Bicycloheptenylamino-substituted azaheterocyclic compounds and medical uses thereof

Abstract

The present application relates to bicyclic heptenyl amino substituted azaheterocyclic compounds and their medical uses, the structure is shown as formula (I). The present application also relates to the preparation method of the compounds, pharmaceutical compositions and their use as FGFR4 inhibitors in the treatment of cancer.

Description

Technical Field

[0001] This application relates to bicyclic heptenylamino-substituted nitrogen-containing aromatic 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] W is selected from N or CH;

[0010] X is selected from N or CR a ;

[0011] Y is selected from N or CR b ;

[0012] Z is selected from N or CR. c ;

[0013] R a R b R c Each is independently selected from H, halogens, -CN, -OH, -NH2, and C. 1-4Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 alkylamino, or di-C 1-4 Alkylamino;

[0014] R 1 R 2 Each is independently selected from H and C. 1-4 Alkyl, deuterated C 1-4 Alkyl or halogenated C 1-4 alkyl;

[0015] R 3 Selected from H, halogens, -CN, -OH, -NH2, or optionally by one or more R d1 The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamino, or di-C 1-6 Alkylamino, or optionally by one or more R d2 Substitution with the following groups: 3-12 membered cycloalkyl, 3-10 membered cycloalkyl-C 1-3 Alkyl, 4-12 membered heterocyclic alkyl, 4-10 membered heterocyclic alkyl-C 1-3 Alkyl, 4-7 membered heterocyclic alkyl substituted with 4-7 membered heterocyclic alkyl, 4-7 membered heterocyclic alkyl substituted with 3-7 membered heterocyclic alkyl, or 3-7 membered heterocyclic alkyl substituted with 4-7 membered heterocyclic alkyl;

[0016] Each R d1 Each is independently selected from oxo, halogen, -CN, -OH, -NH2, and halogenated C. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 alkylamino, or di-C 1-4 Alkylamino;

[0017] Each R d2 Each is independently selected from oxo, halogen, -CN, -OH, -NH2, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C 1-3 Alkyloxy-C 1-3 Alkyl, Halogenated C 1-4 Alkoxy, C 1-4 Alkylamino, diC 1-4 Alkylamino, C 1-3 Alkylamino-C 1-3 Alkyl or di-C 1-3 Alkylamino-C1-3 alkyl;

[0018] Or R 3 R b Connected together to form an optional combination of one or more R e The following groups are substituted: 3-12 membered cycloalkenes, 6-10 membered aromatic rings, 4-12 membered heterocycles, or 4-8 membered heteroaromatic rings;

[0019] Each R e Each is independently selected from oxo, halogen, -CN, -OH, -NH2, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 alkylamino, or di-C 1-4 Alkylamino;

[0020] R 4 Selected from H, deuterium, halogen, cyano, C 1-3 Alkyl or halogenated C 1-3 alkyl.

[0021] In some implementations, W is selected from N. In some implementations, W is selected from CH.

[0022] In some implementations, X is selected from CR a Y is selected from CR b Z is selected from CR c .

[0023] In some implementations, one of X, Y, and Z is selected from N. In some implementations, X is selected from N; Y is selected from CR. b Z is selected from CR c In some implementations, X is selected from CR. a Y is selected from N; Z is selected from CR. c In some implementations, X is selected from CR. a Y is selected from CR b Z is selected from N.

[0024] In some implementations, two of X, Y, and Z are selected from N. In some implementations, X is selected from CR. a Y is selected from N; Z is selected from N. In some implementations, X is selected from N; Y is selected from CR. b Z is selected from N. In some implementations, X is selected from N; Y is selected from N; Z is selected from CR. c .

[0025] In some implementation schemes, R a R b Rc Each is independently selected from H, halogen, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 alkoxy or halogenated C 1-4 Alkyl group.

[0026] In some implementation schemes, R a R b R c Each is independently selected from H, halogen, C 1-4 Alkyl, or C 1-4 Alkyl group.

[0027] In some implementation schemes, R a Selected from H, or halogens. In some embodiments, R a Selected from H, F, Cl, or Br. In some embodiments, R a Selected from H or F. In some implementations, R a Selected from H.

[0028] In some implementation schemes, R b Selected from H, halogen, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy. In some embodiments, R b Selected from H, F, Cl, Br, methyl, ethyl, methoxy, or ethoxy. In some embodiments, R b Selected from H.

[0029] In some implementation schemes, R c Selected from H, halogen, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy. In some embodiments, R c Selected from H, F, Cl, methyl, or methoxy. In some embodiments, R c Selected from H.

[0030] In some implementation schemes, R a R b R c Selected from H.

[0031] In some implementation schemes, R 1 R 2 Each is independently selected from H, methyl, ethyl, deuterated methyl, deuterated ethyl, halomethyl, or haloethyl. In some embodiments, R 1 R 2 Each is independently selected from H, methyl, or -CD3. In some embodiments, R 1 R 2 Each is independently selected from H or methyl. In some embodiments, R1 R 2 All are H.

[0032] In some implementation schemes, R 3 Selected from one or more R d1 The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamino, or di-C 1-6 Alkylamino, or optionally by one or more R d2 Substitution with the following groups: 3-12 membered cycloalkyl, 3-10 membered cycloalkyl-C 1-3 Alkyl, 4-12 membered heterocyclic alkyl, 4-10 membered heterocyclic alkyl-C 1-3 Alkyl, or 4-7 membered heterocyclic alkyl substituted with alkyl or heterocyclic alkyl.

[0033] In some implementation schemes, R 3 Selected from one or more R d1 Replacement of C 1-6 Alkylamino, or optionally by one or more R d2 Substitution with the following groups: 4-12 membered heterocyclic alkyl, 4-10 membered heterocyclic alkyl-C 1-3 Alkyl, or 4-7 membered heterocyclic alkyl substituted with alkyl or heterocyclic alkyl.

[0034] In some implementation schemes, R 3 Selected from one or more R d1 The following groups are substituted: methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, or methylethylamino, or optionally, replaced by one or more R groups. d2 The following groups may be substituted: 5-9 membered cycloalkyl, 5-9 membered cycloalkylmethyl, 5-9 membered heterocycloalkyl, 5-9 membered heterocycloalkylmethyl, or 4-7 membered heterocycloalkyl substituted with one of the 4-7 membered heterocycloalkyl groups.

[0035] In some implementation schemes, R 3 Selected from one or more R d1 Substituted ethyl or methylethylamino, or optionally, by one or more R d2 The following groups are substituted:

[0036] In some implementation schemes, R 3 Selected from one or more R d1 The substituted methylethylamino group, or optionally, the methylethylamino group, is substituted with one or more R groups. d2 The following groups are substituted:

[0037] In some implementations, each R d1 Each is independently selected from oxo, F, Cl, Br, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, halomethyl, haloethyl, methoxy, ethoxy, halomethoxy, methylamino, ethylamino, dimethylamino, or diethylamino.

[0038] In some implementations, each R d1 Each is independently selected from oxo, F, Cl, Br, -CN, -OH, -NH2, halomethyl, haloethyl, methoxy, ethoxy, halomethoxy, methylamino, ethylamino, dimethylamino, or diethylamino.

[0039] In some implementations, each R d1 Each is independently selected from oxo, F, Cl, Br, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CF2CH3, methoxy, ethoxy, -OCF3, methylamino, ethylamino, dimethylamino, or diethylamino.

[0040] In some implementations, each R d1 Each is independently selected from oxo, F, Cl, Br, -CN, -OH, -NH2, -CF3, -CHF2, -CF2CH3, methoxy, ethoxy, -OCF3, methylamino, ethylamino, dimethylamino, or diethylamino.

[0041] In some implementations, each R d1 Each is independently selected from oxo, F, Cl, Br, -CN, -OH, -NH2, methoxy, ethoxy, -OCF3, methylamino, ethylamino, dimethylamino, or diethylamino.

[0042] In some implementations, each R d1 Each is independently selected from C 1-4 Alkylamino or diC 1-4 Alkylamino. In some embodiments, each R d1 Each is independently selected from methylamino, ethylamino, dimethylamino, or diethylamino.

[0043] In some implementations, each R d2 Each is independently selected from oxo, F, Cl, Br, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, halomethyl, haloethyl, methoxy, ethoxy, methoxy-C 1-3Alkyl, halomethoxy, methylamino, ethylamino, dimethylamino, diethylamino, methylamino-C 1-3 Alkyl, ethylamino-C 1-3 Alkyl, dimethylamino-C 1-3 Alkyl, or diethylamino-C 1-3 alkyl.

[0044] In some implementations, each R d2 Each is independently selected from oxo, F, Cl, Br, -CN, -OH, -NH2, methyl, ethyl, isopropyl, -CF3, -CHF2, -CF2CH3, methoxy, ethoxy, methoxymethyl, methoxyethyl, -OCF3, methylamino, ethylamino, dimethylamino, diethylamino, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, or methylethylaminomethyl.

[0045] In some implementations, each R d2 Each is independently selected from oxidative, halogenated, and C-type compounds. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 alkylamino, or di-C 1-4 Alkylamino.

[0046] In some implementations, each R d2 Each is independently selected from oxo, F, Cl, Br, methyl, ethyl, -CF3, -CHF2, methoxy, methylamino, or dimethylamino.

[0047] In some implementation schemes, R 3 Selected from the following groups:

[0048]

[0049] In some implementation schemes, R 3 Selected from the following groups:

[0050] In some implementation schemes, R 3 Selected from the following groups:

[0051] In some implementation schemes, R 3 R b Connected together to form an optional combination of one or more R e Substituted 3-12-membered cyclic enes or 4-12-membered heterocyclic enes. In some embodiments, R 3R b Connected together to form an optional combination of one or more R e Substituted 3-7 membered cycloenes. In some embodiments, R 3 R b Connected together to form an optional combination of one or more R e The following cyclic alkenes can be substituted: cyclopropylene, cyclobutene, cyclopentene, cyclohexene, or cycloheptene.

