Preparation method and application of 1, 3, 5-triazine derivative

Abstract

The invention provides a compound which is used as a TYK2 inhibitor and has a brand new structure, a preparation method of the compound and application of the compound to treatment of TYK2-mediated diseases. Experiments prove that the compounds have a relatively strong inhibition effect on TYK2 kinase and can be used as promising compounds for treating TYK2-mediated diseases.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically, to a method for preparing compounds as TYK2 inhibitors, particularly 1,3,5-triazine derivatives, and their uses. Background Technology

[0002] Tyrosine kinase 2 (TYK2) is a member of the Janus kinase family (JAK), which also includes three other kinase targets: JAK1, JAK2, and JAK3.

[0003] Janus kinase (JAK) plays an important role in immune regulation by regulating the signal transduction of cytokines such as interleukin (IL) and interferon (IFN) through the JAK-signal transduction and activating transcription factor (STAT) signaling pathway.

[0004] Known small-molecule JAK inhibitors are all site-directed inhibitors. They bind to the ATP-binding site of the catalytic domain (also known as the JH1 domain) of the JAK protein, inhibiting the catalytic activity of the kinase by blocking the binding of ATP to the JAK protein, thereby inhibiting the signal transduction of related pathways.

[0005] TYK2 is a non-receptor tyrosine kinase that mediates immune signaling, primarily acting as a signaling pathway driven by interleukins IL-23, IL-12, and type I interferon. IL-23, IL-12, and type I interferon are natural cytokines associated with inflammation and immune responses. These targets have been clinically demonstrated to be involved in many immune system-related diseases, including psoriasis, psoriatic arthritis, cutaneous lupus erythematosus, ulcerative colitis, and Crohn's disease. Selectively targeting and inhibiting TYK2 without affecting other JAK family enzymes may alleviate inflammatory responses and maintain protective immune function. The main indications for TyK2 inhibitors are psoriasis, systemic lupus erythematosus (SLE), ulcerative colitis, and other immune-inflammatory diseases.

[0006] Because the JAK family mediates the signaling of multiple cytokines, and different receptors are associated with different JAK subtypes, comprehensive inhibition of the JAK family can lead to a variety of side effects. First-generation JAK inhibitors, targeting multiple JAK family targets, may affect more than 57 cytokines. Clinical trials of multi-target JAK inhibitors have reported dose-related safety issues, including increased risk of infection, lymphopenia, thromboembolism, dyslipidemia, and altered liver function metabolism, and even an increased risk of malignancy. The FDA has required the first-generation JAK inhibitors marketed by Pfizer and Eli Lilly to include boxed warnings in their product information, clearly stating that taking the drug increases the risk of infection, pulmonary embolism, and even death.

[0007] TYK2 inhibitors can selectively bind to the TYK2 regulatory domain, strongly and specifically inhibiting TYK2 activation without affecting the function of other JAK family targets, and can effectively reduce adverse events caused by JAK kinase 1-3 inhibition.

[0008] By enhancing specificity, TYK2 is expected to effectively reduce toxic side effects while maintaining efficacy, representing a future direction and trend for drug optimization.

[0009] Although some small TYK2 inhibitors have been disclosed, there are currently few TYK2 inhibitors that have been developed and marketed. Therefore, it is still urgent to develop new compounds with market potential and better efficacy and pharmacokinetic results. Summary of the Invention

[0010] The purpose of this invention is to provide a novel TYK2 inhibitor compound, a method for preparing the compound, and its use in treating TYK2-mediated diseases.

[0011] In a first aspect, the present invention provides a compound of formula (I) as follows, wherein the compound is a stereoisomer, a geometric isomer, a tautomer, a pharmaceutical salt, a prodrug, a hydrate, a solvate, or an isotopically labeled analogue.

[0012]

[0013] Where X1 and X2 are respectively N or CR x And X1 and X2 are not both N at the same time;

[0014] R X For H, deuterium, or optional substitution: C 1-4 Alkyl, C 2-6 alkenyl, C 1-4 oxane, C 1-4 Thionyl, C 3-6 cycloalkyl, C 3-6Cycloalkenyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2;

[0015] R1 and R2 are independently H, deuterium, and optionally substituted C, respectively. 1-6 Alkyl, C 1-6 oxane, C 2-6 alkenyl, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, C 4-6 Heterocyclic group; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo group, CN, OH, NH2;

[0016] R3 is

[0017] Ring P is C 6-12 Aryl, C 5-12 heteroaryl, C 5-12 Unsaturated heterocyclic groups;

[0018] Ring G is C 6-12 Aryl, C 5-12 heteroaryl, C 5-12 Unsaturated heterocyclic groups, C 4-12 Heterocyclic groups;

[0019] R P For independent deuterium, halogen, oxo group, or optional substitution: C 1-4 Alkyl, C 1-4 oxane, C 2-6 alkenyl, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, C 4-6 Heterocyclic group; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo group, CN, OH, NH2;

[0020] R G For independent deuterium, halogen, oxo group, or optional substitution: C 1-4 Alkyl, C 1-4 oxane, C 2-6 alkenyl, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, C 4-6 Heterocyclic group, phenyl, C 5-6 heteroaryl, C 5-6 Unsaturated heterocyclic group; wherein optional substitution refers to being replaced by one or more groups selected from deuterium, halogen, oxo group, -CN, -OH, -NHR g -C(=O)R gg C 1-4 Alkyl, C 1-4 Oxyalkyl, halogenated C1-4 Alkyl, Halogenated C 1-4 Substituents of oxaalkyl groups;

[0021] R g For H, deuterium, or optional substitution: C 1-4 Alkyl, C 3-6 Cycloalkyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2;

[0022] R gg For optional substitution: C 1-4 Alkyl, C 1-4 oxane, C 2-6 Alkenyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2;

[0023] R4 is

[0024] Ring A is C 4-6 cycloalkyl, C 3-6 Cycloalkenyl, C 4-6 Heterocyclic groups;

[0025] R A Independently, it can be deuterium, halogen, oxo group, or optionally substituted: C 1-4 Alkyl, C 1-4 oxane, C 2-6 Alkenyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2;

[0026] L represents bond, O, NR a ;

[0027] R a For H, deuterium, or optional substitution: C 1-4 Alkyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2;

[0028] a is 1, 2, or 3;

[0029] p is 1, 2, or 3;

[0030] g is 0, 1, 2, or 3;

[0031] The heteroatoms in the heterocyclic group and heteroaryl group are independently selected from O, N or S, and the number of heteroatoms is preferably 1, 2 or 3.

[0032] In a preferred embodiment of the present invention, X1 and X2 are both CR x ,

[0033] In a preferred embodiment of the present invention, X1 is N and X2 is CR. x ;

[0034] In a preferred embodiment of the present invention, X1 is CR x X2 is N;

[0035] In a preferred embodiment of the present invention, R X For H, deuterium, or optional substitution: C 1-4 Alkyl, C 2-6 Alkenyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2;

[0036] In a preferred embodiment of the present invention, R X For H and deuterium;

[0037] In a preferred embodiment of the present invention, R X For H;

[0038] In a preferred embodiment of the present invention, both X1 and X2 are CH;

[0039] In a preferred embodiment of the present invention, X1 is N and X2 is CH;

[0040] In a preferred embodiment of the present invention, X1 is CH and X2 is N;

[0041] In a preferred embodiment of the present invention, R1 and R2 are independently H, deuterium, or optionally substituted C. 1-6 Alkyl, C 2-6 alkenyl, C 3-6 Cycloalkyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2;

[0042] In a preferred embodiment of the present invention, R1 and R2 are independently H, deuterium, or optionally substituted C. 1-4 Alkyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2;

[0043] In a preferred embodiment of the present invention, R1 and R2 are independently H, deuterium, methyl, ethyl, deuterated methyl, and deuterated ethyl, respectively.

[0044] In a preferred embodiment of the present invention, R1 is methyl or deuterated methyl;

[0045] In a preferred embodiment of the present invention, R2 is H;

[0046] In a preferred embodiment of the present invention, ring P is a phenyl group, C 5-6 heteroaryl, C 5-6 Unsaturated heterocyclic groups;

[0047] In a preferred embodiment of the present invention, ring P is phenyl, a 6-membered heteroaryl, or a 6-membered unsaturated heterocyclic group;

[0048] In a preferred embodiment of the present invention, ring P is...

[0049] In a preferred embodiment of the present invention, ring G is a phenyl or C. 5-6 heteroaryl, C 5-6 Unsaturated heterocyclic groups, C 4-6 Heterocyclic groups;

[0050] In a preferred embodiment of the present invention, ring G is C. 5-6 Mixed aromatics;

[0051] In a preferred embodiment of the present invention, ring G is...

