WO2022095909A1

WO2022095909A1 - Compound used as ntrk inhibitor and application thereof

Info

Publication number: WO2022095909A1
Application number: PCT/CN2021/128500
Authority: WO
Inventors: 沈毅; 朱必成; 万义良
Original assignee: 上海瑶琪生物科技有限公司
Priority date: 2020-11-03
Filing date: 2021-11-03
Publication date: 2022-05-12
Also published as: CN114437075A

Abstract

The present invention relates to a compound used as an NTRK inhibitor and an application thereof. Specifically, the present invention relates to a compound as shown in formula I or a stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug, or solvate thereof, and also relates to a pharmaceutical composition of the compound and using the compound as an NTRK inhibitor, and a use of the compound in preparation of a drug for preventing and/or treating an NTRK-related disease.

Description

Compounds useful as NTRK kinase inhibitors and their applications

technical field

The invention relates to the technical field of medicine, in particular to a compound used as an NTRK kinase inhibitor, a preparation method thereof, and an application in the preparation of a medicament for treating NTRK and other kinase-mediated diseases.

Background technique

The tropomyosin receptor kinase (TRK) family belongs to the transmembrane receptor tyrosine kinases (RTKs), which are involved in the regulation of synaptic growth and functional maintenance of the mammalian nervous system, the occurrence and development of memory, and the protection of neurons from damage, etc. . TRK kinase is a class of nerve growth factor receptors, and its family consists of highly homologous tropomyosin-related kinase A (TRKA), tropomyosin-related kinase B (Tropomyosin-related kinase B, TRKB) and Tropomyosin-related kinase C (TRKC), which are encoded by NTRK1, NTRK2 and NTRK3 genes respectively. The complete TRK kinase includes three parts: the extracellular domain, the transmembrane domain and the intracellular domain. Like other RTKs, the extracellular domain of the TRK kinase binds to the corresponding ligand to form a dimer, which can cause TRK kinase activation. The intracellular region undergoes autophosphorylation to activate its own kinase activity and further activate downstream signal transduction pathways. TRK kinase affects cell proliferation, differentiation, metabolism and apoptosis through downstream pathways such as Ras/MAPK, PI3K/AKT and PLcγ. When the NTRKs gene is fused or mutated, it will change or eliminate the extracellular domain receptor (Greco, A. et. al, Mol. Cell. Biol. 1995, 15, 6118; Oncogene 1998, 16, 809), while fusion or mutation TRK protein itself is in a highly activated kinase activity state without ligand binding, so that it can continuously activate the downstream signal transduction pathway, which can lead to abnormal regulation of the downstream signaling pathway of TRK kinase, induce cell proliferation, and promote The occurrence and development of tumors.

NTRKs 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. In common cancers, such as non-small cell lung cancer, colorectal cancer, etc., the incidence of NTRK gene fusion is low, roughly 1%-3%, but in some rare cancers, such as infantile fibrosarcoma, breast secretion Type cancer, etc., the incidence of NTRK gene fusion can reach more than 90%. The earliest TPM3-TRKA fusion proteins were found in colon cancer cells. Later, more types of NTRK fusion proteins, such as CD74-NTRKA, MPRIP- NTEKA, QKI-NTRKB, ETV6-NTRKC, BTB1-NTRKC, etc.

Therefore, in recent years, NTRK fusion protein has become an effective anticancer target and a hot spot in the development of anticancer drugs. For example, WO2010048314, WO2010033941, WO2012116217, WO2011146336, etc. all disclose a series of TRK kinase inhibitors with different structures.

However, with the further in-depth understanding of TRK kinase in recent years, more TRK fusion protein types and mutation types have been discovered (Russo, M. et. al Cancer Discovery, 2016, 6, 36; Drilon, A. et al. al, Annals of Oncology, 2016, 27, 920), so there is an urgent need to develop new NTRK inhibitors with better activity and wider effect in clinical practice, so as to solve the problem of the treatment of tumors caused by these NTRK protein fusions or mutations.

SUMMARY OF THE INVENTION

The main purpose of the present invention is to provide a selective NTRK kinase inhibitor.

The first aspect of the present invention provides a compound represented by formula I, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug,

In the formula,

R1 is selected from _:

R ₂ is selected from the group consisting of substituted or unsubstituted groups: C6-C14 aryl, 5-14-membered heteroaryl; wherein, the substitution refers to being substituted by one or more R _r ;

R _m , R _n , R ₃ and R ₄ are each independently selected from the group consisting of substituted or unsubstituted groups: H, halogen, NR _p R _p' , -CN, -OH,

C1-C6 alkyl group, C1-C6 alkoxy group, C3-C12 cycloalkyl group, 3-12-membered heterocyclic group, C6-C14 aryl group, 5-14-membered heteroaryl group; wherein, the substitution refers to being replaced by One or more R _r substitutions;

Or R _m and R _n together with the C atom to which they are attached form a substituted or unsubstituted group of the following group: C3-C12 cycloalkyl, 3-12 membered heterocyclyl or oxo (=O); wherein the said Substituted means replaced by one or more R _r ;

Or R ₃ and R ₄ together with the C atom to which they are attached form a substituted or unsubstituted group of the following group: C3-C12 cycloalkyl, 3-12 membered heterocyclyl or oxo (=O); wherein the said Substituted means replaced by one or more R _r ;

R _p and R _p' are each independently selected from the group consisting of substituted or unsubstituted groups: H, C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl , C6-C14 aryl, 5-14-membered heteroaryl; wherein, the substitution refers to being substituted by one or more R _r ;

Or R ₃ and R _p together with the atoms to which they are attached form a substituted or unsubstituted group of the following groups: C3-C12 cycloalkyl, 3-12 membered heterocyclyl; wherein, the substitution refers to substitution by one or more R _r substituted;

Or R ₃ and R _p' together with the atoms to which they are attached form a substituted or unsubstituted group of the following group: C3-C12 cycloalkyl, 3-12 membered heterocyclyl; wherein, the substitution refers to being replaced by one or more R _r substitutions;

Or R ₃ and R _m together with the atoms to which they are attached form a substituted or unsubstituted group of the following group: C3-C12 cycloalkyl, 3-12 membered heterocyclyl; wherein, the substitution refers to being replaced by one or more R _r substituted;

R ₈ is each independently selected from the group consisting of substituted or unsubstituted: halogen, NR _p R _p' , -CN, -OH,

C1-C6 alkyl, C1-C6 alkoxy; wherein, the substitution refers to being substituted by one or more R _r ;

Or two R ₈ located on the same C atom together with the C atom to which they are attached form a substituted or unsubstituted group of the following groups: C3-C12 cycloalkyl, 3-12 membered heterocyclyl or oxo (=O ); wherein, the substitution refers to being replaced by one or more R _r ;

Or the two R ₈ located on the adjacent two C atoms together with the C atoms to which they are attached form a substituted or unsubstituted group of the following group: C3-C12 cycloalkyl, 3-12-membered heterocyclyl; wherein, the said Substituted means replaced by one or more R _r ;

n is 0, 1, 2 or 3;

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

s is 1, 2 or 3;

R _{r is} selected from: deuterium, halogen, NR _p R _p' , -CN, -OH,

C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12-membered heterocyclyl, C6-C14 aryl, 5-14-membered heteroaryl;

R', R" are each independently selected from: H, C1-C6 alkyl, halogenated C1-C6 alkyl; or R', R" together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic Cyclic group, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy;

R is selected from: H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, ( CH ₂ ) _s C6-C10 aryl.

In another preferred embodiment, the compound of formula I, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, wherein, R ₂ Selected from the group consisting of substituted or unsubstituted groups: phenyl, naphthyl, pyridinyl, pyridyl, pyrimidinyl, benzofuranyl, benzotetrahydrofuranyl, chromanyl, benzodioxy Hexacyclyl, chroman, benzopyrazine; wherein, the substitution refers to being substituted by one or more groups selected from the group consisting of deuterium, halogen, NR _p R _p' , -CN, -OH,

Wherein, R _p , R _p' , R, R' and R" are defined as above.

In another preferred embodiment, the compound of formula I, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has formula II Structure shown:

in,

* indicates R or S configuration;

The definitions of R ₁ , R ₂ , R ₈ and m are as described above.

In another preferred embodiment, the compound of formula I, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has formula III Structure shown:

in,

* indicates R or S configuration;

R ₉ is 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;

X is selected from: N, CR ₁₀ , wherein, R ₁₀ is selected from: H, halogen, CN, OH, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenated alkoxy base, C1-C6 alkylamino, C1-C6 haloalkylamino,

R ₁ , R ₈ , R', R" and m are as defined above.