[0052] In some implementations, each R e Each is independently selected from oxo, halogen, -OH, -NH2, methyl, ethyl, halomethyl, haloethyl, methoxy, ethoxy, halomethoxy, methylamino, ethylamino, dimethylamino, or diethylamino.

[0053] In some implementations, each R e Each is independently selected from oxo, halogen, -OH, -NH2, methyl, fluoromethyl, methoxy, fluoromethoxy, methylamino, or dimethylamino.

[0054] In some implementation schemes, R e Selected from dimethylamino.

[0055] In some implementation schemes, R 4 Selected from H, deuterium, F, Cl, Br, or C 1-3 Alkyl group. In some embodiments, R 4 Selected from H, deuterium, F, Cl, Br, or methyl. In some embodiments, R 4 Selected from H or F. In some implementations, R 4 Selected from H.

[0056] 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.

[0057] 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 two N atoms. In some embodiments, the heterocyclic alkyl group contains one N atom and one O atom.

[0058] In some embodiments, the heterocycle contains one or two heteroatoms selected from N, O, or S. In some embodiments, the heterocycle contains one or two heteroatoms selected from N or O. In some embodiments, the heterocycle contains one N atom. In some embodiments, the heterocycle contains two N atoms. In some embodiments, the heterocycle contains one N atom and one O atom.

[0059] 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.

[0060] 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... 1-3 "Selected from "C" 1-2 ".

[0061] In some implementations, the "3-10 yuan" is selected from "5-9 yuan".

[0062] In some implementations, the "4-10 yuan" is selected from "4-10 yuan" or "5-9 yuan".

[0063] In some implementations, the "4-10 yuan" is selected from "5-9 yuan".

[0064] In some implementations, the "4-7 yuan" is selected from "5-6 yuan".

[0065] This application relates to compounds of formulas (Ia), (Ib), (Ic), and (Id), or pharmaceutically acceptable salts thereof, or tautomers, or stereoisomers, or deuterated compounds, and mixtures thereof.

[0066]

[0067] Among them, R 1 R 2 R 3 R 4 X, Y, and Z are defined as above.

[0068] This application also relates to the following compounds or their pharmaceutically acceptable salts, tautomers, stereoisomers, deuterated derivatives, and mixtures thereof:

[0069]

[0070]

[0071]

[0072] On the other hand, this application relates to pharmaceutical compositions comprising a compound of formula (I), (Ia), (Ib), (Ic), or (Id) 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.

[0073] On the other hand, this application relates to a method for treating FGFR4-related diseases in mammals, comprising administering to a mammal, preferably a human, a therapeutically effective amount of a compound of formula (I) or (Ia) or (Ib) or (Ic) or (Id) 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.

[0074] On the other hand, this application relates to the use of compounds of formula (I) or (Ia) or (Ib) or (Ic) or (Id) 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.

[0075] On the other hand, this application relates to the use of compounds of formula (I) or (Ia) or (Ib) or (Ic) or (Id) 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.

[0076] On the other hand, this application relates to compounds of formula (I) or (Ia) or (Ib) or (Ic) or (Id) for treating FGFR4-related diseases, or pharmaceutically acceptable salts thereof, or tautomers, or stereoisomers, or deuterated compounds thereof, mixtures thereof, or pharmaceutical compositions thereof.

[0077] In some embodiments of this application, the FGFR4-related disease is preferably cancer.

[0078] In some embodiments of this application, the cancer is liver cancer.

[0079] The compounds of this application achieve selective inhibition between FGFR1 and FGFR4, and have good inhibitory activity against FGFR4 or FGFR4V550L mutants; in addition, the compounds of this application have good absorption and metabolic properties, which can meet the requirements of drug development.

[0080] definition

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] When the number of a linking group is 0, such as -(CH2)0-, it indicates that the linking group is a covalent bond.

[0087] 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.

[0088] 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.

[0089] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0090] The term "hydroxyl group" refers to the -OH group.

[0091] The term "cyano" refers to the -CN group.

[0092] The term "thiol" refers to the -SH group.

[0093] The term "amino" refers to the -NH2 group.

[0094] The term "nitro" refers to the -NO2 group.

[0095] The term "alkyl" refers to a compound with the general formula C10. 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.

[0096] The term "alkoxy" refers to -O-alkyl.

[0097] The term "alkylamino" refers to -NH-alkyl.

[0098] The term "dialkylamino" refers to -N(alkyl)2, where the alkyl groups may be the same or different.

[0099] The term "alkylsulfonyl" refers to -SO2-alkyl.

[0100] The term "alkylthio" refers to -S-alkyl.

[0101] 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.

[0102] 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).

[0103] 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.

[0104] The term "cycloalkenyl" or "cycloalkene" 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.

[0105] The term "heterocycle" or "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 4- to 12-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, and / or nitrogen (preferably 1 or 2 heteroatoms). Non-limiting examples of heterocycles include, but are not limited to, ethylene oxide, tetrahydrofuranyl, dihydrofuranyl, pyrrolyl, N-methylpyrrolyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophene, etc.

[0106] 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 12-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, oxacycloheptyl, thioheptyl, 1,3-azioxacycloheptane, 1,4-azioxacycloheptane, 1,3-azithioheptane, 1,4-azithioheptane, 1,3-diazacycloheptane, and 1,4-diazacycloheptane.

[0107] The term "aryl" or "aromatic ring" 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.

[0108] The term "heteroaryl" or "heteroary ring" 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.

[0109] 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:

[0110] (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;

[0111] (ii) To suppress the disease or disease state, that is, to curb its development;

[0112] (iii) Alleviate the disease or disease state, even if the disease or disease state subsides.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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”.

[0119] 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.

[0120] 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.

[0121] In addition, heavier isotopes (such as deuterium) are used. 2 H)) 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:

[0122]

[0123] 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:

[0124]

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] 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.

[0130] The pharmaceutical composition may also be suitable for parenteral administration, such as in suitable unit dosage forms of sterile solutions, suspensions or lyophilized products.

[0131] 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.

[0132] 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.

[0133] 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.

[0134] When W is selected from CH, the compounds of general formula (I) of this application can be prepared by those skilled in the art of organic synthesis via route 1:

[0135]

[0136] Using compound 1 as a raw material, compound 2 is generated through a substitution reaction, followed by reduction to obtain compound 3. Compound 3 is then coupled to obtain compound 4, which is then deprotected by the Boc protecting group to obtain compound 5. Finally, it reacts with the corresponding acyl halide compound to obtain compound (I).

[0137] This application uses the following abbreviations:

[0138] Me represents methyl; Boc represents tert-butyloxycarbonyl; TFA represents trifluoroacetic acid; DMSO represents dimethyl sulfoxide.

[0139] Compounds artificially or Software naming conventions are used; commercially available compounds use supplier catalog names.

[0140] 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.

[0141] All reagents used in this application are commercially available and can be used without further purification. Example

[0142] Preparation Example 1

[0143] Intermediate I: (1S,2S,3R,4R)-3-((2-chloro-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide

[0144]

[0145] Step 1: (1S,2S,3R,4R)-3-((tert-Butoxycarbonyl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid methyl ester

[0146]

[0147] In a 25 mL single-necked flask, add (1R, 2R, 5S, 6S)-4-oxo-3-azatricyclic [4.2.1.0] sequentially. 2,5 1.5 g of non-7-ene-3-carboxylic acid tert-butyl ester, 15 mL of methanol, and 0.413 g of sodium methoxide were reacted at room temperature with stirring for 1 hour. The reaction mixture 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 silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give 1.367 g of the title compound. 1 H NMR(500MHz,DMSO-d6)δ6.73(d,J=8.5Hz,1H),6.21-6.17(m,2H),3.77(t,J=8.5Hz,1H),3.53(s,3H),2.84(brs,1H), 2.57(brs,1H),2.47(d,J=8Hz,1H),2.11(d,J=8.5Hz,1H),1.40-1.38(m,1H),1.37(s,9H).MS(ESI)m / z:290.4[M+Na] + .

[0148] Step 2: (1S,2S,3R,4R)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylic acid methyl ester trifluoroacetate

[0149]

[0150] In a 25 mL single-necked flask, methyl (1S, 2S, 3R, 4R)-3-((tert-butyloxycarbonyl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxylate (0.2 g), dichloromethane (5 mL), and trifluoroacetic acid (1.480 g) were added sequentially, and the mixture was stirred at room temperature for 1 hour. The reaction solution was directly concentrated, and methyl tert-butyl ether (20 mL) was added to the residue. The mixture was then slurried, filtered, and 0.184 g of the title compound was obtained. 1 HNMR(500MHz,DMSO-d6)δ8.10(s,3H),6.33-6.30(m,1H),6.24-6.19(m,1H),3.66(s,3H),3.25(d,J=8Hz,1H),3.05(b rs,1H),2.92(brs,1H),2.62(d,J=9.5Hz,1H),2.02(d,J=9.5Hz,1H),1.47(d,J=9.5Hz,1H).MS(ESI)m / z:168.4[M+H]+ .

[0151] Step 3: (1S,2S,3R,4R)-3-((5-carbamoyl-2-chloropyridin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid methyl ester

[0152]

[0153] In a 50 mL single-necked flask, 0.3 g of 4,6-dichloronicotinamide, 0.663 g of (1S,2S,3R,4R)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylic acid methyl ester trifluoroacetate, 1.015 g of N,N'-diisopropylethylamine, and 7 mL of N-methylpyrrolidone were added sequentially. The mixture was heated to 100 °C for 24 hours under a nitrogen atmosphere. 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, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give 0.314 g of the title compound. 1 H NMR(500MHz,DMSO-d6)δ9.05(d,J=9Hz,1H),8.39(s,1H),8.07(s,1H),7.46(s,1H),6.87(s,1H),6.28-6.24(m,2H),3.98(t,J =8.5Hz,1H),3.33(s,3H),2.97(brs,1H),2.75-2.71(m,2H),1.98(d,J=9Hz,1H),1.58(d,J=9Hz,1H).MS(ESI)m / z:322.2[M+H] + .

