Small molecules as KCNQ2 / 3 (Kv7.2 / 3) channel activators and their pharmaceutical applications

Abstract

This invention relates to a class of novel bicyclic derivatives that serve as small-molecule KCQN2 / 3 (Kv7.2 / 3) potassium channel activators, as well as pharmaceutical compositions thereof, methods of preparation, and therapeutic uses. These compounds are represented by formula (I) and defined by specific substituents and structural features described in the specification. These derivatives have therapeutic potential in treating seizure disorders and other diseases affected by potassium ion channel regulation by modulating or enhancing the activation of Kv7.2 / 3 potassium channels.

Description

Cross-reference to related applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 566,668, filed March 18, 2024, entitled “A novel small molecule as a KCNQ2 / 3 (Kv7.2 / 3) channel activator and its pharmaceutical use thereof,” and U.S. Provisional Application No. 63 / 682,521, filed August 13, 2024, entitled “A small molecule as a KCNQ2 / 3 (Kv7.2 / 3) channel activator and its pharmaceutical use thereof,” both of which are incorporated herein by reference in their entirety. Technical Field

[0002] This disclosure generally relates to novel KCNQ2 / 3 (Kv7.2 / 3) channel activators for the treatment of medical conditions. Background Technology

[0003] The Kv7 subfamily of potassium channels comprises five members, encoded by genes KCNQ-1 through KCNQ-5. All five are voltage-gated ion channels, playing crucial roles in membrane excitability across various cell types. Kv7 channels can assemble into homotetramers of identical subunits or heterotetramers of specific subunit combinations (Delmas, P., Brown, DA, “pathwaysmodulation neural KCNQ / M(Kv7) potassium channels”). Nature Reviews Neuroscience , 2005, 6, 850). Each Kv7 subunit consists of six transmembrane segments (S1-S6) and cytoplasmic N-terminus and C-terminus; among which, segments S1, S2, S3 and S4 constitute the voltage-sensing domain (VSD), while segments S5 and S6 and their connecting loops participate in the formation of the pore domain (PD). The characteristic long intracellular C-terminus in Kv7 channels contains the domain required for tetramerization and participates in the binding and transduction of key regulatory factors, such as phosphatidylinositol 4,5-bisphosphate (PIP2), calmodulin (CaM), synaptic protein, A kinase anchoring protein, protein kinase C and ankyrin G (Barrese, V., Stott, JB, Greenwood, IA, “KCNQ-encoded potassium channels as therapeutic targets” Annu. Rev.Pharmacol. Toxicol. 2018, 6(58), 625-648).

[0004] Kv7 channels have attracted considerable attention due to their association with a variety of diseases. In particular, the Kv7.2 / 3 heterotetramer, the most abundant Kv7.2 assembly in the neocortex and hippocampus, has been shown to be closely associated with epilepsy, pain, and other central nervous system disorders due to its crucial contribution to M-currents and its role in maintaining the resting membrane potential of neurons. Since activation of Kv7.2 / 3 channels can act as a brake on neuronal firing, Kv7.2 / 3 channel activators hold great potential for treating central nervous system disorders such as epilepsy and pain (Jepps, TA, Barrese, V., and Miceli, F. “Editorial: Kv7 Channels: Structure, Physiology, and Pharmacology”). Frontiers in Physiology , 2021, 12, Article 679317).

[0005] The exploration of Kv7 channel openers began in the early 1980s; the first selective Kv7 channel activator, retigabine, was approved in the EU in 2011 for the treatment of epilepsy (Trobalt), and in the US in 2010 as adjunctive therapy for adult partial seizures (Potiga) (Stafstrom, CE, Crippon, S., Kirkpatrick, P. "Ezogabine (retigabine)"). Nature Review Drug Discovery , 2011, 10, 729; Jankovic, S., and Llickovic, I. “the preclinical discovery and development of ezogabine for the treatment of epilepsy” Exper. Opin. Drug Discov. 2013, 8(11), 1). This compound was initially discovered by ASTA Medica (DE4200259) in Germany and jointly developed by Valeant and GSK; however, it was withdrawn from the market in June 2017 due to the blue discoloration side effect caused by the deposition of pigments in the skin by the retigabine metabolite dimer (Clark, S., Antell, A., Kaufman, K. “new antiepileptic medication linked to blue discoloration of the skin and eyes”). Ther. Adv. Drug Safety.2015, 6(1) 15). To overcome these side effects, many different molecules were designed based on the molecular structure of retigabine and evaluated in preclinical and clinical studies (Borgini, M., Mondal, P., Liu, R., and Wipf, P. “Chemical modulation of Kv7 potassium channels”). RSC Med.Chem . 2021, 12, 483; Suru, AS et al., “Flupirtine and retigabine astemplates for ligand-based drug design of Kv7.2 / 3 activators” Org. Biomol. Chem. (2019, 17, 4512-4522). Among them, XEN1101 developed by Xenon has advanced to a Phase III clinical trial for the treatment of epilepsy and seizures (US11135214); BHV-7000 developed by Biohaven has advanced to a Phase II clinical trial for the treatment of epilepsy (WO2023133256); Pynegabine developed by Haikou Pharmaceutical Factory / Shanghai Institute of Materia Medica has advanced to a Phase I clinical trial for the treatment of epilepsy (Zhang, Y.-M., et al., 2019, 17, 4512-4522). J. Med. Chem , 2021, 64, 5816, WO20151653521); CB03-154, developed by Zhimeng Pharmaceutical Technology Co., Ltd., has also advanced to a Phase I clinical trial for the treatment of epilepsy (WO2022028548). Several other companies and universities are also researching Kv7.2 / 3 channel activators to discover novel molecules with potential pharmaceutical uses (WO2023125935, WO2019183148, CN108863893, WO2023025276).

[0006] This article discloses a novel small molecule Kv7.2 / 3 activator and its use in the treatment of epilepsy, pain and a variety of other diseases. Summary of the Invention

[0007] The following is an overview of the subject matter described in detail in this invention. This overview is not intended to limit the scope of protection defined by the claims.

[0008] This invention relates to novel small molecule Kv7.2 / 3 activators and related pharmaceutical compositions. The pharmaceutical compositions comprise a therapeutically effective amount of the compound and pharmaceutically acceptable excipients. These compositions are intended to treat diseases or conditions such as epilepsy, amyotrophic lateral sclerosis (ALS), various types of pain, migraines, depression, bipolar disorder, and any neurodegenerative disease. Attached Figure Description

[0009] The accompanying drawings are provided to aid in understanding the technical content of this application and form part of this specification. The drawings are used in conjunction with the embodiments described in this application to illustrate technical features and should not be considered as limiting the scope of the technology of this application.

[0010] Figure 1 The effects of the compounds of this invention on Racine IV and VI grade seizures in a PTZ-induced ICR mouse epilepsy model were investigated. Experimental results showed that oral administration of the compounds of this invention at 10 mg / kg in the mouse PTZ epilepsy model exhibited significant activity, superior to the control compound.

[0011] Figure 2 The maximum possible analgesic effect of the compound of the present invention in a formalin model of SD rats. Experimental results show that, in a rat formalin model, oral administration of the compound of the present invention at 10 mg / kg exhibits significant analgesic activity, which is superior to that of the control compound.

[0012] Figure 3 Compare the structures of compounds 1, 2 and 3. Detailed Implementation

[0013] Some implementation schemes include compounds as shown in formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, deuterated derivatives, metabolites, or prodrugs thereof;

[0014] in,

[0015] The value of n ranges from 0 to 5;

[0016] R 1 The group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, Ar, C3-C8 cycloalkenyl, or C3-C8 heterocyclic groups is selected, wherein each occurrence of R... 1Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, nitro (-NO2), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O) and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl;

[0017] R 2 Choose from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C3-C8 heterocyclic groups or Ar, wherein each occurrence of R 2 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O) and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl;

[0018] L is optionally selected from -NHCO- or -NHSO2-;

[0019] A is a C1-C8 alkyl group, wherein A is optionally substituted by one or more substituents independently selected from fluorine (-F), chlorine (-Cl), and bromine (-Br);

[0020] X1, X2, X3, and X4 are each independently selected freely -CR 3 -、-CR 4 R 5 -、-N-、-NR 6 Groups consisting of -, -O-, or -S-;

[0021] in, Choose a group consisting of the following structures:

[0022] , ,

[0023] In one implementation, R 3 R 4 and R 5 Each can be independently selected from hydrogen (H), halogen, hydroxyl (-OH), amino (-NH2), cyano (-CN), -C(=O)OH, and NHCOR. 7 -(C=O)R 8 -C(=O)OR 9 The group consists of C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 heterocyclic groups, wherein each group is optionally substituted by one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -C(=O)OR', -C(=O)R', -NHR', or -NR'R"; wherein R 4 and R 5 They can together form a carbonyl (-C=O) functional group; R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl groups;

[0024] R 7 R 8 and R 9 Each is independently selected from the group consisting of -NH2 or C1-C3 alkyl groups;

[0025] R 6 Choose from the group consisting of hydrogen (H), -(C=O)(C1-C6 alkyl), C2-C6 alkenyl, C1-C6 alkyl, or C3-C8 cycloalkyl, wherein each occurrence of R 6 Optionally substituted with one or more substituents, wherein the substituents are independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -C(=O)OR', -C(=O)R', -NHR' or -NR'R"; R' and R" are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl.

[0026] Any one or two X atoms, together with the carbon atoms they are attached to, form a ring optionally containing one to three heteroatoms independently selected from nitrogen (N), oxygen (O), and sulfur (S), including

[0027] , , , , , ,

[0028] in,

[0029] The value of m ranges from 0 to 6;

[0030] R x Selected from the group consisting of hydrogen (H), halogens, cyano (-CN), and C1-C6 alkyl groups;

[0031] Y1, Y2, Y3, and Y4 are each independently selected from groups composed of C, N, O, or S;

[0032] More preferably, Y1, Y2, Y3, and Y4 are each independently selected from C or N, examples of which include:

[0033] When Y1 and Y4 are N, Y2 and Y3 are C;

[0034] When Y1 and Y3 are N, Y2 and Y4 are C;

[0035] When Y1 and Y2 are N, Y3 and Y4 are C;

[0036] When Y1, Y2, and Y3 are C, Y4 is N.

[0037] in, Choose a group consisting of the following structures:

[0038] , , ,

[0039] Among them, when for When L is -NHSO2-

[0040] Among them, when for hour,

[0041] Choose a group consisting of the following structures:

[0042] , ,

[0043] In another, more specific embodiment, the present invention provides or relates to a compound as shown in formula (I-1), or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, deuterated derivative, metabolite, or prodrug thereof;

[0044]

[0045] in,

[0046] The value of n ranges from 0 to 3;

[0047] R 1 The group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, Ar, C3-C8 cycloalkenyl, or C3-C8 heterocyclic groups is selected, wherein each occurrence of R... 1 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, nitro (-NO2), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O) and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl;

[0048] R 2 Choose from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C3-C8 heterocyclic groups or Ar, wherein each occurrence of R 2 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O) and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl;

[0049] In some preferred embodiments, R 2 Choose from groups composed of C3-C8 heterocyclic groups or Ar, where R appears each time. 2Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O) and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl;

[0050]

[0051] A is a C1-C6 alkyl group, wherein A is optionally substituted by one or more substituents, the substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, nitro (-NO2), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R"; R' and R" are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl groups;

[0052] X1, X2, X3, and X4 are each independently selected -CR 4 R 5 -、-NR 6 Groups consisting of -, -O-, or -S-;

[0053] In the preferred embodiment, X1, X2, X3 and X4 are each independently -CH2-;

[0054] In one implementation, R 4 and R 5 Each can be independently selected from hydrogen (H), halogen, hydroxyl (-OH), amino (-NH2), cyano (-CN), -C(=O)OH, and NHCOR. 7 -(C=O)R 8 -C(=O)OR 9The group consists of C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 heterocyclic groups, wherein each group is optionally substituted by one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -C(=O)OR', -C(=O)R', -NHR', or -NR'R"; R 4 and R 5 They can together form a carbonyl (-C=O) functional group; R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl groups;

[0055] R 7 R 8 and R 9 Each is independently selected from the group consisting of NH2, methyl, ethyl, propyl, or isopropyl.

[0056] R 6 The group is selected from the group consisting of H, -(C=O)(C1-C4 alkyl), optionally substituted C2-C6 alkenyl, optionally substituted C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl, wherein the optional substituent is independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -C(=O)OR', -C(=O)R', -NHR', or -NR'R"; R' and R" are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl.

[0057] In some implementations, n is 0, 1, or 2;

[0058] In some implementation schemes, R 1 Optionally, it is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C1-C6 alkoxy or halo-C1-C6 alkoxy;

[0059] In some implementation schemes, R 2 Optionally, it may be methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, or the following groups;

[0060]

[0061] In some implementations, A is optionally CH2, CH2CH2, CH(CH3), C(CH3)2, CH2CH(CH3), CH2CH2CH2, CH2CH2CH2CH2;

[0062] In some implementation schemes, R 3 The fluorine, chlorine, bromine, iodine, CH2F, CF2H, CF3, or two adjacent Rs are optionally present. 3 The group and the atoms to which they are attached together form a C3-C8 heterocyclic alkyl ring or a C3-C8 heterocyclic alkenyl ring;

[0063] Preferably, n is 0 or 1;

[0064] Preferably, R 1 Optionally, it is methyl, ethyl, tert-butyl, cyclopropyl, cyclobutyl, cyclohexyl, C1-C6 alkoxy, or halo-C1-C6 alkoxy;

[0065] Preferably, R 2 Optionally, it is a methyl group or the following groups;

[0066]

[0067] Preferably, A is selected from the group consisting of CH2, CH2CH2, CH(CH3), C(CH3)2, CH2CH(CH3), and CH2CH2CH2;

[0068] Preferably, n is 1;

[0069] Preferably, R 1 Optionally methyl, ethyl, tert-butyl or cyclobutyl;

[0070] Preferably, R 2 Optionally, the following groups may be used;

[0071]

[0072] Preferably, A is CH2;

[0073] In another, more specific embodiment, the present invention provides or relates to a compound as shown in formula (I-2), or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, deuterated derivative, metabolite, or prodrug thereof;

[0074]

[0075] in,

[0076] The value of n ranges from 0 to 3;

[0077] R 1 The group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, Ar, C3-C8 cycloalkenyl, or C3-C8 heterocyclic groups is selected, wherein each occurrence of R... 1Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), nitro (-NO2), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O) and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl;

[0078] R 2 Choose from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C3-C8 heterocyclic groups or Ar, wherein each occurrence of R 2 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 cyclic heteroatoms, said cyclic heteroatoms being independently selected from nitrogen (N), oxygen (O) and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl;

[0079] A is a C1-C6 alkyl group, wherein A is optionally substituted by one or more substituents, the substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, nitro (-NO2), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R"; R' and R" are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl groups;

[0080] X1, X2, X3, and X4 are each independently selected -CR 4 R 5 -、-NR 6 Groups consisting of -, -O-, or -S-;

[0081] In one implementation, R 4 and R 5 Each can be independently selected from hydrogen (H), halogen, hydroxyl (-OH), amino (-NH2), cyano (-CN), -C(=O)OH, and NHCOR. 7 -(C=O)R 8 -C(=O)OR 9 The group consists of C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 heterocyclic groups, wherein each group is optionally substituted by one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -C(=O)OR', -C(=O)R', -NHR', or -NR'R"; wherein R 4 and R 5 They can together form a carbonyl (-C=O) functional group; R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl groups;

[0082] R 7 R 8 and R 9 Each is independently selected from the group consisting of NH2, methyl, ethyl, propyl, or isopropyl.

[0083] R 6 The group is selected from the group consisting of H, -(C=O)(C1-C4 alkyl), optionally substituted C2-C6 alkenyl, optionally substituted C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl, wherein the optional substituent is independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -C(=O)OR', -C(=O)R', -NHR', or -NR'R"; R' and R" are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl.

[0084] In the preferred embodiment, X1, X2, X3 and X4 are each independently -CH2-.

