Targeted ubiquitination ALK degradation compound and pharmaceutical composition thereof

Abstract

The invention provides a compound for targeted ubiquitination degradation of ALK, a preparation method of the compound, a pharmaceutical composition containing the compound and application of the compound in prevention or treatment of ALK-related diseases.

Description

[0001] Cross-references to related applications

[0002] This invention claims priority to the earlier application filed on October 22, 2024, with China National Intellectual Property Administration, patent application number 202411477201.0, entitled "Compounds and Pharmaceutical Compositions Thereof Targeting Ubiquitination and Degradation of ALK". The entire contents of the aforementioned earlier application are incorporated herein by reference. Technical Field

[0003] This invention relates to compounds that target ubiquitination and degrade ALK, pharmaceutical compositions thereof, and their use in the prevention or treatment of ALK-related diseases. Background Technology

[0004] Lung cancer is the most common cancer worldwide, with over 2 million new cases each year, of which non-small cell lung cancer accounts for 80%-85%. In recent years, the incidence of lung cancer in my country has been rising annually. Major driver genes for lung cancer include EGFR, KRAS, ALK, ROS1, and BRAF.

[0005] Anaplastic lymphoma kinase (ALK) is a member of the receptor tyrosine kinase family. It is activated upon binding to an extracellular ligand, thereby regulating cell growth. The ALK protein contains 1620 amino acids, including a ligand-recognizing extracellular domain and a tyrosine kinase domain (TKD) for signal transduction. In non-small cell lung cancer (NSCLC), ALK fuses with the microtubule-associated protein-like 4 (EML4) gene to form a driver gene. The incidence of EML4-ALK gene fusion in NSCLC is 3%–5%.

[0006] In recent years, treatment strategies for ALK-positive non-small cell lung cancer have rapidly evolved, leading to the emergence of ALK tyrosine kinase inhibitors with enhanced activity and selectivity. Multiple randomized studies have demonstrated that next-generation ALK tyrosine kinase inhibitors exhibit better efficacy in newly treated ALK-positive non-small cell lung cancer patients, significantly improving patient survival rates. Currently, several ALK tyrosine kinase inhibitors have been approved as first-line treatment for ALK-positive tumors.

[0007] Protein degradation-targeting chimeras (PROTACs) are heterobifunctional molecules that degrade target proteins by hijacking the ubiquitin-proteasome system. They consist of three parts: an E3 ligand that recruits E3 ubiquitin ligases, a warhead that binds to the target protein (POI), and a linker that connects the two parts. Traditional small molecules exert their pharmacological effects by occupancy-driven degradation of target proteins, requiring high in vivo drug concentrations. Long-term clinical use of small molecule drugs can easily lead to decreased affinity and acquired resistance. PROTACs achieve their pharmacodynamic effects by degrading the target protein, catalyzing the degradation process before escaping from the proteasome.

[0008] Although most patients achieve a good clinical response to initial treatment with ALK tyrosine kinase inhibitors, the development of resistance mutations during treatment can lead to ALK reactivation and disease progression. 50%-60% of patients develop resistance mutations during treatment with second-generation ALK tyrosine kinase inhibitors. Therefore, developing highly active, highly selective ALK tyrosine kinase PROTACs that can significantly degrade ALK resistance mutations can further meet the market demand for ALK-positive non-small cell lung cancer. Summary of the Invention

[0009] This invention relates to compounds of formula (I), their stereoisomers, or pharmaceutically acceptable salts thereof.

[0010]

[0011] in,

[0012] Ring A is selected from phenylene or 5-6-membered heteroaryl groups;

[0013] Ring B is a five-membered heteroaryl group containing at least one N atom;

[0014] Ring C is selected from 5-15 membered heterocyclic rings or 5-12 membered heteroaromatic rings;

[0015] Y 1 Selected from O, NR 6 or CR 7 R 7b ;

[0016] Y 2 Selected from O, NR 8 or CR 9 R 9b ;

[0017] R1 and R 2 Independently selected from H or C1-C6 alkyl groups;

[0018] Each R 3 Independently selected from halogens or C1-C6 alkyl groups;

[0019] Or, R 1 R 3 The atoms bonded to it together form C5-C 10 Cycloalkenyl or 5-10 membered heterocycles;

[0020] Each R 4 Independently selected from C1-C6 alkyl groups;

[0021] Or, R 3 R 4 The atoms bonded to it together form C5-C 10 Cycloalkenyl or 5-10 membered heterocycles;

[0022] Each R 5 Independently selected from halogens, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic groups, wherein the OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic group is optionally replaced by R. 5a replace;

[0023] Each R 5a It is independently selected from halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, or 4-7 membered heterocyclic groups;

[0024] R 6 and R 8 Independently selected from H or C1-C6 alkyl groups;

[0025] R 7 R 7b R 9 R 9b Independently selected from H, halogens, or C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted with halogens; or, R 9 R 9b The atoms connected to it form together Or C3-C6 cycloalkyl, the Alternatively, the C3-C6 cycloalkyl group may be replaced by a halogen or a C1-C6 alkyl group; or, R 5 R 9 The atoms bonded to it together form C5-C 10 Cycloalkenyl or 5-10 membered heterocycles;

[0026] m, n, and p are independently selected from 0, 1, 2, or 3;

[0027] L is the connecting unit, and its structure is -X 1 -Het 1 -X 2 -Het 2 -X 3 -Het 3 -X 4 -Het 4 -X 5 -;

[0028] X 1 X 2 X 3 X 4 X 5 Independently selected from bonds, O, S, NR 10 , C(O), C(S) or C1-C6 alkylene;

[0029] R 10 It is a C1-C6 alkyl group;

[0030] Het 1 Het 2 Het 3 Het 4 Independently selected from the bond, C3-C 12 Cycloalkylene or 4-12 membered heterocyclic alkylene, wherein the C3-C 12 The cycloalkyl or 4-12 membered heterocyclic group may optionally be substituted with halogen or C1-C6 alkyl;

[0031] ULM is the E3 ubiquitin ligase binding unit, and its structure is as follows:

[0032] X 6 Selected from bonds, -C(O)NH-, -NH-, or O;

[0033] Z 6 Selected from N or CH;

[0034] Het 5 Selected from phenylene, 5-15-membered heterocyclic group or 5-15-membered heteroaryl group, wherein the phenylene, 5-15-membered heterocyclic group or 5-15-membered heteroaryl group is optionally R 11 replace;

[0035] R 11 Selected from =O or R 12 ;R 12 Selected from halogens, NH2, OH, C1-C6 alkyl or C3-C6 cycloalkyl, wherein the NH2, OH, C1-C6 alkyl or C3-C6 cycloalkyl is optionally converted by R. 12areplace;

[0036] R 12a It is selected from halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, or C3-C6 cycloalkyl groups.

[0037] In some implementation schemes, Y 1 Selected from O.

[0038] In some implementation schemes, Y 2 Selected from CH2.

[0039] In some implementation schemes, R 1 and R 2 It is independently selected from H or CH3.

[0040] In some implementations, ring A is phenylene.

[0041] In some implementation schemes, R 3 Halogens such as F.

[0042] In some embodiments, ring B is an imidazolyl group. In some embodiments, ring B is...

[0043] In some implementation schemes, R 4 It is CH3.

[0044] In some embodiments, ring C is selected from 5-membered heteroaryl rings or 6-membered 5-membered heteroaryl rings. In some embodiments, ring C is selected from 6-membered 5-membered heteroaryl rings. In some embodiments, ring C is selected from... In some implementations, ring C is selected from... Where a is the site covalently linked to the pyridyl group, and b is the site covalently linked to the Y group. 2 The covalently linked site, c, is the site covalently linked to ULM-L. In some embodiments, ring C is selected from... In some implementations, ring C is selected from... Where a is the site covalently linked to the pyridyl group, and b is the site covalently linked to the Y group. 2 The covalently linked site, c is the site covalently linked to ULM-L.

[0045] In some implementation schemes, R 5 Selected from halogens, C1-C6 alkyl groups, or C3-C6 cycloalkyl groups, wherein the C1-C6 alkyl group or C3-C6 cycloalkyl group is optionally converted by R. 5a replace.

[0046] In some implementation schemes, R 5a Selected from C3-C6 cycloalkyl groups. In some embodiments, R 5a Selected from

[0047] In some implementation schemes, R 5 Selected from Cl, CH3, CH2CH3, CH(CH3)2, In some implementation schemes, R 5 Selected from Cl.

[0048] In some implementation schemes, Selected from

[0049] In some implementations, L is selected from -Het 1 -Het 2 -X 3 -Het 3 -、-Het 1 -X 2 -Het 2 -、-Het 1 -X 2 -Het 2 -X 3 -or-Het 1 -Het 2 -X 3 -Het 3 -X 4 -

[0050] In some implementations, L is selected from key,

[0051]

[0052]

[0053]

[0054] In some implementations, L is Among them, Het 2 Selected from C4-C6 cycloalkyl or 4-6 membered heterocyclic groups; X 3 X 4 Independently selected from bonds, CH2, C(O), or O; T, U, V, and W independently selected from CH or N; q and r independently selected from 0 or 1. In some embodiments, Het 2 Selected from alkyl or cyclobutylene.

[0055] In some implementation schemes, L is selected from

[0056] In some implementation schemes, L is selected from

[0057] In some implementations, ULM is selected from

[0058] The Optionally R 12 Replace; Z 1 Z 2 Z 3 Z 4 Z 5 Z 6 Independently selected from N or CR 12 W 1 W 2 Independently selected from CH2 or C(O), W 3 Selected from CH2, CH2CH2 or C(O), W 4 Selected from O, CH2 or NR 12 X 6 and R 12 As defined above.

[0059] In some implementations, ULM is selected from

[0060]

[0061]

[0062] In some implementations, ULM is selected from The Optionally R 12 Replace; Z 1 Z 2 Z 3 Z 4 Z 5 Z 6 Independently selected from N or CR 12 W 1 W 2 Independently selected from CH2 or C(O), X 6 and R 12 As defined above.

[0063] In some implementations, ULM is selected from

[0064] In some implementations, ULM is selected from

[0065] In some implementations, ULM is selected from

[0066] In some embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof are selected from the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof:

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077] In some embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof are selected from the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof.

[0078]

[0079] Among them, R 1 R 2 R 3 R 4 R 5 The definitions of m, n, p, L and ULM are the same as in formula (I).

[0080] In some embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof are selected from the compound of formula (III), its stereoisomers, or pharmaceutically acceptable salts thereof.

[0081]

[0082] Among them, R 1 R 2 R 3 R 4R 5 The definitions of m, n, p, L and ULM are the same as in formula (I).

[0083] On the other hand, the present invention provides a pharmaceutical composition comprising a compound of formula (I) of the present invention, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0084] On the other hand, the present invention provides a method for treating ALK-related diseases in mammals, comprising administering to a mammal, preferably a human, a therapeutically effective amount of a compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0085] On the other hand, the present invention provides the use of compounds of formula (I), their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of medicaments for the prevention or treatment of ALK-related diseases.

[0086] On the other hand, the present invention provides the use of compounds of formula (I), their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the prevention or treatment of ALK-related diseases.

[0087] On the other hand, the present invention provides a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the prevention or treatment of ALK-related diseases.

[0088] In some implementations, ALK-related diseases are selected from tumors, preferably lung cancer, and more preferably non-small cell lung cancer.