[0154] Step 4: (1S,2S,3R,4R)-3-((2-chloro-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid methyl ester

[0155]

[0156] In a 100 mL single-necked flask, methyl (1S, 2S, 3R, 4R)-3-((5-carbamoyl-2-chloropyridin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxylate (0.3 g), Burgess reagent (0.555 g), and dichloromethane (12 mL) were added sequentially, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into water (50 mL), and dichloromethane (50 mL) was added for extraction. The organic phase was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1) to give 0.237 g of the title compound. 1 H NMR(500MHz,DMSO-d6)δ8.34(s,1H),7.10-6.84(m,2H),6.32-6.25(m,2H),4.03(s,1H),3.37(s,3H),2.99(brs ,1H),2.90(brs,1H),2.76(d,J=7.5Hz,1H),2.13(d,J=9Hz,1H),1.54(d,J=9.5Hz,1H).MS(ESI)m / z:304.0[M+H] + .

[0157] Step 5: (1S,2S,3R,4R)-3-((2-chloro-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxylic acid

[0158]

[0159] In a 25 mL single-necked flask, methyl (1S, 2S, 3R, 4R)-3-((2-chloro-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxylate (0.2 g), tetrahydrofuran (4 mL), methanol (1 mL), and 2N sodium hydroxide aqueous solution (0.105 g) were added sequentially, and the mixture was stirred at room temperature for 4 hours. The reaction solution was directly concentrated, and the residue was adjusted to acidic pH with 1N hydrochloric acid solution and extracted with ethyl acetate (20 mL). The organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give 0.148 g of the title compound. 1H NMR (500MHz, DMSO-d6): δ12.65(s,1H),8.34(s,1H),7.33(s,1H),6.97(s,1H),6.31-6.23(m,2H),3.92(brs,1H),2.99 (brs,1H),2.85(brs,1H),2.63(d,J=8Hz,1H),2.04(d,J=8.5Hz,1H),1.49(d,J=9.5Hz,1H).MS(ESI)m / z:289.95[M+H] + .

[0160] Step 6: (1S,2S,3R,4R)-3-((2-chloro-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0161]

[0162] In a 25 mL single-necked flask, (1S, 2S, 3R, 4R)-3-((2-chloro-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxylic acid (0.05 g), dichloromethane (1 mL), and oxalyl chloride (0.033 g) were added sequentially, and the mixture was stirred at room temperature for 1 hour. The reaction solution was directly concentrated, and the residue was dissolved in dichloromethane (2 mL). Ammonia water (0.085 g) was added dropwise to the solution under ice bath conditions, and the mixture was stirred at room temperature for 1 hour. After filtration, 0.039 g of the title compound was obtained. 1 H-NMR (500MHz, CDCl3) δ8.17 (s, 1H), 8.07 (d, J = 7Hz, 1H), 7.43 (s, 1H), 6.51 (s, 1H), 6.36-6.33 (m, 1H), 6.32-6.29 (m, 1H), 6.02 (s, 1H), 3.57 (t,J=7.5Hz,1H),3.08(brs,1H),2.83(brs,1H),2.48(d,J=8Hz,1H),2.20(d,J=9.5Hz,1H),1.62(d,J=9.5Hz,1H).MS(ESI)m / z:288.96[M+H] + .

[0163] Example 1

[0164] (1S,2S,3R,4R)-3-((2-((2-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide

[0165]

[0166] Step 1: (5-((2-(dimethylamino)ethyl)(methyl)amino)-2-nitrophenyl)carbamate tert-butyl ester

[0167] In a 100 mL single-necked flask, N,N-di-tert-butoxycarbonyl-2-nitro-5-fluoroaniline (2.2 g) and N1,N1,N2-trimethylethane-1,2-diamine (0.631 g) were dissolved sequentially in N,N-dimethylformamide (20 mL), and the mixture was heated to 120 °C and reacted for 9 hours. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (200 mL). The organic phase was washed with water (200 mL) and saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give 1.85 g of the title compound. MS (ESI) m / z: 339.01 [M+H] + .

[0168] Step 2: (2-Amino-5-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)carbamate tert-butyl ester

[0169] In a 250 mL single-necked flask, tert-butyl (5-((2-(dimethylamino)ethyl)(methyl)amino)-2-nitrophenyl)carbamate (1 g), ethanol (100 mL), tetrahydrofuran (20 mL), ammonium chloride (14.23 g), and zinc powder (5.22 g) were added sequentially, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered, concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give 0.9 g of the title compound. 1 ¹H NMR (500MHz, DMSO-d⁶) δ 8.29 (s, 1H), 6.84 (s, 1H), 6.63 (d, J = 8.5Hz, 1H), 6.52–6.48 (m, 1H), 3.42 (t, J = 7Hz, 2H), 3.02 (t, J = 7Hz, 2H), 2.73 (s, 3H), 2.68 (s, 6H), 1.46 (s, 9H). (Active hydrogen did not elute).

[0170] Step 3: (2-((4-(((1R,2R,3S,4S)-3-carbamoylbicyclo[2.2.1]hept-5-en-2-yl)amino)-5-cyanopyridin-2-yl)amino)-5-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)tert-butyl carbamate

[0171] In a 25 mL single-necked flask, (1S, 2S, 3R, 4R)-3-((2-chloro-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide (0.2 g), (2-amino-5-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)carbamate tert-butyl ester (0.320 g), sodium carbonate (0.220 g), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tris-1-propyl-11'-biphenyl (0.074 g), tris(dibenzylideneacetone)dipalladium (0.063 g), 1,4-dioxane (4 mL), and water (0.1 mL) were added sequentially. The mixture was heated to 100 °C and reacted for 11 hours under a nitrogen atmosphere. The reaction solution was directly concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give 0.331 g of the title compound. 1 H NMR(500MHz,DMSO-d6)δ8.18(s,1H),8.08(s,1H),8.04(s,1H),7.76(s,1H),7.37(d,J=7Hz,1H),7.28(s,1H) ,7.10(d,J=8.5Hz,1H),7.04(s,1H),6.50-6.46(m,1H),6.29-6.27(m,1H),6.07-6.03(m,1H),6.56(s,1H),3. 43-3.37(m,2H),3.31-3.27(m,1H),2.90(s,3H),2.84(brs,1H),2.69(brs,1H),2.47(d,J=8Hz,1H),2.39(t, J=7.5Hz,2H),2.19(s,6H),2.01(d,J=8.5Hz,1H),1.43(s,9H),1.37(d,J=9Hz,1H).MS(ESI)m / z:561.22[M+H] + .

[0172] Step 4: (1S,2S,3R,4R)-3-((2-((2-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide

[0173] In a 25 mL single-necked flask, tert-butyl (2-((4-(((1R,2R,3S,4S)-3-carbamoylbicyclo[2.2.1]hept-5-en-2-yl)amino)-5-cyanopyridin-2-yl)amino)-5-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)carbamate (0.24 g), dichloromethane (7 mL), and trifluoroacetic acid (4.39 g) were added sequentially, and the mixture was stirred at room temperature for 1 hour. The pH was adjusted to alkaline by adding saturated sodium bicarbonate solution to the reaction mixture under ice bath conditions, and then extracted with dichloromethane (20 mL). The organic phase was washed with water (20 mL) and saturated brine (20 mL), respectively, and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give 0.182 g of the title compound. 1 H NMR(500MHz,DMSO-d6)δ8.05(s,1H),8.01(s,1H),7.74(s,1H),7.27(s,1H),7.20(d,J=7.5Hz, 1H),6.84(d,J=9Hz,1H),6.29-6.26(m,1H),6.17-6.13(m,1H),6.05-5.99(m,2H),5.48(s,1H) ,4.65(s,2H),3.41-3.36(m,2H),3.27-3.22(m,1H),2.85-2.82(m,4H),2.72(brs,1H),2.49-2 .44(m,3H),2.26(s,6H),2.00(d,J=8.5Hz,1H),1.37(d,J=9Hz,1H).MS(ESI)m / z:461.26[M+H] + .

[0174] Step 5: (1S,2S,3R,4R)-3-((2-((2-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide

[0175] At 0 °C, (1S,2S,3R,4R)-3-((2-((2-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide (0.17 g) was dissolved in tetrahydrofuran (9 mL), and then pyridine (0.058 g) and acryloyl chloride (0.040 g) were added dropwise to the solution, and the mixture was stirred at 0 °C for 1 hour. The reaction solution was directly concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give 0.054 g of the title compound. 1H NMR (500MHz, DMSO-d6) δ9.55(s,1H),8.08(s,1H),8.03(s,1H),7.75(s,1H),7.29(d,J=7.5Hz,1H),7.27(s,1H),7.18( d,J=7.5Hz,1H),7.14(s,1H),6.59-6.55(m,1H),6.52-6.46(m,1H),6.29-6.26(m,1H),6.24-6.19(m,1H),6.10-6.08(m ,1H),5.73-5.69(m,1H),5.59(s,1H),3.43-3.38(m,2H),3.30-3.25(m,1H),2.90(s,3H),2.83(s,1H),2.65(s,1H),2.4 6(d,J=8Hz,1H),2.39(t,J=7Hz,2H),2.18(s,6H),2.00(d,J=8.5Hz,1H),1.36(d,J=9Hz,1H).MS(ESI)m / z:515.22[M+H] + .

