Pyrazolopyrimidine compounds as TYK2 inhibitors

Abstract

The present invention relates to pyrazolopyrimidine compounds as TYK2 inhibitors. Specifically, the present invention provides pyrazolopyrimidine compounds of general formula (I), or pharmaceutically acceptable salts, enantiomers, diastereoisomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotope variants thereof. The invention further provides a pharmaceutical composition containing the compound, a preparation method of the pharmaceutical composition and application of the pharmaceutical composition in treatment or prevention of TYK2 kinase mediated diseases. # imgabs0 #

Description

[0001] This application claims the priority of Chinese Patent Application No. 202410149124X filed on February 1, 2024. The text of this priority is incorporated herein by reference. Technical Field

[0002] The present invention relates to the field of medicinal chemistry, and specifically to pyrazolopyrimidine compounds, compositions containing the same, methods for their preparation, and their use as TYK2 inhibitors. Background Art

[0003] The Janus kinase family (JAK) is an intracellular non-receptor tyrosine kinase that mediates the signal transduction and activation of various cytokines. Gain-of-function expression or mutation of JAK is associated with many autoimmune diseases, inflammation, and cancers. This family includes JAK1, JAK2, JAK3, and TYK2. Among them, JAK1, JAK2, and TYK2 are widely present in various tissues and cells of the human body, and JAK3 is mainly present in myeloid cells, thymocytes, NK cells, and activated B cells and T cells.

[0004] The JAK-mediated signaling pathway includes three key parts: cytokine receptors on the cell surface, JAK, and downstream proteins. Cytokines such as various interferons (IFNs) and interleukins (ILs) bind to cytokine receptors on the cell surface, bringing JAK, which binds to the intracellular domain of the receptor, closer. Then, tyrosine residues of JAK are phosphorylated, increasing the activity of the kinase domain. Subsequently, the activated JAK phosphorylates tyrosine residues of the receptor, creating a binding site for proteins with SH2 domains. STAT (signal transducer and activator of transcription) binds to phosphorylated tyrosine on the receptor through its SH2 domain, is phosphorylated by JAK, generating phosphorylated STAT dimers, and then the dimers translocate to the nucleus to induce the transcription of target genes. In addition, other proteins with SH2 domains can also bind to the activated JAK, thus cross-linking with other signaling pathways, such as PI3K / AKT, MAPK / ERK, etc.

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

[0006] Common 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 the JAK family kinases and the similarity of the ATP-binding regions in the human kinome, there is generally a problem of low selectivity.

[0007] Through research, the pseudokinase domain (JH2) with obvious catalytic activity in the JAK family can provide an ideal allosteric site for the discovery of TYK2 selective inhibitors. Compound BMS-986165 is a currently known compound that can selectively bind to the JH2 of TYK2 and inhibits the kinase function of TYK2 through an allosteric effect.

[0008] Currently, drugs with better activity that selectively inhibit TYK2 by binding to JH2 are needed to provide 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 through neurological therapies are major topics regarding how effective central nervous system drugs are. TYK2 inhibitors with brain penetration properties can be used for the treatment of neurological diseases such as recurrent and progressive Alzheimer's disease, Parkinson's disease, systemic lupus erythematosus, amyotrophic lateral sclerosis, or multiple sclerosis. From the perspective of medicinal chemistry, the ability to design drugs that can penetrate the BBB and achieve the desired biological responses is a huge challenge, and currently, drugs capable of achieving this purpose are needed. Summary of the Invention

[0010] Based on this, the present invention provides a pyrazolopyrimidine compound that has excellent activity in selectively inhibiting TYK2 and treats various TYK2-mediated diseases. In addition, the compounds of the present invention can penetrate the BBB.

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

[0012]

[0013] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound as defined in the present invention, 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.

[0014] In one embodiment, the present invention provides the use of a compound as defined in the present invention or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, and a pharmaceutical composition comprising the same, in the preparation of a medicament for the treatment and / or prevention of a TYK2 kinase-mediated disease.

[0015] In one embodiment, the present invention provides a compound as defined in the present invention 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 the treatment and / or prevention of a TYK2 kinase-mediated disease.

[0016] In one embodiment, the present invention provides a method for treating and / or preventing a TYK2 kinase-mediated disease in a subject with a compound as defined in the present invention, comprising administering to the subject the 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.

[0017] The TYK2 kinase-mediated diseases as described in the present invention are selected from autoimmune diseases, skin diseases, allergic diseases, organ rejection, cancer, dry eye disease, myelofibrosis, polycythemia. Further, 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 allograft rejection or graft-versus-host disease; 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.

[0018] In some embodiments, the diseases mediated by the TYK2 kinase in the present method are selected from rheumatoid arthritis, psoriasis, ulcerative colitis, and Crohn's disease. Detailed Description of Embodiments

[0019] Definitions

[0020] The compounds of the present invention, their preparation methods, and their uses are further described in detail below in conjunction with specific examples. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, these embodiments are provided to make the disclosure of the present invention more thorough and comprehensive.

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the technical field to which this invention belongs. The terms used herein in the 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 means any one and all combinations of one or more of the related listed items.

[0022] The term "alkyl" refers to a saturated hydrocarbon containing primary (normal) carbon atoms, or secondary carbon atoms, or tertiary carbon atoms, or quaternary carbon atoms, or a combination thereof. The alkyl is preferably, for example, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, and C1-C3 alkyl. Taking "C1-C4 alkyl" as an example, it refers to an alkyl containing 1 to 4 carbon atoms, and each occurrence can independently be C1 alkyl, C2 alkyl, C3 alkyl, or 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).

[0023] "Alkenyl" is an alkyl as defined in the present invention that contains at least one carbon-carbon double bond. In one example, the alkenyl 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 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, etc. When substituted, the substituents are 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] "Alkynyl" means an alkyl group as defined in the present invention containing at least one carbon-carbon triple bond. In one example, 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, etc. 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.

[0025] "Carbocyclic group" or "cycloalkyl group" 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 or partially unsaturated carbocyclic ring. Preferably, the cycloalkyl group 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, the carbocyclic group is a 3-4 membered monocyclic ring, 3-5 membered monocyclic ring, 3-6 membered monocyclic ring, 3-7 membered monocyclic ring, 3-8 membered monocyclic ring, 3-10 membered monocyclic ring, 5-8 membered monocyclic ring, 5-6 membered monocyclic ring, 4-12 membered bicyclic ring or 10-15 membered tricyclic system. The carbocyclic ring includes bridged rings or spiro rings. Non-limiting examples of carbocyclic groups 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. The carbocyclic group may be optionally substituted. When substituted, the number of substituents is 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.

[0026] The term "halogen" refers to -F, -Cl, -Br or -I. Further, the term "haloalkyl" refers to an alkyl group substituted by a halogen group, where the alkyl group is as defined above, preferably C 1-6 haloalkyl, C 1-5 haloalkyl, C 1-4 haloalkyl, C 1-3 haloalkyl and C1-2 Halogenated alkyl group.

[0027] The term "aryl" refers to an aromatic hydrocarbon group derived by removing one hydrogen atom from an aromatic ring compound, which may be a monocyclic aryl group, a fused-ring aryl group, or a polycyclic aryl group, preferably a 6- to 10-membered aryl group. For polycyclic ring species, at least one is an aromatic ring system. Phrases containing this term, for example, "6-membered aryl" means that the aromatic ring system contains 6 ring atoms. Preferably, the aryl group is a phenyl group.

[0028] The term "heteroaryl" refers to an aryl group containing heteroatoms, which may be monocyclic or fused rings, and the heteroatoms are independently selected from N, O, and S, preferably a 5- to 12-membered heteroaryl group, preferably a 5- to 10-membered heteroaryl group, preferably a 5- to 8-membered heteroaryl group, preferably a 5- to 6-membered heteroaryl group, preferably a 5-membered heteroaryl group. Heteroaryl groups include but are not limited to pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, triazolyl, tetrahydropyrrolyl, and thiadiazolyl. In one embodiment, typically a 5- to 6-membered monocyclic heteroaryl group containing one or more, preferably 1-3, preferably 1-2 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, furyl, 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.

[0029] "Heterocyclic group" or "heterocycle" refers to a substituted or unsubstituted saturated or partially unsaturated cyclic group containing heteroatoms selected from N, O, and S. Further, the term "heterocyclic group" refers to a group of a stable 3- to 10-membered saturated heterocyclic system in which one or more ring-forming atoms of a non-aromatic ring are heteroatoms and the rest are carbon. The heteroatoms include, but are not limited to, nitrogen atoms, oxygen atoms, sulfur atoms, etc. For example, the heterocyclic group is preferably a 3- to 7-membered heterocyclic group, a 3- to 6-membered heterocyclic group, a 3- to 5-membered heterocyclic group, a 3- to 4-membered heterocyclic group, a 4- to 7-membered heterocyclic group, a 4- to 6-membered heterocyclic group, a 4- to 5-membered heterocyclic group, a 5- to 6-membered heterocyclic group, or a 6- to 7-membered heterocyclic group, each containing 1 to 4, preferably 1 to 3, preferably 1 to 2 heteroatoms selected from N, O, or S. The heterocyclic group may 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 system, preferably a 3- to 10-membered heterocyclic group, and containing at least 1, preferably 1 to 4 heteroatoms selected from N, O, or S. In one embodiment, a 3- to 7-membered heterocyclic group is preferred, which contains 1 to 3, preferably 1 to 2 heteroatoms selected from N, O, or S. In one embodiment, a 5- to 6-membered heterocyclic group is preferred, which contains 1 to 3, preferably 1 to 2 heteroatoms selected from N, O, or S. Unless otherwise specifically specified in this specification, the heterocyclic group may be monocyclic ("monocyclic heteroalkyl"), or a bicyclic, tricyclic, or more-ringed ring system, which may include fused (condensed), bridged (bridged-ring), or spiro ring systems (e.g., bicyclic systems ("bicyclic heteroalkyl"). The ring system of the bicyclic heteroalkyl may include one or more heteroatoms in one or two rings; and is saturated. Exemplary 3-membered heterocyclic groups include, but are not limited to, aziridinyl, oxiranyl, and thiiranyl, or their stereoisomers; exemplary 4-membered heterocyclic groups include, but are not limited to, azetidinyl, oxopropyl, thiethanyl, or their isomers and stereoisomers; exemplary 5-membered heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, imidazolidinyl, pyrazolidinyl, dioxolanyl, oxathiolanyl, dithiolanyl, or their isomers and stereoisomers. Exemplary 6-membered heterocyclic groups include, but are not limited to, piperidinyl, tetrahydropyranyl, thianyl, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, piperazinyl, triazinyl, or their isomers and stereoisomers; exemplary 7-membered heterocyclic groups include, but are not limited to, azepanyl, oxepanyl, thiepanyl, and diazepanyl, or their isomers and stereoisomers. In one embodiment, a typical heterocyclic group is a 3- to 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, "heterocyclic group" is a 4- to 6-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S. In one embodiment, "heterocyclic group" is a 5- to 6-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0030] The term "oxo" refers to the =O group.

[0031] The term "CN" refers to the cyano group.

[0032] The term "aromatic" includes aryl and heteroaryl as defined above.

[0033] The term "non-aromatic" includes cycloalkyl and heterocyclic group as defined above.

[0034] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for that group should be understood as linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively. In some specific structures, when an alkyl group is clearly indicated as a linking group, then the alkyl group represents a linked alkylene group. For example, the alkyl in the group "-C1-C3 haloalkyl" should be understood as an alkylene group.

[0035] The term "pharmaceutically acceptable salt" refers to a salt into which a compound can be converted by conventional methods, which is chemically and physically compatible with the other ingredients of a pharmaceutical dosage form and physiologically compatible with the receptor. The salt can be an acid and / or base salt formed by the compound with inorganic and / or organic acids and / or with inorganic and / or organic bases, including zwitterionic salts (inner salts), and also including quaternary ammonium salts, such as alkylammonium salts. These salts can be directly obtained in the final isolation 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 solution and be collected by filtration, or recovered after evaporation of the solvent, or prepared by reaction in an aqueous medium followed by cooling and drying. Specifically, the salt is preferably a water-soluble pharmaceutically acceptable non-toxic acid addition salt, examples being salts formed by an amino group with 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 by using other conventional methods in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactates, lactobionates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, etc. When appropriate, additional pharmaceutically acceptable salts may also include salts derived from suitable 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, etc. When appropriate, additional pharmaceutically acceptable salts include salts formed with non-toxic ammonium, quaternary ammonium, and amine cations using counterions such as halide ions, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0036] The term "solvate" may also be referred to as "solvent compound", "solvated compound", and refers to a compound containing solvent molecules, where the solvent molecules can combine 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 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 solvates will be able to be isolated, for example, when one or more solvent molecules are incorporated into the lattice of the crystalline solid. "Solvate" includes solvates in solution state and isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0037] The term "hydrate" refers to a compound 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 that compound in the hydrate is determined. Thus, the hydrate of a compound can be represented, for example, by the general formula R·xH₂O, 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, monohydrate (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, dihydrate (R·2H₂O) and hexahydrate (R·6H₂O)).

[0038] The term "prodrug" refers to any compound that produces a drug, i.e., the active ingredient, when administered to a living organism due to spontaneous chemical reactions, enzyme-catalyzed chemical reactions, photolysis, and / or metabolic chemical reactions. A prodrug is thus a covalently modified analogue or potential form of a therapeutically active compound. Suitable examples include, but are not limited to: forms such as carboxylic acid esters, carbonates, phosphates, nitrates, sulfates, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, etc. of the compound.

[0039] The present invention also includes isotopically labeled compounds (isotope variants) that are equivalent to those general formulas or specific compounds described in this application, but one or more atoms are replaced by atoms with an atomic mass or mass number different from the atomic mass or mass number commonly found in nature. Examples of isotopes that can be introduced 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). The compounds of the present invention containing the above isotopes and / or other isotopes of other atoms, their prodrugs, and the pharmaceutically acceptable salts of said compounds or said prodrugs all fall within the scope of the present invention. Certain isotopically labeled compounds of the present invention, for example those incorporating radioactive isotopes (e.g., 3 H and 14 C), can be used for drug and / or substrate tissue distribution assays. Tritium, i.e., 3 H and carbon-14, i.e., 14 C isotopes are particularly preferred because they are readily prepared and detected. Additionally, substitution with heavier isotopes such as deuterium (i.e., 2 H) can provide therapeutic benefits, such as extended in vivo half-life or reduced dose requirements, due to higher metabolic stability, and is thus preferred in some cases. Isotopically labeled compounds of the present invention and their prodrugs can generally be prepared by using readily available isotopically labeled reagents in place of non-isotopically labeled reagents when carrying out the processes and / or the procedures and preparation examples disclosed below.

[0040] The compounds of the present invention include one or more asymmetric centers and can thus exist in various stereoisomeric forms, e.g., enantiomeric and / or diastereomeric forms. For example, the compounds of the present invention can be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or can be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. The isomers can be separated from the mixture by methods known to those skilled in the art, including: chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred isomers can be prepared by asymmetric synthesis.

[0041] "Optional" or "optionally" means that the subsequent described event or circumstance can but does not have to occur, including the instances where the event or circumstance occurs or does not occur. For example, "aryl is optionally substituted by alkyl" means that alkyl can but does not have to be present, and the term includes the case where aryl is substituted by alkyl and the case where aryl is not substituted by alkyl.

[0042] "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-cyclodextrin; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) diols, 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 non-toxic compatible substances used in pharmaceutical formulations.

[0043] The term "polymorph" refers to a crystalline form of a compound (or its salt, hydrate or solvate) with a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, photoelectric properties, stabilities and solubilities. The recrystallization solvent, crystallization rate, storage temperature and other factors can result in one crystalline form being dominant. The various polymorphs of a compound can be prepared by crystallization under different conditions.

[0044] Unless otherwise specified, all technical and scientific terms used herein have the standard meanings in the field to which the claimed subject matter belongs. If there are multiple definitions for a term, the definition herein shall prevail. It should be understood that the singular forms used in the present invention, such as "a", include plural referents unless otherwise specified.

[0045] In addition, the terms "comprising" and "including" are open-ended and not closed, that is, they include what is specified in the present invention, but do not exclude other aspects.

[0046] Unless otherwise stated, the compounds of the present invention are identified by conventional methods such as mass spectrometry and nuclear magnetic resonance, and the steps and conditions can refer to the conventional operating steps and conditions in the art.

[0047] Unless otherwise specified, the present invention employs standard nomenclature and standard laboratory procedures and techniques in analytical chemistry, organic synthetic chemistry, and optics. In certain cases, standard techniques are used for chemical synthesis, chemical analysis, and detection of the performance of light-emitting devices.

[0048] In addition, it should be noted that, unless otherwise explicitly indicated, the description method “... are each independently” used in the present invention should be understood in a broad sense, meaning that the described individuals are independent of each other and can independently be the same or different specific groups. More specifically, the description method “... are each independently” can either mean that among different groups, the specific options expressed between the same symbols do not affect each other; or it can mean that within the same group, the specific options expressed between the same symbols do not affect each other.

[0049] Specifically, the present invention relates to the following technical solutions.

[0050] In one embodiment, the present invention relates to a compound of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof:

[0051]

[0052] Wherein,

[0053] R1 is selected from H, halogen, -OR, -SR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, 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] R2 is -L2–R 2A ;

[0055] 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- to 7-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1 to 3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo and CN;

[0056] 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- to 7-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1 to 3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo and CN;

[0057] 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-;

[0058] R 1A is independently selected from H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl;

[0059] R 1Bindependently selected from H, halogen, C each time it appears 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl;

[0060] R 2A selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl;

[0061] R 2B selected from C 3-6 cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with 1-5 R 2b ' substituents;

[0062] R 2b ' is selected from hydrogen, halogen, oxo, -CN, -NO2, -OR, -SR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo and CN;

[0063] R 3A selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl;

[0064] R 3B selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl;

[0065] Alternatively, R 3A and R 3B together form a 3-7 membered heterocyclic group or a 5-10 membered heteroaryl;

[0066] R 4A selected from H, C 1-6 alkyl, C2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl;

[0067] R 4B is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl;

[0068] Alternatively, R 4A and R 4B together form a ⒊⒎-membered heterocyclic group or a ⒌⒑-membered heteroaryl group;

[0069] Each occurrence of R is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, a ⒊⒎-membered heterocyclic group, C 6-10 aryl, and a ⒌⒑-membered heteroaryl group, wherein said cycloalkyl, heterocyclic group, aryl, and heteroaryl group are optionally substituted with 1 - 3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, oxo, and CN;

[0070] Each hydrogen bonded to carbon may optionally and independently be replaced by deuterium;

[0071] n is 0, 1, 2, 3, 4, 5, or 6,

[0072] provided that when R1 is -OR or -SR, n is not 0.

[0073] 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 (II),

[0074]

[0075] wherein,

[0076] indicates that the ring in which it is located is aromatic or non-aromatic;

[0077] X is C(R 2b1 ), O, S, N, or N(R 2b1 );

[0078] Y is C(R2b2 )), O, S, N or N(R 2b2 );

[0079] Z is C(R 2b3 ), O, S, N or N(R 2b3 );

[0080] R 2b1 is selected from H, halogen, oxo, -CN, -NO2, -OR, -SR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo and CN;

[0081] R 2b2 is selected from H, halogen, oxo, -CN, -NO2, -OR, -SR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo and CN;

[0082] R 2b3 is selected from H, halogen, oxo, -CN, -NO2, -OR, -SR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0083] 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 haloalkyl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0084] 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 haloalkyl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0085] Each R, when it appears, is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, oxo, and CN;

[0086] Each hydrogen bonded to carbon may optionally and independently be replaced by deuterium;

[0087] Other groups are as defined in claim 1.

[0088] 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,

[0089] wherein R1 is selected from -OMe, -OEt,

[0090] 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 (III),

[0091]

[0092] R1 is selected from H, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo and CN;

[0093] R 2A is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl;

[0094] R 2b1 is selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C1-6 haloalkyl, halogen, -OR, oxo and CN;

[0095] R 2b2 selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1 to 3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo and CN;

[0096] R 2b3 selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1 to 3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo and CN;

[0097] R 2b4 selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1 to 3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo and CN;

[0098] R 2b5 selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0099] 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 );

[0100] 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 );

[0101] R 3A is H or C 1-6 alkyl;

[0102] R 3B is H or C 1-6 alkyl;

[0103] R 4A is H or C 1-6 alkyl;

[0104] R 4B is H or C 1-6 alkyl;

[0105] Each R, when it appears, is independently C 1-6 alkyl or C 3-6 cycloalkyl;

[0106] Each hydrogen attached to carbon may optionally and independently be replaced by deuterium;

[0107] n is 0, 1, 2, 3, or 4;

[0108] Provided that when R1 is -OR, n is not 0.

