WO2023125473A1 - Indoline compounds and derivatives thereof, preparation method therefor, pharmaceutical composition and use thereof - Google Patents

Indoline compounds and derivatives thereof, preparation method therefor, pharmaceutical composition and use thereof Download PDF

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WO2023125473A1
WO2023125473A1 PCT/CN2022/142154 CN2022142154W WO2023125473A1 WO 2023125473 A1 WO2023125473 A1 WO 2023125473A1 CN 2022142154 W CN2022142154 W CN 2022142154W WO 2023125473 A1 WO2023125473 A1 WO 2023125473A1
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dihydro
ethyl
indol
acid
reduced pressure
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赖宜生
胡碧云
马雪薇
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中国药科大学
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Definitions

  • Bin1 gene can inhibit the expression of IDO1 (Muller AJ, et al. NatMed, 2005, 11:312-319), and some cytokines and immune checkpoint molecules, such as interferon- ⁇ , toll-like receptor (TLR) 3, TLR4 and interleukin-6 can up-regulate the expression of IDO1 (Bernhardt R, Chem Rev, 1996, 96(1):2841-2888).
  • IDO1 Interferon- ⁇ , toll-like receptor (TLR) 3
  • TLR4 and interleukin-6 can up-regulate the expression of IDO1 (Bernhardt R, Chem Rev, 1996, 96(1):2841-2888).
  • the F group is hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino or C 1 - C 6 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 alkylamino.
  • E group is hydrogen, halogen or C 1 -C 6 alkyl
  • the administration method of the pharmaceutical composition of the present invention is not particularly limited, and preparations in various dosage forms can be selected for administration according to the patient's age, gender and other conditions and symptoms.
  • the indoline compound and its derivatives can be used in combination with one or more other types of therapeutic agents and/or treatment methods for the treatment of related diseases mediated by IDO1.
  • the other types of therapeutic agents and/or treatment methods include, but are not limited to, one or more chemotherapeutic agents, targeted anti-tumor drugs, immune checkpoint inhibitors, immune checkpoint agonists, anti-tumor vaccines, antiviral agents, Antiviral vaccines, cytokine therapy, adoptive cellular immunotherapy or radiation therapy.

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Abstract

Provided are indoline compounds and derivatives thereof, a preparation method therefor, a pharmaceutical composition and the use thereof. The structures of the indoline compounds are shown as formula (I). The derivatives relate to stereoisomers, tautomers, metabolites, metabolic precursors, prodrugs, solvates, salts of the solvates, crystals, pharmaceutically acceptable salts or a mixture thereof of the indoline compounds. The indoline compounds and the derivatives thereof have a remarkable inhibitory effect on the activity of indoleamine 2,3-dioxygenase 1, and thereby can be used for preparing drugs for treating indoleamine 2,3-dioxygenase 1-mediated immunosuppressive related diseases, realizing an anti-tumor activity by means of activating a host immune response.

Description

吲哚啉化合物及其衍生物、制备方法、药物组合物和应用Indoline compound and its derivative, preparation method, pharmaceutical composition and application 技术领域technical field
本发明涉及一类吲哚啉化合物及其衍生物、制备方法、药物组合物和应用，尤其涉及一种可制备为吲哚胺2,3-双加氧酶1抑制剂药物的吲哚啉化合物及其衍生物、制备方法、药物组合物和应用。The present invention relates to a class of indoline compounds and their derivatives, preparation methods, pharmaceutical compositions and applications, in particular to an indoline compound that can be prepared as an indoleamine 2,3-dioxygenase 1 inhibitor drug And derivatives thereof, preparation method, pharmaceutical composition and application.
背景技术Background technique
吲哚胺2,3-双加氧酶1(IDO1)是人体内催化L-色氨酸氧化代谢的限速酶。IDO1可以催化L-色氨酸代谢生成具有免疫抑制作用的犬尿氨酸及其下游代谢产物，因此IDO1在维护机体免疫稳态和耐受方面发挥重要的作用。此外，如细胞毒性T淋巴细胞相关蛋白4(CTLA-4)、程序性死亡受体1(PD-1)及其配体PD-L1一样，IDO1在肿瘤免疫逃逸中起重要作用。研究表明IDO1在多种人类肿瘤中过度表达。Bin1基因可以抑制IDO1的表达(Muller AJ,et al.NatMed,2005,11:312-319)，而一些细胞因子及免疫检查点分子，如干扰素-γ，toll样受体(TLR)3、TLR4和白介素-6等可上调IDO1的表达(Bernhardt R,Chem Rev,1996,96(1):2841-2888)。Indoleamine 2,3-dioxygenase 1 (IDO1) is the rate-limiting enzyme that catalyzes the oxidative metabolism of L-tryptophan in humans. IDO1 can catalyze the metabolism of L-tryptophan to produce kynurenine and its downstream metabolites with immunosuppressive effect, so IDO1 plays an important role in maintaining the body's immune homeostasis and tolerance. Furthermore, like cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed death receptor 1 (PD-1) and its ligand PD-L1, IDO1 plays an important role in tumor immune evasion. Studies have shown that IDO1 is overexpressed in a variety of human tumors. Bin1 gene can inhibit the expression of IDO1 (Muller AJ, et al. NatMed, 2005, 11:312-319), and some cytokines and immune checkpoint molecules, such as interferon-γ, toll-like receptor (TLR) 3, TLR4 and interleukin-6 can up-regulate the expression of IDO1 (Bernhardt R, Chem Rev, 1996, 96(1):2841-2888).
为了营造一种免疫耐受的环境，肿瘤细胞往往可以通过劫持免疫调节因子来躲避机体的免疫攻击，例如上调IDO1的表达(Johnson TS,et al.Immunol Invest,2012,41(6-7):765-797)。事实上，在大多数预后不良的癌症中都发现IDO1过表达和活性增强(Prendergast GC,et al.Cancer Res,2017,77(24):6795-6811)。在肿瘤微环境中，IDO1过表达会导致局部L-色氨酸的消耗和犬尿氨酸及其代谢物的累积，从而导致效应T细胞(Teffs)耗竭，并且促进调节性T(Tregs)细胞的分化和增殖，进而帮助肿瘤细胞逃避免疫攻击(Tang K,et al.J HematolOncol,2021,14(1):68)。In order to create an environment of immune tolerance, tumor cells can often avoid the body's immune attack by hijacking immune regulatory factors, such as up-regulating the expression of IDO1 (Johnson TS, et al. Immunol Invest, 2012, 41 (6-7): 765-797). In fact, IDO1 overexpression and enhanced activity were found in most cancers with poor prognosis (Prendergast GC, et al. Cancer Res, 2017, 77(24):6795-6811). In the tumor microenvironment, IDO1 overexpression leads to local depletion of L-tryptophan and accumulation of kynurenine and its metabolites, leading to exhaustion of effector T cells (Teffs) and promotion of regulatory T (Tregs) cell Differentiation and proliferation, and then help tumor cells escape immune attack (Tang K, et al. J HematolOncol, 2021,14(1):68).
具体而言，IDO1可以通过三种方式影响肿瘤的进展。首先，IDO1促进肿瘤发生和致耐受性抗原呈递细胞(APCs)的形成，增强肿瘤相关抗原的外周血免疫耐受(Pol J,et al.Oncoimmunology,2015,4(4):e974411)。其次，在致耐受性APCs中过表达的IDO1蛋白可以抑制CD8 +T效应细胞(Teffs)和NK细胞的活性，但犬尿氨酸等色氨酸代谢产物具有细胞毒性，可以杀灭T细胞和NK细胞(Frumento G,et al.J Exp Med,2002,196(4):459-468；Munn DH,et al.J Clin Invest,2004,114(2):280-290)，而且这些代谢产物还可以通过激活芳香烃受体(AhR)来诱导初始CD4 +T细胞分化成Tregs(Mezrich JD,et al.J Immunol,2010,185(6):3190-3198；Mezrich JD,et al.J Immunol,2008,181(8):5396-5404)。IDO1还能促进骨髓衍生抑制细胞(MDSCs)的扩张和激活，诱导巨噬细胞向耐受性表型分化(Schmidt SV,et al.Front Immunol,2014,5:384；Carbotti G,et al.Oncotarget,2015,6(41):43267-43280)。因此，过表达的IDO1不仅可以抑制Teffs和NK细胞的增殖和活性，而且可以诱导Tregs和MDSCs增殖(Liu Y,et al.Nat Commun,2017,8:15207；Blache CA,et al.Cancer Res,2012,72(24):6447-6456.)。此外，MDSCs可通过炎症环境进一步抑制Teffs和NK细胞的功能，诱导肿瘤迁移(Wei L,et al.Front Immunol,2018,9:724)。 Specifically, IDO1 can affect tumor progression in three ways. First, IDO1 promotes tumorigenesis and the formation of tolerogenic antigen-presenting cells (APCs), enhancing peripheral blood immune tolerance to tumor-associated antigens (Pol J, et al. Oncoimmunology, 2015, 4(4):e974411). Second, overexpressed IDO1 protein in tolerogenic APCs can inhibit the activity of CD8 + T effector cells (Teffs) and NK cells, but tryptophan metabolites such as kynurenine are cytotoxic and can kill T cells and NK cells (Frumento G, et al.J Exp Med,2002,196(4):459-468; Munn DH,et al.J Clin Invest,2004,114(2):280-290), and these metabolic The product can also induce naive CD4 + T cells to differentiate into Tregs by activating the aryl hydrocarbon receptor (AhR) (Mezrich JD, et al.J Immunol, 2010,185(6):3190-3198; Mezrich JD, et al.J Immunol, 2008, 181(8):5396-5404). IDO1 can also promote the expansion and activation of myeloid-derived suppressor cells (MDSCs), and induce the differentiation of macrophages into a tolerant phenotype (Schmidt SV, et al. Front Immunol, 2014, 5:384; Carbotti G, et al. Oncotarget , 2015, 6(41):43267-43280). Therefore, overexpressed IDO1 can not only inhibit the proliferation and activity of Teffs and NK cells, but also induce the proliferation of Tregs and MDSCs (Liu Y, et al. Nat Commun, 2017, 8:15207; Blache CA, et al. Cancer Res, 2012,72(24):6447-6456.). In addition, MDSCs can further inhibit the function of Teffs and NK cells through the inflammatory environment and induce tumor migration (Wei L, et al. Front Immunol, 2018, 9:724).
众多研究表明，IDO1与很多生理病理过程有关，包括肿瘤免疫逃逸、病毒感染、寄生虫感染、移植耐受、神经退行性疾病、自身免疫性疾病、神经精神疾病、白内障和血压调节等(Platten M,et al.Science,2005,310(5749):850-855；Wang Y,et al.Nat Med,2010,16(3):279-285；Favre D,et al.SciTransl Med,2010,2(32):32-36)。研究还表明麻疹、流感、巨细胞病毒和单纯疱疹病毒感染易受L-色氨酸水平的影响(Schmidt SV,et al.Front Immunol,2014,5:384；Zhang YJ,et al.Cell Microbiol,2013,15(7):1079-1087)。Favre等研究发现，HIV感染后髓系抗原呈递树突状细胞诱导IDO1表达，进而L-色氨酸分解的代谢物3-羟基邻氨基苯甲酸会导致辅助性T细胞(T H)17丧失，促进微生物转移和持续炎症，同时T H17/Treg比例失调导致了患者的免疫抑制(Favre D,et al.SciTransl Med,2010,2(32):32-36)。此外，IDO1催化的色氨酸代谢产物如犬尿氨酸和喹啉酸等具有神经毒性，并且这些代谢产物与神经退行性疾病如记忆障碍症、阿尔茨海默病、认知障碍症、老年痴呆症、帕金森病、帕金森综合症和运动障碍性疾病的发生密切相关(Malpass K.Nat Rev Neurol,2011,7(8):417；Maddison DC,et al.Semin Cell Dev Biol,2015,40:134-141)。神经精神疾病如抑郁症、精神分裂症、焦虑症也与IDO1过度表达和犬尿氨酸等代谢产物水平升高有关(Myint AM.FEBS J,2012,279(8):1375-1385)。在类风湿关节炎患者滑膜关节组织的DCs高表达IDO1，患者血清中色氨酸浓度降低， 而犬尿氨酸浓度和犬尿氨酸/色氨酸比值均明显升高(Widner B,et al.Immunobiology,2000,201(5):621-630)。多项研究表明，在黑色素瘤、肺癌、乳腺癌、胃癌、结肠癌、膀胱癌、胰腺癌、淋巴癌、前列腺癌、肾癌、脑癌、头颈癌、卵巢癌、宫颈癌、子宫内膜癌、间皮癌、甲状腺瘤、肝癌、食管癌和白血病等人类肿瘤中存在IDO1过表达现象，并且发现肿瘤组织内IDO1的表达量与肿瘤的恶性程度以及患者的预后不良密切相关(Uyttenhove C,et al.Nat Med,2003,9(10):1269-1274；Théate I,et al.Cancer Immunol Res,2015,3(2):161-172；Curti A,et al.Blood,2007,109(7):2871-2877.)。 Many studies have shown that IDO1 is related to many physiological and pathological processes, including tumor immune escape, viral infection, parasitic infection, transplant tolerance, neurodegenerative diseases, autoimmune diseases, neuropsychiatric diseases, cataracts and blood pressure regulation, etc. (Platten M , et al.Science,2005,310(5749):850-855; Wang Y, et al.Nat Med,2010,16(3):279-285; Favre D,et al.SciTransl Med,2010,2( 32):32-36). Studies have also shown that measles, influenza, cytomegalovirus, and herpes simplex virus infections are susceptible to L-tryptophan levels (Schmidt SV, et al. Front Immunol, 2014, 5:384; Zhang YJ, et al. Cell Microbiol, 2013, 15(7):1079-1087). Favre et al. found that after HIV infection, myeloid antigen-presenting dendritic cells induce the expression of IDO1, and then the metabolite 3-hydroxyanthranilic acid decomposed by L-tryptophan can lead to the loss of helper T cells ( TH ) 17, Promote microbial transfer and persistent inflammation, and at the same time, the imbalance of TH 17/Treg ratio leads to immunosuppression in patients (Favre D, et al. SciTransl Med, 2010, 2(32):32-36). In addition, tryptophan metabolites catalyzed by IDO1, such as kynurenine and quinolinic acid, are neurotoxic, and these metabolites are associated with neurodegenerative diseases such as memory impairment, Alzheimer's disease, cognitive impairment, old age Dementia, Parkinson's disease, Parkinson's syndrome and dyskinesia are closely related (Malpass K.Nat Rev Neurol, 2011,7(8):417; Maddison DC, et al.Semin Cell Dev Biol, 2015, 40:134-141). Neuropsychiatric diseases such as depression, schizophrenia, and anxiety are also associated with overexpression of IDO1 and elevated levels of metabolites such as kynurenine (Myint AM. FEBS J, 2012, 279(8): 1375-1385). In synovial joint DCs of patients with rheumatoid arthritis, IDO1 was highly expressed, and the serum tryptophan concentration was decreased, while the kynurenine concentration and kynurenine/tryptophan ratio were significantly increased (Widner B, et al al. Immunobiology, 2000, 201(5):621-630). A number of studies have shown that in melanoma, lung cancer, breast cancer, stomach cancer, colon cancer, bladder cancer, pancreatic cancer, lymph cancer, prostate cancer, kidney cancer, brain cancer, head and neck cancer, ovarian cancer, cervical cancer, endometrial cancer Overexpression of IDO1 exists in human tumors such as mesothelial carcinoma, thyroid tumor, liver cancer, esophageal cancer and leukemia, and it is found that the expression of IDO1 in tumor tissue is closely related to the malignancy of the tumor and the poor prognosis of the patient (Uyttenhove C, et al. al.Nat Med,2003,9(10):1269-1274; Théate I, et al.Cancer Immunol Res,2015,3(2):161-172; Curti A, et al.Blood,2007,109(7 ):2871-2877.).
早期研发的第一代IDO1抑制剂主要是作用于含有血红素的IDO1蛋白(holo-IDO1)。至今为止，先后有4款holo-IDO1抑制剂进入临床开发。其中，Epacadostat与PD-1单抗Keytruda联用治疗黑色素瘤III期试验(ECHO-301)曾深受人们瞩目。然而，遗憾的是，ECHO-301试验最终未能达到临床终点。此外，其他3款holo-IDO1抑制剂的临床试验也显示阴性结果。The first-generation IDO1 inhibitors developed in the early stage mainly act on the IDO1 protein (holo-IDO1) containing heme. So far, four holo-IDO1 inhibitors have entered clinical development. Among them, the phase III trial (ECHO-301) of the combination of Epacadostat and PD-1 monoclonal antibody Keytruda in the treatment of melanoma has attracted much attention. Unfortunately, however, the ECHO-301 trial ultimately failed to meet its clinical endpoints. In addition, clinical trials of other 3 holo-IDO1 inhibitors also showed negative results.
发明内容Contents of the invention
发明目的：针对现有holo-IDO1抑制剂普遍存在的活性较低、成药性不足等问题，本发明旨在提供一类具有高效的apo-IDO1抑制活性以及优异的成药性的吲哚啉化合物及其衍生物、制备方法、药物组合物和应用。Purpose of the invention: In view of the low activity and insufficient druggability of existing holo-IDO1 inhibitors, the present invention aims to provide a class of indoline compounds with high apo-IDO1 inhibitory activity and excellent druggability and Its derivatives, preparation methods, pharmaceutical compositions and applications.
技术方案：作为本发明的涉及的第一方面，本发明的吲哚啉化合物及其衍生物具有式(I)的结构，其衍生物涉及其立体异构体、互变异构体、代谢产物、代谢前体、前药、溶剂化物、溶剂化物的盐、结晶、药学上可接受的盐或它们的混合物：Technical solution: As the first aspect of the present invention, the indoline compound and its derivatives of the present invention have the structure of formula (I), and its derivatives relate to its stereoisomers, tautomers, and metabolites , metabolic precursors, prodrugs, solvates, salts of solvates, crystals, pharmaceutically acceptable salts or mixtures thereof:
Figure PCTCN2022142154-appb-000001
Figure PCTCN2022142154-appb-000001
其中：in:
X为-C(O)NH-、-S(O) 2NH-或-CH 2C(O)NH-； X is -C(O)NH-, -S(O) 2 NH- or -CH 2 C(O)NH-;
R为氢、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷氨基或C 3-C 8环烷基； R is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino or C 3 -C 8 cycloalkyl;
Figure PCTCN2022142154-appb-000002
为C 3-C 8环烷基、芳基或杂芳基，所述杂芳基含有一个或多个O、S或N原子，所述芳基或杂芳基被一个或多个D基团取代；
Figure PCTCN2022142154-appb-000002
is C 3 -C 8 cycloalkyl, aryl or heteroaryl, the heteroaryl contains one or more O, S or N atoms, the aryl or heteroaryl is surrounded by one or more D groups replace;
所述D基团为氢、卤素、氰基、羟基、巯基、羧基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷氨基或者为被一个或多个卤素取代的C 1-C 6烷基、C 1-C 6烷氧基或C 1-C 6烷氨基； The D group is hydrogen, halogen, cyano, hydroxyl, mercapto, carboxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino or is replaced by one or more Halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 alkylamino;
Figure PCTCN2022142154-appb-000003
为芳基、杂芳基或C 3-C 8环烷基，所述C 3-C 8环烷基被一个或多个E基团取代，所述芳基或杂芳基被一个或多个F基团取代；
Figure PCTCN2022142154-appb-000003
is aryl, heteroaryl or C 3 -C 8 cycloalkyl, said C 3 -C 8 cycloalkyl is substituted by one or more E groups, said aryl or heteroaryl is substituted by one or more F group substitution;
所述E基团为氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷氨基或者为被一个或多个卤素取代的C 1-C 6烷基、C 1-C 6烷氧基或C 1-C 6烷氨基； The E group is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino or C 1 -C 6 alkane substituted by one or more halogens Group, C 1 -C 6 alkoxy or C 1 -C 6 alkylamino;
所述F基团为氢、卤素、氰基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷氨基或者为被一个或多个卤素取代的C 1-C 6烷基、C 1-C 6烷氧基或C 1-C 6烷氨基。 The F group is hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino or C 1 - C 6 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 alkylamino.
本发明设计的吲哚啉化合物为不含血红素的IDO1蛋白(apo-IDO1)的新一代抑制剂，可用于治疗IDO1介导的免疫抑制所引起的上述相关疾病。与holo-IDO1抑制剂相比，apo-IDO1抑制剂具有更高的选择性、更强的结合亲和力、更持久的结合时间和更有效的靶点覆盖率。The indoline compound designed in the present invention is a new generation inhibitor of the heme-free IDO1 protein (apo-IDO1), and can be used to treat the above-mentioned related diseases caused by IDO1-mediated immunosuppression. Compared with holo-IDO1 inhibitors, apo-IDO1 inhibitors have higher selectivity, stronger binding affinity, longer-lasting binding time and more effective target coverage.
优选，所述吲哚啉化合物及其衍生物结构中：Preferably, in the structure of the indoline compound and its derivatives:
X为-C(O)NH-；X is -C(O)NH-;
R为C 1-C 6烷基； R is C 1 -C 6 alkyl;
Figure PCTCN2022142154-appb-000004
为C 3-C 8环烷基、芳基或杂芳基，所述杂芳基含有一个或多个O、S或N原子，所述芳基或杂芳基被一个或多个D基团取代；
Figure PCTCN2022142154-appb-000004
is C 3 -C 8 cycloalkyl, aryl or heteroaryl, the heteroaryl contains one or more O, S or N atoms, the aryl or heteroaryl is surrounded by one or more D groups replace;
所述D基团为氢、卤素、氰基、羟基、巯基、羧基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷氨基或者为被一个或多个卤素取代的C 1-C 6烷基、C 1-C 6烷氧基或C 1-C 6烷氨基； The D group is hydrogen, halogen, cyano, hydroxyl, mercapto, carboxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino or is replaced by one or more Halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 alkylamino;
Figure PCTCN2022142154-appb-000005
为芳基、杂芳基或C 3-C 8环烷基，所述C 3-C 8环烷基被一个或多个E基团取代，所述芳基或杂芳基被一个或多个F基团取代；
Figure PCTCN2022142154-appb-000005
is aryl, heteroaryl or C 3 -C 8 cycloalkyl, said C 3 -C 8 cycloalkyl is substituted by one or more E groups, said aryl or heteroaryl is substituted by one or more F group substitution;
所述E基团为氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷氨基或者被一个或多个卤素取代的C 1-C 6烷基、C 1-C 6烷氧基或C 1-C 6烷氨基； The E group is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino or C 1 -C 6 alkyl substituted by one or more halogens , C 1 -C 6 alkoxy or C 1 -C 6 alkylamino;
所述F基团为氢、卤素、氰基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷氨基或者为被一个或多个卤素取代的C 1-C 6烷基、C 1-C 6烷氧基或C 1-C 6烷氨基。 The F group is hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino or C 1 - C 6 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 alkylamino.
进一步优选，所述吲哚啉化合物及其衍生物结构中：Further preferably, in the structure of the indoline compound and its derivatives:
R为甲基；R is methyl;
E基团为氢、卤素或C 1-C 6烷基； E group is hydrogen, halogen or C 1 -C 6 alkyl;
F基团为氢、卤素、氰基或C 1-C 6烷氧基。 The F group is hydrogen, halogen, cyano or C 1 -C 6 alkoxy.
更进一步优选，所述吲哚啉化合物及其衍生物结构中：More preferably, in the structure of the indoline compound and its derivatives:
Figure PCTCN2022142154-appb-000006
为苯基或吡啶基，所述苯基或吡啶基被一个或多个D基团取代；
Figure PCTCN2022142154-appb-000006
is phenyl or pyridyl, which is substituted by one or more D groups;
所述D基团为氟、氯、溴或氰基；The D group is fluorine, chlorine, bromine or cyano;
Figure PCTCN2022142154-appb-000007
为苯基、吡啶基或环己基，所述环己基被一个或多个E基团取代，所述苯基或吡啶基被一个或多个F基团取代；
Figure PCTCN2022142154-appb-000007
is phenyl, pyridyl or cyclohexyl, the cyclohexyl is substituted by one or more E groups, and the phenyl or pyridyl is substituted by one or more F groups;
所述E基团为氢、卤素或甲基；The E group is hydrogen, halogen or methyl;
所述F基团为氢、卤素、氰基或甲氧基。The F group is hydrogen, halogen, cyano or methoxy.
更具体地，所述吲哚啉化合物为以下任一化合物：More specifically, the indoline compound is any of the following compounds:
Figure PCTCN2022142154-appb-000008
Figure PCTCN2022142154-appb-000008
Figure PCTCN2022142154-appb-000009
Figure PCTCN2022142154-appb-000009
Figure PCTCN2022142154-appb-000010
Figure PCTCN2022142154-appb-000010
Figure PCTCN2022142154-appb-000011
Figure PCTCN2022142154-appb-000011
Figure PCTCN2022142154-appb-000012
Figure PCTCN2022142154-appb-000012
其中，所述药学上可接受的盐为所述吲哚啉化合物与酸形成的盐，所述酸为盐酸、氢溴酸、硫酸、磷酸、碳酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、苹果酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸。Wherein, the pharmaceutically acceptable salt is a salt formed by the indoline compound and an acid, and the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid naphthalenesulfonic acid, malic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid.
作为本发明涉及的第二方面，本发明的吲哚啉化合物及其衍生物的制备方法为以下任一方法：As the second aspect involved in the present invention, the preparation method of the indoline compound and its derivatives of the present invention is any of the following methods:
方法一：method one:
以2,3-二氢吲哚为原料经酰化反应、傅-克酰基化反应、水解反应、酰化反应、缩合反应、还原反应、水解反应、酰化反应得到化合物(I)：Using 2,3-dihydroindole as a raw material to obtain compound (I) through acylation reaction, Friedel-Crafts acylation reaction, hydrolysis reaction, acylation reaction, condensation reaction, reduction reaction, hydrolysis reaction and acylation reaction:
Figure PCTCN2022142154-appb-000013
Figure PCTCN2022142154-appb-000013
方法二：Method Two:
以化合物C为原料，经酰化反应、缩合反应、还原反应、水解反应、酰化反应、水解反应、酰化反应得到化合物(Ⅰ)：Using compound C as a raw material, compound (I) is obtained through acylation reaction, condensation reaction, reduction reaction, hydrolysis reaction, acylation reaction, hydrolysis reaction, and acylation reaction:
Figure PCTCN2022142154-appb-000014
Figure PCTCN2022142154-appb-000014
其中，
Figure PCTCN2022142154-appb-000015
X的定义如前所述； in,
Figure PCTCN2022142154-appb-000015
X is defined as before;
将相应的酸与以上方法制备的化合物(I)成盐，即得所述吲哚啉化合物的药学上可接受的盐。The corresponding acid is salted with the compound (I) prepared by the above method to obtain the pharmaceutically acceptable salt of the indoline compound.
更具体地，酰化反应是在碱的作用下进行，所述碱为三乙胺、二异丙基乙胺、吡啶、K2CO3或Cs2CO3；傅-克酰基化反应是在Lewis酸的作用下进行，所述Lewis酸为AlCl 3；缩合反应是在手性试剂及脱水剂的作用下进行，所述手性试剂为叔丁基亚磺酰胺，所述脱水剂为钛酸乙酯；还原反应是在金属还原剂的作用下进行，所述金属还原剂为二氯双(4-甲基异丙基苯基)钌(Ⅱ)；水解反应是在酸的作用下进行，所述酸为盐酸、氢溴酸等。 More specifically, the acylation reaction is carried out under the action of a base such as triethylamine, diisopropylethylamine, pyridine, K2CO3 or Cs2CO3; the Friedel-Crafts acylation reaction is carried out under the action of a Lewis acid , the Lewis acid is AlCl 3 ; the condensation reaction is carried out under the action of a chiral reagent and a dehydrating agent, the chiral reagent is tert-butylsulfinamide, and the dehydrating agent is ethyl titanate; the reduction reaction is Carry out under the effect of metal reducing agent, described metal reducing agent is dichloro bis (4-methyl isopropyl phenyl) ruthenium (II); Hydrolysis reaction is carried out under the effect of acid, and described acid is hydrochloric acid, hydrobromic acid etc.
作为本发明涉及的第三方面，本发明的药物组合物包含所述吲哚啉化合物和/或其衍生物以及药学上可 接受的载体。As the third aspect of the present invention, the pharmaceutical composition of the present invention comprises the indoline compound and/or its derivatives and a pharmaceutically acceptable carrier.
根据治疗目的可将药物组合物制成各种类型的给药单位剂型，如片剂、丸剂、粉剂、液体、悬浮液、乳液、颗粒剂、胶囊、栓剂和针剂(溶液和悬浮液)等，优选片剂、胶囊、液体、悬浮液和针剂(溶液和悬浮液)。为了使片剂、丸剂或栓剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋形剂。According to the purpose of treatment, the pharmaceutical composition can be made into various types of administration unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories and injections (solutions and suspensions), etc., Tablets, capsules, liquids, suspensions and injections (solutions and suspensions) are preferred. For shaping pharmaceutical compositions in the form of tablets, pills or suppositories, any excipient known and widely used in the art may be used.