[0085] In some implementations, n is 0, 1, or 2;

[0086] In some implementation schemes, R 1The group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Ar, C3-C8 cycloalkenyl, or C3-C8 heterocyclic groups is selected, wherein each occurrence of R... 1 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), nitro (-NO2), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O) and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl;

[0087] In some implementation schemes, R 2 Choose from the group consisting of C1-C6 alkyl groups, where R appears each time. 2 Optionally substituted with one or more substituents, wherein the substituents are independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R"; R' and R" are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl;

[0088] In some implementations, X1, X2, X3, and X5 are each independently CH2;

[0089] Preferably, n is 0 or 1.

[0090] Preferably, R 1 Choose from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or Ar, where R appears each time. 1Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), methyl, ethyl, propyl, isopropyl, -CH2F, -CHF2, -CF3 and -OCF3; Ar is a 5 to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O) and sulfur (S);

[0091] Preferably, R 2 Choose from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, or C1-C6 alkyl groups, wherein each occurrence of R... 2 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of OH, F, Cl, Br, I, CH2F, CHF2, or CF3;

[0092] More preferably, n is 1;

[0093] More preferably, R 1 Choose from the group consisting of cyclohexyl or p-trifluoromethoxyphenyl;

[0094] More preferably, R 2 It is tert-butyl.

[0095] In another more specific embodiment, the present invention provides or relates to a compound as shown in formula (I-3), or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, deuterated derivative, metabolite or prodrug thereof;

[0096]

[0097] in,

[0098] The value of n ranges from 0 to 3;

[0099] R 1 The group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, Ar, C3-C8 cycloalkenyl, or C3-C8 heterocyclic groups is selected, wherein each occurrence of R... 1Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), nitro (-NO2), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O) and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl;

[0100] R 2 Choose from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C3-C8 heterocyclic groups or Ar, wherein each occurrence of R 2 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O) and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl;

[0101] A is a C1-C6 alkyl group, wherein A is optionally substituted by one or more substituents, the substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, nitro (-NO2), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R"; R' and R" are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl groups;

[0102] X1, X2, X3, and X4 are each independently selected -CR 4 R 5 -、-NR 6 Groups consisting of -, -O-, or -S-;

[0103] In one implementation, R 4 and R 5 Each can be independently selected from hydrogen (H), halogen, hydroxyl (-OH), amino (-NH2), cyano (-CN), -C(=O)OH, and NHCOR. 7 -(C=O)R 8 -C(=O)OR 9 The group consists of C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 heterocyclic groups, wherein each group is optionally substituted by one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -C(=O)OR', -C(=O)R', -NHR', or -NR'R"; wherein R 4 and R 5 They can together form a carbonyl (-C=O) functional group; R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl groups;

[0104] R 7 R 8 and R 9 Each is independently selected from the group consisting of NH2, methyl, ethyl, propyl, or isopropyl.

[0105] R 6 Choose from the group consisting of hydrogen (H), -(C=O)(C1-C4 alkyl), C2-C6 alkenyl, C1-C6 alkyl, or C3-C8 cycloalkyl, wherein each occurrence of R 6 Optionally substituted with one or more substituents, wherein the substituents are independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -C(=O)OR', -C(=O)R', -NHR' or -NR'R"; R' and R" are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl.

[0106] Any one or two X atoms together with the carbon atoms they are attached to form a C3-C6 ring, optionally containing 1-3 heteroatoms independently selected from nitrogen (N), oxygen (O), and sulfur (S), including but not limited to the following structures:

[0107] , , ,

[0108] in,

[0109] The value of m ranges from 0 to 6;

[0110] R x Selected from the group consisting of hydrogen (H), halogens, cyano (-CN), and C1-C6 alkyl groups;

[0111] Preferably, R 4 and R 5 Together with the carbon atoms it is attached to, it can form a ring of the following formula.

[0112] ;or

[0113] Any two X's can be connected to form the following structure.

[0114]

[0115] In some implementations, n is 0, 1, or 2.

[0116] In some implementation schemes, R 1 Choose from the group consisting of C3-C8 cycloalkyl, Ar, C3-C8 cycloalkenyl, or C3-C8 heterocyclic groups, wherein each occurrence of R 1 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), nitro (-NO2), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O) and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl;

[0117] In some implementation schemes, R 2 Selected from the group consisting of C1-C6 alkyl and C3-C8 heterocyclic groups, wherein each occurrence of R 2 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), methyl, ethyl, propyl, isopropyl, CH2F, CHF2 or CF3;

[0118] In some implementations, A is selected from the group consisting of CH2, CH2CH2, CH(CH3), C(CH3)2, CH2CH(CH3), CH2CH2CH2, CH2CH2CH2CH2, CH(F), CH(Cl), CH(Br) or CH2C(OH)(CH3);

[0119] Preferably, R 1 Choose from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C3-C8 heterocyclic and Ar, wherein each occurrence of R 1 Optionally substituted with one or more substituents, the substituents being independently selected from the group consisting of CN, F, and methyl; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, wherein the heteroatoms are independently selected from nitrogen (N), oxygen (O), and sulfur (S);

[0120] Preferably, R 2 The group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, C1-C6 alkyl, or C3-C8 heterocyclic groups, wherein each occurrence of R... 2 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of F, methyl, or CF3;

[0121] Preferably, A is selected from the group consisting of CH2, CH2CH2, CH(CH3), C(CH3)2, CH2CH(CH3), CH2CH2CH2, CH2CH2CH2CH2, CH(F), CH(Cl), or CH(Br);

[0122] Preferably, R 1 The group consisting of cyclobutyl, cyclohexyl, p-fluorophenyl, p-cyanophenyl, 4-fluoro-2-methylphenyl, 3-methylisoxazole, cyclohex-1-enyl, pyridyl or p-fluoropyridyl is selected.

[0123] Preferably, R 2 Choose from the following groups:

[0124] ;

[0125] Preferably, A is CH2;

[0126] In another, more specific embodiment, the present invention provides or relates to a compound as shown in formula (I-4), wherein X3 is optionally -CR 4 R 5 -、-NR 6 -;

[0127]

[0128] In addition, some implementation schemes may include compounds as shown below,

[0129]

[0130] In one implementation, R 4 and R 5 Each can be independently selected from hydrogen (H), halogen, hydroxyl (-OH), amino (-NH2), cyano (-CN), -C(=O)OH, and NHCOR. 7 -(C=O)R 8 -C(=O)OR 9 The group consists of C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 heterocyclic groups, wherein each group is optionally substituted by one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -C(=O)OR', -C(=O)R', -NHR', or -NR'R"; wherein R 4 and R 5 They can together form a carbonyl (-C=O) functional group; R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl groups;

[0131] Preferably, R 4 and R 5 Each group is independently selected from the group consisting of hydrogen (H), halogen, hydroxyl (-OH), amino (-NH2), cyano (-CN), -C(=O)OH, C1-C6 alkyl, or C1-C6 alkoxy, wherein each group is optionally substituted by one or more substituents, wherein the substituents are independently selected from the group consisting of fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I); wherein R 4 and R 5 Together with the carbon atom to which it is attached, it forms a C3-C6 ring, which optionally contains 1-3 heteroatoms independently selected from nitrogen (N), oxygen (O) and sulfur (S);

[0132] Preferably, R 6 The group consisting of (C=O)methyl, -(C=O)ethyl, -(C=O)propyl, vinyl, propenyl, allyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C2-C6 alkenyl, C1-C6 alkyl, or C3-C8 cycloalkyl, wherein each occurrence of R... 6Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of halogen, methyl, ethyl, propyl, and isopropyl;

[0133] Preferably, R 4 For H, R 5 Selected from H, F, Cl, Br, I, OH, CN, -C(=O)OH, CF3, methoxy; or R 4 and R 5 Together with the carbon atom to which it is attached, it forms a C3-C6 ring, which may contain 1-3 heteroatoms independently selected from nitrogen (N), oxygen (O) and sulfur (S);

[0134] Preferably, R 6 Optionally, it may be CH2CH=CH2, methyl, -(C=O)methyl, cyclopropyl, cyclobutyl, methylcyclobutane, or ;

[0135] Preferably, R 4 and R 5 Together with the carbon atoms it is attached to, it forms a ring as shown in the following formula.

[0136] ;

[0137] Alternatively, any one or two X atoms, together with the carbon atoms they are attached to, can form the following structure.

[0138]

[0139] In another more specific embodiment, the present invention provides or relates to a compound as shown in formula (I-5), or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, deuterated derivative, metabolite or prodrug thereof;

[0140]

[0141] in,

[0142] The value of n ranges from 0 to 3;

[0143] R 1 The group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, Ar, C3-C8 cycloalkenyl, or C3-C8 heterocyclic groups is selected, wherein each occurrence of R... 1Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), nitro (-NO2), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O) and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl;

[0144] R 2 Choose from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C3-C8 heterocyclic groups or Ar, wherein each occurrence of R 2 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O) and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl;

[0145] A is a C1-C6 alkyl group, wherein A is optionally substituted by one or more substituents, the substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, nitro (-NO2), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R"; R' and R" are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl groups;

[0146] Preferably, R 1 For C(CH3)3, R 2 The form is C(CH3)2CF3, and A is CH2.

[0147] X1, X2, X3, and X4 are each independently selected -CR 3 Groups consisting of - or -N-;

[0148] R 3 Choose from hydrogen (H), halogen, hydroxyl (-OH), amino (-NH2), cyano (-CN), -C(=O)OH, and NHCOR. 7 -(C=O)R 8 -C(=O)OR 9 The group consisting of C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 heterocyclic groups, wherein each occurrence of R 3 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -C(=O)OR', -C(=O)R', -NHR', or -NR'R"; wherein R 4 and R 5 They can together form a carbonyl (-C=O) functional group; R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl groups;

[0149] R 7 R 8 and R 9 Each is independently selected from the group consisting of NH2, methyl, ethyl, propyl, or isopropyl.

[0150] Two adjacent R 3 The group and the atoms to which they are attached together form a C3-C8 heterocyclic alkyl or C3-C8 heterocyclic alkenyl group, including but not limited to the following groups:

[0151] , , ,

[0152] In another, more specific embodiment, the present invention provides or relates to a compound as shown in formula (I-6), or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, deuterated derivative, metabolite, or prodrug thereof:

[0153]

[0154] in,

[0155] The value of n ranges from 0 to 3;

[0156] R 1The group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, Ar, C3-C8 cycloalkenyl, or C3-C8 heterocyclic groups is selected, wherein each occurrence of R... 1 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), nitro (-NO2), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O) and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl;

[0157] R 2 Choose from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C3-C8 heterocyclic groups or Ar, wherein each occurrence of R 2 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O) and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl;

[0158] A is a C1-C6 alkyl group, wherein A is optionally substituted by one or more substituents, the substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, nitro (-NO2), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R"; R' and R" are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl groups;

[0159] X1, X2, X3, and X4 are each independently selected -CR 3 Groups consisting of - or -N-;

[0160] R 3 Choose from hydrogen (H), halogen, hydroxyl (-OH), amino (-NH2), cyano (-CN), -C(=O)OH, and NHCOR. 7 -(C=O)R 8 -C(=O)OR 9 The group consisting of C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 heterocyclic groups, wherein each occurrence of R 3 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, and halo-C1-C6 alkoxy, 9 R 4 and R 5 They can together form a carbonyl (-C=O) functional group; R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl groups;

[0161] R 7 R 8 and R 9 Each is independently selected from the group consisting of NH2, methyl, ethyl, propyl, or isopropyl.

[0162] In some implementations, n is 0, 1, or 2;

[0163] Preferably, n is 0 or 1;

[0164] Specifically, n is 1;

[0165] In some implementation schemes, R 1 Choose from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C1-C6 alkyl, C3-C8 cycloalkyl, or Ar, wherein each occurrence of R... 1Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), nitro (-NO2), methyl, ethyl, propyl, isopropyl, CH2F, CHF2, CF3, OCF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C1-C6 alkoxy, -C(=O)OR', -C(=O)R', -NHR', or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O), and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl;

[0166] Preferably, R 1 Choose from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C1-C6 alkyl, C3-C8 cycloalkyl, or Ar, wherein each occurrence of R... 1 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), methyl, ethyl, propyl, isopropyl, CH2F, CHF2, CF3, OCF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C1-C6 alkoxy, -C(=O)OR', -C(=O)R', -NHR', or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O), and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl;

[0167] Specifically, R 1 It is p-fluorophenyl;

[0168] In some implementation schemes, R 2 Choose from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, C1-C6 alkyl, C3-C8 heterocyclic groups, or Ar, wherein each occurrence of R... 2Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), methyl, ethyl, propyl, isopropyl, CH2F, CHF2, CF3, OCF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C1-C6 alkoxy, -C(=O)OR', -C(=O)R', -NHR', or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O), and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl;

[0169] Preferably, R 2 The group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and C1-C6 alkyl groups is selected, wherein each occurrence of R... 2 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I);

[0170] Specifically, R 2 For tert-butyl;

[0171] In some implementations, A is selected from the group consisting of CH2, CH2CH2, CH(CH3), C(CH3)2, CH2CH(CH3) or CH2CH2CH2;

[0172] Preferably, A is selected from the group consisting of CH2, CH2CH2, CH(CH3), C(CH3)2, CH2CH(CH3), and CH2CH2CH2;

[0173] Specifically, A is CH2;

[0174] In some preferred embodiments, X1, X2, X3, and X4 are each independently selected from -CH- or -N- to form a group consisting of the following structures:

[0175] ;

[0176] In another, more specific embodiment, the present invention provides or relates to a compound as shown in formula (I-7), or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, deuterated derivative, metabolite, or prodrug thereof:

[0177]

[0178] in,

[0179] The value of n ranges from 0 to 3;

[0180] R 1 The group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, Ar, C3-C8 cycloalkenyl, or C3-C8 heterocyclic groups is selected, wherein each occurrence of R... 1 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), nitro (-NO2), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O) and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl;

[0181] R 2 Choose from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C3-C8 heterocyclic groups or Ar, wherein each occurrence of R 2 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O) and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl;

[0182] L is -NHSO2-;

[0183] A is a C1-C8 alkyl group, wherein A is optionally substituted by one or more substituents independently selected from fluorine (-F), chlorine (-Cl), and bromine (-Br);

[0184] X1, X2, X3, and X4 are each independently selected -CR 3Groups consisting of - or -N-;

[0185] R 3 Choose from hydrogen (H), halogen, hydroxyl (-OH), amino (-NH2), cyano (-CN), -C(=O)OH, and NHCOR. 7 -(C=O)R 8 -C(=O)OR 9 The group consisting of C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 heterocyclic groups, wherein each occurrence of R 3 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -C(=O)OR', -C(=O)R', -NHR', or -NR'R"; wherein R 4 and R 5 They can together form a carbonyl (-C=O) functional group; R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl groups;

[0186] R 7 R 8 and R 9 Each is independently selected from the group consisting of NH2, methyl, ethyl, propyl, or isopropyl.

[0187] In some implementations, n is 0, 1, or 2;

[0188] In some implementation schemes, R 1 Choose from groups consisting of cyclobutyl, cyclopentyl, cyclohexyl, or Ar, where R appears each time. 1 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), nitro (-NO2), methyl, ethyl, propyl, isopropyl, CH2F, CHF2, CF3, OCF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C1-C6 alkoxy, -C(=O)OR', -C(=O)R', -NHR', or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O), and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl;

[0189] In some implementation schemes, R 2Choose from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, C1-C6 alkyl, C3-C8 heterocyclic groups, or Ar, wherein each occurrence of R... 2 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), methyl, ethyl, propyl, isopropyl, CH2F, CHF2, CF3, OCF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C1-C6 alkoxy, -C(=O)OR', -C(=O)R', -NHR', or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O), and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl;

[0190] In some implementations, A is selected from the group consisting of CH2, CH2CH2, CH(CH3), C(CH3)2, CH2CH(CH3), CH2CH2CH2, CH2CH2CH2CH2, CH(F), CH(Cl), or CH(Br);

[0191] Preferably, n is 0 or 1.

