Bicyclic heterocyclic fgfr4 inhibitors, pharmaceutical compositions and formulations comprising the same, and uses thereof

Abstract

Bicyclic heterocyclic FGFR4 inhibitors are provided, as are pharmaceutical compositions and formulations comprising the same, and uses thereof. In particular, provided is a compound having the structure of Formula (I), which can act as an FGFR4 inhibitor for the prevention and / or treatment of a disease (e.g., cancer, etc.) mediated at least in part by FGFR4.

Description

[0001] Cross-reference to related applications

[0002] This invention claims priority to Chinese patent application No. 202110326618.7, filed on March 26, 2021, entitled "Bicyclic Heterocyclic FGFR4 Inhibitor, Pharmaceutical Composition and Formulation Containing the Same, and Application Thereto", the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention belongs to the field of medicinal chemistry, specifically relating to bicyclic heterocyclic FGFR4 inhibitors, pharmaceutical compositions and formulations containing them, and their applications. Background Technology

[0004] Fibroblast growth factor receptor (FGFR) is a receptor-type tyrosine kinase (RTK). Its family includes four FGFR protein members: FGFR1, FGFR2, FGFR3, and FGFR4, which are involved in different stages of embryonic development, organogenesis, tissue homeostasis, angiogenesis, and inflammation. When bound to fibroblast growth factor (FGF) ligands, FGFR undergoes dimerization and phosphorylation, thereby stimulating protein kinase activity and recruiting many intracellular docking proteins. These interactions affect cell growth, proliferation, and differentiation through the activation of a series of intracellular signaling pathways (including Ras-MAPK, AKT-PI3K, and phospholipase C, etc.) (Eswarakumar VP et al. Cytokine Growth Factor Reviews, 2005, 16(2):139-149).

[0005] FGFR4 plays an important role in embryonic development, central nervous control, tissue repair, and tumor invasion and angiogenesis (Ho, H. K. et, al. Journal of Hepatology, 2009, 50: 118-127). In addition, overexpression of FGFR4 has been observed in a variety of tumor types, including hepatocellular carcinoma, gastric cancer, renal cell carcinoma, colorectal cancer, breast cancer, pancreatic cancer, prostate cancer, lung cancer, ovarian cancer, etc. It is currently believed that FGFR4 is the only receptor that shows specificity for FGF19, which exerts activity by binding to FGFR4 and activating FGFR4. Under pathological conditions, overexpression of FGF19, FGFR4 or mutations in activated FGFR4 will cause overactivity of the MAPK and PI3K / AKT pathways, leading to tumor development, progression and resistance to conventional cancer therapy (Heinzle et. al. Cur. Pharm. Des. 2014, 20: 2881).

[0006] Studies have found that about 30% of hepatocellular carcinoma patients have abnormally activated FGFR4 in the tumor. Desnoyers et al. found that a FGF19 monoclonal antibody can selectively block the interaction of FGF19 with FGFR4, and this antibody can inhibit the growth of human colon cancer xenografts in nude mice and effectively prevent FGF19 transgenic mice from developing liver cancer (Desnoyers, L. R. et, al. Oncogene, 2008, 27: 85-97), which also confirms the feasibility of using small molecule FGFR4 inhibitors to block the binding of extracellular ligand molecules to FGFR4 or intracellular kinase signaling to inhibit FGFR4-mediated signals, thereby achieving the treatment of malignant tumors such as liver cancer. At present, there are several FGFR4 inhibitors in clinical research, such as FGF401 developed by Novartis, which can selectively inhibit FGFR4 and shows good prospects; BLU554, an FGFR4-specific inhibitor developed by Blueprint Medicines, has strong anti-tumor activity and selectivity, and shows good safety; H3B6527, an FGFR4-specific inhibitor developed by H3 Biomedicine, also shows good anti-tumor activity.

[0007] Based on the in-depth understanding of the structure, function and mechanism of action of FGFR4 and the interaction with other kinases by researchers, the development of FGFR4 inhibitors with strong specificity, good therapeutic effect and low adverse reactions will have very important significance for the prevention and / or treatment of diseases related to FGFR4, such as tumors SUMMARY

[0008] Problems to be solved by the invention

[0009] The present application aims to provide a series of novel compounds having inhibitory effect on FGFR4 activity, pharmaceutical compositions and preparations containing the compounds, and medical uses of the series of compounds.

[0010] Solutions to the problems

[0011] <First aspect>

[0012] The present application provides a compound having the structure of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof, the structural general formula of the formula (I) compound is:

[0013]

[0014] Wherein:

[0015] X is CH or N;

[0016] Y is 2 H or 1 O;

[0017] Z is C(R 6 )2 or N(R 6 );

[0018] m is 0 or 1;

[0019] L is -C(R 7 )2- or

[0020] n is 0, 1 or 2;

[0021] Each R 1 is independently C 1-3 alkyl or C 1-3 haloalkyl;

[0022] R 2 and R 3 are each independently hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalkyl, cyano or C 1-3 alkoxy;

[0023] R 4 is hydrogen, C 1-6 alkyl or C 6-10 aryl;

[0024] R 5 is hydrogen, halogen, cyano, nitro, trifluoromethyl, amino, C 1-6 alkyl, C 2-8 alkenyl, C 6-10 aryl, C l-8 alkylamino, di(C 2-8alkyl)amino, C 2-8 alkynyl, C 1-8 haloalkyl or C 3-8 cycloalkyl;

[0025] each R 6 is each independently hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 6-10 aryl, substituted C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocycloalkyl; wherein the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocycloalkyl each independently comprises 1 to 3 ring-forming heteroatoms that are each independently N, O, or S;

[0026] or two R 6 and the carbon atom to which they are attached together form a C 3-8 cycloalkyl or 4- to 10-membered heterocycloalkyl; wherein the 4- to 10-membered heterocycloalkyl comprises 1 to 3 ring-forming heteroatoms that are N, O, or S; the C 3-8 cycloalkyl and the 4- to 10-membered heterocycloalkyl each independently are optionally substituted with 1 to 4 substituents that are each independently halogen, cyano, hydroxyl, amino, C 1-8 carboxamido, C 1-8 carboxyl, C 1-8 alkyl or C 1-8 alkoxy;

[0027] each R 7 is each independently hydrogen, halogen, amino, cyano, C 1-8 alkyl, substituted C 1-8 alkyl, C 1-8 alkoxy, substituted C l-8 alkoxy, C l-8 alkylamino, di(C 2-8 alkyl)amino, C 2-8 alkenyl, substituted C 2-8 alkenyl, C 2-8 alkynyl, substituted C 2-8 alkynyl, C 6-10 aryl, substituted C 6-10 aryl, C 3-8 cycloalkyl, substituted C 3-8cycloalkyl, 3- to 10-membered heterocycloalkyl, substituted 3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, or substituted 5- to 10-membered heteroaryl; wherein the 3- to 10-membered heterocycloalkyl and the 5- to 10-membered heteroaryl each independently comprises 1 to 3 ring-forming heteroatoms, each independently N, O, or S.

[0028] Preferably, the compound has a structure according to Formula (II):

[0029]

[0030] wherein X, Y, Z, m, L, R 2 and R 3 are as defined above.

[0031] Preferably, the compound has a structure according to Formula (III):

[0032]

[0033] wherein Z, m, L, R 2 and R 3 are as defined above.

[0034] Further preferably, the compound has a structure according to Formula (III-1) or Formula (III-2):

[0035]

[0036] wherein Z, L, R 2 and R 3 are as defined above.

[0037] Further preferably, the compound according to Formula (III-1) has a structure according to Formula (III-1-1):

[0038]

[0039] wherein R 2 , R 3 and R 6 are as defined above, and R 7 is hydrogen, C 1-4 alkyl, piperazinyl, piperidinyl, or morpholinyl, wherein the C 1-4 alkyl, piperazinyl, piperidinyl, and morpholinyl are each optionally substituted with at least one R 8 , each R 8 is independently hydrogen, C 1-4Alkyl (preferably methyl or ethyl), morpholinyl, bridged morpholinyl, piperazine, substituent-containing piperazine, bridged morpholinyl, substituent-containing bridged morpholinyl, oxecyclobutyl or substituent-containing oxecyclobutyl, wherein the substituent is C 1-4 Alkyl groups (preferably methyl or ethyl);

[0040] Preferably, R 2 R 3 and R 6 As defined above, R 7 For hydrogen, C 1-4 alkyl, piperazine, piperidinyl, or morpholinyl, wherein the C 1-4 Alkyl, piperazine, piperidinyl, and morpholino groups are each optionally surrounded by at least one R 8 Replace, each R 8 Each of the following groups is independently hydrogen, morpholino, bridged morpholino, piperazine, a substituent-containing piperazine, a bridged morpholino, a substituent-containing bridged morpholino, an oxecyclobutane, or a substituent-containing oxecyclobutane, wherein the substituent is C. 1-4 alkyl;

[0041] More preferably, R 2 R 3 and R 6 As defined above, R 7 It is one of the following segments:

[0042]

[0043] More preferably, the compound of formula (III-2) has the structure shown in formula (III-2-1) or formula (III-2-2):

[0044]

[0045] Among them, R 2 R 3 and R 6 The definition is as described above.

[0046] Preferably, the compound has the structure shown in formula (IV):

[0047]

[0048] Among them, Z, m, L, R 2 and R 3 The definition is as described above.

[0049] More preferably, the compound has the structure shown in formula (IV-1) or formula (IV-2):

[0050]

[0051] wherein Z, L, R 2 and R 3 are as defined above;

[0052] Further preferably, the compound of formula (IV-1) has the structure of formula (IV-1-1):

[0053]

[0054] wherein R 2 , R 3 and R 6 are as defined above, R 7 is hydrogen, C 1-4 alkyl, piperazinyl, piperidinyl or morpholinyl, wherein the C 1-4 alkyl, piperazinyl, piperidinyl and morpholinyl are each optionally substituted with at least one R 8 each R 8 is independently hydrogen, morpholinyl, bridged morpholinyl, piperazinyl, substituted piperazinyl, bridged piperazinyl, substituted bridged piperazinyl, oxetanyl or substituted oxetanyl, the substituents being C 1-4 alkyl;

[0055] More preferably, R 2 , R 3 and R 6 are as defined above, R 7 is one of the following moieties:

[0056]

[0057] Further preferably, the compound of formula (IV-2) has the structure of formula (IV-2-1) or formula (IV-2-2):

[0058]

[0059] wherein R 2 , R 3 and R 6 are as defined above, R 7 is hydrogen, C 1-4 alkyl or

[0060] wherein R 2 , R 3 and R 6 are as defined above.

[0061] <Second aspect>

[0062] The present application provides the following compounds or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, chelates, non-covalent complexes or prodrugs thereof:

[0063]

[0064]

[0065]

[0066]

[0067] A third aspect

[0068] The present application provides a pharmaceutical composition comprising the compound according to the <first aspect>, the <second aspect> or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof.

[0069] A fourth aspect

[0070] The present application provides a pharmaceutical preparation comprising the compound according to the <first aspect>, the <second aspect> or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof or the pharmaceutical composition according to the <third aspect>, which is any one of a tablet, a capsule, an injection, a granule, a powder, a suppository, a pill, a gel, a powder, an oral solution, an inhalant, a suspension or a dry suspension.

[0071] A fifth aspect

[0072] The present application provides the use of the compound according to the <first aspect>, the <second aspect> or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof or the pharmaceutical composition according to the <third aspect> or the pharmaceutical preparation according to the <fourth aspect> in the preparation of a medicament for preventing and / or treating a disease mediated at least in part by FGFR4.

[0073] Preferably, the disease mediated at least in part by FGFR4 comprises a cancer.

[0074] Further preferred, the cancer is selected from the group consisting of hepatocellular carcinoma, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myeloid leukemia, Hodgkin's or non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, hairy cell lymphoma, Burkitt's lymphoma, glioblastoma, melanoma, mesothelioma, neuroblastoma, testicular cancer, squamous cell carcinoma, glioblastoma and rhabdomyosarcoma.

[0075] <Sixth aspect>

[0076] The present application provides a compound according to <first aspect>, <second aspect> or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof, or a pharmaceutical composition according to <third aspect>, or a pharmaceutical preparation according to <fourth aspect> for use as an EGFR4 inhibitor.

[0077] <Seventh aspect>

[0078] The present application provides a method for preventing and / or treating a disease mediated at least in part by FGFR4, comprising the step of administering to a patient in need thereof a prophylactically and / or therapeutically effective amount of a compound according to <first aspect>, <second aspect> or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof, or a pharmaceutical composition according to <third aspect>, or a pharmaceutical preparation according to <fourth aspect>.

[0079] <Eighth aspect>

[0080] The present application provides a method for preventing and / or treating a cancer, comprising the step of administering to a patient in need thereof a prophylactically and / or therapeutically effective amount of a compound according to <first aspect>, <second aspect> or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof, or a pharmaceutical composition according to <third aspect>, or a pharmaceutical preparation according to <fourth aspect>, and at least one additional cancer therapeutic.

[0081] Preferably, the cancer is selected from hepatocellular carcinoma, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myeloid leukemia, Hodgkin's or non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, hairy cell lymphoma, Burkitt's lymphoma, glioblastoma, melanoma, mesothelioma, neuroblastoma, testicular cancer, squamous cell carcinoma, glioblastoma, and rhabdomyosarcoma.

[0082] <the ninth aspect>

[0083] The present application provides a pharmaceutical combination comprising a compound according to <the first aspect>, <the second aspect> or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof, or a pharmaceutical composition according to <the third aspect>, or a pharmaceutical preparation according to <the fourth aspect>, and at least one additional cancer therapeutic agent.

[0084] Effects of the invention

[0085] The present application provides a novel compound of formula (I) which can be used for preparing pharmaceutical compositions and pharmaceutical preparations for preventing and / or treating diseases (such as tumors) mediated at least in part by FGFR4, with high specificity, good therapeutic effect and low adverse reactions. DETAILED DESCRIPTION

[0086] Before further describing the present application, it should be understood that the application is not limited to the particular embodiments described herein; it should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0087] [definitions of terms]

[0088] Unless otherwise defined, the following terms have the following meanings:

[0089] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present application that is substantially non-toxic to the organism. Pharmaceutically acceptable salts usually include, but are not limited to, salts of compounds of the present application with pharmaceutically acceptable inorganic / organic acids or inorganic / organic bases, which are also known as acid or base addition salts. Common inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like, common organic acids include, but are not limited to, trifluoroacetic acid, citric acid, maleic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, oxalic acid, formic acid, acetic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like, common inorganic bases include, but are not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide and the like, common organic bases include, but are not limited to, diethylamine, triethylamine, ethylamine butanol and the like.

[0090] The term "ester" is used to denote organic esters, including monoesters, diesters, triesters and more generally polyesters.

[0091] The term "stereoisomer" (or "optical isomer") refers to a stable isomer that is capable of rotating the plane of plane-polarized light due to the presence of at least one chiral element (including chiral centers, chiral axes, chiral planes, etc.). Because of the presence of asymmetric centers in the compounds of the present application and other chemical structures that can lead to stereoisomerism, the present application also includes these stereoisomers and mixtures thereof. Because the compounds of the present application and salts thereof include asymmetric carbon atoms, they can exist in the form of a single stereoisomer, a racemic mixture, an enantiomeric mixture, and a diastereomeric mixture. Generally, these compounds can be prepared in the form of a racemic mixture. However, if desired, such compounds can be prepared or isolated to provide pure stereoisomers, i.e., single enantiomers or diastereomers, or mixtures enriched in single stereoisomers (purity > 98%, > 95%, > 93%, > 90%, > 88%, > 85%, or > 80%). Single stereoisomers of compounds are prepared either synthetically from optically pure starting materials containing the desired chiral center(s), or by preparing a mixture of enantiomeric products and separating it by means of separation techniques, such as conversion to a mixture of diastereomers and then separation by chromatography, crystallization, or other standard techniques, or by direct separation of the enantiomers on a chiral chromatography column. Starting compounds having particular stereochemistry can be obtained either commercially or by the methods described below or by the methods described herein or by the methods well known in the art.

