Pyrimido pyrazole compound and preparation method, pharmaceutical composition and application thereof

Abstract

The invention belongs to the field of medicines, and particularly relates to a pyrimido pyrazole compound, a preparation method thereof, a pharmaceutical composition of the pyrimido pyrazole compound and application of the pyrimido pyrazole compound. Specifically, the invention relates to a compound shown in a formula (I), or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound shown in the formula (I), and each variable has the meaning described in the invention. As a TYK2 inhibitor, the compound and the pharmaceutical composition thereof can be used for preparing drugs for preventing or treating TYK2 related diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicine. Specifically, the present invention relates to a pyrimidopyrazole compound as a TYK2 inhibitor, a preparation method thereof, a pharmaceutical composition thereof, and the use of the compound and the pharmaceutical composition thereof in preparing a drug for preventing or treating TYK2-related diseases. Background Art

[0002] Janus kinases (JAKs) are a family of intracellular non-receptor tyrosine kinases that regulate important events such as cell proliferation, differentiation, apoptosis, and immune responses through activation of the JAK-STAT pathway. The four members of the JAK family are Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2). Studies have found that TYK2 is closely associated with the development of various inflammatory diseases such as inflammatory bowel disease, psoriasis, dermatitis, and rheumatoid arthritis. TYK2 deletion mutations can inhibit the development of autoimmune diseases and inflammation related to the IL-12 and IL-23 pathways. Currently, Ventyx Biosciences' TAK-279 has excellent TYK2 inhibitory activity and is still in clinical development. The development of TYK2 inhibitors that can be used as therapeutic agents is still needed. Summary of the Invention

[0003] The present invention provides a compound, or a pharmaceutical composition thereof, that is useful as a TYK2 inhibitor. The present invention further relates to the use of the compound or pharmaceutical composition thereof for preparing a medicament for treating a disease and / or condition by inhibiting TYK2 activity. The disease or condition includes those described herein.

[0004] In a first aspect, the present invention provides a pyrimidopyrazole compound, which is a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I).

[0005]

[0006] in,

[0007] R 1 C 6-10 Aryl, 5-10 membered heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; wherein the R 1 Optionally, 1, 2, 3 or 4 selected from D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C1-6 alkoxy, -C(=O)OC 1-6 alkyl, -C(=O)C 1-6 alkyl, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2.

[0008] R 2 is H, C 1-6 alkyl, C 3-7 cycloalkyl or a 3- to 7-membered heterocyclic group, wherein said R 2 is independently optionally substituted by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, CN, OH, NH2, COOH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 hydroxyalkyl and -C(=O)NH2.

[0009] R 3 is C 1-6 alkyl, C 3-7 cycloalkyl, a 3- to 7-membered heterocyclic group, C 6-10 aryl or a 5- to 10-membered heteroaryl, said R 3 is optionally substituted by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, CN, OH, NH2, COOH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 hydroxyalkyl, -C(=O)OC 1-6 alkyl, -C(=O)C 1-6 alkyl, -S(=O)2C 1-6 alkyl, -S(=O)C 1-6 alkyl, -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NH(C 1-6 alkyl) and -N(C 1-6 alkyl)2.

[0010] In some embodiments, R 2 is H, C 1-4 alkyl, C 3-6 cycloalkyl or a 3- to 6-membered heterocyclic group, wherein said R 2 is optionally substituted by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, CN, OH, NH2, COOH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4Deuterated alkoxy, C 1-4 substituted by substituents of hydroxyalkyl and -C(=O)NH2.

[0011] In some embodiments, R 2 is H, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2-epoxyethyl, 1,4-dioxanyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiopyranyl, piperidinyl, piperazinyl, morpholinyl or hexahydropyrimidinyl, wherein the R 2 is optionally substituted by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, CN, OH, NH2, COOH, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -CH2OH, -CH2CH2OH, -(CH2)2CH2OH, -CH(CH3)2OH, -(CH2)3CH2OH and -C(=O)NH2.

[0012] In some embodiments, R 3 is C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-10 aryl or 5-6 membered heteroaryl, wherein the R 3 is optionally substituted by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, CN, OH, NH2, COOH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 deuterated alkoxy, C 1-4 hydroxyalkyl, -C(=O)OC 1-4 alkyl, -C(=O)C 1-4 alkyl, -S(=O)2C 1-4 alkyl, -S(=O)C 1-4 alkyl, -C(=O)NH2, -C(=O)NH(C 1-4 alkyl), -C(=O)N(C 1-4 alkyl)2, -NH(C 1-4 alkyl) and -N(C 1-4 alkyl)2.

[0013] In some embodiments, R 3 is -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -CH2CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-oxabicyclo[3.2.0]heptanyl, bicyclo[3.1.0]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 2-oxaspiro[3.3]heptane, 1,2-epoxyethyl, 1,4-dioxanyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiopyranyl, piperidinyl, piperazinyl, morpholinyl, hexahydropyrimidinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thiopyranyl, pyridyl, pyrimidinyl or pyrazinyl, wherein said R 5 and R 6 are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, CN, OH, NH2, COOH, -CD3, -CH3, -CH2CH3, -CD2CD3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -CH2OH, -CH2CH2OH, -(CH2)2CH2OH, -CH(CH3)2OH, -(CH2)3CH2OH, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)O(CH2)2CH3, -C(=O)OCH(CH3)2, -C(=O)CH3, -C(=O)CH2CH3, -S(=O)2CH3, -S(=O)2CH2CH3, -S(=O)CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -NHCH3, -NHCH2CH3, -N(CH3)2 and -N(CH2CH3)2.

[0014] In some embodiments, R 1 is

[0015] wherein said R 1 is optionally substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4Alkoxy, -C(=O)OC 1-4 Alkyl, -C(=O)C 1-4 Alkyl, -NH(C 1-4 Alkyl) and -N(C 1-4 Alkyl)2, and is substituted by substituents of

[0016] In some embodiments, R 1 is

[0017] wherein said R 1 is optionally substituted by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -CF3, -CHF2, -CH2F, -CH2CF3, -CCl3, -CH2Cl3, -CH2CH2F, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OCH(CH3)2, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)OCH(CH3)2, -NH(CH2CH3), -N(CH3)(CH2CH3) and -N(CH3)2.

[0018] In some embodiments, the compound of the present invention is a compound of the following structure, or its stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug,

[0019]

[0020]

[0021]

[0022] In a second aspect, the present invention provides a method for preparing the compound represented by formula (I), and the synthetic route is as follows:

[0023]

[0024] wherein, R 1 , R 2 , R 3 are defined and represent the same groups as described above.

[0025] The specific preparation steps are as follows:

[0026] (1) Add raw material a (1.0 eq) and dimethyl malonate (4.0 eq) to ethanol. Add sodium ethoxide (3.0 eq) in batches under stirring. React at 80 °C for 15 h, stop the reaction, concentrate the reaction solution, then add water to dissolve it, cool down to 0 °C, adjust the pH to 3 with an acid, precipitate the solid, filter by suction, wash the filter cake with water, and dry the solid in a blast dryer at 50 °C to obtain b;

[0027] (2) Add acetonitrile to b (1.0 eq), heat up to 50 °C under nitrogen protection, add phosphorus oxychloride (3.0 eq), then dropwise add pyridine (1.0 eq). After dropping, heat up to 100 °C for reaction. The reaction is complete in 3 h. Cool down to room temperature, add ice water, then extract with dichloromethane. Concentrate the organic phase and purify it by silica gel column chromatography (eluent: PE:EA (V:V) = 1:0 - 20:1) to obtain c;

[0028] (3) Add c (1.0 eq) and methylamine hydrochloride (1.75 eq) to acetonitrile, then add N,N - diisopropylethylamine (3.0 eq). React at 80 °C. The reaction is complete in 2 h. Add water, extract with dichloromethane. Concentrate the organic phase and purify it by preparative thin - layer chromatography plate to obtain d;

[0029] (4) Add N,N - dimethylformamide to d (1.0 eq). After dissolution, dropwise add a DMF dilution of phosphorus oxychloride (1.5 eq). After dropping, react at 70 °C for about 8 h, stop the reaction, cool down to 0 °C, add water, adjust the pH to 9 - 10 with a base, extract with ethyl acetate. Combine the organic phases, concentrate, and purify by silica gel column chromatography (PE:EA = 3:1) to obtain e;

[0030] (5) Add N,N - dimethylformamide to e (1.0 eq) and cesium carbonate (2.0 eq), cool down to - 5 °C, dropwise add a DMF dilution of 4 - methoxybenzyl chloride (1.5 eq). After dropping, keep the temperature for reaction for 10 min, transfer to room temperature for reaction, react for 20 h, stop the reaction, cool down to 0 °C, add ice water, then extract with ethyl acetate. Combine the organic phases, concentrate, and purify by silica gel column chromatography (DCM:MeOH = 30:1) to obtain f;

[0031] (6) Add tert - butanol to f (1.0 eq), then add 2 - methyl - 2 - butene (10 eq) and sodium chlorite (7.0 eq). Dissolve sodium dihydrogen phosphate anhydrous (2.5 eq) in water and add it to the reaction solution. After adding, stir for 10 minutes, transfer to room temperature for reaction for 1 h, then heat up to 50 °C for reaction for 10 h, stop the reaction, concentrate under reduced pressure, then add ice water, adjust the pH to 3 with an acid, then extract with dichloromethane. Combine the organic phases, purify by column chromatography to obtain g;

[0032] (7) Dichloromethane was added to g (1.0 eq), j (1.5 eq) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 eq) were added, and the reaction was carried out at room temperature for 10 h. It was washed with water, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain h;

[0033] (8) h (1.0 eq), k (1.0 eq), BrettPhos-G3-Pd (0.1 eq), BrettPhos (0.2 eq) and cesium carbonate (2 eq) were added to a flask, protected by nitrogen, 1,4-dioxane was added, and the reaction was carried out at 110 °C. The reaction was stopped after 3 h, cooled to room temperature, washed with water, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (DCM / MeOH) to obtain i;

[0034] (9) Dichloromethane was added to i (1.0 eq), and then trifluoroacetic acid (60 eq) was slowly added dropwise. The reaction was carried out at room temperature. After the reaction was completed, it was cooled to 0 °C, water was added, and the pH was adjusted to weakly alkaline with potassium phosphate solution. The aqueous phase was extracted with dichloromethane once again, the organic phases were combined, the organic phase was concentrated, and purified by column chromatography to obtain I.

[0035] In a third aspect, the present invention provides a pharmaceutical composition comprising the compound of formula (I) as described in the present invention.

[0036] In some embodiments, the pharmaceutical composition as described in the present invention further comprises a pharmaceutically acceptable adjuvant of the compound of formula (I).

[0037] In some embodiments, the adjuvants as described in the present invention include, but are not limited to, carriers, excipients, diluents, solvents, or combinations thereof.

[0038] In some embodiments, the pharmaceutical composition as described in the present invention can be in liquid, solid, semi-solid, gel or spray dosage forms.

[0039] In a fourth aspect, the present invention provides the use of the pharmaceutical composition as described in the present invention in the preparation of a drug for preventing, treating or alleviating TYK2-related diseases.

[0040] In some embodiments, the TYK2-related diseases as described in the present invention are autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders or transplantation-related disorders.

[0041] In some embodiments, the TYK2-mediated diseases as described in the present invention are rheumatoid arthritis, psoriasis, diabetes, ankylosing spondylitis, vitiligo, atopic dermatitis, lupus, multiple sclerosis, psoriasis, Crohn's disease, ulcerative colitis, cancer, transplant rejection or neurological disorders.

[0042] In a fifth aspect, the present invention also provides a method for preventing or treating TYK2-related diseases, the method comprising administering to a patient a therapeutically effective amount of a compound or a pharmaceutical composition thereof as described in the present invention.

[0043] Unless otherwise indicated, all stereoisomers, tautomers, N-oxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are within the scope of the present invention.