为了制备针剂形式的药物组合物，可将溶液或悬浮液消毒后(最好加入适量的氯化钠，葡萄糖或甘油)，制成与血液等渗压的针剂。在制备针剂时，也可以使用本领域内任何常用的载体。例如：水、乙醇、丙二醇、乙氧基化的异硬脂醇、聚乙氧基化的异硬脂醇和聚乙烯脱水山梨醇的脂肪酸酯等。此外，还可以加入通常溶解剂和缓冲剂等。In order to prepare the pharmaceutical composition in the form of injection, the solution or suspension can be sterilized (preferably adding an appropriate amount of sodium chloride, glucose or glycerin) to make an injection with isotonic pressure with blood. When preparing injections, any commonly used carrier in the art can also be used. For example: water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyethoxylated isostearyl alcohol, fatty acid esters of polyethylene sorbitan, and the like. In addition, general dissolving agents, buffering agents and the like may be added.
本发明所述的吲哚啉化合物和/或其衍生物在药物组合物中的含量可在很宽的范围内进行选择，通常为5％～95％，优先为30％～85％。The content of the indoline compound and/or its derivatives in the pharmaceutical composition of the present invention can be selected within a wide range, usually 5%-95%, preferably 30%-85%.
本发明所述的药物组合物的给药方法没有特殊限制，可根据患者年龄、性别和其它条件及症状，选择各种剂型的制剂给药。The administration method of the pharmaceutical composition of the present invention is not particularly limited, and preparations in various dosage forms can be selected for administration according to the patient's age, gender and other conditions and symptoms.
作为本发明涉及的第四方面，本发明的吲哚啉化合物及其衍生物或者药物组合物应用于制备吲哚胺2,3-双加氧酶1抑制剂药物；所述药物用于治疗吲哚胺2,3-双加氧酶1介导的免疫抑制相关疾病，具体疾病为癌症、病毒感染、神经变性疾病、白内障、器官移植排斥、抑郁症或自身免疫性疾病。其中，所述癌症为恶性黑色瘤、肺癌、乳腺癌、胃癌、结肠癌、膀胱癌、胰腺癌、淋巴癌、白血病、前列腺癌、睾丸癌、肾癌、脑癌、头颈癌、卵巢癌、宫颈癌、子宫内膜癌、间皮癌、甲状腺瘤、肝癌、食管癌中的一种或多种；所述病毒感染为人类免疫缺陷病毒、乙型肝炎病毒、丙型肝炎病毒、流感病毒、脊髓灰质病毒、巨细胞病毒、柯萨奇病毒、人类乳头状瘤病毒、爱泼斯坦-巴尔病毒、水痘-带状疱疹病毒中的一种或多种引起的感染；所述神经变性疾病为记忆障碍症、阿尔茨海默病、认知障碍症、老年痴呆症、帕金森症、运动障碍性疾病中的一种或多种；所述自身免疫性疾病为类风湿性关节炎、系统性红斑狼疮、皮肌炎、硬皮病、结节性脉管炎、多发性硬化症、重症肌无力、混合性结缔组织病、银屑病、由于感染引起的自身免疫反应中的一种或多种。As the fourth aspect involved in the present invention, the indoline compound and its derivatives or pharmaceutical composition of the present invention are applied to the preparation of indoleamine 2,3-dioxygenase 1 inhibitor drugs; the drugs are used for the treatment of Indylamine 2,3-dioxygenase 1-mediated immunosuppression-related diseases, specifically cancer, viral infection, neurodegenerative disease, cataract, organ transplant rejection, depression or autoimmune disease. Wherein, the cancer is malignant melanoma, lung cancer, breast cancer, gastric cancer, colon cancer, bladder cancer, pancreatic cancer, lymphoma, leukemia, prostate cancer, testicular cancer, kidney cancer, brain cancer, head and neck cancer, ovarian cancer, cervical cancer Cancer, endometrial cancer, mesothelial cancer, thyroid tumor, liver cancer, esophageal cancer; the virus infection is human immunodeficiency virus, hepatitis B virus, hepatitis C virus, influenza virus, spinal cord Infection caused by one or more of poliovirus, cytomegalovirus, coxsackievirus, human papillomavirus, Epstein-Barr virus, varicella-zoster virus; said neurodegenerative disorder is memory impairment one or more of Alzheimer's disease, cognitive impairment, senile dementia, Parkinson's disease, movement disorders; the autoimmune diseases are rheumatoid arthritis, systemic lupus erythematosus One or more of , dermatomyositis, scleroderma, vasculitis nodosa, multiple sclerosis, myasthenia gravis, mixed connective tissue disease, psoriasis, autoimmune response due to infection.
进一步地，所述吲哚啉化合物及其衍生物可以与一种或多种其他种类的治疗剂和/或治疗方法联合用于治疗由IDO1介导的相关疾病。所述其他种类的治疗剂和/或治疗方法包括但不限于一种或多种化疗剂、靶向抗肿瘤药物、免疫检查点抑制剂、免疫检查点激动剂、抗肿瘤疫苗、抗病毒剂、抗病毒疫苗、细胞因子疗法、过继性细胞免疫治疗或放射治疗。其中，所述化疗剂不限于烷化剂、微管蛋白抑制剂、拓扑酶抑制剂、铂类药物、抗代谢类药物或激素类抗肿瘤药物；所述靶向抗肿瘤药物不限于蛋白激酶抑制剂、蛋白酶抑制剂、蛋白酶体抑制剂、异柠檬酸脱氢酶抑制剂、基于表观遗传学的抗肿瘤药物或细胞周期信号通路抑制剂；所述免疫检查点抑制剂不限于CTLA-4抑制剂、PD-1抑制剂、PD-L1抑制剂、PD-L2抑制剂、TIM-3抑制剂、VISTA抑制剂、LAG3抑制剂、TIGIT抑制剂、A2AR抑制剂或VTCN1抑制剂；所述免疫检查点激动剂不限于STING激动剂、4-1BB激动剂、OX40激动剂、RORγ激动剂或ICOS激动剂。Furthermore, the indoline compound and its derivatives can be used in combination with one or more other types of therapeutic agents and/or treatment methods for the treatment of related diseases mediated by IDO1. The other types of therapeutic agents and/or treatment methods include, but are not limited to, one or more chemotherapeutic agents, targeted anti-tumor drugs, immune checkpoint inhibitors, immune checkpoint agonists, anti-tumor vaccines, antiviral agents, Antiviral vaccines, cytokine therapy, adoptive cellular immunotherapy or radiation therapy. Wherein, the chemotherapeutic agents are not limited to alkylating agents, tubulin inhibitors, topoase inhibitors, platinum-based drugs, antimetabolite drugs or hormonal anti-tumor drugs; the targeted anti-tumor drugs are not limited to protein kinase inhibitors agents, protease inhibitors, proteasome inhibitors, isocitrate dehydrogenase inhibitors, epigenetics-based antineoplastic agents, or cell cycle signaling pathway inhibitors; the immune checkpoint inhibitors are not limited to CTLA-4 inhibition agent, PD-1 inhibitor, PD-L1 inhibitor, PD-L2 inhibitor, TIM-3 inhibitor, VISTA inhibitor, LAG3 inhibitor, TIGIT inhibitor, A2AR inhibitor or VTCN1 inhibitor; the immune test Point agonists are not limited to STING agonists, 4-1BB agonists, OX40 agonists, RORγ agonists or ICOS agonists.
有益效果：与现有技术相比，本发明具有如下显著优点：Beneficial effect: compared with the prior art, the present invention has the following significant advantages:
(1)该类吲哚啉化合物及其衍生物、药物组合物可有效抑制吲哚胺2,3-双加氧酶1活性(IC 50最优小于10pM，甚至达到1.7pM)，能够有效逆转IDO1介导的免疫抑制作用； (1) The indoline compounds and their derivatives and pharmaceutical compositions can effectively inhibit the activity of indoleamine 2,3-dioxygenase 1 (IC 50 optimally less than 10pM, even up to 1.7pM), and can effectively reverse IDO1-mediated immunosuppression;
(2)该类吲哚啉化合物及其衍生物、药物组合物应用广泛，可制备为治疗吲哚胺2,3-双加氧酶1介导的免疫抑制相关疾病药物；所述药物通过激活宿主免疫应答，在分子水平发挥药效，并且疗效优异，最优可达到皮摩尔浓度级别；(2) The indoline compounds and their derivatives and pharmaceutical compositions are widely used, and can be prepared as drugs for treating indoleamine 2,3-dioxygenase 1-mediated immunosuppression-related diseases; the drugs activate The host immune response exerts the drug effect at the molecular level, and the curative effect is excellent, and the optimal concentration can reach the picomolar concentration level;
(3)化合物制备方法简便，易操作。(3) The preparation method of the compound is simple and easy to operate.
具体实施方式Detailed ways
下面结合实施例对本发明的技术方案作进一步说明。The technical solutions of the present invention will be further described below in conjunction with the embodiments.
试剂与材料：实验所需要的所有试剂未经特别说明均为市售化学纯或分析纯产品。Reagents and materials: All reagents required for the experiment are commercially available chemically pure or analytically pure products unless otherwise specified.
仪器：1HNMR用BrukerAV-300和400MHz型核磁共振仪测定，化学位移值(δ)以ppm为单位，耦合常数(J)值以Hz为单位，TMS为内标。质谱(MS)分析仪器为岛津LCMS-2020型质谱仪测定；薄 层层析(TLC)使用青岛海洋化学有限公司生产HG/T2354-92型GF254薄层层析硅胶，ZF7型三用紫外分析仪254nm显色；柱色谱使用青岛海洋化工厂粗孔(ZCX-II)型300-400目柱层析硅胶；高效液相色谱(HPLC)分析仪器为Agilent1220InfinityⅡ，手性柱使用大赛路HPLC用多糖衍生物涂敷型手性色谱柱(正相)(AD-H)，流速设置为1mL/min，检测时长为20min。Instruments: 1HNMR was determined by BrukerAV-300 and 400MHz nuclear magnetic resonance apparatus, the chemical shift value (δ) was in ppm, the coupling constant (J) was in Hz, and TMS was the internal standard. The mass spectrometry (MS) analysis instrument was determined by Shimadzu LCMS-2020 mass spectrometer; the thin layer chromatography (TLC) used HG/T2354-92 type GF254 thin layer chromatography silica gel produced by Qingdao Ocean Chemical Co., Ltd., and ZF7 type three-purpose ultraviolet analysis Instrument 254nm color development; column chromatography uses Qingdao Ocean Chemical Factory Coarse Pore (ZCX-II) 300-400 mesh column chromatography silica gel; high performance liquid chromatography (HPLC) analysis instrument is Agilent1220InfinityⅡ, chiral column uses Dalu HPLC polysaccharide Derivative coated chiral chromatographic column (normal phase) (AD-H), the flow rate was set at 1mL/min, and the detection time was 20min.
实施例1：(R)-N-(1-(1-(环己烷羰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(1)合成Embodiment 1: (R)-N-(1-(1-(cyclohexanecarbonyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-fluorobenzamide ( 1) synthesis
Figure PCTCN2022142154-appb-000016
Figure PCTCN2022142154-appb-000016
N-乙酰基吲哚啉(1A)合成Synthesis of N-acetylindoline (1A)
将2,3-二氢-1H-吲哚(10.00g,83.91mmol)和三乙胺(25.47g,251.73mmol)溶于40mL无水二氯甲烷中，冰浴下缓慢滴加乙酰氯(9.88g,125.87mmol)的无水二氯甲烷(10mL)溶液，室温反应过夜，减压浓缩，加入100mL水，二氯甲烷(3×80mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体11.78g，收率87.1％。MS(ESI)m/z:160.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.05(d,J＝8.1Hz,1H),7.21(d,J＝7.2Hz,1H),7.14(t,J＝7.5Hz,1H),6.97(t,J＝7.5Hz,1H),4.05(t,J＝7.8Hz,2H),3.12(t,J＝8.4Hz,2H),2.14(s,3H). 2,3-Dihydro-1H-indole (10.00g, 83.91mmol) and triethylamine (25.47g, 251.73mmol) were dissolved in 40mL of anhydrous dichloromethane, and acetyl chloride (9.88 g, 125.87mmol) in anhydrous dichloromethane (10mL), react overnight at room temperature, concentrate under reduced pressure, add 100mL of water, extract with dichloromethane (3×80mL), combine the organic phases, wash with saturated brine, and anhydrous sulfuric acid Dry over magnesium, filter with suction, concentrate under reduced pressure, and separate and purify by column chromatography to obtain 11.78 g of white solid with a yield of 87.1%. MS (ESI) m/z: 160.1 [MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ (ppm) 8.05 (d, J = 8.1 Hz, 1H), 7.21 (d, J = 7.2 Hz, 1H), 7.14(t, J=7.5Hz, 1H), 6.97(t, J=7.5Hz, 1H), 4.05(t, J=7.8Hz, 2H), 3.12(t, J=8.4Hz, 2H) ,2.14(s,3H).
1,5-二乙酰基吲哚啉(1B)合成Synthesis of 1,5-Diacetylindoline (1B)
将1A(6.60g,40.94mmol)溶于25mL无水二氯甲烷中，0℃及氮气氛围下加入无水氯化铝(16.38g,122.83mmol)，缓慢滴加乙酰氯(4.82g,61.41mmol)的无水二氯甲烷溶液(10mL)，半小时后撤去冰浴，回流16h，在冰浴下用水(70mL)淬灭，二氯甲烷(3×60mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得黄色固体7.32g，收率88.0％。MS(ESI)m/z:202.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.09(d,J＝8.4Hz,1H),7.83-7.81(m,2H),4.15(t,J＝8.7Hz,2H),3.18(t,J＝8.7Hz,2H),2.52(s,3H),2.20(s,3H). Dissolve 1A (6.60g, 40.94mmol) in 25mL of anhydrous dichloromethane, add anhydrous aluminum chloride (16.38g, 122.83mmol) at 0°C under a nitrogen atmosphere, slowly add acetyl chloride (4.82g, 61.41mmol) ) in anhydrous dichloromethane solution (10mL), remove the ice bath after half an hour, reflux for 16h, quench with water (70mL) under ice bath, extract with dichloromethane (3×60mL), combine organic phases, and saturated saline After washing, drying over anhydrous magnesium sulfate, suction filtration, concentration under reduced pressure, separation and purification by column chromatography, 7.32 g of a yellow solid was obtained, with a yield of 88.0%. MS (ESI) m/z: 202.1 [MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ (ppm) 8.09 (d, J=8.4Hz, 1H), 7.83-7.81 (m, 2H), 4.15(t, J=8.7Hz, 2H), 3.18(t, J=8.7Hz, 2H), 2.52(s, 3H), 2.20(s, 3H).
1-乙酰基吲哚啉(1C)合成Synthesis of 1-acetylindoline (1C)
将1B(7.24g,35.62mmol)和浓盐酸(40mL,0.48mol)分别加入120mL封管中，80℃下反应3h，加水(20mL)，2M氢氧化钠溶液调节pH至8，乙酸乙酯(3×70mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得黄色固体4.62g，收率80.5％。MS(ESI)m/z:160.1[M-H] -； 1H NMR(300MHz,Chloroform-d)δ(ppm)7.74(s,2H),6.54(s,1H),4.19(s,1H),3.67(s,2H),3.08(s,2H),2.50(s,3H). Add 1B (7.24g, 35.62mmol) and concentrated hydrochloric acid (40mL, 0.48mol) into 120mL sealed tube respectively, react at 80°C for 3h, add water (20mL), adjust pH to 8 with 2M sodium hydroxide solution, ethyl acetate ( 3×70 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered with suction, concentrated under reduced pressure, separated and purified by column chromatography to obtain 4.62 g of a yellow solid with a yield of 80.5%. MS (ESI) m/z: 160.1 [MH] - ; 1 H NMR (300 MHz, Chloroform-d) δ (ppm) 7.74 (s, 2H), 6.54 (s, 1H), 4.19 (s, 1H), 3.67 (s,2H),3.08(s,2H),2.50(s,3H).
1-(1-(环己烷羰基)-2,3-二氢-1H-吲哚-5-基)乙酮(1D)合成Synthesis of 1-(1-(cyclohexanecarbonyl)-2,3-dihydro-1H-indol-5-yl)ethanone (1D)
将1C(1.50g,9.31mmol)和三乙胺(1.41g,13.96mmol)溶于无水二氯甲烷(10mL)中，冰浴下缓慢滴加环己甲酰氯(1.63g,11.17mmol)的无水二氯甲烷(2mL)溶液，室温反应过夜，减压浓缩，加入50mL水，二氯甲烷(3×40mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体2.28g，收率90.3％。MS(ESI)m/z:270.2[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.15(d,J＝7.2Hz,1H),7.82-7.80(m,2H),4.22(t,J＝8.7Hz,2H),3.18(t,J＝8.4Hz,2H),2.62-2.56(m,1H),2.51(s,3H),1.84-1.65(m,5H),1.46-1.18(m,5H). 1C (1.50g, 9.31mmol) and triethylamine (1.41g, 13.96mmol) were dissolved in anhydrous dichloromethane (10mL), and cyclohexanecarbonyl chloride (1.63g, 11.17mmol) was slowly added dropwise under ice-cooling Anhydrous dichloromethane (2 mL) solution, react at room temperature overnight, concentrate under reduced pressure, add 50 mL of water, extract with dichloromethane (3×40 mL), combine organic phases, wash with saturated brine, dry over anhydrous magnesium sulfate, and suction filter, Concentrate under reduced pressure, separate and purify by column chromatography to obtain 2.28 g of white solid with a yield of 90.3%. MS (ESI) m/z: 270.2[MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ (ppm) 8.15 (d, J = 7.2Hz, 1H), 7.82-7.80 (m, 2H), 4.22(t, J=8.7Hz, 2H), 3.18(t, J=8.4Hz, 2H), 2.62-2.56(m, 1H), 2.51(s, 3H), 1.84-1.65(m, 5H), 1.46 -1.18(m,5H).
(R)-2-甲基-N-(1-(1-(环己烷羰基)-2,3-二氢-1H-吲哚-5-基)亚乙基)丙烷-2-亚磺酰胺(1E)合成(R)-2-Methyl-N-(1-(1-(cyclohexanecarbonyl)-2,3-dihydro-1H-indol-5-yl)ethylidene)propane-2-sulfin Amide (1E) Synthesis
向1D(3.10g,11.42mmol)的无水四氢呋喃(15mL)溶液中加入(R)-(+)-叔丁基亚磺酰胺(2.08g,17.14 mmol)和钛酸乙酯(5.21g,22.85mmol)，85℃回流12h。向反应液中加入100mL水，80mL乙酸乙酯，剧烈搅拌15min，抽滤，乙酸乙酯(20mL)洗涤滤饼，滤液减压浓缩，乙酸乙酯(3×30mL)萃取，柱层析分离纯化，得黄色固体3.47g，收率81.1％。MS(ESI)m/z:373.2[M-H] -； 1H NMR(300MHz,Chloroform-d)δ(ppm)8.19(d,J＝7.8Hz,1H),7.73(s,1H),7.65(d,J＝8.4Hz,1H),4.12(t,J＝8.7Hz,2H),3.15(t,J＝8.1Hz,2H),2.65(s,3H),2.44-2.37(m,1H),1.79(d,J＝9.9Hz,5H),1.69-1.45(m,5H),1.24(s,9H). To a solution of 1D (3.10 g, 11.42 mmol) in anhydrous THF (15 mL) was added (R)-(+)-tert-butylsulfinamide (2.08 g, 17.14 mmol) and ethyl titanate (5.21 g, 22.85 mmol), reflux at 85°C for 12h. Add 100mL of water and 80mL of ethyl acetate to the reaction solution, stir vigorously for 15min, filter with suction, wash the filter cake with ethyl acetate (20mL), concentrate the filtrate under reduced pressure, extract with ethyl acetate (3×30mL), and separate and purify by column chromatography , to obtain 3.47 g of yellow solid, yield 81.1%. MS (ESI) m/z: 373.2[MH] - ; 1 H NMR (300MHz, Chloroform-d) δ (ppm) 8.19 (d, J = 7.8Hz, 1H), 7.73 (s, 1H), 7.65 (d ,J=8.4Hz,1H),4.12(t,J=8.7Hz,2H),3.15(t,J=8.1Hz,2H),2.65(s,3H),2.44-2.37(m,1H),1.79 (d,J=9.9Hz,5H),1.69-1.45(m,5H),1.24(s,9H).
(R)-2-甲基-N-(1-(1-(环己烷羰基)-2,3-二氢-1H-吲哚-5-基)乙基)丙烷-2-亚磺酰胺(1F)合成(R)-2-Methyl-N-(1-(1-(cyclohexanecarbonyl)-2,3-dihydro-1H-indol-5-yl)ethyl)propane-2-sulfinamide (1F) Synthesis
取
Figure PCTCN2022142154-appb-000017
分子筛(2.20g)于100mL圆底烧瓶中，加入8mL异丙醇，2-甲基-2-氨基-1-丙醇(26.18mg,0.29mmol)和二氯双(4-甲基异丙基苯基)钌(Ⅱ)(0.097g,0.16mmol)，回流5min，冷却至55℃，加入1E(2.20g,5.87mmol)及叔丁醇钾(0.08g,0.70mmol)，55℃反应12h，加入15mL二氯甲烷稀释，硅藻土抽滤，21mL二氯甲烷：甲醇混合溶液(20:1,V/V)洗涤滤饼，滤液减压浓缩，二氯甲烷(3×40mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，柱层析分离纯化，得油状液体1.96g，收率88.7％。MS(ESI)m/z:375.2[M-H] -； 1H NMR(300MHz,Chloroform-d)δ(ppm)8.23(d,J＝9.0Hz,1H),7.19-7.17(m,2H),4.55-4.48(m,1H),4.15(t,J＝8.4Hz,2H),3.37(d,J＝2.4Hz,1H),3.20(t,J＝8.4Hz,2H),2.47(m,1H),1.86(d,J＝9.6Hz,4H),1.67-1.51(m 3H),1.50(d,J＝6.6Hz,3H),1.35-1.28(m,3H),1.24(s,9H). Pick
Figure PCTCN2022142154-appb-000017
Molecular sieves (2.20g) were placed in a 100mL round bottom flask, and 8mL of isopropanol, 2-methyl-2-amino-1-propanol (26.18mg, 0.29mmol) and dichlorobis(4-methylisopropyl Phenyl) ruthenium (II) (0.097g, 0.16mmol), reflux for 5min, cool to 55°C, add 1E (2.20g, 5.87mmol) and potassium tert-butoxide (0.08g, 0.70mmol), react at 55°C for 12h, Add 15mL of dichloromethane to dilute, filter with diatomaceous earth, wash the filter cake with 21mL of dichloromethane:methanol mixed solution (20:1, V/V), concentrate the filtrate under reduced pressure, extract with dichloromethane (3×40mL), and combine The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, separated and purified by column chromatography to obtain 1.96 g of oily liquid with a yield of 88.7%. MS (ESI) m/z: 375.2[MH] - ; 1 H NMR (300MHz, Chloroform-d) δ (ppm) 8.23 (d, J = 9.0Hz, 1H), 7.19-7.17 (m, 2H), 4.55 -4.48(m,1H),4.15(t,J=8.4Hz,2H),3.37(d,J=2.4Hz,1H),3.20(t,J=8.4Hz,2H),2.47(m,1H) ,1.86(d,J=9.6Hz,4H),1.67-1.51(m 3H),1.50(d,J=6.6Hz,3H),1.35-1.28(m,3H),1.24(s,9H).
(R)-(5-(1-氨基乙基)-2,3-二氢-1H-吲哚-1-基)(环己烷)甲酮(1G)合成Synthesis of (R)-(5-(1-aminoethyl)-2,3-dihydro-1H-indol-1-yl)(cyclohexane)methanone (1G)
将原料1F(0.51g,1.35mmol)溶于无水甲醇(1.5mL)中，加入盐酸二氧六环溶液(1.7M,10mL)，室温反应3h，减压浓缩，饱和NaHCO 3溶液调节pH至9，乙酸乙酯(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，得黄色油状液体0.37g，收率100％。MS(ESI)m/z:271.2[M-H] -. Dissolve raw material 1F (0.51g, 1.35mmol) in anhydrous methanol (1.5mL), add dioxane hydrochloride solution (1.7M, 10mL), react at room temperature for 3h, concentrate under reduced pressure, adjust pH to 9. Extract with ethyl acetate (3×30 mL), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter with suction, and concentrate under reduced pressure to obtain 0.37 g of a yellow oily liquid with a yield of 100%. MS(ESI)m/z:271.2[MH] - .
(R)-N-(1-(1-(环己烷羰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(1)合成Synthesis of (R)-N-(1-(1-(cyclohexanecarbonyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-fluorobenzamide (1)
将1G(0.20g,0.77mmol)和三乙胺(0.23g,2.31mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氟苯甲酰氯(0.15g,0.92mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.26g(95.0％ee)，收率86.7％。MS(ESI)m/z:393.2[M-H] -； 1H NMR(300MHz,Chloroform-d)δ(ppm)8.16(d,J＝9.0Hz,1H),7.78-7.65(m,2H),7.14-7.12(m,2H),7.02(t,J＝8.7Hz,2H),6.19(d,J＝6.9Hz,1H),5.23-5.14(m,1H),4.06(t,J＝8.4Hz,2H),3.11(t,J＝8.4Hz,2H),2.42-2.33(m,1H),1.79-1.76(m,4H),1.66-1.64(m,1H),1.56-1.50(m,5H),1.26-1.19(m,3H). Dissolve 1G (0.20g, 0.77mmol) and triethylamine (0.23g, 2.31mmol) in 3mL of anhydrous dichloromethane, slowly add 4-fluorobenzoyl chloride (0.15g, 0.92mmol) dropwise at 0°C Anhydrous dichloromethane (2 mL) solution, reacted at room temperature for 3 h, concentrated under reduced pressure, added 30 mL of water, extracted with dichloromethane (3×20 mL), combined the organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and suction filtered. Concentrate under reduced pressure, separate and purify by column chromatography to obtain 0.26 g (95.0% ee) of white solid, yield 86.7%. MS (ESI) m/z: 393.2[MH] - ; 1 H NMR (300MHz, Chloroform-d) δ (ppm) 8.16 (d, J = 9.0Hz, 1H), 7.78-7.65 (m, 2H), 7.14 -7.12(m,2H),7.02(t,J=8.7Hz,2H),6.19(d,J=6.9Hz,1H),5.23-5.14(m,1H),4.06(t,J=8.4Hz, 2H), 3.11(t, J=8.4Hz, 2H), 2.42-2.33(m, 1H), 1.79-1.76(m, 4H), 1.66-1.64(m, 1H), 1.56-1.50(m, 5H) ,1.26-1.19(m,3H).
实施例2：(R)-N-(1-(1-(环己烷羰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(2)合成Embodiment 2: (R)-N-(1-(1-(cyclohexanecarbonyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-chlorobenzamide ( 2) synthesis
Figure PCTCN2022142154-appb-000018
Figure PCTCN2022142154-appb-000018
将1G(0.080g,0.29mmol)和三乙胺(0.088g,0.87mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氯苯甲酰氯(0.061g,0.35mmol)的无水二氯甲烷(1mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.10g(99.1％ee)，收率83.3％。MS(ESI)m/z:409.2[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.82(d,J＝8.1Hz,1H),8.01(d,J＝8.1Hz,1H),7.90(d,J＝8.4Hz,2H),7.54(d,J＝8.7Hz,2H),7.24(s,1H),7.14(d,J＝8.4Hz,1H),5.12-5.08(m,1H),4.14(t,J＝8.4Hz,2H),3.11(t,J＝8.4Hz,2H),1.79-1.64(m,5H),1.44(d,J＝6.9Hz,3H),1.36-1.15(m,5H). Dissolve 1G (0.080g, 0.29mmol) and triethylamine (0.088g, 0.87mmol) in 3mL of anhydrous dichloromethane, slowly add 4-chlorobenzoyl chloride (0.061g, 0.35mmol) dropwise at 0°C Anhydrous dichloromethane (1 mL) solution, reacted at room temperature for 3 h, concentrated under reduced pressure, added 30 mL of water, extracted with dichloromethane (3×20 mL), combined organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and suction filtered. Concentrate under reduced pressure, and separate and purify by column chromatography to obtain 0.10 g (99.1% ee) of white solid with a yield of 83.3%. MS (ESI) m/z: 409.2[MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ (ppm) 8.82 (d, J = 8.1 Hz, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.90(d, J=8.4Hz, 2H), 7.54(d, J=8.7Hz, 2H), 7.24(s, 1H), 7.14(d, J=8.4Hz, 1H), 5.12-5.08( m,1H),4.14(t,J=8.4Hz,2H),3.11(t,J=8.4Hz,2H),1.79-1.64(m,5H),1.44(d,J=6.9Hz,3H), 1.36-1.15(m,5H).