In another preferred embodiment, the compound of formula I, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has formula IV Structure shown:

in,

* indicates R or S configuration;

R1 is selected from _:

R, R', R", _Rm , _Rn , _Rp , _R3 and _R4 are as defined above.

In another preferred embodiment, the compound of formula I, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug has the formula V and the structure shown in formula VI:

in,

* indicates R or S configuration;

X is selected from: N, CR ₁₀ ;

R ₁₀ and R ₉ are each independently selected from: H, halogen, CN, OH, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 Alkylamino, C1-C6 halogenated alkylamino;

R ₃ and R ₄ are each independently selected from the group consisting of substituted or unsubstituted groups: H, halogen, NR _p R _p' , -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C3 -C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the substitution refers to being substituted by one or more R _r ;

Or R ₃ and R ₄ together with the C atom to which they are attached form a substituted or unsubstituted group of the following group: C3-C8 cycloalkyl, 3-8 membered heterocyclyl or oxo (=O); wherein the said Substituted means replaced by one or more R _r ;

R _{r is} selected from: deuterium, halogen, NR _p R _p' , -CN, -OH,

C1-C6 alkyl, C1-C6 alkoxy;

Wherein, R _p , R _p' , R, R' and R" are defined as above.

In another preferred embodiment, in formula I, R ₁ , R ₂ , R ₈ , m and n are specific groups corresponding to the specific compounds in the embodiments.

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

In another preferred embodiment, the compound represented by formula I is selected from the compounds shown in the examples.

The second aspect of the present invention provides a pharmaceutical composition, which contains i) a therapeutically effective amount of the compound represented by formula I, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable and ii) one or more pharmaceutically acceptable carriers.

In another preferred example, the pharmaceutical composition further comprises a drug selected from the group consisting of PD-1 inhibitors (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.), PD-L1 inhibitors (such as durvalumab, Atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumumab, 131I-tositumumab, tiimumab, 90Y - tiimumab, 90In-tiimumab, ibritumomab tiuxetan, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172 , SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, ocartinib) Nitrogen), PI3K inhibitors (such as Idelaris, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipalisib, Buparlisib, etc.), BTK inhibitors (such as ibrutinib, Tirabrutinib, acalatinib, zabrutinib, Vecabrutinib) etc.), EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, canetinib, sapritinib, Naquotinib, Pyrotinib, Roletinib, Osimertinib, etc.), VEGFR inhibitors (such as Sorafenib, Pazopanib, Regorafenib, Seletinib, Ningetinib, Cabozantinib, Suni tinib, donafenib, etc.), HDAC inhibitors (such as Givinostat, Tucidinostat, vorinostat, Fimepinostat, Droxinostat, entinostat, darxilast, Quisinostat, tycodinaline, etc.), CDK inhibitors (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 (eg, Vistusertib, etc.), SHP2 inhibitors (eg, RMC-4630, JAB-3068, TNO155, etc.), or a combination thereof.

The third aspect of the present invention provides a preparation method of a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound described in the first aspect of the present invention or its stereoisomer or optical isomer, The pharmaceutically acceptable salts, prodrugs or solvates are mixed to form a pharmaceutical composition.

In another preferred embodiment, the compounds of the present invention can be prepared into powders, tablets, granules, capsules, solutions, emulsions, suspensions and the like.

The fourth aspect of the present invention provides a compound of formula I according to the first aspect, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof for the preparation of a medicament for the prevention and/or treatment of diseases characterized by NTRK-mediated pathology.

In another preferred embodiment, the diseases characterized by NTRK-mediated pathology include cancer, sarcoma and pain.

In another preferred embodiment, the cancer is selected from: breast cancer, cervical cancer, colon cancer, lung cancer, stomach 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, mastoid nephroma, leukemia, lymphoma, myeloma, thyroid tumor.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (eg, the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, it is not repeated here.

Detailed ways

After extensive and in-depth research, the inventors have unexpectedly discovered a new selective NTRK kinase inhibitor, which has good selective inhibitory ability on NTRK kinase, and has better pharmacodynamics and pharmacokinetics Because of its chemical properties and lower toxic and side effects, it has great potential to be developed into a drug targeting NTRK that is urgently needed in clinical practice.

the term

In the present invention, unless otherwise specified, the terms used have the ordinary meanings known to those skilled in the art.

When substituents are described by conventional chemical formulae written from left to right, the substituents also include the chemically equivalent substituents obtained when the structural formula is written from right to left. For example, _-CH2O- is equivalent to _-OCH2- .

As used herein, when used in reference to a specifically recited value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).

As used herein, the terms "containing" or "including (including)" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of," or "consisting of."

As used herein, the term "alkyl" includes straight or branched chain alkyl groups. For example C ₁ -C ₆ alkyl means straight or branched chain alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl Wait.

"Haloalkyl" refers to an alkyl group, as defined herein, wherein one or more hydrogens are replaced by the same or different halogen. Examples _of haloalkyl groups include _-CH2Cl , _-CH2CF3 , _-CH2CCl3 , perfluoroalkyl (eg, _-CF3 ₎ , and the like.

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

As used herein, the term "alkynyl" includes straight or branched chain alkynyl groups. For example, C2 _- _C6alkynyl refers to a straight or branched chain alkynyl group having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.

As used herein, the term "cycloalkyl" refers to a cyclic alkyl group containing the specified number of C atoms, eg "C3-C10 cycloalkyl" refers to a cyclic alkyl group having 3-10 (preferably 3, 4, 5, 6, 7 or 8) carbon atoms cycloalkyl. It may be a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. Bicyclic forms, such as bridged or spiro forms, are also possible. In the present invention, cycloalkyl is intended to include substituted cycloalkyl.

As used herein, the term "C1-C6alkoxy" refers to a straight or branched chain alkoxy group having 1-6 carbon atoms; it has the formula C1-C6alkyl-O- or -C1-C5alkane Alkyl-O-C1-C5 alkyl (eg, _-CH2 -O- _CH2CH3 , _-CH2 _- _O- ( _CH2 ) _2CH3 , -CH2CH2 _- O _- _CH2CH3 ₎ Structure, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, and the like.

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

As used herein, "heterocyclyl" refers to a saturated or partially saturated cyclic group having heteroatoms selected from N, S, and O, and "3-10 membered heterocyclyl" refers to 3-10 atoms A saturated or partially saturated cyclic group of which 1-3 atoms are heteroatoms selected from the following groups N, S and O. It may be monocyclic or bicyclic, eg bridged or spirocyclic. The 3-10-membered heterocyclic group is preferably a 3-8-membered heterocyclic group, more preferably a 6-8-membered heterocyclic group. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, and the like.

As used herein, "aryl" refers to an aromatic ring group containing no heteroatoms in the ring, and "C6-C12 aryl" refers to an aromatic ring group having 6 to 12 carbon atoms that contains no heteroatoms in the ring , the aryl group can be fused to a heteroaryl group, a heterocyclic group or a cycloalkyl ring, wherein the ring connected with the parent structure is an aryl ring. Such as phenyl (ie, six-membered aromatic ring), naphthyl, etc., wherein six-membered aryl is also intended to include six-membered aryl and 5-6 membered cycloalkyl and six-membered aryl and 5-6 membered heterocycloalkyl . The C6-C12 aryl group is preferably a C6-C10 aryl group. Aryl groups can be optionally substituted or unsubstituted.

As used herein, "heteroaryl" refers to a cyclic aromatic group having 1-3 atoms that are heteroatoms selected from the following groups of N, S, and O, and "5-12 membered heteroaryl" refers to a group having 5-12 atoms A cyclic aromatic group of atoms wherein 1-3 atoms are heteroatoms selected from the following groups N, S and O. It may be a single ring or a fused ring form. Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2, 4)-triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring. Heteroaryl groups can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio , alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, amido, sulfonamido, Formyl, formamide, carboxyl and carboxylate, etc.

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

In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent. Particular substituents are those described correspondingly in the preceding paragraphs, or the substituents appearing in the various examples. Unless otherwise specified, a substituted group may have at any substitutable position of the group a substituent selected from a particular group, which may be the same or different at each position. It will be understood by those skilled in the art that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable.

Unless specifically stated that the group described in the present invention is "substituted or unsubstituted", the group of the present invention can be substituted by a substituent selected from the following group: deuterium, halogen, cyano, nitro, hydroxyl , amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl base, C6-C12 aryl.

In the present invention, the term "plurality" refers independently to 2, 3, 4, 5.

