Heterocyclic compound as TRPM3 antagonist

Abstract

The invention provides a compound as shown in a formula I, and a tautomer, a stereoisomer, a solvate, a pharmaceutically acceptable salt or a prodrug thereof. The compound can be used as an antagonist of TRPM3.

Description

Technical Field

[0001] This invention belongs to the field of medicine, specifically, it relates to a heterocyclic compound as a transient receptor potential m-type 3 (TRPM3) antagonist and its uses. Background Technology

[0002] The TRP (transient receptor potential) superfamily consists of proteins with six transmembrane domains (6TMs), which assemble into homotetramers or heterotetramers to form cation-permeable ion channels. The TRP superfamily comprises 27 cation channels, divided into seven families: typical TRP channel (TRPC), vanillin receptor-associated TRP channel (TRPV), melanoma-associated TRP channel (TRPM), transient receptor potential A1 (TRPA1), mucoprotein-associated TRP channel (TRPML), and polycystic kidney disease-associated TRP protein (TRPP) and TRPN1.

[0003] Members of the TRP superfamily are expressed in all mammalian organs and cell types, and significant progress has been made in understanding their physiological roles in recent years. The sensitivity of TRP channels to a wide range of chemical and physical stimuli allows them to function as dedicated biosensors involved in processes ranging from vision to taste and touch. In particular, several members of the TRP superfamily exhibit extremely high sensitivity to temperature. These so-called ThermoTRPs are highly expressed in sensory neurons and / or skin keratinocytes, where they act as thermal sensors for detecting harmless and harmful (painful) temperatures. Dysfunction of TRP channels is directly associated with the etiology of various genetic and acquired diseases.

[0004] TRPM subfamily members are divalent cations (Zn) 2+ Mg 2+ and Ca 2+ ) and Na + TRPM channels are crucial regulators of phosphatidylinositol PI(4,5)P2. TRPM channels, as important cellular sensors, participate in many physiological processes, including ion homeostasis, blood pressure, heart rhythm, immunity, and central nervous system function. TRPM3 (transient receptor potential m-type 3) is a Ca2+ channel. 2+A permeable, non-selective cation channel expressed in nociceptive neurons of the dorsal root ganglion (DRG) and trigeminal ganglion (TG). The neurosteroid pregnenolone sulfate is a known TRPM3 agonist. Pregnenolone sulfate induces pain in wild-type mice but not in TRPM3 knockout mice. Recently, it has also been shown that complete Freund's adjuvant (CFA)-induced inflammation and inflammatory pain are eliminated in TRPM3 knockout mice. Therefore, TRPM3 antagonists could be used as analgesics to counteract pain, such as inflammatory pain. The relationship between TRPM3 and epilepsy has also been confirmed.

[0005] There remains an urgent need for new, alternative, and / or better TRPM3 antagonists to prevent or treat TRPM3-mediated diseases, especially pain, such as inflammatory pain and epilepsy. Summary of the Invention

[0006] The object of this invention is to provide a heterocyclic compound as a TRPM3 antagonist and its use therein, the heterocyclic compound having the structure shown in the first aspect of this invention, the heterocyclic compound being used to prepare a medicament, pharmaceutical composition or preparation for treating and / or preventing diseases or conditions related to TRPM3; or for treating and / or preventing diseases or conditions related to TRPM3.

[0007] In a first aspect, the present invention provides compounds of Formula I, their tautomers, stereoisomers, solvates, pharmaceutically acceptable salts, or prodrugs:

[0008]

[0009] Among them, ring B is selected from 5-14 membered heteroaromatic rings and 5-14 membered heteroene rings;

[0010] The 5-14 membered heteroaromatic ring and the 5-14 membered heteroene ring contain at least one nitrogen atom;

[0011] R1 is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, oxo (=O), C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, -OR a -OC(=O)R a -NR b C(=O)R a -SR a -S(=O)R a -S(=O)2R a -S(=O)-NR a -、-S(=O)2-NR a -、-C(=O)Ra -C(=O)OR a -C(=O)NR a R b The C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, and 3-14 membered heterocycloalkyl are optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following: deuterium, hydroxyl, halogen, C1-C6 alkyl, and C1-C6 alkoxy.

[0012] m is selected from 1, 2, 3, 4, 5, 6;

[0013] L is selected from -C(=O)-, -S(=O)-, -S(=O)2-, -P(=O)-, -P(=O)2-;

[0014] R2 is selected from NR 21 R 22 ;

[0015] R 21 R 22 Each is independently selected from hydrogen, deuterium, hydroxyl, and -SR. a -S(=O)R a -S(=O)2R a C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl are optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following: deuterium, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)NR a R b -OC(=O)R a -NR b C(=O)R a -SR a -S(=O)R a -S(=O)2R a -C(=O)R a -C(=O)OR a -C(=NH)S(=O)2R a ;

[0016] Or, R 21 R 22The N atom attached thereto forms a 4-8 membered heterocyclic alkyl group or a 5-8 membered heteroaryl group; the 4-8 membered heterocyclic alkyl group or the 5-8 membered heteroaryl group is optionally substituted by 1, 2, 3, 4 or 5 substituents selected from the following: deuterium, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy;

[0017] M is selected from the bond, -O-, -S(=O)R a -、-S(=O)2R a -、-S(=O)NR a -、-S(=O)2NR a -、-C(=O)R a -、-C(=O)OR a -、-C(=O)NR a -, C1-C6 alkylene, -C1-C6 alkyl-S-, -C1-C6 alkyl-S(=O)-, -C1-C6 alkyl-S(=O)2-, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkyneyl, C1-C6 alkyloxy, C0-C6 alkyl-3-6 membered cycloalkyl-C0-C6 alkyl, C0-C6 alkyl-3-6 membered heterocycloalkyl-C0-C6 alkyl, C0-C6 alkylene-5-8 membered heteroaryl-C0-C6 alkylene, C0-C6 alkylene-6-8 membered aryl-C0-C6 alkylene; wherein the C1-C6 alkylene, -C1-C6 alkylene-S-, -C1-C6 alkylene-S(=O)-, -C1 -C6 alkylene-S(=O)2-, C1-C6 haloalkylene, C2-C6 alkenylene, C2-C6 alkynylene, C1-C6 alkyleneoxy, C0-C6 alkylene-3-6 membered cycloalkyl-C0-C6 alkylene, C0-C6 alkylene-3-6 membered heterocycloalkyl-C0-C6 alkylene, C0-C6 alkylene-5-8 membered heteroaryl-C0-C6 alkylene, C0-C6 alkylene-6-8 membered aryl-C0-C6 alkylene may optionally be substituted by 1, 2, 3, 4, or 5 substituents selected from the following groups: deuterium, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, oxo(=O), 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0018] Ring A is selected from 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, and 5-14 membered heteroaryl;

[0019] R3 is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, and 3-14 membered heterocycloalkyl; wherein the C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, and 3-14 membered heterocycloalkyl are optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following groups: deuterium, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, oxo, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl;

[0020] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9;

[0021] R a R b Each group is independently selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, and 3-14 membered heterocycloalkyl; the C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, and 3-14 membered heterocycloalkyl are optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following groups: deuterium, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, oxo, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl;

[0022] When L is selected from -C(=O)- Not for

[0023] When M is selected from C1-C5 alkyleneoxy groups, and the C1-C5 alkyleneoxy group is optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following groups: C1-C6 alkyl, C1-C6 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, ring B is not a C1-C6 alkyleneoxy group.

[0024] In a preferred embodiment of the present invention, compounds of Formula I, their tautomers, stereoisomers, solvates, pharmaceutically acceptable salts, or prodrugs are provided:

[0025]

[0026] Among them, ring B is selected from 5-14 membered heteroaromatic rings and 5-14 membered heteroene rings;

[0027] The 5-14 membered heteroaromatic ring and the 5-14 membered heteroene ring contain at least one nitrogen atom;

[0028] R1 is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, oxo (=O), C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, -OR a -OC(=O)Ra -NR b C(=O)R a -SR a -S(=O)R a -S(=O)2R a -S(=O)-NR a -、-S(=O)2-NR a -、-C(=O)R a -C(=O)OR a -C(=O)NR a R b The C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, and 3-14 membered heterocycloalkyl are optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following: deuterium, hydroxyl, halogen, C1-C6 alkyl, and C1-C6 alkoxy.

[0029] m is selected from 1, 2, 3, 4, 5, 6;

[0030] L is selected from -C(=O)-, -S(=O)-, -S(=O)2-, -P(=O)-, -P(=O)2-;

[0031] R2 is selected from NR 21 R 22 ;

[0032] R 21 R 22 Each is independently selected from hydrogen, deuterium, hydroxyl, and -SR. a -S(=O)R a -S(=O)2R a C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl are optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following: deuterium, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)NR a R b -OC(=O)R a -NR b C(=O)R a -SR a -S(=O)R a -S(=O)2R a -C(=O)R a -C(=O)OR a -C(=NH)S(=O)2R a;

[0033] Or, R 21 R 22 The N atom attached thereto forms a 4-8 membered heterocyclic alkyl group or a 5-8 membered heteroaryl group; the 4-8 membered heterocyclic alkyl group or the 5-8 membered heteroaryl group is optionally substituted by 1, 2, 3, 4 or 5 substituents selected from the following: deuterium, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy;

[0034] M is selected from the bond, -O-, -S(=O)R a -、-S(=O)2R a -、-S(=O)NR a -、-S(=O)2NR a -、-C(=O)R a -、-C(=O)OR a -、-C(=O)NR a -, C1-C6 alkylene, -C1-C6 alkyl-S-, -C1-C6 alkyl-S(=O)-, -C1-C6 alkyl-S(=O)2-, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkyneyl, C1-C6 alkyloxy, C0-C6 alkyl-3-6 membered cycloalkyl-C0-C6 alkyl, C0-C6 alkyl-3-6 membered heterocycloalkyl-C0-C6 alkyl, C0-C6 alkylene-5-8 membered heteroaryl-C0-C6 alkylene, C0-C6 alkylene-6-8 membered aryl-C0-C6 alkylene; wherein the C1-C6 alkylene, -C1-C6 alkylene-S-, -C1-C6 alkylene-S(=O)-, -C1 -C6 alkylene-S(=O)2-, C1-C6 haloalkylene, C2-C6 alkenylene, C2-C6 alkynylene, C1-C6 alkyleneoxy, C0-C6 alkylene-3-6 membered cycloalkyl-C0-C6 alkylene, C0-C6 alkylene-3-6 membered heterocycloalkyl-C0-C6 alkylene, C0-C6 alkylene-5-8 membered heteroaryl-C0-C6 alkylene, C0-C6 alkylene-6-8 membered aryl-C0-C6 alkylene may optionally be substituted by 1, 2, 3, 4, or 5 substituents selected from the following groups: deuterium, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, oxo(=O), 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0035] Ring A is selected from 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, and 5-14 membered heteroaryl;

[0036] R3 is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, and 3-14 membered heterocycloalkyl; wherein the C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, and 3-14 membered heterocycloalkyl are optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following groups: deuterium, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, oxo, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl;

[0037] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9;

[0038] R a R b Each group is independently selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, and 3-14 membered heterocycloalkyl; the C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, and 3-14 membered heterocycloalkyl are optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following groups: deuterium, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, oxo, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl;

[0039] When M is selected from C1-C5 alkyleneoxy groups, and the C1-C5 alkyleneoxy group is optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following groups: C1-C6 alkyl, C1-C6 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, ring B is not a C1-C6 alkyleneoxy group.