[0052] In a preferred embodiment of the present invention, R P For independent deuterium, halogen, oxo group, or optional substitution: C 1-4 Alkyl, C 1-4 Oxyalkyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2;

[0053] In a preferred embodiment of the present invention, R P For independent deuterium, halogen, oxo group, or optional substitution: C 1-3 Alkyl, C 1-3 Oxyalkyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2;

[0054] In a preferred embodiment of the present invention, R P The independent groups are F, oxo group, and methoxy group;

[0055] In a preferred embodiment of the present invention, R G For independent deuterium, halogen, or optional substitution: C 1-4 Alkyl, C 1-4 oxane, C 2-6 alkenyl, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, C 4-6 Heterocyclic group, C 5-6Heteroaryl groups; wherein optional substitution refers to being replaced by one or more groups selected from deuterium, halogen, oxo group, -CN, -OH, -NHR g -C(=O)R gg C 1-3 Alkyl, C 1-3 Oxyalkyl, halogenated C 1-3 Alkyl, Halogenated C 1-3 Substituents of oxaalkyl groups;

[0056] In a preferred embodiment of the present invention, R G For independent deuterium, F, Cl, Br, or optionally substituted C 1-4 Alkyl, C 1-4 oxane, C 3-6 cycloalkyl, C 4-6 Heterocyclic group, C 5-6 Heteroaryl groups; wherein optional substitution refers to being replaced by one or more groups selected from deuterium, F, Cl, oxo, -CN, -OH, -NHR. g -C(=O)R gg C 1-3 Alkyl, C 1-3 Oxyalkyl, halogenated C 1-3 Alkyl, Halogenated C 1-3 Substituents of oxaalkyl groups;

[0057] In a preferred embodiment of the present invention, R g For H, deuterium, or optional substitution: C 1-4 Alkyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2;

[0058] In a preferred embodiment of the present invention, R g For H, deuterium, methyl, ethyl;

[0059] In a preferred embodiment of the present invention, R g It is methyl;

[0060] In a preferred embodiment of the present invention, R gg For optional substitution: C 1-4 Alkyl, C 2-6 Alkenyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2;

[0061] In a preferred embodiment of the present invention, R gg Optional substitution: methyl, ethyl, vinyl, propenyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2;

[0062] In a preferred embodiment of the present invention, R gg The methyl group is optionally substituted;

[0063] In a preferred embodiment of the present invention, R G For independent F, methyl, deuterated methyl,

[0064] In a preferred embodiment of the present invention, R3 is...

[0065] In a preferred embodiment of the present invention, ring A is C. 4-6 cycloalkyl, C 4-6 Heterocyclic groups;

[0066] In a preferred embodiment of the present invention, ring A is cyclobutyl, cyclopentyl, oxacyclobutyl, tetrahydrofuranyl, or tetrahydropyrroleyl;

[0067] In a preferred embodiment of the present invention, R A Independently, for deuterium, halogens, or optional substitutions: C 1-4 Alkyl, C 1-4 Oxyalkyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2;

[0068] In a preferred embodiment of the present invention, R A Independently, it can be deuterium, F, Cl, Br, or optionally substituted: C. 1-3 Alkyl, C 1-3 Oxyalkyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2;

[0069] In a preferred embodiment of the present invention, R A It is F, methyl, or methoxy;

[0070] In a preferred embodiment of the present invention, R4 is...

[0071] In a preferred embodiment of the present invention, R4 is...

[0072] In a preferred embodiment of the present invention, R4 is...

[0073] In a preferred embodiment of the present invention, L represents bond, -O, or -NR. a- Optional replacement: C 1-4 Alkylene, C 1-4 Heteroalkyl; wherein optional substitution refers to being substituted with one or more radicals selected from deuterium, halogen, oxo group, -CN, -OH, -NH2, C 1-3 Alkyl, Halogenated C 1-3 Substituents of alkyl groups;

[0074] In a preferred embodiment of the present invention, L represents bond, -O, or -NR. a - Optional replacement: C 1-4 Alkylene; wherein optional substitution refers to being substituted with one or more radicals selected from deuterium, halogen, oxo group, -CN, -OH, -NH2, C 1-3 Alkyl, Halogenated C 1-3 Substituents of alkyl groups;

[0075] In a preferred embodiment of the present invention, L is -NR a -;

[0076] In a preferred embodiment of the present invention, R a For H, deuterium, or optional substitution: C 1-4 Alkyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2;

[0077] In a preferred embodiment of the present invention, R a For H and deuterium;

[0078] In a preferred embodiment of the present invention, R a For H;

[0079] In a preferred embodiment of the present invention, L is -NH-;

[0080] In a preferred embodiment of the present invention, a is 1;

[0081] In a preferred embodiment of the present invention, p is 1 or 2;

[0082] In a preferred embodiment of the present invention, p is 1;

[0083] In a preferred embodiment of the present invention, g is 0, 1, or 2;

[0084] In a preferred embodiment of the present invention, g is 0 or 1;

[0085] The present invention also provides a compound represented by formula (II) below, wherein the stereoisomer, geometric isomer, tautomer, pharmaceutical salt, prodrug, hydrate, solvate, or isotopically labeled analogue of the compound,

[0086]

[0087] Among them, X1, X2, R1, R2, ring P, ring G, ring A, R P R G R A p, g, a are as described in compound (I);

[0088] The present invention also provides a compound represented by formula (Ⅲ) below, wherein the stereoisomer, geometric isomer, tautomer, pharmaceutical salt, prodrug, hydrate, solvate, or isotopically labeled analogue of the compound,

[0089]

[0090] Among them, X1, X2, R1, ring P, ring G, ring A, R P R G R A p, g, a are as described in compound (I);

[0091] The present invention also provides compounds represented by formulas (Ⅳ-A), (Ⅳ-B), and (Ⅳ-C), wherein the stereoisomers, geometric isomers, tautomers, pharmaceutical salts, prodrugs, hydrates, solvates, or isotopically labeled analogs of the compounds are provided.

[0092]

[0093] Among them, R1, ring P, ring G, ring A, and R P R G R A p, g, a are as described in compound (I);

[0094] The present invention also provides compounds represented by formulas (V-a), (V-b), (V-c), (V-d), (V-e), (V-f), (V-g), (V-h), and (V-i), wherein the stereoisomers, geometric isomers, tautomers, pharmaceutical salts, prodrugs, hydrates, solvates, or isotopically labeled analogs of the compounds are provided.

[0095]

[0096]

[0097] Among them, R1, ring G, ring A, and R P R G R A p, g, a, as described in compound (Ⅰ);

[0098] The present invention further provides compounds represented by formulas (Ⅵ-a), (Ⅵ-b), (Ⅵ-c), (Ⅵ-d), (Ⅵ-e), (Ⅵ-f), (Ⅵ-g), (Ⅵ-h), and (Ⅵ-i), wherein the stereoisomers, geometric isomers, tautomers, pharmaceutical salts, prodrugs, hydrates, solvates, or isotopically labeled analogs of the compounds are provided.

[0099]

[0100] Among them, R1, ring G, ring A, and R G R A p, g, a, as described in compound (I).

[0101] The compounds described in this invention, and their stereoisomers, geometric isomers, tautomers, pharmaceutical salts, prodrugs, hydrates, solvates, or isotopically labeled analogs, are selected from the following compounds:

[0102]

[0103]

[0104]

[0105] The object of the present invention also includes providing a method for preparing compounds of formulas (I), (II), (III), (IV), (IV-A), (IV-B), (IV-C), (V-a), (V-b), (V-c), (V-d), (V-e), (V-f), (V-g), (V-h), (V-i), (VI-a), (VI-b), (VI-c), (VI-d), (VI-e), (VI-f), (VI-g), (VI-h), and (VI-i), stereoisomers, tautomers, or mixtures thereof of the compounds, or pharmaceutically acceptable salts of the compounds.

[0106] The compound of the general formula can be prepared by a variety of methods, including but not limited to the following:

[0107] Option A:

[0108]

[0109] 1. Starting compound A1 reacts with ethoxycarbonyl isocyanate via a condensation reaction to give A2; 2. A2 undergoes a cyclization reaction in sodium ethoxide ethanol solution to give A3; 3. A3 reacts with phosphorus oxychloride (POCl3) for chlorination to give A4; 4. A4 undergoes a substitution reaction with a substituted amino group to give A5; 5. A5 undergoes a substitution reaction with an aromatic amine or hydroxyl group to give A6; 6. The ester group in A6 is hydrolyzed to give A7; 7. A7 undergoes a condensation reaction with a substituted amino group to give the compound of formula (I).

