Pyridocyclic compounds and their medical uses

Abstract

This application relates to pyridocyclic compounds and their medical uses, the structure of which is shown in Formula (I). This application also relates to methods for preparing the compounds, pharmaceutical compositions, and their use as FGFR4 inhibitors in the treatment of cancer. #imgabs0#

Description

Technical Field

[0001] The present application relates to pyridocyclic compounds, methods for preparing the same, pharmaceutical compositions containing the same, and their use as FGFR4 inhibitors in the treatment of cancer. Background Art

[0002] Fibroblast growth factor receptor 4 (FGFR4) is a tyrosine kinase receptor for FGF, involved in the regulation of multiple cellular processes, including cell proliferation, differentiation, migration, metabolism, and bile acid biosynthesis. Recent studies have confirmed that elevated FGFR4 levels are closely associated with the development and progression of cancer, making FGFR4 a popular target for the development of novel anti-cancer therapies.

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

[0004]

[0005] Among them, research related to H3B-6527 showed that drug resistance caused by mutations in the key FGFR4 sites V550L or V550 reduces or even renders the drug's efficacy ineffective. How to break through the limitations of these gene mutations that cause drug resistance will become the focus of the next stage of FGFR4 inhibitor research. Detailed Description of the Invention

[0006] In one aspect, the present application relates to a compound of formula (I) or a pharmaceutically acceptable salt, or tautomer, or stereoisomer, or deuterated form thereof, and a mixture thereof,

[0007]

[0008] in,

[0009] X is selected from N or CH;

[0010] Z 1 , Z 2 , Z 3 Each independently selected from N or CR 1 , where Z 1 , Z 2 , Z 3 At least one selected from CR 1 ;

[0011] L 1 Selected from -S-, -O-, -NH-, or -N(C 1-3 alkyl)-;

[0012] A is selected from 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-12 membered aryl, 4-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl, or 4-12 membered heteroaryl;

[0013] Each R 1 Each is independently selected from H, halogen, -OH, -NH2, cyano, nitro, C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 alkyl;

[0014] R 2 Selected from H, carbamoyl, single C 1-6 Alkylcarbamoyl, di-C 1-6 Alkylcarbamoyl, C 1-6 Alkoxycarbonyl, C 1-6 Alkylsulfonyl, or di-C 1-6 Alkylphosphoryl;

[0015] R 3 Selected from optionally one or more R a Substituted with the following groups: C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Alkylamino, or di-C 1-10 Alkylamino;

[0016] Each R a are each independently selected from halogen, oxo, -OH, -NH2, cyano, or the following groups optionally substituted with one or more halogens: C 1-4 Alkyl, C 1-4 Alkoxy, single C 1-4 Alkylamino, di-C 1-4 Alkylamino, C 2-4 Alkynyl, C 2-4 alkenyl, 3-7 membered cycloalkyl, or 4-7 membered heterocycloalkyl;

[0017] R 4 Selected from H, halogen, -OH, or -NR b R c ;

[0018] R b 、R c Each independently selected from H, or optionally substituted by one or more R d Substituted with the following groups: C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-10 membered cycloalkyl-C 1-3 alkyl, 4-12 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C 1-3alkyl, 4-7 membered heterocycloalkyl substituted by 4-7 membered heterocycloalkyl, 4-7 membered heterocycloalkyl substituted by 3-7 membered cycloalkyl, or 3-7 membered cycloalkyl substituted by 4-7 membered heterocycloalkyl;

[0019] Each R d Each independently selected from halogen, oxo, -OH, -NH2, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, or di-C 1-4 Alkylamino;

[0020] Or, R b 、R c Together with the attached N atom, it forms a e substituted 4-12 membered heterocycloalkyl;

[0021] Each R e are each independently selected from halogen, oxo, -OH, -NH2, cyano, or the following groups optionally substituted with one or more halogens: C 1-4 Alkyl, C 1-4 Alkoxy, hydroxy-C 1-4 Alkyl, C 1-3 Alkoxy-C 1-3 Alkyl, single C 1-4 Alkylamino, di-C 1-4 Alkylamino, or optionally one or more R e1 Substituted groups: 3-7 membered cycloalkyl, 3-7 membered cycloalkyl-C 1-3 alkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocycloalkyl-C 1-3 alkyl;

[0022] Each R e1 Each independently selected from halogen, oxo, -OH, -NH2, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, single C 1-4 Alkylamino, or di-C 1-4 Alkylamino.

[0023] In some embodiments, Z 1 , Z 2 , Z 3 Each independently selected from CR 1 In some embodiments, Z 2 Selected from CR 1 .

[0024] In some embodiments, Z 1 , Z 2 , Z3 At least one of Z is selected from N. In some embodiments, Z 1 is selected from N. In some embodiments, Z 2 is selected from N. In some embodiments, Z 3 Selected from N.

[0025] In some embodiments, L 1 Selected from -NH- or -N(C 1-3 alkyl)-.

[0026] In some embodiments, A is selected from 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, or 6-12 membered aryl. In some embodiments, A is selected from 5-10 membered cycloalkyl, 5-10 membered cycloalkenyl, or phenyl. In some embodiments, A is selected from 7-8 membered bridged cycloalkyl, 7-8 membered bridged cycloalkenyl, or phenyl.

[0027] In some embodiments, A is selected from In some embodiments, A is selected from In some embodiments, A is selected from

[0028] In some embodiments, each R 1 are each independently selected from H or halogen. In some embodiments, each R 1 are each independently selected from H or fluorine.

[0029] In some embodiments, R 2 Selected from H, carbamoyl, single C 1-4 Alkylcarbamoyl, di-C 1-4 Alkylcarbamoyl, C 1-4 Alkylsulfonyl, or di-C 1-4 Alkylphosphoryl.

[0030] In some embodiments, R 2 Selected from H, carbamoyl, C 1-4 Alkylsulfonyl, or di-C 1-4 In some embodiments, R 2 is selected from H, carbamoyl, methylsulfonyl, or dimethylphosphoryl. In some embodiments, R 2 Selected from carbamoyl.

[0031] In some embodiments, R 3 Selected from optionally one or more R a Substituted with the following groups: C 1-10 Alkoxy, or C 1-10 In some embodiments, R3 Selected from optionally one or more R a Substituted C 1-6 In some embodiments, R 3 Selected from C 1-6 Alkoxy.

[0032] In some embodiments, each R a are each independently selected from halogen, or the following groups optionally substituted by one or more halogens: C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkynyl, 3-7 membered cycloalkyl.

[0033] In some embodiments, each R a Each is independently selected from fluorine, chlorine, bromine, or the following groups optionally substituted with one or more fluorines: methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, 2-propynyl, 1-propynyl, 2-propenyl, 1-propenyl, cyclopropanyl, cyclohexanyl, cyclopentanyl. In some embodiments, each R a Each is independently selected from fluorine, or the following groups optionally substituted by one or more F: methyl, methoxy, 1-propynyl, cyclopropanyl.

[0034] In some embodiments, each R a Each R is independently selected from fluoro, trifluoromethyl, methoxy, 1-propynyl, or cyclopropane. a Each is independently selected from fluoro, trifluoromethyl, or cyclopropane.

[0035] In some embodiments, R 3 Selected from

[0036] In some embodiments, R 4 Selected from H or -NR b R c .

[0037] In some embodiments, R 4 Selected from-NR b R c .

[0038] In some embodiments, R b 、R c Each independently selected from H, or optionally substituted by one or more R d Substituted with the following groups: C 1-6 alkyl, 4-12 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C 1-3 alkyl.

[0039] In some embodiments, R b 、R c Each independently selected from H, or optionally substituted by one or more R d Substituted: methyl, ethyl, propyl, cyclopropane, cyclopentane, cyclohexane, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrofuranylmethyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl. In some embodiments, R b 、R c Each independently selected from H, or optionally substituted by one or more R d Substituted groups include: methyl, ethyl, tetrahydrofurylmethyl, piperidinyl, tetrahydropyranyl.

[0040] In some embodiments, R b Selected from H, or optionally one or more R d Substituted C 1-6 alkyl.

[0041] In some embodiments, R c Selected from optionally one or more R d Substituted with the following groups: C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-10 membered cycloalkyl-C 1-3 alkyl, 4-12 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C 1-3 In some embodiments, R c Selected from optionally one or more R d Substituted with the following groups: C 1-6 alkyl, 4-12 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C 1-3 In some embodiments, R c Selected from optionally one or more R d Substituted groups include: methyl, ethyl, tetrahydrofurylmethyl, piperidinyl, tetrahydropyranyl.

[0042] In some embodiments, each R d Each independently selected from halogen, oxo, -OH, -NH2, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, or di-C 1-4 In some embodiments, each R d are each independently selected from halogen, C1-4 Alkyl, or di-C 1-4 In some embodiments, each R d Each is independently selected from methyl or dimethylamino.

[0043] In some embodiments, R b 、R c Together with the attached N atom, it forms a e Substituted 4-12 membered heterocycloalkyl, the 4-12 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N or O. In some embodiments, the 4-12 membered heterocycloalkyl is selected from 5-10 membered heterocycloalkyl.

[0044] In some embodiments, R b 、R c Together with the attached N atom, it forms a e Substituted rings include 5-7 membered monoheterocycloalkyl, 7-10 membered bridged heterocycloalkyl, and 7-10 membered spiroheterocycloalkyl.

[0045] In some embodiments, R b 、R c Together with the attached N atom, it forms a e A substituted 6-7 membered monoheterocycloalkyl group containing 1 or 2 nitrogen heteroatoms.

[0046] In some embodiments, R b 、R c Together with the attached N atom, it forms a e The following rings are substituted:

[0047] In some embodiments, R b 、R c Together with the attached N atom, it forms a e The following rings are substituted:

[0048] In some embodiments, each R e Each is independently selected from halogen, oxo, -OH, -NH2, cyano, or the following groups optionally substituted by one or more halogens: methyl, ethyl, isopropyl, C 1-3 Alkoxy, methoxymethyl, methoxyethyl, methylamino, ethylamino, dimethylamino, diethylamino, or optionally substituted by one or more R e1Substituted groups include cycloalkyl, cyclobutyl, azetidine, oxetane, piperidinyl, piperazinyl, pyrrolidinyl, and morpholinyl.

[0049] In some embodiments, each R e Each independently selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-3 Alkoxy-C 1-3 Alkyl, di-C 1-4 Alkylamino, or optionally one or more R e1 In some embodiments, each R e are each independently selected from methyl, isopropyl, methoxy, methoxymethyl, methoxyethyl, dimethylamino, or optionally substituted by one or more R e1 Substituted with the following groups: oxetane, piperazinyl, pyrrolidinyl, morpholinyl. In some embodiments, each R e Each independently selected from methyl, isopropyl, methoxymethyl, methoxyethyl, dimethylamino, or optionally substituted by one or more R e1 Substituted groups include: oxetane, piperazinyl.

[0050] In some embodiments, each R e1 are each independently selected from halogen, C 1-4 alkyl.

[0051] In some embodiments, R 4 Selected from H,

[0052] In some embodiments, R 4 Selected from H,

[0053] In some embodiments, R 4 Selected from H,

[0054] In some embodiments, the halogen is selected from fluorine, chlorine, and bromine. In some embodiments, the halogen is selected from fluorine. In some embodiments, the halo refers to being substituted with one or more halogens. In some embodiments, the halo refers to being substituted with one or more halogens selected from fluorine, chlorine, and bromine. In some embodiments, the halo refers to being substituted with one or more fluorines.

[0055] In some embodiments, the heterocycloalkyl group includes a monocyclic, spirocyclic, or bridged ring. In some embodiments, the heterocycloalkyl group or heterocycloalkenyl group contains 1 or 2 heteroatoms selected from N or O.

[0056] In some embodiments, the "one or more" is selected from 1, 2, 3, 4, 5, or 6. In some embodiments, the "one or more" is selected from 1, 2, or 3. The "one or more" is selected from 1, or 2.

[0057] In some embodiments, the "C 1-10 ”Selected from “C 1-6 In some embodiments, the "C 1-6 ”Selected from “C 1-4 In some embodiments, the "C 1-4 ”Selected from “C 1-3 ” or “C 1-2 In some embodiments, the "C 2-4 ”Selected from “C 2-3 In some embodiments, the "C 1-3 ”Selected from “C 1-2 ”.

[0058] In some embodiments, the “3-12 yuan” is selected from “3-10 yuan” or “5-10 yuan”. In some embodiments, the “4-12 yuan” is selected from “3-10 yuan” or “5-10 yuan”. In some embodiments, the “3-10 yuan” is selected from “3-7 yuan” or “5-10 yuan”. In some embodiments, the “4-10 yuan” is selected from “4-7 yuan” or “5-10 yuan”. In some embodiments, the “3-7 yuan” is selected from “3-6 yuan” or “5-6 yuan”. In some embodiments, the “4-7 yuan” is selected from “4-6 yuan” or “5-6 yuan”. In some embodiments, the “6-12 yuan” is selected from “6-10 yuan”.

