TW201932472A - Compound having macrocyclic molecular structure and use thereof - Google Patents

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

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.

The disclosure relates to the field of medicinal chemistry, and in particular 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.

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 signal transduction, 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.

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 receptor can induce receptor dimerization, phosphorylation and initiate downstream signal transduction pathways of PI3K, RAS/MAPK/ERK and PLC-γ by binding to neurotrophic factors, and neural cell growth and development, pain perception So closely related. In rare cases, the NTRK gene is also fused to other genes, resulting in uncontrolled TRK signaling pathways, thereby 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.

The current rapid advances in NTRK inhibitors are 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 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. It is a powerful 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 initiating RAS and PI3K signaling cascades. RAS activation may result in more aggressive features of the tumor and a worse clinical outcome.

Pfizer's Crizotinib is the first FDA-approved ALK small molecule inhibitor. Later, Novartis's Ceritinib, Roche's Alectinib, and recently approved Ariad's Brigatinib are second-generation, second-line targeted drugs that can be effective after Crizotinib. Overcome the resistance of 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.

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. The rearrangement of ROS1 leads to the sustained initiation of kinases, 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 cell lung cancer, were also found in several other malignant tumors. Among them, the frequency of mutation in non-small cell lung cancer is 1% to 2%.

Crizotinib, which has been approved by the FDA for its positive 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 resistance mutations produced by Crizotinib first-line therapy, such as Solvent front mutation etc. Therefore, they are also mainly conducting clinical trials of initial patients.

There is an urgent need to develop compounds having the desired inhibitory activity, particularly compounds having inhibitory activity against a variety of kinases.

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), Wherein: R ₁ , R ₂ , R ₃ , and R ₄ are each independently hydrogen, hydrazine, fluorine, chlorine, bromine, iodine, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, nitro, cyanide Or an amino group, wherein the C _1-6 alkyl or C _1-6 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; L is , Or -(CH ₂ ) _n -NH-B-, wherein: 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, a hydroxy, nitro, cyano or amino group, 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 polysubstituted; R ₇ is hydrogen, hydrazine, fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy , nitro, cyano or amino, 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 alkane Oxyl, hydroxy, nitro, cyano, amino is mono- or polysubstituted; m, n are each independently 1, 2, 3, 4 or 5.

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 any of the compounds of the formula (I) A compound obtained by its isotopic substitution, and a pharmaceutically acceptable carrier or excipient.

The present disclosure also relates to the preparation of a compound of the formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate or a compound of the formula (I) obtained by isotopic substitution thereof. Use in the treatment of a disease or condition or a medicament for alleviating the severity of the disease or condition, or in the preparation of an inhibitor as one or more of a tyrosine kinase (including NTRK (eg, NTRK1, NTRK2, NTRK3), ALK or ROS1) Use of the drug.

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 stereo A compound obtained by isomer substitution of an isomer, a solvate or any of the compounds of the formula (I).

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 subjecting a cell comprising the kinase to an effective amount of at least one of the above formulas (I) a compound, a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate or a compound obtained by isotopic substitution of any of the compounds of the formula (I), or with at least one of the present disclosure The pharmaceutical composition is contacted, wherein the contact is in vitro, ex vivo or in vivo.

The present disclosure also relates to at least one 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), The 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 the treatment of a disease or condition or amelioration of the disease or condition Severity, or used to inhibit tyrosine kinases (including one or more of NTRK (eg, NTRK1, NTRK2, NTRK3), ALK, or ROS1).

In some embodiments, the disease or condition is a plurality of childhood and/or adult solid tumors, such as breast cancer, colorectal cancer, lung cancer, that carry NTRK (eg, NTRK1, NTRK2, NTRK3), ALK, ROS1 gene fusion mutations. Pancreatic cancer, thyroid cancer, glioma, various sarcomas, and tumors of brain metastasis.

This disclosure is now described in detail. It should be understood that the present disclosure may be embodied in various forms and should not be construed as being limited to the embodiments herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.

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, Wherein: R ₁ , R ₂ , R ₃ , and R ₄ are each independently hydrogen, hydrazine, fluorine, chlorine, bromine, iodine, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, nitro, cyanide Or an amino group, wherein the C _1-6 alkyl or C _1-6 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; L is , Or -(CH ₂ ) _n -NH-B-, wherein: 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, a hydroxy, nitro, cyano or amino group, 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 polysubstituted; R ₇ is hydrogen, hydrazine, fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy , nitro, cyano or amino, 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 alkane Oxyl, hydroxy, nitro, cyano, amino is mono- or polysubstituted; m, n are each independently 1, 2, 3, 4 or 5.

In one embodiment, the present disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of a compound of formula (I), which is obtained by isotopic substitution thereof a compound, or any suitable embodiment of the present disclosure, wherein: R ₁ , R ₂ , R ₃ , R ₄ are each independently hydrogen, deuterium, fluorine, C _1-6 alkyl or C _1-6 alkoxy, Wherein the C _1-6 alkyl or C _1-6 alkoxy group may be optionally fluoro, chloro, bromo, iodo, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyanide Mono- or poly-substituted; for example, the C _1-6 alkyl or C _1-6 alkoxy group may be optionally substituted by fluorine, chlorine, bromine, iodine, hydroxy, nitro, cyano, amino Or polysubstituted; for example, the C _1-6 alkyl or C _1-6 alkoxy group may be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.

In another embodiment, the present disclosure relates to a 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 are each independently hydrogen, fluoro, 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 Or a mono- or poly-substituted amino; for example, the C _1-4 alkyl or C _1-4 alkoxy group may be optionally monosubstituted by fluorine, chlorine, bromine, iodine, hydroxy, nitro, cyano, amino or Polysubstituted; for example, the C _1-4 alkyl or C _1-4 alkoxy group may be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.

In another embodiment, the present disclosure relates to a 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 ₁ , R ₂ , R ₃ , R ₄ are each independently hydrogen, fluoro or C _1-6 alkyl, wherein the C _1-6 alkyl group can 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 _1-4 alkane The group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxy, nitro, cyano, amino; for example, the C _1-4 alkyl may be optionally fluoro, chloro, bromo, hydroxy , nitro, amino monosubstituted or polysubstituted.

In another embodiment, the present disclosure relates to a 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 are each independently hydrogen, fluoro or C _1-4 alkyl, wherein the C _1-4 alkyl group can 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 _1-4 alkane The group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxy, nitro, cyano, amino; for example, the C _1-4 alkyl may be optionally fluoro, chloro, bromo, hydroxy , nitro, amino monosubstituted or polysubstituted.

In another embodiment, the present disclosure relates to a 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 are each independently hydrogen, fluoro or C _1-6 alkyl.

In another embodiment, the present disclosure relates to a 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 are each independently hydrogen, fluoro or C _1-4 alkyl.

In another embodiment, the present disclosure relates to a 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 are each independently hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy or Hexyloxy.

In another embodiment, the present disclosure relates to a 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 are each independently hydrogen, fluoro, chloro, bromo, iodo.

In another embodiment, the present disclosure relates to a 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 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl Base, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl.

In another embodiment, the present disclosure relates to a 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 are each independently methoxy, ethoxy, propoxy, butoxy, pentyloxy or Hexyloxy.