实施例3：(R)-N-(1-(1-(环己烷羰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氰基苯甲酰胺(3)合成Example 3: (R)-N-(1-(1-(cyclohexanecarbonyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-cyanobenzamide (3) synthesis
Figure PCTCN2022142154-appb-000019
Figure PCTCN2022142154-appb-000019
将1G(0.13g,0.48mmol)和三乙胺(0.14g,1.43mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氰基苯甲酰氯(0.080g,0.48mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.17g(99.5％ee)，收率89.5％。MS(ESI)m/z:400.2[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ(ppm)9.00(d,J＝7.8Hz,1H),8.04-7.95(m,5H),7.25(s,1H),7.15(d,J＝8.7Hz,1H),5.15-5.06(m,1H),4.14(t,J＝8.4Hz,2H),3.11(t,J＝8.1Hz,2H),1.79-1.64(m,5H),1.45(d,J＝7.2Hz,3H),1.40-1.20(m,5H). 1G (0.13g, 0.48mmol) and triethylamine (0.14g, 1.43mmol) were dissolved in 3mL of anhydrous dichloromethane, and 4-cyanobenzoyl chloride (0.080g, 0.48mmol) was slowly added dropwise at 0°C Anhydrous dichloromethane (2mL) solution, reacted at room temperature for 3h, concentrated under reduced pressure, added 30mL of water, extracted with dichloromethane (3×20mL), combined organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and suction filtered , concentrated under reduced pressure, and separated and purified by column chromatography to obtain 0.17 g (99.5% ee) of a white solid, with a yield of 89.5%. MS (ESI) m/z: 400.2[MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ (ppm) 9.00 (d, J = 7.8Hz, 1H), 8.04-7.95 (m, 5H), 7.25(s,1H),7.15(d,J=8.7Hz,1H),5.15-5.06(m,1H),4.14(t,J=8.4Hz,2H),3.11(t,J=8.1Hz,2H ),1.79-1.64(m,5H),1.45(d,J＝7.2Hz,3H),1.40-1.20(m,5H).
实施例4：(R)-N-(1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(4)合成Example 4: (R)-N-(1-(1-(4,4-difluorocyclohexane-1-carbonyl)-2,3-dihydro-1H-indol-5-yl)ethyl )-4-fluorobenzamide (4) synthesis
Figure PCTCN2022142154-appb-000020
Figure PCTCN2022142154-appb-000020
1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-5-基)乙酮(4D)合成Synthesis of 1-(1-(4,4-difluorocyclohexane-1-carbonyl)-2,3-dihydro-1H-indol-5-yl)ethanone (4D)
将1C(2.00g,12.41mmol)和三乙胺(1.88g,18.62mmol)溶于10mL无水二氯甲烷中，冰浴下缓慢滴加4,4-二氟环己甲酰氯(2.72g,14.90mmol)的无水二氯甲烷(4mL)溶液，室温反应3h，减压浓缩，加入100mL水，二氯甲烷(3×40mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体3.30g，收率86.6％。MS(ESI)m/z:306.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.15(d,J＝9.0Hz,1H),7.84-7.81(d,J＝6.1Hz,2H),4.26(t,J＝8.4Hz,2H),3.20(t,J＝8.4Hz,2H),2.83-2.76(m,1H),2.52(s,3H),2.12-2.03(m,2H),1.96-1.82(m,4H),1.72-1.60(m,2H). 1C (2.00g, 12.41mmol) and triethylamine (1.88g, 18.62mmol) were dissolved in 10mL of anhydrous dichloromethane, and 4,4-difluorocyclohexyl chloride (2.72g, 14.90 mmol) in anhydrous dichloromethane (4 mL), react at room temperature for 3 h, concentrate under reduced pressure, add 100 mL of water, extract with dichloromethane (3×40 mL), combine organic phases, wash with saturated brine, and dry over anhydrous magnesium sulfate , filtered with suction, concentrated under reduced pressure, and separated and purified by column chromatography to obtain 3.30 g of white solid with a yield of 86.6%. MS (ESI) m/z: 306.1[MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ (ppm) 8.15 (d, J = 9.0Hz, 1H), 7.84-7.81 (d, J = 6.1 Hz, 2H), 4.26(t, J=8.4Hz, 2H), 3.20(t, J=8.4Hz, 2H), 2.83-2.76(m, 1H), 2.52(s, 3H), 2.12-2.03(m ,2H),1.96-1.82(m,4H),1.72-1.60(m,2H).
(R)-2-甲基-N-(1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-5-基)亚乙基)丙烷-2-亚磺酰胺(4E)合成(R)-2-Methyl-N-(1-(1-(4,4-difluorocyclohexane-1-carbonyl)-2,3-dihydro-1H-indol-5-yl)ylidene Synthesis of Ethyl)propane-2-sulfinamide (4E)
向4D(3.10g,10.09mmol)的无水四氢呋喃(15mL)溶液中加入(R)-(+)-叔丁基亚磺酰胺(1.47g,12.11mmol)和钛酸乙酯(4.60g,20.18mmol)，85℃回流12h，向反应液中加入100mL水，80mL乙酸乙酯，剧烈搅拌15min，抽滤，乙酸乙酯(10mL)洗涤滤饼，滤液减压浓缩，乙酸乙酯(3×40mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，柱层析分离纯化，得黄色固体3.69g，收率89.1％。MS(ESI)m/z:409.2[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.13(d,J＝8.1Hz,1H),7.81-7.77(m,2H),4.25(t,J＝8.4Hz,2H),3.21(t,J＝8.4Hz,2H),2.82-2.76(m,1H),2.67(s,3H),2.11-2.04(m,2H),1.96-1.82(m,4H),1.72-1.60(m,2H),1.21(s,9H). To a solution of 4D (3.10 g, 10.09 mmol) in anhydrous tetrahydrofuran (15 mL) was added (R)-(+)-tert-butylsulfinamide (1.47 g, 12.11 mmol) and ethyl titanate (4.60 g, 20.18 mmol), reflux at 85°C for 12h, add 100mL water, 80mL ethyl acetate to the reaction solution, stir vigorously for 15min, filter with suction, wash the filter cake with ethyl acetate (10mL), concentrate the filtrate under reduced pressure, ethyl acetate (3×40mL ) extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, concentrated under reduced pressure, separated and purified by column chromatography to obtain 3.69 g of a yellow solid with a yield of 89.1%. MS (ESI) m/z: 409.2[MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ (ppm) 8.13 (d, J = 8.1Hz, 1H), 7.81-7.77 (m, 2H), 4.25(t, J=8.4Hz, 2H), 3.21(t, J=8.4Hz, 2H), 2.82-2.76(m, 1H), 2.67(s, 3H), 2.11-2.04(m, 2H), 1.96 -1.82(m,4H),1.72-1.60(m,2H),1.21(s,9H).
(R)-2-甲基-N-(1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-5-基)乙基)丙烷-2-亚磺酰胺(4F)合成(R)-2-Methyl-N-(1-(1-(4,4-difluorocyclohexane-1-carbonyl)-2,3-dihydro-1H-indol-5-yl)ethyl base) propane-2-sulfinamide (4F) synthesis
取
Figure PCTCN2022142154-appb-000021
分子筛(2.20g)于50mL圆底烧瓶中，加入10mL异丙醇，2-甲基-2-氨基-1-丙醇(23.76mg,0.27mmol)和二氯双(4-甲基异丙基苯基)钌(Ⅱ)(88.13mg,0.14mmol)，回流5min，冷却至55℃，加入4E(2.20g,5.36mmol)及叔丁醇钾(71.81mg,0.64mmol)，55℃反应12h，冷却，加入15mL二氯甲烷稀释，硅藻土抽滤，21mL二氯甲烷：甲醇混合溶液(20:1,V/V)洗涤滤饼，滤液减压浓缩，二氯甲烷(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，柱层析分离纯化，得油状液体1.95g，收率88.2％。MS(ESI)m/z:411.2[M-H] -； 1H NMR(300MHz,Chloroform-d)δ(ppm)8.21(d,J＝8.4Hz,1H),7.21-7.19(m,2H),4.55-4.49(m,1H),4.16(t,J＝8.4Hz,2H),3.37(d,J＝2.4Hz,1H),3.23(t,J＝8.4Hz,2H),2.59-2.54(m,1H),2.31-2.24(m,2H),2.06-1.96(m,4H),1.88-1.75(m,2H),1.50(d,J＝6.6Hz,3H),1.24(s,9H). Pick
Figure PCTCN2022142154-appb-000021
Molecular sieves (2.20g) In a 50mL round bottom flask, add 10mL of isopropanol, 2-methyl-2-amino-1-propanol (23.76mg, 0.27mmol) and dichlorobis(4-methylisopropyl Phenyl) ruthenium (Ⅱ) (88.13mg, 0.14mmol), reflux for 5min, cool to 55°C, add 4E (2.20g, 5.36mmol) and potassium tert-butoxide (71.81mg, 0.64mmol), react at 55°C for 12h, Cool, add 15mL dichloromethane to dilute, filter with diatomaceous earth, wash the filter cake with 21mL dichloromethane:methanol mixed solution (20:1, V/V), concentrate the filtrate under reduced pressure, extract with dichloromethane (3×30mL) , the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, concentrated under reduced pressure, separated and purified by column chromatography to obtain 1.95 g of an oily liquid with a yield of 88.2%. MS (ESI) m/z: 411.2[MH] - ; 1 H NMR (300MHz, Chloroform-d) δ (ppm) 8.21 (d, J = 8.4Hz, 1H), 7.21-7.19 (m, 2H), 4.55 -4.49(m,1H),4.16(t,J=8.4Hz,2H),3.37(d,J=2.4Hz,1H),3.23(t,J=8.4Hz,2H),2.59-2.54(m, 1H), 2.31-2.24(m, 2H), 2.06-1.96(m, 4H), 1.88-1.75(m, 2H), 1.50(d, J=6.6Hz, 3H), 1.24(s, 9H).
(R)-(5-(1-氨基乙基)-2,3-二氢-1H-吲哚-1-基)(4,4-二氟环己烷-1-基)甲酮(4G)合成(R)-(5-(1-aminoethyl)-2,3-dihydro-1H-indol-1-yl)(4,4-difluorocyclohexane-1-yl)methanone (4G )synthesis
将原料4F(0.65g,1.58mmol)溶于2mL无水甲醇中，加入盐酸二氧六环溶液(1.7M,16mL)，室温反应3h，减压浓缩，饱和NaHCO 3溶液调节pH至9，乙酸乙酯(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，得黄色油状液体0.49g，收率100％。MS(ESI)m/z:307.2[M-H] -. Dissolve raw material 4F (0.65g, 1.58mmol) in 2mL of anhydrous methanol, add dioxane hydrochloride solution (1.7M, 16mL), react at room temperature for 3h, concentrate under reduced pressure, adjust the pH to 9 with saturated NaHCO 3 solution, and acetic acid Ethyl ester (3×20 mL) was extracted, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and concentrated under reduced pressure to obtain 0.49 g of a yellow oily liquid with a yield of 100%. MS(ESI)m/z:307.2[MH] - .
(R)-N-(1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(4)合成(R)-N-(1-(1-(4,4-difluorocyclohexane-1-carbonyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4- Synthesis of fluorobenzamide (4)
将4G(0.15g,0.49mmol)和三乙胺(0.15g,1.44mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氟苯甲酰氯(0.092g,0.58mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.19g(96.2％ee)，收率90.5％。MS(ESI)m/z:429.2[M-H] -； 1H NMR(300MHz,Chloroform-d)δ(ppm)8.78(d,J＝8.1Hz,1H),8.08-7.88(m,3H),7.38-7.22(m,3H),7.16(d,J＝8.4Hz,1H),5.16-5.06(m,1H),4.18(t,J＝8.4Hz,2H),3.14(t,J＝8.4Hz,2H),2.79-2.71(m,1H),2.12-1.97(m,3H),1.92-1.81(m,3H),1.71-1.59(m,2H),1.45(d,J＝6.9Hz,3H). 4G (0.15g, 0.49mmol) and triethylamine (0.15g, 1.44mmol) were dissolved in 3mL of anhydrous dichloromethane, and 4-fluorobenzoyl chloride (0.092g, 0.58mmol) was slowly added dropwise at 0°C Anhydrous dichloromethane (2 mL) solution, reacted at room temperature for 3 h, concentrated under reduced pressure, added 30 mL of water, extracted with dichloromethane (3×20 mL), combined the organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and suction filtered. It was concentrated under reduced pressure, separated and purified by column chromatography to obtain 0.19 g (96.2% ee) of a white solid, and the yield was 90.5%. MS (ESI) m/z: 429.2[MH] - ; 1 H NMR (300MHz, Chloroform-d) δ (ppm) 8.78 (d, J = 8.1Hz, 1H), 8.08-7.88 (m, 3H), 7.38 -7.22(m,3H),7.16(d,J=8.4Hz,1H),5.16-5.06(m,1H),4.18(t,J=8.4Hz,2H),3.14(t,J=8.4Hz, 2H), 2.79-2.71(m, 1H), 2.12-1.97(m, 3H), 1.92-1.81(m, 3H), 1.71-1.59(m, 2H), 1.45(d, J＝6.9Hz, 3H) .
实施例5：(R)-N-(1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(5)合成Example 5: (R)-N-(1-(1-(4,4-difluorocyclohexane-1-carbonyl)-2,3-dihydro-1H-indol-5-yl)ethyl )-4-chlorobenzamide (5) synthesis
Figure PCTCN2022142154-appb-000022
Figure PCTCN2022142154-appb-000022
将4G(0.15g,0.49mmol)和三乙胺(0.15g,1.44mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氯苯甲酰氯(0.10g,0.58mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.18g(95.4％ee)，收率81.0％。MS(ESI)m/z:445.2[M-H] -； 1H NMR(300MHz,Chloroform-d)δ(ppm)8.13(d,J＝8.7Hz,1H),7.63(d,J＝8.7Hz,2H),7.32(d,J＝8.4Hz,2H),7.15-7.13(m,2H),6.23(d,J＝7.2Hz,1H),5.22-5.15(m,1H),4.07(t,J＝8.4Hz,2H),3.14(t,J＝8.4Hz,2H),2.50-2.44(m,1H),2.22-2.14(m,2H),1.94-1.86(m,4H),1.79-1.64(m,2H),1.51(d,J＝6.9Hz,3H). 4G (0.15g, 0.49mmol) and triethylamine (0.15g, 1.44mmol) were dissolved in 3mL of anhydrous dichloromethane, and 4-chlorobenzoyl chloride (0.10g, 0.58mmol) was slowly added dropwise at 0°C Anhydrous dichloromethane (2 mL) solution, reacted at room temperature for 3 h, concentrated under reduced pressure, added 30 mL of water, extracted with dichloromethane (3×20 mL), combined the organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and suction filtered. It was concentrated under reduced pressure, separated and purified by column chromatography to obtain 0.18 g (95.4% ee) of a white solid, and the yield was 81.0%. MS (ESI) m/z: 445.2[MH] - ; 1 H NMR (300MHz, Chloroform-d) δ (ppm) 8.13 (d, J = 8.7Hz, 1H), 7.63 (d, J = 8.7Hz, 2H ), 7.32(d, J=8.4Hz, 2H), 7.15-7.13(m, 2H), 6.23(d, J=7.2Hz, 1H), 5.22-5.15(m, 1H), 4.07(t, J= 8.4Hz, 2H), 3.14(t, J＝8.4Hz, 2H), 2.50-2.44(m, 1H), 2.22-2.14(m, 2H), 1.94-1.86(m, 4H), 1.79-1.64(m ,2H),1.51(d,J=6.9Hz,3H).
实施例6：(R)-N-(1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氰基苯甲酰胺(6)合成Example 6: (R)-N-(1-(1-(4,4-difluorocyclohexane-1-carbonyl)-2,3-dihydro-1H-indol-5-yl)ethyl )-4-cyanobenzamide (6) synthesis
Figure PCTCN2022142154-appb-000023
Figure PCTCN2022142154-appb-000023
将4G(0.15g,0.49mmol)和三乙胺(0.15g,1.44mmol)溶于5mL无水二氯甲烷中，0℃下缓慢滴加4-氰基苯甲酰氯(0.095g,0.58mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.18g(99.1％ee)，收率85.7％。MS(ESI)m/z:436.2[M-H] -； 1H NMR(300MHz,Chloroform-d)δ(ppm)8.22(d,J＝8.7Hz,1H),7.88(d,J＝8.7Hz,2H),7.72(d,J＝8.4Hz,2H),7.24-7.21(m,2H),6.51(d,J＝7.5Hz,1H),5.32-5.23(m,1H),4.16(t,J＝8.4Hz,2H),3.23(t,J＝8.4Hz,2H),2.61-2.52(m,1H),2.32-2.19(m,2H),2.01-1.94(m,4H),1.91-1.75(m,2H),1.61(d,J＝6.9Hz,3H). 4G (0.15g, 0.49mmol) and triethylamine (0.15g, 1.44mmol) were dissolved in 5mL of anhydrous dichloromethane, and 4-cyanobenzoyl chloride (0.095g, 0.58mmol) was slowly added dropwise at 0°C Anhydrous dichloromethane (2mL) solution, reacted at room temperature for 3h, concentrated under reduced pressure, added 30mL of water, extracted with dichloromethane (3×20mL), combined organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and suction filtered , concentrated under reduced pressure, and separated and purified by column chromatography to obtain 0.18 g (99.1% ee) of a white solid, with a yield of 85.7%. MS (ESI) m/z: 436.2[MH] - ; 1 H NMR (300MHz, Chloroform-d) δ (ppm) 8.22 (d, J = 8.7Hz, 1H), 7.88 (d, J = 8.7Hz, 2H ), 7.72(d, J=8.4Hz, 2H), 7.24-7.21(m, 2H), 6.51(d, J=7.5Hz, 1H), 5.32-5.23(m, 1H), 4.16(t, J= 8.4Hz, 2H), 3.23(t, J=8.4Hz, 2H), 2.61-2.52(m, 1H), 2.32-2.19(m, 2H), 2.01-1.94(m, 4H), 1.91-1.75(m ,2H),1.61(d,J=6.9Hz,3H).
实施例7：(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(7)合成Example 7: (R)-N-(1-(1-(3-chlorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-fluorobenzoyl Amide (7) Synthesis
Figure PCTCN2022142154-appb-000024
Figure PCTCN2022142154-appb-000024
1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙酮(7D)合成Synthesis of 1-(1-(3-chlorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethanone (7D)
将1C(2.00g,12.41mmol)和三乙胺(3.77g,37.23mmol)溶于15mL无水二氯甲烷中，冰浴下缓慢 滴加3-氯苯甲酰氯(2.61g,14.90mmol)的无水二氯甲烷(8mL)溶液，室温反应3h，减压浓缩，加入50mL水，二氯甲烷(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体3.58g，收率96.2％。MS(ESI)m/z:298.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ8.21-7.49(m,7H),4.21-4.00(m,2H),3.15(t,J＝8.4Hz,2H),2.54(s,3H). 1C (2.00g, 12.41mmol) and triethylamine (3.77g, 37.23mmol) were dissolved in 15mL of anhydrous dichloromethane, and 3-chlorobenzoyl chloride (2.61g, 14.90mmol) was slowly added dropwise under ice bath Anhydrous dichloromethane (8 mL) solution, reacted at room temperature for 3 h, concentrated under reduced pressure, added 50 mL of water, extracted with dichloromethane (3×30 mL), combined organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and suction filtered. Concentrate under reduced pressure, and separate and purify by column chromatography to obtain 3.58 g of white solid with a yield of 96.2%. MS (ESI) m/z: 298.1 [MH] - ; 1 H NMR (300 MHz, DMSO-d 6 ) δ8.21-7.49 (m, 7H), 4.21-4.00 (m, 2H), 3.15 (t, J =8.4Hz,2H),2.54(s,3H).
(R)-2-甲基-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)亚乙基)丙烷-2-亚磺酰胺(7E)合成(R)-2-Methyl-N-(1-(1-(3-chlorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethylidene)propane-2- Synthesis of sulfenamide (7E)
向7D(3.58g,11.94mmol)的无水四氢呋喃(15mL)溶液中加入(R)-(+)-叔丁基亚磺酰胺(1.88g,15.52mmol)和钛酸乙酯(5.45g,23.88mmol)，85℃回流12h。向反应液中加入100mL水，80mL乙酸乙酯，剧烈搅拌15min，抽滤，乙酸乙酯(10mL)洗涤滤饼，滤液减压浓缩，乙酸乙酯(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，柱层析分离纯化，得黄色固体3.78g，收率78.6％。MS(ESI)m/z:401.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ7.89-7.54(m,7H),4.07(t,J＝5.7Hz,2H),3.20-3.13(m,2H),2.70(s,3H),1.22(s,9H). To a solution of 7D (3.58 g, 11.94 mmol) in anhydrous tetrahydrofuran (15 mL) was added (R)-(+)-tert-butylsulfinamide (1.88 g, 15.52 mmol) and ethyl titanate (5.45 g, 23.88 mmol), reflux at 85°C for 12h. Add 100 mL of water and 80 mL of ethyl acetate to the reaction solution, stir vigorously for 15 min, filter with suction, wash the filter cake with ethyl acetate (10 mL), concentrate the filtrate under reduced pressure, extract with ethyl acetate (3×30 mL), combine the organic phases, and saturate Wash with brine, dry over anhydrous sodium sulfate, filter with suction, concentrate under reduced pressure, and separate and purify by column chromatography to obtain 3.78 g of a yellow solid with a yield of 78.6%. MS (ESI) m/z: 401.1 [MH] - ; 1 H NMR (300 MHz, DMSO-d 6 ) δ7.89-7.54 (m, 7H), 4.07 (t, J = 5.7Hz, 2H), 3.20- 3.13(m,2H),2.70(s,3H),1.22(s,9H).
(R)-2-甲基-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)丙烷-2-亚磺酰胺(7F)合成(R)-2-Methyl-N-(1-(1-(3-chlorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)propane-2-ylidene Synthesis of Sulfonamide (7F)
取
Figure PCTCN2022142154-appb-000025
分子筛(3.70g)于100mL圆底烧瓶中，加入8mL异丙醇，2-甲基-2-氨基-1-丙醇(40.92mg,0.46mmol)和二氯双(4-甲基异丙基苯基)钌(Ⅱ)(0.15g,0.25mmol)，回流5min，冷却至55℃，加入7E(3.70g,9.18mmol)及叔丁醇钾(0.13g,1.19mmol)，55℃下反应12h，加入15mL二氯甲烷稀释，硅藻土抽滤，21mL二氯甲烷：甲醇混合溶液(20:1,V/V)洗涤滤饼，滤液减压浓缩，二氯甲烷(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，柱层析分离纯化，得油状液体1.97g，收率53.0％。MS(ESI)m/z:403.1[M-H] -； 1H NMR(400MHz,DMSO-d 6)δ8.01(s,1H),7.76-7.50(m,4H),7.31(s,1H),5.57(d,J＝7.6Hz,1H),5.32(s,1H),4.42-4.30(m,1H),4.08-3.93(m,2H),3.08(t,J＝8.2Hz,2H),1.38(d,J＝6.8Hz,3H),1.11(s,9H). Pick
Figure PCTCN2022142154-appb-000025
Molecular sieves (3.70g) were placed in a 100mL round bottom flask, and 8mL of isopropanol, 2-methyl-2-amino-1-propanol (40.92mg, 0.46mmol) and dichlorobis(4-methylisopropyl Phenyl)ruthenium (Ⅱ) (0.15g, 0.25mmol), reflux for 5min, cool to 55°C, add 7E (3.70g, 9.18mmol) and potassium tert-butoxide (0.13g, 1.19mmol), react at 55°C for 12h , add 15mL of dichloromethane to dilute, filter with diatomaceous earth, wash the filter cake with 21mL of dichloromethane:methanol mixed solution (20:1, V/V), concentrate the filtrate under reduced pressure, extract with dichloromethane (3×30mL), The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, concentrated under reduced pressure, separated and purified by column chromatography to obtain 1.97 g of an oily liquid, with a yield of 53.0%. MS(ESI)m/z:403.1[MH] - ; 1 H NMR(400MHz,DMSO-d 6 )δ8.01(s,1H),7.76-7.50(m,4H),7.31(s,1H), 5.57(d, J=7.6Hz, 1H), 5.32(s, 1H), 4.42-4.30(m, 1H), 4.08-3.93(m, 2H), 3.08(t, J=8.2Hz, 2H), 1.38 (d,J=6.8Hz,3H),1.11(s,9H).
(R)-(5-(1-氨基乙基)-2,3-二氢-1H-吲哚-1-基)(3-氯苯基)甲酮(7G)合成Synthesis of (R)-(5-(1-aminoethyl)-2,3-dihydro-1H-indol-1-yl)(3-chlorophenyl)methanone (7G)
将原料7F(0.85g,2.10mmol)溶于2mL无水甲醇中，加入盐酸二氧六环溶液(14mL,1.7M)，室温反应3h，减压浓缩，饱和NaHCO 3溶液调节pH至9，乙酸乙酯(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，得黄色油状液体0.63g，收率100％。MS(ESI)m/z:299.1[M-H] -.(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(7)合成 Dissolve raw material 7F (0.85g, 2.10mmol) in 2mL of anhydrous methanol, add dioxane hydrochloride solution (14mL, 1.7M), react at room temperature for 3h, concentrate under reduced pressure, adjust the pH to 9 with saturated NaHCO 3 solution, acetic acid Ethyl ester (3×30 mL) was extracted, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and concentrated under reduced pressure to obtain 0.63 g of a yellow oily liquid with a yield of 100%. MS(ESI) m/z:299.1[MH] - .(R)-N-(1-(1-(3-chlorobenzoyl)-2,3-dihydro-1H-indol-5-yl ) ethyl) -4-fluorobenzamide (7) synthesis
将7G(0.11g,0.37mmol)和三乙胺(0.15g,1.48mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氟苯甲酰氯(0.070g,0.44mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.14g(95.0％ee)，收率87.5％。MS(ESI)m/z:421.1[M-H] -； 1H NMR(400MHz,Chloroform-d)δ7.86-7.74(m,2H),7.61-7.53(m,1H),7.50-7.38(m,2H),7.27(s,3H),7.20-7.09(m,3H),6.28(s,1H),5.36-5.22(m,1H),4.21-3.92(m,2H),3.16(d,J＝8.2Hz,2H),1.60(d,J＝7.2Hz,3H). 7G (0.11g, 0.37mmol) and triethylamine (0.15g, 1.48mmol) were dissolved in 3mL of anhydrous dichloromethane, and 4-fluorobenzoyl chloride (0.070g, 0.44mmol) was slowly added dropwise at 0°C Anhydrous dichloromethane (2 mL) solution, reacted at room temperature for 3 h, concentrated under reduced pressure, added 30 mL of water, extracted with dichloromethane (3×20 mL), combined the organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and suction filtered. Concentrate under reduced pressure, separate and purify by column chromatography to obtain 0.14 g (95.0% ee) of white solid, yield 87.5%. MS (ESI) m/z: 421.1 [MH] - ; 1 H NMR (400 MHz, Chloroform-d) δ7.86-7.74 (m, 2H), 7.61-7.53 (m, 1H), 7.50-7.38 (m, 2H),7.27(s,3H),7.20-7.09(m,3H),6.28(s,1H),5.36-5.22(m,1H),4.21-3.92(m,2H),3.16(d,J= 8.2Hz, 2H), 1.60(d, J=7.2Hz, 3H).
实施例8：(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(8)合成Example 8: (R)-N-(1-(1-(3-chlorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-chlorobenzoyl Amide (8) Synthesis
Figure PCTCN2022142154-appb-000026
Figure PCTCN2022142154-appb-000026
将7G(0.11g,0.37mmol)和三乙胺(0.15g,1.48mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氯苯甲酰氯(0.078g,0.44mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.15g(96.8％ee)，收率93.8％。MS(ESI)m/z:437.1[M-H] -； 1H NMR(400MHz,Chloroform-d)δ(ppm)7.72(d,J＝8.4Hz,2H),7.58-7.34(m,7H),7.26(s,2H),6.34(s,1H),5.34-5.19(m,1H),4.16-3.98(m,2H),3.14(t,J＝9.6Hz,2H),1.59(d,J＝5.2Hz,3H). 7G (0.11g, 0.37mmol) and triethylamine (0.15g, 1.48mmol) were dissolved in 3mL of anhydrous dichloromethane, and 4-chlorobenzoyl chloride (0.078g, 0.44mmol) was slowly added dropwise at 0°C Anhydrous dichloromethane (2 mL) solution, reacted at room temperature for 3 h, concentrated under reduced pressure, added 30 mL of water, extracted with dichloromethane (3×20 mL), combined the organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and suction filtered. Concentrate under reduced pressure, separate and purify by column chromatography to obtain 0.15 g (96.8% ee) of white solid, yield 93.8%. MS (ESI) m/z: 437.1 [MH] - ; 1 H NMR (400MHz, Chloroform-d) δ (ppm) 7.72 (d, J = 8.4 Hz, 2H), 7.58-7.34 (m, 7H), 7.26 (s,2H),6.34(s,1H),5.34-5.19(m,1H),4.16-3.98(m,2H),3.14(t,J=9.6Hz,2H),1.59(d,J=5.2 Hz,3H).
