A five-membered and six-membered bicyclic compound, a preparation method and application thereof

Abstract

The present disclosure provides a kind of five-membered and six-membered bicyclic compound, its preparation method and application.The present disclosure specifically provides a kind of compound as shown in formula (I) or its isomer, pharmaceutically acceptable salt, prodrug, solvate, isotopically labeled derivative, metabolite, nitrogen oxide, its preparation method and the pharmaceutical composition containing the compound, and its application in the preparation of treating disease drugs.

Description

Technical Field

[0001] This disclosure belongs to the field of medicinal chemistry, specifically relating to a five-membered and six-membered bicyclic compound, its preparation method, and its application. Background Technology

[0002] Human epidermal growth factor receptor 2 (HER2), also known as ErbB2, is a receptor tyrosine kinase encoded by the ERBB2 proto-oncogene located on the long arm of chromosome 17 (17q21). It is a member of the EGFR / ErbB family, which includes HER1 / EGFR, HER2, HER3, and HER4. Unlike other members of the EGFR / ErbB family, HER2 has no known ligand. It is activated through homodimerization or heterodimerization with another ligand-binding HER family member, leading to cross-phosphorylation and activation of its tyrosine kinase catalytic domain. Activated downstream signaling pathways such as ERK-MAPK, PI3K-Akt, and STAT regulate processes such as cell proliferation, survival, differentiation, and migration. Therefore, aberrant overexpression or mutations leading to upregulation of HER2 activity (including small-frame insertions or specific point mutations in exon 20) are closely associated with tumor progression.

[0003] It is currently known that HER2 alterations are closely associated with poor prognosis in tumors such as breast cancer, gastrointestinal cancer, ovarian cancer, endometrial cancer, bladder cancer, lung cancer, colon cancer, and head and neck cancer. Three types of HER2 aberrations have been identified in non-small cell lung cancer (NSCLC): HER2 gene amplification (3%); HER2 protein overexpression (2.4%–38%); and HER2 mutation (3%–6%). HER2 mutation is a major driver gene in HER2-mutant NSCLC; HER2 exon20 is the most common mutated region in the HER2 tyrosine kinase domain in NSCLC (accounting for 50–90% of all mutations), and HER2 A775_G776insYVMA is the most common mutation type in HER2 exon20. HER2 overexpression occurs in approximately 15-20% of breast cancer patients, indicating a clear clinical need. Currently, most HER2 TKIs target both EGFR and HER2, leading to EGFR-related limiting toxicities in treating HER2-positive or mutated patients, thus limiting efficacy. Tucatinib has good EGFR selectivity, but its inhibitory effect on mutant HER2 is limited. Therefore, there is a need to develop a TKI with good EGFR selectivity that can effectively target mutated HER2. Summary of the Invention

[0004] This disclosure provides a compound of formula (I) or an isomer thereof, a pharmaceutically acceptable salt, a prodrug, a solvate, an isotope-labeled derivative, a metabolite, or a nitrogen oxide.

[0005]

[0006] in,

[0007] It can be a single bond or a double bond;

[0008] M1 is selected from -N-, -N=, or -C=;

[0009] M2 is selected from -N=, -N-, and -C(R). 6-1 = or -C(=O)-;

[0010] M3 is selected from -N(R) 6-2 )-、-C(R 6-3 R 6-4 - or -C(R) 6-5 = ;

[0011] L1 is selected from the bond, -(CH2). n1 -、-O(CH2) n2 -、-NH(CH2) n3 -;

[0012] Ring A is selected from 5-6-membered heteroaryl, 3-10-membered heterocyclic alkyl, and 3-10-membered heterocyclic alkenyl; or, ring A is absent.

[0013] Ring B is selected from 3-10 membered heterocyclic alkyl or 3-10 membered heterocyclic alkenyl;

[0014] Ring C is selected from C 6-14 Aryl, 5-14 heteroaryl;

[0015] R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl;

[0016] R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl;

[0017] R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl;

[0018] R 4-1 R 4-2 R 4-3 and R 4-4 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl;

[0019] R 5-1 R 5-2 and R 5-3 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic alkyl groups, are optionally further modified by amino groups, -NH(C) 1-6 alkyl), -N(C) 1-6 One or more substitutions are made from alkyl groups, 2-, 3-, 8-membered heterocyclic alkyl groups, and halogenated 3-, 8-membered heterocyclic alkyl groups;

[0020] R 6-1 R 6-2 R 6-3 R 6-4 and R 6-5 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl;

[0021] n1, n2, and n3 are each independently selected from 0, 1, 2, or 3;

[0022] x is selected from 0, 1, 2, 3 or 4;

[0023] y is selected from 0, 1, 2, 3 or 4;

[0024] w can be selected from 0, 1, 2, 3 or 4.

[0025] In some embodiments of this disclosure, structural fragments Selected from The definitions of other groups are the same as those described in any of the technical solutions disclosed herein.

[0026] In some embodiments of this disclosure, structural fragments Selected from The definitions of other groups are the same as those described in any of the technical solutions disclosed herein.

[0027] In some embodiments of this disclosure, ring A is selected from... The α-terminus is connected to L1; the definitions of other groups are the same as those described in any of the technical solutions disclosed herein.

[0028] In some embodiments of this disclosure, ring A is absent; the definitions of other groups are the same as those described in any of the technical solutions of this disclosure.

[0029] In some embodiments of this disclosure, L1 is selected from bonds; the definitions of other groups are the same as those described in any of the technical solutions of this disclosure.

[0030] In some embodiments of this disclosure, ring B is selected from 6-membered heterocyclic alkenyl, 6-membered heterocyclic alkyl, 4-membered heterocyclic alkyl, 5-membered heterocyclic alkyl, cyclopentyl-5-membered heterocyclic alkyl, cyclohexylspiro-4-membered heterocyclic alkyl, 7-membered heterocyclic alkyl, and 5-membered heterocyclic alkenyl; the definitions of other groups are the same as those described in any of the technical solutions of this disclosure.

[0031] In some embodiments of this disclosure, ring B is selected from... The α-terminus is connected to the A-terminus of the ring; the definitions of other groups are the same as those described in any of the technical solutions disclosed herein.

[0032] In some embodiments of this disclosure, the ring C is selected from 6-membered heteroaryl-5-membered heteroaryl, phenyl-5-membered heteroaryl, 6-membered heteroaryl, phenyl-5-membered heterocyclic alkenyl-cyclopropyl, and phenyl-5-membered heterocyclic alkenyl-spirocyclopropyl; the definitions of other groups are the same as those described in any of the technical solutions of this disclosure.

[0033] In some embodiments of this disclosure, ring C is selected from... The definitions of other groups are the same as those described in any of the technical solutions disclosed herein.

[0034] In certain embodiments of this disclosure, R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic alkyl groups; other groups are defined as described in any of the technical solutions disclosed herein.

[0035] In some embodiments of this disclosure, R1 is independently selected from hydrogen; the definitions of other groups are the same as those described in any of the technical solutions of this disclosure.

[0036] In certain embodiments of this disclosure, R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic alkyl groups; other groups are defined as described in any of the technical solutions disclosed herein.

[0037] In some embodiments of this disclosure, R2 is independently selected from hydrogen or methyl; other groups are defined as described in any of the technical solutions of this disclosure.

[0038] In certain embodiments of this disclosure, R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic alkyl groups; other groups are defined as described in any of the technical solutions disclosed herein.

[0039] In some embodiments of this disclosure, R3 is independently selected from hydrogen, methyl, methoxy, and difluoromethyl; the definitions of other groups are the same as those described in any of the technical solutions of this disclosure.

[0040] In some embodiments of this disclosure, R 4-1 R 4-2 R 4-3 and R 4-4 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic alkyl groups; other groups are defined as described in any of the technical solutions disclosed herein.

[0041] In some embodiments of this disclosure, R 4-1 Selected from hydrogen; other groups are defined as described in any of the technical solutions disclosed herein.

[0042] In some embodiments of this disclosure, R4-2 Selected from hydrogen and fluorine; other groups are defined as described in any of the technical solutions disclosed herein.

[0043] In some embodiments of this disclosure, R 4-3 Selected from methyl groups; other groups are defined as described in any of the technical solutions disclosed herein.

[0044] In some embodiments of this disclosure, R 4-4 Selected from hydrogen and fluorine; other groups are defined as described in any of the technical solutions disclosed herein.

[0045] In some embodiments of this disclosure, R 5-1 R 5-2 and R 5-3 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl; the C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic alkyl groups, are optionally further modified by amino groups, -NH(C) 1-3 alkyl), -N(C) 1-3 One or more of the following are substituted: alkyl groups, 2-, 3-, and 6-membered heterocyclic alkyl groups, and halogenated 3-, 6-membered heterocyclic alkyl groups; other groups are defined as described in any of the technical solutions disclosed herein.

[0046] In some embodiments of this disclosure, R 5-1 Selected from hydrogen; other groups are defined as described in any of the technical solutions disclosed herein.

[0047] In some embodiments of this disclosure, R 5-2 Selected from hydrogen, -CH2N(CH3)2, The definitions of other groups are the same as those described in any of the technical solutions disclosed herein.

[0048] In some embodiments of this disclosure, R 5-3 Selected from hydrogen; other groups are defined as described in any of the technical solutions disclosed herein.

[0049] In some embodiments of this disclosure, R 6-1 R 6-2 R 6-3 R 6-4 and R 6-5 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic alkyl groups; other groups are defined as described in any of the technical solutions disclosed herein.

[0050] In some embodiments of this disclosure, R 6-1 The radical is selected from hydrogen, methyl, difluoromethyl, and cyano; the definitions of other radicals are the same as those described in any of the technical solutions disclosed herein.

[0051] In some embodiments of this disclosure, R 6-2 Selected from hydrogen; other groups are defined as described in any of the technical solutions disclosed herein.

[0052] In some embodiments of this disclosure, R 6-3 Selected from hydrogen; other groups are defined as described in any of the technical solutions disclosed herein.

[0053] In some embodiments of this disclosure, R 6-4 Selected from hydrogen; other groups are defined as described in any of the technical solutions disclosed herein.

[0054] In some embodiments of this disclosure, R 6-5 Selected from hydrogen; other groups are defined as described in any of the technical solutions disclosed herein.

[0055] This disclosure also provides a pharmaceutical composition comprising the compound described herein or an isomer thereof, a pharmaceutically acceptable salt, a prodrug, a solvate, an isotope-labeled derivative, a metabolite, a nitrogen oxide, and a pharmaceutically acceptable carrier.

[0056] In some embodiments of this disclosure, the content of the compound or its isomers, pharmaceutically acceptable salts, prodrugs, solvates, isotope-labeled derivatives, metabolites, and nitrogen oxides in the pharmaceutical composition is selected from 0.1 mg to 1000 mg.

[0057] In some embodiments of this disclosure, the pharmaceutically acceptable carrier in the pharmaceutical composition includes one or more of fillers, disintegrants, binders, flow aids, and lubricants.