[0092] The term "tautomer" (or "tautomeric form") refers to structural isomers that exist in equilibrium with one another through low energy barriers. If tautomerism is possible (as in solution), a chemical equilibrium of tautomers can be achieved. For example, prototropic tautomers (or proton-shift tautomers) include, but are not limited to, interconversions by proton migration, such as keto-enol isomerization, imine-enamine isomerization, amide-imidol isomerization, and the like. Unless otherwise indicated, all tautomeric forms of the compounds of the application are within the scope of the application.

[0093] The term "solvate" refers to a molecular complex of a compound of the application or a pharmaceutically acceptable salt thereof with one or more solvent molecules. Common solvates include, but are not limited to, hydrates, ethanolates, acetoneates, and the like.

[0094] The term "chelate" refers to a complex having a cyclic structure, formed by chelation, the formation of several coordinate covalent bonds between a single central atom and several surrounding atoms or molecules.

[0095] The term "non-covalent complex" refers to a complex formed by the interaction of a compound with another molecule, wherein no covalent bond is formed between the compound and the molecule. Complexation can occur, for example, by van der Waals interactions, hydrogen bonding, and electrostatic interactions (also known as ionic bonding).

[0096] The term "prodrug" refers to a derivative of a compound of the application that is applicable to a patient and that can provide either directly or indirectly the compound of the application. Particularly preferred derivatives or prodrugs are compounds that increase the bioavailability of the compound of the application when administered to a patient (e.g., are more readily absorbed into the blood), or that facilitate the delivery of the parent compound to the site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the application are within the scope of the application, and various prodrug forms are well known in the art.

[0097] The term "each independently" refers to at least two groups (or ring systems) present in a structure that have the same or similar range of values and can have the same or different meaning in a particular context. For example, substituent X and substituent Y are each independently hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl, then when substituent X is hydrogen, substituent Y can be either hydrogen or halogen, hydroxyl, cyano, alkyl, or aryl; similarly, when substituent Y is hydrogen, substituent X can be either hydrogen or halogen, hydroxyl, cyano, alkyl, or aryl.

[0098] The term "halogen" refers to the four atoms fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0099] The term "alkyl" includes straight chain, branched chain saturated alkyl groups. For example, alkyl includes, but is not limited to, methyl, ethyl, propyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, and the like. "C 1-8 The term "alkyl" includes straight chain, branched chain saturated alkyl groups. For example, alkyl includes, but is not limited to, methyl, ethyl, propyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, and the like. "C 1-8 The term "alkyl" includes straight chain, branched chain saturated alkyl groups. For example, alkyl includes, but is not limited to, methyl, ethyl, propyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, and the like. "C

[0100] The term "alkenyl" refers herein to a group having and having at least one alkenyl unsaturation site. For example, alkenyl includes, but is not limited to, ethenyl, propenyl, allyl, isopropenyl, butenyl, isobutenyl, and the like. "C 2-8 The term "alkenyl" refers herein to a group having and having at least one alkenyl unsaturation site. For example, alkenyl includes, but is not limited to, ethenyl, propenyl, allyl, isopropenyl, butenyl, isobutenyl, and the like. "C

[0101] The term "alkynyl" refers herein to a group having and having at least one alkynyl unsaturation site. For example, alkynyl includes, but is not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. "C 2-8 The term "alkynyl" refers herein to a group having and having at least one alkynyl unsaturation site. For example, alkynyl includes, but is not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. "C

[0102] The term "haloalkyl" refers to an alkyl group having up to the full valence of halo atom substituents, which can be the same or different. Non-limiting examples of haloalkyl include -CF3, -C2F5, -CHF2, -CC13, -CHC12, -C2C15, and the like. "C 1-8 The term "haloalkyl" refers to an alkyl group having up to the full valence of halo atom substituents, which can be the same or different. Non-limiting examples of haloalkyl include -CF3, -C2F5, -CHF2, -CC13, -CHC12, -C2C15, and the like. "C

[0103] The term "aryl" refers herein to an unsubstituted or substituted monocyclic or polycyclic aromatic group of 6 to 10 membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups. For example, aryl includes, but is not limited to, phenyl, 1-naphthyl, 2-naphthyl, and the like.

[0104] The term "heteroaryl" refers herein to a monocyclic or polycyclic (e.g., having 2 or 3 fused rings) aromatic hydrocarbon moiety having one or more ring members that are independently selected from N, S, and O that is unsubstituted or substituted. For example, heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyrrolyl, oxazolyl, quinolinyl, isoquinolinyl, benzisoxazolyl, imidazo[l,2-b]thiazolyl, and the like.

[0105] The term "cycloalkyl" refers herein to non-aromatic cyclic alkyl groups having a single ring or multiple rings (including fused, bridged, and spiro systems), including cyclized alkyl and alkenyl groups. For example, cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl heptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, tetrahydronaphthyl, octahydronaphthyl, dihydroindenyl, norpinyl, and the like.

[0106] The term "heterocycloalkyl" refers herein to a non-aromatic ring or ring system having at least one heteroatom selected from O, N, and S and optionally having one or more alkenylene or alkynylene groups as part of the ring structure. The heterocycloalkyl group as a whole can have from 3 to 10 ring atoms. The heterocycloalkyl group can be covalently attached to the defined chemical structure at any heteroatom or carbon atom that results in a stable structure. For example, heterocycloalkyl groups include, but are not limited to, pyrrolinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyranyl, and the like. One or more N or S atoms on the heterocycloalkyl group can be oxidized (e.g., morpholine N-oxide, thiomorpholine S-oxide, thiomorpholine S,S-dioxide). The heterocycloalkyl group can also contain one or more oxo groups, such as phthalimido, piperidinonyl, oxazolidinonyl, 2,4(lH,3H)-dioxo-pyrimidinyl, pyridine-2(lH)-ketone, and the like.

[0107] The term "alkylamino" refers to a group having the formula -NH(alkyl). In some embodiments, the alkylamino group has from 1 to 8 carbon atoms. Non-limiting examples of alkylamino groups include methylamino, ethylamino, propylamino (e.g., n-propylamino and isopropylamino), and the like.

[0108] The term "dialkylamino" refers to a group having the formula -N(alkyl)2. Non-limiting examples of dialkylamino groups include dimethylamino, diethylamino, dipropylamino (e.g., di(n-propyl)amino and di(isopropyl)amino), and the like.

[0109] The term "alkoxy" refers herein to an alkyl group attached to the remainder of the molecule through an oxygen atom (-O-alkyl), wherein the alkyl group is as defined herein. Non-limiting examples of alkoxy groups include methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, n-pentoxy, and the like.

[0110] R 6 The term "substituted" in the context of the optionally substituted groups "substituted C 6-10 The term "substituent" in the context of the optionally substituted groups "substituted aryl" and R 7 The term "substituent" in the context of the optionally substituted groups includes acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. For appropriate organic compounds, one or more, and the same or different, substituents can be permitted. Non-limiting examples of substituents include any of the substituents described herein, e.g., halogen, hydroxyl, carbon-based (such as carboxyl, alkoxy carbon-based, formyl, or acyl), sulfur-based (such as thioester, thioacetate, or thiocarbamate), alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, phosphoryl, phosphate, phosphonate, phosphinite, amino, alkylamino, dialkylamino, amido, amidino, imino, cyano, nitro, azido, mercapto, alkylthio, sulfate, sulfonate, sulfamoyl, sulfamide, sulfonyl, cycloalkyl, heterocyclyl, aralkyl, aryl, or heteroaryl moieties. It will be understood by those skilled in the art that moieties substituted on a hydrocarbon chain can themselves be substituted as appropriate. For example, cycloalkyl groups can be further substituted with alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbon-based substituted alkyl, cyano, and the like; for example, alkenyl and alkynyl groups can be similarly substituted to yield aminoalkenyl, aminoalkynyl, amidoalkenyl, amidoalkynyl, iminoalkenyl, iminoalkynyl, thioalkenyl, thioalkynyl, carbon-based substituted alkenyl or alkynyl.

[0111] The term "protecting group" in the context of "protecting groups (PG) associated with hydroxyl, amino, mercapto, carboxyl, and the like," refers to the protection of hydroxyl, amino, mercapto, carboxyl, and the like, from undesired reactions by functional groups, and the protecting groups used are well known to those skilled in the art, such as those mentioned in Protective Groups in Organic Synthesis (John Wiley & Sons, New York, Third Edition, 1999).

[0112] The term "prevention" refers to the complete or nearly complete prevention of the occurrence of a disease or condition (e.g., an infection, ischemic or reperfusion injury), for example, when a patient or subject is susceptible to or at risk of a disease or condition; prevention can also include inhibition, i.e., the prevention of the development of a condition.

[0113] The term "treatment" refers to: 1) inhibiting the disease; for example, inhibiting a disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition, or disorder (i.e., arresting further development of the pathology and / or symptomatology); or 2) ameliorating the disease; for example, ameliorating a disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition, or disorder (i.e., reversing the pathology and / or symptomatology).

[0114] The term "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

[0115] The following abbreviations can be used in the present application: (Boc)20(di-tert-butyl dicarbonate); DCM (dichloromethane); tBuOH (tert-butanol); NaBH(OAc)3(sodium triacetoxyborohydride); DIPEA (N,N-diisopropylethylamine); DMAP (4-dimethylaminopyridine); DMF (N,N-dimethylformamide); DMSO (dimethyl sulfoxide); EA or EtOAc (ethyl acetate); HOAc (acetic acid); LCMS or LC-MS (liquid chromatography mass spectrometry); TLC (thin layer chromatography); MeOH (methanol); NaOMe (sodium methoxide); NaH (sodium hydride); Pd(dcpf)Cl2(dichloro[l,l'-bis(dicyclohexylphosphino) ferrocene] palladium(II)); Pd2(dba)3(tris(dibenzylideneacetone)dipalladium); PdCl2(dppf)CH2Cl2([l,l'-bis(diphenylphosphino) ferrocene] palladium dichloride dichloromethane complex); Pd(OAc)2(palladium(II) acetate); Pd(PPh3)4(tetrakis(triphenylphosphine)palladium); Pd(OH)2(palladium hydroxide); DPPF (l,l'-bis(diphenylphosphino) ferrocene); Rt, r.t. or RT (room temperature); h, hr or hrs (hour(s)); min (minute(s)); BnNH2(benzylamine); TEA (triethylamine); TFA (trifluoroacetic acid); BH3THF (borane tetrahydrofuran solution); THF (tetrahydrofuran); NaOtBu (sodium tert-butoxide); Cs2CO3(cesium carbonate); BrettPhos (dicyclohexyl[3,6-dimethoxy-2',4',6'-triisopropyl[l,l'- biphenyl]-2-yl]phosphine).

[0116] The starting materials for the examples of the present application are generally commercially available, for example, from Aldrich, Alfa Aesar, Bide, etc., or prepared by methods known to those skilled in the art. Substituents not compatible with the reaction conditions will be apparent to those skilled in the art, and alternate methods are indicated herein.

[0117] The commercially available solvents and reagents used in the experiments are directly used without further purification or treatment if no special instructions are given. When referring to other examples or synthetic methods, the reaction conditions (reaction temperature, reaction solvent, molar ratio of reactants or / and reaction duration) can be different. Generally, the reaction progress can be monitored by TLC, and the reaction is terminated at the appropriate time and post-treated according to the Rf value of TLC. The purification conditions of the compounds can also be changed, and generally, the corresponding compounds are purified by preparative TLC according to the Rf value of TLC.

[0118] [General compounds]

[0119] The present application provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof, the structure of formula (I) is as follows:

[0120]

[0121] Wherein:

[0122] X is CH or N;

[0123] Y is 2 H or 1 O;

[0124] Z is C(R 6 )2 or N(R 6 );

[0125] m is 0 or 1;

[0126] L is -C(R 7 )2- or

[0127] n is 0, 1 or 2;

[0128] Each R 1 is independently C 1-3 alkyl or C 1-3 haloalkyl;

[0129] R 2 and R 3 are each independently hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalkyl, cyano or C 1-3 alkoxy;

[0130] R 4 is hydrogen, C 1-6 alkyl or C 6-10 aryl;

[0131] R 5 is hydrogen, halogen, cyano, nitro, trifluoromethyl, amino, C1-6 alkyl, C 2-8 alkenyl, C 6-10 aryl, C l-8 alkylamino, di(C 2-8 alkyl)amino, C 2-8 alkynyl, C 1-8 haloalkyl or C 3-8 cycloalkyl;

[0132] each R 6 is each independently hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 6-10 aryl, substituted C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocycloalkyl; wherein the 5- to 10-membered heteroaryl and the 4- to 10-membered heterocycloalkyl each independently comprises 1 to 3 ring-forming heteroatoms that are each independently N, O, or S;

[0133] or two R 6 and the carbon atom to which they are attached together form a C 3-8 cycloalkyl or 4- to 10-membered heterocycloalkyl; wherein the 4- to 10-membered heterocycloalkyl comprises 1 to 3 ring-forming heteroatoms that are N, O, or S; the C 3-8 cycloalkyl and the 4- to 10-membered heterocycloalkyl each independently are optionally substituted with 1 to 4 substituents that are each independently halogen, cyano, hydroxyl, amino, C 1-8 carboxamido, C 1-8 carboxyl, C 1-8 alkyl or C 1-8 alkoxy;

[0134] each R 7 is each independently hydrogen, halogen, amino, cyano, C 1-8 alkyl, substituted C 1-8 alkyl, C 1-8 alkoxy, substituted C l-8 alkoxy, C l-8 alkylamino, di(C 2-8 alkyl)amino, C 2-8 alkenyl, substituted C 2-8 alkenyl, C 2-8 alkynyl, substituted C 2-8 alkynyl, C 6-10 aryl, substituted C 6-10 aryl, C 3-8 cycloalkyl, substituted C 3-8Cycloalkyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkyl with substituents, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryl with substituents; wherein the 3- to 10-membered heterocycloalkyl and the 5- to 10-membered heteroaryl each independently contain 1 to 3 cyclic heteroatoms, and each heteroatom is independently N, O, or S.

[0135] In some specific embodiments of the present invention, in the compound of formula (I) above, each R 1 Each independently is C 1-3 Alkyl or C 1-3 Halogenated alkanes, preferably C 1-3 Alkyl group. Wherein, C 1-3 The alkyl group is methyl, ethyl, or propyl, preferably methyl; C 1-3 The haloalkane is -CF3, -C2F5, -CHF2, -CCl3, -CHCl2 or -C2Cl5.

[0136] In some specific embodiments of the present invention, in the compound of formula (I) above, R 2 and R 3 Each is independently hydrogen, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, cyano or C 1-3 Alkyl group, preferably halogen. The halogen is -F, -Cl, or -Br, preferably -F or -Cl; C 1-3 The alkyl group is methyl, ethyl, or propyl; C 1-3 The alkyl halogroup is -CF3, -C2F5, -CHF2, -CCl3, -CHCl2, or -C2Cl5; C 1-3 The alkoxy group can be methoxy, ethoxy, n-propoxy, or isopropoxy.

[0137] In some specific embodiments of the present invention, in the compound of formula (I) above, R 4 For hydrogen, C 1-6 Alkyl or C 6-10 Aryl group, preferably H. Wherein, C 1-6 The alkyl group is methyl, ethyl, or propyl; C 6-10 The aryl group is phenyl, 1-naphthyl, or 2-naphthyl.

[0138] In some specific embodiments of the present invention, in the compound of formula (I) above, R 5 It can be hydrogen, halogen, cyano, nitro, trifluoromethyl, amino, C 1-6 Alkyl, C 2-8 alkenyl, C 6-10 Aryl, C l-8 Alkylamino, di(C) 2-8 Alkyl)amino, C 2-8 alkynyl group, C 1-8haloalkyl or C 3-8 cycloalkyl, preferably hydrogen. Wherein halo is -F, -Cl or -Br; C 1-6 alkyl is methyl, ethyl or propyl; C 2-8 alkenyl is ethenyl, propenyl, allyl or isopropenyl; C 6-10 aryl is phenyl, 1-naphthyl or 2-naphthyl; C l-8 alkylamino is methylamino, ethylamino or propylamino; di(C 2-8 alkyl)amino is dimethylamino, diethylamino or dipropylamino; C 2-8 alkynyl is ethynyl, propyn-1-yl or propyn-2-yl; C 1-8 haloalkyl is -CF3, -C2F5, -CHF2, -CC13, -CHC12 or -C2C15; C 3-8 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclopentenyl.

