2-formylquinoline carboxamide compounds and medical uses thereof

Abstract

The present application relates to 2-formylquinoline carboxamide compounds and medical uses thereof, the structure is shown as formula (I). The present application also relates to the preparation method of the compounds, pharmaceutical compositions and the use thereof as FGFR4 inhibitors in the treatment of cancer.

Description

Technical Field

[0001] This application relates to 2-formylquinoline carboxamide compounds, methods for their preparation, pharmaceutical compositions containing these compounds, and their use as FGFR4 inhibitors in the treatment of cancer. Background Technology

[0002] Fibroblast growth factor receptor 4 (FGFR4) is the tyrosine kinase receptor for fibroblast growth factor (FGF) and participates in the regulation of various cellular processes, including cell proliferation, differentiation, migration, metabolism, and bile acid biosynthesis. Recent studies have confirmed a close association between elevated FGFR4 levels and the occurrence and progression of cancer, making FGFR4 a popular target for developing novel anticancer therapies.

[0003] Currently, some of the FGFR4 selective inhibitors under development have entered the clinical stage, such as FGF-401, H3B-6527, BLU554, and BLU9931, with the following specific structures:

[0004]

[0005] Among them, studies related to H3B-6527 have shown that drug resistance caused by mutations at key FGFR4 sites V550L or V550 reduces or eliminates efficacy. Overcoming the limitations of these gene mutations that lead to drug resistance will be the focus of the next stage of FGFR4 inhibitor research. Invention Details

[0006] On the one hand, this application relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, or tautomers, or stereoisomers, or deuterated derivatives thereof, and mixtures thereof.

[0007]

[0008] in,

[0009] X is selected from O or S;

[0010] Y is selected from O, S, CH2, or NH;

[0011] R 1 Selected from -SR a -OR a -CHR a R b , or -NR a R b ;

[0012] R a R b Each is independently selected from H and C.1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkyl-C 1-3 Alkyl, 4-7 membered heterocyclic alkyl, or 4-7 membered heterocyclic alkyl-C 1-3 Alkyl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, or C 2-6 The alkynyl group is optionally surrounded by one or more R c Substitution, the 3-7 membered cycloalkyl, 3-7 membered cycloalkyl-C 1-3 Alkyl, 4-7 membered heterocyclic alkyl, or 4-7 membered heterocyclic alkyl-C 1-3 Alkyl groups are optionally surrounded by one or more R d replace;

[0013] Or, R a R b Together with the connected N atoms, they form an optional structure consisting of one or more R atoms. d Substituted 4-7 membered heterocyclic alkyl groups;

[0014] Each R c Each is independently selected from halogen, oxo, -OH, -NH2, cyano, and halogenated C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 alkylamino, or di-C 1-4 Alkylamino;

[0015] Each R d Each is independently selected from halogen, oxo, -OH, -NH2, cyano, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 alkylamino, or di-C 1-4 Alkylamino.

[0016] In some implementations, Y is selected from O or S.

[0017] In some implementation schemes, R 1 Selected from -CHR a R b , or -NR a R b .

[0018] In some implementation schemes, R a R b Each is independently selected from H and C. 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl, 3-7 membered cycloalkyl, or 3-7 membered cycloalkyl-C 1-3 Alkyl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, or C 2-6 The alkynyl group is optionally surrounded by one or more R c The 3-7 membered cycloalkyl group or the 3-7 membered cycloalkyl-C group is replaced. 1-3 Alkyl groups are optionally surrounded by one or more R d replace.

[0019] In some implementation schemes, R a R b Each is independently selected from H and C. 1-6 Alkyl, C 2-6 Alkyne group, or 3-7 membered cycloalkyl group, wherein the C 1-6 Alkyl, or C 2-6 The alkynyl group is optionally surrounded by one or more R c The 3-7 membered cycloalkyl group is optionally replaced by one or more R... d replace.

[0020] In some implementation schemes, R a R b Each of the following is independently selected from H, methyl, ethyl, propyl, butyl, ethynyl, propynyl, butynyl, butyynyl, cyclopropane, cyclobutane, cyclopentane, or cyclohexane, wherein the methyl, ethyl, propyl, butyl, ethynyl, propynyl, butynyl, or butyynyl groups are optionally separated by one or more R groups. c The cyclopropane, cyclobutane, cyclopentane, or cyclohexane may optionally be replaced by one or more R d replace.

[0021] In some implementation schemes, R a R b Each is independently selected from H, methyl, ethyl, isopropyl, 2-propynyl, or cyclopropane, wherein the methyl, ethyl, isopropyl, or 2-propynyl group is optionally separated by one or more R groups. c The cyclopropane is optionally replaced by one or more R d replace.

[0022] In some implementation schemes, R a Selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkyl-C 1-3 Alkyl, 4-7 membered heterocyclic alkyl, or 4-7 membered heterocyclic alkyl-C 1-3 Alkyl, wherein the C1-6 Alkyl, C 2-6 alkenyl, or C 2-6 The alkynyl group is optionally surrounded by one or more R c Substitution, the 3-7 membered cycloalkyl, 3-7 membered cycloalkyl-C 1-3 Alkyl, 4-7 membered heterocyclic alkyl, or 4-7 membered heterocyclic alkyl-C 1-3 Alkyl groups are optionally surrounded by one or more R d replace.

[0023] In some implementation schemes, R a Selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-7 membered cycloalkyl, or 3-7 membered cycloalkyl-C 1-3 Alkyl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, or C 2-6 The alkynyl group is optionally surrounded by one or more R c The 3-7 membered cycloalkyl group or the 3-7 membered cycloalkyl-C group is replaced. 1-3 Alkyl groups are optionally surrounded by one or more R d replace.

[0024] In some implementation schemes, R a Selected from C 1-6 Alkyl, C 2-6 Alkyne group, or 3-7 membered cycloalkyl group, wherein the C 1-6 Alkyl, or C 2-6 The alkynyl group is optionally surrounded by one or more R c The 3-7 membered cycloalkyl group is optionally replaced by one or more R... d replace.

[0025] In some implementation schemes, R a The group is selected from methyl, ethyl, propyl, butyl, ethynyl, propynyl, butynyl, butadiynyl, cyclopropane, cyclobutane, cyclopentane, or cyclohexaneyl, wherein the methyl, ethyl, propyl, butyl, ethynyl, propynyl, butynyl, or butadiynyl group is optionally separated by one or more R groups. c The cyclopropane, cyclobutane, cyclopentane, or cyclohexane may optionally be replaced by one or more R d replace.

[0026] In some implementation schemes, R a Selected from ethyl, isopropyl, 2-propynyl, or cyclopropane, wherein the ethyl, isopropyl, or 2-propynyl group is optionally surrounded by one or more R groups. c The cyclopropane is optionally replaced by one or more R d replace.

[0027] In some implementation schemes, R b Selected from H or C 1-6 alkyl.

[0028] In some implementation schemes, R b Selected from H or C 1-3 alkyl.

[0029] In some implementation schemes, R b Selected from H or methyl.

[0030] In some implementation schemes, R a R b Together with the connected N atoms, they form an optional structure consisting of one or more R atoms. d The following groups may be substituted: aziridine, pyrrolidinyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, imidazolyl, tetrahydropyrazolyl, piperidinyl, morpholinyl, piperazine, thiomorpholinyl, or aziridine-heptyl.

[0031] In some implementation schemes, R a R b Together with the connected N atoms, they form an optional structure consisting of one or more R atoms. d Substituted piperidinyl group.

[0032] In some implementations, each R c Each is independently selected from -F, -Cl, -Br, oxo, -OH, -NH2, cyano, halomethyl, haloethyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, and diethylamino.

[0033] In some implementations, each R c Each is independently selected from -F, -Cl, -Br, -OH, -NH2, methoxy, methylthio, methylamino, ethylamino, or dimethylamino.

[0034] In some implementations, each R c Each is independently selected from methoxy or methylthio.

