙酸乙酯 = 1 ：0 到 0 ：1)分離得到化合物90-3。(1) Compound 90-2 (538 mg, 6.27 mmol), potassium phosphate (2.56 g, 12.1 mmol), sodium acetate (108 mg, 482 μmol), and tricyclohexylphosphine (946 mg, 3.37 mmol, 1.09 mL) were added to a toluene (15 mL) solution of compound 90-1 (1.00 g, 4.82 mmol). The reaction solution was stirred at 120°C for 12 hours under nitrogen protection. Water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 0:1) to obtain compound 90-3.

MS-ESI [M+H] ⁺，計算值169，實測值169。 MS-ESI [M+H] ⁺ , calcd. 169, found 169.

¹H NMR (400 MHz, CDCl ₃) δ7.67 (d, J= 2.8 Hz, 1H), 6.56 (d, J= 2.8 Hz, 1H), 2.05-2.14 (m, 1H), 0.99-1.07 (m, 2H), 0.60-0.68 (m, 2H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.67 (d, J = 2.8 Hz, 1H), 6.56 (d, J = 2.8 Hz, 1H), 2.05-2.14 (m, 1H), 0.99-1.07 (m, 2H), 0.60-0.68 (m, 2H).

(2)02下向化合物90-3(500 mg, 2.97 mmol)的乙腈(10.0 mL)溶液中，加入N-溴代丁二醯亞胺(528 mg, 2.97 mmol)。反應液在氮氣保護下25應攪拌1小時。反應液加入水(200 mL)，用二氯甲烷(500 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/乙酸乙酯 = 1 ：0 到 0 ：1) 分離得到化合物90-4。(2) N-bromosuccinimide (528 mg, 2.97 mmol) was added to a solution of compound 90-3 (500 mg, 2.97 mmol) in acetonitrile (10.0 mL) at 0.2 °C. The reaction solution was stirred for 1 hour at 25 °C under nitrogen protection. Water (200 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 0:1) to obtain compound 90-4.

MS-ESI [M+H] ⁺，計算值249，實測值249。 MS-ESI [M+H] ⁺ , calcd. 249, found 249.

¹H NMR (400 MHz, CDCl ₃) δ6.58 (s, 1H), 4.02 (br s, 2H), 2.05 (tt, J= 8.4, 5.3 Hz, 1H), 1.01-1.08 (m, 2H), 0.60-0.67 (m, 2H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.58 (s, 1H), 4.02 (br s, 2H), 2.05 (tt, J = 8.4, 5.3 Hz, 1H), 1.01-1.08 (m, 2H), 0.60-0.67 (m, 2H).

(3)向化合物90-4(550 mg, 2.22 mmol)的二氧六環(8.0 mL)溶液中，加入丙酮酸(587 mg, 6.67 mmol)、三乙胺(967 mg, 9.55 mmol, 1.33 mL)、醋酸鈀(99.8 mg, 444 μmol)、三苯基膦(117 mg, 444 μmol)。反應液在氮氣保護下100℃攪拌12小時。反應液加入氫氧化鈉水溶液(50.0 mL, 2 mol/L)，用甲基第三丁基醚(200 mL)洗滌，有機相用氫氧化鈉水溶液(30.0 mL, 2 mol/L)萃取，合併水相加入稀鹽酸酸化至棕色固體析出，過濾得到化合物90-5。(3) Pyruvic acid (587 mg, 6.67 mmol), triethylamine (967 mg, 9.55 mmol, 1.33 mL), sodium acetate (99.8 mg, 444 μmol), and triphenylphosphine (117 mg, 444 μmol) were added to a solution of compound 90-4 (550 mg, 2.22 mmol) in dioxane (8.0 mL). The reaction solution was stirred at 100°C for 12 hours under nitrogen protection. Sodium hydroxide aqueous solution (50.0 mL, 2 mol/L) was added to the reaction solution, and the mixture was washed with methyl tert-butyl ether (200 mL). The organic phase was extracted with sodium hydroxide aqueous solution (30.0 mL, 2 mol/L), and the aqueous phases were combined and acidified with dilute hydrochloric acid until a brown solid precipitated. Compound 90-5 was obtained by filtration.

MS-ESI [M+H] ⁺，計算值237，實測值237。 MS-ESI [M+H] ⁺ , calcd. 237, found 237.

¹H NMR (400 MHz, CDCl ₃) δ11.97 (br s, 1H), 7.45 (s, 1H), 7.01 (s, 1H), 2.15 (tt, J= 8.4, 5.2 Hz, 1H), 1.01-1.07 (m, 2H), 0.67-0.72 (m, 2H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.97 (br s, 1H), 7.45 (s, 1H), 7.01 (s, 1H), 2.15 (tt, J = 8.4, 5.2 Hz, 1H), 1.01-1.07 (m, 2H), 0.67-0.72 (m, 2H).

(4)04下向化合物90-5(470 mg, 1.99 mmol)的甲醇(5.0 mL)溶液中，加入硫酸(584 mg, 5.96 mmol, 318 μL)。反應液在氮氣保護下80應攪拌12小時。反應液加入碳酸氫鈉水溶液調節pH值到8，用乙酸乙酯(100 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/乙酸乙酯 = 1 ：0 到 6 ：1) 分離得到化合物90-6。(4) Sulfuric acid (584 mg, 5.96 mmol, 318 μL) was added to a solution of compound 90-5 (470 mg, 1.99 mmol) in methanol (5.0 mL) at 0.4 °C. The reaction solution was stirred at 80 °C for 12 hours under nitrogen protection. Sodium bicarbonate aqueous solution was added to the reaction solution to adjust the pH value to 8, and the solution was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 6:1) to obtain compound 90-6.

MS-ESI [M+H] ⁺，計算值251，實測值251。 MS-ESI [M+H] ⁺ , calcd. 251 , found 251 .