[0044] Specifically, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes that the substance or composition must be suitable chemically or toxicologically and relevant to the other components of the formulated preparation and the mammal to be treated.

[0045] The salts of the compounds of the present invention also include salts of intermediates used in the preparation or purification of the compounds of formula (I) or the separated enantiomers of the compounds of formula (I), including but not limited to pharmaceutically acceptable salts.

[0046] The definitions and general terms in the specification of the present invention

[0047] Certain embodiments of the present invention will now be described in detail, with examples illustrated by the attached structural and chemical formulas. The present invention is intended to cover all alternative, modified and equivalent technical solutions, which are all included within the scope of the present invention as defined in the claims. Those skilled in the art should recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the case where one or more of the incorporated documents, patents and similar materials are different from or contradictory to the present application (including but not limited to the defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0048] It should be further recognized that certain features of the present invention, for the sake of clarity, are described in multiple separate embodiments, but may also be provided in combination in a single embodiment. Conversely, the various features of the present invention, for the sake of brevity, are described in a single embodiment, but may also be provided separately or in any suitable sub-combination.

[0049] Unless otherwise specified, all scientific and technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention pertains. All patents and published publications referred to in the present invention are incorporated herein by reference in their entirety.

[0050] As used herein, the term "subject" refers to an animal. Typically, the animal is a mammal. A subject also refers to, for example, a primate (e.g., a human, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0051] As used herein, the term "patient" refers to a human (including adults and children) or other animal. In some embodiments, the "patient" is a human.

[0052] The term "comprising" is an open-ended expression, meaning including the content specified in the present invention, but not excluding other aspects.

[0053] "Stereoisomers" refer to compounds having the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), atropisomers, etc. Unless otherwise indicated, all stereoisomers or mixtures of stereoisomers of the structural formulas described in the present invention are within the scope of the present invention. Additionally, unless otherwise indicated, the structural formulas of the compounds described in the present invention include one or more different atoms of enriched isotopes.

[0054] The stereochemical definitions and rules used in the present invention generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

[0055] Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography and / or fractional crystallization, based on differences in the physicochemical properties of the components.

[0056] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can be interconverted through a low energy barrier. If tautomerism is possible (e.g., in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions that occur through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur through reorganization of some of the bonding electrons. A specific example of keto-enol tautomerism is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion between pyridin-4-ol and pyridin-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

[0057] As described in the present invention, the compounds of the present invention can independently and optionally be substituted by one or more substituents, such as the compounds of the general formula above, or as in the specific examples, subclasses, and a class of compounds included in the present invention. It should be understood that the terms "independently and optionally substituted by..." or "optionally substituted by..." can be used interchangeably with the term "substituted or unsubstituted". Generally, the term "substituted" means that one or more hydrogen atoms in the given structure are replaced by specific substituents. Unless otherwise indicated, an optional substituent group can be substituted at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents can be the same or different at each position.

[0058] In addition, it should be noted that unless otherwise explicitly indicated, in the present invention, the description methods "each... independently is", "... each independently is", and "... independently is" can be interchanged and should be understood in a broad sense. It 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.

[0059] In each part of this specification, the substituents of the disclosed compounds of the present invention are disclosed according to the group types or ranges. In particular, the present invention includes each independent secondary combination of each member of these group types and ranges. For example, the term "C 1-6 alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl independently disclosed.

[0060] Throughout the various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables recited 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 recites "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively.

[0061] The term "alkyl" means a saturated straight-chain or branched-chain monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein said alkyl group may optionally be substituted with one or more substituents described in the present invention. In one embodiment, the alkyl group contains 1-6 carbon atoms and is designated as C 1-6 alkyl; in yet another embodiment, the alkyl group contains 1-4 carbon atoms and is designated as C 1-4 alkyl; still in one embodiment, the alkyl group contains 1-3 carbon atoms and is designated as C 1-3Alkyl. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, and the like.

[0062] The term "hydroxyalkyl" means an alkyl group substituted with one or more hydroxy groups, wherein the alkyl and hydroxy groups have the definitions as described in the present invention. In some embodiments, hydroxyalkyl means an alkyl group substituted with 1, 2, 3, or 4 hydroxy groups. In some embodiments, hydroxyalkyl means an alkyl group substituted with one or two hydroxy groups. In some embodiments, hydroxyalkyl means C 1-6 Hydroxyalkyl, i.e., C 1-6 Alkyl substituted with one or more hydroxy groups, preferably, C 1-6 Hydroxyalkyl means C 1-6 Alkyl substituted with one hydroxy group. In some embodiments, hydroxyalkyl means C 1-4 Hydroxyalkyl. In some embodiments, hydroxyalkyl means C 1-3Hydroxyalkyl. Examples of hydroxyalkyl include, but are not limited to, -CH2OH, -CH2CH2CH2CH2OH, -CH2CH2OH, -CH2CH(OH)CH2CH2OH, -CH2CH(OH)CH2CH(CH3)OH, and the like.

[0063] The term "haloalkyl" means that an alkyl group is substituted with one or more halogen atoms, wherein the alkyl and halogen have the definitions as described in the present invention. In some embodiments, the haloalkyl is C 1-6 Haloalkyl, means C 1-6 An alkyl group substituted with one or more halogen atoms; in other embodiments, the haloalkyl is C 1-4 Haloalkyl, means C 1-4 An alkyl group substituted with one or more halogen atoms; in other embodiments, the haloalkyl is C 1-3 Haloalkyl, means C 1-3 An alkyl group substituted with one or more halogen atoms. Such examples include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl, 1-chloroethyl, 1,2-dichloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl, 1,1-dibromoethyl, and the like.

[0064] The term "alkoxy" means that an alkyl group is connected to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described in the present invention. Unless otherwise specified in detail, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms, representing C 1-6 Alkoxy; in another embodiment, the alkoxy group contains 1-4 carbon atoms, representing C 1-4 Alkoxy; in yet another embodiment, the alkoxy group contains 1-3 carbon atoms, representing C 1-3Alkoxy group. The alkoxy group may optionally be substituted by one or more substituents described in the present invention. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH3)3), 1-pentyloxy (n-pentyloxy, -OCH2CH2CH2CH2CH3), 2-pentyloxy (-OCH(CH3)CH2CH2CH3), 3-pentyloxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-1-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-1-butoxy (-OCH2CH(CH3)CH2CH3), and the like.

[0065] The term "deuterated alkoxy" refers to an alkoxy group substituted with deuterium (D), wherein the alkoxy group has the definition as described in the present invention.

[0066] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group and the halogen have the definitions as described in the present invention. In some embodiments, the haloalkoxy refers to a haloalkoxy containing 1-6 carbon atoms, i.e., C 1-6 haloalkoxy; in other embodiments, the haloalkoxy refers to a haloalkoxy containing 1-4 carbon atoms, i.e., C 1-4 haloalkoxy; in other embodiments, the haloalkoxy refers to a haloalkoxy containing 1-3 carbon atoms, i.e., C 1-3 haloalkoxy. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy (-OCF3), fluoromethoxy (-OCH2F), 2-fluoroethoxy (-OCH2CH2F), etc.

[0067] The term "cycloalkyl" refers to a monovalent saturated monocyclic or bicyclic carbocyclic system having 3-12 carbon atoms, and the -CH2- group in the carbocyclic ring may optionally be replaced by -C(=O)- (or -(CO)-). In one embodiment, the cycloalkyl contains 3-10 ring carbon atoms, i.e., C 3-10Cycloalkyl; in another embodiment, the cycloalkyl contains 3 to 6 ring carbon atoms, i.e., C 3-6 Cycloalkyl; in another embodiment, the cycloalkyl contains 3 to 5 ring carbon atoms, i.e., C 3-5 Cycloalkyl. Examples of cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydro-1H-indenyl, octahydrobicyclopentadienyl, etc. Examples where the -CH2- group in the carbocyclic ring can be replaced by -C(=O)- include but are not limited to: cyclopentanone, cyclobutanone, etc.

[0068] The terms "heterocycle" and "heterocyclic group" refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic system containing 3 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms; wherein, the heterocycle or heterocyclic group is non-aromatic and does not contain any aromatic rings. When the heterocycle is connected to other parts of the molecule through a linking site, the heterocycle is represented as a monovalent heterocyclic group. Unless otherwise specified, the heterocyclic group can be a carbon-based or nitrogen-based group, and the -CH2- group can be optionally replaced by -C(=O)-. The sulfur atom in the ring can be optionally oxidized to S-oxide. The nitrogen atom in the ring can be optionally oxidized to N-oxide. In some embodiments, the heterocycle or heterocyclic group consists of 3 to 10 atoms, represented as a 3- to 10-membered heterocycle or 3- to 10-membered heterocyclic group; in other embodiments, the heterocycle or heterocyclic group consists of 3 to 9 atoms, represented as a 3- to 9-membered heterocycle or 3- to 9-membered heterocyclic group; in other embodiments, the heterocycle or heterocyclic group consists of 5 to 9 atoms, represented as a 5- to 9-membered heterocycle or 5- to 9-membered heterocyclic group; in other embodiments, the heterocycle or heterocyclic group consists of 3 to 6 atoms, represented as a 3- to 6-membered heterocycle or 3- to 6-membered heterocyclic group; in other embodiments, the heterocycle or heterocyclic group consists of 5 to 6 atoms, represented as a 5- to 6-membered heterocycle or 5- to 6-membered heterocyclic group. Examples of the heterocycle include but are not limited to ethylene oxide, aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, thiazolidine, pyrazolidine, pyrazoline, oxazolidine, imidazolidine, piperidine, piperazine, morpholine, 3,8-diazabicyclo[3.2.1]octane, 3,6-diazabicyclo[3.1.1]heptane, 2,5-diazabicyclo[2.2.2]octane. The heterocyclic groups include but are not limited to, ethylene oxide group, aziridine group, azetidine group, oxetane group, pyrrolidinyl group, tetrahydrofuranyl group, tetrahydrothiophenyl group, thiazolidinyl group, pyrazolidinyl group, pyrazolinyl group, oxazolidinyl group, imidazolidinyl group, piperidinyl group, piperazinyl group or morpholinyl group, etc.

[0069] The term "aryl" refers to a monocyclic, bicyclic, and tricyclic carbocyclic system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic, and each ring system contains a ring composed of 3-7 atoms. In some embodiments, aryl contains 6-12 ring atoms, denoted as C 6-12 aryl or 6-12 membered aryl. In some embodiments, aryl contains 6-10 ring atoms, denoted as C 6-10 aryl or 6-10 membered aryl. Examples of aryl groups can include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, and anthracene. When aryl is a linking group, the term "aryl" is denoted as arylene, for example, A in formula (I) 2 As a linking group, can be C 6-10 arylene.

[0070] The term "heteroaryl" or "heteroaromatic ring" refers to a monovalent monocyclic, bicyclic, or tricyclic system containing 5-14 ring atoms, or 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring is aromatic and at least one ring contains one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryl groups are generally, but not necessarily, linked to the parent molecule through the aromatic ring of the heteroaryl group. When a -CH2- group is present in the heteroaryl group, the -CH2- group can optionally be replaced by -C(=O)-. Unless otherwise specified, the heteroaryl group can be linked to the rest of the molecule (such as the main structure in the formula) at any reasonable site (which can be C or N). The term "heteroaryl" can be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, heteroaryl is a heteroaryl containing 5-12 ring atoms, denoted as 5-12 membered heteroaryl; in other embodiments, heteroaryl is a heteroaryl containing 5-10 ring atoms, denoted as 5-10 membered heteroaryl; in other embodiments, heteroaryl is a heteroaryl containing 5-6 ring atoms, denoted as 5-6 membered heteroaryl. Examples of heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, triazolyl, tetrazolyl, benzopyridyl, benzimidazolyl, benzopyrrolyl, benzopyrazolyl, benzopyrrolidinyl, etc.

[0071] The term "halogen" refers to F (fluorine), Cl (chlorine), Br (bromine), or I (iodine).