[0110] Option B:

[0111]

[0112] 1. Starting compound B1 reacts with ethyl isothiocyanate to give B2; 2. B2 is cyclized with a base to give B3; 3. B3 is methylated to give B4; 4. B4 is chlorinated with phosphorus oxychloride (POCl3) to give B5; 5. B5 undergoes a substitution reaction with a substituted amino group to give B5; 6. B6 undergoes an oxidation reaction with an oxidizing agent to give B7; 7. B7 undergoes a substitution reaction with an aromatic amine or hydroxyl group to give B8; 8. The ester group in B8 is hydrolyzed to give B9; 9. B9 undergoes a condensation reaction with a substituted amino group to give the compound of formula (I).

[0113] The present invention also provides a pharmaceutical composition comprising the compound shown in the present invention, a stereoisomer, geometric isomer, tautomer, pharmaceutical salt, prodrug, hydrate, solvate, or isotopically labeled analogue of the compound.

[0114] The present invention also provides a pharmaceutical composition comprising the compound shown in the present invention, a stereoisomer, geometric isomer, tautomer, pharmaceutical salt, prodrug, hydrate, solvate or isotopically labeled analog of the compound, or a pharmaceutically acceptable salt of the compound and a pharmaceutically acceptable excipient.

[0115] The object of the present invention also includes providing the compound shown in the present invention, a method for providing stereoisomers, geometric isomers, tautomers, pharmaceutical salts, prodrugs, hydrates, solvates or isotopically labeled analogs of the compound, or the use of pharmaceutically acceptable salts of the compound in the preparation of medicaments for treating or preventing TYK2-mediated diseases.

[0116] In some embodiments, the TYK2-mediated disease is an immune-related disease or an inflammatory disease.

[0117] The object of the present invention also includes providing a method for preventing and / or treating TYK2-mediated diseases, comprising administering to a patient a therapeutically effective dose of a compound of the present invention, a stereoisomer, geometric isomer, tautomer, pharmaceutical salt, prodrug, hydrate, solvate, or isotopically labeled analog of the compound, or a pharmaceutically acceptable salt of the compound or a pharmaceutical composition of the present invention.

[0118] The compounds shown in this invention, stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts of the compounds may be used additionally to treat or prevent TYK2-mediated diseases such as psoriasis, lupus, inflammatory bowel disease, arthritis, and psoriasis.

[0119] When the compounds of the present invention, stereoisomers, geometric isomers, tautomers, pharmaceutical salts, prodrugs, hydrates, solvates or isotopically labeled analogs of the compounds, or pharmaceutically acceptable salts of the compounds are administered in combination with other inhibitors for the treatment of diseases such as autoimmune diseases or inflammation.

[0120] The beneficial effects of this invention are:

[0121] This invention designs a class of novel compounds, providing a new direction for the development of TYK2 inhibitor drugs. In vitro biochemical and cellular enzyme activity inhibitory studies show that these compounds have strong inhibitory effects on TYK2 enzymes with good selectivity. Therefore, they can be considered promising compounds for the treatment of TYK2-mediated diseases. Detailed Implementation

[0122] [Terminology Definition]

[0123] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight-chain or branched group containing 1 to 20 carbon atoms, preferably containing 1 to 10 carbon atoms (i.e., C10). 1-10 Alkyl groups, more preferably containing 1-8 carbon atoms (C64- ... 1-8 Alkyl groups, more preferably containing 1-6 carbon atoms (i.e., C64-C ... 1-6 Alkyl), for example, "C 1-6 "Alkyl" refers to a group that is alkyl and has 1 to 6 carbon atoms in its carbon chain (specifically, 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.

[0124] Unless otherwise specified, the term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one double bond. Alkenyl groups may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C2H2O). 2-10 Alkenyl), further preferably containing 2-8 carbon atoms (C 2-8 Alkenyl), more preferably containing 2-6 carbon atoms (i.e., C14-C2 ... 2-6 alkenyl), 2-5 carbon atoms (i.e., C) 2-5 alkenyl), 2-4 carbon atoms (i.e., C) 2-4 alkenyl), 2-3 carbon atoms (i.e., C) 2-3 Alkenyl), 2 carbon atoms (i.e., C2 alkenyl), for example "C 2-6"Alkenyl" refers to a group that is alkenyl and has 2 to 6 carbon atoms in its carbon chain (specifically 2, 3, 4, 5, or 6). Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1,3-butadienyl.

[0125] Unless otherwise specified, the term "alkynyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one triple bond. The alkynyl group may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C2H2O). 2-10 Alkyne group), further preferably containing 2-8 carbon atoms (C 2-8 Alkyne group), more preferably containing 2-6 carbon atoms (i.e., C64-C ... 2-6 acetylenic group), 2-5 carbon atoms (i.e., C 2-5 acetylsyl group), 2-4 carbon atoms (i.e., C44) 2-4 acetylsyl group), 2-3 carbon atoms (i.e., C64) 2-3 Alkynyl group), 2 carbon atoms (i.e., C2 alkynyl group), for example "C 2-6 "Alynyl" refers to a group that is alkynyl and has 2 to 6 carbon atoms in its carbon chain (specifically 2, 3, 4, 5, or 6). Non-limiting examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl.

[0126] Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms, preferably containing 3 to 12 carbon atoms (i.e., C64-C64). 3-12 cycloalkyl), more preferably containing 3-10 carbon atoms (C 3-10 Cycloalkyl groups, more preferably 3-6 carbon atoms (C 3-6 cycloalkyl groups), 4-6 carbon atoms (C 4-6 cycloalkyl groups), 5-6 carbon atoms (C 5-6 (Cycloalkyl). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, etc.

[0127] Unless otherwise specified, the term "oxaalkyl" refers to an alkyl residue in which one or more carbon atoms (and associated hydrogens) are replaced by oxygen, such as "alkoxy" or "alkoxyalkyl". Examples include methoxy, ethoxy, propoxy, methoxypropyl, etc. The term oxaalkyl means as understood in the art [see Nomenclature and Index of Chemical Substances for Chemical Extraction, published by the American Chemical Society, 196, but not limited to 127(a)], that is, it refers to a compound in which oxygen is bonded to its adjacent atoms by a single bond (forming an ether bond); it does not refer to the double oxygen bond found in the carbonyl group.

[0128] Unless otherwise specified, the terms "thioalkyl" and "azialkyl" refer to the replacement of oxygen with sulfur or nitrogen in the term "oxaalkyl".

[0129] Unless otherwise specified, "alkoxy" refers to -O-alkyl, and the alkyl group is defined as above, i.e., containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, and even more preferably 1 to 6 carbon atoms (specifically 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, etc.

[0130] Unless otherwise specified, the terms "halogen" or "halogenated" refer to F, Cl, Br, and I. The term "halogenated alkyl" refers to an alkyl group as defined above in which one, two, or more hydrogen atoms, or all hydrogen atoms, are replaced by a halogen. Representative examples of halogenated alkyl groups include CCl3, CF3, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, and CF2CF3.

[0131] Unless otherwise specified, the term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cyclic hydrocarbon substituent, which is a non-aromatic structure containing 3 to 20 ring atoms, wherein one, two, three, or more ring atoms are selected from N, O, or S, and the remaining ring atoms are C. Preferably, it contains 3 to 12 ring atoms, more preferably 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 4 to 6 ring atoms, or 5 to 6 ring atoms. The number of heteroatoms is preferably 1 to 4, more preferably 1 to 3 (i.e., 1, 2, or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, pyranyl, etc. Bicyclic or polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0132] Unless otherwise specified, the term "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic carbocyclic system containing 6 to 16 carbon atoms, or 6 to 14 carbon atoms, or 6 to 12 carbon atoms, or 6 to 10 carbon atoms, preferably 6 to 10 carbon atoms. The term "aryl" may be used interchangeably with the term "aromatic ring." Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthraceneyl, phenanthryl, or pyrene.

[0133] Unless otherwise specified, the term "heteroaryl" refers to an aromatic monocyclic, bicyclic, or polycyclic cyclic system containing a 5-16 member structure, or a 5-14 member structure, a 5-12 member structure, a 5-10 member structure, a 5-8 member structure, or a 5-6 member structure, wherein one, two, three, or more ring atoms are heteroatoms and the remaining atoms are carbon atoms, the heteroatoms being independently selected from O, N, or S, and the number of heteroatoms is preferably one, two, or three. Examples of heteroaryl groups may include, but are not limited to, furanyl, thiophene, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiazolyl, pyrrole, pyrazolyl, imidazole, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purine, indoleyl, isoindoleyl, indazoleyl, benzofuranyl, benzothiophene, benzopyridyl, benzopyrimidinyl, and benzene. Pyrazinyl, benzimidazolyl, benziphthalazolyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridyl, etc.

[0134] Unless otherwise specified, the terms "pharmaceutically acceptable salt," "medicinal salt," or "medicinal salt" refer to salts that, within the bounds of reasonable medical judgment, are suitable for contact with mammalian, particularly human, tissues without excessive toxicity, irritation, allergic reactions, etc., and for which a reasonable benefit / risk ratio is appropriate. Medically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of this invention, or solely by reacting a free base or free acid with a suitable reagent, as outlined below. For example, the free base function can react with a suitable acid.

