Compounds useful as ntrk kinase inhibitors and uses thereof

Abstract

This invention relates to a compound used as an NTRK kinase inhibitor and its applications. Specifically, this invention relates to compounds as shown in Formula I or their stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates, pharmaceutical compositions of said compounds and their use as NTRK kinase inhibitors, and their use in the preparation of medicaments for the prevention and / or treatment of NTRK-related diseases.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to compounds as NTRK kinase inhibitors, processes for their preparation, and the use in the manufacture of medicaments for the treatment of diseases mediated by NTRK and other kinases. BACKGROUND

[0002] The tropomyosin receptor kinases (TRK) family belongs to transmembrane receptor tyrosine kinases (RTKs), which are involved in the regulation of synaptic growth and maintenance of function of mammalian nervous system, development of memory, and protection of neurons from injury, etc. TRK kinases are a class of nerve growth factor receptors, which are composed of highly homologous tropomyosin-related kinase A (TRKA), tropomyosin-related kinase B (TRKB), and tropomyosin-related kinase C (TRKC), encoded by NTRK1, NTRK2 and NTRK3 genes, respectively. The complete TRK kinase includes extracellular region, transmembrane region and intracellular region, and like other RTKs, the extracellular region of TRK kinase binds to the corresponding ligand to form a dimer, which can cause autophosphorylation of the intracellular region of TRK kinase to activate its kinase activity, and further activate the downstream signal transduction pathway. TRK kinases affect cell proliferation, differentiation, metabolism and apoptosis through downstream pathways such as Ras / MAPK, PI3K / AKT and PLcγ. When NTRKs gene fusion or mutation occurs, it will change or eliminate the extracellular region receptor (Greco, A. et. al, Mol. Cell. Biol. 1995, 15, 6118; Oncogene 1998, 16, 809), and the fusion or mutant TRK protein is in a highly active kinase activity state without the need for ligand binding, thereby continuously activating the downstream signal transduction pathway, which can lead to abnormal regulation of TRK kinase downstream signal transduction pathway, induce cell proliferation, and promote the occurrence and development of tumors.

[0003] NTRK gene fusions occur in a variety of adult and pediatric solid tumors, including breast cancer, colorectal cancer, non-small cell lung cancer, papillary thyroid cancer, Spitz-like melanoma, glioma, and various sarcomas, etc. In common cancers, such as non-small cell lung cancer, colorectal cancer, etc., the incidence of NTRK gene fusion is low, about 1%-3%, but in some rare cancers, such as infantile fibrosarcoma, breast secretory carcinoma, etc., the incidence of NTRK gene fusion can be more than 90%. The earliest TPM3-TRKA fusion protein was found in colon cancer cells. Later, more types of NTRK fusion proteins were found in different clinical tumor patient samples, such as breast cancer, non-small cell lung cancer, papillary thyroid cancer, Spitz-like melanoma, glioma, etc., such as CD74-NTRKA, MPRIP-NTEKA, QKI-NTRKB, ETV6-NTRKC, BTB1-NTRKC, etc.

[0004] Therefore, in recent years, NTRK fusion protein has become an effective anticancer target and a hot spot for anti-cancer drug research and development. For example, WO2010048314, WO2010033941, WO2012116217, WO2011146336, etc. disclose a series of TRK kinase inhibitors with different structures.

[0005] However, with the further understanding of TRK kinase in recent years, more types of TRK fusion proteins and mutation types have been found (Russo, M. et. al Cancer Discovery, 2016, 6, 36; Drilon, A. et. al, Annals of Oncology, 2016, 27, 920), so there is an urgent need in the clinic to develop new NTRK inhibitors with better activity and broader action to solve the treatment problems of tumors caused by these NTRK protein fusions or mutations. SUMMARY

[0006] The main purpose of the present application is to provide a selective NTRK kinase inhibitor.

[0007] In a first aspect of the present application, a compound represented by Formula I, stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof are provided,

[0008]

[0009] In the formula,

[0010] R1is selected from:

[0011] R2is selected from the group consisting of substituted or unsubstituted C6-C14aryl, 5-14 membered heteroaryl; wherein the substitution is by one or more R r substituted;

[0012] R m , R n , R3and R4are each independently selected from the group consisting of substituted or unsubstituted H, halogen, NR p R p' , -CN, -OH, C1-C6alkyl, C1-C6alkoxy, C3-C12cycloalkyl, 3-12 membered heterocyclyl, C6-C14aryl, 5-14 membered heteroaryl; wherein the substitution is by one or more R r substituted;

[0013] or R m and R n together with the C atom to which they are attached form a substituted or unsubstituted group consisting of C3-C12cycloalkyl, 3-12 membered heterocyclyl, or oxo (=0); wherein the substitution is by one or more R r substituted;

[0014] or R3and R4together with the C atom to which they are attached form a substituted or unsubstituted group consisting of C3-C12cycloalkyl, 3-12 membered heterocyclyl, or oxo (=0); wherein the substitution is by one or more R r substituted;

[0015] R p and R p' are each independently selected from the group consisting of substituted or unsubstituted H, C1-C6alkyl, C1-C6alkoxy, C3-C12cycloalkyl, 3-12 membered heterocyclyl, C6-C14aryl, 5-14 membered heteroaryl; wherein the substitution is by one or more R r substituted;

[0016] or R3and R p together with the atoms to which they are attached form a substituted or unsubstituted group consisting of C3-C12cycloalkyl, 3-12 membered heterocyclyl; wherein the substitution is by one or more R r substituted;

[0017] or R3and R p' together with the atoms to which they are attached form a substituted or unsubstituted group consisting of C3-C12cycloalkyl, 3-12 membered heterocyclyl; wherein the substitution is by one or more R r substituted;

[0018] or R3and Rm together with the atom to which they are attached, form a substituted or unsubstituted group selected from the group consisting of C3-C12cycloalkyl, 3-12 membered heterocyclyl; wherein the substitution means substituted by one or more groups selected from the group consisting of deuterium, halogen, NR r substituted;

[0019] R8is each independently selected from the group consisting of substituted or unsubstituted halogen, NR p R p' , -CN, -OH, C1-C6alkyl, C1-C6alkoxy; wherein the substitution means substituted by one or more groups selected from the group consisting of deuterium, halogen, NR r substituted;

[0020] or two R8on the same C atom together with the C atom to which they are attached form a substituted or unsubstituted group selected from the group consisting of C3-C12cycloalkyl, 3-12 membered heterocyclyl or oxo (=0); wherein the substitution means substituted by one or more groups selected from the group consisting of deuterium, halogen, NR r substituted;

[0021] or two R8on adjacent C atoms together with the C atoms to which they are attached form a substituted or unsubstituted group selected from the group consisting of C3-C12cycloalkyl, 3-12 membered heterocyclyl; wherein the substitution means substituted by one or more groups selected from the group consisting of deuterium, halogen, NR r substituted;

[0022] n is 0, 1, 2 or 3;

[0023] m is 0, 1, 2, 3, 4, 5 or 6;

[0024] s is 1, 2 or 3;

[0025] R r is selected from the group consisting of deuterium, halogen, NR p R p' , -CN, -OH, C1-C6alkyl, C1-C6alkoxy, C3-C12cycloalkyl, 3-12 membered heterocyclyl, C6-C14aryl, 5-14 membered heteroaryl;

[0026] R', R" are each independently selected from the group consisting of H, C1-C6alkyl, halogenated C1-C6alkyl; or R', R" together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclyl, wherein the substitution means substituted by one or more groups selected from the group consisting of deuterium, halogen, C1-C6alkyl, halogenated C1-C6alkyl, C1-C6alkoxy;

[0027] R is selected from the group consisting of H, C1-C6alkyl, halogenated C1-C6alkyl, C3-C6cycloalkyl, 3-6 membered heterocyclyl, C6-C10aryl, 5-10 membered heteroaryl, (CH2)s C6-C10aryl.

[0028] In another preferred embodiment, the compound of Formula I, stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, wherein R2is selected from the group consisting of substituted or unsubstituted phenyl, naphthyl, pyridinone, pyridyl, pyrimidinyl, benzofuranyl, benzotetrahydrofuranyl, benzotetrahydropyranyl, benzodioxanyl, chromenyl, benzopyrazine; wherein the substitution is with one or more groups selected from deuterium, halogen, NR p R p' , -CN, -OH, C1-C6alkyl, C1-C6alkoxy, C3-C12cycloalkyl, 3-12 membered heterocyclyl, C6-C14aryl, 5-14 membered heteroaryl;

[0029] wherein R p , R p' , R, R' and R" are as defined above.

[0030] In another preferred embodiment, the compound of Formula I, stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, has the structure of Formula II:

[0031]

[0032] wherein,

[0033] * indicates R or S configuration;

[0034] R1, R2, R8and m are as defined above.

[0035] In another preferred embodiment, the compound of Formula I, stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, has the structure of Formula III:

[0036]

[0037] wherein,

[0038] * indicates R or S configuration;

[0039] R9is selected from: H, halogen, CN, OH, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6alkylamino, C1-C6haloalkylamino;

[0040] X is selected from: N, CR 10 wherein R10 Selected from: H, halogen, CN, OH, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, C1-C6 haloalkylamino

[0041]

[0042] The definitions of R1, R8, R', R” and m are as described above.

[0043] In another preferred embodiment, the compound of formula I, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs have the structure shown in formula IV:

[0044]

[0045] in,

[0046] * indicates R or S configuration;

[0047] R9 is selected from: H, halogen, CN, OH, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, C1-C6 haloalkylamino;

[0048] X is selected from: N, CR 10 , where R 10 Selected from: H, halogen, CN, OH, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, C1-C6 haloalkylamino

[0049]

[0050] R1 is selected from:

[0051] R, R', R”, R m R n R p The definitions of R3 and R4 are as described above.

[0052] In another preferred embodiment, the compound of formula I, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs have the structures shown in formulas V and VI:

[0053]

[0054] in,

[0055] * indicates R or S configuration;

[0056] X is selected from: N, CR 10 ;

[0057] R 10 and R9are each independently selected from: H, halogen, CN, OH, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6alkylamino, C1-C6haloalkylamino;

[0058] R3and R4are each independently selected from the following group of substituted or unsubstituted: H, halogen, NR p R p' , -CN, -OH, C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C10aryl, 5-10 membered heteroaryl; wherein the substitution means substituted with one or more R r substituents;

[0059] or R3and R4together with the C atom to which they are attached form a substituted or unsubstituted group selected from: C3-C8cycloalkyl, 3-8 membered heterocyclyl, or oxo (=O); wherein the substitution means substituted with one or more R r substituents;

[0060] R r is selected from: deuterium, halogen, NR p R p' , -CN, -OH, C1-C6alkyl, C1-C6alkoxy;

[0061] wherein R p , R p' , R, R' and R" are as defined above.

[0062] In another preferred embodiment, in formula I, R1, R2, R8, m and n are the specific groups corresponding to each of the specific compounds in the Examples.

