Pyrazolopyrimidine compounds as TYK2 inhibitor

Abstract

Provided are pyrazolopyrimidine compounds of general formula (I), or pharmaceutically acceptable salts, enantiomers, diastereoisomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants thereof. Also provided are a pharmaceutical composition comprising the compounds, a preparation method therefor and the use thereof in the preparation of drugs for treating or preventing TYK2 kinase-mediated diseases.

Description

Pyrazolopyrimidine compounds as TYK2 inhibitors

[0001] This application claims priority to Chinese patent application No. 202410149124X filed on February 1, 2024. The text of this priority is incorporated into this application by reference.

[0002] The present invention relates to the field of medicinal chemistry, and in particular to a pyrazolopyrimidine compound, a composition containing the same, a preparation method thereof, and use thereof as a TYK2 inhibitor. Background Art

[0003] The Janus kinase family (JAK) is an intracellular, non-receptor tyrosine kinase that mediates signaling and activation of various cytokines. Gain-of-function expression or mutations in JAKs are associated with numerous autoimmune diseases, inflammation, and cancer. This family includes JAK1, JAK2, JAK3, and TYK2. JAK1, JAK2, and TYK2 are widely present in various tissues and cells throughout the body, while JAK3 is primarily found in bone marrow cells, thymocytes, natural killer (NK) cells, and activated B and T cells.

[0004] The JAK-mediated signaling pathway includes three key components: cytokine receptors on the cell surface, JAKs, and downstream proteins. Cytokines, such as various interferons (IFNs) and interleukins (ILs), bind to cytokine receptors on the cell surface, bringing JAKs bound to the intracellular domain of the receptor close. The tyrosine residues of the JAKs are then phosphorylated, increasing the activity of the kinase domain. Subsequently, the activated JAKs phosphorylate the tyrosine residues of the receptors, creating binding sites for proteins with SH2 domains. STATs (signal transducers and activators of transcription) bind to the phosphorylated tyrosine residues on the receptors through their SH2 domains and are phosphorylated by JAKs, producing phosphorylated STAT dimers. The dimers then translocate to the nucleus to induce transcription of target genes. In addition, other proteins with SH2 domains can also bind to activated JAKs, thereby cross-linking with other signaling pathways, such as PI3K / AKT and MAPK / ERK.

[0005] TYK2 is a non-receptor tyrosine kinase that mediates immune signals, primarily regulating signaling pathways driven by IL-23, IL-12, and type I interferon (IFNα). It is used as an IL-12, IL-23, and / or IFNα regulator by inhibiting TYK2-mediated signal transduction. TYK2 plays an important role in transmitting inflammatory and immune response signals and is involved in the pathophysiology of various immune-related diseases, such as psoriasis (PS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD). TYK2 does not mediate cytokine responses driven by other kinases (such as IL-6, hematopoietic growth factors, and IL-2). Therefore, TYK2 inhibitors can avoid the adverse reactions of currently marketed JAK inhibitors by not acting on other subtypes.

[0006] Conventional small-molecule JAK inhibitors are active-site-directed inhibitors that bind to the adenosine triphosphate (ATP) site of the catalytic domain (JH1) of the JAK protein. Due to the high homology of the ATP sites of JAK family kinases and the similarity of the ATP-binding regions of the human kinase group, they generally suffer from low selectivity.

[0007] Research has shown that the pseudokinase domain (JH2) within the JAK family, which possesses significant catalytic activity, provides an ideal allosteric site for the discovery of selective TYK2 inhibitors. BMS-986165 is currently known to selectively bind to JH2 of TYK2, inhibiting TYK2 kinase function through an allosteric effect.

[0008] There is a need for more active drugs that selectively inhibit TYK2 by binding to JH2, thereby providing therapeutic benefits in the treatment of diseases.

[0009] The "blood-brain barrier" (BBB) ​​refers to the interface between the blood and the brain. The BBB and its penetration by neurotherapeutics are major topics in how central nervous system drugs are effective. TYK2 inhibitors with brain-penetrating properties could be used to treat relapsing and progressive neurological diseases such as Alzheimer's disease, Parkinson's disease, systemic lupus erythematosus, amyotrophic lateral sclerosis, or multiple sclerosis. From a medicinal chemistry perspective, the ability to design drugs that can penetrate the BBB and achieve the desired biological response is a huge challenge, and drugs that can achieve this goal are currently needed. Summary of the Invention

[0010] Based on this, the present invention provides a pyrazolopyrimidine compound that has excellent selective inhibition of TYK2 activity and can treat a variety of TYK2-mediated diseases. In addition, the compound of the present invention can penetrate the BBB.

[0011] The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof:

[0012] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, and a pharmaceutically acceptable excipient; preferably, it further comprises other therapeutic agents.

[0013] In one embodiment, the present invention provides a compound as defined herein or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, and use of a pharmaceutical composition comprising the same in the preparation of a medicament for treating and / or preventing TYK2 kinase-mediated diseases.

[0014] In one embodiment, the present invention provides a compound as defined herein or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising said compound, for use in treating and / or preventing TYK2 kinase-mediated diseases.

[0015] In one embodiment, the present invention provides a method for treating and / or preventing a TYK2 kinase-mediated disease in a subject using a compound as defined herein, comprising administering to the subject said compound or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising the same.

[0016] The TYK2 kinase-mediated disease of the present invention is selected from the group consisting of autoimmune diseases, skin diseases, allergic diseases, organ rejection, cancer, dry eye disease, myelofibrosis, and polycythemia vera. Furthermore, the autoimmune disease is lupus, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriasis, ulcerative colitis, Crohn's disease, or autoimmune thyroid disease; the skin disease is psoriasis, rash, or atopic dermatitis; the allergic disorder is asthma or rhinitis; the organ transplant rejection is allogeneic rejection or graft-versus-host disease; and the cancer is renal cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, prostate cancer, head and neck cancer, thyroid cancer, lung cancer, glioblastoma, melanoma, lymphoma, or leukemia.

[0017] In some embodiments, the method involves the TYK2 kinase-mediated disease being selected from rheumatoid arthritis, psoriasis, ulcerative colitis, and Crohn's disease. DETAILED DESCRIPTION

[0018] definition

[0019] The compounds of the present invention, their preparation methods, and uses are further described in detail below with reference to specific examples. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided for the purpose of providing a more thorough and comprehensive understanding of the present disclosure.

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention pertains. The terms used in this specification are for the purpose of describing specific embodiments only and are not intended to limit the present invention. The term "and / or" as used herein refers to any and all combinations of one or more of the associated listed items.

[0021] The term "alkyl" refers to a saturated hydrocarbon comprising a primary (normal) carbon atom, a secondary carbon atom, a tertiary carbon atom, a quaternary carbon atom, or a combination thereof. Alkyl is preferably, for example, a C1-C6 alkyl, a C1-C5 alkyl, a C1-C4 alkyl, and a C1-C3 alkyl. Taking "C1-C4 alkyl" as an example, it refers to an alkyl comprising 1 to 4 carbon atoms, which, when occurring each time, can be independently of one another a C1 alkyl, a C2 alkyl, a C3 alkyl, or a C4 alkyl. Suitable examples include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2).

[0022] "Alkenyl" is an alkyl group as defined herein that contains at least one carbon-carbon double bond. In one embodiment, the alkenyl group contains 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms, and even more preferably 2 to 6 carbon atoms. Non-limiting examples of alkenyl groups include substituted or unsubstituted vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, or 4-decenyl. When substituted, the number of substituents is preferably 1 to 5, and the substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.

[0023] "Alkynyl" is an alkyl group as defined herein that contains at least one carbon-carbon triple bond. In one embodiment, the alkynyl group contains 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms, and even more preferably 2 to 6 carbon atoms. Non-limiting examples of alkynyl groups include substituted or unsubstituted ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 3-butynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, or 4-decynyl. When substituted, the number of substituents is preferably 1 to 5, and the substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.

[0024] "Carbocyclyl" or "cycloalkyl" refers to a saturated or partially unsaturated cyclic carbon-containing group, such as a 3-6-membered, 4-6-membered, 5-6-membered, 3-4-membered, 3-5-membered or 4-5-membered saturated carbocyclic ring or a partially unsaturated carbocyclic ring. Preferably, the cycloalkyl is C 3-6 Cycloalkyl, C 4-6 Cycloalkyl, C 5-6 Cycloalkyl, C 3-4 Cycloalkyl, C 3-5 Cycloalkyl or C 4-5 Cycloalkyl. In one embodiment, carbocyclyl is a 3-4-membered monocycle, a 3-5-membered monocycle, a 3-6-membered monocycle, a 3-7-membered monocycle, a 3-8-membered monocycle, a 3-10-membered monocycle, a 5-8-membered monocycle, a 5-6-membered monocycle, a 4-12-membered bicyclic ring or a 10-15-membered tricyclic ring system. Carbocycle includes a bridged ring or a spirocycle. Non-limiting examples of carbocyclyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclopentenyl, cyclohexadienyl, cycloheptatrienyl, benzocyclopentyl, bicyclo [3.2.1] octyl, bicyclo [5.2.0] nonyl, tricyclo [5.3.1.1] dodecyl, adamantyl or spiro [3.3] heptyl etc. Carbocyclyl can be optionally substituted. When substituted, the substituents are preferably 1 to 5, more preferably 1-4, more preferably 1-3, more preferably 1-2, more preferably 1, and the substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, hydroxy, nitro, cyano and amino.

[0025] The term "halogen" refers to -F, -Cl, -Br or -I. Further, the term "haloalkyl" refers to an alkyl group substituted with a halogen group, wherein the alkyl group is as defined above, preferably C 1-6 Halogenated alkyl, C 1-5 Halogenated alkyl, C 1-4 Halogenated alkyl, C 1-3 Haloalkyl and C1-2 Halogenated alkyl.

[0026] The term "aryl" refers to an aromatic hydrocarbon group derived from an aromatic ring compound by removing a hydrogen atom. It can be a monocyclic aryl, a condensed ring aryl, or a polycyclic aryl, preferably a 6-10 membered aryl group. In polycyclic rings, at least one is an aromatic ring system. Phrases containing this term, for example, "6-membered aryl" refers to an aromatic ring system containing 6 ring atoms. Preferably, the aryl group is a phenyl group.

[0027] The term "heteroaryl" refers to an aromatic group containing heteroatoms, which may be monocyclic or fused rings, wherein the heteroatoms are independently selected from N, O, and S, and are preferably 5-12 membered heteroaryls, preferably 5-10 membered heteroaryls, preferably 5-8 membered heteroaryls, preferably 5-6 membered heteroaryls, and preferably 5 membered heteroaryls. Heteroaryls include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, triazolyl, tetrahydropyrrolyl, and thiadiazolyl. In one embodiment, a 5-6 membered monocyclic heteroaryl group typically contains one or more, preferably one to three, and preferably one to two, heteroatoms independently selected from N, O, and S. Unless otherwise specified, exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl; exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolinyl, isoxazolinyl, thiazolyl, and isothiazolyl; exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, thiazolyl, oxadiazolyl, thiadiazolyl, and triazolyl; exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl.

[0028] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or partially unsaturated cyclic group containing heteroatoms, wherein the heteroatoms are selected from N, O and S. Furthermore, the term "heterocyclyl" refers to a group of a stable 3-10 membered saturated heterocyclic ring system in which one or more atoms constituting the non-aromatic ring are heteroatoms and the rest are carbon atoms. The heteroatoms include, but are not limited to, nitrogen atoms, oxygen atoms and sulfur atoms. For example, the heterocyclyl is preferably a 3-7 membered heterocyclyl, a 3-6 membered heterocyclyl, a 3-5 membered heterocyclyl, a 3-4 membered heterocyclyl, a 4-7 membered heterocyclyl, a 4-6 membered heterocyclyl, a 4-5 membered heterocyclyl, a 5-6 membered heterocyclyl or a 6-7 membered heterocyclyl, each of which contains 1 to 4, preferably 1 to 3, and preferably 1 to 2 heteroatoms selected from N, O or S. The heterocyclyl group can be a 3- to 7-membered monocyclic ring, a 5- to 8-membered monocyclic ring, a 5- to 6-membered monocyclic ring, a 4- to 12-membered bicyclic ring or a 10- to 15-membered tricyclic ring system, preferably a 3- to 10-membered heterocyclyl group, and contains at least 1, preferably 1 to 4, heteroatoms selected from N, O or S. In a certain embodiment, a 3- to 7-membered heterocyclyl group is preferred, which contains 1 to 3, preferably 1 to 2, heteroatoms selected from N, O or S. In a certain embodiment, a 5- to 6-membered heterocyclyl group is preferred, which contains 1 to 3, preferably 1 to 2, heteroatoms selected from N, O or S. Unless otherwise indicated in the specification, a heterocyclic group can be monocyclic ("monocyclic heteroalkyl"), or a bicyclic, tricyclic or higher ring system, which can include a fused, bridged or spiro ring system (e.g., a bicyclic system ("bicyclic heteroalkyl"). The ring system of a bicyclic heteroalkyl group can include one or more heteroatoms in one or both rings; and is saturated. Exemplary 3-membered heterocyclic groups include, but are not limited to, aziridine, oxiranyl and thiirane, or stereoisomers thereof; exemplary 4-membered heterocyclic groups include, but are not limited to, azetidinyl, oxiranyl, thiirane, or isomers and stereoisomers thereof; exemplary 5-membered heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, Thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, imidazolidinyl, pyrazolidinyl, dioxolanyl, oxathiolanyl, dithiolanyl, or isomers and stereoisomers thereof. Exemplary 6-membered heterocyclic groups include, but are not limited to, piperidinyl, tetrahydropyranyl, thiolanyl, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, piperazinyl, triazinyl, or isomers and stereoisomers thereof; exemplary 7-membered heterocyclic groups include, but are not limited to, azepanyl, oxepanyl, thiolanyl, and diazepanyl, or isomers and stereoisomers thereof. In a certain embodiment, a typical heterocyclic group is a 3-7 membered monocyclic heterocyclic group containing 1 or more, preferably 1-4, more preferably 1-3 heteroatoms independently selected from N, O and S.In one embodiment, "heterocyclyl" is a 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S. In one embodiment, "heterocyclyl" is a 5-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0029] The term "oxo" refers to a =0 group.

[0030] The term "CN" refers to a cyano group.

[0031] The term "aromatic" includes aryl and heteroaryl groups as defined above.

[0032] The term "non-aromatic" includes cycloalkyl and heterocyclyl groups as defined above.

[0033] In various parts of the present invention, connecting substituents are described. When the structure clearly requires a linking group, the Markush variables listed for the group should be understood as a linking group. For example, if the structure requires a linking group and the Markush group definition for the variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represent the alkylene group or arylene group connected respectively. In some specific structures, when an alkyl group is clearly expressed as a linking group, the alkyl group represents the alkylene group connected, for example, the alkyl in the group "-C1-C3 haloalkyl" should be understood as an alkylene group.

[0034] The term "pharmaceutically acceptable salt" means that the compound can be converted into a corresponding salt by conventional methods, which is chemically or physically compatible with the other ingredients constituting a certain pharmaceutical dosage form and physiologically compatible with the receptor. The salt can be an acidic and / or basic salt formed by the compound with an inorganic and / or organic acid and / or an inorganic and / or organic base, and also includes zwitterionic salts (inner salts), and also includes quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final separation and purification of the compound. They can also be obtained by appropriately mixing the compound of the present invention or its stereoisomers or solvates with a certain amount of acid or base. These salts may form a precipitate in the solution and be collected by filtration, or recovered after evaporation of the solvent, or obtained by cooling and drying after reaction in an aqueous medium. In particular, the salt is preferably a water-soluble, pharmaceutically acceptable, non-toxic acid addition salt, examples of which are salts formed between an amino group and an inorganic acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with an organic acid (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed using other conventional methods in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Where appropriate, additional pharmaceutically acceptable salts may also include salts derived from appropriate bases, including alkali metal salts, alkaline earth metal salts, and ammonium salts. Representative alkali metal or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, and the like. Where appropriate, additional pharmaceutically acceptable salts include salts formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates with non-toxic ammonium, quaternary ammonium, and amine cations.

[0035] The term "solvate" may also be referred to as "solvate" or "solvate", and refers to a compound containing solvent molecules, wherein the solvent molecules can be combined with the compound molecules in ways including coordination bonds, covalent bonds, van der Waals forces, ionic bonds, hydrogen bonds, etc. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein can be prepared, for example, in a crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be able to separate, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes solvates in the solution state and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0036] The term "hydrate" refers to a compound that is combined with water. Generally, the ratio of the number of water molecules contained in the hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Therefore, the hydrate of a compound can be represented by the general formula R·x H2O, for example, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, for example, hemihydrate (R·0.5H2O)) and polyhydrates (x is a number greater than 1, for example, dihydrates (R·2H2O) and hexahydrates (R·6H2O)).

[0037] The term "prodrug" refers to any compound that, when administered to an organism, produces a drug, i.e., an active ingredient, as a result of a spontaneous chemical reaction, an enzyme-catalyzed chemical reaction, photolysis, and / or metabolic chemical reaction. Prodrugs are therefore covalently modified analogs or latent forms of therapeutically active compounds. Suitable examples include, but are not limited to, carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone, sulfoxide, amide, carbamate, azo compound, phosphoramide, glucoside, ether, acetal, etc. forms of the compound.

[0038] The present invention also includes isotopically labeled compounds (isotopic variants) which are identical to those of the general formulae or specific compounds described herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O.31 P. 32 P. 35 S. 18 F and 36 Cl, preferably 2 H (i.e., deuterium, D). Compounds of the present invention, their prodrugs, and pharmaceutically acceptable salts of the compounds or prodrugs containing the above-mentioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those incorporating radioactive isotopes (e.g., 3 H and 14 C) can be used in drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred because they are easy to prepare and detect. In addition, heavier isotopes such as deuterium (i.e. 2 H) substitution may be preferred in some cases because greater metabolic stability may provide therapeutic benefits, such as increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents when performing the processes disclosed in the following schemes and / or the Examples and Preparations.

[0039] The compounds of the present invention include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomers and / or diastereomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0040] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and includes instances where the event or circumstance occurs or does not occur. For example, "aryl is optionally substituted with alkyl" means that the alkyl group may but need not be present, and the term includes instances where the aryl group is substituted with alkyl and instances where the aryl group is not substituted with alkyl.

[0041] A "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. As used herein, the term "pharmaceutically acceptable excipient" includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, that are compatible with drug administration. Each excipient must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients in the formulation and not harmful to the patient. Suitable examples include, but are not limited to: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch, potato starch, and substituted or unsubstituted β-cyclodextrins; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn starch, and maltose. Rice oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other nontoxic compatible substances used in pharmaceutical formulations.

[0042] The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof) with a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, photoelectric properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can lead to one crystalline form being dominant. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0043] Unless otherwise specified, all technical and scientific terms used herein have the standard meanings in the art to which the claimed subject matter belongs. If multiple definitions exist for a term, the definition herein shall prevail. It should be understood that the singular forms used herein, such as "a," "an," and "the" include plural references unless otherwise specified.

[0044] In addition, the terms “include” and “comprising” are open definitions rather than closed definitions, that is, they include the contents specified in the present invention but do not exclude other contents.

[0045] Unless otherwise stated, the present invention uses conventional methods such as mass spectrometry and nuclear magnetic resonance to identify compounds, and each step and condition can refer to conventional operating steps and conditions in the art.

[0046] Unless otherwise indicated, the present invention employs standard nomenclature and standard laboratory procedures and techniques for analytical chemistry, synthetic organic chemistry, and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and light-emitting device performance testing.

[0047] Additionally, it should be noted that, unless explicitly stated otherwise, the term "respectively and independently" used in this disclosure should be broadly interpreted to mean that the individual entities described are independent of one another and may independently represent the same or different specific groups. More specifically, the term "respectively and independently" can mean that the specific options represented by the same symbol in different groups do not affect each other, or that the specific options represented by the same symbol in the same group do not affect each other.

[0048] Specifically, the present invention relates to the following technical solutions.

[0049] In one embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof:

[0050] in,

[0051] R1 is selected from H, halogen, -OR, -SR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0052] R2 is -L2–R 2A ;

[0053] R3 is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR, -SR, halogen, -CN, -NO2, -N(R 3A )(R 3B ),-NHC(O)R 3A 、C3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0054] R4 is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR, -SR, halogen, -CN, -NO2, -N(R 4A )(R 4B ),-NHC(O)R 4A 、C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0055] L2 is a covalent bond or C 1-6 Alkylene, wherein one or two methylene units in the alkylene are optionally and independently replaced by: -C(R 2B )2-、-CH(R 2B )-、-N(R 2B )-、-N(R 2B )C(O)-、-C(O)N(R 2B )-、-N(R 2B )S(O)2-、-S(O)2N(R 2B )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

[0056] R 1A Each occurrence is independently selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 alkyl halide;

[0057] R 1B Each occurrence is independently selected from H, halogen, C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 alkyl halide;

[0058] R 2A Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 alkyl halide;

[0059] R 2B Selected from C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, which are optionally substituted with 1-5 R 2b 'Substituent substitution;

[0060] R 2b 'Selected from hydrogen, halogen, oxo, -CN, -NO2, -OR, -SR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0061] R 3A Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 alkyl halide;

[0062] R 3B Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 alkyl halide;

[0063] Or, R 3A and R 3B Together they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl;

[0064] R 4A Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl and C 1-6 alkyl halide;

[0065] R 4B Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 alkyl halide;

[0066] Or, R 4A and R 4B Together they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl;

[0067] Each occurrence of R is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, oxo, and CN;

[0068] Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium;

[0069] n is 0, 1, 2, 3, 4, 5 or 6,

[0070] Provided that when R1 is -OR or -SR, n is not 0.

[0071] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, which is formula (II),

[0072] in,

[0073] Indicates whether the ring in which it is located is aromatic or non-aromatic;

[0074] X is C(R 2b1 ), O, S, N or N(R 2b1 );

[0075] Y is C(R 2b2 ), O, S, N or N(R 2b2 );

[0076] Z is C(R 2b3 ), O, S, N or N(R 2b3 );

[0077] R 2b1 Selected from H, halogen, oxo, -CN, -NO2, -OR, -SR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0078] R 2b2 Selected from H, halogen, oxo, -CN, -NO2, -OR, -SR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0079] R 2b3 Selected from H, halogen, oxo, -CN, -NO2, -OR, -SR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0080] R 2b4 Selected from H, halogen, oxo, -CN, -NO2, -OR, -SR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0081] R 2b5 Selected from H, halogen, oxo, -CN, -NO2, -OR, -SR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0082] Each occurrence of R is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, oxo, and CN;

[0083] Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium;

[0084] Other groups are as defined in claim 1.

