Polysubstituted pyrrolidine derivative as well as preparation method and application thereof

Abstract

The invention discloses a polysubstituted pyrrolidine derivative represented by a general formula (I), a stereoisomer, a tautomer, a deuterated derivative or a pharmaceutically acceptable salt thereof, and a preparation method and application of the compound. The invention also relates to pharmaceutical compositions comprising these compounds, stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, uses of the compounds as sodium channel subtype Nav1.8 inhibitors, and uses thereof in the treatment and prevention of pain-related diseases. # imgabs0 #

Description

Polysubstituted pyrrolidine derivatives, preparation methods and uses thereof

[0001] Citation of Related Applications

[0002] This application claims the priority benefit of the Chinese invention patents filed with the National Intellectual Property Administration of China, entitled “Polysubstituted pyrrolidine derivatives, their preparation methods and uses”, application number 202310925595.0, filed on July 26, 2023, entitled “Polysubstituted pyrrolidine derivatives, their preparation methods and uses”, application number 202311351390.2, filed on October 18, 2023, and entitled “Polysubstituted pyrrolidine derivatives, their preparation methods and uses”, application number 202311541338.3, filed on November 17, 2023. The contents of the above two applications are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates to the field of drug synthesis, and in particular to a class of polysubstituted pyrrolidine derivatives, stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, as well as preparation methods and uses of the compounds, and pharmaceutical compositions comprising the compounds, stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof. The compounds can be used as inhibitors of the sodium ion channel subtype Nav1.8, and their pharmaceutical uses in treating and preventing pain-related diseases. Background Art

[0004] Pain is one of the most common clinical symptoms. The National Institutes of Health (NIH) estimates that 100 million people in the United States suffer from chronic pain, and the global medical expenses for pain treatment have reached as high as US$75 billion each year. In China, the number of chronic pain patients has exceeded 300 million, and is increasing at a rate of 20 million per year. Currently, commonly used analgesics are mainly non-steroidal anti-inflammatory drugs and opioid analgesics. The analgesic effect of non-steroidal anti-inflammatory drugs is weak and there is a ceiling effect. Opioid analgesics generally have problems such as constipation, respiratory depression and addiction, and drug abuse is serious. There is a huge unmet clinical demand in the analgesia market.

[0005] Pain is a crucial protective mechanism in healthy individuals to prevent further tissue damage. However, chronic, pathological pain, such as neuropathic pain, can sometimes be useless and long-lasting. The main causes of neuropathic pain include physical damage to neurons, metabolic or nutritional changes, abnormal neuronal structure, and neurotransmitter dysfunction. Herpes, diabetes, and medications can sometimes induce metabolic or nutritional changes in neurons.

[0006] Pain perception occurs when noxious stimuli are generated and transmitted between neurons. Sodium channel activity is a key factor in neuronal transmission of excitatory stimuli. Voltage-gated sodium channels (VGSCs) are multisubunit transmembrane glycoproteins expressed on the cell membrane, composed of α subunits (functional units) and β subunits. Based on differences in the α subunits, they are classified into nine subtypes: Nav1.1 to 1.9, the nine members of type 1 sodium channel (Nav1). The Nav1 α subunit is composed of four homologous transmembrane domains (I to IV), each containing six transmembrane hydrophobic α-helices (S1-S6). The positively charged S4 segment functions as a voltage sensor, regulating the hydrophilic pore between S5 and S6 that allows sodium ions to pass through, causing cell depolarization or hyperpolarization and completing transmembrane signal transmission. When neurons are stimulated, the Nav1 channel opens, allowing positively charged sodium ions to cross the cell membrane and enter the previously negatively charged cell. Changes in electrical charge across the cell membrane generate an electrical current, increasing the excitability of the neuron and initiating downstream signaling that leads to pain.

[0007] Different isoforms of Nav1 are expressed in different tissues and participate in different types of pain transmission. For example, some are expressed exclusively in peripheral neurons, while others mediate signaling in both central and peripheral neurons. Based on their sensitivity to tetrodotoxin (TTX), Nav1.1-1.4, Nav1.6, and Nav1.7 are TTX-sensitive channels (TTX-S), while Nav1.5, Nav1.8, and Nav1.9 are TTX-resistant channels (TTX-R). Studies have shown that broad-spectrum sodium channel blockers can produce severe side effects after blocking Nav1.4, which is associated with skeletal muscle, and Nav1.5, which is associated with myocardium. Therefore, designing selective blockers for specific Nav channels is a promising direction for pain drug development. As an important ion channel in pain receptors, Nav1.8 is exclusively distributed in peripheral neurons and plays a key role in pain signaling in the peripheral nervous system. It is a major pathogenic factor involved in neuropathic pain, chronic pruritus, inflammatory pain, atrial fibrillation, and Budd-Chiari syndrome. Currently, inhibitors targeting Nav1.8, such as WO2021113627A1, WO2022256622A1, WO2022256676A1, WO2022256679A1, WO2022256702A1, and WO2022256842A1, are all furan derivatives. Currently, there are no pain medications targeting the Nav1.8 subtype specifically on the market. Clinical studies have shown that Nav1.8 selective blockers have a good inhibitory effect on neuropathic pain. Therefore, further design of highly active and specific Nav1.8 inhibitors is expected to provide a highly effective treatment option for the pain field.

[0008] Summary of the Invention

[0009] According to one aspect of the present invention, an object of the present invention is to provide a compound represented by general formula (I), its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts:

[0010] Wherein, R1 is selected from hydrogen atom, C 1-15 Alkyl, C 1-15 Alkoxy, C 1-15 Alkylcarbonyl, C 3-15 Cycloalkyl, a four- to eight-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, wherein the C 1-15 Alkyl, C 1-15 Alkoxy, C 1-15 Alkylcarbonyl, C 3-15 Cycloalkyl, four to eight membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S may be replaced by one or more R a Substituted by a substituent, the R aSelected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl group, halogen atom, amino group, hydroxyl group, amide group;

[0011] R2 is selected from hydrogen atom, C 1-8 Alkyl, C 1-8 Alkoxy, deuterated C 1-8 Alkyl, halogenated C 1-8 Alkyl, halogenated C 1-8 Alkoxy, C 3-6 Cycloalkyl;

[0012] R3 is selected from hydrogen atom, C 1-8 Alkyl, deuterated C 1-8 Alkyl, halogenated C 1-8 Alkyl, C 3-6 Cycloalkyl, a three- to eight-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S;

[0013] R4 is selected from C 6-14 aryl, a five- to eight-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, a five- to eight-membered heteroaryl oxide containing 1 to 3 heteroatoms selected from N, O and S, wherein the C 6-14 Aryl, five to eight membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S may be replaced by one or more R b Substituted by a substituent, wherein the R b Selected from hydrogen atoms, C 1-6 Alkyl, C 3-6 Cycloalkyl, halogen atom, nitro, amino, hydroxyl, carbonyl, cyano, formamide, oxy, sulfonamide, N-hydroxyformamidino, N-hydroxyamidino, C-substituted with 1 to 3 halogen atoms 1-6 Alkyl, C substituted by 1 to 3 halogen atoms 3-6 Cycloalkyl, C substituted by 1 to 3 hydroxyl groups 1-6 Alkyl, C substituted by 1 to 3 hydroxyl groups 3-6 Cycloalkyl, 1 to 3 C 1-6 an alkyl-substituted or unsubstituted four- to six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S;

[0014] R5 is selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl;

[0015] R6 is selected from hydrogen atom, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl;

[0016] R7 is selected from hydrogen atom, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl group, halogen atom, cyano group, amide group;

[0017] R8 is selected from hydrogen atom, C 1-6 Alkyl, halogenated C 1-6 Alkyl group, halogen atom, cyano group.

[0018] Preferably, R1 is selected from hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylcarbonyl, C 3-8 Cycloalkyl, a four- to six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylcarbonyl, C 3-8 Cycloalkyl, four to six membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S may be substituted by 1 to 3 R a Substituted by a substituent, the R a Selected from hydrogen atoms, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl group, halogen atom, amino group, hydroxyl group, amide group;

[0019] Preferably, R1 is selected from hydrogen atom, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylcarbonyl, C 3-6 Cycloalkyl, a four- to six-membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O and S, wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylcarbonyl, C 3-6 Cycloalkyl, four to six membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O and S may be substituted by 1 to 3 R a Substituted by a substituent, the R a Selected from hydrogen atoms, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl group, halogen atom, amino group, hydroxyl group, amide group;

[0020] Preferably, R1 is selected from hydrogen atom, methyl, trifluoroacetyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein the above substituents may be replaced by 1 or 2 R a Substituted by a substituent, the R a is selected from the group consisting of a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a n-butyl group, a sec-butyl group, a tert-butyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a n-butoxy group, a sec-butoxy group, a tert-butoxy group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a fluorine atom, a chlorine atom, a bromine atom, an amino group, a hydroxyl group, and an amide group;

[0021] Preferably, R1 is selected from hydrogen atom, methyl, trifluoroacetyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl, wherein the above substituents may be replaced by 1 or 2 R a Substituted by a substituent, the R a Selected from hydrogen atom, methyl group, methoxy group, fluorine atom, chlorine atom, bromine atom, amino group, hydroxyl group, cyano group and amide group.

[0022] Preferably, R2 is selected from hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl;

[0023] Preferably, R2 is selected from hydrogen atom, C 1-4 Alkyl, C 1-4 Alkoxy, deuterated C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, C 3-6 Cycloalkyl;

[0024] Preferably, R2 is selected from a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a sec-butoxy group, a tert-butoxy group, a deuterated methyl group, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a monofluoroethyl group, a difluoroethyl group, a trifluoroethyl group, a tetrafluoroethyl group, a pentafluoroethyl group, a difluoropropyl group, a trifluoropropyl group, a tetrafluoropropyl group, a pentafluoropropyl group, a hexafluoropropyl group, a perfluoropropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

[0025] Preferably, R3 is selected from hydrogen atom, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, a three- to six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S;

[0026] Preferably, R3 is selected from hydrogen atom, C 1-4 Alkyl, deuterated C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl, a three- to six-membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O;

[0027] Preferably, R3 is selected from a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, a deuterated methyl group, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a monofluoroethyl group, a difluoroethyl group, a trifluoroethyl group, a tetrafluoroethyl group, a pentafluoroethyl group, a difluoropropyl group, a trifluoropropyl group, a tetrafluoropropyl group, a pentafluoropropyl group, a hexafluoropropyl group, a perfluoropropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

[0028] Preferably, R4 is selected from C 6-10 aryl, a five- to six-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O, a five- to six-membered heteroaryl oxide containing 1 to 3 heteroatoms selected from N, O and S, wherein the C 6-10 Aryl, five- to six-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O, five- to six-membered heteroaryl oxide containing 1 to 3 heteroatoms selected from N, O and S may be substituted by one or more R b Substituted by a substituent, wherein the R b Selected from hydrogen atoms, C 1-4 Alkyl, C 3-6 Cycloalkyl, halogen atom, nitro, amino, hydroxyl, carbonyl, cyano, formamide, oxy, sulfonamide, N-hydroxyformamidino, N-hydroxyamidino, C-substituted with 1 to 3 halogen atoms 1-4 Alkyl, C substituted by 1 to 3 halogen atoms 3-6 Cycloalkyl, C substituted by 1 to 2 hydroxyl groups 1-4 Alkyl, C substituted by 1 to 2 hydroxyl groups 3-6 Cycloalkyl, 1 to 3 C 1-4 Alkyl-substituted or unsubstituted four- to six-membered heterocyclic group containing 1 or 2 heteroatoms selected from N or O.

[0029] Preferably, R4 is selected from phenyl, naphthyl, anthracenyl, furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, imidazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, quinolyl, isoquinolyl, pyridyl oxide, imidazolyl oxide, pyrrolyl oxide, pyrazolyl oxide, oxazolyl oxide, isoxazolyl oxide, isothiazolyl oxide, thiazolyl oxide, pyridazinyl oxide, pyrimidinyl oxide, pyrazinyl oxide, indolyl oxide, quinolyl oxide, isoquinolyl oxide, wherein the above substituents may be replaced by one or more R b Substituted by a substituent, wherein the Rb Selected from hydrogen atoms, C 1-4 Alkyl, C 3-6 Cycloalkyl, halogen atom, amino, carbonyl, hydroxyl, cyano, formamide, oxy, sulfonamide, N-hydroxyformamidino, N-hydroxyamidino, C-substituted with 1 to 3 halogen atoms 1-4 Alkyl, C substituted by 1 to 3 halogen atoms 3-6 Cycloalkyl, C substituted by 1 to 3 hydroxyl groups 1-4 Alkyl, C substituted by 1 to 3 hydroxyl groups 3-6 Cycloalkyl, 1 to 3 C 1-4 Alkyl-substituted or unsubstituted four- to six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S.

[0030] Preferably, R5 is selected from C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl;

[0031] Preferably, R5 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, difluoropropyl, trifluoropropyl, tetrafluoropropyl, pentafluoropropyl, hexafluoropropyl, perfluoropropyl;

[0032] Preferably, R5 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, trifluoromethyl.

[0033] Preferably, R6 is selected from C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl;

[0034] Preferably, R6 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, difluoropropyl, trifluoropropyl, tetrafluoropropyl, pentafluoropropyl, hexafluoropropyl, perfluoropropyl;

[0035] Preferably, R6 is selected from hydrogen atom, methyl, ethyl, n-propyl, isopropyl.

[0036] Preferably, R7 is selected from C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 3-6 Cycloalkyl group, halogen atom, cyano group, amide group;

[0037] Preferably, R7 is selected from a halogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a sec-butoxy group, a tert-butoxy group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a monofluoroethyl group, a difluoroethyl group, a trifluoroethyl group, a tetrafluoroethyl group, a pentafluoroethyl group, a monofluorooxymethyl group, a difluoromethoxy group, a trifluoromethoxy group, a monofluoroethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a tetrafluoroethoxy group, a pentafluoroethoxy group;

[0038] Preferably, R7 is selected from a hydrogen atom, a methyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a fluorine atom, a chlorine atom, a bromine atom, a methoxy group, and a trifluoromethoxy group.

[0039] Preferably, R8 is selected from hydrogen atom, C 1-4 Alkyl, halogenated C 1-4 Alkyl group, halogen atom, cyano group.

[0040] Preferably, R8 is selected from hydrogen atom, halogen atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl.

[0041] Preferably, R8 is selected from a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, and a methyl group.

[0042] Preferably, the compound represented by general formula (I) according to the present invention, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts can be represented by the following general formula (II):

[0043] Wherein, the definitions of R1 to R8 are the same as those in the general formula (I);

[0044] X1 to X5 are each independently CH, O or N or N + -O - , provided that at most 3 of X1 to X5 are N, and the rest are C;

[0045] R9 is selected from the group consisting of hydrogen atom, halogen atom, amino group, hydroxyl group, carbonyl group, cyano group, formamide group, oxy group, sulfonamide group, nitrogen-hydroxyformamidino group, nitrogen-hydroxyamidino group, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-14 aryl, a four- to six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, a five- to six-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-14Aryl, a four- to six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, a five- to six-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, which may be replaced by 1 to 3 R c Substituted by a substituent, the R c Selected from hydrogen atoms, C 1-4 Alkyl, C 3-6 cycloalkyl group, halogen atom, nitro group, amino group, hydroxyl group, cyano group, formamide group, oxy group, sulfonamide group, nitrogen-hydroxyformamidino group, nitrogen-hydroxyamidino group;

[0046] n is an integer selected from 0, 1, 2, 3 or 4.

[0047] Preferably, X3 and X4 are CH or N;

[0048] Preferably, X1, X2 or X5 are each independently selected from CH or N or N + -O - ;

[0049] Preferably, R9 is selected from hydrogen atom, halogen atom, amino group, hydroxyl group, carbonyl group, cyano group, amide group, oxy group, sulfonamide group, nitrogen-hydroxycarbamimido group, nitrogen-hydroxyamidino group, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-14 aryl, a four- to six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, a five- to six-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-14 Aryl, a four- to six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, a five- to six-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, which may be replaced by 1 to 3 R c Substituted by a substituent, the R c Selected from hydrogen atoms, C 1-4 Alkyl, C 3-6 Cycloalkyl group, halogen atom, amino group, hydroxyl group, cyano group, formamide group, oxy group, sulfonamide group, nitrogen-hydroxyformamidino group;

[0050] Preferably, R9 is selected from hydrogen atom, halogen atom, amino group, hydroxyl group, carbonyl group, cyano group, formamide group, oxy group, sulfonamide group, nitrogen-hydroxyformamidino group, nitrogen-hydroxyamidino group, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 aryl, a four- to six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, a five- to six-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, wherein the C 1-4 Alkyl, C 3-6 Cycloalkyl, C6-10 Aryl, a four- to six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, a five- to six-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, which may be replaced by 1 to 3 R c Substituted by a substituent, the R c Selected from hydrogen atoms, C 1-3 Alkyl, C 3-6 Cycloalkyl group, halogen atom, amino group, hydroxyl group, cyano group, formamide group, oxy group, sulfonamide group, N-hydroxyformamidino group, N-hydroxyamidino group;

[0051] Preferably, R9 is selected from hydrogen atom, halogen atom, amino group, hydroxyl group, carbonyl group, cyano group, formamide group, oxy group, sulfonamide group, nitrogen-hydroxyformamidino group, nitrogen-hydroxyamidino group, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 aryl, a four- to six-membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O, a five- to six-membered heteroaryl group containing 1 or 2 heteroatoms selected from N and O, wherein the C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, a four- to six-membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O, a five- to six-membered heteroaryl group containing 1 or 2 heteroatoms selected from N and O, which may be replaced by 1 to 3 R c Substituted by a substituent, the R c Selected from hydrogen atoms, C 1-3 Alkyl, C 3-6 Cycloalkyl group, halogen atom, amino group, hydroxyl group, cyano group, formamide group, oxy group, sulfonamide group, N-hydroxyformamidino group, N-hydroxyamidino group;

[0052] Preferably, R9 is selected from hydrogen atom, halogen atom, amino, hydroxyl, carbonyl, cyano, formamide, oxy, sulfonamide, nitrogen-hydroxyformamidino, nitrogen-hydroxyamidino, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl The above substituents may be replaced by 1 or 2 R c Substituted by a substituent, the R c Selected from hydrogen atom, methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, fluorine atom, chlorine atom, bromine atom, amino group, hydroxyl group, cyano group and formamide group.

