Novel sodium channel regulator compound and application thereof

Abstract

The invention provides a novel sodium channel regulator compound and application thereof, and the sodium channel regulator has a brand new structure and has an excellent in-vitro inhibition effect on Nav 1.8. The compound or the pharmaceutically acceptable salt thereof can be used for treating sodium channel related diseases, including pain, multiple sclerosis, fibula amyotrophy, incontinence, pathological cough, arrhythmia and the like.

Description

[0001] This application claims the priority of Chinese Patent Application No. 2024101375145 with an application date of January 31, 2024, and Chinese Patent Application No. 2024115635044 with an application date of November 04, 2024. This application incorporates the entire texts of the above-mentioned Chinese patent applications by reference. Technical Field

[0002] The present invention relates to the field of medicine, and particularly to novel compounds of sodium channel modulators, their preparation methods, and therapeutic uses in the treatment of diseases. Background Art

[0003] Pain is a complex sensation, usually an uncomfortable feeling caused by physical injury, illness, or adverse external stimuli. For the needs of clinical research, the International Association for the Study of Pain (ISAP) defines pain as, "an unpleasant sensory and emotional experience, often associated with actual or potential tissue damage". As a warning signal, pain can alert the body to potential dangers and plays an indispensable protective role in normal life activities. Pain is also a common clinical symptom. After the external stimulus that causes pain disappears, intense or persistent pain can cause physiological function disorders and seriously affect the quality of life of the living body. Data shows that about one-fifth of the people in the world are troubled by moderate or severe chronic pain.

[0004] Pain originates from nociceptors in the peripheral nervous system. These are free nerve endings widely distributed in the skin, muscles, joints, and visceral tissues throughout the body. They can convert the perceived thermal, mechanical, or chemical stimuli into nerve impulses (action potentials) and transmit them via afferent nerve fibers to the cell body part located in the dorsal root ganglia (DRG), and finally transmit them to the higher nerve centers, causing the sensation of pain. The generation and conduction of action potentials in neurons depend on voltage-gated sodium channels (VGSCs) on the cell membrane. When the cell membrane depolarizes, the sodium channels are activated, the channels open, causing sodium ions to flow in, further depolarizing the cell membrane and resulting in the generation of action potentials. Therefore, inhibiting abnormal sodium channel activity helps in the treatment and relief of pain.

[0005] Voltage-gated sodium channels are widely present on the cell membranes of excitable cells such as neurons and skeletal muscle cells. They are a type of transmembrane glycoprotein complex composed of an α subunit and several β subunits. The α subunit is the functional carrier of the sodium channel and consists of 1,700 - 2,000 amino acids. The β subunit mainly plays an auxiliary role and can modify the kinetics of ion channels and voltage-gated dependence. Sodium channels can be classified according to different α subunits. Currently, 9 sodium channel subtypes have been identified in mammals, namely Na v 1 (Na v 1.1 - Na v 1.9). Different subtypes exhibit different tissue distributions and electrophysiological and pharmacological characteristics. According to whether they can be effectively inhibited by nanomolar tetrodotoxin (TTX), sodium channels are divided into TTX-sensitive (TTX-S) and TTX-resistant (TTX-R). Among them, Na v 1.1, Na v 1.2, Na v 1.3, and Na v 1.7 are TTX-S types, and their encoding genes are located on human chromosome 2q23 - 24, and they are highly expressed in neurons. Na v 1.5, Na v 1.8, and Na v 1.9 are TTX-R types, and their encoding genes are located on human chromosome 3p21 - 24. Among them, Na v 1.5 mainly exists in cardiomyocytes, and Na v 1.8, Na v 1.9 exist in the peripheral nervous system (PNS).

[0006] Na v 1.8 is an important ion channel involved in chronic pain, atrial fibrillation, and Brugada syndrome, and is a highly selective target for the treatment of pain. It has been proven to act as a carrier of sodium current, maintaining the action potential firing of neurons in small dorsal root ganglia, and also participating in the spontaneous electrical signal firing of damaged neurons, such as driving the generation of neuropathic pain, etc. Currently reported small molecule inhibitors of Na v 1.8 include PF-01247324, A-803467, PF-06305591, VX-150, HRS-4800, JMKX-000623, HBW-004, and VX-548, etc. PF-01247324, A-803467, and PF-06305591 have disadvantages such as poor selectivity, poor pharmacokinetic data, and low bioavailability. Summary of the Invention

[0007] In a first aspect of the present invention, there is provided a compound of formula I

[0008]

[0009] or a pharmaceutically acceptable salt thereof. When there are chiral centers, the compound further includes its stereoisomers and racemates.

[0010] In some embodiments of the present invention, the above compound is further represented by formula I-A or I-B:

[0011]

[0012] In the above compound, R a1 and R a3 are each independently selected from hydrogen, halogen, hydroxyl, C1-C5 alkyl, C1-C5 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, -N(R c3 R c4 ) m , and the alkyl, alkoxy, cycloalkyl, and cycloalkoxy are optionally substituted by one or more halogens, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, or amino; R a2 is selected from C1-C6 alkyl substituted with one or more deuteriums or fluorines.

[0013] In some embodiments of the present invention, any two adjacent R a1 and R a3 are connected to form a 5- to 7-membered ring, which can be a saturated or unsaturated carbocyclic or heterocyclic ring; the heterocyclic ring optionally contains one or more N, O, S(=O) m heteroatoms; the 5- to 7-membered ring can be optionally substituted by one or more halogens, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, or amino.

[0014] In some specific embodiments of the present invention, R a1 and R a3 are each independently selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, difluoromethoxy, and amino.

[0015] In some specific embodiments, R a2 is arbitrarily selected from methyl substituted with 1, 2, or 3 deuteriums or fluorines.

[0016] In some specific embodiments, any two adjacent R a1 and R a3 are connected to form a 5- or 6-membered carbocyclic or heterocyclic ring.

[0017] In some embodiments, the 5-membered or 6-membered heterocyclic ring contains one or two N, O, S (=O) m heteroatom.

[0018] In some specific embodiments, the 5-membered or 6-membered carbocyclic or heterocyclic ring is optionally substituted by one or more halogen, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, or amino.

[0019] In the above compounds, R b1 、R b2 、R b3 、R b4 Each is independently selected from hydrogen, halogen, hydroxy, C1-C5 alkyl, C1-C5 alkoxy, and the alkyl and alkoxy groups are optionally substituted with one or more halogen, hydroxy, cyano, C1-C5 alkyl, C1-C5 alkoxy, and amino groups.

[0020] In a specific embodiment of the present invention, R b1 、R b2 、R b3 、R b4 Each is independently selected from hydrogen, methyl, trifluoromethyl, ethyl, methoxy, and ethoxy.

[0021] In some embodiments, R b1 、R b2 Each is independently selected from hydrogen, methyl, trifluoromethyl;

[0022] In some embodiments, R b3 、R b4 Each is independently selected from hydrogen, methyl, and trifluoromethyl.