[0072] The term "oxo" refers to =O.

[0073] The term "cyano" refers to -CN or -C≡N.

[0074] The term "hydroxy" refers to -OH.

[0075] The term "carboxyl" means -C(=O)OH or COOH.

[0076] The term "amino" means -NH2.

[0077] The term "composed of j-k atoms" or "j-k membered" means that the cyclic group is composed of j-k ring atoms, and the ring atoms include carbon atoms and / or heteroatoms such as O, N, S, P, etc.; j and k are each independently any non-zero natural number, and k > j; the "j-k" includes j, k, and any natural number between the two. For example, "composed of 3-8 atoms" or "3-8 membered", "composed of 3-6 atoms" or "3-6 membered", "composed of 5-10 atoms" or "5-10 membered", or "composed of 5-6 atoms" or "5-6 membered" means that the cyclic group is composed of 3-8 (i.e., 3, 4, 5, 6, 7, or 8), 3-6 (i.e., 3, 4, 5, or 6), 5-10 (i.e., 5, 6, 7, 8, 9, or 10), or 5-6 (i.e., 5 or 6) ring atoms, and the ring atoms include carbon atoms and / or heteroatoms such as O, N, S, P, etc.

[0078] The term "prodrug" used in the present invention represents a compound that is converted in vivo into the compound represented by formula (I). Such conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion in the blood or tissue into the parent structure. The prodrug compounds of the present invention can be esters, and in the existing inventions, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound in the present invention contains a hydroxyl group, and it can be acylated to obtain a compound in the prodrug form. Other prodrug forms include phosphate esters, such as these phosphate ester compounds are obtained by phosphorylating the hydroxyl groups on the parent body.

[0079] "Metabolite" refers to the product obtained by the metabolism of a specific compound or its salt in vivo. The metabolites of a compound can be identified by techniques well-known in the art, and its activity can be characterized by experimental methods as described in the present invention. Such products can be obtained by methods such as oxidation, reduction, hydrolysis, amidation, deamidation, esterification, degreasing, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes the metabolites of the compound, including the metabolites produced by contacting the compound of the present invention with a mammal for a sufficient period of time.

[0080] The "pharmaceutically acceptable salts" used in the present invention refer to the organic salts and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: S.M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. The salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reacting with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or these salts can be obtained by other methods described in books and literature such as ion exchange method. The present invention also contemplates quaternary ammonium salts formed by compounds of any group containing N. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counterbalancing ions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-C8 sulfonates and aromatic sulfonates.

[0081] The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compounds of the present invention. The solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine or mixtures thereof. The term "hydrate" refers to an association formed when the solvent molecule is water.

[0082] When the solvent is water, the term "hydrate" can be used. In one embodiment, a molecule of a compound of the present invention can combine with one water molecule, such as a monohydrate; in another embodiment, a molecule of a compound of the present invention can combine with more than one water molecule, such as a dihydrate; in yet another embodiment, a molecule of a compound of the present invention can combine with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates described in the present invention retain the biological effectiveness of the compound in the non-hydrated form.

[0083] As used herein, the term "treat" or "treatment" of any disease or disorder, in some embodiments, refers to ameliorating a disease or disorder (i.e., slowing down or arresting or reducing the development of the disease or at least one of its clinical symptoms). In other embodiments, "treat" refers to alleviating or ameliorating at least one physical parameter, including physical parameters that may not be perceptible to the patient. In other embodiments, "treat" refers to modulating the disease or disorder physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a physical parameter) or both. In other embodiments, "treat" refers to preventing or delaying the onset, occurrence or worsening of a disease or disorder.

[0084] The term "prevent" or "prevention" refers to a reduction of the risk of acquiring a disease or disorder (i.e., causing at least one clinical symptom of the disease to stop developing in a subject who may be at risk of or predisposed to the disease but has not yet experienced or manifested symptoms of the disease).

[0085] The term "therapeutically effective amount" means that, when administered to a subject to treat a disease, the amount of the compound is sufficient to effect a treatment of such disease. A "therapeutically effective amount" may vary with the compound, the disease and its severity, and the condition, age, weight, sex, etc. of the subject to be treated.

[0086] Unless otherwise specified, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, pharmaceutically acceptable salts and prodrugs of the compounds of the present invention are included within the scope of the present invention.

[0087] In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated within the present invention and are included in the compounds disclosed herein as the present invention. When the stereochemistry is specified by a solid wedge or a dashed line representing a particular configuration, then the stereoisomers of that structure are thereby defined and specified.

[0088] The N-oxides of the compounds of the present invention are also included within the scope of the present invention. The N-oxides of the compounds of the present invention can be prepared by oxidizing the corresponding nitrogenous basic substance with a conventional oxidizing agent (e.g., hydrogen peroxide) at an elevated temperature in the presence of an acid such as acetic acid, or by reacting with a peracid in a suitable solvent, e.g., reacting with peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or reacting with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

[0089] The compounds represented by formula (I) may exist in the form of salts.

[0090] Any structural formula given by the present invention is also intended to represent both the non-isotopically enriched form and the isotopically enriched form of these compounds. The isotopically enriched compounds have the structures depicted by the general formula given by the present invention, except that one or more atoms are replaced by atoms having a selected atomic weight or mass number. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.

[0091] Formulation, administration, and use of pharmaceutical compositions of the compounds of the present invention

[0092] The pharmaceutical compositions of the present invention feature compounds represented by formula (I), the compounds listed in the present invention, or the compounds of the examples, and a pharmaceutically acceptable carrier. The amount of the compound in the pharmaceutical compositions of the present invention can effectively treat or alleviate TYK2-mediated diseases in patients.

[0093] The compounds of the present invention exist in free form, or as suitable, pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adducts or derivatives that can be administered directly or indirectly as needed by the patient, the compounds described in other aspects of the present invention, their metabolites, or residues thereof.

[0094] As described herein, the pharmaceutically acceptable compositions of the present invention further comprise pharmaceutically acceptable adjuvants which, as used herein, include any solvent, diluent, or other liquid excipient, dispersing or suspending agent, surfactant, isotonic agent, thickening agent, emulsifying agent, preservative, solid binder or lubricant, etc., suitable for the particular target dosage form. As described in the following references: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988 - 1999, Marcel Dekker, New York, the combined teachings of these references indicate that different adjuvants can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. Except to the extent that any conventional adjuvant is incompatible with the compounds of the present invention, e.g., any adverse biological effects produced or interactions that occur in a harmful manner with any other component of the pharmaceutically acceptable composition, their use is also contemplated by the present invention.

[0095] Substances which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered gum; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol, phosphate buffer solutions, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, release agents, coating materials, sweetening agents, flavoring agents and perfumes, preservatives and antioxidants.

[0096] In preparing the pharmaceutical composition provided by the present invention, the active ingredient is usually mixed with an excipient, diluted by the excipient or encapsulated in such a carrier in the form of, for example, a capsule, sachet, paper or other container. If the excipient is used as a diluent, it can be a solid, semi-solid or liquid material, which serves as a vehicle, carrier or medium for the active ingredient. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting point wax, cocoa butter, etc. Thus, the composition can be tablets, pills, powders, lozenges, capsules, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders. In one embodiment, the composition is formulated for oral administration. In one embodiment, the composition is formulated as tablets or capsules.

[0097] The compounds or pharmaceutical compositions of the present invention can be administered in the form of oral dosage forms, such as tablets, capsules (each of which includes a sustained release or timed release formulation), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They can also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously or intramuscularly, and all dosage forms used are well known to those of ordinary skill in the pharmaceutical art. They can be administered alone, but generally a pharmaceutical carrier will be selected and administered together based on the chosen mode of administration and standard pharmaceutical practice.

[0098] The compounds or pharmaceutical compositions of the present invention can be administered in nasal form by topical use with a suitable intranasal carrier, or by percutaneous route using a transdermal patch. When administered in the form of a transdermal delivery system, the dose administered during the entire course of treatment is continuous rather than intermittent.

[0099] The compounds or pharmaceutical compositions of the present invention can also be administered in the form of a liposome delivery system, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from different phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine.

[0100] The compounds or pharmaceutical compositions of the present invention are also conjugated with soluble polymers, which serve as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylasparagine phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Moreover, the compounds of the present invention can be conjugated with a class of biodegradable polymers for controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0101] The dosing regimens of the compounds or pharmaceutical compositions of the present invention will vary with various factors known in the art, such as the pharmacokinetic characteristics of the particular agent and its mode and route of administration; the race, age, sex, health status, medical condition, and body weight of the recipient; the nature and extent of the symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the desired effect. A physician or veterinarian can make a determination and prescribe an effective amount of the drug to prevent, counteract, or arrest the development of cancer.

[0102] According to general guidelines, for achieving the specified effect, the dose of each active ingredient used ranges from about 0.001 to 1000 mg / kg body weight in the daily oral dose, preferably from about 0.01 to 100 mg / kg body weight. The compounds of the present invention can be administered once daily, or can be administered in two, three, or four divided doses per day.

[0103] Each unit dose of a suitable dosage form (pharmaceutical composition) can contain from about 1 mg to about 100 mg of the active ingredient. In these pharmaceutical compositions, the weight of the active ingredient will generally account for about 0.5 - 95% of the total weight of the composition.

[0104] The compounds and compositions of the present invention can be administered alone or in combination with other compounds or other therapeutic agents. The compounds or compositions of the present invention can be administered simultaneously or sequentially with other therapeutic agents by the same or different routes of administration. The compounds of the present invention can be included in a single formulation or in separate formulations together with other therapeutic agents.

[0105] When the compounds of the present invention are administered together with other therapeutic agents, generally, considering the additional or synergistic effects of the therapeutic agents upon combined administration, the amount of each component in the typical daily dose and typical dosage form can be decreased relative to the usual dose when administered alone.

[0106] The compounds of the present invention, or their pharmaceutically acceptable salts, hydrates, or pharmaceutical compositions thereof, can be effectively used for preventing, treating, or alleviating TYK2-mediated diseases in patients.

[0107] In some embodiments, TYK2-mediated diseases include, but are not limited to, autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, or transplantation-related disorders.

[0108] In some embodiments, the TYK2-mediated disease is rheumatoid arthritis, psoriasis, diabetes, ankylosing spondylitis, vitiligo, atopic dermatitis, lupus, multiple sclerosis, psoriasis, Crohn's disease, ulcerative colitis, cancer, transplant rejection, or a neurological disorder.

[0109] In some embodiments, the inflammatory disorder is selected from rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0110] In some embodiments, the proliferative disorder is cancer.

[0111] In some embodiments, the proliferative disorder is blood cancer.

[0112] In some embodiments, the endocrine disorder is polycystic ovary syndrome, Crouzon syndrome, or type 1 diabetes.

[0113] In some embodiments, the neurological disorder is Alzheimer's disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0114] Figures 1 to 8 1H NMR spectra of Compounds 1 to 8, respectively. DETAILED DESCRIPTION OF THE INVENTION

[0115] To describe the present invention, the technical solutions of the present invention will be further elaborated with the following examples. The following examples are only used to illustrate the specific implementation methods of the present invention, so that those skilled in the art can understand the present invention, but are not used to limit the protection scope of the present invention. In the specific implementation methods of the present invention, the technical means or methods not specifically described are conventional technical means or methods in the art.

[0116] Unless otherwise stated, the definitions of substituents are as described in the present invention. The following reaction schemes and examples are used to further illustrate the content of the present invention.

[0117] Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare other compounds of the present invention, and that other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modifications, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also generally applicable to the preparation of other compounds of the present invention.

[0118] In the following examples, all temperatures are in degrees Celsius (°C) unless otherwise indicated. Room temperature in the examples refers to 15°C to 30°C; in some examples, room temperature is 20°C to 30°C. Unless otherwise indicated, all reagents and materials used in the present invention were commercially available.