[0089] Terminology Definitions and Explanations

[0090] Unless otherwise stated, the terminology used in this invention has the following meanings: the definitions of groups and terms described herein, including definitions as examples, exemplary definitions, preferred definitions, definitions listed in tables, definitions of specific compounds in the examples, etc., can be arbitrarily combined and combined with each other. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood according to its ordinary meaning in the art. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

[0091] In this article Indicates the connection site.

[0092] The representation of racemic or enantiomerically pure compounds in this article is derived from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise specified, wedge bonds and virtual wedge bonds are used. The absolute configuration of a solid center is represented by black solid bonds and imaginary bonds. It indicates the relative configuration of a stereocenter (such as the cis-trans configuration of alicyclic compounds).

[0093] The term "stereoisomer" refers to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0094] The compounds of this invention may have asymmetric atoms such as carbon, sulfur, nitrogen, and phosphorus atoms, or asymmetric double bonds, and therefore may exist in specific geometric or stereoisomer forms. Specific geometric or stereoisomer forms may be cis and trans isomers, E- and Z-type geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof or other mixtures, such as mixtures enriched with enantiomers or diastereomers. All such isomers and mixtures thereof are within the scope of the definition of the compounds of this invention. Alkyl groups and other substituents may contain additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms, or asymmetric phosphorus atoms. All such isomers involved in all substituents and mixtures thereof are also included within the scope of the definition of the compounds of this invention. The compounds containing asymmetric atoms of the present invention can be isolated in optically active pure form or in racemic form. The optically active pure form can be separated from racemic mixtures or synthesized using chiral raw materials or chiral reagents.

[0095] The term "substituted" refers to the substitution of one or more hydrogen atoms on a particular atom by a substituent, provided that the valence state of the particular atom is normal and the substituted compound is stable.

[0096] The terms “optional” or “optionally” mean that the event or condition subsequently described may or may not occur, including both the occurrence and non-occurrence of said event or condition. For example, “optionally” substituted with a halogen means that the ethyl group can be unsubstituted (CH2CH3), monosubstituted (CH2CH2F, CH2CH2Cl, etc.), polysubstituted (CHFCH2F, CH2CHF2, CHFCH2Cl, CH2CHCl2, etc.), or fully substituted (CF2CF3, CF2CCl3, CCl2CCl3, etc.). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized is introduced.

[0097] When any variable (e.g., R) 3 R 4 When a group appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is surrounded by two R...3 Replaced, then each R 3 Each has its own independent options.

[0098] When a substituent is cross-bonded to two atoms on a ring, it can bond to any atom on that ring. For example, structural units. This indicates that R can be substituted at any position on the benzene ring.

[0099] Unless otherwise specified, the linking direction of the linking groups mentioned in this article is arbitrary. For example, when structural units... L in the text is selected from At this time, L can connect ULM and ULM in a direction from left to right. constitute Alternatively, the ULM ring can be connected from right to left. constitute

[0100] C in this article m -C n It refers to having an integer number of carbon atoms in the range mn. For example, "C1-C6" means that the group can have 1, 2, 3, 4, 5, or 6 carbon atoms.

[0101] The term "E3 ubiquitin ligase" is also known as ubiquitin-protein ligase or ubiquitin ligase E3. E3 has the ability to specifically recognize target proteins. It mediates the transfer of ubiquitin from E2 to the target protein and covalently binds to the target protein by recruiting substrate proteins and E2 ubiquitin-binding enzymes. The proteasome catalyzes the degradation of the ubiquitin-target protein coupling.

[0102] The term "E3 ubiquitin ligase binding unit" refers to a group or part that specifically binds to E3 ubiquitin ligase.

[0103] The term "alkyl" refers to a compound with the general formula C1. n H 2n+1 The alkyl group can be straight-chain or branched. The term "C1-C6 alkyl" can be understood as referring to a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc. The term "C1-C3 alkyl" can be understood as referring to a straight-chain or branched saturated monovalent hydrocarbon group having 1 to 3 carbon atoms. The "C1-C6 alkyl" may further include "C1-C3 alkyl".

[0104] The term "halogenated alkyl" includes monohalogenated or polyhalogenated alkyl groups, specific examples of which include, but are not limited to, trifluoromethyl, 2,2,2-trichloroethyl, or 3-fluoropropyl.

[0105] The term "cycloalkyl" refers to a fully saturated or partially saturated monocyclic or polycyclic cyclic hydrocarbon substituent. Polycyclic cyclic hydrocarbons include cyclic hydrocarbons existing in the form of fused rings, bridged rings, or spirocyclic rings. The term "C3-C..." 12 "Cycloalkyl" should be understood to mean a fully saturated or partially saturated monocyclic, fused, spirocyclic, or bridged ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. The term "C5-C" is also relevant. 10 "Cycloalkyl" should be understood to mean a fully saturated or partially saturated monocyclic, fused, spirocyclic, or bridged ring having 5, 6, 7, 8, 9, or 10 carbon atoms. The term "C3-C6 cycloalkyl" should be understood to mean a fully saturated or partially saturated monocyclic, fused, spirocyclic, or bridged ring having 3, 4, 5, or 6 carbon atoms. Specific examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl. etc. The term "cycloalkylene" refers to a divalent cycloalkyl group.

[0106] The term "cycloalkenyl" refers to a non-aromatic carbon ring that is not fully saturated and exists in the form of a monocyclic, fused, bridged, or spirocyclic ring. Specific examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, or cycloheptadienyl.

[0107] The term "heterocyclic group" refers to a fully saturated or partially saturated (not aromatic as a whole) monovalent monocyclic, fused, spirocyclic, or bridged ring group containing 1 to 5 heteroatoms or heteroatom groups (i.e., groups containing heteroatoms). The "heteroatoms or heteroatom groups" include, but are not limited to, nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), -S(=O)2-, -S(=O)-, and optionally substituted -NH-, -S(=O)(=NH)-, -C(=O)NH-, -C(=NH)-, -S(=O)2NH-, S(=O)NH-, or -NHC(=O)NH-, etc. The term "5-15 membered heterocyclic group" should be understood to include monovalent monocyclic, bicyclic, or tricyclic non-aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring atoms, particularly 5, 6, 9, or 10 ring atoms, and containing 1-5, preferably 1-3, heteroatoms independently selected from N, O, and S. The term "4-12 membered heterocyclic group" should be understood to include monovalent monocyclic, bicyclic, or tricyclic non-aromatic ring systems having 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, particularly 5, 6, 9, or 10 ring atoms, and containing 1-5, preferably 1-3, heteroatoms independently selected from N, O, and S. The term "5-10 membered heterocyclic group" should be understood to include monovalent monocyclic, bicyclic, or tricyclic non-aromatic ring systems having 5, 6, 7, 8, 9, or 10 ring atoms, particularly 5, 6, 9, or 10 ring atoms, and containing 1-5, preferably 1-3, heteroatoms independently selected from N, O, and S. The term "4-7 membered heterocyclic group" should be understood to include monovalent monocyclic or bicyclic non-aromatic ring systems having 4, 5, 6, or 7 ring atoms, and containing 1-3 heteroatoms independently selected from N, O, and S. Specific examples of 5-membered heterocyclic groups include, but are not limited to, tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoyl, pyrazolyl, pyrrolinyl, 4,5-dihydrooxazolyl, or 2,5-dihydro-1H-pyrrolyl; specific examples of 6-membered heterocyclic groups include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazine, trithiaalkyl, tetrahydropyridinyl, or 4H-[1,3,4]thiadiazinyl; specific examples of 7-membered heterocyclic groups include, but are not limited to, diazacycloheptyl. The heterocyclic group can also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include, but are not limited to, hexahydrocyclopentano[c]pyrrolo-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl. Optionally, the heterocyclic group can be a benzofused cyclic group of the above-mentioned 4-7-membered heterocyclic groups, specific examples of which include, but are not limited to, dihydroisoquinolinyl, etc.The term "5-15 membered heterocyclic group" can include the ranges of "5-13 membered heterocyclic group", "5-10 membered heterocyclic group", "5-6 membered heterocyclic group", and "6-8 membered heterocyclic group"; the term "4-12 membered heterocyclic group" can include the ranges of "4-7 membered heterocyclic group", "5-12 membered heterocyclic group", "5-10 membered heterocyclic group", "5-6 membered heterocyclic group", and "6-8 membered heterocyclic group"; "5-10 membered heterocyclic group" can include the ranges of "5-6 membered heterocyclic group" and "6-8 membered heterocyclic group"; "4-7 membered heterocyclic group" can further include the ranges of "4-6 membered heterocyclic group" and "5-6 membered heterocyclic group". Although some bicyclic heterocyclic groups in this invention partially contain a benzene ring or a heteroaromatic ring, the heterocyclic group as a whole is still non-aromatic. The term "hypocyclic group" refers to a divalent heterocyclic group.

[0108] The term "heteroaryl" refers to an aromatic monocyclic or fused polycyclic system containing at least one ring atom selected from N, O, or S, with the remaining ring atoms being C. The term "5-15-membered heteroaryl" should be understood to include monovalent monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring atoms, particularly 5, 6, 9, or 10 ring atoms, and containing 1-5, preferably 1-3, heteroatoms independently selected from N, O, and S. The term "5-12-membered heteroaryl" should be understood to include monovalent monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, particularly 5, 6, 9, or 10 ring atoms, and containing 1-5, preferably 1-3, heteroatoms independently selected from N, O, and S. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, or thiadiazolyl, as well as their benzo[derivatives], such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzoisoxazolyl, benzoimidazolyl, benzotriazolyl, indazole, indolyl, or isindolyl; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, as well as their benzo[derivatives], such as quinolinyl, quinazolinyl, or isoquinolinyl; or acryloxynyl, inazinyl, purinyl, as well as their benzo[derivatives]; or terpineyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphthidyl, pteridinyl, carbazolyl, acryloxynyl, phenazinyl, phenothiazinyl, or phenothiazinyl. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms, and containing 1-3, preferably 1-2, heteroatoms independently selected from N, O, and S. The term "hybrid aryl" refers to a divalent heteroaryl group. The term "6-membered 5-membered heteroaromatic ring" refers to an aromatic heterocyclic system formed by a six-membered aromatic ring and a five-membered aromatic ring sharing two adjacent atoms, containing at least one ring atom selected from N, O, and S.

[0109] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0110] The term "therapeutic effective amount" means the amount of the compound of the present invention used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of the present invention constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by those skilled in the art based on their own knowledge and the content of this disclosure.

[0111] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0112] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt of an acid or base, including salts formed by a compound with an inorganic or organic acid, and salts formed by a compound with an inorganic or organic base.

[0113] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present invention or their salts with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of the present invention to an organism.

[0114] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0115] The word “comprise” or “include” and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, meaning “including but not limited to”.

[0116] This invention also includes compounds of the invention that are identical to those described herein, but in which one or more atoms are labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.

[0117] The compounds of the present invention labeled with certain isotopes (e.g., using) 3 H and 14 C-labeling can be used in the analysis of compound and / or substrate tissue distribution. Tritiumization (i.e., 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes, such as... 15 O、 13 N、 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. The isotopically labeled compounds of the present invention can typically be prepared by replacing the unlabeled reagent with an isotopically labeled reagent using a procedure similar to those disclosed in the schemes and / or examples below.

