CRBN binding compound for degrading target protein and use of compound

Abstract

The present application relates to the technical field of medicines, and specifically relates to a CRBN binding compound for degrading a target protein and a use of the compound. In the present application, a bifunctional compound containing a target protein binding moiety and an E3 ubiquitin ligase (such as CRBN) binding moiety is directionally bound to a target protein and CRBN, such that the protein is placed in close proximity to E3, the ligase mediates ubiquitination of the target protein, and then the target protein is degraded by a proteasome. The compound has a structure represented by formula (A), wherein the definition of each group is the same as that in the description.

Description

CRBN-binding compounds for degrading target proteins and their applications This application claims priority to international patent application PCT / CN2024 / 105162, filed on July 12, 2024, the entire contents of which are incorporated herein by reference. Technical Field This disclosure belongs to the field of pharmaceutical technology, specifically relating to a CRBN-binding compound for degrading target proteins and its applications. Background Technology Diseases such as cancer, inflammation, and neurodegeneration stem from the disruption of protein homeostasis and function. Small molecule drugs are commonly used to treat these diseases, modulating the function of pathogenic proteins by inhibiting their enzymatic activity. This approach requires high-affinity binding and sustained drug exposure to be effective, is limited to target proteins with active binding sites, and its activity is often insufficient to completely block protein function. Degrading target proteins, on the other hand, aims to utilize innate cellular mechanisms to destroy pathogenic proteins through substoichiometric catalysis. Protein degradation targeting chimeras (PROTACs) are an attractive targeted protein degradation technology. They are bifunctional small molecules with an E3 ubiquitin ligase-binding moiety (e.g., CRBN ligand) linked to a protein of interest (POI)-binding moiety. PROTACs achieve targeted degradation by recruiting ubiquitin ligases to ubiquitinate the target protein. PROTAC molecules are characterized by high efficiency and low drug resistance, and can target proteins that are previously untreatable, making their application prospects very broad. Summary of the Invention In view of this, this disclosure relates to novel bifunctional compounds that can be used to degrade target proteins by recruiting them to E3 ubiquitin ligases via the endogenous cellular ubiquitin-proteasome system (UPS). Specifically, this article discloses bifunctional compounds that promote the targeted ubiquitination and degradation of ALK and / or ROS1 (target proteins) while exhibiting inhibition of ALK and / or ROS1 activity. A first aspect of this disclosure provides a compound of formula (A) or a pharmaceutically acceptable salt thereof: In the formula, R 1 Selected from hydrogen, deuterium, and C 1-6 Alkyl, C 6-10 aryl, 5- or 6-membered heteroaryl and 4- to 7-membered heterocyclic, wherein the 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclic or C 6-10Aryl groups are optionally separated by 1, 2 or 3 independently selected from halogens, C 1-6 Alkyl or halogenated C 1-6 Alkyl substituent substitution; wherein the 5- or 6-membered heteroaryl or 4- to 7-membered heterocyclic group comprises 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S as ring atoms, p1 is 1, 2, or 3, and p1 has R 1 Same or different; R 2 Selected from halogens, C 1-6 Alkyl and Halogenated C 1-6 alkyl; R 7 It is a halogen; R 3 For -NR a R b , where R a R b Each is independently selected from hydrogen and C. 1-3 alkyl; R 4 Selected from halogens, C 1-6 Alkyl and Halogenated C 1-6 Alkyl group, p2 is selected from 1, 2 and 3, p2 R 4 Same or different; Y is selected from N and CH; R 5 Selected from hydrogen and halogens, p3 is selected from 1, 2 and 3, p3 R 5 Same or different; R 6 Selected from hydrogen, C 1-6 Alkyl and Halogenated C 1-6 alkyl; L is a linking group. A second aspect of this disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the first aspect or a pharmaceutically acceptable salt thereof. A third aspect of this disclosure provides the use of the compound of the first aspect or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the second aspect in the preparation of ALK and / or ROS1 inhibitors. A fourth aspect of this disclosure provides a method for treating ALK and / or ROS1-mediated diseases, the method comprising administering to a subject in need a therapeutically effective amount of a compound of the first aspect or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the second aspect. The fifth aspect of this disclosure provides the use of the compound of the first aspect or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the second aspect in the preparation of a medicament for treating ALK and / or ROS1-mediated diseases. A sixth aspect of this disclosure provides a method for simultaneously degrading ALK and / or ROSL proteins in a biological sample, comprising contacting the biological sample with a compound of the first aspect or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the second aspect. The seventh aspect of this disclosure provides a compound of the first aspect or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the second aspect for treating ALK and / or ROS1-mediated diseases. The eighth aspect of this disclosure provides the use of a compound of the first aspect or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the second aspect for treating a subject in need of ALK and / or ROS1-mediated disease. The ninth aspect of this disclosure provides intermediates for synthesizing the compounds disclosed herein and synthetic methods thereof. The tenth aspect of this disclosure provides a synthetic scheme for preparing the disclosed final compound. Attached Figure Description The accompanying drawings, which are incorporated in and form part of this specification, illustrate embodiments consistent with this specification and, together with the description, serve to explain the principles of this specification. Figure 1 illustrates the dose-dependent degradation of ALK protein by exemplary compound 1 of this disclosure in H2228 cells; Figure 2 illustrates the dose-dependent degradation of ALK and phosphate-ALK in BaF3 cells expressing mutant ALK (G1202R / L1196M) by exemplary compounds 3 and 4 of this disclosure. Figure 3 illustrates the dose-dependent degradation of ALK and phosphate-ALK in BaF3 cells expressing mutant ALK (G1202R / L1196M) by exemplary compounds 9 and 11 of this disclosure. Figure 4 illustrates the dose-dependent degradation of ALK and phosphate-ALK in BaF3 cells expressing mutant ALK (G1202R / L1198F) by exemplary compounds 3 and 4 of this disclosure. Figure 5 illustrates the dose-dependent degradation of ALK and phosphate-ALK in BaF3 cells expressing the exemplary compound 1 of this disclosure, in a mutant ALK cell line (G1202R / L1198F). Figure 6 illustrates the dose-dependent degradation of ALK and phosphate-ALK in BaF3 cells expressing the exemplary compound 14 of this disclosure, in a mutant ALK cell line (G1202R / L1198F). Figure 7 illustrates the dose-dependent degradation of ROS1 and phosphate-ROS1 by exemplary compound 14 and Repotrectinib in BaF3 cells expressing the mutant CD74-ROS1 (D2033N). Figure 8 illustrates the dose-dependent degradation of ROS1 and phosphorylated ROS1 by exemplary compounds 22 and 23 of this disclosure in BaF3 cells expressing the mutant CD74-ROS1 (D2033N); Figure 9 illustrates the dose-dependent degradation of ROS1 and phosphate-ROS1 by exemplary compounds 5 and 7 of this disclosure in BaF3 cells expressing the mutant CD74-ROS1 (G2032R). Figure 10 illustrates the dose-dependent degradation of ROS1 and phosphate-ROS1 by exemplary compounds 5 and 7 of this disclosure in BaF3 cells expressing the mutant SLC34A2-ROS1 (G2032R / F2075V). Detailed Implementation I. Definition In this invention, unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, the related terms and laboratory procedures used herein are all widely used terms and routine procedures in the respective fields. To better understand this invention, definitions and explanations of related terms are provided below. In the description herein, references to “some embodiments,” “some implementations,” or “some implementation schemes” describe a subset of all possible embodiments. However, it is understood that “some embodiments” may be the same subset or different subsets of all possible embodiments and may be combined with each other without conflict. As used herein and unless otherwise stated, the terms “comprising,” “including,” “having,” “containing,” and their grammatical equivalents, including their grammatical equivalents, should generally be understood as open-ended and non-restrictive, e.g., not excluding other unlisted elements or steps. In this specification and the claims reported herein, the phrase “and / or” is interpreted as meaning “any one or both” of the elements, that is, the elements may exist together in some cases or the elements may exist separately in other cases. When listing a range of values, it is assumed that each value and the subranges within that range are included. For example, "C 1-6 Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C4-5 and C 5-6 alkyl. The term "heteroatom" is selected from nitrogen, oxygen, or sulfur. Nitrogen may optionally be substituted; sulfur may also optionally be substituted, for example, by oxidation, thus forming S(O). t3 (where t3 is an integer from 0 to 2). The term "alkyl" refers to a chain-like (straight-chain or branched) saturated aliphatic hydrocarbon group. The term "alkyl" can refer to a straight-chain or branched alkyl group containing 1 to 10 carbon atoms. 1-10 Alkyl groups, preferably alkyl groups containing 1 to 6 carbon atoms (C 1-6 Alkyl groups. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various branched isomers thereof. More preferably are lower alkyl groups containing 1 to 3 carbon atoms (C... 1-3 Alkyl groups, including methyl, ethyl, n-propyl, isopropyl, etc., are used in non-limiting embodiments. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups described in this application. In one embodiment, the substituent is independently selected from oxo, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, alkyl (including straight-chain, branched and / or unsaturated alkyl), substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, fluoroalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, fluoroalkoxy, -S-alkyl, S(=O)2alkyl, -C(=O)NH (substituted or unsubstituted alkyl, or substituted or unsubstituted). -Phenyl), -C(=O)N(H or alkyl)2, -OC(=O)N(substituted or unsubstituted alkyl)2, NHC(=O)NH(substituted or unsubstituted alkyl, or substituted or unsubstituted phenyl), -NHC(=O)alkyl, -N(substituted or unsubstituted alkyl)C(=O)(substituted or unsubstituted alkyl), -NHC(=O)(substituted or unsubstituted alkyl), -C(OH)(substituted or unsubstituted alkyl)2 and -C(NH2)(substituted or unsubstituted alkyl)2. In another embodiment, for example, the optional substituents are selected from oxo, fluorine, chlorine, bromine, iodine, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CH(CH3)2, -CF3, -CH2CF3, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -OCH2CF3, -S(=O)2-CH3, -C(=O)NH2, -C(=O)-NHCH3, -NHC(=O)NHCH3, -C(=O)CH3, -ON(O)2, and C(=O)OH. In yet another embodiment, the substituents are independently selected from C1-6 alkyl, -OH, C1-6 alkoxy, halogen, amino, acetamino, oxo, and nitro. In yet another embodiment, the substituents are independently selected from C1-6 alkyl, C1-6 alkoxy, halogen, acetamino, and nitro. As used herein, when the substituent is alkyl or alkoxy, the carbon chain can be branched, straight, or cyclic. The terms "heterocyclic alkyl" and "heterocyclic alkyl ring" are used interchangeably to refer to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, wherein one or more (preferably 1 to 4, 1 to 3, or 1 to 2) ring atoms are selected from nitrogen, oxygen, or S(O). t3 (Where t3 is an integer from 0 to 2) heteroatoms, but excluding the ring moiety of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. The term "heterocyclic alkyl" preferably refers to a 3- to 6-membered heterocyclic alkyl group; wherein one or more (preferably 1 to 4) ring atoms are selected from nitrogen, oxygen, or S(O). t3(where t3 is an integer from 0 to 2) heteroatoms, excluding the ring portion of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is hydrogen or any substituent already defined herein). The ring carbon atoms of the said heterocyclic alkyl group may optionally be substituted with 1, 2, or 3 oxo groups to form cyclic ketones, cyclic lactones, or cyclic lactam structures. In some embodiments of the invention, "heterocyclic alkyl" refers to a monocyclic heterocyclic alkyl group that is saturated or partially unsaturated, preferably comprising 3 to 8 ring atoms (i.e., 3 to 8 members), wherein one, two, or three of the ring atoms are heteroatoms. More preferably, it comprises 3 to 6 ring atoms (i.e., 3 to 6 members), wherein one, two, or three of the ring atoms are heteroatoms. Most preferably, it comprises 5 or 6 ring atoms (i.e., 5 or 6 members), wherein one, two, or three of the ring atoms are heteroatoms. As used herein, the terms "3 to 6 membered heterocyclic alkyl" and "3 to 6 membered monocyclic heterocyclic alkyl" are used interchangeably. When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is hydrogen or other substituents as defined herein). Typically, 3- to 6-membered heterocyclic alkyl groups are 3- to 6-membered monocyclic heterocyclic alkyl groups. As used herein, "3- to 6-membered monocyclic" or "3- to 6-membered monocyclic heterocyclic alkyl" are used interchangeably, referring to a 3- to 6-membered saturated or partially unsaturated monocyclic ring in which one, two, or three carbon atoms are selected from nitrogen, oxygen, or S(O). t5 The heterocycle is substituted with heteroatoms (where t5 is an integer from 0 to 2), but does not include the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon; preferably 4 to 6 members, more preferably 5 to 6 members. The ring carbon atoms of the monoheterocycle may optionally be substituted with 1, 2, or 3 oxo groups to form cyclic ketones, cyclic lactones, or cyclic lactam structures. Examples of 3 to 6-membered monoheterocycles include (but are not limited to) aziridine, aziridine butane, tetrahydropyrrole, piperidine, pyrrolidone, piperazine, 2,5-dihydro-1H-pyrrole, 2,3-dihydro-1H-pyrrole, 1,2,3,4-tetrahydropyridine, 1,2,3,6-tetrahydropyridine, etc. In one disclosed embodiment, the 4- to 8-membered nitrogen-containing heterocyclic alkyl group is a 4- to 6-membered nitrogen-containing heterocyclic alkyl group, and non-limiting examples include: Preferably, the "4 to 8-membered nitrogen-containing heterocyclic alkyl group" is connected to the rest of the molecule through the nitrogen atom that must be present. As used herein, the term "aryl" refers to a fully unsaturated aliphatic hydrocarbon group. It can contain 6 to 14 ring atoms (i.e., 6 to 14 members or C atoms). 6-14The ring system comprises an all-carbon monocyclic ring, an all-carbon polycyclic ring (rings connected by covalent bonds, not fused), or an all-carbon fused polycyclic ring (i.e., rings sharing adjacent carbon atom pairs), wherein at least one ring in the ring system is aromatic, i.e., has a conjugated π-electron system. Preferably, it contains 6 to 10 ring atoms (i.e., 6 to 10 cyclic or C atoms). 6-10 The aryl group of the ring system. Each ring in the ring system contains 5 or 6 ring atoms. As used herein, the terms "heteroaryl," "heteroaryl ring," and "heteroaryl ring" are used interchangeably to refer to a fully unsaturated aliphatic hydrocarbon group containing a heteroatom. It can be a monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atoms or heteroatom pairs) group having 5 to 14 ring atoms (i.e., 5 to 14 members), preferably 5 to 10 ring atoms (i.e., 5 to 10 members), more preferably 5, 6, 8, 9, or 10 ring atoms, containing 1 to 4 heteroatoms as ring atoms, the heteroatoms being selected from oxygen, sulfur, and nitrogen. The nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atom may optionally be quaternized. The heteroaryl group preferably has 6, 10, or 14 shared π electrons in the ring system. At least one ring in the ring system is aromatic. In some embodiments of the present invention, "heteroaryl" refers to a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring). Non-limiting examples of monocyclic heteroaryl groups include: thiophene, N-alkylpyrrolidone, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazolium, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, etc. In some embodiments of the present invention, non-limiting examples of heteroaryl rings (preferably 5- or 6-membered monocyclic heteroaryl rings) include: For example, "halogenated C" 1-10 "Alkyl" refers to an alkyl group that has been substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogens, as defined above. Halogenated C-type halogens are preferred. 