(5)05下向化合物90-6(200 mg, 798 μmol)的四氫呋喃(3.0 mL)溶液中，加入雙(三甲基矽烷基)胺基鉀(1.6 mL, 1 mol/L)。反應液在氮氣保護下5反攪拌0.5小時。加入2-(三甲基矽烷基)乙氧甲基氯(200 mg, 1.20 mmol, 212 μL)，繼續在氮氣保護下5氮攪拌1小時。反應液加入氯化銨水溶液(20.0 mL)，用乙酸乙酯(100 mL)萃取, 有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/乙酸乙酯 = 1 ：0 到 6 ：1) 分離得到化合物90-7。(5) To a solution of compound 90-6 (200 mg, 798 μmol) in tetrahydrofuran (3.0 mL) was added potassium bis(trimethylsilyl)amine (1.6 mL, 1 mol/L). The reaction solution was stirred for 0.5 h under nitrogen protection. 2-(Trimethylsilyl)ethoxymethyl chloride (200 mg, 1.20 mmol, 212 μL) was added and continued to be stirred for 1 h under nitrogen protection. An aqueous solution of ammonium chloride (20.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 6:1) to give compound 90-7.

MS-ESI [M+H] ⁺，計算值381，實測值381。 MS-ESI [M+H] ⁺ , calcd. 381 , found 381 .

(6)06下向化合物90-7(195 mg, 512 μmol)的二氯甲烷(4.0 mL)溶液中，加入二異丁基氫化鋁(1.28 mL, 1 mol/L)。反應液在氮氣保護下25℃攪拌0.5小時。反應液加入鹽酸水溶液(5.0 mL, 1 mol/L)，用二氯甲烷 (30 mL) 萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/乙酸乙酯 = 1 ：0 到 3 ：1) 分離得到化合物90-8。(6) Add diisobutylaluminum hydroxide (1.28 mL, 1 mol/L) to a solution of compound 90-7 (195 mg, 512 μmol) in dichloromethane (4.0 mL) at 0.6 °C. The reaction solution was stirred at 25 °C for 0.5 h under nitrogen protection. Add hydrochloric acid aqueous solution (5.0 mL, 1 mol/L) to the reaction solution, extract with dichloromethane (30 mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 3:1) to obtain compound 90-8.

(7)07下向化合物90-8(170 mg, 482 μmol)的二氯甲烷(2.0 mL)溶液中，加入二氯亞碸(115 mg, 963 μmol, 70.1 μL)。反應液在氮氣保護下25應攪拌0.5小時。反應液加入碳酸氫鈉水溶液(50.0 mL)，用二氯甲烷(100 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。得到化合物90-9。(7) To a solution of compound 90-8 (170 mg, 482 μmol) in dichloromethane (2.0 mL) was added dichlorosulfoxide (115 mg, 963 μmol, 70.1 μL) at 0.7 °C. The reaction solution was stirred for 0.5 h at 25 °C under nitrogen protection. Aqueous sodium bicarbonate solution (50.0 mL) was added to the reaction solution, which was extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 90-9.

MS-ESI [M+H] ⁺, 計算值371, 實測值371。 MS-ESI [M+H] ⁺ , calcd. 371, found 371.

(8)08下向化合物90-9(173 mg, 466 μmol)的 N,N-二甲基甲醯胺(3.0 mL)溶液中，加入碳酸銫(455 mg, 1.40 mmol)和中間體F(102 mg, 466 μmol)。反應液在氮氣保護下60反攪拌2小時。反應液加入水(10.0 mL)，用乙酸乙酯(100 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/乙酸乙酯 = 1 ：0 到 2 ：1)分離得到化合物90-10。 (8) To a solution of compound 90-9 (173 mg, 466 μmol) in N,N -dimethylformamide (3.0 mL) at 08, cesium carbonate (455 mg, 1.40 mmol) and intermediate F (102 mg, 466 μmol) were added. The reaction solution was stirred at 60°C for 2 hours under nitrogen protection. Water (10.0 mL) was added to the reaction solution, which was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 2:1) to obtain compound 90-10.

MS-ESI [M+H] ⁺，計算值554，實測值554。 MS-ESI [M+H] ⁺ , calcd. 554, found 554.

(9)向化合物90-10(80.0 mg, 144 μmol)的甲苯 (5.0 mL)溶液中，加入2,4-二甲氧基苄胺(48.3 mg, 289 μmol, 43.4 μL)，碳酸銫(94.1 mg, 289 μmol)，三(二亞苄基丙酮)二鈀(13.2 mg, 14.4 μmol)，1,1'-聯萘-2,2'-雙二苯膦(18.0 mg, 29.0 μmol)。反應液在氮氣保護下120℃攪拌16小時，反應液加入水(50.0 mL)，用乙酸乙酯(200 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/乙酸乙酯 = 1 ：0 到 3 ：1)分離得到化合物90-11。(9) To a toluene (5.0 mL) solution of compound 90-10 (80.0 mg, 144 μmol) were added 2,4-dimethoxybenzylamine (48.3 mg, 289 μmol, 43.4 μL), cesium carbonate (94.1 mg, 289 μmol), tri(dibenzylideneacetone)dipalladium (13.2 mg, 14.4 μmol), and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (18.0 mg, 29.0 μmol). The reaction solution was stirred at 120°C for 16 hours under nitrogen protection. Water (50.0 mL) was added to the reaction solution, and the solution was extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 3:1) to give compound 90-11.

MS-ESI [M+H] ⁺，計算值685，實測值685。 MS-ESI [M+H] ⁺ , calcd. 685, found 685.

(10)向化合物90-11(67.0 mg, 97.8 μmol)的四氫呋喃(1.5 mL)溶液中，加入一水合氫氧化鋰(2 mol/L, 0.50 mL)。反應液在氮氣保護下25應攪拌12小時。反應液在0℃下加入鹽酸水溶液調節pH值到7，用二氯甲烷(100 mL × 2)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。得到化合物90-12。(10) To a solution of compound 90-11 (67.0 mg, 97.8 μmol) in tetrahydrofuran (1.5 mL), lithium hydroxide monohydrate (2 mol/L, 0.50 mL) was added. The reaction solution was stirred at 25°C for 12 hours under nitrogen protection. Aqueous hydrochloric acid solution was added to the reaction solution at 0°C to adjust the pH value to 7, and the solution was extracted with dichloromethane (100 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 90-12.

