IRAK4 inhibitors and uses thereof

Abstract

The invention relates to an interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor and application of the IRAK4 inhibitor in preparation of a medicine for treating IRAK4-associated diseases. Specifically, the invention relates to a compound as shown in a formula (I) and an isomer, nitrogen oxide, hydrate, solvate, deuterated compound, metabolite, pharmaceutically acceptable salt or prodrug thereof. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a compound having IRAK4 kinase inhibitory activity and application thereof. Background Art

[0002] Interleukin 1 receptor kinase 4 (IRAK4) is a threonine / serine protein kinase composed of 460 amino acids, containing a kinase domain and a death domain. Typically, the N-terminal lobe and the C-terminal lobe can be found in the kinase domain, which converge to form an ATP binding site. The death domain exists to bind and interact with MyD88 during protein recruitment. In addition, there are three phosphorylation sites on the protein that participate in trans-phosphorylation. IRAK4 is considered to be a key protein kinase for early activation of IL-1 receptors and TLRs downstream, initiating signal transduction by rapidly activating IRAK1 and IRAK2, leading to an innate immune response. In addition, other interleukins, such as IL-18 and IL-33, rely on IRAK4 for signal transduction. Clinical pathological studies have shown that individuals with IRAK4 mutations are protected against chronic lung disease and inflammatory bowel disease. IRAK4 deficiency itself is not lethal, and individuals can survive to adulthood, and the risk of infection decreases with age. A lot of evidence shows that inhibiting IRAK4-mediated signal transduction will be a promising treatment method. IRAK4 has become an important therapeutic target and attracted widespread research and development interest.

[0003] Despite extensive research, there is currently no drug targeting this target on the market, and the compounds disclosed in the prior art are still unsatisfactory in terms of effectiveness, safety or applicability. It is still necessary to continue researching and developing new IRAK4 inhibitors to meet people's growing medical and health needs. Summary of the invention

[0004] The present invention provides a compound, or a pharmaceutical composition thereof, which can be used as an IRAK4 inhibitor. The present invention further relates to the use of the compound or the pharmaceutical composition thereof for preparing a drug for treating a disease and / or a condition by inhibiting the receptor IRAK4 by the compound.

[0005] Specific:

[0006] In one aspect, a compound is disclosed, which is a compound as shown in formula (I), or an isomer, nitrogen oxide, hydrate, solvate, deuterated compound, metabolite, pharmaceutically acceptable salt or prodrug of the compound as shown in formula (I),

[0007]

[0008] in:

[0009] Ring A is an 8-13 membered spiro ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0010] G1 is N or CR 6 ;

[0011] G2 is N or CR 7 ;

[0012] R 1 , R 2 and R 3 are independently hydrogen, deuterium, halogen, CN, OH, NO2, NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, -(C 0-3 Alkylene)-C 3-6 Cycloalkyl or -(C 0-3 Alkylene)-3-8 membered heterocyclic group, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, -(C 0-3 Alkylene)-C 3-6 Cycloalkyl and -(C 0-3 The 3- to 8-membered heterocyclic group may be independently and optionally substituted by 1, 2 or 3 groups selected from deuterium, halogen, oxo, CN, OH, NO2, NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl and C 1-3 Substituted by a haloalkyl substituent;

[0013] Each R a , R 4 , R 5 , R 6 and R 7 are independently hydrogen, deuterium, halogen, oxo, CN, NO2, -R b 、-OR c 、-SR c 、-N(R c )2、-C(R c )3, -S(=O)2R c 、-S(=O)2N(R c )2, -S(=O)R c ,-S(=O)(NR c )R c 、-P(=O)(OR c )2、-P(=O)(N(R c )2)2、-CF(Rc )2, -CF2(R c )、-CF3、-C(R c )2-OR c ,-C(R c )2-N(R c )2, -C(=O)R c 、-C(=O)OR c or -C(=O)N(R c )2; each R b Independently for C 1-6 Alkyl, C 2-6 Alkenyl, phenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group or 5-6 membered heteroaryl, said R b can be independently optionally replaced by 1, 2 or 3 selected from deuterium, halogen, CN, OH, NO2, NH2, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy and C 1-3 Substituted by a haloalkyl substituent;

[0014] Each R c are independently hydrogen, deuterium, C 1-6 Alkyl, phenyl, C 4-7 Cycloalkyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, the C 1-6 Alkyl, phenyl, C 4-7 Cycloalkyl, 4-7 membered heterocyclyl and 5-6 membered heteroaryl may be independently optionally substituted by 1, 2 or 3 radicals selected from deuterium, halogen, oxo, CN, OH, NO2, NH2, C 1-3 Aliphatic group, C 1-3 Alkoxy, C 1-3 Haloalkoxy and C 1-3 or two R on the same atom c The group is optionally combined with its intermediate atom to form a C 4-7 Cycloalkyl, a 4-11 membered bridged bicyclic or spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, said C 4-7 Cycloalkyl and 4-11 membered bridged bicyclic or spirocyclic rings having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur may be further optionally substituted by 1, 2 or 3 atoms selected from hydrogen, deuterium, halogen, oxo, CN, OH, NO2, NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy and C 1-3 Substituted by a haloalkyl substituent;

[0015] m is 0, 1, 2, 3, 4, 5 or 6.

[0016] In some embodiments, wherein R 1 For hydrogen, deuterium, halogen, CN, OH, NO2, NH2, C 1-6 Alkyl or C 3-6 Cycloalkyl; R 2 For hydrogen, deuterium, halogen, CN, OH, NO2, NH2, C 1-6 Alkyl or C 3-6 Cycloalkyl. Preferably R 1 is hydrogen, deuterium, halogen, CN, OH, NO2, NH2, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R 2 is hydrogen, deuterium, halogen, CN, OH, NO2, NH2, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0017] In some embodiments, wherein R 3 For hydrogen, deuterium, halogen, CN, OH, NO2, NH2, C 1-6 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 5-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl and 5-6 membered heterocyclic groups may be independently optionally substituted by 1, 2 or 3 groups selected from deuterium, halogen, oxo, CN, OH, NO2, NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl and C 1-3 Preferably R 3 R is hydrogen, deuterium, halogen, CN, OH, NO2, methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl or morpholinyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl and morpholinyl may be independently and optionally substituted with 1, 2 or 3 substituents selected from deuterium, halogen, oxo, CN, OH, NO2, NH2, methyl, methoxy, -CH2OH, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -OCHF2 and -OCF3. Or R 3 is piperidinyl, piperazinyl or morpholinyl, and the piperidinyl, piperazinyl and morpholinyl may be independently optionally substituted by 1, 2 or 3 substituents selected from -CH2CHF2 and -C(CH3)2OH.

[0018] In some embodiments, wherein each Ra are independently hydrogen, deuterium, halogen, oxo, CN, OH, NO2, NH2, -COOH, -CF3 or C 1-6 Alkyl; R 4 , R 5 , R 6 and R 7 are independently hydrogen, deuterium, halogen, oxo, CN, OH, NO2, NH2, -COOH, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group or 7-8 membered bridged bicyclic ring, the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl and 7-8 membered bridged bicyclic ring may be independently optionally substituted by 1, 2 or 3 groups selected from deuterium, halogen, OH, CN, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy and C 1-3 The alkyl group is substituted with a haloalkyl substituent.

[0019] Optimize each R a R is independently hydrogen, deuterium, halogen, oxo, CN, OH, NO2, NH2, -COOH, -CF3, methyl, ethyl, n-propyl or isopropyl; 4 , R 5 , R 6 and R 7 are each independently hydrogen, deuterium, halogen, oxo, CN, OH, NO2, NH2, -COOH, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl or The methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl and It may be optionally substituted independently with 1, 2 or 3 substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, NO2, NH2, methyl, ethyl, methoxy, ethoxy, -CHF2, -CF3, -OCHF2 and -OCF3.

[0020] Some other solutions of the present invention are obtained by arbitrarily combining the above variables.

[0021] In some embodiments, the compound has a structure represented by formula (II), formula (III), formula (IV), formula (V) or formula (VI):

[0022]

[0023]

[0024] in:

[0025] Each of X1, X2, X3 and X4 is independently CH2, -C(=O)-, NH, O or S;

[0026] Each p and q is independently 1 or 2.

[0027] The R 1 , R 2 , R 3 , R 4 , R 5 , R a , G1, G2 and m have the meanings described in the present invention.

[0028] In some embodiments, the compound is a compound having one of the following structures or an isomer, nitrogen oxide, hydrate, solvate, deuterated substance, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound having one of the following structures:

[0029]

[0030]

[0031]

[0032]

[0033] On the other hand, the present invention relates to a pharmaceutical composition, which comprises a compound of formula (I) of the present invention, or its isomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, and a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof.

[0034] In another aspect, the present invention relates to the use of the aforementioned compound or a pharmaceutical composition thereof in the preparation of a medicament for preventing, treating or alleviating a disease in a patient that is responsive to the inhibition of IRAK4.

[0035] In some embodiments, the disease is an inflammatory disease, an infection such as viral, bacterial, fungal and parasitic infection, HIV-1 infection, sepsis, an autoimmune disorder or disease such as rheumatoid arthritis and multiple sclerosis, gout, juvenile idiopathic arthritis, Muckle-Wells disease, familial Mediterranean fever, Behcet's disease, adult Still's disease, a proliferative disease such as cancer, hyperplasia, restenosis, cardiac hypertrophy, leukemia, intravascular coagulation, bone disease, metabolic disease, neurological and neurodegenerative disease, cardiovascular disease, fibrotic and allergic disease, asthma, atopic dermatitis, hidradenitis suppurativa, Alzheimer's disease, hormone-related diseases, trauma, hemodialysis, ischemic disease, non-infectious hepatitis, ultraviolet radiation, closed head injury, pancreatitis, periodontitis, graft-versus-host disease and / or transplant rejection.

[0036] The invention obtains a series of compounds with high activity, low toxicity, good metabolic stability and excellent drug properties.

[0037] Related definitions:

[0038] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be indefinite or unclear in the absence of special definition, but should be understood according to the ordinary meaning. The present invention is intended to cover all alternatives, variations and equivalents that may be included in the present invention as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which can be applied in the practice of the present invention. The present invention is in no way limited to the description of methods and materials.

[0039] Unless otherwise indicated, the structural formulae and compounds described herein include all isomeric forms, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs. Therefore, the compounds of the present invention are also within the scope of the present invention in their individual stereochemical isomers, enantiomers, diastereomers, geometric isomers, conformers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include one or more different isotopically enriched atoms.

[0040] Unless otherwise indicated, the "isomers" of the present invention include all isomeric forms (such as enantiomers, diastereomers, geometric isomers or conformational isomers): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, geometric isomers or conformational isomers are all within the scope of the present invention.

[0041] Unless otherwise indicated, the term "nitrogen oxide" used in the present invention means that when a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide.

[0042] Unless otherwise indicated, the "hydrate" of the present invention refers to an association formed when the solvent molecule is water.

[0043] Unless otherwise indicated, the "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to: water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol.

[0044] "Deuterated compound" refers to a compound obtained by replacing one or more hydrogen atoms in the compound of the present invention with deuterium, so as to improve the drug metabolism cycle, reduce the production of toxic metabolites or drug interactions, thereby reducing the dosage, improving safety and obtaining better therapeutic effects.

[0045] "Metabolite" refers to a product obtained by metabolism in vivo of a specific compound described in the present invention or a pharmaceutically acceptable salt, analog or derivative thereof, which exhibits similar activity in vivo or in vitro to the compound of formula (I). The metabolite of a compound can be identified by techniques known in the art, and its activity can be characterized by experimental methods as described in the present invention. Such a product can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, or enzymatic cleavage. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting the compounds of the present invention with mammals for a period of time.

[0046] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound of formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or by the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compounds of the present invention may be esters. In the prior invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, which can be acylated to obtain a prodrug form of the compound. Other prodrug forms include phosphates, such as these phosphate compounds obtained by phosphorylation of the hydroxyl group on the parent.