[0035] In some implementations, each R d Each is independently selected from -F, -Cl, -Br, oxo, -OH, -NH2, cyano, halomethyl, haloethyl, methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, and diethylamino.

[0036] In some implementations, each R d Each is independently selected from -F, -Cl, -Br, -OH, -NH2, methyl, or ethyl.

[0037] In some implementations, each R d Each is independently selected from -OH or methyl.

[0038] In some implementation schemes, R 1 Selected from

[0039] In some implementation schemes, R 1 Selected from

[0040] In some embodiments, the halogen is selected from fluorine, chlorine, and bromine. In some embodiments, the halogen is selected from fluorine. In some embodiments, halogenation refers to substitution by one or more halogens. In some embodiments, halogenation refers to substitution by one or more halogens selected from fluorine, chlorine, and bromine. In some embodiments, halogenation refers to substitution by one or more fluorines.

[0041] In some embodiments, the heterocyclic alkyl group contains one or two heteroatoms selected from N, O, or S. In some embodiments, the heterocyclic alkyl group contains one or two heteroatoms selected from N or O. In some embodiments, the heterocyclic alkyl group contains one N atom. In some embodiments, the heterocyclic alkyl group contains one N atom and one oxygen atom.

[0042] In some embodiments, "one or more" is selected from 1, 2, 3, 4, 5, or 6. In some embodiments, "one or more" is selected from 1, 2, or 3. In some embodiments, "one or more" is selected from 1 or 2.

[0043] In some implementations, the "C" 1-6 "Selected from "C" 1-4 In some implementations, the "C" is... 1-4 "Selected from "C" 1-3 "or "C 1-2 In some implementations, the "C" is... 2-4 "Selected from "C" 2-3 In some implementations, the "C" is... 1-3 "Selected from "C" 1-2 ".

[0044] In some implementations, "3-7 yuan" is selected from "3-6 yuan". In some implementations, "4-7 yuan" is selected from "4-6 yuan" or "5-6 yuan".

[0045] This application relates to compounds of formulas (Ia), (Ib), and (Ic), or pharmaceutically acceptable salts thereof, or tautomers, or stereoisomers, or deuterated compounds, and mixtures thereof.

[0046]

[0047] Among them, R 1 R a R b X and Y are defined as above.

[0048] This application also relates to the following compounds or their pharmaceutically acceptable salts, tautomers, stereoisomers, deuterated derivatives, and mixtures thereof:

[0049]

[0050]

[0051] On the other hand, this application relates to pharmaceutical compositions comprising a compound of formula (I), (Ia), (Ib), or (Ic) of this application, or a pharmaceutically acceptable salt thereof, or a tautomer, or a stereoisomer, or a deuterated compound thereof, or a mixture thereof. In some embodiments, the pharmaceutical compositions of this application further include pharmaceutically acceptable excipients.

[0052] On the other hand, this application relates to a method for treating FGFR4-related diseases in mammals, including administering to a mammal, preferably a human, a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), or (Ic) or a pharmaceutically acceptable salt thereof, or a tautomer, or a stereoisomer, or a deuterated compound thereof, or a mixture thereof, or a pharmaceutical composition thereof.

[0053] On the other hand, this application relates to the use of compounds of formula (I) or (Ia) or (Ib) or (Ic) or pharmaceutically acceptable salts thereof, or tautomers, or stereoisomers, or deuterated compounds thereof, mixtures thereof, or pharmaceutical compositions thereof in the preparation of medicaments for treating FGFR4-related diseases.

[0054] On the other hand, this application relates to the use of compounds of formula (I) or (Ia) or (Ib) or (Ic) or pharmaceutically acceptable salts thereof, or tautomers, or stereoisomers, or deuterated compounds thereof, mixtures thereof, or pharmaceutical compositions thereof in the treatment of FGFR4-related diseases.

[0055] On the other hand, this application relates to compounds of formula (I), (Ia), (Ib), or (Ic) for treating FGFR4-related diseases, or pharmaceutically acceptable salts thereof, or tautomers, or stereoisomers, or deuterated compounds thereof, mixtures thereof, or pharmaceutical compositions thereof.

[0056] In some embodiments of this application, the FGFR4-related disease is preferably cancer.

[0057] In some embodiments of this application, the cancer is liver cancer.

[0058] definition

[0059] Unless otherwise stated, the following terms as used in this application shall have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0060] The term "substituted" refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted; oxo substitution does not occur on aromatic groups.

[0061] The terms “optional” or “optionally” mean that the event or condition subsequently described may or may not occur, including both the occurrence and non-occurrence of said event or condition. For example, the ethyl group “optionally” being halogenated means that the ethyl group can be unsubstituted (CH2CH3), monosubstituted (e.g., CH2CH2F), polysubstituted (e.g., CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized is introduced.

[0062] C in this article m-n This means that the part has an integer number of carbon atoms within a given range. For example, "C 1-6 "" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.

[0063] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by two Rs, each R has an independent option.

[0064] When the number of a linking group is 0, such as -(CH2)0-, it indicates that the linking group is a covalent bond.

[0065] When one of the variables is selected as a covalent bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a covalent bond, it means that the structure is actually AZ.

[0066] When a substituent is cross-bonded to two atoms on a ring, it can bond to any atom on that ring. For example, structural units. This indicates that it can be substituted at any position on the cyclohexyl group or cyclohexadiene.

[0067] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0068] The term "hydroxyl group" refers to the -OH group.

[0069] The term "cyano" refers to the -CN group.

[0070] The term "thiol" refers to the -SH group.

[0071] The term "amino" refers to the -NH2 group.

[0072] The term "nitro" refers to the -NO2 group.

[0073] The term "alkyl" refers to a compound with the general formula C1. n H 2n+1 The alkyl group. This alkyl group can be straight-chain or branched. For example, the term "C 1-6 "Alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups has the same definition as above.

[0074] The term "alkoxy" refers to -O-alkyl.

[0075] The term "alkylamino" refers to -NH-alkyl.

[0076] The term "dialkylamino" refers to -N(alkyl)2.

[0077] The term "alkylsulfonyl" refers to -SO2-alkyl.

[0078] The term "alkylthio" refers to -S-alkyl.

[0079] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one double bond. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc.

[0080] The term "alkynyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one triple bond. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH3), 2-propynyl (-CH2-C≡CH), and 1,3-butyrynyl (-C≡CC≡CH).

[0081] The term "cycloalkyl" refers to a fully saturated carbon ring that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 10-membered ring. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, etc.

[0082] The term "cycloalkenyl" refers to an incompletely saturated non-aromatic carbon ring that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 5- to 8-membered ring. Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, and cycloheptadienyl.

[0083] The term "heterocyclic group" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated) and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3- to 7-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, and / or nitrogen (preferably 1 or 2 heteroatoms). Non-limiting examples of heterocyclic groups include, but are not limited to, ethylene oxide, tetrahydrofuranyl, dihydrofuranyl, pyrrolyl, N-methylpyrrolyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophene, etc.

[0084] The term "heterocyclic alkyl" refers to a fully saturated cyclic group that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 4- to 7-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, and / or nitrogen. Non-limiting examples of 4-membered heterocyclic alkyl groups include, but are not limited to, acridineyl, oxadiazolyl, and thiobutylyl; examples of 5-membered heterocyclic alkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolylyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, imidazolyl, and tetrahydropyrazolyl; examples of 6-membered heterocyclic alkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl, piperazineyl, and 1,4-thiazolyl. Examples of oxalyl, 1,4-dioxane, thiomorpholinyl, 1,3-dithiaalkyl, 1,4-dithiaalkyl, and 7-membered heterocyclic alkyl groups include, but are not limited to, azirheptanyl, oxacycloheptanyl, thioheptanyl, 1,3-azioxacycloheptanane, 1,4-azioxacycloheptanane, 1,3-azithioheptanane, 1,4-azithioheptanane, 1,3-diazacycloheptanane, and 1,4-diazacycloheptanane. Monocyclic heterocyclic alkyl groups having 5 or 6 ring atoms are preferred.