[0058] This disclosure also provides the use of compounds or isomers thereof, pharmaceutically acceptable salts, prodrugs, solvates, isotope-labeled derivatives, metabolites, and nitrogen oxides, or pharmaceutical compositions as described herein, in the preparation of medicaments for treating cancer.

[0059] In some embodiments of this disclosure, the cancer is a HER2-mutated or HER2-positive cancer.

[0060] In some embodiments of this disclosure, the cancer is selected from non-small cell lung cancer, breast cancer, or colon cancer.

[0061] In some embodiments of this disclosure, the cancer is selected from HER2-mutant non-small cell lung cancer, HER2-positive breast cancer, or HER2-positive colon cancer.

[0062] Technical effect

[0063] The compounds disclosed herein exhibit good HER2 inhibitory activity and good selectivity.

[0064] Explanation and Definition

[0065] Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense.

[0066] The term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in human and animal tissues to the extent of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0067] The term "pharmaceutically acceptable salt" refers to derivatives obtained from the compounds of this disclosure prepared with relatively non-toxic acids or bases. These salts can be prepared during the synthesis, isolation, and purification of the compounds, or by reacting the purified free form of the compounds with suitable acids or bases. When the compounds contain relatively acidic functional groups, they react with alkali metal, alkaline earth metal hydroxides, or organic amines to yield base addition salts, including alkali metal and alkaline earth metal-based cations, as well as non-toxic ammonium, quaternary ammonium, and amine cations, and also encompassing amino acid salts. When the compounds contain relatively basic functional groups, they react with organic or inorganic acids to yield acid addition salts.

[0068] The term "pharmaceutically acceptable carrier" refers to a medium generally acceptable in the art for delivering a bioactive pharmaceutical agent to animals, particularly mammals. Depending on the route of administration and dosage form, this includes, for example, adjuvants, excipients, or excipients such as diluents, preservatives, fillers, flow modifiers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatizers, antibacterial agents, antifungal agents, lubricants, and dispersants. Pharmaceutically acceptable carriers are formulated based on a multitude of factors, within the scope of those skilled in the art. These include, but are not limited to, the type and nature of the formulated active pharmaceutical agent, the recipient to whom the composition containing the pharmaceutical agent is to be administered, the intended route of administration of the composition, and the target therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media, as well as various solid and semi-solid dosage forms. In addition to the active pharmaceutical agent, such carriers include many different components and additives, and the inclusion of such additional components in the formulation for various reasons (e.g., stabilizing active pharmaceutical agents, binders, etc.) is well known to those skilled in the art.

[0069] The compounds disclosed herein and their isomers are all within the scope of this application, including geometric isomers and stereoisomers, such as cis-trans isomers, enantiomers, diastereomers, racemic mixtures and other mixtures, all of which are within the scope of this application.

[0070] The compounds of this application contain "tautomers". The term "tautomer" refers to a functional group isomer that has different connection points through one or more double bond shifts. For example, ketones and their enol forms are ket-enol tautomers.

[0071] The term "enantiomer" refers to stereoisomers that are mirror images of each other.

[0072] The term "diastereomer" refers to a stereoisomer of a molecule that has two or more chiral centers and is not a mirror image of the molecule.

[0073] The term "cis-trans isomer" refers to the configuration in which the double bonds or single bonds of cyclic carbon atoms in a molecule cannot rotate freely.

[0074] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key Represents the relative configuration of the center of a solid.

[0075] The stereoisomers of the compounds in this application can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. For example, an enantiomer of a certain compound in this application can be prepared by asymmetric catalysis or chiral derivative derivatization. Alternatively, a single stereoisomer can be obtained from a mixture using chiral resolution techniques. Alternatively, it can be prepared directly from chiral starting materials. The separation of optically pure compounds in this application is typically accomplished using preparative chromatography, employing a chiral column to achieve the separation of chiral compounds.

[0076] The absolute stereoconfiguration of a compound can be confirmed using conventional techniques in the art. For example, single-crystal X-ray diffraction (SFC) can be used, or the absolute configuration of the compound can be confirmed by examining the chiral structure of the starting material and the reaction mechanism of asymmetric synthesis. Alternatively, after resolution, the stereoconfiguration can be determined by comparing it with a product whose absolute configuration is known. Compounds marked "absolute configuration unknown" in this article are typically racemic compounds resolved into single isomers via chiral preparative SFC, followed by characterization and testing.

[0077] The term “optionally” means that it may or may not be substituted, unless otherwise specified. The type and number of substituents may be arbitrary on the basis of chemical feasibility. For example, the term “optionally substituted with one or more Rs” means that it may or may not be substituted with one or more Rs.

[0078] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, This indicates that the cyclopentyl group is replaced by three Rs, and each R has an independent option.

[0079] When a substituent's bond can be cross-linked to two atoms on a ring, this substituent can bond to any atom on that ring. For example, structural units. This indicates that the substituent R1 can be substituted at any position on the benzene ring.

[0080] When the listed substituents do not specify which atom they are attached to in a compound included but not specifically mentioned in the general chemical formula, such substituents can be bonded to any of their atoms. For example, pyrazole as a substituent means that any carbon or nitrogen atom on the pyrazole ring is attached to the substituted group; when the structure contains... When, it indicates that the atom is a bonding atom, for example This indicates that the N atom on the morpholine ring is a bonding atom.

[0081] Unless otherwise specified, the term "halogen" refers to a fluorine, chlorine, bromine, or iodine atom.

[0082] Unless otherwise specified, the term "alkyl" refers to a branched or straight-chain saturated aliphatic alkane with a specified number of carbon atoms, minus a hydrogen-derived group. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, and C6 alkyl groups. 1-6 Alkyl", C 1-3 Alkyl; specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, sec-butyl, 2-methylbutyl, 1,1-dimethylbutyl, etc.

[0083] Unless otherwise specified, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms. C is preferred. 1-6 Halogenated alkyl, more preferably C 1-3 Alkyl halogens. Examples of alkyl halogens include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, etc. Alkyl groups are as defined above.

[0084] Unless otherwise specified, the term "deuterated alkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by deuterium atoms. Alkyl groups are as defined above.

[0085] Unless otherwise specified, the term "hydroxyalkyl" refers to a group derived from an alkyl group by replacing one or more hydrogen atoms with a hydroxyl group, and "hydroxyalkyl" as used in this disclosure includes "C 1-6 Hydroxyalkyl, C 1-3 "Hydroxyalkyl"; specific examples include, but are not limited to, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CH2CH2OH, wait.

[0086] Unless otherwise specified, the term "alkoxy" refers to an alkyl group as defined herein, in which an alkyl group is attached to another group by an oxygen atom, i.e., "alkyl-O-". This includes "C". 1-6 Alkoxy (structure is C) 1-6 alkyl-O-), "C 1-3"Alkoxy" is a suffix, specifically including but not limited to methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, etc.; preferably, the "alkoxy" in this disclosure is preferably C 1-3 Alkyl group.

[0087] Unless otherwise specified, the term "haloalkoxy" refers to a group obtained by substituting one or more hydrogen atoms in an alkoxy group with a halogen. Preferably, the "haloalkoxy" described in this disclosure is "haloC". 1-6 Alkoxy, halogenated C 1-3 Alkyl groups. Specific examples described in this disclosure include: fluoromethoxy groups (including monofluoromethoxy, difluoromethoxy, and trifluoromethoxy), -OCH2CF3, -OCHFCH3, etc. Alkyl groups are as defined above.

[0088] Unless otherwise specified, the term "deuterated alkoxy" refers to the group obtained by replacing one or more hydrogen atoms in an alkoxy group with a deuterium atom. Alkoxy groups are as defined above.

[0089] Unless otherwise specified, the term "alkenyl" refers to a group derived from a straight-chain or branched alkene (containing at least one carbon-carbon double bond) by removing one hydrogen atom, including "C". 2-6 "alkenyl", "C" 2-5 "alkenyl", "C" 2-4 "alkenyl", "C" 2-3 "Alkenyl", specific examples include but are not limited to: -CH=CH2, -CH=CHCH3, -C(CH2)=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, etc.

[0090] Unless otherwise specified, the term "alkynyl" refers to a group derived from a straight-chain or branched alkyne (containing at least one carbon-carbon triple bond) by removing one hydrogen atom, including "C". 2-6 "Alkyne", "C" 2-4 "Alkyne", "C" 2-3 "Alkyne group", specific examples include but are not limited to: -C≡CH, -C≡CHCH3, HC≡CHCH2-, HC≡CC≡C-, etc.

[0091] Unless otherwise specified, the term "cycle" refers to a saturated, partially saturated, or unsaturated monocyclic or polycyclic ring, including spirocyclic, fused, or bridged rings. A group derived from a ring by removing a hydrogen atom is called a "cycloyl group," which includes monovalent, divalent (commonly referred to as a subcyclic ring), trivalent, and tetravalent rings, with the specific valence depending on the number of substituents attached to the ring. This disclosure no longer specifically distinguishes the valence of the ring in its description of "cycloyl groups." Representative "cycloyl groups" include substituted or unsubstituted cycloalkyl, heterocyclic alkyl, cycloalkenyl, heterocyclic alkenyl, cycloynyl, heterocyclic alynyl, aryl, or heteroaryl groups.

[0092] Unless otherwise specified, the term "cycloalkyl" refers to a saturated cyclic alkyl group derived from a cycloalkane by removing a hydrogen atom, including monocyclic or polycyclic saturated hydrocarbon groups; the polycyclic saturated hydrocarbon group refers to a polycyclic group formed by two or more cyclic alkyl structures linked by spiro, bridging, fusion, or other means. The cycloalkyl group includes "C 3-8 cycloalkyl, C 3-6 cycloalkyl, C 3-5 "Cycloalkyl". Preferably, the cycloalkyl group is a monocyclic, saturated structure; specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0093] Unless otherwise specified, "cycloalkenyl" refers to one or more double bonds in a "cycloalkyl" group, and the cycloalkenyl group is not aromatic. The carbon atom in the cycloalkenyl group may be further oxidized, forming C(O). The cycloalkenyl group includes "3-8 membered cycloalkenyl", "3-6 membered cycloalkenyl", "3-5 membered cycloalkenyl", and "5-6 membered cycloalkenyl". Specific examples include, but are not limited to, those mentioned above.

[0094] Unless otherwise specified, the term "heterocyclic alkyl" refers to a saturated cyclic group derived from which one or more cyclic carbon atoms in a cycloalkyl group are replaced by heteroatoms and / or heteroatom groups. The heteroatoms and / or heteroatom groups are generally selected from -C(O), N, O, S, NO, SO, S(O)2, P(O), and NR; preferably, the heteroatoms are independently selected from 1-3 N and / or O atoms. Heterocyclic alkyl groups include "3-10-membered heterocyclic alkyl", "3-8-membered heterocyclic alkyl", "3-6-membered heterocyclic alkyl", "3-5-membered heterocyclic alkyl", "4-6-membered heterocyclic alkyl", and "5-6-membered heterocyclic alkyl". Specific examples include, but are not limited to, nitrogen-containing heterocyclic butyl, oxocyclic butane, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, etc. wait.