[0139] In some specific embodiments of the present application, in the above-mentioned compound of formula (I), each R 6 is each independently hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 6-10 aryl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl, preferably hydrogen, C 1-8 alkyl, C 6-10 aryl or C 3-10 cycloalkyl. Wherein C 1-8 alkyl is methyl, ethyl or propyl, preferably methyl or ethyl; C 2-8 alkenyl is ethenyl, propenyl, allyl or isopropenyl; C 2-8 alkynyl is ethynyl, propyn-1-yl or propyn-2-yl; C 1-8 haloalkyl is -CF3, -C2F5, -CHF2, -CC13, -CHC12 or -C2C15; C 6-10 aryl is phenyl, 1-naphthyl or 2-naphthyl, preferably phenyl; C 6-10aryl is a substituted phenyl, 1-naphthyl or 2-naphthyl, which can be substituted with halogen, hydroxy, carbon-based (such as carboxy, alkoxy carbon-based, formyl or acyl), sulfur carbon-based (such as thioester, thioacetate or thiocarbamate), alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, phosphoryl, phosphate, phosphonate, phosphinite, amino, alkylamino, dialkylamino, amide, amidine, imine, cyano, nitro, azido, mercapto, alkylthio, sulfate, sulfonate, sulfonamide, sulfamide, sulfonyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl moiety; C 3-10 cycloalkyl is cyclopropyl, cyclobutyl or cyclopentyl, preferably cyclopropyl; 5- to 10-membered heteroaryl is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl or oxazolyl; 4- to 10-membered heterocycloalkyl is pyrrolinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyranyl, morpholine N-oxide, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, phthalimido, piperidinonyl, oxazolidinonyl, 2,4-(1H,3H)-dioxo-pyrimidinyl or pyridin-2(1H)-onyl.

[0140] In some embodiments of the present application, in the above-mentioned compound of formula (I), two R 6 and the carbon atom to which they are attached together form a C 3-8 cycloalkyl or 4- to 10-membered heterocycloalkyl, preferably C 3-8 cycloalkyl. Among them, the 4- to 10-membered heterocycloalkyl contains 1 to 3 ring-forming heteroatoms, which are N, O or S. C 3-8 cycloalkyl and 4- to 10-membered heterocycloalkyl are each independently optionally substituted with 1 to 4 substituents, each independently halogen, cyano, hydroxy, amino, C 1-8 carboxamide, C 1-8 carboxyl, C 1-8 alkyl or C 1-8 alkoxy; wherein C 3-8 cycloalkyl is cyclopropyl, cyclobutyl or cyclopentyl, preferably cyclopropyl; 4- to 10-membered heterocycloalkyl is pyrrolinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyranyl, morpholine N-oxide, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, phthalimido, piperidinonyl, oxazolidinonyl, 2,4-(1H,3H)-dioxo-pyrimidinyl or pyridin-2(1H)-onyl; C 1-8 carboxamide is formamide or acetamide; C 1-8 carboxyl is formyl or acetyl; C 1-8 alkyl is methyl, ethyl or propyl; C 1-8Alkoxy is methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy or n-pentoxy.

[0141] In some embodiments of the application, each R 7 is hydrogen, halogen, amino, cyano, C 1-8 alkyl, substituted C 1-8 alkyl, C 1-8 alkoxy, substituted C l-8 alkoxy, C l-8 alkylamino, di(C 2-8 alkyl)amino, C 2-8 alkenyl, substituted C 2-8 alkenyl, C 2-8 alkynyl, substituted C 2-8 alkynyl, C 6-10 aryl, substituted C 6-10 aryl, C 3-8 cycloalkyl, substituted C 3-8 cycloalkyl, 3- to 10-membered heterocycloalkyl, substituted 3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl or substituted 5- to 10-membered heteroaryl, preferably hydrogen, halogen, C 1-8 alkyl, C 6-10 aryl, substituted C 6-10 aryl, 3- to 10-membered heterocycloalkyl or substituted 3- to 10-membered heterocycloalkyl, more preferably hydrogen, C 6-10 aryl, substituted C 6-10 aryl, 3- to 10-membered heterocycloalkyl or substituted 3- to 10-membered heterocycloalkyl. Wherein halogen is -F, -Cl or -Br; C 1-8 alkyl is methyl, ethyl or propyl; C 1-8 alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy or n-pentoxy; C l-8 alkylamino is methylamino, ethylamino or propylamino; di(C 2-8 alkyl)amino is dimethylamino, diethylamino or dipropylamino; C 2-8 alkenyl is ethenyl, propenyl, allyl or isopropenyl; C 2-8 alkynyl is ethynyl, propyn-1-yl or propyn-2-yl; C 6-10 aryl is phenyl, 1-naphthyl or 2-naphthyl; C 3-8Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclopentenyl; 3- to 10-membered heterocycloalkyl is pyrrolinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl or pyranyl; 5- to 10-membered heteroaryl is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl or oxazolyl; wherein the substituted C 1-8 Alkyl, substituted C l-8 Alkoxy, substituted C 2-8 Alkenyl, substituted C 2-8 Alkynyl, substituted C 6-10 Aryl, substituted C 3-8 Cycloalkyl, 3- to 10-membered heterocycloalkyl and 5- to 10-membered heteroaryl, substituted with a substituent, are the above C 1-8 Alkyl, C l-8 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 6-10 Aryl, C 3-8 Cycloalkyl, 3- to 10-membered heterocycloalkyl and 5- to 10-membered heteroaryl, substituted with a substituent, are the above C

[0142] In some specific embodiments of the present application, the above-mentioned compound of formula (I) has a structure represented by formula (II):

[0143]

[0144] wherein X, Y, Z, m, L, R 2 and R 3 are defined as in formula (I).

[0145] In some specific embodiments of the present application, the above-mentioned compound of formula (II) has a structure represented by formula (III):

[0146]

[0147] wherein Z, m, L, R 2 and R 3 are defined as in formula (II).

[0148] In some embodiments of the application, the compound of formula (III) has the structure of formula (III-1):

[0149]

[0150] wherein Z, L, R 2 , R 3 and R 6 are as defined in formula (III).

[0151] In some embodiments of the application, the compound of formula (III-1) has the structure of formula (III-1-1):

[0152]

[0153] wherein R 2 , R 3 and R 6 are as defined in formula (III-1), and R 7 is hydrogen, C 1-4 alkyl, piperazinyl, piperidinyl or morpholinyl, wherein each of said C 1-4 alkyl, piperazinyl, piperidinyl and morpholinyl is optionally substituted with at least one R 8 , each R 8 is independently hydrogen, C 1-4 alkyl (preferably methyl or ethyl), morpholinyl, bridged morpholinyl, piperazinyl, substituted piperazinyl, bridged piperazinyl, substituted bridged piperazinyl, oxetanyl or substituted oxetanyl, said substituents being C 1-4 alkyl (preferably methyl or ethyl).

[0154] In some embodiments of the application, the compound of formula (III-1-1), R 2 , R 3 and R 6 are as defined in formula (III-1), and R 7 is hydrogen, C 1-4 alkyl, piperazinyl, piperidinyl or morpholinyl, wherein each of said C 1-4 alkyl, piperazinyl, piperidinyl and morpholinyl is optionally substituted with at least one R 8 , each R 8 is independently hydrogen, morpholinyl, bridged morpholinyl, piperazinyl, substituted piperazinyl, bridged piperazinyl, substituted bridged piperazinyl, oxetanyl or substituted oxetanyl, said substituents being C 1-4 alkyl.

[0155] In some embodiments of the application, in the compound of formula (III-1-1), R 2 , R 3 and R 6 are as defined in formula (III-1), and R 7 is one of the following moieties:

[0156]

[0157] In some embodiments of the application, the compound of formula (III) has the structure of formula (III-2):

[0158]

[0159] wherein Z, L, R 2 and R 3 are as defined in formula (III).

[0160] In some embodiments of the application, the compound of formula (III-2) has the structure of formula (III-2-1):

[0161]

[0162] wherein R 2 , R 3 and R 6 are as defined in formula (III-2).

[0163] In some embodiments of the application, the compound of formula (III-2) has the structure of formula (III-2-2):

[0164]

[0165] wherein R 2 , R 3 and R 6 are as defined in formula (III-2).

[0166] In some embodiments of the application, the compound of formula (II) has the structure of formula (IV):

[0167]

[0168] wherein Z, m, L, R 2 and R 3 are as defined in formula (II).

[0169] In some embodiments of the application, the compound of formula (IV) has the structure of formula (IV-1):

[0170]

[0171] Among them, Z, L, R 2 and R 3 The definition is as defined in equation (IV).

[0172] In some specific embodiments of the present invention, the compound of formula (IV-1) has the structure shown in formula (IV-1-1):

[0173]

[0174] Among them, R 2 R 3 and R 6 As defined in equation (IV-1), R 7 For hydrogen, C 1-4 alkyl, piperazine, piperidinyl, or morpholinyl, wherein the C 1-4 Alkyl, piperazine, piperidinyl, and morpholino groups are each optionally surrounded by at least one R 8 Replace, each R 8 Each of the following groups is independently hydrogen, morpholino, bridged morpholino, piperazine, a substituent-containing piperazine, a bridged morpholino, a substituent-containing bridged morpholino, an oxecyclobutane, or a substituent-containing oxecyclobutane, wherein the substituent is C. 1-4 alkyl.

[0175] In some specific embodiments of the present invention, in the compound of formula (IV-1-1), R 2 R 3 and R 6 As defined in equation (IV-1), R 7 It is one of the following segments:

[0176]

[0177] In some specific embodiments of the present invention, the compound of formula (IV) has the structure shown in formula (IV-2):

[0178]

[0179] Among them, Z, L, R 2 and R 3 The definition is as defined in equation (IV).

[0180] In some specific embodiments of the present invention, the compound of formula (IV-2) has the structure shown in formula (IV-2-1):

[0181]

[0182] wherein R 2 , R 3 and R 6 are as defined in formula (IV-2), R 7 is hydrogen, C 1-4 alkyl or

[0183] In some embodiments of the present application, the compound of formula (IV-2) above has a structure represented by formula (IV-2-2):

[0184]

[0185] wherein R 2 , R 3 and R 6 are as defined in formula (IV-2).

[0186] In some more preferred embodiments of the present application, the compound is any one of:

[0187]

[0188]

[0189]

[0190]

[0191] [Pharmaceutical composition]

[0192] The present application also provides a pharmaceutical composition comprising the above-mentioned compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof.

[0193] In some embodiments of the present application, the above-mentioned pharmaceutical composition further comprises a pharmaceutically acceptable carrier or diluent.

[0194] In some preferred embodiments of the present application, the above-mentioned pharmaceutical composition further comprises:

[0195] - a pharmaceutically acceptable carrier; and / or

[0196] - an excipient.

[0197] The term "pharmaceutically acceptable carrier" refers to a pharmaceutical adjuvant that is compatible with the pharmaceutical active ingredient and is not harmful to the subject, including (but not limited to) diluents (or fillers), binders, disintegrants, lubricants, wetting agents, thickening agents, glidants, flavoring agents, odorizing agents, preservatives, antioxidants, pH adjusting agents, solvents, co-solvents, and surfactants, etc.

[0198] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose.

[0199] [Pharmaceutical preparation]

[0200] The present application provides a pharmaceutical preparation comprising the above-mentioned compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof or a pharmaceutical composition.

[0201] In some embodiments of the present application, the pharmaceutical preparation is any one of a tablet, a capsule, an injection, a granule, a powder, a suppository, a pill, a gel, a powder, an oral solution, an inhalant, a suspension or a dry suspension.

[0202] [Medical use]

[0203] Regardless of whether it is the above-mentioned compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof or a pharmaceutical composition, or a pharmaceutical preparation, it can exhibit FGFR4 activity inhibition, and thus the present application provides the above-mentioned compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof or the above-mentioned pharmaceutical composition or the above-mentioned pharmaceutical preparation, which is used as an FGFR4 inhibitor.

[0204] The present application also provides the use of the above-mentioned compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof or the above-mentioned pharmaceutical composition or the above-mentioned pharmaceutical preparation in the preparation of a medicament for preventing and / or treating a disease mediated at least in part by FGFR4.

[0205] In some embodiments of the present application, the disease mediated at least in part by FGFR4 includes cancer.

[0206] In some embodiments of the application, the cancer is selected from hepatocellular carcinoma, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myelogenous leukemia, Hodgkin's or non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, hairy cell lymphoma, Burkitt's lymphoma, glioblastoma, melanoma, mesothelioma, neuroblastoma, testicular cancer, squamous cell carcinoma, glioblastoma, and rhabdomyosarcoma.

[0207] [Therapeutic methods]

[0208] The present application also provides a method for preventing and / or treating a disease mediated at least in part by FGFR4, comprising the step of administering to a patient in need thereof a prophylactically and / or therapeutically effective amount of a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, chelate, non-covalent complex, or prodrug thereof, or a pharmaceutical composition or a pharmaceutical preparation described above.

[0209] The amount of the compound, pharmaceutical composition, or pharmaceutical preparation administered to a patient will vary depending on the drug administered, the purpose of the administration (e.g., prophylactic or therapeutic), the state of the patient, the mode of administration, and the like. In therapeutic applications, the compositions can be administered to a patient already suffering from the disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The therapeutically effective amount will be governed by such factors as the disease state, the age, body weight, and general health of the patient, and the like, and will be ultimately at the discretion of the attending clinician.

[0210] The present application also provides a method for preventing and / or treating cancer, comprising the step of administering to a patient in need thereof a prophylactically and / or therapeutically effective amount of a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, chelate, non-covalent complex, or prodrug thereof, or a pharmaceutical composition or a pharmaceutical preparation described above, and at least one additional cancer therapeutic agent.

[0211] In some embodiments of the present application, the cancer is selected from hepatocellular carcinoma, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myeloid leukemia, Hodgkin's or non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, hairy cell lymphoma, Burkitt's lymphoma, glioblastoma, melanoma, mesothelioma, neuroblastoma, testicular cancer, squamous cell carcinoma, glioblastoma, and rhabdomyosarcoma.

[0212] [Pharmaceutical combination]

[0213] The present application provides a pharmaceutical combination comprising the above-mentioned compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof, or a pharmaceutical composition comprising the above-mentioned compound, or a pharmaceutical preparation comprising the above-mentioned compound, and at least one additional cancer therapeutic agent.

[0214] [Preparation method]

[0215] The present application provides a preparation method of the above-mentioned compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof, and a typical synthesis route of the compound of general formula (I) is described below to further describe the technical solutions of the present application.

[0216] Preparation scheme of intermediate A5

[0217] The intermediate A5 can be prepared by the following scheme, and the specific synthesis route is as follows:

[0218]

[0219] In the above scheme, the starting material A1 is reacted with a primary amine with a protecting group to obtain the intermediate A2, the intermediate A2 is substituted with an alkoxy group to obtain the intermediate A3, the intermediate A3 is deprotected to obtain the intermediate A4, and the intermediate A4 is reacted with 4,6-dichlorobenzaldehyde (X is CH) or 2,4-dichloropyrimidine-5-carbaldehyde (X is N) to obtain the intermediate A5. Among them, the starting material A1 is obtained by commercialization.

[0220] Preparation scheme of intermediate A8

[0221] The synthesis route of the intermediate A8 is as follows:

[0222]

[0223] Intermediate A6 can be prepared by treating intermediate A5 with ethylmalonyl chloride under alkaline conditions. Under strongly alkaline conditions, intermediate A6 undergoes intramolecular cyclization to give intermediate A7, which is then subjected to acid (such as HCl)-mediated decarboxylation to prepare intermediate A8.

