A class of pyridine compounds containing nitrogen heterocycles

Abstract

A kind of nitrogen-containing heterocyclic protein inhibitor compound, its stereoisomer, tautomer or pharmaceutically acceptable salt, also provides preparation of nitrogen-containing heterocyclic compound and its use, the drug prepared using the compound is widely used in the treatment of diseases, wherein the diseases include multiple types of autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, lupus erythematosus, neurodermatitis, dermatitis, psoriasis, psoriatic arthritis, Crohn's disease, Sjogren's syndrome and scleroderma.

Description

Technical Field

[0001] This invention relates to a nitrogen-containing heterocyclic compound that can regulate the signal transduction of various cytokines by inhibiting TYK2. The invention also relates to a method for preparing such a compound and its application in disease treatment. Background Technology

[0002] Nitrogen-containing heterocyclic compounds are a class of nitrogen-containing heterocyclic compounds with unique structures and broad biological activities. Since the successful development of nitrogen-containing heterocyclic herbicides, research on these compounds has progressed rapidly. For example, nitrogen-containing heterocyclic mycotoxins were the first nitrogen-containing heterocyclic compounds to possess natural fungicidal activity. Studies have found that nitrogen-containing heterocyclic compounds exhibit good biological activities in pesticides and pharmaceuticals, such as herbicides, insecticides, antibacterial agents, antivirals, and hypotensive agents.

[0003]

[0004] Cytokines interleukins IL-12 and IL-23 activate antigen-presenting cells and play an important role in the differentiation and proliferation of T cells. These cytokines are involved in mediating a variety of autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and lupus erythematosus.

[0005] Tyrosine kinase 2 (TYK2), a member of the JAK family (other members include JAK1, JAK2, and JAK3), is responsible for IFN-α, IL-6, IL-10, and IL-12 signaling. TYK2 can promote the phosphorylation of STAT proteins downstream of IL-12, IL-23, and type I interferon receptors. Inhibiting TYK2 activity can effectively treat a variety of autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, lupus erythematosus, neurodermatitis, dermatitis, psoriasis, psoriatic arthritis, Crohn's disease, Sjögren's syndrome, and scleroderma.

[0006] Designing TYK2 inhibitors with better efficacy, pharmacokinetic properties, and superior drug-like characteristics is a significant challenge for medicinal chemists. Although a series of TYK2 inhibitors have been disclosed in recent years, there is still a need to discover and develop new compounds with better efficacy, pharmacokinetic properties, and physicochemical characteristics. This invention designs compounds with the general formula (I) and finds that these compounds exhibit excellent TYK2 inhibitory effects and overall performance. Summary of the Invention

[0007] This invention provides a compound of formula (I), its stereoisomer, tautomer, or pharmaceutically acceptable salt.

[0008]

[0009] L represents alkyl, deuterated alkyl, haloalkyl, amino, alkylamino, deuterated alkylamino, cycloalkyl, cycloalkylamino, deuterated cycloalkylamino;

[0010] Ring B is aryl, heteroaryl, or heterocyclic, and ring B is selected from the following groups:

[0011]

[0012] Among them, T, G, Y, Z, and M are each independently selected from oxygen atoms, and CR A1 CR A2 nitrogen atom or NR B ;

[0013] E can be a nitrogen atom or a carbon atom;

[0014] R A1 R A2 Selected from hydrogen, deuterium, and C 1-6 Alkyl, halogen, and the following structures:

[0015]

[0016] R B Selected from hydrogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkyl-C(O)-, C 1-6 Haloalkyl-C(O)-, cycloalkyl-C(O)-, aryl-C(O)-, substituted amino-C(O)-, C 1-6 Alkyl-S(O)2-, alkenyl, deuterated alkenyl, ynyl, deuterated ynyl, and the following structures:

[0017]

[0018]

[0019] Q represents a chemical bond or -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -C(NR)2-. 8 )-, that is:

[0020]

[0021] P can be an oxygen atom or a sulfur atom;

[0022] X represents a chemical bond, an oxygen atom, or NH or NR. A ;

[0023] R A It is an alkyl group, a deuterated alkyl group, or a haloalkyl group;

[0024] U can be a nitrogen atom or a carbon atom;

[0025] Ring A can be aryl, heteroaryl, or heterocyclic, and ring A can be selected from the following groups:

[0026]

[0027] C is an alkyl, cycloalkyl, amino, substituted amino, aryl, heteroaryl, or heterocyclic group. C is selected from the following groups:

[0028]

[0029] Among them, R 1 R 2 R 3 R 4 R 5 R 7 R 8 Selected from hydrogen, deuterium, halogen, amino, alkynyl, deuterated alkynyl, alkenyl, deuterated alkenyl, alkenyl carbonyl, deuterated alkenyl carbonyl, alkyl, deuterated alkyl, alkyl carbonyl, deuterated alkyl carbonyl; wherein, alkynyl, alkenyl, deuterated alkynyl, deuterated alkenyl, alkyl and deuterated alkyl are arbitrarily substituted by halogen, alkyl, hydroxyl, amino, cycloalkyl, aryl, heteroaryl;

[0030] n = 1, 2, 3, 4, 5, 6.

[0031] The present invention includes the following compounds, their stereoisomers, tautomers, and pharmaceutically acceptable salts.

[0032]

[0033]

[0034] This invention relates to a compound of formula (I-1), its stereoisomers, tautomers, and pharmaceutically acceptable salts.

[0035]

[0036] Wherein, L represents alkyl, deuterated alkyl, haloalkyl, amino, alkylamino, deuterated alkylamino, cycloalkyl, cycloalkylamino, and deuterated cycloalkylamino.

[0037] P can be an oxygen atom or a sulfur atom;

[0038] X is an oxygen atom, or NH or NR. 9 ;

[0039] V, U, and W are nitrogen atoms, and CR 6 ;

[0040] R D1 Selected from hydrogen, C1-6 Alkyl groups, halogens;

[0041] F1, F2, and F3 are nitrogen atoms and carbon atoms, respectively.

[0042] E1 can be hydrogen, deuterium, alkyl, or deuterated alkyl.

[0043] C is an alkyl, cycloalkyl, amino, substituted amino, aryl, heteroaryl, heterocyclic group, and the ring C is selected from the following groups:

[0044]

[0045] Among them, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 Selected from hydrogen, deuterium, halogen, amino, alkynyl, alkenyl, deuterated alkenyl, alkyl, deuterated alkyl; wherein, alkynyl, alkenyl, alkyl and deuterated alkyl are arbitrarily substituted by halogen, alkyl, hydroxyl, amino, cycloalkyl, aryl, heteroaryl;

[0046] R 9 Selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CH2). n1 R aa ,-(CH2) n1 OR aa -SR aa ,-(CH2) n1 C(O)R aa -(CD2) n1 R aa -(CD2) n1 OR aa -SR aa -(CD2) n1 C(O)R aa -C(O)OR aa , -C(O)R aa , -S(O) m1 R aa ,-(CH2) n1 S(O) m1 R aa -(CD2) n1 S(O) m1 R aa -NR aa R bb , -C(O)NRaa R bb -NR aa C(O)R bb -NR aa S(O) m1 R bb ;

[0047] R aa R bb Each is independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally further substituted by one or more substituents selected from hydrogen, deuterium, silyl, alkylsilyl, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

[0048] n = 1, 2, 3, 4;

[0049] n1 = 0, 1, 2, 3, 4;

[0050] m1 = 0, 1, 2, 3, 4.

[0051] The present invention includes the following compounds, their stereoisomers, tautomers, and pharmaceutically acceptable salts.

[0052]

[0053]

[0054] This invention relates to a compound of formula (II-1), its stereoisomers, tautomers, and pharmaceutically acceptable salts.

[0055]

[0056] Among them, ring B is aryl, heteroaryl, or heterocyclic;

[0057] X1, E is a nitrogen atom or a carbon atom;

[0058] L represents alkyl, deuterated alkyl, haloalkyl, amino, alkylamino, deuterated alkylamino, cycloalkyl, cycloalkylamino, deuterated cycloalkylamino;

[0059] R 10It can be hydrogen, deuterium, alkyl, deuterated alkyl, or halogen;

[0060] E1 can be hydrogen, deuterium, alkyl, or deuterated alkyl.

[0061] Q represents a chemical bond or -C(O)-, -C(S)-, -S(O)-, -S(O)2-, that is:

[0062]

[0063] C is an alkyl, cycloalkyl, amino, substituted amino, aryl, heteroaryl, or heterocyclic group. C is selected from the following groups:

[0064]

[0065] Among them, R 1 R 2 R 3 R 4 R 5 R 7 Selected from hydrogen, deuterium, halogen, amino, alkynyl, deuterated alkynyl, alkenyl, deuterated alkenyl, alkyl, deuterated alkyl; wherein, alkynyl, alkenyl, deuterated alkynyl, deuterated alkenyl, alkyl and deuterated alkyl are arbitrarily substituted by halogen, alkyl, hydroxyl, amino, cycloalkyl, aryl, heteroaryl.

[0066] R 9 Selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CH2). n1 R aa ,-(CH2) n1 OR aa -SR aa ,-(CH2) n1 C(O)R aa -(CD2) n1 R aa -(CD2) n1 OR aa -SR aa -(CD2) n1 C(O)R aa -C(O)OR aa , -C(O)R aa , -S(O) m1 R aa ,-(CH2) n1 S(O) m1 R aa -(CD2) n1 S(O) m1 Raa -NR aa R bb , -C(O)NR aa R bb -NR aa C(O)R bb -NR aa S(O) m1 R bb ;

[0067] R aa R bb Each is independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally further substituted by one or more substituents selected from hydrogen, deuterium, silyl, alkylsilyl, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

[0068] n = 1, 2, 3, 4;

[0069] n1 = 0, 1, 2, 3, 4;

[0070] m1 = 0, 1, 2, 3, 4.

[0071] This invention relates to a compound of formula (II-1A), its stereoisomers, tautomers, and pharmaceutically acceptable salts.

[0072]

[0073] Among them, ring B is aryl, heteroaryl, or heterocyclic;

[0074] X1, E is a nitrogen atom or a carbon atom;

[0075] L represents alkyl, deuterated alkyl, haloalkyl, amino, alkylamino, deuterated alkylamino, cycloalkyl, cycloalkylamino, deuterated cycloalkylamino;

[0076] R 10 It can be hydrogen, deuterium, alkyl, deuterated alkyl, or halogen;

[0077] E1 can be hydrogen, deuterium, alkyl, or deuterated alkyl.

[0078] C is an alkyl, cycloalkyl, amino, substituted amino, aryl, heteroaryl, or heterocyclic group. C is selected from the following groups:

[0079]

[0080] Among them, R 1 R 2 R 3 R 4 R 5 R 7 Selected from hydrogen, deuterium, halogen, amino, alkynyl, deuterated alkynyl, alkenyl, deuterated alkenyl, alkyl, deuterated alkyl; wherein, alkynyl, alkenyl, deuterated alkynyl, deuterated alkenyl, alkyl and deuterated alkyl are arbitrarily substituted by halogen, alkyl, hydroxyl, amino, cycloalkyl, aryl, heteroaryl.

[0081] R 9 Selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CH2). n1 R aa ,-(CH2) n1 OR aa -SR aa ,-(CH2) n1 C(O)R aa -(CD2) n1 R aa -(CD2) n1 OR aa -SR aa -(CD2) n1 C(O)R aa -C(O)OR aa , -C(O)R aa , -S(O) m1 R aa ,-(CH2) n1 S(O) m1 R aa -(CD2) n1 S(O) m1 R aa -NR aa R bb , -C(O)NR aa R bb -NR aa C(O)R bb -NR aa S(O) m1 R bb ;

[0082] Raa R bb Each is independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally further substituted by one or more substituents selected from hydrogen, deuterium, silyl, alkylsilyl, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

[0083] n = 1, 2, 3, 4;

[0084] n1 = 0, 1, 2, 3, 4;

[0085] m1 = 0, 1, 2, 3, 4.

[0086] The present invention includes the following compounds, their stereoisomers, tautomers, and pharmaceutically acceptable salts.

[0087]

[0088]

[0089] This invention relates to a compound of formula (II-1B), its stereoisomers, tautomers, and pharmaceutically acceptable salts.

[0090]

[0091] Among them, ring B is aryl, heteroaryl, or heterocyclic;

[0092] X1, E is a nitrogen atom or a carbon atom;

[0093] L represents alkyl, deuterated alkyl, haloalkyl, amino, alkylamino, deuterated alkylamino, cycloalkyl, cycloalkylamino, deuterated cycloalkylamino;

[0094] R 10 It can be hydrogen, deuterium, alkyl, deuterated alkyl, or halogen;

[0095] E1 can be hydrogen, deuterium, alkyl, or deuterated alkyl.

[0096] C is an alkyl, cycloalkyl, amino, substituted amino, aryl, heteroaryl, or heterocyclic group. C is selected from the following groups:

[0097]

[0098] Among them, R 1 R 2 R 3 R 4 R 5 R 7 Selected from hydrogen, deuterium, halogen, amino, alkynyl, deuterated alkynyl, alkenyl, deuterated alkenyl, alkyl, deuterated alkyl; wherein, alkynyl, alkenyl, deuterated alkynyl, deuterated alkenyl, alkyl and deuterated alkyl are arbitrarily substituted by halogen, alkyl, hydroxyl, amino, cycloalkyl, aryl, heteroaryl.

[0099] R 9a R 9b R 9c Selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, cycloalkyl, deuterated cycloalkyl, alkynyl, deuterated alkynyl, or R 9a and R 9b Together with the attached carbon atom, it forms a cycloalkyl group;

[0100] n = 1, 2, 3.

[0101] The present invention includes the following compounds, their stereoisomers, tautomers, and pharmaceutically acceptable salts.

[0102]

[0103]

[0104] This invention relates to a compound of formula (II-2), its stereoisomers, tautomers, and pharmaceutically acceptable salts.

[0105]

[0106] Wherein, L represents alkyl, deuterated alkyl, haloalkyl, amino, alkylamino, deuterated alkylamino, cycloalkyl, cycloalkylamino, and deuterated cycloalkylamino.

[0107] R 10 R 11 R D1 Selected from hydrogen, deuterium, alkyl, deuterated alkyl, and halogen;

[0108] E1 can be hydrogen, deuterium, alkyl, or deuterated alkyl.

[0109] Q represents a chemical bond, specifically a carbonyl group.

[0110] C is an alkyl, cycloalkyl, amino, substituted amino, aryl, heteroaryl, or heterocyclic group. C is selected from the following groups:

[0111]

[0112] Among them, R 1 R 2 R 3 R 4 R 5 R 7 Selected from hydrogen, deuterium, halogen, amino, alkynyl, deuterated alkynyl, alkenyl, deuterated alkenyl, alkyl, deuterated alkyl; wherein, alkynyl, alkenyl, deuterated alkynyl, deuterated alkenyl, alkyl and deuterated alkyl are arbitrarily substituted by halogen, alkyl, hydroxyl, amino, cycloalkyl, aryl, heteroaryl.