[0095] Unless otherwise specified, the term "heterocyclic alkenyl" refers to one or more double bonds in a "heterocyclic alkyl" group, wherein the heterocycle is not aromatic. Preferably, the heteroatoms are independently selected from 1-3 N and / or O atoms. The heterocyclic alkenyl groups include "3-10-membered heterocyclic alkenyl," "3-8-membered heterocyclic alkenyl," "3-6-membered heterocyclic alkenyl," "3-5-membered heterocyclic alkenyl," and "5-6-membered heterocyclic alkenyl." Specific examples include, but are not limited to: wait.

[0096] Unless otherwise specified, the term "aryl" refers to an unsaturated, usually aromatic, hydrocarbon group, which can be a monocyclic or fused ring. The fused rings on the "aryl" group can be cycloalkenyl, heterocyclic alkenyl, or aryl, but the portion attached to the parent compound must be aromatic. C is preferred. 6-14 Aryl, C 6-10 Aryl; examples of aryl groups include, but are not limited to, phenyl, naphthyl,

[0097] The term "heteroaryl" as used in this disclosure refers to an aromatic monocyclic or polycyclic group having at least one heteroatom and / or heteroatomic group. The heteroatom and / or heteroatomic group is generally selected from N, O, S, P, NO, SO, S(O)2, P(O), -C(O), and NR, where R is H or any possible substituent. Preferably, the heteroatom is independently selected from 1-3 N and / or O atoms. The heteroaryl includes "5-14-membered heteroaryl," "5-10-membered heteroaryl," and "5-6-membered heteroaryl"; specific examples include, but are not limited to, pyrroleyl, furanyl, thiopheneyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridinyl, pyrimidinyl, and pyrimidinyl groups.

[0098] Linking substituents are described in various parts of this disclosure. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0099] The combinations of substituents and / or variables described in this disclosure are permitted only when these combinations produce stable compounds or usable synthetic intermediates. A stable compound or stable structure is a compound that is sufficiently stable to withstand chemical reactions, be isolated with useful purity, and be formulated into an effective therapeutic agent.

[0100] If there is a discrepancy between the compound name and the compound structure, the determination can be made by combining relevant information and reaction routes; if it cannot be confirmed by other means, the given compound structural formula shall prevail.

[0101] The preparation methods of some compounds in this disclosure reference the preparation methods of the aforementioned similar compounds. Those skilled in the art should understand that when using or referring to the referenced preparation methods, the reactant ratios, reaction solvents, reaction temperatures, etc., can be appropriately adjusted according to the different reactants.

[0102] The compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of this application. Detailed Implementation

[0103] The structures of the compounds in this application were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS), or ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR determinations were performed using a Bruker Neo 400M or Bruker Ascend 400 NMR spectrometer, with solvents including deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3), heavy water (D2O), and tetramethylsilane (TMS) as the internal standard.

[0104] The starting materials used in the embodiments of this application are known and commercially available, or can be synthesized using methods known in the art.

[0105] I. Preparation Examples

[0106] Example 1:

[0107] 1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one

[0108]

[0109] Reaction route:

[0110]

[0111] Operating steps:

[0112] Step A: Dissolve 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline (3g, 12.49mmol) and 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2.90g, 12.49mmol) in dioxane (30mL), add p-toluenesulfonic acid (107.5mg, 0.62mmol), and microwave at 130℃ for 0.5 hours.

[0113] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that the reaction of the starting materials was complete, and the reaction solution was concentrated under reduced pressure. The crude product was purified by recrystallization from ethanol (10 mL) to obtain 1.7 g of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-bromo-7H-pyrrolo[2,3-d]pyrimidine-4-amine.

[0114] MS(ESI)M / Z:436.0[M+H] + .

[0115] Step B: N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.5 g, 3.44 mmol) and N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (3.19 g, 10.31 mmol) were dissolved in dioxane (10 mL) and water (2 mL), purged with nitrogen, and potassium carbonate (2.38 g, 17.19 mmol) and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium(II) dichloride (224.09 mg, 343.83 μmol) were added. The mixture was stirred at 90 °C for 1 hour.

[0116] After the reaction of the raw materials was complete, the reaction solution was poured into water (30 mL), and the mixture was extracted with ethyl acetate (25 mL × 3 times). The organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 0 / 1) to give 1.2 g of 4-[4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester.

[0117] MS(ESI)M / Z:539.1[M+H] + .

[0118] Step C: Dissolve 100 mg (185.67 μmol) of 4-[4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester in dichloromethane (5 mL), add trifluoroacetic acid (1 mL), and stir at 25 °C for 1 hour.

[0119] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that after the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure, and 80 mg of crude N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine was obtained without purification.

[0120] MS(ESI)M / Z:439.2[M+H] + .

[0121] Step D: Dissolve N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (80 mg, 182.45 μmol) and triethylamine (92.31 mg, 912.23 μmol) in dichloromethane (2 mL), add acryloyl chloride (18.16 mg, 200.69 μmol) dropwise, and stir at 0 °C for 1 hour.

[0122] After the reaction of the raw materials was complete, the reaction solution was purified by preparative high performance liquid chromatography (CHPLC) (column: C18 150×30 mm; mobile phase: [water (ammonia and ammonium bicarbonate)-acetonitrile]; gradient: phase B increased from 30% to 60% within 7 minutes) to obtain 1.83 mg of 1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one).

[0123] MS(ESI)M / Z:493.3[M+H] + .

[0124] 1H NMR (400MHz, DMSO-d6): δ11.97(br s,1H),8.92(d,J=7.5Hz,1H),8.35(d,J=14.3Hz,2H),8.02(br d,J=11.1Hz,1H),7.75(br d,J=8.2Hz,1H),7.67(br d,J=6.7Hz,1H),7.39(br d,J=3.8Hz,1H),7.15(dd,J=8.5,3.0Hz,1H),7.01(dd,J=7.5,2.7Hz,1H),6.80-6.98(m,1H),6.76(s,1H),6.16(dd,J=16.7,2.3Hz,1H),5.86(br d,J=18.2Hz,1H),5.72(br d,J=10.1Hz,1H),4.21-4.37(m,2H),3.76-3.91(m,2H),2.53-2.63(m,2H),2.16(s,3H).

[0125] Example 2:

[0126] 1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one

[0127]

[0128] Reaction route:

[0129]

[0130] Operating steps:

[0131] Step A: Dissolve 1.2 g (2.23 mmol) of 4-[4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester in methanol (12 mL), add 10% wet palladium on carbon (474 ​​mg), and stir at 65 °C for 12 hours under a hydrogen atmosphere (45 psi).

[0132] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that the reaction of the raw materials was complete. The reaction solution was filtered, and the filter cake was washed with methanol (10 mL × 2). The filtrate was concentrated under reduced pressure. 1 g of crude 4-[4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]piperidine-1-carboxylic acid tert-butyl ester was obtained without further purification.

[0133] MS(ESI)M / Z:541.2[M+H] + .

[0134] Step B: Dissolve 74 mg, 137 μmol of 4-[4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]piperidine-1-carboxylic acid tert-butyl ester in dichloromethane (2 mL), add trifluoroacetic acid (2 mL), and stir at 25 °C for 1 hour.

[0135] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that after the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure, and 60 mg of crude N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine was obtained without purification.

[0136] MS(ESI)M / Z:441.1[M+H] + .

[0137] Step C: Dissolve N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (55 mg, 124.8 μmol) and triethylamine (126.3 mg, 1.25 mmol) in dichloromethane (2 mL), and add acryloyl chloride (11.30 mg, 124.8 μmol) dropwise. Stir at 0 °C for 1 hour.

[0138] After the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography (HPLC) (column: C18 150×30 mm; mobile phase: [water (formic acid)-acetonitrile]; gradient: phase B increased from 29% to 59% within 7 minutes) to obtain 2.93 mg of 1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one).

[0139] MS(ESI)M / Z:495.3[M+H] + .

[0140] 1 H NMR (400MHz, DMSO-d6): δ11.62(s,1H),8.92(d,J=7.2Hz,1H),8.37(s,1H),8.22(s,1H),8.06(s,1H) ,7.75-7.59(m,2H),7.07(s,1H),7.02(dd,J=7.6,2.8Hz,1H),6.83(dd,J=16.4,10.4Hz,1H),6.77(d, J=2.4Hz,1H),6.12(dd,J=16.4,2.4Hz,1H),5.67(dd,J=16.4,10.4Hz,1H),4.63-4.49(m,1H),4.25-4 .04(m,1H),3.60-3.45(m,2H),2.92-2.77(m,1H),2.16(s,3H),2.11-1.99(m,2H),1.53-1.34(m,2H).

[0141] Example 3:

[0142] (E)-1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one

[0143]

[0144] Reaction route:

[0145]

[0146] Operating steps:

[0147] Step A: N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (122 mg, 276.96 μmol) and (E)-4-(dimethylamino)but-2-enoate (55.04 mg, 332.35 μmol) were dissolved in N,N-dimethylformamide (1 mL), followed by the addition of triethylamine (140.13 mg, 1.38 mmol) and 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazine-4-one (165.74 mg, 553.92 μmol). The mixture was stirred at 25 °C for 12 hours.

[0148] After the reaction of the raw materials was monitored by liquid chromatography-mass spectrometry (LC-MS) to ensure complete reaction, the reaction solution was purified by preparative high performance liquid chromatography (LC-MS) (column: C18 150×30 mm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; gradient: phase B increased from 8% to 65% within 7 minutes) to obtain 66.21 mg of (E)-1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one).

[0149] MS(ESI)M / Z:552.4[M+H] + .

[0150] 1 H NMR (400MHz, DMSO-d6): δ11.64(s,1H),8.94(d,J=7.5Hz,1H),8.38(s,1H),8.23(s,1H),8.07(s,1H),7.66(br d,J=2.5Hz,2H),7.17(d,J=8.3Hz,1H),7.07(d,J=1.7Hz,1H),7.03(dd,J=7. 5,2.6Hz,1H),6.78(d,J=2.5Hz,1H),6.58-6.64(m,2H),4.52-4.64(m,1H),4. 08-4.23(m,1H),3.49-3.60(m,1H),3.21-3.31(m,1H),3.02(d,J=4.8Hz,2H) ,2.77-2.91(m,1H),2.13-2.19(m,9H),2.00-2.11(m,2H),1.38-1.55(m,2H).