[0040] In a preferred embodiment of the present invention, compounds of Formula I, their tautomers, stereoisomers, solvates, pharmaceutically acceptable salts, or prodrugs are provided:

[0041]

[0042] Among them, ring B is selected from 5-14 membered heteroaromatic rings and 5-14 membered heteroene rings;

[0043] The 5-14 membered heteroaromatic ring and the 5-14 membered heteroene ring contain at least one nitrogen atom;

[0044] R1 is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, oxo (=O), C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, -OR a -OC(=O)R a -NR b C(=O)R a -SR a-S(=O)R a -S(=O)2R a -S(=O)-NR a -、-S(=O)2-NR a -、-C(=O)R a -C(=O)OR a -C(=O)NR a R b The C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, and 3-14 membered heterocycloalkyl are optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following: hydroxyl, halogen, C1-C6 alkyl, and C1-C6 alkoxy.

[0045] m is selected from 1, 2, 3, 4, 5, 6;

[0046] L is selected from -C(=O)-, -S(=O)-, -S(=O)2-, -P(=O)-, -P(=O)2-;

[0047] R2 is selected from NR 21 R 22 ;

[0048] R 21 R 22 Each is independently selected from hydrogen, hydroxyl, and -SR a -S(=O)R a -S(=O)2R a C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl are optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following: hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)NR a R b -OC(=O)R a -NR b C(=O)R a -SR a -S(=O)R a -S(=O)2R a -C(=O)R a -C(=O)OR a -C(=NH)S(=O)2R a ;

[0049] Or, R 21 R 22The N atom attached thereto forms a 4-8 membered heterocyclic alkyl group or a 5-8 membered heteroaryl group; the 4-8 membered heterocyclic alkyl group or the 5-8 membered heteroaryl group is optionally substituted by 1, 2, 3, 4 or 5 substituents selected from the following: hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy;

[0050] M is selected from the bond, -O-, -S(=O)R a -、-S(=O)2R a -、-S(=O)NR a -、-S(=O)2NR a -、-C(=O)R a -、-C(=O)OR a -、-C(=O)NR a -, C1-C6 alkylene, -C1-C6 alkyl-S-, -C1-C6 alkyl-S(=O)-, -C1-C6 alkyl-S(=O)2-, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyloxy, C0-C6 alkyl-3-6 membered cycloalkyl-C0-C6 alkyl, C0-C6 alkyl-3-6 membered heterocycloalkyl-C0-C6 alkyl, C0-C6 alkylene-5-8 membered heteroaryl-C0-C6 alkylene, C0-C6 alkylene-6-8 membered aryl-C0-C6 alkylene; wherein the C1-C6 alkylene, -C1-C6 alkylene-S-, -C1-C6 alkylene-S(=O)-, -C 1-C6 alkylene-S(=O)2-, C1-C6 haloalkylene, C2-C6 alkenylene, C2-C6 alkynylene, C1-C6 alkyleneoxy, C0-C6 alkylene-3-6 membered cycloalkyl-C0-C6 alkylene, C0-C6 alkylene-3-6 membered heterocycloalkyl-C0-C6 alkylene, C0-C6 alkylene-5-8 membered heteroaryl-C0-C6 alkylene, C0-C6 alkylene-6-8 membered aryl-C0-C6 alkylene may optionally be substituted by 1, 2, 3, 4, or 5 substituents selected from the following groups: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, oxo(=O), 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;

[0051] Ring A is selected from 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, and 5-14 membered heteroaryl;

[0052] R3 is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, and 3-14 membered heterocycloalkyl; wherein the C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, and 3-14 membered heterocycloalkyl are optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following groups: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, oxo, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl;

[0053] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9;

[0054] R a R b Each is independently selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, and 3-14 membered heterocycloalkyl;

[0055] The C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, and 3-14 membered heterocycloalkyl are optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following groups: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, oxo, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl.

[0056] When M is selected from C1-C5 alkyleneoxy groups, and the C1-C5 alkyleneoxy group is optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following groups: C1-C6 alkyl, C1-C6 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, ring B is not a C1-C6 alkyleneoxy group.

[0057] In a preferred embodiment of the present invention, the Selected from 3-14 membered heterocyclic alkyl groups, 6-10 membered aryl groups, and 5-10 membered heteroaryl groups substituted with n R3s.

[0058] In a preferred embodiment of the present invention, the 3-14 membered heterocyclic alkyl and 6-10 membered heteroaryl groups in ring A are selected from 3-14 membered heterocyclic alkyl monocyclic rings, 7-14 membered heterocyclic alkyl bicyclic rings, 6-10 membered heteroaryl monocyclic rings, and 8-10 membered heteroaryl bicyclic rings containing 1, 2, 3, or 4 heteroatoms, and the heteroatoms are selected from N, O, and S.

[0059] In a preferred embodiment of the present invention, ring A is selected from furan, pyrrole, thiophene, oxazole, oxadiazole, thiazole, thiadiazole, pyrazole, imidazole, triazole, tetrazolium, pyridine, pyrimidine, pyridazine, triazine, dihydropyrrole, dihydropyrazole, dihydroimidazolium, dihydrotriazole, dihydrotetrazolium, dihydrotriazolyl, dihydrotetrazolyl, tetrahydropyridyl, dihydropyridyl, tetrahydropyrazinyl, dihydropyrazinyl, tetrahydropyrimidinyl, dihydropyrimidinyl, tetrahydropyrrole, tetrahydropyrazole, tetrahydroimidazolium, piperidine, piperazine, hexahydropyridazine, hexahydropyrimidine, benzocyclopentyl, benzocyclohexyl, tetrahydroquinoline, tetrahydroisoquinoline, quinoline, isoquinoline, dihydrochromene, dihydroisochromene, indole, benzofuran, pyridofuran, dihydrofuranopyridine, benzene ring, indene, and naphthalene.

[0060] In a preferred embodiment of the present invention, ring A is selected from pyridine, pyrimidine, pyridazine, pyrazine, thiadiazole, benzene, benzocyclopentyl, benzocyclohexyl, tetrahydroquinoline, and tetrahydroisoquinoline.

[0061] In a preferred embodiment of the present invention, R3 is selected from deuterium, hydrogen, halogen, C1-C6 alkyl, and C1-C6 alkoxy; the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following groups: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, oxo, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl.

[0062] In a preferred embodiment of the present invention, R3 is selected from halogens, C1-C6 alkyl groups, and C1-C6 haloalkyl groups.

[0063] In a preferred embodiment of the present invention, R3 is selected from C1-C3 alkyl and C1-C3 haloalkyl.

[0064] In a preferred embodiment of the present invention, R3 is selected from -CF3, -CHF2, and -CH2F.

[0065] In a preferred embodiment of the present invention, R4 is selected from deuterium, hydrogen, halogen, C1-C6 alkyl, and C1-C6 alkoxy; the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following groups: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, oxo, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl.

[0066] In a preferred embodiment of the present invention, R4 is selected from halogens, C1-C6 alkyl groups, and C1-C6 haloalkyl groups.

[0067] In a preferred embodiment of the present invention, R4 is selected from C1-C3 alkyl and C1-C3 haloalkyl.

[0068] In a preferred embodiment of the present invention, R4 is selected from -CF3, -CHF2, and -CH2F.

[0069] In a preferred embodiment of the present invention, n is selected from 0, 1, 2, and 3.

[0070] In a preferred embodiment of the present invention, n is selected from 1.

[0071] In a preferred embodiment of the present invention, the Selected from

[0072] In a preferred embodiment of the present invention, M is a bond, -O-, or -S(=O)2R. a -、-S(=O)2NR a -、-C(=O)NR a -、-C1-C6 alkylene-S-、-C1-C6 alkylene-S(=O)2-、C1-C6 alkylene、C1-C6 haloalkylene、C1-C6 alkyleneoxy、C2-C6 alkenyl、C0-C6 alkylene-3-6 membered cycloalkyl-C0-C6 alkylene、C0-C6 alkylene-3-6 membered heterocycloalkyl-C0-C6 alkylene、C0-C6 alkylene-5-8 membered heteroaryl-C0-C6 alkylene

[0073] In a preferred embodiment of the present invention, M is selected from bond, -O-, -S(=O)2NR a -、-C(=O)NR a -、-C1-C3 alkylene-S-、-C1-C3 alkylene-S(=O)2-、C1-C3 alkylene、C1-C3 haloalkylene、C1-C3 alkyleneoxy、C2-C4 alkenyl、C0-C3 alkylene-3-6 membered cycloalkyl-C0-C3 alkylene、C0-C3 alkylene-3-6 membered heterocycloalkyl-C0-C3 alkylene、C0-C3 alkylene-5-8 membered heteroaryl.

[0074] In a preferred embodiment of the present invention, the 5-8 member heteroaryl group in M ​​contains 1, 2, or 3 identical or different heteroatoms; the heteroatoms are selected from N, O, and S.

[0075] In a preferred embodiment of the present invention, M is selected from the following: -O-, -S(=O)2NH-, -C(=O)NH-, -CH2-S-, -CH2-S(=O)2-, methylene, ethylene, propylene, isopropylene, -CF2-, -CHF-, -CH2CHF-, -CH2CF2-, -CH2-O-, ethylene, propylene, CO-C3 alkylene-3-5 membered cycloalkyl-CO-C3 alkylene, CO-C3 alkylene-3-5 membered heterocycloalkyl-CO-C3 alkylene, CO -C6 alkylene-furan, C0-C6 alkylene-pyrrole, C0-C6 alkylene-thiophene, C0-C6 alkylene-oxazole, C0-C6 alkylene-oxadiazole, C0-C6 alkylene-thiazole, C0-C6 alkylene-thiadiazole, C0-C6 alkylene-pyrazole, C0-C6 alkylene-imidazolium, C0-C6 alkylene-triazole, C0-C6 alkylene-tetrazole, C0-C6 alkylene-pyridine, C0-C6 alkylene-pyrimidine, C0-C6 alkylene-pyridazine, C0-C6 alkylene-triazine.

[0076] In a preferred embodiment of the present invention, the 3-6 membered cycloalkyl group in M ​​is selected from cyclopropyl, butyl, cyclopentyl, and cyclohexyl.

[0077] In a preferred embodiment of the present invention, the 3-6 membered heterocyclic alkyl group in M ​​contains 1, 2, or 3 identical or different heteroatoms; the heteroatoms are selected from N, O, and S.

[0078] In a preferred embodiment of the present invention, the 3-6 membered heterocyclic alkyl group in M ​​is selected from oxetyl, oxetyl, oxetylpentyl, azirmetyl, and azirmetyl.

[0079] In a preferred embodiment of the present invention, M is selected from the following: -O-, -S(=O)2NH-, -C(=O)NH-, -CH2-S-, -CH2-S(=O)2-, methylene, ethylene, -CH2CH2CH2-, -CH(CH3)-CH2-, -CH2CF2-, -CH=CH-, -CH2-O-. Pyridine, methylene-pyridine.

[0080] In a preferred embodiment of the present invention, M is selected from -CH2-O-, methylene, ethylene, ...

[0081] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0082]

[0083] M is selected from C1-C6 alkylene, C1-C6 haloalkylene, and C1-C6 alkyleneoxy;

[0084] The rings B, R1, R2, R3, L, m, and n are defined as described in the first aspect of this invention.

[0085] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0086]

[0087] M is selected from C1-C6 alkylene, C1-C6 haloalkylene, and C1-C6 alkyleneoxy;

[0088] The definitions of rings B, R1, R3, m, and n are as described in the first aspect of this invention.

[0089] In a preferred embodiment of the present invention, the ring B is selected from 5-10 membered heteroaromatic rings and 5-10 membered heteroenes, and the ring B contains at least one N atom.