In another embodiment, the present disclosure relates to a 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 are each independently hydrogen, fluoro, methyl, ethyl, n-propyl, isopropyl, n-butyl Base, isobutyl, tert-butyl, methoxy, ethoxy, propoxy or butoxy.

In another embodiment, the present disclosure relates to a 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 are each independently hydrogen, fluoro, methyl, ethyl, n-propyl, isopropyl, n-butyl Base, isobutyl, tert-butyl.

In another embodiment, the present disclosure relates to a 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 are each independently hydrogen, fluoro, methyl, ethyl, n-propyl or isopropyl.

In another embodiment, the present disclosure relates to a 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 are each independently hydrogen, fluoro, methyl, ethyl.

In another embodiment, the present disclosure relates to a 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 are each independently hydrogen, fluoro or methyl.

In one embodiment, the present disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of a compound of formula (I), which is obtained by isotopic substitution thereof A compound, or any suitable embodiment of the invention, wherein: R ₁ is hydrogen, deuterium, C _1-6 alkyl or C _1-6 alkoxy, wherein the C _1-6 alkyl or C _1-6 alkane The oxy 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 The -6} alkyl or C _1-6 alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxy, nitro, cyano, amino; for example, the C _1-6 alkyl group or The C _1-6 alkoxy group may be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.

In another embodiment, the present disclosure relates to a 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 invention, wherein: R ₁ is hydrogen, C _1-4 alkyl or C _1-4 alkoxy, wherein the 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; for example, the C _{1- The 4-} alkyl or C _1-4 alkoxy group may be optionally mono- or polysubstituted by fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino; for example, the C _1-4 alkyl or C _{The 1-4} alkoxy group may be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.

In another embodiment, the present disclosure relates to a 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 or C _1-6 alkyl, wherein the C _1-6 alkyl group can be optionally fluoro, chloro, bromo, iodo, C _{1 -4} alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino mono- or polysubstituted; for example, the C _1-4 alkyl may be optionally fluoro, chloro, bromo, iodo, The hydroxy, nitro, cyano, amino group is mono- or polysubstituted; for example, the C _1-4 alkyl group may be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.

In another embodiment, the present disclosure relates to a 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 or C _1-4 alkyl, wherein the C _1-4 alkyl group can be optionally fluoro, chloro, bromo, iodo, C _{1 -4} alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino mono- or polysubstituted; for example, the C _1-4 alkyl may be optionally fluoro, chloro, bromo, iodo, The hydroxy, nitro, cyano, amino group is mono- or polysubstituted; for example, the C _1-4 alkyl group may be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.

In another embodiment, the present disclosure relates to a 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 or C _1-6 alkyl.

In another embodiment, the present disclosure relates to a 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 or C _1-4 alkyl.

In another embodiment, the present disclosure relates to a 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 invention, 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.

In another embodiment, the present disclosure relates to a 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 invention, wherein: R ₁ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, Ethoxy, propoxy or butoxy.

In another embodiment, the present disclosure relates to a 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, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.

In another embodiment, the present disclosure relates to a 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, methyl, ethyl, n-propyl or isopropyl.

In another embodiment, the present disclosure relates to a 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, methyl, ethyl.

In another embodiment, the present disclosure relates to a 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 or methyl.

In another embodiment, the present disclosure relates to a 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.

In another embodiment, the present disclosure relates to a 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 methyl.

In another embodiment, the present disclosure relates to a 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 ethyl.

In another embodiment, the present disclosure relates to a 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 n-propyl.

In another embodiment, the present disclosure relates to a 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 isopropyl.

In another embodiment, the present disclosure relates to a 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 n-butyl.

In another embodiment, the present disclosure relates to a 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 isobutyl.

In another embodiment, the present disclosure relates to a 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 tert-butyl.

In one embodiment, the present disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of a compound of formula (I), which is obtained by isotopic substitution thereof a compound, or any suitable embodiment of the present invention, wherein: R ₂ is hydrogen, deuterium, C _1-6 alkyl or C _1-6 alkoxy, wherein the C _1-6 alkyl or C _1-6 alkane The oxy 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 The -6} alkyl or C _1-6 alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxy, nitro, cyano, amino; for example, the C _1-6 alkyl group or The C _1-6 alkoxy group may be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.

In another embodiment, the present disclosure relates to a 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, C _1-4 alkyl or C _1-4 alkoxy, wherein the 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; for example, the C _{1- The 4-} alkyl or C _1-4 alkoxy group may be optionally mono- or polysubstituted by fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino; for example, the C _1-4 alkyl or C _{The 1-4} alkoxy group may be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.

In another embodiment, the present disclosure relates to a 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 or C _1-6 alkyl, wherein the C _1-6 alkyl group can be optionally fluoro, chloro, bromo, iodo, C _{1 -4} alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino mono- or polysubstituted; for example, the C _1-4 alkyl may be optionally fluoro, chloro, bromo, iodo, The hydroxy, nitro, cyano, amino group is mono- or polysubstituted; for example, the C _1-4 alkyl group may be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.

In another embodiment, the present disclosure relates to a 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 or C _1-4 alkyl, wherein the C _1-4 alkyl group can be optionally fluoro, chloro, bromo, iodo, C _{1 -4} alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino mono- or polysubstituted; for example, the C _1-4 alkyl may be optionally fluoro, chloro, bromo, iodo, The hydroxy, nitro, cyano, amino group is mono- or polysubstituted; for example, the C _1-4 alkyl group may be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.

In another embodiment, the present disclosure relates to a 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 or C _1-6 alkyl.

In another embodiment, the present disclosure relates to a 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 or C _1-4 alkyl.

In another embodiment, the present disclosure relates to a 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, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, Isoamyl, neopentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy or hexyloxy.

In another embodiment, the present disclosure relates to a 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, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, Ethoxy, propoxy or butoxy.

In another embodiment, the present disclosure relates to a 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, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.

In another embodiment, the present disclosure relates to a 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, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.

In another embodiment, the present disclosure relates to a 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, methyl, ethyl, n-propyl or isopropyl.

In another embodiment, the present disclosure relates to a 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, methyl, ethyl.

In another embodiment, the present disclosure relates to a 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 or methyl.

In another embodiment, the present disclosure relates to a 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 H.

In another embodiment, the present disclosure relates to a 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 methyl.

In another embodiment, the present disclosure relates to a 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 ethyl.

In another embodiment, the present disclosure relates to a 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 n-propyl.

In another embodiment, the present disclosure relates to a 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 isopropyl.

In another embodiment, the present disclosure relates to a 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 n-butyl.

In another embodiment, the present disclosure relates to a 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 isobutyl.

In another embodiment, the present disclosure relates to a 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 a tert-butyl group.

In one embodiment, the present disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of a compound of formula (I), which is obtained by isotopic substitution thereof A compound, or any suitable embodiment of the invention, wherein: R ₃ is hydrogen, deuterium, C _1-6 alkyl or C _1-6 alkoxy, wherein the C _1-6 alkyl or C _1-6 alkane The oxy 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 The -6} alkyl or C _1-6 alkoxy group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxy, nitro, cyano, amino; for example, the C _1-6 alkyl group or The C _1-6 alkoxy group may be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.