[0059] The present application relates to a compound of formula (Ia) or a pharmaceutically acceptable salt, or tautomer, or stereoisomer, or deuterated substance and a mixture thereof.

[0060]

[0061] Among them, R 2 、R 3 、R 4 , L 1 , Part A is as defined above.

[0062] The present application relates to a compound of formula (Ib) or a pharmaceutically acceptable salt, or tautomer, or stereoisomer, or deuterated substance and a mixture thereof.

[0063]

[0064] Among them, R2 、R 3 、R b 、R c , L 1 , Part A is as defined above.

[0065] The present application relates to a compound of formula (Ic) or a pharmaceutically acceptable salt, or tautomer, or stereoisomer, or deuterated substance and a mixture thereof.

[0066]

[0067] Among them, R 2 、R 3 、R b 、R c , L 1 Part is as defined above.

[0068] The present application relates to a compound of formula (Id) or a pharmaceutically acceptable salt, or tautomer, or stereoisomer, or deuterated substance and a mixture thereof.

[0069]

[0070] Among them, R 3 、R b 、R c , L 1 Part is as defined above.

[0071] The present application relates to a compound of formula (Ie) or a pharmaceutically acceptable salt, or tautomer, or stereoisomer, or deuterated substance and a mixture thereof.

[0072]

[0073] Among them, R 3 、R b 、R c , L 1 Part is as defined above.

[0074] The present application also relates to the following compounds or pharmaceutically acceptable salts, tautomers, stereoisomers, deuterated derivatives and mixtures thereof:

[0075]

[0076]

[0077]

[0078]

[0079] On the other hand, the present application relates to a pharmaceutical composition comprising a compound of formula (I) or formula (Ia) or formula (Ib) or formula (Ic) or formula (Id) or formula (Ie) of the present application, or a pharmaceutically acceptable salt, or tautomer, or stereoisomer, or deuterated compound, and mixtures thereof. In some embodiments, the pharmaceutical composition of the present application further comprises a pharmaceutically acceptable excipient.

[0080] On the other hand, the present application relates to a method for treating FGFR4-related diseases in mammals, comprising administering to a mammal, preferably a human, in need of such treatment, a therapeutically effective amount of a compound of Formula (I) or Formula (Ia) or Formula (Ib) or Formula (Ic) or Formula (Id) or Formula (Ie) or a pharmaceutically acceptable salt, or tautomer, or stereoisomer, or deuterated form, and mixtures thereof, or a pharmaceutical composition thereof.

[0081] On the other hand, the present application relates to the use of a compound of formula (I) or formula (Ia) or formula (Ib) or formula (Ic) or formula (Id) or formula (Ie) or a pharmaceutically acceptable salt, or tautomer, or stereoisomer, or deuterated form and a mixture thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating FGFR4-related diseases.

[0082] On the other hand, the present application relates to the use of a compound of formula (I) or formula (Ia) or formula (Ib) or formula (Ic) or formula (Id) or formula (Ie) or a pharmaceutically acceptable salt, or tautomer, or stereoisomer, or deuterated form and mixtures thereof, or a pharmaceutical composition thereof in the treatment of FGFR4-related diseases.

[0083] On the other hand, the present application relates to a compound of formula (I) or formula (Ia) or formula (Ib) or formula (Ic) or formula (Id) or formula (Ie) or a pharmaceutically acceptable salt, or tautomer, or stereoisomer, or deuterated form and a mixture thereof, or a pharmaceutical composition thereof for treating FGFR4-related diseases.

[0084] In some embodiments of the present application, the FGFR4-related disease is preferably cancer.

[0085] In some embodiments of the present application, the cancer is liver cancer.

[0086] The compounds of the present application can effectively inhibit FGFR4 activity and also have good inhibitory activity against FGFR4 V550L mutant or FGFR4N535K mutant; at the same time, the compounds of the present application have good absorption and metabolic properties, which can meet the needs of drug development.

[0087] definition

[0088] Unless otherwise indicated, the following terms used in this application have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0089] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0090] The term "optionally" or "optionally" means that the event or circumstance described subsequently may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that would be sterically impossible and / or incomposable to synthesize will be introduced.

[0091] In this article, C m-n , means that the moiety has an integer number of carbon atoms in 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.

[0092] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition on each occurrence is independent. Thus, for example, if a group is substituted with two R's, each R has an independent alternative.

[0093] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a covalent bond.

[0094] When one of the variables is selected from 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.

[0095] When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. It means that it can be substituted at any position on the cyclohexyl group or cyclohexadiene.

[0096] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0097] The term "hydroxy" refers to an -OH group.

[0098] The term "cyano" refers to a -CN group.

[0099] The term "mercapto" refers to a -SH group.

[0100] The term "amino" refers to a -NH2 group.

[0101] The term "nitro" refers to a -NO2 group.

[0102] The term "alkyl" refers to a group of the formula C n H 2n+1 The alkyl group may be straight chain or branched. For example, the term "C 1-6 The term "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 has the same definition as above.

[0103] The term "alkoxy" refers to an -O-alkyl group.

[0104] The term "alkylamino" refers to an -NH-alkyl group.

[0105] The term "dialkylamino" refers to -N(alkyl)2.

[0106] The term "alkylsulfonyl" refers to an -SO2-alkyl group.

[0107] The term "alkylthio" refers to an -S-alkyl group.

[0108] The term "dialkylphosphoryl" refers to -PO-(alkyl)2.

[0109] The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. Non-limiting examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.

[0110] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and 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), 1,3-butadiynyl (-C≡C≡CH), and the like.

[0111] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 12-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, and the like.

[0112] The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3 to 12-membered ring, preferably a 5 to 10-membered ring. Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclo [2.2.1] hepta-2-enyl, bicyclo [2.2.2] oct-2-enyl, etc.

[0113] The term "heterocyclic radical" refers to a non-aromatic ring that is fully saturated or partially undersaturated (but not fully unsaturated heteroaromatic) and can exist as a monocycle, a bridged ring or a spirocycle. 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 sulphur, oxygen and / or nitrogen. The limiting examples of heterocyclic radicals include but are not limited to oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl etc.

[0114] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated 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 (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and / or nitrogen. Non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl; examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl; examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl; and examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxepanyl, and thiepanyl.

[0115] The term "bridged ring" refers to a polycyclic ring that shares two or more carbon atoms. The shared carbon atoms are called bridgehead carbons, and the bridgehead carbons can be connected by a carbon chain or a bond. Preferred bridged rings are bicyclic, and to convert them into chain-like compounds, the carbon chain must be broken twice. Examples include bicyclo[1.1.0]butane and bicyclo[3.2.1]octane.

[0116] The term "spirocyclic" refers to polycyclic rings that share a common carbon atom, for example, spiro[4.5]decane.

[0117] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, 6-12, or 6-10 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetrahydronaphthalene.

[0118] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, with the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryl groups have single 4 to 8-membered rings, especially 5 to 8-membered rings, or multiple fused rings containing 6 to 14, especially 6 to 10, ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.

[0119] The term "treatment" means administering the compound or formulation described herein to prevent, improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0120] (i) preventing a disease or disease state from occurring in a mammal, particularly where such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state;

[0121] (ii) inhibiting the disease or disease state, i.e., curbing its development;

[0122] (iii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0123] The term "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and this disclosure.

[0124] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0125] As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

[0126] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0127] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0128] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0129] The compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as prototransfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by the reorganization of some bonding electrons. The present application also includes isotope-labeled compounds of the present application that are identical to those described herein, but in which one or more atoms are replaced by atoms having an atomic weight or mass number different from that typically found in nature. Examples of isotopes that can be incorporated into compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as, respectively 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 et al.

[0130] Certain isotope-labeled compounds of the present application (e.g. 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 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. Isotopically labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0131] In addition, the use of heavier isotopes such as deuterium (i.e. 2H)) substitution may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, with partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium. Exemplary deuterated compounds are shown below, but are not limited thereto:

[0132]

[0133] The compounds of the present invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of the present invention containing asymmetric carbon atoms can be isolated in optically pure forms or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents. Non-limiting examples of stereoisomers include, but are not limited to:

[0134]

[0135] The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0136] Typical routes of administration of the compounds of the present invention, or pharmaceutically acceptable salts thereof, 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.

[0137] The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0138] 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 the present application to be formulated into tablets, pills, lozenges, dragees, capsules, gels, slurries, suspensions, and the like for oral administration to a patient.

[0139] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0140] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0141] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0142] The chemical reactions described in the specific embodiments of the present application are carried out in a suitable solvent that is compatible with the chemical transformations described herein and the reagents and materials required. To obtain the compounds described herein, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0143] An important consideration in synthetic route planning in the art is the selection of a suitable protecting group for a reactive functional group (such as the amino group in this application). For example, reference may be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc. All references cited in this application are incorporated herein in their entirety.

[0144] When X is selected from N, the compound of the general formula (I) of the present application can be prepared by those skilled in the art of organic synthesis via route 1:

[0145]

[0146] Compound 1 and compound 4 are used as raw materials, wherein compound 1 undergoes substitution reaction with the corresponding halide to obtain compound 2, and then F is HR 4 Substitution to generate compound 3; compound 4 undergoes substitution reaction with compound 5 to obtain compound 6, which is then subjected to cyanation reaction to obtain compound 7, followed by nitro reduction to generate compound 8, which is finally reacted with compound 3 to obtain a compound of formula (I).

[0147] This application uses the following abbreviations:

[0148] DMSO represents dimethyl sulfoxide; CDCl3 represents deuterated chloroform; TsO represents p-toluenesulfonyl; Me represents methyl; and Xantphos represents 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

[0149] Compounds are artificially or Software naming, commercially available compounds use supplier catalog names.

[0150] For the sake of clarity, the present invention is further illustrated by examples, but the examples 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 will be made to the embodiments of this application without departing from the spirit and scope of this application.

[0151] All reagents used in this application were commercially available and used without further purification. Example

[0152] Intermediate 1: (1S,2S,3R,4R)-3-(((2,3-diamino-5-bromopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0153]

[0154] Synthesis route:

[0155]

[0156] Step 1: Combine 5-bromo-4-chloro-3-nitropyridin-2-amine (1.5 g), (1R,2R,3S,4S)-3-carbamoylbicyclo[2.2.1]hept-5-en-2-aminium 2,2,2-trifluoroacetate (1.740 g), isopropyl alcohol (10 ml), and diisopropylethylamine (6.14 g). Heat to 60°C for 3 hours. Cool to room temperature, filter, and wash the filter cake with cold isopropyl alcohol (2 ml). Dry to give the title compound (1.9 g). 1H NMR (500MHz, DMSO-d6): δ7.94(s,1H),7.76(d,J=9.1Hz,1H),7.70(d,J=2.6Hz, 1H),7.18(d,J=2.7Hz,1H),7.03(s,2H),6.30(dd,J=5.7,2.9Hz,1H),6.10(dd, J=5.8,3.1Hz,1H),3.58(t,J=8.7Hz,1H),2.83(s,1H),2.56(s,1H),2.51(d,J= 1.8Hz,1H),2.17(d,J=8.9Hz,1H),1.39(dt,J=9.1,1.8Hz,1H).MS:368.4[M+H] + .

[0157] Step 2: Combine (1S,2S,3R,4R)-3-((2-amino-5-bromo-3-nitropyridin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide (1.0 g, 2.72 mmol), reduced iron powder (0.61 g, 10.8 mmol), ammonium chloride (0.30 g, 5.43 mmol), ethanol (15 ml), and purified water (5 ml). Heat to 70°C for 1 hour. After the reaction, filter and dilute the filtrate with water. Extract with ethyl acetate. The organic phase is washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate. Filter and concentrate the filtrate to obtain the title compound (1.6 g). 1 H NMR(500MHz,DMSO-d6)7.54(d,J=2.5Hz,1H),7.39(s,1H),6.98(d,J=2.4Hz,1H), 6.20(dd,J=5.7,2.9Hz,1H),6.07(dd,J=5.7,3.1Hz,1H),5.50(s,2H),4.24(s,2H ),4.06(d,J=12.2Hz,1H),3.77-3.62(m,1H),2.75(d,J=2.7Hz,1H),2.53-2.50(m ,1H),2.41(d,J=8.7Hz,1H),2.36-2.28(m,1H),1.47-1.35(m,1H).MS:338.4[M+H] + .