[0090] In a preferred embodiment of the present invention, the ring B is selected from pyrrole, oxazole, oxadiazole, thiazole, thiadiazole, pyrazole, imidazole, triazole, tetrazolium, pyridine, pyrimidine, pyridazine, triazine, dihydrofuranopyridine, dihydropyrrolopyridine, indole, quinoline, isoquinoline, dihydroquinoline, dihydroisoquinoline, pyrrolopyridazine, imidazopyridine, benzoxazole, benzoisoxazole, benzothiazole, benzothiadiazole, and benzoimidazole.

[0091] In a preferred embodiment of the present invention, the ring B is selected from pyrrole, oxazole, oxadiazole, thiazole, thiadiazole, pyrazole, imidazole, triazole, tetrazolium, pyridine, pyrimidine, pyridazine, triazine, dihydrofuranopyridine, dihydropyrrolopyridine, indole, quinoline, isoquinoline, dihydroquinoline, dihydroisoquinoline, pyrrolopyridazine, and imidazopyridine.

[0092] In a preferred embodiment of the present invention, the ring B is selected from quinoline, pyrrolopyridazine, imidazopyridine, dihydropyrrolopyridine, benzoxazole, and benzoisoxazole.

[0093] In a preferred embodiment of the present invention, the ring B is selected from quinoline, pyrrolopyridazine, imidazopyridine, and dihydropyrrolopyridine.

[0094] In a preferred embodiment of the present invention, ring B is selected from...

[0095] In a preferred embodiment of the present invention, ring B is selected from...

[0096] In a preferred embodiment of the present invention, when M is selected from C1-C5 alkyleneoxy groups, and the C1-C5 alkyleneoxy group is optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following groups: C1-C6 alkyl, C1-C6 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, ring B is not...

[0097] In a preferred embodiment of the present invention, when L is selected from -C (=O)-, Not for

[0098] In a preferred embodiment of the present invention, R1 is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, oxo (=O), C1-C6 alkyl, and C1-C6 alkoxy.

[0099] The C1-C6 alkyl and C1-C6 alkoxy groups are optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following: hydroxyl, halogen, and C1-C6 alkyl.

[0100] In a preferred embodiment of the present invention, R1 is selected from deuterium, hydrogen, halogen, oxo (=O), C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy.

[0101] In a preferred embodiment of the present invention, R1 is selected from hydrogen, methyl, ethyl, oxo (=O), -CF3, -CHF2, and -CH2F.

[0102] In a preferred embodiment of the present invention for

[0103] In a preferred embodiment of the present invention, the Selected from

[0104] In a preferred embodiment of the present invention, m is selected from 1, 2, 3, 4, 5, and 6.

[0105] In a preferred embodiment of the present invention, m is selected from 1, 2, and 3.

[0106] In a preferred embodiment of the present invention, L-R2 is selected from L-NR. 21 R 22 ;

[0107] The R 21 R 22 Each is independently selected from hydrogen, hydroxyl group, and -S(=O)2R aC1-C6 alkyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-8 membered aryl, 5-8 membered heteroaryl;

[0108] The C1-C6 alkyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-8 membered aryl, and 5-8 membered heteroaryl groups are optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following: hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)NR a R b -NR b C(=O)R a -S(=O)2R a -C(=NH)S(=O)2R a .

[0109] In a preferred embodiment of the present invention, the R 21 R 22 It forms 4-8 membered heterocyclic alkyl groups and 5-8 membered heteroaryl groups with the attached N atom.

[0110] In a preferred embodiment of the present invention, the R 21 R 22 Each is independently selected from hydrogen, hydroxyl, and C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents selected from the following: hydroxyl, halogen, C1-C6 alkyl, -C(=O)NR. a R b -C(=NH)S(=O)2R a .

[0111] In a preferred embodiment of the present invention, L is selected from -C(=O)- and -S(=O)2-.

[0112] In a preferred embodiment of the present invention, the L-R2 is selected from -C(=O)-NHR. 22 -S(=O)2-NHR 22 The R 22 Selected from C1-C6 alkyl groups, wherein the C1-C6 alkyl group is optionally substituted by 1, 2, or 3 substituents selected from the following: hydroxyl, halogen, C1-C3 alkyl, -C(=O)NR a R b -C(=NH)S(=O)2R a .

[0113] In a preferred embodiment of the present invention, the L-R2 is selected from -C(=O)-NHR. 22 -S(=O)2-NHR 22 The R 22The alkyl group is selected from C1-C6 alkyl groups, which are optionally substituted by 1, 2, or 3 substituents selected from the following: hydroxyl, -C(=O)NH2, -C(=NH)S(=O)2CH3.

[0114] In a preferred embodiment of the present invention, L-R2 is selected from...

[0115] In a preferred embodiment of the present invention, L-R2 is selected from...

[0116] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0117]

[0118] The rings B, R1, R3, M, m, and n are defined as described in the first aspect.

[0119] In a preferred embodiment of the present invention, the compound is selected from the following structures:

[0120]

[0121] The rings B, R1, R3, m, and n are defined as described in the first aspect.

[0122] In a preferred embodiment of the present invention, compound III-1 has a structure III-1a or III-1b:

[0123]

[0124] In a preferred embodiment of the present invention, the compound represented by Formula I, its tautomers, stereoisomers, solvates, pharmaceutically acceptable salts, or prodrugs are characterized in that the compound comprises:

[0125]

[0126] In a preferred embodiment of the present invention, the compound represented by Formula I, its tautomers, stereoisomers, solvates, pharmaceutically acceptable salts, or prodrugs are characterized in that the compound comprises:

[0127]

[0128]

[0129] In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula I as described in the first aspect, a tautomer, a stereoisomer, a solvate, a pharmaceutically acceptable salt or a prodrug thereon, and a pharmaceutically acceptable carrier.

[0130] A third aspect of the invention relates to the use of compounds of formula I as described in the first aspect, their tautomers, stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions as described in the second aspect, said use comprising:

[0131] As a TRPM3 antagonist;

[0132] And / or, to prevent and / or treat TRPM3-mediated diseases;

[0133] And / or, to prepare a drug, pharmaceutical composition or formulation as a TRPM3 antagonist.

[0134] A third aspect of the invention relates to the use of compounds of formula I as described in the first aspect, their tautomers, stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions as described in the second aspect, said use comprising:

[0135] As a TRPM3 antagonist;

[0136] And / or, to prevent and / or treat TRPM3-mediated diseases;

[0137] And / or, to prepare a drug, pharmaceutical composition or formulation as a TRPM3 antagonist;

[0138] And / or, drugs, pharmaceutical compositions or preparations for the prevention and / or treatment of diseases in which TRPM3 is expressed and which are desired or necessary to be inhibited.

[0139] The compound of Formula I as described in the first aspect, its tautomers, stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition described in the second aspect are intended for use in the treatment of pain or epilepsy.

[0140] The types of pain that should be mentioned include nociceptive pain, inflammatory pain, neuropathic pain, and chronic pain.

[0141] The compounds of Formula I, tautomers, stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions of the second aspect of the present invention are suitable for the treatment and / or preventive treatment of the aforementioned diseases.

[0142] A fourth aspect of the invention provides a method for treating a disease, the disease being a TRPM3-mediated disease, the method comprising using a therapeutically effective amount of a compound of formula I of the first aspect of the invention, its tautomers, stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs, or a pharmaceutical composition of the second aspect, on a person who has or is susceptible to the disease.

[0143] A fourth aspect of the invention provides a method for treating a disease, the disease being a TRPM3-mediated disease, and / or a disease in which TRPM3 expression and inhibition are desired or necessary, the method comprising using a therapeutically effective amount of a compound of formula I of the first aspect of the invention, its tautomers, stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs, or a pharmaceutical composition of the second aspect, on a person suffering from or susceptible to said disease.

[0144] Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.

[0145] Terms and Definitions

[0146] Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures shall fall within the scope of this application specification.

[0147] Unless otherwise defined, all technical terms in this document have the same meanings as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent applications, and publications cited in this document are incorporated herein by reference in their entirety. If multiple definitions exist for terms in this document, the definitions in this chapter shall prevail.

[0148] It should be understood that the above brief description and the following detailed description are exemplary and for illustrative purposes only, and do not limit the subject matter of the invention in any way. In this application, unless specifically stated otherwise, the singular is used to include the plural. It must be noted that unless clearly stated otherwise, the singular form used in this specification and claims includes the plural form of the referred to. It should also be noted that unless otherwise stated, the use of “or” or “or” means “and / or”. Furthermore, the use of the term “comprising” and other forms such as “including,” “containing,” and “contains” are not limiting.

[0149] Definitions of standard chemical terms can be found in the references (including Carey and Sundberg, "Advanced Organic Chemistry 4th Edition," Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise stated, conventional methods within the scope of the art, such as mass spectrometry, NMR, IR, UV / VIS spectroscopy, and pharmacological methods, are used. Unless specifically defined, the terminology used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry is known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and in the treatment of patients. For example, reactions and purifications can be carried out using the manufacturer's instructions for use of kits, or in accordance with methods known in the art or the description of this invention. The techniques and methods described above can generally be carried out according to conventional methods well known in the art, based on the descriptions in the various summary and more specific references cited and discussed in this specification. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0150] When a substituent is described using a conventional chemical formula written from left to right, that substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2. As used herein, Indicates the linking site of a group. As used herein, "R1", "R1", and "R" indicate the linking site of the group. 1 The meanings of "" are the same and they can be used interchangeably. The same definition applies to other symbols such as R2.

[0151] The chapter headings used in this document are for organizational purposes only and should not be construed as limiting the subject matter. All references or portions thereof cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are incorporated herein by reference in their entirety.

[0152] Except as otherwise specified, when used in the specification and claims of this application, the following terms shall have the following meanings.

[0153] The numerical ranges described in this application specification and claims, when interpreted as "integers," should be understood to include the two endpoints of the range and every integer within that range. For example, "integers from 1 to 6" should be understood to include every integer of 0, 1, 2, 3, 4, 5, and 6.

[0154] In this application, when specifying the number of substituents, the term "one or more" means from one substitution to the maximum possible number of substitutions, i.e., from substituting one hydrogen to substituting all hydrogens. When specifying the number of substituents, the term "1 to 4" means 1, 2, 3, or 4 substitutions, i.e., 1, 2, 3, or 4 hydrogens are substituted by substituents.

[0155] In this application, "saturated, partially saturated or unsaturated" includes substituents saturated with hydrogen, substituents that are completely unsaturated with hydrogen, and substituents that are partially saturated with hydrogen.

[0156] In this application, the term "halogen" refers to fluorine, chlorine, bromine, or iodine, either alone or as part of other substituents.

[0157] In this application, the term "amino" means -NH2, either alone or as part of other substituents.

[0158] In this application, the term "hydroxyl" means -OH, either alone or as part of other substituents.

[0159] In this application, the term "cyano" means -CN, either alone or as part of other substituents.

[0160] In this application, the term "alkyl" as alone or as part of other substituents means a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 6 carbon atoms, and connected to the rest of the molecule by single bonds. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl. Alkyl groups may be unsubstituted or substituted with one or more suitable substituents. Alkyl groups may also be isotopic isomers of naturally abundant alkyl groups rich in carbon and / or hydrogen isotopes (i.e., deuterium or tritium). As used herein, the term "alkenyl" refers to a straight or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds. "Alkenyl" or "alkenylene" is intended to include hydrocarbon chains with straight or branched configurations and having one or more carbon-carbon double bonds that may occur at any stable point along the chain. For example, "C2-C6 alkenyl" (or C2-C6 alkenylene) is intended to include alkenyl groups with 2, 3, 4, 5, or 6 carbons. Examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, etc. Examples of alkenyl groups include, but are not limited to, vinylene, 1-propenylene, 2-propenylene, 2-butenylene, 3-butenylene, 2-pentenylene, 3-pentenylene, 4-pentenylene, 2-hexenylene, 3-hexenylene, 4-hexenylene, 5-hexenylene, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, etc.