[0176] Example 2

[0177] (1S,2S,3R,4R)-3-((2-((2-acrylamido-4-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)phenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide

[0178]

[0179] Step 1: (5-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)-2-nitrophenyl)tert-butyl carbamate

[0180] In a 100 mL single-necked flask, N,N-di-tert-butoxycarbonyl-2-nitro-5-fluoroaniline (2.0 g), (1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (2.235 g), and N,N-diisopropylethylamine (3.63 g) were dissolved sequentially in N,N-dimethylformamide (20 mL), and the mixture was heated to 120 °C and reacted for 9 hours. The reaction mixture was poured into water (200 mL), and extracted with ethyl acetate (200 mL). The organic phase was washed with water (200 mL) and saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give 0.96 g of the title compound. 1H NMR (500MHz, CDCl3) δ10.38(s,1H),8.13(d,J=9.6Hz,1H),7.84(d,J=2.6Hz,1H),6.33(dd,J=9.6,2.7Hz,1H),2.66(dd,J=11.1,2.3Hz,2H),2.35 (dd,J=11.0,1.7Hz,2H),2.20(s,3H),2.07(d,J=7.3Hz,1H),2.00–1.98( m,1H),1.60(s,2H),1.53(s,9H),1.42(s,2H).MS(ESI)m / z:363.20[M+H] + .

[0181] Step 2: (2-amino-5-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)phenyl)tert-butyl carbamate

[0182] In a 250 mL single-necked flask, 0.5 g of (5-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)-2-nitrophenyl)carbamate tert-butyl ester, 40 mL of ethanol, 8 mL of tetrahydrofuran, 6.6 g of ammonium chloride, and 2.4 g of zinc powder were added sequentially, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered, concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give 0.4 g of the title compound. 1 H NMR (500MHz, CDCl3) δ7.14(s,1H),6.78(d,J=8.4Hz,1H),6.76–6.63(m,1H),6.39(dd,J=8.5,2.7Hz,1H),4.19(dd,J=4.8,2.5Hz,2H),3.32(d,J=11. 8Hz,2H),3.06(d,J=11.8Hz,2H),2.68(s,3H),2.53(d,J=8.2Hz,2H),2.16 (dd,J=9.0,4.6Hz,2H),1.52(s,9H),1.45(s,2H).MS(ESI)m / z:333.3[M+H] + .

[0183] Step 3: (2-((4-(((1R,2R,3S,4S)-3-carbamoylbicyclo[2.2.1]hept-5-en-2-yl)amino)-5-cyanopyridin-2-yl)amino)-5-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)phenyl)tert-butyl carbamate

[0184] In a 25 mL single-necked flask, 0.253 g of (2-amino-5-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)phenyl)carbamate tert-butyl ester and (1S,2S,3R,4R)-3-((2-chloro-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide were added sequentially. 0.200 g of sodium carbonate (0.220 g), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tris-1-propyl-11'-biphenyl (0.074 g), tris(dibenzylacetone)dipalladium (0.063 g), 1,4-dioxane (4 mL), and water (0.1 mL) were reacted under a nitrogen atmosphere at 100 °C for 11 hours. The reaction solution was directly concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give 0.18 g of the title compound. 1 H NMR (500MHz, CDCl3) δ7.92(s,1H),7.65–7.56(m,1H),7.47(s,1H),7.05(d,J=8.6Hz,1H),6.90(s,1H),6.78(d,J=8.0Hz,1H),6.48(dd,J= 8.7,2.7Hz,1H),6.36(s,1H),6.20(dd,J=5.7,2.9Hz,1H),6.05(dd,J=5.8,3.0Hz,1H),5.98(s,1H),5.28(s,1H),4.22(s,2H),3.35(td,J= 8.1,1.9Hz,1H),2.97(d,J=2.6Hz,1H),2.65(s,1H),2.60(d,J=2.3Hz,1H),2.59–2.53(m,1H),2.48(d,J=1.6Hz,1H),2.46(d,J=1.6Hz,1H ),2.38(d,J=8.0Hz,1H),2.19(s,3H),2.16(d,J=9.3Hz,1H),2.05–1.93(m,4H),1.52–1.49(m,1H),1.47(s,9H).MS(ESI)m / z:585.26[M+H] + .

[0185] Step 4: Preparation of (1S,2S,3R,4R)-3-((2-((2-amino-4-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)phenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide

[0186] In a 25 mL single-necked flask, tert-butyl (2-((4-(((1R,2R,3S,4S)-3-carbamoylbicyclo[2.2.1]hept-5-en-2-yl)amino)-5-cyanopyridin-2-yl)amino)-5-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)phenyl)carbamate (170 mg), dichloromethane (7 mL), and trifluoroacetic acid (4.39 g) were added sequentially, and the mixture was stirred at room temperature for 1 hour. The pH was adjusted to alkaline by adding saturated sodium bicarbonate solution to the reaction mixture under ice bath conditions. Extraction was performed by adding dichloromethane (20 mL) and drying over anhydrous sodium sulfate. The mixture was filtered and concentrated to give 0.12 g of the title compound. 1 H NMR (500MHz, DMSO-d6) δ8.03(d,J=9.9Hz,2H),7.73(d,J=2.6Hz,1H),7.27(s,1H),7.19(d,J=7.5Hz,1H),6.83(d, J=8.5Hz,1H),6.30–6.21(m,2H),6.10(dd,J=8.6,2.6Hz,1H),6.04(dd,J=5.9,3.0Hz,1H),5.47(s,1H),4.61(s,2 H), 4.07 (s, 2H), 3.25 (t, J = 7.8Hz, 1H), 2.77 (dd, J = 67.5, 2.7Hz, 2H), 2.45 (dd, J = 12.4, 9.2Hz, 3H), 2.31 (t, J = 10. 3Hz,2H),2.07(s,3H),2.00(d,J=9.0Hz,1H),1.91-1.76(m,4H),1.36(d,J=8.8Hz,1H).MS(ESI)m / z:485.25[M+H] +

[0187] Step 5: Preparation of (1S,2S,3R,4R)-3-((2-((2-acrylamido-4-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)phenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide

[0188] At 0 °C, (1S,2S,3R,4R)-3-((2-((2-amino-4-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)phenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide (90 mg) was dissolved in tetrahydrofuran (4 mL), and then pyridine (0.029 g) and acryloyl chloride (0.018 g) were added dropwise to the solution. The mixture was stirred at 0 °C for 1 hour. The reaction solution was directly concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give 0.028 g of the title compound. 1 H NMR(500MHz,DMSO-d6)δ10.43(s,1H),10.14(s,2H),9.88(s,1H),8.57(s,1H),8.05(s,1H),7.81(s,1H),7.34(s,1H),7.28 -7.22(m,1H),6.78(dd,J=8.8,2.8Hz,1H),6.58(dd,J=17.0,10.2Hz,1H),6.30(dd,J=5.7,2.9Hz,1H),6.23(dd,J=17.0,2. 0Hz,1H),6.17(dd,J=5.7,3.0Hz,1H),5.85(s,1H),5.77-5.69(m,1H),4.37(s,2H),2.84(d,J=3.0Hz,1H),2.67(d,J=29.2H z,4H),2.50(s,3H),2.22(s,2H),2.03(d,J=8.8Hz,3H),1.38(d,J=9.0Hz,1H),1.30(d,J=6.7Hz,1H),1.28(t,J=3.7Hz,1H).

[0189] MS(ESI) m / z: 539.23 [M+H] + .

[0190] Example 3

[0191] (1S, 2S, 3R, 4R)-3-((2-((2-acrylamide-4-(4-ethyl-4,7-diazaspiro[2.5]octane-7-yl)phenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide

[0192]

[0193] Step 1: N-(4-bromo-2-nitrophenyl)acetamide

[0194] In a 500 mL single-necked flask, 18 g of 4-bromo-2-nitroaniline, 135 mL of acetic acid, and 12.70 g of acetic anhydride were added sequentially. The mixture was heated to 100 °C and reacted for 5 hours. The reaction solution was poured into 1000 mL of water and filtered to obtain 20 g of the title compound. MS (ESI) m / z: 258.82 [M+H] + .

[0195] Step 2: Preparation of tert-butyl 7-(4-acetamido-3-nitrophenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate

[0196] In a 250 mL single-necked flask, N-(4-bromo-2-nitrophenyl)acetamide (5 g), 4,7-diazaspiro[2.5]octane-4-carboxylic acid tert-butyl ester (4.10 g), tris(dibenzylacetone)dipalladium (1.767 g), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (2.234 g), sodium carbonate (18.41 g), and toluene (100 mL) were added sequentially. The mixture was heated to 120 °C for 5 hours under a nitrogen atmosphere. The reaction solution was directly concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give 3.8 g of the title compound. MS (ESI) m / z: 391.44 [M+H] + .

[0197] Step 3: N-(2-nitro-4-(4,7-diazaspiro[2.5]octane-7-yl)phenyl)acetamide

[0198] In a 250 mL single-necked flask, tert-butyl 7-(4-acetamido-3-nitrophenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate (3.8 g), dichloromethane (60 mL), and trifluoroacetic acid (44.4 g) were added sequentially, and the mixture was stirred at room temperature for 1 hour. The pH was adjusted to alkaline by adding saturated sodium bicarbonate solution to the reaction mixture under ice bath conditions, and then extracted with dichloromethane (60 mL). The organic phase was washed with water (20 mL) and saturated brine (20 mL), respectively, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to give 2.8 g of the title compound. 1 H NMR (500MHz, CDCl3) δ9.95 (s, 1H), 8.55 (d, J = 9.3Hz, 1H), 7.56 (d, J = 3.0Hz, 1H), 7.20 (dd, J = 9.3, 3.0Hz, 1H), 3. 27–3.06(m,4H),2.99(s,2H),2.25(s,3H),0.78–0.68(m,2H),0.62(t,J=5.6Hz,2H).MS(ESI)m / z:291.11[M+H] + .