[0158] Intermediate 2: (1S,2S,3R,4R)-3-(((2,3-diamino-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0159]

[0160] Synthesis route:

[0161]

[0162] Step 1: (1S,2S,3R,4R)-3-((2-amino-5-cyano-3-nitropyridin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0163] Combine (1S,2S,3R,4R)-3-((2-amino-5-bromo-3-nitropyridin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide (1 g), cuprous cyanide (0.730 g), and N,N-dimethylformamide (10 ml). Heat the mixture to 160°C in a microwave oven for 1.5 hours. The reaction mixture is cooled to room temperature, and aqueous ammonia (30 ml) is added under ice-cooling. The reaction mixture is extracted with ethyl acetate, and the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which is then purified by silica gel column chromatography (dichloromethane:methanol = 50:1) to afford the title compound (0.65 g). 1 H NMR (500MHz, DMSO-d6): 10.27(d,J=8.3Hz,1H),8.58(s,2H),8.17(s,1H),7.61(d,J=2.5Hz,1H),7.26-7.02(m,1H),6.33(ddd,J=26.8,5.7,2. 8Hz,2H),4.51(t,J=8.2Hz,1H),2.94(s,1H),2.88(s,1H),2.58(d,J=8.0Hz,1H),2.18(d,J=8.9Hz,1H),1.46(d,J=9.0Hz,1H).MS:314.98[M+H] + .

[0164] Step 2: (1S,2S,3R,4R)-3-(((2,3-Diamino-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0165] Combine (1S,2S,3R,4R)-3-((2-amino-5-cyano-3-nitropyridin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide (1.78 g), reduced iron powder (1.265 g), ammonium chloride (0.606 g), ethanol (30 ml), and water (10 ml), and heat to 70°C for 1 hour. After the reaction, cool to room temperature, filter, and wash the filter cake with methanol. The filtrate is concentrated to obtain the title compound (2.1 g). 1H NMR(500MHz,DMSO-d6)δ10.33(s,1H),7.68(d,J=11.8Hz,2H),7.22-7.05(m ,1H),6.28(dt,J=6.0,2.7Hz,2H),6.25-6.18(m,1H),6.12(s,2H),4.18-4.0 8(m,1H),3.65(s,1H),2.86-2.76(m,1H),2.72-2.65(m,1H),2.54(dd,J=8.2 ,1.5Hz,1H),2.21(dt,J=8.8,1.6Hz,1H),1.43-1.35(m,1H).MS:285.0[M+H] + .

[0166] Intermediate 3: 2-isobutoxybenzaldehyde

[0167]

[0168] Synthesis route:

[0169]

[0170] Salicylaldehyde (5g), 1-iodo-2-methylpropane (8.29g), potassium carbonate (11.32g), and N,N-dimethylformamide (100ml) were mixed and heated to 100°C for 24 hours. After the reaction was completed, the mixture was cooled to room temperature and the insoluble matter was filtered out. Water and ethyl acetate were added to the filtrate. The aqueous phase was separated and extracted with ethyl acetate. The organic phases were combined, washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to obtain the title compound (4.8g). GCMS: 178[M] + .

[0171] Intermediate 4: 2-isopentyloxybenzaldehyde

[0172]

[0173] Synthesis route:

[0174]

[0175] Salicylaldehyde (0.5 g), 1-bromoisopentane (0.68 g), potassium carbonate (0.849 g), and N,N-dimethylformamide (5 ml) were mixed and heated to 80°C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and the insoluble matter was filtered out. Water and ethyl acetate were added to the filtrate. The aqueous phase was separated and extracted with ethyl acetate. The organic phases were combined, washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to obtain the title compound (345 mg). 1H-NMR (500MHz, CDCl3): δ10.51(s,1H),7.83(dd,J1=7.8Hz,J2=1.3Hz,1H),7.53(td,J1=8.5Hz,J2=1.5Hz,1H),7.0 2-6.98(m,2H),4.11(t,J=6.5Hz,2H),1.91-1.83(m,1H),1.75(q,J=6.5Hz,2H),0.99(d,J=6.5Hz,6H).GCMS:192[M] + .

[0176] Intermediate 5: 4-Fluoro-2-isobutoxybenzaldehyde

[0177]

[0178] Synthesis route:

[0179]

[0180] Step 1: 4-Fluoro-2-isobutoxybenzaldehyde

[0181] Combine 4-fluoro-2-hydroxybenzaldehyde (5g), potassium carbonate (7.40g), 1-bromo-2-methylpropane (5.38g), and N,N-dimethylformamide (60ml) and heat to 80°C overnight. After the reaction is complete, filter the mixture with suction. Dilute the filtrate with water, extract with ethyl acetate, wash with water, then with saturated sodium chloride solution, and dry over anhydrous sodium sulfate. Filter and concentrate to obtain the title compound (6.9g). 1 H NMR (500MHz, CDCl3): δ10.35 (s, 1H), 7.78 (dd, J = 8.7, 6.9Hz, 1H), 6.68-6.52 (m, 2H), 3 .74(d,J=6.4Hz,2H),2.11(dp,J=13.3,6.7Hz,1H),1.00(d,J=6.7Hz,6H).GCMS:196[M] + .

[0182] Intermediate 6: 4-Fluoro-2-(isopentyloxy)benzaldehyde

[0183]

[0184] Synthesis route:

[0185]

[0186] Salicylaldehyde (5g), 1-bromoisopentane (5.93g), potassium carbonate (7.4g), and N,N-dimethylformamide (50ml) were mixed and heated to 80°C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature and the insoluble matter was filtered out. Water and ethyl acetate were added to the filtrate. The aqueous phase was separated and extracted with ethyl acetate. The organic phases were combined, washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to obtain the title compound (7.5g). 1 H-NMR (500MHz, CDCl3): δ10.39 (s, 1H), 7.85 (dd, J1=8.5Hz, J2=6.5Hz, 1H), 6.72-6.66 (m, 2H), 4. 09(t,J=6.5Hz,2H),1.90-1.82(m,1H),1.76(q,J=6.5Hz,2H),0.99(d,J=6.5Hz,6H).GCMS:210[M] + .

[0187] Intermediate 7: 4-Bromo-2-(pent-3-yn-1-yloxy)benzaldehyde

[0188]

[0189] Synthesis route:

[0190]

[0191] Step 1: 4-Methylbenzenesulfonic acid pent-3-yn-1-yl ester

[0192] Mix 3-pentyn-1-ol (0.26 g), triethylamine (0.469 g), and dichloromethane (20 ml). Then, add p-toluenesulfonyl chloride (0.648 g) portionwise at 0°C. Warm the mixture to room temperature and allow to react overnight. After completion of the reaction, dilute with water and extract with dichloromethane. The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (620 mg). 1 H NMR (500MHz, CDCl3): δ7.80(d,J=8.4Hz,2H),7.35(d,J=8.0Hz,2H),4.05(t,J =7.2Hz,2H),2.49(dp,J=7.2,2.4Hz,2H),2.45(s,3H),1.72(t,J=2.5Hz,3H).

[0193] Step 2: 4-Bromo-2-(pent-3-yn-1-yloxy)benzaldehyde

[0194] Combine pent-3-yn-1-yl 4-methylbenzenesulfonate (287 mg), 4-bromo-2-hydroxybenzaldehyde (220 mg), potassium carbonate (454 mg), and acetonitrile (5 ml) and heat to 70°C overnight. After completion of the reaction, add water and extract with ethyl acetate. The organic phase is washed with saturated brine and dried over anhydrous sodium sulfate. Filter, concentrate, and purify by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the title compound (120 mg). 1 H NMR (500MHz, CDCl3): δ10.44(d,J=0.9Hz,1H),7.70(d,J=8.3Hz,1H),7.24-7.11(m, 2H), 4.16 (t, J=6.9Hz, 2H), 2.69 (ddt, J=6.9, 4.4, 2.5Hz, 2H), 1.79 (t, J=2.5Hz, 3H).

[0195] Intermediate 8: 4-Bromo-2-(2-cyclopropylethoxy)benzaldehyde

[0196]

[0197] Synthesis route:

[0198]

[0199] Step 1: 2-Cyclopropylethyl 4-methylbenzenesulfonate

[0200] Dissolve 2-cyclopropylethanol (0.5 g) and triethylamine (0.881 g) in dichloromethane (20 ml). Add p-toluenesulfonyl chloride (1.217 g) portionwise at 0°C. Warm the mixture to room temperature and allow to react overnight. After completion of the reaction, dilute with water and extract with dichloromethane. The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (1.1 g). 1 H NMR (500MHz, CDCl3): δ7.78(d,J=8.3Hz,2H),7.32(d,J=8.1Hz,2H),4.06(t,J=6.6Hz,2H),2 .43(s,3H),1.52(p,J=7.0Hz,2H),0.69-0.59(m,1H),0.45-0.30(m,2H),-0.03-0.04(m,2H).

[0201] Step 2: 4-Bromo-2-(2-cyclopropylethoxy)benzaldehyde

[0202] Combine 2-cyclopropylethyl 4-methylbenzenesulfonate (430 mg), 4-bromo-2-hydroxybenzaldehyde (300 mg), potassium carbonate (619 mg), and acetonitrile (5 ml) and heat to 70°C overnight. After completion of the reaction, add water and extract with ethyl acetate. The organic phase is washed with saturated brine and dried over anhydrous sodium sulfate. Filter, concentrate, and purify by silica gel column chromatography (petroleum ether:ethyl acetate = 95:5) to obtain the title compound (210 mg). 1 H NMR (500MHz, CDCl3): δ10.44(d,J=0.8Hz,1H),7.69(d,J=8.1Hz,1H),7.22-7.12(m,2H),4.15(t,J=6 .4Hz,2H),1.76(d,J=6.7Hz,2H),0.93-0.79(m,1H),0.59-0.46(m,2H),0.15(dt,J=5.8,4.5Hz,2H).

[0203] Intermediate 9: 4-Fluoro-2-(4,4,4-trifluorobutoxy)benzaldehyde

[0204]

[0205] Synthesis route:

[0206]

[0207] Step 1: 4-Fluoro-2-(4,4,4-trifluorobutoxy)benzaldehyde

[0208] Combine 4-fluoro-2-hydroxybenzaldehyde (0.3 g), potassium carbonate (0.444 g), 4-bromo-1,1,1-trifluorobutane (0.573 g), and N,N-dimethylformamide (3 ml). Heat to 80°C and allow to react overnight. After completion of the reaction, dilute with water and extract with ethyl acetate. The organic phase is washed with water and saturated brine, then dried over anhydrous sodium sulfate. Filter and concentrate to obtain the title compound (480 mg). 1 H NMR (500MHz, CDCl3): δ10.38(s,1H),7.87(dd,J=8.6,6.8Hz,1H),6.76(td,J=8.3,2.3Hz,1H),6.67( dd,J=10.6,2.3Hz,1H),4.13(t,J=6.1Hz,2H),2.35(ddd,J=10.6,8.0,5.8Hz,2H),2.23-2.10(m,2H).

[0209] Intermediate 10: 2-Butoxy-4-fluorobenzaldehyde

[0210]

[0211] Synthesis route:

[0212]

[0213] Step 1: 2-Butoxy-4-fluorobenzaldehyde

[0214] 4-Fluoro-2-hydroxybenzaldehyde (500 mg), potassium carbonate (740 mg), 1-bromobutane (538 mg), and N,N-dimethylformamide (5 ml) were heated to 80°C for reaction. After completion of the reaction, the filtrate was filtered, diluted with water, and extracted with ethyl acetate. The combined organic phases were washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate. The residue was filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain the title compound (500 mg). 1 H NMR (500MHz, CDCl3): δ10.40(s,1H),7.85-8.00(m,1H),6.50-7.00(m,2H),4.00-4. 51(m,2H),1.60-2.00(m,2H),1.10-1.30(m,2H),1.00-1.10(m,3H).MS:197.22[M+H] + .

[0215] Intermediate 11: 4-Fluoro-2-(3-methoxypropoxy)benzaldehyde

[0216]

[0217] Synthesis route:

[0218]

[0219] Step 1: 4-Fluoro-2-(3-methoxypropoxy)benzaldehyde

[0220] Mix 4-fluoro-2-hydroxybenzaldehyde (500 mg), 1-bromo-3-methylpropane (546 mg), potassium carbonate (740 mg), and N,N-dimethylformamide (5 ml) and heat to 80°C for reaction. After completion of the reaction, filter and dilute the filtrate with water. Extract with ethyl acetate. The organic phase is washed sequentially with water and saturated brine, then dried over anhydrous sodium sulfate. Filter and concentrate, then purify by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain the title compound (450 mg). 1H NMR (500MHz, CDCl3): δ10.39(s,1H),7.87(s,1H),6.30-6.90(m,2H),4.00-4.51(m,2H),3.56(s,2H),3.37(s,3H),2.00-2.35(m,2H).

[0221] Intermediate 12: 4-Fluoro-2-(4-fluorobutoxy)benzaldehyde

[0222]

[0223] Synthesis route:

[0224]

[0225] Step 1: 4-Fluoro-2-(4-fluorobutoxy)benzaldehyde

[0226] Combine 4-fluoro-2-hydroxybenzaldehyde (0.3g), potassium carbonate (0.44g), 1-bromo-4-fluorobutane (0.36g), and N,N-dimethylformamide (3ml) and heat to 80°C overnight. After completion of the reaction, filter and dilute the filtrate with water. Extract with ethyl acetate. The organic phase is washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate. Filter and concentrate to obtain the title compound (0.48g). 1 H NMR (500MHz, CDCl3): δ10.39(s,1H),7.86(dd,J=8.6,6.9Hz,1H),6.78-6.59(m,2H),4.59(t,J=5.7Hz,1H ),4.50(t,J=5.8Hz,1H),4.12(t,J=6.1Hz,2H),2.11-1.99(m,2H),1.99-1.92(m,1H),1.92-1.82(m,1H).

