Heterocyclic compounds as tyrosine kinase inhibitors

Abstract

The invention relates to a heterocyclic compound, a pharmaceutical composition containing the heterocyclic compound, a preparation method of the heterocyclic compound and application of the heterocyclic compound as a TRK inhibitor. The compound is a heterocyclic compound as shown in formula I, or pharmaceutically acceptable salt, prodrug, solvent compound, polymorph, isomer and stable isotope derivative thereof. The present invention also relates to the use of said compounds for the treatment or prevention of TRK-mediated related diseases, such as cancer, and methods of using the same to treat said diseases.

Description

Technical Field

[0001] This invention relates to a class of heterocyclic compounds, pharmaceutical compositions containing the same, methods for their preparation, and their use as TRK inhibitors. The invention also relates to methods for treating or preventing TRK-mediated diseases (e.g., cancer) using said compounds. Background Technology

[0002] This invention provides novel compounds as inhibitors of TRK (Tropomyosin-related kinase). TRK is a tyrosine kinase of neurotrophic receptors present in various tissues, activating multiple downstream processes during cell proliferation and survival. The TRK proto-oncogene family has three members: TRK A, B, and C, encoded by NTRK1, NTRK2, and NTRK3, respectively. The binding of neurotrophic factors to TRK proteins leads to receptor dimerization, phosphorylation, and activation of downstream signaling pathways, including the Ras / MAPK, PI3K / AKT, and PLCγ pathways, thereby regulating cell proliferation, differentiation, metabolism, and apoptosis (Brodeur GM, Minturn JE, Ho R, et al. Clinical Cancer Research, 2009, 15, 3244-50). Genomic analysis of kinase fusions has confirmed that NTRK gene fusions occur in a variety of cancers, including glioma, hepatobiliary carcinoma, papillary thyroid carcinoma, colon cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, pancreatic cancer, sarcoma, and melanoma (Khotskaya, YB et al. Pharmacology & Therapeutics, 2017, 173, 58-66). Therefore, the research and development of TRK inhibitors has great potential and a broad market prospect for treating various tumors containing NTRK fusion proteins.

[0003] Larotrectinib is the first oral TRK inhibitor approved by the U.S. Food and Drug Administration (FDA) with a strong and long-term clinical profile, indicated for patients with TRK fusion-positive tumors of all ages and in multiple tumor types. An evaluation of 206 evaluable adult and pediatric patients with TRK fusion-positive tumors across 21 different tumor types showed an overall response rate (ORR) of 75%, including 22% complete responses (n=45). The median duration of response (DoR) was 49.3 months, and the median progression-free survival (PFS) was 35.4 months. Entrectinib received accelerated approval from the U.S. Food and Drug Administration (FDA) in August 2019 for the treatment of NTRK fusion-positive solid tumors and ROS1-positive metastatic non-small cell lung cancer (NSCLC). Clinical results showed an overall response rate (ORR) of 57.4% for entrectinib, with 25% of patients achieving a complete response (CR), including an ORR of 54.5% in patients with brain metastases. In patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC), the objective response rate (ORR) was as high as 77.4%, with a median duration of response (mDOR) of 24.6 months. Although larotrectinib and entrectinib have demonstrated excellent clinical efficacy, acquired resistance has been reported. Therefore, further development of highly active, low-side-effect, and mutation-resistant TRK small molecule inhibitors is of great significance. Summary of the Invention

[0004] The object of this invention is to provide a compound of Formula I, isomers thereof, prodrugs, solvates, stable isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, which can be used as TRK inhibitors. in: R 1 R 2 Each of the following groups is independently selected from hydrogen, halogen, cyano, -C(O)NH2, C1-C4 alkyl, C1-C4 alkoxy, phenyl, 5-6 heteroaryl, C3-C6 cycloalkyl, and 4-8 heterocyclic groups; wherein the C1-C4 alkyl, C1-C4 alkoxy, phenyl, 5-6 heteroaryl, C3-C6 cycloalkyl, and 4-8 heterocyclic groups are optionally substituted by one or more substituents selected from halogen, cyano, alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, and 4-6 heterocyclic groups; Y is selected from O or -C(R) 4a R 4b )-; where R 4a R 4b Each is independently selected from hydrogen, C1-C3 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic groups; X 1 X2 Each is independently selected from C or N; and X 1 X 2 Not both N; R 3 Selected from C6-C10 aryl or 5-10 heteroaryl groups; wherein the C6-C10 aryl or 5-10 heteroaryl groups are unsubstituted or surrounded by 1-3 R groups. x Replaced; wherein R x Each is independently selected from halogen, cyano, C1-C4 alkoxy, C1-C4 alkylamine, C1-C4 alkyl, C3-C6 cycloalkyl, and 4-6 membered saturated heterocyclic groups; wherein the C1-C4 alkoxy, C1-C4 alkylamine, C1-C4 alkyl, C3-C6 cycloalkyl, and 4-6 membered saturated heterocyclic groups are unsubstituted or surrounded by 1-3 halogens, C1-C3 alkoxy groups, or -NR groups. 5a R 5b Replaced; where R 5a R 5b Each is independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, and 4-6 membered saturated heterocyclic groups;

[0005] Preferably, the present invention relates to the aforementioned compound of formula (I), its isomers, prodrugs, solvates, stable isotopic derivatives, or pharmaceutically acceptable salts, wherein: R 1 R 2 Each is independently selected from hydrogen, fluorine, chlorine, and bromine; Y is selected from O or -C(R) 4a R 4b )-; where R 4a R 4b Each is independently selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic groups; X 1 X 2 Each is independently selected from C or N; and X 1 X 2 Not both N; R 3 Selected from phenyl or a 6-membered heteroaryl group containing 1-2 nitrogen atoms; wherein the phenyl or 6-membered heteroaryl group is unsubstituted or surrounded by 1-3 R atoms. x Replaced; wherein R x Each is independently selected from fluorine, chlorine, C1-C4 alkoxy, and C1-C4 alkylamine; wherein the C1-C4 alkoxy and C1-C4 alkylamine are unsubstituted or surrounded by 1-3 halogens, C1-C3 alkoxy, or -NR. 5a R 5b Replaced; where R 5a R 5bEach is independently selected from hydrogen, C1-C3 alkyl, C3-C4 cycloalkyl, and 4-6 membered saturated heterocyclic groups;

[0006] More preferably, the present invention relates to the aforementioned compound of formula (I), its isomers, prodrugs, solvates, stable isotopic derivatives, or pharmaceutically acceptable salts, wherein: R 1 R 2 Each is independently selected from hydrogen, fluorine, and chlorine; Y is selected from O or -CH2-; X 1 X 2 Each is independently selected from C or N; and X 1 X 2 Not both N; R 3 Selected from phenyl, pyridyl, or pyrimidinyl; wherein the phenyl, pyridyl, or pyrimidinyl group is unsubstituted or surrounded by one R group. x Replaced; wherein R x Selected from C1-C2 alkoxy and C1-C2 alkylamine groups; wherein the C1-C2 alkoxy and C1-C2 alkylamine groups are unsubstituted or substituted with hydroxyl or dimethylamine groups.

[0007] More preferably, the present invention relates to the aforementioned compound of formula (I), its isomers, prodrugs, solvates, stable isotopic derivatives, or pharmaceutically acceptable salts, wherein: R 1 R 2 Each is independently selected from hydrogen and fluorine; Y is selected from O or -CH2-; X 1 X 2 Each is independently selected from C or N; and X 1 X 2 Not both N; R 3 Selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyrimidinyl, or 5-pyrimidinyl; wherein the phenyl, 2-pyridyl, 3-pyridyl, 4-pyrimidinyl, or 5-pyrimidinyl group is unsubstituted or surrounded by one R group. x Replaced; wherein R x Selected from dimethylaminoethylamino, dimethylaminoethoxy, and hydroxyethylamino.

[0008] More preferably, the present invention relates to the aforementioned compound of formula (I), its isomers, prodrugs, solvates, stable isotopic derivatives, or pharmaceutically acceptable salts, wherein: R 1 R 2 Each is independently selected from hydrogen and fluorine; Y is selected from O or -CH2-; X 1 X 2 Each is independently selected from C or N; and X 1 X 2 Not both N; R 3 Selected from

[0009] Most preferably, the present invention relates to the aforementioned compound of formula (I), its isomers, prodrugs, solvates, stable isotopic derivatives, or pharmaceutically acceptable salts selected from:

[0010] The compounds of this invention are TRK inhibitors, and therefore can be used to treat or prevent TRK-mediated diseases, such as tumors, especially hematologic malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, and glioma.

[0011] The present invention further relates to a pharmaceutical composition comprising the compound of the present invention or an isomer thereof, a prodrug, a stable isotope derivative thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, and excipient.