[0113] R 9a R 9b R 9c Selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, cycloalkyl, deuterated cycloalkyl, alkynyl, deuterated alkynyl, or R 9a and R 9b Together with the attached carbon atom, it forms a cycloalkyl group;

[0114] n = 1, 2, 3.

[0115] This invention relates to a compound of formula (II-2-1), its stereoisomers, tautomers, and pharmaceutically acceptable salts.

[0116]

[0117] Among them, R 12 The following are the possible values: deuterium, hydrogen, alkyl, deuterated alkyl, haloalkyl, amino, alkylamino, deuterated alkylamino, cycloalkyl, cycloalkylamino, and deuterated cycloalkylamino.

[0118] R 10 R 11 R D1 Selected from hydrogen, deuterium, alkyl, deuterated alkyl, and halogen;

[0119] E1 can be hydrogen, deuterium, alkyl, or deuterated alkyl.

[0120] Q represents a chemical bond, specifically a carbonyl group.

[0121] C is an alkyl, cycloalkyl, amino, substituted amino, aryl, heteroaryl, or heterocyclic group. C is selected from the following groups:

[0122]

[0123] Among them, R 1 R 2 R 3 R 4 R 5 R 7Selected from hydrogen, deuterium, halogen, amino, alkynyl, deuterated alkynyl, alkenyl, deuterated alkenyl, alkyl, deuterated alkyl; wherein, alkynyl, alkenyl, deuterated alkynyl, deuterated alkenyl, alkyl and deuterated alkyl are arbitrarily substituted by halogen, alkyl, hydroxyl, amino, cycloalkyl, aryl, heteroaryl.

[0124] R 9a R 9b R 9c Selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, cycloalkyl, deuterated cycloalkyl, alkynyl, deuterated alkynyl, or R 9a and R 9b Together with the attached carbon atom, it forms a cycloalkyl group;

[0125] n = 1, 2, 3.

[0126] This invention relates to a compound of formula (II-2-2), its stereoisomers, tautomers, and pharmaceutically acceptable salts.

[0127]

[0128] Among them, R 12 The following are the possible values: deuterium, hydrogen, alkyl, deuterated alkyl, haloalkyl, amino, alkylamino, deuterated alkylamino, cycloalkyl, cycloalkylamino, and deuterated cycloalkylamino.

[0129] R 10 R 11 R D1 Selected from hydrogen, deuterium, alkyl, deuterated alkyl, and halogen;

[0130] E1 can be hydrogen, deuterium, alkyl, or deuterated alkyl.

[0131] Among them, R 1 R 2 R 3 R 4 R 5 R 7 Selected from hydrogen, deuterium, halogen, amino, alkynyl, deuterated alkynyl, alkenyl, deuterated alkenyl, alkyl, deuterated alkyl; wherein, alkynyl, alkenyl, deuterated alkynyl, deuterated alkenyl, alkyl and deuterated alkyl are arbitrarily substituted by halogen, alkyl, hydroxyl, amino, cycloalkyl, aryl, heteroaryl.

[0132] R 9a R 9b R 9c Selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, cycloalkyl, deuterated cycloalkyl, alkynyl, deuterated alkynyl, or R 9a and R 9b Together with the attached carbon atom, it forms a cycloalkyl group;

[0133] n1 = 1, 2, 3;

[0134] n2 = 1, 2, 3.

[0135] The following compounds of the present invention, their stereoisomers, tautomers, pharmaceutically acceptable salts,

[0136]

[0137]

[0138] The present invention provides a pharmaceutical composition comprising one or more compounds of any one of the present invention and a pharmaceutically acceptable carrier or diluent.

[0139] Use of a compound of any one of the present invention in the preparation of a medicament for treating a disease, wherein the disease is an inflammatory or autoimmune disease mediated by the kinase TYK2, a tumor, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, lupus erythematosus, neurodermatitis, dermatitis, atopic dermatitis, psoriasis, psoriatic arthritis, Crohn's disease, Sjogren's syndrome or scleroderma. Detailed Description of the Invention

[0141] All technical and scientific terms used in this specification have the meanings commonly understood by those of ordinary skill in the art.

[0142] The term "hydrogen" as used herein refers to -H.

[0143] The term "deuterium" as used herein refers to -D.

[0144] The term "halogen" as used herein refers to -F, -Cl, -Br and -I.

[0145] The term "oxygen atom" as used herein refers to O.

[0146] The term "carbon atom" as used herein refers to C.

[0147] The term "nitrogen atom" as used herein refers to N.

[0148] The term "sulfur atom" as used herein refers to S.

[0149] The term "carbonyl" as used herein refers to -C(O)-.

[0150] The term "amino" as used herein refers to -NH2.

[0151] The term "hydroxyl" as used herein refers to -OH.

[0152] The term "alkyl" herein refers to a saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, including both straight-chain and branched hydrocarbon groups. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, etc. The alkyl groups described herein may optionally be substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, acyloxy, oxo, amide, ester, amino, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aryl, or heteroaryl.

[0153] The term "cycloalkyl" refers to an alkyl group substituted with a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 10 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0154] The term "aryl" herein refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group, or a polycyclic (i.e., a ring with adjacent carbon atom pairs) group having a conjugated π-electron system. An aryl group can be covalently linked to a defined chemical structure at any carbon atom to produce a stable structure. The aryl group described herein may optionally be substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, amino, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl, and cycloalkoxy.

[0155] The term "heteroaryl" herein refers to an aromatic group consisting of 5 to 10 atoms and containing at least one heteroatom selected from N, O, or S. The term may have a single ring (non-limiting examples include furan, thiophene, imidazole, pyrazole, pyridine, pyrazine, oxazole, thiazole, etc.) or multiple fused rings (non-limiting examples include benzothiophene, benzofuran, indole, isoindole, etc.), wherein the fused rings may or may not be aromatic groups containing heteroatoms, assuming the connecting point is through an atom of the aromatic heteroaryl group. The heteroaryl group described herein may optionally be substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, amino, alkyl, alkoxy, acyl, acyloxy, amide, ester, amino, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl, and cycloalkoxy.

[0156] The term "alkenyl" herein refers to an alkenyl group having 2 to 8 carbon atoms and having at least one alkenyl unsaturated site. Non-limiting examples of alkenyl groups include vinyl, propenyl, allyl, isopropenyl, butenyl, isobutenyl, etc. The alkenyl groups described herein may optionally be substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, amino, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkoxy, mercapto, alkyl mercapto, deuterated alkyl mercapto, sulfone, sulfoxide, amino, silyl, phosphono, deuterated alkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl, ester.

[0157] The term "alkynyl" herein refers to an alkyl group in which two adjacent carbon atoms are linked by a triple bond, wherein the alkyl group is as defined herein. Alynyl means an unsaturated alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, etc. Alynyl groups can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, amino, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkoxy, mercapto, alkyl mercapto, deuterated alkyl mercapto, sulfone, sulfoxide, amino, silyl, phosphono, deuterated alkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl, ester. Detailed implementation method:

[0158] The present invention is further illustrated below with examples, but is not limited thereto. Throughout this application, various embodiments of the compounds and methods of the present invention are mentioned. The present invention is not limited to these embodiments; the following embodiments are merely illustrative of methods for practicing the present invention and do not limit the scope of the invention in any way.

[0159] The compounds provided in this invention can be prepared using standard synthetic methods known in the art, and this specification provides a general method for preparing the compounds of this invention. Starting materials are generally commercially available or prepared using methods well known to those skilled in the art.

[0160] Process 1 is as follows:

[0161]

[0162] First, starting with SM-1, it reacts with SM2 to obtain IM-1, and then reacts with SM-3 to obtain compound I.

[0163] Process 2 is as follows:

[0164]

[0165]

[0166] First, starting with SM-1, it reacts with SM-2A to obtain IM-1A, then reacts with SM-3 to obtain IM-2A, and after removing the protecting group, it obtains IM-3A, and then further reacts to obtain compound IA.

[0167] The following examples further explain and illustrate the compounds of the present invention and their corresponding preparation methods. It should be understood that although typical or preferred reaction conditions are given in the specific examples, other reaction conditions may be used by those skilled in the art. Optimal reaction conditions may vary depending on the specific reaction substrate or solvent used, but these conditions can be determined by those skilled in the art through conventional optimization.

[0168] intermediate preparation

[0169] Deuterated propyne bromide was prepared from 3-bromopropyne according to the preparation method described in the reference (Journal of Medicinal Chemistry (2004), 47(2), 400-410). MS: m / z 262.1, [M+H] + .

[0170]

[0171] The preparation method described in the reference (Journal of the Chinese Chemical Society (Taipei) (1998), 45(2), 307-312) and the corresponding deuterated reagent (deuterated water) were used to prepare deuterated propargyl bromide.

[0172]

[0173] The preparation method in the reference (Bioorganic & Medicinal Chemistry (2013), 21(21), 6634-6641) and the corresponding deuterated reagent (deuterated lithium aluminum hydride) were used to prepare deuterated propargyl bromide.

[0174]

[0175] Step 1:

[0176] 2.4 g of lithium aluminum hydride deuterated was dispersed in 150 ml of diethyl ether and cooled to -50 °C. A solution of 6.0 g of methyl propynate in 150 ml of diethyl ether was slowly added dropwise. After the addition was complete, the mixture was stirred at -30 °C, then brought to room temperature and stirred overnight. 3 ml of heavy water, 0.22 g of sodium hydroxide dissolved in 1.5 ml of heavy water, and 2 ml of heavy water were added dropwise to the reaction mixture. The mixture was filtered, and the filter cake was washed twice with 30 ml of diethyl ether. The filtrate was collected and concentrated under reduced pressure to obtain a deep yellow oily product. This product was then distilled under reduced pressure at 130 °C to obtain 2.3 g of a colorless oily substance.

[0177] Step 2:

[0178] 1.2 g of deuterated propargyl alcohol was dissolved in 15 ml of dichloromethane under nitrogen protection. The mixture was cooled to -5 °C, and 6.0 g of phosphorus tribromide was slowly added dropwise. After the addition was complete, the mixture was stirred at -5 °C for 1 hour, and then brought to room temperature with stirring. 15 ml of ice water was added to the reaction mixture, and the layers were separated. The organic layer was washed successively with 25 ml of saturated sodium bicarbonate solution and 25 ml of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding 1.6 g of a pale yellow oily liquid.

[0179] Alternatively, the following method can be used for preparation:

[0180]

[0181] In a 50 mL single-necked flask, (300 mg, 1.55 mmol) of (3-bromoprop-1-yn-1-yl-3,3-d2)trimethylsilane, 644 mg, 4.7 mmol of potassium carbonate, and 3 mL of methanol-OD were added. The mixture was stirred at room temperature for 30 min after the addition was complete. The insoluble matter in the reaction solution was removed by filtration. 50 mL of heavy water was added to the filtrate, and the mixture was extracted with diethyl ether. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product.

[0182] The preparation methods in the references (WO2017181918; Journal of the American Chemical Society (1990), 112(8), 3156-3162; Journal of Organic Chemistry (1988), 53(20), 4748-4758); Organic Letters (2007), 9(16), 2981-2984; Bulletin of the Chemical Society of Japan (2003), 76(2), 347-353; Angewandte Chemie, International Edition (2016), 55(9), 3171-3175) yielded the following deuterated intermediates:

[0183]

[0184] Cyanocyclopropane was added dropwise to a deuterated methanol solution containing sodium methoxide, and the mixture was refluxed for 16 h. The deuterated methanol was removed by concentration under reduced pressure, and the resulting solution was a yellow solution (GC-MS: 69.1). Then, a mixed solution of deuterated methanol and deuterated water was added, and the mixture was refluxed for another 8 h. The solvent was removed by concentration under reduced pressure, yielding the target product.

[0185]

[0186] Add 50g of SMD1 and 35ml of heavy water to a 500ml three-necked flask. Under nitrogen protection, heat to 100℃ to dissolve the solution. Remove most of the water (approximately 25ml-30ml) by vacuum distillation. Add 25ml of heavy water to the system and remove water again by vacuum distillation. Repeat this process three times to ensure sufficient exchange between the carboxyl hydrogen and the deuterium in the heavy water. Heat the system to 160℃ and continue vacuum distillation to remove water. Heat the system to 200℃ and collect the fraction between 180℃ and 200℃ by vacuum distillation. Complete the distillation in 5-10 minutes to obtain 22g of a colorless oily fraction.

[0187] In a 250 mL three-necked flask, add SMD2 (6.5 g), dichloromethane (30 mL), and DMF (0.5 mL). Under nitrogen protection, cool to 0–-10 °C, and add oxaloyl chloride (9.5 g) dropwise while maintaining the internal temperature below 0 °C. After the addition is complete, maintain the reaction temperature at 0 °C for 2–3 h. Monitor the reaction by TLC until complete, and concentrate under reduced pressure to remove dichloromethane. In another reaction flask, add 150 mL of THF, under nitrogen protection, cool to 0 °C, and purge with ammonia until saturated. Add the concentrated oxaloyl chloride solution in portions to the THF solution. After the addition is complete, warm to 20 °C and stir for 20 min. Filter, and concentrate the filtrate to obtain 1.6 g of the target product.

[0188]

[0189] Step 1

[0190] In a 250 ml three-necked flask, add 10.0 g of trimethylsilyne and 100 ml of dry tetrahydrofuran, cool to -80 °C, and add 40 ml of n-butyllithium dropwise. After the addition is complete, react at -80 °C for 30 min. Continue to add 10.6 g of methyl chloroformate dropwise. After the addition is complete, naturally warm to about -50 °C and maintain the temperature for 30 min. Quench the reaction solution in 200 ml of ammonium chloride aqueous solution, extract with 200 ml of diethyl ether, separate the layers, dry, concentrate to obtain crude product, and purify by silica gel column chromatography to obtain 8.0 g of pale yellow liquid. 1 H NMR (400MHz, CDCl3): δ3.79 (s, 3H), 0.26 (s, 9H).

[0191] Step 2

[0192] In a 500ml single-necked flask, add the product from the previous step (7.0g) and diethyl ether (300ml), cool to 0℃, and add LiAlD4 (1.5g) in portions. After the addition is complete, maintain the temperature for 1h. Slowly add an appropriate amount of water to the reaction solution to quench the reaction. After the addition is complete, add an appropriate amount of anhydrous sodium sulfate to dry the solution, filter, concentrate the filtrate to obtain the crude product, and purify by column chromatography to obtain 4.0g of colorless liquid. 1 H NMR (400MHz, CDCl3): δ1.95 (br s, 1H), 0.18 (s, 9H).

[0193] Step 3

[0194] In a 250 ml single-necked flask, add the product from the previous step (4.0 g), triphenylphosphine (8.1 g), and dichloromethane (100 ml). Cool to 0 °C, and add NBS (5.5 g, 30.9 mmol) in portions, stirring for 30 min after each addition. Concentrate the reaction solution under reduced pressure at 0 °C to remove most of the dichloromethane solvent. Add 100 ml of n-hexane to the remaining solution, stir, and filter. Directly precipitate the filtrate by column chromatography. Concentrate the eluent under reduced pressure at 10 °C to obtain approximately 3.0 g of a colorless liquid.