[0161] In this application, the term "alkynyl" refers to a straight or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds, either alone or as part of other substituents. "Alynyl" or "acetylenyl" is intended to include hydrocarbon chains with a straight or branched configuration and having one or more carbon-carbon triple bonds that can occur at any stable point along the chain. For example, "C2-C6 alkynyl" (or C2-C6 acetylenyl) is intended to include alkynyl groups with 2, 3, 4, 5, or 6 carbons; such as ethynyl, propynyl, butynyl, pentylenyl, hexynyl, etc. Examples of acetylenyl groups include, but are not limited to, ethynylene, propynylene, butynylene, pentylenyl, hexynyl, etc.

[0162] To avoid ambiguity, alkyl, alkenyl and alkynyl groups as described herein may also be used as linking groups (i.e., groups that link two or more parts of a compound as described), in which case such groups may be referred to as "alkylene", "alkenyl" and / or "alkynyl", respectively.

[0163] In this application, the term "C1-C6 alkyl" shall be understood, either alone or as part of other substituents, to mean a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or isomers thereof. In particular, the group has 1, 2 or 3 carbon atoms (“C1-C3 alkyl”), such as methyl, ethyl, n-propyl or isopropyl.

[0164] In this application, the term "alkylene" should be understood to mean a straight-chain divalent hydrocarbon group having 1-6 carbon atoms or a branched divalent hydrocarbon group having 3-6 carbon atoms, unless otherwise specified, such as methylene, ethylene, propylene, isopropylene, 1-methylpropylene, butylene, etc.

[0165] In this application, the term "C1-C6 alkoxy" should be understood, either alone or as part of other substituents, to represent a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms and an oxygen atom, or to represent a C1-C6 alkyl-O-C1-C6 alkyl group as defined in this specification, wherein the oxygen atom may be attached to any carbon atom of the straight-chain or branched C1-C6 alkyl group. This includes, but is not limited to: methoxy (CH3-O-), ethoxy (C2H5-O-), propoxy (C3H7-O-), butoxy (C4H9-O-), and ethyloxymethyl (C2H5-O-CH3).

[0166] In this application, the term "C1-C6 alkylene oxide" should be understood to mean a straight-chain divalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms, or a branched divalent hydrocarbon group having 3-6 carbon atoms, and an oxygen atom, wherein the oxygen atom may be attached to any carbon atom of the straight-chain or branched C1-C6 alkylene oxide. This includes, but is not limited to: methyleneoxy (-CH2-O-), ethyleneoxy (-C2H4-O-), propyleneoxy (-C3H6-O-), butyloxy (-C4H8-O-), and ethyleneoxymethylene (-C2H4-O-CH2-). The term "C0-C6 alkylene oxide" is understood to mean the absence of an alkylene oxide or a straight-chain divalent hydrocarbon group with 1, 2, 3, 4, 5, or 6 carbon atoms, or a branched divalent hydrocarbon group with 3-6 carbon atoms and an oxygen atom, wherein the oxygen atom may be attached to any carbon atom of the straight-chain or branched C1-C6 alkylene oxide. The term "C0-C3 alkylene oxide" is understood to mean the absence of an alkylene oxide or a straight-chain divalent hydrocarbon group with 1, 2, or 3 carbon atoms, or a branched divalent hydrocarbon group with 3 carbon atoms and an oxygen atom, wherein the oxygen atom may be attached to any carbon atom of the straight-chain or branched C1-C3 alkylene oxide. This includes, but is not limited to: methyleneoxy (-CH2-O-), ethylideneoxy (-C2H4-O-), propylideneoxy (-C3H6-O-), and ethylideneoxymethylene (-C2H4-O-CH2-).

[0167] In this application, "haloalkoxy" refers to an alkoxy group as described above, either alone or as part of other substituents, wherein any number (at least one) of the hydrogen atoms attached to the alkoxy group are replaced by fluorine, chlorine, bromine or iodine.

[0168] In this application, the term "oxo" refers to the substitution of two hydrogens on the methylene group by oxygen, either alone or as part of other substituents, that is, the methylene group is replaced by a carbonyl group, denoted as =O.

[0169] In this application, "haloalkyl" refers to a saturated aliphatic hydrocarbon group (such as -CvFw, where v = 1 to 3 and w = 1 to (2v+1)) that comprises a specific number of carbon atoms and is branched and straight-chained and substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.

[0170] In this application, the term "aryl" or "aromatic ring," whether alone or as part of other substituents, refers to a monocyclic or polycyclic carbon ring having 6 to 20 carbon atoms, wherein at least one ring is an aromatic ring. When one of the rings is a non-aromatic ring, the group may be linked by an aromatic ring or by a non-aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydroindenyl, biphenyl, phenanthryl, anthracene, and acenaphthene.

[0171] In this application, the term "6-14-membered aromatic ring" or "6-14-membered aryl" refers to a monocyclic or polycyclic carbon ring having 6 to 14 carbon atoms, wherein at least one ring is an aromatic ring. The polycyclic carbon ring can be bicyclic or tricyclic, wherein the bicyclic ring can be spirocyclic, fused, or fused. When one of the rings is a non-aromatic ring, the group can be linked by an aromatic ring or by a non-aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydroindenyl, biphenyl, phenanthryl, anthracene, and acenaphthene.

[0172] In this application, the term "heteroaromatic ring," whether alone or as part of other substituents, refers to a monocyclic or polycyclic carbon ring, wherein at least one ring atom is a heteroatom independently selected from N, O, S, and P, and the remaining ring atoms are C, wherein at least one ring is an aromatic ring. The group can be a carbon group or a heteroatom group (i.e., it can be C-linked or N-linked, whichever is possible). When one of the rings is a non-aromatic ring, the group can be linked by an aromatic ring or by a non-aromatic ring. Examples of heteroaromatic groups include, but are not limited to: imidazolyl, acridinel, carbazolyl, cenolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thiophenyl, benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridinyl, pyrimidinel, pyrroleyl, N-methylpyrroleyl, and tetrahydroquinoline. The term “heteroaromatic ring” can be used interchangeably with the terms “heteroaromatic ring”, “heteroaryl”, or “heteroaromatic ring group”.

[0173] In this application, the term "5-14 membered heteroaryl ring" is used interchangeably with "5-14 membered heteroaryl ring" when used alone or as part of other substituents, and should be understood as an aromatic cyclic group having 5-14 ring atoms and containing 1-5 heteroatoms independently selected from N, O, S, and P. The term "5-8 membered heteroaryl ring" should be understood as an aromatic cyclic group having 5, 6, 7, or 8 ring atoms—and containing 1-3—heteroatoms independently selected from N, O, S, and P. In particular, the heteroaryl group is selected from thiophene, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyridinyl, pyrazinyl.

[0174] In this application, the term "5-14 membered heterocyclic ring" refers to a monocyclic or bicyclic ring having 5-14 ring atoms and containing 1-5 heteroatoms independently selected from N, O, S, and P, possessing double bonds but not aromaticity. Preferably, it is a monocyclic ring containing 1, 2, or 3 heteroatoms independently selected from N, O, S, and P. Examples of heterocyclic alkenyl groups include: dihydrofuranyl, dihydrothiopheneyl, dihydropyrroleyl, dioxacyclopentenyl, dihydroimidazolyl, dihydropyrazolyl, dihydrothiazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrothiadiazolyl, dihydrotriazolyl, dihydrotetraazolyl, tetrahydropyridyl, 3,4-dihydro-2H-pyran, pyranyl, thiaranyl, dihydropyridyl, dihydropyrazinyl, dihydropyrimidinyl, oxazinyl, dihydrotetraazolyl, etc. The term "heterocyclic olefin" can be used interchangeably with the term "heterocyclic alkenyl".

[0175] In this application, the term "heterocyclic alkyl" refers to a saturated cycloalkyl group in which one or more (in some embodiments, 1 to 3) carbon atoms are replaced by heteroatoms, such as, but not limited to, N, O, S, and P. "Heterocyclic alkyl" can also contain 1, 2, or 3 rings, including bridged and spirocyclic structures. The terms "3-14 membered heterocyclic group" or "3-14 membered heterocyclic alkyl" should be understood to mean a monocyclic, bicyclic, or tricyclic group having 3 to 14 atoms, wherein the heteroatoms are preferably N, O, and S. It should be understood that when the total number of S and O atoms in the heterocyclic group exceeds 1, these heteroatoms are not adjacent to each other. Examples of heterocyclic alkyl groups include, but are not limited to, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyranyl, tetrahydrofuranyl, and tetrahydrothiaranyl.

[0176] In this application, the term "cycloalkyl" or "carbocycloalkyl" refers to a cyclic alkyl group, either alone or as part of other substituents. The terms "mn-membered cycloalkyl" or "C" refer to a cyclic alkyl group. m -C n "Cycloalkyl" should be understood to mean a saturated carbon ring having m to n atoms. For example, "3-14 membered cycloalkyl" refers to a cyclic alkyl group containing 3 to 14, 3 to 10, 3 to 6, or 3 to 5 carbon atoms, which may contain 1 to 4 rings. "5-8 membered cycloalkyl" contains 5 to 8 carbon atoms. It includes monocyclic, bicyclic, tricyclic, spirocyclic, or bridged rings. Examples of unsubstituted cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl, or bicyclic hydrocarbon groups such as decahydronaphthalene. Cycloalkyl groups may be substituted by one or more substituents. In some embodiments, the cycloalkyl group may be a cycloalkyl group fused with an aryl or heteroaryl group. The term "3-6 membered cycloalkyl" should be understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic systems. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0177] In this application, "halocycloalkyl" refers to a cycloalkyl group as described above, wherein any number (at least one) of the hydrogen atoms attached to the cycloalkyl group are replaced by fluorine, chlorine, bromine or iodine.

[0178] In this application, the term "monocyclic" means, either alone or as part of other substituents, a group that can be saturated, unsaturated or partially saturated and has only one ring, and can be a carbocyclic (all ring atoms are carbon atoms) or a heterocyclic (in addition to carbon atoms, the ring atoms include, for example, 1, 2 or 3 heteroatoms, such as N, O or S).

[0179] In this application, the term "bicyclic" refers to a group having two connecting rings, either alone or as part of other substituents. A bicyclic ring can be a carbocyclic ring (all ring atoms are carbon atoms) or a heterocyclic ring (in addition to carbon atoms, the ring atoms include, for example, one, two, or three heteroatoms, such as N, O, or S). Both rings can be aliphatic (e.g., naphthane and norbornane), or aromatic (e.g., naphthalene), or a combination of aliphatic and aromatic (e.g., tetrahydronaphthalene). Bicyclic rings include fused bicyclic compounds in which the two rings share two adjacent atoms. In other words, the rings share a covalent bond, i.e., the bridgehead atoms are directly connected (e.g., α-thuenene and naphthane). Examples of fused bicyclic rings include, but are not limited to:

[0180]

[0181] The compounds described herein include intermediates that can be used to prepare the compounds described herein, containing reactive functional groups (e.g., but not limited to carboxyl, hydroxyl, and amino moieties), and also their protected derivatives. A “protected derivative” is a compound in which one or more reactive sites are blocked by one or more protecting groups (also called protecting groups). Suitable carboxyl moieties include benzyl, tert-butyl, etc., and isotopes, etc. Suitable amino and amide protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl, benzyloxycarbonyl, etc. Suitable hydroxyl protecting groups include benzyl, etc. Other suitable protecting groups are well known to those skilled in the art.