[0012] Another aspect of the present invention relates to the use of compounds of general formula (I) or isomers thereof, prodrugs, solvates, stable isotope derivatives thereof or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions thereof in the preparation of medicaments, wherein the medicaments are used to treat or prevent TRK-mediated diseases, such as tumors, especially hematologic malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, and glioma.

[0013] Another aspect of the invention relates to the use of a compound of general formula (I) or a tautomer thereof, meso, racemic, enantiomer, diastereomer, mixture thereof, pharmaceutically usable salt thereof, or the use of said pharmaceutical composition in the preparation of a medicament for treating and / or preventing tumors.

[0014] According to the present invention, the drug can be any dosage form, including but not limited to tablets, capsules, solutions, lyophilized preparations, and injections.

[0015] The pharmaceutical formulations of the present invention can be administered in dose units containing a predetermined amount of the active ingredient per dose unit. Such units may contain, for example, 0.5 mg to 1 gram, preferably 1 mg to 700 mg, and particularly preferably 5 mg to 300 mg of the compound of the present invention, depending on the condition being treated, the method of administration, and the patient's age, weight, and condition. Alternatively, the pharmaceutical formulation can be administered in dose units containing a predetermined amount of the active ingredient per dose unit. Preferred dose unit formulations are those containing the daily dose or fractional dose, or a corresponding fraction thereof, as indicated above. Furthermore, this type of pharmaceutical formulation can be prepared using methods known in the pharmaceutical industry.

[0016] The pharmaceutical formulations of the present invention are suitable for administration by any desired and suitable method, such as oral (including oral or sublingual), rectal, nasal, local (including oral, sublingual, or percutaneous), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) administration. Such formulations can be prepared using all methods known in the pharmaceutical field, for example, by combining the active ingredient with one or more excipients or one or more adjuvants.

[0017] The present invention also relates to a method for treating or preventing TRK-mediated diseases (e.g., tumors, especially hematologic malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, glioma), comprising administering to a patient in need a therapeutically effective amount of the compound of the present invention or an isomer thereof, a prodrug, a solvate, a stable isotope derivative or a pharmaceutically acceptable salt, or a pharmaceutical composition of the present invention.

[0018] Another aspect of the present invention relates to compounds of general formula (I), or isomers thereof, prodrugs, solvates, stable isotope derivatives or pharmaceutically acceptable salts, or pharmaceutical compositions thereof, for the treatment or prevention of TRK-mediated diseases, such as tumors, especially hematologic malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, and glioma.

[0019] Another aspect of the present invention relates to compounds of general formula (I) for the treatment and / or prevention of diseases such as tumors, or tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, and pharmaceutically usable salts thereof. Preparation process

[0020] The present invention also provides a method for preparing the compound.

[0021] Process 1

[0022] Where R 1 R 2 R 3 X 1 X2 Y is defined as described above; Z represents borate group, borate ester group, or alkyltin group; X 3 It is a halogen such as F, Cl, Br, or a leaving group such as methanesulfonate group, trifluoromethanesulfonate group, benzyl sulfonate group, etc.; X 4 It consists of halogens such as Cl, Br, and I.

[0023] first step:

[0024] Compound (I) is dissolved in a solvent (such as tetrahydrofuran), and under the protection of an inert gas (such as nitrogen or argon), a base (such as sodium hydrogen) is added and stirred for 0 to 2 hours. Compound (II) is then added to the reaction solution and reacted at 0°C to 50°C for 0.5 to 20 hours to obtain compound (III).

[0025] Step Two:

[0026] Compound (III) was dissolved in a solvent (such as acetonitrile and N,N-dimethylformamide), and under the protection of an inert gas (such as nitrogen or argon), a halogenating agent (such as bromosuccinimide) was added, and the mixture was reacted at 0℃ to 60℃ for 1 to 20 hours to obtain compound (IV).

[0027] Step 3:

[0028] Compound (IV) and compound (V) are dissolved in a solvent (such as dioxane / water or toluene), and a base (such as potassium carbonate) or no base is added. A catalyst (such as [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride or tetraphenylphosphinopalladium) is added. The system is purged three times with an inert gas (such as nitrogen or argon), and the reaction is carried out at 60-130°C for 1-20 hours to obtain compound (VI).

[0029] Process 2

[0030] Where R 1 R 2 R 3 X 1 X 2 The definitions are as described above; Z represents borate group, borate ester group, alkyltin group, etc.; X 3 It is a halogen such as Cl, Br, or a leaving group such as methanesulfonate group, trifluoromethanesulfonate group, benzylmethanesulfonate group, etc.; X 4 It consists of halogens such as Cl, Br, and I.

[0031] first step:

[0032] Compounds (VII) and (II) were dissolved in a solvent (such as N,N-dimethylacetamide), and a catalyst (such as cuprous iodide and palladium dichloride bis(triphenylphosphine)) and a base (such as triethylamine) were added under the protection of an inert gas (such as nitrogen or argon). The system was evacuated and replaced three times with an inert gas (such as nitrogen or argon). The reaction was carried out in an oil bath (60-130°C) for 1-20 hours to obtain compound (VIII).

[0033] Step Two:

[0034] Compound (VIII) is dissolved in a solvent (such as methanol), a catalyst (such as palladium acetate) is added, and the mixture is replaced three times with hydrogen. The reaction is carried out at 0–60 °C for 1–10 hours under a hydrogen atmosphere to obtain compound (IX).

[0035] Step 3: Compound (IX) is dissolved in a solvent (such as acetonitrile and N,N-dimethylformamide), and under the protection of an inert gas (such as nitrogen or argon), a halogenating agent (such as bromosuccinimide) is added, and the reaction is carried out at 0℃ to 60℃ for 1 to 20 hours to obtain compound (X).

[0036] Step 4: Compounds (X) and (V) are dissolved in a solvent (such as dioxane / water or toluene), with the addition of a base (such as potassium carbonate) or without the addition of a base, and a catalyst ([1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride or tetraphenylphosphinopalladium). The system is evacuated and purged three times with an inert gas (such as nitrogen or argon). The reaction is carried out in an oil bath (60-130°C) for 1-20 hours to obtain compound (XI). Detailed Implementation

[0037] Unless otherwise stated, the terms used in the specification and claims have the following meanings. The notation “Cx-Cy” as used herein represents a range of carbon atoms, where x and y are integers. For example, C3-C8 cyclogroups represent cyclogroups having 3-8 carbon atoms, and -C0-C2 alkyl groups represent alkyl groups having 0-2 carbon atoms, where -C0 alkyl refers to a single chemical bond.

[0038] "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 20 carbon atoms, such as straight-chain and branched groups with 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, and their various branched isomers. The alkyl group may be optionally substituted or unsubstituted.

[0039] "Cycloyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group comprising 3 to 12 ring atoms, for example, 3 to 12, 3 to 10, 3 to 8, or 3 to 6 ring atoms, or 3, 4, 5, or 6-membered rings. Non-limiting examples of monocyclic cyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc. Cycloyl groups can be optionally substituted or unsubstituted.

[0040] "Heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group comprising 3 to 20 ring atoms, for example, 3 to 16, 3 to 12, 3 to 10, 3 to 8, or 3 to 6 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), but excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, it comprises 3 to 12 ring atoms, wherein 1 to 4 are heteroatoms; more preferably, the heterocyclic group comprises 3 to 10 ring atoms; even more preferably, it comprises 3 to 8 ring atoms; most preferably, it is a 5-membered or 6-membered ring, wherein 1 to 4 are heteroatoms; more preferably, 1 to 3 are heteroatoms; and most preferably, 1 to 2 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include heterocyclic groups of spirocyclic, fused, and bridged rings.

[0041] The heterocyclic ring may be fused to an aryl, heteroaryl, or cyclocyclic ring, wherein the ring connected to the parent structure is a heterocyclic group. Non-limiting examples include: The heterocyclic group can be optionally substituted or unsubstituted.

[0042] "Aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group, a polycyclic (i.e., a ring with adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl, with phenyl being the most preferred. The aryl ring may be fused to a heteroaryl, heterocyclic, or cyclocyclic ring, wherein the ring connected to the parent structure is an aryl ring. Non-limiting examples include: The aryl group can be substituted or unsubstituted.

[0043] "Heteroaryl" refers to a heteroaryl system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur, and nitrogen. Preferably, it is 5 to 10-membered. More preferably, the heteroaryl group is 5- or 6-membered, such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, etc., wherein the heteroaryl ring can be fused to an aryl, heterocyclic, or cyclic ring, wherein the ring connected to the parent structure is the heteroaryl ring. Non-limiting examples include: The heteroaryl group can be optionally substituted or unsubstituted.

[0044] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0045] “Cyano” refers to -CN.