[0023] In some embodiments, R b1 、R b2 、R b3 、R b4 Any two of them are connected to form a 3-7 membered ring; the 3-7 membered ring may be a saturated or unsaturated carbocyclic ring or heterocyclic ring; the heterocyclic ring may optionally contain one or more N, O, S (=O) m Heteroatom; the 3-7 membered ring may be further optionally substituted by one or more halogen, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, amino.

[0024] In some embodiments, R b1 、R b2 The 3-7 membered saturated carbon ring is connected to form a 3-7 membered ring, and the 3-7 membered ring can be optionally substituted by one or more halogen, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, and amino.

[0025] In some specific embodiments, R b1 and R b2 are connected to form a 3-membered saturated carbon ring, and the 3-membered ring may be optionally substituted with one or more halogens, hydroxyl groups, cyano groups, C1-C5 alkyl groups, C1-C5 alkoxy groups, or amino groups.

[0026] In some specific embodiments, R b3 and R b4 are connected to form a 3- to 7-membered saturated carbon ring, and the 3- to 7-membered ring may be optionally substituted with one or more halogens, hydroxyl groups, cyano groups, C1-C5 alkyl groups, C1-C5 alkoxy groups, or amino groups.

[0027] In some specific embodiments, R b1 and R b2 and R b3 and R b4 are arbitrarily connected in pairs to form a 3- to 7-membered ring, and the 3- to 7-membered ring may be optionally substituted with one or more halogens, hydroxyl groups, cyano groups, C1-C5 alkyl groups, C1-C5 alkoxy groups, or amino groups.

[0028] In some specific embodiments, R b1 and R b2 and R b3 and R b4 are arbitrarily connected in pairs to form a 3- to 7-membered saturated carbon ring, and the 3- to 7-membered saturated carbon ring may be optionally substituted with one or more halogens, hydroxyl groups, cyano groups, C1-C5 alkyl groups, C1-C5 alkoxy groups, or amino groups.

[0029] In some specific embodiments, R b1 and R b2 and R b3 and R b4 are arbitrarily connected in pairs to form a 3- to 6-membered saturated carbon ring, and the 3- to 6-membered saturated carbon ring may be optionally substituted with one or more halogens, hydroxyl groups, cyano groups, C1-C5 alkyl groups, C1-C5 alkoxy groups, or amino groups.

[0030] In the present invention, R b1 and R b2 and R b3 and R b4 any two connections can be R b1 and R b3 and R b1 and R b4 and R b2 and R b3 and R b2 and R b4 connected.

[0031] M1 and M2 are independently selected from C, O, S(=O) m , N-Rn , wherein R n is optionally selected from hydrogen, C1-C5 alkyl; in a specific embodiment, R n is optionally selected from hydrogen, methyl or ethyl.

[0032] In the above compounds of the present invention, ring A has the structure as A1:

[0033]

[0034] Any represents a single bond or a double bond, provided that it does not violate the principles of chemical bonding;

[0035] X1, X2, X3, X4, X5 are each independently selected from a bond, C, N, O, C=O, S(=O) m ;

[0036] X1, X2, X3, X4, X5 being selected from "bond" means directly connecting in the form of a bond, provided that it does not violate the principles of chemical bonding. For example, when X2 is selected from a bond, X1 is directly connected to X3 by a bond, and at this time ring A is a five-membered ring;

[0037] In some specific embodiments of the present invention, X1, X2, X3, X4, X5 are each independently selected from a bond, C, N, C=O, S(=O)2;

[0038] In some specific embodiments of the present invention, X1, X2, X3, X4, X5 are all selected from C atoms;

[0039] In some specific embodiments of the present invention, any one or two of X1, X2, X3, X4, X5 contain N atoms;

[0040] In some specific embodiments of the present invention, any one of X1, X2, X3, X4, X5 contains a C=O; [[ID=X37]]

[0041] In some specific embodiments of the present invention, any one of X1, X2, X3, X4, X5 contains an S(=O)2;

[0042] In some specific embodiments of the present invention, X1, X2, X3, X4, X5 are optionally selected from a bond, C, S, O;

[0043] In some specific embodiments of the present invention, ring A has the following structure:

[0044]

[0045] In the above compounds of the present invention, ring A has the structure as A2

[0046]

[0047] wherein, any represents a single bond or a double bond, provided that it does not violate the principles of chemical bonding; X1, X2, X3, X4 have the same definitions as in formula A1. X1, X2, X3, X4 are selected from "bond" which means directly connecting in the form of a bond. For example, when X3 is selected from a bond, X2 is directly connected to X4 by a bond to form a five-membered ring; Y1, Y2 can be the same or different and are each independently selected from a C atom or an N atom.

[0048] In some specific embodiments of the present invention, in formula A2, X1, X2, X3, X4 are each independently selected from a bond, C, N, C═O;

[0049] In some specific embodiments of the present invention, in formula A2, X1, X2, X3, X4 are each independently selected from a bond, C, N, O;

[0050] In some specific embodiments of the present invention, in formula A2, X1, X2, X3, X4 are each independently selected from a bond, C, N, S(═O) m ;

[0051] In some specific embodiments of the present invention, in formula A2, X1, X2, X3, X4 are each independently selected from C, N, C═O;

[0052] In some specific embodiments of the present invention, ring A has the following structure:

[0053]

[0054] R c1 、R c2 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, C1-C5 alkyl, C1-C5 alkoxy, -S(═O) m -R c3 R c4 、-C(═O)-NR c3 R c4 、-C(═S)-NR c3 R c4 、-N(R c3 R c4 ) m 、-P(═O) m -R c3 R c4 、-C(═N)-NR c3 R c4 、-S(═O)2NR c3 R c4 、-CH2NR c3 R c4 、-S(═O)(═NR c3 )Rc4 ; and the C1-C5 alkyl group and C1-C5 alkoxy group may be further substituted by any one or more of the following substituents: halogen, hydroxyl, cyano, amino, C1-C5 alkyl group, C1-C5 alkoxy group;

[0055] R c1 and R c2 are substituted at any substitutable position on ring A, including substitution at X1, X2, X3, X4, Y1, Y2; in some specific embodiments of the present invention, R c1 and R c2 are substituted on a carbon atom; in some specific embodiments of the present invention, R c1 and R c2 are substituted on a heteroatom.

[0056] R c3 and R c4 are each independently selected from hydrogen, hydroxyl, amino, C1-C5 alkyl group, C1-C5 alkoxy group, 3- to 7-membered ring, or R c3 and R c4 are connected to form a 3- to 7-membered ring; the 3- to 7-membered ring may be a saturated or unsaturated carbocyclic or heterocyclic ring; the heterocyclic ring optionally contains one or more N, O, S(=O) m heteroatoms; the 3- to 7-membered ring may be further optionally substituted by one or more halogen, hydroxyl, cyano, C1-C5 alkyl group, C1-C5 alkoxy group, amino.

[0057] In the substituent -S(=O) m -R c3 R c4 , when m = 2, R c4 does not exist.

[0058] In some specific embodiments of the present invention, the compound of formula I described above is further as shown in general formula II:

[0059]

[0060] wherein: M1, ring A, R a1 and R a2 and R a3 and R b1 and R b2 and R b3 and R b4 and R c1 and R c2 are as defined above.