Unless otherwise specified, the structural formulas described herein are intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, those containing asymmetric R, S configuration of the center, (Z), (E) isomer of double bond, etc. Accordingly, individual stereochemical isomers or mixtures of enantiomers, diastereomers or geometric isomers (or conformational isomers) of the compounds of the present invention are within the scope of the present invention.

As used herein, the term "tautomer" means that structural isomers having different energies can exceed a low energy barrier, thereby interconverting. For example, proton tautomers (ie, protonation) include interconversion by migration of protons, such as 1H-indazole and 2H-indazole. Valence tautomers include interconversion by some bonding electron recombination.

As used herein, the term "solvate" refers to a complex in which a compound of the present invention coordinates with solvent molecules to form a complex in specified proportions.

Active ingredient

As used herein, the terms "compound of the present invention" or "active ingredient of the present invention" are used interchangeably to refer to a compound of formula I, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts , hydrate, solvate or prodrug.

A compound of formula I, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, has the following structure,

In the formula, R ₁ , R ₂ , R ₈ , m and n are as defined above.

Preferably, the compound of formula I has the structure shown in formula II:

The definitions of R ₁ , R ₂ , R ₈ and m are as described above.

Preferably, in the above formulas, R ₂ is selected from the group consisting of substituted or unsubstituted groups: phenyl, naphthyl, pyridone, pyridyl, pyrimidinyl, benzofuranyl, benzotetrahydrofuranyl, benzoyl Tetrahydropyranyl, chromanyl, chroman, benzopyrazine;

Wherein, the substitution refers to being substituted by one or more groups selected from the group consisting of deuterium, halogen, NR _p R _p' , -CN,

Wherein, R _p , R _p' , R, R' and R" are defined as above.

Preferably, the compound described in formula I has the structure shown in formula III:

in,

The definitions of X, R ₉ , R ₁ , R ₈ and m are as described above.

Preferably, the compound described in formula I has the structure shown in formula IV:

in,

The definitions of X, R ₉ and R ₁ are as described above.

Preferably, the compound of formula I has the structure shown in formula V or formula VI:

in,

* indicates R or S configuration;

X is selected from: N, CR ₁₀ ;

R ₁₀ and R ₉ are each independently selected from: H, halogen, CN, OH, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy;

R ₁ is selected from: H, C1-C6 alkyl;

R _{r is} selected from: deuterium, halogen, NR _p R _p' , -CN, -OH,

C1-C6 alkyl, C1-C6 alkoxy;

Wherein, R _p , R _p' , R, R' and R" are defined as above.

The salts that the compounds of the present invention may form are also within the scope of the present invention. Unless otherwise specified, compounds in the present invention are understood to include their salts. As used herein, the term "salt" refers to salts formed with inorganic or organic acids and bases in the acid or basic form. In addition, when a compound of the present invention contains a basic moiety, which includes, but is not limited to, pyridine or imidazole, and when it contains an acidic moiety, including, but is not limited to, a carboxylic acid, the zwitterion ("inner salt") that may be formed is contained in within the scope of the term "salt". Pharmaceutically acceptable (ie, non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, eg, in isolation or purification steps in the manufacturing process. The compounds of the present invention may form salts, for example, by reacting Compound I with an amount, eg, an equivalent, of an acid or base, salting out in a medium, or lyophilizing in an aqueous solution.

As used herein, "pharmaceutically acceptable salts" refer to salts of compounds of the present invention with acids or bases that are suitable for use as pharmaceuticals. Pharmaceutically acceptable salts include inorganic and organic salts. A preferred class of salts are the salts of the compounds of the present invention with acids. Acids suitable for forming salts include, but are not limited to, inorganic acids such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, nitric, phosphoric, formic, acetic, propionic, oxalic, malonic, succinic, fumaric, Maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenemethanesulfonic acid, benzenesulfonic acid and other organic acids; and acidic amino acids such as aspartic acid and glutamic acid.

Prodrugs and solvates of the compounds of the present invention are also contemplated. The term "prodrug" as used herein refers to a compound that undergoes chemical transformation through a metabolic or chemical process to yield the compound, salt, or solvate of the present invention in the treatment of a related disease. The compounds of the present invention include solvates, such as hydrates.

The compounds, salts or solvates of the present invention may exist in tautomeric forms (eg amides and imine ethers). All of these tautomers are part of the present invention.

Stereoisomers of all compounds (eg, those due to asymmetric carbon atoms that may exist for various substitutions), including their enantiomeric and diastereomeric forms, are contemplated by the present invention. Individual stereoisomers of the compounds of the present invention may not exist concurrently with other isomers (eg, as a pure or substantially pure optical isomer with specific activity), or may be mixtures such as Racemates, or mixtures with all other stereoisomers or a part thereof. The chiral center of the present invention has two configurations, S or R, as defined by the 1974 recommendation of the International Union of Theoretical and Applied Chemistry (IUPAC). The racemic form can be resolved by physical methods, such as fractional crystallization, or by derivatization to diastereomer separation crystallization, or by chiral column chromatography. The individual optical isomers can be obtained from the racemates by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by crystallization.

The compound in the present invention, the compound obtained by successively preparing, isolating and purifying the compound whose weight content is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compound), is described in the text List. Herein such "very pure" compounds of the invention are also intended to be part of the invention.

All configurational isomers of the compounds of the present invention are contemplated, whether in admixture, pure or very pure form. The definition of compounds of the present invention includes both cis (Z) and trans (E) olefin isomers, as well as carbocyclic and heterocyclic cis and trans isomers.

Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.

Specific functional groups and chemical term definitions are detailed below. For purposes of the present invention, chemical elements are as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, ^75th Ed. Definitions of specific functional groups are also described therein. In addition, basic principles of organic chemistry and specific functional groups and reactivity are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, which is incorporated by reference in its entirety.

Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention covers all compounds including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, Spin mixtures and other mixtures. Additionally asymmetric carbon atoms may represent substituents such as alkyl groups. All isomers, as well as mixtures thereof, are encompassed by the present invention.

In accordance with the present invention, a mixture of isomers may contain isomers in various ratios. For example, in a mixture of only two isomers you can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: All ratios of 2, 99:1, or 100:0, isomers are within the scope of the present invention. Similar ratios readily understood by those of ordinary skill in the art, as well as ratios that are mixtures of more complex isomers, are also within the scope of the invention.

The present invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. In practice, however, it usually occurs that one or more atoms are replaced by atoms with different atomic weights or mass numbers. Examples of isotopes that may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as ² H, ³ H, ¹³ C, ¹¹ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, respectively , ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl. Compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the aforementioned compounds are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as radioisotopes ^of3H ^and14C , are also among them and are useful in drug and substrate tissue distribution experiments. Tritium, ie ³ H and carbon-14, ie ¹⁴ C, are relatively easy to prepare and detect. Is the first choice among isotopes. In addition, heavier isotopic substitutions such as deuterium, ie, ² H, may be preferred in some cases due to their good metabolic stability in certain therapeutics, such as increased half-life or reduced dosage in vivo. Isotopically-labeled compounds can be prepared by conventional methods by substituting readily available isotopically-labeled reagents for non-isotopically-labeled reagents using the protocols disclosed in the Examples.

If a synthesis of a particular enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, separation of the resulting diastereomeric mixture, and removal of the chiral auxiliary to obtain pure enantiomer. In addition, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, a suitable optically active acid or base can be used to form diastereomeric salts with it, and then the diastereomeric salts can be formed by separation crystallization or chromatography, etc. Separation by conventional means then yields the pure enantiomer.

As described herein, the compounds of the present invention may be taken with any number of substituents or functional groups to extend their encompassing scope. Generally, whether the term "substituted" appears before or after the term "optional", the general formula for including substituents in the formulations of the present invention refers to the replacement of a hydrogen radical with a specified structural substituent. When multiples of a particular structure are substituted at positions with multiple specified substituents, the substituents may be the same or different at each position. The term "substituted" as used herein includes all permissible substitutions of organic compounds. In a broad sense, permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, eg heteroatom nitrogen may have hydrogen substituents or any permissible organic compound as described above to supplement its valence. Furthermore, the present invention is not intended to limit in any way the permissible substituted organic compounds. The present invention contemplates that the combination of substituents and variable groups is well suited for the treatment of diseases in the form of stable compounds. As used herein, the term "stable" refers to compounds that are stable enough to be detected for a sufficient period of time to maintain the structural integrity of the compound, preferably for a sufficient period of time, as used herein for the above-mentioned purposes.

The metabolites of the compounds involved in the present application and their pharmaceutically acceptable salts, as well as prodrugs that can be converted into the structures of the compounds involved in the present application and their pharmaceutically acceptable salts in vivo, are also included in the claims of the present application middle.