[0227] Example 1: (1S,2S,3R,4R)-3-((6-cyano-2-(2-isobutyloxyphenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0228]

[0229] Synthesis route:

[0230]

[0231] Step 1: (1S,2S,3R,4R)-3-((6-bromo-2-(2-isobutyloxyphenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0232] (1S,2S,3R,4R)-3-(((2,3-diamino-5-bromopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide (520 mg), 2-isobutoxybenzaldehyde (301 mg), ammonium acetate (148 mg) and ethanol (8 ml) were mixed and heated to 70°C for 3 hours. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration, the mixture was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain the title compound (0.61 g). 1 H NMR (500MHz, DMSO-d6): δ12.14(s,1H),8.03(s,1H),8.01(dd,J=7.7,1.8Hz,1H),7.75(d,J=2.5Hz,1H),7.46(dd d,J=8.8,7.3,1.8Hz,1H),7.23-7.17(m,2H),7.17-7.09(m,2H),6.35(qd,J=5.5,2.7Hz,2H),5.26(td,J=8.6,1. 6Hz,1H),4.00-3.92(m,2H),2.93-2.86(m,1H),2.79(d,J=2.9Hz,1H),2.62(dd,J=8.4,1.4Hz,1H),2.27(d,J=8. 7Hz,1H),2.20(dt,J=13.4,6.7Hz,1H),1.39(dt,J=8.8,1.7Hz,1H),0.96(d,J=6.7Hz,6H).HRMS:496.1350[M+H] + .

[0233] Step 2: (1S,2S,3R,4R)-3-((6-cyano-2-(2-isobutyloxyphenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0234] Combine (1S,2S,3R,4R)-3-((6-bromo-2-(2-isobutoxyphenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide (300 mg), cuprous cyanide (1083 mg), and N,N-dimethylformamide (10 ml) and microwave-heat at 160°C for 4 hours. After cooling to room temperature, ammonia (5 ml) was added, and the mixture was filtered through celite. The filtrate was diluted with water and extracted with ethyl acetate. The organic phase was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate. Filtration and concentration gave the crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to afford the title compound (46 mg). 1 H NMR(500MHz,DMSO-d6):12.56(s,1H),8.20(s,1H),7.97(dd,J=7.7,1.8Hz,2H),7.81(d,J=2.3Hz,1H ),7.48(ddd,J=8.8,7.4,1.8Hz,1H),7.38-7.27(m,1H),7.22(d,J=8.4Hz,1H),7.13(t,J=7.5Hz,1H) ,6.37(s,2H),5.15(s,1H),4.02-3.84(m,2H),2.92(q,J=1.8Hz,1H),2.89(d,J=6.8Hz,1H),2.61(d, J=8.2Hz,1H),2.25-2.12(m,2H),1.42(d,J=8.8Hz,1H),0.95(d,J=6.7Hz,6H).HRMS:443.2166[M+H] + .

[0235] Example 2: (1S,2S,3R,4R)-3-((6-cyano-2-(4-(4-(dimethylamino)piperidin-1-yl)-2-isobutoxyphenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0236]

[0237] Synthesis route:

[0238]

[0239] Step 1: 4-(4-(dimethylamino)piperidin-1-yl)-2-isobutoxybenzaldehyde

[0240] Combine 4-fluoro-2-isobutoxybenzaldehyde (300 mg), potassium carbonate (634 mg), N,N-dimethylpiperidin-4-amine (392 mg), and N,N-dimethylformamide (5 ml) and heat to 80°C overnight. After completion of the reaction, filter and dilute the filtrate with water, then extract with ethyl acetate. The organic phase is washed sequentially with water and saturated brine, then dried over anhydrous sodium sulfate. Filter, concentrate, and purify by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain the title compound (360 mg). 1 H NMR (500MHz, CDCl3): δ10.19(s,1H),7.65(d,J=8.8Hz,1H),6.40(dd,J=8.8,2.2Hz,1 H),6.18(d,J=2.3Hz,1H),3.96-3.83(m,2H),3.72(d,J=6.3Hz,2H),2.85(td,J=12.6, 2.6Hz,2H),2.32(td,J=11.1,5.7Hz,1H),2.25(s,6H),2.08(dt,J=13.2,6.6Hz,1H),1 .92-1.81(m,2H),1.51(qd,J=12.1,4.0Hz,2H),0.99(d,J=6.7Hz,6H).MS:305.1[M+H] + .

[0241] Step 2: (1S,2S,3R,4R)-3-((6-cyano-2-(4-(4-(dimethylamino)piperidin-1-yl)-2-isobutoxyphenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0242] (1S,2S,3R,4R)-3-(((2,3-diamino-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide (100 mg), 4-(4-(dimethylamino)piperidin-1-yl)-2-isobutoxybenzaldehyde (118 mg), ammonium acetate (54.2 mg) and ethanol (1.0 ml) were mixed and heated to 70°C for overnight reaction. After completion of the reaction, the mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane:methanol = 99:1) to give the title compound (40 mg). 1H NMR (500MHz, DMSO-d6): δ10.67(s,1H),8.20(d,J=8.8Hz,1H),8.10(s,1H),6.65(dd,J=8.9,2.2Hz,1H),6.46(d,J=2.2Hz ,1H),6.35(ddd,J=19.4,5.6,2.9Hz,2H),6.30-6.21(m,1H),6.00(s,1H),5.09(s,1H),3.96(d,J=6.6Hz,2H),3.89(d,J= 12.7Hz,2H),3.12(s,1H),2.95(s,1H),2.88(td,J=12.5,2.5Hz,2H),2.73(d,J=8.1Hz,1H),2.59(ddd,J=11.6,8.0,3.4H z,1H),2.43(s,6H),2.37-2.25(m,2H),2.09-2.03(m,2H),1.80-1.59(m,4H),1.13(d,J=6.7Hz,6H).HRMS:569.3375[M+H] + .

[0243] Example 3: (1S,2S,3R,4R)-3-((2-(4-(1,4-diazepin-1-yl)-2-isobutoxyphenyl)-6-cyano-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0244]

[0245] Synthesis route:

[0246]

[0247] The title compound (65 mg) was synthesized by a similar method to that described in Example 2, using 1,4-diazepane instead of N,N-dimethylpiperidin-4-amine in Step 1 of Example 2. 1H NMR(500MHz,Methanol-d4)δ8.00(d,J=9.4Hz,2H),6.48(dd,J=9.0,2.3Hz,1H),6.39(ddd,J=26.0,5 .7,2.9Hz,2H),6.30(d,J=2.2Hz,1H),5.09(br,1H),3.96(t,J=6.7Hz,2H),3.66(dt,J=12.1,5.7Hz, 4H),3.10(d,J=4.9Hz,2H),2.99(d,J=2.8Hz,1H),2.92(dd,J=11.5,5.7Hz,3H),2.73(d,J=8.1Hz,1H ),2.37-2.24(m,2H),2.01(s,2H),1.55(d,J=9.2Hz,1H),1.10(d,J=6.7Hz,6H).HRMS:541.3043[M+H] + .

[0248] Example 4: (1S,2S,3R,4R)-3-((6-cyano-2-(2-isobutoxy-4-(piperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0249]

[0250] Synthesis route:

[0251]

[0252] The title compound (95 mg) was synthesized by a similar procedure to that described in Example 2, substituting piperazine for N,N-dimethylpiperidin-4-amine in Step 1 of Example 2. 1 H NMR (500MHz, Methanol-d4) δ8.02 (t, J=4.5Hz, 2H), 6.64 (dd, J=8.8, 2.2Hz, 1H), 6.53 (d, J=2. 3Hz,1H),6.39(ddd,J=22.5,5.7,2.9Hz,2H),5.13(br,1H),3.95(dd,J=6.8,3.9Hz,2H),3.33 (d,J=4.7Hz,4H),3.05(t,J=5.1Hz,4H),2.99(s,1H),2.92(s,1H),2.73(d,J=8.0Hz,1H),2.2 9(dt,J=20.1,7.8Hz,2H),1.55(d,J=9.1Hz,1H),1.09(d,J=6.7Hz,6H).HRMS:527.2878[M+H]+ .

[0253] Example 5: (1S,2S,3R,4R)-3-((6-cyano-2-(2-isobutoxy-4-(1,4-oxazepine-4-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0254]

[0255] Synthesis route:

[0256]

[0257] The title compound (57 mg) was synthesized by a method similar to that described in Example 2, using 1,4-oxazepane hydrochloride instead of N,N-dimethylpiperidin-4-amine in Step 1 of Example 2. 1 H NMR (500MHz, CDCl3): δ10.60 (s, 1H), 8.19 (d, J = 8.8Hz, 1H), 8.09 (s, 1H), 6 .65-6.15(m,6H),6.07(s,1H),3.91(d,J=41.9Hz,4H),3.79-3.57(m,6H), 3.03(d,J=85.9Hz,2H),2.82-2.53(m,1H),2.34(d,J=9.9Hz,2H),2.07(s, 2H),1.97(s,1H),1.67(d,J=9.4Hz,1H),1.14(s,6H).HRMS:542.2898[M+H] + .

[0258] Example 6: (1S,2S,3R,4R)-3-((6-cyano-2-(2-isobutoxy-4-morpholinophenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0259]

[0260] Synthesis route:

[0261]

[0262] The title compound (89 mg) was synthesized by a similar method to that described in Example 2, substituting morpholine for N,N-dimethylpiperidin-4-amine in Step 1 of Example 2. 1H NMR(500MHz,DMSO-d6)δ12.13(s,1H),8.15(s,1H),7.94-7.66(m,3H),7.31(s, 1H),6.71(d,J=8.8Hz,1H),6.65(s,1H),6.36(s,2H),5.17(s,1H),4.07-3.90(m ,2H),3.76(s,5H),3.33(s,3H),2.88(d,J=28.6Hz,2H),2.60(d,J=8.2Hz,1H), 2.22(s,2H),1.41(d,J=8.8Hz,1H),0.97(d,J=6.7Hz,6H).HRMS:528.2745[M+H] + .

[0263] Example 7: (1S,2S,3R,4R)-3-((6-cyano-2-(4-(((2-(dimethylamino)ethyl)(methyl)amino)-2-isobutoxyphenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0264]

[0265] Synthesis route:

[0266]

[0267] The title compound (45 mg) was synthesized by a similar method to that described in Example 2, using N,N,N'-trimethylethylenediamine instead of N,N-dimethylpiperidin-4-amine in Step 1 of Example 2. 1 H-NMR (500MHz, CDCl3): δ10.57(s,1H),8.16(d,J=8.5Hz,1H),8.06(s,1H),6.46(dd,J1=9.0Hz,J2 =1.5Hz,1H),6.37-6.33(m,4H),6.23(s,1H),6.06(s,1H),5.08(s,1H),3.96(d,J=6.5Hz,2H),3.5 8-3.49(m,2H),3.11(s,1H),3.06(s,3H),2.93(s,1H),2.73(d,J=8.0Hz,1H),2.57-2.51(m,2H),2 .35(s,6H),2.31-2.27(m,2H),1.66(d,J=9.0Hz,1H),1.12(d,J=7.0Hz,6H).HRMS:543.3190[M+H] + .

[0268] Example 8: (1S,2S,3R,4R)-3-((6-cyano-2-(4-(((2S,6R)-2,6-dimethylmorpholino)-2-isobutoxyphenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0269]

[0270] Synthesis route:

[0271]

[0272] The title compound (75 mg) was synthesized by a similar method to that described in Example 2, substituting (2S,6R)-2,6-dimethylmorpholine for N,N-dimethylpiperidin-4-amine in Step 1 of Example 2. 1 H NMR (500MHz, DMSO-d6): δ12.09(s,1H),8.14(s,1H),7.85-7.80(m,3H),7.31(s,1H),6.71(d,J= 8.5Hz,1H),6.64(s,1H),6.36(s,2H),5.18(s,1H),4.00-3.93(m,2H),3.76(d,J=11.5Hz,2H),3. 69(s,2H),2.91(s,1H),2.85(s,1H),2.60(d,J=8.0Hz,1H),2.35(t,J=11.0Hz,2H),2.25-2.20( m,2H),1.40(d,J=8.0Hz,1H),1.18(d,J=6.0Hz,6H),0.97(d,J=6.0Hz,6H).HRMS:556.3052[M+H] + .