[0061] In some specific embodiments of the present invention, R c1 and R c2Each independently selected from hydrogen, hydroxy, amino, fluoro, cyano, oxo, methyl, -C(=O)NH2, -C(=O)NHCH3, -C(=O)NHC2H5, -S(O)2CH3, -S(O)2NH2, -S(O)2NHCH3, -S(O)2NHCD3, -P(O)(CH3)2,

[0062] In some specific embodiments of the present invention, R c1 、R c2 Each independently selected from hydrogen, fluoro, chloro, amino, cyano, -C(=O)NH2. In the above compounds of the present invention, m and n are each independently 0, 1 or 2.

[0063] In a specific embodiment of the present invention, the specific compound of the present invention has the following structure:

[0064]

[0065]

[0066]

[0067]

[0068]

[0069] In a second aspect of the present invention, there is provided the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a drug for inhibiting voltage-gated sodium channels. The voltage-gated sodium channel is Nav1.8.

[0070] In a third aspect of the present invention, there is provided the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating, preventing or alleviating voltage-gated sodium channel-related diseases, said related diseases including but not limited to: pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or arrhythmia, etc.

[0071] The pain includes: acute pain, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain. Accordingly, the present invention further provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating, preventing or alleviating pain.

[0072] In the fourth aspect of the present invention, a pharmaceutical composition is provided, which contains a compound of formula I or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients include fillers, disintegrants, surfactants, and solubilizers.

[0073] The pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to the present invention can be administered in various known ways, such as orally, topically, rectally, parenterally, by inhalation or implantation, etc. The pharmaceutical composition can be prepared into dosage forms such as tablets, capsules, sachet granules, dragees, powders, granules, lozenges, powder injections, liquid preparations, or suppositories.

[0074] In the fifth aspect of the present invention, there is provided the use of a pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating, preventing or alleviating voltage-gated sodium channel-related diseases, including but not limited to: pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or arrhythmia, etc.

[0075] The pain includes: acute pain, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain. Therefore, the present invention further provides the use of a pharmaceutical combination containing a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating, preventing or alleviating pain. Detailed Description of the Invention

[0076] Glossary of Terms

[0077] "Halogen" or "halo atom" includes fluorine, chlorine, bromine, iodine; the preferred halogen in the present invention is fluorine or chlorine.

[0078] "C1-C5 alkyl" refers to a straight-chain or branched-chain alkyl containing 1-5 carbon atoms, specifically such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, etc.; the preferred C1-C5 alkyl is C1-C3 alkyl, including methyl, ethyl, propyl, isopropyl.

[0079] "C1-C5 alkoxy" refers to a straight-chain or branched-chain alkoxy containing 1-5 carbon atoms, specifically such as methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, etc. The preferred C1-C5 alkoxy is C1-C3 alkoxy, including methoxy, ethoxy, propoxy, isopropoxy. "C3-C6 cycloalkyl" refers to a cycloalkyl containing 3-6 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; on the said cycloalkyl, it can be further substituted with the following substituents: one or more halogens, hydroxyl groups, cyano groups, C1-C5 alkyls, C1-C5 alkoxys, amino groups.

[0080] "C3-C6 cycloalkyloxy" means a cycloalkyloxy group containing 3 to 6 carbon atoms, including cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy; on the said cycloalkyloxy group, it may further be substituted by the following substituents: one or more halogens, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, amino.

[0081] "3-7 membered ring" means a saturated or unsaturated ring containing 3 to 7 carbon atoms, such as a three-membered ring, four-membered ring, five-membered ring, six-membered ring, seven-membered ring; in the present invention, the carbon atoms on the ring may be arbitrarily substituted by one or more C(=O), N, O, S(=O) m to form a 3-7 membered heterocyclic ring; the said 3-7 membered ring may further be optionally substituted by one or more halogens, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, amino, and m is 0, 1, 2.

[0082] "5-7 membered ring" means a saturated or unsaturated ring containing 5 to 7 carbon atoms, such as a five-membered ring, six-membered ring, seven-membered ring; in the present invention, the carbon atoms on the ring may be arbitrarily substituted by one or more N, O, S(=O) m to form a 5-7 membered heterocyclic ring; the said 5-7 membered ring may further be optionally substituted by one or more halogens, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, amino, and m is 0, 1, 2.

[0083] "Plural" may be two, three, four or more. In the present invention, plural halogen substitutions may be, for example, trifluoromethyl, difluoromethyl.

[0084] In the present invention, the alkyl, alkoxy, cycloalkyl, cycloalkyloxy, 5-7 membered ring, 3-7 membered ring may be optionally substituted by one or more deuterium, halogen, hydroxyl, cyano, oxo, C1-C5 alkyl, C1-C5 alkoxy, amino.

[0085] As used herein, in any chemical structure or formula, a bold or hash straight bond (respectively ) connected to a stereoisomeric center of a compound, such as in

[0086]

[0087] represents the relative stereochemistry of the stereoisomeric center relative to other stereoisomeric centers connected to the bold or hash straight bond.

[0088] As used herein, in any chemical structure or formula, a bold or hash wedge bond (respectively ) connected to a stereoisomeric center of a compound, such as in

[0089]

[0090] Represents the absolute stereochemistry of a stereogenic center and the relative stereochemistry of the stereogenic center relative to other stereogenic centers attached to the bold or hash wedge bond.

[0091] As used herein, when used in combination with a chiral compound, the prefix "rel-" refers to a single enantiomer of unknown absolute configuration. In a compound with the "rel-" prefix, the (R)- and (S)- indicators in the chemical name reflect the relative stereochemistry of the compound, but not necessarily the absolute stereochemistry of the compound.

[0092] "Pharmaceutically acceptable salts" include, but are not limited to: acid addition salts formed by the compounds of formula (I) with inorganic acids, such as hydrochloride, hydrobromide, phosphate, sulfate, nitrate, etc.; and acid addition salts formed by the compounds of formula (I) with organic acids, such as formate, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, mesylate, tosylate, 2-hydroxyethanesulfonate, benzoate.

[0093] The compounds in the present invention are the enol form of the compound and are the same compound.

[0094] The general preparation method of the compounds of the present invention is as follows:

[0095]

[0096] The reaction of the compound of formula (A) with the compound of formula (B) gives the compound of formula (I-B-1) of the present invention, wherein ring A, M1, R a1 , R a2 , R a3 , R b1 , R b2 , R b3 , R b4 , R c1 , R c2 and n are as defined above in the present invention.

[0097] The present invention further prepares specific compounds by the following methods. Unless otherwise specified, the compounds, reagents, etc. used in the examples of the present invention are all purchased from qualified suppliers or synthesized by referring to the methods disclosed in the prior art. The synthesis of some intermediate compounds can refer to the methods described in WO2022256660A1, such as preparing intermediate 1a by referring to the methods of the prior art.