[0085] The term "aryl" refers to an aromatic ring group consisting of an all-carbon monocyclic or fused polycyclic ring with a conjugated π-electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, and 1,2,3,4-tetrahydronaphthalene.

[0086] The term "heteroaryl" refers to a monocyclic or fused polycyclic system containing at least one ring atom selected from N, O, and S, with the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryls have a single 4- to 8-membered ring, particularly a 5- to 8-membered ring, or multiple fused rings containing 6 to 14, particularly 6 to 10, ring atoms. Non-limiting examples of heteroaryls include, but are not limited to, pyrroleyl, furanyl, thiopheneyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothiopheneyl, indoleyl, isoindoleyl, etc.

[0087] The term "treatment" means administering the compound or preparation described in this application to prevent, improve, or eliminate a disease or one or more symptoms related to said disease, and includes:

[0088] (i) To prevent the occurrence of disease or disease state in mammals, especially when such mammals are susceptible to the disease state but have not yet been diagnosed with the disease state;

[0089] (ii) To suppress the disease or disease state, that is, to curb its development;

[0090] (iii) Alleviate the disease or disease state, even if the disease or disease state subsides.

[0091] The term "therapeutic effective amount" means the amount of the compound of this application used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the present disclosure.

[0092] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0093] As pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, and salts formed with basic or acidic amino acids may be mentioned.

[0094] The term "pharmaceutical composition" refers to a mixture of one or more compounds of this application or their salts with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of this application to an organism.

[0095] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0096] The word “comprise” or “include” and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, meaning “including but not limited to”.

[0097] The compounds and intermediates of this application may also exist in different tautomer forms, and all such forms are included within the scope of this application. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is the imidazole moiety, where a proton can migrate between two ring nitrogens. Valence tautomers include interconversions via the recombination of some bonding electrons. This application also includes compounds of this application that are identical to those described herein, but with one or more atoms labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds of this application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.

[0098] Certain isotope-labeled compounds of this application (e.g., using...) 3 H and 14 Those labeled with C can be used in the analysis of compound and / or substrate tissue distribution. Tritiumization (i.e. 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes, such as... 15 O、 13 N、 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. The isotopically labeled compounds of this application can typically be prepared by replacing the unlabeled reagent with an isotopically labeled reagent using a procedure similar to those disclosed in the schemes and / or examples below.

[0099] In addition, heavier isotopes (such as deuterium) are used. 2H)) substitution can provide certain therapeutic advantages resulting from increased metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and is therefore preferred in some cases, where deuterium substitution can be partial or complete, with partial deuterium substitution referring to at least one hydrogen atom being substituted with at least one deuterium atom. Exemplary deuterated compounds are shown below, but are not limited to:

[0100]

[0101] The compounds of this application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds containing asymmetric carbon atoms of this application can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized using chiral starting materials or chiral reagents. Non-limiting examples of stereoisomers include, but are not limited to:

[0102]

[0103] The pharmaceutical compositions of this application can be prepared by combining the compounds of this application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0104] Typical routes of administration for the compounds of this application or their pharmaceutically acceptable salts or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0105] The pharmaceutical composition of this application can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.

[0106] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of this application to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, gels, pastes, suspensions, etc., for oral administration to patients.

[0107] Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated formulation. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0108] The pharmaceutical composition may also be suitable for parenteral administration, such as in suitable unit dosage forms of sterile solutions, suspensions or lyophilized products.

[0109] The compounds of this application can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of this application.

[0110] The chemical reactions in the specific embodiments of this application are carried out in a suitable solvent, which must be suitable for the chemical changes and the reagents and materials required in this application. In order to obtain the compounds of this application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction process based on existing embodiments.

[0111] An important consideration in synthetic route planning in this field is selecting appropriate protecting groups for reactive functional groups (such as amino groups in this application). For example, see Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0112] When ring A is selected At that time, compounds of general formula (I) of this application can be prepared by those skilled in the art of organic synthesis via route 1:

[0113]

[0114] Using compounds 1, 2, and 4 as raw materials, compound 1 and compound 2 undergo a Claisen condensation reaction to generate compound 3; compound 4 is reduced to give compound 5, which is then oxidized to give compound 6. Compound 3 and compound 6 react to give compound 7, which is reduced to give compound 8, then oxidized to give compound 9. Compound 9 then undergoes a reductive amination reaction with 4-aminobut-1-ol to give compound 10, followed by cyclization to give compound 11, which then undergoes cyanidation to give compound 12. Compound 12 is converted to compound 13, which then reacts with 4,6-dichloronicotinonitrile to give compound 14, followed by a substitution reaction to give compound 15, which is finally converted to compound (I).

[0115] This application uses the following abbreviations:

[0116] DMSO stands for dimethyl sulfoxide; CDCl3 stands for deuterated trichloromethane; Me stands for methyl.

[0117] Compounds artificially or Software naming conventions are used; commercially available compounds use supplier catalog names.

[0118] For clarity, the present invention is further illustrated by embodiments, but these embodiments are not intended to limit the scope of this application. This application has been described in detail herein, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the embodiments of this application without departing from the spirit and scope of this application.

[0119] All reagents used in this application are commercially available and can be used without further purification. Example

[0120] Example 1

[0121] N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-2-formyl-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide

[0122]

[0123] Step 1: Ethyl 4,4-dimethoxy-3-oxobutyrate

[0124]

[0125] In a 500 ml single-necked flask, methyl 2,2-dimethoxyacetate (74 g) and ethyl acetate (72.9 g) were added and stirred until well mixed. Then, sodium lumps (20.29 g) were added, and the mixture was heated to 60 degrees Celsius and stirred for 7 h. After concentration, the reaction solution yielded 77.16 g of the title compound, which was used directly in the next reaction without further purification.

[0126] Step 2: (2-Amino-3-bromophenyl)methanol

[0127]

[0128] In a 3L three-necked flask, 60g of 2-amino-3-bromobenzoic acid was dissolved in 500ml of tetrahydrofuran. The solution was cooled to 0°C, and 700g of borane was added dropwise, maintaining a temperature not exceeding 5°C. After the addition was complete, the temperature was raised to 60°C and the reaction was allowed to proceed for 30 hours. The reaction was quenched with 150ml of purified water, stirred for 10 minutes, and then concentrated under reduced pressure to obtain a crude product. This crude product was purified by column chromatography (petroleum ether:ethyl acetate = 7:3) to give 46.11g of the title compound. MS (ESI) m / z 202.0 [M+H] +

[0129] Step 3: 2-Amino-3-bromobenzaldehyde

[0130]

[0131] In a 1000 ml single-necked flask, 46 g of (2-amino-3-bromophenyl)methanol was dissolved in 450 ml of dichloromethane. 99 g of manganese dioxide was then added, and the mixture was stirred overnight at room temperature. The reaction solution was filtered, and the filtrate was concentrated and dried to give 43 g of the title compound. 1 H NMR (500MHz, CDCl3): δ9.82 (s, 1H), 7.61 (dd, J=7.8, 1.5Hz, 1H), 7.47 (dd, J=7.8, 1.5Hz, 1H), 6.70-6.49 (m, 3H).