[0063] In another preferred embodiment, the compound of formula I, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, wherein the compound is selected from the following compounds:

[0064]

[0065] In another preferred embodiment, the compound of formula I is selected from the compounds shown in the Examples.

[0066] In a second aspect, the present application provides a pharmaceutical composition comprising i) a therapeutically effective amount of a compound of Formula I, a stereoisomer, a tautomer, a salt, a hydrate, a solvate or a prodrug thereof; and ii) one or more pharmaceutically acceptable carriers.

[0067] In another preferred embodiment, the pharmaceutical composition further comprises a drug selected from the group consisting of a PD-1 inhibitor (such as Nivolumab, Pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009, or biosimilars of the above drugs, etc.), a PD-L1 inhibitor (such as Durvalumab, Atezolizumab, Avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311, or biosimilars of the above drugs, etc.), a CD20 antibody (such as Rituximab, Obinutuzumab, Ofatumumab, Veltuzumab, Tositumomab, 131I-Tositumomab, Ibritumomab tiuxetan, etc.), a CD47 antibody (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), an ALK inhibitor (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, Oclacitinib), a PI3K inhibitor (such as Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipalisib, Buparlisib, etc.), a BTK inhibitor (such as Ibrutinib, Tirabrutinib, Acalabrutinib, Zanabrutinib, Vecabrutinib, etc.), an EGFR inhibitor (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Egfrinib, Canertinib, Sapitinib, Naquotinib, Pyrotinib, Rolloitinib, Osimertinib, etc.), a VEGFR inhibitor (such as Sorafenib, Pazopanib, Regorafenib, Sitravatinib, Ningetinib, Cabozantinib, Sunitinib, Donafenib, etc.), an HDAC inhibitor (such as Givinostat, Tucidinostat, Vorinostat, Fimepinostat, Droxinostat, Entinostat, Dacinostat, Quisinostat, Tacedinaline, etc.), a CDK inhibitor (such as Palbociclib, Ribociclib, Abemaciclib, etc.),MEK inhibitors (such as selumetinib (AZD6244), trametinib (GSK1120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.), or a combination thereof.

[0068] In a third aspect, the present application provides a method for preparing a pharmaceutical composition, comprising the step of mixing a pharmaceutically acceptable carrier with the compound of the first aspect of the present application, or a stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug or solvate thereof, to form a pharmaceutical composition.

[0069] In another preferred embodiment, the compound of the present application can be prepared into powders, tablets, granules, capsules, solutions, emulsions, suspensions, etc.

[0070] In a fourth aspect, the present application provides the use of the compound of the first aspect of the present application, or a stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, for the preparation of a medicament for preventing and / or treating a disease characterized by NTRK-mediated pathology.

[0071] In another preferred embodiment, the disease characterized by NTRK-mediated pathology includes cancer, sarcoma and pain.

[0072] In another preferred embodiment, the cancer is selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, peritoneal tumor, melanoma, glioma, glioblastoma, head and neck cancer, renal cell carcinoma, leukemia, lymphoma, myeloma, thyroid tumor.

[0073] It should be understood that, within the scope of the present application, each of the technical features described above and in the following (such as the examples) can be combined with each other to form a new or preferred technical solution. Due to the limited space, they will not be listed one by one here. DETAILED DESCRIPTION

[0074] The present inventors have made extensive and in-depth research and unexpectedly found a new selective NTRK kinase inhibitor, which has good selective inhibition ability on NTRK kinase and has better pharmacodynamics, pharmacokinetics and lower side effects, and has great potential to develop into a drug for NTRK in urgent need in current clinical practice.

[0075] The term

[0076] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0077] When a substituent is described using a conventional chemical formula written from left to right, it also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0078] As used herein, when referring to a specific enumerated value, the term “about” means that the value can vary by no more than 1% from the enumerated values. For example, as used herein, the expression “about 100” includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0079] As used herein, the terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed. In other words, the terms also include “consistently made of” or “composed of”.

[0080] As used herein, the term "alkyl" includes straight-chain or branched alkyl groups. For example, C1-C6 alkyl groups refer to straight-chain or branched alkyl groups having 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.

[0081] "Halogenated alkyl" refers to an alkyl group as defined herein in which one or more hydrogen atoms are replaced by the same or different halogens. Examples of halogenated alkyl groups include -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl groups (e.g., -CF3), etc.

[0082] As used herein, the term "alkenyl" includes straight-chain or branched alkenyl groups. For example, C2-C6 alkenyl refers to straight-chain or branched alkenyl groups having 2-6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or similar groups.

[0083] As used herein, the term "alkynyl" includes straight-chain or branched alkynyl groups. For example, C2-C6 alkynyl refers to straight-chain or branched alkynyl groups having 2-6 carbon atoms, such as ethynyl, propynyl, butynyl, or similar groups.

[0084] As used herein, the term "cycloalkyl" refers to a cyclic alkyl group containing a specific number of carbon atoms, such as "C3-C10 cycloalkyl," which refers to a cycloalkyl group having 3 to 10 (preferably 3, 4, 5, 6, 7, or 8) carbon atoms. It can be monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar groups. It can also be bicyclic, such as bridged or spirocyclic. In this invention, cycloalkyl is intended to include substituted cycloalkyl groups.

[0085] As used herein, the term "C1-C6alkoxy" refers to a straight or branched chain alkoxy group having from 1 to 6 carbon atoms; having the formula C1-C6alkyl-O- or -C1-C5alkyl-O-C1-C5alkyl (e.g., -CH2-O-CH2CH3, -CH2-O-(CH2)2CH3, -CH2CH2-O-CH2CH3), for example, methoxy, ethoxy, propyloxy, isopropoxy, butoxy, isobutoxy, t-butoxy, and the like.

[0086] "Alkylamino" refers to a group of the formula -NRaRbwhere Ra is H or alkyl as defined herein, and Rb is alkyl as defined herein, or Ra and Rb together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclyl group.

[0087] As used herein, "heterocyclyl" refers to a saturated or partially saturated cyclic group having a heteroatom selected from N, S and O, "3-10 membered heterocyclyl" refers to a saturated or partially saturated cyclic group having from 3 to 10 atoms and wherein from 1 to 3 atoms are heteroatoms selected from the group consisting of N, S and O. It can be monocyclic or bicyclic, e.g., bridged or spirocyclic. 3-10 membered heterocyclyl is preferably 3-8 membered heterocyclyl, more preferably 6-8 membered heterocyclyl. Specific examples can be oxetanyl, azetidinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl and pyrrolidinyl, and the like.

[0088] As used herein, "aryl" refers to an aromatic cyclic group having no heteroatoms in the ring, "C6-C12aryl" refers to an aromatic cyclic group having from 6 to 12 carbon atoms in the ring having no heteroatoms, which aryl group can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure together is an aryl ring. Such as phenyl (i.e., six-membered aryl), naphthyl, and the like, wherein six-membered aryl is also meant to include six-membered aryl and 5-6 membered cycloalkyl and six-membered aryl and 5-6 membered heterocycloalkyl. C6-C12aryl is preferably C6-C10aryl. The aryl group can be optionally substituted or unsubstituted.

[0089] As used herein, "heteroaryl" refers to a cyclic aromatic group having 1-3 atoms that are heteroatoms selected from the group consisting of N, S, and O, and "5-12 membered heteroaryl" refers to a cyclic aromatic group having 5-12 atoms and wherein 1-3 atoms are heteroatoms selected from the group consisting of N, S, and O. It can be monocyclic or fused ring form. Specific examples can be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl, and (1,2,4)-triazolyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, and the like. The heteroaryl ring can be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring that is attached to the parent structure along with the heteroaryl ring is an aryl, heterocyclyl, or cycloalkyl ring. The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halo, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, amido, sulfonamido, formyl, carboxamido, carboxy, and carboxy ester groups, and the like.

[0090] As used herein, "halogen" or "halo" refers to F, Cl, Br, and I. More preferably, the halogen or halo is selected from F, Cl, and Br.

[0091] In the present application, the term "substituted" means that one or more hydrogen atoms on a particular group are replaced with a particular substituent. The particular substituent is the substituent described in the immediately preceding paragraph, or the substituent that appears in the respective example. Unless otherwise specified, a substituted group can have at one substituent selected from a particular group at any substitutable position on the group, and the substituents can be the same or different at each position. Those skilled in the art will appreciate that combinations of substituents contemplated by the present application are those combinations that are stable or chemically feasible.

[0092] Unless otherwise specified, the groups described in the present application are "substituted or unsubstituted". The groups of the present application can be substituted with a substituent selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxy, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl.

[0093] In the present application, the term "plurality" independently refers to 2, 3, 4, 5.

[0094] Unless otherwise stated, the structural formulae described herein are intended to include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomers) of the structure: for example, the R, S configurations for asymmetric centers, the (Z), (E) isomers for double bonds, and the like. Thus, a single stereochemical isomer or a mixture of enantiomeric, diastereomeric, or geometric (or conformational) isomers of a compound of the present application are within the scope of the present application.

[0095] As used herein, the term "tautomer" means structural isomers that differ in energy by a small amount, such that interconversion can occur. For example, prototropic tautomers (i.e., proton shift) include interconversion by proton migration, such as IH-indazole and 2H-indazole. Valence tautomers include interconversion by reorganization of some of the bonding electrons.

[0096] As used herein, the term "solvate" means a complex of a compound of the present application with solvent molecules in a specific stoichiometric ratio.

[0097] Active Ingredient

[0098] As used herein, the terms "compound of the present application" or "active ingredient of the present application" are used interchangeably to refer to a compound of Formula I, a stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

[0099] A compound of Formula I, a stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, has the structure,

[0100]

[0101] wherein R1, R2, R8, m, and n are as defined above.

[0102] Preferably, the compound of Formula I has the structure of Formula II:

[0103]

[0104] R1, R2, R8, and m are as defined above.

[0105] Preferably, in each of the above formulae, R2is selected from the group consisting of substituted or unsubstituted phenyl, naphthyl, pyridinonyl, pyridyl, pyrimidinyl, benzofuranyl, benzotetrahydrofuranyl, benzotetrahydropyranyl, benzodioxanyl, chroman, benzopyrazine;

[0106] wherein the substitution is with one or more groups selected from the group consisting of deuterium, halogen, NR p R p' , -CN, -OH, C1-C6alkyl, C1-C6alkoxy, C3-C12cycloalkyl, 3-12 membered heterocyclyl, C6-C14aryl, 5-14 membered heteroaryl;

[0107] wherein R p , R p' , R, R' and R" are as defined above.

[0108] Preferably, the compound of formula I has the structure of formula III:

[0109]

[0110] wherein,

[0111] X, R9, R1, R8 and m are as defined above.

[0112] Preferably, the compound of formula I has the structure of formula IV:

[0113]

[0114] wherein,

[0115] X, R9, R1 are as defined above.