[0085] In a more specific embodiment, the present invention provides a compound of formula (I) or formula (II) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof,

[0086] Wherein, R1 is selected from -OMe, -OEt,

[0087] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, which is formula (III),

[0088] R1 is selected from H, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0089] R 2A Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 alkyl halide;

[0090] R 2b1 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0091] R2b2 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0092] R 2b3 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0093] R 2b4 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0094] R 2b5 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0095] R3 is selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl and -N(R 3A )(R 3B );

[0096] R4 is selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl and -N(R 4A )(R 4B );

[0097] R 3A H or C 1-6 alkyl;

[0098] R 3B H or C 1-6 alkyl;

[0099] R 4A H or C 1-6 alkyl;

[0100] R 4B H or C 1-6 alkyl;

[0101] Each occurrence of R is independently C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0102] Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium;

[0103] n is 0, 1, 2, 3 or 4;

[0104] Provided that when R1 is -OR, n is not 0.

[0105] In a more specific embodiment, the present invention provides a compound of formula (III) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof,

[0106] in,

[0107] R1 is selected from -OR and C 3-4 Cycloalkyl, wherein the cycloalkyl is optionally substituted with 1-2 substituents selected from the group consisting of: C 1-4 Alkyl, -OR, oxo, and CN;

[0108] R 2A is H;

[0109] R 2b1 is selected from H, halogen and -OR;

[0110] R 2b2 is a 5-6 membered heteroaryl group, which is optionally C 1-4 Alkyl substitution;

[0111] R 2b3 is H;

[0112] R 2b4 is H;

[0113] R 2b5 is H;

[0114] R3 is H;

[0115] R4 is -N(R 4A )(R 4B );

[0116] R 4A H or C 1-4 alkyl;

[0117] R 4B H or C 1-4 alkyl;

[0118] Each occurrence of R is independently C 1-4 Alkyl or C 3-4 Cycloalkyl;

[0119] Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium;

[0120] n is 1.

[0121] In a more specific embodiment, the present invention provides a compound of formula (III) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof,

[0122] in,

[0123] R1 is -OR,

[0124] R 2A is H;

[0125] R2b1 is halogen or -OR,

[0126] R 2b2 is a 5-6 membered heteroaryl group, such as a triazolyl group, which is C 1-4 Alkyl substituted, preferably, R 2b2 for

[0127] R 2b3 is H;

[0128] R 2b4 is H;

[0129] R 2b5 is H;

[0130] R3 is H;

[0131] R4 is -N(R 4A )(R 4B );

[0132] R 4A is H;

[0133] R 4B C 1-4 an alkyl group, preferably a methyl group;

[0134] Each occurrence of R is independently C 1-4 Alkyl or C 3-4 Cycloalkyl, preferably methyl or cyclopropyl;

[0135] Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium;

[0136] n is 1.

[0137] In a more specific embodiment, the present invention provides a compound of formula (III) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof,

[0138] in,

[0139] R1 is -OR,

[0140] R 2A is H;

[0141] R 2b1 For -OR,

[0142] R 2b2 is a 5-6 membered heteroaryl group, such as a triazolyl group, which is C 1-4 Alkyl substituted, preferably, R 2b2 for

[0143] R 2b3 is H;

[0144] R 2b4 is H;

[0145] R 2b5 is H;

[0146] R3 is H;

[0147] R4 is -N(R 4A )(R 4B );

[0148] R 4A is H;

[0149] R 4B C 1-4 an alkyl group, preferably a methyl group;

[0150] Each occurrence of R is independently C 1-4 alkyl;

[0151] Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium;

[0152] n is 1.

[0153] In a more specific embodiment, the present invention provides a compound of formula (III) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof,

[0154] in,

[0155] R1 is -OR,

[0156] R 2A is H;

[0157] R 2b1 For halogen,

[0158] R 2b2 is a 5-6 membered heteroaryl group, such as a triazolyl group, which is C 1-4 Alkyl substituted, preferably, R 2b2 for

[0159] R 2b3 is H;

[0160] R 2b4 is H;

[0161] R 2b5 is H;

[0162] R3 is H;

[0163] R4 is -N(R 4A )(R 4B );

[0164] R 4A is H;

[0165] R 4B C 1-4 an alkyl group, preferably a methyl group;

[0166] R is C 3-4 Cycloalkyl, preferably cyclopropyl;

[0167] Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium;

[0168] n is 1.

[0169] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, which is of formula (IV), preferably formula (IV-1):

[0170] in,

[0171] R1 is selected from H, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0172] R 2A Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 alkyl halide;

[0173] R 2b2 Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0174] R 2b3 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, -OR, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0175] R 2b4 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, -OR, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0176] R 2b5 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, -OR, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6haloalkyl, halogen, -OR, oxo, and CN;

[0177] R3 is selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl and -N(R 3A )(R 3B );

[0178] R4 is selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl and -N(R 4A )(R 4B );

[0179] R 3A H or C 1-6 alkyl;

[0180] R 3B H or C 1-6 alkyl;

[0181] R 4A H or C 1-6 alkyl;

[0182] R 4B H or C 1-6 alkyl;

[0183] Each occurrence of R is independently C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0184] Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium;

[0185] n is 0, 1, 2, 3 or 4;

[0186] Provided that when R1 is -OR, n is not 0.

[0187] In a more specific embodiment, the present invention provides a compound of formula (IV) or formula (IV-1) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof,

[0188] in,

[0189] R1 is selected from -OR and 5-6 membered heterocyclic groups, wherein the heterocyclic groups are optionally substituted with 1-2 substituents selected from the following: 1-4 Alkyl, -OR, oxo, and CN;

[0190] R2A is H;

[0191] R 2b2 is a 5-6 membered heteroaryl group, which is optionally C 1-4 Alkyl substitution;

[0192] R 2b3 is H;

[0193] R 2b4 is H;

[0194] R 2b5 is H;

[0195] R3 is H;

[0196] R4 is -N(R 4A )(R 4B );

[0197] R 4A H or C 1-4 alkyl;

[0198] R 4B H or C 1-4 alkyl;

[0199] Each occurrence of R is independently C 1-4 Alkyl or C 3-4 Cycloalkyl;

[0200] Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium;

[0201] n is 1.

[0202] In a more specific embodiment, the present invention provides a compound of formula (IV) or formula (IV-1) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof,

[0203] in,

[0204] R1 is selected from -OR and 5-6 membered heterocyclic group, preferably, the 5-6 membered heterocyclic group is oxacyclopentyl, preferably

[0205] R 2A is H;

[0206] R 2b2 is a 5-6 membered heteroaryl group, which is optionally C 1-4 Alkyl substitution;

[0207] R 2b3 is H;

[0208] R 2b4 is H;

[0209] R 2b5 is H;

[0210] R3 is H;

[0211] R4 is -N(R 4A )(R 4B );

[0212] R 4A is H;

[0213] R 4B C 1-4 an alkyl group, preferably a methyl group;

[0214] R is C 1-4 alkyl;

[0215] Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium;

[0216] n is 1.

[0217] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, which is of formula (V), preferably (V-1):

[0218] in,

[0219] R1 is selected from H, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0220] R 2A Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 alkyl halide;

[0221] R 2b1 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0222] R 2b3 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0223] R 2b4 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0224] R 2b5 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0225] R3 is selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl and -N(R 3A )(R 3B );

[0226] R4 is selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl and -N(R 4A )(R 4B );

[0227] R 3A H or C 1-6 alkyl;

[0228] R 3B H or C 1-6 alkyl;

[0229] R 4A H or C 1-6 alkyl;

[0230] R 4B H or C 1-6 alkyl;

[0231] Each occurrence of R is independently C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0232] Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium;

[0233] n is 0, 1, 2, 3 or 4;

[0234] Provided that when R1 is -OR, n is not 0.

[0235] In a more specific embodiment, the present invention provides a compound of formula (V) or formula (V-1) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof,

[0236] Wherein, R1 is selected from -OMe, -OEt,

[0237] In a more specific embodiment, the present invention provides a compound of formula (V) or formula (V-1) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof,

[0238] in,

[0239] R1 is selected from -OR, C 3-4 Cycloalkyl, 5-6 membered heterocyclyl and 5-6 membered heteroaryl, wherein the cycloalkyl, heterocyclyl and heteroaryl are optionally substituted with 1-2 substituents selected from the following: 1-4 Alkyl, -OR, oxo, and CN;

[0240] R 2A is H;

[0241] R 2b1 for -OR;

[0242] R 2b3 is H;

[0243] R 2b4 is H;

[0244] R 2b5 is H;

[0245] R3 is H;

[0246] R4 is -N(R 4A )(R 4B );

[0247] R 4A H or C 1-4 alkyl;

[0248] R 4B H or C 1-4 alkyl;

[0249] Each occurrence of R is independently C 1-4 Alkyl or C 3-4 Cycloalkyl;

[0250] Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium;

[0251] n is 0, 1, or 2;

[0252] Provided that when R1 is -OR, n is not 0.

[0253] In a more specific embodiment, the present invention provides a compound of formula (V) or formula (V-1) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof,

[0254] in,

[0255] R1 is -OR;

[0256] R 2A is H;

[0257] R 2b1 for -OR;

[0258] R 2b3 is H;

[0259] R 2b4 is H;

[0260] R 2b5 is H;

[0261] R3 is H;

[0262] R4 is -N(R 4A )(R 4B );

[0263] R 4A is H;

[0264] R 4B C 1-4 an alkyl group, preferably a methyl group;

[0265] Each occurrence of R is independently C 1-4 Alkyl, preferably methyl or ethyl;

[0266] Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium;

[0267] n is 1.

[0268] In a more specific embodiment, the present invention provides a compound of formula (V) or formula (V-1) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof,

[0269] in,

[0270] R1 is -OR, where R is C 1-4 an alkyl group, preferably a methyl group;

[0271] R 2A is H;

[0272] R 2b1 -OR, where R is C3-4 Cycloalkyl, preferably cyclopropyl;

[0273] R 2b3 is H;

[0274] R 2b4 is H;

[0275] R 2b5 is H;

[0276] R3 is H;

[0277] R4 is -N(R 4A )(R 4B );

[0278] R 4A is H;

[0279] R 4B C 1-4 an alkyl group, preferably a methyl group;

[0280] Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium;

[0281] n is 1.

[0282] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, which is formula (VI), preferably formula (VI-1),

[0283] R1 is selected from H, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0284] R 2A Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 alkyl halide;

[0285] R 2b2Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0286] R 2b3 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0287] R 2b4 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0288] R 2b5 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0289] R3 is selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl and -N(R 3A )(R 3B );

[0290] R4 is selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl and -N(R 4A )(R 4B );

[0291] R 3A H or C 1-6 alkyl;

[0292] R 3B H or C 1-6 alkyl;

[0293] R 4A H or C 1-6 alkyl;

[0294] R 4B H or C 1-6 alkyl;

[0295] Each occurrence of R is independently C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0296] Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium;

[0297] n is 0, 1, 2, 3 or 4;

[0298] Provided that when R1 is -OR, n is not 0.

[0299] In a more specific embodiment, the present invention provides a compound of formula (VI) or formula (VI-1) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof,

[0300] in,

[0301] R1 is -OR;

[0302] R 2A is H;

[0303] R 2b2 for -OR;

[0304] R 2b3 is H;

[0305] R 2b4 is H or a 5-6 membered heteroaryl group, which is optionally C 1-4 Alkyl substitution;

[0306] R 2b5 is H or halogen;

[0307] R3 is H;

[0308] R4 is -N(R 4A )(R 4B );

[0309] R 4A is H;

[0310] R 4B H or C 1-4 an alkyl group, preferably a methyl group;

[0311] Each occurrence of R is independently C 1-4 alkyl;

[0312] Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium;

[0313] n is 1.

[0314] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, wherein the compound is selected from the following: wherein the compound is selected from:

[0315] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, and a pharmaceutically acceptable excipient; preferably, it further comprises other therapeutic agents.

[0316] In one embodiment, the present invention provides a compound as defined herein or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, and use of a pharmaceutical composition comprising the same in the preparation of a medicament for treating and / or preventing TYK2 kinase-mediated diseases.

[0317] In one embodiment, the present invention provides a compound as defined herein or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising said compound, for use in treating and / or preventing TYK2 kinase-mediated diseases.

[0318] In one embodiment, the present invention provides a method for treating and / or preventing a TYK2 kinase-mediated disease in a subject using a compound as defined herein, comprising administering to the subject said compound or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising the same.

[0319] The TYK2 kinase-mediated disease of the present invention is selected from the group consisting of a neurological disease, an autoimmune disease, a skin disease, an allergic disease, an organ rejection, a cancer, dry eye disease, myelofibrosis, and polycythemia. Furthermore, the neurological disease is Alzheimer's disease, Parkinson's disease, systemic lupus erythematosus, amyotrophic lateral sclerosis, or multiple sclerosis; the autoimmune disease is lupus, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriasis, ulcerative colitis, Crohn's disease, or autoimmune thyroid disease; the skin disease is psoriasis, rash, or atopic dermatitis; the allergic condition is asthma or rhinitis; the organ transplant rejection is allogeneic rejection or graft-versus-host disease; and the cancer is renal cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, prostate cancer, head and neck cancer, thyroid cancer, lung cancer, glioblastoma, melanoma, lymphoma, or leukemia.

[0320] In some embodiments, the method involves the TYK2 kinase-mediated disease being selected from Alzheimer's disease, Parkinson's disease, systemic lupus erythematosus, amyotrophic lateral sclerosis, or multiple sclerosis.

[0321] Those skilled in the art will appreciate that, without violating common sense in the art, the above-mentioned preferred conditions may be arbitrarily combined to obtain preferred embodiments of the present invention.

[0322] Drug administration

[0323] The compound (I) of the present invention can be administered by any means suitable for the disease state to be treated, which may depend on the need for site-specific treatment or the amount of drug to be delivered. Although other modes of delivery are contemplated, topical administration is generally preferred for skin-related diseases, and systemic treatment is preferred for cancerous or precancerous disease states. For example, the compound can be delivered in the following ways: oral, for example, in the form of tablets, capsules, granules, powders, or liquid preparations (including syrups); topical, for example, in the form of solutions, suspensions, gels, or ointments; sublingual; buccal; parenteral, for example, by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (for example, in the form of sterile injectable aqueous or non-aqueous solutions or suspensions); nasal, for example, by inhalation spray; topical, for example, in the form of creams or ointments; rectal, for example, in the form of suppositories; or liposomes. A unit dose formulation containing a non-toxic pharmaceutically acceptable carrier or diluent can be administered. The compound can be administered in a form suitable for immediate release or extended release. Immediate release or extended release can be achieved using suitable pharmaceutical compositions or, particularly in the case of extended release, using, for example, subcutaneous implants or osmotic pump devices.

[0324] Exemplary compositions for topical administration include a topical carrier.

[0325] Exemplary compositions for oral administration include suspensions, which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity increasing agent, and sweeteners or flavorings, such as those known in the art; and immediate release tablets, which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, and / or lactose, and / or other excipients, binders, extenders, disintegrants, diluents, and lubricants, such as those known in the art. The compounds of the present invention may also be delivered orally by sublingual and / or buccal administration, for example, using molded, compressed, or freeze-dried tablets. Exemplary compositions may include rapidly dissolving diluents, such as mannitol, lactose, sucrose, and / or cyclodextrins. These formulations may also include high molecular weight excipients, such as cellulose (AV1CEL ) or polyethylene glycol (PEG); excipients to aid mucoadhesion, such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (SCMC), and / or maleic anhydride copolymers (e.g., GANTREZ ); and agents for controlled release, such as polyacrylic acid copolymers (e.g., CARBOPOL 934 Lubricants, glidants, flavoring agents, coloring agents and stabilizers may also be added to facilitate preparation and use.

[0326] Exemplary compositions for nasal aerosol or inhalation administration include solutions, which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance absorption and / or bioavailability, and / or other solubilizing or dispersing agents, such as those known in the art.

[0327] Exemplary compositions for parenteral administration include injectable solutions or suspensions, which may contain, for example, suitable non-toxic parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, or other suitable dispersing or wetting agents and suspending agents, including synthetic mono- or diglycerides and fatty acids, including oleic acid.

[0328] Exemplary compositions for rectal administration include suppositories, which may contain, for example, suitable non-irritating excipients such as cocoa butter, synthetic glycerides or polyethylene glycols which are solid at ordinary temperatures but liquefy and / or dissolve in the rectal cavity to release the drug.

[0329] Therapeutically effective amounts of the compounds of the present invention can be determined by one skilled in the art and include exemplary doses of about 0.05-1000 mg / kg, 1-1000 mg / kg, 1-50 mg / kg, 5-250 mg / kg, 250-1000 mg / kg body weight of active compound per day for mammals, which can be administered as a single dose or in individual divided doses (e.g., 1 to 4 times per day). It should be understood that the specific dose level and frequency of administration for any particular individual may vary and will depend on various factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, the species, age, weight, general health, sex and diet of the individual, the mode and timing of administration, the rate of excretion, the drug combination, and the severity of the particular disease state. Preferred individuals for treatment include animals, most preferably mammalian species, such as humans and domestic animals, such as dogs, cats, horses, etc. Therefore, when the term "patient" is used herein, this term is meant to include all individuals, most preferably mammalian species, who suffer from TYK2 kinase-mediated diseases.

[0330] Example

[0331] The materials and reagents used herein are either commercially available or prepared by synthetic methods generally known in the art.

[0332] Abbreviations NBS: N-bromosuccinimide ACN: acetonitrile DIEA: N,N-diisopropylethylamine IPA: isopropyl alcohol DMAP: 4-dimethylaminopyridine (Boc)2O: di-tert-butyl dicarbonate nBu-Li: n-butyllithium THF: tetrahydrofuran TEA: triethylamine TEP: tri(2-furyl)phosphine Pd(OAc)2: palladium acetate Cs2CO3: cesium carbonate DCM: dichloromethane TFA: trifluoroacetic acid SOCl2: thionyl chloride MTBE: tert-butyl methyl ether PBr3: phosphorus tribromide EtOH: ethanol NaCN: sodium cyanide DMF: N,N-dimethylformamide DCC: N,N'-dicyclohexylcarbodiimide NaH: sodium hydride MeOH: methanol Pd / C: palladium on carbon K2CO3: potassium carbonate CuI: cuprous iodide KOAc: Potassium acetate Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Ruphos-Pd-G3: Methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) rt: Room temperature hrs / hr: Hours

[0333] Example 1

[0334] 1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-(tetrahydrofuran-2-yl)ethan-1-one (Compound 1)

[0335] Synthesis of intermediate 1E

[0336] Step 1: 3-Bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine

[0337] 5,7-Dichloropyrazolo[1,5-a]pyrimidine (6.8 g, 36.168 mmol) was dissolved in acetonitrile (50 mL), and N-bromosuccinimide (6.76 g, 37.9 mmol) was added. After nitrogen substitution, the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (silica gel, petroleum ether:ethyl acetate = 9:1) to obtain the title compound (9.5 g, yield: 98.4%) as a yellow solid.

[0338] MS (ESI): m / z 265.9 [M+H] + ;

[0339] Step 2: 3-Bromo-5-chloro-N-methylpyrazolo[1,5-a]pyrimidin-7-amine

[0340] 3-Bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (9.5 g, 35.593 mmol) was dissolved in isopropanol (250 mL). After nitrogen substitution, the temperature was lowered to 0°C, and N,N-diisopropylethylamine (12.4 mL, 71.185 mmol) and methylamine hydrochloride (2.88 g, 42.654 mmol) were added. The reaction mixture was stirred in an oil bath at 80°C for 16 hours. The reaction was terminated and concentrated under reduced pressure to afford the crude product. The mixture was diluted with water (300 mL), and the aqueous phase was extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed with saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound (9.36 g, a yellow oil).

[0341] MS (ESI): m / z 261.0 [M+H] + ;

[0342] Step 3: tert-Butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0343] 3-Bromo-5-chloro-N-methylpyrazolo[1,5-a]pyrimidin-7-amine (9.36 g, 35.792 mmol) was dissolved in dioxane (200 mL), and di-tert-butyl dicarbonate (15.6 g, 71.56 mmol) and 4-dimethylaminopyridine (437 mg, 3.577 mmol) were added. After nitrogen substitution, the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was poured into water (200 mL), and the aqueous phase was extracted with ethyl acetate (150 mL x 3). The combined organic phases were washed with saturated brine (150 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the title compound (13 g, yield: 100%) as a yellow solid.

[0344] MS (ESI): m / z 361.0 [M+H] + ;

[0345] Step 4: (7-((tert-Butoxycarbonyl)(methyl)amino)-5-chloropyrazolo[1,5-a]pyrimidin-3-yl)boronic acid

[0346] Dissolve tert-butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (1 g, 2.765 mmol) and triisopropyl borate (1.04 g, 5.53 mmol) in tetrahydrofuran (20 mL). After nitrogen substitution, the temperature was cooled to -78°C, and n-butyllithium (3.45 mL, 5.526 mmol) was slowly added dropwise. The reaction mixture was stirred at -78°C for 2 hours. After completion, saturated aqueous ammonium chloride (20 mL) was added to quench the reaction, which was then diluted with water (60 mL). The aqueous phase was extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with saturated brine (60 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to afford the title compound (550 mg, yield: 60.9%) as a yellow oil.

[0347] MS (ESI): m / z 327.1 [M+H] + ;

[0348] Synthesis of compound 1

[0349] Step 1: 2-(Tetrahydrofuran-2-yl)acetic acid

[0350] 2-(Tetrahydrofuran-2-yl)acetonitrile (3 g, 26.993 mmol) was dissolved in an aqueous solution of tetrahydrofuran (30 mL). Aqueous potassium hydroxide (30 mL, 2 M) was added, and the reaction mixture was stirred at 55°C for 16 hours. After completion of the reaction, the reaction mixture was diluted with water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The pH of the aqueous phase was adjusted to 1-2 with 1 M aqueous HCl, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to provide the title compound (2.1 g, yield: 60%) as a yellow oil.

[0351] Step 2: 2-(Tetrahydrofuran-2-yl)acetyl chloride

[0352] Dissolve 2-(tetrahydrofuran-2-yl)acetic acid (2 g, 15.385 mmol) in thionyl chloride (20 mL) and cool the system to 0°C for 4 hours. Stop the reaction and concentrate the reaction mixture under reduced pressure to obtain the crude title compound (1.6 g, yield: 70.3%, yellow oil).