[0109] 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,

[0110] wherein,

[0111] R1 is selected from -OR and C 3-4 cycloalkyl, wherein the cycloalkyl is optionally substituted with 1-2 substituents selected from: C 1-4 alkyl, -OR, oxo and CN;

[0112] R 2A is H;

[0113] R 2b1 is selected from H, halogen and -OR;

[0114] R 2b2 is a 5-6 membered heteroaryl, which is optionally substituted with C 1-4 alkyl;

[0115] R 2b3 is H;

[0116] R 2b4 is H;

[0117] R 2b5 is H;

[0118] R3 is H;

[0119] R4 is -N(R 4A )(R 4B );

[0120] R 4A is H or C 1-4 alkyl;

[0121] R 4B is H or C 1-4 alkyl;

[0122] Each R, when it appears independently, is C 1-4 alkyl or C 3-4 cycloalkyl;

[0123] Each hydrogen bonded to carbon can optionally and independently be replaced by deuterium;

[0124] n is 1.

[0125] 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,

[0126] Among them,

[0127] R1 is -OR,

[0128] R 2A is H;

[0129] R 2b1 is halogen or -OR,

[0130] R 2b2 is a 5- or 6-membered heteroaryl group, such as a triazolyl group, which is substituted by C 1-4 alkyl, preferably, R 2b2 is

[0131] R 2b3 is H;

[0132] R 2b4 is H;

[0133] R 2b5 is H;

[0134] R3 is H;

[0135] R4 is -N(R 4A )(R 4B );

[0136] R 4A is H;

[0137] R 4B is C 1-4 alkyl, preferably methyl;

[0138] Each hydrogen bonded to carbon may optionally and independently be replaced by deuterium; 1-4 alkyl or C[[ID=Z7]] 3-4 cycloalkyl, preferably methyl or cyclopropyl;

[0139] Each hydrogen bonded to carbon may optionally and independently be replaced by deuterium;

[0140] n is 1.

[0141] In a more specific embodiment, the present invention provides the compound of formula (III) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope variant thereof,

[0142] Among them,

[0143] R1 is -OR,

[0144] R 2A is H;

[0145] R 2b1 is -OR,

[0146] R 2b2 is a 5- or 6-membered heteroaryl group, such as a triazolyl group, which is substituted by C 1-4 alkyl, and preferably, R 2b2 is

[0147] R 2b3 is H;

[0148] R 2b4 is H;

[0149] R 2b5 is H;

[0150] R3 is H;

[0151] R4 is -N(R 4A )(R 4B );

[0152] R 4A is H;

[0153] R 4B is C 1-4 alkyl, preferably methyl;

[0154] Each occurrence of R is independently C 1-4 alkyl;

[0155] Each hydrogen bonded to carbon may optionally and independently be replaced by deuterium;

[0156] n is 1.

[0157] 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,

[0158] wherein,

[0159] R1 is -OR,

[0160] R 2A is H;

[0161] R 2b1 is halogen,

[0162] R 2b2 is a 5- or 6-membered heteroaryl group, such as a triazolyl group, which is substituted by C 1-4 alkyl, and preferably, R 2b2 is

[0163] R 2b3 is H;

[0164] R2b4 is H;

[0165] R 2b5 is H;

[0166] R3 is H;

[0167] R4 is -N(R 4A )(R 4B );

[0168] R 4A is H;

[0169] R 4B is C 1-4 alkyl, preferably methyl;

[0170] R is C 3-4 cycloalkyl, preferably cyclopropyl;

[0171] Each hydrogen bonded to carbon may optionally and independently be replaced by deuterium;

[0172] n is 1.

[0173] 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 of formula (IV-1):

[0174]

[0175] wherein,

[0176] R1 is selected from H, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo and CN;

[0177] R 2A is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl;

[0178] R2b2 Selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7-membered heterocyclic group, C 6-10 aryl and 5-10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo and CN;

[0179] R 2b3 Selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -OR, C 3-6 cycloalkyl, 3-7-membered heterocyclic group, C 6-10 aryl and 5-10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo and CN;

[0180] R 2b4 Selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -OR, C 3-6 cycloalkyl, 3-7-membered heterocyclic group, C 6-10 aryl and 5-10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo and CN;

[0181] R 2b5 Selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -OR, C 3-6 cycloalkyl, 3-7-membered heterocyclic group, C6-10 Aryl and 5- to 10-membered heteroaryl, wherein said cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1 to 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;

[0182] 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 );

[0183] 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 );

[0184] R 3A is H or C 1-6 alkyl;

[0185] R 3B is H or C 1-6 alkyl;

[0186] R 4A is H or C 1-6 alkyl;

[0187] R 4B is H or C 1-6 alkyl;

[0188] Each R, when it appears independently, is C 1-6 alkyl or C 3-6 cycloalkyl;

[0189] Each hydrogen bonded to carbon can optionally and independently be replaced by deuterium;

[0190] n is 0, 1, 2, 3 or 4;

[0191] Provided that when R1 is -OR, n is not 0.

[0192] 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,

[0193] wherein,

[0194] R1 is selected from -OR and 5- to 6-membered heterocyclic groups, wherein said heterocyclic group is optionally substituted with 1 to 2 substituents selected from: C 1-4 alkyl, -OR, oxo and CN;

[0195] R 2A is H;

[0196] R 2b2 is a 5- to 6-membered heteroaryl group, which is optionally substituted with C 1-4 alkyl;

[0197] R 2b3 is H;

[0198] R 2b4 is H;

[0199] R 2b5 is H;

[0200] R3 is H;

[0201] R4 is -N(R 4A )(R 4B );

[0202] R 4A is H or C 1-4 alkyl;

[0203] R 4B is H or C 1-4 alkyl;

[0204] Each occurrence of R is independently C 1-4 alkyl or C 3-4 cycloalkyl;

[0205] Each hydrogen bonded to carbon can be optionally and independently replaced by deuterium;

[0206] n is 1.

[0207] 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,

[0208] wherein,

[0209] R1 is selected from -OR and 5- to 6-membered heterocyclic groups, preferably, said 5- to 6-membered heterocyclic group is oxolanyl, preferably

[0210] R 2A is H;

[0211] R 2b2is a 5- or 6-membered heteroaryl, which is optionally substituted with a C 1-4 alkyl;

[0212] R 2b3 is H;

[0213] R 2b4 is H;

[0214] R 2b5 is H;

[0215] R3 is H;

[0216] R4 is -N(R 4A )(R 4B );

[0217] R 4A is H;

[0218] R 4B is C 1-4 alkyl, preferably methyl;

[0219] R is C 1-4 alkyl;

[0220] Each hydrogen bonded to carbon can be optionally and independently replaced by deuterium;

[0221] n is 1.

[0222] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, which is of formula (V), preferably (V-1):

[0223]

[0224] Wherein,

[0225] R1 is selected from H, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1 to 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;

[0226] R 2A is selected from H, C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl;

[0227] R 2b1 selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1 to 3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo and CN;

[0228] R 2b3 selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1 to 3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo and CN;

[0229] R 2b4 selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1 to 3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo and CN;

[0230] R 2b5 selected from H, halogen, -OR, C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, where the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1 to 3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo and CN;

[0231] 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 );

[0232] 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 );

[0233] R 3A is H or C 1-6 alkyl;

[0234] R 3B is H or C 1-6 alkyl;

[0235] R 4A is H or C 1-6 alkyl;

[0236] R 4B is H or C 1-6 alkyl;

[0237] R is independently C 1-6 alkyl or C 3-6 cycloalkyl;

[0238] each hydrogen attached to carbon can optionally and independently be replaced by deuterium;

[0239] n is 0, 1, 2, 3 or 4;

[0240] provided that when R1 is -OR, n is not 0.

[0241] In a more specific embodiment, the present invention provides the compound of formula (V) or formula (V-1) above, or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof,

[0242] wherein R1 is selected from -OMe, -OEt,

[0243] In a more specific embodiment, the present invention provides the compound of formula (V) or formula (V-1) above, or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof,

[0244] wherein,

[0245] R1 is selected from -OR, C 3-4 cycloalkyl, 5- to 6-membered heterocyclic group and 5- to 6-membered heteroaryl, wherein the cycloalkyl, heterocyclic group and heteroaryl are optionally substituted with 1 to 2 substituents selected from: C 1-4 alkyl, -OR, oxo and CN;

[0246] R 2A is H;

[0247] R 2b1 is -OR;

[0248] R 2b3 is H;

[0249] R 2b4 is H;

[0250] R 2b5 is H;

[0251] R3 is H;

[0252] R4 is -N(R 4A )(R 4B );

[0253] R 4A is H or C 1-4 alkyl;

[0254] R 4B is H or C 1-4 alkyl;

[0255] R is independently C 1-4 alkyl or C 3-4 cycloalkyl each time it appears;

[0256] Each hydrogen bonded to carbon may optionally and independently be replaced by deuterium;

[0257] n is 0, 1 or 2;

[0258] Provided that when R1 is -OR, n is not 0.

[0259] 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,

[0260] wherein,

[0261] R1 is -OR;

[0262] R 2A is H;

[0263] R 2b1 is -OR;

[0264] R 2b3 is H;

[0265] R 2b4 is H;

[0266] R 2b5 is H;

[0267] R3 is H;

[0268] R4 is -N(R 4A )(R 4B );

[0269] R 4A is H;

[0270] R 4B is C 1-4 alkyl, preferably methyl;

[0271] Each hydrogen bonded to carbon may optionally and independently be replaced by deuterium; 1-4 alkyl, preferably methyl or ethyl;

[0272] Each hydrogen bonded to carbon may optionally and independently be replaced by deuterium;

[0273] n is 1.

[0274] 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,

[0275] wherein,

[0276] R, wherein R is C 1-4 alkyl, preferably methyl;

[0277] R 2A is H;

[0278] R 2b1 is -OR, where R is C 3-4 cycloalkyl, preferably cyclopropyl;

[0279] R 2b3 is H;

[0280] R 2b4 is H;

[0281] R 2b5 is H;

[0282] R3 is H;

[0283] R4 is -N(R 4A )(R 4B );

[0284] R 4A is H;

[0285] R 4B is C 1-4 alkyl, preferably methyl;

[0286] Each hydrogen bonded to carbon may optionally and independently be replaced by deuterium;

[0287] n is 1.

[0288] 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 (VI), preferably of formula (VI-1),

[0289]

[0290] R1 is selected from H, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo and CN;

[0291] R 2A is selected from H, C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl;

[0292] R 2b2 selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo and CN;

[0293] R 2b3 selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo and CN;

[0294] R 2b4 selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo and CN;

[0295] R 2b5 selected from H, halogen, -OR, C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl, and 5- to 10-membered heteroaryl, where the cycloalkyl, heterocyclic group, aryl, and heteroaryl are optionally substituted with 1 to 3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;

[0296] 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 );

[0297] 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 );

[0298] R 3A is H or C 1-6 alkyl;

[0299] R 3B is H or C 1-6 alkyl;

[0300] R 4A is H or C 1-6 alkyl;

[0301] R 4B is H or C 1-6 alkyl;

[0302] R, each occurrence independently, is C 1-6 alkyl or C 3-6 cycloalkyl;[[ID=8V]]

[0303] Each hydrogen attached to carbon may optionally and independently be replaced by deuterium;

[0304] n is 0, 1, 2, 3, or 4;

[0305] Provided that when R1 is -OR, n is not 0.

[0306] In a more specific embodiment, the present invention provides a compound of the above formula (VI) or formula (VI-1), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof,

[0307] wherein,

[0308] R1 is -OR;

[0309] R 2A is H;

[0310] R 2b2 is -OR;

[0311] R 2b3 is H;

[0312] R 2b4 is H or a 5- or 6-membered heteroaryl, which is optionally substituted by C 1-4 alkyl;

[0313] R 2b5 is H or a halogen;

[0314] R3 is H;

[0315] R4 is -N(R 4A )(R 4B );

[0316] R 4A is H;

[0317] R 4B is H or C 1-4 alkyl, preferably methyl;

[0318] R, each occurrence, is independently C 1-4 alkyl;

[0319] Each hydrogen bonded to carbon can be optionally and independently replaced by deuterium;

[0320] n is 1.

[0321] In a more specific embodiment, the present invention provides a compound of the above formula (I), 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:

[0322]

[0323]

[0324]

[0325] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound as defined in the present invention, 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.

[0326] In one embodiment, the present invention provides the use of a compound as defined in the present invention, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, and a pharmaceutical composition comprising the same, in the preparation of a medicament for the treatment and / or prevention of a TYK2 kinase-mediated disease.

[0327] In one embodiment, the present invention provides a compound as defined in the present invention, 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 compound, for the treatment and / or prevention of a TYK2 kinase-mediated disease.

[0328] In one embodiment, the present invention provides a method for treating and / or preventing a TYK2 kinase-mediated disease in a subject, comprising administering to the subject the 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.

[0329] The TYK2 kinase-mediated diseases as described in the present invention are selected from neurological diseases, autoimmune diseases, skin diseases, allergic diseases, organ rejection, cancer, dry eye disease, myelofibrosis, polycythemia. Further, 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 disorder is asthma or rhinitis; the organ transplant rejection is allograft rejection or graft-versus-host disease; 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.

[0330] In some embodiments, the TYK2 kinase-mediated diseases involved in the present method are selected from Alzheimer's disease, Parkinson's disease, systemic lupus erythematosus, amyotrophic lateral sclerosis or multiple sclerosis.

[0331] Those skilled in the art can understand that, without violating the common general knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain various preferred examples of the present invention.

[0332] Administration

[0333] The compound of formula (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 delivery modes are covered, topical administration is generally preferred for skin-related diseases, and systemic treatment is preferred for cancerous or pre-cancerous disease states. For example, the compound can be delivered in the following ways: orally, for example, in the form of tablets, capsules, granules, powders or liquid preparations (including syrups); topically, for example, in the form of solutions, suspensions, gels or ointments; sublingually; buccally; parenterally, for example, by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (for example, in the form of a sterile injectable aqueous solution or non-aqueous solution or suspension); nasally, for example, by inhalation spray; topically, for example, in the form of creams or ointments; rectally, for example, in the form of suppositories; or liposomes. Unit dose formulations containing non-toxic pharmaceutically acceptable carriers or diluents can be administered. The compound can be administered in an immediate release or extended release form. Immediate release or extended release can be achieved using suitable pharmaceutical compositions or, especially in the case of extended release, using, for example, subcutaneous implants or osmotic pump devices.

[0334] Exemplary compositions for topical administration include topical carriers.

[0335] Exemplary compositions for oral administration include suspensions, which may contain, for example, microcrystalline cellulose for imparting volume, alginic acid or sodium alginate as a suspending agent, methylcellulose as a thickening agent, and sweetening or flavoring agents, 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 can also be delivered orally by sublingual and / or buccal administration, for example, using molded, compressed or lyophilized tablets. Exemplary compositions may include rapidly dissolving diluents, such as mannitol, lactose, sucrose and / or cyclodextrin. These formulations may also include high molecular weight excipients, such as cellulose or polyethylene glycol (PEG); excipients for aiding mucosal adhesion such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose (SCMC), and / or maleic anhydride copolymers (e.g., ); and reagents for controlled release such as polyacrylic acid copolymers (e.g., ). Lubricants, glidants, flavoring agents, coloring agents, and stabilizers may also be added to facilitate preparation and use.

[0336] Exemplary compositions for nasal aerosol or inhalation administration include solutions which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters for enhancing absorption and / or bioavailability, and / or other solubilizing or dispersing agents such as those known in the art.

[0337] 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.

[0338] 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 ambient temperature but liquefy and / or dissolve in the rectal cavity to release the drug.

[0339] A therapeutically effective amount of the compounds of the present invention can be determined by those skilled in the art and, for mammals, includes exemplary doses of the active compound 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 per day, which can be administered as a single dose or in the form of individual divided doses (e.g., 1 to 4 times per day). It should be understood that the specific dosage levels and dosing frequencies 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 status, sex and diet of the individual, the mode and time of administration, the rate of excretion, drug combinations, 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. Thus, when the term "patient" is used herein, this term refers to all individuals, most preferably mammalian species suffering from a TYK2 kinase-mediated disease.

[0340] Examples

[0341] The materials or reagents used in this article are commercially available or prepared by synthetic methods commonly known in the art.

[0342] Abbreviations

[0343] NBS: N-Bromosuccinimide

[0344] ACN: Acetonitrile

[0345] DIEA: N,N-Diisopropylethylamine

[0346] IPA: Isopropanol

[0347] DMAP: 4-Dimethylaminopyridine

[0348] (Boc)2O: Di-tert-butyl dicarbonate

[0349] nBu-Li: n-Butyllithium

[0350] THF: Tetrahydrofuran

[0351] TEA: Triethylamine

[0352] TEP: Tris(2-furyl)phosphine

[0353] Pd(OAc)2: Palladium(II) acetate

[0354] Cs2CO3: Cesium carbonate

[0355] DCM: Dichloromethane

[0356] TFA: Trifluoroacetic acid

[0357] SOCl2: Thionyl chloride

[0358] MTBE: Methyl tert-butyl ether

[0359] PBr3: Phosphorus tribromide

[0360] EtOH: Ethanol

[0361] NaCN: Sodium cyanide

[0362] DMF: N,N-Dimethylformamide

[0363] DCC: N,N'-Dicyclohexylcarbodiimide

[0364] NaH: Sodium hydride

[0365] MeOH: Methanol

[0366] Pd / C: Palladium on carbon

[0367] K2CO3: Potassium carbonate

[0368] CuI: Copper(I) iodide

[0369] KOAc: Potassium acetate

[0370] Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0)

[0371] Pd(dppf)Cl2: Dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium(II); Xantphos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0372] Ruphos-Pd-G3: Palladium(II) (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) methanesulfonate

[0373] rt: Room temperature

[0374] hrs / hr: Hour

[0375] Example 1

[0376] 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)

[0377] Synthesis of Intermediate 1E

[0378]

[0379] First step: 3-Bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine

[0380]

[0381] Dissolve 5,7-dichloropyrazolo[1,5-a]pyrimidine (6.8 g, 36.168 mmol) in acetonitrile (50 mL), add N-bromosuccinimide (6.76 g, 37.9 mmol), after purging with nitrogen, stir the reaction mixture at room temperature for 2 hours. After completion of the reaction, concentrate the reaction mixture under reduced pressure to obtain a crude product, and purify the crude product by silica gel column chromatography (silica gel, petroleum ether: ethyl acetate = 9:1) to obtain the title compound (9.5 g, yield: 98.4%, yellow solid).

[0382] MS(ESI): m / z 265.9 [M+H] + ;

[0383] Second step: 3-Bromo-5-chloro-N-methylpyrazolo[1,5-a]pyrimidin-7-amine

[0384]

[0385] Dissolve 3-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine (9.5 g, 35.593 mmol) in isopropanol (250 mL). After purging with nitrogen, cool the solution to 0 °C and add N,N-diisopropylethylamine (12.4 mL, 71.185 mmol) and methylamine hydrochloride (2.88 g, 42.654 mmol). Stir the reaction mixture at 80 °C in an oil bath for 16 hours. Stop the reaction and concentrate the reaction mixture under reduced pressure to obtain a crude product. Dilute the crude product with water (300 mL), and extract the aqueous phase with ethyl acetate (200 mL × 3). Wash the combined organic phases with saturated brine (200 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title compound (9.36 g, yellow oil).

[0386] MS(ESI): m / z 261.0 [M+H] + ;

[0387] Step 3: tert-Butyl (3-bromo-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0388]

[0389] Dissolve 3-bromo-5-chloro-N-methylpyrazolo[1,5-a]pyrimidin-7-amine (9.36 g, 35.792 mmol) in dioxane (200 mL), and add di-tert-butyl dicarbonate (15.6 g, 71.56 mmol) and 4-dimethylaminopyridine (437 mg, 3.577 mmol). After purging with nitrogen, stir the reaction mixture at room temperature for 16 hours. After completion of the reaction, pour the reaction mixture into water (200 mL), and extract the aqueous phase with ethyl acetate (150 mL × 3). Wash the combined organic phases with saturated brine (150 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. Purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the title compound (13 g, yield: 100%, yellow solid).