[0118] The pharmaceutical compositions of the present invention can be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0119] Typical routes of administration of the compounds of the present invention or their pharmaceutically acceptable salts or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0120] The pharmaceutical compositions of the present invention can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, emulsification, freeze drying, etc.

[0121] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present invention to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, liquids, gels, pastes, suspensions, etc., for oral administration to patients.

[0122] Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated formulation. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, flow aids, or flavoring agents.

[0123] The pharmaceutical composition may also be suitable for parenteral administration, such as in suitable unit dosage forms of sterile solutions, suspensions or lyophilized products.

[0124] In all methods of administration of the compound of general formula (I) described herein, the daily dose is from 0.01 mg / kg to 200 mg / kg body weight, preferably from 0.05 mg / kg to 50 mg / kg body weight, more preferably from 0.1 mg / kg to 30 mg / kg body weight, in the form of single or separate doses.

[0125] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0126] The chemical reactions in the specific embodiments of this invention are carried out in a suitable solvent, which must be suitable for the chemical changes of this invention and the reagents and materials required therefor. To obtain the compounds of this invention, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction flow based on existing embodiments.

[0127] This invention uses the following abbreviations:

[0128] DME: Dimethyl ethylene glycol; Boc: tert-Butoxycarbonyl; EtOH: Ethanol; MeOH: Methanol; CbzCl: Benzyl chloroformate; Cbz: Benzyloxycarbonyl; DIEA: N,N-Diisopropylethylamine; THF: Tetrahydrofuran; Et3SiH: Triethylsilane; DMP: Dys-Martin oxidant; DCM: Dichloromethane; DMF: N,N-Dimethylformamide; Pd(Amphos)2Cl2: Dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium(II); t-BuOK: Potassium tert-Butoxide; t-BuO Na: Sodium tert-butoxide; t-BuOLi: Lithium tert-butoxide; EtOH: Ethanol; t-AmOH: Tert-amyl alcohol; Pd(OAc)2: Palladium acetate; NaOAc: Sodium acetate; PivOK: Potassium tert-valerate; cataCXiumA: n-Butyl di(1-adamantyl)phosphine; NaBH3CN: Sodium cyanoborohydride; NaOAc: Sodium acetate; DMSO: Dimethyl sulfoxide; NIS: N-iodosuccinimide; MeCN: Acetonitrile; i-PrMgCl·LiCl: Isopropyl magnesium chloride lithium chloride complex; P(tBu)3Pd G2: Chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; cataCXium A Pd G3: Methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II); Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium; RuPhos: 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl; TFA: trifluoroacetic acid; toluene: toluene. Detailed Implementation

[0129] The invention is described in detail below with reference to embodiments, but this does not imply any adverse limitation on the invention. The invention has been described in detail herein, and specific embodiments thereof have also been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the invention without departing from the spirit and scope thereof. All reagents used in this invention are commercially available and can be used without further purification.

[0130] Unless otherwise stated, proportions expressed for mixed solvents are volume-based. Unless otherwise stated, % refers to wt%.

[0131] Compounds are processed manually or Software naming conventions are used; commercially available compounds use supplier catalog names.

[0132] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts are measured in units of 10⁻⁶. -6(ppm). The solvents used for NMR determination were deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., with tetramethylsilane (TMS) as the internal standard; "IC 50 "Half-inhibition concentration" refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0133] The eluent described below may be a mixture of two or more solvents, with the ratio being the volume ratio of each solvent. For example, "0-40% tetrahydrofuran / petroleum ether" indicates that in the gradient elution process, the volume ratio of tetrahydrofuran to petroleum ether in the mixed eluent is 0:100 to 40:60.

[0134] Example 1: Synthesis of Compound 1

[0135]

[0136] Step 1: Synthesis of 4-(2-dichloromethyl)-2-hydroxy-2,3-dihydroimidazo[1,2-a]pyridin-6-yl)piperazine-1-carboxylic acid tert-butyl ester (intermediates 1-2)

[0137] Compound 1-1 (8.0 g, 28.74 mmol), 1,1,3-trichloroprop-2-one (5.57 g, 34.49 mmol) and DME (20 mL) were added to a reaction flask and reacted overnight at room temperature. The mixture was filtered, and the filter cake was washed with water (30 mL × 3) to give the title compound (10.3 g).

[0138] MS m / z (ESI): 403.12 [M+H] + .

[0139] Step 2: Synthesis of 2-(diethoxymethyl)-6-(piperazin-1-yl)imidazo[1,2-a]pyridine (intermediates 1-3)

[0140] Intermediate 1-2 (10.3 g, 25.54 mmol) and ethanol (25 mL) were added to a reaction flask, stirred at 80 °C for 12 h, cooled to room temperature, and concentrated under reduced pressure to give the title compound (7.1 g).

[0141] MS m / z (ESI): 305.19 [M+H] + .

[0142] Step 3: Synthesis of 4-(2-formylimidazo[1,2-a]pyridin-6-yl)piperazine-1-carboxylic acid benzyl ester (intermediates 1-4)

[0143] Intermediate 1-3 (7.1 g, 23.33 mmol), CbzCl (5.17 g, 30.33 mmol), DIEA (6.03 g, 46.66 mmol), and THF (30 mL) were added to a reaction flask at 0 °C. The mixture was heated to room temperature and stirred for 1 h. The reaction solution was quenched with water, and 20 mL of saturated citric acid aqueous solution was added. After stirring for 10 min, the mixture was allowed to stand and separate into layers. The aqueous phase was purified by C18 silica gel column chromatography (mobile phase: water / acetonitrile = 1:2) to give the title compound (7.4 g).

[0144] MS m / z (ESI): 365.14 [M+H] + .

[0145] Step 4: Synthesis of 4-(2-((3-bromo-1-methyl-1H-pyrazol-4-yl)(hydroxy)methyl)imidazo[1,2-a]pyridin-6-yl)piperazine-1-carboxylic acid benzyl ester (intermediates 1-5)

[0146] 3-Bromo-4-iodo-1-methyl-1H-pyrazole (568 mg, 1.98 mmol) was dissolved in tetrahydrofuran (4 mL) at room temperature. The resulting mixture was cooled to 0 °C, and a solution of isopropyl magnesium chloride-lithium chloride complex (1.52 mL, 2 M) was added dropwise. The mixture was stirred for 0.5 h, and intermediate 1-4 (600 mg, 1.65 mmol) was added. The mixture was heated to room temperature and stirred for another 1 h. The reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (10 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: PE / EA = 1 / 1) to give the title compound (800 mg).

[0147] MS m / z(ESI):525.12, 527.11[M+H] + .

[0148] Step 5: Synthesis of 4-(2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridin-6-yl)piperazine-1-carboxylic acid benzyl ester (intermediates 1-6)

[0149] Intermediate 1-5 (800 mg, 1.52 mmol) was dissolved in trifluoroacetic acid (2 mL) at room temperature, and triethylsilane (2 mL) was added. The mixture was stirred at 60 °C for 12 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: PE / EA = 1 / 1) to give the title compound (480 mg).

[0150] MS m / z(ESI):509.11,511.12[M+H] + .

[0151] Step 6: Synthesis of (R)-4-(2-((3-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridin-6-yl)piperazine-1-carboxylic acid benzyl ester (intermediates 1-7)

[0152] Intermediate 1-6 (480 mg, 942.29 μmol), (R)-5-fluoro-3-methylbenzo[c][1,2]oxaborane-1(3H)-ol (312.76 mg, 1.88 mmol), Pd(Amphos)2Cl2 (13.38 mg, 18.85 μmol), and potassium carbonate (260.46 mg, 1.88 mmol) were added to dioxane (2 mL) and water (0.2 mL) at room temperature. The resulting reaction solution was stirred at 100 °C for 12 h, and the reaction solution was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography (mobile phase: water / acetonitrile = 1 / 2) to give the title compound (340 mg).

[0153] MS m / z(ESI): 569.24 [M+H] + .

[0154] Step 7: Synthesis of (R)-4-(2-((3-(2-(1-(((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridin-6-yl)piperazine-1-carboxylic acid benzyl ester (intermediates 1-8)

[0155] Intermediate 1-7 (340 mg, 597.92 μmol), 5-bromo-3-fluoro-2-nitropyridine (264.26 mg, 1.20 mmol), and t-BuOK (134.19 mg, 1.20 mmol, dissolved in THF (1 mL)) were added to toluene (3 mL) at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: PE / EA = 1 / 1) to give the title compound (340 mg).

[0156] MS m / z(ESI):769.17,771.18[M+H] + .

[0157] Step 8: Synthesis of (R)-4-(2-((3-(2-(1-(((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridin-6-yl)piperazine-1-carboxylic acid benzyl ester (intermediates 1-9)

[0158] Intermediate 1-8 (340 mg, 441.78 μmol), iron powder (123.36 mg, 2.21 mmol), and ammonium chloride (118.16 mg, 2.21 mmol) were dissolved in ethanol (4 mL) and water (1 mL) at room temperature. The reaction solution was stirred at 80 °C for 1 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: PE / EA = 1 / 2) to give the title compound (145 mg).

[0159] MS m / z(ESI):739.21,741.20[M+H] + .

[0160] Step 9: Synthesis of intermediates 1-10

[0161] Intermediate 1-9 (145 mg, 196.04 μmol) was dissolved in t-AmOH (2 mL) at room temperature, and Pd(OAc)2 (4.40 mg, 19.60 μmol), cataCXium A (14.06 mg, 39.21 μmol), and PivOK (54.98 mg, 392.09 μmol) were added. The reaction mixture was stirred at 100 °C for 10 h under an argon atmosphere. H2O (10 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL × 3). The extract was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by C18 silica gel column chromatography (mobile phase: water / acetonitrile = 1 / 2) to give the title compound (90 mg).

[0162] MS m / z (ESI): 659.28 [M+H] + .

[0163] Step 10: Synthesis of intermediates 1-11

[0164] Intermediate 1-10 (90 mg, 136.63 μmol) and Pd(OH)₂ (18.92 mg, 134.71 μmol) were dissolved in MeOH (3 mL) at room temperature and stirred at 45 °C for 3 h under a hydrogen atmosphere. Pd(OH)₂ was removed by filtration, and the mixture was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography (mobile phase: water / acetonitrile = 1 / 2) to give the title compound (51 mg).

[0165] MS m / z(ESI): 525.63 [M+H] + .

[0166] 1H NMR(400MHz,DMSO-d6)δ7.74(d,J=1.7Hz,1H),7.70(dd,J=10.4,2.6Hz,1H),7.55(s,1H),7 .53(d,J=2.1Hz,1H),7.44(d,J=9.7Hz,1H),7.25–7.19(m,2H),7.18(d,J=2.5Hz,1H),6.32( d,J=1.8Hz,1H),6.05(s,2H),5.33(d,J=5.7Hz,1H),3.82(s,3H),3.79(s,1H),3.10(d,J=15 .0Hz,1H),2.88(t,J=4.1Hz,4H),2.81(t,J=4.8Hz,4H),1.72(d,J=6.2Hz,3H),1.39(s,1H).