实施例9：(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-2-氯苯甲酰胺(9)合成Example 9: (R)-N-(1-(1-(3-chlorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-2-chlorobenzoyl Amide (9) Synthesis
Figure PCTCN2022142154-appb-000027
Figure PCTCN2022142154-appb-000027
将7G(0.10g,0.33mmol)和三乙胺(0.13g,1.32mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加2-氯苯甲酰氯(0.081g,0.46mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.12g(98.3％ee)，收率80.0％。MS(ESI)m/z:437.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ8.87(d,J＝7.5Hz,1H),7.86(s,1H),7.65(s,1H),7.56(d,J＝8.7Hz,3H),7.49-7.38(m,5H),7.32(s,1H),5.13-5.01(m,1H),4.08-3.95(m,2H),3.09(t,J＝8.1Hz,2H),1.41(d,J＝6.9Hz,3H). Dissolve 7G (0.10g, 0.33mmol) and triethylamine (0.13g, 1.32mmol) in 3mL of anhydrous dichloromethane, slowly add 2-chlorobenzoyl chloride (0.081g, 0.46mmol) dropwise at 0°C Anhydrous dichloromethane (2 mL) solution, reacted at room temperature for 3 h, concentrated under reduced pressure, added 30 mL of water, extracted with dichloromethane (3×20 mL), combined the organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and suction filtered. It was concentrated under reduced pressure, separated and purified by column chromatography to obtain 0.12 g (98.3% ee) of a white solid, and the yield was 80.0%. MS(ESI) m/z: 437.1[MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ8.87(d, J=7.5Hz, 1H), 7.86(s, 1H), 7.65(s, 1H), 7.56(d, J=8.7Hz, 3H), 7.49-7.38(m, 5H), 7.32(s, 1H), 5.13-5.01(m, 1H), 4.08-3.95(m, 2H), 3.09 (t,J=8.1Hz,2H),1.41(d,J=6.9Hz,3H).
实施例10：(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-3-氯苯甲酰胺(10)合成Example 10: (R)-N-(1-(1-(3-chlorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-3-chlorobenzoyl Amide (10) Synthesis
Figure PCTCN2022142154-appb-000028
Figure PCTCN2022142154-appb-000028
将7G(0.13g,0.43mmol)和三乙胺(0.17g,1.72mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加3-氯苯甲酰氯(0.098g,0.56mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.14g(99.6％ee)，收率73.7％。MS(ESI)m/z:437.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ8.88(d,J＝6.3Hz,1H),7.98-7.79(m,3H),7.67-7.48(m,6H),7.31(s,1H),7.20(s,1H),5.20-5.04(m,1H),4.08-3.90(m,2H),3.08(t,J＝8.1Hz,2H),1.47(d,J＝6.9Hz,3H). 7G (0.13g, 0.43mmol) and triethylamine (0.17g, 1.72mmol) were dissolved in 3mL of anhydrous dichloromethane, and 3-chlorobenzoyl chloride (0.098g, 0.56mmol) was slowly added dropwise at 0°C Anhydrous dichloromethane (2 mL) solution, reacted at room temperature for 3 h, concentrated under reduced pressure, added 30 mL of water, extracted with dichloromethane (3×20 mL), combined the organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and suction filtered. It was concentrated under reduced pressure, separated and purified by column chromatography to obtain 0.14 g (99.6% ee) of a white solid, and the yield was 73.7%. MS (ESI) m/z: 437.1[MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ8.88 (d, J=6.3Hz, 1H), 7.98-7.79 (m, 3H), 7.67- 7.48(m,6H),7.31(s,1H),7.20(s,1H),5.20-5.04(m,1H),4.08-3.90(m,2H),3.08(t,J＝8.1Hz,2H) ,1.47(d,J=6.9Hz,3H).
实施例11：(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氰基苯甲酰胺(11)合成Example 11: (R)-N-(1-(1-(3-chlorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-cyanobenzene Synthesis of formamide (11)
Figure PCTCN2022142154-appb-000029
Figure PCTCN2022142154-appb-000029
将7G(0.11g,0.37mmol)和三乙胺(0.15g,1.48mmol)溶于无水二氯甲烷(3mL)中，0℃下缓慢滴加4-氰基苯甲酰氯(0.061g,0.44mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.13g(95.0％ee)，收率81.3％。MS(ESI)m/z:428.1[M-H] -； 1H NMR(400MHz,Chloroform-d)δ7.88(d,J＝8.4Hz,2H),7.73(d,J＝6.4Hz,2H),7.55-7.38(m,4H),7.27(s,3H),6.50(s,1H),5.34-5.18(m,1H),4.19-3.93(m,2H),3.15(t,J＝8.4Hz,2H),1.62(d,J＝6.8Hz,3H). 7G (0.11g, 0.37mmol) and triethylamine (0.15g, 1.48mmol) were dissolved in anhydrous dichloromethane (3mL), and 4-cyanobenzoyl chloride (0.061g, 0.44 mmol) in anhydrous dichloromethane (2 mL), react at room temperature for 3 h, concentrate under reduced pressure, add 30 mL of water, extract with dichloromethane (3×20 mL), combine the organic phases, wash with saturated brine, and dry over anhydrous magnesium sulfate. Suction filtration, concentration under reduced pressure, separation and purification by column chromatography gave 0.13 g (95.0% ee) of white solid, yield 81.3%. MS (ESI) m/z: 428.1[MH] - ; 1 H NMR (400MHz, Chloroform-d) δ7.88 (d, J = 8.4Hz, 2H), 7.73 (d, J = 6.4Hz, 2H), 7.55-7.38(m,4H),7.27(s,3H),6.50(s,1H),5.34-5.18(m,1H),4.19-3.93(m,2H),3.15(t,J＝8.4Hz, 2H), 1.62(d, J=6.8Hz, 3H).
实施例12：(R)-N-(1-(1-(3-氟苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(12)合成Example 12: (R)-N-(1-(1-(3-fluorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-fluorobenzoyl Amide (12) Synthesis
Figure PCTCN2022142154-appb-000030
Figure PCTCN2022142154-appb-000030
1-(1-(3-氟苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙酮(12D)合成Synthesis of 1-(1-(3-fluorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethanone (12D)
将1C(1.20g,7.44mmol)和三乙胺(2.26g,22.32mmol)溶于20mL无水二氯甲烷中，冰浴下缓慢滴加3-氟苯甲酰氯(1.42g,8.93mmol)的无水二氯甲烷(8mL)溶液，室温反应3h，减压浓缩，加入50mL 水，二氯甲烷(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体2.00g，收率94.8％。MS(ESI)m/z:282.1[M-H] -； 1H NMR(400MHz,Chloroform-d)δ7.86(s,1H),7.81(s,1H),7.50-7.45(m,1H),7.36(d,J＝7.6Hz,1H),7.31-7.19(m,3H),4.14(t,J＝8.4Hz,2H),3.19(t,J＝9.0Hz,2H),2.59(s,3H). 1C (1.20g, 7.44mmol) and triethylamine (2.26g, 22.32mmol) were dissolved in 20mL of anhydrous dichloromethane, and 3-fluorobenzoyl chloride (1.42g, 8.93mmol) was slowly added dropwise under ice bath Anhydrous dichloromethane (8 mL) solution, reacted at room temperature for 3 h, concentrated under reduced pressure, added 50 mL of water, extracted with dichloromethane (3×30 mL), combined organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and suction filtered. Concentrate under reduced pressure, and separate and purify by column chromatography to obtain 2.00 g of white solid with a yield of 94.8%. MS (ESI) m/z: 282.1 [MH] - ; 1 H NMR (400 MHz, Chloroform-d) δ7.86 (s, 1H), 7.81 (s, 1H), 7.50-7.45 (m, 1H), 7.36 (d, J=7.6Hz, 1H), 7.31-7.19(m, 3H), 4.14(t, J=8.4Hz, 2H), 3.19(t, J=9.0Hz, 2H), 2.59(s, 3H) .
(R)-2-甲基-N-(1-(1-(3-氟苯甲酰基)-2,3-二氢-1H-吲哚-5-基)亚乙基)丙烷-2-亚磺酰胺(12E)合成(R)-2-Methyl-N-(1-(1-(3-fluorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethylidene)propane-2- Synthesis of sulfenamide (12E)
向12D(2.00g,7.06mmol)的无水四氢呋喃(15mL)溶液中加入(R)-(+)-叔丁基亚磺酰胺(1.03g,8.47mmol)和钛酸乙酯(3.22g,14.12mmol)，85℃回流12h。向反应液中加入100mL水，80mL乙酸乙酯，剧烈搅拌15min，抽滤，乙酸乙酯(10mL)洗涤滤饼，滤液减压浓缩，乙酸乙酯(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，柱层析分离纯化，得黄色固体2.44g，收率89.2％。MS(ESI)m/z:385.2[M-H] -； 1H NMR(400MHz,DMSO-d 6)δ7.84(m,3H),7.61-7.53(m,1H),7.52-7.44(m,2H),7.43-7.32(m,1H),4.06(t,J＝8.2Hz,2H),3.15(t,J＝8.4Hz,2H),2.69(s,3H),1.22(s,9H). To a solution of 12D (2.00 g, 7.06 mmol) in anhydrous tetrahydrofuran (15 mL) was added (R)-(+)-tert-butylsulfinamide (1.03 g, 8.47 mmol) and ethyl titanate (3.22 g, 14.12 mmol), reflux at 85°C for 12h. Add 100 mL of water and 80 mL of ethyl acetate to the reaction solution, stir vigorously for 15 min, filter with suction, wash the filter cake with ethyl acetate (10 mL), concentrate the filtrate under reduced pressure, extract with ethyl acetate (3×30 mL), combine the organic phases, and saturate Washed with brine, dried over anhydrous sodium sulfate, filtered with suction, concentrated under reduced pressure, separated and purified by column chromatography to obtain 2.44 g of a yellow solid with a yield of 89.2%. MS(ESI)m/z:385.2[MH] - ; 1 H NMR(400MHz,DMSO-d 6 )δ7.84(m,3H),7.61-7.53(m,1H),7.52-7.44(m,2H ),7.43-7.32(m,1H),4.06(t,J=8.2Hz,2H),3.15(t,J=8.4Hz,2H),2.69(s,3H),1.22(s,9H).
(R)-2-甲基-N-(1-(1-(3-氟苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)丙烷-2-亚磺酰胺(12F)合成(R)-2-Methyl-N-(1-(1-(3-fluorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)propane-2-ylidene Synthesis of Sulfonamide (12F)
取
Figure PCTCN2022142154-appb-000031
分子筛(1.80g)于100mL圆底烧瓶中，加入6mL异丙醇，2-甲基-2-氨基-1-丙醇(20.64mg,0.23mmol)和二氯双(4-甲基异丙基苯基)钌(Ⅱ)(76.55g,0.13mmol)，回流5min，冷却至55℃，加入12E(1.80g,4.66mmol)及叔丁醇钾(62.34g,0.56mmol)，55℃下反应12h，冷却，加入15mL二氯甲烷稀释，硅藻土抽滤，21mL二氯甲烷：甲醇混合溶液(20:1,V/V)洗涤滤饼，滤液减压浓缩，二氯甲烷(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，柱层析分离纯化，得油状液体1.09g，收率60.2％。MS(ESI)m/z:387.2[M-H] -； 1H NMR(400MHz,DMSO-d 6)δ8.01(s,1H),7.70-7.48(m,4H),7.31(s,1H),5.57(d,J＝7.6Hz,1H),5.32(s,1H),4.42-4.30(m,1H),4.12-3.94(m,2H),3.08(t,J＝8.2Hz,2H),1.38(d,J＝6.0Hz,3H),1.11(s,9H). Pick
Figure PCTCN2022142154-appb-000031
Molecular sieves (1.80g) were placed in a 100mL round bottom flask, and 6mL of isopropanol, 2-methyl-2-amino-1-propanol (20.64mg, 0.23mmol) and dichlorobis(4-methylisopropyl Phenyl) ruthenium (Ⅱ) (76.55g, 0.13mmol), reflux for 5min, cool to 55°C, add 12E (1.80g, 4.66mmol) and potassium tert-butoxide (62.34g, 0.56mmol), react at 55°C for 12h , cooled, added 15mL dichloromethane to dilute, diatomaceous earth suction filtration, 21mL dichloromethane: methanol mixed solution (20:1, V/V) washed the filter cake, the filtrate was concentrated under reduced pressure, dichloromethane (3 × 30mL) Extract, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter with suction, concentrate under reduced pressure, and separate and purify by column chromatography to obtain 1.09 g of oily liquid with a yield of 60.2%. MS(ESI)m/z:387.2[MH] - ; 1 H NMR(400MHz,DMSO-d 6 )δ8.01(s,1H),7.70-7.48(m,4H),7.31(s,1H), 5.57(d, J=7.6Hz, 1H), 5.32(s, 1H), 4.42-4.30(m, 1H), 4.12-3.94(m, 2H), 3.08(t, J=8.2Hz, 2H), 1.38 (d,J=6.0Hz,3H),1.11(s,9H).
(R)-(5-(1-氨基乙基)-2,3-二氢-1H-吲哚-1-基)(3-氟苯基)甲酮(12G)合成Synthesis of (R)-(5-(1-aminoethyl)-2,3-dihydro-1H-indol-1-yl)(3-fluorophenyl)methanone (12G)
将原料12F(1.09g,2.81mmol)溶于无水甲醇(1.0mL)中，加入盐酸/1,4-二氧六环溶液(1.7M,14mL)，室温反应3h，减压浓缩，饱和NaHCO 3溶液调节pH至9，乙酸乙酯(3×40mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，得黄色油状液体0.80g，收率100％。MS(ESI)m/z:283.1[M-H] -. Dissolve raw material 12F (1.09g, 2.81mmol) in anhydrous methanol (1.0mL), add hydrochloric acid/1,4-dioxane solution (1.7M, 14mL), react at room temperature for 3h, concentrate under reduced pressure, and saturate with NaHCO 3. Adjust the pH of the solution to 9, extract with ethyl acetate (3×40 mL), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter with suction, and concentrate under reduced pressure to obtain 0.80 g of a yellow oily liquid with a yield of 100%. . MS(ESI)m/z:283.1[MH] - .
(R)-N-(1-(1-(3-氟苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(12)合成(R)-N-(1-(1-(3-fluorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-fluorobenzamide (12) synthesis
将12G(0.13g,0.46mmol)和三乙胺(0.14g,1.38mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氟苯甲酰氯(0.081g,0.51mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.15g(97.8％ee)，收率78.9％。MS(ESI)m/z:405.2[M-H] -； 1H NMR(400MHz,DMSO-d 6)δ8.80(d,J＝8.0Hz,1H),8.18-7.87(m,3H),7.71-7.13(m,8H),5.21-5.02(m,1H),4.06-3.84(m,2H),3.07(t,J＝8.2Hz,2H),1.46(d,J＝6.8Hz,3H). 12G (0.13g, 0.46mmol) and triethylamine (0.14g, 1.38mmol) were dissolved in 3mL of anhydrous dichloromethane, and 4-fluorobenzoyl chloride (0.081g, 0.51mmol) was slowly added dropwise at 0°C Anhydrous dichloromethane (2 mL) solution, reacted at room temperature for 3 h, concentrated under reduced pressure, added 30 mL of water, extracted with dichloromethane (3×20 mL), combined the organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and suction filtered. Concentrate under reduced pressure, separate and purify by column chromatography to obtain 0.15 g (97.8% ee) of white solid, yield 78.9%. MS (ESI) m/z: 405.2[MH] - ; 1 H NMR (400MHz, DMSO-d 6 ) δ8.80 (d, J=8.0Hz, 1H), 8.18-7.87 (m, 3H), 7.71- 7.13(m,8H),5.21-5.02(m,1H),4.06-3.84(m,2H),3.07(t,J=8.2Hz,2H),1.46(d,J=6.8Hz,3H).
实施例13：(R)-N-(1-(1-(3-氟苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(13)合成Example 13: (R)-N-(1-(1-(3-fluorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-chlorobenzyl Amide (13) Synthesis
Figure PCTCN2022142154-appb-000032
Figure PCTCN2022142154-appb-000032
将12G(0.13g,0.46mmol)和三乙胺(0.14g,1.38mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氯苯甲酰氯(0.097g,0.55mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.17g(98.8％ee)，收率89.5％。MS(ESI)m/z:421.1[M-H] -； 1H NMR(400MHz,DMSO-d 6)δ8.86(d,J＝7.6Hz,1H),7.91(d,J＝8.8Hz,3H),7.55(d,J＝8.4Hz,4H),7.47-7.17(m,4H),5.20-5.06(m,1H),4.07-3.91(m,2H),3.07(t,J＝8.2Hz,2H),1.46(d,J＝7.2Hz,3H). 12G (0.13g, 0.46mmol) and triethylamine (0.14g, 1.38mmol) were dissolved in 3mL of anhydrous dichloromethane, and 4-chlorobenzoyl chloride (0.097g, 0.55mmol) was slowly added dropwise at 0°C Anhydrous dichloromethane (2 mL) solution, reacted at room temperature for 3 h, concentrated under reduced pressure, added 30 mL of water, extracted with dichloromethane (3×20 mL), combined the organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and suction filtered. It was concentrated under reduced pressure, separated and purified by column chromatography to obtain 0.17 g (98.8% ee) of white solid, and the yield was 89.5%. MS (ESI) m/z: 421.1[MH] - ; 1 H NMR (400MHz, DMSO-d 6 ) δ8.86 (d, J = 7.6Hz, 1H), 7.91 (d, J = 8.8Hz, 3H) ,7.55(d,J=8.4Hz,4H),7.47-7.17(m,4H),5.20-5.06(m,1H),4.07-3.91(m,2H),3.07(t,J=8.2Hz,2H ), 1.46(d, J=7.2Hz, 3H).
实施例14：(R)-N-(1-(1-(3-氟苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氰基苯甲酰胺(14)合成Example 14: (R)-N-(1-(1-(3-fluorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-cyanobenzene Synthesis of formamide (14)
Figure PCTCN2022142154-appb-000033
Figure PCTCN2022142154-appb-000033
将12G(0.13g,0.46mmol)和三乙胺(0.14g,1.38mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氰基苯甲酰氯(0.091g,0.55mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.16g(99.6％ee)，收率84.2％。MS(ESI)m/z:412.2[M-H] -； 1H NMR(400MHz,DMSO-d 6)δ9.05(d,J＝8.0Hz,1H),8.04(d,J＝8.4Hz,2H),7.97(d,J＝8.4Hz,2H),7.58-7.52(m,1H),7.49-7.19(m,6H),5.17-5.08(m,1H),4.04-3.95(m,2H),3.07(t,J＝8.4Hz,2H),1.47(d,J＝7.2Hz,3H). 12G (0.13g, 0.46mmol) and triethylamine (0.14g, 1.38mmol) were dissolved in 3mL of anhydrous dichloromethane, and 4-cyanobenzoyl chloride (0.091g, 0.55mmol) was slowly added dropwise at 0°C Anhydrous dichloromethane (2mL) solution, reacted at room temperature for 3h, concentrated under reduced pressure, added 30mL of water, extracted with dichloromethane (3×20mL), combined organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and suction filtered , concentrated under reduced pressure, and separated and purified by column chromatography to obtain 0.16 g (99.6% ee) of a white solid, with a yield of 84.2%. MS (ESI) m/z: 412.2[MH] - ; 1 H NMR (400MHz, DMSO-d 6 ) δ9.05 (d, J = 8.0Hz, 1H), 8.04 (d, J = 8.4Hz, 2H) ,7.97(d,J＝8.4Hz,2H),7.58-7.52(m,1H),7.49-7.19(m,6H),5.17-5.08(m,1H),4.04-3.95(m,2H),3.07 (t,J=8.4Hz,2H),1.47(d,J=7.2Hz,3H).
实施例15：(R)-N-(1-(1-(3-氰基苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(15)合成Example 15: (R)-N-(1-(1-(3-cyanobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-fluorobenzene Synthesis of formamide (15)
Figure PCTCN2022142154-appb-000034
Figure PCTCN2022142154-appb-000034
1-(1-(3-氰基苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙酮(15D)合成Synthesis of 1-(1-(3-cyanobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethanone (15D)
将1C(1.20g,7.44mmol)和三乙胺(2.26g,22.32mmol)溶于15mL无水二氯甲烷中，冰浴下缓慢滴加3-氰基苯甲酰氯(1.48g,8.93mmol)的无水二氯甲烷(8mL)溶液，室温反应3h，减压浓缩，加入100mL水，二氯甲烷(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体2.00g，收率92.6％。MS(ESI)m/z:289.1[M-H] -； 1H NMR(400MHz,DMSO-d 6)δ8.22-7.67(m,7H),4.07(t,J＝8.4Hz,2H),3.15(t,J＝8.4Hz,2H),2.51(d,J＝4.0Hz,3H). 1C (1.20g, 7.44mmol) and triethylamine (2.26g, 22.32mmol) were dissolved in 15mL of anhydrous dichloromethane, and 3-cyanobenzoyl chloride (1.48g, 8.93mmol) was slowly added dropwise under ice-cooling Anhydrous dichloromethane (8mL) solution, reacted at room temperature for 3h, concentrated under reduced pressure, added 100mL of water, extracted with dichloromethane (3×30mL), combined organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and suction filtered , concentrated under reduced pressure, and separated and purified by column chromatography to obtain 2.00 g of a white solid with a yield of 92.6%. MS (ESI) m/z: 289.1 [MH] - ; 1 H NMR (400 MHz, DMSO-d 6 ) δ8.22-7.67 (m, 7H), 4.07 (t, J = 8.4 Hz, 2H), 3.15 ( t,J=8.4Hz,2H),2.51(d,J=4.0Hz,3H).
(R)-2-甲基-N-(1-(1-(3-氰基苯甲酰基)-2,3-二氢-1H-吲哚-5-基)亚乙基)丙烷-2-亚磺酰胺(15E)合成(R)-2-Methyl-N-(1-(1-(3-cyanobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethylidene)propane-2 -Synthesis of sulfenamide (15E)
向15D(1.45g,4.99mmol)的无水四氢呋喃(15mL)溶液中加入(R)-(+)-叔丁基亚磺酰胺(0.73g,5.99mmol)和钛酸乙酯(2.28g,9.98mmol)，85℃回流12h。向反应液中加入100mL水，80mL乙酸乙酯，剧烈搅拌15min，抽滤，乙酸乙酯(10mL)洗涤滤饼，滤液减压浓缩，乙酸乙酯(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，柱层析分离纯化，得黄色固体1.41g，收率71.6％。MS(ESI)m/z:392.2[M-H] -； 1H NMR(400MHz,DMSO-d 6)δ8.34-7.52(m,7H),4.06(t,J＝8.4Hz,2H),3.15(t,J＝8.4Hz,2H),2.70(s,3H),1.22(s,9H). To a solution of 15D (1.45 g, 4.99 mmol) in anhydrous tetrahydrofuran (15 mL) was added (R)-(+)-tert-butylsulfinamide (0.73 g, 5.99 mmol) and ethyl titanate (2.28 g, 9.98 mmol), reflux at 85°C for 12h. Add 100 mL of water and 80 mL of ethyl acetate to the reaction solution, stir vigorously for 15 min, filter with suction, wash the filter cake with ethyl acetate (10 mL), concentrate the filtrate under reduced pressure, extract with ethyl acetate (3×30 mL), combine the organic phases, and saturate Wash with brine, dry over anhydrous sodium sulfate, filter with suction, concentrate under reduced pressure, and separate and purify by column chromatography to obtain 1.41 g of a yellow solid with a yield of 71.6%. MS (ESI) m/z: 392.2[MH] - ; 1 H NMR (400MHz, DMSO-d 6 ) δ8.34-7.52 (m, 7H), 4.06 (t, J = 8.4Hz, 2H), 3.15 ( t,J=8.4Hz,2H),2.70(s,3H),1.22(s,9H).
(R)-2-甲基-N-(1-(1-(3-氰基苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)丙烷-2-亚磺酰胺(15F)合成(R)-2-Methyl-N-(1-(1-(3-cyanobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)propane-2- Synthesis of sulfenamide (15F)
取
Figure PCTCN2022142154-appb-000035
分子筛(1.30g)于100mL圆底烧瓶中，加入8mL异丙醇，2-甲基-2-氨基-1-丙醇(15.15mg,0.17mmol)和二氯双(4-甲基异丙基苯基)钌(Ⅱ)(54.56g,0.089mmol)，回流5min，冷却至55℃，加入15E(1.30g,3.30mmol)及叔丁醇钾(44.44g,0.40mmol)，55℃下反应12h，加入15mL二氯甲烷稀释，硅藻土抽滤，21mL二氯甲烷：甲醇混合溶液(20:1,V/V)洗涤滤饼，滤液减压浓缩，二氯甲烷(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩得油状液体1.31g，收率100％。MS(ESI)m/z:394.2[M-H] -. Pick
Figure PCTCN2022142154-appb-000035
Molecular sieves (1.30g) were placed in a 100mL round bottom flask, and 8mL of isopropanol, 2-methyl-2-amino-1-propanol (15.15mg, 0.17mmol) and dichlorobis(4-methylisopropyl Phenyl) ruthenium (Ⅱ) (54.56g, 0.089mmol), reflux for 5min, cool to 55°C, add 15E (1.30g, 3.30mmol) and potassium tert-butoxide (44.44g, 0.40mmol), react at 55°C for 12h , add 15mL of dichloromethane to dilute, filter with diatomaceous earth, wash the filter cake with 21mL of dichloromethane:methanol mixed solution (20:1, V/V), concentrate the filtrate under reduced pressure, extract with dichloromethane (3×30mL), The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and concentrated under reduced pressure to obtain 1.31 g of an oily liquid with a yield of 100%. MS(ESI)m/z:394.2[MH] - .
(R)-(5-(1-氨基乙基)-2,3-二氢-1H-吲哚-1-基)(3-氰基苯基)甲酮(15G)合成Synthesis of (R)-(5-(1-aminoethyl)-2,3-dihydro-1H-indol-1-yl)(3-cyanophenyl)methanone (15G)
将原料15F(0.28g,0.71mmol)溶于2mL无水甲醇中，加入盐酸二氧六环溶液(1.7M,8mL)，室温反应3h，减压浓缩，饱和NaHCO 3溶液调节pH至9，乙酸乙酯(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，得黄色油状液体0.21g，收率100％。MS(ESI)m/z:290.1[M-H] -. Dissolve raw material 15F (0.28g, 0.71mmol) in 2mL of anhydrous methanol, add dioxane hydrochloride solution (1.7M, 8mL), react at room temperature for 3h, concentrate under reduced pressure, adjust the pH to 9 with saturated NaHCO 3 solution, acetic acid Ethyl ester (3×20 mL) was extracted, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and concentrated under reduced pressure to obtain 0.21 g of a yellow oily liquid with a yield of 100%. MS(ESI)m/z:290.1[MH] - .
(R)-N-(1-(1-(3-氰基苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(15)合成(R)-N-(1-(1-(3-cyanobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-fluorobenzamide (15 )synthesis
将15G(0.14g,0.48mmol)和三乙胺(0.15g,1.44mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氟苯甲酰氯(0.091g,0.58mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.17g(97.9％ee)，收率85.0％。MS(ESI)m/z:412.2[M-H] -； 1H NMR(400MHz,DMSO-d 6)δ8.80(d,J＝8.0Hz,1H),8.09(s,1H),8.04-7.89(m,5H),7.71(t,J＝7.6Hz,1H),7.30(q,J＝8.0Hz,4H),5.18-5.09(m,1H),4.04-3.94(m,2H),3.08(t,J＝8.2Hz,2H),1.47(d,J＝7.2Hz,3H). 15G (0.14g, 0.48mmol) and triethylamine (0.15g, 1.44mmol) were dissolved in 3mL of anhydrous dichloromethane, and 4-fluorobenzoyl chloride (0.091g, 0.58mmol) was slowly added dropwise at 0°C Anhydrous dichloromethane (2 mL) solution, reacted at room temperature for 3 h, concentrated under reduced pressure, added 30 mL of water, extracted with dichloromethane (3×20 mL), combined the organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and suction filtered. Concentrate under reduced pressure, separate and purify by column chromatography to obtain 0.17 g (97.9% ee) of white solid, yield 85.0%. MS(ESI) m/z: 412.2[MH] - ; 1 H NMR (400MHz, DMSO-d 6 ) δ8.80(d, J=8.0Hz, 1H), 8.09(s, 1H), 8.04-7.89( m,5H),7.71(t,J=7.6Hz,1H),7.30(q,J=8.0Hz,4H),5.18-5.09(m,1H),4.04-3.94(m,2H),3.08(t ,J=8.2Hz,2H),1.47(d,J=7.2Hz,3H).
实施例16：(R)-N-(1-(1-(3-氰基苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(16)合成Example 16: (R)-N-(1-(1-(3-cyanobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-chlorobenzene Formamide (16) Synthesis
Figure PCTCN2022142154-appb-000036
Figure PCTCN2022142154-appb-000036
将16G(0.14g,0.48mmol)和三乙胺(0.15g,1.44mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氯苯甲酰氯(0.096g,0.55mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.19g(99.7％ee)，收率90.5％。MS(ESI)m/z:428.1[M-H] -； 1H NMR(400MHz,DMSO-d 6)δ8.87(d,J＝8.0Hz,1H),8.20-7.83(m,5H),7.71(t,J＝7.8Hz,1H),7.55(d,J＝8.5Hz,2H),7.41-7.03(m,2H),5.21-5.05(m,1H),4.15-3.89(m,2H),3.08(t,J＝8.2Hz,2H),1.47(d,J＝7.2Hz,3H). Dissolve 16G (0.14g, 0.48mmol) and triethylamine (0.15g, 1.44mmol) in 3mL of anhydrous dichloromethane, slowly add 4-chlorobenzoyl chloride (0.096g, 0.55mmol) dropwise at 0°C Anhydrous dichloromethane (2 mL) solution, reacted at room temperature for 3 h, concentrated under reduced pressure, added 30 mL of water, extracted with dichloromethane (3×20 mL), combined the organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and suction filtered. It was concentrated under reduced pressure, separated and purified by column chromatography to obtain 0.19 g (99.7% ee) of a white solid, and the yield was 90.5%. MS (ESI) m/z: 428.1 [MH] - ; 1 H NMR (400 MHz, DMSO-d 6 ) δ8.87 (d, J = 8.0 Hz, 1 H), 8.20-7.83 (m, 5 H), 7.71 ( t,J=7.8Hz,1H),7.55(d,J=8.5Hz,2H),7.41-7.03(m,2H),5.21-5.05(m,1H),4.15-3.89(m,2H),3.08 (t,J=8.2Hz,2H),1.47(d,J=7.2Hz,3H).
