A pyrazine acyl cyclopropyl amine Nav1.8 and / or Nav1.7 inhibitor and methods of making and uses thereof

Abstract

This invention relates to a pyrazinylcyclopropylamine Nav1.8 and / or Nav1.7 inhibitor, which can be used to prevent and / or treat Nav1.8 and / or Nav1.7-related diseases, such as treating or relieving pain.

Description

Technical Field

[0001] This invention relates to the field of biochemistry, specifically to a pyrazinylcyclopropylamine Nav1.8 and / or Nav1.7 inhibitor, its preparation method, and its uses. Background Technology

[0002] Voltage-gated sodium channels (Nav), particularly the Nav1.7, Nav1.8, and Nav1.9 subtypes, play a crucial role in the transmission of pain-related stimuli (Physiol Rev. 2019, 99(2): 1079-1151). Nav1.7 is widely expressed in sympathetic ganglia and DRG neurons. Gain-of-function mutations in the encoding gene SCN9A lead to congenital pain hypersensitivity, paroxysmal extreme pain syndromes, and erythromelalgia primary (Brain. 2005 Aug; 128(Pt 8): 1847-54). In addition, loss of function of the SCN9A gene results in congenital insensitivity to pain (Nature. 2006 Dec 14; 444(7121): 894-8.; J Neurosci. 2018 Nov 21; 38(47): 10180-10201.). Nav1.8 is mainly found in trigeminal ganglion neurons and DRG neurons. Nerve damage increases the expression level of Nav1.8 in axons and neuronal cell bodies. In animals, knocking out Nav1.8 reduces pain sensitivity (Mol Pain. 2006 Feb 14; 2:5.). Acquired functional mutations in the human Nav1.8 gene can lead to peripheral neuralgia (PNAS. 2012 Nov 20; 109(47):19444-9.). Therefore, Nav1.7 and Nav1.8 are considered potential targets for pain treatment.

[0003] However, clinical trials of Nav1.7 inhibitors for treating various chronic and acute pain have shown poor efficacy (Pain. 2018, 159(8): 1465-1476.). In PhIII clinical trials of Nav1.8 inhibitors alone in patients undergoing abdominoplasty and bunion removal, although significant relative to placebo was achieved, VX-548 alone did not significantly improve pain relief compared to standard therapy (N Engl J Med. 2023, 389(5): 393-405.).

[0004] Therefore, there is still a need to develop new Nav1.8 and / or Nav1.7 inhibitors to more effectively block the transmission of pain signals, exert stronger analgesic effects, and cover a wider range of pain types. Summary of the Invention

[0005] This invention provides a novel Nav1.8 and / or Nav1.7 inhibitor that can be used to prevent and / or treat Nav1.8 and / or Nav1.7-related diseases, such as treating or relieving pain.

[0006] According to one aspect of the invention, the invention provides compounds of formula (I) or their stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof:

[0007]

[0008] in:

[0009] The A ring and B ring may be the same or different, and are independently selected from phenyl, 5-11-membered heteroaryl, C3-7 cycloalkyl, C3-7 cycloalkenyl, and 3-7-membered heterocyclic alkyl containing 1-3 independently selected from N, O, and S, connected by C or N to a carbon atom of a proximal pyrazinyl or cyclopropane group;

[0010] R1 and R2 may be the same or different, and are independently selected from F, Cl, Br, -CN, -NO2, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, C3-7 cycloalkyl, 3-7 membered heterocyclic alkyl containing 1-3 cyclic heteroatoms independently selected from N, O, S connected by C or N to a carbon atom or nitrogen atom of a proximal A or B ring, 5-11 membered heteroaryl containing 1-3 cyclic heteroatoms independently selected from N, O, S connected by C or N to a carbon atom of a proximal A or B ring, phenyl, -OR3, -C(O)R3, -C(O)OR3, -C(O)N(R3)R4, -SR3, -S(O)2R3, -S(O)2N(R3)R4. -N(R3)R4, -N(R3)C(O)R4, -N(R3)S(O)2R4, -P(O)(R3)R4, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, or phenyl group is optionally substituted by one or more substituents independently selected from F, Cl, Br, -OH, -CN, -NH2, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, C1-4 straight-chain or branched alkoxy, C3-7 cycloalkyl, or a 3-7 membered heterocycloalkyl group containing 1-3 cyclic heteroatoms independently selected from N, O, or S, connected by a C or N group to a proximal group;

[0011] Two R1 atoms attached to two adjacent atoms on ring A, together with the two adjacent atoms on ring A to which they are attached, can form a 5-7 membered cycloalkyl group, or a 5-7 membered heterocycloalkyl group containing 1-3 independent cycloheteroatoms selected from N, O, and S. The cycloalkyl group or heterocycloalkyl group may optionally be substituted by one or more substituents selected from F, Cl, Br, -OH, -CN, -NH2, =O, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, or C1-4 straight-chain or branched alkoxy groups. The alkyl, alkenyl, alkynyl, or alkoxy substituents may optionally be substituted by one or more substituents selected from F, Cl, Br, -OH, -CN, -NH2, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, or C1-4 straight-chain or branched alkoxy groups.

[0012] Two R2 atoms attached to two adjacent atoms on the B ring, together with the two adjacent atoms on the B ring to which they are attached, can form a 5-7 membered cycloalkyl group, or a 5-7 membered heterocycloalkyl group containing 1-3 independent cycloheteroatoms selected from N, O, and S. The cycloalkyl group or heterocycloalkyl group may optionally be substituted by one or more substituents selected from F, Cl, Br, -OH, -CN, -NH2, =O, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, or C1-4 straight-chain or branched alkoxy groups. The alkyl, alkenyl, alkynyl, or alkoxy substituents may optionally be substituted by one or more substituents selected from F, Cl, Br, -OH, -CN, -NH2, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, or C1-4 straight-chain or branched alkoxy groups.

[0013] R3 and R4 may be the same or different, and are independently selected from H, -OH, -NH2, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, C3-7 cycloalkyl, 3-7-membered heterocyclic alkyl containing 1-3 cyclic heteroatoms independently selected from N, O, S, P connected by a C or N group to a proximal group, phenyl, 5-11-membered heteroaryl containing 1-3 cyclic heteroatoms independently selected from N, O, S connected by a C or N group to a proximal group, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic alkyl, phenyl, or heteroaryl group may optionally be selected by one or more independently selected from F, Cl, Br, OH, CN, NH2, = O, a C1-4 straight-chain or branched alkyl group optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH2; a C1-4 straight-chain or branched alkoxy group optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH2; a C3-7 cycloalkyl group optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH2; or a 3-7 membered heterocyclic alkyl group containing 1-3 cyclic heteroatoms independently selected from N, O, S, substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH2.

[0014] When R3 and R4 are attached to the same atom, R3 and R4 together with the atom they are attached to can form a 3-7 membered heterocyclic alkyl group containing 1-3 independent cyclic heteroatoms selected from N, O, and S. The heterocyclic alkyl group is optionally replaced by one or more substituents selected from F, Cl, Br, -OH, -CN, -NH2, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, and C1-4 straight-chain or branched alkoxy groups. The alkyl, alkenyl, alkynyl, and alkoxy substituents are optionally replaced by one or more substituents selected from F, Cl, Br, -OH, -CN, -NH2, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, and C1-4 straight-chain or branched alkoxy groups.

[0015] m can be 0, 1, 2, 3, 4, or 5;

[0016] n can be 0, 1, 2, 3, 4, or 5.

[0017] In a preferred embodiment

[0018] Rings A and B are phenyl groups;

[0019] R1 and R2 may be the same or different, and are independently selected from F, Cl, Br, -CN, -NO2, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, C3-7 cycloalkyl, 3-7 membered heterocyclic alkyl containing 1-3 cyclic heteroatoms independently selected from N, O, and S connected to a carbon atom of the proximal A or B ring via C or N, 5-11 membered heteroaryl, phenyl, -OR 3. -SR3, -N(R3)R4, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, or phenyl group is optionally substituted by one or more substituents independently selected from F, Cl, Br, -OH, -CN, -NH2, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, C1-4 straight-chain or branched alkoxy, C3-7 cycloalkyl, or a 3-7 membered heterocycloalkyl group containing 1-3 cyclic heteroatoms independently selected from N, O, or S, connected to a proximal group via C or N;

[0020] Two R1 atoms attached to two adjacent atoms on ring A, together with the two adjacent atoms on ring A to which they are attached, can form a 5-7 membered cycloalkyl group, or a 5-7 membered heterocycloalkyl group containing 1-3 independent cycloheteroatoms selected from N, O, and S. The cycloalkyl group or heterocycloalkyl group may optionally be substituted by one or more substituents selected from F, Cl, Br, -OH, -CN, -NH2, =O, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, or C1-4 straight-chain or branched alkoxy groups. The alkyl, alkenyl, alkynyl, or alkoxy substituents may optionally be substituted by one or more substituents selected from F, Cl, Br, -OH, -CN, -NH2, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, or C1-4 straight-chain or branched alkoxy groups.