[0224] Preparation scheme of compound A13

[0225] The synthetic route for compound A13 is as follows:

[0226]

[0227] Under alkaline conditions, intermediate A8 can react with R... 6 The reaction of X (where X is a halogenated group, such as Cl, Br, or I) yields a product containing R. 6 Intermediate A9 (the need for alkylation depends on the synthetic requirements; if alkylation is not needed, proceed directly to the next step). Under Zn(CN)₂ as the reactant and palladium as the catalyst, intermediate A9 is converted to intermediate A10. The cyano group in intermediate A10 can be reduced under nickel chloride hexahydrate / NaBH₄ conditions to obtain intermediate A11 where Y represents an oxygen atom, or when intermediate A10 is treated with BH₃·THF, both the carbon and cyano groups are reduced simultaneously to obtain intermediate A11 where Y represents two hydrogen atoms. Intermediate A11 reacts with acyl chloride A12 at low temperature to give compound A13.

[0228] Preparation scheme of compound A18

[0229] The synthetic route for compound A18 is as follows:

[0230]

[0231] Compound A9 was treated with BH3·THF to obtain intermediate A14 (whether a reduction reaction is required depends on the synthetic needs; if not, proceed directly to the next step). Intermediate A14 and intermediate A15 underwent Suzuki coupling with [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride as a catalyst to obtain intermediate A16. Intermediate A16 reacted with acyl chloride A17 at low temperature to give compound A18.

[0232] Preparation scheme of compound A25

[0233] The synthetic route for compound A25 is as follows:

[0234]

[0235] Under alkaline conditions, R is added to the solution of A19. 6X (X is halogen, such as Cl, Br or I) to obtain compound A20 (determine whether the alkylation reaction is needed according to the synthesis requirement, if not, directly proceed to the next step). When BH3-THF is used as the reducing agent, the carbon group of A20 can be reduced to methylene to obtain compound A21 (if the reduction reaction is not needed, skip this step and directly proceed to the next step). Compound A21 is coupled with A22 to obtain compound A23. The nitro group in compound A23 can be reduced to obtain A24. Compound A25 can be smoothly obtained by adding acyl chloride dropwise to the solution of A24 under low temperature condition. 6 - of compound A20 (determine whether the alkylation reaction is needed according to the synthesis requirement, if not, directly proceed to the next step). When BH3-THF is used as the reducing agent, the carbon group of A20 can be reduced to methylene to obtain compound A21 (if the reduction reaction is not needed, skip this step and directly proceed to the next step). Compound A21 is coupled with A22 to obtain compound A23. The nitro group in compound A23 can be reduced to obtain A24. Compound A25 can be smoothly obtained by adding acyl chloride dropwise to the solution of A24 under low temperature condition.

[0236] Preparation scheme of compound A30

[0237] The synthesis route of compound A30 is as follows:

[0238]

[0239] Compound A5 is coupled with amine under the condition of palladium as catalyst to obtain compound A26. Compound A26 is intramolecularly cyclized under the action of triphosgene to obtain compound A27. Intermediate A27 is converted into intermediate A28 under the condition of Zn(CN)2 as reaction reagent and palladium as catalyst. Intermediate A28 is reduced to intermediate A29, and intermediate A29 is reacted with acyl chloride A12 under low temperature to obtain compound A30.

[0240] Example 1: Synthesis of N-((2'-(3,5-difluoro-2,6-dimethoxy-pyridin-4-yl)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-6'-yl)methyl)acrylamide (Compound 1)

[0241] The synthesis route is as follows:

[0242]

[0243] Step 1: Synthesis of intermediate 1-1

[0244] Pentafluoropyridine (3.6 g, 21.30 mmol) was added to acetonitrile (150 mL) under stirring at room temperature, then benzylamine (4.5 g, 42.00 mmol) was added, and the stirring was continued at room temperature for 1 hour, and the reaction was warmed to 60 °C. After 3 hours, the reaction was cooled to room temperature, and concentrated under reduced pressure. DCM (100 mL) and water (100 mL) were added to the concentrate, and the solution was stirred, layered, and the organic phase was collected. The organic phase was washed once with saturated NaCl solution (100 mL), dried over anhydrous Na2SO4, and concentrated to obtain white solid product (5.3 g, 20.69 mmol), with a yield of 97.1%.

[0245] The identification data of the specific compound are as follows:

[0246] LC-MS: m / z 257.1 [M+H] + (Calculated value 257.1, C 12 H8F4N2).

[0247] Step 2: Synthesis of intermediate 1-2

[0248] Sodium methoxide (28.5 g, 527.54 mmol) was added to stirring anhydrous methanol (250 mL) at room temperature, then intermediate 1-1 (9.0 g, 35.13 mmol) was added, the resulting mixture was warmed to 60 °C and reacted for 12 hours, after which the reaction was cooled to room temperature, quenched with glacial acetic acid (31.6 g, 526.23 mmol), and concentrated. Water (600 mL) and DCM (300 mL) were added to the residue, stirred to dissolve, the layers were separated, the organic phase was collected, the aqueous phase was extracted once more with DCM (300 mL), the combined organic phases were washed with water (3 x 300 mL), dried over anhydrous Na2SO4, and concentrated to obtain the desired product (9.5 g, 33.89 mmol) with a yield of 96.5%.

[0249] The identification data of the specific compound are as follows:

[0250] LC-MS: m / z 281.1 [M+H] + (Calculated value 281.1, C 14 H 14 F2N2O2).

[0251] Step 3: Synthesis of intermediate 1-3

[0252] Intermediate 1-2 (3.0 g, 10.71 mmol) was added to stirring acetic acid (60 mL) at room temperature, then Pd(OH)2(0.6 g, 4.28 mmol) was added, replaced with H2three times, protected with an H2balloon, and stirred at room temperature for 4 hours. The reaction was filtered and concentrated to obtain the acetate salt of the desired product (2.1 g, 8.60 mmol) with a yield of 80.3%.

[0253] The identification data of the specific compound are as follows:

[0254] LC-MS: m / z 191.1 [M+H] + (Calculated value 191.1, C7H8F2N2O2).

[0255] Step 4: Synthesis of intermediate 1-4

[0256] To a stirred solution of intermediate 1-3 acetate salt (10.6 g, 42.37 mmol) and 4,6-dichlorobenzaldehyde (6.0 g, 34.09 mmol) in toluene (70 mL) was added glacial acetic acid (3 mL) and anhydrous magnesium sulfate (24.0 g, 199.40 mmol) at room temperature and the resulting mixture was warmed to 110 °C. After 24 h, the reaction was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure. To the resulting concentrate was added DCM (70 mL) and stirred to dissolve, then trifluoroacetic acid (11.7 g, 102.61 mmol) was added and the temperature was lowered to -5-0 °C. To the reaction was slowly added sodium triacetoxyborohydride (26.5 g, 125.04 mmol). After stirring the reaction at room temperature for 4 h, it was quenched with saturated aqueous NH4Cl and extracted with DCM (3 x 100 mL), the organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified on silica gel (eluting with 0-5% (v / v) EtOAc in hexanes) to give the desired product (10.3 g, 29.42 mmol), yield: 69.4%.

[0257] The characterization data for the specific compound are as follows:

[0258] LC-MS: m / z 463.9 [M+H] + (Calculated: 464.1, C 13 H 11 Cl2F2N3O5).

[0259] Step 5: Synthesis of intermediate 1-5

[0260] To a stirred solution of intermediate 1-4 (5.0 g, 14.28 mmol) in tetrahydrofuran (25 mL) was added NaH (60% w / w in mineral oil, 600.0 mg, 15.0 mmol) at room temperature. After 10 min, ethyl malonyl chloride (2.64 mL, 18.68 mmol) was added dropwise. After the addition was complete, the reaction was stirred for 4 h, quenched with saturated aqueous NH4Cl and extracted with EA (2 x 100 mL), the organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified on silica gel (eluting with 0-20% (v / v) EtOAc in hexanes) to give the desired product (5.7 g, 12.28 mmol), yield: 86.0%.

[0261] The characterization data for the specific compound are as follows:

[0262] LC-MS: m / z 463.9 [M+H] + (Calculated: 464.1, C 18 H 17 Cl2F2N3O5).

[0263] Step 6: Synthesis of Intermediate 1-6

[0264] Intermediate 1-5 (3.0 g, 6.46 mmol) was added to a stirred solution of DMF (100 mL) at room temperature, followed by potassium phosphate (9.0 g, 42.40 mmol), and the resulting mixture was then warmed to 90 °C. After 6 h, the reaction was cooled to room temperature, 2% aqueous acetic acid (100 mL) was added to quench the reaction, and the organic layers were combined, dried over Na2S04, and concentrated. The residue was purified on silica gel (eluting with 0-20% (v / v) EtOAc in hexanes) to give the desired product (1.5 g, 3.51 mmol) in 54.3% yield.

[0265] The identification data of the specific compound are as follows:

[0266] LC-MS: m / z 428.0 [M+H] + (Calculated 428.1, C 18 H 16 CIF2N3O5).

[0267] Step 7: Synthesis of Intermediate 1-7

[0268] Intermediate 1-6 (120 mg, 0.28 mmol) was added to a stirred solution of 1,4-dioxane (6 mL) at room temperature, followed by concentrated hydrochloric acid (4 mL), and the resulting mixture was then warmed to 100 °C. After 1 h, the reaction was cooled to room temperature, quenched with saturated aqueous NaHC03, and extracted with EA (2 x 100 mL), and the organic layers were combined, dried over Na2S04, and concentrated. The residue was purified on silica gel (eluting with 0-25% (v / v) EtOAc in hexanes) to give the desired product (62.3 mg, 0.18 mmol) in 62.5% yield.

[0269] The identification data of the specific compound are as follows:

[0270] LC-MS: m / z 356.0 [M+H] + (Calculated 356.1, C 15 H 12 CIF2N3O3).

[0271] Step 8: Synthesis of Intermediate 1-8

[0272] Intermediate 1-7 (2.6 g, 7.31 mmol) was added to DMF (45 mL) stirred at room temperature, followed by the addition of cesium carbonate (5.2 g, 15.95 mmol) and 1-bromo-2-chloroethane (12.1 mL, 140.48 mmol) successively. After 2 h, the reaction was quenched with saturated aqueous NH4Cl and extracted with EA (2 x 100 mL), the combined organic layers were dried over Na2SO4 and concentrated. The residue was purified on silica gel (eluting with 0-20% (v / v) EtOAc in hexanes) to give the desired product (2.0 g, 5.23 mmol) in 71.7% yield.

[0273] The identification data of the specific compound are as follows:

[0274] LC-MS: m / z 382.0 [M+H] + (Calculated 382.1, C 17 H 14 ClF2N3O3).

[0275] Step 9: Synthesis of intermediate 1-9

[0276] A reaction mixture of intermediate 1-8 (150 mg, 0.39 mmol), zinc cyanide (100 mg, 0.85 mmol), zinc powder (14.3 mg, 0.22 mmol), Pd2(dba)3 (40 mg, 0.04 mmol) and DPPF (47 mg, 0.08 mmol) in N,N-dimethylformamide (3 mL) was stirred at 130 °C under N2atmosphere for 2 h. The reaction was cooled to room temperature, quenched with saturated aqueous NaHCO3and extracted with ethyl acetate (3 x 50 mL), the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (eluting with 0-20% (v / v) EtOAc in hexanes) to give the desired product (115 mg, 0.31 mmol) in 79.2% yield.

[0277] The identification data of the specific compound are as follows:

[0278] LC-MS: m / z 373.0 [M+H] + (Calculated 373.1, C 18 H 14 F2N4O3).

[0279] Step 10: Synthesis of intermediate 1-10

[0280] To a stirred solution of intermediate 1-9 (60 mg, 0.16 mmol), nickel chloride hexahydrate (7.7 mg, 0.03 mmol) and trifluoroacetic acid (147 mg, 1.29 mmol) in anhydrous methanol (6 mL) was added sodium borohydride (182.9 mg, 4.83 mmol) slowly at room temperature under N2atmosphere. After stirring at room temperature for 4 h, the reaction was filtered and concentrated to get the desired product (54.0 mg, 0.14 mmol) in 87.5% yield.

[0281] The characterization data of the specific compound are as follows:

[0282] LC-MS: m / z 377.1 [M+H] + (Calculated 377.1, C 18 H 18 F2N4O3).

[0283] Step 11: Synthesis of compound 1

[0284] To a stirred solution of intermediate 1-10 (54.0 mg, 0.14 mmol) and tetrahydrofuran (6 mL) was added acryloyl chloride (12.6 mg, 0.14 mmol) at 0-5 °C under N2atmosphere, warmed to room temperature, stirred for ten minutes, quenched with saturated aqueous NaHC03solution and extracted with ethyl acetate (3 x 50 mL), the combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified on silica gel eluting with 0-75% (v / v) EtOAc in hexane to get the desired product (27 mg, 0.06 mmol) in 44.8% yield.

[0285] The characterization data of the specific compound are as follows:

[0286] 1 H NMR (500 MHz, DMSO-d6): d 8.60 (t, J = 5.8 Hz, 1H), 8.37 (s, 1H), 6.93 (s, 1H), 6.33 (dd, J = 17.1, 10.2 Hz, 1H), 6.12 (dd, J = 17.1, 2.1 Hz, 1H), 5.62 (dd, J = 10.2, 2.2 Hz, 1H), 5.01 (s, 2H), 4.42 (d, J = 5.8 Hz, 2H), 3.99 (s, 6H), 1.77 (q, J = 4.0 Hz, 2H), 1.48 (q, J = 4.1 Hz, 2H).

[0287] LC-MS: m / z 431.0 [M+H] + (Calculated 431.2, C 21 H 20F2N4O4).

[0288] Example 2: Synthesis of N-(3-(2'-(3,5-difluoro-2,6-dimethoxy-pyridin-4-yl)-2',3'- dihydro-1'H-spiro[cyclopropyl-1,4'-[2,7]naphthyridin]-6'-yl)phenyl)acrylamide (Compound 2)

[0289] The synthetic route is as follows:

[0290]

[0291] Step 1: Synthesis of intermediate 2-1

[0292] Intermediate 1-8 (300 mg, 0.79 mmol) was added to borane tetrahydrofuran complex (7 mL) at 68 °C and stirred overnight. The reaction was cooled to room temperature, quenched with methanol, hydrochloric acid aqueous solution (1.3 ml, 1 mol / L) was added, re-warmed to 68 °C and stirred for 1 hour. The reaction was cooled to room temperature, quenched with saturated NaHC03 aqueous solution and extracted with ethyl acetate (2 x 15 mL), the organic phases were combined, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified on silica gel (eluted with 0-10% (v / v) EtOAc in hexane) to give the desired product (110 mg, 0.30 mmol) in 38.0% yield.

[0293] The identification data of the specific compound are as follows:

[0294] LC-MS: m / z 368.0 [M+H] + (Calculated 368.1, C 17 H 16 ClF2N3O2).

[0295] Step 2: Synthesis of intermediate 2-2

[0296] Intermediate 2-1 (60 mg, 0.16 mmol), 3-aminobenzenboronic acid (27 mg, 0.20 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (18 mg, 0.02 mmol) and Na2C03 (38 mg, 0.36 mmol) were added to tert-butanol (6 mL) and water (6 ml) at 90 °C under N2atmosphere and stirred for 1 hour. The reaction was quenched with saturated NH4CI aqueous solution and extracted with DCM (3 x 10 mL), the organic layers were combined, dried over Na2S04and concentrated to give the desired product (55.0 mg, 0.13 mmol) in 81.3% yield.

[0297] The identification data of the specific compound are as follows:

[0298] LC-MS: m / z 425.1 [M+H] + (Calculated 425.2, C 23 H 22 F2N4O2).

[0299] Step 3: Synthesis of compound 2

[0300] Intermediate 2-2 (55.0 mg, 0.13 mmol) was added to tetrahydrofuran (10 mL) under stirring at 0-5 °C under N2atmosphere, then acryloyl chloride (11.1 mg, 0.12 mmol) was added, warmed to room temperature, stirred for ten minutes, then quenched with saturated NaHC03aqueous solution, and extracted with DCM (2 x 20 mL), the combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was subjected to preparative separation purification to give the desired product (44 mg, 0.09 mmol) in 70.7% yield.