1-6 Alkyl, more preferably halogenated C 1-3 Alkyl group. Halogenated C 1-8 Examples of alkyl groups include (but are not limited to) monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, etc. The term "hydroxyl group" refers to -OH. The term "hydroxymethyl" refers to -CH2OH, and "hydroxyethyl" refers to -CH2CH2OH or -CHOHCH3. As used in this article, the term "halogen" refers to fluorine, chlorine, bromine, or iodine. As used in this article, the term "amino" refers to -NH2. As used in this article, the term "carboxyl group" refers to -C(O)OH. In this text, the wavy line on a group, regardless of its form, indicates a connection point with other parts of the molecule. If no wavy line is marked on a group, it means that any position within that group could potentially connect with other positions in the molecule. "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the cases in which the event or environment occurs or does not occur. For example, "optionally alkyl-substituted heterocyclic alkyl group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic alkyl group is substituted with an alkyl group and cases where the heterocyclic alkyl group is not substituted with an alkyl group. "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene). Unless otherwise defined, when a group described in this invention is substituted by a substituent, it means that all identical groups appearing in this invention can be substituted by the substituent. This means that the group can be substituted whether it exists alone or in combination with other groups. For example, R is -C. 1-6 Alkyl, C 6-10 Aryl, C 3-6 Monocyclic cycloalkyl, -C(O)C 1-6 Alkyl, -C 1-4 Alkyl-C 6-10 Aryl or -S(O)2-C 3-6 Monocyclic cycloalkyl, wherein the C 1-6 Alkyl, C 6-10 Aryl, C 3-6 The monocyclic cycloalkyl group is optionally substituted, and the description also includes -C(O)C 1-6 Alkyl, -C 1-4 Alkyl-C 6-10 Aryl and -S(O)2-C 3-6 C in monocyclic cycloalkyl 1-6 Alkyl, C 6-10 Aryl and C 3-6 The monocyclic cycloalkyl group may optionally be substituted. Unless otherwise defined, the phrase "...same or different" in this invention means that when there are more than one identical substituent group in the general formula, the substituent group can be the same or different. Unless otherwise defined, the phrase "substituents selected independently of each other" in this invention means that when one or more hydrogen atoms on a group are replaced by substituents, the types of substituents may be the same or different, and the selected substituents are of independent types. In this article, C 1-10 C can be preferred. 1-6 More preferably, C 1-4 More preferably, C 1-3 For example, C 1-10 Alkyl groups can preferably be C10-30 ... 1-6 Alkyl; more preferably C 1-4 Alkyl; more preferably C 1-3 alkyl. The present invention refers to compounds of formula (I), and also includes their tautomers, stereoisomers, mixtures of stereoisomers, solvates or derivatives, etc. The "compounds" of this invention also include tautomer forms. A tautomer form arises from the exchange of a single bond with an adjacent double bond, accompanied by the migration of a proton. The terms "tautomer" or "tautomer form" refer to isomers of different functional groups in dynamic equilibrium at room temperature that can rapidly interconvert. It refers to one of two or more structural isomers that exist in equilibrium and readily transform from one isomer form to another. This transformation results in the formal migration of a hydrogen atom, accompanied by the conversion of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomer groups in solution. In solutions where tautomerization is possible, chemical equilibrium of the tautomers will be reached. The exact proportions of the tautomers depend on several factors, including temperature, solvent, and pH conditions. The concept of tautomers that can interconvert through tautomerization is called tautomerism. When this specification describes compounds that are readily tautomerizable, but only one of the tautomers is described, it should be understood that all tautomers are included as part of the chemical meaning described. It should be understood that the compounds disclosed herein can be described as different tautomers. It should also be understood that when a compound has tautomeric forms, all tautomeric forms are intended to be included, and the naming of the compound does not exclude any tautomeric form. Of the various possible types of tautomerism, two are typically observed. In keto-enol tautomerism, both electrons and hydrogen atoms move simultaneously. Common tautomer pairs are: keto-enol, amide-nitrile, lactam-lactam, amide-imine tautomer in heterocycles, imine-enamine, and enamine-enamine. The term "isomer" refers to different compounds having the same molecular formula but different atomic arrangements and configurations. The compounds containing asymmetric carbon atoms of the present invention can be isolated in optically active pure form or in the form of a mixture of two or more isomers. The optically active pure form can be resolved from a mixture of two or more isomers, or synthesized using chiral starting materials or chiral reagents. Depending on their structure, the compounds of the present invention can exist in different stereoisomeric forms. These forms include configurational isomers or optical conformational isomers (enantiomers and / or diastereomers, including those with inhibited transisomers). Therefore, the present invention includes enantiomers, diastereomers, and mixtures thereof. Pure stereoisomers can be isolated from those mixtures of enantiomers and / or diastereomers using methods known in the art, preferably chromatography, especially high-performance liquid chromatography (HPLC) using achiral or chiral phases. The present invention further includes all mixtures of the above-described stereoisomers, regardless of proportions, including racemic mixtures. According to their structure, the compounds of the present invention can exist in various stable isotopic forms. These forms include those in which one or more hydrogen atoms are replaced by deuterium atoms, those in which one or more nitrogen atoms are replaced by 15N atoms, or those in which one or more carbon, fluorine, chlorine, bromine, sulfur, or oxygen are replaced by stable isotopes of their respective original atoms. Some compounds and salts according to the present invention may exist in different crystalline forms (polymorphs), which are within the scope of the present invention. In this invention, using and It represents the absolute configuration of the center of a solid. In It refers to the junction of chemical bonds. When the ring appears Furthermore, if the connection location is uncertain, it indicates that the connection site is located at... Any atom on the monocyclic ring, as long as its valence allows. The term "solvent" as used in this invention refers to a complex formed by the compounds of this invention with a solvent. These complexes either react in the solvent or precipitate or crystallize from the solvent. For example, a complex formed with water is called a "hydrate". Solvents of the compounds represented by formula (I) of this invention are within the scope of this invention. This invention includes prodrugs of the above-mentioned compounds. The prodrugs include known amino and carboxyl protecting groups, and are released by hydrolysis under physiological conditions or via enzymatic reactions to yield the parent compound. Typically, the compounds of this invention, or their pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs, can be formulated with one or more pharmaceutical carriers into suitable dosage forms for administration. These dosage forms are suitable for oral, rectal, topical, intraoral, and other non-gastrointestinal administration (e.g., subcutaneous, intramuscular, intravenous, etc.). For example, suitable dosage forms for oral administration include capsules, tablets, granules, and syrups. The compounds of this invention contained in these formulations can be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water emulsions, etc. The above dosage forms can be prepared from the active compound and one or more carriers or excipients using common pharmaceutical methods. The carriers described above need to be compatible with the active compound or other excipients. For solid dosage forms, commonly used non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, and sucrose. Carriers used for liquid dosage forms include water, physiological saline, glucose aqueous solution, ethylene glycol, and polyethylene glycol. The active compound can form solutions or suspensions with the above carriers. The compositions of the present invention are formulated, quantified, and administered in accordance with medical practice guidelines. The "therapeutic effective amount" of the compound administered is determined by factors such as the specific condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the route of administration. As used herein, "therapeutic effective amount" means the amount of the compound of the present invention that will elicit a biological or medical response in an individual, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease. As used herein, “pharmaceuticalally acceptable carrier” means a non-toxic, inert, solid, or semi-solid substance or liquid filling machine, diluent, encapsulation material, or excipient or any type of excipient that is compatible with patients, preferably mammalian, more preferably human, and suitable for delivering an active agent to a target site without terminating the agent’s activity. As used in this article, "patient" or "subject" refers to an animal, preferably a mammal, and more preferably a human. The term "mammal" refers to warm-blooded vertebrate mammals, including animals such as cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, rats, pigs, and humans. As used in this article, the term "disease" is a state of health in an animal in which the animal is unable to maintain homeostasis and the animal's health continues to deteriorate if the disease does not improve. As used herein, “treatment” means to reduce, slow the progression of, attenuate, prevent, or maintain an existing disease or condition (e.g., cancer). Treatment also includes curing, preventing the development of, or reducing to some extent one or more symptoms of a disease or condition. As used herein, the term “treatment” or “treatment” is defined as the administration or application of a therapeutic agent, namely a compound of this disclosure (alone or in combination with another pharmaceutical agent), or the administration or application of a therapeutic agent to an isolated tissue or cell from a patient who suffers from a disease or condition considered herein, a sign or symptom of a disease or condition considered herein, or has the potential to develop a disease or condition considered herein, with the aim of curing, resolving, alleviating, reducing, altering, remedying, improving, ameliorating, or influencing the disease or condition considered herein, a sign or symptom of a disease or condition considered herein, or the possibility of developing a disease or condition considered herein. Such treatments can be specifically tailored or modified based on knowledge obtained from the field of pharmacogenomics. As used herein, the term “treatment” for a disease refers to reducing the frequency or severity of at least one sign or symptom of a disease or condition experienced by a subject. As used in this article, the term "cancer" refers to any of the various types of malignant tumors, most of which invade surrounding tissues, can metastasize to several sites, and may recur after attempted resection, leading to the patient's death unless adequately treated. As used in this article, tumor formation includes cancer. Representative cancers include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma and renal cell carcinoma, bladder cancer, colorectal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, and stomach cancer; leukemia, including non-acute and acute leukemia, such as acute myeloid leukemia, acute lymphoblastic leukemia, acute promyelocytic leukemia (APL), acute T-cell lymphoblastic leukemia, T-cell acute lymphoblastic leukemia (T-ALL), adult T-cell leukemia, basophilic leukemia, eosinophilic leukemia, granulocytic leukemia, hairy cell leukemia, leukopenic leukemia, lymphocytic leukemia, lymphocytic leukemia, megakaryocytic leukemia, microcytic leukemia, monocytic leukemia, neutrophilic leukemia, and stem cell leukemia; Benign and malignant lymphomas, particularly Burkitt lymphoma and non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative disorders; sarcomas, including Ewing sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, sarcoma, myoma, peripheral neuroepithelial tumor, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell carcinoma, hemangioma, meningeal sarcoma, neurofibroma, and schwannoma; colorectal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, nephroblastoma, and teratoma, etc., can be treated with one or more compounds of the present invention. The disease or condition is "reduced" if the severity of the signs or symptoms of the disease or condition, the frequency with which the patient experiences such signs or symptoms, or both are reduced. As used herein, the term "inhibition" means an inhibition or blocking of activity or function by at least about 10 percent relative to a control. Preferably, the activity is inhibited or blocked by 50%, more preferably 75%, and even more preferably 95% or more compared to a control. The term "pharmaceutical composition" refers to a mixture of at least one compound that can be used in this invention with a pharmaceutically acceptable carrier. This pharmaceutical composition facilitates the administration of the compound to a patient or subject. Various techniques for administering the compound exist in the art, including but not limited to intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration. The terms "pharmaceutical composition," "therapeutic composition," "therapeutic formulation," or "pharmaceuticalally acceptable formulation" can refer to, but are by no means limited to, compositions or formulations that allow for the effective distribution of the pharmaceutical agents provided by this invention, in a form suitable for administration to the physical site most optimal for their desired activity, such as systemic administration. Non-limiting examples of reagents suitable for formulation with compounds such as those provided in this invention include: cinnamyl groups, PEGs, phospholipids or lipophilic moieties, thiophosphates, P-glycoprotein inhibitors (e.g., Pluronic P85) that can enhance entry into various tissues, such as the CNS; biodegradable polymers, such as poly(DL-lactide-co-glycolic acid) microspheres for sustained post-implantation delivery; and loaded nanoparticles, such as nanoparticles made of polybutylene cyanoacrylate, which can cross the blood-brain barrier to deliver drugs and can alter neuronal uptake mechanisms. "Therapeutic" treatment refers to treatment applied to a subject who exhibits signs or symptoms of a pathological disease or condition, with the aim of reducing or eliminating those signs or symptoms. As used herein, the terms “analog,” “parameter,” or “derivative” mean a chemical compound or molecule prepared from a parent compound or molecule through one or more chemical reactions. Therefore, an analog may be a structure having a structure similar to that of the small molecule therapeutic agent described herein, or may be based on a scaffold of the small molecule therapeutic agent described herein but differ from it in some components or structures. It may also be a cosmetic, potentially having similar or opposite effects in terms of metabolism. Analogs or derivatives may also be small molecules with structures different from the reference molecule but retaining the essential properties of the reference molecule. Analogs or derivatives may alter their interactions with certain other molecules relative to the reference molecule. Analogs or derived molecules may also include salts, adducts, tautomers, isomers, or other variants of the reference molecule. II. Examples The bifunctional compounds described below regulate target proteins, anaplastic lymphoma kinase (ALK) and ROS1 kinase (ROS1), by eliminating the kinase proteins through ubiquitination and subsequent proteasomal degradation. Each bifunctional compound contains one ligand that binds to either ALK or ROS1, and another ligand that binds to an E3 ubiquitin ligase, the two ligands linked by a linker. These bifunctional compounds can simultaneously bind to ALK or ROS1 and the cereblon (CRBN) E3 ubiquitin ligase, promoting the ubiquitination of ALK and ROS1, thereby leading to proteasomal degradation of ALK and ROS1. In various respects, the present invention provides the disclosed bifunctional compounds that can be applied to the targeted degradation of ALK and ROS1 and can be used to treat or prevent diseases of ALK and ROS1 dysregulation. Compounds and pharmaceutical compositions A first aspect of the invention provides a compound of formula (A) or a pharmaceutically acceptable salt thereof: In the formula, R 1 Selected from hydrogen, deuterium, and C 1-6 Alkyl, C 6-10 aryl, 5- or 6-membered heteroaryl and 4- to 7-membered heterocyclic, wherein the 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclic or C 6-10 Aryl groups are optionally separated by 1, 2 or 3 independently selected from halogens, C 1-6 Alkyl or halogenated C 1-6 Alkyl substituent substitution; wherein the 5- or 6-membered heteroaryl or 4- to 7-membered heterocyclic group comprises 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S as ring atoms, p1 is 1, 2, or 3, and p1 has R 1 Same or different; R 2 Selected from halogens, C 1-6 Alkyl and Halogenated C 1-6 alkyl; R 7 It is a halogen; R 3 For -NR a R b , where R a R b Each is independently selected from hydrogen and C. 1-3 alkyl; R 4 Selected from halogens, C 1-6 Alkyl and Halogenated C 1-6 Alkyl group, p2 is selected from 1, 2 and 3, p2 R 4 Same or different; Y is selected from N and CH; R 5 Selected from hydrogen and halogens, p3 is selected from 1, 2 and 3, p3 R 5 Same or different; R 6 Selected from hydrogen, C 1-6 Alkyl and Halogenated C 1-6 alkyl; L is a linking group. In some implementation schemes, It is a ubiquitin ligase binding group. In some implementation schemes, It is an E3 ligase-binding group. In some implementation schemes, It is a CRBN binding group. In some implementation schemes, It is an ALK-binding group. In some implementation schemes, It is a ROS1 binding group. In some implementation schemes, It is an ALK and ROS1 binding group. In some embodiments, the compound of formula (A) has the structure shown in formula (A-1): In the formula, R 1 R 2 R 3 R 4 R 5 R 6 R 7 Y, p1, p2 and p3 are each compounds of formula (A); X1, X2, X3, and X4 are each independently selected from N and CH; n1, n2, n3, and n4 are each independently selected from 1, 2, and 3; Q1 is selected from single bonds, -(CH2) 0-3 -NR c -(CH2) 0-3 -、-(CH2) 0-3 -(C=O)-(CH2) 0-3 -、C 1-3 Alkylene, -4 to 8-membered nitrogen-containing heterocyclic alkyl groups, -(CH2) 0-3 -4 to 8-membered nitrogen-containing heterocyclic alkyl groups -(CH2) 0-3 -、-(CH2) 0-3 -4 to 8-membered nitrogen-containing heterocyclic alkyl groups -(C=O)-(CH2) 0-3 - and -(CH2) 0-3 -(C=O)-4 to 8-membered nitrogen-containing heterocyclic alkyl-(CH2) 0-3 - The 4 to 8-membered nitrogen-containing heterocyclic alkyl group contains 1, 2 or 3 N atoms as ring atoms; Q2 is selected from single bond, -(CH2) 0-3 -(C=O)-(CH2) 0-3 -and C 1-3 Alkylene; R L1 RL2 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, Halogenated C 1-6 alkyl and hydroxy substituted C 1-6 Alkyl group, q1 is selected from 1, 2 and 3, q1 R L1 Whether the numbers are the same or different, q2 is selected from 1, 2, and 3, and q2 are R. L2 Same or different; R c Selected from hydrogen and C 1-3 alkyl. In some implementations, Q1 is a single bond; in others, Q1 is -(CH2). 