[0195] Step 4

[0196] In a 50ml single-necked flask, add the product from the previous step (2.0g), acetone (40ml), water (1ml), and silver trifluoromethanesulfonate (270mg). After addition, stir at room temperature for 1 hour. Pour the reaction solution into 200ml of saturated ammonium chloride aqueous solution, extract with 200ml of diethyl ether, separate the layers, dry, and concentrate under reduced pressure at 0℃ to obtain 2.0g of colorless liquid (containing a small amount of solvent), which can be used directly.

[0197] Compound preparation

[0198] Example 1:

[0199]

[0200] Step 1

[0201] Add 3.0 g of 2-aminopyridine compound and 50 ml of N,N-dimethylformamide to the reaction flask, cool to 0°C, and add sodium hydride (1.5 g) in portions. After the addition is complete, stir for 20 min, then slowly raise the temperature to room temperature and stir for another 30 min. Cool the reaction solution to 0°C, and slowly add 40 ml of tetrahydrofuran solution of 3.9 g of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide, controlling the temperature to be below 5°C. Stir overnight after the addition is complete. Add 20 ml of ammonium chloride aqueous solution and 40 ml of water to the reaction solution, stir for 30 min, filter, wash the filter cake twice with water, and dry to obtain 3.95 g of grayish-white solid. 1 H NMR (400MHz, CDCl3): δ12.53 (s, 1H), 9.39 (s, 1H), 8.38 (s, 1H), 8.34 (s, 1H), 8.22 (d, J = 5.2Hz, 1H), 7.65 (d ,J=5.2Hz,1H),5.62(s,2H),4.04(s,3H),3.74(t,J=8.2Hz,2H),0.98(t,J=8.2Hz,2H),0.02(s,9H).MS:m / z 494.2[M+H] + .

[0202] Step 2

[0203] The product from the previous step (2.4 g), DCPF (1.1 g), palladium acetate (111 mg), cesium carbonate (8 g), and DME (90 ml) were added sequentially to the reaction flask. After purging with nitrogen, the mixture was heated to 90 °C and reacted for 1 hour. The reaction solution was cooled to room temperature, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give 2.76 g of a pale yellow solid compound. MS: m / z 543.3 [M+H] + .

[0204] Step 3

[0205] Add the product from the previous step (2.7 g) and trifluoroacetic acid (60 ml) sequentially to the reaction flask, stir overnight at 70°C, concentrate under reduced pressure to dryness, add toluene (100 ml) and concentrate again to dryness. Add tetrahydrofuran (100 ml) to the concentrate, slowly add sodium bicarbonate at room temperature to adjust the pH to 7-8, filter under vacuum to remove solids, concentrate the filtrate and use it directly in the next step.

[0206] Step 4

[0207] Add N,N-dimethylformamide (50 ml) and bromopropyne (3.6 g) to the product from the previous step, and stir at room temperature for 30 min. Add potassium carbonate (2.8 g) in portions, and after the addition is complete, react at room temperature for 2 h. Add water (100 ml) to the reaction solution, extract three times with methyl tert-butyl ether, combine the organic phases, concentrate to dryness, and purify by silica gel column chromatography to give 450 mg of a pale yellow solid, compound 7. 1 H NMR (400MHz, DMSO-d6): δ12.46(s,1H),11.36(s,1H),9.89(s,1H),9.25(s,1H),8.79(s,1H),8.16(d,J=5.2Hz,1H),7.50 (d,J=5.2Hz,1H),5.29(d,J=2.5Hz,2H),3.91(s,3H),3.63(t,J=2.5Hz,1H),2.19–2.08(m,1H),0.98–0.81(m,4H).MS:m / z 451.2[M+H] + .

[0208] Example 2:

[0209]

[0210] Compound 8 can be prepared according to the preparation method described in Example 1. MS: m / z 453.2, [M+H] + The specific preparation method is as follows:

[0211] In a 50 ml single-necked flask, 310 mg of a triazole compound, 45 ml of N,N-dimethylformamide, and 1.2 g of 3-bromoprop-1-yne-3,3-d2 were added. While stirring, 310 mg of potassium carbonate was added in portions. After the addition was complete, the mixture was stirred at room temperature for 1 h. The reaction solution was quenched in 400 ml of water, extracted with 200 ml of ethyl acetate, separated, and the organic phase was washed three times with 200 ml of water. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 120 mg of a pale yellow solid. 1 H NMR (400MHz, DMSO-d6): δ12.47(s,1H),11.37(s,1H),9.90(s,1H),9.26(s,1H),8.80(s,1H),8.16(d, J=5.2Hz,1H),7.51(d,J=5.2Hz,1H),3.91(s,3H),3.63(s,1H),2.18-2.09(m,1H),0.94-0.84(m,4H).

[0212] Example 3:

[0213]

[0214] Compound 9 can be prepared according to the preparation method described in Example 1. MS: m / z 454.4, [M+H] + The specific preparation method is as follows:

[0215] In a 25 ml single-necked flask, 200 mg of a triazole compound, 15 ml of N,N-dimethylformamide, and 1.0 g of 3-bromoprop-1-yne-1,3,3-d3 were added. While stirring, 210 mg of potassium carbonate was added in portions. After the addition was complete, the mixture was stirred at room temperature for 1 h. The reaction solution was quenched in 200 ml of water, extracted with 100 ml of ethyl acetate, separated, and the organic phase was washed three times with 100 ml of water. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 80 mg of a pale yellow solid. 1 H NMR (400MHz, CDCl3): δ12.47(s,1H),11.37(s,1H),9.90(s,1H),9.26(s,1H),8.80(s,1H),8.16(d, J=5.2Hz,1H),7.51(d,J=5.2Hz,1H),3.90(s,3H),2.15-2.12(m,1H),0.95-0.82(m,4H).HR-MS:m / z 454.2226[M+H] + .

[0216] Example 4:

[0217]

[0218] Compound 10 can be prepared according to the preparation method described in Example 1. MS: m / z 453.4 [M+H] + .

[0219] Example 5:

[0220]

[0221] Compound 11 can be prepared according to the preparation method described in Example 1. MS: m / z 452.3 [M+H] + The specific preparation method is as follows:

[0222]

[0223] Step 1

[0224] Triazole compound (1.20 g), cyclopropane-1-d-1-carboxamide (0.42 g), Xanthpos (0.28 g), Cs₂CO₃ (1.58 g), Pd₂(dba)₃ (0.22 g), and 1,4-dioxane (30 mL) were added sequentially to a reaction flask. Under nitrogen protection, the mixture was heated to 100 °C and stirred. After the reaction was complete, the mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layers were combined, concentrated under reduced pressure to obtain an oily substance, and purified by silica gel column chromatography to give 0.74 g of a yellow solid. MS: m / z 544.3 [M+H] + .

[0225] Step 2

[0226] The product from the previous step (0.72 g), dichloromethane (2.2 ml), and tetraethylammonium fluoride (2.16 g) were added sequentially to the reaction flask. Trifluoroacetic acid (5.04 ml) was added dropwise while stirring. After the addition was complete, the reaction was stirred at room temperature. After the reaction was complete, the mixture was concentrated, water was added, and impurities were extracted with methyl tert-butyl ether. The aqueous phase was collected, and the pH was adjusted with saturated sodium bicarbonate. The precipitated solid was filtered, dried, and yielded 0.44 g of a pale yellow solid. MS: m / z 414.2 [M+H] + .

[0227] Step 3

[0228] The product from the previous step (0.43 g), N,N-dimethylacetamide (20 ml), and bromopropyne (0.99 g) were added sequentially to the reaction flask. The mixture was stirred until dissolved, and potassium carbonate (1.01 g) was added in portions. The reaction was carried out at room temperature. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water, dried, and concentrated under reduced pressure to obtain a yellow oily substance. The substance was purified by silica gel column chromatography to obtain 81 mg of a white solid. 1 H NMR (400MHz, DMSO-d6): δ12.47(s,1H),11.37(s,1H),9.90(s,1H),9.26(s,1H),8.80(s,1H),8.16(d,J=5.2 Hz, 1H), 7.51 (d, J = 5.2Hz, 1H), 5.29 (d, J = 2.6Hz, 2H), 3.91 (s, 3H), 3.64 (t, J = 2.5Hz, 1H), 0.94-0.83 (m, 4H).

[0229] Under appropriate reaction conditions, in the preparation process of structures such as those in Example 1 and Example 5, the final step of the triazole propargylation chemical reaction exhibits better chemoselectivity than that of substituents such as methyl; and better chemoselectivity than the reaction of triazole nitrogen atoms in similar structures where "ring A" in general formula (I) is another ring system; the resulting compound product is easily crystallized. These characteristics facilitate post-processing and purification.

[0230] Example 6:

[0231]

[0232] Step 1

[0233] In a 500 ml single-necked flask, 9.66 g of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide, 10.0 g of triazole compound, and 200 ml of ethylene glycol dimethyl ether were added. The mixture was stirred until dissolved, cooled to 10-20 °C, and LiHMDS (1 M in THF, 110 ml) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC until complete. The reaction solution was poured into 300 ml of saturated ammonium chloride aqueous solution, extracted with ethyl acetate, separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 500 ml of methyl tert-butyl ether was added to the residue, precipitating a solid. The solid was filtered, and the filtrate was concentrated to dryness. 500 ml of a solvent of n-hexane:ethyl acetate = 4:1 was added to the concentrate, and the mixture was allowed to stand overnight to crystallize, yielding 5.3 g of a pale yellow solid.

[0234] Step 2

[0235] In a 250 ml single-necked flask, add the product from the previous step (4.0 g), cyclopropionamide (1.4 g), potassium phosphate (5.16 g), BINAP (2.0 g), palladium acetate (182 mg), aluminum trifluoromethanesulfonate (192 mg), and ethylene glycol dimethyl ether (150 ml). After purging with nitrogen, heat to 90 °C and react overnight. Cool the reaction solution to room temperature, pour into 500 ml of water, extract with ethyl acetate, separate, dry, and concentrate to obtain 6.5 g of crude product, which can be used directly in the next step.

[0236] Step 3

[0237] In a 250 ml single-necked flask, add the crude product from the previous step (6.5 g), dichloromethane (70 ml), and tetraethylammonium fluoride (4.2 g). Stir for 10 minutes, then add trifluoroacetic acid (60 ml) and stir overnight at room temperature. Concentrate the reaction solution under reduced pressure, pour the residue into 100 ml of saturated sodium bicarbonate aqueous solution, extract with ethyl acetate, dry to anhydrous sodium sulfate, filter, concentrate to dryness under reduced pressure, and then beat with 50 ml of ethyl acetate to obtain 3.5 g of yellow solid. 1 H NMR (400MHz, DMSO-d6): δ = 11.36 (br s,1H),11.00(s,1H),9.17(s,1H),8.32(s,1H),8.16(s,1H),7.76(dd,J=7.9,1.5Hz,1H),7.55( dd,J=8.0,1.5Hz,1H),7.31(t,J=7.9Hz,1H),3.69(s,3H),2.14-2.02(m,1H),0.88-0.75(m,4H).13 C NMR (100MHz, DMSO-d6) δ = 174.2, 167.0, 156.3, 154.5, 150.9, 148.6, 145.2, 135.5, 132.6, 126.4, 125.1, 124.7, 124.0, 97.2, 61.6, 14.9, 8.6.

[0238] Step 4

[0239] In a 50 ml single-necked flask, add the product from the previous step (1.3 g), 2-chloroethyl methyl sulfide (1.4 g), N,N-dimethylacetamide (30 ml), potassium carbonate (1.1 g), and sodium iodide (100 mg). After addition, heat to 100 °C and react for 1 h. Pour the reaction solution into 500 ml of water, extract with ethyl acetate, combine the organic phases, wash three times with water, dry to anhydrous sodium sulfate, filter, concentrate under reduced pressure to dryness, and purify by silica gel column chromatography to give 400 mg of a pale yellow solid. 1 H NMR (400MHz, DMSO-d6): δ = 11.35 (s, 1H), 11.01 (s, 1H), 9.16 (s, 1H), 8.66 (s, 1H), 8.18 (s, 1H), 7.67 (dd, J = 7.8, 1.5Hz, 1H), 7.53 (dd, J = 7.9, 1. 4Hz,1H),7.30(t,J=7.9Hz,1H),4.46(t,J=6.5Hz,2H),3.72(s,3H),2.99(t,J=6.6Hz,2H),2.13-2.06(m,1H),2.05(s,3H),0.87-0.79(m,4H). 13 C NMR (100MHz, DMSO-d6): δ=174.2,167.0,159.4,156.3,151.0,145.6,145.2,135 .5,133.0,126.6,126.5,124.8,123.2,97.2,61.6,48.6,33.4,14.8,8.6.MS:m / z 486.2[M+H] + .

[0240] Step 5

[0241] In a 50 ml single-necked flask, add the product from the previous step (360 mg), acetic acid (10 ml), NaIO4 (500 mg), and 2 drops of water. After the addition is complete, heat to 50 °C and react for 2 h. Pour the reaction solution into 100 ml of saturated sodium bicarbonate aqueous solution, extract with ethyl acetate, dry to anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 250 mg of a pale yellow solid. 1H NMR (400MHz, DMSO-d6): δ = 11.35 (s, 1H), 11.01 (s, 1H), 9.16 (s, 1H), 8.70 (s, 1H), 8.17 (s, 1H), 7.67 (dd, J = 7.9, 1.6Hz, 1H), 7.53 (dd, J = 8.0, 1. 5Hz,1H),7.29(t,J=7.9Hz,1H),4.68(t,J=6.6Hz,2H),3.73(s,3H),3.38(t,J=6.6Hz,2H),2.62(s,3H),2.13-2.03(m,1H),0.89-0.75(m,4H). 13 C NMR (100MHz, DMSO-d6): δ=174.2,167.0,159.6,156.3,151.0,145.6,145.2,135.5,1 33.0,126.51,126.48,124.8,123.3,97.2,61.6,52.6,43.2,38.6,14.9,8.6.MS:m / z 502.2[M+H] + .

[0242] Example 7:

[0243]

[0244] Step 1

[0245] 55 g of methyl 2-methoxy-3-nitrobenzoate, 1200 ml of ammonia-methanol solution (7 M), and 500 ml of ammonia water were added to a 2000 ml single-necked flask. After the addition was complete, the mixture was stirred at room temperature for 17 hours. After the reaction was complete, the mixture was concentrated to dryness, 1000 ml of water was added, and the mixture was stirred for 10 minutes. The mixture was then filtered, the filter cake was washed twice with water, collected, and dried to obtain 50 g of a yellow solid. 1 H NMR (400MHz, CDCl3): δ8.27(dd,J=7.9,1.8Hz,1H),7.95(dd,J=8.1,1.8Hz,1H),7.43(br s,1H),7.36(t,J=8.0Hz,1H),6.85(br s,1H),4.01(s,3H).MS:m / z197.1[M+H] + .