[0353] Step 3: 2-(tetrahydrofuran-2-yl)thioacetic acid S-(p-tolyl) ester

[0354] Dissolve 2-(tetrahydrofuran-2-yl)acetyl chloride (1.6 g, 10.811 mmol) and 4-methylthiophenol (1.34 g, 10.811 mmol) in n-hexane (15 mL). Cool the mixture to 0°C and slowly add triethylamine (1.2 g, 11.891 mmol) dropwise. After the addition is complete, warm the mixture to room temperature and allow to react overnight. Stop the reaction, concentrate the reaction mixture under reduced pressure to obtain the crude product, which is then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to afford the title compound (1.7 g, yield: 66.7%) as a colorless oil.

[0355] MS (ESI): m / z 237.0 [M+H] + ;

[0356] Step 4: tert-Butyl (5-chloro-3-(2-(tetrahydrofuran-2-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0357] (7-((tert-Butoxycarbonyl)(methyl)amino)-5-chloropyrazolo[1,5-a]pyrimidin-3-yl)boronic acid (500 mg, 1.534 mmol) and S-(p-tolyl) 2-(tetrahydrofuran-2-yl)thioacetate (724 mg, 3.068 mmol) were dissolved in tetrahydrofuran (10 mL). Tri(2-furyl)phosphine (TFP) (107 mg, 0.460 mmol), copper(I) thiophene-2-carboxylate (CuTC) (470 mg, 2.454 mmol), and tris(dibenzylideneacetone)dipalladium (140 mg, 0.153 mmol) were added. After nitrogen substitution, the reaction mixture was stirred in an oil bath at 50°C for 2 hours. The reaction was stopped and the reaction mixture was poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3) and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain the title compound (50 mg, yield: 8.3%, yellow solid).

[0358] MS (ESI): m / z 394.9 [M+H] + ;

[0359] Step 5: Tert-butyl (5-((2-methoxypyridin-3-yl)amino)-3-(2-(tetrahydrofuran-2-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0360] Tert-butyl (5-chloro-3-(2-(tetrahydrofuran-2-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (40 mg, 0.102 mmol) was dissolved in dioxane (5 mL). 2-methoxypyridin-3-amine (15 mg, 0.122 mmol), palladium acetate (5 mg, 0.020 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (23 mg, 0.041 mmol), and cesium carbonate (99 mg, 0.035 mmol) were added. After nitrogen substitution, the reaction solution was stirred in an oil bath at 110°C for 1 hour. The reaction solution was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to give the title compound (46 mg, yield: 93.9%, yellow solid).

[0361] MS (ESI): m / z 483.2 [M+H] + ;

[0362] Step 6: 1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-(tetrahydrofuran-2-yl)ethan-1-one (Compound 1)

[0363] Tert-butyl (5-((2-methoxypyridin-3-yl)amino)-3-(2-(tetrahydrofuran-2-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (46 mg, 0.095 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water (20 mL), and the aqueous phase was adjusted to pH 6-7 with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (8.91 mg, yield: 24.7%) as a white solid.

[0364] MS (ESI): m / z 383.1 [M+H] + ;

[0365] 1 H NMR(400MHz,DMSO-d6)δ8.84(s,1H),8.75(dd,J=7.6,1.6Hz,1H),8.26(s,1H),7.86(d,J=4.8Hz,1H),7 .82(dd,J=4.8,1.6Hz,1H),6.94(dd,J=7.8,4.9Hz,1H),6.10(s,1H),4.29(dd,J=13.2,6.8Hz,1H),3.9 8(s,3H),3.72(dd,J=14.0,7.2Hz,1H),3.57(dd,J=14.4,7.6Hz,1H),3.03(dd,J=15.2,6.0Hz,1H),2.9 1(d,J=4.8Hz,3H),1.97(td,J=12.0,6.4Hz,1H),1.87–1.74(m,2H),1.56–1.42(m,1H),1.23(brs,1H).

[0366] Example 2

[0367] 1-(5-((2-methoxypyridin-3-yl)amino)-7-methylaminopyrazolo[1,5-a]pyrimidin-3-yl)-2-(tetrahydrofuran-3-yl)ethan-1-one (Compound 2)

[0368] Step 1: 2-(Tetrahydrofuran-3-yl)acetyl chloride

[0369] Dissolve 2-(tetrahydrofuran-3-yl)acetic acid (500 mg, 3.84 mmol) in thionyl chloride (5 mL). After nitrogen replacement, cool to 0°C and stir the reaction mixture at 0°C for 1 hour, then at room temperature for 4 hours. After completion of the reaction, spin dry the reaction mixture to obtain the title compound (380 mg, colorless, transparent oil).

[0370] Step 2: 2-(tetrahydrofuran-3-yl)thioacetate S-(p-tolyl)

[0371] 2-(Tetrahydrofuran-3-yl)acetyl chloride (380 mg, 2.567 mmol) and 4-methylthiophenol (320 mg, 2.581 mmol) were dissolved in n-hexane (6 mL). The temperature was cooled to 0°C. Triethylamine (285 mg, 2.83 mmol) was dissolved in dichloromethane (2 mL) and added dropwise. After the addition was complete, the mixture was slowly warmed to room temperature and allowed to react overnight. The reaction mixture was poured into water (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the title compound (370 mg, yield: 61.1%) as a colorless oil.

[0372] MS (ESI): m / z 237.1 [M+H] + ;

[0373] Step 3: tert-Butyl (5-((tert-butoxycarbonyl)(2-methoxypyridin-3-yl)amino)-3-(2-(tetrahydrofuran-3-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0374] S-(p-tolyl) 2-(tetrahydrofuran-3-yl)thioacetate (104 mg, 0.441 mmol) and (5-((tert-butoxycarbonyl)(2-methoxypyridin-3-yl)amino)-7-((tert-butoxycarbonyl)(methyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)boronic acid (150 mg, 0.292 mmol) were dissolved in tetrahydrofuran (3 mL). After nitrogen substitution, tri(2-furyl)phosphine (TFP) (20 mg, 0.086 mmol), tris(dibenzylideneacetone)dipalladium (27 mg, 0.029 mmol), and copper(I) thiophene-2-carboxylate (CuTC) (89 mg, 0.466 mmol) were added, and the reaction solution was stirred at 50°C for 3 hours. After the reaction is completed, water (20 mL) is added to dilute the mixture, and the aqueous phase is extracted with ethyl acetate (20 mL × 3). The combined organic phases are washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the title compound (37 mg, yield: 21.7%, yellow solid).

[0375] MS (ESI): m / z 583.2 [M+H] + ;

[0376] Step 4: 1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-(tetrahydrofuran-3-yl)ethan-1-one (Compound 2)

[0377] Tert-butyl (5-((tert-butoxycarbonyl)(2-methoxypyridin-3-yl)amino)-3-(2-(tetrahydrofuran-3-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (37 mg, 0.064 mmol) was dissolved in dichloromethane (0.7 mL). Trifluoroacetic acid (0.3 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and diluted with water (10 mL). The aqueous phase was adjusted to pH 6-7 with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (8.67 mg, yield: 36.1%) as a white solid.

[0378] MS (ESI): m / z 383.1 [M+H] + ;

[0379] 1H NMR (400MHz, DMSO-d6) δ8.85(s,1H),8.73(d,J=7.9Hz,1H),8.26(s,1H),7.86(d,J=4.8Hz,1H),7.84 –7.78(m,1H),6.95(dd,J=7.7,5.0Hz,1H),6.10(s,1H),3.98(s,3H),3.84(t,J=7.6Hz,1H),3.76–3. 67(m,1H),3.63(dd,J=15.3,7.6Hz,1H),3.31–3.16(m,2H),3.08(dd,J=16.6,7.6Hz,1H),2.91(d,J= 4.8Hz, 3H), 2.62 (dt, J=14.4, 7.1Hz, 1H), 2.03 (dd, J=12.3, 5.0Hz, 1H), 1.51 (dd, J=12.1, 7.5Hz, 1H).

[0380] Example 3

[0381] 1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-(2-methyl-2H-1,2,3-triazol-4-yl)ethan-1-one (Compound 3)

[0382] Step 1: 2-Methyl-2H-1,2,3-triazole-4-carboxylic acid

[0383] 4-Bromo-2-methyl-2H-1,2,3-triazole (5 g, 30.864 mmol) was dissolved in tetrahydrofuran (100 mL). The reaction system was cooled to -30°C and n-butyllithium (17.4 mL, 27.778 mmol) was added dropwise. The reaction solution was stirred at -30°C for 40 minutes, then poured onto dry ice. After the dry ice evaporated, the reaction was checked for completion. The reaction solution was quenched with water, and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The pH of the aqueous phase was adjusted to 1-2 with 1M HCl aqueous solution and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (2.477 g, yield: 63.2%) as a white solid.

[0384] MS (ESI): m / z 128.1 [M+H] + ;

[0385] Step 2: (2-Methyl-2H-1,2,3-triazol-4-yl)methanol

[0386] Dissolve 2-methyl-2H-1,2,3-triazole-4-carboxylic acid (2.477 g, 19.504 mmol) in tetrahydrofuran (20 mL). Cool the mixture to 0°C and add lithium aluminum tetrahydride (2.965 g, 78.016 mmol). Warm the reaction mixture to room temperature for 2 hours. After completion, quench the reaction with saturated aqueous sodium sulfate solution, dry over anhydrous sodium sulfate, and add ethyl acetate (50 mL). Filter the filtrate, and concentrate under reduced pressure to obtain the crude title compound (2 g, yield: 90.9%) as a yellow oil.

[0387] MS (ESI): m / z 114.0 [M+H] + ;

[0388] Step 3: 4-(Bromomethyl)-2-methyl-2H-1,2,3-triazole

[0389] Dissolve (2-methyl-2H-1,2,3-triazol-4-yl)methanol (2 g, 17.699 mmol) in methyl tert-butyl ether (50 mL). After nitrogen substitution, slowly add phosphorus tribromide (4.8 g, 17.699 mmol) dropwise. Allow to react overnight at room temperature. After completion, quench the reaction with water, extract the aqueous phase with ethyl acetate (50 mL x 2), and wash the combined organic phases with saturated brine (50 mL x 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. This crude product is then isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to afford the title compound (2.334 g, yield: 75.4%) as a yellow oil.

[0390] MS (ESI): m / z 176.0 [M+H] + ;

[0391] Step 4: 2-(2-methyl-2H-1,2,3-triazol-4-yl)acetonitrile

[0392] 4-(Bromomethyl)-2-methyl-2H-1,2,3-triazole (2.334 g, 13.337 mmol) was dissolved in ethanol (50 mL), and sodium cyanide (720 mg, 14.671 mmol) was added. The mixture was allowed to react overnight at 100°C. After completion, the reaction solution was quenched with water, and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude title compound (1.5 g, yield: 92.0%) as a yellow oil.

[0393] MS (ESI): m / z 123.0 [M+H] + ;

[0394] Step 5: 2-(2-methyl-2H-1,2,3-triazol-4-yl)acetic acid

[0395] 2-(2-Methyl-2H-1,2,3-triazol-4-yl)acetonitrile (1.5 g, 12.295 mmol) was dissolved in water (30 mL), and aqueous sodium hydroxide (30 mL, 2 M) was added. The reaction mixture was stirred at 100°C for 2 hours. After completion of the reaction, the reaction mixture was diluted with water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The pH of the aqueous phase was adjusted to 1-2 with 1 M aqueous HCl, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.2 g, yield: 69.4%) as a yellow oil.

[0396] MS (ESI): m / z 140.0 [MH] - ;

[0397] Step 6: 2-(2-methyl-2H-1,2,3-triazol-4-yl)thioacetic acid S-(p-tolyl) ester

[0398] Dissolve 2-(2-methyl-2H-1,2,3-triazol-4-yl)acetic acid (1.2 g, 8.511 mmol) in acetonitrile (30 mL), cool to 0°C, and add N,N'-dicyclohexylcarbodiimide (2.63 g, 12.766 mmol), 4-dimethylaminopyridine (104 mg, 0.851 mmol), and 4-methylthiophenol (1.055 g, 8.511 mmol). The reaction mixture was warmed to room temperature and stirred for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude product, which was then isolated and purified by silica gel column chromatography (petroleum ether:dichloromethane = 2:1) to obtain the title compound (531 mg, yield: 25.3%) as a white solid.

[0399] MS (ESI): m / z 248.1 [M+H] + ;

[0400] Step 7: tert-Butyl (5-chloro-3-(2-(2-methyl-2H-1,2,3-triazol-4-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0401] (7-((tert-Butoxycarbonyl)(methyl)amino)-5-chloropyrazolo[1,5-a]pyrimidin-3-yl)boronic acid (300 mg, 0.920 mmol) and S-(p-tolyl) 2-(2-methyl-2H-1,2,3-triazol-4-yl)thioacetate (455 mg, 1.840 mmol) were dissolved in tetrahydrofuran (30 mL). Tri(2-furyl)phosphine (TFP) (64 mg, 0.276 mmol), copper(I) thiophene-2-carboxylate (CuTC) (191 mg, 1.472 mmol) and tris(dibenzylideneacetone)dipalladium (84 mg, 0.092 mmol) were added. After nitrogen substitution, the reaction solution was stirred in an oil bath at 50°C for 2 hours. After completion of the reaction, the reaction solution was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain the title compound (102 mg, yield: 27.4%, yellow oil).

[0402] MS (ESI): m / z 406.1 [M+H] + ;

[0403] Step 8: tert-Butyl (5-((2-methoxypyridin-3-yl)amino)-3-(2-(2-methyl-2H-1,2,3-triazol-4-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0404] Dissolve tert-butyl (5-chloro-3-(2-(2-methyl-2H-1,2,3-triazol-4-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (80 mg, 0.198 mmol) in dioxane (10 mL), and add 2-methoxypyridin-3-amine (30 mg, 0.237 mmol), palladium acetate (9 mg, 0.040 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (46 mg, 0.079 mmol), and cesium carbonate (193 mg, 0.593 mmol). After nitrogen substitution, the reaction mixture was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction solution was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the title compound (45 mg, yield: 46.2%), as a yellow solid.

[0405] MS (ESI): m / z 494.2 [M+H] + ;

[0406] Step 9: 1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-(2-methyl-2H-1,2,3-triazol-4-yl)ethan-1-one (Compound 3)

[0407] Tert-butyl (5-((2-methoxypyridin-3-yl)amino)-3-(2-(2-methyl-2H-1,2,3-triazol-4-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (35 mg, 0.071 mmol) was dissolved in dichloromethane (8 mL). Trifluoroacetic acid (2 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water (20 mL), and the aqueous phase was adjusted to pH 6-7 with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (13.87 mg, yield: 49.7%) as a white solid.

[0408] MS (ESI): m / z 394.1 [M+H] + ;

[0409] 1 H NMR (400MHz, DMSO-d6) δ8.89(s,1H),8.70(d,J=7.6Hz,1H),8.32(s,1H),7.90(d,J=4.4Hz,1H),7.78(d,J=4.8Hz ,1H),7.53(s,1H),6.95–6.78(m,1H),6.09(s,1H),4.41(s,2H),4.08(s,3H),3.97(s,3H),2.91(d,J=4.8Hz,3H).

[0410] Example 4

[0411] (5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)(tetrahydro-2H-pyran-4-yl)methanone (Compound 4)

[0412] Step 1: Tetrahydro-2H-pyran-4-thiocarboxylic acid S-(p-tolyl) ester

[0413] Dissolve tetrahydropyran-4-carbonyl chloride (1 g, 6.73 mmol) and 4-methylthiophenol (836 mg, 6.73 mmol) in n-hexane (25 mL). After nitrogen replacement, cool to 0°C and slowly add triethylamine (1 mL, 7.402 mmol) dropwise. Stir the reaction mixture at room temperature for 16 hours. After completion of the reaction, concentrate the mixture under reduced pressure to obtain a crude product, which is then purified by silica gel column chromatography (petroleum ether:dichloromethane = 1:1) to afford the title compound (1.4 g, 88% yield, as a white solid).

[0414] MS (ESI): m / z 237.1 [M+H] + ;

[0415] Step 2: tert-Butyl (5-chloro-3-(tetrahydro-2H-pyran-4-carbonyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0416] (7-((tert-Butoxycarbonyl)(methyl)amino)-5-chloropyrazolo[1,5-a]pyrimidin-3-yl)boronic acid (500 mg, 1.531 mmol) and tetrahydro-2H-pyran-4-carboxylic acid S-(p-tolyl) ester (543 mg, 2.298 mmol) were dissolved in tetrahydrofuran (30 mL), and tri(2-furyl)phosphine (TFP) (107 mg, 0.461 mmol), thiophene-2-carboxylate copper(I) (CuTC) (467 mg, 2.449 mmol) and tris(dibenzylideneacetone)dipalladium (140 mg, 0.153 mmol) were added. After nitrogen substitution, the reaction solution was stirred in an oil bath at 50°C for 2 hours. After completion of the reaction, the reaction solution was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to obtain the title compound (170 mg, yield: 28.1%, yellow oil).

[0417] MS (ESI): m / z 395.1 [M+H] + ;

[0418] Step 3: tert-Butyl (5-((2-methoxypyridin-3-yl)amino)-3-(tetrahydro-2H-pyran-4-carbonyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0419] Tert-butyl (5-chloro-3-(tetrahydro-2H-pyran-4-carbonyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (170 mg, 0.431 mmol) was dissolved in dioxane (15 mL), and 2-methoxypyridin-3-amine (64 mg, 0.516 mmol), palladium acetate (19.4 mg, 0.0864 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (100 mg, 0.173 mmol), and cesium carbonate (421 mg, 1.292 mmol) were added. After nitrogen substitution, the reaction solution was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction solution was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to give the title compound (70 mg, yield: 33.7%, white solid).

[0420] MS (ESI): m / z 483.3 [M+H] + ;

[0421] Step 4: 5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)(tetrahydro-2H-pyran-4-yl)methanone (Compound 4)

[0422] Tert-butyl (5-((2-methoxypyridin-3-yl)amino)-3-(tetrahydro-2H-pyran-4-carbonyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (70 mg, 0.145 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water (15 mL), and the aqueous phase was adjusted to pH 6-7 with saturated sodium bicarbonate. The aqueous phase was extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (21.38 mg, yield: 38.5%) as a white solid.

[0423] MS (ESI): m / z 383.1 [M+H] + ;

[0424] 1H NMR(400MHz,DMSO-d6)δ8.85(s,1H),8.63–8.56(m,1H),8.26(s,1H),7.91–7.81(m,2H),7.03(dd,J=7.7,5.0Hz ,1H),6.04(s,1H),3.96(s,3H),3.87–3.77(m,3H),3.27–3.22(m,2H),2.90(d,J=4.8Hz,3H),1.64–1.51(m,4H).

[0425] Example 5

[0426] 1-(2-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-oxoethyl)-1H-pyrazole-4-cyano (Compound 5)

[0427] Step 1: tert-Butyl 2-(4-cyano-1H-pyrazol-1-yl)acetate

[0428] 4-Cyanopyrazole (2 g, 21.485 mmol) was dissolved in N,N-dimethylformamide (20 mL), and tert-butyl bromoacetate (5.03 g, 25.788 mmol) and potassium carbonate (5.94 g, 42.981 mmol) were added. After nitrogen substitution, the reaction mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was poured into water (80 mL), and the aqueous phase was extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with saturated brine (60 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:dichloromethane = 3:1) to obtain the title compound (3.6 g, yield: 80.9%) as a colorless, transparent oil.

[0429] MS (ESI): m / z 208.1 [M+H] + ;

[0430] Step 2: 2-(4-cyano-1H-pyrazol-1-yl)acetic acid

[0431] Dissolve tert-butyl 2-(4-cyano-1H-pyrazol-1-yl)acetate (3.6 g, 17.372 mmol) in a hydrochloric acid-dioxane solution (60 mL). Stir the reaction mixture at room temperature for 16 hours. After completion, concentrate the mixture under reduced pressure to obtain the title compound (2.9 g, yellow solid), which is used directly in the next reaction.

[0432] MS (ESI): m / z 152.0 [M+H] +;

[0433] Step 3: 2-(4-cyano-1H-pyrazol-1-yl)thioacetic acid S-(p-tolyl) ester

[0434] 2-(4-cyano-1H-pyrazol-1-yl)acetic acid (2.9 g, 19.189 mmol) was dissolved in acetonitrile (60 mL) and N,N-dimethylformamide (10 mL), and the temperature was lowered to 0°C. N,N'-dicyclohexylcarbodiimide (5.94 g, 28.789 mmol), 4-dimethylaminopyridine (DMAP) (234 mg, 1.915 mmol) and 4-methylthiophenol 5 (2.38 g, 19.1 63 mmol). After nitrogen substitution, the reaction solution was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was poured into water (100 mL), and the aqueous phase was extracted with dichloromethane (60 mL × 3). The combined organic phases were washed with saturated brine (80 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:dichloromethane = 1:1) to obtain the title compound (2.3 g, yield: 46.5%, colorless oil).

[0435] 1 H NMR (400MHz, CDCl3) δ7.97(s,1H),7.88(s,1H),7.30–7.23(m,4H),5.15(s,2H),2.38(s,3H).

[0436] Step 4: tert-Butyl (5-chloro-3-(2-(4-cyano-1H-pyrazol-1-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0437] (7-((tert-Butoxycarbonyl)(methyl)amino)-5-chloropyrazolo[1,5-a]pyrimidin-3-yl)boronic acid (600 mg, 1.837 mmol) and S-(p-tolyl)-2-(4-cyano-1H-pyrazol-1-yl)thioacetate (945 mg, 3.673 mmol) were dissolved in tetrahydrofuran (15 mL). Tri(2-furyl)phosphine (TFP) (128 mg, 0.551 mmol), copper(I) thiophene-2-carboxylate (CuTC) (560 mg, 2.937 mmol), and tris(dibenzylideneacetone)dipalladium (168 mg, 0.183 mmol) were added. After nitrogen substitution, the reaction mixture was stirred in an oil bath at 50°C for 2 hours. After completion of the reaction, the reaction solution was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the title compound (140 mg, yield: 18.3%, yellow solid).

[0438] MS (ESI): m / z 416.0 [M+H] + ;

[0439] Step 5: Tert-butyl (3-(2-(4-cyano-1H-pyrazol-1-yl)acetyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0440] Tert-butyl (5-chloro-3-(2-(4-cyano-1H-pyrazol-1-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (140 mg, 0.337 mmol) was dissolved in dioxane (8 mL), and 2-methoxypyridin-3-amine (50 mg, 0.403 mmol), palladium acetate (15 mg, 0.0668 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (78 mg, 0.135 mmol), and cesium carbonate (329 mg, 1.01 mmol) were added. After nitrogen substitution, the reaction solution was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction solution was poured into water (30 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to give the title compound (50 mg, yield: 29.4%, white solid).