In another embodiment, the present disclosure relates to a 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 ₃ is hydrogen, C _1-4 alkyl or C _1-4 alkoxy, wherein the 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; for example, the C _{1- The 4-} alkyl or C _1-4 alkoxy group may be optionally mono- or polysubstituted by fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino; for example, the C _1-4 alkyl or C _{The 1-4} alkoxy group may be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.

In another embodiment, the present disclosure relates to a 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 or C _1-6 alkyl, wherein the C _1-6 alkyl group can be optionally fluoro, chloro, bromo, iodo, C _{1 -4} alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino mono- or polysubstituted; for example, the C _1-4 alkyl may be optionally fluoro, chloro, bromo, iodo, The hydroxy, nitro, cyano, amino group is mono- or polysubstituted; for example, the C _1-4 alkyl group may be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.

In another embodiment, the present disclosure relates to a 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 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 polysubstituted; for example, the C _1-4 alkyl may be optionally fluoro, chloro, bromo, iodo, The hydroxy, nitro, cyano, amino group is mono- or polysubstituted; for example, the C _1-4 alkyl group may be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.

In another embodiment, the present disclosure relates to a 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 or C _1-6 alkyl.

In another embodiment, the present disclosure relates to a 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 or C _1-4 alkyl.

In another embodiment, the present disclosure relates to a 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, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, Isoamyl, neopentyl, hexylmethoxy, ethoxy, propoxy, butoxy, pentyloxy or hexyloxy.

In another embodiment, the present disclosure relates to a 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, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, Ethoxy, propoxy or butoxy.

In another embodiment, the present disclosure relates to a 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, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.

In another embodiment, the present disclosure relates to a 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, methyl, ethyl, n-propyl or isopropyl.

In another embodiment, the present disclosure relates to a 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, methyl or ethyl.

In another embodiment, the present disclosure relates to a 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 or methyl.

In another embodiment, the present disclosure relates to a 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 H.

In another embodiment, the present disclosure relates to a 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 methyl.

In another embodiment, the present disclosure relates to a 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 ethyl.

In another embodiment, the present disclosure relates to a 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 n-propyl.

In another embodiment, the present disclosure relates to a 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 isopropyl.

In another embodiment, the present disclosure relates to a 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 n-butyl.

In another embodiment, the present disclosure relates to a 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 isobutyl.

In another embodiment, the present disclosure relates to a 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 tert-butyl.

In one embodiment, the present disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of a compound of formula (I), which is obtained by isotopic substitution thereof a compound, or any suitable embodiment of the present invention, wherein: R ₄ is hydrazine, fluorine, chlorine, bromine, iodine, C _1-6 alkyl or C _1-6 alkoxy, wherein the C _1-6 alkyl Or a C _1-6 alkoxy group may be optionally monosubstituted or substituted by 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, hydroxy, nitro, cyano, amino; for example, the C _{The 1-6} alkyl or C _1-6 alkoxy group may be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.

In another embodiment, the present disclosure relates to a 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 ₄ is fluoro, chloro, bromo, iodo, C _1-4 alkyl or C _1-4 alkoxy, wherein the 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; 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; for example, the C _{1 The -4} alkyl or C _1-4 alkoxy group may be optionally mono- or polysubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino.

In another embodiment, the present disclosure relates to a 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 ₄ is fluoro, chloro, bromo, iodo, or C _1-6 alkyl, wherein the C _1-6 alkyl can be optionally fluoro, chloro , bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino, monosubstituted or polysubstituted; for example, the C _1-4 alkyl may be optionally fluorinated Mono- or poly-substituted with chlorine, bromine, iodine, hydroxy, nitro, cyano, amino; for example, the C _1-4 alkyl group may be optionally substituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino Or more replacement.

In another embodiment, the present disclosure relates to a 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 ₄ is fluoro, chloro, bromo, iodo or C _1-4 alkyl, wherein the C _1-4 alkyl group may be optionally fluoro, chloro, Bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino mono- or polysubstituted; for example, the C _1-4 alkyl may be optionally fluoro, Mono- or poly-substituted with chlorine, bromine, iodine, hydroxy, nitro, cyano, amino; for example, the C _1-4 alkyl group may be optionally monosubstituted by fluorine, chlorine, bromine, hydroxyl, nitro, amino or More substitution.

In another embodiment, the present disclosure relates to a 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 ₄ is fluoro, chloro, bromo, iodo or C _1-6 alkyl.

In another embodiment, the present disclosure relates to a 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 ₄ is fluoro, chloro, bromo, iodo or C _1-4 alkyl.

In another embodiment, the present disclosure relates to a 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 ₄ is fluoro, chloro, bromo, iodo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl Base, n-pentyl, isopentyl, neopentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy or hexyloxy.

In another embodiment, the present disclosure relates to a 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 ₄ is fluoro, chloro, bromo, iodo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl Base, methoxy, ethoxy, propoxy or butoxy.

In another embodiment, the present disclosure relates to a 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 ₄ is fluoro, chloro, bromo, iodo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl base.

In another embodiment, the present disclosure relates to a 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 ₄ is fluoro, chloro, bromo, iodo, methyl, ethyl, n-propyl or isopropyl.

In another embodiment, the present disclosure relates to a 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 ₄ is fluoro, chloro, bromo, iodo, methyl or ethyl.

In another embodiment, the present disclosure relates to a 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 ₄ is methyl.

In another embodiment, the present disclosure relates to a 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 ₄ is ethyl.

In another embodiment, the present disclosure relates to a 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 ₄ is n-propyl.

In another embodiment, the present disclosure relates to a 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 ₄ is isopropyl.

In another embodiment, the present disclosure relates to a 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 ₄ is fluoro, chloro, bromo or iodo.

In another embodiment, the present disclosure relates to a 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 ₄ is fluoro.

In another embodiment, the present disclosure relates to a 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 ₄ is chloro.

In another embodiment, the present disclosure relates to a 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 ₄ is bromine.

In another embodiment, the present disclosure relates to a 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 ₄ is iodine.

In another embodiment, the present disclosure relates to a 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: L is . In another embodiment, the present disclosure relates to a 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:

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

In another embodiment, the present disclosure relates to a 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: L is -(CH ₂ ) _n -NH-B-, wherein: n, B are as defined in any suitable embodiment of the present disclosure.

In another embodiment, the present disclosure relates to a 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: A is -(CH ₂ ) _m -, wherein m is as defined in any suitable embodiment of the present disclosure.

In another embodiment, the present disclosure relates to a 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: A is -CHR ₅ -, wherein R _{5 is} as defined in any suitable embodiment of the present disclosure.

In another embodiment, the present disclosure relates to a 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 to give a compound of the present disclosure or any suitable embodiment, wherein: X is -CH ₂ -.

In another embodiment, the present disclosure relates to a 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: X is -NH-.

In another embodiment, the present disclosure relates to a 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: X is -NR ₆ -, wherein R _{6 is} as defined in any suitable embodiment of the present disclosure.

In another embodiment, the present disclosure relates to a 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: Y is -C(=O)-.

In another embodiment, the present disclosure relates to a 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: Y is -S(=O)-.

In another embodiment, the present disclosure relates to a 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: Y is -S(=O) _2- .

In another embodiment, the present disclosure relates to a 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: Z is -NH-.