[0301] The identification data of the specific compound are as follows:

[0302] 1 H NMR (500 MHz, DMSO-d6): δ 10.26 (s, 1H), 8.41 (s, 1H), 8.29 (t, J = 2.0 Hz, 1H), 7.87-7.83 (m, 1H), 7.75 (dt, J = 8.0, 1.3 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.24 (s, 1H), 6.46 (dd, J = 17.0, 10.1 Hz, 1H), 6.28 (dd, J = 17.0, 2.0 Hz, 1H), 5.77 (dd, J = 10.1, 2.0 Hz, 1H), 4.70 (s, 2H), 3.90 (s, 6H), 3.48 (s, 2H), 1.23 (t, J = 4.5 Hz, 2H), 1.07 (q, J = 4.5 Hz, 2H).

[0303] LC-MS: m / z 479.1 [M+H] + (Calculated 479.2, C 26 H 24 F2N4O3).

[0304] Example 3: Synthesis of N-(2-((2'-(3,5-difluoro-2,6-dimethoxy-pyridin-4-yl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-6'-yl)amino)-5-morpholino- phenyl)acrylamide (Compound 3)

[0305] The synthesis route is as follows:

[0306]

[0307] Step 1: Synthesis of intermediate 3-1

[0308] Sodium methoxide (28.5 g, 527.54 mmol) was added to anhydrous methanol (250 mL) stirred at room temperature, then compound 3-1 (9.0 g, 35.13 mmol) was added, the resulting mixture was warmed to 60 °C. After 12 hours, the reaction was cooled to room temperature, quenched with glacial acetic acid (31.6 g, 526.23 mmol), the reaction was concentrated, water (600 mL) and DCM (300 mL) were added to the residue, stirred to dissolve, separated into layers, the organic phase was collected, the aqueous phase was extracted with DCM (300 mL) again, the organic phases were combined, washed with water (3 x 300 mL), dried over anhydrous Na2S04and concentrated to give the desired product (9.5 g, 33.89 mmol), yield: 96.5%.

[0309] The identification data of the specific compound are as follows:

[0310] LC-MS: m / z 281.1 [M+H] + (Calculated value 281.1, C 12 H + F2N2O2).

[0311] Step 3: Synthesis of intermediate 3-3

[0312] Sodium methoxide (28.5 g, 527.54 mmol) was added to anhydrous methanol (250 mL) stirred at room temperature, then compound 3-1 (9.0 g, 35.13 mmol) was added, the resulting mixture was warmed to 60 °C. After 12 hours, the reaction was cooled to room temperature, quenched with glacial acetic acid (31.6 g, 526.23 mmol), the reaction was concentrated, water (600 mL) and DCM (300 mL) were added to the residue, stirred to dissolve, separated into layers, the organic phase was collected, the aqueous phase was extracted with DCM (300 mL) again, the organic phases were combined, washed with water (3 x 300 mL), dried over anhydrous Na2S04and concentrated to give the desired product (9.5 g, 33.89 mmol), yield: 96.5%.

[0313] The identification data of the specific compound are as follows:

[0314] LC-MS: m / z 281.1 [M+H] + (Calculated value 281.1, C 14 H 14 F2N2O2).

[0315] Step 3: Synthesis of intermediate 3-3

[0316] Intermediate 3-2 (6.0 g, 21.41 mmol) was added to stirring acetic acid (120 mL) at room temperature, followed by Pd(OH)2(1.2 g, 8.55 mmol), purged with H2three times, protected with H2balloon, and stirred at room temperature for 4 h. The reaction was filtered and concentrated to give the desired product as an acetate salt (4.3 g, 17.19 mmol) in 80.3% yield.

[0317] The identification data of the specific compound are as follows:

[0318] LC-MS: m / z 191.1 [M+H] + (Calculated value 191.1, C7H8F2N2O2).

[0319] Step 4: Synthesis of intermediate 3-4

[0320] The acetate salt of intermediate 3-3 (10.6 g, 42.37 mmol) and 4,6-dichlorobenzaldehyde (6.0 g, 34.09 mmol) were added to stirring toluene (70 mL) at room temperature, followed by glacial acetic acid (3 mL) and anhydrous magnesium sulfate (24.0 g, 199.40 mmol), and the resulting mixture was warmed to 110 °C. After 24 h, the reaction was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. To the resulting concentrate was added DCM (70 mL), stirred to dissolve, and trifluoroacetic acid (11.7 g, 102.61 mmol) was added, and the temperature was lowered to -5-0 °C. To the reaction was slowly added sodium triacetoxyborohydride (26.5 g, 125.04 mmol). After the reaction was stirred at room temperature for 4 h, it was quenched with saturated aqueous NH4Cl and extracted with DCM (3 x 100 mL). The combined organic layers were dried over Na2SO4and concentrated. The residue was purified on silica gel (eluted with 0-5% (v / v) EtOAc in hexanes) to give the desired product (10.3 g, 29.42 mmol) in 69.4% yield.

[0321] The identification data of the specific compound are as follows:

[0322] LC-MS: m / z 349.9 [M+H] + (Calculated value 350.0, C 13 H 11 Cl2F2N3O2).

[0323] Step 5: Synthesis of intermediate 3-5

[0324] Intermediate 3-4 (5.0 g, 14.28 mmol) was added to stirring tetrahydrofuran (25 mL) at room temperature, followed by NaH (60% w / w in mineral oil, 600.0 mg, 15.0 mmol). After 10 minutes, ethyl malonyl chloride (2.64 mL, 18.68 mmol) was added dropwise. After 4 hours, the reaction was quenched with saturated aqueous NH4Cl and extracted with EA (2 x 100 mL), the organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified on silica gel (eluting with 0-20% (v / v) EtOAc in hexanes) to give the desired product (5.7 g, 12.28 mmol), yield: 86.0%.

[0325] The identification data for a specific compound are as follows:

[0326] LC-MS: m / z 463.9 [M+H]+ (calculated 464.1, C 18 H 17 Cl2F2N3O5).

[0327] Step 6: Synthesis of intermediate 3-6

[0328] Intermediate 3-5 (3.0 g, 6.46 mmol) was added to stirring DMF (100 mL) at room temperature, followed by potassium phosphate (9.0 g, 42.40 mmol), then the resulting mixture was warmed to 90 °C. After 6 hours, the reaction was cooled to room temperature, 2% aqueous acetic acid (100 mL) was added to quench the reaction, and extracted with EA (2 x 100 mL), the organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified on silica gel (eluting with 0-20% (v / v) EtOAc in hexanes) to give the desired product (1.5 g, 3.51 mmol), yield: 54.3%.

[0329] The identification data for a specific compound are as follows:

[0330] LC-MS: m / z 428.0 [M+H] + (calculated 428.1, C 18 H 16 ClF2N3O5).

[0331] Step 7: Synthesis of intermediate 3-7

[0332] Intermediate 3-6 (120 mg, 0.28 mmol) was stirred in 1,4-dioxane (6 mL) at room temperature, then concentrated HCl (4 ml) was added, the resulting mixture was warmed to 100 °C. After 1 h, the reaction was cooled to room temperature, quenched with saturated aqueous NaHC03solution, and extracted with EA (2 x 100 mL), the combined organic layers were dried over Na2S04and concentrated. The residue was purified on silica gel (eluting with 0-25% (v / v) EtOAc in hexanes) to give the desired product (62.3 mg, 0.18 mmol), yield: 62.5%.

[0333] The identification data for a specific compound are as follows:

[0334] LC-MS: m / z 356.0 [M+H] + (Calculated 356.1, C 15 H 12 CIF2N3O3).

[0335] Step 8: Synthesis of intermediate 3-8

[0336] Intermediate 3-7 (2.6 g, 7.31 mmol) was added to DMF (45 mL) and stirred at room temperature, then cesium carbonate (5.2 g, 15.95 mmol) and 1-bromo-2-chloroethane (12.1 mL, 140.48 mmol) were added sequentially. After 2 h, the reaction was quenched with saturated aqueous NH4C1 solution, and extracted with EA (2 x 100 mL), the combined organic layers were dried over Na2S04and concentrated. The residue was purified on silica gel (eluting with 0-20% (v / v) EtOAc in hexanes) to give the desired product (2.0 g, 5.23 mmol), yield: 71.7%.

[0337] The identification data for a specific compound are as follows:

[0338] LC-MS: m / z 382.0 [M+H] + (Calculated 382.1, C 17 H 14 CIF2N3O3).

[0339] Step 9: Synthesis of intermediate 3-9

[0340] To a sealed tube containing intermediate 3-8 (250 mg, 0.65 mmol) was added 1.0 mol / L borane tetrahydrofuran complex (5.3 mL, 5.3 mmol) at room temperature. The resulting mixture was warmed to 67 °C and stirred for 12 h. It was quenched with methanol, acidified with hydrochloric acid solution (1 mL, 1 mol / L), warmed to 67 °C and stirred for 1 h before cooling to room temperature. The pH was adjusted to pH > 7 with saturated aqueous NaHC03solution and the mixture was extracted with EA (2 x 15 mL). The combined organic layers were dried over Na2S04and concentrated. The residue was purified on silica gel (eluting with 0-10% (v / v) EtOAc in hexanes) to give the desired product (134 mg, 0.36 mmol) in 55.6% yield.

[0341] The identification data of the specific compound are as follows:

[0342] LC-MS: m / z 368.0 [M+H] + (Calculated 368.1, C 17 H 16 CIF2N302).

[0343] Step 10: Synthesis of intermediate 3-10

[0344] Intermediate 3-9 (60 mg, 0.16 mmol), 4-morpholinyl-2-nitroaniline (43.8 mg, 0.20 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-triisopropyl-11'- biphenyl (9.0 mg, 0.02 mmol), Pd2(dba)3(15.0 mg, 0.02 mmol) and sodium tert-butoxide (31.3 mg, 0.33 mmol) were added to toluene (6 mL) and stirred at 110 °C for 3 h under N2atmosphere. The reaction was cooled to room temperature, filtered and concentrated. The residue was purified on silica gel (eluting with 0-20% (v / v) EtOAc in hexanes) to give the desired product (40 mg, 0.07 mmol) in 45.0% yield.

[0345] The identification data of the specific compound are as follows:

[0346] LC-MS: m / z 555.2 [M+H] + (Calculated 555.2, C 27 H 28 F2N605).

[0347] Step 11: Synthesis of intermediate 3-11

[0348] Intermediate 3-10 (34 mg, 0.06 mmol) was added to THF (4 mL) stirred at room temperature under N2atmosphere, followed by the addition of zinc powder (260.6 mg, 3.99 mmol) and 9% aqueous ammonium chloride solution (2.1 mL) successively. After 1 h, the reaction was filtered, the filtrate was dried over Na2SO4and concentrated to give the desired product (27.2 mg, 0.05 mmol).

[0349] The identification data of the specific compound are as follows:

[0350] LC-MS: m / z 525.3 [M+H] + (Calculated value 525.2, C 27 H 30 F2N6O3).

[0351] Step 12: Synthesis of compound 3

[0352] Intermediate 3-11 (27.2 mg, 0.05 mmol) was added to tetrahydrofuran (3 mL) stirred at 0-5 °C under N2atmosphere, followed by the addition of acryloyl chloride (4.53 mg, 0.05 mmol), warmed to room temperature, stirred for 10 min, quenched with saturated aqueous NaHCO3solution, and extracted with ethyl acetate (3 x 50 mL), the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (eluted with 0-50% (v / v) EtOAc in hexanes) to give the desired product (7 mg, 0.01 mmol), yield: 24.2%.

[0353] The identification data of the specific compound are as follows:

[0354] LC-MS: m / z 579.2 [M+H] + (Calculated value 579.3, C 30 H 32 F2N6O4).

[0355] Example 4: Synthesis of N-(2-((2'-(3,5-difluoro-2,6-dimethoxy-pyridin-4-yl)-2',3'- dihydro-1'H-spiro[cyclopropane-1,4'-[2,7]naphthridin]-6'-yl)amino)-4-morpholinophenyl) acrylamide (Compound 4)

[0356] The synthesis route is as follows:

[0357]

[0358] Step 1: Synthesis of intermediate 4-1

[0359] Intermediate 4-1 was prepared in analogy to the procedure described in Example 3, Step 10.

[0360] The identification data of the specific compound are as follows:

[0361] LC-MS: m / z 555.2 [M+H] + (Calculated 555.2, C 27 H 28 F2N6O5).

[0362] Step 2: Synthesis of intermediate 4-2

[0363] Intermediate 4-2 was prepared in analogy to the procedure described in Example 3, Step 11.

[0364] The identification data of the specific compound are as follows:

[0365] LC-MS: m / z 525.3 [M+H] + (Calculated 525.2, C 27 H 30 F2N6O3).

[0366] Step 3: Synthesis of compound 4

[0367] Compound 4 was prepared in analogy to the procedure described in Example 3, Step 12.

[0368] The identification data of the specific compound are as follows:

[0369] 1 H NMR (500 MHz, DMSO-d6): δ 9.64 (s, 1H), 7.98 - 7.94 (m, 2H), 7.39 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 2.8 Hz, 1H), 6.71 (dd, J = 8.8, 2.8 Hz, 1H), 6.47 (dd, J = 17.0, 10.2 Hz, 1H), 6.26 (dd, J = 17.0, 2.0 Hz, 1H), 6.23 (s, 1H), 5.75 (dd, J = 10.2, 2.0 Hz, 1H), 4.59 (s, 2H), 3.95 (s, 6H), 3.79 (d, J = 4.4 Hz, 4H), 3.46 (s, 2H), 3.14 - 3.08 (m, 4H), 1.08 - 1.03 (m, 2H), 0.99 - 0.94 (m, 2H).

[0370] LC-MS: m / z 579.2 [M+H] + (Calculated 579.3, C 30 H 32 F2N6O4).

[0371] Example 5: Synthesis of N-(2-((2'-(3,5-difluoro-2,6-dimethoxy-pyridin-4-yl)-3'- oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-6'-yl)-amino)-5-(4- morpholinopiperidin-1-yl)phenyl)acrylamide (Compound 5)

[0372] The synthesis route is as follows:

[0373]

[0374] Step 1: Synthesis of Intermediate 5-1

[0375] Intermediate 5-1 was prepared similarly to the method of Example 3, Step 10.

[0376] The identifying data of the specific compound are as follows:

[0377] LC-MS: m / z 652.2 [M+H] + (Calculated 652.3, C 32 H 35 F2N7O6).

[0378] Step 2: Synthesis of Intermediate 5-2

[0379] Intermediate 5-2 was prepared similarly to the method of Example 3, Step 11.

[0380] The identifying data of the specific compound are as follows:

[0381] LC-MS: m / z 622.3 [M+H] + (Calculated 622.3, C 32 H 37 F2N7O4).

[0382] Step 3: Synthesis of Compound 5

[0383] Compound 5 was prepared similarly to the method of Example 3, Step 12.

[0384] The identifying data of the specific compound are as follows:

[0385] LC-MS: m / z 676.2 [M+H] + (Calculated 676.3, C 35 H 39 F2N7O5).

[0386] Example 6: Synthesis of N-(2-((2'-(3,5-difluoro-2,6-dimethoxy-pyridin-4-yl)-3'- oxo-2',3'-dihydro-1 'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-6'-yl)-amino)-4-(4- morpholinopiperidin-1 -yl)phenyl)acrylamide (Compound 6)

[0387] The synthesis route is as follows:

[0388]

[0389] Step 1 : Synthesis of intermediate 6-1

[0390] Intermediate 6-1 was prepared similarly to the method of Example 3, Step 10.

[0391] The identifying data of the specific compound are as follows:

[0392] LC-MS: m / z 652.2 [M+H] + (Calculated 652.3, C 32 H 35 F2N7O6).

[0393] Step 2: Synthesis of intermediate 6-2

[0394] Intermediate 6-2 was prepared similarly to the method of Example 3, Step 11.

[0395] The identifying data of the specific compound are as follows:

[0396] LC-MS: m / z 622.2 [M+H] + (Calculated 622.3, C 32 H 37 F2N7O4).

[0397] Step 3: Synthesis of Compound 6

[0398] Compound 6 was prepared similarly to the method of Example 3, Step 12.

[0399] The identifying data of the specific compound are as follows:

[0400] LC-MS: m / z 676.2 [M+H] + (Calculated 676.3, C 35 H 39 F2N7O5).