MS-ESI [M+H] ⁺，計算值671，實測值671。 MS-ESI [M+H] ⁺ , calcd. 671 , found 671 .

(11)向化合物90-12(70.0 mg, 104 μmol)的 N,N-二甲基甲醯胺(2.0 mL) 溶液中加入二異丙基乙基胺(12.7 mg, 104 μmol)和 N,N,N' mg,-四甲基- O-(7-氮雜苯并三唑-1-基)六氟磷酸脲(59.5 mg, 157 μmol)，室溫下攪拌25分鐘，隨後加入甲基環丁基胺(47.3 mg, 293 μmol)，反應液在氮氣保護下25液攪拌3小時。反應液加入水(30.0 mL)，用乙酸乙酯(100 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析法(石油醚/四氫呋喃 = 1 ：0 到 30 ：1)分離得到化合物90-13。 (11) Diisopropylethylamine (12.7 mg, 104 μmol) and N,N, N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (59.5 mg, 157 μmol) were added to a solution of compound 90-12 (70.0 mg, 104 μmol ) in N,N- dimethylformamide (2.0 mL), and the mixture was stirred at room temperature for 25 minutes. Methylcyclobutylamine (47.3 mg, 293 μmol) was then added, and the reaction mixture was stirred for 3 hours under nitrogen protection. Water (30.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/tetrahydrofuran = 1:0 to 30:1) to obtain compound 90-13.

MS-ESI [M+H] ⁺，計算值738，實測值738。 MS-ESI [M+H] ⁺ , calcd. 738, found 738.

(11)01下將化合物90-13(80.0 mg, 108 μmol)的二氯甲烷(3.0 mL)溶液中，加入三氟乙酸(500 μL)。反應液在氮氣保護下25應攪拌1小時。反應液加入甲醇(1.0 mL)和氨水(1.0 mL)並在氮氣保護下25氮攪拌8小時。反應液加入水(50.0 mL)，用乙酸乙酯(50.0 mL)萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經製備高效液相色譜法(F-Prepulite XP tC, 200 mm × 40 mm 7 μm, A:水(甲酸)；B:乙腈, 0%-40%：25分鐘) 分離得到化合物90的甲酸鹽。(11) Trifluoroacetic acid (500 μL) was added to a solution of compound 90-13 (80.0 mg, 108 μmol) in dichloromethane (3.0 mL) at 0.1 °C. The reaction solution was stirred at 25 °C for 1 hour under nitrogen protection. Methanol (1.0 mL) and aqueous ammonia (1.0 mL) were added to the reaction solution and stirred at 25 °C for 8 hours under nitrogen protection. Water (50.0 mL) was added to the reaction solution, and the solution was extracted with ethyl acetate (50.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative HPLC (F-Prepulite XP tC, 200 mm × 40 mm 7 μm, A: water (formic acid); B: acetonitrile, 0%-40%: 25 min) to give the formate salt of compound 90.

¹H NMR (400 MHz, CDCl ₃) δ8.75 (s, 1H), 7.40-7.44 (m, 2H), 7.34-7.38 (m, 2H), 7.12-7.17 (m, 2H), 6.90-7.03 (m, 1H), 5.30-5.35 (m, 1H), 4.58 (br d, J= 15.6 Hz, 1H), 3.90-3.94 (m, 1H), 3.07 (s, 3H), 2.83-2.93 (m, 1H), 2.61-2.65 (m, 1H), 2.58-2.60 (m, 1H), 2.43 (ddd, J= 13.2, 8.8, 4.4 Hz, 1H), 2.22-2.27 (m, 1H), 2.11-2.18 (m, 1H), 1.96-2.08 (m, 1H), 1.59-1.70 (m, 2H), 1.48 (br s, 1H), 1.27-1.36 (m, 1H), 0.96-1.00 (m, 2H), 0.57-0.60 (m, 2H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.75 (s, 1H), 7.40-7.44 (m, 2H), 7.34-7.38 (m, 2H), 7.12-7.17 (m, 2H), 6.90-7.03 (m, 1H), 5.30-5.35 (m, 1H), 4.58 (br d, J = 15.6 Hz, 1H), 3.90-3.94 (m, 1H), 3.07 (s, 3H), 2.83-2.93 (m, 1H), 2.61-2.65 (m, 1H), 2.58-2.60 (m, 1H), 2.43 (ddd, J = 13.2, 8.8, 4.4 Hz, 1H), 2.22-2.27 (m, 1H), 2.11-2.18 (m, 1H), 1.96-2.08 (m, 1H), 1.59-1.70 (m, 2H), 1.48 (br s, 1H), 1.27-1.36 (m, 1H), 0.96-1.00 (m, 2H), 0.57-0.60 (m, 2H).

實施例91 合成化合物91Example 91 Synthesis of Compound 91

化合物91的製備參考實施例77，使用中間體M替換中間體K，並且不進行掌性拆分。 MS-ESI [M+H] ⁺，計算值435，實測值435。 ¹H NMR (400 MHz, MeOD) δ7.69 (d, J= 8.8 Hz, 1H), 7.22-7.35 (m, 5H), 6.48 (d, J= 8.8 Hz, 1H), 6.06 (s, 1H), 4.99 (d, J= 16.0 Hz, 1H), 4.16 (d, J= 16.0 Hz, 1H), 3.98 (quin, J= 8.4 Hz, 1H), 3.03-3.11 (m, 3H), 2.65-2.78 (m, 1H), 2.38-2.62 (m, 3H), 2.06-2.36 (m, 3H), 1.16-1.86 (m, 3H)。 Compound 91 was prepared according to Example 77, using intermediate M instead of intermediate K, and chiral resolution was not performed. MS-ESI [M+H] ⁺ , calcd. 435, found 435. ¹ H NMR (400 MHz, MeOD) δ 7.69 (d, J = 8.8 Hz, 1H), 7.22-7.35 (m, 5H), 6.48 (d, J = 8.8 Hz, 1H), 6.06 (s, 1H), 4.99 (d, J = 16.0 Hz, 1H), 4.16 (d, J = 16.0 Hz, 1H), 3.98 (quin, J = 8.4 Hz, 1H), 3.03-3.11 (m, 3H), 2.65-2.78 (m, 1H), 2.38-2.62 (m, 3H), 2.06-2.36 (m, 3H), 1.16-1.86 (m, 3H).