[0192] Preferably, R 1 Choose from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or Ar, where R appears each time. 1 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I);

[0193] Preferably, R 2 Choose from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, C1-C6 alkyl, or Ar, wherein each occurrence of R... 2 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), methyl, ethyl, propyl, isopropyl, CH2F, CHF2 or CF3;

[0194] Preferably, A is selected from the group consisting of CH2, CH2CH2, CH(CH3), C(CH3)2, CH2CH(CH3), CH2CH2CH2, CH(F), CH(Cl), or CH(Br);

[0195] More preferably, n is 1;

[0196] More preferably, R 1 Choose from the group consisting of cyclobutyl, cyclohexyl, or p-fluorophenyl;

[0197] More preferably, R 2 The group consisting of ethyl, isopropyl, tert-butyl, hydroxy-substituted tert-butyl, or phenyl groups is selected.

[0198] More preferably, A is CH2 or CH(Cl);

[0199] Some implementation schemes are further illustrated by the following compounds or their stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, deuterated derivatives, metabolites, or prodrugs:

[0200]

[0201]

[0202]

[0203]

[0204] In some embodiments of the invention, one or more hydrogen atoms may be substituted with deuterium. It has been well demonstrated that deuteration of physiologically active compounds can both preserve the pharmacological properties of their hydrogen counterparts and positively impact their metabolic outcomes. In the compounds of the present invention, selectively replacing one or more hydrogen atoms with deuterium atoms can improve the safety, tolerability, and efficacy of the compound compared to its all-hydrogen counterpart.

[0205] Methods for introducing deuterium into compounds are well-established. The compounds of this invention can be tested using metabolic studies known in the art to determine sites where deuterium isotopes are selectively introduced, where the isotopes are not metabolized. Furthermore, these studies can pinpoint metabolic sites as locations where deuterium atoms will be inserted. How to use

[0206] This invention provides a pharmaceutical composition comprising a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), or (I-7), a stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, a deuterated derivative, a metabolite or prodrug, and at least one pharmaceutically acceptable excipient. In a specific embodiment, the compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), or (I-7) is present in the pharmaceutical composition in an effective amount. In a specific embodiment, the compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), or (I-7) is provided in a therapeutically effective amount. In specific implementations, compounds as shown in formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), or (I-7) are provided in a preventative effective amount.

[0207] This invention provides the use of compounds, stereoisomers thereof, pharmaceutically acceptable salts, solvates, deuterated derivatives, metabolites or prodrugs, or pharmaceutical compositions thereof, as shown in formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6) or (I-7), in the preparation of medicaments for the prevention and / or treatment of diseases related to the KCNQ2 / 3 (Kv7.2 / 3) channel.

[0208] In some implementations, these related diseases include epilepsy, smooth muscle contraction disorders, neuropathic pain, inflammatory pain, persistent pain, cancer pain, postoperative pain, migraine, depression, anxiety, substance abuse, schizophrenia, bladder disorders, vascular disorders, movement disorders, dystonia, mania, hearing impairment, bipolar disorder, neurodegenerative diseases, or combinations thereof.

[0209] The present invention provides the use of compounds of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6) or (I-7), their stereoisomers, pharmaceutically acceptable salts, solvates, deuterated derivatives, metabolites or prodrugs, or pharmaceutical compositions described herein, in the preparation of KCNQ2 / 3 (Kv7.2 / 3) channel activators.

[0210] These medications can be used to treat, relieve, or prevent epilepsy, smooth muscle contraction disorders, neuropathic pain, inflammatory pain, persistent pain, cancer pain, postoperative pain, migraine, depression, anxiety, substance abuse, schizophrenia, bladder disorders, vascular disorders, movement disorders, dystonia, mania, hearing impairment, bipolar disorder, neurodegenerative diseases, or combinations thereof.

[0211] The compounds of this invention possess novel structures, and in vitro studies have confirmed their excellent potassium channel regulatory activity. Preferably, they exhibit potent agonistic activity against KCNQ2 / 3 (Kv7.2 / 3) channels, thus making them suitable for the preparation of medicaments for the treatment and / or prevention of KCNQ2 / 3 (Kv7.2 / 3) channel-related diseases and conditions. Specifically, these diseases and conditions include epilepsy, smooth muscle contraction disorders, neuropathic pain, inflammatory pain, persistent pain, cancer pain, postoperative pain, migraine, depression, anxiety disorders, substance abuse, schizophrenia, bladder disorders, vascular disorders, movement disorders, dystonia, mania, hearing impairment, bipolar disorder, neurodegenerative diseases, or combinations thereof. Terms and Definitions

[0212] Unless otherwise stated, the definitions of groups and terms described in this specification and claims, including examples, illustrations, preferred forms, descriptions in tables, and specific compounds in the examples, are freely combined and integrated. Therefore, subsequent definitions of groups and compound structures should be considered within the scope of the specification.

[0213] The compounds described herein may have asymmetric centers. The compounds of this invention containing asymmetric substituted atoms can be isolated in optically active or racemic forms. Unless otherwise explicitly stated for stereochemical or isomeric forms, all chiral isomers, diastereomers, racemates, and geometric isomers of the described structures apply.

[0214] As used in this article, the term "halogen" refers to F, Cl, Br, or I.

[0215] As used herein, the term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon containing 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neopentyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl, and their various branched isomers. The alkyl group may optionally be substituted with 0 to 6 substituents selected from fluorine, chlorine, bromine, iodine, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, amide, alkenyl, alkynyl, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, 3 to 8-membered carbocyclic, 3 to 8-membered heterocyclic, 3 to 8-membered carboepoxy, 3 to 8-membered heteroepoxy, carboxyl, or carboxylic acid esters. For example, a "C1-C6 alkyl" group is an alkyl group having one to six carbon atoms.

[0216] As used herein, the term "halogenated alkyl" refers to an alkyl group having a specified number of carbon atoms, wherein one or more hydrogen atoms of the alkyl group are substituted with halogen groups. For example, a "halogenated C1-C3 alkyl" group is an alkyl group having one to six carbon atoms, wherein one or more hydrogen atoms of the alkyl group are substituted with halogen groups.

[0217] As used herein, the term "cycloalkyl" refers to a stable, non-aromatic monocyclic or bicyclic (fused, bridged, or spirocyclic) saturated hydrocarbon group consisting only of carbon and hydrogen atoms, having a specified number of cyclic carbon atoms, and connected to the rest of the molecule by a single bond. For example, a "C3-C8 cycloalkyl" group can be a saturated, monovalent monocyclic or bicyclic hydrocarbon ring containing 3 to 6 carbon atoms, including fused or bridged polycyclic systems such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. C3-C6 cycloalkyl groups may optionally be substituted with 0 to 6 substituents selected from fluorine, chlorine, bromine, iodine, carbonyl, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, amide, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclic, heterocyclic, carboepoxy, heteroepoxy, carboxyl, or carboxylic acid esters. The term "C3-C6 cycloalkyl" as used herein has the same meaning as defined herein.

[0218] As used herein, the term "alkoxy" refers to an -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy. The alkyl group may optionally be substituted with 0 to 6 substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclic, heterocyclic, carboepoxy, heteroepoxy, carboxyl, or carboxylic acid esters. The term "alkoxy" as used herein has the same meaning as defined herein.

[0219] As used herein, the term "alkenyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing one or more carbon-carbon double bonds, having a specified number of carbon atoms, and connected to the rest of the molecule by single bonds. For example, a "C2-C6 alkenyl" group is an alkenyl group having two to six carbon atoms and at least one carbon-carbon double bond. Non-limiting examples include vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, and 3-hexenyl.

[0220] As used herein, the term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group containing 3 to 8 carbon atoms and having at least one carbon-carbon double bond. It includes monocyclic and bicyclic systems, wherein bicyclic systems may comprise spirocyclic, fused, or bridged rings. In some embodiments, C4-C6 cycloalkenyl groups are particularly preferred, referring to partially unsaturated cyclic hydrocarbon groups containing 4 to 6 carbon atoms and having at least one carbon-carbon double bond. Examples of C4-C6 cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclohexadienyl.

[0221] As used herein, the term "aromatic," whether used alone or as part of another group, refers to a conjugated planar ring or ring system containing delocalized electrons, of optional substitution, either homocyclic or heterocyclic. These aromatic groups preferably contain 5 to 14 atoms in the ring moiety, including monocyclic (such as furan or benzene), bicyclic, or tricyclic groups. The term "aromatic" includes the definition of "aryl" below.

[0222] As used herein, the term "aryl" or "Ar," when used alone or as part of another group, refers to an optionally substituted homocyclic aromatic group, preferably a monocyclic or bicyclic group containing 6 to 10 carbon atoms, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl, or substituted naphthyl.

[0223] As used herein, the term "carbocyclic" or "carbocyclic group" refers to an optionally substituted, aromatic or non-aromatic homocyclic ring or ring system, wherein all atoms in the ring are carbon atoms, preferably 5 or 6 carbon atoms per ring. Exemplary substituents include one or more of the following groups: hydrocarbon group, substituted hydrocarbon group, alkyl group, alkoxy group, acyloxy group, alkenyl group, alkenyloxy group, aryl group, aryloxy group, amino group, amide group, aldehyde group, carbamoyl group, carbocyclic group, cyano group, ester group, ether group, halogen group, heterocyclic group, hydroxyl group, ketol group, ketal group, phosphate ester group, nitro group, and thio group.

[0224] As used herein, the term "heteroaryl," when used alone or as part of another group, refers to an optionally substituted aromatic group containing at least one heteroatom in the ring, preferably a monocyclic or bicyclic group containing 5 or 6 atoms per ring. The heteroaryl group preferably contains 1 or 2 oxygen atoms and / or 1 to 4 nitrogen atoms, and is bonded to the remainder of the molecule via carbon atoms. Examples include furanyl, benzofuranyl, oxazolyl, isoxazolyl, oxadiazolyl, benzooxazolyl, benzooxadiazolyl, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indoleyl, isindoleyl, inazinyl, benzimidazoleyl, indazoleyl, benzotriazolyl, tetrazolopyrazinyl, carbazoleyl, purineyl, quinolinyl, isoquinolinyl, imidazolepyridyl, etc.

[0225] As used herein, the term "heterocyclic" or "heterocyclic group" refers to an optionally substituted, fully saturated or unsaturated monocyclic or bicyclic group containing at least one heteroatom in at least one ring, preferably a monocyclic or bicyclic group containing 5 or 6 atoms per ring. The heterocyclic group preferably contains 1 or 2 oxygen atoms and / or 1 to 4 nitrogen atoms, and is bonded to the remainder of the molecule via carbon atoms or heteroatoms. Exemplary heterocyclic groups include the heteroaryl compounds mentioned above.

[0226] As used in this article, the term "stereoisomer" refers to isomers that differ only in the spatial arrangement of atoms, including cis-trans isomers, enantiomers, and conformational isomers.

[0227] As used herein, the term “optional substitution” refers to a group that is either unsubstituted or substituted by a substituent subsequently specified. For example, a group “optionally substituted by 1-2 halogens” means that it is unsubstituted, substituted by 1 halogen group, or substituted by 2 halogen groups.

[0228] Unless otherwise stated, the compounds of this invention, whether identified by chemical name or chemical structure, include all stereoisomers (e.g., enantiomers and diastereomers), double bond isomers (e.g., (Z) and (E)), conformational isomers, and tautomers of the compounds identified by the chemical names and chemical structures provided herein. Furthermore, single stereoisomers, double bond isomers, conformational isomers, and tautomers, as well as mixtures of stereoisomers, double bond isomers, conformational isomers, and tautomers, are all within the scope of this invention.

[0229] The term "therapeutic effective amount" refers to an amount sufficient to effectively treat a disease. Effective amounts vary depending on the type of compound, the type of disease, its severity, and the patient's age, but those skilled in the art can adjust accordingly.

[0230] The term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within reasonable medical judgment, are suitable for contact with patient tissues without causing excessive toxicity, irritation, allergic reactions, or other complications, have a favorable benefit-risk ratio, and are effective for their intended use. Example Section

[0231] The following sections provide a detailed description of the general formula compounds of the present invention, their preparation methods, and applications, based on specific embodiments. These embodiments are illustrative and explanatory and should not be construed as limiting the scope of the invention. Any techniques implemented based on the content of this invention fall within its intended scope of protection.

[0232] Unless otherwise stated, the raw materials and reagents used in the examples are commercially available or can be prepared by known methods.

[0233] Compounds are named according to conventional nomenclature rules in the art, while commercially available reagents are referred to by their supplier catalog names.

[0234] Data were collected using various instruments. NMR was recorded on a Bruker Avance Neo 400 MHz liquid superconducting NMR spectrometer at 400 MHz and 600 MHz, with TMS (δ = 0) as the internal standard and DMSO-d6 or CDCl3 as the solvent. Mass spectrometry data were acquired using a Waters ACQUITY UPLC system equipped with an ACQUITY UPLCBEH C8 column (50 mm × 2.1 mm, 1.7 μm, 20180306-C8-08), with mobile phase A of 0.01% TFA / H2O and mobile phase B of acetonitrile, at a flow rate of 0.2 mL / min, a column temperature of 30°C, and a detection wavelength of UV-210 nm. HPLC analysis was performed using a ThermoUltiMate 3000 liquid chromatograph with a Venusil ASB C18 column (4.6 × 250 mm, 5 μm). Mobile phase A was an aqueous phosphoric acid solution (pH = 1.5), and mobile phase B was acetonitrile. The flow rate was 1.0 mL / min, the column temperature was 35°C, the detection wavelength was UV-215 nm, and the injection volume was 2 μL. Gradient elution conditions included an initial phase of 95% A and 5% B for 10 minutes, followed by a transition to 20% A and 80% B over 5 minutes, and finally a return to 95% A and 5% B over 5 minutes. The percentages represent the volume fraction of the mobile phase in the elution solvent. Abbreviations

[0235] AcOH: Acetic acid

[0236] ACN: Acetonitrile

[0237] DCM: Dichloromethane

[0238] DIEA: N,N-Diisopropylethylamine

[0239] DMF: Dimethylformamide

[0240] DPPA: Diphenyl azidophosphate

[0241] EtOAc: Ethyl acetate

[0242] MTBE: tert-butyl methyl ether

[0243] NaBH3CN: Sodium cyanoborohydride

[0244] NIS: N-iodosuccinimide

[0245] TEA: Triethylamine

[0246] TFA: Trifluoroacetic acid

[0247] THF: Tetrahydrofuran

[0248] SFC: Supercritical Fluid Chromatography

[0249] %MPE: Percentage of maximum possible effect

[0250] LCMS: Liquid Chromatography-Mass Spectrometry

[0251] NMR: Nuclear Magnetic Resonance

[0252] HPLC: High Performance Liquid Chromatography

[0253] TMS: Tetramethylsilane

[0254] min: minutes

[0255] mmol: millimole

[0256] mg: milligram

[0257] μg: micrograms

[0258] g: grams

[0259] kg: kilogram

[0260] eq: equivalent

[0261] mm: millimeter

[0262] µm: micrometer

[0263] nm: nanometer

[0264] mL: milliliters

[0265] μL: microliters

[0266] hr / h, h: hour

[0267] M: Moles per liter

[0268] μM: micromoles per liter

[0269] μmol: micromolar

[0270] mV: millivolt

[0271] ms: milliseconds

[0272] MHz: Megahertz

[0273] TLC: Thin-layer chromatography

[0274] Rt: Retention time

[0275] Rf: Retention factor

[0276] EtOH: Ethanol

[0277] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate

[0278] ESI: Electrospray Ionization

[0279] HCl: Hydrogen chloride

[0280] MTBE: Methyl tert-butyl ether

[0281] NH4Cl: Ammonium chloride

[0282] NaHMDS: Sodium hexamethyldisilamide

[0283] Na2SO4: Sodium sulfate

[0284] HClO4: perchloric acid

[0285] K2CO3: Potassium carbonate

[0286] SiO2: Silicon dioxide

[0287] H2: Hydrogen gas

[0288] PdCl2(PPh3)2: Bis(triphenylphosphine)palladium chloride

[0289] MeOH: Methanol

[0290] t-BuOK: Potassium tert-butoxide

[0291] NaHCO3: Sodium bicarbonate

[0292] NH2NH2.H2O: hydrazine hydrate

[0293] KOH: Potassium hydroxide

[0294] t-BuONa: Sodium tert-butoxide

[0295] NH4HCO3: Ammonium bicarbonate

[0296] Pd(dppf)Cl2: [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride

[0297] Pd / C: Palladium on carbon

[0298] DPPA: Diphenyl azidophosphate

[0299] Cs2CO3: Cesium carbonate

[0300] t-BuOH: tert-butanol

[0301] DMEM: Duchenne Modified Eagle Medium

[0302] FBS: Fetal bovine serum

[0303] DMSO: Dimethyl sulfoxide

[0304] NaCl: Sodium chloride

[0305] KCl: Potassium chloride

[0306] MgCl2: Magnesium chloride

[0307] CaCl2: Calcium chloride

[0308] HEPES: 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid

[0309] NaH2PO4 2H₂O: Sodium dihydrogen phosphate dihydrate

[0310] EGTA: Ethylene glycol tetraacetic acid

[0311] Mg-ATP: Magnesium adenosine 5′-triphosphate

[0312] EDTA: Disodium ethylenediaminetetraacetate

[0313] rpm: revolutions per minute

[0314] KCNQ: Q subfamily of potassium channels

[0315] SPF: Specific Pathogen-Free

[0316] ICR: Cancer Research Institute

[0317] SD: Sprague Dowley

[0318] SnCl2·2H2O: Tin(II) chloride dihydrate

[0319] CbzCl: Benzyl chloroformate

[0320] N2: Nitrogen gas

[0321] IP: Intraperitoneal cavity

[0322] PTZ: Pentyltetrazole Example Example 1: Synthesis of Compound 1

[0323]