Preparation

The compounds of the present invention can optionally be conveniently prepared by combining various synthetic methods described in this specification or known in the art, and such combinations can be readily performed by those skilled in the art to which the present invention pertains.

Usually, in the preparation process, each reaction is usually carried out in an inert solvent at -60°C to 100°C, preferably -60°C to 80°C. The reaction time is usually 0.1 to 60 hours, preferably 0.5 to 48 hours.

The preferred synthetic route is as follows:

route one

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

(2) In an inert solvent (such as ethanol, methanol), in the presence of an acid (such as hydrochloric acid, etc.), compound 3 reacts with the solvent of the system to generate compound 4;

(3) In an inert solvent (such as toluene or xylene, etc.), compound 4 and the corresponding reagent

The reaction occurs under the catalysis of acid to obtain the final product 5;

route two

(1) In an inert solvent (such as toluene), in 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 the presence of , compound 1 and compound 2 undergo a nucleophilic substitution reaction to generate compound 3;

(2) in an inert solvent (such as toluene), in the presence of trimethylaluminum, compound 3 and

Reaction occurs to obtain final product 4;

route three

(2) in an inert solvent (such as ethanol, methanol), in the presence of a base (such as sodium carbonate, potassium carbonate, sodium hydroxide, triethylamine, pyridine, etc.), compound 3 reacts with hydroxylamine hydrochloride to generate compound 4;

(3) In an inert solvent (such as 1,2-dichloroethane and/or glacial acetic acid), compound 4 reacts with the corresponding reagent (such as dimethoxyacetal, dimethoxyacetal) to obtain final product 5;

In the above formulas,

X is selected from: Cl, Br, I;

R _t is C1-C6 alkyl;

R ₁ , R ₂ , R ₈ , R _m , R _n , R _p , R ₃ , R ₄ , m and n are as defined above.

The starting materials of the present invention are all known and commercially available, or can be synthesized according to literature data reported in the art.

Pharmaceutical compositions and methods of administration

The pharmaceutical composition of the present invention is used for preventing and/or treating the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease.

The compounds of the present invention may be used in combination with other drugs known to treat or ameliorate similar conditions. In the case of combined administration, the mode of administration and dosage of the original drug may remain unchanged, while the compound of the present invention is administered concurrently or subsequently. When the compound of the present invention is administered concomitantly with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compound of the present invention at the same time can be preferably used. Drug combinations also include administration of a compound of the present invention with one or more other known drugs at overlapping time periods. When a compound of the present invention is administered in combination with one or more other drugs, the dose of the compound of the present invention or known drugs may be lower than the doses of the compounds of the present invention administered alone.

The dosage form of the pharmaceutical composition of the present invention includes (but is not limited to): injection, tablet, capsule, aerosol, suppository, film, drop pill, external liniment, controlled-release or sustained-release or nanometer preparation.

The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount. The "safe and effective amount" refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/dose, more preferably, 10-1000 mg of the compound of the present invention/dose. Preferably, the "one dose" is a capsule or tablet.

"Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler or gelling substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility" as used herein means that the components of the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as

), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.

Besides these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.

The therapeutic methods of the present invention may be administered alone or in combination with other therapeutic means or therapeutic agents.

When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as people) in need of treatment, and the dose is a pharmaceutically considered effective dose when administered, and for a person with a body weight of 60kg, the daily dose is The administered dose is usually 1-2000 mg, preferably 10-1000 mg. Of course, the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.

The present invention also provides a preparation method of a pharmaceutical composition, comprising the steps of: carrying out a pharmaceutically acceptable carrier with the compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof. mixed to form a pharmaceutical composition.

The present invention also provides a method of treatment comprising the steps of: administering to a subject in need of treatment a compound described in the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or administering the present invention The pharmaceutical composition of the invention is used to selectively inhibit the fusion mutation of NTRK and its drug resistance mutation.

The present invention has the following main advantages:

(1) the compounds of the present invention have good selective inhibitory ability to NTRK kinase,

(2) the compound of the present invention has better inhibitory ability on the activity of NTRK drug resistance mutation;

(3) the compound of the present invention has better pharmacodynamics, pharmacokinetic properties and lower toxic and side effects;

(4) The compounds of the present invention have great potential to be developed into drugs targeting NTRK that are urgently needed in clinical practice.

The technical solutions of the present invention are further described below, but the protection scope of the present invention is not limited thereto.

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions, or in accordance with the conditions suggested by the manufacturer. Percentages and parts are by weight unless otherwise indicated.

Example 1

The synthetic route and experimental process are as follows:

1. Synthesis of INT

INT-1 (200 mg, 1.94 mmol) and absolute ethanol (1 mL) were added to a 50 mL single-necked bottle.

Under ice bath condition, thionyl chloride (0.35 mL, 4.85 mmol) was added dropwise, and then the reaction was performed at 75° C. for 6 h. TLC detected the end of the reaction, concentrated the reaction solution, adjusted pH=8 with potassium carbonate aqueous solution, extracted three times with DCM, combined the organic phases, dried the organic phases with anhydrous sodium sulfate, filtered and concentrated to obtain 100 mg of light yellow oil.

2. Synthesis of C-10-2

C-10-1 (200 mg, 0.615 mmol), absolute ethanol (82 mg, 1.84 mmol), HCl/dioxane (1 mL, 4 M) and toluene (1 mL) were added to a 100 mL single-necked flask. The reaction was carried out at 25° C. for 16 hours. LC-MS showed that the reaction was completed. The reaction solution was concentrated and adjusted to pH=9 with a 15% NaOH aqueous solution. EA was extracted three times, the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (DCM:MeOH=30:1) to obtain 50 mg of off-white foam.

3. Synthesis of C-10

C-10-2531 mg, 1.43 mmol), INT (750 mg, 5.72 mmol), glacial acetic acid (5 uL) and xylene (5 mL) were added to a 50 mL single-necked bottle. Under nitrogen protection, the reaction was carried out at 130 °C for 6 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated, adjusted to pH=7 with saturated aqueous NaHCO ₃ solution, extracted three times with EA, combined with the organic phases, dried with anhydrous ammonium sulfate, filtered, and concentrated. Column chromatography (DCM:MeOH=30:1) gave 200 mg of white solid.

Nuclear magnetic analysis data of compound C-10: ¹ H NMR (400MHz, CDCl ₃ ): δ9.50(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).

Example 2

The synthetic route and experimental process are as follows:

1. Synthesis of C2-1

C1-1 (450mg, 2.78mmol), diethylzinc (4mL, 4.16mmol), Pd(PPh ₃ ) ₂ Cl ₂ , dichloromethane (227mg, 0.278mmol) and dioxane were added to a 50mL single-neck flask (3 mL). Under nitrogen protection, the reaction was carried out at 80°C overnight. LC-MS showed that the reaction was completed, pure water (30 mL) was added to quench the reaction, extracted with ethyl acetate (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (PE:EA=2:1 -1:1), get 150mg.

2. Synthesis of C2-2

C2-1 (150 mg, 1.0 mmol), IBX (677 mg, 2.5 mmol), and EA (5 mL) were added to a 50 mL single-necked bottle, the temperature was raised to 80° C., and the reaction was carried out for 2.5 hours. LC-MS showed that the reaction was completed, filtered, and the filter cake was washed three times with EA, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (PE:EA=2:1-1:1) to obtain 120 mg.

3. Synthesis of C2-3

C2-2 (120 mg, 0.78 mmol), R-tert-butylsulfinamide (118 mg, 0.80 mmol), cesium carbonate (228 mg, 0.54 mmol) and DCM (2 mL) were added to a 50 mL single-necked flask. The reaction was carried out at 25°C for 4 hours. LC-MS showed that the reaction was complete, filtered, and the filter cake was washed three times with DCM, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 150 mg of yellow oil.

4. Synthesis of C2-4

C2-3 (150 mg, 0.41 mmol) and THF (5 mL) were added to a 50 mL three-necked flask, C1-11 (1.64 mL, 0.82 mmol) was added dropwise at 0° C., and the reaction was performed at room temperature for 2 hours after the dropwise addition. LC-MS showed that the reaction was completed, a saturated solution of NH ₄ Cl (30 mL) was added, extracted with EA, the organic phase was dried, and concentrated to obtain 180 mg of crude product, [M+H]: 373.3.

5. Synthesis of C2-5

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

Nuclear magnetic analysis data of compound C2-5: ¹ H NMR (400MHz, CDCl ₃ ): δ8.24-8.23(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).

6. Synthesis of C2-6

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

Nuclear magnetic analysis data of compound C2-6: ¹ H NMR (400MHz, d6-DMSO): δ8.82-8.59 (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).