[0182] In this application, the term "substituted" means that any one or more hydrogen atoms on a particular atom are substituted by a substituent, including deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable.

[0183] In this application, the terms "optional" or "optionally" mean that the event or condition described below may or may not occur, and the description includes both the occurrence and non-occurrence of the event or condition. For example, "optionally substituted aryl" means that the aryl group is substituted or not substituted, and the description includes both substituted and unsubstituted aryl groups.

[0184] In this application, the terms "optionally substituted with..." or "optionally substituted with..." mean that the specified group is unsubstituted or substituted with one or more substituents selected independently from the possible substituents. For example, "aryl group is optionally substituted with 1 to 4 substituents selected independently from the following groups: halogen, cyano, hydroxyl, C..." 1-6 "alkyl" indicates that the aryl group is either unsubstituted or substituted by 1, 2, 3, or 4 independent substituents selected from the following groups: halogen, cyano, hydroxyl, C 1-6 Alkyl groups, and the description includes both substituted and unsubstituted aryl groups.

[0185] In this application, the term "salt" or "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that, to the extent of reliable medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0186] In this application, the term "pharmaceutically acceptable acid addition salt" refers to a salt formed with an inorganic or organic acid that retains the bioavailability of the free base without other side effects. "Pharmaceutically acceptable base addition salt" refers to a salt formed with an inorganic or organic base that retains the bioavailability of the free acid without other side effects. Besides pharmaceutically acceptable salts, other salts are also contemplated in this invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts, or may be used for the identification, characterization, or purification of the compounds of this invention.

[0187] In this application, the term "amine salt" refers to the product obtained by neutralizing an alkyl primary amine, secondary amine, or tertiary amine with an acid. The acid includes the inorganic or organic acids described in this application.

[0188] In this application, the term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, non-corresponding isomers, and conformational isomers.

[0189] Depending on the choice of raw materials and methods, the compounds of the present invention can exist as one or a mixture of possible isomers, for example as purely optical isomers, or as mixtures of isomers, such as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral centers (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are symbols used to specify the plane-polarized rotation induced by the compound, where (–) or L indicates that the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory.

[0190] When the bonds of the chiral carbon in the formulas of this invention are depicted as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the resulting enantiomerically pure compounds and mixtures thereof are included within the scope of the general formula. The illustration of racemic or enantiomerically pure compounds in this document is derived from Maehr, J. Chem. Ed. 1985, 62:114-120. The absolute configuration of a stereocenter is represented by wedge-shaped and dashed bonds.

[0191] In this application, the term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions in a molecule. The compounds of this invention can exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible forms. Proton-transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium form, and attempts to isolate a single tautomer typically produce a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form is dominant; while in phenols, the enol form is dominant. This invention encompasses all tautomeric forms of compounds.

[0192] In examples of the present invention, the proton can occupy two or more positions in the cyclic form of the heterocyclic system, for example, 1H- and 3H-imidazolium, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, tetrazolium, and 1H- and 2H-pyrazole. The tautomer form can be in equilibrium or spatially fixed in one form through appropriate substitution. For example:

[0193]

[0194] Due to resonance, the hydrogen atom of nitrogen in tetrazolium can be on any of the four nitrogen atoms.

[0195] In this application, the term "pharmaceutical composition" refers to a formulation of the compounds of the present invention with a medium generally accepted in the art for delivering bioactive compounds to mammals (e.g., humans). This medium includes pharmaceutically acceptable carriers. The purpose of a pharmaceutical composition is to facilitate administration to the organism, thereby promoting the absorption of the active ingredient and the exertion of its bioactivity.

[0196] In this application, the term "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, flow aid, sweetener, diluent, preservative, dye / coloring agent, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that is permitted by the relevant government regulatory authority to be acceptable for human or animal use.

[0197] In this application, the term "solvent" refers to a compound of the present invention or a salt thereof comprising a stoichiometric or non-stoichiometric solvent bound by intermolecular noncovalent forces, and a hydrate when the solvent is water.

[0198] In this application, the term "prodrug" refers to a compound of the present invention that can be converted into a biologically active form under physiological conditions or by solvation. The prodrugs of the present invention are prepared by modifying functional groups in the compound; such modification can be performed conventionally or removed in vivo to obtain the parent compound. Prodrugs comprise compounds formed by attaching a hydroxyl or amino group to any group within the compound of the present invention. When a prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is cleaved to form free hydroxyl and free amino groups, respectively.

[0199] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium. 2 H), tritium ( 3 H), Iodine-125 125 I) or C-14 14 C). All isotopic variations of the compounds of the present invention, regardless of radioactivity, are included within the scope of the present invention.

[0200] In this application, the term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, without limitation, binders, disintegrants, lubricants, flow aids, stabilizers, fillers, and diluents. Excipients enhance the handling properties of pharmaceutical formulations, i.e., by increasing flowability and / or adhesion, making the formulation more suitable for direct compression.

[0201] The term "treatment" and other similar synonyms used in this article include the following meanings:

[0202] (i) To prevent the occurrence of disease or condition in mammals, especially when such mammals are susceptible to the disease or condition but have not yet been diagnosed with it;

[0203] (ii) To suppress a disease or symptom, that is, to curb its development;

[0204] (iii) To alleviate a disease or symptom, that is, to cause the condition of the disease or symptom to subside; or

[0205] (iv) To alleviate the symptoms caused by the disease or condition.

[0206] Beneficial effects

[0207] Through extensive and in-depth research, the inventors have unexpectedly developed a heterocyclic compound as a TRPM3 antagonist, having the structure shown in this invention. The compound of this invention can prevent or treat diseases or conditions related to TRPM3, exhibits excellent pharmacokinetic properties, and possesses high safety and pharmaceutical properties. Detailed Implementation

[0208] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that the following description is merely the most preferred embodiment of the present invention and should not be considered as a limitation on the scope of protection of the present invention. Based on a full understanding of the present invention, experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer. Those skilled in the art can make non-essential modifications to the technical solutions of the present invention, and such modifications should be considered to be included within the scope of protection of the present invention.

[0209] This application has the following definitions:

[0210] Symbols or units:

[0211] IC 50 The half-maximum inhibitory concentration (MCC) refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0212] M: mol / L, for example, n-butyllithium (14.56 mL, 29.1 mmol, 2.5 M n-hexane solution) means a n-butyllithium n-hexane solution with a molar concentration of 2.5 mol / L.

[0213] N: Equivalent concentration, for example, 2N hydrochloric acid represents a 2 mol / L hydrochloric acid solution.

[0214] RT: Retention Time

[0215] Reagents:

[0216] DMF: N,N-dimethylformamide

[0217] DIPEA: N,N-Diisopropylethylamine

[0218] EA: Ethyl acetate

[0219] PE: Petroleum ether

[0220] DCM: Dichloromethane

[0221] Pd(dppf)Cl2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride

[0222] Pd(PPh3)4: Tetra(triphenylphosphine)palladium(0)

[0223] HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate

[0224] BBr3: Boron tribromide

[0225] POCl3: Phosphorus oxychloride

[0226] TEA: Triethylamine

[0227] CO: Carbon monoxide

[0228] Test method:

[0229] LCMS: Liquid chromatography-mass spectrometry

[0230] TLC: Thin-layer chromatography

[0231] Example 1: Preparation of target compound I-1A

[0232] N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-3-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)quinoline-4-carboxamide

[0233]

[0234] The synthetic route for the target compound I-1A is shown below:

[0235]

[0236] Step 1: Synthesis of 3-iodo-6-methoxyquinoline-4-ol

[0237]

[0238] Iodine (2.32 g, 18.28 mmol) and morpholine (1.44 ml, 16.46 mmol) were added to a methanol (40 mL) solution of 6-methoxyquinoline-4-ol (1.0 g, 5.70 mmol), respectively. The mixture was stirred at 35 °C for 22.5 h and filtered through methanol cooled at 5 °C to obtain 3-iodo-6-methoxyquinoline-4-ol.

[0239] LC-MS, M / Z (ESI): 302.1 [M+H] +

[0240] Step 2: Synthesis of 4-chloro-3-iodo-6-methoxyquinoline

[0241]

[0242] 3-Iodo-6-methoxyquinoline-4-ol (1.35 g, 44.7 mmol) was added to dry DMF (30 mL), followed by slow dropwise addition of POCl3 (1.4 g, 90 mmol). The reaction was stirred at 50 °C for 2 h. After cooling to room temperature, the reaction solution was slowly poured into ice water to quench the stirring for 30 min. The mixture was then filtered and dried to obtain 4-chloro-3-iodo-6-methoxyquinoline.

[0243] LC-MS, M / Z (ESI): 320.2 [M+H] +

[0244] Step 3: Synthesis of 4-chloro-6-methoxy-3-methylquinoline

[0245]

[0246] 4-Chloro-3-iodo-6-methoxyquinoline (1.1 g, 3.4 mmol), trimethylcycloboroxane (0.6 g, 5.0 mmol), potassium carbonate (1.0 g, 6.8 mmol), and Pd(PPh3)4 (400 mg, 0.4 mmol) were added sequentially to a 1,4-dioxane / water mixture (20 mL / 4 mL). The mixture was reacted at 100 °C for 16 h under nitrogen protection. After cooling, the mixture was directly concentrated to obtain the crude product, which was then purified by silica gel column chromatography to obtain 4-chloro-6-methoxy-3-methylquinoline.

[0247] LC-MS, M / Z (ESI): 207.6 [M+H] +

[0248] Step 4: Synthesis of methyl 6-methoxy-3-methylquinoline-4-carboxylic acid ester

[0249]

[0250] 4-Chloro-6-methoxy-3-methylquinoline (420 mg, 2.02 mmol), TEA (1.5 mL), and Pd(dppf)Cl2 (240 mg, 0.3 mmol) were added sequentially to 10 mL of dry methanol. The reaction was carried out under CO protection at 65 °C for 16 hours. After cooling, the crude product was directly concentrated and purified by silica gel column chromatography to obtain methyl 6-methoxy-3-methylquinoline-4-carboxylate.

[0251] LC-MS, M / Z (ESI): 232.1 [M+H] +

[0252] Step 5: Synthesis of methyl 6-hydroxy-3-methylquinoline-4-carboxylic acid ester

[0253]

[0254] 180 mg (0.77 mmol) of methyl 6-methoxy-3-methylquinoline-4-carboxylate and 370 mg (1.5 mmol) of BBr3 were added sequentially to 10 mL of dry DCM and reacted in an ice-water bath for 4 hours. The reaction system was quenched with 20 mL of saturated sodium bicarbonate solution. After extraction twice with ethyl acetate (30 mL), the organic phases were combined, dried, and concentrated to obtain crude product. The crude product was purified by silica gel column chromatography to obtain methyl 6-hydroxy-3-methylquinoline-4-carboxylate.

[0255] LC-MS, M / Z (ESI): 232.1 [M+H] +

[0256] Step 6: Synthesis of methyl 3-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)quinoline-4-carboxylic acid ester

[0257]

[0258] Methyl 6-hydroxy-3-methylquinoline-4-carboxylate (82.8 mg, 0.38 mmol), potassium carbonate (104 mg, 0.76 mmol), and 2-trifluoromethyl-3-(bromomethyl)pyridine (114 mg, 0.57 mmol) were sequentially added to 3 mL of dry acetonitrile and reacted at room temperature for 16 hours. The reaction solution was directly concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain methyl 3-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)quinoline-4-carboxylate.