[0390] MS(ESI): m / z 361.0 [M+H] + ;

[0391] Step 4: (7-((tert-Butoxycarbonyl)(methyl)amino)-5-chloropyrazolo[1,5-a]pyrimidin-3-yl)boronic acid

[0392]

[0393] 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 purging with nitrogen, cool the reaction mixture to -78 °C and slowly add n-butyllithium (3.45 mL, 5.526 mmol). Stir the reaction mixture at -78 °C for 2 hours. After completion of the reaction, quench the reaction with saturated aqueous ammonium chloride solution (20 mL), dilute with water (60 mL), extract the aqueous phase with ethyl acetate (60 mL × 3), wash the combined organic phases with saturated brine (60 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate 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 obtain the title compound (550 mg, yield: 60.9%, yellow oil).

[0394] MS(ESI):m / z 327.1[M+H] + ;

[0395] Synthesis of Compound 1

[0396]

[0397] First step: 2-(tetrahydrofuran-2-yl)acetic acid

[0398]

[0399] Dissolve 2-(tetrahydrofuran-2-yl)acetonitrile (3 g, 26.993 mmol) in an aqueous solution of tetrahydrofuran (30 mL), add an aqueous solution of potassium hydroxide (30 mL, 2 M), and stir the reaction mixture at 55 °C for 16 hours. After completion of the reaction, dilute the reaction mixture with water (50 mL), extract the aqueous phase with ethyl acetate (50 mL × 2), adjust the pH of the aqueous phase to 1 - 2 with 1 M aqueous HCl solution, extract with ethyl acetate (50 mL × 3), wash the combined organic phases with saturated brine (50 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title compound (2.1 g, yield: 60%, yellow oil).

[0400] Second step: 2-(tetrahydrofuran-2-yl)acetyl chloride

[0401]

[0402] Dissolve 2-(tetrahydrofuran-2-yl)acetic acid (2 g, 15.385 mmol) in thionyl chloride (20 mL), cool the system to 0 °C and react 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).

[0403] Step 3: S-(p-Tolyl) 2-(tetrahydrofuran-2-yl)thioacetate

[0404]

[0405] Dissolve 2-(tetrahydrofuran-2-yl)acetyl chloride (1.6 g, 10.811 mmol) and 4-methylbenzenethiol (1.34 g, 10.811 mmol) in n-hexane (15 mL). Cool the system to 0 °C and slowly add triethylamine (1.2 g, 11.891 mmol). After the addition, warm the system to room temperature and react overnight. Stop the reaction, concentrate the reaction solution under reduced pressure to obtain the crude product. The crude product is separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the title compound (1.7 g, yield: 66.7%, colorless oil).

[0406] MS(ESI): m / z 237.0 [M+H] + ;

[0407] Step 4: tert-Butyl (5-chloro-3-(2-(tetrahydrofuran-2-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0408]

[0409] Dissolve (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) in tetrahydrofuran (10 mL). Add tris(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). After purging with nitrogen, stir the reaction solution in an oil bath at 50 °C for 2 hours. Stop the reaction, pour the reaction solution into water (50 mL), extract the aqueous phase with ethyl acetate (50 mL × 3), wash the combined organic phases with saturated brine (50 mL × 3), dry over anhydrous sodium sulfate, filter the filtrate and concentrate under reduced pressure to obtain the crude product. The crude product is separated 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).

[0410] MS(ESI): m / z 394.9 [M+H] + ;

[0411] 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

[0412]

[0413] Dissolve tert-butyl (5-chloro-3-(2-(tetrahydrofuran-2-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (40 mg, 0.102 mmol) in dioxane (5 mL), add 2-methoxypyridin-3-amine (15 mg, 0.122 mmol), palladium(II) 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). After purging with nitrogen, stir the reaction mixture in an oil bath at 110 °C for 1 h. Pour the reaction mixture into water (40 mL), extract the aqueous phase with ethyl acetate (40 mL × 3). Wash the combined organic phases with saturated brine (40 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the title compound (46 mg, yield: 93.9%, yellow solid).

[0414] MS(ESI): m / z 483.2 [M+H] + ;

[0415] 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)

[0416]

[0417] Dissolve 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) in dichloromethane (5 mL), add trifluoroacetic acid (1 mL), and stir the reaction mixture at room temperature for 1 h. After completion of the reaction, pour the reaction mixture into water (20 mL), adjust the pH of the aqueous phase to 6 - 7 with saturated aqueous sodium bicarbonate, extract the aqueous phase with dichloromethane (20 mL × 3). Wash the combined organic phases with saturated brine (20 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. Purify the crude product by preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (8.91 mg, yield: 24.7%, white solid).

[0418] MS(ESI): m / z 383.1 [M+H] + ;

[0419] 1 H NMR(400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.75 (dd, J = 7.6, 1.6 Hz, 1H), 8.26 (s, 1H), 7.86 (d, J = 4.8 Hz, 1H), 7.82 (dd, J = 4.8, 1.6 Hz, 1H), 6.94 (dd, J = 7.8, 4.9 Hz, 1H), 6.10 (s, 1H), 4.29 (dd, J = 13.2, 6.8 Hz, 1H), 3.98 (s, 3H), 3.72 (dd, J = 14.0, 7.2 Hz, 1H), 3.57 (dd, J = 14.4, 7.6 Hz, 1H), 3.03 (dd, J = 15.2, 6.0 Hz, 1H), 2.91 (d, J = 4.8 Hz, 3H), 1.97 (td, J = 12.0, 6.4 Hz, 1H), 1.87–1.74 (m, 2H), 1.56–1.42 (m, 1H), 1.23 (brs, 1H).

[0420] Example 2

[0421] 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)

[0422]

[0423] First step: 2-(Tetrahydrofuran-3-yl)acetyl chloride

[0424]

[0425] Dissolve 2-(tetrahydrofuran-3-yl)acetic acid (500 mg, 3.84 mmol) in thionyl chloride (5 mL). After purging with nitrogen, cool the reaction mixture to 0 °C and stir the reaction solution at 0 °C for 1 hour, then stir at room temperature for 4 hours. After completion of the reaction, directly evaporate the reaction solution to dryness to obtain the title compound (380 mg, colorless transparent oil).

[0426] Second step: S-(p-Tolyl) 2-(tetrahydrofuran-3-yl)thioacetate

[0427]

[0428] 2-(Tetrahydrofuran-3-yl)acetyl chloride (380 mg, 2.567 mmol) and 4-methylbenzenethiol (320 mg, 2.581 mmol) were dissolved in n-hexane (6 mL). The system was cooled to 0 °C. Triethylamine (285 mg, 2.83 mmol) was dissolved in dichloromethane (2 mL) and then added dropwise to the system. After the addition, the system was slowly warmed to room temperature and reacted overnight. The reaction solution 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 separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the title compound (370 mg, yield: 61.1%, colorless oily liquid).

[0429] MS(ESI): m / z 237.1 [M+H] + ;

[0430] 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

[0431]

[0432] 2-(Tetrahydrofuran-3-yl)thioacetate S-(p-tolyl) ester (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 purging with nitrogen, tris(2-furyl)phosphine (TFP) (20 mg, 0.086 mmol), tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.029 mmol), and copper(I) thiophene-2-carboxylate (CuTC) (89 mg, 0.466 mmol) were added. The reaction solution was stirred at 50 °C for 3 hours. After completion of the reaction, water (20 mL) was added for dilution, 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 the crude product. The crude product was obtained by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the title compound (37 mg, yield: 21.7%, yellow solid).

[0433] MS(ESI): m / z 583.2 [M+H] + ;

[0434] 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)

[0435]

[0436] Dissolve 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) in dichloromethane (0.7 mL), add trifluoroacetic acid (0.3 mL), and stir the reaction mixture at room temperature for 1 hour. Concentrate the reaction mixture under reduced pressure, dilute with water (10 mL), adjust the aqueous phase to pH = 6 - 7 with saturated aqueous sodium bicarbonate, extract the aqueous phase with ethyl acetate (10 mL × 3), wash the combined organic phases with saturated brine (20 mL × 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. Purify the crude product by preparative high-performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (8.67 mg, yield: 36.1%, white solid).

[0437] MS(ESI): m / z 383.1 [M+H] + ;

[0438] 1 1H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.73 (d, J = 7.9 Hz, 1H), 8.26 (s, 1H), 7.86 (d, J = 4.8 Hz, 1H), 7.84–7.78 (m, 1H), 6.95 (dd, J = 7.7, 5.0 Hz, 1H), 6.10 (s, 1H), 3.98 (s, 3H), 3.84 (t, J = 7.6 Hz, 1H), 3.76–3.67 (m, 1H), 3.63 (dd, J = 15.3, 7.6 Hz, 1H), 3.31–3.16 (m, 2H), 3.08 (dd, J = 16.6, 7.6 Hz, 1H), 2.91 (d, J = 4.8 Hz, 3H), 2.62 (dt, J = 14.4, 7.1 Hz, 1H), 2.03 (dd, J = 12.3, 5.0 Hz, 1H), 1.51 (dd, J = 12.1, 7.5 Hz, 1H).

[0439] Example 3

[0440] 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)

[0441]

[0442] Step 1: 2-Methyl-2H-1,2,3-triazole-4-carboxylic acid

[0443]

[0444] Dissolve 4-bromo-2-methyl-2H-1,2,3-triazole (5 g, 30.864 mmol) in tetrahydrofuran (100 mL). Cool the reaction system to -30 °C and add n-butyllithium (17.4 mL, 27.778 mmol). After stirring the reaction solution at -30 °C for 40 minutes, pour the reaction solution onto dry ice. After the dry ice has evaporated, monitor the reaction until it is complete. Quench the reaction solution with water. Extract the aqueous phase with ethyl acetate (50 mL × 2). Adjust the pH of the aqueous phase to 1 - 2 with 1 M HCl aqueous solution, and then extract with ethyl acetate (50 mL × 3). The combined organic phases are washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the title compound (2.477 g, yield: 63.2%, white solid).

[0445] MS(ESI): m / z 128.1 [M+H] + ;

[0446] Step 2: (2-Methyl-2H-1,2,3-triazol-4-yl)methanol

[0447]

[0448] Dissolve 2-methyl-2H-1,2,3-triazole-4-carboxylic acid (2.477 g, 19.504 mmol) in tetrahydrofuran (20 mL). Cool the system to 0 °C and add lithium aluminum hydride (2.965 g, 78.016 mmol). Warm the reaction solution to room temperature and react for 2 hours. After the reaction is complete, quench the reaction with saturated sodium sulfate aqueous solution, dry over anhydrous sodium sulfate, add ethyl acetate (50 mL), filter, and concentrate the filtrate under reduced pressure to obtain the crude title compound (2 g, yield: 90.9%, yellow oil).

[0449] MS(ESI): m / z 114.0 [M+H] + ;

[0450] Step 3: 4-(Bromomethyl)-2-methyl-2H-1,2,3-triazole

[0451]

[0452] Dissolve (2-methyl-2H-1,2,3-triazol-4-yl)methanol (2 g, 17.699 mmol) in methyl tert-butyl ether (50 mL). After purging with nitrogen, slowly add phosphorus tribromide (4.8 g, 17.699 mmol). After the addition, react overnight at room temperature. After completion of the reaction, quench the reaction mixture with water. Extract the aqueous phase with ethyl acetate (50 mL × 2). Wash the combined organic phases with saturated brine (50 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the title compound (2.334 g, yield: 75.4%, yellow oil).

[0453] MS(ESI): m / z 176.0 [M+H] + ;

[0454] Step 4: 2-(2-methyl-2H-1,2,3-triazol-4-yl)acetonitrile

[0455]

[0456] Dissolve 4-(bromomethyl)-2-methyl-2H-1,2,3-triazole (2.334 g, 13.337 mmol) in ethanol (50 mL), add sodium cyanide (720 mg, 14.671 mmol), and react overnight at 100 °C. After completion of the reaction, quench the reaction mixture with water. Extract the aqueous phase with ethyl acetate (50 mL × 2). Wash the combined organic phases with saturated brine (50 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product of the title compound (1.5 g, yield: 92.0%, yellow oil).

[0457] MS(ESI): m / z 123.0 [M+H] + ;

[0458] Step 5: 2-(2-methyl-2H-1,2,3-triazol-4-yl)acetic acid

[0459]

[0460] Dissolve 2-(2-methyl-2H-1,2,3-triazol-4-yl)acetonitrile (1.5 g, 12.295 mmol) in water (30 mL), add aqueous sodium hydroxide solution (30 mL, 2 M), and stir the reaction mixture at 100 °C for 2 hours. After completion of the reaction, dilute the reaction mixture with water (50 mL), extract the aqueous phase with ethyl acetate (50 mL × 2), adjust the pH of the aqueous phase to 1 - 2 with 1 M HCl aqueous solution, extract with ethyl acetate (50 mL × 3), wash the combined organic phases with saturated brine (50 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title compound (1.2 g, yield: 69.4%, yellow oil).

[0461] MS(ESI): m / z 140.0[M - H] - ;

[0462] Step 6: S-(p-tolyl) 2-(2-methyl-2H-1,2,3-triazol-4-yl)thioacetate

[0463]

[0464] 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, add N,N'-dicyclohexylcarbodiimide (2.63 g, 12.766 mmol), 4-dimethylaminopyridine (104 mg, 0.851 mmol), and 4-methylbenzenethiol (1.055 g, 8.511 mmol), and stir the reaction mixture at room temperature for 2 hours. After completion of the reaction, concentrate the reaction mixture under reduced pressure to obtain a crude product, and purify the crude product by silica gel column chromatography (petroleum ether:dichloromethane = 2:1) to obtain the title compound (531 mg, yield: 25.3%, white solid).

[0465] MS(ESI): m / z 248.1[M + H] + ;

[0466] 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

[0467]

[0468] (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). Tris(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 purging with nitrogen, the reaction mixture was stirred in an oil bath at 50 °C for 2 h. 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 = 4:1) to obtain the title compound (102 mg, yield: 27.4%, yellow oil).

[0469] MS(ESI): m / z 406.1 [M+H] + ;

[0470] 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

[0471]

[0472] 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) was dissolved in dioxane (10 mL). 2-Methoxypyridin-3-amine (30 mg, 0.237 mmol), palladium(II) 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) were added. After purging with nitrogen, the reaction mixture was stirred in an oil bath at 110 °C for 1 h. 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, 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 obtain the title compound (45 mg, yield: 46.2%, yellow solid).

[0473] MS(ESI): m / z 494.2 [M+H] + ;

[0474] 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)

[0475]

[0476] Dissolve 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) in dichloromethane (8 mL), add trifluoroacetic acid (2 mL), and stir the reaction mixture at room temperature for 1 hour. After completion of the reaction, pour the reaction mixture into water (20 mL), adjust the aqueous phase to pH = 6 - 7 with saturated aqueous sodium bicarbonate solution, extract the aqueous phase with dichloromethane (20 mL × 3), wash the combined organic phases with saturated brine (20 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (13.87 mg, yield: 49.7%, white solid).

[0477] MS(ESI): m / z 394.1 [M+H] + ;

[0478] 1 1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.70 (d, J = 7.6 Hz, 1H), 8.32 (s, 1H), 7.90 (d, J = 4.4 Hz, 1H), 7.78 (d, J = 4.8 Hz, 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 = 4.8 Hz, 3H).

[0479] Example 4

[0480] (5-((2-Methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)(tetrahydro-2H-pyran-4-yl)methanone (Compound 4)

[0481]

[0482] Step 1: S-(p-Tolyl) tetrahydro-2H-pyran-4-thiocarboxylate

[0483]

[0484] Dissolve tetrahydropyran-4-carbonyl chloride (1 g, 6.73 mmol) and 4-methylbenzenethiol (836 mg, 6.73 mmol) in n-hexane (25 mL). After purging with nitrogen, cool the solution to 0 °C and slowly add triethylamine (1 mL, 7.402 mmol). Stir the reaction mixture at room temperature for 16 h. After completion of the reaction, concentrate the reaction mixture under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography (petroleum ether:dichloromethane = 1:1) to obtain the title compound (1.4 g, yield: 88%, white solid).

[0485] MS(ESI): m / z 237.1 [M+H] + ;

[0486] Step 2: tert-Butyl (5-chloro-3-(tetrahydro-2H-pyran-4-carbonyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0487]

[0488] Dissolve (7-((tert-butoxycarbonyl)(methyl)amino)-5-chloropyrazolo[1,5-a]pyrimidin-3-yl)boronic acid (500 mg, 1.531 mmol) and S-(p-tolyl) tetrahydro-2H-pyran-4-thiocarboxylate (543 mg, 2.298 mmol) in tetrahydrofuran (30 mL). Add tris(2-furyl)phosphine (TFP) (107 mg, 0.461 mmol), copper(I) thiophene-2-carboxylate (CuTC) (467 mg, 2.449 mmol) and tris(dibenzylideneacetone)dipalladium (140 mg, 0.153 mmol). After purging with nitrogen, stir the reaction mixture in an oil bath at 50 °C for 2 h. After completion of the reaction, pour the reaction mixture into water (50 mL), and extract the aqueous phase with ethyl acetate (50 mL×3). Wash the combined organic phases with saturated brine (50 mL×3), dry over anhydrous sodium sulfate and concentrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to obtain the title compound (170 mg, yield: 28.1%, yellow oil).

[0489] MS(ESI): m / z 395.1 [M+H] + ;

[0490] 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

[0491]

[0492] 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).

[0493] MS (ESI): m / z 483.3 [M+H] + ;

[0494] 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)

[0495]

[0496] 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.

[0497] MS(ESI): m / z 383.1 [M+H] + ;

[0498] 1 H NMR(400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.63–8.56 (m, 1H), 8.26 (s, 1H), 7.91–7.81 (m, 2H), 7.03 (dd, J = 7.7, 5.0 Hz, 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 = 4.8 Hz, 3H), 1.64–1.51 (m, 4H).

[0499] Example 5

[0500] 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)

[0501]

[0502] First step: tert-Butyl 2-(4-cyano-1H-pyrazol-1-yl)acetate

[0503]

[0504] Dissolve 4-cyanopyrazole (2 g, 21.485 mmol) in N,N-dimethylformamide (20 mL), add tert-butyl bromoacetate (5.03 g, 25.788 mmol) and potassium carbonate (5.94 g, 42.981 mmol); after purging with nitrogen, stir the reaction mixture at room temperature for 16 hours. After completion of the reaction, pour the reaction mixture into water (80 mL), extract the aqueous phase with ethyl acetate (60 mL × 3), wash the combined organic phases with saturated brine (60 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether: dichloromethane = 3:1) to obtain the title compound (3.6 g, yield: 80.9%, colorless transparent oil).

[0505] MS(ESI): m / z 208.1 [M+H] + ;

[0506] Second step: 2-(4-Cyano-1H-pyrazol-1-yl)acetic acid

[0507]

[0508] tert-Butyl 2-(4-cyano-1H-pyrazol-1-yl)acetate (3.6 g, 17.372 mmol) was dissolved in hydrochloric acid-dioxane solution (60 mL), and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the title compound (2.9 g, yellow solid), which was directly used in the next step without further purification.

[0509] MS (ESI): m / z 152.0 [M+H] + ;

[0510] Step 3: S-(p-Tolyl) 2-(4-cyano-1H-pyrazol-1-yl)thioacetate

[0511]

[0512] 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). The temperature was lowered to 0 °C, and N,N'-dicyclohexylcarbodiimide (5.94 g, 28.789 mmol), 4-dimethylaminopyridine (DMAP) (234 mg, 1.915 mmol), and 4-methylthiophenol (2.38 g, 19.163 mmol) were added successively. After purging with nitrogen, the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture 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 a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:dichloromethane = 1:1) to obtain the title compound (2.3 g, yield: 46.5%, colorless oil).

[0513] 1 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.88 (s, 1H), 7.30–7.23 (m, 4H), 5.15 (s, 2H), 2.38 (s, 3H).

[0514] Step 4: tert-Butyl (5-chloro-3-(2-(4-cyano-1H-pyrazol-1-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0515]

[0516] (7-((tert-Butoxycarbonyl)(methyl)amino)-5-chloropyrazolo[1,5-a]pyrimidin-3-yl)boronic acid (600 mg, 1 mmol) and S-(p-tolyl) 2-(4-cyano-1H-pyrazol-1-yl)thioacetate (945 mg, 3 mmol) were dissolved in tetrahydrofuran (15 mL), and tris(2-furyl)phosphine (TFP) (128 mg, 0.5 mmol), copper(I) thiophene-2-carboxylate (CuTC) (560 mg, 2 mmol) and tris(dibenzylideneacetone)dipalladium (168 mg, 0.1 mmol) were added. After purging with nitrogen, the reaction mixture was stirred at 50 °C in an oil bath for 2 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×), and the combined organic phases were washed with saturated brine (40 mL×), 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 = 3:1) to obtain the title compound (140 mg, yield: 18.3%, yellow solid).