[0053] Preferably, n is an integer selected from 0, 1 or 2.

[0054] Preferably, n is an integer selected from 0 or 1.

[0055] Preferably, the compound represented by general formula (I) according to the present invention, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts can be represented by the following general formula (III):

[0056] Wherein, the definitions of R1, R2, R3, R5, and R6 are the same as those in the general formula (I);

[0057] R9, X1, and X2 are defined the same as in the general formula (II).

[0058] Preferably, the compound represented by general formula (I) according to the present invention, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts can be represented by the following general formula (IVa), general formula (IVb), general formula (IVc) or general formula (IVd):

[0059] Wherein, the definitions of R1, R2, and R3 are the same as those in the general formula (I); and the definition of R5 is the same as that in the general formula (II).

[0060] Preferably, the compound represented by general formula (I) according to the present invention, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts are selected from the following compounds:

[0061] According to another aspect of the present invention, another object of the present invention is to provide a method for preparing a compound represented by general formula (I), its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts, the method comprising the steps of:

[0062] Step 1: Compound Ia, whose amino group is protected by an amino protecting group PG, where PG is Boc or Cbz, is subjected to electrophilic addition with an alkyl metal reagent (e.g., alkyl lithium, alkyl Grignard reagent, trimethylsilyl lithium, etc.) to obtain a compound of formula Ib;

[0063] Step 2: Remove the amino protecting group PG in Ib under strong acidic conditions (such as hydrochloric acid / dioxane solution) or metal palladium carbon in a hydrogen atmosphere to obtain the compound of formula Ic

[0064] Step 3: Ic reacts with a phenylacetic acid compound Id via amide condensation to obtain a compound of formula Ie;

[0065] Step 4: Under alkaline conditions (such as potassium hydroxide, sodium hydroxide, sodium hydride, etc.), Ie undergoes molecular ring closure dehydration to obtain a compound represented by the general formula If;

[0066] Step 5: Reduce the double bond on the ring using sodium borohydride and nickel chloride or palladium catalytic hydrogenation conditions to obtain a compound represented by formula Ig;

[0067] Step 6: The lactam in Ig is reduced to an imine using a Schwartz reagent, and then reacted with sodium cyanide or potassium cyanide to obtain a pyrrolidine compound represented by the general formula Ih;

[0068] Step 7: Compound Ih is hydrolyzed to form acid Ii under strongly acidic conditions (such as hydrochloric acid / dioxane) or strongly alkaline conditions (such as aqueous potassium hydroxide solution);

[0069] Step 8: Ii reacts with an aldehyde under palladium-catalyzed hydrogenation conditions or in the presence of a borohydride reducing agent to undergo reductive amination to alkylate the pyrrolidine NH to obtain a compound represented by the general formula Ii';

[0070] Step 9: Ii or Ii' is reacted with an amine by amide condensation to obtain the final product represented by formula I.

[0071] According to another aspect of the present invention, the present invention provides use of a compound represented by general formula (I), a stereoisomer, a tautomer, a deuterated derivative or a pharmaceutically acceptable salt thereof as a Nav1.8 inhibitor.

[0072] According to another aspect of the present invention, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by general formula (I) according to the present invention, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts as an active ingredient, and pharmaceutically acceptable excipients.

[0073] According to another aspect of the present invention, the present invention provides the use of a compound represented by general formula (I), its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts, or the pharmaceutical composition according to the present invention in the preparation of a drug for treating acute pain and chronic pain.

[0074] According to another aspect of the present invention, the present invention provides a method for treating chronic pain, comprising providing to a subject a therapeutically effective amount of a compound represented by general formula (I) according to the present invention, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts, or the pharmaceutical composition according to the present invention. Beneficial effects

[0075] Compared with the compounds in the prior art, the compounds according to the present invention have a high activity of inhibiting NaV1.8 and can be used to treat acute pain and chronic pain. BRIEF DESCRIPTION OF THE DRAWINGS

[0076] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following is a brief introduction to the drawings required for use in the specific embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0077] FIG1 is a diagram showing the absolute configuration of compound 5a prepared in Example 3. DETAILED DESCRIPTION

[0078] The present invention will be described in detail below. Before describing, it should be understood that the terms used in this specification and the appended claims should not be interpreted as limited to the general meaning and dictionary meaning, but should be interpreted according to the meaning and concept corresponding to the technical aspects of the present invention on the basis of the principle that allows the inventor to appropriately define the terms for the best interpretation. Therefore, the descriptions presented here are merely preferred examples for illustrative purposes and are not intended to limit the scope of the present invention. It should be understood that other equivalents or improvements can be obtained therefrom without departing from the spirit and scope of the present invention.

[0079] As used herein, the terms "comprise," "include," "have," "contain," or any similar terms are open-ended transitional phrases that are intended to encompass non-exclusive inclusions. For example, a composition or article containing multiple elements is not limited to the elements listed herein, but may also include other elements not expressly listed but generally inherent to the composition or article. In addition, unless expressly stated to the contrary, the term "or" refers to an inclusive "or" rather than an exclusive "or." For example, any of the following situations satisfies the condition "A or B": A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), and both A and B are true (or exist). In addition, as used herein, the terms "comprise," "include," "have," and "contain" should be interpreted as specifically disclosing and encompassing closed or semi-closed transitional phrases such as "consisting of" and "consisting essentially of."

[0080] Throughout this document, all features or conditions defined as numerical ranges or percentage ranges are for simplicity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered to encompass and specifically disclose all possible subranges and individual values ​​within those ranges, particularly integer values. For example, a description of a range "1 to 8" should be considered to specifically disclose all possible subranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, and so forth, particularly those defined by all integer values, and should be considered to specifically disclose individual values ​​within those ranges such as 1, 2, 3, 4, 5, 6, 7, and 8. Unless otherwise indicated, the foregoing interpretation applies to all of the present disclosure, regardless of whether the ranges are comprehensive or not.

[0081] If a quantity or other value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that all ranges consisting of any upper limit or preferred value of the range and any lower limit or preferred value of the range have been specifically disclosed herein, regardless of whether these ranges are disclosed separately. In addition, when a numerical range is mentioned herein, unless otherwise specified, the range should include its endpoints and all integers and fractions within the range.

[0082] In this document, numerical values ​​should be understood to have the accuracy of the number of significant digits of the numerical value, provided that the purpose of the invention can be achieved. For example, the number 40.0 should be understood to cover the range from 39.50 to 40.49.

[0083] In this document, where Markush groups or optional terms are used to describe features or embodiments of the present invention, those skilled in the art will appreciate that any combination of all subgroups or individual elements within the Markush group or optional list can also be used to describe the present invention. For example, if X is described as "selected from the group consisting of X1, X2, and X3," this fully describes the claim that X is X1 and the claim that X is X1 and / or X2. Furthermore, where Markush groups or optional terms are used to describe features or embodiments of the present invention, those skilled in the art will appreciate that any combination of all subgroups or individual elements within the Markush group or optional list can also be used to describe the present invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, X2, and X3," and Y is described as "selected from the group consisting of Y1, Y2, and Y3," this fully describes the claim that X is X1, X2, or X3, and Y is Y1, Y2, or Y3.

[0084] definition

[0085] The definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described therein. The present invention is not intended to be limited in any way by the exemplary list of substituents described herein.

[0086] The compounds described herein may contain one or more asymmetric centers and may therefore exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferably, isomers may be prepared by asymmetric synthesis. The present disclosure further encompasses compounds described herein as individual isomers that are substantially free of other isomers, or as mixtures of various isomers.

[0087] When a range of values ​​is listed, it is intended to encompass every value and sub-range within that range. For example, "C 1-6 "Aims to cover C1, C2, C3, C4, C5, C6, C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5 and C 5-6 .

[0088] The term "alkyl" refers to a group of straight-chain or branched saturated hydrocarbon groups having 1 to 15 carbon atoms ("C 1-15 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C 2-6 C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl) and hexyl (C6) (e.g., n-hexyl). Unless otherwise specified, each instance of alkyl is independently unsubstituted or substituted with one or more substituents (e.g., halogen, such as F). In certain embodiments, alkyl is unsubstituted C 1-6 In certain embodiments, the alkyl group is a substituted C 1-6 Alkyl groups, such as -CF3.

[0089] "Alkoxy" refers to a monovalent -O-alkyl group, wherein the alkyl portion has the specified number of carbon atoms. In the present disclosure, alkoxy groups typically contain 1-6 carbon atoms ("C1-6 alkoxy"), and include, for example, methoxy, ethoxy, isopropoxy, tert-butyloxy, and the like. Unless otherwise indicated, each instance of alkoxy is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkoxy") or substituted ("substituted alkoxy") with one or more substituents, such as halogen atoms, nitro, amino, hydroxyl, cyano, amido, and the like. In certain embodiments, alkoxy is an unsubstituted C1-6 alkoxy group. 1-6 In certain embodiments, alkoxy is substituted C 1-6 Alkoxy.

[0090] "Cycloalkyl" refers to a non-aromatic ring system having 3 to 6 ring carbon atoms ("C 3-6 cycloalkyl”) and a non-aromatic cyclic hydrocarbon group having zero heteroatoms. Exemplary C 3-6 Cycloalkyl includes but is not limited to cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6) etc. As shown in the aforementioned examples, in certain embodiments, cycloalkyl is a monocycle ("monocyclic cycloalkyl") or contains a fused ring, a bridged ring or a spirocyclic ring system, such as a bicyclic ring system ("bicyclic cycloalkyl") and can be saturated or can be partially unsaturated. "Cycloalkyl" also includes a ring system in which the point of attachment of the cycloalkyl as defined above to one or more aryl or heteroaryl groups is fused to the carbocyclic ring, and in this case, the carbon number continues to refer to the carbon number in the carbocyclic ring system. Unless otherwise indicated, each example of a cycloalkyl group is independently optionally substituted, i.e., unsubstituted or substituted by one or more substituents.

[0091] "Heterocycloalkyl" refers to a group of a four to eight-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("four to eight-membered heterocyclyl"). In heterocyclyls containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom as long as valence permits. Heterocycloalkyl may be a monocyclic ring ("monocyclic heterocycloalkyl") or a fused ring, bridged ring or spirocyclic ring system, such as a bicyclic ring system ("bicyclic heterocycloalkyl"), and may be saturated or partially unsaturated. A heterocycloalkyl bicyclic ring system may contain one or more heteroatoms in one or both rings. "Heterocycloalkyl" also includes ring systems in which the point of attachment of a heterocycle as defined above to one or more carbocyclyl groups is fused to a carbocyclyl or heterocycle, or a ring system in which the point of attachment of a heterocycle as defined above to one or more aryl or heteroaryl groups is fused to a heterocycle, and in this case, the number of ring members continues to refer to the number of ring members in the heterocycle system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, ie, unsubstituted or substituted with one or more substituents.

[0092] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiirane. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thiirane. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, dithiolanyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiohexyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiohexyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, triazinyl. Exemplary groups of 5-membered heterocycloalkyl fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycles) include, but are not limited to, dihydroindolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary groups of 6-membered heterocycloalkyl fused to an aromatic ring (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0093] "Aryl" refers to a group having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system, either monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the cyclic array) ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 "Aryl"; for example, anthracenyl). "Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups, and in which case the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl") with one or more substituents, such as halogen atoms, nitro groups, amino groups, hydroxyl groups, cyano groups, amide groups, and the like. In certain embodiments, an aryl group is an unsubstituted C 6-14 In certain embodiments, aryl is a substituted C 6-14 Aryl.

[0094] "Heteroaryl" refers to a group of a five- to eight-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("five- to eight-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom as long as valence permits. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, wherein the point of attachment is on the heteroaryl ring, and in this case, the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl groups wherein the point of attachment is on the aryl or heteroaryl ring, and in such cases the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system.

[0095] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0096] Unless otherwise specifically provided, atoms, moieties or groups described herein may be unsubstituted or substituted as far as valence permits.

[0097] "Halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0098] The term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods known in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydrogen iodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, dodecylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 Alkyl)4 - Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, as appropriate.

[0099] The term "tautomer" or "tautomeric" refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valence (e.g., a single bond becomes a double bond, a triple bond becomes a single bond, and vice versa). The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerization reactions (i.e., reactions that provide tautomeric pairs) can be catalyzed by acids or bases. Exemplary tautomerization reactions include keto-enol, amide-imide, lactam-lactim, enamine-imine, and enamine-(different enamine) tautomerization reactions.

[0100] It is also understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0101] Stereoisomers that are not mirror images of each other are termed "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are termed "enantiomers." When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers may exist. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by Cahn and Prelog's rules of R- and S-sequencing or by the way the molecule rotates the plane of polarized light, and are denoted as right- or left-handed (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is termed a "racemic mixture."

[0102] The term "inhibit" or "inhibitor" refers to the ability of a compound to reduce, slow, arrest or prevent the activity of a particular biological process (eg, the activity of Nav1.8 in a tissue).

[0103] A "subject" intended for administration is a human (i.e., male or female of any age group, such as a pediatric subject (e.g., infant, child, or adolescent) or an adult subject (e.g., young adult, middle-aged, or elderly)). A "patient" is a human subject in need of treatment for a disease.

[0104] The term "biological sample" refers to any sample including tissue samples (e.g., tissue sections and needle biopsies of tissue); cell samples (e.g., cytological smears (e.g., Pap smears or blood smears) or cell samples obtained by microdissection); samples of whole organisms (e.g., yeast or bacterial samples); or cell parts, fragments, or organelles (e.g., obtained by lysing cells and separating their components by centrifugation or other means). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical biopsy or needle biopsy), nipple aspirate, milk, vaginal fluid, saliva, swabs (e.g., buccal swabs), or any material containing biomolecules derived from a first biological sample.

[0105] The term "administering" refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, into or onto a subject.

[0106] The term "treat" refers to reversing, alleviating, delaying the onset of a disease described herein, or inhibiting the development of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., based on a history of symptoms and / or based on exposure to a pathogen) to delay or prevent the onset of the disease. Treatment may also be continued after symptoms subside, for example, to delay or prevent recurrence.

[0107] A "therapeutically effective amount" of a compound described herein is an amount sufficient to provide a therapeutic benefit in treating a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound refers to an amount of the therapeutic agent that, alone or in combination with other therapies, provides a therapeutic benefit in treating the condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids symptoms, signs, or causes, and / or enhances the therapeutic efficacy of another therapeutic agent.

[0108] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. Generally speaking, such preparation methods include combining the compound described herein (i.e., the "active ingredient") with a carrier or excipient, and / or contacting one or more other auxiliary agents, and then, if necessary and / or desired, shaping and / or packaging the product into the desired single- or multi-dose units.

[0109] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as multiple single unit doses. The relative amounts of the active ingredient, pharmaceutically acceptable excipient, and / or any additional ingredients in the pharmaceutical compositions described herein will vary depending on the subject, size, and / or condition of the subject to be treated, as well as the route by which the composition is to be administered. The composition may contain 0.1% to 100% (w / w) active ingredient.

[0110] Pharmaceutically acceptable excipients used in the preparation of the provided pharmaceutical compositions include inert diluents, dispersants and / or granulating agents, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants and / or oils. Excipients such as cocoa butter and suppository waxes, colorants, coatings, sweeteners, flavorings, and fragrances may also be present in the compositions.

[0111] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in the art, for example, water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, fatty acid esters of propylene glycol and sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may include adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavorings, and spices. In certain embodiments of parenteral administration, the conjugates described herein are mixed with solubilizers (e.g., alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof).

[0112] Injectable preparations, for example, sterile injectable aqueous or oily suspensions can be prepared using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable preparations can be sterile injectable solutions, suspensions or emulsions in nontoxic parenteral acceptable diluents or solvents, for example, solutions of 1,3-butanediol. Acceptable carriers and solvents that can be used are water, Ringer's solution, USP and physiological saline solutions. In addition, sterile, fixed oils are generally used as solvents or suspending media. For this purpose, any mild fixed oil that can be used includes synthetic monoglycerides or diglycerides. In addition, fatty acids (such as oleic acid) are used for the preparation of injectable preparations.

[0113] In order to prolong the effect of the drug, it is generally desirable to reduce absorption from subcutaneous or intramuscular injections. This can be achieved by using liquid suspensions of crystalline or amorphous materials with poor water solubility. The absorption rate of the drug depends on the dissolution rate, which in turn depends on the crystal size and crystalline form. Alternatively, delayed absorption of parenteral drug forms can be achieved by dissolving or suspending the drug in an oily vehicle.

[0114] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and / or (a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia, (c) humectants, such as glycerol, (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retardants, such as petrolatum, (f) absorption accelerators, such as quaternary ammonium compounds, (g) wetting agents, such as, for example, cetyl alcohol and glyceryl monostearate, (h) absorbents, such as kaolin and bentonite, and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets or pills, the dosage form may comprise buffering agents.

[0115] The active ingredient can be in the form of microcapsules with one or more of the excipients described above. Tablets, dragees, capsules, pills, and granules in the form of solid dosage forms can be prepared using coatings and shells (such as enteric coatings, release control agent coatings, and other coatings known in the pharmaceutical formulation field). In such solid dosage forms, the active ingredient can be mixed with at least one inert diluent (e.g., sucrose, lactose, or starch). Conventionally, such dosage forms can contain other substances in addition to inert diluents, for example, tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, or pills, the dosage form can contain a buffer. They can optionally contain opacifiers and can be compositions with the following properties: they release the active ingredient only, or preferably, in certain parts of the intestinal tract, optionally in a delayed manner. Examples of encapsulating agents that can be used include polymers and waxes.

[0116] Although the descriptions of pharmaceutical compositions provided herein are primarily directed to pharmaceutical compositions suitable for administration to humans, such compositions are generally suitable for administration to all types of animals. Modifications of pharmaceutical compositions suitable for administration to humans to make the compositions suitable for administration to a variety of animals are readily understood, and those skilled in the art can design and / or perform such modifications using routine experimentation.

[0117] The compounds provided herein are generally formulated in dosage unit form for ease of administration and uniformity of dosage. However, it is understood that all daily uses of the compositions described herein will be determined by a physician within the scope of reasonable medical judgment. The specific therapeutically effective dosage level for any particular subject or organism depends on a number of factors including: the severity of the disease and condition to be treated; the activity of the specific active ingredient used; the specific composition used; the age, weight, health status, sex and diet of the subject; the time of administration, route of administration and excretion rate of the specific active ingredient; the duration of treatment; the combination or consistent drug with the specific active ingredient used; and other factors known in the medical field.