0-3 -NR c -(CH2) 0-3 -; In some implementations, Q1 is -(CH2). 0-3 -(C=O)-(CH2) 0-3 -; In some implementations, Q1 is C 1-3 Alkylene; in some embodiments, Q1 is a 4- to 8-membered nitrogen-containing heterocyclic alkyl group; in some embodiments, Q1 is (CH2). 0-3 -4 to 8-membered nitrogen-containing heterocyclic alkyl groups -(CH2) 0-3 -; In some implementations, Q1 is -(CH2). 0-3 -4 to 8-membered nitrogen-containing heterocyclic alkyl groups -(C=O)-(CH2) 0-3 -; In some implementations, Q1 is -(CH2). 0-3 -(C=O)-4 to 8-membered nitrogen-containing heterocyclic alkyl-(CH2) 0-3 - In some embodiments, the 4- to 8-membered nitrogen-containing heterocyclic alkyl group contains 1, 2, or 3 nitrogen atoms as ring atoms; in some embodiments, the 4- to 8-membered nitrogen-containing heterocyclic alkyl group contains 1 or 2 nitrogen atoms as ring atoms; in some embodiments, the 4- to 8-membered nitrogen-containing heterocyclic alkyl group contains 1 nitrogen atom as a ring atom; in some embodiments, the 4- to 8-membered nitrogen-containing heterocyclic alkyl group contains 2 nitrogen atoms as ring atoms. In some implementations, Q2 is a single bond; in others, Q2 is -(CH2). 0-3 -(C=O)-(CH2) 0-3 -; In some implementations, Q2 is C 1-3 Alkylene. In some implementation schemes, R L1 Selected from hydrogen, halogens, C 1-6 Alkyl, Halogenated C 1-6 alkyl and hydroxy substituted C 1-6 Alkyl group, q1 is selected from 1, 2 and 3, q1 RL1 Same or different. In some implementation schemes, R L1 For hydrogen; in some implementations, R L1 For halogen; in some implementations, R L1 It is fluorine, chlorine, or bromine; in some embodiments, R L1 It is fluorine; in some implementations, R L1 C substituted with hydroxyl group 1-6 Alkyl; in one embodiment, R L1 It is hydroxymethyl or hydroxyethyl; in one embodiment, R L1 It is hydroxymethyl. In some implementation schemes, R L2 Selected from hydrogen, halogens, C 1-6 Alkyl, Halogenated C 1-6 alkyl and hydroxy substituted C 1-6 Alkyl group, q2 is selected from 1, 2 and 3, q2 R L2 Same or different. In some implementation schemes, R L2 It is hydrogen. In some implementation schemes, R c Selected from hydrogen and C 1-3 alkyl. In some implementation schemes, R c It is hydrogen. In some embodiments, Q1 is methylene; in some embodiments, Q1 is -(C=O)-; in some embodiments, Q1 is -NH(CH3)-. In some implementations, Q2 is a single bond; in other implementations, Q2 is a methylene group. In some implementations, n1 is 1; in some implementations, n1 is 2; in some implementations, n1 is 3. In some implementations, n2 is 1; in some implementations, n2 is 2; and in some implementations, n2 is 3. In some implementations, n3 is 1; in some implementations, n3 is 2; and in some implementations, n3 is 3. In some implementations, n4 is 1; in some implementations, n4 is 2; and in some implementations, n4 is 3. In some implementations, Q1 is a methylene group and Q2 is a single bond. In some implementations, Q1 is -(C=O) and Q2 is a single bond. In some implementations, Q1 is -NH(CH3)- and Q2 is a single bond. In some implementations, Q1 is a methylene group, Q2 is a single bond, n1 is 1, and n2 is 1. In some implementations, Q2 is a single bond, n3 is 1, and n4 is 1. In some implementation schemes, L is selected from: Wherein, * indicates linkage with ubiquitin ligase binding groups, and ** indicates linkage with ALK and / or ROS1 binding groups; Among them, X1, X2, X3, X4, n1, n2, n3, n4, R L1 R L2 q1, q2, R c Each of the following isoform (A-1) compounds is defined. X5 and X6 are each independently selected from N and CH; n5 and n6 are each independently selected from 1, 2 and 3. In some embodiments, X5 is selected from N and CH; in some embodiments, X5 is N; in some embodiments, X5 is CH; in some embodiments, X6 is selected from N and CH; in some embodiments, X6 is N; in some embodiments, X6 is CH. In some implementations, L is In some implementations, L is In some implementations, L is In some implementations, L is In some implementations, L is In one implementation scheme, L is In some implementations, L is In some implementations, L is In some implementation schemes, L is selected from: In this context, * indicates a connection to a ubiquitin ligase binding group, and ** indicates a connection to an ALK and / or ROS1 binding group. In some implementation schemes, R 1 It is a 5- or 6-membered heteroaryl group. In some embodiments, the 5- or 6-membered heteroaryl group comprises 1, 2, 3, or 4 N atoms as ring atoms; in some embodiments, the 5- or 6-membered heteroaryl group comprises 1, 2, or 3 N atoms as ring atoms; in some embodiments, the 5- or 6-membered heteroaryl group comprises 2 or 3 N atoms as ring atoms; in some embodiments, the 5- or 6-membered heteroaryl group comprises 2 N atoms as ring atoms; and in some embodiments, the 5- or 6-membered heteroaryl group comprises 3 N atoms as ring atoms. In some embodiments, the 5- or 6-membered heteroaryl ring forming the 5- or 6-membered heteroaryl group is selected from pyrrole, pyrazole, imidazole, triazole, tetraazole, pyridine, pyrimidine, pyridazine, and pyrazine; in some embodiments, the 5- or 6-membered heteroaryl ring forming the 5- or 6-membered heteroaryl group is a diazole; in some embodiments, the 5- or 6-membered heteroaryl ring forming the 5- or 6-membered heteroaryl group is a triazole. In some embodiments, the 5- or 6-membered heteroaryl ring forming the 5- or 6-membered heteroaryl group is selected from... In some embodiments, the 5- or 6-membered heteroaryl ring forming the 5- or 6-membered heteroaryl group is... In some embodiments, the 5- or 6-membered heteroaryl ring forming the 5- or 6-membered heteroaryl group is... In some implementation schemes, R 1 Selected from In some implementation schemes, R 1 Selected from In some implementation schemes, R 1 for In some implementation schemes, R 1 for In some implementation schemes, R 7 Selected from fluorine, chlorine, and bromine; in some embodiments, R 7 It is fluorine; in some implementations, R 7 It is chlorine. In some implementation schemes, R 2 C 1-3 Alkyl; in some embodiments, R 2 It is methyl or ethyl; in some embodiments, R 2 It is a methyl group. In some implementation schemes, R 2 for In some implementation schemes, R 2 for In some implementation schemes, R 3 For -NR a R b R a R b Each can be either hydrogen or methyl. In some implementation schemes, R 3 It is -NH2. In some implementation schemes, R 4 C 1-3 Alkyl; in some embodiments, R 4 It is methyl or ethyl; in some embodiments, R 4 It is a methyl group. In some implementations, Y is CH. In some implementation schemes, R 5 It is hydrogen. In some implementation schemes, R 6 C 1-3 Alkyl; in some embodiments, R 6 It is methyl, ethyl, propyl, or isopropyl; in some embodiments, R 6 It is a methyl group. In some embodiments, the compound of formula (A-1) has the structure shown in formula (I): In the formula, R 1 ,X1,X2,X3,X4,n1,n2,n3,n4,Q1,Q2,R L1 R L2 Each of q1 and q2 defines an isoform (A-1) compound; In some implementations, q1 is 0 or 1, and q2 is 0; In some implementations, q1 is 1, R L1 Selected from fluorine and hydroxymethyl. In some implementations, n1 is 1, n2 is 1, n3 is 2, and n4 is 2; in some implementations, n1 is 2, n2 is 2, n3 is 2, and n4 is 2; in some implementations, n1 is 2, n2 is 2, n3 is 1, and n4 is 1; in some implementations, n1 is 2, n2 is 1, n3 is 2, and n4 is 2; in some implementations, n1 is 1, n2 is 1, n3 is 1, and n4 is 1; in some implementations, n1 is 2, n2 is 2, n3 is 2, and n4 is 1. In one embodiment, the compound of formula (A) is selected from compounds 1 to 40 or below in Table 1: 3-(6-(3-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-((1-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperidin-4-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(3-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(1H-pyrazol-1-yl)phenyl)ethoxy)pyridine)-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(4-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(4-((1-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(4-((1-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperidin-4-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(4-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(1H-pyrazol-1-yl)phenyl)ethoxy)pyridine)-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(4-((1-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)azacyclobutane-3-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(4-((1-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)azacyclobutane-3-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(3-((1-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)azacyclobutane-3-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-yl)methyl)pyrrolidine-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-((1-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperidin-4-yl)methyl)pyrrolidine-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(3-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)-2-fluoropiperazin-1-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(3-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl)-1,4-diazacyclo-1-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(3-((1-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperidin-4-yl)(methyl)amino)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(3-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)-2-(hydroxymethyl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)-2-(fluoromethyl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-(4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-carbonyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-((4-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-((1-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperidin-4-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(3-((4-((5-(6-amino-5-((R)-1-(5-fluoro-2-(1H-pyrazol-1-yl)phenyl)ethoxy)))pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(4-((4-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(4-((1-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(4-((1-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(4-((4-((5-(6-amino-5-((R)-1-(5-fluoro-2-(1H-pyrazol-1-yl)phenyl)ethoxy)))pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(4-((1-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)azacyclobutane-3-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(4-((1-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)azacyclobutane-3-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(3-((1-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)azacyclobutane-3-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-((4-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperazin-1-yl)methyl)pyrrolidine-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-((1-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperidin-4-yl)methyl)pyrrolidine-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(3-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-yl)methyl)-[1,3'-azitrazine]-1'-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-(4-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(1-(4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-carbonyl)azacyclobutane-3-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(1-(4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(1-(4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperidine-1-carbonyl)azacyclobutane-3-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(4-(4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperidine-1-carbonyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(4-((1-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)pyrrolidine-3-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(4-((1-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)pyrrolidine-3-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(4-(4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-carbonyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; And 3-(6-(3-(1-(4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2)-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-carbonyl)piperidin-4-yl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione. This disclosure also relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of the first aspect or a pharmaceutically acceptable salt thereof. This disclosure also relates to the use of compounds of formula (A), formula (A-1) or formula (I) or pharmaceutically acceptable salts thereof in the preparation of ALK and / or ROS1 inhibitors. This disclosure also relates to a method for treating ALK-mediated diseases, the method comprising administering to a subject in need a therapeutically effective amount of a compound of formula (A), formula (A-1) or formula (I) or a pharmaceutically acceptable salt thereof. This disclosure also relates to a method for treating ROS1-mediated disease, the method comprising administering to a subject in need a therapeutically effective amount of a compound of formula (A), formula (A-1) or formula (I) or a pharmaceutically acceptable salt thereof. This disclosure also relates to a method for treating ALK and ROS1-mediated diseases, the method comprising administering to a subject in need a therapeutically effective amount of a compound of formula (A), formula (A-1) or formula (I) or a pharmaceutically acceptable salt thereof. In some implementations, the subject expresses anaplastic lymphoma kinase (ALK) and / or ROS1 protein. In some specific implementations, the subject expresses the ALK protein. In some specific implementations, the subject expresses the ROS1 protein. In some specific implementations, the subject expresses ALK and ROS1 proteins. This disclosure also relates to the use of compounds of formula (A), formula (A-1) or formula (I) or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating ALK and / or ROS1-mediated diseases. This disclosure also relates to the use of compounds of formula (A), formula (A-1) or formula (I) or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment of ALK-mediated diseases. This disclosure also relates to the use of compounds of formula (A), formula (A-1) or formula (I) or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating ROS1-mediated diseases. This disclosure also relates to the use of compounds of formula (A), formula (A-1) or formula (I) or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment of ALK and ROS1-mediated diseases. This disclosure also relates to the use of compounds of formula (A), formula (A-1) or formula (I) or pharmaceutically acceptable salts thereof for the treatment of subjects in need of ALK and / or ROS1-mediated diseases. This disclosure also relates to compounds of formula (A), formula (A-1) or formula (I) or pharmaceutically acceptable salts thereof for the treatment of ALK and / or ROS1-mediated diseases. In some implementations, the ALK-mediated disease is non-small cell lung cancer. In some implementations, the ROS1-mediated disease is non-small cell lung cancer. In some implementations, the non-small cell lung cancer expresses ALK. In some implementations, the non-small cell lung cancer expresses the ROS1 protein. In some implementations, the non-small cell lung cancer expresses ALK and ROS1 proteins. This disclosure also relates to a method for degrading ALK in a biological sample, comprising contacting the biological sample with a compound of formula (A), formula (A-1) or formula (I) or a pharmaceutically acceptable salt thereof. This disclosure also relates to a method for degrading ROS1 protein in a biological sample, comprising contacting the biological sample with a compound of formula (A), formula (A-1) or formula (I) or a pharmaceutically acceptable salt thereof. This disclosure also relates to a method for simultaneously degrading ALK and ROS1 proteins in a biological sample, comprising contacting the biological sample with a compound of formula (A), formula (A-1) or formula (I) or a pharmaceutically acceptable salt thereof. This disclosure also relates to intermediates used in synthesizing the compounds disclosed herein. In some implementations, the intermediate is This disclosure also relates to methods for preparing the compounds of this disclosure, selected from the following synthetic routes: Synthesis Route 1: The reductive amination reaction of compound Ia with compound Ib yields