[0517] MS(ESI):m / z 416.0[M+H] + ;

[0518] 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

[0519]

[0520] tert-Butyl (5-chloro-3-(2-(4-cyano-1H-pyrazol-1-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (140 mg, mmol) was dissolved in dioxane (8 mL), and 2-methoxypyridin-3-amine (50 mg, mmol), palladium acetate (15 mg, mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (78 mg, mmol) and cesium carbonate (329 mg, mmol) were added. After purging with nitrogen, the reaction mixture was stirred at 110 °C in an oil bath for 1 hour. After completion of the reaction, the reaction mixture was poured into water (30 mL), and the aqueous phase was extracted with ethyl acetate (30 mL×), and the combined organic phases were washed with saturated brine (30 mL×), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (50 mg, yield: 29.4%, white solid).

[0521] MS(ESI): m / z 504.1 [M+H] + ;

[0522] 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)

[0523]

[0524] Dissolve 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) in dichloromethane (6 mL), add trifluoroacetic acid (1.5 mL), and stir the reaction mixture at room temperature for 1 hour. After completion of the reaction, pour the reaction mixture into water (20 mL), adjust the aqueous phase to pH = 6 - 7 with saturated aqueous sodium bicarbonate solution, extract the aqueous phase with dichloromethane (20 mL × 3), wash the combined organic phases with saturated brine (20 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (2.06 mg, yield: 5.1%, white solid).

[0525] MS(ESI): m / z 404.2 [M+H] + ;

[0526] 1 H NMR(400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.63 (d, J = 7.2 Hz, 1H), 8.53 (s, 1H), 8.36 (s, 1H), 8.08 (s, 1H), 7.98 (d, J = 4.6 Hz, 1H), 7.80 (d, J = 4.0 Hz, 1H), 6.88 (dd, J = 7.7, 4.9 Hz, 1H), 6.07 (s, 1H), 5.74 (s, 2H), 3.96 (s, 3H), 2.92 (d, J = 4.6 Hz, 3H).

[0527] Example 6

[0528] 2-Methoxy-1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 6)

[0529]

[0530] Step 1: S-(p-Tolyl) 2-Methoxy Thioacetate

[0531]

[0532] Dissolve methoxyacetyl chloride (500 mg, 4.607 mmol) and 4-methylbenzenethiol (572 mg, 4.605 mmol) in n-hexane (13 mL). After purging with nitrogen, cool the solution to 0 °C and slowly add triethylamine (0.7 mL, 5.07 mmol). Stir the reaction mixture at room temperature for 16 h. After completion of the reaction, concentrate the reaction mixture under reduced pressure to obtain the crude product. The crude product is separated and purified by silica gel column chromatography (petroleum ether:dichloromethane = 2:1) to obtain the title compound (760 mg, yield: 84%, yellow oil).

[0533] MS(ESI): m / z 197.0 [M+H] + ;

[0534] Step 2: tert-Butyl (5-Chloro-3-(2-methoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0535]

[0536] Dissolve (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-methoxy thioacetate (586 mg, 2.985 mmol) in tetrahydrofuran (20 mL). Add tris(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). After purging with nitrogen, stir the reaction mixture in an oil bath at 50 °C for 2 h. After completion of the reaction, pour the reaction mixture into water (50 mL). Extract the aqueous phase with ethyl acetate (50 mL×3). Wash the combined organic phases with saturated brine (50 mL×3), dry over anhydrous sodium sulfate and concentrate under reduced pressure to obtain the crude product. The crude product is separated 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).

[0537] MS(ESI): m / z 355.0 [M+H] + ;

[0538] Step 3: tert-Butyl (3-(2-Methoxyacetyl)-5-((2-methylpyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0539]

[0540] (5-Chloro-3-(2-methoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamic acid tert-butyl ester (190 mg, 0.536 mmol) was dissolved in dioxane (12 mL), and 2-methoxypyridin-3-amine (80 mg, 0.645 mmol), palladium(II) 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 purging with nitrogen, the reaction mixture was stirred at 110 °C in an oil 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, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the title compound (120 mg, yield: 56.6%, yellow solid).

[0541] MS(ESI): m / z 443.2 [M+H] + ;

[0542] 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)

[0543]

[0544] (3-(2-Methoxyacetyl)-5-((2-methylpyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamic acid tert-butyl ester (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 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, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (42.91 mg, yield: 46.2%, white solid).

[0545] MS(ESI): m / z 343.1 [M+H] + ;

[0546] 11H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.72 (dd, J = 7.8, 1.5 Hz, 1H), 8.29 (s, 1H), 7.93–7.80 (m, 2H), 7.00 (dd, J = 7.8, 4.9 Hz, 1H), 6.07 (s, 1H), 4.66 (s, 2H), 3.97 (s, 3H), 3.36 (s, 3H), 2.90 (d, J = 4.8 Hz, 3H).

[0547] Example 7

[0548] 2-Ethoxy-1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 7)

[0549]

[0550] The first step: S-(p-tolyl) 2-ethoxythioacetate

[0551]

[0552] Dissolve 2-ethoxyacetyl chloride (500 mg, 3.84 mmol) and 4-methylbenzenethiol (504 mg, 4.065 mmol) in n-hexane (8 mL). After purging with nitrogen, cool the solution to 0 °C. Slowly add triethylamine (452 mg, 4.475 mmol) dropwise at 0 °C. After the addition, allow the reaction mixture to warm to room temperature and stir overnight. After completion of the reaction, directly evaporate the solvent to obtain the crude product. The crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the title compound (700 mg, yield: 81.3%, colorless transparent oily liquid).

[0553] The second step: tert-Butyl (5-chloro-3-(2-ethoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0554]

[0555] Dissolve 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) in tetrahydrofuran (15 mL). After purging with nitrogen, add tris(2-furyl)phosphine (TFP) (128 mg, 0.552 mmol), tris(dibenzylideneacetone)dipalladium(0) (168 mg, 0.184 mmol) and copper(I) thiophene-2-carboxylate (CuTC) (562 mg, 2.944 mmol). Stir the reaction mixture at 50 °C for 2 h. After completion of the reaction, dilute with water (20 mL), extract the aqueous phase with ethyl acetate (20 mL×3). Wash the combined organic phases with saturated brine (30 mL×2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is 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).

[0556] MS(ESI): m / z 369.0 [M+H] + ;

[0557] Step 3: tert-Butyl (3-(2-ethoxyacetyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0558]

[0559] 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 purging with nitrogen, add cesium carbonate (345 mg, 1.059 mmol), palladium(II) 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 h. After completion of the reaction, dilute with water (20 mL), extract the aqueous phase with ethyl acetate (20 mL×3). Wash the combined organic phases with saturated brine (30 mL×2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the 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).

[0560] MS(ESI): m / z 457.1 [M+H] + ;

[0561] 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)

[0562]

[0563] Dissolve 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) in dichloromethane (2 mL), add trifluoroacetic acid (0.5 mL), and stir the reaction mixture at room temperature for 1 hour. After completion of the reaction, concentrate the reaction mixture under reduced pressure, dilute with water (10 mL), adjust the aqueous phase to pH = 6 - 7 with saturated aqueous sodium bicarbonate solution, extract the aqueous phase with ethyl acetate (10 mL × 3), wash the combined organic phases with saturated brine (20 mL × 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (18.33 mg, yield: 10.6%, white solid).

[0564] MS(ESI): m / z 357.1 [M+H] + ;

[0565] 1 H NMR(400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.73 (dd, J = 7.8, 1.4 Hz, 1H), 8.29 (s, 1H), 7.88 (d, J = 4.9 Hz, 1H), 7.83 (dd, J = 4.9, 1.5 Hz, 1H), 6.98 (dd, J = 7.8, 4.9 Hz, 1H), 6.07 (s, 1H), 4.70 (s, 2H), 3.98 (s, 3H), 3.55 (q, J = 7.0 Hz, 2H), 2.90 (d, J = 4.8 Hz, 3H), 1.17 (t, J = 7.0 Hz, 3H).

[0566] Example 8

[0567] 3-Methoxy-1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)propan-1-one (Compound 8)

[0568]

[0569] Step 1: S-(p-Tolyl) 3-Methoxythiopropionate

[0570]

[0571] Dissolve 3-methoxypropionyl chloride (1 g, 8.197 mmol) and 4-methylbenzenethiol (1.22 g, 9.836 mmol) in n-hexane (20 mL). After purging with nitrogen, cool the solution to 0 °C and slowly add triethylamine (3.4 mL, 24.590 mmol). Stir the reaction mixture at room temperature for 16 hours. After completion of the reaction, concentrate the reaction mixture under reduced pressure to obtain a crude product. The crude product is separated and purified by silica gel column chromatography (petroleum ether:dichloromethane = 2:1) to obtain the title compound (1.457 g, yield: 84.7%, yellow oil).

[0572] MS(ESI): m / z 211.1[M + H] + ;

[0573] Step 2: tert-Butyl (5-chloro-3-(3-methoxypropionyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0574]

[0575] Dissolve (7-((tert-butoxycarbonyl)(methyl)amino)-5-chloropyrazolo[1,5-a]pyrimidin-3-yl)boronic acid (65 mg, 1.991 mmol) and S-(p-tolyl) 3-methoxypropionate (836 mg, 3.982 mmol) in tetrahydrofuran (20 mL). Add tris(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). After purging with nitrogen, stir the reaction mixture in an oil bath at 50 °C for 2 hours. After completion of the reaction, pour the reaction mixture into water (50 mL). Extract the aqueous phase with ethyl acetate (50 mL × 3). Wash the combined organic phases with saturated brine (50 mL × 3), dry over anhydrous sodium sulfate and concentrate under reduced pressure to obtain a crude product. The crude product is separated 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).

[0576] MS(ESI): m / z 369.1[M + H] + ;

[0577] Step 3: tert-Butyl (3-(3-methoxypropionyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0578]

[0579] (5-Chloro-3-(3-methoxypropanoyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamic acid tert-butyl ester (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 purging with nitrogen, 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, 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 obtain the title compound (66 mg, yield: 44.3%, yellow solid).

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

[0581] 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)

[0582]

[0583] (3-(3-Methoxypropanoyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamic acid tert-butyl ester (66 mg, 0.145 mmol) was dissolved in dichloromethane (8 mL), and 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 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, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (9.58 mg, yield: 18.6%, white solid).

[0584] MS(ESI): m / z 357.1 [M+H] + ;

[0585] 11H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.75 (d, J = 7.6 Hz, 1H), 8.27 (d, J = 1.6 Hz, 1H), 7.86 (d, J = 4.4 Hz, 1H), 7.81 (d, J = 4.8 Hz, 1H), 6.98–6.92 (m, 1H), 6.10 (s, 1H), 3.98 (d, J = 1.6 Hz, 3H), 3.68 (t, J = 6.8 Hz, 2H), 3.26 (d, J = 6.4 Hz, 2H), 3.22 (d, J = 1.6 Hz, 3H), 2.91 (d, J = 4.4 Hz, 3H).

[0586] Example 9

[0587] 3-(2-(5-((2-Methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-oxoethyl)oxazolidin-2-one (Compound 9)

[0588]

[0589] First step: tert-Butyl 2-(2-oxooxazolidin-3-yl)acetate

[0590]

[0591] Oxazolidin-2-one (2.5 g, 28.709 mmol) was dissolved in tetrahydrofuran (75 mL), the temperature was lowered to 0 °C, sodium hydride (1.72 g, 43 mmol) was added. After purging with nitrogen, the reaction mixture was stirred at 0 °C for 30 minutes, and then tert-butyl bromoacetate 2 (8.4 g, 43.066 mmol) was added. After purging with nitrogen, the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was poured into water (110 mL), and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 50:1) to obtain the title compound (4.53 g, yield: 78.5%, white solid).

[0592] 1 H NMR (400 MHz, CDCl3) δ 4.38 (t, J = 8.0 Hz, 2H), 3.92 (s, 2H), 3.70 (t, J = 8.0 Hz, 2H), 1.48 (s, 9H).

[0593] Second step: 2-(2-oxooxazolidin-3-yl)acetic acid

[0594]

[0595] tert-Butyl 2-(2-oxooxazolidin-3-yl)acetate (4.53 g, 22.513 mmol) was dissolved in hydrochloric acid-dioxane solution (60 mL), and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the title compound (3.68 g, yellow solid), which was directly used in the next step without further purification.

[0596] 1 1H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H), 4.29 (t, J = 8.0 Hz, 2H), 3.90 (s, 2H), 3.60 (t, J = 8.0 Hz, 2H).

[0597] Step 3: S-(p-Tolyl) 2-(2-oxooxazolidin-3-yl)thioacetate

[0598]

[0599] 2-(2-Oxooxazolidin-3-yl)acetic acid (2.08 g, 14.334 mmol) was dissolved in acetonitrile (50 mL), and the temperature was cooled to 0 °C. N,N'-Dicyclohexylcarbodiimide (4.44 g, 21.519 mmol), 4-dimethylaminopyridine (DMAP) (175 mg, 1.432 mmol), and 4-methylbenzenethiol (1.78 g, 14.332 mmol) were added successively. After purging with nitrogen, the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, 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 a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:dichloromethane = 1:4) to obtain the title compound (660 mg, yield: 18.3%, white solid).

[0600] MS (ESI): m / z 252.0 [M+H] + ;

[0601] Step 4: tert-Butyl (5-chloro-3-(2-(2-oxooxazolidin-3-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0602]

[0603] (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), and tris(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 purging with nitrogen, the reaction mixture was stirred at 50 °C in an oil bath for 2 h. 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, 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 = 3:1) to obtain the title compound (190 mg, yield: 36%, yellow oil).

[0604] MS(ESI):m / z 410.0[M+H] + ;

[0605] 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

[0606]

[0607] 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(II) 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 purging with nitrogen, the reaction mixture was stirred at 110 °C in an oil bath for 1 h. After completion of the reaction, the reaction mixture 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 obtain the title compound (100 mg, yield: 43.3%, yellow solid).

[0608] MS(ESI): m / z 498.1 [M+H] + ;

[0609] 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)

[0610]

[0611] Dissolve 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) in dichloromethane (10 mL), add trifluoroacetic acid (2.5 mL), and stir the reaction mixture at room temperature for 1 h. After completion of the reaction, pour the reaction mixture into water (15 mL), adjust the aqueous phase to pH = 6 - 7 with saturated aqueous sodium bicarbonate solution, extract the aqueous phase with dichloromethane (15 mL × 3), wash the combined organic phases with saturated brine (15 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (10.35 mg, yield: 12.9%, white solid).

[0612] MS(ESI): m / z 398.1 [M+H] + ;

[0613] 1 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.71 (d, J = 7.4 Hz, 1H), 8.32 (s, 1H), 7.93 (d, J = 4.5 Hz, 1H), 7.82 (d, J = 4.4 Hz, 1H), 6.97 (dd, J = 7.5, 5.0 Hz, 1H), 6.09 (s, 1H), 4.64 (s, 2H), 4.35 (t, J = 7.8 Hz, 2H), 3.98 (s, 3H), 3.65 (t, J = 7.8 Hz, 2H), 2.91 (d, J = 4.5 Hz, 3H).

[0614] Example 10

[0615] 2-(1-Methoxycyclobutyl)-1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 10)

[0616]

[0617] Step 1: S-(p-Tolyl) 2-(1-Methoxycyclobutyl)thioacetate

[0618]

[0619] Dissolve 2-(1-methoxycyclobutyl)acetic acid (500 mg, 3.468 mmol) in acetonitrile (15 mL), cool to 0 °C, and successively add N,N'-dicyclohexylcarbodiimide (1.07 g, 5.186 mmol), 4-dimethylaminopyridine (DMAP) (42 mg, 0.344 mmol), and 4-methylbenzenethiol (431 mg, 3.47 mmol). After purging with nitrogen, stir the reaction mixture at room temperature for 16 h. After completion of the reaction, concentrate the reaction mixture under reduced pressure to obtain the crude product. The crude product is separated and purified by silica gel column chromatography (petroleum ether:dichloromethane = 1:1) to obtain the title compound (720 mg, yield: 82.9%, white solid).

[0620] MS(ESI): m / z 251.0 [M+H] + ;

[0621] Step 2: tert-Butyl (5-Chloro-3-(2-(1-methoxycyclobutyl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0622]

[0623] Dissolve (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) in tetrahydrofuran (15 mL), add tris(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). After purging with nitrogen, stir the reaction mixture in an oil bath at 50 °C for 2 h. After completion of the reaction, pour the reaction mixture into water (50 mL), extract the aqueous phase with ethyl acetate (50 mL × 3), wash the combined organic phases with saturated brine (50 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is separated 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).

[0624] MS(ESI): m / z 409.0 [M+H] + ;

[0625] Step 3: tert-Butyl (3-(2-(1-methoxycyclobutyl)acetyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0626]

[0627] Dissolve tert-butyl (5-chloro-3-(2-(1-methoxycyclobutyl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (80 mg, 0.196 mmol) in dioxane (6 mL), and add 2-methoxypyridin-3-amine (29 mg, 0.234 mmol), palladium(II) 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). After purging with nitrogen, the reaction mixture is stirred in an oil bath at 110 °C for 1 h. After completion of the reaction, the reaction mixture is filtered and concentrated under reduced pressure to obtain a crude product. The crude product is separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the title compound (55 mg, yield: 56.7%, yellow solid).

[0628] MS(ESI): m / z 497.1 [M+H] + ;

[0629] 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)

[0630]

[0631] Dissolve 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) in dichloromethane (4 mL), add trifluoroacetic acid (1 mL), and stir the reaction mixture at room temperature for 1 h. After completion of the reaction, the reaction mixture is concentrated under reduced pressure to obtain a crude product. The crude product is purified by preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (7.72 mg, yield: 17.5%, white solid).

[0632] MS(ESI): m / z 397.1 [M+H] + ;

[0633] 11H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.70 (dd, J = 7.8, 1.6 Hz, 1H), 8.24 (s, 1H), 7.89–7.80 (m, 2H), 6.95 (dd, J = 7.7, 5.0 Hz, 1H), 6.08 (s, 1H), 3.97 (s, 3H), 3.45 (s, 2H), 3.02 (s, 3H), 2.91 (d, J = 4.8 Hz, 3H), 2.14–2.03 (m, 4H), 1.66–1.49 (m, 2H).

[0634] Example 11

[0635] 2-Cyclopropoxy-1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 11)

[0636] Step 1: 2-Cyclopropoxyacetic acid

[0637]

[0638] Dissolve cyclopropanol (2.5 g, 43.478 mmol) in tetrahydrofuran (70 mL), cool to 0 °C, add sodium hydride (3.8 g, 90.580 mmol), stir the reaction mixture at 0 °C for 2 hours, then add 2-bromoacetic acid (5 g, 36.232 mmol), and warm the reaction mixture to room temperature and stir for 16 hours. After completion of the reaction, quench the reaction mixture with water (50 mL), extract the aqueous phase with ethyl acetate (50 mL × 2), adjust the pH of the aqueous phase to 1 - 2 with 1 M hydrochloric acid solution, extract with ethyl acetate (50 mL × 3), and wash the combined organic phases with saturated brine (50 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the title compound (3.45 g, yield: 82.1%, yellow oil).

[0639] Step 2: S-(p-Tolyl) 2-cyclopropoxythioacetate

[0640]

[0641] Dissolve 2-cyclopropoxyacetic acid (3.45 g, 29.741 mmol) in acetonitrile (50 mL), cool the temperature to 0 °C, add N,N'-dicyclohexylcarbodiimide (9.19 g, 44.612 mmol), 4-dimethylaminopyridine (363 mg, 2.974 mmol) and 4-methylbenzenethiol (3.7 g, 29.741 mmol), and warm the reaction solution to room temperature and stir for 2 hours. After the reaction is completed, the reaction solution is concentrated under reduced pressure to obtain a crude product, and the crude product is separated and purified by silica gel column chromatography (petroleum ether:dichloromethane = 2:1) to obtain the title compound (1.2 g, yield: 18.2%, yellow oil).

[0642] MS(ESI): m / z 223.1[M+H] + ;

[0643] Step 3: tert-Butyl (5-chloro-3-(2-cyclopropoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0644]

[0645] Dissolve (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-cyclopropoxythioacetate (1.6 g, 7.362 mmol) in tetrahydrofuran (40 mL), add tris(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). After purging with nitrogen, stir the reaction solution in an oil bath at 50 °C for 2 hours. After the reaction is completed, pour the reaction solution into water (50 mL), extract the aqueous phase with ethyl acetate (50 mL×3), wash the combined organic phases with saturated brine (50 mL×3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product is separated 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).