[0324] Step 1. Preparation of intermediate 1a

[0325]

[0326] At 0°C, compound 1-(tert-butyl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-amine (100 mg, 435 μmol, 1.00 μmol) was subjected to oxidation. eq DIEA (141 mg, 1.09 mmol, 190 μL, 2.50 mmol) was added to a DCM (1.00 mL) solution containing HCl. eq ) and 3,3-dimethylbutyryl chloride (117 mg, 871 μmol, 121 μL, 2.00 eq The mixture was stirred at 20°C for 2 hours. The reaction mixture was poured into H2O (20.0 mL) and extracted with DCM (20.0 mL × 3). The combined organic layers were washed with saturated brine (20.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was analyzed by preparative TLC (SiO2, petroleum ether / ethyl acetate = 6 / 1, R...). f Purification with 0.57 yielded compound 1a (110 mg, 282 μmol, yield 64.9%) as a yellow solid.

[0327] LCMS: Rt = 0.428 min, m / z: 390.6, M+H +

[0328] Step 2. Preparation of Compound 1

[0329]

[0330] Compound 1a (110 mg, 282 μmol, 1.00 mg) was subjected to treatment. eq Add K₂CO₃ (78.1 mg, 565 μmol, 2.00 mL) to a MeOH (2.00 mL) solution. eq The mixture was stirred at 50°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was analyzed by preparative HPLC (HCl conditions; column: Phenomenex luna C18 150). 25 mm The compound was obtained by stirring in HCl / MeOH (2M, 0.5 mL, 5.00 eq) for 10 µm; mobile phase: [water (HCl)-ACN]; gradient: phase B from 16% to 46% over 10 minutes). The compound was then added to HCl / MeOH (2M, 0.5 mL, 5.00 eq) and stirred at 20°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give compound 1 (58.0 mg, 172 μmol, yield 60.8%, purity 97.1%, HCl) as a white solid.

[0331] LCMS: Rt = 0.296 min, m / z: 292.2, M+H +

[0332] HPLC: Rt = 1.199 min

[0333] 1 H NMR: 400 MHz, DMSO-d6

[0334] δ 14.3 (s, 1H), 12.2 (s, 1H), 2.86 (s, 2H), 2.58 (s, 2H), 2.35 (s,2H), 1.76-1.77 (m, 4H), 1.66 (s, 9H), 1.05 (s, 9H).

[0335] The preparation methods for the compounds listed below are described in Example 1. Example 2: Synthesis of Compound 7

[0336]

[0337] Step 1. Preparation of intermediate 7a

[0338]

[0339] At 0°C, acetonitrile (1.21 g, 29.4 mmol, 1.55 mL, 1.30 eq) was added dropwise to a toluene (40.0 mL) solution of 2-chloro-4-(trifluoromethyl)pyridine (4.10 g, 22.6 mmol, 1.00 eq). After the addition was complete, the mixture was stirred at this temperature for 30 min, and then NaHMDS (1 M, 33.9 mL, 1.50 eq) was added dropwise at 0°C. The resulting mixture was stirred at 0°C for 3.5 h. The reaction mixture was diluted with an aqueous solution of NH4Cl (200 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with saturated brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was analyzed by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1, R f = 0.36) purification yielded compound 7a (2.70 g, 14.2 mmol, yield 62.8%, purity 97.7%), a yellow oily substance.

[0340] LCMS: Rt = 0.267 min, m / z: 187.1 M+H +

[0341] 1 H NMR: 400 MHz, CDCl3

[0342] δ 8.82 (d, J = 5.2 Hz, 1H), 7.68 (s, 7.2H), 7.54 (d, J = 4.4 Hz, 1H), 4.07 (s, 9H).

[0343] Step 2. Preparation of intermediate 7b

[0344]

[0345] To a solution of compound (E)-N-((tris(benzenesulfonyl)oxy)ethyliminolate (6.21 g, 21.8 mmol, 1.50 eq) in dioxane (50.0 mL), HClO4 (4.37 g, 43.5 mmol, 2.63 mL, 3.00 eq) was added, and the mixture was stirred at 0°C for 0.5 h. After adding ice water, the precipitate was collected. The filter cake was dissolved in dichloromethane (20.0 mL) and dried over Na2SO4. To this mixture, a solution of compound 7a (2.70 g, 14.5 mmol, 1.00 eq) in DCM (20.0 mL) was added, and the mixture was stirred at 20°C for 12 h. At 0°C, a methanol (20.0 mL) solution of the crude product was added with K2CO3 (500 mg), and the mixture was stirred at 20°C for 2 h. After adding water, the mixture was extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with saturated brine (30.0 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was analyzed by column chromatography (SiO₂, petroleum ether / ethyl acetate = 80 / 1 to 10 / 1, R₂). f =0.27) was purified to give compound 7b (1.35 g, 6.68 mmol, yield 46.1%, purity 99.6%), as a yellow solid.

[0346] LCMS: Rt = 0.314 min, m / z: 202.0, M+H +

[0347] LCMS: Rt = 0.318 min, m / z: 202.1, M+H +

[0348] Step 3. Preparation of intermediate 7c

[0349]

[0350] Under a nitrogen atmosphere, PtO2 (564 mg, 2.49 mmol, 1.00 eq) was added to a MeOH (5.00 mL) solution of compound 7b (500 mg, 2.49 mmol, 1.00 eq) and HCl (12 M, 207 μL, 1.00 eq). The suspension was degassed and purged three times with H2. The mixture was stirred at 60°C for 12 hours under a H2 (50 Psi) atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give the residue. The residue was analyzed by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1, R... f = 0.04) purification yielded compound 7c (334 mg, 1.63 mmol, yield 65.5%, purity 100%), a white solid.

[0351] LCMS: Rt = 0.145 min, m / z: 206.1 M+H +

[0352] LCMS: Rt = 0.144 min, m / z: 206.1 M+H +

[0353] Step 4. Preparation of intermediate 7d

[0354]

[0355] At 0°C, NIS (472 mg, 2.10 mmol, 1.00 eq) was added to a solution of compound 7c (430 mg, 2.10 mmol, 1.00 eq) in ACN (5.00 mL). The mixture was stirred at 20°C under a N2 atmosphere for 2 hours. The reaction mixture was diluted with H2O (20.0 mL) and extracted with EtOAc (10.0 mL × 3). The combined organic layers were washed with saturated brine (10.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was analyzed by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 0 / 1, R... f = 0.48) purification yielded compound 7d (610 mg, 1.75 mmol, yield 83.7%, purity 95.2%) as a yellow solid.

[0356] LCMS: Rt = 0.342 min, m / z: 332.0, M+H +

[0357] Step 5. Preparation of intermediate 7e

[0358]

[0359] To a solution of compound 7d (610 mg, 1.84 mmol, 1.00 eq) and (4-fluorophenyl)boronic acid (258 mg, 1.84 mmol, 1.00 eq) in dioxane (3.00 mL) and H2O (3.00 mL), Na2CO3 (391 mg, 3.68 mmol, 2.00 eq) and PdCl2(PPh3)2 (129 mg, 184 μmol, 0.1 eq) were added. The mixture was stirred at 100°C under a N2 atmosphere for 2 hours. The reaction mixture was diluted with H2O (20.0 mL) and extracted with EtOAc (20.0 mL × 3). The combined organic layers were washed with saturated brine (20.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was analyzed by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 0 / 1, R... f Purification with 0.18 yielded compound 7e (245 mg, 819 μmol, yield 44.4%) as a yellow solid.

[0360] LCMS: Rt = 0.368 min, m / z: 300.1, M+H +

[0361] Step 6. Preparation of intermediate 7f

[0362]

[0363] To a DCM solution of compound 7e (245 mg, 819 μmol, 1.00 eq) in 3.00 mL of DCM, DIEA (317 mg, 2.46 mmol, 428 μL, 3.00 eq) and 3,3-dimethylbutyryl chloride (220 mg, 1.64 mmol, 227 μL, 2.00 eq) were added. The mixture was stirred at 20°C for 12 hours. The reaction mixture was diluted with H₂O (50.0 mL) and extracted with DCM (20.0 mL × 3). The combined organic layers were washed with saturated brine (20.0 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue, compound 7f (405 mg, crude), as a yellow oil.

[0364] LCMS: Rt = 0.582 min, m / z: 496.3, M+H +

[0365] Step 7. Preparation of Compound 7

[0366]

[0367] K₂CO₃ (226 mg, 1.63 mmol, 2.00 eq) was added to a MeOH solution of compound 7f (405 mg, 817 μmol, 1.00 eq) in 5.00 mL. The mixture was stirred at 50°C for 2 hours. The reaction mixture was quenched by adding H₂O (20.0 mL) and then extracted with EtOAc (20.0 mL × 2). The combined organic layers were washed with saturated brine (20.0 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was analyzed by preparative HPLC (HCl conditions; column: CD04-Welch Ultimate C18 150). 25 The compound was obtained by stirring in HCl / MeOH (2M, 0.5 mL, 5.00 eq) at 20°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give compound 7 (280 mg, 705 μmol, yield 86.2%, purity 100%) as a white solid. (Mobile phase: [water (HCl)-ACN]; gradient: phase B from 39% to 69% within 10 minutes)

[0368] LCMS: Rt = 0.456 min, m / z: 398.2, M+H +

[0369] LCMS: Rt = 2.450 min, m / z: 398.2, M+H +

[0370] 1 H NMR: 400 MHz, DMSO- d 6

[0371] 19 F NMR: 400 MHz, DMSO- d 6

[0372] δ9.42 (s, 1H), 7.35-7.38 (m, 2H), 7.16-7.20 (m, 2H), 4.23-4.26 (m,1H), 4.04-4.09 (m, 1H), 2.91-3.01 (m, 3H), 2.28 (d, J = 12.4H, 1H), 2.03-2.08(m, 3H), 0.94 (s, 9H).

[0373] The preparation methods for the compounds listed below are described in Example 2. Example 3: Synthesis of Compound 40

[0374]

[0375] Step 1. Preparation of intermediate 40a

[0376]

[0377] To a solution of 1H-pyrazole-3,5-dicarboxylate (2.00 g, 9.42 mmol, 1.00 eq) in ACN (10.0 mL), K₂CO₃ (1.30 g, 9.42 mmol, 1.00 eq) and ethyl 5-bromopentanoate (1.97 g, 9.42 mmol, 1.51 mL, 1.00 eq) were added. The mixture was stirred at 90°C for 2 hours. LCMS showed that 1H-pyrazole-3,5-dicarboxylate was completely consumed and the target molecular weight was detected. The reaction mixture was diluted with H₂O (20.0 mL) and extracted with DCM (20.0 mL × 3). The combined organic layers were washed with saturated brine (20.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 40a (2.90 g, 8.52 mmol, yield 90.4%) as a yellow solid.

[0378] LCMS: Rt = 0.398 min, m / z: 341.3, M+H +

[0379] Step 2. Preparation of intermediate 40b

[0380]

[0381] t-BuOK (1M, 5.88 mL, 1.00 eq) was added to a THF (20.0 mL) solution of compound 40a (2.00 g, 5.88 mmol, 1.00 eq). The mixture was stirred at 0°C for 4 hours. The mixture was quenched with NaHCO3 (15.00 mL) and extracted with DCM (15.00 mL). The organic layer was washed with saturated brine (15.0 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give compound 40b (1.73 g, crude product) as a white solid.

[0382] LCMS: Rt = 2.455 min, m / z: 295.1, M+H +

[0383] Step 3. Preparation of intermediate 40c

[0384]

[0385] HCl (12M, 2.45 mL, 5.00 eq) was added to a solution of compound 40b (1.73 g, 5.88 mmol, 1.00 eq) in H₂O (20.0 mL). The mixture was stirred at 100°C for 12 hours. The mixture was quenched with NaHCO₃ (20.0 mL), extracted with DCM (20.0 mL × 3), the organic layer was washed with saturated brine (15.0 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The extract was then subjected to column chromatography (SiO₂, petroleum ether / ethyl acetate = 0 / 1, R₂). f =0.18) The residue was purified to give compound 40c (857 mg, 4.41 mmol, yield 75.0%) as a white solid.

[0386] LCMS: Rt = 0.834 min, m / z: 195.0, M+H +

[0387] Step 4. Preparation of intermediate 40d

[0388]

[0389] TEA (1.56 g, 15.4 mmol, 2.15 mL, 3.50 eq) and DPPA (2.06 g, 7.49 mmol, 1.62 mL, 1.70 eq) were added dropwise to a t-BuOH (10.0 mL) solution of compound 40c (856 mg, 4.41 mmol, 1.00 eq). After the addition was complete, the mixture was stirred at 70°C for 12 hours. The mixture was quenched with H2O (20.0 mL) and extracted with DCM (20.0 × 3 mL). The organic layer was washed with saturated brine (15.0 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Then, it was analyzed by column chromatography (SiO2, petroleum ether / ethyl acetate = 0 / 1, R...). f =0.45) The residue was purified to give compound 40d (550 mg, 2.07 mmol, yield 47.0%) as a white solid.

[0390] LCMS: Rt = 0.341 min, m / z: 210.2, M-56+H +

[0391] Step 5. Preparation of intermediate 40e

[0392]

[0393] At 25°C, NH₂NH₂·H₂O (235 mg, 4.71 mmol, 228 μL, 5.00 eq) was added dropwise to a diethylene glycol (2.50 mL) solution of compound 40d (250 mg, 942 μmol, 1.00 eq). After the addition was complete, the mixture was stirred at 140°C for 1 hour, and then KOH (185 mg, 3.30 mmol, 3.5 eq) was added dropwise at 25°C. The resulting mixture was stirred at 140°C for 2 hours. The mixture was quenched with H₂O (20.0 mL) and extracted with DCM (20.0 × 3 mL). The organic layer was washed with saturated brine (15.0 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The extract was then subjected to column chromatography (SiO₂, petroleum ether / ethyl acetate = 0 / 1, R...). f =0.24) The residue was purified to give compound 40e (250 mg, 1.65 mmol, yield 87.7%) as a white solid.

[0394] LCMS: Rt = 0.126 min, m / z: 152.2, M+H +

[0395] Step 6. Preparation of intermediate 40f

[0396]

[0397] At 0°C, NIS (297 mg, 1.32 mmol, 1.00 eq) was added to a solution of compound 40e (200 mg, 1.32 mmol, 1.00 eq) in ACN (2.00 mL). The mixture was stirred at 25°C for 1 hour. The reaction was quenched by adding H2O (20.0 mL), extracted with DCM (20.0 mL × 3), the organic layer was washed with saturated brine (15.0 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The extract was then subjected to column chromatography (SiO2, petroleum ether / ethyl acetate = 0 / 1, R...). f =0.82) The residue was purified to give compound 40f (180 mg, 649 μmol, yield 39.3%) as a white solid.