[0119] 1 H NMR spectra were recorded using a Bruker 400 MHz or 600 MHz nuclear magnetic resonance spectrometer. 1 H NMR spectra were obtained using CDC13, DMSO-d6, CD3OD, or acetone-d6 as solvents (in ppm) and referenced to TMS (0 ppm) or chloroform (7.26 ppm). When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), brs (broadened singlet, br.s), dd (doublet of doublets), and dt (doublet of triplets). Coupling constants, J, are expressed in Hertz (Hz).

[0120] Low-resolution mass spectrometry (MS) data were collected using an Agilent 6120 quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1 x 30 mm, 3.5 μm, 6 min, flow rate: 0.6 mL / min). Mobile phase: 5%-95% (CH 3 CN containing 0.1% formic acid) in (H 2 O containing 0.1% formic acid), electrospray ionization (ESI), UV detection at 210 nm / 254 nm.

[0121] The pure compound was detected by UV at 210 nm / 254 nm using an Agilent 1260 pre-HPLC or a Calesep pump 250 pre-HPLC (column model: NOVASEP 50 / 80 mm DAC).

[0122] The following English or abbreviated terms are used throughout this invention:

[0123]

[0124]

[0125] Example 1: Synthesis of Compound N-Cyclobutyl-2-fluoro-7-(methylamino)-5-[(2-oxo-1-(pyridin-2-yl)-1,2-dihydropyridin-3-yl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 1)

[0126]

[0127] Step 1: Synthesis of 2-Fluoropyrazolo[1,5-a]pyrimidine-5,7-diol

[0128] The raw materials 5-Fluoro-1H-pyrazol-3-amine (1.0 g, 9.89 mmol) and dimethyl 1,3-propanedioate (5.23 g, 39.58 mmol) were added to ethanol (25 mL). Sodium ethoxide (2.02 g, 29.67 mmol) was added portionwise with stirring. After addition, the temperature was raised to 80 °C and the mixture was refluxed for 16 h. The reaction was stopped, the reaction solution was concentrated, 10 mL of water was added, and the mixture was stirred until dissolved. The temperature was lowered to 0 °C, and the pH was adjusted to 3 with concentrated hydrochloric acid. A solid precipitated, and the mixture was stirred at this temperature for 20 min, then filtered. The filter cake was washed with 5 mL of water and 2 mL of dichloromethane, and then dried under suction. The solid was dried in a blast dryer at 50 °C for 17 h to obtain 170 mg of a yellowish-brown solid. The aqueous phase of the filtrate was extracted with a mixed solvent of DCM:i-PrOH (V:V) = 4:1 (20 mL × 3). The organic phases were combined, evaporated to dryness, and 2.4 g of a brown oily substance was obtained. The total yield of the solid and the oily substance was 2.57 g. MS (ESI, neg. ion) m / z: 168.10 [M-H] - .

[0129] Step 2: Synthesis of 5,7-Dichloro-2-fluoropyrazolo[1,5-a]pyrimidine

[0130] Add 2-fluoropyrazolo[1,5-a]pyrimidine-5,7-diol (100 mg, 0.59 mmol) and acetonitrile (2 mL) to a 10 mL two-necked flask. Under nitrogen protection, heat the mixture to 50 °C, add phosphorus oxychloride (0.27 g, 1.77 mmol), and then dropwise add pyridine (0.047 g, 0.59 mmol). After the addition is complete, heat the reaction mixture to 100 °C for reaction. Monitor the reaction by TLC until the raw materials are completely reacted, and then rotary evaporate the reaction solution. Cool the reaction solution to room temperature, add 5 mL of water, and extract with dichloromethane (15 mL × 3). Combine the organic phases, rotary evaporate, and purify by silica gel column chromatography (eluent: PE:EA(V:V) = 1:0 - 20:1)) to obtain 49 mg of a gray solid with a yield of 40.23%. MS(ESI,pos.ion) m / z: 205.9[M+H] + .

[0131] Step 3: Synthesis of 5-chloro-2-fluoro-N-methylpyrazolo[1,5-a]pyrimidin-7-amine

[0132] Add 5,7-dichloro-2-fluoropyrazolo[1,5-a]pyrimidine (20 mg, 0.097 mmol) and methylamine hydrochloride (0.012 g, 0.17 mmol) to acetonitrile (3 mL), then add N,N-diisopropylethylamine (0.038 g, 0.29 mmol), and heat the reaction mixture to 80 °C for reaction. After 2 h, monitor the reaction by TLC. When the raw materials are completely reacted, stop the reaction, add 5 mL of water, and extract with dichloromethane (15 mL × 3). Combine the organic phases, concentrate, purify the product spot by preparative thin-layer chromatography plate, rotary evaporate, and obtain 15 mg of an off-white solid with a yield of 77.02%. MS(ESI,pos.ion) m / z: 201.1[M+H] + .

[0133] Step 4: Synthesis of 5-chloro-2-fluoro-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde

[0134] Add N,N-dimethylformamide (2 mL) to the raw material 5-chloro-2-fluoro-N-methylpyrazolo[1,5-a]pyrimidin-7-amine (50 mg, 0.25 mmol). After stirring and dissolving, dropwise add a 0.3 mL DMF dilution of phosphorus oxychloride (0.057 g, 0.38 mmol). After the addition is complete, heat the reaction mixture to 70 °C for about 8.5 h. Stop the reaction, cool the reaction mixture to 0 °C, add 3 mL of water, and adjust the pH to 9 - 10 with 1 M sodium hydroxide solution. Extract with ethyl acetate (15 mL × 3). Combine the organic phases and concentrate. Purify the concentrate by silica gel column chromatography (eluent: PE:EA = 10:1 - 3:1) to obtain 30 mg of a white solid with a yield of 52.65%. MS(ESI,pos.ion) m / z: 229.15[M+H] + .

[0135] Step 5: Synthesis of 5-chloro-2-fluoro-7-((4-methoxybenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde

[0136] To the raw materials 5-chloro-2-fluoro-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (52 mg, 0.23 mmol) and cesium carbonate (0.15 g, 0.46 mmol) was added N,N-dimethylformamide (2 mL). The temperature was lowered to -5 °C, and a 0.5 mL DMF dilution of 4-methoxybenzyl chloride (0.054 g, 0.35 mmol) was slowly added dropwise. After the addition, the reaction was kept at a constant temperature for 10 min, then transferred to room temperature for reaction. After 23 h of reaction, the reaction was stopped, the temperature was lowered to 0 °C, 5 mL of ice water was added, and then extracted with ethyl acetate (15 mL × 3). The organic phases were combined and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH (V:V) = 30:1) to obtain 60 mg of a yellow solid. The yield was 75.63%. MS (ESI, pos. ion) m / z: 349.15 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 7.27 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.6 Hz, 2H), 6.72 (s, 1H), 5.12 (s, 2H), 3.75 (s, 3H), 3.19 (s, 3H).

[0137] Step 6: Synthesis of 5-chloro-2-fluoro-7-((4-methoxybenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

[0138] To the raw material 5-chloro-2-fluoro-7-((4-methoxybenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (60 mg, 0.17 mmol) was added tert-butanol (2.5 mL), then 2-methyl-2-butene (0.12 g, 1.70 mmol) and sodium chlorite (0.11 g, 1.19 mmol). Sodium dihydrogen phosphate anhydrous (0.051 g, 0.43 mmol) was dissolved in water (1 mL) and then added to the reaction solution. After the addition, the reaction was stirred at a constant temperature for 10 min, then transferred to room temperature for reaction for 1 h and then heated to 50 °C for reaction for 13.5 h. TLC detection showed that the raw materials were basically reacted completely. The reaction was stopped, concentrated under reduced pressure, then 4 mL of ice water was added, the pH was adjusted to 3 with 1 M hydrochloric acid, and then extracted with dichloromethane (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by preparative TLC to obtain 59 mg of a white solid. The yield was 94.02%. MS (ESI, pos. ion) m / z: 365.1 [M+H] + .

[0139] Step 7: Synthesis of 5-chloro-N-cyclobutyl-2-fluoro-7-((4-methoxybenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0140] To the raw material 5-chloro-2-fluoro-7-((4-methoxybenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (59 mg, 0.16 mmol), add dichloromethane (2 mL). After stirring until dissolved and clear, add cyclobutylamine (0.017 g, 0.24 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.046 g, 0.24 mmol). React at room temperature for 10.5 h. Monitor the reaction by TLC until completion. Add 15 mL of dichloromethane. Wash the organic phase once with 8 mL of water, and then back-extract the aqueous phase once with 15 mL of dichloromethane. Combine the organic phases, dry over anhydrous sodium sulfate, concentrate. Purify the concentrate by silica gel column chromatography (eluent: PE:EA (V:V) = 15:1 - 3:1) to obtain 33 mg of a yellow solid. Yield: 48.82%. MS (ESI, pos.ion) m / z: 369.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.2 Hz, 1H), 7.19 (d, J = 8.5 Hz, 2H), 6.91 (t, J = 7.5 Hz, 2H), 6.13 (s, 1H), 5.18 (s, 2H), 4.61 (dt, J = 15.8, 7.8 Hz, 1H), 3.82 (s, 3H), 3.19 (s, 3H), 2.45 (d, J = 8.5 Hz, 2H), 2.04 (dt, J = 24.2, 13.7 Hz, 2H), 1.78 (d, J = 7.6 Hz, 1H).

[0141] Step 8: Synthesis of N-cyclobutyl-2-fluoro-7-((4-methoxybenzyl)(methyl)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0142] The raw materials 5-chloro-N-cyclobutyl-2-fluoro-7-((4-methoxybenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (50 mg, 0.12 mmol), 3-amino-1-(pyridin-2-yl)-1,2-dihydropyridin-2-one (0.022 g, 0.12 mmol), BrettPhos-G3-Pd (0.011 g, 0.012 mmol), BrettPhos (0.013 g, 0.024 mmol) and cesium carbonate (0.078 g, 0.24 mmol) were added to a 10 mL two-necked flask. After purging with nitrogen, 1,4-dioxane (3 mL) was added, and then purged with nitrogen again. The temperature was raised to 110 °C for reaction. After 3 h, TLC detection showed that the raw materials had completely reacted, and the reaction was stopped and cooled to room temperature. 4 mL of water was added, and then extracted with EA (15 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and purified by preparative thin-layer chromatography (eluent: dichloromethane / methanol = 50 / 1) to obtain 45 mg of a green solid. The yield was 66.14%. MS (ESI, pos.ion) m / z: 569.30 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 4.3 Hz, 1H), 8.38 (d, J = 7.2 Hz, 1H), 7.92 (t, J = 9.5 Hz, 3H), 7.61 (d, J = 6.9 Hz, 1H), 7.44 - 7.34 (m, 1H), 7.17 (d, J = 8.3 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 6.44 (t, J = 7.3 Hz, 1H), 5.57 (s, 1H), 5.00 (s, 2H), 4.79 - 4.60 (m, 1H), 3.79 (s, 3H), 3.05 (s, 3H), 2.50 (d, J = 5.4 Hz, 2H), 2.00 (dd, J = 19.9, 9.9 Hz, 2H), 1.82 (d, J = 9.5 Hz, 2H).

