WO2019149131A1

WO2019149131A1 - Compound having macrocyclic molecular structure and use thereof

Info

Publication number: WO2019149131A1
Application number: PCT/CN2019/072950
Authority: WO
Inventors: 林菊芳; 应永铖; 廖敬礼; 张秀; 李宗然; 袁纪军; 贾伟; 汪伟
Original assignee: Shanghai Genbase Biotechnology Co Ltd
Current assignee: Shanghai Genbase Biotechnology Co Ltd
Priority date: 2018-01-30
Filing date: 2019-01-24
Publication date: 2019-08-08
Anticipated expiration: 2020-07-30
Also published as: TW201932472A; CN111511749A; CN111511749B

Abstract

The present disclosure relates to a compound represented by general formula (1), the compound being a small molecular kinase inhibitor having a macrocyclic molecular structure. The present disclosure also relates to a pharmaceutical composition comprising the compound and a therapeutic use thereof.

Description

Compound having macrocyclic molecular structure and use thereof

本申请是以CN申请号为201810088895.7，申请日为2018年1月30日的申请为基础，并主张其优先权，该CN申请的公开内容在此作为整体引入本申请中。The present application is based on the application of the CN application number 201810088895.7, filed on January 30, 2018, and the priority of which is hereby incorporated by reference.

Technical field

本公开属于医药化工领域，具体涉及一种化合物，该化合物是具有大环分子结构的小分子激酶抑制剂，还涉及包含该化合物的药物组合物以及该化合物的治疗用途。The present disclosure belongs to the field of medicinal chemistry, and in particular relates to a compound which is a small molecule kinase inhibitor having a macrocyclic molecular structure, a pharmaceutical composition comprising the compound, and a therapeutic use of the compound.

Background technique

复发性基因融合是驱动各种恶性肿瘤生长和存活的主要因素。融合基因的产生主要有三种情况：易位、中间缺失或染色体倒位。在结构上，这些融合体一般包含其上游基因以及完整的酪氨酸激酶域，能够在不依赖配体的作用下形成二聚体，启动并维持下游信号传导，导致肿瘤生长和增殖。基因融合突变分布于几乎所有的癌症类型。伴随NGS(next-generation sequencing)测序技术的发展，可检测的这些融合事件的数量大幅上升，肿瘤融合基因突变不仅在诊断和预后过程中起重要的指导作用，还逐渐成为一个有效的靶向药物研发对象。Recurrent gene fusion is a major factor driving the growth and survival of various malignancies. There are three main types of fusion genes: translocation, intermediate deletion or chromosomal inversion. Structurally, these fusions generally contain their upstream genes as well as intact tyrosine kinase domains that are capable of forming dimers independent of ligands, initiate and maintain downstream signaling, leading to tumor growth and proliferation. Gene fusion mutations are distributed in almost all cancer types. With the development of NGS (next-generation sequencing) sequencing technology, the number of detectable fusion events has increased dramatically. Tumor fusion gene mutations not only play an important role in the diagnosis and prognosis, but also become an effective targeted drug. Research and development objects.

原肌球蛋白受体激酶(tropomyosin receptor kinase,TRK)是调节哺乳动物神经系统中突触强度和可塑性的酪氨酸激酶家族，而NTRK(neurotrophic receptor tyrosine kinase)是编码TRK的基因。NTRK基因包括NTRK1、NTRK2、NTRK3，分别负责编码原肌球蛋白受体激酶家族蛋白TRKA、TRKB、TRKC。Trk受体通过与神经营养因子的结合可以诱导受体二聚化、磷酸化并激活下游PI3K、RAS/MAPK/ERK和PLC-γ的信号级联通路，与神经细胞的生长发育，痛觉感知等密切相关。在罕见情况下，NTRK基因还会与其它基因融合，导致TRK信号通路不受控制，因而促进肿瘤的生长，越来越多的研究表明TRK是治疗癌症的一个有潜力的靶点。虽然TRK融合非常罕见，但是它会在很多种成人和儿童罕见肿瘤中广泛出现。由于TRK受体在神经系统以及肿瘤细胞生长及存活中的重要作用，TRK抑制剂有望成为有效的治疗疼痛和癌症的药物。Tropomysin receptor kinase (TRK) is a family of tyrosine kinases that regulate synaptic strength and plasticity in the mammalian nervous system, while NTRK (neurotrophic receptor tyrosine kinase) is a gene encoding TRK. The NTRK gene includes NTRK1, NTRK2, and NTRK3, which are responsible for encoding the tropomyosin receptor kinase family proteins TRKA, TRKB, and TRKC, respectively. Trk receptors can induce receptor dimerization, phosphorylation and activation of downstream PI3K, RAS/MAPK/ERK and PLC-γ signaling cascades, and neural cell growth and development, pain perception, etc. through binding to neurotrophic factors. closely related. In rare cases, the NTRK gene is also fused to other genes, resulting in uncontrolled TRK signaling pathways, thus promoting tumor growth. More and more studies have shown that TRK is a potential target for the treatment of cancer. Although TRK fusion is very rare, it is widespread in a wide variety of rare tumors in adults and children. Due to the important role of TRK receptors in the nervous system and tumor cell growth and survival, TRK inhibitors are expected to be effective drugs for the treatment of pain and cancer.

目前NTRK抑制剂临床进展较快的是Loxo Oncology公司的Larotrectinib(LOXO-101)以及Ignyta公司的Entrectinib(RXDX-101)，二者在临床试验中均显示了较高的应答率，且Ignyta公司的Entrectinib有穿透血脑屏障的活性，可以对脑转移的肿瘤有积极作用。但与此同时，临床上也已经出现了针对NTRK小分子抑制剂的耐药突变，用来克服一代NTRK小分子抑制剂的耐药性的二代药物已经进入临床，包括Loxo Oncology公司的LOXO-195，以及TP Therapeutics公司的TPX-0005。At present, the rapid progress of NTRK inhibitors is Loxo Oncology's Larotrectinib (LOXO-101) and Ignyta's Entrectinib (RXDX-101), both of which show higher response rates in clinical trials, and Ignyta's Entrectinib has an activity that penetrates the blood-brain barrier and can have a positive effect on tumors that metastasize to the brain. At the same time, however, drug-resistant mutations against NTRK small molecule inhibitors have emerged in the clinic. The second-generation drugs used to overcome the resistance of a generation of NTRK small molecule inhibitors have entered the clinic, including Loxo Oncology's LOXO- 195, and TP Therapeutics' TPX-0005.

ALK最早是在间变性大细胞淋巴瘤(ALCL)的一个亚型中被发现的，因此定名为间变性淋巴瘤激酶(anaplasticlymphoma kinase，ALK)。随后，在发现非小细胞肺癌中有ALK基因重排之前，在弥漫性大B细胞淋巴瘤和炎症性肌纤维母细胞瘤(IMT)中分别发现了有多种类型的ALK基因重排，至此证明ALK是强力致癌驱动基因。ALK基因相关易位可见于约2-7％的非小细胞肺癌(NSCLC)，最常见的是EML4-ALK易位。重排导致自体磷酸化及ALK的持续活化，从而激活RAS和PI3K信号级联。RAS活化则可能导致肿瘤更具侵袭性特征、临床预后可能更差。ALK was first discovered in a subtype of anaplastic large cell lymphoma (ALCL), hence the name anaplasticlymphoma kinase (ALK). Subsequently, prior to the discovery of ALK gene rearrangement in non-small cell lung cancer, multiple types of ALK gene rearrangements were found in diffuse large B-cell lymphoma and inflammatory myofibroblastic tumor (IMT), respectively. ALK is a potent carcinogenic driver gene. ALK gene-associated translocations can be found in approximately 2-7% of non-small cell lung cancer (NSCLC), the most common being the EML4-ALK translocation. Rearrangement results in autophosphorylation and sustained activation of ALK, thereby activating the RAS and PI3K signaling cascades. RAS activation may result in more aggressive features of the tumor and a worse clinical outcome.

辉瑞的Crizotinib是最早获得FDA批准的ALK小分子抑制剂，后来诺华的Ceritinib，罗氏的Alectinib，以及最近获得加速审批的Ariad的Brigatinib均是在Crizotinib之后的二代，二线靶向药，可以有效克服Crizotinib的耐药性。最新刚刚获得突破性疗法的辉瑞的ALK抑制剂三代Lorlatinib的ALK激酶活性最高，能够较有效地克服一代和二代ALK抑制剂的耐药性。在临床上表现活跃还有贝达的Ensartinib，和TP Therapeutics的TPX-0005。Pfizer's Crizotinib was the first FDA-approved ALK small molecule inhibitor. Later, Novartis's Ceritinib, Roche's Alectinib, and recently approved Ariad's Brigatinib were the second generation of Crizotinib, a second-line targeted drug that can effectively overcome Resistance to Crizotinib. The latest ALK inhibitor of the Pfizer ALK inhibitor, which has just acquired breakthrough therapy, has the highest ALK kinase activity and can more effectively overcome the resistance of first- and second-generation ALK inhibitors. Also clinically active is Beida's Ensartinib, and TP Therapeutics' TPX-0005.

ROS1基因编码一种受体酪氨酸激酶(RTK)，与细胞的生长、增殖、存活、分化有关。ROS1基因可与多个基因发生融合突变，ROS1与其他基因发生融合时，一般会保留激酶结构域，而且在断裂点上较为保守。ROS1的重排导致激酶持续激活，上调SHP-1、SHP2以及PI3K、AKT、mTOR、MAPK和ERK信号通路，导致细胞持续增殖，肿瘤发生。ROS1基因的重排最开始是在人脑胶质瘤细胞系里被鉴定出来，后续在其他几个恶性肿瘤里也发现了ROS1基因的重排，如胆管癌、卵巢癌、胃癌和非小细胞肺癌，其中在非小细胞肺癌里的突变频率为1％-2％。The ROS1 gene encodes a receptor tyrosine kinase (RTK) that is involved in cell growth, proliferation, survival, and differentiation. The ROS1 gene can be fused to multiple genes. When ROS1 is fused with other genes, the kinase domain is generally retained and conserved at the breakpoint. Rearrangement of ROS1 leads to sustained activation of the kinase, up-regulation of SHP-1, SHP2, and PI3K, AKT, mTOR, MAPK, and ERK signaling pathways, resulting in sustained cell proliferation and tumorigenesis. The rearrangement of the ROS1 gene was first identified in human glioma cell lines, and subsequent rearrangements of ROS1 genes, such as cholangiocarcinoma, ovarian cancer, gastric cancer, and non-small cells, were also found in several other malignant tumors. Lung cancer, wherein the frequency of mutation in non-small cell lung cancer is 1% to 2%.

凭借积极临床数据获得FDA加速批准的Crizotinib有较好的ROS1抑制活性，此外Ignyta公司的Entrectinib和诺华的Ceritinib也有不错的ROS1抑制活性，但他们不能有效地克服Crizotinib一线治疗产生的耐药突变，如solvent front突变等。所以它们也主要在进行初始患者的临床试验。Crizotinib, which has been approved by the FDA for accelerated clinical data, has better ROS1 inhibitory activity. In addition, Ignyta's Entrectinib and Novartis's Ceritinib also have good ROS1 inhibitory activity, but they cannot effectively overcome the drug-resistant mutations produced by the first-line treatment of Crizotinib. Solvent front mutation etc. Therefore, they are also mainly conducting clinical trials of initial patients.

目前亟需开发具有所需抑制活性的化合物，特别是对多种激酶具有抑制活性的化合物。There is an urgent need to develop compounds having the desired inhibitory activity, particularly compounds having inhibitory activity against a variety of kinases.

公开内容Public content

本公开涉及通式(I)所示化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，The present disclosure relates to a compound of the formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or a compound obtained by isotopic substitution of any atom in the compound of the formula (I),

其中：among them:

R ₁、R ₂、R ₃、R ₄各自独立地为氢、氘、氟、氯、溴、碘、C _1-6烷基、C _1-6烷氧基、羟基、硝基、氰基或氨基，其中所述C _1-6烷基或C _1-6烷氧基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代； R ₁ , R ₂ , R ₃ , R ₄ are each independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, nitro, cyano or An amino group, wherein the C _1-6 alkyl group or C _1-6 alkoxy group may be optionally fluoro, chloro, bromo, iodo, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro Mono- or poly-substituted with a cyano group;

L为

或-(CH ₂) _n-NH-B-，其中： L is

Or -(CH ₂ ) _n -NH-B-, where:

A为-(CH ₂) _m-或-CHR ₅-； A is -(CH ₂ ) _m - or -CHR ₅ -;

X为-CH ₂-、-NH-或-NR ₆-； X is -CH ₂ -, -NH- or -NR ₆ -;

Y为-C(＝O)-、-S(＝O)-或-S(＝O) ₂-； Y is -C(=O)-, -S(=O)- or -S(=O) ₂ -;

Z为-NH-或

Z is -NH- or

B为-C(＝S)-或-CHR ₇-； B is -C(=S)- or -CHR ₇ -;

R ₅、R ₆各自独立地为氘、氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基或氨基，其中所述C _1-4烷基或C _1-4烷氧基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代； R ₅ and R ₆ are each independently hydrazine, fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano or amino, wherein said C _{1- The 4-} alkyl or C _1-4 alkoxy group may be optionally monosubstituted by fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino Or multiple substitutions;

R ₇为氢、氘、氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基或氨基，其中所述C _1-4烷基或C _1-4烷氧基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代； R ₇ is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano or amino, wherein said C _1-4 alkyl or The C _1-4 alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino;

m、n各自独立地为1、2、3、4或5。m, n are each independently 1, 2, 3, 4 or 5.

本公开还涉及药物组合物，所述药物组合物包含至少一种上述通式(I)化合物、其药学上可接受的盐、立体异构体、溶剂合物或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，以及药学上可接受的载体或赋形剂。The present disclosure also relates to a pharmaceutical composition comprising at least one compound of the above formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate or a compound of the formula (I) A compound obtained by replacement of any atom with its isotope, and a pharmaceutically acceptable carrier or excipient.

本公开还涉及所述通式(I)化合物、其药学上可接受的盐、立体异构体、溶剂合物或通式(I)化合物中的任意原子经其同位素替换后得到的化合物在制备用于治疗疾病或病症或减轻所述疾病或病症严重性的药物中的用途，或者在制备作为酪氨酸激酶(包括NTRK(例如NTRK1、NTRK2、NTRK3)、ALK或ROS1中的一种或多种)抑制剂的药物中的用途。The present disclosure also relates to the preparation of a compound of the formula (I), a pharmaceutically acceptable salt, a stereoisomer, a solvate thereof or a compound obtained by isotopically replacing any of the compounds of the formula (I) Use in a medicament for treating or ameliorating the severity of the disease or condition, or in the preparation of one or more of tyrosine kinases including NTRK (eg NTRK1, NTRK2, NTRK3), ALK or ROS1 Use of a drug for an inhibitor.

本公开还涉及治疗疾病或病症或减轻所述疾病或病症严重性的方法，所述方法包括给予需要这种治疗的受试者治疗有效量的通式(I)化合物其药学上可接受的盐、立体异构体、溶剂合物或通式(I)化合物中的任意原子经其同位素替换后得到的化合物。The present disclosure also relates to a method of treating or lessening the severity of a disease or condition, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof , a stereoisomer, a solvate or a compound obtained by replacing any of the compounds of the formula (I) with an isotope thereof.

本公开还涉及抑制酪氨酸激酶(包括NTRK(例如NTRK1、NTRK2、NTRK3)、ALK或ROS1中的一种或多种)的方法，包括使包含所述激酶中的细胞与有效量的至少一种上述通式(I)化合物、其药学上可接受的盐、立体异构体、溶剂合物或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或者与至少一种本公开所述的药物组合物接触，其中所述接触是在活体外、离体或活体内。The present disclosure also relates to a method of inhibiting tyrosine kinases, including one or more of NTRK (eg, NTRK1, NTRK2, NTRK3), ALK, or ROS1, comprising causing at least one of the cells comprising the kinase and an effective amount a compound of the above formula (I), a pharmaceutically acceptable salt, a stereoisomer, a solvate thereof or a compound obtained by isotopically replacing any of the compounds of the formula (I), or at least one The pharmaceutical compositions of the present disclosure are in contact, wherein the contacting is in vitro, ex vivo or in vivo.