實施例92 合成化合物92Example 92 Synthesis of Compound 92

化合物92的製備參考實施例77，使用中間體N替換中間體K，並且不進行掌性拆分。 MS-ESI [M+H] ⁺，計算值435，實測值435。 ¹H NMR (400 MHz, MeOD) δ7.43 (d, J= 8.8 Hz, 1H), 7.23-7.34 (m, 5H), 6.46 (d, J= 8.8 Hz, 1H), 5.94 (s, 1H), 4.94 (d, J= 15.6 Hz, 1H), 4.01-4.14 (m, 1H), 3.85-4.00 (m, 1H), 3.06 (s, 3H), 2.64-2.74 (m, 1H), 2.35-2.61 (m, 3H), 2.05-2.34 (m, 3H), 1.15-1.83 (m, 3H)。 Compound 92 was prepared according to Example 77, using intermediate N in place of intermediate K, and chiral resolution was not performed. MS-ESI [M+H] ⁺ , calcd. 435, found 435. ¹ H NMR (400 MHz, MeOD) δ 7.43 (d, J = 8.8 Hz, 1H), 7.23-7.34 (m, 5H), 6.46 (d, J = 8.8 Hz, 1H), 5.94 (s, 1H), 4.94 (d, J = 15.6 Hz, 1H), 4.01-4.14 (m, 1H), 3.85-4.00 (m, 1H), 3.06 (s, 3H), 2.64-2.74 (m, 1H), 2.35-2.61 (m, 3H), 2.05-2.34 (m, 3H), 1.15-1.83 (m, 3H).

實施例95 化合物95的合成 Example 95 Synthesis of Compound 95

將化合物71(150 mg, 0.33 mmol)和4,4,5,5-四甲基-2-乙烯基-1,3,2-二噁硼烷(151.02 mg, 0.98 mmol)溶於水(0.3 mL)和二氧六環(3 mL)中。向反應液中加入碳酸銫(266.23 mg, 0.82 mmol)和甲烷磺酸(2-二環己基膦基-2',4',6'-三-異丙基-1,1'-聯苯基)(2'-胺基-1,1'-聯苯-2-基)鈀(II)(138.97 mg, 0.16 mmol)，然後在氮氣保護110 ℃下攪拌16小時。反應液倒入水中，用乙酸乙酯萃取，合併有機相，飽和食鹽水洗滌，無水硫酸鈉乾燥，過濾，濾液減壓除去溶劑。柱層析(二氯甲烷：甲醇=10:1) 純化得到化合物95。Compound 71 (150 mg, 0.33 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (151.02 mg, 0.98 mmol) were dissolved in water (0.3 mL) and dioxane (3 mL). Csium carbonate (266.23 mg, 0.82 mmol) and (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) methanesulfonate (138.97 mg, 0.16 mmol) were added to the reaction solution, and then stirred at 110 °C for 16 hours under nitrogen protection. The reaction solution was poured into water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was depressurized to remove the solvent. Compound 95 was purified by column chromatography (dichloromethane: methanol = 10:1) to obtain compound 95.

MS-ESI [M+H] ⁺，計算值451，實測值451。 MS-ESI [M+H] ⁺ , calcd. 451 , found 451 .

¹H NMR (400 MHz, CDCl ₃) δ9.66 - 9.43 (m, 1H), 7.59 - 7.48 (m, 1H), 7.40 - 7.31 (m, 1H), 7.16 - 7.08 (m, 1H), 7.05 - 6.87 (m, 2H), 6.75 - 6.64 (m, 1H), 5.68 - 5.59 (m, 1H), 5.48 - 5.14 (m, 4H), 4.80 - 4.67 (m, 1H), 4.12 - 4.00 (m, 1H), 2.67 (m, 5H), 1.05 - 0.82 (m, 4H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.66 - 9.43 (m, 1H), 7.59 - 7.48 (m, 1H), 7.40 - 7.31 (m, 1H), 7.16 - 7.08 (m, 1H), 7.05 - 6.87 (m, 2H), 6.75 - 6.64 (m, 1H), 5.68 - 5.59 (m, 1H), 5.48 - 5.14 (m, 4H), 4.80 - 4.67 (m, 1H), 4.12 - 4.00 (m, 1H), 2.67 (m, 5H), 1.05 - 0.82 (m, 4H).

實施例96 化合物96的合成 Example 96 Synthesis of Compound 96

將化合物95(25 mg, 0.06 mmol)溶於甲醇(2 mL)，向反應液加入鈀碳(20 mg, 0.19 mmol, 10%)。反應液在15psi氫氣氛圍下25 ℃攪拌3小時。監測反應完全後，反應液用濾頭過濾，濾液減壓除去溶劑得到粗品。粗品化合物通過高效液相色譜法(waters-xbridge-C18, 250 mm × 19 mm 10 μm, A:水(10 mM NH ₄HCO ₃/H ₂O)；B:乙腈, 80%-50%-80%：0-11.3-17.4 (min))製備得到化合物96。 Compound 95 (25 mg, 0.06 mmol) was dissolved in methanol (2 mL), and palladium carbon (20 mg, 0.19 mmol, 10%) was added to the reaction solution. The reaction solution was stirred at 25 °C for 3 hours under a 15 psi hydrogen atmosphere. After the reaction was monitored to be complete, the reaction solution was filtered with a filter, and the filtrate was depressurized to remove the solvent to obtain a crude product. The crude compound was prepared by high performance liquid chromatography (waters-xbridge-C18, 250 mm × 19 mm 10 μm, A: water (10 mM NH ₄ HCO ₃ /H ₂ O); B: acetonitrile, 80%-50%-80%: 0-11.3-17.4 (min)) to obtain compound 96.