[0246] Step 2

[0247] 50 g of 2-methoxy-3-nitro-benzamide and 300 ml of N,N-dimethylformamide dimethyl acetal (DMF-DMA) were added to a 3000 ml single-necked flask. After addition, the mixture was stirred at 95 °C for 1 hour and concentrated to dryness. The solution was then azeotropically treated twice with 1,2-dichloroethane. 2000 ml of anhydrous ethanol and 250 ml of acetic acid were added to the concentrate. 120 ml of hydrazine hydrate was slowly added dropwise under ice bath conditions. After addition, the mixture was stirred at room temperature for 6 hours. After the reaction was complete, the solution was concentrated to dryness. 1000 ml of water was added and the mixture was stirred for 10 minutes. The mixture was filtered, the filter cake was washed with water, collected, and dried to give 55 g of a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ8.55(s,1H),8.22(dd,J=7.9,1.6Hz,1H),7.99(dd,J=8.0,1.4Hz,1H),7.46(t,J=8.0Hz,1H),3.81(s,3H).MS:m / z221.1[M+H] + .

[0248] Step 3

[0249] Add the product from the previous step (10 g), N,N-diisopropylethylamine (8.2 g), 4-dimethylaminopyridine (55.5 mg), and dichloromethane (150 ml) to a 500 ml single-necked flask. Add 2-(trimethylsilyl)ethoxymethyl chloride (9.1 g) dropwise at room temperature. After the addition is complete, stir at room temperature for 3 hours. TLC monitoring shows the reaction is approximately 50% complete. Filter the reaction solution, concentrate under reduced pressure, dissolve the residue in 200 ml of ethyl acetate, wash three times with water (200 ml each time), dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 5.3 g of a yellow oil. The product is a mixture of isomers in a ratio of approximately 62:38. The proton NMR spectra of the more abundant isomer are shown below: 1 H NMR (400MHz, CDCl3): δ8.36 (s, 1H), 8.26 (dd, J=7.8, 1.7Hz, 1H), 7.83 (dd, J=8.1, 1.7Hz, 1H), 7.32 (t, J= 8.0Hz,1H),5.60(s,2H),3.96(s,3H),3.73(t,J=8.2Hz,2H),0.97(t,J=8.3Hz,2H),0.01(s,9H).MS:m / z 351.2[M+H] + .

[0250] Step 4

[0251] Add 5.3 g of the product from the previous step, 150 ml of ethanol, and 530 mg of 5% palladium on carbon to a 500 ml single-necked flask. After the addition is complete, purge the mixture with hydrogen gas and react at room temperature for 3 hours. After the reaction is complete, filter the reaction solution through a diatomaceous earth liner. Concentrate the filtrate to obtain 4.8 g of a yellow oily substance. MS: m / z 321.2 [M+H] + .

[0252] Step 5

[0253] Add the product from the previous step (4.8 g), 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (2.97 g), and tetrahydrofuran (20 ml) to a 250 ml single-necked flask. Purge with nitrogen and slowly add bis(trimethylsilyl)aminolithium (35.7 ml) dropwise under ice bath conditions. After the addition is complete, continue the reaction for 0.5 hours. After the reaction is complete, pour the reaction solution into 50 ml of ammonium chloride aqueous solution, then add 200 ml of water and 200 ml of ethyl acetate. Stir, allow to stand, separate the layers, dry to anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 5 g of a yellow oil. MS: m / z 493.2 [M+H] + .

[0254] Step 6

[0255] Add the product from the previous step (5 g), cyclopropionamide (1.2 g), cesium carbonate (19 g), BINAP (1.6 g), toluene (150 ml), and palladium acetate (262 mg) to a 500 ml single-necked flask. After the addition is complete, purge with nitrogen and react at 90 °C for 1.5 h. After the reaction is complete, cool to room temperature, dilute with 200 ml of water, extract three times with ethyl acetate, combine the organic phases, dry to anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to give 3 g of a yellow oil. MS: m / z 542.3 [M+H] + .

[0256] Example 8:

[0257]

[0258] Step 1

[0259] In a 100 mL single-necked flask, 6-(cyclopropylamide)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (3 g), 2-(Boc-amino)-bromoethane (4.8 g), potassium carbonate (2.18 g), sodium iodide (200 mg), and DMSO (70 mL) were added. The mixture was heated to 100 °C and stirred for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic layers were combined. The mixture was washed three times with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to give 800 mg of a pale yellow solid, in 19% yield. MS: m / z 555.3 [M+H] + .

[0260] Step 2

[0261] Add the product from the previous step (800 mg) and dichloromethane (20 ml) to a 100 ml single-necked flask, then slowly add TFA (10 ml) dropwise and stir at room temperature for 2 hours. After the reaction is complete, concentrate under reduced pressure, add saturated aqueous sodium bicarbonate solution to the concentrate, extract with ethyl acetate, combine the organic layers, wash once with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by silica gel column chromatography (ethyl acetate) to obtain 600 mg of a white solid product.

[0262] Step 3

[0263] Add carbon disulfide (0.5 g) and tetrahydrofuran (50 ml) to a 100 ml single-necked flask, purge with nitrogen, and slowly add methyl magnesium bromide (1 M) dropwise at room temperature. After the addition is complete, heat to 65 °C and stir for 1 hour. After the reaction is complete, cool to room temperature, add 1-chlorobenzotriazole (1 g), and continue stirring at room temperature for 20 minutes. Set aside for later use.

[0264] Add the product from the previous step (350 mg) and DMF (35 ml) to a 50 ml single-necked flask, and slowly add the prepared reagent (9 ml) dropwise at room temperature, stirring for 30 minutes. After the reaction is complete, slowly pour the solution into water to quench the reaction, extract with ethyl acetate, combine the organic layers, wash once with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by silica gel column chromatography to obtain 180 mg of a reddish-brown solid. 1H NMR (400MHz, CDCl3): δ10.99(s,1H),9.86(s,1H),8.70(s,1H),8.17-8.10(m,3H),7.83(dd,J=7.9,1.5Hz,1H),7.52(dd,J=7.9,1.4Hz,1H),7. 29(t,J=7.9Hz,1H),4.57-4.54(m,2H),4.22-4.18(m,2H),3.83(s,3H) ,2.55(s,3H),1.87-1.81(m,1H),1.09-1.05(m,2H),0.95-0.88(m,2H). 13 C NMR (100MHz, CDCl3): δ202.4,173.6,166.8,160.5,155.7,151.4,146.0,144.2,134.8,132 .2,127.2,125.7,124.9,124.3,98.1,61.5,47.0,45.1,34.0,16.0,8.9.MS:m / z513.2[M+H] + .

[0265] Example 9:

[0266]

[0267] Step 1

[0268] In a 500ml three-necked flask, add 40ml of concentrated hydrochloric acid and 40ml of water. Slowly add 20ml of an aqueous solution of sodium nitrite (2.1g, 30.4mmol) dropwise under ice bath conditions, stirring at 0–5°C for 1 hour. Then, slowly add 20ml of a concentrated hydrochloric acid solution of stannous chloride (17.1g, 90.2mmol), stirring at 0–5°C for 2 hours. After the reaction is complete, filter through a diatomaceous earth liner. Adjust the pH of the filtrate to approximately 8 with a saturated sodium hydroxide solution, extract with ethyl acetate, combine the organic layers, wash once with saturated brine, dry to anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, add 30ml of methyl tert-butyl ether, stir at room temperature for 20 minutes, filter, and dry the filter cake to obtain 2.4g of a yellow solid. MS: m / z 184.1 [M+H] + .

[0269] Step 2

[0270] Add the product from the previous step (2.4 g), 1,1,3,3-tetramethoxypropane (2.6 g), and anhydrous ethanol (60 ml) to a 100 ml single-necked flask, and heat to 80 °C with stirring for 2 hours. Slowly add concentrated hydrochloric acid (1.5 ml) dropwise, and stir at 80 °C for 2 hours. After the reaction is complete, cool to room temperature, concentrate to dryness, slowly add saturated NaHCO3 aqueous solution to adjust the pH of the aqueous phase to 7-8, extract with ethyl acetate, combine the organic layers, wash once with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by silica gel column chromatography to give 2.8 g of pink solid. MS: m / z 220.1 [M+H] + .

[0271] Step 3

[0272] The product from the previous step (2.8 g, 12.8 mmol), 5% Pd / C (1 g), and methanol (60 ml) were added to a 100 ml single-necked flask. The mixture was purged with hydrogen and stirred at room temperature for 5 hours. After the reaction was complete, the mixture was filtered through a diatomaceous earth filter, and the filtrate was concentrated to give 1.8 g of a pink solid. MS: m / z 190.1 [M+H] + .

[0273] Step 4

[0274] Add the product from the previous step (1.8 g, 9.6 mmol), 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (3.0 g, 14.4 mmol), and ethylene glycol dimethyl ether (70 ml) to a 250 ml three-necked flask. Purge with nitrogen, cool to 10–15 °C, and slowly add LiHMDS (1 M in THF, 38.4 ml). React at room temperature for 30 minutes. After the reaction is complete, quench with saturated ammonium chloride aqueous solution, extract with ethyl acetate, wash once with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, add methyl tert-butyl ether (60 ml), stir at room temperature for 20 minutes, filter, and dry the filter cake to give 2.8 g of a pale yellow solid. MS: m / z 362.1 [M+H] + .

[0275] Step 5

[0276] Add the product from the previous step (1.5 g), cyclopropionamide (530 mg), cesium carbonate (6.8 g), ethylene glycol dimethyl ether (60 ml), 1,1'-bis(dicyclohexylphosphine)-ferrocene (961 mg), and palladium acetate (95 mg) to a 100 ml single-necked flask. Heat to 90 °C and stir for 2 hours. After the reaction is complete, cool to room temperature, add water, extract with ethyl acetate, wash once with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, add methyl tert-butyl ether (60 ml), stir at room temperature for 20 minutes, filter, dissolve the filter cake in dichloromethane (20 ml), slowly add methyl tert-butyl ether (80 ml), stir at room temperature for 20 minutes, filter, dry the filter cake, and obtain 950 mg of an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ11.38(s,1H),11.07(s,1H),9.18(s,1H),8.22(d,J=2.4Hz,1H),8.21(s,1H),7.78(d,J=1.7Hz,1H), 7.47(td,J=8.5,1.6Hz,2H), 7.32(t,J=8.1Hz,1H), 6.57(t,J=2.1Hz, 1H), 3.46(s, 3H), 2.14-2.04(m,1H), 0.88-0.79(m, 4H). 13 CNMR (100MHz, DMSO-d6): δ174.2,167.0,156.4,145.2,144.9,141.1,135.5,1 34.8,133.1,131.9,125.2,121.6,121.3,107.8,97.5,61.2,14.9,8.6.MS:m / z 411.2[M+H] + .

[0277] Example 10:

[0278]

[0279]

[0280] Step 1

[0281] Add 32.8 g of 80% hydrazine hydrate and 60 ml of water to a 250 ml three-necked flask. Slowly add a 30 ml solution of tetrahydrofuran containing 10.0 g of p-toluenesulfonyl chloride under ice bath conditions. Stir at room temperature for 30 minutes. After the reaction is complete, concentrate off the tetrahydrofuran, cool to room temperature, filter, and dry the filter cake to give 8.3 g of a white solid. MS: m / z 187.1 [M+H] + .

[0282] Step 2

[0283] The product from the previous step (4.8 g), 2,2-dimethoxyacetaldehyde (3.6 g), and methanol (60 ml) were added to a 100 ml single-necked flask. The mixture was purged with nitrogen and stirred at room temperature for 3 hours. Acetic acid (1.3 g) and 2-methoxy-3-nitroaniline (3 g) were then added, and the mixture was heated to 75 °C and stirred for 16 hours. After the reaction was complete, the mixture was concentrated to dryness. A saturated NaHCO3 aqueous solution was slowly added to adjust the pH of the aqueous phase to 7–8. The mixture was extracted with ethyl acetate, and the organic layers were combined. The mixture was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to give 3.8 g of an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ8.63(d,J=1.2Hz,1H),8.16(dd,J=8.2,1.6Hz,1H),8.05(d, J=1.1Hz, 1H), 8.03 (dd, J=8.1, 1.6Hz, 1H), 7.57 (t, J=8.2Hz, 1H), 3.53 (s, 3H).MS: m / z 221.1[M+H] + .

[0284] Step 3

[0285] The product from the previous step (3.7 g), 5% Pd / C (2 g), and methanol (70 ml) were added to a 100 ml single-necked flask. The mixture was purged with hydrogen and stirred at room temperature for 5 hours. After the reaction was complete, the mixture was filtered through a diatomaceous earth liner, and the filtrate was concentrated to give 3.0 g of an off-white solid. MS: m / z 191.1 [M+H] + .

[0286] Step 4

[0287] Add the product from the previous step (3.0 g), 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (5.0 g), and ethylene glycol dimethyl ether (80 ml) to a 250 °C three-necked flask. Purge with nitrogen, cool to 10–15 °C, and slowly add LiHMDS (1 M in THF). React at room temperature for 30 minutes. After the reaction is complete, quench with saturated ammonium chloride aqueous solution, extract with ethyl acetate, wash once with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, add methyl tert-butyl ether (100 ml), stir at room temperature for 20 minutes, filter, and dry the filter cake to obtain 4.6 g of yellow solid. MS: m / z 363.1 [M+H] + .

[0288] Step 5

[0289] The product from the previous step (1.5 g), cyclopropionamide (529 mg), cesium carbonate (6.8 g), ethylene glycol dimethyl ether (60 ml), 1,1'-bis(dicyclohexylphosphine)-ferrocene (961 mg), and palladium acetate (95 mg) were added to a 100 ml single-necked flask. The mixture was heated to 90 °C and stirred for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, extracted with water and ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 230 mg of an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ11.41(s,1H),11.09(s,1H),9.20(s,1H),8.56(s,1H),8.22(s,1H),8.01(s,1H),7.66( d,J=8.0Hz,1H),7.49(d,J=8.1Hz,1H),7.41(t,J=8.0Hz,1H),3.47(s,3H),2.14-2.05(m,1H),0.90-0.78(m,4H). 13 C NMR (100MHz, DMSO-d6): δ174.3,167.0,156.4,146.0,144.8,135.5,134.3,133. 3,131.8,127.1,125.5,123.6,122.4,97.5,61.7,14.9,8.7.MS:m / z412.2[M+H] + .

[0290] Example 11:

[0291]

[0292] Step 1

[0293] In a 500 ml single-necked flask, add 18 g of tetrazolium compound, 15 g of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide, 5.8 g of lithium chloride, and 350 ml of dry tetrahydrofuran. After addition, purge with nitrogen and cool to 0 °C in an ice bath. Add 150 ml of bis(trimethylsilyl)aminolithium dropwise, and allow to warm naturally to room temperature for 2 h. Pour the reaction mixture into 500 ml of saturated ammonium chloride aqueous solution, extract with 500 ml of ethyl acetate, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Add 200 ml of dichloromethane solution, 3 g of triethylamine, and 8 g of triphenylchloromethane to the concentrate, and stir at room temperature for 30 min to remove unreacted tetrazolium starting material. After the reaction was complete, the reaction solution was washed with 200 ml of water, separated, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 19.0 g of a pale yellow oil.