[0116] Preferably, the compound of formula I has the structure of formula V or VI:

[0117]

[0118]

[0119] wherein,

[0120] * indicates R or S configuration;

[0121] X is selected from: N, CR 10 ;

[0122] R 10 and R9 are each independently selected from: H, halogen, CN, OH, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy;

[0123] R1 is selected from: H, C1-C6alkyl;

[0124] R3 and R4 are each independently selected from the group consisting of substituted or unsubstituted: H, halogen, NR p R p', -CN, -OH, C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C10aryl, 5-10 membered heteroaryl; wherein the substitution means substituted with one or more R r substitution;

[0125] or R3and R4together with the C atom to which they are attached form a substituted or unsubstituted group selected from C3-C8cycloalkyl, 3-8 membered heterocyclyl, or oxo (=0); wherein the substitution means substituted with one or more R r substitution;

[0126] R r is selected from: deuterium, halogen, NR p R p' , -CN, -OH, C1-C6alkyl, C1-C6alkoxy;

[0127] wherein R p , R p' , R, R' and R" are as defined above.

[0128] The salts that can be formed by the compounds of the present application are also within the scope of the present application. Unless otherwise specified, the compounds of the present application are understood to include salts thereof. The term "salt(s)", as used herein, refers to acid or base salts formed with inorganic or organic acids and bases. In addition, when a compound of the present application contains both a basic moiety, such as pyridine or imidazole, and an acidic moiety, such as carboxylic acid, zwitterions can be formed and are also included within the scope of the term "salt(s)". Pharmaceutically acceptable (i.e. non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g. in isolation and purification steps. Salts of the compounds of the present application can be formed by reacting a compound of the present application, such as Compound I, with an amount of an acid or a base, such as an equivalent amount of an acid or a base, in a medium such as one listed below, or by co-precipitating with an excess of an alternate salt form of the compound.

[0129] As used herein, "pharmaceutically acceptable salts" refer to salts that are suitable for use in medical therapy, that are derived from compounds of the present application and acids or bases. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is the acid addition salt of the compounds of the present application. Suitable acids for the formation of salts include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, phosphoric, formic, acetic, propionic, oxalic, malonic, succinic, fumaric, maleic, lactic, malic, tartaric, citric, picric, methanesulfonic, benzenesulfonic, benzenesulfonic, and the like; as well as aspartic acid, glutamic acid and the like acidic amino acids.

[0130] Prodrugs and solvates of the compounds of the application are also within the scope of the application. The term "prodrug" means a compound that is converted into the compounds, salts, or solvates of the application in vivo after administration to the subject. The compounds of the application include solvates, such as hydrates.

[0131] The compounds, salts, or solvates of the application can exist in tautomeric forms (e.g., amide and imine ether). All such tautomers are intended to be encompassed within the scope of the application.

[0132] All stereoisomers (e.g., those that result from the presence of an asymmetric carbon atom in the compounds of the application) are intended to be encompassed within the scope of the application. The individual stereoisomers of the compounds of the application can be isolated by physical methods such as preparative chromatography or by derivation followed by separation of the resultant diastereomers. Chiral centers of the application have the S or R configuration as defined by the International Union of Pure and Applied Chemistry (IUPAC) Recommendations 1974. Racemic forms can be resolved by physical methods such as fractional crystallization or by separation of the diastereomeric derivatives or by chromatography on a chiral support. Individual optical isomers can be obtained from the racemates by conventional methods, including but not limited to, salt formation with an optically active acid, followed by crystallization.

[0133] The compounds of the application are obtained by preparation, isolation, and purification, and are described herein in amounts equal to or greater than 90%, e.g., equal to or greater than 95%, equal to or greater than 99% ("very pure") of the compound. Such "very pure" compounds of the application are also intended to be encompassed by the application.

[0134] All configurational isomers of the compounds of the application are intended to be encompassed within the scope of the application, whether in admixture or in pure or very pure form. The definition of the compounds of the application includes both cis (Z) and trans (E) isomers of alkenes, as well as cis and trans isomers of carbocyclic and heterocyclic rings.

[0135] Throughout the specification, groups and substituents are chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0136] Specific functional group and chemical terms are defined below. For the purposes of the present application, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional group terms are used as defined by S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms, McGraw-Hill Single Available on the World Wide Web at http: / / www.mhhe.com / academic / chemistry / ehd_toc. thThe definitions of specific functional groups are also described in Ed. In addition, the principles of organic chemistry and the specific functional groups and reactivity are illustrated in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, the entire contents of which are incorporated herein by reference.

[0137] Certain compounds of the present application can exist in particular geometric or stereoisomeric forms. The present application contemplates all such isomers, including cis, and trans isomers, R and S enantiomers, diastereomers, (D) and (L) isomers, racemic mixtures and other mixtures thereof. Additionally, an asymmetric carbon atom can represent a substituent group, such as an alkyl group. All isomers and mixtures thereof are contemplated by the present application.

[0138] According to the present application, mixtures of isomers can contain a variety of ratios of isomers. For example, mixtures of only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0, and all ratios of isomers are within the scope of the present application. Similar ratios, as would be readily understood by one of ordinary skill in the art, and ratios for more complex mixtures of isomers are also within the scope of the present application.

[0139] The present application also includes isotopically-labelled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl. The present application also includes the prodrugs, salts, and solvates of the compounds of the present application and the compounds of the present application containing certain isotopic substitutions as set forth above. Certain isotopically-labeled compounds of the present application, for example, 3 H and 14 C, are useful in drug and substrate tissue distribution assays. Tritiated, i.e.,3 H and carbon-14, i.e. 14 C, are easier to make and detect. C is the preferred isotope. In addition, heavier isotope substitution, such as deuterium, i.e. 2 H, can be preferred in certain instances because of its superior metabolic stability, which results in advantages in therapy, such as increased half-life in vivo or reduced dosage, and the like. Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art, by substituting one or more of the hydrogen atoms normally present in the compounds with its isotope, e.g., tritium, i.e.

[0140] If a compound of the application is designed to be synthesized as a specific enantiomer, it can be prepared by asymmetric synthesis, or derivatized with a chiral auxiliary to form a diastereomeric mixture, which can then be separated and the chiral auxiliary removed to yield the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, it can be resolved by formation of a diastereomeric salt with a suitable optically active acid or base, and separated by conventional means, such as fractional crystallization or chromatography, to yield the pure enantiomer.

[0141] As described herein, the compounds of the application can be expanded to include any number of substituents or functional groups. In general, the term "substituted" whether preceded by an "optionally" or not, is intended to refer to the replacement of hydrogen radicals in the compounds of the application with the specified substituents. When a number of substituents are present in a particular structure, each substituent can be the same or different. The term "substituted" as used herein includes all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic moieties. In the present application, for example, the heteroatom nitrogen can have a hydrogen substituent or any permissible organic moiety as described above to complete its valence. In no way is the application intended to be limited to any specific grouping of permissible substituents. The application contemplates that the combination of substituents and variables is in the form of a stable compound that is useful for the treatment of disease. The term "stable" is intended to refer to compounds that are sufficiently robust to survive isolation from a reaction mixture, and formulation into an efficacious therapeutic agent. The term is used herein to refer to compounds that are sufficiently robust to survive isolation from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0142] Metabolites of compounds of the application and their pharmaceutically acceptable salts, as well as in vivo biohydrolyzable prodrugs of any of the foregoing, are considered within the scope of the application. The term "prodrug" is used in its broadest sense to refer to any compound that upon administration to a mammal is capable of providing, either directly or indirectly, a compound of the application or a pharmaceutically acceptable salt thereof. Thus, prodrugs of the application can be useful for increasing the half-life of the active drug in the body, or for improving the bioavailability of the active drug.

[0143] Methods of preparation

[0144] The compounds of the present application can be readily prepared using the methods described in this application or by modifications thereof, by combinations of these methods, or by methods known to those skilled in the art. Such modifications of the synthetic routes described in the preceding Schemes would be readily apparent to one skilled in the art, and are encompassed within the scope of the present application. The starting materials used in the following preparations can be obtained from commercial sources or synthesized by techniques generally known in the art.

[0145] Generally, in the preparative sequences, the reactions are typically carried out in an inert solvent at temperatures ranging from -60 °C to 100 °C, preferably from -60 °C to 80 °C. The reaction time is typically from 0.1 hour to 60 hours, preferably from 0.5 to 48 hours.

[0146] Preferred synthetic routes are as follows:

[0147] Route One

[0148] (1) Compound 1 and compound 2 undergo a nucleophilic substitution reaction in the presence of a base (such as sodium carbonate, potassium carbonate, sodium hydroxide, triethylamine, pyridine, etc.) in an inert solvent (such as ethanol, methanol) to form compound 3;

[0149] (2) Compound 3 reacts with the solvent system in the presence of an acid (such as hydrochloric acid, etc.) in an inert solvent (such as ethanol, methanol) to form compound 4;

[0150] (3) Compound 4 reacts with the corresponding reagent in the presence of an acid catalyst in an inert solvent (such as toluene or xylene, etc.) to form the final product 5;

[0151]

[0152] Route Two

[0153] (1) Compound 1 and compound 2 undergo a nucleophilic substitution reaction in the presence of a base (such as sodium tert-butoxide, potassium tert-butoxide, sodium hydride, potassium hydride, potassium carbonate, cesium carbonate, potassium phosphate, potassium hydroxide, sodium hydroxide, etc.) in an inert solvent (such as toluene) to form compound 3;

[0154] (2) Compound 3 reacts with in the presence of trimethylaluminum in an inert solvent (such as toluene) to form the final product 4;

[0155]

[0156] Route Three

[0157] (1) Compound 1 and compound 2 undergo a nucleophilic substitution reaction in the presence of a base (such as sodium carbonate, potassium carbonate, sodium hydroxide, triethylamine, pyridine, etc.) in an inert solvent (such as ethanol, methanol) to form compound 3;

[0158] (2) Compound 3 is reacted with hydroxylamine hydrochloride in the presence of a base (e.g. sodium carbonate, potassium carbonate, sodium hydroxide, triethylamine, pyridine, etc.) in an inert solvent (e.g. ethanol, methanol) to form compound 4;

[0159] (3) Compound 4 is reacted with a corresponding reagent (e.g. dimethoxyacetal, dimethoxyacetal) in an inert solvent (e.g. 1,2-dichloroethane and / or glacial acetic acid) to obtain the final product 5;

[0160]

[0161] In the above formulae,

[0162] X is selected from: Cl, Br, I;

[0163] R t is C1-C6 alkyl;

[0164] R1, R2, R8, R m , R n , R p , R3, R4, m and n are defined as above.

[0165] The starting materials of the present application are known and commercially available, or can be synthesized according to the literature reported in the art.

[0166] Pharmaceutical composition and administration method

[0167] The pharmaceutical composition of the present application is used for preventing and / or treating the following diseases: inflammation, cancer, cardiovascular disease, infection, immunological disease, metabolic disease.