[0646] MS(ESI): m / z 381.0[M+H] + ;

[0647] Step 4: tert-Butyl (3-(2-cyclopropoxyacetyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0648]

[0649] Dissolve tert-butyl (5-chloro-3-(2-cyclopropoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (100 mg, 0.263 mmol) in dioxane (10 mL), and add 2-methoxypyridin-3-amine (40 mg, 0.316 mmol), palladium(II) 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). After purging with nitrogen, stir the reaction mixture in an oil bath at 110 °C for 1 hour. After completion of the reaction, pour the reaction mixture into water (40 mL), extract the aqueous phase with ethyl acetate (40 mL × 3), wash the combined organic phases with saturated brine (40 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the title compound (84 mg, yield: 68.3%, yellow solid).

[0650] MS(ESI): m / z 469.1 [M+H] + ;

[0651] Step 5: 2-Cyclopropoxy-1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 11)

[0652]

[0653] Dissolve tert-butyl (3-(2-cyclopropoxyacetyl)-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 of the reaction, pour the reaction mixture into water (20 mL), adjust the pH of the aqueous phase to 6-7 with saturated aqueous sodium bicarbonate solution, extract the aqueous phase with dichloromethane (20 mL × 3), wash the combined organic phases with saturated brine (20 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (25.12 mg, yield: 49.9%, white solid).

[0654] MS(ESI): m / z 369.1 [M+H] + ;

[0655] 11H NMR (400 MHz, CD3OD) δ 8.79–8.77 (m, 1H), 8.25 (d, J = 6.0 Hz, 1H), 7.77 (d, J = 5.2 Hz, 1H), 7.02–6.88 (m, 1H), 5.83 (d, J = 6.0 Hz, 1H), 4.87 (s, 2H), 4.04 (s, 3H), 3.54–3.53 (m, 1H), 3.00 (d, J = 6.0 Hz, 3H), 0.66 (brs, 2H), 0.56–0.53 (m, 2H).

[0656] Example 12

[0657] 1-(5-((2-Cyclopropoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxyethan-1-one (Compound 12)

[0658]

[0659] Step 1: 2-Cyclopropoxynitro-pyridine

[0660]

[0661] Dissolve cyclopropanol (450 mg, 7.75 mmol) in tetrahydrofuran (15 mL). After purging with nitrogen, cool the solution to 0 °C, add sodium hydride (310 mg, 7.75 mmol), and then add 2-fluoro-3-nitropyridine (1 g, 7.038 mmol). After purging with nitrogen again, stir the reaction mixture at room temperature for 2 h. After completion of the reaction, pour the reaction mixture into water (50 mL), extract the aqueous phase with ethyl acetate (50 mL × 3). Wash the combined organic phases with saturated brine (50 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product was separated 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).

[0662] MS (ESI): m / z 181.1 [M+H] + ;

[0663] Step 2: 2-Cyclopropoxypyridin-3-amine

[0664]

[0665] Dissolve 2-cyclopropoxy-3-nitropyridine (1 g, 5.551 mmol) in methanol (20 mL), add palladium on carbon catalyst (200 mg, 20%), and after purging with hydrogen, stir the reaction solution at room temperature for 3 hours. After completion of the reaction, filter the reaction solution, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 50:1) to obtain the title compound (660 mg, yield: 79.1%, yellow oil).

[0666] MS(ESI): m / z 151.1[M+H] + ;

[0667] Step 3: tert-Butyl (5-((2-cyclopropoxypyridin-3-yl)amino)-3-(2-methoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0668]

[0669] Dissolve tert-butyl (5-chloro-3-(2-methoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (170 mg, 0.479 mmol) in dioxane (12 mL), and add 2-cyclopropoxypyridin-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). After purging with nitrogen, stir the reaction solution in an oil bath at 110 °C for 1 hour. After completion of the reaction, pour the reaction solution into water (30 mL), extract the aqueous phase with ethyl acetate (30 mL × 3), wash the combined organic phases with saturated brine (30 mL × 3), dry over anhydrous sodium sulfate, and concentrate 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 obtain the title compound (60 mg, yield: 26.7%, yellow oil).

[0670] MS(ESI): m / z 469.2[M+H] + ;

[0671] Step 4: 1-(5-((2-cyclopropoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxyethan-1-one (Compound 12)

[0672]

[0673] (5 - ((2 - cyclopropoxypyridin - 3 - yl)amino)-3-(2 - methoxyacetyl)pyrazolo[1,5 - a]pyrimidin - 7 - yl)(methyl)carbamic acid tert - butyl ester (60 mg, 0.128 mmol) was dissolved in dichloromethane (4.8 mL), trifluoroacetic acid (1.2 mL) was added, and the reaction mixture was stirred at room temperature for 1 h. 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 aqueous sodium bicarbonate. The aqueous phase was extracted with dichloromethane (30 mL × 3), and 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 high - performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (18.35 mg, yield: 38.9%, white solid).

[0674] MS(ESI): m / z 369.1[M + H] + ;

[0675] 1 H NMR(400 MHz, DMSO - d6) δ 8.71(s, 1H), 8.64(s, 1H), 8.29(s, 1H), 7.93–7.83(m, 2H), 7.02(dd, J = 7.9, 4.9 Hz, 1H), 6.03(s, 1H), 4.66(s, 2H), 4.38–4.31(m, 1H), 3.36(s, 3H), 2.90(d, J = 4.8 Hz, 3H), 0.79(d, J = 4.6 Hz, 4H).

[0676] Example 13

[0677] 1-(5 - ((2 - cyclopropoxypyridin - 3 - yl)amino)-7-(methylamino)pyrazolo[1,5 - a]pyrimidin - 3 - yl)-2 - ethoxyethan - 1 - one (Compound 13)

[0678]

[0679] The first step: (5 - ((2 - cyclopropoxypyridin - 3 - yl)amino)-3-(2 - ethoxyacetyl)pyrazolo[1,5 - a]pyrimidin - 7 - yl)(methyl)carbamic acid tert - butyl ester

[0680]

[0681] (5-Chloro-3-(2-ethoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamic acid tert-butyl ester (80 mg, 0.217 mmol) was dissolved in dioxane (12 mL), and 2-cyclopropoxypyridin-3-amine (40 mg, 0.261 mmol), palladium(II) 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 purging with nitrogen, the reaction mixture was stirred in an oil bath at 110 °C for 1 h. 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, 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 obtain the title compound (70 mg, yield: 66.7%, yellow solid).

[0682] MS(ESI): m / z 483.2 [M+H] + ;

[0683] Step 2: 1-(5-((2-Cyclopropoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-ethoxyethan-1-one (Compound 13)

[0684]

[0685] (5-((2-Cyclopropoxypyridin-3-yl)amino)-3-(2-ethoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamic acid tert-butyl ester (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 h. 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 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, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (20.03 mg, yield: 46.2%, white solid).

[0686] MS(ESI): m / z 383.1 [M+H] + ;

[0687] 11H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J = 7.2 Hz, 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 = 6.8 Hz, 2H), 2.91 (s, 3H), 1.17 (t, J = 6.4 Hz, 3H), 0.80 (brs, 4H).

[0688] Example 14

[0689] 2-Methoxy-1-(5-((6-methoxypyridin-2-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 14)

[0690]

[0691] First step: tert-Butyl (3-(2-methoxyacetyl)-5-((6-methoxypyridin-2-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0692]

[0693] Dissolve tert-butyl (5-chloro-3-(2-methoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (170 mg, 0.479 mmol) in dioxane (12 mL), add 6-methoxypyridin-2-amine (71 mg, 0.572 mmol), palladium(II) 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). After purging with nitrogen, the reaction mixture is stirred in an oil bath at 110 °C for 1 hour. After completion of the reaction, the reaction mixture is poured into water (30 mL), and the aqueous phase is extracted with ethyl acetate (30 mL × 3). The combined organic phases are washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product is separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the title compound (130 mg, yield: 61.3%, yellow solid).

[0694] MS (ESI): m / z 443.1 [M+H] + ;

[0695] 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)

[0696]

[0697] Dissolve 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) in dichloromethane (10 mL), add trifluoroacetic acid (2.5 mL), and stir the reaction mixture at room temperature for 1 hour. After completion of the reaction, pour the reaction mixture into water (30 mL), adjust the aqueous phase to pH = 6 - 7 with saturated aqueous sodium bicarbonate solution, extract the aqueous phase with dichloromethane (30 mL × 3), wash the combined organic phases with saturated brine (30 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (30.69 mg, yield: 30.5%, white solid).

[0698] MS(ESI): m / z 343.1 [M+H] + ;

[0699] 1 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.35 (s, 1H), 8.03 (d, J = 4.8 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H), 6.70 (s, 1H), 6.41 (d, J = 7.9 Hz, 1H), 4.76 (s, 2H), 3.92 (s, 3H), 3.40 (s, 3H), 2.93 (d, J = 4.8 Hz, 3H).

[0700] Example 15

[0701] 2-Ethoxy-1-(5-((6-methoxypyridin-2-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 15)

[0702]

[0703] First step: tert-butyl (3-(2-ethoxyacetyl)-5-((6-methoxypyridin-2-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0704]

[0705] Dissolve tert-butyl (5-chloro-3-(2-ethoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (100 mg, 0.270 mmol) in dioxane (8 mL), and add 6-methoxypyridin-2-amine (40 mg, 0.326 mmol), palladium(II) 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). After purging with nitrogen, stir the reaction mixture in an oil bath at 110 °C for 1 hour. After completion of the reaction, pour the reaction mixture into water (40 mL), extract the aqueous phase with ethyl acetate (40 mL × 3), wash the combined organic phases with saturated brine (40 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the title compound (106 mg, yield: 85.5%, yellow solid).

[0706] MS(ESI): m / z 457.1 [M+H] + ;

[0707] 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)

[0708]

[0709] Dissolve 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) in dichloromethane (8 mL), add trifluoroacetic acid (2 mL), and stir the reaction mixture at room temperature for 1 hour. After completion of the reaction, pour the reaction mixture into water (20 mL), adjust the aqueous phase to pH = 6 - 7 with saturated aqueous sodium bicarbonate, extract the aqueous phase with dichloromethane (20 mL × 3), wash the combined organic phases with saturated brine (20 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is separated and purified by preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (23.65 mg, yield: 35.3%, white solid).

[0710] MS(ESI): m / z 357.1 [M+H] + ;

[0711] 11H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.37 (s, 1H), 8.11 (s, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 6.65 (s, 1H), 6.43 (d, J = 8.0 Hz, 1H), 4.78 (s, 2H), 3.93 (s, 3H), 3.60 (q, J = 6.8 Hz, 2H), 2.94 (d, J = 4.4 Hz, 3H), 1.20 (t, J = 6.8 Hz, 3H).

[0712] Example 16

[0713] 3 - ((7-(Methylamino)-3-(2-(tetrahydrofuran-3-yl)acetyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-2H-[1,2'-bipyridin]-2-one (Compound 16)

[0714]

[0715] Step 1: 3-Amino-2H-[1,2'-bipyridin]-2-one

[0716]

[0717] Dissolve 3-aminopyridin-2(1H)-one (5 g, 45.409 mmol) and 2-bromopyridine (17.9 g, 113.291 mmol) in dioxane (100 mL), add potassium carbonate (18.8 g, 136.035 mmol), N,N'-dimethylethylenediamine (1.6 g, 18.151 mmol) and copper(I) iodide (1.73 g, 9.084 mmol). After purging with nitrogen, the reaction mixture is stirred at 110 °C in an oil bath for 16 h. After completion of the reaction, the reaction mixture is filtered, diluted with water (100 mL), and the aqueous phase is extracted with ethyl acetate (100 mL × 3). The combined organic phases are washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product is separated and purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to obtain the title compound (2.1 g, yield: 24.7%, yellow solid).

[0718] MS (ESI): m / z 188.0 [M + H] + ;

[0719] Step 2: tert-Butyl methyl(5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-3-(2-(tetrahydrofuran-3-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)carbamate

[0720]

[0721] Dissolve 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'-bipyridin]-2-one (97 mg, 0.519 mmol) in dioxane (4 mL). After purging with nitrogen, add palladium(II) 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). Stir the reaction mixture at 110 °C for 2 hours. After completion of the reaction, directly filter the system, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the title compound (140 mg, yield: 59.6%, yellow solid).

[0722] MS(ESI): m / z 546.3 [M+H] + ;

[0723] Step 3: 3-((7-(methylamino)-3-(2-(tetrahydrofuran-3-yl)acetyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-2H-[1,2'-bipyridin]-2-one (Compound 16)

[0724]

[0725] Dissolve tert-butyl methyl(5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-3-(2-(tetrahydrofuran-3-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)carbamate (140 mg, 0.257 mmol) in dichloromethane (4 mL). Add trifluoroacetic acid (0.8 mL). Stir the reaction mixture at room temperature for 1 hour. After completion of the reaction, concentrate the reaction mixture under reduced pressure, dilute with water (10 mL), adjust the pH of the aqueous phase to 6 - 7 with saturated aqueous sodium bicarbonate solution, extract the aqueous phase with ethyl acetate (10 mL × 3). The combined organic phases are 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 is purified by preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (72.75 mg, yield: 63.2%, white solid).

[0726] MS(ESI): m / z 446.0 [M+H] + ;

[0727] 11H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.73 (dd, J = 7.4, 1.8 Hz, 1H), 8.64 (ddd, J = 4.9, 1.8, 0.8 Hz, 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 = 7.2 Hz, 1H), 6.33 (s, 1H), 3.91 (dd, J = 8.2, 7.2 Hz, 1H), 3.77 (td, J = 8.1, 5.3 Hz, 1H), 3.69–3.61 (m, 1H), 3.37 (dd, J = 8.3, 6.6 Hz, 1H), 3.29 (d, J = 7.1 Hz, 1H), 3.15 (dd, J = 16.8, 7.5 Hz, 1H), 2.90 (d, J = 4.9 Hz, 3H), 2.69 (dt, J = 14.4, 7.2 Hz, 1H), 2.11 (dtd, J = 12.9, 7.7, 5.3 Hz, 1H), 1.59 (ddd, J = 14.8, 12.2, 7.1 Hz, 1H).

[0728] Example 17

[0729] 3 - ((7-(Methylamino)-3-(2-(tetrahydrofuran-2-yl)acetyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-2H-[1,2'-bipyridin]-2-one (Compound 17)

[0730]

[0731] Step 1: tert-Butyl methyl(5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-3-(2-(tetrahydrofuran-2-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)carbamate

[0732]

[0733] Dissolve tert-butyl (5-chloro-3-(2-(tetrahydrofuran-2-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (100 mg, 0.254 mmol) in dioxane (8 mL), and add 3-amino-2H-[1,2'-bipyridin]-2-one (56 mg, 0.304 mmol), palladium(II) 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). After purging with nitrogen, the reaction mixture was stirred in an oil bath at 110 °C for 1 h. 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 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 obtain the title compound (114 mg, yield: 82.6%, yellow solid).

[0734] MS(ESI): m / z 546.2 [M+H] + ;

[0735] Step 2: 3-((7-(methylamino)-3-(2-(tetrahydrofuran-2-yl)acetyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-2H-[1,2'-bipyridin]-2-one (Compound 17)

[0736]

[0737] Dissolve tert-butyl methyl(5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-3-(2-(tetrahydrofuran-2-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)carbamate (94 mg, 0.172 mmol) in dichloromethane (8 mL), add trifluoroacetic acid (2 mL), and stir the reaction mixture at room temperature for 1 h. 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 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 and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (10.11 mg, yield: 13.2%, white solid).

[0738] MS(ESI): m / z 446.1 [M+H] + ;

[0739] 11H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.77 (d, J = 7.2 Hz, 1H), 8.64 (s, 1H), 8.31 (s, 1H), 8.05 (t, J = 7.6 Hz, 1H), 7.94–7.81 (m, 2H), 7.54 (d, J = 6.8 Hz, 2H), 6.38 (dd, J = 15.6, 9.2 Hz, 2H), 4.42–4.28 (m, 1H), 3.79 (dd, J = 14.0, 6.4 Hz, 1H), 3.66–3.58 (m, 1H), 3.51 (dd, J = 15.2, 7.2 Hz, 1H), 3.10 (dd, J = 14.8, 5.6 Hz, 1H), 2.91 (d, J = 3.6 Hz, 3H), 2.04 (brs, 1H), 1.95–1.80 (m, 2H), 1.60 (d, J = 11.6 Hz, 1H).

[0740] Example 18

[0741] 3 - ((3-(2-Methoxyacetyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-2H-[1,2'-bipyridin]-2-one (Compound 18)

[0742]

[0743] Step 1: tert-Butyl (3-(2-methoxyacetyl)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0744]

[0745] (5-Chloro-3-(2-methoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamic acid tert-butyl ester (230 mg, 0.648 mmol) was dissolved in dioxane (14 mL), and 3-amino-2H-[1,2'-bipyridin]-2-one (146 mg, 0.78 mmol), palladium(II) 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 purging with nitrogen, the reaction mixture was stirred in an oil bath at 110 °C for 1 h. After completion of the reaction, the reaction mixture 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 obtain the title compound (230 mg, yield: 70.1%, yellow solid).

[0746] MS(ESI): m / z 506.1 [M+H] + ;

[0747] Step 2: 3-((3-(2-Methoxyacetyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-2H-[1,2'-bipyridin]-2-one (Compound 18)

[0748]

[0749] (3-(2-Methoxyacetyl)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamic acid tert-butyl ester (230 mg, 0.455 mmol) was dissolved in dichloromethane (18 mL), and trifluoroacetic acid (4.5 mL) was added. The reaction mixture was stirred at room temperature for 1 h. 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 aqueous sodium bicarbonate. 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 trituration with N,N-dimethylformamide and acetonitrile to obtain the title compound (13.74 mg, yield: 7.4%, yellow solid).

[0750] MS(ESI): m / z 406.1 [M+H] + ;

[0751] 11H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.77–8.71 (m, 1H), 8.64 (d, J = 4.9 Hz, 1H), 8.35 (s, 1H), 8.08–8.01 (m, 1H), 7.91 (d, J = 4.9 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.54 (dd, J = 7.5, 5.7 Hz, 2H), 6.46 (t, J = 7.2 Hz, 1H), 6.33 (s, 1H), 4.76 (s, 2H), 3.43 (s, 3H), 2.90 (d, J = 4.8 Hz, 3H).

[0752] Example 19

[0753] 3 - ((3-(2-Ethoxyacetyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-2H-[1,2'-bipyridin]-2-one (Compound 19)

[0754]

[0755] First step: tert-Butyl (3-(2-ethoxyacetyl)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0756]

[0757] Dissolve tert-butyl (5-chloro-3-(2-ethoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (80 mg, 0.217 mmol) in dioxane (12 mL), add 3-amino-2H-[1,2'-bipyridin]-2-one (49 mg, 0.261 mmol), palladium(II) 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). After purging with nitrogen, the reaction mixture was stirred in an oil bath at 110 °C for 1 h. 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 and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give the title compound (60 mg, yield: 53.1%, yellow solid).

[0758] MS (ESI): m / z 520.1 [M + H] + ;

[0759] Step 2: 3-((3-(2-Ethoxyacetyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-2H-[1,2'-bipyridin]-2-one (Compound 19)

[0760]

[0761] Dissolve tert-butyl (3-(2-ethoxyacetyl)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (60 mg, 0.116 mmol) in dichloromethane (8 mL), add trifluoroacetic acid (2 mL), and stir the reaction mixture at room temperature for 1 hour. After completion of the reaction, pour the reaction mixture into water (20 mL), adjust the aqueous phase to pH = 6 - 7 with saturated aqueous sodium bicarbonate solution, extract the aqueous phase with dichloromethane (20 mL × 3), wash the combined organic phases with saturated brine (20 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (6.29 mg, white solid, 13.1% yield).

[0762] MS(ESI): m / z 420.1 [M+H] + ;

[0763] 1 H NMR(400 MHz, DMSO-d6) δ 9.02(s, 1H), 8.75(d, J = 7.6 Hz, 1H), 8.64(s, 1H), 8.35(s, 1H), 8.04(t, J = 7.6 Hz, 1H), 7.91(s, 1H), 7.85(d, J = 8.0 Hz, 1H), 7.54(d, J = 6.8 Hz, 2H), 6.44(t, J = 6.8 Hz, 1H), 6.33(s, 1H), 4.80(s, 2H), 3.65–3.60(m, 2H), 2.90(d, J = 3.6 Hz, 3H), 1.22(t, J = 6.8 Hz, 3H).

[0764] Example 20

[0765] 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)

[0766]

[0767] First step: tert-butyl (3-bromo-2-fluorophenyl)carbamate

[0768]

[0769] Dissolve 3-bromo-2-fluoroaniline (5 g, 26.316 mmol) in di-tert-butyl dicarbonate (20 mL), and stir the reaction solution in an oil bath at 80 °C for 16 hours. After the reaction is completed, concentrate the reaction solution under reduced pressure to obtain a crude product, and purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate = 7:1) to obtain the title compound (7 g, yield: 92.1%, yellow oil).