[0398] LCMS: Rt = 0.304min, m / z: 278.0, M+H +

[0399] Step 7. Preparation of 40g of intermediate

[0400]

[0401] Under a nitrogen atmosphere, Catacxium PdG3 (44.6 mg, 61.3 μmol, 0.10 eq) and t-BuONa (117 mg, 1.23 mmol, 2.00 eq) were added to a solution of compound 40f (170 mg, 613 μmol, 1.00 eq) and compound 4-fluorophenylboronic acid (257 mg, 1.84 mmol, 3.00 eq) in H2O (1.50 mL) and dioxane (1.50 mL). The mixture was stirred at 100°C for 2 hours. The mixture was quenched with H2O (20.0 mL), extracted with DCM (20.0 mL × 3), the organic layer was washed with saturated brine (15.0 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The results were then obtained by column chromatography (SiO2, petroleum ether / ethyl acetate = 0 / 1, R...). f = 0.82) The residue was purified to give 40 g of the compound (136 mg, 542 μmol, yield 88.4%, purity 97.9%) as a white solid.

[0402] LCMS: Rt = 0.314 min, m / z: 246.2, M+H +

[0403] Step 8. Preparation of Compound 40

[0404]

[0405] To a solution of 40 g (136 mg, 554 μmol, 1.00 eq) of compound in DCM (2.00 mL), DIEA (143 mg, 1.11 mmol, 193 μL, 2.00 eq) and compound 3,3-dimethylbutyryl chloride (111 mg, 831 μmol, 115 μL, 1.50 eq) were added. The mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with H₂O (10.0 mL) and extracted with DCM (20.0 mL × 3). The combined organic layers were washed with saturated brine (20.0 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. To a solution of the residue in MeOH (5.00 mL), K₂CO₃ (152 mg, 1.11 mmol, 2.00 eq) was added. The mixture was stirred at 50°C for 1 hour. The mixture was diluted with saturated aqueous H₂O (10.0 mL) and extracted with EtOAc (10.0 mL × 3). The combined organic layers were washed with saturated brine (10.0 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (neutral conditions; column: CD02-Waters Xbridge BEH C18 150). 25 10 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: phase B from 34% to 64% over 10 minutes) to give compound 40 (160 mg, 465 μmol, yield 84.2%, purity 99.9%), as a white solid.

[0406] LCMS: Rt = 0.590 min, m / z: 442.3, M+H +

[0407] LCMS: Rt = 2.088 min, m / z: 344.2, M+H +

[0408] 1 H NMR: 400 MHz, DMSO- d 6

[0409] 19 F NMR: 400 MHz, DMSO- d6

[0410] δ 9.19 (s, 1H), 7.17-7.25 (m, 4H), 4.18-4.21 (m, 2H), 2.67-2.69 (m,2H), 2.02 (s, 2H), 1.80-1.82 (m, 2H), 1.67-1.69 (m, 2H), 1.57-1.59 (m, 2H),0.90 (s, 9H).

[0411] The preparation methods for the compounds listed below are described in Example 3. Example 4: Synthesis of Compound 43

[0412]

[0413] Step 1. Preparation of intermediate 43a

[0414]

[0415] NIS (1.89 g, 8.39 mmol, 1.00 eq) was added to a 20.0 mL solution of 2-amino-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (2.00 g, 8.39 mmol, 1.00 eq) in ACN (at 0°C). The mixture was stirred at 0°C for 2 hours. TLC (petroleum ether: ethyl acetate = 1 / 1, R f = 0.38) showed that compound 2-amino-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester was completely consumed, and a new spot was formed. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (50.0 mL × 3). The combined organic layers were washed with saturated brine (50.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was analyzed by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1, R f = 0.38) purification yielded compound 43a (3.00 g, 8.24 mmol, yield 98.2%) as a yellow solid.

[0416] Step 2. Preparation of intermediate 43b

[0417]

[0418] To a solution of compound 43a (3.00 g, 8.24 mmol, 1.00 eq) and compound 4-fluorophenylboronic acid (3.46 g, 24.7 mmol, 3.00 eq) in dioxane (30.0 mL) and H₂O (10.0 mL), CataCXium A Pd G3 (599 mg, 823 μmol, 0.10 eq) and t-BuONa (1.58 g, 16.4 mmol, 2.00 eq) were added. The mixture was stirred at 100°C under a N₂ atmosphere for 2 hours. LCMS showed that compound 43a was completely consumed and the target molecular weight was detected. The reaction mixture was diluted with H₂O (50.0 mL) and extracted with EtOAc (30.0 mL × 3). The combined organic layers were washed with saturated brine (30.0 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was analyzed by column chromatography (SiO2, petroleum ether / ethyl acetate = 0 / 1, R...). f = 0.14) purification yielded compound 43b (2.50 g, 7.52 mmol, yield 91.3%, purity 100%), as a yellow solid.

[0419] LCMS: Rt = 0.399 min, m / z: 333.2, M+H +

[0420] LCMS: Rt = 0.387 min, m / z: 333.1, M+H +

[0421] Step 3. Preparation of intermediate 43c

[0422]

[0423] At 0°C, DIEA (1.94 g, 15.0 mmol, 2.62 mL, 2.00 eq) and compound 3,3-dimethylbutyryl chloride (2.02 g, 15.0 mmol, 2.09 mL, 2.00 eq) were added to a DCM (25.0 mL) solution of compound 43b (2.50 g, 7.52 mmol, 1.00 eq). The mixture was stirred at 20°C for 2 hours. LCMS showed that compound 43b was completely consumed and the target molecular weight was detected. The reaction mixture was diluted with H2O (50.0 mL) and extracted with DCM (20.0 mL × 3). The combined organic layers were washed with saturated brine (20.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 43c (4.00 g, crude product) as a yellow oil.

[0424] LCMS: m / z: 529.7, M+H +

[0425] Step 4. Preparation of intermediate 43d

[0426]

[0427] K₂CO₃ (1.57 g, 11.3 mmol, 1.50 eq) was added to a MeOH (40.0 mL) solution of compound 43c (4.00 g, 7.57 mmol, 1.00 eq). The mixture was stirred at 50°C for 2 hours. LCMS showed that compound 43c was completely consumed and the target molecular weight was detected. The reaction mixture was diluted with H₂O (100 mL) and extracted with DCM (50.0 mL × 3). The combined organic layers were washed with saturated brine (50.0 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was analyzed by column chromatography (SiO₂, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1, R f Purification with 0.51 yielded compound 43d (3.00 g, 6.96 mmol, 92.0% yield) as a yellow solid.

[0428] LCMS: Rt = 0.462 min, m / z: 431.7, M+H +

[0429] Step 5. Preparation of Compound 46

[0430]

[0431] To a solution of compound 43d (3.00 g, 6.96 mmol, 92.0% yield) in EtOAc (10.0 mL), HCl / EtOAc (2 M, 20.0 mL, 5.00 eq) was added. The mixture was stirred at 20°C for 2 hours. LCMS showed that compound 43d was completely consumed and the target molecular weight was detected. The reaction mixture was concentrated under reduced pressure to give compound 46 (2.69 g, 8.14 mmol, 100% yield) as a pale yellow solid.

[0432] LCMS:Rt = 0.277 min, m / z: 331.2, M+H +

[0433] Step 6. Preparation of Compound 43

[0434]

[0435] To a solution of compound 46 (2.69 g, 8.14 mmol, 1.00 eq) in MeOH (2.00 mL), compound (1-ethoxycyclopropoxy)trimethylsilane (8.52 g, 48.8 mmol, 9.82 mL, 6.00 eq), NaBH3CN (2.05 g, 32.5 mmol, 4.00 eq), and AcOH (4.89 g, 81.4 mmol, 4.66 mL, 10.0 eq) were added. The mixture was stirred at 60°C for 3 hours. LCMS showed that compound 46 was completely consumed and the target molecular weight was detected. The reaction mixture was diluted with H2O (50.0 mL) and extracted with DCM (20.0 mL × 3). The combined organic layers were washed with saturated brine (20.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was analyzed by column chromatography (SiO2, petroleum ether / ethyl acetate = 0 / 1, R...). f = 0.27) purification yielded compound 43 (2.20 g, 6.42 mmol, yield 69.4%, purity 95.2%), a white solid.

[0436] LCMS: m / z = 371.2, M+H +

[0437] 1 H NMR: 400 MHz, DMSO- d 6 δ 9.37 (s, 1H), 7.29-7.33 (m, 2H), 7.16-7.20(m, 2H), 4.03 (t, J = 5.2 Hz, 2H), 3.78 (s, 2H), 3.11 (t, J = 5.6 Hz, 2H), 2.08 (s, 2H), 1.93-1.96 (m, 1H), 0.95 (s, 9H), 0.48-0.52 (m, 2H), 0.40-0.42(m, 2H).

[0438] The preparation methods for the compounds listed below are described in Example 4. Example 5: Synthesis of Compound 53

[0439]

[0440] Step 1. Preparation of Compound 53

[0441]

[0442] Under a nitrogen atmosphere, PtO2 (27.7 mg, 122 μmol, 1.00 eq) and HCl (12 M, 10.1 μL, 1.00 eq) were added to a MeOH solution of N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutyramide (50.0 mg, 122 μmol, 1.00 eq) (5.00 mL). The suspension was degassed and purged three times with H2. The mixture was stirred at 20°C under a nitrogen atmosphere (50 Psi). The mixture was stirred at 20°C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC (neutral conditions; column: CD02-Waters Xbidge BEHC18 150). 25 10 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: phase B from 28% to 58% over 10 minutes), yielded compound 53 (14.0 mg, 43.1 μmol, yield 35.3%, purity 97.9%), as a white solid.

[0443] LCMS: EC6665-1394-P1A4. Rt = 0.337 min, m / z: 318.3, M+H +

[0444] HPLC: Rt = 2.200 min

[0445] 1 H NMR: 400 MHz, DMSO-d 6 δ 10.17 (s, 1H), 8.48 (s, 1H), 7.81-7.83 (m, 1H), 7.63-7.66 (m, 1H), 7.37-7.39 (m, 1H), 7.27-7.29 (m, 2H), 3.22 (s, 4H), 2.20 (s, 2H), 0.98 (s, 9H).