[0047] The term "pharmaceutically acceptable" as used in the present invention 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 human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0048] The term "pharmaceutically acceptable salt" refers to salts of compounds of the invention, prepared from compounds of the invention having specific substituents with relatively nontoxic acids or bases. When the compounds of the invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid, and salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, and thus can be converted into any base or acid addition salt.

[0049] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.

[0050] The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include variants of deuterium and hydrogen, as long as the valence state of the specific atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or not substituted, and unless otherwise specified, the type and number of substituents can be arbitrary on the basis of chemical achievable. When any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent. Therefore, for example, if a group is substituted by 0-2 R, the group can be optionally substituted by up to two R, and R in each case has independent options. In addition, the combination of substituents and / or their variants is only allowed if such a combination will produce a stable compound.

[0051] "Cycloalkyl" or "cycloalkane" means a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic carbon ring system containing 3-12 carbon atoms, which is a saturated ring or a ring containing one or more unsaturated bonds, but never an aromatic ring. "Cycloalkyl" or "cycloalkane" can also be a spirocyclic and bridged bicyclic ring. In one embodiment, the cycloalkyl contains 3-10 carbon atoms; in another embodiment, the cycloalkyl contains 3-8 carbon atoms; in yet another embodiment, the cycloalkyl contains 3-6 carbon atoms. Such examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl group can be independently unsubstituted or substituted with one or more substituents described herein.

[0052] "Heterocyclyl" and "heterocycle" are used interchangeably herein and both refer to saturated or partially unsaturated monocyclic, bicyclic or tricyclic rings containing 3-12 ring atoms, never aromatic rings, in which at least one ring atom is a heteroatom. "Heterocyclyl" and "heterocycle" may also be spirocyclic heterocycles and bridged bicyclic heterocycles. In one embodiment, "heterocyclyl" or "heterocycle" contains 3-10 ring atoms; in one embodiment, "heterocyclyl" or "heterocycle" contains 3-8 ring atoms; in another embodiment, "heterocyclyl" or "heterocycle" contains 5-8 ring atoms; in yet another embodiment, "heterocyclyl" or "heterocycle" contains 3-6 ring atoms; in yet another embodiment, "heterocyclyl" or "heterocycle" contains 5-6 ring atoms; in yet another embodiment, "heterocyclyl" or "heterocycle" contains 4-6 ring atoms; unless otherwise specified, heterocyclyl may be carbon or nitrogen radicals, and heteroatoms have the meanings as described herein. Examples of heterocyclic groups include, but are not limited to, oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine Base, diazepine Thiazepine Examples of heterocyclic groups in which the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinone, 3,5-dioxopiperidinyl, and pyrimidinedione. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, cyclopentanesulfonyl and 1,1-dioxothiomorpholinyl. The heterocyclic group may be optionally substituted by one or more substituents described herein.

[0053] "Aryl" refers to monocyclic, bicyclic and tricyclic carbon ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring is aromatic, wherein each ring contains 3-7 ring atoms, and has one or more points of attachment to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups can include phenyl, naphthyl and anthracene. The aryl groups can be independently optionally substituted with one or more substituents described herein.

[0054] "Heteroaryl" means monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring contains 5-7 atoms and has one or more points of attachment to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, the 5-10 atom heteroaryl contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, wherein the nitrogen atom can be further oxidized.

[0055] Examples of heteroaryl groups include, but are not limited to, furanyl, imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl, oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (e.g., N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridinyl, pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl, thiazole 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, 1,2,4-thiodiazolyl, 1,2,3-thiodiazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, 1,2,3 ... The following bicyclic rings are also included, but are by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), 1,2,3,4-tetrahydroisoquinolyl, 1,3-benzodioxolyl, indolyl, isoquinolyl (such as 1-isoquinolyl), [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, and [1,2,4]triazolo[1,5-a]pyridinyl, and the like.

[0056] "Spiro" means a 5 to 20-membered polycyclic group in which saturated or partially unsaturated monocyclic rings share a carbon atom (called a spiro atom), and may contain 0 to 5 heteroatoms. Preferably, it is 6 to 14 members, more preferably 8 to 13 members, and more preferably 8 to 10 members. Unless otherwise specified, the spiro group is optionally substituted by one or more substituents as described in the present invention. Non-limiting examples include:

[0057] etc.

[0058] "Bridged bicyclic" means a saturated or partially unsaturated bicyclic system with at least one bridge, which may contain 0 to 5 heteroatoms. "Bridge" is an atom that is not branched or connects two bridgeheads or a valence bond, wherein "bridgehead" is any skeleton atom of a ring system bonded to three or more skeleton atoms (except hydrogen). In certain embodiments, the bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. This type of bridged bicyclic group is well known in the art, wherein each group is connected to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, the bridged bicyclic group is optionally substituted by one or more substituents as described in the present invention. Additionally or alternatively, any substitutable nitrogen of the bridged bicyclic group is optionally substituted. Its non-limiting examples include: etc.

[0059] "Heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; the quaternized form of any basic nitrogen; a substitutable nitrogen of a heterocycle, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl)).

[0060] "Halogen" refers to F, Cl, Br or I.

[0061] "Deuterium" means heavy hydrogen, D.

[0062] "Alkyl" refers to a straight or branched chain saturated hydrocarbon group consisting of several carbon atoms.

[0063] "Alkenyl" refers to a straight or branched hydrocarbon group consisting of multiple carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group.

[0064] "Alkylene" means a saturated divalent hydrocarbon radical derived from a straight or branched chain saturated hydrocarbon by eliminating two hydrogen atoms.

[0065] "Alkoxy" means a linear or branched monovalent residue of the formula -OR, wherein R is an alkyl group as defined above.

[0066] "Haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted with one or more halogen atoms.

[0067] "Hydroxyalkyl" means an alkyl group substituted with one or more hydroxy groups.

[0068] As used herein, a substituent is connected to a ring by a bond to form a ring system, which means that the substituent can be substituted at any substitutable position on the ring. For example, formula (a) means that the substituent R can be substituted mono- or poly-substituted at any substitutable position on the pyridine ring.

[0069]

[0070] As used herein, a wavy line intersecting a bond in a chemical structure represents the point in the chemical structure at which the atom to which the wavy bond is attached is attached to the rest of the molecule or to the rest of a fragment of a molecule.

[0071] As used herein, a ring system formed by a linker attached to a ring (as shown in formula b) represents that the linker can be attached to the rest of the molecule at any available position on the ring system. Formula b represents that any available position on the octahydrocyclopenta[c]pyrrole ring can be attached to the rest of the molecule.

[0072]

[0073] The order in which chemical groups are written or named does not indicate or imply directionality unless required chemically or structurally.

[0074] If there is a discrepancy between the structure and the name, the structure shall prevail.

[0075] General synthesis process

[0076] The compounds of the present invention 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 substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present invention.

[0077] The present invention uses the following abbreviations:

[0078] mg milligram mmol millimole

[0079] DIEA N,N-DiisopropylethylamineDMF N,N-Dimethylformamide

[0080] HATU 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate h hours

[0082] min minute wt% mass percentage

[0083] DCM Dichloromethane ACN Acetonitrile

[0084] PE Petroleum ether EA Ethyl acetate

[0085] MeOH Methanol Pd / C Palladium on carbon

[0086] (Boc)2O Di-tert-butyl dicarbonate TEA Triethylamine

[0087] NaBH(OAc)3 Sodium triacetoxyborohydride KOAc Potassium acetate

[0088] LDA Lithium diisopropylamide PdCl2(dppf) 1,1-Bis(diphenylphosphino)ferrocene palladium chloride

[0089] NaBH3CN Sodium cyanoborohydride THF Tetrahydrofuran

[0090] Et3SiH Triethylsilane TFA Trifluoroacetic acid

[0091] TPSA p-Toluenesulfonic acid Et2O Ether

[0092] tBuOK Potassium tert-butoxide TCFH Tetramethylchlorouronium hexafluorophosphate

[0093] NMI N-Methylimidazole

[0094] Unless otherwise specified, the raw materials, reagents, etc. used in the following examples are derived from commercially available or known synthetic routes in the literature.

[0095] The equipment and testing conditions are described as follows: 1 H NMR spectra were recorded using a BRukeR 500 MHz NMR spectrometer. 1H NMR spectra were recorded in CDCl3, DMSO-d6, CD3OD or acetone-d6 as solvents (in ppm) and TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (tRiplet), q (quaRtet), m (multiplet), bR (bRoadened), bRs (bRoadened singlet), dd (doublet of doublets), dt (doublet of tRiplets). Coupling constants, J, are expressed in Hertz (Hz).

[0096] The measurement conditions of low-resolution mass spectrometry (MS) data are: Agilent G6125C quadrupole HPLC-MS (chromatographic column model: XBRidge BEH C18, 4.6x 50mm, 2.5 microns, 6min, flow rate of 1mL / min. Mobile phase: 0%-95% (CH3CN) in (H2O containing 0.1% formic acid:CH3CN=90:10), using electrospray ionization (ESI), at 210nm / 254nm, with DAD detection.

[0097] The compounds were named according to conventional nomenclature in the art or using software, and commercially available compounds were named according to the supplier's catalog name.

[0098] The following synthetic schemes describe the steps for preparing the compounds of the present invention. Unless otherwise indicated, each ring A, R a , R 1 , R 2 , R 3 , R 4 , R 5 , G1, G2 and m have the definitions as described in the present invention.

[0099] Synthesis scheme

[0100]

[0101] The compound represented by formula (1) and the compound represented by formula (2) are subjected to condensation reaction to obtain the compound represented by formula (I). DETAILED DESCRIPTION

[0102] The examples provide the preparation of representative compounds represented by formula (I) and related structural identification data. It must be noted that the following examples are only used to illustrate the present invention and are not intended to limit the present invention.

[0103] Intermediate synthesis

[0104] Intermediate 1 (M1):

[0105]

[0106] The synthesis process refers to step 2 of Example 11 of WO2018166993A2.

[0107] Intermediate 2 (M2):

[0108]

[0109] The synthesis process refers to the preparation method in Example 371 of WO2017108723A2.

[0110] Intermediate 3 (M3):

[0111]

[0112] The synthesis process refers to step G of Example 152 of WO2017108723A2.

[0113] Intermediate 4 (M4):

[0114]

[0115] The synthesis process refers to step E of Example 142 of WO2017108723A2.

[0116] Embodiment 1:

[0117]

[0118] M1 (73.82 mg, 0.45 mmol), M2 (100 mg, 0.30 mmol) and DIEA (117 mg, 0.91 mmol) were added to a 25 mL two-necked bottle, DMF (2 mL) was added, nitrogen was replaced, and HATU (172 mg, 0.045 mmol) was added. Nitrogen was replaced again and stirred at room temperature for 3 h. After the reaction was completed, the product was filtered and prepared by HPLC (ACN: 0.1% formic acid aqueous solution = 70:30-60:40) to obtain a yellow solid product (50 mg), with a yield of 34.8%.

[0119] ESI-MS (m / z): 477.4 [M+H] + .

[0120] 1 H NMR (500MHz, DMSO-d6) δ10.93(s,1H),8.96(s,1H),8.75(d,J=4.4Hz,1H),8.37(s,1H),8.26(d,J=8 .5Hz,1H),7.57(dd,J=8.4,4.8Hz,1H),6.73(s,1H),3.44(d,J=12.0Hz,2H),3.38(d,J=5.8Hz,2H),3 .19(s,3H),3.10(s,2H),2.96(d,J=10.4Hz,2H),2.87(d,J=4.5Hz,3H),2.64(t,J=10.9Hz,2H),2.1 3(d,J=14.2Hz,2H),1.97(d,J=13.2Hz,2H),1.72(d,J=11.6Hz,2H),1.62–1.56(m,2H),1.51(s,1H).