[0770] MS(ESI): m / z 290.1[M+H] + ;

[0771] Step 2: tert-Butyl (2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate

[0772]

[0773] Dissolve tert-butyl (3-bromo-2-fluorophenyl)carbamate (7 g, 24.138 mmol) and 4,4,4',4',5,5,5',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]dichloropalladium (883 mg, 1.207 mmol). After purging with nitrogen, stir the reaction solution in an oil bath at 100 °C for 16 hours. After the reaction is completed, pour the reaction solution into water (100 mL), extract the aqueous phase with ethyl acetate (100 mL×3), wash the combined organic phases with saturated brine (100 mL×3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. Purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the title compound (5.28 g, yield: 64.9%, yellow oil).

[0774] MS(ESI): m / z 282.0[M+H-56] + ;

[0775] Step 3: tert-Butyl (2-fluoro-3-(pyridin-2-yl)phenyl)carbamate

[0776]

[0777] 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]dichloropalladium (109 mg, 0.148 mmol). After purging with nitrogen, stir the reaction mixture in an oil bath at 90 °C for 2 h. After completion of the reaction, pour the reaction mixture into water (50 mL), extract the aqueous phase with ethyl acetate (50 mL × 3), wash the combined organic phases with saturated brine (50 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the title compound (410 mg, yield: 96%, colorless oil).

[0778] MS(ESI): m / z 289.0 [M+H] + ;

[0779] Step 4: 2-Fluoro-3-(pyridin-2-yl)aniline

[0780]

[0781] 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 h. After completion of the reaction, pour the reaction mixture into water (20 mL), adjust the aqueous phase to pH = 6 - 7 with saturated aqueous sodium bicarbonate, extract the aqueous phase with dichloromethane (20 mL × 3), wash the combined organic phases with saturated brine (20 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the title compound (263 mg, yield: 98.1%, yellow oil).

[0782] MS(ESI): m / z 189.1 [M+H] + ;

[0783] 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

[0784]

[0785] 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-(pyridin-2-yl)aniline (57 mg, 0.305 mmol), palladium(II) 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 purging with nitrogen, stir the reaction mixture in an oil bath at 110 °C for 1 h. After completion of the reaction, pour the reaction mixture into water (40 mL), extract the aqueous phase with ethyl acetate (40 mL × 3), wash the combined organic phases with saturated brine (40 mL × 3), dry over anhydrous sodium sulfate, and concentrate 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 obtain the title compound (53 mg, yield: 41.2%, yellow solid).

[0786] MS(ESI): m / z 507.1 [M+H] + ;

[0787] Step 6: 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)

[0788]

[0789] Dissolve 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) in dichloromethane (8 mL), add trifluoroacetic acid (2 mL), and stir the reaction mixture at room temperature for 1 h. After completion of the reaction, pour the reaction mixture into water (20 mL), adjust the aqueous phase to pH = 6 - 7 with saturated aqueous sodium bicarbonate solution, extract the aqueous phase with dichloromethane (20 mL × 3), wash the combined organic phases with saturated brine (20 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (16.1 mg, yield: 37.9%, white solid).

[0790] MS(ESI): m / z 407.1 [M+H] + ;

[0791] 11H NMR (400 MHz, CD3OD) δ 8.82 (d, J = 5.2 Hz, 1H), 8.48 (t, J = 8.0 Hz, 1H), 8.36 (t, J = 7.6 Hz, 1H), 8.30 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.83–7.77 (m, 1H), 7.51 (t, J = 6.4 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 5.76 (s, 1H), 4.73 (s, 2H), 3.43 (s, 3H), 3.03 (s, 3H).

[0792] Example 21

[0793] 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-methoxyethan-1-one (Compound 21)

[0794]

[0795] Step 1: tert-Butyl (2-fluoro-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)carbamate

[0796]

[0797] 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 4-bromo-2-methyl-2H-1,2,3-triazole (361 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]dichloropalladium (109 mg, 0.148 mmol). After purging with nitrogen, the reaction mixture is stirred in an oil bath at 90 °C for 2 h. After completion of the reaction, the reaction mixture is poured into water (50 mL), and the aqueous phase is extracted with ethyl acetate (50 mL × 3). The combined organic phases are 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 is separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the title compound (370 mg, yield: 85.5%, colorless oil).

[0798] MS (ESI): m / z 237.1 [M + H - 56] + ;

[0799] Step 2: 2-Fluoro-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline

[0800]

[0801] 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 h. After completion of the reaction, pour the reaction mixture into water (20 mL), adjust the aqueous phase to pH = 6 - 7 with saturated aqueous sodium bicarbonate, extract the aqueous phase with dichloromethane (20 mL × 3), wash the combined organic phases with saturated brine (20 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the title compound (230 mg, yield: 94.7%, yellow oil).

[0802] MS(ESI): m / z 193.1 [M + H] + ;

[0803] 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

[0804]

[0805] 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), add 2-fluoro-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (50 mg, 0.305 mmol), palladium(II) 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 purging with nitrogen, stir the reaction mixture in an oil bath at 110 °C for 1 h. After completion of the reaction, pour the reaction mixture into water (40 mL), extract the aqueous phase with ethyl acetate (40 mL × 3), wash the combined organic phases with saturated brine (40 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is separated 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).

[0806] MS(ESI): m / z 511.1 [M + H] + ;

[0807] 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-methoxyethan-1-one (Compound 21)

[0808]

[0809] Dissolve 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) in dichloromethane (8 mL), add trifluoroacetic acid (2 mL), and stir the reaction mixture at room temperature for 1 h. After completion of the reaction, pour the reaction mixture into water (20 mL), adjust the aqueous phase to pH = 6 - 7 with saturated aqueous sodium bicarbonate solution, extract the aqueous phase with dichloromethane (20 mL × 3), wash the combined organic phases with saturated brine (20 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (15.34 mg, yield: 19.1%, white solid).

[0810] MS(ESI): m / z 411.1 [M+H] + ;

[0811] 1 1H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.28 (s, 1H), 8.22 (t, J = 7.2 Hz, 1H), 8.08 (d, J = 3.6 Hz, 1H), 7.93 (d, J = 4.8 Hz, 1H), 7.62 (t, J = 6.8 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 5.87 (s, 1H), 4.60 (s, 2H), 4.25 (s, 3H), 3.24 (s, 3H), 2.92 (d, J = 4.8 Hz, 3H).

[0812] Example 22

[0813] 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)

[0814]

[0815] First step: tert-butyl (3-bromo-2-methoxyphenyl)carbamate

[0816]

[0817] 3-Bromo-2-methoxyaniline (2 g, 9.899 mmol) was dissolved in ethanol (30 mL), and di-tert-butyl dicarbonate (3.24 g, 14.845 mmol) was added. After purging with nitrogen, 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. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to obtain the title compound (2.4 g, yield: 80.2%, colorless transparent oil).

[0818] 1 H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.2 Hz, 1H), 7.17 (dd, J = 8.1, 1.4 Hz, 1H), 7.05 (s, 1H), 6.96 (t, J = 8.2 Hz, 1H), 3.86 (s, 3H), 1.53 (s, 9H).

[0819] Step 2: tert-Butyl (2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate

[0820]

[0821] tert-Butyl (3-bromo-2-methoxyphenyl)carbamate (2.2 g, 7.281 mmol) was dissolved in dioxane (35 mL), and 4,4,4',4′,5,5,5′,5′-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (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) were added. After purging with nitrogen, 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 a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain the title compound (1.7 g, yield: 70%, yellow oil).

[0822] MS (ESI): m / z 294.1 [M + H - 56] + ;

[0823] Step 3: tert-Butyl (2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)carbamate

[0824]

[0825] Dissolve tert-butyl (2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (1.7 g, 4.868 mmol) in dioxane (30 mL) and water (6 mL). Add 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). After purging with nitrogen, stir the reaction mixture in an oil bath at 90 °C for 2 hours. After completion of the reaction, pour the reaction mixture into water (50 mL). Extract the aqueous phase with ethyl acetate (50 mL × 3). Wash the combined organic phases with saturated brine (50 mL × 3), dry over anhydrous sodium sulfate and concentrate under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate = 7:1) to obtain the title compound (1 g, yield: 67.5%, white solid).

[0826] MS(ESI): m / z 249.0 [M+H-56] + ;

[0827] Step 4: 2-Methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline

[0828]

[0829] 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). Stir the reaction mixture at room temperature for 1 hour. After completion of the reaction, pour the reaction mixture into water (30 mL). Adjust the pH of the aqueous phase to 6 - 7 with saturated aqueous sodium bicarbonate. Extract the aqueous phase with dichloromethane (20 mL × 3). Wash the combined organic phases with saturated brine (20 mL × 3), dry over anhydrous sodium sulfate and concentrate under reduced pressure to obtain the title compound (0.6 g, yield: 89.5%, yellow solid).

[0830] MS(ESI): m / z 205.1 [M+H] + ;

[0831] 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

[0832]

[0833] 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), add 2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (76 mg, 0.372 mmol), palladium(II) 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 purging with nitrogen, stir the reaction mixture in an oil bath at 110 °C for 1 h. After completion of the reaction, pour the reaction mixture into water (30 mL), extract the aqueous phase with ethyl acetate (20 mL × 3), wash the combined organic phases with saturated brine (20 mL × 3), dry over anhydrous sodium sulfate and concentrate 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 obtain the title compound (120 mg, yield: 74%, yellow solid).

[0834] MS(ESI): m / z 523.3 [M+H] + ;

[0835] 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)

[0836]

[0837] Dissolve 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) in dichloromethane (6 mL), add trifluoroacetic acid (1.5 mL), and stir the reaction mixture at room temperature for 1 h. After completion of the reaction, concentrate the reaction mixture under reduced pressure to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (27.93 mg, yield: 28.8%, white solid).

[0838] MS(ESI): m / z 423.0 [M+H] + ;

[0839] 11H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.39 (dd, J = 8.1, 1.4 Hz, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 7.86 (q, J = 4.6 Hz, 1H), 7.56 (dd, J = 7.8, 1.5 Hz, 1H), 7.21 (t, J = 8.0 Hz, 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 = 4.8 Hz, 3H).

[0840] Example 23

[0841] 2-Cyclopropoxy-1-(5-((2-fluoro-3-(pyridin-2-yl)phenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 23)

[0842]

[0843] First step: tert-Butyl (3-(2-cyclopropoxyacetyl)-5-((2-fluoro-3-(pyridin-2-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0844]

[0845] Dissolve tert-butyl (5-chloro-3-(2-cyclopropoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (100 mg, 0.263 mmol) in dioxane (1 mL), add 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). After purging with nitrogen, 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, 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 (120 mg, yield: 85.7%, yellow solid).

[0846] MS (ESI): m / z 533.1 [M+H] + ;

[0847] Step 2: 2-Cyclopropoxy-1-(5-((2-fluoro-3-(pyridin-2-yl)phenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 23)

[0848]

[0849] Dissolve tert-butyl (3-(2-cyclopropoxyacetyl)-5-((2-fluoro-3-(pyridin-2-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (100 mg, 0.188 mmol) in dichloromethane (8 mL), add trifluoroacetic acid (2 mL), and stir the reaction mixture at room temperature for 1 hour. After completion of the reaction, pour the reaction mixture into water (20 mL), adjust the aqueous phase to pH = 6 - 7 with saturated sodium bicarbonate aqueous solution, extract the aqueous phase with dichloromethane (20 mL × 3), wash the combined organic phases with saturated brine (20 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (16.68 mg, yield: 20.6%, white solid).

[0850] MS(ESI): m / z 433.1 [M+H] + ;

[0851] 1 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.72 (s, 1H), 8.31–8.29 (m, 2H), 7.93 (s, 2H), 7.80 (d, J = 6.8 Hz, 1H), 7.59 (d, J = 6.4 Hz, 1H), 7.45–7.36 (m, 1H), 7.30 (t, J = 7.6 Hz, 1H), 5.90 (s, 1H), 4.73 (s, 2H), 3.39 (brs, 1H), 2.92 (d, J = 4.4 Hz, 3H), 0.45 (brs, 2H), 0.37 (d, J = 4.4 Hz, 2H).

[0852] Example 24

[0853] 2-Cyclopropoxy-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)

[0854]

[0855] Step 1: tert-Butyl (3-(2-cyclopropoxyacetyl)-5-((2-fluoro-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0856]

[0857] Dissolve tert-butyl (5-chloro-3-(2-cyclopropoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (110 mg, 0.289 mmol) in dioxane (7 mL), and add 2-fluoro-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (67 mg, 0.349 mmol), palladium(II) 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). After purging with nitrogen, the reaction mixture is stirred in an oil bath at 110 °C for 1 h. After completion of the reaction, the reaction mixture is concentrated under reduced pressure to obtain a crude product. The crude product is separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1) and high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (30 mg, yield: 19.3%, white solid).

[0858] MS(ESI): m / z 537.2 [M+H] + ;

[0859] Step 2: 2-Cyclopropoxy-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)

[0860]

[0861] Dissolve tert-butyl (3-(2-cyclopropoxyacetyl)-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) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL), and stir the reaction mixture at room temperature for 1 h. After completion of the reaction, the reaction mixture is concentrated under reduced pressure to obtain a crude product. The crude product is purified by preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (11.05 mg, yield: 45.2%, white solid).

[0862] MS(ESI): m / z 437.1 [M+H] + ;

[0863] 1 1H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.29 (s, 1H), 8.23 (t, J = 7.3 Hz, 1H), 8.08 (d, J = 3.8 Hz, 1H), 7.95–7.93 (m, 1H), 7.62 (t, J = 6.6 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 5.88 (s, 1H), 4.68 (s, 2H), 4.24 (s, 3H), 3.38–3.35 (m, 1H), 2.92 (d, J = 4.8 Hz, 3H), 0.42–0.40 (m, 2H), 0.38–0.33 (m, 2H).

[0864] Example 25

[0865] 2-Cyclopropoxy-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)

[0866]

[0867] The first step: (2-Methyl-2H-1,2,3-triazol-4-yl)boronic acid

[0868]

[0869] Dissolve 4-bromo-2-methyl-2H-1,2,3-triazole (50 mg, 3.087 mmol) in tetrahydrofuran (5 mL). After purging with nitrogen, slowly add isopropylmagnesium chloride-lithium chloride complex (2.85 mL, 3.072 mmol) under an ice bath. The reaction mixture was stirred at the ice bath for 2 hours. Then cool down to -20 °C and slowly add trimethyl borate (0.08 mL, 0.616 mmol). The reaction mixture was stirred at -20 °C for 1 hour. After the reaction was completed, adjust the reaction mixture to pH = 1 - 2 with concentrated hydrochloric acid, dilute with water (30 mL), extract the aqueous phase with chloroform / isopropanol (3 / 1) (50 mL × 3), and 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%, yellow solid).

[0870] MS (ESI): m / z 128.2 [M+H] + ;

[0871] The second step: 3-Fluoro-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-amine

[0872]

[0873] (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), and potassium carbonate (261 mg, 1.889 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (46 mg, 0.0629 mmol) were added. After purging with nitrogen, 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 = 1:1) to obtain the title compound (80 mg, yield: 65.5%, white solid).

[0874] MS(ESI): m / z 194.1 [M+H] + ;

[0875] Step 3: tert-Butyl (3-(2-cyclopropoxyacetyl)-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

[0876]

[0877] tert-Butyl (5-chloro-3-(2-cyclopropoxyacetyl)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) (17 mg, 0.020 mmol), and cesium carbonate (193 mg, 0.592 mmol) were added. After purging with nitrogen, 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, 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 obtain the title compound (70 mg, yield: 66.0%, yellow solid).

[0878] MS(ESI): m / z 538.1 [M+H] + ;

[0879] Step 4: 2-Cyclopropoxy-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)

[0880]

[0881] Dissolve tert-butyl (3-(2-cyclopropoxyacetyl)-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) in dichloromethane (8 mL), add trifluoroacetic acid (2 mL), and stir the reaction mixture at room temperature for 1 h. After completion of the reaction, pour the reaction mixture into water (20 mL), adjust the aqueous phase to pH = 6 - 7 with saturated aqueous sodium bicarbonate solution, extract the aqueous phase with dichloromethane (20 mL × 3), wash the combined organic phases with saturated brine (20 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (10.13 mg, yield: 20.7%, yellow solid).

[0882] MS(ESI): m / z 438.1 [M+H] + ;

[0883] 1 H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 8.31–8.25 (m, 3H), 8.06 (d, J = 4.8 Hz, 1H), 7.69 (t, J = 5.2 Hz, 1H), 6.21 (s, 1H), 4.54 (s, 2H), 4.28 (s, 3H), 3.19–3.14 (m, 1H), 2.95 (d, J = 4.8 Hz, 3H), 0.26–0.16 (m, 4H).

[0884] Example 26

[0885] 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)

[0886]

[0887] Step 1: ((1S,2R)-2-Methoxycyclobutyl)methyl methanesulfonate

[0888]

[0889] Dissolve (1S,2R)-2-methoxycyclobutanemethanol (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 and stir for 2 h. After completion of the reaction, pour the reaction mixture into water (50 mL), extract the aqueous phase with dichloromethane (50 mL × 3), wash the combined organic phases with saturated brine (50 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give the title compound (1.2 g, yield: 93.2%, colorless oil).

[0890] MS(ESI): m / z 195.0 [M+H] + ;

[0891] Step 2: 2-((1S,2R)-2-Methoxycyclobutyl)acetonitrile

[0892]

[0893] 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 warm the reaction mixture to 85 °C and stir for 16 h. After completion of the reaction, pour the reaction mixture into water (50 mL), extract the aqueous phase with ethyl acetate (50 mL × 3), wash the combined organic phases with saturated brine (50 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title compound (723 mg, yield: 93.5%, yellow oil).

[0894] Step 3: 2-((1S,2R)-2-Methoxycyclobutyl)acetic acid

[0895]

[0896] Dissolve 2-((1S,2R)-2-methoxycyclobutyl)acetonitrile (523 mg, 4.184 mmol) in sodium hydroxide solution (5 M, 10 mL), and heat the reaction mixture to 100 °C and stir for 2 hours. After the reaction is completed, pour the reaction mixture into water (50 mL). Extract the aqueous phase with ethyl acetate (50 mL × 2), then adjust the pH of the aqueous phase to 1 with concentrated hydrochloric acid, and extract again with ethyl acetate (50 mL × 3). Wash the combined organic phases with saturated brine (50 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title compound (450 mg, yellow oil).

[0897] Step 4: S-(p-tolyl) 2-((1S,2R)-2-methoxycyclobutyl)thioacetate

[0898]

[0899] Dissolve 2-((1S,2R)-2-methoxycyclobutyl)acetic acid (1 g, 6.944 mmol) in acetonitrile (50 mL), cool to 0 °C, 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). Heat the reaction mixture to room temperature and stir for 2 hours. After the reaction is completed, concentrate the reaction mixture under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography (petroleum ether:dichloromethane = 2:1) to obtain the title compound (576 mg, yield: 33.2%, yellow oil).

[0900] MS(ESI): m / z 251.1 [M+H] + ;

[0901] Step 5: tert-Butyl (5-chloro-3-(2-((1S,2R)-2-methoxycyclobutyl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0902]

[0903] (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)ethanethiolate (690 mg, 2.761 mmol) were dissolved in tetrahydrofuran (40 mL), and tris(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 purging with nitrogen, the reaction mixture was stirred in an oil bath at 50 °C for 2 h. 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 separated 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).

[0904] MS(ESI): m / z 409.1 [M+H] + ;

[0905] 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

[0906]

[0907] (5-Chloro-3-(2-((1S,2R)-2-methoxycyclobutyl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamic acid tert-butyl ester (120 mg, 0.294 mmol) was dissolved in dioxane (10 mL), and 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) were added. After purging with nitrogen, the reaction mixture was stirred in an oil bath at 110 °C for 1 h. 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 obtain the title compound (94 mg, yield: 64.4%, yellow solid).

[0908] MS(ESI): m / z 497.1 [M+H] + ;

[0909] 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)

[0910]

[0911] Dissolve 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) in dichloromethane (8 mL), add trifluoroacetic acid (2 mL), and stir the reaction mixture at room temperature for 1 hour. After completion of the reaction, pour the reaction mixture into water (20 mL), adjust the aqueous phase to pH = 6 - 7 with saturated aqueous sodium bicarbonate solution, extract the aqueous phase with dichloromethane (20 mL × 3), wash the combined organic phases with saturated brine (20 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product is purified by preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (26.39 mg, yield: 39.4%, white solid).