[0046] "Alynyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon triple bond, which may include 2 to 20 carbon atoms, for example, straight-chain or branched groups with 2 to 18, 2 to 12, 2 to 8, 2 to 6, or 2 to 4 carbon atoms. It may contain 1 to 3 carbon-carbon triple bonds, preferably 1. The term "C2-4 ynyl" refers to an ynyl group having 2 to 4 carbon atoms. Non-limiting examples include ethynyl, propynyl, butynyl, and butyn-2-yl, 3-methylbutynyl.

[0047] "Heteroalkyl" refers to a stable straight-chain or branched hydrocarbon group composed of a specified number of carbon atoms and at least one heteroatom selected from oxygen, nitrogen, and sulfur. The nitrogen and sulfur atoms may be oxidized or quaternized. The heteroatoms oxygen, nitrogen, and sulfur may be located at any internal position of the heteroalkyl group or at a position where the alkyl group is attached to the rest of the molecule. Two or more heteroatoms may be independent or continuous.

[0048] "Alkoxy" refers to the alkyl group connected by an oxygen bridge, including alkyloxy, cycloalkyloxy and heterocycloalkyloxy, and thus "alkoxy" includes the definitions of the above alkyl, heterocycloalkyl and cycloalkyl groups.

[0049] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0050] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0051] The substituents include, but are not limited to, alkyl, alkenyl, alkoxy, halogen, hydroxyl, amino, cyano, and mercapto groups.

[0052] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0053] The "room temperature" mentioned in this invention refers to 15-30℃.

[0054] The "stable isotope derivatives" described in this invention include: isotope-substituted derivatives obtained by replacing any hydrogen atom in Formula I with 1-5 deuterium atoms, isotope-substituted derivatives obtained by replacing any carbon atom in Formula I with 1-3 carbon-14 atoms, or isotope-substituted derivatives obtained by replacing any oxygen atom in Formula I with 1-3 oxygen-18 atoms.

[0055] The “pharmaceutically acceptable salts” described in this invention are discussed in Berge, et al., “Pharmaceutically Acceptable Salts”, J. Pharm. Sci., 1977, 66, 1-19, and are obvious to medicinal chemists. The salts described are substantially non-toxic and provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism, or excretion. The pharmaceutically acceptable salts of this invention can be synthesized by conventional chemical methods.

[0056] Generally, salts can be prepared by reacting a free base or acid with an equistoichiometric or excess amount of an acid (inorganic or organic) or base in a suitable solvent or solvent combination.

[0057] The "optical isomers" of this invention include meso compounds, racemic compounds, enantiomers, diastereomers, and mixtures thereof of the compounds of formula (I) of this invention.

[0058] This invention includes any polymorph of the compound or its salts, as well as any hydrates or other solvates.

[0059] In this invention, the term "patient" generally refers to mammals, especially humans.

[0060] In this article, the term "tumor" includes both benign and malignant tumors, such as cancer.

[0061] In this article, the term "cancer" includes various TRK-mediated tumors, including but not limited to hematologic malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, and glioma.

[0062] In this document, the term "therapeuticly effective amount" refers to the amount of the compound of the present invention that can effectively treat or prevent related diseases mediated by TRK.

[0063] Example

[0064] The present invention is further illustrated below by way of examples, but these examples do not limit the invention to the scope of the embodiments described. Experimental methods not specifically described in the following examples were performed according to conventional methods and conditions, or as selected according to the trade instructions. The structures of all compounds of the present invention can be determined by nuclear magnetic resonance (NMR). 1 Identification by 1H NMR and / or mass spectrometry (MS). 1 ¹H NMR chemical shifts (δ) were recorded in ppm (parts per million). NMR was performed using a Bruker AVANCE III 400 MHz spectrometer. Suitable solvents were selected from deuterated chloroform (CDCl₃), deuterated methanol (CD₃OD), and deuterated dimethyl sulfoxide (DMSO-d). 6 Tetramethylsilane was used as an internal standard (TMS).

[0065] Low-resolution mass spectrometry (MS) was performed using an Agilent 1260 HPLC / 6120 mass spectrometer with an Agilent ZORBAXXDB-C18 lens, 4.6 × 50 mm, 3.5 μm.

[0066] Gradient elution conditions 1: 0 minutes: 95% solvent A1 and 5% solvent B1; 1-2 minutes: 5% solvent A1 and 95% solvent B1; 2.01-2.50 minutes: 95% solvent A1 and 5% solvent B1. Percentages represent the volume percentage of a specific solvent in the total solvent volume. Solvent A1: 0.01% formic acid aqueous solution; Solvent B1: 0.01% formic acid in acetonitrile solution; percentages represent the volume percentage of the solute in the solution.

[0067] Thin-layer silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. Column chromatography generally uses Yantai Huanghai 100-200 or 200-300 mesh silica gel as the support.

[0068] Preparative liquid chromatography (prep-HPLC) was performed using a Waters SQD2 mass spectrometry-guided high-performance liquid chromatograph, XBridge-C18; 30 x 150 mm preparative column, 5 μm; Method 1: acetonitrile-water (0.2% formic acid), flow rate 25 mL / min; Method 2: acetonitrile-water (0.8% ammonium bicarbonate), flow rate 25 mL / min.

[0069] The microwave reaction was performed using a CEM Discover-S 909105 microwave reactor.

[0070] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Shanghai Bid Pharmaceutical, Shanghai Aladdin Chemical, Shanghai Mairui Chemical, Bailingwei Chemical, and Anai Chemical.

[0071] Unless otherwise specified in the examples, all solvents used in the reactions are anhydrous solvents, purchased from Anai Chemical and Bailingwei Chemical. Unless otherwise specified, all transfers and uses of anhydrous solvents must be carried out under nitrogen protection.

[0072] Unless otherwise specified in the examples, the reactions were carried out under an argon or nitrogen atmosphere.

[0073] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0074] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0075] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0076] Unless otherwise specified in the examples, the reaction temperature is room temperature, and the temperature range is 15℃-30℃.

[0077] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent systems used in the reactions were A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system. The volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0078] The eluent system for column chromatography and the developing solvent system for thin-layer chromatography used to purify the compound include A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and small amounts of triethylamine and acidic or basic reagents can also be added for adjustment.

[0079] Intermediate 1

[0080] 3-Bromo-5-((2,5-difluorobenzyl)oxo)pyrazolo[1,5-a]pyrimidine

[0081] first step

[0082] 5-((2,5-difluorobenzyl)oxo)pyrazolo[1,5-a]pyrimidine 1a

[0083] Under nitrogen-protected ice-water bath conditions, compound 2,5-difluorobenzyl alcohol (1.00 g, 6.94 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), and sodium hydride (0.47 g, 9.47 mmol, dispersed in 60% kerosene) was added. After stirring for 30 minutes, 5-chloro-pyrazolo[1,5-a]pyrimidine (1.23 g, 6.32 mmol) was added. The reaction was brought to room temperature and stirred for 12 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution (5 mL), diluted with dichloromethane (50 mL), and then washed with saturated brine (50 mL × 3). The organic phase was dried with anhydrous sodium sulfate, filtered to remove the drying agent, and dissolved under reduced pressure to obtain the target product 5-((2,5-difluorobenzyl)oxo)pyrazolo[1,5-a]pyrimidine 1a (1.60 g, pale yellow solid), yield: 97%.

[0084] MS m / z(ESI): 262[M+1]

[0085] Step 2

[0086] 3-Bromo-5-((2,5-difluorobenzyl)oxo)pyrazolo[1,5-a]pyrimidine intermediate 1

[0087] Compound 5-((2,5-difluorobenzyl)oxo)pyrazolo[1,5-a]pyrimidine 1a (0.30 g, 1.15 mmol) and bromosuccinimide (0.23 g, 1.26 mmol) were dissolved in acetonitrile (5 mL) and N,N-dimethylformamide (1 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was quenched with saturated sodium sulfite aqueous solution (30 mL) and filtered. The filter cake was washed with water (10 mL) and dried to give the target product 3-bromo-5-((2,5-difluorobenzyl)oxo)pyrazolo[1,5-a]pyrimidine intermediate 1 (0.35 g, white solid), yield: 98%.

[0088] MS m / z(ESI):341&343[M+1];

[0089] 1 H NMR (400MHz, CDCl3) δ8.40(d,J=7.6Hz,1H),7.95(s,1H),7.40-7.28(m,1H),7.09-7.01(m,2H),6.41(d,J=7.6Hz,1H),5.55(s,2H).

