Substituted heterocyclic derivatives and uses thereof

Abstract

The present application belongs to the field of medicine, and relates to a kind of substituted heterocyclic derivatives and purposes thereof. Specifically, the present application relates to a compound of formula (I), or stereoisomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound shown in formula (I). The present application relates to the compound and pharmaceutical composition thereof as P2X3 receptor selective modulator, which can be used for preparing medicaments for preventing or treating P2X3 receptor related diseases, and can be especially used for preparing medicaments for treating chronic recurrent cough.(I)

Description

Technical Field

[0001] This invention belongs to the field of pharmaceuticals. Specifically, this invention relates to a new class of substituted heterocyclic derivatives as selective modulators of P2X3 receptors, pharmaceutical compositions thereof, and the use of such compounds and pharmaceutical compositions thereof in the preparation of medicaments for treating P2X3 receptor-related diseases. Background Technology

[0002] The P2X receptor is a non-selective ATP-gated ion channel receptor, i.e., a purinergic receptor, that binds to extracellular ATP, primarily derived from damaged or inflamed tissues. This receptor is widely expressed in the nervous, immune, cardiovascular, skeletal, gastrointestinal, respiratory, and endocrine systems, and participates in various physiological processes, including regulation of heart rhythm and contractility, regulation of vascular tone, regulation of nociception, especially chronic pain, vas deferens contraction during ejaculation, bladder contraction during urination, platelet aggregation, macrophage activation, apoptosis, and neuron-glial interactions. The P2X3 receptor is a member of the P2X receptor family and was initially cloned from the rat dorsal root ganglion (Chen et al., Nature, Vol. 377, pp. 428-431 (1995)). The nucleotide and amino acid sequences of both rat P2X3 and human P2X3 are now known (Lewis et al., Nature, Vol. 377, pp. 432-435 (1995); and Garcia-Guzman et al., Brain Res. Mol. Brain Res., Vol. 47, pp. 59-66 (1997)).

[0003] P2X3 can be selectively expressed on nociceptive, small-diameter sensory neurons (i.e., neurons stimulated by pain or injury), which is consistent with its role in pain sensitivity. Furthermore, blocking P2X3 receptors has been reported to have analgesic effects in animal models of chronic inflammatory and neuropathic pain (Jarvis et al., PNAS, 99, 17179-17184 (2002)). Therefore, methods to reduce P2X3 levels or activity could be used to modulate pain perception in painful subjects.

[0004] P2X3 can also form the P2X2 / 3 heterotrimer with P2X2, another member of the P2X purinergic ligand-gated ion channel family. P2X2 / 3 is highly expressed at the terminals (central and peripheral) of sensory neurons (Chen et al., Nature, Vol. 377, pp. 428-431 (1995)). Recent findings also indicate that P2X2 / 3 is primarily expressed (more than P2X3) in bladder sensory neurons and may play a role in the sensation of bladder fullness and nociceptive responses (Zhong et al., Neuroscience, Vol. 120, pp. 667-675 (2003)).

[0005] Selective modulators that inhibit specific signaling pathways activated by the P2X3 receptor (P2X3R) are candidate drugs for the treatment of respiratory diseases, including asthma, COPD, and cough, especially chronic cough. Clinical trials have shown that P2X3 receptor (P2X3R) modulators are effective in treating patients with recurrent chronic cough (Abdulqawi et al., Supra; US Pat. 9, 284, 279), but significant side effects, particularly taste disturbances, are observed. Developing highly active and selective P2X3 receptor (P2X3R) modulators is of great and positive significance for the effective prevention and treatment of related diseases, and for providing safe and low-side-effect medications. Summary of the Invention

[0006] This invention provides substituted heterocyclic derivatives or pharmaceutical compositions thereof that can act as selective modulators of the P2X3 receptor. The compounds or pharmaceutical compositions thereof described in this invention can treat diseases and / or conditions, particularly chronic cough, by inhibiting P2X3 receptor activity; therefore, this invention also relates to the use of the compounds or pharmaceutical compositions thereof in the preparation of such medicaments.

[0007] On the one hand, the present invention provides compounds of formula (I), or stereoisomers, tautomers, nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of compounds of formula (I).

[0008] (I), in, Ring A is a 5-membered heteroaryl group; Indicates a single bond or a double bond; When X is C, Y is N; Or, when X is N, Y is C; Ring B is selected from or ; R 1 It is a 3-8 membered heterocyclic group, C 6-10Aryl or 5-12-membered heteroaryl, wherein the 3-8-membered heterocyclic group, C 6-10 The aryl and 5-12 heteroaryl groups are each independently and optionally replaced by 1, 2, 3, 4 or 5 Rs; Each R is independently H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, oxo, , -OR a -C(=O)R a -C(=O)OR a -NR b R c -C(=O)NR b R c -NR b C(=O)R c -S(O)R a -S(O)2R a -S(O)2NR b R c -NR b S(O)2R c C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 cycloalkyl or 3-8 membered heterocyclic group; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3, 4 or 5 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-8 Substituents of cycloalkyl groups; R 2 is D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, -OR d -C(=O)R d-C(=O)-C(=O)R d -C(=O)OR d -C(=O)NR e R f -NR e C(=O)R f -P(=O)R e R f -S(O)R d -S(O)2R d -S(O)2NR e R f -NR e S(O)2R f Oxygen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-12 heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-12 heteroaryl group are each independently and optionally surrounded by 1, 2, 3, 4 or 5 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups; R 3 is H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl or 3-10 membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C1-6 Halogenated alkoxy groups, C 3-8 The cycloalkyl group and the 3-10 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3, 4 or 5 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups; R a R b R c R d R e and R f Each is independently H, D, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 The aryl group and the 5-12 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups; n is 0, 1, 2, 3, 4 or 5; The condition is that when R 1 It is a phenyl group, R 2 -C(=O)R d or -C(=O)OR d At that time, R d Not methyl, ethyl or isopropyl.

[0009] In some implementation schemes, R 1 It is a 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the 3-6 membered heterocyclic group, C 6-10The aryl and 5-10 heteroaryl groups are each independently and optionally replaced by 1, 2, 3, 4 or 5 Rs; Each R is independently H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, oxo, , -OR a -C(=O)R a -C(=O)OR a -NR b R c -C(=O)NR b R c -NR b C(=O)R c -S(O)R a -S(O)2R a -S(O)2NR b R c -NR b S(O)2R c C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups and C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3, 4 or 5 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups and C 3-6 Substituents of cycloalkyl groups; wherein, R a R b and R c Each has the definition as described in this invention.

[0010] In some implementation schemes, R 1The oxocyclobutyl, azacyclobutyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazine, morpholinyl, dihydropyridinyl, phenyl, naphthyl, indazole, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyrazinyl, wherein each of the oxocyclobutyl, azacyclobutyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazine, morpholinyl, dihydropyridinyl, phenyl, naphthyl, indazole, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyrazinyl groups is independently and optionally substituted with 1, 2, 3, 4, or 5 Rs. Each R is independently H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, oxo, , -OR a -C(=O)R a -C(=O)OR a -NR b R c -C(=O)NR b R c -NR b C(=O)R c -S(O)R a -S(O)2R a -S(O)2NR b R c -NR b S(O)2R cMethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl, oxetyl, azirone, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2 -CH2CHF2, -CH2CF3, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziridine, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, and morpholinyl are each independently and optionally surrounded by 1, 2, 3, 4, or 5 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, methyl, ethyl, n-propyl, isopropyl Substituents of alkyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; wherein, R a R b and R c Each has the definition as described in this invention.

[0011] In some implementation schemes, R 2 is D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, -OR d -C(=O)R d -C(=O)-C(=O)R d -C(=O)OR d -C(=O)NR e R f -NR e C(=O)R f -P(=O)R e R f -S(O)R d -S(O)2R d -S(O)2NR e Rf -NR e S(O)2R f Oxygen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl; wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently and optionally surrounded by 1, 2, 3, 4 or 5 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are replaced; wherein, R d R e and R f Each has the definition as described in this invention.

[0012] In some implementation schemes, R 2 is D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, -OR d -C(=O)R d -C(=O)-C(=O)R d -C(=O)OR d -C(=O)NR e R f -NR e C(=O)R f -P(=O)R e R f -S(O)R d -S(O)2R d -S(O)2NR e R f -NR e S(O)2R fOxygenated, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanebutyl, aziranebutyl, pyrroleyl, tetrahydrofuran The following are listed: methyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrroleyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, methoxy, ethoxy, isopropoxy, -C H2F, -CHF2, -CH2CHF2, -CH2CF3, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziridine, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazine, morpholinyl, phenyl, naphthyl, pyrroleyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl are each independently and optionally selected by 1, 2, 3, 4, or 5 from D, -F, The substituents of -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propynyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, and trifluoromethoxy are substituted; among which, R d R e and R f Each has the definition as described in this invention.

[0013] In some implementation schemes, R 3 is H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl or 3-8 membered heterocyclic group; wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C1-4 Halogenated alkoxy groups, C 3-6 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3, 4 or 5 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are replaced.

[0014] In some implementation schemes, R 3 The following are not directly related to the preceding text: H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxy, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CH2CHF2, -CH2CF3 are not directly related to the preceding text. The difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziridine, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, and morpholinyl groups are each independently and optionally substituted by 1, 2, 3, 4, or 5 substituents selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, and trifluoromethoxy groups.

[0015] In some implementation schemes, R a R b R c R d R e and R f Each is independently H, D, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 3-6Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl, wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are replaced.

[0016] In some implementation schemes, R a R b R c R d R e and R fEach of the following is independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, 2-methylpropenyl, ethynyl, propynyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziridine pyrroloyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrroloyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, 2-methylpropenyl, ethynyl, propargyl, 1-propynyl, 1-Oynyl-Butyl, 2-Oynyl-Butyl, 3-Oynyl-Butyl, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Oxycyclobutyl, Azacyclobutyl, Pyrrolidinyl, Tetrahydrofuranyl, Piperidinyl, Piperazinyl, Morpholinyl, Phenyl, Naphthyl, Pyrrolidinyl, Pyrazolyl, Imidazolyl, Triazolyl, Tetraazolyl, Furanyl, Thiopheneyl, Thiazolyl, Oxazolyl, Pyridinyl, Pyrimidinyl, Pyrazinyl Each of the pyridazinyl groups is independently and optionally substituted by 1, 2, 3 or 4 substituents selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy and trifluoromethoxy.

[0017] In some embodiments, the compound of the present invention is a compound of formula (II), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof. (II) Among them, R 1 R 2 and R 3 Each has the meaning described in this invention.

[0018] In some embodiments, the compound of the present invention is a compound of formula (III), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof. (III) Among them, R 1 R 2 and R3 Each has the meaning described in this invention.

[0019] On one hand, the present invention provides a pharmaceutical composition comprising a compound represented by formula (I), formula (II) or formula (III) of the present invention, or a stereoisomer, tautomer, nitride, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof.

[0020] In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable diluent, carrier, or excipient.

[0021] On the other hand, the present invention relates to the use of compounds of formula (I), formula (II) or formula (III) or pharmaceutical compositions thereof in the preparation of medicaments for the prevention, treatment or relief of P2X3 receptor-mediated diseases.

[0022] In some embodiments, the P2X3 receptor-mediated diseases described in this invention are pain, cough, respiratory diseases, or genitourinary diseases; the pain is chronic pain, acute pain, endometriosis pain, neuropathic pain, back pain, cancer pain, inflammatory pain, surgical pain, migraine, or visceral pain; the cough is refractory chronic cough or acute cough; the respiratory diseases are chronic obstructive pulmonary disease, pulmonary hypertension, pulmonary fibrosis, asthma, or obstructive sleep apnea; the genitourinary diseases are reduced bladder capacity, frequent urination, urge incontinence, stress incontinence, bladder hyperresponsiveness, benign prostatic hyperplasia, prostatitis, detrusor hyperreflexia, urinary frequency, nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatodynia, cystitis, or idiopathic bladder hypersensitivity.

[0023] In another aspect, the present invention relates to methods for the preparation, separation and purification of compounds represented by formula (I), formula (II) or formula (III).

[0024] The foregoing description only outlines certain aspects of the invention, but is not limited to these aspects. These and other aspects will be described in more detail below.

[0025] Detailed Description of the Invention Definitions and general terms Certain embodiments of the invention will now be described in detail, with examples illustrated by the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0026] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0027] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0028] As used in this invention, the term "test subject" refers to an animal. Typically, the animal is a mammal. Test subjects also include, for example, primates (e.g., humans, males or females), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some embodiments, the test subject is a primate. In other embodiments, the test subject is a human.

[0029] As used in this invention, the term "patient" refers to a person (including adults and children) or other animal. In some embodiments, "patient" refers to a person.

[0030] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0031] "Stereoisomers" refer to compounds that have the same chemical structure but differ in the spatial arrangement of their atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometrical isomers (cis / trans isomers), trans-blocking isomers, and so on. Unless otherwise stated, all stereoisomers or mixtures of stereoisomers of the structures described in this invention are within the scope of this invention. Furthermore, unless otherwise stated, the structural formulas of the compounds described in this invention include enriched isotopes of one or more different atoms.

[0032] The stereochemical definitions and rules used in this invention generally follow those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994.

[0033] Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0034] The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. A specific example of keto-enol tautomers is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is pyridine-4-ol and pyridine-4(1... H Tautomerism of keto tautomers. Unless otherwise indicated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0035] As described in this invention, the compounds of this invention can be independently and optionally substituted by one or more substituents, such as the general formula compounds above, or as the specific examples, subclasses, and classes of compounds included in this invention, as described in the embodiments. It should be understood that the terms "independently and optionally substituted" or "optionally substituted" are used interchangeably with the term "substituted or unsubstituted." Generally, the term "substituted" means that one or more hydrogen atoms in the given structure are substituted by a specific substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substituted position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted at the same or different positions.

[0036] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive terms “each…independently is”, “…each independently is”, and “…independently is” used in this invention are interchangeable and should be interpreted broadly. They can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0037] In various parts of this specification, the substituents of the compounds disclosed herein are disclosed according to the type or scope of the groups. In particular, the invention includes every independent secondary combination of the various members of these group types and scopes. For example, the term "C..." 1-6 "Alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0038] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0039] The term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally be substituted by one or more substituents described in this invention. In one embodiment, the alkyl group contains 1 to 6 carbon atoms, denoted as C1. 1-6 Alkyl group; in yet another embodiment, the alkyl group contains 1-4 carbon atoms, denoted as C1 1-4 Alkyl group; in another embodiment, the alkyl group contains 1-3 carbon atoms, denoted as C1 1-3Alkyl groups. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (... n -Pr, -CH2CH2CH3), isopropyl ( i -Pr, -CH(CH3)2), n-butyl ( n -Bu、-CH2CH2CH2CH3), isobutyl ( i -Bu、-CH2CH(CH3)2), sec-butyl( s -Bu、-CH(CH3)CH2CH3), tert-butyl( t -Bu、-C(CH3)3), n-pentyl(-CH2CH2CH2CH2CH3), 2-pentyl(-CH(CH3)CH2CH2CH3), 3-pentyl(-CH(CH2CH3)2), 2-methyl-2-butyl(-C(CH3)2CH2CH3), 3-methyl-2-butyl(-CH(CH3)CH (CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl ( -CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, etc.

[0040] The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, with at least one unsaturated site, i.e., one carbon-carbon sp. 2 A double bond, wherein the alkenyl group may optionally be replaced by one or more substituents described in this invention, including " cis "and" trans The positioning of "or " E "and" Z The positioning of "". In one embodiment, the alkenyl group contains 2-6 carbon atoms, denoted as C 2-6Alkenyl group; in yet another embodiment, the alkenyl group comprises 2-4 carbon atoms, denoted as C1 2-4 Alkenyl groups. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and 1-propenyl (i.e., propenyl, -CH=C). H- CH3), etc.

[0041] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, i.e., one carbon-carbon sp triple bond, wherein the alkynyl group may optionally be substituted by one or more substituents described in this invention. In one embodiment, the alkynyl group comprises 2-6 carbon atoms, denoted as C1. 2-6 Alkynyl group; in yet another embodiment, the alkynyl group comprises 2-4 carbon atoms, denoted as C0. 2-4 Alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), etc.

[0042] The term "haloalkyl" indicates that an alkyl group is replaced by one or more halogen atoms, wherein the alkyl group and the halogen atom have the definitions described herein. In some embodiments, the haloalkyl group is C10. 1-6 Haloalkyl, indicating C 1-6 The alkyl group is replaced by one or more halogen atoms; in other embodiments, the haloalkyl group is C10. 1-4 Haloalkyl, indicating C 1-4 The alkyl group is replaced by one or more halogen atoms; in other embodiments, the haloalkyl group is C10. 1-3 Haloalkyl, indicating C 1-3 The alkyl group is replaced by one or more halogen atoms. Examples of such groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl, 1-chloroethyl, 1,2-dichloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl, 1,1-dibromoethyl, and so on.

[0043] The term "alkoxy group" indicates that an alkyl group is attached to the remainder of the molecule by an oxygen atom, wherein the alkyl group has the meaning as described in this invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms, representing C0. 1-6 Alkoxy group; in another embodiment, the alkoxy group contains 1-4 carbon atoms, representing C 1-4Alkoxy group; in yet another embodiment, the alkoxy group contains 1-3 carbon atoms, representing C 1-3 Alkoxy group. The alkoxy group may optionally be replaced by one or more substituents described in this invention. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy ( n -PrO、 n -propoxy, -OCH2CH2CH3), 2-propoxy ( i -PrO、 i -propoxy, -OCH(CH3)2), 1-butoxy n -BuO、 n -Butoxy, -OCH2CH2CH2CH3), 2-Methyl-1-propoxy ( i -BuO、 i -butoxy, -OCH2CH(CH3)2), 2-butoxy ( s -BuO、 s -Butoxy, -OCH(CH3)CH2CH3), 2-Methyl-2-propoxy t -BuO、 t -Butoxy, -OC(CH3)3), 1-Pentoxy ( n -Pentoxy, -OCH2CH2CH2CH2CH3), 2-Pentoxy (-OCH(CH3)CH2CH2CH3), 3-Pentoxy (-OCH(CH2CH3)2), 2-Methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-Methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-Methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-Methyl-l-butoxy (-OCH2CH(CH3)CH2CH3), etc.

[0044] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group and the halogen have the definitions as defined in this invention. In some embodiments, a haloalkoxy group refers to a haloalkoxy group containing 1-6 carbon atoms, i.e., C6. 1-6 Haloalkoxy group; in other embodiments, haloalkoxy group refers to a haloalkoxy group containing 1-4 carbon atoms, i.e., C646-C ... 1-4 Haloalkoxy group; in other embodiments, haloalkoxy group refers to a haloalkoxy group containing 1-3 carbon atoms, i.e., C646-C ... 1-3Halogenated alkoxy groups. Examples of halogenated alkoxy groups include, but are not limited to, monofluoromethoxy (-OCH2F), difluoromethoxy (-OCF2), trifluoromethoxy (-OCF3), 2-fluoroethoxy (-OCH2CH2F), etc.

[0045] The term "cycloalkyl" refers to a monocyclic or bicyclic carbocyclic system with 3-12 carbon atoms, wherein the -CH2- group in the carbocyclic ring may optionally be replaced by -C(=O)- (or -(CO)-). In one embodiment, the cycloalkyl group comprises 3-10 carbon atoms, i.e., C2... 3-10 Cycloalkyl; in another embodiment, the cycloalkyl group comprises 3-7 carbon atoms, i.e., C64-C75. 3-7 Cycloalkyl; in another embodiment, the cycloalkyl group comprises 3-6 carbon atoms, i.e., C64-C ... 3-6 Cycloalkyl; in another embodiment, the cycloalkyl group comprises 3-5 carbon atoms, i.e., C64-C74-C6 ... 3-5 Cycloalkyl. In another embodiment, the cycloalkyl group is a monocyclic cycloalkyl group containing 3-7 carbon atoms, i.e., C10-C2 ... 3-7 Monocyclic cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and octahydro-1-ylyl groups. H -Indenyl, octahydrocyclopentadienyl, bicyclo[1.1.0]butyl, bicyclo[3.1.0]hexyl, etc. Examples of -CH2- groups in the carbide ring that can be replaced by -C(=O)- include, but are not limited to: cyclopentanone, cyclobutanone, etc.