[0199] Step 4: N-(4-(4-ethyl-4,7-diazaspiro[2.5]octane-7-yl)-2-nitrophenyl)acetamide

[0200] In a 250 mL single-necked flask, N-(2-nitro-4-(4,7-diazaspiro[2.5]octane-7-yl)phenyl)acetamide (3.2 g), methanol (100 mL), acetaldehyde (40% aqueous solution) (12.14 g), sodium cyanoborohydride (1.385 g), and acetic acid (1.324 g) were added sequentially, and the mixture was stirred at room temperature for 4 hours. The reaction solution was directly concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give 3.3 g of the title compound. 1 H NMR(500MHz, CDCl3)δ9.94(s,1H),8.54(d,J=9.3Hz,1H),7.56(s,1H),7.19(d,J=9.3Hz,1H),3.37–3.08(m,4H),2.94(s,2H) ,2.76(q,J=7.2Hz,2H),2.25(s,3H),1.08(t,J=7.2Hz,3H),0.82–0.73(m,2H),0.65–0.53(m,2H).MS(ESI)m / z:319.05[M+H] + .

[0201] Step 5: 4-(4-ethyl-4,7-diazaspiro[2.5]octane-7-yl)-2-nitroaniline

[0202] In a 250 mL single-necked flask, N-(4-(4-ethyl-4,7-diazaspiro[2.5]octane-7-yl)-2-nitrophenyl)acetamide (3.3 g), ethanol (100 mL), and 2 M potassium hydroxide solution (22.28 mL) were added sequentially, and the mixture was heated to 90 °C for 3 hours. The reaction solution was directly concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give 2 g of the title compound.

[0203] MS(ESI) m / z: 277.09 [M+H] + .

[0204] Step Six: (1S,2S,3R,4R)-3-((5-cyano-2-((4-(4-ethyl-4,7-diazaspiro[2.5]octane-7-yl)-2-nitrophenyl)amino)pyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide

[0205] In a 15 mL sealed tube, (1S, 2S, 3R, 4R)-3-((2-chloro-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide (220 mg), 4-(4-ethyl-4,7-diazaspiro[2.5]octane-7-yl)-2-nitroaniline (232 mg), tris(dibenzylideneacetone)dipalladium (34.9 mg), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (41 mg), sodium carbonate (242 mg), water (0.8 mL), and 1,4-dioxane (3.2 mL) were added sequentially. The mixture was heated to 100 °C and reacted for 6 hours under a nitrogen atmosphere. The reaction solution was directly concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain 300 mg of the title compound. 1 H NMR(500MHz,DMSO-d6)δ8.28(s,1H),8.14(s,1H),7.44(s,1H),7.41-7.27(m,2H),6.91(s,1H),6 .29-6.06(m,3H),5.75(s,1H),4.31(s,1H),3.24-3.12(m,2H),3.10-2.96(m,4H),2.76(s,1H),2 .69(t,J=7.2Hz,2H),2.53-2.52(m,1H),2.40(d,J=8.2Hz,1H),2.16(s,1H),1.35(d,J=8.6Hz,1H ),1.18(t,J=7.1Hz,1H),0.99(t,J=7.2Hz,3H),0.59(d,J=16.3Hz,4H).MS(ESI)m / z:529.61[M+H] + .

[0206] Step 7: Preparation of (1S, 2S, 3R, 4R)-3-((2-((2-amino-4-(4-ethyl-4,7-diazaspirocyclic[2.5]octane-7-yl)phenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide

[0207] In a 100 mL single-necked flask, (1S, 2S, 3R, 4R)-3-((5-cyano-2-((4-(4-ethyl-4,7-diazaspiro[2.5]octane-7-yl)-2-nitrophenyl)amino)pyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide (300 mg), tetrahydrofuran (10 mL), ethanol (10 mL), ammonium chloride (602 mg), and zinc powder (371 mg) were added sequentially. The mixture was stirred at room temperature for 1 hour. After filtration and concentration, 250 mg of the crude title compound was obtained and used directly in the next reaction. MS (ESI) m / z: 499.24 [M+H] + .

[0208] Step 8: (1S, 2S, 3R, 4R)-3-((2-((2-acrylamide-4-(4-ethyl-4,7-diazaspirocyclic[2.5]octane-7-yl)phenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0209] At 0 °C, (1S,2S,3R,4R)-3-((2-((2-amino-4-(4-ethyl-4,7-diazaspiro[2.5]octane-7-yl)phenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide (250 mg) was dissolved in dichloromethane (2.5 mL), and pyridine (79 mg) and acryloyl chloride (59 mg) were added dropwise to the solution. The mixture was stirred at 0 °C for 1 hour. The reaction solution was directly concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give 20 mg of the title compound. 1H NMR (500MHz, CDCl3) δ10.03(s,1H),7.86(s,1H),7.62(s,1H),7.13–6.93(m,2H),6.60(s,2H),6.32(d,J=18.7Hz,1H ),6.25(s,2H),6.08–5.93(m,2H),5.62(d,J=9.9Hz,1H),3.34(t,J=7.9Hz,1H),3.20(d,J=15.0Hz,4H),3.05(d,J=1 1.8 Hz, 1H), 2.96 (d, J = 10.3 Hz, 2H), 2.77 (t, J = 9.9 Hz, 2H), 2.53 (s, 1H), 2.45 (d, J = 7.8 Hz, 1H), 2.12 (d, J = 8.9 Hz, 1H), 1.53 (d, J = 9.0 Hz, 1H), 1.07 (d, J = 14.1 Hz, 3H), 0.77 (s, 2H), 0.64–0.45 (m, 2H). (Active hydrogen did not elute) MS (ESI) m / z: 553.23 [M+H] + .

[0210] Example 4

[0211] (1S,2S,3R,4R)-3-((2-((2-acrylamido-4-morpholinophenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0212]

[0213] Step 1: (5-morpholino-2-nitrophenyl) tert-butyl carbamate

[0214] In a 100 mL single-necked flask, N,N-di-tert-butoxycarbonyl-2-nitro-5-fluoroaniline (3.3 g) and morpholine (3.63 g) were added sequentially. The mixture was heated to 120 °C and reacted for 7 hours. The reaction solution was poured into water (200 mL) and extracted with ethyl acetate (200 mL). The organic phase was washed with water (200 mL) and saturated brine (200 mL), respectively, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to give 6 g of the title compound. 1 H NMR (500MHz, CDCl3) δ10.24(s,1H),8.15(d,J=9.6Hz,1H),8.03(s,1H),6.47(d,J=12. 4Hz,1H),3.92-3.71(m,4H),3.52-3.38(m,4H),1.54(s,9H).MS(ESI)m / z:323.94[M+H] + .

[0215] Step 2: (2-Amino-5-morpholinophenyl) tert-butyl carbamate

[0216] In a 100 mL single-necked flask, 1 g of (5-morpholino-2-nitrophenyl)carbamate tert-butyl ester was dissolved in 15 mL of ethanol, and then Pd / C (palladium on carbon, 700 mg) was added. The mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. After filtration through diatomaceous earth and concentration, 0.75 g of the title compound was obtained. 1 ¹H NMR (500MHz, CDCl₃) δ 7.19 (s, 1H), 6.74 (d, J = 8.5Hz, 1H), 6.58 (d, J = 11.2Hz, 2H), 3.88–3.75 (m, 4H), 3.15–2.95 (m, 4H), 1.52 (s, 9H). No peaks were observed for active hydrogen. MS (ESI) m / z: 294.02 [M+H] + .

[0217] Step 3: (2-((4-(((1R,2R,3S,4S)-3-carbamoylbicyclo[2.2.1]hept-5-en-2-yl)amino)-5-cyanopyridin-2-yl)amino)-5-morpholinophenyl)tert-butyl carbamate

[0218] In a 15 mL sealed tube, (1S, 2S, 3R, 4R)-3-((2-chloro-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide (200 mg), (2-amino-5-morpholinophenyl)carbamate tert-butyl ester (224 mg), tris(dibenzylacetone)palladium (63.4 mg), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (120 mg), sodium carbonate (220 mg), water (1 mL), and 1,4-dioxane (5 mL) were added sequentially. The reaction mixture was heated to 100 °C for 11 hours under a nitrogen atmosphere. The reaction solution was directly concentrated, and the crude product obtained was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give 0.35 g of the title compound. 1H NMR (500MHz, CDCl3) δ7.86(s,1H),7.75(d,J=15.5Hz,2H),7.12(d,J=8.7Hz,1H),7.02(s,1 H),6.74(d,J=7.9Hz,1H),6.68–6.46(m,2H),6.23(d,J=8.5Hz,1H),6.13–5.87(m,2H),3.9 4–3.81(m,4H),3.34(t,J=7.6Hz,1H),3.29–3.17(m,4H),2.97(s,1H),2.64(s,1H),2.40(d ,J=8.1Hz,1H),2.15(d,J=9.3Hz,1H),1.79(s,2H),1.45(s,9H).MS(ESI)m / z:546.18[M+H] + .

[0219] Step 4: (1S,2S,3R,4R)-3-((2-((2-amino-4-morpholinophenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0220] In a 25 mL single-necked flask, tert-butyl (2-((4-(((1R,2R,3S,4S)-3-carbamoylbicyclo[2.2.1]hept-5-en-2-yl)amino)-5-cyanopyridin-2-yl)amino)-5-morpholinophenyl)carbamate (0.35 g), dichloromethane (7 mL), and trifluoroacetic acid (6.583 g) were added sequentially, and the mixture was stirred at room temperature for 1 hour. The pH was adjusted to alkaline by adding saturated sodium bicarbonate solution to the reaction mixture under ice bath conditions, and then extracted with dichloromethane (20 mL). The organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain 0.15 g of the title compound. 1H NMR (500MHz, DMSO-d6) δ8.13(s,1H),8.02(s,1H),7.75(s,1H),7.24(d,J=7.3Hz,1H),6.92(d,J= 8.6Hz,1H),6.36(s,1H),6.29(d,J=2.9Hz,1H),6.22(d,J=11.2Hz,1H),6.05(d,J=8.1Hz,1H),5.5 3(s,1H),4.77(s,2H),3.80–3.61(m,5H),3.3-3.25(m,1H),3.06–2.96(m,4H),2.84(s,1H),2.73( s,1H),2.47(d,J=8.0Hz,1H),2.01(d,J=8.6Hz,1H),1.40–1.35(m,1H).MS(ESI)m / z:446.52[M+H] + .