[0021] Two R2 atoms attached to two adjacent atoms on the B ring, together with the two adjacent atoms on the B ring to which they are attached, can form a 5-7 membered cycloalkyl group, or a 5-7 membered heterocycloalkyl group containing 1-3 independent cycloheteroatoms selected from N, O, and S. The cycloalkyl group or heterocycloalkyl group may optionally be substituted by one or more substituents selected from F, Cl, Br, -OH, -CN, -NH2, =O, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, or C1-4 straight-chain or branched alkoxy groups. The alkyl, alkenyl, alkynyl, or alkoxy substituents may optionally be substituted by one or more substituents selected from F, Cl, Br, -OH, -CN, -NH2, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, or C1-4 straight-chain or branched alkoxy groups.

[0022] R3 and R4 may be the same or different, and are independently selected from H, -OH, -NH2, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, C3-7 cycloalkyl, 3-7-membered heterocyclic alkyl containing 1-3 cyclic heteroatoms independently selected from N, O, S, P connected by a C or N group to a proximal group, phenyl, 5-11-membered heteroaryl containing 1-3 cyclic heteroatoms independently selected from N, O, S connected by a C or N group to a proximal group, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic alkyl, phenyl, or heteroaryl group may optionally be selected by one or more independently selected from F, Cl, Br, OH, CN, NH2, = O, a C1-4 straight-chain or branched alkyl group optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH2; a C1-4 straight-chain or branched alkoxy group optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH2; a C3-7 cycloalkyl group optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH2; or a 3-7 membered heterocyclic alkyl group containing 1-3 cyclic heteroatoms independently selected from N, O, S, substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH2.

[0023] When R3 and R4 are attached to the same atom, R3 and R4 together with the atom they are attached to can form a 3-7 membered heterocyclic alkyl group containing 1-3 independent cyclic heteroatoms selected from N, O, and S. The heterocyclic alkyl group is optionally replaced by one or more substituents selected from F, Cl, Br, -OH, -CN, -NH2, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, and C1-4 straight-chain or branched alkoxy groups. The alkyl, alkenyl, alkynyl, and alkoxy substituents are optionally replaced by one or more substituents selected from F, Cl, Br, -OH, -CN, -NH2, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, and C1-4 straight-chain or branched alkoxy groups.

[0024] m is 1, 2, or 3;

[0025] n is 1, 2, or 3.

[0026] In a preferred embodiment

[0027] Rings A and B are phenyl groups;

[0028] R1 and R2 may be the same or different, and are independently selected from F, Cl, Br, -CN, -NO2, C1-4 straight-chain or branched alkyl, C3-7 cycloalkyl, 3-7-membered heterocyclic alkyl containing 1-3 cyclic heteroatoms independently selected from N, O, S connected to a carbon atom of the proximal A or B ring via C or N, 5-11-membered heteroaryl, phenyl, -OR3, -SR3, -N(R3)R4 containing 1-3 cyclic heteroatoms independently selected from N, O, S connected to a carbon atom of the proximal A or B ring via C or N, wherein the alkyl, cycloalkyl, heterocyclic alkyl, heteroaryl, or phenyl may optionally be substituted by one or more substituents independently selected from F, Cl, Br, -OH, -CN, -NH2, C1-4 straight-chain or branched alkyl, or C1-4 straight-chain or branched alkoxy.

[0029] R3 and R4 may be the same or different, and are independently selected from H, -OH, -NH2, C1-4 straight-chain or branched alkyl, C3-7 cycloalkyl, 3-7-membered heterocyclic alkyl containing 1-3 cyclic heteroatoms independently selected from N, O, S, P connected to a proximal group via C or N, phenyl, 5-11-membered heteroaryl containing 1-3 cyclic heteroatoms independently selected from N, O, S connected to a proximal group via C or N, wherein the alkyl, cycloalkyl, heterocyclic alkyl, phenyl, or heteroaryl group is optionally selected by one or more independently selected from F, Cl, Br, OH, CN, NH2, =O, or optionally selected by one or more independently selected groups. C1-4 straight-chain or branched alkyl groups substituted by groups of F, Cl, Br, OH, CN, NH2; C1-4 straight-chain or branched alkoxy groups substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH2; C3-7 cycloalkyl groups substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH2; and 3-7 membered heterocyclic alkyl groups containing 1-3 cyclic heteroatoms independently selected from N, O, S, substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH2.

[0030] m is 1, 2, or 3;

[0031] n is 1, 2, or 3.

[0032] In a preferred embodiment, the present invention provides a compound of formula (II) or a stereoisomer thereof, a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof:

[0033]

[0034] R2 is independently selected from F, Cl, Br, -CN, -NO2, C1-4 straight-chain or branched alkyl, and -OR3;

[0035] R3 is independently selected from H, C1-4 straight-chain or branched alkyl groups, and phenyl groups;

[0036] n is 1 or 2.

[0037] In a preferred embodiment, the present invention provides a compound of formula (III) or a stereoisomer thereof, a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof:

[0038]

[0039] R2 is selected from F, Cl, Br, -CN, -NO2, C1-4 straight-chain or branched alkyl groups, and -OR3;

[0040] R3 is selected from H, C1-4 straight-chain or branched alkyl groups, and phenyl groups.

[0041] In a preferred embodiment, the present invention provides compounds of formula (IV) or their stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof:

[0042]

[0043] R2 is independently selected from F, Cl, Br, -CN, -NO2, C1-4 straight-chain or branched alkyl, and -OR3;

[0044] R3 is independently selected from H, C1-4 straight-chain or branched alkyl groups, and phenyl groups.

[0045] In a preferred embodiment, the present invention provides compounds of formula (V) or their stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof:

[0046]

[0047] R2 is independently selected from F, Cl, Br, -CN, -NO2, C1-4 straight-chain or branched alkyl, and -OR3;

[0048] R3 is independently selected from H, C1-4 straight-chain or branched alkyl groups, and phenyl groups.

[0049] In a preferred embodiment, the compounds of the present invention are selected from the following compounds or their pharmaceutically acceptable salts or deuterated derivatives:

[0050]

[0051]

[0052]

[0053]

[0054] In this invention, although substituents are disclosed as groups or ranges, the groups or ranges of this invention specifically refer to each particular group covered therein. For example, the term "C" 1-4 "Straight-chain or branched alkyl" specifically refers to independently disclosed methyl (i.e., C1 alkyl), ethyl (i.e., C2 alkyl), straight-chain or branched propyl (i.e., C3 alkyl), and straight-chain or branched butyl (i.e., C4 alkyl). The term "C" 1-4 "Straight-chain or branched alkoxy groups" can be interpreted similarly.

[0055] In this invention, alkenyl and alkynyl groups include cis and trans.

[0056] In this invention, "C" 2-4Examples of "straight-chain or branched alkenyl" include vinyl, allyl, propenyl, 1-butenyl, 2-butenyl, isobutenyl, etc.

[0057] In this invention, "C" 2-4 Examples of "straight-chain or branched alkynyl groups" include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, isobutynyl, etc.

[0058] In this invention, examples of "3-7 membered cycloalkyl" or "C3-7 cycloalkyl" include cyclopropane, cyclobutane, cyclopentane, cyclohexane, and cycloheptane. The term "C3-7 cycloalkenyl" is interpreted similarly.

[0059] In this invention, examples of "3-7 membered heteroalkyl cyclogroups containing 1-3 independently selected cyclic heteroatoms from N, O, and S" include ethylene oxide, cyclothioethane, aziridine, oxacyclobutane, N-heterocyclobutane, α-lactam ring, β-lactam ring, β-lactone, tetrahydrofuran, thiocyclopentane, pyrrolidine, pyrrolidone, pyrrolidone, dioxolane, oxazolidinone, oxazolidinone, isoxazolidinone, thiazolinone, isotoxazolidinone, thiazolinone, isothiazolidinone, thiazolinone, imidazolinone, imidazolinone, pyrazolone, tetrahydropyran, dihydropyran, pyran, piperidine, piperidinone, 1,4-dioxane, morpholinone, morpholinone, piperazine, aziridine, hexane, thiocycloheptane, 1,4-oxazane, 1,4-thiazolinone, etc.

[0060] In this invention, examples of "5-11 membered heteroaryl groups containing 1-3 independently selected cyclic heteroatoms from N, O, and S" include furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxadiazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyrazine, triazine, benzozahexacyclobutane, benzoβ-lactam ring, benzoβ-lactone, benzoxadiclofen, benzofuran, benzothiophene, indole, indazole, isoinazole, benzimidazole, benzothiazole, benzoisothiazole, benzoxazole, benzoisoxazole, benzotriazole, benzoxadiazole, benzothiadiazole, benzodioxazole, benzodioxane ... Phosphine, benzopiperidine, benzopyran, benzopyridine, benzopyrimidine, benzotriazine, benzozacyclohexanone, benzozacycloheptanone, pyridazazecyclobutane, pyrido-β-lactam ring, pyrido-β-lactone, pyrido-oxadiclopentazoline, pyrido-furan, pyrido-thiophene, pyrido-pyrrole, pyrido-pyrazole, pyrido-imidazolium, pyrido-thiazole, pyrido-isothiazole, pyrido-oxazole, pyrido-isothiazole, pyrido-triazole, pyrido-oxadiazole, pyrido-thiadiazole, pyrido-dioxane, pyrido-morpholine, pyridopiperidine, pyrido-pyran, pyrido-pyridine, pyrido-pyrimidine, pyrido-triazine, pyrido-azacyclohexanone, furan-pyrrole, thiazole-pyrimidine, etc.