[0046] The term "heterocycle" or "heterocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic system comprising 3 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms; wherein the heterocycle or heterocyclic group is non-aromatic and does not contain any aromatic ring. When a heterocycle is attached to other parts of a molecule via a linking site, the heterocycle is represented as a monovalent heterocyclic group. Unless otherwise stated, the heterocyclic group can be carbonyl or nitrogenyl, and the -CH2- group may optionally be replaced by -C(=O)-. The sulfur atom of the ring may optionally be oxidized to... S -Oxides. The nitrogen atom in the ring can optionally be oxidized to... N-Oxides. In some embodiments, the heterocycle or heterocyclic group consists of 3-10 atoms, represented as a 3-10 membered heterocycle or a 3-10 membered heterocyclic group; in other embodiments, the heterocycle or heterocyclic group consists of 3-9 atoms, represented as a 3-9 membered heterocycle or a 3-9 membered heterocyclic group; in other embodiments, the heterocycle or heterocyclic group consists of 5-9 atoms, represented as a 5-9 membered heterocycle or a 5-9 membered heterocyclic group; in other embodiments, the heterocycle or heterocyclic group consists of 3-6 atoms, represented as a 3-6 membered heterocycle or a 3-6 membered heterocyclic group; in other embodiments, the heterocycle or heterocyclic group consists of 5-6 atoms, represented as a 5-6 membered heterocycle or a 5-6 membered heterocyclic group. In still other embodiments, the heterocycle or heterocyclic group is a monocyclic ring consisting of 3-7 atoms, represented as a 3-7 membered monocyclic heterocycle or a 3-7 membered monocyclic heterocyclic group. Examples of the heterocycles include, but are not limited to, ethylene oxide, aziridine, aziridine, oxacyclobutane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, thiazoline, pyrazolidine, pyrazolidine, pyrazoline, oxazolidine, imidazoline, piperidine, piperazine, morpholine, 3,8-diazabicyclo[3.2.1]octane, 3,6-diazabicyclo[3.1.1]heptane, and 2,5-diazabicyclo[2.2.2]octane. The heterocyclic groups include, but are not limited to, ethylene oxide, aziridine, aziridine, oxazolidine, pyrrolidine, tetrahydrofuranyl, tetrahydrothiopheneyl, thiazoline, pyrazolidine, pyrazolidine, pyrazolidine, oxazolidine, imidazoline, piperidinyl, piperazinyl, or morpholinyl.

[0047] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic system containing 6-14, 6-12, or 6-10 ring atoms, wherein at least one ring system is aromatic, and each ring system comprises a ring of 3-7 atoms. In some embodiments, the aryl group contains 6-12 ring atoms, denoted as C 6-12 Aryl or 6-12-membered aryl. In some embodiments, the aryl group contains 6-10 ring atoms, denoted as C. 6-10 Aryl or 6-10 aryl groups. Examples of aryl groups may include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, and anthracene.

[0048] The term "heteroaryl" or "heteroaromatic ring" refers to a monovalent monocyclic, bicyclic, or tricyclic system containing 5-14, 5-12, 5-10, or 5-6 ring atoms, wherein at least one ring is aromatic and at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, and sulfur. The heteroaryl group is typically, but not necessarily, linked to the parent molecule via its aromatic ring. When a -CH2- group is present in the heteroaryl group, the -CH2- group may optionally be replaced by -C(=O)-. Unless otherwise stated, the heteroaryl group may be linked to the remainder of the molecule (e.g., the main structure in the general formula) through any reasonable site (which may be C or N). The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, the heteroaryl group is a heteroaryl group containing 5-12 ring atoms, denoted as a 5-12-membered heteroaryl group; in other embodiments, the heteroaryl group is a heteroaryl group containing 5-10 ring atoms, denoted as a 5-10-membered heteroaryl group; in still other embodiments, the heteroaryl group is a heteroaryl group containing 5-6 ring atoms, denoted as a 5-6-membered heteroaryl group. Examples of heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophene, thiazolyl, triazolyl, tetrazolyl, benzofuran, benzothiazole, benzopyridinyl, benzoimidazolyl, benzopyrrolyl, benzopyrazolyl, benzopyrrolylalkyl, 2,3-dihydrobenzofuran, benzo[2,3-b][1,4]dioxin, pyrido[2,3-b][1,4]dioxin, benzo[2,3-b][1,4]oxazine, pyrido[2,3-b][1,4]oxazine, etc.

[0049] The term "halogen" refers to F (fluorine), Cl (chlorine), Br (bromine), or I (iodine).

[0050] The term "oxo" means =O.

[0051] The term "cyano" means -CN or -C≡N.

[0052] The term "thiol" represents -SH.

[0053] The term "hydroxyl group" represents -OH.

[0054] The term "carboxyl group" represents -C(=O)OH.

[0055] The term "composed of jk atoms" or "of jk elements" means that the cyclic group is composed of jk ring atoms, including carbon atoms and / or heteroatoms such as O, N, S, P, etc.; j and k are each independently any non-zero natural number, and k > j; "jk" includes j, k, and any natural number between them. For example, "composed of 3-8 atoms" or "3-8-element", "composed of 3-6 atoms" or "3-6-element", "composed of 5-10 atoms" or "5-10-element", or "composed of 5-6 atoms" or "5-6-element" indicates that the cyclic group is composed of 3-8 (i.e., 3, 4, 5, 6, 7 or 8), 3-6 (i.e., 3, 4, 5 or 6), 5-10 (i.e., 5, 6, 7, 8, 9 or 10), or 5-6 (i.e., 5 or 6) ring atoms, wherein the ring atoms include carbon atoms and / or heteroatoms such as O, N, S, P, etc.

[0056] As used in this invention, the term "prodrug" refers to the conversion of a compound into a compound represented by formula (I), (II), or (III) in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C) esters. 1-24 Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound in this invention contains a hydroxyl group, meaning it can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a parent compound with a hydroxyl group.

[0057] "Metabolic products" refer to the products obtained from the metabolism of a specific compound or its salt in the body. The metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized by experimental methods as described in this invention. Such products can be obtained by subjecting the compound to oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this invention includes the metabolites of compounds, including metabolites produced by sufficiently exposing the compounds of this invention to mammals for a period of time.

[0058] The term "pharmaceutically acceptable salt" as used in this invention refers to the organic and inorganic salts of the compounds of this invention. Pharmaceutically acceptable salts are well-known in the field, as described in references such as SM Berge. et al.The invention describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable salts formed from non-toxic acids include, but are not limited to, inorganic acid salts formed by reactions with amino groups. The invention also contemplates quaternary ammonium salts formed from any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations that resist the formation of equilibrium ions.

[0059] In this invention, "solvent" refers to an association formed by one or more solvent molecules and a compound of this invention. Solvents forming solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term "hydrate" refers to an association formed when the solvent molecules are water.

[0060] When the solvent is water, the term "hydrate" may be used. In one embodiment, a molecule of the compound of the present invention may bind to one water molecule, such as a monohydrate; in another embodiment, a molecule of the compound of the present invention may bind to more than one water molecule, such as a dihydrate; in yet another embodiment, a molecule of the compound of the present invention may bind to fewer than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the bioavailability of the non-hydrated form of the compound. As used herein, the term "treatment" refers to any disease or condition, in some embodiments meaning to improve the disease or condition (i.e., slow down or stop or alleviate the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" means to alleviate or improve at least one bodily parameter, including bodily parameters that may not be perceptible to the patient. In other embodiments, "treatment" means to regulate the disease or condition from a physical (e.g., stabilizing perceptible symptoms) or physiological (e.g., stabilizing bodily parameters) or both. In other embodiments, "treatment" means to prevent or delay the onset, occurrence, or worsening of the disease or condition.

[0061] The term “prevention” or “avoidance” refers to the reduction of the risk of acquiring a disease or disorder (i.e., stopping the development of at least one clinical symptom of the disease in a subject who may be facing or predisposed to facing the disease, but has not yet experienced or exhibited symptoms of the disease).

[0062] The term "therapeutic effective dose" refers to the amount of a compound that is sufficient to treat a disease when administered to a subject. The "therapeutic effective dose" can vary depending on the compound, the disease and its severity, and the condition, age, weight, and sex of the subject being treated.

[0063] Unless otherwise stated, all suitable isotopic variations, stereoisomers, tautomers, hydrates, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs of the compounds of this invention are included within the scope of this invention.

[0064] In the structures disclosed in this invention, when the stereochemistry of any particular chiral atom is not specified, all stereoisomers of that structure are considered within the scope of this invention and are included in this invention as disclosed compounds. When the stereochemistry is indicated by a solid wedge or dashed line representing a particular configuration, the stereoisomers of that structure are thus clearly defined.

[0065] The nitrogen oxides of the compounds of this invention are also included within the scope of this invention. The nitrogen oxides of the compounds of this invention can be prepared by oxidizing the corresponding nitrogen-containing basic substances in the presence of an acid, such as acetic acid, using a common oxidizing agent (e.g., hydrogen peroxide) at elevated temperature, or by reacting with a peracid in a suitable solvent, such as with peracetic acid in dichloromethane, ethyl acetate, or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

[0066] The compounds described in (I), (II) or (III) of this invention may exist in the form of salts.

[0067] Any structural formulas provided in this invention are intended to represent both the unenriched and isotopically enriched forms of these compounds. Isotopically enriched compounds have the structures described by the general formulas provided in this invention, except that one or more atoms are replaced by atoms having a chosen atomic weight or mass number. Exemplary isotopes that may be introduced into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as... 2 H, 3 H, 11 C 13 C 14 C 15 N、 17 O、 18 O、 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.

[0068] Description of the compounds of the present invention The present invention provides a compound, or a pharmaceutical composition thereof, which can act as a selective modulator of the P2X3 receptor.

[0069] The present invention further relates to the use of the said compound or a pharmaceutical composition thereof in the preparation of a medicament that treats diseases and / or conditions by means of the compound inhibiting P2X3 receptor activity.

[0070] The excellent properties of the compounds of this invention, such as half-life, clearance rate, selectivity, bioavailability, chemical stability, metabolic stability, membrane permeability, and solubility, can promote the reduction of side effects, the expansion of the therapeutic index, or the improvement of tolerability.

[0071] On the one hand, the present invention provides compounds of formula (I), or stereoisomers, tautomers, nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of compounds of formula (I). (I), Among them, R 1 R 2 R 3 X, Y, ring A, ring B and n each have the definitions as described in this invention.

[0072] In some implementations, when R 1 When it is phenyl, R 2 -C(=O)R d or -C(=O)OR d At that time, R d Not methyl, ethyl or isopropyl.

[0073] In some implementations, ring A is a 5-membered heteroaryl group.

[0074] In some implementation schemes, Indicates a single bond or a double bond.

[0075] In some implementations, when X is C, Y is N.

[0076] In some implementations, Y is C when X is N.

[0077] In some implementation schemes, ring B is selected from... or .

[0078] In some implementation schemes, R 1 It is a 3-8 membered heterocyclic group, C 6-10 Aryl or 5-12-membered heteroaryl, wherein the 3-8-membered heterocyclic group, C 6-10The aryl and 5-12 heteroaryl groups are each optionally replaced by 1, 2, 3, 4 or 5 Rs; wherein the Rs have the definitions described in this invention.

[0079] In some implementation schemes, R 1 It is a 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the 3-6 membered heterocyclic group, C 6-10 The aryl and 5-10 heteroaryl groups are each optionally replaced by 1, 2, 3, 4 or 5 Rs; wherein the Rs have the definitions described in this invention.

[0080] In other implementations, R 1 The compounds are oxetyl, azaecyclobutyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, dihydropyridinyl, phenyl, naphthyl, indazoleyl, pyrrolidinyl, pyrazolyl, imidazoleyl, triazolyl, tetraazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, wherein the oxetyl, azaecyclobutyl, or pyrrolidinyl compounds are... The tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazine, morpholinyl, dihydropyridinyl, phenyl, naphthyl, indazole, pyrroleyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl are each independently and optionally replaced by 1, 2, 3, 4, or 5 Rs; wherein the Rs have the definitions described in this invention.

[0081] In some implementations, each R is independently H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, oxo, , -OR a -C(=O)R a -C(=O)OR a -NR b R c -C(=O)NR b R c -NR b C(=O)R c -S(O)R a -S(O)2R a -S(O)2NR b R c -NR b S(O)2R c C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 cycloalkyl or 3-8 membered heterocyclic group; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3, 4 or 5 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-8 Substituents of cycloalkyl groups; wherein, R a R b and R c It has the definition as described in this invention.

[0082] In some implementations, each R is independently H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, oxo, , -OR a -C(=O)R a -C(=O)OR a -NR b R c -C(=O)NR b R c -NR b C(=O)R c -S(O)R a -S(O)2R a -S(O)2NR b R c -NR b S(O)2R c C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; wherein the C 1-4 Alkyl, C 2-4 alkenyl, C2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3, 4 or 5 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups and C 3-6 Substituents of cycloalkyl groups; wherein, R a R b and R c It has the definition as described in this invention.

[0083] In other embodiments, each R is independently H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, oxo, , -OR a -C(=O)R a -C(=O)OR a -NR b R c -C(=O)NR b R c -NR b C(=O)R c -S(O)R a -S(O)2R a -S(O)2NR b R c -NR b S(O)2R cMethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl, oxetyl, azirone, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2 -CH2CHF2, -CH2CF3, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are each independently and optionally separated by 1, 2, 3, 4, or 5 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propenyl The substituents are alkynyl, 1-alkynylbutyl, 2-alkynylbutyl, 3-alkynylbutyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxybutyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, and morpholinyl; wherein, R a R b and R c It has the definition as described in this invention.

[0084] In some implementation schemes, R 2 is D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, -OR d -C(=O)R d -C(=O)-C(=O)R d -C(=O)OR d -C(=O)NR e R f -NR e C(=O)R f -P(=O)R e R f -S(O)R d -S(O)2R d -S(O)2NR e R f-NR e S(O)2R f Oxygen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-12 heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-12 heteroaryl group are each independently and optionally surrounded by 1, 2, 3, 4 or 5 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 The substituents of the haloalkoxy group are replaced; wherein, R d R e and R f It has the definition as described in this invention.

[0085] In some implementation schemes, R 2 is D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, -OR d -C(=O)R d -C(=O)-C(=O)R d -C(=O)OR d -C(=O)NR e R f -NR e C(=O)R f -P(=O)R e R f -S(O)R d -S(O)2R d -S(O)2NR e R f -NR e S(O)2R f Oxygen, C1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl; wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently and optionally surrounded by 1, 2, 3, 4 or 5 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are replaced; wherein, R d R e and R f It has the definition as described in this invention.

[0086] In other implementations, R 2 is D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, -OR d -C(=O)R d -C(=O)-C(=O)R d -C(=O)OR d -C(=O)NR e R f -NR e C(=O)R f -P(=O)R e R f -S(O)R d -S(O)2R d -S(O)2NR e R f -NR e S(O)2R fOxygenated, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanebutyl, aziranebutyl, pyrroleyl, tetrahydrofuran The following are listed: methyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrroleyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, methoxy, ethoxy, isopropoxy, -C H2F, -CHF2, -CH2CHF2, -CH2CF3, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziridine, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazine, morpholinyl, phenyl, naphthyl, pyrroleyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl are each independently and optionally selected by 1, 2, 3, 4, or 5 from D, -F, The substituents of -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propynyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, and trifluoromethoxy are substituted; among which, R d R e and R f It has the definition as described in this invention.

[0087] In some implementation schemes, R 3 is H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl or 3-10 membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C1-6 Halogenated alkoxy groups, C 3-8 The cycloalkyl group and the 3-10 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3, 4 or 5 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 The substituents of the haloalkoxy group are replaced.

[0088] In some implementation schemes, R 3 is H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl or 3-8 membered heterocyclic group; wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3, 4 or 5 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are replaced.

[0089] In other implementations, R 3The following are not directly related to the preceding text: H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxy, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CH2CHF2, -CH2CF3 are not directly related to the preceding text. The difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziridine, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, and morpholinyl groups are each independently and optionally substituted by 1, 2, 3, 4, or 5 substituents selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, and trifluoromethoxy groups.

[0090] In some implementation schemes, R a R b R c R d R e and R f Each is independently H, D, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 The aryl group and the 5-12 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy and C 1-6 The substituents of the haloalkoxy group are replaced.

[0091] In some implementation schemes, R a R b R c R d R e and R f Each is independently H, D, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl, wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are replaced.

[0092] In other implementations, R a R b R c R d R e and R fEach of the following is independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, 2-methylpropenyl, ethynyl, propynyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziridine pyrroloyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrroloyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, 2-methylpropenyl, ethynyl, propargyl, 1-propynyl, 1-Oynyl-Butyl, 2-Oynyl-Butyl, 3-Oynyl-Butyl, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Oxycyclobutyl, Azacyclobutyl, Pyrrolidinyl, Tetrahydrofuranyl, Piperidinyl, Piperazinyl, Morpholinyl, Phenyl, Naphthyl, Pyrrolidinyl, Pyrazolyl, Imidazolyl, Triazolyl, Tetraazolyl, Furanyl, Thiopheneyl, Thiazolyl, Oxazolyl, Pyridinyl, Pyrimidinyl, Pyrazinyl Each of the pyridazinyl groups is independently and optionally substituted by 1, 2, 3 or 4 substituents selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy and trifluoromethoxy.

[0093] In some implementations, n is 0, 1, 2, 3, 4, or 5.

[0094] In some embodiments, the compound of the present invention is a compound of formula (II), or a stereoisomer, geometric isomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof. (II) Among them, R 1 R 2 and R 3 Each has the meaning described in this invention.

[0095] In some embodiments, the compound of the present invention is a compound of formula (III), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof. (III) Among them, R 1 R 2 and R 3 Each has the meaning described in this invention.

[0096] In some embodiments, the compound of the present invention is a compound of formula (IV), or a stereoisomer, geometric isomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof. (IV) Among them, R 1 R 2 and R 3 Each has the meaning described in this invention.

[0097] In some embodiments, the compound of the present invention is a compound of formula (V), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof. (V) Among them, R 1 R 2 and R 3 Each has the meaning described in this invention.

[0098] On the other hand, the compounds described in this invention have the following structures, or stereoisomers, tautomers, nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs, but are by no means limited to: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (twenty one), (twenty two), (twenty three), (twenty four), , , , , or .

[0099] On the other hand, the present invention provides a pharmaceutical composition comprising the compounds described herein.

[0100] In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable diluent, carrier, or excipient.

[0101] On the other hand, the present invention provides the use of the pharmaceutical composition described herein in the preparation of a medicament for the prevention, treatment or relief of P2X3 receptor-mediated diseases.

[0102] In some embodiments, the P2X3 receptor-mediated diseases described in this invention are pain, cough, respiratory diseases, or genitourinary diseases.

[0103] In some embodiments, the pain described in this invention is chronic pain, acute pain, endometriosis pain, neuropathic pain, back pain, cancer pain, inflammatory pain, surgical pain, migraine, or visceral pain; The cough is either a refractory chronic cough or an acute cough; The respiratory diseases mentioned are chronic obstructive pulmonary disease, pulmonary hypertension, pulmonary fibrosis, asthma, or obstructive sleep apnea. The urogenital system diseases mentioned include reduced bladder capacity, frequent urination, urge incontinence, stress incontinence, bladder hyperresponsiveness, benign prostatic hyperplasia, prostatitis, detrusor hyperreflexia, urinary frequency, nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatodynia, cystitis, or idiopathic bladder hypersensitivity.

[0104] On the other hand, the present invention also provides a method for preventing or treating P2X3 receptor-mediated diseases, the method comprising administering to a patient a therapeutically effective amount of the compound or pharmaceutical composition thereof described in the present invention.

[0105] On the other hand, the present invention relates to methods for the preparation, separation and purification of compounds represented by formula (I), formula (II), formula (III), formula (IV) or formula (V).

[0106] Pharmaceutical compositions, formulations, administration and uses of the compounds of this invention The pharmaceutical compositions of the present invention are characterized by compounds represented by formula (I), (II), (III), (IV), or (V), compounds listed in the present invention, or compounds of the examples, and pharmaceutically acceptable carriers. The amounts of compounds in the pharmaceutical compositions of the present invention are effective in treating or alleviating P2X3 receptor-mediated diseases in patients.

[0107] The compounds of the present invention exist in free form or as suitable, pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adducts or derivatives that can be administered directly or indirectly as needed by a patient, compounds described in other aspects of the present invention, their metabolites, or their residues.

[0108] As described in this invention, pharmaceutically acceptable compositions of the present invention further comprise pharmaceutically acceptable excipients, such as those used in this invention, including any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for a particular target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JCBoylan, 1988-1999, Marcel Dekker, New York, the contents of which, taken together, show that various excipients can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. The use of any conventional excipients, except those incompatible with the compounds of the present invention, such as any adverse biological effects or harmful interactions with any other component of the pharmaceutically acceptable composition, is also within the scope of this invention.

[0109] Substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering agents such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl cellulose. Sodium thiosulfate, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol, phosphate buffer solution, and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and spices, preservatives and antioxidants.

[0110] In preparing the pharmaceutical compositions provided by this invention, the active ingredient is typically mixed with an excipient, diluted by the excipient, or packaged in a carrier, such as a capsule, sachet, paper, or other container. If the excipient is used as a diluent, it can be a solid, semi-solid, or liquid material, serving as a carrier, container, or medium for the active ingredient. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose, low-melting-point wax, cocoa butter, etc. Therefore, the composition can be in the form of tablets, pills, powders, lozenges, capsules, flat capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterilely packaged powders. In one embodiment, the composition is formulated for oral administration. In one embodiment, the composition is formulated as a tablet or capsule.

[0111] The compounds or pharmaceutical compositions of this invention can be administered in oral dosage forms, such as tablets, capsules (each comprising a sustained-release or timed-release formulation), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsifiers. They can also be administered intravenously (in pills or infusions), intraperitoneally, subcutaneously, or intramuscularly, all dosage forms used being well known to those skilled in the art of pharmacy. They can be administered alone, but generally a pharmaceutical carrier will be selected for co-administration based on the chosen route of administration and standard pharmaceutical practice.

[0112] The compounds or pharmaceutical compositions of the present invention can be administered intranasally via a suitable intranasal carrier or transdermally via a transdermal patch. When administered via a transdermal delivery system, the dose is continuous rather than intermittent throughout the course of treatment.