[0151] Example 4:

[0152] 1-(3-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1H-pyrazol-1-yl)azacyclobut-1-yl)prop-2-en-1-one

[0153]

[0154] Reaction route:

[0155]

[0156] Operating steps:

[0157] Step A: N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (230 mg, 0.53 mmol) and 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester (0.18 g, 0.53 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1 mL), purged with nitrogen, and potassium carbonate (219 mg, 1.58 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (38.6 mg, 0.053 mmol) were added sequentially. The reaction was carried out at 120 °C for 8 hours.

[0158] Product formation was monitored by liquid chromatography-mass spectrometry (LC-MS / MS). The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain 83 mg of tert-butyl 3-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid.

[0159] MS(ESI)M / Z:579.2[M+H] + .

[0160] Step B: Dissolve 3-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester (83 mg, 0.14 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (1 mL) dropwise, and stir at 25 °C for 1 hour.

[0161] After the reaction of the raw materials was monitored by liquid chromatography-mass spectrometry (LC-MS) until complete, the reaction solution was concentrated under reduced pressure, and 80 mg of crude N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(1-(azacyclobut-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine was obtained without purification.

[0162] MS(ESI)M / Z:479.2[M+H] + .

[0163] Step C: Dissolve N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(1-(azacyclobut-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50 mg, 0.1 mmol) and N,N-diisopropylethylamine (68 mg, 0.52 mmol) in dichloromethane (5 mL), add acryloyl chloride (9.4 mg, 0.1 mmol) dropwise, and stir at 0 °C for 1 hour.

[0164] After the reaction of the raw materials was monitored to be complete by liquid chromatography-mass spectrometry, water (10 mL) was added to the reaction system at 0 °C to quench the reaction. The mixture was extracted with dichloromethane (20 mL × 2 times), and the organic phases were combined. The organic phase was dried with anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was purified by C18 reversed-phase column chromatography (eluent: water / acetonitrile = 0-70%) to obtain 10 mg of 1-(3-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1H-pyrazol-1-yl)azacyclobut-1-yl)prop-2-en-1-one.

[0165] MS(ESI)M / Z:533.2[M+H] + .

[0166] 1 H NMR (400MHz, DMSO-d6): δ12.02(d,J=2.5Hz,1H),8.92(d,J=7.4Hz,1H),8.36(d,J=9.7Hz,2H),8.22(s,1H),7.84(s,1H), 7.73(s,1H),7.66-7.57(m,2H),7.34(d,J=2.2Hz,1H),7.16-7.10(m,1H),7.00(dd,J=7.5,2.6Hz,1H),6.74(d,J=2.6Hz, 1H),6.37(dd,J=17.0,10.3Hz,1H),6.14(dd,J=17.0,2.2Hz,1H),5.69(dd,J=10.3,2.2Hz,1H),5.40(tt,J=8.2,5.3Hz,1 H),4.74(t,J=8.6Hz,1H),4.59(dd,J=9.2,5.2Hz,1H),4.44(t,J=9.3Hz,1H),4.31(dd,J=10.6,5.4Hz,1H),2.14(s,3H).

[0167] Example 5:

[0168] 1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one

[0169]

[0170] Reaction route:

[0171]

[0172] Operating steps:

[0173] Step A: Dissolve 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline (783.25 mg, 3.26 mmol) and 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (0.5 g, 3.26 mmol) in isopropanol (5 mL), add p-toluenesulfonic acid (56 mg, 0.33 mmol), and microwave at 110 °C for 1 hour.

[0174] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that the reaction of the raw materials was complete, and the reaction solution was concentrated under reduced pressure. The crude product was recrystallized from ethanol (10 mL) to give 1.1 g N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine.

[0175] MS(ESI)M / Z:358.13[M+H] + .

[0176] Step B: N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (100 mg, 0.28 mmol) and tert-butyl 4-bromo-3,6-dihydropyridine-1(2H)-carboxylic acid (110.10 mg, 0.42 mmol) were dissolved in dimethyl sulfoxide (5 mL), purged with nitrogen, and cesium carbonate (273.69 mg, 0.84 mmol), 2,2,6,6-tetramethyl-3,5-heptadecyl dione (103.20 mg, 0.56 mmol) and cuprous iodide (53.33 mg, 0.28 mmol) were added. The mixture was then microwaved at 110 °C for 1 hour.

[0177] After the reaction of the raw materials was complete, water (20 mL) was added to the reaction system. The mixture was extracted with ethyl acetate (20 mL × 2 times), and the organic phases were combined. The organic phase was first washed with saturated brine (20 mL × 1 time), then dried with anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 80 mg of 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester.

[0178] MS(ESI)M / Z:539.24[M+H] + .

[0179] Step C: Dissolve 80 mg (0.15 mmol) of 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester in methanol (5 mL), and add 5 mL of 4M hydrochloric acid-methanol solution. React the mixture at 40 °C for 2 hours.

[0180] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that after the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure, and saturated saline (10 mL) was added. The pH of the aqueous phase was adjusted to 10 with saturated sodium bicarbonate solution, and then extracted with ethyl acetate / tetrahydrofuran 1:1 mixed solvent (10 mL × 3 times). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. 40 mg of crude N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine was obtained without purification.

[0181] MS(ESI)M / Z:439.24[M+H] + .

[0182] Step D: N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (40 mg, 0.091 mmol) was dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (35.28 mg, 0.27 mmol) and acryloyl chloride (8.24 mg, 0.091 mmol) were added. The mixture was stirred at 25 °C for 1 hour.

[0183] After the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 25 mg of 1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one.

[0184] MS(ESI)M / Z:493.20[M+H] + .

[0185] 1 H NMR (400MHz, DMSO-d6): δ8.93(d,J=7.5Hz,1H),8.44(s,1H),8.37(s,1H),8.03(d,J=25.4Hz,1H),7.87(d, J=4.1Hz,1H),7.65(t,J=10.5Hz,1H),7.52(d,J=2.6Hz,1H),7.15(d,J=8.7Hz,1H),7.01(dd,J=7.5,2.6Hz ,1H),6.89(ddd,J=37.6,16.5,10.4Hz,1H),6.76(d,J=3.2Hz,1H),6.66(d,J=3.3Hz,1H),6.18(dd,J=16.7 ,2.4Hz,1H),5.85-5.67(m,2H),4.31(d,J=20.7Hz,2H),3.92-3.84(m,2H),2.75-2.67(m,2H),2.15(s,3H).

[0186] Example 6:

[0187] 1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one

[0188]

[0189] Reaction route:

[0190]

[0191] Operating steps:

[0192] Step A: Dissolve 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (5 g, 32.7 mmol), triphenylphosphine (34.2 g, 130.7 mmol), and tert-butyl 4-hydroxypiperidine-1-carboxylate (19.7 g, 98.0 mmol) in tetrahydrofuran (200 mL), purge with nitrogen, add diethyl azodicarbonate (22.7 g, 130.7 mmol) dropwise at 0 °C, and then raise the temperature to 25 °C and stir for 6 hours.

[0193] Liquid chromatography-mass spectrometry (LC-MS) showed the formation of a product. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain 7 g of tert-butyl 4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)piperidine-1-carboxylic acid.

[0194] MS(ESI)M / Z:337.2[M+H] + .

[0195] Step B: Dissolve 4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)piperidine-1-carboxylic acid tert-butyl ester (640 mg, 1.90 mmol) and 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline (0.46 g, 1.90 mmol) in 1,4-dioxane (10 mL), add p-toluenesulfonic acid (33 mg, 0.19 mmol), and microwave at 150 °C for 30 minutes.

[0196] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that the reaction of the raw materials was complete, and the reaction solution was concentrated under reduced pressure. The crude product was purified by recrystallization with ethanol (10 mL) to obtain 0.8 g of 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)piperidine-1-carboxylic acid tert-butyl ester.

[0197] MS(ESI)M / Z:541.3[M+H] + .

[0198] Step C: Dissolve 500 mg (0.92 mmol) of 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)piperidine-1-carboxylic acid tert-butyl ester in dichloromethane (10 mL), add trifluoroacetic acid (2 mL) dropwise, and stir at 25 °C for 2 hours.

[0199] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that the reaction of the raw materials was complete, and the reaction solution was concentrated under reduced pressure. 630 mg of crude N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine was obtained without purification.

[0200] MS(ESI)M / Z:441.2[M+H] + .

[0201] Step D: Dissolve N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (400 mg, 0.91 mmol) and N,N-diisopropylethylamine (591 mg, 4.55 mmol) in dichloromethane (10 mL), add acryloyl chloride (98 mg, 1.1 mmol) dropwise, and stir at 0 °C for 2 hours.

[0202] After the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure by liquid chromatography-mass spectrometry (LC-MS). The crude product was purified by C18 reversed-phase column chromatography (eluent: water / acetonitrile = 0-45%) to obtain 66 mg of 1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one.

[0203] MS(ESI)M / Z:495.2[M+H] + .

[0204] 1H NMR (400MHz, Methanol-d4): δ8.73(d,J=7.5Hz,1H),8.28(s,2H),7.79(d,J=3.3Hz,1H),7.45(d,J=2.6Hz,1 H),7.38(t,J=9.3Hz,1H),7.16(d,J=8.6Hz,1H),7.08(dd,J=7.5,2.6Hz,1H),6.87-6.77(m,2H),6.58(d,J= 3.3Hz,1H),6.22(dd,J=16.8,2.0Hz,1H),5.77(dd,J=10.6,2.0Hz,1H),5.08(s,1H),4.77(s,1H),4.31(d,J =14.0Hz,1H),3.36(d,J=12.8Hz,1H),2.92(t,J=13.0Hz,1H),2.25(s,1H),2.22(s,3H),2.07-1.89(m,3H).

[0205] Example 7:

[0206] 1-(3-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-pyrazol-1-yl)azacyclobut-1-yl)prop-2-en-1-one

[0207]

[0208] Reaction route:

[0209]

[0210] Operating steps:

[0211] Step A: N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (150 mg, 0.42 mmol) and 3-(4-bromo-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester (0.13 g, 0.42 mmol) were dissolved in dimethyl sulfoxide (10 mL), and cesium carbonate (0.27 g, 0.84 mmol), 2,2,6,6-tetramethyl-3,5-heptadecanedione (77 mg, 0.42 mmol) and cuprous iodide (80 mg, 0.42 mmol) were added. The mixture was heated at 120 °C for 16 hours.

[0212] After liquid chromatography-mass spectrometry (LC-MS) showed that the reactants had reacted completely, water (20 mL) was added to the reaction system. The mixture was extracted with ethyl acetate (20 mL × 2 times), and the organic phases were combined. The organic phase was first washed with saturated brine (20 mL × 1 time), then dried with anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 73 mg of 3-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester.

[0213] MS(ESI)M / Z:579.2[M+H] + .

[0214] Step B: Dissolve 73 mg, 0.12 mmol of 3-(4-(4-(([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester in dichloromethane (5 mL), add trifluoroacetic acid (1 mL) dropwise, and stir at 25 °C for 1 hour.