[0259] LC-MS, M / Z (ESI): 377.2 [M+H] +

[0260] Step 7: Synthesis of 3-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)quinoline-4-carboxylic acid

[0261]

[0262] Methyl 3-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)quinoline-4-carboxylic acid (104 mg, 0.27 mmol) was dissolved in a mixed solution of tetrahydrofuran:methanol:water = 1 mL:0.5 mL:1 mL. Lithium hydroxide monohydrate (23 mg, 0.582 mmol) was added, and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the solution was concentrated and evaporated to dryness. Then, dilute hydrochloric acid was added to adjust the pH to approximately 3, followed by extraction three times with 3 mL of DCM. The liquid and liquid phases were separated and combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 3-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)quinoline-4-carboxylic acid.

[0263] LC-MS, M / Z (ESI): 363.2 [M+H] +

[0264] Step 8: Synthesis of N-((2S)-1-amino-3-hydroxy-1-oxopropane-2-yl)-3-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)quinoline-4-carboxamide

[0265]

[0266] 3-Methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)quinoline-4-carboxylic acid (91.1 mg, 0.25 mmol) and L-serineamide hydrochloride (57.6 mg, 0.4 mmol) were dissolved in N,N-dimethylformamide (4 mL), followed by the addition of HATU (135 mg, 0.356 mmol) and N,N-diisopropylethylamine (57.6 mg, 0.445 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (8 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (5 mL). The liquid and liquid phases were separated and combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was prepared and purified by reversed-phase high-performance liquid chromatography (column: YMC-Triart Prep C18 7μm 30mm×40cm); mobile phase A: water + 0.1% formic acid; mobile phase B: acetonitrile; flow rate: 42mL / min; gradient: 30%-80%, 6 min) to obtain N-((2S)-1-amino-3-hydroxy-1-oxopropane-2-yl)-3-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)quinoline-4-carboxamide.

[0267] LC-MS, M / Z (ESI): 449.2 [M+H] +

[0268] 1 H NMR (400MHz, DMSO-d6) δ8.82–8.69(m,2H),8.65(d,J=4.4Hz,1H),8.28(d,J=7.8Hz,1 H),7.90(dd,J=11.6,6.0Hz,1H),7.77(dd,J=7.8,4.8Hz,1H),7.60(dd,J=9.0,3.6Hz ,1H),7.51–7.42(m,1H),7.37(dd,J=9.2,2.8Hz,1H),7.16(d,J=8.0Hz,1H),5.46–5. 27(m,2H),4.93(s,1H),4.57(td,J=7.4,5.0Hz,1H),3.79–3.60(m,2H),2.38(s,3H).

[0269] Example 2: Preparation of target compound I-5A

[0270] N-((2S)-1-amino-3-hydroxy-1-oxopropan-2-yl)-2-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxamide

[0271]

[0272] The synthetic route for the target compound I-5A is shown below:

[0273]

[0274] Step 1: Synthesis of ethyl 6-methoxy-2-methylimidazo[1,2-a]pyridine-3-carboxylate

[0275]

[0276] 5-Methoxy-2-aminopyridine (600 mg, 4.8 mmol) and ethyl 2-chloro-3-oxobutyrate (800 mg, 4.8 mmol) were added to 8 mL of ethanol, and the mixture was microwaved at 120 °C for 30 min. After cooling, the reaction solution was concentrated and purified to obtain ethyl 6-methoxy-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid.

[0277] LC-MS, M / Z (ESI): 235.3 [M+H] +

[0278] Step 2: Synthesis of ethyl 6-hydroxy-2-methylimidazo[1,2-a]pyridine-3-carboxylate

[0279]

[0280] Ethyl 6-methoxy-2-methylimidazo[1,2-a]pyridine-3-carboxylate (710 mg, 3.03 mmol) and BBr3 (1.5 g, 6.0 mmol) were added sequentially to 15 mL of dry DCM and reacted in an ice-water bath for 4 hours. The reaction system was quenched with 20 mL of saturated sodium bicarbonate solution. After extraction twice with ethyl acetate (20 mL), the organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain ethyl 6-hydroxy-2-methylimidazo[1,2-a]pyridine-3-carboxylate.

[0281] LC-MS, M / Z (ESI): 221.1 [M+H] +

[0282] Step 3: Synthesis of ethyl 2-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylic acid

[0283]

[0284] Ethyl 6-hydroxy-2-methylimidazo[1,2-a]pyridine-3-carboxylate (240 mg, 1.09 mmol), potassium carbonate (300 mg, 2.18 mmol), and 2-trifluoromethyl-3-benzylbromopyridine (320 mg, 1.6 mmol) were added sequentially to 5 mL of dry acetonitrile and reacted at room temperature for 16 hours. The reaction solution was directly concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain ethyl 2-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylate.

[0285] LC-MS, M / Z (ESI): 380.3 [M+H] +

[0286] Step 4: Synthesis of 2-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylic acid

[0287]

[0288] Ethyl 2-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (270 mg, 0.71 mmol) was dissolved in a mixture of tetrahydrofuran:methanol:water = 2 mL:1 mL:2 mL, and lithium hydroxide monohydrate (98 mg, 2.3 mmol) was added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the solution was concentrated and evaporated to dryness. Then, dilute hydrochloric acid was added to adjust the pH to approximately 3, and DCM (10 mL) was added for extraction three times. The liquid and liquid phases were separated and combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylic acid.

[0289] LC-MS, M / Z (ESI): 352.3 [M+H] +

[0290] Step 5: Synthesis of N-((2S)-1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxamide

[0291]

[0292] 2-Methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (200 mg, 0.56 mmol) and L-serineamide hydrochloride (114.6 mg, 0.8 mmol) were dissolved in N,N-dimethylformamide (8 mL), followed by the addition of HATU (304 mg, 0.8 mmol) and N,N-diisopropylethylamine (210 mg, 1.6 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (10 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (10 mL). The liquid and liquid phases were separated and combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was prepared and purified by reversed-phase high-performance liquid chromatography (column: YMC-Triart Prep C18 7μm 30mm×40cm); mobile phase A: water + 0.1% formic acid; mobile phase B: acetonitrile; flow rate: 42mL / min; gradient: 30%-80%, 6min) to obtain N-((2S)-1-amino-3-hydroxy-1-oxopropane-2-yl)-2-methyl-6-((2-(trifluoromethyl)pyridin-3-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxamide.

[0293] LC-MS, M / Z (ESI): 438.4 [M+H] +

[0294] 1 H NMR(400MHz, DMSO-d4)δ8.99(d,J=2.4Hz,1H),8.75(d,J=4.6Hz,1H),8.29(d, J=7.8Hz,1H),7.80(dd,J=7.8,4.7Hz,1H),7.58(d,J=9.8Hz,1H),7.53(s,1H) ,7.44(d,J=7.8Hz,1H),7.32(dd,J=9.8,2.6Hz,1H),7.22(s,1H),5.31(s,2H) ,5.05(s,1H),4.48(dt,J=7.8,4.8Hz,1H),3.77(d,J=3.6Hz,2H),2.62(s,3H).

[0295] Example 3: Synthesis of target compound I-9A

[0296] N-((2S)-1-amino-3-hydroxy-1-oxopropane-2-yl)-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)-1,2-benzoxazole-3-carboxamide

[0297]

[0298] The synthetic route for the target compound I-9A is shown below:

[0299]

[0300] Step 1: Synthesis of methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1,2-benzoxazole-3-carboxylate

[0301]

[0302] 5-Bromobenzo[d]isoxazole-3-carboxylate methyl ester (500 mg, 1.95 mmol) was dissolved in dioxane (5 mL), followed by the addition of bis(diphenylphosphine)boronic acid ester (744 mg, 2.93 mmol) and potassium acetate (575 mg, 5.86 mmol). The reaction was purged with nitrogen three times, and then 1,1-bis(diphenylphosphine)ferrocene palladium chloride (142 mg, 195 μmol) was added. The reaction was carried out under a nitrogen atmosphere at 100 °C for 2 hours with stirring. After the reaction was complete, the reaction solution was directly concentrated to obtain the crude product, which was then purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10:1, R...). fp1 (0.44) yielded methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1,2-benzoxazole-3-carboxylate.

[0303] LC-MS, M / Z (ESI): 304.1 [M+H] +

[0304] Step 2: Synthesis of methyl 5-hydroxy-1,2-benzoxazole-3-carboxylate

[0305]

[0306] Methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1,2-benzoxazole-3-carboxylate (300 mg, 989 μmol) was dissolved in tetrahydrofuran (6 mL) and water (3 mL). Hydrogen peroxide (11.2 g, 98.9 mmol) was added at 0 °C, and the reaction was stirred at 25 °C for 12 hours. After the reaction was complete, the reaction solution was poured into an aqueous sodium sulfite solution (20 mL) under a nitrogen atmosphere at 0 °C, extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and directly concentrated to obtain methyl 5-hydroxy-1,2-benzoxazole-3-carboxylate.

[0307] LC-MS, M / Z (ESI): 194.2 [M+H] +

[0308] Step 3: Synthesis of methyl 5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)-1,2-benzoxazole-3-carboxylate

[0309]

[0310] 5-Hydroxy-1,2-benzoxazole-3-carboxylate (180 mg, 931 μmol) was dissolved in tetrahydrofuran (4 mL). 2-(trifluoromethyl)-3-pyridinemethanol (198 mg, 1.12 mmol), 1,1-azodicarbonylpiperidine (352 mg, 1.40 mmol), and tributylphosphine (282 mg, 1.40 mmol) were added at 0 °C, and the reaction was stirred at 25 °C for 2 hours. After the reaction was complete, the reaction solution was poured into water (20 mL) under a nitrogen atmosphere at 0 °C and extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Then, the crude product was slurried at 25 °C with ethyl acetate (10 mL) for 10 minutes to obtain 5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)-1,2-benzoxazole-3-carboxylate.

[0311] LC-MS, M / Z (ESI): 353.1 [M+H] +

[0312] Step 4: Synthesis of 5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)-1,2-benzoxazole-3-carboxylic acid

[0313]

[0314] 140 mg (397 μmol) of 5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)-1,2-benzoxazole-3-carboxylic acid was dissolved in dichloromethane (4.5 mL) and methanol (0.5 mL), and sodium hydroxide (1 M, 3.97 mL) was added. The reaction mixture was stirred at 25 °C for 12 hours. After the reaction was complete, the reaction solution was poured into water (20 mL) at 0 °C and extracted with dichloromethane (10 mL × 2). The pH was then adjusted to 1 with 1 M dilute hydrochloric acid, and the solid precipitated. The solid was filtered to obtain 5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)-1,2-benzoxazole-3-carboxylic acid.

[0315] LC-MS, M / Z (ESI): 339.0 [M+H] +

[0316] Step 5: Synthesis of N-((2S)-1-amino-3-hydroxy-1-oxopropane-2-yl)-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)-1,2-benzoxazole-3-carboxamide

[0317]

[0318] 5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)-1,2-benzoxazole-3-carboxylic acid (60.0 mg, 177 μmol) and L-serineamide hydrochloride (27.7 mg, 266 μmol) were dissolved in N,N-dimethylformamide (2 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (80.9 mg, 212 μmol) and N,N-diisopropylethylamine (114 mg, 886 μmol) were added. The reaction was stirred at 25 °C for 2 hours. After the reaction was complete, the reaction solution was purified by high performance liquid chromatography (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: solvent A = water + 0.225% formic acid, B = acetonitrile; gradient: 20%-50%, 15min) to obtain N-((2S)-1-amino-3-hydroxy-1-oxopropane-2-yl)-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)-1,2-benzoxazole-3-carboxamide).