[0294] Step 2

[0295] In a 500 ml single-necked flask, the product from the previous step (19 g), cyclopropionamide (6.6 g), BINAP (9.6 g), cesium carbonate (62.8 g), and toluene (450 ml) were added. After the addition was complete, the mixture was completely purged with nitrogen. The temperature was raised to 60 °C, and palladium acetate (865 mg) was added. The temperature was then raised to 90 °C and the reaction was carried out for 5 h. The remaining starting material was monitored by TLC. The reaction solution was poured into 500 ml of water, extracted with ethyl acetate (300 ml), and the organic phase was concentrated and purified by silica gel column chromatography to obtain 10 g of yellow solid.

[0296] Step 3

[0297] 100 g of tetraethylammonium fluoride dihydrate was added to a 250 ml single-necked flask and heated to 85 °C to melt it. 10 g of the product from the previous step was added, and the reaction was maintained at this temperature for 3 hours. The remaining starting material was monitored by TLC. The reaction solution was poured into 500 ml of water and stirred for 20 minutes, resulting in the precipitation of a large amount of solid. The solid was filtered, and the filter cake was washed with 200 ml of water. The filter cake was transferred to a 250 ml single-necked flask, and 100 ml of ethyl acetate was added. The mixture was stirred at room temperature for 30 minutes, filtered, and the filter cake was dried to obtain 5 g of a pale yellow solid.

[0298] Step 4

[0299] In a 100 ml single-necked flask, the product from the previous step (2.5 g), N,N-dimethylacetamide (50 ml), and bromopropyne (5.7 g) were added. After the addition was complete, the mixture was stirred at room temperature for 20 min. Then, potassium carbonate (5.9 g) was added in portions, and the mixture was stirred at room temperature for 3 h after the addition was complete. The reaction was monitored for completeness by LTC. The reaction solution was poured into 500 ml of ice water and extracted twice with 200 ml of ethyl acetate. The organic phase was then washed three times with 300 ml of water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1.5 g of crude product. The crude product was purified by silica gel column chromatography and then slurryed with 50 ml of ethyl acetate to obtain 650 mg of off-white solid. 1 H NMR (400MHz, DMSO-d6): δ11.38(s,1H),11.06(s,1H),9.18(s,1H),8.18(s,1H),7.73(dd,J=7.8,1.5Hz,1H),7.67(dd,J=8.0,1. 4Hz,1H),7.39(t,J=7.9Hz,1H),5.83(d,J=2.6Hz,2H),3.77(t,J=5.2Hz,1H),3.75(s,3H),2.15-2.03(m,1H),0.90-0.75(m,4H). 13C NMR (100MHz, DMSO-d6): δ174.2,167.0,162.5,156.3,151.2,145.0,135.5,133 .3,126.3,125.5,125.0,122.4,97.3,78.8,76.0,61.9,43.2,14.9,8.6.MS:m / z 451.2[M+H] + .

[0300] Example 12:

[0301]

[0302] Step 1

[0303] Ethyl 5-hydroxy-3-(methylthio)-1,2,4-triazine-6-carboxylate (4 g) and tetrahydrofuran (70 ml) were added to a reaction flask and cooled to 0°C. DIPEA (6.5 ml) and NMM (94 mg) were then slowly added sequentially, with the temperature controlled below 3°C. Phosphorus oxychloride (2.6 ml) was added dropwise, and the reaction was allowed to proceed for 1 hour after the addition was complete. Hexane was added to the reaction solution and stirred for 10 min. The mixture was then filtered through a diatomaceous earth filter. The filter cake was washed once with hexane, and the filtrate was concentrated to obtain 3.13 g of a pale yellow solid.

[0304] NMP (30 ml) and a triazole-SEM compound (4.7 g) were added to the concentrate, and the mixture was reacted at room temperature for 1 h. Saturated ammonium chloride (10 ml) and water (20 ml) were added to the reaction mixture, and the mixture was stirred in an ice bath for 30 min. The mixture was then filtered, the filter cake was washed twice with water, and dried to obtain 6.9 g of a pale yellow solid. MS: m / z 518.2 [M+H] + .

[0305] Step 2

[0306] The product from the previous step (6.9 g), deuterated methylamine hydrochloride (1.32 g, 18.7 mmol), lithium bromide (4.6 g), acetonitrile (120 ml), and DIPEA (12 ml) were added sequentially to the reaction flask. After purging with nitrogen, the mixture was stirred at room temperature for 45 minutes. Saturated ammonium chloride (50 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 × 3). The solution was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give 4.65 g of a pale yellow solid. MS: m / z 506.2 [M+H] + .

[0307] Step 3

[0308] Add 4.5 g of the product from the previous step, 7 M ammonia-methanol solution, and 70 ml of ammonia water to the reaction flask. After the addition is complete, slowly heat to 110 °C and react for 6 hours. Concentrate the reaction solution to a small volume, filter under vacuum, and extract the filtrate twice with dichloromethane. Combine the filter cake solids, dissolve them in dichloromethane, combine the dichloromethane solutions, dry with anhydrous sodium sulfate, filter, and concentrate to obtain 4.2 g of a yellow solid. MS: m / z 475.2 [M+H] + .

[0309] Step 4

[0310] The product from the previous step (4.2 g), dichloromethane (80 ml), and 2,6-dimethylpyridine (5.7 g) were added sequentially to the reaction flask. After purging with nitrogen, the mixture was cooled to 0 °C, and cyclopropionyl chloride (2.3 g) was slowly added dropwise. The reaction mixture was allowed to react for 30 min after the addition was complete. The reaction solution was quenched with saturated ammonium chloride, extracted three times with MTBE, and the organic phases were combined. The mixture was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and purified by silica gel column chromatography to give 4.2 g of a pale yellow solid. MS: m / z 543.3 [M+H] + .

[0311] Step 5

[0312] Add the product from the previous step (4.2 g), dichloromethane (4 ml), and TFA (80 ml) to the reaction flask, and heat to 40°C and react for 30 minutes. Concentrate to dryness under reduced pressure, add THF (80 ml) and sodium bicarbonate (20 g), stir until no more bubbles are released, filter, dry the filtrate, and concentrate to dryness. This solution can be used directly in the next step.

[0313] Step 6

[0314] The product from the previous step, DMF (40 ml), and potassium carbonate (2.1 g) were added sequentially to the reaction flask. Bromopropyne (7.4 g) was then added dropwise at room temperature, and the reaction was allowed to proceed for 1 hour at room temperature. The reaction was quenched with water, and the mixture was extracted three times with MTBE. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, purified by silica gel column chromatography, and then purified by preparative liquid chromatography to obtain 134 mg of a pale yellow solid. 1 H NMR (400MHz, DMSO-d6): δ12.15(s,1H),11.43(s,1H),9.29–9.18(m,2H),8.70(s,1H),7.60(dd,J=7.8,1.4Hz,1H),7.23( t,J=8.1Hz,1H),5.24(d,J=2.4Hz,2H),3.84(s,3H),3.61(t,J=2.5Hz,1H),2.25–2.14(m,1H),0.98–0.87(m,4H).MS:m / z 451.2[M+H] + .

[0315] Example 13:

[0316]

[0317]

[0318] Step 1

[0319] To a 1000 ml three-necked flask, 30 g of 2-hydroxy-3-nitroacetophenone, 46 g of potassium carbonate, and 300 ml of N,N-dimethylformamide were added sequentially, and the mixture was stirred at room temperature after the addition was complete. 38.4 g of iodomethane was slowly added dropwise, and the mixture was allowed to react at room temperature for 20 min after the addition was complete. The temperature was then raised to 50 °C and stirred overnight. After the reaction was complete, the mixture was cooled to room temperature, and 500 ml of saturated brine was added to the system. The mixture was extracted three times with methyl tert-butyl ether, and the organic phases were combined. The mixture was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 34.9 g of a pale yellow solid. 1 H NMR (400MHz, CDCl3): δ7.94 (dd, J=8.0, 1.8Hz, 1H), 7.82 (dd, J=7.8, 1.8Hz, 1H), 7.30 (t, J=7.9Hz, 1H), 3.95 (s, 3H), 2.67 (s, 3H).

[0320] Step 2

[0321] Add the product from the previous step (32 g), DMF-DMA (39 g), and toluene (200 ml) sequentially to a 500 ml three-necked flask. After purging with nitrogen, reflux at 110 °C for 6 h. Concentrate under reduced pressure to remove most of the solvent. Add acetic acid (20.8 g), 80% hydrazine hydrate (16.4 g), and tetrahydrofuran (300 ml) to the concentrate. Heat to 65 °C and stir overnight. After the reaction is complete, concentrate to remove most of the solvent. Add ethyl acetate (1000 ml), wash three times with water (300 ml), dry with anhydrous sodium sulfate, filter, concentrate the filtrate to remove most of the solvent, add petroleum ether (600 ml), stir at room temperature for 30 min, filter, and dry to obtain 32.5 g of yellow solid. 1 HNMR (400MHz, DMSO-d6): δ13.20 (s, 1H), 8.17 (d, J = 7.6Hz, 1H), 7.90 (s, 1H), 7.83 ( d,J=7.7Hz,1H),7.38(t,J=7.9Hz,1H),6.77(d,J=2.1Hz,1H),3.71(s,3H).MS:m / z 242.1[M+Na] + .

[0322] Step 3

[0323] In a 1000 ml three-necked flask, the product from the previous step (21 g), diisopropylethylamine (18.6 g), DMAP (1.17 g), and dichloromethane (210 ml) were added sequentially, and the mixture was stirred for 10 min after the addition was complete. A solution of SEM-Cl (38.4 g) in dichloromethane (50 ml) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature. A saturated ammonium chloride solution (400 ml) was added to quench the reaction. The mixture was separated from the liquid, and the organic phase was washed twice with NH4Cl solution (400 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain 38 g of a yellow oily substance (containing a small amount of SEM-Cl). MS: m / z 372.1 [M+Na] + .

[0324] Step 4

[0325] Add 38 g of the product from the previous step, 3.8 g of 5% palladium on carbon, and 380 ml of ethanol to a 1000 ml single-necked flask. After the addition is complete, purge with hydrogen gas and react overnight at room temperature. After the reaction is complete, filter, concentrate the filtrate under reduced pressure, and then purify by silica gel column chromatography to obtain 22 g of a dark red liquid. MS: m / z 320.2 [M+H] + .

[0326] Step 5

[0327] Add the product from the previous step (22 g), 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (18.9 g), lithium chloride (8 g), and 2-methyltetrahydrofuran (400 ml) to a 3-liter three-necked flask. After the addition is complete, cool to 0°C and slowly add LiHMDS (194 ml). After the addition is complete, allow the mixture to return to room temperature and react for 1 h. TLC monitoring showed that a small amount of the starting material had not reacted completely. Add saturated ammonium chloride solution (400 ml) to the reaction system and extract with ethyl acetate (400 ml). Wash the organic phase twice with saturated brine (300 ml), dry with anhydrous sodium sulfate, and filter. Add triphenylchloromethane (19.2 g) and triethylamine (20 ml) to the filtrate. After the addition is complete, stir at room temperature to remove unreacted aniline compounds. The reaction system was washed three times with 400 ml of saturated ammonium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to give 26.3 g of a yellow solid. MS: m / z 492.2 [M+H] + .

[0328] Step 6

[0329] The product from the previous step (14.3 g), cyclopropionamide (4.76 g), BINAP (7.15 g), palladium acetate (0.66 g), cesium carbonate (47.6 g), and toluene (200 ml) were added to a 250 ml single-necked flask. After addition, the mixture was completely purged with nitrogen, and the temperature was raised to 90 °C for 8 h. The reaction was monitored by TLC. After the reaction was complete, water (400 ml) was added to the reaction system, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed once with saturated brine (300 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to give 10.8 g of a pale yellow solid. MS: m / z 541.3 [M+H] + .

[0330] Step 7

[0331] The product from the previous step (5.4 g) and tetraethylammonium fluoride trihydrate (25 g) were added to a 250 ml single-necked flask and reacted overnight at 85 °C under TLC monitoring. After the reaction was complete, a large amount of water was added and stirred for 30 min, resulting in the precipitation of a white solid. The solid was filtered, and the filter cake was dissolved in ethyl acetate (200 ml), washed three times with water (200 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. A suitable amount of a mixed solvent of ethyl acetate and methanol (80:1) was added and the mixture was stirred for 30 min, followed by filtration to obtain a white solid. The white solid was placed in a 50 ml single-necked flask, 20 ml of ethyl acetate was added, and the mixture was stirred for 1 h. The mixture was then filtered and dried to obtain 1.7 g of an off-white solid. MS: m / z 411.2 [M+H] + .

[0332] Step 8

[0333] In a 50 ml single-necked flask, add N,N-dimethylacetamide (15 ml), the product from the previous step (2.0 g), and 3-bromopropyne (5.2 g), stir until dissolved, then add potassium carbonate (5.4 g) in portions. After the addition is complete, react at room temperature for 24 h. After the reaction is complete, add water (300 ml), extract three times with ethyl acetate, combine the organic phases, wash three times with saturated brine (200 ml), dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify by silica gel column chromatography to give 0.5 g of a pale yellow solid. 1H NMR (400MHz, DMSO-d6): δ11.34(s,1H),11.00(s,1H),9.16(s,1H),8.18(s,1H),7.90(s,1H),7.69(d,J=7.5Hz,1H),7.41(d,J =7.3Hz,1H),7.24(t,J=7.7Hz,1H),6.79(s,1H),5.13(s,2H),3.61(s,3H),3.53(s,1H),2.19-1.99(m,1H),0.96-0.73(m,4H). MS:m / z 449.2126[M+H] + .

[0334] Example 14:

[0335]

[0336]

[0337] Step 1

[0338] 2-Chloro-3-methoxypyridine (250.0 g) and tetrahydrofuran (2.5 L) were added sequentially to the reaction flask under nitrogen protection and the temperature was lowered to -75±5℃. LDA (1.13 L) was added dropwise while maintaining the temperature at -75±5℃. After the addition was complete, the reaction was maintained at -75±5℃ for 2.5–3 hours. Iodine (274.5 g) in tetrahydrofuran (500 ml) solution was added dropwise while maintaining the temperature at -75±5℃. After the addition was complete, the temperature was naturally raised to 20–30℃ and the reaction was allowed to proceed for 2–3 hours. After the reaction was complete, saturated ammonium chloride aqueous solution (4.0 L) and saturated sodium thiosulfate aqueous solution (4.0 L) were added dropwise sequentially while maintaining the temperature at 20±5℃. The mixture was stirred after the addition was complete. The mixture was extracted twice with n-hexane, the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 420.0 g of a brown oil-solid mixture. This mixture was then pulped and dried to obtain 274.0 g of a yellow solid. MS:m / z269.9,[M+H] + . 1 H NMR (400MHz, CDCl3): δ7.78 (d, J = 5.0 Hz, 1H), 7.66 (d, J = 5.0 Hz, 1H), 3.91 (s, 3H).