[0273] Example 9: (1S,2S,3R,4R)-3-((6-cyano-2-(4-(((3S,5R)-3,5-dimethylpiperazin-1-yl)-2-isobutoxyphenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0274]

[0275] Synthesis route:

[0276]

[0277] The title compound (70 mg) was synthesized by a similar method to that described in Example 2, using (2S,6R)-2,6-dimethylpiperazine instead of N,N-dimethylpiperidin-4-amine in Step 1 of Example 2. 1 H-NMR (500MHz, DMSO-d6): δ12.05(s,1H),8.14(s,1H),7.85-7.80(m,3H),7.32(s,1H), 6.69(d,J=9.0Hz,1H),6.60(s,1H),6.37(s,2H),5.15(s,1H),4.00-3.95(m,2H),3.73( d,J=11.0Hz,2H),2.92(s,1H),2.85(s,3H),2.61(d,J=8.0Hz,1H),2.27-2.21(m,4H),1 .41(d,J=8.5Hz,1H),1.06(d,J=6.5Hz,6H),0.98(d,J=6.5Hz,6H).HRMS:555.3216[M+H] + .

[0278] Example 10: (1S,2S,3R,4R)-3-((6-cyano-2-(2-isobutoxy-4-(4-methoxypiperidin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0279]

[0280] Synthesis route:

[0281]

[0282] The title compound (86 mg) was synthesized by a similar method to that described in Example 2, using 4-methoxypiperidine instead of N,N-dimethylpiperidin-4-amine in Step 1 of Example 2. 1H NMR (500MHz, DMSO-d6): δ12.06(s,1H),8.14(s,1H),7.85-7.80(m,3H),7.32(s,1H),6.70(dd,J1=8.8Hz,J2 =1.8Hz,1H),6.62(d,J=1.5Hz,1H),6.37(s,2H),5.15(s,1H),4.00-3.93(m,2H),3.67-3.64(m,2H),3.42-3. 38(m,1H),3.28(s,3H),3.08-3.04(m,2H),2.92(s,1H),2.86(s,1H),2.61(d,J=8.5Hz,1H),2.25-2.18(m,2 H),1.94-1.93(m,2H),1.55-1.48(m,2H),1.41(d,J=9.0Hz,1H),0.97(d,J=6.0Hz,6H).HRMS:556.3052[M+H] + .

[0283] Example 11: (1S,2S,3R,4R)-3-((6-cyano-2-(2-isobutoxy-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0284]

[0285] Synthesis route:

[0286]

[0287] The title compound (103 mg) was synthesized by a similar method to that described in Example 2, using 1-(2-methoxyethyl)piperazine instead of N,N-dimethylpiperidin-4-amine in Step 1 of Example 2. 1H NMR (500MHz, CDCl3): δ10.64(s,1H),8.22(d,J=8.5Hz,1H),8.11(s,1H),6.65(dd,J1=8.8Hz,J2=2.3Hz ,1H),6.46(d,J=2.0Hz,1H),6.41(s,1H),6.38-6.32(m,2H),6.23(s,1H),5.90(s,1H),5.09(s,1H),3. 96(d,J=6.5Hz,2H),3.57(t,J=5.0Hz,2H),3.39(s,3H),3.38-3.36(m,4H),3.12(s,1H),2.95(s,1H),2 .73-2.65(m,7H),2.36-2.28(m,2H),1.68(d,J=9.5Hz,1H),1.13(d,J=7.0Hz,6H).HRMS:585.3326[M+H] + .

[0288] Example 12: (1S,2S,3R,4R)-3-((6-cyano-2-(2-isobutoxy-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0289]

[0290] Synthesis route:

[0291]

[0292] The title compound (83 mg) was synthesized by a similar method to that described in Example 2, using 1-(oxetan-3-yl)piperazine instead of N,N-dimethylpiperidin-4-amine in Step 1 of Example 2. 1H NMR (500MHz, CDCl3): δ10.65(s,1H),8.24(d,J=8.5Hz,1H),8.11(s,1H),6.67(d,J=8.5Hz,1H),6.47(s 2H),6.37-6.34(m,2H),6.20(s,1H),5.90(s,1H),5.10(s,1H),4.74-4. 66(m,4H),3.97(d,J=6.5Hz,2H),3.57(t,J=6.3Hz,1H),3.37(s,4H),3.1 3(s,1H),2.95(s,1H),2.73(d,J=8.0Hz,1H),2.53(s,4H),2.36-2.29(m ,2H),1.68(d,J=9.0Hz,1H),1.14(d,J=6.5Hz,6H).HRMS:583.3156[M+H] + .

[0293] Example 13: (1S,2S,3R,4R)-3-((6-cyano-2-(2-isobutoxy-4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0294]

[0295] Synthesis route:

[0296]

[0297] The title compound (82 mg) was synthesized by a similar method to that described in Example 2, using 1-methylpiperazine instead of N,N-dimethylpiperidin-4-amine in Step 1 of Example 2. 1 H NMR (500MHz, CDCl3): δ10.64(s,1H),8.22(d,J=8.5Hz,1H),8.11(s,1H),6.66(d,J=8.0Hz, 1H),6.47(s,2H),6.37-6.33(m,2H),6.22(s,1H),5.97(s,1H),5.10(s,1H),3.97(d,J=6.0 Hz,2H),3.35(s,4H),3.13(s,1H),2.95(s,1H),2.73(d,J=7.5Hz,1H),2.60(s,4H),2.38(s ,3H),2.36-2.28(m,2H),1.68(d,J=9.0Hz,1H),1.14(d,J=6.5Hz,6H).HRMS:541.3043[M+H] + .

[0298] Example 14: (1S,2S,3R,4R)-3-((6-cyano-2-(2-isobutoxy-4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0299]

[0300] Synthesis route:

[0301]

[0302] The title compound (78 mg) was synthesized by a method similar to that described in Example 2, using 1-methyl-4-(piperidin-4-yl)piperazine instead of N,N-dimethylpiperidin-4-amine in Step 1 of Example 2. 1 H NMR (500MHz, CDCl3): δ10.64(s,1H),8.20(d,J=9.0Hz,1H),8.11(s,1H),6.65(d,J=10.0Hz,1H),6.46( s,1H),6.37-6.34(m,3H),6.25(s,1H),5.85(s,1H),5.09(s,1H),3.96(d,J=6.5Hz,2H),3.88(d,J=7.5 Hz,2H),3.13(s,1H),2.95(s,1H),2.88(t,J=6.8Hz,2H),2.74(d,J=8.0Hz,1H),2.68-2.46(m,9H),2.3 5-2.28(m,5H),1.97(d,J=12.0Hz,2H),1.69-1.65(m,3H),1.14(d,J=7.0Hz,6H).HRMS:624.3799[M+H] + .

[0303] Example 15: (1S,2S,3R,4R)-3-((2-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-2-isobutyloxyphenyl)-6-cyano-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0304]

[0305] Synthesis route:

[0306]

[0307] The title compound (36 mg) was synthesized by a similar method to that described in Example 2, using (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride instead of N,N-dimethylpiperidin-4-amine in step 1 of Example 2. 1 H NMR(500MHz,DMSO-d6)δ11.98(s,1H),8.13(s,1H),7.99-7.60(m,2H),6.51-6.14(m,4H),5.16(s,1H),4.70( d,J=30.2Hz,2H),3.96(d,J=6.7Hz,2H),3.79(d,J=7.3Hz,1H),3.68(d,J=7.5Hz,1H),3.53(d,J=9.7Hz,1H),3 .30(s,1H),3.11(d,J=9.6Hz,1H),2.91(s,1H),2.85(s,1H),2.60(d,J=8.2Hz,1H),2.34-2.06(m,2H),2.03- 1.82(m,2H),1.38(dd,J=29.8,9.2Hz,1H),1.24(d,J=8.3Hz,1H),0.97(d,J=6.7Hz,6H).HRMS:540.2723[M+H] + .

[0308] Example 16: (1S,2S,3R,4R)-3-(((6-cyano-2-(2-isobutoxy-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0309]

[0310] Synthesis route:

[0311]

[0312] The title compound (65 mg) was synthesized by a similar procedure to that described in Example 2, substituting 4-(pyrrolidin-1-yl)piperidine for N,N-dimethylpiperidin-4-amine in Step 1 of Example 2. 1H NMR (500MHz, CDCl3): δ10.62(s,1H),8.19(d,J=9.0Hz,1H),8.11(s,1H),6.65(dd,J1=9.0Hz,J2=2.0H z,1H),6.46-6.32(m,4H),6.29(s,1H),5.91(s,1H),5.08(s,1H),3.96(d,J=6.5Hz,2H),3.83(d,J=12 .5Hz,2H),3.13(s,1H),2.95-2.89(m,3H),2.76-2.74(m,5H),2.36-2.27(m,3H),2.06(d,J=12.0Hz,2 H),1.87(s,4H),1.78-1.75(m,2H),1.68(d,J=9.5Hz,1H),1.13(d,J=6.5Hz,6H).HRMS:595.3505[M+H] + .

[0313] Example 17: (1S,2S,3R,4R)-3-((6-cyano-2-(2-isobutoxy-4-(4-morpholinopiperidin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0314]

[0315] Synthesis route:

[0316]

[0317] The title compound (65 mg) was synthesized by a similar procedure to that described in Example 2, substituting 4-(piperidin-4-yl)morpholine for N,N-dimethylpiperidin-4-amine in Step 1 of Example 2. 1H NMR (500MHz, CDCl3): δ10.57 (s, 1H), 8.14 (d, J = 8.5Hz, 1H), 8.04 (s, 1H), 6.59 (dd, J1 = 9.0Hz, J2 = 2.0Hz, 1H), 6.40 (d, J = 2.0 Hz,1H),6.30-6.25(m,3H),6.16(s,1H),5.75(s,1H),5.02(s,1H),3.90(d,J=7.0Hz,2H),3.81(d,J=13.0Hz,2H),3.67(t,J =4.5Hz,4H),3.06(s,1H),2.88(s,1H),2.82(td,J1=12.5Hz,J2=1.5Hz,2H),2.67(d,J=8.0Hz,1H),2.52(t,J=4.5Hz,4H),2 .36-2.32(m,1H),2.29-2.21(m,2H),1.91(d,J=12.0Hz,2H),1.62-1.53(m,3H),1.07(d,J=6.5Hz,6H).HRMS:611.3454[M+H] + .

[0318] Example 18: (1S, 2S, 3R, 4R)-3-((6-cyano-2-(4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-isobutyloxyphenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0319]

[0320] Synthesis route:

[0321]

[0322] The title compound (71 mg) was synthesized by a similar method to that described in Example 2, using octahydropyrrolo[1,2-a]pyrazine instead of N,N-dimethylpiperidin-4-amine in Step 1 of Example 2. 1H NMR (500MHz, CDCl3): δ10.65(s,1H),8.23(d,J=8.8Hz,1H),8.13(s,1H),6.68( dd,J=8.9,2.3Hz,1H),6.48(d,J=2.3Hz,1H),6.35(qd,J=5.6,2.7Hz,2H),6.24( br,1H),6.20(s,1H),5.60(s,1H),5.10(s,1H),3.98(dd,J=6.6,1.6Hz,2H),3. 88(dt,J=11.6,2.1Hz,1H),3.75(d,J=12.0Hz,1H),3.23-3.16(m,2H),3.15(d,J =7.5Hz,1H),3.05(td,J=11.6,3.2Hz,1H),2.95(s,1H),2.76(d,J=8.0Hz,1H), 2.68(t,J=10.9Hz,1H),2.41(d,J=11.5Hz,1H),2.38-2.29(m,2H),2.26-2.19(m ,1H),1.93(q,J=10.6,8.4Hz,2H),1.81(t,J=9.4Hz,1H),1.70(dt,J=9.4,1.8Hz ,2H),1.54(dd,J=11.3,7.0Hz,1H),1.15(d,J=6.8Hz,6H).HRMS:567.3190[M+H] + .

[0323] Example 19: (1S,2S,3R,4R)-3-(((6-cyano-2-(2-(isopentyloxy))phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0324]

[0325] Synthesis route:

[0326]

[0327] Step 1: (1S,2S,3R,4R)-3-(((6-cyano-2-(2-(isopentyloxy))phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0328] (1S,2S,3R,4R)-3-(((2,3-diamino-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide (100 mg), 2-isopentyloxybenzaldehyde (74.4 mg), ammonium acetate (33.9 mg), and ethanol (2.0 ml) were mixed and heated to 70°C for overnight reaction. After completion of the reaction, the mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane:methanol = 99:1) to obtain the title compound (43 mg). 1 HNMR (500MHz, CDCl3): δ10.84(s,1H),8.39(d,J=8.0Hz,1H),8.14(s,1H),7.44(t,J=8.5Hz,1H),7.13( t,J=7.3Hz,1H),7.07(d,J=8.5Hz,1H),6.90(s,1H),6.42-6.40(m,1H),6.36-6.34(m,1H),6.31(s,1H), 6.10(s,1H),5.14(s,1H),4.25(t,J=7.0Hz,2H),3.13(s,1H),2.98(s,1H),2.70(d,J=9.0Hz,1H),2.36 (d,J=9.5Hz,1H),1.90-1.83(m,3H),1.66(d,J=9.5Hz,1H),1.02(d,J=6.0Hz,6H).HRMS:457.2343[M+H] + .