[0168] The compound of the present application can be used in combination with other drugs known to treat or ameliorate similar conditions. When administered in combination, the original dosages of the drugs can be kept unchanged, and the compound of the present application is administered at a reduced dosage. When the compound of the present application is used in combination with other drugs, it can be preferable to use a pharmaceutical composition containing the known drug(s) and the compound of the present application in a single formulation. The combination of drugs also includes administration of the compound of the present application and the other known drug(s) in overlapping time periods. When the compound of the present application is used in combination with other drugs, the dosage of the compound of the present application or the known drug(s) can be lowered than that administered alone.

[0169] The dosage form of the pharmaceutical composition of the present application includes (but is not limited to): injection, tablet, capsule, aerosol, suppository, film, dripping pill, external liniment, controlled release or sustained release or nano-preparation.

[0170] The pharmaceutical compositions of the present application comprise a safe and effective amount of a compound of the present application or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. By "safe and effective amount" is meant an amount of the compound sufficient to significantly induce a desired effect, without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of a compound of the present application per dose, more preferably, 10-1000 mg of a compound of the present application per dose. Preferably, the "dose" is a capsule or tablet.

[0171] "Pharmacologically acceptable carrier" means one or more compatible solid or liquid filler or gel materials which are suitable for human use and which are nontoxic, and which are sufficiently pure and sufficiently free from deleterious effects to render it appropriate for use in the present application. By "compatible" is meant that the carrier is not chemically-reactive with the compound of the present application and that the carrier is not deleterious to the activity of the compound of the present application. Examples of suitable pharmacologically acceptable carriers are cellulose and its derivatives (e.g., sodium carboxymethyl cellulose, ethyl cellulose sodium, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., lecithin), wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

[0172] The mode of administration of the compounds or pharmaceutical compositions of the present application is not critical. Representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical.

[0173] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or with such solid or liquid fillers or carriers as are known in the art, such as: (a) fillers or extenders, e.g., starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, e.g., hydroxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, e.g., glycerol; (d) disintegrating agents, e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders, e.g., paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, e.g., cetyl alcohol and glycerol monostearate; (h) absorbents, e.g., kaolin and bentonite clay; and (i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage form can also comprise buffering agents.

[0174] ​Solid dosage forms such as tablets, sugar coated tablets, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other well-known materials. They can contain opacifying agents and can also be of a composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0175] Liquid dosage forms for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms can contain inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and the like, as well as mixtures thereof.

[0176] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0177] Suspensions, in addition to the active compounds, can contain suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, and agar-agar, as well as mixtures thereof.

[0178] The compositions for parenteral injection can contain physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyol, glycols, and suitable mixtures thereof.

[0179] Dosage forms of the compounds of the present application for topical administration include ointments, powders, sprays, and inhalers. The active compound is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as can be required.

[0180] The therapeutic methods of the present application can be administered by themselves or in conjunction with other treatment modalities or therapeutic agents.

[0181] The pharmaceutical compositions are administered in a safe and effective amount, which is a quantity sufficient to treat the condition in a mammal, such as a human, to which the compositions are applied, and which is a quantity that is pharmaceutically effective when administered in the dosages contemplated, generally 1-2000 mg, preferably 10-1000 mg, per day for a 60 kg body weight human. The specific dose level and frequency of dosage will depend on the nature of the pharmaceutical compositions, on the particular patient treated, and on the severity of the condition to be treated. These factors are within the skill of a competent physician.

[0182] The present application also provides a method for preparing a pharmaceutical composition, comprising the step of mixing a pharmaceutically acceptable carrier with a compound of the present application or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, thereby forming a pharmaceutical composition.

[0183] The present application also provides a method for treatment, comprising the step of administering to a subject in need thereof a compound of the present application or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or a pharmaceutical composition of the present application, for selectively inhibiting NTRK fusion mutations and drug-resistant mutations thereof.

[0184] The present application has the following main advantages:

[0185] (1) The compound of the present application has good selective inhibitory ability on NTRK kinase,

[0186] (2) The compound of the present application has good inhibitory ability on the activity of NTRK drug-resistant mutations;

[0187] (3) The compound of the present application has better pharmacodynamics, pharmacokinetics and lower side effects;

[0188] (4) The compound of the present application has great potential to develop into a drug for NTRK which is in urgent need in current clinical treatment.

[0189] The technical solutions of the present application are further described below, but the scope of protection of the present application is not limited thereto.

[0190] The present application is further described below in combination with specific examples. It should be understood that these examples are only used to illustrate the present application and not to limit the scope of the present application. The experimental methods in the following examples are not specified, which are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturers. Unless otherwise specified, percentages and parts are calculated by weight.

[0191] Example 1

[0192]

[0193] The synthetic route and experimental process are as follows:

[0194]

[0195] 1. Synthesis of INT

[0196] INT-1 (200 mg, 1.94 mmol) and anhydrous ethanol (1 mL) were added into a 50 mL single-neck flask.

[0197] Add dropwise thionyl chloride (0.35 mL, 4.85 mmol) under ice bath condition, then react at 75 °C for 6 h. TLC shows the reaction is complete, concentrate the reaction, adjust pH = 8 with K2C03aq, extract with DCM for 3 times, combine the organic phase, dry the organic phase with anhydrous Na2S04, filter, concentrate to give 100 mg of light yellow oil.

[0198] 2. Synthesis of C-10-2

[0199] Add C-10-1 (200 mg, 0.615 mmol), anhydrous ethanol (82 mg, 1.84 mmol), HC1 / dioxane (1 mL, 4 M) and toluene (1 mL) in a 100 mL single neck flask. React at 25 °C for 16 h, LC-MS shows the reaction is complete, concentrate the reaction, adjust pH = 9 with 15% NaOH aq. Extract with EA for 3 times, combine the organic phase, dry the organic phase with anhydrous Na2S04, filter, concentrate, column chromatography (DCM:MeOH = 30:1) to give 50 mg of white foam.

[0200] 3. Synthesis of C-10

[0201] Add C-10-2 (531 mg, 1.43 mmol), INT (750 mg, 5.72 mmol), glacial acetic acid (5 uL) and toluene (5 mL) in a 50 mL single neck flask. Protect with nitrogen, react at 130 °C for 6 h, LC-MS shows the reaction is complete, concentrate the reaction, adjust pH = 7 with saturated NaHC03aq, extract with EA for 3 times, combine the organic phase, dry the organic phase with anhydrous Na2S04, filter, concentrate, column chromatography (DCM:MeOH = 30:1) to give 200 mg of white solid.

[0202] NMR analysis data of compound C-10: 1 H NMR (400 MHz, CDC13): δ 9.50 (s, 0.15H), 8.66 (s, 0.15), 8.52-8.34 (m, 1.5H), 8.24-8.17 (m, 0.3H), 7.22-7.09 (m, 1H), 6.76-6.72 (m, 1H), 6.64-6.44 (d. 0.5H), 6.39-6.38 (d, 0.2H), 5.98-5.91 (m, 0.3H), 5.63-5.61 (d, 0.5H), 5.54 (br, 0.2H), 5.24 (br, 0.3H), 4.07-4.05 (br, 0.3H), 3.99-3.90 (m, 1H), 3.77-3.71 (m, 0.7H), 2.60-2.50 (m, 1H), 2.31-2.04 (m, 3H), 1.52-1.32 (m, 4.5H), 1.24 (s, 1.5H).

[0203] Example 2

[0204]

[0205] The synthetic route and experimental procedure are as follows:

[0206]

[0207] 1. Synthesis of C2-1

[0208] Into a 50 mL single neck flask was placed C1-1 (450 mg, 2.78 mmol), diethylzinc (4 mL, 4.16 mmol), Pd(PPh3)2Cl2, dichloromethane (227 mg, 0.278 mmol) and dioxane (3 mL). The reaction was carried out at 80 °C overnight under nitrogen protection. LC-MS showed the reaction was completed. The reaction was quenched by adding pure water (30 mL), extracted by ethyl acetate (30 mL x 3), the organic phase was dried by anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography (PE:EA = 2:1-1:1) to give 150 mg.

[0209] 2. Synthesis of C2-2

[0210] Into a 50 mL single neck flask was placed C2-1 (150 mg, 1.0 mmol), IBX (677 mg, 2.5 mmol), and EA (5 mL), and the temperature was raised to 80 °C, and the reaction was carried out for 2.5 hours. LC-MS showed the reaction was completed. The reaction was filtered, the filter cake was washed with EA three times, the organic phase was dried by anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography (PE:EA = 2:1-1:1) to give 120 mg.

[0211] 3. Synthesis of C2-3

[0212] Into a 50 mL single neck flask was placed C2-2 (120 mg, 0.78 mmol), R- tert-butylsulfmide (118 mg, 0.80 mmol), cesium carbonate (228 mg, 0.54 mmol) and DCM (2 mL). The reaction was carried out at 25 °C for 4 hours. LC-MS showed the reaction was completed. The reaction was filtered, the filter cake was washed with DCM three times, the organic phase was dried by anhydrous sodium sulfate, concentrated under reduced pressure to give 150 mg of yellow oil.

[0213] 4. Synthesis of C2-4

[0214] In a 50 mL flask, C2-3 (150 mg, 0.41 mmol) and THF (5 mL) were added, C1-11 (1.64 mL, 0.82 mmol) was added dropwise at 0 °C, after the addition was completed, the reaction was stirred at room temperature for 2 hours. LC-MS showed that the reaction was completed, NH4Cl saturated solution (30 mL) was added, EA was extracted, the organic phase was dried and concentrated to give 180 mg of crude product, [M+H]: 373.3.

[0215] 5. Synthesis of C2-5

[0216] The crude product of C2-4 was dissolved in trifluoroacetic acid (1 mL) and water (0.2 mL), under nitrogen protection, the temperature was raised to 40 °C, stirred for 1 hour, then triethylsilane (137.8 mg, 0.82 mmol) was added dropwise, stirred at 40 °C for 12 hours. LC-MS showed that the reaction was completed, concentrated, 2M hydrochloric acid (10 mL) and EA (10 mL) were added, and the liquid was separated. Adjust the pH to 13 with 15% NaOH, extract with EA (10 mL) for three times, separate, dry and concentrate the EA phase to give 60 mg, which was used directly in the next step, [M+H]: 195.2.

[0217] NMR analysis data of compound C2-5: 1 H NMR (400 MHz, CDCl3): δ 8.24-8.23 (d, 1H), 7.69-7.66 (dd, 1H), 4.37-4.33 (m, 1H), 3.22-3.04 (m, 2H), 2.29-2.28 (m, 1H), 1.94-1.85 (m, 3H), 1.53-1.46 (m, 3H), 1.30-1.26 (m, 3H).

[0218] 6. Synthesis of C2-6

[0219] In a 50 mL flask, C1-5 (140 mg, 0.72 mmol), C1-9 (131 mg, 0.73 mmol), triethylamine (0.6 mL, 4.32 mmol) and EtOH (5 mL) were added, and the reaction was placed at 55 °C for 2 hours. LC-MS showed that the reaction was completed, water (15 mL) was added and stirred for 30 min, then cooled to room temperature and filtered to give a white solid 200 mg, [M+H]: 337.2.