[0113] The compounds or pharmaceutical compositions of the present invention can also be administered in the form of liposome delivery systems, such as small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. Liposomes can be formed from different phospholipids, such as cholesterol, stearamine, or phosphatidylcholine.

[0114] The compounds or pharmaceutical compositions of the present invention are also coupled with soluble polymers that act as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylate-phenol, polyhydroxyethyl asparagine, or polyvinyl oxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention can be coupled with a class of biodegradable polymers for controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polycaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and crosslinked or amphiphilic blocking copolymers of hydrogels.

[0115] The administration regimen of the compounds or pharmaceutical compositions of this invention will vary depending on a variety of known factors, such as the pharmacokinetic characteristics and patterns of the specific agent and the route of administration; the recipient's race, age, sex, health status, medical condition, and weight; the nature and severity of symptoms; the types of concurrent treatments; the frequency of treatment; the route of administration; the patient's renal and hepatic function; and the desired effect. A physician or veterinarian can make a decision and prescribe an effective amount of the drug to prevent, counteract, or halt the progression of a disease.

[0116] According to general guidelines, in order to achieve the specified effect, the dosage of each active ingredient used is in the range of approximately 0.001 to 1000 mg / kg body weight per day, preferably between approximately 0.01 and 100 mg / kg body weight. The compounds of the present invention can be administered once daily, or in two, three, or four divided doses per day.

[0117] Each unit dose of a suitable dosage form (pharmaceutical composition) may contain from about 1 mg to about 100 mg of the active ingredient. In these pharmaceutical compositions, the weight of the active ingredient will generally account for about 0.5-95% of the total weight of the composition.

[0118] The compounds and compositions described in this invention can be administered alone or in combination with other compounds or other therapeutic agents. The compounds or compositions of this invention can be administered simultaneously or sequentially with other therapeutic agents via the same or different routes of administration. The compounds of this invention can be included in a single formulation along with other therapeutic agents or in a separate formulation.

[0119] When the compounds of the present invention are administered together with other therapeutic agents, the amount of each component in a typical daily dose and typical dosage form may generally be reduced relative to the usual dose when administered alone, taking into account the additional or synergistic effects of the therapeutic agents when administered in combination.

[0120] The compounds, pharmaceutical salts, hydrates, or pharmaceutical compositions thereof involved in this invention are effective in preventing, treating, or alleviating diseases mediated by P2X3 receptors, particularly cough.

[0121] In some embodiments, the compounds of the present invention or pharmaceutical compositions thereof are effective in preventing, treating or alleviating P2X3 receptor-mediated symptoms in patients, including, but not limited to: refractory chronic cough, acute cough, chronic obstructive pulmonary disease, pulmonary hypertension, pulmonary fibrosis, asthma, obstructive sleep apnea, decreased bladder capacity, frequent urination, urge incontinence, stress incontinence, bladder hyperresponsiveness, benign prostatic hyperplasia, prostatitis, detrusor hyperreflexia, urinary frequency, nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatodynia, cystitis, or idiopathic bladder hypersensitivity.

[0122] General Synthesis Process To describe this invention, the following embodiments will be used to further illustrate the technical solution of this invention. These embodiments are only used to illustrate specific implementation methods of this invention so that those skilled in the art can understand it, but are not intended to limit the scope of protection of this invention. In the specific implementation methods of this invention, technical means or methods not specifically described are conventional technical means or methods in the art.

[0123] Unless otherwise specified, the substituents are defined as described in this invention. The following reaction schemes and examples are provided to further illustrate the content of this invention.

[0124] Those skilled in the art will recognize that the chemical reactions described in this invention can be suitably used to prepare other compounds of this invention, and that other methods for preparing the compounds of this invention are considered to be within the scope of this invention. For example, the synthesis of those non-illustrative compounds according to this invention can be successfully accomplished by those skilled in the art through modification methods, such as by appropriately protecting interfering groups, by utilizing other known reagents besides those described in this invention, or by making some conventional modifications to the reaction conditions. Furthermore, the reactions disclosed in this invention or the known reaction conditions are also generally accepted to be applicable to the preparation of other compounds of this invention.

[0125] In the examples described below, unless otherwise specified, all temperatures are in degrees Celsius (°C). Room temperature in the examples represents 15 °C–30 °C; in some examples, room temperature is 20 °C–30 °C. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company, and Alfa Chemical Company, and were used without further purification. Unless otherwise specified, common reagents are commercially available.

[0126] When this invention relates to one or more of the following reagents and solvents, the solvents can be used in experiments after being treated as follows: anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether are obtained by reflux drying with metallic sodium; anhydrous dichloromethane and chloroform are obtained by reflux drying with calcium hydride; ethyl acetate, petroleum ether, and n-hexane... N , N -dimethylacetamide and N , N - Dimethylformamide is used after being dried with anhydrous sodium sulfate.

[0127] The reaction can be carried out under positive pressure of nitrogen or argon or over anhydrous solvent with a drying tube attached (unless otherwise indicated). All reaction flasks are sealed with suitable rubber stoppers, and the substrate is injected via syringe. All glassware is dried.

[0128] The chromatographic column used was a silica gel column. The silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

[0129] 1 H NMR spectra were recorded using a Bruker 400 MHz, 600 MHz, or 599 MHz nuclear magnetic resonance spectrometer. 1 ¹H NMR spectra with CDCl₃ and DMSO- d 6. CD3OD or acetone - d6 represents the solvent (in ppm), with TMS (0 ppm) or chloroform (7.26 ppm) as the reference standard. When multiplets are observed, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), br s (broadened singlet), dd (doublet of doublets), dt (doublet of triplets), qt (quartet of triplets). Coupling constant. J It is represented by Hertz (Hz).

[0130] The determination conditions for low-resolution mass spectrometry (MS) data were as follows: Agilent 6120 quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1 × 30 mm, 3.5 μm, 6 min, flow rate: 0.6 mL / min; mobile phase: 5%–95% (CH3CN containing 0.1% formic acid) in (H2O containing 0.1% formic acid), electrospray ionization (ESI) at 210 nm / 254 nm, detection by UV.

[0131] Pure compounds were detected using UV at 210 nm / 254 nm using an Agilent 1260 pre-HPLC or a Calesep pump 250 pre-HPLC (column model: NOVASEP 50 / 80 mm DAC).

[0132] The following abbreviations or English words are used throughout this invention:

[0133] Synthesis Scheme 1

[0134] Compound (Ia) can be synthesized according to the method of synthetic scheme 1; wherein R x R y and R z Each of the following can be independently H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups; R d R2 R 3 And n has the definition as described in this invention. Compound (I-1) reacts with methanesulfonyl chloride under suitable conditions (e.g., with triethylamine) to give compound (I-2); compound (I-2) reacts with potassium phthalimide under suitable conditions (e.g., at 110 °C) to give compound (I-3); compound (I-3) reacts with hydrazine hydrate under suitable conditions (e.g., at 80 °C) to give compound (I-4); compound (I-4) reacts with compound (I-5) under suitable conditions (e.g., with calcium carbonate) to give compound (I-6); compound (I-6) reacts with compound (I-7) under suitable conditions (e.g., with sodium dithionite) to give compound (I-8); compound (I-8) reacts with hydrochloric acid under suitable conditions (e.g., with hydrochloric acid) to give compound (I-9); compound (I-9) reacts with compound (I-10) under suitable conditions (e.g., with triethylamine) to give compound (Ia).

[0135] Synthesis Scheme 2

[0136] Compound (Ia) can be synthesized according to the method of synthetic scheme 2; wherein R x R y and R z Each of the following can be independently H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups; R d R 2 R 3 And n has the definition as described in this invention. Compound (I-9) reacts with compound (I-11) under suitable conditions (such as the action of DIPEA and HATU) to give compound (Ia).

[0137] Synthesis Scheme 3

[0138] Compound (Ib) can be synthesized according to the method in Scheme 3; wherein R x R y and R z Each of the following can be independently H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups; R dR 2 R 3 And n has the definition as described in this invention. Compound (I-12) reacts with compound (I-11) under suitable conditions (such as the action of DIPEA and HATU) to give compound (Ib).

[0139] The following examples further illustrate the compounds, pharmaceutical compositions, and their applications provided by the present invention.

[0140] Example intermediate ( S )-3,5-difluoro- N -Methyl-4-(7-methyl-3-(morpholin-2-ylmethyl)imidazo[1,2-] a pyridin-2-yl)benzamide

[0141] It was obtained by referring to the synthesis method of intermediate V9 in patent CN116635389A.

[0142] Example 1 ( S )-3,5-difluoro-4-(1-((4-(2-fluoroacryloyl)morpholin-2-yl)methyl)-5-methyl-1 H -benzo[ d [Imidazol-2-yl]- N -Methylbenzamide

[0143]

[0144] Step 1: ( R Synthesis of tert-butyl morpholine-4-carboxylic acid ester (((methanesulfonyl)oxy)methyl)morpholine-4-carboxylic acid) At 0°C, under nitrogen protection, towards ( R Triethylamine (6.99 g, 69.05 mmol) and methanesulfonyl chloride (6.85 g, 59.84 mmol) were added dropwise to a solution of tert-butyl 4-(hydroxymethyl)morpholine-4-carboxylic acid (10 g, 46.03 mmol) in dichloromethane (100 mL). After the addition was complete, the mixture was stirred at room temperature for 3 h. After the reaction was completed, water (100 mL) was added to quench the reaction mixture, and the mixture was extracted with dichloromethane (200 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 3:1) to give a colorless oil (13.0 g, yield 95.63%).

[0145] Step 2: ( SSynthesis of tert-butyl morpholine-4-carboxylic acid ester ((1,3-dioxoisoindoline-2-yl)methyl)morpholine-4-carboxylic acid) Potassium phthalimide (3.45 g, 18.62 mmol) was added to ( R 2-(((methanesulfonyl)oxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (5.0 g, 16.93 mmol) N , N The reaction was carried out in a 50 mL solution of dimethylformamide at 110 °C with stirring for 10 h. After the reaction was completed, the mixture was quenched with 200 mL of water, extracted with ethyl acetate, and the organic phases were combined. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 5:1) to give a white solid (4.6 g, yield 78.45%).

[0146] Step 3: ( S Synthesis of tert-butyl 2-(aminomethyl)morpholine-4-carboxylic acid Towards( S In a 50 mL ethanol solution of tert-butyl 2-((1,3-dioxoisoindololin-2-yl)methyl)morpholine-4-carboxylic acid (4.0 g, 11.55 mmol), hydrazine hydrate (0.036 g, 0.58 mmol) was added, and the reaction mixture was stirred at 80 °C for 8 h. After the reaction was complete, insoluble impurities were removed by filtration, and the mixture was washed with ethanol (50 mL). The filtrate was collected, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (v:v) = 10:1) to give a yellow oil (1.2 g, yield 48.05%).

[0147] Step 4: ( S Synthesis of tert-butyl 4-morpholine-4-carboxylic acid Towards( S Calcium carbonate (0.17 g, 1.67 mmol) was added to a solution of tert-butyl 2-(aminomethyl)morpholine-4-carboxylic acid (0.3 g, 1.39 mmol) and 1-fluoro-4-methyl-2-nitrobenzene (0.26 g, 1.67 mmol) in acetonitrile (3.0 mL). The reaction mixture was stirred at 80 °C for 8 h. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 5:1) to give a yellow solid (0.39 g, yield 80.01%).

[0148] Step 5: ( S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-5-methyl-1 H -benzo[ d Synthesis of imidazo-1-yl)methyl)morpholine-4-carboxylic acid tert-butyl ester Towards( S A solution of tert-butyl 4-morpholine-4-carboxylic acid (0.39 g, 1.11 mmol) and 3,5-difluoro-4-formyl-N-methylbenzamide (0.22 g, 1.11 mmol) in ethanol (5.0 mL) was prepared, and sodium dithionite (0.97 g, 5.55 mmol) was added. The mixture was stirred at 80 °C for 12 h. After the reaction was complete, water (50 mL) and ethyl acetate (50 mL × 3) were added to the reaction solution. The organic phase was collected, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate (v:v) = 1:1) to give a yellow solid (0.34 g, yield 61.20%).

[0149] Step 6: ( R )-3,5-difluoro- N -Methyl-4-(5-methyl-1-(morpholin-2-ylmethyl)-1H-benzo[ d Synthesis of imidazole-2-yl)benzamide Towards( S )-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-5-methyl-1 H -benzo[ d A solution of 1,4-dioxane in 4 M hydrochloric acid (1.7 mL) was added to a 2 mL solution of 1,4-dioxane in imidazo-1-yl)methyl)morpholine-4-carboxylic acid tert-butyl ester (0.34 g, 0.68 mmol). The mixture was stirred at room temperature for 4 h. After the reaction was complete, the solvent was removed under reduced pressure. The remaining residue was used directly in the next reaction. Thin-layer chromatography showed no residual starting material.

[0150] Step 7: ( S )-3,5-difluoro-4-(1-((4-(2-fluoroacryloyl)morpholin-2-yl)methyl)-5-methyl-1 H -benzo[ d [Imidazol-2-yl]- N Synthesis of methylbenzamide At 0 ℃, towards ( R )-3,5-difluoro-N-methyl-4-(5-methyl-1-(morpholin-2-ylmethyl)-1 H -benzo[ dIn a solution of imidazole-2-yl)benzamide (0.27 g, 0.67 mmol) in dichloromethane (10 mL), triethylamine (0.20 g, 2.01 mmol) was added. After stirring for 10 min, 2-fluoropropionic-2-enoyl chloride (0.095 g, 0.87 mmol) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 8 h. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate (v:v) = 1:1) to give a white solid (0.22 g, yield 69.06%). MS (ESI, pos.ion) m / z: 473 [M+H] + .

[0151] 1 H NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 7.64 (s, 1H), 7.44 (d, J = 8.3Hz, 2H), 7.37 (d, J = 8.3 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 5.18 (m, 2H), 4.19(s, 1H), 4.19 – 4.00 (m, 3H), 3.67 (d, J = 28.3 Hz, 3H), 3.30 (t, J = 10.7 Hz, 1H), 3.03 (d, J = 4.7 Hz (4H), 2.53 (s, 3H). Example 2: ( Z )-3,5-difluoro-4-(1-((4-(methoxyimino)tetrahydro-2 H -pyran-2-yl)methyl)-5-methyl-1 H -benzo[ d [Imidazol-2-yl]- N -Methylbenzamide

[0152]

[0153] Step 1: Synthesis of 2-(benzyloxy)methyltetrahydro-2H-pyran-4-ol 2-(benzyloxy)acetaldehyde (20 g, 133.18 mmol) and 3-buten-1-ol (9.60 g, 133.18 mmol) were added to a single-necked flask and dissolved in dichloromethane (200 mL). The mixture was cooled to 0 °C, and a solution of trifluoroacetic acid (45.56 g, 399.54 mmol) in dichloromethane (200 mL) was added dropwise. After the addition was complete, the mixture was stirred for 30 min and then allowed to react at room temperature for 16 h. The solvent was removed by rotary evaporation, and the mixture was dissolved in methanol (200 mL). Potassium carbonate (64.42 g, 466.13 mmol) was added and stirred. After the reaction was complete, the mixture was filtered, and the solvent was removed by rotary evaporation to obtain a pale yellow semi-solid. Dichloromethane (400 mL) was added and stirred for 3 h. The insoluble solid was filtered off, and the resulting solution was used directly for the next reaction. The yield was calculated as 100%.

[0154] Step 2: 2-(benzyloxy)methyl)tetrahydro-4 H Synthesis of pyran-4-one Add 2-(benzyloxy)methyl)tetrahydro-2- H 4-pyran-4-ol (29.6 g, 133.17 mmol) and dichloromethane (400 mL) were added to pyridinium chlorochromate (57.41 g, 266.34 mmol), and the mixture was stirred at room temperature for 16 h. The mixture was filtered, the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 8:1) to give a colorless oil (9.0 g, yield 30.68%).

[0155] Step 3: Synthesis of 7-(benzyloxy)methyl)-1,4,8-trioxroso[4.5]decane Add 2-(benzyloxy)methyl)tetrahydro-4- H 4-pyran-4-one (9.0 g, 40.86 mmol) was dissolved in toluene (200 mL), and ethylene glycol (2.54 g, 40.86 mmol) and p-toluenesulfonic acid (0.070 g, 0.41 mmol) were added. The mixture was heated to 120 °C and stirred for 16 h. Water produced during the reaction was separated using a water separator. After the reaction was complete, the mixture was cooled to room temperature and washed with water (200 mL × 2). The organic phase was evaporated to dryness to give a colorless oil (9.2 g, yield 85.18%).

[0156] Step 4: Synthesis of (1,4,8-trioxroso[4,5]dec-7-yl)methanol At room temperature, 7-(benzyloxy)methyl)-1,4,8-trioxspiro[4.5]decane (9.60 g, 36.32 mmol), methanol (150 mL), and palladium on carbon (4.11 g, 1.82 mmol) were added to a reaction vessel. After the addition was complete, hydrogen gas (3.0 MPa) was introduced into the reaction vessel, and the mixture was stirred at room temperature for 27.5 h. The palladium on carbon was removed by filtration, and the filtrate was evaporated to dryness under reduced pressure to obtain a pale yellow oil (6.3 g, yield 99.58%).

[0157] Step 5: Synthesis of (1,4,8-trioxroso[4,5]dec-7-yl)methylmethanesulfonate Under nitrogen protection at 0 °C, methanesulfonyl chloride (5.39 g, 47.02 mmol) was added dropwise to a solution of (1,4,8-trioxrospor[4.5]dec-7-yl)methanol (6.3 g, 36.17 mmol) and triethylamine (5.49 g, 54.26 mmol) in 100 mL of dichloromethane. After the addition was complete, the mixture was stirred for 15 min and then allowed to react at room temperature for 19 h. The reaction solution was washed with water (150 mL × 3), and the solvent was evaporated under reduced pressure to obtain a yellow oil (9.0 g, yield 98.64%). MS (ESI, pos.ion) m / z: 253.1 [M+H] + . Step 6: Synthesis of 2-((1,4,8-trioxspiro[4.5]dec-7-yl)methyl)isoindoline-1,3-dione Potassium phthalimide (4.84 g, 26.16 mmol) was added to (1,4,8-trioxspiro[4.5]dec-7-yl)methylmethanesulfonate (6.0 g, 23.78 mmol). N , N The reaction mixture was stirred at 110 °C for 16 h in a 120 mL solution of dimethylformamide. Water (400 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 mL × 3). The organic phases were combined, washed once with water (300 mL), and the solvent was removed under reduced pressure to give a pale yellow solid (6.40 g, yield 88.72%).

[0158] 1 H NMR (400 MHz, DMSO- d 6) δ 7.91 – 7.81 (m, 4H), 3.94 – 3.80 (m, 5H), 3.79 – 3.66 (m, 2H), 3.56 – 3.46 (m, 1H), 3.39 (dd, J= 11.8, 2.9 Hz, 1H), 1.74(dt, J = 13.1, 2.2 Hz, 1H), 1.68 – 1.50 (m, 2H), 1.47 – 1.36 (m, 1H). Step 7: Synthesis of (1,4,8-trioxspiro[4,5]dec-7-yl)methylamine Hydrazine hydrate (0.50 g, 9.90 mmol) was added to an ethanol (15 mL) solution of 2-((1,4,8-trioxspiro[4.5]dec-7-yl)methyl)isoindoline-1,3-dione (1.00 g, 3.30 mmol), and the mixture was refluxed for 12 h. After confirming the reaction was complete, the ethanol was removed under reduced pressure, and dichloromethane (50 mL) was added. The mixture was stirred at room temperature for 30 min, and insoluble impurities were removed by filtration. The filtrate was washed with saturated brine (50 mL × 3), the organic phase was separated, dried over sodium sulfate, and the solvent was removed under reduced pressure to obtain a yellow oil (0.38 g, yield 66.54%).

[0159] Step 8: N Synthesis of -((1,4,8-trioxorhexano[4,5]dec-7-yl)methyl)-4-methyl-2-nitroaniline Calcium carbonate (0.44 g, 4.38 mmol) was added to a solution of (1,4,8-trioxspiro[4.5]dec-7-yl)methylamine (0.38 g, 2.19 mmol) and 4-fluoro-3-nitrotoluene (0.41 g, 2.63 mmol) in acetonitrile (5 mL). The reaction mixture was stirred at 80 °C for 8 h. Insoluble impurities were filtered off, the filtrate was collected, and the reaction solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 5:1) to give a yellow solid (0.22 g, yield 32.52%). MS (ESI, pos.ion) m / z: 309.34 [M+H] + . Step 9: 4-(1-((1,4,8-trioxorhexano[4.5]dec-7-yl)methyl)-5-methyl-1 H -benzo[ d [Imidazol-2-yl)-3,5-difluoro- N Synthesis of methylbenzamide Towards N -((1,4,8-trioxospiro[4,5]dec-7-yl)methyl)-4-methyl-2-nitroaniline (0.30 g, 0.97 mmol) and 3,5-difluoro-4-formyl- NSodium dithionite (0.84 g, 4.85 mmol) was added to an ethanol (5.0 mL) solution of methylbenzamide (0.19 g, 0.97 mmol), and the mixture was stirred at 80 °C for 12 h. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was collected, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate (v:v) = 1:1) to give a yellow solid (0.13 g, yield 29.21%).