[0215] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that the reaction of the raw materials was complete, and the reaction solution was concentrated under reduced pressure. 80 mg of crude N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(1-(azacyclobut-3-yl)-1H-pyrazol-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine was obtained without purification.

[0216] MS(ESI)M / Z:479.2[M+H] + .

[0217] Step C: Dissolve N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(1-(azacyclobut-3-yl)-1H-pyrazol-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (80 mg, 0.17 mmol) and N,N-diisopropylethylamine (108 mg, 0.84 mmol) in dichloromethane (5 mL), add acryloyl chloride (15 mg, 0.17 mmol) dropwise, and stir at 0 °C for 1 hour.

[0218] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that the reaction of the raw materials was complete, and the reaction solution was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (eluent: dichloromethane / methanol = 15 / 1) to obtain 17 mg of 1-(3-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-pyrazol-1-yl)azacyclobut-1-yl)prop-2-en-1-one.

[0219] MS(ESI)M / Z:533.2[M+H] + .

[0220] 1 H NMR (400MHz, Methanol-d4): δ8.72(d,J=7.5Hz,1H),8.40(s,1H),8.28(d,J=4.5Hz,2H ),7.98(s,1H),7.57(d,J=3.2Hz,1H),7.46-7.29(m,2H),7.16-6.98(m,2H),6.74(dd, J=35.7,2.9Hz,2H),6.48-6.20(m,2H),5.77(dd,J=10.2,2.1Hz,1H),5.49-5.30(m,1H ),4.83-4.71(m,2H),4.58(t,J=9.5Hz,1H),4.49(dd,J=11.0,5.3Hz,1H),2.18(s,3H).

[0221] Example 8:

[0222] 1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one

[0223]

[0224] Reaction route:

[0225]

[0226] Operating steps:

[0227] Step A: Dissolve 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline (550 mg, 2.29 mmol) and 3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (534.60 mg, 2.29 mmol) in dioxane (10 mL), add p-toluenesulfonic acid (39.43 mg, 0.23 mmol), and microwave at 150 °C for 0.5 hours.

[0228] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that the reaction of the raw materials was complete, and the reaction solution was concentrated under reduced pressure. The crude product was recrystallized from ethanol (5 mL) to give 580 mg of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-3-bromo-1H-pyrazolo[3,4-d]pyrimidine-4-amine.

[0229] MS(ESI)M / Z:437.0[M+H] + .

[0230] Step B: N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-3-bromo-1H-pyrazolo[3,4-d]pyrimidine-4-amine (500 mg, 1.14 mmol) and N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (1.41 g, 4.56 mmol) were dissolved in dioxane (5 mL) and water (2 mL), purged with nitrogen, and potassium carbonate (787.80 mg, 5.70 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (83.41 mg, 0.11 mmol) were added. The mixture was then microwaved at 140 °C for 1 hour.

[0231] After the reaction of the raw materials was complete, the reaction solution was poured into water (20 mL), and the mixture was extracted with ethyl acetate (30 mL × 3 times). The organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to give 400 mg of 4-[4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester.

[0232] MS(ESI)M / Z:540.2[M+H] + .

[0233] 1H NMR (400MHz, DMSO-d6): δ13.70(s,1H),8.94(d,J=7.5Hz,1H),8.57(s,1H),8.42(s,1H),8.39(s,1H),7.70(d,J=7.4Hz,2H),7.20(d,J=8.9 Hz,1H),7.03(dd,J=7.5,2.7Hz,1H),6.79(d,J=2.6Hz,1H),6.20(s,1H),4.09(s,2H),3.63(s,2H),2.67(s,2H),2.19(s,3H),1.45(s,9H).

[0234] Step C: Dissolve 70 mg, 0.13 mmol of 4-[4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester in methanol (1 mL), add 5 mL of 4M hydrochloric acid-methanol solution, and stir at 35 °C for 3 hours.

[0235] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that after the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure, and 57 mg of crude N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine was obtained without purification.

[0236] MS(ESI)M / Z:440.2[M+H] + .

[0237] Step D: Dissolve N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine (57 mg, 0.13 mmol) in dichloromethane (5 mL), add N,N-diisopropylethylamine (84.01 mg, 0.65 mmol) and acryloyl chloride (12.94 mg, 0.14 mmol), and stir at 25 °C for 1 hour.

[0238] After the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 30 mg of 1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one.

[0239] MS(ESI)M / Z:494.2[M+H] + .

[0240] 1 H NMR (400MHz, DMSO-d6): δ13.71(s,1H),8.94(d,J=7.5Hz,1H),8.58(d,J=11.9Hz,1 H),8.42(s,1H),8.38(s,1H),7.75-7.66(m,2H),7.20(d,J=8.3Hz,1H),7.02(dd,J =7.5,2.6Hz,1H),6.99-6.80(m,1H),6.80-6.75(m,1H),6.25-6.12(m,2H),5.77-5 .69(m,1H),4.46-4.19(m,2H),3.89-3.79(m,2H),2.80-2.65(m,2H),2.18(s,3H).

[0241] Example 9:

[0242] (E)-1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3,6-dihydropyridin-1(2H)-yl)-4-(dimethylamino)but-2-en-1-one

[0243]

[0244] Reaction route:

[0245]

[0246] Operating steps:

[0247] Step A: N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (70 mg, 0.15 mmol) and (E)-4-(dimethylamino)but-2-enoate (24.84 mg, 0.15 mmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (193.86 mg, 1.5 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (68 mg, 0.18 mmol) were added. The mixture was stirred at 25 °C for 2 hours.

[0248] After the reaction of the raw materials was monitored by liquid chromatography-mass spectrometry (LC-MS) to ensure complete reaction, the reaction solution was purified by preparative high performance liquid chromatography (LC-MS) (column: C18 150×30 mm; mobile phase: [water (formic acid)-acetonitrile]; gradient: phase B increased from 8% to 65% within 7 minutes) to obtain 38 mg of (E)-1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3,6-dihydropyridin-1(2H)-yl)-4-(dimethylamino)but-2-en-1-one formate.

[0249] MS(ESI)M / Z:551.2[M+H] + .

[0250] 1 H NMR (400MHz, DMSO-d6): δ13.73(s,1H),8.93(d,J=7.4Hz,1H),8.56(d,J=15.7Hz,1H),8 .42(s,1H),8.38(s,1H),8.30(s,1H),7.73-7.66(m,2H),7.19(d,J=8.0Hz,1H),7.02(d d,J=7.5,2.6Hz,1H),6.79(s,1H),6.76-6.55(m,2H),6.25-6.20(m,1H),4.34(s,1H),4 .26(s,1H),3.83(s,2H),3.06(s,2H),2.71(d,J=18.4Hz,2H),2.19(s,3H),2.16(s,6H).

[0251] Example 10:

[0252] 1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-1-yl)prop-2-en-1-one

[0253]

[0254] Reaction route:

[0255]

[0256] Operating steps:

[0257] Step A: 4-[4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (250 mg, 0.46 mmol) was dissolved in methanol (5 mL), and 4M hydrochloric acid methanol solution (5 mL) and 10% wet palladium on carbon (474 ​​mg) were added. The mixture was stirred at 70 °C for 16 hours under a hydrogen atmosphere (45 psi).

[0258] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that the reaction mixture was completely reacted. The reaction mixture was filtered, and the filter cake was washed with methanol (10 mL × 2). The filtrate was concentrated under reduced pressure. 80 mg of crude N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-3-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was obtained without further purification.

[0259] MS(ESI)M / Z:442.2[M+H] + .

[0260] Step B: Dissolve N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-3-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.068 mmol) and N,N-diisopropylethylamine (43.94 mg, 0.34 mmol) in dichloromethane (5 mL), and add acryloyl chloride (6.15 mg, 0.068 mmol) dropwise. Stir at 25 °C for 1 hour.

[0261] After the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: C18 150×30mm; mobile phase: [water (formic acid)-acetonitrile]; gradient: phase B increased from 29% to 59% within 7 minutes) to obtain 4 mg of 1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)piperidin-1-yl)prop-2-en-1-one).

[0262] MS(ESI)M / Z:496.2[M+H] + .

[0263] 1 H NMR (400MHz, DMSO-d6): δ13.36(s,1H),8.95(dd,J=7.5,0.7Hz,1H),8.64(s,1H),8.39(s,1H),8.32(s,1H) ,7.70-7.60(m,2H),7.22(d,J=8.5Hz,1H),7.04(dd,J=7.5,2.6Hz,1H),6.86(dd,J=16.7,10.5Hz,1H),6.8 0(dd,J=2.6,0.7Hz,1H),6.12(dd,J=16.7,2.5Hz,1H),5.68(dd,J=10.5,2.5Hz,1H),4.55-4.45(m,1H),4. 21-4.09(m,1H),3.86-3.76(m,1H),3.01-2.89(m,1H),2.20(s,3H),2.11-2.03(m,2H),1.74-1.59(m,2H).

[0264] Example 11:

[0265] (E)-1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3,6-dihydropyridin-1(2H)-yl)-4-(dimethylamino)but-2-en-1-one

[0266]

[0267] Reaction route:

[0268]

[0269] Operating steps:

[0270] Step A: N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-3-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.11 mmol) and (E)-4-(dimethylamino)but-2-enoate (18.22 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (142.16 mg, 1.1 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (46 mg, 0.12 mmol) were added. The mixture was stirred at 25 °C for 2 hours.

[0271] After the reaction of the raw materials was monitored by liquid chromatography-mass spectrometry (LC-MS) to ensure complete reaction, the reaction solution was purified by preparative high performance liquid chromatography (HPLC) (column: C18 150×30 mm; mobile phase: [water (formic acid)-acetonitrile]; gradient: phase B increased from 8% to 65% within 7 minutes) to obtain 5 mg of (E)-1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3,6-dihydropyridin-1(2H)-yl)-4-(dimethylamino)but-2-en-1-one formate).

[0272] MS(ESI)M / Z:553.3[M+H] + .

[0273] 1 H NMR (400MHz, DMSO-d6): δ13.37(s,1H),8.94(d,J=7.5Hz,1H),8.65(s,1H),8.38(s,1H),8.32(s,1H), 8.30(s,2H),7.67(s,1H),7.64(d,J=8.6Hz,1H),7.22(d,J=8.6Hz,1H),7.04(dd,J=7.5,2.6Hz,1H),6 .80(d,J=2.6Hz,1H),6.69-6.55(m,2H),4.54-4.43(m,1H),4.19-4.08(m,1H),3.37-3.27(m,1H),3.0 5(d,J=4.9Hz,2H),2.99-2.88(m,2H),2.20(s,3H),2.16(s,6H),2.11-2.02(m,2H),1.73-1.52(m,2H).