[0446] The preparation methods for the compounds listed below are described in Example 5. Example 6: Synthesis of Compound 55 Step 1. Preparation of intermediate 55a To a solution of compound 1-(tert-butyl)-2-methyl-4-oxopiperidin-1,2-dicarboxylic acid ester (15.0 g, 58.3 mmol, 1.00 eq) in dioxane (20.0 mL), HCl / dioxane (2 M, 29.1 mL, 1.00 eq) was added. The mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give compound 55a (11.5 g, crude product, HCl) as a white solid. LCMS: m / z: 158.3, M+H + Step 2. Preparation of intermediate 55b To a DCM (110 mL) solution of compound 55a (11.5 g, 59.3 mmol, 1.00 eq, HCl), DIEA (15.3 g, 118 mmol, 20.6 mL, 2.00 eq) and CbzCl (11.1 g, 65.3 mmol, 9.33 mL, 1.10 eq) were added. The mixture was stirred at 25°C for 12 hours. The reaction mixture was extracted with DCM (50.0 mL). The combined organic layers were washed with saturated brine (30.0 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1, Rf = 0.33) to give compound 55b (14.0 g, 47.4 mmol, yield 79.9%, purity 98.8%) as a white solid. LCMS: m / z: 292.2, M+H + Step 3. Preparation of intermediate 55c At 0°C, t-BuOK (1 M, 50.4 mL, 1.05 eq) was added dropwise to a THF (100 mL) solution of methyltriphenylphosphine iodide (18.9 g, 52.8 mmol, 1.10 eq). After the addition was complete, the mixture was stirred at 0°C for 0.5 h, and then compound 55b (14.0 g, 48.0 mmol, 1.00 eq) was added dropwise at 0°C. The resulting mixture was stirred at 20°C for 3 h. The reaction mixture was then diluted with water and extracted with EtOAc (5 × 50.0 mL). The combined ether layers were washed with saturated brine (2 × 50.0 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1, Rf = 0.72) to give compound 55c (8.30 g, 26.8 mmol, yield 55.8%, purity 93.6%) as a white solid. LCMS: m / z: 290.2, M+H + Step 4. Preparation of intermediate 55d A solution of compound 55c (5.00 g, 17.2 mmol, 1.00 eq) in dioxane (50.0 mL) was degassed and purged three times with N2. Zn (3.39 g, 51.8 mmol, 3.00 eq) was added fractionally under N2 atmosphere, followed by fractional addition of 2,2,2-trichloroacetyl chloride (4.08 g, 22.4 mmol, 2.50 mL, 1.30 eq) at 75°C. The mixture was then stirred at 75°C for 3 hours under N2 atmosphere. The reaction mixture was diluted with an aqueous solution of NaHCO3 (30.0 mL) and extracted with EtOAc (20.0 mL × 3). The combined organic layers were washed with saturated brine (30.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 55d (6.90 g, crude) as a white solid. Step 5. Preparation of intermediate 55e The compound 55d (6.90 g, 17.2 mmol, 1.00 eq) was degassed in a solution of AcOH (20 mL) and H₂O (20.0 mL) and purged three times with N₂. Zn (3.49 g, 53.4 mmol, 3.10 eq) was added in portions at 0°C under an N₂ atmosphere. The mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with H₂O (30.0 mL) and extracted with EtOAc (30.0 mL × 3). The combined organic layers were washed with saturated brine (30.0 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 2 / 1, Rf = 0.39) to give compound 55e (3.50 g, 7.69 mmol, yield 44.6%, purity 72.8%) as a yellow solid. LCMS: m / z: 332.1, M+H+ Step 6. Preparation of intermediate 55f At 0°C, DAST (17.0 g, 105 mmol, 13.9 mL, 10.0 eq) was added to a DCM (35.0 mL) solution of compound 55e (3.50 g, 10.5 mmol, 1.00 eq). The mixture was stirred at 25°C for 24 hours. The reaction mixture was diluted with H2O (20.0 mL) and extracted with EtOAc (20.0 mL × 3). The combined organic layers were washed with saturated brine (10.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 2 / 1, Rf = 0.65) to give compound 55f (2.81 g, 7.67 mmol, yield 72.6%, purity 96.5%) as a yellow solid. LCMS: m / z: 354.1, M+H+ Step 7. Preparation of 55g of intermediate To a solution of compound 55f (2.81 g, 7.95 mmol, 1.00 eq) in MeOH (30.0 mL), LiOH·H₂O (667 mg, 15.9 mmol, 2.00 eq) was added. The mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with H₂O (50.0 mL) and extracted with EtOAc (30.0 mL × 3). The combined organic layers were washed with saturated brine (30.0 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give compound 55 g (2.70 g, 7.96 mmol, 100% yield) as a yellow solid. LCMS: m / z: 340.1, M+H + Step 8. Preparation of intermediates over 55 hours Under a nitrogen atmosphere, Pd / C (846 mg, 795 μmol, 10% purity, 0.1 eq) was added to a 25.0 mL solution of 55 g (2.70 g, 7.96 mmol, 1.00 eq) of the compound in MeOH. The suspension was degassed and purged three times with H2. The mixture was stirred at 25°C for 12 h under a H2 atmosphere (15 Psi or atm). The reaction mixture was filtered and concentrated under reduced pressure to give compound 55h (1.63 g, 7.94 mmol, 100% yield) as a white solid. LCMS: m / z: 206.1, M+H + Step 9. Preparation of intermediate 55i At 0°C, NaNO2 (1.10 g, 15.8 mmol, 2.00 eq) and HCl (12 M, 661 μL, 1.00 eq) were added to a solution of compound 55h (1.63 g, 7.94 mmol, 1.00 eq) in H2O (20.0 mL). The mixture was stirred at 25°C for 5 hours. The reaction mixture was diluted with H2O (10.0 mL) and extracted with DCM (10.0 mL × 3). The combined organic layers were washed with saturated brine (10.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 55i (1.86 g, 7.94 mmol, 100% yield) as a pale yellow solid. LCMS: m / z: 235.0, M+H + Step 10. Preparation of intermediate 55j TFAA (2.17 g, 10.3 mmol, 1.44 mL, 1.30 eq) was added to a DCM (20.0 mL) solution of compound 55i (1.86 g, 7.94 mmol, 1.00 eq). The mixture was stirred at 0°C for 5 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was slurried with MTBE (10.0 mL) at 0°C for 10 minutes to give compound 55j (1.40 g, 6.48 mmol, yield 81.5%) as a white solid. LCMS: m / z: 217.0, M+H + Step 11. Preparation of intermediate 55k To a solution of compound 55j (1.40 g, 6.48 mmol, 1.00 eq) in o-xylene (15.0 mL), tert-butylpropynate (8.17 g, 64.7 mmol, 8.89 mL, 10.0 eq) was added. The mixture was stirred at 130°C for 3 hours. The reaction mixture was diluted with H₂O (30.0 mL) and extracted with EtOAc (30.0 mL × 3). The combined organic layers were washed with saturated brine (30.0 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 2 / 1, Rf = 0.43) to give compound 55k (1.80 g, 6.03 mmol, yield 74.5%, purity 100%) as a yellow solid. LCMS: m / z: 243.0, M-56+H + Step 12. Preparation of intermediate 55L At 0°C, NIS (2.31 g, 10.2 mmol, 1.7 eq) was added to a solution of compound 55k (1.80 g, 6.03 mmol, 1.00 eq) in ACN (15.0 mL). The mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with H2O (20.0 mL) and extracted with DCM (10.0 mL × 3). The combined organic layers were washed with saturated brine (20.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1, Rf = 0.54) to give compound 55l (2.40 g, 5.66 mmol, yield 93.7%) as a pale yellow solid. LCMS: Rt = 0.471 min, m / z: 368.9, M-56+H + Step 13. Preparation of intermediate 55m To a solution of compound 55l (500 mg, 1.18 mmol, 1.00 eq) and compound (4-fluorophenyl)boronic acid (494 mg, 3.54 mmol, 3.00 eq) in H2O (3.00 mL) and dioxane (5.00 mL), CataCxium A PdG3 (85.8 mg, 117 μmol, 0.10 eq) and t-BuONa (226 mg, 2.36 mmol, 2.00 eq) were added. The mixture was stirred at 100°C for 2 hours. The reaction mixture was diluted with H2O (20.0 mL) and extracted with DCM (10.0 mL × 3). The combined organic layers were washed with saturated brine (20.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 2 / 1, Rf = 0.30) to give compound 55m (452 ​​mg, 1.08 mmol, yield 91.6%, purity 93.8%), which was a pale yellow oil. LCMS: m / z: 337.2, M-56+H + Step 14. Preparation of intermediate 55n TFA (1.42 g, 12.4 mmol, 924 μL, 10.8 eq) was added to a DCM (5.00 mL) solution of compound 55m (452 ​​mg, 1.15 mmol, 1.00 eq). The mixture was stirred at 0°C for 2 hours. The reaction mixture was diluted with H2O (20.0 mL) and extracted with DCM (10.0 mL × 3). The combined organic layers were washed with saturated brine (20.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 55n (426 mg, 920 μmol, yield 79.9%, purity 97.3%, TFA) as a pale yellow solid. LCMS: m / z: 337.2, M+H + Step 15. Preparation of intermediate 55o DPPA (592 mg, 2.15 mmol, 464 μL, 1.70 eq) and TEA (448 mg, 4.43 mmol, 617 μL, 3.50 eq) were added to a t-BuOH solution of compound 55n (426 mg, 1.27 mmol, 1.00 eq) in 5.00 mL of t-BuOH. The mixture was stirred at 80°C for 12 hours. The reaction mixture was diluted with H2O (20.0 mL) and extracted with DCM (10.0 mL × 3). The combined organic layers were washed with saturated brine (20.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 0:1, Rf = 0.68) to give compound 55o (337 mg, 827 μmol, yield 65.3%) as a pale yellow solid. LCMS: m / z: 408.2, M+H + Step 16. Preparation of intermediate 55p To a solution of compound 55o (337 mg, 827 μmol, 1.00 eq) in EtOAc (1.00 mL), HCl / EtOAc (2 M, 2.00 mL, 4.84 eq) was added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give compound 55p (284 mg, 826 μmol, 99.8% yield, HCl) as a pale yellow solid. LCMS: m / z: 308.1 M+H + Step 17. Preparation of intermediate 56 To a DCM solution of compound 55p (284 mg, 924 μmol, 1.00 eq) in 3.00 mL, DIEA (238 mg, 1.85 mmol, 321 μL, 2.00 eq) and compound 3,3-dimethylbutyryl chloride (186 mg, 1.39 mmol, 192 μL, 1.50 eq) were added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched by adding H2O (20.0 mL) and then extracted with EtOAc (20.0 mL × 2). The combined organic layers were washed with saturated brine (20.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. To a MeOH solution of the residue (465 mg, 923 μmol, 1.00 eq) in 5.00 mL, K2CO3 (127 mg, 923 μmol, 1.00 eq) was added. The mixture was stirred at 50°C for 2 hours. The residue was purified by preparative HPLC (neutral conditions; column: CD24-WePure Biotech XPT C18 150×25×7 μm; mobile phase: [H2O (10 mM NH4OAc)-ACN]; gradient: phase B from 37% to 67% over 11.0 min) to give compound 55 (78.0 mg, 228 μmol, yield 71.2%, purity 99.9%) as a white solid. LCMS: Rt = 2.091 min, m / z: 406.1, M+H + 1H NMR: 400 MHz, DMSO- d6 δ 9.31 (s, 1H), 7.31-7.34 (m, 2H), 7.15-7.19(m, 2H), 4.07-4.10 (m, 2H), 2.92 (s, 2H), 2.60-2.66 (m, 2H), 2.44-2.49 (m, 2H), 2.13-2.14 (m, 2H), 2.06 (s, 2H), 0.93 (s, 9H). Example 7: Synthesis of Compound 56 Step 1. Preparation of intermediate 56a The mixture was degassed in a solution of 55 μL (500 mg, 1.18 mmol, 1.00 eq), 2-propenboric acid (396 mg, 2.36 mmol, 2.00 eq), and Cs₂CO₃ (1.15 g, 3.54 mmol, 3.00 eq) in dioxane (8 mL) and H₂O (2 mL), and purged three times with N₂. Pd(dppf)Cl₂ (86.2 mg, 117 μmol, 0.10 eq) was added, and the mixture was stirred at 80°C for 12 hours under N₂ atmosphere. The residue was diluted with ethyl acetate (10 mL) and water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, commercial grade hexane / ethyl acetate = 100 / 1 to 1 / 1) to give compound 56a (390 mg, 1.15 mmol, yield 97.7%) as a yellow solid. LCMS: Rt = 0.604 min, m / z = 283.0, M-56+H + 1H NMR: (400 MHz, DMSO-d6) δ 5.15 - 5.10 (m, 1H), 4.76 (d, J = 1.2Hz, 1H), 4.15 (t, J = 6.4 Hz, 2H), 3.32 (s, 3H), 2.81 (s, 2H), 2.66 - 2.55(m, 2H), 2.47 - 2.35 (m, 2H), 2.14 - 2.08 (m, 2H), 1.47 (s, 9H) Step 2. Preparation of intermediate 56b Pd / C (40.0 mg, 37.5 μmol, 10% purity) was added to a MeOH (10 mL) solution of compound 56a (390 mg, 1.15 mmol, 1.00 eq), and the mixture was stirred at 25°C and H2 (40 psi) for 2 hours. The mixture was filtered through MeOH and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, commercial grade hexane:ethyl acetate = 100 / 1 to 1 / 1) to give compound 56b (340 mg, 998 μmol, 86.6% yield) as a yellow oil. LCMS: Rt = 2.820 min, m / z = 341.2 M+H + 1H NMR: (400 MHz, DMSO- d6 ) δ 4.15 - 4.09 (m, 2H), 3.40 - 3.33 (m,1H), 3.33 - 3.31 (m, 2H), 2.66 - 2.55 (m, 2H), 2.48 - 2.37 (m, 2H), 2.08 (t,J = 6.0 Hz, 2H), 1.49 (s, 9H), 1.18 (d, J = 7.2 Hz, 6H) Step 3. Preparation of intermediate 56c TFA (1.23 g, 10.7 mmol, 801 μL) was added to a DCM (5.00 mL) solution of 56b (340 mg, 998 μmol, 1.00 eq), and the mixture was stirred at 20°C for 6 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM: MeOH = 10:1) to give compound 56c (230 mg, 809 μmol, yield 81.0%) as an off-white solid. LCMS: Rt = 0.458 min, m / z = 285.1 M+H + Step 4. Preparation of intermediate 56d DPPA (329 mg, 1.20 mmol, 258 μL, 1.70 eq) was added dropwise to a solution of compound 56c (200 mg, 703 μmol, 1.00 eq) and TEA (249 mg, 2.46 mmol, 342 μL, 3.50 eq) in t-BuOH (4.00 mL). The mixture was stirred at 80°C for 3 hours under a nitrogen atmosphere. The reaction mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine (5.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, commercial grade hexane:ethyl acetate = 0 / 1) to give compound 56d (170 mg, 478.3 μmol, yield 67.9%) as a white solid. LCMS: Rt = 0.559 min, m / z = 356.2 M+H + 1H NMR: (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 3.96 (t, J = 6.0 Hz, 2H), 2.85 (s, 2H), 2.69 - 2.56(m, 3H), 2.45 - 2.36 (m, 2H), 2.09 - 2.02 (m, 2H), 1.40 (s, 9H), 1.11 (d, J =7.2 Hz, 6H) Step 5. Preparation of intermediate 56e TFA (767 mg, 6.73 mmol, 0.50 mL, 14.1 eq) was added to a 2 mL solution of DCM containing 56d (170 mg, 478 μmol, 1.00 eq), and the mixture was stirred at 20°C for 5 hours. The reaction mixture was concentrated under reduced pressure to give compound 56e (100 mg, 391 μmol, TFA salt, crude product) as a yellow oil. LCMS: Rt = 0.353 min, m / z = 256.1 M+H + Step 6. Preparation of intermediate 56 At 0°C, DIEA (101 mg, 783 μmol, 136 μL, 2.00 eq) and 3,3-dimethylbutyryl chloride (63.2 mg, 470 μmol, 65.2 μL, 1.20 eq) were added to a DCM (2 mL) solution of compound 56e (100 mg, 391 μmol, 1.00 eq). The mixture was stirred at 0°C for 20 min. The reaction mixture was quenched with H2O (10.0 mL) and then extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with saturated brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was analyzed by preparative HPLC (column: CD24-WePure Biotech XPT C18 150). 25 7 μm; mobile phase: [H2O (10 mM NH4HCO3)-MeCN]; gradient: phase B from 35% to 65% over 12.0 min) purification yielded compound 56 (62.0 mg, 175 μmol, yield 44.7%, purity 99%) as a white solid. LCMS: m / z: 354.6, M+H + HPLC: Rt = 2.310 min 1H NMR: (400 MHz, DMSO- d6 ) δ 9.11 (s, 1H), 3.98 (s, 2H), 2.88 (s,2H), 2.70 - 2.57 (m, 3H), 2.46 - 2.37 (m, 2H), 2.11 (s, 2H), 2.08 - 2.02 (m,2H), 1.11 (d, J = 7.1 Hz, 6H), 1.01 (s, 9H). Example 8: Synthesis of Compound 57 Step 1. Preparation of intermediate 57a HNO3 (492 mg, 7.82 mmol, 351 μL, 1.20 eq) was added to a solution of 6-fluoro-2,3-dihydrobenzofuran (900 mg, 6.52 mmol, 1.00 eq) in AcOH (1.00 mL) at 20°C. The mixture was stirred at 70°C for 1 hour. The residue was diluted with ice water (30.0 mL) and extracted with EtOAc (30.0 mL × 3). The combined organic layers were washed with saturated brine (30.0 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 2:1, Rf = 0.60) to give compound 57a (390 mg, 2.13 mmol, yield 32.7%, purity 100%) as a yellow solid. LCMS: Rt = 0.356 min, m / z: 184.2, M+H + Step 2. Preparation of intermediate 57b DIEA (550 mg, 4.26 mmol, 741 μL, 2.00 eq) was added to a solution of compound 57a (390 mg, 2.13 mmol, 1.00 eq) and 2-methylpropyl-2-amine (311 mg, 4.26 mmol, 447 μL, 2.00 eq) in ACN (5.00 mL). The mixture was stirred at 70°C for 12 hours. The reaction mixture was quenched at 0°C by adding H2O (2.00 mL), diluted with EtOAc, and extracted with EtOAc (2.00 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 57b (530 mg, crude) as a yellow solid. LCMS: Rt = 0.464 min, m / z: 259.2, M+Na + Step 3. Preparation of intermediate 57c Cyanogen bromide (2.02 g, 8.97 mmol, 4.00 eq) was added to a solution of compound 57b (530 mg, 2.24 mmol, 1.00 eq) in EtOH (5.00 mL). The mixture was stirred at 80°C for 2 hours. The reaction mixture was diluted with NaHCO3 (3.00 mL) and extracted with EtOAc (3.00 mL × 3). The combined organic layers were washed with saturated brine (3.00 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 57c (430 mg, 2.08 mmol, yield 92.9%) as a yellow solid. LCMS: Rt = 0.215 min, m / z: 151.3, M-56+H + Step 4. Preparation of intermediate 57d Cyanogen bromide (431 mg, 4.07 mmol, 298 μL, 2.00 eq) was added to a solution of compound 57c (420 mg, 2.04 mmol, 1.00 eq) in EtOH (2.00 mL). The mixture was stirred at 40°C for 16 hours. The reaction mixture was diluted with NaHCO3 (3.00 mL) and extracted with EtOAc (3.00 mL × 3). The combined organic layers were washed with saturated brine (3.00 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 57d (493 mg, 2.02 mmol, yield 99.1%, purity 94.7%) as a yellow solid. LCMS: Rt = 0.259 min, m / z: 232.3, M+H + Step 5. Preparation of compound 57 To a DMF (1.00 mL) solution of compound 57d (150 mg, 648 μmol, 1.00 eq) and compound 4,4,4-trifluoro-3,3-dimethylbutyric acid (132 mg, 778 μmol, 1.20 eq), HATU (295 mg, 778 μmol, 1.20 eq) and DIEA (251 mg, 1.95 mmol, 338 μL, 3.00 eq) were added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with H₂O (3.00 mL) and extracted with EtOAc (3.00 mL × 3). The combined organic layers were washed with saturated brine (3.00 mL × 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC (neutral conditions; column: Waters XBridge 150×25 mm 10 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: phase B from 53% to 83% over 10 minutes) to give compound 57 (155 mg, 404 μmol, yield 62.3%, purity 100%) as a white solid. LCMS: Rt = 0.384 min, m / z: 384.3, M+H + HPLC: Rt = 2.385 min 1 H NMR: 400 MHz, CDCl3 δ 12.9 (s, 1H), 7.14 (s, 1H), 7.03 (s, 1H), 4.60 (t, j = 8.8 Hz, 2H), 3.26 (t, j = 8.8 Hz, 2H), 2.59 (s, 2H), 1.89 (s, 9H), 1.26 (s, 6H). The preparation methods for the compounds listed below are described in Example 8. Example 9: Synthesis of Compound 60 Step 1. Preparation of intermediate 60a At -65°C, n-BuLi (2.5 M, 12.6 mL, 1.50 eq) was added dropwise to a solution of acetonitrile (1.30 g, 31.6 mmol, 1.67 mL, 1.50 eq) in THF (50.0 mL). After the addition was complete, the mixture was stirred at -65°C for 1 hour, and then compound 2,3-dibromopyridine (5.00 g, 21.1 mmol, 1.00 eq) was added dropwise at -65°C. The resulting mixture was stirred at 25°C for 11 hours. The reaction mixture was diluted with an aqueous solution of NH4Cl (80.0 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with saturated brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was analyzed by column chromatography (SiO2, petroleum ether / ethyl acetate = 2:1, R... f = 0.37) purification yielded compound 60a (1.01 g, 5.13 mmol, yield 24.3%) as a white solid. LCMS: Rt = 0.251 min, m / z: 197.1, M+H + Step 2. Preparation of intermediate 60b To a toluene (1.00 mL) solution of compound 60a (400 mg, 2.03 mmol, 1.00 eq) and 4-fluoroaniline (270 mg, 2.44 mmol, 233 μL, 1.20 eq), K₂CO₃ (561 mg, 4.06 mmol, 2.00 eq), Brettphos (108 mg, 203 μmol, 0.10 eq), and BrettPhos (Pd, G4) (186 mg, 203 μmol, 0.10 eq) were added. The mixture was stirred at 110°C for 12 hours. The reaction mixture was quenched at 0°C with H₂O (30.0 mL), followed by extraction with EtOAc (20.0 mL × 3). The combined organic layers were washed with saturated brine (20.0 mL × 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was analyzed by column chromatography (SiO2, petroleum ether / ethyl acetate = 0:1, R...). f Purification with 0.10 yielded compound 60b (100 mg, 440 μmol, yield 21.7%) as a yellow solid. LCMS: Rt = 1.144 min, m / z: 228.1, M+H + Step 3. Preparation of Compound 60 To a DCM (3.00 mL) solution of compound 60b (90.0 mg, 396 μmol, 1.00 eq), DIEA (51.1 mg, 396 μmol, 68.9 μL, 1.00 eq) and 3,3-dimethylbutyryl chloride (53.3 mg, 396 μmol, 55.0 μL, 1.00 eq) were added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched at 0°C by adding H2O (10.0 mL), followed by extraction with EtOAc (10.0 mL × 3). The combined organic layers were washed with saturated brine (10.0 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was analyzed by column chromatography (SiO2, petroleum ether / ethyl acetate = 2:1, R... f Purification with 0.35 yielded compound 60 (95.0 mg, 291 μmol, yield 73.7%) as a yellow solid. To a solution of compound 60 (90.0 mg, 276 μmol, 1.00 eq) in MeOH (2.00 mL), HCl / MeOH (2 M, 2.00 mL) was added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give 60 (80.0 mg, 243 μmol, yield 88.2%, purity 99.2%) as a yellow solid. LCMS: Rt = 0.327 min, m / z: 326.2, M+H + HPLC: 10-80AB_6 min, Rt = 1.680 min 1 H NMR: 400 MHz, DMSO-d 6 δ 10.26 (s, 1H), 8.54 (d, J =5.2 Hz, 1H), 7.92(d, J =8.0 Hz, 1H), 7.61-7.65 (m, 2H), 7.50-7.55 (m, 2H), 7.45-7.46 (m, 1H), 7.20 (s, 1H), 2.32 (s, 2H), 0.97 (s, 9H). The preparation methods for the compounds listed below are described in Example 9. Example 10: Synthesis of Compound 62 At 0°C, i-PrMgCl (2 M, 573 μL, 2.00 eq) was added dropwise to a THF (1.00 mL) solution of 5-chloro-3-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-2-amine (150 mg, 573 μmol, 1.00 eq) (150 mg, 573 μmol, 1.00 eq). After the addition, the mixture was stirred at 0°C for 0.5 h, and then 2-methylpropane-1-sulfonyl chloride (897 mg, 5.73 mmol, 10.0 eq) was added dropwise at 0°C. The resulting mixture was stirred at 20°C for 2 h. The reaction mixture was quenched by adding H2O (20.0 mL) and then extracted with EtOAc (20.0 mL × 2). The combined organic layers were washed with saturated brine (20.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC (neutral conditions; column: CD 02 - Waters Xbridge BEH C18 150). 25 10 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: phase B from 42% to 72% over 10 minutes) to obtain 62 (20.0 mg, 48.5 μmol, yield 8.47%, purity 92.7%). LCMS: Rt = 0.477 min, m / z: 382.1, Rt = 0.503 min, m / z: 416.0, M+H + 1 H NMR: 400 MHz, DMSO- d 6 δ 9.99 (s, 1H), 8.72 (d, J = 7.2 Hz, 1H), 7.62-7.69 (m, 3H), 7.30-7.35 (m, 2H), 7.00-7.02 (m, 1H), 3.33 (s, 2H), 2.22-2.24 (m, 1H), 1.06 (s, 6H). The preparation methods for the compounds listed below are described in Example 10. Biological testing evaluation Test Example 1: KNCQ2 / 3 Activation Measurement On the QPatch automated screening platform, patch-clamp technology was used to evaluate the ability of compounds to enhance potassium currents in HEK293 cells overexpressing KNCQ2 / 3 (Kv7.2 / 7.3). Cell line: The HEK293 cell line overexpressing Kv7.2 / 7.3 was obtained from ICE Bioscience. This cell line was genetically engineered to overexpress the Kv7.2 / 3 ion channel. Cell culture: Cells were maintained in DMEM (Corning, catalog number: 10-013-CV), 10% fetal bovine serum (Gibco, catalog number: 10099141C), 800 μg / mL G418 (GPC, catalog number: AK108), and 200 μg / mL hygromycin B (Solarbio, catalog number: H8080). Cells were cultured in a humidified incubator at 37°C with 5% CO2. Cells were cultured in 6 cm culture dishes to approximately 80% confluence. Current was recorded 24 hours after channel induction. Compound plates: Test compounds were prepared by serial dilution with DMSO (Sigma, catalog number: D4540). The final dilution was prepared using the external solution, with a final DMSO concentration of 0.1%. In single-concentration screening, 10 μM retigabin (Selleck Chemicals, catalog number: S4733) was included as a positive control on each plate. Electrophysiology: The external solution contained 140 mM NaCl (Sigma, catalog number: S5886), 3.5 mM KCl (Sigma, catalog number: P5405), 1 mM MgCl2·6H2O (Sigma, catalog number: M2393), 2 mM CaCl2·2H2O (Sigma, catalog number: C7902), 10 mM D-glucose (Sigma, catalog number: G8270), 10 mM HEPES (Santa Cruz, catalog number: SC-29097A), and 1.25 mM NaH2PO4·2H2O, and the pH was adjusted to 7.4 with NaOH. The internal solution contained 125 mM potassium aspartate (Sigma, catalog number: G4500), 20 mM KCl, 10 mM EGTA (Sigma, catalog number: E3889), 1 mM MgCl2·6H2O, 5 mM Mg-ATP (Sigma, catalog number: A9187), and 5 mM HEPES, and the pH was adjusted to 7.2 with KOH. On the day of the experiment, cells were washed with external solution and then digested with 0.25% trypsin-EDTA (Gibco, catalog number: 25200-072) to collect the cells. The cells were then centrifuged at 1000 rpm for 5 minutes and discharged at approximately 2.5 × 10⁻⁶ cells / min. 6 Cells were resuspended in the external solution at a density of 100 cells / mL. Before the experiment, the cells were placed on a balancing stirrer and equilibrated at room temperature for 20 minutes. Potassium channel activity was detected on a QPatch 48X (Sophion Bioscience) system equipped with 48-well QPlates. The KCNQ current recording protocol was as follows: the voltage was initially maintained at -80 mV for 3 seconds, then stepped to -30 mV for 500 milliseconds, and then returned to 80 mV. This process was repeated in 10 mV increments between -80 mV and +40 mV. Each cell was treated as an independent experiment, and only one compound was tested per well. Single-concentration screening: Baseline conditions were obtained by recording five scans in the external solution only, a process repeated for each of the three external solution applications. Subsequently, five scans were recorded under conditions containing a 1 µM compound solution to assess the effect of the test compound on the induced current. The steady-state current at the end of a +40 mV pulse lasting 2 s was measured to determine the fold increase relative to the baseline. The data from the Kv7.2 / 7.3 activation assays are summarized in the table below. Table 1 The fold increase in current relative to baseline in HEK293 cells overexpressing Kv7.2 / 3 under the action of a 1 µM compound was graded as follows: ≤100% was (-), 100%-199.99% was (+), 200%-299.99% was (++), and ≥300% was (+++). Test Example 2: Epilepsy Model Experimental steps: SPF-grade male ICR mice (22-24 g) were purchased from Hunan Silek Jingda Experimental Animal Co., Ltd., China. After passing veterinary inspection, they were transferred to the breeding facility to acclimatize to the environment. Mice were housed in cages for 3 days under suitable conditions (temperature 22±1°C, humidity 40-70%, ample water and food, 12-hour light). On the day of the formal test, all mice were weighed, and those meeting the weight standard were numbered at the base of their tails. Mice that did not meet the weight standard continued to acclimatize until they reached the required weight, while overweight mice were culled. Thirty minutes before epilepsy modeling, animals were orally administered compound 34 (10 mg / kg). Seizure responses were assessed according to epilepsy grading standards. The latency and incidence of each seizure grade were recorded, lasting 30 minutes. After the experiment, the animals were euthanized using carbon dioxide. The results are shown in Tables 2 and 30. Figure 1 middle. Experimental results: Table 2 Experimental results show that, in the PTZ mouse model, oral administration of the compound of the present invention at a dose of 10 mg / kg exhibits significant activity, effectively prolonging the latency period of epileptic seizures and reducing epilepsy-related mortality to a certain extent, with better effects than the control compound. Test Example 3: In vivo activity in a 2% formalin rat model SPF-grade male SD rats (170-190 g) were purchased from Hunan Slack Jingda Experimental Animal Co., Ltd., China. The rats were housed in cages for 3 days under suitable conditions (temperature 22±1°C, humidity 40-70%, ample water and food, 12-hour light). Rats weighing 220-240 g were numbered for subsequent experiments. The rats were then placed in a ZH-PAN801 automated rodent behavior tracking system (Anhui Zhenghua Biological Instrument Equipment Co., Ltd.) for 60 minutes daily for 3 consecutive days. Paw-licking behavior, as an indicator of spontaneous pain, was tracked using the ZH-PAN801 automated rodent behavior tracking system. This system can distinguish different behaviors and locomotor activities in individually housed rats. The ZH-PAN801 system consists of a sensor platform supported by two orthogonally placed force sensors and a third fixed point on a base plate. Each force sensor converts the mechanical vibrations caused by animal activity into electrical signals, which are amplified, filtered, and digitized by the ZH-PAN801 system. Characteristic movements have their own unique vibration patterns, which can be distinguished by the ZH-PAN801 software. The cylindrical cage (75 mm radius × 310 mm height) is composed of upper and lower halves to improve the sensitivity of vibration detection. Therefore, the cage bottom is separate from the cage walls and lid; the cage bottom rests directly on the sensor platform, while the cage walls and lid are suspended from supports on the base plate. Fifteen minutes prior to drug administration, force sensors were fitted to rats. Fifteen minutes before formalin injection, animal compound 21 (10 mg / kg) was orally administered. Acute pain was induced by a plantar injection of formalin (50 μL, 2.0%, Sigma-Aldrich, USA) into the hind paws fitted with force sensors, followed by placement of the rats in an automated rodent behavior tracking system. Paw-licking behavior was monitored for 60 minutes using a ZH-PAN801 behavior tracking system. The duration of paw-licking behavior (in minutes) was collected from two different time phases: the early nociceptive phase (0–10 minutes after formalin injection) and the late phase (considered to be associated with central sensitization, peaking 11–60 minutes after formalin injection). Using GraphPad 9.0 software, unpaired t-tests and one-way ANOVA were used to compare the treatment effects with the solvent control group. The results are shown in Tables 3 and 4. Figure 2 middle. Experimental results: Table 3 .