[0098] Synthesis of intermediate 1d:

[0099]

[0100] Step 1: (2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1b)

[0101] Add (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1a, 1.5 g, 4.23 mmol, 1.0 eq), TBAB (1.5 g, 4.7 mmol, 1.1 eq) and 48% aqueous hydrobromic acid solution (25 mL) into a single-neck reaction flask. The reaction solution is reacted at 100 °C for 18 hours under nitrogen protection. LCMS detection shows that most of the raw materials have reacted. Extract with water and dichloromethane, take the dichloromethane layer, concentrate and then perform column chromatography (PE / EA = 0 - 100%) to obtain compound 1b (1.2 g, 83.3% yield) as a yellow liquid. LCMS: m / z (254 nm): 339.3 [M-H] - 。

[0102] Step 2: (2R,3S,4S,5R)-3-(3,4-difluoro-2-trideuteriomethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid trideuteriomethyl ester (1c)

[0103] Add 1b (0.5 g, 1.5 mmol, 1.0 eq), trideuteriomethyliodide (1.0 g, 7.4 mmol, 5.0 eq), potassium carbonate (1.9 g, 14.7 mmol, 10.0 eq) and acetonitrile (25 mL) into a single-neck reaction flask. React at room temperature for 18 hours. LCMS detection shows that the reaction is complete. Extract with water and ethyl acetate, take the ethyl acetate layer, concentrate to obtain compound 1c (0.7 g, crude product) as a yellow liquid. LCMS: m / z (254 nm): 375.3 [M+H] + 。

[0104] Step 3: (2R,3S,4S,5R)-3-(3,4-difluoro-2-trideuteriomethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1d)

[0105] Compound 1c (0.7 g, 1.5 mmol, 1.0 eq), sodium hydroxide (0.3 g, 7.4 mmol, 5.0 eq), water (20 mL), and methanol (20 mL) were added to a single-necked reaction flask. The reaction was allowed to react at room temperature for 16 hours. LCMS confirmed the reaction was complete, and the methanol was removed by concentration. The pH was adjusted to 1 with hydrochloric acid, and the mixture was extracted with water and ethyl acetate. The ethyl acetate layer was concentrated and purified by column chromatography (PE / EA = 0-100%) to afford compound 1d (0.46 g, 86% yield for the two-step reaction) as a yellow liquid. LCMS: m / z (254 nm): 356.3 [MH] - .

[0106] Synthesis of intermediate 3d:

[0107]

[0108] Step 1: 3-Bromo-6-nitrobenzofuran-1(3H)-one (3b)

[0109] To a 100 mL reaction flask, 3a (3.0 g) and CCl₄ (30 mL) were added, followed by NBS (3.28 g) and AIBN (275 mg) with stirring. The mixture was heated to 78°C and stirred for 12 hours. TLC was used to monitor the reaction until complete conversion of the starting material. The reaction solution was cooled to room temperature and filtered through celite. The filtrate was concentrated and separated by column chromatography (EA / PE, 0% to 30%) to give 3.3 g of a yellow solid, in a 77% yield. LCMS: m / z (254 nm): 257.9 [M+H] +

[0110] Step 2: 7-nitrophthalazin-1(2H)-one (3c)

[0111] 3b (1.0 g) and 5% HCl (5 mL / mmol) were added to the reaction flask and stirred at 80°C for 3 hours. The reaction was monitored by TLC until the conversion of the starting material was complete. The reaction solution was cooled to room temperature, and N₂H₄·H₂O (274 mg) was added. Stirring was continued at room temperature for another 3 hours. The reaction was monitored by TLC until the conversion of the starting material was complete. The reaction solution was filtered, washed with water, and the solid residue was separated by column chromatography to obtain 237 mg of a white solid, a 32% yield. LCMS: m / z (254 nm): 192.0 [M+H] +

[0112] Step 3: 7-aminophthalazin-1(2H)-one (3d)

[0113] Add 3c (200 mg), MeOH (10 mL) and THF (10 mL) to a reaction flask. After stirring evenly, add palladium / carbon (20 mg), and conduct hydrogen replacement three times. Stir at room temperature for 4 hours, and monitor the reaction by TLC until the raw materials are completely converted. Filter the reaction solution through diatomaceous earth, concentrate the filtrate to obtain 120 mg of white solid with a yield of 71%. LCMS: m / z (254 nm): 162.0 [M+H] +

[0114] Synthesis of intermediate 5e:

[0115]

[0116] Step 1: Methyl 2-hydroxy-5-nitrobenzoate (5b)

[0117] Add methanol (50 mL) and 5a (5.0 g) to a three-necked flask, slowly drop thionyl chloride (10 mL), react at 65 °C for 16 hours, concentrate to dryness, add water and ethyl acetate for extraction, take the ethyl acetate layer, and concentrate to obtain 6.0 g of white solid with a yield of 111%. ESI-MS m / z: 198.1 (M+1) + 。

[0118] Step 2: (2-Hydroxy-5-nitrophenyl)methanohydroxamic acid (5c)

[0119] Add methanol (500 mL) and potassium hydroxide (21 g) to a reaction flask, add hydroxylamine hydrochloride (17.5 g) under ice bath, stir for 1.5 h, filter and take the filtrate, add 5b (5 g), react for 16 h, detect by LCMS, and the reaction is complete. Concentrate to remove methanol, adjust the pH to 2 with hydrochloric acid, extract with water and ethyl acetate, take the ethyl acetate layer, dry and concentrate to obtain 4.8 g of light yellow solid with a yield of 96%. ESI-MS m / z: 198.9 (M+1) + 。

[0120] Step 3: 5-Nitro-2,3-dihydro-1,2-benzisoxazol-3-one (5d)

[0121] Add THF (100 mL) and 5c (2.76 g) to a reaction flask, add triphenylphosphine (4.8 g) under nitrogen protection, stir for 20 minutes under ice bath, then add DIAD (3.7 g), react for 4 h, detect by LCMS, and the reaction is complete. Concentrate to remove the solvent, add water, adjust the pH to 13 with sodium hydroxide, extract with DCM; take the aqueous layer, adjust the pH to 1 with hydrochloric acid, extract with DCM, wash with saturated brine, and concentrate to obtain 1.6 g of white solid with a yield of 64%. ESI-MS m / z: 181.0 (M+1) + 。

[0122] Step 4: 5-Amino-2,3-dihydrobenzo[d]isoxazol-3-one (5e)

[0123] Add methanol (50 mL) and 5d (800 mg), 5% palladium on carbon (200 mg) to the reaction flask, and react under hydrogenation conditions for 36 h. The reaction is monitored by LCMS until completion. Filter and concentrate the filtrate to obtain 400 mg of white solid, yield: 60.6%. ESI-MS m / z: 151.0 (M+1) + .

[0124] Synthesis of Intermediate 8b: 6-Aminobenzo[d]isothiazol-3(2H)-one-1,2-dioxide

[0125]

[0126] Adding 8a (650 mg) and concentrated hydrochloric acid (9 mL) to the reaction flask under an ice bath, adding zinc powder (1.1 g) in portions within about 30 minutes, and continuing to stir at room temperature for 2 hours. The raw materials are monitored by LCMS and are basically completely converted. Add saturated sodium bicarbonate solution to the reaction solution under an ice bath until weakly alkaline, extract with ethyl acetate (50 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, to obtain 320 mg of brown solid (purity about 70%), yield 37.0%. LCMS: MS m / z (254 nm): 185.0 [M+H] + .