[0167] Step 11: Synthesis of Compound 1

[0168] Intermediate 1-11 (15 mg, 28.59 μmol), intermediate 1-12 (10.16 mg, 28.59 μmol), NaBH3CN (3.59 mg, 57.19 μmol), and NaOAc (4.69 mg, 57.19 μmol) were dissolved in DMF (2 mL) at room temperature and stirred at room temperature for 1 h. The reaction solution was purified by C18 silica gel column chromatography (mobile phase: water / acetonitrile = 1 / 2) to obtain compound 1 (2 mg).

[0169] MS m / z (ESI): 864.81 [M+H] + .

[0170] 1H NMR(400MHz, DMSO-d6)δ10.97(s,1H),7.70(dd,J=10.6,2.7Hz,1H),7.56(d,J=4.7Hz,2H),7.49–7.37(m,2H),7.29–7.15(m,5H),7 .15(dd,J=6.4,2.3Hz,1H),6.32(s,1H),6.04(s,2H),5.40–5.28(m,1H),5.09(dd,J=13.2,5.1Hz,1H),4.37–4.15(m,2H),3.88(s,2 H),3.82(s,4H),3.74(d,J=11.4Hz,1H),3.63–3.50(m,3H),3.47(s,4H),3.15(dd,J=11.0,6.4Hz,1H),3.00(s,3H),2.75–2.65(m, 1H),2.64–2.55(m,1H),2.42–2.30(m,1H),2.21(d,J=7.1Hz,2H),2.03–1.94(m,4H),1.80(d,J=13.1Hz,1H),1.72(d,J=6.2Hz,3H).

[0171] Example 2: Synthesis of Compound 2

[0172]

[0173] Step 1: Synthesis of (R)-3-((6-nitropyridin-3-yl)oxy)pyrrolidine-1-carboxylic acid benzyl ester (intermediate 2-2)

[0174] Compound 2-1 (2.5 g, 17.59 mmol), (R)-3-hydroxypyrrolidine-1-carboxylic acid benzyl ester (4.67 g, 21.11 mmol), and potassium carbonate (4.86 g, 35.19 mmol) were added to DMSO (10 mL) and stirred at 80 °C for 5 h. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: PE / EA = 1 / 1) to give the title compound (3.9 g).

[0175] MS m / z (ESI): 344.12 [M+H] + .

[0176] Step 2: Synthesis of (R)-3-((6-aminopyridin-3-yl)oxy)pyrrolidine-1-carboxylic acid benzyl ester (intermediate 2-3)

[0177] Intermediate 2-2 (3.3 g, 9.61 mmol), iron powder (2.68 g, 48.06 mmol), and ammonium chloride (2.57 g, 48.06 mmol) were added to ethanol (8 mL) and water (2 mL) at room temperature, and the mixture was heated to 80 °C and stirred for 1 h. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: PE / EA = 1 / 2) to give the title compound (2.1 g).

[0178] MS m / z(ESI): 314.14 [M+H] + .

[0179] Step 3: Synthesis of 3-bromo-4-iodo-1-methyl-1H-pyrazole (intermediates 2-5)

[0180] Compounds 2-4 (5.0 g, 31.06 mmol) and NIS (13.97 g, 62.11 mmol) were dissolved in acetonitrile (20 mL) at room temperature and stirred at 60 °C for 12 h. The reaction solution was poured into a saturated sodium thiosulfate aqueous solution (40 mL), extracted with ethyl acetate (30 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: PE / EA = 1 / 1) to give the title compound (7.6 g).

[0181] MS m / z(ESI):287.12,289.14[M+H] + .

[0182] Step 4: Synthesis of 1-bromo-3-(3-bromo-1-methyl-1H-pyrazol-4-yl)prop-2-ol (intermediate 2-6)

[0183] Intermediate 2-5 (1.5 g, 5.23 mmol) was dissolved in THF (5 mL) at room temperature. A solution of isopropyl magnesium chloride-lithium chloride complex (4.02 mL, 1.3 M, 5.23 mmol) was added dropwise at 0 °C, and the mixture was stirred at 0 °C for 1 h. Cuprous iodide (198.96 mg, 1.04 mmol) and epibromopropane (1.07 g, 7.83 mmol) were added at -50 °C, and the mixture was slowly brought to room temperature and stirred for another 1 h. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: PE / EA = 1 / 1) to give the title compound (780 mg).

[0184] MS m / z(ESI):297.13,299.15,301.12[M+H] + .

[0185] Step 5: Synthesis of 1-bromo-3-(3-bromo-1-methyl-1H-pyrazol-4-yl)prop-2-one (intermediate 2-7)

[0186] Intermediate 2-6 (780 mg, 2.62 mmol) was dissolved in dichloromethane (5 mL) at room temperature. DMP (4.44 g, 10.47 mmol) was added in portions at 0 °C. The mixture was stirred for 12 h after reaching room temperature. The reaction mixture was poured into a saturated sodium thiosulfate aqueous solution (10 mL), extracted with dichloromethane (10 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: PE / EA = 1 / 2) to give the title compound (680 mg).

[0187] MS m / z(ESI):295.08,297.07,299.04[M+H] + .

[0188] Step 6: Synthesis of (R)-3-((2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridin-6-yl)oxy)pyrrolidine-1-carboxylic acid benzyl ester (intermediate 2-8)

[0189] Intermediate 2-7 (680 mg, 2.30 mmol), intermediate 2-3 (863.95 mg, 2.76 mmol), and sodium bicarbonate (386.03 mg, 4.60 mmol) were added to dioxane (5 mL) at room temperature and stirred at room temperature for 12 h. The mixture was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: PE / EA = 1 / 2) to give the title compound (680 mg).

[0190] MS m / z(ESI):510.42,512.37[M+H] + .

[0191] The preparation process of intermediates 2-9 to compound 2 is the same as that of intermediates 1-7 to compound 1 in Example 1. Only intermediates 1-6 need to be replaced with intermediate 2-8 to obtain compound 2 (3 mg).

[0192] MS m / z (ESI): 865.85 [M+H] + .

[0193] 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),7.76(dd,J=7.4,2.0Hz,2H),7.70(dd,J=10.4,2.6Hz,1H),7.57(s,1H),7.50(d,J=9.6Hz,1H),7.40(d ,J=8.5Hz,1H),7.25–7.17(m,3H),7.14(d,J=2.3Hz,1H),7.02(dd,J=9.7,2.2Hz,1H),6.34(d,J=1.8Hz,1H),6.08(s,2H),5.32(d,J=6.8Hz,1 H),5.09(dd,J=13.3,5.1Hz,1H),4.37–4.14(m,2H),3.82(s,4H),3.70(s,3H),3.12(d,J=14.9Hz,1H),2.91(ddd,J=18.1,13.6,5.4Hz,1H), 2.80–2.54(m,4H),2.43–2.23(m,4H),2.17–1.92(m,2H),1.79(d,J=12.7Hz,3H),1.71(d,J=6.2Hz,3H),1.60(s,1H),1.21(d,J=20.5Hz,4H).

[0194] Example 3: Synthesis of Compound 3

[0195]

[0196] Step 1: Synthesis of 4-((3-chloro-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylic acid benzyl ester (intermediate 3-2)

[0197] Under a nitrogen atmosphere, compound 3-1 (510 mg, 4.97 mmol), benzyl 4-(bromomethyl)piperidinecarboxylate (1.55 g, 4.97 mmol), and cesium carbonate (2.5 g, 7.67 mmol) were added to MeCN (10 mL), and the mixture was stirred at room temperature for 7 h. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (EA / PE = 0:1 to 1:0) to give the title compound (1.04 g).

[0198] LC-MS: m / z (ESI): 334.32 [M+H] +

[0199] Step 2: Synthesis of 4-((3-chloro-4-iodo-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylic acid benzyl ester (intermediate 3-3)

[0200] Under a nitrogen atmosphere, intermediate 3-2 (700 mg, 2.10 mmol) and NIS (0.95 g, 4.22 mmol) were dissolved in MeCN (10 mL), and the resulting mixture was stirred at 80 °C for 16 h. A saturated aqueous solution of sodium thiosulfate (2 mL) was added to the reaction mixture, and the solvent was removed by concentration under reduced pressure. The residue was purified by column chromatography (EA / PE = 0:1 to 1:0) to give the title compound (824 mg).

[0201] LC-MS: m / z (ESI): 460.34 [M+H] +

[0202] Step 3: Synthesis of 4-((3-chloro-4-(hydroxy(3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylic acid benzyl ester (intermediate 3-4)

[0203] Under a nitrogen atmosphere, intermediate 3-3 (823 mg, 1.79 mmol) was dissolved in THF (5 mL) and cooled to -20 °C. At this temperature, isopropyl magnesium chloride-lithium chloride complex (1.3 M in THF, 1.7 mL) was added dropwise, and the reaction was stirred for 1 h. A solution of 3-iodo-1-methyl-1H-pyrazole-4-carboxaldehyde (508 mg, 2.15 mmol) in THF (5 mL) was added, and the resulting mixture was heated to room temperature and stirred for 1 h. A saturated aqueous solution of ammonium chloride (1 mL) was added to the reaction mixture, and the solvent was removed by concentration under reduced pressure. The residue was purified by column chromatography (EA / PE = 0:1 to 1:0) to give the title compound (583 mg).

[0204] LC-MS: m / z (ESI): 570.24 [M+H] +

[0205] The preparation process of intermediates 3-5 to compound 3 is the same as that of intermediates 1-6 to compound 1 in Example 1, except that intermediates 1-5 are replaced by intermediates 3-4 to obtain compound 3 (3 mg).

[0206] m / z(ESI): 861.98 [M+H] + .

[0207] 1H NMR (400MHz, DMSO-d6) δ10.95(s,1H),7.75–7.68(m,1H),7.59(s,1H),7.47(d,J=1.7Hz,1H),7.40(d,J=8.4Hz,1H),7.23(d,J=8.7Hz,1H),7 .18–7.12(m,2H),6.25(s,1H),6.21(s,2H),5.32(d,J=6.6Hz,1H),5.09(dd,J=13.2,5.1Hz,1H),4.38–4.14(m,2H),3.88(s,4H),3.71(d,J=1 2.1 Hz, 2H), 3.55 (d, J = 23.6 Hz, 2H), 2.97–2.74 (m, 1H), 2.69 (d, J = 13.7 Hz, 3H), 2.65–2.56 (m, 1H), 2.15–2.04 (m, 2H), 2.01 (d, J = 8.6 Hz, 2H), 1.71 (d, J = 6.1 Hz, 3H), 1.63 (s, 2H), 1.46 (d, J = 12.2 Hz, 2H), 1.30 (d, J = 43.8 Hz, 5H), 1.16 (d, J = 11.8 Hz, 2H), 1.00–0.83 (m, 4H). Example 4: Synthesis of Compound 4

[0208]

[0209] Step 1: Synthesis of 3-bromo-1-methyl-1H-pyrazole-4-carboxaldehyde (intermediate 4-1)

[0210] At 0°C, phosphorus oxychloride (1 mL) was slowly added dropwise to an N,N-dimethylformamide solution (1 mL) containing intermediate 2-4 (2.0 g, 12.42 mmol). The reaction mixture was stirred at 95°C for 4 hours. The reaction mixture was cooled to room temperature, quenched with water, and purified by reversed-phase column chromatography (water (containing 1.0‰ formic acid): acetonitrile = 95:5 to 5:95) to give the title compound (1.01 g).