[0220] NMR analysis data of compound C2-6: 1H NMR (400 MHz, d6-DMSO): δ 8.82-8.59 (m, 1H), 8.43-8.27 (m, 2H), 7.35-7.17 (m, 1H), 6.74-6.72 (d, 1H), 6.02-5.94 (m, 1H), 5.50-5.35 (m, 1H), 4.13-4.08 (m, 1H), 3.79-3.62 (m, 1H), 3.06-2.96 (m, 1H), 2.90-2.83 (m, 1H), 2.08-1.77 (m, 3H), 1.30-1.31 (m, 3H).

[0221] 7. Synthesis of C2-7

[0222] In a 50 mL single-necked flask, C2-6 (800 mg, 2.38 mmol), hydroxylamine hydrochloride (1.15 g, 13.3 mmol), potassium carbonate (2.32 g, 13.3 mmol) and EtOH (20 mL), dioxane (10 mL) were added, and the reaction was placed at 80 °C for overnight. LC-MS showed the reaction was completed, 30 mL water was added, and EA was extracted three times, dried over anhydrous sodium sulfate, concentrated, and column chromatography (DCM:MeOH = 100:1-20:1) to give 600 mg, [M+H]: 370.3.

[0223] 8. Synthesis of C2

[0224] In a 50 mL single-necked flask, C2-7 (600 mg, 1.62 mmol), 2,2-dimethoxypropane (676 mg, 6.50 mmol) and acetic acid (5 mL), DCE (5 mL) were added, and the reaction was placed at 80 °C for 2 h. LC-MS showed the reaction was completed, concentrated, saturated aqueous sodium bicarbonate solution was added to adjust the pH value to 7, EA was extracted, and column chromatography (DCM:MeOH = 150:1-50:1) to give 200 mg of light yellow solid, [M+H]: 410.3.

[0225] NMR analysis data of compound C2: 1 H NMR (400 MHz, d6-DMSO): δ 8.82-8.59 (m, 1H), 8.43-8.27 (m, 2H), 7.35-7.17 (m, 1H), 6.74-6.72 (d, 1H), 6.02-5.94 (m, 1H), 5.50-5.35 (m, 1H), 4.13-4.08 (m, 1H), 3.79-3.62 (m, 1H), 3.06-2.96 (m, 1H), 2.90-2.83 (m, 1H), 2.08-1.77 (m, 3H), 1.30-1.31 (m, 3H).

[0226] Example 3

[0227]

[0228] The synthetic route and experimental process are as follows:

[0229]

[0230] 1. Synthesis of C3-1

[0231] Into a 50 mL single-necked flask was added 2-methoxy-5-fluorobenzaldehyde (1.0 g, 6.45 mmol), R-tert-butylsulfonamide (820 mg, 6.78 mmol), cesium carbonate (1.46 g, 4,49 mmol) and DCM (10 mL), and the mixture was reacted at 25 °C for 3 hours. LC-MS showed that the reaction was complete, the filter cake was washed with DCM three times, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2.55 g.

[0232] NMR analysis data of compound C3-1: 1 H NMR (400 MHz, CDCl3): δ 8.89-8.88 (d, 1H), 8.16-8.15 (d, 1H), 7.99-7.96 (dd, 1H), 4.01 (s, 3H), 1.27 (m, 9H).

[0233] 2. Synthesis of C3-2

[0234] Into a 50 mL three-necked flask was added C3-1 (200 mg, 0.78 mmol) and THF (5 mL), and C1-11 (3.12 mL, 1.56 mmol) was added dropwise at 0 °C. After the addition was completed, the mixture was reacted at room temperature for 2 hours. LC-MS showed that the reaction was complete, saturated NH4Cl solution (30 mL) was added, the organic phase was dried and concentrated to obtain 220 mg of a crude product.

[0235] NMR analysis data of compound C3-2: 1 H NMR (400 MHz, CDCl3): δ 7.84-7.83 (d, 1H), 7.58-7.54 (dd, 1H), 4.31-4.27 (m, 1H), 3.93 (s, 3H), 3.15-3.01 (m, 2H), 2.38 (s, 1H), 1.87-1.79 (m, 2H), 1.60-1.53 (m, 1H).

[0236] 3. Synthesis of C3-3

[0237] C3-2 was dissolved in trifluoroacetic acid (1 mL) and water (0.2 mL) under nitrogen protection, and stirred at 40 °C for 1 h, then triethylsilane (202 mg, 1.20 mmol) was added dropwise, and stirred at 40 °C for 12 h. LC-MS showed the reaction was completed, and concentrated. The pH was adjusted to 13 with 15% NaOH, and extracted with EA (10 mL) for three times, separated, dried, and concentrated the EA phase to get 100 mg, which was used directly in the next step.

[0238] 4. Synthesis of C3-4

[0239] C3-3 (100 mg, 0.51 mmol), C1-9 (95.3 mg, 0.54 mmol), triethylamine (154.5 mg, 1.53 mmol) and EtOH (2 mL), THF (0.5 mL) were added into a 50 mL single-neck flask, and the reaction was placed at 55 °C for 2 h. LC-MS showed the reaction was completed, water (15 mL) was added and stirred for 30 min, and then filtered after cooling to room temperature to get 260 mg of white solid.

[0240] NMR analysis data of compound C3-4: 1 H NMR (400 MHz, CDC13): δ 8.15-8.13 (s, 1H), 7.93 (s, 1H), 6.98-6.77 (d, 1H), 5.90-5.89 (m, 1H), 4.09 (s, 3H), 4.07 (s, 3H), 4.01 (s, 1H), 2.48-2.39 (m, 1H), 2.07-1.83 (m, 3H).

[0241] 5. Synthesis of C3-5

[0242] C3-4 (100 mg, 0.30 mmol), hydroxylamine hydrochloride (40.8 mg, 0.59 mmol), potassium carbonate (82.2 mg, 0.59 mmol) and EtOH (2 mL), dioxane (1 mL) were added into a 50 mL single-neck flask, and the reaction was placed at 80 °C overnight. LC-MS showed the reaction was completed, water (10 mL) was added, and extracted with EA for three times, dried with anhydrous sodium sulfate, concentrated, and column chromatography (DCM:MeOH = 100:1-20:1) to get 104 mg.

[0243] 8. Synthesis of C3

[0244] Into a 50 mL single neck flask was added C3-5 (240 mg, 0.65 mmol), 2,2-dimethoxypropane (269 mg, 2.59 mmol) and acetic acid (2 mL), the reaction was placed at 45 °C for 16 h. LC-MS showed the reaction was complete, concentrated, saturated aqueous sodium bicarbonate solution was added to adjust the pH to 7, EA extraction, column chromatography (DCM:MeOH = 150:1-30:1), to get 160 mg of light yellow solid, [M+H]: 372.2.

[0245] NMR analysis data of compound C3: 1 H NMR (400 MHz, CDCl3): δ 8.34-8.18 (m, 2H), 7.90 (s, 1H), 7.06-6.89 (m, 1H), 6.34-6.17 (m, 1H), 5.89-5.64 (m, 1H), 5.42-5.01 (m, 1H), 4.05 (s, 3H), 3,86-3.63 (m, 2H), 2.44 (m, 1H), 2.13-2.01 (m, 3H), 1.49 (s, 3H), 1.07 (s, 3H).

[0246] Example 4

[0247]

[0248] The synthesis route and experimental process are as follows:

[0249]

[0250] 1. Synthesis of C4-1

[0251] Into a 100 mL single neck flask was added 2-chloro-5-fluoro nicotinic acid (10 g, 52.91 mmol), iodoethane (9.90 g, 63.49 mmol), potassium carbonate (22.06 g, 158.73 mmol) and DMF (50 mL). The reaction was placed at 50 °C for 16 h, LC-MS showed the reaction was complete, water (200 mL) was added, EA extraction three times, the organic phase was combined, the organic phase was washed with water five times. The organic phase was dried with anhydrous ammonium sulfate, filtered, concentrated, column chromatography (PE:EA = 50:1), to get 9.6 g of light yellow oil.

[0252] NMR analysis data of compound C4-1: 1 H NMR (400 MHz, CDCl3): δ 8.34-8.18 (m, 2H), 7.90 (s, 1H), 7.06-6.89 (m, 1H), 6.34-6.17 (m, 1H), 5.89-5.64 (m, 1H), 5.42-5.01 (m, 1H), 4.05 (s, 3H), 3,86-3.63 (m, 2H), 2.44 (m, 1H), 2.13-2.01 (m, 3H), 1.49 (s, 3H), 1.07 (s, 3H).

[0253] 2. Synthesis of C4-2

[0254] Into a 50 mL single-necked flask was placed C4-1 (500 mg, 2.46 mmol), NaH (296 mg, 7.40 mmol) and toluene (10 mL), and EtOH (340 mg, 7.39 mmol) was added dropwise under ice-bath conditions, followed by reaction overnight at 25 °C. TLC detection showed that the reaction was completed, and the mixture was filtered, concentrated, and subjected to column chromatography (PE:EA = 10:1) to give 210 mg of a light yellow oil.

[0255] NMR analysis data of compound C4-2: 1 H NMR (400 MHz, CDCl3): δ 8.13-8.12 (d, 1H), 7.91-7.98 (dd, 1H), 4.45-4.43 (q, 2H), 4.38-4.36 (q, 2H), 1.44-1.37 (m, 6H).

[0256] 3. Synthesis of C4-3

[0257] Into a 50 mL three-necked flask was placed C4-2 (200 mg, 0.94 mmol) and DCM (3 mL) under nitrogen protection, and DIBAL-H (0.14 mL, 1.41 mmol) was added dropwise under cooling to -20 °C, followed by reaction overnight at 25 °C. TLC detection showed that the reaction was completed, 10% NaOH (10 mL) was added, stirred for 10 min, extracted with dichloromethane three times, dried, filtered, concentrated, and subjected to column chromatography (PE:EA = 20:1) to give 160 mg of a light yellow oil.

[0258] NMR analysis data of compound C4-3: 1 H NMR (400 MHz, CDCl3): δ 7.87-7.88 (d, 1H), 7.43-7.40 (dd, 1H), 4.64-4.63 (m, 2H), 4.39-4.37 (q, 2H), 1.40-1.37 (t, 3H).

[0259] 4. Synthesis of C4-4

[0260] Into a 250 mL single-necked flask was placed C4-3 (3.0 g, 17.54 mmol), IBX (12.3 g, 43.93 mmol) and EA (100 mL), and the mixture was heated to 80 °C, and reacted for 2.5 h. LC-MS showed that the reaction was completed, the mixture was filtered, the filter cake was washed with EA three times, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 3.0 g.