[0401] Example 7: Synthesis of N-(2-((2'-(3,5-difluoro-2,6-dimethoxypyridin-4-yl)-3'- oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-[2,7]naphthridin]-6'-yl)amino)phenyl)acrylamide (Compound 7)

[0402] The synthetic route is as follows:

[0403]

[0404] Step 1: Synthesis of Intermediate 7-1

[0405] Under N2protection, 6'-chloro-2'-(2,6-difluoro-3,5-dimethoxypyridin)-1',2'-dihydro-3'H- spiro[cyclopropane-1,4'-[2,7]naphthridin]-3'-one (200 mg, 0.52 mmol), 1,2-phenylenediamine (60 mg, 0.55 mmol), palladium acetate (25 mg, 0.11 mmol), Brettphos (59 mg, 0.11 mmol) and sodium tert-butoxide (200 mg, 2.08 mmol) were added into anhydrous dioxane (10 mL) and the reaction was heated at 110 °C for 1 h in microwave. After the reaction was completed, it was filtered and washed with EA (5 mL) for 2 times, the filtrate was collected and concentrated, and then separated by thin layer chromatography to give 7-1 (80 mg) as an oil.

[0406] The identification data of the specific compound are as follows:

[0407] LC-MS: m / z 454.1 [M+H] + (Calculated value 454.2, C 23 H 21 F2N5O3).

[0408] Step 2: Synthesis of Compound 7

[0409] Intermediate 7-1 (80 mg) was dissolved in 3 mL of dry THF, and 10 μL of acryloyl chloride was added dropwise while cooling to 0 °C, and the reaction was allowed to proceed for 10 min. Then 0.1 mL of water was added to quench the reaction, and the solvent was evaporated. The residue was then subjected to preparative separation and purification to obtain the desired product 7 (5.6 mg).

[0410] The identification data of the specific compound are as follows:

[0411] 1H NMR (500 MHz, DMSO-d6): δ 9.71 (s, 1H), 8.22 (s, 1H), 7.99 (s, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.15 (td, J = 7.7, 1.6 Hz, 1H), 7.05 (td, J = 7.6, 1.5 Hz, 1H), 6.48 (dd, J = 17.0, 10.2 Hz, 1H), 6.30 (s, 1H), 6.24 (dd, J = 17.0, 2.0 Hz, 1H), 5.73 (dd, J = 10.2, 2.0 Hz, 1H), 4.88 (s, 2H), 3.98 (s, 6H), 1.69 (q, J = 4.0 Hz, 2H), 1.38 (q, J = 4.1 Hz, 2H).

[0412] LC-MS: m / z 508.2 [M+H] + (Calculated on C 26 H 23 F2N5O4).

[0413] Example 8: Synthesis of N-(2-((2'-(3,5-difluoro-2,6-dimethoxy-pyridin-4-yl)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-[2,7]naphthridin]-6'-yl)amino)-3-methyl-phenyl)acrylamide (Compound 8)

[0414] The synthesis route is as follows:

[0415]

[0416] Step 1: Synthesis of Intermediate 8-1

[0417] A mixture of 6'-chloro-2'-(2,6-difluoro-3,5-dimethoxy-pyridin-4-yl)-1',2'-dihydro-3'H- spiro[cyclopropane-1,4'-[2,7]naphthridin]-3'-one (100 mg, 0.26 mmol), 2-methyl-6- nitroaniline (47 mg, 0.31 mmol), sodium tert-butoxide (50 mg, 0.52 mmol) and Brettphos (14 mg, 0.026 mmol), Pd2(dba)3(24 mg, 0.026 mmol) in super dry toluene (5 mL) was stirred at 110 °C for 1 h under N2atmosphere. After TLC indicated the reaction was complete, it was cooled down, diluted with EA (5 mL), filtered through celite and washed with EA (5 mL) twice, the filtrate was concentrated to dryness under reduced pressure to get a red brown oil, which was purified on silica gel (eluted with 0 to 0-20% EtOAc in hexanes) to get Intermediate 8-1 (80 mg).

[0418] The characterization data of the specific compound is as follows:

[0419] LC-MS: m / z 498.2 [M+H] + (Calculated value 498.2, C 24 H 21 F2N5O5).

[0420] Step 2: Synthesis of intermediate 8-2

[0421] Intermediate 8-1 (80 mg, 0.16 mmol) was added to a mixture solvent of tetrahydrofuran (6 mL) and water (3 mL) at room temperature, ammonium chloride (500 mg, 9.35 mmol), zinc powder (600 mg, 9.17 mmol) were added, and the reaction was carried out at room temperature for 1 hour. After TLC detection of the complete reaction, the reaction mixture was filtered through celite, washed twice with THF (5 mL), the filtrate was collected, the filtrate was alkalized with saturated NaHCO3 aqueous solution, and extracted with ethyl acetate (3 x 10 mL). The organic phase was combined, dried, concentrated, and intermediate 8-2 (60 mg) was obtained.

[0422] The characterization data of the specific compound is as follows:

[0423] LC-MS: m / z 468.3 [M+H] + (Calculated value 468.2, C 24 H 23 F2N5O3).

[0424] Step 3: Synthesis of compound 8

[0425] To a stirred solution of intermediate 8-2 (80 mg, 0.17 mmol) in tetrahydrofuran (4.0 mL) was added acryloyl chloride (14 μL, 0.17 mmol) dropwise at 0-5 °C. After 5 minutes, the reaction was quenched with saturated NaHCO3 aqueous solution and extracted with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The crude product was purified by preparative separation to obtain the desired product 8 (40 mg).

[0426] The characterization data of the specific compound is as follows:

[0427] 1H NMR (500 MHz, DMSO-d6): δ 9.43 (s, 1H), 7.87 (d, J = 4.3 Hz, 2H), 7.65 (d, J = 8.1 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 7.07 (d, J = 7.3 Hz, 1H), 6.45 (dd, J = 17.0, 10.2 Hz, 1H), 6.18 (dd, J = 17.0, 2.0 Hz, 1H), 5.90 (s, 1H), 5.67 (dd, J = 10.2, 2.0 Hz, 1H), 4.83 (s, 2H), 3.97 (s, 6H), 2.13 (s, 3H), 1.66 (q, J = 4.0 Hz, 2H), 1.27 (q, J = 4.1 Hz, 2H).

[0428] LC-MS: m / z 522.3 [M+H] + (Calculated on C 27 H 25 F2N5O4).

[0429] Example 9: Synthesis of N-(2-((2'-(3,5-difluoro-2,6-dimethoxy-pyridin-4-yl)-3'- oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-[2,7]naphthridin]-6'-yl)amino)-4- morpholinophenyl)acrylamide (Compound 9)

[0430] The synthesis route is as follows:

[0431]

[0432] Step 1: Synthesis of Intermediate 9-1

[0433] A mixture of 6'-chloro-2'-(2,6-difluoro-3,5-dimethoxy-pyridin-4-yl)-1',2'-dihydro-3'H- spiro[cyclopropane-1,4'-[2,7]naphthridin]-3'-one (100 mg, 0.26 mmol), 5-morpholin-2- nitroaniline (69 mg, 0.31 mmol), sodium tert-butoxide (50 mg, 0.52 mmol) and Brettphos (14 mg, 0.026 mmol), Pd2(dba)3(24 mg, 0.026 mmol) in super dry toluene (5 mL) was stirred at 110 °C for 1 h under N2atmosphere. After TLC detection of the reaction was complete, it was cooled, diluted with EA (5 mL), filtered through celite and washed with EA (5 mL) twice, the filtrate was collected and concentrated to dryness under reduced pressure to get a red brown oil which was purified by column chromatography (eluted with gradient of 0-20% EtOAc in n-hexane) to get the intermediate 9-1 (80 mg).

[0434] The identification data of the specific compound are as follows:

[0435] LC-MS: m / z 569.2 [M+H] + (Calculated value 569.2, C 27 H 26 F2N6O6)

[0436] Step 2: synthesis of intermediate 9-2

[0437] Intermediate 9-1 (80 mg, 0.14 mmol) was added to a mixture solvent of tetrahydrofuran (6 mL) and water (3 mL) at room temperature, ammonium chloride (500 mg, 9.35 mmol), zinc powder (600 mg, 9.17 mmol) were added, after reaction at room temperature for 1 hour, filter through celite, wash with THF (5 mL) for 2 times, collect the filtrate, the filtrate was alkalized with saturated NaHCO3 aqueous solution, and extracted with ethyl acetate (3 x 10 mL), dried, concentrated to obtain intermediate 9-2 (60 mg).

[0438] The identification data of the specific compound are as follows:

[0439] LC-MS: m / z 539.3 [M+H] + (Calculated value 539.2, C 27 H 28 F2N6O4).

[0440] Step 3: synthesis of compound 9

[0441] Compound 9 was prepared in analogy to the procedure of Example 8, step 3. The identification data of the specific compound are as follows:

[0442] 1 H NMR (500 MHz, DMSO-d6): δ 9.60 (s, 1H), 8.15 (s, 1H), 8.00 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.23 (d, J = 2.7 Hz, 1H), 6.68 (dd, J = 8.9, 2.7 Hz, 1H), 6.43 (dd, J = 17.0, 10.1 Hz, 1H), 6.30 (s, 1H), 6.21 (dd, J = 17.0, 2.1 Hz, 1H), 5.69 (dd, J = 10.1, 2.1 Hz, 1H), 4.87 (s, 2H), 3.98 (s, 6H), 3.73 (t, J = 4.7 Hz, 4H), 3.06 (t, J = 4.8 Hz, 4H), 1.69 (q, J = 4.0 Hz, 2H), 1.36 (q, J = 4.1 Hz, 2H).

[0443] LC-MS: m / z 593.3 [M+H]+ (Calcd 593.2, C 30 H 30 F2N6O5).

[0444] Example 10: Synthesis of N-(2-((2'-(3,5-difluoro-2,6-dimethoxy-pyridin-4-yl)-3'- oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-[2,7]naphthridin]-6'-yl)amino)-5- morpholinophenyl)acrylamide (Compound 10)

[0445] The synthetic route is as follows:

[0446]

[0447] Step 1: Synthesis of Intermediate 10-1

[0448] A mixture of 6'-chloro-2'-(2,6-difluoro-3,5-dimethoxy-pyridin-4-yl)-1',2'-dihydro-3'H- spiro[cyclopropane-1,4'-[2,7]naphthridin]-3'-one (130 mg, 0.35 mmol), 4-morpholin-2- nitroaniline (100 mg, 0.45 mmol), palladium acetate (11.8 mg, 0.05 mmol), Brettphos (28.1 mg, 0.05 mmol) and sodium tert-butoxide (134 mg, 1.4 mmol) in super dry toluene (10 mL) was stirred at 130 °C under microwave for 30 min. After reaction was completed, it was filtered and washed with EA (10 mL) for 2 times, the filtrate was concentrated to dryness under reduced pressure and purified by column chromatography to give Intermediate 10-1 (47 mg, 0.08 mmol).

[0449] The identification data of the specific compound are as follows:

[0450] LC-MS m / z: 569.3 [M+H] + (Calcd 569.2, C 27 H 26 F2N6O6).

[0451] Step 2: Synthesis of Intermediate 10-2

[0452] Intermediate 10-2 (47 mg, 0.08 mmol), zinc powder (250 mg, 3.83 mmol) and ammonium chloride (300 mg, 5.61 mmol) were added to methanol (3 mL) and stirred at room temperature for 2 h, filtered and the solvent was evaporated under reduced pressure to give crude solid of Intermediate 10-2 (55 mg).

[0453] The identification data of the specific compound are as follows:

[0454] LC-MSC m / z:539.3[M+H] + (Calculated 539.2, C 27 H 28 F2N6O4).

[0455] Step 3: Synthesis of compound 10

[0456] The solid residue 10-2 (55 mg) was dissolved in dry THF (5 mL), cooled in ice bath, 7 μL of acryloyl chloride was added dropwise, the reaction was allowed to proceed for 10 min, quenched by the addition of 0.1 mL of water, and the solvent was evaporated. The residual solid material was purified by preparative separation to give the desired product 10 (13.62 mg).

[0457] The identification data of the specific compound are as follows:

[0458] 1 H NMR (500 MHz, DMSO-d6): δ 9.61 (s, 1H), 7.95 (s, 1H), 7.92 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 2.9 Hz, 1H), 6.79 (dd, J = 8.9, 2.9 Hz, 1H), 6.45 (dd, J = 17.0, 10.2 Hz, 1H), 6.22 (dd, J = 17.0, 2.0 Hz, 1H), 6.10 (s, 1H), 5.71 (dd, J = 10.1, 2.0 Hz, 1H), 4.84 (s, 2H), 3.98 (s, 6H), 3.74 (t, J = 4.7 Hz, 4H), 3.06 (t, J = 4.8 Hz, 4H), 1.66 (q, J = 4.0 Hz, 2H), 1.32 (q, J = 4.2 Hz, 2H).

[0459] LC-MS: m / z 593.3 [M+H] + (Calculated 593.2, C 30 H 30 F2N6O5).

[0460] Example 11: Synthesis of N-((2'-(3,5-difluoro-2,6-dimethoxy-pyridin-4-yl)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclopentane-1,4'-[2,7]naphthyridin]-6'-yl)methyl)acrylamide (Compound 11)

[0461] The synthetic route is as follows:

[0462]

[0463] Step 1: Synthesis of intermediate 11-1

[0464] A mixture of 6'-chloro-2'-(2,6-difluoro-3,5-dimethoxy-pyridin)-1',2'-dihydro-3'H- spiro[cyclopropane-1,4'-[2,7]naphthridin]-3'-one (355 mg, 1.00 mmol), 1,4- dibromobutane (432 mg, 2.00 mmol), cesium carbonate (651 mg, 2 mmol) in DMF (5 mL) was stirred at room temperature for 2 h. After TLC spot plate reaction was complete, 20 mL water was added to the reaction solution, which was extracted with EA (3 x 20 mL), and the organic phases were combined and washed with 20 mL water and 20 mL saturated brine once each. The organic phase was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure, and column chromatography gave intermediate 11-1 (350 mg, 0.85 mmol).

[0465] The identification data of the specific compound are as follows:

[0466] LC-MS: m / z 410.1 [M+H] + (Calculated value 410.1, C 19 H 18 ClF2N3O3).

[0467] Step 2: synthesis of intermediate 11-2

[0468] Under N2protection, intermediate 11-1 (330 mg, 0.80 mmol), Pd2(dba)3 (110 mg, 0.12 mmol), DPPF (67 mg, 0.12 mmol), Zn(CN)2 (140 mg, 1.2 mmol) and Zn powder (20 mg, 0.30 mmol) were added to a reaction bottle, DMF (6 mL) was added, and the mixture was reacted at 140 °C for 45 min under microwave conditions. After the reaction was completed, 20 mL of water was added, and the mixture was extracted with EA (3 x 20 mL), and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated brine once each, and dried over anhydrous MgSO4, filtered and concentrated under reduced pressure, and the residue was purified by column chromatography to give intermediate 11-2 (190 mg, 0.48 mmol).

[0469] The identification data of the specific compound are as follows:

[0470] LC-MS: m / z 401.1 [M+H] + (Calculated value 401.1, C 20 H 18 F2N4O3).

[0471] Step 3: synthesis of intermediate 11-3

[0472] Under N2protection, intermediate 11-2 (90 mg, 0.23 mmol), nickel chloride hexahydrate (9 mg, 0.04 mmol) were added to anhydrous methanol (5 mL), 0.1 mL of trifluoroacetic acid was added dropwise, and after stirring for 10 minutes, sodium borohydride (90 mg, 2.4 mmol) was added in three portions, and the reaction was stirred for 90 min. After the reaction was completed, the solid was removed by suction filtration, the methanol was removed under reduced pressure, 5 mL of anhydrous THF was added, and then evaporated again. Without further purification, it was directly used for the next step. The residue was about 100 mg.

[0473] The identification data of the specific compound are as follows:

[0474] LC-MS: m / z 405.2 [M+H] + (Calculated value 405.2, C 20 H 22 F2N4O3).