[0211] m / z(ESI): 189 / 191 [M+H] +

[0212] Step 2: Synthesis of 1-(cyclopropylmethyl)-1H-pyrazole-3-nitrile (intermediate 4-3)

[0213] Compound 4-2 (2.0 g, 21.49 mmol) and potassium carbonate (5.94 g, 42.97 mmol) were added to N,N-dimethylformamide (25 mL), followed by the addition of bromomethylcyclopropane (3.19 g, 23.63 mmol, 2.29 mL) at room temperature. The reaction mixture was stirred at 80 °C for 5.5 hours. The reaction mixture was cooled to room temperature, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by normal-phase column chromatography (ethyl acetate: petroleum ether = 0:100 to 1:5) to give the title compound (2.37 g).

[0214] m / z(ESI): 148 [M+H] +

[0215] Step 3: Synthesis of 1-(cyclopropylmethyl)-4-iodo-1H-pyrazole-3-nitrile (intermediate 4-4)

[0216] At 0 °C, trifluoroacetic acid (2.44 g, 21.38 mmol, 1.65 mL) and N-iodosuccinimide (5.25 g, 23.32 mmol) were added sequentially to an acetonitrile (20 mL) solution of intermediate 4-3 (2.86 g, 19.43 mmol). The reaction mixture was stirred at 65 °C for two days. The reaction mixture was cooled to room temperature, quenched with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reversed-phase column chromatography (water (containing 1.0‰ formic acid): acetonitrile = 95:5 to 5:95) to give the title compound (4.12 g).

[0217] m / z(ESI): 274[M+H] +

[0218] Step 4: Synthesis of 4-((3-bromo-1-methyl-1H-pyrazol-4-yl)(hydroxy)methyl)-1-(cyclopropylmethyl)-1H-pyrazol-3-onitrile (intermediates 4-5)

[0219] Intermediate 4-4 (557 mg, 2.04 mmol) was dissolved in tetrahydrofuran (5.0 mL). Isopropyl magnesium chloride-lithium chloride complex (1.3 M tetrahydrofuran solution, 1.57 mL, 2.04 mmol) was added at 0 °C. After stirring at 0 °C under argon protection for 0.5 hours, a tetrahydrofuran solution of intermediate 4-1 (462.64 mg, 2.45 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by normal-phase column chromatography (tetrahydrofuran: petroleum ether = 0:1 to 2:3) to give the title compound (297 mg).

[0220] m / z(ESI): 336 / 338 [M+H] +

[0221] Step 5: Synthesis of 4-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-1-(cyclopropylmethyl)-1H-pyrazol-3-onitrile (intermediates 4-6)

[0222] At 0 °C, trifluoroacetic acid (548.43 mg, 4.81 mmol, 370.56 μL) and triethylsilane (745.70 mg, 6.41 mmol, 1.02 mL) were sequentially added to a dichloromethane (5 mL) solution of intermediate 4-5 (539 mg, 1.60 mmol). The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by normal-phase column chromatography (tetrahydrofuran: petroleum ether = 1:2) to give the title compound (363 mg).

[0223] m / z(ESI): 320 / 322[M+H] +

[0224] Step 6: Synthesis of 4-((3-bromo-1-methyl-1H-pyrazole-4-yl)methyl)-1-(cyclopropylmethyl)-1H-pyrazole-3-carboxylic acid (intermediates 4-7)

[0225] Intermediate 4-6 (343 mg, 1.07 mmol) was dissolved in concentrated hydrochloric acid (2 mL) and stirred at 80 °C for 4 hours. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by normal-phase column chromatography (tetrahydrofuran: petroleum ether = 1:1) to give the title compound (376 mg).

[0226] m / z(ESI): 339 / 341 [M+H] +

[0227] Step 7: Synthesis of methyl 4-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-1-(cyclopropylmethyl)-1H-pyrazol-3-carboxylic acid (intermediates 4-8)

[0228] Intermediate 4-7 (319 mg, 940.48 μmol) was dissolved in methanol (5 mL), and thionyl chloride (559.45 mg, 4.70 mmol, 341.13 μL) was added dropwise at 0 °C, followed by stirring overnight at 60 °C. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by normal-phase column chromatography (tetrahydrofuran: petroleum ether = 1:1) to give the title compound (376 mg).

[0229] m / z(ESI): 353 / 355 [M+H] +

[0230] Step 8: Synthesis of (R)-1-(cyclopropylmethyl)-4-((3-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-3-carboxylic acid methyl ester (intermediate 4-9)

[0231] Intermediate 4-8 (356 mg, 1.01 mmol), (R)-5-fluoro-3-methylbenzo[c][1,2]oxabor-1(3H)-ol (200.72 mg, 1.21 mmol), chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (51.65 mg, 100.79 μmol), and potassium phosphate (427.89 mg, 2.02 mmol) were added to N,N-dimethylformamide (10 mL), and stirred overnight at 80 °C under an argon atmosphere. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by normal-phase column chromatography (ethyl acetate: petroleum ether = 4:1) to give the title compound (201 mg).

[0232] m / z(ESI): 413[M+H] +

[0233] Step 9: Synthesis of (R)-4-((3-(2-(1-(((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazole-4-yl)methyl)-1-(cyclopropylmethyl)-1H-pyrazole-3-carboxylic acid methyl ester (intermediate 4-10)

[0234] Intermediate 4-9 (181 mg, 438.83 μmol) and 5-bromo-3-fluoro-2-nitropyridine (145.46 mg, 658.25 μmol) were dissolved in toluene (5 mL). A tetrahydrofuran solution of lithium tert-butoxide (2.2 M, 484 μmol, 0.22 mL) was added dropwise to the reaction mixture at -78 °C, and the mixture was stirred at 0 °C for 2 hours. The reaction was quenched by adding saturated ammonium chloride aqueous solution at 0 °C. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by normal-phase column chromatography (ethyl acetate: petroleum ether = 1:1) to give the title compound (184 mg).

[0235] m / z(ESI): 613 / 615 [M+H] +

[0236] Step 10: Synthesis of (R)-4-((3-(2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1-(cyclopropylmethyl)-1H-pyrazol-3-carboxylic acid methyl ester (intermediate 4-11)

[0237] Intermediate 4-10 (164 mg, 267.35 μmol), iron powder (74.65 mg, 1.34 mmol), and ammonium chloride (143.00 mg, 2.67 mmol) were added to ethanol (10 mL) and water (2 mL). The reaction mixture was stirred at 80 °C for 2 hours under an argon atmosphere. The reaction mixture was cooled to room temperature, filtered, concentrated under reduced pressure, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by normal-phase column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the title compound (165 mg).

[0238] m / z(ESI): 583 / 585 [M+H] +

[0239] Step 11: Synthesis of intermediates 4-12

[0240] Intermediate 4-11 (135 mg, 231.38 μmol), palladium acetate (15.72 mg, 69.41 μmol), n-butyldi(1-adamantyl)phosphine (49.78 mg, 138.83 μmol), and potassium tert-pentanoate (65.82 mg, 462.76 μmol) were added to tert-amyl alcohol (5 mL), and stirred at 120 °C for 18 hours under an argon atmosphere. The reaction solution was cooled to room temperature, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by normal-phase column chromatography (tetrahydrofuran: petroleum ether = 1:1) to give the title compound (115 mg).

[0241] m / z(ESI): 503 [M+H] +

[0242] Step 12: Synthesis of intermediates 4-13

[0243] Intermediate 4-12 (99 mg, 197.00 μmol) and lithium hydroxide (23.59 mg, 985.00 μmol) were dissolved in methanol (2.5 mL) and water (0.5 mL) and stirred at 40 °C for 4 hours. The reaction solution was concentrated under reduced pressure, the pH was adjusted to 5-6 with dilute hydrochloric acid (1 M), lyophilized, and purified by reversed-phase column chromatography (water (containing 0.1% formic acid): acetonitrile = 95:5 to 5:95) to give the title compound (41 mg).

[0244] m / z(ESI): 489[M+H]+

[0245] Step 13: Synthesis of intermediates 4-14

[0246] Intermediate 4-13 (31 mg, 63.46 μmol), 4-(dimethoxymethyl)-piperidine (20.21 mg, 126.92 μmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (28.95 mg, 76.15 μmol) were dissolved in N,N-dimethylformamide (1.0 mL). Under argon protection, N,N-diisopropylethylamine (32.81 mg, 253.83 μmol) was added to the reaction solution at 0 °C, and the mixture was stirred at room temperature for 2 hours. The solution was purified by reversed-phase column chromatography (water (containing 0.1% ammonia): acetonitrile = 95:5 to 5:95) to give the title compound (30 mg).

[0247] m / z(ESI): 630[M+H] +

[0248] Step 14: Synthesis of intermediates 4-15

[0249] Intermediate 4-14 (30 mg, 47.64 μmol) was dissolved in formic acid (2 mL) and stirred at 37 °C for 2 hours. The solution was concentrated under reduced pressure to give the title compound (27.8 mg).

[0250] m / z(ESI): 584 [M+H] +

[0251] Step 15: Synthesis of Compound 4

[0252] Intermediates 4-15 (27.8 mg, 47.64 μmol), 4-16 (31.51 mg, 95.95 μmol), and sodium acetate (7.87 mg, 95.95 μmol) were added to N,N-dimethylformamide (1.0 mL). Sodium cyanoborohydride (6.03 mg, 95.95 μmol) was added to the reaction mixture at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by preparative high performance liquid chromatography (C18 column, eluent: water (containing 0.1% ammonia): acetonitrile = 95:5 to 5:95) to give compound 4 (4.76 mg).

[0253] m / z(ESI): 896[M+H] +

[0254] 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),7.81(d,J=36.0Hz,1H),7.70(d,J=10.0Hz,1H),7.52(d,J=14.4Hz,2H),7.16–7.07(m,4H),6.32(s,1H) ,6.16(s,2H),5.36(s,1H),5.05(dd,J=13.5,5.0Hz,1H),4.60(s,1H),4.33(d,J=16.9Hz,2H),4.20(d,J=16.9Hz,1H),4.08–3.95(m,1H),3.8 7 (s, 4H), 3.74–3.60 (m, 1H), 3.29 (s, 3H), 2.71–2.64 (m, 2H), 2.46–2.43 (m, 2H), 2.43–2.37 (m, 2H), 2.35–2.31 (m, 2H), 2.30–2.18 (m, 2H), 2.00–1.85 (m, 4H), 1.71 (d, J = 6.1 Hz, 4H), 1.23 (s, 2H), 1.18–1.03 (m, 3H), 0.49–0.34 (m, 2H), 0.33–0.22 (m, 1H), 0.17–0.05 (m, 1H). Example 5: Synthesis of Compound 5

[0255]

[0256] Step 1: Synthesis of 5-(4-(dimethoxymethyl)piperidin-1-yl)-2-nitropyridine (intermediate 5-2)

[0257] Under a nitrogen atmosphere, 5-1 (2.40 g, 11.8 mmol), 4-(dimethoxymethyl)piperidine (2.82 g, 17.7 mmol), and potassium carbonate (3.27 g, 23.7 mmol) were added to DMSO (8 mL), and the resulting mixture was stirred at 80 °C for 4 h. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude residue was purified by column chromatography (EA:PE = 0:1 to 1:0) to give the title compound (3.20 g).