[0121] Embodiment 2:

[0122]

[0123] M3 (60 mg, 0.20 mmol), M1 (32 mg, 0.20 mmol), HATU (98 mg, 0.26 mmol), DIEA (127 mg, 0.99 mmol) were placed in a 25 mL single-mouth bottle, DCM (1 mL) was added, and the mixture was stirred at room temperature for 1 h. Water (20 mL) was added to the reaction solution, and DCM (30 mL) was added for extraction and separation, and the aqueous phase was extracted with DCM (30 mL) again, and the organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography (DCM: MeOH = 100: 0 to 90: 10) to obtain 67 mg of a yellow solid with a yield of 75.4%.

[0124] ESI-MS (m / z): 449.5 [M+H] + .

[0125] 1 H NMR((500MHz, CDCl3)δ10.97(s,1H),8.73(d,J=4.5Hz,1H),8.58(s,1H),8.44(s,1H),7.89(d,J=8.3Hz,1H),7.39(dd,J=8.3,4.8Hz,1H),6.68(s,1H ),4.05–3.96(m,4H),3.30–3.10(m,2H),3.07(s,2H),3.02(t,J=11.1Hz,2 H),2.97–2.86(m,4H),2.66(s,3H),2.26–2.16(m,2H),2.11–2.02(m,2H).

[0126] Embodiment 3:

[0127]

[0128] The synthesis of compound 3-1 refers to step C in Example 393 of patent WO2017108723 A2.

[0129] Step 1:

[0130] 3-1 (5.5 g, 23.09 mmol) and DCM (125 mL) were placed in a 500 mL single-mouth bottle, cooled in an ice bath, fuming nitric acid (25 mL) was added dropwise, and the mixture was stirred in an ice bath for 10 min, then naturally returned to room temperature and stirred for 1 h. After the reaction was completed, the mixture was concentrated under reduced pressure, DCM (20 mL) was added to dissolve, cooled in an ice bath, di-tert-butyl dicarbonate (7.56 g, 34.63 mmol) was added, and triethylamine (7.01 g, 69.26 mmol) was slowly added dropwise, and the mixture was stirred in an ice bath for 5 min, then the ice bath was removed, and the mixture was naturally returned to room temperature and stirred for 2 h. Under an ice bath, saturated ammonium chloride solution (30 mL) and saturated sodium chloride solution (30 mL) were slowly added, EA (50 mL) was added, and the liquids were extracted. The aqueous phase was extracted with EA (50 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography. The eluent was: PE:EA = 100:0 ~ 85:15, to obtain 3-2 as a white solid 3.3 g, yield: 42.2%.

[0131] ESI-MS(m / z-55):282.9[M-55] + .

[0132] 1 H NMR(500MHz, CDCl3)δ7.94(d,J=7.6Hz,1H),6.61(d,J=11.2Hz,1H),3.87–3.74(m,1H),3.70–3.53(m,2H),3.4 6(d,J=12.3Hz,1H),3.27(t,J=16.6Hz,2H),2.33(dd,J=13.3,6.5Hz,1H),2.06(d,J=20.0Hz,1H),1.48(s,9H).

[0133] Step 2:

[0134] 3-2 (2.8 g, 8.28 mmol) was placed in a 100 mL single-mouth bottle, and 4-hydroxymethylpiperidine (1.91 g, 16.55 mmol), potassium carbonate (2.86 g, 20.69 mmol), and acetonitrile (30 mL) were added respectively, and the mixture was heated to an external temperature of 60°C for 1 h. The reaction solution was filtered to obtain a filtrate, and the residue was dissolved in water (50 mL), and EA (50 mL × 2) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography. The eluent was PE:EA = 92:8 to 60:40, and 3-3 was obtained as an orange solid of 3.3 g, with a yield of 92.0%.

[0135] ESI-MS (m / z): 434.3 [M+H] + .

[0136] 1H NMR (500MHz, CDCl3) δ7.76 (s, 1H), 6.42 (s, 1H), 3.65 (s, 2H), 3.50 (d, J = 6.3 Hz,2H),3.35(d,J=12.1Hz,1H),3.22(d,J=11.8Hz,2H),3.11(dd,J=28.2,1 2.8Hz,2H),2.73(t,J=11.7Hz,2H),2.21(dd,J=13.1,6.3Hz,1H),1.96(d,J =5.4Hz,1H),1.74(d,J=12.2Hz,2H),1.60(s,2H),1.44(s,2H),1.40(s,9H).

[0137] Step 3:

[0138] 3-3 (3.2 g, 7.38 mmol) and Pd / C (10 wt%, 60% water) (640 mg) were placed in a 500 mL single-mouth bottle, methanol (100 mL) was added, and hydrogen was replaced 3 times with a hydrogen balloon and the hydrogen atmosphere was maintained, and the reaction was carried out at an external temperature of 35°C for 2 h. The reaction solution was filtered through diatomaceous earth to remove palladium carbon, and washed with methanol (200 mL) until the filter cake was colorless, the organic phases were combined, and concentrated under reduced pressure to obtain 3-4 as a gray solid of 2.8 g, with a yield of 94.0%.

[0139] ESI-MS (m / z): 404.1 [M+H] + .

[0140] 1 H NMR (500MHz, CDCl3) δ6.53(s,1H),6.46(s,1H),3.70–3.60(m,1H),3.51(t,J=11.8Hz,4H),3.30(t,J=11.6Hz,1H),3.04(dd,J=27.7,1 4.1Hz,4H),2.50(t,J=11.2Hz,2H),2.20–2.15(m,1H),1.91–1.85(m,1H),1.77(d,J=12.5Hz,2H),1.56(s,2H),1.39(d,J=10.5Hz,9H).

[0141] Step 4:

[0142] 3-4 (600 mg, 1.49 mmol), furan[3,2-b]pyridine-3-carboxylic acid (485 mg, 2.97 mmol), HATU (848 mg, 2.23 mmol), N,N-diisopropylethylamine (575 mg, 4.46 mmol) were placed in a 25 mL single-mouth bottle, DCM (6 mL) was added, and the reaction was stirred at 25°C for 1 h. Water (10 mL) was added to the reaction solution, and it was extracted with DCM (30 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography, the eluent was: DCM:MeOH=100:0~96:4, and 3-5 was obtained as a light yellow solid 300 mg, yield: 36.8%.

[0143] ESI-MS (m / z): 549.3 [M+H] + .

[0144] 1 H NMR (500MHz, CDCl3) δ11.00 (s, 1H), 8.72 (d, J = 4.4Hz, 1H), 8.65 (s, 1H), 8.38 (s, 1H), 7.90 ( d,J=8.4Hz,1H),7.39(dd,J=8.3,4.8Hz,1H),6.75(s,1H),3.65(d,J=5.8Hz,2H),3.61(s,1H ),3.44(d,J=11.7Hz,1H),3.29(d,J=11.6Hz,1H),3.20(d,J=11.4Hz,2H),2.76(s,2H),2.31 (d,J=11.1Hz,1H),2.03(s,1H),1.84(s,4H),1.65(d,J=35.8Hz,4H),1.50(d,J=8.4Hz,9H).

[0145] Step 5:

[0146] 3-5 (130 mg, 0.24 mmol) was placed in a 25 mL single-necked bottle, DCM (3 mL) was added, and a hydrogen chloride-dioxane solution (0.5 mL, 0.24 mmol) was added dropwise. The mixture was concentrated under reduced pressure to obtain 3-6 as a yellow solid (120 mg). Yield: 100%.

[0147] ESI-MS (m / z): 449.0 [M+H] + .

[0148] Step 6:

[0149] KOAc (54.70 mg, 0.56 mmol), 3-6 (100 mg, 0.14 mmol), 37% wt formaldehyde aqueous solution (0.5 mL), sodium triacetoxyborohydride (146.96 mg, 0.70 mmol) and DMF (3 mL) were added to a 25 mL single-mouth bottle and stirred at room temperature for 2 h. After the reaction was completed, water (10 mL) was added to the reaction solution, extracted with EA (10 mL × 2), concentrated under reduced pressure, and separated by TLC preparation to obtain the product, the developing solvent: DCM: MeOH ~ 5: 1, to obtain Example 3, 20 mg of white solid, yield: 31.25%.

[0150] ESI-MS (m / z): 463.3 [M+H] + .

[0151] 1 H NMR (500MHz, DMSO-d6) δ10.92(s,1H),8.95(s,1H),8.74(d,J=4.0Hz,1H),8.33(s,1H),8.25(d,J=8.3Hz, 1H),7.56(dd,J=8.4,4.8Hz,1H),6.72(s,1H),4.50(t,J=5.2Hz,1H),3.37(t,J=5.4Hz,2H),3.25(d,J=12. 0Hz,2H),2.94(d,J=11.3Hz,2H),2.81(s,1H),2.71(d,J=10.5Hz,1H),2.63(d,J=8.6Hz,2H),2.36(s,3H) ,2.18(dd,J=12.8,6.0Hz,1H),2.11–2.07(m,1H),1.72(d,J=11.1Hz,2H),1.62–1.56(m,2H),1.50(s,2H).

[0152] Embodiment 4:

[0153]

[0154] Step 1:

[0155] M4 (1000 mg, 2.84 mmol) was placed in a 50 mL single-mouth bottle, potassium carbonate (1176 mg, 8.51 mmol), 1-(2,2-difluoroethyl)piperazine (469 mg, 3.12 mmol), and acetonitrile (15 mL) were added respectively, and the mixture was heated to an external temperature of 40°C for 1 h. The filtrate was filtered to obtain a filtrate, and the residue was dissolved in water and extracted with EA (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and separated by column chromatography. DCM:MeOH = 100:0 to 90:10 to obtain 4-1, 1.06 g of an orange-yellow oily liquid, with a yield of 77.4%.

[0156] ESI-MS (m / z): 483.3 [M+H] + .

[0157] 1 H NMR (500MHz, CDCl3) δ7.86 (s, 1H), 6.50 (s, 1H), 5.95 (t, J = 55.2Hz, 1H), 3.79 (d, J = 10.3Hz, 2H), 3.42 (t, J = 10. 8Hz,2H),3.10(s,4H),2.99(s,2H),2.91–2.75(m,6H),1.93(d,J=13.4Hz,2H),1.80–1.72(m,2H),1.50(s,9H).

[0158] Step 2:

[0159] 4-1 (1.06 g, 2.20 mmol) was placed in a 100 mL single-mouth bottle, methanol (41 mL) was added, and then 10% palladium carbon (269 mg) was added. The hydrogen balloon was replaced three times and then kept in the hydrogen balloon, and the reaction was heated to an external temperature of 35°C for 2 hours. The palladium carbon was removed by filtration through diatomaceous earth, and the diatomaceous earth was washed with methanol and the organic phase was combined and the solvent was removed by distillation under reduced pressure to obtain 4-2, a brown foamy solid 937.2 mg, with a yield of 94.3%. ESI-MS (m / z): 453.4 [M+H] + .

[0160] 1 H NMR(500MHz, CDCl3)δ6.51(s,1H),6.44(s,1H),5.86(tt,J=55.9,4.1Hz,1H),3.63(d,J=7.0Hz,2H),3.36–3.30(m,2H),2 .82(d,J=7.2Hz,6H),2.74(td,J=15.0,4.2Hz,3H),2.67(s,3H),1.80(d,J=13.3Hz,2H),1.62–1.55(m,2H),1.40(s,9H).

[0161] Step 3:

[0162] 4-2 (528 mg, 1.17 mmol), furan[3,2-b]pyridine-3-carboxylic acid (317 mg, 1.51 mmol), HATU (576 mg, 1.52 mmol), and DIEA (754 mg, 5.83 mmol) were placed in a 25 mL single-mouth bottle, and DCM (17 mL) was added, and the mixture was stirred at 25°C for 1 h. DCM (20 mL) was added to the reaction solution, and the mixture was washed with saturated sodium chloride solution (15 mL×2), and purified by column chromatography, with the eluent being PE:EA=98:2-66:34, to obtain 4-3 as an orange-yellow oil (413 mg), with a yield of 59.2%.

[0163] ESI-MS (m / z): 598.3 [M+H] + .