[0061] The compounds of this invention can be asymmetric, for example, having one or more stereocenters. All stereoisomers, such as enantiomers and diastereomers, are included within the scope of this invention unless otherwise specified. In this invention, compounds containing asymmetrically substituted carbon atoms can be isolated in either optically active or racemic form. Various methods for preparing the optically active form are known in the art, for example, by resolution of racemic mixtures or by stereoselective synthesis.

[0062] The present invention also includes the compounds in all forms where the atoms are various isotopes. Isotopes include all atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium.

[0063] This invention also includes pharmaceutically acceptable salts of the said compounds. The compounds of this invention can be prepared into pharmaceutically acceptable salts by reacting with non-toxic inorganic or organic acids. Inorganic acids include, for example, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid, hydrogen sulfate, boric acid, hemisulfate, etc.; organic acids include, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, hexanoic acid, heptanoic acid, undecanoic acid, palmitic acid, stearic acid, oleic acid, oxalic acid, malonic acid, adipic acid, lactic acid, malic acid, maleic acid, hippuric acid, tartaric acid, citric acid, succinic acid, ascorbic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, benzoic acid, p-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, galacturonic acid, dodecyl sulfate, and various amino acids, etc.

[0064] Those skilled in the art will understand that the compounds of the present invention can be prepared by various methods disclosed in the literature. The compounds of the present invention can be prepared by reaction in a suitable solvent, and those skilled in the art of organic synthesis can readily select a suitable solvent that does not substantially react with the reactants, intermediates, or products. The reaction can be carried out in one solvent or a mixture of more than one solvent. The compounds of the present invention can be prepared by reaction at a suitable temperature, for example, between the solidification temperature and the boiling point of the solvent. Methods for preparing the compounds of the present invention involve the protection and deprotection of various chemical groups, and those skilled in the art of organic synthesis can readily determine whether protection and deprotection of chemical groups are necessary and to select suitable protecting groups. The reaction for preparing the compounds of the present invention can be monitored using any method known in the art, such as nuclear magnetic resonance spectroscopy, infrared spectroscopy, mass spectrometry, chromatography, etc.

[0065] The compounds of the present invention can be prepared, for example, by the following method:

[0066] Method I:

[0067]

[0068] The definitions of the groups in each formula are as described above.

[0069] The synthesis reaction of Ib can be carried out in a solvent in the presence of DPPA, tert-butanol and a base. The base can be selected from DMAP, HOBt, HOAt, TEA, DIEA, 4PPY, NMM, etc., and the solvent can be selected from benzene, toluene, xylene, dichloromethane, chloroform, dimethyl sulfoxide, N,N-dimethylformamide, etc. or any mixture thereof.

[0070] The synthesis reaction of Ic can be carried out in a solvent in the presence of an acid or a base. The acid can be selected from hydrochloric acid, trifluoroacetic acid, sulfuric acid, hydrofluoric acid, etc., and the base can be selected from tetrabutylammonium fluoride, sodium hydride, potassium cyanide, etc. The solvent can be selected from dichloromethane, chloroform, acetonitrile, ethyl acetate, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, n-propanol, isopropanol, n-butanol, DME, dimethyl sulfoxide, N,N-dimethylformamide, etc., or any mixture thereof.

[0071] The synthesis of compound I can be carried out in a solvent in the presence of a catalyst and a base. The catalyst can be selected from CDI, DCC, DIC, EDCI, HATU, HBTU, HCTU, HSTU, HAPyU, BOP, PyBOP, PyAOP, BOPCl, DPPCCl, DPPA, T3P, TCCA, CDMT, EEDQ, etc., and the base can be selected from DMAP, HOBt, HOAt, TEA, DIEA, 4PPY, NMM, etc., and the solvent can be selected from 1,4-dioxane, tetrahydrofuran, dichloromethane, chloroform, toluene, xylene, dimethyl sulfoxide, N,N-dimethylformamide, etc., or any mixture thereof.

[0072] Method II:

[0073]

[0074] The definitions of the groups in each formula are as described above.

[0075] The synthesis of II-b can be carried out in a solvent in the presence of a base, a ligand, and a catalyst. The solvent can be selected from 1,4-dioxane, tetrahydrofuran, water, methanol, toluene, xylene, dimethyl sulfoxide, N,N-dimethylformamide, or any mixture thereof; the base can be selected from potassium phosphate, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, etc.; the ligand can be selected from triphenylphosphine, dppp, dppf, etc.; and the catalyst can be selected from palladium acetate, tetratriphenylphosphine palladium, Pd2(dba)3, Pd(dppf)Cl2, Pd(PPh3)2Cl2, etc.

[0076] The synthesis reaction of II-c can be carried out in solvents such as hydrazine hydrate, hydrazine, hydrochloric acid, and hydrobromic acid. The solvent can be selected from water, tetrahydrofuran, 1,4-dioxane, acetic acid, dichloromethane, methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, DME, dimethyl sulfoxide, N,N-dimethylformamide, or any mixture thereof.

[0077] The synthesis of compound I can be carried out in a solvent in the presence of a catalyst and a base. The catalyst can be selected from CDI, DCC, DIC, EDCI, HATU, HBTU, HCTU, HSTU, HAPyU, BOP, PyBOP, PyAOP, BOPCl, DPPCCl, DPPA, T3P, TCCA, CDMT, EEDQ, etc., and the base can be selected from DMAP, HOBt, HOAt, TEA, DIPEA, 4PPY, NMM, etc., and the solvent can be selected from 1,4-dioxane, tetrahydrofuran, dichloromethane, chloroform, toluene, xylene, dimethyl sulfoxide, N,N-dimethylformamide, etc., or any mixture thereof.

[0078] The compounds of the present invention can inhibit (or antagonize) Nav1.8 and / or Nav1.7, and in particular can inhibit Nav1.8 and Nav1.7 simultaneously, thereby more effectively blocking the transmission of pain signals, exerting a stronger analgesic effect, and treating a wider range of pain types.

[0079] According to another aspect of the invention, the invention provides a method for suppressing Nav1.8 and / or Nav1.7, wherein the compounds of the invention are used.

[0080] According to another aspect of the invention, the invention provides a method for preventing and / or treating Nav1.8 and / or Nav1.7 related diseases, wherein an effective amount of the compound of the invention or a pharmaceutical composition containing the compound of the invention is administered to an individual in need for prevention and / or treatment.

[0081] According to another aspect of the invention, the invention provides a method for preventing and / or treating pain, wherein an individual in need is given an effective amount of the compound of the invention or a pharmaceutical composition containing the compound of the invention for prevention and / or treatment.

[0082] According to another aspect of the invention, the invention provides the use of the compounds of the invention in the preparation of Nav1.8 and / or Nav1.7 inhibitors.

[0083] According to another aspect of the invention, the invention provides the use of the compounds of the invention or pharmaceutical compositions containing the compounds of the invention in the preparation of medicaments for the prevention and / or treatment of Nav1.8 and / or Nav1.7 related diseases.

[0084] According to another aspect of the invention, the invention provides the use of the compounds of the invention or pharmaceutical compositions containing the compounds of the invention in the preparation of medicaments for the prevention and / or treatment of pain.

[0085] Nav1.8 and / or Nav1.7 related diseases include, but are not limited to, pain. The compounds of this invention or pharmaceutical compositions containing the compounds of this invention are capable of preventing and / or treating pain of various types and degrees in various parts of the body caused by various factors.

[0086] The compounds of this invention can be used in combination with one or more other drugs.

[0087] The compounds of the present invention can be administered in the form of a pharmaceutical composition. Therefore, according to another aspect of the present invention, a pharmaceutical composition is provided comprising the compounds of the present invention and a pharmaceutically acceptable carrier.

[0088] Those skilled in the art will understand that the pharmaceutical compositions of the present invention can be prepared by various methods disclosed in the literature. The compounds or pharmaceutical compositions of the present invention can be administered via a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. For example, they can be administered orally, parenterally (e.g., intravenously, arterially, subcutaneously, intraperitoneally, intramuscularly, or by infusion), intracranially (e.g., intrathecal or intraventricular), transdermally, through the eyes, nose, vagina, rectum, or lungs (e.g., by inhalation or blowing in powder or aerosol).

[0089] For oral administration, the pharmaceutical compositions of the present invention are typically provided in the form of tablets, capsules, or solutions. Tablets may contain the compounds of the present invention or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers. These carriers include, but are not limited to, diluents, disintegrants, binders, lubricants, colorants, or preservatives. Capsules include hard capsules and soft capsules. For parenteral administration, the pharmaceutical compositions of the present invention may be administered by intravenous, intramuscular, or subcutaneous injection. They are typically provided as sterile aqueous solutions or suspensions or lyophilized powders, adjusted to a suitable pH and isotonicity.

[0090] The effective amount of the compounds of this invention can be determined based on the specific therapeutic use, the method of administration, and the individual's condition, such as the patient's. Those skilled in the art are capable of determining the effective amount of the compounds of this invention. Typical dosage ranges are, for example, from 1 μg / kg / day to 1000 mg / kg / day. Detailed Implementation

[0091] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the contents of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by this invention.