[0441] MS (ESI): m / z 504.1 [M+H]+ ;

[0442] Step 6: 1-(2-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (Compound 5)

[0443] Tert-butyl (3-(2-(4-cyano-1H-pyrazol-1-yl)acetyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (50 mg, 0.0993 mmol) was dissolved in dichloromethane (6 mL). Trifluoroacetic acid (1.5 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After completion, the reaction mixture was poured into water (20 mL), and the aqueous phase was adjusted to pH 6-7 with saturated sodium bicarbonate. The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (2.06 mg, yield: 5.1%) as a white solid.

[0444] MS (ESI): m / z 404.2 [M+H] + ;

[0445] 1 H NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.63(d,J=7.2Hz,1H),8.53(s,1H),8.36(s,1H),8.08(s,1H),7.98(d,J=4.6Hz, 1H),7.80(d,J=4.0Hz,1H),6.88(dd,J=7.7,4.9Hz,1H),6.07(s,1H),5.74(s,2H),3.96(s,3H),2.92(d,J=4.6Hz,3H).

[0446] Example 6

[0447] 2-Methoxy-1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 6)

[0448] Step 1: 2-methoxythioacetic acid S-(p-tolyl) ester

[0449] Methoxyacetyl chloride (500 mg, 4.607 mmol) and 4-methylthiophenol (572 mg, 4.605 mmol) were dissolved in n-hexane (13 mL). After nitrogen replacement, the temperature was lowered to 0°C, and triethylamine (0.7 mL, 5.07 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was then isolated and purified by silica gel column chromatography (petroleum ether:dichloromethane = 2:1) to obtain the title compound (760 mg, yield: 84%, yellow oil).

[0450] MS (ESI): m / z 197.0 [M+H] + ;

[0451] Step 2: tert-Butyl (5-chloro-3-(2-methoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0452] (7-((tert-Butoxycarbonyl)(methyl)amino)-5-chloropyrazolo[1,5-a]pyrimidin-3-yl)boronic acid (650 mg, 1.991 mmol) and S-(p-tolyl) 2-methoxythioacetate (586 mg, 2.985 mmol) were dissolved in tetrahydrofuran (20 mL). Tri(2-furyl)phosphine (TFP) (139 mg, 0.599 mmol), copper(I) thiophene-2-carboxylate (CuTC) (607 mg, 3.183 mmol), and tris(dibenzylideneacetone)dipalladium (182 mg, 0.199 mmol) were added. After nitrogen substitution, the reaction mixture was stirred in an oil bath at 50°C for 2 hours. After completion of the reaction, the reaction solution was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain the title compound (190 mg, yield: 26.9%, yellow oil).

[0453] MS (ESI): m / z 355.0 [M+H] + ;

[0454] Step 3: tert-Butyl (3-(2-methoxyacetyl)-5-((2-methylpyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0455] Tert-butyl (5-chloro-3-(2-methoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (190 mg, 0.536 mmol) was dissolved in dioxane (12 mL), and 2-methoxypyridin-3-amine (80 mg, 0.645 mmol), palladium acetate (24 mg, 0.107 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (124 mg, 0.214 mmol), and cesium carbonate (524 mg, 1.608 mmol) were added. After nitrogen substitution, the reaction solution was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction solution was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to give the title compound (120 mg, yield: 56.6%, yellow solid).

[0456] MS (ESI): m / z 443.2 [M+H] + ;

[0457] Step 4: 2-methoxy-1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 6)

[0458] Tert-butyl (3-(2-methoxyacetyl)-5-((2-methylpyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (120 mg, 0.271 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water (20 mL), and the aqueous phase was adjusted to pH 6-7 with saturated sodium bicarbonate. The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (42.91 mg, yield: 46.2%) as a white solid.

[0459] MS (ESI): m / z 343.1 [M+H] + ;

[0460] 1H NMR(400MHz, DMSO-d6)δ8.88(s,1H),8.72(dd,J=7.8,1.5Hz,1H),8.29(s,1H),7.93–7.80(m,2H),7. 00(dd,J=7.8,4.9Hz,1H),6.07(s,1H),4.66(s,2H),3.97(s,3H),3.36(s,3H),2.90(d,J=4.8Hz,3H).

[0461] Example 7

[0462] 2-Ethoxy-1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 7)

[0463] Step 1: 2-ethoxythioacetic acid S-(p-tolyl) ester

[0464] Dissolve 2-ethoxyacetyl chloride (500 mg, 3.84 mmol) and 4-methylthiophenol (504 mg, 4.065 mmol) in n-hexane (8 mL). After nitrogen replacement, cool the mixture to 0°C. Slowly add triethylamine (452 ​​mg, 4.475 mmol) dropwise at 0°C. After complete addition, slowly warm the reaction mixture to room temperature and stir overnight. After completion of the reaction, the reaction mixture was directly dried to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to afford the title compound (700 mg, yield: 81.3%) as a colorless, transparent oil.

[0465] Step 2: tert-Butyl (5-chloro-3-(2-ethoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0466] S-(p-Tolyl) 2-ethoxythioacetate (600 mg, 1.840 mmol) and (7-((tert-butoxycarbonyl)(methyl)amino)-5-chloropyrazolo[1,5-a]pyrimidin-3-yl)boronic acid (580 mg, 2.762 mmol) were dissolved in tetrahydrofuran (15 mL). After nitrogen substitution, tri(2-furyl)phosphine (TFP) (128 mg, 0.552 mmol), tris(dibenzylideneacetone)dipalladium (168 mg, 0.184 mmol) and copper(I) thiophene-2-carboxylate (CuTC) (562 mg, 2.944 mmol) were added, and the reaction solution was stirred at 50°C for 2 hours. After the reaction was completed, water (20 mL) was added to dilute the reaction, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the title compound (150 mg, yield: 61.1%, yellow oily liquid).

[0467] MS (ESI): m / z 369.0 [M+H] + ;

[0468] Step 3: tert-Butyl (3-(2-ethoxyacetyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0469] Dissolve tert-butyl (5-chloro-3-(2-ethoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (130 mg, 0.353 mmol) and 2-methoxypyridin-3-amine (52 mg, 0.423 mmol) in dioxane (5 mL). After nitrogen purge, add cesium carbonate (345 mg, 1.059 mmol), palladium acetate (16 mg, 0.071 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (82 mg, 0.141 mmol). Heat the reaction mixture to 110°C and stir for 1 hour. After the reaction is completed, water (20 mL) is added to dilute the reaction, and the aqueous phase is extracted with ethyl acetate (20 mL × 3). The combined organic phases are washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the title compound (80 mg, yield: 83.3%, yellow solid).

[0470] MS (ESI): m / z 457.1 [M+H] + ;

[0471] Step 4: 2-ethoxy-1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 7)

[0472] Tert-butyl (3-(2-ethoxyacetyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (100 mg, 0.219 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and diluted with water (10 mL). The aqueous phase was adjusted to pH 6-7 with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (18.33 mg, yield: 10.6%) as a white solid.

[0473] MS (ESI): m / z 357.1 [M+H] + ;

[0474] 1 H NMR (400MHz, DMSO-d6) δ8.87(s,1H),8.73(dd,J=7.8,1.4Hz,1H),8.29(s,1H),7.88(d,J=4.9Hz,1H),7.83(dd,J=4.9,1.5Hz,1H),6. 98(dd,J=7.8,4.9Hz,1H),6.07(s,1H),4.70(s,2H),3.98(s,3H),3.55(q,J=7.0Hz,2H),2.90(d,J=4.8Hz,3H),1.17(t,J=7.0Hz,3H).

[0475] Example 8

[0476] 3-Methoxy-1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)propan-1-one (Compound 8)

[0477] Step 1: 3-methoxythiopropionic acid S-(p-tolyl) ester

[0478] Dissolve 3-methoxypropionyl chloride (1 g, 8.197 mmol) and 4-methylthiophenol (1.22 g, 9.836 mmol) in n-hexane (20 mL). After nitrogen replacement, cool to 0°C and slowly add triethylamine (3.4 mL, 24.590 mmol) dropwise. Stir the reaction mixture at room temperature for 16 hours. After completion of the reaction, concentrate the mixture under reduced pressure to obtain a crude product, which is then purified by silica gel column chromatography (petroleum ether:dichloromethane = 2:1) to afford the title compound (1.457 g, yield: 84.7%) as a yellow oil.

[0479] MS (ESI): m / z 211.1 [M+H] + ;

[0480] Step 2: tert-Butyl (5-chloro-3-(3-methoxypropionyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0481] (7-((tert-Butoxycarbonyl)(methyl)amino)-5-chloropyrazolo[1,5-a]pyrimidin-3-yl)boronic acid (650 mg, 1.991 mmol) and S-(p-tolyl) 3-methoxypropionic acid (836 mg, 3.982 mmol) were dissolved in tetrahydrofuran (20 mL). Tri(2-furyl)phosphine (TFP) (139 mg, 0.599 mmol), copper(I) thiophene-2-carboxylate (CuTC) (607 mg, 3.183 mmol), and tris(dibenzylideneacetone)dipalladium (182 mg, 0.199 mmol) were added. After nitrogen substitution, the reaction mixture was stirred in an oil bath at 50°C for 2 hours. After completion of the reaction, the reaction solution was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain the title compound (120 mg, yield: 16.4%, yellow oil).

[0482] MS (ESI): m / z 369.1 [M+H] + ;

[0483] Step 3: tert-Butyl (3-(3-methoxypropionyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0484] Tert-butyl (5-chloro-3-(3-methoxypropionyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (120 mg, 0.326 mmol) was dissolved in dioxane (12 mL), and 2-methoxypyridin-3-amine (50 mg, 0.391 mmol), palladium acetate (15 mg, 0.065 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (75 mg, 0.130 mmol), and cesium carbonate (319 mg, 0.978 mmol) were added. After nitrogen substitution, the reaction solution was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction solution was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to give the title compound (66 mg, yield: 44.3%, yellow solid).

[0485] MS (ESI): m / z 457.1 [M+H] + ;

[0486] Step 4: 3-methoxy-1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)propan-1-one (Compound 8)

[0487] Dissolve tert-butyl (3-(3-methoxypropanoyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (66 mg, 0.145 mmol) in dichloromethane (8 mL). Add trifluoroacetic acid (2 mL), and stir the reaction mixture at room temperature for 1 hour. After completion, pour the reaction mixture into water (20 mL). The aqueous phase is adjusted to pH 6-7 with saturated sodium bicarbonate solution and extracted with dichloromethane (20 mL x 3). The combined organic phases are washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the crude product. The crude product is purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to yield the title compound (9.58 mg, yield: 18.6%) as a white solid.

[0488] MS (ESI): m / z 357.1 [M+H] + ;

[0489] 1H NMR (400MHz, DMSO-d6) δ8.84(s,1H),8.75(d,J=7.6Hz,1H),8.27(d,J=1.6Hz,1H),7.86(d,J=4.4Hz,1H),7.81(d,J=4.8Hz,1H),6.98–6. 92(m,1H),6.10(s,1H),3.98(d,J=1.6Hz,3H),3.68(t,J=6.8Hz,2H),3.26(d,J=6.4Hz,2H),3.22(d,J=1.6Hz,3H),2.91(d,J=4.4Hz,3H).

[0490] Example 9

[0491] 3-(2-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-oxoethyl)oxazolidin-2-one (Compound 9)

[0492] Step 1: tert-Butyl 2-(2-oxooxazolidin-3-yl)acetate

[0493] Dissolve oxazolidin-2-one (2.5 g, 28.709 mmol) in tetrahydrofuran (75 mL), cool to 0°C, and add sodium hydride (1.72 g, 43 mmol). After nitrogen purge, the reaction mixture was stirred at 0°C for 30 minutes, followed by the addition of tert-butyl bromoacetate 2 (8.4 g, 43.066 mmol). After nitrogen purge, the reaction mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was poured into water (110 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (dichloromethane:methanol = 50:1) to obtain the title compound (4.53 g, yield: 78.5%) as a white solid.

[0494] 1 H NMR (400MHz, CDCl3) δ4.38 (t, J = 8.0 Hz, 2H), 3.92 (s, 2H), 3.70 (t, J = 8.0 Hz, 2H), 1.48 (s, 9H).

[0495] Step 2: 2-(2-oxooxazolidin-3-yl)acetic acid

[0496] Dissolve tert-butyl 2-(2-oxooxazolidin-3-yl)acetate (4.53 g, 22.513 mmol) in hydrochloric acid-dioxane solution (60 mL). Stir the reaction mixture at room temperature for 16 hours. After completion, concentrate the mixture under reduced pressure to obtain the title compound (3.68 g, yellow solid), which is used directly in the next reaction.

[0497] 1 H NMR (400MHz, DMSO-d6) δ12.91(s,1H),4.29(t,J=8.0Hz,2H),3.90(s,2H),3.60(t,J=8.0Hz,2H).

[0498] Step 3: 2-(2-oxooxazolidin-3-yl)thioacetic acid S-(p-tolyl) ester

[0499] 2-(2-Oxooxazolidin-3-yl)acetic acid (2.08 g, 14.334 mmol) was dissolved in acetonitrile (50 mL) and cooled to 0°C. N,N'-dicyclohexylcarbodiimide (4.44 g, 21.519 mmol), 4-dimethylaminopyridine (DMAP) (175 mg, 1.432 mmol), and 4-methylthiophenol (1.78 g, 14.332 mmol) were added sequentially. After nitrogen substitution, the reaction mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was poured into water (80 mL), and the aqueous phase was extracted with dichloromethane (80 mL × 3). The combined organic phases were washed with saturated brine (80 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:dichloromethane = 1:4) to obtain the title compound (660 mg, yield: 18.3%) as a white solid.

[0500] MS (ESI): m / z 252.0 [M+H] + ;

[0501] Step 4: tert-Butyl (5-chloro-3-(2-(2-oxooxazolidin-3-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0502] (7-((tert-Butoxycarbonyl)(methyl)amino)-5-chloropyrazolo[1,5-a]pyrimidin-3-yl)boronic acid (420 mg, 1.286 mmol) and S-(p-tolyl)-2-(2-oxooxazolidin-3-yl)thioacetate (646 mg, 2.571 mmol) were dissolved in tetrahydrofuran (14 mL). Tri(2-furyl)phosphine (TFP) (90 mg, 0.388 mmol), copper(I) thiophene-2-carboxylate (CuTC) (392 mg, 2.056 mmol), and tris(dibenzylideneacetone)dipalladium (118 mg, 0.129 mmol) were added. After nitrogen substitution, the reaction mixture was stirred in an oil bath at 50°C for 2 hours. After completion of the reaction, the reaction solution was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the title compound (190 mg, yield: 36%, yellow oil).

[0503] MS (ESI): m / z 410.0 [M+H] + ;

[0504] Step 5: tert-Butyl (5-((2-methoxypyridin-3-yl)amino)-3-(2-(2-oxooxazolidin-3-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0505] Tert-butyl (5-chloro-3-(2-(2-oxooxazolidin-3-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (190 mg, 0.464 mmol) was dissolved in dioxane (10 mL), and 2-methoxypyridin-3-amine (69 mg, 0.556 mmol), palladium acetate (21 mg, 0.0935 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (107 mg, 0.185 mmol), and cesium carbonate (454 mg, 1.393 mmol) were added. After nitrogen substitution, the reaction solution was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction solution was poured into water (30 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=30:1) to give the title compound (100 mg, yield: 43.3%, yellow solid).

[0506] MS (ESI): m / z 498.1 [M+H] + ;

[0507] Step 6: 3-(2-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-oxoethyl)oxazolidin-2-one (Compound 9)

[0508] Tert-butyl (5-((2-methoxypyridin-3-yl)amino)-3-(2-(2-oxooxazolidin-3-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (100 mg, 0.201 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (2.5 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water (15 mL), and the aqueous phase was adjusted to pH 6-7 with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (10.35 mg, yield: 12.9%) as a white solid.

[0509] MS (ESI): m / z 398.1 [M+H] + ;

[0510] 1 H NMR (400MHz, DMSO-d6) δ8.91(s,1H),8.71(d,J=7.4Hz,1H),8.32(s,1H),7.93(d,J=4.5Hz,1H),7.82(d,J=4.4Hz,1H),6.97(dd ,J=7.5,5.0Hz,1H),6.09(s,1H),4.64(s,2H),4.35(t,J=7.8Hz,2H),3.98(s,3H),3.65(t,J=7.8Hz,2H),2.91(d,J=4.5Hz,3H).

[0511] Example 10

[0512] 2-(1-methoxycyclobutyl)-1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 10)

[0513] Step 1: 2-(1-methoxycyclobutyl)thioacetate S-(p-tolyl)

[0514] Dissolve 2-(1-methoxycyclobutyl)acetic acid (500 mg, 3.468 mmol) in acetonitrile (15 mL) and cool to 0°C. Add N,N′-dicyclohexylcarbodiimide (1.07 g, 5.186 mmol), 4-dimethylaminopyridine (DMAP) (42 mg, 0.344 mmol), and 4-methylthiophenol (431 mg, 3.47 mmol) in sequence. After nitrogen substitution, the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:dichloromethane = 1:1) to obtain the title compound (720 mg, yield: 82.9%) as a white solid.

[0515] MS (ESI): m / z 251.0 [M+H] + ;

[0516] Step 2: tert-Butyl (5-chloro-3-(2-(1-methoxycyclobutyl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0517] (7-((tert-Butoxycarbonyl)(methyl)amino)-5-chloropyrazolo[1,5-a]pyrimidin-3-yl)boronic acid (470 mg, 1.439 mmol) and S-(p-tolyl) 2-(1-methoxycyclobutyl)thioacetate (720 mg, 2.876 mmol) were dissolved in tetrahydrofuran (15 mL). Tri(2-furyl)phosphine (TFP) (100 mg, 0.431 mmol), copper(I) thiophene-2-carboxylate (CuTC) (439 mg, 2.302 mmol), and tris(dibenzylideneacetone)dipalladium (132 mg, 0.144 mmol) were added. After nitrogen substitution, the reaction mixture was stirred in an oil bath at 50°C for 2 hours. After completion of the reaction, the reaction solution was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain the title compound (80 mg, yield: 13.6%, yellow oil).

[0518] MS (ESI): m / z 409.0 [M+H] + ;

[0519] Step 3: tert-Butyl (3-(2-(1-methoxycyclobutyl)acetyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0520] Tert-butyl (5-chloro-3-(2-(1-methoxycyclobutyl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (80 mg, 0.196 mmol) was dissolved in dioxane (6 mL), and 2-methoxypyridin-3-amine (29 mg, 0.234 mmol), palladium acetate (9 mg, 0.0401 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (45 mg, 0.0778 mmol), and cesium carbonate (192 mg, 0.589 mmol) were added. After nitrogen substitution, the reaction mixture was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the title compound (55 mg, yield: 56.7%) as a yellow solid.

[0521] MS (ESI): m / z 497.1 [M+H] + ;

[0522] Step 4: 2-(1-methoxycyclobutyl)-1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 10)

[0523] Tert-butyl (3-(2-(1-methoxycyclobutyl)acetyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (55 mg, 0.111 mmol) was dissolved in dichloromethane (4 mL). Trifluoroacetic acid (1 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (7.72 mg, yield: 17.5%) as a white solid.

[0524] MS (ESI): m / z 397.1 [M+H] + ;

[0525] 1 H NMR(400MHz, DMSO-d6)δ8.85(s,1H),8.70(dd,J=7.8,1.6Hz,1H),8.24(s,1H),7.89–7.80(m,2H),6.95(dd,J=7.7,5.0H z,1H),6.08(s,1H),3.97(s,3H),3.45(s,2H),3.02(s,3H),2.91(d,J=4.8Hz,3H),2.14–2.03(m,4H),1.66–1.49(m,2H).

[0526] Example 11

[0527] 2-Cyclopropyloxy-1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 11)

[0528] Step 1: 2-Cyclopropyloxyacetic acid

[0529] Dissolve cyclopropanol (2.5 g, 43.478 mmol) in tetrahydrofuran (70 mL), cool to 0°C, and add sodium hydride (3.8 g, 90.580 mmol). The reaction mixture is stirred at 0°C for 2 hours, followed by the addition of 2-bromoacetic acid (5 g, 36.232 mmol). The reaction mixture is warmed to room temperature and stirred for 16 hours. After completion of the reaction, the reaction mixture is quenched with water (50 mL), and the aqueous phase is extracted with ethyl acetate (50 mL x 2). The pH of the aqueous phase is adjusted to 1-2 with 1M hydrochloric acid solution, and the mixture is extracted with ethyl acetate (50 mL x 3). The combined organic phases are washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the title compound (3.45 g, yield: 82.1%) as a yellow oil.

[0530] Step 2: 2-cyclopropyloxythioacetic acid S-(p-tolyl) ester

[0531] Dissolve 2-cyclopropoxyacetic acid (3.45 g, 29.741 mmol) in acetonitrile (50 mL), cool to 0°C, and add N,N'-dicyclohexylcarbodiimide (9.19 g, 44.612 mmol), 4-dimethylaminopyridine (363 mg, 2.974 mmol), and 4-methylthiophenol (3.7 g, 29.741 mmol). Warm the reaction mixture to room temperature and stir for 2 hours. After completion of the reaction, concentrate the mixture under reduced pressure to obtain a crude product, which is then purified by silica gel column chromatography (petroleum ether:dichloromethane = 2:1) to afford the title compound (1.2 g, yield: 18.2%) as a yellow oil.

[0532] MS (ESI): m / z 223.1 [M+H] + ;

[0533] Step 3: tert-Butyl (5-chloro-3-(2-cyclopropyloxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0534] (7-((tert-Butoxycarbonyl)(methyl)amino)-5-chloropyrazolo[1,5-a]pyrimidin-3-yl)boronic acid (1.2 g, 3.681 mmol) and S-(p-tolyl) 2-cyclopropyloxythioate (1.6 g, 7.362 mmol) were dissolved in tetrahydrofuran (40 mL). Tri(2-furyl)phosphine (TFP) (256 mg, 1.104 mmol), copper(I) thiophene-2-carboxylate (CuTC) (1.1 g, 5.890 mmol), and tris(dibenzylideneacetone)dipalladium (337 mg, 0.368 mmol) were added. After nitrogen substitution, the reaction mixture was stirred in an oil bath at 50°C for 2 hours. After completion of the reaction, the reaction solution was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain the title compound (359 mg, yield: 25.6%, yellow oil).