[0258] LC-MS: m / z(ESI): 282.2 [M+H] +

[0259] Step 2: Synthesis of 5-(4-(dimethoxymethyl)piperidin-1-yl)pyridine-2-amine (intermediate 5-3)

[0260] Intermediate 5-2 (1.60 g, 5.69 mmol), iron powder (1.59 g, 28.4 mmol), and ammonium chloride (1.52 g, 28.4 mmol) were added to ethanol (8 mL) and water (2 mL) at room temperature. The mixture was then heated to 80 °C and stirred for 1 h. After cooling to room temperature, the mixture was filtered, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 1:2) to give the title compound (1.06 g).

[0261] LC-MS: m / z (ESI): 252.3 [M+H] +

[0262] Step 3: Synthesis of 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-(4-(dimethoxymethyl)piperidin-1-yl)imidazo[1,2-a]pyridine (intermediates 5-4)

[0263] Intermediate 5-3 (800 mg, 3.18 mmol), intermediate 2-7 (1.13 g, 3.82 mmol), and sodium bicarbonate (534 mg, 6.37 mmol) were added to 1,4-dioxane (5 mL) at room temperature, stirred overnight, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: PE:EA = 1:2) to give the title compound (680 mg).

[0264] LC-MS:m / z(ESI):448.4 / 450.3[M+H] +

[0265] Step 4: Synthesis of (R)-1-(2-(4-((6-(4-(dimethoxymethyl)piperidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethane-1-ol (intermediate 5-5)

[0266] Under an argon atmosphere, a mixture of intermediate 5-4 (680 mg, 1.52 mmol), (R)-5-fluoro-3-methylbenzo[c][1,2]oxaborane-1(3H)-ol (755 mg, 4.55 mmol), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II) (21.5 mg, 30.3 μmol), potassium carbonate (419 mg, 3.03 mmol), 1,4-dioxane (4 mL), and water (2 mL) was heated to 80 °C and reacted for 1 h. After cooling to room temperature, the solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography (THF:PE = 0:1 to 1:0) to give the title compound (340 mg).

[0267] LC-MS: m / z (ESI): 508.3 [M+H] +

[0268] Step 5: Synthesis of (R)-2-((3-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-6-(4-(dimethoxymethyl)piperidin-1-yl)imidazo[1,2-a]pyridine (intermediates 5-6)

[0269] Under an argon atmosphere, a solution of potassium tert-butoxide (150 mg, 1.34 mmol) in tetrahydrofuran (2 mL) was added to a mixture of intermediate 5-5 (340 mg, 670 μmol), 5-bromo-3-fluoro-2-nitropyridine (296 mg, 1.34 mmol), and toluene (5 mL). The resulting mixture was allowed to react at room temperature for 0.5 h. The reaction was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (THF:PE = 0:1 to 1:0) to give the title compound (360 mg).

[0270] LC-MS:m / z(ESI):708.4 / 710.3[M+H] +

[0271] Step 6: Synthesis of (R)-5-bromo-3-(1-(2-(4-((6-(4-(dimethoxymethyl)piperidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)pyridine-2-amine (intermediates 5-7)

[0272] Under an argon atmosphere, a mixture of intermediate 5-6 (360 mg, 508 μmol), iron powder (142 mg, 2.54 mmol), ammonium chloride (136 mg, 2.54 mmol), EtOH (4 mL), and water (1 mL) was heated to 80 °C and stirred for 1 h. The mixture was filtered, the filtrate was evaporated to dryness, and the residue was purified by column chromatography (THF:PE = 0:1 to 1:0) to give the title compound (344 mg).

[0273] LC-MS:m / z(ESI):678.3 / 680.3[M+H] +

[0274] Step 7: Synthesis of intermediates 5-8

[0275] Under an argon atmosphere, a mixture of intermediate 5-7 (210 mg, 309 μmol), palladium acetate (6.96 mg, 31.0 μmol), n-butyldi(1-adamantyl)phosphine (22.2 mg, 61.9 μmol), potassium tert-pentanoate (88 mg, 619 mmol), and tert-amyl alcohol (3 mL) was heated to 120 °C and stirred for 4 h. The mixture was then concentrated under reduced pressure to remove the solvent, and the residue was purified by reversed-phase column chromatography (C18 column, acetonitrile:water = 1:2 to 2:1) to give the title compound (88 mg).

[0276] LC-MS: m / z (ESI): 598.3 [M+H] +

[0277] Step 8: Synthesis of intermediates 5-9

[0278] The mixture of intermediate 5-8 (20.0 mg, 33.5 μmol) and formic acid (1 mL) was stirred for 30 min at room temperature. The solvent was removed by concentration under reduced pressure to give the title compound (18.4 mg).

[0279] LC-MS: m / z (ESI): 552.6 [M+H] +

[0280] Step 11: Synthesis of Compound 5

[0281] A mixture of intermediates 5-9 (18.4 mg, 33.4 μmol), 5-10 (13.2 mg, 40.3 μmol), sodium cyanoborohydride (4.19 mg, 66.7 μmol), sodium acetate (5.5 mg, 66.7 μmol), glacial acetic acid (50 μL), and DMF (2 mL) was stirred at room temperature for 1 h. The residue was purified by reversed-phase column chromatography (C18 column, acetonitrile:water = 1:2 to 2:1) to give compound 5 (3.1 mg).

[0282] LC-MS: m / z (ESI): 864.1 [M+H] +

[0283] 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),7.74(d,J=1.7Hz,1H),7.70(dd,J=10.3,2.6Hz,1H),7.56(d,J=7.4Hz,2H),7.43(dd,J =9.0,5.4Hz,2H),7.37(d,J=10.7Hz,1H),7.25(d,J=9.8Hz,1H),7.23–7.17(m,2H),7.15(d,J=2.2Hz,1H),6.32(s,1H),6.05 (s,1H),5.33(d,J=5.8Hz,1H),5.09(dd,J=13.3,5.1Hz,1H),4.39–4.15(m,2H),3.82(s,4H),3.47(s,3H),3.24–3.06(m,4H) ,2.61(s,1H),2.38(d,J=13.4Hz,2H),2.22(d,J=7.3Hz,2H),2.08–1.93(m,2H),1.86–1.58(m,5H),1.45(s,1H),1.23(s,8H).

[0284] Example 6: Synthesis of Compound 6

[0285]

[0286] Step 1: Synthesis of 5-bromo-4-(4-(dimethoxymethyl)piperidin-1-yl)pyridine-2-amine (intermediate 6-2)

[0287] Using the same method as step 1 of Example 5, compound 6-1 (3.00 g, 15.7 mmol) and 4-(dimethoxymethyl)piperidine (3.75 g, 23.6 mmol) as starting materials, the title compound (4.8 g) was synthesized and post-treated to obtain the title compound.

[0288] LC-MS: m / z (ESI): 330.1 [M+H] +

[0289] Step 2: Synthesis of 4-(4-(dimethoxymethyl)piperidin-1-yl)-5-methylpyridin-2-amine (intermediate 6-3)

[0290] Under an argon atmosphere, a mixture of intermediate 6-2 (2.50 g, 7.57 mmol), methylboronic acid (2.27 g, 37.9 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (1.10 g, 1.51 mmol), potassium phosphate (3.21 g, 15.1 mmol), 1,4-dioxane (5 mL), and water (0.5 mL) was heated to 120 °C and stirred for 4 h. The solvent was removed by concentration under reduced pressure, and the residue was purified by reversed-phase column chromatography (C18 column, acetonitrile:water = 1:2 to 2:1) to give the title compound (1.60 g).

[0291] LC-MS: m / z (ESI): 266.2 [M+H] +

[0292] Step 3: Synthesis of 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-7-(4-(dimethoxymethyl)piperidin-1-yl)-6-methylimidazo[1,2-a]pyridine (intermediate 6-4)

[0293] Using the same method as step 3 of Example 5, intermediate 6-3 (890 mg, 3.35 mmol) and intermediate 2-7 (1.19 g, 4.02 mmol) as starting materials, the title compound (570 mg) was synthesized and post-treated to obtain the compound.

[0294] LC-MS:m / z(ESI):462.3 / 464.2[M+H] +

[0295] Step 4: Synthesis of (R)-1-(2-(4-((7-(4-(dimethoxymethyl)piperidin-1-yl)-6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethane-1-ol (intermediate 6-5)

[0296] Using the same method as step 4 of Example 5, intermediate 6-4 (517 mg, 1.12 mmol) and (R)-5-fluoro-3-methylbenzo[c][1,2]oxaborane-1(3H)-ol (560 mg, 3.37 mmol) were used as starting materials to synthesize and post-process the title compound (370 mg).

[0297] LC-MS: m / z (ESI): 522.3 [M+H] +

[0298] Step 5: Synthesis of (R)-2-((3-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-7-(4-(dimethoxymethyl)piperidin-1-yl)-6-methylimidazo[1,2-a]pyridine (intermediate 6-6)

[0299] Using the same method as step 5 of Example 5, intermediate 6-5 (370 mg, 709 μmol) and 5-bromo-3-fluoro-2-nitropyridine (314 mg, 1.42 mmol) were used as starting materials to synthesize and post-process the title compound (510 mg).

[0300] LC-MS:m / z(ESI):722.3 / 724.2[M+H] +

[0301] Step 6: Synthesis of (R)-5-bromo-3-(1-(2-(4-((7-(4-(dimethoxymethyl)piperidin-1-yl)-6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)pyridine-2-amine (intermediates 6-7)

[0302] Using the same method as step 6 of Example 5, intermediate 6-6 (510 mg, 706 μmol) was used as a starting material to synthesize and post-process the title compound (320 mg).

[0303] LC-MS:m / z(ESI):692.2 / 694.3[M+H] +

[0304] Step 7: Synthesis of intermediates 6-8

[0305] Using the same method as step 7 of Example 5, intermediate 6-7 (35 mg, 50.5 μmol) was used as a starting material to synthesize and post-process the title compound (25 mg).

[0306] LC-MS: m / z (ESI): 612.3 [M+H] +

[0307] Step 8: Synthesis of intermediates 6-9

[0308] Using the same method as step 8 of Example 5, intermediate 6-8 (30 mg, 49.0 μmol) was used as a starting material to synthesize and post-process the title compound (26 mg).

[0309] LC-MS: m / z (ESI): 566.4 [M+H] +

[0310] Step 9: Synthesis of Compound 6

[0311] Compound 6 (2.72 mg) was synthesized and post-treated using intermediates 6-9 (10 mg, 17.7 μmol) and 4-16 (5.81 mg, 17.7 mmol) as starting materials, in accordance with step 9 of Example 5.

[0312] LC-MS: m / z (ESI): 878.6 [M+H] +

[0313] 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.08(s,1H),7.73–7.63(m,2H),7.59–7.49(m,2H),7.25–7.15(m,2H),7.07(d,J=9. 0Hz,2H),6.94(s,1H),6.31(s,1H),6.03(s,2H),5.31(d,J=7.0Hz,1H),5.05(dd,J=13.4,5.0Hz,1H),4.40–4.14(m,2H),3 .82 (s, 4H), 3.18 (d, J = 11.9 Hz, 2H), 3.08 (d, J = 14.9 Hz, 1H), 2.97–2.85 (m, 1H), 2.61 (s, 4H), 2.39 (dd, J = 15.6, 10.7 Hz, 3H), 2.27 (d, J = 7.0 Hz, 2H), 2.18 (s, 3H), 1.92 (d, J = 45.7 Hz, 4H), 1.72 (d, J = 6.2 Hz, 4H), 1.27 (d, J = 25.2 Hz, 6H). Example 7: Synthesis of Compound 7

[0314]

[0315] Step 1: Synthesis of 3-bromo-1-ethyl-1H-pyrazole (intermediate 7-2)

[0316] At 0 °C, iodoethane (2.55 g, 16.33 mmol) was added dropwise to a mixture of compound 7-1 (2 g, 13.61 mmol) and cesium carbonate (6.65 g, 20.41 mmol) in acetonitrile (20 mL). The reaction mixture was stirred at room temperature for 2.5 hours. The solution was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (2.2 g).