[0329] Example 20: (1S,2S,3R,4R)-3-((6-cyano-2-(2-(2-cyclopropylethoxy)-4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0330]

[0331] Synthesis route:

[0332]

[0333] Step 1: 4-(Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-(isopentyloxy)benzaldehyde

[0334] Combine 4-fluoro-2-isopentyloxybenzaldehyde (500 mg), potassium carbonate (986 mg), octahydropyrrolo[1,2-a]pyrazine (360 mg), and N,N-dimethylformamide (5 ml) and heat to 100°C overnight. After the reaction is complete, filter and dilute the filtrate with water, then extract with ethyl acetate. The organic phase is washed sequentially with water and saturated brine, then dried over anhydrous sodium sulfate. Filter, concentrate, and purify by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain the title compound (510 mg). 1 H NMR (500MHz, CDCl3): δ10.23(s,1H),7.73(d,J=8.9Hz,1H),6.50(dd,J=8.9,2.2Hz,1H),6.28(d,J=2.2Hz,1H),4.07 (t,J=6.4Hz,2H),3.94(ddd,J=12.0,3.2,1.6Hz,1H),3.84-3.76(m,1H),3.15(ddt,J=8.7,5.9,2.6Hz,2H),3.11-3. 02(m,1H),2.70(dd,J=11.8,10.3Hz,1H),2.34(td,J=11.3,3.4Hz,1H),2.19(q,J=8.9Hz,1H),2.10(tdd,J=10.2,6. 1,3.1Hz,1H),1.94-1.85(m,3H),1.84-1.76(m,1H),1.73(q,J=6.6Hz,2H),1.57-1.42(m,1H),0.98(d,J=6.6Hz,6H).

[0335] Step 2: (1S,2S,3R,4R)-3-((6-cyano-2-(2-(2-cyclopropylethoxy)-4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0336] (1S,2S,3R,4R)-3-(((2,3-diamino-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide (100 mg), 4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-(isopentyloxy)benzaldehyde (122 mg), ammonium acetate (81 mg) and ethanol (2.0 ml) were mixed and heated to 70°C for overnight reaction. After completion of the reaction, the mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give the title compound (40 mg). 1H NMR (500MHz, CDCl3): δ10.68(s,1H),8.22(d,J=8.8Hz,1H),8.13(s,1H),6.67(d,J=8.9Hz,1H),6.49(s,1H),6.41–6.30(m,2H) ,6.26(s,1H),6.20(s,1H),5.65(s,1H),5.09(s,1H),4.23(t,J=6.6Hz,2H),3.88(d,J=11.5Hz,1H),3.75(d,J=12.0Hz,1H),3.2 0(d,J=12.3Hz,2H),3.12(d,J=18.7Hz,1H),3.08(s,1H),2.95(s,1H),2.76(d,J=8.3Hz,1H),2.71(s,1H),2.43(s,1H),2.35(d ,J=9.3Hz,1H),2.25(s,2H),1.89(d,J=6.8Hz,6H),1.70(d,J=9.5Hz,1H),1.62–1.48(m,1H),1.03(d,J=6.0Hz,6H).HRMS:[M+H] + 581.3365.

[0337] Example 21: (1S,2S,3R,4R)-3-((6-cyano-2-(4-(((3S,5R)-3,5-dimethylpiperazin-1-yl)-2-(isopentyloxy)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0338]

[0339] Synthesis route:

[0340]

[0341] The title compound (89 mg) was synthesized by a similar method to that described in Example 20, substituting (2S,6R)-2,6-dimethylpiperazine for octahydropyrrolo[1,2-a]pyrazine in Step 1 of Example 20. 1H NMR (500MHz, Methanol-d4): δ8.03 (t, J=4.3Hz, 2H), 6.65 (dd, J1=8.8Hz, J2=2.3Hz, 1 H),6.54(s,1H),6.42-6.36(m,2H),5.14(s,1H),4.22(s,2H),3.72(d,J=6.5Hz,2H), 2.99-2.93(m,4H),2.74(d,J=8.0Hz,1H),2.39-2.32(m,3H),1.85-1.81(m,3H),1.56 (d,J=9.0Hz,1H),1.18(d,J=6.5Hz,6H),1.01(d,J=6.0Hz,6H).HRMS:569.3375[M+H] + .

[0342] Example 22: (1S,2S,3R,4R)-3-((6-cyano-2-(2-(isopentyloxy)-4-morpholinophenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0343]

[0344] Synthesis route:

[0345]

[0346] The title compound (35 mg) was synthesized by a similar method to that described in Example 20, substituting morpholine for octahydropyrrolo[1,2-a]pyrazine in Step 1 of Example 20. 1 H NMR (500MHz, CDCl3): δ10.64(s,1H),8.25(d,J=9.0Hz,1H),8.12(s,1H),6.65(dd,J1=9.0Hz,J2=1.5H z,1H),6.48(s,2H),6.38-6.33(m,2H),6.20(s,1H),5.92(s,1H),5.09(s,1H),4.22(t,J=6.8Hz,2H), 3.89(t,J=4.5Hz,4H),3.29(t,J=4.5Hz,4H),3.13(s,1H),2.95(s,1H),2.73(d,J=8.0Hz,1H),2.35(d ,J=9.0Hz,1H),1.91-1.82(m,3H),1.68(d,J=9.5Hz,1H),1.30(d,J=6.5Hz,6H).HRMS:542.2898[M+H] + .

[0347] Example 23: (1S,2S,3R,4R)-3-((6-cyano-2-(2-(isopentyloxy)-4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0348]

[0349] Synthesis route:

[0350]

[0351] The title compound (86 mg) was synthesized by a similar procedure to that described in Example 20, substituting 1-methylpiperazine for octahydropyrrolo[1,2-a]pyrazine in Step 1 of Example 20. 1 H-NMR (500MHz, CDCl3): δ10.65(s,1H),8.22(d,J=8.5Hz,1H),8.12(s,1H),6.66(dd,J1=9.0Hz,J2=2.0 Hz,1H),6.48(d,J=1.5Hz,1H),6.36-6.34(m,3H),6.22(s,1H),5.83(s,1H),5.09(s,1H),4.22(d,J=6.3 Hz,2H),3.35(d,J=4.8Hz,4H),3.13(s,1H),2.95(s,1H),2.74(d,J=8.0Hz,1H),2.60(d,J=4.8Hz,4H),2 .37-2.34(m,4H),1.91-1.85(m,3H),1.68(d,J=9.5Hz,1H),1.03(d,J=6.5Hz,6H).HRMS:555.3216[M+H] + .

[0352] Example 24: (1S,2S,3R,4R)-3-((6-cyano-2-(4-(4-(dimethylamino)piperidin-1-yl)-2-(isopentyloxy)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0353]

[0354] Synthesis route:

[0355]

[0356] The title compound (48 mg) was synthesized by a similar procedure to that described in Example 20, substituting N,N-dimethylpiperidin-4-amine for octahydropyrrolo[1,2-a]pyrazine in Step 1 of Example 20. 1 H NMR (500MHz, CDCl3): δ10.62(s,1H),8.20(d,J=8.5Hz,1H),8.11(s,1H),6.66(d,J=8.0Hz,1H),6.48(s,1H) ,6.38-6.34(m,3H),6.25(s,1H),5.88(s,1H),5.08(s,1H),4.21(t,J=6.5Hz,2H),3.88(d,J=12.5Hz,2H),3. 13(s,1H),2.95(s,1H),2.89(t,J=6.8Hz,2H),2.74(d,J=8.0Hz,1H),2.51-2.39(m,8H),2.35(d,J=9.5Hz,1H ),2.01(d,J=11.5Hz,2H),1.90-1.82(m,3H),1.71-1.64(m,2H),1.03(d,J=6.0Hz,6H).HRMS:583.3502[M+H] + .

[0357] Example 25: (1S,2S,3R,4R)-3-((6-cyano-2-(2-(isopentyloxy)-4-(1,4-oxazepan-4-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0358]

[0359] Synthesis route:

[0360]

[0361] The title compound (65 mg) was synthesized by a similar method to that described in Example 20, substituting 1,4-oxazepane hydrochloride for octahydropyrrolo[1,2-a]pyrazine in Step 1 of Example 20. 1H NMR (500MHz, CDCl3): δ10.59(s,1H),8.19(d,J=9.0Hz,1H),8.11(s,1H),6.49(d,J=9.0Hz,1H), 6.36-6.27(m,5H),5.79(s,1H),5.08(s,1H),4.21(t,J=6.3Hz,2H),3.87(t,J=9.3Hz,2H),3.73- 3.68(m,6H),3.13(s,1H),2.94(s,1H),2.75(d,J=7.5Hz,1H),2.35(d,J=9.5Hz,1H),2.07(t,J=5 .8Hz,2H),1.89-1.80(m,3H),1.69(d,J=9.0Hz,1H),1.03(d,J=6.0Hz,6H).HRMS:556.3052[M+H] + .

[0362] Example 26: (1S,2S,3R,4R)-3-((6-cyano-2-(4-(3-(dimethylamino)pyrrolidin-1-yl)-2-(isopentyloxy)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0363]

[0364] Synthesis route:

[0365]

[0366] The title compound (76 mg) was synthesized by a similar method to that described in Example 20, substituting N,N-dimethylpyrrolidin-3-amine dihydrochloride for octahydropyrrolo[1,2-a]pyrazine in Step 1 of Example 20. 1H NMR (500MHz, CDCl3): δ10.60(s,1H),8.19(d,J=8.5Hz,1H),8.10(s,1H),6.35-6.31(m,4H),6.14(s,1H ),6.07(s,1H),5.69(s,1H),5.08(s,1H),4.22(s,2H),3.57-3.54(m,2H),3.43-3.38(m,1H),3.23(t,J =8.3Hz,1H),3.13(s,1H),2.94-2.88(m,2H),2.77(d,J=7.0Hz,1H),2.34(s,6H),2.27-2.25(m,1H),1. 99-1.95(m,1H),1.89-1.85(m,4H),1.70(d,J=8.5Hz,1H),1.03(d,J=5.5Hz,6H).HRMS:569.3375[M+H] + .

[0367] Example 27: (1S,2S,3R,4R)-3-((6-cyano-2-(2-(isopentyloxy)-4-(8-oxa-2-azaspiro[4.5]dec-2-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0368]

[0369] Synthesis route:

[0370]

[0371] The title compound (59 mg) was synthesized by a similar method to that described in Example 20, substituting 8-oxa-2-azaspiro[4.5]decane hydrochloride for octahydropyrrolo[1,2-a]pyrazine in Step 1 of Example 20. 1H NMR (500MHz, CDCl3): δ10.59(s,1H),8.20(d,J=8.5Hz,1H),8.10(s,1H),6.35-6.31(m,4H),6.15(s ,1H),6.08(s,1H),5.65(s,1H),5.08(s,1H),4.23(t,J=6.3Hz,2H),3.77-3.70(m,4H),3.47(t,J=6. 8Hz,2H),3.28(s,2H),3.13(s,1H),2.94(s,1H),2.77(d,J=7.5Hz,1H),2.35(d,J=9.0Hz,1H),1.99 (t,J=6.8Hz,2H),1.90-1.83(m,3H),1.71-1.67(m,5H),1.04(d,J=6.0Hz,6H).HRMS:596.3340[M+H] + .

[0372] Example 28: (1S,2S,3R,4R)-3-((6-cyano-2-(2-(isopentyloxy))-4-(2-oxa-7-azaspiro[3.5]nonyl-7-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0373]

[0374] Synthesis route:

[0375]

[0376] The title compound (53 mg) was synthesized by a similar method to that described in Example 20, substituting 2-oxa-7-azaspiro[3.5]nonane for octahydropyrrolo[1,2-a]pyrazine in Step 1 of Example 20. 1H NMR (500MHz, CDCl3): δ10.63 (s, 1H), 8.21 (d, J = 9.0Hz, 1H), 8.12 (s, 1H), 6.66 (dd, J1 = 9.0Hz, J2 = 2.0Hz, 1H ),6.48(d,J=1.5Hz,1H),6.37-6.33(m,3H),6.19(s,1H),5.76(s,1H),5.08(s,1H),4.50(s,4H),4.21(t,J= 6.8Hz,2H),3.26(t,J=5.5Hz,4H),3.13(s,1H),2.95(s,1H),2.74(d,J=7.5Hz,1H),2.35(d,J=9.5Hz,1H),2 .02(t,J=5.5Hz,4H),1.91-1.82(m,3H),1.69(d,J=9.5Hz,1H),1.03(d,J=6.0Hz,6H).HRMS:582.3182[M+H] + .