本公开还涉及至少一种上述通式(I)化合物、其药学上可接受的盐、立体异构体、溶剂合物或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，所述化合物、其药学上可接受的盐、立体异构体、溶剂合物或通式(I)化合物中的任意原子经其同位素替换后得到的化合物用于治疗疾病或病症或减轻所述疾病或病症严重性，或者用于抑制酪氨酸激酶(包括NTRK(例如NTRK1、NTRK2、NTRK3)、ALK或ROS1中的一种或多种)。The present disclosure also relates to a compound obtained by at least one compound of the above formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate or a compound of the formula (I) which has been subjected to isotopic substitution thereof. a compound, a pharmaceutically acceptable salt, a stereoisomer, a solvate thereof or a compound obtained by isotopically replacing any of the compounds of the formula (I) for use in treating a disease or condition or alleviating said The severity of the disease or condition, or for inhibiting tyrosine kinases (including one or more of NTRK (eg, NTRK1, NTRK2, NTRK3), ALK, or ROS1).

在部分实施方式中，本公开所述疾病或病症为携带NTRK(例如NTRK1、NTRK2、NTRK3)、ALK、ROS1基因融合突变的多种儿童和/或成人实体瘤，例如乳腺癌、结直肠癌、肺癌、胰腺癌、甲状腺癌、脑胶质瘤、各种肉瘤以及脑转移的肿瘤。In some embodiments, the disease or condition of the present disclosure is a plurality of childhood and/or adult solid tumors, such as breast cancer, colorectal cancer, that carry NTRK (eg, NTRK1, NTRK2, NTRK3), ALK, ROS1 gene fusion mutations, Lung cancer, pancreatic cancer, thyroid cancer, glioma, various sarcomas, and tumors of brain metastasis.

公开详述Publicly detailed

现就本公开进行详细描述。应理解，本公开可以不同形式体现并且不应解释为仅限于本文所提及的实施方案。相反地，提供这些实施方案使得本公开充分且完整并将本公开的范围充分传达给本领域技术人员。The present disclosure will now be described in detail. It is understood that the present disclosure may be embodied in various forms and should not be construed as limited to the embodiments herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.

一方面，本公开涉及通式(I)所示化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，In one aspect, the present disclosure relates to a compound of the formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of the formula (I), which is obtained by isotopic substitution thereof Compound,

其中：among them:

L为

或-(CH ₂) _n-NH-B-，其中： L is

Or -(CH ₂ ) _n -NH-B-, where:

A为-(CH ₂) _m-或-CHR ₅-； A is -(CH ₂ ) _m - or -CHR ₅ -;

X为-CH ₂-、-NH-或-NR ₆-； X is -CH ₂ -, -NH- or -NR ₆ -;

Z为-NH-或

Z is -NH- or

B为-C(＝S)-或-CHR ₇-； B is -C(=S)- or -CHR ₇ -;

在一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：In one embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I) after its isotopic substitution The resulting compound, or any suitable embodiment of the present disclosure, wherein:

R ₁、R ₂、R ₃、R ₄各自独立地为氢、氘、氟、C _1-6烷基或C _1-6烷氧基，其中所述C _1-6烷基或C _1-6烷氧基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代； R ₁ , R ₂ , R ₃ , R ₄ are each independently hydrogen, deuterium, fluorine, C _1-6 alkyl or C _1-6 alkoxy, wherein said C _1-6 alkyl or C _1-6 The alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino;

例如，所述C _1-6烷基或C _1-6烷氧基可以任选地被氟、氯、溴、碘、羟基、硝基、氰基、氨基单取代或多取代； For example, the C _1-6 alkyl or C _1-6 alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxy, nitro, cyano, amino;

例如，所述C _1-6烷基或C _1-6烷氧基可以任选地被氟、氯、溴、羟基、硝基、氨基单取代或多取代。 For example, the C _1-6 alkyl or C _1-6 alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, hydroxyl, nitro, amino.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein:

R ₁、R ₂、R ₃、R ₄各自独立地为氢、氟、C _1-4烷基或C _1-4烷氧基，其中所述C _1-4烷基或C _1-4烷氧基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代； R ₁ , R ₂ , R ₃ , R ₄ are each independently hydrogen, fluoro, C _1-4 alkyl or C _1-4 alkoxy, wherein said C _1-4 alkyl or C _1-4 alkoxy The group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino;

例如，所述C _1-4烷基或C _1-4烷氧基可以任选地被氟、氯、溴、碘、羟基、硝基、氰基、氨基单取代或多取代； For example, the C _1-4 alkyl or C _1-4 alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino;

例如，所述C _1-4烷基或C _1-4烷氧基可以任选地被氟、氯、溴、羟基、硝基、氨基单取代或多取代。 For example, the C _1-4 alkyl or C _1-4 alkoxy group can be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.

R ₁、R ₂、R ₃、R ₄各自独立地为氢、氟或C _1-6烷基，其中所述C _1-6烷基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代； R ₁ , R ₂ , R ₃ , R ₄ are each independently hydrogen, fluoro or C _1-6 alkyl, wherein the C _1-6 alkyl group may be optionally fluoro, chloro, bromo, iodo, C _{1 -4} alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino mono- or poly-substituted;

例如，所述C _1-4烷基可以任选地被氟、氯、溴、碘、羟基、硝基、氰基、氨基单取代或多取代； For example, the C _1-4 alkyl group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino;

例如，所述C _1-4烷基可以任选地被氟、氯、溴、羟基、硝基、氨基单取代或多取代。 For example, the C _1-4 alkyl group can be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.

R ₁、R ₂、R ₃、R ₄各自独立地为氢、氟或C _1-4烷基，其中所述C _1-4烷基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代； R ₁ , R ₂ , R ₃ , R ₄ are each independently hydrogen, fluoro or C _1-4 alkyl, wherein the C _1-4 alkyl group may be optionally fluoro, chloro, bromo, iodo, C _{1 -4} alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino mono- or poly-substituted;

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁、R ₂、R ₃、R ₄各自独立地为氢、氟或C _1-6烷基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₁ , R ₂ , R ₃ , R ₄ are each independently hydrogen, fluoro or C _1-6 alkyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁、R ₂、R ₃、R ₄各自独立地为氢、氟或C _1-4烷基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₁ , R ₂ , R ₃ , R ₄ are each independently hydrogen, fluoro or C _1-4 alkyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁、R ₂、R ₃、R ₄各自独立地为氢、氟、氯、溴、碘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、己基、甲氧基、乙氧基、丙氧基、丁氧基、戊氧基或己氧基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₁ , R ₂ , R ₃ , R ₄ are each independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy Or hexyloxy.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁、R ₂、R ₃、R ₄各自独立地为氢、氟、氯、溴、碘。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₁ , R ₂ , R ₃ , R ₄ are each independently hydrogen, fluorine, chlorine, bromine, iodine.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁、R ₂、R ₃、R ₄各自独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、己基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₁ , R ₂ , R ₃ , R ₄ are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁、R ₂、R ₃、R ₄各自独立地为甲氧基、乙氧基、丙氧基、丁氧基、戊氧基或己氧基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₁ , R ₂ , R ₃ , R ₄ are each independently methoxy, ethoxy, propoxy, butoxy, pentyloxy Or hexyloxy.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁、R ₂、R ₃、R ₄各自独立地为氢、氟、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、丙氧基或丁氧基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₁ , R ₂ , R ₃ , R ₄ are each independently hydrogen, fluoro, methyl, ethyl, n-propyl, isopropyl, or Butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy or butoxy.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁、R ₂、R ₃、R ₄各自独立地为氢、氟、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₁ , R ₂ , R ₃ , R ₄ are each independently hydrogen, fluoro, methyl, ethyl, n-propyl, isopropyl, or Butyl, isobutyl, tert-butyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁、R ₂、R ₃、R ₄各自独立地为氢、氟、甲基、乙基、正丙基或异丙基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₁ , R ₂ , R ₃ , R ₄ are each independently hydrogen, fluoro, methyl, ethyl, n-propyl or isopropyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁、R ₂、R ₃、R ₄各自独立地为氢、氟、甲基、乙基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₁ , R ₂ , R ₃ , R ₄ are each independently hydrogen, fluoro, methyl, ethyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁、R ₂、R ₃、R ₄各自独立地为氢、氟或甲基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₁ , R ₂ , R ₃ , R ₄ are each independently hydrogen, fluoro or methyl.

在一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁为氢、氘、C _1-6烷基或C _1-6烷氧基，其中所述C _1-6烷基或C _1-6烷氧基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代； In one embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I) after its isotopic substitution The resulting compound, or any suitable embodiment of the present disclosure, wherein: R ₁ is hydrogen, deuterium, C _1-6 alkyl or C _1-6 alkoxy, wherein said C _1-6 alkyl or C _{1- 6} alkoxy can be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino;

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁为氢、C _1-4烷基或C _1-4烷氧基，其中所述C _1-4烷基或C _1-4烷氧基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代； In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₁ is hydrogen, C _1-4 alkyl or C _1-4 alkoxy, wherein said C _1-4 alkyl or C _1-4 The alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino;

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁为氢或C _1-6烷基，其中所述C _1-6烷基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代； In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₁ is hydrogen or C _1-6 alkyl, wherein said C _1-6 alkyl group may be optionally fluoro, chloro, bromo, iodo, a mono- or poly-substituted C _1-4 alkyl group, a C _1-4 alkoxy group, a hydroxyl group, a nitro group, a cyano group, or an amino group;

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁为氢或C _1-4烷基，其中所述C _1-4烷基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代； In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₁ is hydrogen or C _1-4 alkyl, wherein said C _1-4 alkyl group may be optionally fluoro, chloro, bromo, iodo, a mono- or poly-substituted C _1-4 alkyl group, a C _1-4 alkoxy group, a hydroxyl group, a nitro group, a cyano group, or an amino group;

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁为氢或C _1-6烷基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₁ is hydrogen or C _1-6 alkyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁为氢或C _1-4烷基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₁ is hydrogen or C _1-4 alkyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、己基、甲氧基、乙氧基、丙氧基、丁氧基、戊氧基或己氧基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: R ₁ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl , isoamyl, neopentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy or hexyloxy.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、丙氧基或丁氧基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₁ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy , ethoxy, propoxy or butoxy.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope The compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₁ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁为氢、甲基、乙基、正丙基或异丙基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₁ is hydrogen, methyl, ethyl, n-propyl or isopropyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁为氢、甲基、乙基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₁ is hydrogen, methyl, ethyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁为氢或甲基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₁ is hydrogen or methyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁为氢。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₁ is hydrogen.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁为甲基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₁ is methyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁为乙基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₁ is ethyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁为正丙基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₁ is n-propyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁为异丙基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₁ is isopropyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁为正丁基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₁ is n-butyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁为异丁基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: R ₁ is isobutyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₁为叔丁基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₁ is a tert-butyl group.

在一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₂为氢、氘、C _1-6烷基或C _1-6烷氧基，其中所述C _1-6烷基或C _1-6烷氧基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代； In one embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I) after its isotopic substitution The resulting compound, or any suitable embodiment of the present disclosure, wherein: R ₂ is hydrogen, deuterium, C _1-6 alkyl or C _1-6 alkoxy, wherein said C _1-6 alkyl or C _{1- 6} alkoxy can be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino;

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₂为氢、C _1-4烷基或C _1-4烷氧基，其中所述C _1-4烷基或C _1-4烷氧基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代； In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₂ is hydrogen, C _1-4 alkyl or C _1-4 alkoxy, wherein said C _1-4 alkyl or C _1-4 The alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino;

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₂为氢或C _1-6烷基，其中所述C _1-6烷基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代； In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₂ is hydrogen or C _1-6 alkyl, wherein said C _1-6 alkyl group may be optionally fluoro, chloro, bromo, iodo, a mono- or poly-substituted C _1-4 alkyl group, a C _1-4 alkoxy group, a hydroxyl group, a nitro group, a cyano group, or an amino group;

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₂为氢或C _1-4烷基，其中所述C _1-4烷基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代； In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₂ is hydrogen or C _1-4 alkyl, wherein said C _1-4 alkyl group may be optionally fluoro, chloro, bromo, iodo, a mono- or poly-substituted C _1-4 alkyl group, a C _1-4 alkoxy group, a hydroxyl group, a nitro group, a cyano group, or an amino group;

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₂为氢或C _1-6烷基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₂ is hydrogen or C _1-6 alkyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₂为氢或C _1-4烷基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₂ is hydrogen or C _1-4 alkyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₂为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、己基、甲氧基、乙氧基、丙氧基、丁氧基、戊氧基或己氧基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: R ₂ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl , isoamyl, neopentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy or hexyloxy.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₂为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、丙氧基或丁氧基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: R ₂ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy , ethoxy, propoxy or butoxy.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₂为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₂ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₂为氢、甲基、乙基、正丙基或异丙基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₂ is hydrogen, methyl, ethyl, n-propyl or isopropyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₂为氢、甲基、乙基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₂ is hydrogen, methyl, ethyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₂为氢或甲基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₂ is hydrogen or methyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₂为H。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₂ is H.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₂为甲基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₂ is methyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₂为乙基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₂ is ethyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₂为正丙基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₂ is n-propyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₂为异丙基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₂ is isopropyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₂为正丁基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₂ is n-butyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₂为异丁基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: R ₂ is isobutyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₂为叔丁基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₂ is a tert-butyl group.

在一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₃为氢、氘、C _1-6烷基或C _1-6烷氧基，其中所述C _1-6烷基或C _1-6烷氧基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代； In one embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I) after its isotopic substitution The resulting compound, or any suitable embodiment of the present disclosure, wherein: R ₃ is hydrogen, deuterium, C _1-6 alkyl or C _1-6 alkoxy, wherein said C _1-6 alkyl or C _{1- 6} alkoxy can be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino;

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₃为氢、C _1-4烷基或C _1-4烷氧基，其中所述C _1-4烷基或C _1-4烷氧基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代； In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₃ is hydrogen, C _1-4 alkyl or C _1-4 alkoxy, wherein said C _1-4 alkyl or C _1-4 The alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino;

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₃为氢或C _1-6烷基，其中所述C _1-6烷基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代； In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₃ is hydrogen or C _1-6 alkyl, wherein said C _1-6 alkyl group may be optionally fluoro, chloro, bromo, iodo, a mono- or poly-substituted C _1-4 alkyl group, a C _1-4 alkoxy group, a hydroxyl group, a nitro group, a cyano group, or an amino group;

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₃为氢或C _1-4烷基，其中所述C _1-4烷基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代； In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₃ is hydrogen or C _1-4 alkyl, wherein said C _1-4 alkyl group may be optionally fluoro, chloro, bromo, iodo, a mono- or poly-substituted C _1-4 alkyl group, a C _1-4 alkoxy group, a hydroxyl group, a nitro group, a cyano group, or an amino group;

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₃为氢或C _1-6烷基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₃ is hydrogen or C _1-6 alkyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₃为氢或C _1-4烷基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₃ is hydrogen or C _1-4 alkyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₃为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、己基甲氧基、乙氧基、丙氧基、丁氧基、戊氧基或己氧基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₃ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl , isoamyl, neopentyl, hexylmethoxy, ethoxy, propoxy, butoxy, pentyloxy or hexyloxy.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₃为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、丙氧基或丁氧基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: R ₃ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy , ethoxy, propoxy or butoxy.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₃为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope The compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₃ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₃为氢、甲基、乙基、正丙基或异丙基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope The compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₃ is hydrogen, methyl, ethyl, n-propyl or isopropyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₃为氢、甲基或乙基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₃ is hydrogen, methyl or ethyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₃为氢或甲基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₃ is hydrogen or methyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₃为H。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₃ is H.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₃为甲基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: R ₃ is methyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₃为乙基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₃ is ethyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₃为正丙基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₃ is n-propyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₃为异丙基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₃ is isopropyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₃为正丁基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: R ₃ is n-butyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₃为异丁基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: R ₃ is isobutyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₃为叔丁基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₃ is a tert-butyl group.