[0090] Intermediate 2

[0091] 3-Bromo-6-(2,5-difluorophenylethyl)imidazo[1,2-b]pyridazine

[0092] first step

[0093] 6-((2,5-difluorophenyl)ethynyl)imidazo[1,2-b]pyridazine 2a

[0094] Compound 2,5-difluorophenylacetylene (2.10 g, 15.00 mmol) and compound 6-chloroimidazolo[1,2-b]pyridazine (1.53 g, 10.00 mmol) were dissolved in N,N-dimethylacetamide (50 mL). Cuprous iodide (0.10 g, 0.50 mmol), dichlorobis(triphenylphosphine)palladium (0.35 g, 0.50 mmol), and triethylamine (3 mL) were added. The mixture was heated to 80 °C for 4 hours under nitrogen protection. The reaction was cooled to room temperature. The reaction was quenched with water (30 mL), extracted with ethyl acetate (30 mL × 2), and the combined organic phases were washed with saturated brine (50 mL × 2). The organic phase was dried with anhydrous sodium sulfate, the desiccant was removed by filtration, and the crude product was obtained by desolvation under reduced pressure. The crude product was further purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the target product 6-((2,5-difluorophenyl)ethynyl)imidazo[1,2-b]pyridazine 2a (1.90 g, yellow solid), yield: 76%.

[0095] MS m / z(ESI): 256[M+1];

[0096] 1 H NMR (400MHz, CDCl3) δ7.43-7.41(m,3H),7.28-7.26(m,1H),7.21-7.19(m,1H),5.86-5.84(m,1H),5.71-5.69(m,1H).

[0097] Step 2

[0098] 6-((2,5-difluorophenyl)ethyl)imidazo[1,2-b]pyridazine 2b

[0099] Compound 6-((2,5-difluorophenyl)ethynyl)imidazo[1,2-b]pyridazine 2a (1.25 g, 5.00 mmol) was dissolved in methanol (60 mL), and palladium acetate (0.23 g, 1.00 mmol) was added. The mixture was stirred at room temperature under hydrogen atmosphere for 4 hours. The reaction solution was filtered directly through diatomaceous earth, and the filtrate was desolvated under reduced pressure to obtain the target product 6-((2,5-difluorophenyl)ethyl)imidazo[1,2-b]pyridazine 2b (1.05 g, yellow solid), yield: 81%.

[0100] MS m / z(ESI): 260[M+1].

[0101] Step 3

[0102] 3-Bromo-6-(2,5-difluorophenylethyl)imidazo[1,2-b]pyridazine intermediate 2

[0103] Compound 6-((2,5-difluorophenyl)ethyl)imidazo[1,2-b]pyridazine intermediate 2b (0.50 g, 2.00 mmol) was dissolved in dichloromethane (30 mL), and N-bromosuccinimide (0.48 g, 2.60 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was desolvated under reduced pressure to obtain the crude product. The crude product was further purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to give the target product 3-bromo-6-(2,5-difluorophenylethyl)imidazo[1,2-b]pyridazine intermediate 2 (1.92 g, yellow solid), yield: 76%.

[0104] MS m / z(ESI): 338 & 340 [M+1];

[0105] 1 H NMR (400MHz, CDCl3) δ7.89-7.83(m,1H),7.75(s,1H),6.92-6.78(m,4H),3.28-3.20(m,4H).

[0106] The synthesis of intermediates 3-4 follows the steps of intermediate 2, except that the 6-chloroimidazolo[1,2-b]pyridazine in the first step is replaced with the corresponding halide and the 2,5-difluorophenylacetylene is replaced with the corresponding alkynyl group.

[0107] Intermediate 3

[0108] 3-Bromo-5-(2,5-difluorophenylethyl)pyrazolo[1,5-a]pyrimidine

[0109] MS m / z(ESI): 338 & 340 [M+1].

[0110] 1 H NMR (400MHz, CDCl3) δ8.49(d,J=7.6Hz,1H),8.07(s,1H),7.00-6.96(m,2H),6.89-6.87(m,1H),6.67(d,J=7.6Hz,1H),3.19-3.10(m,4H).

[0111] Intermediate 4

[0112] 3-Bromo-5-(3-fluorophenylethyl)pyrazolo[1,5-a]pyrimidine

[0113] MS m / z(ESI): 320 & 322 [M+1].

[0114] 1 H NMR (400MHz, CDCl3) δ8.48(d,J=7.6Hz,1H),8.09(s,1H),7.02-6.86(m,4H),6.63(d,J=7.6Hz,1H),3.22-3.10(m,4H).

[0115] Example 1

[0116] 5-((2,5-difluorobenzyl)oxo)-3-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine

[0117] To compound 3-bromo-5-((2,5-difluorobenzyl)oxo)pyrazolo[1,5-a]pyrimidine (intermediate 1) (50 mg, 0.15 mmol), pyridine-3-boronic acid (18 mg, 0.15 mmol), potassium carbonate (61 mg, 0.44 mmol), dioxane (3 mL) and water (0.05 mL) were added. Under nitrogen protection, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (11 mg, 0.02 mmol) was added. The mixture was reacted at 100 °C for 8 hours. The reaction solution was diluted with dichloromethane (10 mL) and filtered. The filtrate was desolventized under reduced pressure, and the residue was purified using preparative silica gel filtration (petroleum ether / ethyl acetate = 2:1) to give the target product 5-((2,5-difluorobenzyl)oxo)-3-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine 1 (15 mg, white solid), yield 31%.

[0118] MS m / z(ESI): 339[M+1];

[0119] 1 H NMR (400MHz, CDCl3) δ9.23(s,1H),8.49(d,J=7.6Hz,1H),8.48(s,1H),8.34(s,1H),8.24(d,J=7.6Hz,1H),7. 38-7.33(m,1H),7.24-7.20(m,1H),7.12-7.06(m,1H),7.04-7.00(m,1H),6.47(d,J=7.4Hz,1H),5.56(s,2H).

[0120] The synthesis steps of Examples 2 to 6 are the same as those of Example 1, except that the corresponding boric acid and bromide intermediates are replaced to obtain the target product.

[0121] Example 2

[0122] 5-((2,5-difluorobenzyl)oxo)-3-(pyrimidin-5-yl)pyrazolo[1,5-a]pyrimidine 2

[0123] MS m / z(ESI): 340[M+1];

[0124] 1 H NMR (400MHz, CDCl3) δ9.25 (s, 2H), 9.01 (s, 1H), 8.45 (d, J = 7.6Hz, 1H), 8.29 (s, 1H), 7.14 -7.10(m,1H),7.05-6.99(m,1H),6.97-6.93(m,1H),6.45(d,J=7.6Hz,1H),5.48(s,2H).

[0125] Example 3

[0126] 5-((2,5-difluorobenzyl)oxo)-3-phenylpyrazolo[1,5-a]pyrimidine

[0127] MS m / z(ESI): 338[M+1]

[0128] 1 H NMR (400MHz, CDCl3) δ8.38(d,J=7.2Hz,1H),8.24(s,1H),7.88(d,J=7.6Hz,2H),7.36(t,J=7.6Hz, 2H),7.19-7.15(m,2H),7.03-6.97(m,1H),6.97-6.87(m,1H),6.35(d,J=7.2Hz,1H),5.49(s,2H).

[0129] Example 4

[0130] 5-(3-fluorophenylethyl)-3-phenylpyrazolo[1,5-a]pyrimidine

[0131] MS m / z(ESI): 318[M+1];

[0132] 1 H NMR(400MHz, CDCl3)δ8.52(d,J=6.8Hz,1H),8.40(s,1H),8.12-8.06(m,2H),7.45(t,J=7.2Hz,2H),7 .28-7.23(m,2H),7.03-6.95(m,2H),6.90(t,J=8.4Hz,1H),6.62(d,J=6.8Hz,1H),3.24-3.15(m,4H).

[0133] Example 5

[0134] 5-(3-fluorophenylethyl)-3-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine

[0135] MS m / z(ESI): 319[M+1];

[0136] 1H NMR (400MHz, CDCl3) δ9.35 (s, 1H), 8.67-8.36 (m, 3H), 7.45 (s, 1H), 7.25 (d, J = 7.2 Hz, 1H), 7.12-6.82 (m, 3H), 6.71 (d, J = 5.6Hz, 1H), 6.19 (s, 1H), 3.25-3.18 (m, 4H).

[0137] Example 6

[0138] 5-(3-fluorophenylethyl)-3-(pyrimidin-5-yl)pyrazolo[1,5-a]pyrimidine

[0139] MS m / z(ESI): 320[M+1];

[0140] 1 H NMR (400MHz, CDCl3) δ9.44 (s, 2H), 9.11 (s, 1H), 8.59 (d, J = 8.0Hz, 1H), 8.47 (s, 1H) ),7.67-7.53(m,2H),7.02-6.90(m,2H),6.74(d,J=8.0Hz,1H),3.27-3.18(m,4H).