In another embodiment, the present disclosure relates to a 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: Z is .

In another embodiment, the present disclosure relates to a 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: B is -C(=S)-.

In another embodiment, the present disclosure relates to a 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: B is -CHR ₇ -, wherein R _{7 is} as defined in any of the applicable embodiments of the present disclosure.

In another embodiment, the present disclosure relates to a 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 ₅ is hydrazine, fluorine, chlorine, bromine or iodine.

In another embodiment, the present disclosure relates to a 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 ₅ is C _1-4 alkyl or C _1-4 alkoxy, wherein the C _1-4 alkyl or C _1-4 alkoxy group can be Optionally, it is mono- or polysubstituted by fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino.

In another embodiment, the present disclosure relates to a 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 ₅ is C _1-4 alkyl, wherein the C _1-4 alkyl group can be optionally fluoro, chloro, bromo, iodo, C _1-4 Alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino mono- or poly-substituted.

In another embodiment, the present disclosure relates to a 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 ₅ is C _1-4 alkyl, wherein the C _1-4 alkyl group can be optionally mono- or polysubstituted by fluorine, chlorine, bromine, iodine .

In another embodiment, the present disclosure relates to a 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 ₅ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, wherein the R ₅ may be The ground is mono- or polysubstituted by fluorine, chlorine, bromine or iodine.

In another embodiment, the present disclosure relates to a 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 ₅ is methyl, ethyl, n-propyl, isopropyl.

In another embodiment, the present disclosure relates to a 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 ₅ is n-propyl or isopropyl.

In another embodiment, the present disclosure relates to a 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 ₅ is isopropyl.

In another embodiment, the present disclosure relates to a 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 ₅ is hydroxy, nitro, cyano or amino.

In another embodiment, the present disclosure relates to a 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 ₆ is hydrazine, fluorine, chlorine, bromine or iodine.

In another embodiment, the present disclosure relates to a 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 ₆ is C _1-4 alkyl or C _1-4 alkoxy, wherein the C _1-4 alkyl or C _1-4 alkoxy group can be Optionally, it is mono- or polysubstituted by fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino.

In another embodiment, the present disclosure relates to a 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 ₆ is C _1-4 alkyl, wherein the C _1-4 alkyl group can be optionally fluoro, chloro, bromo, iodo, C _1-4 Alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino mono- or poly-substituted.

In another embodiment, the present disclosure relates to a 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 invention, wherein: R ₆ is C _1-4 alkyl, wherein the C _1-4 alkyl group may be optionally substituted or substituted by fluorine, chlorine, bromine or iodine. .

In another embodiment, the present disclosure relates to a 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 ₆ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, wherein the R ₆ may be The ground is mono- or polysubstituted by fluorine, chlorine, bromine or iodine.

In another embodiment, the present disclosure relates to a 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 ₆ is methyl, ethyl, n-propyl, isopropyl.

In another embodiment, the present disclosure relates to a 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 ₆ is methyl or ethyl.

In another embodiment, the present disclosure relates to a 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 ₆ is methyl.

In another embodiment, the present disclosure relates to a 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 ₆ is hydroxy, nitro, cyano or amino.

In another embodiment, the present disclosure relates to a 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 ₇ is hydrazine, fluorine, chlorine, bromine or iodine.

In another embodiment, the present disclosure relates to a 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 ₇ is C _1-4 alkyl or C _1-4 alkoxy, wherein the C _1-4 alkyl or C _1-4 alkoxy group can be Optionally, it is mono- or polysubstituted by fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino.

In another embodiment, the present disclosure relates to a 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 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, cyano, amino mono- or poly-substituted.

In another embodiment, the present disclosure relates to a 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 invention, wherein: R ₇ is C _1-4 alkyl, wherein the C _1-4 alkyl group may be optionally substituted or substituted by fluorine, chlorine, bromine or iodine. .

In another embodiment, the present disclosure relates to a 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 ₇ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl, wherein R ₇ may be any The ground is mono- or polysubstituted by fluorine, chlorine, bromine or iodine.

In another embodiment, the present disclosure relates to a 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 ₇ is ethyl, n-propyl or isopropyl.

In another embodiment, the present disclosure relates to a 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 ₇ is methyl, monofluoromethyl, difluoromethyl or trifluoromethyl.

In another embodiment, the present disclosure relates to a 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 ₇ is methyl.

In another embodiment, the present disclosure relates to a 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 ₇ is trifluoromethyl.

In another embodiment, the present disclosure relates to a 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 ₇ is hydroxy, nitro, cyano or amino.

In another embodiment, the present disclosure relates to a 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: m is 1, 2 or 3.

In another embodiment, the present disclosure relates to a 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: m is 4 or 5.

In another embodiment, the present disclosure relates to a 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: m is 1 or 2.

In another embodiment, the present disclosure relates to a 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: m is 1.

In another embodiment, the present disclosure relates to a 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: m is 2.

In another embodiment, the present disclosure relates to a 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: n is 1, 2 or 3.

In another embodiment, the present disclosure relates to a 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: n is 4 or 5.

In another embodiment, the present disclosure relates to a 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: n is 1 or 2.

In another embodiment, the present disclosure relates to a 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: n is 1.

In another embodiment, the present disclosure relates to a 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: n is 2.

In another embodiment, the present disclosure relates to a 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: L is Wherein: 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 And 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 the 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; m is 1, 2, 3, 4 or 5.

In another embodiment, the present disclosure relates to a 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: L is Wherein: 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 And 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 the 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; m is 1 or 2.

In another embodiment, the present disclosure relates to a 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: L is Wherein: 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 And 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 polysubstituted; m is 1 or 2.

In another embodiment, the present disclosure relates to a 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: L is Wherein: 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 And 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 Multiple substitution; m is 1 or 2.

In another embodiment, the present disclosure relates to a 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: L is Wherein: 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 And 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 or iodine; m is 1 or 2.

In another embodiment, the present disclosure relates to a 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: L is Wherein: 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 And R ₅ and R ₆ are each independently methyl, ethyl, n-propyl, isopropyl, methylpropyl, n-butyl, isobutyl or t-butyl; m is 1 or 2.

In another embodiment, the present disclosure relates to a 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: L is Wherein: 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-; R ₅ and R ₆ are each independently hydrazine, fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy a hydroxy, nitro, cyano or amino group, 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; m is 1 or 2.

In another embodiment, the present disclosure relates to a 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: L is Wherein: A is -(CH ₂ ) _m - or -CHR ₅ -; X is -NH- or -NR ₆ -; Y is -C(=O)-, -S(=O)- or -S( =O) ₂ -; Z is -NH-; 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 alkoxy, hydroxy, nitro, cyano, amino mono- or polysubstituted; m is 1 or 2.

In another embodiment, the present disclosure relates to a 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: L is Wherein: A is -(CH ₂ ) _m - or -CHR ₅ -; X is -NH- or -NR ₆ -; Y is -C(=O)-, -S(=O)- or -S( =O) ₂ -; Z is -NH-; 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, hydroxy , nitro, cyano, amino mono- or polysubstituted; m is 1 or 2.

In another embodiment, the present disclosure relates to a 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: L is Wherein: A is -(CH ₂ ) _m - or -CHR ₅ -; X is -NH- or -NR ₆ -; Y is -C(=O)-, -S(=O)- or -S( =O) ₂ -; Z is -NH-; 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 or iodine Or multiple substitutions; m is 1 or 2.