[0535] MS (ESI): m / z 381.0 [M+H] + ;

[0536] Step 4: tert-Butyl (3-(2-cyclopropyloxyacetyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0537] Tert-butyl (5-chloro-3-(2-cyclopropyloxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (100 mg, 0.263 mmol) was dissolved in dioxane (10 mL), and 2-methoxypyridin-3-amine (40 mg, 0.316 mmol), palladium acetate (12 mg, 0.053 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (61 mg, 0.105 mmol), and cesium carbonate (257 mg, 0.789 mmol) were added. After nitrogen substitution, the reaction solution was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction solution was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to give the title compound (84 mg, yield: 68.3%, yellow solid).

[0538] MS (ESI): m / z 469.1 [M+H] + ;

[0539] Step 5: 2-cyclopropyloxy-1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 11)

[0540] Dissolve tert-butyl (3-(2-cyclopropyloxyacetyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (64 mg, 0.137 mmol) in dichloromethane (8 mL). Add trifluoroacetic acid (2 mL), and stir the reaction mixture at room temperature for 1 hour. After completion, pour the reaction mixture into water (20 mL). The aqueous phase is adjusted to pH 6-7 with saturated sodium bicarbonate solution and extracted with dichloromethane (20 mL x 3). The combined organic phases are washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the crude product. The crude product is purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to yield the title compound (25.12 mg, yield: 49.9%) as a white solid.

[0541] MS (ESI): m / z 369.1 [M+H] + ;

[0542] 1 H NMR (400MHz, CD3OD) δ8.79–8.77(m,1H),8.25(d,J=6.0Hz,1H),7.77(d,J=5.2Hz,1H),7.02–6.88(m,1H),5.83(d,J =6.0Hz,1H),4.87(s,2H),4.04(s,3H),3.54–3.53(m,1H),3.00(d,J=6.0Hz,3H),0.66(brs,2H),0.56–0.53(m,2H).

[0543] Example 12

[0544] 1-(5-((2-cyclopropyloxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxyethane-1-one (Compound 12)

[0545] Step 1: 2-Cyclopropyloxy-3-nitropyridine

[0546] Dissolve cyclopropanol (450 mg, 7.75 mmol) in tetrahydrofuran (15 mL). After nitrogen purge, cool to 0°C, add sodium hydride (310 mg, 7.75 mmol), followed by 2-fluoro-3-nitropyridine (1 g, 7.038 mmol). After nitrogen purge, stir the reaction mixture at room temperature for 2 hours. After completion, pour the reaction mixture into water (50 mL), extract the aqueous phase with ethyl acetate (50 mL x 3), and wash the combined organic phases with saturated brine (50 mL x 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain the title compound (1 g, yield: 78.7%, yellow oil).

[0547] MS (ESI): m / z 181.1 [M+H] + ;

[0548] Step 2: 2-cyclopropyloxypyridin-3-amine

[0549] 2-Cyclopropyloxy-3-nitropyridine (1 g, 5.551 mmol) was dissolved in methanol (20 mL), and palladium-on-carbon catalyst (200 mg, 20%) was added. After hydrogen substitution, the reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (dichloromethane:methanol = 50:1) to obtain the title compound (660 mg, yield: 79.1%) as a yellow oil.

[0550] MS (ESI): m / z 151.1 [M+H] + ;

[0551] Step 3: (5-((2-cyclopropyloxypyridin-3-yl)amino)-3-(2-methoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamic acid tert-butyl ester

[0552] Tert-butyl (5-chloro-3-(2-methoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (170 mg, 0.479 mmol) was dissolved in dioxane (12 mL), and 2-cyclopropyloxypyridin-3-amine (86 mg, 0.573 mmol), palladium acetate (21.5 mg, 0.0958 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (111 mg, 0.192 mmol), and cesium carbonate (468 mg, 1.436 mmol) were added. After nitrogen substitution, the reaction solution was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction solution was poured into water (30 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to give the title compound (60 mg, yield: 26.7%, yellow oil).

[0553] MS (ESI): m / z 469.2 [M+H] + ;

[0554] Step 4: 1-(5-((2-cyclopropyloxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxyethane-1-one (Compound 12)

[0555] Tert-butyl (5-((2-cyclopropyloxypyridin-3-yl)amino)-3-(2-methoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (60 mg, 0.128 mmol) was dissolved in dichloromethane (4.8 mL), and trifluoroacetic acid (1.2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water (30 mL), and the aqueous phase was adjusted to pH 6-7 with saturated sodium bicarbonate. The aqueous phase was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (18.35 mg, yield: 38.9%) as a white solid.

[0556] MS (ESI): m / z 369.1 [M+H] + ;

[0557] 1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.64(s,1H),8.29(s,1H),7.93–7.83(m,2H),7.02(dd,J=7.9,4.9Hz,1 H),6.03(s,1H),4.66(s,2H),4.38–4.31(m,1H),3.36(s,3H),2.90(d,J=4.8Hz,3H),0.79(d,J=4.6Hz,4H).

[0558] Example 13

[0559] 1-(5-((2-cyclopropyloxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-ethoxyethane-1-one (Compound 13)

[0560] Step 1: tert-Butyl (5-((2-cyclopropyloxypyridin-3-yl)amino)-3-(2-ethoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0561] Tert-butyl (5-chloro-3-(2-ethoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (80 mg, 0.217 mmol) was dissolved in dioxane (12 mL), and 2-cyclopropyloxypyridin-3-amine (40 mg, 0.261 mmol), palladium acetate (10 mg, 0.043 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (50 mg, 0.087 mmol), and cesium carbonate (213 mg, 0.652 mmol) were added. After nitrogen substitution, the reaction solution was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction solution was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to give the title compound (70 mg, yield: 66.7%, yellow solid).

[0562] MS (ESI): m / z 483.2 [M+H] + ;

[0563] Step 2: 1-(5-((2-cyclopropyloxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-ethoxyethane-1-one (Compound 13)

[0564] Tert-butyl (5-((2-cyclopropyloxypyridin-3-yl)amino)-3-(2-ethoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (70 mg, 0.145 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water (20 mL), and the aqueous phase was adjusted to pH 6-7 with saturated sodium bicarbonate. The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (20.03 mg, yield: 46.2%) as a white solid.

[0565] MS (ESI): m / z 383.1 [M+H] + ;

[0566] 1 H NMR (400MHz, DMSO-d6) δ8.74(d,J=7.2Hz,1H),8.63(s,1H),8.30(s,1H),7.91-7.86(m,2H),7.01(s,1H),6.03 (s,1H),4.71(s,2H),4.36(brs,1H),3.55(q,J=6.8Hz,2H),2.91(s,3H),1.17(t,J=6.4Hz,3H),0.80(brs,4H).

[0567] Example 14

[0568] 2-Methoxy-1-(5-((6-methoxypyridin-2-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 14)

[0569] Step 1: tert-Butyl (3-(2-methoxyacetyl)-5-((6-methoxypyridin-2-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0570] Tert-butyl (5-chloro-3-(2-methoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (170 mg, 0.479 mmol) was dissolved in dioxane (12 mL), and 6-methoxypyridin-2-amine (71 mg, 0.572 mmol), palladium acetate (21.5 mg, 0.0958 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (111 mg, 0.192 mmol), and cesium carbonate (468 mg, 1.436 mmol) were added. After nitrogen substitution, the reaction solution was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction solution was poured into water (30 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to give the title compound (130 mg, yield: 61.3%, yellow solid).

[0571] MS (ESI): m / z 443.1 [M+H] + ;

[0572] Step 2: 2-methoxy-1-(5-((6-methoxypyridin-2-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 14)

[0573] Tert-butyl (3-(2-methoxyacetyl)-5-((6-methoxypyridin-2-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (130 mg, 0.294 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2.5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water (30 mL), and the aqueous phase was adjusted to pH 6-7 with saturated sodium bicarbonate. The aqueous phase was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (30.69 mg, yield: 30.5%) as a white solid.

[0574] MS (ESI): m / z 343.1 [M+H] + ;

[0575] 1H NMR (400MHz, DMSO-d6) δ9.87(s,1H),8.35(s,1H),8.03(d,J=4.8Hz,1H),7.65(t,J=7.9Hz,1H),7.52(d,J=8 .2Hz,1H),6.70(s,1H),6.41(d,J=7.9Hz,1H),4.76(s,2H),3.92(s,3H),3.40(s,3H),2.93(d,J=4.8Hz,3H).

[0576] Example 15

[0577] 2-Ethoxy-1-(5-((6-methoxypyridin-2-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 15)

[0578] Step 1: tert-Butyl (3-(2-ethoxyacetyl)-5-((6-methoxypyridin-2-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0579] Tert-butyl (5-chloro-3-(2-ethoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (100 mg, 0.270 mmol) was dissolved in dioxane (8 mL), and 6-methoxypyridin-2-amine (40 mg, 0.326 mmol), palladium acetate (12 mg, 0.054 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (63 mg, 0.100 mmol), and cesium carbonate (266 mg, 0.815 mmol) were added. After nitrogen substitution, the reaction solution was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction solution was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to give the title compound (106 mg, yield: 85.5%, yellow solid).

[0580] MS (ESI): m / z 457.1 [M+H] + ;

[0581] Step 2: 2-Ethoxy-1-(5-((6-methoxypyridin-2-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 15)

[0582] Tert-butyl (3-(2-ethoxyacetyl)-5-((6-methoxypyridin-2-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (86 mg, 0.189 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water (20 mL), and the aqueous phase was adjusted to pH 6-7 with saturated sodium bicarbonate. The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (23.65 mg, yield: 35.3%) as a white solid.

[0583] MS (ESI): m / z 357.1 [M+H] + ;

[0584] 1 H NMR (400MHz, DMSO-d6) δ9.95(s,1H),8.37(s,1H),8.11(s,1H),7.65(t,J=7.6Hz,1H),7.50(d,J=7.2Hz,1H),6.65(s,1H ), 6.43 (d, J = 8.0Hz, 1H), 4.78 (s, 2H), 3.93 (s, 3H), 3.60 (q, J = 6.8Hz, 2H), 2.94 (d, J = 4.4Hz, 3H), 1.20 (t, J = 6.8Hz, 3H).

[0585] Example 16

[0586] 3-((7-(Methylamino)-3-(2-(tetrahydrofuran-3-yl)acetyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-2H-[1,2'-bipyridyl]-2-one (Compound 16)

[0587] Step 1: 3-amino-2H-[1,2'-bipyridyl]-2-one

[0588] 3-Aminopyridin-2(1H)-one (5 g, 45.409 mmol) and 2-bromopyridine (17.9 g, 113.291 mmol) were dissolved in dioxane (100 mL). Potassium carbonate (18.8 g, 136.035 mmol), N,N'-dimethylethylenediamine (1.6 g, 18.151 mmol), and cuprous iodide (1.73 g, 9.084 mmol) were added. After nitrogen substitution, the reaction mixture was stirred in an oil bath at 110°C for 16 hours. After completion of the reaction, the reaction mixture was filtered and diluted with water (100 mL). The aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=30:1) to give the title compound (2.1 g, yield: 24.7%, yellow solid).

[0589] MS (ESI): m / z 188.0 [M+H] + ;

[0590] Step 2: tert-butyl methyl(5-((2-oxo-2H-[1,2'-bipyridyl]-3-yl)amino)-3-(2-(tetrahydrofuran-3-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)carbamate

[0591] Tert-butyl (5-chloro-3-(2-(tetrahydrofuran-3-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (170 mg, 0.431 mmol) and 3-amino-2H-[1,2'-bipyridyl]-2-one (97 mg, 0.519 mmol) were dissolved in dioxane (4 mL). After nitrogen substitution, palladium acetate (20 mg, 0.089 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (100 mg, 0.173 mmol) and cesium carbonate (420 mg, 1.288 mmol) were added, and the reaction solution was stirred at 110°C for 2 hours. After the reaction was completed, the system was directly filtered, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the title compound (140 mg, yield: 59.6%, yellow solid).

[0592] MS (ESI): m / z 546.3 [M+H] + ;

[0593] Step 3: 3-((7-(methylamino)-3-(2-(tetrahydrofuran-3-yl)acetyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-2H-[1,2′-bipyridyl]-2-one (Compound 16)

[0594] Tert-butyl methyl (5-((2-oxo-2H-[1,2'-bipyridyl]-3-yl)amino)-3-(2-(tetrahydrofuran-3-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)carbamate (140 mg, 0.257 mmol) was dissolved in dichloromethane (4 mL). Trifluoroacetic acid (0.8 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and diluted with water (10 mL). The aqueous phase was adjusted to pH 6-7 with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (72.75 mg, yield: 63.2%) as a white solid.

[0595] MS (ESI): m / z 446.0 [M+H] + ;

[0596] 1 H NMR (400MHz, DMSO-d6) δ9.01(s,1H),8.73(dd,J=7.4,1.8Hz,1H),8.64(ddd,J=4.9,1.8,0.8Hz,1H),8.30(s,1H),8.09–8. 00(m,1H),7.93–7.82(m,2H),7.58–7.49(m,2H),6.40(t,J=7.2Hz,1H),6.33(s,1H),3.91(dd,J=8.2,7.2Hz,1H),3.77(td, J=8.1,5.3Hz,1H),3.69–3.61(m,1H),3.37(dd,J=8.3,6.6Hz,1H),3.29(d,J=7.1Hz,1H),3.15(dd,J=16.8,7.5Hz,1H),2. 90(d,J=4.9Hz,3H), 2.69(dt,J=14.4,7.2Hz,1H), 2.11(dtd,J=12.9,7.7,5.3Hz,1H), 1.59(ddd,J=14.8,12.2,7.1Hz,1H).

[0597] Example 17

[0598] 3-((7-(Methylamino)-3-(2-(tetrahydrofuran-2-yl)acetyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-2H-[1,2'-bipyridyl]-2-one (Compound 17)

[0599] Step 1: tert-Butyl methyl(5-((2-oxo-2H-[1,2'-bipyridyl]-3-yl)amino)-3-(2-(tetrahydrofuran-2-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)carbamate

[0600] Tert-butyl (5-chloro-3-(2-(tetrahydrofuran-2-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (100 mg, 0.254 mmol) was dissolved in dioxane (8 mL), and 3-amino-2H-[1,2'-bipyridyl]-2-one (56 mg, 0.304 mmol), palladium acetate (11 mg, 0.051 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (60 mg, 0.101 mmol), and cesium carbonate (250 mg, 0.760 mmol) were added. After nitrogen substitution, the reaction mixture was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction solution was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the title compound (114 mg, yield: 82.6%, yellow solid).

[0601] MS (ESI): m / z 546.2 [M+H] + ;

[0602] Step 2: 3-((7-(methylamino)-3-(2-(tetrahydrofuran-2-yl)acetyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-2H-[1,2′-bipyridyl]-2-one (Compound 17)

[0603] Tert-butyl methyl (5-((2-oxo-2H-[1,2'-bipyridyl]-3-yl)amino)-3-(2-(tetrahydrofuran-2-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)carbamate (94 mg, 0.172 mmol) was dissolved in dichloromethane (8 mL). Trifluoroacetic acid (2 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water (20 mL), and the aqueous phase was adjusted to pH 6-7 with saturated sodium bicarbonate. The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (10.11 mg, yield: 13.2%) as a white solid.

[0604] MS (ESI): m / z 446.1 [M+H] + ;

[0605] 1 H NMR(400MHz, DMSO-d6)δ9.01(s,1H),8.77(d,J=7.2Hz,1H),8.64(s,1H),8.31(s,1H),8.05(t,J= 7.6Hz,1H),7.94–7.81(m,2H),7.54(d,J=6.8Hz,2H),6.38(dd,J=15.6,9.2Hz,2H),4.42–4.28(m, 1H),3.79(dd,J=14.0,6.4Hz,1H),3.66–3.58(m,1H),3.51(dd,J=15.2,7.2Hz,1H),3.10(dd,J=1 4.8,5.6Hz,1H),2.91(d,J=3.6Hz,3H),2.04(brs,1H),1.95–1.80(m,2H),1.60(d,J=11.6Hz,1H).

[0606] Example 18

[0607] 3-((3-(2-methoxyacetyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-2H-[1,2'-bipyridyl]-2-one (Compound 18)

[0608] Step 1: tert-Butyl (3-(2-methoxyacetyl)-5-((2-oxo-2H-[1,2'-bipyridyl]-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0609] Tert-butyl (5-chloro-3-(2-methoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (230 mg, 0.648 mmol) was dissolved in dioxane (14 mL), and 3-amino-2H-[1,2'-bipyridyl]-2-one (146 mg, 0.78 mmol), palladium acetate (29 mg, 0.129 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (150 mg, 0.259 mmol), and cesium carbonate (633 mg, 1.943 mmol) were added. After nitrogen substitution, the reaction solution was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction solution was poured into water (30 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=20:1) to give the title compound (230 mg, yield: 70.1%, yellow solid).

[0610] MS (ESI): m / z 506.1 [M+H] + ;

[0611] Step 2: 3-((3-(2-methoxyacetyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-2H-[1,2'-bipyridyl]-2-one (Compound 18)

[0612] Tert-butyl (3-(2-methoxyacetyl)-5-((2-oxo-2H-[1,2'-bipyridyl]-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (230 mg, 0.455 mmol) was dissolved in dichloromethane (18 mL), and trifluoroacetic acid (4.5 mL) was added. The reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into water (30 mL), and the aqueous phase was adjusted to pH 6-7 with saturated sodium bicarbonate aqueous solution. The aqueous phase was extracted with dichloromethane (40 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by slurrying with N,N-dimethylformamide and acetonitrile to obtain the title compound (13.74 mg, yield: 7.4%) as a yellow solid.

[0613] MS (ESI): m / z 406.1 [M+H] + ;

[0614] 1H NMR(400MHz, DMSO-d6)δ9.03(s,1H),8.77–8.71(m,1H),8.64(d,J=4.9Hz,1H),8.35(s,1H),8.08–8.01(m,1H),7.91(d,J=4.9Hz,1H),7 .85(d,J=8.1Hz,1H),7.54(dd,J=7.5,5.7Hz,2H),6.46(t,J=7.2Hz,1H),6.33(s,1H),4.76(s,2H),3.43(s,3H),2.90(d,J=4.8Hz,3H).

[0615] Example 19

[0616] 3-((3-(2-ethoxyacetyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-2H-[1,2'-bipyridyl]-2-one (Compound 19)

[0617] Step 1: tert-Butyl (3-(2-ethoxyacetyl)-5-((2-oxo-2H-[1,2'-bipyridyl]-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0618] Tert-butyl (5-chloro-3-(2-ethoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (80 mg, 0.217 mmol) was dissolved in dioxane (12 mL), and 3-amino-2H-[1,2'-bipyridyl]-2-one (49 mg, 0.261 mmol), palladium acetate (10 mg, 0.043 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (50 mg, 0.087 mmol), and cesium carbonate (213 mg, 0.652 mmol) were added. After nitrogen substitution, the reaction solution was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction solution was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to give the title compound (60 mg, yield: 53.1%, yellow solid).

[0619] MS (ESI): m / z 520.1 [M+H] + ;

[0620] Step 2: 3-((3-(2-ethoxyacetyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-2H-[1,2'-bipyridyl]-2-one (Compound 19)

[0621] Tert-butyl (3-(2-ethoxyacetyl)-5-((2-oxo-2H-[1,2'-bipyridyl]-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (60 mg, 0.116 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water (20 mL), and the aqueous phase was adjusted to pH 6-7 with saturated sodium bicarbonate. The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (6.29 mg, white solid, 13.1% yield).

[0622] MS (ESI): m / z 420.1 [M+H] + ;

[0623] 1 H NMR (400MHz, DMSO-d6) δ9.02(s,1H),8.75(d,J=7.6Hz,1H),8.64(s,1H),8.35(s,1H),8.04(t,J=7.6Hz,1H),7.91(s,1H),7.85(d,J=8.0Hz, 1H),7.54(d,J=6.8Hz,2H),6.44(t,J=6.8Hz,1H),6.33(s,1H),4.80(s,2H),3.65–3.60(m,2H),2.90(d,J=3.6Hz,3H),1.22(t,J=6.8Hz,3H).

[0624] Example 20

[0625] 1-(5-((2-fluoro-3-(pyridin-2-yl)phenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxyethan-1-one (Compound 20)

[0626] Step 1: tert-Butyl (3-bromo-2-fluorophenyl)carbamate

[0627] 3-Bromo-2-fluoroaniline (5 g, 26.316 mmol) was dissolved in di-tert-butyl dicarbonate (20 mL). The reaction mixture was stirred in an oil bath at 80°C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 7:1) to afford the title compound (7 g, yield: 92.1%) as a yellow oil.

[0628] MS (ESI): m / z 290.1 ​​[M+H] + ;

[0629] Step 2: tert-Butyl (2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate

[0630] Dissolve tert-butyl (3-bromo-2-fluorophenyl)carbamate (7 g, 24.138 mmol) and 4,4,4',4',5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (9.2 g, 36.207 mmol) in dioxane (150 mL). Add potassium acetate (7.1 g, 72.414 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (883 mg, 1.207 mmol). After nitrogen substitution, the reaction mixture was stirred in an oil bath at 100°C for 16 hours. After completion of the reaction, the reaction mixture was poured into water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to give the title compound (5.28 g, yield: 64.9%, yellow oil).

[0631] MS (ESI): m / z 282.0 [M+H-56] + ;

[0632] Step 3: tert-Butyl (2-fluoro-3-(pyridin-2-yl)phenyl)carbamate

[0633] Dissolve tert-butyl (2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (500 mg, 1.484 mmol) and 2-bromopyridine (352 mg, 2.226 mmol) in dioxane (10 mL) and water (2 mL). Add potassium carbonate (614 mg, 4.451 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (109 mg, 0.148 mmol). After nitrogen substitution, the reaction mixture was stirred in an oil bath at 90°C for 2 hours. After completion of the reaction, the reaction mixture was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to give the title compound (410 mg, yield: 96%, colorless oil).

[0634] MS (ESI): m / z 289.0 [M+H] + ;

[0635] Step 4: 2-Fluoro-3-(pyridin-2-yl)aniline

[0636] Dissolve tert-butyl (2-fluoro-3-(pyridin-2-yl)phenyl)carbamate (410 mg, 1.424 mmol) in dichloromethane (8 mL), add trifluoroacetic acid (2 mL), and stir the reaction mixture at room temperature for 2 hours. After completion, pour the reaction mixture into water (20 mL), adjust the aqueous phase to pH 6-7 with saturated sodium bicarbonate solution, and extract with dichloromethane (20 mL x 3). The combined organic phases are washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (263 mg, yield: 98.1%) as a yellow oil.