[0092] Synthesis of the common intermediate common int-1

[0093]

[0094] Synthesis of methyl 6-(4-ethoxy-2-methoxyphenyl)pyrazine-2-carboxylic acid (2):

[0095] A solution of methyl 6-chloropyrazine-2-carboxylate (2.0 g, 11.59 mmol), 4-ethoxy-2-methoxyphenylboronic acid (2.2 g, 11.22 mmol), and potassium carbonate (3.2 g, 23.15 mmol) in toluene (32.0 mL) and methanol (8.0 mL) was added to tetrakis(triphenylphosphine)palladium (1.3 g, 1.12 mmol). The gas in the flask was purged with an argon balloon, and the mixture was stirred at 80 °C for 3 hours. After the reaction was complete and the temperature was allowed to cool to room temperature, the resulting mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude oily product. The crude product was purified by silica gel chromatography (ethyl acetate:petroleum ether = 1:2) to give a white solid (2.5 g). LC-MS: [M+H] + :289.1.

[0096] Synthesis of 6-(4-ethoxy-2-methoxyphenyl)pyrazine-2-carboxylic acid (common int-1):

[0097] A mixture of methyl 6-(4-ethoxy-2-methoxyphenyl)pyrazine-2-carboxylate (500.0 mg, 1.73 mmol) and lithium hydroxide monohydrate (363.7 mg, 8.67 mmol) in tetrahydrofuran (5.0 mL) and water (0.5 mL) was stirred at 25 °C for 16 hours. After the reaction was complete, the pH of the mixture was adjusted to 2–3 with 1 M hydrochloric acid aqueous solution. The solid was filtered, washed with water, and dried to give a white solid (400.0 mg). LC-MS: [M+H] + :275.1.

[0098] Synthesis of the common intermediate common int-2

[0099]

[0100] Synthesis of (E)-2-(2-boronate pinacol ester-vinyl)isoindoline-1,3-dione(2):

[0101] To a solution of 2-vinylisoindoline-1,3-dione (700.0 mg, 4.04 mmol) in 1,4-dioxane (15.0 mL), vinylboronic acid pinacol ester (1867.7 mg, 12.13 mmol), methoxy(cyclooctadiene) rhodium(I) dimer (76.2 mg, 0.16 mmol), and 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (185.2 mg, 0.32 mmol) were added. The reaction mixture was stirred at 90 °C under an argon atmosphere for 48 hours. After the reaction was complete, the mixture was diluted with water, extracted three times with ethyl acetate and washed twice with brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:1) to give a yellow solid (1.0 g). 1 H NMR (400MHz, CD3Cl) δ7.87–7.84(m,2H),7.75–7.73(m,2H),7.44(d,J=16.0Hz,1H),6.43(d,J=16.0Hz,1H),1.27(s,12H).

[0102] Synthesis of 2-(trans-2-boronate pinacol ester-cyclopropyl)isoindoline-1,3-dione (common int-2):

[0103] Compound (E)-2-(2-boronate-vinyl)isoindoline-1,3-dione (660.0 mg, 2.21 mmol) and palladium acetate (24.7 mg, 0.11 mmol) were dissolved in diethyl ether (5.0 mL). A solution of diazomethane (20.0 mL) in diethyl ether (10.0 mL) was added dropwise at 25 °C, and the mixture was stirred for 20 minutes at 25 °C. After the reaction was complete, the reaction mixture was evaporated to dryness. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:1) to give a yellow solid (320.0 mg). LC-MS: [M+H] + :314.1.

[0104] Example 1: Synthesis of compound BS-06-018

[0105] Synthesis of (trans-2-(3-methoxyphenyl)cyclopropyl)carbamate tert-butyl ester (2):

[0106] A solution of trans-2-(3-methoxyphenyl)cyclopropane-1-carboxylic acid (300.0 mg, 1.56 mmol) and toluene (20.0 mL) was reacted with diphenyl azide phosphate (473.0 mg, 1.72 mmol), triethylamine (174.0 mg, 1.72 mmol), and tert-butanol (127.5 mg, 1.72 mmol). The mixture was heated to 85 °C and stirred for 16 hours. The reaction solution was distilled under reduced pressure, the organic phase was removed by vortexing, and the extract was obtained with ethyl acetate (30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a white solid product (300.0 mg). LC-MS: [M+H] + :264.2.

[0107] Synthesis of trans-2-(3-methoxyphenyl)cyclopropyl-1-amine (3):

[0108] To a solution of tert-butyl (trans-2-(3-methoxyphenyl)cyclopropyl)carbamate (200.0 mg, 0.76 mmol), trifluoroacetic acid (2.0 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was evaporated to dryness under reduced pressure to give a white solid product (100.0 mg). LC-MS: [M+H] + :164.2.

[0109] Synthesis of 6-(4-ethoxy-2-methoxyphenyl)-N-(trans-2-(3-methoxyphenyl)cyclopropyl)pyrazine-2-carboxamide (BS-06-018):

[0110] To a solution of 6-(4-ethoxy-2-methoxyphenyl)pyrazine-2-carboxylic acid (50.0 mg, 0.18 mmol) in N,N-dimethylformamide (2.0 mL), trans-2-(3-methoxyphenyl)cyclopropyl-1-amine (31.0 mg, 0.19 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (88.0 mg, 0.23 mmol), and N,N-diisopropylethylamine (75.0 mg, 0.58 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with water, extracted with ethyl acetate (30 mL × 3), and the combined organic layers were washed with brine (60 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:1) and then purified by high-performance preparative chromatography to give a white solid product (4.1 mg). 1H NMR (400MHz, CD3OD) δ9.28(s,1H),9.00(s,1H),8.03(d,J=8.5Hz,1H),7.19(t,J=7.8Hz,1H),6.79–6.69(m,6H),4.13(d,J=7.0Hz,2H),3 .93(s,3H),3.78(s,3H),3.11–3.08(m,1H),2.28–2.24(m,1H),1.43(t,J=7.0Hz,3H),1.36–1.31(m,1H),1.05–1.02(m,1H).LC-MS:[M+H] + :420.1.

[0111] Example 2: Synthesis of compounds BS-06-105-P1 and BS-06-105-P2

[0112]

[0113] Synthesis of 2-(trans-2-(3-phenoxyphenyl)cyclopropyl)isoindoline-1,3-dione (1):

[0114] To a solution of 2-(trans-2-boranopinal ester-cyclopropyl)isoindoline-1,3-dione (80.0 mg, 0.255 mmol), 1-bromo-3-phenoxybenzene (63.6 mg, 0.255 mmol), and potassium carbonate (106.4 mg, 0.77 mmol) in toluene (5.0 mL) and water (0.5 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (41.65 mg, 0.051 mmol) was added. The gas in the flask was purged with an argon balloon, and the mixture was stirred at 100 °C for 4 hours. After the reaction was completed and the temperature was allowed to cool to room temperature, the resulting mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude oily product. The crude product was purified by silica gel chromatography (ethyl acetate:petroleum ether = 1:5) to give a yellow solid (40.0 mg). LC-MS: [M+H] + :356.1.

[0115] Synthesis of trans-2-(3-phenoxyphenyl)cyclopropyl-1-amine (2):

[0116] Compound 2-(trans-2-(3-phenoxyphenyl)cyclopropyl)isoindoline-1,3-dione (40.0 mg, 0.11 mmol) was dissolved in ethanol (2.0 mL), and hydrazine hydrate (13.8 mg, 0.22 mmol, 80% w) was added at room temperature. The mixture was stirred at 50 °C for 3 hours. The reaction solution was filtered directly, and the filtrate was concentrated under vacuum. The resulting crude product, a white solid (20.0 mg), was used directly in the next step. LC-MS: [M+H] + :226.1.

[0117] Synthesis of 6-(4-ethoxy-2-methoxyphenyl)-N-(trans-2-(3-phenoxyphenyl)cyclopropyl)pyrazine-2-carboxamide (BS-06-107):

[0118] To a solution of 6-(4-ethoxy-2-methoxyphenyl)pyrazin-2-carboxylic acid (25.0 mg, 0.091 mmol) in N,N-dimethylformamide (2.0 mL), N-methylmorpholine (18.2 mg, 0.18 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26.8 mg, 0.14 mmol), and 1-hydroxybenzotriazole (18.9 mg, 0.14 mmol) were added, and the mixture was stirred at 25 °C for 0.5 h. Then, trans-2-(3-phenoxyphenyl)cyclopropyl-1-amine (20.0 mg, 0.089 mmol) was added, and the mixture was stirred at 25 °C for 3 h. After the reaction was complete, the resulting mixture was diluted with water, extracted twice with ethyl acetate, the organic phases were combined and washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified to obtain a white solid (20.0 mg). LC-MS: [M+H] + :482.1.

[0119] Racemic BS-06-105 was separated and purified by SFC (column: CHIRALPAK AD-H 250mm×20mm, 5μm; mobile phase: A phase: 40% EtOH (NH4OH 0.2%); B phase: 60% CO2); yielding 6-(4-ethoxy-2-methoxyphenyl)-N-((1S,2R)-2-(3-phenoxyphenyl)cyclopropyl)pyrazine-2-carboxamide and 6-(4-ethoxy-2-methoxyphenyl)-N-((1R,2S)-2-(3-phenoxyphenyl)cyclopropyl)pyrazine-2-carboxamide.