[0143] Step 9: Synthesis of N-cyclobutyl-2-fluoro-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0144] To the raw material N-cyclobutyl-2-fluoro-7-((4-methoxybenzyl)(methyl)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (41 mg, 0.072 mmol), dichloromethane (2 mL) was added. After stirring until clear, trifluoroacetic acid (0.49 g, 4.32 mmol) was slowly added dropwise. After completion of the addition, the reaction was carried out at room temperature for 12 h, then 100 mg of trifluoroacetic acid was added, and the reaction was continued for 9.5 h before stopping the reaction. 10 mL of dichloromethane was added, the temperature was lowered to 0 °C, 2 mL of water was added, and the pH was adjusted to 9 with potassium phosphate solution. After liquid separation, the aqueous phase was extracted once more with 10 mL of dichloromethane. The organic phases were combined, concentrated, and purified by preparative thin-layer chromatography to obtain 26 mg of a blue solid with a yield of 80.40%. HRMS (ESI, pos. ion) m / z: 449.1887 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 4.0 Hz, 1H), 8.43 (dd, J = 7.3, 1.5 Hz, 1H), 8.16 (s, 1H), 7.94 (dt, J = 13.5, 7.2 Hz, 2H), 7.78 (s, 1H), 7.63 (d, J = 5.8 Hz, 1H), 7.45 - 7.35 (m, 1H), 6.46 (t, J = 7.2 Hz, 1H), 6.03 (s, 1H), 5.54 (s, 1H), 4.70 (dd, J = 16.0, 8.0 Hz, 1H), 3.09 (d, J = 5.2 Hz, 2H), 2.52 (d, J = 2.8 Hz, 2H), 2.02 (dd, J = 20.4, 9.1 Hz, 2H), 1.87 - 1.78 (m, 2H).

[0145] Example 2: Synthesis of compound N-(2-oxabicyclo[3.2.0]heptan-7-yl)-2-fluoro-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 2)

[0146]

[0147] Step 1: Synthesis of N-(2-oxabicyclo[3.2.0]heptan-7-yl)-5-chloro-2-fluoro-7-((4-methoxybenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0148] The raw materials 5-chloro-2-fluoro-7-((4-methoxybenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (76.53 mg, 0.21 mmol, see the product in Step 6 of Example 1), 2-oxabicyclo[3.2.0]heptan-7-amine (0.038 g, 0.34 mmol) were added to dichloromethane (3 mL), and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.064 g, 0.34 mmol) was added. The reaction was carried out at room temperature. After 4 h, TLC detection showed that the raw materials were basically reacted completely. The reaction was stopped, 15 mL of DCM was added, and then washed twice with 5 mL of water, concentrated, and purified by column chromatography (eluent: PE:EA (V:V) = 10:1 - 5:1) to obtain 50 mg of a light yellow solid with a yield of 51.82%. MS(ESI, pos.ion) m / z: 460.35 [M+H] + .

[0149] Step 2: Synthesis of N-(2-oxabicyclo[3.2.0]heptan-7-yl)-2-fluoro-7-((4-methoxybenzyl)(methyl)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0150] The raw materials N-(2-oxabicyclo[3.2.0]heptan-7-yl)-5-chloro-2-fluoro-7-((4-methoxybenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (50 mg, 0.11 mmol), 3-amino-1-(pyridin-2-yl)-1,2-dihydropyridin-2-one (0.021 g, 0.11 mmol), BrettPhos-G3-Pd (0.010 g, 0.011 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (0.012 g, 0.022 mmol) and cesium carbonate (0.072 g, 0.22 mmol) were added to a 10 mL two-necked flask, purged with nitrogen, then 1,4-dioxane (3 mL) was added, and purged with nitrogen again. The temperature was raised to 110 °C for reaction. TLC detection showed that the raw materials were completely reacted. The reaction was stopped, cooled to room temperature, filtered by suction, the filtrate was concentrated, and the concentrate was purified by column chromatography (eluent: DCM:MeOH (V:V) = 1:0 - 70:1) to obtain 48 mg of a yellow solid with a yield of 72.30%. MS(ESI, pos.ion) m / z: 611.30 [M+H] + .

[0151] Synthesis of N-(2-oxabicyclo[3.2.0]heptan-7-yl)-2-fluoro-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0152] To the raw material N-(2-oxabicyclo[3.2.0]heptan-7-yl)-2-fluoro-7-((4-methoxybenzyl)(methyl)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (48 mg, 0.079 mmol), add dichloromethane (2 mL). After stirring until dissolved clearly, slowly dropwise add trifluoroacetic acid (0.54 g, 4.74 mmol). After dropping, react at room temperature and monitor the reaction completion by TLC. Stop the reaction, add 10 mL of DCM, cool down to 0 °C, add 2 mL of water, adjust the pH = 9 with potassium phosphate solution, separate the layers, extract the aqueous phase with 10 mL of DCM once again, combine the organic phases, concentrate, and purify the concentrate by preparative thin-layer chromatography to obtain 20 mg of blue solid. The yield is 51.87%. LC-MS (ESI, pos.ion) m / z: 491.20 [M+H] + ; 1 HNMR (400 MHz, CDCl3) δ 8.62 (d, J = 4.2 Hz, 1H), 8.57 (d, J = 7.5 Hz, 1H), 8.14 (s, 1H), 7.95 - 7.86 (m, 2H), 7.72 (d, J = 6.6 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.40 - 7.36 (m, 1H), 6.54 (t, J = 7.2 Hz, 1H), 5.97 (d, J = 4.5 Hz, 1H), 5.50 (s, 1H), 4.82 - 4.75 (m, 1H), 4.62 - 4.53 (m, 1H), 4.16 (t, J = 7.7 Hz, 1H), 4.01 (dd, J = 15.2, 9.4 Hz, 1H), 3.05 (d, J = 5.2 Hz, 3H), 2.94 (d, J = 6.3 Hz, 1H), 2.88 - 2.78 (m, 2H), 2.02 (s, 1H), 1.89 - 1.79 (m, 2H), 1.75 (dd, J = 12.0, 5.9 Hz, 2H).

[0153] Example 3: Synthesis of 2-fluoro-N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 3)

[0154]

[0155] Step 1: Synthesis of 3-amino-2H-[1,2'-bipyridin]-2-one

[0156] 3-Amino-2-hydroxypyridine (2.27 g, 20.6 mmol), 2-fluoropyridine (2 g, 20.6 mmol) and cesium carbonate (13.42 g, 47.2 mmol) were added to N,N-dimethylacetamide (20 mL). The reaction was carried out at 95 °C for about 21 h, then the temperature was lowered and the reaction was stopped. The mixture was filtered by suction, and the filter cake was washed with 30 mL of ethyl acetate. The organic phase was collected, 10 mL of water was added, and then 20 mL of ethyl acetate was used for extraction. It was washed with water three times (10 mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (eluent: PE:EA (V:V) = 10:1 - 1:1) to obtain 0.8 g of a yellow solid with a yield of 20.75%. MS (ESI, pos.ion) m / z: 188.1 [M+H] + .

[0157] Step 2: Synthesis of 5-chloro-2-fluoro-7-((4-methoxybenzyl)(methyl)amino)-N-((1R,2R)-2-methoxycyclobutyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0158] 5-Chloro-2-fluoro-7-((4-methoxybenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.6 g, 1.64 mmol, see the product of step 6 of the example) and dichloromethane (10 mL) were added to a 100 mL single-necked flask. After cooling to -5 °C and stirring until clear, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.5 g, 2.62 mmol), ethyl 2-oximinoacetate (0.047 g, 0.33 mmol), (1R,2R)-2-methoxycyclobutylamine hydrochloride (0.27 g, 1.97 mmol) were added. Finally, N,N-diisopropylethylamine (0.53 g, 4.1 mmol) was added dropwise. After keeping the temperature for 10 min, it was transferred to room temperature and reacted for about 3 h. TLC detection showed that the raw materials were basically completely reacted, and the reaction was stopped. It was washed twice with 10 mL of water, the organic phase was dried over anhydrous sodium sulfate, and concentrated. Purification by column chromatography (DCM / EA = 100 / 30) gave 0.2 g of a yellow solid. The yield was 27.15%. MS (ESI, pos.ion) m / z: 448.0 [M+H] + .

[0159] Step 3: Synthesis of 2-fluoro-7-((4-methoxybenzyl)(methyl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0160] Add 5-chloro-2-fluoro-7-((4-methoxybenzyl)(methyl)amino)-N-((1R,2R)-2-methoxycyclobutyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.23 mmol), 3-amino-1-(pyridin-2-yl)-1,2-dihydropyridin-2-one (40 mg, 0.21 mmol), BrettPhos-G3-Pd (19 mg, 0.021 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-11'-biphenyl (23 mg, 0.042 mmol) and cesium carbonate (140 mg, 0.42 mmol) into a 50 mL three-necked flask. Replace the air with nitrogen, then add 1,4-dioxane (5 mL), and heat the mixture to 80 °C for reaction. After 16 h, monitor the reaction by TLC. When the raw materials are completely reacted, stop the reaction, filter by suction, wash the filter cake with 20 mL of dichloromethane, then wash it once with 10 mL of saturated brine, and extract it once with 20 mL of dichloromethane. Collect the organic phase, dry it with anhydrous sodium sulfate, concentrate it, and obtain 0.1 g of yellow solid. The yield is 78.18%. MS(ESI,pos.ion) m / z: 599.0 [M+H] + .

[0161] Step 4: Synthesis of 2-fluoro-N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0162] Add 2-fluoro-7-((4-methoxybenzyl)(methyl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.1 g, 0.17 mmol) and dichloromethane (4 mL) into a 100 mL single-necked flask. After stirring until clear, slowly add trifluoroacetic acid (1.16 g, 10.2 mmol). After the addition, react at room temperature. After 2 h, take a sample, neutralize it with potassium phosphate solution, and then monitor the reaction by TLC. When the raw materials are basically completely reacted, stop the reaction. Cool it to 0 °C, adjust the pH to 10 with 1 M potassium phosphate solution, then extract it with 20 mL of dichloromethane. Dry the organic phase with anhydrous sodium sulfate, concentrate it, and purify the concentrate by preparative thin-layer chromatography (DCM:CH3OH(V:V)=25:1) to obtain 35 mg of green solid. The yield is 43.79%. MS(ESI,pos.ion) m / z: 479.0 [M+H]+; 11H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 4.5 Hz, 1H), 8.40 - 8.34 (m, 1H), 8.12 (s, 1H), 7.94 (dd, J = 17.0, 8.0 Hz, 3H), 7.65 - 7.60 (m, 1H), 7.42 (dd, J = 8.4, 3.3 Hz, 1H), 6.45 (t, J = 7.2 Hz, 1H), 6.08 (d, J = 4.9 Hz, 1H), 5.52 (s, 1H), 4.63 - 4.52 (m, 1H), 3.86 (dd, J = 15.2, 7.7 Hz, 1H), 3.40 (s, 3H), 3.08 (d, J = 5.1 Hz, 3H), 2.32 (dd, J = 19.1, 9.4 Hz, 1H), 2.16 (dd, J = 18.5, 9.2 Hz, 1H), 1.74 (d, J = 9.0 Hz, 1H), 1.56 - 1.49 (m, 1H). Example 4: Synthesis of Compound N-Cyclopropyl-2-fluoro-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 4)

[0163]

[0164] Step 1: Synthesis of 5-Chloro-N-cyclopropyl-2-fluoro-7-((4-methoxybenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0165] Add 5-chloro-2-fluoro-7-((4-methoxybenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.16 g, 0.44 mmol, see Step 6 of Example 1), cyclopropylamine (0.056 g, 0.66 mmol), and dichloromethane (3 mL) into a 50 mL single-necked flask. After stirring until clear, add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.13 g, 0.66 mmol). React at room temperature for about 2 h. Monitor the reaction by TLC. When the raw materials are basically completely reacted, stop the reaction. Add 20 mL of dichloromethane and wash three times with 5 mL of water. Extract the aqueous phase once with 20 mL of dichloromethane. Collect the organic phase, dry it with anhydrous sodium sulfate, concentrate it, and purify it by column chromatography (PE:EA (V:V) = 4:1 - 2:1) to obtain 0.09 g of a white solid. The yield is 50.81%. MS (ESI, pos.ion) m / z: 404.0 [M+H] + .