[0160] Step 10: 3,5-Difluoro- N -Methyl-4-(5-methyl-1-((4-oxotetrahydro-2-) H -pyran-2-yl)methyl)-1H-benzo[ d Synthesis of imidazole-2-yl)benzamide To 4-(1-((1,4,8-trioxorpi[4.5]dec-7-yl)methyl)-5-methyl-1 H -benzo[ d [Imidazol-2-yl)-3,5-difluoro- N A solution of methylbenzamide (0.2 g, 0.44 mmol) in water (2.5 mL) was added with trifluoroacetic acid (7.67 g, 67.31 mmol), and the reaction was carried out at room temperature for 4 h. After the reaction was complete, saturated sodium bicarbonate (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was collected, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate (v:v) = 1:1) to give a white solid (0.1 g, yield 55.33%).

[0161] MS (ESI, pos.ion) m / z: 414.16 [M+H] + . Step 11: ( Z )-3,5-difluoro-4-(1-((4-(methoxyimino)tetrahydro-2 H -pyran-2-yl)methyl)-5-methyl-1 H -benzo[ d [Imidazol-2-yl]- N Synthesis of methylbenzamide To 3,5-difluoro- N -Methyl-4-(5-methyl-1-((4-oxotetrahydro-2-) H -pyran-2-yl)methyl)-1 H -benzo[ dImidazol-2-yl)benzamide (0.05 g, 0.12 mmol) was dissolved in methanol (1.0 mL), and methoxyamine hydrochloride (0.015 g, 0.18 mmol) and sodium bicarbonate (0.015 g, 0.18 mmol) were added. The mixture was refluxed for 8 h. TLC analysis showed no residue of the starting material. Saturated brine (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was collected, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate (v:v) = 1:1) to give a white solid (0.044 g, yield 82.22%). MS (ESI, pos.ion) m / z: 443.19 [M+H] + . 1 H NMR (400 MHz, Chloroform- d ) δ 7.74 (s, 1H), 7.64 (s, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.37 (t, J = 8.6 Hz, 1H), 7.21 (ddd, J = 8.4, 4.0, 1.6 Hz, 1H), 4.17 – 4.04 (m, 2H), 3.93 – 3.82 (m, 1H), 3.78 (d, J = 5.7 Hz, 3H), 3.65 – 3.48(m, 1H), 3.29 – 3.06 (m, 2H), 3.03 (d, J = 4.6 Hz, 3H), 2.98 (d, J = 15.0 Hz,1H), 2.53 (s, 3H), 2.20 (t, J = 12.3 Hz, 1H), 1.94 – 1.85 (m, 1H). Example 3: ( S )-3,5-difluoro-4-(1-(4-(1-fluorocyclopropane-1-carbonyl)morpholin-2-yl)methyl)-5-methyl-1 H -benzo[ d [Imidazol-2-yl]- N -Methylbenzamide

[0162]

[0163] Step 1: (S )-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-5-methyl-1 H -benzo[ d Synthesis of imidazo-1-yl)methyl)morpholine-4-carboxylic acid tert-butyl ester Towards( S 4-(((4-methyl-2-nitrophenyl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester (0.5 g, 1.42 mmol) and 3,5-difluoro-4-formyl- N Sodium dithionite (1.24 g, 7.1 mmol) was added to an ethanol (5.0 mL) solution of methylbenzamide (0.28 g, 1.42 mmol), and the mixture was stirred at 80 °C for 12 h. After the reaction was complete, the mixture was cooled to room temperature, and water (50 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (50 mL × 3), and the organic phase was collected. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate (v:v) = 1:1) to give a yellow solid (0.42 g, yield 58.97%).

[0164] Step 2: ( R )-3,5-difluoro- N -Methyl-4-(5-methyl-1-(morpholin-2-ylmethyl)-1 H -benzo[ d Synthesis of imidazole-2-yl)benzamide Towards( S )-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-5-methyl-1 H -benzo[ d Imidazol-1-yl)methyl)morpholine-4-carboxylic acid tert-butyl ester (0.42 g, 0.84 mmol) was added to a 1,4-dioxane solution (2.0 mL) containing 4 M hydrochloric acid, and the reaction was carried out at room temperature for 4 h. After the reaction was completed, the solvent was removed under reduced pressure to give a yellow solid (0.33 g, yield 98.22%).

[0165] Step 3: ( S )-3,5-difluoro-4-(1-(4-(1-fluorocyclopropane-1-carbonyl)morpholin-2-yl)methyl)-5-methyl-1 H -benzo[ d [Imidazol-2-yl]- N Synthesis of methylbenzamide Towards( R )-3,5-difluoro- N -Methyl-4-(5-methyl-1-(morpholin-2-ylmethyl)-1H -benzo[ d Add [imidazol-2-yl]benzamide (0.07 g, 0.17 mmol) to a solution of dichloromethane (2 mL) N , N -Diisopropylethylamine (0.044 g, 0.34 mmol) was stirred for 10 min, followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (0.084 g, 0.22 mmol) and 1-fluorocyclopropanecarboxylic acid (0.023 g, 0.22 mmol). The mixture was stirred at room temperature for 8 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate (v:v) = 1:1) to give a white solid (0.08 g, yield 94.07%). MS (ESI, pos.ion) m / z: 487.20 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 8.74 (d, J = 4.6 Hz, 1H), 7.70 (d, J = 9.3 Hz, 2H), 7.62 (d, J = 8.3 Hz, 1H), 7.48 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 4.37 (dd, J = 15.4, 3.3 Hz, 1H), 4.12 (dd, J = 15.3, 7.5 Hz, 2H), 3.89 (d, J = 13.3 Hz, 1H), 3.66 – 3.51 (m, 2H), 3.27 – 3.16 (m, 3H), 2.81 (d, J = 4.5 Hz, 3H), 2.42 (s, 3H), 1.18 (t, J = 8.8 Hz, 2H), 1.08 (d, J = 14.0 Hz, 2H). Example 4: ( S )-1-(2-((2-(4,6-difluoro-1-methyl-1H-indazol-5-yl)-5-methyl-1H-benzo[ d [Imidazol-1-yl)methyl)morpholino)ethane-1-one]

[0166]

[0167] Step 1: Synthesis of 3,5-difluoro-2-methylaniline 3,5-Difluoro-2-methylbenzoic acid (25.0 g, 145.24 mmol) and toluene (300 mL) were added to a single-necked flask, followed by triethylamine (19.11 g, 188.81 mmol). Diphenyl azidophosphate (45.97 g, 167.03 mmol) was added dropwise with stirring. After the addition was complete, the reaction proceeded at room temperature for 4 h. TLC analysis showed that all the starting material was converted to the azide intermediate. The mixture was then heated to 90 °C and reacted for 2 h until the azide intermediate was converted to isocyanate. A solution of sodium hydroxide (23.24 g, 580.96 mmol) in water (150 mL) was then added. The reaction was continued at 90 °C for 16 h. After cooling to room temperature, the mixture was filtered, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined organic phases were evaporated to dryness to give a brown semi-solid (15.68 g, yield 75.43%).

[0168] Step 2: N Synthesis of 3,5-difluoro-2-methylphenyl)acetamide 3,5-Difluoro-2-methylaniline (15.68 g, 109.55 mmol) and toluene (300 mL) were added to a single-necked flask, followed by acetic anhydride (14.54 g, 142.41 mmol). The mixture was heated to 90 °C and reacted for 8 h. After the starting material reacted completely, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation. The crude product was then mixed with petroleum ether (100 mL) and stirred for 3 h. The mixture was filtered to give a white solid (10.9 g, yield 53.73%).

[0169] Step 3: N Synthesis of 4-bromo-3,5-difluoro-2-methylphenyl)acetamide At room temperature, to N Add thiourea (0.21 g, 2.7 mmol) to a solution of 10 g (54.00 mmol) of 3,000 mL of acetonitrile and... N - Bromosuccinimide (12.49 g, 70.2 mmol) was stirred at room temperature for 8 h. A saturated sodium sulfite solution (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was collected, and the solvent was removed under reduced pressure to give a yellow solid. Dichloromethane (50 mL) was added, and the mixture was stirred at room temperature for 30 min. Filtration was performed to give a white solid (12.0 g, yield 84.15%).

[0170] Step 4: Synthesis of 4-bromo-3,5-difluoro-2-methylaniline Towards N In a solution of 10 g (37.87 mmol) of 4-bromo-3,5-difluoro-2-methylphenyl)acetamide in 350 mL of ethanol, potassium hydroxide (12.75 g, 227.22 mmol) was added, and the mixture was reacted at 80 °C for 6 h. Water (400 mL) was added, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phase was collected and washed with saturated brine (200 mL × 2). The solvent was removed from the organic phase under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 5:1) to give a yellow solid (6.5 g, yield 77.31%).

[0171] Step 5: Synthesis of 5-bromo-4,6-difluoro-1H-indazole Sodium nitrite (0.75 g, 10.81 mmol) was added to a solution of 4-bromo-3,5-difluoro-2-methylaniline (2.0 g, 9.01 mmol) in acetic acid (100 mL) at 10 °C, and the mixture was reacted at room temperature for 8 h. The pH was adjusted to 8 with 50% sodium hydroxide solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was collected, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 5:1) to give a yellow solid (1.25 g, yield 59.55%).

[0172] Step 6: Synthesis of 5-bromo-4,6-difluoro-1-methyl-1H-indazole At 0°C, 5-bromo-4,6-difluoro-1-dichlorofluorocarbons were added to a 60 mL solution of sodium hydride (1.16 g, 28.97 mmol) in tetrahydrofuran. H A solution of 5-bromo-4,6-difluoro-1-methyl-1H-indazole (6.75 g, 28.97 mmol) in tetrahydrofuran (10 mL) was stirred for 20 min, followed by the addition of iodomethane (6.17 g, 43.45 mmol), and the reaction was allowed to proceed at room temperature for 4 h. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was collected, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 5:1) to give 5-bromo-4,6-difluoro-1-methyl-1H-indazole yellow solid (3.6 g, yield 50.30%) and 5-bromo-4,6-difluoro-2-methyl-2H-indazole white solid (2.7 g, yield 37.73%).

[0173] Step 7: Synthesis of 4,6-difluoro-1-methyl-5-vinyl-1H-indazole At room temperature, tetraphenylphosphine palladium (0.058 g, 0.051 mmol), cesium carbonate (0.99 g, 3.03 mmol), and potassium ethylenetrifluoroborate (0.18 g, 1.31 mmol) were added to a solution of 5-bromo-4,6-difluoro-1-methyl-1H-indazole (0.25 g, 1.01 mmol) in tert-butanol (6 mL) and water (2 mL), and the reaction was carried out at 100 °C for 8 h. The mixture was filtered through diatomaceous earth, and extracted with 100 mL of saturated brine (100 mL × 3). The organic phase was collected, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 5:1) to give a yellow solid (0.19 g, yield 96.69%).

[0174] Step 8: Synthesis of 4,6-difluoro-1-methyl-1H-indazole-5-carboxaldehyde To a solution of 4,6-difluoro-1-methyl-5-vinyl-1H-indazole (1.15 g, 5.92 mmol) in tetrahydrofuran (20 mL) and water (20 mL), 2,6-dimethylpyridine (1.27 g, 11.84 mmol), sodium periodate (5.06 g, 23.68 mmol), and potassium osmium tetroxide dihydrate (0.22 g, 0.59 mmol) were added. The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was quenched with saturated sodium sulfite aqueous solution (100 mL), extracted with ethyl acetate (100 mL × 3), and the organic phase was collected. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 5:1) to give a white solid (0.65 g, yield 55.95%).

[0175] Step 9: Synthesis of 4,6-difluoro-1-methyl-1H-indazole-5-carboxylic acid At 0 °C, a solution of 4,6-difluoro-1-methyl-1H-indazole-5-carboxaldehyde (0.8 g, 4.08 mmol) and 2-methyl-2-butene (7.15 g, 102 mmol) in tetrahydrofuran (10 mL) and tert-butanol (10 mL) was added to a solution of sodium chlorite (2.21 g, 24.48 mmol) and sodium dihydrogen phosphate (3.43 g, 28.56 mmol) in water (20 mL). After the addition was complete, the reaction was allowed to proceed at room temperature for 6 h. TLC showed no residue of the starting material. The pH was adjusted to 4.0 with 4 M HCl, and the mixture was extracted with ethyl acetate (50 mL × 3). The mixture was washed with saturated brine (50 mL), and the organic phases were combined. The solvent was removed under reduced pressure to give a white solid (0.86 g, yield 99.39%).

[0176] Step 10: ( R Synthesis of tert-butyl morpholine-4-carboxylic acid ester (((2-amino-4-methylphenyl)amino)methyl)morpholine-4-carboxylic acid) Towards( R Zinc powder (2.33 g, 35.55 mmol) and ammonium chloride (1.60 g, 29.86 mmol) were added to an ethanol (60 mL) solution of tert-butyl 4-morpholine-4-carboxylic acid (2.5 g, 7.11 mmol). The mixture was refluxed for 16 h. After the reaction was completed, the mixture was filtered through diatomaceous earth, washed with ethyl acetate, and the organic phase was collected. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 3:1) to give a yellow oil (2.2 g, yield 96.21%).

[0177] Step 11: ( R )-2-(((2-(4,6-difluoro-1-methyl-1 H Synthesis of tert-butyl morpholine-4-carboxylic acid (-imidazolium-5-carboxamide)-4-methylphenyl)amino)methyl)morpholine-4-carboxylic acid To 4,6-difluoro-1-methyl-1 H -Indazole-5-carboxylic acid (1.2 g, 5.66 mmol), ( R Add tert-butyl morpholine-4-carboxylic acid (1.82 g, 5.66 mmol) to a solution of tert-butyl morpholine-4-carboxylic acid in 20 mL of dichloromethane. N , N -Diisopropylethylamine (2.19 g, 16.98 mmol) and N , N , N ',N '-Tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (2.15 g, 5.66 mmol) was stirred at room temperature for 8 h. Saturated brine (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was collected, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 3:1) to give a yellow solid (2.0 g, yield 68.58%).

[0178] Step 12: ( R )-2-((2-(4,6-difluoro-1-methyl-1H-indazol-5-yl)-5-methyl-1 H -benzo[ d Synthesis of imidazo-1-yl)methyl)morpholine Add ( to the reaction flask) R )-2-(((2-(4,6-difluoro-1-methyl-1 H (-Imidazol-5-carboxamide)-4-methylphenyl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester (1.0 g, 1.94 mmol) and acetic acid (20 mL) were reacted at 70 °C with stirring for 8 h. The reaction was complete by TLC. Saturated brine (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was collected, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 2:1) to give a yellow solid (0.30 g, yield 38.92%). MS (ESI, pos.ion) m / z: 398.10 [M+H] + . Step 13: ( S )-1-(2-((2-(4,6-difluoro-1-methyl-1 H -indazole-5-yl)-5-methyl-1 H -benzo[ d Synthesis of imidazol-1-yl)methyl)morpholino)ethane-1-one At 0℃, towards ( R )-2-((2-(4,6-difluoro-1-methyl-1 H -Indazole-5-yl)-5-methyl-1 H -benzo[ dTriethylamine (0.091 g, 0.90 mmol) was added to a solution of imidazo-1-yl)methyl)morpholine (0.07 g, 0.18 mmol) in dichloromethane (5 mL). After stirring for 10 min, acetyl chloride (0.018 g, 0.23 mmol) was added dropwise. After the addition was complete, the mixture was allowed to react at room temperature for 4 h. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (v:v) = 10:1) to give a yellow solid (0.05 g, yield 64.60%). MS (ESI, pos.ion) m / z: 440.20 [M+H] + . 1 H NMR (400 MHz, Chloroform- d ) δ 8.12 (d, J = 6.8 Hz, 1H), 7.65 (d, J =10.6 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.23 – 7.16 (m, 1H), 7.05 (dd, J = 14.0,8.7 Hz, 1H), 4.41 – 4.22 (m, 2H), 4.13 (t, J = 4.4 Hz, 1H), 4.10 (d, J = 5.5 Hz,3H), 3.82 – 3.70 (m, 1H), 3.60 (d, J = 31.7 Hz, 1H), 3.46 (d, J = 13.2 Hz, 1H), 3.39 – 3.26 (m, 2H), 3.13 – 3.04 (m, 1H), 2.52 (d, J = 5.6 Hz, 3H), 2.02 (s, 3H). Example 5: ( S )-1-(2-((2-(4,6-difluoro-2-methyl-2 H -Indazole-5-yl)-5-methyl-1 H -benzo[ d [Imidazol-1-yl)methyl)morpholino)ethane-1-one]

[0179]

[0180] Step 1: 4,6-Difluoro-2-methyl-5-vinyl-2 H Synthesis of -indazole At room temperature, 5-bromo-4,6-difluoro-2-methyl-2 H A solution of 1,4-dioxane (15 mL) and water (1.5 mL) of 1,1-bis(diphenylphosphine)diphenylferric palladium dichloride dichloromethane complex (0.25 g, 0.30 mmol), cesium carbonate (2.97 g, 9.12 mmol), and potassium trifluoroborate (0.61 g, 4.56 mmol) was added to the solution of 1,4-dioxane (15 mL) and water, and the mixture was reacted at 100 °C for 8 h. The reaction proceeded to completion by TLC. The mixture was filtered through diatomaceous earth, and extracted with ethyl acetate (100 mL × 3 times). The organic phase was collected, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 3:1) to give a yellow solid (0.58 g, 98% yield).

[0181] Step 2: 4,6-Difluoro-2-methyl-2 H Synthesis of 5-indazole-5-formaldehyde To 4,6-difluoro-2-methyl-5-vinyl-2 H In a solution of β-indazole (0.7 g, 3.6 mmol) in tetrahydrofuran (10 mL) and water (10 mL), 2,6-dimethylpyridine (0.77 g, 7.2 mmol), sodium periodate (3.08 g, 14.4 mmol), and potassium osmium tetroxide dihydrate (0.13 g, 0.36 mmol) were added. The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was quenched with saturated sodium sulfite aqueous solution (100 mL), extracted with ethyl acetate (100 mL × 3), and the organic phase was collected. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 5:1) to give a white solid (0.2 g, yield 28%).

[0182] Step 3: 4,6-Difluoro-2-methyl-2 H Synthesis of 5-indazole carboxylic acid At 0°C, 4,6-difluoro-2-methyl-2 HIn a solution of 5-indazole-5-carboxaldehyde (0.4 g, 2.04 mmol) and 2-methyl-2-butene (3.58 g, 51 mmol) in tetrahydrofuran (10 mL) and tert-butanol (10 mL), a solution of sodium chlorite (1.11 g, 12.24 mmol) and sodium dihydrogen phosphate (1.71 g, 14.28 mmol) in water (20 mL) was added. After the addition was complete, the reaction was allowed to proceed at room temperature for 6 h. TLC showed no residue of the starting material. The pH was adjusted to 4.0 with 4 M HCl, and the mixture was extracted with ethyl acetate (50 mL × 3). The mixture was washed with saturated brine (50 mL), and the organic phases were combined. The solvent was removed under reduced pressure to give a white solid (0.4 g, 92% yield).

[0183] Step 4: ( R Synthesis of tert-butyl morpholine-4-carboxylic acid ester (((2-amino-4-methylphenyl)amino)methyl)morpholine-4-carboxylic acid) Towards( R Zinc powder (2.33 g, 35.55 mmol) and ammonium chloride (1.60 g, 29.86 mmol) were added to an ethanol (60 mL) solution of tert-butyl 4-morpholine-4-carboxylic acid (2.5 g, 7.11 mmol). The mixture was refluxed for 16 h. After the reaction was completed, the mixture was filtered through diatomaceous earth, washed with ethyl acetate, and the organic phase was collected. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 3:1) to give a yellow oil (2.2 g, yield 96.21%).

[0184] Step 5: ( R )-2-(((2-(4,6-difluoro-2-methyl-2 H Synthesis of tert-butyl morpholine-4-carboxylic acid (-imidazolium-5-carboxamide)-4-methylphenyl)amino)methyl)morpholine-4-carboxylic acid To 4,6-difluoro-2-methyl-2 H -Indazole-5-carboxylic acid (0.4 g, 1.89 mmol) and ( R Add 2-(((2-amino-4-methylphenyl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester (0.61 g, 1.89 mmol) to a dichloromethane (20 mL) solution. N , N -Diisopropylethylamine (0.73 g, 5.67 mmol) and N , N , N ', N'-Tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (0.72 g, 1.89 mmol) was stirred at room temperature for 8 h. Saturated brine (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was collected, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 3:1) to give a yellow solid (0.66 g, yield 67.90%).

[0185] Step 6: ( S )-2-((2-(4,6-difluoro-2-methyl-2 H -Indazole-5-yl)-5-methyl-1 H -benzo[ d Synthesis of imidazo-1-yl)methyl)morpholine-4-carboxylic acid tert-butyl ester Add ( to the reaction flask) R )-2-(((2-(4,6-difluoro-2-methyl-1 H (-Imidazol-5-carboxamide)-4-methylphenyl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester (0.66 g, 1.28 mmol) and acetic acid (20 mL) were reacted at 70 °C with stirring for 8 h. The reaction was confirmed to be complete by TLC. The pH was adjusted to 8 by adding 50% NaOH solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was collected, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 2:1) to give a yellow oil (0.16 g, yield 25.12%).