[0127] Synthesis of Intermediate 11c:

[0128]

[0129] Step 1: 5-Amino-2-[amino(imino)methyl]benzoic acid (11b)

[0130] Dissolve compound 4-aminophthalonitrile 11a (500 mg, 3.49 mmol, 1.0 eq) in methanol:water = 3:2 (5 mL), add sodium hydroxide (139 mg, 3.49 mmol, 1.0 eq). The reaction solution is reacted at 100 °C for 1 hour under nitrogen protection. The reaction is monitored by LCMS until the raw materials are completely reacted. The reaction solution is cooled to room temperature and concentrated. The residue is separated and purified by prep-HPLC (0.01% FA) to obtain compound 5-amino-2-carbamoylbenzoic acid 11b (733 mg, 82% yield) as a yellow solid. LCMS: [M+H] + = 180.1

[0131] Step 2: 4,7-Diamino-1,2-dihydrobenzo[2,1-d][1,2]diazepin-1-one (11c)

[0132] Compound 5-amino-2-carbamoylbenzoic acid 11b (680 mg, 3.79 mmol, 1.0 eq) was dissolved in methanol (10 mL), and hydrazine hydrate (7 mL) was added. The reaction mixture was stirred at 25 °C for 4 h. After completion of the reaction monitored by LCMS, the reaction mixture was concentrated, and the residue was extracted with water (10 mL) and ethyl acetate (10 mL × 5). Then it was washed successively with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was filtered, and the filter cake was dried in vacuo to obtain compound 4,7-diaminophthalazin-1-ol 11c (100 mg, 13% yield) as a yellow solid. LCMS: [M+H] + = 177.1

[0133] Synthesis of intermediate 13c:

[0134]

[0135] Step 1: 4-(Bis(4-methoxybenzyl)amino)-N-hydroxypicolylamide (13b)

[0136] Compound 4-(bis(4-methoxybenzyl)amino)picolinate 13a (800 mg, 2.1 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (10 mL), and N,N'-carbonyldiimidazole (411.32 mg, 2.5 mmol, 1.2 eq) was added. The mixture was stirred at 25 °C for 2 h. Then hydroxylamine hydrochloride (882.81 mg, 10.6 mmol, 5.0 eq) was added. The reaction mixture was stirred at 25 °C for 2 h. After completion of the reaction monitored by LCMS, the reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 13b (500 mg, 60% yield) as a brown solid. LCMS: [M+H] + = 394.2

[0137] Step 2: 4-Amino-N-hydroxypicolylamide (13c)

[0138] Compound 13b (500 mg, 1.3 mmol, 1.0 eq) was dissolved in trifluoroacetic acid (3 mL). The reaction mixture was stirred at 60 °C for 4 h. After completion of the reaction monitored by LCMS, the reaction mixture was concentrated. The residue was dissolved in dichloromethane, and hydrochloric acid ethyl ether solution (2 mL) was added and concentrated to obtain compound 13c (260 mg, 93% yield) as a brown solid in the form of hydrochloride. LCMS: [M+H] + = 154.2

[0139] Synthesis of intermediate 14d:

[0140]

[0141] Step 1: Methyl 4-(bis(4-methoxybenzyl)amino)picolinate (14a)

[0142] In a microwave tube, successively add bis(4-methoxybenzyl)amine (4 g, 1.8 mmol, 1.0 eq), methyl 4-bromopicolinate (6.2 g, 2.4 mmol, 1.3 eq), 1,1′-[1,1′-dinaphthalene]-2,2′-diylbis[1,1-diphenyl-(ACI)phosphine (580 mg, 0.09 mmol, 0.05 eq), palladium(II) acetate (210 mg, 0.09 mmol, 0.05 eq), cesium carbonate (12.06 g, 3.7 mmol, 2.0 eq), and toluene (40 mL). React and stir at 100 °C for 4 hours. Monitor the reaction by LCMS. After the reaction is completed, filter the reaction solution and concentrate the filtrate. The residue is separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 14a (3.2 g, 44% yield) as a yellow solid. LCMS: [M+H] + = 393.2

[0143] Step 2: 4-(Bis(4-methoxybenzyl)amino)picolinic acid (14b)

[0144] Dissolve compound methyl 4-(bis(4-methoxybenzyl)amino)picolinate 14a (3.2 g, 8.2 mmol, 1.0 eq) in methanol / tetrahydrofuran / water = 3 / 3 / 1 (30 mL), add lithium hydroxide monohydrate (1 g, 24.6 mmol, 3.0 eq), and react and stir at 25 °C for 16 hours. Monitor the reaction by LCMS. After the reaction is completed, pour the reaction solution into water, adjust the pH value to ~5 with 1N dilute hydrochloric acid, extract with ethyl acetate, wash the organic phase with brine, dry the organic phase, and concentrate to obtain compound 4-(bis(4-methoxybenzyl)amino)picolinic acid 14b (2 g, 65% yield) as a yellow solid. LCMS: [M+H] + = 379.1

[0145] Step 3: 4-(Bis(4-methoxybenzyl)amino)-N-methoxypyridinecarboxamide (14c)

[0146] Dissolve compound 4-(bis(4-methoxybenzyl)amino)picolinate 14b (200 mg, 0.53 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), add N,N'-carbonyldiimidazole (102.8 mg, 0.63 mmol, 1.2 eq), and stir at 25 °C for 2 hours. Then add methoxyamine hydrochloride (221 mg, 10.6 mmol, 5.0 eq). The reaction mixture is stirred at room temperature for 2 hours. After monitoring the completion of the reaction by LCMS, pour the reaction mixture into water, extract with ethyl acetate, wash the organic phase with brine, dry the organic phase, and concentrate. The residue is separated and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 4-(bis(4-methoxybenzyl)amino)-N-methoxypicolinamide 14c (140 mg, 65% yield) as a brown solid. LCMS: [M+H] + = 408.1

[0147] Step 4: 4-Amino-N-methoxypicolinamide (14d)

[0148] Dissolve compound 4-(bis(4-methoxybenzyl)amino)-N-methoxypicolinamide 14c (100 mg, 0.24 mmol, 1.0 eq) in trifluoroacetic acid (2 mL). The reaction mixture is stirred at 60 °C for 4 hours. After monitoring the completion of the reaction by LCMS, concentrate the reaction mixture. Dissolve the residue in dichloromethane, add hydrochloric acid ether (2 mL), and concentrate to obtain compound 4-amino-N-methoxypicolinamide 14d (80 mg, 78% yield) as a brown solid in the form of hydrochloride. LCMS: [M+H] + = 168.1

[0149] Synthesis of intermediate 18d:

[0150]

[0151] Step 1: Methyl 2-cyano-5-nitrobenzoate (18b)

[0152] Add 18a (3 g), cuprous cyanide (2 g), and DMF (30 mL) to a reaction flask, stir well, and sequentially add Pd2(dba)3 (527 mg) and dppf (638 mg). Perform nitrogen displacement three times, and stir at 115 °C for 16 hours. Cool the reaction mixture to room temperature, add water (70 mL), extract with ethyl acetate (40 mL × 3), combine the organic phases, concentrate, and separate by column chromatography (EA / PE, 0% - 15%) to obtain 2 g of a white solid with a yield of 84.4%. LCMS: m / z (254 nm): 207.0 [M+H] +