[0261] 5. Synthesis of C4-5

[0262] Into a 100 mL single neck flask was added C4-4 (2.8 g, 16.57 mmol), R- tert-butylsulfonamide (2.18 g, 18.01 mmol), cesium carbonate (4.0 g, 12.27 mmol) and DCM (30 mL). The reaction was stirred at 25 °C for 4 h. LC-MS showed the reaction was complete. The reaction was filtered, the filter cake was washed with DCM three times, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 5.0 g of yellow oil.

[0263] 6. Synthesis of C4-6

[0264] Into a 250 mL three neck flask was added C4-5 (5.0 g, 18.38 mmol) and THF (50 mL), under nitrogen protection, C1-11 (73.53 mL) was added. LC-MS showed the reaction was complete. The reaction was quenched with saturated solution of ammonium chloride, extracted with EA three times, dried and concentrated to give 8.0 g of crude product.

[0265] 7. Synthesis of C4-7

[0266] The crude product was dissolved in trifluoroacetic acid (15 mL) and water (3 mL), under nitrogen protection, the temperature was raised to 40 °C and stirred for 1 h. Then triethylsilane (5.496 g, 47.26 mmol) was added dropwise, the reaction was stirred at 40 °C for 12 h. LC-MS showed the reaction was complete. The reaction was concentrated, 2 M hydrochloric acid (20 mL) and EA (20 mL) were added, the mixture was separated. The aqueous phase was adjusted to pH 13 with 15% NaOH, extracted with EA three times, the EA phase was concentrated to give 2.0 g of crude product which was used directly in the next step.

[0267] 8. Synthesis of C4-8

[0268] Into a 50 mL single neck flask was added C4-7 (1.05 g, 0.50 mmol), C1-9 (0.91, 0.50 mmol), triethylamine (4.2 mL, 1.50 mmol) and EtOH (20 mL), the reaction was stirred at 55 °C for 2 h. LC-MS showed the reaction was complete. Water (100 mL) was added and stirred for 30 min, the temperature was lowered to room temperature and filtered to give 1.4 g of white solid.

[0269] 9. Synthesis of C4-9

[0270] In a 100 mL single-neck flask, C4-8 (1.4 g, 4.26 mmol), hydroxylamine hydrochloride (1.5 g, 21.7 mmol), potassium carbonate (3.0 g, 21.6 mmol) and EtOH (40 mL), dioxane (20 mL) were added. The reaction was placed at 80 °C overnight. LC-MS showed the reaction was completed, 100 mL water was added, EA extraction, dried over anhydrous sodium sulfate, concentrated, column chromatography (DCM:MeOH = 100:1-20:1), 900 mg was obtained.

[0271] 10. Synthesis of C4

[0272] In a 50 mL single-neck flask, C4-9 (900 mg, 2.51 mmol), 2,2-dimethoxypropane (870 mg, 8.36 mmol) and acetic acid (10 mL), DCE (10 mL) were added. The reaction was placed at 80 °C for 3 h. LC-MS showed the reaction was completed, concentrated, saturated aqueous sodium bicarbonate solution was added to adjust the pH value to 7, EA extraction, column chromatography (DCM:MeOH = 150:1-50:1), 350 mg of light yellow solid was obtained.

[0273] NMR analysis data of compound C4: 1H NMR (400 MHz, d6-DMSO): δ 8.76-8.51 (m, 1H), 8.06-8.01 (m, 1H), 7.40-7.33 (m, 1H), 6.67-6.61 (m, 1H), 5.91-5.75 (m, 1H), 5.28-5.12 (m, 1H), 4.45-4.33 dd, 2H), 3.98-3.97 (d, 1H), 3.70-3.58 (m, 1H), 2.40-2.47 (m, 1H), 2.01-1.86 (m, 3H), 1.46-1.34 (m, 7H), 2.39 (s, 2H).

[0274] Example 5

[0275]

[0276] The synthesis route and experimental process are as follows:

[0277]

[0278] The specific steps are as follows:

[0279] Step 1 (first step)

[0280] Compound 1 (5 g, 0.015 mol, 1 eq) and INT-TRN (3.72 g, 0.016 mol, 1.05 eq) were added into EtOH / THF (40 ml, volume ratio 4:1), triethylamine (4.7 g, 0.047 mol, 3 eq) was added under stirring, then the temperature was raised to 55 °C for 16 h, after the raw material was completely reacted, the reaction solution was spin-dried, diluted with ethyl acetate, washed with brine three times, the organic phase was combined, dried over anhydrous sodium sulfate, the organic phase was spin-dried, purified by column (petroleum ether: ethyl acetate = 1:1) to obtain compound 2 (4.5 g of white solid, purity 98%, yield 76.6%).

[0281] NMR analysis data of compound 2: 1 H-NMR (400 MHz, CDCl3): δ 8.28 (s, J = 2.8 Hz, 1H), 8.16 (s, J = 5.6 Hz, 1H), 7.15-6.82 (d, J = 6.4 Hz, 2H), 6.81-6.70 (m, 1H), 6.01-5.07 (m, 1H), 4.49-3.77 (m, 4H), 2.53 (s, J = 11.6 Hz, 1H), 2.07 (t, J = 10.0 Hz, 3H), 1.53-1.11 (m, 3H); MS: 373 (M+H + ).

[0282] Step 2 (second step)

[0283] 1,2-propanediamine (0.12 g, 0.016 mol, 2 eq) was dissolved in dry toluene (2 ml), the reaction system was reduced to 0 °C under argon protection, then trimethylaluminum (0.9 ml, 2M, dissolved in toluene) was slowly added dropwise, after the addition was completed, the temperature was raised to room temperature and the reaction was continued for 2 h, then the temperature was reduced to 0 °C again, and a toluene solution (3 ml) of compound 2 (0.3 g, 0.0080 mol, 1 eq) was slowly added dropwise, after the addition was completed, the reaction was continued for 30 min, then the temperature was raised to 80 °C and the reaction was continued for 16 h, after the raw material was completely reacted, the reaction system was reduced to 0 °C, then methanol was added to quench, filtered, the filtrate was spin-dried and purified by column twice to obtain compound C-5 (80 mg, brown-yellow solid, purity 98.6%, yield 26%).

[0284] NMR analysis data of compound C-5: 1H-NMR (400 MHz, CDC13): δ 8.28 (s, J = 2.8 Hz, 1H), 8.16 (s, J = 5.6 Hz, 1H), 7.15-6.82 (d, J = 6.4 Hz, 2H), 6.81-6.70 (m, 1H), 6.01-5.07 (m, 1H), 5.59-5.39 (m, 1H), 4.23-3.55 (m, 4H), 2.61-2.38 (m, 1H), 2.27-2.07 (m, 2H), 1.38-0.70 (m, 6H). MS: 383 (M+H + ).

[0285] Example 6

[0286]

[0287] The synthetic route and experimental process are as follows:

[0288]

[0289] Step 1 (first step)

[0290] Compound C-6 (60 mg, white solid, purity 98.4%, yield 18.7%) was obtained by dissolving 1,2-diamino-2-methylpropane (0.14 g, 0.016 mol, 2 eq) in dry toluene (2 ml), and then slowly adding trimethylaluminum (1.1 ml, 2M, dissolved in toluene) dropwise under argon protection at 0°C, and then continuing to react for 2 h at room temperature, and then again lowering the temperature to 0°C, and then slowly adding a toluene solution (3 ml) of compound 2 (0.3 g, 0.0080 mol, 1 eq) dropwise, and then continuing to react for 30 min, and then raising the temperature to 80°C and reacting for 16 h, and then lowering the temperature to 0°C after the completion of the reaction of the raw material, and then adding methanol to quench the reaction, and then filtering, and then drying the filtrate by rotary evaporation, and then purifying by column twice to obtain compound C-6 (60 mg, white solid, purity 98.4%, yield 18.7%).

[0291] Analytical data of compound C-6: 1 H-NMR (400 MHz, CDC13): δ 8.28 (s, J = 2.8 Hz, 1H), 8.16 (s, J = 5.6 Hz, 1H), 7.15-6.82 (d, J = 6.4 Hz, 2H), 6.81-6.70 (m, 1H), 6.01-5.07 (m, 1H), 5.59-5.39 (m, 1H), 4.23-3.55 (m, 4H), 2.61-2.38 (m, 1H), 2.27-2.07 (m, 2H), 1.38-0.70 (m, 6H). MS: 383 (M+H + ).

[0292] Example 7

[0293]

[0294] Synthetic route and experimental process are as follows:

[0295]

[0296] Step 1 (first step)

[0297] Under argon protection, dry toluene (10 ml) was reduced to 0 ℃, then ammonia was slowly introduced for 20 min, then trimethylaluminum (2.6 ml, 2M, dissolved in toluene) was added dropwise, after the dropwise addition was completed, it was warmed to room temperature and continued to react for 2 h, then it was reduced to 0 ℃ again, and a toluene solution (10 ml) of compound 2 (1 g, 0.0080 mol, 1 eq) was slowly added dropwise, after the dropwise addition was completed, it was continued to react for 30 min, then it was warmed to 80 ℃ and reacted for 16 h, after the raw material was reacted, the reaction system was reduced to 0 ℃, then methanol was added to quench, filtered, the filtrate was rotary evaporated, then column purification was performed, and compound 5 (0.52 g, yellow foam, purity 94.6%, yield 54%) was obtained.

[0298] NMR and other analysis data of compound 5: 1 H-NMR (400MHz, CDCl3): δ 8.28 (s, J = 2.8 Hz, 1H), 8.16 (s, J = 5.6 Hz, 1H), 7.15-6.82 (d, J = 6.4 Hz, 2H), 6.81-6.70 (m, 1H), 6.01-5.07 (m, 1H), 5.74-5.07 (m, 2H), 4.08-3.59 (m, 4H), 2.63-2.38 (m, 1H), 2.27-2.07 (m, 2H), 1.28-1.21 (m, 1H), 0.91-0.75 (m, 1H). MS: 344 (M+H + ).

[0299] Step 2 (second step)

[0300] Compound 5 (0.5 g, 0.0145 mol, 1 eq) was dissolved in phosphorus oxychloride (5 ml), then it was warmed to 80 ℃ and reacted for 3 h, after the raw material was reacted, the phosphorus oxychloride was rotary evaporated, then it was diluted with ethyl acetate, the mixture was reduced to 0 ℃, neutralized with 1M sodium hydroxide aqueous solution, the aqueous phase was extracted with ethyl acetate three times, the organic phases were combined, washed with brine once, dried with anhydrous sodium sulfate, rotary evaporated, and purified to obtain compound 6 (0.44 g, brown oil, purity 96%, yield 92.8%).

[0301] NMR and other analysis data of compound 6: 1H-NMR (400 MHz, CDC13): δ 8.28 (s, J = 2.8 Hz, 1H), 8.16 (s, J = 5.6 Hz, 1H), 7.15-6.82 (d, J = 6.4 Hz, 2H), 6.81-6.70 (m, 1H), 6.01-5.07 (m, 1H), 4.08-3.59 (m, 4H), 2.63-2.38 (m, 1H), 2.27-2.07 (m, 2H), 1.28-1.21 (m, 1H), 0.91-0.75 (m, 1H). MS: 326 (M+H + ).