[0120] BS-06-105-P1:

[0121] Chiral analysis conditions: Column: CHIRALPAK AD-H 250mm×20mm, 5μm; Mobile phase: Phase A: 40% EtOH (NH4OH 0.2%); Phase B: 60% CO2; Retention time: 6.32 min; ee% = 100%; White solid (8.7 mg);

[0122] 1 H NMR(400MHz,MeOD)δ9.27(s,1H),8.99(s,1H),8.01(d,J=8.4Hz,1H),7.36–7.31(m,2H),7. 26(t,J=7.9Hz,1H),7.09(t,J=7.4Hz,1H),6.97–6.95(m,3H),6.87–6.85(m,1H),6.79(dd, J=7.9,2.0Hz,1H),6.71–6.67(m,2H),4.13(q,J=7.0Hz,2H),3.92(s,3H),3.12–3.05(m,1H ),2.26(ddd,J=9.7,6.3,3.5Hz,1H),1.42(t,J=7.1Hz,3H),1.33–1.28(m,2H).LC-MS:[M+H] + :482.2.

[0123] BS-06-105-P2:

[0124] Chiral analysis conditions: Column: CHIRALPAK AD-H 250mm×20mm, 5μm; Mobile phase: Phase A: 40% EtOH (NH4OH 0.2%); Phase B: 60% CO2; Retention time: 6.76 min; ee% = 98.73%; White solid (10.7 mg);

[0125] 1H NMR(400MHz,MeOD)δ9.27(s,1H),8.99(s,1H),8.01(d,J=8.3Hz,1H),7.34(dd,J=8.4,7.6 Hz,2H),7.26(t,J=7.9Hz,1H),7.09(t,J=7.4Hz,1H),6.97–6.95(m,3H),6.87(d,J=1.9Hz, 1H),6.79(dd,J=8.0,2.1Hz,1H),6.71–6.67(m,2H),4.13(q,J=7.0Hz,2H),3.92(s,3H),3. 11–3.06(m,1H),2.27–2.25(m,1H),1.42(t,J=7.1Hz,3H),1.32–1.28(m,2H).LC-MS:[M+H] + :482.2.

[0126] Example 3: Synthesis of compounds BS-06-107-P1 and BS-06-107-P2

[0127]

[0128] Synthesis of 2-(trans-2-(2-fluoro-5-methoxyphenyl)cyclopropyl)isoindoline-1,3-dione (1):

[0129] To a solution of 2-(trans-2-boranopinal ester-cyclopropyl)isoindoline-1,3-dione (80.0 mg, 0.255 mmol), 3-bromo-4-fluoroanisole (104.6 mg, 0.51 mmol), and potassium carbonate (70.5 mg, 0.51 mmol) in toluene (5.0 mL) and water (0.5 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (41.65 mg, 0.051 mmol) was added. The gas in the flask was purged with an argon balloon, and the mixture was stirred at 100 °C for 5 hours. After the reaction was completed and the temperature was allowed to drop to room temperature, the resulting mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude oily product. The crude product was purified by silica gel chromatography (ethyl acetate:petroleum ether = 1:1) to give a yellow oil (25.0 mg). LC-MS: [M+H] + :312.1. Synthesis of trans-2-(2-fluoro-5-methoxyphenyl)cyclopropyl-1-amine (2):

[0130] Compound 2-(trans-2-(2-fluoro-5-methoxyphenyl)cyclopropyl)isoindoline-1,3-dione (25.0 mg, 0.080 mmol) was dissolved in ethanol (2.0 mL), and hydrazine hydrate (6.0 mg, 0.096 mmol, 80% w) was added at room temperature. The mixture was stirred at 50 °C for 3 hours. The reaction solution was filtered directly, and the filtrate was concentrated under vacuum. The resulting crude product, a white solid (10.0 mg), was used directly in the next step. LC-MS: [M+H] + :182.1.

[0131] Synthesis of 6-(4-ethoxy-2-methoxyphenyl)-N-(trans-2-(2-fluoro-5-methoxyphenyl)cyclopropyl)pyrazine-2-carboxamide (BS-06-107):

[0132] To a solution of 6-(4-ethoxy-2-methoxyphenyl)pyrazin-2-carboxylic acid (20.0 mg, 0.073 mmol) in N,N-dimethylformamide (2.0 mL), N-methylmorpholine (22.3 mg, 0.22 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21.1 mg, 0.11 mmol), and 1-hydroxybenzotriazole (14.9 mg, 0.11 mmol) were added, and the mixture was stirred at 25 °C for 0.5 h. Then, trans-2-(2-fluoro-5-methoxyphenyl)cyclopropane-1-amine (10.0 mg, 0.055 mmol) was added, and the mixture was stirred at 25 °C for 3 h. After the reaction was complete, the resulting mixture was diluted with water, extracted twice with ethyl acetate, the organic phases were combined and washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified to give a white solid (18.0 mg). LC-MS: [M+H] + :438.2.

[0133] Racemic BS-06-107 was separated and purified by SFC (column: CHIRALPAK AD-H 250mm×20mm, 5μm; mobile phase: A phase: 40% MeOH (NH4OH 0.2%); B phase: 60% CO2) to obtain 6-(4-ethoxy-2-methoxyphenyl)-N-((1R,2S)-2-(2-fluoro-5-methoxyphenyl)cyclopropyl)pyrazine-2-carboxamide and 6-(4-ethoxy-2-methoxyphenyl)-N-((1S,2R)-2-(2-fluoro-5-methoxyphenyl)cyclopropyl)pyrazine-2-carboxamide.

[0134] BS-06-107-P1:

[0135] Chiral analysis conditions: Column: CHIRALPAK AD-H 250mm×20mm, 5μm; Mobile phase: Phase A: 40% MeOH (NH4OH 0.2%); Phase B: 60% CO2; Retention time: 5.24 min; ee% = 100%; White solid (7.2 mg);

[0136] 1 H NMR(400MHz,MeOD)δ9.27(s,1H),9.00(s,1H),8.03(d,J=8.5Hz,1H),6.96(t,J =9.4Hz,1H),6.75–6.67(m,3H),6.64(dd,J=6.1,3.1Hz,1H),4.13(q,J=7.0Hz, 2H),3.92(s,3H),3.76(s,3H),3.28–3.24(m,1H),2.40(ddd,J=9.9,6.4,3.7Hz ,1H),1.53–1.47(m,1H),1.43(t,J=7.0Hz,3H),1.30–1.28(m,1H).LC-MS:[M+H] + :438.1.

[0137] BS-06-107-P2:

[0138] Chiral analysis conditions: Column: CHIRALPAK AD-H 250mm×20mm, 5μm; Mobile phase: Phase A: 40% MeOH (NH4OH 0.2%); Phase B: 60% CO2; Retention time: 9.35min; ee% = 100%; White solid (7.4mg);

[0139] 1 H NMR(400MHz,MeOD)δ9.27(s,1H),9.00(s,1H),8.03(d,J=8.5Hz,1H),6.96(t,J=9 .4Hz,1H),6.74–6.68(m,3H),6.65(dd,J=6.1,3.0Hz,1H),4.13(q,J=7.0Hz,2H), 3.93(s,3H),3.76(s,3H),3.28–3.24(m,1H),2.40(ddd,J=9.8,6.4,3.6Hz,1H),1 .50(dd,J=9.8,5.1Hz,1H),1.43(t,J=7.0Hz,3H),1.32–1.30(m,1H).LC-MS:[M+H] + :438.2.

[0140] Example 4: Synthesis of compounds BS-06-115-P1 and BS-06-115-P2

[0141]

[0142] Synthesis of 2-(trans-2-(5-methoxy-2-methylphenyl)cyclopropyl)isoindoline-1,3-dione (1):

[0143] To a solution of 2-(trans-2-boranopinal ester-cyclopropyl)isoindoline-1,3-dione (100.0 mg, 0.32 mmol), 3-bromo-4-methylanisole (96.3 mg, 0.48 mmol), and potassium carbonate (132.7 mg, 0.96 mmol) in toluene (5.0 mL) and water (0.5 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (52.3 mg, 0.064 mmol) was added. The gas in the flask was purged with an argon balloon, and the mixture was stirred at 100 °C for 5 hours. After the reaction was completed and the temperature was allowed to drop to room temperature, the resulting mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude oily product. The crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1:1) to give a yellow oil (30.0 mg). 1 H NMR(400MHz, CDCl3)δ7.86–7.83(m,2H),7.73–7.71(m,2H)7.10(d,J=8.0Hz,1H),6.71–6.69(m,2H),3 .79(s,3H),3.01–2.99(m,1H),2.67–2.65(m,1H),2.41(s,3H),1.75–1.70(m,1H),1.42–1.40(m,1H).