In another embodiment, the present disclosure relates to a 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: L is Wherein: 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-; R ₅ and R ₆ are each independently methyl, ethyl, n-propyl, isopropyl, methylpropyl, n-butyl, iso Butyl or tert-butyl; m is 1 or 2.

In another embodiment, the present disclosure relates to a 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: L is Wherein: A is -(CH ₂ ) _m - or -CHR ₅ -; X is -NH- or -NR ₆ -; Y is -C(=O)-, -S(=O)- or -S( =O) ₂ -; Z is -NH-; R ₅ and R ₆ are each independently methyl, ethyl, n-propyl or isopropyl, wherein R ₅ , R ₆ may optionally be fluorine or chlorine , bromine, iodine monosubstituted or polysubstituted; m is 1 or 2.

In another embodiment, the present disclosure relates to a 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: L is Wherein: A is -(CH ₂ ) _m - or -CHR ₅ -; X is -NH- or -NR ₆ -; Y is -C(=O)-, -S(=O)- or -S( =O) ₂ -; Z is -NH-; R ₅ is n-propyl or isopropyl; R ₆ is methyl, trifluoromethyl, difluoromethyl or monofluoromethyl; m is 1 or 2 .

In another embodiment, the present disclosure relates to a 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: L is Wherein: A is -(CH ₂ ) _m - or -CHR ₅ -; X is -NH- or -NR ₆ -; Y is -C(=O)-, -S(=O)- or -S( =O) ₂ -; Z is -NH-; R ₅ is n-propyl or isopropyl; R ₆ is methyl; m is 1 or 2.

In another embodiment, the present disclosure relates to a 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: L is Wherein: A is -(CH ₂ ) _m - or -CHR ₅ -; X is -NH- or -NR ₆ -; Y is -C(=O)-, -S(=O)- or -S( =O) ₂ -; Z is -NH-; R ₅ is isopropyl; R ₆ is methyl; m is 1 or 2.

In another embodiment, the present disclosure relates to a 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: L is Wherein: A is -(CH ₂ ) _m - or -CHR ₅ -; X is -CH ₂ -, -NH- or -NR ₆ -; Y is -C(=O)-; Z is -NH-; 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 the C _1-4 The 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 substitution; m is 1 or 2.

In another embodiment, the present disclosure relates to a 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: L is Wherein: A is -(CH ₂ ) _m - or -CHR ₅ -; X is -NH- or -NR ₆ -; Y is -C(=O)-; Z is -NH-; R ₅ , R ₆ Each independently is a C _1-4 alkyl group, 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; m is 1 or 2.

In another embodiment, the present disclosure relates to a 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: L is Wherein: A is -(CH ₂ ) _m - or -CHR ₅ -; X is -NH- or -NR ₆ -; Y is -C(=O)-; Z is -NH-; R ₅ , R ₆ Each independently is a C _1-4 alkyl group, wherein the C _1-4 alkyl group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino; m is 1 Or 2.

In another embodiment, the present disclosure relates to a 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: L is Wherein: A is -(CH ₂ ) _m - or -CHR ₅ -; X is -NH- or -NR ₆ -; Y is -C(=O)-; Z is -NH-; R ₅ , R ₆ Each is independently C _1-4 alkyl, wherein the C _1-4 alkyl group may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine; m is 1 or 2.

In another embodiment, the present disclosure relates to a 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: L is Wherein: A is -(CH ₂ ) _m - or -CHR ₅ -; X is -CH ₂ -, -NH- or -NR ₆ -; Y is -C(=O)-; Z is -NH-; R ₅ and R ₆ are each independently methyl, ethyl, n-propyl, isopropyl, methylpropyl, n-butyl, isobutyl or t-butyl; m is 1 or 2.

In another embodiment, the present disclosure relates to a 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: L is Wherein: A is -(CH ₂ ) _m - or -CHR ₅ -; X is -NH- or -NR ₆ -; Y is -C(=O)-; Z is -NH-; R ₅ , R ₆ Each is independently methyl, ethyl, n-propyl or isopropyl, wherein R ₅ , R ₆ may be optionally mono- or polysubstituted with fluorine, chlorine, bromine, iodine; m is 1 or 2.

In another embodiment, the present disclosure relates to a 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: L is Wherein: A is -(CH ₂ ) _m - or -CHR ₅ -; X is -NH- or -NR ₆ -; Y is -C(=O)-; Z is -NH-; R ₅ is n-propyl Or isopropyl; R ₆ is methyl, trifluoromethyl, difluoromethyl or fluoromethyl; m is 1 or 2.

In another embodiment, the present disclosure relates to a 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: L is Wherein: A is -(CH ₂ ) _m - or -CHR ₅ -; X is -NH- or -NR ₆ -; Y is -C(=O)-; Z is -NH-; R ₅ is n-propyl Or isopropyl; R ₆ is methyl; m is 1 or 2.

In another embodiment, the present disclosure relates to a 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: L is Wherein: A is -(CH ₂ ) _m - or -CHR ₅ -; X is -NH- or -NR ₆ -; Y is -C(=O)-; Z is -NH-; R ₅ is isopropyl R ₆ is a methyl group; m is 1 or 2.

In another embodiment, the present disclosure relates to a 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: L is -(CH ₂ ) _n -NH-B-, wherein: B is -C(=S)- or -CHR ₇ -; R ₇ is C _{a 1-4} alkyl group, 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, The amino group is mono- or polysubstituted; n is 1, 2, 3, 4 or 5.

In another embodiment, the present disclosure relates to a 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: L is -(CH ₂ ) _n -NH-B-, wherein: B is -C(=S)- or -CHR ₇ -; R ₇ is C _1-4 alkyl (for example methyl, ethyl, n-propyl, isopropyl, methylpropyl, n-butyl, isobutyl or tert-butyl), wherein the C _1-4 alkyl group is optional The ground is mono- or polysubstituted with fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino; n is 1 or 2.

In another embodiment, the present disclosure relates to a 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: L is -(CH ₂ ) _n -NH-B-, wherein: B is -C(=S)- or -CHR ₇ -; R ₇ is A Base, ethyl, n-propyl, isopropyl, trifluoromethyl; n is 1 or 2.

In another embodiment, the present disclosure relates to a 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: L is -(CH ₂ ) _n -NH-B-, wherein: B is -C(=S)- or -CHR ₇ -; R ₇ is A Or a trifluoromethyl group; n is 1 or 2.

In another embodiment, the present disclosure relates to a 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: L is -(CH ₂ ) _n -NH-B-, wherein: B is -C(=S)- or -CHR ₇ -; R ₇ is three Fluoromethyl; n is 1 or 2.

In another embodiment, the present disclosure relates to a 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: L is -(CH ₂ ) _n -NH-B-, wherein: B is -C(=S); n is 1 or 2.

In another embodiment, the present disclosure relates to a 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: L is -(CH ₂ ) _n -NH-B-, wherein: B is -C(=S); n is 1.