在一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₄为氘、氟、氯、溴、碘、C _1-6烷基或C _1-6烷氧基，其中所述C _1-6烷基或C _1-6烷氧基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代； In one embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I) after its isotopic substitution The compound obtained, or any suitable embodiment of the present disclosure, wherein: R ₄ is hydrazine, fluorine, chlorine, bromine, iodine, C _1-6 alkyl or C _1-6 alkoxy, wherein said C _1-6 The alkyl or C _1-6 alkoxy group may be optionally monosubstituted by fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino or Multi-substitution

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₄为氟、氯、溴、碘、C _1-4烷基或C _1-4烷氧基，其中所述C _1-4烷基或C _1-4烷氧基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代； In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₄ is fluoro, chloro, bromo, iodo, C _1-4 alkyl or C _1-4 alkoxy, wherein said C _1-4 alkane Or a C _1-4 alkoxy group may be optionally substituted by fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino or more Replace

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₄为氟、氯、溴、碘、或C _1-6烷基，其中所述C _1-6烷基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代； In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₄ is fluoro, chloro, bromo, iodo, or C _1-6 alkyl, wherein said C _1-6 alkyl may be optionally fluorinated , chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino mono- or poly-substituted;

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₄为氟、氯、溴、碘或C _1-4烷基，其中所述C _1-4烷基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代； In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₄ is fluoro, chloro, bromo, iodo or C _1-4 alkyl, wherein said C _1-4 alkyl may be optionally fluoro, Chloro, bromo, iodo, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino mono- or poly-substituted;

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₄为氟、氯、溴、碘或C _1-6烷基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₄ is fluorine, chlorine, bromine, iodine or a C _1-6 alkyl group.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₄为氟、氯、溴、碘或C _1-4烷基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope The compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₄ is fluorine, chlorine, bromine, iodine or a C _1-4 alkyl group.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₄为氟、氯、溴、碘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、己基、甲氧基、乙氧基、丙氧基、丁氧基、戊氧基或己氧基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₄ is fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert Butyl, n-pentyl, isopentyl, neopentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy or hexyloxy.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₄为氟、氯、溴、碘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、丙氧基或丁氧基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₄ is fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert Butyl, methoxy, ethoxy, propoxy or butoxy.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₄为氟、氯、溴、碘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₄ is fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert Butyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₄为氟、氯、溴、碘、甲基、乙基、正丙基或异丙基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope The compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₄ is fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl or isopropyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₄为氟、氯、溴、碘、甲基或乙基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₄ is fluorine, chlorine, bromine, iodine, methyl or ethyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₄为甲基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₄ is methyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₄为乙基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₄ is ethyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₄为正丙基. In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: R ₄ is n-propyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₄为异丙基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₄ is isopropyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₄为氟、氯、溴或碘。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₄ is fluorine, chlorine, bromine or iodine.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₄为氟。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₄ is fluoro.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₄为氯。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₄ is chloro.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₄为溴。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₄ is bromine.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₄为碘。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₄ is iodine.

L为

L is

L为

其中：A、X、Y、Z的定义如本公开中任意适用的实施方案中所述。 L is

Wherein: A, X, Y, Z are as defined in any suitable embodiment of the present disclosure.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：L为-(CH ₂) _n-NH-B-，其中：n、B的定义如本公开中任意适用的实施方案中所述。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope The resulting compound, or any suitable embodiment of the present disclosure, wherein: L is -(CH ₂ ) _n -NH-B-, wherein: n, B are as defined in any suitable embodiment of the present disclosure.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：A为-(CH ₂) _m-，其中m的定义如本公开中任意适用的实施方案中所述。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope The compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: A is -(CH ₂ ) _m -, wherein m is as defined in any of the applicable embodiments of the present disclosure.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：A为-CHR ₅-，其中R ₅的定义如本公开中任意适用的实施方案中所述。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope The compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: A is -CHR ₅ -, wherein R _{5 is} as defined in any of the applicable embodiments of the present disclosure.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：X为-CH ₂-。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope after the obtained compound, or any suitable embodiment disclosed in the present embodiment, wherein: X is -CH ₂ -.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：X为-NH-。In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: X is -NH-.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：X为-NR ₆-，其中R ₆的定义如本公开中任意适用的实施方案中所述。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope The compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: X is -NR ₆ -, wherein R _{6 is} as defined in any of the applicable embodiments of the present disclosure.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：Y为-C(＝O)-。In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: Y is -C(=O)-.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：Y为-S(＝O)-。In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: Y is -S(=O)-.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：Y为-S(＝O) ₂-。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: Y is -S(=O) _2- .

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：Z为-NH-。In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: Z is -NH-.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：Z为

In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: Z is

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：B为-C(＝S)-。In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: B is -C(=S)-.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：B为-CHR ₇-，其中R ₇的定义如本公开中任意适用的实施方案中所述。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope The compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: B is -CHR ₇ -, wherein R _{7 is} as defined in any of the applicable embodiments of the present disclosure.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₅为氘、氟、氯、溴或碘。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₅ is hydrazine, fluorine, chlorine, bromine or iodine.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₅为C _1-4烷基或C _1-4烷氧基，其中所述C _1-4烷基或C _1-4烷氧基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₅ is C _1-4 alkyl or C _1-4 alkoxy, wherein said C _1-4 alkyl or C _1-4 alkoxy The group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₅为C _1-4烷基，其中所述C _1-4烷基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₅ is C _1-4 alkyl, wherein said C _1-4 alkyl group may be optionally fluoro, chloro, bromo, iodo, C _{1 -4} alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino mono- or poly-substituted.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₅为C _1-4烷基，其中所述C _1-4烷基可以任选地被氟、氯、溴、碘单取代或多取代。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₅ is C _1-4 alkyl, wherein said C _1-4 alkyl group may be optionally monosubstituted by fluorine, chlorine, bromine, iodine or More substitution.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₅为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，其中所述R ₅可以任选地被氟、氯、溴、碘单取代或多取代。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₅ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl, wherein said R ₅ It may optionally be mono- or polysubstituted by fluorine, chlorine, bromine or iodine.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₅为甲基、乙基、正丙基、异丙基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₅ is methyl, ethyl, n-propyl, isopropyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₅为正丙基或异丙基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₅ is n-propyl or isopropyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₅为异丙基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₅ is isopropyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₅为羟基、硝基、氰基或氨基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₅ is hydroxy, nitro, cyano or amino.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₆为氘、氟、氯、溴或碘。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₆ is hydrazine, fluorine, chlorine, bromine or iodine.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₆为C _1-4烷基或C _1-4烷氧基，其中所述C _1-4烷基或C _1-4烷氧基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₆ is C _1-4 alkyl or C _1-4 alkoxy, wherein said C _1-4 alkyl or C _1-4 alkoxy The group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₆为C _1-4烷基，其中所述C _1-4烷基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₆ is C _1-4 alkyl, wherein said C _1-4 alkyl group may be optionally fluoro, chloro, bromo, iodo, C _{1 -4} alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino mono- or poly-substituted.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₆为C _1-4烷基，其中所述C _1-4烷基可以任选地被氟、氯、溴、碘单取代或多取代。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₆ is C _1-4 alkyl, wherein said C _1-4 alkyl group may be optionally monosubstituted by fluorine, chlorine, bromine or iodine or More substitution.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₆为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，其中所述R ₆可以任选地被氟、氯、溴、碘单取代或多取代。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₆ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl, wherein said R ₆ It may optionally be mono- or polysubstituted by fluorine, chlorine, bromine or iodine.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₆为甲基、乙基、正丙基、异丙基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₆ is methyl, ethyl, n-propyl, isopropyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₆为甲基或乙基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₆ is methyl or ethyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₆为甲基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₆ is methyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₆为羟基、硝基、氰基或氨基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₆ is hydroxy, nitro, cyano or amino.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₇为氘、氟、氯、溴或碘。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₇ is hydrazine, fluorine, chlorine, bromine or iodine.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₇为C _1-4烷基或C _1-4烷氧基，其中所述C _1-4烷基或C _1-4烷氧基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₇ is C _1-4 alkyl or C _1-4 alkoxy, wherein said C _1-4 alkyl or C _1-4 alkoxy The group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₇为C _1-4烷基，其中所述C _1-4烷基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₇ is C _1-4 alkyl, wherein said C _1-4 alkyl group may be optionally fluoro, chloro, bromo, iodo, C _{1 -4} alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino mono- or poly-substituted.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₇为C _1-4烷基，其中所述C _1-4烷基可以任选地被氟、氯、溴、碘单取代或多取代。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₇ is C _1-4 alkyl, wherein said C _1-4 alkyl group may be optionally monosubstituted by fluorine, chlorine, bromine or iodine or More substitution.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₇为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，其中所述R ₇可以任选地被氟、氯、溴、碘单取代或多取代。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope a compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₇ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl, wherein said R ₇ It may optionally be mono- or polysubstituted by fluorine, chlorine, bromine or iodine.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₇为乙基、正丙基或异丙基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₇ is ethyl, n-propyl or isopropyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₇为甲基、单氟代甲基、二氟代甲基或三氟甲基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₇ is methyl, monofluoromethyl, difluoromethyl or trifluoromethyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₇为甲基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₇ is methyl.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₇为三氟甲基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope A compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₇ is a trifluoromethyl group.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：R ₇为羟基、硝基、氰基或氨基。 In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: R ₇ is hydroxy, nitro, cyano or amino.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：m为1、2或3。In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: m is 1, 2 or 3.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：m为4或5。In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: m is 4 or 5.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：m为1或2。In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: m is 1 or 2.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：m为1。In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope The compound obtained hereinafter, or any suitable embodiment of the present disclosure, wherein: m is 1.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：m为2。In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: m is 2.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：n为1、2或3。In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: n is 1, 2 or 3.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：n为4或5。In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: n is 4 or 5.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：n为1或2。In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: n is 1 or 2.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：n为1。In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope The compound obtained afterwards, or any suitable embodiment of the present disclosure, wherein: n is 1.

在另一个实施方案中，本公开涉及所述式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物，或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或本公开任意适用的实施方案，其中：n为2。In another embodiment, the present disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of formula (I), substituted by its isotope Compounds obtained afterwards, or any suitable embodiment of the present disclosure, wherein: n is 2.

L为

其中： L is

among them:

A为-(CH ₂) _m-或-CHR ₅-； A is -(CH ₂ ) _m - or -CHR ₅ -;

X为-CH ₂-、-NH-或-NR ₆-； X is -CH ₂ -, -NH- or -NR ₆ -;

Z为-NH-或

Z is -NH- or

m为1、2、3、4或5。m is 1, 2, 3, 4 or 5.

L为

其中： L is

among them:

A为-(CH ₂) _m-或-CHR ₅-； A is -(CH ₂ ) _m - or -CHR ₅ -;

X为-CH ₂-、-NH-或-NR ₆-； X is -CH ₂ -, -NH- or -NR ₆ -;

Z为-NH-或

Z is -NH- or

m为1或2。m is 1 or 2.

L为

其中： L is

among them:

A为-(CH ₂) _m-或-CHR ₅-； A is -(CH ₂ ) _m - or -CHR ₅ -;

X为-CH ₂-、-NH-或-NR ₆-； X is -CH ₂ -, -NH- or -NR ₆ -;

Z为-NH-或

Z is -NH- or

R ₅、R ₆各自独立地为C _1-4烷基，其中所述C _1-4烷基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代； R ₅ and R ₆ are each independently C _1-4 alkyl, wherein the C _1-4 alkyl group may be optionally fluoro, chloro, bromo, iodo, C _1-4 alkyl, C _1-4 alkane Oxyl, hydroxy, nitro, cyano, amino mono- or poly-substituted;

m为1或2。m is 1 or 2.

L为

其中： L is

among them:

A为-(CH ₂) _m-或-CHR ₅-； A is -(CH ₂ ) _m - or -CHR ₅ -;

X为-CH ₂-、-NH-或-NR ₆-； X is -CH ₂ -, -NH- or -NR ₆ -;

Z为-NH-或

Z is -NH- or

R ₅、R ₆各自独立地为C _1-4烷基，其中所述C _1-4烷基可以任选地被氟、氯、溴、碘、羟基、硝基、氰基、氨基单取代或多取代； R ₅ and R ₆ are each independently C _1-4 alkyl, wherein the C _1-4 alkyl group may be optionally monosubstituted by fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino or Multi-substitution

m为1或2。m is 1 or 2.

L为

其中： L is

among them:

A为-(CH ₂) _m-或-CHR ₅-； A is -(CH ₂ ) _m - or -CHR ₅ -;

X为-CH ₂-、-NH-或-NR ₆-； X is -CH ₂ -, -NH- or -NR ₆ -;

Z为-NH-或

Z is -NH- or

R ₅、R ₆各自独立地为C _1-4烷基，其中所述C _1-4烷基可以任选地被氟、氯、溴、碘单取代或多取代； R ₅ and R ₆ are each independently C _1-4 alkyl, wherein the C _1-4 alkyl group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine;

m为1或2。m is 1 or 2.

L为

其中： L is

among them:

A为-(CH ₂) _m-或-CHR ₅-； A is -(CH ₂ ) _m - or -CHR ₅ -;

X为-CH ₂-、-NH-或-NR ₆-； X is -CH ₂ -, -NH- or -NR ₆ -;

Y为-C(＝O)-、-S(＝O)-或-S(＝O) ₂- Y is -C(=O)-, -S(=O)- or -S(=O) ₂ -

Z为-NH-或

Z is -NH- or

R ₅、R ₆各自独立地为甲基、乙基、正丙基、异丙基、甲基丙基、正丁基、异丁基或叔丁基； R ₅ and R ₆ are each independently methyl, ethyl, n-propyl, isopropyl, methylpropyl, n-butyl, isobutyl or t-butyl;

m为1或2。m is 1 or 2.

L为

其中： L is

among them:

A为-(CH ₂) _m-或-CHR ₅-； A is -(CH ₂ ) _m - or -CHR ₅ -;

X为-CH ₂-、-NH-或-NR ₆-； X is -CH ₂ -, -NH- or -NR ₆ -;

Z为-NH-；Z is -NH-;

m为1或2。m is 1 or 2.

L为

其中： L is

among them:

A为-(CH ₂) _m-或-CHR ₅-； A is -(CH ₂ ) _m - or -CHR ₅ -;

X为-NH-或-NR ₆-； X is -NH- or -NR ₆ -;

Z为-NH-；Z is -NH-;

m为1或2。m is 1 or 2.

L为

其中： L is

among them:

A为-(CH ₂) _m-或-CHR ₅-； A is -(CH ₂ ) _m - or -CHR ₅ -;

X为-NH-或-NR ₆-； X is -NH- or -NR ₆ -;

Z为-NH-；Z is -NH-;

m为1或2。m is 1 or 2.

L为

其中： L is

among them:

A为-(CH ₂) _m-或-CHR ₅-； A is -(CH ₂ ) _m - or -CHR ₅ -;

X为-NH-或-NR ₆-； X is -NH- or -NR ₆ -;

Z为-NH-；Z is -NH-;

m为1或2。m is 1 or 2.

L为

其中： L is

among them:

A为-(CH ₂) _m-或-CHR ₅-； A is -(CH ₂ ) _m - or -CHR ₅ -;

X为-CH ₂-、-NH-或-NR ₆-； X is -CH ₂ -, -NH- or -NR ₆ -;

Z为-NH-；Z is -NH-;

m为1或2。m is 1 or 2.

L为

其中： L is

among them:

A为-(CH ₂) _m-或-CHR ₅-； A is -(CH ₂ ) _m - or -CHR ₅ -;

X为-NH-或-NR ₆-； X is -NH- or -NR ₆ -;

Z为-NH-；Z is -NH-;

R ₅、R ₆各自独立地为甲基、乙基、正丙基或异丙基，其中所述R ₅、R ₆可以任选地被氟、氯、溴、碘单取代或多取代； R ₅ and R ₆ are each independently methyl, ethyl, n-propyl or isopropyl, wherein said R ₅ and R ₆ may be optionally mono- or polysubstituted by fluorine, chlorine, bromine or iodine;

m为1或2。m is 1 or 2.

L为

其中： L is

among them:

A为-(CH ₂) _m-或-CHR ₅-； A is -(CH ₂ ) _m - or -CHR ₅ -;

X为-NH-或-NR ₆-； X is -NH- or -NR ₆ -;

Z为-NH-；Z is -NH-;

R ₅为正丙基或异丙基； R ₅ is n-propyl or isopropyl;

R ₆为甲基、三氟甲基、二氟甲基或单氟代甲基； R ₆ is methyl, trifluoromethyl, difluoromethyl or monofluoromethyl;

m为1或2。m is 1 or 2.

L为

其中： L is

among them:

A为-(CH ₂) _m-或-CHR ₅-； A is -(CH ₂ ) _m - or -CHR ₅ -;

X为-NH-或-NR ₆-； X is -NH- or -NR ₆ -;

Z为-NH-；Z is -NH-;

R ₅为正丙基或异丙基； R ₅ is n-propyl or isopropyl;

R ₆为甲基； R ₆ is a methyl group;

m为1或2。m is 1 or 2.

L为

其中： L is

among them:

A为-(CH ₂) _m-或-CHR ₅-； A is -(CH ₂ ) _m - or -CHR ₅ -;

X为-NH-或-NR ₆-； X is -NH- or -NR ₆ -;

Z为-NH-；Z is -NH-;

R ₅为异丙基； R ₅ is an isopropyl group;

R ₆为甲基； R ₆ is a methyl group;

m为1或2。m is 1 or 2.