7. Synthesis of C2-7

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

8. Synthesis of C2

C2-7 (600mg, 1.62mmol), 2,2-dimethoxypropane (676mg, 6.50mmol), acetic acid (5mL), DCE (5mL) were added to a 50mL single-neck flask, and the reaction was placed at 80°C to react 2h. LC-MS showed that the reaction was complete, concentrated, adjusted pH to 7 with saturated aqueous sodium bicarbonate solution, extracted with EA, and column chromatography (DCM:MeOH=150:1-50:1) to obtain 200 mg of pale yellow solid, [M+H ]:410.3.

Nuclear magnetic analysis data of compound C2: ¹ H NMR (400MHz, d6-DMSO): δ8.77-8.76 (d, 0.7H), 8.51-8.42 (m, 1.3H), 8.07-8.01 (m, 1H), 7.32 -7.24(m,1H),6.66-6.64(m,1H),5.85-5.34(m,2H),4.05(br,1H),3.75-3.62(m,1H),2.96-2.91(m,2H) , 2.04-1.84(m, 3H), 1.47-1.24(m, 8.5), 1.06(s, 2.5H).

Example 3

The synthetic route and experimental process are as follows:

1. Synthesis of C3-1

2-Methoxy-5-fluoronicotinic aldehyde (1.0g, 6.45mmol), R-tert-butylsulfinamide (820mg, 6.78mmol), cesium carbonate (1.46g, 4,49mmol) were added to a 50mL single-neck flask and DCM (10 mL) at 25°C for 3 hours. LC-MS showed that the reaction was completed, filtered, and the filter cake was washed three times with DCM, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2.55 g.

Nuclear magnetic analysis data of compound C3-1: ¹ H NMR (400MHz, CDCl ₃ ): δ8.89-8.88(d,1H), 8.16-8.15(d,1H), 7.99-7.96(dd,1H), 4.01( s, 3H), 1.27 (m, 9H).

2. Synthesis of C3-2

C3-1 (200 mg, 0.78 mmol) and THF (5 mL) were added to a 50 mL three-necked flask, C1-11 (3.12 mL, 1.56 mmol) was added dropwise at 0° C., and the reaction was performed at room temperature for 2 hours after the dropwise addition. LC-MS showed that the reaction was completed, a saturated solution of NH ₄ Cl (30 mL) was added, extracted with EA, the organic phase was dried and concentrated to obtain 220 mg of crude product.

Nuclear magnetic analysis data of compound C3-2: ¹ H NMR (400MHz, CDCl ₃ ): 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).

3. Synthesis of C3-3

The crude product of C3-2 was dissolved in trifluoroacetic acid (1 mL) and water (0.2 mL), heated to 40 °C under nitrogen protection, stirred for 1 hour, and then added dropwise triethylsilane (202 mg, 1.20 mmol), 40 °C under stirring for 12 hours. LC-MS showed the reaction was complete and concentrated. Adjust the pH to 13 with 15% NaOH, extract three times with EA (10 mL), separate the layers, dry, and concentrate the EA phase to obtain 100 mg, and the crude product is directly used in the next reaction.

4. Synthesis of C3-4

C3-3 (100mg, 0.51mmol), C1-9 (95.3mg, 0.54mmol), triethylamine (154.5mg, 1.53mmol), EtOH (2mL), THF (0.5mL) were added to a 50mL single-neck flask, and the 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, and the mixture was cooled to room temperature and filtered to obtain 260 mg of an off-white solid.

Nuclear magnetic analysis data of compound C3-4: ¹ H NMR (400MHz, CDCl ₃ ): 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).

5. Synthesis of C3-5

C3-4 (100 mg, 0.30 mmol), hydroxylamine hydrochloride (40.8 mg, 0.59 mmol), potassium carbonate (82.2 mg, 0.59 mmol), EtOH (2 mL) and Dioxane (1 mL) were added to a 50 mL single-necked flask. The reaction was left at 80°C overnight. LC-MS showed that the reaction was completed, 10 mL of water was added, extracted with EA three times, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (DCM:MeOH=100:1-20:1) to obtain 104 mg.

8. Synthesis of C3

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

Nuclear magnetic analysis data of compound C3: ¹ H NMR (400MHz, CDCl ₃ ): δ8.34-8.18(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).

Example 4

The synthetic route and experimental process are as follows:

1. Synthesis of C4-1

2-Chloro-5-fluoronicotinic 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) were added to a 100 mL single-necked bottle. The reaction was carried out at 50° C. for 16 hours. LC-MS showed that the reaction was completed. Water (200 mL) was added, extracted with EA three times, the organic phases were combined, and the organic phases were washed five times with water. The organic phase was dried over anhydrous ammonium sulfate, filtered, concentrated, and subjected to column chromatography (PE:EA=50:1) to obtain 9.6 g of light yellow oil.

Nuclear magnetic analysis data of compound C4-1: ¹ H NMR (400MHz, CDCl ₃ ): δ8.39-8.40(d, 1H), 7.94-7.91(dd, 1H), 4.45-4.43(q, 2H), 1.45- 1.41(t, 3H).

2. Synthesis of C4-2

C4-1 (500 mg, 2.46 mmol), NaH (296 mg, 7.40 mmol) and toluene (10 mL) were added to a 50 mL single-necked flask, and under ice bath conditions, EtOH (340 mg, 7.39 mmol) was added dropwise, and then the reaction was performed at 25° C. overnight. TLC detected the end of the reaction, filtered, concentrated, and chromatographed (PE:EA=10:1) to obtain 210 mg of light yellow oil.

Nuclear magnetic analysis data of compound C4-2: ¹ H NMR (400MHz, CDCl ₃ ): δ8.13-8.12(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).

3. Synthesis of C4-3

Under nitrogen protection, C4-2 (200 mg, 0.94 mmol) and DCM (3 mL) were added to a 50 mL three-necked flask, cooled to -20° C., DIBAL-H (0.14 mL, 1.41 mmol) was added dropwise, and then the reaction was performed at 25° C. overnight. TLC detected the end of the reaction, added 10% NaOH (10 mL), stirred for 10 min, extracted with dichloride three times, dried, filtered, concentrated, and chromatographed (PE:EA=20:1) to obtain 160 mg of light yellow oil.

Nuclear magnetic analysis data of compound C4-3: ¹ H NMR (400MHz, CDCl ₃ ): δ7.87-7.88(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).

4. Synthesis of C4-4

C4-3 (3.0 g, 17.54 mmol), IBX (12.3 g, 43.93 mmol) and EA (100 mL) were added to a 250 mL single-neck flask. The temperature was raised to 80°C, and the reaction was carried out for 2.5 hours. LC-MS showed that the reaction was completed, filtered, and the filter cake was washed three times with EA, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3.0 g.

5. Synthesis of C4-5

C4-4 (2.8 g, 16.57 mmol), R-tert-butylsulfinamide (2.18 g, 18.01 mmol), cesium carbonate (4.0 g, 12.27 mmol) and DCM (30 mL) were added to a 100 mL single-necked flask. The reaction was carried out at 25°C for 4 hours. LC-MS showed that the reaction was completed, filtered, and the filter cake was washed three times with DCM, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5.0 g of a yellow oil.

6. Synthesis of C4-6

C4-5 (5.0 g, 18.38 mmol) and THF (50 mL) were added to a 250 mL three-necked flask, and C1-11 (73.53 mL) was added under nitrogen protection. LC-MS showed that the reaction was completed, the reaction was quenched by saturated ammonium chloride solution, extracted three times with EA, dried and concentrated to obtain 8.0 g of crude product.

7. Synthesis of C4-7

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

8. Synthesis of C4-8

In a 50mL single-neck flask, C4-7 (1.05g, 0.50mmol), C1-9 (0.91, 0.50mmol), triethylamine (4.2mL, 1.50mmol) and EtOH (20mL) were added, and the reaction was placed at 55°C React for 2 hours. LC-MS showed that the reaction was completed, water (100 mL) was added, and the mixture was stirred for 30 min, cooled to room temperature and filtered to obtain 1.4 g of an off-white solid.

9. Synthesis of C4-9

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

10. Synthesis of C4

C4-9 (900mg, 2.51mmol), 2,2-dimethoxypropane (870mg, 8.36mmol) and acetic acid (10mL), DCE (10mL) were added to a 50mL single-neck flask, and the reaction was placed at 80°C to react 3h. LC-MS showed that the reaction was completed, concentrated, adjusted pH to 7 with saturated aqueous sodium bicarbonate solution, extracted with EA, and column chromatography (DCM:MeOH=150:1-50:1) to obtain 350 mg of pale yellow solid.