[0912] MS(ESI): m / z 397.1 [M+H] + ;

[0913] 1 H NMR(400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.73 (dd, J = 7.6, 1.6 Hz, 1H), 8.24 (s, 1H), 7.90–7.81 (m, 2H), 6.97 (dd, J = 8.0, 4.8 Hz, 1H), 6.08 (s, 1H), 3.98 (s, 3H), 3.53 (q, J = 7.2 Hz, 1H), 3.20 (qd, J = 15.6, 7.2 Hz, 2H), 3.09 (s, 3H), 2.91 (d, J = 4.8 Hz, 3H), 2.61–2.53 (m, 1H), 2.07 (dd, J = 16.4, 8.0 Hz, 1H), 1.81 (q, J = 9.2 Hz, 1H), 1.72–1.53 (m, 1H), 1.17 (dd, J = 18.8, 9.6 Hz,

[0914] Example 27

[0915] 2-Cyclobutyl-1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 27)

[0916]

[0917] Step 1: S-(p-Tolyl) 2-cyclobutylthioacetate

[0918]

[0919] Dissolve 2-cyclobutylacetic acid (1 g, 8.772 mmol) in acetonitrile (50 mL), cool to 0 °C, 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). Warm the reaction mixture to room temperature and stir for 2 h. After completion of the reaction, concentrate the reaction mixture under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:dichloromethane = 2:1) to give the title compound (1.9 g, yield: 98.4%, yellow oil).

[0920] Step 2: tert-Butyl 5-chloro-3-(2-cyclobutylacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0921]

[0922] Dissolve (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-cyclobutylthioacetate (945 mg, 4.294 mmol) in tetrahydrofuran (40 mL), add tris(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). After purging with nitrogen, stir the reaction mixture in an oil bath at 50 °C for 2 h. After completion of the reaction, pour the reaction mixture into water (50 mL), extract the aqueous phase with ethyl acetate (50 mL × 3), wash the combined organic phases with saturated brine (50 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to give the title compound (213 mg, yield: 26.2%, yellow oil).

[0923] MS(ESI): m / z 379.0 [M+H] + ;

[0924] Step 3: tert-Butyl (3-(2-cyclobutylacetyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0925]

[0926] 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), add 2-methoxypyridin-3-amine 6 (75 mg, 0.603 mmol), palladium(II) 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 purging with nitrogen, the reaction mixture is stirred at 110 °C in an oil bath for 1 h. After completion of the reaction, the reaction mixture is poured into water (40 mL), and the aqueous phase is extracted with ethyl acetate (40 mL × 3). The combined organic phases are washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the crude product. The crude product is separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the title compound (132 mg, yield: 56.4%, yellow solid).

[0927] MS(ESI): m / z 467.1 [M+H] + ;

[0928] 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)

[0929]

[0930] 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), trifluoroacetic acid (2 mL) was added, and the reaction mixture was stirred at room temperature for 1 h. 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 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 preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (56.69 mg, yield: 65.9%, white solid).

[0931] MS(ESI): m / z 367.1 [M + H] + ;

[0932] 1 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.78 (dd, J = 7.6, 1.6 Hz, 1H), 8.23 (s, 1H), 7.89–7.78 (m, 2H), 6.94 (dd, J = 7.6, 4.8 Hz, 1H), 6.11 (s, 1H), 3.98 (s, 3H), 3.14 (d, J = 7.6 Hz, 2H), 2.91 (d, J = 4.8 Hz, 3H), 2.75 (dt, J = 15.2, 7.6 Hz, 1H), 2.11–2.00 (m, 2H), 1.88–1.76 (m, 2H), 1.75–1.64 (m, 2H).

[0933] Example 28

[0934] 2-Cyclobutoxy-1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 28)

[0935]

[0936] The first step: 2-cyclobutoxyacetic acid

[0937]

[0938] Cyclobutanol (1.0 g, 14.388 mmol) was dissolved in tetrahydrofuran (70 mL). The temperature was lowered to 0 °C, and sodium hydride (1.2 g, 28.777 mmol) was added. After stirring for 2 hours, 2-bromoacetic acid (2.0 g, 14.388 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for 16 hours. After completion of the reaction, the reaction mixture was quenched with water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 2), and the pH of the aqueous phase was adjusted to 1 - 2 with 1 M HCl aqueous solution. Then it 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 title compound (1.6 g, yield: 85.6%, yellow oil).

[0939] Step 2: S-(p-tolyl) 2-cyclobutoxyethanethioate

[0940]

[0941] 2-Cyclobutoxyacetic acid (1.5 g, 11.538 mmol) was dissolved in acetonitrile (50 mL). The temperature was lowered to 0 °C, and 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) were added. 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 separated and purified by silica gel column chromatography (petroleum ether:dichloromethane = 2:1) to obtain the title compound (1.5 g, yield: 55.6%, yellow oil).

[0942] MS(ESI): m / z 237.1 [M + H] + ;

[0943] Step 3: tert-Butyl (5-chloro-3-(2-cyclobutoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0944]

[0945] (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-cyclobutoxysulfanylacetate (870 mg, 3.681 mmol) were dissolved in tetrahydrofuran (40 mL), and tris(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 purging with nitrogen, the reaction mixture was stirred in an oil bath at 50 °C for 2 h. 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 separated 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).

[0946] MS(ESI): m / z 395.0 [M+H] + ;

[0947] Step 4: tert-Butyl (3-(2-cyclobutoxyacetyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0948]

[0949] (5-Chloro-3-(2-cyclobutoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamic acid tert-butyl ester (120 mg, 0.305 mmol) was dissolved in dioxane (10 mL), and 2-methoxypyridin-3-amine (45 mg, 0.365 mmol), palladium(II) 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 purging with nitrogen, the reaction mixture was stirred in an oil bath at 110 °C for 1 h. 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 obtain the title compound (112 mg, yield: 76.2%, yellow solid).

[0950] MS(ESI): m / z 483.1 [M+H] + ;

[0951] 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)

[0952]

[0953] 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 of the reaction, pour the reaction mixture into water (20 mL), adjust the aqueous phase to pH = 6 - 7 with saturated aqueous sodium bicarbonate solution, extract the aqueous phase with dichloromethane (20 mL × 3), wash the combined organic phases with saturated brine (20 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (39.53 mg, yield: 26.4%, white solid).

[0954] MS(ESI): m / z 383.1 [M+H] + ;

[0955] 1 1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.68 (dd, J = 7.6, 1.6 Hz, 1H), 8.29 (s, 1H), 7.95–7.80 (m, 2H), 6.99 (dd, J = 8.0, 4.8 Hz, 1H), 6.07 (s, 1H), 4.61 (s, 2H), 4.06–4.00 (m, 1H), 3.98 (s, 3H), 2.90 (d, J = 4.8 Hz, 3H), 2.19–2.08 (m, 2H), 1.87 (qd, J = 10.0, 2.4 Hz, 2H), 1.65 (q, J = 10.0 Hz, 1H), 1.54–1.41 (m, 1H).

[0956] Example 29

[0957] 2-Cyclopropoxy-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)

[0958]

[0959] Step 1: tert-Butyl (3-(2-cyclopropoxyacetyl)-5-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0960]

[0961] Dissolve tert-butyl (5-chloro-3-(2-cyclopropoxyacetyl)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(II) 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 purging with nitrogen, the reaction mixture was stirred at 110 °C in an oil bath for 1 h. 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 obtain the title compound (117 mg, yield: 74.9%, yellow solid).

[0962] MS(ESI): m / z 496.3 [M+H] + ;

[0963] Step 2: 2-Cyclopropoxy-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)

[0964]

[0965] tert-Butyl (3-(2-cyclopropoxyacetyl)-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), 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 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 preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (15.57 mg, yield: 18.3%, white solid).

[0966] MS(ESI): m / z 396.1 [M+H] + ;

[0967] 1 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.26 (s, 1H), 7.86 (d, J = 7.2 Hz, 1H), 7.81 (d, J = 4.8 Hz, 1H), 6.79 (t, J = 8.4 Hz, 1H), 6.60 (dd, J = 8.0, 1.2 Hz, 1H), 5.97 (s, 1H), 4.77 (s, 2H), 4.37–4.31 (m, 2H), 4.31–4.24 (m, 2H), 3.46 (dd, J = 6.0, 2.8 Hz, 1H), 2.89 (d, J = 4.8 Hz, 3H), 0.52 (dd, J = 7.2, 4.4 Hz, 2H), 0.45 (t, J = 5.2 Hz, 2H).

[0968] Example 30

[0969] 2-Cyclopropoxy-1-(5-((2-fluoro-3-morpholinophenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 30)

[0970]

[0971] First step: 4-(2-Fluoro-3-nitrophenyl)morpholine

[0972]

[0973] 1-Bromo-2-fluoro-3-nitrobenzene (1.5 g, 6.818 mmol) was dissolved in dioxane (15 mL), and morpholine (840 mg, 9.642 mmol), palladium(II) 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) were added. After purging with nitrogen, the reaction mixture was stirred in an oil bath at 110 °C for 6 h. 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 = 6:1) to obtain the title compound (690 mg, yield: 44.7%, yellow solid).

[0974] MS(ESI): m / z 227.1 [M+H] + ;

[0975] Step 2: 2-Fluoro-3-morpholinoaniline

[0976]

[0977] 4-(2-Fluoro-3-nitrophenyl)morpholine (690 mg, 3.05 mmol) was dissolved in methanol (15 mL), and ammonium formate (769 mg, 12.196 mmol), 10% palladium on carbon (76 mg) and water (1.05 mL) were added. After purging with nitrogen, the reaction mixture was stirred at room temperature for 16 h. 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 (petroleum ether:ethyl acetate = 6:1) to obtain the title compound (570 mg, yield: 95.1%, yellow solid).

[0978] MS(ESI): m / z 197.1 [M+H] + ;

[0979] Step 3: tert-Butyl (3-(2-cyclopropoxyacetyl)-5-((2-fluoro-3-morpholinophenyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0980]

[0981] Dissolve tert-butyl (5-chloro-3-(2-cyclopropoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (150 mg, 0.394 mmol) in dioxane (10 mL), add 2-fluoro-3-morpholinoaniline (93 mg, 0.474 mmol), palladium(II) 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 purging with nitrogen, stir the reaction mixture in an oil bath at 110 °C for 1 hour. After completion of the reaction, pour the reaction mixture into water (30 mL), extract the aqueous phase with dichloromethane (30 mL × 3), wash the combined organic phases with saturated brine (30 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate 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 obtain the title compound (95 mg, yield: 44.6%, yellow oil).[[ID=~1]] [[ID=~2]]

[0982] [[ID=~3]]MS(ESI): m / z 541.2[M+H][[ID=~4]] + [[ID=~5]];[[ID=~6]] [[ID=~7]]

[0983] [[ID=~8]]Step 4: 2-Cyclopropoxy-1-(5-((2-fluoro-3-morpholinophenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 30)[[ID=~9]] [[ID=~10]]

[0984] [[ID=~11]] [[ID=~12]] [[ID=~13]]

[0985] [[ID=~14]]Dissolve tert-butyl (3-(2-cyclopropoxyacetyl)-5-((2-fluoro-3-morpholinophenyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (95 mg, 0.176 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 reaction mixture under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (28.6 mg, yield: 36.9%, white solid).[[ID=~15]] [[ID=~16]]

[0986] [[ID=~17]]MS(ESI): m / z 441.2[M+H][[ID=~18]] + [[ID=~19]];[[ID=~20]] [[ID=~21]]

[0987] [[ID=~22]] 11H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.27 (s, 1H), 7.87 (dd, J = 8.5, 6.2 Hz, 2H), 7.07 (t, J = 7.7 Hz, 1H), 6.78 (t, J = 7.5 Hz, 1H), 5.84 (s, 1H), 4.71 (s, 2H), 3.78–3.73 (m, 4H), 3.45 (ddd, J = 9.1, 6.0, 3.0 Hz, 1H), 3.04–2.99 (m, 4H), 2.90 (d, J = 4.8 Hz, 3H), 0.50 (dt, J = 6.2, 3.1 Hz, 2H), 0.41 (dt, J = 6.1, 4.7 Hz, 2H).

[0988] Example 31

[0989] 2-Cyclopropoxy-1-(7-(methylamino)-5-(quinoxalin-5-ylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 31)

[0990]

[0991] Step 1: Quinoxalin-5-amine

[0992]

[0993] 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 purging with nitrogen, the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, 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), and 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 = 3:1) to obtain the title compound (180 mg, yield: 36.2%, yellow solid).

[0994] MS (ESI): m / z 146.1 [M+H] + ;

[0995] Step 2: tert-Butyl (3-(2-cyclopropoxyacetyl)-5-(quinoxalin-5-ylamino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[0996]

[0997] Dissolve tert-butyl (5-chloro-3-(2-cyclopropoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (150 mg, 0.394 mmol) in dioxane (10 mL), add quinoxalin-5-amine (69 mg, 0.475 mmol), palladium(II) 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 purging with nitrogen, the reaction mixture is stirred in an oil bath at 110 °C for 1 hour. After completion of the reaction, the reaction mixture is filtered, and the filtrate is concentrated under reduced pressure to obtain the crude product. The crude product is separated and purified by silica gel column chromatography (dichloromethane:methanol = 24:1) to obtain the title compound (150 mg, yield: 77.7%, yellow solid).

[0998] MS(ESI): m / z 490.2 [M+H] + ;

[0999] Step 3: 2-Cyclopropoxy-1-(7-(methylamino)-5-(quinoxalin-5-ylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 31)

[1000]

[1001] Dissolve tert-butyl (3-(2-cyclopropoxyacetyl)-5-(quinoxalin-5-ylamino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (150 mg, 0.306 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, pour the reaction mixture into water (20 mL), adjust the pH to 7 with saturated aqueous sodium bicarbonate solution, extract the aqueous phase with dichloromethane (20 mL × 3), wash the combined organic phases with saturated brine (20 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product is purified by trituration with acetonitrile to obtain the title compound (44.82 mg, yield: 37.5%, yellow solid).

[1002] MS(ESI): m / z 390.1 [M+H] + ;

[1003] 11H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 9.11 (d, J = 7.9 Hz, 1H), 9.05 (d, J = 1.8 Hz, 1H), 8.98 (d, J = 1.8 Hz, 1H), 8.37 (s, 1H), 7.98 (d, J = 4.9 Hz, 1H), 7.85 (t, J = 8.2 Hz, 1H), 7.72 (dd, J = 8.4, 1.0 Hz, 1H), 6.45 (s, 1H), 4.92 (s, 2H), 3.58 (tt, J = 5.9, 3.0 Hz, 1H), 2.96 (d, J = 4.8 Hz, 3H), 0.63–0.58 (m, 2H), 0.55–0.49 (m, 2H).

[1004] Example 32

[1005] 3-((3-(2-Cyclopropoxyacetyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-1-(difluoromethyl)pyridin-2(1H)-one (Compound 32)

[1006]

[1007] First step: 1-(Difluoromethyl)-3-nitropyridin-2(1H)-one

[1008]

[1009] Dissolve 3-nitropyridin-2(1H)-one (1.5 g, 10.714 mmol) in triethylene glycol dimethyl ether (43 mL). After purging with nitrogen, cool the solution to -15 °C, add sodium tert-butoxide (2.3 g, 23.571 mmol), and stir the reaction mixture in a -15 °C dry ice bath for 10 minutes. Then, add bromodifluoromethyltrimethylsilane (2.6 g, 12.857 mmol) dropwise and stir the reaction mixture in a -15 °C dry ice bath for 1 hour. After completion of the reaction, pour the reaction mixture into water (40 mL), and extract the aqueous phase with ethyl acetate (40 mL × 3). Wash the combined organic phases with saturated brine (40 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the title compound (725 mg, yield: 35.6%, yellow oil).

[1010] MS (ESI): m / z 191.0 [M+H] + ;

[1011] Second step: 3-Amino-1-(difluoromethyl)pyridin-2(1H)-one

[1012]

[1013] Dissolve 1-(difluoromethyl)-3-nitropyridin-2(1H)-one (725 mg, 3.816 mmol) in ethanol (15 mL), and add Pd / C (75 mg). After purging with hydrogen, 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 a crude product. The crude product was separated 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).

[1014] MS(ESI): m / z 161.1 [M+H] + ;

[1015] Step 3: tert-Butyl (3-(2-cyclopropoxyacetyl)-5-((1-(difluoromethyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[1016]

[1017] Dissolve tert-butyl (5-chloro-3-(2-cyclopropoxyacetyl)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 purging with nitrogen, 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 a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the title compound (55 mg, yield: 34.6%, yellow solid).

[1018] MS(ESI): m / z 505.1 [M+H] + ;

[1019] Step 4: 3-((3-(2-cyclopropoxyacetyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-1-(difluoromethyl)pyridin-2(1H)-one (Compound 32)

[1020]

[1021] Dissolve tert-butyl (3-(2-cyclopropoxyacetyl)-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) in dichloromethane (8 mL), add trifluoroacetic acid (2 mL), and stir the reaction mixture at room temperature for 1 hour. After completion of the reaction, pour the reaction mixture into water (20 mL), adjust the aqueous phase to pH = 6 - 7 with saturated aqueous sodium bicarbonate, extract the aqueous phase with dichloromethane (20 mL × 3), wash the combined organic phases with saturated brine (20 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product is purified by preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (11.85 mg, yield: 32.9%, white solid).

[1022] MS(ESI): m / z 405.1 [M+H] + ;

[1023] 1 H NMR(400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.75 (d, J = 6.0 Hz, 1H), 8.36 (s, 1H), 8.22–7.81 (m, 2H), 7.43 (d, J = 6.0 Hz, 1H), 6.48 (t, J = 7.2 Hz, 1H), 6.36 (s, 1H), 4.82 (s, 2H), 3.54 (dt, J = 9.2, 3.2 Hz, 1H), 2.90 (d, J = 4.8 Hz, 3H), 0.58 (s, 2H), 0.49 (d, J = 4.8 Hz, 2H).

[1024] Example 33

[1025] 2-Cyclopropoxy-1-(5-((2-(methoxy-d3)phenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 33)

[1026]

[1027] First step: N-(2-(methoxy-d3)phenyl)acetamide

[1028]

[1029] Dissolve N-(2-hydroxyphenyl)acetamide (3 g, 19.845 mmol) in acetonitrile (20 mL), and add iodomethane-d3 (4.89 g, 33.733 mmol) and potassium carbonate (5.49 g, 39.725 mmol). After purging with nitrogen, the reaction mixture was stirred at room temperature for 16 h. 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 10% aqueous potassium carbonate solution (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 separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain the title compound (2.7 g, yield: 80.8%, yellow solid).

[1030] MS(ESI): m / z 169.2 [M+H] + ;

[1031] Step 2: 2-(methoxy-d3)aniline

[1032]

[1033] Dissolve N-(2-(methoxy-d3)phenyl)acetamide (400 mg, 2.378 mmol) in water (3 mL), and add hydrochloric acid (1 mL). After purging with nitrogen, the reaction mixture was stirred in an oil bath at 90 °C for 2 h. After completion of the reaction, the reaction mixture was poured into water (30 mL), and the aqueous phase was adjusted to pH = 14 with 4N aqueous sodium hydroxide 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, 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 = 99:1) to obtain the title compound (240 mg, yield: 80%, yellow oil).

[1034] MS(ESI): m / z 127.2 [M+H] + ;

[1035] Step 3: tert-butyl (3-(2-cyclopropoxyacetyl)-5-((2-(methoxy-d3)phenyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[1036]

[1037] Dissolve tert-butyl (5-chloro-3-(2-cyclopropoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (150 mg, 0.394 mmol) in dioxane (8 mL), add 2-(methoxy-d3)aniline (60 mg, 0.476 mmol), palladium(II) 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 purging with nitrogen, 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 (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 obtain the title compound (100 mg, yield: 54%, yellow solid).

[1038] MS(ESI): m / z 471.2 [M+H] + ;

[1039] Step 4: 2-Cyclopropoxy-1-(5-((2-(methoxy-d3)phenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 33)

[1040]

[1041] Dissolve tert-butyl (3-(2-cyclopropoxyacetyl)-5-((2-(methoxy-d3)phenyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (100 mg, 0.213 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, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (9.76 mg, yield: 12.4%, white solid).

[1042] MS(ESI): m / z 371.2 [M+H] + ;

[1043] 11H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.36 (d, J = 7.3 Hz, 1H), 8.26 (s, 1H), 7.80 (q, J = 4.6 Hz, 1H), 7.09–7.01 (m, 2H), 6.97–6.90 (m, 1H), 5.99 (s, 1H), 4.78 (s, 2H), 3.47 (tt, J = 6.0, 3.0 Hz, 1H), 2.89 (d, J = 4.8 Hz, 3H), 0.56–0.50 (m, 2H), 0.49–0.42 (m, 2H).