MS-ESI [M+H] ⁺，計算值453，實測值453。 MS-ESI [M+H] ⁺ , calcd. 453, found 453.

¹H NMR (400 MHz, CDCl ₃) δ9.25 (s, 1H), 7.32 - 7.27 (m, 2H), 7.16 - 7.07 (m, 1H), 7.06 - 6.86 (m, 2H), 5.49 - 5.17 (m, 2H), 4.80 (d, J= 16 Hz, 1H), 4.60 (s, 2H), 4.05 (d, J= 16 Hz, 1H), 3.00 - 2.72 (m, 2H), 2.58 - 2.47 (m, 4H), 1.28 - 1.27 (m, 3H), 1.00 - 0.86 (m, 2H), 0.79 - 0.66 (m, 2H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.25 (s, 1H), 7.32 - 7.27 (m, 2H), 7.16 - 7.07 (m, 1H), 7.06 - 6.86 (m, 2H), 5.49 - 5.17 (m, 2H), 4.80 (d, J = 16 Hz, 1H), 4.60 (s, 2H), 4.05 (d, J = 16 Hz, 1H), 3.00 - 2.72 (m, 2H), 2.58 - 2.47 (m, 4H), 1.28 - 1.27 (m, 3H), 1.00 - 0.86 (m, 2H), 0.79 - 0.66 (m, 2H).

生物實驗例Biological Experiment Examples

I.HCT116 MTAP ^-/-和HCT 116 ^wt細胞增殖抑制活性 I. Proliferation inhibitory activity of HCT116 MTAP ^-/- and HCT 116 ^wt cells

實驗原理：HCT116 MTAP ^-/-細胞MTAP缺失，MTA位準升高；HCT 116 ^wt細胞MTAP未缺失，MTA位準正常。通過這兩株細胞確定化合物是否表現出MTA協同抑制活性。 Experimental principle: HCT116 MTAP ^-/- cells lack MTAP and have elevated MTA levels; HCT 116 ^wt cells do not lack MTAP and have normal MTA levels. These two cell lines are used to determine whether the compound exhibits MTA synergistic inhibitory activity.

實驗材料：HCT116 MTAP ^-/-和HCT 116 ^wt細胞購自Horizon；CellTiter-Glo試劑購自Promega (貨號為G7571)；RPMI-1640購自ATCC (貨號為30-2001)：胎牛血清 (FBS) 購自EXCELL (貨號為FND500)；青黴素-鏈黴素購自Gibco (貨號為15140-122)；0.25%胰蛋白酶-乙二胺四乙酸消化液 (Trypsin-EDTA) 購自Gibco (貨號為25200-072)；二甲亞碸 (DMSO) 購自Sigma (貨號為D2650)；96孔板購自Corning (貨號為3610)；培養箱購自NuAire (型號為NU-5700E)；倒置顯微鏡購自Nikon (型號為 TS-100)；自動細胞計數儀購自Life technologies (型號為Countess II)；酶素標示讀取儀購自PerkinElmer (型號為Envision)；數據處理軟體為GraphPad Prism 5.0。 Experimental materials: HCT116 MTAP ^-/- and HCT 116 ^wt cells were purchased from Horizon; CellTiter-Glo reagent was purchased from Promega (Cat. No. G7571); RPMI-1640 was purchased from ATCC (Cat. No. 30-2001); fetal bovine serum (FBS) was purchased from EXCELL (Cat. No. FND500); penicillin-streptomycin was purchased from Gibco (Cat. No. 15140-122); 0.25% trypsin-ethylenediaminetetraacetic acid digestion solution (Trypsin-EDTA) was purchased from Gibco (Cat. No. 25200-072); dimethyl sulfoxide (DMSO) was purchased from Sigma (Cat. No. D2650); 96-well plates were purchased from Corning (Cat. No. 3610); incubator purchased from NuAire (model NU-5700E); inverted microscope purchased from Nikon (model TS-100); automatic cell counter purchased from Life technologies (model Countess II); enzyme label reader purchased from PerkinElmer (model Envision); data processing software was GraphPad Prism 5.0.