实施例17：(R)-N-(1-(1-(2-氯吡啶-4-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(17)合成Example 17: (R)-N-(1-(1-(2-chloropyridine-4-formyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4- Synthesis of Fluorobenzamide (17)
Figure PCTCN2022142154-appb-000037
Figure PCTCN2022142154-appb-000037
1-(1-(2-氯吡啶-4-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙酮(17D)合成Synthesis of 1-(1-(2-chloropyridine-4-formyl)-2,3-dihydro-1H-indol-5-yl)ethanone (17D)
将1C(1.29g,8.00mmol)和三乙胺(2.43g,24.01mmol)溶于10mL无水二氯甲烷中，冰浴下缓慢滴加2-氯吡啶-4-甲酰氯(1.69g,9.60mmol)的无水二氯甲烷(8mL)溶液，室温反应3h，减压浓缩，加入100mL水，二氯甲烷(3×40mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体2.00g，收率83.0％。MS(ESI)m/z:299.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ11.40(s,1H),8.21(s,1H),7.78(d,J＝8.1Hz,1H),7.45(d,J＝8.7Hz,2H),6.69-6.52(m,1H),3.52-3.43(m,2H),2.85-2.72(s,3H),2.67-2.41(m,2H). 1C (1.29g, 8.00mmol) and triethylamine (2.43g, 24.01mmol) were dissolved in 10mL of anhydrous dichloromethane, and 2-chloropyridine-4-formyl chloride (1.69g, 9.60 mmol) in anhydrous dichloromethane (8 mL), react at room temperature for 3 h, concentrate under reduced pressure, add 100 mL of water, extract with dichloromethane (3×40 mL), combine the organic phases, wash with saturated brine, and dry over anhydrous magnesium sulfate. Suction filtration, concentration under reduced pressure, separation and purification by column chromatography gave 2.00 g of white solid, yield 83.0%. MS (ESI) m/z: 299.1 [MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ11.40 (s, 1H), 8.21 (s, 1H), 7.78 (d, J＝8.1Hz, 1H), 7.45(d, J=8.7Hz, 2H), 6.69-6.52(m, 1H), 3.52-3.43(m, 2H), 2.85-2.72(s, 3H), 2.67-2.41(m, 2H) .
(R)-2-甲基-N-(1-(1-(2-氯吡啶-4-甲酰基)-2,3-二氢-1H-吲哚-5-基)亚乙基)丙烷-2-亚磺酰胺(17E)合成(R)-2-Methyl-N-(1-(1-(2-chloropyridine-4-formyl)-2,3-dihydro-1H-indol-5-yl)ethylidene)propane -Synthesis of 2-sulfinamide (17E)
向17D(1.82g,6.05mmol)的无水四氢呋喃(15mL)溶液中加入(R)-(+)-叔丁基亚磺酰胺(0.88g,7.26mmol)和钛酸乙酯(2.76g,12.10mmol)，85℃回流12h。向反应液中加入100mL水，80mL乙酸乙酯，剧烈搅拌15min，抽滤，乙酸乙酯(10mL)洗涤滤饼，滤液减压浓缩，乙酸乙酯(3×40mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，柱层析分离纯化，得黄色固体1.70g，收率69.7％。MS(ESI)m/z:402.1[M-H] -； 1H NMR(400MHz,DMSO-d 6)δ8.59(d,J＝5.6Hz,1H),8.15(d,J＝6.8Hz,1H),7.88(s,2H),7.80(s,1H),7.65(d,J＝5.2Hz,1H),4.03(t,J＝8.8Hz,2H),3.16(t,J＝8.2Hz,2H),2.70(s,3H),1.22(s,9H). To a solution of 17D (1.82 g, 6.05 mmol) in anhydrous tetrahydrofuran (15 mL) was added (R)-(+)-tert-butylsulfinamide (0.88 g, 7.26 mmol) and ethyl titanate (2.76 g, 12.10 mmol), reflux at 85°C for 12h. Add 100 mL of water and 80 mL of ethyl acetate to the reaction solution, stir vigorously for 15 min, filter with suction, wash the filter cake with ethyl acetate (10 mL), concentrate the filtrate under reduced pressure, extract with ethyl acetate (3×40 mL), combine the organic phases, and saturate Washed with brine, dried over anhydrous sodium sulfate, filtered with suction, concentrated under reduced pressure, separated and purified by column chromatography to obtain 1.70 g of a yellow solid with a yield of 69.7%. MS (ESI) m/z: 402.1[MH] - ; 1 H NMR (400MHz, DMSO-d 6 ) δ8.59 (d, J = 5.6Hz, 1H), 8.15 (d, J = 6.8Hz, 1H) ,7.88(s,2H),7.80(s,1H),7.65(d,J=5.2Hz,1H),4.03(t,J=8.8Hz,2H),3.16(t,J=8.2Hz,2H) ,2.70(s,3H),1.22(s,9H).
(R)-2-甲基-N-(1-(1-(2-氯吡啶-4-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)丙烷-2-亚磺酰胺(17F)合成(R)-2-Methyl-N-(1-(1-(2-chloropyridine-4-formyl)-2,3-dihydro-1H-indol-5-yl)ethyl)propane- Synthesis of 2-sulfinamide (17F)
取
Figure PCTCN2022142154-appb-000038
分子筛(1.65g)于100mL圆底烧瓶中，加入6mL异丙醇，2-甲基-2-氨基-1-丙醇(18.18mg,0.20mmol)和二氯双(4-甲基异丙基苯基)钌(Ⅱ)(67.46mg,0.11mmol)，回流5min，冷却至55℃，加入17E(1.65g,4.08mmol)及叔丁醇钾(54.94mg,0.49mmol)，55℃下反应12h，冷却，加入15mL二氯甲烷稀释，抽滤，硅藻土助滤，21mL二氯甲烷：甲醇混合溶液(20:1,V/V)洗涤滤饼，滤液减压浓缩，二氯甲烷(3×30mL)萃取，合并有机相，无水硫酸钠干燥，抽滤，减压浓缩，得油状液体1.48g，收率89.2％。MS(ESI)m/z:404.1[M-H] -. Pick
Figure PCTCN2022142154-appb-000038
Molecular sieves (1.65g) were placed in a 100mL round bottom flask, and 6mL of isopropanol, 2-methyl-2-amino-1-propanol (18.18mg, 0.20mmol) and dichlorobis(4-methylisopropyl Phenyl)ruthenium (Ⅱ) (67.46mg, 0.11mmol), reflux for 5min, cool to 55°C, add 17E (1.65g, 4.08mmol) and potassium tert-butoxide (54.94mg, 0.49mmol), react at 55°C for 12h , cooled, added 15mL dichloromethane for dilution, suction filtration, diatomaceous earth filter aid, 21mL dichloromethane:methanol mixed solution (20:1, V/V) washed the filter cake, the filtrate was concentrated under reduced pressure, dichloromethane (3 × 30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered with suction, and concentrated under reduced pressure to obtain 1.48 g of an oily liquid with a yield of 89.2%. MS(ESI)m/z:404.1[MH] - .
(R)-(5-(1-氨基乙基)-2,3-二氢-1H-吲哚-1-基)(2-氯吡啶基)甲酮(17G)合成Synthesis of (R)-(5-(1-aminoethyl)-2,3-dihydro-1H-indol-1-yl)(2-chloropyridyl)methanone (17G)
将原料17F(1.48g,3.65mmol)溶于3mL无水甲醇中，加入盐酸二氧六环溶液(1.7M,8mL)，室温反应3h，减压浓缩，加水(10mL)，饱和NaHCO 3溶液调节pH至9，乙酸乙酯(3×40mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，得淡黄色油状物1.10g，收率100％。MS(ESI)m/z:300.1[M-H] -. Dissolve raw material 17F (1.48g, 3.65mmol) in 3mL of anhydrous methanol, add dioxane hydrochloride solution (1.7M, 8mL), react at room temperature for 3h, concentrate under reduced pressure, add water (10mL), and adjust with saturated NaHCO 3 solution When the pH was reached to 9, extracted with ethyl acetate (3×40 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and concentrated under reduced pressure to obtain 1.10 g of a light yellow oil with a yield of 100%. MS(ESI)m/z:300.1[MH] - .
(R)-N-(1-(1-(2-氯吡啶-4-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(17)合成(R)-N-(1-(1-(2-chloropyridine-4-formyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-fluorobenzamide (17)Synthesis
将17G(0.10g,0.33mmol)和三乙胺(0.13g,1.32mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氟苯甲酰氯(0.063g,0.40mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.11g(98.7％ee)，收率78.6％。MS(ESI)m/z:422.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ8.79(d,J＝7.8Hz,1H),8.56(d,J＝5.1Hz,1H),8.07-7.90(m,3H),7.74(s,1H),7.60(d,J＝5.1Hz,1H),7.31(d,J＝8.7Hz,4H),5.20-5.06(m,1H),3.96(t,J＝7.8Hz,2H),3.08(t,J＝8.1Hz,2H),1.47(d,J＝6.6Hz,3H). Dissolve 17G (0.10g, 0.33mmol) and triethylamine (0.13g, 1.32mmol) in 3mL of anhydrous dichloromethane, slowly add 4-fluorobenzoyl chloride (0.063g, 0.40mmol) dropwise at 0°C Anhydrous dichloromethane (2 mL) solution, reacted at room temperature for 3 h, concentrated under reduced pressure, added 30 mL of water, extracted with dichloromethane (3×20 mL), combined the organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and suction filtered. It was concentrated under reduced pressure, separated and purified by column chromatography to obtain 0.11 g (98.7% ee) of white solid, and the yield was 78.6%. MS (ESI) m/z: 422.1[MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ8.79(d, J=7.8Hz, 1H), 8.56(d, J=5.1Hz, 1H) ,8.07-7.90(m,3H),7.74(s,1H),7.60(d,J=5.1Hz,1H),7.31(d,J=8.7Hz,4H),5.20-5.06(m,1H), 3.96(t, J=7.8Hz, 2H), 3.08(t, J=8.1Hz, 2H), 1.47(d, J=6.6Hz, 3H).
实施例18：(R)-N-(1-(1-(2-氯吡啶-4-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(18)合成Example 18: (R)-N-(1-(1-(2-chloropyridine-4-formyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4- Synthesis of Chlorobenzamide (18)
Figure PCTCN2022142154-appb-000039
Figure PCTCN2022142154-appb-000039
将17G(0.10g,0.33mmol)和三乙胺(0.13g,1.32mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氯苯甲酰氯(0.069g,0.40mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.12g(98.6％ee)，收率80.0％。MS(ESI)m/z:438.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ8.85(d,J＝7.5Hz,1H),8.56(d,J＝5.1Hz,1H),8.02(d,J＝7.8Hz,1H),7.91(d,J＝8.4Hz,2H),7.74(s,1H),7.56(t,J＝9.6Hz,3H),7.36-7.22(m,2H),5.15(q,J＝7.8Hz,1H),3.96(t,J＝7.8Hz,3H),3.08(t,J＝8.1Hz,2H),1.47(d,J＝6.6Hz,3H). 17G (0.10g, 0.33mmol) and triethylamine (0.13g, 1.32mmol) were dissolved in 3mL of anhydrous dichloromethane, and 4-chlorobenzoyl chloride (0.069g, 0.40mmol) was slowly added dropwise at 0°C Anhydrous dichloromethane (2 mL) solution, reacted at room temperature for 3 h, concentrated under reduced pressure, added 30 mL of water, extracted with dichloromethane (3×20 mL), combined the organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and suction filtered. It was concentrated under reduced pressure, separated and purified by column chromatography to obtain 0.12 g (98.6% ee) of a white solid, and the yield was 80.0%. MS (ESI) m/z: 438.1[MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ8.85 (d, J = 7.5Hz, 1H), 8.56 (d, J = 5.1Hz, 1H) ,8.02(d,J=7.8Hz,1H),7.91(d,J=8.4Hz,2H),7.74(s,1H),7.56(t,J=9.6Hz,3H),7.36-7.22(m, 2H), 5.15(q, J=7.8Hz, 1H), 3.96(t, J=7.8Hz, 3H), 3.08(t, J=8.1Hz, 2H), 1.47(d, J=6.6Hz, 3H) .
实施例19：(R)-N-(1-(1-(4-氯吡啶-2-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(19)合成Example 19: (R)-N-(1-(1-(4-chloropyridine-2-formyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4- Synthesis of Chlorobenzamide (19)
Figure PCTCN2022142154-appb-000040
Figure PCTCN2022142154-appb-000040
5-乙酰-2,3-二氢-1H-吲哚-1-羧酸苄酯(19D)合成Synthesis of Benzyl 5-Acetyl-2,3-dihydro-1H-indole-1-carboxylate (19D)
将1C(1.54g,9.55mmol)和三乙胺(1.93g,19.10mmol)溶于15mL无水二氯甲烷中，冰浴下缓慢滴加氯甲酸苄酯(2.44g,14.33mmol)的无水二氯甲烷(8mL)溶液，室温反应3h，减压浓缩，加入80mL水，二氯甲烷(3×40mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体2.67g，收率94.7％。MS(ESI)m/z:294.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ7.89-7.31(m,8H),5.26(s,2H),4.07(t,J＝8.7Hz,2H),3.15(t,J＝8.7Hz,2H),2.51(s,3H). Dissolve 1C (1.54g, 9.55mmol) and triethylamine (1.93g, 19.10mmol) in 15mL of anhydrous dichloromethane, slowly add benzyl chloroformate (2.44g, 14.33mmol) dropwise in anhydrous Dichloromethane (8mL) solution, reacted at room temperature for 3h, concentrated under reduced pressure, added 80mL of water, extracted with dichloromethane (3×40mL), combined the organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, suction filtered, and reduced pressure Concentrate, separate and purify by column chromatography to obtain 2.67 g of white solid with a yield of 94.7%. MS (ESI) m/z: 294.1 [MH] - ; 1 H NMR (300 MHz, DMSO-d 6 ) δ7.89-7.31 (m, 8H), 5.26 (s, 2H), 4.07 (t, J＝8.7 Hz,2H),3.15(t,J=8.7Hz,2H),2.51(s,3H).
(R,E)-5-(1-((叔丁基亚磺酰基)亚氨基)乙基)-2,3-二氢-1H-吲哚-1-羧酸苄酯(19E)合成Synthesis of (R,E)-5-(1-((tert-butylsulfinyl)imino)ethyl)-2,3-dihydro-1H-indole-1-carboxylic acid benzyl ester (19E)
向19D(1.70g,5.76mmol)的无水四氢呋喃(15mL)溶液中加入(R)-(+)-叔丁基亚磺酰胺(0.91g,7.49mmol)和钛酸乙酯(2.63g,11.52mmol)，在氮气氛围下85℃回流12h。向反应液中加入100mL水，80mL乙酸乙酯，剧烈搅拌15min，抽滤，乙酸乙酯(10mL)洗涤滤饼，滤液减压浓缩，乙酸乙酯(3×40mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，柱层析分离纯化，得黄色固体1.73g，收率75.2％。MS(ESI)m/z:397.2[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ7.80(s,3H),7.49-7.31(m,5H),5.30(s,2H),4.06(t,J＝6.6Hz,2H),3.16(t,J＝8.4Hz,2H),2.67(s,3H),1.21(s,9H). To a solution of 19D (1.70 g, 5.76 mmol) in anhydrous tetrahydrofuran (15 mL) was added (R)-(+)-tert-butylsulfinamide (0.91 g, 7.49 mmol) and ethyl titanate (2.63 g, 11.52 mmol), refluxed at 85° C. for 12 h under nitrogen atmosphere. Add 100 mL of water and 80 mL of ethyl acetate to the reaction solution, stir vigorously for 15 min, filter with suction, wash the filter cake with ethyl acetate (10 mL), concentrate the filtrate under reduced pressure, extract with ethyl acetate (3×40 mL), combine the organic phases, and saturate Wash with brine, dry over anhydrous sodium sulfate, filter with suction, concentrate under reduced pressure, and separate and purify by column chromatography to obtain 1.73 g of a yellow solid with a yield of 75.2%. MS(ESI)m/z:397.2[MH] - ; 1 H NMR(300MHz,DMSO-d 6 )δ7.80(s,3H),7.49-7.31(m,5H),5.30(s,2H), 4.06(t, J=6.6Hz, 2H), 3.16(t, J=8.4Hz, 2H), 2.67(s, 3H), 1.21(s, 9H).
(R)-5-(1-((R)-叔丁基亚磺酰胺基)乙基)-2,3-二氢-1H-吲哚-1-羧酸苄酯(19F)合成Synthesis of (R)-5-(1-((R)-tert-butylsulfinamido)ethyl)-2,3-dihydro-1H-indole-1-carboxylic acid benzyl ester (19F)
取
Figure PCTCN2022142154-appb-000041
分子筛(0.76g)于100mL圆底烧瓶中，加入6mL异丙醇，2-甲基-2-氨基-1-丙醇(8.51mg,0.096mmol)和二氯双(4-甲基异丙基苯基)钌(Ⅱ)(31.58mg,0.052mmol)，回流5min，冷却至55℃，加入19E(0.76g,1.91mmol)及叔丁醇钾(25.72mg,0.23mmol)，55℃下反应12h，加入15mL二氯甲烷稀释，硅藻土抽滤，21mL二氯甲烷：甲醇混合溶液(20:1,V/V)洗涤滤饼，滤液减压浓缩，二氯甲烷(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩后，柱层析分离纯化，得油状液体0.70g，收率90.9％。MS(ESI)m/z:399.2[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ7.65(s,1H),7.48-7.30(m,5H),7.25(s,1H),7.16(d,J＝8.1Hz,1H),5.50(d,J＝6.9Hz,1H),5.23(s,2H),4.29(q,J＝6.9Hz,1H),4.02(t,J＝8.4Hz,2H),3.09(t,J＝8.7Hz,2H),1.36(d,J＝6.6Hz,3H),1.10(s,9H). Pick
Figure PCTCN2022142154-appb-000041
Molecular sieves (0.76g) were placed in a 100mL round bottom flask, and 6mL of isopropanol, 2-methyl-2-amino-1-propanol (8.51mg, 0.096mmol) and dichlorobis(4-methylisopropyl Phenyl)ruthenium (Ⅱ) (31.58mg, 0.052mmol), reflux for 5min, cool to 55°C, add 19E (0.76g, 1.91mmol) and potassium tert-butoxide (25.72mg, 0.23mmol), react at 55°C for 12h , add 15mL of dichloromethane to dilute, filter with diatomaceous earth, wash the filter cake with 21mL of dichloromethane:methanol mixed solution (20:1, V/V), concentrate the filtrate under reduced pressure, extract with dichloromethane (3×30mL), The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, concentrated under reduced pressure, separated and purified by column chromatography to obtain 0.70 g of an oily liquid with a yield of 90.9%. MS(ESI)m/z:399.2[MH] - ; 1 H NMR(300MHz,DMSO-d 6 )δ7.65(s,1H),7.48-7.30(m,5H),7.25(s,1H), 7.16(d, J=8.1Hz, 1H), 5.50(d, J=6.9Hz, 1H), 5.23(s, 2H), 4.29(q, J=6.9Hz, 1H), 4.02(t, J=8.4 Hz, 2H), 3.09(t, J=8.7Hz, 2H), 1.36(d, J=6.6Hz, 3H), 1.10(s, 9H).
(R)-5-(1-氨基乙基)-2,3-二氢-1H-吲哚-1-羧酸苄酯(19G)合成Synthesis of (R)-5-(1-aminoethyl)-2,3-dihydro-1H-indole-1-carboxylic acid benzyl ester (19G)
将原料19F(0.62g,1.55mmol)溶于2mL无水甲醇中，加入盐酸二氧六环溶液(1.7M,15mL)，室温反应3h，减压浓缩，加水(10mL)，饱和NaHCO 3溶液调节pH至8，乙酸乙酯(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，得黄色固体0.46g，收率100％。MS(ESI)m/z:295.2[M-H] -. Dissolve raw material 19F (0.62g, 1.55mmol) in 2mL of anhydrous methanol, add dioxane hydrochloride solution (1.7M, 15mL), react at room temperature for 3h, concentrate under reduced pressure, add water (10mL), and adjust with saturated NaHCO 3 solution When the pH was reached to 8, extracted with ethyl acetate (3×30 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and concentrated under reduced pressure to obtain 0.46 g of a yellow solid with a yield of 100%. MS(ESI)m/z:295.2[MH] - .
(R)-N-5-(1-(4-氯苯甲酰胺基)乙基)-2,3-二氢-1H-吲哚-1-羧酸苄酯(19H)合成Synthesis of (R)-N-5-(1-(4-chlorobenzamido)ethyl)-2,3-dihydro-1H-indole-1-carboxylic acid benzyl ester (19H)
将19G(0.15g,0.51mmol)和三乙胺(0.15g,1.53mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氯苯甲酰氯(0.11g,0.61mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.19g，收率86.4％。MS(ESI)m/z:433.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ8.81(d,J＝8.0Hz,1H),8.03-7.86(m,3H),7.60-7.50(m,3H),7.41(d,J＝8.0Hz,4H),7.29-7.13(m,2H),5.23(s,2H),5.12(q,J＝7.5Hz,1H),4.02(t,J＝9.6Hz,2H),3.09(t,J＝6.9Hz,2H),1.45(d,J＝6.6Hz,3H). Dissolve 19G (0.15g, 0.51mmol) and triethylamine (0.15g, 1.53mmol) in 3mL of anhydrous dichloromethane, slowly add 4-chlorobenzoyl chloride (0.11g, 0.61mmol) dropwise at 0°C Anhydrous dichloromethane (2 mL) solution, reacted at room temperature for 3 h, concentrated under reduced pressure, added 30 mL of water, extracted with dichloromethane (3×20 mL), combined the organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and suction filtered. Concentrate under reduced pressure, and separate and purify by column chromatography to obtain 0.19 g of white solid with a yield of 86.4%. MS (ESI) m/z: 433.1[MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ8.81 (d, J=8.0Hz, 1H), 8.03-7.86 (m, 3H), 7.60- 7.50(m,3H),7.41(d,J=8.0Hz,4H),7.29-7.13(m,2H),5.23(s,2H),5.12(q,J=7.5Hz,1H),4.02(t , J=9.6Hz, 2H), 3.09(t, J=6.9Hz, 2H), 1.45(d, J=6.6Hz, 3H).
(R)-N-(1-(2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺氢溴酸盐(19I)合成Synthesis of (R)-N-(1-(2,3-dihydro-1H-indol-5-yl)ethyl)-4-chlorobenzamide hydrobromide (19I)
将19H(0.13g,0.30mmol)和33％HBr的乙酸溶液(4mL)加入50mL圆底烧瓶中，室温反应3h，减压浓缩，饱和NaHCO 3溶液调节pH至8，乙酸乙酯(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，得棕色油状物0.090g，收率100％。MS(ESI)m/z:299.1[M-H] -. Add 19H (0.13g, 0.30mmol) and 33% HBr in acetic acid solution (4mL) into a 50mL round bottom flask, react at room temperature for 3h, concentrate under reduced pressure, adjust the pH to 8 with saturated NaHCO 3 solution, ethyl acetate (3×20mL ) extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and concentrated under reduced pressure to obtain 0.090 g of a brown oil, with a yield of 100%. MS(ESI)m/z:299.1[MH] - .
(R)-N-(1-(1-(4-氯吡啶-2-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(19)合成(R)-N-(1-(1-(4-chloropyridine-2-formyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-chlorobenzamide (19)Synthesis
将19I(0.055g,0.18mmol)和三乙胺(0.093g,0.90mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氯吡啶-2-甲酰氯(0.045g,0.25mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×10mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.078g(97.7％ee)，收率96.3％。MS(ESI)m/z:438.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ8.87(d,J＝8.1Hz,1H),8.64(d,J＝5.4Hz,1H),8.08(d,J＝8.4Hz,1H),7.91(t,J＝ 6.9Hz,3H),7.73(d,J＝5.4Hz,1H),7.56(d,J＝8.1Hz,2H),7.37-7.24(m,2H),5.23-5.10(m,1H),4.18(t,J＝7.8Hz,2H),3.11(t,J＝8.1Hz,2H),1.49(d,J＝5.1Hz,3H). 19I (0.055g, 0.18mmol) and triethylamine (0.093g, 0.90mmol) were dissolved in 3mL of anhydrous dichloromethane, and 4-chloropyridine-2-formyl chloride (0.045g, 0.25 mmol) in anhydrous dichloromethane (2 mL), react at room temperature for 3 h, concentrate under reduced pressure, add 30 mL of water, extract with dichloromethane (3×10 mL), combine the organic phases, wash with saturated brine, and dry over anhydrous magnesium sulfate. Suction filtration, concentration under reduced pressure, separation and purification by column chromatography yielded 0.078 g (97.7% ee) of white solid, yield 96.3%. MS(ESI) m/z: 438.1[MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ8.87(d, J=8.1Hz, 1H), 8.64(d, J=5.4Hz, 1H) ,8.08(d,J=8.4Hz,1H),7.91(t,J=6.9Hz,3H),7.73(d,J=5.4Hz,1H),7.56(d,J=8.1Hz,2H),7.37 -7.24(m,2H),5.23-5.10(m,1H),4.18(t,J=7.8Hz,2H),3.11(t,J=8.1Hz,2H),1.49(d,J=5.1Hz, 3H).
实施例20：(R)-N-(1-(1-(6-氯吡啶-2-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(20)合成Example 20: (R)-N-(1-(1-(6-chloropyridine-2-formyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4- Synthesis of Chlorobenzamide (20)
Figure PCTCN2022142154-appb-000042
Figure PCTCN2022142154-appb-000042
将19I(0.10g,0.33mmol)和三乙胺(0.17g,1.65mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加6-氯-2-吡啶甲酰氯(0.070g,0.40mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.13g(98.5％ee)，收率89.7％。MS(ESI)m/z:438.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ8.86(d,J＝6.9Hz,1H),8.06(t,J＝6.9Hz,2H),7.92(d,J＝8.1Hz,2H),7.81(d,J＝7.4Hz,1H),7.70(d,J＝8.1Hz,1H),7.55(d,J＝8.1Hz,2H),7.36-7.23(m,2H),5.17(q,J＝8.4,1H),4.17(t,J＝8.1Hz,2H),3.12(t,J＝8.1Hz,2H),1.48(d,J＝6.9Hz,3H). 19I (0.10g, 0.33mmol) and triethylamine (0.17g, 1.65mmol) were dissolved in 3mL of anhydrous dichloromethane, and 6-chloro-2-pyridinecarbonyl chloride (0.070g, 0.40 mmol) in anhydrous dichloromethane (2 mL), react at room temperature for 3 h, concentrate under reduced pressure, add 30 mL of water, extract with dichloromethane (3×20 mL), combine the organic phases, wash with saturated brine, and dry over anhydrous magnesium sulfate. Suction filtration, concentration under reduced pressure, separation and purification by column chromatography yielded 0.13 g (98.5% ee) of a white solid with a yield of 89.7%. MS (ESI) m/z: 438.1[MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ8.86(d, J=6.9Hz, 1H), 8.06(t, J=6.9Hz, 2H) ,7.92(d,J=8.1Hz,2H),7.81(d,J=7.4Hz,1H),7.70(d,J=8.1Hz,1H),7.55(d,J=8.1Hz,2H),7.36 -7.23(m,2H),5.17(q,J=8.4,1H),4.17(t,J=8.1Hz,2H),3.12(t,J=8.1Hz,2H),1.48(d,J=6.9 Hz,3H).
实施例21：(R)-N-(1-(1-(5-氯吡啶-3-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(21)合成Example 21: (R)-N-(1-(1-(5-chloropyridine-3-formyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4- Synthesis of chlorobenzamide (21)
Figure PCTCN2022142154-appb-000043
Figure PCTCN2022142154-appb-000043
将19I(0.10g,0.33mmol)和三乙胺(0.13g,1.32mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加5-氯吡啶-3-甲酰氯(0.067g,0.40mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.12g(99.1％ee)，收率82.8％。MS(ESI)m/z:438.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ9.00-8.58(m,3H),8.21(s,1H),8.10-7.80(m,3H),7.57-7.54(m,2H),7.32-7.29(m,2H),5.14(q,J＝9.3Hz,1H),4.05(t,J＝9.6Hz,2H),3.11(t,J＝7.5Hz,2H),1.48(d,J＝5.7Hz,3H). 19I (0.10g, 0.33mmol) and triethylamine (0.13g, 1.32mmol) were dissolved in 3mL of anhydrous dichloromethane, and 5-chloropyridine-3-formyl chloride (0.067g, 0.40 mmol) in anhydrous dichloromethane (2 mL), react at room temperature for 3 h, concentrate under reduced pressure, add 30 mL of water, extract with dichloromethane (3×20 mL), combine the organic phases, wash with saturated brine, and dry over anhydrous magnesium sulfate. Suction filtration, concentration under reduced pressure, separation and purification by column chromatography yielded 0.12 g (99.1% ee) of a white solid with a yield of 82.8%. MS(ESI)m/z:438.1[MH] - ; 1 H NMR(300MHz,DMSO-d 6 )δ9.00-8.58(m,3H),8.21(s,1H),8.10-7.80(m,3H ), 7.57-7.54(m, 2H), 7.32-7.29(m, 2H), 5.14(q, J=9.3Hz, 1H), 4.05(t, J=9.6Hz, 2H), 3.11(t, J= 7.5Hz, 2H), 1.48(d, J=5.7Hz, 3H).