Claims

1. Some embodiments include a compound as shown in formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, deuterated derivative, metabolite, or prodrug thereof; in, The value of n ranges from 0 to 5; R 1 is selected from the group consisting of C1-C6alkyl, C2-C6alkenyl, C3-C8cycloalkyl, Ar, C3-C8cycloalkenyl, or C3-C8heterocyclyl, wherein each occurrence of R 1 is optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, nitro (-NO2), C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, C3-C8cycloalkyl, haloC3-C8cycloalkyl, -C(=O)OR’, -C(=O)R’, -NHR’, or -NR’R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, wherein the heteroatoms are independently selected from nitrogen (N), oxygen (O), and sulfur (S); R’ and R” are each independently selected from the group consisting of C1-C6alkyl or haloC1-C6alkyl; R 2 is selected from the group consisting of C1-C6alkyl, C2-C6alkenyl, C3-C8cycloalkyl, C3-C8cycloalkenyl, C3-C8heterocyclyl, or Ar, wherein each occurrence of R 2 is optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, C3-C8cycloalkyl, haloC3-C8cycloalkyl, -C(=O)OR’, -C(=O)R’, -NHR’, or -NR’R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, wherein the heteroatoms are independently selected from nitrogen (N), oxygen (O), and sulfur (S); R’ and R” are each independently selected from the group consisting of C1-C6alkyl or haloC1-C6alkyl; L is optionally selected from -NHCO- or -NHSO2-; A is a C1-C6 alkyl group, wherein A is optionally substituted by one or more substituents, the substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, nitro (-NO2), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R"; R' and R" are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl groups; X1, X2, X3and X4are each independently selected from the group consisting of -CR 3 -, -CR 4 R 5 -, -N-, -NR 6 -, -O- or -S-; in, Choose a group consisting of the following structures: 、 、 In one embodiment, R 3 , R 4 , and R 5 are each independently selected from the group consisting of hydrogen (H), halogen, hydroxyl (-OH), amino (-NH2), cyano (-CN), -C(=0)OH, NHCOR 7 , -(C=0)R 8 , -C(=0)OR 9 , C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 heterocyclyl, wherein each group is optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, C1-C6 alkyl, haloC1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, -C(=0)OR’, -C(=0)R’, -NHR’, or -NR’R”; wherein R 4 and R 5 may collectively form a carbonyl (-C=0) functional group; R’ and R” are each independently selected from the group consisting of C1-C6 alkyl or haloC1-C6 alkyl; R 7 , R 8 , and R 9 are each independently selected from the group consisting of -NH2or C1-C3alkyl; R 6 R is selected from the group consisting of hydrogen (H), -(C=0)(Ci-C6alkyl), C2-C6alkenyl, Ci-C6alkyl, or C3-C8cycloalkyl, wherein each occurrence of R 6 optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, Ci-C6alkyl, halo-Ci-C6alkyl, C3-C8cycloalkyl, Ci-C6alkoxy, halo-Ci-C6alkoxy, -C(=0)OR', -C(=0)R', -NHR', or -NR'R" ; R' and R" are each independently selected from the group consisting of Ci-C6alkyl or halo-Ci-C6alkyl; Any one or two X atoms together with the carbon atoms they are attached to form a ring optionally containing 1-3 heteroatoms independently selected from nitrogen (N), oxygen (O), and sulfur (S), including: 、 、 、 、 、 ， in, The value of m ranges from 0 to 6; R x selected from the group consisting of hydrogen (H), halogen, cyano (-CN), Ci-C6alkyl; Y1, Y2, Y3, and Y4 are each independently selected from groups composed of C, N, O, or S; More preferably, Y1, Y2, Y3, and Y4 are each independently selected from C or N, examples of which include: When Y1 and Y4 are N, Y2 and Y3 are C; When Y1 and Y3 are N, Y2 and Y4 are C; When Y1 and Y2 are N, Y3 and Y4 are C; When Y1, Y2, and Y3 are C, Y4 is N; in, Choose a group consisting of the following structures: 、 、 、 Among them, when for When L is -NHSO2- Among them, when for hour, Choose a group consisting of the following structures: 、 、 。 2. The compound of formula (I) according to claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, deuterated derivative, metabolite, or prodrug thereof, wherein the compound is a compound of formula (I-1), or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, deuterated derivative, metabolite, or prodrug thereof: in, The value of n ranges from 0 to 5; R 1 is selected from the group consisting of C1-C6alkyl, C2-C6alkenyl, C3-C8cycloalkyl, Ar, C3-C8cycloalkenyl, or C3-C8heterocyclyl, wherein each occurrence of R 1 is optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, nitro (-NO2), C1-C6alkyl, halo C1-C6alkyl, C1-C6alkoxy, halo C1-C6alkoxy, C3-C8cycloalkyl, halo C3-C8cycloalkyl, -C(=O)OR’, -C(=O)R’, -NHR’, or -NR’R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, wherein the heteroatoms are independently selected from nitrogen (N), oxygen (O), and sulfur (S); R’ and R” are each independently selected from the group consisting of C1-C6alkyl or halo C1-C6alkyl; R 2 is selected from the group consisting of C1-C6alkyl, C2-C6alkenyl, C3-C8cycloalkyl, C3-C8heterocyclyl, or Ar, wherein each occurrence of R 2 is optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluoro (-F), chloro (-Cl), bromo (-Br), iodo (-I), C1-C6alkyl, halo-C1-C6alkyl, C1-C6alkoxy, halo-C1-C6alkoxy, C3-C8cycloalkyl, halo-C3-C8cycloalkyl, -C(=O)OR’, -C(=O)R’, -NHR’, or -NR’R”, Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, wherein the heteroatoms are independently selected from nitrogen (N), oxygen (O), and sulfur (S); R’ and R” are each independently selected from the group consisting of C1-C6alkyl or halo-C1-C6alkyl; In some preferred embodiments, R 2 is selected from the group consisting of C3-C8heterocyclyl or Ar, wherein each occurrence of R 2 is optionally substituted with one or more substituents independently selected from the group consisting of fluoro (-F), chloro (-CI), bromo (-Br), iodo (-I), C1-C6alkyl, haloC1-C6alkyl; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, wherein the heteroatoms are independently selected from nitrogen (N), oxygen (O), and sulfur (S); A is a C1-C6 alkyl group, wherein A is optionally substituted by one or more substituents, the substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, nitro (-NO2), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R"; R' and R" are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl groups; X1, X2, X3and X4are each independently selected from the group consisting of -CR 4 R 5 -, -NR 6 -, -O- or -S-; In one embodiment, R 4 and R 5 are each independently selected from the group consisting of hydrogen (H), halogen, hydroxyl (-OH), amino (-NH2), cyano (-CN), -C(=0)OH, NHCOR 7 , -(C=0)R 8 , -C(=0)OR 9 , C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 heterocyclyl, wherein each group is optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, C1-C6 alkyl, haloC1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, -C(=0)OR’, -C(=0)R’, -NHR’, or -NR’R”; wherein R 4 and R 5 may collectively form a carbonyl (-C=0) functional group; R’ and R” are each independently selected from the group consisting of C1-C6 alkyl or haloC1-C6 alkyl; R 7 , R 8 , and R 9 are each independently selected from the group consisting of NH2, methyl, ethyl, propyl, or isopropyl; R 6 is selected from the group consisting of H, -(C=0)(Ci-C4alkyl), C2-C6alkenyl, Ci-C6alkyl, or C3-C8cycloalkyl, wherein each occurrence of R 6 optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, Ci-C6alkyl, halo-Ci-C6alkyl, C3-C8cycloalkyl, Ci-C6alkoxy, halo-Ci-C6alkoxy, -C(=0)OR', -C(=0)R', -NHR', or -NR'R" ; R' and R" are each independently selected from the group consisting of Ci-C6alkyl or halo-Ci-C6alkyl; In the preferred embodiment, X1, X2, X3 and X4 are each independently -CH2-.