[0118] The compounds and compositions provided herein can be administered by conventional routes, including intestinal (e.g., oral) administration, parenteral administration, intravenous administration, intramuscular administration, intra-arterial administration, intramedullary administration, intracapsular administration, subcutaneous administration, intraventricular administration, transdermal administration, subcutaneous administration, rectal administration, intravaginal administration, intraperitoneal administration, topical administration (e.g., by powder, ointment, cream and / or droplets). Particularly contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), topical administration supplied by blood and / or lymph and / or direct administration to a predetermined site. In general, the most appropriate route of administration will depend on a range of factors, including: the nature of the medicament (e.g., stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether oral administration is permitted).

[0119] The exact amount of compound required to achieve an effective dose will vary according to the subject, depending on, for example, the race, age and general condition of the subject, the severity of the side effect or disease, the confirmation of the specific compound, the mode of administration, etc. An effective amount can be included in a single dose (e.g., a single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue or cell, any two doses of the multiple doses comprise different or substantially identical compounds as described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue or cell, the frequency of multiple doses administered to the subject or multiple doses applied to tissue or cells is three doses per day, two doses per day, one dose per day, one dose every two days, one dose every three days, or one dose per week. In certain embodiments, the frequency of multiple doses administered to a subject or multiple doses applied to tissue or cells is one dose per day. In certain embodiments, the frequency of multiple doses administered to a subject or multiple doses applied to tissue or cells is two doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, the duration between the first dose and the last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the life of the subject, biological sample, tissue, or cell. In certain embodiments, the duration between the first dose and the last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and the last dose of the multiple doses is the life of the subject, biological sample, tissue, or cell. In certain embodiments, the doses described herein (e.g., any dose in a single dose or multiple doses) independently comprise 1 mg to 3 mg, 3 mg to 10 mg, 10 mg to 30 mg, 30 mg to 100 mg, 100 mg to 300 mg, 300 mg to 1,000 mg, or 1 g to 10 g of a compound described herein. In certain embodiments, the doses described herein independently comprise 3 mg to 10 mg of a compound described herein. In certain embodiments, the doses described herein independently comprise 10 mg to 30 mg of a compound described herein. In certain embodiments, the doses described herein independently comprise 30 mg to 100 mg of a compound described herein. In certain embodiments, the doses described herein independently comprise 100 mg to 300 mg of a compound described herein. In certain embodiments, the doses described herein independently comprise 300 mg to 1000 mg of a compound described herein.

[0120] The following examples are merely examples of embodiments of the present invention and do not constitute any limitation thereto. Those skilled in the art will appreciate that modifications without departing from the spirit and scope of the present invention fall within the scope of protection of the present invention. Unless otherwise specified, the reagents and instruments used in the following examples are commercially available products.

[0121] 1 H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm using tetramethylsilane as an internal standard (0.00 ppm). 1 HNMR notation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of a doublet, dt = doublet of a triplet. Coupling constants, when given, are given in Hz.

[0122] Mass spectra were obtained using LC / MS, and the ionization method could be ESI or APCI.

[0123] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0124] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0125] In the following examples, unless otherwise indicated, all temperatures are in degrees Celsius. Unless otherwise indicated, various starting materials and reagents are commercially available or synthesized according to known methods. Commercially available raw materials and reagents are used directly without further purification, unless otherwise indicated. Commercial manufacturers include but are not limited to Aldrich Chemical Company, ABCR GmbH & Co.KG, Acros Organics, Shanghai Bid Pharmaceutical Technology Co., Ltd. and Shanghai Titan Technology Co., Ltd.

[0126] Unless otherwise specified or the context indicates otherwise, the following abbreviations should be understood to have the following meanings: CD3OD: deuterated methanol. CDCl3: deuterated chloroform. DMSO-d6: deuterated dimethyl sulfoxide. D2O: heavy water. NMR: nuclear magnetic resonance ESI-MS: electrospray ionization mass spectrometry LCMS: liquid chromatography-mass spectrometry TLC: thin layer chromatography HPLC: high performance liquid chromatography prep-HPLC: preparative high performance liquid chromatography SFC: supercritical fluid chromatography g: gram mg: milligram L: liter mL: milliliter μL: microliter mmol: millimole hr, h: hour min: minute mm: millimeter μm: micrometer MHz: megahertz Hz: hertz eq.Equivalents (M): moles / liter (concentration): DCM: dichloromethane; DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; EtOH: ethanol; EtOAc, EA: ethyl acetate; NMI: N-methylimidazole; TCFH: N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate; MeOH: methanol; MTBE: methyl tert-butyl ether; THF: tetrahydrofuran; ACN: acetonitrile; TEA: triethylamine; TGA: thioglycolic acid; RT, rt: room temperature; MeMgBr: methylmagnesium bromide; Schwartz's reagent: bis(cyclopentadienyl)zirconium(IV) hydrochloride.

[0127] Argon atmosphere can be achieved by connecting an argon balloon to the reaction flask.

[0128] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0129] The compound is purified using a C18 reverse phase column for preparative or semi-preparative purification, a silica gel column chromatography eluent system, and thin layer chromatography, wherein the eluent system is selected from: A: petroleum ether and tetrahydrofuran system; B: acetonitrile and water system; C: petroleum ether and ethyl acetate system; wherein the volume ratio of the solvent varies according to the polarity of the compound and can also be adjusted by adding a small amount of acidic or alkaline reagent, such as trifluoroacetic acid, acetic acid, or triethylamine.

[0130] Preparation Example 1: Synthesis of Intermediate 2-(3,4-difluoro-2-methoxyphenyl)acetyl chloride (Int1):

[0131] Step 1: 3,4-difluoro-2-methoxybenzyl alcohol

[0132] In an ice bath, slowly add a 1 M solution of borane in tetrahydrofuran (213 mL) dropwise to a solution of 3,4-difluoro-2-methoxybenzoic acid (20 g, 106 mmol) in anhydrous tetrahydrofuran (240 mL). After complete addition, warm to 25°C and stir for 2 hours. Slowly add methanol dropwise to quench the reaction. After concentration, 3,4-difluoro-2-methoxybenzyl alcohol (Int1a) (18 g, crude) is obtained as a colorless oil.

[0133] Step 2: 3,4-difluoro-2-methoxybenzyl ester

[0134] Under ice bath conditions, methanesulfonyl chloride (14 g, 124 mmol) was slowly added dropwise to a solution of 3,4-difluoro-2-methoxybenzyl alcohol Int1a (18 g, crude) and diisopropylethylamine (40 g, 310 mmol) in anhydrous dichloromethane (128 mL). After the addition, the mixture was stirred in an ice bath for 30 minutes. After addition of aqueous hydrochloric acid (1 M, 60 mL), the layers were separated and the aqueous phase was extracted with dichloromethane (60 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a brown oily compound 3,4-difluoro-2-methoxybenzyl methanesulfonate Int1b (20.00 g, crude).

[0135] Step 3: 2-(3,4-difluoro-2-methoxyphenyl)acetonitrile

[0136] Sodium cyanide (6.61 g, 134.80 mmol) was added to a solution of 3,4-difluoro-2-methoxybenzyl methanesulfonate Int1b (crude product, 17 g, 67.40 mmol) in N,N-dimethylformamide (150 mL). After stirring at 25°C for 1 hr, ethyl acetate (150 mL) and water (150 mL) were added sequentially. The layers were separated, and the aqueous phase was extracted with ethyl acetate (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The combined organic phases were purified by silica gel column chromatography (PE:THF=1:0 to 3:1) to obtain a yellow oily compound 2-(3,4-difluoro-2-methoxyphenyl)acetonitrile Int1c (9.30 g, 71.57% yield).

[0137] 1 H-NMR (400MHz, CDCl3) δ7.25-7.03(m,1H),6.90-6.83(m,1H),4.07(d,J=2.8H Z ,3H),3.65(s,2H).

[0138] Step 4: 2-(3,4-difluoro-2-methoxyphenyl)acetic acid

[0139] NaOH (15.5 g, 387 mmol) was added to a mixture of 2-(3,4-difluoro-2-methoxyphenyl)acetonitrile Int1c (9.3 g, 50.78 mmol) and water (350 mL). The mixture was heated under reflux for 16 hours and then cooled. The pH was adjusted to 4 with aqueous hydrochloric acid (4 M). The mixture was extracted three times with ethyl acetate (200 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a light yellow solid compound 2-(3,4-difluoro-2-methoxyphenyl)acetic acid Int1d (10.20 g, 94.4% yield).

[0140] 1 H-NMR (400MHz, DMSO-d6) δ12.41 (s, 1H), 7.13-7.05 (m, 2H), 3.86 (d, J = 2.0H Z ,3H),3.56(s,2H).

[0141] Step 5: 2-(3,4-difluoro-2-methoxyphenyl)acetyl chloride

[0142] 2-(3,4-difluoro-2-methoxyphenyl)acetic acid 1d (500 mg, 2.47 mmol, 1 equivalent) was dissolved in thionyl chloride (5.0 mL) and stirred at room temperature for 16 hours. LCMS analysis (the reaction solution was concentrated to dryness and a solution of dimethylamine in tetrahydrofuran was added) indicated that the reaction was complete. The reaction solution was concentrated to dryness under vacuum, and anhydrous dichloromethane (5.0 mL) was added to the residue. The mixture was evaporated to dryness under vacuum again to give 2-(3,4-difluoro-2-methoxyphenyl)acetyl chloride Int1 (540 mg, crude product) as a yellow oil, which was used directly in the next reaction.

[0143] Preparation Example 2: Synthesis of Intermediate 2-((tert-Butyloxycarbonyl)amino)-3,3,3-trifluoro-2-methylpropionic acid methyl ester (Int2):

[0144] Step 1: 2-((tert-Butyloxycarbonyl)imino)-3,3,3-trifluoropropionic acid methyl ester

[0145] Methyl trifluoropyruvate (10.0 g, 64.08 mmol, 1.05 equivalents) was added to a solution of tert-butyl triphenylphosphinoimide (23.1 g, 61.19 mmol, 1 equivalent) in tetrahydrofuran (200 mL). After the addition, the reaction system was protected with nitrogen and stirred at 50°C for 10 minutes, then cooled to 20°C and stirred for 2 hours. TLC (petroleum ether:ethyl acetate = 5:1, R f=0.6) The disappearance of the starting material was detected. The reaction solution was concentrated to dryness and then slurried in a mixed solvent (petroleum ether:diethyl ether = 1:1). The mixture was filtered and the filtrate was concentrated under vacuum to afford methyl 2-((tert-butyloxycarbonyl)imino)-3,3,3-trifluoropropionate Int2a (16.8 g, crude product, 100% yield) as a colorless oil.

[0146] 1 H NMR (400MHz, CDCl3), δ: 3.95 (s, 3H), 1.58 (s, 9H).

[0147] Step 2: Methyl rac-2-((tert-butyloxycarbonyl)amino)-3,3,3-trifluoro-2-methylpropionate

[0148] Compound 2-((tert-butyloxycarbonyl)imino)-3,3,3-trifluoropropionic acid methyl ester Int2a (6.0 g, 23.51 mmol, 1 equivalent) was dissolved in tetrahydrofuran (60.0 mL), cooled to -70°C, and methylmagnesium bromide (7.84 mL, 23.51 mmol, 3 mol / L 2-methyltetrahydrofuran solution, 1 equivalent) was slowly added dropwise. After the addition was complete, stirring was continued at -70°C for 1 hour, then the temperature was raised to 20°C and stirred for 30 minutes. TLC (petroleum ether:ethyl acetate = 5:1, R f =0.5) the disappearance of the starting material was detected. Under ice bath conditions, saturated ammonium chloride solution (200.0 mL) was added to quench the reaction, followed by extraction with ethyl acetate (200 mL) three times. The organic phases were combined, washed with saturated brine, dried, and concentrated, and purified by normal phase silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the compound rac-2-((tert-butoxycarbonyl)amino)-3,3,3-trifluoro-2-methylpropanoic acid methyl ester Int2 (5.2 g, crude product, 81.54% yield) as a white solid.

[0149] 1 H NMR (400MHz, CDCl3), δ: 5.13 (s, 1H), 3.83 (s, 3H), 1.74 (s, 3H), 1.44 (s, 9H).

[0150] Example 1: Synthesis of 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxamido)picolinamide (1) and 4-((2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxamido)picolinamide (2):

[0151] Step 1: rac-(1,1,1-trifluoro-2-methyl-3-oxobutan-2-yl)amine methyl tert-butyl ester

[0152] To a solution of rac-2-((tert-butoxycarbonyl)amino)-3,3,3-trifluoro-2-methylpropanoic acid methyl ester Int2 (20.0 g, 73.747 mmol, 1.0 equivalent) in tetrahydrofuran (400 mL) was slowly added dropwise trimethylsilylmethyl lithium (408.2 mL, 228.6 mmol, 0.56 mol / L n-hexane solution, 3.1 equivalents) at -70°C. After the addition was complete, the mixture was stirred at -70°C for 40 minutes. TLC (petroleum ether:ethyl acetate = 5:1, R f =0.3) was detected when most of the starting material disappeared. The reaction solution was heated to 0°C, quenched with anhydrous methanol (20.0 mL) and stirred for 30 minutes. Saturated ammonium chloride solution (1000 mL) was then added and extracted three times with ethyl acetate (400 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain rac-(1,1,1-trifluoro-2-methyl-3-oxobutan-2-yl)amine methyl tert-butyl ester 1a (20.1 g crude product) as a pale yellow oil.

[0153] 1 H NMR (400MHz, CDCl3), δ: 5.15 (m, 1H), 2.21 (s, 3H), 1.53 (s, 3H), 1.35 (s, 9H).

[0154] Step 2: rac-3-amino-4,4,4-trifluoro-3-methylbutan-2-one

[0155] Compound rac-(1,1,1-trifluoro-2-methyl-3-oxobutan-2-yl)amine methyl tert-butyl ester 1a (19.1 g crude, 74.83 mmol, 1.0 equivalent) was dissolved in 4 M hydrochloric acid / dioxane solution (191.0 mL) and stirred at room temperature for 2 hours. TLC analysis indicated the disappearance of the starting material. The reaction mixture was concentrated to dryness, slurried with diethyl ether, and filtered. The filter cake was vacuum-dried to yield rac-3-amino-4,4,4-trifluoro-3-methylbutan-2-one 1b (9.64 g crude) as a white solid.

[0156] 1 H NMR (400MHz, DMSO-d6), δ: 2.45 (s, 3H), 1.70 (s, 3H).

[0157] Step 3: rac-2-(3,4-difluoro-2-methoxyphenyl)-N-(1,1,1-trifluoro-2-methyl-3-oxobutan-2-yl)acetamide

[0158] To a suspension of compound rac-3-amino-4,4,4-trifluoro-3-methylbutan-2-one 1b (9.52 g crude product, 49.69 mmol, 1.0 equivalent) in dichloromethane (90.0 mL) was added pyridine (39.3 g, 496.86 mmol, 10.0 equivalents) at -10°C, followed by a solution of 2-(3,4-difluoro-2-methoxyphenyl)acetyl chloride Int1 (12.06 g, 54.65 mmol, 1.1 equivalents) in dichloromethane (40.0 mL) that was slowly added dropwise to the reaction solution. The reaction solution was allowed to warm to room temperature and stirred for 16 hours. LC / MS analysis indicated that the reaction was complete. 1 mol / L hydrochloric acid (1000.0 mL) was added to the reaction solution, and the mixture was extracted three times with dichloromethane (300.0 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a yellow solid compound rac-2-(3,4-difluoro-2-methoxyphenyl)-N-(1,1,1-trifluoro-2-methyl-3-oxobutan-2-yl)acetamide 1c (11.7 g, 69.4% yield).

[0159] MS (ESI): m / z calculated [M+H + ]:340.09, measured value: 340.2

[0160] 1 H NMR (400MHz, DMSO-d6), δ: 9.15 (s, 1H), 7.13-7.04 (m, 2H), 3.86-3.84 (m, 3H), 3.62-3.53 (m, 2H), 2.05 (s, 3H), 1.49 (s, 3H).

[0161] Step 4: rac-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-1,5-dihydro-2-hydro-pyrrol-2-one

[0162] Compound rac-2-(3,4-difluoro-2-methoxyphenyl)-N-(1,1,1-trifluoro-2-methyl-3-oxobutan-2-yl)acetamide 1c (11.7 g, 4.72 mmol, 1.0 equiv) was dissolved in hot ethanol (120.0 mL), followed by the addition of potassium hydroxide (1.94 g, 34.49 mmol, 1.0 equiv). The reaction mixture was heated to 80°C and stirred for 20 minutes. LC / MS analysis indicated the reaction was complete. The reaction mixture was cooled to room temperature, poured into water (1000.0 mL), and extracted three times with dichloromethane (400.0 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a pale yellow solid compound rac-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-1,5-dihydro-2hydro-pyrrol-2-one 1d (8.8 g, 79.4% yield).

[0163] MS (ESI): m / z calculated [M+H + ]:322.08, Actual value:322.2

[0164] 1 H NMR (400MHz, DMSO-d6), δ: 9.13 (s, 1H), 7.27-7.21 (m, 1H), 7.04-6.99 (m, 1H), 3.75 (d, J = 1.2Hz, 3H), 1.88 (s, 3H), 1.56 (s, 3H).

[0165] Step 5: rac-(3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidin-2-one

[0166] Compound rac-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-1,5-dihydro-2-hydro-pyrrol-2-one 1d (14.63 g, 45.54 mmol, 1.0 equivalent) was dissolved in a mixed solvent (tetrahydrofuran:methanol = 1:5, 540.0 mL) and cooled to -40°C. Nickel chloride hexahydrate (10.82 g, 45.54 mmol, 1.0 equivalent) and sodium borohydride (5.17 g, 136.62 mmol, 3.0 equivalent) were then added sequentially. The reaction mixture was stirred for 1 hour, and then additional amounts of nickel chloride hexahydrate and sodium borohydride were added at -40°C until LC / MS indicated complete consumption of the starting material. The reaction solution was filtered, and the filtrate was concentrated. Saturated ammonium chloride solution (1000.0 mL) was added, and the mixture was extracted three times with dichloromethane (300.0 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. A mixed solvent (100.0 mL, petroleum ether:ethyl acetate = 20:1) was added to the residue and slurried for 1 hour. The mixture was filtered and the filter cake was dried to obtain the compound rac-(3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidin-2-one 1e (11.17 g, 75.9% yield) as a white solid.