[0166] Synthesis of N-cyclopropyl-2-fluoro-7-((4-methoxybenzyl)(methyl)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0167] Add 3-amino-1-(pyridin-2-yl)-1,2-dihydropyridin-2-one (20 mg, 0.11 mmol), BrettPhos-G3-Pd (10 mg, 0.011 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-1,1'-biphenyl (12 mg, 0.022 mmol) and cesium carbonate (72 mg, 0.22 mmol) into a 10 mL two-necked flask. Replace the air with nitrogen, then dissolve 5-chloro-N-cyclopropyl-2-fluoro-7-((4-methoxybenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (44 mg, 0.11 mmol) in 1,4-dioxane (2 mL) and add it to the flask. Heat the reaction mixture to 80 °C. After 3.5 h, monitor the reaction by TLC. When the raw materials are completely reacted, stop the reaction, filter by suction, wash the filter cake with 20 mL of dichloromethane, then wash it once with 10 mL of saturated brine, and extract it once with 20 mL of dichloromethane. Collect the organic phase, dry it with anhydrous sodium sulfate, and concentrate to obtain 50 mg of green solid with a yield of 84.39%. MS (ESI, pos. ion) m / z: 478.0 [M+H] + .

[0168] Synthesis of N-cyclopropyl-2-fluoro-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0169] Add N-cyclopropyl-2-fluoro-7-((4-methoxybenzyl)(methyl)amino)-5-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (50 mg, 0.09 mmol) and dichloromethane (2 mL) into a 100 mL single-necked flask. After stirring until clear, slowly add trifluoroacetic acid (0.62 g, 5.40 mmol). After the addition, react at room temperature for 6 h, then stop the reaction. Cool it to 0 °C, adjust the pH to 10 with 1 M potassium phosphate solution, then extract it with 20 mL of dichloromethane. Dry the organic phase with anhydrous sodium sulfate, concentrate, and purify the concentrate by preparative thin-layer chromatography (DCM:CH3OH (V:V) = 25:1) to obtain 25 mg of light blue solid with a yield of 63.83%. MS (ESI, pos. ion) m / z: 435.0 [M+H]+; 11H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 4.7 Hz, 1H), 8.29 (d, J = 6.1 Hz, 1H), 8.08 (s, 1H), 7.98 - 7.89 (m, 2H), 7.76 (s, 1H), 7.62 (d, J = 5.8 Hz, 1H), 7.42 (dd, J = 7.9, 3.3 Hz, 1H), 6.48 (t, J = 7.3 Hz, 1H), 6.01 (d, J = 4.9 Hz, 1H), 5.50 (s, 1H), 3.08 (d, J = 5.1 Hz, 3H), 3.02 (dd, J = 7.2, 3.7 Hz, 1H), 0.92 (d, J = 5.4 Hz, 2H), 0.68 (d, J = 6.9 Hz, 2H).

[0170] Example 5: Synthesis of 2-Fluoro-N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-phenyl-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 5)

[0171]

[0172] Step 1: Synthesis of 3-Amino-1-phenylpyridin-2(1H)-one

[0173] Add 3-amino-2-hydroxypyridine (0.89 g, 8.09 mmol), copper(I) iodide (0.42 g, 2.2 mmol) and potassium carbonate (2.03 g, 14.7 mmol) to a 100 mL two-necked flask. Replace the air with nitrogen, then add iodobenzene (1.5 g, 7.35 mmol), N,N'-dimethylethylenediamine (0.32 g, 3.67 mmol) and 1,4-dioxane (10 mL). React at 100 °C for about 17 h. Monitor the reaction by TLC. When the raw materials are completely reacted, stop the reaction. Filter by suction, wash the filter cake with 10 mL of ethyl acetate, collect the organic phase, and wash it twice with water (10 mL * 2). Dry the organic phase with anhydrous sodium sulfate and concentrate. Purify by silica gel column chromatography (PE / EA = 10 / 1 - 1 / 1) to obtain 1 g of orange solid with a yield of 73.04%. MS (ESI, pos.ion) m / z: 187.1 [M + H] + .

[0174] Step 2: Synthesis of 5-Chloro-2-fluoro-7-((4-methoxybenzyl)(methyl)amino)-N-((1R,2R)-2-methoxycyclobutyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0175] Add 5-chloro-2-fluoro-7-((4-methoxybenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.6 g, 1.64 mmol, see Step 6 of Example 1) and dichloromethane (10 mL) to a 100 mL single-necked flask. Cool to -5 °C. After stirring until dissolved clearly, add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.5 g, 2.62 mmol), ethyl 2-oximinoacetate (0.047 g, 0.33 mmol), (1R,2R)-2-methoxycyclobutylamine hydrochloride (0.27 g, 1.97 mmol) and N,N-diisopropylethylamine (0.53 g, 4.1 mmol). After maintaining the temperature for 10 min, transfer to room temperature and react for about 3 h. Detect by TLC. When the raw materials are basically completely reacted, stop the reaction. Wash twice with 10 mL of water. Dry the organic phase with anhydrous sodium sulfate, concentrate, and purify by silica gel column chromatography (DCM:EA (V:V) = 100:30) to obtain 0.2 g of yellow solid, with a yield of 27.15%. MS (ESI, pos.ion) m / z: 448.0 [M+H] + .

[0176] Step 3: Synthesis of 2-fluoro-7-((4-methoxybenzyl)(methyl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-5-((2-oxo-1-phenyl-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0177] Add 5-chloro-2-fluoro-7-((4-methoxybenzyl)(methyl)amino)-N-((1R,2R)-2-methoxycyclobutyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.23 mmol), 3-amino-1-phenylpyridin-2(1H)-one (40 mg, 0.21 mmol), BrettPhos-G3-Pd (19 mg, 0.021 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (23 mg, 0.042 mmol) and cesium carbonate (140 mg, 0.42 mmol) to a 50 mL three-necked flask. Replace with nitrogen, then add 1,4-dioxane (5 mL), and heat to 80 °C for reaction. After 4.5 h, detect by TLC. When the raw materials are completely reacted, stop the reaction, filter by suction, wash the filter cake with 20 mL of dichloromethane, collect the organic phase, and concentrate. Purify by silica gel column chromatography (DCM / CH3OH (V:V) = 100:1) to obtain 100 mg of yellow solid, with a yield of 77.89%. MS (ESI, pos.ion) m / z: 598.0 [M+H] + .

[0178] Step 4: Synthesis of 2-Fluoro-N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-phenyl-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0179] Add 2-Fluoro-7-((4-methoxybenzyl)(methyl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-5-((2-oxo-1-phenyl-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.1 g, 0.17 mmol) and dichloromethane (4 mL) into a 100 mL single-necked flask. After stirring until clear, slowly add trifluoroacetic acid (1.16 g, 10.2 mmol). After dropping, react at room temperature. Take a sample after 2 h, neutralize it with potassium phosphate solution and detect by TLC. The raw material has basically reacted completely, then stop the reaction. Place it in an ice bath to cool down, adjust the pH to 10 with 1 M potassium phosphate solution, then extract with 20 mL of dichloromethane. The organic phase is dried with anhydrous sodium sulfate and concentrated. Purify by flash chromatography (DCM / CH3OH = 25 / 1) to obtain 30 mg of light gray solid, with a yield of 37.55%. MS(ESI,pos.ion) m / z: 478.0 [M+H] + ; 1 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 7.4 Hz, 1H), 8.13 (s, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.57 (t, J = 7.4 Hz, 2H), 7.51 (d, J = 7.2 Hz, 1H), 7.47 (t, J = 7.4 Hz, 2H), 7.12 (dd, J = 6.9, 1.6 Hz, 1H), 6.40 (t, J = 7.2 Hz, 1H), 6.03 (d, J = 5.2 Hz, 1H), 5.51 (s, 1H), 4.64 - 4.54 (m, 1H), 3.88 (dd, J = 15.3, 7.7 Hz, 1H), 3.40 (s, 3H), 3.08 (d, J = 5.2 Hz, 3H), 2.33 (dd, J = 19.3, 9.8 Hz, 1H), 2.17 (dd, J = 18.5, 9.4 Hz, 1H), 1.78 - 1.71 (m, 1H), 1.53 (d, J = 9.3 Hz, 1H).

[0180] Example 6: Synthesis of Compound 2-Fluoro-N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((1-(oxazol-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 6)

[0181]

[0182] Step 1: Synthesis of 3-amino-1-(oxazol-2-yl)pyridin-2(1H)-one

[0183] Add 3-amino-2-hydroxypyridine (0.74 g, 6.76 mmol), copper(I) iodide (0.64 g, 3.38 mmol) and potassium carbonate (1.87 g, 13.52 mmol) to a 100 mL two-necked flask. Replace the air with nitrogen. Then dissolve 2-bromooxazole (1 g, 6.76 mmol) and trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (0.58 g, 4.06 mmol) in toluene (15 mL) and add it to the flask. React at 80 °C for about 15.5 h. Stop the reaction, filter by suction, wash the filter cake with 10 mL of dichloromethane, collect the organic phase, and wash it twice with water (10 mL × 2). Dry the organic phase with anhydrous sodium sulfate and concentrate. Purify by column chromatography (DCM:CH3OH(V:V) = 100:1 - 50:1) to obtain 60 mg of a yellow solid with a yield of 5.01%. MS(ESI,pos.ion) m / z: 178.1[M+H] + .

[0184] Step 2: Synthesis of 2-fluoro-7-((4-methoxybenzyl)(methyl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-5-((1-(oxazol-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0185] Add 5-chloro-2-fluoro-7-((4-methoxybenzyl)(methyl)amino)-N-((1R,2R)-2-methoxycyclobutyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (99 mg, 0.22 mmol, see Step 2 of Example 3), 3-amino-1-(oxazol-2-yl)pyridin-2(1H)-one (35 mg, 0.20 mmol), BrettPhos-G3-Pd (18 mg, 0.02 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-11'-biphenyl (21 mg, 0.04 mmol) and cesium carbonate (130 mg, 0.40 mmol) to a 50 mL two-necked flask. Replace the air with nitrogen, then add 1,4-dioxane (4 mL). Heat to 80 °C and react for 4 h, then stop the reaction. Filter by suction, wash the filter cake with 20 mL of dichloromethane, collect the organic phase, and concentrate. Purify by column chromatography (DCM / CH3OH = 100 / 1.5) to obtain 90 mg of a yellow solid. The yield is 77.40%. MS(ESI,pos.ion) m / z: 589.0[M+H] + .

[0186] Step 3: Synthesis of 2-Fluoro-N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((1-(oxazol-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0187] Add 2-Fluoro-7-((4-methoxybenzyl)(methyl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-5-((1-(oxazol-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.09 g, 0.15 mmol) and dichloromethane (4 mL) to a 100 mL single-necked flask. After stirring until clear, slowly add trifluoroacetic acid (1.03 g, 9 mmol). After completion of the addition, react at room temperature for 2 h and then stop the reaction. Place it in an ice bath at 0 °C and adjust the pH to 10 with 1 M potassium phosphate solution. Then extract with 20 mL of dichloromethane. The organic phase is dried over anhydrous sodium sulfate and concentrated. The concentrate is purified by preparative thin-layer silica gel chromatography plate (DCM:CH3OH (V:V) = 25:1) to obtain 40 mg of a white solid, with a yield of 55.84%. MS(ESI,pos.ion) m / z: 469.0 [M+H] + ; 1 1H NMR(400 MHz, CDCl3) δ 8.37 (d, J = 6.0 Hz, 1H), 7.98 (s, 1H), 7.80 (s, 2H), 7.32 (d, J = 7.3 Hz, 2H), 6.42 (t, J = 7.2 Hz, 1H), 6.06 (s, 1H), 5.53 (s, 1H), 4.61 - 4.51 (m, 1H), 3.84 (dd, J = 15.0, 7.7 Hz, 1H), 3.39 (s, 3H), 3.11 (d, J = 5.2 Hz, 3H), 2.37 - 2.28 (m, 1H), 2.15 (d, J = 8.7 Hz, 1H), 1.77 - 1.71 (m, 1H), 1.53 - 1.47 (m, 1H).