[0274] Example 12:

[0275] 1-(3-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-pyrazol-1-yl)azacyclobut-1-yl)prop-2-en-1-one

[0276]

[0277] Reaction route:

[0278]

[0279] Operating steps:

[0280] Step A: N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (300 mg, 0.69 mmol) and 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester (0.27 g, 0.76 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1 mL), purged with nitrogen, and potassium carbonate (0.29 g, 2.07 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (50 mg, 0.069 mmol) were added sequentially. The reaction was carried out at 120 °C for 8 hours.

[0281] Product formation was monitored by liquid chromatography-mass spectrometry (LC-MS / MS). The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 142 mg of tert-butyl 3-(4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid.

[0282] MS(ESI)M / Z:580.2[M+H] + .

[0283] Step B: Dissolve 142 mg, 0.24 mmol of tert-butyl 3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid in dichloromethane (5 mL), add trifluoroacetic acid (1 mL) dropwise, and stir at 25 °C for 1 hour.

[0284] After the reaction of the raw materials was monitored by liquid chromatography-mass spectrometry (LC-MS) until complete, the reaction solution was concentrated under reduced pressure, and 130 mg of crude N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-3-(1-(azacyclobut-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine was obtained without purification.

[0285] MS(ESI)M / Z:480.2[M+H] + .

[0286] Step C: Dissolve N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-3-(1-(azacyclobut-3-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (130 mg, 0.27 mmol) and N,N-diisopropylethylamine (176 mg, 1.35 mmol) in dichloromethane (5 mL), add acryloyl chloride (24.4 mg, 0.27 mmol) dropwise, and stir at 0 °C for 1 hour.

[0287] After the reaction of the raw materials was monitored to be complete by liquid chromatography-mass spectrometry, water (10 mL) was added to the reaction system at 0 °C to quench the reaction. The mixture was extracted with dichloromethane (20 mL × 2 times), and the organic phases were combined. The organic phase was dried with anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was purified by C18 reversed-phase column chromatography (eluent: water / acetonitrile = 0-70%) to obtain 34 mg of 1-(3-(4-(4-(([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-pyrazol-1-yl)azacyclobut-1-yl)prop-2-en-1-one.

[0288] MS(ESI)M / Z:534.2[M+H] + .

[0289] 1H NMR (400MHz, Methanol-d4): δ8.72(d,J=7.5Hz,1H),8.39(s,1H),8.26(d,J=9.0Hz,2H) ,8.05(s,1H),7.67-7.52(m,2H),7.13(d,J=8.6Hz,1H),7.05(dd,J=7.5,2.7Hz,1H),6. 81(d,J=2.6Hz,1H),6.47-6.24(m,2H),5.77(dd,J=10.2,2.1Hz,1H),5.44(tt,J=8.1,5 .2Hz,1H),4.84(d,J=8.8Hz,1H),4.75(d,J=9.3Hz,1H),4.63-4.47(m,2H),2.21(s,3H).

[0290] Example 13:

[0291] 1-(4-(7-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one

[0292]

[0293] Reaction route:

[0294]

[0295] Operating steps:

[0296] Step A: 1H-pyrazolo[4,3-d]pyrimidine-7-ol (3 g, 22.04 mmol) was suspended in pyridine (60 mL), and phosphorus pentasulfide (14.70 g, 66.12 mmol) was added. The mixture was refluxed at 120 °C for 3 hours. The reaction solution was concentrated under reduced pressure, cooled to 25 °C, and water (60 mL) was added. The suspension was stirred at 25 °C for 2 hours, and then refluxed at 110 °C for 3 hours. The reaction solution was cooled to 25 °C, and the aqueous phase was extracted with ethyl acetate (60 mL × 3 times). The organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 1.2 g of 1H-pyrazolo[4,3-d]pyrimidine-7-thiol.

[0297] MS(ESI)M / Z:153.0[M+H] + .

[0298] Step B: Dissolve 1H-pyrazolo[4,3-d]pyrimidine-7-thiol (1.2 g, 7.89 mmol) in N,N-dimethylformamide (10 mL), cool to 0 °C in an ice bath, add potassium carbonate (1.20 g, 8.68 mmol) and iodomethane (1.12 g, 7.89 mmol), and stir at 0 °C for 1 hour.

[0299] Liquid chromatography-mass spectrometry (LC-MS) was used to detect the completion of the reaction. Water (10 mL) and ethyl acetate (30 mL) were added to the reaction system for extraction. The organic phase was washed with saturated brine (10 mL × 2 times), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20:1) to obtain 0.73 g of 7-methylthio-1H-pyrazolo[4,3-d]pyrimidine.

[0300] MS(ESI)M / Z:167.0[M+H] + .

[0301] Step C: Dissolve 7-methylthio-1H-pyrazolo[4,3-d]pyrimidine (630 mg, 3.79 mmol) and 4-bromo-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.49 g, 5.69 mmol) in dimethyl sulfoxide (10 mL), purge with nitrogen, add cesium carbonate (2.47 g, 7.58 mmol), 2,2,6,6-tetramethyl-3,5-heptadecane (349.21 mg, 1.90 mmol) and cuprous iodide (144.36 mg, 0.76 mmol), and microwave at 120 °C for 1 hour.

[0302] After the reaction of the raw materials was complete as monitored by liquid chromatography-mass spectrometry (LC-MS), water (20 mL) was added to the reaction system. The mixture was extracted with ethyl acetate (20 mL × 2 times), and the organic phases were combined. The organic phase was first washed with saturated brine (20 mL × 1 time), then dried with anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain compound one 280 mg 4-(7-methylthio-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester and compound two 780 mg 4-(7-methylthio-2H-pyrazolo[4,3-d]pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (after 2D chromatography). NOESY NMR spectroscopy analysis revealed that in compound 2, the hydrogen atom at position 3 of the pyrazolo[4,3-d]pyrimidine ring showed a NOE-related signal with the hydrogen atom on the six-membered unsaturated ring, indicating a spatial interaction between the two. Compound 1, however, did not exhibit this NOE-related signal, thus distinguishing the two compounds.

[0303] MS(ESI)M / Z:348.1[M+H] + .

[0304] Compound 1:

[0305] 1 H NMR (400MHz, DMSO-d6): δ8.84(s,1H),8.50(s,1H),6.07(s,1H),4.16(q,J=3.0Hz, 2H),3.68(t,J=5.7Hz,2H),2.66(s,3H),2.59(tt,J=5.0,2.5Hz,2H),1.46(s,9H).

[0306] Compound 2:

[0307] 1 H NMR (400MHz, DMSO-d6): δ9.02(s,1H),8.71(s,1H),6.67(s,1H),4.13(q,J=3. 0Hz, 2H), 3.66 (t, J = 5.7Hz, 2H), 2.88-2.79 (m, 2H), 2.68 (s, 3H), 1.44 (s, 9H).

[0308] Step D: Dissolve 200 mg, 0.58 mmol of 4-(7-methylthio-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester in dichloromethane (10 mL), cool to 0 °C in an ice bath, add m-chloroperoxybenzoic acid (0.18 g, 0.87 mmol, 85% purity), and stir at 0 °C for 1 hour.

[0309] Liquid chromatography-mass spectrometry (LC-MS) was used to detect the completion of the reaction of the raw materials. Water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (20 mL × 2 times). The organic phases were combined, washed with saturated brine (20 mL × 1 time), dried with anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20:1) to obtain 0.18 g of 4-(7-methylsulfinyl-2H-pyrazolo[4,3-d]pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester.

[0310] MS(ESI)M / Z:364.1[M+H] + .

[0311] Step E: Dissolve 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline (132.14 mg, 0.55 mmol) and 4-(7-methylsulfinyl-2H-pyrazolo[4,3-d]pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (180 mg, 0.50 mmol) in isopropanol (5 mL), add p-toluenesulfonic acid (8.61 mg, 0.050 mmol), and microwave at 120 °C for 0.5 hours.

[0312] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that the reaction of the raw materials was complete, and the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20:1) to obtain 200 mg of tert-butyl 4-(7-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid.

[0313] MS(ESI)M / Z:540.2[M+H] + .

[0314] Step F: Dissolve 100 mg (0.19 mmol) of 4-(7-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester in methanol (5 mL), and add 5 mL of 4M hydrochloric acid-methanol solution. React at 40 °C for 2 hours.

[0315] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that after the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure, and saturated saline (10 mL) was added. The pH of the aqueous phase was adjusted to 10 with saturated sodium bicarbonate solution, and then extracted with ethyl acetate / tetrahydrofuran 1:1 mixed solvent (10 mL × 3 times). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. 81 mg of crude N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-1-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[4,3-d]pyrimidine-7-amine was obtained without purification.

[0316] MS(ESI)M / Z:440.2[M+H] + .

[0317] Step G: Dissolve N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-1-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[4,3-d]pyrimidine-7-amine (81 mg, 0.18 mmol) in dichloromethane (5 mL), add N,N-diisopropylethylamine (69.79 mg, 0.54 mmol) and acryloyl chloride (16.29 mg, 0.18 mmol), and stir at 25 °C for 1 hour.

[0318] After the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to give 49 mg of 1-(4-(7-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one.

[0319] MS(ESI)M / Z:494.20[M+H] + .

[0320] 1 H NMR (400MHz, DMSO-d6): δ8.94(d,J=7.5Hz,1H),8.67-8.50(m,2H),8.42(s,1H),8.38(s,1H) ,7.69(dd,J=20.8,11.3Hz,2H),7.22(dd,J=8.5,2.8Hz,1H),7.02(dd,J=7.5,2.7Hz,1H),6.9 1(ddd,J=38.5,16.6,10.5Hz,1H),6.79(d,J=2.6Hz,1H),6.24-6.15(m,1H),5.86-5.69(m,2 H),4.33(d,J=31.1Hz,2H),3.98-3.87(m,2H),2.88(d,J=17.2Hz,2H),2.19(d,J=3.3Hz,3H).

[0321] Example 14:

[0322] 1-(4-(7-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one

[0323]

[0324] Reaction route:

[0325]

[0326] Operating steps:

[0327] Step A: Dissolve 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline (194.61 mg, 0.81 mmol) and 4-(7-methylthio-2H-pyrazolo[4,3-d]pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (280 mg, 0.81 mmol) in isopropanol (5 mL), add p-toluenesulfonic acid (13.95 mg, 0.081 mmol), and microwave at 120 °C for 3 hours.

[0328] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that the reaction of the raw materials was complete, and the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20:1) to obtain 200 mg of tert-butyl 4-(7-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid.

[0329] MS(ESI)M / Z:540.2[M+H] + .

[0330] Step B: Dissolve 200 mg (0.37 mmol) of 4-(7-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester in methanol (5 mL), and add 5 mL of 4M hydrochloric acid-methanol solution. React at 40 °C for 2 hours.

[0331] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that after the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure, and saturated saline (10 mL) was added. The pH of the aqueous phase was adjusted to 10 with saturated sodium bicarbonate solution, and then extracted with ethyl acetate / tetrahydrofuran 1:1 mixed solvent (10 mL × 3 times). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. 162 mg of crude N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-2-(1,2,3,6-tetrahydropyridin-4-yl)-2H-pyrazolo[4,3-d]pyrimidine-7-amine was obtained without purification.