[0167] MS (ESI): m / z calculated [M+H + ]:324.09, measured value: 324.2;

[0168] 1 H NMR(400MHz,DMSO-d6),δ:8.90(s,1H),7.16-7.09(m,1H),6.85-6.83(m,1H),4.22(d, J=10.4Hz,1H),3.92(d,J=1.6Hz,3H),2.85(m,1H),1.48(s,3H),0.68(d,J=6.0Hz,3H).

[0169] Step 6: rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidine-2-carbonitrile

[0170] To a suspension of biscyclopentadienylzirconium chloride (Schwartz reagent) (3.52 g, 13.64 mmol, 5.0 equiv) in tetrahydrofuran (20.0 mL) under nitrogen at -30°C was added a solution of rac-(3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidin-2-one 1e (882.0 mg, 2.73 mmol, 1.0 equiv) in tetrahydrofuran (8.0 mL). After stirring for 0.25 hours, the reaction mixture was naturally warmed to 20°C and stirred for an additional 16 hours. LC / MS analysis indicated that the starting material had been fully converted to the imine. The filtrate was filtered and concentrated in vacuo to yield the crude imine intermediate. The crude imine was dissolved in dichloromethane (10.0 mL) and cooled to 5°C. TMSCN (5.41 g, 54.57 mmol, 20.0 equiv) was added, and the mixture was naturally warmed to 20°C and stirred for 4 days. LC / MS analysis showed complete conversion of the imine. Saturated sodium bicarbonate solution (100.0 mL) was added, and the mixture was extracted three times with dichloromethane (50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by normal phase silica gel chromatography (petroleum ether:ethyl acetate = 20:1) to afford rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidine-2-carbonitrile 1f (516.0 mg, 56.6% yield) as a colorless oil.

[0171] MS (ESI): m / z calculated [M+H + ]:335.11, measured value: 335.2;

[0172] 1 H NMR (400MHz, DMSO-d6), δ:7.21-7.14(m,2H),4.55-4.52(m,1H),4.12(d,J=4.4H z,1H),3.96(d,J=2.4Hz,3H),2.71-2.64(m,1H),1.48(s,3H),0.70-0.68(m,3H).

[0173] Step 7: rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxylic acid

[0174] To a solution of rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidine-2-carbonitrile 1f (516.0 mg, 1.54 mmol, 1.0 equivalent) in 1,4-dioxane (3.0 mL) was added concentrated hydrochloric acid (15.0 mL), and the reaction mixture was stirred at 55° C. for 6 hours. LCMS analysis indicated the reaction was complete. The reaction mixture was concentrated to dryness under vacuum, and the residue was dissolved in a mixture of water (20.0 mL) and ethyl acetate (10.0 mL). The pH was adjusted to 5 with sodium bicarbonate, and then extracted three times with ethyl acetate (5.0 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 1 g (540.0 mg, 99.0% yield) of the compound rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxylic acid as a light yellow oil.

[0175] MS (ESI): m / z calculated [M+H + ]:354.11, measured value:354.2;

[0176] 1 H NMR (400MHz, CDCl3), δ: 7.06-7.00 (m, 1H), 6.89-6.82 (m, 1H), 4.28 (d, J = 9.6H z,1H),4.00-3.92(m,4H),2.58-2.50(m,1H),1.53(s,3H),0.75-0.73(m,3H).

[0177] Step 8: rac-methyl-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxamide)picolinate

[0178] To a solution of methyl 4-aminopyridine-2-carboxylate (2.45 g, 16.13 mmol, 30.0 equiv), 1 g (190.0 mg, 537.8 μmol, 1.0 equiv) of the compound rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxylic acid and N-methylimidazole (441.54 mg, 5.38 mmol, 10.0 equiv) in acetonitrile (40 mL) was added N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (301.79 mg, 1.08 mmol, 2.0 equiv) in portions, and the reaction mixture was stirred at 20°C for 16 hours. LCMS analysis showed that the starting material was completely consumed. 200.0 mL of water was added to the reaction solution, and the pH was adjusted to 7-8 with dilute hydrochloric acid. The mixture was then extracted three times with ethyl acetate (100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (column model: Welch Xtimate C18 250*30 mm*10 μm; mobile phase: water (0.05% HCl)-ACN; gradient: 30%-60% over 15 minutes; flow rate: 40 mL / min) to obtain rac-methyl-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxamide)picolinate 1h (30.0 mg, 11.4% yield) as a white solid.

[0179] MS (ESI): m / z calculated [M+H + ]:487.15, measured value:488.3;

[0180] Step 9: Synthesis of 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxamido)picolinamide (1) and 4-((2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxamido)picolinamide (2):

[0181] Compound rac-methyl-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxamide)picolinate 1h (30.0 mg, 61.55 μmol, 1.0 equiv) was dissolved in 7M NH3 / MeOH solution (3.0 mL) and stirred at 20°C for 16 hours. LCMS analysis showed that the starting material was completely consumed. The reaction solution was concentrated to dryness under vacuum, and the residue was subjected to chiral separation by SFC (column model: ChiralPakWhelk-O1 (S,S) column from Daicel Chemical Industries, 5 μm particle size, 250 × 30 mm dimensions; mobile phase: solvent A: supercritical carbon dioxide, solvent B: HPLC-grade ethanol containing 0.1% aqueous ammonia, A:B = 70:30; flow rate: 50 mL / min; column temperature: 38°C; detection wavelength: 220 nm) to obtain two single isomers with unknown absolute configurations:

[0182] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxamido)picolinamide (1) (first eluting isomer, 7.12 mg, 24.5% yield).

[0183] MS (ESI): m / z calculated [M+H + ]:473.15, measured value:473.1;

[0184] 1 H NMR (400MHz, CDCl3), δ: 9.60 (s, 1H), 8.42 (d, J = 5.2Hz, 1H), 8.15 (d, J = 4.0Hz, 1H), 7.93 (s, 1H), 7.88 (s, 1H), 7.16-7.13 (m, 1H), 6.93-6.87 (m ,1H),5.71(s,1H),4.47(d,J=9.6Hz,1H),4.06(t,J=9.2Hz,1H),3.95(d,J=2.4Hz,3H),2.61(q,J=7.6Hz,1H),1.62(s,3H),0.75-0.74(m,3H)

[0185] and 4-((2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxamido)picolinamide (2) (second eluting isomer, 6.03 mg, 20.7% yield).

[0186] MS (ESI): m / z calculated [M+H +]:473.15, measured value:473.2;

[0187] 1H NMR (400MHz, CDCl3), δ: 9.53 (s, 1H), 8.43 (d, J = 5.2Hz, 1H), 8.18 (d, J = 3.6Hz, 1H), 7.92 (d, J = 1.6Hz, 1H), 7.86 (s, 1H), 7.13-7.10 (m, 1H), 6.92-6. 86(m,1H),5.69(s,1H),4.42(d,J=10.4Hz,1H),4.04(t,J=9.2Hz,1H),3. 95(d,J=2.4Hz,3H),2.60(q,J=7.6Hz,1H),1.60(s,3H),0.75-0.73(m,3H)

[0188] Example 2: Synthesis of 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-1,4,5-trimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxamido)picolinamide (3) and 4-((2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-1,4,5-trimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxamido)picolinamide (4):

[0189] Step 1: rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-1,4,5-trimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxylic acid

[0190] 1 g (100.0 mg, 283.05 μmol, 1.0 equivalent) of the compound rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxylic acid was dissolved in methanol (5.0 mL), and 18% formaldehyde aqueous solution (944.46 mg, 5.66 mmol, 20.0 equivalent) and palladium on carbon (60.25 mg, 28.31 μmol, 0.1 equivalent, catalyst palladium loading of 10%, water content of 50%) were added sequentially. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (5.0 MPa) for 16 hours. LCMS detection showed that the starting material was completely consumed. The reaction solution was filtered, and the filtrate was concentrated to dryness under vacuum to give a light yellow solid compound rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-1,4,5-trimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxylic acid 3a (102.0 mg, 98.1% yield).

[0191] MS (ESI): m / z calculated [M+H+ ]:368.12, measured value:368.3;

[0192] Step 2: rac-methyl 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-1,4,5-trimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxamide)picolinate

[0193] To a suspension of rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-1,4,5-trimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxylic acid 3a (1.66 g, 10.89 mmol, 40.0 equiv), compound 12 (100.0 mg, 272.24 μmol, 1.0 equiv) and N-methylimidazole (335.27 mg, 4.08 mmol, 15 equiv) in acetonitrile (10.0 mL) was added N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (152.77 mg, 544.48 μmol, 2.0 equiv) in portions. The reaction mixture was ultrasonically shaken at 20°C for 24 h. LCMS analysis indicated the formation of the product. The reaction mixture was then added with 200.0 mL of water, the pH adjusted to 7-8 with dilute hydrochloric acid, and extracted three times with ethyl acetate (100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was then purified by prep-HPLC (Phenomenex Luna C18 column, 150 x 25 mm x 10 μm; mobile phase: water (0.1% TFA)-ACN; gradient: 30% to 60% over 15 minutes; flow rate: 40 mL / min) to afford rac-methyl 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-1,4,5-trimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxamide)picolinate 3b (59.0 mg, 43.2% yield) as a white solid.

[0194] MS (ESI): m / z calculated [M+H + ]:502.17, measured value:502.5;

[0195] Step 3: 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-1,4,5-trimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxamido)picolinamide (3) and rel-4-((2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-1,4,5-trimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxamido)picolinamide (4)

[0196] Compound rac-methyl 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-1,4,5-trimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxamide)picolinate 3b (59.0 mg, 117.66 μmol, 1.0 equiv) was dissolved in 7 M NH3 / MeOH solution (3.0 mL) and stirred at 20°C for 16 hours. LCMS analysis showed complete consumption of the starting material. The reaction solution was concentrated to dryness under vacuum, and the residue was subjected to chiral separation by SFC (column model: ChiralPak Whelk-O1 (S,S) column from Daicel Chemical Industries, 5 μm particle size, 250 × 30 mm dimensions; mobile phase: solvent A: supercritical carbon dioxide, solvent B: HPLC-grade ethanol containing 0.1% aqueous ammonia, A:B = 80:20; flow rate: 50 mL / min; column temperature: 38°C; detection wavelength: 220 nm) to obtain two single isomers with unknown absolute configurations:

[0197] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-1,4,5-trimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxamido)picolinamide (3) (first eluting isomer, 14.81 mg, 25.9% yield)

[0198] MS (ESI): m / z calculated [M+H + ]:487.17, measured value:487.2;

[0199] 1 H NMR (400MHz, CDCl3) δ8.99(s,1H),8.47(d,J=5.6Hz,1H),8.29(dd,J=5.6,2.1Hz,1H),7.92(m,2H),7.17(t,J=7.4Hz,1H),6.89(td,J=9.3,7.5Hz,1H ),5.55(s,1H),4.03(d,J=8.3Hz,1H),3.99-3.90(m,1H),3.87(d,J=2.7Hz ,3H),2.74(q,J=7.9Hz,1H),2.59(m,3H),1.57(s,3H),0.83-0.69(m,3H).

[0200] and 4-((2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-1,4,5-trimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxamido)picolinamide (4) (second eluting isomer, 11.84 mg, 20.7% yield)

[0201] MS (ESI): m / z calculated [M+H+ ]:487.17, measured value:487.2;

[0202] 1 H NMR (400MHz, CDCl3) δ8.98 (s, 1H), 8.46 (d, J = 5.6 Hz, 1H), 8.29 (dd, J = 5.6, 2. 1Hz,1H),7.91(d,J=2.2Hz,1H),7.88(s,1H),7.18(t,J=7.2Hz,1H),6.96-6.8 6(m,1H),5.49(s,1H),4.02(d,J=8.1Hz,1H),3.98-3.89(m,1H),3.87(d,J=2. 6Hz, 3H), 2.75 (q, J = 8.0Hz, 1H), 2.59 (m, 3H), 1.56 (s, 3H), 0.83-0.64 (m, 3H).

[0203] Example 3: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-nitrogen-(6-((R)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxamide (5):

[0204] Step 1: 2.0 g of the racemic compound 1e was subjected to chiral separation by SFC (column model: ChiralPak AD-H column from Daicel Chemical Industries, 5 μm particle size, 250 × 30 mm dimensions; mobile phase: solvent A: supercritical carbon dioxide, solvent B: HPLC-grade ethanol containing 0.1% ammonia, A:B = 90:10; flow rate: 60 mL / min; injection pressure: 100 bar; column temperature: 38°C; detection wavelength: 220 nm) to obtain compound 5a (first eluting isomer, 940 mg) with a single configuration. The absolute configuration of the compound 5a was characterized by single crystal X-ray diffraction. The single crystal preparation process and SC-XRD data are as follows: 50 mg of compound 2 was dissolved in 0.5 mL of diethyl ether and slowly evaporated over 7 days, resulting in the precipitation of several single crystals of compound 2. A single crystal without defects was subjected to SC-XRD testing and data analysis. The absolute configuration of compound 5a is shown in FIG1 , and the unit cell parameters are listed in Table 1 below:

[0205] MS (ESI): m / z calculated [M+H + ]:324.09, measured value:324.2;

[0206] 1HNMR(400MHz,DMSO-d6)δ8.90(s,1H),7.13(ddd,J=10.3,8.9,7.8Hz,1H),6.91-6.74(m,1H),4.2 2(d,J=10.5Hz,1H),3.92(d,J=2.4Hz,3H),2.84(q,J=8.4Hz,1H),1.48(s,3H),0.70-0.67(m,3H).

[0207] Table 1

[0208] Step 2: At -30 ° C, to a suspension of biscyclopentadienyl zirconium chloride (Schwartz reagent) reagent (3.15 g, 12.22 mmol, 5.0 equivalents) in THF (15.0 mL) under nitrogen protection, a solution of compound 5a (790 mg, 2.44 mmol, 1.0 equivalents) in THF (5.0 mL) was added. After stirring for 0.25 hours, the reaction mixture was naturally warmed to 20 ° C and continued to stir for 16 hours. LCMS detection showed that all the raw materials were converted into imines. It was then filtered and the filtrate was concentrated in vacuo to obtain a crude imine intermediate. The prepared crude imine was dissolved in dichloromethane (10.0 mL) and cooled to 5 ° C. After adding TMSCN (3.64 g, 36.66 mmol, 15.0 equivalents), it was naturally warmed to 20 ° C and stirred for 4 days. LCMS analysis showed that the imine conversion was complete. Saturated sodium bicarbonate solution (100.0 mL) was added and extracted three times with dichloromethane (50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by normal phase silica gel column (petroleum ether:ethyl acetate = 20:1) to give compound 5b (430.0 mg, 52.63% yield) as a colorless oil.

[0209] MS (ESI): m / z calculated value [M+H+]: 335.11, found value: 335.1;

[0210] 1H NMR(400MHz, DMSO-d6)δ7.28-7.09(m,2H),4.53(dd,J=7.0,4.6Hz,1H),4.12(d,J=4.7Hz,1H),3 .96(d,J=2.4Hz,3H),3.95-3.88(m,1H),2.67(q,J=7.6Hz,1H),1.48(s,3H),0.70-0.68(m,3H).

[0211] Step 3: Concentrated hydrochloric acid (10.0 mL) was added to a solution of 1,4-dioxane (2.0 mL) of compound 5b (430.0 mg, 1.29 mmol, 1.0 equivalent), and the reaction mixture was stirred at 55 ° C for 16 hours. LCMS detection showed that the reaction was complete. The reaction mixture was concentrated to dryness under vacuum, and the residue was dissolved in a mixed solution of water (20.0 mL) and ethyl acetate (10.0 mL). After adjusting the pH value to 5 with sodium bicarbonate, the mixture was extracted three times with ethyl acetate (5.0 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give compound 5c (410.0 mg, 90.22% yield) as a light yellow solid.

[0212] MS (ESI): m / z calculated [M+H + ]:354.11, measured value:354.1;

[0213] 1 HNMR (400MHz, DMSO-d6) δ12.81(s,1H),7.23(ddd,J=8.3,6.0,2.0Hz,1H),7.13(td,J=9.6,7.6Hz,1H),4.12(d,J=8.9 Hz,1H),3.90(d,J=2.0Hz,3H),3.88-3.82(m,1H),2.80(s,1H),2.46(d,J=7.6Hz,1H),1.47(s,3H),0.68-0.65(m,3H).

[0214] Step 4: To a solution of compound 5d (109.96 mg, 566.11 μmol, 10.0 equivalents; for the preparation of compound 5d, refer to WO2022256842A1, pages 110-113), compound 5c (20.0 mg, 56.61 μmol, 1.0 equivalents) and N-methylimidazole (46.48 mg, 566.11 μmol, 10.0 equivalents) in acetonitrile (4.0 mL) was added in batches of N, N, N', N'-tetramethylchloroformamidine hexafluorophosphate (31.77 mg, 113.22 μmol, 2.0 equivalents), and the reaction mixture was stirred at 20 ° C for 16 hours. LCMS detection showed that the product was generated, and then 50.0 mL of water was added to the reaction solution, the pH was adjusted to 7-8 with dilute hydrochloric acid, and extracted three times with ethyl acetate (100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum, and the residue was purified by prep-HPLC (column model: Welch Xtimate C18 250*30mm*10um; mobile phase: water (0.05% HCl)-ACN; gradient: 50%-80% over 15 minutes; flow rate: 40 mL / min) to obtain compound 5e (20.0 mg, 66.7% yield) as a white solid.

[0215] MS (ESI): m / z calculated [M+H + ]:530.20, measured value:530.2;

[0216] Step 5: At 20 ° C, to a solution of compound 5d (20 mg, 37.02 μmol, 1.0 equivalent) in dichloromethane (1.0 mL) was added TFA (84.41 mg, 740.31 μmol, 20 equivalents), and the reaction mixture was stirred at 20 ° C for 16 hours. LCMS detection showed that the reaction was complete, and the reaction solution was concentrated to dryness under vacuum. After adding a small amount of methanol to dissolve the residue, the pH value was adjusted to 8 with saturated sodium bicarbonate solution, and the resulting solution was purified by RP-TLC (C18, ACN:H2O=3:1) to give white solid compound 5 (5.00 mg 27.6% yield).