[0132] Step 4: Ethyl 8-bromo-2-(dimethoxymethyl)quinoline-3-carboxylic acid

[0133]

[0134] In a 500 ml single-necked flask, 43 g of 2-amino-3-bromobenzaldehyde, 49.1 g of ethyl 4,4-dimethoxy-3-oxobutyrate, and 24.75 g of L-proline were dissolved in 300 ml of ethanol, and the mixture was heated to 90 °C and reacted for 6 h. The reaction solution was cooled to room temperature and concentrated. Ethyl acetate (300 ml) was added to the residue, and the mixture was stirred for 5 min and then filtered. The filtrate was concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give 38 g of the title compound. 1H NMR (500MHz, CDCl3): δ8.52(s,1H),8.12(dd,J=7.5,1.3Hz,1H),7.83(dd,J=8.1,1.3Hz,1H),7.49 -7.42(m,1H),6.12(s,1H),4.45(q,J=7.1Hz,2H),3.63(s,6H),1.45(t,J=7.2Hz,3H).MS(ESI)m / z 353.9[M+H] +

[0135] Step 5: (8-bromo-2-(dimethoxymethyl)quinoline-3-yl)methanol

[0136]

[0137] In a 1000 ml single-necked flask, 38 g of ethyl 8-bromo-2-(dimethoxymethyl)quinoline-3-carboxylic acid was dissolved in 490 ml of ethanol. Then, sodium borohydride (10.2 g) and calcium chloride (11.91 g) were added, and the mixture was stirred at room temperature for 6 h. After concentrating the reaction solution, water (1000 ml) and ethyl acetate (800 ml) were added. The organic phase was concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give 20 g of the title compound. 1 H NMR (500MHz, CDCl3): δ8.16(s,1H),8.02(dd,J=7.5,1.4Hz,1H),7.76(dd,J=8.1,1.3Hz,1H),7.39( t,J=7.8Hz,1H),5.54(s,1H),4.98(d,J=6.7Hz,2H),3.57(s,6H),3.50(t,J=6.9Hz,1H).MS(ESI)m / z 311.8[M+H] + .

[0138] Step 6: 8-Bromo-2-(dimethoxymethyl)quinoline-3-carboxaldehyde

[0139]

[0140] In a 1000 ml single-necked flask, 20 g of (8-bromo-2-(dimethoxymethyl)quinoline-3-yl)methanol was dissolved in 150 ml of dichloromethane, followed by the addition of 61.3 g of manganese dioxide. The mixture was stirred overnight at room temperature. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to give 16.5 g of the title compound. MS (ESI) m / z 309.8 [M+H] + .

[0141] Step 7: 4-(((8-bromo-2-(dimethoxymethyl)quinoline-3-yl)methyl)amino)but-1-ol

[0142]

[0143] In a 50 ml single-necked flask, 5 g of (8-bromo-2-(dimethoxymethyl)quinoline-3-yl)methanol was dissolved in 60 ml of 1,2-dichloroethane, followed by the addition of 1.724 g of 4-aminobut-1-ol. The mixture was stirred at room temperature for 2 h. 5.13 g of sodium triacetoxyborohydride was then added to the reaction solution, and the mixture was reacted overnight at room temperature. The reaction solution was concentrated to obtain a crude product, which was purified by column chromatography (dichloromethane:methanol = 20:1) to give 2 g of the title compound. 1 H NMR (500MHz, CDCl3): δ8.73(s,1H),8.04(dd,J=7.6,1.2Hz,1H),7.85(dd,J=8.2,1.3Hz,1H),7.39(t,J=7.8Hz,1H),5.51 (s,1H),4.59(s,2H),3.62-3.58(m,8H),3.07(t,J=7.0Hz,2H),1.95(p,J=6.9Hz,2H),1.62(p,J=6.2Hz,2H).MS(ESI)m / z 383.0[M+H] + .

[0144] Step 8: 3-((8-bromo-2-(dimethoxymethyl)quinoline-3-yl)methyl)-1,3-oxazacycloheptan-2-one

[0145]

[0146] In a 100 ml single-necked flask, 2 g of 4-((((8-bromo-2-(dimethoxymethyl)quinoline-3-yl)methyl)amino)but-1-ol was dissolved in 50 ml of 1,2-dichloroethane. Triphosgene (0.619 g) and triethylamine (2.112 g) were added sequentially. After the addition was complete, the mixture was heated to 80 °C and stirred for 3 h. After the reaction solution cooled to room temperature, it was poured into 100 ml of water and extracted with 200 ml of dichloromethane. The organic phase was washed with 100 ml of water and 100 ml of saturated brine, respectively, and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 100:1) to give 1.13 g of the title compound. 1H NMR (500MHz, CDCl3): δ8.16(s,1H),8.01(d,J=7.5,1.2Hz,1H),7.76(d,J=8.2,1.3Hz,1H),7.39(t,J=7.8Hz,1H),5.50(s ,1H),5.01(s,2H),4.29–4.15(m,2H),3.54(s,6H),3.34–3.23(m,2H),1.94–1.85(m,2H),1.70–1.65(m,2H).MS(ESI)m / z 409.1[M+H] + .

[0147] Step 9: 2-(dimethoxymethyl)-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxynitrile

[0148]

[0149] In a 100 ml single-necked flask, 1.1 g of 3-((8-bromo-2-(dimethoxymethyl)quinoline-3-yl)methyl)-1,3-oxazacycloheptan-2-one was dissolved in 15 ml of N,N-dimethylformamide. Then, 0.379 g of zinc cyanide, 0.246 g of tris(dibenzylacetone)palladium, 0.298 g of 1,1'-bis(diphenylphosphine)ferrocene, and 0.338 g of cuprous iodide were added sequentially. The mixture was heated to 155 °C and stirred for 4 h under nitrogen protection. After cooling to room temperature, the reaction mixture was poured into 50 ml of water and extracted with 50 ml of ethyl acetate. The organic phase was washed with 50 ml of water and 50 ml of saturated brine, respectively, and dried over anhydrous sodium sulfate. The crude product was filtered, concentrated, and purified by column chromatography (dichloromethane:methanol = 100:1) to obtain 480 mg of the title compound. 1 H NMR (500MHz, CDCl3): δ8.24(s,1H),8.10(d,J=7.2,1.4Hz,1H),8.04(d,J=8.3,1.4Hz,1H),7.61(t,J=8.2,7.2Hz,1H),5.52 (s,1H),5.02(s,2H),4.28–4.19(m,2H),3.55(s,6H),3.35–3.25(m,2H),1.95–1.87(m,2H),1.72–1.71(m,2H).MS(ESI)m / z 378.1[M+Na] + .

[0150] Step 10: 2-(dimethoxymethyl)-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide

[0151]

[0152] In a 50 ml single-necked flask, 160 mg of 2-(dimethoxymethyl)-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxynitrile was dissolved in 2 ml of water and 10.00 ml of methanol. Then, 160 mg of acetaldehyde oxime and 165 mg of copper oxide were added, and the mixture was heated to 85°C and stirred for 10 h. The reaction solution was concentrated to obtain a crude product, which was purified by column chromatography (dichloromethane:methanol = 20:1) to give 100 mg of the title compound. 1 H NMR (500MHz, DMSO-d6): δ10.41(s,1H),8.59(d,J=7.3,1.6Hz,1H),8.37(s,1H),8.29(d,J=8.2,1.6Hz,1H),7.90(d,J=4.0Hz,1H),7.76(t,J=8 .1,7.3Hz,1H),5.69(s,1H),4.79(s,2H),4.22–4.12(m,2H),3.44(s,6H) ),3.34–3.31(m,2H),1.83–1.79(m,2H),1.65–1.61(m,2H).MS(ESI)m / z 374.1[M+H] + .

[0153] Step 11: N-(4-chloro-5-cyanopyridin-2-yl)-2-(dimethoxymethyl)-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide

[0154]

[0155] In a 50 ml single-necked flask, 100 mg of 2-(dimethoxymethyl)-3-((2-oxo-1,3-oxazacycloheptan-3-yl)methyl)quinoline-8-carboxamide was dissolved in 2 ml of 1,4-dioxane. Then, 55.6 mg of 4,6-dichloronicotinonitrile, 27.0 mg of tris(dibenzylacetone)dipalladium, and 262 mg of cesium carbonate were added. The mixture was heated to 90 °C and stirred for 3.5 h under nitrogen protection. The reaction solution was directly concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give 70 mg of the title compound. MS (ESI) m / z 532.4 [M+Na] + .