[0164] 1 H NMR (500MHz, CDCl3) δ10.83(s,1H),8.69(d,J=4.5Hz,1H),8.59(s,1H),8.38(s,1H),7.90(d,J=8.0Hz,1H),7.41(dd,J=8.0,4.7Hz,1H),6.69( s,1H),6.01–5.91(m,1H),3.74(s,3H),3.49–3.32(m,4H),3.03–2.94( m,6H),2.04(s,1H),1.96–1.84(m,3H),1.76–1.65(m,3H),1.48(s,9H).

[0165] Step 4:

[0166] 4-3 (413 mg, 0.69 mmol) was placed in a 100 mL single-necked bottle, DCM (10 mL) was added to dissolve, and a hydrochloric acid dioxane solution (4.4 mL) was slowly added, and the mixture was stirred under ice bath for 1 h. The reaction solution was distilled under reduced pressure at 48 ° C to remove the solvent, and 4-4 was obtained as a dark orange solid (561 mg).

[0167] ESI-MS (m / z): 498.2 [M+H] + .

[0168] Step 5:

[0169] In a 25 mL single-mouth bottle, potassium acetate (28 mg, 0.30 mmol), 4-4 (60 mg, 0.07 mmol), 37% formaldehyde aqueous solution (7 mg, 0.08 mmol) were mixed in DMF (1 mL), stirred at room temperature for 1 h, sodium triacetoxyborohydride (77 mg, 0.37 mmol) was added, and the reaction was continued at room temperature for 2 h. DCM (10 mL) was added to the reaction solution, washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, and purified by column chromatography, DCM: MeOH = 100: 0 to 90: 10, to obtain Example 4, 22 mg of off-white solid, yield: 60.1%.

[0170] ESI-MS (m / z): 512.3 [M+H] + .

[0171] 1 H NMR (500MHz, CDCl3) δ10.79(s,1H),8.62(d,J=4.6Hz,1H),8.51(s,1H),8.32(s,1H),7.83(d,J=8.3Hz,1H),7.33(dd,J=8.4,4.8Hz,1H ),6.60(s,1H),5.86(tt,J=55.9,4.2Hz,1H),2.99(s,3H),2.95–2.73(m,13H),2.56(s,3H),2.24–2.14(m,2H),2.01(d,J=13.7Hz,2H).

[0172] Embodiment 5:

[0173]

[0174] Step 1:

[0175] LDA (2.46 mL, 18.6 mmol, 5.29 eq) was added dropwise to a mixture of THF (7 mL) and N-Boc-4-cyanopiperidine (0.61 g, 2.92 mmol, 0.83 eq) at -72 °C. After the addition of the reaction solution, the mixture was stirred at -72 °C for 1 h before the addition of 1-bromo-2-(bromomethyl)-4-chlorobenzene (1.00 g, 3.52 mmol, 1.00 eq) was started. After the addition of the solution, the mixture was stirred at room temperature for 16 h. The reaction solution was slowly poured into water (10 mL), extracted with ethyl acetate (10 mL × 3), the organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100:1 to 10:1) to obtain 5-1 (920 mg, 2.22 mmol, yield 63.2%) as a light yellow viscous oil.

[0176] ESI-MS (m / z): 313.0 [M-100+1] + .

[0177] 1 H NMR (400MHz, CDCl3) δ7.54(d,J=8.58Hz,1H),7.48(d,J=2.50Hz,1H),7.17(dd,J=8.58,2.50Hz,1H),4.12-4.29(m,2H),3.10(s,2H),3.01(br s,2H),1.89(br d,J=12.99Hz,2H),1.67(td,J=13.11,4.29Hz,2H),1.47(s,9H).

[0178] Step 2:

[0179] 5-1 (20.0 g, 48.34 mmol, 1.00 eq) was dissolved in a mixed solution of DMA (140 mL) and water (14.0 mL), and TEA (26.9 mL, 193 mmol, 4.00 eq) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (3.54 g, 4.83 mmol, 0.10 eq) were added. After replacing the nitrogen, the mixture was heated to 130 °C and reacted for 12 h. Water (150 mL) was added to the reaction solution, and solids precipitated. After filtering out the solids, the filtrate was extracted with ethyl acetate (150 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (SiO2, petroleum ether / ethyl acetate = 100:1 to 10:1). 5-2 (13.00 g, 31.97 mmol) was obtained as a light yellow solid. Yield: 66.2%.

[0180] ESI-MS (m / z): 280.1 [M-55] + .

[0181] Step 3:

[0182] 5-2 (14.0 g, 41.69 mmol, 1.00 eq) was placed in a 100 mL single-mouth bottle, DCM (9 mL) was added, and then dioxane hydrochloride solution (20.0 mL, 4 M) was added, and the reaction solution was stirred at room temperature for 12 h. The reaction solution was concentrated under reduced pressure and purified by HPLC. 5-3 (2.15 g, 8.97 mmol) was obtained as a light yellow solid. Yield: 21.5%.

[0183] ESI-MS (m / z): 236.1 [M+1] + .

[0184] 1H NMR (400MHz, CDCl3) δ7.70(d,J=8.13Hz,1H)7.46(d,J=0.63Hz,1H),7.36(dt,J=8.19,0.78Hz,1H),3.18(dt ,J=13.01,3.63Hz,2H),3.07(s,2H),2.80(td,J=12.41,2.69Hz,2H),1.85-1.93(m,2H),1.30-1.43(m,2H).

[0185] Step 4:

[0186] 5-3 (1.00 g, 4.24 mmol, 1.00 eq) was placed in a 100 mL single-mouth bottle, and DCM (7.0 mL) was added. Fuming nitric acid (10 mL, 220.61 mmol, 53 eq) was slowly added dropwise at 0°C. After the addition was complete, the reaction solution was stirred at 0°C for 10 min, then heated to 45°C and continued to stir for 12 h. The reaction solution was concentrated under reduced pressure to obtain 5-4 (1.30 g, 4.63 mmol) as an orange solid.

[0187] ESI-MS (m / z): 281.0 [M+1] + .

[0188] Step 5:

[0189] 4-Hydroxymethylpiperidine (4.1 mL, 35.09 mmol, 5.00 eq) was dissolved in DCM (14 mL), 5-4 (1.97 g, 7.02 mmol, 1.00 eq) was added, and stirred at 25°C for 2 h. The reaction solution of 5-5 (2.52 g, 7.01 mmol) was directly used for the next step.

[0190] ESI-MS (m / z): 360.2 [M+1] +

[0191] Step 6:

[0192] Boc anhydride (4.5 mL, 21.03 mmol, 3.00 eq) was directly added to the reaction solution of the previous step and stirred at 25°C for 12 h. The reaction solution was concentrated under reduced pressure and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5:1 to 0:1) to obtain 5-6 (1.58 g, 3.09 mmol) as a yellow solid. Two-step yield: 44.1%

[0193] ESI-MS (m / z): 460.2 [M+1] + .

[0194] Step 7:

[0195] THF (20 mL) was added to a 250 mL single-mouth bottle, wet palladium carbon (1.1 g, 10.34 mmol, 3.01 eq) was added under argon protection, 5-6 (1.58 g, 3.44 mmol, 1.00 eq) was dissolved in THF (20 mL) and added to the above reaction solution, and the reaction solution was stirred at room temperature for 3 h under hydrogen (15 psi) pressure. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 5-7 (1.50 g, 3.32 mmol, yield 96.5%) as an off-white solid.

[0196] ESI-MS (m / z): 430.3 [M+1] + .

[0197] Step 8:

[0198] 5-7 (1.50 g, 3.49 mmol, 1.00 eq) and furano[3,2-b]pyridine-3-carboxylic acid (572 mg, 3.49 mmol, 1.00 eq) were added to a 100 mL single-mouth bottle, and DMF (10 mL), DIEA (1.2 mL, 6.98 mmol, 2.0 eq), HATU (1.46 g, 3.84 mmol, 1.10 eq) were added, and the reaction solution was stirred at 25° C. for 2 h. The reaction solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate = 3:1-1:2) to obtain 5-8 (1.05 g, yield 45%) as a white solid.

[0199] ESI-MS (m / z): 575.3 [M+1] + .

[0200] 1 H NMR (400MHz, CDCl3) δ10.92 (s, 1H), 8.84 (s, 1H), 8.68 (dd, J = 4.77, 1.19Hz, 1H), 8.63 (s, 1H),7.90(dd,J=8.40,1.13Hz,1H),7.38(dd,J=8.40,4.83Hz,1H),7.21(s,1H),4.14(br d,J=1.55Hz,2H),3.63(d,J=5.36Hz,2H),3.30(br d,J=11.80Hz,2H),3.01(s,4H),2.72-2.80(m,2H),1.85-1.98(m,3H),1.35-1.55(m,13H),0.99(t,J=7.27Hz,2H).

[0201] Step 9:

[0202] 5-8 (43 mg, 0.07 mmol) was placed in a 40 mL single-necked bottle, and a dioxane solution of DCM (1 mL) and HCl (1 mL, 4.00 mmol) was added, and the reaction solution was stirred at 20°C for 1 h. The reaction solution was concentrated under reduced pressure to obtain 5-9 (35 mg, 0.07 mmol, 97.8%) as a yellow solid.

[0203] ESI-MS (m / z): 475.1 [M+1] +

[0204] Step 10:

[0205] 5-9 (30 mg, 0.06 mmol) was dissolved in MeOH (2 mL), DIEA (16 mg, 0.13 mmol, 2.0 eq) and paraformaldehyde (20 mg) were added, the pH was adjusted to 5-6 with acetic acid, sodium cyanoborohydride (8 mg, 0.13 mmol, 2.0 eq) was added, and the reaction was stirred at 25°C for 16 h. The reaction solution was directly filtered, separated and purified by high performance liquid chromatography (FA condition), and Example 5 (10.41 mg, 0.02 mmol, yield 32.2%) was obtained as a light yellow solid.

[0206] ESI-MS (m / z): 489.3 [M+1] +

[0207] 1 H NMR (400MHz, CD3OD) δ8.78-8.82(m,2H),8.76(s,1H),8.53(s,1H),8.12(dd,J=8.50,1. 00Hz,1H),7.55(dd,J=8.50,4.75Hz,1H),7.43(s,1H),3.54(d,J=5.75Hz,2H),3.45(br d,J=12.01Hz,2H),3.29(br d,J=12.13Hz,2H),3.16(s,2H),3.00(br d,J=9.13Hz,2H),2.75-2.89(m,5H),2.08-2.20(m,2H),1.67-1.91(m,7H).

[0208] Embodiment 6:

[0209]

[0210] Step 1:

[0211] 5-8 (200 mg, 0.35 mmol) was placed in a 50 mL single-mouth bottle, and DCM (3 mL) and MeOH (3 mL) were added. NaBH4 (26 mg, 0.70 mmol, 2.0 eq) was added, and the reaction solution was stirred at 25 ° C for 2 h. H2O (10 mL) was added to the reaction solution, and dichloromethane (15 mL × 2) was used for extraction. The organic phases were combined and concentrated under reduced pressure. Thin layer chromatography separation and purification (petroleum ether: ethyl acetate = 1: 1) was performed to obtain 6-1 (100 mg, 0.17 mmol, yield 49.8%) as a white solid.

[0212] ESI-MS (m / z): 577.2 [M+H] +

[0213] Step 2:

[0214] TFA (1.5 mL) was added to the mixture of 6-1 (60 mg, 0.10 mmol), triethylsilane (110 mg, 0.52 mmol, 5.0 eq) was added to the reaction solution, and the reaction solution was stirred at 60° C. for 3 h. The reaction solution was concentrated under reduced pressure to obtain 6-2 (60 mg, 0.11 mmol) as a colorless oil.

[0215] ESI-MS (m / z): 557.3 [M+H] +

[0216] Step 3:

[0217] 6-2 (60 mg, 0.11 mmol) was placed in a 40 mL single-mouth bottle, MeOH (2 mL) and DIEA (28 mg, 0.22 mmol, 2.0 eq) were added, and paraformaldehyde (20 mg) and sodium cyanoborohydride (14 mg, 0.22 mmol, 2.0 eq) were added, and the reaction solution was stirred at 25° C. for 16 h. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure and purified by high performance liquid chromatography to obtain Example 6 (13.09 mg, 0.03 mmol, 24.3%) as a white solid.