[0317] LC-MS: m / z (ESI): 175 / 177 [M+H] +

[0318] Step 2: Synthesis of 4-(1-ethyl-1H-pyrazol-3-yl)piperazine-1-carboxylic acid benzyl ester (intermediate 7-3)

[0319] Intermediate 7-2 (1.0 g, 5.71 mmol), tris(dibenzylacetone)palladium (523.18 mg, 571.34 μmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (531.97 mg, 1.14 mmol), and sodium tert-butoxide (1.10 g, 11.43 mmol) were dissolved in 20 mL of 1,4-dioxane solution. After purging with argon, the mixture was stirred overnight at 100 °C. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by normal-phase column chromatography (ethyl acetate: petroleum ether = 1:1) to give the title compound (542 mg).

[0320] LC-MS: m / z (ESI): 315 [M+H] +

[0321] Step 3: Synthesis of 4-(1-ethyl-4-formyl-1H-pyrazole-3-yl)piperazine-1-carboxylic acid benzyl ester (intermediate 7-4)

[0322] At 0 °C, phosphorus oxychloride (893.64 mg, 5.83 mmol) was slowly added dropwise to a 5 mL solution of intermediate 7-3 (610 mg, 1.94 mmol) in N,N-dimethylformamide. The reaction mixture was stirred at 95 °C for 4 hours. The reaction mixture was cooled to room temperature, quenched with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by normal-phase column chromatography (tetrahydrofuran: petroleum ether = 1:2) to give the title compound (590 mg).

[0323] LC-MS: m / z(ESI): 343 [M+H] +

[0324] Step 4: Synthesis of 4-(4-((3-bromo-1-methyl-1H-pyrazol-4-yl)(hydroxy)methyl)-1-ethyl-1H-pyrazol-3-yl)piperazine-1-carboxylic acid benzyl ester (intermediate 7-5)

[0325] Intermediate 2-5 (904.95 mg, 3.15 mmol) was dissolved in tetrahydrofuran (10 mL). Isopropyl magnesium chloride-lithium chloride complex (1.3 M tetrahydrofuran solution, 2.43 mL, 3.16 mmol) was added at 0 °C. After stirring at 0 °C for 0.5 hours under argon protection, a tetrahydrofuran solution of intermediate 7-4 (540 mg, 1.58 mmol) (1 mL) was added dropwise. The reaction mixture was stirred at 30 °C for 0.5 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by normal-phase column chromatography (tetrahydrofuran: petroleum ether = 0:1 to 2:3) to give the title compound (623 mg).

[0326] LC-MS: m / z (ESI): 503 / 505 [M+H] +

[0327] Step 5: Synthesis of 4-(4-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-1-ethyl-1H-pyrazol-3-yl)piperazine-1-carboxylic acid benzyl ester (intermediate 7-6)

[0328] At 0 °C, trifluoroacetic acid (389.36 mg, 3.41 mmol) and triethylsilane (529.44 mg, 4.55 mmol) were added sequentially to a solution of intermediate 7-5 (573 mg, 1.14 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at 50 °C for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by normal-phase column chromatography (tetrahydrofuran: petroleum ether = 2:3) to give the title compound (265 mg).

[0329] LC-MS: m / z(ESI): 487 / 489 [M+H] +

[0330] Step 6: Synthesis of (R)-4-(1-ethyl-4-((3-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-3-yl)piperazine-1-carboxylic acid benzyl ester (intermediate 7-7)

[0331] Intermediate 7-6 (204 mg, 418.64 μmol), (R)-5-fluoro-3-methylbenzo[c][1,2]oxaborane-1(3H)-ol (83.37 mg, 502.37 μmol), chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (21.45 mg, 41.86 μmol), and potassium carbonate (115.72 mg, 837.29 μmol) were added to 1,4-dioxane (2.5 mL) and water (5 drops). The mixture was stirred overnight at 80 °C under an argon atmosphere. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by normal-phase column chromatography (tetrahydrofuran: petroleum ether = 2:1) to give the title compound (246 mg).

[0332] LC-MS: m / z (ESI): 547 [M+H] +

[0333] Step 7: Synthesis of (R)-4-(4-((3-(2-(1-(((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1-ethyl-1H-pyrazol-3-yl)piperazine-1-carboxylic acid benzyl ester (intermediate 7-8)

[0334] Intermediate 7-7 (223 mg, 407.24 μmol) and 5-bromo-3-fluoro-2-nitropyridine (107.99 mg, 488.69 μmol) were dissolved in toluene (2 mL). A tetrahydrofuran solution of lithium tert-butoxide (2.2 M, 484 μmol, 0.22 mL) was added dropwise to the reaction mixture at -78 °C, and the mixture was stirred at 0 °C for 2 hours. The reaction was quenched by adding saturated ammonium chloride aqueous solution at 0 °C. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by normal-phase column chromatography (ethyl acetate: petroleum ether = 2:1) to give the title compound (196 mg).

[0335] LC-MS: m / z (ESI): 747 / 749 [M+H] +

[0336] Step 8: Synthesis of (R)-4-(4-((3-(2-(1-(((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1-ethyl-1H-pyrazol-3-yl)piperazine-1-carboxylic acid benzyl ester (intermediate 7-9)

[0337] Intermediate 7-8 (196 mg, 262.17 μmol), iron powder (73.20 mg, 1.31 mmol), and ammonium chloride (140.23 mg, 2.62 mmol) were added to ethanol (10 mL) and water (2 mL). The resulting mixture was stirred at 80 °C for 2 hours under an argon atmosphere. The reaction solution was cooled to room temperature, filtered, concentrated under reduced pressure, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (156 mg).

[0338] LC-MS: m / z(ESI): 717 / 719 [M+H] +

[0339] Step 9: Synthesis of intermediates 7-10

[0340] Under an argon atmosphere, a mixture of intermediate 7-9 (156 mg, 217 μmol), palladium acetate (14.6 mg, 65.2 μmol), n-butyldi(1-adamantyl)phosphine (46.6 mg, 130 μmol), potassium tert-pentanoate (61.7 mg, 434 mmol), and tert-amyl alcohol (3 mL) was heated to 120 °C and stirred for 4 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by reversed-phase column chromatography (C18 column, acetonitrile:water = 1:2 to 2:1) to give the title compound (90 mg).

[0341] LC-MS: m / z (ESI): 637.5 [M+H] +

[0342] Step 10: Synthesis of intermediates 7-11

[0343] Under a hydrogen atmosphere, a mixture of intermediate 7-10 (45.0 mg, 71.7 μmol), palladium on carbon (10% palladium loading, 15 mg, 14.1 μmol), and methanol (2 mL) was heated to 45 °C and stirred for 8 h. The palladium on carbon was removed by filtration, and the solvent was removed by concentration under reduced pressure. The residue was purified by reversed-phase column chromatography (C18 column, acetonitrile:water = 1:2 to 2:1) to give the title compound (10 mg).

[0344] LC-MS: m / z (ESI): 503.3 [M+H] +

[0345] Step 13: Synthesis of Compound 7

[0346] A mixture of intermediates 7-11 (9.00 mg, 17.9 μmol), 7-12 (9.56 mg, 26.9 μmol), sodium cyanoborohydride (2.25 mg, 35.8 μmol), sodium acetate (2.94 mg, 35.8 μmol), and DMF (2 mL) was stirred at room temperature for 1 h and purified by reversed-phase column chromatography (C18 column, acetonitrile:water = 1:2 to 2:1) to obtain compound 7 (4.6 mg).

[0347] LC-MS: m / z (ESI): 842.8 [M+H] +

[0348] 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),7.69(dd,J=10.5,2.7Hz,1H),7.62(dd,J=11.8,7.1Hz,1H),7.57(s,1H),7.51(d,J=8 .3Hz,1H),7.36(d,J=1.7Hz,1H),7.22–7.11(m,2H),7.07(s,1H),6.26(s,1H),6.08(s,2H),5.30(d,J=6.8Hz,1H),5.05(dd ,J=13.2,5.1Hz,1H),4.39–4.12(m,2H),3.88(s,7H),3.23(s,4H),2.98–2.72(m,3H),2.70–2.53(m,2H),2.42–2.30(m,3H) ,2.23(s,2H),2.06–1.91(m,1H),1.83(d,J=12.2Hz,2H),1.69(d,J=6.2Hz,3H),1.45(d,J=12.3Hz,1H),1.27–1.15(m,8H).

[0349] Biological activity and related property test examples

[0350] Test Example 1: Experiment on the inhibition of tumor cell proliferation by the disclosed compound

[0351] Brief introduction to the experimental principle:

[0352] The compound was co-incubated with EML4-ALK V1[G1202R / L1196M] / BaF3 (ALK[G1202R / L1196M] mutant tumor cells) and NCI-H3122 (ALK wild-type tumor cells) for 3 or 5 days, respectively. After incubation, ATP levels in the live cells were quantified using a Cell Viability Detection Kit to reflect the effect of the compound on tumor cell proliferation.

[0353] Experimental apparatus:

[0354] Perkin Elmer Envision microplate reader; Eppendorf 5810R centrifuge; Countstar automated cell counter.

[0355] Experimental materials:

[0356]

[0357] Experimental methods:

[0358] NCI-H3122 cells were diluted with RPMI 1640 medium containing 10% FBS and added to 96-well plates (90 μL / well), with a cell count of 1000 cells / well. The cells were incubated overnight at 37°C in a 5% CO2 incubator. The test compounds were diluted to different concentrations in dimethyl sulfoxide (DMSO) (test compound preparation: starting with a final concentration of 1 μM, serially diluted 4-fold, with the compound concentration ranging from 1000 nM to 0.02 nM, and the final DMSO concentration being 0.25% v / v), and then added to the 96-well plates. After 5 days of incubation, 50 μL / well of a CellViability Detection Kit was added and incubated at room temperature for 10 minutes. The light signal value (Lum) was read using an Envision microplate reader, and the inhibition rate and half-maximal inhibitory concentration (IC50) were calculated. 50 ).

[0359] EML4-ALK V1[G1202R / L1196M] / BaF3 cells were diluted with RPMI 1640 medium containing 10% FBS and added to 96-well plates (90 μL / well), with a cell count of 5000 cells / well. The test compounds were diluted to different concentrations in dimethyl sulfoxide (DMSO) (test compound preparation: starting with a final concentration of 1 μM, serially diluted 3-fold, with the compound concentration ranging from 1000 nM to 0.15 nM, and the final DMSO concentration being 0.25% v / v), and then added to the 96-well plates. After 3 days of incubation, 50 μL / well of a Cell Viability Detection Kit was added and incubated at room temperature for 10 minutes. The light signal value (Lum) was read using an Envision microplate reader, and the inhibition rate and half-maximal inhibitory concentration (IC50) were calculated. 50 ).