[0156] Step 12: N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-2-(dimethoxymethyl)-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline 8-carboxamide

[0157]

[0158] In a 50 ml single-necked flask, N-(4-chloro-5-cyanopyridin-2-yl)-2-(dimethoxymethyl)-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide (70 mg) was dissolved in N,N-dimethylacetamide (2 ml), followed by the addition of 2-methoxyethane-1-amine (155 mg) and N,N-diisopropylethylamine (89 mg). The mixture was heated to 70 °C and stirred for 2 h. After cooling to room temperature, the reaction solution was poured into water (50 ml) and extracted with ethyl acetate (50 ml). The organic phase was washed with water (50 ml) and saturated brine (50 ml), respectively, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated to obtain a crude product, and purified by column chromatography (petroleum ether:ethyl acetate = 0:1) to give 60 mg of the title compound. MS (ESI) m / z 549.1 [M+H] + .

[0159] Step 13: N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-2-formyl-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide

[0160]

[0161] In a 25 ml single-necked flask, 100 mg of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-2-(dimethoxymethyl)-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline 8-carboxamide was dissolved in 1 ml of water and 3 ml of acetonitrile. Concentrated hydrochloric acid (177 mg) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was poured into 50 ml of saturated sodium bicarbonate solution and extracted with 50 ml of ethyl acetate. The organic phase was washed with 50 ml of water and 50 ml of saturated brine, respectively, and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by column chromatography (dichloromethane:methanol = 100:1) to give 22 mg of the title compound. 1H NMR (500MHz, DMSO-d6): δ13.65(s,1H),10.28(s,1H),8.75(dd,J=7.4,1.5Hz,1H),8.59(s,1H),8. 51(dd,J=8.4,1.5Hz,1H),8.35(d,J=2.9Hz,1H),7.98(t,J=7.7Hz,1H),7.83(s,1H),7.11(t,J=5.7 Hz,1H),5.00(s,2H),4.17(q,J=5.1,4.4Hz,2H),3.59(d,J=5.9Hz,2H),3.46(dd,J=10.9,5.2Hz,3 H),3.41–3.36(m,2H),1.82(q,J=5.7Hz,2H),1.68(d,J=7.7Hz,2H),1.21–1.14(m,2H).MS(ESI)m / z 525.1[M+Na] + .

[0162] Example 2

[0163] Synthesis of (S)-N-(5-cyano-4-((1-methoxypropane-2-yl)amino)pyridin-2-yl)-2-formyl-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide

[0164]

[0165] Step 1: Synthesis of (S)-N-(5-cyano-4-((1-methoxypropane-2-yl)amino)pyridin-2-yl)-2-(dimethoxymethyl)-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide

[0166]

[0167] In a 50 ml single-necked flask, N-(4-chloro-5-cyanopyridin-2-yl)-2-(dimethoxymethyl)-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide (0.1 g), N,N-dimethylacetamide (2 ml), (S)-1-methoxypropane-2-amine (0.262 g), and N,N-diisopropylethylamine (0.127 g) were added sequentially. The mixture was heated to 70 °C and stirred for 2 hours. After cooling to room temperature, the reaction solution was poured into water (50 ml) and extracted with ethyl acetate (50 ml). The organic phase was washed with water (50 ml) and saturated brine (50 ml), respectively, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 0:1) to give 0.1 g of the title compound. MS(ESI) m / z 563.1 [M+H] + .

[0168] Step 2: Synthesis of (S)-N-(5-cyano-4-((1-methoxypropane-2-yl)amino)pyridin-2-yl)-2-formyl-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide

[0169]

[0170] In a 25 ml single-necked flask, (S)-N-(5-cyano-4-((1-methoxypropane-2-yl)amino)pyridin-2-yl)-2-(dimethoxymethyl)-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide (100 mg), water (1 ml), acetonitrile (3 ml), and concentrated hydrochloric acid (1 ml) were added sequentially. The mixture was stirred at room temperature for 2 h. The reaction solution was poured into a saturated sodium bicarbonate solution (50 ml) and extracted with ethyl acetate (50 ml). The organic phase was washed with water (50 ml) and saturated brine (50 ml), respectively, and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by column chromatography (dichloromethane:methanol = 100:1) to give 60 mg of the title compound. 1H-NMR (500MHz, DMSO-d6): δ13.63(s,1H),10.25(s,1H),8.73-8.68(m,1H),8.61-8.54(m,1H), 8.49-8.45(m,1H),8.34-8.30(m,1H),7.98-7.92(m,1H),7.86-7.85(m,1H),6.79-6.70(m,1H), 4.99(s,2H),4.22-4.13(m,2H),3.97-3.88(m,1H),3.56-3.50(m,1H),3.45-3.42(m,1H),3.41- 3.37(m,2H),3.32(s,3H),1.87-1.79(m,2H),1.72-1.63(m,2H),1.27-1.22(m,3H).MS(ESI)m / z 517.3[M+H] + .

[0171] Example 3

[0172] Synthesis of N-(5-cyano-4-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-2-yl)-2-formyl-3-((2-oxo-1,3-oxaza-3-yl)methyl)quinoline-8-carboxamide

[0173]

[0174] Step 1: Synthesis of N-(5-cyano-4-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-2-yl)-2-(dimethoxymethyl)-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide

[0175]

[0176] In a 50 mL single-necked flask, N-(4-chloro-5-cyanopyridin-2-yl)-2-(dimethoxymethyl)-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide (150 mg), 4-methylpiperidin-4-ol (508 mg), N,N-dimethylacetamide (2 mL), and N,N-diisopropylethylamine (1141 mg) were added sequentially. Under nitrogen protection, the mixture was heated to 80 °C and stirred for 3 h. After cooling to room temperature, the reaction solution was poured into 100 mL of water and filtered. The filter cake was washed three times with 100 mL of water and evaporated to dryness under reduced pressure to obtain 150 mg of the title compound. MS (ESI) m / z 589.2 [M+H] + .

[0177] Step 2: Synthesis of N-(5-cyano-4-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-2-yl)-2-formyl-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide

[0178]

[0179] In a 50 mL single-necked flask, N-(5-cyano-4-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-2-yl)-2-(dimethoxymethyl)-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide (100 mg), acetonitrile (2 mL), and water (2 mL), along with 4 M hydrochloric acid (1 mL), were added sequentially. The mixture was reacted at room temperature for 4 h under nitrogen protection. 4 M hydrochloric acid (1 mL) was added again, and the temperature was raised to 50 °C for 30 minutes. After cooling to room temperature, the reaction mixture was poured into a saturated sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (50 mL). The organic phase was washed with water (50 mL) and saturated brine (50 mL), respectively, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and the crude product was purified by column chromatography (dichloromethane:methanol = 100:1) to give 17 mg of the title compound. 1 HNMR (500MHz, DMSO-d6): δ13.73(s,1H),10.28(s,1H),8.78–8.68(m,1H),8.5 9(s,1H),8.56–8.46(m,1H),8.48(s,1H),8.07(s,1H),7.99(t,J=7.8Hz,1H),5 .00(s,2H),4.54(s,1H),4.17(t,J=5.2Hz,2H),3.75–3.66(m,2H),3.36(t,J=1 6.2Hz,6H),1.83(t,J=5.6Hz,2H),1.67–1.64(m,4H),1.23(s,3H).MS(ESI)m / z 543.1[M+H] + .

[0180] Example 4

[0181] Synthesis of N-(5-cyano-4-((2-methoxyethyl)(methyl)amino)pyridin-2-yl)-2-formyl-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide

[0182]

[0183] Step 1: Synthesis of N-(5-cyano-4-((2-methoxyethyl)(methyl)amino)pyridin-2-yl)-2-(dimethoxymethyl)-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide

[0184]

[0185] In a 50 mL single-necked flask, N-(4-chloro-5-cyanopyridin-2-yl)-2-(dimethoxymethyl)-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide (150 mg), 2-methoxy-N-methylethyl-1-amine (393 mg), N,N-dimethylacetamide (2 mL), and N,N-diisopropylethylamine (1141 mg) were added sequentially. Under nitrogen protection, the mixture was heated to 80 °C and stirred for 3 h. After cooling to room temperature, the reaction solution was poured into 100 mL of water and filtered. The filter cake was washed three times with 100 mL of water and evaporated to dryness under reduced pressure to give 152 mg of the title compound. MS (ESI) m / z 563.2 [M+H] + .