3. The compound of formula (I) according to claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, deuterated derivative, metabolite, or prodrug thereof, wherein the compound is a compound of formula (I-2), or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, deuterated derivative, metabolite, or prodrug thereof: in, The value of n ranges from 0 to 5; R 1 The group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, Ar, C3-C8 cycloalkenyl, or C3-C8 heterocyclic groups is selected, wherein each occurrence of R... 1 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), nitro (-NO2), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O) and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl; R 2 Choose from the group consisting of C1-C6 alkyl groups, C3-C8 heterocyclic groups, or Ar, wherein each occurrence of R 2 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 cyclic heteroatoms, said cyclic heteroatoms being independently selected from nitrogen (N), oxygen (O) and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl; A is a C1-C6 alkyl group, wherein A is optionally substituted by one or more substituents, the substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, nitro (-NO2), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R"; R' and R" are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl groups; X1, X2, X3, and X4 are each independently selected -CR 4 R 5 -、-NR 6 Groups consisting of -, -O-, or -S-; In one implementation, R 4 and R 5 Each can be independently selected from hydrogen (H), halogen, hydroxyl (-OH), amino (-NH2), cyano (-CN), -C(=O)OH, and NHCOR. 7 -(C=O)R 8 -C(=O)OR 9 The group consists of C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 heterocyclic groups, wherein each group is optionally substituted by one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -C(=O)OR', -C(=O)R', -NHR', or -NR'R"; wherein R 4 and R 5 They can together form a carbonyl (-C=O) functional group; R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl groups; R 7 R 8 and R 9 Each is independently selected from the group consisting of NH2, methyl, ethyl, propyl, or isopropyl. R 6 Choose from the group consisting of H, -(C=O)(C1-C4 alkyl), C2-C6 alkenyl, C1-C6 alkyl, or C3-C8 cycloalkyl, wherein each occurrence of R 6 Optionally substituted with one or more substituents, wherein the substituents are independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -C(=O)OR', -C(=O)R', -NHR' or -NR'R"; R' and R" are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl. In the preferred embodiment, X1, X2, X3 and X4 are each independently -CH2-.

4. The compound of formula (I) according to claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, deuterated derivative, metabolite, or prodrug thereof, wherein the compound is a compound of formula (I-3), or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, deuterated derivative, metabolite, or prodrug thereof: in, The value of n ranges from 0 to 5; R 1 The group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, Ar, C3-C8 cycloalkenyl, or C3-C8 heterocyclic groups is selected, wherein each occurrence of R... 1 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), nitro (-NO2), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O) and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl; R 2 Choose from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C3-C8 heterocyclic groups or Ar, wherein each occurrence of R 2 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O) and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl; A is a C1-C6 alkyl group, wherein A is optionally substituted by one or more substituents, the substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, nitro (-NO2), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R"; R' and R" are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl groups; X1, X2, X3, and X4 are each independently selected -CR 4 R 5 -、-NR 6 Groups consisting of -, -O-, or -S-; In one implementation, R 4 and R 5 Each can be independently selected from hydrogen (H), halogen, hydroxyl (-OH), amino (-NH2), cyano (-CN), -C(=O)OH, and NHCOR. 7 -(C=O)R 8 -C(=O)OR 9 The group consists of C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 heterocyclic groups, wherein each group is optionally substituted by one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -C(=O)OR', -C(=O)R', -NHR', or -NR'R"; wherein R 4 and R 5 They can together form a carbonyl (-C=O) functional group; R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl groups; R 7 R 8 and R 9 Each is independently selected from the group consisting of NH2, methyl, ethyl, propyl, or isopropyl. R 6 Choose from the group consisting of H, -(C=O)(C1-C4 alkyl), C2-C6 alkenyl, C1-C6 alkyl, or C3-C8 cycloalkyl, wherein each occurrence of R 6 Optionally substituted with one or more substituents, wherein the substituents are independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -C(=O)OR', -C(=O)R', -NHR' or -NR'R"; R' and R" are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl. Any one or two X atoms, together with the carbon atoms they are attached to, form a C3-C6 ring, optionally containing one to three heteroatoms independently selected from nitrogen (N), oxygen (O), and sulfur (S), including: 、 、 ， in, The value of m ranges from 0 to 6; R x Selected from the group consisting of hydrogen (H), halogens, cyano (-CN), and C1-C6 alkyl groups; Preferably, R 4 and R 5 Together with the carbon atoms it is attached to, it can form the following ring. ;or Any two X's can be connected to form the following structure. 。 5. The compound of formula (I) or (I-3) according to claim 1 or 4, or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, deuterated derivative, metabolite, or prodrug thereof, wherein the compound is a compound of formula (I-4), or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, deuterated derivative, metabolite, or prodrug thereof: in, R 1 The group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, Ar, C3-C8 cycloalkenyl, or C3-C8 heterocyclic groups is selected, wherein each occurrence of R... 1 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), nitro (-NO2), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O) and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl; R 2 Choose from the group consisting of C1-C6 alkyl or C3-C8 heterocyclic groups, wherein each occurrence of R 2 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), C1-C6 alkyl, and halo-C1-C6 alkyl; A is a C1-C6 alkyl group, wherein A is optionally substituted by one or more substituents, the substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, nitro (-NO2), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R"; R' and R" are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl groups; X3 is -CR 4 R 5 -、-NR 6 -; In one implementation, R 4 and R 5 Each can be independently selected from hydrogen (H), halogen, hydroxyl (-OH), amino (-NH2), cyano (-CN), -C(=O)OH, and NHCOR. 7 -(C=O)R 8 -C(=O)OR 9 The group consists of C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 heterocyclic groups, wherein each group is optionally substituted by one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -C(=O)OR', -C(=O)R', -NHR', or -NR'R"; wherein R 4 and R 5 They can together form a carbonyl (-C=O) functional group; R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl groups; R 7 R 8 and R 9 Each is independently selected from the group consisting of NH2, methyl, ethyl, propyl, or isopropyl. R 6 Choose from the group consisting of H, -(C=O)(C1-C4 alkyl), C2-C6 alkenyl, C1-C6 alkyl, or C3-C8 cycloalkyl, wherein each occurrence of R 6 Optionally substituted with one or more substituents, wherein the substituents are independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -C(=O)OR', -C(=O)R', -NHR' or -NR'R"; R' and R" are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl. R 4 and R 5 Each group is independently selected from the group consisting of H, F, Cl, Br, I, OH, CN, -C(=O)OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, CH2F, CHF2, CF3, methoxy, ethoxy, propoxy, butoxy, substituted C1-C6 alkyl, substituted C1-C6 alkoxy, wherein each group is optionally substituted by one or more substituents, said substituents being independently selected from the group consisting of fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I); R 6 The group consisting of H, -(C=O)methyl, -(C=O)ethyl, -(C=O)propyl, vinyl, propenyl, allyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutylmethyl, C2-C6 alkenyl, C1-C6 alkyl, or C3-C8 cycloalkyl, wherein each occurrence of R... 6 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of halogen, methyl, ethyl, propyl, and isopropyl.

6. The compound of formula (I) according to claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, deuterated derivative, metabolite, or prodrug thereof, wherein the compound is a compound of formula (I-5), or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, deuterated derivative, metabolite, or prodrug thereof: in, The value of n ranges from 0 to 3; R 1 The group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, Ar, C3-C8 cycloalkenyl, or C3-C8 heterocyclic groups is selected, wherein each occurrence of R... 1 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), nitro (-NO2), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O) and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl; R 2 Choose from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C3-C8 heterocyclic groups or Ar, wherein each occurrence of R 2 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O) and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl; A is a C1-C6 alkyl group, wherein A is optionally substituted by one or more substituents, the substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, nitro (-NO2), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R"; R' and R" are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl groups; Preferably, R 1 For C(CH3)3, R 2 The form is C(CH3)2CF3, and A is CH2; X1, X2, X3, and X4 are each independently selected -CR 3 Groups consisting of - or -N-; R 3 Choose from hydrogen (H), halogen, hydroxyl (-OH), amino (-NH2), cyano (-CN), -C(=O)OH, and NHCOR. 7 -(C=O)R 8 -C(=O)OR 9 The group consisting of C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 heterocyclic groups, wherein each occurrence of R 3 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -C(=O)OR', -C(=O)R', -NHR', or -NR'R"; wherein R 4 and R 5 They can together form a carbonyl (-C=O) functional group; R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl groups; R 7 R 8 and R 9 Each is independently selected from the group consisting of NH2, methyl, ethyl, propyl, or isopropyl. Two adjacent R 3 The group and the atoms to which they are attached together form a C3-C8 heterocyclic alkyl or a C3-C8 heterocyclic alkenyl group, wherein the group is selected from the group consisting of the following structures: 、 、 。 7. The compound of formula (I) according to claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, deuterated derivative, metabolite, or prodrug thereof, wherein the compound is a compound of formula (I-6), or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, deuterated derivative, metabolite, or prodrug thereof: in, The value of n ranges from 0 to 3; R 1 The group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, Ar, C3-C8 cycloalkenyl, or C3-C8 heterocyclic groups is selected, wherein each occurrence of R... 1 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), nitro (-NO2), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O) and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl; R 2 Choose from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C3-C8 heterocyclic groups or Ar, wherein each occurrence of R 2 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O) and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl; A is a C1-C6 alkyl group, wherein A is optionally substituted by one or more substituents, the substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, nitro (-NO2), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R"; R' and R" are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl groups; X1, X2, X3, and X4 are each independently selected -CR 3 Groups consisting of - or -N-; R 3 Choose from hydrogen (H), halogen, hydroxyl (-OH), amino (-NH2), cyano (-CN), -C(=O)OH, and NHCOR. 7 -(C=O)R 8 -C(=O)OR 9 The group consisting of C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 heterocyclic groups, wherein each occurrence of R 3 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -C(=O)OR', -C(=O)R', -NHR', or -NR'R"; wherein R 4 and R 5 They can together form a carbonyl (-C=O) functional group; R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl groups; R 7 R 8 and R 9 Each is independently selected from the group consisting of NH2, methyl, ethyl, propyl, or isopropyl. In some preferred embodiments, X1, X2, X3, and X4 are each independently selected from -CH- or -N-, to form a group consisting of the following structures: 。 8. The compound of formula (I) according to claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, deuterated derivative, metabolite, or prodrug thereof, wherein the compound is a compound of formula (I-7), or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, deuterated derivative, metabolite, or prodrug thereof: in, The value of n ranges from 0 to 3; R 1 The group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, Ar, C3-C8 cycloalkenyl, or C3-C8 heterocyclic groups is selected, wherein each occurrence of R... 1 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), nitro (-NO2), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O) and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl; R 2 Choose from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C3-C8 heterocyclic groups or Ar, wherein each occurrence of R 2 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I), C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, -C(=O)OR', -C(=O)R', -NHR' or -NR'R”; Ar is a 5- to 10-membered monocyclic or bicyclic aromatic group, optionally containing 1 to 4 heteroatoms as part of the ring structure, said heteroatoms being independently selected from nitrogen (N), oxygen (O) and sulfur (S); R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl; L is -NHSO2-; A is a C1-C8 alkyl group, wherein A is optionally substituted by one or more substituents independently selected from fluorine (-F), chlorine (-Cl), and bromine (-Br); X1, X2, X3, and X4 are each independently selected -CR 3 Groups consisting of - or -N-; R 3 Choose from hydrogen (H), halogen, hydroxyl (-OH), amino (-NH2), cyano (-CN), -C(=O)OH, and NHCOR. 7 -(C=O)R 8 -C(=O)OR 9 The group consisting of C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 heterocyclic groups, wherein each occurrence of R 3 Optionally substituted with one or more substituents, said substituents being independently selected from the group consisting of hydroxyl (-OH), amino (-NH2), cyano (-CN), halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, -C(=O)OR', -C(=O)R', -NHR', or -NR'R"; wherein R 4 and R 5 They can together form a carbonyl (-C=O) functional group; R' and R” are each independently selected from the group consisting of C1-C6 alkyl or halo-C1-C6 alkyl groups; R 7 R 8 and R 9 Each is independently selected from the group consisting of NH2, methyl, ethyl, propyl, or isopropyl.

9. The compound according to claims 1-8, or its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, deuterated derivatives, metabolites, or prodrugs, claims protection for compounds selected from the group consisting of: 。 10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable excipient.

11. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, or the pharmaceutical composition of claim 10, in the preparation of a Kv7 potassium channel activator, said use comprising administering an effective amount of the compound to a mammal to treat and / or alleviate symptoms of related diseases: epilepsy, pain, migraine, depression, bipolar disorder, amyotrophic lateral sclerosis (ALS), neurodegenerative diseases, and combinations thereof.

12. The method of claim 11, wherein the condition is epilepsy, neuropathic pain, inflammatory pain, persistent pain, cancer pain, postoperative pain, migraine, depression, bipolar disorder, amyotrophic lateral sclerosis (ALS), or a neurodegenerative disease.

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