compound (I); Among them, R 1 ,X1,X2,X3,X4,n1,n2,n3,n4,Q1,Q2,R L1 R L2 Each of q1 and q2 is a custom compound of formula (I). Synthesis Route 2: The reductive amination reaction of compound Ic with compound Id yields compound (I); Among them, R 1 ,X1,X2,X3,X4,n1,n2,n3,n4,Q1,Q2,R L1 R L2 Each of q1 and q2 is a custom compound of formula (I). Synthesis Route 3: Compound of formula (I) is obtained by reacting compound of formula (If) and compound of formula (Ig) via amide coupling reaction to form a urea group; Among them, R 1 ,X1,X2,X3,X4,n1,n2,n3,n4,Q1,Q2,R L1 R L2 Each of q1 and q2 is a custom compound of formula (I). Synthesis Route 4: The reaction of compound Ih with compound Ij yields compound (I) by Suzuki. Among them, R 1 ,X1,X2,X3,X4,n1,n2,n3,n4,Q1,Q2,R L1 R L2Each of q1 and q2 is a custom compound of formula (I). G is a halogen. A second aspect of this disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the first aspect or a pharmaceutically acceptable salt thereof. In one embodiment, this disclosure provides a pharmaceutical composition comprising at least one compound of formula (A), formula (A-1) or formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, this disclosure provides a pharmaceutical composition comprising a compound selected from compounds 1 to 40 of Table 1 or the following group: 3-(6-(3-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-((1-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperidin-4-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(3-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(1H-pyrazol-1-yl)phenyl)ethoxy)pyridine)-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(4-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(4-((1-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(4-((1-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperidin-4-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(4-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(1H-pyrazol-1-yl)phenyl)ethoxy)pyridine)-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(4-((1-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)azacyclobutane-3-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(4-((1-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)azacyclobutane-3-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(3-((1-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)azacyclobutane-3-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-yl)methyl)pyrrolidine-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-((1-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperidin-4-yl)methyl)pyrrolidine-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(3-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)-2-fluoropiperazin-1-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(3-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl)-1,4-diazacyclo-1-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(3-((1-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperidin-4-yl)(methyl)amino)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(3-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)-2-(hydroxymethyl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)-2-(fluoromethyl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-(4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-carbonyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-((4-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-((1-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperidin-4-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(3-((4-((5-(6-amino-5-((R)-1-(5-fluoro-2-(1H-pyrazol-1-yl)phenyl)ethoxy)))pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(4-((4-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(4-((1-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(4-((1-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(4-((4-((5-(6-amino-5-((R)-1-(5-fluoro-2-(1H-pyrazol-1-yl)phenyl)ethoxy)))pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(4-((1-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)azacyclobutane-3-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(4-((1-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)azacyclobutane-3-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(3-((1-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)azacyclobutane-3-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-((4-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperazin-1-yl)methyl)pyrrolidine-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-((1-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperidin-4-yl)methyl)pyrrolidine-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(3-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-yl)methyl)-[1,3'-azitrazine]-1'-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-(4-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(1-(4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-carbonyl)azacyclobutane-3-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(1-(4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(1-(4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperidine-1-carbonyl)azacyclobutane-3-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(4-(4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperidine-1-carbonyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(4-((1-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)pyrrolidine-3-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(4-((1-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)pyrrolidine-3-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(4-(4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-carbonyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; And 3-(6-(3-(1-(4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2)-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-carbonyl)piperidin-4-yl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione. In one embodiment, the pharmaceutical compound is used to treat proliferative diseases, such as cancers, such as non-small cell lung cancer. This disclosure also relates to the use of the pharmaceutical composition in the preparation of ALK and / or ROS1 inhibitors. This disclosure also relates to a method for treating ALK-mediated diseases, the method comprising administering a therapeutically effective amount of the pharmaceutical composition to a subject in need. This disclosure also relates to a method for treating ROS1-mediated diseases, the method comprising administering a therapeutically effective amount of the pharmaceutical composition to a subject in need. This disclosure also relates to a method for treating ALK and ROS1-mediated diseases, the method comprising administering a therapeutically effective amount of the pharmaceutical composition to a subject in need. This disclosure also relates to a pharmaceutical composition for treating ALK and ROS1-mediated diseases. This disclosure also relates to the use of the pharmaceutical composition for treating ALK and / or ROS1-mediated diseases in subjects of need. In some specific implementations, the subject expresses ALK. In some specific implementations, the subject expresses the ROS1 protein. In some specific implementations, the subject expresses ALK and ROS1 proteins. This disclosure also relates to the use of the pharmaceutical composition in the preparation of a medicament for treating ALK-mediated diseases. This disclosure also relates to the use of the pharmaceutical composition in the preparation of a medicament for treating ROS1-mediated diseases. This disclosure also relates to the use of the pharmaceutical composition in the preparation of medicaments for treating ALK and ROS1-mediated diseases. In some implementations, the ALK-mediated disease is non-small cell lung cancer. In some implementations, the ROS1-mediated disease is non-small cell lung cancer. In some implementations, the non-small cell lung cancer expresses ALK. In some implementations, the non-small cell lung cancer expresses the ROS1 protein. In some implementations, the non-small cell lung cancer expresses ALK and ROS1 proteins. This disclosure also relates to a method for degrading ALK protein in a biological sample, comprising contacting the biological sample with the pharmaceutical composition. This disclosure also relates to a method for degrading ROS1 protein in a biological sample, comprising contacting the biological sample with the pharmaceutical composition. This disclosure also relates to a method for simultaneously degrading ALK and ROS1 proteins in a biological sample, comprising contacting the biological sample with the pharmaceutical composition. Further embodiments may provide a method of treating lung cancer, including administering a compound according to any of the foregoing paragraphs to a subject requiring treatment or improvement. In some embodiments, the compound described above is used to prepare a medicament for treating lung cancer in a patient or subject (e.g., a human or an animal). The pharmaceutical compositions of the present invention can be in any form known to those skilled in the art, and can be administered via suitable routes and dosage forms. For example, in some embodiments, the pharmaceutical compositions are in the form of a product for oral delivery, selected from the group consisting of concentrates, dry powders, liquids, capsules, pills, and pellets. In other embodiments, the pharmaceutical compositions of the present invention are in the form of a product for parenteral administration, including intravenous, intradermal, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, and subcutaneous administration. The compounds described herein can be administered as a single dose or in multiple doses over a period of time. The pharmaceutical compositions disclosed herein may further comprise a carrier, a binder, a diluent, and excipients. The carrier, diluent, and excipients may include dried corn starch or lactose, the binder may include microcrystalline cellulose, tragacanth gum, or gelatin, and the excipients may also include dispersants, lubricants, flow aids, sweeteners, or flavorings. Additionally, in other respects, this disclosure provides methods for modulating kinases, including contacting the kinase with a bifunctional compound disclosed herein or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or with a pharmaceutical composition disclosed herein. In some embodiments, the kinase is ALK. In some embodiments, the kinase is ROS1. The compounds disclosed herein can be used to slow the growth rate of primary tumors. The disclosed compounds can also be used to prevent, mitigate, minimize, control, and / or reduce tumor metastasis in humans and animals. When administered to a subject requiring treatment, the disclosed compounds can be used to stop the spread of cancer cells. Therefore, the disclosed compounds can be administered as part of a combination therapy with one or more drugs or other agents. When used as part of a combination therapy, the reduction in metastasis and primary tumor growth provided by the disclosed compounds allows for more effective and efficient use of any drug or drug therapy used to treat the patient. Furthermore, the control of metastasis by the disclosed compounds provides the subject with a greater ability to focus the disease in one location. The following are non-limiting examples of cancers that can be treated by the disclosed methods and compositions: acute lymphoblastic carcinoma; acute myeloid leukemia; adrenocortical carcinoma; adrenocortical carcinoma in children; appendix cancer; basal cell carcinoma; extrahepatic bile duct carcinoma; bladder cancer; bone cancer; osteosarcoma and malignant fibrous histiocytoma; childhood brainstem glioma; adult brain tumor; brain tumor, childhood brainstem glioma; brain tumor, atypical teratoma-like / rhabdoid tumor of the central nervous system in children; embryonic tumor of the central nervous system; cerebellar astrocytoma; brain astrocytoma / malignant glioma; craniopharyngioma; ependymoblastoma; ependymoma; medulloblastoma; medullary epithelial tumor; intermediately differentiated pineal parenchymal tumor; supratentorial primitive neuroectodermal tumor and pineal blastoma; visual Pathway and hypothalamic glioma; brain and spinal cord tumors; breast cancer; bronchial tumors; Burkitt lymphoma; carcinoid; gastrointestinal carcinoid; atypical teratoma-like / rhabdoid tumors of the central nervous system; embryonic tumors of the central nervous system; lymphoma of the central nervous system; cerebellar astrocytoma in children; astrocytoma / malignant glioma; cervical cancer; childhood chordoma; chronic lymphocytic leukemia; chronic myeloid leukemia; chronic myeloproliferative disorders; colon cancer; colorectal cancer; craniopharyngioma; cutaneous T-cell lymphoma; esophageal cancer; Ewing tumor family; gonadal germ cell tumors; extrahepatic bile duct carcinoma; ocular cancer, intraocular melanoma; ocular cancer, retinoblastoma; gallbladder cancer; gastric cancer; gastrointestinal carcinoid; gastrointestinal stromal tumor (GIST); extracranial germ cell tumors; Extragonadal germ cell tumors; ovarian germ cell tumors; gestational trophoblastic tumors; gliomas; pediatric brainstem gliomas; gliomas, pediatric astrocytomas; gliomas, pediatric visual pathway and hypothalamus; hairy cell leukemia; head and neck cancer; hepatocellular carcinoma; Langerhans cell histiocytosis; Hodgkin's lymphoma; hypopharyngeal cancer; hypothalamic and visual pathway gliomas; intraocular melanoma; islet cell tumors; renal (renal cell) carcinoma; Langerhans cell histiocytosis; laryngeal cancer; leukemia, acute lymphoblastic; leukemia, acute myeloid leukemia; leukemia, chronic lymphocytic; leukemia, chronic myeloid; leukemia, hairy cell; lip and oral cancer; liver cancer; lung cancer, non-small cell; lung cancer, small cell; AIDS-related. Lymphoma; Lymphoma, Burkitt; Lymphoma, Cutaneous T-cell; Lymphoma, Hodgkin; Lymphoma, Non-Hodgkin; Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenström; Malignant fibrous histiocytoma and osteosarcoma of bone; Medulloblastoma; Melanoma; Intraocular melanoma (eye); Merkel cell carcinoma; Mesothelioma; Occult primary metastatic squamous neck carcinoma; Oral cancer; Multiple endocrine neoplasia syndrome (childhood); Multiple myeloma / plasma cell tumor; Fungal disease; Mycosis fungoides; Myelodysplastic syndrome; Myelodysplastic / myeloproliferative disorders; Chronic myeloid leukemia; Adult acute myeloid leukemia; Myeloid leukemia, childhood acute; Multiple myeloma; Chronic myeloproliferative disorders; Nasal and paranasal sinus carcinoma;Nasopharyngeal carcinoma; neuroblastoma; non-small cell lung cancer; oral cavity cancer; oral cavity cancer; oropharyngeal carcinoma; osteosarcoma and malignant fibrous histiocytoma of bone; ovarian cancer; ovarian epithelial carcinoma; ovarian germ cell tumors; low-grade malignant potential ovarian tumors; pancreatic cancer; pancreatic cancer, islet cell tumors; papilloma; parathyroid carcinoma; penile cancer; pharyngeal cancer; pheochromocytoma; intermediate differentiated pineal parenchymal tumors; pineal blastoma and supratentorial primitive neuroectodermal tumors; pituitary adenoma; plasma cell tumors / multiple myeloma; pleural pulmonary blastoma; primary central nervous system lymphoma; prostate cancer; rectal cancer; renal cell carcinoma; renal pelvis and ureter, transitional cell carcinoma; respiratory tract cancers involving the NUT gene on chromosome 15. Retinoblastoma; Rhabdomyosarcoma; Salivary gland carcinoma; Sarcoma, Ewing tumor family; Sarcoma, Kaposi's; Sarcoma, soft tissue; Sarcoma, uterus; Cézari syndrome; Skin cancer (non-melanoma); Skin cancer (melanoma); Skin cancer, Merkel cell; Small cell lung cancer; Small bowel cancer; Soft tissue sarcoma; Squamous cell carcinoma, occult primary, metastatic squamous neck carcinoma; Gastric cancer; Supratentorial primitive neuroectodermal tumor; Cutaneous T-cell lymphoma; Testicular cancer; Pharyngeal cancer; Thymoma and thymic carcinoma; Thyroid cancer; Transitional cell carcinoma of the renal pelvis and ureter; Gestational trophoblastic tumor; Urethral cancer; Uterine cancer; Endometrium; Uterine sarcoma; Vaginal cancer; Vulvar cancer; Waldenström macroglobulinemia and nephroblastoma. Treatment The method of treating clinical indications with the ALK and / or ROS1 degradation compounds disclosed herein can be achieved by administering a therapeutically effective amount of the disclosed compound or the above-described pharmaceutical composition to a patient in need. This therapeutically effective amount may include administration at about 1 mg / kg (subject weight) / day, about 2 mg / kg / day, about 3 mg / kg / day, about 4 mg / kg / day, about 5 mg / kg / day, or about 10 mg / kg / day. A prodrug may be administered to the patient at about 10 mg / kg / day or about 20 mg / kg / day. Or the dosage range is from about 0.001 mg / kg / day to about 0.01 mg / kg / day, or from about 0.01 mg / kg / day to about 0.1 mg / kg / day, or from about 0.1 mg / kg / day to about 1 mg, or about 1 mg / kg / day, or about 1 mg / kg / day to about 10 mg / kg / day, or about 10 mg / kg / day to about 100 mg / kg / day. This disclosure also provides a kit comprising a composition containing at least one ALK and / or ROS1 degradation compound for the treatment and / or prevention of cancer and cancer-related conditions. The kit composition may comprise at least one carrier, at least one binder, at least one diluent, at least one excipient, at least one other therapeutic agent, or a mixture thereof. The kit may be designed, developed, distributed, or marketed as a unit for performing the methods of this disclosure and delivering drugs to target cells to treat and / or prevent cancer and related diseases. The kit may also include instructions for customers to correctly use the kit to treat patients exhibiting desired disease symptoms, such as lung