[0186] Step 2: Synthesis of N-(5-cyano-4-((2-methoxyethyl)(methyl)amino)pyridin-2-yl)-2-formyl-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide

[0187]

[0188] In a 50 mL single-necked flask, N-(5-cyano-4-((2-methoxyethyl)(methyl)amino)pyridin-2-yl)-2-(dimethoxymethyl)-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide (100 mg), acetonitrile (2 mL), and water (2 mL), along with 4 M hydrochloric acid (1 mL), were added sequentially. The mixture was reacted at room temperature for 4 h under nitrogen protection. 4 M hydrochloric acid (1 mL) was then added, and the temperature was raised to 50 °C for 30 minutes. After cooling to room temperature, the reaction mixture was poured into a saturated sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (50 mL). The organic phase was washed with water (50 mL) and saturated brine (50 mL), respectively, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and the crude product was purified by column chromatography (dichloromethane:methanol = 100:1) to give 32 mg of the title compound. 1HNMR (500MHz, CDCl3): δ13.81 (s, 1H), 10.55 (s, 1H), 8.94 (d, J = 7.4Hz, 1H), 8.43 ( s,1H),8.36(s,1H),8.31(s,1H),8.13(d,J=8.2Hz,1H),8.01(s,1H),7.94–7.84(m ,1H),5.17(s,2H),4.23–4.17(m,2H),3.91(t,J=5.3Hz,2H),3.75(t,J=5.3Hz,2H ),3.49–3.42(m,4H),3.34(s,3H),2.0–1.9(m,2H),1.85–1.75(m,2H).MS(ESI)m / z 517.2[M+H] + .

[0189] Example 5

[0190] Synthesis of N-(5-cyano-4-(isopropylamino)pyridin-2-yl)-2-formyl-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide

[0191]

[0192] Step 1: N-(5-cyano-4-(isopropylamino)pyridin-2-yl)-2-(dimethoxymethyl)-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide

[0193]

[0194] In a 50 ml single-necked flask, 100 mg of N-(4-chloro-5-cyanopyridin-2-yl)-2-(dimethoxymethyl)-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide was dissolved in 3 ml of N,N-dimethylacetamide. Isopropylamine (174 mg) and N,N-diisopropylethylamine (127 mg) were then added, and the mixture was heated to 70 °C and stirred for 2 h. After cooling to room temperature, the reaction solution was poured into 50 ml of water and extracted with 50 ml of ethyl acetate. The organic phase was washed with 50 ml of water and 50 ml of saturated brine, respectively, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated to obtain a crude product, and purified by column chromatography (petroleum ether:ethyl acetate = 0:1) to give 84 mg of the title compound. 1H NMR (500MHz, CDCl3): δ14.21(s,1H),8.86(dd,J=7.3,1.5Hz,1H),8.34(s,1H),8.29(s, 1H),8.04(dd,J=8.2,1.5Hz,1H),7.94(s,1H),7.74(t,J=7.8Hz,1H),5.68(s,1H),5.02 (s,2H),4.80(d,J=7.6Hz,1H),4.26–4.20(m,2H),4.00–3.94(m,1H),3.58(s,6H),3.35 –3.29(m,2H),1.95–1.90(m,2H),1.75–1.69(m,2H),1.35(d,J=6.3Hz,6H).MS(ESI)m / z 533.1[M+H] + .

[0195] Step 2: N-(5-cyano-4-(isopropylamino)pyridin-2-yl)-2-formyl-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide

[0196]

[0197] In a 25 ml single-necked flask, N-(5-cyano-4-(isopropylamino)pyridin-2-yl)-2-(dimethoxymethyl)-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide (84 mg) was dissolved in water (1 ml) and tetrahydrofuran (3 ml). Concentrated hydrochloric acid (0.15 ml) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was poured into a saturated sodium bicarbonate solution (50 ml) and extracted with ethyl acetate (50 ml). The organic phase was washed with water (50 ml) and saturated brine (50 ml), respectively, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated to obtain a crude product, and purified by column chromatography (dichloromethane:methanol = 100:1) to give 40 mg of the title compound. 1H NMR (500MHz, CDCl3): δ13.84 (s, 1H), 10.56 (s, 1H), 8.96 (dd, J = 7.3, 1.5Hz, 1H), 8.44 (s, 1H),8.26(s,1H),8.14(dd,J=8.2,1.5Hz,1H),7.93(s,1H),7.89(t,J=7.8Hz,1H),5.24–5 .12(m,2H),4.86(d,J=7.6Hz,1H),4.25–4.17(m,2H),3.96(dp,J=13.1,6.5Hz,1H),3.48– 3.40(m,2H),1.95(p,J=5.7Hz,2H),1.83–1.75(m,2H),1.36(d,J=6.4Hz,6H).MS(ESI)m / z 487.2[M+H]+.

[0198] Example 6

[0199] Synthesis of N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-2-formyl-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide

[0200]

[0201] Step 1: N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-2-(dimethoxymethyl)-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide

[0202]

[0203] In a 50 ml single-necked flask, 100 mg of N-(4-chloro-5-cyanopyridin-2-yl)-2-(dimethoxymethyl)-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide was dissolved in 3 ml of N,N-dimethylacetamide. Then, 268 mg of 2-(methylthio)ethane-1-amine and 127 mg of N,N-diisopropylethylamine were added, and the mixture was heated to 70 °C and stirred for 2 h. After cooling to room temperature, the reaction solution was poured into 50 ml of water and extracted with 50 ml of ethyl acetate. The organic phase was washed with 50 ml of water and 50 ml of saturated brine, respectively, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated to obtain a crude product, and purified by column chromatography (petroleum ether:ethyl acetate = 0:1) to give 48 mg of the title compound. 1H NMR (500MHz, CDCl3): δ14.26(s,1H),8.85(dd,J=7.4,1.5Hz,1H),8.33(d,J=15.7Hz,2H) ,8.04(dd,J=8.2,1.5Hz,1H),7.96(s,1H),7.75(t,J=7.8Hz,1H),5.68(s,1H),5.41(t,J= 5.4Hz,1H),5.02(s,2H),4.26–4.20(m,2H),3.59(s,8H),3.33(dd,J=6.8,3.3Hz,2H),2.8 6(t,J=6.5Hz,2H),2.20(s,3H),1.93(p,J=5.7Hz,2H),1.73(q,J=5.4Hz,2H).MS(ESI)m / z 565.1[M+H] + .

[0204] Step 2: N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-2-formyl-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide

[0205]

[0206] In a 25 ml single-necked flask, N-(5-cyano-4-((2-(methylthio)ethyl)amino)pyridin-2-yl)-2-(dimethoxymethyl)-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide (48 mg) was dissolved in water (1 ml) and tetrahydrofuran (3 ml). Concentrated hydrochloric acid (0.15 ml) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was poured into a saturated sodium bicarbonate solution (50 ml) and extracted with ethyl acetate (50 ml). The organic phase was washed with water (50 ml) and saturated brine (50 ml), respectively, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated to obtain a crude product, and purified by column chromatography (dichloromethane:methanol = 100:1) to give 44 mg of the title compound. 1H NMR (500MHz, CDCl3): δ13.89 (s, 1H), 10.57 (s, 1H), 8.96 (dd, J = 7.4, 1.6Hz, 1H), 8.44 (s, 1H), 8.28(s,1H),8.14(dd,J=8.2,1.5Hz,1H),7.95(d,J=3.8Hz,1H),7.90(t,J=7.8Hz,1H),5.46(t ,J=5.5Hz,1H),5.17(s,2H),4.22–4.19(m,2H),3.63–3.59(m,2H),3.46–3.42(m,2H),2.87(t, J=6.5Hz,2H),2.20(d,J=2.8Hz,3H),1.95(q,J=5.7Hz,2H),1.80(d,J=4.2Hz,2H).MS(ESI)m / z 519.2[M+H]+.