[0339] Step 2

[0340] 2-Chloro-4-iodo-3-methoxypyridine (100 g), N-methylpyrrolidone (500 ml), and cuprous cyanide (66.3 g, 0.74 mol) were added sequentially to the reaction flask. The mixture was heated to 120 ± 5 °C and stirred for 4–6 hours. After the reaction was complete, the mixture was cooled to room temperature, and 500 ml of ammonia solution was added dropwise, maintaining the temperature at 20 ± 5 °C. After the addition was complete, the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 54.3 g of a brownish-yellow solid. This solid was purified by silica gel column chromatography to give 32.1 g of a white solid. MS: m / z 169.0, [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.35 (d, J = 5.0 Hz, 1H), 7.90 (d, J = 4.9 Hz, 1H), 4.09 (s, 3H).

[0341] Step 3

[0342] 2-Chloro-3-methoxyisononiarin (3.0 g), methylformylhydrazine (3.9 g), and tetrahydrofuran (80 ml) were added sequentially to the reaction flask. The mixture was cooled to 0 °C, and a tetrahydrofuran solution (50 ml) of potassium tert-butoxide (4.4 g) was slowly added dropwise while maintaining the temperature at 0 ± 5 °C. After the addition was complete, the mixture was kept at 0 ± 5 °C for 0.5–1 hour. After the reaction was complete, the solution was poured into a saturated ammonium chloride aqueous solution (130 ml), extracted with ethyl acetate, combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3.5 g. The solution was purified by column chromatography to give 1.1 g of a white solid. MS: m / z 225.1, [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ 8.68 (s, 1H), 8.25 (d, J = 5.0 Hz, 1H), 7.90 (d, J = 5.0 Hz, 1H), 3.99 (s, 3H), 3.87 (s, 3H).

[0343] Step 4

[0344] The product from the previous step (1.0 g), 4-methoxybenzylamine (10.8 g), tris(dibenzylacetone)dipalladium-chloroform adduct (0.46 g), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (1.1 g), cesium carbonate (4.35 g), and 1,4-dioxane (30 ml) were added sequentially to the reaction flask. Under nitrogen protection, the mixture was heated to 90±5℃ and reacted for 14–16 hours. After the reaction was complete, the temperature was lowered to 20–30℃, water was added, and the mixture was extracted with ethyl acetate and concentrated to obtain 4.5 g of crude oil. MS: m / z 326.2 [M+H] + .

[0345] Step 5

[0346] The crude product from the previous step (4.5 g) and trifluoroacetic acid (45 ml) were added sequentially to the reaction flask, and the mixture was heated to 90 ± 5 °C and maintained at this temperature for 1–2 hours. After the reaction was complete, the mixture was concentrated to dryness, dissolved in methanol (110 ml), and the pH was adjusted to 7–8 with sodium bicarbonate. The mixture was stirred for 30 minutes, filtered, and concentrated to obtain 2.51 g of a brown oily substance. This was purified by silica gel column chromatography to obtain 2.1 g of a yellow oil-solid mixture. MS: m / z 206.1, [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ 8.62 (s, 1H), 7.73 (d, J = 5.6 Hz, 1H), 7.05 (d, J = 5.8 Hz, 1H), 6.77 (br s, 2H), 3.96 (s, 3H), 3.73 (s, 3H).

[0347] Step 6

[0348] 3-Methoxy-4-(1-methyl-1H-1,2,4-triazol-3-yl)pyridine-2-amine (1.2 g, 5.85 mmol), 4,6-dibromo-N-(methyl-d3)pyridazine-3-carboxamide (2.27 g), and N,N-dimethylformamide (24 ml) were added sequentially to a reaction flask. Under nitrogen protection, the mixture was cooled to 0 ± 5 °C, and sodium hydride (0.94 g) was added. The mixture was stirred at 0 ± 5 °C for 0.5–1 hour, then naturally heated to 20 ± 5 °C and maintained at this temperature for 3–4 hours. After the reaction was complete, the reaction solution was added dropwise to a saturated ammonium chloride solution, maintaining the temperature at 10 ± 5 °C. After the addition was complete, the mixture was stirred for 1–2 hours, filtered, and the solid was washed twice with water and dried to obtain 0.84 g of a brownish-yellow solid. MS: m / z 424.1, [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ12.56(s,1H),9.48(s,1H),9.37(s,1H),8.68(s,1 H), 8.22 (d, J = 5.3Hz, 1H), 7.56 (d, J = 5.2Hz, 1H), 3.99 (s, 3H), 3.91 (s, 3H).

[0349] Step 7

[0350] The product from the previous step (400 mg), N-methylpyrrolidone (16 ml), cyclopropanethioformamide (288.3 mg, 2.85 mmol), tricyclohexylphosphine (106.6 mg), N-methyldicyclohexylamine (556.7 mg), and bis(tert-butylphosphine)palladium (97.5 mg) were added sequentially to the reaction flask. Under nitrogen protection, the mixture was heated to 110 ± 5 °C and maintained at this temperature for 1–2 hours. After the reaction was complete, the temperature was lowered to 20 ± 5 °C, and the reaction solution was added dropwise to glacial acetic acid solution. The mixture was extracted three times with dichloromethane, and the organic layers were combined. The layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1.2 g of a brown oily substance. This was purified by silica gel column chromatography to give 30.0 mg of a yellow solid. MS m / z 443.2 [M+H] + .

[0351] Example 15:

[0352]

[0353] Step 1

[0354] In a 250 ml single-necked flask, ethyl 4,6-dihydroxypyridazine-3-carboxylate (8.5 g) and acetonitrile (100 ml) were added. Under nitrogen protection, the mixture was cooled to 0 °C, and a solution of phosphine tribromooxy (39.7 g) in acetonitrile was added dropwise. After the addition was complete, the mixture was allowed to warm naturally to room temperature. The mixture was stirred at 25 °C, 55 °C, 75 °C, and 95 °C for 40 min each. TLC monitoring showed that the reaction was complete. 50 ml of ethyl acetate was added to the system, and the mixture was filtered. The filtrate was concentrated to dryness, and the concentrate was dissolved in 100 ml of dichloromethane. The pH was adjusted to 7–8 with saturated sodium bicarbonate solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and purified by silica gel column chromatography to give 9.36 g of a yellow solid product.

[0355] Step 2

[0356] In a 100 ml single-necked flask, add the product from the previous step (7.3 g), DMA (75 ml), trifluoroethanol (2.61 g), and potassium carbonate (4.9 g). After addition, stir overnight at room temperature. Add 200 ml of water to the system, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure to dryness, and slurry the concentrate with a mixture of methyl tert-butyl ether and n-hexane to give 4.86 g of brown solid. 1 H NMR (400MHz, CDCl3): δ7.29 (d, J=6.9Hz, 1H), 4.62-4.45 (m, 4H), 1.43 (t, J=7.1Hz, 3H). MS: m / z 329.0 [M+H] + .

[0357] Step 3

[0358] In a 250 ml single-necked flask, the product from the previous step (4.86 g), acetonitrile (100 ml), and lithium bromide (5.15 g) were added. Under nitrogen protection, the mixture was stirred at room temperature for 30 min, then cooled to -26 °C. Diisopropylethylamine (9.58 g) was added, and the mixture was stirred for 10 min. Deuterated methylamine hydrochloride (1.04 g) was added in portions at -30 °C. After the addition was complete, the reaction was continued at -25 °C for 2 h. TLC showed that the reaction was essentially complete. 200 ml of ice water was added to the system, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was slurried with petroleum ether to give 2.93 g of an off-white solid.

[0359] Step 4

[0360] In a 100 mL single-necked flask, the product from the previous step (2.22 g), an aromatic amine compound (1.5 g), lithium bromide (814 mg), and 2-methyltetrahydrofuran (30 mL) were added. Under nitrogen protection, the mixture was cooled to 0 °C, and LiHMDS (18.75 mL) was added dropwise. After the addition was complete, the mixture was allowed to stand at room temperature for 3 h. TLC showed that the reaction was essentially complete. The reaction was quenched with 10% ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give 2.1 g of a pale yellow solid. 1 H NMR (400MHz, DMSO-d6): δ11.10(s,1H),9.38(s,1H),8.83(s,1H),7.74(dd,J=7.8,4.1Hz,1H),7.62(dd,J=7.9,1.0Hz ,1H),7.34-7.31(m,2H),5.58(s,2H),3.71(s,3H),3.66(t,J=8.0Hz,2H),0.87(t,J=8.0Hz,2H),-0.06(s,9H).MS:m / z 537.2[M+H] + .

[0361] Step 5

[0362] In a 100 mL single-necked flask, add the product from the previous step (1.42 g), cyclopropanethioformamide (400 mg), tricyclohexylphosphine (222 mg), N,N-dicyclohexylmethylamine (1.55 g), di(tri-tert-butylphosphine)palladium (200 mg), and N-methylpyrrolidone (14 mL). Purge with nitrogen and react at 110 °C for 2 h. After cooling, add water, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to give 1.0 g of a yellow oily product. MS: m / z 558.1 [M+H] + .

[0363] Step 6

[0364] In a 100 mL single-necked flask, add the product from the previous step (900 mg), dichloromethane (16 mL), tetraethylammonium fluoride (2.7 g), and trifluoroacetic acid (40 mL). After addition, stir the mixture at room temperature for 2 h. Concentrate the system under reduced pressure, dissolve the concentrate in ethyl acetate, wash three times with water, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to give 300 mg of a pale yellow solid. 1 H NMR (400MHz, DMSO-d6): δ14.13(s,1H),12.76(s,1H),11.15(s,1H),9.29(s,1H),8.90(s,1H),8.16(brs,1H),7.74(d,J=6.7Hz,1H),7 .65 (d, J=7.7Hz, 1H), 7.32 (t, J=7.6Hz, 1H), 3.72 (s, 3H), 2.80-2.62 (m, 1H), 1.17-1.13 (m, 2H), 1.05-1.01 (m, 2H).MS: m / z428.2[M+H] + .

[0365] Step 7

[0366] In a 100 mL single-necked flask, add the product from the previous step (270 mg), DMA (5 mL), and bromopropyne (600 mg). After the addition is complete, heat to 50 °C, and add potassium carbonate (610 mg) in portions. Continue stirring for 3 h after the addition is complete. Quench the reaction with water, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to give 30 mg of a yellow solid. MS: m / z 466.2, [M+H] + .

[0367] Example 16:

[0368]

[0369] To a clean 25 ml single-necked flask, add 100 mg of triazole compound, 10 ml of N,N-dimethylformamide, 70 mg of methyl 2,4-dibromobutyrate, and 317 mg of cesium carbonate sequentially. After addition, purge with nitrogen and react at 45 °C, monitoring the reaction by TLC until complete. Add the reaction mixture to 50 ml of saturated ammonium chloride solution, extract with 30 ml of ethyl acetate, combine the organic phases, wash with 30 ml of saturated brine, dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain approximately 200 mg of crude product. Further purification by silica gel column chromatography yields 80 mg of the product. 1H NMR (400MHz, CDCl3): δ11.04(s,1H),9.63(s,1H),8.30(s,1H),8.25(s,1H),8.07(s,1H),7.80(dd,J=7.8,1.5Hz,1H),7.55(dd,J=8.0,1.5Hz,1H),7. 28(t,J=7.9Hz,1H),3.81(s,3H),3.73(s,3H),1.99-1.92(m,2H),1.87-1. 78(m,1H),1.78-1.71(m,2H),1.16-1.08(m,2H),0.95-0.87(m,2H).MS:m / z 510.2[M+H] + .

[0370] Example 17:

[0371]

[0372] Add 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (500 mg, 1.33 mmol), cyclopropanesulfonamide (322 mg), potassium phosphate (560 mg), 1,1'-bis(diphenylphosphino)ferrocene (150 mg), tris(dibenzylacetone)dipalladium (119 mg), and 1,4-dioxane (15 ml) to a 100 ml single-necked flask. After addition, purge with nitrogen and stir at 100 °C for 24 hours. Concentrate the reaction solution to dryness, add 20 ml of water, extract with dichloromethane, combine the organic layers, dry to dryness with anhydrous sodium sulfate, concentrate to dryness, and purify by silica gel column chromatography to give 330 mg of yellow solid. 1 H NMR(400MHz, CDCl3): δ12.61(br s,1H),11.08(s,1H),8.15(s,1H),7.88(dd,J=7.8,1.6Hz,1H),7.66(s,1H),7.45(dd,J=8.0,1.5Hz,1H), 7.27(t,J=7.9Hz,1H),4.03(s,3H),3.82(s,3H),2.65-2.52(m,1H),1.22-1.13(m,2H),0.99-0.90(m,2H). 13 C NMR (100MHz, CDCl3): δ164.7,160.0,155.9,151.8,146.9,144.0,131.3,131.0 ,128.2,126.2,124.6,124.3,98.5,61.8,36.5,31.7,5.47.MS:m / z462.2,[M+H]+ .

[0373] Example 18:

[0374]

[0375] first step:

[0376] In a 250 ml single-necked flask, add the following ingredients: starting material (1 g), benzophenone imine (3.0 g), palladium acetate (185 mg), cesium carbonate (13.4 g), 1,1'-di(dicyclohexylphosphine)-ferrocene (1.9 g), aluminum trifluoromethanesulfonate (195 mg), and 120 ml of dioxane. Under nitrogen purging protection, heat to 100 °C and react for 10 h. After cooling, wash with 300 ml of water, extract with 300 ml of ethyl acetate, separate, concentrate, and column chromatography to obtain 2 g of a pale yellow solid product. MS: m / z 522.24, [M+H] + ;

[0377] Step Two:

[0378] In a 100 ml single-necked flask, add the starting material (2.2 g), 80 ml of THF, and slowly add 16 ml of 2 M / L HClaq at room temperature. After the addition is complete, stir the mixture at room temperature for 2 h. Wash the mixture with 200 ml of saturated sodium bicarbonate solution, extract with 200 ml of ethyl acetate, separate the layers, dry, concentrate, and perform column chromatography to obtain 1.1 g of a reddish-brown solid product. MS: m / z 358.18, [M+H] + ;

[0379] Step 3:

[0380] In a 250 ml single-necked flask, add the starting material (500 mg), dissolve in 80 ml of dichloromethane, add DIPEA (180 mg), cool to 0°C in an ice bath, and add dropwise 20 ml of a dichloromethane solution of allyl chloride (130 mg). After the addition is complete, stir the reaction at room temperature. Wash the system with 100 ml of water, separate the layers, dry, concentrate, and perform column chromatography to obtain 150 mg of a yellow solid product. 1H NMR (400MHz, CDCl3): δ11.26(s,1H),11.01(s,1H),9.17(s,1H),8.57(s,1H),8.28(s,1H),7.69(dd,J=1.5,7.8Hz,1H),7.58(dd,J=1.4,7.9H z,1H),7.32(t,J=7.9Hz,1H),6.69-6.62(m,1H),6.33(dd,J=1.7,17.0Hz,1H),5.84(dd,J=1.6,10.1Hz,1H),3.95(s,3H),3.73(s,3H); MS:m / z 412.19,[M+H] + .