cancer. the term As used herein, “treatment” means administering a pharmaceutical composition to a subject to improve, reduce, or alleviate symptoms of a disease. As used herein, “treatment” or “prevention” describes the administration and care of a subject to combat a disease, condition, or symptom of a condition, and includes the administration of the compounds disclosed herein, or pharmaceutically acceptable salts, polymorphs, or solvates thereof, with the aim of alleviating or eliminating symptoms or complications of the disease, condition, or symptom. The term “treatment” may also include treatment in in vitro cell or animal models. As used herein, “subject” refers to any animal, such as a mammal, including rodents (e.g., mice or rats), dogs, primates, lemurs, or humans. Cancer treatment can lead to a reduction in tumor size. This reduction in tumor size can also be referred to as "tumor regression." Preferably, after treatment, the tumor size is reduced by about 5% or more compared to its pre-treatment size; more preferably, the tumor size is reduced by about 10% or more; even more preferably, by about 20% or more; more preferably, by about 30% or more; even more preferably, by about 40% or more; and most preferably, by about 50% or more; and most preferably, by more than about 75% or more. The size of the tumor can be measured by any repeatable measurement method. The size of the tumor can be defined as its diameter. Cancer treatment can lead to a reduction in tumor volume. Preferably, after treatment, the tumor volume is reduced by about 5% or more relative to its pre-treatment size; more preferably, the tumor volume is reduced by about 10% or more; even more preferably, by about 20% or more; more preferably, by about 30% or more; even more preferably, by about 40% or more; even more preferably, by about 50% or more; most preferably, by about 75% or more. Tumor volume can be measured by any repeatable measurement method. Cancer treatment can lead to a reduction in the number of tumors. Preferably, after treatment, the number of tumors is reduced by about 5% or more compared to the number before treatment; more preferably, the number of tumors is reduced by about 10% or more; even more preferably, by about 20% or more; more preferably, by about 30% or more; even more preferably, by about 40% or more; and still more preferably, by about 50% or more; most preferably, by more than about 75%. The number of tumors can be measured by any repeatable measurement method. The number of tumors can be measured by counting tumors that are visible to the naked eye or visible at a specific magnification. Preferably, the specified magnification is 2x, 3x, 4x, 5x, 10x, or 50x. Treating cancer can lead to a reduction in the number of metastatic lesions in other tissues or organs far from the primary tumor site. Preferably, after treatment, the number of metastatic lesions is reduced by about 5% or more compared to the number before treatment; more preferably, the number of metastatic lesions is reduced by about 10% or more; more preferably, by about 20% or more; more preferably, by about 30% or more; more preferably, by about 40% or more; even more preferably, by 50% or more; most preferably, by more than about 75%. The number of metastatic lesions can be measured by any repeatable measurement method. The number of metastatic lesions can be measured by counting metastatic lesions visible to the naked eye or at a specific magnification. Preferably, the specified magnification is 2x, 3x, 4x, 5x, 10x, or 50x. Cancer treatment can lead to an increase in the mean survival time of the treated subject population compared to a population receiving the drug alone. Preferably, the mean survival time increase is greater than about 30 days; more preferably, greater than about 60 days; even more preferably, greater than about 90 days; and most preferably, greater than about 120 days. The increase in mean survival time can be measured by any reproducible method. The increase in mean survival time can be measured, for example, by calculating the mean survival length of the population after initiating treatment with the active compound. The increase in mean survival time can also be measured, for example, by calculating the mean survival length of the population after completing the first round of treatment with the active compound. Cancer treatment can lead to an increase in the mean survival time of the treated group compared to the untreated group. Preferably, the increase in mean survival time is greater than about 30 days; more preferably, greater than about 60 days; even more preferably, greater than about 90 days; and most preferably, greater than about 120 days. The increase in mean survival time can be measured by any repeatable method. The increase in mean survival time can be measured, for example, by calculating the mean survival length of the group after initiating treatment with the active compound. The increase in mean survival time can also be measured, for example, by calculating the mean survival length of the group after completing the first round of treatment with the active compound. Cancer treatment can lead to an increase in the mean survival time of the treated subject population compared to a population receiving monotherapy with a compound not disclosed herein or a pharmaceutically acceptable salt thereof. Preferably, the mean survival time increase is greater than about 30 days; more preferably, greater than about 60 days; even more preferably, greater than about 90 days; and most preferably, greater than about 120 days. The increase in mean survival time can be measured by any reproducible method. The increase in mean survival time can be measured, for example, by calculating the mean survival length of the population after initiation of treatment with the active compound. The increase in mean survival time can also be measured, for example, by calculating the mean survival length of the population after completion of the first round of treatment with the active compound. Compared to a group receiving the carrier alone, treatment of cancer with the active compound of this disclosure can result in a reduced mortality rate in the treated subject population. Compared to an untreated population, cancer treatment can result in a reduced mortality rate in the treated subject population. Compared to a group receiving monotherapy with a compound not disclosed herein, or a pharmaceutically acceptable salt, prodrug, metabolite, analogue, or derivative thereof, cancer treatment can result in a reduced mortality rate in the treated subject population. Preferably, the mortality rate reduction exceeds about 2%; more preferably, exceeds about 5%; even more preferably, exceeds about 10%; most preferably, exceeds about 25%. The reduction in mortality rate in the treated subject population can be measured by any reproducible method. The reduction in population mortality rate can be measured, for example, by calculating the average number of disease-related deaths per unit time in the population after initiation of treatment with the active compound. The reduction in population mortality rate can also be measured, for example, by calculating the average number of disease-related deaths per unit time in the population after completion of the first round of treatment with the active compound. Cancer treatment can lead to a reduction in tumor growth rate. Preferably, after treatment, the tumor growth rate is reduced by at least about 5% relative to the pre-treatment level; more preferably, the tumor growth rate is reduced by at least about 10%; more preferably, by at least about 20%; more preferably, by at least about 30%; more preferably, by at least about 40%; more preferably, by at least about 50%; even more preferably, by at least about 50%; most preferably, by at least about 75%. The tumor growth rate can be measured by any repeatable measurement method. The tumor growth rate can be measured based on the change in tumor diameter per unit time. Cancer treatment can lead to a reduction in tumor regrowth, for example, after an attempt to surgically remove a tumor. Preferably, tumor regrowth is less than about 5% after treatment; more preferably, less than about 10%; even more preferably, less than about 20%; more preferably, less than about 30%; even more preferably, less than about 40%; even more preferably, less than about 50%; most preferably, less than about 75%. Tumor regrowth can be measured by any repeatable measurement method. For example, tumor regeneration can be measured by measuring the increase in tumor diameter after previous tumor shrinkage following treatment. No recurrence of the tumor after treatment cessation indicates reduced tumor regeneration. Treatment or prevention of cell proliferation disorders can lead to a reduction in the cell proliferation rate. Preferably, after treatment, the cell proliferation rate is reduced by at least about 5%; more preferably, at least about 10%; more preferably, at least about 20%; more preferably, at least about 30%; more preferably, at least about 40%; more preferably, at least about 50%; even more preferably, at least about 50%; most preferably, at least about 75%. The cell proliferation rate can be measured by any reproducible measurement method. For example, the cell proliferation rate can be measured by measuring the number of dividing cells per unit time in a tissue sample. Treatment or prevention of cell proliferation disorders can lead to a reduction in the proportion of proliferating cells. Preferably, after treatment, the proportion of proliferating cells is reduced by at least about 5%; more preferably, at least about 10%; more preferably, at least about 20%; more preferably, at least about 30%; more preferably, at least about 40%; more preferably, at least about 50%; even more preferably, at least 50%; most preferably, at least about 75%. The proportion of proliferating cells can be measured by any reproducible measurement method. Preferably, for example, the proportion of proliferating cells is measured by quantifying the number of dividing cells relative to the number of non-dividing cells in a tissue sample. The proportion of proliferating cells may be equivalent to the mitotic index. Treatment or prevention of cell proliferation disorders can result in a reduction in the size of the cell proliferation region or area. Preferably, after treatment, the size of the cell proliferation region or area is reduced by at least about 5% compared to its pre-treatment size; more preferably, by at least about 10%; more preferably, by at least about 20%; more preferably, by at least about 30%; more preferably, by at least about 40%; more preferably, by at least about 50%; even more preferably, by at least about 50%; most preferably, by at least about 75%. The size of the cell proliferation region or area can be measured by any repeatable measurement method. The size of the cell proliferation region or area can be measured as the diameter or width of the cell proliferation region or area. Treatment or prevention of cell proliferation disorders can result in a reduction in the number or proportion of cells with abnormal appearance or morphology. Preferably, after treatment, the number of cells with abnormal morphology is reduced by at least about 5% relative to their pre-treatment size; more preferably, by at least about 10%; more preferably, by at least about 20%; more preferably, by at least about 30%; more preferably, by at least about 40%; more preferably, by at least about 50%; even more preferably, by at least about 50%; most preferably, by at least about 75%. Abnormal cell appearance or morphology can be measured by any reproducible measurement method. Abnormal cell morphology can be measured by microscopy, for example, using an inverted tissue culture microscope. Abnormal cell morphology can take the form of nuclear pleomorphism. Specific Implementation To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be described in further detail below. The described embodiments should not be considered as limitations on the invention. All other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention. Before providing a further detailed description of the embodiments of the present invention, the nouns and terms involved in the embodiments of the present invention will be explained, and the nouns and terms involved in the embodiments of the present invention shall be interpreted as follows. The raw materials and equipment used in the specific embodiments of this disclosure are all known products, obtained by purchasing commercially available products. General synthesis scheme The chemical entities described herein can be synthesized according to one or more illustrative schemes herein and / or techniques well known in the art. Unless otherwise stated, the reactions described herein occur at atmospheric pressure and generally within a temperature range of about -10°C to about 200°C. Furthermore, unless otherwise stated, the limitation of reaction time and conditions is approximate; for example, at about atmospheric pressure, the duration of the reaction can be from about 1 to about 24 hours; in some embodiments, allowing the reaction to proceed overnight can result in an average duration of about 16 hours. If desired, the separation and purification of the chemical entities and intermediates described herein can be carried out by any suitable separation or purification procedure, such as filtration, extraction, crystallization, column chromatography, thin-layer chromatography, or thick-layer chromatography, or a combination of these procedures. See, for example, Carey et al., *Advanced Organic Chemistry*, 3rd ed., 1990, New York; Mundy et al., *Reactions and Reagents in Organic Synthesis*, 2nd ed., Hoboken, NJ, 2005. Specific descriptions of suitable separation and purification procedures are given with reference to the examples below. However, other equivalent separation or purification systems may also be used. In all methods, it is well known that, according to general principles of chemistry, protecting groups of sensitive or reactive groups may be used when necessary. Protecting groups are handled according to standard methods of organic synthesis (TW Greene and PGM Uts (1999) Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons). These groups may be used during the synthesis of the compound and are removed by methods known to those skilled in the art. In some embodiments, the disclosed compounds can typically be synthesized by appropriate combinations of well-known synthetic methods. Based on this disclosure, the techniques for synthesizing these chemical entities are readily apparent and available to those skilled in the art. Many optionally substituted starting compounds and other reactants are commercially available or can be readily prepared by those skilled in the art using commonly used synthetic methods. The following discussion is provided to illustrate some of the different methods that can be used to prepare the disclosed compounds and is not intended to limit the range of reactions or reaction sequences that can be used to prepare the compounds provided herein. Those skilled in the art will understand that, unless otherwise stated, standard valences apply to all compounds in the genus or named compounds disclosed herein. Abbreviations and abbreviations The general schemes for synthesizing the exemplary compounds disclosed herein are as follows: Example 1: Synthesis of a novel CRBN intermediate Synthesis of intermediate 3-(6-(3-(dimethoxymethyl)azacyclobutan-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione Preparation of 3-formylazine-1-carboxylic acid benzyl ester DMSO (7.06 g, 90.39 mmol, 7.06 mL, 4 equivalents) was added dropwise to a cooled solution of oxaloyl chloride (8.61 g, 67.80 mmol, 5.93 mL, 3 equivalents) in 50 mL of DCM (at -70 °C) under a nitrogen atmosphere and stirred for 30 minutes. Then, a solution of 3-(hydroxymethyl)azacyclobutane-1-carboxylic acid benzyl ester (5 g, 22.60 mmol, 1 equivalent) in 10 mL of DCM was added, while maintaining the reaction temperature below -60 °C and stirring the solution at -70 °C for 2 hours. TEA (18.29 g, 180.79 mmol, 25.16 mL, 8 equivalents) was slowly added, and the reaction was then heated to 25 °C and stirred for another 30 minutes. The reaction was complete when the main spot appeared on TLC (PE:EA = 5:1). The solution was poured into 100 mL of ice water and the mixture was extracted with DCM (100 mL × 2). The combined organic compounds were washed with 100 mL of brine and dried over Na₂SO₄. The solvent was removed to give crude benzyl 3-formylazine-1-carboxylate (4.8 g, 21.89 mmol, 97% yield), a pale yellow oil that can be used directly without further purification. LC-MS: 238, [M+H+H₂O] + ESI + . Preparation of 3-(dimethoxymethyl)azacyclobutane-1-carboxylic acid benzyl ester TsOH was added to a solution of 3-formylazetane-1-carboxylate (2.5 g, 11.40 mmol, 1 equivalent) and trimethoxymethane (6.05 g, 57.02 mmol, 6.25 mL, 5 equivalents) in MeOH (30 mL). H₂O (108.45 mg, 570.16 μmol, 0.05 equivalents) was added at 25 °C, and the reaction mixture was stirred at 25 °C for 16 h. LC-MS showed a peak (65%) with the desired MS value of 266.1 ([M+H)). + ESI + The reaction proceeded to completion. The solvent was removed, and the residue was dissolved in 50 mL of EA. The organic matter was washed successively with 20 mL of NaHCO3 aqueous solution and 20 mL of brine. The organic matter was then dried with Na2SO4 to remove the solvent, yielding a crude product. This crude product was purified by rapid column chromatography (12 g silica gel, PE:EA = 10:1–3:1) to give 3-(dimethoxymethyl)azacyclobutane-1-carboxylic acid benzyl ester (1.8 g, 6.45 mmol, yield 56%, purity 95%), as a pale yellow oil. LC-MS: 266.1, [M+H] + ESI + . Preparation of 3-(dimethoxymethyl)azacyclobutane A mixture of 3-(dimethoxymethyl)azacyclobutane-1-carboxylic acid benzyl ester (1.3 g, 4.90 mmol, 1 equivalent) and Pd / C catalyst (130.00 mg) in 2,2,2-trifluoroethanol (50 mL) was stirred at 45 °C under a hydrogen atmosphere (15 Psi). TLC (PE:EtOAc = 3:1) indicated that the starting material was consumed and a principal spot (Rf = 0.01) appeared, indicating the completion of the reaction. The solid was filtered off, the filter cake was washed with 10 mL of DCM, and the filtrate was concentrated to give 3-(dimethoxymethyl)azacyclobutane (0.64 g, 4.8 mmol, 99% yield), a colorless oil, which could be used directly without further purification. Preparation of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-(3-(dimethoxymethyl)azacyclobutane-1-yl)-1-methyl-1H-indazole Add 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (20.7 g, 41.3 mmol, 1.00 equivalent) and 3-(dimethoxymethyl)azacyclobutane (dissolved in 200 mL T mol, 8.14 g, 62.0 mmol, 1.50 equivalent), RuPhos Pd G3 (1.73 g, 2.07 mmol, 0.05 equivalent) catalyst and Cs2CO3 (40.4 g, 124 mmol, 3.00 equivalent). Stir the mixture at 100 °C for 12 hours. LCMS showed the desired mass. Quench the reaction mixture by adding 100 mL of H2O at 0 °C, then dilute with 100 mL of EtOAc and extract with 600 mL of EtOAc (200 mL × 3). The combined organic layers were washed with 300 mL of brine (150 mL × 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO₂, PE / EA = 100 / 1 to 2 / 1). 