[0302] Step 3 (third step)

[0303] Compound 6 (0.2 g, 0.00062 mol, 1 eq) and hydroxylamine hydrochloride (0.042 g, 0.00124 mol, 2 eq) were dissolved in ethanol, potassium carbonate (0.085 g, 0.00124 mol, 2 eq) was added under stirring, then the temperature was raised to 80 °C for 16 h. After the raw material was completely reacted, ethyl acetate and water were added to the reaction system, and the organic phase was extracted with ethyl acetate three times, dried with anhydrous sodium sulfate, and rotary evaporated. After drying, compound 7 (0.14 g, light yellow solid, purity 90%) was obtained by column purification twice. MS: 359 (M+H + ).

[0304] Step 4 (fourth step)

[0305] Compound 7 (0.14 g, 0.00039 mol, 1 eq) and 2,2-dimethoxypropane (0.081 g, 0.00078 mol, 2 eq) were dissolved in acetic acid under argon protection, and then the temperature was raised to 40 °C for 20 h. After the raw material was completely reacted, most of the acetic acid was removed, and then saturated sodium bicarbonate aqueous solution was added to the reaction system, and the organic phase was extracted with ethyl acetate three times, and the organic phase was washed with brine, dried with anhydrous sodium sulfate, and rotary evaporated to obtain compound C-7 (40 mg, white solid, purity 94%, yield 25.6%).

[0306] NMR analysis data of compound C-7: 1H-NMR (400 MHz, CDC13): δ 8.28 (s, J = 2.8 Hz, 1H), 8.16 (s, J = 5.6 Hz, 1H), 7.15-6.82 (d, J = 6.4 Hz, 2H), 6.81-6.70 (m, 1H), 6.01-5.07 (m, 1H), 5.59-5.39 (m, 1H), 3.96-3.54 (m, 2H), 2.62-2.38 (m, 1H), 2.27-1.95 (m, 2H), 1.36-1.11 (m, 6H), 0.88-0.64 (m, 2H). MS: 399 (M+H + ).

[0307] Example 8

[0308]

[0309] The synthetic route and experimental process are as follows:

[0310]

[0311] Step 1 (first step)

[0312] Compound 1 (2 g) was weighed into a reaction bottle, intermediate 1 (8.25 g, N-Boc piperidone) (6 eq) was added, 1,2-dichloroethane (15 ml) and acetic acid (15 ml) were measured as mixed solvents, and reflux heating was carried out at 76°C overnight. A small amount of water was added, and saturated sodium bicarbonate was added to neutralize the acetic acid in the reaction system, followed by dichloromethane extraction. Then column chromatography was carried out with petroleum ether: ethyl acetate = 1:2 to obtain 0.5 g of compound 2, MS: 540.2 (M+H + ).

[0313] Step 2 (second step)

[0314] Compound 2 (0.5 g) was weighed into a 50 ml round-bottom flask, and HCl / 1,4-dioxane (6 ml) was added as a solvent, and stirred at room temperature for 2 hours. A small amount of water was added, and saturated sodium bicarbonate was added to neutralize the hydrochloric acid in the reaction system, followed by ethyl acetate extraction. Then column chromatography was carried out with petroleum ether: ethyl acetate = 1:2 to obtain compound 3 (0.36 g), 440.2 (M+H + ).

[0315] Step 3 (third step)

[0316] Compound 3 (50 mg) was weighed into a 50 ml round bottom flask, methyl chloroformate (12.9 mg, 1.2 eq) and triethylamine (17.3 mg, 1.5 eq) were added, dichloromethane (5 ml) was added as solvent, stirred at room temperature for 2 hours, the reaction was monitored to completion. Water was added and extracted with ethyl acetate, then column chromatography was performed with petroleum ether: ethyl acetate = 1:1, to obtain compound C-8 (43 mg), HPLC purity 96.7%, MS: 498.2 (M+H + ).

[0317] Example 9

[0318]

[0319] The synthetic route and process are as follows:

[0320] I. Synthesis of intermediate C1-9

[0321] The synthetic route and process are as follows:

[0322]

[0323] 1. Synthesis of C1-10

[0324] Into a 1000 ml single neck flask was added 2-amino-3-cyanopyrazole (20.0 g, 0.185 mol), ethoxy ethyl acrylate (53.3 g, 0.37 mol), cesium carbonate (126.8 g, 0.389 mol) and DMF (500 ml), reacted at 110 °C for 6 h, cooled to room temperature, poured into water, filtered, dried, to obtain 27.5 g of yellow solid.

[0325] 2. Synthesis of C1-9

[0326] Into a 1000 ml single neck flask was added C1-10 (27.5 g, 0.172 mol), phosphorus oxychloride (129 g, 0.02 mol) and acetonitrile (350 ml), reacted at 100 °C for 16 h, cooled to room temperature, poured into water, filtered, dried, to obtain 18.0 g of C1-9. The mother liquor was concentrated to remove acetonitrile, extracted with DCM, recovered from the filtrate again, concentrated to obtain 8.0 g of C1-9.

[0327] II. Synthesis of intermediate C-11

[0328] The synthetic route and process are as follows:

[0329]

[0330] In a 500 mL three-necked flask, under nitrogen protection, was added magnesium ribbon (14.776 g, 0.616 mol), THF (200 mL) and DIBAL-H (1 M, 2 mL), and the mixture was warmed to 40 °C. 2-(2-bromoethyl)-1,3-dioxane (40.0 g, 0.205 mol) was added dropwise, and the dropping speed was controlled to ensure that the temperature change was controlled within ±5 °C. After the addition was completed, the reaction was continued for 2 hours. The reaction solution was directly used in the subsequent reaction.

[0331] III. Synthesis of compound C1

[0332] The synthetic route is as follows:

[0333]

[0334] 1. Synthesis of C1-1

[0335] In a 50 mL single-necked flask was added 2-chloro-5-fluoronicotinic acid (500 mg, 2.84 mmol), sodium borohydride (16 mg, 2.84 mmol) and THF (5 mL). Boron trifluoride ether (0.36 mL, 2.84 mmol) was added dropwise at room temperature, and then the mixture was warmed to 70 °C and reacted for 16 hours. LC-MS showed that the reaction was completed. Pure water (50 mL) was added to quench the reaction, and ethyl acetate (50 mL x 3) was used for extraction. The organic phase was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and column chromatography was performed using PE:EA = 2:1-1:1 to obtain 320 mg.

[0336] NMR analysis data of compound C1-1: 1 H NMR (400 MHz, CDCl3): δ 8.17-8.16 (d, 1H), 7.73-7.70 (dd, 1H), 4.77 (s, 2H).

[0337] 2. Synthesis of C1-2

[0338] In a 50 mL single-necked flask was added C1-1 (200 mg, 1.24 mmol), methyl boronic acid (223 mg, 3.72 mmol), Pd(PPh3)2Cl2 (87 mg, 0.124 mmol), potassium carbonate (514 mg, 3.72 mmol), dioxane (5 mL) and water (0.5 mL). The mixture was reacted at 90 °C for 12 hours under nitrogen protection. LC-MS showed that the reaction was completed. Pure water (50 mL) was added to quench the reaction, and ethyl acetate (50 mL x 3) was used for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography was performed using PE:EA = 2:1-1:1 to obtain 50 mg.

[0339] NMR analysis data of compound C1-2: 1H NMR (400 MHz, CDC13): δ 8.24-8.23 (d, 1H), 7.55-7.52 (dd, 1H), 4.72 (s, 2H), 2.84 (s, 3H).

[0340] 3. Synthesis of C1-3

[0341] Into a 100 mL single neck flask was added C1-2 (3.0 g, 21.43 mmol), IBX (17.37, 535.7 mmol), and EA (150 mL). The temperature was raised to 80 °C and the reaction was allowed to proceed for 2.5 hours. LC-MS showed the reaction was complete. The reaction mixture was filtered, the filter cake was washed with EA three times, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA = 2:1-1:1 to give 1.2 g.

[0342] NMR analysis data of compound C1-2: 1 H NMR (400 MHz, CDC13): δ 8.24-8.23 (d, 1H), 7.55-7.52 (dd, 1H), 4.72 (s, 2H), 2.84 (s, 3H).

[0343] 4. Synthesis of C1-4

[0344] Into a 100 mL single neck flask was added C1-3 (1.2 g, 8.57 mmol), R- tert-butylsulfonamide (1.08 g, 8.74 mmol), cesium carbonate (2 g, 6.00 mmol), and DCM (12 mL). The reaction was allowed to proceed at 25 °C for 4 hours. LC-MS showed the reaction was complete. The reaction mixture was filtered, the filter cake was washed with DCM three times, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2.0 g of yellow oil.

[0345] 5. Synthesis of C1-5

[0346] Into a 50 mL three neck flask was added C1-4 (200 mg, 0.65 mmol) and THF (10 mL) at 0 °C. C-11 (2.6 mL, 1.30 mmol) was added dropwise and the reaction was allowed to proceed at room temperature for 2 hours. LC-MS showed the reaction was complete. NH4CI saturated solution (30 mL) was added, the organic phase was extracted, dried, and concentrated to give 241 mg of crude product.

[0347] 6. Synthesis of C1-6

[0348] C1-5 crude was dissolved in trifluoroacetic acid (0.5 mL) and water (0.1 mL) under nitrogen protection, and stirred at 40 °C for 1 h. Then triethylsilane (151.2 mg, 1.30 mmol) was added dropwise, and the reaction was stirred at 40 °C for 12 h. LC-MS showed the reaction was completed. The reaction was concentrated, and 2 M hydrochloric acid (5 mL) and EA (5 mL) were added. The aqueous phase was concentrated to obtain 72 mg. The crude product was directly used in the next step.

[0349] 7. Synthesis of C1-7

[0350] C1-5 (180 mg, 1 mmol), C-9 (187 mg, 1.05 mmol), triethylamine (0.8 mL, 6.0 mmol) and EtOH (5 mL) were added into a 50 mL single-neck flask, and the reaction was stirred at 55 °C for 2 h. LC-MS showed that the reaction was completed. Water (15 mL) was added, and the mixture was stirred for 30 min, and then filtered at room temperature to obtain a white solid (160 mg).

[0351] 8. Synthesis of C1-8

[0352] C1-6 (160 mg, 0.49 mmol), hydroxylamine hydrochloride (70 mg, 0.99 mmol), potassium carbonate (140 mg, 0.99 mmol) and EtOH (2 mL), dioxane (1 mL) were added into a 50 mL single-neck flask, and the reaction was stirred at 80 °C overnight. LC-MS showed that the reaction was completed. Water (30 mL) was added, and the mixture was extracted with EA, dried over anhydrous sodium sulfate, concentrated, and column chromatography (DCM:MeOH=100:1-20:1) to obtain 100.0 mg.