L为

其中： L is

among them:

A为-(CH ₂) _m-或-CHR ₅-； A is -(CH ₂ ) _m - or -CHR ₅ -;

X为-CH ₂-、-NH-或-NR ₆-； X is -CH ₂ -, -NH- or -NR ₆ -;

Y为-C(＝O)-；Y is -C(=O)-;

Z为-NH-；Z is -NH-;

m为1或2。m is 1 or 2.

L为

其中： L is

among them:

A为-(CH ₂) _m-或-CHR ₅-； A is -(CH ₂ ) _m - or -CHR ₅ -;

X为-NH-或-NR ₆-； X is -NH- or -NR ₆ -;

Y为-C(＝O)-；Y is -C(=O)-;

Z为-NH-；Z is -NH-;

m为1或2。m is 1 or 2.

L为

其中： L is

among them:

A为-(CH ₂) _m-或-CHR ₅-； A is -(CH ₂ ) _m - or -CHR ₅ -;

X为-NH-或-NR ₆-； X is -NH- or -NR ₆ -;

Y为-C(＝O)-；Y is -C(=O)-;

Z为-NH-；Z is -NH-;

m为1或2。m is 1 or 2.

L为

其中： L is

among them:

A为-(CH ₂) _m-或-CHR ₅-； A is -(CH ₂ ) _m - or -CHR ₅ -;

X为-NH-或-NR ₆-； X is -NH- or -NR ₆ -;

Y为-C(＝O)-；Y is -C(=O)-;

Z为-NH-；Z is -NH-;

m为1或2。m is 1 or 2.

L为

其中： L is

among them:

A为-(CH ₂) _m-或-CHR ₅-； A is -(CH ₂ ) _m - or -CHR ₅ -;

X为-CH ₂-、-NH-或-NR ₆-； X is -CH ₂ -, -NH- or -NR ₆ -;

Y为-C(＝O)-；Y is -C(=O)-;

Z为-NH-；Z is -NH-;

m为1或2。m is 1 or 2.

L为

其中： L is

among them:

A为-(CH ₂) _m-或-CHR ₅-； A is -(CH ₂ ) _m - or -CHR ₅ -;

X为-NH-或-NR ₆-； X is -NH- or -NR ₆ -;

Y为-C(＝O)-；Y is -C(=O)-;

Z为-NH-；Z is -NH-;

m为1或2。m is 1 or 2.

L为

其中： L is

among them:

A为-(CH ₂) _m-或-CHR ₅-； A is -(CH ₂ ) _m - or -CHR ₅ -;

X为-NH-或-NR ₆-； X is -NH- or -NR ₆ -;

Y为-C(＝O)-；Y is -C(=O)-;

Z为-NH-；Z is -NH-;

R ₅为正丙基或异丙基； R ₅ is n-propyl or isopropyl;

R ₆为甲基、三氟甲基、二氟甲基或氟代甲基； R ₆ is methyl, trifluoromethyl, difluoromethyl or fluoromethyl;

m为1或2。m is 1 or 2.

L为

其中： L is

among them:

A为-(CH ₂) _m-或-CHR ₅-； A is -(CH ₂ ) _m - or -CHR ₅ -;

X为-NH-或-NR ₆-； X is -NH- or -NR ₆ -;

Y为-C(＝O)-；Y is -C(=O)-;

Z为-NH-；Z is -NH-;

R ₅为正丙基或异丙基； R ₅ is n-propyl or isopropyl;

R ₆为甲基； R ₆ is a methyl group;

m为1或2。m is 1 or 2.

L为

其中： L is

among them:

A为-(CH ₂) _m-或-CHR ₅-； A is -(CH ₂ ) _m - or -CHR ₅ -;

X为-NH-或-NR ₆-； X is -NH- or -NR ₆ -;

Y为-C(＝O)-；Y is -C(=O)-;

Z为-NH-；Z is -NH-;

R ₅为异丙基； R ₅ is an isopropyl group;

R ₆为甲基； R ₆ is a methyl group;

m为1或2。m is 1 or 2.

L为-(CH ₂) _n-NH-B-，其中： L is -(CH ₂ ) _n -NH-B-, where:

B为-C(＝S)-或-CHR ₇-； B is -C(=S)- or -CHR ₇ -;

R ₇为C _1-4烷基，其中所述C _1-4烷基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代； R ₇ is C _1-4 alkyl, wherein the C _1-4 alkyl group may be optionally fluoro, chloro, bromo, iodo, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro Mono- or poly-substituted with a cyano group;

n为1、2、3、4或5。n is 1, 2, 3, 4 or 5.

L为-(CH ₂) _n-NH-B-，其中： L is -(CH ₂ ) _n -NH-B-, where:

B为-C(＝S)-或-CHR ₇-； B is -C(=S)- or -CHR ₇ -;

R ₇为C _1-4烷基(例如甲基、乙基、正丙基、异丙基、甲基丙基、正丁基、异丁基或叔丁基)，其中所述C _1-4烷基可以任选地被氟、氯、溴、碘、C _1-4烷基、C _1-4烷氧基、羟基、硝基、氰基、氨基单取代或多取代； R ₇ is C _1-4 alkyl (for example methyl, ethyl, n-propyl, isopropyl, methylpropyl, n-butyl, isobutyl or tert-butyl), wherein said C _1-4 An alkyl group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino;

n为1或2。n is 1 or 2.

L为-(CH ₂) _n-NH-B-，其中： L is -(CH ₂ ) _n -NH-B-, where:

B为-C(＝S)-或-CHR ₇-； B is -C(=S)- or -CHR ₇ -;

R ₇为甲基、乙基、正丙基、异丙基、三氟甲基； R ₇ is methyl, ethyl, n-propyl, isopropyl, trifluoromethyl;

n为1或2。n is 1 or 2.

L为-(CH ₂) _n-NH-B-，其中： L is -(CH ₂ ) _n -NH-B-, where:

B为-C(＝S)-或-CHR ₇-； B is -C(=S)- or -CHR ₇ -;

R ₇为甲基或三氟甲基； R ₇ is methyl or trifluoromethyl;

n为1或2。n is 1 or 2.

L为-(CH ₂) _n-NH-B-，其中： L is -(CH ₂ ) _n -NH-B-, where:

B为-C(＝S)-或-CHR ₇-； B is -C(=S)- or -CHR ₇ -;

R ₇为三氟甲基； R ₇ is a trifluoromethyl group;

n为1或2。n is 1 or 2.

L为-(CH ₂) _n-NH-B-，其中： L is -(CH ₂ ) _n -NH-B-, where:

B为-C(＝S)；B is -C(=S);

n为1或2。n is 1 or 2.

L为-(CH ₂) _n-NH-B-，其中： L is -(CH ₂ ) _n -NH-B-, where:

B为-C(＝S)；B is -C(=S);

n为1。n is 1.

R ₁为氢或甲基； R ₁ is hydrogen or methyl;

R ₂为氢或甲基； R ₂ is hydrogen or methyl;

R ₃为氢或甲基； R ₃ is hydrogen or methyl;

R ₄为氟； R ₄ is fluorine;

L为

或-(CH ₂) _n-NH-B-，其中： L is

Or -(CH ₂ ) _n -NH-B-, where:

A为-(CH ₂) _m-或-CHR ₅-； A is -(CH ₂ ) _m - or -CHR ₅ -;

X为-CH ₂-、-NH-或-NR ₆-； X is -CH ₂ -, -NH- or -NR ₆ -;

Y为-C(＝O)-、-S(＝O)-或-S(＝O) ₂- Y is -C(=O)-, -S(=O)- or -S(=O) ₂ -

Z为-NH-或

Z is -NH- or

B为-C(＝S)-或-CHR ₇-； B is -C(=S)- or -CHR ₇ -;

R ₅为异丙基； R ₅ is an isopropyl group;

R ₆为甲基； R ₆ is a methyl group;

R ₇为三氟甲基； R ₇ is a trifluoromethyl group;

m为1或2；m is 1 or 2;

n为1。n is 1.

在另一个实施方案中，本公开涉及所述式(I)化合物，其选自：In another embodiment, the present disclosure is directed to the compound of formula (I) selected from:

以及，

as well as,

这些化合物的药学上可接受的盐、立体异构体、溶剂合物。Pharmaceutically acceptable salts, stereoisomers, solvates of these compounds.

在另一个实施方案中，本公开涉及所述式(I)化合物为：In another embodiment, the present disclosure is directed to the compound of formula (I) being:

另一方面，本公开还涉及药物组合物，所述药物组合物包含至少一种上述通式(I)化合物、其药学上可接受的盐、立体异构体、溶剂合物或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，以及药学上可接受的载体或赋形剂。In another aspect, the present disclosure is also directed to a pharmaceutical composition comprising at least one compound of the above formula (I), a pharmaceutically acceptable salt, stereoisomer, solvate thereof or formula (I) a compound obtained by replacing an arbitrary atom of a compound with its isotope, and a pharmaceutically acceptable carrier or excipient.

本公开所述的药物组合物可含有一种或多种本公开化合物。在一些实施方案中，所述药物组合物可含有一种以上的本公开化合物。例如，在一些实施方案中，所述药物组合物可含有两种或多种本公开化合物。此外，所述药物组合物可任选地还包含一种或多种额外的药物活性化合物。The pharmaceutical compositions described herein may contain one or more compounds of the present disclosure. In some embodiments, the pharmaceutical composition may contain more than one compound of the present disclosure. For example, in some embodiments, the pharmaceutical composition can contain two or more compounds of the present disclosure. Furthermore, the pharmaceutical composition may optionally further comprise one or more additional pharmaceutically active compounds.

根据本公开，所述药物组合物包含本公开通式(I)化合物与常规药用载体或赋形剂。该药物组合物可通过例如口服或非肠道等途径给药。本公开的药物组合物可按本领域常规方法制备成各种剂型，包括但不限于片剂、胶囊、溶液、悬浮液、颗粒剂或注射剂等，经例如口服或非肠道等途径给药。According to the present disclosure, the pharmaceutical composition comprises a compound of formula (I) of the present disclosure and a conventional pharmaceutical carrier or excipient. The pharmaceutical composition can be administered by, for example, oral or parenteral routes. The pharmaceutical compositions of the present disclosure can be prepared in a variety of dosage forms including, but not limited to, tablets, capsules, solutions, suspensions, granules or injections, etc., by conventional methods in the art, for example, by oral or parenteral routes.

本公开所述药物组合物可以每单位剂量含有预定量的活性成分的单位剂型存在。这种单位可含有0.001－1000mg，例如，0.05mg、0.1mg、0.5mg、1mg、10mg、20mg、50mg、80mg、100mg、150mg、200mg、250mg、300mg、500mg、750mg或1000mg的本公开化合物，其取决于所治疗的疾病、给药途径和受试者的年龄、体重和症状，或者药物组合物可以每单位剂量含有预定量的活性成分的单位剂型存在。在另一实施方案中，所述单位剂量组合物是含有本文所述的每日剂量或亚剂量或其适当分数的活性成分的那些。此外，这种药物组合物可通过本领域技术人员熟知的任意方法制备。The pharmaceutical compositions of the present disclosure may be presented in unit dosage forms containing a predetermined amount of active ingredient per unit dose. Such units may contain from 0.001 to 1000 mg, for example, 0.05 mg, 0.1 mg, 0.5 mg, 1 mg, 10 mg, 20 mg, 50 mg, 80 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 500 mg, 750 mg or 1000 mg of the compound of the present disclosure, It depends on the disease being treated, the route of administration and the age, weight and condition of the subject, or the pharmaceutical composition may be present in unit dosage form containing a predetermined amount of active ingredient per unit dose. In another embodiment, the unit dose composition is those containing a daily or sub-dose as described herein, or an appropriate fraction thereof, of the active ingredient. Furthermore, such pharmaceutical compositions can be prepared by any method known to those skilled in the art.

本公开所述通式(I)化合物对NTRK1、NTRK2、NTRK3、ALK以及ROS1具有抑制活性，通过抑制其相关信号通路，从而抑制肿瘤的生长和转移，可以应用于治疗携带NTRK、ALK、ROS1基因融合突变的多种儿童和成人实体瘤中，包括乳腺癌、结直肠癌、肺癌、胰腺癌、甲状腺癌、脑胶质瘤以及各种肉瘤等。此外，本公开所述通式(I)化合物，对脑转移的肿瘤也能够有积极的疗效。The compound of the general formula (I) of the present disclosure has an inhibitory activity against NTRK1, NTRK2, NTRK3, ALK and ROS1, and inhibits tumor growth and metastasis by inhibiting its related signaling pathway, and can be used for treating NTRK, ALK, and ROS1 genes. A variety of solid tumors in children and adults, including breast cancer, colorectal cancer, lung cancer, pancreatic cancer, thyroid cancer, glioma, and various sarcomas. Furthermore, the compounds of the general formula (I) described in the present disclosure can also have a positive therapeutic effect on tumors of brain metastasis.

另一方面，本公开还涉及所述通式(I)化合物、其药学上可接受的盐、立体异构体、溶剂合物或通式(I)化合物中的任意原子经其同位素替换后得到的化合物在制备用于治疗疾病或病症或减轻所述疾病或病症严重性的药物中的用途，或者在制备作为酪氨酸激酶(包括NTRK(例如NTRK1、NTRK2、NTRK3)、ALK或ROS1中的一种或多种)抑制剂的药物中的用途。In another aspect, the present disclosure relates to a compound of the formula (I), a pharmaceutically acceptable salt, a stereoisomer, a solvate thereof or any of the compounds of the formula (I) which is obtained by isotopic substitution thereof Use of a compound in the manufacture of a medicament for treating or ameliorating the severity of the disease or condition, or in the preparation as a tyrosine kinase (including NTRK (eg, NTRK1, NTRK2, NTRK3), ALK or ROS1) Use of a drug of one or more inhibitors.

另一方面，本公开还涉及治疗疾病或病症或减轻所述疾病或病症严重性的方法，所述方法包括给予需要这种治疗的受试者治疗有效量的通式(I)化合物其药学上可接受的盐、立体异构体、溶剂合物或通式(I)化合物中的任意原子经其同位素替换后得到的化合物。In another aspect, the present disclosure is also directed to a method of treating or ameliorating the severity of a disease or condition, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I), which is pharmaceutically acceptable An acceptable salt, stereoisomer, solvate or a compound obtained by replacing any of the compounds of the formula (I) with an isotope thereof.

另一方面，本公开还涉及抑制酪氨酸激酶(包括NTRK(例如NTRK1、NTRK2、NTRK3)、ALK或ROS1中的一种或多种)的方法，包括使包含所述激酶中的细胞与有效量的至少一种上述通式(I)化合物、其药学上可接受的盐、立体异构体、溶剂合物或通式(I)化合物中的任意原子经其同位素替换后得到的化合物，或者与至少一种本公开所述的药物组合物接触，其中所述接触是在活体外、离体或活体内。In another aspect, the present disclosure relates to methods of inhibiting tyrosine kinases, including one or more of NTRK (eg, NTRK1, NTRK2, NTRK3), ALK, or ROS1, comprising efficaciously containing cells in said kinase An amount of at least one compound of the above formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate or a compound obtained by isotopically replacing any of the compounds of the formula (I), or Contact with at least one pharmaceutical composition of the present disclosure, wherein the contacting is in vitro, ex vivo or in vivo.

在一个实施方案中，本公开所述疾病或病症为携带NTRK(例如NTRK1、NTRK2、NTRK3)、ALK、ROS1基因融合突变的多种儿童和/或成人实体瘤，例如乳腺癌、结直肠癌、肺癌、胰腺癌、甲状腺癌、脑胶质瘤、各种肉瘤以及脑转移的肿瘤。In one embodiment, the disease or condition of the present disclosure is a plurality of childhood and/or adult solid tumors, such as breast cancer, colorectal cancer, that carry NTRK (eg, NTRK1, NTRK2, NTRK3), ALK, ROS1 gene fusion mutations, Lung cancer, pancreatic cancer, thyroid cancer, glioma, various sarcomas, and tumors of brain metastasis.