[0207] Example 7

[0208] Synthesis of N-(5-cyano-4-(cyclopropylamino)pyridin-2-yl)-2-formyl-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide

[0209]

[0210] Step 1: N-(5-cyano-4-(cyclopropylamino)pyridin-2-yl)-2-(dimethoxymethyl)-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide

[0211]

[0212] In a 50 ml single-necked flask, 100 mg of N-(4-chloro-5-cyanopyridin-2-yl)-2-(dimethoxymethyl)-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide was dissolved in 3 ml of N,N-dimethylacetamide. Cyclopropylamine (168 mg) and N,N-diisopropylethylamine (127 mg) were then added, and the mixture was heated to 70 °C and stirred for 2 h. After cooling to room temperature, the reaction solution was poured into 50 ml of water and extracted with 50 ml of ethyl acetate. The organic phase was washed with 50 ml of water and 50 ml of saturated brine, respectively, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated to obtain a crude product, and purified by column chromatography (petroleum ether:ethyl acetate = 0:1) to give 74 mg of the title compound. 1H NMR (500MHz, CDCl3): δ14.25(s,1H),8.88(dd,J=7.4,1.5Hz,1H),8.35(s,1H),8.29(d,J=14. 3Hz,2H),8.04(dd,J=8.1,1.5Hz,1H),7.74(t,J=7.8Hz,1H),5.68(s,1H),5.02(s,2H),4.27–4 .19(m,2H),3.59(s,6H),3.37–3.31(m,2H),3.01(s,1H),2.72–2.68(m,1H),1.93(p,J=5.8Hz, 2H),1.73(dd,J=11.4,5.6Hz,2H),1.01(td,J=7.0,5.2Hz,2H),0.76–0.64(m,2H).MS(ESI)m / z 531.1[M+H] + .

[0213] Step 2: N-(5-cyano-4-(cyclopropylamino)pyridin-2-yl)-2-formyl-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide

[0214]

[0215] In a 25 ml single-necked flask, N-(5-cyano-4-(cyclopropylamino)pyridin-2-yl)-2-(dimethoxymethyl)-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide (74 mg) was dissolved in water (1 ml) and tetrahydrofuran (3 ml). Concentrated hydrochloric acid (0.15 ml) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was poured into a saturated sodium bicarbonate solution (50 ml) and extracted with ethyl acetate (50 ml). The organic phase was washed with water (50 ml) and saturated brine (50 ml), respectively, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated to obtain a crude product, and purified by column chromatography (dichloromethane:methanol = 100:1) to give 35 mg of the title compound. 1H NMR (500MHz, CDCl3): δ13.89 (s, 1H), 10.58 (d, J = 0.7Hz, 1H), 8.99 (dd, J = 7.4, 1.5Hz, 1H), 8. 44(s,1H),8.27(d,J=4.1Hz,2H),8.14(dd,J=8.2,1.5Hz,1H),7.90(t,J=7.8Hz,1H),5.38(d ,J=11.1Hz,1H),5.18(d,J=0.9Hz,2H),4.22–4.19(m,2H),3.48–3.39(m,2H),2.72–2.69(m, 1H),1.97–1.92(m,2H),1.81–1.79(m,2H),1.04–1.00(m,2H),0.73–0.69(m,2H).MS(ESI)m / z 485.2[M+H] + .

[0216] Example 8

[0217] Synthesis of N-(5-cyano-4-(prop-2-yn-1-ylamino)pyridin-2-yl)-2-formyl-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide

[0218]

[0219] Step 1: N-(5-cyano-4-(prop-2-yn-1-ylamino)pyridin-2-yl)-2-(dimethoxymethyl)-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide

[0220]

[0221] In a 50 ml single-necked flask, 100 mg of N-(4-chloro-5-cyanopyridin-2-yl)-2-(dimethoxymethyl)-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide was dissolved in 3 ml of N,N-dimethylacetamide. Then, 162 mg of propargylamine and 127 mg of N,N-diisopropylethylamine were added, and the mixture was heated to 70 °C and stirred for 2 h. After cooling to room temperature, the reaction solution was poured into 50 ml of water and extracted with 50 ml of ethyl acetate. The organic phase was washed with 50 ml of water and 50 ml of saturated brine, respectively, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated to obtain a crude product, and purified by column chromatography (petroleum ether:ethyl acetate = 0:1) to give 64 mg of the title compound. 1H NMR (500MHz, CDCl3): δ14.31 (s, 1H), 8.87 (dd, J = 7.4, 1.5Hz, 1H), 8.35 (s, 2H ),8.08–8.00(m,2H),7.75(t,J=7.7Hz,1H),5.68(s,1H),5.21(t,J=5.6Hz,1 H),5.06–4.98(m,2H),4.28–4.17(m,4H),3.58(s,6H),3.34–3.32(m,2H),2. 38(t,J=2.5Hz,1H),1.93(p,J=5.9Hz,2H),1.71(t,J=4.0Hz,2H).MS(ESI)m / z 529.12[M+H] + .

[0222] Step 2: N-(5-cyano-4-(prop-2-yn-1-ylamino)pyridin-2-yl)-2-formyl-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide

[0223]

[0224] In a 25 ml single-necked flask, N-(5-cyano-4-(prop-2-yn-1-ylamino)pyridin-2-yl)-2-(dimethoxymethyl)-3-((2-oxo-1,3-oxazacycloheptane-3-yl)methyl)quinoline-8-carboxamide (64 mg) was dissolved in water (1 ml) and tetrahydrofuran (3 ml). Concentrated hydrochloric acid (0.15 ml) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was poured into a saturated sodium bicarbonate solution (50 ml) and extracted with ethyl acetate (50 ml). The organic phase was washed with water (50 ml) and saturated brine (50 ml), respectively, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated to obtain a crude product, and purified by column chromatography (dichloromethane:methanol = 100:1) to give 30 mg of the title compound. 1H NMR (500MHz, CDCl3): δ13.72(s,1H),10.30(s,1H),8.78(dd,J=7.3,1.5Hz,1H),8.60(s,1 H),8.52(dd,J=8.3,1.5Hz,1H),8.43(s,1H),7.99(t,J=7.8Hz,1H),7.96(s,1H),7.62(t,J =5.8Hz,1H),5.00(s,2H),4.17(t,J=5.2Hz,2H),4.09(dd,J=5.9,2.4Hz,2H),3.41–3.37(m ,2H),3.27(t,J=2.4Hz,1H),1.83(q,J=5.6Hz,2H),1.68(q,J=5.3,4.9Hz,2H).MS(ESI)m / z 483.1[M+H] + .

[0225] Experiment Example 1: In vitro kinase inhibitory activity test

[0226] 1.1 Screening for FGFR1 kinase inhibitory activity

[0227] Dilute 50 ng / μL of FGFR1 stock solution with kinase buffer (50 mM HEPES, 10 mM MgCl2, 2 mM DTT, 1 mM EGTA, 0.01% Tween 20). Add 6 μL of 1.67× 0.0025 ng / μL working solution to each well (final concentration 0.0015 ng / μL). Add different compounds dissolved in DMSO to the wells using a nanoparticle pipette to achieve a final concentration gradient of 1000 nM to 0.24 nM, for a total of 7 concentrations. Also include blank control wells (without enzyme) and negative control wells (containing enzyme, with DMSO as solvent), with 2 replicates. After the enzyme reacts with the compound or solvent for 30 min, 50 μM ATP (final concentration 10 μM) prepared with kinase buffer and 0.5 μM substrate (final concentration 0.1 μM, U Light-poly GT) are mixed at a 1:1 ratio and added to each well at a concentration of 4 μL. After sealing with a sealing membrane, the plate is incubated at room temperature for 2 h. Then, 5 μL of 40 mM EDTA (final concentration 10 mM) is added to each well, and the plate is incubated at room temperature for 5 min. Next, 5 μL of 8 nM 4× assay reagent (final concentration 2 nM, Eμ-anti-phospho-tyrosine antibody) is added to each well, and the plate is incubated at room temperature for 1 h. The plate is read using a PE instrument (excitation 320 or 340 nm, emission 665 nm), and the IC50 is calculated using four-parameter fitting. 50 .