[0188] Example 7: Synthesis of Compound 2-Fluoro-N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(thiazol-5-yl)-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 7)

[0189]

[0190] Step 1: Synthesis of 3-Amino-1-(thiazol-5-yl)pyridin-2(1H)-one

[0191] 3-Amino-2-hydroxypyridine (0.74 g, 6.71 mmol), copper(I) iodide (0.46 g, 2.44 mmol), and potassium carbonate (1.69 g, 12.2 mmol) were added to a 100 mL two-necked flask. After purging with nitrogen, 5-bromothiazole (1 g, 6.1 mmol) and N,N'-dimethylethylenediamine (0.32 g, 3.66 mmol) were dissolved in 1,4-dioxane (10 mL) and added to the flask. The reaction was carried out at 90 °C for about 15 h. The reaction was stopped, and the mixture was filtered by suction. The filter cake was washed with 20 mL of dichloromethane. The organic phase was washed once with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated. Purification by silica gel column chromatography (DCM:CH3OH (V:V) = 100:1 - 50:1) gave 80 mg of an orange solid with a yield of 6.79%. MS (ESI, pos. ion) m / z: 194.1 [M+H] + .

[0192] Step 2: Synthesis of 2-fluoro-7-((4-methoxybenzyl)(methyl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-5-((2-oxo-1-(thiazol-5-yl)-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0193] 5-Chloro-2-fluoro-7-((4-methoxybenzyl)(methyl)amino)-N-((1R,2R)-2-methoxycyclobutyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (89 mg, 0.20 mmol, see Step 2 of Example 3), 3-amino-1-(thiazol-2-yl)pyridin-2(1H)-one (35 mg, 0.18 mmol), BrettPhos-G3-Pd (16 mg, 0.018 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-11'-biphenyl (19 mg, 0.036 mmol), and cesium carbonate (120 mg, 0.36 mmol) were added to a 50 mL three-necked flask. After purging with nitrogen, 1,4-dioxane (4 mL) was added, and the temperature was raised to 80 °C for reaction. After 4 h, TLC detection showed that the raw materials had completely reacted. The reaction was stopped, and the mixture was filtered by suction. The filter cake was washed with 20 mL of dichloromethane, and the organic phase was collected and concentrated. Purification by column chromatography (DCM / CH3OH = 100 / 1.5) gave 100 mg of a yellow solid with a yield of 91.31%. MS (ESI, pos. ion) m / z: 605.0 [M+H] + .

[0194] Step 3: Synthesis of 2-Fluoro-N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(thiazol-5-yl)-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0195] Add 2-Fluoro-7-((4-methoxybenzyl)(methyl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-5-((2-oxo-1-(thiazol-5-yl)-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.1 g, 0.17 mmol) and dichloromethane (4 mL) into a 100 mL single-necked flask. After stirring until clear, slowly add trifluoroacetic acid (1.16 g, 10.2 mmol). After addition, react at room temperature. After 2.5 h, take a sample, neutralize it with potassium phosphate solution and detect by TLC. The raw material has basically reacted completely, then stop the reaction. Place it in an ice bath at 0 °C, adjust the pH to 10 with 1 M potassium phosphate solution, then extract with 20 mL of dichloromethane. The organic phase is dried over anhydrous sodium sulfate, concentrated, and the concentrate is purified by preparative TLC silica gel plate (DCM:CH3OH (V:V) = 25:1) to obtain 40 mg of green solid, with a yield of 49.92%. MS(ESI,pos.ion) m / z: 485.0 [M+H] + ; 1 1H NMR(400 MHz, CDCl3) δ 8.86 (s, 1H), 8.40 (d, J = 7.6 Hz, 1H), 8.09 (s, 1H), 8.05 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 7.1 Hz, 1H), 6.51 (t, J = 7.3 Hz, 1H), 6.07 (s, 1H), 5.53 (s, 1H), 4.60 - 4.54 (m, 1H), 3.85 (dd, J = 15.1, 7.4 Hz, 1H), 3.40 (s, 3H), 3.10 (d, J = 5.2 Hz, 3H), 2.37 - 2.30 (m, 1H), 2.19 - 2.12 (m, 1H), 1.79 - 1.72 (m, 1H), 1.50 (d, J = 9.2 Hz, 1H).

[0196] Example 8: Synthesis of Compound 2-Fluoro-N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(thiophen-2-yl)-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 8)

[0197]

[0198] Step 1: Synthesis of 3-amino-1-(thiophen-2-yl)pyridin-2(1H)-one

[0199] Add 3-amino-2-hydroxypyridine (1.49 g, 13.5 mmol), copper(I) iodide (0.7 g, 3.68 mmol) and potassium carbonate (3.39 g, 24.54 mmol) into a 100 mL two-necked flask. Replace the air with nitrogen, then dissolve 2-bromothiophene (2 g, 12.27 mmol) and N,N'-dimethylethylenediamine (0.43 g, 4.91 mmol) in 1,4-dioxane (20 mL) and add it into the flask. React at 90 °C for about 15.5 h. Monitor the reaction by TLC plate. When the raw materials are basically completely reacted, stop the reaction, filter by suction, wash the filter cake with 30 mL of dichloromethane. Wash the organic phase once with 20 mL of water, then extract with 20 mL of dichloromethane. Dry the organic phase with anhydrous sodium sulfate and concentrate. The concentrate is purified by silica gel column chromatography (PE:EA(V:V)=4:1) to obtain 1.2 g of brown solid with a yield of 50.89%. MS(ESI,pos.ion) m / z: 193.1[M+H] + .

[0200] Step 2: Synthesis of 2-fluoro-7-((4-methoxybenzyl)(methyl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-5-((2-oxo-1-(thiophen-2-yl)-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0201] Add 5-chloro-2-fluoro-7-((4-methoxybenzyl)(methyl)amino)-N-((1R,2R)-2-methoxycyclobutyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (85 mg, 0.19 mmol, see Step 2 of Example 3), 3-amino-1-(thiophen-2-yl)pyridin-2(1H)-one (36 mg, 0.19 mmol), BrettPhos-G3-Pd (17 mg, 0.019 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (20 mg, 0.038 mmol) and cesium carbonate (120 mg, 0.38 mmol) into a 50 mL two-necked flask. Replace the air with nitrogen, then add 1,4-dioxane (4 mL), and heat up to 80 °C to react. After 4.5 h, monitor the reaction by TLC. When the raw materials are completely reacted, stop the reaction, filter by suction, wash the filter cake with 20 mL of dichloromethane, collect the organic phase and concentrate. The concentrate is purified by column chromatography (DCM / CH3OH(V:V)=100 / 1) to obtain 100 mg of yellow solid with a yield of 88.46%. MS(ESI,pos.ion) m / z: 604.0[M+H] + .

[0202] Step 3: Synthesis of 2-Fluoro-N-((1R,2R)-2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-1-(thiophen-2-yl)-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0203] Add 2-Fluoro-7-((4-methoxybenzyl)(methyl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-5-((2-oxo-1-(thiophen-2-yl)-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.1 g, 0.17 mmol) and dichloromethane (3 mL) into a 100 mL single-necked flask. After stirring until clear, slowly add trifluoroacetic acid (1.16 g, 10.2 mmol). After addition, react at room temperature. Take a sample after 2 h, neutralize with potassium phosphate solution and detect by TLC. The raw material has basically reacted completely, then stop the reaction. Place it in an ice bath at 0 °C, adjust the pH to 10 with 1 M potassium phosphate solution, then extract with 20 mL of dichloromethane. The organic phase is dried over anhydrous sodium sulfate and concentrated. The concentrate is purified by preparative thin-layer silica gel chromatography plate (DCM:CH3OH (V:V) = 25:1) to obtain 40 mg of light blue solid. The yield is 49.94%. MS(ESI,pos.ion) m / z: 484.0 [M+H] + ; 1 1H NMR(400 MHz, CDCl3) δ 8.35 (d, J = 7.3 Hz, 1H), 8.11 (s, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.36 (t, J = 5.9 Hz, 2H), 7.20 (d, J = 3.8 Hz, 1H), 7.08 (dd, J = 5.4, 4.0 Hz, 1H), 6.43 (t, J = 7.3 Hz, 1H), 6.04 (d, J = 5.4 Hz, 1H), 5.51 (s, 1H), 4.61 - 4.54 (m, 1H), 3.86 (dd, J = 15.1, 7.7 Hz, 1H), 3.40 (s, 3H), 3.09 (d, J = 5.1 Hz, 3H), 2.33 (dd, J = 18.9, 9.6 Hz, 1H), 2.16 (dd, J = 18.4, 8.9 Hz, 1H), 1.78 - 1.72 (m, 1H), 1.51 (d, J = 9.3 Hz, 1H).

[0204] Examples of Activity Tests

[0205] I. Testing the inhibitory effect of compounds on TYK2 JH2 or JAK1 JH2 pseudokinase by fluorescence resonance energy transfer (TR-FRET) method

[0206] 1. Experimental principle:

[0207] The TYK2 JH2 or JAK1 JH2 pseudokinase can simultaneously bind to the fluorescently labeled Tracer and the Tb antibody. The Tb antibody, as a fluorescent donor, generates fluorescence with a wavelength of 495 nm under the action of excitation light at a certain wavelength. The Tracer, as a fluorescent acceptor, can receive the 495-nm wavelength fluorescence and generate fluorescence with a wavelength of 520 nm only when it is close enough to the Tb antibody, that is, a fluorescence resonance energy transfer signal. When a compound is added to compete with the Tracer for binding to the JH2 region of the pseudokinase, the TR-FRET signal weakens due to the reduced binding of the Tracer. The inhibitory activity of the compound binding to the pseudokinase can be reflected by the ratio of the 520 nm / 495 nm signals.

[0208] 2. The experimental instruments, experimental reagents or working solutions are as shown in Tables 1 and 2 below:

[0209] Table 1 Experimental Reagents

[0210]

[0211] Experimental Instruments

[0212] · Micro pipetting instrument: Echo (LABCYTE Echo550)

[0213] · Microplate reader: Envision 2105 (Perkin Elmer)

[0214] · Incubator: CIMO, SPX-60BS-II

[0215] · Thermo MATRIX multichannel pipette: Thermo Fisher, 2 - 125 μl

[0216] · Centrifuge: Thermo Centrifuge ST 40R

[0217] · Water purification instrument: Millipore Milli Q Reference system

[0218] · Ultra-low temperature freezer: Haier ultralow temperature freezer

[0219] · Refrigerator: Haier 4-degree freezer; Haier - 20-degree freezer

[0220] Table 2 Experimental Working Solutions (1X)

[0221]

[0222] 3. The experimental method is as follows:

[0223] 1. Dissolve the compound in DMSO to a storage concentration of 10 mM.

[0224] 2. Prepare 10 concentration gradients of the compound in a compound dilution plate, with the starting concentration of 298.8 nM, and sequentially dilute it three-fold to obtain 10 concentration gradients of the compound, and transfer them to an Echo plate.

[0225] 3. Use the Echo instrument to transfer 75 nL of the compound from the Echo plate to a 384-well experimental plate.

[0226] 4. Prepare the TYK2 JH2 pseudokinase or JAK1 JH2 pseudokinase, Tb antibody, and Tracer solution with 1x experimental working solution.

[0227] 5. Set up three groups: the experimental group, the high-signal control group, and the low-signal control group. Experimental group: Add 5 μL of 3 times the final concentration (0.5 nM as the final concentration) of the TYK2 JH2 or JAK1 JH2 pseudokinase to the 384-well experimental plate containing different concentrations of the compound solution, centrifuge at 1000 rpm for 30 seconds, then add 5 μL of 3 times the final concentration (1x as the final concentration) of the Tb antibody (fluorescent donor) to the 384-well experimental plate, centrifuge at 1000 rpm for 30 seconds, and finally add 5 μL of 3 times the final concentration of Tracer (fluorescent acceptor) to the 384-well experimental plate, centrifuge at 1000 rpm for 30 seconds. High-signal control group: Without the compound compared to the experimental group. Low-signal control group: Without the compound, TYK2 JH2, and JAK1 JH2 pseudokinase compared to the experimental group.