[0319] LC-MS, M / Z (ESI): 425.1 [M+H] +

[0320] 1H NMR (400MHz, DMSO-d6) δ8.75 (d, 1H, J = 4.4Hz), 8.50 (d, 1H, J = 7.9Hz), 8.29 (brd, 1H, J = 7. 9Hz),7.86(d,1H,J=9.1Hz),7.80(dd,1H,J=4.4,7.9Hz),7.61(d,1H,J=2.5Hz),7.55(br s,1H),7.46(dd,1H,J=2.5,9.1Hz),7.23(s,1H),5.38(s,2H),5.06(t,1H,J=5.8Hz),4.4-4.5(m,1H),3.78(t,2H,J=5.4Hz)

[0321] Example 4: The following compounds can be prepared by referring to the preparation method of the compounds in the above formula.

[0322]

[0323]

[0324]

[0325]

[0326] Biological testing

[0327] The following testing methods can be used.

[0328] Test Example 1: Compound Inhibits TRPM3 Ion Channel Activity

[0329] Construction of stable transgenic cell lines HEK293-Human TRPM3 and HEK293-Mouse TRPM3α2: The coding sequences of Human TRPM3 (NM_001366141) and Mouse TRPM3α2 (NM_001035242) were synthesized and inserted between the BamHI and NotI sites of the empty vector pcDNA3.1 Zeo(+) to obtain overexpression plasmids pcDNA3.1 Zeo(+)-Human TRPM3 and pcDNA3.1 Zeo(+)-Mouse TRPM3α2. The two overexpression plasmids were transfected into HEK293 cells. After 24 hours, the culture medium was replaced with fresh medium and Zeocin (#ant-zn-05, InvivoGen) was added to a final concentration of 200 μg / mL as a selection antibiotic. After one week, a stable cell bank was obtained. After single-clone selection, the stable cell lines HEK293-Human TRPM3 and HEK293-Mouse TRPM3α2 were obtained.

[0330] HEK293-Human TRPM3 cells and HEK293-Mouse TRPM3α2 cells in logarithmic growth phase were incubated with 1 μM Fluo-4 AM (#HY-101896, MCE) dye at 37°C for 60 minutes. Then, they were digested into single-cell suspensions with 0.25% trypsin-EDTA (#25200-072, Gibco) solution, centrifuged, and resuspended in calcium-free Krebs-Ringer buffer (#G0430, Solarbio). Different concentrations of the test compounds and 50 μM pregnenolone sulfate (#HY-B1739, MCE) were added to black 384-well plates. Krebs-Ringer buffer containing calcium ions was added to bring the final calcium ion concentration to 2.4 mM. Cells were added to each well at a density of 2000 cells / well. Fluorescence signals were detected using a Perkin Elmer microplate reader with excitation wavelength of 485 nm and detection wavelength of 526 nm. The inhibition rate of the compound in each well was calculated as {1 - [(RFU of the test compound sample - RFU of the positive inhibitor) / (RFU of the solvent sample - RFU of the positive inhibitor)]} * 100%. The IC50 was calculated using GraphPad Prism8 software. 50 Numerical values: X: logarithm of compound concentration; Y: inhibition rate.

[0331] Experimental results show that the compound of this invention has a strong inhibitory effect on TRPM3 ion channel activity.

[0332] Test Example 2: Patch-clamp assay of the inhibitory activity of compounds on TRPM3 ion channels

[0333] Construction of stable transgenic cell lines HEK293-Human TRPM3 and HEK293-Mouse TRPM3α2: The coding sequences of Human TRPM3 (NM_001366141) and Mouse TRPM3α2 (NM_001035242) were synthesized and inserted between the BamHI and NotI sites of the empty vector pcDNA3.1 Zeo(+) to obtain overexpression plasmids pcDNA3.1 Zeo(+)-Human TRPM3 and pcDNA3.1 Zeo(+)-Mouse TRPM3α2. The two overexpression plasmids were transfected into HEK293 cells. After 24 hours, the culture medium was replaced with fresh medium and Zeocin (#ant-zn-05, InvivoGen) was added to a final concentration of 200 μg / mL as a selection antibiotic. After one week, a stable cell bank was obtained. After single-clone selection, the stable cell lines HEK293-Human TRPM3 and HEK293-Mouse TRPM3α2 were obtained.

[0334] Before patch-clamp assay, HEK293-Human TRPM3 cells were digested into a single-cell suspension using trypsin, and 8 × 10⁸ cells were then subjected to the assay. 3 Cells were seeded onto cell spreaders and cultured in 24-well plates (final culture volume 500 μL). After 18 hours, patch-clamp assays were performed. Once the TRPM3 current recorded in whole cells stabilized, drug administration began. Each drug concentration was applied until the current stabilized before moving to the next concentration. At least two concentrations (10 nM and 1000 nM) were measured for each test compound. A coverslip containing cells was placed in a recording bath under an inverted microscope. Blank control solution and working solution of the test compound were perfused sequentially from low to high concentration through the recording bath using gravity perfusion, with fluid exchange performed using a peristaltic pump during recording. The current measured in the compound-free solution for each cell served as its control group. Each concentration was measured twice independently using at least two cells. All electrophysiological experiments were performed at room temperature.

[0335] Inhibition rate calculation: The TRPM3 current and the current induced by the agonist CIM0216 10 μM after each drug concentration were normalized. Then calculate the inhibition rate corresponding to each drug concentration. The mean and standard error (SE) of the inhibition rate were calculated for each concentration.

[0336] The activities of the test compounds are described in the table below. Activity ranges A, B, and C refer to the IC50 values ​​in patch-clamp assays. 50 Values ​​are as follows: "A": IC 50 <1μM; "B": 1μM≤IC 50 ≤20μM; "C": IC 50 >20μM.

[0337] Experimental results show that the compound of this invention has a strong inhibitory effect on TRPM3 ion channel activity.

[0338] Test Example 3: Calcium flow assay to detect the inhibitory activity of compounds on TRPM3 ion channels

[0339] The assay was performed using the FLIPR Calcium 6 Assay Kit (Molecular Devices, R8191) and the FLIPR Pentainstrument (Molecular Devices, 5). HEK cells stably transfected with the TRPM3 receptor (adherent cells) were cultured and passaged in 10 cm culture dishes. Approximately 24 hours before the experiment, the cells were digested, centrifuged, resuspended in plating medium (DMEM + 10% FBS), and counted. Cells were seeded at 1.2 × 10⁶ cells per well in a 384-well plate (Corning, 3764). 4Cells, 25 μL in volume, were incubated in a 5% CO2, 37°C incubator for 16-20 h. AssayBuffer was prepared according to the FLIPR Calcium 6 Assay Kit instructions. Component A was diluted with AssayBuffer to a final 2× loading buffer. The culture medium in the 384-well plate was removed by inverted centrifugation, and 20 μL of AssayBuffer was added. 20 μL / well of the prepared 2× loading buffer was added to each well, centrifuged, and incubated at 37°C in the dark for 2 h. A 5× positive compound and agonist CIM-0216 mixture was prepared. Using an ECHO apparatus (LABCYTE, 655), 100 nmol / well of the 5× positive compound and 2.5 mM CIM-0216 were dispensed into a source plate (Nunc, 264573), followed by 20 μL of AssayBuffer in each well. After incubation, 10 μL of the prepared compound was added to each well using a FLIPR Penta instrument, and the fluorescence signal was detected (excitation wavelength 470 nm-495 nm, emission wavelength 515 nm-575 nm). The highest concentration of the positive control was taken as 100% inhibition rate, and DMSO data as 0% inhibition rate. A curve was plotted between the signal value and the compound concentration. Curve fitting and IC50 analysis were performed using the nonlinear regression method in XLFit software. 50 calculate.

[0340] The activities of the test compounds are described in the table below. Activity ranges A, B, and C refer to the IC50 values ​​in the calcium flow assay. 50 Values ​​are as follows: "A": IC 50 <1μM; "B": 1μM≤IC 50 ≤20μM; "C": IC 50 >20μM.

[0341] Table 1. Inhibitory activity of the test compounds against TRPM3 in the calcium flow assay

[0342] Compound numbering <![CDATA[IC 50 ]]> I-9A A

[0343] Experimental results show that the compound of this invention has a strong inhibitory effect on TRPM3 ion channel activity.

[0344] 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.