[0221] Step 5: (1S,2S,3R,4R)-3-((2-((2-acrylamido-4-morpholinophenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0222] At 0 °C, (1S,2S,3R,4R)-3-((2-((2-amino-4-morpholinophenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide (0.17 g) was dissolved in tetrahydrofuran (20 mL), and then pyridine (0.053 g) and acryloyl chloride (0.040 g) were added dropwise to the solution, and the mixture was stirred at 0 °C for 1 hour. The reaction solution was directly concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give 0.025 g of the title compound. 1H NMR (500MHz, CDCl3) δ10.23(s,1H),7.95(s,1H),7.60(s,1H),7.08(s,1H),6.99(d,J=8.3Hz,1H),6.63(d d,J=29.6,9.3Hz,2H),6.29(dd,J=30.8,20.1Hz,3H),6.05(d,J=8.0Hz,1H),5.94(d,J=2.6Hz,1H),5.62( d, J = 10.3 Hz, 1H), 3.97–3.73 (m, 4H), 3.32 (d, J = 16.1 Hz, 1H), 3.30–3.07 (m, 4H), 2.95 (s, 1H), 2.55 (s, 1H), 2.46 (d, J = 8.2 Hz, 1H), 2.11 (d, J = 9.2 Hz, 1H), 1.53 (d, J = 9.2 Hz, 1H). (Active hydrogen did not elute) MS (ESI) m / z: 500.20 [M+H] + .

[0223] Example 5

[0224] (1S,2S,3R,4R)-3-((2-((2-acrylamido-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide

[0225]

[0226] Step 1: (5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-nitrophenyl)tert-butyl carbamate

[0227] In a 100 mL single-necked flask, N,N-di-tert-butoxycarbonyl-2-nitro-5-fluoroaniline (2 g), octahydropyrrolo[1,2-a]pyrazine (1.417 g), and N,N'-diisopropylethylamine (1.813 g) were dissolved sequentially in N,N-dimethylformamide (20 mL), and the mixture was heated to 120 °C and reacted for 12 hours. The reaction mixture was poured into water (100 mL), and extracted with ethyl acetate (100 mL). The organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give 1.52 g of the title compound. 1H NMR (500MHz, CDCl3) δ10.29(s,1H),8.13(d,J=10.0Hz,1H),8.01(d,J=3.0Hz,1H),6.49(dd ,J1=9.8Hz, J2=2.8Hz,1H),4.06(d,J=12.0Hz,1H),3.93(d,J=14.0Hz,1H),3.17-3.12(m,3H ),2.78(t,J=11.5Hz,1H),2.34-2.29(m,1H),2.19(q,J=9.0Hz,1H),2.11-2.05(m,1H),1.96 -1.86(m,2H),1.82-1.77(m,1H),1.54(s,9H),1.51-1.48(m,1H).MS(ESI)m / z:363.15[M+H] + .

[0228] Step 2: (2-amino-5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)tert-butyl carbamate

[0229] In a 250 mL single-necked flask, tert-butyl (5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-nitrophenyl)carbamate (1 g), ethanol (60 mL), tetrahydrofuran (12 mL), ammonium chloride (13.28 g), and zinc powder (4.51 g) were added sequentially, and the mixture was stirred at room temperature for 0.5 hours. The mixture was filtered, concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give 0.683 g of the title compound. 1 ¹H NMR (500MHz, CDCl₃) δ 7.21 (s, 1H), 6.74 (d, J = 8.5Hz, 1H), 6.58 (dd, J₁ = 8.5Hz, J₂ = 2.0Hz, 2H), 3.57–3.55 (m, 2H), 3.44–3.42 (m, 2H), 3.34 (s, 2H), 3.15 (s, 2H), 2.19–2.06 (m, 5H), 1.52 (s, 9H). (Active hydrogen did not elute.)

[0230] Step 3: In a 25 mL single-necked flask containing (2-((4-(((1R,2R,3S,4S)-3-carbamoylbicyclo[2.2.1]hept-5-en-2-yl)amino)-5-cyanopyridin-2-yl)amino)-5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)tert-butyl carbamate, add (1S,2S,3R,4R)-3-((2-chloro-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide (0 The reaction mixture was prepared by heating to 70°C for 12 hours under a nitrogen atmosphere. The reaction solution was directly concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give 0.190 g of the title compound. 1 H NMR (500MHz, CDCl3) δ7.88(s,1H),7.71(d,J=12.0Hz,2H),7.09(d,J=8.5Hz,1H),6.90(s,1H),6.72(d,J=7.5Hz, 1H),6.65(dd,J=8.8,2.3Hz,1H),6.46(s,1H),6.21(dd,J=5.5,2.0Hz,1H),6.02(s,2H),5.27(s,1H),3.84(d,J=1 1.0Hz,1H),3.70(d,J=11.0Hz,1H),3.34(t,J=7.8Hz,1H),3.18-3.13(m,2H),2.97(s,2H),2.64-2.58(m,2H),2. 40-2.36(m,2H),2.21-2.14(m,3H),1.94–1.78(m,2H),1.51–1.50(m,3H),1.49(s,9H).MS(ESI)m / z:585.30[M+H] + .

[0231] Step 4: (1S,2S,3R,4R)-3-((2-((2-amino-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide

[0232] In a 25 mL single-necked flask, 0.15 g of (2-((4-(((1R,2R,3S,4S)-3-carbamoylbicyclo[2.2.1]hept-5-en-2-yl)amino)-5-cyanopyridin-2-yl)amino)-5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)carbamate tert-butyl ester, 3 mL of dichloromethane, and 1 mL of trifluoroacetic acid were added sequentially, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain 0.165 g of crude product, which was directly used in the next step of the reaction.

[0233] Step 5: (1S,2S,3R,4R)-3-((2-((2-acrylamido-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide

[0234] At 0 °C, (1S,2S,3R,4R)-3-((2-((2-amino-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide (0.165 g) was dissolved in tetrahydrofuran (4 mL), and acryloyl chloride (0.039 g) was added dropwise. The mixture was stirred at 0 °C for 1 hour. The reaction solution was directly concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give 0.041 g of the title compound. 1 H NMR(500MHz,DMSO-d6)δ9.65(s,1H),8.30(s,1H),8.05(s,1H),7.77(s,1H),7.38(s,1H),7.30-7.25(s,3H),6.82(d, J=8.5Hz,1H),6.54-6.48(m,1H),6.31-6.29(m,1H),6.22(d,J=17.0Hz,1H),6.13-6.12(m,1H),6.46(s,1H),5.71(s,2 H),3.72(d,J=11.0Hz,1H),3.58(d,J=11.5Hz,1H),3.12-3.05(m,3H),2.84-2.81(m,2H),2.67(s,1H),2.49-2.47(m, 1H),2.07(d,J=8.5Hz,1H),1.86(s,1H),1.74(s,2H),1.41–1.45(m,3H),1.20–1.16(m,2H).MS(ESI)m / z:539.21[M+H] + .

[0235] Example 6

[0236] (1S,2S,3R,4R)-3-((2-((4-([1,4'-bipiperidine]-1'-yl)-2-acrylamidophenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide

[0237]

[0238] Step 1: (5-([1,4'-bipiperidine]-1'-yl)-2-nitrophenyl)tert-butyl carbamate

[0239] In a 100 mL single-necked flask, N,N-di-tert-butoxycarbonyl-2-nitro-5-fluoroaniline (1 g), 1,4'-bipiperidine (0.944 g), and N,N-diisopropylethylamine (0.907 g) were dissolved sequentially in N,N-dimethylformamide (10 mL), and the mixture was heated to 120 °C for 5 hours. The reaction mixture was then poured into water (50 mL), precipitating a solid. The solid was filtered and slurried with petroleum ether / ethyl acetate (6 mL, 2:1) to give 0.755 g of the title compound. MS (ESI) m / z: 405.11 [M+H] + .

[0240] Step 2: (5-([1,4'-bipiperidine]-1'-yl)-2-aminophenyl)tert-butyl carbamate

[0241] In a 250 mL single-necked flask, 0.7 g of (5-([1,4'-bipiperidin]-1'-yl)-2-nitrophenyl)carbamate tert-butyl ester, 60 mL of ethanol, 12 mL of tetrahydrofuran, 8.33 g of ammonium chloride, and 2.83 g of zinc powder were added sequentially, and the mixture was stirred at room temperature for 0.5 hours. The mixture was filtered, concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give 0.459 g of the title compound. 1 H NMR (500MHz, CDCl3) δ7.16(s,1H),6.71(d,J=8.5Hz,1H),6.61(dd,J1=8.5Hz,J2=2.0Hz,1H),6.51(s,1H),3.57(d,J=12.5Hz,2H),3.31(s,2H),2 .62-2.57(m,2H),2.53(s,4H),2.37-2.32(m,1H),1.88(d,J=12.5Hz,2H ),1.74-1.69(m,2H),1.62-1.57(m,4H),1.51(s,9H),1.46-1.44(m,2H).