在制备本文通式(I)化合物所用的方法取决于所需化合物。一般而言，本公开化合物可通过本领域已知的标准技术和已知的类似方法进行制备。在本公开合成通式(I)化合物的方法中，反应所用的各种原材料是本领域技术人员根据已有知识可以制备得到的，或者是可以通过文献公知的方法制得的，或者是可以通过商业购得的。反应方案中所用的中间体、原材料、试剂、反应条件等均可以根据本领域技术人员已有知识可以作适当改变的。The method used in the preparation of the compounds of formula (I) herein depends on the desired compound. In general, the compounds of the present disclosure can be prepared by standard techniques known in the art and similar methods known in the art. In the method of synthesizing the compound of the formula (I) in the present disclosure, the various starting materials used in the reaction can be prepared by those skilled in the art based on prior knowledge, or can be obtained by methods well known in the literature, or can be passed. Commercially available. The intermediates, starting materials, reagents, reaction conditions and the like used in the reaction scheme can be appropriately changed according to the knowledge of those skilled in the art.

以下提供制备本公开化合物的示例性合成方法。其中所述的起始原料和试剂是市售可得的或可通过本领域技术人员已知的方法进行制备。Exemplary synthetic methods for preparing the compounds of the present disclosure are provided below. The starting materials and reagents described therein are either commercially available or can be prepared by methods known to those skilled in the art.

一个实施方案中，通式(I)化合物制备方法，如下面的合成路线所示。In one embodiment, the method of preparing the compound of formula (I) is as shown in the synthetic scheme below.

其中：L为

其中： Where: L is

among them:

A为-(CH ₂) _m-或-CHR ₅-； A is -(CH ₂ ) _m - or -CHR ₅ -;

X为-NH-或-NR ₆-； X is -NH- or -NR ₆ -;

Y为-C(＝O)-；Y is -C(=O)-;

Z为-NH。Z is -NH.

其中m，R ₅和R ₆的定义如本公开任意适用的实施方案中所述。 Wherein m, R ₅ and R ₆ are as defined in any suitable embodiment of the present disclosure.

1)X ¹＝OH的情况 1) Case where X ¹ = OH

将中间体7c、IA和三乙胺加入到适量乙醇中，置换氮气保护。升温至40-60℃(例如50℃)，搅拌反应5-8小时(例如6小时)。冷至室温，反应液过滤，所得滤饼用异丙醚润洗，干燥，得粗品标题产物IB，不经纯化直接进行下一步反应。将IB加入到二氯甲烷中，置换氮气保护。加入三苯基磷，冰水浴下搅拌10-20分钟(例如15分钟)。滴加偶氮二甲酸二异丙酯。撤去冰水浴，室温下搅拌反应15-20小时(例如18小时)。减压浓缩反应液，用硅胶柱色谱法纯化得到产物化合物I-1(X ¹＝OH)。 Intermediates 7c, IA and triethylamine were added to an appropriate amount of ethanol and replaced with nitrogen. The temperature is raised to 40-60 ° C (for example, 50 ° C), and the reaction is stirred for 5-8 hours (for example, 6 hours). After cooling to room temperature, the reaction mixture was filtered, and the obtained cake was washed with isopropyl ether and dried to give crude title product IB. IB was added to dichloromethane and replaced with nitrogen. Add triphenylphosphine and stir for 10-20 minutes (for example, 15 minutes) in an ice water bath. Diisopropyl azodicarboxylate was added dropwise. The ice water bath was removed and the reaction was stirred at room temperature for 15-20 hours (e.g., 18 hours). The reaction solution was concentrated under reduced pressure to give the product compound ^{I-1 (X 1 = OH} ) was purified by silica gel column chromatography.

2)X ¹＝Br的情况 2) Case where X ¹ = Br

将中间体7c、IA和三乙胺加入到适量乙醇中，置换氮气保护。升温至40-60℃(例如50℃)，搅拌反应5-8小时(例如7小时)。冷至室温，减压浓缩反应液，用硅胶柱色谱法纯化得到产物化合物I-1(X ¹＝Br)。 Intermediates 7c, IA and triethylamine were added to an appropriate amount of ethanol and replaced with nitrogen. The temperature is raised to 40-60 ° C (for example, 50 ° C), and the reaction is stirred for 5-8 hours (for example, 7 hours). Cooled to room temperature, the reaction solution was concentrated under reduced pressure to give the product compound ^{I-1 (X 1 = Br} ) was purified by silica gel column chromatography.

关于本公开所述通式(I)化合物的更多的制备方法请参见本文的具体实施方式，例如实施例1至实施例9。Further examples of the preparation of the compounds of the general formula (I) described in the present disclosure can be found in the specific embodiments herein, such as Examples 1 to 9.

术语定义Definition of Terms

在本文中用于本公开描述中的术语仅是为了描述具体实施方案而不旨在限制本公开。通常，本文使用的各种术语和短语具有本领域技术人员公知的一般含义，即便如此，本文仍然希望在此对这些术语和短语作更详尽的说明和解释，提及的术语和短语如有与公知含义不一致的，以本文所表述的含义为准。The terminology used in the description of the disclosure herein is for the purpose of description In general, the various terms and phrases used herein have the ordinary meanings that are well known to those skilled in the art, and even though, it is intended that the terms and phrases are described and explained in more detail herein. In the case of a known inconsistency, the meaning expressed in this document shall prevail.

在本文中，“和/或”是指和包括一或多个相关的所列项目的任意和所有可能的组合。将进一步理解，当用于本说明书时，术语“包含”和/或“包括”指定所述特征、整数、步骤、操作、元素和/或成分的存在，但不排除一或多个其他特征、整数、步骤、操作、元素、成分和/或它们的组的存在或添加。In this document, "and/or" refers to any and all possible combinations of the listed items that are associated with one or more. It will be further understood that the term "comprises" and/or "comprises", when used in the specification, is intended to mean the presence of the features, integers, steps, operations, elements and/or components, but does not exclude one or more other features, The presence or addition of integers, steps, operations, elements, components, and/or groups thereof.

本文中，“烷基”是指具有指定碳原子数的一价饱和烃链。例如，C _1-6烷基是指具有1-6个碳原子的烷基。C _1-4烷基是指具有1-4个碳原子的烷基。所述烷基可为直链或支链的。在一些实施方案中，支链烷基可能具有一个、两个或三个分支。示例性烷基包括，但不限于，甲基、甲基乙基、乙基、丙基(包括正丙基和异丙基)、甲基丙基、丁基(包括正丁基、异丁基和叔丁基)、戊基(包括正戊基、异戊基和新戊基)和己基。 As used herein, "alkyl" refers to a monovalent saturated hydrocarbon chain having the specified number of carbon atoms. For example, a C _1-6 alkyl group means an alkyl group having 1 to 6 carbon atoms. The C _1-4 alkyl group means an alkyl group having 1 to 4 carbon atoms. The alkyl group can be straight or branched. In some embodiments, a branched alkyl group may have one, two or three branches. Exemplary alkyl groups include, but are not limited to, methyl, methyl ethyl, ethyl, propyl (including n-propyl and isopropyl), methylpropyl, butyl (including n-butyl, isobutyl) And tert-butyl), pentyl (including n-pentyl, isopentyl and neopentyl) and hexyl.

本文中，“烷氧基”是指基团-O-烷基。例如，C _1-6烷氧基含有1-6个碳原子。C _1-4烷氧基含有1-4个碳原子。示例性的烷氧基包括，但不限于，甲氧基、乙氧基、丙氧基、丁氧基、戊氧基和己氧基。 As used herein, "alkoxy" refers to the group -O-alkyl. For example, a C _1-6 alkoxy group contains from 1 to 6 carbon atoms. The C _1-4 alkoxy group has 1 to 4 carbon atoms. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, and hexyloxy.

本文中使用的术语“氨基”意指-NH ₂。 The term "amino" as used herein means -NH _2.

本文中使用的术语“羟基”意指-OH。The term "hydroxy" as used herein means -OH.

本文中使用的术语“氰基”意指-CN。The term "cyano" as used herein means -CN.

本文中使用的术语“硝基”意指-NO ₂。 The term "nitro" as used herein means -NO ₂ .

在本文中使用的英文缩写具有下面的含义：The English abbreviations used in this article have the following meanings:

HATU：2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；HATU: 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

TEA：Triethylamine，三乙胺；TEA: Triethylamine, triethylamine;

DCM：Dichloromethane，二氯甲烷；DCM: Dichloromethane, dichloromethane;

DAST：Diethylaminosulfurtrifluoride，二乙胺基三氟化硫；DAST: Diethylaminosulfurtrifluoride, diethylaminosulfur trifluoride;

TFA：Trifluoroacetic acid，三氟乙酸；TFA: Trifluoroacetic acid, trifluoroacetic acid;

FDPP：Pentafluorophenyl diphenylphosphinate，五氟苯基二苯基磷酸酯；FDPP: Pentafluorophenyl diphenylphosphinate, pentafluorophenyl diphenyl phosphate;

DIPEA：Diisopropylethylamine，N,N-二异丙基乙胺；DIPEA: Diisopropylethylamine, N,N-diisopropylethylamine;

DMF：N,N-Dimethylformamide，N,N-二甲基甲酰胺；DMF: N, N-Dimethylformamide, N,N-dimethylformamide;

DIAD：Diisopropyl azodicarboxylate，偶氮二甲酸二异丙酯；DIAD: Diisopropyl azodicarboxylate, diisopropyl azodicarboxylate;

TFAA：Trifluoroacetic anhydride，三氟乙酸酐；TFAA: Trifluoroacetic anhydride, trifluoroacetic anhydride;

THF：Tetrahydrofuran，四氢呋喃；THF: Tetrahydrofuran, tetrahydrofuran;

TLC：薄层层析法；TLC: thin layer chromatography;

DMSO：二甲基亚砜；DMSO: dimethyl sulfoxide;

ATP：腺嘌呤核苷三磷酸，简称三磷酸腺苷；ATP: adenosine triphosphate, adenosine triphosphate;

Tyr：Tyrosine，酪氨酸。Tyr: Tyrosine, tyrosine.

本文中，单位“M”代表mol/L，“μM”代表μmol/L,“nM”代表nmol/L。Herein, the unit "M" represents mol/L, "μM" represents μmol/L, and "nM" represents nmol/L.

本文中，“受试者”是指哺乳动物受试者(例如，狗、猫、马、牛、绵羊、山羊、猴等)和人受试者，包括男性和女性受试者且包括新生儿、婴儿、少年、青少年、成人和老年受试者且还包括各种种族和族裔，包括，但不限于，白人、黑人、亚洲人、美洲印第安人和西班牙裔。As used herein, "subject" refers to mammalian subjects (eg, dogs, cats, horses, cows, sheep, goats, monkeys, etc.) and human subjects, including male and female subjects, and includes newborns. , infants, adolescents, adolescents, adults and elderly subjects and also include a variety of races and ethnicities, including, but not limited to, whites, blacks, Asians, American Indians, and Hispanics.

本文中，“药学上可接受的盐”是指保留目标化合物的所需生物活性并表现出最小的不希望的毒理学效应的盐。这些药学上可接受的盐可在该化合物的最终分离和纯化过程中原位制备或者通过单独地将其游离酸或游离碱形式的纯化的化合物分别与合适的碱或酸反应进行制备。As used herein, "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the target compound and exhibits minimal undesirable toxicological effects. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid.

本文中，提及本公开化合物或其他药物活性剂的“治疗有效量”是指在合理的医学判断范围内，足以治疗或预防患者疾病但足够低地避免严重副作用(在合理的利益/风险比)的量。化合物的治疗有效量将根据所选择的具体化合物(例如考虑化合物的效力、有效性和半衰期)；所选择的给药途径；所治疗的疾病；所治疗的疾病的严重性；所治疗的患者的年龄、大小、体重和身体疾病；所治疗的患者的医疗史；治疗持续时间；并行疗法的性质；所需的治疗效果；和类似因素而变化，但仍可由本领域技术人员进行常规确定。Reference herein to a "therapeutically effective amount" of a compound or other pharmaceutically active agent of the present disclosure is meant to be within a reasonable medical judgment sufficient to treat or prevent a disease in a patient but to be sufficiently low to avoid serious side effects (at a reasonable benefit/risk ratio) The amount. The therapeutically effective amount of the compound will depend on the particular compound selected (eg, considering the potency, effectiveness, and half-life of the compound); the route of administration selected; the condition being treated; the severity of the condition being treated; the patient being treated Age, size, weight and physical condition; medical history of the patient being treated; duration of treatment; nature of concurrent therapy; desired therapeutic effect; and similar factors, but still routinely determined by one skilled in the art.

另外需要指出，本公开化合物使用剂量和使用方法取决于诸多因素，包括患者的年龄、体重、性别、自然健康状况、营养状况、化合物的活性强度、服用时间、代谢速率、病症的严重程度以及诊治医师的主观判断。优选的使用剂量介于0.001－1000mg/kg体重/天。该使用量以每天单一剂量进行给药或以每天若干亚剂量进行给药，例如每天给药2、3、4、5或6个剂量。或者所述给药可间歇进行，例如每隔一天一次、每周一次或每月一次。盐或溶剂合物等的治疗有效量可确定为通式(I)化合物本身的治疗有效量的比例。It should also be noted that the dosage and method of use of the compounds of the present disclosure depend on a number of factors, including the age, weight, sex, natural health, nutritional status of the compound, the strength of the compound, the time of administration, the rate of metabolism, the severity of the condition, and the diagnosis and treatment. Subjective judgment of the physician. A preferred dosage is from 0.001 to 1000 mg/kg body weight per day. The amount administered is administered in a single daily dose or in several sub-doses per day, for example, 2, 3, 4, 5 or 6 doses per day. Alternatively, the administration can be carried out intermittently, for example once every other day, once a week or once a month. A therapeutically effective amount of a salt or solvate or the like can be determined as a ratio of a therapeutically effective amount of the compound of the formula (I) itself.

本文中，所用术语“化合物”是指如上所定义的通式(I)化合物，其呈任意形式，包括各种立体异构体、任意盐或非盐形式(例如，作为游离酸或游离碱的形式，或作为盐，尤其是其药学上可接受的盐)及其任意物理形式(例如，包括非固体形式(例如，液体或半固体形式)和固体形式(例如，无定形或结晶形式，具体的多晶物形式、溶剂合物形式，包括水合物形式(例如，单-、二-和半-水合物))，以及各种形式的混合物。As used herein, the term "compound" refers to a compound of formula (I) as defined above, in any form, including various stereoisomers, any salt or non-salt form (eg, as a free acid or a free base). Form, or as a salt, especially a pharmaceutically acceptable salt thereof, and any physical form thereof (for example, including a non-solid form (eg, a liquid or semi-solid form) and a solid form (eg, an amorphous or crystalline form, specifically Polymorphic forms, solvate forms, including hydrated forms (e.g., mono-, di-, and hemi-hydrates), as well as mixtures of various forms.

Detailed ways

下面将结合实施例对本公开的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本公开，而不应视为限定本公开的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。The embodiments of the present disclosure will be described in detail below with reference to the embodiments, but those skilled in the art will understand that the following examples are only intended to illustrate the disclosure, and are not intended to limit the scope of the disclosure. Those who do not specify the specific conditions in the examples are carried out according to the conventional conditions or the conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are conventional products that can be obtained commercially.

实施例1化合物1的制备Preparation of Compound 1 of Example 1

第一步first step

向反应瓶中依次投入1a(1.00g，2.18mmol，采用专利申请“WO2015/112806A2”公开的方法制备而得)、HATU(1.24g，3.26mmol)和二氯甲烷(10mL)，氮气置换保护下，冰浴滴加三乙胺(0.77g，7.63mmol)，滴毕，室温搅拌反应0.5小时，加入DL-丝氨酸甲酯盐酸盐(0.51g，3.26mmol)，搅拌反应4小时。加入水，用二氯甲烷萃取，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法纯化得1b(0.80g，白色固体)。1a (1.00 g, 2.18 mmol, prepared by the method disclosed in the patent application "WO2015/112806A2"), HATU (1.24 g, 3.26 mmol) and dichloromethane (10 mL) were sequentially added to the reaction flask under nitrogen substitution protection. Triethylamine (0.77 g, 7.63 mmol) was added dropwise to an ice bath, and the mixture was stirred and stirred at room temperature for 0.5 hr. DL-serine methyl ester hydrochloride (0.51 g, 3.26 mmol) was added, and the reaction was stirred for 4 hours. Water was added, and the mixture was extracted with methylene chloride. EtOAc (EtOAc)

第二步Second step

向反应瓶中依次投入1b(0.40g，0.71mmol)和二氯甲烷(8mL)，氮气置换保护下-78℃滴加DAST(0.13g，0.78mmol)，反应完毕。加入饱和碳酸氢钠溶液，用二氯甲烷萃取，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法纯化得1c(190.0mg，白色固体)。1b (0.40 g, 0.71 mmol) and dichloromethane (8 mL) were successively added to the reaction flask, and DAST (0.13 g, 0.78 mmol) was added dropwise at -78 ° C under nitrogen substitution, and the reaction was completed. A saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was evaporated, evaporated, evaporated, evaporated

LC-MS(ESI)m/z 543.1[M+1]LC-MS (ESI) m/z 543.1 [M+1]

第三步third step

向反应瓶中投入1c(190.0mg)、2mol/L NaOH(3mL)和甲醇(10mL)，室温反应，反应毕，浓缩除甲醇，加水溶解，1mol/L的盐酸水溶液调节PH约2～3，搅拌0.5小时，抽滤，干燥得1d(110.0mg，白色固体)，产率：59.4％。1 c (190.0 mg), 2 mol/L NaOH (3 mL) and methanol (10 mL) were added to the reaction flask, and the reaction was carried out at room temperature. After the reaction was completed, the methanol was concentrated, dissolved in water, and the pH was adjusted to about 2 to 3 with a 1 mol/L aqueous solution of hydrochloric acid. After stirring for 0.5 hours, suction filtration and drying gave 1 d (110.0 mg, white solid), yield: 59.4%.