[0217] MS (ESI): m / z calculated [M+H + ]:490.17, measured value:490.2;

[0218] 1H NMR (400MHz, chloroform-d) δ9.06 (s, 1H), 8.55 (d, J = 2.4Hz, 1H), 8.11 (dd, J = 8.5, 2.4Hz, 1H), 7.3 1(d,J=8.5Hz,1H),7.11(t,J=7.3Hz,1H),6.90(q,J=8.8Hz,1H),4.79(t,J=4.8Hz,1H),4. 41(d,J=10.5Hz,1H),4.07-3.99(m,1H),3.95(d,J=2.6Hz,3H),3.89(dd,J=11.4,3.8Hz, 1H), 3.73 (dd, J=11.3, 5.6Hz, 1H), 2.60 (d, J=7.8Hz, 1H), 1.59 (s, 3H), 0.79-0.68 (m, 3H).

[0219] Example 4: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-nitrogen-(6-((S)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxamide (6):

[0220] Step 1: To a solution of compound 6d (109.96 mg, 566.11 μmol, 10.0 equivalents; for the preparation of compound 6d, refer to WO2022256842A1, pages 110-113), compound 5c (20.0 mg, 56.61 μmol, 1.0 equivalents) and N-methylimidazole (46.48 mg, 566.11 μmol, 10.0 equivalents) in acetonitrile (4.0 mL) was added in batches of N, N, N', N'-tetramethylchloroformamidine hexafluorophosphate (31.77 mg, 113.22 μmol, 2.0 equivalents), and the reaction mixture was stirred at 20 ° C for 16 hours. LCMS detection showed that the product was generated, and then 50.0 mL of water was added to the reaction solution, the pH was adjusted to 7-8 with dilute hydrochloric acid, and extracted three times with ethyl acetate (100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum, and the residue was purified by prep-HPLC (column model: Welch Xtimate C18 250*30mm*10um; mobile phase: water (0.05% HCl)-ACN; gradient: 50%-80% over 15 minutes; flow rate: 40 mL / min) to obtain compound 6a (14.2 mg, 47.3% yield) as a white solid.

[0221] MS (ESI): m / z calculated [M+H + ]:530.20, measured value:530.2;

[0222] Step 2: At 20 ° C, TFA (61.15 mg, 536.34 μmol, 20 equivalents) was added to a solution of compound 6a (14.2 mg, 26.82 μmol, 1.0 equivalent) in dichloromethane (0.7 mL), and the reaction mixture was stirred at 20 ° C for 16 hours. LCMS detection showed that the reaction was complete, and the reaction solution was concentrated to dryness under vacuum. After adding a small amount of methanol to dissolve the residue, the pH value was adjusted to 8 with saturated sodium bicarbonate solution, and the resulting solution was purified by RP-TLC (C18, ACN:H2O=3:1) to give a white solid compound 6 (3.50 mg, 26.7% yield).

[0223] MS (ESI): m / z calculated [M+H + ]:490.17, measured value:490.2;

[0224] 1 H NMR (400MHz, chloroform-d) δ9.03 (s, 1H), 8.55 (d, J = 2.5Hz, 1H), 8.12 (dd, J = 8.6, 2.5Hz, 1H), 7.31 ( d,J=8.6Hz,1H),7.11(t,J=7.3Hz,1H),6.91(q,J=8.8Hz,1H),4.79(t,J=4.7Hz,1H),4.41( d,J=10.5Hz,1H),4.02(t,J=9.5Hz,1H),3.95(d,J=2.6Hz,3H),3.90(dd,J=11.3,3.8Hz,1H ),3.74(dd,J=11.3,5.6Hz,1H),2.59(t,J=7.9Hz,1H),1.59(s,3H),0.74(d,J=6.7Hz,3H).

[0225] Example 5: Synthesis of 3-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxamido)pyridine 1-oxide (7):

[0226] Step 1: To a solution of 3-aminopyridine N-oxide hydrochloride 7a (165.95 mg, 1.13 mmol, 20.0 equiv), compound 5c (20.0 mg, 56.61 μmol, 1.0 equiv) and N-methylimidazole (139.43 mg, 1.70 mmol, 30.0 equiv) in acetonitrile (4.0 mL) was added portionwise N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (31.77 mg, 113.22 μmol, 2.0 equiv). The reaction mixture was stirred at 20°C for 16 hours. LCMS analysis showed the formation of the product. 50.0 mL of water was then added to the reaction solution, the pH was adjusted to 7-8 with dilute hydrochloric acid, and the mixture was extracted three times with ethyl acetate (100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum, and the residue was purified by prep-HPLC (column model: Welch Xtimate C18 250*30mm*10um; mobile phase: water (0.05% HCl)-ACN; gradient: 30%-60% over 15 minutes; flow rate: 40 mL / min) to obtain compound 7 (11.0 mg, 43.63% yield) as a white solid.

[0227] MS (ESI): m / z calculated [M+H + ]:446.14, measured value:446.1;

[0228] 1 H NMR (400MHz, DMSO-d6) δ10.72(s,1H),8.74(t,J=1.8Hz,1H),8.04(ddd,J=6.4,1.8,0.9Hz,1H),7.53(ddd,J=8.6,1.9,0.9Hz,1H),7.41(dd,J=8.5,6.3 Hz,1H),7.26-7.10(m,2H),4.25(d,J=8.3Hz,1H),3.96(d,J=8.2Hz,1H),3. 91(d,J=1.9Hz,3H),2.58(q,J=7.5Hz,1H),1.52(s,3H),0.72-0.61(m,3H).

[0229] Example 6: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-nitrogen-(3-aminosulfonylphenyl)-5-(trifluoromethyl)pyrrolidine-2-carboxamide (8):

[0230] Step 1: To a solution of 3-aminobenzenesulfonamide (97.48 mg, 566.11 μmol, 10.0 equiv), compound 5c (20.0 mg, 56.61 μmol, 1.0 equiv) and N-methylimidazole (46.48 mg, 566.11 μmol, 10.0 equiv) in acetonitrile (5.0 mL) was added portionwise N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (31.77 mg, 113.22 μmol, 2.0 equiv). The reaction mixture was stirred at 20°C for 16 hours. LCMS analysis showed the formation of the product. 50.0 mL of water was then added to the reaction solution, the pH was adjusted to 7-8 with dilute hydrochloric acid, and the mixture was extracted three times with ethyl acetate (100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum, and the residue was purified by prep-HPLC (column model: Welch Xtimate C18 250*30mm*10um; mobile phase: water (0.05% HCl)-ACN; gradient: 30%-60%, 15 minutes; flow rate: 40 mL / min) to obtain white solid compound 8 (4.50 mg, 15.66% yield).

[0231] MS (ESI): m / z calculated [M+H + ]:508.13, measured value:508.3;

[0232] 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),8.17(s,1H),7.72(dt,J=6.8,2.3Hz,1H),7.55-7.44(m,2H),7.36(s,2H),7.29-7.10(m, 2H), 4.26 (d, J = 8.8Hz, 1H), 3.96 (t, J = 8.4Hz, 1H), 3.91 (d, J = 2.1Hz, 3H), 2.58 (q, J = 7.4Hz, 1H), 1.53 (s, 3H), 0.75-0.63 (m, 3H).

[0233] Example 7: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-nitrogen-(2-aminosulfonylpyridin-4-yl)-5-(trifluoromethyl)pyrrolidine-2-carboxamide (9):

[0234] Step 1: To a solution of 4-amino-2-pyridinesulfonamide hydrochloride (118.68 mg, 566.11 μmol, 10.0 equiv; the synthesis of compound 2 is described in J. Med. Chem. 1980, 23, 12, 1376-1380), compound 5c (20.0 mg, 56.61 μmol, 1.0 equiv) and N-methylimidazole (92.95 mg, 1.13 mmol, 20.0 equiv) in N,N-dimethylformamide (3.0 mL) was added acetonitrile (1.0 mL), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (31.77 mg, 113.22 μmol, 2.0 equiv) was added portionwise. The reaction mixture was stirred at 20°C for 16 hours. LCMS analysis showed the formation of the product. 50.0 mL of water was then added to the reaction solution, the pH was adjusted to 7-8 with dilute hydrochloric acid, and the mixture was extracted three times with ethyl acetate (100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum, and the residue was purified by prep-HPLC (column model: Welch Xtimate C18 250*30mm*10um; mobile phase: water (0.05% HCl)-ACN; gradient: 20-50% over 15 minutes; flow rate: 40 mL / min) to obtain compound 9 as a white solid (9.30 mg, 32.31% yield).

[0235] MS (ESI): m / z calculated [M+H + ]:509.12, measured value:509.2;

[0236] 1 H NMR(400MHz,DMSO-d6+drop D2O) δ7.97(d,J=6.8Hz,1H),7.23-7.14(m,2H),7.13(d,J=2.5Hz,1H),6.77(dd,J=6.8,2.5Hz,1H),4.34(d,J=9.7 Hz,1H),4.02(dd,J=9.8,7.6Hz,1H),3.90(d,J=1.8Hz,3H),2.59(q,J=7.4Hz,1H),1.58(s,3H),0.71-0.57(m,3H).

[0237] Example 8: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-nitrogen-(4-fluoro-3-(nitrogen-hydroxycarbamimidoyl)phenyl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxamide hydrochloride (10):

[0238] Step 1: To a solution of 4-amino-2-fluorobenzonitrile 10c (963.3 mg, 7.8 mmol, 50.0 equiv), compound 5c (50.0 mg, 141.53 μmol, 1.0 equiv) and N-methylimidazole (116.19 mg, 1.42 mmol, 10.0 equiv) in acetonitrile (5.0 mL) was added portionwise N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (79.42 mg, 283.05 μmol, 2.0 equiv). The reaction mixture was stirred at 20°C for 16 hours. LCMS analysis showed the formation of the product. 50.0 mL of water was then added to the reaction solution, the pH was adjusted to 6-7 with dilute hydrochloric acid, and the mixture was extracted three times with ethyl acetate (100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum, and the residue was purified by prep-HPLC (column model: Welch Xtimate C18 250*30mm*10um; mobile phase: water (0.05% HCl)-ACN; gradient: 50%-80% over 15 minutes; flow rate: 40 mL / min) to obtain compound 10a (35.0 mg, 52.46% yield) as a white solid.

[0239] MS (ESI): m / z calculated [M+H + ]:472.14, measured value:472.2;

[0240] Step 2: Compound 10a (35.0 mg, 74.25 μmol, 1.0 equivalent), hydroxylamine hydrochloride (15.48 mg, 222.74 μmol, 3.0 equivalent) and triethylamine (67.62 mg, 668.22 μmol, 9.0 equivalent) were added to ethanol (0.5 mL) and heated under reflux for 2 hours. LCMS detection showed that the reaction was complete, and the reaction solution was concentrated to dryness under vacuum. After adding a small amount of methanol to dissolve the residue, the pH value was adjusted to 3 with dilute hydrochloric acid. The resulting solution was purified by prep-HPLC (column model: YMC-Triart Prep C18 150*30mm*10um; mobile phase: water (0.05% HCl)-ACN; gradient: 30%-60%, 15 minutes; flow rate: 40 mL / min) to obtain white solid compound 10 (19.7 mg, 52.60% yield).

[0241] MS (ESI): m / z calculated [M+H + ]:505.16, measured value:505.3;

[0242] 1H NMR(400MHz,DMSO-d6)δ13.03(s,1H),11.44(s,1H),10.90(s,1H),9.29(s,H),7.96 (dd,J=6.1,2.7Hz,1H),7.87(ddd,J=9.1,4.6,2.7Hz,1H),7.44(t,J=9.3z,1H),7.3 7-7.29(m,1H),7.14(td,J=9.4,7.8Hz,1H),4.37(d,J=9.1Hz,1H),3.97(t,J=8.5Hz ,1H),3.91(d,J=2.0Hz,3H),2.58(q,J=7.6Hz,1H),1.55(s,3H),0.77-0.57(m,3H).

[0243] Example 9: Synthesis of 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxamido)picolinamide (11):

[0244] Step 1: Boron tribromide (0.42 mL, 424.58 μmol, 3.0 eq., 1 mol / L in dichloromethane) was added dropwise to a solution of compound 5c (50.0 mg, 141.53 μmol, 1.0 eq.) in dichloromethane (0.2 mL) at 0°C. The reaction mixture was naturally warmed to 20°C and stirred for 16 hours. LCMS analysis indicated the formation of the product. The reaction solution was concentrated under vacuum to dryness, and the residue was purified by prep-HPLC (column model: Synergi Max-RP 250*40 mm*10 μm; mobile phase: water (0.05% HCl)-ACN; gradient: 30%-60% over 15 minutes; flow rate: 60 mL / min) to afford compound 11a (25.0 mg, 52.07% yield) as a white solid.

[0245] MS (ESI): m / z calculated [M+H + ]:340.09, measured value:340.2;

[0246] Step 2: Compound 11a (25.0 mg, 73.69 μmol, 1.0 equivalent) and potassium carbonate (30.55 mg, 221.07 μmol, 3.0 equivalent) were stirred at room temperature in N,N-dimethylformamide (0.3 mL) for 30 minutes, and deuterated iodomethane (26.71 mg, 184.22 μmol, 2.5 equivalents) was added thereto, and then stirring was continued at room temperature for 3 hours. LCMS detection showed that the starting material was consumed. Potassium hydroxide (0.37 mL, 1.11 mmol, 15.0 equivalents, 3 mol / L aqueous solution) was added to the reaction mixture, and the temperature was raised to 50°C and stirring was continued for 2 hours. LCMS detection showed that the hydrolysis was complete. The reaction solution was cooled to 5°C and the pH was adjusted to 2 with dilute hydrochloric acid. The mixture was then extracted three times with ethyl acetate (5.0 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (column model: Welch Xtimate C18 250*30mm*10um; mobile phase: water (0.05% HCl)-ACN; gradient: 30%-60% over 15 minutes; flow rate: 40 mL / min) to obtain compound 11b as a white solid (15.0 mg, 57.13% yield).

[0247] MS (ESI): m / z calculated [M+H + ]:357.12, measured value:357.2;

[0248] 1 H NMR (400MHz, DMSO-d6) δ7.26-7.21(m,1H),7.19-7.08(m,1H),4.26(d,J=9.3Hz ,1H),3.93(t,J=8.6Hz,1H),2.55-2.51(m,1H),1.51(s,3H),0.79-0.57(m,3H).

[0249] Step 3: To a solution of methyl 4-aminopyridine-2-carboxylate (222.05 mg, 1.46 mmol, 40.0 equiv), compound 11b (13.0 mg, 36.49 μmol, 1.0 equiv) and N-methylimidazole (29.95 mg, 364.85 μmol, 10.0 equiv) in acetonitrile (2.0 mL) was added portionwise N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (20.47 mg, 72.97 μmol, 2.0 equiv). The reaction mixture was stirred at 20° C. for 16 hours. LCMS analysis showed that the starting material was consumed. 100.0 mL of water was added to the reaction solution, the pH was adjusted to 7-8 with dilute hydrochloric acid, and then extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (column model: Welch Xtimate C18 250*30mm*10um; mobile phase: water (0.05% HCl)-ACN; gradient: 30%-60% over 15 minutes; flow rate: 40 mL / min) to obtain compound 11c (2.8 mg, 15.65% yield) as a white solid.

[0250] MS (ESI): m / z calculated [M+H + ]:491.17, measured value:491.2;

[0251] Step 4: Compound 11c (2.80 mg, 5.71 μmol, 1.0 equivalent) was dissolved in 7 M NH3 / MeOH solution (2.0 mL) and stirred at 20°C for 16 hours. LCMS analysis showed that the starting material was completely consumed. The reaction solution was concentrated under vacuum and the residue was analyzed by RP-TLC (C18, ACN:0.5% HCl = 3:1, R f =0.5) to give white solid compound 11 (0.82 mg, 30.21% yield).

[0252] MS (ESI): m / z calculated [M+H + ]:476.17, measured value:476.2;

[0253] 1H NMR (400MHz, methanol-d4) δ8.40(d,J=5.5Hz,1H),8.12(d,J=2.1Hz,1H),7.78(dd,J=5.5,2.1Hz,1H),7.18-7.09(m,1H),6.96-6 .85(m,1H),4.24(d,J=9.8Hz,1H),4.03(t,J=9.1Hz,1H),2.56(p,J=8.1Hz,1H),1.52(s,3H),0.70(dt,J=7.4,2.5Hz,3H).

[0254] Example 10: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(2-(methylsulfonyl)pyridin-4-yl)-5-(trifluoromethyl)pyrrolidine-2-carboxamide (12):

[0255] Step 1: At room temperature, m-chloroperbenzoic acid (1.86 mg, 9.15 mmol, 3.0 equiv) was added in portions to a solution of 2-(methylthio)-4-aminopyridine 12a (450.0 mg, 3.05 mmol, 1.0 equiv) in tetrahydrofuran (10.0 mL). The reaction mixture was stirred at 20 ° C for 3 hours. LCMS detection showed that the reaction was complete. The reaction solution was directly wet-loaded and purified by silica gel column (100% ethyl acetate, R f =0.5) and purified to give yellow solid compound 12b (380.0 mg, 72.37% yield).

[0256] MS (ESI): m / z calculated [M+H + ]:173.03, measured value:172.9;

[0257] 1 H NMR (400MHz, DMSO-d6) δ8.10(d,J=5.6Hz,1H),7.14(d,J=2.3Hz,1H),6.72(s,2H),6.66(dd,J=5.6,2.3Hz,1H),3.15(s,3H).

[0258] Step 2: To a solution of compound 12b (341.19 mg, 1.98 mmol, 20.0 equiv), compound 5c (35.0 mg, 99.07 μmol, 1.0 equiv) and N-methylimidazole (162.67 mg, 1.98 mmol, 2.0 equiv) in acetonitrile (2.0 mL) was added portionwise N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (55.59 mg, 198.14 μmol, 2.0 equiv). The reaction mixture was stirred at 20°C for 16 hours. LCMS analysis showed the formation of the product. 50.0 mL of water was then added to the reaction solution, the pH was adjusted to 7-8 with dilute hydrochloric acid, and then extracted three times with ethyl acetate (30.0 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum, and the residue was purified by prep-HPLC (column model: Welch Xtimate C18 250*30mm*10um; mobile phase: water (0.05% HCl)-ACN; gradient: 50%-80% over 15 minutes; flow rate: 40 mL / min) to obtain compound 12 (2.14 mg, 4.26% yield) as a white solid.