Nuclear magnetic analysis data of compound C4: 1H NMR (400MHz, d6-DMSO): δ8.76-8.51(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),4.45-4.33dd,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).

Example 5

The synthetic route and experimental process are as follows:

Specific steps are as follows:

Step 1 (the first step)

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

NMR analysis data of compound 2: ¹ H-NMR (400MHz, CDCl ₃ ): δ8.28(s, J=2.8Hz, 1H), 8.16(s, J=5.6Hz, 1H), 7.15-6.82(d, J=6.4Hz, 2H), 6.81-6.70(m, 1H), 6.01-5.07(m, 1H), 4.49-3.77(m, 4H), 2.53(s, J=11.6Hz, 1H), 2.07(t , J=10.0 Hz, 3H), 1.53-1.11 (m, 3H); MS: 373 (M+H ⁺ ).

Step 2 (the second step)

1,2-Propanediamine (0.12g, 0.016mol, 2eq) was dissolved in dry toluene (2ml), the reaction system was lowered to 0°C under argon protection, and then trimethylaluminum (0.9 ml, 2M, dissolved in toluene), after the dropwise addition, the temperature was raised to room temperature and continued to react for 2h, then lowered to 0°C, and the toluene solution (3ml) of compound 2 (0.3g, 0.0080mol, 1eq) was slowly added dropwise. After the addition was completed, the reaction was continued for 30 min, and then the temperature was raised to 80 °C for 16 h. After the reaction of the raw materials, the reaction system was lowered to 0 °C, and then methanol was added to quench, filter, spin dry the filtrate, and purify the filtrate twice to obtain compound C. -5 (80 mg, tan solid, purity 98.6%, yield 26%).

NMR and other analytical data of compound C-5: ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.28 (s, J=2.8 Hz, 1H), 8.16 (s, J=5.6 Hz, 1H), 7.15-6.82 ( d, J＝6.4Hz, 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 ⁺ ).

Example 6

The synthetic route and experimental process are as follows:

Step 1 (the first step)

1,2-Diamino-2-methylpropane (0.14g, 0.016mol, 2eq) was dissolved in dry toluene (2ml), and the reaction system was lowered to 0°C under argon protection, followed by the slow dropwise addition of three Methylaluminum (1.1ml, 2M, dissolved in toluene) was added dropwise and the temperature was raised to room temperature to continue the reaction for 2h, then lowered to 0°C, and the toluene solution of compound 2 (0.3g, 0.0080mol, 1eq) was slowly added dropwise (3ml), after the dropwise addition was completed, the reaction was continued for 30min, then the temperature was raised to 80°C for 16h. After the reaction of the raw materials, the reaction system was lowered to 0°C, and then methanol was added to quench, filter, spin dry the filtrate, and then purify through a column Twice, compound C-6 was obtained (60 mg, off-white solid, purity 98.4%, yield 18.7%).

NMR and other analytical data of compound C-6: ¹ H-NMR (400MHz, CDCl ₃ ): δ8.28 (s, J=2.8Hz, 1H), 8.16 (s, J=5.6Hz, 1H), 7.15-6.82 ( d, J＝6.4Hz, 2H), 6.81-6.70(m, 1H), 6.01-5.07(m, 1H), 5.59-5.39(m, 1H), 4.15-3.25(m, 4H), 2.62-2.38( m, 1H), 2.27-1.95 (m, 2H), 1.44-0.73 (m, 8H). MS: 397 (M+H ⁺ ).

Example 7

The synthetic route and experimental process are as follows:

Step 1 (the first step)

Under the protection of argon, dry toluene (10ml) was lowered to 0°C, then ammonia gas was slowly passed in for 20min, then trimethylaluminum (2.6ml, 2M, dissolved in toluene) was added dropwise, and the temperature was raised after the dropwise addition was completed. The reaction was continued at room temperature for 2 hours, then lowered to 0 °C, and the toluene solution (10 ml) of compound 2 (1 g, 0.0080 mol, 1 eq) was slowly added dropwise. After the reaction of the raw materials was completed, the reaction system was lowered to 0°C, then quenched by adding methanol, filtered, and the filtrate was spin-dried and purified by column to obtain compound 5 (0.52 g, yellow foam, purity 94.6%, yield 54%).

NMR and other analytical data of compound 5: ¹ H-NMR (400MHz, CDCl ₃ ): δ8.28(s, J=2.8Hz, 1H), 8.16(s, J=5.6Hz, 1H), 7.15-6.82(d , J=6.4Hz, 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 ⁺ ).

Step 2 (the second step)

Compound 5 (0.5g, 0.0145mol, 1eq) was dissolved in phosphorus oxychloride (5ml), then the temperature was raised to 80°C for 3h reaction, when the reaction of the raw materials was completed, the phosphorus oxychloride was spin-dried, and then diluted with ethyl acetate , the mixture was lowered to 0°C, neutralized with 1M aqueous sodium hydroxide solution, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed once with brine, dried over anhydrous sodium sulfate, spin-dried, and after purification, Compound 6 was obtained (0.44 g, brown oil, 96% purity, 92.8% yield).

NMR and other analytical data of compound 6: ¹ H-NMR (400MHz, CDCl ₃ ): δ8.28(s, J=2.8Hz, 1H), 8.16(s, J=5.6Hz, 1H), 7.15-6.82(d , J=6.4Hz, 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 ⁺ ).

Step 3 (third step)

Compound 6 (0.2g, 0.00062mol, 1eq) and hydroxylamine hydrochloride (0.042g, 0.00124mol, 2eq) were dissolved in ethanol, potassium carbonate (0.085g, 0.00124mol, 2eq) was added under stirring, and then the temperature was raised to 80°C for reaction 16h, after the reaction of the raw materials, ethyl acetate and water were added to the reaction system, extracted three times with ethyl acetate, the organic phase was washed with brine, dried over anhydrous sodium sulfate, spin-dried, and purified by column twice to obtain compound 7 (0.14 g, pale yellow solid, 90% pure). MS: 359 (M+H ⁺ ).

Step 4 (the fourth step)

Under argon protection, compound 7 (0.14g, 0.00039mol, 1eq) and 2,2-dimethoxypropane (0.081g, 0.00078mol, 2eq) were dissolved in acetic acid and then heated to 40°C for 20h reaction. After the completion of the reaction, spin off most of the acetic acid, then in the reaction system, the aqueous solution of saturated sodium bicarbonate is extracted three times with ethyl acetate, and the organic phase is washed with brine, dried over anhydrous sodium sulfate, and spin-dried to obtain compound C-7 ( 40 mg, off-white solid, purity 94%, yield 25.6%).

NMR and other analytical data of compound C-7: ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.28 (s, J=2.8 Hz, 1H), 8.16 (s, J=5.6 Hz, 1H), 7.15-6.82 (d, J＝6.4Hz, 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 ⁺ ).

Example 8

The synthetic route and experimental process are as follows:

Step1 (the first step)

Weigh compound 1 (2g) into a reaction flask, add intermediate 1 (8.25g, N-Boc piperidine ketal) (6eq), measure 1,2-dichloroethane (15ml) and acetic acid ( 15ml) as a mixed solvent, heated under reflux at 76°C overnight, and monitored the completion of the reaction. A small amount of water was added, and then saturated sodium bicarbonate was added to neutralize the acetic acid in the reaction system, followed by extraction with dichloromethane. Then use petroleum ether:ethyl acetate=1:2 to pass through the column to obtain 0.5g of compound 2, MS: 540.2 (M+H ⁺ ).

Step2 (the second step)

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

Step3 (third step)

Weigh compound 3 (50mg) into a 50ml round bottom flask, add methyl chloroformate (12.9mg, 1.2eq) and triethylamine (17.3mg, 1.5eq), and then add dichloromethane (5ml) as a solvent, Stir at room temperature for 2 hours and monitor the completion of the reaction. Add water and ethyl acetate for extraction, then use petroleum ether: ethyl acetate = 1:1 to pass through the column to obtain compound C-8 (43 mg), the HPLC purity is 96.7%, MS: 498.2 (M+H ⁺ ).

Example 9

The synthetic route and process are as follows:

1. Synthesis of intermediate C1-9

The synthetic route and process are as follows:

1. Synthesis of C1-10

In a 1000mL single-necked flask, add 2-amino-3-cyanopyrazole (20.0g, 0.185mol), ethyl ethoxyacrylate (53.3g, 0.37mol), cesium carbonate (126.8g, 0.389mol) and DMF ( 500 mL), reacted at 110 °C for 6 h, cooled to room temperature, poured into water, filtered and dried to obtain 27.5 g of a yellow solid.