第四步the fourth step

向反应瓶中投入1d(110.0mg，0.21mmol)、三氟乙酸(237.3mg，2.08mmol)和二氯甲烷(8mL)，室温搅拌反应16小时，减压浓缩反应液，得粗品1e(110.0mg)，产物不经纯化直接进行下一步反应。1 d (110.0 mg, 0.21 mmol), trifluoroacetic acid (237.3 mg, 2.08 mmol), and dichloromethane (8 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours, and the reaction mixture was concentrated under reduced vacuo. The product was directly subjected to the next reaction without purification.

第五步the fifth step

向反应瓶中依次投入1e(110.0mg，0.20mmol)、二氯甲烷(6mL)、N，N-二甲基甲酰胺(1.5mL)和N，N-二异丙基乙胺(215.0mg，1.66mmol)，搅拌加入FDPP(92.0mg，0.24mmol)，TLC检测反应完全，向体系中加入水，用二氯甲烷萃取，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法纯化得化合物1(26.7mg，白色固体)。1e (110.0 mg, 0.20 mmol), dichloromethane (6 mL), N,N-dimethylformamide (1.5 mL) and N,N-diisopropylethylamine (215.0 mg, 1.66mmol), FDPP (92.0mg, 0.24mmol) was added to the mixture. The reaction was completed by TLC. Water was added to the system, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, filtrate reduced Concentration by pressure and purification by silica gel column chromatography to afford compound 1 (26.7mg, white solid).

LC-MS(ESI)m/z 411.1[M+1]LC-MS (ESI) m/z 411.1 [M+1]

1H NMR(400MHz,CDCl3)δppm 2.77-2.99(m,2H),3.03-3.24(m,3H),3.55(d,J＝14.18Hz,1H),4.00-4.15(m,1H),4.15-4.33(m,2H),4.75(s,1H),6.20(d,J＝14.18Hz,1H),6.25(d,J＝8.07Hz,1H),6.68-6.82(m,1H),6.93(td,J＝8.31,2.93Hz,1H),7.01(dd,J＝8.31,2.45Hz,1H),7.79(s,1H),8.23(d,J＝7.83Hz,1H)。1H NMR (400MHz, CDCl3) δppm 2.77-2.99 (m, 2H), 3.03-3.24 (m, 3H), 3.55 (d, J = 14.18 Hz, 1H), 4.00-4.15 (m, 1H), 4.15-4.33 (m, 2H), 4.75 (s, 1H), 6.20 (d, J = 14.18 Hz, 1H), 6.25 (d, J = 8.07 Hz, 1H), 6.68-6.82 (m, 1H), 6.93 (td, J = 8.31, 2.93 Hz, 1H), 7.01 (dd, J = 8.31, 2.45 Hz, 1H), 7.79 (s, 1H), 8.23 (d, J = 7.83 Hz, 1H).

实施例2化合物2的制备Preparation of Compound 2 of Example 2

第一步first step

向反应瓶中依次投入2a(350.0mg，1.10mmol，采用专利申请“WO2015/112806A2”公开的方法制备而得)、HATU(631.2mg，1.66mmol)和N,N-二甲基甲酰胺(7mL)，置换氮气保护下，冰浴滴加三乙胺(168.0mg，1.66mmol)，滴毕，室温反应0.5小时。加入2-氨基-1,3-丙二醇(151.2mg，1.66mmol)，反应4小时，减压浓缩除去溶剂，用硅胶柱色谱法纯化得2b(0.41g，白色固体)，产率:95.3％。2a (350.0 mg, 1.10 mmol, prepared by the method disclosed in the patent application "WO2015/112806A2"), HATU (631.2 mg, 1.66 mmol) and N,N-dimethylformamide (7 mL) were sequentially added to the reaction flask. Under the protection of nitrogen, triethylamine (168.0 mg, 1.66 mmol) was added dropwise in an ice bath, and the mixture was reacted at room temperature for 0.5 hour. 2-Amino-1,3-propanediol (151.2 mg, 1.66 mmol) was added, and the mixture was stirred for 4 hr.

LC-MS(ESI)m/z 390.1[M+1]LC-MS (ESI) m/z 390.1 [M+1]

第二步Second step

向反应瓶中依次投入2b(200.0mg，0.51mmol)和二氯甲烷(10mL)，置换氮气保护下，-78℃下滴加DAST(248.4mg，1.54mmol)，滴毕，保持-78℃反应。TLC检测反应完全，加入饱和碳酸氢钠溶液淬灭，用二氯甲烷萃取，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法纯化得2c(56.0mg，白色固体)，产率29.3％。2b (200.0 mg, 0.51 mmol) and dichloromethane (10 mL) were sequentially placed in a reaction flask, and DAST (248.4 mg, 1.54 mmol) was added dropwise at -78 ° C under a nitrogen atmosphere, and the reaction was completed at -78 ° C. . The reaction was completed by TLC, EtOAc (EtOAc m.) 56.0 mg, white solid), yield 29.3%.

LC-MS(ESI)m/z 371.9[M+1]LC-MS (ESI) m/z 371.9 [M+1]

第三步third step

向反应瓶中依次投入2c(56.0mg，0.15mmol)、三苯基膦(99.0mg，0.38mmol)和二氯甲烷(5mL)，置换氮气保护下，滴加偶氮二甲酸二异丙酯(76.8mg，0.38mmol)，室温反应。减压浓缩反应液，用硅胶柱色谱法纯化得化合物2(5.0mg，淡红色固体)。2c (56.0 mg, 0.15 mmol), triphenylphosphine (99.0 mg, 0.38 mmol) and dichloromethane (5 mL) were sequentially placed in a reaction flask, and diisopropyl azodicarboxylate was added dropwise under a nitrogen atmosphere. 76.8 mg, 0.38 mmol), reacted at room temperature. The reaction mixture was concentrated under reduced vacuo.

1H NMR(400MHz,CDCl3)δppm 2.77-2.99(m,2H)，3.03-3.24(m,3H),3.55(d,J＝14.18Hz,1H),4.00-4.15(m,1H),4.15-4.33(m,2H),4.75(s,1H)，6.20(d,J＝14.18Hz,1H),6.25(d,J＝8.07Hz,1H),6.68-6.82(m,1H),6.93(td,J＝8.31,2.93Hz,1H),7.01(dd,J＝8.31,2.45Hz,1H),7.79(s,1H),8.23(d,J＝7.83Hz,1H)。1H NMR (400MHz, CDCl3) δppm 2.77-2.99 (m, 2H), 3.03-3.24 (m, 3H), 3.55 (d, J = 14.18 Hz, 1H), 4.00-4.15 (m, 1H), 4.15-4.33 (m, 2H), 4.75 (s, 1H), 6.20 (d, J = 14.18 Hz, 1H), 6.25 (d, J = 8.07 Hz, 1H), 6.68-6.82 (m, 1H), 6.93 (td, J = 8.31, 2.93 Hz, 1H), 7.01 (dd, J = 8.31, 2.45 Hz, 1H), 7.79 (s, 1H), 8.23 (d, J = 7.83 Hz, 1H).

实施例3化合物3的制备Preparation of Compound 3 of Example 3

第一步first step

向反应瓶中投入3a(1.21g，7.81mmol，采用专利申请“WO2015/112806A2”公开的方法制备而得)、3b(1.2g，7.81mmol，采用专利申请“WO2004/043940A1”公开的方法制备而得)、N,N-二异丙基乙胺(5.0g，39.05mmol)和正丁醇(18mL)，氮气置换保护下，升温至120℃，回流搅拌反应1小时。降温至室温，减压浓缩反应液，用硅胶柱色谱法纯化得3c(0.82g，白色固体)，产率：40％。3a (1.21 g, 7.81 mmol, prepared by the method disclosed in the patent application "WO2015/112806A2"), 3b (1.2 g, 7.81 mmol, prepared by the method disclosed in the patent application "WO2004/043940A1", was prepared in the reaction flask. N,N-diisopropylethylamine (5.0 g, 39.05 mmol) and n-butanol (18 mL) were heated under reduced pressure to 120 ° C and stirred for 1 hour under reflux. The mixture was cooled to room temperature, and the mixture was evaporated. mjjjjjj

第二步Second step

向反应瓶中依次投入3c(0.82g，2.94mmol)、BOC-2-氯乙胺(1.05g，5.88mmol)、碳酸钾(1.22g，8.82mmol)、碘化钠(0.13g，0.88mmol)和N,N-二甲基甲酰胺(8mL)，升温至80℃反应12小时。向反应体系中加入水，乙酸乙酯萃取，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得粗品3d(1.90g)。3 c (0.82 g, 2.94 mmol), BOC-2-chloroethylamine (1.05 g, 5.88 mmol), potassium carbonate (1.22 g, 8.82 mmol), sodium iodide (0.13 g, 0.88 mmol) were sequentially added to the reaction flask. N,N-dimethylformamide (8 mL) was heated to 80 ° C for 12 hours. Water was added to the reaction mixture, and the mixture was evaporated.

第三步third step

向反应瓶中依次投入3d粗品(1.90g)和1,4-二氧六环(25mL)，通HCl(g)，约1.5小时，TLC检测反应完全，过滤，滤饼用硅胶柱色谱法纯化得3e(1.0g，泛红白色固体)，两步产率：90％。3d crude product (1.90g) and 1,4-dioxane (25mL) were sequentially added to the reaction flask, and HCl (g) was passed for about 1.5 hours. The reaction was completely detected by TLC, and the filter cake was purified by silica gel column chromatography. 3e (1.0 g, reddish white solid), two-step yield: 90%.

第四步the fourth step

向反应瓶中依次投入3e(200.0mg，0.57mmol)、三氟乙酸酐(3mL)和1,2-二氯乙烷(3mL)，升温至50℃回流反应12小时，减压浓缩反应液，得粗品3f，产物不经纯化直接进行下一步反应。3e (200.0 mg, 0.57 mmol), trifluoroacetic anhydride (3 mL) and 1,2-dichloroethane (3 mL) were sequentially added to the reaction flask, and the mixture was heated to 50 ° C for 12 hours under reflux, and the reaction mixture was concentrated under reduced pressure. The crude product was obtained as 3f, and the product was subjected to the next reaction without purification.

LC-MS(ESI)m/z 508.1[M+1]LC-MS (ESI) m/z 508.1 [M+1]

第五步the fifth step

向反应瓶中依次投入粗品3f、2mol/L NaOH(aq)(0.5mL)、四氢呋喃(3mL)和甲醇(1mL)，室温搅拌反应2小时，TLC检测反应完全，加入乙酸乙酯萃取，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法纯化得3g(165.0mg)。Into the reaction flask, the crude product 3f, 2mol/L NaOH (aq) (0.5mL), tetrahydrofuran (3mL) and methanol (1mL) were added, and the reaction was stirred at room temperature for 2 hours. The reaction was complete by TLC, and extracted with ethyl acetate. The mixture was washed with a sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated.

第六步Step 6

向反应瓶中依次投入3g(143.0mg，0.35mmol)和二氯甲烷(4mL)，置换氮气保护下冰水降温，滴加三氟乙酸(118.9mg，1.04mmol)，后加入四甲基三乙酰氧基硼氢化铵，室温反应5小时，向体系中加入1mol/L HCl(aq)，二氯甲烷萃取，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法纯化得3(35.0mg)。3 g (143.0 mg, 0.35 mmol) and dichloromethane (4 mL) were sequentially added to the reaction flask, and the ice water was cooled under a nitrogen atmosphere, and trifluoroacetic acid (118.9 mg, 1.04 mmol) was added dropwise, followed by the addition of tetramethyl triacetyl. Ammonium oxyborohydride, reacted at room temperature for 5 hours, 1 mol/L HCl (aq) was added to the system, extracted with dichloromethane, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated. Purification by silica gel column chromatography gave 3 (35.0 mg).

LC-MS(ESI)m/z 396.2[M+1]LC-MS (ESI) m/z 396.2 [M+1]

实施例4化合物4的制备Preparation of Compound 4 of Example 4

第一步first step

向反应瓶中投入4a(1.1g，7.81mmol，采用文献Phytochemistry,2010,vol.71,#7,p.823-830公开的方法制备而得)、4b(1.55g,7.81mmol，采用专利申请“US2016/0137654A1”公开的方法制备而得)、N,N-二异丙基乙胺(5.0g,39.05mmol)和正丁醇(18mL),置换氮气保护下，升温至120℃回流搅拌反应1小时。降温至室温，减压浓缩反应液，用硅胶柱色谱法纯化得4c(2.12g,黄色固体)，产率：89.4％。4a (1.1 g, 7.81 mmol, prepared by the method disclosed in the literature Phytochemistry, 2010, vol. 71, #7, p. 823-830), 4b (1.55 g, 7.81 mmol) were used for the application of the patent application. Prepared by the method disclosed in "US2016/0137654A1", N,N-diisopropylethylamine (5.0g, 39.05mmol) and n-butanol (18mL), under the protection of nitrogen, the temperature is raised to 120 ° C, and the reaction is stirred under reflux. hour. The mixture was cooled to room temperature, and the mixture was evaporated,jjjjjjjjj

第二步Second step

向反应瓶中依次投入4c(200.0mg，0.66mmol)、4-溴丁酸乙酯(193.0mg，0.99mmol)、碳酸钾(273.6mg，1.98mmol)、碘化钠(10.0mg，0.07mmol)和N,N-二甲基甲酰胺(2mL)，升温至55℃反应4小时。向反应体系中加入水，乙酸乙酯萃取，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法纯化得4d(168mg，油状物)。4 c (200.0 mg, 0.66 mmol), 4-bromobutyric acid ethyl ester (193.0 mg, 0.99 mmol), potassium carbonate (273.6 mg, 1.98 mmol), sodium iodide (10.0 mg, 0.07 mmol) were sequentially added to the reaction flask. N,N-dimethylformamide (2 mL) was heated to 55 ° C for 4 hours. Water was added to the reaction mixture, and ethyl acetate was evaporated. EtOAc (EtOAc m.

第三步third step

向反应瓶中投入4d(168.0mg，0.4mmol)、氢氧化锂(30.0mg，1.2mmol)、水(1mL)、四氢呋喃(2mL)和甲醇(6mL)，升温回流反应5小时。降温，减压浓缩除去有机溶剂，剩余物用乙酸乙酯反萃，水相冰浴下用1mol/L稀盐酸调节PH约2～3，过滤，晾干，得4e(140mg，白色固体)。4 d (168.0 mg, 0.4 mmol), lithium hydroxide (30.0 mg, 1.2 mmol), water (1 mL), tetrahydrofuran (2 mL) and methanol (6 mL) were placed in a reaction flask, and the mixture was refluxed and reacted for 5 hours. The mixture was cooled, concentrated under reduced pressure to remove organic solvent, and the residue was taken from ethyl acetate. The mixture was adjusted to pH 2 to 3 with 1 mol/L of dilute hydrochloric acid, and filtered and dried to give 4e (140 mg, white solid).

第四步the fourth step

向反应瓶中依次投入4e(140.0mg，0.36mmol)、Pd/C(28mg，20％)和浓盐酸 (2mL)，置换氢气氛，升温至55℃反应1小时。减压浓缩得粗品4f(154mg，淡黄色固体)，产物不经纯化直接进行下一步反应。4e (140.0 mg, 0.36 mmol), Pd/C (28 mg, 20%) and concentrated hydrochloric acid (2 mL) were successively added to the reaction flask, and the hydrogen atmosphere was replaced, and the mixture was heated to 55 ° C for 1 hour. Concentration under reduced pressure afforded EtOAc (EtOAc m.