試驗方法：將處於對數生長期的HCT116 MTAP ^-/-或者HCT116 ^wt細胞重新懸浮於生長培養基 (RPMI-1640+10%FBS) 並稀釋至目標密度 (5000/mL)。將上述細胞懸浮液按照每孔100 μL接種至 96 孔板中；在 37；在L懸浮液按照 ₂培養箱中培育過夜。培養基作為背景對照組。用80 μL無血清的培養基饑餓細胞4小時。將待測化合物溶解在DMSO 中，配製成濃度為10 mmol/L 的儲備液。首先用DMSO 將儲備液稀釋至2 mmol/L（200X），再3倍梯度稀釋，共10 個濃度。取各濃度的上述溶液3 μL，分別用297 μL 生長培養基稀釋(2X)。然後按80 μL/孔加入接種細胞的96 孔板中。將加入待測化合物的細胞置於37 ℃，5% CO ₂培養箱中培育120 小時。室溫下平衡96 孔板，每孔中加入 40 μL CellTiter-Glo 試劑，渦旋器上混合 2 分鐘，室溫培育 60 分鐘，EnVision酶素標示讀取儀讀取發光值，用GraphPad Prism 5.0 software 軟體計算化合物的IC ₅₀。其結果見表2。其中A代表IC ₅₀＜ 100 nM, B代表100 nM ＜ IC ₅₀＜ 1 μM, C代表1 μM ＜ IC ₅₀＜ 10 μM, D代表IC ₅₀＞ 10 μM。 Experimental method: HCT116 MTAP ^-/- or HCT116 ^wt cells in logarithmic growth phase were resuspended in growth medium (RPMI-1640 + 10% FBS) and diluted to the target density (5000/mL). 100 μL of the cell suspension was inoculated into a 96-well plate per well; the suspension was cultured overnight in a _2- well incubator at 37 °C. The medium was used as a background control group. Cells were starved for 4 hours with 80 μL of serum-free medium. The compound to be tested was dissolved in DMSO to prepare a stock solution with a concentration of 10 mmol/L. First, the stock solution was diluted to 2 mmol/L (200X) with DMSO, and then diluted 3 times in a gradient, with a total of 10 concentrations. Take 3 μL of the above solution of each concentration and dilute it with 297 μL growth medium (2X). Then add 80 μL/well to the 96-well plate inoculated with cells. The cells added with the test compound were placed in a 37 ℃, 5% CO ₂ incubator for 120 hours. The 96-well plate was equilibrated at room temperature, and 40 μL CellTiter-Glo reagent was added to each well. The mixture was mixed on a vortexer for 2 minutes, and incubated at room temperature for 60 minutes. The luminescence value was read by EnVision enzyme label reader, and the IC ₅₀ of the compound was calculated using GraphPad Prism 5.0 software. The results are shown in Table 2. Among them, A represents IC ₅₀ ＜ 100 nM, B represents 100 nM ＜ IC ₅₀ ＜ 1 μM, C represents 1 μM ＜ IC ₅₀ ＜ 10 μM, and D represents IC ₅₀ ＞ 10 μM.

表2 化合物 IC ₅₀(nM) HCT116 MTAP ^-/- HCT116 ^wt 1的甲酸鹽 B ND 2 C ND 3 A ND 4-P1 C ND 4-P2 A ND 5 C ND 6 D ND 7 A ND 8 A ND 9 B ND 10 B ND 11 B ND 12 D ND 13 C ND 14 B ND 15 B ND 16 D ND 17 C ND 18 B ND 19 A ND 20 B ND 21 C ND 22 B ND 23 C ND 24 B ND 25 C ND 26 B ND 1-P1 B ND 1-P2 D ND 3-P1 A ND 3-P2 D ND 7-P1 B ND 7-P2 D ND 8-P1 A ND 8-P2 D ND 31-P1 A ND 31-P2 D ND 32-P1 D ND 32-P2 B ND 33-P1 B ND 33-P2 D ND 34-P1 B ND 34-P2 C ND 35-P1 A ND 35-P2 D ND 40-P1 C ND 41-P1 B ND 42-P1 C ND 43-P2 B ND 44-P1 C ND 45-P1 A ND 46-P1 B ND 47-P1 B ND 48-P1 B ND 49-P1 B ND 50-P1 B ND 52-P1 B ND 53-P1 B ND 54-P1 B ND 55 B ND 56 B ND 57 C ND 58 B ND 59 C ND 63-P1 A ND 64 A ND 65 C ND 66-P1 A ND 67-P1 A C 68-P1 A ND 69-P1 B ND 70-P1 B ND 71-P1 A C 72-P1 B ND 73-P1 A ND 74-P1 B ND 77-P1 B ND 78-P1 A ND 79-P1 B ND 80-P1 B ND 81-P2 B ND 83-P1 A ND 84-P1 B ND 85-P1 B ND 86-P1 A ND 87-P1 A ND 88-P1 B ND 89-P1 B ND 90 B ND 95 A ND 96 A ND Table 2 Compound IC ₅₀ (nM) HCT116 MTAP ^-/- HCT116 ^wt 1% formate B ND 2 C ND 3 A ND 4-P1 C ND 4-P2 A ND 5 C ND 6 D ND 7 A ND 8 A ND 9 B ND 10 B ND 11 B ND 12 D ND 13 C ND 14 B ND 15 B ND 16 D ND 17 C ND 18 B ND 19 A ND 20 B ND twenty one C ND twenty two B ND twenty three C ND twenty four B ND 25 C ND 26 B ND 1-P1 B ND 1-P2 D ND 3-P1 A ND 3-P2 D ND 7-P1 B ND 7-P2 D ND 8-P1 A ND 8-P2 D ND 31-P1 A ND 31-P2 D ND 32-P1 D ND 32-P2 B ND 33-P1 B ND 33-P2 D ND 34-P1 B ND 34-P2 C ND 35-P1 A ND 35-P2 D ND 40-P1 C ND 41-P1 B ND 42-P1 C ND 43-P2 B ND 44-P1 C ND 45-P1 A ND 46-P1 B ND 47-P1 B ND 48-P1 B ND 49-P1 B ND 50-P1 B ND 52-P1 B ND 53-P1 B ND 54-P1 B ND 55 B ND 56 B ND 57 C ND 58 B ND 59 C ND 63-P1 A ND 64 A ND 65 C ND 66-P1 A ND 67-P1 A C 68-P1 A ND 69-P1 B ND 70-P1 B ND 71-P1 A C 72-P1 B ND 73-P1 A ND 74-P1 B ND 77-P1 B ND 78-P1 A ND 79-P1 B ND 80-P1 B ND 81-P2 B ND 83-P1 A ND 84-P1 B ND 85-P1 B ND 86-P1 A ND 87-P1 A ND 88-P1 B ND 89-P1 B ND 90 B ND 95 A ND 96 A ND

在本發明提及的所有文獻都在本申請中引用作為參考，就如同每一篇文獻被單獨引用作為參考那樣。此外應理解，在閱讀了本發明的上述講授內容之後，本領域技術人員可以對本發明作各種改動或修改，這些等價形式同樣落於本申請所附申請專利範圍所限定的範圍。All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teaching content of the present invention, a person skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the scope of the patent application attached to this application.