[0135] Unless otherwise specified, the term "solvent" refers to the physical association of the compound of the present invention with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. The solvent molecules in the solvate may be present in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric solvent molecules. "Solvent" encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0136] Unless otherwise specified, the term "isotope-labeled analog" refers to isotope-labeled molecules of compounds of formulas I to II, thereby providing isotope-labeled analogs that may have improved pharmacological activity. The isotopes commonly used for isotope labeling are: hydrogen isotopes, 2 H and 3 H; Carbon isotopes: 11 C, 13 C and 14 C; Chlorine isotopes: 35 Cl and 37 Cl; Fluorine isotopes: 18 F; Iodine isotopes: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. Especially deuterium. 3 H and carbon 13 C, because they are easy to label and convenient to detect, are more widely used. Some heavy isotopes, such as deuterium (… 2 Substitution with H can enhance metabolic stability and prolong the half-life, thereby achieving the goal of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques, just like non-isotope-labeled compounds.

[0137] Unless otherwise specified, the term "prodrug" refers to a drug that is converted into a parent drug in the body. Prodrugs are often useful because, in some cases, they may be easier to administer than the parent drug. For example, they can be bioavailable via oral administration, whereas the parent drug cannot. Prodrugs also have increased solubility in pharmaceutical compositions compared to the parent drug. An example of a prodrug, but not limited to, is any compound of formula (I) that is administered as an ester ("prodrug") to facilitate transmembrane transport, where water solubility is detrimental to migration but beneficial once inside the cell, and which is subsequently metabolized and hydrolyzed into a carboxylic acid, the active entity. Another example of a prodrug can be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to exhibit the active moiety.

[0138] Unless otherwise specified, the term "stereoisomer" refers to compounds having the same chemical structure but with different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and inhibited isomers. Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0139] Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also known as prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons.

[0140] Unless otherwise indicated, the structural formulas described in this invention include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compounds of this invention, or its enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers), is within the scope of this invention.

[0141] Unless otherwise specified, the term "optional substitution" means that the hydrogen at the substituted site of the group is not substituted, or is substituted by one or more substituents, preferably selected from the group consisting of: halogen, hydroxyl, mercapto, cyano, nitro, amino, azide, oxo, carboxyl, C 2-6 Alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl or 5-10 membered heteroaryl rings, wherein the C 2-6 Alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 3-10Cycloalkylsulfonyl, 3-10 membered heterocyclic alkyl, C 6-14 The aryl or 5-10 membered heteroaryl group may optionally be selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl or C 1-6 One or more of the alkoxy groups are substituted, wherein the oxo group refers to two H groups at the same substitution position being replaced by the same O group to form a double bond.

[0142] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of the present invention. The preferred embodiments and materials shown herein are for illustrative purposes only.

[0143] Unless otherwise stated, temperatures are in Celsius. Reagents were purchased from commercial suppliers such as Chem Blocks Inc., Astressch Inc., or Maclean's, and are ready for use without further purification, unless otherwise stated.

[0144] Unless otherwise stated, the following reactions shall be carried out at room temperature, in anhydrous solvent, under positive pressure of nitrogen, or using a drying tube; glassware shall be dried by drying and / or heating.

[0145] Unless otherwise specified, column chromatography purification uses 300-400 mesh silica gel from Qingdao Marine Chemical Plant; preparative thin-layer chromatography uses thin-layer chromatography silica gel pre-plates (HSGF254) produced by Yantai Chemical Industry Research Institute.

[0146] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS) using a Therno LCD Fleet (ESI) system.

[0147] NMR data (¹H NMR) were obtained using a Bruker Avance-400MHz or Varian Oxford-400Hz NMR spectrometer. Solvents used included CDCl₃, CD₃OD, D₂O, and DMSO-d₆, with tetramethylsilane (0.000ppm) or residual solvents as the reference (CDCl₃: 7.26ppm; CD₃OD: 3.31ppm; D₂O: 4.79ppm; DMSO-d₆: 2.50ppm). When indicating peak shape diversity, the following abbreviations are used to represent different peak shapes: s (singleton), d (doublet), t (triplet), q (quartet), m (multiplex), br (broad peak), dd (double doublet), dt (double triplet). If coupling constants are given, they are expressed in Hertz (Hz).

[0148] This invention also provides a method for preparing the compound. The preparation of the compound of formula (I) of this invention can be accomplished by the following exemplary methods and examples, but these methods and examples should not be considered in any way as limiting the scope of this invention. The compound of this invention can also be synthesized by synthetic techniques known to those skilled in the art, or by combining methods known in the art with the methods described in this invention. The product obtained in each step is obtained using separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, etc. The starting materials and chemical reagents required for synthesis can be conventionally synthesized or purchased according to literature (reaxys).

[0149] This invention provides a method for preparing the compound. The compound can be prepared by the following steps.

[0150] Preparation Example 1

[0151] Preparation of ethyl 2-chloro-4-(methylamino)pyrrolo[1,2-a][1,3,5]triazine-8-carboxylate (1e):

[0152]

[0153] Step 1: Preparation of compound 1b

[0154] Compound ethyl 2-amino-1H-pyrrole-3-carboxylate 1a (15.4 g, 0.1 mol) and anhydrous DMF (100 mL) were added to a 500 mL single-necked flask. Then, 17.2 g (0.15 mol) of DMF was added with stirring, and the mixture was stirred overnight at room temperature. Water (100 mL) was added, and the mixture was stirred for 0.5 hours. The mixture was filtered under reduced pressure, and the resulting compound was separated by column chromatography to give compound 1b (21 g, 78% yield). LC / MS (ESI): m / z = 270.1 [M+H] + .

[0155] Step 2: Preparation of compound 1c

[0156] Compound 1b (20 g, 0.074 mol) and anhydrous ethanol (150 mL) were added to a 500 mL single-necked flask. Solid sodium ethoxide (12.6 g, 0.185 mol) was added in portions, and the mixture was stirred and refluxed for 0.5 hours. After cooling to room temperature, a white solid precipitated. The solid was filtered under reduced pressure, dissolved in water (100 mL), and the pH was adjusted to approximately 4 with dilute hydrochloric acid. The mixture was then filtered under reduced pressure. The solid was recrystallized from ethanol and water and dried in an oven to give compound 1c (10.78 g, 65% yield). LC / MS (ESI): m / z = 224.1 [M+H] + .

[0157] Step 3: Preparation of compound 1d

[0158] Phosphorus oxychloride (60 mL) was added to a 500 mL single-necked flask, followed by fractional addition of compound 1c (10 g, 0.044 mol). The mixture was refluxed with stirring for 3 hours. After cooling to room temperature, excess phosphorus oxychloride was removed under reduced pressure. The remaining black oily substance was poured into a large amount of ice water. The reaction solution was extracted with chloroform / methanol (10:1, v / v). The resulting organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give compound 1d (8.2 g, 70% yield). LC / MS (ESI): m / z = 261.0 [M+H] + .

[0159] Step 4: Preparation of ethyl 2-chloro-4-(methylamino)pyrrolo[1,2-a][1,3,5]triazine-8-carboxylate (1e):

[0160] Add 1d (8 g, 0.03 mol), ethanol (15 mL), and methylamine ethanol solution (28%, 15 mL) to a 500 mL single-necked flask. React the mixture at 70 °C for 12 hours. Remove the solvent under reduced pressure to obtain a brown oil. Purify the residue by column chromatography to give compound 1e (4.6 g, 59% yield). LC / MS (ESI): m / z = 255.6 [M+H] + .

[0161] Preparation Example 2

[0162] Preparation of ethyl 2-chloro-4-(methylamino)pyrazolo[1,5-a][1,3,5]triazine-8-carboxylate (4e):

[0163]

[0164] Step 1: Preparation of compound 4b

[0165] Add 15.5 g of compound ethyl 3-amino-1H-pyrazole-4-carboxylate 1a (0.1 g) to a 500 mL single-necked flask.

[0166] 17.2 g (0.15 mol) of anhydrous DMF (100 mL) was added with stirring, and the mixture was stirred overnight at room temperature.

[0167] Add water (100 mL), stir for 0.5 hours, filter under reduced pressure, and recrystallize the obtained compound from acetonitrile to give compound 4b (21 g, yield 77.8%). LC / MS (ESI): m / z = 271.1 [M+H] + .