[0637] MS (ESI): m / z 189.1 [M+H] + ;

[0638] Step 5: tert-Butyl (5-((2-fluoro-3-(pyridin-2-yl)phenyl)amino)-3-(2-methoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0639] Tert-butyl (5-chloro-3-(2-methoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (90 mg, 0.254 mmol) was dissolved in dioxane (10 mL), and 2-fluoro-3-(pyridin-2-yl)aniline (57 mg, 0.305 mmol), palladium acetate (11 mg, 0.051 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (59 mg, 0.102 mmol), and cesium carbonate (250 mg, 0.763 mmol) were added. After nitrogen substitution, the reaction solution was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction solution was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to give the title compound (53 mg, yield: 41.2%, yellow solid).

[0640] MS (ESI): m / z 507.1 [M+H] + ;

[0641] Step 6: 1-(5-((2-fluoro-3-(pyridin-2-yl)phenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxyethane-1-one (Compound 20)

[0642] Tert-butyl (5-((2-fluoro-3-(pyridin-2-yl)phenyl)amino)-3-(2-methoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (53 mg, 0.105 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water (20 mL), and the aqueous phase was adjusted to pH 6-7 with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (16.1 mg, yield: 37.9%) as a white solid.

[0643] MS (ESI): m / z 407.1 [M+H] + ;

[0644] 1H NMR (400MHz, CD3OD) δ8.82(d,J=5.2Hz,1H),8.48(t,J=8.0Hz,1H),8.36(t,J=7.6Hz,1H),8.30(s,1H),8.10(d,J=8.0Hz, 1H),7.83–7.77(m,1H),7.51(t,J=6.4Hz,1H),7.42(t,J=8.0Hz,1H),5.76(s,1H),4.73(s,2H),3.43(s,3H),3.03(s,3H).

[0645] Example 21

[0646] 1-(5-((2-fluoro-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxyethane-1-one (Compound 21)

[0647] Step 1: tert-Butyl (2-fluoro-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)carbamate

[0648] Tert-butyl (2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (500 mg, 1.484 mmol) and 4-bromo-2-methyl-2H-1,2,3-triazole (361 mg, 2.226 mmol) were dissolved in dioxane (10 mL) and water (2 mL). Potassium carbonate (614 mg, 4.451 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (109 mg, 0.148 mmol) were added. After nitrogen substitution, the reaction mixture was stirred in an oil bath at 90°C for 2 hours. After completion of the reaction, the reaction mixture was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to give the title compound (370 mg, yield: 85.5%, colorless oil).

[0649] MS (ESI): m / z 237.1 [M+H-56] + ;

[0650] Step 2: 2-Fluoro-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline

[0651] Dissolve tert-butyl (2-fluoro-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)carbamate (370 mg, 1.267 mmol) in dichloromethane (8 mL), add trifluoroacetic acid (2 mL), and stir the reaction mixture at room temperature for 1 hour. After completion, pour the reaction mixture into water (20 mL), adjust the aqueous phase to pH 6-7 with saturated sodium bicarbonate solution, and extract with dichloromethane (20 mL x 3). The combined organic phases are washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (230 mg, yield: 94.7%, yellow oil).

[0652] MS (ESI): m / z 193.1 [M+H] + ;

[0653] Step 3: tert-butyl (5-((2-fluoro-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-3-(2-methoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0654] Dissolve tert-butyl (5-chloro-3-(2-methoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (90 mg, 0.254 mmol) in dioxane (10 mL), and add 2-fluoro-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (50 mg, 0.305 mmol), palladium acetate (11 mg, 0.051 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (59 mg, 0.102 mmol), and cesium carbonate (250 mg, 0.763 mmol). After nitrogen substitution, the reaction mixture was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction solution was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the title compound (120 mg, yield: 92.3%, yellow solid).

[0655] MS (ESI): m / z 511.1 [M+H] + ;

[0656] Step 4: 1-(5-((2-fluoro-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxyethane-1-one (Compound 21)

[0657] Tert-butyl (5-((2-fluoro-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-3-(2-methoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (100 mg, 0.196 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (2 mL) was added. The reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into water (20 mL), and the aqueous phase was adjusted to pH 6-7 with saturated sodium bicarbonate aqueous solution. The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (15.34 mg, yield: 19.1%) as a white solid.

[0658] MS (ESI): m / z 411.1 [M+H] + ;

[0659] 1 H NMR (400MHz, DMSO-d6) δ9.37(s,1H),8.28(s,1H),8.22(t,J=7.2Hz,1H),8.08(d,J=3.6Hz,1H),7.93(d,J=4.8Hz,1H),7 .62(t,J=6.8Hz,1H),7.28(t,J=8.0Hz,1H),5.87(s,1H),4.60(s,2H),4.25(s,3H),3.24(s,3H),2.92(d,J=4.8Hz,3H).

[0660] Example 22

[0661] 2-Methoxy-1-(5-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 22)

[0662] Step 1: tert-Butyl (3-bromo-2-methoxyphenyl)carbamate

[0663] Dissolve 3-bromo-2-methoxyaniline (2 g, 9.899 mmol) in ethanol (30 mL) and add di-tert-butyl dicarbonate (3.24 g, 14.845 mmol). After nitrogen substitution, the reaction mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to obtain the title compound (2.4 g, yield: 80.2%) as a colorless, transparent oil.

[0664] 1 H NMR (400MHz, CDCl3) δ8.06(d,J=8.2Hz,1H),7.17(dd,J=8.1,1.4Hz,1H),7.05(s,1H),6.96(t,J=8.2Hz,1H),3.86(s,3H),1.53(s,9H).

[0665] Step 2: tert-Butyl (2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate

[0666] Dissolve tert-butyl (3-bromo-2-methoxyphenyl)carbamate (2.2 g, 7.281 mmol) in dioxane (35 mL), add 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) 3 (2.77 g, 10.906 mmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (533 mg, 0.728 mmol), and potassium acetate (2.14 g, 21.806 mmol). After nitrogen substitution, the reaction mixture was stirred in an oil bath at 100°C for 16 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain the title compound (1.7 g, yield: 70%) as a yellow oil.

[0667] MS (ESI): m / z 294.1 [M+H-56] + ;

[0668] Step 3: tert-Butyl (2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)carbamate

[0669] Tert-butyl (2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (1.7 g, 4.868 mmol) was dissolved in dioxane (30 mL) and water (6 mL). 4-Bromo-2-methyl-2H-1,2,3-triazole (1.18 g, 7.284 mmol), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (356 mg, 0.487 mmol), and potassium carbonate (2.02 g, 14.616 mmol) were added. After nitrogen substitution, the reaction solution was stirred in an oil bath at 90°C for 2 hours. After completion of the reaction, the reaction solution was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=7:1) to give the title compound (1 g, yield: 67.5%, white solid).

[0670] MS (ESI): m / z 249.0 [M+H-56] + ;

[0671] Step 4: 2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline

[0672] Dissolve tert-butyl (2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)carbamate (1 g, 3.286 mmol) in dichloromethane (20 mL), add trifluoroacetic acid (5 mL), and stir the reaction mixture at room temperature for 1 hour. After completion, pour the reaction mixture into water (30 mL), adjust the aqueous phase to pH 6-7 with saturated sodium bicarbonate solution, and extract with dichloromethane (20 mL x 3). The combined organic phases are washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (0.6 g, yield: 89.5%) as a yellow solid.

[0673] MS (ESI): m / z 205.1 [M+H] + ;

[0674] Step 5: tert-Butyl (5-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-3-(2-methoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0675] Dissolve tert-butyl (5-chloro-3-(2-methoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (110 mg, 0.31 mmol) in dioxane (6 mL), and add 2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (76 mg, 0.372 mmol), palladium acetate (14 mg, 0.0624 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (72 mg, 0.124 mmol), and cesium carbonate (303 mg, 0.93 mmol). After nitrogen substitution, the reaction mixture was stirred in an oil bath at 110°C for 1 hour. After the reaction was complete, the reaction solution was poured into water (30 mL), and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was isolated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain the title compound (120 mg, yield: 74%), as a yellow solid.

[0676] MS (ESI): m / z 523.3 [M+H] + ;

[0677] Step 6: 2-methoxy-1-(5-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 22)

[0678] Tert-butyl (5-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-3-(2-methylacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (120 mg, 0.23 mmol) was dissolved in dichloromethane (6 mL). Trifluoroacetic acid (1.5 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (27.93 mg, yield: 28.8%) as a white solid.

[0679] MS (ESI): m / z 423.0 [M+H] + ;

[0680] 1H NMR (400MHz, DMSO-d6) δ9.02(s,1H),8.39(dd,J=8.1,1.4Hz,1H),8.28(s,1H),8.11(s,1H),7.86(q,J=4.6Hz,1H),7.56(dd,J= 7.8,1.5Hz,1H),7.21(t,J=8.0Hz,1H),6.08(s,1H),4.69(s,2H),4.23(s,3H),3.67(s,3H),3.34(s,3H),2.92(d,J=4.8Hz,3H).

[0681] Example 23

[0682] 2-Cyclopropyloxy-1-(5-((2-fluoro-3-(pyridin-2-yl)phenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 23)

[0683] Step 1: tert-Butyl (3-(2-cyclopropyloxyacetyl)-5-((2-fluoro-3-(pyridin-2-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0684] Tert-butyl (5-chloro-3-(2-cyclopropyloxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (100 mg, 0.263 mmol) was dissolved in dioxane (10 mL), and 2-fluoro-3-(pyridin-2-yl)aniline (60 mg, 0.316 mmol), palladium acetate (12 mg, 0.053 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (61 mg, 0.105 mmol), and cesium carbonate (257 mg, 0.789 mmol) were added. After nitrogen substitution, the reaction solution was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction solution was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to give the title compound (120 mg, yield: 85.7%, yellow solid).

[0685] MS (ESI): m / z 533.1 [M+H] + ;

[0686] Step 2: 2-cyclopropyloxy-1-(5-((2-fluoro-3-(pyridin-2-yl)phenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 23)

[0687] Tert-butyl (3-(2-cyclopropyloxyacetyl)-5-((2-fluoro-3-(pyridin-2-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (100 mg, 0.188 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water (20 mL), and the aqueous phase was adjusted to pH 6-7 with saturated sodium bicarbonate. The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (16.68 mg, yield: 20.6%) as a white solid.

[0688] MS (ESI): m / z 433.1 [M+H] + ;

[0689] 1 H NMR (400MHz, DMSO-d6) δ9.34(s,1H),8.72(s,1H),8.31–8.29(m,2H),7.93(s,2H),7.80(d,J=6.8Hz,1H),7.59(d,J=6.4Hz,1H),7.45–7. 36(m,1H),7.30(t,J=7.6Hz,1H),5.90(s,1H),4.73(s,2H),3.39(brs,1H),2.92(d,J=4.4Hz,3H),0.45(brs,2H),0.37(d,J=4.4Hz,2H).

[0690] Example 24

[0691] 2-Cyclopropyloxy-1-(5-((2-fluoro-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 24)

[0692] Step 1: tert-Butyl (3-(2-cyclopropyloxyacetyl)-5-((2-fluoro-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0693] Tert-butyl (5-chloro-3-(2-cyclopropyloxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (110 mg, 0.289 mmol) was dissolved in dioxane (7 mL), and 2-fluoro-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (67 mg, 0.349 mmol), palladium acetate (13 mg, 0.0579 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (67 mg, 0.116 mmol), and cesium carbonate (282 mg, 0.866 mmol) were added. After nitrogen substitution, the reaction mixture was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=20:1) and HPLC (elution system: water, formic acid, acetonitrile) to give the title compound (30 mg, yield: 19.3%, white solid).

[0694] MS (ESI): m / z 537.2 [M+H] + ;

[0695] Step 2: 2-cyclopropyloxy-1-(5-((2-fluoro-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 24)

[0696] Tert-butyl (3-(2-cyclopropyloxyacetyl)-5-((2-fluoro-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (30 mg, 0.0559 mmol) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (1 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (11.05 mg, yield: 45.2%) as a white solid.

[0697] MS (ESI): m / z 437.1 [M+H] + ;

[0698] 1H NMR (400MHz, DMSO-d6) δ9.37(s,1H),8.29(s,1H),8.23(t,J=7.3Hz,1H),8.08(d,J=3.8Hz,1H),7.95–7.93(m,1H),7.62(t,J=6.6Hz,1H),7. 27(t,J=8.0Hz,1H),5.88(s,1H),4.68(s,2H),4.24(s,3H),3.38–3.35(m,1H),2.92(d,J=4.8Hz,3H),0.42–0.40(m,2H),0.38–0.33(m,2H).

[0699] Example 25

[0700] 2-Cyclopropyloxy-1-(5-((3-fluoro-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 25)

[0701] Step 1: (2-Methyl-2H-1,2,3-triazol-4-yl)boronic acid

[0702] 4-Bromo-2-methyl-2H-1,2,3-triazole (50 mg, 3.087 mmol) was dissolved in tetrahydrofuran (5 mL). After nitrogen substitution, isopropylmagnesium chloride-lithium chloride complex (2.85 mL, 3.072 mmol) was slowly added under ice-cooling. The reaction solution was stirred under ice-cooling for 2 hours. The temperature was then cooled to -20°C, and trimethyl borate (0.08 mL, 0.616 mmol) was slowly added dropwise. The reaction solution was stirred at -20°C for 1 hour. After completion of the reaction, the pH was adjusted to 1-2 with concentrated hydrochloric acid and diluted with water (30 mL). The aqueous phase was extracted with chloroform / isopropanol (3 / 1) (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (130 mg, yield: 33.2%) as a yellow solid.

[0703] MS (ESI): m / z 128.2 [M+H] + ;

[0704] Step 2: 3-Fluoro-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-amine

[0705] (2-Methyl-2H-1,2,3-triazol-4-yl)boronic acid (80 mg, 0.63 mmol) and 4-bromo-3-fluoropyridin-2-amine (144 mg, 0.754 mmol) were dissolved in dioxane (10 mL) and water (2 mL). Potassium carbonate (261 mg, 1.889 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (46 mg, 0.0629 mmol) were added. After nitrogen substitution, the reaction solution was stirred in an oil bath at 90°C for 2 hours. After completion of the reaction, the reaction solution was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to give the title compound (80 mg, yield: 65.5%, white solid).

[0706] MS (ESI): m / z 194.1 [M+H] + ;

[0707] Step 3: tert-Butyl (3-(2-cyclopropyloxyacetyl)-5-((3-fluoro-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0708] Tert-butyl (5-chloro-3-(2-cyclopropyloxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (75 mg, 0.197 mmol) was dissolved in dioxane (10 mL), and 3-fluoro-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-amine (45 mg, 0.237 mmol), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (17 mg, 0.020 mmol), and cesium carbonate (193 mg, 0.592 mmol) were added. After nitrogen substitution, the reaction mixture was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction solution was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the title compound (70 mg, yield: 66.0%), as a yellow solid.

[0709] MS (ESI): m / z 538.1 [M+H] + ;

[0710] Step 4: 2-cyclopropyloxy-1-(5-((3-fluoro-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 25)

[0711] Tert-butyl (3-(2-cyclopropyloxyacetyl)-5-((3-fluoro-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (60 mg, 0.112 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (2 mL) was added. The reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into water (20 mL), and the aqueous phase was adjusted to pH 6-7 with saturated sodium bicarbonate aqueous solution. The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (10.13 mg, yield: 20.7%), as a yellow solid.

[0712] MS (ESI): m / z 438.1 [M+H] + ;

[0713] 1 H NMR (400MHz, DMSO-d6) δ9.81 (s, 1H), 8.31–8.25 (m, 3H), 8.06 (d, J = 4.8Hz, 1H), 7.69 (t, J = 5.2Hz, 1H) ,6.21(s,1H),4.54(s,2H),4.28(s,3H),3.19–3.14(m,1H),2.95(d,J=4.8Hz,3H),0.26–0.16(m,4H).

[0714] Example 26

[0715] 2-((1S,2R)-2-methoxycyclobutyl)-1-(5-(((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 26)

[0716] Step 1: ((1S,2R)-2-methoxycyclobutyl)methyl methanesulfonate

[0717] Dissolve (1S,2R)-2-methoxycyclobutyl)methanol (770 mg, 6.638 mmol) in dichloromethane (50 mL), cool to 0°C, add triethylamine (1.3 g, 13.276 mmol) and methanesulfonyl chloride (1.4 g, 7.966 mmol), and warm the reaction mixture to room temperature with stirring for 2 hours. After completion, pour the reaction mixture into water (50 mL), extract the aqueous phase with dichloromethane (50 mL x 3), and wash the combined organic phases with saturated brine (50 mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain the title compound (1.2 g, yield: 93.2%, colorless oil).

[0718] MS (ESI): m / z 195.0 [M+H] + ;

[0719] Step 2: 2-((1S,2R)-2-methoxycyclobutyl)acetonitrile

[0720] Dissolve ((1S,2R)-2-methoxycyclobutyl)methyl methanesulfonate (1.2 g, 6.082 mmol) in dimethyl sulfoxide (50 mL), add sodium cyanide (328 mg, 6.691 mmol), and heat the reaction mixture to 85°C with stirring for 16 hours. After completion, pour the reaction mixture into water (50 mL), extract the aqueous phase with ethyl acetate (50 mL x 3), and wash the combined organic phases with saturated brine (50 mL x 3), dry over anhydrous sodium sulfate, and filter. The filtrate is concentrated under reduced pressure to obtain the title compound (723 mg, yield: 93.5%) as a yellow oil.

[0721] Step 3: 2-((1S,2R)-2-methoxycyclobutyl)acetic acid

[0722] 2-((1S,2R)-2-methoxycyclobutyl)acetonitrile (523 mg, 4.184 mmol) was dissolved in sodium hydroxide solution (5 M, 10 mL). The reaction mixture was heated to 100°C and stirred for 2 hours. After completion of the reaction, the reaction mixture was poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 2). The pH of the aqueous phase was adjusted to 1 with concentrated hydrochloric acid and extracted again with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (450 mg, yellow oil).

[0723] Step 4: 2-((1S,2R)-2-methoxycyclobutyl)thioacetate S-(p-tolyl)

[0724] Dissolve 2-((1S,2R)-2-methoxycyclobutyl)acetic acid (1 g, 6.944 mmol) in acetonitrile (50 mL), cool to 0°C, and add N,N'-dicyclohexylcarbodiimide (2.2 g, 10.417 mmol), 4-dimethylaminopyridine (85 mg, 0.694 mmol), and 4-methylbenzenethiol (861 mg, 6.944 mmol). The reaction mixture was warmed to room temperature and stirred for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was then isolated and purified by silica gel column chromatography (petroleum ether:dichloromethane = 2:1) to afford the title compound (576 mg, 33.2% yield, as a yellow oil).

[0725] MS (ESI): m / z 251.1 [M+H] + ;

[0726] Step 5: tert-Butyl (5-chloro-3-(2-((1S,2R)-2-methoxycyclobutyl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0727] (7-((tert-Butoxycarbonyl)(methyl)amino)-5-chloropyrazolo[1,5-a]pyrimidin-3-yl)boronic acid (600 mg, 1.840 mmol) and S-(p-tolyl) 2-((1S,2R)-2-methoxycyclobutyl)ethanethiol ester (690 mg, 2.761 mmol) were dissolved in tetrahydrofuran (40 mL). Tri(2-furyl)phosphine (TFP) (128 mg, 0.552 mmol), copper(I) thiophene-2-carboxylate (CuTC) (562 mg, 2.945 mmol), and tris(dibenzylideneacetone)dipalladium (168 mg, 0.184 mmol) were added. After nitrogen substitution, the reaction mixture was stirred in an oil bath at 50°C for 2 hours. After completion of the reaction, the reaction mixture was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain the title compound (141 mg, yield: 18.8%, yellow oil).

[0728] MS (ESI): m / z 409.1 [M+H] + ;

[0729] Step 6: tert-Butyl (3-(2-((1S,2R)-2-methoxycyclobutyl)acetyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0730] Dissolve tert-butyl (5-chloro-3-(2-((1S,2R)-2-methoxycyclobutyl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (120 mg, 0.294 mmol) in dioxane (10 mL), and add 2-methoxypyridin-3-amine (44 mg, 0.353 mmol), palladium acetate (13 mg, 0.059 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (68 mg, 0.118 mmol), and cesium carbonate (288 mg, 0.882 mmol). After nitrogen substitution, the reaction mixture was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction mixture was poured into water (40 mL). The aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the title compound (94 mg, yield: 64.4%), as a yellow solid.

[0731] MS (ESI): m / z 497.1 [M+H] + ;

[0732] Step 7: 2-((1S,2R)-2-methoxycyclobutyl)-1-(5-(((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 26)

[0733] Tert-butyl (3-(2-((1S,2R)-2-methoxycyclobutyl)acetyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (84 mg, 0.169 mmol) was dissolved in dichloromethane (8 mL). Trifluoroacetic acid (2 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water (20 mL), and the aqueous phase was adjusted to pH 6-7 with saturated sodium bicarbonate. The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (26.39 mg, yield: 39.4%) as a white solid.

[0734] MS (ESI): m / z 397.1 [M+H] + ;

[0735] 1H NMR(400MHz, DMSO-d6)δ8.85(s,1H),8.73(dd,J=7.6,1.6Hz,1H),8.24(s,1H),7.90–7.81 (m,2H),6.97(dd,J=8.0,4.8Hz,1H),6.08(s,1H),3.98(s,3H),3.53(q,J=7.2Hz,1H),3.20 (qd,J=15.6,7.2Hz,2H),3.09(s,3H),2.91(d,J=4.8Hz,3H),2.61–2.53(m,1H),2.07(dd,J =16.4,8.0Hz,1H),1.81(q,J=9.2Hz,1H),1.72–1.53(m,1H),1.17(dd,J=18.8,9.6Hz,1H).

[0736] Example 27

[0737] 2-Cyclobutyl-1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 27)

[0738] Step 1: S-(p-tolyl) 2-cyclobutanethioacetate

[0739] Dissolve 2-cyclobutylacetic acid (1 g, 8.772 mmol) in acetonitrile (50 mL), cool to 0°C, and add N,N'-dicyclohexylcarbodiimide (2.7 g, 13.158 mmol), 4-dimethylaminopyridine (107 mg, 0.877 mmol), and 4-methylbenzenethiol (1.1 g, 8.772 mmol). The reaction mixture is warmed to room temperature and stirred for 2 hours. After completion of the reaction, the reaction mixture is concentrated under reduced pressure to obtain a crude product, which is then purified by silica gel column chromatography (petroleum ether:dichloromethane = 2:1) to afford the title compound (1.9 g, yield: 98.4%) as a yellow oil.