[1044] Example 34

[1045] 3 - ((3-(2-Cyclopropoxyacetyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-1-cyclopropylpyridin-2(1H)-one (Compound 34)

[1046]

[1047] Step 1: 1-Cyclopropyl-3-nitropyridin-2(1H)-one

[1048]

[1049] Dissolve 3-nitropyridin-2(1H)-one (2.2 g, 15.703 mmol) in acetonitrile (40 mL), add cyclopropylboronic acid 2 (4.05 g, 47.148 mmol), 2,2'-bipyridine (2.45 g, 15.687 mmol), copper(II) acetate (2.85 g, 15.691 mmol) and sodium carbonate (4.99 g, 47.08 mmol). After replacing with oxygen, the reaction mixture was stirred in an oil bath at 70 °C for 16 h. 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 × 3). The combined organic phases were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 32:1) to obtain the title compound (1 g, yield: 35.3%, yellow solid).

[1050] MS (ESI): m / z 181.1 [M + H] + ;

[1051] Step 2: 3-Amino-1-cyclopropylpyridin-2(1H)-one

[1052]

[1053] 1-Cyclopropyl-3-nitropyridin-2(1H)-one (1 g, 5.551 mmol) was dissolved in methanol (30 mL), palladium on carbon catalyst (100 mg) was added, and after replacement with hydrogen, the reaction solution was stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 32:1) to obtain the title compound (790 mg, yield: 94.7%, yellow solid).

[1054] MS(ESI): m / z 151.2 [M+H] + ;

[1055] Step 3: tert-Butyl (3-(2-cyclopropoxyacetyl)-5-((1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[1056]

[1057] tert-Butyl (5-chloro-3-(2-cyclopropoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (150 mg, 0.394 mmol) was dissolved in dioxane (8 mL), 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) were added. After replacement with nitrogen, 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 a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 32:1) to obtain the title compound (120 mg, yield: 61.6%, yellow solid).

[1058] MS(ESI): m / z 495.4 [M+H] + ;

[1059] Step 4: 3-((3-(2-Cyclopropoxyacetyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-1-cyclopropylpyridin-2(1H)-one (Compound 34)

[1060]

[1061] (3-(2-Cyclopropoxyacetyl)-5-((1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamic acid tert-butyl ester (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 a crude product. The crude product was separated and purified by preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (43.45 mg, yield: 45.4%, white solid).

[1062] MS(ESI): m / z 395.2[M+H] + ;

[1063] 1 H NMR(400 MHz, DMSO-d6) δ 8.92(s, 1H), 8.62(dd, J = 7.4, 1.6 Hz, 1H), 8.32(s, 1H), 7.87(q, J = 4.6 Hz, 1H), 7.19(dd, J = 7.0, 1.6 Hz, 1H), 6.30(s, 1H), 6.23(t, J = 7.2 Hz, 1H), 4.82(s, 2H), 3.53(ddd, J = 9.0, 6.0, 3.0 Hz, 1H), 3.47(ddd, J = 11.5, 7.5, 4.3 Hz, 1H), 2.90(d, J = 4.8 Hz, 3H), 1.04(q, J = 7.3 Hz, 2H), 0.93–0.86(m, 2H), 0.62–0.55(m, 2H), 0.52–0.45(m, 2H).

[1064] Example 35

[1065] 3-((3-(2-Cyclobutoxyacetyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-1-(difluoromethyl)pyridin-2(1H)-one (Compound 35)

[1066]

[1067] First step: (3-(2-Cyclobutoxyacetyl)-5-((1-(difluoromethyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamic acid tert-butyl ester

[1068]

[1069] 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), add 3-amino-1-(difluoromethyl)pyridin-2(1H)-one (58 mg, 0.365 mmol), palladium(II) 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 purging with nitrogen, 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 = 3:1) to obtain the title compound (135 mg, yield: 85.4%, yellow solid).

[1070] MS(ESI): m / z 519.2 [M+H] + ;

[1071] Step 2: 3-((3-(2-Cyclobutoxyacetyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-1-(difluoromethyl)pyridin-2(1H)-one (Compound 35)

[1072]

[1073] Dissolve 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) in dichloromethane (8 mL), add trifluoroacetic acid (2 mL), and stir the reaction mixture 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 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 preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (23.77 mg, yield: 25.6%, white solid).

[1074] MS(ESI): m / z 419.1 [M+H] + ;

[1075] 11H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.69 (dd, J = 7.6, 1.2 Hz, 1H), 8.35 (s, 1H), 8.23–7.84 (m, 2H), 7.54–7.41 (m, 1H), 6.48 (t, J = 7.2 Hz, 1H), 6.35 (s, 1H), 4.66 (s, 2H), 4.09 (p, J = 7.2 Hz, 1H), 2.90 (d, J = 4.8 Hz, 3H), 2.26–2.11 (m, 2H), 1.91 (qd, J = 10.0, 2.4 Hz, 2H), 1.75–1.40 (m, 2H).

[1076] Example 36

[1077] 2-Cyclopropoxy-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)

[1078]

[1079] First step: tert-Butyl (3-(2-cyclopropoxyacetyl)-5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[1080]

[1081] Dissolve tert-butyl (5-chloro-3-(2-cyclopropoxyacetyl)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(II) acetate (22 mg, 0.098 mmol), 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) (124 mg, 0.199 mmol) and cesium carbonate (976 mg, 2.996 mmol). After purging with nitrogen, the reaction mixture is stirred in an oil bath at 110 °C for 1 hour. After completion of the reaction, the reaction mixture is poured into water (40 mL), and the aqueous phase is extracted with dichloromethane (40 mL × 3). The combined organic phases are washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain a crude product. The crude product is separated and purified by silica gel column chromatography (dichloromethane:methanol = 99:1) to obtain the title compound (160 mg, yield: 31.2%, yellow solid).

[1082] MS(ESI): m / z 514.2 [M+H] + ;

[1083] Step 2: 2-Cyclopropoxy-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)

[1084]

[1085] Dissolve tert-butyl 3-(2-cyclopropoxyacetyl)-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 reaction mixture under reduced pressure to obtain the crude product. The crude product is purified by preparative high performance liquid chromatography (elution system: water, formic acid, acetonitrile) to obtain the title compound (61.23 mg, yield: 47.4%, white solid).

[1086] MS(ESI): m / z 414.1 [M+H] + ;

[1087] 1 1H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.31 (s, 1H), 7.99 (dd, J = 11.8, 3.0 Hz, 1H), 7.90 (q, J = 4.4 Hz, 1H), 6.46 (dd, J = 9.5, 3.0 Hz, 1H), 6.13 (s, 1H), 4.80 (s, 2H), 4.33 (dd, J = 9.9, 4.8 Hz, 4H), 3.51 (tt, J = 5.9, 2.9 Hz, 1H), 2.90 (d, J = 4.8 Hz, 3H), 0.57–0.51 (m, 2H), 0.46–0.39 (m, 2H).

[1088] Example 37

[1089] 3-((3-(2-Cyclopropoxyacetyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-1-(pyrazin-2-yl)pyridin-2(1H)-one (Compound 37)

[1090]

[1091] Step 1: 3-Amino-1-(pyrazin-2-yl)pyridin-2(1H)-one

[1092]

[1093] 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), and potassium carbonate (1.88 g, 13.603 mmol), N,N'-dimethylethylenediamine (160 mg, 1.815 mmol) and copper(I) iodide (173 mg, 0.908 mmol) were added. After purging with nitrogen, the reaction mixture was stirred in an oil bath at 110 °C for 16 h. 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 (dichloromethane:methanol = 49:1) to obtain the title compound (310 mg, yield: 36.2%, yellow solid).

[1094] MS(ESI): m / z 189.0 [M+H] + ;

[1095] Step 2: tert-Butyl (3-(2-cyclopropoxyacetyl)-5-((2-oxo-1-(pyrazin-2-yl)-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

[1096]

[1097] tert-Butyl (5-chloro-3-(2-cyclopropoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (130 mg, 0.341 mmol) was dissolved in dioxane (8 mL), and 3-amino-1-(pyrazin-2-yl)pyridin-2(1H)-one (77 mg, 0.409 mmol), palladium(II) acetate (8 mg, 0.0356 mmol), 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) (42 mg, 0.0674 mmol) and cesium carbonate (333 mg, 1.022 mmol) were added. After purging with nitrogen, the reaction mixture was stirred in an oil bath at 110 °C for 1 h. 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 obtain the title compound (110 mg, yield: 60.4%, yellow solid).

[1098] MS(ESI): m / z 533.2 [M+H] + ;

[1099] Step 3: 3-((3-(2-Cyclopropoxyacetyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-1-(pyrazin-2-yl)pyridin-2(1H)-one (Compound 37)

[1100]

[1101] Dissolve tert-butyl (3-(2-cyclopropoxyacetyl)-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) in dichloromethane (6 mL), add trifluoroacetic acid (2 mL), and stir the reaction mixture at room temperature for 1 h. After completion of the reaction, concentrate the reaction mixture under reduced pressure to obtain the crude product. The crude product is purified by preparative high performance liquid chromatography (elution system: water, ammonium bicarbonate, acetonitrile) to obtain the title compound (15.37 mg, yield: 17.2%, white solid).

[1102] MS(ESI): m / z 433.2 [M+H] + ;

[1103] 1 1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 9.10 (s, 1H), 8.79 (dd, J = 7.5, 1.4 Hz, 1H), 8.76 (d, J = 3.5 Hz, 2H), 8.36 (s, 1H), 7.94 (s, 1H), 7.58 (dd, J = 7.0, 1.5 Hz, 1H), 6.51 (t, J = 7.3 Hz, 1H), 6.36 (s, 1H), 4.86 (s, 2H), 3.57 (tt, J = 6.0, 2.9 Hz, 1H), 2.90 (s, 3H), 0.63–0.58 (m, 2H), 0.54–0.48 (m, 2H).

[1104] Biological Test Evaluation

[1105] Test Example A: In Vitro Enzyme Binding Experiment of the Compounds of the Present Invention to TYK2 JH2

[1106] Experimental Purpose: The purpose of this test example is to test the inhibitory effect of the compound on the TYK2 JH2 pseudokinase by using the method of fluorescence resonance energy transfer (TR-FRET).

[1107] Experimental Method:

[1108] Dissolve the compound in DMSO to prepare a 10 mM stock solution, then prepare different gradient concentrations of the compound at 200X in a compound dilution plate and transfer it to an Echo plate. Transfer 75 nL of the compound from the Echo plate to a 384-well assay plate by an Echo instrument. Add 5 μL of 3X TYK2 JH2 kinase (Bioduro), 5 μL of 3X Tb antibody (Cisbio), and 5 μL of 3X TRACER (Bioduro) to the 384-well assay plate, centrifuge for 30 seconds, and incubate at room temperature for 60 minutes. Read the fluorescence signal ratio at 495 nm / 520 nm using an Envision microplate reader (PerkinElmer), perform data analysis using XL-Fit software, and calculate the IC50 of the compound.

[1109] Experimental results:

[1110]

[1111] It can be seen from the experimental data results that the compound of the present invention has a good binding effect on the TYK2 JH2 pseudokinase.

Claims

1. A compound of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof: Wherein, R1 is selected from H, halogen, -OR, -SR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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- to 7-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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 an alkylene group, wherein one or two methylene units in the alkylene group 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 haloalkyl; 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 haloalkyl; R 2A selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl; R 2B selected from C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl, and 5- to 10-membered heteroaryl, which is optionally substituted with 1 to 5 R 2b ' substituents; R 2b ’ is selected from hydrogen, halogen, oxo, -CN, -NO2, -OR, -SR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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 haloalkyl; R 3B selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl; Alternatively, R 3A and R 3B together form a 3- to 7-membered heterocyclic group or a 5- to 10-membered heteroaryl group; R 4A selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl; R 4B selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl; Alternatively, R 4A and R 4B together form a 3- to 7-membered heterocyclic group or a 5- to 10-membered heteroaryl group; Each occurrence of R is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, oxo and CN; Each hydrogen bonded to carbon may optionally and independently be replaced by deuterium; n is 0, 1, 2, 3, 4, 5 or 6, Provided that when R1 is -OR or -SR, n is not 0; Preferably, the compound is of formula (II), Wherein, indicating that 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 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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 haloalkyl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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 haloalkyl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, oxo, and CN; Each hydrogen bonded to carbon may optionally and independently be replaced by deuterium; The other groups are as defined above; Preferably, in the above compounds, Among them, R1 is selected from -OMe, -OEt, 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 (III), R1 is selected from H, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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 haloalkyl; R 2b1 selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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 haloalkyl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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 haloalkyl, C 3-6 cycloalkyl, 3-7-membered heterocyclic group, C 6-10 aryl and 5-10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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 haloalkyl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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 haloalkyl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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 is H or C 1-6 alkyl; R 3B is H or C 1-6 alkyl; R 4A is H or C 1-6 alkyl; R 4B is H or C 1-6 alkyl; R is independently C each time it appears 1-6 alkyl or C 3-6 cycloalkyl; Each hydrogen bonded to carbon may optionally and independently be replaced by deuterium; n is 0, 1, 2, 3 or 4; Provided that when R1 is -OR, n is not 0; Preferably, wherein, 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 selected from H, halogen, and -OR; R 2b2 is a 5- or 6-membered heteroaryl, which is optionally substituted with a C 1-4 alkyl group; 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 or C 1-4 alkyl; R 4B is H or C 1-4 alkyl; R is independently C each time it appears 1-4 alkyl or C 3-4 cycloalkyl; Each hydrogen bonded to carbon may optionally and independently be replaced by deuterium; n is 1; Preferably, wherein, R1 is -OR, R 2A is H; R 2b1 is a halogen or -OR, R 2b2 is a 5- or 6-membered heteroaryl group, such as a triazolyl group, which is substituted with a C 1-4 alkyl group, preferably, R 2b2 is 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 is C 1-4 alkyl, preferably methyl; R is independently C each time it appears 1-4 alkyl or C 3-4 cycloalkyl, preferably methyl or cyclopropyl; Each hydrogen bonded to carbon may optionally and independently be replaced by deuterium; n is 1; Preferably, wherein, R1 is -OR, R 2A is H; R 2b1 is -OR, R 2b2 is a 5- or 6-membered heteroaryl group, such as a triazolyl group, which is substituted by a C 1-4 alkyl group, preferably, R 2b2 is 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 is C 1-4 alkyl, preferably methyl; R is independently C each time it appears 1-4 alkyl; Each hydrogen bonded to carbon may optionally and independently be replaced by deuterium; n is 1; Preferably, wherein, R1 is -OR, R 2A is H; R 2b1 is a halogen, R 2b2 is a 5- or 6-membered heteroaryl, such as a triazolyl group, which is substituted by a C 1-4 alkyl group, preferably, R 2b2 is 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 is C 1-4 alkyl, preferably methyl; R is C 3-4 cycloalkyl, preferably cyclopropyl; Each hydrogen bonded to carbon may optionally and independently be replaced by deuterium; n is 1.

3. 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 of formula (IV-1): Wherein, R1 is selected from H, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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 haloalkyl; R 2b2 selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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 haloalkyl, -OR, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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 haloalkyl, -OR, C 3-6 cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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 haloalkyl, -OR, C 3-6 cycloalkyl, 3-7-membered heterocyclic group, C 6-10 aryl and 5-10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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 is H or C 1-6 alkyl; R 3B is H or C 1-6 alkyl; R 4A is H or C 1-6 alkyl; R 4B is H or C 1-6 alkyl; Each occurrence of R is independently C 1-6 alkyl or C 3-6 cycloalkyl; Each hydrogen bonded to carbon may optionally and independently be replaced by deuterium; n is 0, 1, 2, 3 or 4; Provided that when R1 is -OR, n is not 0; Preferably, wherein, R1 is selected from -OR and 5- to 6-membered heterocyclic groups, wherein said heterocyclic group is optionally substituted with 1 to 2 substituents selected from the following: C 1-4 alkyl, -OR, oxo, and CN; R 2A is H; R 2b2 is a 5- or 6-membered heteroaryl, which is optionally substituted with a C 1-4 alkyl group; 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 or C 1-4 alkyl; R 4B is H or C 1-4 alkyl; R is independently C each time it appears 1-4 alkyl or C 3-4 cycloalkyl; Each hydrogen bonded to carbon may optionally and independently be replaced by deuterium; n is 1; Preferably, wherein, R1 is selected from -OR and 5- to 6-membered heterocyclic groups. Preferably, the 5- to 6-membered heterocyclic group is oxolanyl, preferably R 2A is H; R 2b2 is a 5- or 6-membered heteroaryl, which is optionally substituted with C 1-4 alkyl; 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 is C 1-4 alkyl, preferably methyl; R is C 1-4 alkyl; Each hydrogen bonded to carbon may optionally and independently be replaced by deuterium; n is 1.

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 (V), preferably of formula (V-1): Wherein, R1 is selected from H, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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 haloalkyl; R 2b1 selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7-membered heterocyclic group, C 6-10 aryl and 5-10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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 haloalkyl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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 haloalkyl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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 haloalkyl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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 is H or C 1-6 alkyl; R 3B is H or C 1-6 alkyl; R 4A is H or C 1-6 alkyl; R 4B is H or C 1-6 alkyl; R is independently C each time it appears 1-6 alkyl or C 3-6 cycloalkyl; Each hydrogen bonded to carbon may optionally and independently be replaced by deuterium; n is 0, 1, 2, 3 or 4; Provided that when R1 is -OR, n is not 0; Preferably, wherein, R1 is selected from -OMe, -OEt, Preferably, wherein, R1 is selected from -OR, C 3-4 cycloalkyl, 5- to 6-membered heterocyclic group and 5- to 6-membered heteroaryl group, wherein said cycloalkyl, heterocyclic group and heteroaryl group are optionally substituted with 1 to 2 substituents selected from: C 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 is H or C 1-4 alkyl; R 4B is H or C 1-4 alkyl; R is independently C each time it appears 1-4 alkyl or C 3-4 cycloalkyl; Each hydrogen bonded to carbon may optionally and independently be replaced by deuterium; n is 0, 1 or 2; Provided that when R1 is -OR, n is not 0; Preferably, wherein, 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 is C 1-4 alkyl, preferably methyl; R is independently C each time it appears 1-4 alkyl, preferably methyl or ethyl; Each hydrogen bonded to carbon may optionally and independently be replaced by deuterium; n is 1; Preferably, wherein, R1 is -OR, where R is C 1-4 alkyl, preferably methyl; R 2A is H; R 2b1 is -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 is C 1-4 alkyl, preferably methyl; Each hydrogen bonded to carbon may optionally and independently be replaced by deuterium; n is 1.

5. 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 of formula (VI-1), R1 is selected from H, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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 haloalkyl; R 2b2 selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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 haloalkyl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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 haloalkyl, C 3-6 cycloalkyl, 3-7-membered heterocyclic group, C 6-10 aryl and 5-10-membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from: 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 is H or C 1-6 alkyl; R 3B is H or C 1-6 alkyl; R 4A is H or C 1-6 alkyl; R 4B is H or C 1-6 alkyl; R is independently C each time it appears 1-6 alkyl or C 3-6 cycloalkyl; each hydrogen bonded to carbon may optionally and independently be replaced by deuterium; n is 0, 1, 2, 3 or 4; with the proviso that when R1 is -OR, n is not 0; preferably, wherein, R1 is -OR; R 2A is H; R 2b2 is - OR; R 2b3 is H; R 2b4 is H or a 5- or 6-membered heteroaryl group, which is optionally substituted with a C 1-4 alkyl group; R 2b5 is H or a halogen; R3 is H; R4 is -N(R 4A )(R 4B ); R 4A is H; R 4B is H or C 1-4 alkyl, preferably methyl; R is independently C each time it appears 1-4 alkyl; each hydrogen bonded to carbon may optionally and independently be replaced by deuterium; n is 1.

6. 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:

7. A pharmaceutical composition comprising the compound of any one of claims 1-6, 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.

8. Use of the compound of any one of claims 1-6 or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof or the pharmaceutical composition of claim 7 in the manufacture of a medicament for the treatment and / or prevention of a TYK2-mediated disease Preferably, wherein the TYK2-mediated disease is selected from neurological diseases, autoimmune diseases, skin diseases, allergic diseases, organ rejection, cancer, dry eye disease, myelofibrosis, 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 condition is asthma or rhinitis; the organ transplant rejection is allograft rejection or graft-versus-host disease; 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; preferably, wherein the TYK2-mediated disease is selected from Alzheimer's disease, Parkinson's disease, systemic lupus erythematosus, amyotrophic lateral sclerosis or multiple sclerosis.

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