[0168] Step 2: Preparation of compound 4c

[0169] Compound 4b (20 g, 0.074 mol) and anhydrous ethanol (150 mL) were added to a 500 mL single-necked flask. Solid sodium ethoxide (12.6 g, 0.185 mol) was added in portions, and the mixture was stirred and refluxed for 0.5 hours. After cooling to room temperature, a white solid precipitated. The solid was filtered under reduced pressure, dissolved in water (100 mL), and the pH was adjusted to approximately 4 with dilute hydrochloric acid. The mixture was then filtered under reduced pressure. The solid was recrystallized from ethanol and water and dried in an oven to give compound 4c (10.78 g, 65% yield). LC / MS (ESI): m / z = 225.05 [M+H] + .

[0170] Step 3: Preparation of compound 4d

[0171] Phosphorus oxychloride (60 mL) was added to a 500 mL single-necked flask, followed by fractional addition of compound 4c (10 g, 0.044 mol). The mixture was refluxed with stirring for 3 hours. After cooling to room temperature, excess phosphorus oxychloride was removed under reduced pressure. The remaining black oily substance was poured into a large amount of ice water. The reaction solution was extracted with chloroform / methanol (10:1). The resulting organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give compound 4d (8.2 g, 70% yield). LC / MS (ESI): m / z = 262.1 [M+H] + .

[0172] Step 4: Preparation of ethyl 2-chloro-4-(methylamino)pyrazolo[1,5-a][1,3,5]triazine-8-carboxylate (4e)

[0173] 4d (8 g, 0.03 mol), ethanol (15 mL), and methylamine ethanol solution (28%, 15 mL) were added to a 500 mL single-necked flask. The reaction mixture was reacted at 70°C for 12 hours. The solvent was removed by vacuum distillation to obtain a brown oil. The residue was purified by column chromatography to give compound 4e (4.6 g, yield 59%). LC / MS (ESI): m / z = 256.6 [M+H] + .

[0174] Preparation Example 3

[0175] Preparation of ethyl 4-(methylamino)-2-(methanesulfonyl)imidazo[1,5-a][1,3,5]triazine-8-carboxylate (5 g):

[0176]

[0177] Step 1: Preparation of compound 5b

[0178] Compound ethyl 4-amino-1H-imidazolium-5-carboxylate 5a (15.5 g, 0.1 mol) and anhydrous DMF (100 mL) were added to a 500 mL single-necked flask. Then, 15 g (0.11 mol) of DMF was added with stirring, and the mixture was stirred overnight at room temperature. Water (100 mL) was added, and the mixture was stirred for 0.5 hours. The mixture was then filtered under reduced pressure to give compound 5b (22 g, 77% yield). LC / MS (ESI): m / z = 287.3 [M+H] + .

[0179] Step 2: Preparation of compound 5c

[0180] Compound 5b (20 g, 0.07 mol), anhydrous acetonitrile (150 mL), and solid potassium carbonate (20 g, 0.14 mol) were added to a 500 mL single-necked flask and stirred under reflux for 18 hours. After cooling to room temperature, acetic acid (50 mL) was slowly added, and the mixture was evaporated to dryness. The resulting solid was slurryed with water, filtered under reduced pressure, washed with ice water, and dried in an oven to give compound 5c (12.5 g, 74% yield). LC / MS (ESI): m / z = 241.2 [M+H] + .

[0181] Step 3: Preparation of compound 5d

[0182] Compound 5c (12 g, 0.05 mol), anhydrous DMF (100 mL), solid potassium carbonate (20 g, 0.14 mol), and methyl iodoform (10.7 g, 0.075 mol) were added to a 500 mL single-necked flask. The mixture was heated and stirred at 80 °C for 18 hours under an inert gas atmosphere. After cooling to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The resulting organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered under reduced pressure, and concentrated to dryness. The solid was slurried with ethyl acetate / petroleum ether (1:3), filtered, collected, and dried to give compound 5d (9.6 g, 75% yield). LC / MS (ESI): m / z = 255.1 [M+H] + .

[0183] Step 4: Preparation of compound 5e

[0184] Phosphorus oxychloride (60 mL) was added to a 500 mL single-necked flask, followed by fractional addition of compound 5d (9 g, 0.035 mol). The mixture was refluxed with stirring for 3 hours. After cooling to room temperature, excess phosphorus oxychloride was removed under reduced pressure. The remaining black oily substance was poured into a large amount of ice water. The reaction solution was extracted with ethyl acetate (100 mL * 3). The resulting organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to dryness, yielding crude compound 4d (8.2 g, 85% yield). LC / MS (ESI): m / z = 273.0 [M + H] + .

[0185] Step 5: Preparation of compound 5f

[0186] 5d (8 g, 0.029 mol) and 28% methylamine alcohol solution (30 mL) were added to a 500 mL single-necked flask, and the reaction mixture was reacted at 70°C for 12 hours. The solvent was removed by vacuum distillation to obtain a brown oil. The residue was purified by column chromatography to give compound 5f (6.7 g, 85% yield). LC / MS (ESI): m / z = 268.3 [M+H] + .

[0187] Step 6: Preparation of ethyl 4-(methylamino)-2-(methanesulfonyl)imidazo[1,5-a][1,3,5]triazine-8-carboxylate (5g)

[0188] 5f (6 g, 0.02 mol) and dichloromethane (150 mL) were added to a 500 mL single-necked flask. The reaction solution was cooled in an ice-salt bath. Oxidant m-CPBA (85%, 5.5 g) was added in portions. After the addition was complete, the mixture was stirred at room temperature for 5 hours. The reaction was monitored by TLC until completion. A saturated aqueous solution of Na₂SO₃ (30 mL) and a saturated solution of potassium carbonate (30 mL) were added. The layers were separated. The aqueous layer was extracted with dichloromethane (150 mL). The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum evaporation to obtain a brown crude product. Purification by column chromatography yielded 5 g (5.8 g, 86% yield) of the compound. LC / MS (ESI): m / z = 300.3 [M+H] + .

[0189] Example 1

[0190] Synthesis of N-((1R,2R)-2-2-methoxycyclobutyl)-4-(methylamino)-2-((2-oxo-2H-[1,2'-bipyridine]-3-yl)amino)pyrrole[1,2-a][1,3,5]triazine-8-carboxamide (compound 1):

[0191]

[0192] Step 1: Synthesis of compound 1f

[0193] Intermediate 1e (4.2 g, 0.016 mol), 3-amino-2H-[1,2'-bipyridine]-2-one (3.7 g, 0.02 mol), cesium carbonate (13.3 g, 0.04 mol), Brettphos Pd G4 (CAS#1599466-83-7, 151 mg, 0.16 mmol), and 1,4-dioxane solution (50 mL) were added to a 250 mL single-necked flask. The reaction mixture was purged with high-purity nitrogen, heated to 100 °C and stirred for 15 hours. After cooling to room temperature, the reaction mixture was evaporated to dryness, separated into layers with dichloromethane and water, and the resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography to give compound 1f (4.5 g, 68% yield). LC / MS (ESI): m / z = 406.1 [M+H]+.

[0194] Step 2: Synthesis of 1g of compound

[0195] Intermediate 1f (4 g, 0.01 mol) and 50 mL of tetrahydrofuran were added to a 250 mL single-necked flask. 10 mL of 2N lithium hydroxide solution was added, and the mixture was stirred overnight at room temperature. The reaction solution was evaporated to dryness, and 20 mL of water was added. The pH was adjusted to approximately 5 with 1N dilute hydrochloric acid. The mixture was filtered under reduced pressure, washed with ice water, and dried in an oven to obtain 1 g of the compound (3 g, yield 82%). LC / MS (ESI): m / z = 378.1 [M+H]+.

[0196] Step 3: Synthesis of Compound 1

[0197] 1 g (200 mg, 0.53 mmol) of compound, (1R,2R)-2-methoxycyclobutylamine hydrochloride (86 mg, 0.63 mmol), DIPEA (500 mg, 3.8 mmol), and DMF (10 mL) were added to a 100 mL reaction flask. After cooling in an ice-water bath, HATU (305 mg, 0.8 mmol) was added in one go. The mixture was stirred for 4 hours after the addition was complete. The reaction solution was quenched with water. The mixture was extracted with ethyl acetate, and the organic layer was evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give compound 1 (163 mg, 67% yield). 1 H NMR(400MHz,DMSO-d6)δ:8.85(m,1H),8.65(m,1H),8.10(m,1H),8.03(m,1H),7.87(m,1H),7.56(m,1H),6.86(d,1H),6.44(m,1H),6 .38(d,1H),4.35(m,1H),3.76(m,1H),3.40(s,3H),2.92(s,3H),2.15-2.02(m,2H),1.50-1.41(m,2H); LC / MS(ESI):m / z=461.2[M+H] + .