[0218] ESI-MS (m / z): 475.3 [M+H] +

[0219] 1H NMR (400MHz, CD3OD) δ8.80(d,J=4.83Hz,1H),8.75(s,1H),8.58(s,1H),8.33(s,1H),8.11(d,J=8.41H z,1H),7.54(dd,J=8.41,4.82Hz,1H),7.20(s,1H),3.56(d,J=5.94Hz,2H),2.96-3.13(m,6H),2.90(br d,J=9.16Hz,4H),2.74-2.83(m,2H),2.70(s,3H),1.80-1.90(m,6H),1.60-1.79(m,3H).

[0220] Embodiment 7:

[0221]

[0222] Step 1:

[0223] 7-1 (5.14 g, 30.00 mmol), 7-2 (3.85 g, 30.00 mmol), p-toluenesulfonic acid (0.86 g, 4.50 mmol) were placed in a 100 mL single-mouth bottle, toluene (80 mL) was added, a water separator was added, the temperature was raised to an external temperature of 135 ° C, and the mixture was refluxed for 20 h. After concentration under reduced pressure, water (40 mL) was added to the residue, and the mixture was extracted with EA (80 mL × 2), and the organic phases were combined and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the mixture was separated by column chromatography, and the eluent was PE: EA = 100: 0 to 92: 8, to obtain 7-3, 5.05 g of white crystalline solid, with a yield of 59.8%. ESI-MS (m / z): 282.1 [M+H] + .

[0224] 1 H NMR(500MHz, CDCl3) δ6.67(dd,J=8.5,4.5Hz,1H),6.56(dd,J=8.2,2.4Hz,1H),6.50(td,J=9.6,2 .5Hz,1H),4.19(q,J=7.1Hz,2H),3.77–3.61(m,4H),2.00(t,J=5.4Hz,4H),1.30(t,J=7.1Hz,3H).

[0225] Step 2:

[0226] 7-3 (4.57 g, 16.25 mmol) was placed in a 100 mL single-mouth bottle, ethanol (64 mL) was added, ice-cooled, and a solution of NaOH (2.60 g, 64.99 mmol) in water (8 mL) was slowly added. After the addition was complete, the temperature was raised to 80 °C and the reaction was refluxed overnight. The mixture was concentrated under reduced pressure, and DCM (100 mL) and water (40 mL) were added to the residue. After sufficient stirring, the mixture was allowed to stand for separation. The upper aqueous phase was extracted once with DCM (50 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure to obtain 7-4, an off-white solid of 3.38 g, with a yield of 99.5%. ESI-MS (m / z): 210.0 [M+H] + .

[0227] 1 H NMR (500MHz, CDCl3) δ6.66 (dd, J=8.5, 4.5Hz, 1H), 6.55 (dd, J=8.3, 2.5Hz, 1H), 6.48(td,J=9.6,2.5Hz,1H),3.12–3.04(m,4H),2.07(s,2H),2.04–1.98(m,4H).

[0228] Step 3:

[0229] Place 7-4 (3.00 g, 14.34 mmol) in a 100 mL single-mouth bottle, add DCM (30 mL), cool in an ice bath, slowly drop fuming nitric acid (3 mL), and keep in an ice bath for 2 h. After the reaction is complete, concentrate under reduced pressure to remove DCM, then heat to a water bath temperature of 60 ° C and continue to concentrate to remove excess fuming nitric acid. After concentration, 7-5 is obtained as a yellow solid, which is directly used in the next step. ESI-MS (m / z): 255.1 [M+H] + .

[0230] Step 4:

[0231] The yellow solid 7-5 obtained in step 3 was placed in a 100mL single-mouth bottle, DCM (50mL) was added and mixed, cooled in an ice bath, di-tert-butyl dicarbonate (4.69g, 21.51mmol) was added, triethylamine (4.35mg, 43.01mmol) was slowly added dropwise, and the temperature was naturally raised to react overnight after the addition was completed. Water (30mL) was added to the reaction solution, and after sufficient extraction, the liquid was allowed to stand and separate. The upper aqueous phase was extracted once with DCM (30mL), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. Column chromatography separation, PE: EA = 100: 0 ~ 85: 15, 7-6 off-white solid 4.59g, yield: 85.3%.

[0232] ESI-MS (m / z): 299.0 [M-55] + .

[0233] 1 H NMR (500MHz, CDCl3) δ7.50 (d, J = 6.4Hz, 1H), 6.70 (d, J = 10.3Hz, 1H), 3.73–3.59 (m, 4H), 2.03 (t, J = 5.6Hz, 4H), 1.51 (s, 9H).

[0234] Step 5:

[0235] 7-6 (354 mg, 1.00 mmol) was placed in a 50 mL single-mouth bottle, potassium carbonate (414 mg, 3.00 mmol), 4-hydroxymethylpiperidine (230 mg, 2.00 mmol), and acetonitrile (10 mL) were added in sequence, and the mixture was heated to an external temperature of 60°C for 1 h. Saturated brine (15 mL) was added to the reaction solution, and the mixture was extracted with EA (30 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography. The eluent was PE:EA=100:0-50:50, and 449 mg of 7-7 orange-yellow solid was obtained. The yield was 100%.

[0236] ESI-MS (m / z): 450.2 [M+H] + .

[0237] 1 H NMR (500MHz, CDCl3) δ7.41(s,1H),6.69(s,1H),3.68-3.62(m,4H),3.59(d,J=6.3Hz,2H),3.27(d,J=11.6Hz,2H),2.83(t,J =11.4Hz,2H),2.00(t,J=5.3Hz,4H),1.84(d,J=12.4Hz,2H),1.72-1.64(m,2H),1.55(td,J=12.2,2.8Hz,2H),1.51(s,9H).

[0238] Step 6:

[0239] 7-7 (440 mg, 0.98 mmol) was placed in a 50 mL single-mouth bottle, methanol (10 mL) was added, and then 10% palladium carbon (100 mg) was added. The hydrogen balloon was replaced three times and then kept the hydrogen balloon, and the reaction was heated to an external temperature of 35°C for 2 hours until the yellow color completely faded. The reaction solution was filtered through diatomaceous earth, and the filter residue was washed with methanol until the filtrate was colorless. The filtrates were combined and concentrated under reduced pressure to obtain 400 mg of gray-dark green foamy solid 7-8 with a yield of 97.4%, which was directly used for the next step reaction.

[0240] ESI-MS (m / z): 420.3 [M+H] + .

[0241] Step 7:

[0242] 7-8 (420 mg, 1.00 mmol), furano[3,2-b]pyridine-3-carboxylic acid (320 mg, 1.00 mmol), HATU (419 mg, 1.10 mmol), DIEA (388 mg, 3.00 mmol) were placed in a 25 mL single-mouth bottle, DMF (4 mL) was added, and the mixture was stirred at room temperature for 3 h. DCM (60 mL) and water (25 mL) were added to the reaction solution, and the mixture was allowed to stand for separation after sufficient stirring. The DCM phase was washed with saturated sodium chloride (20 mL × 3), and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography. The eluent was PE:EA = 100:0 to 60:40 to obtain 7-9 as a light yellow solid (427 mg). The two-step yield was 75.6%.

[0243] ESI-MS (m / z): 565.3 [M+H] + .

[0244] 1 H NMR (500MHz, CDCl3) δ11.12(s,1H),8.72(d,J=4.6Hz,1H),8.63(s,1H),8.12(s,1H),7.90(d,J=8.3Hz,1H),7.38(dd,J=8.3,4.8Hz,1H),6.83 (s,1H),3.70-3.60(m,6H),3.14(d,J=10.5Hz,2H),2.84-2.71(m,2H), 2.05-1.95(m,4H),1.90–1.75(m,4H),1.76–1.63(m,2H),1.51(s,9H).

[0245] Step 8:

[0246] 7-9 (420 mg, 0.74 mmol) was placed in a 50 mL single-mouth bottle, DCM (10 mL) was added to dissolve, 4 M hydrochloric acid dioxane solution (2 mL) was slowly added, and the mixture was stirred at room temperature for 2 h. The reaction solution was directly spin-dried to obtain 7-10 as an off-white solid (520 mg), which was directly used in the next step.

[0247] ESI-MS (m / z): 465.2 [M+H] + .

[0248] Step 9:

[0249] In a 50mL single-mouth bottle, KOAc (129mg, 1.32mmol), 7-10 (152.90mg, 0.33mmol), 37% formaldehyde aqueous solution (0.5mL, 2.28mmol) were mixed in anhydrous DMF (3mL), and stirred at room temperature for 30min. Sodium triacetoxyborohydride (347mg, 1.65mmol) was added, and the reaction was continued overnight with stirring at room temperature. The reaction solution was directly sent to the preparative separation and purification, and freeze-dried to obtain Example 7, 101mg of off-white solid, yield: 64.1%, purity: 99.82%.

[0250] ESI-MS (m / z): 479.3 [M+H] + .

[0251] 1 H NMR (500 MHz, CDCl3) δ 11.04 (s, 1H), 8.62 (d, J = 4.2 Hz, 1H), 8.50 (s, 1H), 8.11 (s, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.27 (dd, J = 8.3, 4.8 Hz, 1H), 6.67 (s, 1H), 3.56 (d, J = 5.7 Hz, 2H), 2.97 (d, J = 11.3 Hz, 2H), 2.67-2.52 (m, 6H), 2.32 (s, 3H), 2.03 (t, J = 5.1 Hz, 6H), 1.78-1.53 ​​(m, 6H)., Example 8:

[0252]

[0253] Step 1:

[0254] Weigh 2,4-difluorobenzyl bromide (14.51g, 70.09mmol) and dissolve it in ether (70mL), and transfer it to a 250mL dropping funnel. Place magnesium chips (4.26g, 175.23mmol) in a 500mL three-necked flask, add iodine (0.30g, 1.17mmol), add ether (100mL) to the flask, replace nitrogen 3 times, transfer to a 35℃ oil bath, and drop 2,4-difluorobenzyl bromide in ether solution into the three-necked flask. After the addition is complete, keep warm and stir for 1h to obtain a gray turbid Grignard reagent. Transfer it to an external temperature of -78℃ to cool down, and at the same time, dissolve 1-Boc-3-azetidinone (10g, 58.41mmol) in ether (100mL), slowly drop it into the Grignard reagent, and after the addition is complete, transfer it to room temperature and stir for 1.5h. Water (300 mL) was added to the reaction system, the solution gradually became clear, the organic phase was retained after separation, sufficient 1N HCl solution was added to the aqueous phase until the pH of the system was 7.0, the aqueous phase was extracted with EA (200 mL × 2), the organic phases were combined after separation, and dried over anhydrous sodium sulfate to obtain compound 8-1, 17.0 g of orange oily liquid, yield: 97.3%.

[0255] ESI-MS (m / z): 200.2 [M-100+H] +

[0256] Step 2:

[0257] Anhydrous THF (32 mL) and potassium tert-butoxide (4.51 g, 40.17 mmol) were placed in a 100 mL two-necked flask, nitrogen was replaced, 8-1 (4.81 g, 16.07 mmol) was added dropwise to the reaction system under ice bath, and after the addition was completed, the reaction was allowed to proceed overnight at 0°C. Saturated ammonium chloride solution (60 mL) was added under ice bath, and EA (100 mL) was added. After extraction and separation, the organic phase was retained, and the aqueous phase was extracted with EA (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and separated by column chromatography. PE:EA=98:2-85:15, and compound 8-2 was obtained as a yellow transparent oily liquid (211 mg), with a yield of 4.7%.