[0475] Step 4: Synthesis of compound 11

[0476] Compound 11 was prepared in a similar manner to the method of Example 10, step 3.

[0477] The identification data of the specific compound are as follows:

[0478] 1 H NMR (500 MHz, DMSO-d6): δ 8.71 (t, J = 5.9 Hz, 1H), 8.45 (s, 1H), 7.30 (s, 1H), 6.34 (dd, J = 17.1, 10.2 Hz, 1H), 6.13 (dd, J = 17.1, 2.1 Hz, 1H), 5.64 (dd, J = 10.3, 2.1 Hz, 1H), 4.92 (s, 2H), 4.48 (d, J = 5.9 Hz, 2H), 3.98 (s, 6H), 2.37 (dt, J = 13.1, 6.5 Hz, 2H), 1.98 (dt, J = 12.4, 5.6 Hz, 2H), 1.81-1.78 (m, 2H), 1.78-1.69 (m, 2H).

[0479] LC-MS: m / z 459.2 [M+H] + (Calculated value 459.2, C 23 H 24 F2N4O4).

[0480] Example 12: Synthesis of N-((7-(3,5-difluoro-2,6-dimethoxypyridin-4-yl)-5,5- dimethyl-6-oxo-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)methyl)acrylamide (Compound 12)

[0481] The synthetic route is as follows:

[0482]

[0483] Step 1: Synthesis of intermediate 12-1

[0484] A mixture of 6'-chloro-2'-(2,6-difluoro-3,5-dimethoxy-pyridin)-1',2'-dihydro-3'H- spiro[cyclopropane-1,4'-[2,7]naphthridin]-3'-one (500 mg, 1.41 mmol), iodomethane (700 mg, 5.00 mmol), cesium carbonate (1.10 g, 3.38 mmol) in DMF (10 mL) was stirred at room temperature for 2 h. After TLC detection of the reaction was complete, 40 mL of water was added to the reaction solution, extracted with EA (3 x 40 mL) three times, combined organic phase, and washed with 40 mL of water and 40 mL of saturated brine each time. The organic phase was dried over anhydrous MgSO4, suction filtered and concentrated under reduced pressure to obtain the crude product of intermediate 12-1 (460 mg, 1.20 mmol).

[0485] The identification data of the specific compound are as follows:

[0486] LC-MS: m / z 384.0 [M+H] + (Calculated value 384.1, C 17 H 16 ClF2N3O3)

[0487] Step 2: Synthesis of intermediate 12-2

[0488] A mixture of intermediate 12-1 (400 mg, 1.04 mmol), Pd2(dba)3 (140 mg, 0.15 mmol), DPPF (83.1 mg, 0.15 mmol), Zn(CN)2 (176 mg, 1.5 mmol), Zn powder (30 mg, 0.46 mmol) in DMF (6 mL) was reacted in a microwave at 140 °C for 45 min. After the reaction was completed, 20 mL of water was added to quench, extracted with EA (3 x 20 mL) three times, combined organic phase, and washed with 20 mL of water and 20 mL of saturated brine each time. The organic phase was dried over anhydrous MgSO4, suction filtered and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain intermediate 12-2 (210 mg, 0.56 mmol).

[0489] The identification data of the specific compound are as follows:

[0490] LC-MS: m / z 375.1 [M+H] + (Calculated value 375.1, C 18 H 16 F2N4O3).

[0491] Step 3: synthesis of intermediate 12-3

[0492] Under N2protection, intermediate 12-2 (150 mg, 0.40 mmol), nickel chloride hexahydrate (14.2 mg, 0.06 mmol) were added into 5 mL anhydrous methanol, 0.2 mL trifluoroacetic acid was added dropwise, after stirring for 10 min, sodium borohydride (151 mg, 4.0 mmol) was added in three portions, and the reaction was allowed to proceed for 90 min. After the reaction was completed, the solid was removed by suction filtration, the methanol was removed by distillation under reduced pressure, 5 mL anhydrous THF was added, and then distilled again. The obtained residue of intermediate 12-3 crude product (160 mg) was used directly in the next step without further purification.

[0493] The identification data of the specific compound are as follows:

[0494] LC-MS: m / z 379.1 [M+H] + (Calculated value 379.2, C 18 H 20 F2N4O3).

[0495] Step 4: synthesis of compound 12

[0496] The residue 12-3 (160 mg) of the previous step was dissolved in 5 mL THF, and the temperature was lowered to about 0°C in an ice bath, 15 μL acryloyl chloride was added dropwise, and stirred for 10 min. After the reaction was completed, 0.1 mL water was added to quench the reaction. Distillation was performed under reduced pressure until no obvious solvent residue was left, and the residual solid material was purified by preparative separation to obtain the desired product 12 (20.29 mg).

[0497] The identification data of the specific compound are as follows:

[0498] 1 H NMR (500 MHz, DMSO-d6): δ 8.71 (t, J = 5.9 Hz, 1H), 8.46 (s, 1H), 7.41 (s, 1H), 6.34 (dd, J = 17.1, 10.2 Hz, 1H), 6.13 (dd, J = 17.1, 2.1 Hz, 1H), 5.63 (dd, J = 10.2, 2.1 Hz, 1H), 4.95 (s, 2H), 4.48 (d, J = 5.8 Hz, 2H), 3.99 (s, 6H), 1.49 (s, 6H).

[0499] LC-MS: m / z 433.2 [M+H] + (Calculated value 433.2, C 21 H 22 F2N4O4).

[0500] Example 13: Synthesis of N-((2'-(3,5-difluoro-2,6-dimethoxy-pyridin-4-yl)-3'- oxo-2,2',3,3',5,6-hexahydro-1'H-spiro[pyrane-4,4'-[2,7]naphthrydine]-6'-yl) methyl)acrylamide (Compound 13)

[0501] The synthetic route is as follows:

[0502]

[0503] Step 1: Synthesis of Intermediate 13-1

[0504] A mixture of 6'-chloro-2'-(2,6-difluoro-3,5-dimethoxy-pyridin)-1',2'-dihydro-3'H- spiro[cyclopropane-1,4'-[2,7]naphthrydine]-3'-one (150 mg, 0.42 mmol), bis(2- bromoethyl) ether (195 mg, 0.84 mmol), cesium carbonate (390 mg, 1.20 mmol) in DMF (5 mL) was stirred at room temperature for 2 h. After TLC detection of the reaction was complete, the reaction solution was added to 20 mL water, extracted with EA (3x20 mL) for three times, the organic phase was combined and washed with 20 mL water and 20 mL saturated brine for one time. The organic phase was dried over anhydrous MgSO4, then was filtered and concentrated under reduced pressure to give the crude of intermediate 13-1 (153 mg, 0.36 mmol).

[0505] The identification data of the specific compound are as follows:

[0506] LC-MS: m / z 426.0 [M+H] + (Calculated value 426.1, C 19 H 18 ClF2N3O4).

[0507] Step 2: Synthesis of Intermediate 13-2

[0508] Intermediate 13-2 was prepared in analogy to the procedure of Example 12, Step 2.

[0509] The identification data of the specific compound are as follows:

[0510] LC-MS: m / z 417.1 [M+H] + (Calculated value 417.1, C 20 H 18 F2N4O4).

[0511] Step 3: Synthesis of Intermediate 13-3

[0512] Intermediate 13-3 was prepared in analogy to the procedure of Example 11, Step 3.

[0513] The identification data for a specific compound is as follows:

[0514] LC-MS: m / z 421.1 [M+H] + (Calculated value 421.2, C 20 H 22 F2N4O4).

[0515] Step 4: Synthesis of compound 13

[0516] Compound 13 was prepared in analogy to the procedure of Example 10, Step 3.

[0517] The identification data for a specific compound is as follows:

[0518] 1 H NMR (500 MHz, DMSO-d6): δ 8.70 (t, J = 5.9 Hz, 1H), 8.50 (s, 1H), 7.50 (s, 1H), 6.34 (dd, J = 17.1, 10.2 Hz, 1H), 6.14 (dd, J = 17.1, 2.1 Hz, 1H), 5.64 (dd, J = 10.2, 2.1 Hz, 1H), 4.96 (s, 2H), 4.50 (d, J = 5.8 Hz, 2H), 3.99 (s, 6H), 3.90-3.77 (m, 4H), 2.18-2.08 (m, 2H), 2.01-1.92 (m, 2H).

[0519] LC-MS: m / z 475.2 [M+H] + (Calculated value 475.2, C 23 H 24 F2N4O5).

[0520] Example 14: Synthesis of N-(2-((2'-(3,5-difluoro-2,6-dimethoxy-pyridin-4-yl)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-[2,7]naphthridin]-6'-yl)amino)-4-fluoro-5-morpholinophenyl)acrylamide (Compound 14)

[0521] The synthesis route is as follows:

[0522]

[0523] Step 1: Synthesis of intermediate 14-1

[0524] 4-Bromo-5-fluoro-2-nitroaniline (4.70 g, 20 mmol), DMAP (732 mg, 6 mmol), and TEA (4 mL) were dissolved in DCM (60 mL), followed by the dropwise addition of Boc anhydride (21.8 g, 100 mmol), and the reaction was carried out at room temperature for 1 h. After the reaction was completed, the mixture was quenched with saturated ammonium chloride solution, and the organic layer was collected and washed once with 30 mL of water and once with 30 mL of saturated brine. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated by reduced distillation to give a yellow solid 14-1 (5.22 g, 15.5 mmol).

[0525] The specific identification data for the compounds are as follows:

[0526] LC-MS: m / z 335.0 [M+H] + (Calculated value 335.0, C) 16 H 20 BrFN2O6).

[0527] Step 2: Synthesis of intermediate 14-2

[0528] Under nitrogen protection, intermediate 14-1 (2.51 g, 7.50 mmol), morpholine (1.26 g, 15.0 mmol), Ruphos (0.50 g, 1.14 mmol), Pd2(dba)3 (1.00 g, 1.14 mmol), and cesium carbonate (7.3 g, 23 mmol) were added to 15 mL of dry dioxane and reacted at 110 °C for 30 min. After the reaction was complete, the mixture was filtered, distilled under reduced pressure to dryness, and the residue was purified by column chromatography to obtain intermediate 14-2 (2.00 g, 5.86 mmol).

[0529] The specific identification data for the compounds are as follows:

[0530] LC-MS: m / z 442.2 [M+Na] + (Calculated value 442.2, C) 20 H 28 FN3O7).

[0531] Step 3: Synthesis of intermediate 14-3

[0532] At room temperature, intermediate 14-2 (1.50 g, 4.4 mmol) was dissolved in 20 mL of DCM, stirred, and 12 mL of trifluoroacetic acid was added dropwise. The reaction was allowed to proceed for 1 h. After the reaction was complete, the solvent was completely evaporated to obtain intermediate 14-3 (942 mg, 4.01 mmol).

[0533] The specific identification data for the compounds are as follows:

[0534] LC-MS: m / z 242.2[M+H]+(calculated value 242.1, C10 H 12 FN3O3).

[0535] Step 4: Synthesis of intermediate 14-4

[0536] Under nitrogen protection, intermediate 3-8 (178 mg, 0.5 mmol, see example 3), intermediate 14-3 (144 mg, 0.6 mmol), palladium acetate (18.6 mg, 0.08 mmol), Ruphos (37.3 mg, 0.08 mmol) and sodium tert-butoxide (192 mg, 2 mmol) were added into 10 mL of toluene, and the mixture was reacted at 130 °C in a microwave reactor for 30 min. After the reaction was completed, the residue was dried under reduced pressure, and the residue was purified by column chromatography to obtain intermediate 14-4 (96 mg, 0.17 mmol).

[0537] The identification data of the specific compound are as follows:

[0538] LC-MS: m / z 587.3 [M+H] + (Calculated value 587.2, C 27 H 25 F3N6O6).

[0539] Step 5: Synthesis of intermediate 14-5

[0540] Under room temperature, intermediate 14-4 (96 mg, 0.17 mmol), zinc powder (500 mg, 7.65 mmol), ammonium chloride (600 mg, 9.18 mmol) in methanol (10 mL) were stirred for 2 h, filtered, dried under reduced pressure, added 10 mL of THF, and dried again to obtain solid residue 14-5 (108 mg).

[0541] The identification data of the specific compound are as follows:

[0542] LC-MS: m / z 557.4 [M+H] + (Calculated value 557.2, C 27 H 27 F3N6O4).

[0543] Step 6: Synthesis of compound 14

[0544] Compound 14 was prepared in analogy to the procedure of example 10, step 3.

[0545] The identification data of the specific compound are as follows:

[0546] 1H NMR (500 MHz, DMSO-d6): δ 9.63 (s, 1H), 8.12 (s, 1H), 7.99 (s, 1H), 7.61 (d, J = 14.7 Hz, 1H), 7.22 (d, J = 9.3 Hz, 1H), 6.47 (dd, J = 17.0, 10.2 Hz, 1H), 6.33 (s, 1H), 6.24 (dd, J = 17.0, 2.0 Hz, 1H), 5.77-5.71 (m, 1H), 4.88 (s, 2H), 3.98 (s, 6H), 3.74 (t, J = 4.6 Hz, 4H), 2.95 (t, J = 4.6 Hz, 4H), 1.70 (q, J = 4.0 Hz, 2H), 1.39 (q, J = 4.2 Hz, 2H).

[0547] LC-MS: m / z 611.3 [M+H]+ (calculated 611.2, C 30 H 29 F3N6O5).

[0548] Example 15: Synthesis of N-(2-((2'-(3,5-difluoro-2,6-dimethoxy-pyridin-4-yl)-3'- oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-6'-yl)amino)-5-(3- methylmorpholino)-phenyl)-acrylamide (Compound 15)

[0549] The synthesis route is as follows:

[0550]

[0551] Step 1: Synthesis of Intermediate 15-1

[0552] Compound was prepared as a yellow solid 15-1 (5.12 g, 16.2 mmol) in analogy to the method of Example 14, Step 1.

[0553] The identification data of the specific compound are as follows:

[0554] LC-MS: m / z 439.0 [M+Na] + (calculated 439.0, C 16 H 21 BrN2O6).

[0555] Step 2: Synthesis of Intermediate 15-2

[0556] Compound was prepared as a yellow solid 15-2 (2.45 g, 5.86 mmol) in analogy to the method of Example 14, Step 2, substituting 3-methylmorpholine for morpholine.

[0557] The identification data of the specific compound are as follows:

[0558] LC-MS: m / z 438.3 [M+H] + (Calculated value 438.2, C) 21 H 31 N3O7).

[0559] Step 3: Synthesis of Intermediate 15-3

[0560] Similar to step 3 of Example 14, intermediate 15-3 (1104 mg, 4.65 mmol) was obtained.

[0561] The specific identification data for the compounds are as follows:

[0562] LC-MS: m / z 238.2 [M+H] + (Calculated value 238.1, C) 11 H 15 N3O3)

[0563] Step 4: Synthesis of intermediate 15-4

[0564] Similar to step 4 of Example 14, intermediate 15-4 (482 mg, 0.83 mmol) was obtained.

[0565] The specific identification data for the compounds are as follows:

[0566] LC-MS: m / z 583.2 [M+H] + (Calculated value 583.2, C) 28 H 28 F2N6O6).

[0567] Step 5: Synthesis of intermediate 15-5

[0568] Similar to step 5 of Example 14, solid residue 15-5 (508 mg) was obtained.

[0569] The specific identification data for the compounds are as follows:

[0570] LC-MS: m / z 553.3 [M+H] + (Calculated value 553.2, C) 28 H 30 F2N6O4).

[0571] Step 6: Synthesis of Compound 15

[0572] Compound 15 (256.48 mg, 0.42 mmol) was prepared using a method similar to step 3 of Example 10.

[0573] The identification data for the specific compounds are as follows.