[0144] Synthesis of trans-2-(5-methoxy-2-methylphenyl)cyclopropyl-1-amine (2):

[0145] Compound 2-(trans-2-(5-methoxy-2-methylphenyl)cyclopropyl)isoindoline-1,3-dione (21.2 mg, 0.069 mmol) was dissolved in ethanol (2.0 mL). Hydrazine hydrate (43.2 mg, 0.69 mmol, 80% w) was added to the mixture at room temperature, and the mixture was stirred at 50 °C for 5 hours. The reaction solution was directly filtered, and the filtrate was concentrated under vacuum. The resulting crude product, a white solid (20.0 mg), was used directly in the next step. LC-MS: [M+H] +:178.1. Synthesis of 6-(4-ethoxy-2-methoxyphenyl)-N-(trans-2-(5-methoxy-2-methylphenyl)cyclopropyl)pyrazine-2-carboxamide (BS-06-115):

[0146] To a solution of 6-(4-ethoxy-2-methoxyphenyl)pyrazin-2-carboxylic acid (30.2 mg, 0.11 mmol) in N,N-dimethylformamide (2.0 mL), N-methylmorpholine (22.3 mg, 0.22 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (32.6 mg, 0.17 mmol), and 1-hydroxybenzotriazole (23.0 mg, 0.17 mmol) were added, and the mixture was stirred at room temperature for 0.5 h. Then, trans-2-(5-methoxy-2-methylphenyl)cyclopropyl-1-amine (20.0 mg, 0.11 mmol) was added, and the mixture was stirred at room temperature for 12 h. After the reaction was complete, the resulting mixture was diluted with water, extracted twice with ethyl acetate, the organic phases were combined and washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the crude product was subjected to silica gel chromatography (petroleum ether:ethyl acetate = 1:1) to give a white solid (10.0 mg). LC-MS: [M+H] + :434.1.

[0147] Racemic BS-06-115 was separated and purified by SFC (column: CHIRALPAK AD-H 250mm×20mm, 5μm; mobile phase: A phase: 40% MeOH (NH4OH 0.2%); B phase: 60% CO2) to obtain 6-(4-ethoxy-2-methoxyphenyl)-N-((1S,2R)-2-(5-methoxy-2-methylphenyl)cyclopropyl)pyrazine-2-carboxamide and 6-(4-ethoxy-2-methoxyphenyl)-N-((1R,2S)-2-(5-methoxy-2-methylphenyl)cyclopropyl)pyrazine-2-carboxamide.

[0148] BS-06-115-P1:

[0149] Chiral analysis conditions: Column: CHIRALPAK AD-H 250mm×20mm, 5μm; Mobile phase: Phase A: 40% MeOH (NH4OH 0.2%); Phase B: 60% CO2; Retention time: 5.21 min; ee% = 100%; White solid (5.0 mg);

[0150] 1H NMR (400MHz, CD3OD) δ9.28(s,1H),9.02(s,1H),8.03(d,J=8.4Hz,1H),7.06(d,J=9.1Hz,1H),6.73–6.66(m,4H),4.15(t,J=7.0Hz,2H),3.9 3(s,3H),3.76(s,3H),3.18(dd,J=7.9,4.0Hz,1H),2.36(s,3H),2.31–2.26(m,1H),1.43(t,J=7.0Hz,3H),1.27–1.24(m,2H).LC-MS:[M+H] + :434.3.

[0151] BS-06-115-P2:

[0152] Chiral analysis conditions: Column: CHIRALPAK AD-H 250mm×20mm, 5μm; Mobile phase: Phase A: 40% MeOH (NH4OH 0.2%); Phase B: 60% CO2; Retention time: 6.58 min; ee% = 98.91%; White solid (4.1 mg);

[0153] 1 H NMR (400MHz, CD3OD) δ9.28(s,1H),9.02(s,1H),8.03(d,J=8.4Hz,1H),7.06(d,J=9.2Hz,1H),6.69–6.66(m,4H),4.15(q,J=7.0Hz,2H),3.9 3(s,3H),3.76(s,3H),3.17(dd,J=7.9,4.0Hz,1H),2.36(s,3H),2.33–2.27(m,1H),1.44(t,J=7.0Hz,3H),1.27–1.24(m,2H).LC-MS:[M+H] + :434.3.

[0154] Example 5: Synthesis of compounds BS-06-120-P1 and BS-06-120-P2

[0155]

[0156] Synthesis of 2-(trans-2-(3,5-dimethylphenyl)cyclopropyl)isoindoline-1,3-dione (1):

[0157] To a solution of 2-(trans-2-boranopinal ester-cyclopropyl)isoindoline-1,3-dione (100.0 mg, 0.32 mmol), 1-bromo-3,5-dimethylbenzene (59.1 mg, 0.32 mmol), and potassium carbonate (132.7 mg, 0.96 mmol) in toluene (5.0 mL) and water (0.5 mL), a [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (52.3 mg, 0.064 mmol) was added. The gas in the flask was purged with an argon balloon, and the mixture was stirred at 100 °C for 5 hours. After the reaction was completed and the temperature was allowed to drop to room temperature, the resulting mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude oily product. The crude product was purified by silica gel chromatography (ethyl acetate:petroleum ether = 1:3) to give a yellow solid (50.0 mg). LC-MS: [M+H] + :292.1.

[0158] Synthesis of trans-2-(3,5-dimethylphenyl)cyclopropyl-1-amine (2):

[0159] Compound 2-(trans-2-(3,5-dimethylphenyl)cyclopropyl)isoindoline-1,3-dione (50.0 mg, 0.17 mmol) was dissolved in ethanol (2.0 mL), and hydrazine hydrate (13.14 mg, 0.21 mmol, 80% w) was added at room temperature. The mixture was stirred at 50 °C for 3 hours. The reaction solution was filtered directly, and the filtrate was concentrated under vacuum. The resulting crude product, a white solid (20.0 mg), was used directly in the next step. LC-MS: [M+H] + :162.1.

[0160] Synthesis of N-(trans-2-(3,5-dimethylphenyl)cyclopropyl)-6-(4-ethoxy-2-methoxyphenyl)pyrazine-2-carboxamide (BS-06-120):

[0161] To a solution of 6-(4-ethoxy-2-methoxyphenyl)pyrazin-2-carboxylic acid (50.0 mg, 0.18 mmol) in N,N-dimethylformamide (3.0 mL), N-methylmorpholine (55.6 mg, 0.55 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (51.76 mg, 0.27 mmol), and 1-hydroxybenzotriazole (36.5 mg, 0.27 mmol) were added, and the mixture was stirred at 25 °C for 0.5 h. Then, trans-2-(3,5-dimethylphenyl)cyclopropyl-1-amine (20.0 mg, 0.124 mmol) was added, and the mixture was stirred at 25 °C for 3 h. After the reaction was complete, the resulting mixture was diluted with water, extracted twice with ethyl acetate, the organic phases were combined and washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified to obtain a white solid (40.0 mg). LC-MS: [M+H] + :418.2.

[0162] Racemic BS-06-120 was separated and purified by SFC (column: CHIRALPAK AD-H 250mm×20mm, 5μm; mobile phase: A phase: 40% MeOH (NH4OH 0.2%); B phase: 60% CO2); yielding N-((1R,2S)-2-(3,5-dimethylphenyl)cyclopropyl)-6-(4-ethoxy-2-methoxyphenyl)pyrazine-2-carboxamide and N-((1S,2R)-2-(3,5-dimethylphenyl)cyclopropyl)-6-(4-ethoxy-2-methoxyphenyl)pyrazine-2-carboxamide).

[0163] BS-06-120-P1:

[0164] Chiral analysis conditions: Column: CHIRALPAK AD-H 250mm×20mm, 5μm; Mobile phase: Phase A: 40% MeOH (NH4OH 0.2%); Phase B: 60% CO2; Retention time: 4.03 min; ee% = 100%; White solid (19.2 mg);

[0165] 1H NMR(400MHz,MeOD)δ9.26(s,1H),8.99(s,1H),8.01(d,J=8.4Hz,1H),6.80–6.78(m,3H),6.69(dd,J=11.5,2.2Hz,2H),4.12(q,J=7.0Hz,2H) ,3.92(s,3H),3.10–3.04(m,1H),2.26(s,6H),2.19–2.17(m,1H),1.43(t,J=7.0Hz,3H),1.40–1.35(m,1H),1.30–1.28(m,1H).LC-MS:[M+H] + :418.2.

[0166] BS-06-120-P2:

[0167] Chiral analysis conditions: Column: CHIRALPAK AD-H 250mm×20mm, 5μm; Mobile phase: Phase A: 40% MeOH (NH4OH 0.2%); Phase B: 60% CO2; Retention time: 11.21 min; ee% = 100%; White solid (16.3 mg);

[0168] 1 H NMR(400MHz,MeOD)δ9.26(s,1H),8.99(s,1H),8.01(d,J=8.4Hz,1H),6.80–6.78(m,3H),6.71–6.67(m,2H),4.12(q,J=7.0Hz,2H),3.9 2(s,3H),3.10–3.04(m,1H),2.26(s,6H),2.22–2.17(m,1H),1.43(t,J=7.0Hz,3H),1.40–1.36(m,1H),1.31–1.28(m,1H).LC-MS:[M+H] + :418.2.

[0169] Example 6: Nav1.8 Inhibitory Activity Test

[0170] (1) Cell culture and treatment

[0171] HEK293 cells stably expressing hNav1.8 were cultured in 35 mm diameter cell culture dishes at 37°C in a 5% CO2 incubator. The culture medium consisted of 90% DMEM (Invitrogen), 10% fetal bovine serum (Gibco), and 100 μg / mL Hygromycin B (Invitrogen). On the day of the experiment, the cell culture medium was aspirated, and the cells were washed once with extracellular fluid (140×NaCl, 5×KCl, 1×CaCl2, 1.25×MgCl2, 10×HEPES, and 10×Glucose, adjusted to pH 7.4 with NaOH). Then, 0.25% Trypsin-EDTA (Invitrogen) solution was added, and the cells were digested for 3-5 minutes at room temperature. The digestion solution was aspirated, the cells were resuspended in extracellular fluid, and then transferred to experimental dishes for electrophysiological recording.