[0258] ESI-MS (m / z): 224.1 [M-55+H] +

[0259] 1 H NMR (500MHz, CDCl3) δ7.21–7.15(m,2H),7.05(td,J=8.7,2.0Hz,1H),5.09(s,2H),4.33(d,J=9.6Hz,2H),4.14(d,J=9.7Hz,2H),1.50(s,9H).

[0260] Step 3:

[0261] 8-2 (21 mg, 0.08 mmol) was mixed in DCM (1 mL), and TFA (53 mg, 0.47 mmol) was added under stirring at room temperature, and the mixture was stirred at room temperature after the addition was complete. The solvent and TFA were removed by distillation under reduced pressure at 65°C to obtain compound 8-3 as a colorless transparent oil (14 mg).

[0262] ESI-MS (m / z): 180.1 [M+H] +

[0263] 1 H NMR(500MHz, CDCl3)δ7.52(dd,J=8.3,1.8Hz,1H),7.18–7.09(m,1H),7.03(td,J=8.7, 2.1Hz,1H),5.06(s,2H),4.27(d,J=10.1Hz,2H),4.07(s,1H),3.97(d,J=10.1Hz,2H).

[0264] Step 4:

[0265] 8-3 (10 mg, 0.08 mmol) was placed in a 25 mL single-mouth bottle, DCM (1.5 mL) was added to dissolve, ice-cooled, fuming nitric acid (0.05 mL) was slowly added dropwise, and the mixture was stirred in an ice bath for 10 min. After the raw material disappeared, the reaction solution was distilled under reduced pressure to remove the solvent to obtain a dark gray oily substance. The gray oily substance was placed in a 100 mL single-mouth bottle, ice-cooled, di-tert-butyl dicarbonate (26 mg, 0.12 mmol) was added, triethylamine (24 mg, 0.24 mmol) was slowly added dropwise, and the mixture was stirred in an ice bath for 10 min, and then stirred at room temperature for 1 h. Saturated ammonium chloride solution (15 mL) was added to the reaction solution, and DCM (15 mL) was added for extraction. After separation, the organic phase was retained, dried over anhydrous sodium sulfate, and purified by column chromatography. PE:EA=100:0-80:20 to obtain compound 8-4, a light yellow oily liquid of 17 mg, with a yield of 65.6%. ESI-MS (m / z): 269.1 [M-55+H] +

[0266] 1 H NMR (500MHz, CDCl3) δ7.84(d,J=6.2Hz,1H),7.34(d,J=9.7Hz,1H),5.06(s,2H),4.28(d,J=9.7Hz,2H),4.04(d,J=9.7Hz,2H),1.41(s,9H).

[0267] Step 5:

[0268] 8-4 (267 mg, 0.82 mmol) was placed in a 250 mL single-mouth bottle, and 4-hydroxymethylpiperidine (190 mg, 1.65 mmol), potassium carbonate (285 mg, 2.06 mmol), and acetonitrile (7 mL) were added respectively, and heated to an external temperature of 60°C for 4 hours. The reaction solution was purified by column chromatography, and the eluent was: DCM:EA = 100:0 to 90:10, to obtain compound 8-5, a yellow solid of 187 mg, with a yield of 54.0%.

[0269] ESI-MS (m / z): 420.2 [M+H] +

[0270] 1 H NMR (500MHz, CDCl3) δ7.60(s,1H),7.22(s,1H),5.08(s,2H),4.34(d,J=9.6Hz,2H),4.14(d,J=9.6Hz,2H),3.60(d,J=6.4Hz,2 H),3.33(d,J=11.9Hz,2H),2.89(t,J=11.4Hz,2H),1.87(d,J=12.6Hz,2H),1.77–1.64(m,2H),1.52(s,9H),1.49–1.44(m,2H).

[0271] Step 6:

[0272] 8-5 (323 mg, 0.77 mmol) was placed in a 100 mL single-mouth bottle, methanol (13 mL) was added, and then 10% palladium carbon (94 mg) was added. After hydrogen replacement three times, a hydrogen balloon was maintained and the mixture was heated to an external temperature of 35°C for 4 hours. The palladium carbon was removed by filtration through diatomaceous earth, and the diatomaceous earth was washed with methanol until no product remained. Compound 8-6 was obtained by vacuum distillation as a light gray solid of 295.1 mg, with a yield of 98.4%.

[0273] ESI-MS (m / z): 390.3 [M+H] +

[0274] 1 H NMR (500MHz, CDCl3) δ6.99(s,1H),6.47(s,1H),4.92(s,2H),4.19(d,J=9.4Hz,2H),4.06–3.94(m,3H),3.52(d,J=6.2Hz,2H) ,3.09(d,J=11.5Hz,2H),2.59(t,J=11.5Hz,2H),1.81(d,J=12.6Hz,2H),1.64–1.57(m,2H),1.41(s,9H),1.39–1.28(m,3H).

[0275] Step 7:

[0276] 8-6 (282 mg, 0.72 mmol), furano[3,2-b]pyridine-3-carboxylic acid (44 mg, 0.23 mmol), HATU (357 mg, 0.94 mmol), DIEA (467 mg, 3.62 mmol) were placed in a 25 mL single-mouth bottle, DCM (5 mL) was added, and the mixture was stirred at 25 °C for overnight reaction. DCM (10 mL) was added to the reaction solution, and the mixture was washed with saturated ammonium chloride solution (10 mL × 2) and dried over anhydrous sodium sulfate. Column chromatography was used to purify DCM: MeOH = 100: 0 to 98: 2 to obtain compound 8-7 as an orange solid (217 mg) with a yield of 56.1%.

[0277] ESI-MS (m / z): 535.3 [M+H] +

[0278] 1 H NMR (500MHz, CDCl3) δ11.22(s,1H),8.74(d,J=4.5Hz,1H),8.62(s,1H),8.54(s,1H),7.91(d,J=8.4Hz,1H),7.40(dd,J=8.5,4.9Hz ,1H),7.33(s,1H),5.13(s,2H),4.35(d,J=9.4Hz,2H),3.76–3.71(m,2H),3.69(d,J=5.6Hz,2H),2.01–1.69(m,10H),1.53(s,9H).

[0279] Step 8:

[0280] 8-7 (217 mg, 0.41 mmol) was placed in a 100 mL single-mouth bottle, DCM (7 mL) was added to dissolve, and dioxane hydrochloride solution (2.0 mL) was slowly added, and the mixture was stirred under ice bath for 1 h. The reaction solution was distilled under reduced pressure at 48 ° C to remove the solvent to obtain compound 8-8, 247 mg of dark orange solid.

[0281] ESI-MS (m / z): 435.2 [M+H] +

[0282] Step 9:

[0283] In a 25 mL single-mouth bottle, KOAc (45 mg, 0.46 mmol), 8-8 (70 mg, 0.12 mmol), 37% formaldehyde aqueous solution (11 mg, 0.14 mmol) were mixed in anhydrous DMF (1 mL), stirred at room temperature for 45 min, then sodium triacetoxyborohydride (121 mg, 0.58 mmol) was added, and the reaction was continued at room temperature for 1 h. DCM (10 mL) was added to the reaction solution, saturated brine (15 mL × 2) was added for washing, dried over anhydrous sodium sulfate, and purified by column chromatography, the eluent was: DCM: MeOH = 100: 0-90: 10, and the crude product was purified by preparative liquid chromatography to obtain Example 8, an off-white solid 23 mg, yield: 44.6%.

[0284] ESI-MS (m / z): 449.2 [M+H] +

[0285] 1 H NMR (500MHz, CDCl3) δ11.20 (s, 1H), 8.67 (d, J = 3.9Hz, 1H), 8.52 (s, 1H), 8.47 ( s,1H),8.18(s,1H),7.82(d,J=8.3Hz,1H),7.32(dd,J=8.3,4.8Hz,1H),5.07( s,3H),4.83(dd,J=11.9,6.6Hz,2H),4.05–3.96(m,2H),3.58(d,J=3.8Hz,2H) ,3.15–2.82(m,6H),1.99–1.88(m,1H),1.84–1.64(m,4H),1.40–1.34(m,1H).

[0286] Embodiment 9:

[0287]

[0288] The synthesis of compound 9-1 refers to patent WO2019183367 A1 intermediate FI step D.

[0289] Step 1:

[0290] 9-1 (0.76 g, 2.49 mmol) and DCM (6 mL) were placed in a 50 mL single-necked bottle, TFA (1 mL) was added dropwise, and the mixture was stirred at 25°C for 1 h. The mixture was concentrated under reduced pressure to obtain intermediate 9-2 as a light yellow solid (1.0 g).

[0291] ESI-MS (m / z): 222.0 [M+H] + .

[0292] Step 2:

[0293] 9-2 (1.0 g, 2.49 mmol) was placed in a 50 mL single-mouth bottle, DCM (12.5 mL) was added to dissolve, ice-cooled, fuming nitric acid (25 mL) was added dropwise, and stirred at 0°C for 10 min, and stirred at room temperature for 1 h. After nitration was completed, it was concentrated under reduced pressure, DCM (8 mL) was added to dissolve, cooled to 0°C, di-tert-butyl dicarbonate (0.81 g, 3.72 mmol) was added, triethylamine (0.75 g, 7.44 mmol) was added dropwise, and stirred at 0°C for 10 min, and then stirred at room temperature for 2 h. At 0°C, saturated ammonium chloride solution (10 mL) and saturated sodium chloride solution (10 mL) were slowly added, and extracted with EA (10 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography, the eluent was: PE: EA = 100: 0 ~ 85: 15, and intermediate 9-3 was obtained as a white solid 0.4 g, yield: 44.0%.

[0294] ESI-MS (m / z-100): 367.0 [M+H] + .

[0295] 1 H NMR (500MHz, CDCl3) δ8.52 (d, J = 7.7Hz, 1H), 7.04 (d, J = 10.6Hz, 1H), 4.15 (d, J = 7. 2Hz,2H),3.26(s,2H),2.97(s,1H),2.90(s,1H),2.03–1.97(m,2H),1.51(s,9H).

[0296] Step 3:

[0297] 9-3 (400 mg, 1.09 mmol), 4-(hydroxymethyl)piperidine (252 mg, 2.18 mmol), potassium carbonate (377 mg, 2.73 mmol), and acetonitrile (4 mL) were placed in a 10 mL single-mouth bottle and stirred at an external temperature of 60°C for 16 hours. The mixture was concentrated under reduced pressure and purified by column chromatography with an eluent of PE:EA=100:0-60:40 to obtain intermediate 9-4 as a yellow solid (300 mg) with a yield of 59.5%.

[0298] ESI-MS (m / z): 462.2 [M+H] + .

[0299] 1H NMR (500MHz, CDCl3) δ8.21(s,1H),6.60(s,1H),4.15(s,2H),3.60(d,J=6.2Hz,2H),3.47(d,J=12.8Hz,2H),3.22(s,2H) ,3.05(t,J=11.8Hz,2H),2.00–1.94(m,2H),1.88(d,J=12.8Hz,2H),1.84–1.76(m,1H),1.64–1.58(m,4H),1.51(s,9H).

[0300] Step 4:

[0301] 9-4 (2700 mg, 5.85 mmol), Pd / C (600 mg) and methanol (100 mL) were placed in a 250 mL single-mouth bottle, hydrogen was replaced, and stirred at room temperature for 5 hours. Filtered and concentrated under reduced pressure to obtain intermediate 9-5 as a white solid (2524 mg), yield: 100%.

[0302] ESI-MS (m / z): 432.3 [M+H] + .

[0303] Step 5:

[0304] 9-5 (1400 mg, 3.24 mmol), furano[3,2-b]pyridine-3-carboxylic acid (530 mg, 3.24 mmol), HATU (1850 mg, 4.87 mmol), TEA (1310 mg, 12.98 mmol) and DMF (20 mL) were placed in a 50 mL single-mouth bottle and stirred at room temperature for 16 hours. Saturated sodium chloride solution (120 mL) was added, extracted with EA (120 mL × 3), concentrated under reduced pressure, and purified by column chromatography with an eluent of PE:EA = 100:0 to 50:50 to obtain intermediate 9-6 as a yellow solid 900 mg, yield: 48%.