[0332] MS(ESI)M / Z:440.2[M+H] + .

[0333] Step C: N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-2-(1,2,3,6-tetrahydropyridin-4-yl)-2H-pyrazolo[4,3-d]pyrimidine-7-amine (162 mg, 0.37 mmol) was dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (143.46 mg, 1.11 mmol) and acryloyl chloride (33.49 mg, 0.37 mmol) were added. The mixture was stirred at 25 °C for 1 hour.

[0334] After the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 57 mg of 1-(4-(7-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one.

[0335] MS(ESI)M / Z:494.20[M+H] + .

[0336] 1 H NMR (400MHz, DMSO-d6): δ10.15(s,1H),8.93(d,J=7.5Hz,1H),8.85(d,J=4.4Hz,1H),8.38(s,1H),8.37(s, 1H),8.09(d,J=2.6Hz,1H),8.00(d,J=9.2Hz,1H),7.20(d,J=8.8Hz,1H),7.02(dd,J=7.5,2.6Hz,1H),6.91 (ddd,J=40.3,16.6,10.4Hz,1H),6.79(d,J=2.6Hz,1H),6.67(s,1H),6.18(dd,J=16.7,2.3Hz,1H),5.76(d d,J=10.5,2.3Hz,1H),4.36(d,J=39.3Hz,2H),3.91(t,J=7.9Hz,2H),2.94(d,J=18.3Hz,2H),2.18(s,3H).

[0337] Example 15:

[0338] 1-(3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)azacyclobut-1-yl)prop-2-en-1-one

[0339]

[0340] Reaction route:

[0341]

[0342] Operating steps:

[0343] Step A: Dissolve tert-butyl 3-iodozacyclobutane-1-carboxylic acid (1.38 g, 4.89 mmol) and 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (500 mg, 3.26 mmol) in N,N-dimethylformamide (10 mL), add cesium carbonate (3.18 g, 9.78 mmol), and heat at 110 °C for 5 hours.

[0344] After the reaction of the raw materials was complete, water (20 mL) was added to the reaction system. The mixture was extracted with ethyl acetate (20 mL × 2 times), and the organic phases were combined. The organic phase was first washed with saturated brine (20 mL × 1 time), then dried with anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50:1) to give 0.7 g of tert-butyl 3-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)azacyclobutane-1-carboxylic acid.

[0345] MS(ESI)M / Z:309.1[M+H] + .

[0346] Step B: Dissolve 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline (156.17 mg, 0.65 mmol) and 3-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)azacyclobutane-1-carboxylic acid tert-butyl ester (200 mg, 0.65 mmol) in isopropanol (5 mL), add p-toluenesulfonic acid (11.19 mg, 0.065 mmol), and microwave at 110 °C for 1 hour.

[0347] After the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20:1) to obtain 180 mg of tert-butyl 3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)azacyclobutane-1-carboxylic acid.

[0348] MS(ESI)M / Z:513.2[M+H] + .

[0349] Step C: Dissolve 180 mg (0.35 mmol) of 3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)azacyclobutane-1-carboxylic acid tert-butyl ester in methanol (5 mL), add 4 M hydrochloric acid methanol solution (5 mL), and react at 40 °C for 2 hours.

[0350] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that after the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure, and saturated saline (10 mL) was added. The pH of the aqueous phase was adjusted to 10 with saturated sodium bicarbonate solution, and then extracted with ethyl acetate / tetrahydrofuran 1:1 mixed solvent (10 mL × 3 times). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. 100 mg of crude N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(azacyclobut-3-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine was obtained without purification.

[0351] MS(ESI)M / Z:413.2[M+H] + .

[0352] Step D: Dissolve N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(azacyclobut-3-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (100 mg, 0.24 mmol) in dichloromethane (5 mL), and add N,N-diisopropylethylamine (93.05 mg, 0.72 mmol) and acryloyl chloride (21.72 mg, 0.24 mmol). Stir at 25 °C for 1 hour.

[0353] After the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 52 mg of 1-(3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)azacyclobut-1-yl)prop-2-en-1-one.

[0354] MS(ESI)M / Z:467.2[M+H] + .

[0355] 1H NMR (400MHz, DMSO-d6): δ8.93(dd,J=7.5,0.7Hz,1H),8.69(s,1H),8.38(s,1H),8.36(s,1H),8.18(d,J= 3.4Hz,1H),7.52(d,J=8.0Hz,2H),7.20-7.13(m,1H),7.03(dd,J=7.5,2.6Hz,1H),6.78(d,J=2.6Hz,1H) ,6.67(d,J=3.3Hz,1H),6.38(dd,J=17.0,10.3Hz,1H),6.15(dd,J=17.0,2.2Hz,1H),5.96-5.84(m,1H), 5.71(dd,J=10.3,2.2Hz,1H),4.75(t,J=8.8Hz,1H),4.53-4.43(m,2H),4.28-4.20(m,1H),2.16(s,3H).

[0356] Example 16:

[0357] (R)-1-(3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)pyrrolidin-1-yl)prop-2-en-1-one

[0358]

[0359] Reaction route:

[0360]

[0361] Operating steps:

[0362] Step A: Dissolve 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (500 mg, 3.27 mmol) and (S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (611 mg, 3.27 mmol) in anhydrous toluene (10 mL), purge with nitrogen, add cyanomethylene tri-n-butylphosphine (1.2 g, 4.9 mmol) dropwise, and stir at 100 °C for 6 hours.

[0363] Liquid chromatography-mass spectrometry (LC-MS) showed the formation of a product. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain 1.2 g of (R)-3-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)pyrrolidine-1-carboxylic acid tert-butyl ester.

[0364] MS(ESI)M / Z:323.2[M+H] + .

[0365] Step B: Dissolve 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline (0.22 g, 0.93 mmol) and (R)-3-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (0.3 g, 0.93 mmol) in isopropanol (10 mL), add p-toluenesulfonic acid (16 mg, 0.093 mmol), and microwave at 110 °C for 0.5 hours.

[0366] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that the reaction of the raw materials was complete, and the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20:1) to obtain 130 mg of (R)-3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)pyrrolidine-1-carboxylic acid tert-butyl ester.

[0367] MS(ESI)M / Z:527.3[M+H] + .

[0368] Step C: Dissolve (R)-3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (130 mg, 0.25 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (1 mL) dropwise, and react at 25 °C for 1 hour.

[0369] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that after the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure, and 130 mg of crude product (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(pyrrolidine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine was obtained without purification.

[0370] MS(ESI)M / Z:427.2[M+H] + .

[0371] Step D: Dissolve (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(pyrrolidine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine (130 mg, 0.3 mmol) in dichloromethane (5 mL), and add N,N-diisopropylethylamine (198 mg, 1.53 mmol) and acryloyl chloride (27.5 mg, 0.3 mmol). Stir at 25 °C for 1 hour.

[0372] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that the reaction of the raw materials was complete, and the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to give 15 mg (R)-1-(3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)pyrrolidine-1-yl)prop-2-en-1-one.

[0373] MS(ESI)M / Z:481.2[M+H] + .

[0374] 1 H NMR (400MHz, Methanol-d4): δ8.73(d,J=7.5Hz,1H),8.28(s,2H),7.70(dd,J=27.0,3 .4Hz,1H),7.52–7.38(m,2H),7.16(d,J=8.8Hz,1H),7.08(dd,J=7.5,2.5Hz,1H),6.8 6(t,J=2.8Hz,1H),6.63–6.58(m,1H),6.31(ddd,J=16.8,9.1,2.0Hz,1H),5.84–5.66 (m,2H),4.30–3.61(m,5H),2.54(dddd,J=54.0,24.9,13.3,7.0Hz,2H),2.22(s,3H).

[0375] Example 17:

[0376] (S)-1-(3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)pyrrolidin-1-yl)prop-2-en-1-one

[0377]

[0378] Reaction route:

[0379]

[0380] Operating steps:

[0381] Step A: Dissolve 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (500 mg, 3.27 mmol) and (R)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (611 mg, 3.27 mmol) in anhydrous toluene (10 mL), purge with nitrogen, add cyanomethylene tri-n-butylphosphine (1.2 g, 4.9 mmol) dropwise, and stir at 100 °C for 6 hours.

[0382] Liquid chromatography-mass spectrometry (LC-MS) showed the formation of a product. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain 0.65 g of (S)-3-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)pyrrolidine-1-carboxylic acid tert-butyl ester.

[0383] MS(ESI)M / Z:323.2[M+H] + .

[0384] Step B: Dissolve 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline (0.15 g, 0.62 mmol) and (S)-3-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (0.2 g, 0.62 mmol) in isopropanol (10 mL), add p-toluenesulfonic acid (11 mg, 0.062 mmol), and microwave at 110 °C for 0.5 hours.

[0385] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that the reaction of the raw materials was complete, and the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20:1) to obtain 285 mg of (S)-3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)pyrrolidine-1-carboxylic acid tert-butyl ester.

[0386] MS(ESI)M / Z:527.3[M+H] + .

[0387] Step C: Dissolve (S)-3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (285 mg, 0.54 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (1 mL) dropwise, and react at 25 °C for 1 hour.

[0388] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that after the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure, and 220 mg of crude product (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(pyrrolidine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine was obtained without purification.

[0389] MS(ESI)M / Z:427.2[M+H] + .

[0390] Step D: Dissolve (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(pyrrolidine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-amine (220 mg, 0.52 mmol) in dichloromethane (5 mL), and add N,N-diisopropylethylamine (335 mg, 2.58 mmol) and acryloyl chloride (46 mg, 0.52 mmol). Stir at 25 °C for 1 hour.

[0391] Liquid chromatography-mass spectrometry (LC-MS) monitoring showed that the reaction of the raw materials was complete, and the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 63 mg of (S)-1-(3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)pyrrolidine-1-yl)prop-2-en-1-one.

[0392] MS(ESI)M / Z:481.2[M+H] + .

[0393] 1H NMR (400MHz, DMSO-d6): δ8.93(dd,J=7.4,1.7Hz,1H),8.60(s,1H),8.42-8.30(m,2H),7.79(dd,J=29.7,3.3H z,1H),7.55-7.45(m,2H),7.16(d,J=8.5Hz,1H),7.07-6.99(m,1H),6.78(dd,J=7.4,2.6Hz,1H),6.61-6.55(m ,1H),6.17(ddd,J=16.6,6.1,2.4Hz,1H),5.70(ddd,J=17.8,10.3,2.5Hz,2H),4.15(dd,J=11.0,6.9Hz,1H),3 .97(dd,J=12.8,6.6Hz,1H),3.84(dd,J=10.8,6.0Hz,1H),3.77-3.50(m,3H),2.16(s,3H),2.02-1.95(m,1H).