Claims

1. A compound of Formula I, a tautomer, a stereoisomer, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof: Formula I wherein: Ring B is selected from a 5-14 membered heteroaromatic ring, a 5-14 membered heteroalkene ring; said 5-14 membered heteroaromatic ring and 5-14 membered heteroalkene ring contains at least one N atom; m is selected from 1, 2, 3, 4, 5, 6; L is selected from -C(=O)-, -S(=O)-, -S(=O)2-, -P(=O)-, -P(=O)2-; Ring A is selected from a 3-14 membered cycloalkyl ring, a 3-14 membered heterocycloalkyl ring, a 6-14 membered aryl ring, a 5-14 membered heteroaryl ring; R3 is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl; said C1-C6 alkyl, C1-C6 alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; and / or, said 3-14 membered heterocycloalkyl ring, 6-10 membered heteroaryl ring in said Ring A is selected from a 3-14 membered heterocycloalkyl monocyclic ring, a 7-14 membered heterocycloalkyl bicyclic ring, a 6-10 membered heteroaryl monocyclic ring, a 8-10 membered heteroaryl bicyclic ring, containing 1, 2, 3, or 4 heteroatoms, said heteroatoms are selected from N, O, S; and / or, said Ring A is selected from furan, pyrrole, thiophene, oxazole, oxadiazole, thiazole, thiadiazole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, triazine, dihydropyrrole, dihydropyrazole, dihydroimidazole, dihydrotriazole, dihydrotetrazole, dihydrothiazolyl, dihydrotetrazolyl, tetrahydropyridyl, dihydropyridyl, tetrahydropyrazinyl, dihydropyrazinyl, tetrahydropyrimidinyl, dihydropyrimidinyl, tetrahydropyrrole, tetrahydropyrazole, tetrahydroimidazole, piperidine, piperazine, hexahydropyridazine, hexahydropyrimidine, benzocyclopentyl, benzocyclohexyl, tetrahydroquinoline, tetrahydroisoquinoline, quinoline, isoquinoline, dihydrochromene, dihydroisochromene, indole, benzofuran, pyridofuran, dihydrofurodipyridine, benzene ring, indene, naphthalene; and / or, said Ring A is selected from pyridine, pyrimidine, pyridazine, pyrazine, thiadiazole, benzene, benzocyclopentyl, benzocyclohexyl, tetrahydroquinoline, tetrahydroisoquinoline; and / or, said R3 is selected from deuterium, hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy; said C1-C6 alkyl, C1-C6 alkoxy is optionally substituted with 1, 2, 3, 4, 5 substituents selected from halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; and / or, said R3 is selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl; and / or, said R3 is selected from C1-C3 alkyl, C1-C3 haloalkyl; and / or, said R3 is selected from -CF3, -CHF2, -CH2F; wherein ​ ​ R1is selected from the group consisting of deuterium, hydrogen, halogen, hydroxyl, amino, cyano, oxo (=0), C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, -OR a , -OC(=0)R a , -NR b C(=0)R a , -SR a , -S(=0)R a , -S(=0)2R a , -S(=0)-NR a -, -S(=0)2-NR a , -C(=0)R a , -C(=0)OR a , -C(=0)NR a R b ; said C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl are optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, hydroxyl, halogen, C1-C6alkyl, C1-C6alkoxy; ​ ​ R2is selected from NR 21 R 22 ; R 21 , R 22 each independently is selected from the group consisting of hydrogen, deuterium, hydroxyl, -SR a , -S(=O)R a , -S(=O)2R a , C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl; said C1-C6alkyl, C1-C6alkoxy, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, hydroxyl, halogen, C1-C6alkyl, C1-C6alkoxy, -C(=O)NR a R b , -OC(=O)R a , -NR b C(=O)R a , -SR a , -S(=O)R a , -S(=O)2R a , -C(=O)R a , -C(=O)OR a , -C(=NH)S(=O)2R a ; or R 21 , R 22 and the N atom to which it is attached form a 4-8 membered heterocycloalkyl, 5-8 membered heteroaryl; said 4-8 membered heterocycloalkyl, 5-8 membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy; M is selected from the group consisting of a bond, -O-, -S(=O)R a -, -S(=O)2R a -, -S(=O)NR a -, -S(=O)2NR a -, -C(=O)R a -, -C(=O)OR a -, - C(=O)NR a C1-C6alkylene, -C1-C6alkylene-S-, -C1-C6alkylene-S(=O)-, -C1-C6alkylene-S(=O)2-, C1-C6haloalkylene, C2-C6alkenylene, C2-C6alkynylene, C1-C6alkyleneoxy, C0-C6alkylene-3- to 6-membered cycloalkyl-C0-C6alkylene, C0-C6alkylene-3- to 6-membered heterocycloalkyl-C0-C6alkylene, C0-C6alkylene-5- to 8-membered heteroaryl-C0-C6alkylene, C0-C6alkylene-6- to 8-membered aryl-C0-C6alkylene; said C1-C6alkylene, -C1-C6alkylene-S-, -C1-C6alkylene-S(=O)-, -C1-C6alkylene-S(=O)2-, C1-C6haloalkylene, C2-C6alkenylene, C2-C6alkynylene, C1-C6alkyleneoxy, C0-C6alkylene-3- to 6-membered cycloalkyl-C0-C6alkylene, C0-C6alkylene-3- to 6-membered heterocycloalkyl-C0-C6alkylene, C0-C6alkylene-5- to 8-membered heteroaryl-C0-C6alkylene, C0-C6alkylene-6- to 8-membered aryl-C0-C6alkylene are optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, oxo, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl; ​ ​ ​ R a , R b each independently is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxyl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl; said C1-C6alkyl, C1-C6alkoxyl, 3-14 membered cycloalkyl, 3-14 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from deuterium, halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxyl, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl; when L is selected from -C(=O)-, is not when M is selected from C1-C5alkyleneoxy, said C1-C5alkyleneoxy is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, then ring B is not 2. The compound of Formula I as claimed in claim 1, its tautomers, stereoisomers, solvates, pharmaceutically acceptable salts, or prodrugs, characterized in that, the selected from 3-14 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl substituted with n R3; ​ ​ ​ ​ ​ ​ ​ and / or, n is selected from 0, 1, 2, 3; and / or, n is selected from 1; and / or, the selected from 3. The compound of claim 1, a tautomer, stereoisomer, solvate, pharmaceutically acceptable salt, or prodrug thereof, wherein said M is selected from the group consisting of a bond, -0-, -S(=0)2R a -, -S(=0)2NR a -, -C(=0)NR a -, -C1-C6alkylene-S-, -C1-C6alkylene-S(=0)2-, C1-C6alkylene, C1-C6haloalkylene, C1-C6alkyleneoxy, C2-C6alkenylene, C0-C6alkylene-3-6 membered cycloalkyl-C0-C6alkylene, C0-C6alkylene-3-6 membered heterocycloalkyl-C0-C6alkylene, C0-C6alkylene-5-8 membered heteroaryl-C0-C6alkylene; and / or, said M is selected from a bond, -0-, -S(=0)2NR a -, -C(=0)NR a -, -C1-C3alkylene-S-, -C1-C3alkylene-S(=0)2-, C1-C3alkylene, C1-C3haloalkylene, C1-C3alkyleneoxy, C2-C4alkenylene, C0-C3alkylene-3-6 membered cycloalkyl-C0-C3alkylene, C0-C3alkylene-3-6 membered heterocycloalkyl-C0-C3alkylene, C0-C6alkylene-5-8 membered heteroaryl; and / or, the 5-8 membered heteroaryl in M contains 1, 2, 3 same or different heteroatoms; the heteroatoms are selected from N, O, S; and / or, M is selected from a bond, -O-, -S(=O)2NH-, -C(=O)NH-, -CH2-S-, -CH2-S(=O)2-, methylene, ethylene, propylene, isopropylene, -CF2-, -CHF-, -CH2CHF-, -CH2CF2-, -CH2-O-, vinylene, propenylene, C0-C3alkylene-3-5 membered cycloalkyl-C0-C3alkylene, C0-C3alkylene-3-5 membered heterocycloalkyl-C0-C3alkylene, C0-C6alkylene-furan, C0-C6alkylene-pyrrole, C0-C6alkylene-thiophene, C0-C6alkylene-oxazole, C0-C6alkylene-oxadiazole, C0-C6alkylene-thiazole, C0-C6alkylene-thiadiazole, C0-C6alkylene-pyrazole, C0-C6alkylene-imidazole, C0-C6alkylene-triazole, C0-C6alkylene-tetrazole, C0-C6alkylene-pyridine, C0-C6alkylene-pyrimidine, C0-C6alkylene-pyridazine, C0-C6alkylene-triazine; and / or, the 3-6 membered cycloalkyl in M is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; and / or, the 3-6 membered heterocycloalkyl in M contains 1, 2, 3 same or different heteroatoms; the heteroatoms are selected from N, O, S; and / or, the 3-6 membered heterocycloalkyl in M is selected from oxiranyl, oxetanyl, oxetanyl, aziridinyl, azetidinyl; and / or, said M is selected from a bond, -0-, -S(=0)2NH-, -C(=0)NH-, -CH2-S-, -CH2-S(=0)2-, methylene, ethylene, -CH2CH2CH2-, -CH(CH3)-CH2-, -CH2CF2-, -CH=CH-, -CH2-0-, pyridine, methylene-pyridine; and / or, said M is selected from -CH2-O-, methylene, ethylene, 4. The compound of claim 1, a tautomer, stereoisomer, solvate, pharmaceutically acceptable salt, or prodrug thereof, wherein the compound is selected from the following structures: M is selected from C1-C6alkylene, C1-C6haloalkylene, C1-C6alkyleneoxy; ring B, R1, R2, R3, L, m and n have the definitions as described in claim 1.

5. The compound, tautomer, stereoisomer, solvate, pharmaceutically acceptable salt, or prodrug thereof, of claim 1 or claim 4, wherein, ring B is selected from 5-10 membered heteroaromatic ring, 5-10 membered heteroalkene, ring B contains at least 1 N atom; and / or, ring B is selected from pyrrole, oxazole, oxadiazole, thiazole, thiadiazole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, triazine, dihydrofuro[3,2-b]pyridine, dihydropyrrolo[3,2-b]pyridine, indole, quinoline, isoquinoline, dihydroquinoline, dihydroisoquinoline, pyrrolopyridazine, imidazopyridine, benzoxazole, benzisoxazole, benzothiazole, benzothiadiazole, benzimidazole; and / or, ring B is selected from imidazole, quinoline, pyrrolopyridazine, imidazopyridine, dihydropyrrolopyridine, benzoxazole, benzisoxazole; and / or, said ring B is selected from and / or, To 6. The compound, tautomer, stereoisomer, solvate, pharmaceutically acceptable salt, or prodrug thereof, of claim 1 or claim 4, wherein, R1is selected from deuterium, hydrogen, halogen, hydroxyl, amino, cyano, oxo(=O), C1-C6alkyl, C1-C6alkoxy; C1-C6alkyl, C1-C6alkoxy is optionally substituted with 1, 2, 3, 4, 5 substituents selected from hydroxyl, halogen, C1-C6alkyl; and / or, said R1is selected from deuterium, hydrogen, halogen, oxo (=0), C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy; and / or, said R1is selected from hydrogen, methyl, ethyl, oxo (=0), -CF3, -CHF2, -CH2F.

7. The compound, tautomer, stereoisomer, solvate, pharmaceutically acceptable salt, or prodrug thereof, of claim 1 or claim 4, wherein, said L-R2is selected from L-NR 21 R 22 ; R 21 , R 22 each independently is selected from the group consisting of hydrogen, hydroxyl, -S(=0)2R a , C1-C6alkyl, C1-C6alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-8 membered aryl, 5-8 membered heteroaryl; said C1-C6alkyl, C1-C6alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-8 membered aryl, 5-8 membered heteroaryl is optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of: hydroxy, halogen, C1-C6alkyl, C1-C6alkoxy, -C(=O)NR a R b , -NR b C(=O)R a , -S(=O)2R a , -C(=NH)S(=O)2R a ; and / or, R 21 , R 22 with the N atom to which it is attached forms a 4-8 membered heterocycloalkyl, 5-8 membered heteroaryl; and / or, said R 21 , R 22 each independently is selected from the group consisting of hydrogen, hydroxyl, C1-C6alkyl, said C1-C6alkyl being optionally substituted with 1, 2, 3, 4, 5 substituents selected from the group consisting of hydroxyl, halogen, C1-C6alkyl, -C(=O)NR a R b , -C(=NH)S(=O)2R a ; and / or, said L is selected from -C(=0)-, -S(=0)2-; and / or, said L-R2is selected from -C(=O)-NHR 22 , -S(=O)2-NHR 22 ; said R 22 is selected from C1-C6alkyl, said C1-C6alkyl being optionally substituted with 1, 2, 3 substituents selected from the group consisting of hydroxy, halogen, C1-C3alkyl, -C(=O)NR a R b , -C(=NH)S(=O)2R a ; and / or, said L-R2is selected from -C(=O)-NHR 22 , -S(=O)2-NHR 22 ; said R 22 is selected from C1-C6alkyl, said C1-C6alkyl being optionally substituted with 1, 2, 3 substituents selected from the group consisting of: hydroxy, -C(=O)NH2, -C(=NH)S(=O)2CH3; and / or, said L-R2is selected from and / or, said L-R2is selected from 8. The compound of claim 1, a tautomer, stereoisomer, solvate, pharmaceutically acceptable salt, or prodrug thereof, wherein, said compound has the following structure: ring B, R1, R3, M, m and n have the definitions as described in claim 1; and / or, said compound III-1 compound has the structure III-1a or III-1b:

9. The compound, tautomer, stereoisomer, solvate, pharmaceutically acceptable salt, or prodrug thereof, of claim 1, wherein said compound includes:

10. The compound, tautomer, stereoisomer, solvate, pharmaceutically acceptable salt, or prodrug thereof, of claim 1, wherein said compound includes:

11. A pharmaceutical composition, characterized by, said pharmaceutical composition includes: a compound, a tautomer, a stereoisomer, a solvate, a pharmaceutically acceptable salt or a prodrug thereof as described in any one of claims 1-10; and a pharmaceutically acceptable carrier.

12. Use of a compound, a tautomer, a stereoisomer, a solvate, a pharmaceutically acceptable salt or a prodrug thereof as described in any one of claims 1-10 or a pharmaceutical composition of claim 11, said use includes: as a TRPM3 antagonist; and / or, preventing and / or treating a TRPM3 mediated disease; and / or, preparing a medicament, a pharmaceutical composition or a formulation as a TRPM3 antagonist.

13. The use according to claim 12, characterized in that, said disease is pain or epilepsy.

14. The use of claim 13, said disease is nociceptive pain, inflammatory pain, neuropathic pain, chronic pain, epilepsy.

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