[0305] ESI-MS (m / z): 577.2 [M+H] + .

[0306] 1H NMR (500MHz, CDCl3) δ10.59(s,1H),8.59(s,1H),8.55(d,J=4.7Hz,1H),8.50(s,1H),7.78(d,J =8.4Hz,1H),7.26(dd,J=8.3,4.8Hz,1H),6.74(s,1H),4.10–3.99(m,2H),3.48(d,J=5.0Hz,2H) ,3.25(d,J=11.6Hz,2H),3.10–3.04(m,2H),2.63(t,J=10.8Hz,2H),1.89–1.86(m,1H),1.83(d d,J=12.9,4.1Hz,2H),1.71(d,J=10.0Hz,2H),1.60(d,J=7.4Hz,2H),1.48(s,2H),1.38(s,9H).

[0307] Step 6:

[0308] 9-6 (970 mg, 1.68 mmol) and dichloromethane (16 mL) were placed in a 25 mL single-necked bottle, HCl / 1,4-dioxane (2 mL, 1 mol / L) was added dropwise, and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain intermediate 9-7 as a yellow solid (980 mg).

[0309] ESI-MS (m / z): 477.2 [M+H] + .

[0310] Step 7:

[0311] 9-7 (100 mg, 0.15 mmol), formaldehyde (1 mL, 37%), palladium acetate (60 mg, 0.61 mmol) and DMF (3 mL) were placed in a 50 mL two-necked bottle, nitrogen was replaced, sodium triacetoxyborohydride (161 mg, 0.84 mmol) was added, and stirred at room temperature for 3 h. After the reaction was completed, saturated sodium chloride solution (20 mL) was added, extracted with EA (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography, the eluent was: PE: EA = 100: 0 ~ 10: 1, and Example 9 was obtained as a yellow solid 20 mg, yield: 26.6%.

[0312] ESI-MS (m / z): 491.2 [M+H] + .

[0313] 1H NMR(500MHz,DMSO-d6)δ10.78(s,1H),9.05(s,1H),8.75(d,J=4.6Hz,1H),8.57(s,1H),8.28 (d,J=8.4Hz,1H),7.59(dd,J=8.4,4.8Hz,1H),7.12(s,1H),4.51(t,J=5.0Hz,1H),3.35(d,J =5.0 Hz, 2H), 3.21 (d, J = 11.6 Hz, 2H), 2.83 (d, J = 8.3 Hz, 2H), 2.73 (t, J = 11.0 Hz, 2H), 2.28 (s, 3H), 1.91-1.85 (m, 2H), 1.74 (d, J = 10.8 Hz, 2H), 1.62-1.56 (m, 4H), 1.27-1.21 (m, 2H). Example 10:

[0314]

[0315] The synthesis process of compound 10-1 refers to step E of Example 152 of WO2017108723A2.

[0316] Step 1:

[0317] 10-1 (120 mg, 0.45 mmol) was placed in a 50 mL single-mouth bottle, potassium carbonate (186 mg, 1.35 mmol), 2-oxa-6-aza-spiro[3,3]heptane (44 mg, 0.45 mmol), and acetonitrile (3 mL) were added, and the mixture was heated to an external temperature of 60°C for 2 h. The filtrate was filtered to obtain a filtrate, and the residue was dissolved in water (15 mL), and EA (30 mL) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and separated by column chromatography. The eluent was DCM:MeOH=100:0-95:5, and compound 10-2 was obtained as an orange-yellow solid of 151 mg. The yield was 97.0%. ESI-MS (m / z): 346.1 [M+H] + .

[0318] 1 H NMR(500MHz, CDCl3)δ7.69(s,1H),5.87(s,1H),4.74(s,4H),4.04(s,4H),2 .85(s,2H),2.50(s,4H),2.29(s,3H),1.95–1.86(m,2H),1.85–1.76(m,2H).

[0319] Step 2:

[0320] 10-2 (151 mg, 0.38 mmol) was placed in a 100 mL single-mouth bottle, methanol (6.3 mL) was added, and then 10% palladium carbon (46 mg) was added. The hydrogen balloon was replaced three times and then kept in a hydrogen balloon. The mixture was heated to an external temperature of 35°C and reacted for 2 h. The palladium carbon was removed by filtering with filter paper, and the filter residue was washed with methanol until no product remained. The compound 10-3 was obtained as a dark green solid of 128 mg, with a yield of 98.2%. ESI-MS (m / z): 316.2 [M+H] + .

[0321] 1 H NMR(500MHz, CDCl3)δ6.48(s,1H),6.10(s,1H),4.80(s,4H),3.92(s,4H), 3.46(s,2H),2.88(s,3H),2.75(s,3H),2.46(s,3H),1.97(d,J=4.6Hz,4H).

[0322] Step 3:

[0323] 10-3, furan[3,2-b]pyridine-3-carboxylic acid (127 mg, 0.40 mmol), N-methylimidazole (103 mg, 1.26 mmol), TCFH (121 mg, 0.43 mmol) were placed in a 100 mL single-mouth bottle, acetonitrile (7 mL) was added, and the mixture was stirred at room temperature for 1 h. Most of the acetonitrile was removed by concentration under reduced pressure, EA (15 mL) was added to the residue, and the mixture was washed with saturated ammonium chloride solution (15 mL). After separation, saturated brine (15 mL) was added to the organic phase for washing, the organic phase was retained, dried over anhydrous sodium sulfate, and purified by column chromatography, the eluent being: DCM:MeOH=100:0-95:5, and then purified by preparative liquid chromatography to obtain Example 10, 140 mg of a light gray solid, with a yield of 84.1%.

[0324] ESI-MS (m / z): 461.2 [M+H] + .

[0325] 1 H NMR (500MHz, CDCl3) δ9.86 (s, 1H), 8.66 (d, J = 4.2Hz, 1H), 8.62 (s, 1H), 7.94 (d, J = 8.4Hz, 1H), 7.54 (s, 1H), 7.41 (dd, J = 8.4, 4. 8Hz,1H),6.15(s,1H),4.77(s,4H),4.05(s,4H),2.98(s,2H),2.65(s,4H),2.40(s,3H),2.02(d,J=13.1Hz,2H),1.91(s,2H).

[0326] Embodiment 11:

[0327]

[0328] Step 1:

[0329] M4 (1.10 g, 3.12 mmol) was placed in a 25 mL single-mouth bottle, potassium carbonate (1.29 g, 9.37 mmol), 2-(4-piperidinyl)-2-propanol (0.45 g, 3.12 mmol), and acetonitrile (10 mL) were added respectively, and the mixture was heated to an external temperature of 60°C for 3 h. The reaction solution was filtered to obtain a filtrate, the residue was dissolved in water (15 mL), and then extracted with EA (30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and separated by column chromatography, with the eluent being: DCM:MeOH=100:0-95:5. Compound 11-1 was obtained, 1 g of orange-yellow liquid, with a yield of 67.5%.

[0330] ESI-MS (m / z): 476.2 [M+H] + .

[0331] 1 H NMR (500MHz, CDCl3) δ7.82 (s, 1H), 6.48 (s, 1H), 3.76 (d, J = 11.4Hz, 2H), 3.37 (dd, J = 29.9, 11.4Hz, 4H), 2.95 (s, 2H), 2.76 (t, J = 11.6Hz, 2H),1.90(d,J=13.5Hz,2H),1.82(d,J=12.3Hz,2H),1.77–1.66(m,2H),1.65–1.60(m,2H),1.48(s,9H),1.44–1.39(m,1H),1.22(s,6H).

[0332] Step 2:

[0333] 11-1 (1000.00 mg, 2.10 mmol) was placed in a 100 mL single-mouth bottle, methanol (30 mL) was added, and then 10% palladium carbon (219 mg) was added. The hydrogen gas was replaced three times with a hydrogen balloon and the hydrogen balloon was maintained. The mixture was heated to an external temperature of 35°C and reacted for 2 h. The palladium carbon was removed by filtering with filter paper, and the filter residue was washed with methanol until no product remained. The mixture was concentrated under reduced pressure to obtain compound 11-2 as a dark green solid of 1.0 g.

[0334] ESI-MS (m / z): 446.4 [M+H] + .

[0335] 1H NMR (500MHz, CDCl3) δ6.60(s,1H),6.53(s,1H),3.72(s,2H),3.43(t,J=10.6Hz,2H),3.20(d,J=11.5Hz,2H),2.91(s,2H ),2.55(t,J=11.3Hz,2H),1.88(t,J=12.3Hz,4H),1.74–1.62(m,5H),1.49(s,9H),1.44(d,J=12.0Hz,1H),1.25(s,6H).

[0336] Step 3:

[0337] 11-2 (400 mg, 0.90 mmol), furan [3,2-b] pyridine-3-carboxylic acid (163 mg, 0.99 mmol), N-methylimidazole (257 mg, 3.14 mmol), TCFH (302 mg, 1.08 mmol) were placed in a 100 mL single-mouth bottle, acetonitrile (20 mL) was added, and the mixture was stirred at room temperature for reaction. Most of the acetonitrile was removed by concentration under reduced pressure, EA (10 mL) was added to the residue, and the residue was washed with saturated ammonium chloride solution (10 mL), and then with saturated brine (10 mL). The organic phase was retained, dried over anhydrous sodium sulfate, and purified by column chromatography. The eluent was PE: EA = 90:10 to 50:50 to obtain compound 11-3, 570 mg of a light yellow solid, with a yield of 74.5%.

[0338] ESI-MS (m / z): 591.3 [M+H] + .

[0339] 1 H NMR (500MHz, CDCl3) δ10.81 (s, 1H), 8.70 (d, J = 4.0Hz, 1H), 8.55 (s, 1H), 8.28 (s, 1H), 7.83(d,J=8.2Hz,1H),7.30(dd,J=8.3,4.8Hz,1H),6.65(s,1H),3.69(s,2H),3.40(t ,J=10.6Hz,2H),3.17(d,J=10.9Hz,2H),2.98(s,2H),2.63(t,J=10.0Hz,2H),1.88(d ,J=13.2Hz,2H),1.83–1.64(m,6H),1.45(s,9H),1.38(d,J=10.7Hz,1H),1.20(s,6H).

[0340] Step 4:

[0341] Place 11-3 (80 mg, 0.14 mmol) in a 50 mL single-mouth bottle, add DCM (5 mL) to dissolve, slowly add 4.0 M hydrochloric acid dioxane solution (0.7 mL), and stir the reaction at room temperature. Concentrate under reduced pressure to obtain compound 11-4, 103 mg of off-white solid. ESI-MS (m / z): 491.2 [M+H] + .

[0342] Step 5:

[0343] In a 25 mL single-mouth bottle, KOAc (54 mg, 0.56 mmol), 11-4 (68 mg, 0.14 mmol), 37% formaldehyde aqueous solution (13 mg, 0.17 mmol) were mixed in DMF (1 mL), stirred at room temperature for 1 h, sodium triacetoxyborohydride (147.65 mg, 0.70 mmol) was added, and the reaction was continued at room temperature for 2 h. DCM (15 mL) was added to the reaction solution, and saturated ammonium chloride solution (15 mL) was added for washing. After separation, saturated brine (15 mL×3) was added to the organic phase for washing, dried over anhydrous sodium sulfate, and separated by column chromatography. The eluent was: DCM:MeOH=100:0-94:6. Example 11 was obtained as an off-white solid of 26 mg, with a yield of 36.8%.

[0344] ESI-MS (m / z): 505.3 [M+H] + .

[0345] 1 H NMR (500MHz, CDCl3) δ10.86 (s, 1H), 8.75 (d, J = 4.1Hz, 1H), 8.60 (s, 1H), 8.34 ( s,1H),7.88(d,J=8.3Hz,1H),7.35(dd,J=8.3,4.8Hz,1H),6.69(s,1H),3.72(s ,2H),3.20(d,J=11.2Hz,2H),3.04(s,2H),2.69–2.59(m,4H),2.42(s,3H),2.0 3(s,2H),1.94(s,2H),1.80(d,J=11.5Hz,4H),1.45–1.39(m,1H),1.25(s,6H).