[0259] MS (ESI): m / z calculated [M+H + ]:508.13, measured value:508.1;

[0260] 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),8.62(d,J=5.5Hz,1H),8.36(s,1H),7.84(d,J=6.8Hz,1H),7.24-7.14(m,2H),4.3 0(d,J=7.5Hz,1H),3.99(t,J=8.2Hz,1H),3.91(s,3H),3.24(s,3H),2.62-2.55(m,1H),1.53(s,3H),0.82-0.57(m,3H).

[0261] Example 11: Synthesis of 4-((2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxamido)picolinamide (13):

[0262] Step 1: To a solution of compound 11a (26.0 mg, 76.64 mmol, 1.0 equiv) in dichloromethane (2.0 mL) was added a 3 mol / L aqueous solution of KOH (0.072 mL, 1.15 mmol, 15.0 equiv). After cooling to zero degrees, difluorobromomethyltrimethylsilane (63.53 mg, 98% purity, 306.55 μmol, 4.0 equiv) was added. The reaction mixture was naturally warmed to 20°C and stirred for 16 hours. The dichloromethane was then evaporated to dryness under reduced pressure, and 1,4-dioxane (1.0 mL) and 6 mol / L aqueous hydrochloric acid (1.0 mL) were added to the residue. The resulting mixture was heated to 60°C and stirred for 16 hours. LCMS analysis showed that most of the product was converted. The reaction mixture was concentrated to dryness under vacuum, and the residue was purified by prep-HPLC (column model: Welch Xtimate C18 150*30mm*10um; mobile phase: water (0.05% HCl)-ACN; gradient: 30%-60%, 15 minutes; flow rate: 40 mL / min) to obtain white solid compound 13a (12.0 mg, 40.22% yield).

[0263] MS (ESI): m / z calculated [M+H + ]:390.09, measured value:390.1;

[0264] 1 H NMR(400MHz,DMSO-d6)δ12.77(s,1H),7.48-7.33(m,2H),7.26(s,0.6H),7.08(s,0.4H),4.22( d,J=9.3Hz,1H),3.90(t,J=8.6Hz,1H),2.48(d,J=7.5Hz,1H),1.47(s,3H),0.81-0.61(m,3H).

[0265] Step 2: To a solution of methyl 4-aminopyridine-2-carboxylate (143.58 mg, 924.81 μmol, 30.0 equiv), compound 13a (12.0 mg, 30.83 μmol, 1.0 equiv) and N-methylimidazole (51.13 mg, 616.54 μmol, 20.0 equiv) in acetonitrile (1.0 mL) was added portionwise N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (17.65 mg, 61.65 μmol, 2.0 equiv). The reaction mixture was stirred at 20° C. for 16 hours. LCMS analysis showed product formation, and then 50.0 mL of water was added to the reaction solution. The pH was adjusted to 7-8 with dilute hydrochloric acid, and then extracted three times with ethyl acetate (30.0 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum, and the residue was purified by prep-HPLC (column model: Welch Xtimate C18 250*30mm*10um; mobile phase: water (0.05% HCl)-ACN; gradient: 30%-60% over 15 minutes; flow rate: 40 mL / min) to obtain compound 13b (8.0 mg, 49.58% yield) as a white solid.

[0266] MS (ESI): m / z calculated [M+H + ]:524.13, measured value:524.1;

[0267] Step 3: Compound 13b (8.0 mg, 15.28 μmol, 1.0 equivalent) was dissolved in 7 M NH3 / MeOH solution (1.0 mL) and stirred at 20°C for 16 hours. LCMS analysis showed that the starting material was completely consumed. The reaction solution was concentrated under vacuum and the residue was analyzed by RP-TLC (C18, ACN:0.5% HCl = 3:1, R f =0.5) to give white solid compound 13 (1.80 mg, 23.2% yield).

[0268] MS (ESI): m / z calculated [M+H + ]:509.13, measured value:509.2;

[0269] 1 H NMR (400 MHz, methanol-d4) δ 8.71-8.54 (m, 2H), 8.21 (dd, J = 6.4, 2.4 Hz, 1H), 7.47-7.22 (m, 2H), 6.91 (t, J = 72.8 Hz, 1H), 4.51 (d, J = 9.1 Hz, 1H), 4.24 (t, J = 8.9 Hz, 1H), 2.71 (q, J = 7.6 Hz, 1H), 1.63 (s, 3H), 0.93-0.77 (m, 3H).

[0270] Example 12: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-N-(4-fluoro-3-(N-hydroxyaminocarboximidoyl)phenyl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxamide (14):

[0271] Step 1: Under ice bath conditions, to a solution of acetonitrile (120.0 mL) containing N-hydroxysuccinimide (3.96 g, 98% purity, 33.68 mmol, 1.5 equivalents, Bid's reagent), compound 11b (8.0 g, 22.45 mmol, 1.0 equivalents) and N-methylimidazole (5.64 g, 98% purity, 67.36 mmol, 3.0 equivalents), N, N, N', N'-tetramethylchloroformamidine hexafluorophosphate (9.64 g, 98% purity, 33.68 mmol, 1.5 equivalents) was added in batches. The addition process was exothermic. After addition, the system automatically warmed to room temperature, and the reaction mixture was stirred at room temperature for 2 hours. LCMS detection showed that the raw material was completely consumed. 500.0 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (150.0 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by normal phase silica gel column (petroleum ether:ethyl acetate = 5:1) to give compound 14a (8.6 g, 84.48% yield) as a white solid.

[0272] MS(ESI):m / z Calcd.for[M+H + ]:454.14,found:454.2;

[0273] Step 2: Compound 14a (50.0 mg, 0.11 mmol, 1.0 equiv) was dissolved in tetrahydrofuran (1.0 mL), and 2-fluoro-5-aminobenzonitrile (74.87 mg, 0.55 mmol, 5.0 equiv) was added. The reaction mixture was heated to 70°C and stirred for 16 hours. LC-MS analysis showed that most of the starting material had been consumed. The reaction solution was concentrated under vacuum, and the residue was purified on a normal phase silica gel column (petroleum ether:ethyl acetate = 2:1) to afford compound 14b (20.0 mg, 38.23% yield) as a white solid.

[0274] MS(ESI):m / z Calcd.for[M+H + ]:475.16,found:474.7;

[0275] Step 3: Compound 14b (20.0 mg, 42.16 μmol, 1.0 eq) was added to a solution of hydroxylamine hydrochloride (14.59 mg, 210.00 μmol, 5.0 eq) and N,N-diisopropylethylamine (27.14 mg, 210.00 μmol, 5.0 eq) in methanol (1.0 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction solution was concentrated under vacuum, and the residue was purified by prep-HPLC (column model: Welch Xtimate C18, 21.2*150 mm, 5 μm; mobile phase: Water (0.1% FA)-ACN; gradient: 45%-65% over 13 minutes; flow rate: 15 mL / min) to obtain compound 14 (17.6 mg, 82.3% yield) as a white solid.

[0276] MS(ESI):m / z Calcd.for[M+H + ]:508.18,found:508.44;

[0277] 1 H NMR(400MHz,DMSO-d6)δ10.26(s,1H),9.61(s,1H),7.71(dd,J=6.5,2.8Hz,1H),7 .61(ddd,J=8.9,4.4,2.8Hz,1H),7.29-7.08(m,3H),5.77(s,2H),4.20(dd,J=8.9, 6.3Hz,1H),3.93(t,J=8.5Hz,1H),3.01(d,J=6.3Hz,1H),2.57(q,J=7.6Hz,1H),1.52(s,3H),0.80-0.60(m,3H).

[0278] Example 13: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-N-(2-(N-methoxycarbamoyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxamide (15):

[0279] Step 1: Compound 1 (50 mg, 419.74 μmol, 1.0 equiv) and thioglycolic acid (38.69 mg, 419.74 μmol, 1.0 equiv) were added to methylhydroxylamine hydrochloride 15a (70.16 mg, 840.04 μmol, 2.0 equiv) and triethylamine (127.50 mg, 1.26 mmol, 3.0 equiv) in ethanol (1.0 mL). The reaction mixture was stirred at 65°C for 16 hours. LCMS analysis showed that most of the starting material had been consumed and the product was generated. The reaction solution was concentrated under vacuum and the residue was purified on a normal phase silica gel column (petroleum ether:ethyl acetate = 1:1, 0.5% 7 M ammonia in methanol) to afford compound 15b (55.0 mg, 78.85% yield) as a white solid.

[0280] MS(ESI):m / z Calcd.for[M+H + ]:167.09,found:167.1;

[0281] Step 2: Compound 15b (45.70 mg, 275.00 μmol, 5.0 equivalents) and compound 14a (25 mg, 55.14 μmol, 1.0 equivalents) were dissolved in dimethyl sulfoxide (1.0 mL), and the reaction mixture was stirred at 100°C for 16 hours. LC-MS monitoring showed that compound 14a was almost completely consumed and product was generated. 5 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate (8 mL*5). The organic phases were combined, dried over saturated brine, and the solvent was removed under reduced pressure. The residue was purified by prep-HPLC (column model: Welch Xtimate C18, 21.2*150 mm, 5 μm; mobile phase: Water (0.1% FA)-ACN; gradient: 55%-80% over 13 minutes; flow rate: 15 mL / minute) to obtain compound 15 as a white solid (0.75 mg, 2.70% yield).

[0282] MS(ESI):m / z Calcd.for[M+H + ]:505.20,found:505.49;

[0283] 1H NMR (400MHz, DMSO-d6) δ10.62(s,1H),8.42(d,J=5.6Hz,1H),8.06(d,J=2.1Hz,1H),7.67(dd,J=5.6,2.1Hz,1H),7.25-7.08(m,2H),6.05(s,2H) ,4.23(dd,J=8.2,5.5Hz,1H),3.96(t,J=8.2Hz,1H),3.78(s,3H),3.22(d,J=5.5Hz,1H),2.59(q,J=7.7Hz,1H),1.53(s,3H),0.78-0.61(m,3H).

[0284] Example 14: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-N-(2-(N-hydroxycarbamoyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxamide (16):

[0285] Step 1: Compound 11 (100.0 mg, 0.21 mmol, 1.0 equiv) was dissolved in tetrahydrofuran (2.0 mL). The nitrogen atmosphere was replaced three times. Pyridine (156.14 mg, 1.97 mmol, 9.4 equiv) and trifluoroacetic anhydride (207.30 mg, 0.99 mmol, 4.7 equiv) were added sequentially at 0°C. The reaction mixture was stirred at 25°C for 3 hours. LC-MS analysis showed that the starting material was consumed. Water (5.0 mL) was added, and the mixture was extracted with ethyl acetate (10.0 mL*2). The mixture was washed with saturated brine (10.0 mL). The organic phases were combined, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified on a normal phase silica gel column (petroleum ether:ethyl acetate = 3:1) to obtain compound 16a (85.0 mg, 88.35% yield) as a yellow solid.

[0286] MS(ESI):m / z Calcd.for[M+H + ]:554.14,found:554.3;

[0287] Step 2: Compound 16a (50.0 mg, 90.35 μmol, 1.0 equiv) was added to hydroxylamine hydrochloride (62.54 mg, 900.00 μmol, 10.0 equiv) and N,N-diisopropylethylamine (109.29 mg, 1.08 mmol, 12.0 equiv) in methanol (1.0 mL). The reaction mixture was stirred at 25°C for 16 hours. LCMS analysis showed that most of the starting material had been consumed, and product was generated. The reaction solution was concentrated under vacuum, and the residue was purified on a normal phase silica gel column (petroleum ether:ethyl acetate = 2:1) to afford compound 16b (45 mg, 84.93% yield) as a white solid.

[0288] MS(ESI):m / z Calcd.for[M+H + ]:587.17,found:587.1;

[0289] Step 3: Compound 16b (30.0 mg, 51.16 μmol, 1.0 eq) was dissolved in methanol (1.0 mL), and sodium borohydride (17.36 mg, 459.00 μmol, 9 eq) was added portionwise. The reaction mixture was stirred at 25°C for 22 hours. LC-MS analysis indicated the formation of the product. The reaction solution was concentrated under vacuum, and the residue was purified by prep-HPLC (column model: Welch Xtimate C18, 21.2*150 mm, 5 μm; mobile phase: Water (0.1% FA)-ACN; gradient: 45%-65% over 13 minutes; flow rate: 15 mL / min) to afford compound 16 (7.48 mg, 29.81% yield) as a white solid.

[0290] MS(ESI):m / z Calcd.for[M+H + ]:491.18,found:491.37;

[0291] 1 H NMR (400MHz, DMSO-d6) δ10.59(s,1H),9.84(s,1H),8.40(d,J=5.6Hz,1H),8.11(d,J=2.1Hz,1H),7.59(dd,J=5.6,2.2Hz,1H),7.26-7.13(m,2H) ,5.78(s,2H),4.23(dd,J=8.1,5.4Hz,1H),3.95(t,J=8.1Hz,1H),3.22(d,J=5.4Hz,1H),2.64-2.54(m,1H),1.52(s,3H),0.69(d,J=7.5Hz,3H).

[0292] Example 15: Synthesis of 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-1-(2,2,2-trifluoroacetyl)-5-(trifluoromethyl)pyrrolidine-2-carboxamido)picolinamide (17):

[0293] Step 1: Compound 16a (50.0 mg, 90.35 μmol, 1.0 equiv) was dissolved in methanol (2 mL), and potassium carbonate (37.32 mg, 270 μmol, 3.0 equiv) and 30% hydrogen peroxide solution (290 mg, 2.60 mmol, 28.9 equiv) were added sequentially, and the mixture was stirred at 25°C for 16 hours. LCMS detection showed that the starting material was completely consumed. Ice water (5.0 mL) was added to the reaction system, and the methanol was spin-dried and extracted with ethyl acetate (15.0 mL*4). The organic phases were combined, dried over sodium sulfate, and concentrated under reduced pressure to give 45 mg of a crude product. The residue was purified by prep-HPLC (column model: Welch Xtimate C18, 21.2*150 mm, 5 um; mobile phase: Water (0.1% FA)-ACN; gradient: 60%-75%, 13 minutes; flow rate: 15 mL / minute) to give compound 17 (24.76 mg, 47.96% yield) as a white solid.

[0294] MS(ESI):m / z Calcd.for[M+H + ]:572.15,found:572.41;

[0295] 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),8.51(d,J=5.5Hz,1H),8.20(d,J=2.2Hz,1H),8.08(d,J=2.8Hz,1H),7.73-7.55(m,2H),7 .35-7.20(m,1H),7.02(s,1H),5.24(s,1H),4.08(dd,J=7.9,2.3Hz,1H),2.82(t,J=7.6Hz,1H),1.97(s,3H),1.03-0.83(m,3H).

[0296] Example 16: Synthesis of 2-carbamoyl-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxamido)pyridine 1-oxide (18):

[0297] Step 1: Compound 16a (200 mg, 361.39 μmol, 1.0 equiv) was dissolved in dichloromethane (4 mL), and m-chloroperbenzoic acid (497.01 mg, 2.88 mmol, 8.0 equiv) was added in two portions. The reaction mixture was stirred at 25°C for 3 days. LC-MS analysis indicated complete consumption of the starting material. 10.0 mL of water was added to the reaction solution, followed by three extractions with ethyl acetate (20.0 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified on a normal phase silica gel column (petroleum ether:ethyl acetate = 1:2) to afford compound 18a (110.0 mg, 53.5% yield) as a yellow solid.

[0298] MS(ESI):m / z Calcd.for[M+H + ]:470.14,found:570.0;

[0299] Step 2: Compound 18a (45 mg, 79.03 μmol, 1.0 equiv) was dissolved in methanol (2 mL). Potassium carbonate (32.76 mg, 237.00 μmol, 3.0 equiv) and 30% hydrogen peroxide solution (230 μL, 2.28 mmol, 28.9 equiv) were added sequentially under ice-cooling conditions. The reaction mixture was stirred at 25°C for 1 hour. LC-MS analysis indicated complete consumption of the starting material. 5.0 mL of water was added to the reaction solution, followed by extraction three times with ethyl acetate (10.0 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified on a normal phase silica gel column (petroleum ether:ethyl acetate = 1:4) to afford compound 18b (35.0 mg, 75.4% yield) as an off-white solid.

[0300] MS(ESI):m / z Calcd.for[M+H + ]:588.15,found:588.2;

[0301] Step 3: Compound 18b (27.00 mg, 45.96 μmol, 1.0 equiv) was dissolved in methanol (1 mL), and sodium borohydride (29.00 mg, 766.59 μmol, 16.7 equiv) was added in three portions. The reaction mixture was stirred at 25°C for 16 hours. LC-MS analysis indicated the formation of the product. The reaction solution was concentrated under vacuum, and the residue was purified by prep-HPLC (column model: Welch Xtimate C18, 21.2*150 mm, 5 μm; mobile phase: Water (0.1% FA)-ACN; gradient: 45%-60% over 13 minutes; flow rate: 15 mL / min) to afford compound 18 (2.31 mg, 10.23% yield) as a white solid.

[0302] MS(ESI):m / z Calcd.for[M+H + ]:492.17,found:492.38;

[0303] 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),10.64(d,J=4.6Hz,1H),8.48(d,J=3.2Hz,1H),8.30(d,J=7.2Hz,1H),8.23(d,J=4.7Hz,1H),7.83(dd,J= 7.1,3.3Hz,1H),7.24-7.10(m,2H),4.23(dd,J=8.1,5.1Hz,1H),3.97(t,J=8.1Hz,1H),2.59(q,J=7.6Hz,1H),1.52(s,3H),0.76-0.62(m,3H).

[0304] Example 17: Synthesis of 4-((2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)pyrrolidine-2-carboxamido)picolinamide (19):

[0305] Step 1: Compound 18a (60 mg, 105.37 μmol, 1.0 equiv) was added to a solution of hydroxylamine hydrochloride (76.44 mg, 1.10 mmol, 10.0 equiv) and triethylamine (133.57 mg, 1.32 mmol, 12.0 equiv) in methanol (1.0 mL). The reaction mixture was stirred at 25°C for 2 hours. LCMS analysis showed that most of the starting material had been consumed, and product was generated. The reaction solution was concentrated under vacuum, and the residue was purified on a normal phase silica gel column (dichloromethane:methanol = 20:1) to afford compound 19a (250 mg, crude) as a white solid.