2. Synthesis of C1-9

Add C1-10 (27.5g, 0.172mol), phosphorus oxychloride (129g, 0.02mol) and acetonitrile (350mL) to a 1000mL single-neck flask, react at 100°C for 16h, cool to room temperature, pour into water, filter, and dry , 18.0g of C1-9 was obtained. The mother liquor was concentrated to remove acetonitrile, extracted with DCM, recovered from the filtrate again, and concentrated to obtain 8.0 g of C1-9.

2. Synthesis of intermediate C-11

The synthetic route and process are as follows:

Under nitrogen protection, add magnesium strips (14.776g, 0.616mol), THF (200mL) and DIBAL-H (1M, 2mL) to a 500mL three-necked flask, heat up to 40°C, add 2-(2-bromoethyl) dropwise )-1,3-dioxane (40.0g, 0.205mol), control the drop rate, ensure that the temperature change is controlled at ±5°C, continue the reaction for 2 hours after the dropwise addition, and the reaction solution is directly used for the subsequent reaction.

3. Synthesis of Compound C1

The synthetic route is as follows:

1. Synthesis of C1-1

2-Chloro-5-fluoronicotinic acid (500mg, 2.84mmol), sodium borohydride (16mg, 2.84mmol) and THF (5mL) were added to a 50mL single-neck bottle, and boron trifluoride ether (0.36mL, 2.84 mmol), and then the temperature was raised to 70 °C for 16 hours. LC-MS showed that the reaction was completed, 50 mL of pure water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), the organic phase was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and column chromatography PE:EA=2:1-1: 1, get 320mg.

Nuclear magnetic analysis data of compound C1-1: ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.17-8.16 (d, 1H), 7.73-7.70 (dd, 1H), 4.77 (s, 2H).

2. Synthesis of C1-2

In a 50mL single-necked flask, C1-1 (200mg, 1.24mmol), methylboronic acid (223mg, 3.72mmol), Pd(PPh ₃ ) ₂ Cl ₂ (87mg, 0.124mmol), potassium carbonate (514mg, 3.72mmol) were added, Dioxane (5 mL) and water (0.5 mL) were reacted at 90° C. for 12 hours under nitrogen protection. LC-MS showed that the reaction was completed, 50 mL of pure water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography PE:EA=2:1-1: 1, get 50mg.

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

3. Synthesis of C1-3

In a 100 mL single-neck flask, C1-2 (3.0 g, 21.43 mmol), IBX (17.37, 535.7 mmol), and EA (150 mL) were added. The temperature was raised to 80°C, and the reaction was carried out for 2.5 hours. LC-MS showed that the reaction was completed, filtered, and the filter cake was washed three times with EA, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and 1.2 g was obtained by column chromatography PE:EA=2:1-1:1.

Nuclear magnetic analysis data of compound C1-2: ¹ H NMR (400MHz, CDCl ₃ ): δ10.34-10.33(d,1H), 8.57-8.56(d,1H), 7.83-7.80(dd,1H), 2.88( s, 3H).

4. Synthesis of C1-4

In a 100mL single-necked flask, C1-3 (1.2g, 8.57mmol), R-tert-butylsulfinamide (1.08g, 8.74mmol), cesium carbonate (2g, 6.00mmol) and DCM (12mL) were added, and the mixture was heated at 25°C. The reaction was continued for 4 hours. LC-MS showed that the reaction was completed, filtered, and the filter cake was washed three times with DCM, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2.0 g of a yellow oil.

5. Synthesis of C1-5

At 0°C, C1-4 (200 mg, 0.65 mmol) and THF (10 mL) were added to a 50 mL three-necked flask, C-11 (2.6 mL, 1.30 mmol) was added dropwise, and the reaction was performed at room temperature for 2 hours. LC-MS showed that the reaction was completed, a saturated solution of NH ₄ Cl (30 mL) was added, extracted with EA, the organic phase was dried and concentrated to obtain 241 mg of crude product.

6. Synthesis of C1-6

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

7. Synthesis of C1-7

C1-5 (180mg, 1mmol), C-9 (187mg, 1.05mmol) triethylamine (0.8mL, 6.0mmol) and EtOH (5mL) were added in a 50mL single-neck flask, 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 obtain 160 mg of an off-white solid.

8. Synthesis of C1-8

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

Nuclear magnetic analysis data of compound C1-8: ¹ H NMR (400MHz, CDCl ₃ ): δ8.29(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) .

9. Synthesis of C1

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

Nuclear magnetic analysis data of compound C1: ¹ H NMR (400MHz, CDCl ₃ ): δ8.40-8.19(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).

Example 10

The synthetic route and experimental process are as follows:

1. Synthesis of C-11-1

Add C4-8 (600mg, 2.38mmol), the acetic acid solution (5.0mL, 23.80mmol) and acetic acid (10mL) of hydrogen bromide in the 100mL single-necked bottle, there is solid precipitation, LC-MS shows that the reaction is completed, the concentrated reaction solution, directly Proceed to the next step.

2. Synthesis of C-11-2

C-11-1 (600 mg, 2.38 mmol) and phosphorus oxychloride (10 mL) were added to a 100 mL single-neck flask, and the reaction was carried out at 80° C. for 3 hours. TLC detected the end of the reaction, concentrated the reaction solution, adjusted pH=8～9 with 15% NaOH, extracted 5 times with DCM, combined the organic phases, dried over anhydrous sodium sulfate, filtered, concentrated, and chromatographed (DCM:MeOH=25:1 ) to get 445mg.

3. Synthesis of C-11-3

C-11-2 (445 mg, 1.37 mmol), cesium carbonate (4.46 g, 13.73 mmol) and DMF (10 mL) were added to a 50 mL single-necked flask. At room temperature, iodomethane (3.9 g, 27.47 mmol) was added dropwise, the drop was completed, and the reaction was carried out at room temperature overnight. TLC detected the end of the reaction, filtered, added water to the mother liquor, extracted twice with DCM, combined the organic phases, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (DCM:MeOH=25:1) to obtain 310 mg.

4. Synthesis of C-11-4

C-11-3 (310 mg, 0.917 mmol), hydroxylamine hydrochloride (506 mg, 7.337 mmol), potassium carbonate (1.02 g, 7.337 mmol), EtOH (8 mL) and Dioxane (4 mL) were added to a 100 mL single-necked flask. The reaction was left at 80°C overnight. LC-MS showed that the reaction was completed, 20 mL of water was added, extracted with EA, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (DCM:MeOH=100:1-20:1) to obtain 251 mg.

5. Synthesis of C-11

C-11-4 (251mg, 0.676mmol), 2,2-dimethoxypropane (563mg, 5.412mmol) and acetic acid (2.5mL), DCE (5mL) were added to a 50mL single-neck flask, and the reaction was placed at 80 The reaction was carried out at ℃ for 3h. LC-MS showed that the reaction was completed, concentrated, adjusted pH to 7 with saturated aqueous sodium bicarbonate solution, extracted with EA, and column chromatography (DCM:MeOH=150:1-50:1) to obtain 60 mg of pale yellow solid.

Nuclear magnetic analysis data of compound C11: ¹ H NMR (400MHz, CD3OD): δ8.50-8.48(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).

Example 11

The synthetic route and experimental process are as follows:

1. Synthesis of C-12

C7 (500 mg, 1.256 mmol), sodium hydride (60 mg, 1.507 mmol) and DMF (5 mL) were added to a 50 mL single-neck flask, and the reaction was carried out at 0° C. for 1 h. Then, methyl iodide (214 mg, 1.507 mmol) was added dropwise, the dropping was completed, and the reaction was carried out at room temperature for 1 h. LC-MS showed that the reaction was completed, water was added, extracted three times with DCM, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (DCM:MeOH=25:1) to obtain 180 mg of white solid.

Nuclear magnetic analysis data of compound C-12: ¹ H NMR (400MHz, CD3OD): δ8.53(br,0.7H), 8.35(br,0.3H), 8.19(s,1H), 7.16(s,1H), 6.97(br,1H),6.81(s,1H),6.65(s,0.7H),6.11(br,0.3),5.72(s,0.7H),5.34(br,0.3H),4.19-3.71(m , 2H), 2.60(s, 3H), 2.48(br, 1H), 2.13-2.01(m, 3H), 1.55-1.45(m, 6H).

With reference to Examples 1-11, Examples 13-35 were further specifically synthesized, as shown in Table 1.