[0377] Example 29: (1S,2S,3R,4R)-3-((6-cyano-2-(4-(((2S,5R)-2,5-dimethylpiperazin-1-yl)-2-(isopentyloxy)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0378]

[0379] Synthesis route:

[0380]

[0381] The title compound (31 mg) was synthesized by a similar procedure to that described in Example 20, substituting (2R,5S)-2,5-dimethylpiperazine for octahydropyrrolo[1,2-a]pyrazine in Step 1 of Example 20. 1H NMR (500MHz, CDCl3): δ10.74(s,1H),8.28(d,J=9.0Hz,1H),8.12(s,1H),6.81(d,J=8.0Hz,1H),6. 69-6.61(m,2H),6.39-6.35(m,2H),6.18-6.13(m,2H),5.12(s,1H),4.23(s,2H),3.31-3.18(m,4H) ,3.13(s,1H),2.96(s,1H),2.75-2.69(m,3H),2.36-2.33(m,2H),1.89-1.85(m,3H),1.67(d,J=8. 5Hz,1H),1.16(d,J=5.5Hz,3H),1.07(d,J=4.5Hz,3H),1.03(d,J=6.0Hz,6H).HRMS:569.3375[M+H] + .

[0382] Example 30: (1S,2S,3R,4R)-3-(((6-cyano-2-(2-(isopentyloxy))-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0383]

[0384] Synthesis route:

[0385]

[0386] The title compound (15 mg) was synthesized by a similar procedure to that described in Example 20, substituting 1-methyl-4-(piperidin-4-yl)piperazine for octahydropyrrolo[1,2-a]pyrazine in Step 1 of Example 20. 1H NMR (500MHz, CDCl3): δ10.62(s,1H),8.20(d,J=8.5Hz,1H),8.12(s,1H),6.65(d,J=7.5Hz,1H),6.47 (s,1H),6.36-6.34(m,3H),6.24(s,1H),5.76(s,1H),5.09(s,1H),4.21(s,2H),3.88(d,J=10.5Hz,2 H),3.13(s,1H),2.95(s,1H),2.88(t,J=11.5Hz,2H),2.75-2.68(m,5H),2.56-2.48(m,4H),2.34-2. 19(m,5H),1.97(d,J=10.0Hz,2H),1.88(s,3H),1.69-1.65(m,3H),1.03(s,6H).HRMS:638.3939[M+H] + .

[0387] Example 31: (1S,2S,3R,4R)-3-((6-cyano-2-(2-(isopentyloxy)-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0388]

[0389] Synthesis route:

[0390]

[0391] The title compound (30 mg) was synthesized by a similar procedure to that described in Example 20, substituting 1-(oxetan-3-yl)piperazine for octahydropyrrolo[1,2-a]pyrazine in Step 1 of Example 20. 1H NMR (500MHz, CDCl3): δ10.65(s,1H),8.23(d,J=8.5Hz,1H),8.11(s,1H),6.66(d,J=8.0Hz,1H),6.53-6. 48(m,2H),6.37-6.33(m,2H),6.23(s,1H),6.03(s,1H),5.09(s,1H),4.73-4.65(m,4H),4.22(t,J=6.5Hz ,2H),3.59-3.54(m,1H),3.37(s,4H),3.12(s,1H),2.95(s,1H),2.72(d,J=8.0Hz,1H),2.52(s,4H),2.3 5(d,J=8.5Hz,1H),1.89-1.86(m,3H),1.67(d,J=9.0Hz,1H),1.03(d,J=6.0Hz,6H).HRMS:597.3333[M+H] + .

[0392] Example 32: (1S,2S,3R,4R)-3-((6-cyano-2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-(isopentyloxy)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0393]

[0394] Synthesis route:

[0395]

[0396] The title compound (68 mg) was synthesized by a similar method to that described in Example 20, substituting N,N,N'-trimethylethylenediamine for octahydropyrrolo[1,2-a]pyrazine in Step 1 of Example 20. 1H NMR (500MHz, CDCl3): δ10.60 (s, 1H), 8.18 (d, J = 9.0Hz, 1H), 8.09 (s, 1H), 6.46 (dd, J1 = 9.0Hz, J2 = 2.0Hz ,1H),6.37-6.33(m,3H),6.26(d,J=2.0Hz,2H),5.86(s,1H),5.08(s,1H),4.22(d,J=6.5Hz,2H),3.55( d,J=7.3Hz,2H),3.13(s,1H),3.06(s,3H),2.94(s,1H),2.76(d,J=8.0Hz,1H),2.53(d,J=7.5Hz,2H),2 .35-2.30(m,7H),1.90-1.82(m,3H),1.69(d,J=9.5Hz,1H),1.03(d,J=6.5Hz,6H).HRMS:557.3332[M+H] + .

[0397] Example 33: (1S,2S,3R,4R)-3-((2-(4-(1,4-diazepin-1-yl)-2-(isopentyloxy)phenyl)-6-cyano-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0398]

[0399] Synthesis route:

[0400]

[0401] The title compound (40 mg) was synthesized by a similar procedure to that described in Example 20, substituting 1,4-diazepane for octahydropyrrolo[1,2-a]pyrazine in Step 1 of Example 20. 1H NMR(500MHz,DMSO-d6)δ12.03(br,1H),8.14(s,1H),7.89(d,J=8.8Hz,1H),7.82(s,1H),7.77(br,1H),7.34–7.25(m,1H),6.56( dd,J=8.9,2.3Hz,1H),6.38(dd,J=14.7,2.4Hz,3H),5.14(br,1H),4.23(d,J=6.6Hz,2H),3.75(t,J=5.0Hz,2H),3.62(t,J=6.2H z,2H),3.14(t,J=5.1Hz,2H),2.98(t,J=5.7Hz,2H),2.91(s,1H),2.85(s,1H),2.61(d,J=8.2Hz,1H),2.21(d,J=8.7Hz,1H),2.0 3(t,J=5.8Hz,2H),1.91(s,1H),1.75(dd,J=6.5,3.7Hz,3H),1.40(d,J=8.8Hz,1H),0.94(d,J=4.2Hz,6H).HRMS:555.3216[M+H] + .

[0402] Example 34: (1S,2S,3R,4R)-3-((6-cyano-2-(2-(isopentyloxy))-4-(piperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0403]

[0404] Synthesis route:

[0405]

[0406] The title compound (8 mg) was synthesized by a similar method to that described in Example 20, substituting piperazine for octahydropyrrolo[1,2-a]pyrazine in Step 1 of Example 20. 1H NMR(500MHz,DMSO-d6)δ12.12(s,1H),8.15(s,1H),7.94-7.68(m,3H),7.32(s,1H) ,6.70(d,J=8.9Hz,1H),6.63(s,1H),6.37(s,2H),5.15(s,1H),4.31-4.14(m,2H),3 .27(s,5H),2.92(s,5H),2.85(s,1H),2.68(s,1H),2.61(d,J=8.4Hz,1H),2.21(d,J =8.8Hz,1H),1.90(s,2H),1.41(d,J=8.6Hz,1H),0.94(s,6H).HRMS:541.3043[M+H] + .

[0407] Example 35: (1S,2S,3R,4R)-3-((6-cyano-2-(4-(4-methylpiperazin-1-yl)-2-(4,4,4-trifluorobutoxy)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0408]

[0409] Synthesis route:

[0410]

[0411] Step 1: 4-(4-Methylpiperazin-1-yl)-2-(4,4,4-trifluorobutoxy)benzaldehyde

[0412] Combine 4-fluoro-2-(4,4,4-trifluorobutoxy)benzaldehyde (300 mg), potassium carbonate (331 mg), 1-methylpiperazine (144 mg), and N,N-dimethylformamide (5 ml) and heat to 80°C overnight. After completion of the reaction, dilute with water and extract with ethyl acetate. The organic phase is washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate. Filtration and concentration afford the crude product, which is then purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to afford the title compound (150 mg). 1H NMR (500MHz, CDCl3): δ10.22(d,J=0.7Hz,1H),7.74(d,J=8.8Hz,1H),6.52(ddd,J=8.9,2.3,0.8Hz,1H),6.25(d, J=2.2Hz,1H),4.12(t,J=6.0Hz,2H),3.45-3.33(m,4H),2.60-2.49(m,4H),2.41-2.28(m,5H),2.18-2.07(m,2H).

[0413] Step 2: (1S,2S,3R,4R)-3-((6-cyano-2-(4-(4-methylpiperazin-1-yl)-2-(4,4,4-trifluorobutoxy)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0414] (1S,2S,3R,4R)-3-(((2,3-diamino-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide (80 mg), 4-(4-methylpiperazin-1-yl)-2-(4,4,4-trifluorobutoxy)benzaldehyde (121 mg), ammonium acetate (43.4 mg) and ethanol (2 ml) were mixed and heated to 80°C for reaction. After completion of the reaction, the mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give the title compound (59 mg). 1 H NMR (500MHz, CDCl3): δ10.62(s,1H),8.22(d,J=8.9Hz,1H),8.11(s,1H),6.69(dd,J=8.9,2.2Hz,1H),6 .46(d,J=2.3Hz,1H),6.41-6.28(m,3H),6.14(s,1H),5.68(s,1H),5.09(br,1H),4.29(t,J=6.6Hz,2H), 3.42-3.29(m,4H),3.13(d,J=2.5Hz,1H),2.95(d,J=3.5Hz,1H),2.74(dd,J=8.1,1.7Hz,1H),2.60(t,J= 5.1Hz,4H),2.38(s,3H),2.37-2.29(m,3H),2.28-2.20(m,2H),1.74-1.65(m,1H).HRMS:595.2756[M+H] + .

[0415] Example 36: (1S,2S,3R,4R)-3-((2-(2-butoxy-4-(4-methylpiperazin-1-yl)phenyl)-6-cyano-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0416]

[0417] Synthesis route:

[0418]

[0419] The title compound (70 mg) was synthesized by a similar procedure to that described in Example 35, substituting 2-butoxy-4-fluorobenzaldehyde for 4-fluoro-2-(4,4,4-trifluorobutoxy)benzaldehyde in Step 1 of Example 35. 1 H NMR (500MHz, DMSO-d6): δ10.68(s,1H),8.22(d,J=8.8Hz,1H),8.11(s,1H),6.60-6.70(m,1H),6.48(d,J=2. 2Hz,1H),6.30-6.45(m,4H),6.29-6.06(m,1H),6.06-5.80(m,1H),4.20(t,J=6.8Hz,2H),3.34(t,J=5.1Hz, 4H),3.18-3.07(m,1H),2.95(d,J=4.8Hz,1H),2.79-2.69(m,1H),2.60(t,J=5.1Hz,4H),2.30-2.45(m,5H), 2.08-1.89(m,2H),1.68(dt,J=9.5,1.8Hz,1H),1.63-1.48(m,2H),1.41-0.17(m,3H).HRMS:541.3043[M+H] + .

[0420] Example 37: (1S,2S,3R,4R)-3-((6-cyano-2-(2-(3-methoxypropoxy)-4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0421]

[0422] Synthesis route:

[0423]

[0424] The title compound (60 mg) was synthesized by a similar procedure to that described in Example 35, substituting 4-fluoro-2-(3-methoxypropoxy)benzaldehyde for 4-fluoro-2-(4,4,4-trifluorobutoxy)benzaldehyde in Step 1 of Example 35. 1 H NMR (500MHz, DMSO-d6): δ12.21(s,1H),8.15(s,1H),8.03(d,J=8.8Hz,1H),7.83-7.78(m,2H),7 .33(s,1H),6.73(dd,J=8.9,2.2Hz,1H),6.61(d,J=2.4Hz,1H),6.41-6.35(m,2H),4.28(t,J=5.6 Hz,2H),3.64(t,J=5.3Hz,2H),3.45(s,3H),3.31-3.41(m,5H),2.94-2.90(m,1H),2.86(s,1H), 2.62(d,J=8.2Hz,1H),2.46(t,J=4.9Hz,4H),2.40-2.20(m,4H),2.15-2.08(m,2H),1.50-1.30(m 1H).HRMS:557.2994[M+H] + .

[0425] Example 38: (1S,2S,3R,4R)-3-((6-cyano-2-(2-(4-fluorobutoxy)-4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0426]

[0427] Synthesis route:

[0428]

[0429] The title compound (40 mg) was synthesized by a similar procedure to that described in Example 35, substituting 4-fluoro-2-(4-fluorobutoxy)benzaldehyde for 4-fluoro-2-(4,4,4-trifluorobutoxy)benzaldehyde in Step 1 of Example 35.

[0430] 1H NMR (500MHz, DMSO-d6): δ10.68(s,1H),8.22(d,J=8.8Hz,1H),8.11(s,1H),6.67(dd,J=8.8,2.2Hz,1H),6 .48(d,J=2.2Hz,1H),6.43-6.27(m,3H),6.20(s,1H),5.86(s,1H),4.62(t,J=5.7Hz,1H),4.52(t,J=5.7Hz ,1H),4.27(t,J=6.6Hz,2H),3.34(t,J=4.9Hz,4H),3.13(s,1H),2.95(s,1H),2.85-2.70(m,1H),2.60-2.7 0(m,4H),2.86-2.53(m,5H),2.20-2.10(m,2H),2.0-1.80(m,2H),1.80-1.60(m,1H).HRMS:559.2952[M+H] + .