Claims

A compound of formula I, or a pharmaceutically acceptable salt, chiral isomer, non-chiral isomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated form or a combination thereof, wherein R ¹ and R ² are each independently hydrogen, halogen, cyano, hydroxyl, C1-C3 alkyl, C1-C3 halogenated alkyl, C2-C4 alkenyl, C2-C4 halogenated alkenyl, C2-C4 alkynyl, C2-C4 halogenated alkynyl, 3-6 membered cycloalkyl, 3-6 membered halogenated cycloalkyl, 3-6 membered heterocyclic group, C1-C3 alkoxy, -NH ₂ , -NH(C1-C3 alkyl), -N(C1-C3 alkyl) ₂ , C1-C6 alkyl-S-, -S(O) ₂ -C1-C6 alkyl, -S(O)-C1-C6 alkyl, -S(O) ₂ NH ₂ , S(O) ₂ NH(C1-C6 alkyl), -NHS(O) ₂ (C1-C6 alkyl), -C(O)H, -C(O)-C1-C6 alkyl, -C(O)-3-6 cycloalkyl, -C(O)-3-6 membered heterocyclic group, -C(O)O-C1-C6 alkyl, -CONR ^1a R ^1b (wherein R ^1a and R ^1b are H, D, C1-C3 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group), -SF ₅ , -P(O)(C1-C3 alkyl) ₂ ; wherein said alkyl, cycloalkyl and heterocyclic group may be optionally further substituted by one or more substituents selected from the following: hydrogen, deuterium, halogen, C1-C3 alkyl; Ring A is an optionally substituted 5-7 membered heterocyclic group, an optionally substituted benzene ring or an optionally substituted 5-7 membered heteroaromatic ring; the substitution refers to substitution by one or more ^RA ; each ^RA is independently selected from hydrogen, deuterium, C1-C4 alkyl, halogenated C1-C4 alkyl, C3-C6 cycloalkyl, 3-8 membered heterocyclic group, oxo, halogen, C1-C4 alkoxy, hydroxyl and amino; ^R3 is ; ^L1 is absent, C1-C3 alkylene or C1-C3 halogenated alkylene; n is the number of methylene groups, and n is selected from 0, 1, 2, 3, and 4; ^R4 is an optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, an optionally substituted C3-C12 carbocyclic group, an optionally substituted C3-C12 heterocyclic group, an optionally substituted 6-10 membered aromatic ring group, or an optionally substituted 5-10 membered heteroaromatic ring group; the substitution means substitution by one or more R; ^R5 is an optionally substituted C1-C6 alkyl, an optionally substituted C3-C12 carbocyclic group, an optionally substituted C3-C12 heterocyclic group, an optionally substituted 6-10 aromatic ring, an optionally substituted 5-10 membered heteroaromatic ^ring , ^-NRaRb , -OR ^a or -SR ^a ; each ^Ra and R ^b are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 carbocyclic group, optionally substituted C3-C6 heterocyclic group, optionally substituted 6-10 aromatic ring or optionally substituted 5-10 aromatic heterocyclic ring; the substitution means substitution by one or more R; each R ⁶ is independently hydrogen, halogen, hydroxyl, C1-C3 alkyl, C1-C3 halogenated alkyl, C3-C4 cycloalkyl, C3-C4 halogenated cycloalkyl, C1-C3 alkoxy, -NH ₂ , -NH(C1-C3 alkyl) or -N(C1-C3 alkyl) ₂ ; m is the number of R ⁶ , m is selected from 0, 1, 2, 3, 4; R ⁷ , R ^{R 8} is independently hydrogen, deuterium, C1-C3 alkyl, C1-C3 halogenated alkyl, 3-4-membered cycloalkyl or 3-4-membered halogenated cycloalkyl; or R ⁷ , R ⁸ and the carbon atom to which they are connected form a 3-5-membered carbocyclic ring; each R is independently selected from: H, deuterium, halogen, cyano, amine, hydroxyl, nitro, oxo ( ), thio (=S), -SF ₅ , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, -OC2-C6 alkenyl, O-cycloalkyl, O-heterocyclo, O-aryl, O-heteroaryl, -N(optionally substituted C ₁ -C ₆ alkyl) ₂ , NH(optionally substituted C ₁ -C ₆ alkyl), N(optionally substituted C ₁ -C ₆ alkyl)(optionally substituted C ₁ -C ₆ alkylphenyl), NH(optionally substituted C ₁ -C ₆ alkylphenyl), N(C1-C6 alkyl)(aryl), N(C1-C6 alkyl)(heteroaryl), NH(aryl), -NH(heteroaryl), -P(O)(C1-C3 alkyl) ₂ , optionally substituted C1-C6 alkyl-S-, -S(O) ₂ -optionally substituted C1-C6 alkyl, -S(O)-optionally substituted C1-C6 alkyl, -S(O) ₂ -optionally substituted phenyl, -S(O) ₂ NH ₂ , S(O) ₂ NH(optionally substituted C1-C6 alkyl), S(O) ₂ NH(optionally substituted phenyl), -NHS(O) ₂ (optionally substituted C1-C6 alkyl), -NHS(O) ₂ (optionally substituted phenyl), optionally substituted C3-C16 carbocyclic group, optionally substituted 4-16 membered heterocyclic group, optionally substituted C6-C16 aryl group or optionally substituted 5-16 membered heteroaryl group; or any two adjacent R and the atoms connected thereto form an optionally substituted 4-8 membered heterocyclic group or an optionally substituted C3-C8 membered carbocyclic group; wherein the substitution in R refers to substitution by one or more groups selected from the following group: H, deuterium, halogen, cyano, amine, hydroxyl, nitro, oxo ( ), thio (=S), -SF ₅ , -P(O)(C1-C3 alkyl) ₂ , R' substituted or unsubstituted C1-C6 alkyl, R' substituted or unsubstituted C1-C6 alkoxy, R' substituted or unsubstituted C1-C6 alkylsulfonyl, R' substituted or unsubstituted C3-C16 carbocyclic group, R' substituted or unsubstituted 4-16 membered heterocyclic group, R' substituted or unsubstituted C6-C16 aryl, R' substituted or unsubstituted 5-16 membered heteroaryl, NH(R' substituted or unsubstituted C1-C6 alkyl), N(R' substituted or unsubstituted C1-C6 alkyl) ₂ , CH ₂ -NH(R' substituted or unsubstituted C1-C6 alkyl) and CH ₂ -N(R' substituted or unsubstituted C1-C6 alkyl) ₂ , wherein R' is selected from one or more groups of the following groups: H, halogen, deuterium (D), halogen, OH, nitro, amine, oxo (=O), alkynyl, cyano, -CD ₃ , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl and 4-8 membered heterocyclic groups, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclic groups is optionally further substituted with one or more substituents selected from the following groups: H, deuterium, C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, oxo (=O), -NH ₂ , N(R'' substituted or unsubstituted C1-C6 alkyl) ₂ , NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkylphenyl), NH(C1-C6 alkylphenyl), N(C1-C6 alkyl)(aryl), NH(aryl), C3-C8 cycloalkyl, 4-8 membered heterocyclic group, C1-C4 halogenated alkyl-, -C1-C4 alkylOH, -C1-C4 alkylO-C1-C4 alkyl, OC1-C4 halogenated alkyl, cyano, nitro, -C(O)-OH, C(O)OC1-C6 alkyl, CON(C1-C6 alkyl) ₂ , CONH(C1-C6 alkyl), CONH ₂ , NHC(O)(C1-C6 alkyl), NH(C1-C6 alkyl)C(O)(C1-C6 alkyl), -SO ₂ (C1-C6 alkyl), -SO ₂ (phenyl), -SO ₂ (C1-C6 halogenated alkyl), -SO ₂ NH ₂ , SO ₂ NH(C1-C6 alkyl), SO ₂ NH(phenyl), -NHSO ₂ (C1-C6 alkyl), -NHSO ₂ (phenyl), NHSO ₂ (C1-C6 halogenated alkyl) or C1-C6 alkylNH ₂ , wherein R '' is one or more groups selected from the following group: H, halogen, cyano, amine, hydroxyl, oxo ( ), C1-C6 alkyl and C1-C6 alkoxy; Indicates the attachment position of the group.