[0346] Comparative Example 1

[0347]

[0348] For the synthesis process, see Example 371 of WO2017108723A2.

[0349] ESI-MS (m / z): 477.2 [M+H]+ .

[0350] 1 H NMR (400MHz, CDCl3) δ10.51 (s, 1H), 8.88-8.75 (m, 3H), 8.43 (s, 1H), 7.02 (dd, J = 7.0, 4.3Hz, 1H), 6.69 (s, 1H), 3.71-3.56 (m,2H),3.10(d,J=11.4Hz,2H),3.01(s,2H),2.76–2.42(m,6H),2.34(s,3H),2.00(d,J=13.2Hz,3H),1.90-1.67(m,6H),.

[0351] Comparative Example 2

[0352]

[0353] For the synthesis process, see Example 152 of WO2017108723A2.

[0354] ESI-MS (m / z): 449.3 [M+H] + .

[0355] 1 H NMR (400MHz, CDCl3) δ10.46(s,1H),8.83(dd,J=1.6,6.8Hz,1H),8.78(s,1H),8.77(dd,J=1.6,4.4Hz,1H),8.43(s,1H),7.06(dd,J=4.4,7.2H z,1H),6.69(s,1H),3.99-3.91(m,4H),3.02(s,2H),2.94-2.88(m,4H) ,2.66-2.44(m,4H),2.35(s,3H),2.05-1.95(m,2H),1.89-1.79(m,2H).

[0356] Comparative Example 3

[0357]

[0358] For the synthesis process, see Example 146 of WO2017108723A2.

[0359] ESI-MS (m / z): 421.3 [M+H] + .

[0360] 1H NMR (400MHz, DMSO-d6): δ10.46 (s, 1H), 9.37 (dd, J=1.6, 6.8Hz, 1H), 8.95 (dd, J=1.6, 4.0Hz, 1H), 8.68 (s, 1H), 8.34 (s, 1H), 7.35 ( dd,J=4.0,6.8Hz,1H),6.80(s,1H),3.84(t,J=8.8Hz,4H),3.46-3.42(m,4H),3.27-3.25(m,2H),2.86-2.76(m,4H),2.31(s,3H).

[0361] Comparative Example 4

[0362]

[0363] For the synthesis process, see Example 390 of WO2017108723A2.

[0364] ESI-MS (m / z): 435.3 [M+H] + .

[0365] 1 H NMR (400MHz, CDCl3) δ10.48 (s, 1H), 8.84 (dd, J = 7.0, 1.7Hz, 1H), 8.79-8.72 (m, 2H) ,8.45(s,1H),7.07(dd,J=7.0,4.1Hz,1H),6.69(s,1H),4.01-3.90(m,4H),3.34-3. 20(m,2H),3.09(d,J=10.6Hz,1H),3.02(q,J=8.0Hz,1H),2.91(t,J=4.5Hz,4H),2. 77(s,2H),2.51(s,3H),2.41(dt,J=13.3,6.5Hz,1H),2.13(dt,J=14.0,7.7Hz,1H).

[0366] Experimental Example 1 IRAK4 kinase activity inhibition experiment

[0367] IRAK4 kinase (purchased from Signalchem, catalog number: I12-10G-10) was diluted with reaction buffer to a final concentration of 5 nM and added to a 384-well plate at 2 μL / well. The test compound was diluted 5-fold from 10 μM, 10 concentration points were set, and 20 nL / well were added to the experimental wells of the 384-well plate. After incubation at 25°C for 10 minutes, 180 μM ATP and 0.1 μg / μL enzyme reaction substrate myelin basic protein MBP (myelin basic protein) (purchased from SignalChem, catalog number: M42-51N) were added at 2 μL / well and reacted at 25°C for 60 minutes. After the reaction, the kinase activity was detected using the ADP-GloTM kinase detection kit (purchased from PRomega, catalog number: V9101) according to the instructions. First, 4 μL of ADP-Glo ​​reaction reagent was added, reacted at 25°C for 40 minutes, and then 8 μL of detection solution was added and mixed. After reacting at 25°C for 40 minutes, the detection was performed and the IC values ​​of the tested examples and comparative examples were calculated. 50 The experimental results are shown in Table 1:

[0368] Table 1 Inhibitory activity of the compounds of the present invention on IRAK4 protein kinase

[0369] Example <![CDATA[IC 50 (nM)]]> Example 1 0.59 Example 2 0.44 Example 3 0.33 Example 4 0.06 Example 6 0.72 Example 7 0.76 Example 8 2.87 Embodiment 11 0.74 Comparative Example 1 6.01 Comparative Example 2 7.03 Comparative Example 3 11.24 Comparative Example 4 8.99

[0370] The results showed that the compounds of the present invention had a good inhibitory effect on the kinase activity of IRAK4.

Claims

1. A compound, which is a compound as represented by formula (I), or an isomer, nitrogen oxide, hydrate, solvate, deuterated compound, metabolite, pharmaceutically acceptable salt or prodrug of the compound as represented by formula (I), in: Ring A is an 8-13 membered spiro ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; G1 is N or CR 6 ; G2 is N or CR 7 ; R 1 , R 2 and R 3 are independently hydrogen, deuterium, halogen, CN, OH, NO2, NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, -(C 0-3 Alkylene)-C 3-6 Cycloalkyl or -(C 0-3 Alkylene)-3-8 membered heterocyclic group, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, -(C 0-3 Alkylene)-C 3-6 Cycloalkyl and -(C 0-3 The 3- to 8-membered heterocyclic group may be independently and optionally substituted by 1, 2 or 3 groups selected from deuterium, halogen, oxo, CN, OH, NO2, NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl and C 1-3 Substituted by a haloalkyl substituent; Each R a , R 4 , R 5 , R 6 and R 7 are independently hydrogen, deuterium, halogen, oxo, CN, NO2, -R b 、-OR c 、-SR c 、-N(R c )2、-C(R c )3, -S(=O)2R c 、-S(=O)2N(R c )2, -S(=O)R c ,-S(=O)(NR c )R c 、-P(=O)(OR c )2、-P(=O)(N(R c )2)2、 -CF(R c )2, -CF2(R c ), -CF3, -C(R c )2-OR c , -C(R c )2-N(R c )2, -C(=O)R c , -C(=O)OR c or -C(=O)N(R c )2; Each R b Independently for C 1-6 Alkyl, C 2-6 Alkenyl, phenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group or 5-6 membered heteroaryl, said R b can be independently optionally replaced by 1, 2 or 3 selected from deuterium, halogen, CN, OH, NO2, NH2, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy and C 1-3 Substituted by a haloalkyl substituent; Each R c are independently hydrogen, deuterium, C 1-6 Alkyl, phenyl, C 4-7 Cycloalkyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, the C 1-6 Alkyl, phenyl, C 4-7 Cycloalkyl, 4-7 membered heterocyclyl and 5-6 membered heteroaryl may be independently optionally substituted by 1, 2 or 3 radicals selected from deuterium, halogen, oxo, CN, OH, NO2, NH2, C 1-3 Aliphatic group, C 1-3 Alkoxy, C 1-3 Haloalkoxy and C 1-3 or two R on the same atom c The group is optionally combined with its intermediate atom to form a C 4-7 Cycloalkyl, a 4-11 membered bridged bicyclic or spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, said C 4-7 Cycloalkyl and 4-11 membered bridged bicyclic or spirocyclic rings having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur may be further optionally substituted by 1, 2 or 3 atoms selected from hydrogen, deuterium, halogen, oxo, CN, OH, NO2, NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy and C 1-3 Substituted by a haloalkyl substituent; m is 0, 1, 2, 3, 4, 5 or 6.

2. The compound of claim 1, wherein R 1 For hydrogen, deuterium, halogen, CN, OH, NO2, NH2, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl; R 2 For hydrogen, deuterium, halogen, CN, OH, NO2, NH2, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl.

3. The compound according to claim 1 or 2, wherein R 1 is hydrogen, deuterium, halogen, CN, OH, NO2, NH2, methyl, ethyl, n-propyl, isopropyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R 2 is hydrogen, deuterium, halogen, CN, OH, NO2, NH2, methyl, ethyl, n-propyl, isopropyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

4. The compound as claimed in claim 1, wherein R 3 For hydrogen, deuterium, halogen, CN, OH, NO2, NH2, C 1-6 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 5-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl and 5-6 membered heterocyclic groups may be independently optionally substituted by 1, 2 or 3 groups selected from deuterium, halogen, oxo, CN, OH, NO2, NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl and C 1-3 The alkyl group is substituted with a haloalkyl substituent.

5. The compound as claimed in claim 4, wherein R 3 is hydrogen, deuterium, halogen, CN, OH, NO2, NH2, methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl or morpholinyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl and morpholinyl may be independently and optionally substituted with 1, 2 or 3 substituents selected from deuterium, halogen, oxo, CN, OH, NO2, NH2, methyl, methoxy, -CH2OH, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -OCHF2 and -OCF3.

6. The compound of claim 4, wherein R 3 is piperidinyl, piperazinyl or morpholinyl, and the piperidinyl, piperazinyl and morpholinyl may be independently optionally substituted by 1, 2 or 3 substituents selected from -CH2CHF2 and -C(CH3)2OH.

7. The compound of claim 1, wherein each R a are independently hydrogen, deuterium, halogen, oxo, CN, OH, NO2, NH2, -COOH, -CF3 or C 1-6 alkyl; R 4 , R 5 , R 6 and R 7 are independently hydrogen, deuterium, halogen, oxo, CN, OH, NO2, NH2, -COOH, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group or 7-8 membered bridged bicyclic ring, the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl and 7-8 membered bridged bicyclic ring may be independently optionally substituted by 1, 2 or 3 groups selected from deuterium, halogen, OH, CN, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy and C 1-3 The alkyl group is substituted with a haloalkyl substituent.

8. The compound of claim 7, wherein each R a are independently hydrogen, deuterium, halogen, oxo, CN, OH, NO2, NH2, -COOH, -CF3, methyl, ethyl, n-propyl or isopropyl; R 4 , R 5 , R 6 and R 7 are each independently hydrogen, deuterium, halogen, oxo, CN, OH, NO2, NH2, -COOH, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl or The methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl and It may be optionally substituted independently with 1, 2 or 3 substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, NO2, NH2, methyl, ethyl, methoxy, ethoxy, -CHF2, -CF3, -OCHF2 and -OCF3.

9. The compound according to claim 1, which has a structure represented by formula (II), formula (III), formula (IV), formula (V) or formula (VI): in: Each of X1, X2, X3 and X4 is independently CH2, -C(=O)-, NH, O or S; Each p and q is independently 1 or 2.

10. The compound according to claim 1, which is a compound having one of the following structures or an isomer, nitrogen oxide, hydrate, solvate, deuterated compound, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound having one of the following structures:

11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10, wherein the pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof.

12. Use of the compound according to any one of claims 1 to 10 or the pharmaceutical composition according to claim 11 in the preparation of a medicament for preventing, treating or alleviating a disease in a patient that is responsive to inhibition of IRAK4.

13. The use as claimed in claim 12, wherein the disease is selected from inflammatory diseases, infections such as viral, bacterial, fungal and parasitic infections, HIV-1 infection, sepsis, autoimmune disorders or diseases such as rheumatoid arthritis and multiple sclerosis, gout, juvenile idiopathic arthritis, Muckle-Wells disease, familial Mediterranean fever, Behcet's disease, adult Still's disease, proliferative diseases such as cancer, hyperplasia, restenosis, cardiac hypertrophy, leukemia, intravascular coagulation, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cardiovascular diseases, fibrotic and allergic diseases, asthma, atopic dermatitis, hidradenitis suppurativa, Alzheimer's disease, hormone-related diseases, trauma, hemodialysis, ischemic diseases, non-infectious hepatitis, ultraviolet radiation, closed head injury, pancreatitis, periodontitis, graft-versus-host disease and / or transplant rejection.

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