[0198] Example 2

[0199] Synthesis of 2-((2-methoxy-3-(pyridin-2-yl)phenyl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-4-(methylamino)pyrrolo[1,2-a][1,3,5]triazine-8-carboxamide (compound 2):

[0200]

[0201] Step 1: Synthesis of compound 2a

[0202] Intermediate 1e (4.2 g, 0.016 mol), 2-methoxy-3-(pyridin-2-yl)aniline (4.0 g, 0.02 mol), cesium carbonate (13.3 g, 0.04 mol), Brettphos Pd G4 (CAS#1599466-83-7, 151 mg, 0.16 mmol), and 1,4-dioxane solution (50 mL) were added to a 250 mL single-necked flask. The reaction mixture was purged with high-purity nitrogen, heated to 100 °C and stirred for 15 hours. After cooling to room temperature, the reaction mixture was evaporated to dryness, separated into layers with dichloromethane and water, and the extracted organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography to give compound 2a (5.4 g, 78% yield). LC / MS (ESI): m / z = 419.4 [M+H]+.

[0203] Step 2: Synthesis of compound 2b

[0204] Intermediate 2a (2.09 g, 0.005 mol), tetrahydrofuran (25 mL), and 2N lithium hydroxide solution (5 mL) were added to a 250 mL single-necked flask. The mixture was stirred overnight at room temperature. The reaction solution was evaporated to dryness, and water (20 mL) was added. The pH was adjusted to approximately 5 with 1N dilute hydrochloric acid. The mixture was filtered under reduced pressure, washed with ice water, and dried in an oven to obtain compound 2b (1.5 g, yield 77%). LC / MS (ESI): m / z = 391.4 [M+H]+.

[0205] Step 3: Synthesis of Compound 2

[0206] 1 g (200 mg, 0.51 mmol) of compound, (1R,2R)-2-methoxycyclobutylamine hydrochloride (86 mg, 0.63 mmol), DIPEA (500 mg, 3.8 mmol), and DMF (10 mL) were added to a 100 mL reaction flask. After cooling in an ice-water bath, HATU (305 mg, 0.8 mmol) was added in one go. The mixture was stirred for 4 hours after the addition was complete. The reaction solution was quenched with water. The mixture was extracted with ethyl acetate, and the organic layer was evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give compound 2 (128 mg, 53% yield). 1H NMR(400MHz,DMSO-d6)δ:8.85(m,1H),8.65(m,1H),8.47(m,1H),8.37(m,1H),7.27(m,1H),7.28(m,1H),6.91(m,1H),6.86(d,1H),6.38(d ,1H),4.35(m,1H),3.83(s,3H)3.76(m,1H),3.40(s,3H),2.92(s,3H),2.15-2.02(m,2H),1.50-1.41(m,2H); LC / MS(ESI):m / z=474.2[M+H] + .

[0207] Example 3:

[0208] Synthesis of 2-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-4-(methylamino)pyrrole[1,2-a][1,3,5]triazine-8-carboxamide (compound 3):

[0209]

[0210] Step 1: Synthesis of compound 3a

[0211] Intermediate 1e (4.2 g, 0.016 mol), (4.0 g, 0.02 mol), cesium carbonate (13.3 g, 0.04 mol), Brettphos Pd G4 (CAS#1599466-83-7, 151 mg, 0.16 mmol), and 1,4-dioxane solution (50 mL) were added to a 250 mL single-necked flask. The reaction mixture was purged with high-purity nitrogen, heated to 100 °C and stirred for 15 hours. After cooling to room temperature, the reaction mixture was evaporated to dryness, separated into layers with dichloromethane and water, and the resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography to give compound 3a (5.6 g, 80% yield). LC / MS (ESI): m / z = 423.4 [M+H]+.

[0212] Step 2: Synthesis of compound 3b

[0213] Intermediate 3a (2.1 g, 0.005 mol), tetrahydrofuran (25 mL), and 2N lithium hydroxide solution (5 mL) were added to a 250 mL single-necked flask. The mixture was stirred overnight at room temperature. The reaction solution was evaporated to dryness, and water (20 mL) was added. The pH was adjusted to approximately 5 with 1N dilute hydrochloric acid. The mixture was filtered under reduced pressure, washed with ice water, and dried in an oven to obtain compound 3b (1.6 g, yield 81%). LC / MS (ESI): m / z = 395.1 [M+H]+.

[0214] Step 3: Synthesis of Compound 3

[0215] Compound 3b (200 mg, 0.50 mmol), (1R,2R)-2-methoxycyclobutylamine hydrochloride (86 mg, 0.63 mmol), DIPEA (500 mg, 3.8 mmol), and DMF (10 mL) were added to a 100 mL reaction flask. After cooling in an ice-water bath, HATU (305 mg, 0.8 mmol) was added in one batch. The mixture was stirred for 4 hours after the addition was complete. The reaction solution was quenched with water. The mixture was extracted with ethyl acetate, and the organic layer was evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give compound 3 (135 mg, 55.8% yield). 1 H NMR(400MHz,DMSO-d6)δ:7.48(d,1H),7.27(d,1H),7.23(m,1H),6.86(d,1H),6.22(d,1H),4.35(m,1H),3.83(s,3H),3 .78(s,3H),3.76(m,1H),3.40(s,3H),2.92(s,3H),2.15-2.02(m,2H),1.50-1.41(m,2H); LC / MS(ESI):m / z=478.2[M+H] + .

[0216] Example 4

[0217] Synthesis of N-((1R,2R)-2-methoxycyclobutyl)-4-(methylamino)-2-((2-carbonyl-2H-[1,2'-bipyridine]-3-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-8-carboxamide (compound 19):

[0218]

[0219] Step 1: Synthesis of compound 4f

[0220] Intermediate 4e (4.2 g, 0.016 mol), 3-amino-2H-[1,2'-bipyridine]-2-one (3.7 g, 0.02 mol), cesium carbonate (13.3 g, 0.04 mol), Brettphos Pd G4 (CAS#1599466-83-7, 151 mg, 0.16 mmol), and 1,4-dioxane solution (50 mL) were added to a 250 mL single-necked flask. The reaction mixture was purged with high-purity nitrogen, heated to 100 °C and stirred for 15 hours. After cooling to room temperature, the reaction mixture was evaporated to dryness, separated into layers with dichloromethane and water, and the resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography to give compound 4f (4.5 g, 68% yield). LC / MS (ESI): m / z = 407.1 [M+H]+.

[0221] Step 2: Synthesis of 4g of compound

[0222] Intermediate 4f (4 g, 0.01 mol), tetrahydrofuran (50 mL), and 2N lithium hydroxide solution (10 mL) were added to a 250 mL single-necked flask. The mixture was stirred overnight at room temperature. The reaction solution was evaporated to dryness, and water (20 mL) was added. The pH was adjusted to approximately 5 with 1N dilute hydrochloric acid. The mixture was filtered under reduced pressure, washed with ice water, and dried in an oven to obtain 4 g of the compound (3 g, yield 82%). LC / MS (ESI): m / z = 379.3 [M+H]+.

[0223] Step 3: Synthesis of Compound 19

[0224] 4 g (200 mg, 0.53 mmol) of compound, (1R,2R)-2-methoxycyclobutylamine hydrochloride (86 mg, 0.63 mmol), DIPEA (500 mg, 3.8 mmol), and DMF (10 mL) were added to a 100 mL reaction flask. After cooling in an ice-water bath, HATU (305 mg, 0.8 mmol) was added in one go. The mixture was stirred for 4 hours after the addition was complete. The reaction solution was quenched with water. The mixture was extracted with ethyl acetate, and the organic layer was evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give compound 19 (163 mg, 67% yield). 1 H NMR(400MHz,DMSO-d6)δ:8.85(m,1H),8.65(m,1H),8.10(m,1H),8.03(m,1H),7.87(m,1H),7.56(m,1H),6.44(m,1H),6.38(s, 1H),4.35(m,1H),3.76(m,1H),3.40(s,3H),2.92(s,3H),2.15-2.02(m,2H),1.50-1.41(m,2H); LC / MS(ESI):m / z=462.7[M+H]+ .

[0225] Example 5

[0226] Synthesis of N-((1R,2R)-2-methoxycyclobutyl)-4-(methylamino)-2-((2-carbonyl-2H-[1,2'-bipyridine]-3-yl)amino)pyrazolo[1,5-a][1,3,5]triazine-8-carboxamide (compound 28):

[0227]

[0228] Step 1: Synthesis of compound 5h

[0229] In a 250 mL single-necked flask, 5 g (1.5 g, 5 mmol) of intermediate, 1 g (5 mmol) of 3-amino-2H-[1,2'-bipyridine]-2-one, 10 mmol of potassium tert-butoxide, and 50 mL of anhydrous THF were added. The reaction mixture was purged with high-purity nitrogen, heated to 70 °C and stirred for 8 hours. After cooling to room temperature, the reaction mixture was quenched with water, separated by separation with ethyl acetate and water, and the resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography to give compound 5 h (0.7 g, 35% yield). LC / MS (ESI): m / z = 407.1 [M+H]+.