[0186] Step 7: ( R )-2-((2-(4,6-difluoro-2-methyl-2 H -Indazole-5-yl)-5-methyl-1 H -benzo[ d Synthesis of imidazo-1-yl)methyl)morpholine Towards( S )-2-((2-(4,6-difluoro-2-methyl-2 H -Indazole-5-yl)-5-methyl-1 H -benzo[ d In a solution of 0.32 g (0.64 mmol) of imidazo-1-yl)methyl)morpholine-4-carboxylic acid tert-butyl ester in dioxane (5 mL), hydrochloric acid (0.23 g, 6.4 mmol) was added, and the mixture was stirred at room temperature for 4 h. After the reaction was complete, the solvent was removed under reduced pressure, and the next step was carried out to give a yellow solid (0.25 g, yield 97.81%).

[0187] Step 8: (S )-1-(2-((2-(4,6-difluoro-2-methyl-2 H -Indazole-5-yl)-5-methyl-1 H -benzo[ d Synthesis of imidazol-1-yl)methyl)morpholino)ethane-1-one At 0℃, towards ( R )-2-((2-(4,6-difluoro-2-methyl-2 H -indazole-5-yl)-5-methyl-1 H -benzo[ d Triethylamine (0.13 g, 1.26 mmol) was added to a solution of imidazo-1-yl)methyl)morpholine (0.25 g, 0.63 mmol) in dichloromethane (2.0 mL). After stirring for 10 min, acetyl chloride (0.049 g, 0.63 mmol) was added dropwise. After the addition was complete, the mixture was allowed to react at room temperature for 6 h. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (v:v) = 10:1) to give a yellow solid (0.20 g, yield 72.35%). MS (ESI, pos.ion) m / z: 440.20 [M+H] + . 1 H NMR (400 MHz, Chloroform- d ) δ 8.11 (d, J = 8.6 Hz, 1H), 7.67 (d, J =9.2 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 9.7 Hz, 1H), 7.21 (dd, J =14.3, 8.2 Hz, 1H), 4.40 (d, J = 13.1 Hz, 1H), 4.27 (d, J = 7.3 Hz, 3H), 4.23 –4.09 (m, 2H), 3.87 – 3.56 (m, 3H), 3.51 – 3.39 (m, 1H), 3.36 – 3.28 (m, 1H), 3.17 – 3.06 (m, 1H), 2.53 (d, J = 6.2 Hz, 3H), 2.04 (s, 3H). Example 6: ( S)-3,5-difluoro-4-(1-((4-(2-fluoro-3-methylbut-2-enyl)morpholin-2-yl)methyl)-5-methyl-1 H -benzo[ d [Imidazol-2-yl]- N -Methylbenzamide

[0188]

[0189] Step 1: Synthesis of ethyl 2-fluoro-3-methylbut-2-enoate At 0 °C, triethyl 2-fluoro-2-phosphorylacetate (5.0 g, 20.65 mmol) was added dropwise to a suspension of sodium hydride (0.91 g, 22.71 mmol) in ethylene glycol dimethyl ether (25 mL). After reacting at room temperature for 20 min, acetone (1.20 g, 20.65 mmol) was added, and the reaction was continued at room temperature for 4 h. After the reaction was complete, saturated brine (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was collected, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 20:1) to give a yellow oil (1.0 g, yield 33.14%).

[0190] Step 2: Synthesis of 2-fluoro-3-methylbut-2-enoic acid A solution of sodium hydroxide (0.41 g, 10.26 mmol) in water (2.5 mL) was added to an ethanol (2.5 mL) solution of ethyl 2-fluoro-3-methylbut-2-enoate (0.5 g, 3.42 mmol), and the reaction was carried out at room temperature for 6 h. The remaining starting material was heated to 60 °C and the reaction was continued. After the reaction was complete, 2 M HCl aqueous solution was added to the reaction solution to adjust the pH to 2, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was collected, and the solvent was removed under reduced pressure to give a yellow oil (0.11 g, yield 27.22%).

[0191] Step 3: ( R )-3,5-difluoro- N -Methyl-4-(5-methyl-1-(morpholin-2-ylmethyl)-1 H -benzo[ d Synthesis of imidazole-2-yl)benzamide Towards( S )-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-5-methyl-1 H -benzo[ dImidazol-1-yl)methyl)morpholine-4-carboxylic acid tert-butyl ester (0.4 g, 0.8 mmol) was added to a 1,4-dioxane solution (2.0 mL) containing 4 M hydrochloric acid, and the reaction was carried out at room temperature for 4 h. After the reaction was completed, the solvent was removed under reduced pressure to give a yellow solid (0.32 g, 100% yield).

[0192] Step 4: ( S )-3,5-difluoro-4-(1-((4-(2-fluoro-3-methylbut-2-enyl)morpholin-2-yl)methyl)-5-methyl-1 H -benzo[ d [Imidazol-2-yl]- N Synthesis of methylbenzamide Towards( R )-3,5-difluoro- N -Methyl-4-(5-methyl-1-(morpholin-2-ylmethyl)-1 H -benzo[ d Add to a solution of imidazole-2-yl)benzamide (0.32 g, 0.8 mmol) in dichloromethane (10 mL) N , N -Diisopropylethylamine (0.21 g, 1.6 mmol), stirred for 10 min, N , N , N ′, N ′-Tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (0.4 g, 1.04 mmol) and 2-fluoro-3-methylbut-2-enoic acid (0.012 g, 1.04 mmol) were stirred at room temperature for 8 h. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate (v:v) = 1:1) to give a white solid (0.36 g, yield 90.00%). MS (ESI, pos.ion) m / z: 501.20 [M+H] + . 1 H NMR (600 MHz, Chloroform- d ) δ 8.09 (s, 1H), 7.66 (s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.27 (d, J= 6.8 Hz, 1H), 4.41 – 4.22(m, 1H), 4.22 – 4.12 (m, 1H), 4.11 – 4.06 (m, 1H), 3.70 (dd, J = 75.1, 12.5 Hz,1H), 3.62 – 3.46 (m, 2H), 3.28 (dt, J = 50.1, 11.9 Hz, 1H), 3.01 (d, J = 4.5 Hz, 3H), 2.74 (d, J = 12.6 Hz, 2H), 2.54 (s, 3H), 1.75 – 1.62 (m, 6H). Example 7: ( S )-3,5-difluoro- N -Methyl-4-(5-methyl-1-(4-(3-methylbut-2-enyl)morpholin-2-yl)methyl)-1 H -benzo[ d Imidazol-2-yl)benzamide

[0193]

[0194] Step 1: ( R )-3,5-difluoro- N -Methyl-4-(5-methyl-1-(morpholin-2-ylmethyl)-1 H -benzo[ d Synthesis of imidazole-2-yl)benzamide Towards( S )-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-5-methyl-1 H -benzo[ d Imidazol-1-yl)methyl)morpholine-4-carboxylic acid tert-butyl ester (0.26 g, 0.52 mmol) was added to a solution of 1,4-dioxane (1.3 mL) in 4 M hydrochloric acid, and the mixture was stirred at room temperature for 4 h. After the reaction was complete, the solvent was removed under reduced pressure, and the remaining residue was used directly for the next reaction.

[0195] Step 2: ( S )-3,5-difluoro- N -Methyl-4-(5-methyl-1-(4-(3-methylbut-2-enyl)morpholin-2-yl)methyl)-1 H -benzo[ d Synthesis of imidazole-2-yl)benzamide Towards(R )-3,5-difluoro- N -Methyl-4-(5-methyl-1-(morpholin-2-ylmethyl)-1 H -benzo[ d Add [imidazol-2-yl]benzamide (0.2 g, 0.50 mmol) to a solution of dichloromethane (10 mL) N , N -Diisopropylethylamine (0.13 g, 1 mmol), stirred for 10 min, then added N , N , N ′, N ′-Tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (0.25 g, 0.65 mmol), 3,3-dimethicone (0.065 g, 0.65 mmol), stirred at room temperature for 8 h. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate (v:v) = 1:1) to give a white solid (0.20 g, yield 82.99%). MS (ESI, pos.ion) m / z: 483 [M+H] + . 1 H NMR (600 MHz, Chloroform- d ) δ 7.73 (s, 1H), 7.65 (d, J = 11.1 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.6 Hz, 1H), 5.68 (s, 1H), 4.54 (dd, J = 68.9, 14.3 Hz, 2H), 4.20 (dd, J = 15.1, 8.7 Hz, 1H), 3.92 (s, 1H), 3.64 (d, J =11.1 Hz, 2H), 3.11 (dt, J = 90.6, 12.8 Hz, 2H), 2.97 (d, J = 4.1 Hz, 3H), 2.71(d, J = 104.1 Hz, 1H), 2.57 (s, 3H), 1.83 (d, J = 13.2 Hz, 6H). Example 8: (S )-2-((2-(4,6-difluoro-1-methyl-1 H -indazole-5-yl)-5-methyl-1 H -benzo[ d Imidazol-1-yl)methyl)morpholine-4-carboxylic acid methyl ester

[0196]

[0197] Towards( R )-2-((2-(4,6-difluoro-1-methyl-1 H -indazole-5-yl)-5-methyl-1 H -benzo[ d Triethylamine (0.51 g, 5.05 mmol) was added to a solution of imidazo-1-yl)methyl)morpholine (0.4 g, 1.01 mmol) in dichloromethane (20 mL). After stirring for 10 min, dimethyl dicarbonate (0.16 g, 1.21 mmol) was added dropwise at 0 °C. After the addition was complete, the mixture was allowed to react at room temperature for 6 h. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate (v:v) = 1:1) to give a yellow solid (0.19 g, yield 41.45%). MS (ESI, pos.ion) m / z: 456.20 [M+H] + . 1 H NMR (400 MHz, Chloroform- d ) δ 8.11 (d, J = 1.0 Hz, 1H), 7.64 (s,1H), 7.38 (d, J = 8.3 Hz, 1H), 7.22 – 7.15 (m, 1H), 7.04 (d, J = 8.7 Hz, 1H), 4.13 (d, J = 5.7 Hz, 2H), 4.09 (s, 3H), 3.86 – 3.66 (m, 3H), 3.65 (s, 3H), 3.62– 3.56 (m, 1H), 3.31 (s, 1H), 2.82 (d, J = 13.4 Hz, 1H), 2.51 (s, 3H), 2.50 –2.44 (m, 1H). Example 9: ( S)-3,5-difluoro-4-(3-((4-(2-fluoro-3-methylbut-2-enoyl)morpholin-2-yl)methyl)-7-methylimidazo[1,2- a ]pyridin-2-yl)- N -Methylbenzamide

[0198]

[0199] Step 1: ( R Synthesis of tert-butyl 2-formylmorpholine-4-carboxylic acid Will( R )- N Boc-2-hydroxymethylmorpholine (5.0 g, 23.01 mmol) and dichloromethane (100 mL) were added to a reaction flask. At room temperature, Desmond-Martin oxidant (10.74 g, 25.31 mmol) was added, and the mixture was stirred for 8 h at room temperature. After the reaction was complete, saturated sodium thiosulfate aqueous solution (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (100 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 2:1) to give a yellow oil (4.95 g, yield 99.92%).

[0200] Step 2: ( S Synthesis of tert-butyl 2-ethynylmorpholine-4-carboxylic acid Dimethyl (1-diazo-2-oxopropyl)phosphonate (7.85 g, 40.88 mmol) and methanol (300 mL) were added to a reaction flask. At room temperature, (…) R A methanol (200 mL) solution of 4.4 g (20.44 mmol) of tert-butyl 4-carboxylate (2-formylmorpholine-4-carboxylic acid) was added, followed by the addition of potassium carbonate (14.13 g, 102.2 mmol). The mixture was stirred at room temperature for 16 h. After the reaction was complete, the solvent was removed under reduced pressure. Ethyl acetate (200 mL) and water (200 mL) were added to the residue, and the organic phase was separated. The residue was extracted with ethyl acetate (300 mL × 2), and the organic phase was collected. The solvent was removed, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 10:1) to give a white solid (3.6 g, yield 83.36%).

[0201] Step 3: ( S )-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2- aSynthesis of tert-butyl pyridin-3-yl)methyl)morpholine-4-carboxylic acid Add 3,5-difluoro-4-formyl- to the reaction flask N -Methylbenzamide (0.71 g, 3.57 mmol), ( S 2-Ethynylmorpholine-4-carboxylic acid tert-butyl ester (0.75 g, 3.57 mmol), 4-methylpyridin-2-amine (0.39 g, 3.57 mmol), cuprous chloride (0.11 g, 1.07 mmol), copper trifluoromethanesulfonate (0.39 g, 1.07 mmol), nitrogen purged three times, toluene (20 mL) added, followed by three more nitrogen purgings. The reaction mixture was stirred at 100 °C for 5 minutes, and then... N , N -Dimethylacetamide (0.2 mL), purged with nitrogen again, and then stirred for 16 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate (v:v) = 1:1) to give a yellow solid (0.48 g, yield 26.90%).

[0202] Step 4: ( S )-3,5-difluoro-N-methyl-4-(7-methyl-3-(morpholin-2-ylmethyl)imidazo[1,2- a Synthesis of pyridin-2-yl)benzamide Add ( to the reaction flask) S )-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2- a 0.95 g (1.90 mmol) of tert-butyl pyridin-3-yl)methyl)morpholine-4-carboxylic acid and 5 ml (4 M) of 1,4-dioxane hydrochloric acid were reacted with the mixture at room temperature and stirred for 4 h. After the reaction was complete, the solvent was removed under reduced pressure, and the remaining residue was used directly for the next reaction.

[0203] Step 5: ( S )-3,5-difluoro-4-(3-((4-(2-fluoro-3-methylbut-2-enoyl)morpholin-2-yl)methyl)-7-methylimidazo[1,2- a ]pyridin-2-yl)- N Synthesis of methylbenzamide Towards( S )-3,5-difluoro- N -Methyl-4-(7-methyl-3-(morpholin-2-ylmethyl)imidazo[1,2-] aAdd pyridin-2-yl)benzamide (0.17 g, 0.42 mmol) to a solution of dichloromethane (20 mL). N , N -Diisopropylethylamine (0.11 g, 0.84 mmol), stirred for 10 min, then added N , N , N ′, N ′-Tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (0.21 g, 0.55 mmol) and 2-fluoro-3-methyl-but-2-enoic acid (0.064 g, 0.55 mmol) were stirred at room temperature for 8 h. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate (v:v) = 1:1) to give a white solid (0.18 g, yield 84.7%). MS (ESI, pos.ion) m / z: 501 [M+H] + . 1 H NMR (600 MHz, DMSO- d 6) δ 8.76 (s, 1H), 8.51 (dd, J = 27.8, 7.0 Hz, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.44 (s, 1H), 6.95 (d, J = 7.0 Hz, 1H), 4.08 (dd, J = 77.0, 13.2 Hz, 2H), 3.78 – 3.66 (m, 2H), 3.15 – 3.05 (m, 3H), 2.83 (d, J =4.5 Hz, 4H), 2.54 (d, J = 14.9 Hz, 1H), 2.42 (s, 3H), 1.70 – 1.59 (m, 3H), 1.59– 1.46 (m, 3H). Example 10: ( S )-3,5-difluoro- N -Methyl-4-(7-methyl-3-((4-(3-methylbut-2-enoyl)morpholin-2-yl)methyl)imidazo[1,2- a pyridin-2-yl)benzamide

[0204]

[0205] Towards( S )-3,5-difluoro- N -Methyl-4-(7-methyl-3-(morpholin-2-ylmethyl)imidazo[1,2-] a Add pyridin-2-yl)benzamide (0.1 g, 0.25 mmol) to a solution of dichloromethane (10 mL) N , N -Diisopropylethylamine (0.065 g, 0.5 mmol), stirred for 10 min, then added N , N , N ′, N ′-Tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (0.12 g, 0.33 mmol) and 3,3-dimethicone (0.033 g, 0.33 mmol) were stirred at room temperature for 8 h. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate (v:v) = 1:1) to give a white solid (0.09 g, yield 74.7%). MS (ESI, pos.ion) m / z: 483 [M+H] + . 1 H NMR (400 MHz, Chloroform- d ) δ 8.61 (d, J = 26.8 Hz, 1H), 7.77 (s,1H), 7.56 (d, J = 25.7 Hz, 1H), 7.49 (d, J = 8.7 Hz, 2H), 7.20 (d, J = 7.0 Hz, 1H), 5.69 (s, 1H), 4.40 (dd, J = 31.0, 13.6 Hz, 1H), 3.87 – 3.65 (m, 2H), 3.60 (s,1H), 3.31 (t, J = 11.8 Hz, 1H), 3.21 – 3.04 (m, 2H), 2.96 (d, J = 4.6 Hz, 4H), 2.58 (s, 4H), 1.86 – 1.75 (m, 6H). Example 11: ( R )-3,5-difluoro- N-Methyl-4-(5-methyl-1-((4-(oxecyclobutan-3-yl)morpholin-2-yl)methyl)-1 H -benzo[ d Imidazol-2-yl)benzamide

[0206]

[0207] Under nitrogen protection, towards ( R )-3,5-difluoro- N -Methyl-4-(5-methyl-1-(morpholin-2-ylmethyl)-1 H -benzo[ d Imidazol-2-yl)benzamide (0.2 g, 0.50 mmol) was added to a methanol (5.0 mL) solution, followed by acetic acid (0.30 g, 5 mmol) and 3-oxetane (0.043 g, 0.60 mmol). The reaction was carried out at room temperature for 30 min, then sodium cyanoborohydride (0.038 g, 0.60 mmol) was added, and the reaction was continued at room temperature for 6 h. After the reaction was complete, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was collected, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (v:v) = 10:1) to give a white solid (0.1 g, yield 43.86%). MS (ESI, pos.ion) m / z: 457 [M+H] + . 1 H NMR (600 MHz, Chloroform- d ) δ 8.76 (q, J = 4.7 Hz, 1H), 7.62 (s,1H), 7.44 (d, J = 8.6 Hz, 2H), 7.39 (d, J = 8.3 Hz, 1H), 7.24 – 7.19 (m, 1H), 4.55 (dt, J = 15.1, 6.6 Hz, 2H), 4.46 (dt, J = 13.0, 6.2 Hz, 2H), 4.04 (qd, J =15.0, 5.8 Hz, 2H), 3.78 – 3.72 (m, 1H), 3.69 – 3.64 (m, 1H), 3.44 (td, J =11.5, 2.4 Hz, 1H), 3.35 (p,J = 6.4 Hz, 1H), 2.99 (d, J = 4.6 Hz, 3H), 2.53 (s, 3H), 2.41 (d, J = 11.0 Hz, 2H), 1.87 (td, J = 11.4, 3.3 Hz, 1H), 1.53 (t, J = 10.5Hz, 1H). Example 12: ( R )-3,5-difluoro- N -Methyl-4-(5-methyl-1-((4-(pyridin-2-yl)morpholin-2-yl)methyl)-1 H -benzo[ d Imidazol-2-yl)benzamide

[0208]

[0209] Towards( R )-3,5-difluoro- N -Methyl-4-(5-methyl-1-(morpholin-2-ylmethyl)-1 H -benzo[ d A mixture of imidazole-2-yl)benzamide (0.16 g, 0.40 mmol), 2-fluoropyridine (0.095 g, 0.60 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.037 g, 0.060 mmol), palladium acetate (0.013 g, 0.060 mmol) in toluene (3.0 mL) was added, and the mixture was reacted at 110 °C for 8 h. After the reaction was complete, water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was collected, and the residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate (v:v) = 1:1) to give a white solid (0.1 g, yield 52.41%). MS (ESI, pos.ion) m / z: 478 [M+H] + . 1 H NMR (600 MHz, DMSO- d 6) δ 8.78 (q, J = 4.5 Hz, 1H), 8.08 – 8.01 (m,1H), 7.74 – 7.69 (m, 2H), 7.67 (d, J= 8.3 Hz, 1H), 7.52 – 7.48 (m, 1H), 7.48(d, J = 1.7 Hz, 1H), 7.15 (dd, J = 8.4, 1.6 Hz, 1H), 6.70 (d, J = 8.6 Hz, 1H), 6.63(dd, J = 7.1, 4.9 Hz, 1H), 4.38 (dd, J = 15.2, 3.1 Hz, 1H), 4.18 – 4.10 (m, 2H), 3.82 (d, J = 12.6 Hz, 1H), 3.67 – 3.63 (m, 1H), 3.60 (ddd, J = 13.3, 6.5, 3.7 Hz,1H), 3.26 (dd, J = 11.6, 2.8 Hz, 1H), 2.80 (d, J = 4.4 Hz, 3H), 2.59 (td, J = 12.3,3.4 Hz, 1H), 2.41 (s, 3H), 2.34 (dd, J = 12.7, 10.5 Hz, 1H). Example 13: ( S )-3,5-difluoro- N -Methyl-4-(5-methyl-1-((4-(2-oxopropionyl)morpholin-2-yl)methyl)-1 H -benzo[ d Imidazol-2-yl)benzamide

[0210]