The compound as claimed in claim 1, or a pharmaceutically acceptable salt, chiral isomer, non-chiral isomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated product or a combination thereof, wherein the A ring is selected from: an optionally substituted benzene ring, an optionally substituted pyridine, an optionally substituted thiophene, an optionally substituted pyrrole, an optionally substituted furan, an optionally substituted imidazole, an optionally substituted pyrazole and an optionally substituted thiazole; preferably, the A ring is an optionally substituted pyrrole; the substitution refers to substitution by one or more ^RA ; each R ^A is independently selected from hydrogen, deuterium, C1-C4 alkyl, halogenated C1-C4 alkyl, C3-C6 cycloalkyl, 3-8 membered heterocyclic group, oxo, halogen, C1-C4 alkoxy, hydroxyl and amine.

The compound as described in claim 1, or a pharmaceutically acceptable salt, chiral isomer, dichiral isomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated product or a combination thereof, wherein R ¹ is hydrogen, halogen, cyano, C1-C3 alkyl, C1-C3 halogenated alkyl, 3-4-membered cycloalkyl, -C(O)NH ₂ , -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl) ₂ ; R ² is hydrogen, halogen, cyano, C1-C3 alkyl.

The compound as claimed in claim 1, or a pharmaceutically acceptable salt, chiral isomer, non-chiral isomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated product or a combination thereof, wherein: ^L1 is absent or is a methyl group; n is selected from 1 and 2; ^R4 is an optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, an optionally substituted C3-C8 carbocyclic group, an optionally substituted C3-C8 heterocyclic group, an optionally substituted benzene ring or an optionally substituted 5-7 membered aromatic heterocyclic group; the substitution means substitution by one or more R; ^R5 is an optionally substituted C1-C6 alkyl, an optionally substituted C3-C8 carbocyclic group, an optionally substituted C3-C8 heterocyclic ^group or ^-NRaRb ; each ^Ra and ^Rb is independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 carbocyclic group, optionally substituted C3-C6 heterocyclic group, optionally substituted 6-10 aromatic ring or optionally substituted 5-10 membered aromatic heterocyclic ring; the substitution refers to substitution by one or more R; R is defined as described in claim 1.

The compound as claimed in claim 1, or a pharmaceutically acceptable salt, a chiral isomer, a non-chiral isomer, a tautomer, a cis-trans isomer, a solvate, a polymorph, a deuterated compound or a combination thereof, wherein the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

A pharmaceutical composition comprising: (1) a therapeutically effective amount of one or more of the compounds described in any one of claims 1 to 5, their pharmaceutically acceptable salts, chiral isomers, non-chiral isomers, tautomers, cis-trans isomers, solvates, polymorphs and deuterated compounds as active ingredients; and (2) an optional pharmaceutically acceptable carrier.

Use of a compound as described in any one of claims 1 to 5, its pharmaceutically acceptable salt, chiral isomer, non-chiral isomer, tautomer, cis-trans isomer, solvate, polymorph or deuterated form, or the pharmaceutical composition as described in claim 6 in the preparation of a medicament for preventing or treating MTAP ^-/- related cancers.

The use as described in claim 7, wherein the cancer is selected from: liver cancer, breast cancer, skin cancer, pancreatic cancer, head and neck cancer, intestinal cancer, lung cancer, gastric cancer, esophageal cancer, kidney cancer, bladder cancer, urethral cancer, prostate cancer, testicular cancer, uterine cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, bile duct cancer, multiple myeloma, spinal neurofibroma, astrocytoma, neuroglioma, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, sarcoma.