实施例22：(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-5-氯-2-吡啶甲酰胺(22)合成Example 22: (R)-N-(1-(1-(3-chlorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-5-chloro-2 -Synthesis of pyridinecarboxamide (22)
Figure PCTCN2022142154-appb-000044
Figure PCTCN2022142154-appb-000044
将7G(0.15g,0.50mmol)和三乙胺(0.15g,1.50mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加5-氯-2-吡啶甲酰氯(0.11g,0.60mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.17g(99.0％ee)，收率77.3％。MS(ESI)m/z:438.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ9.01(d,J＝8.1Hz,1H),8.71(s,1H),8.14-8.11(m,1H),8.02(d,J＝8.4Hz,1H),7.73-7.44(m,4H),7.31-7.28(m,2H),5.20-5.07(m,1H),4.07-3.92(m,2H),3.06(t,J＝8.2Hz,2H),1.51(d,J＝6.6Hz,3H). 7G (0.15g, 0.50mmol) and triethylamine (0.15g, 1.50mmol) were dissolved in 3mL of anhydrous dichloromethane, and 5-chloro-2-pyridinecarbonyl chloride (0.11g, 0.60 mmol) in anhydrous dichloromethane (2 mL), react at room temperature for 3 h, concentrate under reduced pressure, add 30 mL of water, extract with dichloromethane (3×20 mL), combine the organic phases, wash with saturated brine, and dry over anhydrous magnesium sulfate. Suction filtration, concentration under reduced pressure, separation and purification by column chromatography gave 0.17 g (99.0% ee) of white solid, yield 77.3%. MS(ESI) m/z: 438.1[MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ9.01(d, J=8.1Hz, 1H), 8.71(s, 1H), 8.14-8.11( m,1H),8.02(d,J＝8.4Hz,1H),7.73-7.44(m,4H),7.31-7.28(m,2H),5.20-5.07(m,1H),4.07-3.92(m, 2H), 3.06(t, J=8.2Hz, 2H), 1.51(d, J=6.6Hz, 3H).
实施例23：(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-6-氯吡啶-3-甲酰胺(23)合成Example 23: (R)-N-(1-(1-(3-chlorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-6-chloropyridine- Synthesis of 3-formamide (23)
Figure PCTCN2022142154-appb-000045
Figure PCTCN2022142154-appb-000045
(R)-N-5-(1-(6-氯吡啶-3-甲酰胺基)乙基)-2,3-二氢-1H-吲哚-1-羧酸苄酯(23H)合成Synthesis of (R)-N-5-(1-(6-chloropyridine-3-carboxamido)ethyl)-2,3-dihydro-1H-indole-1-carboxylic acid benzyl ester (23H)
将19G(0.15g,0.51mmol)和三乙胺(0.21g,2.04mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加6-氯吡啶-3-甲酰氯(0.13g,0.71mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.17g，收率77.3％。MS(ESI)m/z:434.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ8.99(d,J＝7.8Hz,1H),8.85(d,J＝2.4Hz,1H),8.25(d,J＝5.7Hz,1H),7.63(d,J＝8.4Hz,2H),7.40(d,J＝7.8Hz,4H),7.24-7.21(m,2H),5.22(s,2H),5.12(q,J＝7.2Hz,1H),4.02-3.97(m,2H),3.17-2.98(m,2H),1.45(d,J＝6.9Hz,3H). 19G (0.15g, 0.51mmol) and triethylamine (0.21g, 2.04mmol) were dissolved in 3mL of anhydrous dichloromethane, and 6-chloropyridine-3-formyl chloride (0.13g, 0.71 mmol) in anhydrous dichloromethane (2 mL), react at room temperature for 3 h, concentrate under reduced pressure, add 30 mL of water, extract with dichloromethane (3×20 mL), combine the organic phases, wash with saturated brine, and dry over anhydrous magnesium sulfate. Suction filtration, concentration under reduced pressure, separation and purification by column chromatography gave 0.17 g of white solid, yield 77.3%. MS (ESI) m/z: 434.1[MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ8.99 (d, J = 7.8Hz, 1H), 8.85 (d, J = 2.4Hz, 1H) ,8.25(d,J=5.7Hz,1H),7.63(d,J=8.4Hz,2H),7.40(d,J=7.8Hz,4H),7.24-7.21(m,2H),5.22(s, 2H), 5.12(q, J=7.2Hz, 1H), 4.02-3.97(m, 2H), 3.17-2.98(m, 2H), 1.45(d, J=6.9Hz, 3H).
(R)-N-(1-(2,3-二氢-1H-吲哚-5-基)乙基)-6-氯吡啶-3-甲酰胺氢溴酸盐(23I)合成Synthesis of (R)-N-(1-(2,3-dihydro-1H-indol-5-yl)ethyl)-6-chloropyridine-3-carboxamide hydrobromide (23I)
将23H(0.12g,0.28mmol)和33％HBr的乙酸溶液(6mL)加入50mL圆底烧瓶中，室温反应3h，减压浓缩，加水(3mL)，饱和NaHCO 3溶液调节pH至8，乙酸乙酯(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，得棕色油状物0.084g，收率100％。MS(ESI)m/z:300.1[M-H] -. Add 23H (0.12g, 0.28mmol) and 33% HBr in acetic acid solution (6mL) into a 50mL round bottom flask, react at room temperature for 3h, concentrate under reduced pressure, add water (3mL), adjust the pH to 8 with saturated NaHCO 3 solution, and diethyl acetate The ester (3×20 mL) was extracted, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and concentrated under reduced pressure to obtain 0.084 g of a brown oil, with a yield of 100%. MS(ESI)m/z:300.1[MH] - .
(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-6-氯吡啶-3-甲酰胺(23)合成(R)-N-(1-(1-(3-chlorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-6-chloropyridine-3-carboxamide (23)Synthesis
将23I(0.084g,0.28mmol)和三乙胺(0.11g,1.12mmol)溶于无水二氯甲烷(3mL)中，0℃下缓慢滴加3-氯苯甲酰氯(0.069g,0.39mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.093g(98.6％ee)，收率77.5％。MS(ESI)m/z:438.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ9.02(d,J＝7.4Hz,1H),8.84(d,J＝7.1Hz,1H),8.29-8.13(m,1H),7.78(d,J＝8.2Hz,1H),7.59-7.56(m,5H),7.27-7.23(m,2H),5.20-5.07(m,1H),3.99(t,J＝8.1Hz,2H),3.07(t,J＝8.3Hz,2H),1.47(d,J＝6.8Hz,3H). 23I (0.084g, 0.28mmol) and triethylamine (0.11g, 1.12mmol) were dissolved in anhydrous dichloromethane (3mL), and 3-chlorobenzoyl chloride (0.069g, 0.39mmol) was slowly added dropwise at 0°C ) solution in anhydrous dichloromethane (2mL), react at room temperature for 3h, concentrate under reduced pressure, add 30mL of water, extract with dichloromethane (3×20mL), combine the organic phases, wash with saturated brine, dry over anhydrous magnesium sulfate, and extract Filter, concentrate under reduced pressure, and separate and purify by column chromatography to obtain 0.093 g (98.6% ee) of a white solid, with a yield of 77.5%. MS (ESI) m/z: 438.1[MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ9.02 (d, J = 7.4Hz, 1H), 8.84 (d, J = 7.1Hz, 1H) ,8.29-8.13(m,1H),7.78(d,J＝8.2Hz,1H),7.59-7.56(m,5H),7.27-7.23(m,2H),5.20-5.07(m,1H),3.99 (t, J=8.1Hz, 2H), 3.07(t, J=8.3Hz, 2H), 1.47(d, J=6.8Hz, 3H).
实施例24：(R)-N-(1-(1-苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(24)合成Example 24: (R)-N-(1-(1-benzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-fluorobenzamide (24) synthesis
Figure PCTCN2022142154-appb-000046
Figure PCTCN2022142154-appb-000046
(R)-N-5-(1-(4-氟苯甲酰胺基)乙基)-2,3-二氢-1H-吲哚-1-羧酸苄酯(24H)合成Synthesis of (R)-N-5-(1-(4-fluorobenzamido)ethyl)-2,3-dihydro-1H-indole-1-carboxylic acid benzyl ester (24H)
将19G(0.70g,2.36mmol)和三乙胺(0.95g,9.44mmol)溶于10mL无水二氯甲烷中，0℃下缓慢滴加4-氟苯甲酰氯(0.52g,3.30mmol)的无水二氯甲烷(5mL)溶液，室温反应3h，减压浓缩，加入80mL水，二氯甲烷(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.73g，收率73.9％。MS(ESI)m/z:417.2[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ8.76(d,J＝7.8Hz,1H),8.00-7.91(m,2H),7.65(s,1H),7.42(d,J＝7.5Hz,3H),7.38-7.32(m,2H),7.31-7.22(m,3H),7.19(d,J＝7.8Hz,1H),5.24(s,2H),5.12(q,J＝7.2Hz,1H),4.01(t,J＝6.6Hz,2H),3.10(t,J＝8.4Hz,2H),1.46(d,J＝6.6Hz,3H). Dissolve 19G (0.70g, 2.36mmol) and triethylamine (0.95g, 9.44mmol) in 10mL of anhydrous dichloromethane, slowly add 4-fluorobenzoyl chloride (0.52g, 3.30mmol) dropwise at 0°C Anhydrous dichloromethane (5 mL) solution, reacted at room temperature for 3 h, concentrated under reduced pressure, added 80 mL of water, extracted with dichloromethane (3×30 mL), combined the organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and suction filtered. Concentrate under reduced pressure, separate and purify by column chromatography to obtain 0.73 g of white solid with a yield of 73.9%. MS (ESI) m/z: 417.2[MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ8.76 (d, J=7.8Hz, 1H), 8.00-7.91 (m, 2H), 7.65 ( s,1H),7.42(d,J=7.5Hz,3H),7.38-7.32(m,2H),7.31-7.22(m,3H),7.19(d,J=7.8Hz,1H),5.24(s ,2H),5.12(q,J=7.2Hz,1H),4.01(t,J=6.6Hz,2H),3.10(t,J=8.4Hz,2H),1.46(d,J=6.6Hz,3H ).
(R)-N-(1-(2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺氢溴酸盐(24I)合成Synthesis of (R)-N-(1-(2,3-dihydro-1H-indol-5-yl)ethyl)-4-fluorobenzamide hydrobromide (24I)
将24H(0.15g,0.36mmol)和33％HBr的乙酸溶液(6mL)加入50mL圆底烧瓶中，室温反应2h，减压浓缩，加水(3mL)，饱和NaHCO 3溶液调节pH至8，乙酸乙酯(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩得棕色油状物0.10g，收率100％。MS(ESI)m/z:283.1[M-H] -.(R)-N-(1-(1-(苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(24)合成 Add 24H (0.15g, 0.36mmol) and 33% HBr in acetic acid solution (6mL) into a 50mL round bottom flask, react at room temperature for 2h, concentrate under reduced pressure, add water (3mL), adjust the pH to 8 with saturated NaHCO 3 solution, and diethyl acetate Esters (3×30 mL) were extracted, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and concentrated under reduced pressure to obtain 0.10 g of a brown oil, with a yield of 100%. MS(ESI) m/z:283.1[MH] - .(R)-N-(1-(1-(benzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl )-4-Fluorobenzamide (24) Synthesis
将24I(0.10g,0.35mmol)和三乙胺(0.14g,1.40mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加苯甲酰氯(0.069g,0.49mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入40mL水，二氯甲烷(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.12g(98.7％ee)，收率85.7％。MS(ESI)m/z:387.2[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ8.77(d,J＝7.8Hz,1H),7.97-7.93(m,3H),7.52(d,J＝8.7Hz,5H),7.38-7.08(m,4H),5.12(q,J＝7.2Hz,1H),3.98(t,J＝7.5Hz,2H),3.07(t,J＝8.1Hz,2H),1.46(d,J＝6.9Hz,3H). 24I (0.10g, 0.35mmol) and triethylamine (0.14g, 1.40mmol) were dissolved in 3mL of anhydrous dichloromethane, and a solution of benzoyl chloride (0.069g, 0.49mmol) in anhydrous dichloromethane was slowly added dropwise at 0°C. Chloromethane (2mL) solution, react at room temperature for 3h, concentrate under reduced pressure, add 40mL of water, extract with dichloromethane (3×30mL), combine the organic phases, wash with saturated brine, dry over anhydrous magnesium sulfate, filter with suction, and concentrate under reduced pressure , separated and purified by column chromatography to obtain 0.12 g (98.7% ee) of a white solid, with a yield of 85.7%. MS (ESI) m/z: 387.2[MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ8.77(d, J=7.8Hz, 1H), 7.97-7.93(m, 3H), 7.52( d, J=8.7Hz, 5H), 7.38-7.08(m, 4H), 5.12(q, J=7.2Hz, 1H), 3.98(t, J=7.5Hz, 2H), 3.07(t, J=8.1 Hz,2H),1.46(d,J=6.9Hz,3H).
实施例25：(R)-N-(1-(1-(2-氟苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(25)合成Example 25: (R)-N-(1-(1-(2-fluorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-fluorobenzoyl Amide (25) Synthesis
Figure PCTCN2022142154-appb-000047
Figure PCTCN2022142154-appb-000047
将24I(0.16g,0.56mmol)和三乙胺(0.17g,1.69mmol)溶于8mL无水二氯甲烷中，0℃下缓慢滴加2-氟苯甲酰氯(0.12g,0.73mmol)的无水二氯甲烷(4mL)溶液，室温反应3h，减压浓缩，加入50mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.21g(98.9％ee)，收率91.3％。MS(ESI)m/z:405.2[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ8.79(d,J＝7.8Hz,1H),8.11-7.87(m,3H),7.55(d,J＝7.2Hz,2H),7.45-7.13(m,6H),5.16-5.12(m,1H),3.83(t,J＝7.8Hz,2H),3.09(t,J＝8.1Hz,2H),1.47(d,J＝7.2Hz,3H). 24I (0.16g, 0.56mmol) and triethylamine (0.17g, 1.69mmol) were dissolved in 8mL of anhydrous dichloromethane, and 2-fluorobenzoyl chloride (0.12g, 0.73mmol) was slowly added dropwise at 0°C Anhydrous dichloromethane (4 mL) solution, reacted at room temperature for 3 h, concentrated under reduced pressure, added 50 mL of water, extracted with dichloromethane (3×20 mL), combined organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and suction filtered. It was concentrated under reduced pressure, separated and purified by column chromatography to obtain 0.21 g (98.9% ee) of a white solid, and the yield was 91.3%. MS (ESI) m/z: 405.2 [MH] - ; 1 H NMR (300 MHz, DMSO-d 6 ) δ8.79 (d, J = 7.8 Hz, 1 H), 8.11-7.87 (m, 3 H), 7.55 ( d,J=7.2Hz,2H),7.45-7.13(m,6H),5.16-5.12(m,1H),3.83(t,J=7.8Hz,2H),3.09(t,J=8.1Hz,2H ), 1.47(d, J=7.2Hz, 3H).
实施例26：(R)-N-(1-(1-(4-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(32)合成Example 26: (R)-N-(1-(1-(4-chlorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-fluorobenzoyl Amide (32) Synthesis
Figure PCTCN2022142154-appb-000048
Figure PCTCN2022142154-appb-000048
将24I(0.12g,0.42mmol)和三乙胺(0.13g,1.26mmol)溶于5mL无水二氯甲烷中，0℃下缓慢滴加4-氯苯甲酰氯(0.080g,0.50mmol)的无水二氯甲烷(3mL)溶液，室温反应5h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.16g(96.9％ee)，收率88.9％。MS(ESI)m/z:421.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ8.77(d,J＝7.8Hz,1H),7.98-7.94(m,3H),7.58(q,J＝8.1Hz,4H),7.37-7.15(m,4H),5.12(q,J＝5.7Hz,1H),3.98(t,J＝8.1Hz,2H),3.07(t,J＝8.1Hz,2H),1.46(d,J＝6.9Hz,3H). 24I (0.12g, 0.42mmol) and triethylamine (0.13g, 1.26mmol) were dissolved in 5mL of anhydrous dichloromethane, and 4-chlorobenzoyl chloride (0.080g, 0.50mmol) was slowly added dropwise at 0°C. Anhydrous dichloromethane (3 mL) solution, react at room temperature for 5 h, concentrate under reduced pressure, add 30 mL of water, extract with dichloromethane (3×20 mL), combine organic phases, wash with saturated brine, dry over anhydrous magnesium sulfate, and suction filter, It was concentrated under reduced pressure, separated and purified by column chromatography to obtain 0.16 g (96.9% ee) of a white solid, and the yield was 88.9%. MS (ESI) m/z: 421.1 [MH] - ; 1 H NMR (300 MHz, DMSO-d 6 ) δ8.77 (d, J = 7.8 Hz, 1 H), 7.98-7.94 (m, 3 H), 7.58 ( q,J=8.1Hz,4H),7.37-7.15(m,4H),5.12(q,J=5.7Hz,1H),3.98(t,J=8.1Hz,2H),3.07(t,J=8.1 Hz,2H),1.46(d,J=6.9Hz,3H).
实施例27：(R)-N-(1-(1-(3-溴苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(27)合成Example 27: (R)-N-(1-(1-(3-bromobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-fluorobenzoyl Amide (27) Synthesis
Figure PCTCN2022142154-appb-000049
Figure PCTCN2022142154-appb-000049
将24I(0.096g,0.34mmol)和三乙胺(0.10g,1.02mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加3-溴苯甲酰氯(0.097g,0.44mmol)的无水二氯甲烷(3mL)溶液，室温反应4h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.14g(99.1％ee)，收率87.5％。MS(ESI)m/z:465.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ8.78(d,J＝7.5Hz,1H),8.17-7.84(m,3H),7.82-7.63(m,2H),7.58(d,J＝7.5Hz,1H),7.45(t,J＝7.8Hz,1H),7.35-6.99(m,4H),5.20-5.06(m,1H),3.98(t,J＝7.8Hz,2H),3.07(t,J＝8.1Hz,2H),1.46(d,J＝ 6.9Hz,3H). 24I (0.096g, 0.34mmol) and triethylamine (0.10g, 1.02mmol) were dissolved in 3mL of anhydrous dichloromethane, and 3-bromobenzoyl chloride (0.097g, 0.44mmol) was slowly added dropwise at 0°C. Anhydrous dichloromethane (3 mL) solution, reacted at room temperature for 4 h, concentrated under reduced pressure, added 30 mL of water, extracted with dichloromethane (3×20 mL), combined the organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and suction filtered. It was concentrated under reduced pressure, separated and purified by column chromatography to obtain 0.14 g (99.1% ee) of a white solid, and the yield was 87.5%. MS (ESI) m/z: 465.1[MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ8.78 (d, J=7.5Hz, 1H), 8.17-7.84 (m, 3H), 7.82- 7.63(m,2H),7.58(d,J=7.5Hz,1H),7.45(t,J=7.8Hz,1H),7.35-6.99(m,4H),5.20-5.06(m,1H),3.98 (t, J=7.8Hz, 2H), 3.07(t, J=8.1Hz, 2H), 1.46(d, J=6.9Hz, 3H).
实施例28：(R)-N-(1-(1-(3-氯-2-氟苯甲酰基)-2,3-二氢-1H-5-基)乙基)-4-氟苯甲酰胺(28)合成Example 28: (R)-N-(1-(1-(3-chloro-2-fluorobenzoyl)-2,3-dihydro-1H-5-yl)ethyl)-4-fluorobenzene Synthesis of formamide (28)
Figure PCTCN2022142154-appb-000050
Figure PCTCN2022142154-appb-000050
将24I(0.097g,0.34mmol)和三乙胺(0.10g,1.02mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加3-氯-2-氟苯甲酰氯(0.097g,0.44mmol)的无水二氯甲烷(3mL)溶液，室温反应5h，减压浓缩，加入40mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.12g(98.7％ee)，收率80.0％。MS(ESI)m/z:439.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ8.80(d,J＝8.1Hz,1H),8.08-7.90(m,3H),7.73(t,J＝7.8Hz,1H),7.53(d,J＝6.6Hz,1H),7.42-7.18(m,5H),5.15(q,J＝7.2Hz,1H),3.84(t,J＝7.8Hz,3H),3.11(d,J＝8.4Hz,2H),1.47(d,J＝7.2Hz,3H). 24I (0.097g, 0.34mmol) and triethylamine (0.10g, 1.02mmol) were dissolved in 3mL of anhydrous dichloromethane, and 3-chloro-2-fluorobenzoyl chloride (0.097g, 0.44 mmol) in anhydrous dichloromethane (3 mL), react at room temperature for 5 h, concentrate under reduced pressure, add 40 mL of water, extract with dichloromethane (3×20 mL), combine organic phases, wash with saturated brine, and dry over anhydrous magnesium sulfate , filtered with suction, concentrated under reduced pressure, separated and purified by column chromatography to obtain 0.12 g (98.7% ee) of a white solid, with a yield of 80.0%. MS (ESI) m/z: 439.1 [MH] - ; 1 H NMR (300 MHz, DMSO-d 6 ) δ8.80 (d, J = 8.1 Hz, 1 H), 8.08-7.90 (m, 3 H), 7.73 ( t, J=7.8Hz, 1H), 7.53(d, J=6.6Hz, 1H), 7.42-7.18(m, 5H), 5.15(q, J=7.2Hz, 1H), 3.84(t, J=7.8 Hz, 3H), 3.11(d, J=8.4Hz, 2H), 1.47(d, J=7.2Hz, 3H).
实施例29：(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-5-基)乙基)-4-氯-2-氟苯甲酰胺(29)合成Example 29: (R)-N-(1-(1-(3-chlorobenzoyl)-2,3-dihydro-1H-5-yl)ethyl)-4-chloro-2-fluorobenzene Synthesis of formamide (29)
Figure PCTCN2022142154-appb-000051
Figure PCTCN2022142154-appb-000051
(R)-N-5-(1-(4-氯-2-氟苯甲酰胺基)乙基)-2,3-二氢-1H-吲哚-1-羧酸苄酯(29H)合成Synthesis of (R)-N-5-(1-(4-chloro-2-fluorobenzamido)ethyl)-2,3-dihydro-1H-indole-1-carboxylic acid benzyl ester (29H)
将19G(0.20g,0.67mmol)和三乙胺(0.27g,2.68mmol)溶于8mL无水二氯甲烷中，0℃下缓慢滴加4-氯-2-氟苯甲酰氯(0.16g,0.80mmol)的无水二氯甲烷(3mL)溶液，室温反应3h，减压浓缩，加入50mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.27g，收率93.1％。MS(ESI)m/z:451.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ8.77(d,J＝7.8Hz,1H),7.63-7.50(m,3H),7.44-7.38(m,6H),7.27-7.13(m,2H),5.24(s,2H),5.05(q,J＝7.5Hz,1H),4.01(t,J＝8.1Hz,2H),3.09(t,J＝8.7Hz,2H),1.41(d,J＝7.2Hz,3H). 19G (0.20g, 0.67mmol) and triethylamine (0.27g, 2.68mmol) were dissolved in 8mL of anhydrous dichloromethane, and 4-chloro-2-fluorobenzoyl chloride (0.16g, 0.80 mmol) in anhydrous dichloromethane (3 mL), react at room temperature for 3 h, concentrate under reduced pressure, add 50 mL of water, extract with dichloromethane (3×20 mL), combine the organic phases, wash with saturated brine, and dry over anhydrous magnesium sulfate , filtered with suction, concentrated under reduced pressure, and separated and purified by column chromatography to obtain 0.27 g of white solid with a yield of 93.1%. MS (ESI) m/z: 451.1[MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ8.77 (d, J=7.8Hz, 1H), 7.63-7.50 (m, 3H), 7.44- 7.38(m,6H),7.27-7.13(m,2H),5.24(s,2H),5.05(q,J=7.5Hz,1H),4.01(t,J=8.1Hz,2H),3.09(t ,J=8.7Hz,2H),1.41(d,J=7.2Hz,3H).
(R)-N-(1-(2,3-二氢-1H-吲哚-5-基)乙基)-4-氯-2-氟苯甲酰胺氢溴酸盐(29I)合成Synthesis of (R)-N-(1-(2,3-dihydro-1H-indol-5-yl)ethyl)-4-chloro-2-fluorobenzamide hydrobromide (29I)
将29H(0.093g,0.21mmol)和33％HBr的乙酸溶液(3mL)加入圆底烧瓶中，室温反应2h，减压浓缩，加水(5mL)，饱和NaHCO 3溶液调节pH至8，乙酸乙酯(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩后得棕色固体0.067g，收率100％。MS(ESI)m/z:317.1[M-H] -. Add 29H (0.093g, 0.21mmol) and 33% HBr in acetic acid solution (3mL) into a round bottom flask, react at room temperature for 2h, concentrate under reduced pressure, add water (5mL), adjust the pH to 8 with saturated NaHCO 3 solution, ethyl acetate (3×20 mL) extraction, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, concentrated under reduced pressure to obtain 0.067 g of brown solid, yield 100%. MS(ESI)m/z:317.1[MH] - .
(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯-2-氟苯甲酰胺(29)合成(R)-N-(1-(1-(3-chlorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-chloro-2-fluorobenzoyl Amide (29) Synthesis
将29I(0.067g,0.21mmol)和三乙胺(0.085g,0.84mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加3-氯苯甲酰氯(0.048g,0.27mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入20mL水，二氯甲烷(3×10mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.089g(98.0％ee)，收率92.7％。MS(ESI)m/z:455.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ8.81(d,J＝7.8Hz,1H),8.14-7.05(m,10H),5.17-5.00(m,1H),4.00(t,J＝8.1Hz,2H),3.09(t,J＝8.1Hz,2H),1.42(d,J＝6.9Hz,3H). 29I (0.067g, 0.21mmol) and triethylamine (0.085g, 0.84mmol) were dissolved in 3mL of anhydrous dichloromethane, and 3-chlorobenzoyl chloride (0.048g, 0.27mmol) was slowly added dropwise at 0°C Anhydrous dichloromethane (2 mL) solution, reacted at room temperature for 3 h, concentrated under reduced pressure, added 20 mL of water, extracted with dichloromethane (3×10 mL), combined organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and suction filtered. Concentrate under reduced pressure, separate and purify by column chromatography to obtain 0.089 g (98.0% ee) of white solid, yield 92.7%. MS (ESI) m/z: 455.1[MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ8.81 (d, J=7.8Hz, 1H), 8.14-7.05 (m, 10H), 5.17- 5.00(m,1H),4.00(t,J=8.1Hz,2H),3.09(t,J=8.1Hz,2H),1.42(d,J=6.9Hz,3H).
实施例30：(R)-N-(1-(1-(3-氯-2-氟苯甲酰基)-2,3-二氢-1H-5-基)乙基)-4-氯-2-氟苯甲酰胺(30)合成Example 30: (R)-N-(1-(1-(3-chloro-2-fluorobenzoyl)-2,3-dihydro-1H-5-yl)ethyl)-4-chloro- Synthesis of 2-fluorobenzamide (30)
Figure PCTCN2022142154-appb-000052
Figure PCTCN2022142154-appb-000052
将29I(0.080g,0.25mmol)和三乙胺(0.10g,1.00mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加3-氯-2-氟苯甲酰氯(0.063g,0.33mmol)的无水二氯甲烷(3mL)溶液，室温反应5h，减压浓缩，加入40mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.097g(98.3％ee)，收率80.8％。MS(ESI)m/z:473.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ8.83(d,J＝7.5Hz,1H),8.07(d,J＝8.1Hz,1H),7.74(t,J＝7.8Hz,1H),7.58-7.51(m,3H),7.41-7.25(m,4H),5.15-5.03(m,1H),3.86(t,J＝8.1Hz,2H),3.12(t,J＝8.1Hz,2H),1.43(d,J＝6.3Hz,3H). 29I (0.080g, 0.25mmol) and triethylamine (0.10g, 1.00mmol) were dissolved in 3mL of anhydrous dichloromethane, and 3-chloro-2-fluorobenzoyl chloride (0.063g, 0.33mmol) in anhydrous dichloromethane (3mL), react at room temperature for 5h, concentrate under reduced pressure, add 40mL of water, extract with dichloromethane (3×20mL), combine the organic phases, wash with saturated brine, and dry over anhydrous magnesium sulfate , filtered with suction, concentrated under reduced pressure, separated and purified by column chromatography to obtain 0.097 g (98.3% ee) of a white solid, with a yield of 80.8%. MS(ESI) m/z: 473.1[MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ8.83(d, J=7.5Hz, 1H), 8.07(d, J=8.1Hz, 1H) ,7.74(t,J=7.8Hz,1H),7.58-7.51(m,3H),7.41-7.25(m,4H),5.15-5.03(m,1H),3.86(t,J=8.1Hz,2H ), 3.12(t, J=8.1Hz, 2H), 1.43(d, J=6.3Hz, 3H).