[0172] (2) Preparation of compound solution

[0173] On the day of the test, the compound was prepared into a 10mM stock solution using DMSO, then diluted with DMSO to an intermediate concentration, and finally diluted with extracellular fluid to obtain the final concentration to be tested.

[0174] (3) Electrophysiological recording process

[0175] HEK293 cells stably expressing the hNav1.8 sodium channel were used to record sodium channel currents at room temperature using whole-cell voltage-clamp technique. Glass microelectrodes were fabricated from glass electrode blanks (BF150-86-10, Sutter) using a stretching device. The tip resistance after perfusion with electrode fluid was approximately 2-5 MΩ. The glass microelectrodes were inserted into the amplifier probe to connect to the patch-clamp amplifier. Clamping voltage and data recording were controlled and recorded by computer using pClamp software, with a sampling frequency of 20 kHz and a filtering frequency of 2 kHz. After obtaining whole-cell recordings, the cells were clamped at -120 mV. A 20 ms depolarization voltage to 0 mV was applied to induce a sodium current (T1), followed by an inactivation voltage of -40 mV for 5 s, repolarizing to -120 mV. After 100 ms, another 20 ms depolarization voltage to 0 mV was applied to induce a sodium current (T2). This voltage stimulation was applied every 10 s. Once the sodium current stabilized (1 minute), the drug delivery process began. For each test concentration of the compound, administer for 1 minute to reach steady state or a maximum of 3 minutes. Test at least 3 cells (n≥3) for each compound concentration.

[0176] (4) Data processing

[0177] Data analysis and processing were performed using pClamp, GraphPad Prism 8, and Excel software. The degree of inhibition of sodium current (peak sodium current induced at 0 mV, T2) by different compound concentrations was calculated using the following formula:

[0178] Inhibition%=[1–(I / Io)]×100%

[0179] Wherein, Inhibition% represents the percentage of sodium current inhibition by the compound, and I and Io represent the amplitude of sodium current before and after drug administration, respectively. The results are shown in Table 1 below.

[0180] Example 7: Nav1.7 Inhibitory Activity Test

[0181] (1) Cell culture and treatment

[0182] HEK293 cells stably expressing hNav1.7 were cultured in 35 mm diameter cell culture dishes at 37°C in a 5% CO2 incubator. The culture medium consisted of 90% DMEM (Invitrogen), 10% fetal bovine serum (Gibco), and 300 μg / mL Hygromycin B (Invitrogen). On the day of the experiment, the cell culture medium was aspirated, and the cells were washed once with extracellular fluid (140×NaCl, 5×KCl, 1×CaCl2, 1.25×MgCl2, 10×HEPES, and 10×Glucose, adjusted to pH 7.4 with NaOH). Then, 0.25% Trypsin-EDTA (Invitrogen) solution was added, and the cells were digested for 3-5 minutes at room temperature. The digestion solution was aspirated, the cells were resuspended in extracellular fluid, and then transferred to experimental dishes for electrophysiological recording.

[0183] (2) Preparation of compound solution

[0184] On the day of the test, the 10mM stock solution of the compound was diluted with DMSO to an intermediate concentration, and then diluted with extracellular fluid to obtain the final concentration to be tested.

[0185] (3) Electrophysiological recording process

[0186] HEK293 cells stably expressing the hNav1.7 sodium channel were used to record sodium channel currents at room temperature using whole-cell voltage-clamp technique. Glass microelectrodes were fabricated from glass electrode blanks (BF150-86-10, Sutter) using a stretching device. The tip resistance after perfusion with electrode fluid was approximately 2-5 MΩ. The glass microelectrodes were inserted into the amplifier probe to connect to the patch-clamp amplifier. Clamping voltage and data recording were controlled and recorded by computer using pClamp software, with a sampling frequency of 20 kHz and a filtering frequency of 2 kHz. After obtaining whole-cell recordings, the cells were clamped at -100 mV. A 20 ms depolarization voltage to -20 mV was applied to induce a sodium current (T1), followed by an inactivation voltage of -40 mV for 5 s, repolarizing to -120 mV. After 50 ms, another 20 ms depolarization voltage to -20 mV was applied to induce a sodium current (T2). This voltage stimulation was applied every 10 s. Once the sodium current stabilized (1 minute), the drug delivery process began. Compounds are administered continuously starting from a low test concentration, with each test concentration administered for 1 minute to reach steady state or for a maximum of 3 minutes. Each compound concentration must be tested on at least 3 cells (n≥3).

[0187] (4) Data processing

[0188] Data analysis and processing were performed using pClamp, GraphPad Prism 8, and Excel software. The degree of inhibition of sodium current (peak sodium current induced at 0 mV, T2) by different compound concentrations was calculated using the following formula:

[0189] Inhibition%=[1–(I / Io)]×100%

[0190] Wherein, Inhibition% represents the percentage of sodium current inhibition by the compound, and I and Io represent the amplitude of sodium current before and after drug administration, respectively. The results are shown in Table 1 below.

[0191] Table 1: Inhibition of channel activity of the compounds of the present invention on Nav1.8 and Nav1.7 channels

[0192] Compound numbering Nav1.8(T2) inhibition% @100nM Nav1.7(T2) inhibition% @100nM BS-06-018 96.4 17.8 BS-06-105-P1 81.0 BS-06-105-P2 88.0 96.8 BS-06-107-P1 99.8 65.2 BS-06-107-P2 79.7 24.8 BS-06-115-P1 89.3 58.5 BS-06-115-P2 25.8 BS-06-120-P1 100.1 92.8 BS-06-120-P2 79.6

[0193] Test results show that the compounds of this invention have strong inhibitory effects on both Nav1.8 and Nav1.7 ion channels.