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-(3-(dimethoxymethyl)azacyclobutan-1-yl)-1-methyl-1H-indazole (yellow solid, 15.0 g, 27.2 mmol, yield 65%) was given. LCMS: MS (ESI) m / z = 551.3 [M + H] + ; 1HNMR (400MHz, DMSO-d6) δ = 7.87 (d, J = 8.00Hz, 1H) 7.43-7.51 (m, 3H) 7.24-7.43 (m, 8H) 6.56 (d, J = 8.00Hz, 1H) 6.34 (s, 1H) 6.27 (d, J = 8.76Hz, 1H) 5.42 (d, J = 14.13Hz, 4H) 4.62 (d, J = 6.88Hz, 1H) 3.86-3.95 (m, 5H) 3.67 (t, J = 6.63Hz, 2H) 3.30 (s, 6H) 2.95-3.07 (m, 1H). Preparation of 3-(6-(3-(dimethoxymethyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-(3-(dimethoxymethyl)azacyclobutan-1-yl)-1-methyl-1H-indazole (15.0 g) was added to Pd / C (3.00 g, 2.82 mmol, 10% purity, 0.1 equivalent) in THF (150 mL) under N2 atmosphere. The suspension was degassed and purged three times with H2. The mixture was stirred at 25 °C for 72 h under H2 (15 Psi). LCMS showed complete consumption of compound 3 and the desired mass was detected. The reaction mixture was filtered under reduced pressure and then concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, PE / EA = 100 / 1 to 3 / 1). A white solid, 3-(6-(3-(dimethoxymethyl)azacyclobutan-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (4.51 g, 12.1 mmol, 44.5% yield, 100% purity) was obtained. LCMS:MS(ESI) m / z = 373.1 [M+H] + ; 1 H NMR: (400MHz, MeOD) δ = 10.83 (s, 1H) 7.47 (d, J = 8.63Hz, 1H) 6.28-6.42 (m, 2H) 4.61 (d, J = 6.88Hz, 1H) 4.23 (dd, J = 9.07, 5.07Hz, 1H) 3.93 ( t,J=7.75Hz,2H)3.84(s,3H)3.67(t,J=6.57Hz,2H)3.29(s,6H)2.96-3.06(m,1H)2.57-2.65(m,2H)2.22-2.35(m,1H)2.09-2.20(m,1H). Using the above method, 2,3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione was synthesized using different starting materials and solvents. Preparation of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazole 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (20.0 g, 39.9 mmol, 1 equivalent) and 4-(dimethoxymethyl)piperidine (12.7 g, 79.9 mmol, 2.00 equivalent, dissolved in 200 mL Tol) were added with Cs₂CO₃ (39.0 g, 119 mmol, 3 equivalent) and RuPhos Pd G₃ (1.67 g, 2.00 mmol, 0.05 equivalent). The mixture was stirred at 100 °C for 16 h. LCMS showed complete consumption of the bromine starting material and the desired mass was detected. The reaction mixture was quenched by adding 100 mL of H₂O at 0 °C, diluted with 100 mL of EA, and extracted with 600 mL of EA (200 mL × 3). The combined organic layers were washed with 150 mL of brine (75 mL × 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 100 / 1 to 3 / 1). A white solid, 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazole (17.0 g, 29.3 mmol, yield 73.5%, purity 98.4%), was obtained. LCMS:MS(ESI) m / z = 579.3 [M+H] +1 H NMR (400MHz, DMSO-d6) δ = 7.88 (d, J = 8.00Hz, 1H) 7.43-7.52 (m, 3H) 7.24-7.41 (m, 8H) 6.75-6.87 ( m,2H)6.56(d,J=8.13Hz,1H)5.42(d,J=14.38Hz,4H)4.09(d,J=6.50Hz,1H)3.95(s,3H)3.78(br d,J=12.13Hz,2H)3.28(s,6H)2.67(br t,J=11.63Hz,2H)1.73(br d,J=9.63Hz,3H)1.24-1.48(m,2H). Preparation of 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione 17.0 g of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazole was suspended in 250 mL of THF solution and 10% Pd / C (5.86 g, 5.51 mmol) was added under a nitrogen atmosphere with thorough stirring. The suspension was degassed and purged three times with H2. The mixture was stirred at 25 °C for 16 h under H2 (15 Psi). The reaction mixture was filtered under reduced pressure and then concentrated under reduced pressure to give a crude product. The crude product was milled in 30 mL of petroleum ether at 25 °C for 30 min to give a white solid 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (5.20 g, 12.9 mmol, 44.2% yield, 100% purity). LCMS:MS(ESI)m / z=401.1[M+H] + ,1H NMR (400MHz, DMSO-d6) δ = 10.85 (s, 1H) 7.48 (d, J = 8.88Hz, 1H) 6.90 (dd, J = 9.01, 1.75Hz, 1H) 6. 83(d,J=1.38Hz,1H)4.25(dd,J=9.19,5.07Hz,1H)4.10(d,J=6.50Hz,1H)3.89(s,3H)3.80(br d,J=12.26Hz,2H)3.28(s,6H)2.57-2.75(m,4H)2.24-2.36(m,1H)2.09-2.22(m,1H)1.69-1.81(m,3H)1.29-1.47(m,2H). Using different starting materials, 3,3-(1-methyl-6-(piperazin-1-yl)-1H-indazole-3-yl)piperidine-2,6-dione was synthesized according to the method described above. Preparation of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (20.0 g, 39.9 mmol, 1.00 equivalent) and tert-butylpiperazine-1-carboxylic acid ester (14.9 g, 79.9 mmol, 2.00 equivalent, dissolved in 200 mL Tol) were added, along with Cs₂CO₃ (39.0 g, 119 mmol, 3.00 equivalent) and RuPhos Pd G₃ (1.67 g, 2.00 mmol, 0.05 equivalent). The mixture was stirred at 100 °C for 16 h. LC-MS showed complete consumption of the bromine starting material and the desired mass was detected. The reaction mixture was quenched by adding 100 mL of H₂O at 0 °C, diluted with 100 mL of EtOAc, and extracted with 600 mL of EtOAc (200 mL × 3). The combined organic layers were washed with 150 mL (75 mL × 2) of brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO₂, PE / EA = 100 / 1 to 3 / 1). A white solid, tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (18.1 g, 75% yield), was obtained. LCMS:MS(ESI) m / z = 606 [M + H] + . Preparation of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate 12.0 g of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazole-6-yl)piperazine-1-carboxylate was added to a THF (250 mL) solution, and Pd / C (5.8 g, 5.51 mmol) was added under N2 atmosphere. The suspension was degassed and purged three times with H2. The mixture was stirred at 25 °C for 16 h under H2 (15 Psi). The reaction mixture was filtered under reduced pressure, and then concentrated under reduced pressure to give a crude product. The crude product was ground with 30 mL of petroleum ether at 25 °C for 30 min. 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione was given as a white solid (6.0 g, 14 mmol, 70% yield). LCMS:MS(ESI) m / z = 428 [M+H] + . Example 2: Synthesis of (R)-(6-amino-5-(1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)boronic acid Preparation of 1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethane-1-one K₂CO₃ (66.39 g, 480.37 mmol, 1 equivalent) and 2H-triazole (49.77 g, 720.56 mmol, 41.75 mL, 1.5 equivalent) were added to a solution of 1-(2,5-difluorophenyl)ethyl ketone (75 g, 480.37 mmol, 60.83 mL, 1 equivalent) in NMP (750 mL). The mixture was heated to 140 °C and maintained for 3 h. TLC showed complete consumption of the starting material (PE / EA = 10:1, Rf = 0.8) and a major new spot (PE / EA = 10:1, Rf = 0.5) was detected. The reaction was cooled and then partitioned between ethyl acetate (1000 mL) and an aqueous solution of ammonium chloride (1 M, 300 mL). The organic phase was washed with water (200 mL × 3), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EA = 10 / 1 to 5 / 1), followed by vacuum concentration to give the product 1-[5-fluoro-2-(triazol-2-yl)phenyl]acetone (35 g, 167.16 mmol, yield 34.80%, purity 98%), as a yellow oil. LC-MS: 206.0 [M+H] + ESI + Preparation of (S)-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)1-ethanol At -35°C, a solution of 1-[5-fluoro-2-(triazol-2-yl)phenyl]ethyl ketone (15 g, 73.10 mmol, 1 equivalent) in THF (30 mL) was added dropwise to a solution of (-)-diisopinepine phenylborane chloride (1.7 M, 107.51 mL, 2.5 equivalents) in THF (120 mL) while maintaining the temperature below -27°C. The resulting mixture was stirred at -35°C for 6 h, then slowly heated to 25°C over 2 h, and then stirred at 30°C for 16 h. TLC showed complete consumption of the starting material (PE / EA = 10:1, Rf = 0.5) and a major new spot (PE / EA = 10:1, Rf = 0.3) was detected. The mixture was evaporated under reduced pressure to remove most of the THF. The resulting residue was dissolved in MTBE (500 mL) and rapidly stirred with a top stirrer. Wild-type diethanolamine (38.4 g, 5 equivalents) was added, and the temperature was raised to 50 °C during the addition. The resulting mixture was stirred for 1 hour and then filtered. The filter cake was washed with MTBE (200 mL × 2) and discarded. The combined filtrates were evaporated under reduced pressure, and the crude product was purified by column chromatography (SiO2, PE / EA = 10 / 1 to 5 / 1) to give the product (1S)-1-[5-fluoro-2-(triazol-2-yl)phenyl]ethanol (13 g, 59.60 mmol, 81% yield) as a yellow oil. LC-MS: 391.3 [M+H] + ESI + .H NMR (400MHz, CDCl3) δ = 7.80 (s, 2H), 7.54 (dd, J = 5.2, 8.8Hz, 1H), 7.32 (dd, J = 2.8, 9.6Hz, 1 H),7.04(ddd,J=2.8,7.2,8.8Hz,1H),4.79(dd,J=1.2,6.4Hz,1H),1.38(d,J=6.8Hz,3H). Preparation of (S)-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethyl ethanesulfonate Et3N (9.52 g, 94.11 mmol, 13.10 mL, 1.5 equivalent) was added to a solution of (1S)-1-[5-fluoro-2-(triazol-2-yl)phenyl]ethanol (13 g, 62.74 mmol, 1 equivalent) in DCM (120 mL). The solution was cooled to -20 °C, and a solution of ethanesulfonyl chloride (12.1 g, 94.11 mmol, 8.92 mL, 1.5 equivalent) in DCM (90 mL) was added through a feeding funnel. The reaction mixture was maintained at -10 °C for 1 h, and the mixture was stirred at 25 °C for 16 h. LC-MS showed a starting material of 22% and a main peak (76%) with the desired MS value of 190.0 ([M+H-110]).+ ESI + The reaction was quenched with water (200 mL), and the product was separated and washed with saturated NaHCO3 (200 mL) and 0.1 M HCl (2 × 100 mL). The organic phase was dried over Na2SO4, filtered, and evaporated to give the product [(1S)-1-[5-fluoro-2-(triazol-2-yl)phenyl]ethyl]ethanesulfonate (18 g, 45.10 mmol, 72% yield) as a yellow oil, which could be used without further purification. LC-MS: 190.0 [M + H - 110] + ESI + Preparation of (R)-5-bromo-3-(1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridine-2-amine Add [(1S)-1-[5-fluoro-2-(triazol-2-yl)phenyl]ethyl]ethanesulfonate (18 g, 43.30 mmol, 1 equivalent) to a suspension of Cs₂CO₃ (16.93 g, 51.96 mmol, 1.2 equivalent) in acetone (200 mL). The reaction mixture was heated at 60 °C for 16 h. The reaction mixture was cooled to room temperature. The mixture was quenched with water (40 mL). The mixture was extracted with EtOAc (30 mL × 2). The combined organic phases were washed with brine (60 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to give the residue. The residue was purified by column chromatography (SiO2, PE / EA = 5 / 1 to 1 / 1) to give the product 5-bromo-3-[(1R)-1-[5-fluoro-2-(triazol)-2-yl)phenyl]ethoxy]pyridine-2-amine (9.5 g, 23.36 mmol, 54% yield), as a yellow oil. LC-MS: 380.0 [M+2+H] + ESI + . Preparation of (R)-(6-amino-5-(1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)boronic acid To a DMSO (15 mL) solution of a mixture of 5-bromo-3-[(1R)-1-[5-fluoro-2-(triazol-2-yl)phenyl]ethoxy]pyridine-2-amine (1.60 g, 4.23 mmol, 1.0 equivalence), KOAc (1.45 g, 14.8 mmol, 3.5 eq), B2Pin (1.83 g, 7.19 mmol, 1.7 eq), and Pd(dppf)Cl2 (309 mg, 423 μmol, 0.1 eq) were added, the mixture was degassed, and purged three times with N2. The mixture was then stirred at 80 °C for 3 h under N2 atmosphere. The reaction mixture was filtered to obtain the residue. The crude product was purified by reversed-phase HPLC (0.1% FA conditions). The crude product (R)-(6-amino-5-(1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)boronic acid (3.50 g, 10.2 mmol, 48.2% yield) was used as a white solid in the next step without further purification. LCMS:MS(ESI) m / z = 344.2 [M+1] + . Example 3: Synthesis of the tert-butyl 4-(5-bromo-4-methylthiazolyl)piperazine-1-carboxylate fragment Preparation of tert-butyl 4-(4-methylthiazolyl)piperazine-1-carboxylate To a solution of 2-bromo-4-methylthiazole (4 g, 22.47 mmol, 1 equivalent) in dioxane (40 mL), tert-butyl piperazine-1-carboxylate (6.28 g, 33.70 mmol, 1.5 equivalent) and t-BuONa (5.40 g, 56.16 mmol, 2.5 equivalent) were added. Then, at 0 °C, [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (3.57 g, 4.49 mmol, 0.2 equivalent) was added. The solution was heated to 100 °C at 25 °C under a nitrogen atmosphere and stirred for 2 hours to obtain a black suspension. The suspension was filtered, and the filter cake was washed with EA (350 mL). Water (50 mL) was added to the filter, and the solution was extracted with EA (70 mL × 3). The organic layers were combined, dried over Na₂SO₄, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO₂ 80 g, PE / EA = 5 / 1, Rf = 0.5) and concentrated under reduced pressure to give the product tert-butyl 4-(4-methylthiazol-2-yl)piperazine-1-carboxylate, as a yellow solid (4.2 g, 13 mmol, yield 59%). LC-MS: 284.1, [M+H] + ESI + Preparation of tert-butyl 4-(5-bromo-4-methyl-thiazo-2-yl)piperazine-1-carboxylate NBS (3.03 g, 17.01 mmol, 1.05 equivalent) was added to a solution of 4-(4-methylthiazol-2-yl)piperazine-1-carboxylate (4.59 g, 16.20 mmol, 1 equivalent) in DCM (30 mL), dissolved in DCM (10 mL) and DMF (3 mL). The solution was stirred at 0 °C for 2 hours. Water (30 mL) was added to the solution and extracted with DCM (50 mL × 3). The organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2 80 g, PE / EA = 10 / 1, Rf = 0.5) and concentrated under reduced pressure to give a pale yellow solid product, 4-(5-bromo-4-methyl-thiazol-2-yl)piperazine-1-carboxylate (5.2 g, 12.92 mmol, 79% yield). LC-MS: 364.0, [M+2+H] + ESI + . Example 4: Synthesis of Compound 19 3-(6-(3-((4-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-)triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine -2,6-Diketone & Compound 253-(6-(4-((4-((5-(6-amino-5-((R)-1-(5-fluoro-2)-(1H-pyrazol-1-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazo-2-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione Preparation of 5-bromo-4-methyl-2-(piperazin-1-ylmethyl)thiazole NBS (1.50 g, 8.41 mmol, 1 equivalent) was slowly added to a solution of tert-butyl piperazine-1-carboxylate (2.5 g, 8.41 mmol, 1 equivalent) in TFA (20 mL). The mixture was stirred at 20 °C for 6 h. LC-MS showed residual starting material and detected a small amount of the desired mass. NBS (2.24 g, 12.61 mmol, 1.5 equivalent) was added to the mixture and stirred for another 16 h. LC-MS showed that the starting material was consumed and detected a main peak with the desired mass. The reaction mixture was concentrated under vacuum to give crude 5-bromo-4-methyl-2-(piperazine-1-ylmethyl)thiazole (6.7 g, crude) as a yellow oil. No further purification was required for the next step. LC-MS: 276.1, [M+H] + ESI+ . Preparation of tert-butyl 4-((5-bromo-4-methylthiazolyl-2-yl)methyl)piperazine-1-carboxylate TEA (3.52 g, 34.76 mmol) was added to a DCM (50 mL) solution of 5-bromo-4-methyl-2-(piperazin-1-ylmethyl)thiazole (8 g, crude). The mixture was stirred at 20 °C for 10 min. Then Boc₂O (2.84 g, 13.03 mmol) was added to the mixture and stirred at 20 °C for 2 h. LC-MS showed that the starting material was consumed and the desired mass was detected. TLC (PE / EA = 1 / 1) showed that the starting material was consumed and a major new spot was formed. The reaction mixture was washed with water (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (SiO₂, PE / EA = 1 / 1) to give the product 4-((5-bromo-4-methylthiazole-2-yl)methyl)piperazin-1-carboxylic acid tert-butyl ester (2.7 g, 7.17 mmol) as a yellow oil. LC-MS: 378.2, [M+H] + ESI + . Preparation of tert-butyl(R)-4-((5-(6-amino-5-(1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin)-3-yl)-4-methylthiazolyl-2-yl)methyl)piperazine-1-carboxylic acid ester A mixture of (R)-(6-amino-5-(1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)boronic acid (840 mg, 1.62 mmol, 1 equivalent) and 4-((5-bromo-4-methylthiazolyl)methyl)piperazine-1-carboxylic acid tert-butyl ester (912.04 mg, 2.42 mmol, 1.5 equivalent) was suspended in dioxane (9 mL) and water (1 mL), and an aqueous solution of NaHCO3 (271.47 mg, 3.23 mmol, 2 equivalent) (1 mL) was added. Pd(PPh3)4 (186.71 mg, 161.58 μmol, 0.1 equivalent) was added under N2 atmosphere. The mixture was stirred at 100 °C for 16 hours. LCMS showed that the starting material was consumed and the desired mass was detected. TLC (PE / EA = 1 / 1) showed that the starting material had been consumed and a major new spot had formed. The mixture was poured into water (30 mL) and extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (SiO₂, PE / EA = 0 / 1) to give tert-butyl(R)-4-((5-(6-amino-5-(1-(5-fluoro))-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperazine-1-carboxylic acid ester (737 mg, 879.89 μmol, 54% yield) as a brown solid. LC-MS: 595.3, [M+H] + ESI + . Preparation of (R)-3-(1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)-5-(4-methyl-2-(piperazin-1-)ylmethyl)thiazolyl-5-yl)pyridine-2-amine tert-Butyl(R)-4-((5-(6-amino-5-(1-(5-fluoro-2-(2H-1,2,3-triazole-2-)