In another embodiment, the present disclosure relates to a 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 or methyl; R ₂ is hydrogen or methyl; R ₃ is hydrogen or methyl; R ₄ is fluorine; , Or -(CH ₂ ) _n -NH-B-, wherein: 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 isopropyl; R ₆ is methyl; R ₇ is trifluoromethyl; m is 1 or 2; n is 1.

In another embodiment, the present disclosure relates to a compound of formula (I) selected from: And pharmaceutically acceptable salts, stereoisomers, solvates of these compounds.

In another embodiment, the present disclosure relates to the compound of formula (I): .

In another embodiment, the present disclosure relates to the compound of formula (I): .

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 thereof, a stereoisomer, a solvate 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.

The pharmaceutical compositions described herein may contain one or more of the disclosed compounds. In some embodiments, the pharmaceutical composition may contain more than one of the disclosed compounds. For example, in some embodiments, the pharmaceutical composition can contain two or more of the disclosed compounds. Furthermore, the pharmaceutical composition may optionally further comprise one or more additional pharmaceutically active compounds.

According to the present disclosure, the pharmaceutical composition comprises a compound of the formula (I) 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 into various dosage forms including, but not limited to, tablets, capsules, solutions, suspensions, granules or injections, etc., by methods conventional in the art, for example, by oral or parenteral routes.

The pharmaceutical compositions of the present disclosure may be presented in unit dosage form containing a predetermined amount of active ingredient per unit dosage. Such a unit may contain 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 present disclosure. A compound, depending 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.

The compound of the formula (I) has inhibitory activity against NTRK1, NTRK2, NTRK3, ALK and ROS1, and inhibits tumor growth and metastasis by inhibiting the related signal pathway, and can be applied to treat NTRK, ALK and ROS1. Gene fusion mutations in a variety of children and adult solid tumors, including breast cancer, colorectal cancer, lung cancer, pancreatic cancer, thyroid cancer, glioma, and various sarcomas. Further, the present compound of the above formula (I) can also have a positive effect on tumors of brain metastasis.

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 atom of the compound of the formula (I) which is obtained by isotopic substitution thereof. The use of a compound in the manufacture of a medicament for the treatment or amelioration of the severity of the disease or condition, or in the preparation of a tyrosine kinase (including NTRK (eg NTRK1, NTRK2, NTRK3), ALK or ROS1 or Use in a variety of drugs for inhibitors.

In another aspect, the disclosure 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) which is pharmaceutically acceptable a salt, a stereoisomer, a solvate or a compound obtained by replacing any of the compounds of the formula (I) with an isotope thereof.

In another aspect, the disclosure relates to methods 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 thereof 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 composition is disclosed as being contacted, wherein the contact is in vitro, ex vivo or in vivo.

The present disclosure also relates to at least one 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), The 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 the treatment of a disease or condition or amelioration of the disease or condition Severity, or used to inhibit tyrosine kinases (including one or more of NTRK (eg, NTRK1, NTRK2, NTRK3), ALK, or ROS1).

In one embodiment, the disease or condition is a plurality of childhood and/or adult solid tumors, such as breast cancer, colorectal cancer, lung cancer, that carry NTRK (eg, NTRK1, NTRK2, NTRK3), ALK, ROS1 gene fusion mutations. Pancreatic cancer, thyroid cancer, glioma, various sarcomas, and tumors of brain metastasis.

The method used in the preparation of the compounds of formula (I) herein depends on the desired compound. In general, the presently disclosed compounds can be prepared by standard techniques known in the art and by analogous methods known in the art. In the method of synthesizing the compound of the general formula (I), 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 a method known in the literature, or can be borrowed. 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.

Exemplary synthetic methods for preparing the disclosed compounds 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.

In one embodiment, the method of preparing the compound of formula (I) is as shown in the synthetic scheme below.

Where: L is Wherein: A is -(CH ₂ ) _m - or -CHR ₅ -; X is -NH- or -NR ₆ -; Y is -C(=O)-; Z is -NH.

Wherein m, R ₅ and R ₆ are as defined in any applicable embodiment of the present disclosure. 1) Case where 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, the product was purified to give Compound ^{I-1 (X 1 = OH} ) by silica gel column chromatography. 2) Case where 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 column chromatography using silica gel.

For further preparation of the compounds of the general formula (I) disclosed herein, please refer to the specific embodiments herein, such as Examples 1 to 9. Definition of Terms

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, such terms and phrases are Inconsistent with the well-known meaning, the meaning expressed in this article shall prevail.

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 existence of the feature, integer, step, operation, element and / or component, but does not exclude one or more other features, integers The presence or addition of steps, operations, elements, ingredients, and/or groups thereof.

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.

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.

The term "amino" as used herein means -NH _2.

The term "hydroxy" as used herein means -OH.

The term "cyano" as used herein means -CN.

The term "nitro" as used herein means -NO ₂ .

The English abbreviations used herein have the following meanings: HATU: 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; TEA:Triethylamine, Triethylamine; DCM: Dichloromethane, dichloromethane; DAST: Diethylaminosulfurtrifluoride, diethylaminosulfur trifluoride; TFA: Trifluoroacetic acid, trifluoroacetic acid; FDPP: Pentafluorophenyl diphenylphosphinate, pentafluorophenyl diphenyl phosphate; DIPEA :Diisopropylethylamine, N,N-diisopropylethylamine; DMF: N,N-Dimethylformamide, N,N-dimethylformamide; DIAD: Diisopropyl azodicarboxylate, diisopropyl azodicarboxylate; TFAA: Trifluoroacetic Anhydride, trifluoroacetic anhydride; THF: Tetrahydrofuran, tetrahydrofuran; TLC: thin layer chromatography; DMSO: dimethyl hydrazine; ATP: adenine nucleoside triphosphate, adenosine triphosphate; Tyr: Tyrosine, tyrosine.

Herein, the unit "M" represents mol/L, "μM" represents μmol/L, and "nM" represents nmol/L.

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.

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.

As used herein, reference to a "therapeutically effective amount" of a compound or other pharmaceutically active agent of the present disclosure is sufficient to treat or prevent a patient's disease within a reasonable medical judgment but to avoid serious side effects sufficiently (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.

In addition, it should be noted that the dosage and method of use of the present invention depend on a number of factors, including the patient's age, weight, sex, natural health, nutritional status, strength of the compound, time of administration, rate of metabolism, severity of the condition, and diagnosis and treatment. Subjective judgment of the physician. A preferred dosage is between 0.001 and 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 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.

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) Or as a salt, especially a pharmaceutically acceptable salt thereof, and any physical form thereof (for example, including a non-solid form (for example, a liquid or semi-solid form) and a solid form (for example, an amorphous or crystalline form, specific Polymorph forms, solvate forms, including hydrated forms (eg, mono-, di-, and hemi-hydrate), as well as mixtures of various forms.