[0230] Step 2: Synthesis of compound 5j

[0231] Intermediate 5h (0.7 g, 1.7 mmol), tetrahydrofuran (50 mL), and 2N lithium hydroxide solution (5 mL) were added to a 250 mL single-necked flask. The mixture was stirred overnight at room temperature. The reaction solution was evaporated to dryness, and water (20 mL) was added. The pH was adjusted to approximately 5 with 1N dilute hydrochloric acid. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give compound 5j (0.35 g, yield 53%). LC / MS (ESI): m / z = 379.1 [M+H]+.

[0232] Step 3: Synthesis of Compound 28

[0233] Compound 5j (200 mg, 0.53 mmol), (1R,2R)-2-methoxycyclobutylamine hydrochloride (86 mg, 0.63 mmol), DIPEA (500 mg, 3.8 mmol), and DMF (10 mL) were added to a 100 mL reaction flask. After cooling in an ice-water bath, HATU (305 mg, 0.8 mmol) was added in one go. The mixture was stirred for 4 hours after the addition was complete. The reaction solution was quenched with water. The mixture was extracted with ethyl acetate, and the organic layer was evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give compound 28 (163 mg, 67% yield).1 H NMR(400MHz,DMSO-d6)δ:8.85(m,1H),8.65(m,1H),8.10(m,1H),8.03(m,1H),7.87(m,1H),7.56(m,1H),6.44(m,1H),6.38(s, 1H),4.35(m,1H),3.76(m,1H),3.40(s,3H),2.92(s,3H),2.15-2.02(m,2H),1.50-1.41(m,2H); LC / MS(ESI):m / z=462.7[M+H] + .

[0234] Compounds 4-18, 20-27, and 29-34 were synthesized using the same method as in Examples 1-5. Their structures and specific characterization data (LC-MS) are as follows:

[0235]

[0236]

[0237]

[0238] Biological testing evaluation

[0239] Test Example 1: TYK2 Enzyme Activity Detection Experiment

[0240] Recombinant human TYK2 protein (Carna biosciences, 08-147) and the corresponding substrate IRS1 (Signalchem, I40-58-1MG) were used. In white 384-well plates (Perkin Elmer, 6007290), 10 ng of TYK2 protein dissolved in reaction buffer (Promega, V915B) and 1 μL of the test compound (maximum concentration 5 μM, serially diluted 3-fold, 10 concentrations per well, double-dilution) were added. The reaction was incubated at room temperature for 120 min, with a reaction volume of 5 μL. 5 μL of ADPGlo reagent (Promega, V912B) was added to each well to terminate the reaction and consume all remaining ATP. After incubation at room temperature for 40 min, 10 μL of enzyme assay reagent (Promega, V914B) dissolved in enzyme assay buffer (Promega, V913B) was added, and the amount of newly generated ATP (ADP converted to ATP) was detected in a luciferase / luciferin reaction. After incubation at room temperature for 30 min, the luminescence values ​​were read using an Envision multi-functional microplate reader. Finally, the IC50 (half-maximal inhibitory concentration) of the compound was obtained using a non-linear fitting formula with XLFIT software. Enzyme activity was calculated from relative light units (RUL). The ability of the test compound to inhibit enzyme activity was represented by the inhibition rate. The results are shown in Table 2.

[0241] Negative control: No TYK2 enzyme

[0242] Positive control: No inhibitor

[0243] A is the control compound NDI-034858. IC50 values: A < 10 nM; 10 nM <B<100nM;100nM<C<500nM.

[0244] Table 1: IC50 values ​​of compounds binding to the TYK2-JH2 pseudokinase domain in vitro

[0245] compound TYK2-JH2 combination / IC50(nM) Compound 1 B Compound 2 B Compound 3 B Compound 4 A Compound 5 A Compound 6 B Compound 7 C Compound 8 B Compound 9 A Compound 10 B Compound 11 A Compound 12 A Compound 13 B Compound 14 B Compound 15 C Compound 16 B Compound 17 B Compound 18 B Compound 19 A Compound 20 A Compound 21 B Compound 22 A Compound 23 A Compound 24 A Compound 25 C Compound 26 A Compound 27 A Compound 28 A Compound 29 B Compound 30 A Compound 31 B Compound 32 A Compound 33 B Compound 34 B

[0246] Test Example 2: IL-12-induced pSTAT4 experiment in human PBMCs

[0247] Human PBMCs were isolated from leukocytes and frozen for assays as needed. Cells intended for assays were thawed and resuspended in complete culture medium containing serum, then diluted to 1.67 × 10⁻⁶. 6Cells / mL were selected to ensure 200,000 cells per 120 μL well. 15 μL of the compound or DMSO was added to the wells at the desired concentration and incubated at 37°C for 1 hour. 15 μL of the stimulant (IL-12 at a final stimulation of 1.7 ng / mL) was added and incubated for 30 min. pSTAT4 and total STAT4 in the cell lysates were prepared and analyzed using MSD reagents according to the manufacturer's protocol. The final DMSO concentration of the compound was determined to be 0.1%.

[0248] The IL-12-induced pSTAT4 assay assessed the inhibition of IL-12-induced STAT4 phosphorylation mediated by TYK2 / JAK2 (heterodimeric complex). Results of the IL-12-induced pSTAT4 assay in human PBMCs are presented in Table 2. IC50 values: A < 0.1 μM; 0.1 μM <B<0.5μM;0.5μM<C<5μM.

[0249] Table 2: IC50 Values

[0250] compound PMBC IL-12-pSTAT4 (IC50, μM) Compound 1 B Compound 2 C Compound 3 B Compound 4 A Compound 5 A Compound 6 B Compound 7 C Compound 8 B Compound 9 A Compound 10 B Compound 11 B Compound 12 A Compound 13 B Compound 14 B Compound 15 C Compound 16 B Compound 17 B Compound 18 B Compound 19 A Compound 20 C Compound 21 B Compound 22 A Compound 23 A Compound 24 B Compound 25 C Compound 26 A Compound 27 A Compound 28 B Compound 29 C Compound 30 A Compound 31 B Compound 32 A Compound 33 C Compound 34 B

[0251] The above biological test examples further illustrate the present invention, but these embodiments are not intended to limit the scope of the invention.

Claims

1. A compound of formula (I) below, wherein the stereoisomers, geometric isomers, tautomers, pharmaceutical salts, prodrugs, hydrates, solvates, or isotopically labeled analogs of the compound are: in, X1 and X2 are independently N or CR. x And X1 and X2 are not both N at the same time; R X For H, deuterium, or optional substitution: C 1-4 Alkyl, C 2-6 alkenyl, C 1-4 oxane, C 1-4 Thioalkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2; R1 and R2 are independently H, deuterium, and optionally substituted C, respectively. 1-6 Alkyl, C 1-6 oxane, C 2-6 alkenyl, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, C 4-6 Heterocyclic group; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo group, CN, OH, NH2; R3 is Ring P is C 6-12 Aryl, C 5-12 heteroaryl, C 5-12 Unsaturated heterocyclic groups; Ring G is C 6-12 Aryl, C 5-12 heteroaryl, C 5-12 Unsaturated heterocyclic groups, C 4-12 Heterocyclic groups; R P For independent deuterium, halogen, oxo group, or optional substitution: C 1-4 Alkyl, C 1-4 oxane, C 2-6 alkenyl, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, C 4-6 Heterocyclic group; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo group, CN, OH, NH2; R G For independent deuterium, halogen, oxo group, or optional substitution: C 1-4 Alkyl, C 1-4 oxane, C 2-6 alkenyl, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, C 4-6 Heterocyclic group, phenyl, C 5-6 heteroaryl, C 5-6 Unsaturated heterocyclic group; wherein optional substitution refers to being replaced by one or more groups selected from deuterium, halogen, oxo group, -CN, -OH, -NHR g -C(=O)R gg C 1-4 Alkyl, C 1-4 Oxyalkyl, halogenated C 1-4 Alkyl, Halogenated C 1-4 Substituents of oxaalkyl groups; R g For H, deuterium, or optional substitution: C 1-4 Alkyl, C 3-6 Cycloalkyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2; R gg For optional substitution: C 1-4 Alkyl, C 1-4 oxane, C 2-6 Alkenyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2; R4 is Ring A is C 4-6 cycloalkyl, C 3-6 Cycloalkenyl, C 4-6 Heterocyclic groups; R A Independently, it can be deuterium, halogen, oxo group, or optionally substituted: C 1-4 Alkyl, C 1-4 oxane, C 2-6 Alkenyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2; L represents bond, O, NR a ; R a For H, deuterium, or optional substitution: C 1-4 Alkyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2; a is 1, 2, or 3; p is 1, 2, or 3; g is 0, 1, 2, or 3; The heteroatoms in the heterocyclic group and heteroaryl group are independently selected from O, N or S, and the number of heteroatoms is preferably 1, 2 or 3.