[0306] MS(ESI):m / z Calcd.for[M+H + ]:603.16,found:603.2;

[0307] Step 2: Compound 19a (220.00 mg, crude product, 1.0 equivalent) was dissolved in methanol (5 mL), and sodium borohydride (839.83 mg, 22.20 mmol, 60.0 equivalent) was added in 8 batches. The reaction mixture was stirred at 25°C for 16 hours. LC-MS analysis showed the formation of the product. The reaction solution was concentrated under vacuum, 5.0 mL of water was added, and then extracted three times with ethyl acetate (10.0 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by prep-HPLC (column model: Welch Xtimate C18, 21.2*150 mm, 5 μm; mobile phase: Water (0.1% FA)-ACN; gradient: 40%-65% over 13 minutes; flow rate: 15 mL / minute) to obtain compound 19 as a white solid (12.21 mg, 6.60% yield).

[0308] MS(ESI):m / z Calcd.for[M+H + ]:507.19,found:507.40;

[0309] 1 H NMR (400MHz, DMSO-d6) δ10.71(s,1H),10.16(s,1H),8.21-8.07(m,2H),7.63(dd,J=7.2,3.2Hz,1H),7.16(dd,J=9.0,6.3Hz,2 H),6.80(s,2H),4.19(dd,J=7.9,5.2Hz,1H),3.95(t,J=8.1Hz,1H),3.27(d,J=5.2Hz,1H),2.59(q,J=7.7Hz,1H),1.51(s,3H), 0.79-0.59(m,3H).

[0310] Test Example:

[0311] 1. Inhibitory activity of the test compound on human NaV1.8

[0312] The manual patch clamp technique was used to detect the effect of the test substance on the stably overexpressed Nav1.8 channel current and determine its blocking activity on NaV1.8.

[0313] Cell culture

[0314] The experiment used a CHO cell line stably expressing the human Nav1.8 sodium channel. Gene information: Sodium channel, voltage-gated, type 8, alpha (SCN10A), cDNA strictly similar to GenBank accession number: NM_006514.

[0315] Cells were cultured in Ham's / F-12 medium supplemented with 10% fetal bovine serum, 10 μg / mL blasticidin, 200 μg / mL hygromycin B, and 100 μg / mL zeocin at 37°C in a 5% CO2 atmosphere. For expansion or maintenance, cells were treated with 0.25% trypsin-EDTA, washed, centrifuged, and seeded onto 6-cm culture dishes at a seeding density of 2.5 × 10 cells per dish. 5 To maintain the electrophysiological activity of the cells, the cell density should not exceed 80%.

[0316] Before patch clamp detection, cells were detached with 0.25%-Trypsin-EDTA and 6.5×10 3 Cells were plated on coverslips and cultured in 24-well plates (final volume: 500 μL) for 18 hours before testing.

[0317] 1.2 Electrophysiological recording

[0318] Extracellular fluid: K-007-1

[0319] 140 mM NaCl, 3.5 mM KCl, 1 mM MgCl2·6H2O, 2 mM CaCl2·2H2O, 10 mM D-Glucose, 10 mM HEPES, 1.25 mM NaH2PO4·2H2O, NaOH adjusted to pH = 7.4.

[0320] Intracellular fluid: Nav-001-2

[0321] 50 mM CsCl, 10 mM NaCl, 10 mM HEPES, 60 mM CsF, 20 mM EGTA, CsOH adjusted to pH = 7.2.

[0322] ●Instrument information is as follows Table 2:

[0323] Table 2: Instrument information

[0324] ●Patch clamp assay

[0325] Before measuring Nav1.8 channel currents, dilute the blank control solution (DMSO) into 10 ml of extracellular fluid as a working solution. The positive control and test substances were diluted with varying doses of DMSO according to their final concentrations and then diluted into extracellular fluid to prepare working solutions. 100 nM TTX was added to each working solution to block TTX-S currents. The working solutions were sonicated for 20 minutes before patch clamp testing.

[0326] The patch clamp procedure begins by pulling a recording electrode from a glass capillary using a microelectrode puller. The electrode, filled with intracellular fluid, is then placed in a microelectrode holder. Under an inverted microscope, the microelectrode manipulator is used to immerse the electrode in the extracellular fluid and record the electrode resistance (Rpip). The electrode is then slowly brought into contact with the cell surface, and negative pressure is applied to create a GΩ seal. Fast capacitance compensation is then performed, and negative pressure is continued to rupture the cell membrane, establishing whole-cell recording mode. Finally, slow capacitance compensation is performed, and experimental parameters such as series resistance (Rs) are recorded. No leakage compensation is performed.

[0327] When the Nav1.8 current recorded in the whole cell is stable, the drug is administered. Each drug concentration acts for about 5 minutes (or the current stabilizes) before the next concentration is detected. The coverslip with cells is placed in a recording bath under an inverted microscope. The blank control external solution and the working solution of the compound to be tested are passed through the recording bath in sequence from low concentration to high concentration by gravity perfusion to act on the cells. A peristaltic pump is used for liquid exchange during recording. The current detected for each cell in the external solution without the compound serves as its own control group. Each concentration is repeated 2-3 times independently. All electrophysiological experiments were performed at room temperature.

[0328] The voltage stimulation protocol for whole-cell patch-clamp recordings of Nav1.8 currents was as follows: after whole-cell seal formation, the voltage was clamped at -120 mV. Resting-state sodium current recordings were performed by maintaining the voltage for 5 s before depolarization to 0 mV. A depolarizing pulse (TP1) to 0 mV for 50 ms was then applied to measure resting-state sodium currents. Half-inactivated state recordings were performed by first applying different voltage steps for 5 s before applying a 0 mV depolarizing pulse to obtain the half-inactivation voltage (Vhalf). Vhalf was then maintained for 5 s before the voltage was returned to -120 mV and held for 20 ms. A depolarizing pulse (TP2) to 0 mV for 50 ms was then applied to measure half-inactivated sodium currents. Data were acquired using an EPC 10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.

[0329] 1.3 Data Analysis

[0330] First, the current after each drug concentration is normalized to the blank control current. Then calculate the inhibition rate corresponding to each drug concentration The mean (Mean), standard deviation (SD) and standard error (SE) of the inhibition rate at each concentration were calculated, and the data were expressed as mean ± SE. Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope))

[0331] The IC of each compound was calculated using the above equation 50 The concentration-effect curve was fitted nonlinearly, where IC 50 IC is the half inhibitory concentration. 50 The calculation and curve fitting were completed using GraphPadPrism software.

[0332] The blocking rate of the compounds of the present invention on NaV1.8 at a concentration of 10 nM is shown in Table 3 below:

[0333] Table 3

[0334] Conclusion: From the data in Table 3, it can be seen that the disclosed compounds have a significant inhibitory effect on human NaV1.8 channels.

[0335] 2. Stability of the compound in liver microsomes:

[0336] 2.1 Preparation of intermediate stock solution of test compound:

[0337] 2.1.1. Working solution: 5 μL of the test compound or control compound stock solution (10 mM DMSO solution) was diluted with 495 μL of acetonitrile (ACN) to obtain an intermediate stock solution (100 μM, 99% ACN).

[0338] 2.2. Preparation of NADPH coenzyme working solution:

[0339] 2.2.1. Materials: NADPH·4Na (supplier: BONTAC, Cat. No. BT04);

[0340] 2.2.2. Preparation process: Weigh an appropriate amount of NADPH powder and dilute it with 10mM MgCl2 buffer (working solution concentration: 10mM; final reaction system concentration: 1mM)

[0341] 2.3. Preparation of liver microsome working solution:

[0342] 2.3.1. Materials:

[0343] Table 4: Liver microsome information

[0344] 2.3.2. Preparation process: Prepare liver microsome working solution of appropriate concentration in 100 mM potassium phosphate buffer;

[0345] 2.4. Stop solution:

[0346] 4°C acetonitrile (ACN) solution containing 200 ng / mL tolbutamide and 200 ng / mL labetalol as internal standards

[0347] 2.5. Operation steps:

[0348] 2.5.1. Preheat empty T60 and NCF60 incubation plates for 10 minutes.

[0349] Dilute liver microsomes to a concentration of 0.56 mg / mL with 100 mM potassium phosphate buffer.

[0350] 2.5.3. Transfer 445 μL of liver microsome working solution (0.56 mg / mL) to preheated T60 and NCF60 plates. Preheat the T60 and NCF60 plates again at 37°C while shaking for 10 minutes. Transfer 54 μL of liver microsomes to each well of a blank plate, add 6 μL of NAPDH coenzyme solution to this blank plate, and finally transfer 180 μL of stop solution to this blank plate.

[0351] 2.5.4 Add 5 μL of compound working solution (100 μM) to the incubation plates T60 and NCF60 containing liver microsomes and mix three times.

[0352] 2.5.5. Add 50 μL of buffer to the NCF60 incubation plate and mix three times. Start the timer and incubate at 37°C for 60 min while shaking the incubation plate.

[0353] 2.5.6. Add 180 μL of quenching solution and 6 μL of NAPDH coenzyme working solution to the quenching plate T0 in sequence. Make sure the plate is cold to prevent the incubation solution from evaporating.

[0354] 2.5.7. For the T60 plate, mix thoroughly three times and immediately transfer 54 μL of the mixture (0-min time point) to the quenching plate T0, then add 44 μL of NAPDH coenzyme working solution to the incubation plate T60. Start timing:

[0355] Table 5: Final concentration of each component in the reaction solution

[0356] 2.5.8. At the 5, 15, 30, 45, and 60 minute time points, add 180 μL of quenching solution to the quenching plate. At each time point, transfer 60 μL of the reaction solution from the T60 plate to the quenching plate.

[0357] Table 6: Reaction solution incubation time

[0358] 2.5.9. For NCF60 plates, mix thoroughly and at 60 minutes, transfer 60 μL of the reaction solution from the NCF60 incubation solution to the quenching plate containing 180 μL of quenching solution.

[0359] Table 7: NCF60 incubation

[0360] 2.5.10. All sample plates were mixed on a shaker for 10 min and then centrifuged at 4000 rpm at 4°C for 20 min.

[0361] 2.5.11. Transfer 80 μL of supernatant to 240 μL of HPLC water and mix on a shaker for 10 minutes.

[0362] 2.5.12. Seal each sample to be analyzed and mix it on a shaker for 10 minutes before injecting it into the LC-MS / MS for analysis.

[0363] 2.6 Data Analysis

[0364] 2.6.1. Calculation of t based on first-order elimination kinetics 1 / 2 and Clint(mic) value:

[0365] The first-order elimination kinetic equation is:

[0366] when

[0367] Table 8: Liver microsome stability results of some compounds:

[0368] The reference compound VX-548 (synthesized with reference to Example 7 of WO2021113627A1) has the following structural formula:

[0369] Conclusion: From the data in Table 8, it can be seen that the compounds of the present invention have good liver microsome stability.

[0370] 3. Human liver microsomal cytochrome CYP inhibition experiment:

[0371] 3.1 Buffer solution: (1) potassium phosphate, 100 mM; (2) magnesium chloride, 33 mM;

[0372] 3.2. Compounds:

[0373] 3.2.1 Substrate stock solution:

[0374] 3.2.2 Standard inhibitor stock solution:

[0375] 3.2.3 Stock solution of test compound: Dissolve the test compound in DMSO to form a 10 mM DMSO solution.

[0376] 3.3 Preparation of test compound and positive reference compound solutions:

[0377] Prepare the test compound working solution (100× final concentration).

[0378] 3.3.2. Preparation of positive reference compound working solution (100× final concentration)

[0379] 3.3.3. Preparation of substrate solution (10× final concentration)

[0380] 3.4. Preparation of human liver microsome mixture:

[0381] 3.4.1. Preparation of human liver microsome working solution (1.27×) (final concentration: 0.2 mg / mL)

[0382] 3.5 Test method:

[0383] 3.5.1 Prepare the test compound and positive reference working solution (100×);

[0384] 3.5.2 Remove liver microsomes from the -80°C freezer and thaw on ice;

[0385] 3.5.3 Add 20 μL of substrate solution to the corresponding wells and 20 μL of potassium phosphate buffer to the blank wells;

[0386] 3.5.4 Add 2 μL of target compound (final concentration ranges from 0.05 μM to 50 μM, 7 concentrations in total) or standard inhibitor to each well. Add 2 μL of methanol solution to non-inhibitory wells and blank wells.

[0387] 3.5.5 Add 1.012 mL of liver microsomes to 78.988 mL of potassium phosphate buffer, then add 158 μL of liver microsome solution to all wells. Preheat the plate in a 37°C water bath for 10 minutes.

[0388] 3.5.6 Weigh 129.1 mg of NADPH (purchased from SyncoZymes Co., Ltd.) and add it to 15.0 mL of 33 mM MgCl2 solution to a concentration of 10 mM. Add 20 μL to each well.

[0389] 3.5.7 Mix wells and incubate the plate in a 37°C water bath for 10 minutes, then add 400 μL of cold stop solution at appropriate time points.

[0390] 3.5.8 Centrifuge the sample at 4000 rpm for 20 minutes to precipitate the protein. Transfer 200 μL of the supernatant to 100 μL of HPLC water and shake for 10 minutes. Analyze the sample by LC / MS / MS.

[0391] 3.6 Data Analysis

[0392] Use XL Fit or SigmaPlot to plot the percentage inhibition of blank control and target compound at different concentrations, and perform nonlinear regression analysis on the data. 50 The values ​​were determined using a 3-parameter or 4-parameter logistic equation. When the percentage inhibition at the highest concentration (50 μM) was less than 50%, the IC 50 Values ​​are reported as ">50 μM;

[0393] The equation of the parametric logistic S-shaped curve is:

[0394] The equation of the 4-parameter logistic S-shaped curve is:

[0395] Table 9: Human liver microsome CYP inhibition test data of some compounds

[0396] Conclusion: From the data in Table 9, it can be seen that the compounds of the present invention have weak CYP inhibition. Some example compounds, such as Examples 8 and 11, have weaker inhibition on CYP2C19 than VX-548, indicating that these example compounds have better drug-drug interaction safety.

[0397] 4. Pharmacokinetic experiments:

[0398] 4.1 Rat Experiment

[0399] 4.1.1 Summary: SD rats were used as test animals. The drug concentrations in the plasma of rats at different times after oral administration of the example compounds were determined by LC / MS / MS. The pharmacokinetic behavior of the compounds of the present invention in rats was studied and their pharmacokinetic characteristics were evaluated.

[0400] 4.1.2, Test Plan:

[0401] 4.1.2.1 Test drugs: Compound 11 and reference substance VX-548

[0402] 4.1.2.2 Experimental Animals: 6 male SD rats and 6 female rats, all provided by Shanghai Jihui Experimental Animal Breeding Co., Ltd. The animals were fasted for at least 12 hours before administration and resumed feeding 4 hours after administration.

[0403] 4.1.2.3 Drug preparation: Weigh a certain amount of the test compound and prepare a completely clear solution with a final concentration of 1 mg / mL using a mixed solvent of DMSO:Solutol:normal saline (5%:5%:90%).

[0404] 4.1.2.4 Administration: The dosage is 10 mg / kg, and the administration volume is 10 mL / kg.

[0405] 4.1.3 Experimental Procedure: 0.1 mL of blood was collected from the eye sockets of male rats before administration and at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h after administration, and placed in tubes containing EDTA-K2 anticoagulant. 0.03 mL of blood was collected from the eye sockets of female rats before administration and at 0.5 h, 1 h, 2 h, 3 h, 6 h, 10 h, and 24 h after administration. After collection, the blood samples were placed in labeled centrifuge tubes bathed in ice water and rapidly centrifuged at 4000 rpm for 10 min at 4°C to separate the plasma. The plasma was then stored at -70°C until analysis.

[0406] After thawing the plasma sample at room temperature, 50 μL was added to 400 μL of acetonitrile containing the internal standard (40 ng / mL, terfenadine). After vortex mixing for 1 min, the sample was centrifuged at 15,400 g for 10 min at 4°C. 1 μL of the supernatant was injected for analysis.

[0407] 4.1.4 Pharmacokinetic results:

[0408] Table 10: Pharmacokinetic parameters of compound in SD rats:

[0409] Conclusion: From the data in Table 10, it can be seen that compound 11 according to the present invention has better oral absorption exposure in rats than VX-548.

[0410] 4.2 Dog Test

[0411] 4.2.1 Abstract: Beagle dogs were used as test animals. The LC / MS / MS method was used to determine the drug concentration in the plasma of beagle dogs at different times after intravenous injection of the example compound. The pharmacokinetic behavior of the compound of the present invention in beagle dogs was studied and its pharmacokinetic characteristics were evaluated.

[0412] 4.2.2 Test plan:

[0413] 4.2.2.1 Test drugs: Compound 11 and reference substance VX-548

[0414] 4.2.2.2 Experimental Animals: 4 male beagle dogs, provided by Jiangsu Lingfu Zhaoshengyuan Biotechnology Co., Ltd. They were fasted from 5:00 PM on the day before administration for at least 12 hours and resumed eating 4 hours after administration.

[0415] 4.2.2.3 Drug preparation: Weigh a certain amount of the test compound and prepare a completely clear solution with a final concentration of 1 mg / mL using a mixed solvent of DMSO:Solutol:normal saline (5%:5%:90%).

[0416] 4.2.2.4 Administration: The dosage is 0.5 mg / kg and the administration volume is 0.5 mL / kg.

[0417] 4.2.3 Experimental Procedure: 0.4 mL of blood was collected from the forelimb vein of male beagle dogs before intravenous administration and at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 24 hours after administration. The blood samples were placed in tubes containing EDTA-K2 anticoagulant. After collection, the blood samples were placed in labeled centrifuge tubes in an ice-water bath and rapidly centrifuged to separate plasma at 4000 rpm for 10 minutes at 4°C. The plasma was then stored at or below -70°C until testing.

[0418] After thawing the plasma sample at room temperature, 50 μL was added to 400 μL of acetonitrile containing the internal standard (40 ng / mL, terfenadine). After vortex mixing for 1 min, the sample was centrifuged at 15,400 g for 10 min at 4°C. The supernatant was diluted 10-fold with 80% acetonitrile-water and 1 μL was injected for analysis.