[0211] Towards( R )-3,5-difluoro- N -Methyl-4-(5-methyl-1-(morpholin-2-ylmethyl)-1 H -benzo[ d Add [imidazol-2-yl]benzamide (0.20 g, 0.50 mmol) to a solution of dichloromethane (20 mL) N , N -Diisopropylethylamine (0.13 g, 1.0 mmol), N , N , N′, N ′-Tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (0.25 g, 0.65 mmol) and pyruvate (0.057 g, 0.65 mmol) were reacted at room temperature for 8 h. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate (v:v) = 1:1) to give a white solid (0.20 g, yield 85.11%). MS (ESI, pos.ion) m / z: 471 [M+H] + . 1 H NMR (600 MHz, Acetone- d 6) δ 8.13 (s, 1H), 7.99 (dd, J = 64.6, 8.5 Hz,1H), 7.80 – 7.75 (m, 3H), 7.49 (td, J = 7.8, 7.1, 1.5 Hz, 1H), 4.86 (ddd, J =40.8, 15.1, 2.7 Hz, 1H), 4.56 – 4.42 (m, 2H), 4.14 – 3.94 (m, 1H), 3.93 –3.84 (m, 1H), 3.79 – 3.68 (m, 1H), 3.40 – 3.31 (m, 1H), 3.13 – 3.00 (m, 1H), 2.97 (dd, J = 4.6, 1.9 Hz, 3H), 2.76 – 2.58 (m, 1H), 2.56 (d, J = 2.1 Hz, 3H), 2.31 (d, J = 8.6 Hz, 3H). Example 14: ( S )-4-(1-((4-(but-2-ynyl)morpholin-2-yl)methyl)-5-methyl-1 H -benzo[ d [Imidazol-2-yl)-3,5-difluoro- N -Methylbenzamide

[0212]

[0213] Towards( R )-3,5-difluoro- N-Methyl-4-(5-methyl-1-(morpholin-2-ylmethyl)-1 H -benzo[ d Add [imidazol-2-yl]benzamide (0.20 g, 0.50 mmol) to a solution of dichloromethane (20 mL) N , N -Diisopropylethylamine (0.13 g, 1.0 mmol), N , N , N ′, N ′-Tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (0.25 g, 0.65 mmol) and 2-butynic acid (0.055 g, 0.65 mmol) were reacted at room temperature for 8 h. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate (v:v) = 1:1) to give a white solid (0.18 g, yield 77.25%). MS (ESI, pos.ion) m / z: 467 [M+H] + . 1 H NMR (600 MHz, Acetone- d 6) δ 8.04 (dd, J = 66.2, 8.5 Hz, 2H), 7.78(dd, J = 9.7, 6.1 Hz, 3H), 7.56 – 7.50 (m, 1H), 4.91 (ddd, J = 24.2, 15.2, 2.9Hz, 1H), 4.55 (dd, J = 15.2, 8.7 Hz, 1H), 4.45 (ddt, J = 23.6, 13.2, 2.3 Hz, 1H),4.15 – 4.07 (m, 1H), 3.93 – 3.76 (m, 1H), 3.76 – 3.71 (m, 1H), 3.37 – 3.23(m, 1H), 3.11 – 2.93 (m, 4H), 2.66 – 2.49 (m, 4H), 1.96 (d, J = 5.0 Hz, 3H). Example 15: ( S )-4-(1-((4-(dimethylphosphoryl)morpholin-2-yl)methyl)-5-methyl-1 H -benzo[ d[Imidazol-2-yl)-3,5-difluoro- N -Methylbenzamide

[0214]

[0215] At 0 ℃, ( R )-3,5-difluoro- N -Methyl-4-(5-methyl-1-(morpholin-2-ylmethyl)-1 H -benzo[ d Imidazol-2-yl)benzamide (0.26 g, 0.65 mmol) and triethylamine (0.20 g, 1.95 mmol) were added to a solution of dichloromethane (10 mL), and dimethylphosphorus chloride (0.073 g, 0.65 mmol) was added. The reaction was carried out at room temperature for 4 h. The reaction was monitored by TLC until complete. Saturated brine (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was collected, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate (v:v) = 1:1) to give a white solid (0.16 g, yield 51.72%). MS (ESI, pos.ion) m / z: 477 [M+H] + . 1 H NMR (599 MHz, Chloroform- d ) δ 8.21 (q, J = 4.7 Hz, 1H), 7.63 (s,1H), 7.46 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.3 Hz, 1H), 7.21 (dd, J = 8.3, 1.6 Hz,1H), 4.10 – 4.02 (m, 2H), 3.71 – 3.65 (m, 1H), 3.62 (ddt, J = 10.3, 6.9, 3.3Hz, 1H), 3.34 (td, J = 11.5, 2.7 Hz, 1H), 3.16 – 3.11 (m, 1H), 3.00 (d, J = 4.7Hz, 3H), 2.94 (dd, J = 12.7, 7.2 Hz, 1H), 2.63 (tt, J= 12.1, 3.3 Hz, 1H), 2.52(s, 3H), 2.27 (ddd, J = 12.2, 10.4, 3.1 Hz, 1H), 1.37 (d, J = 13.2 Hz, 3H), 1.33(d, J = 13.0 Hz, 3H). Example 16: ( S )-3,5-difluoro-4-(7-methyl-3-((4-(3-methylbut-2-enoyl)morpholin-2-yl)methyl)imidazo[1,2- a pyridin-2-yl)benzonitrile

[0216]

[0217] Step 1: tert-butyl ( S )-2-((2-(4-cyano-2,6-difluorophenyl)-7-methylimidazo[1,2- a Synthesis of pyridin-3-yl)methyl)morpholine-4-carboxylic acid ester Add 2.0 g (11.97 mmol) of 4-cyano-2,6-difluorobenzaldehyde to the reaction flask. S 2-Ethynylmorpholine-4-carboxylic acid tert-butyl ester (2.53 g, 11.97 mmol), 2-amino-4-methylpyridine (1.29 g, 11.97 mmol), cuprous chloride (0.36 g, 3.59 mmol), copper trifluoromethanesulfonate (1.30 g, 3.59 mmol), nitrogen purged three times, toluene (100 mL) added, followed by nitrogen purging three more times, the reaction solution was stirred at 100 °C for 5 min, and then... N,N Dimethylformamide (1.0 mL) was added, and nitrogen was used to replace the nitrogen atmosphere. The mixture was then stirred for 16 h. TLC analysis showed that no raw material remained. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (v:v) = 10:1) to give a yellow solid (1.8 g, yield 32.10%).

[0218] Step 2: ( S )-3,5-difluoro-4-(7-methyl-3-(morpholin-2-ylmethyl)imidazo[1,2- a Synthesis of pyridin-2-yl)benzonitrile Add tert-butyl ( S )-2-((2-(4-cyano-2,6-difluorophenyl)-7-methylimidazo[1,2-a A solution of pyridin-3-yl)methyl)morpholine-4-carboxylic acid ester (1.8 g, 3.84 mmol) and hydrochloric acid (1.57 g, 43.05 mmol, 4 M) in ethyl acetate (6.0 mL) was reacted with the mixture at room temperature and stirred for 4 h. After the reaction was complete, the solvent was removed under reduced pressure to give a yellow solid (1.4 g, yield 98.92%).

[0219] Step 3: ( S )-3,5-difluoro-4-(7-methyl-3-((4-(3-methylbut-2-enoyl)morpholin-2-yl)methyl)imidazo[1,2- a pyridin-2-yl)benzonitrile Synthesis Towards( S )-3,5-difluoro-4-(7-methyl-3-(morpholin-2-ylmethyl)imidazo[1,2- a Add pyridin-2-yl)benzonitrile (1.8 g, 4.89 mmol) to a solution of dichloromethane (20 mL). N,N -Diisopropylethylamine (1.26 g, 9.78 mmol), stirred for 10 min, then 2-(7-aza-1-diisopropylethylamine) was added. H (-benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate (2.42 g, 6.36 mmol), 3-methylbut-2-enoic acid (0.64 g, 6.36 mmol), stirred at room temperature for 8 h. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate (v:v) = 1:1) to give a yellow oil. The obtained yellow oil was dissolved in dichloromethane (100 mL), washed with 2 M hydrochloric acid aqueous solution (50 mL × 2), washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give a yellow solid (0.6 g, yield 27.26%). MS (ESI, pos.ion) m / z: 451 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 6.8 Hz, 1H), 7.40 (s, 1H), 7.36 (d, J = 6.2 Hz, 2H), 6.71 (d, J = 6.7 Hz, 1H), 5.66 (d, J = 42.2 Hz, 1H), 4.49 – 4.35 (m,1H), 3.85 (dd,J = 39.6, 10.6 Hz, 1H), 3.77 – 3.65 (m, 1H), 3.64 – 3.41 (m, 2H), 3.34 (dd, J = 23.4, 11.8 Hz, 1H), 3.23 – 2.88 (m, 2H), 2.82 – 2.66 (m, 1H), 2.44 (s, 3H), 1.86 (d, J = 20.6 Hz, 6H).

[0220] Example 17: ( S )-3,5-difluoro- N -Methyl-4-(7-methyl-3-((4-(3-methylbut-2-en-1-yl)morpholin-2-yl)methyl)imidazo[1,2-] a pyridin-2-yl)benzamide

[0221]

[0222] Step 1: Synthesis of 3-methylbut-2-enal At 0 °C, pyridine dichromate (6.55 g, 17.41 mmol) was added in portions to a solution of 3-methyl-2-buten-1-ol (1.0 g, 11.61 mmol) in dichloromethane (25 mL), followed by reaction at room temperature for 2 h. After the reaction was confirmed to be complete by TLC, without quenching, the supernatant was rapidly passed through a column and washed with a small amount of DCM. The resulting DCM solution of 3-methylbuten-2-enal was used directly for the next step of reductive amination.

[0223] Step 2: ( S )-3,5-difluoro- N -Methyl-4-(7-methyl-3-((4-(3-methylbut-2-en-1-yl)morpholin-2-yl)methyl)imidazo[1,2-] a Synthesis of pyridin-2-yl)benzamide Towards( S )-3,5-difluoro- N -Methyl-4-(7-methyl-3-(morpholin-2-ylmethyl)imidazo[1,2-] aA solution of pyridin-2-yl)benzamide (0.3 g, 0.75 mmol), 3-methylbut-2-enal (0.13 g, 1.5 mmol), and acetic acid (0.45 g, 7.5 mmol) in dichloromethane (10 mL) was added in portions with sodium cyanoborohydride (0.057 g, 0.90 mmol), and the reaction was carried out at room temperature for 4 h. The formation of the target product was detected by TLC. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (v:v) = 10:1) to give a yellow oil (0.18 g, yield 51.28%). MS (ESI, pos.ion) m / z: 469 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.17 (d, J = 7.0 Hz, 1H), 7.44 – 7.32(m, 4H), 6.67 (dd, J = 7.1, 1.7 Hz, 1H), 5.13 – 5.07 (m, 1H), 3.76 (ddd, J =11.5, 3.3, 1.5 Hz, 1H), 3.72 – 3.63 (m, 1H), 3.51 (td, J = 11.5, 2.4 Hz, 1H), 3.01 (d, J = 4.7 Hz, 3H), 2.99 – 2.90 (m, 2H), 2.89 – 2.77 (m, 2H), 2.66 – 2.53(m, 2H), 2.42 (d, J = 1.1 Hz, 3H), 1.98 (td, J = 11.5, 3.3 Hz, 1H), 1.71 – 1.64(m, 4H), 1.57 (d, J = 1.4 Hz, 3H). Example 18: ( S )-4-(3-((4-(1-cyanocyclopropane-1-carbonyl)morpholin-2-yl)methyl)-7-methylimidazo[1,2- a ]pyridin-2-yl)-3,5-difluoro- N -Methylbenzamide

[0224]

[0225] Towards( S )-3,5-difluoro- N -Methyl-4-(7-methyl-3-(morpholin-2-ylmethyl)imidazo[1,2-] a Add pyridin-2-yl)benzamide (0.2 g, 0.5 mmol) to a solution of dichloromethane (10 mL). N , N -Diisopropylethylamine (0.13 g, 1.0 mmol), stirred for 10 min, then added N , N , N′ , N′ Tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (0.25 g, 0.65 mmol), 1-cyanocyclopropanecarboxylic acid (0.072 g, 0.65 mmol), stirred at room temperature for 8 h. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate (v:v) = 1:1) to give a white solid (0.15 g, yield 60.85%). MS (ESI, pos.ion) m / z: 494 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.76 (q, J = 4.4 Hz, 1H), 8.71 (d, J = 7.1 Hz, 1H), 7.74 (d, J = 8.7 Hz, 2H), 7.63 (s, 1H), 7.20 (d, J = 7.1 Hz, 1H), 4.05 (dd, J = 64.8, 13.1 Hz, 3H), 3.78 – 3.53 (m, 3H), 3.33 – 3.25 (m, 1H), 3.24 – 3.13(m, 2H), 2.83 (d, J = 4.5 Hz, 3H), 2.49 (s, 3H), 1.53 (q, J = 4.2, 3.6 Hz, 2H), 1.44 (q, J = 4.7, 4.1 Hz, 2H). Example 19: ( S , E)-3,5-difluoro-4-(7-methyl-3-((4-(3-methylbut-2-enoyl)morpholin-2-yl)methyl)imidazo[1,2- a ]pyridin-2-yl)benzaldehyde O-methyl oxime

[0226]

[0227] Step 1: Synthesis of 2-(4-bromo-3,5-difluorophenyl)-1,3-dioxacyclopentane To a solution of 4-bromo-3,5-difluorobenzaldehyde (10 g, 45.25 mmol), ethylene glycol (8.43 g, 135.75 mmol), and toluene (100 mL), p-toluenesulfonic acid (15.58 g, 90.5 mmol) was added, and the mixture was refluxed for 8 h. After the reaction was complete, the mixture was cooled to room temperature, and the pH was adjusted to 7 by adding saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (100 mL × 3 times), and the organic phase was collected. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 20:1) to give a colorless oil (10.25 g, yield 85.46%).

[0228] Step 2: Synthesis of 2-(3,5-difluoro-4-vinylphenyl)-1,3-dioxane At room temperature, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (3.16 g, 3.87 mmol), cesium carbonate (37.80 g, 116.01 mmol), and potassium ethylene trifluoroborate (7.77 g, 58.01 mmol) were added to a solution of 2-(4-bromo-3,5-difluorophenyl)-1,3-dioxane (10.25 g, 38.67 mmol) in dioxane (200 mL) and water (20 mL), and the reaction was carried out at 100 °C for 8 h. TLC analysis showed that the reaction proceeded completely. The mixture was filtered through diatomaceous earth, and saturated brine (100 mL) was added. The mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was collected, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 3:1) to give a yellow solid (7.0 g, yield 85.31%).

[0229] Step 3: Synthesis of 4-(1,3-dioxacyclopentan-2-yl)-2,6-difluorobenzaldehyde To a solution of 2-(3,5-difluoro-4-vinylphenyl)-1,3-dioxane (6.5 g, 30.63 mmol) in tetrahydrofuran (100 mL) and water (100 mL), 2,6-dimethylpyridine (6.56 g, 61.26 mmol), sodium periodate (26.21 g, 122.52 mmol), and potassium osmium tetroxide dihydrate (1.13 g, 3.06 mmol) were added. The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was quenched with saturated sodium sulfite aqueous solution (100 mL), extracted with ethyl acetate (200 mL × 3), and the organic phase was collected. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 5:1) to give a white solid (3.25 g, yield 49.54%).

[0230] Step 4: tert-butyl ( S )-2-((2-(4-(1,3-dioxacyclopentan-2-yl)-2,6-difluorophenyl)-7-methylimidazo[1,2- a Synthesis of pyridin-3-yl)methyl)morpholine-4-carboxylic acid ester Add 4-(1,3-dioxacyclopentan-2-yl)-2,6-difluorobenzaldehyde (2.0 g, 9.34 mmol) and tert-butyl (2...) to the reaction flask. S 2-Ethynyl-4-carboxylic acid-2-methylpiperidin ester (1.97 g, 9.34 mmol), 2-amino-4-methylpyridine (1.01 g, 9.34 mmol), cuprous chloride (0.28 g, 2.80 mmol), copper(II) trifluoromethanesulfonate (1.01 g, 2.80 mmol), nitrogen purged three times, toluene (100 mL) added, followed by three more purgings, the reaction solution was stirred at 100 °C for 5 min, and then... N , N - Dimethylacetamide (1.0 mL), purged with nitrogen again, and then stirred at 100 °C for 12 h. The reaction was complete by TLC, and the target molecular weight was detected by LC-MS. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate (v:v) = 1:1) to give a yellow solid (1.35 g, yield 28.04%). MS (ESI, pos.ion) m / z: 516 [M+H] + . Step 5: ( S )-3,5-difluoro-4-(7-methyl-3-(morpholin-2-ylmethyl)imidazo[1,2- a Synthesis of pyridin-2-yl)benzaldehyde tert-butyl ( S )-2-((2-(4-(1,3-dioxacyclopentan-2-yl)-2,6-difluorophenyl)-7-methylimidazo[1,2- a In a solution of pyridin-3-yl)methyl)morpholine-4-carboxylic acid ester (1.35 g, 2.61 mmol) and tetrahydrofuran (10 mL), trifluoroacetic acid (15.41 g, 135.14 mmol) was added, and the reaction was carried out at room temperature for 4 h. The pH of the reaction solution was adjusted to 8.0 with 10% sodium hydroxide aqueous solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was collected, and the solvent was removed under reduced pressure to give a yellow oily substance (0.9 g, yield 92.55%).

[0231] Step 6: ( S , E )-3,5-difluoro-4-(7-methyl-3-(morpholin-2-ylmethyl)imidazo[1,2- a pyridin-2-yl)benzaldehyde O Synthesis of methyl oxime Towards( S )-3,5-difluoro-4-(7-methyl-3-(morpholin-2-ylmethyl)imidazo[1,2- a In a methanol (50 mL) solution of pyridin-2-yl)benzaldehyde (0.9 g, 2.42 mmol) and methylamine hydrochloride (0.30 g, 3.63 mmol), sodium bicarbonate (0.30 g, 3.63 mmol) was added, and the mixture was refluxed at 60 °C for 6 h. LC-MS showed no residue of the starting material and the formation of the target product. The reaction solution was cooled to room temperature, methanol was removed under reduced pressure, water (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to give a yellow solid (0.8 g, yield 82.44%). MS (ESI, pos.ion) m / z: 401 [M+H] + . Step 7: ( S , E )-3,5-difluoro-4-(7-methyl-3-((4-(3-methylbut-2-enoyl)morpholin-2-yl)methyl)imidazo[1,2- a pyridin-2-yl)benzaldehyde O Synthesis of methyl oxime Towards( S , E )-3,5-difluoro-4-(7-methyl-3-(morpholin-2-ylmethyl)imidazo[1,2- a pyridin-2-yl)benzaldehydeO 3,3-Methyloxime (0.8 g, 2.00 mmol), 3,3-dimethicone (0.20 g, 2 mmol), N,N,N', N’ Add 0.76 g, 2 mmol of tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (20 mL) to a solution of dichloromethane. N,N -Diisopropylethylamine (0.39 g, 3 mmol) was reacted at room temperature for 8 h. The reaction was complete and the target product was observed by TLC and LC-MS. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate (v:v) = 1:1) to give a yellow solid (0.34 g, yield 35.27%). MS (ESI, pos.ion) m / z: 483 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 7.1 Hz, 1H), 8.26 (s, 1H), 7.69(d, J = 10.6 Hz, 2H), 7.36 (s, 1H), 6.83 (s, 1H), 5.90 (d, J = 10.5 Hz, 1H), 4.11(dd, J = 41.3, 13.2 Hz, 1H), 3.95 (s, 3H), 3.75 (d, J = 10.3 Hz, 1H), 3.65 (s,1H), 3.41 (t, J = 14.4 Hz, 2H), 3.27 (d, J = 17.0 Hz, 2H), 3.04 (dt, J = 44.9, 12.1Hz, 1H), 2.74 – 2.54 (m, 1H), 2.40 – 2.34 (m, 3H), 1.80 (d, J = 8.9 Hz, 6H). Example 20: ( S )-3,5-difluoro- N -Methyl-4-(5-methyl-1-((3-methyl-2-oxooxazolidine-5-yl)methyl)-1 H -benzo[ d Imidazol-2-yl)benzamide

[0232]

[0233] Step 1: ( R Synthesis of 2-((2-oxooxazolidine-5-yl)methyl)isoindoline-1,3-dione Under nitrogen protection, add (5) to the double-necked flask R 5-(hydroxymethyl)-1,3-oxazolidin-2-one (1.5 g, 12.81 mmol), potassium phthalimide (2.26 g, 15.37 mmol), triphenylphosphine (5.04 g, 19.21 mmol), and tetrahydrofuran (30 mL) were added dropwise at 0 °C, followed by the addition of diethyl azodicarbonate (2.68 g, 15.37 mmol). After the addition was complete, the reaction was allowed to proceed at room temperature for 6 h. The reaction was stopped by TLC. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 3:1) to give a white solid (2.6 g, yield 82.44%).