[0228] 6. Incubate at room temperature for 60 minutes and overnight at 4°C.

[0229] 7. Read the fluorescence signal ratio of 520 nm / 495 nm with an Envision microplate reader (PerkinElmer).

[0230] 4. Experimental data analysis

[0231] The test data was processed and analyzed using the software XLfit developed by IDBS and integrated into the Microsoft Excel environment. First, the average reaction signals of the high-signal control wells and the low-signal control wells were calculated separately. Then, the reaction inhibition rate of each compound well was calculated according to the formula "Inhibition rate % of single well = 100 - (Average value of high-signal control group - Signal value of experimental group) / (Average value of high-signal control group - Average value of low-signal control group)". Then, the concentration and corresponding inhibition rate data were imported into the XLfit software. Using the Dose Response One Site 205 model in the software, a four-parameter method was used to fit the inhibition rate-concentration curve, and the IC 50 value was calculated.

[0232] Table 3 Inhibitory activities of the compounds of the present invention against TYK2 JH2 and JAK1 JH2 pseudokinases

[0233]

[0234] The TYK2 JH2 kinase inhibitory activity of the positive drug BMS-986165 (IC 50 = 0.10 nM), JAK1 JH2 (IC 50 > 298.5). The inhibitory activities of the compounds in the examples in Table 3 are close to those of the positive drug, and some are even better. Conclusion: The compounds of the present invention have good inhibitory effects on TYK2 JH2.

[0235] II. Pharmacodynamic evaluation of the compounds inhibiting the secretion of IFNγ by NK92 cells

[0236] 1. Experimental purpose: To test the pharmacodynamic evaluation of the compounds inhibiting the secretion of IFNγ by NK92 cells.

[0237] 2. The experimental reagents and experimental instruments used are as follows:

[0238] (1) Experimental reagents

[0239] Material Supplier Cat No. NK92 Procell CL-0530 NK92 Special medium Procell CM-0530 DMSO Sigma D4540-1L human IL-2 ACRO IL2-H5215 human IL-12 ACRO IL2-H5210 IFN-γ ELISA Kit Sizhengbai CHE0017 PBS Solarbio P1020 96-well Bottom Corning 3599

[0240] (2) Experimental instruments

[0241]

[0242]

[0243] 3. Experimental steps:

[0244] (1)Drug preparation method: The test compound was dissolved in DMSO to prepare a 20 mM stock solution, which was stored at -20 °C for later use. After diluting the stock solution 10-fold with DMSO to a 2 mM solution, it was further diluted with the culture medium to an initial concentration of 105 nM, and then serially diluted 3-fold with the culture medium containing 5% DMSO to obtain a concentration gradient of 105 nM, 33333.3 nM, 11111.1 nM, 3703.70 nM, 1234.57 nM, 411.523 nM, 137.174 nM, 45.7247 nM, 15.2416 nM; 10 μL of the drug at the above concentrations was added to a 96-well plate to obtain a final concentration of 104 nM, 3333.3 nM, 1111.1 nM, 370.4 nM, 123.5 nM, 41.1 nM, 13.7 nM, 4.6 nM, 1.52 nM.

[0245] (2) Resuscitate and culture NK92 cells. Sixteen hours before the experiment, change the culture medium to a medium without IL-2. Centrifuge and resuspend the cells with the culture medium containing IL-12, plate 90 μL at a density of 20,000 cells / well in a 96-well plate, add 10 μL of the test sample, incubate for 24 h, centrifuge and take the supernatant, and detect the concentration of IFNγ in the supernatant by ELISA to calculate the IC 50 value. Some experimental results are shown in Table 4.

[0246] Table 4: Inhibitory effect of the compounds of the present invention on the secretion of IFN-γ by rhIL-12-induced NK92 cells

[0247] Example compound <![CDATA[IC 50 (nM)]]> Example compound <![CDATA[IC 50 (nM)]]> Example 1 6.828 Example 5 7.967 Example 2 5.265 Example 6 3.655 Example 3 4.506 Example 7 7.223 Example 4 6.798 Example 8 4.862

[0248] The inhibitory effect of the positive drug BMS-986165 on the secretion of IFN-γ by rhIL-12-induced NK92 cells (IC50 = 4.464). The inhibitory activity of the compounds in Example in Table 4 is close to that of the positive drug, and some are even better. Conclusion: The compounds of the present invention have a good inhibitory effect on the secretion of IFN-γ by rhIL-12-induced NK92 cells.

[0249] In the description of this specification, the description referring to terms such as "one embodiment", "some embodiments", "some implementation schemes", "example", "specific example" or "some examples" means that the specific features, structures, materials or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in a suitable manner in any one or more embodiments or examples. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments, implementation schemes or examples described in this specification and the features of different embodiments, implementation schemes or examples.

[0250] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention without departing from the principles and spirit of the present invention. The scope of the present invention is defined by the claims and their equivalents.

Claims

1. A pyrimidopyrazole compound, characterized in that: It is a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I), in, R 1 is C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-6 cycloalkyl or 3- to 6-membered heterocyclic group; wherein said R 1 is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, -C(=O)OC 1-6 alkyl, -C(=O)C 1-6 alkyl, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2; R 2 is H, C 1-6 alkyl, C 3-7 cycloalkyl or a 3- to 7-membered heterocyclic group, wherein said R 2 is independently optionally substituted by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, CN, OH, NH2, COOH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 hydroxyalkyl and -C(=O)NH2; R 3 is C 1-6 alkyl, C 3-7 cycloalkyl, a 3- to 7-membered heterocyclic group, C 6-10 aryl or a 5- to 10-membered heteroaryl, wherein said R 3 is optionally substituted by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, CN, OH, NH2, COOH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 hydroxyalkyl, -C(=O)OC 1-6 alkyl, -C(=O)C 1-6 alkyl, -S(=O)2C 1-6 alkyl, -S(=O)C 1-6 alkyl, -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NH(C 1-6 alkyl) and -N(C 1-6 alkyl)2.

2. The pyrimidine-pyrazole compound according to claim 1, wherein R 2 is H, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2-epoxyethyl, 1,4-dioxanyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothiopyranyl, piperidinyl, piperazinyl, morpholinyl or hexahydropyrimidinyl, wherein the R 2 is optionally substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, CN, OH, NH2, COOH, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -CH(CH3)2OH, -(CH2)3CH2OH and -C(=O)NH2.

3. The pyrimidine-pyrazole compound according to claim 1, wherein R 3 is -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -CH2CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-oxabicyclo[3.2.0]heptyl, bicyclo[3.1.0]hexyl, 3-oxabicyclo[3.1.0]hexyl, 2-oxaspiro[3.3]heptane, 1,2-epoxyethyl, 1,4-dioxanyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothiopyranyl, piperidinyl, piperazinyl, morpholinyl, hexahydropyrimidinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, thiopyranyl, pyridyl, pyrimidinyl or pyrazinyl, wherein said R 5 and R 6 are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, CN, OH, NH2, COOH, -CD3, -CH3, -CH2CH3, -CD2CD3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -CH2OH, -CH2CH2OH, -(CH2)2CH2OH, -CH(CH3)2OH, -(CH2)3CH2OH, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)O(CH2)2CH3, -C(=O)OCH(CH3)2, -C(=O)CH3, -C(=O)CH2CH3, -S(=O)2CH3, -S(=O)2CH2CH3, -S(=O)CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -NHCH3, -NHCH2CH3, -N(CH3)2 and -N(CH2CH3)2.

4. The pyrimidopyrazole compound according to claim 1, characterized in that wherein said R 1 is optionally substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -CF3, -CHF2, -CH2F, -CH2CF3, -CCl3, -CH2Cl3, -CH2CH2F, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OCH(CH3)2, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)OCH(CH3)2, -NH(CH2CH3), -N(CH3)(CH2CH3) and -N(CH3)2.

5. The pyrimidine-pyrazole compound according to claim 1, wherein It is a compound of the following structure, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, 6. The method for preparing the pyrimidopyrazole compound according to any one of claims 1 to 5, characterized in that: The synthetic route is as follows: Among them, R 1 , R 2 , R 3 are defined and represent groups as in claims 1-5.

7. The preparation method according to claim 6, characterized in that, The method comprises the following preparation steps: (1) Add raw material a and dimethyl 1,3-malonate to ethanol, add sodium ethoxide in batches while stirring, react at 80°C for 15 hours, stop the reaction, concentrate the reaction solution, add water to dissolve, cool to 0°C, adjust the pH to acidic with acid, precipitate solid, filter, rinse the filter cake with water, and dry to obtain b; (2) Add acetonitrile to b, heat to 50°C under nitrogen protection, add phosphorus oxychloride, and then add pyridine dropwise. After the addition is complete, heat to 100°C to react. The reaction is complete after 3 hours, cool to room temperature, add ice water, and extract with dichloromethane. The organic phase is concentrated and purified by silica gel column chromatography to obtain c; (3) c and methylamine hydrochloride were added to acetonitrile, and then N,N-diisopropylethylamine was added. The reaction was carried out at 80°C for 2 h. Water was added, and the mixture was extracted with dichloromethane. The organic phase was concentrated and purified by thin layer preparative chromatography to obtain d. (4) Add N,N-dimethylformamide to d, dissolve it, and then dropwise add phosphorus oxychloride diluted in DMF. After the addition is complete, react at 70°C for about 8 hours, stop the reaction, cool to 0°C, add water, adjust the pH to alkaline with alkali, extract with ethyl acetate, combine the organic phases, concentrate, and purify by silica gel column chromatography to obtain e; (5) Add N,N-dimethylformamide to e and cesium carbonate, cool to -5°C, add dropwise a DMF dilution of 4-methoxybenzyl chloride, keep warm for 10 minutes after the addition is complete, move to room temperature for reaction, react for 20 hours, stop the reaction, cool to 0°C, add ice water, extract with ethyl acetate, combine the organic phases, concentrate, and purify by silica gel column chromatography to obtain f; (6) Add tert-butanol to f, then add 2-methyl-2-butene and sodium chlorite, dissolve anhydrous sodium dihydrogen phosphate in water, add to the reaction solution, stir for 10 minutes after addition, move to room temperature to react for 1 hour, then heat to 50°C and react for about 10 hours, stop the reaction, concentrate under reduced pressure, add ice water, adjust the pH to acidic with acid, extract with dichloromethane, combine the organic phases, and purify by column chromatography to obtain g; (7) Dichloromethane was added to g, and j and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added, and the mixture was reacted at room temperature for 10 h. The mixture was washed with water, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain h. (8) h, k, BrettPhos-G3-Pd, BrettPhos and cesium carbonate were added to a bottle under nitrogen protection, 1,4-dioxane was added, and the reaction was carried out at 110°C for 3 hours to stop the reaction. The reaction was cooled to room temperature, washed with water, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain i; (9) Dichloromethane was added to i, and then trifluoroacetic acid was slowly added dropwise. The reaction was allowed to proceed at room temperature. After the reaction was completed, the temperature was lowered to 0°C, water was added, and the pH was adjusted to a weakly alkaline state with potassium phosphate solution. The aqueous phase was extracted once with dichloromethane, and the organic phases were combined, concentrated, and purified by column chromatography to obtain I.

8. A pharmaceutical composition, characterized in that, The invention comprises the pyrimidopyrazole compound according to any one of claims 1 to 5, and a pharmaceutically acceptable carrier and adjuvant.

9. Use of the pyrimidopyrazole compound according to any one of claims 1 to 5 or the pharmaceutical composition according to claim 8 in the preparation of a medicament for preventing, treating or alleviating TYK2-related diseases.

10. The application according to claim 9, characterized in that, The TYK2-related diseases include rheumatoid arthritis, psoriasis, diabetes, ankylosing spondylitis, vitiligo, atopic dermatitis, lupus, multiple sclerosis, psoriasis, Crohn's disease, ulcerative colitis, cancer, transplant rejection or neurological disorders.

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