[0381] Example 19:

[0382]

[0383] In a 250 ml single-necked flask, 1.5 g of 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 5.2 g of cesium carbonate, 962 mg of cyclopropylformamidinium hydrochloride, 89 mg of palladium acetate, 884 mg of 1,1'-di(dicyclohexylphosphine)-ferrocene, and 100 ml of ethylene glycol dimethyl ether were added. After purging with nitrogen, the mixture was heated to 90 °C. The reaction mixture was cooled and poured into 200 ml of water. It was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 800 mg of a pale yellow solid. 1 H NMR (400MHz, DMSO-d6): δ = 10.70 (s, 1H), 9.44 (br s, 1H), 9.12 (s, 1H), 8.57 (s, 1H), 8.28 (br s,1H),7.64(dd,J=7.8,1.4Hz,1H),7.51(d,J=7.9Hz,1H),7.27(t,J=7.9Hz,1H),6.50(s ,1H),3.95(s,3H),3.72(s,3H),1.69-1.57(m,1H),0.98-0.89(m,2H),0.83-0.74(m,2H). 13 C NMR (100MHz, DMSO-d6): δ=167.4,167.0,166.5,159.4,150.9,145.6,144.9,1 34.3,133.3,126.7,126.2,124.8,123.7,102.9,61.6,36.5,16.0,8.4.MS:m / z 425.2,[M+H]+ .

[0384] Example 20:

[0385]

[0386] Step 1

[0387] Add 1.4 g of 3-methoxy-4-(1-methyl-1H-1,2,4-triazol-3-yl)pyridine-2-amine and 50 ml of N,N-dimethylformamide to a reaction flask. Cool to 0°C, and add sodium hydride (1.1 g) in portions. After the addition is complete, stir for 20 min, then slowly raise the temperature to room temperature and stir for another 30 min. Cool the reaction solution to 0°C, and slowly add 40 ml of a tetrahydrofuran solution of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (4.3 g) dropwise, controlling the temperature to be below 5°C. Complete the addition over 3 hours and stir overnight. Add 20 ml of ammonium chloride aqueous solution and 40 ml of water to the reaction solution. Stir for 30 min, then filter. Wash the filter cake twice with water, and dry the filter cake to obtain 1.82 g of a grayish-white solid. MS: m / z 378.1 [M+H] + .

[0388] Step 2

[0389] The product from the previous step (1.82 g, 4.8 mmol), DCPF (1.1 g), palladium acetate (108 mg), cesium carbonate (7.9 g), and DME (60 ml) were added sequentially to the reaction flask. After purging with nitrogen, the mixture was heated to 90 °C and reacted for 1 hour. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain 430 mg of a pale yellow solid compound. 1 H NMR (400MHz, DMSO-d6): δ12.44(s,1H),11.36(s,1H),9.89(s,1H),9.25(s,1H),8.67(s,1H),8.14(d, J=5.2Hz,1H),7.50(d,J=5.2Hz,1H),4.00(s,3H),3.91(s,3H),2.20-2.09(m,1H),0.96-0.81(m,4H). 13 C NMR (100MHz, DMSO-d6): δ173.8,167.0,157.6,156.6,150.1,146.2,142.6,142.5,142.0,135.5,131.4,117.2,102.2,61.7,36.8,14.9,8.6.MS: m / z 427.2[M+H] + .

[0390] Example 21:

[0391]

[0392] Step 1

[0393] Ethyl 5-hydroxy-3-methylthio-1,2,4-triazine-6-carboxylate (4.62 g) and acetonitrile (50 ml) were added to a reaction flask. The mixture was cooled to 0°C, and DIPEA (5.17 g) and N-methylmorpholine (101 mg) were added. Then, phosphorus oxychloride (4.6 g) was slowly added dropwise. After the addition was complete, the mixture was slowly warmed back to room temperature and reacted for 1 hour. After the reaction was complete, the reaction solution was cooled to 0°C, and DIPEA was added to adjust the pH to approximately 7–8. Then, a tetrahydrofuran solution (10 ml) of 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (3.27 g) was added dropwise. After the addition was complete, the mixture was warmed back to 30°C and reacted for 4 hours. The system was washed with saturated ammonium chloride aqueous solution, extracted with dichloromethane, dried and concentrated the organic phase, and purified by silica gel column chromatography to obtain 5.0 g.

[0394] Step 2

[0395] Add the product from the previous step (5.0 g), deuterated methylamine hydrochloride (1.02 g), and acetonitrile (50 ml) to a reaction flask, cool to 0 °C, add DIPEA (4.65 g) and lithium bromide (2.08 g), and slowly warm to room temperature for 1 hour. Add saturated ammonium chloride aqueous solution to the system, extract with dichloromethane, dry and concentrate the organic phase, and purify by silica gel column chromatography to obtain 4.18 g.

[0396] Step 3

[0397] In a 50 mL single-necked flask, 600 mg of a methyl sulfide compound and 20 mL of dichloromethane were added. Under nitrogen purging protection, 800 mg of MCPBA was added in portions, and the mixture was stirred at room temperature for 3 h. The mixture was then poured into an aqueous sodium bicarbonate solution, and 1 g of sodium thiosulfate was added. The mixture was stirred for 10 min, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 200 mg of a yellow solid. MS: m / z 422.1, [M+H] + .

[0398] Step 4

[0399] In a 50 ml single-necked flask, add the product from the previous step (100 mg), cyclopropionamide (50 mg), potassium tert-butoxide (150 mg), and toluene (10 ml). Under nitrogen protection, heat to 80 °C and react for 3 h. Pour the system into an aqueous solution of ammonium chloride, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to give 30 mg of a yellow solid. 1H NMR (400MHz, CDCl3): δ12.10(s,1H),8.85(dd,J=8.2,1.2Hz,1H),8.71(s,1H),8.14(s,1H),7.92(s,1H),7.78(dd,J=7.9,1 .5Hz,1H),7.31(t,J=8.1Hz,1H),4.04(s,3H),3.93(s,3H),2.37-2.27(m,1H),1.26-1.21(m,2H),1.01-0.95(m,2H).MS:m / z 427.2[M+H] + .

[0400] Example 22

[0401]

[0402] Add 6-(cyclopropylamide)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (500 mg, 1.2 mmol), N,N-dimethylacetamide (20 ml), propargyl bromide (1.3 g, 10.9 mmol), and potassium carbonate (1.3 g, 9.4 mmol) to a 50 ml single-necked flask, and react at room temperature for 2 hours. After the reaction is complete, quench the reaction mixture in 400 ml of water, extract twice with ethyl acetate, combine the organic phases, dry to anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 250 mg of an off-white solid. 1 H NMR (400MHz, CDCl3): δ11.01(s,1H),9.81(s,1H),8.39(s,1H),8.25(s,1H),8.06(s,1H),7.82(dd,J=7.9,1.6Hz,1H),7.55(dd,J=8.0,1.5Hz, 1H),7.28(t,J=7.9Hz,1H),5.08(d,J=2.5Hz,2H),3.83(s,3H),2.64(t, J=2.6Hz,1H),1.91-1.82(m,1H),1.15-1.08(m,2H),0.94-0.87(m,2H). 13 C NMR (100MHz, CDCl3): δ173.2,166.7,160.6,155.7,151.5,146.1,143.0,135.0,1 32.4,127.1,125.7,124.6,123.6,97.8,76.1,75.1,61.6,39.7,16.0,8.8, MS:m / z 450.2102[M+H] + .

[0403] Biological testing and other application examples

[0404] Biological Test Example 1: Determination of Drug Efficacy in a Mouse Psoriasis-like Model

[0405] Experimental animals: Balb / c mice;

[0406] Animal grouping:

[0407] (1) Negative control group (applied petroleum jelly, administered solvent via gavage),

[0408] (2) Model control group [applied imiquimod (IMQ)],

[0409] (3) Drug administration group (applied IMQ, compounds 7, 8, 9, 10, and 146 administered by gavage);

[0410] Among them, "compound 146" is compound 146 in Example 1 of reference WO2014074661, which was prepared according to the method in that reference.

[0411] Dosage and administration method: 20 mg / kg, BID, by gavage;

[0412] Experimental Procedure: On Day 0, the test sites on the backs of the animals were shaved and divided into groups. From Day 1 to Day 7, one hour after the first administration each morning, 40 mg of 5% imiquimod cream was applied once to the test sites on the backs of the mice, followed by a second administration on the same day. The symptoms of psoriasis and the efficacy of the medication were assessed using the Psoriasis Area and Severity Index (PASI) score (erythema, scaling, and degree of thickening), with higher scores indicating more severe symptoms.

[0413] The PASI score results on day 7 are listed in the table below.

[0414] "+" indicates a score of ≥6;

[0415] "++" represents a score greater than 5 and less than 6;

[0416] "++" represents a score greater than 4 and less than or equal to 5;

[0417] "++++" indicates a score of 4 or less.

[0418] Dosage group PASI score Model control group + Compound 146 ++ Compound 7 ++++ Compound 8 ++++ Compound 9 ++++ Compound 10 ++++

[0419] The data above indicate that compounds 7, 8, 9, and 10 improved psoriasis symptoms in an imiquimod-induced mouse psoriasis-like model, as did compound 146. Compounds 7, 8, 9, and 10 showed better efficacy than compound 146.

[0420] Biological Test Example 2: Determination of Drug Efficacy in a Mouse Psoriasis-like Model

[0421] Using the same protocol as in Test Example 1, the efficacy of compound 11 in an imiquimod-induced mouse psoriasis-like model was studied. The data showed that compound 11 could improve psoriasis symptoms in an imiquimod-induced mouse psoriasis-like model, and compound 11 was more effective than compound 146.

[0422] Among them, "compound 146" is compound 146 in Example 1 of reference WO2014074661, which was prepared according to the method in that reference.

[0423] The PASI score results on day 7 are listed in the table below.

[0424] "+" indicates a score of ≥6;

[0425] "++" represents a score greater than 5 and less than 6;

[0426] "++" represents a score greater than 4 and less than or equal to 5;

[0427] "++++" indicates a score of 4 or less.

[0428] Dosage group PASI score Model control group + Compound 146 ++ Compound 11 ++++

[0429] Biological Test Example 3: In Vitro Enzyme Experiment

[0430] Experimental Procedure: Dissolve the compound in DMSO to a storage concentration of 10 mM. Prepare different concentration gradients of the compound (200 times the final concentration) in compound dilution plates and transfer them to Echo plates. Transfer 75 nL of the compound from the Echo plate to a 384-well plate using an Echo instrument. Add 5 μl of TYK2-JH2 kinase (3 times the final concentration) to the 384-well plate. Add 5 μl of Tb antibody (3 times the final concentration) to the 384-well plate. Add 5 μl of Tracer (3 times the final concentration) to the 384-well plate. Centrifuge for 30 seconds and incubate at room temperature for 60 minutes. Read the fluorescence signal ratio at 495 nm / 520 nm using an Envision microplate reader (PerkinElmer). Analyze the data using XL-Fit software and calculate the IC50 of the compound.

[0431] Where “A” indicates that the TYK2-JH2 binding inhibitory activity (IC50 value) is less than 0.10 nM;

[0432] "B" indicates that the TYK2-JH2 binding inhibitory activity (IC50 value) ranges from 0.10 nM to 0.50 nM;

[0433] “C” indicates that the TYK2-JH2 binding inhibitory activity (IC50 value) ranges from 0.50 nM to 1 nM;

[0434] “D” indicates that the TYK2-JH2 binding inhibitory activity (IC50 value) is greater than 1 nM.

[0435] Compound numbering TYK2-JH2 binding inhibitory activity (IC50) Compound 7 A Compound 8 A Compound 9 A Compound 2-1A-1 A Compound 11 A Compound 2-1B-1 B Compound 2-1B-2 C Compound 2-1B-7 B Compound X-1 B

[0436] The data above indicate that compounds 7, 8, 9, 10, 11, 2-1B-1, 2-1B-2, 2-1B-7, and X-1 inhibit the activity of TYK2-JH2. Some of these compounds show significant effects.

[0437] Biological Test Example 4: Flow Cytometry Fluorescence Sorting (FACS) Detection of Compound Effects on pSTAT5 Expression in CD3+ Cells Inhibition of daphne

[0438] Compound dilution preparation: The compound was prepared into a 10 mM solution using DMSO, and then diluted in DMSO to different concentration gradient solutions 500 times the final concentration. 5 μL of the diluted compound was transferred to 120 μL of PBS solution containing 0.1% BSA. Positive and negative control groups were set up, and both the positive and negative control groups ultimately contained 0.2% DMSO.

[0439] Experimental steps:

[0440] 1) Add 0.5 million human PBMC cells with a volume of 67.5 uL to each well of a 96-well cell culture plate.

[0441] 2) Add 3.5 μl of the diluted compound and mix well.

[0442] 3) Incubate at 37°C for 60 minutes.

[0443] 4) Dilute IFN-alpha to 600 ng / mL in DPBS containing 0.1% BSA. After the above 60-minute incubation, add 5 μL of PE-anti-hCD3 antibody per well and 4 μL of diluted IFN-alpha per well.

[0444] 5) Incubate at 37°C for 30 minutes.

[0445] 6) Transfer all cells to a 96-well deep plate and add 1 mL of Lyse / fix buffer preheated at 37°C.

[0446] 7) Incubate at 37℃ in the dark for 10 minutes.

[0447] 8) After centrifuging at 600g for 5 minutes, discard the supernatant, add 1mL of PBS to wash twice and centrifuge again.

[0448] 9) Add 1 mL of Perm buffer III to the cell pellet.

[0449] 10) Incubate at 4℃ in the dark for 30 minutes.

[0450] 11) After centrifuging at 600g for 5 minutes, discard the supernatant, add 1mL of PBS to wash twice and centrifuge again.

[0451] 12) Dilute the APC anti-human pSTAT5 antibody 200-fold in staining buffer, add 100 μL to each well, and mix well.

[0452] 13) Incubate at room temperature for 40 minutes.

[0453] 14) Add staining buffer and wash twice, 1 mL per well, centrifuge at 600g for 5 minutes.

[0454] 15) After discarding the supernatant, the cell pellet was resuspended in 300uL of staining buffer.

[0455] 16) Samples were loaded and analyzed in a Beckman CytoFlex flow cytometer.