[0360] Data Analysis:

[0361] The inhibition rate was calculated, and the IC50 of the compound was obtained by fitting the data using XLfit software. 50 .

[0362] The experiment included blank wells and DMSO wells. The blank wells contained 100 μL of RPMI Medium 1640 medium with 10% FBS, which was considered to have an inhibitory effect of 100% on tumor cell growth. The DMSO wells contained 0.25% v / v DMSO, which was considered to have an inhibitory effect of 0% on tumor cell growth.

[0363] Inhibition rate = 100 * (Lum) max -Lum 化合物 ) / (Lum max -Lum min )%

[0364] Among them, Lum max Lum refers to the light signal value containing cells and a 0.25% v / v DMSO aperture. 化合物 Lum refers to the light signal value of pores containing compounds and cells. min This refers to the light signal value in wells containing culture medium and 0.25% v / v DMSO.

[0365] The inhibitory effect of this disclosed compound on tumor cell growth was determined through the above experiments, and the measured IC50 value was... 50 value.

[0366] Table 1. IC50 of the compounds in the examples against tumor cell growth inhibition

[0367]

[0368] In the table above, the symbols used to indicate inhibitory activity have the following meanings:

[0369] "++++" indicates the IC50 value of the test compound on the enzyme inhibitory activity. 50 The range is: IC 50 <100nM.

[0370] "+++" indicates the IC50 value of the test compound on the enzyme inhibitory activity. 50 The range is: 100≤IC 50 <500nM.

[0371] "++" indicates the IC50 value of the test compound on the enzyme inhibitory activity. 50 The range is: 500≤IC 50 <1000nM.

[0372] A "+" indicates that the test compound has an inhibitory effect on the enzyme (IC50). 50 The range is: 1000≤IC 50 <10000nM.

[0373] "-" indicates the IC50 value of the test compound on the enzyme inhibitory activity. 50The range is: 10000nM <IC 50 .

[0374] Tests have shown that the disclosed compounds have an inhibitory effect on tumor cells with ALK WT and ALK[G1202R / L1196M] mutations.

[0375] Test Example 2: Assay of the ALK degradation activity of the disclosed compound against BaF3 EML4-ALK V1 [G1202R / L1196M] cells

[0376] Cells and Materials: Mouse BaF3 EML4-ALK V1 [G1202R / L1196M] (CBP73271) was purchased from Nanjing Kebai. RPMI 1640 medium (L240KJ) was purchased from Yuanpei, fetal bovine serum (S211201) was purchased from Longsa, and 0.25% Trypsin-EDTA (25200-072) was purchased from Gibco (USA). ALK (31F12) Mouse mAb (3791S) and β-Actin (13E5) Rabbit mAb (4970S) were purchased from CST (USA).

[0377] Cell culture: BaF3 EML4-ALK V1 [G1202R / L1196M] cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum at 37°C and 5% CO2. Only cells in the logarithmic growth phase could be used for experiments.

[0378] Experimental methods: Western blot was used to detect the degradation activity of the compound on intracellular ALK.

[0379] BaF3 EML4-ALK V1 [G1202R / L1196M] cells in logarithmic growth phase were resuspended in fresh RPMI 1640 medium containing 10% fetal bovine serum, and the cell density was adjusted. The cells were then cultured at a density of 5 × 10⁶ cells / year. 5 Cells were seeded per well in 12-well plates. The compound was diluted with DMSO and added to the cell plate to a final concentration of 50 nM for the compound and 0.1% for the DMSO. Control wells contained 0.1% DMSO. After culturing the 12-well plates at 37°C and 5% CO2 for 16 hours, cells were harvested, and the expression level of ALK in each well was detected by Western blot.

[0380] ImageJ software was used to perform grayscale analysis on the Western blotting bands.

[0381] Target protein degradation rate (%) = 100% - 100% × Normalized reading of experimental wells / Normalized reading of control wells

[0382] Normalized read value = Target protein read value / Internal reference β-Actin read value

[0383] Table 2 ALK protein degradation activity

[0384] serial number ALK protein degradation rate (%) Compound 4 99.68

Claims

1. A compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, in, Ring A is selected from phenylene or 5-6-membered heteroaryl groups; Ring B is a five-membered heteroaryl group containing at least one N atom; Ring C is selected from 5-15 membered heterocyclic rings or 5-12 membered heteroaromatic rings; Y 1 Selected from O, NR 6 or CR 7 R 7b ; Y 2 Selected from O, NR 8 or CR 9 R 9b ; R 1 and R 2 Independently selected from H or C1-C6 alkyl groups; Each R 3 Independently selected from halogens or C1-C6 alkyl groups; Or, R 1 R 3 The atoms bonded to it together form C5-C 10 Cycloalkenyl or 5-10 membered heterocycles; Each R 4 Independently selected from C1-C6 alkyl groups; Or, R 3 R 4 The atoms bonded to it together form C5-C 10 Cycloalkenyl or 5-10 membered heterocycles; Each R 5 Independently selected from halogens, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic groups, wherein the OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic group is optionally replaced by R. 5a replace; Each R 5a It is independently selected from halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, or 4-7 membered heterocyclic groups; R 6 and R 8 Independently selected from H or C1-C6 alkyl groups; R 7 R 7b R 9 R 9b Independently selected from H, halogens, or C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted with halogens; or, R 9 R 9b The atoms connected to it form together Or C3-C6 cycloalkyl, the Alternatively, the C3-C6 cycloalkyl group may be replaced by a halogen or a C1-C6 alkyl group; or, R 5 R 9 The atoms bonded to it together form C5-C 10 Cycloalkenyl or 5-10 membered heterocycles; m, n, and p are independently selected from 0, 1, 2, or 3; L is the connecting unit, and its structure is -X 1 -Het 1 -X 2 -Het 2 -X 3 -Het 3 -X 4 -Het 4 -X 5 -; X 1 X 2 X 3 X 4 X 5 Independently selected from bonds, O, S, NR 10 , C(O), C(S) or C1-C6 alkylene; R 10 It is a C1-C6 alkyl group; Het 1 Het 2 Het 3 Het 4 Independently selected from the bond, C3-C 12 Cycloalkylene or 4-12 membered heterocyclic alkylene, wherein the C3-C 12 The cycloalkyl or 4-12 membered heterocyclic group may optionally be substituted with halogen or C1-C6 alkyl; ULM is the E3 ubiquitin ligase binding unit, and its structure is as follows: X 6 Selected from bonds, -C(O)NH-, -NH-, or O; Z 6 Selected from N or CH; Het 5 Selected from phenylene, 5-15-membered heterocyclic group or 5-15-membered heteroaryl group, wherein the phenylene, 5-15-membered heterocyclic group or 5-15-membered heteroaryl group is optionally R 11 replace; R 11 Selected from =O or R 12 ;R 12 Selected from halogens, NH2, OH, C1-C6 alkyl or C3-C6 cycloalkyl, wherein the NH2, OH, C1-C6 alkyl or C3-C6 cycloalkyl is optionally converted by R. 12a replace; R 12a It is selected from halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, or C3-C6 cycloalkyl groups.

2. The compound of formula (I) according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, wherein, Y 1 Selected from O.

3. The compound of formula (I) according to claim 1 or 2, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, Y 2 Selected from CH2.

4. The compound of formula (I) according to any one of claims 1 to 3, its stereoisomers or pharmaceutically acceptable salts thereof, wherein, R 1 and R 2 It is independently selected from H or CH3.

5. The compound of formula (I) according to any one of claims 1 to 4, its stereoisomers or pharmaceutically acceptable salts thereof, wherein, Ring A is a phenylene oxide.

6. The compound of formula (I) according to any one of claims 1 to 5, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R 3 It is a halogen.

7. The compound of formula (I) according to any one of claims 1 to 6, its stereoisomers or pharmaceutically acceptable salts thereof, wherein, Ring B is an imidazolyl group; or ring B is 8. The compound of formula (I) according to any one of claims 1 to 7, its stereoisomers or pharmaceutically acceptable salts thereof, wherein, R 4 It is CH3.

9. The compound of formula (I) according to any one of claims 1 to 8, its stereoisomers or pharmaceutically acceptable salts thereof, wherein, Cycle C is selected from 5-membered heteroaryl rings or 6-membered 5-membered heteroaryl rings; or cycle C is selected from... Where a is the site covalently linked to the pyridyl group, and b is the site covalently linked to the Y group. 2 The covalently linked site, c is the site covalently linked to ULM-L.

10. The compound of formula (I) according to any one of claims 1 to 9, its stereoisomers or pharmaceutically acceptable salts thereof, wherein, R 5 Selected from halogens, C1-C6 alkyl groups, or C3-C6 cycloalkyl groups, wherein the C1-C6 alkyl group or C3-C6 cycloalkyl group is optionally converted by R. 5a replace.

11. The compound of formula (I) according to any one of claims 1 to 10, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R 5a Selected from C3-C6 cycloalkyl groups.

12. The compound of formula (I) according to any one of claims 1 to 11, its stereoisomers or pharmaceutically acceptable salts thereof, wherein, Selected from 13. The compound of formula (I) according to any one of claims 1 to 12, its stereoisomers or pharmaceutically acceptable salts thereof, wherein, L is selected from key, 14. The compound of formula (I) according to any one of claims 1 to 12, its stereoisomers or pharmaceutically acceptable salts thereof, wherein, L is selected from L is selected from -Het 1 -Het 2 -X 3 -Het 3 -、-Het 1 -X 2 -Het 2 -、-Het 1 -X 2 -Het 2 -X 3 -or-Het 1 -Het 2 -X 3 -Het 3 -X 4 -; or, L is Among them, Het 2 Selected from C4-C6 cycloalkyl or 4-6 membered heterocyclic groups; X 3 X 4 Independently selected from bond, CH2, C(O) or O; T, U, V, W independently selected from CH or N; q and r independently selected from 0 or 1; or, L selected from 15. The compound of formula (I) according to any one of claims 1 to 14, its stereoisomers or pharmaceutically acceptable salts thereof, wherein, ULM is selected from The Optionally R 12 Replace; Z 1 Z 2 Z 3 Z 4 Z 5 Z 6 Independently selected from N or CR 12 W 1 W 2 Independently selected from CH2 or C(O), W 3 Selected from CH2, CH2CH2 or C(O), W 4 Selected from O, CH2 or NR 12 X 6 and R 12 As defined in claim 1; or, ULM is selected from 16. The compound of formula (I) according to any one of claims 1 to 15, its stereoisomers or pharmaceutically acceptable salts thereof, selected from the group consisting of compounds, their stereoisomers or pharmaceutically acceptable salts thereof.

17. The compound of formula (I) according to any one of claims 1 to 15, its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound is selected from the compound of formula (II), its stereoisomers or pharmaceutically acceptable salts thereof. in, R 1 R 2 R 3 R 4 R 5 The definitions of m, n, p, L and ULM are the same as in claim 1.

18. The compound of formula (I) according to any one of claims 1 to 15, its stereoisomers or pharmaceutically acceptable salts thereof, selected from the compound of formula (III), its stereoisomers or pharmaceutically acceptable salts thereof. in, R 1 R 2 R 3 R 4 R 5 The definitions of m, n, p, L and ULM are the same as in claim 1.

19. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 18, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

20. Use of the compound of formula (I) according to any one of claims 1 to 18, its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19 in the preparation of a medicament for the prevention or treatment of ALK-related diseases.

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