[0153] Step 2: 2-Cyano-5-nitrobenzamide (18c)

[0154] Add 18b (1 g) and ammonia methanol solution (7 M, 10 mL) to the reaction flask, and stir at room temperature for 16 hours. Filter the reaction solution by suction, wash with methanol to obtain 720 mg of light yellow solid, with a yield of 77.6%. LCMS: m / z (254 nm): 192.0 [M+H] +

[0155] Step 3: 2-Cyano-5-aminobenzamide (18d)

[0156] Add 18c (300 mg), MeOH (10 mL) and THF (10 mL) to the reaction flask. After stirring evenly, add palladium / carbon (30 mg), and perform three hydrogen displacements. Stir at room temperature for 6 hours, and monitor the reaction by TLC until the raw materials are completely converted. Filter the reaction solution through diatomaceous earth, concentrate the filtrate to obtain 179 mg of yellow solid, with a yield of 71%. LCMS: m / z (254 nm): 162.0 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 2H), 7.58 (d, 1H), 6.77 (d, 1H), 6.73 (dd, 1H), 5.99 (s, 2H).

[0157] Synthesis of intermediate 20f:

[0158]

[0159] Step 1: 2-Bromo-3-fluoro-5-nitrobenzoic acid (20a)

[0160] Dissolve compound 2-bromo-3-fluorobenzoic acid (5 g, 22.8 mmol, 1.0 eq) in concentrated sulfuric acid (15 mL), and add fuming nitric acid (1 mL) at 0 °C. Stir the reaction mixture at 25 °C for 4 hours, and monitor the reaction by LCMS until completion. Slowly pour the reaction solution into ice water, extract with dichloromethane (50 mL x 3), and collect the organic phase. Wash the organic phase with saturated brine (50 mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate to obtain a residue. Purify the residue by C18 column chromatography (0.1% FA / acetonitrile = 1 / 4) to obtain compound 2-bromo-3-fluoro-5-nitrobenzoic acid 20a (800 mg, 13%) as a yellow solid. LCMS: [M+H] + = 263.9。

[0161] Step 2: Methyl 2-bromo-3-fluoro-5-nitrobenzoate (20b)

[0162] Dissolve compound 2-bromo-3-fluoro-5-nitrobenzoic acid 20a (800 mg, 3.03 mmol, 1.0 eq) in methanol (5 mL), and add thionyl chloride (1 mL). The reaction mixture was stirred at 80 °C for 6 hours. The reaction was monitored by LCMS until completion. The reaction solution was filtered to obtain a filtrate. After concentration of the filtrate, compound methyl 2-bromo-3-fluoro-5-nitrobenzoate 20b (800 mg, 95%) was obtained as a yellow solid. LCMS: [M+H] + = 277.9.

[0163] Step 3: Dimethyl 3-fluoro-5-nitrobenzoate (20c)

[0164] Dissolve compound methyl 2-bromo-3-fluoro-5-nitrobenzoate 20b (400 mg, 1.43 mmol, 1.0 eq) in methanol (10 mL), and add Pd(dppf)Cl2 (32 mg, 0.143 mmol, 0.1 eq) and Et3N (437 mg, 4.32 mmol, 3.0 eq). The reaction solution was stirred at 80 °C for 16 hours in the presence of carbon monoxide (0.1 MPa). The reaction solution was concentrated to obtain a residue, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound dimethyl 3-fluoro-5-nitrobenzoate 20c (40 mg, 11%) as a brown oil. LCMS: [M+H]+ = 258.1.

[0165] Step 4: Ammonium 3-fluoro-5-nitrophthalate (20d)

[0166] Dissolve compound dimethyl 3-fluoro-5-nitrobenzoate 20c (40 mg, 0.155 mmol, 1.0 eq) in ammonia-methanol (5 mL). The reaction solution was stirred at 25 °C for 16 hours. The reaction solution was concentrated to obtain a residue, and the residue was washed with dichloromethane, filtered, and the solid was collected to obtain compound ammonium 3-fluoro-5-nitrophthalate 20d (20 mg, 57%) as a white solid. LCMS: [M+H]+ = 228.1.

[0167] Step 5: Ammonium 3-fluoro-5-aminophthalate (20f)

[0168] Dissolve compound ammonium 3-fluoro-5-nitrophthalate 20d (20 mg, 0.088 mmol, 1.0 eq) in methanol (5 mL). The reaction solution was stirred at 25 °C for 1 hour in the presence of hydrogen. The reaction solution was filtered, and the filtrate was collected and concentrated to obtain compound ammonium 3-fluoro-5-aminophthalate 20f (13 mg, 75%) as a yellow solid. LCMS: [M+H] + = 198.1.

[0169] Synthesis of Intermediate 21c:

[0170]

[0171] Step 1: 2-Fluoro-5-nitrobenzenesulfonamide (21b)

[0172] Dissolve p-fluoronitrobenzene 21a (2.0 g, 14.2 mmol, 1.0 eq) in chlorosulfonic acid (10 mL). Stir the reaction mixture at 110 °C for 24 h, and then cool the reaction solution to room temperature. Slowly pour the reaction solution into an ice bath. After all the ice cubes have melted, extract with ethyl acetate (50 mL x 3), and collect the organic phase. Wash the organic phase with saturated brine (50 mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate to obtain a residue. Dissolve the residue in ethyl acetate (60 mL), and slowly add ammonia water (60 mL) at 0 °C. Stir the reaction mixture at 25 °C for 16 h. After monitoring the completion of the reaction by TLC, pour the reaction solution into water, extract with ethyl acetate (50 mL x 3), and collect the organic phase. Wash the organic phase with saturated brine (50 mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate to obtain a residue. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 3) to obtain compound 2-fluoro-5-nitrobenzenesulfonamide 21b (400 mg, 13% yield) as a yellow solid. 1 1H NMR (400 MHz, DMSO) δ 8.56 - 8.53 (m, 2H), 8.06 (s, 2H), 7.86 - 7.65 (m, 1H).

[0173] Step 2: 5-Amino-2-fluorobenzenesulfonamide (21c)

[0174] Dissolve compound 2-fluoro-5-nitrobenzenesulfonamide 21b (200 mg, 0.90 mmol, 1.0 eq) in methanol (5 mL), and add wet palladium on carbon (193 mg, 1.80 mmol, 2.0 eq). Stir the reaction mixture at 25 °C for 1 h in the presence of hydrogen. Monitor the completion of the reaction by LCMS. Filter the reaction solution to obtain a filtrate. Concentrate the filtrate to obtain compound 5-amino-2-fluorobenzenesulfonamide 21c (160 mg, 92% yield) as a black solid. LCMS: [M+H] + = 191.1

[0175] Preparation of Intermediate 25g:

[0176]

[0177] Step 1: (3Z)-4-(3,4-Difluoro-2-methoxyphenyl)-1,1,1-trifluoro-3-methylbut-3-en-2-one (25a)

[0178] Add toluene (25 mL), 3,4-difluoro-2-methoxybenzaldehyde (5.0 g, 29.0 mmol, 1.0 eq), 1,1,1-trifluorobutan-2-one (11 g, 87.2 mmol, 3.0 eq), piperidine acetate (4.2 g, 29.0 mmol, 1.0 eq), and acetic acid (0.9 g, 14.5 mmol, 0.5 eq) into the reaction flask in sequence. Seal the flask and react at room temperature for 2 hours. Then heat the temperature to 75 °C and continue the reaction for 16 hours. Monitor the reaction by TLC until it is complete. Extract with water and ethyl acetate, take the ethyl acetate layer, concentrate it, and separate it by column chromatography (PE:EA = 20:1) to obtain 25a (7.5 g, 92% yield) as a yellow liquid.