[0740] Step 2: tert-Butyl 5-chloro-3-(2-cyclobutylacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0741] (7-((tert-Butoxycarbonyl)(methyl)amino)-5-chloropyrazolo[1,5-a]pyrimidin-3-yl)boronic acid (700 mg, 2.147 mmol) and S-(p-tolyl)-2-cyclobutanethioacetate (945 mg, 4.294 mmol) were dissolved in tetrahydrofuran (40 mL). Tri(2-furyl)phosphine (TFP) (149 mg, 0.644 mmol), copper(I) thiophene-2-carboxylate (CuTC) (656 mg, 3.436 mmol), and tris(dibenzylideneacetone)dipalladium (196 mg, 0.215 mmol) were added. After nitrogen substitution, the reaction mixture was stirred in an oil bath at 50°C for 2 hours. After completion of the reaction, the reaction mixture was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain the title compound (213 mg, yield: 26.2%, yellow oil).

[0742] MS (ESI): m / z 379.0 [M+H] + ;

[0743] Step 3: tert-Butyl (3-(2-cyclobutylacetyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0744] Dissolve tert-butyl 5-chloro-3-(2-cyclobutylacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (190 mg, 0.503 mmol) in dioxane (10 mL), and add 2-methoxypyridin-3-amine 6 (75 mg, 0.603 mmol), palladium acetate (23 mg, 0.101 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (116 mg, 0.201 mmol), and cesium carbonate (492 mg, 1.508 mmol). After nitrogen substitution, the reaction mixture was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction mixture was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to give the title compound (132 mg, yield: 56.4%, yellow solid).

[0745] MS (ESI): m / z 467.1 [M+H] + ;

[0746] Step 4: 2-cyclobutyl-1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 27)

[0747] Tert-butyl (3-(2-cyclobutylacetyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (110 mg, 0.236 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water (20 mL), and the aqueous phase was adjusted to pH 6-7 with saturated sodium bicarbonate. The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (56.69 mg, yield: 65.9%) as a white solid.

[0748] MS (ESI): m / z 367.1 [M+H] + ;

[0749] 1 H NMR (400MHz, DMSO-d6) δ8.84(s,1H),8.78(dd,J=7.6,1.6Hz,1H),8.23(s,1H),7.89–7.78(m,2H),6.94(dd,J=7.6,4.8Hz,1H),6.11(s,1H),3. 98(s,3H),3.14(d,J=7.6Hz,2H),2.91(d,J=4.8Hz,3H),2.75(dt,J=15. 2,7.6Hz,1H),2.11–2.00(m,2H),1.88–1.76(m,2H),1.75–1.64(m,2H).

[0750] Example 28

[0751] 2-Cyclobutoxy-1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 28)

[0752] Step 1: 2-cyclobutoxyacetic acid

[0753] Dissolve cyclobutanol (1.0 g, 14.388 mmol) in tetrahydrofuran (70 mL), cool to 0°C, add sodium hydride (1.2 g, 28.777 mmol), and stir for 2 hours. Then, add 2-bromoacetic acid (2.0 g, 14.388 mmol). The reaction mixture is warmed to room temperature and stirred for 16 hours. After completion, the reaction mixture is quenched with water (50 mL), and the aqueous phase is extracted with ethyl acetate (50 mL x 2). The pH of the aqueous phase is adjusted to 1-2 with 1M HCl aqueous solution, and the mixture is extracted with ethyl acetate (50 mL x 3). The combined organic phases are washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to afford the title compound (1.6 g, yield: 85.6%) as a yellow oil.

[0754] Step 2: 2-cyclobutoxythioacetic acid S-(p-tolyl) ester

[0755] Dissolve 2-cyclobutoxyacetic acid (1.5 g, 11.538 mmol) in acetonitrile (50 mL), cool to 0°C, and add N,N'-dicyclohexylcarbodiimide (3.6 g, 17.308 mmol), 4-dimethylaminopyridine (141 mg, 1.154 mmol), and 4-methylbenzenethiol (1.4 g, 11.538 mmol). The reaction mixture was warmed to room temperature and stirred for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (petroleum ether:dichloromethane = 2:1) to obtain the title compound (1.5 g, yield: 55.6%, yellow oil).

[0756] MS (ESI): m / z 237.1 [M+H] + ;

[0757] Step 3: tert-Butyl (5-chloro-3-(2-cyclobutoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0758] (7-((tert-Butoxycarbonyl)(methyl)amino)-5-chloropyrazolo[1,5-a]pyrimidin-3-yl)boronic acid (600 mg, 1.840 mmol) and S-(p-tolyl) 2-cyclobutoxythioate (870 mg, 3.681 mmol) were dissolved in tetrahydrofuran (40 mL). Tri(2-furyl)phosphine (TFP) (128 mg, 0.552 mmol), copper(I) thiophene-2-carboxylate (CuTC) (562 mg, 2.945 mmol), and tris(dibenzylideneacetone)dipalladium (168 mg, 0.184 mmol) were added. After nitrogen substitution, the reaction mixture was stirred in an oil bath at 50°C for 2 hours. After completion of the reaction, the reaction mixture was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain the title compound (141 mg, yield: 19.4%, yellow oil).

[0759] MS (ESI): m / z 395.0 [M+H] + ;

[0760] Step 4: tert-Butyl (3-(2-cyclobutoxyacetyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0761] Tert-butyl (5-chloro-3-(2-cyclobutoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (120 mg, 0.305 mmol) was dissolved in dioxane (10 mL), and 2-methoxypyridin-3-amine (45 mg, 0.365 mmol), palladium acetate (14 mg, 0.061 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (70 mg, 0.122 mmol), and cesium carbonate (298 mg, 0.914 mmol) were added. After nitrogen substitution, the reaction solution was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction solution was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to give the title compound (112 mg, yield: 76.2%, yellow solid).

[0762] MS (ESI): m / z 483.1 [M+H] + ;

[0763] Step 5: 2-cyclobutoxy-1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 28)

[0764] Dissolve tert-butyl (3-(2-cyclobutoxyacetyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (190 mg, 0.394 mmol) in dichloromethane (8 mL). Add trifluoroacetic acid (2 mL), and stir the reaction mixture at room temperature for 1 hour. After completion, pour the reaction mixture into water (20 mL). The aqueous phase is adjusted to pH 6-7 with saturated sodium bicarbonate solution and extracted with dichloromethane (20 mL x 3). The combined organic phases are washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the crude product. The crude product is purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (39.53 mg, yield: 26.4%) as a white solid.

[0765] MS (ESI): m / z 383.1 [M+H] + ;

[0766] 1 H NMR (400MHz, DMSO-d6) δ8.86(s,1H),8.68(dd,J=7.6,1.6Hz,1H),8.29(s,1H),7.95–7.80(m,2H),6.99(dd,J=8.0,4.8Hz,1H),6.07(s,1H),4.61(s,2 H),4.06–4.00(m,1H),3.98(s,3H),2.90(d,J=4.8Hz,3H),2.19–2.08(m,2H ),1.87(qd,J=10.0,2.4Hz,2H),1.65(q,J=10.0Hz,1H),1.54–1.41(m,1H).

[0767] Example 29

[0768] 2-Cyclopropyloxy-1-(5-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 29)

[0769] Step 1: tert-Butyl (3-(2-cyclopropyloxyacetyl)-5-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0770] Dissolve tert-butyl (5-chloro-3-(2-cyclopropyloxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (120 mg, 0.316 mmol) in dioxane (10 mL). Add 2,3-dihydrobenzo[b][1,4]dioxin-5-amine (57 mg, 0.379 mmol), palladium acetate (14 mg, 0.063 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (73 mg, 0.126 mmol), and cesium carbonate (309 mg, 0.947 mmol). After nitrogen substitution, the reaction mixture was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction mixture was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the title compound (117 mg, yield: 74.9%, yellow solid).

[0771] MS (ESI): m / z 496.3 [M+H] + ;

[0772] Step 2: 2-cyclopropyloxy-1-(5-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 29)

[0773] Tert-butyl (3-(2-cyclopropyloxyacetyl)-5-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (107 mg, 0.216 mmol) was dissolved in dichloromethane (8 mL). Trifluoroacetic acid (2 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water (20 mL), and the aqueous phase was adjusted to pH 6-7 with saturated sodium bicarbonate. The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (15.57 mg, yield: 18.3%) as a white solid.

[0774] MS (ESI): m / z 396.1 [M+H] + ;

[0775] 1 H NMR (400MHz, DMSO-d6) δ8.70 (s, 1H), 8.26 (s, 1H), 7.86 (d, J = 7.2Hz, 1H), 7.81 (d,J=4.8Hz,1H),6.79(t,J=8.4Hz,1H),6.60(dd,J=8.0,1.2Hz,1H),5.97(s,1 H),4.77(s,2H),4.37–4.31(m,2H),4.31–4.24(m,2H),3.46(dd,J=6.0,2.8Hz, 1H), 2.89 (d, J = 4.8Hz, 3H), 0.52 (dd, J = 7.2, 4.4Hz, 2H), 0.45 (t, J = 5.2Hz, 2H).

[0776] Example 30

[0777] 2-Cyclopropyloxy-1-(5-((2-fluoro-3-morpholinophenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 30)

[0778] Step 1: 4-(2-fluoro-3-nitrophenyl)morpholine

[0779] Dissolve 1-bromo-2-fluoro-3-nitrobenzene (1.5 g, 6.818 mmol) in dioxane (15 mL), and add morpholine (840 mg, 9.642 mmol), palladium acetate (160 mg, 0.713 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (620 mg, 1.072 mmol), and cesium carbonate (4.44 g, 13.627 mmol). After nitrogen substitution, the reaction mixture was stirred in an oil bath at 110°C for 6 hours. After completion of the reaction, the reaction mixture was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated brine (40 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=6:1) to give the title compound (690 mg, yield: 44.7%, yellow solid).

[0780] MS (ESI): m / z 227.1 [M+H] + ;

[0781] Step 2: 2-Fluoro-3-morpholinoaniline

[0782] Dissolve 4-(2-fluoro-3-nitrophenyl)morpholine (690 mg, 3.05 mmol) in methanol (15 mL), then add ammonium formate (769 mg, 12.196 mmol), 10% palladium on carbon (76 mg), and water (1.05 mL). After nitrogen substitution, the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 6:1) to obtain the title compound (570 mg, yield: 95.1%), as a yellow solid.

[0783] MS (ESI): m / z 197.1 [M+H] + ;

[0784] Step 3: tert-Butyl (3-(2-cyclopropyloxyacetyl)-5-((2-fluoro-3-morpholinophenyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0785] Tert-butyl (5-chloro-3-(2-cyclopropyloxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (150 mg, 0.394 mmol) was dissolved in dioxane (10 mL), and 2-fluoro-3-morpholinoaniline (93 mg, 0.474 mmol), palladium acetate (18 mg, 0.0802 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (91 mg, 0.157 mmol), and cesium carbonate (385 mg, 1.182 mmol) were added. After nitrogen substitution, the reaction solution was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction solution was poured into water (30 mL), and the aqueous phase was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=30:1) to give the title compound (95 mg, yield: 44.6%, yellow oil).

[0786] MS (ESI): m / z 541.2 [M+H] + ;

[0787] Step 4: 2-cyclopropyloxy-1-(5-((2-fluoro-3-morpholinophenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 30)

[0788] Tert-butyl (3-(2-cyclopropyloxyacetyl)-5-((2-fluoro-3-morpholinophenyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (95 mg, 0.176 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (28.6 mg, yield: 36.9%) as a white solid.

[0789] MS (ESI): m / z 441.2 [M+H] + ;

[0790] 1 H NMR(400MHz,DMSO-d6)δ9.14(s,1H),8.27(s,1H),7.87(dd,J=8.5,6.2Hz,2 H),7.07(t,J=7.7Hz,1H),6.78(t,J=7.5Hz,1H),5.84(s,1H),4.71(s,2H),3 .78–3.73(m,4H),3.45(ddd,J=9.1,6.0,3.0Hz,1H),3.04–2.99(m,4H),2.9 0(d,J=4.8Hz,3H),0.50(dt,J=6.2,3.1Hz,2H),0.41(dt,J=6.1,4.7Hz,2H).

[0791] Example 31

[0792] 2-Cyclopropyloxy-1-(7-(methylamino)-5-(quinoxalin-5-ylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 31)

[0793] Step 1: Quinoxaline-5-amine

[0794] 5-Nitroquinoxaline (600 mg, 3.426 mmol) was dissolved in tetrahydrofuran (13 mL) and 1N aqueous hydrochloric acid (13 mL), and zinc powder (2.24 g, 34.261 mmol) was added. After nitrogen substitution, the reaction mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was poured into water (50 mL), and the aqueous phase was adjusted to pH 12 with 4N aqueous sodium hydroxide. The aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the title compound (180 mg, yield: 36.2%) as a yellow solid.

[0795] MS (ESI): m / z 146.1 [M+H] + ;

[0796] Step 2: tert-Butyl (3-(2-cyclopropyloxyacetyl)-5-(quinoxalin-5-ylamino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0797] Dissolve tert-butyl (5-chloro-3-(2-cyclopropyloxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (150 mg, 0.394 mmol) in dioxane (10 mL), and add quinoxalin-5-amine (69 mg, 0.475 mmol), palladium acetate (18 mg, 0.0802 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (91 mg, 0.157 mmol), and cesium carbonate (385 mg, 1.182 mmol). After nitrogen substitution, the reaction mixture was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (dichloromethane:methanol = 24:1) to obtain the title compound (150 mg, yield: 77.7%) as a yellow solid.

[0798] MS (ESI): m / z 490.2 [M+H] + ;

[0799] Step 3: 2-cyclopropyloxy-1-(7-(methylamino)-5-(quinoxalin-5-ylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 31)

[0800] Tert-butyl (3-(2-cyclopropyloxyacetyl)-5-(quinoxalin-5-ylamino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (150 mg, 0.306 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added. The reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into water (20 mL) and adjusted to pH 7 with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by acetonitrile slurrying to obtain the title compound (44.82 mg, yield: 37.5%) as a yellow solid.

[0801] MS (ESI): m / z 390.1 [M+H] + ;

[0802] 1 H NMR (400MHz, DMSO-d6) δ9.91 (s, 1H), 9.11 (d, J = 7.9Hz, 1H), 9.05 (d, J = 1.8Hz ,1H),8.98(d,J=1.8Hz,1H),8.37(s,1H),7.98(d,J=4.9Hz,1H),7.85(t,J=8. 2Hz, 1H), 7.72 (dd, J=8.4, 1.0Hz, 1H), 6.45 (s, 1H), 4.92 (s, 2H), 3.58 (tt, J= 5.9,3.0Hz,1H),2.96(d,J=4.8Hz,3H),0.63–0.58(m,2H),0.55–0.49(m,2H).

[0803] Example 32

[0804] 3-((3-(2-cyclopropyloxyacetyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-1-(difluoromethyl)pyridin-2(1H)-one (Compound 32)

[0805] Step 1: 1-(difluoromethyl)-3-nitropyridin-2(1H)-one

[0806] 3-Nitropyridin-2(1H)-one (1.5 g, 10.714 mmol) was dissolved in triethylene glycol dimethyl ether (43 mL). After nitrogen replacement, the temperature was lowered to -15°C and sodium tert-butoxide (2.3 g, 23.571 mmol) was added. The reaction mixture was stirred in a -15°C dry ice bath for 10 minutes. Difluorobromomethyltrimethylsilane (2.6 g, 12.857 mmol) was added dropwise, and the reaction mixture was stirred in a -15°C dry ice bath for 1 hour. After completion of the reaction, the reaction mixture was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the title compound (725 mg, yield: 35.6%, yellow oil).

[0807] MS (ESI): m / z 191.0 [M+H] + ;

[0808] Step 2: 3-amino-1-(difluoromethyl)pyridin-2(1H)-one

[0809] 1-(Difluoromethyl)-3-nitropyridin-2(1H)-one (725 mg, 3.816 mmol) was dissolved in ethanol (15 mL) and Pd / C (75 mg) was added. After hydrogen substitution, the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the title compound (416 mg, yield: 68.2%, brown oil).

[0810] MS (ESI): m / z 161.1 [M+H] + ;

[0811] Step 3: tert-Butyl (3-(2-cyclopropyloxyacetyl)-5-((1-(difluoromethyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0812] Dissolve tert-butyl (5-chloro-3-(2-cyclopropyloxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (120 mg, 0.316 mmol) in dioxane (10 mL), and add 3-amino-1-(difluoromethyl)pyridin-2(1H)-one (61 mg, 0.379 mmol), palladium acetate (14 mg, 0.063 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (73 mg, 0.126 mmol), and cesium carbonate (309 mg, 0.947 mmol). After nitrogen substitution, the reaction mixture was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction solution was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the title compound (55 mg, yield: 34.6%, as a yellow solid).

[0813] MS (ESI): m / z 505.1 [M+H] + ;

[0814] Step 4: 3-((3-(2-cyclopropyloxyacetyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-1-(difluoromethyl)pyridin-2(1H)-one (Compound 32)

[0815] Tert-butyl (3-(2-cyclopropyloxyacetyl)-5-((1-(difluoromethyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (45 mg, 0.089 mmol) was dissolved in dichloromethane (8 mL). Trifluoroacetic acid (2 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water (20 mL), and the aqueous phase was adjusted to pH 6-7 with saturated sodium bicarbonate. The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (11.85 mg, yield: 32.9%) as a white solid.

[0816] MS (ESI): m / z 405.1 [M+H] + ;

[0817] 1H NMR(400MHz, DMSO-d6)δ9.10(s,1H),8.75(d,J=6.0Hz,1H),8.36(s,1H),8.22–7.81(m,2H),7.43(d,J=6.0Hz,1H),6.48(t,J= 7.2Hz,1H),6.36(s,1H),4.82(s,2H),3.54(dt,J=9.2,3.2Hz,1H),2.90(d,J=4.8Hz,3H),0.58(s,2H),0.49(d,J=4.8Hz,2H).

[0818] Example 33

[0819] 2-Cyclopropyloxy-1-(5-((2-(methoxy-d3)phenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 33)

[0820] Step 1: N-(2-(Methoxy-d3)phenyl)acetamide

[0821] N-(2-Hydroxyphenyl)acetamide (3 g, 19.845 mmol) was dissolved in acetonitrile (20 mL), and deuterated iodomethane (4.89 g, 33.733 mmol) and potassium carbonate (5.49 g, 39.725 mmol) were added. After nitrogen substitution, the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with 10% aqueous potassium carbonate (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain the title compound (2.7 g, yield: 80.8%), as a yellow solid.

[0822] MS (ESI): m / z 169.2 [M+H] + ;

[0823] Step 2: 2-(Methoxy-d3)aniline

[0824] Dissolve N-(2-(Methoxy-d3)phenyl)acetamide (400 mg, 2.378 mmol) in water (3 mL) and add hydrochloric acid (1 mL). After nitrogen substitution, the reaction mixture was stirred in an oil bath at 90°C for 2 hours. After completion, the reaction mixture was poured into water (30 mL). The aqueous phase was adjusted to pH 14 with 4N sodium hydroxide solution and extracted with dichloromethane (40 mL x 3). The combined organic phases were washed with saturated brine (40 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (dichloromethane:methanol = 99:1) to obtain the title compound (240 mg, yield: 80%) as a yellow oil.

[0825] MS (ESI): m / z 127.2 [M+H] + ;

[0826] Step 3: tert-Butyl (3-(2-cyclopropyloxyacetyl)-5-((2-(methoxy-d3)phenyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0827] Tert-butyl (5-chloro-3-(2-cyclopropyloxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (150 mg, 0.394 mmol) was dissolved in dioxane (8 mL), and 2-(methoxy-d3)aniline (60 mg, 0.476 mmol), palladium acetate (18 mg, 0.0802 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (91 mg, 0.157 mmol), and cesium carbonate (385 mg, 1.182 mmol) were added. After nitrogen substitution, the reaction solution was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction solution was poured into water (30 mL), and the aqueous phase was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=49:1) to give the title compound (100 mg, yield: 54%, yellow solid).

[0828] MS (ESI): m / z 471.2 [M+H] + ;

[0829] Step 4: 2-cyclopropyloxy-1-(5-((2-(methoxy-d3)phenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 33)

[0830] Tert-butyl (3-(2-cyclopropyloxyacetyl)-5-((2-(methoxy-d3)phenyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (100 mg, 0.213 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (9.76 mg, yield: 12.4%) as a white solid.

[0831] MS (ESI): m / z 371.2 [M+H] + ;

[0832] 1 H NMR(400MHz, DMSO-d6)δ8.69(s,1H),8.36(d,J=7.3Hz,1H),8.26(s,1H),7.80(q,J=4.6Hz,1H),7.09–7.01(m,2H),6.97–6.9 0(m,1H),5.99(s,1H),4.78(s,2H),3.47(tt,J=6.0,3.0Hz,1H),2.89(d,J=4.8Hz,3H),0.56–0.50(m,2H),0.49–0.42(m,2H).

[0833] Example 34

[0834] 3-((3-(2-cyclopropyloxyacetyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-1-cyclopropylpyridin-2(1H)-one (Compound 34)

[0835] Step 1: 1-cyclopropyl-3-nitropyridin-2(1H)-one

[0836] 3-Nitropyridin-2(1H)-one (2.2 g, 15.703 mmol) was dissolved in acetonitrile (40 mL), and cyclopropylboronic acid 2 (4.05 g, 47.148 mmol), 2,2'-bipyridine (2.45 g, 15.687 mmol), copper acetate (2.85 g, 15.691 mmol), and sodium carbonate (4.99 g, 47.08 mmol) were added. After oxygen substitution, the reaction solution was stirred in an oil bath at 70°C for 16 hours. After completion of the reaction, the reaction solution was poured into water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=32:1) to give the title compound (1 g, yield: 35.3%, yellow solid).

[0837] MS (ESI): m / z 181.1 [M+H] + ;

[0838] Step 2: 3-amino-1-cyclopropylpyridin-2(1H)-one

[0839] 1-Cyclopropyl-3-nitropyridin-2(1H)-one (1 g, 5.551 mmol) was dissolved in methanol (30 mL) and palladium-on-carbon catalyst (100 mg) was added. After hydrogen substitution, the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (dichloromethane:methanol = 32:1) to obtain the title compound (790 mg, yield: 94.7%), as a yellow solid.

[0840] MS (ESI): m / z 151.2 [M+H] + ;

[0841] Step 3: tert-Butyl (3-(2-cyclopropyloxyacetyl)-5-((1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0842] Dissolve tert-butyl (5-chloro-3-(2-cyclopropyloxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (150 mg, 0.394 mmol) in dioxane (8 mL), and add 3-amino-1-cyclopropylpyridin-2(1H)-one (71 mg, 0.473 mmol), palladium acetate (18 mg, 0.0802 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (91 mg, 0.157 mmol), and cesium carbonate (385 mg, 1.182 mmol). After nitrogen substitution, the reaction mixture was stirred in an oil bath at 110°C for 1 hour. After the reaction was complete, the reaction mixture was poured into water (30 mL). The aqueous phase was extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (dichloromethane:methanol = 32:1) to obtain the title compound (120 mg, yield: 61.6%, as a yellow solid).