Table 1

Test Example 1: Inhibitory activity of the compounds of the present invention on NTRK and its drug-resistant kinase NTRK1-G667C

The activity inhibition experiments of compounds on protein kinases were carried out on the HotSpot kinase experimental platform radiolabeled by Reaction Biology Corporation. Prepare a fresh reaction solution containing the corresponding substrate (20 mM HEPES pH 7.5, 10 mM MgCl ₂ , 1 mM EGTA, 0.02% Brij35, 0.02 mg/mL BSA, 0.1 mM Na ₃ VO ₄ , 2 mM DTT, 1% DMSO), add the required auxiliary The factor and the kinase to be tested were added to the above solution and mixed gently. Using the Echo550 pipetting system, the DMSO solution of the test compound was added to each well (the blank control group was added with the corresponding volume of DMSO), and 33P-ATP (final specific activity 0.01 μCi/ μL) 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 the remaining radioactive phosphorylated substrate on the chromatography paper was detected.

Table 2 shows the IC50 values of the inhibitory activities of some compounds of the present invention on NTRK1, NTRK2 and NTRK3 and the drug resistance mutation NTRK1-G667C, where A<1.0nM, 1.0nM≤B≤20nM, 20nM<C<100nM, D≥ 100 nM.

Table 2

Note: ND stands for unmeasured activity

Table 3 shows the specific IC50 values of the inhibitory activities of some compounds of the present invention on NTRK1, NTRK2 and NTRK3 and the drug resistance mutation NTRK1-G667C.

table 3

Through the biological activity test, it is found that the series of compounds of the present invention have good inhibitory activity on various fused NTRKs, and also have good inhibitory activity on various NTRK mutations. At the same time, it has good selectivity for other kinases such as ALK and/or ROS1. It has great potential for the treatment of diseases mediated by NTRK.

All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

The compound represented by formula I, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug,

In the formula,

R1 is selected from :

R 2 is selected from the group consisting of substituted or unsubstituted groups: C6-C14 aryl, 5-14-membered heteroaryl; wherein, the substitution refers to being substituted by one or more R r ;

R m , R n , R 3 and R 4 are each independently selected from the group consisting of substituted or unsubstituted groups: H, halogen, NR p R p' , -CN, -OH,

C1-C6 alkyl group, C1-C6 alkoxy group, C3-C12 cycloalkyl group, 3-12-membered heterocyclic group, C6-C14 aryl group, 5-14-membered heteroaryl group; wherein, the substitution refers to being replaced by One or more R r substitutions;

Or R m and R n together with the C atom to which they are attached form a substituted or unsubstituted group of the following group: C3-C12 cycloalkyl, 3-12 membered heterocyclyl or oxo (=O); wherein the said Substituted means replaced by one or more R r ;

Or R 3 and R 4 together with the C atom to which they are attached form a substituted or unsubstituted group of the following group: C3-C12 cycloalkyl, 3-12 membered heterocyclyl or oxo (=O); wherein the said Substituted means replaced by one or more R r ;

R p and R p' are each independently selected from the group consisting of substituted or unsubstituted groups: H, C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl , C6-C14 aryl, 5-14-membered heteroaryl; wherein, the substitution refers to being substituted by one or more R r ;

Or R 3 and R p together with the atoms to which they are attached form a substituted or unsubstituted group of the following groups: C3-C12 cycloalkyl, 3-12 membered heterocyclyl; wherein, the substitution refers to substitution by one or more R r substituted;

Or R 3 and R p' together with the atoms to which they are attached form a substituted or unsubstituted group of the following group: C3-C12 cycloalkyl, 3-12 membered heterocyclyl; wherein, the substitution refers to being replaced by one or more R r substitutions;

Or R 3 and R m together with the atoms to which they are attached form a substituted or unsubstituted group of the following group: C3-C12 cycloalkyl, 3-12 membered heterocyclyl; wherein, the substitution refers to being replaced by one or more R r substituted;

R 8 is each independently selected from the group consisting of substituted or unsubstituted: halogen, NR p R p' , -CN, -OH,

C1-C6 alkyl, C1-C6 alkoxy; wherein, the substitution refers to being substituted by one or more R r ;

Or two R 8 located on the same C atom together with the C atom to which they are attached form a substituted or unsubstituted group of the following groups: C3-C12 cycloalkyl, 3-12 membered heterocyclyl or oxo (=O ); wherein, the substitution refers to being replaced by one or more R r ;

Or the two R 8 located on the adjacent two C atoms together with the C atoms to which they are attached form a substituted or unsubstituted group of the following group: C3-C12 cycloalkyl, 3-12-membered heterocyclyl; wherein, the said Substituted means replaced by one or more R r ;

n is 0, 1, 2 or 3;

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

s is 1, 2 or 3;

R r is selected from: deuterium, halogen, NR p R p' , -CN, -OH,

C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12-membered heterocyclyl, C6-C14 aryl, 5-14-membered heteroaryl;

R', R" are each independently selected from: H, C1-C6 alkyl, halogenated C1-C6 alkyl; or R', R" together with the N atom to which they are attached form a substituted or unsubstituted 3-8 membered heterocyclic Cyclic group, wherein the substitution refers to being substituted by one or more groups selected from the group consisting of deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy;

R is selected from: H, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, ( CH 2 ) s C6-C10 aryl.
The compound of formula I, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug according to claim 1, wherein R 2 is selected from Self-substituted or unsubstituted groups of the following groups: phenyl, naphthyl, pyridone, pyridyl, pyrimidinyl, benzofuranyl, benzotetrahydrofuranyl, chromanyl, benzodioxane Cyclyl, chroman, benzopyrazine; wherein, the substitution refers to substitution by one or more groups selected from the group consisting of deuterium, halogen, NR p R p' , -CN, - OH,

C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12-membered heterocyclyl, C6-C14 aryl, 5-14-membered heteroaryl;

Wherein, the definitions of R p , R p' , R, R' and R" are as described in claim 1 .
The compound of formula I, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug according to claim 1, characterized in that it has the formula The structure shown in II:

in,

* indicates R or S configuration;

R 1 , R 2 , R 8 and m are as defined in claim 1 .
The compound of formula I, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug according to claim 1, characterized in that it has the formula The structure shown in III:

in,

* indicates R or S configuration;

R 9 is 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;

X is selected from: N, CR 10 , wherein, R 10 is selected from: H, halogen, CN, OH, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenated alkoxy base, C1-C6 alkylamino, C1-C6 haloalkylamino,

R 1 , R 8 , R, R', R" and m are as defined in claim 1 .
The compound of formula I, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug according to claim 1, characterized in that it has the formula The structure shown in IV:

in,

* indicates R or S configuration;

R 9 is 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;

X is selected from: N, CR 10 , wherein, R 10 is selected from: H, halogen, CN, OH, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenated alkoxy base, C1-C6 alkylamino, C1-C6 haloalkylamino,

R1 is selected from :

R, R', R", R m , R n , R p , R 3 and R 4 are as defined in claim 1 .
The compound of formula I, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug according to claim 1, characterized in that it has the formula The structure shown by V and formula VI:

in,

* indicates R or S configuration;

X is selected from: N, CR 10 ;

R 10 and R 9 are each independently selected from: H, halogen, CN, OH, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 Alkylamino, C1-C6 halogenated alkylamino;

R 3 and R 4 are each independently selected from the group consisting of substituted or unsubstituted groups: H, halogen, NR p R p' , -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C3 -C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the substitution refers to being substituted by one or more R r ;

Or R 3 and R 4 together with the C atom to which they are attached form a substituted or unsubstituted group of the following group: C3-C8 cycloalkyl, 3-8 membered heterocyclyl or oxo (=O); wherein the said Substituted means replaced by one or more R r ;

R r is selected from: deuterium, halogen, NR p R p' , -CN, -OH,

C1-C6 alkyl, C1-C6 alkoxy;

Wherein, the definitions of R p , R p' , R, R' and R" are as described in claim 1 .
The compound of formula I, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug according to claim 1, wherein said compound selected from the following compounds:
A pharmaceutical composition comprising i) a therapeutically effective amount of the compound represented by the formula I, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvents compound or prodrug; and ii) one or more pharmaceutically acceptable carriers.
Use of the compound of formula I, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs as claimed in claim 1, characterized in that the use of For the preparation of medicaments for the prevention and/or treatment of diseases characterized by NTRK-mediated pathology.
9. The use of claim 9, wherein the disease characterized by NTRK-mediated pathology includes cancer, sarcoma, and pain.
The use of claim 10, wherein the cancer is selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, and prostate cancer , bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, peritoneal tumor, melanoma, glioma, glioblastoma, head and neck cancer, mastoid nephroma, leukemia, lymphoma, bone marrow tumor, thyroid tumor.