[0431] Example 39: (1S,2S,3R,4R)-3-((6-cyano-2-(4-(4-methylpiperazin-1-yl)-2-(pent-3-yn-1-yloxy)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0432]

[0433] Synthesis route:

[0434]

[0435] Step 1: 4-(4-methylpiperazin-1-yl)-2-(pent-3-yn-1-yloxy)benzaldehyde

[0436] Combine 4-bromo-2-(pent-3-yn-1-yloxy)benzaldehyde (117 mg), palladium acetate (9.86 mg), Xantphos (50.8 mg), cesium carbonate (429 mg), N-methylpiperazine (44 mg), and dioxane (2 ml). Under nitrogen, heat the mixture to 90°C overnight. After completion of the reaction, filter through celite, dilute the filtrate with water, extract with ethyl acetate, and wash the organic phase with water and saturated brine, then dry over anhydrous sodium sulfate. Filtration, concentration, and purification by silica gel column chromatography (dichloromethane:methanol = 15:1) yield the title compound (56 mg). 1H NMR (500MHz, CDCl3): δ10.25 (s, 1H), 7.74 (d, J = 8.8Hz, 1H), 6.51 (dd, J = 8.8, 2.2Hz, 1H), 6.28 (d, J = 2.3Hz, 1H), 4.13 (t, J = 7. 1Hz,2H),3.40(t,J=5.2Hz,4H),2.67(ddt,J=7.2,4.7,2.6Hz,2H),2.55(t,J=5.1Hz,4H),2.36(s,3H),1.80(t,J=2.6Hz,3H).

[0437] Step 2: (1S,2S,3R,4R)-3-((6-cyano-2-(4-(4-methylpiperazin-1-yl)-2-(pent-3-yn-1-yloxy)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0438] (1S,2S,3R,4R)-3-(((2,3-diamino-5-cyanopyridin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide (50 mg), 4-(4-methylpiperazin-1-yl)-2-(pent-3-yn-1-yloxy)benzaldehyde (55 mg), ammonium acetate (41 mg) and ethanol (1 mL) were mixed and heated to 70°C for overnight reaction. After completion of the reaction, the mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain the title compound (38 mg). 1 H NMR (500MHz, CDCl3): 11.13 (s, 1H), 8.24 (d, J = 8.8Hz, 1H), 8.14 (s, 1H), 6.68 (dd, J = 8.9, 2.2Hz, 1H),6.45(d,J=2.2Hz,1H),6.35(d,J=2.3Hz,2H),6.31-6.19(m,1H),6.11(s,1H),5.53-5.39(m, 1H),5.09(s,1H),4.25(t,J=5.9Hz,2H),3.34(t,J=4.9Hz,4H),3.14(s,1H),2.95(s,1H),2.86- 2.73(m,3H),2.59(t,J=4.9Hz,4H),2.37(s,3H),1.91(s,3H),1.72(s,2H).HRMS:551.2902[M+H] + .

[0439] Example 40: (1S,2S,3R,4R)-3-((6-cyano-2-(2-(2-cyclopropylethoxy)-4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide

[0440]

[0441] Synthesis route:

[0442]

[0443] The title compound (15 mg) was synthesized by a similar procedure to that described in Example 39, substituting 4-bromo-2-(2-cyclopropylethoxy)benzaldehyde for 4-bromo-2-(pent-3-yn-1-yloxy)benzaldehyde in Step 1 of Example 39. 1 H NMR (500MHz, CDCl3): δ10.74(s,1H),8.18(d,J=56.6Hz,2H),6.81-6.57(m,1H),6.52(s ,1H),6.35(s,2H),6.21(s,2H),5.59(s,1H),5.09(s,1H),4.28(s,2H),3.64(s,1H),3. 35(s,4H),3.14(s,1H),2.95(s,1H),2.76(s,1H),2.60(s,4H),2.38(s,3H),2.02(d,J= 23.0Hz,2H),1.70(s,1H),0.61(s,1H),0.21(s,2H),0.00(s,2H).HRMS:553.3040[M+H] + .

[0444] Experimental Example 1 In vitro FGFR4 kinase inhibitory activity screening

[0445] 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) and add 6 μL of 1.67× 0.0835 ng / μL working solution to each well (final concentration 0.05 ng / μL). Use a nanoliter pipette to add different compounds dissolved in DMSO to the wells to make the final concentration of the compound range from 1000 nM to 0.24 nM, with a positive concentration of 100 nM to 0.024 nM, a 4-fold gradient, and a total of 7 concentrations. At the same time, set up blank control wells (no enzyme) and negative control wells (containing enzyme, with solvent DMSO). After the enzyme reacted with the compound or solvent for 30 minutes, 5× 50μM ATP (final concentration 10μM) and 5× 0.5μM substrate (final concentration 0.1μM, ULight-polyGT) prepared in kinase buffer were mixed at a ratio of 1:1 and added to each well at a rate of 4μL. After sealing the plate with a sealing film and reacting at room temperature for 2 hours, 5μL of 4× 40mM EDTA (final concentration 10mM) was added to each well and incubated at room temperature for 5 minutes. Then, 5μL of 4× 8nM detection reagent (final concentration 2nM, Eμ-anti-phospho-tyrosine antibody) was added to each well and incubated at room temperature for 1 hour. The plate was read on a PE instrument (excitation 320 or 340nm, emission 665nm), and the IC was calculated using a four-parameter fit. 50 .

[0446] Table 1 lists the results of the determination of the inhibitory activity of the compounds of the present application on FGFR4 kinase, where A represents IC 50 Less than or equal to 10nM, B represents IC 50 Greater than 10 nM but less than or equal to 100 nM.

[0447] Table 1. Inhibitory activity of the compounds in the examples on FGFR4 kinase

[0448]

[0449]

[0450] Experimental Example 2 In vitro FGFR4 kinase mutant inhibitory activity screening

[0451] 1. Screening of FGFR4 (V550L) inhibitory activity

[0452] Dilute 50 ng / μL of FGFR4 (V550L) stock solution with kinase buffer (50 mM HEPES, 10 mM MgCl2, 2 mM DTT, 1 mM EGTA, 0.01% Tween 20) and add 6 μL of 1.67× 0.05 ng / μL working solution to each well (final concentration 0.03 ng / μL). Use a nanoliter pipette to add different compounds dissolved in DMSO to the wells to make the final concentration of the compound range from 1000 nM to 0.24 nM, with a 4-fold gradient for a total of 7 concentrations. At the same time, set up blank control wells (without enzyme) and negative control wells (with enzyme, with solvent DMSO). After the enzyme reacted with the compound or solvent for 30 minutes, 5× 50μM ATP (final concentration 10μM) and 5× 0.5μM substrate (final concentration 0.1μM, U Light-poly GT) prepared in kinase buffer were mixed at a ratio of 1:1 and added to each well at a rate of 4μL. After sealing the plate with a sealing film and reacting at room temperature for 2 hours, 5μL of 4× 40mM EDTA (final concentration 10mM) was added to each well and incubated at room temperature for 5 minutes. Then, 5μL of 4× 8nM detection reagent (final concentration 2nM, Eμ-anti-phospho-tyrosine antibody) was added to each well and incubated at room temperature for 1 hour. The plate was read using a PE instrument (excitation 320 or 340nm, emission 665nm), and the IC was calculated using a four-parameter fit. 50 .

[0453] 2. FGFR4(N535K) inhibitory activity screening

[0454] Dilute 50 ng / μL of FGFR4 (N535K) stock solution with kinase buffer (50 mM HEPES, 10 mM MgCl2, 2 mM DTT, 1 mM EGTA, 0.01% Tween 20) and add 6 μL of 1.67× 0.00668 ng / μL working solution to each well (final concentration 0.004 ng / μL). Use a nanoliter pipette to add different compounds dissolved in DMSO to the wells to make the final concentration of the compound range from 1000 nM to 0.24 nM, with a 4-fold gradient, for a total of 7 concentrations. At the same time, set up blank control wells (without enzyme) and negative control wells (with enzyme, with solvent DMSO). After the enzyme reacted with the compound or solvent for 30 minutes, 5× 50μM ATP (final concentration 10μM) and 5× 0.5μM substrate (final concentration 0.1μM, U Light-poly GT) prepared in kinase buffer were mixed at a ratio of 1:1 and added to each well at a rate of 4μL. After sealing the plate with a sealing film and reacting at room temperature for 2 hours, 5μL of 4× 40mM EDTA (final concentration 10mM) was added to each well and incubated at room temperature for 5 minutes. Then, 5μL of 4× 8nM detection reagent (final concentration 2nM, Eμ-anti-phospho-tyrosine antibody) was added to each well and incubated at room temperature for 1 hour. The plate was read using a PE instrument (excitation 320 or 340nm, emission 665nm), and the IC was calculated using a four-parameter fit. 50 .

[0455] Table 2 lists the results of the determination of the inhibitory activity of some compounds of the present application on FGFR4 kinase mutants, where A represents IC 50 Less than or equal to 10nM, B represents IC 50 Greater than 10 nM but less than or equal to 100 nM.

[0456] Table 2. Inhibitory activity of the example compounds against FGFR4 kinase mutants

[0457]

[0458]

Claims

1. A compound of formula (Ia) or a pharmaceutically acceptable salt, or stereoisomer, or a mixture thereof, in, L 1 Selected from -NH- or -N(C 1-3 alkyl)-; A is selected from R 2 is selected from carbamoyl; R 3 Selected from optionally one or more R a Substituted C 1-6 alkoxy; Each R a Each is independently selected from fluoro, or the following groups optionally substituted with one or more F: methyl, methoxy, 1-propynyl, or cyclopropanyl; R 4 Selected from H or -NR b R c ; R b selected from methyl or ethyl; R c Selected from optionally one or more R d Substituted as follows: methyl, or ethyl; Each R d Each independently selected from methyl or dimethylamino; Or, R b 、R c Together with the attached N atom, it forms a e The following rings are substituted: Each R e are each independently selected from methyl, isopropyl, methoxy, methoxymethyl, methoxyethyl, dimethylamino, or optionally substituted by one or more R e1 Substituted groups: oxetane, piperazine, pyrrolidinyl, morpholinyl; each R e1 Each is independently selected from halogen, or methyl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a mixture thereof, characterized in that: L 1 Selected from -NH-.

3. The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, or mixture thereof, wherein: A is selected from 4. The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, or mixture thereof, wherein: A is selected from 5. The compound according to claim 4 or its pharmaceutically acceptable salt, stereoisomer, or mixture thereof, wherein: A is selected from 6. The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, or mixture thereof, wherein: R 3 Selected from C 1-6 Alkoxy.

7. The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, or mixture thereof, wherein: R 3 Selected from 8. The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, or mixture thereof, wherein: Each R a Each is independently selected from fluoro, trifluoromethyl, methoxy, 1-propynyl, or cyclopropane.

9. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a mixture thereof, wherein: Each R a Each is independently selected from fluoro, trifluoromethyl, or cyclopropane.

10. The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, or mixture thereof, wherein: R 4 Selected from-NR b R c .

11. The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, or mixture thereof, wherein: Each R e are each independently selected from methyl, isopropyl, methoxymethyl, methoxyethyl, dimethylamino, or optionally substituted by one or more R e1 Substituted groups include: oxetane, piperazinyl.

12. The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, or mixture thereof, wherein: R 4 Selected from H, 13. The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, or mixture thereof, wherein: R 4 Selected from H, 14. The compound according to claim 1 or a pharmaceutically acceptable salt, or stereoisomer, or a mixture thereof, which is selected from the compound of formula (Id) or a pharmaceutically acceptable salt, or stereoisomer, or a mixture thereof, in, R 2 、R 3 、R b 、R c 、L 1 , Part A as defined in claim 1.

15. The compound according to claim 1 or a pharmaceutically acceptable salt, or stereoisomer, or a mixture thereof, which is selected from the compound of formula (Ie) or a pharmaceutically acceptable salt, or stereoisomer, or a mixture thereof, in, R 3 、R b 、R c 、L 1 As defined in claim 1.

16. The compound according to claim 1 or its pharmaceutically acceptable salt, or stereoisomer, and mixtures thereof, selected from the following compounds or their pharmaceutically acceptable salts, or stereoisomers, and mixtures thereof:

17. A pharmaceutical composition comprising the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof.

18. Use of the compound according to any one of claims 1 to 16 or its pharmaceutically acceptable salt, stereoisomer, or mixture thereof, or the pharmaceutical composition according to claim 17 in the preparation of a medicament for treating FGFR4-related diseases.

19. The use according to claim 18, characterized in that The FGFR4-related disease is selected from cancer.

20. The use according to claim 19, characterized in that The cancer is selected from liver cancer.

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