[0353] NMR analysis data of compound C1-8: 1 H NMR (400 MHz, CDCl3): δ 8.29 (s, 1H), 8.14 (s, 1H), 8.05 (s, 1H), 7.00 (m, 1H), 6.42-5.76 (m, 1H), 5.61-5.04 (m, 1H), 3.96-3.72 (m, 2H), 2.67 (s, 3H), 2.58-2.51 (m, 1H), 2.16-2.00 (m, 3H).

[0354] 9. Synthesis of C1

[0355] In a 50 mL single neck flask, C1-8 (100 mg, 0.28 mmol), 2,2-dimethoxypropane (117 mg, 1.12 mmol) and acetic acid (1.5 mL) were added, and the reaction was placed at 45 °C overnight. LC-MS showed that the reaction was complete, concentrated, saturated aqueous sodium bicarbonate solution was adjusted to pH 7, EA extraction, column chromatography (DCM:MeOH = 150:1-50:1), to get 20 mg of light yellow solid.

[0356] NMR analysis data of compound C1: 1 H NMR (400 MHz, CDCl3): δ 8.40-8.19 (m, 3H), 7.00-7.99 (d, 1H), 6.36-6.34 (d, 0.8H), 6.13 (br, 0.16H), 5.36-5.34 (d, 0.9H), 5.24 (br, 0.1H), 5.08 (s, 1H), 3.93 (br, 1H), 3.74-3.68 (m, 1H), 2.69 (s, 3H), 2.55 (br, 1H), 2.18-1.97 (m, 3H), 1.57 (s, 3H), 1.25 (br. 0.5H), 1.14 (s. 2.5H).

[0357] Example 10

[0358]

[0359] The synthesis route and experimental process are as follows:

[0360]

[0361] 1. Synthesis of C-11-1

[0362] In a 100 mL single neck flask, C4-8 (600 mg, 2.38 mmol), hydrogen bromide in acetic acid solution (5.0 mL, 23.80 mmol) and acetic acid (10 mL) were added, and a solid was precipitated. LC-MS showed that the reaction was complete, the reaction was concentrated, and the next step was directly carried out.

[0363] 2. Synthesis of C-11-2

[0364] In a 100 mL single neck flask, C-11-1 (600 mg, 2.38 mmol) and phosphorus oxychloride (10 mL) were added, and the reaction was carried out at 80 °C for 3 hours. TLC showed that the reaction was complete, the reaction was concentrated, 15% NaOH was used to adjust the pH to 8-9, DCM was extracted 5 times, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (DCM:MeOH = 25:1) to obtain 445 mg.

[0365] 3. Synthesis of C-11-3

[0366] In a 50 mL single neck flask was added C-11-2 (445 mg, 1.37 mmol), cesium carbonate (4.46 g, 13.73 mmol) and DMF (10 mL). Iodomethane (3.9 g, 27.47 mmol) was added dropwise at room temperature. After the addition was complete, the reaction was allowed to stir at room temperature overnight. The reaction was monitored by TLC. The reaction mixture was filtered, the mother liquor was diluted with water and extracted with DCM twice. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (DCM:MeOH = 25:1) to give 310 mg.

[0367] 4. Synthesis of C-11-4

[0368] In a 100 mL single neck flask was added C-11-3 (310 mg, 0.917 mmol), hydroxylamine hydrochloride (506 mg, 7.337 mmol), potassium carbonate (1.02 g, 7.337 mmol) and EtOH (8 mL), Dioxane (4 mL). The reaction was heated at 80 °C overnight. LC-MS showed the reaction was complete. The reaction mixture was diluted with water (20 mL) and extracted with EA. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (DCM:MeOH = 100:1-20:1) to give 251 mg.

[0369] 5. Synthesis of C-11

[0370] In a 50 mL single neck flask was added C-11-4 (251 mg, 0.676 mmol), 2,2-dimethoxypropane (563 mg, 5.412 mmol) and acetic acid (2.5 mL), DCE (5 mL). The reaction was heated at 80 °C for 3 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated, the pH was adjusted to 7 with saturated aqueous sodium bicarbonate solution and extracted with EA. The residue was purified by column chromatography (DCM:MeOH = 150:1-50:1) to give 60 mg of a light yellow solid.

[0371] NMR analysis data of compound C11: 1H NMR (400 MHz, CD3OD): δ 8.50-8.48 (d, 0.75H), 8.33 (m, 0.25H), 8.02 (m, 1H), 7.66 (m, 1H), 7.26-7.24 (t, 1H), 6.64-6.59 (t. 0.75H), 6.04 (m, 0.25H), 5.51-5.48 (t, 0.75H), 5.13 (m, 0.25H), 4.01-3.98 (t, 1H), 3.75 (m, 0.3H), 3.65-3.57 (m, 0.7H), 3.60 (s, 3H), 2.42-2.38 (t, 1H), 2.12 (m, 2H), 1.92-1.89 (m, 1H), 1.56-1.50 (m, 3H), 1.33-1.28 (m, 3H).

[0372] Example 11

[0373]

[0374] The synthetic route and experimental procedure are as follows:

[0375]

[0376] 1. Synthesis of C-12

[0377] Into a 50 mL single necked flask was added C7 (500 mg, 1.256 mmol), sodium hydride (60 mg, 1.507 mmol) and DMF (5 mL), 0 °C for 1 h. Then, iodomethane (214 mg, 1.507 mmol) was added dropwise, after dropwise, room temperature for 1 h. LC-MS showed the reaction was completed, added water, extracted with DCM for 3 times, dried over anhydrous sodium sulfate, filtered, concentrated, column chromatography (DCM:MeOH=25:1), to get white solid 180 mg.

[0378] NMR analysis data of compound C-12: 1 H NMR (400 MHz, CD3OD): δ 8.50-8.48 (d, 0.75H), 8.33 (m, 0.25H), 8.02 (m, 1H), 7.66 (m, 1H), 7.26-7.24 (t, 1H), 6.64-6.59 (t. 0.75H), 6.04 (m, 0.25H), 5.51-5.48 (t, 0.75H), 5.13 (m, 0.25H), 4.01-3.98 (t, 1H), 3.75 (m, 0.3H), 3.65-3.57 (m, 0.7H), 3.60 (s, 3H), 2.42-2.38 (t, 1H), 2.12 (m, 2H), 1.92-1.89 (m, 1H), 1.56-1.50 (m, 3H), 1.33-1.28 (m, 3H).

[0379] Referring to Examples 1-11, Examples 13-35 were further specifically synthesized, see Table 1.

[0380] Table 1

[0381]

[0382]

[0383]

[0384]

[0385] Test Example 1: Inhibitory activity of compounds of the present application on NTRK, its drug-resistant kinase NTRK1-G667C

[0386] The experiment of inhibiting the activity of the compound on the protein kinase was carried out on the radiolabeled HotSpot kinase experiment platform of Reaction Biology Corporation. Fresh reaction solution containing the corresponding substrate (20 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg / mL BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO) was prepared, the required cofactor and the tested kinase were added to the above solution and gently mixed, the DMSO solution of the tested compound was added to each well using the Echo550 pipetting system (the corresponding volume of DMSO was added to the blank control group), 33P-ATP (final specific activity 0.01 μCi / μL) was added to start the reaction, and the reaction solution was incubated at room temperature for 120 minutes. The incubated reaction solution was transferred to P81 ion exchange chromatography paper (Whatman #3698-915), eluted with 0.75% phosphoric acid solution, and the amount of phosphorylated substrate containing radioactivity remaining on the chromatography paper was detected.

[0387] Table 2 gives the inhibitory activity IC50 values of some compounds of the present application on NTRK1, NTRK2 and NTRK3 and drug-resistant mutant NTRK1-G667C, wherein A < 1.0 nM, 1.0 nM ≤ B ≤ 20 nM, 20 nM < C < 100 nM, D ≥ 100 nM.

[0388] Table 2

[0389]

[0390]

[0391]

[0392]

[0393]

[0394] Note: ND represents no activity tested

[0395] Table 3 provides the specific IC50 values of the inhibition activity of some of the compounds of the present application against NTRK1, NTRK2 and NTRK3 and the drug resistant mutant NTRK1-G667C.

[0396] Table 3

[0397]

[0398]

[0399] The series of compounds of the present application were found to have good inhibition activity against a variety of fusion NTRKs and also have good inhibition activity against a variety of NTRK mutants. At the same time, they have good selectivity against other kinases such as ALK and / or ROS1. They are very promising for the treatment of diseases mediated by NTRK.

[0400] All documents referred to in this application are incorporated herein by reference as if each were individually incorporated by reference. In addition, it is to be understood that the application can be carried out by specifically different embodiments and that these equivalents ypes do not depart from the spirit and scope of the application. Accordingly, other than in the Examples, or where otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and associated claims are to be understood as modified in all instances by the term "about".

Claims

1. A compound, a tautomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that, having the structure of Formula IV: wherein, * denotes the R configuration; R1is selected from: R3and R4are each independently selected from the group consisting of H, C1-C6alkyl; R m and R n is H; or R3and R4together with the C atom to which they are attached form a group selected from C3-C12cycloalkyl, 3-12 membered heterocyclyl, or oxo (=0); R p selected from H; or R3and R4together with the atom to which they are attached form a C3-C12cycloalkyl; m C3-C12cycloalkyl; or R3and R4together with the atom to which they are R9is selected from: halogen, CN, OH, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6alkylamino, C1-C6haloalkylamino; X is selected from: N, CR 10 wherein R 10 is selected from: H, halogen.

2. The compound, tautomer, or pharmaceutically acceptable salt of claim 1, wherein having the structure of Formula V and Formula VI: wherein, * denotes the R configuration; X is selected from: N, CR 10 ; R 10 is selected from: H, halogen; R9is selected from: halogen, CN, OH, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6alkylamino, C1-C6haloalkylamino; R3and R4are each independently selected from the group consisting of H, C1-C6alkyl; or R3and R4together with the C atom to which they are attached form a group selected from C3-C8cycloalkyl, 3-8 membered heterocyclyl, or oxo (=0).

3. A compound, a tautomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that, said compound is selected from the group consisting of:

4. A pharmaceutical composition comprising i) a therapeutically effective amount of a compound according to claim 1 or a compound according to claim 3, a tautomer thereof, or a pharmaceutically acceptable salt; and ii) one or more pharmaceutically acceptable carriers.

5. Use of a compound according to claim 1 or a compound according to claim 3, a tautomer, or a pharmaceutically acceptable salt thereof, wherein for the preparation of a medicament for the prevention and / or treatment of a disease characterized by NTRK-mediated pathology.

6. Use according to claim 5, characterized in that, said disease characterized by NTRK-mediated pathology comprises cancer, sarcoma, and pain.

7. Use according to claim 6, characterized in that, said cancer is selected from the group consisting of: breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, peritoneal tumor, melanoma, glioma, glioblastoma, head and neck cancer, renal cell carcinoma, leukemia, lymphoma, myeloma, thyroid tumor.

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