The embodiments of the present disclosure will be described in detail below with reference to the embodiments. However, those skilled in the art will understand that the following embodiments are only used to illustrate the disclosure, and should not be construed as limiting 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 which are commercially available. Example 1 Preparation of Compound 1 first step

To the reaction flask, 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 placed in this order under nitrogen replacement. 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 EtOAc (EtOAc m. Second step

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

1c (190.0mg), 2mol/L NaOH (3mL) and methanol (10mL) were added to the reaction flask, and reacted at room temperature. After the reaction was completed, the methanol was concentrated and dissolved in water, and the pH was adjusted to about 2~3 by a 1 mol/L hydrochloric acid aqueous solution. After stirring for 0.5 hours, suction filtration and drying to give 1d (110.0 mg, white solid), yield: 59.4%. the fourth step

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 hr. (mg), the product was directly subjected to the next reaction without purification. the fifth step

1e (110.0 mg, 0.20 mmol), dichloromethane (6 mL), N,N-dimethylformamide (1.5 mL) and N,N-diisopropylethylamine (215.0 mg) were sequentially placed in a reaction flask. , 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 column chromatography to give compound 1 (26.7 mg, white solid). LC-MS (ESI) m/z 411.1 [M+1]

1H NMR (400 MHz, CDCl3) δ ppm 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=14.18Hz,1H), 6.25(d,J=8.07Hz,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). Example 2 Preparation of Compound 2 first step

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 were sequentially introduced into the reaction flask. 7 mL), under a nitrogen atmosphere, 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]

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) (EtOAc) Mg, white solid), yield 29.3%. LC-MS (ESI) m/z 371.9 [M+1]

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 = 14.18 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). Example 3 Preparation of Compound 3 first step

3a (1.21g, 7.81mmol, prepared by the method disclosed in the patent application "WO2015/112806A2"), 3b (1.2g, 7.81mmol, prepared by the method disclosed in the patent application "WO2004/043940A1") 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. mjjjjjjj Second step

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. third step

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%. the fourth step

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] Step 5

To 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 completely detected by TLC. The mixture was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Step 6

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 tetramethyltriethyl Ammonium borohydride, which was reacted at room temperature for 5 hours. To the system was added 1 mol/L HCl (aq), extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated. Purification by gel column chromatography gave 3 (35.0 mg). LC-MS (ESI) m/z 396.2 [M+1]

1H NMR (400 MHz, CDCl3) δ ppm 2.77-2.99 (m, 2H), 3.03-3.24 (m, 3 H), 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=14.18Hz,1H), 6.25(d,J=8.07Hz,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, 1 H). Example 4 Preparation of Compound 4 first step

4a (1.1g, 7.81mmol, prepared by the method disclosed in Phytochemistry, 2010, vol. 71, #7, p. 823-830), 4b (1.55g, 7.81mmol), was applied to the reaction flask. "Prepared by the method disclosed in US2016/0137654 A1", N,N-diisopropylethylamine (5.0g, 39.05mmol) and n-butanol (18mL), under the protection of nitrogen, the temperature is raised to 120 ° C and reflux stirring reaction 1 hour. The mixture was cooled to room temperature, and the mixture was evaporated. mjjjjjjj Second step

4c (200.0 mg, 0.66 mmol), ethyl 4-bromobutyrate (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 the mixture was evaporated, evaporated, evaporated, evaporated, evaporated third step

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). the fourth step

4e (140.0 mg, 0.36 mmol), Pd/C (28 mg, 20%) and concentrated hydrochloric acid (2 mL) were sequentially 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. the fifth step

4f (154.0 mg, 0.36 mmol), dichloromethane (11 mL), N,N-dimethylformamide (7.5 mL), N,N-diisopropylethylamine (368.0 mg) were sequentially added to the reaction flask. , 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) 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). Example 5 Preparation of Compound 5 and Compound 6 first step

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 vacuo. Second step

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 silica gel column chromatography gave 5b (60 mg, dark brown solid). third step

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. the fourth step

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 pressure and purified mjjjjlililililili

1H NMR (400MHz, CDCl3) δppm 3.81-3.85 (m, 2H), 4.11-4.14 (m, 2 H), 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). the fifth step

5c (75 mg, 0.24 mmol) was dissolved in pyridine (7.5 mL) and sulfonamide (159 mg, 1.66 mmol) 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) δ ppm 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). Example 6 Preparation of Compound 7 1) Preparation of intermediate 7c first step

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]

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. third step

To the crude reaction mixture of 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)EtOAc. The residue was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc) LC-MS (ESI) m/z 408.1 [M+1] 2) Preparation of Compound 7

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]

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 min. 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]

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).

Compounds 8-11 in the following table were prepared by the method described in Example 6. Example 7 Preparation of Compound 12

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]

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) . Example 8 Preparation of Compound 13

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

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). Example 9 Preparation of Compound 14

Compound 14 was prepared by the preparation method described in Example 13.

Analytical data for Compound 14 was obtained as follows: LC-MS (ESI) m/z </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> NMR (400 MHz, 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). Example 10 In vitro enzyme activity inhibition experiment

In this experiment, the enzyme inhibitory activity of the test compound was determined using a Z'-LYTE® Kinase Assay Kit (available from Thermo Fisher Scientific, Cat. No. PV3190).

The test compounds were the compounds 1-14 prepared in Examples 1 to 9 herein, as well as 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).

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 configuration: Mix 5×Kinase Buffer in the kit with 1.33×Kinase Bufferr in deionized water, and dilute 10 mM ATP with 1.33×Kinase Buffer to prepare the final concentration of different target experiments. 4 times, the final concentrations of ATP in different target experiments were NTRK1: 400 uM; NTRK2: 25 uM; NTRK3: 50 uM.

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 final concentration was 1 μg/ml, substrate Tyr 01 The final concentration was 2 μM; the final concentration of NTRK2 was 0.3 μg/ml, the final concentration of substrate Tyr 01 was 2 μM; the final concentration of NTRK3 was 1 μg/ml, and the final concentration of substrate Tyr 01 was 2 μM.

Preparation of Phospho-peptide solution: Tyr 1 Phospho-peptide was diluted 250-fold with 1.33 x Kinase Buffer.

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), develop development reagent B with development buffer, add 5 μl per well, incubate for 1 hour at room temperature (20 °C - 25 °C), and use Tecan microplate reader. (purchased from Tecan, model: Spark10M) The values of the two conditions (Ex. 400 nm, Em. 445 nm) and (Ex. 400 nm, Em. 520 nm) were calculated and the IC ₅₀ values were calculated. The results are shown in Table 2. . Table 1 Table 2

Although the specific embodiments of the present disclosure have been described in detail, those skilled in the art will understand. Various modifications and alterations may be made to those details in light of the teachings disclosed herein. The full scope of the disclosure is given by the scope of the appended claims and any equivalents thereof.