[0141] Example 7

[0142] N 1 -(6-(5-((2,5-difluorobenzyl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-yl)-N 2 N 2 -Dimethyl-1,2-ethylenediamine

[0143] first step

[0144] N 1 -(6-bromopyridin-2-yl)-N 2 N 2 -Dimethyl-1,2-ethylenediamine 7a

[0145] The compound 2-bromo-6-fluoropyridine (1.60 g, 10 mmol), N 1 N 1Dimethyl-1,2-ethylenediamine (8.80 g, 50 mmol) was mixed and stirred at 80 °C for 2 hours under nitrogen protection. The reaction was cooled to room temperature, quenched with 30 mL of water, and extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine (50 mL × 2). The organic phases were dried over anhydrous sodium sulfate, filtered to remove the drying agent, and dissolved under reduced pressure to obtain the target product N. 1 -(6-bromopyridin-2-yl-N 2 N 2 -Dimethyl-1,2-ethylenediamine 7a (0.70 g, yellow oil), yield: 92%. The product was used directly in the next reaction without purification.

[0146] MS m / z(ESI):244&246[M+1].

[0147] Step 2

[0148] (6-((2-(dimethylamino)ethyl)amino)pyridin-2-yl)boronic acid intermediate 7b Compound N 1 -(6-bromopyridin-2-yl)-N 2 N 2 Dimethyl-1,2-ethylenediamine 7a (0.24 g, 1 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran solution. The solution was cooled in a dry ice-ethanol bath, and under nitrogen protection, n-butyllithium (1 mL, 2.5 mmol, 2.5 M n-hexane solution) was slowly added dropwise, with stirring for 0.5 hours. Triisopropyl borate (0.28 g, 1.5 mmol) was added, and the reaction was allowed to proceed overnight at room temperature. The reaction was quenched with 30 mL of methanol, and the product was directly dissolved under reduced pressure to obtain the target product (6-((2-(dimethylamino)ethyl)amino)pyridin-2-yl)boronic acid intermediate 7b (0.20 g, yellow oil, crude product). This product was used directly in the next reaction without purification.

[0149] MS m / z(ESI):210[M+1].

[0150] Step 3

[0151] N 1 -(6-(5-((2,5-difluorobenzyl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-yl)-N 2 N 2 -Dimethyl-1,2-ethylenediamine

[0152] Compound (6-((2-(dimethylamino)ethyl)amino)pyridin-2-yl)boronic acid 7b (42 mg, 0.20 mmol), 3-bromo-5-(2,5-difluorobenzyloxy)pyrazolo[1,5-a]pyrimidine (intermediate 1) (33 mg, 0.10 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (82 mg, 0.01 mmol), and potassium phosphate (64 mg, 0.3 mmol) were dissolved in 1,4-dioxane (5 mL), and 0.1 mL of pure water was added dropwise. The mixture was stirred in a microwave at 110 °C for 1 hour under nitrogen protection. The reaction solution was diluted with dichloromethane (10 mL) and filtered through diatomaceous earth. The solvent was removed under reduced pressure, and the residue was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to obtain the target product N. 1 -(6-(5-((2,5-difluorobenzyl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-yl)-N 2 N 2 1,2-Dimethyl-1,2-ethylenediamine 7 (9 mg, yellow oil). Yield: 22%.

[0153] MS m / z (ESI): 425 [M+1];

[0154] 1 H NMR (400MHz, CD3OD) δ8.70(d,J=7.6Hz,1H),8.58(s,1H),7.59(d,J=7.6Hz,1H),7.49(d,J=8.0Hz,1H),7.34(d,J=8.4Hz,1H),7.19(s,1 H),7.09(d,J=8.4Hz,1H),6.61(d,J=7.2Hz,1H),6.42(d,J=8.0Hz,1H),5.60(s,2H),3.80-3.75(m,2H),3.25-3.20(m,2H),2.77(s,6H).

[0155] The synthesis steps of Examples 8-9 are the same as those in Example 7, except that the corresponding amine compounds and bromide intermediates are replaced to obtain the target products.

[0156] Example 8

[0157] N 1 -(6-(5-(2,5-difluorophenylethyl)pyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-yl)-N 2 N 2 -Dimethylethyl-1,2-diamine

[0158] MS m / z (ESI): 423 [M+1];

[0159] 1 H NMR (400MHz, CD3OD) δ8.76(d,J=7.2Hz,1H),8.69(s,1H),7.69-7.62(m,1H),7.52-7.46(m,1H),7.09-7.02(m,2H) ,6.89-6.85(m,2H),6.37(d,J=6.0Hz,1H),5.38-5.32(m,2H),3.69-3.65(m,2H),3.28-3.20(m,4H),2.73(s,6H).

[0160] Example 9

[0161] 2-((6-(5-(2,5-difluorophenylethyl)pyrazolopyrimidin-3-yl)pyridin-2-yl)amino)ethyl-1-ol

[0162] MS m / z(ESI): 396[M+1];

[0163] 1 H NMR (400MHz, CDCl3) δ8.69 (s, 1H), 8.51 (d, J = 7.6Hz, 1H), 7.63-7.59 (m, 1H), 7.55-7.50 (m, 1H), 7.26-7.24 (m, 1H), 7.11-7.01 (m ,2H),6.46(d,J=7.2Hz,1H),6.35(d,J=7.6Hz,1H),5.61-5.59(m,2H),5.36-5.33(m,2H),3.90-3.86(m,2H),3.63-3.61(m,2H).

[0164] Example 10

[0165] 2-((6-(5-((2,5-difluorobenzyl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-yl)oxy)-N,N-dimethylethyl-1-amine

[0166] first step

[0167] 2-((6-bromopyridin-2-yl)oxy)-N,N-dimethyl-1-amine 10a

[0168] 2-(dimethylamino)ethyl-1-ol (0.46 g, 5.10 mmol) was dissolved in tetrahydrofuran (50 mL), sodium hydride (0.16 g, 6.80 mmol, 60% dispersed in mineral oil) was added, and the mixture was stirred at room temperature for 35 minutes. 2-fluoro-6-bromopyridine (0.60 g, 3.40 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 2), and the organic phase was washed with saturated brine (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and dissolved under reduced pressure to obtain the target product 2-((6-bromopyridin-2-yl)oxy)-N,N-dimethyl-1-amine 10a (0.80 g, colorless oil).

[0169] MS m / z(ESI):245&247[M+1];

[0170] 1 H NMR (400MHz, CDCl3) δ 7.41-7.37 (m, 1H), 7.04 (d, J = 7.2Hz, 1H), 6.73 (d, J = 7.2Hz, 1H), 4.39 (t, J = 5.2Hz, 2H), 2.69 (t, J = 5.2Hz, 2H), 2.23 (s, 6H).

[0171] Step 2

[0172] (6-(2-(dimethylamino)ethoxy)pyridin-2-yl)boronic acid 10b

[0173] Compound 2-(6-bromopyridin-2-yl)oxy-N,N-dimethyl-1-amine 10a (0.36 g, 2.52 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), cooled in a dry ice-ethanol bath, and under nitrogen protection, n-butyllithium (2.7 mL, 6.78 mmol, 2.5 M n-hexane solution) was added. The mixture was stirred for 25 minutes, and then triethyl orthoborate (0.52 g, 3.83 mmol) was added. The reaction was gradually increased to room temperature and stirred at room temperature for 2 hours. The reaction was quenched with 10 mL of methanol, and the product was directly dissolved under reduced pressure to obtain the target product (6-(2-(dimethylamino)ethoxy)pyridin-2-yl)boronic acid 10b (0.35 g, yellow oil, crude product). No purification was required; proceed directly to the next step.

[0174] MS m / z(ESI):211[M+1];

[0175] Step 3

[0176] 2-((6-(5-((2,5-difluorophenylmethyl)oxo)pyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-yl)oxo)-N,N-dimethylethyl-1-amine 10

[0177] Compound (6-(2-(dimethylamino)ethoxy)pyridin-2-yl)boronic acid 10b (90 mg, 0.43 mmol) and compound 3-bromo-5-((2,5-difluorophenyl)oxy)pyrazolo[1,5-a]pyrimidine (intermediate 1) (60 mg, 0.17 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1 mL). Potassium phosphate (0.17 g, 6.86 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (25 mg, 0.03 mmol) were added. The mixture was stirred at 80 °C for 3 hours under nitrogen protection. The reaction solution was diluted with dichloromethane (10 mL) and filtered through diatomaceous earth. Desolvent under reduced pressure, and purify the residue by reversed-phase chromatography (water: acetonitrile (0.1% formic acid) = 10%–30%) to give the target product 2-(6-((5-((2,5-difluorobenzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-yl)oxy)-N,N-dimethyl-1-amine 10 (6.7 mg, white solid), yield: 9%.