[0101] (R)-3-(1-(5-fluoro-2-(2H-1,2,3-triazol-2)-yl)phenyl)ethoxy)-5-(4-methyl-2-(piperazin-1-ylmethyl)thiazolyl)pyridine-2-amine (737.00 mg, 879.89 μmol, 1 equivalent) was added to a DCM (9 mL) solution with TFA (3 mL). The mixture was stirred at 20 °C for 1 hour. LC-MS showed that the starting material was consumed and a main peak with the desired mass was detected. The mixture was concentrated under vacuum. The residue was dissolved in methanol (30 mL) and the solution was adjusted to pH > 7 using an anion exchange resin. After stirring for 2 hours, the mixture was filtered, and the filtrate was concentrated under vacuum to give the product (R)-3-(1-(5-fluoro-2-(2H-1,2,3-triazol-2)-yl)phenyl)ethoxy)-5-(4-methyl-2-(piperazin-1-ylmethyl)thiazolyl-5-yl)pyridine-2-amine (511 mg, 743.89 μmol, 84% yield) as a brown solid. LC-MS: 495, [M+H] + ESI + . Preparation of 3-(6-(3-((4-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (Compound 19) TFA / DCM (v / v 1:1) was added to a mixture of (R)-3-(1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)-5-(4-methyl-2-(piperazin-1-ylmethyl)thiazolyl-5-yl)pyridin-2-amine (100 mg, 0.2 mmol) and 3-(6-(3-(dimethoxymethyl)azacyclobutan-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (120 mg, 0.4 mmol) at room temperature. After stirring for 5 hours, the solvent was removed under vacuum. The residue was dissolved in DCM and excess triethylamine was added at 0 °C, followed by STAB (100 mg, 0.5 mmol). After stirring for another 2 hours, the mixture was treated with silica gel and eluted with EA / MeOH to provide the crude product. The product was further purified by Prep-HPLC (Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water(FA)-ACN]; gradient: 33%-63% B, over 20 minutes) and lyophilized to give 45 mg of 3-(6-(3-((4-((5-(6-amino-5-(((R)-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione, as a light-colored solid. LC-MS: 805, [M+H] + ESI + . 1 H NMR: (400MHz, DMSO-d6) δppm 11.21-10.91(m,1H),8.20(s,2H),7.68(dd,J=5.1,8.9Hz,1H),7.65-7.58(m,2H),7.56-7.51(m, 1H),7.36(dt,J=2.9,8.3Hz,1H),6.77(d,J=1.6Hz,1H),6.67-6.60(m,2H),6.21(s,2H),5.61(br d,J=6.5Hz,1H),5.05(dd,J=5.3,12.9Hz,1H),4.12(t,J=8.0Hz,2H),3.70 (s,4H),3.43-3.41(m,2H),3.02-2.95(m,1H),2.91-2.81(m,1H),2.61(br d,J=7.3Hz,3H),2.55(br d,J=9.6Hz,2H),2.44(br d,J=1.1Hz,3H),2.08(s,3H),2.05-1.97(m,1H),1.63-1.56(m,3H). Preparation of 3-(6-(4-((4-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (Compound 25) TFA / DCM (v / v 1:1) was added to a mixture of (R)-3-(1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)-5-(4-methyl-2-(piperazin-1-ylmethyl)thiazolyl-5-yl)pyridin-2-amine (100 mg, 0.2 mmol) and 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (120 mg, 0.4 mmol) at room temperature. After stirring for 5 hours, the solvent was removed under vacuum. The residue was dissolved in DCM and excess triethylamine was added at 0 °C, followed by STAB (100 mg, 0.5 mmol). After stirring for another 2 hours, the mixture was treated with silica gel and eluted with EA / MeOH to provide the crude product. The product was further purified by Prep-HPLC (Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water(FA)-ACN]; gradient: 33%-63% B, over 20 minutes) and lyophilized to give 60 mg of 3-(6-(4-((4-((5-(6-amino-5-(((R)-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione, as a white solid. LC-MS: 833, [M+H] + ESI +.1H NMR:(400MHz,DMSO-d6)δppm 11.21-10.92(m,1H),8.21(s,2H),7.66(dd,J=5.1,8.9Hz,1H),7.65-7.58(m,2H),7.56-7.51(m, 1H),7.36(dt,J=2.9,8.3Hz,1H),6.77(d,J=1.6Hz,1H),6.67-6.60(m,2H),6.21(s,2H),5.61(br d,J=6.5Hz,1H),5.05(dd,J=5.3,12.9Hz,1H),4.12(t,J=8.0Hz,2H),3.70 (s,4H),3.43-3.41(m,2H),3.02-2.95(m,3H),2.91-2.81(m,4H),2.63(br d,J=7.3Hz,3H),2.55(br d,J=9.6Hz,2H),2.49(br d,J=1.1Hz,3H),2.07(s,3H),2.00-1.96(m,1H),1.62-1.55(m,3H). Example 5: 3-(6-(3-((4-(5-(6-amino-5-((R)-1-(5-fluoro-2-(2H-1,2,3-triazol-2)-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (Compound 1) Preparation of 1-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazol-6-yl)azacyclobutane-3-carboxaldehyde To a solution of 200 mg (537 μmol) of 3-(6-(3-(dimethoxymethyl)azacyclobutan-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione in CH2Cl2 (2.0 mL), a mixture of TFA (61.2 mg, 537 μmol, 39.8 μL, 1.0 eq) was added, followed by degassing and purging three times with N2. The mixture was then stirred at 40 °C for 2 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to obtain the residue. The crude product 1-(3-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-indazol-6-yl)azacyclobutan-3-carboxaldehyde (180 mg, crude) was used in the next step without further purification to a yellow oil. LCMS MS (ESI) m / z = 345.1 [M+19] + . Preparation of 3-(6-(3-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (Compound 1) A solution of 1-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazol-6-yl)azacyclobutane-3-carboxaldehyde (177 mg, 544 μmol, 1.8 equivalents) and (R)-3-(1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)-5-(4-methyl-2-(piperazin-1-yl)thiazolyl)pyridine-2-amine (180 mg, 302.73 μmol, 1 equivalent) in CH2Cl2 (4.0 mL) was mixed with TEA (91.9 mg, 908 μmol, 126 μL, 3.0 equivalents) at 0 °C and stirred for 30 min. Then NaBH(OAc)3 (128 mg, 605 μmol, 2.0 equivalents) was added to the above mixture. The mixture was stirred at 25°C for 8 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (FA conditions: column: Phenomenex luna C18 150×40mm×15um; mobile phase: [water (FA)-ACN]; gradient: 10%-40% B, 22 min) and then lyophilized to obtain another residue. The residue was purified by preparative HPLC (neutral conditions: column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 38%-68% B, 9 min). Compound 1 (35.18 mg, 44.48 μmol, yield 14.69%, purity 100%) was given as a white solid. LCMS: MS (ESI) m / z = 791.3 [M+1] + , 1H NMR (400MHz, DMSO-d6) δ = 10.84 (s, 1H), 8.22 (s, 2H), 7.68 (dd, J = 5.2, 8.8Hz ,1H),7.60(dd,J=2.8,9.6Hz,1H),7.49-7.43(m,2H),7.35(dt,J=2.8,8.4Hz ,1H),6.54(d,J=1.6Hz,1H),6.39-6.29(m,2H),6.08(s,2H),5.66-5.46(m,1 H),4.23(dd,J=5.2,9.2Hz,1H),4.01(t,J=7.6Hz,2H),3.84(s,3H),3.54(br t,J=6.4Hz,2H),3.34(br s,4H),3.04-2.88(m,1H),2.68-2.52(m,6H),2.38-2.23(m,1H),2.20-2.10(m,1H),1.91(s,3H),1.59(d,J=6.4Hz,3H). Example 6: 3-(6-(4-((4-(5-(6-amino-5-((R)-1-(5-fluoro-2-(2H-1,2,3-triazol-2)-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (compound 4) Preparation of 1-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-4-carboxaldehyde A mixture (200 mg, 499 μmol) of 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione was degassed by adding TFA (1.54 g, 13.4 mmol, 1.0 mL, 26.9 equivalents) to a CH2Cl2 solution and purged three times with N2. The mixture was then stirred at 40 °C for 2 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give the residue. The crude product 1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazole-6-yl)piperidin-4-carboxaldehyde (180 mg, crude) was used in the next step without further purification to a yellow oil. LCMS MS (ESI) m / z = 373.1 [M+19] + . Preparation of 3-(6-(4-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione TEA (91.9 mg, 908 μmol, 126 μL, 3.0 equivalent) was added to a mixture of 1-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-4-carboxaldehyde solution (180 mg, 302 μmol, 1.0 equivalent, TFA) and (R)-3-(1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)-5-(4-methyl-2-(piperazin-1-yl)thiazolyl)pyridine-2-amine in CH2Cl2 (5.0 mL) at 0 °C. The mixture was stirred at 20 °C for 2 hours. Then NaBH(OAc)3 (128 mg, 605 μmol, 2.0 equivalent) was added to the above mixture. The mixture was then stirred at 20°C for 8 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (FA conditions: column: Phenomenex luna C18 150×25mm×10um; mobile phase: [water (FA)-ACN]; gradient: 12%-42% B, 9 min) and lyophilized to obtain a residue. The residue was purified by preparative HPLC twice under neutral conditions (column: Waters Xbridge 150×25mm×5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 45%-75% B, 9 min) and lyophilized to obtain a residue. A white solid, 3-(6-(4-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione, was obtained (43.48 mg, 53.0 μmol, yield 17.5%, purity 100%). LCMS, MS (ESI) m / z = 819.4 [M+1] + , 1H NMR(400MHz,DMSO-d6)δ=10.85(br s,1H),8.22(s,2H),7.68(dd,J=5.2,8.8Hz,1H),7.60(dd,J=2.8,9.6Hz,1H),7.50-7.42(m,2H),7.35(dt,J=2.8,8.4Hz,1H),6.90(br d,J=9.2Hz,1H),6.83(s,1H),6.54(d,J=1.6Hz,1H),6.08(s,2H),5.69-5.41(m,1H),4.25(dd,J=5.2,9.2Hz,1H),3.88(s,3H),3.79(br d,J=12.4Hz,2H),3.35(br s,3H),2.80-2.58(m,4H),2.47(br d,J=4.0Hz,4H),2.37-2.11(m,5H),1.90(s,3H),1.86-1.79(m,2H),1.77-1.68(m,1H),1.59(d,J=6.4Hz,3H),1.35-1.17(m,2H). Following the general synthetic scheme and the preparation methods in Examples 2-6, the compounds listed in Table 1 were prepared as follows: Table 1 Test Example 1: Degradation of ALK and ROS1 proteins H2228 cells were obtained from the American Type Culture Collection (ATCC, Manassas, VA) and maintained in RPMI 1640 culture supplemented with 10% FBS. BaF3 cells were cultured in DMEM containing 10% FBS, with or without (parental) IL3 (EML4–ALK or CD74-ROS1) (0.5 ng / mL). Expression constructs (Addgene) encoding native EML4-ALK (variant 3), ROS1, and their mutant variants were synthesized, cloned into the pLVX-IRESpuro vector (Clontech), and introduced into Ba / F3 cells via lentiviral transduction. After selection with puromycin, cells were grown in the absence of IL3. Cells were then cultured at 10 5 Cells were seeded at a density of 100 cells / well in 24-well plates. On the second day after seeding (Day 0), culture medium containing different drug concentrations was added and incubated for 2–24 hours for Western blotting. The culture medium was removed and the plates were washed with 1×DPBS. Lysates were prepared by adding 150 μL of complete lysis solution and scraping cells into 1.5 mL microcentrifuge tubes. The lysates were placed on a 4°C baking tray for 30 minutes, then rotated at 12000 rcf for 10 minutes at 4°C. The protein content of the supernatant was determined, and the cells were flash-frozen or stored at -80°C if not run immediately. Western blotting was then performed on 50 μg of protein. The membranes were blocked and incubated overnight at 4°C with a 1:200 dilution of ALK antibody, followed by incubation at room temperature for 1 hour with a 1:10000 dilution of secondary antibody. The membranes were then imaged on a LICOR infrared scanner. Figures 1 through 10 show the ALK or ROS1 degradation efficiencies of compounds 1, 3, 4, 5, 7, 9, 11, 14, and 22. ALK or ROS1 degradation is expressed as DC. 50 The values ​​were determined by calculating the compound concentration required to reduce ALK or ROS1 expression levels by 50%, and the exemplary compound DC in Table 2 was used to identify it. 50 The maximum degradation of ALK or ROS1 is expressed as a Dmax value by measuring the highest percentage reduction in ALK or ROS1 achieved by the exemplary compounds within the treatment concentration range. Table 2 lists the DC values ​​for each compound. 50 And Dmax value. Test Example 2: In vitro antiproliferative activity study of example compounds The antiproliferative effects of exemplary compounds were evaluated in ALK-positive or ROS1-positive cancer cell models. BaF3 cells expressing ALK, mutant ALK, ROS1, and mutant ROS1 were treated with specified doses of the exemplary compounds for 72 hours, and the IC50 was determined by MTT assay. 50Values. Data are expressed as mean ± SD of repeated independent experiments. The exemplary compounds attenuated BaF3 cell viability in a concentration-dependent manner 72 hours after treatment. Results for each exemplary compound are shown in Table 2. A:IC 50 <50nM; B:50nM <IC 50 <200nM; C:IC 50 >200nM; ALK half-maximal degradation concentration (ALKDC) 50 ):A:<50nM; B:50-200nM; C:>200nM; Maximum ALK degradation activity (ALKDmax): A: >80%; B: >60%; C: >50%; D: <50%; ROS1 half-degradation concentration (ROS1 DC) 50 ):A:<50nM; B:50-200nM; C:>200nM; ROS1 maximum degradation activity (ROS1 Dmax): A: >80%; B: >60%; C: >50%; D: <50%; ND: Untested; Table 2: Bioactivity of Example Compounds The foregoing description of specific exemplary embodiments of the invention is for illustrative and explanatory purposes. These descriptions are not intended to limit the invention to the precise forms disclosed, and it will be apparent that many changes and variations can be made in accordance with the foregoing teachings. The exemplary embodiments were chosen and described in order to explain the specific principles of the invention and its practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of the invention, as well as various different choices and variations. The scope of the invention is intended to be defined by the claims and their equivalents.