[0242] Step 3: (2-((4-(((1R,2R,3S,4S)-3-carbamoylbicyclo[2.2.1]hept-5-en-2-yl)amino)-5-cyanopyridin-2-yl)amino)-5-([1,4'-bipiperidin]-1'-yl))phenyl)tert-butyl carbamate

[0243] In a 25 mL single-necked flask, (1S, 2S, 3R, 4R)-3-((2-chloro-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide (0.2 g), (5-([1,4'-bipiperidin]-1'-yl)-2-aminophenyl) tert-butyl carbamate (0.285 g), sodium carbonate (0.258 g), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tris-1-propyl-11'-biphenyl (0.112 g), tris(dibenzylideneacetone)dipalladium (0.063 g), 1,4-dioxane (8 mL), and water (0.2 mL) were added sequentially. The mixture was heated to 70 °C and reacted for 12 hours under a nitrogen atmosphere. The reaction solution was directly concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give 0.180 g of the title compound. 1 H NMR (500MHz, CDCl3) δ7.87(s,1H),7.71(s,2H),7.07(d,J=9.0Hz,1H),6.88(s,1H),6.66-6.64(m,2H),6.46(s ,1H),6.22-6.21(m,1H),6.03-6.01(m,2H),5.27(s,1H),3.83-3.81(m,2H),3.35(t,J=7.8Hz,1H),2.96(s,1H) ,2.76(d,J=12.5Hz,2H),2.64(s,1H),2.55(s,4H),2.39(d,J=8.5Hz,2H),2.15(d,J=9.0Hz,1H),1.94(d,J=12. 5Hz,2H),1.69(d,J=12.2Hz,2H),1.62-1.59(m,4H),1.50-1.48(m,3H),1.46(s,9H).MS(ESI)m / z:627.37[M+H] + .

[0244] Step 4: (1S,2S,3R,4R)-3-((2-((4-([1,4'-bipiperidin]-1'-yl)-2-aminophenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide

[0245] In a 25 mL single-necked flask, 0.17 g of (2-((4-(((1R,2R,3S,4S)-3-carbamoylbicyclo[2.2.1]hept-5-en-2-yl)amino)-5-cyanopyridin-2-yl)amino)-5-([1,4'-bipiperidin]-1'-yl))phenyl)carbamate tert-butyl ester, 3 mL of dichloromethane, and 1 mL of trifluoroacetic acid were added sequentially. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain 0.189 g of crude product, which was directly used in the next step of the reaction. MS (ESI) m / z: 527.24 [M+H] + .

[0246] Step 5: (1S,2S,3R,4R)-3-((2-((4-([1,4'-bipiperidin]-1'-yl)-2-acrylamidophenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide

[0247] At 0 °C, (1S,2S,3R,4R)-3-((2-((4-([1,4'-bipiperidin]-1'-yl)-2-aminophenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide (0.189 g) was dissolved in tetrahydrofuran (4 mL), and acryloyl chloride (0.034 g) was added dropwise. The mixture was stirred at 0 °C for 1 hour. The reaction solution was directly concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give 0.030 g of the title compound. 1 H NMR (500MHz, DMSO-d6) δ9.74(s,1H),8.43(s,1H),8.05(s,1H),7.79(s,1H),7.41(s,1H),7.30-7.28(m,3H),6.83(dd,J=9 .0Hz,2.0Hz,1H),6.58-6.52(m,1H),6.31-6.29(m,1H),6.23(d,J=17.0Hz,1H),6.16-6.14(m,1H),5.79(s,1H),5.72(dd,J =10.0Hz,1.5Hz,1H),3.78(d,J=12.5Hz,2H),3.38(d,J=8.0Hz,1H),3.33-3.29(m,2H),2.91-2.85(m,3H),2.73-2.69(m,3 H),2.48(s,1H),2.16-2.14(m,2H),2.02(d,J=8.5Hz,1H),1.80-1.70(m,7H),1.39-1.36(m,3H).MS(ESI)m / z:581.25[M+H] +

[0248] Example 7

[0249] (1S,2S,3R,4R)-3-((2-((2-acrylamido-4-((S)-3-(dimethylamino)pyrrolidinyl-1-yl)phenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide

[0250]

[0251] Step 1: (S)-(5-(3-(dimethylamino)pyrrolidin-1-yl)-2-nitrophenyl)tert-butyl carbamate

[0252] In a 25 mL single-necked flask, N,N-di-tert-butoxycarbonyl-2-nitro-5-fluoroaniline (2 g), dimethyl sulfoxide (8 mL), (3S)-(-)-3-(dimethylamino)pyrrolidine (961 mg), and N,N-diisopropylethylamine (2.176 g) were added sequentially, and the mixture was heated to 110 °C and reacted for 8 hours. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed with water (100 mL) and saturated brine (100 mL), respectively, and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated to give 3.0 g of the title compound. MS (ESI) m / z: 351.02 [M+H] + .

[0253] Step 2: (S)-(2-amino-5-(3-(dimethylamino)pyrrolidone-1-yl)phenyl)tert-butyl carbamate

[0254] In a 100 mL single-necked flask, tert-butyl (S)-(5-(3-(dimethylamino)pyrrolyl-1-yl)-2-nitrophenyl)carbamate (3 g), tetrahydrofuran (10 mL), water (10 mL), ammonium chloride (9.0 g), and zinc powder (5.6 g) were added sequentially. The mixture was stirred at room temperature for 2 hours. The mixture was filtered, concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 94:6) to give 0.44 g of the title compound. MS (ESI) m / z: 321.03 [M+H] + .

[0255] Step 3: (2-((4-(((1R,2R,3S,4S)-3-carbamoylbicyclo[2.2.1]hept-5-en-2-yl)amino)-5-cyanopyridin-2-yl)amino)-5-((S)-3-(dimethylamino)pyrrolidine-1-yl)phenyl)tert-butyl carbamate

[0256] In a 40 mL sealed tube, (1S, 2S, 3R, 4R)-3-((2-chloro-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide (200 mg), (S)-(2-amino-5-(3-(dimethylamino)pyrrolidone-1-yl)phenyl)tert-butyl carbamate (289 mg), 1,4-dioxane (8 mL), water (0.5 mL), tris(dibenzylideneacetone)dipalladium (63.4 mg), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (112 mg), and sodium carbonate (258 mg) were added sequentially. The mixture was heated to 90 °C for 16 hours under a nitrogen atmosphere. The reaction solution was directly concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 93:7) to obtain 0.287 g of the title compound. 1 H NMR(500MHz,DMSO-d6)δ8.14(s,1H),8.09(s,1H),8.04(s,1H),7.83-7.75(m,1H),7.41-7.31(m,1H),7.31-7.27(m,1H),7 .10(d,J=8.7Hz,1H),6.95-6.90(m,1H),6.36-6.25(m,2H),6.11-6.02(m,1H),5.57(s,1H),3.46-3.38(m,1H),3.37-3.27( m,2H),3.28-3.18(m,1H),3.05(t,J=8.5Hz,1H),2.85(d,J=13.6Hz,2H),2.69(d,J=2.9Hz,1H),2.47(t,J=8.6Hz,1H),2.2 3(s,6H),2.17(s,1H),2.04-1.97(m,1H),1.89-1.79(m,1H),1.43(s,9H),1.37(d,J=9.4Hz,1H).MS(ESI)m / z:573.24[M+H] + .

[0257] Step 4: (1S,2S,3R,4R)-3-((2-((2-amino-4-((S)-3-(dimethylamino)pyrrolidinyl-1-yl)phenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide

[0258] In a 25 mL single-necked flask, tert-butyl (270 mg) of (2-((4-((((1R,2R,3S,4S)-3-carbamoylbicyclo[2.2.1]hept-5-en-2-yl)amino)-5-cyanopyridin-2-yl)amino)-5-((S)-3-(dimethylamino)pyrrolidine-1-yl)phenyl)carbamate, 3 mL of dichloromethane, and 1 mL of trifluoroacetic acid were added sequentially. The mixture was reacted at room temperature for 2 hours. At that time, saturated sodium bicarbonate solution was added to the reaction solution under ice bath to adjust the pH to alkaline, and dichloromethane (20 mL) was added for extraction. The organic phase was washed with water (20 mL) and saturated brine (20 mL), respectively, and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 89:11) to give 0.167 g of the title compound. MS (ESI) m / z: 473.4 [M+H] + .

[0259] Step 5: (1S,2S,3R,4R)-3-((2-((2-acrylamido-4-((S)-3-(dimethylamino)pyrrolidin-1-yl)phenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide

[0260] At 0 °C, (1S,2S,3R,4R)-3-((2-((2-amino-4-((S)-3-(dimethylamino)pyrrolidin-1-yl)phenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide (100 mg) was dissolved in tetrahydrofuran (20 mL), and then pyridine (33.5 mg) and acryloyl chloride (22.98 mg) were added dropwise to the solution. The mixture was stirred at 0 °C for 1 hour. The reaction solution was directly concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give 0.007 g of the title compound. 1H NMR(500MHz, Methanol-d4)δ7.95(s,1H),7.18(d,J=8.7Hz,1H),7.04(s,1H),6.57–6.47(m,1H),6.45–6.24(m,3H) ,6.14–6.04(m,1H),5.78–5.68(m,1H),5.51(s,1H),3.60–3.53(m,1H),3.49(t,J=8.7Hz,1H),3.41(d,J=7.9Hz,1H ),3.38–3.33(m,1H),3.19(t,J=8.6Hz,1H),3.00(m,1H),2.88(s,1H),2.65(s,1H),2.52(d,J=7.6Hz,1H),2.37(s, 6H),2.36–2.26(m,1H),2.11(d,J=9.1Hz,1H),2.00–1.89(m,1H),1.48(d,J=9.2Hz,1H).MS(ESI)m / z:527.20[M+H] + .