[0456] The experimental results are summarized as follows:

[0457] Where “A” represents the inhibitory activity (IC50 value) of p-STAT5 expression less than 1 nM;

[0458] “B” indicates that the inhibitory activity (IC50 value) of p-STAT5 expression ranges from 1 nM to 5 nM;

[0459] “C” represents the range of inhibitory activity (IC50 value) of p-STAT5 expression from 5 nM to 10 nM;

[0460] “D” indicates that the inhibitory activity (IC50 value) of p-STAT5 expression is greater than 10 nM.

[0461]

[0462]

[0463] The data above indicate that compounds 7, 8, 9, 10, 11, 2-1A-1, 2-1B-1, 2-1B-2, 2-1B-7, and X-1 have an inhibitory effect on p-STAT5 expression. Among them, some compounds exhibit significant inhibitory activity.

[0464] Biological Test Example 5: In vivo pharmacokinetic study

[0465] Experimental animals: 8-10 week old male SD rats, fasted for 12 hours before administration.

[0466] Drug preparation method

[0467] Gavage administration: A mixed solution (ethanol + TPGS + PEG300 = 5:5:90) was used as the administration solvent.

[0468] Injection administration: A mixed solution (PEG400 + ddH2O = 80:20) was used as the administration solvent.

[0469] Dosage volume: 5 ml / kg

[0470] Animal grouping: The animals were divided into an intravenous group (IV) and a gavage group (PO), with 3 male SD rats in each group.

[0471] Administration route and dosage: The intravenous IV group was administered at 1 mg / kg; the oral PO group was administered at 10 mg / kg.

[0472] Dosage frequency: Single dose.

[0473] sampling:

[0474] IV. Blood collection points: 5, 15, 30 min, 1, 2, 4, 6, 8, and 24 h after drug administration;

[0475] PO blood collection points: 15, 30 min, 1, 2, 4, 6, 8, and 24 h after drug administration;

[0476] Sample processing

[0477] Whole blood from rats was centrifuged at 10,000 rpm for 5 minutes to separate plasma, which was then stored at 4°C. 0.1 ml of plasma was collected, and 0.2 ml of acetonitrile was added. The mixture was vortexed for 1 minute, centrifuged at 10,000 rpm for 5 minutes, and the supernatant was collected. After filtration through a 0.22 μm filter, the supernatant was sent for drug content analysis.

[0478] The experimental results are summarized as follows:

[0479]

[0480]

[0481] Among them, "compound 146" is compound 146 in Example 1 of reference WO2014074661, which was prepared according to the method in that reference.

[0482] In vivo pharmacokinetic studies of compounds 11 and 146 showed that the absolute bioavailability of compound 11 was greater than that of compound 146.

[0483] Biological Test Example 6: Determination of Efficacy of Imiquimod in a Mouse Psoriasis-like Model

[0484] Using the same protocol as in Test Example 1, the efficacy of imiquimod in a mouse psoriasis-like model was studied. The PASI scores on day 7 are shown in the table below.

[0485] "+" indicates a score of ≥6;

[0486] "++" represents a score greater than 5 and less than 6;

[0487] "++" represents a score greater than 4 and less than or equal to 5;

[0488] "++++" indicates a score of 4 or less.

[0489]

[0490]

[0491] The data above indicate that the listed compounds can improve psoriasis symptoms in an imiquimod-induced mouse psoriasis-like model, with some compounds showing particularly significant effects.

[0492] Application Example 7: Ointment Preparation

[0493] The compounds of this invention act through pathways involving autoimmune diseases and other conditions, such as ankylosing spondylitis, atopic dermatitis, and enteritis. Some of these diseases involve skin-related conditions. Developing these compounds into topical formulations makes their use more convenient and direct in certain situations. Ointment formulation composition:

[0494] name Formula proportion Compound 7 or Compound X-1 5％ Vaseline 70％ Light liquid paraffin 23.5％ Antioxidant (BHA) 1.0％ Antibacterial agent (benzyl alcohol) 0.5％ total 100％

[0495] Ointment preparation:

[0496] Homogenization: Add the prescribed amount of petroleum jelly to the main pot, heat at 70℃~90°C until completely melted, and control the temperature at 75±5℃ for later use; add compound 7 or compound X-1, antioxidant BHA (butylated hydroxyanisole), and benzyl alcohol to about 1 / 2 of the light liquid paraffin, and use mechanical stirring to disperse it evenly to obtain mixture 1; add mixture 1, the remaining light liquid paraffin, and the melted petroleum jelly solution to the main pot, turn on the wall-scraping stirring at 30~60 rpm, the homogenizing stirring speed at 1000~2800 rpm, the vacuum degree at -50~-100Kpa, the temperature at 70±5℃, and homogenize for 20~30 minutes; then slowly cool down to below 35℃ to obtain the paste.

[0497] Filling: The prepared ointment was filled into the specified size using a filling machine. During the process, the temperature of the feeding funnel jacket was controlled at 25-30℃, and the sealing temperature was 450±20℃. Following the above formula and ointment preparation scheme, compound 7 ointment and compound X-1 ointment were prepared.

[0498] Summary of the results of long-term stability observation of the ointment:

[0499]

[0500] Comparing the stability of 5% ointment of compound 7 and 5% ointment of compound X-1, it can be seen that the 5% ointment prepared with compound X-1 showed visible granular substances after 20 days of storage, which is likely due to product precipitation after prolonged storage of compound X-1. However, the 5% ointment prepared with compound 7 remained uniform after 30 days of storage, without any visible granular substances. These phenomena indicate that using compound 7 to prepare a 5% ointment is beneficial for storage and use.

[0501] Biological Test Example 8: Efficacy of imiquimod in a rat model of IL-17 elevation induced by gavage administration. Measurement

[0502] Diseases regulated by IL-17 include autoimmune diseases such as ankylosing spondylitis, rheumatoid arthritis, atopic dermatitis, and enteritis. The compounds of this invention have potential therapeutic effects on autoimmune diseases by regulating IL-17 levels.

[0503] Experimental animals: 8-10 week old SD rats, half male and half female;

[0504] Experimental Groups:

[0505] (1) Negative control group (applied petroleum jelly, administered solvent via gavage),

[0506] (2) Model control group [applied imiquimod (IMQ)],

[0507] (3) Drug administration group (applied IMQ, administered the compound of the present invention by gavage);

[0508] Dosage and administration method: 20 mg / kg, BID, by gavage;

[0509] Model establishment: SD rats were established by applying 40 mg of imiquimod ointment to the skin on their backs once daily.

[0510] Experimental testing: On day 6, the level of IL-17F cytokine in the blood was measured.

[0511] Experimental results:

[0512] Where A represents an IL-17F content of less than 30 pg / mL;

[0513] B represents the IL-17F concentration range of 30-100 pg / mL;

[0514] C represents the IL-17F concentration range of 100-300 pg / mL;

[0515] D represents an IL-17F concentration range of 300-400 pg / mL;

[0516] E indicates that the IL-17F content is greater than 400 pg / mL;

[0517] Experimental group IL-17F levels in the skin negative control group A Model control group E Compound 7 treatment group A Compound 11 treatment group A Compound X-1 treatment group C

[0518] Studies on imiquimod-induced rat models using different compounds showed that compound 7 was more effective than compound X-1. After treatment with compound 7 or compound 11 via gavage, the levels of the inflammatory cytokine IL-17F in the experimental animals were close to those in normal animals. Correspondingly, treatment with compound 7 or compound 11 via gavage significantly reduced skin lesions in rats; the area and severity index scores of skin lesions in rats were superior to those in the compound X-1 treatment group; further experiments showed that it was also superior to other compounds with similar scaffolds.

[0519] Biological Test Example 9: Efficacy of imiquimod in a rat model of IL-17 elevation induced by gavage administration. Measurement

[0520] The efficacy of the compounds of the present invention was evaluated using the same protocol as in Example 8 of the biological testing, and the following test results were obtained:

[0521] Experimental results:

[0522] Where A represents an IL-17F content of less than 30 pg / mL;

[0523] B represents the IL-17F concentration range of 30-100 pg / mL;

[0524] C represents the IL-17F concentration range of 100-300 pg / mL;

[0525] D represents an IL-17F concentration range of 300-400 pg / mL;

[0526] E indicates that the IL-17F content is greater than 400 pg / mL;

[0527] Experimental group IL-17F levels in the skin negative control group A Model control group E Compound 2-1A-1 treatment group A Compound 1-1-1 D Compound X-1 treatment group C

[0528] Studies on the therapeutic effects of different compounds on imiquimod-induced rat models showed that compound 2-1A-1 was more effective than compounds 1-1-1 and X-1. Specifically, after treatment with compound 2-1A-1 via gavage, the levels of the inflammatory cytokine IL-17F in the experimental animals were close to those in normal animals. Furthermore, treatment with compound 2-1A-1 via gavage significantly reduced skin lesions in rats; the area and severity index scores of skin lesions in rats were superior to those treated with compounds 1-1-1 and X-1.

[0529] Biological Test Example 10: Efficacy of imiquimod in a rat model of IL-17 elevation induced by topical administration. Measurement

[0530] Experimental animals: 8-10 week old SD rats, half male and half female

[0531] Model establishment: 40 mg of imiquimod ointment was applied to the back skin of SD rats once daily to establish a psoriasis-like rat model.

[0532] Experimental Procedure: Three days prior to the experiment, the skin on the backs of SD rats was shaved. First, 40 mg of imiquimod was applied. Then, an ointment was applied at a dose of 1 g / day / rat (applying area 5 × 15 cm), once daily for 5 consecutive days. The control group received no application. The skin was cleaned before each application.

[0533] Experimental testing: On day 6, the rat skin was wiped clean, and then the skin was taken, mixed with cell lysis buffer and ground. After standing, the supernatant was collected to determine the content of skin IL-17F cytokine.

[0534] Experimental results:

[0535] Where A represents an IL-17F content of less than 2000 pg / g;

[0536] B represents the IL-17F content range of 2000–5000 pg / g;

[0537] C represents the IL-17F content range of 5000-10000 pg / g;

[0538] D represents the IL-17F content range of 15000-20000 pg / g;

[0539] E indicates that the IL-17F content is greater than 20,000 pg / g;

[0540] Experimental group IL-17F levels in the skin negative control group A Model control group E Compound 7 ointment treatment group A Compound 11 ointment treatment group A Compound X-1 ointment treatment group C

[0541] Studies on the treatment of imiquimod-induced rat models with different compound ointments showed that compound 7 ointment was more effective than compound X-1 ointment. After treatment with either compound 7 or compound 11 ointment, the levels of the inflammatory cytokine IL-17F in the skin of the experimental animals were close to those of normal animals. Simultaneously, treatment with either compound 7 or compound 11 ointment significantly reduced skin lesions in rats; the area and severity index scores of skin lesions were superior to those in the compound X-1 ointment treatment group; further experiments also showed that it was superior to other compounds with similar scaffolds.

[0542] Biological Test Example 11: Efficacy of imiquimod in a rat model of IL-17 elevation induced by topical administration. Measurement

[0543] The efficacy of the compounds of the present invention was evaluated using the same protocol as in Example 10 of the biological testing method, and the following test results were obtained:

[0544] Where A represents an IL-17F content of less than 2000 pg / g;

[0545] B represents the IL-17F content range of 2000–5000 pg / g;

[0546] C represents the IL-17F content range of 5000-10000 pg / g;

[0547] D represents the IL-17F content range of 15000-20000 pg / g;

[0548] E indicates that the IL-17F content is greater than 20,000 pg / g;

[0549] Experimental group IL-17F levels in the skin negative control group A Model control group E Compound 2-1A-1 ointment treatment group A Compound 1-1-1 ointment treatment group D Compound X-1 ointment treatment group C

[0550] Studies on the therapeutic effects of different compound ointments on imiquimod-induced rat models showed that compound 2-1A-1 ointment was more effective than compound 1-1-1 ointment and compound X-1 ointment. Specifically, after treatment with compound 2-1A-1 ointment, the levels of the inflammatory factor IL-17F in the skin of the experimental animals were close to those of normal animals. Furthermore, treatment with compound 2-1A-1 ointment significantly reduced skin lesions in rats; the area and severity index scores of skin lesions in rats were superior to those treated with compound 1-1-1 ointment and compound X-1 ointment.

[0551] Formulation Application Example 12: Tablet Preparation of Compound 2-1A-1

[0552] Formula composition:

[0553]

[0554] Tablet preparation method:

[0555] mix: The weighed compound 2-1A-1, starch, microcrystalline cellulose, and sodium carboxymethyl starch were added to a wet granulation machine and mixed.

[0556] Adhesive solution preparation: Weigh out purified water, and slowly add an appropriate amount of povidone K30 while stirring. Stir and disperse evenly to prepare an adhesive—povidone K30 aqueous solution.

[0557] Making soft materials: A wet mixing granulator was used to control the stirring speed and shearing speed. Povidone K30 aqueous solution was slowly added, stirred, and sheared to obtain a mixed material.

[0558] Granulation: The prepared mixture was granulated using a gyratory granulator with a 24-mesh sieve to obtain wet granules.

[0559] dry: Wet particles are added to a fluidized bed for drying.

[0560] Whole grains: The dried granules are granulated using a gyratory granulator sieve to obtain granulated granules, which are then weighed.

[0561] mix: Add the granulated particles to a three-dimensional multi-directional motion mixer. After mixing is complete, add magnesium stearate and continue mixing for about 3 minutes to obtain total mixed particles.

[0562] Tableting: Tablets were prepared by compression using a tablet press, resulting in tablets with a smooth and intact appearance, uniform color, and suitable hardness and abrasion resistance.

[0563] The compounds prepared by this invention have tyrosine kinase 2 (TYK2) inhibitory activity and have broad application prospects in the treatment of autoimmune diseases and tumors.

[0564] The compounds of this invention exhibit outstanding activity and drug-like properties. Different structural types of compounds display varying characteristics in absorption, metabolism, and distribution, which is beneficial for providing more effective, convenient, and diverse treatment options for autoimmune diseases and other related conditions affecting different parts of the body, such as enteritis, ankylosing spondylitis, and skin inflammation. Furthermore, it also brings comprehensive positive effects on raw material and formulation preparation, and product stability.

Claims

1. A compound of formula (II-2-2), its stereoisomer or a pharmaceutically acceptable salt thereof, in, R 12 It is a deuterated methyl group; R 10 R 11 R D1 It is hydrogen; E1 is a methyl group; R 1 R 2 R 3 R 4 R 5 Each is independently selected from either hydrogen or deuterium; R 7 It is hydrogen; R 9a R 9b R 9c Each is independently selected from either hydrogen or deuterium; n1=1； n2=1。 2. A compound, its stereoisomer or a pharmaceutically acceptable salt thereof, selected from: 。 3. The compound according to claim 2, wherein its stereoisomer or a pharmaceutically acceptable salt thereof is selected from: or .

4. The compound according to claim 2 or 3, wherein its stereoisomer or a pharmaceutically acceptable salt thereof is: 。 5. The compound according to claim 2 or 3, wherein its stereoisomer or a pharmaceutically acceptable salt thereof is: 。 6. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier.

7. Use of the compound of any one of claims 1 to 5 in the preparation of a medicament for treating a disease, wherein the disease is psoriasis.

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