[0234] Step 2: ( S Synthesis of 2-((3-methyl-2-oxooxazolidine-5-yl)methyl)isoindoline-1,3-dione Under nitrogen protection at 0 °C, add dropwise ( ) to a suspension of sodium hydride (0.51 g, 12.68 mmol) in tetrahydrofuran (50 mL). R A tetrahydrofuran solution (5.0 mL) of 2-((2-oxooxazolidine-5-yl)methyl)isoindoline-1,3-dione (2.4 g, 9.75 mmol) was reacted at 0 °C for 30 min, followed by the dropwise addition of iodomethane (1.80 g, 12.68 mmol). After the addition was complete, the reaction was allowed to proceed at room temperature for 6 h. The reaction was confirmed to be complete by TLC. The reaction was quenched with saturated brine (50 mL), extracted with EA (50 mL × 3), and the organic phase was collected. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 2:1) to give a yellow oil (1.0 g, yield 39.42%). MS (ESI, pos.ion) m / z: 261 [M+H] + . Step 3: ( S Synthesis of 5-(aminomethyl)-3-methyloxazolidin-2-one Towards( SHydrazine hydrate (0.58 g, 11.52 mmol) was added to an ethanol (30 mL) solution of 1.0 g (3.84 mmol) of 2-((3-methyl-2-oxooxazolidine-5-yl)methyl)isoindoline-1,3-dione, and the reaction was carried out at 80 °C for 12 h. The reaction was confirmed to be complete by TLC. Insoluble impurities were removed by filtration, the mixture was washed with ethanol, the organic phase was collected, and the solvent was removed under reduced pressure to give a yellow oil (0.43 g, yield 85.98%).

[0235] Step 4: ( S Synthesis of 3-methyl-5-(((4-methyl-2-nitrophenyl)amino)methyl)oxazolidin-2-one Towards( S 5-(aminomethyl)-3-methyloxazolidin-2-one (0.6 g, 4.61 mmol) and 1-fluoro-4-methyl-2-nitrobenzene (0.72 g, 4.61 mmol) N,N Cesium carbonate (7.51 g, 23.05 mmol) was added to a 60 mL solution of dimethylformamide, and the mixture was reacted at 100 °C for 8 h. Insoluble impurities were removed by filtration, and the solvent was removed from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 2:1) to give a yellow oil (0.5 g, yield 40.89%).

[0236] Step 5: ( S )-3,5-difluoro- N -Methyl-4-(5-methyl-1-((3-methyl-2-oxooxazolidine-5-yl)methyl)-1 H -benzo[ d Synthesis of imidazole-2-yl)benzamide Towards( S 3-Methyl-5-(((4-methyl-2-nitrophenyl)amino)methyl)oxazolidin-2-one (0.30 g, 1.13 mmol) and 3,5-difluoro-4-formyl- N Sodium dithionite (0.98 g, 5.65 mmol) was added to a 10 mL ethanol solution of methylaniline (0.23 g, 1.13 mmol), and the mixture was stirred at 80 °C for 12 h. TLC analysis showed the formation of the target product, but some starting material remained. The reaction solution was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v:v) = 20:1) to give a yellow solid (0.15 g, yield 32.01%). MS (ESI, pos.ion) m / z: 415 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 4.4 Hz, 1H), 7.62 (s, 1H), 7.48(d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 4.67 (dt, J = 12.9, 6.4 Hz, 1H), 4.30 (dd, J = 14.4, 7.2 Hz, 1H), 4.23 (dd, J = 15.6, 4.7 Hz, 1H), 3.48 (t, J = 8.8 Hz, 1H), 3.06 (dd, J = 9.0, 6.7 Hz, 1H), 2.98 (d, J = 4.6 Hz, 3H), 2.72 (s, 3H), 2.51 (s, 3H). Example 21: ( S )-3,5-difluoro- N -Methyl-4-(5-methyl-1-((2-oxo-3-phenyloxazolidine-5-yl)methyl)-1 H -benzo[ d Imidazol-2-yl)benzamide

[0237]

[0238] Step 1: ( R Synthesis of 5-(((tert-butyldimethylsilyl)oxy)methyl)oxazolidin-2-one Towards( R 5-(hydroxymethyl)oxazolidin-2-one (4.0 g, 34.16 mmol), 1 H To a solution of β-imidazole (5.81 g, 85.40 mmol) in dichloromethane (250 mL), tert-butyldimethylchlorosilane (6.18 g, 40.99 mmol) was added, and the reaction was carried out at room temperature for 4 h. The reaction was stopped by TLC, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 5:1) to give a white solid (7.0 g, yield 88.57%).

[0239] Step 2: ( R Synthesis of 5-(((tert-butyldimethylsilyl)oxy)methyl)-3-phenyloxazolidin-2-one Add to a solution of (R)-5-(((tert-butyldimethylsilyl)oxy)methyl)oxazolidin-2-one (7.0 g, 30.26 mmol) in acetonitrile (100 mL) N,N' Dimethylethylenediamine (1.60 g, 18.16 mmol), cuprous iodide (1.73 g, 9.08 mmol), iodobenzene (8.03 g, 39.34 mmol), potassium carbonate (10.46 g, 75.65 mmol), nitrogen purged three times, reacted at 100 °C for 8 h. TLC showed no residual reactants. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was collected, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 10:1) to give a white solid (7.6 g, yield 81.70%).

[0240] Step 3: ( R Synthesis of 5-(hydroxymethyl)-3-phenyloxazolidine-2-one Towards( R In a solution of 5-(((tert-butyldimethylsilyl)oxy)methyl)-3-phenyloxazolidin-2-one (7.6 g, 24.72 mmol) in tetrahydrofuran (150 mL), tetrabutylammonium fluoride (6.46 g, 24.72 mmol) was added, and the reaction was carried out at room temperature for 4 h. TLC analysis showed no residue of the starting material. The reaction mixture was then extracted with ethyl acetate (50 mL × 3 times), and the organic phase was collected. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 1:1) to give a white solid (3.4 g, yield 71.19%).

[0241] Step 4: ( S Synthesis of 2-((2-oxo-3-phenyloxazolidine-5-yl)methyl)isoindoline-1,3-dione Under nitrogen protection, add ( R5-(hydroxymethyl)-3-phenyloxazolidin-2-one (2.9 g, 15.01 mmol), phthalimide (2.65 g, 18.01 mmol), triphenylphosphine (5.91 g, 22.52 mmol), and tetrahydrofuran (50 mL) were added dropwise at 0 °C with diethyl azodicarbonate (3.14 g, 18.01 mmol). After the addition was complete, the reaction was allowed to proceed at room temperature for 8 h. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 3:1) to give a white solid (4.5 g, yield 93.01%).

[0242] Step 5: ( S Synthesis of 5-(aminomethyl)-3-phenyloxazolidine-2-one Towards( S Hydrazine hydrate (2.10 g, 41.88 mmol) was added to 100 mL of ethanol containing 4.5 g (13.96 mmol) of 2-((2-oxo-3-phenyloxazolidine-5-yl)methyl)isoindoline-1,3-dione, and the reaction was carried out at 80 °C for 12 h. The reaction was confirmed to be complete by TLC. Insoluble impurities were removed by filtration, the mixture was washed with ethanol, the organic phase was collected, and the solvent was removed under reduced pressure to give a yellow oil (1.1 g, yield 40.99%).

[0243] Step 6: ( R Synthesis of 5-(((4-methyl-2-nitrophenyl)amino)methyl)-3-phenyloxazolidine-2-one Towards( S Cesium carbonate (3.61 g, 11.07 mmol) was added to a solution of 5-(aminomethyl)-3-phenyloxazolidin-2-one (0.71 g, 3.69 mmol) and 4-fluoro-3-nitrotoluene (0.57 g, 3.69 mmol) in acetonitrile (30 mL), and the mixture was reacted at 80 °C for 8 h. The reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, filtered to remove insoluble impurities, and the solvent was removed from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 1:1) to give a yellow solid (1.2 g, yield 99.25%).

[0244] Step 7: ( S )-3,5-difluoro- N -Methyl-4-(5-methyl-1-((2-oxo-3-phenyloxazolidine-5-yl)methyl)-1 H -benzo[ d Synthesis of imidazole-2-yl)benzamide Towards(R )-5-(((4-methyl-2-nitrophenyl)amino)methyl)-3-phenyloxazolidin-2-one (0.3 g, 0.92 mmol) and 3,5-difluoro-4-formyl- N Sodium dithionite (0.80 g, 4.60 mmol) was added to a 10 mL ethanol solution of methylbenzamide (0.18 g, 0.92 mmol), and the mixture was stirred at 80 °C for 12 h. TLC analysis showed the formation of the target product, but some starting material remained. The reaction solution was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v:v) = 20:1) to give a yellow solid (0.15 g, yield 34.35%). MS (ESI, pos.ion) m / z: 477 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 7.60 (d, J = 4.6 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.34 – 7.29 (m, 5H), 7.12 (dt, J =8.4, 4.1 Hz, 1H), 4.90 – 4.81 (m, 1H), 4.45 (d, J = 4.0 Hz, 2H), 4.13 (d, J = 7.0Hz, 1H), 3.61 (dd, J = 9.2, 6.6 Hz, 1H), 2.96 (d, J = 4.5 Hz, 3H), 2.51 (s, 3H). Example 22: (S)-4-(1-((3-cyclopropyl-2-oxooxazolidine-5-yl)methyl)-5-methyl-1 H -Benz[d]imidazol-2-yl)-3,5-difluoro- N -Methylbenzamide

[0245]

[0246] Step 1: Synthesis of (S)-2-((3-cyclopropyl-2-oxooxazolidine-5-yl)methyl)isoindoline-1,3-dione Add ( to the reaction flask) R 2-((2-oxooxazolidine-5-yl)methyl)isoindoline-1,3-dione (1.50 g, 6.09 mmol), cyclopropylboronic acid (1.05 g, 12.18 mmol), copper acetate (1.11 g, 6.09 mmol), 2,2-bipyridine (0.95 g, 6.09 mmol), sodium carbonate (1.29 g, 12.18 mmol), and 1,2-dichloroethane (50 mL) were reacted in an open container at 70 °C for 17 h. The mixture was cooled to room temperature, quenched with 1N dilute hydrochloric acid (40 mL), filtered, and the organic phase was separated from the aqueous phase by extraction with dichloromethane (20 mL × 2). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The residue was filtered, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 3:1) to give a white solid (1.23 g, yield 70.53%). MS (ESI, pos.ion) m / z: 287 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.89 (dd, J = 5.3, 3.1 Hz, 2H), 7.77 (dd, J =5.3, 3.1 Hz, 2H), 4.87 – 4.75 (m, 1H), 4.03 (dd, J = 14.0, 6.6 Hz, 1H), 3.87(dd, J = 14.1, 6.1 Hz, 1H), 3.65 (t, J = 8.7 Hz, 1H), 3.41 (dd, J = 9.0, 5.7 Hz,1H), 2.60 – 2.47 (m, 1H), 0.84 – 0.66 (m, 4H). Step 2: ( S Synthesis of 5-(aminomethyl)-3-cyclopropyloxazolidin-2-one (S)-2-((3-cyclopropyl-2-oxooxazolidine-5-yl)methyl)isoindoline-1,3-dione (1.23 g, 4.30 mmol) dissolved in ethanol (50 mL) was added to a reaction flask, followed by the addition of hydrazine hydrate (0.63 mL, 12.90 mmol). The mixture was heated to 80 °C and reacted for 15 h. After cooling to room temperature, the solvent was evaporated from the reaction solution under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v:v) = 10 / 1) to give a yellow oil (0.66 g, yield 98.36%).

[0247] MS (ESI, pos.ion) m / z: 157 [M+H] + . Step 3: ( S Synthesis of 3-cyclopropyl-5-(((4-methyl-2-nitrophenyl)amino)methyl)oxazolidin-2-one 4-fluoro-3-nitrotoluene (0.56 g, 3.61 mmol), (S)-5-(aminomethyl)-3-cyclopropyloxazolidin-2-one (0.56 g, 3.61 mmol), cesium carbonate (3.53 g, 10.83 mmol), and N,N-dimethylformamide (20 mL) were added to a reaction flask, and the mixture was heated to 80 °C and reacted for 23 h. After cooling to room temperature, the solvent was evaporated from the reaction solution under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v:v) = 2 / 1) to give a yellow oil (0.54 g, yield 51.35%). MS (ESI, pos.ion) m / z: 292 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.98 (s, 1H), 7.31 (dd, J = 8.7, 1.3 Hz, 1H), 6.84 (d, J = 8.7 Hz, 1H), 4.74 (dq, J = 11.2, 5.6 Hz, 1H), 3.71 (t, J = 8.8 Hz, 1H), 3.66 – 3.54 (m, 2H), 3.40 (dd, J = 8.9, 6.3 Hz, 1H), 2.58 – 2.51(m, 1H), 2.28 (s, 3H), 0.82 – 0.72 (m, 4H). Step 4: ( S)-4-(1-((3-cyclopropyl-2-oxooxazolidine-5-yl)methyl)-5-methyl-1 H -benzo[ d [Imidazol-2-yl)-3,5-difluoro- N Synthesis of methylbenzamide Add ( to the reaction flask) S 3-Cyclopropyl-5-((((4-methyl-2-nitrophenyl)amino)methyl)oxazolidin-2-one (0.54 g, 1.85 mmol) and 3,5-difluoro-4-formyl-N-methylbenzamide (0.41 g, 2.04 mmol) were dissolved in ethanol (15 mL), and sodium dithionite (1.61 g, 9.25 mmol) was added. After purging with nitrogen three times, the mixture was heated to 80 °C and reacted for 15 h. The mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified twice by silica gel column chromatography (dichloromethane / methanol (v:v) = 20 / 1) to give a pale yellow solid (0.13 g, yield 15.92%). MS (ESI, pos.ion) m / z: 441 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 4.5 Hz, 1H), 7.66 (s, 1H), 7.51(d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 1H), 7.28 (s, 1H), 4.71 – 4.62 (m, 1H), 4.29 (d, J = 5.2 Hz, 2H), 3.49 (t, J = 8.9 Hz, 1H), 3.09 – 3.05 (m, 1H), 3.04 (d, J = 4.6 Hz, 3H), 2.55 (s, 3H), 2.37 (dq, J = 10.5, 3.6 Hz, 1H), 0.72 – 0.64 (m,2H), 0.47 (s, 2H). Example 23: ( S )-4-(1-((3-(6-chloropyridin-3-yl)-2-oxooxazolidine-5-yl)methyl)-5-methyl-1 H -benzo[ d [Imidazol-2-yl)-3,5-difluoro- N -Methylbenzamide

[0248]

[0249] Step 1: ( R Synthesis of 5-(((tert-butyldimethylsilyl)oxy)methyl)oxazolidin-2-one To (5) R 5-(hydroxymethyl)-1,3-oxazolidin-2-one (4.0 g, 34.16 mmol), 1 H To a solution of β-imidazole (5.0 g, 42.70 mmol) in dichloromethane (300 mL), tert-butyldimethylchlorosilane (7.72 g, 51.24 mmol) was added, and the reaction was carried out at room temperature for 4 h. The reaction was stopped by TLC, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 5:1) to give a white solid (7.0 g, yield 88.57%).

[0250] Step 2: ( R Synthesis of 5-(((tert-butyldimethylsilyl)oxy)methyl)-3-(6-chloropyridin-3-yl)oxazolidin-2-one Towards( R Add 5-(((tert-butyldimethylsilyl)oxy)methyl)oxazolidin-2-one (1.0 g, 4.32 mmol) to a 20 mL solution of acetonitrile (20 mL). N,N' Dimethylethylenediamine (0.23 g, 2.59 mmol), cuprous iodide (0.25 g, 1.30 mmol), 2-chloro-5-iodopyridine (1.03 g, 4.32 mmol), potassium carbonate (1.49 g, 10.8 mmol), nitrogen purged three times, reacted at 100 °C for 9 h. TLC showed no residual reactants. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was collected, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 5:1) to give a white solid (1.4 g, yield 94.46%).

[0251] Step 3: ( R Synthesis of 3-(6-chloropyridin-3-yl)-5-(hydroxymethyl)oxazolidin-2-one Towards( RIn a tetrahydrofuran (2 mL) solution of 5-(((tert-butyldimethylsilyl)oxy)methyl)-3-(6-chloropyridin-3-yl)oxazolidin-2-one (1.4 g, 4.08 mmol), tetrabutylammonium fluoride (1.07 g, 4.08 mmol) was added, and the reaction was carried out at room temperature for 4 h. TLC analysis showed no residue of the starting material. The reaction mixture was then diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phase was collected. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 1:1) to give a white solid (0.9 g, yield 96.41%).

[0252] Step 4: ( S Synthesis of 2-((3-(6-chloropyridin-3-yl)-2-oxooxazolidine-5-yl)methyl)isoindoline-1,3-dione Under nitrogen protection, (R)-3-(6-chloropyridin-3-yl)-5-(hydroxymethyl)oxazolidin-2-one (0.9 g, 3.94 mmol), phthalimide (0.70 g, 4.73 mmol), triphenylphosphine (1.55 g, 5.91 mmol), and tetrahydrofuran (3.0 mL) were added to a two-necked flask. Diethyl azodicarbonate (0.82 g, 4.73 mmol) was added dropwise at 0 °C. After the addition was complete, the reaction was allowed to proceed at room temperature for 8 h. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 3:1) to give a white solid (1.4 g, yield 99.41%).

[0253] Step 5: ( S Synthesis of 5-(aminomethyl)-3-(6-chloropyridin-3-yl)oxazolidin-2-one Towards( S Hydrazine hydrate (0.59 g, 11.73 mmol) was added to an ethanol (40 mL) solution of 1.4 g (3.91 mmol) of 2-((3-(6-chloropyridin-3-yl)-2-oxooxazolidine-5-yl)methyl)isoindoline-1,3-dione. The reaction was carried out at 80 °C for 12 h. The reaction was confirmed to be complete by TLC. Insoluble impurities were removed by filtration, the mixture was washed with ethanol, and the organic phase was collected. The solvent was removed under reduced pressure to give a yellow oil (0.8 g, yield 89.80%).

[0254] Step 6: ( R Synthesis of 3-(6-chloropyridin-3-yl)-5-(((4-methyl-2-nitrophenyl)amino)methyl)oxazolidin-2-one Towards( SCesium carbonate (5.72 g, 17.55 mmol) was added to a solution of 5-(aminomethyl)-3-(6-chloropyridin-3-yl)oxazolidin-2-one (0.8 g, 3.51 mmol) and 4-fluoro-3-nitrotoluene (0.54 g, 3.51 mmol) in N,N-dimethylformamide (10 mL), and the reaction was carried out at 80 °C for 8 h. The reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, filtered to remove insoluble impurities, and the solvent was removed from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 1:1) to give a yellow solid (0.44 g, yield 34.51%). MS (ESI, pos.ion) m / z: 363 [M+H] + . Step 7: ( S )-4-(1-((3-(6-chloropyridin-3-yl)-2-oxooxazolidine-5-yl)methyl)-5-methyl-1 H -benzo[ d [Imidazol-2-yl)-3,5-difluoro- N Synthesis of methylbenzamide Towards( R In a 2.5 mL ethanol solution of 3,5-difluoro-4-carboxybenzamide (0.054 g, 0.27 mmol) and 3-(((4-methyl-2-nitrophenyl)amino)methyl)oxazolidin-2-one (0.09 g, 0.25 mmol), sodium dithionite (0.22 g, 1.25 mmol) was added, and the mixture was stirred at 80 °C for 8 h. TLC analysis showed the formation of the target product, but some starting material remained. The reaction solution was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v:v) = 20:1) to give a yellow solid (0.08 g, yield 62.99%). MS (ESI, pos.ion) m / z: 512 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 8.76 (d, J = 4.5 Hz, 1H), 8.38 (d, J = 2.8 Hz, 1H), 7.95 (dd, J = 8.8, 2.9 Hz, 1H), 7.73 (d, J = 8.9 Hz, 3H), 7.52 (s, 1H), 7.50(d,J = 8.8 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 4.90 (d, J = 8.7 Hz, 1H), 4.64 –4.55 (m, 1H), 4.49 (dd, J = 15.4, 9.1 Hz, 1H), 4.13 (t, J = 9.0 Hz, 1H), 3.74(dd, J = 8.9, 6.5 Hz, 1H), 2.81 (d, J = 4.4 Hz, 3H), 2.44 (s, 3H). Example 24: ( S )-3,5-difluoro- N -Methyl-4-(5-methyl-1-((3-(1-methyl-1H-imidazol-4-yl)-2-oxooxazolidine-5-yl)methyl)-1 H -benzo[ d Imidazol-2-yl)benzamide

[0255]

[0256] Step 1: ( R Synthesis of 5-(((tert-butyldimethylsilyl)oxy)methyl)oxazolidin-2-one Towards( R 5-(hydroxymethyl)oxazolidin-2-one (4.0 g, 34.16 mmol), 1 H To a solution of β-imidazole (5.0 g, 42.70 mmol) in dichloromethane (300 mL), tert-butyldimethylchlorosilane (7.72 g, 51.24 mmol) was added, and the reaction was carried out at room temperature for 4 h. The reaction was stopped by TLC, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 5:1) to give a white solid (7.0 g, yield 88.57%).

[0257] Step 2: ( R )-5-(((tert-butyldimethylsilyl)oxy)methyl)-3-(1-methyl-1 H Synthesis of 1-imidazol-4-yl)oxazolidin-2-one Add ( to the reaction flask) R)-5-(((tert-butyldimethylsilyl)oxy)methyl)oxazolidin-2-one (1.5 g, 6.48 mmol), 4-iodo-1-methylimidazolium (1.42 g, 6.80 mmol), trans-(1 R ,2 R )- N , N The mixture of '-dimethyl-1,2-cyclohexanediamine (0.37 g, 2.59 mmol), cuprous iodide (0.25 g, 1.30 mmol), potassium carbonate (1.79 g, 12.96 mmol), and 1,4-dioxane (100 mL) was purged with nitrogen three times and then heated to 105 °C with stirring for 8 h. After cooling to room temperature, the reaction solution was filtered through a diatomaceous earth filter to remove insoluble matter. Ethyl acetate (250 mL) was added to the filter residue for washing, followed by vacuum filtration. The filtrates were combined and washed successively with ammonia (200 mL, wt 17%) and water (200 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give an off-white solid (1.70 g, yield 84.19%).