[0178] MS m / z(ESI): 426[M+1];

[0179] 1 H NMR (400MHz, CDCl3) δ8.63(s,1H),8.53(d,J=7.2Hz,1H),7.92(d,J=7.6Hz,1H),7.69-7.67(m,1H),7.26-7.24(m,1H),7.09-7.06(m, 1H),7.03-7.01(m,1H),6.60(d,J=7.6Hz,1H),6.48(d,J=7.2Hz,1H),5.60(s,2H),4.83-4.81(m,2H),3.47-3.45(m,2H),2.85(s,6H).

[0180] Example 11

[0181] 2-((6-(5-(2,5-difluorophenylethyl)pyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-yl)oxy)-N,N-dimethylethyl-1-amine

[0182] The synthesis steps of Example 11 are the same as those in Example 10, except that the 3-bromo-5-((2,5-difluorophenyl)oxy)pyrazolo[1,5-a]pyrimidine intermediate 1 in the third step is replaced with 3-bromo-5-(2,5-difluorophenylethyl)imidazo[1,5-a]pyrimidine intermediate 3 to obtain the target product.

[0183] MS m / z(ESI): 424[M+1]; 1 H NMR (400MHz, CDCl3) δ8.75(s,1H),8.59(d,J=7.2Hz,1H),8.09(d,J=7.2Hz,1H),7.68-7.66(m,1H),7.00-6.97(m,2H),6.92-6. 90(m,1H),6.72(d,J=7.2Hz,1H),6.62(d,J=7.2Hz,1H),4.79-4.77(m,2H),3.31-3.29(m,2H),3.24-3.22(m,4H),2.73(s,6H).

[0184] Example 12

[0185] (2,5-Difluorophenylmethyl)oxo)-3-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine

[0186] Compound 3-bromo-5-((2,5-difluorobenzyl)oxo)pyrazolo[1,5-a]pyrimidine intermediate 1 (50 mg, 0.15 mmol), 2-tri-n-butyltinylpyridine (54 mg, 0.15 mmol), and toluene (2 mL) were mixed, and tetrakis(triphenylphosphine)palladium (17 mg, 0.02 mmol) was added under nitrogen protection. The mixture was reacted in a microwave reactor at 105 °C for 1 hour. The reaction solution was quenched with saturated potassium fluoride aqueous solution (10 mL), extracted with ethyl acetate (30 mL × 2), and the organic phase was washed with saturated brine (20 mL). The organic phase was dried with anhydrous sodium sulfate and filtered to remove the desiccant. The solvent was removed under reduced pressure, and the residue was purified by reversed-phase preparative chromatography (acetonitrile / water (0.1% formic acid = 35%-45%)) to give the target product 5-((2,5-difluorobenzyl)oxo)-3-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine 12 (13 mg, white solid), yield: 27%.

[0187] MS m / z(ESI): 339[M+1]; 1 H NMR (400MHz, CDCl3) δ8.74(s,1H),8.60(d,J=4.8Hz,1H),8.51(d,J=7.6Hz,1H),8.29(d,J=8.0Hz,1H),7.74( t,J=8.0Hz,1H),7.26-7.20(m,1H),7.16-7.06(m,2H),7.05-6.99(m,1H),6.47(d,J=7.6Hz,1H),5.60(s,2H).

[0188] The synthesis steps of Examples 13-16 are the same as those in Example 12, except that the corresponding tin reagents and bromide intermediates are replaced to obtain the target products.

[0189] Example 13

[0190] 5-((2,5-difluorobenzyl)oxo)-3-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrimidin

[0191] MS m / z(ESI): 340[M+1];

[0192] 1 H NMR (400MHz, CDCl3) δ9.14(s,1H),8.79(s,1H),8.70(s,1H),8.53(t,J=7.6Hz,1H),8.25( d,J=5.2Hz,1H),7.25-7.19(m,1H),7.15-6.97(m,2H),6.55(d,J=7.6Hz,1H),5.62(s,2H).

[0193] Example 14

[0194] 6-(2,5-Difluorophenylethyl)-3-(pyridin-2-yl)imidazo[1,2-b]pyridazine 14

[0195] MS m / z(ESI): 337[M+1];

[0196] 1 H NMR(400MHz, CDCl3)δ8.70(d,J=7.6Hz,1H),8.53-8.51(m,2H),7.98-7.96(m,1H),7.81-7.79(m,1 H),7.55-7.53(m,1H),6.99-6.93(m,3H),6.89-6.87(m,1H),3.27-3.25(m,2H),3.21-3.19(m,2H).

[0197] Example 15

[0198] 5-(2,5-difluorophenyl)-3-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine

[0199] MS m / z (ESI): 337 [M+1];

[0200] 1 H NMR (400MHz, CDCl3) δ8.84(s,1H),8.71-8.67(m,1H),8.59(d,J=7.6Hz,1H),8.48(d,J=8.0Hz,1H),7.76(t,J= 7.6Hz,1H),7.16-7.13(m,1H),7.02-6.96(m,2H),6.89-6.87(m,1H),6.72(d,J=7.2Hz,1H),3.27-3.20(m,4H).

[0201] Example 16

[0202] 5-(3-fluorophenylethyl)-3-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine

[0203] MS m / z(ESI): 318[M+1];

[0204] 1 H NMR (400MHz, CDCl3) δ8.94 (s, 1H), 8.70 (d, J = 4.4Hz, 1H), 8.62-8.56 (m, 2H), 7.86 (t, J = 7.6Hz, 1H), 7 .25-7.18(m,2H),7.03-6.97(m,2H),6.91(t,J=8.4Hz,1H),6.73(d,J=7.2Hz,1H),3.34-3.16(m,4H). Biological experiments

[0205] TRKA activity inhibition test

[0206] The effect of the compounds of this invention on TRKA activity was evaluated using in vitro kinase assays.

[0207] The experimental methods are summarized as follows:

[0208] The in vitro activity of TRKA was determined by detecting the phosphorylation level of the substrate in the kinase reaction using a homogeneous time-resolved fluorescence (HTRF) kinase assay kit (Cisbio, catalog number 62TK0PEC). The reaction buffer contained the following components: the kit's own enzyme reaction buffer (1×), 5 mM MgCl2, and 1 mM DTT; the human recombinant TRKA protein was expressed and purified at Tsinghua University's protein purification and identification platform and diluted with the reaction buffer to a kinase solution of 3 ng / μl; the substrate reaction solution consisted of 0.23 μM biotin-labeled tyrosine kinase substrate diluted with the reaction buffer and 8.4 μM ATP; the assay buffer consisted of 0.1 ng / μl Eu3+-labeled cage antibody and 14.375 nM streptavidin-labeled XL665 diluted with the reaction buffer.

[0209] Dissolve and dilute the compound in 100% DMSO to 100 μM or 10 μM, then perform a 4-fold serial dilution with DMSO to the lowest concentration of 6.1 nM or 0.61 nM. Each concentration point is then diluted 40-fold with reaction buffer.

[0210] Add 4 μl of the compound solution and 2 μl of TRKA kinase solution to a 384-well detection plate (Corning, catalog number 4512), mix thoroughly, and incubate at room temperature for 15 minutes. Then add 4 μl of substrate reaction solution and incubate the reaction mixture at room temperature for 60 minutes. Next, add 10 μl of detection buffer (equal volume to the reaction mixture), mix thoroughly, and let stand at room temperature for 30 minutes. Detect the reaction progress using an Envision plate reader (Perkin Elmer) at wavelengths of 620 nm and 665 nm. The 665 / 620 ratio is positively correlated with the degree of phosphorylation of the substrate, thus detecting TRKA kinase activity. In this experiment, the group without TRKA kinase protein served as a negative control (100% inhibition), and the group with TRKA kinase protein but without the compound served as a positive control (0% inhibition). The percentage inhibition of TRKA activity by the compound can be calculated using the following formula: Inhibition percentage = 100 - 100 * (Signal value of the test compound at a specific concentration - Signal value of the negative control) / (Signal value of the positive control - Signal value of the negative control) The IC50 values ​​of the compounds were calculated using the following formula at eight concentration points with XLfit (ID Business Solutions Ltd., UK) software: Y=Bottom+(Top-Bottom) / (1+10^((logIC50-X)*slope factor)) Where Y is the inhibition percentage, X is the logarithm of the concentration of the analyte, Bottom is the maximum inhibition percentage, Top is the minimum inhibition percentage, and slope factor is the curve slope coefficient.

[0211] TRKB activity inhibition test

[0212] The effect of the compounds of this invention on TRKB activity was evaluated using in vitro kinase assays.

[0213] The experimental methods are summarized as follows:

[0214] The in vitro activity of TRKB was determined by detecting the phosphorylation level of the substrate in the kinase reaction using the HTRF kinase assay kit (Cisbio, catalog number 62TK0PEC). The reaction buffer contained the following components: the kit's own enzyme reaction buffer (1×), 5 mM MgCl2, 1 mM MnCl2, and 1 mM DTT; human recombinant TRKB protein (catalog number 08-187) purchased from CarnaBiosciences, diluted with reaction buffer to a kinase solution of 0.162 ng / μl; the substrate reaction solution consisted of 0.18 μM biotin-labeled tyrosine kinase substrate diluted with reaction buffer and 5 μM ATP; the assay buffer consisted of 0.1 ng / μl Eu3+-labeled cage antibody diluted with reaction buffer and 11.25 nM streptavidin-labeled XL665.