[0261] Example 8

[0262] (1S,2S,3R,4R)-3-((2-((2-acrylamido-4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide

[0263]

[0264] Step 1: 4-Amino-3-nitrobenzaldehyde

[0265] In a 500 mL single-necked flask, 5.7 g of 4-fluoro-3-nitrobenzaldehyde, 200 mL of tetrahydrofuran, and 45.0 g of ammonia (50 mL) were added sequentially, and the mixture was stirred at room temperature for 12 hours. The mixture was then filtered to give 2.1 g of the title compound. MS (ESI) m / z: 164.87 [MH] - .

[0266] Step 2: 4-((4-methylpiperazin-1-yl)methyl)-2-nitroaniline

[0267] In a 50 mL single-necked flask, 0.8 g of 4-amino-3-nitrobenzaldehyde, 20 mL of dichloromethane, 0.965 g of 1-methylpiperazine, and 2.55 g of sodium triacetoxyborohydride were added sequentially, and the mixture was stirred at room temperature for 12 hours. The reaction solution was directly concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 40:1) to give 1.084 g of the title compound.1 H NMR (500MHz, DMSO-d6) δ7.82(s,1H),7.39(s,2H),7.33(d,J=10.5Hz,1H),6.98(d,J=8.5Hz,1H),3.32(s,2H),2.47-2.19(m,8H),2.14(s,3H).

[0268] Step 3: (1S,2S,3R,4R)-3-((5-cyano-2-((4-((4-methylpiperazin-1-yl)methyl)-2-nitrophenyl)amino)pyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide

[0269] In a 25 mL single-necked flask, (1S, 2S, 3R, 4R)-3-((2-chloro-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide (200 mg), 4-((4-methylpiperazin-1-yl)methyl)-2-nitroaniline (225 mg), 1,4-dioxane (8 mL), water (0.5 mL), tris(dibenzylacetone)dipalladium (63.4 mg), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (112 mg) and sodium carbonate (258 mg) were added sequentially. The mixture was heated to 90 °C and reacted for 16 hours under a nitrogen atmosphere. The reaction solution was directly concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give 0.355 g of the title compound. 1 H NMR(500MHz, Methanol-d4)δ8.22(d,J=8.7Hz,1H),8.13–8.06(m,2H),7.63–7.53(m,1H),6.38–6.28(m,3H),3.56(s,2H),2.95(d, J=2.9Hz,1H),2.86(d,J=2.8Hz,1H),2.65–2.46(m,9H),2.31(s,3H),2.21(d,J=9.3Hz,1H),1.62–1.52(m,1H),1.37–1.27(m,1H). MS(ESI)m / z:503.21[M+H] + .

[0270] Step 4: (1S,2S,3R,4R)-3-((2-((2-amino-4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0271] In a 25 mL single-necked flask, (1S, 2S, 3R, 4R)-3-((5-cyano-2-((4-(((4-methylpiperazin-1-yl)methyl)-2-nitrophenyl)amino)pyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide (355 mg), tetrahydrofuran (3 mL), anhydrous ethanol (3 mL), zinc powder (462 mg), and ammonium chloride (749 mg) were added sequentially, and the mixture was reacted at room temperature for 0.5 hours. The mixture was filtered and concentrated to give 0.32 g of the title compound. MS (ESI) m / z: 473.21 [M+H] + .

[0272] Step 5: (1S,2S,3R,4R)-3-((2-((2-acrylamido-4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0273] At 0 °C, (1S,2S,3R,4R)-3-((2-((2-amino-4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-en-2-carboxamide (200 mg) was dissolved in tetrahydrofuran (20 mL), and then pyridine (73.6 mg) and acryloyl chloride (49.8 mg) were added dropwise to the solution. The mixture was stirred at 0 °C for 1 hour. The reaction solution was directly concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give 0.045 g of the title compound. 1 H NMR(500MHz,Methanol-d4)δ8.00(s,1H),7.63(s,1H),7.42(d,J=8.2Hz,1H) ,7.29–7.19(m,1H),6.49–6.26(m,3H),6.19–6.09(m,1H),5.76(d,J=8.5Hz,2 H),3.55(s,2H),3.50(d,J=8.0Hz,1H),2.91(s,1H),2.75–2.39(m,9H),2.30 (s, 3H), 2.14 (d, J = 9.1Hz, 1H), 1.51 (d, J = 9.1Hz, 1H), 1.32 (d, J = 16.2Hz, 1H). MS(ESI) m / z: 527.18 [M+H] + .

[0274] Example 9

[0275] (1S,2S,3R,4R)-3-((2-((2-acrylamido-4-(4-ethylpiperazin-1-yl)phenyl)amino)-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0276]

[0277] Referring to the synthesis method of Example 4, the morpholine in step one of Example 4 was replaced with ethylpiperazine, and the obtained intermediate was used to obtain the title compound of Example 9 by referring to the synthesis method of Example 4. 1 H NMR (500MHz, CDCl3) δ10.14(s,1H),7.96(s,1H),7.62(s,1H),6.99(d,J=10.7Hz,2H),6.60(d,J =8.9Hz,2H),6.35–6.20(m,3H),6.09–5.88(m,2H),5.63(d,J=10.2Hz,1H),5.23(s,1H),3.37–3 .30(m,5H),2.94(d,J=8.8Hz,1H),2.67(s,4H),2.54(d,J=7.9Hz,3H),2.45(d,J=8.2Hz,1H),2. 11(d,J=9.3Hz,1H),2.04–1.99(m,1H),1.52(d,J=9.5Hz,1H),1.17(t,J=7.2Hz,3H).MS(ESI)m / z 527.28[M+H]+.

[0278] Experiment Example 1: In vitro kinase inhibitory activity test

[0279] 1.1 Screening for FGFR1 kinase inhibitory activity

[0280] 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 .

[0281] 1.2 Screening for FGFR4 kinase inhibitory activity

[0282] Dilute 50 ng / μL of 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 compound concentration of 1000 nM-0.24 nM, with positive concentrations ranging from 100 nM to 0.024 nM, a 4-fold gradient, for a total of 7 concentrations. A blank control (without enzyme) and a negative control (containing enzyme, with DMSO as solvent) are also included. 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, Ulight-polyGT) 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 .

[0283] 1.3 Screening for FGFR4 (V550L) kinase inhibitory activity

[0284] 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 four-parameter fitting. 50 .

[0285] Table 1. In vitro kinase inhibitory activity of compounds in the examples

[0286]

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, or a mixture thereof, in, W is selected from CH; X is selected from CR a ; Y is selected from CR b ; Z is selected from CR c ; R a Selected from H; R b selected from H, or halogen; R c selected from H; R 1 , R 2 are each independently selected from H, methyl, or -CD3; R 3 Selected from one or more R d1 The following groups are substituted: ethyl or methylethylamino, or optionally, one or more R groups. d2 The following groups are substituted: Each R d1 Each is independently selected from C 1-4 Alkylamino or diC 1-4 Alkylamino; Each R d2 Each is independently selected from halogens, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 alkylamino, or di-C 1-4 Alkylamino; R 4 selected from H, or F.

2. The compound of claim 1 or its pharmaceutically acceptable salt, or stereoisomer, or mixture thereof, characterized in that, R b is selected from H, F, Cl, or Br.

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

4. The compound of claim 1 or its pharmaceutically acceptable salt, or stereoisomer, or mixture thereof, characterized in that, R 1 R 2 Each is independently selected from H or methyl.

5. The compound of claim 1 or its pharmaceutically acceptable salt, or stereoisomer, or mixture thereof, characterized in that, R 1 R 2 All are H.

6. The compound of claim 1 or its pharmaceutically acceptable salt, or stereoisomer, or mixture thereof, characterized in that, R 3 Selected from one or more R d1 The substituted methylethylamino group, or optionally, the methylethylamino group, is substituted with one or more R groups. d2 The following groups are substituted:

7. The compound of claim 1 or its pharmaceutically acceptable salt, or stereoisomer, or mixture thereof, characterized in that, R 3 Selected from the following groups:

8. The compound of claim 1 or its pharmaceutically acceptable salt, or stereoisomer, or mixture thereof, characterized in that, R 3 Selected from the following groups:

9. The compound of claim 1 or its pharmaceutically acceptable salt, or stereoisomer, or mixture thereof, characterized in that, R 3 Selected from the following groups:

10. The compound of claim 1 or its pharmaceutically acceptable salt, or stereoisomer, or mixture thereof, characterized in that, Each R d1 Each is independently selected from methylamino, ethylamino, dimethylamino, or diethylamino.

11. The compound of claim 1 or its pharmaceutically acceptable salt, or stereoisomer, or mixture thereof, characterized in that, Each R d2 Each is independently selected from F, Cl, Br, methyl, ethyl, -CF3, -CHF2, methoxy, methylamino, or dimethylamino.

12. The compound of claim 1 or its pharmaceutically acceptable salt, or stereoisomer, or mixture thereof, characterized in that, R 4 Selected from H.

13. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, or a mixture thereof, wherein the compound is selected from the compound of formula (Ib) or a pharmaceutically acceptable salt or stereoisomer thereof, or a mixture thereof. in, R 1 R 2 R 3 R 4 As defined in claim 1.

14. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, or a mixture thereof, selected from the following compounds or pharmaceutically acceptable salts or stereoisomers thereof, or mixtures thereof:

15. A pharmaceutical composition comprising a compound as claimed in any one of claims 1-14, or a pharmaceutically acceptable salt or stereoisomer thereof, or a mixture thereof.

16. Use of the compound of any one of claims 1-14, or a pharmaceutically acceptable salt or stereoisomer thereof, or a mixture thereof, or the pharmaceutical composition of claim 15, in the preparation of a medicament for treating FGFR4-related diseases.

17. The use as described in claim 16, wherein, The FGFR4-related diseases mentioned are cancers.

18. The use as described in claim 16, wherein, The FGFR4-related disease is liver cancer.

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