Claims

1. A compound of formula (A) or a pharmaceutically acceptable salt thereof: In the formula, R 1 Selected from hydrogen, deuterium, and C 1-6 Alkyl, C 6-10 aryl, 5- or 6-membered heteroaryl and 4- to 7-membered heterocyclic, wherein the 5- or 6-membered heteroaryl, 4- to 7-membered heterocyclic or C 6-10 Aryl groups are optionally separated by 1, 2 or 3 independently selected from halogens, C 1-6 Alkyl or halogenated C 1-6 Alkyl substituent substitution; wherein the 5- or 6-membered heteroaryl or 4- to 7-membered heterocyclic group comprises 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S as ring atoms, p1 is 1, 2, or 3, and p1 has R 1 Same or different; R 2 Selected from halogens, C 1-6 Alkyl and Halogenated C 1-6 alkyl; R 7 It is a halogen; R 3 For -NR a R b ,in, R a R b Each is independently selected from hydrogen and C. 1-3 alkyl; R 4 Selected from halogens, C 1-6 Alkyl and Halogenated C 1-6 Alkyl group, p2 is selected from 1, 2 and 3, p2 R 4 Same or different; Y is selected from N and CH; R 5 Selected from hydrogen and halogens, p3 is selected from 1, 2 and 3, p3 R 5 Same or different; R 6 Selected from hydrogen, C 1-6 Alkyl and Halogenated C 1-6 alkyl; L is a linking group.

2. The compound according to claim 1, wherein, It is a ubiquitin ligase binding group; It is an ALK and / or ROS1 binding group.

3. The compound according to claim 1 or 2, wherein, The compound of formula (A) has the structure shown in formula (A-1): In the formula, R 1 R 2 R 3 R 4 R 5 R 6 R 7 Y, p1, p2 and p3 are each defined as described in claim 1 or 2; X1, X2, X3, and X4 are each independently selected from N and CH; n1, n2, n3, and n4 are each independently selected from 1, 2, and 3; Q1 is selected from single bonds, -(CH2) 0-3 -NR c -(CH2) 0-3 -、-(CH2) 0-3 -(C=O)-(CH2) 0-3 -、C 1-3 Alkylene, -4 to 8-membered nitrogen-containing heterocyclic alkyl groups, -(CH2) 0-3 -4 to 8-membered nitrogen-containing heterocyclic alkyl groups -(CH2) 0-3 -、-(CH2) 0-3 -4 to 8-membered nitrogen-containing heterocyclic alkyl groups -(C=O)-(CH2) 0-3 - and -(CH2) 0-3 -(C=O)-4 to 8-membered nitrogen-containing heterocyclic alkyl-(CH2) 0-3 - The 4 to 8-membered nitrogen-containing heterocyclic alkyl group contains 1, 2 or 3 N atoms as ring atoms; Q2 is selected from single bond, -(CH2) 0-3 -(C=O)-(CH2) 0-3 -and C 1-3 Alkylene; R L1 R L2 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, Halogenated C 1-6 alkyl and hydroxy substituted C 1-6 Alkyl group, q1 is selected from 1, 2 and 3, q1 R L1 Whether the numbers are the same or different, q2 is selected from 1, 2, and 3, and q2 are R. L2 Same or different; R c Selected from hydrogen and C 1-3 alkyl; Preferably, Q1 is a methylene group and Q2 is a single bond; Q1 is -(C=O)- and Q2 is a single bond; Alternatively, Q1 may be -NH(CH3)- and Q2 may be a single bond; Preferably, Q1 is a methylene group, Q2 is a single bond, n1 is 1, and n2 is 1. Or Q1 is a methylene group, Q2 is a single bond, n3 is 1, and n4 is 1; Preferably, L is selected from: Wherein, * indicates linkage with ubiquitin ligase binding groups, and ** indicates linkage with ALK and / or ROS1 binding groups; Among them, X1, X2, X3, X4, n1, n2, n3, n4, R L1 R L2 q1, q2, R c Each custom definition is the same as claim 3; X5 and X6 are each independently selected from N and CH; n5 and n6 are each independently selected from 1, 2 and 3; Preferably, L is selected from: In this context, * indicates a connection to a ubiquitin ligase binding group, and ** indicates a connection to an ALK and / or ROS1 binding group.

4. The compound according to any one of claims 1-3, wherein, R 1 It is a 5- or 6-membered heteroaryl group; Preferably, the 5- or 6-membered heteroaryl group contains 1, 2, 3, or 4 N atoms as ring atoms; Preferably, the 5- or 6-membered heteroaryl ring forming the 5- or 6-membered heteroaryl group is selected from pyrrole, pyrazole, imidazole, triazole, tetraazole, pyridine, pyrimidine, pyridazine, and pyrazine; Preferably, the 5- or 6-membered heteroaryl ring forming the 5- or 6-membered heteroaryl group is selected from... Preferably, R 1 Selected from Preferably, R 1 Selected from 5. The compound according to any one of claims 1-4, wherein, R 7 Selected from fluorine, chlorine, and bromine; more preferably fluorine; Preferably, R 2 C 1-3 Alkyl; preferably methyl; Preferably, for Preferably, R 3 For -NR a R b R a R b Each can be either hydrogen or methyl; Preferably, R 3 It is -NH2; Preferably, R 4 C 1-3 Alkyl groups, preferably methyl groups; Preferably, Y is CH; Preferably, R 5 It is hydrogen; Preferably, R 6 C 1-3 Alkyl groups, preferably methyl, ethyl, propyl or isopropyl; more preferably methyl.

6. The compound according to claim 3, wherein, The compound of formula (A-1) has the structure shown in formula (I): In the formula, R 1 ,X1,X2,X3,X4,n1,n2,n3,n4,Q1,Q2,R L1 R L2 q1 and q2 are each defined as described in claim 3; Preferably, q1 is 0 or 1, and q2 is 0; Preferably, q1 is 1, R L1 Selected from fluorine and hydroxymethyl.

7. The compound according to any one of claims 3-6, wherein, n1 is 1, n2 is 1, n3 is 2, and n4 is 2; n1 is 2, n2 is 2, n3 is 2, n4 is 2; n1 is 2, n2 is 2, n3 is 1, and n4 is 1; n1 is 2, n2 is 1, n3 is 2, and n4 is 2; n1 is 1, n2 is 1, n3 is 3, and n4 is 2; n1 is 1, n2 is 1, n3 is 1, and n4 is 1; Or n1 is 2, n2 is 2, n3 is 2, and n4 is 1.

8. The compound of claim 1, wherein the compound of formula (A) is selected from: 3-(6-(3-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-((1-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperidin-4-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(3-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(1H-pyrazol-1-yl)phenyl)ethoxy)pyridine)-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(4-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(4-((1-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(4-((1-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperidin-4-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(4-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(1H-pyrazol-1-yl)phenyl)ethoxy)pyridine)-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(4-((1-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)azacyclobutane-3-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(4-((1-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)azacyclobutane-3-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(3-((1-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)azacyclobutane-3-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-yl)methyl)pyrrolidine-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-((1-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperidin-4-yl)methyl)pyrrolidine-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(3-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)-2-fluoropiperazin-1-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(3-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl)-1,4-diazacyclo-1-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(3-((1-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperidin-4-yl)(methyl)amino)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(3-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)-2-(hydroxymethyl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)-2-(fluoromethyl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-(4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-carbonyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-((4-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-((1-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperidin-4-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(3-((4-((5-(6-amino-5-((R)-1-(5-fluoro-2-(1H-pyrazol-1-yl)phenyl)ethoxy)))pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(4-((4-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(4-((1-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(4-((1-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperidin-4-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(4-((4-((5-(6-amino-5-((R)-1-(5-fluoro-2-(1H-pyrazol-1-yl)phenyl)ethoxy)))pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(4-((1-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)azacyclobutane-3-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(4-((1-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)azacyclobutane-3-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(3-((1-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)azacyclobutane-3-yl)methyl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-((4-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperazin-1-yl)methyl)pyrrolidine-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-((1-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)piperidin-4-yl)methyl)pyrrolidine-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(3-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-yl)methyl)-[1,3'-azitrazine]-1'-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(3-(4-((4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(1-(4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-carbonyl)azacyclobutane-3-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(1-(4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(1-(4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperidine-1-carbonyl)azacyclobutane-3-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(4-(4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperidine-1-carbonyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(4-((1-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)pyrrolidine-3-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(6-(4-((1-((5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)methyl)pyrrolidine-3-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione; 3-(6-(4-(4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl))phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-carbonyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; And 3-(6-(3-(1-(4-(5-(6-amino-5-((R))-1-(5-fluoro-2-(2H-1,2,3-triazol-2)-yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazolyl-2-yl)piperazin-1-carbonyl)piperidin-4-yl)azacyclobutane-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione.

9. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

10. The use of any compound of claims 1-8 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 9 in the preparation of ALK and / or ROS1 inhibitors.

11. A method for treating ALK and / or ROS1-mediated diseases, the method comprising administering to a subject in need a therapeutically effective amount of the compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 9; Preferably, the subject expresses ALK and / or ROS1 proteins.

12. The use of any compound of claims 1-8 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 9 in the preparation of a medicament for treating ALK and / or ROS1-mediated diseases; Preferably, the ALK-mediated disease is non-small cell lung cancer; Preferably, the ROS1-mediated disease is non-small cell lung cancer; Preferably, the non-small cell lung cancer expresses ALK and / or ROS1 proteins.

13. A method for degrading ALK and / or ROS1 proteins in a biological sample, comprising contacting the biological sample with a compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 9.

14. A compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 9, for the treatment of ALK and / or ROS1-mediated diseases; Preferably, the ALK-mediated disease is non-small cell lung cancer; Preferably, the ROS1-mediated disease is non-small cell lung cancer; Preferably, the non-small cell lung cancer expresses ALK and / or ROS1 proteins.

15. The use of any compound of claims 1-8 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 9 for the treatment of a subject in need of ALK and / or ROS1-mediated disease; Preferably, the ALK-mediated disease is non-small cell lung cancer; Preferably, the ROS1-mediated disease is non-small cell lung cancer; Preferably, the non-small cell lung cancer expresses ALK and / or ROS1 proteins.

16. The following intermediate compounds:

17. A method for preparing the compound of formula (I) according to claim 6, wherein the compound is selected from the following synthetic routes: Synthesis Route 1: The reductive amination reaction of compound Ia with compound Ib yields compound (I); in, R 1 ,X1,X2,X3,X4,n1,n2,n3,n4,Q1,Q2,R L1 R L2 q1 and q2 are each defined as described in claim 6; Synthesis Route 2: The reductive amination reaction of compound Ic with compound Id yields compound (I); Among them, R 1 ,X1,X2,X3,X4,n1,n2,n3,n4,Q1,Q2,R L1 R L2 q1 and q2 are each defined as described in claim 6; Synthesis Route 3: Compound of formula (I) is obtained by reacting compound of formula (If) and compound of formula (Ig) via amide coupling reaction to form a urea group; Among them, R 1 ,X1,X2,X3,X4,n1,n2,n3,n4,Q1,Q2,R L1 R L2 q1 and q2 are each defined as described in claim 6; Synthesis Route 4: The reaction of compound Ih with compound Ij yields compound (I) by Suzuki. Among them, R 1 ,X1,X2,X3,X4,n1,n2,n3,n4,Q1,Q2,R L1 R L2 q1 and q2 are each defined as described in claim 6; G is a halogen.

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