第五步the fifth step

向反应瓶中依次投入4f(154.0mg，0.36mmol)、二氯甲烷(11mL)、N,N-二甲基甲酰胺(7.5mL)、N,N-二异丙基乙胺(368.0mg，2.85mmol)，和五氟苯基二苯基膦酸酯(150.5，0.39mmol)，反应16小时。向体系中加入水，用二氯甲烷萃取，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法纯化得产物4(4.0mg)。4f (154.0 mg, 0.36 mmol), dichloromethane (11 mL), N,N-dimethylformamide (7.5 mL), N,N-diisopropylethylamine (368.0 mg, 2.85 mmol), and pentafluorophenyl diphenylphosphonate (150.5, 0.39 mmol) were reacted for 16 hours. Water was added to the system, which was extracted with methylene chloride, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and evaporated.

1H NMR(400MHz,CDCl3)δppm 1.93-2.04(m,2H),2.65(t,J＝7.34Hz,2H),3.66(d,J＝6.11Hz,2H),3.98-4.08(m,2H),6.58(s,1H),6.74-6.81(m,1H),6.87-6.98(m,3H),7.18(s,1H)。1H NMR (400MHz, CDCl3) δ ppm 1.93-2.04 (m, 2H), 2.65 (t, J = 7.34 Hz, 2H), 3.66 (d, J = 6.11 Hz, 2H), 3.98-4.08 (m, 2H), 6.58 (s, 1H), 6.74-6.81 (m, 1H), 6.87-6.98 (m, 3H), 7.18 (s, 1H).

实施例5化合物5和化合物6的制备Preparation of Compound 5 and Compound 6 of Example 5

第一步first step

将4c(212mg，0.70mmol)和N-Boc-2-氨基乙醇(169mg，1.05mmol)加入二氯甲烷(10mL)中，置换氮气保护。加入三苯基膦(275mg，1.05mmol)，冰水浴下搅拌15分钟。滴加偶氮二甲酸二异丙酯(212mg，1.05mmol)。撤去冰水浴，室温下搅拌反应18小时。反应液减压浓缩，用硅胶柱色谱法纯化得到5a(200mg，类白色固体)，产率：64.1％。4c (212 mg, 0.70 mmol) and N-Boc-2-aminoethanol (169 mg, 1.05 mmol) were taken in dichloromethane (10 mL). Triphenylphosphine (275 mg, 1.05 mmol) was added and stirred under ice-water bath for 15 min. Diisopropyl azodicarboxylate (212 mg, 1.05 mmol) was added dropwise. The ice water bath was removed and the reaction was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced vacuolululululululululululululululu

第二步Second step

将5a(200mg，0.45mmol)加入到甲醇(10mL)中，加入10％钯碳(50mg)，置换氢气保护。室温常压下搅拌氢化反应48小时。反应液用硅藻土过滤除去钯碳，滤液减压浓缩得粗产物。用硅胶柱色谱法纯化得5b(60mg，深褐色固体)，产率：32％。5a (200 mg, 0.45 mmol) was added to methanol (10 mL) and 10% palladium carbon (50 mg) was added and replaced with hydrogen. The hydrogenation reaction was stirred at room temperature under normal pressure for 48 hours. The reaction solution was filtered through Celite to remove palladium carbon, and the filtrate was concentrated to give a crude product. Purification by column chromatography on silica gel afforded 5b (yield:

第三步third step

将5b(60mg，0.144mmol)加入到二氯甲烷(5mL)中，加入三氟乙酸(0.5mL)，置换氮气保护。室温搅拌反应16小时。减压浓缩反应液，所得残余物加乙酸乙酯溶解，饱和碳酸氢钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得粗品5c(40mg，深褐色固体)，产率：87.7％，产物不经纯化直接进行下一步反应。5b (60 mg, 0.144 mmol) was added to dichloromethane (5 mL). The reaction was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced vacuol~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ %, the product was directly subjected to the next reaction without purification.

第四步the fourth step

将5c(40mg，0.126mmol)加入到二氯甲烷(10mL)中，置换氮气保护。冰水浴下，加入三乙胺(38mg，0.378mmol)和二氯亚砜(15mg，0.126mmol)。室温搅拌反应16小时。减压浓缩反应液，用硅胶柱色谱法纯化得到产物化合物5(7.0mg，白色固体)，产率：15.3％。5c (40 mg, 0.126 mmol) was added to dichloromethane (10 mL). Under ice water, triethylamine (38 mg, 0.378 mmol) and dichloromethane (15 mg, 0.126 mmol) were added. The reaction was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced vacuolulululululululululu

1H NMR(400MHz,CDCl3)δppm 3.81-3.85(m,2H),4.11-4.14(m,2H),4.55-4.56(m,2H),5.29-5.37(m,3H),6.08-6.12(m,1H),6.74-6.78(m,1H),6.94-6.98(m,2H),7.09-7.11(m,1H),8.12-8.14(m,1H),8.41(s,1H)。1H NMR (400MHz, CDCl3) δ ppm 3.81-3.85 (m, 2H), 4.11-4.14 (m, 2H), 4.55-4.56 (m, 2H), 5.29-5.37 (m, 3H), 6.08-6.12 (m, 1H), 6.74-6.78 (m, 1H), 6.94-6.98 (m, 2H), 7.09-7.11 (m, 1H), 8.12 - 8.14 (m, 1H), 8.41 (s, 1H).

第五步the fifth step

将5c(75mg，0.24mmol)溶解于吡啶(7.5mL)中，加入磺酰胺(159mg，1.66mmol)，置换氮气保护。升温至130℃，回流搅拌反应2小时。减压浓缩反应液，用硅胶柱色谱法纯化得到产物化合物6(4.1mg，浅褐色固体)，产率：4.6％。5c (75 mg, 0.24 mmol) was dissolved in pyridine (7.5 mL). The temperature was raised to 130 ° C, and the reaction was stirred under reflux for 2 hours. The reaction mixture was concentrated under reduced vacuolulululululululululu

1H NMR(400MHz,DMSO-d6)δppm 3.19-3.27(m,2H),4.05(t,J＝5.75Hz,2H),4.52(d,J＝4.89Hz,2H),6.30-6.40(m,1H),6.75-6.85(m,1H),6.90-7.04(m,2H),7.11(d,J＝8.56Hz,1H),7.92(s,1H),8.39-8.47(m,1H),10.78(s,1H)。1H NMR (400MHz, DMSO-d6) δppm 3.19-3.27 (m, 2H), 4.05 (t, J = 5.75 Hz, 2H), 4.52 (d, J = 4.89 Hz, 2H), 6.30-6.40 (m, 1H) ), 6.75-6.85 (m, 1H), 6.90-7.04 (m, 2H), 7.11 (d, J = 8.56 Hz, 1H), 7.92 (s, 1H), 8.39-8.47 (m, 1H), 10.78 ( s, 1H).

实施例6化合物7的制备Preparation of Compound 7 of Example 6

1)中间体7c的制备1) Preparation of intermediate 7c

第一步first step

将3a(4.66g，30mmol)、4b(5.96g，30mmol)、N,N-二异丙基乙胺(19.39g，150mmol)和正丁醇(100mL)加入到反应瓶中，置换氮气保护。升温至120℃，回流搅拌反应2小时。冷至室温，减压浓缩反应液，用硅胶柱色谱法纯化得到产物7a(7.1g，类白色固体)，产率：74.6％。3a (4.66 g, 30 mmol), 4b (5.96 g, 30 mmol), N,N-diisopropylethylamine (19.39 g, 150 mmol) and n-butanol (100 mL) were placed in a reaction flask and replaced with nitrogen. The temperature was raised to 120 ° C, and the reaction was stirred under reflux for 2 hours. The mixture was cooled to room temperature, and the mixture was evaporated. mjjjjjjj

LC-MS(ESI)m/z 318.1[M+1]LC-MS (ESI) m/z 318.1 [M+1]

第二步Second step

将7a(206mg，0.65mmol)溶解于四氢呋喃(7mL)中，加入锌粉(425mg，6.5mmol)，置换氮气保护。冰水浴冷至5℃，搅拌下向反应瓶中滴加盐酸水溶液(6mol/L，1.1mL)，控制瓶内温度低于30℃。撤去冰水浴，室温下搅拌反应1小时，得到含7b的粗品反应液，不经纯化直接进行下一步反应。7a (206 mg, 0.65 mmol) was dissolved in tetrahydrofuran (7 mL), and zinc powder (425 mg, 6.5 mmol) was added and replaced with nitrogen. The ice water bath was cooled to 5 ° C, and an aqueous hydrochloric acid solution (6 mol/L, 1.1 mL) was added dropwise to the reaction flask under stirring to control the temperature in the bottle to be lower than 30 °C. The ice water bath was removed, and the reaction was stirred at room temperature for 1 hour to obtain a crude reaction mixture containing 7b, and the next reaction was carried out without purification.

第三步third step

向第二步得到的含7b的粗品反应液中，滴加碳酸钾(179mg，1.3mmol)的水溶液(2mL)。冰水浴冷至5℃，滴加氯甲酸苯酯(122mg，0.78mmol)的四氢呋喃溶液(1mL)。室温下搅拌反应2小时。反应液加乙酸乙酯/水(10mL/5mL)萃取，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。所得残余物用硅胶柱色谱法纯化得到中间体7c(130mg，粉红色固体)，产率：49％。To the crude reaction mixture containing 7b obtained in the second step, an aqueous solution (2 mL) of potassium carbonate (179 mg, 1.3 mmol) was added dropwise. The ice water bath was cooled to 5 ° C, and a solution of phenyl chloroformate (122 mg, 0.78 mmol) in tetrahydrofuran (1 mL) was added dropwise. The reaction was stirred at room temperature for 2 hours. The reaction mixture was extracted with EtOAc EtOAc EtOAc. The obtained residue was purified to silicagel elut elut elut elut elut elut elut

LC-MS(ESI)m/z 408.1[M+1]LC-MS (ESI) m/z 408.1 [M+1]

2)化合物7的制备2) Preparation of Compound 7

第一步first step

将中间体7c(300mg，0.74mmol)、2-氨基乙醇盐酸盐(87mg，0.89mmol)和三乙胺(225mg，2.22mmol)加入到乙醇(15mL)中，置换氮气保护。升温至50℃，搅拌反应6小时。冷至室温，反应液过滤，所得滤饼用异丙醚润洗，干燥，得粗品产物7d(140mg，淡黄色固体)，产率：50.6％，产物不经纯化直接进行下一步反应。Intermediate 7c (300 mg, 0.74 mmol), 2-aminoethanol hydrochloride (87 mg, 0.89 mmol) and triethylamine (225 mg, 2.22 mmol). The temperature was raised to 50 ° C, and the reaction was stirred for 6 hours. After cooling to room temperature, the reaction mixture was filtered, and then filtered and evaporated to ethylamine.

LC-MS(ESI)m/z 375.1[M+1]LC-MS (ESI) m/z 375.1 [M+1]

第二步Second step

将7d(100mg，0.267mmol)加入到二氯甲烷(15mL)中，置换氮气保护。加入三苯基磷(140mg，0.534mmol)，冰水浴下搅拌15分钟。滴加偶氮二甲酸二异丙酯(108mg，0.534mmol)。撤去冰水浴，室温下搅拌反应18小时。减压浓缩反应液，用硅胶柱色谱法纯化得到产物化合物7(5mg，浅褐色固体)，产率：5.3％。7d (100 mg, 0.267 mmol) was added to dichloromethane (15 mL). Triphenylphosphine (140 mg, 0.534 mmol) was added and stirred under ice-water bath for 15 minutes. Diisopropyl azodicarboxylate (108 mg, 0.534 mmol) was added dropwise. The ice water bath was removed and the reaction was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced vacuolulululululululululu

LC-MS(ESI)m/z 357.1[M+1]LC-MS (ESI) m/z 357.1 [M+1]

1H NMR(400MHz,CDCl3)δppm 3.15-3.20(m,4H),3.81-3.86(m,1H),4.58(m,1H),4.67(m,2H),5.33(t,J＝4.52Hz,1H),6.22(d,J＝7.83Hz,1H),6.86-6.95(m,2H),7.42-7.83(m,1H),7.93(s,1H),8.06-8.10(m,1H),8.14-8.21(m,1H)。1H NMR (400MHz, CDCl3) δppm 3.15-3.20 (m, 4H), 3.81-3.86 (m, 1H), 4.58 (m, 1H), 4.67 (m, 2H), 5.33 (t, J = 4.52 Hz, 1H ), 6.22 (d, J = 7.83 Hz, 1H), 6.86-6.95 (m, 2H), 7.42 - 7.83 (m, 1H), 7.93 (s, 1H), 8.06-8.10 (m, 1H), 8.14 8.21 (m, 1H).

参照实施例6所述的方法制备下表中的化合物8-11。Compounds 8-11 in the following table were prepared by the method described in Example 6.

实施例7化合物12的制备Preparation of Compound 12 of Example 7

将中间体7c(300mg，0.74mmol)、3-溴丙胺氢溴酸盐(195mg，0.89mmol)和三乙胺(225mg，2.22mmol)加入到乙醇(15mL)中，置换氮气保护。升温至50℃，搅拌反应7小时。冷至室温，减压浓缩反应液，用硅胶柱色谱法纯化得到化合物12(10mg，黄色固体)，产率：3.6％。Intermediate 7c (300 mg, 0.74 mmol), 3-bromopropylamine hydrobromide (195 mg, 0.89 mmol) and triethylamine (225 mg, 2.22 mmol). The temperature was raised to 50 ° C, and the reaction was stirred for 7 hours. The mixture was cooled to room temperature, and the mixture was evaporated.

LC-MS(ESI)m/z 371.2[M+1]LC-MS (ESI) m/z 371.2 [M+1]

1H NMR(400MHz,DMSO-d6)δppm 2.11(quin,J＝7.52Hz,2H),3.08-3.18(m,3H),3.85(t,J＝7.46Hz,4H),4.68(s,2H),6.48(d,J＝7.83Hz,1H),6.72-6.96(m,3H),7.51(s,1H),7.77(s,1H)，8.41-8.60(m,1H),9.81(s,1H)。1H NMR (400MHz, DMSO-d6) δppm 2.11 (quin, J=7.52Hz, 2H), 3.08-3.18 (m, 3H), 3.85 (t, J = 7.46 Hz, 4H), 4.68 (s, 2H), 6.48 (d, J = 7.83 Hz, 1H), 6.72-6.96 (m, 3H), 7.51 (s, 1H), 7.77 (s, 1H), 8.41-8.60 (m, 1H), 9.81 (s, 1H) .

实施例8化合物13的制备Preparation of Compound 13 of Example 8

将13a(90mg，0.26mmol，采用专利申请“WO2015112806A2”公开的方法制备而得)/劳氏试剂(420mg，1.04mmol)加入到二氯甲烷(5mL)/甲苯(15mL)中，置换氮气保护。升温至90℃，搅拌反应7小时。冷至室温，减压浓缩反应液，用硅胶柱色谱法纯化得到化合物13(10mg，白色固体)，产率：10.8％。13a (90 mg, 0.26 mmol, prepared by the method disclosed in the patent application "WO2015112806A2") / Lloyd's reagent (420 mg, 1.04 mmol) was added to dichloromethane (5 mL) / toluene (15 mL). The temperature was raised to 90 ° C, and the reaction was stirred for 7 hours. The mixture was cooled to room temperature, and the mixture was evaporated.

LC-MS(ESI)m/z 358.1[M+1]LC-MS (ESI) m/z 358.1 [M+1]

1H NMR(400MHz,DMSO-d6)δppm 3.55(s,3H)，3.70-3.88(m,1H)，4.07(d,J＝15.16Hz,1H),4.13-4.22(m,1H),4.23-4.35(m,1H),4.47-4.60(m,1H),5.56(d,J＝14.92Hz,1H),6.70(d,J＝7.83Hz,1H),6.96-7.11(m,2H),7.21(dd,J＝9.17Hz,2.32Hz,1H),8.18(s,1H),8.74(d,J＝7.83Hz,1H),11.10(s,1H)。1H NMR (400MHz, DMSO-d6) δ ppm 3.55 (s, 3H), 3.70-3.88 (m, 1H), 4.07 (d, J = 15.16 Hz, 1H), 4.13-4.22 (m, 1H), 4.23-4.35 (m, 1H), 4.47-4.60 (m, 1H), 5.56 (d, J = 14.92 Hz, 1H), 6.70 (d, J = 7.83 Hz, 1H), 6.96-7.11 (m, 2H), 7.21. Dd, J = 9.17 Hz, 2.32 Hz, 1H), 8.18 (s, 1H), 8.74 (d, J = 7.83 Hz, 1H), 11.10 (s, 1H).