Claims (17)

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), Wherein: R ₁ , R ₂ , R ₃ , and R ₄ are each independently hydrogen, hydrazine, fluorine, chlorine, bromine, iodine, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, nitro, cyanide Or an amino group, wherein the C _1-6 alkyl or C _1-6 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; L is , Or -(CH ₂ ) _n -NH-B-, wherein: 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, a hydroxy, nitro, cyano or amino group, 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 polysubstituted; R ₇ is hydrogen, hydrazine, fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy , nitro, cyano or amino, 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 alkane Oxyl, hydroxy, nitro, cyano, amino is mono- or polysubstituted; m, n are each independently 1, 2, 3, 4 or 5. A compound of the formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of the formula (I), as described in claim 1, of the compound of the formula (I) a compound obtained after the substitution, wherein: R ₁ , R ₂ , R ₃ , and R ₄ are each independently hydrogen, deuterium, fluorine, C _1-6 alkyl or C _1-6 alkoxy, wherein the 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 Multiple substitution; for example, the C _1-6 alkyl or C _1-6 alkoxy group may be optionally mono- or polysubstituted by fluorine, chlorine, bromine, iodine, hydroxy, nitro, cyano, amino. Any of the compounds of the formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or a compound of the formula (I), as described in claim 1 or 2 of the patent application. a compound obtained by replacing an atom with its isotope, wherein: wherein: R ₁ , R ₂ , R ₃ , and R ₄ are each independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, or different. Propyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy or Oxygen. The compound of the formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or the formula (I), according to any one of claims 1 to 3 a compound obtained by replacing any of the compounds with an isotope thereof, wherein: R ₅ is hydrazine, fluorine, chlorine, bromine, iodine, hydroxy, nitro, cyano or amino, or R ₅ is C _1-4 alkyl Or a C _1-4 alkoxy group, wherein the C _1-4 alkyl group or C _1-4 alkoxy group may be optionally fluoro, chloro, bromo, iodo, C _1-4 alkyl, C _1-4 alkane Oxyl, hydroxy, nitro, cyano, amino mono- or polysubstituted; preferably, R ₅ is C _1-4 alkyl, wherein the C _1-4 alkyl may be optionally fluoro, chloro, bromo , iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino mono- or polysubstituted; preferably, R ₅ is C _1-4 alkyl, wherein the C _{The 1-4} alkyl group may be optionally mono- or polysubstituted by fluorine, chlorine, bromine or iodine; preferably, R ₅ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, wherein R ₅ which may be optionally substituted by fluorine, chlorine, bromine, or iodine-substituted Generation; 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), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or formula (I), according to any one of claims 1 to 4 A compound obtained by replacing an arbitrary atom in a compound with an isotope thereof, wherein: R ₆ is hydrazine, fluorine, chlorine, bromine, iodine, hydroxy, nitro, cyano or amino, or R ₆ is C _1-4 alkyl Or a C _1-4 alkoxy group, wherein the C _1-4 alkyl group or C _1-4 alkoxy group may be optionally fluoro, chloro, bromo, iodo, C _1-4 alkyl, C _1-4 alkane Oxyl, hydroxy, nitro, cyano, amino mono- or polysubstituted; preferably, R ₆ is C _1-4 alkyl, wherein the C _1-4 alkyl may be optionally fluoro, chloro, bromo , iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino mono- or polysubstituted; preferably, R ₆ is C _1-4 alkyl, wherein the C _{The 1-4} alkyl group may be optionally mono- or polysubstituted by fluorine, chlorine, bromine or iodine; preferably, R ₆ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, wherein the R ₆ may be optionally substituted by fluorine, chlorine, bromine, or iodine-substituted Generation; Preferably, R ₆ is methyl, ethyl, n-propyl, isopropyl; preferably, R ₆ is methyl or ethyl; preferably, R ₆ is methyl. A compound of the formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or formula (I), according to any one of claims 1 to 5 a compound obtained by replacing any of the compounds with an isotope thereof, 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 a mono- or poly-substitution of a hydroxy group, a nitro group, a cyano group, or an amino group; preferably, R ₇ is a C _1-4 alkyl group, wherein the C _1-4 alkyl group may be optionally fluoro, chloro, bromo, Iodine, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, nitro, cyano, amino mono- or polysubstituted; preferably, R ₇ is C _1-4 alkyl, wherein the C _{1 The -4} alkyl group may be optionally mono- or polysubstituted by fluorine, chlorine, bromine or iodine; preferably, R ₇ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl Or a tert-butyl group, wherein the R ₇ may be optionally mono- or polysubstituted by fluorine, chlorine, bromine or iodine 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), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or formula (I), according to any one of claims 1 to 6 a compound obtained by replacing any of the compounds with an isotope thereof, 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), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or formula (I), according to any one of claims 1 to 7 a compound obtained by replacing any of the compounds with an isotope thereof, 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. A compound of the formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of the formula (I), as described in claim 1, of the compound of the formula (I) a compound obtained after replacement, wherein: L is Wherein: 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 And 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 the 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; m is 1 or 2. A compound of the formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of the formula (I), as described in claim 1, of the compound of the formula (I) a compound obtained after the substitution, wherein: L is -(CH ₂ ) _n -NH-B-, wherein: B is -C(=S)- or -CHR ₇ -; R ₇ is a C _1-4 alkyl group, wherein The C _1-4 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 is 1, 2, 3, 4 or 5. A compound of the formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, or any atom of the compound of the formula (I), as described in claim 1, of the compound of the formula (I) a compound obtained after the substitution, wherein: R ₁ is hydrogen or methyl; R ₂ is hydrogen or methyl; R ₃ is hydrogen or methyl; R ₄ is fluorine; , Or -(CH ₂ ) _n -NH-B-, wherein: 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 isopropyl; R ₆ is methyl; R ₇ is trifluoromethyl; m is 1 or 2; n is 1 or 2. The compound of claim 1, wherein the compound is selected from the group consisting of: And pharmaceutically acceptable salts, stereoisomers, solvates of these compounds. A pharmaceutical composition comprising at least one compound of the formula (I), a pharmaceutically acceptable salt, a stereoisomer, a solvate thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12 A compound obtained by replacing any of the compounds of the formula (I) with an isotope thereof, and a pharmaceutically acceptable carrier or excipient. Any one of the compound 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; A compound obtained by replacing an atom with its isotope, or a pharmaceutical composition according to claim 13 of the patent application, for the preparation of a medicament for treating or ameliorating the severity of the disease or condition, or Use of a medicament for a tyrosine kinase (including one or more of NTRK (e.g., NTRK1, NTRK2, NTRK3), ALK or ROS1), preferably, the disease or condition is to carry NTRK (e.g., NTRK1, NTRK2) NTRK3), ALK, ROS1 gene fusion mutations in a variety of childhood and/or adult solid tumors, such as breast cancer, colorectal cancer, lung cancer, pancreatic cancer, thyroid cancer, glioma, various sarcomas, and brain metastatic tumors. A method of treating or ameliorating the severity of a disease or condition comprising administering to a subject in need of such treatment a therapeutically effective amount of the formula of any one of claims 1 to 12 of the patent application. (I) a compound obtained by pharmaceutically acceptable salts, stereoisomers, solvates thereof or any of the compounds of the formula (I) by isotopic substitution thereof, preferably, the disease or condition is carried Multiple childhood and/or adult solid tumors of 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 brain Metastatic tumor. A method of inhibiting tyrosine kinases, including one or more of NTRK (eg, NTRK1, NTRK2, NTRK3), ALK, or ROS1, comprising: cultivating a cell comprising the kinase with at least one effective amount as in claim 1 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 the items 12, which is obtained by isotopic substitution thereof A compound, or in contact with at least one pharmaceutical composition as described in claim 13 wherein the contact is in vitro, ex vivo or in vivo. Any one of the compound 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; a compound obtained by replacement of an atom with its isotope, for use in treating or ameliorating the severity of the disease or condition, or for inhibiting tyrosine kinases, including NTRK (eg, NTRK1, NTRK2, NTRK3), ALK, or ROS1 Preferably, the disease or condition is a plurality of childhood and/or adult solid tumors, such as breast cancer, colorectal cancer, which 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.