[0394] II. Bioactivity Experiment

[0395] 1. HER2 / EGFR enzyme activity detection method

[0396] 1.1 Experimental Materials

[0397]

[0398] 1.2 Experimental Procedure

[0399] 1) Prepare 1× kinase reaction buffer: 50mM HEPES, pH 7.5, 10mM MgCl2, 2mM DTT, 0.01% Tween-20, 0.01% BSA.

[0400] 2) The compounds disclosed herein are diluted using DMSO.

[0401] 3) Transfer 200 nL of the disclosed compound to a 384 reaction plate using an Echo.

[0402] 4) Prepare a 2× kinase solution using 1× kinase reaction buffer, and transfer 10 μL of HER2 / EGFR (final concentration: 0.005 nM / 0.016 nM) solution into the corresponding well of the 384 reaction plate.

[0403] 5) Centrifuge with shaking and incubate at 25°C for 60 minutes (HER2) and 120 minutes (EGFR), respectively.

[0404] 6) Prepare a 2× substrate (final concentration: 20 nM Fluorescein-Poly GT) and ATP (final concentration: 14 μM (HER2) / 13 μM (EGFR)) mixture using kinase reaction buffer, and add 10 μL to the corresponding well of the reaction plate.

[0405] 7) Centrifuge with shaking and incubate at 25°C for 30 minutes.

[0406] 8) Prepare a 2× detection solution (final concentration: 0.5 nM Tb-PY20 antibody and 10 mM EDTA) using antibody dilution buffer, and add 20 μL to each well of the reaction plate.

[0407] 9) Centrifuge with shaking and incubate at 25°C for 60 minutes.

[0408] 10) Detect fluorescence signals at 520nm and 495nm.

[0409] 11) Analyze ICs using analysis software. 50 The experimental results are shown in Table 1.

[0410] Table 1. Enzymatic inhibitory activities of the compounds disclosed herein against HER2 and EGFR.

[0411]

[0412]

[0413] The results showed that the compounds disclosed herein have a significant inhibitory effect on HER2 kinase, and some compounds have significant selectivity.

[0414] 2. HER2 TKI cell proliferation inhibition experiment

[0415] 1.1 Experimental Materials

[0416]

[0417] 1.2 Experimental Procedure

[0418] HER2 A775_G776insYVMA / BaF3, HER2 WT / BaF3 complete medium: RPMI-1640 liquid medium, 10% FBS, 1% Pen Strep; EGFR WT (EGF Dependent) / BaF3 complete medium: RPMI-1640 liquid medium, 10% FBS, 1% Pen Strep, 100ng / mL EGF.

[0419] 1. After seeding HER2 A775_G776insYVMA / BaF3, HER2 WT / BaF3, EGFR WT (EGFDependent) / BaF3 cells at a density of 1000 cells per well (40uL 1640Growth Media), add the drug.

[0420] 2. Using a compound dispenser, the compound was sequentially diluted nine times at a ratio of 1:3, with 10 μM as the highest initial concentration.

[0421] 3. After drug administration, cells were placed in a 37°C incubator and cultured for 6 days. After 6 days, 25 μL of CTG buffer was added to each well for CTG assay and plate reading analysis was performed using an ELISA reader.

[0422] 4. Use the CTG assay to detect the CTG readings of each well.

[0423] 5. Calculate the inhibition rate (inhibition%) of each concentration of the test compound on cells using the following formula.

[0424] Inhibition%=(bx) / (ba)*100%

[0425] a=CTG value(highest concentration)

[0426] b = CTG value (blank well)

[0427] x = CTG value(nM)

[0428] 6. Use analysis software to analyze the IC. 50 Perform the calculation.

[0429] (1) The concentrations and inhibition rates corresponding to 10000 nM, 3333 nM, 1111 nM, 370 nM, 123 nM, 41 nM, 13.7 nM, 4.6 nM, and 1.5 nM were statistically analyzed. Log10 (A compound concentration) was used for statistical calculation.

[0430] (2) Input the data into the analysis software and select Analysis.

[0431] (3) Select Nonlinear regression (curve fit)

[0432] (4) Select Log(inhibitor) vs. response — Variable slope.

[0433] (5) Select a calculation formula and calculate it according to the following formula.

[0434] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0435] X:log of dose or concentration

[0436] Y:Response,decreasing as X increases

[0437] Top and Bottom:Plateaus in same units as Y.

[0438] TIP:

[0439] -If X is not already the log of dose,go back and transform your data.

[0440] -If you have subtracted off any basal response,consider constrainingBottom to a constant value of 0.0.

[0441] (6) Fit the data to obtain IC. 50 value.

[0442] (7) Adjust the fitting conditions according to the specific data. Make appropriate adjustments to the bottom, top, and hill slope constraints to achieve the curve that best reflects the actual situation.

[0443] The experimental results are shown in Table 2.

[0444] Table 2. Cell inhibitory activities of the disclosed compounds against HER2 and EGFR.

[0445]

[0446] The results showed that the disclosed compound had a significant inhibitory effect and selectivity on HER2 cells.

Claims

1. A compound of formula (I) or an isomer thereof, a pharmaceutically acceptable salt, a prodrug, a solvate, an isotopically labeled derivative, a metabolite, or a nitrogen oxide. in, It can be a single bond or a double bond; M1 is selected from -N-, -N=, or -C=; M2 is selected from -N=, -N-, and -C(R). 6-1 = or -C(=O)-; M3is selected from -N(R 6-2 )-, -C(R 6-3 )-, -C(R 6-4 )=, or -C(R 6-5 )=; L1is selected from the group consisting of a bond, -(CH2) n1 -0(CH2) n2 - NH(CH2) n3 -; Ring A is selected from 5-6-membered heteroaryl, 3-10-membered heterocyclic alkyl, and 3-10-membered heterocyclic alkenyl; or, ring A is absent. Ring B is selected from 3-10 membered heterocyclic alkyl or 3-10 membered heterocyclic alkenyl; Ring C is selected from C 6-14 aryl, 5-14 membered heteroaryl; R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl; R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl; R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl; R 4-1 R 4-2 R 4-3 and R 4-4 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl; R 5-1 R 5-2 and R 5-3 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic alkyl groups, are optionally further modified by amino groups, -NH(C) 1-6 alkyl), -N(C) 1-6 One or more substitutions are made from alkyl groups, 2-, 3-, 8-membered heterocyclic alkyl groups, and halogenated 3-, 8-membered heterocyclic alkyl groups; R 6-1 R 6-2 R 6-3 R 6-4 and R 6-5 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl; n1, n2, and n3 are each independently selected from 0, 1, 2, or 3; x is selected from 0, 1, 2, 3 or 4; y is selected from 0, 1, 2, 3 or 4; w can be selected from 0, 1, 2, 3 or 4.

2. The compound or isomer thereof as claimed in claim 1, a pharmaceutically acceptable salt, a prodrug, a solvate, an isotope-labeled derivative, a metabolite, or a nitrogen oxide, wherein, Structural fragments Selected from or, Ring A is selected from The α end is connected to L1; or, Cycle B is selected from 6-membered heterocyclic alkenyl, 6-membered heterocyclic alkyl, 4-membered heterocyclic alkyl, 5-membered heterocyclic alkyl, cyclopentyl 5-membered heterocyclic alkyl, cyclohexylspiro 4-membered heterocyclic alkyl, 7-membered heterocyclic alkyl, and 5-membered heterocyclic alkenyl; Preferably, Ring B is selected from The α end is connected to the A end of the ring; or, The ring C is selected from 6-membered heteroaryl-5-membered heteroaryl, phenyl-5-membered heteroaryl, 6-membered heteroaryl, phenyl-5-membered heterocyclic alkenyl-cyclopropyl, and phenyl-5-membered heterocyclic alkenyl-spirocyclopropyl. Preferably, Ring C is selected from 3. The compound or isomer thereof, pharmaceutically acceptable salt, prodrug, solvate, isotope-labeled derivative, metabolite, or nitrogen oxide as described in any one of claims 1 to 2, wherein, R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl; Preferably, R2 is independently selected from hydrogen or methyl.

4. The compound or isomer thereof, pharmaceutically acceptable salt, prodrug, solvate, isotope-labeled derivative, metabolite, or nitrogen oxide as described in any one of claims 1 to 3, wherein, R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl; Preferably, R3 is independently selected from hydrogen, methyl, methoxy, and difluoromethyl.

5. The compound or isomer thereof, pharmaceutically acceptable salt, prodrug, solvate, isotope-labeled derivative, metabolite, or nitrogen oxide as described in any one of claims 1 to 4, wherein, R 4-1 R 4-2 R 4-3 and R 4-4 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl; Preferably, R 4-1 selected from hydrogen; or, R 4-2 selected from hydrogen, fluoro; or, R 4-3 selected from methyl; or, R 4-4 selected from hydrogen, fluorine.

6. The compound or isomer thereof, pharmaceutically acceptable salt, prodrug, solvate, isotope-labeled derivative, metabolite, or nitrogen oxide as described in any one of claims 1 to 5, wherein, R 5-1 R 5-2 and R 5-3 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl; the C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic alkyl groups, are optionally further modified by amino groups, -NH(C) 1-3 alkyl), -N(C) 1-3 One or more substitutions are made from alkyl groups, 2-, 3-, and 6-membered heterocyclic alkyl groups, and halogenated 3-, 6-membered heterocyclic alkyl groups. Preferably, R 5-1 Selected from hydrogen; Or, R 5-2 Selected from hydrogen, -CH2N(CH3)2, or, R 5-3 selected from hydrogen.

7. The compound or isomer thereof, pharmaceutically acceptable salt, prodrug, solvate, isotope-labeled derivative, metabolite, or nitrogen oxide as described in any one of claims 1 to 6, wherein, R 6-1 R 6-2 R 6-3 R 6-4 and R 6-5 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl; Preferably, R 6-1 selected from hydrogen, methyl, difluoromethyl, cyano; Or, R 6-2 Selected from hydrogen; Or, R 6-3 Selected from hydrogen; Or, R 6-4 Selected from hydrogen; Or, R 6-5 Selected from hydrogen.

8. The compound or isomer thereof, pharmaceutically acceptable salt, prodrug, solvate, isotope-labeled derivative, metabolite, or nitrogen oxide as described in any one of claims 1 to 7, wherein, The compounds are shown below:

9. A pharmaceutical composition comprising the compound or isomer of any one of claims 1-8, a pharmaceutically acceptable salt, a prodrug, a solvate, an isotopically labeled derivative, a metabolite, a nitrogen oxide, and a pharmaceutically acceptable carrier.

10. Use of the compound or isomer thereof, pharmaceutically acceptable salt, prodrug, solvate, isotope-labeled derivative, metabolite and nitride, or the pharmaceutical composition of claim 9 in the preparation of a medicament for treating cancer; preferably, wherein the cancer is selected from non-small cell lung cancer, breast cancer or colon cancer.

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