[0194] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. The following compounds, stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, as shown in formula (I): in: The A ring and B ring may be the same or different, and are independently selected from phenyl, 5-11-membered heteroaryl, C3-7 cycloalkyl, C3-7 cycloalkenyl, and 3-7-membered heterocyclic alkyl containing 1-3 independently selected from N, O, and S, connected by C or N to a carbon atom of a proximal pyrazinyl or cyclopropane group; R1 and R2 may be the same or different, and are independently selected from F, Cl, Br, -CN, -NO2, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, C3-7 cycloalkyl, 3-7 membered heterocyclic alkyl containing 1-3 cyclic heteroatoms independently selected from N, O, S connected by C or N to a carbon atom or nitrogen atom of a proximal A or B ring, 5-11 membered heteroaryl containing 1-3 cyclic heteroatoms independently selected from N, O, S connected by C or N to a carbon atom of a proximal A or B ring, phenyl, -OR3, -C(O)R3, -C(O)OR3, -C(O)N(R3)R4, -SR3, -S(O)2R3, -S(O)2N(R3)R4. -N(R3)R4, -N(R3)C(O)R4, -N(R3)S(O)2R4, -P(O)(R3)R4, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, or phenyl group is optionally substituted by one or more substituents independently selected from F, Cl, Br, -OH, -CN, -NH2, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, C1-4 straight-chain or branched alkoxy, C3-7 cycloalkyl, or a 3-7 membered heterocycloalkyl group containing 1-3 cyclic heteroatoms independently selected from N, O, or S, connected by a C or N group to a proximal group; Two R1 atoms attached to two adjacent atoms on ring A, together with the two adjacent atoms on ring A to which they are attached, can form a 5-7 membered cycloalkyl group, or a 5-7 membered heterocycloalkyl group containing 1-3 independent cycloheteroatoms selected from N, O, and S. The cycloalkyl group or heterocycloalkyl group may optionally be substituted by one or more substituents selected from F, Cl, Br, -OH, -CN, -NH2, =O, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, or C1-4 straight-chain or branched alkoxy groups. The alkyl, alkenyl, alkynyl, or alkoxy substituents may optionally be substituted by one or more substituents selected from F, Cl, Br, -OH, -CN, -NH2, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, or C1-4 straight-chain or branched alkoxy groups. Two R2 atoms attached to two adjacent atoms on the B ring, together with the two adjacent atoms on the B ring to which they are attached, can form a 5-7 membered cycloalkyl group, or a 5-7 membered heterocycloalkyl group containing 1-3 independent cycloheteroatoms selected from N, O, and S. The cycloalkyl group or heterocycloalkyl group may optionally be substituted by one or more substituents selected from F, Cl, Br, -OH, -CN, -NH2, =O, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, or C1-4 straight-chain or branched alkoxy groups. The alkyl, alkenyl, alkynyl, or alkoxy substituents may optionally be substituted by one or more substituents selected from F, Cl, Br, -OH, -CN, -NH2, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, or C1-4 straight-chain or branched alkoxy groups. R3 and R4 may be the same or different, and are independently selected from H, -OH, -NH2, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, C3-7 cycloalkyl, 3-7-membered heterocyclic alkyl containing 1-3 cyclic heteroatoms independently selected from N, O, S, P connected by a C or N group to a proximal group, phenyl, 5-11-membered heteroaryl containing 1-3 cyclic heteroatoms independently selected from N, O, S connected by a C or N group to a proximal group, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic alkyl, phenyl, or heteroaryl group may optionally be selected by one or more independently selected from F, Cl, Br, OH, CN, NH2, = O, a C1-4 straight-chain or branched alkyl group optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH2; a C1-4 straight-chain or branched alkoxy group optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH2; a C3-7 cycloalkyl group optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH2; or a 3-7 membered heterocyclic alkyl group containing 1-3 cyclic heteroatoms independently selected from N, O, S, substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH2. When R3 and R4 are attached to the same atom, R3 and R4 together with the atom they are attached to can form a 3-7 membered heterocyclic alkyl group containing 1-3 independent cyclic heteroatoms selected from N, O, and S. The heterocyclic alkyl group is optionally replaced by one or more substituents selected from F, Cl, Br, -OH, -CN, -NH2, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, and C1-4 straight-chain or branched alkoxy groups. The alkyl, alkenyl, alkynyl, and alkoxy substituents are optionally replaced by one or more substituents selected from F, Cl, Br, -OH, -CN, -NH2, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, and C1-4 straight-chain or branched alkoxy groups. m can be 0, 1, 2, 3, 4, or 5; n can be 0, 1, 2, 3, 4, or 5. Preferably, Rings A and B are phenyl groups; R1 and R2 may be the same or different, and are independently selected from F, Cl, Br, -CN, -NO2, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, C3-7 cycloalkyl, 3-7 membered heterocyclic alkyl containing 1-3 cyclic heteroatoms independently selected from N, O, and S connected to a carbon atom of the proximal A or B ring via C or N, 5-11 membered heteroaryl, phenyl, -OR 3. -SR3, -N(R3)R4, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, or phenyl group is optionally substituted by one or more substituents independently selected from F, Cl, Br, -OH, -CN, -NH2, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, C1-4 straight-chain or branched alkoxy, C3-7 cycloalkyl, or a 3-7 membered heterocycloalkyl group containing 1-3 cyclic heteroatoms independently selected from N, O, or S, connected to a proximal group via C or N; Two R1 atoms attached to two adjacent atoms on ring A, together with the two adjacent atoms on ring A to which they are attached, can form a 5-7 membered cycloalkyl group, or a 5-7 membered heterocycloalkyl group containing 1-3 independent cycloheteroatoms selected from N, O, and S. The cycloalkyl group or heterocycloalkyl group may optionally be substituted by one or more substituents selected from F, Cl, Br, -OH, -CN, -NH2, =O, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, or C1-4 straight-chain or branched alkoxy groups. The alkyl, alkenyl, alkynyl, or alkoxy substituents may optionally be substituted by one or more substituents selected from F, Cl, Br, -OH, -CN, -NH2, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, or C1-4 straight-chain or branched alkoxy groups. Two R2 atoms attached to two adjacent atoms on the B ring, together with the two adjacent atoms on the B ring to which they are attached, can form a 5-7 membered cycloalkyl group, or a 5-7 membered heterocycloalkyl group containing 1-3 independent cycloheteroatoms selected from N, O, and S. The cycloalkyl group or heterocycloalkyl group may optionally be substituted by one or more substituents selected from F, Cl, Br, -OH, -CN, -NH2, =O, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, or C1-4 straight-chain or branched alkoxy groups. The alkyl, alkenyl, alkynyl, or alkoxy substituents may optionally be substituted by one or more substituents selected from F, Cl, Br, -OH, -CN, -NH2, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, or C1-4 straight-chain or branched alkoxy groups. R3 and R4 may be the same or different, and are independently selected from H, -OH, -NH2, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, C3-7 cycloalkyl, 3-7-membered heterocyclic alkyl containing 1-3 cyclic heteroatoms independently selected from N, O, S, P connected by a C or N group to a proximal group, phenyl, 5-11-membered heteroaryl containing 1-3 cyclic heteroatoms independently selected from N, O, S connected by a C or N group to a proximal group, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic alkyl, phenyl, or heteroaryl group may optionally be selected by one or more independently selected from F, Cl, Br, OH, CN, NH2, = O, a C1-4 straight-chain or branched alkyl group optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH2; a C1-4 straight-chain or branched alkoxy group optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH2; a C3-7 cycloalkyl group optionally substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH2; or a 3-7 membered heterocyclic alkyl group containing 1-3 cyclic heteroatoms independently selected from N, O, S, substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH2. When R3 and R4 are attached to the same atom, R3 and R4 together with the atom they are attached to can form a 3-7 membered heterocyclic alkyl group containing 1-3 independent cyclic heteroatoms selected from N, O, and S. The heterocyclic alkyl group is optionally replaced by one or more substituents selected from F, Cl, Br, -OH, -CN, -NH2, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, and C1-4 straight-chain or branched alkoxy groups. The alkyl, alkenyl, alkynyl, and alkoxy substituents are optionally replaced by one or more substituents selected from F, Cl, Br, -OH, -CN, -NH2, C1-4 straight-chain or branched alkyl, C2-4 straight-chain or branched alkenyl, C2-4 straight-chain or branched alkynyl, and C1-4 straight-chain or branched alkoxy groups. m is 1, 2, or 3; n is 1, 2, or 3. Preferably, Rings A and B are phenyl groups; R1 and R2 may be the same or different, and are independently selected from F, Cl, Br, -CN, -NO2, C1-4 straight-chain or branched alkyl, C3-7 cycloalkyl, 3-7-membered heterocyclic alkyl containing 1-3 cyclic heteroatoms independently selected from N, O, S connected to a carbon atom of the proximal A or B ring via C or N, 5-11-membered heteroaryl, phenyl, -OR3, -SR3, -N(R3)R4 containing 1-3 cyclic heteroatoms independently selected from N, O, S connected to a carbon atom of the proximal A or B ring via C or N, wherein the alkyl, cycloalkyl, heterocyclic alkyl, heteroaryl, or phenyl may optionally be substituted by one or more substituents independently selected from F, Cl, Br, -OH, -CN, -NH2, C1-4 straight-chain or branched alkyl, or C1-4 straight-chain or branched alkoxy. R3 and R4 may be the same or different, and are independently selected from H, -OH, -NH2, C1-4 straight-chain or branched alkyl, C3-7 cycloalkyl, 3-7-membered heterocyclic alkyl containing 1-3 cyclic heteroatoms independently selected from N, O, S, P connected to a proximal group via C or N, phenyl, 5-11-membered heteroaryl containing 1-3 cyclic heteroatoms independently selected from N, O, S connected to a proximal group via C or N, wherein the alkyl, cycloalkyl, heterocyclic alkyl, phenyl, or heteroaryl group is optionally selected by one or more independently selected from F, Cl, Br, OH, CN, NH2, =O, or optionally selected by one or more independently selected groups. C1-4 straight-chain or branched alkyl groups substituted by groups of F, Cl, Br, OH, CN, NH2; C1-4 straight-chain or branched alkoxy groups substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH2; C3-7 cycloalkyl groups substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH2; and 3-7 membered heterocyclic alkyl groups containing 1-3 cyclic heteroatoms independently selected from N, O, S, substituted by one or more groups independently selected from F, Cl, Br, OH, CN, NH2. m is 1, 2, or 3; n is 1, 2, or 3.

2. The compound of claim 1 or its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, characterized in that, It has the structure shown in equation (II): R2 is independently selected from F, Cl, Br, -CN, -NO2, C1-4 straight-chain or branched alkyl, and -OR3; R3 is independently selected from H, C1-4 straight-chain or branched alkyl groups, and phenyl groups; n is 1 or 2.

3. The compound of claim 1 or its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, characterized in that, It has the structure shown in equation (III): R2 is selected from F, Cl, Br, -CN, -NO2, C1-4 straight-chain or branched alkyl groups, and -OR3; R3 is selected from H, C1-4 straight-chain or branched alkyl groups, and phenyl groups.

4. The compound of claim 1 or its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, characterized in that, It has the structure shown in equation (IV): R2 is independently selected from F, Cl, Br, -CN, -NO2, C1-4 straight-chain or branched alkyl, and -OR3; R3 is independently selected from H, C1-4 straight-chain or branched alkyl groups, and phenyl groups.

5. The compound of claim 1 or its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, characterized in that, It has the structure shown in equation (V): R2 is independently selected from F, Cl, Br, -CN, -NO2, C1-4 straight-chain or branched alkyl, and -OR3; R3 is independently selected from H, C1-4 straight-chain or branched alkyl groups, and phenyl groups.

6. The compound of claim 1 or its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, characterized in that, The compounds are selected from the following compounds or their pharmaceutically acceptable salts or deuterated derivatives:

7. A pharmaceutical composition comprising the compound as described in any one of claims 1-6 and a pharmaceutically acceptable carrier.

8. Use of the compound of any one of claims 1-6 or the pharmaceutical composition of claim 7 in the preparation of a medicament for the prevention and / or treatment of Nav1.8 and / or Nav1.7 related diseases.

9. Use of the compound of any one of claims 1-6 or the pharmaceutical composition of claim 7 in the preparation of a medicament for the prevention and / or treatment of pain.

Images