[0843] MS (ESI): m / z 495.4 [M+H] + ;

[0844] Step 4: 3-((3-(2-cyclopropyloxyacetyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-1-cyclopropylpyridin-2(1H)-one (Compound 34)

[0845] Tert-butyl (3-(2-cyclopropyloxyacetyl)-5-((1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (120 mg, 0.243 mmol) was dissolved in dichloromethane (6 mL). Trifluoroacetic acid (2 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (43.45 mg, yield: 45.4%) as a white solid.

[0846] MS (ESI): m / z 395.2 [M+H] + ;

[0847] 1H NMR(400MHz, DMSO-d6)δ8.92(s,1H),8.62(dd,J=7.4,1.6Hz,1H),8.32(s,1H),7.87(q, J=4.6Hz,1H),7.19(dd,J=7.0,1.6Hz,1H),6.30(s,1H),6.23(t,J=7.2Hz,1H),4.82(s,2 H),3.53(ddd,J=9.0,6.0,3.0Hz,1H),3.47(ddd,J=11.5,7.5,4.3Hz,1H),2.90(d,J=4.8 Hz,3H),1.04(q,J=7.3Hz,2H),0.93–0.86(m,2H),0.62–0.55(m,2H),0.52–0.45(m,2H).

[0848] Example 35

[0849] 3-((3-(2-cyclobutoxyacetyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-1-(difluoromethyl)pyridin-2(1H)-one (Compound 35)

[0850] Step 1: tert-Butyl (3-(2-cyclobutoxyacetyl)-5-((1-(difluoromethyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0851] Dissolve tert-butyl (5-chloro-3-(2-cyclobutoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (120 mg, 0.305 mmol) in dioxane (10 mL), and add 3-amino-1-(difluoromethyl)pyridin-2(1H)-one (58 mg, 0.365 mmol), palladium acetate (14 mg, 0.061 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (70 mg, 0.122 mmol), and cesium carbonate (298 mg, 0.914 mmol). After nitrogen substitution, the reaction mixture was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction mixture was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the title compound (135 mg, yield: 85.4%, yellow solid).

[0852] MS (ESI): m / z 519.2 [M+H]+ ;

[0853] Step 2: 3-((3-(2-cyclobutoxyacetyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-1-(difluoromethyl)pyridin-2(1H)-one (Compound 35)

[0854] Tert-butyl (3-(2-cyclobutoxyacetyl)-5-((1-(difluoromethyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (115 mg, 0.222 mmol) was dissolved in dichloromethane (8 mL). Trifluoroacetic acid (2 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water (20 mL), and the aqueous phase was adjusted to pH 6-7 with saturated sodium bicarbonate. The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (23.77 mg, yield: 25.6%) as a white solid.

[0855] MS (ESI): m / z 419.1 [M+H] + ;

[0856] 1 H NMR(400MHz, DMSO-d6)δ9.08(s,1H),8.69(dd,J=7.6,1.2Hz,1H),8.35(s,1H),8.23–7.84(m,2H),7.54–7.41(m,1H),6.48(t,J=7.2Hz,1H), 6.35(s,1H),4.66(s,2H),4.09(p,J=7.2Hz,1H),2.90(d,J=4.8Hz,3H),2.26–2.11(m,2H),1.91(qd,J=10.0,2.4Hz,2H),1.75–1.40(m,2H).

[0857] Example 36

[0858] 2-Cyclopropyloxy-1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 36)

[0859] Step 1: tert-Butyl 3-(2-cyclopropyloxyacetyl)-5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0860] Dissolve tert-butyl (5-chloro-3-(2-cyclopropyloxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (380 mg, 0.998 mmol) in dioxane (14 mL). Add 7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-amine (203 mg, 1.2 mmol), palladium acetate (22 mg, 0.098 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (124 mg, 0.199 mmol), and cesium carbonate (976 mg, 2.996 mmol). After nitrogen substitution, the reaction mixture was stirred in an oil bath at 110°C for 1 hour. After the reaction was complete, the reaction mixture was poured into water (40 mL). The aqueous phase was extracted with dichloromethane (40 mL x 3). The combined organic phases were washed with saturated brine (40 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (dichloromethane:methanol = 99:1) to obtain the title compound (160 mg, yield: 31.2%), as a yellow solid.

[0861] MS (ESI): m / z 514.2 [M+H] + ;

[0862] Step 2: 2-cyclopropyloxy-1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 36)

[0863] Dissolve tert-butyl 3-(2-cyclopropyloxyacetyl)-5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (160 mg, 0.312 mmol) in dichloromethane (6 mL). Add trifluoroacetic acid (2 mL), and stir the reaction mixture at room temperature for 1 hour. After completion of the reaction, concentrate the mixture under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (61.23 mg, yield: 47.4%) as a white solid.

[0864] MS (ESI): m / z 414.1 [M+H] + ;

[0865] 1 H NMR (400MHz, DMSO-d6) δ8.83(s,1H),8.31(s,1H),7.99(dd,J=11.8,3.0Hz,1H),7.90(q,J=4.4Hz,1H),6.46(dd,J=9.5,3.0Hz,1H),6.13( s,1H),4.80(s,2H),4.33(dd,J=9.9,4.8Hz,4H),3.51(tt,J=5.9,2.9Hz,1H),2.90(d,J=4.8Hz,3H),0.57–0.51(m,2H),0.46–0.39(m,2H).

[0866] Example 37

[0867] 3-((3-(2-cyclopropyloxyacetyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-1-(pyrazin-2-yl)pyridin-2(1H)-one (Compound 37)

[0868] Step 1: 3-amino-1-(pyrazin-2-yl)pyridin-2(1H)-one

[0869] 3-Aminopyridin-2(1H)-one (500 mg, 4.541 mmol) and 2-bromopyrazine (1.8 g, 11.322 mmol) were dissolved in dioxane (10 mL). Potassium carbonate (1.88 g, 13.603 mmol), N,N'-dimethylethylenediamine (160 mg, 1.815 mmol), and cuprous iodide (173 mg, 0.908 mmol) were added. After nitrogen substitution, the reaction solution was stirred in an oil bath at 110°C for 16 hours. After completion of the reaction, the reaction solution was poured into water (40 mL). The aqueous phase was extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated brine (40 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=49:1) to give the title compound (310 mg, yield: 36.2%, yellow solid).

[0870] MS (ESI): m / z 189.0 [M+H] + ;

[0871] Step 2: tert-Butyl (3-(2-cyclopropyloxyacetyl)-5-((2-oxo-1-(pyrazin-2-yl)-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0872] Dissolve tert-butyl (5-chloro-3-(2-cyclopropyloxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (130 mg, 0.341 mmol) in dioxane (8 mL), and add 3-amino-1-(pyrazin-2-yl)pyridin-2(1H)-one (77 mg, 0.409 mmol), palladium acetate (8 mg, 0.0356 mmol), 1,1′-binaphthyl-2,2′-bisdiphenylphosphine (42 mg, 0.0674 mmol), and cesium carbonate (333 mg, 1.022 mmol). After nitrogen substitution, the reaction mixture was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=49:1) to give the title compound (110 mg, yield: 60.4%, yellow solid).

[0873] MS (ESI): m / z 533.2 [M+H] + ;

[0874] Step 3: 3-((3-(2-cyclopropyloxyacetyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-1-(pyrazin-2-yl)pyridin-2(1H)-one (Compound 37)

[0875] Tert-butyl (3-(2-cyclopropyloxyacetyl)-5-((2-oxo-1-(pyrazin-2-yl)-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (110 mg, 0.207 mmol) was dissolved in dichloromethane (6 mL). Trifluoroacetic acid (2 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (elution system: water, ammonium bicarbonate, acetonitrile) to obtain the title compound (15.37 mg, yield: 17.2%) as a white solid.

[0876] MS (ESI): m / z 433.2 [M+H] + ;

[0877] 1H NMR (400MHz, DMSO-d6) δ9.21(s,1H),9.10(s,1H),8.79(dd,J=7.5,1.4Hz,1H),8.76(d,J=3.5Hz,2H),8.36(s,1H),7.94(s,1H),7.58(dd,J=7. 0,1.5Hz,1H),6.51(t,J=7.3Hz,1H),6.36(s,1H),4.86(s,2H),3.57(tt ,J=6.0,2.9Hz,1H),2.90(s,3H),0.63–0.58(m,2H),0.54–0.48(m,2H).

[0878] Biological test evaluation

[0879] Test Example A: In vitro enzyme binding assay of the compound TYK2JH2 of the present invention

[0880] Experimental purpose: The purpose of this test example is to use the fluorescence resonance energy transfer (TR-FRET) method to test the inhibitory effect of compounds on TYK2 JH2 pseudokinase.

[0881] Experimental methods:

[0882] Compounds were dissolved in DMSO to a 10 mM stock solution. A 200X compound concentration gradient was prepared on a compound dilution plate and transferred to an Echo plate. Using the Echo instrument, 75 nL of compound was transferred from the Echo plate to a 384-well assay plate. 5 μL of 3X TYK2 JH2 kinase (Bioduro), 5 μL of 3X Tb antibody (Cisbio), and 5 μL of 3X TRACER (Bioduro) were added to the 384-well assay plate. The plate was centrifuged for 30 seconds and incubated at room temperature for 60 minutes. The 495 nm / 520 nm fluorescence signal ratio was read on an Envision microplate reader (PerkinElmer). Data were analyzed using XL-Fit software, and compound IC50 values ​​were calculated.

[0883] Experimental results:

[0884] It can be seen from the experimental data that the compounds of the present invention have a good binding effect on TYK2 JH2 pseudokinase.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof: in, R1 is selected from H, halogen, -OR, -SR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; R2 is -L2–R 2A ; R3 is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR, -SR, halogen, -CN, -NO2, -N(R 3A )(R 3B ),-NHC(O)R 3A 、C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; R4 is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -OR, -SR, halogen, -CN, -NO2, -N(R 4A )(R 4B ),-NHC(O)R 4A 、C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; L2 is a covalent bond or C 1-6 Alkylene, wherein one or two methylene units in the alkylene are optionally and independently replaced by: -C(R 2B )2-、-CH(R 2B )-、-N(R 2B )-、-N(R 2B )C(O)-、-C(O)N(R 2B )-、-N(R 2B )S(O)2-、-S(O)2N(R 2B )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-; R 1A Each occurrence is independently selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 alkyl halide; R 1B Each occurrence is independently selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 alkyl halide; R 2A Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 alkyl halide; R 2B Selected from C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, which are optionally substituted with 1-5 R 2b 'Substituent substitution; R 2b 'Selected from hydrogen, halogen, oxo, -CN, -NO2, -OR, -SR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; R 3A Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 alkyl halide; R 3B Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 alkyl halide; Or, R 3A and R 3B Together they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; R 4A Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 alkyl halide; R 4B Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 alkyl halide; Or, R 4A and R 4B Together they form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl; Each occurrence of R is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, oxo, and CN; Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium; n is 0, 1, 2, 3, 4, 5 or 6, Provided that when R1 is -OR or -SR, n is not 0.

2. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, which is of formula (II), in, Indicates whether the ring in which it is located is aromatic or non-aromatic; X is C(R 2b1 ), O, S, N or N(R 2b1 ); Y is C(R 2b2 ), O, S, N or N(R 2b2 ); Z is C(R 2b3 ), O, S, N or N(R 2b3 ); R 2b1 Selected from H, halogen, oxo, -CN, -NO2, -OR, -SR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; R 2b2 Selected from H, halogen, oxo, -CN, -NO2, -OR, -SR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; R 2b3 Selected from H, halogen, oxo, -CN, -NO2, -OR, -SR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; R 2b4 Selected from H, halogen, oxo, -CN, -NO2, -OR, -SR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; R 2b5 Selected from H, halogen, oxo, -CN, -NO2, -OR, -SR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; Each occurrence of R is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, oxo, and CN; Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium; Other groups are as defined in claim 1.

3. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, in, R1 is selected from -OMe, -OEt, 4. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, which is of formula (III), R1 is selected from H, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; R 2A Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 alkyl halide; R 2b1 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; R 2b2 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; R 2b3 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; R 2b4 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; R 2b5 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; R3 is selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl and -N(R 3A )(R 3B ); R4 is selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl and -N(R 4A )(R 4B ); R 3A H or C 1-6 alkyl; R 3B H or C 1-6 alkyl; R 4A H or C 1-6 alkyl; R 4B H or C 1-6 alkyl; Each occurrence of R is independently C 1-6 Alkyl or C 3-6 Cycloalkyl; Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium; n is 0, 1, 2, 3 or 4; Provided that when R1 is -OR, n is not 0.

5. The compound of claim 4, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, in, R1 is selected from -OR and C 3-4 Cycloalkyl, wherein the cycloalkyl is optionally substituted with 1-2 substituents selected from the group consisting of: C 1-4 Alkyl, -OR, oxo, and CN; R 2A is H; R 2b1 is selected from H, halogen and -OR; R 2b2 is a 5-6 membered heteroaryl group, which is optionally C 1-4 Alkyl substitution; R 2b3 is H; R 2b4 is H; R 2b5 is H; R3 is H; R4 is -N(R 4A )(R 4B ); R 4A H or C 1-4 alkyl; R 4B H or C 1-4 alkyl; Each occurrence of R is independently C 1-4 Alkyl or C 3-4 Cycloalkyl; Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium; n is 1.

6. The compound of claim 4, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, in, R1 is -OR, R 2A is H; R 2b1 is halogen or -OR, R 2b2 is a 5-6 membered heteroaryl group, such as a triazolyl group, which is C 1-4 Alkyl substituted, preferably, R 2b2 for R 2b3 is H; R 2b4 is H; R 2b5 is H; R3 is H; R4 is -N(R 4A )(R 4B ); R 4A is H; R 4B C 1-4 an alkyl group, preferably a methyl group; Each occurrence of R is independently C 1-4 Alkyl or C 3-4 Cycloalkyl, preferably methyl or cyclopropyl; Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium; n is 1.

7. The compound of claim 4, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, in, R1 is -OR, R 2A is H; R 2b1 is -OR, R 2b2 is a 5-6 membered heteroaryl group, such as a triazolyl group, which is C 1-4 Alkyl substituted, preferably, R 2b2 for R 2b3 is H; R 2b4 is H; R 2b5 is H; R3 is H; R4 is -N(R 4A )(R 4B ); R 4A is H; R 4B C 1-4 an alkyl group, preferably a methyl group; Each occurrence of R is independently C 1-4 alkyl; Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium; n is 1.

8. The compound of claim 4, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, in, R1 is -OR, R 2A is H; R 2b1 For halogen, R 2b2 is a 5-6 membered heteroaryl group, such as a triazolyl group, which is C 1-4 Alkyl substituted, preferably, R 2b2 for R 2b3 is H; R 2b4 is H; R 2b5 is H; R3 is H; R4 is -N(R 4A )(R 4B ); R 4A is H; R 4B C 1-4 an alkyl group, preferably a methyl group; R is C 3-4 Cycloalkyl, preferably cyclopropyl; Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium; n is 1.

9. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, which is of formula (IV), preferably formula (IV-1): in, R1 is selected from H, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; R 2A Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 alkyl halide; R 2b2 Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; R 2b3 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, -OR, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; R 2b4 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, -OR, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; R 2b5 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, -OR, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; R3 is selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl and -N(R 3A )(R 3B ); R4 is selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl and -N(R 4A )(R 4B ); R 3A H or C 1-6 alkyl; R 3B H or C 1-6 alkyl; R 4A H or C 1-6 alkyl; R 4B H or C 1-6 alkyl; Each occurrence of R is independently C 1-6 Alkyl or C 3-6 Cycloalkyl; Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium; n is 0, 1, 2, 3 or 4; Provided that when R1 is -OR, n is not 0.

10. The compound of claim 9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, in, R1 is selected from -OR and 5-6 membered heterocyclic groups, wherein the heterocyclic groups are optionally substituted with 1-2 substituents selected from the following: 1-4 Alkyl, -OR, oxo, and CN; R 2A is H; R 2b2 is a 5-6 membered heteroaryl group, which is optionally C 1-4 Alkyl substitution; R 2b3 is H; R 2b4 is H; R 2b5 is H; R3 is H; R4 is -N(R 4A )(R 4B ); R 4A H or C 1-4 alkyl; R 4B H or C 1-4 alkyl; Each occurrence of R is independently C 1-4 Alkyl or C 3-4 Cycloalkyl; Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium; n is 1.

11. The compound of claim 9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, in, R1 is selected from -OR and 5-6 membered heterocyclic group, preferably, the 5-6 membered heterocyclic group is oxacyclopentyl, preferably R 2A is H; R 2b2 is a 5-6 membered heteroaryl group, which is optionally C 1-4 Alkyl substitution; R 2b3 is H; R 2b4 is H; R 2b5 is H; R3 is H; R4 is -N(R 4A )(R 4B ); R 4A is H; R 4B C 1-4 an alkyl group, preferably a methyl group; R is C 1-4 alkyl; Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium; n is 1.

12. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, which is of formula (V), preferably (V-1): in, R1 is selected from H, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; R 2A Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 alkyl halide; R 2b1 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; R 2b3 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; R 2b4 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; R 2b5 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; R3 is selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl and -N(R 3A )(R 3B ); R4 is selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl and -N(R 4A )(R 4B ); R 3A H or C 1-6 alkyl; R 3B H or C 1-6 alkyl; R 4A H or C 1-6 alkyl; R 4B H or C 1-6 alkyl; Each occurrence of R is independently C 1-6 Alkyl or C 3-6 Cycloalkyl; Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium; n is 0, 1, 2, 3 or 4; Provided that when R1 is -OR, n is not 0.

13. The compound of claim 12, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, in, R1 is selected from -OMe, -OEt, 14. The compound of claim 12, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, in, R1 is selected from -OR, C 3-4 Cycloalkyl, 5-6 membered heterocyclyl and 5-6 membered heteroaryl, wherein the cycloalkyl, heterocyclyl and heteroaryl are optionally substituted with 1-2 substituents selected from the following: 1-4 Alkyl, -OR, oxo, and CN; R 2A is H; R 2b1 is -OR; R 2b3 is H; R 2b4 is H; R 2b5 is H; R3 is H; R4 is -N(R 4A )(R 4B ); R 4A H or C 1-4 alkyl; R 4B H or C 1-4 alkyl; Each occurrence of R is independently C 1-4 Alkyl or C 3-4 Cycloalkyl; Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium; n is 0, 1, or 2; Provided that when R1 is -OR, n is not 0.

15. The compound of claim 12, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, in, R1 is -OR; R 2A is H; R 2b1 is -OR; R 2b3 is H; R 2b4 is H; R 2b5 is H; R3 is H; R4 is -N(R 4A )(R 4B ); R 4A is H; R 4B C 1-4 an alkyl group, preferably a methyl group; Each occurrence of R is independently C 1-4 Alkyl, preferably methyl or ethyl; Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium; n is 1.

16. The compound of claim 12, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, in, R1 is -OR, where R is C 1-4 an alkyl group, preferably a methyl group; R 2A is H; R 2b1 -OR, where R is C 3-4 Cycloalkyl, preferably cyclopropyl; R 2b3 is H; R 2b4 is H; R 2b5 is H; R3 is H; R4 is -N(R 4A )(R 4B ); R 4A is H; R 4B C 1-4 an alkyl group, preferably a methyl group; Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium; n is 1.

17. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, which is of formula (VI), preferably formula (VI-1), R1 is selected from H, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; R 2A Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 alkyl halide; R 2b2 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; R 2b3 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; R 2b4 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; R 2b5 Selected from H, halogen, -OR, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN; R3 is selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl and -N(R 3A )(R 3B ); R4 is selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl and -N(R 4A )(R 4B ); R 3A H or C 1-6 alkyl; R 3B H or C 1-6 alkyl; R 4A H or C 1-6 alkyl; R 4B H or C 1-6 alkyl; Each occurrence of R is independently C 1-6 Alkyl or C 3-6 Cycloalkyl; Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium; n is 0, 1, 2, 3 or 4; Provided that when R1 is -OR, n is not 0.

18. The compound of claim 17, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, in, R1 is -OR; R 2A is H; R 2b2 is -OR; R 2b3 is H; R 2b4 is H or a 5-6 membered heteroaryl group, which is optionally C 1-4 Alkyl substitution; R 2b5 is H or halogen; R3 is H; R4 is -N(R 4A )(R 4B ); R 4A is H; R 4B H or C 1-4 an alkyl group, preferably a methyl group; Each occurrence of R is independently C 1-4 alkyl; Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium; n is 1.

19. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, wherein the compound is selected from:

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, and a pharmaceutically acceptable excipient; preferably, it further comprises other therapeutic agents.

21. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, or a pharmaceutical composition according to claim 20, in the preparation of a medicament for treating and / or preventing a TYK2-mediated disease.

22. A compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition according to claim 20 for use in the treatment and / or prevention of TYK2-mediated diseases.

23. A method for treating and / or preventing a TYK2-mediated disease in a subject, comprising administering to the subject a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition according to claim 20.

24. The use of claim 21 or the use of the compound or pharmaceutical composition of claim 22 or the method of claim 23, wherein the TYK2-mediated disease is selected from a neurological disease, an autoimmune disease, a skin disease, an allergic disease, an organ rejection, a cancer, dry eye, myelofibrosis, and polycythemia; preferably, the neurological disease is Alzheimer's disease, Parkinson's disease, systemic lupus erythematosus, amyotrophic lateral sclerosis, or multiple sclerosis; preferably, the autoimmune disease is lupus, rheumatoid arthritis, juvenile arthritis, psoriasis, ulcerative colitis, Crohn's disease, or autoimmune thyroid disease; the skin disease is psoriasis, rash, or atopic dermatitis; the allergic disorder is asthma or rhinitis; the organ transplant rejection is allogeneic rejection or graft-versus-host disease; and the cancer is renal cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, prostate cancer, head and neck cancer, thyroid cancer, lung cancer, glioblastoma, melanoma, lymphoma, or leukemia.

25. The use of claim 21 or the use of the compound or pharmaceutical composition of claim 22 or the method of claim 23, wherein the TYK2-mediated disease is selected from Alzheimer's disease, Parkinson's disease, systemic lupus erythematosus, amyotrophic lateral sclerosis or multiple sclerosis.

Images