[0179] Step 2: rac-(2R,3S)-Ethyl 3-(3,4-difluoro-2-methoxyphenyl)-4-methyl-5-(trifluoromethyl)-2,3-dihydrofuran-2-carboxylate (25b)

[0180] Add acetonitrile (25 mL), compound 25a (2.5 g, 8.9 mmol, 1.0 eq), (ethoxycarbonylmethyl)dimethylsulfonium bromide (2.6 g, 11.6 mmol, 1.3 eq), and cesium carbonate (3.8 g, 11.6 mmol, 1.3 eq) into the reaction flask in sequence. React at room temperature for 16 hours. Monitor the reaction of compound 25a by TLC (PE:EA = 10:1) until it is complete. Filter, take the filtrate, concentrate it, and separate it by column (PE:EA = 20:1) to obtain 2.3 g of a yellow liquid (72% yield).

[0181] Step 3: rac-(2R,3S)-3-(3,4-Difluoro-2-methoxyphenyl)-4-methyl-5-(trifluoromethyl)-2,3-dihydrofuran-2-carboxamide (25c)

[0182] Dissolve compound 25b (5 g, 13.6 mmol, 1.0 eq) in ammonia / methanol (7M, 15 mL). React the reaction solution at 80 °C for 16 hours. Monitor by LCMS until the raw materials are completely reacted. Concentrate the reaction solution, and purify the residue by silica gel column (dichloromethane / methanol = 20 / 1) to obtain compound 25c (3.8 g, 83% yield) as a white solid. LCMS: [M+H] + = 338.0

[0183] Step 4: rac-(1R,3R,4R,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-1-(trifluoromethyl)-6-(trimethylsilyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamide (25d)

[0184] Dissolve compound 25c (2.0 g, 5.9 mmol, 1.0 eq) in dichloroethane (50 mL), and add compound trimethyl(vinyl)silane (11.8 g, 11.8 mmol, 20.0 eq). The reaction solution was irradiated with a mercury lamp and reacted at 25 °C for 16 hours. The reaction mixture was concentrated, and the residue was purified by preparative separation (0.01% FA / acetonitrile = 1 / 1) to obtain compound 25d (600 mg, 23% yield) as a yellow oil. LCMS: [M+H] + = 438.2

[0185] Step 5: rac-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxamide (25e)

[0186] Dissolve compound 25d (500 mg, 3.0 mmol, 1.0 eq) in dimethyl sulfoxide (20 mL), and add tetrabutylammonium fluoride trihydrate (6.4 g, 22.8 mmol, 20 eq). The reaction solution was reacted at 100 °C for 16 hours. The reaction mixture was concentrated, and the residue was purified by preparative separation (0.01% FA / acetonitrile = 3 / 2) to obtain compound 25e (170 mg, 40% yield) as a yellow oil. LCMS: [M+H] + = 366.1

[0187] Step 6: rac-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxylic acid (25f)

[0188] Dissolve compound 25d (170 mg, 0.387 mmol, 1.0 eq) in ethanol / water (3 mL + 1 mL), and add potassium hydroxide (217 mg, 3.87 mmol, 10 eq). The reaction solution was reacted at 100 °C for 4 hours. The reaction was monitored by LCMS until completion. Add 1 M dilute hydrochloric acid to the reaction solution to adjust the pH to 5 - 6, and extract with ethyl acetate (10 mL × 3). Collect the organic phase. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 25f (100 mg, 70% yield) as a yellow oil. LCMS: [M+H] + = 367.1.

[0189] Step 5: rac-(1R,3R,4S,5R)-4-(3,4-difluoro-2-trideuteriomethoxyphenyl)-5-methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxylic acid (25 g)

[0190] Using a method similar to that of intermediate 1d, intermediate 25g was prepared. LCMS: m / z (254 nm): 368.3 [M-H] - 。

[0191] Preparation of intermediate 33b: 5-bromo-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[0192]

[0193] Dissolve 4-bromo-2-fluorobenzenesulfonyl chloride 33a (200 mg, 1.0 eq) in THF (5 mL), cool to 0 °C, and under nitrogen protection, add dropwise NaHMDS (0.9 mL, 1.0 M, 1.2 eq). After 1 hour, add a solution of tert-butyl thiazole-4-carbamate (161 mg, 1.1 eq) in THF (1 mL). After slowly warming to room temperature, add saturated ammonium chloride solution, extract with ethyl acetate (20 mL * 3), combine the organic phases, wash with brine, dry over sodium sulfate, filter, concentrate by evaporation, and purify by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 5-bromo-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide 33b (150 mg, 60% yield) as a white solid. LCMS: [M+H] + = 336.8, 338.8。

[0194] Preparation of intermediate 34c:

[0195]

[0196] Step 1: Benzyl (2-(S-methylsulfinyl)pyridin-4-yl)carbamate (34b)

[0197] Weigh 34a (2.2 g, 8.0 mmol, 1.0 eq) into a reaction flask, add iodobenzene diacetate (8.3 g, 25.7 mmol, 3.2 eq), carbamic amide (4.3 g, 56.2 mmol, 7.0 eq), dichloromethane (150 mL) and methanol (150 mL). React at room temperature for 16 hours, and detect the completion of the reaction by LCMS. After concentrating the reaction solution, purify by column chromatography (petroleum ether:ethyl acetate = 0 - 100%) to obtain 34b as a yellow solid (2.3 g, 94% yield). LCMS: [M+H] + = 306.4。

[0198] Step 2: (4-Aminopyridin-2-yl)(imino)(methyl)-1-6-sulfonic ketone (34c)

[0199] Dissolve compound 34b (300 mg, 0.98 mmol, 1.0 eq) in methanol (10 mL), and add palladium on carbon (314 mg, 2.95 mmol, 3.0 eq). The reaction mixture is reacted under hydrogen at 25 °C for 16 hours. The reaction is monitored by LCMS until completion. The reaction mixture is filtered, and the filtrate is collected and concentrated to obtain a residue. The residue is purified by silica gel column (dichloromethane / methanol = 10 / 1) to obtain compound 34c (100 mg, 59% yield) as a white solid. LCMS: [M+H] + = 172.1

[0200] Preparation of intermediate 35b:

[0201]

[0202] Step 1: Benzyl (2-(N,S-dimethylsulfoximino)pyridin-4-yl)carbamate (35a)