实施例31：(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-5-基)乙基)-4-溴苯甲酰胺(31)合成Example 31: (R)-N-(1-(1-(3-chlorobenzoyl)-2,3-dihydro-1H-5-yl)ethyl)-4-bromobenzamide (31 )synthesis
Figure PCTCN2022142154-appb-000053
Figure PCTCN2022142154-appb-000053
(R)-N-5-(1-(4-溴苯甲酰胺基)乙基)-2,3-二氢-1H-吲哚-1-羧酸苄酯(31H)合成Synthesis of (R)-N-5-(1-(4-bromobenzamido)ethyl)-2,3-dihydro-1H-indole-1-carboxylic acid benzyl ester (31H)
将19G(0.15g,0.51mmol)和三乙胺(0.15g,1.53mmol)溶于6mL无水二氯甲烷中，0℃下缓慢滴加4-溴苯甲酰氯(0.17g,0.77mmol)的无水二氯甲烷(3mL)溶液，室温反应3h，减压浓缩，加入40mL水，二氯甲烷(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.21g，收率87.5％。MS(ESI)m/z:477.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ8.80(d,J＝8.1Hz,1H),7.91-7.66(m,7H),7.44-7.34(m,3H),7.24(s,1H),7.17(d,J＝7.5Hz,1H),5.23(s,2H),5.15-5.00(m,1H),3.99(t,J＝8.7Hz,2H),3.10(t,J＝8.1Hz,2H),1.44(d,J＝6.9Hz,3H). Dissolve 19G (0.15g, 0.51mmol) and triethylamine (0.15g, 1.53mmol) in 6mL of anhydrous dichloromethane, slowly add 4-bromobenzoyl chloride (0.17g, 0.77mmol) dropwise at 0°C Anhydrous dichloromethane (3 mL) solution, reacted at room temperature for 3 h, concentrated under reduced pressure, added 40 mL of water, extracted with dichloromethane (3×30 mL), combined organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, and suction filtered. Concentrate under reduced pressure, and separate and purify by column chromatography to obtain 0.21 g of white solid with a yield of 87.5%. MS (ESI) m/z: 477.1[MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ8.80 (d, J=8.1Hz, 1H), 7.91-7.66 (m, 7H), 7.44- 7.34(m,3H),7.24(s,1H),7.17(d,J=7.5Hz,1H),5.23(s,2H),5.15-5.00(m,1H),3.99(t,J=8.7Hz ,2H),3.10(t,J=8.1Hz,2H),1.44(d,J=6.9Hz,3H).
(R)-N-(1-(2,3-二氢-1H-吲哚-5-基)乙基)-4-溴苯甲酰胺氢溴酸盐(31I)合成Synthesis of (R)-N-(1-(2,3-dihydro-1H-indol-5-yl)ethyl)-4-bromobenzamide hydrobromide (31I)
将31H(0.10g,0.21mmol)和33％HBr的乙酸溶液(5mL)加入圆底烧瓶中，室温反应3h，减压浓缩，饱和NaHCO 3溶液调节pH至8，乙酸乙酯(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩后得棕色油状物0.072g，收率100％。MS(ESI)m/z:343.1[M-H] -. Add 31H (0.10g, 0.21mmol) and 33% HBr in acetic acid solution (5mL) into a round bottom flask, react at room temperature for 3h, concentrate under reduced pressure, adjust the pH to 8 with saturated NaHCO 3 solution, ethyl acetate (3×20mL) Extract, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter with suction, and concentrate under reduced pressure to obtain 0.072 g of a brown oil, with a yield of 100%. MS(ESI)m/z:343.1[MH] - .
(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-溴苯甲酰胺(31)合成(R)-N-(1-(1-(3-chlorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-bromobenzamide (31) synthesis
将31I(0.072g,0.21mmol)和三乙胺(0.064g,0.63mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加苯甲酰氯(0.051g,0.29mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.096g(98.4％ee)，收率95％。MS(ESI)m/z:481.0[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ8.84(d,J＝7.8Hz,1H),8.12-7.77(m,3H),7.75-7.42(m,6H),7.28-7.23(m,2H),5.15-5.11(m,1H),4.00(t,J＝7.8Hz,2H),3.08(t,J＝8.1Hz,2H),1.46(d,J＝5.7Hz,3H). Dissolve 31I (0.072g, 0.21mmol) and triethylamine (0.064g, 0.63mmol) in 3mL of anhydrous dichloromethane, slowly add benzoyl chloride (0.051g, 0.29mmol) in anhydrous dichloromethane at 0°C Chloromethane (2mL) solution, react at room temperature for 3h, concentrate under reduced pressure, add 30mL of water, extract with dichloromethane (3×20mL), combine organic phases, wash with saturated brine, dry over anhydrous magnesium sulfate, suction filter, and concentrate under reduced pressure , separated and purified by column chromatography to obtain 0.096 g (98.4% ee) of a white solid, with a yield of 95%. MS (ESI) m/z: 481.0[MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ8.84 (d, J=7.8Hz, 1H), 8.12-7.77 (m, 3H), 7.75- 7.42(m,6H),7.28-7.23(m,2H),5.15-5.11(m,1H),4.00(t,J=7.8Hz,2H),3.08(t,J=8.1Hz,2H),1.46 (d,J=5.7Hz,3H).
实施例32：(S)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(32)合成Example 32: (S)-N-(1-(1-(3-chlorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-chlorobenzoyl Amide (32) Synthesis
Figure PCTCN2022142154-appb-000054
Figure PCTCN2022142154-appb-000054
(S,E)-5-(1-((叔丁基亚磺酰基)亚氨基)乙基)-2,3-二氢-1H-吲哚-1-羧酸苄酯(32E)合成Synthesis of (S,E)-5-(1-((tert-butylsulfinyl)imino)ethyl)-2,3-dihydro-1H-indole-1-carboxylic acid benzyl ester (32E)
向19D(0.70g,2.37mmol)的无水四氢呋喃(10mL)溶液中加入(S)-(+)-叔丁基亚磺酰胺(0.43g,3.55mmol)和钛酸乙酯(1.08g,4.73mmol)，在氮气氛围下85℃回流12h。向反应液中加入100mL水，80mL乙酸乙酯，剧烈搅拌15min，抽滤，乙酸乙酯(10mL)洗涤滤饼，滤液减压浓缩，乙酸乙酯(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，柱层析分离纯化，得黄色固体0.69g，收率73.4％。MS(ESI)m/z:397.2[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ7.80(s,3H),7.41-7.35(m,5H),5.30(s,2H),4.06(t,J＝6.6Hz,2H),3.16(t,J＝8.4Hz,2H),2.67(s,3H),1.21(s,9H). To a solution of 19D (0.70 g, 2.37 mmol) in anhydrous tetrahydrofuran (10 mL) was added (S)-(+)-tert-butylsulfinamide (0.43 g, 3.55 mmol) and ethyl titanate (1.08 g, 4.73 mmol), refluxed at 85° C. for 12 h under nitrogen atmosphere. Add 100 mL of water and 80 mL of ethyl acetate to the reaction solution, stir vigorously for 15 min, filter with suction, wash the filter cake with ethyl acetate (10 mL), concentrate the filtrate under reduced pressure, extract with ethyl acetate (3×30 mL), combine the organic phases, and saturate Wash with brine, dry over anhydrous sodium sulfate, filter with suction, concentrate under reduced pressure, and separate and purify by column chromatography to obtain 0.69 g of a yellow solid with a yield of 73.4%. MS(ESI)m/z:397.2[MH] - ; 1 H NMR(300MHz,DMSO-d 6 )δ7.80(s,3H),7.41-7.35(m,5H),5.30(s,2H), 4.06(t, J=6.6Hz, 2H), 3.16(t, J=8.4Hz, 2H), 2.67(s, 3H), 1.21(s, 9H).
(S)-5-(1-((S)-叔丁基亚磺酰胺基)乙基)-2,3-二氢-1H-吲哚-1-羧酸苄酯(32F)合成Synthesis of (S)-5-(1-((S)-tert-butylsulfinamido)ethyl)-2,3-dihydro-1H-indole-1-carboxylic acid benzyl ester (32F)
取
Figure PCTCN2022142154-appb-000055
分子筛(0.69g)于100mL圆底烧瓶中，加入10mL异丙醇，2-甲基-2-氨基-1-丙醇(7.8mg,0.087mmol)和二氯双(4-甲基异丙基苯基)钌(Ⅱ)(27.10mg,0.044mmol)，回流5min，冷却至55℃，加入32E(0.69g,1.73mmol)及叔丁醇钾(23.83g,0.21mmol)，55℃下反应12h，冷却，加入15mL二氯甲烷稀释，抽滤，硅藻土助滤，21mL二氯甲烷：甲醇混合溶液(20:1,V/V)洗涤滤饼，滤液减压浓缩，二氯甲烷(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，柱层析分离纯化，得油状液体0.52g，收率75.4％。MS(ESI)m/z:399.2[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ7.65(s,1H),7.38(dd,J＝18.8,7.0Hz,5H),7.25(s,1H),7.16(d,J＝8.1Hz,1H),5.50(d,J＝6.6Hz,1H),5.23(s,2H),4.29(q,J＝6.6Hz,1H),4.02(t,J＝8.4Hz,2H),3.09(t,J＝8.7Hz,2H),1.36(d,J＝6.6Hz,3H),1.10(s,9H). Pick
Figure PCTCN2022142154-appb-000055
Molecular sieves (0.69g) In a 100mL round bottom flask, add 10mL of isopropanol, 2-methyl-2-amino-1-propanol (7.8mg, 0.087mmol) and dichlorobis(4-methylisopropyl Phenyl)ruthenium (Ⅱ) (27.10mg, 0.044mmol), reflux for 5min, cool to 55°C, add 32E (0.69g, 1.73mmol) and potassium tert-butoxide (23.83g, 0.21mmol), react at 55°C for 12h , cooled, added 15mL dichloromethane for dilution, suction filtration, diatomaceous earth filter aid, 21mL dichloromethane:methanol mixed solution (20:1, V/V) washed the filter cake, the filtrate was concentrated under reduced pressure, dichloromethane (3 × 30 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, concentrated under reduced pressure, separated and purified by column chromatography to obtain 0.52 g of oily liquid, with a yield of 75.4%. MS (ESI) m/z: 399.2 [MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ7.65 (s, 1H), 7.38 (dd, J = 18.8, 7.0Hz, 5H), 7.25 ( s,1H),7.16(d,J=8.1Hz,1H),5.50(d,J=6.6Hz,1H),5.23(s,2H),4.29(q,J=6.6Hz,1H),4.02( t, J=8.4Hz, 2H), 3.09(t, J=8.7Hz, 2H), 1.36(d, J=6.6Hz, 3H), 1.10(s, 9H).
(S)-5-(1-氨基乙基)-2,3-二氢-1H-吲哚-1-羧酸苄酯(32G)合成Synthesis of (S)-5-(1-aminoethyl)-2,3-dihydro-1H-indole-1-carboxylic acid benzyl ester (32G)
将原料32F(0.52g,1.30mmol)溶于无水甲醇(1.0mL)中，加入盐酸二氧六环溶液(1.7M,10mL)，室温反应3h，减压浓缩，加水(10mL)，饱和NaHCO 3溶液调节pH至8，乙酸乙酯(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，得黄色油状液体0.38g，收率100％。MS(ESI)m/z:295.2[M-H] -. Dissolve raw material 32F (0.52g, 1.30mmol) in anhydrous methanol (1.0mL), add dioxane hydrochloride solution (1.7M, 10mL), react at room temperature for 3h, concentrate under reduced pressure, add water (10mL), and saturate with NaHCO 3. Adjust the pH of the solution to 8, extract with ethyl acetate (3×30 mL), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter with suction, and concentrate under reduced pressure to obtain 0.38 g of a yellow oily liquid with a yield of 100%. . MS(ESI)m/z:295.2[MH] - .
(S)-N-5-(1-(4-氯苯甲酰胺基)乙基)-2,3-二氢-1H-吲哚-1-羧酸苄酯(32H)合成Synthesis of (S)-N-5-(1-(4-chlorobenzamido)ethyl)-2,3-dihydro-1H-indole-1-carboxylic acid benzyl ester (32H)
将32G(0.15g,0.51mmol)和三乙胺(0.26g,2.55mmol)溶于无水二氯甲烷(3mL)中，0℃下缓慢滴加4-氯苯甲酰氯(0.12g,0.77mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.20g，收率90.9％。MS(ESI)m/z:433.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ8.81(d,J＝8.1Hz,1H),8.03-7.86(m,3H),7.60-7.50(m,3H),7.41(d,J＝8.1Hz,4H),7.25-7.21(m,2H),5.23(s,2H),5.12(q,J＝7.5Hz,1H),4.02(t,J＝9.6Hz,2H),3.09(t,J＝6.9Hz,2H),1.45(d,J＝6.6Hz,3H). 32G (0.15g, 0.51mmol) and triethylamine (0.26g, 2.55mmol) were dissolved in anhydrous dichloromethane (3mL), and 4-chlorobenzoyl chloride (0.12g, 0.77mmol) was slowly added dropwise at 0°C ) solution in anhydrous dichloromethane (2mL), react at room temperature for 3h, concentrate under reduced pressure, add 30mL of water, extract with dichloromethane (3×20mL), combine the organic phases, wash with saturated brine, dry over anhydrous magnesium sulfate, and extract Filter, concentrate under reduced pressure, and separate and purify by column chromatography to obtain 0.20 g of a white solid with a yield of 90.9%. MS (ESI) m/z: 433.1[MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ8.81 (d, J=8.1Hz, 1H), 8.03-7.86 (m, 3H), 7.60- 7.50(m,3H),7.41(d,J=8.1Hz,4H),7.25-7.21(m,2H),5.23(s,2H),5.12(q,J=7.5Hz,1H),4.02(t , J=9.6Hz, 2H), 3.09(t, J=6.9Hz, 2H), 1.45(d, J=6.6Hz, 3H).
(S)-N-(1-(2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺氢溴酸盐(32I)合成Synthesis of (S)-N-(1-(2,3-dihydro-1H-indol-5-yl)ethyl)-4-chlorobenzamide hydrobromide (32I)
将32H(0.13g,0.30mmol)和33％HBr的乙酸溶液(4mL)加入50mL圆底烧瓶中，室温反应3h，减压浓缩，加水(10mL)，饱和NaHCO 3溶液调节pH至8，乙酸乙酯(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，得棕色固体0.090g，收率100％。MS(ESI)m/z:299.1[M-H] -.(S)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(32)合成 Add 32H (0.13g, 0.30mmol) and 33% HBr in acetic acid solution (4mL) into a 50mL round bottom flask, react at room temperature for 3h, concentrate under reduced pressure, add water (10mL), adjust the pH to 8 with saturated NaHCO 3 solution, and diethyl acetate The ester (3×20 mL) was extracted, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.090 g of a brown solid with a yield of 100%. MS(ESI) m/z:299.1[MH] - .(S)-N-(1-(1-(3-chlorobenzoyl)-2,3-dihydro-1H-indol-5-yl ) ethyl) -4-chlorobenzamide (32) synthesis
将32I(0.090g,0.30mmol)和三乙胺(0.12g,1.20mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加3-氯苯甲酰氯(0.068g,0.39mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加水(30mL)， 二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.12g(96.8％ee)，收率92.3％。MS(ESI)m/z:437.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ8.83(d,J＝8.1Hz,1H),7.90(d,J＝8.4Hz,3H),7.75-7.49(m,6H),7.36-7.07(m,2H),5.22-5.05(m,1H),3.99(t,J＝8.4Hz,2H),3.07(t,J＝8.1Hz,2H),1.46(d,J＝6.6Hz,3H). 32I (0.090g, 0.30mmol) and triethylamine (0.12g, 1.20mmol) were dissolved in 3mL of anhydrous dichloromethane, and 3-chlorobenzoyl chloride (0.068g, 0.39mmol) was slowly added dropwise at 0°C. Anhydrous dichloromethane (2mL) solution, react at room temperature for 3h, concentrate under reduced pressure, add water (30mL), extract with dichloromethane (3×20mL), combine organic phases, wash with saturated brine, dry over anhydrous magnesium sulfate, and filter with suction , concentrated under reduced pressure, and separated and purified by column chromatography to obtain 0.12 g (96.8% ee) of a white solid, with a yield of 92.3%. MS (ESI) m/z: 437.1[MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ8.83 (d, J = 8.1Hz, 1H), 7.90 (d, J = 8.4Hz, 3H) ,7.75-7.49(m,6H),7.36-7.07(m,2H),5.22-5.05(m,1H),3.99(t,J＝8.4Hz,2H),3.07(t,J＝8.1Hz,2H ), 1.46(d, J=6.6Hz, 3H).
实施例33：(R)-N-(1-(1-(2-氯吡啶-4-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-6-氯吡啶-3-甲酰胺(33)合成Example 33: (R)-N-(1-(1-(2-chloropyridine-4-formyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-6- Synthesis of Chloropyridine-3-Carboxamide (33)
Figure PCTCN2022142154-appb-000056
Figure PCTCN2022142154-appb-000056
将23I(0.12g,0.40mmol)和三乙胺(0.16g,1.60mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加2-氯吡啶-4-甲酰氯(0.11g,0.60mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.16g(98.9％ee)，收率88.9％。MS(ESI)m/z:439.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ9.06-9.03(m,1H),8.87-8.84(m,1H),8.57(t,J＝4.5Hz,1H),8.17-8.14(m,2H),7.85-7.58(m,3H),7.34-7.31(m,2H),5.22-5.07(m,1H),3.98-3.94(m,2H),3.17-3.02(m,2H),1.48(d,J＝6.6Hz,3H). 23I (0.12g, 0.40mmol) and triethylamine (0.16g, 1.60mmol) were dissolved in 3mL of anhydrous dichloromethane, and 2-chloropyridine-4-formyl chloride (0.11g, 0.60 mmol) in anhydrous dichloromethane (2 mL), react at room temperature for 3 h, concentrate under reduced pressure, add 30 mL of water, extract with dichloromethane (3×20 mL), combine the organic phases, wash with saturated brine, and dry over anhydrous magnesium sulfate. Suction filtration, concentration under reduced pressure, separation and purification by column chromatography yielded 0.16 g (98.9% ee) of a white solid with a yield of 88.9%. MS (ESI) m/z: 439.1 [MH] - ; 1 H NMR (300 MHz, DMSO-d 6 ) δ9.06-9.03 (m, 1H), 8.87-8.84 (m, 1H), 8.57 (t, J ＝4.5Hz,1H),8.17-8.14(m,2H),7.85-7.58(m,3H),7.34-7.31(m,2H),5.22-5.07(m,1H),3.98-3.94(m,2H ),3.17-3.02(m,2H),1.48(d,J＝6.6Hz,3H).
实施例34：(R)-N-(1-(1-(3-氯-2-甲基苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(34)合成Example 34: (R)-N-(1-(1-(3-chloro-2-methylbenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)- Synthesis of 4-chlorobenzamide (34)
Figure PCTCN2022142154-appb-000057
Figure PCTCN2022142154-appb-000057
将19I(0.072g,0.24mmol)和三乙胺(0.073g,0.72mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加3-氯-2-甲基苯甲酰氯(0.054g,0.29mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.089g(97.9％ee)，收率80.9％。MS(ESI)m/z:451.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ8.86(d,J＝7.8Hz,1H),8.10(d,J＝8.1Hz,1H),7.90(d,J＝8.4Hz,2H),7.66-7.51(m,3H),7.40-7.21(m,4H),5.20-5.06(m,1H),4.28-4.10(m,2H),3.11-3.03(m,2H),2.27(s,3H),1.47(d,J＝6.9Hz,3H). 19I (0.072g, 0.24mmol) and triethylamine (0.073g, 0.72mmol) were dissolved in 3mL of anhydrous dichloromethane, and 3-chloro-2-methylbenzoyl chloride (0.054g ,0.29mmol) in anhydrous dichloromethane (2mL), react at room temperature for 3h, concentrate under reduced pressure, add 30mL of water, extract with dichloromethane (3×20mL), combine the organic phases, wash with saturated brine, and anhydrous magnesium sulfate Dry, filter with suction, concentrate under reduced pressure, and separate and purify by column chromatography to obtain 0.089 g (97.9% ee) of a white solid, with a yield of 80.9%. MS(ESI) m/z: 451.1[MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ8.86(d, J=7.8Hz, 1H), 8.10(d, J=8.1Hz, 1H) ,7.90(d,J＝8.4Hz,2H),7.66-7.51(m,3H),7.40-7.21(m,4H),5.20-5.06(m,1H),4.28-4.10(m,2H),3.11 -3.03(m,2H),2.27(s,3H),1.47(d,J＝6.9Hz,3H).
实施例35：(R)-N-(1-(1-(5-氯-2-甲基苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(35)合成Example 35: (R)-N-(1-(1-(5-chloro-2-methylbenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)- Synthesis of 4-chlorobenzamide (35)
Figure PCTCN2022142154-appb-000058
Figure PCTCN2022142154-appb-000058
将19I(0.072g,0.24mmol)和三乙胺(0.073g,0.72mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加5-氯-2-甲基苯甲酰氯(0.054g,0.29mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.093g(98.9％ee)，收率84.5％。MS(ESI)m/z:451.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ8.86(d,J＝7.8Hz,1H),8.09(d,J＝8.1Hz,1H),7.91(d,J＝8.1Hz,2H),7.55(d,J＝8.1Hz,2H),7.46-7.22(m,5H),5.20-5.08(m,1H),3.77-3.66(m,2H),3.14-3.03(m,2H),2.24(s,3H),1.47(d,J＝6.6Hz,3H). 19I (0.072g, 0.24mmol) and triethylamine (0.073g, 0.72mmol) were dissolved in 3mL of anhydrous dichloromethane, and 5-chloro-2-methylbenzoyl chloride (0.054g ,0.29mmol) in anhydrous dichloromethane (2mL), react at room temperature for 3h, concentrate under reduced pressure, add 30mL of water, extract with dichloromethane (3×20mL), combine the organic phases, wash with saturated brine, and anhydrous magnesium sulfate Dry, filter with suction, concentrate under reduced pressure, and separate and purify by column chromatography to obtain 0.093 g (98.9% ee) of a white solid, with a yield of 84.5%. MS(ESI) m/z: 451.1[MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ8.86(d, J=7.8Hz, 1H), 8.09(d, J=8.1Hz, 1H) ,7.91(d,J=8.1Hz,2H),7.55(d,J=8.1Hz,2H),7.46-7.22(m,5H),5.20-5.08(m,1H),3.77-3.66(m,2H ),3.14-3.03(m,2H),2.24(s,3H),1.47(d,J＝6.6Hz,3H).
实施例36：(R)-N-(1-(1-(3-甲氧基苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(36)合成Example 36: (R)-N-(1-(1-(3-methoxybenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-chloro Synthesis of benzamide (36)
Figure PCTCN2022142154-appb-000059
Figure PCTCN2022142154-appb-000059
将19I(0.10g,0.33mmol)和三乙胺(0.10g,0.99mmol)溶于5mL无水二氯甲烷中，0℃下缓慢滴加3-甲氧基苯甲酰氯(0.068g,0.40mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.13g(97.9％ee)，收率92.9％。MS(ESI)m/z:433.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ8.85(d,J＝9.9Hz,1H),8.08-7.82(m,3H),7.54(d,J＝8.4Hz,2H),7.39(d,J＝6.9Hz,1H),7.33-6.91(m,5H),5.17-5.06(m,1H),4.07-3.92(m,2H),3.80(s,3H),3.12-2.99(m,2H),1.46(d,J＝7.5Hz,3H). 19I (0.10g, 0.33mmol) and triethylamine (0.10g, 0.99mmol) were dissolved in 5mL of anhydrous dichloromethane, and 3-methoxybenzoyl chloride (0.068g, 0.40mmol) was slowly added dropwise at 0°C ) solution in anhydrous dichloromethane (2mL), react at room temperature for 3h, concentrate under reduced pressure, add 30mL of water, extract with dichloromethane (3×20mL), combine the organic phases, wash with saturated brine, dry over anhydrous magnesium sulfate, and extract Filter, concentrate under reduced pressure, and separate and purify by column chromatography to obtain 0.13 g (97.9% ee) of a white solid, with a yield of 92.9%. MS (ESI) m/z: 433.1 [MH] - ; 1 H NMR (300 MHz, DMSO-d 6 ) δ8.85 (d, J = 9.9 Hz, 1 H), 8.08-7.82 (m, 3 H), 7.54 ( d,J=8.4Hz,2H),7.39(d,J=6.9Hz,1H),7.33-6.91(m,5H),5.17-5.06(m,1H),4.07-3.92(m,2H),3.80 (s,3H),3.12-2.99(m,2H),1.46(d,J=7.5Hz,3H).
实施例37：(R)-N-(1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-吲哚-5-基)乙基)-6-氟吡啶-3-甲酰胺(37)合成Example 37: (R)-N-(1-(1-(4,4-difluorocyclohexane-1-carbonyl)-2,3-dihydro-1H-indol-indol-5-yl ) ethyl)-6-fluoropyridine-3-carboxamide (37) synthesis
Figure PCTCN2022142154-appb-000060
Figure PCTCN2022142154-appb-000060
(R)-N-5-(1-(6-氟吡啶-3-甲酰胺基)乙基)-2,3-二氢-1H-吲哚-1-羧酸苄酯(37H)合成Synthesis of (R)-N-5-(1-(6-fluoropyridine-3-carboxamido)ethyl)-2,3-dihydro-1H-indole-1-carboxylic acid benzyl ester (37H)
将19G(0.17g,0.57mmol)和N,N-二异丙基乙胺(0.30g,2.29mmol)溶于4mL无水二氯甲烷，0℃下缓慢滴加6-氟吡啶-3-甲酰氯(0.11g,0.69mmol)的无水二氯甲烷(3mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.21g，收率87.5％。MS(ESI)m/z:418.2[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ8.96(d,J＝7.8Hz,1H),8.80-8.69(m,1H),8.47-8.36(m,1H),7.66(s,1H),7.50-7.12(m,8H),5.23(s,2H),5.11(q,J＝7.5Hz,1H),4.00(t,J＝7.5Hz,2H),3.09(t,J＝8.7Hz,2H),1.46(d,J＝6.9Hz,3H). Dissolve 19G (0.17g, 0.57mmol) and N,N-diisopropylethylamine (0.30g, 2.29mmol) in 4mL of anhydrous dichloromethane, slowly add 6-fluoropyridine-3-methanol dropwise at 0°C Acyl chloride (0.11g, 0.69mmol) in anhydrous dichloromethane (3mL) solution, reacted at room temperature for 3h, concentrated under reduced pressure, added 30mL of water, extracted with dichloromethane (3×20mL), combined the organic phases, washed with saturated brine, Dry over anhydrous magnesium sulfate, filter with suction, concentrate under reduced pressure, and separate and purify by column chromatography to obtain 0.21 g of white solid with a yield of 87.5%. MS (ESI) m/z: 418.2[MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ8.96 (d, J=7.8Hz, 1H), 8.80-8.69 (m, 1H), 8.47- 8.36(m,1H),7.66(s,1H),7.50-7.12(m,8H),5.23(s,2H),5.11(q,J=7.5Hz,1H),4.00(t,J=7.5Hz ,2H),3.09(t,J=8.7Hz,2H),1.46(d,J=6.9Hz,3H).
(R)-N-(1-(2,3-二氢-1H-吲哚-5-基)乙基)-6-氟吡啶-3-甲酰胺氢溴酸盐(37I)合成Synthesis of (R)-N-(1-(2,3-dihydro-1H-indol-5-yl)ethyl)-6-fluoropyridine-3-carboxamide hydrobromide (37I)
将37H(0.11g,0.26mmol)和33％HBr的乙酸溶液(5mL)加入50mL圆底烧瓶中，室温反应3h，减压浓缩，加水(3mL)，饱和NaHCO 3溶液调节pH至8，乙酸乙酯(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，得棕色油状物0.075g，收率100％。MS(ESI)m/z:284.1[M-H] -. Add 37H (0.11g, 0.26mmol) and 33% HBr in acetic acid solution (5mL) into a 50mL round bottom flask, react at room temperature for 3h, concentrate under reduced pressure, add water (3mL), adjust the pH to 8 with saturated NaHCO 3 solution, and diethyl acetate The ester (3×20 mL) was extracted, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and concentrated under reduced pressure to obtain 0.075 g of a brown oil, with a yield of 100%. MS(ESI)m/z:284.1[MH] - .