[0215] Dissolve and dilute the compound in 100% DMSO to 100 μM or 50 μM, then perform a 4-fold serial dilution with DMSO to the lowest concentration of 6.1 nM or 3.05 nM. Each concentration point is then diluted 40-fold with reaction buffer.

[0216] Add 4 μl of the compound solution and 2 μl of TRKB kinase solution to a 384-well detection plate (Corning, catalog number 4512), mix thoroughly, and incubate at room temperature for 15 minutes. Then add 4 μl of substrate reaction solution and incubate the reaction mixture at room temperature for 60 minutes. Next, add 10 μl of detection buffer (equal volume to the reaction mixture), mix thoroughly, and let stand at room temperature for 30 minutes. Detect the reaction progress using an Envision plate reader (Perkin Elmer) at wavelengths of 620 nm and 665 nm. The 665 / 620 ratio is positively correlated with the degree of phosphorylation of the substrate, thus detecting TRKB kinase activity. In this experiment, the group without TRKB kinase protein served as a negative control (100% inhibition), and the group with TRKB kinase protein but without the compound served as a positive control (0% inhibition). The percentage inhibition of TRKB activity by the compound can be calculated using the following formula: Inhibition percentage = 100 - 100 * (Signal value of the test compound at a specific concentration - Signal value of the negative control) / (Signal value of the positive control - Signal value of the negative control) The IC50 values ​​of the compounds were calculated using the following formula at eight concentration points with XLfit (ID Business Solutions Ltd., UK) software: Y=Bottom+(Top-Bottom) / (1+10^((logIC50-X)*slope factor)) Where Y is the inhibition percentage, X is the logarithm of the concentration of the analyte, Bottom is the maximum inhibition percentage, Top is the minimum inhibition percentage, and slope factor is the curve slope coefficient.

[0217] TRKC activity inhibition test

[0218] The effect of the compounds of this invention on TRKC activity was evaluated using in vitro kinase assays.

[0219] The experimental methods are summarized as follows:

[0220] The in vitro activity of TRKC was determined by detecting the phosphorylation level of the substrate in the kinase reaction using a homogeneous time-resolved fluorescence (HTRF) kinase assay kit (Cisbio, catalog number 62TK0PEC). The reaction buffer contained the following components: kit-provided enzyme reaction buffer (1×), 5 mM MgCl2, and 1 mM DTT; human recombinant TRKC protein (catalog number 08-197) purchased from Carna Biosciences, diluted with reaction buffer to a kinase solution of 0.145 ng / μl; substrate reaction solution consisting of 0.13 μM biotin-labeled tyrosine kinase substrate diluted with reaction buffer and 4.1 μM ATP; and assay buffer consisting of 0.1 ng / μl Eu3+-labeled cage antibody diluted with reaction buffer and 8.125 nM streptavidin-labeled XL665.

[0221] Dissolve and dilute the compound in 100% DMSO to 100 μM or 50 μM, then perform a 4-fold serial dilution with DMSO to the lowest concentration of 6.1 nM or 3.05 nM. Each concentration point is then diluted 40-fold with reaction buffer.

[0222] Add 4 μl of the compound solution and 2 μl of TRKC kinase solution to a 384-well detection plate (Corning, catalog number 4512), mix thoroughly, and incubate at room temperature for 15 minutes. Then add 4 μl of substrate reaction solution and incubate the reaction mixture at room temperature for 60 minutes. Next, add 10 μl of detection buffer (equal volume to the reaction mixture), mix thoroughly, and let stand at room temperature for 30 minutes. Detect the reaction progress using an Envision plate reader (Perkin Elmer) at wavelengths of 620 nm and 665 nm. The 665 / 620 ratio is positively correlated with the degree of substrate phosphorylation, thus detecting TRKC kinase activity. In this experiment, the group without TRKC kinase protein served as a negative control (100% inhibition), and the group with TRKC kinase protein but without the compound served as a positive control (0% inhibition). The percentage inhibition of TRKC activity by the compound can be calculated using the following formula: Inhibition percentage = 100 - 100 * (Signal value of the test compound at a specific concentration - Signal value of the negative control) / (Signal value of the positive control - Signal value of the negative control) The IC50 values ​​of the compounds were calculated using the following formula at eight concentration points with XLfit (ID Business Solutions Ltd., UK) software: Y=Bottom+(Top-Bottom) / (1+10^((logIC50-X)*slope factor)) Where Y is the inhibition percentage, X is the logarithm of the concentration of the analyte, Bottom is the maximum inhibition percentage, Top is the minimum inhibition percentage, and slope factor is the curve slope coefficient.

[0223] TRKA G595R Activity Inhibition Test

[0224] The effect of the compounds of this invention on the activity of TRKA G595R was evaluated using in vitro kinase assays.

[0225] The experimental methods are summarized as follows:

[0226] The in vitro activity of TRKA G595R was determined by detecting the phosphorylation level of the substrate in the kinase reaction using the HTRF kinase assay kit (Cisbio, catalog number 62TK0PEC). The reaction buffer contained the following components: the kit's own enzyme reaction buffer (1×), 5 mM MgCl2, and 1 mM DTT; human recombinant TRKA G595R protein (catalog number N16-128G) purchased from SignalChem Lifesciences, diluted with reaction buffer to a kinase solution of 0.25 ng / μl; the substrate reaction solution consisted of 0.51 μM biotin-labeled tyrosine kinase substrate diluted with reaction buffer and 2.9 μM ATP; the assay buffer consisted of 0.15 ng / μl Eu3+-labeled cage antibody and 31.875 nM streptavidin-labeled XL665 diluted with reaction buffer.

[0227] The compound was dissolved and diluted in 100% DMSO to 1 mM or 100 μM, and then serially diluted 4-fold with DMSO to the lowest concentration of 61 nM or 6.1 nM. Each concentration point was then diluted 40-fold with reaction buffer.

[0228] Add 4 μl of the compound solution and 2 μl of TRKA G595R kinase solution to a 384-well detection plate (Corning, catalog number 4512), mix thoroughly, and incubate at room temperature for 15 minutes. Then add 4 μl of substrate reaction solution and incubate the reaction mixture at room temperature for 60 minutes. Next, add 10 μl of detection buffer (equal volume to the reaction mixture), mix thoroughly, and let stand at room temperature for 30 minutes. Detect the reaction progress using an Envision plate reader (Perkin Elmer) at wavelengths of 620 nm and 665 nm. The 665 / 620 ratio is positively correlated with the degree of phosphorylation of the substrate, thus detecting the activity of TRKA G595R kinase. In this experiment, the group without TRKA G595R kinase protein served as a negative control (100% inhibition), and the group with TRKA G595R kinase protein but without the compound served as a positive control (0% inhibition). The percentage inhibition of TRKA G595R activity by the compound can be calculated using the following formula: Inhibition percentage = 100 - 100 * (Signal value of the test compound at a specific concentration - Signal value of the negative control) / (Signal value of the positive control - Signal value of the negative control) The IC50 values ​​of the compounds were calculated using the following formula at eight concentration points with XLfit (ID Business Solutions Ltd., UK) software: Y=Bottom+(Top-Bottom) / (1+10^((logIC50-X)*slope factor)) Where Y is the inhibition percentage, X is the logarithm of the concentration of the analyte, Bottom is the maximum inhibition percentage, Top is the minimum inhibition percentage, and slope factor is the curve slope coefficient.

[0229] Determination of the half-maximal inhibitory concentration (GI50) of KM12 cells

[0230] The effect of the compounds of this invention on the proliferation of KM12 cells was evaluated using a luminescent cell viability assay.

[0231] The experimental methods are summarized as follows:

[0232] The CellTilter-Glo (CTG) assay kit was used to detect the cell proliferation status of KM12 cells by employing a unique, stable luciferase to detect the metabolism of viable cells using ATP. The luminescent signal generated in the assay was directly proportional to the number of viable cells in the culture medium.