[0258] Step 3: ( R )-5-(hydroxymethyl)-3-(1-methyl-1 H Synthesis of 1-imidazol-4-yl)oxazolidin-2-one Add ( to the reaction flask) R )-5-(((tert-butyldimethylsilyl)oxy)methyl)-3-(1-methyl-1 H (-Imidazol-4-yl)oxazolidin-2-one (1.70 g, 5.46 mmol), tetrabutylammonium fluoride tetrahydrofuran solution (1.43 g, 5.46 mmol), and tetrahydrofuran (3 mL) were mixed and stirred at room temperature for 4 h. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether (v:v) = 1:1) to give a white solid (1.00 g, yield 92.91%).

[0259] Step 4: ( S Synthesis of )-2-((3-(1-methyl-1H-imidazol-4-yl)-2-oxooxazolidine-5-yl)methyl)isoindoline-1,3-dione Under nitrogen protection, add ( R )-5-(hydroxymethyl)-3-(1-methyl-1 H4-Imidazol-4-yl)oxazolidin-2-one (0.8 g, 4.06 mmol), phthalimide (0.72 g, 4.87 mmol), triphenylphosphine (1.60 g, 6.09 mmol), and tetrahydrofuran (20 mL) were added dropwise at 0 °C with diethyl azodicarbonate (0.85 g, 4.87 mmol). After the addition was complete, the reaction was allowed to proceed at room temperature for 8 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether (v:v) = 3:1) to give a white solid (1.1 g, yield 83.09%). MS (ESI, pos.ion) m / z: 327 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.87 (dd, J = 5.3, 3.1 Hz, 2H), 7.74 (dd, J =5.3, 3.1 Hz, 2H), 7.66 (dd, J = 11.9, 7.4 Hz, 1H), 7.18 (d, J = 13.5 Hz, 1H),5.12 – 4.94 (m, 1H), 4.24 (t, J = 9.3 Hz, 1H), 4.14 (dd, J = 14.1, 7.9 Hz, 1H), 3.98 – 3.86 (m, 2H), 3.66 (s, 3H). Step 5: ( S )-5-(aminomethyl)-3-(1-methyl-1 H Synthesis of 1-imidazol-4-yl)oxazolidin-2-one Towards( S )-2-((3-(1-methyl-1 H Hydrazine (0.64 g, 12.87 mmol) was added to an ethanol (100 mL) solution of (1.4 g, 4.29 mmol) imidazolium-4-yl)-2-oxooxazolidine-5-yl)methyl)isoindoline-1,3-dione (0.4 g, 4.29 mmol) and reacted at 80 °C for 12 h. The reaction was monitored by TLC until complete. Insoluble impurities were removed by filtration, the mixture was washed with ethanol, and the organic phase was collected. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (v:v) = 10:1) to give a yellow oil (0.54 g, yield 64.15%).

[0260] Step 6: Synthesis of (S)-3-(1-methyl-1H-imidazol-4-yl)-5-(((4-methyl-2-nitrophenyl)amino)methyl)oxazolidin-2-one Towards( S )-5-(aminomethyl)-3-(1-methyl-1 H 3-Imidazol-4-yl)oxazolidin-2-one (0.6 g, 3.06 mmol) and 4-fluoro-3-nitrotoluene (0.47 g, 3.06 mmol) N , N Cesium carbonate (2.99 g, 9.18 mmol) was added to a 10 mL solution of dimethylformamide and reacted at 100 °C for 8 h. Insoluble impurities were removed by filtration, and the solvent was removed from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 2:1) to give a yellow oil (0.3 g, yield 29.61%).

[0261] Step 7: ( S )-3,5-difluoro- N -Methyl-4-(5-methyl-1-((3-(1-methyl-1) H -imidazol-4-yl)-2-oxooxazolidine-5-yl)methyl)-1 H -benzo[ d Synthesis of imidazole-2-yl)benzamide Sodium dithionite (1.31 g, 7.55 mmol) was added to a 15 mL ethanol solution of (S)-3-(1-methyl-1H-imidazol-4-yl)-5-(((4-methyl-2-nitrophenyl)amino)methyl)oxazolidin-2-one (0.5 g, 1.51 mmol) and 3,5-difluoro-4-carboxybenzoamide (0.30 g, 1.51 mmol). The mixture was purged with nitrogen three times and stirred at 80 °C for 8 h. TLC analysis showed the formation of the target product, but some reactants remained. The reaction solution was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v:v) = 20:1) to give a yellow solid (0.35 g, yield 48.27%). MS (ESI, pos.ion) m / z: 481 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.44(d, J= 8.4 Hz, 1H), 7.23 (s, 1H), 7.20 (s, 1H), 7.15 (s, 1H), 7.03 (s, 1H), 4.87 (s, 1H), 4.43 – 4.31 (m, 2H), 4.16 (t, J = 9.2 Hz, 1H), 3.74 – 3.68 (m,1H), 3.64 (s, 3H), 3.02 (d, J = 4.4 Hz, 3H), 2.52 (s, 3H). Biological experiments The LC / MS / MS system used for analysis included an Agilent 1200 series vacuum degassing furnace, a binary syringe pump, an autosampler for well plates, a column oven, and an Agilent G6430 triple quadrupole mass spectrometer with an electrospray ionization (ESI) source. Quantitative analysis was performed in MRM mode, and the MRM conversion parameters are shown in Table A. Table A

[0262] Analysis was performed using an Agilent XDB-C18 2.1 × 30 mm 3.5 μM column, with 5 μL of sample injected. Analytical conditions: the mobile phase consisted of 0.1% formic acid aqueous solution (A) and 0.1% formic acid methanol solution (B). The flow rate was 0.4 mL / min. The mobile phase gradient is shown in Table B. Table B

[0263] In addition, an Agilent 6330 series LC / MS / MS spectrometer was used for analysis, equipped with a G1312A binary syringe pump, a G1367A autosampler, and a G1314C UV detector; the LC / MS / MS spectrometer used an ESI radiation source. Standard solutions were used to perform appropriate cation modeling and MRM conversion for each analyte for optimal analysis. A Capcell MP-C18 column (100 x 4.6 mm ID, 5 μM, Phenomenex, Torrance, California, USA) was used during analysis. The mobile phase was 5 mM ammonium acetate, 0.1% methanol aqueous solution (A): 5 mM ammonium acetate, 0.1% methanol acetonitrile solution (B) (70 / 30, v / v); the flow rate was 0.6 mL / min; the column temperature was maintained at room temperature; and 20 μL of sample was injected.

[0264] Example A: Screening of compounds for hP2X3 and hP2X using FLIPR calcium flow method 2 / 3 antagonistic activity of receptors Stable transfection with hP2X3 receptor or stable transfection with hP2X 2 / 3 HEK293 cells containing the recipient were digested with trypsin, centrifuged, resuspended in culture medium, and counted. The cells were then divided into groups of 1.2 × 10⁻⁶ cells. 4 Cells were seeded at a density of 1:1 in 384-well plates. The plates were then incubated at 37°C for 16–20 hours in a 5% CO2 incubator. After 24 hours of incubation, experimental buffer was prepared according to the FLIPR CALCIUM 6 ASSAY KIT (Molecular Devices) instructions. The dye was thawed to room temperature and diluted with the prepared experimental buffer to a 1:1 working buffer. The culture medium was removed, and 36 μL of the 1:1 working buffer was added. After centrifugation, the plates were incubated at 37°C in the dark for 2 hours. The test samples were serially diluted to the working solution concentration. 5 μL of 10× multidrug buffer was added to the corresponding wells, and the plates were centrifuged at 37°C for 30 min. The diluted test samples were added to 384-well plates at a rate of 20 μL / well. 10 μL of FLIPR Tetra was added to each well of the 384-well plate. Fluorescence signals were detected and data were acquired in the wavelength range of 515 nm to 575 nm. Signal values ​​and compound concentrations were plotted, and curve fitting and IC50 analysis were performed using the nonlinear regression method in GraphPad Prism software. 50 Calculations were performed. The results are shown in Table 1.

[0265] Table 1. Compounds provided in the embodiments of the present invention in hP2X3 and hP2X 2 / 3 Results of receptor cell functional calcium flow experiment

[0266] The experimental results show that the compound described in this invention has good properties in hP2X3 and hP2X. 2 / 3 The receptor cell function calcium flow assay showed good inhibitory effect and good selectivity.

[0267] Example B: Stability in liver microsomes of humans, monkeys, and rats The stability of the compounds of the present invention in human, monkey, and rat liver microsomes can be detected by the following methods: Human, monkey, or rat liver microsomes were incubated in duplicate polypropylene tubes. A typical total volume incubation mixture of 45 μL consisted of human, monkey, or rat liver microsomes (final concentration: 0.5 mg protein / mL), the target compound (final concentration: 1 μM), NADPH (final concentration: 2 mM), and potassium phosphate buffer (100 mM, pH 7.4). The compound was dissolved in DMSO and diluted with potassium phosphate buffer before adding the human, monkey, or rat liver microsomes. After a 10-minute pre-incubation, 15 μL of NADPH (final concentration: 2 mM) was added to initiate the enzymatic reaction. The entire experiment was conducted in incubation tubes at 37 °C, with a final DMSO concentration of 0.01%. The reaction was terminated at different time points (0, 15, 30, 60, and 90 minutes) by adding 150 μL of acetonitrile (containing IS). Centrifuge at 4000 rpm for 10 minutes to remove protein, collect the supernatant, and analyze by LC-MS / MS.

[0268] In the above experiments, verapamil (1 μM) was selected as a positive control and incubated at 37 °C. The reaction was terminated at different time points (0, 15, 30, 60, and 90 minutes). The assay method included a positive control to confirm the stability of the liver microsomal incubation system.

[0269] Data Analysis For each reaction, the concentration (expressed as a percentage) of the compound during incubation in human, monkey, or rat liver microsomes was plotted as a percentage of the zero time point to infer the intrinsic hepatic clearance CL in vivo. int (ref.: NaritomiY, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y. Prediction of human hepatic clearance from in vivo animal experiments and in vitrometabolic studies with liver microsomes from animals and humans. Drug Metabolism and Disposition 2001, 29: 1316-1324.). See Table 2 for the results.

[0270] Table 2. Experimental results on the stability of the compounds provided in the embodiments of the present invention in human, monkey, and rat liver microparticles.

[0271] As shown in Table 2, the compounds of the present invention exhibit good stability in human, monkey, and rat liver microsomes, with particularly good stability in human liver microsomes.

[0272] Example C: Pharmacokinetic evaluation of rats after intravenous injection and gavage administration of the compounds of the present invention This invention evaluated the pharmacokinetic studies of the compounds of this invention in rats. The compounds were administered either 10% DMSO + 10% Kolliphor HS15 + 80% sterile water for injection or 10% DMSO + 10% PEG400 + 80% saline. For intravenous (IV) administration, animals were given a dose of 1 mg / kg. For intragastric (IG) administration, animals were given 5 mg / kg. Blood samples (approximately 0.3 mL) were collected at time points of 0.083 (IV group only), 0.25, 0.5, 1.0, 2.0, 5.0, 7.0, and 24 hours, and centrifuged at 4000 rpm for 10 minutes. Plasma was collected and stored at -20 °C or -70 °C until LC / MS / MS analysis. The results showed that, after intravenous or intragastric administration of the compounds of this invention to rats, the bioavailability of Example 10 in rats was slightly higher than that of other compounds. See Table 3 for the results.

[0273] Table 3. Experimental results of the pharmacokinetic characteristics of the compounds provided in the embodiments of the present invention in rats.

[0274] As shown in Table 3, after intravenous injection or gavage administration of the compounds of the present invention to rats, the bioavailability of Example 10 in rats was slightly higher than that of other compounds.

[0275] Example D: Pharmacokinetic evaluation of the compound of the present invention after intravenous injection and gavage administration in beagle dogs This invention evaluated the pharmacokinetic studies of the compounds of the present invention in beagle dogs. The compounds were administered in either 10% DMSO + 10% Kolliphor HS15 + 80% sterile water for injection or 10% DMSO + 90% (2% HPMC-E15). For intravenous (IV) administration, animals were given a dose of 0.5 mg / kg. For intragastric (IG) administration, animals were given 2.5 mg / kg. Blood samples (approximately 0.5 mL) were collected at time points of 0.083 (IV group only), 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 hours, and centrifuged at 4,000 rpm for 10 minutes. Plasma was collected and stored at -20°C or -70°C until LC / MS / MS analysis. The results showed that Example 10 exhibited good bioavailability in beagle dogs after intravenous or intragastric administration of the compounds of the present invention. Results are shown in Table 4.

[0276] Table 4. Experimental results of the pharmacokinetic characteristics of the compounds provided in the embodiments of the present invention in beagle dogs.

[0277] As shown in Table 4, the compounds of the present invention exhibit good bioavailability in beagle dogs after intravenous injection or gavage.

[0278] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "some implementations," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments, implementations, or examples described in this specification, as well as the features of different embodiments, implementations, or examples.

[0279] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention without departing from the principles and spirit of the present invention.

Claims

1. A compound that is a compound of formula (I), or a stereoisomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (I). (I)， in, Ring A is a 5-membered heteroaryl group; Indicates a single bond or a double bond; When X is C, Y is N; Or, when X is N, Y is C; Ring B is selected from or ; R 1 3-8 membered heterocyclic group, C 6-10 Aryl or 5-12-membered heteroaryl, wherein the 3-8-membered heterocyclic group, C 6-10 The aryl and 5-12 heteroaryl groups are each independently and optionally replaced by 1, 2, 3, 4 or 5 Rs; Each R is independently H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, oxo, , -OR a -C(=O)R a -C(=O)OR a -NR b R c -C(=O)NR b R c -NR b C(=O)R c -S(O)R a -S(O)2R a -S(O)2NR b R c -NR b S(O)2R c C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 cycloalkyl or 3-8 membered heterocyclic group; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3, 4 or 5 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-8 Substituents of cycloalkyl groups; R 2 is D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, -OR d -C(=O)R d -C(=O)-C(=O)R d -C(=O)OR d -C(=O)NR e R f -NR e C(=O)R f -P(=O)R e R f -S(O)R d -S(O)2R d -S(O)2NR e R f -NR e S(O)2R f Oxygen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-12 heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-12 heteroaryl group are each independently and optionally surrounded by 1, 2, 3, 4 or 5 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups; R 3 is H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl or 3-10 membered heterocyclic group; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 The cycloalkyl group and the 3-10 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3, 4 or 5 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups; R a R b R c R d R e and R f Each is independently H, D, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 The aryl group and the 5-12 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups; n is 0, 1, 2, 3, 4 or 5; The condition is that when R 1 It is a phenyl group, and R 2 -C(=O)R d or -C(=O)OR d At that time, R d Not methyl, ethyl or isopropyl.

2. The compound according to claim 1, wherein, R 1 It is a 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the 3-6 membered heterocyclic group, C 6-10 The aryl and 5-10 heteroaryl groups are each independently and optionally replaced by 1, 2, 3, 4 or 5 Rs; Each R is independently H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, oxo, , -OR a -C(=O)R a -C(=O)OR a -NR b R c -C(=O)NR b R c -NR b C(=O)R c -S(O)R a -S(O)2R a -S(O)2NR b R c -NR b S(O)2R c C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl or 3-6 membered heterocyclic group; wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3, 4 or 5 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups and C 3-6 Substituents of cycloalkyl groups.

3. The compound according to claim 1 or 2, wherein, R 1 The oxocyclobutyl, azacyclobutyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazine, morpholinyl, dihydropyridinyl, phenyl, naphthyl, indazole, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyrazinyl, wherein each of the oxocyclobutyl, azacyclobutyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazine, morpholinyl, dihydropyridinyl, phenyl, naphthyl, indazole, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyrazinyl groups is independently and optionally substituted with 1, 2, 3, 4, or 5 Rs. Each R is independently H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, oxo, , -OR a -C(=O)R a -C(=O)OR a -NR b R c -C(=O)NR b R c -NR b C(=O)R c -S(O)R a -S(O)2R a -S(O)2NR b R c -NR b S(O)2R c Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl Cyclohexyl, oxetyl, aziridine, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF 2. -CH2CHF2, -CH2CF3, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxybutyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, and morpholinyl are each independently and optionally surrounded by 1, 2, 3, 4, or 5 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, methyl, ethyl, and n-propyl. It is substituted by substituents of isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propynyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

4. The compound according to any one of claims 1-3, wherein, R 2 is D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, -OR d -C(=O)R d -C(=O)-C(=O)R d -C(=O)OR d -C(=O)NR e R f -NR e C(=O)R f -P(=O)R e R f -S(O)R d -S(O)2R d -S(O)2NR e R f -NR e S(O)2R f Oxygen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl; wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently and optionally surrounded by 1, 2, 3, 4 or 5 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are replaced.

5. The compound according to any one of claims 1-4, wherein, R 2 is D, -F, -Cl, -Br, -I, -OH, -NH₂, -CN, -SH, -SF₅, -OR d , -C(=O)R d , -C(=O)-C(=O)R d , -C(=O)OR d , -C(=O)NR e R f , -NR e C(=O)R f , -P(=O)R e R f , -S(O)R d , -S(O)₂R d , -S(O)₂NR e R f , -NR e S(O)₂R f Oxygenated, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanebutyl, azironebutyl, pyrroleyl, tetrahydrofuran yl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, azacyclobutyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazine, morpholinyl, phenyl, naphthyl, pyrroleyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl are each independently and optionally selected from D by 1, 2, 3, 4, or 5. The following are substituents: -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propynyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, and trifluoromethoxy.

6. The compound according to any one of claims 1-5, wherein, R 3 is H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl or 3-8 membered heterocyclic group; wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3, 4 or 5 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are replaced.

7. The compound according to any one of claims 1-6, wherein, R 3 The following are not directly related to the preceding text: H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxy, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CH2CHF2, -CH2CF3 are not directly related to the preceding text. The difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziridine, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, and morpholinyl groups are each independently and optionally substituted by 1, 2, 3, 4, or 5 substituents selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, and trifluoromethoxy groups.

8. The compound according to any one of claims 1-7, wherein, R a R b R c R d R e and R f Each is independently H, D, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl, wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are replaced.

9. The compound according to any one of claims 1-8, wherein, R a R b R c R d R e and R f Each of the following is independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, 2-methylpropenyl, ethynyl, propynyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziridine pyrroloyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrroloyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, 2-methylpropenyl, ethynyl, propargyl, 1-propynyl, 1-Oynyl-Butyl, 2-Oynyl-Butyl, 3-Oynyl-Butyl, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Oxycyclobutyl, Azacyclobutyl, Pyrrolidinyl, Tetrahydrofuranyl, Piperidinyl, Piperazinyl, Morpholinyl, Phenyl, Naphthyl, Pyrrolidinyl, Pyrazolyl, Imidazolyl, Triazolyl, Tetraazolyl, Furanyl, Thiopheneyl, Thiazolyl, Oxazolyl, Pyridinyl, Pyrimidinyl, Pyrazinyl Each of the pyridazinyl groups is independently and optionally substituted by 1, 2, 3 or 4 substituents selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy and trifluoromethoxy.

10. A compound according to any one of claims 1-9, comprising a compound of formula (II) or a stereoisomer, geometric isomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof, (II) R 1 R 2 and R 3 Each has the meaning as described in any one of claims 1-9.

11. A compound according to any one of claims 1-9, comprising a compound of formula (III) or a stereoisomer, geometric isomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof, (III) R 1 R 2 and R 3 Each has the meaning as described in any one of claims 1-9.

12. A compound having the following structures, or stereoisomers, tautomers, nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs thereof, (1)、 (2)、 (3)、 (4)、 (5)、 (6)、 (7)、 (8)、 (9)、 (10)、 (11)、 (12)、 (13) (14) (15) (16) (17) (18) (19) (20) (twenty one), (twenty two), (twenty three), (twenty four), , , , , or .

13. A pharmaceutical composition comprising the compound of any one of claims 1-12; further comprising a pharmaceutically acceptable diluent, carrier, or excipient.

14. Use of the compound of any one of claims 1-12 or the pharmaceutical composition of claim 13 in the preparation of a medicament for the prevention, treatment or relief of P2X3 receptor-mediated diseases.

15. The use according to claim 14, wherein, The diseases mediated by the P2X3 receptor are pain, cough, respiratory diseases, or genitourinary diseases.

16. The use according to claim 15, wherein, The pain can be chronic pain, acute pain, endometriosis pain, neuropathic pain, back pain, cancer pain, inflammatory pain, surgical pain, migraine, or visceral pain. The cough is either a refractory chronic cough or an acute cough; The respiratory diseases mentioned are chronic obstructive pulmonary disease, pulmonary hypertension, pulmonary fibrosis, asthma, or obstructive sleep apnea; The urogenital system diseases mentioned include reduced bladder capacity, frequent urination, urge incontinence, stress incontinence, hyperresponsiveness of the bladder, benign prostatic hyperplasia, prostatitis, detrusor hyperreflexia, urinary frequency, nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatodynia, cystitis, or idiopathic bladder hypersensitivity.

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