2. The compound of claim 1, wherein the stereoisomers, geometric isomers, tautomers, pharmaceutical salts, prodrugs, hydrates, solvates, or isotopically labeled analogs of the compound, wherein: Both X1 and X2 are CR x ; Alternatively, X1 is N and X2 is CR. x ; Alternatively, X1 is CR x X2 is N; And R X For H, deuterium, or optional substitution: C 1-4 Alkyl, C 2-6 Alkenyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2; Or, R X For H and deuterium; Or, R X For H; Preferably, both X1 and X2 are CH; Alternatively, X1 is N and X2 is CH; Alternatively, X1 is CH and X2 is N.

3. The compound according to any one of claims 1-2, wherein the stereoisomers, geometric isomers, tautomers, pharmaceutical salts, prodrugs, hydrates, solvates, or isotopically labeled analogs of the compound, wherein: R1 and R2 are independently H, deuterium, and optionally substituted C, respectively. 1-6 Alkyl, C 2-6 alkenyl, C 3-6 Cycloalkyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2; or, R1 and R2 are independently H, deuterium, or optional substitution: C 1-4 Alkyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2; preferably, R1 and R2 are independently H, deuterium, methyl, ethyl, deuterated methyl, and deuterated ethyl, respectively; more preferably, R1 is methyl and deuterated methyl; and R2 is H.

4. The compound according to any one of claims 1-3, wherein the stereoisomer, geometric isomer, tautomer, pharmaceutical salt, prodrug, hydrate, solvate, or isotopically labeled analogue of the compound, wherein: R3 is Ring P is phenyl, C 5-6 heteroaryl, C 5-6 Unsaturated heterocyclic groups; R P For independent deuterium, halogen, oxo group, or optional substitution: C 1-4 Alkyl, C 1-4 Oxyalkyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2; p is 1 or 2; Ring G is phenyl, C 5-6 heteroaryl, C 5-6 Unsaturated heterocyclic groups, C 4-6 Heterocyclic groups; R G For independent deuterium, halogen, or optional substitution: C 1-4 Alkyl, C 1-4 oxane, C 2-6 alkenyl, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, C 4-6 Heterocyclic group, C 5-6 Heteroaryl groups; wherein optional substitution refers to being replaced by one or more groups selected from deuterium, halogen, oxo group, -CN, -OH, -NHR g -C(=O)R gg C 1-3 Alkyl, C 1-3 Oxyalkyl, halogenated C 1-3 Alkyl, Halogenated C 1-3 Substituents of oxaalkyl groups; R g For H, deuterium, or optional substitution: C 1-4 Alkyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2; R gg For optional substitution: C 1-4 Alkyl, C 2-6 Alkenyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2; g is 0, 1, or 2; Alternatively, ring P can be phenyl, 6-membered heteroaryl, or 6-membered unsaturated heterocyclic group; R P For independent deuterium, halogen, oxo group, or optional substitution: C 1-3 Alkyl, C 1-3 Oxyalkyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2; p is 1 Ring G is C 5-6 Mixed aromatics; R G For independent deuterium, F, Cl, Br, or optionally substituted C 1-4 Alkyl, C 1-4 oxane, C 3-6 cycloalkyl, C 4-6 Heterocyclic group, C 5-6 Heteroaryl groups; wherein optional substitution refers to being replaced by one or more groups selected from deuterium, F, Cl, oxo, -CN, -OH, -NHR. g -C(=O)R gg C 1-3 Alkyl, C 1-3 Oxyalkyl, halogenated C 1-3 Alkyl, Halogenated C 1-3 Substituents of oxaalkyl groups; R g H, deuterium, methyl, ethyl; preferably, R g It is methyl; R gg Optional substitutions include: methyl, ethyl, vinyl, and propenyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, and NH2; preferably, R gg The methyl group is optionally substituted; g is 0 or 1; Preferably, ring P is R P The independent groups are F, oxo group, and methoxy group; Ring G is R G For independent F, methyl, deuterated methyl, More preferably, R3 is 5. The compound according to any one of claims 1-4, a stereoisomer, tautomer, or mixture thereof of the compound, or a pharmaceutically acceptable salt of the compound, wherein: R4 is Ring A is C 4-6 cycloalkyl, C 4-6 Heterocyclic group; or, ring A is cyclobutyl, cyclopentyl, oxetyl, tetrahydrofuranyl, tetrahydropyrroleyl; R A Independently, for deuterium, halogens, or optional substitutions: C 1-4 Alkyl, C 1-4 Oxyalkyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2; a is 1 Or, R A Independently, it can be deuterium, F, Cl, Br, or optionally substituted: C. 1-3 Alkyl, C 1-3 Oxaalkyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2; preferably, R A It is F, methyl, or methoxy; Preferably, R4 is Preferably, R4 is More preferably, R4 is 6. The compound according to any one of claims 1-5, a stereoisomer, tautomer, or mixture thereof of the compound, or a pharmaceutically acceptable salt of the compound, wherein: L represents a key, -O, -NR a - Optional replacement: C 1-4 Alkylene, C 1-4 Heteroalkyl; wherein optional substitution refers to being substituted with one or more radicals selected from deuterium, halogen, oxo group, -CN, -OH, -NH2, C 1-3 Alkyl, Halogenated C 1-3 Substituents of alkyl groups; R a For H, deuterium, or optional substitution: C 1-4 Alkyl; wherein optional substitution means being replaced by one or more substituents selected from deuterium, halogen, oxo, CN, OH, NH2; Alternatively, L can be a key, -O, or -NR. a - Optional replacement: C 1-4 Alkylene; wherein optional substitution refers to being substituted with one or more radicals selected from deuterium, halogen, oxo group, -CN, -OH, -NH2, C 1-3 Alkyl, Halogenated C 1-3 Substituents of alkyl groups; R a For H and deuterium; Preferably, L is -NR a -; R a For H; More preferably, L is -NH-.

7. A compound represented by formula (II) below, wherein the stereoisomers, geometric isomers, tautomers, pharmaceutical salts, prodrugs, hydrates, solvates, or isotopically labeled analogs of the compound are: in, X1, X2, R1, R2, ring P, ring G, ring A, R P R G R A p, g, a, as described in the compound of formula (I) as claimed in claims 1-6.

8. A compound represented by formula (Ⅲ) below, wherein the stereoisomers, geometric isomers, tautomers, pharmaceutical salts, prodrugs, hydrates, solvates, or isotopically labeled analogs of the compound are: in, X1, X2, R1, ring P, ring G, ring A, R P R G R A p, g, a are as described in the compounds of formulas (I) as claimed in claims 1-6.

9. A compound represented by formulas (Ⅳ-A), (Ⅳ-B), and (Ⅳ-C), wherein the stereoisomers, geometric isomers, tautomers, pharmaceutical salts, prodrugs, hydrates, solvates, or isotopically labeled analogs of the compound are: in, R1, ring P, ring G, ring A, R P R G R A p, g, a are as described in the compounds of formulas (I) as claimed in claims 1-6.

10. A compound represented by formulas (V-a), (V-b), (V-c), (V-d), (V-e), (V-f), (V-g), (V-h), (V-i), wherein the stereoisomers, geometric isomers, tautomers, pharmaceutical salts, prodrugs, hydrates, solvates, or isotopically labeled analogs of the compound are: in, R1, ring G, ring A, R P R G R A p, g, a are as described in the compounds of formulas (I) as claimed in claims 1-6.

11. A compound represented by formulas (Ⅵ-a), (Ⅵ-b), (Ⅵ-c), (Ⅵ-d), (Ⅵ-e), (Ⅵ-f), (Ⅵ-g), (Ⅵ-h), (Ⅵ-i), wherein the stereoisomers, geometric isomers, tautomers, pharmaceutical salts, prodrugs, hydrates, solvates, or isotopically labeled analogs of the compound are: in, R1, ring G, ring A, R G R A p, g, a are as described in the compounds of formulas (I) as claimed in claims 1-6.

12. Selected from the following compounds, or stereoisomers, geometric isomers, tautomers, pharmaceutical salts, prodrugs, hydrates, solvates, or isotopically labeled analogs:

13. A pharmaceutical composition comprising the compound of any one of claims 1 to 12, a stereoisomer, geometric isomer, tautomer, pharmaceutical salt, prodrug, hydrate, solvate, or isotopically labeled analogue of the compound.

14. The use of the compound of any one of claims 1 to 13, a stereoisomer, geometric isomer, tautomer, pharmaceutical salt, prodrug, hydrate, solvate, or isotopically labeled analogue of the compound, or the use of the pharmaceutical composition of claim 13 in the preparation of a medicament for treating or preventing TYK2-mediated diseases.

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