(R)-N-(1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-吲哚-5-基)乙基)-6-氟吡啶-3-甲酰胺(37)合成(R)-N-(1-(1-(4,4-difluorocyclohexane-1-carbonyl)-2,3-dihydro-1H-indol-indol-5-yl)ethyl) Synthesis of -6-fluoropyridine-3-carboxamide (37)
将37I(0.075g,0.26mmol)和N,N-二异丙基乙胺(0.14g,1.05mmol)溶于无水二氯甲烷(3mL)中，0℃下缓慢滴加4,4-二氟环己甲酰氯(0.072g,0.39mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入20mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.089g(97.3％ee)，收率80.9％。MS(ESI)m/z:430.2[M-H] -； 1H NMR(300MHz,Chloroform-d)δ8.61(s,1H),8.30-8.17(m,2H),7.30-7.20(m,2H),6.99(d,J＝8.4Hz,1H),6.61(d,J＝6.3Hz,1H),5.38-5.20(m,1H),4.15(t,J＝7.8Hz,2H),3.23(d,J＝6.6Hz,2H),3.19-2.97(m,1H),2.58-2.49(m,1H),2.29-2.24(m,1H),1.98-1.90(m,5H),1.60(d,J＝6.9Hz,3H),0.96-0.82(m,1H). 37I (0.075g, 0.26mmol) and N,N-diisopropylethylamine (0.14g, 1.05mmol) were dissolved in anhydrous dichloromethane (3mL), and 4,4-bis Fluorocyclohexyl chloride (0.072g, 0.39mmol) in anhydrous dichloromethane (2mL) solution, reacted at room temperature for 3h, concentrated under reduced pressure, added 20mL of water, extracted with dichloromethane (3×20mL), combined the organic phases, saturated Wash with brine, dry over anhydrous magnesium sulfate, filter with suction, concentrate under reduced pressure, and separate and purify by column chromatography to obtain 0.089 g (97.3% ee) of white solid with a yield of 80.9%. MS(ESI)m/z:430.2[MH] - ; 1 H NMR(300MHz,Chloroform-d)δ8.61(s,1H),8.30-8.17(m,2H),7.30-7.20(m,2H) ,6.99(d,J=8.4Hz,1H),6.61(d,J=6.3Hz,1H),5.38-5.20(m,1H),4.15(t,J=7.8Hz,2H),3.23(d, J=6.6Hz,2H),3.19-2.97(m,1H),2.58-2.49(m,1H),2.29-2.24(m,1H),1.98-1.90(m,5H),1.60(d,J= 6.9Hz,3H),0.96-0.82(m,1H).
实施例38：(R)-N-(1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-吲哚-5-基)乙基)-6-氯吡啶-3-甲酰胺(38)合成Example 38: (R)-N-(1-(1-(4,4-difluorocyclohexane-1-carbonyl)-2,3-dihydro-1H-indol-indol-5-yl ) ethyl) -6-chloropyridine-3-carboxamide (38) synthesis
Figure PCTCN2022142154-appb-000061
Figure PCTCN2022142154-appb-000061
将23I(0.079g,0.26mmol)和N,N-二异丙基乙胺(0.14g,1.05mmol)溶于无水二氯甲烷(2mL)中，0℃下缓慢滴加4,4-二氟环己甲酰氯(0.057g,0.31mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入20mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.092g(96.8％ee)，收率76.7％。MS(ESI)m/z:446.1[M-H] -； 1H NMR(300MHz,DMSO-d 6)δ9.01(d,J＝7.8Hz,1H),8.84(d,J＝7.5Hz,1H),8.33-8.12(m,1H),7.96(d,J＝8.1Hz,1H),7.81-7.61(m,1H),7.31-7.13(m,2H),5.11(q,J＝7.5Hz,1H),4.07(t,J＝8.1Hz,2H),3.12(t,J＝8.4Hz,2H),3.00-2.56(m,1H),2.50-2.45(m,1H),2.36-1.89(m,4H),1.46(d,J＝6.6Hz,3H),1.42-1.03(m,2H),0.93-0.72(m,1H). 23I (0.079g, 0.26mmol) and N,N-diisopropylethylamine (0.14g, 1.05mmol) were dissolved in anhydrous dichloromethane (2mL), and 4,4-bis Fluorocyclohexyl chloride (0.057g, 0.31mmol) in anhydrous dichloromethane (2mL) solution, reacted at room temperature for 3h, concentrated under reduced pressure, added 20mL of water, extracted with dichloromethane (3×20mL), combined the organic phases, saturated Washed with brine, dried over anhydrous magnesium sulfate, filtered with suction, concentrated under reduced pressure, separated and purified by column chromatography to obtain 0.092 g (96.8% ee) of white solid, yield 76.7%. MS (ESI) m/z: 446.1[MH] - ; 1 H NMR (300MHz, DMSO-d 6 ) δ9.01 (d, J = 7.8Hz, 1H), 8.84 (d, J = 7.5Hz, 1H) ,8.33-8.12(m,1H),7.96(d,J=8.1Hz,1H),7.81-7.61(m,1H),7.31-7.13(m,2H),5.11(q,J=7.5Hz,1H ), 4.07(t, J＝8.1Hz, 2H), 3.12(t, J＝8.4Hz, 2H), 3.00-2.56(m, 1H), 2.50-2.45(m, 1H), 2.36-1.89(m, 4H), 1.46(d, J=6.6Hz, 3H), 1.42-1.03(m, 2H), 0.93-0.72(m, 1H).
实施例39：基于HeLa细胞的IDO1抑制活性测试Example 39: HeLa cell-based IDO1 inhibitory activity test
1、实验材料和主要仪器1. Experimental materials and main instruments
HeLa细胞株：ATCC，离心机：Eppendorf(CHINA)，电热恒温鼓风干燥箱(DHG-924385-Ⅲ)：上海新苗医疗器械制造有限公司，乙酸(冰醋酸)：南京化学试剂股份有限公司，三氟乙酸：上海凌峰化学试剂有限公司，电子天平：Sartorius，对二甲氨基苯甲醛(CAS：100-10-7)：Aladdin，Recombinant Human IFN-γ(Catalog#AF-300-02)：PEPROTECH。HeLa cell line: ATCC, centrifuge: Eppendorf (CHINA), electric constant temperature blast drying oven (DHG-924385-Ⅲ): Shanghai Xinmiao Medical Instrument Manufacturing Co., Ltd., acetic acid (glacial acetic acid): Nanjing Chemical Reagent Co., Ltd., Trifluoroacetic acid: Shanghai Lingfeng Chemical Reagent Co., Ltd., electronic balance: Sartorius, p-dimethylaminobenzaldehyde (CAS: 100-10-7): Aladdin, Recombinant Human IFN-γ (Catalog#AF-300-02): PEPROTECH.
2、实验方法2. Experimental method
从ATCC购买的HeLa细胞保存在最低基础培养基(2mM L-谷氨酰胺和调成含有1.5g/L碳酸氢钠、0.1mM非必需氨基酸、1mM丙铜酸钠和10％胎牛血清的Earle氏BSS)中。在37℃下将HeLa细胞保存在提供5％CO 2的控湿培养箱中。实验设置空白组、模型组组(IFN-γ+L-色氨酸)和加药组(IFN-γ+L-色氨酸+受试化合物)。按5×10 3细胞/孔的密度将HeLa细胞接种在96孔培养板中，并培养过夜。第二天，含有IFN-γ(终浓度100ng/mL)、L-色氨酸(终浓度100μM)和化合物的系列稀释液(总体积200μL培养基)加给细胞。温育24h后将140μL上清液/孔移至新的96孔板中，加入10μL 6.1mol/L的三氯乙酸，在恒温烘箱中50℃温育30min以使产生的N-甲酰基犬尿氨酸水解为犬尿氨酸。然后以4000rpm将反应混合物离心10min以去除沉淀物。将100μL上清液/孔移至另一96孔板中，与等体积2％(w/v)对-二甲氨基苯甲醛的乙酸溶液混合。使用酶标仪在490nm处检测吸光值，所得结果利用GraphPad Prism软件处理。每个浓度设3个复孔，实验重复三次。 HeLa cells purchased from ATCC were stored in minimal basal medium (2 mM L-glutamine and Earle's supplemented with 1.5 g/L sodium bicarbonate, 0.1 mM non-essential amino acids, 1 mM sodium propupuprate, and 10% fetal calf serum). 's BSS). Store HeLa cells at 37 °C in a humidity-controlled incubator supplied with 5% CO2 . The experiment set up blank group, model group (IFN-γ+L-tryptophan) and drug-dosed group (IFN-γ+L-tryptophan+test compound). HeLa cells were seeded in 96-well culture plates at a density of 5×10 3 cells/well and cultured overnight. The next day, serial dilutions (total volume 200 μL of medium) containing IFN-γ (final concentration 100 ng/mL), L-tryptophan (final concentration 100 μM) and compound were added to the cells. After incubation for 24 hours, transfer 140 μL of supernatant/well to a new 96-well plate, add 10 μL of 6.1 mol/L trichloroacetic acid, and incubate in a constant temperature oven at 50°C for 30 minutes to make the N-formyl kynuria produced Amino acid is hydrolyzed to kynurenine. The reaction mixture was then centrifuged at 4000 rpm for 10 min to remove the precipitate. 100 μL of supernatant/well was transferred to another 96-well plate, and mixed with an equal volume of 2% (w/v) p-dimethylaminobenzaldehyde in acetic acid solution. The absorbance was detected at 490 nm using a microplate reader, and the obtained results were processed using GraphPad Prism software. Three replicate wells were set up for each concentration, and the experiment was repeated three times.
IDO1酶活抑制率(％)＝[(模型组-加药组)/(模型组-空白组)]×100％IDO1 enzyme activity inhibition rate (%)=[(model group-dosing group)/(model group-blank group)]×100%
此外，采用MTT法检测各组HeLa细胞的存活率，目的是为了考察化合物是否是通过抑制HeLa细胞的增殖来抑制IDO1的活性。In addition, the survival rate of HeLa cells in each group was detected by MTT method, in order to investigate whether the compound inhibited the activity of IDO1 by inhibiting the proliferation of HeLa cells.
具体操作：在基于HeLa细胞的IDO1抑制活性的实验中，每孔吸取140μL上清液加至96孔板中，每孔加入20μL，4mg/mL MTT溶液，放入细胞培养箱，于37℃孵育4h，终止培养，离心后吸去孔内培养液。每孔加入200μL二甲基亚砜，置摇床上低速振荡10min，使结晶物充分溶解。在酶联免疫检测仪570nm处测量各孔的吸光值。Specific operation: In the experiment based on the IDO1 inhibitory activity of HeLa cells, pipette 140 μL of supernatant per well and add it to a 96-well plate, add 20 μL of 4 mg/mL MTT solution to each well, put it in a cell culture incubator, and incubate at 37°C After 4 hours, the culture was terminated, and the culture medium in the well was aspirated after centrifugation. Add 200 μL of dimethyl sulfoxide to each well, shake on a shaker at low speed for 10 minutes, and fully dissolve the crystals. The absorbance of each well was measured at 570 nm in an enzyme-linked immunosorbent assay.
细胞存活率(％)＝加药组OD值/空白组OD值×100％Cell viability (%) = OD value of drug-dosing group/OD value of blank group × 100%
3、实验结果3. Experimental results
按公式计算受试化合物的抑制率，IC 50由百分抑制率和对数浓度值作图求得，分析结果见表1。指示为“A”的值表示对IDO1的抑制活性(IC 50)介于1×10 -3nM与1×10 -1nM之间，指示为“B”的值表示IC 50介于1×10 -1nM与1nM之间。 The inhibition rate of the test compound was calculated according to the formula, and the IC 50 was obtained by plotting the percentage inhibition rate and the logarithmic concentration value. The analysis results are shown in Table 1. The value indicated as "A" indicates the inhibitory activity (IC 50 ) on IDO1 between 1×10 -3 nM and 1×10 -1 nM, and the value indicated as "B" indicates the IC 50 between 1×10 Between -1 nM and 1 nM.
表1本发明化合物对HeLa细胞增殖和IDO1活性的影响Table 1 Compounds of the present invention have an effect on HeLa cell proliferation and IDO1 activity
Figure PCTCN2022142154-appb-000062
Figure PCTCN2022142154-appb-000062
Figure PCTCN2022142154-appb-000063
Figure PCTCN2022142154-appb-000063
a表示在1μM浓度下HeLa细胞的存活率； bLY-3381916为阳性对照化合物。 a represents the survival rate of HeLa cells at a concentration of 1 μM; b LY-3381916 is a positive control compound.
如表1所示，本发明的化合物对HeLa细胞的IDO1均有显著的抑制作用，所有化合物的IC 50值均达到纳摩尔级别，而且其活性均优于阳性对照组LY-3381916；其中，化合物2、7～8、11、13的IC 50值甚至小于10pM。此外，MTT检测结果表明，各组HeLa细胞在检测浓度下的存活率均保持在90％以上，表明这些化合物并不是通过抑制HeLa细胞的增殖来抑制IDO1活性，而是通过激活宿主免疫应答来发挥抗肿瘤活性。 As shown in Table 1, the compounds of the present invention have a significant inhibitory effect on IDO1 of HeLa cells, and the IC50 values of all compounds have reached the nanomolar level, and their activity is better than that of the positive control group LY-3381916; 2. The IC 50 values of 7-8, 11 and 13 were even less than 10pM. In addition, the MTT test results showed that the survival rate of HeLa cells in each group remained above 90% at the tested concentration, indicating that these compounds did not inhibit the IDO1 activity by inhibiting the proliferation of HeLa cells, but by activating the host immune response. Antitumor activity.

Claims (10)

  1. 一种吲哚啉化合物及其衍生物，其特征在于，具有式(I)的结构，所述衍生物为所述吲哚啉化合物的立体异构体、互变异构体、代谢产物、代谢前体、前药、溶剂化物、溶剂化物的盐、结晶、药学上可接受的盐或它们的混合物：An indoline compound and its derivatives are characterized in that they have a structure of formula (I), and the derivatives are stereoisomers, tautomers, metabolites, and metabolites of the indoline compound. Precursors, prodrugs, solvates, salts of solvates, crystals, pharmaceutically acceptable salts or mixtures thereof:
    Figure PCTCN2022142154-appb-100001
    Figure PCTCN2022142154-appb-100001
    其中：in:
    X为-C(O)NH-、-S(O) 2NH-或-CH 2C(O)NH-； X is -C(O)NH-, -S(O) 2 NH- or -CH 2 C(O)NH-;
    R为氢、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷氨基或C 3-C 8环烷基； R is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino or C 3 -C 8 cycloalkyl;
    Figure PCTCN2022142154-appb-100002
    为C 3-C 8环烷基、芳基或杂芳基，所述杂芳基含有一个或多个O、S或N原子，所述芳基或杂芳基被一个或多个D基团取代；
    Figure PCTCN2022142154-appb-100002
    is C 3 -C 8 cycloalkyl, aryl or heteroaryl, the heteroaryl contains one or more O, S or N atoms, the aryl or heteroaryl is surrounded by one or more D groups replace;
    所述D基团为氢、卤素、氰基、羟基、巯基、羧基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷氨基或者为被一个或多个卤素取代的C 1-C 6烷基、C 1-C 6烷氧基或C 1-C 6烷氨基； The D group is hydrogen, halogen, cyano, hydroxyl, mercapto, carboxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino or is replaced by one or more Halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 alkylamino;
    Figure PCTCN2022142154-appb-100003
    为芳基、杂芳基或C 3-C 8环烷基，所述C 3-C 8环烷基被一个或多个E基团取代，所述芳基或杂芳基被一个或多个F基团取代；
    Figure PCTCN2022142154-appb-100003
    is aryl, heteroaryl or C 3 -C 8 cycloalkyl, said C 3 -C 8 cycloalkyl is substituted by one or more E groups, said aryl or heteroaryl is substituted by one or more F group substitution;
    所述E基团为氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷氨基或者为被一个或多个卤素取代的C 1-C 6烷基、C 1-C 6烷氧基或C 1-C 6烷氨基； The E group is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino or C 1 -C 6 alkane substituted by one or more halogens Group, C 1 -C 6 alkoxy or C 1 -C 6 alkylamino;
    所述F基团为氢、卤素、氰基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷氨基或者为被一个或多个卤素取代的C 1-C 6烷基、C 1-C 6烷氧基或C 1-C 6烷氨基。 The F group is hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino or C 1 - C 6 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 alkylamino.
  2. 根据权利要求1所述的吲哚啉化合物及其衍生物，其特征在于，所述吲哚啉化合物及其衍生物结构中：Indoline compounds and derivatives thereof according to claim 1, characterized in that, in the structure of said indoline compounds and derivatives thereof:
    X为-C(O)NH-；X is -C(O)NH-;
    R为C 1-C 6烷基； R is C 1 -C 6 alkyl;
    Figure PCTCN2022142154-appb-100004
    为C 3-C 8环烷基、芳基或杂芳基，所述杂芳基含有一个或多个O、S或N原子，所述芳基或杂芳基被一个或多个D基团取代；
    Figure PCTCN2022142154-appb-100004
    is C 3 -C 8 cycloalkyl, aryl or heteroaryl, the heteroaryl contains one or more O, S or N atoms, the aryl or heteroaryl is surrounded by one or more D groups replace;
    所述D基团为氢、卤素、氰基、羟基、巯基、羧基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷氨基或者为被一个或多个卤素取代的C 1-C 6烷基、C 1-C 6烷氧基或C 1-C 6烷氨基； The D group is hydrogen, halogen, cyano, hydroxyl, mercapto, carboxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino or is replaced by one or more Halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 alkylamino;
    Figure PCTCN2022142154-appb-100005
    为芳基、杂芳基或C 3-C 8环烷基，所述C 3-C 8环烷基被一个或多个E基团取代，所述芳基或杂芳基被一个或多个F基团取代；
    Figure PCTCN2022142154-appb-100005
    is aryl, heteroaryl or C 3 -C 8 cycloalkyl, said C 3 -C 8 cycloalkyl is substituted by one or more E groups, said aryl or heteroaryl is substituted by one or more F group substitution;
    所述E基团为氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷氨基或者为被一个或多个卤素取代的C 1-C 6烷基、C 1-C 6烷氧基或C 1-C 6烷氨基； The E group is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino or C 1 -C 6 alkane substituted by one or more halogens Group, C 1 -C 6 alkoxy or C 1 -C 6 alkylamino;
    所述F基团为氢、卤素、氰基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷氨基或者为被一个或多个卤素取代的C 1-C 6烷基、C 1-C 6烷氧基或C 1-C 6烷氨基。 The F group is hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino or C 1 - C 6 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 alkylamino.
  3. 根据权利要求1或2所述的吲哚啉化合物及其衍生物，其特征在于，所述吲哚啉化合物及其衍生物结构中：The indoline compound and derivative thereof according to claim 1 or 2, characterized in that, in the structure of the indoline compound and derivative thereof:
    R为甲基；R is methyl;
    E基团为氢、卤素或C 1-C 6烷基； E group is hydrogen, halogen or C 1 -C 6 alkyl;
    F基团为氢、卤素、氰基或C 1-C 6烷氧基。 The F group is hydrogen, halogen, cyano or C 1 -C 6 alkoxy.
  4. 根据权利要求1或2所述的吲哚啉化合物及其衍生物，其特征在于，所述吲哚啉化合物及其衍生物 结构中：Indoline compounds and derivatives thereof according to claim 1 and 2, characterized in that, in the structure of said indoline compounds and derivatives thereof:
    Figure PCTCN2022142154-appb-100006
    为苯基或吡啶基，所述苯基或吡啶基含有一个或多个D基团取代基；
    Figure PCTCN2022142154-appb-100006
    is phenyl or pyridyl, and the phenyl or pyridyl contains one or more D group substituents;
    所述D基团为氟、氯、溴或氰基；The D group is fluorine, chlorine, bromine or cyano;
    Figure PCTCN2022142154-appb-100007
    为苯基、吡啶基或环己基，所述环己基被一个或多个E基团取代，所述苯基或吡啶基被一个或多个F基团取代；
    Figure PCTCN2022142154-appb-100007
    is phenyl, pyridyl or cyclohexyl, the cyclohexyl is substituted by one or more E groups, and the phenyl or pyridyl is substituted by one or more F groups;
    所述E基团为氢、卤素或甲基；The E group is hydrogen, halogen or methyl;
    所述F基团为氢、卤素、氰基或甲氧基。The F group is hydrogen, halogen, cyano or methoxy.
  5. 根据权利要求1或2所述的吲哚啉化合物及其衍生物，其特征在于，所述吲哚啉化合物为以下任一化合物：The indoline compound and derivatives thereof according to claim 1 or 2, wherein the indoline compound is any of the following compounds:
    (R)-N-(1-(1-(环己基羰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(1)，(R)-N-(1-(1-(cyclohexylcarbonyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-fluorobenzamide (1),
    (R)-N-(1-(1-(环己基羰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(2)，(R)-N-(1-(1-(cyclohexylcarbonyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-chlorobenzamide (2),
    (R)-N-(1-(1-(环己基羰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氰基苯甲酰胺(3)，(R)-N-(1-(1-(cyclohexylcarbonyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-cyanobenzamide (3),
    (R)-N-(1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(4)，(R)-N-(1-(1-(4,4-difluorocyclohexane-1-carbonyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4- Fluorobenzamide (4),
    (R)-N-(1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(5)，(R)-N-(1-(1-(4,4-difluorocyclohexane-1-carbonyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4- Chlorobenzamide (5),
    (R)-N-(1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氰基苯甲酰胺(6)，(R)-N-(1-(1-(4,4-difluorocyclohexane-1-carbonyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4- Cyanobenzamide (6),
    (R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(7)，(R)-N-(1-(1-(3-chlorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-fluorobenzamide (7) ,
    (R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(8)，(R)-N-(1-(1-(3-chlorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-chlorobenzamide (8) ,
    (R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-2-氯苯甲酰胺(9)，(R)-N-(1-(1-(3-chlorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-2-chlorobenzamide (9) ,
    (R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-3-氯苯甲酰胺(10)，(R)-N-(1-(1-(3-chlorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-3-chlorobenzamide (10) ,
    (R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氰基苯甲酰胺(11)，(R)-N-(1-(1-(3-chlorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-cyanobenzamide (11 ),
    (R)-N-(1-(1-(3-氟苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(12)，(R)-N-(1-(1-(3-fluorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-fluorobenzamide (12) ,
    (R)-N-(1-(1-(3-氟苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(13)，(R)-N-(1-(1-(3-fluorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-chlorobenzamide (13) ,
    (R)-N-(1-(1-(3-氟苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氰基苯甲酰胺(14)，(R)-N-(1-(1-(3-fluorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-cyanobenzamide (14 ),
    (R)-N-(1-(1-(3-氰基苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(15)，(R)-N-(1-(1-(3-cyanobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-fluorobenzamide (15 ),
    (R)-N-(1-(1-(3-氰基苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(16)，(R)-N-(1-(1-(3-cyanobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-chlorobenzamide (16 ),
    (R)-N-(1-(1-(2-氯吡啶-4-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(17)，(R)-N-(1-(1-(2-chloropyridine-4-formyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-fluorobenzamide (17),
    (R)-N-(1-(1-(2-氯吡啶-4-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(18)，(R)-N-(1-(1-(2-chloropyridine-4-formyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-chlorobenzamide (18),
    (R)-N-(1-(1-(4-氯吡啶-2-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(19)，(R)-N-(1-(1-(4-chloropyridine-2-formyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-chlorobenzamide (19),
    (R)-N-(1-(1-(6-氯吡啶-2-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(20)，(R)-N-(1-(1-(6-chloropyridine-2-formyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-chlorobenzamide (20),
    (R)-N-(1-(1-(5-氯吡啶-3-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(21)，(R)-N-(1-(1-(5-chloropyridine-3-formyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-chlorobenzamide (twenty one),
    (R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-5-氯吡啶-2-甲酰胺(22)，(R)-N-(1-(1-(3-chlorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-5-chloropyridine-2-carboxamide (twenty two),
    (R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-6-氯吡啶-3-甲酰胺(23)，(R)-N-(1-(1-(3-chlorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-6-chloropyridine-3-carboxamide (twenty three),
    (R)-N-(1-(1-苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(24)，(R)-N-(1-(1-benzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-fluorobenzamide (24),
    (R)-N-(1-(1-(2-氟苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(25)，(R)-N-(1-(1-(2-fluorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-fluorobenzamide (25) ,
    (R)-N-(1-(1-(4-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(26)，(R)-N-(1-(1-(4-chlorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-fluorobenzamide (26) ,
    (R)-N-(1-(1-(3-溴苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(27)，(R)-N-(1-(1-(3-bromobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-fluorobenzamide (27) ,
    (R)-N-(1-(1-(3-氯-2-氟苯甲酰基)-2,3-二氢-1H-5-基)乙基)-4-氟苯甲酰胺(28)，(R)-N-(1-(1-(3-chloro-2-fluorobenzoyl)-2,3-dihydro-1H-5-yl)ethyl)-4-fluorobenzamide (28 ),
    (R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-5-基)乙基)-4-氯-2-氟苯甲酰胺(29)，(R)-N-(1-(1-(3-chlorobenzoyl)-2,3-dihydro-1H-5-yl)ethyl)-4-chloro-2-fluorobenzamide (29 ),
    (R)-N-(1-(1-(3-氯-2-氟苯甲酰基)-2,3-二氢-1H-5-基)乙基)-4-氯-2-氟苯甲酰胺(30)，(R)-N-(1-(1-(3-chloro-2-fluorobenzoyl)-2,3-dihydro-1H-5-yl)ethyl)-4-chloro-2-fluorobenzene Formamide (30),
    (R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-5-基)乙基)-4-溴苯甲酰胺(31)，(R)-N-(1-(1-(3-chlorobenzoyl)-2,3-dihydro-1H-5-yl)ethyl)-4-bromobenzamide (31),
    (S)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(32)，(S)-N-(1-(1-(3-chlorobenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-chlorobenzamide (32) ,
    (R)-N-(1-(1-(2-氯吡啶-4-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-6-氯吡啶-3-甲酰胺(33)，(R)-N-(1-(1-(2-chloropyridine-4-formyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-6-chloropyridine-3 - Formamide (33),
    (R)-N-(1-(1-(3-氯-2-甲基苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(34)，(R)-N-(1-(1-(3-chloro-2-methylbenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-chlorobenzene Formamide (34),
    (R)-N-(1-(1-(5-氯-2-甲基苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(35)，(R)-N-(1-(1-(5-chloro-2-methylbenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-chlorobenzene Formamide (35),
    (R)-N-(1-(1-(3-甲氧基苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(36)，(R)-N-(1-(1-(3-methoxybenzoyl)-2,3-dihydro-1H-indol-5-yl)ethyl)-4-chlorobenzamide ( 36),
    (R)-N-(1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-吲哚-5-基)乙基)-6-氟吡啶-3-甲酰胺(37)，(R)-N-(1-(1-(4,4-difluorocyclohexane-1-carbonyl)-2,3-dihydro-1H-indol-indol-5-yl)ethyl) -6-fluoropyridine-3-carboxamide (37),
    (R)-N-(1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-吲哚-5-基)乙基)-6-氯吡啶-3-甲酰胺(38)。(R)-N-(1-(1-(4,4-difluorocyclohexane-1-carbonyl)-2,3-dihydro-1H-indol-indol-5-yl)ethyl) -6-Chloropyridine-3-carboxamide (38).
  6. 根据权利要求1或2所述的吲哚啉化合物，其特征在于，所述药学上可接受的盐为所述吲哚啉化合物与酸形成的盐，所述酸为盐酸、氢溴酸、硫酸、磷酸、碳酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸。The indoline compound according to claim 1 or 2, wherein the pharmaceutically acceptable salt is a salt formed by the indoline compound and an acid, and the acid is hydrochloric acid, hydrobromic acid, sulfuric acid , phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid acid, phenylacetic acid, or mandelic acid.
  7. 一种权利要求1～6任一所述的吲哚啉化合物的制备方法，其特征在于，所述制备方法为以下任一方法：A preparation method of the indoline compound described in any one of claims 1 to 6, characterized in that the preparation method is any of the following methods:
    方法一：method one:
    以2,3-二氢吲哚为原料，经酰化反应、傅-克酰基化反应、水解反应、酰化反应、缩合反应、还原反应、水解反应、酰化反应得到化合物(I)：Using 2,3-dihydroindole as raw material, compound (I) is obtained through acylation reaction, Friedel-Crafts acylation reaction, hydrolysis reaction, acylation reaction, condensation reaction, reduction reaction, hydrolysis reaction and acylation reaction:
    Figure PCTCN2022142154-appb-100008
    Figure PCTCN2022142154-appb-100008
    方法二：Method Two:
    以化合物C为原料，经酰化反应、缩合反应、还原反应、水解反应、酰化反应、水解反应、酰化反应得到化合物(Ⅰ)：Using compound C as a raw material, compound (I) is obtained through acylation reaction, condensation reaction, reduction reaction, hydrolysis reaction, acylation reaction, hydrolysis reaction, and acylation reaction:
    Figure PCTCN2022142154-appb-100009
    Figure PCTCN2022142154-appb-100009
    其中，
    Figure PCTCN2022142154-appb-100010
    X的定义如权利要求1～5任一所述；     in,
    Figure PCTCN2022142154-appb-100010
    The definition of X is as described in any one of claims 1 to 5;
    将相应的酸与以上方法制备的化合物(I)成盐完全，即得所述吲哚啉化合物的药学上可接受的盐。The corresponding acid is completely salted with the compound (I) prepared by the above method to obtain the pharmaceutically acceptable salt of the indoline compound.
  8. 一种药物组合物，其特征在于，所述药物组合物包含权利要求1～6任一所述吲哚啉化合物及其衍生物以及药学上可接受的载体。A pharmaceutical composition, characterized in that the pharmaceutical composition comprises the indoline compound and its derivatives described in any one of claims 1-6 and a pharmaceutically acceptable carrier.
  9. 一种权利要求1～6任一所述的吲哚啉化合物及其衍生物或者权利要求8所述的药物组合物在制备吲哚胺2,3-双加氧酶1抑制剂药物中的应用。An application of the indoline compound and its derivatives described in any one of claims 1 to 6 or the pharmaceutical composition described in claim 8 in the preparation of indoleamine 2,3-dioxygenase 1 inhibitor drugs .
  10. 根据权利要求9所述的应用，其特征在于，所述药物为治疗吲哚胺2,3-双加氧酶1介导的免疫抑制相关疾病的药物。The use according to claim 9, characterized in that the drug is a drug for treating diseases related to immunosuppression mediated by indoleamine 2,3-dioxygenase 1.
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