[0574] 1 H NMR (500 MHz, DMSO-d6): δ 9.59 (s, 1H), 7.92 (d, J = 4.4 Hz, 2H), 7.33 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 2.9 Hz, 1H), 6.75 (dd, J = 8.9, 2.8 Hz, 1H), 6.45 (dd, J = 16.9, 10.2 Hz, 1H), 6.22 (dd, J = 17.0, 2.0 Hz, 1H), 6.09 (s, 1H), 5.71 (dd, J = 10.1, 2.0 Hz, 1H), 4.85 (s, 2H), 3.98 (s, 6H), 3.92-3.86 (m, 1H), 3.76-3.69 (m, 2H), 3.67-3.61 (m, 1H), 3.58 (td, J = 10.8, 3.2 Hz, 1H), 3.10-3.04 (m, 1H), 3.00 (td, J = 11.9, 11.2, 3.5 Hz, 1H), 1.66 (q, J = 3.9 Hz, 2H), 1.32 (q, J = 4.1 Hz, 2H), 1.00 (d, J = 6.3 Hz, 3H).

[0575] LC-MS: m / z 607.3 [M+H] + (Calculated 607.2, C 31 H 32 F2N6O5).

[0576] Example 16: Synthesis of N-((3-(3,5-difluoro-2,6-dimethoxy-pyridin-4-yl)-2-oxo-1- phenyl-1,2,3,4-tetrahydropyridin[4,3-d]pyrimidin-7-yl)methyl)acrylamide (Compound 16)

[0577] The synthesis route is as follows:

[0578]

[0579] Step 1: Synthesis of Intermediate 16-1

[0580] To a stirred mixture of 3,5-difluoro-2,6-dimethoxypyridin-4-amine (200 mg, 1.05 mmol), 4,6-dichlorobenzaldehyde (185 mg, 1.05 mmol) in dichloromethane (5 mL) / trifluoroacetic acid (600 μί) was added sodium triacetoxyborohydride (635 mg, 3.00 mmol) at 0-5 °C and after 1 h, the ice bath was removed and the reaction was allowed to proceed at room temperature. After TLC indicated the completion of the reaction, it was quenched with saturated aqueous ammonium chloride solution and extracted with dichloromethane. The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography to afford intermediate 16-1 (220 mg).

[0581] The characterization data for the specific compound are as follows:

[0582] LC-MS: m / z 350.1 [M+H] + (Calculated 350.0, C 13 H 11 Cl2F2N3O2).

[0583] Step 2: Synthesis of intermediate 16-2

[0584] A mixture of intermediate 16-1 (200 mg, 0.57 mmol), zinc cyanide (45 mg, 0.38 mmol), tris(dibenzylideneacetone)dipalladium(0) (52 mg, 0.057 mmol) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (47 mg, 0.057 mmol) in N,N-dimethylformamide (5 mL) was heated at 125-130 °C under N2atmosphere for 1.5 h. The reaction mixture was then cooled to room temperature, quenched with saturated aqueous NaHC03solution and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The residue was purified on silica gel eluting with 0-25% EtOAc in hexanes to afford intermediate 16-2 (130 mg).

[0585] The characterization data for the specific compound are as follows:

[0586] LC-MS: m / z 340.2 [M+H] + (Calculated 340.1, C 14 H 11 ClF2N4O2).

[0587] Step 3: Synthesis of intermediate 16-3

[0588] In a sealed tube, was placed intermediate 16-2 (100 mg, 0.29 mmol), palladium acetate (20 mg, 0.09 mmol), (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (40 mg, 0.06 mmol), cesium carbonate (300 mg, 0.92 mmol) and dry THF 3 mL, sealed, magnetically stirred, flushed with nitrogen, finally aniline (54 μL, 0.58 mmol) was added with a syringe, placed in a microwave reactor, stirred, 130 °C, for about 1 hour, after the reaction was complete, it was cooled, diluted with EA, filtered through celite, washed with EA, concentrated to dryness under reduced pressure, the red-brown oil was collected, which was the crude intermediate 16-3 (60 mg). The crude was used directly in the next step without further purification.

[0589] The identification data of the specific compound are as follows:

[0590] LC-MS: m / z 398.2 [M+H] + (Calculated value 398.1, C 20 H 17 F2N5O2).

[0591] Step 4: synthesis of intermediate 16-4

[0592] To a stirred solution of intermediate 16-3 (55 mg, 0.14 mmol) in THF (2.0 mL) at 0-5 °C was added N,N-diisopropylethylamine (116 μL, 0.70 mmol), then slowly added triphosgene (42 mg, 0.14 mmol (dissolved in 2 mL THF and added)). After 5 minutes, the ice bath was removed and the reaction was allowed to warm to room temperature. After the reaction was complete, it was quenched with saturated aqueous NaHC03solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated to dryness under reduced pressure. The crude product was purified on column chromatography to give intermediate 16-4 (30 mg).

[0593] The identification data of the specific compound are as follows:

[0594] LC-MS: m / z 424.1 [M+H] + (Calculated value 424.1, C 21 H 15 F2N5O3)

[0595] Step 5: synthesis of intermediate 16-5

[0596] Compound 16-5 (40 mg) was prepared in analogy to the procedure described in example 11, step 3.

[0597] The identification data of the specific compound are as follows:

[0598] LC-MS: m / z 428.2 [M+H] + (Calculated 428.2, C 21 H 19 F2N5O3)

[0599] Step 6: Synthesis of compound 16

[0600] Compound 16 (40 mg) was prepared in analogy to the procedure described in Step 3 of Example 10.

[0601] The identification data of the specific compound is as follows.

[0602] 1 H NMR (500 MHz, DMSO-d6): δ 8.56 (t, J = 5.9 Hz, 1H), 8.31 (s, 1H), 7.55 (t, J = 7.5 Hz, 2H), 7.50 (t, J = 7.3 Hz, 1H), 7.34 (d, J = 7.6 Hz, 2H), 6.14 (dd, J = 17.1, 10.2 Hz, 1H), 6.07 (s, 1H), 6.02 - 5.94 (m, 1H), 5.57 - 5.51 (m, 1H), 5.02 (s, 2H), 4.23 (d, J = 6.0 Hz, 2H), 3.98 (s, 6H).

[0603] LC-MS: m / z 482.2 [M+H] + (Calculated 482.2, C 24 H 21 F2N5O4).

[0604] Example 17: Synthesis of N-((l-cyclopropyl-3-(3,5-difluoro-2,6-dimethoxy-pyridin-4-yl)-2-oxo-l,2,3,4-tetrahydropyridin[4,3-d]pyrimidin-7-yl)methyl)acrylamide (Compound 17)

[0605] The synthesis route is as follows:

[0606]

[0607] Step 1: Synthesis of intermediate 17-1

[0608] A flask was charged with 6'-chloro-2'-(2,6-difluoro-3,5-dimethoxy-pyridin)-1',2'- dihydro-3'H-spiro[cyclopropane-1,4'-[2,7]naphthrydine]-3'-one (100 mg, 0.29 mmol), palladium acetate (20 mg, 0.09 mmol), (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'- binaphthyl (40 mg, 0.06 mmol), cesium carbonate (300 mg, 0.92 mmol) and super dry dioxane (3 mL), sealed, magnetically stirred, flushed with nitrogen, finally cyclopropylamine (40 μL, 0.58 mmol) was added via syringe and placed in a microwave reactor and heated at 130 °C for about 1 hour. After completion of the reaction, it was cooled, diluted with EA, filtered through celite, washed with EA, concentrated to dryness under reduced pressure and the crude red-brown oil was collected as intermediate 17-1 (60 mg). The crude was used directly in the next step without further purification.

[0609] The identification data of the specific compound are as follows:

[0610] LC-MS: m / z 362.1 [M+H] + (Calculated value 362.1, C 17 H 17 F2N5O2).

[0611] Step 2: Synthesis of intermediate 17-2

[0612] Intermediate 17-2 (30 mg) was prepared in analogy to the procedure described in Example 16, step 4.

[0613] The identification data of the specific compound are as follows:

[0614] LC-MS: m / z 388.2 [M+H] + (Calculated value 388.1, C 18 H 15 F2N5O3).

[0615] Step 3: Synthesis of intermediate 17-3

[0616] Intermediate 17-3 (40 mg) was prepared in analogy to the procedure described in Example 11, step 3.

[0617] The identification data of the specific compound are as follows:

[0618] LC-MS: m / z 392.2 [M+H] + (Calculated value 392.2, C 18 H 19 F2N5O3).

[0619] Step 4: Synthesis of compound 17

[0620] Compound 17 (40 mg) was prepared in a similar manner as in Step 3 of Example 10.

[0621] The identification data of the specific compound are as follows:

[0622] 1 H NMR (500 MHz, DMSO-d6): δ 8.73 (t, J = 5.9 Hz, 1H), 8.24 (s, 1H), 7.23 (s, 1H), 6.35 (dd, J = 17.1, 10.2 Hz, 1H), 6.14 (dd, J = 17.1, 2.1 Hz, 1H), 5.64 (dd, J = 10.2, 2.1 Hz, 1H), 4.73 (s, 2H), 4.44 (d, J = 5.9 Hz, 2H), 3.97 (s, 6H), 2.79 (tt, J = 6.9, 3.7 Hz, 1H), 1.04 (td, J = 7.3, 5.4 Hz, 2H), 0.64-0.55 (m, 2H).

[0623] LC-MS: m / z 446.2 [M+H] + (Calculated 446.2, C 21 H 21 F2N5O4).

[0624] Pharmacological test

[0625] Test example A: kinase test

[0626] The influence of the compounds of the present application on the activity of the tyrosine kinases FGFR1 and FGFR4 was assessed using an in vitro kinase assay. The method used in the assay is the homogeneous time-resolved fluorescence (HTRF) method.

[0627] Compound preparation: 45 μL DMSO was added to 5 μL of 10 mM stock solution to prepare a 1000 μM solution of LY2874455, then 12 μL of 1000 μM compound was added to 88 μL of DMSO to prepare a 120 μM solution of LY2874455 as the starting concentration; 48 μL DMSO was added to 2 μL of 10 mM stock solution to prepare a 400 μM solution of BLU554 as the starting concentration; 15 μL DMSO was added to 10 μL of 10 mM sample compound stock solution to prepare a 4 mM solution of sample compound as the starting concentration; the compound solution was transferred to the destination plate using a liquid handler Echo.

[0628] Kinase reaction: 5 μL kinase solution was added to each well, and the compound and the kinase were incubated at room temperature for 60 min, then 5 μL substrate and ATP mixture was added to start the reaction, and the reaction was carried out at 37°C for a certain time (FGFR1 kinase test reaction time was 30 min, and FGFR4 kinase test reaction time was 40 min), then the reaction was stopped by adding 10 μL Xl665 and antibody detection reagent mixture, and incubated at room temperature for 60 min, then the TR-FRET signal at the emission wavelength of 665 nM / 612 nM was read on the plate reader SPARK 10M. The activity of the enzyme was determined at 10 concentrations of each compound, and the IC 50 value of the compound was calculated by using the analysis software, as shown in Table 1.

[0629] Table 1 IC value and selective inhibition of compounds 50

[0630] Compound No. FGFR1 IC 50 (nM) FGFR4 IC 50 (nM) FGFR4 / FGFR1 Compound 1 3658.94 8.57 426 Compound 5 6 0.3 20 Compound 7 4243 5.42 782 Compound 8 8567 2.7 3172 Compound 10 984 0.67 1468 Compound 14 >9926 2.6 3817 Compound 15 2279 0.63 3617 BLU554 624 5.98 104

[0631] Note: BLU554 is compound No. 40 disclosed by Blueprint Medicines Corporation in WO2015061572.

[0632] It can be seen from Table 1 that the compound of the present application has an inhibitory effect on FGFR4 kinase, and the inhibitory effect of the compound on FGFR4 is much stronger than that on FGFR1, and has very good selectivity.

[0633] Example B: cell proliferation test

[0634] The effect of the compound of the present application on the proliferation of human liver cancer cells Hep3B cells was evaluated by in vitro cell test. The method used in the test is CELL TITER-GLO (CTG) luminescence method.

[0635] Cell plating: logarithmically growing Hep3B cells were taken, centrifuged at 1000 rpm at room temperature for 5 min to collect the cells after digestion, then the cells were resuspended and counted with 10% FBS EMEM medium, and inoculated into a 384-well plate (#3765) at a density of 800 cells / well, and 20 μL was inoculated into each well.

[0636] ​Compound preparation: the compound was dissolved in DMSO to prepare a stock solution with a concentration of 10 mM, then the sample compound stock solution was diluted to 2 mM (6 μL stock solution plus 24 μL DMSO) as the starting concentration, and the control compound stock solution was diluted to 200 μM (2 μL stock solution plus 98 μL DMSO) as the starting concentration; the compound was serially diluted 9 times with DMSO by 3 times, and then the compound was diluted to 40 times the final concentration dose (2 μL compound plus 78 μL DMSO) with cell culture medium.

[0637] Cell administration: 5 μL (5x) compound was added to the corresponding well, and the final concentration of the sample compound was 10000 nM, 3333 nM, 1111 nM, 370.37 nM, 123.46 nM, 41.15 nM, 13.72 nM, 4.57 nM, 1.52 nM, 0.50 nM from high to low, and 0.5% DMSO was used as a negative control; the well plate was incubated at 37°C, 5% CO2 for 3 days.

[0638] CTG detection: after 3 days of incubation, 5 μL of reagent was added to each well, and the plate was incubated at room temperature, 300 rpm, for 60 min in the dark; the luminescence signal was read on the plate reader Spark 10M, and the half-inhibitory concentration of the compound on cell proliferation, IC 50 value, was calculated by the analysis software, as shown in Table 2.

[0639] Table 2 IC 50 value of the compound on Hep3B cells

[0640] Compound No. IC50values (nM) for compounds against Hep3B cells 50 (nM)]]> Compound 1 52.58 Compound 8 56.49 Compound 10 13.99 Compound 14 38.07 Compound 15 15.30 BLU554 38.37

[0641] As can be seen from Table 2, the compound of the present application has a good inhibitory effect on the proliferation of Hep3B cells.

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, ， wherein: X is CH; Y is 1 O; Z is C(R 6 )2; m is 1; L is ; n is 1 or 2; Each R 1 Each independently is C 1-3 alkyl; R 2 and R 3 each independently halogen; R 4 is hydrogen; R 5 is hydrogen; two R 6 and the carbon atom to which they are attached together form C 3-8 cycloalkyl; each R 7 each independently halogen, 3- to 10-membered heterocycloalkyl, or substituted 3- to 10-membered heterocycloalkyl, the substituent being C 1-4 alkyl; wherein the 3- to 10-membered heterocycloalkyl comprises 2 ring-forming heteroatoms, the heteroatoms being N and O.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, said compound has a structure represented by Formula (III-1): ， wherein Z, L, R 2 and R 3 are as defined in claim 1.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein, said compound of Formula (III-1) has a structure represented by Formula (III-1-1): ， wherein R 2 , R 3 and R 6 are as defined in claim 1 ; R 7 is morpholinyl, wherein the morpholinyl is optionally substituted with at least one R 8 substituent; Each R 8 Each independently is C 1-4 alkyl.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein, R 7 For .

5. The following compound or a pharmaceutically acceptable salt thereof: , , and .

6. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5.

7. A pharmaceutical preparation comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 or the pharmaceutical composition according to claim 6, which is any one of a tablet, a capsule, an injection, a granule, a powder, a suppository, a pill, a gel, a powder, an oral solution, an inhalant, a suspension or a dry suspension.

8. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 or the pharmaceutical composition according to claim 6 or the pharmaceutical preparation according to claim 7 for the manufacture of a medicament for the prevention and / or treatment of a disease mediated at least in part by FGFR4.

9. Use according to claim 8, wherein, The disease mediated at least in part by FGFR4 includes cancer.

10. Use according to claim 9, wherein, The cancer is selected from the group consisting of hepatocellular carcinoma, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myeloid leukemia, Hodgkin's or non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, hairy cell lymphoma, Burkitt's lymphoma, glioblastoma, melanoma, mesothelioma, neuroblastoma, testicular cancer, squamous cell carcinoma, glioma and rhabdomyosarcoma.

11. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 or the pharmaceutical composition according to claim 6 or the pharmaceutical preparation according to claim 7 for the manufacture of a medicament for FGFR4 inhibitor.

12. A pharmaceutical combination comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 or the pharmaceutical composition according to claim 6 or the pharmaceutical preparation according to claim 7, and at least one additional cancer therapeutic agent.

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