[0419] 4.1.4 Pharmacokinetic results:

[0420] Table 11: Pharmacokinetic parameters of compounds in beagle dogs:

[0421] Conclusion: From the data in Table 11, it can be seen that compound 11 according to the present invention is more stable in metabolism in beagle dogs.

[0422] 5. Test of free drug ratio in human plasma:

[0423] On the day of the experiment, human plasma samples (purchased from Biomex) were thawed under running tap water and centrifuged at 3220 g for 5 minutes to remove clots. The pH of the resulting plasma was measured and adjusted to 7.4 ± 0.1 using 1% phosphoric acid or 1N sodium hydroxide as needed.

[0424] Pretreat the dialysis membrane according to the manufacturer's instructions: Soak the dialysis membrane strips in room temperature ultrapure water for approximately 1 hour. Separate each strip, containing two membrane layers, and soak in ethanol:water (20:80 v:v) for approximately 20 minutes. Use immediately or store at 2-8°C (maximum shelf life for 1 month). Rinse and soak the membrane in ultrapure water for 20 minutes before experimentation.

[0425] Take a 10mM DMSO solution of the test compound or control warfarin, dilute it to 400μM with DMSO, then take 3μl and add it to 597μl of blank plasma matrix solution to obtain a 2μM compound solution. Transfer 50μl of the test compound solution or control solution to the sample collection plate, and replicate for each sample in 3 wells. Add 50μl of blank PBS buffer solution to each well, followed by 500μl of stop solution (acetonitrile containing 250nmol / L tolubutamine and 250nmol / L labetalol). Transfer 100μl of each well to the donor end of the dialysis well of the dialyzer, and add 100μl of dialysate to the receiving end. Then shake the well plate at approximately 100rpm in a humidified incubator at 37±1°C and 5% CO2 for 4 hours.

[0426] After dialysis, 50 μL of sample was taken from each of the buffer and plasma matrix sides of the dialysis device and placed into new 96-well sample collection plates. An equal volume of the opposite blank matrix (buffer or plasma matrix) was added to each sample, resulting in a 1:1 (v:v) plasma matrix to dialysis buffer ratio in each well, for a final volume of 100 μL. All samples were subjected to protein precipitation prior to LC-MS / MS analysis.

[0427] Unbound %, bound %, and recovered % were calculated using the following formulas:

[0428] Unbound % = 100 × F / T

[0429] Bound % = 100 - unbound %

[0430] Recovery rate % = 100 × (F + T) / T0

[0431] F = Peak area ratio of test compound to internal reference compound in buffer solution after 4 h incubation

[0432] T = Peak area ratio of test compound to internal reference compound on plasma matrix side after 4 h incubation

[0433] T0 = ​​Peak area ratio of test compound to internal reference compound at zero point

[0434] Table 12: Free drug ratio of compound 11 and VX-548 in human plasma:

[0435] Conclusion: From the data in Table 12, it can be seen that compound 11 according to the present invention has a better free drug ratio in human plasma and can better exert its pain therapeutic effect.

[0436] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any modifications or substitutions that can be easily conceived by a person skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be based on the scope of protection of the claims.

Claims

1. A compound represented by the general formula (I), its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts: in, R1 is selected from hydrogen atom, C 1-15 Alkyl, C 1-15 Alkoxy, C 1-15 Alkylcarbonyl, C 3-15 Cycloalkyl, a four- to eight-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, wherein the C 1-15 Alkyl, C 1-15 Alkoxy, C 1-15 Alkylcarbonyl, C 3-15 Cycloalkyl, four to eight membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S may be replaced by one or more R a Substituted by a substituent, the R a Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogen atom, amino, hydroxyl, amide; R2 is selected from hydrogen atom, C 1-8 Alkyl, C 1-8 Alkoxy, deuterated C 1-8 Alkyl, halogenated C 1-8 Alkyl, halogenated C 1-8 Alkoxy, C 3-6 Cycloalkyl; R3 is selected from hydrogen atom, C 1-8 Alkyl, deuterated C 1-8 Alkyl, halogenated C 1-8 Alkyl, C 3-6 Cycloalkyl, a three- to eight-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S; R4 is selected from C 6-14 aryl, a five- to eight-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, a five- to eight-membered heteroaryl oxide containing 1 to 3 heteroatoms selected from N, O and S, wherein the C 6-14 Aryl, five to eight membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S may be replaced by one or more R b Substituted by a substituent, wherein R b Selected from hydrogen atoms, C 1-6 Alkyl, C 3-6 Cycloalkyl, halogen atoms, nitro, amino, hydroxyl, carbonyl, cyano, formamido, oxy, sulfonamido, N-hydroxyformamido, N-hydroxyamidino, C-substituted with 1 to 3 halogen atoms 1-6 Alkyl, C substituted by 1 to 3 halogen atoms 3-6 Cycloalkyl, C substituted by 1 to 3 hydroxyl groups 1-6 Alkyl, C substituted with 1 to 3 hydroxyl groups 3-6 Cycloalkyl, 1 to 3 C 1-6 an alkyl-substituted or unsubstituted four- to six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S; R5 is selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl; R6 is selected from hydrogen atom, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl; R7 is selected from hydrogen atom, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl group, halogen atom, cyano group, amide group; R8 is selected from hydrogen atom, C 1-6 Alkyl, halogenated C 1-6 Alkyl group, halogen atom, cyano group.

2. The compound represented by general formula (I) according to claim 1, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts, characterized in that: Preferably, R1 is selected from hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylcarbonyl, C 3-8 Cycloalkyl, a four- to six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylcarbonyl, C 3-8 Cycloalkyl, four to six membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S may be substituted by 1 to 3 R a Substituted by a substituent, the R a Selected from hydrogen atoms, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, halogen atom, amino, hydroxyl, amide; Preferably, R1 is selected from hydrogen atom, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylcarbonyl, C 3-6 Cycloalkyl, a four- to six-membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O and S, wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylcarbonyl, C 3-6 Cycloalkyl, a four- to six-membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O and S, may be substituted by 1 to 3 R a Substituted by a substituent, the R a Selected from hydrogen atoms, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, halogen atom, amino, hydroxyl, amide; Preferably, R1 is selected from hydrogen, methyl, trifluoroacetyl, ethyl, n-propyl, isopropyl, n-butyl, Butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein the above substituents may be replaced by 1 or 2 R a Substituted by a substituent, the R a is selected from the group consisting of a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a n-butyl group, a sec-butyl group, a tert-butyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a n-butoxy group, a sec-butoxy group, a tert-butoxy group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a fluorine atom, a chlorine atom, a bromine atom, an amino group, a hydroxyl group, and an amide group; Preferably, R1 is selected from hydrogen, methyl, trifluoroacetyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl, wherein the above substituents may be replaced by 1 or 2 R a Substituted by a substituent, the R a is selected from the group consisting of a hydrogen atom, a methyl group, a methoxy group, a fluorine atom, a chlorine atom, a bromine atom, an amino group, a hydroxyl group, a cyano group, and an amide group; Preferably, R2 is selected from hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl; Preferably, R2 is selected from hydrogen atom, C 1-4 Alkyl, C 1-4 Alkoxy, deuterated C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, C 3-6 Cycloalkyl; Preferably, R2 is selected from hydrogen atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, deuterated methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, difluoropropyl, trifluoropropyl, tetrafluoropropyl, pentafluoropropyl, hexafluoropropyl, perfluoropropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; Preferably, R3 is selected from hydrogen atom, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, a three- to six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S; Preferably, R3 is selected from hydrogen atom, C 1-4 Alkyl, deuterated C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl, a three- to six-membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O; Preferably, R3 is selected from hydrogen atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, deuterated methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, difluoropropyl, trifluoropropyl, tetrafluoropropyl, pentafluoropropyl, hexafluoropropyl, perfluoropropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; Preferably, R4 is selected from C 6-10 aryl, a five- to six-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O, a five- to six-membered heteroaryl oxide containing 1 to 3 heteroatoms selected from N, O and S, wherein the C 6-10 The aryl group, the five- to six-membered heteroaryl group containing 1 to 3 heteroatoms selected from N and O, and the five- to six-membered heteroaryl oxide group containing 1 to 3 heteroatoms selected from N, O and S may be substituted by one or more R b Substituted by a substituent, wherein R b Selected from hydrogen atoms, C 1-4 Alkyl, C 3-6 Cycloalkyl, halogen atoms, nitro, amino, hydroxyl, carbonyl, cyano, formamido, oxy, sulfonamido, N-hydroxyformamido, N-hydroxyamidino, C-substituted with 1 to 3 halogen atoms 1-4 Alkyl, C substituted by 1 to 3 halogen atoms 3-6 Cycloalkyl, C substituted by 1 to 2 hydroxyl groups 1-4 Alkyl, C substituted by 1 to 2 hydroxyl groups 3-6 Cycloalkyl, 1 to 3 C 1-4 Alkyl-substituted or unsubstituted four- to six-membered heterocyclic group containing 1 or 2 heteroatoms selected from N or O; Preferably, R4 is selected from phenyl, naphthyl, anthracenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, imidazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, quinolyl, isoquinolyl, oxidized pyridyl, oxidized imidazolyl, oxidized pyrrolyl, oxidized pyrazolyl, oxidized oxazolyl, oxidized isoxazolyl, oxidized isothiazolyl, oxidized thiazolyl, oxidized pyridazinyl, oxidized pyrimidinyl, oxidized pyrazinyl, oxidized indolyl, oxidized quinolyl, oxidized isoquinolyl, wherein the above substituents may be replaced by one or more R b Substituted by a substituent, wherein R b Selected from hydrogen atoms, C 1-4 Alkyl, C 3-6 Cycloalkyl, halogen atoms, amino, carbonyl, hydroxyl, cyano, formamido, oxy, sulfonamido, N-hydroxyformamido, N-hydroxyamido, C-substituted with 1 to 3 halogen atoms 1-4 Alkyl, C substituted by 1 to 3 halogen atoms 3-6 Cycloalkyl, C substituted by 1 to 3 hydroxyl groups 1-4 Alkyl, C substituted with 1 to 3 hydroxyl groups 3-6 Cycloalkyl, 1 to 3 C 1-4 an alkyl-substituted or unsubstituted four- to six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S; Preferably, R5 is selected from C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl; Preferably, R5 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, difluoropropyl, trifluoropropyl, tetrafluoropropyl, pentafluoropropyl, hexafluoropropyl, perfluoropropyl; Preferably, R5 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, trifluoromethyl; Preferably, R6 is selected from C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl; Preferably, R6 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, difluoropropyl, trifluoropropyl, tetrafluoropropyl, pentafluoropropyl, hexafluoropropyl, perfluoropropyl; Preferably, R6 is selected from hydrogen atom, methyl, ethyl, n-propyl, isopropyl; Preferably, R7 is selected from C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 3-6 Cycloalkyl group, halogen atom, cyano group, amide group; Preferably, R7 is selected from a halogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a sec-butoxy group, a tert-butoxy group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a monofluoroethyl group, a difluoroethyl group, a trifluoroethyl group, a tetrafluoroethyl group, a pentafluoroethyl group, a monofluorooxymethyl group, a difluoromethoxy group, a trifluoromethoxy group, a monofluoroethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a tetrafluoroethoxy group, a pentafluoroethoxy group; Preferably, R7 is selected from hydrogen atom, methyl group, isopropyl group, cyclopropyl group, cyclobutyl group, fluorine atom, chlorine atom, bromine atom, methoxy group, trifluoromethoxy group; Preferably, R8 is selected from hydrogen atom, C 1-4 Alkyl, halogenated C 1-4 Alkyl group, halogen atom, cyano group; Preferably, R8 is selected from hydrogen atom, halogen atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl; Preferably, R8 is selected from a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, and a methyl group.

3. The compound represented by general formula (I) according to claim 1, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts, characterized in that: It is represented by the following general formula (II): Wherein, the definitions of R1 to R8 are the same as those in any one of claims 1 or 2; X1 to X5 are each independently CH, O or N or N + -O - , provided that at most 3 of X1 to X5 are N, and the rest are C; R9 is selected from the group consisting of a hydrogen atom, a halogen atom, an amino group, a hydroxyl group, a carbonyl group, a cyano group, an amide group, an oxy group, a sulfonamide group, a nitrogen-hydroxycarbamimidyl group, a nitrogen-hydroxyamidyl group, a C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-14 aryl, a four- to six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, a five- to six-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-14 The aryl group, the four- to six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, the five- to six-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S may be 1 to 3 R's c Substituted by a substituent, the R c Selected from hydrogen atoms, C 1-4 Alkyl, C 3-6 Cycloalkyl, halogen atom, nitro, amino, hydroxyl, cyano, formamide; n is an integer selected from 0, 1, 2, 3 or 4; Preferably, X3 and X4 are CH or N; Preferably, X1, X2 or X5 are each independently selected from CH or N or N + -O - ; Preferably, R9 is selected from the group consisting of a hydrogen atom, a halogen atom, an amino group, a hydroxyl group, a carbonyl group, a cyano group, a formamide group, an oxy group, a sulfonamide group, a nitrogen-hydroxyformamidino group, a nitrogen-hydroxyamidino group, a C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-14 aryl, a four- to six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, a five- to six-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-14 An aryl group, a four- to six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, a five- to six-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S may be substituted by 1 to 3 R c Substituted by a substituent, the R c Selected from hydrogen atoms, C 1-4 Alkyl, C 3-6 Cycloalkyl, halogen atom, amino, hydroxyl, cyano, amide; Preferably, R9 is selected from the group consisting of a hydrogen atom, a halogen atom, an amino group, a hydroxyl group, a carbonyl group, a cyano group, a formamide group, an oxy group, a sulfonamide group, a nitrogen-hydroxyformamidino group, a nitrogen-hydroxyamidino group, a C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 aryl, a four- to six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, a five- to six-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, wherein the C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 An aryl group, a four- to six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, a five- to six-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S may be substituted by 1 to 3 R c Substituted by a substituent, the R c Selected from hydrogen atoms, C 1-3 Alkyl, C 3-6 Cycloalkyl, halogen atom, amino, hydroxyl, cyano, amide; Preferably, R9 is selected from the group consisting of a hydrogen atom, a halogen atom, an amino group, a hydroxyl group, a carbonyl group, a cyano group, a formamide group, an oxy group, a sulfonamide group, a nitrogen-hydroxyformamidino group, a nitrogen-hydroxyamidino group, a C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 aryl, a four- to six-membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O, a five- to six-membered heteroaryl group containing 1 or 2 heteroatoms selected from N and O, wherein the C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 An aryl group, a four- to six-membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O, or a five- to six-membered heteroaryl group containing 1 or 2 heteroatoms selected from N and O may be substituted by 1 to 3 R c Substituted by a substituent, the R c Selected from hydrogen atoms, C 1-3 Alkyl, C 3-6 Cycloalkyl, halogen atom, amino, hydroxyl, cyano, formamide; Preferably, R9 is selected from hydrogen atom, halogen atom, amino, hydroxyl, carbonyl, cyano, formamide, oxy, sulfonamide, nitrogen-hydroxyformamidino, nitrogen-hydroxyamidino, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl The above substituents may be replaced by 1 or 2 R c Substituted by a substituent, the R c is selected from the group consisting of a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a fluorine atom, a chlorine atom, a bromine atom, an amino group, a hydroxyl group, a cyano group, and a formamide group; Preferably, n is an integer selected from 0, 1 or 2; Preferably, n is an integer selected from 0 or 1.

4. The compound represented by general formula (I) according to claim 1, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts, characterized in that: It can be represented by the following general formula (III): Wherein, the definitions of R1, R2, R3, R5, and R6 are the same as those in any one of claims 1 or 2; The definitions of R9, X1, and X2 are the same as those in claim 3.

5. The compound represented by general formula (I) according to claim 1, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts, characterized in that: It is represented by the following general formula (IVa), general formula (IVb), general formula (IVc) or general formula (IVd): The definitions of R1, R2, and R3 are the same as those in any one of claims 1 or 2; and the definition of R5 is the same as that in claim 3.

6. The compound represented by general formula (I) according to claim 1, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts, characterized in that: It is selected from the following compounds:

7. A method for preparing a compound according to any one of claims 1 to 6, a stereoisomer, a tautomer, a deuterated derivative or a pharmaceutically acceptable salt thereof, comprising the steps of: Step 1: Compound Ia whose amino group is protected by an amino protecting group PG, where PG is Boc or Cbz, is subjected to electrophilic addition reaction with an alkyl metal reagent (such as alkyl lithium, alkyl Grignard reagent, trimethylsilylmethyl lithium, etc.) to obtain a compound represented by the general formula Ib; Step 2: Remove the amino protecting group PG in Ib under strong acidic conditions (such as hydrochloric acid / dioxane solution) or metal palladium carbon in a hydrogen atmosphere to obtain a compound represented by the general formula Ic; Step 3: Ic and a phenylacetic acid compound Id are subjected to amide condensation to obtain a compound represented by the general formula Ie; Step 4: Under alkaline conditions (such as potassium hydroxide, sodium hydroxide, sodium hydrogen hydride, etc.), Ie undergoes molecular ring closure dehydration to obtain a compound represented by the general formula If; Step 5: Reducing the double bond on the ring under catalytic hydrogenation conditions with sodium borohydride and nickel chloride or palladium to obtain a compound represented by general formula Ig; Step 6: After the lactam in Ig is reduced to an imine using a Schwartz reagent, the imine is subjected to an addition reaction with sodium cyanide or potassium cyanide to obtain a pyrrolidine compound represented by the general formula Ih; Step 7: Compound Ih is subjected to strong acidic conditions (such as hydrochloric acid / dioxane) or strong alkaline conditions (such as potassium hydroxide aqueous solution) to hydrolyze the cyano group to form acid Ii; Step 8: Ii and aldehyde undergo reductive amination under palladium catalytic hydrogenation conditions or in the presence of a borohydride reducing agent to alkylate pyrrolidine NH to obtain a compound represented by the general formula Ii'; Step 9: Reaction Ii or Ii' with amine by amide condensation to obtain the final product represented by formula I.

8. Use of the compound according to any one of claims 1 to 6, its stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt as a Nav1.8 inhibitor.

9. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6, its stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt as an active ingredient, and a pharmaceutically acceptable excipient.

10. Use of the compound according to any one of claims 1 to 6, its stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating acute pain and chronic pain.

11. A method for treating chronic pain, comprising providing a subject with a therapeutically effective amount of the compound according to any one of claims 1 to 6, its stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 9.

Images