[0228] 1.2 Screening for FGFR4 kinase inhibitory activity

[0229] Dilute the 50 ng / μL FGFR4 stock solution with kinase buffer (50 mM HEPES, 10 mM MgCl2, 2 mM DTT, 1 mM EGTA, 0.01% Tween 20). Add 6 μL of 1.67× 0.168 ng / μL working solution to each well (final concentration 0.1 ng / μL). Add different compounds dissolved in DMSO to the wells using a nanoparticle pipette to achieve a final concentration gradient of 1000 nM to 0.24 nM, for a total of 7 concentrations. Also include blank control wells (without enzyme) and negative control wells (containing enzyme, with DMSO as solvent). After the enzyme reacts with the compound or solvent for 30 min, 50 μM ATP (final concentration 10 μM) prepared with kinase buffer and 0.5 μM substrate (final concentration 0.1 μM, U Light-poly GT) are mixed at a 1:1 ratio and added to each well at a concentration of 4 μL. After sealing with a sealing membrane, the plate is incubated at room temperature for 2 h. Then, 5 μL of 40 mM EDTA (final concentration 10 mM) is added to each well, and the plate is incubated at room temperature for 5 min. Next, 5 μL of 8 nM 4× assay reagent (final concentration 2 nM, Eμ-anti-phospho-tyrosine antibody) is added to each well, and the plate is incubated at room temperature for 1 h. The plate is read using a PE instrument (excitation 320 or 340 nm, emission 665 nm), and the IC50 is calculated using a four-parameter fitting method. 50 .

[0230] 1.3 Screening for FGFR4 (V550L) kinase inhibitory activity

[0231] Dilute the 50 ng / μL FGFR4 (V550L) stock solution with kinase buffer (50 mM HEPES, 10 mM MgCl2, 2 mM DTT, 1 mM EGTA, 0.01% Tween 20). Add 6 μL of 1.67× 0.05 ng / μL working solution to each well (final concentration 0.03 ng / μL). Add different compounds dissolved in DMSO to the wells using a nanoparticle pipette to achieve a final concentration gradient of 100 nM to 0.024 nM, for a total of 7 concentrations. Also include blank control wells (without enzyme) and negative control wells (containing enzyme, with DMSO as solvent). After the enzyme reacts with the compound or solvent for 30 min, 50 μM ATP (final concentration 10 μM) prepared with kinase buffer and 0.5 μM substrate (final concentration 0.1 μM, U Light-poly GT) are mixed at a 1:1 ratio and added to each well at a concentration of 4 μL. After sealing with a sealing membrane, the plate is incubated at room temperature for 2 h. Then, 5 μL of 40 mM EDTA (final concentration 10 mM) is added to each well, and the plate is incubated at room temperature for 5 min. Next, 5 μL of 8 nM 4× assay reagent (final concentration 2 nM, Eμ-anti-phospho-tyrosine antibody) is added to each well, and the plate is incubated at room temperature for 1 h. The plate is read using a PE instrument (excitation 320 or 340 nm, emission 665 nm), and the IC50 is calculated using a four-parameter fitting method. 50 .

[0232] Table 1. In vitro kinase inhibitory activity of compounds in the examples.

[0233]

[0234] Experimental Example 2: Screening of ERK phosphorylation inhibition activity in Hep 3B cells

[0235] Hep 3B cells in the logarithmic growth phase were washed with PBS, digested with trypsin, and cultured in MEM complete medium. The cells were centrifuged at 1000 rpm for 5 min using a low-speed benchtop centrifuge. After the supernatant was collected, an appropriate amount of MEM seeding medium without fluorescein was added to resuspend the cells. The cells were counted and the cell density was adjusted to 5*10E5 cells / ml. The cells were then seeded in 96-well plates with 100 μL / well and cultured overnight at 37°C in a 5% CO2 incubator. On the second day, samples were added using a nano-pipette, and the compound was incubated for 3 hours. 10 μL of 50 ng / mL FGF19 was added to each well according to the plate distribution. The blank group was seeded with cells without the compound or FGF19; the control group was seeded with cells without the compound but with FGF19. The cells were incubated for 30 minutes, and the supernatant was discarded. Immediately after incubation, 50 μL of lysis buffer (1X) with blocking buffer was added, and the cells were shaken and incubated for 30 minutes at room temperature. 16 μL of cell lysis buffer was transferred to another 384 low-volume plate, and 4 μL of pre-mixed antibody (vol / vol) prepared with detection buffer was added. The plate was capped, centrifuged to ensure homogeneity, and incubated overnight at room temperature. The PE Envision multi-function plate reader was used to detect the 665 nm / 620 nm signal values, and the IC50 was calculated using a four-parameter fitting method. 50 .

[0236] Table 2. Inhibitory activity of compounds in Hep 3B cells against ERK phosphorylation in the examples.

[0237]

Claims

1. A compound of formula (Ia) or a pharmaceutically acceptable salt or stereoisomer thereof, or a mixture thereof, in, R 1 Selected from -NR a R b ; R a The group is selected from methyl, ethyl, propyl, butyl, ethynyl, propynyl, butynyl, cyclopropane, cyclobutane, cyclopentane, or cyclohexane, wherein the methyl, ethyl, propyl, butyl, ethynyl, propynyl, or butynyl group is optionally separated by one or more R groups. c The cyclopropane, cyclobutane, cyclopentane, or cyclohexane may optionally be replaced by one or more R d replace; R b Selected from H or C 1-3 alkyl; Each R c Each is independently selected from -F, -Cl, -Br, methoxy, methylthio, methylamino, ethylamino, or dimethylamino; Each R d Each is independently selected from -F, -Cl, -Br, -OH, -NH2, methyl, or ethyl.

2. The compound of claim 1 or its pharmaceutically acceptable salt, or stereoisomer, or mixture thereof, characterized in that, R a Selected from ethyl, isopropyl, 2-propynyl, or cyclopropane, wherein the ethyl, isopropyl, or 2-propynyl group is optionally surrounded by one or more R groups. c The cyclopropane is optionally replaced by one or more R d replace.

3. The compound of claim 1 or its pharmaceutically acceptable salt, or stereoisomer, or mixture thereof, characterized in that, R b Selected from H or methyl.

4. The compound of claim 1 or its pharmaceutically acceptable salt, or stereoisomer, or mixture thereof, characterized in that, Each R c Each is independently selected from methoxy or methylthio.

5. The compound of claim 1 or its pharmaceutically acceptable salt, or stereoisomer, or mixture thereof, characterized in that, Each R d Each is independently selected from -OH or methyl.

6. The compound of claim 1 or its pharmaceutically acceptable salt, or stereoisomer, or mixture thereof, characterized in that, R 1 Selected from 7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a mixture thereof, selected from the following compounds or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or mixtures thereof:

8. A pharmaceutical composition comprising a compound as claimed in any one of claims 1-7, or a pharmaceutically acceptable salt or stereoisomer thereof, or a mixture thereof.

9. Use of the compound of any one of claims 1-7, or a pharmaceutically acceptable salt or stereoisomer thereof, or a mixture thereof, or the pharmaceutical composition of claim 8, in the preparation of a medicament for treating FGFR4-related diseases.

10. The use as described in claim 9, characterized in that, The FGFR4-related diseases mentioned are cancers.

11. The use as described in claim 10, characterized in that, The cancer in question is liver cancer.

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