实施例9化合物14的制备Preparation of Compound 14 of Example 9

参考实施例13所述的制备方法制备得到化合物14。Compound 14 was prepared by the preparation method described in Example 13.

化合物14的分析数据如下：The analytical data for Compound 14 is as follows:

LC-MS(ESI)m/z 372.1[M+1]LC-MS (ESI) m/z 3721. [M+1]

1H NMR(400MHz,DMSO-d6)δppm 1.41(d,J＝7.09Hz,3H),1.46(d,J＝6.11Hz,3H),3.49(ddd,J＝14.00Hz,8.50Hz,2.20Hz,1H)4.41(ddd,J＝13.94Hz,7.70Hz,3.79Hz,1H),4.51-4.62(m,1H),5.47(quin,J＝6.48Hz,1H),6.34(d,J＝7.58Hz,1H),6.91-6.98(m,1H),6.99-7.05(m,1H),7.09(dd,J＝9.41Hz,3.06Hz,1H),8.11(s,1H),8.55(d,J＝7.58Hz,1H),8.93(d,J＝6.60Hz,1H),11.47(d,J＝5.62Hz,1H)。1H NMR (400MHz, DMSO-d6) δ ppm 1.41 (d, J = 7.09 Hz, 3H), 1.46 (d, J = 6.11 Hz, 3H), 3.49 (ddd, J = 14.00 Hz, 8.50 Hz, 2.20 Hz, 1H ) 4.41 (ddd, J = 13.94 Hz, 7.70 Hz, 3.79 Hz, 1H), 4.51-4.62 (m, 1H), 5.47 (quin, J = 6.48 Hz, 1H), 6.34 (d, J = 7.58 Hz, 1H) ), 6.91-6.98 (m, 1H), 6.99-7.05 (m, 1H), 7.09 (dd, J = 9.41 Hz, 3.06 Hz, 1H), 8.11 (s, 1H), 8.55 (d, J = 7.58 Hz) , 1H), 8.93 (d, J = 6.60 Hz, 1H), 11.47 (d, J = 5.62 Hz, 1H).

实施例10体外酶活性抑制实验Example 10 In vitro enzyme activity inhibition experiment

本实验使用

Kinase Assay Kit(购自赛默飞世尔科技公司(Thermo Fisher Scientific)，货号：PV3190)测定待测化合物的酶抑制活性。 This experiment uses

The Kinase Assay Kit (purchased from Thermo Fisher Scientific, Cat. No. PV3190) measures the enzyme inhibitory activity of the test compound.

待测化合物为本文实施例1至9制备的化合物1-14，以及阳性对照药物RXDX-101、LOXO-101、TPX-0005(其中：RXDX101购自selleck，货号：S7998；LOXO-101购自selleck，货号：S7960；TPX-0005参照WO2015112806A2公开的方法制备而成)。The test compounds were the compounds 1-14 prepared in Examples 1 to 9 herein, and the positive control drugs RXDX-101, LOXO-101, TPX-0005 (where: RXDX101 was purchased from Selleck, Cat. No. S7998; LOXO-101 was purchased from Selleck , Item No.: S7960; TPX-0005 is prepared according to the method disclosed in WO2015112806A2).

待测化合物的配置：将待测化合物溶解在DMSO中配置成浓度为20mM的母液，使用时先将待测化合物用DMSO稀释成不同浓度梯度，然后分别取4μl化合物加到46μl的H ₂O中，用振荡器混匀； Configuration of the test compound: The test compound was dissolved in DMSO to prepare a mother liquor at a concentration of 20 mM. The test compound was first diluted with DMSO to a different concentration gradient, and then 4 μl of the compound was added to 46 μl of H ₂ O. , mix with the oscillator;

ATP的配置：将试剂盒中的5×Kinase Buffer用去离子水配成1.33×Kinase Bufferr，将10mM ATP用1.33×Kinase Buffer稀释，配成不同靶点实验终浓度的4倍,在不同靶点实验中ATP的终浓度分别为NTRK1：400uM；NTRK2：25uM；NTRK3：50uM。ATP configuration: 5×Kinase Buffer in the kit was made into 1.33×Kinase Bufferr with deionized water, and 10 mM ATP was diluted with 1.33×Kinase Buffer to prepare 4 times of the final concentration of different target experiments at different targets. The final concentrations of ATP in the experiment were NTRK1: 400 uM; NTRK2: 25 uM; NTRK3: 50 uM.

Kinase/Peptide混合溶液的配制：将酶和底物用1.33×Kinase Buffer配成终浓度的2倍，反应体系中酶和底物终浓度分别为：Preparation of Kinase/Peptide mixed solution: The enzyme and substrate were mixed with 1.33×Kinase Buffer to a final concentration of 2 times. The final concentration of enzyme and substrate in the reaction system were:

NTRK1终浓度为1μg/ml，底物Tyr 01终浓度为2μM；The final concentration of NTRK1 was 1 μg/ml, and the final concentration of the substrate Tyr 01 was 2 μM.

NTRK2终浓度为0.3μg/ml，底物Tyr 01终浓度为2μM；The final concentration of NTRK2 was 0.3 μg/ml, and the final concentration of the substrate Tyr 01 was 2 μM.

NTRK3终浓度为1μg/ml，底物Tyr 01终浓度为2μM。The final concentration of NTRK3 was 1 μg/ml, and the final concentration of the substrate Tyr 01 was 2 μM.

Phospho-peptide溶液的配制：用1.33×Kinase Buffer将Tyr 1Phospho-peptide稀释250倍。Preparation of Phospho-peptide solution: Tyr 1 Phospho-peptide was diluted 250-fold with 1.33 x Kinase Buffer.

取384孔板，按照表1所示将Kinase/Peptide混合溶液、ATP以及待测化合物分别加入384孔板中。室温(20℃-25℃)孵育1个小时后，用development buffer配置development reagent B，每孔加入5μl，室温(20℃-25℃)中再孵育1个小时后，用Tecan酶标仪(购自Tecan公司，型号：Spark10M)检测(Ex.400nm,Em.445nm)和(Ex.400nm,Em.520nm)两种条件下的数值，计算IC ₅₀值，结果见表2。 A 384-well plate was taken, and the Kinase/Peptide mixed solution, ATP, and the test compound were separately added to a 384-well plate as shown in Table 1. After incubating for 1 hour at room temperature (20 ° C -25 ° C), use development buffer to configure development reagent B, add 5 μl per well, incubate for 1 hour at room temperature (20 ° C -25 ° C), and use Tecan microplate reader (purchase The values of IC _{50 were} calculated from the values of Tecan Corporation, model: Spark 10M (Ex. 400 nm, Em. 445 nm) and (Ex. 400 nm, Em. 520 nm). The results are shown in Table 2.

表1Table 1

表2Table 2

尽管本公开的具体实施方式已经得到详细的描述，本领域技术人员将会理解。根据已经公开的所有教导，可以对那些细节进行各种修改和替换，这些改变均在本公开的保护范围之内。本公开的全部范围由所附权利要求及其任何等同物给出。Although specific embodiments of the present disclosure have been described in detail, those skilled in the art will understand. Various modifications and alterations of the details are possible in light of the teachings of the invention. The full scope of the disclosure is given by the appended claims and any equivalents thereof.

Claims

a compound of the formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or a compound obtained by isotopically replacing any atom in the compound of the formula (I),

among them:

R ₁ , R ₂ , R ₃ , R ₄ are each independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, nitro, cyano or An amino group, wherein the C _1-6 alkyl group or C _1-6 alkoxy group may be optionally fluoro, chloro, bromo, iodo, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro Mono- or poly-substituted with a cyano group;

L is

Or -(CH ₂ ) _n -NH-B-, where:

A is -(CH ₂ ) _m - or -CHR ₅ -;

X is -CH ₂ -, -NH- or -NR ₆ -;

Y is -C(=O)-, -S(=O)- or -S(=O) ₂ -;

Z is -NH- or

B is -C(=S)- or -CHR ₇ -;

R ₅ and R ₆ are each independently hydrazine, fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano or amino, wherein said C _{1- The 4-} alkyl or C _1-4 alkoxy group may be optionally monosubstituted by fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino Or multiple substitutions;

R ₇ is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano or amino, wherein said C _1-4 alkyl or The C _1-4 alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino;

m, n are each independently 1, 2, 3, 4 or 5.

The compound of the formula (I) according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of the formula (I) obtained by isotopic substitution thereof Compound, where:

R ₁ , R ₂ , R ₃ , R ₄ are each independently hydrogen, deuterium, fluorine, C _1-6 alkyl or C _1-6 alkoxy, wherein said C _1-6 alkyl or C _1-6 The alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino;

For example, the C _1-6 alkyl or C _1-6 alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino.

The compound of the formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of the formula (I) after its isotopic substitution The resulting compound, wherein:

Wherein: R ₁ , R ₂ , R ₃ , R ₄ are each independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert Butyl, n-pentyl, isopentyl, neopentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy or hexyloxy.

A compound of the formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of the formula (I) a compound obtained after isotope substitution, wherein: R ₅ is hydrazine, fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano or amino, or

R ₅ is C _1-4 alkyl or C _1-4 alkoxy, wherein said C _1-4 alkyl or C _1-4 alkoxy group may be optionally fluoro, chloro, bromo, iodo, C _{1 -4} alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino mono- or poly-substituted;

Preferably, R ₅ is C _1-4 alkyl, wherein said C _1-4 alkyl group may be optionally fluoro, chloro, bromo, iodo, C _1-4 alkyl, C _1-4 alkoxy, a single or multiple substitution of a hydroxyl group, a nitro group, a cyano group, or an amino group;

Preferably, R ₅ is C _1-4 alkyl, wherein the C _1-4 alkyl group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine;

Preferably, R ₅ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, wherein said R ₅ may be optionally fluoro, chloro, bromo, iodo Substituted or substituted

Preferably, R ₅ is methyl, ethyl, n-propyl or isopropyl;

Preferably, R ₅ is a hydroxyl group, a nitro group, a cyano group, an amino group;

Preferably, R ₅ is n-propyl or isopropyl;

Preferably, R ₅ is isopropyl.

A compound of the formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of the formula (I) a compound obtained after isotope substitution, wherein: R ₆ is hydrazine, fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano or amino, or

R ₆ is C _1-4 alkyl or C _1-4 alkoxy, wherein the C _1-4 alkyl or C _1-4 alkoxy group may be optionally fluoro, chloro, bromo, iodo, C _{1 -4} alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino mono- or poly-substituted;

Preferably, R ₆ is C _1-4 alkyl, wherein said C _1-4 alkyl group may be optionally fluoro, chloro, bromo, iodo, C _1-4 alkyl, C _1-4 alkoxy, a single or multiple substitution of a hydroxyl group, a nitro group, a cyano group, or an amino group;

Preferably, R ₆ is C _1-4 alkyl, wherein the C _1-4 alkyl group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine;

Preferably, R ₆ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, wherein said R ₆ may optionally be fluoro, chloro, bromo, iodo Substituted or substituted

Preferably, R ₆ is methyl, ethyl, n-propyl or isopropyl;

Preferably, R ₆ is methyl or ethyl;

Preferably, R ₆ is a methyl group.

A compound of the formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of the formula (I) a compound obtained after isotope substitution, wherein: R ₇ is hydrazine, fluorine, chlorine, bromine, iodine, hydroxy, nitro, cyano or amino, or

R ₇ is C _1-4 alkyl or C _1-4 alkoxy, wherein the C _1-4 alkyl or C _1-4 alkoxy group may be optionally fluoro, chloro, bromo, iodo, C _{1 -4} alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino mono- or poly-substituted;

Preferably, R ₇ is C _1-4 alkyl, wherein said C _1-4 alkyl group may be optionally fluoro, chloro, bromo, iodo, C _1-4 alkyl, C _1-4 alkoxy, a single or multiple substitution of a hydroxyl group, a nitro group, a cyano group, or an amino group;

Preferably, R ₇ is C _1-4 alkyl, wherein the C _1-4 alkyl group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine;

Preferably, R ₇ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, wherein said R ₇ may be optionally fluoro, chloro, bromo, iodo Substituted or substituted

Preferably, R ₇ is ethyl, n-propyl or isopropyl;

Preferably, R ₇ is methyl, monofluoromethyl, difluoromethyl or trifluoromethyl;

More preferably, R ₇ is a trifluoromethyl group.

A compound of the formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of the formula (I) a compound obtained after isotope substitution, wherein: m is preferably 1, 2 or 3, or,

m is preferably 4 or 5;

Preferably, m is 1 or 2;

Preferably, m is 1;

Preferably, m is 2.

A compound of the formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of the formula (I) a compound obtained after isotope substitution, wherein: n is preferably 1, 2 or 3, or,

n is preferably 4 or 5;

Preferably, n is 1 or 2;

Preferably, n is 1;

Preferably, n is 2.

L is

among them:

A is -(CH ₂ ) _m - or -CHR ₅ -;

X is -CH ₂ -, -NH- or -NR ₆ -;

Y is -C(=O)-, -S(=O)- or -S(=O) ₂ -;

Z is -NH- or

m is 1 or 2.

L is -(CH ₂ ) _n -NH-B-, where:

B is -C(=S)- or -CHR ₇ -;

R ₇ is C _1-4 alkyl, wherein the C _1-4 alkyl group may be optionally fluoro, chloro, bromo, iodo, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro Mono- or poly-substituted with a cyano group;

n is 1, 2, 3, 4 or 5.

R ₁ is hydrogen or methyl;

R ₂ is hydrogen or methyl;

R ₃ is hydrogen or methyl;

R ₄ is fluorine;

L is

Or -(CH ₂ ) _n -NH-B-, where:

A is -(CH ₂ ) _m - or -CHR ₅ -;

X is -CH ₂ -, -NH- or -NR ₆ -;

Y is -C(=O)-, -S(=O)- or -S(=O) ₂ -

Z is -NH- or

B is -C(=S)- or -CHR ₇ -;

R ₅ is an isopropyl group;

R ₆ is a methyl group;

R ₇ is a trifluoromethyl group;

m is 1 or 2;

n is 1 or 2.

The compound of claim 1 which is selected from the group consisting of:

as well as,

Pharmaceutically acceptable salts, stereoisomers, solvates of these compounds.

A pharmaceutical composition comprising at least one compound of the formula (I) according to any one of claims 1 to 12, a pharmaceutically acceptable salt, a stereoisomer, a solvate thereof or a compound of the formula (I) A compound obtained by replacing any of its atoms with its isotope, and a pharmaceutically acceptable carrier or excipient.

Any one of the compounds of the formula (I), a pharmaceutically acceptable salt, a stereoisomer, a solvate thereof or a compound of the formula (I) according to any one of claims 1 to 12, which is obtained by isotopic substitution thereof a compound, or a pharmaceutical composition of claim 13, for use in the manufacture of a medicament for treating or ameliorating the severity of the disease or condition, or in the preparation as a tyrosine kinase (including NTRK (eg NTRK1) Use of a drug for one or more of the inhibitors of NTRK2, NTRK3), ALK or ROS1,

Preferably, the disease or condition is a plurality of childhood and/or adult solid tumors carrying NTRK (eg, NTRK1, NTRK2, NTRK3), ALK, ROS1 gene fusion mutations, such as breast cancer, colorectal cancer, lung cancer, pancreatic cancer, Thyroid cancer, glioma, various sarcomas, and tumors of brain metastasis.

A method of treating or lessening the severity of a disease or condition comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 12; An acceptable salt, stereoisomer, solvate or compound obtained by isotopic substitution of any of the compounds of formula (I),

A method of inhibiting a tyrosine kinase, including one or more of NTRK (eg, NTRK1, NTRK2, NTRK3), ALK, or ROS1, comprising: cultivating a cell comprising the kinase with an effective amount of at least one claim a compound of any one of the above formulas (I), a pharmaceutically acceptable salt, a stereoisomer, a solvate thereof or a compound of the formula (I), which has been subjected to isotopic substitution thereof, in any one of 1 to 12; Or in contact with at least one pharmaceutical composition of claim 13, wherein the contacting is in vitro, ex vivo or in vivo.

Any one of the compounds of the formula (I), a pharmaceutically acceptable salt, a stereoisomer, a solvate thereof or a compound of the formula (I) according to any one of claims 1 to 12, which is obtained by isotopic substitution thereof a compound for use in or ameliorating the severity of the disease or condition, or for inhibiting one or more of tyrosine kinases, including NTRK (eg, NTRK1, NTRK2, NTRK3), ALK, or ROS1 ),