[0233] KM12 cells (purchased from Shanghai Xinyu Biotechnology Co., Ltd.) were cultured in IMDM complete medium (Thermofisher, 12440053) containing 10% FBS (GBICO, 10099-141) and 100 units / ml penicillin-streptomycin mixture (Thermofisher, 15140122). When the cell coverage in the culture vessel reached 80-90%, the cells were digested with 0.25% trypsin (containing EDTA) (Thermofisher, 25200056), dispersed, and seeded into white 384-well plates (Thermofisher, 164610). 27 μl of IMDM complete medium containing 1000 cells was added to each well, and the 384-well plates were then placed in an incubator containing 5% CO2 and incubated overnight at 37°C. The compound was dissolved and diluted to 1 mM in 100% DMSO, then serially diluted 4-fold with DMSO to a minimum concentration of 0.061 μM, and each concentration point was further diluted 50-fold with 1MDM medium. If the compound IC50... 50The value is very low, allowing for a reduction in the initial concentration of the compound. Add 3 μl of the diluted compound to each well and gently centrifuge to mix. The culture medium without cells serves as a negative control (100% inhibition), and the group with 0.2% DMSO serves as a positive control (0% inhibition). The 384-well plate is incubated at 37°C with 5% CO2 for 96 hours. After 96 hours, it is removed and allowed to equilibrate to room temperature for 30 minutes. The CTG reagent is also removed and brought to room temperature. Add 15 μl of CTG reagent to each well, gently shake on a shaker for 5 minutes to ensure adequate cell lysis, and allow to stand for 10 minutes to stabilize the cryo-light signal. The cryo-light signal is then read using EnVision (Perkin Elmer). Additionally, to correct for cell counts, a T0 control is set up, including a blank control containing only culture medium and a control with added cells. The difference between the two is defined as the T0 control, obtained by detecting the CTG reagent value before adding the drug.

[0234] The percentage of inhibition of KM12 cell proliferation by the compound can be calculated using the following formula: Inhibition percentage = 100 - 100 * {[(signal 化合物 -Signal 阴性对照 )-T 0对照 ] / [(signal 阳性对照 -Signal 阴性对照 )-T 0对照 ]} Compound IC 50 The values ​​were calculated from eight concentration points using XLfit (ID Business Solutions Ltd., UK) software via the following formula: Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*slope factor)) Where Y represents the inhibition percentage, Bottom is the bottom plateau of the curve, Top is the top plateau of the curve, and X is the logarithm of the concentration of the analyte.

[0235] The results of the experiment are shown in Table 1. Table 1: Results of enzyme activity and cell viability assays

[0236] The data in Table 1 further demonstrate that the compounds of this patent have high enzyme activity, and some compounds also maintain high inhibitory activity in KM12 cells.

[0237] The experimental results above demonstrate that the compounds in the embodiments of this invention can effectively inhibit TRK activity. They can be used to treat or prevent TRK-mediated diseases, such as tumors, especially hematologic malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, and glioma.

[0238] It will be apparent to those skilled in the art that this disclosure is not limited to the illustrative embodiments described above, and that it may be embodied in other specific forms without departing from the essential characteristics of this disclosure. Therefore, it is intended that these embodiments be considered illustrative and non-limiting in all respects, and that reference be made to the appended claims rather than the foregoing embodiments, and that all variations therein within the equivalent meaning and scope of the claims are included therein.

Claims

1. A compound of formula (I), its isomers, prodrugs, solvates, stable isotopic derivatives, or pharmaceutically acceptable salts. in: R 1 R 2 Each of the following groups is independently selected from hydrogen, halogen, cyano, -C(O)NH2, C1-C4 alkyl, C1-C4 alkoxy, phenyl, 5-6 heteroaryl, C3-C6 cycloalkyl, and 4-8 heterocyclic groups; wherein the C1-C4 alkyl, C1-C4 alkoxy, phenyl, 5-6 heteroaryl, C3-C6 cycloalkyl, and 4-8 heterocyclic groups are optionally substituted by one or more substituents selected from halogen, cyano, alkoxy, C1-C4 alkyl, C3-C6 cycloalkyl, and 4-6 heterocyclic groups; Y is selected from O or -C(R) 4a R 4b )-; where R 4a R 4b Each is independently selected from hydrogen, C1-C3 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic groups; X 1 X 2 Each is independently selected from C or N; and X 1 X 2 Not both N; R 3 Selected from C6-C10 aryl or 5-10 heteroaryl groups; wherein the C6-C10 aryl or 5-10 heteroaryl groups are unsubstituted or surrounded by 1-3 R groups. x Replaced; wherein R x Each is independently selected from halogen, cyano, C1-C4 alkoxy, C1-C4 alkylamine, C1-C4 alkyl, C3-C6 cycloalkyl, and 4-6 membered saturated heterocyclic groups; wherein the C1-C4 alkoxy, C1-C4 alkylamine, C1-C4 alkyl, C3-C6 cycloalkyl, and 4-6 membered saturated heterocyclic groups are unsubstituted or surrounded by 1-3 halogens, C1-C3 alkoxy groups, or -NR groups. 5a R 5b Replaced; where R 5a R 5b Each is independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, and 4-6 membered saturated heterocyclic groups.

2. The compound according to claim 1, wherein its isomers, prodrugs, solvates, stable isotopic derivatives, or pharmaceutically acceptable salts, wherein: R 1 R 2 Each is independently selected from hydrogen, fluorine, chlorine, and bromine; Y is selected from O or -C(R) 4a R 4b )-; where R 4a R 4b Each is independently selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic groups; X 1 X 2 Each is independently selected from C or N; and X 1 X 2 Not both N; R 3 Selected from phenyl or a 6-membered heteroaryl group containing 1-2 nitrogen atoms; wherein the phenyl or 6-membered heteroaryl group is unsubstituted or surrounded by 1-3 R atoms. x Replaced; wherein R x Each is independently selected from fluorine, chlorine, C1-C4 alkoxy, and C1-C4 alkylamine groups; among which The C1-C4 alkoxy and C1-C4 alkylamine groups are unsubstituted or surrounded by 1-3 halogens, C1-C3 alkoxy groups, and -NR groups. 5a R 5b Replaced; where R 5a R 5b Each is independently selected from hydrogen, C1-C3 alkyl, C3-C4 cycloalkyl, and 4-6 membered saturated heterocyclic groups.

3. The compound according to claim 1, its isomers, prodrugs, solvates, stable isotopic derivatives, or pharmaceutically acceptable salts, wherein: R 1 R 2 Each is independently selected from hydrogen, fluorine, and chlorine; Y is selected from O or -CH2-; X 1 X 2 Each is independently selected from C or N; and X 1 X 2 Not both N; R 3 Selected from phenyl, pyridyl, or pyrimidinyl; wherein the phenyl, pyridyl, or pyrimidinyl group is unsubstituted or surrounded by one R group. x Replaced; wherein R x It is selected from C1-C2 alkoxy and C1-C2 alkylamine groups; wherein the C1-C2 alkoxy and C1-C2 alkylamine groups are unsubstituted or substituted by hydroxy or dimethylamine groups.

4. The compound according to claim 1, its isomers, prodrugs, solvates, stable isotopic derivatives, or pharmaceutically acceptable salts, wherein: R 1 R 2 Each is independently selected from hydrogen and fluorine; Y is selected from O or -CH2-; X 1 X 2 Each is independently selected from C or N; and X 1 X 2 Not both N; R 3 Selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyrimidinyl, or 5-pyrimidinyl; wherein the phenyl, 2-pyridyl, 3-pyridyl, 4-pyrimidinyl, or 5-pyrimidinyl group is unsubstituted or surrounded by one R group. x Replaced; wherein R x Selected from dimethylaminoethylamino, dimethylaminoethoxy, and hydroxyethylamino.

5. The compound according to claim 1, wherein its isomers, prodrugs, solvates, stable isotopic derivatives, or pharmaceutically acceptable salts, wherein: R 1 R 2 Each is independently selected from hydrogen and fluorine; Y is selected from O or -CH2-; X 1 X 2 Each is independently selected from C or N; and X 1 X 2 Not both N; R 3 Selected from 6. The compound according to claim 1, wherein its isomers, prodrugs, solvates, stable isotopic derivatives, or pharmaceutically acceptable salts are selected from:

7. A pharmaceutical composition comprising the compound according to any one of claims 1-6, its isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent or excipient.

8. Use of the compound or isomer thereof, prodrug, stable isotope derivative or pharmaceutically acceptable salt of any one of claims 1-6, or the pharmaceutical composition of claim 7, in the preparation of a medicament, wherein the medicament is used to treat or prevent TRK-mediated diseases, such as cancer, especially hematologic malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, and glioma.

9. A method of treating or preventing TRK-mediated diseases (e.g., cancer), comprising administering to a patient in need a therapeutically effective amount of the compound or isomers thereof, prodrugs, stable isotope derivatives or pharmaceutically acceptable salts, or the pharmaceutical composition of claim 7.

10. The compound or isomers thereof, prodrugs, stable isotope derivatives or pharmaceutically acceptable salts according to any one of claims 1-6, or the pharmaceutical composition according to claim 7, for the treatment or prevention of TRK-mediated diseases, such as cancer, especially hematologic malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, and glioma.

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