[0203] Dissolve compound 34b (300 mg, 0.98 mmol, 1.0 eq) in acetonitrile (20 mL), and add tetraethylsilane (283 mg, 1.96 mmol, 2.0 eq), formaldehyde (294 mg, 4.91 mmol, 5.0 eq) and trifluoroacetic acid (233 mg, 2.94 mmol, 3.0 eq). The reaction mixture is reacted at 25 °C for 16 hours. The reaction is monitored by LCMS until completion. The reaction mixture is concentrated to obtain a residue. The residue is purified by silica gel column (dichloromethane / methanol = 30 / 1) to obtain compound 35a (300 mg, 95% yield) as a colorless oil. LCMS: [M+H] + = 320.1

[0204] Step 2: (4-Aminopyridin-2-yl)(methyl)(methylimino)-1-6-sulfonic ketone (35b)

[0205] Dissolve compound 35a (300 mg, 0.94 mmol, 1.0 eq) in methanol (10 mL), and add palladium on carbon (300 mg, 2.82 mmol, 3.0 eq). The reaction mixture is reacted under hydrogen at 25 °C for 16 hours. The reaction is monitored by LCMS until completion. The reaction mixture is filtered, and the filtrate is collected and concentrated to obtain a residue. The residue is purified by silica gel column (dichloromethane / methanol = 10 / 1) to obtain compound 35b (150 mg, 86% yield) as a white solid. LCMS: [M+H] + = 186.1

[0206] Preparation of Intermediate 42b:

[0207]

[0208] Step 1: 2-(Methylthio)pyridin-4-amine (42b)

[0209] Sodium methylthiolate (1.9 g, 27.0 mmol, 1.7 eq) was dissolved in 1-methylpyrrolidone (10 mL), and 2-chloropyridin-4-amine 42a (2.0 g, 16.0 mmol, 1.0 eq) was added. The container was sealed and heated to 200 °C in a microwave oven for 15 minutes. Purification by silica gel flash chromatography eluted with 8% methanol / dichloromethane gave 2-(methylthio)pyridin-4-amine 42b (1.5 g, 55% yield) as a yellow solid. LCMS: [M+H] + = 141.0.

[0210] Step 2: 2-(Methylsulfonyl)pyridin-4-amine (42c)

[0211] 2-(Methylthio)pyridin-4-amine (100 mg, 0.7 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL), and m-chloroperbenzoic acid (369 mg, 2.1 mmol, 3.0 eq) was added. The mixture was stirred at 25 °C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to give a mixture. The mixture was purified by column chromatography (dichloromethane / methanol = 10 / 1) to give 2-(methylsulfonyl)pyridin-4-amine 42c (30 mg, 22% yield) as a yellow solid. LCMS: [M+H] + = 173.0.

[0212] Preparation of Intermediate 43b: (4-Aminopyridin-2-yl)dimethylphosphine oxide

[0213]

[0214] In a microwave tube, compound 2-bromopyridin-4-amine 43a (200 mg, 1.16 mmol, 1.0 eq) was dissolved in 1,4-dioxane (3 mL), and then compound dimethylphosphine oxide (180 mg, 2.31 mmol, 2.0 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (67 mg, 0.12 mmol, 0.1 eq), tris(dibenzylideneacetone)palladium (106 mg, 0.12 mmol, 0.1 eq) and potassium carbonate (320 mg, 2.3 mmol, 2.0 eq) were added. The reaction mixture was subjected to microwave reaction at 130 °C for 2 hours under a nitrogen atmosphere. The reaction was monitored by LCMS until the raw materials were completely reacted. The reaction solution was concentrated, and the residue was purified by silica gel column (petroleum ether / ethyl acetate = 8 / 1) to obtain compound (4-aminopyridin-2-yl)dimethylphosphine oxide 43b (150 mg, 76% yield) as a yellow solid.

[0215] Preparation of intermediate 44d:

[0216]

[0217] Step 1: 2-Amino-5-nitrobenzenesulfonamide (44b)

[0218] To the reaction flask were added 44a (2.0 g, 8.45 mmol, 1.0 eq), ammonium carbonate (1.62 g, 16.9 mmol, 2.0 eq), copper sulfate (405 mg, 2.54 mmol, 0.3 eq) and ammonia water (10 mL). The mixture was stirred at 120 °C for 6 hours, and the reaction was monitored by TLC until the raw materials were basically completely converted. The reaction solution was cooled to room temperature, poured into water, and a solid was precipitated. The mixture was filtered by suction, and the filter cake was washed with water and dried to obtain compound 44b (1.3 g, 71% yield) as a nitrogen-yellow solid. LCMS: 218.1 [M+H] + .

[0219] Step 2: 7-Nitro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (44c)

[0220] To the reaction flask were added 44b (600 mg, 2.76 mmol, 1.0 eq) and trimethyl orthoformate (10 mL). The mixture was stirred at 140 °C for 8 hours, and the reaction was monitored by TLC until the raw materials were basically completely converted. The reaction solution was cooled to room temperature, poured into water, and a solid was precipitated. The mixture was filtered by suction, and the filter cake was washed with water and dried to obtain compound 44c (230 mg, 37% yield) as a pale white solid. LCMS: 228.1 [M+H] + .

[0221] Step 3: 7-Amino-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (44d)

[0222] 44c (200 mg, 0.88 mmol, 1.0 eq), iron powder (246 mg, 4.4 mmol, 5.0 eq), ammonium chloride (141 mg, 2.64 mmol, 3.0 eq), ethanol (5 mL) and water (2 mL) were added to a reaction flask, and the mixture was stirred at 75 °C for 2 h. The raw materials were monitored by LCMS and were basically completely converted. The reaction solution was filtered through diatomaceous earth while it was hot, the filtrate was concentrated, and column chromatography separation (MeOH / DCM, 0-10%) gave compound 44d (82 mg, yield 47%) as a light yellow solid. LCMS: 198.2 [M+H] + .

[0223] Preparation of intermediate 54b:

[0224]

[0225] Step 1: Synthesis of (2R,3S,4S,5R)-3-{(3,4-difluoro-2-[(fluoromethyl)oxy]phenyl)}-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid fluoromethyl ester (54a)

[0226] 1b (100 mg, 0.29 mmol, 1.0 eq), fluoromethyliodide (0.23 g, 1.5 mmol, 5.0 eq), potassium carbonate (0.38 g, 2.9 mmol, 10.0 eq) and acetonitrile (10 mL) were added to a reaction flask, and the reaction was carried out at room temperature for 18 h. The raw materials were monitored by LCMS and the reaction was complete (the product had no MS response). Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 54a (0.145 g, crude product) as a yellow liquid.

[0227] Step 2: Synthesis of compound (2R,3S,4S,5R)-3-{(3,4-difluoro-2-[(fluoromethyl)oxy]phenyl)}-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (54b)

[0228] Compound 54a (0.145 g, 0.29 mmol, 1.0 eq), sodium hydroxide (0.06 g, 1.5 mmol, 5.0 eq), water (10 mL) and methanol (10 mL) were added to a reaction flask, and the reaction was carried out at room temperature for 16 h. The reaction was monitored by LCMS until the raw materials were completely reacted. The reaction solution was concentrated, adjusted to pH = 1 with hydrochloric acid (2 M), water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (EA / PE, 0 - 100%) to obtain compound 54b (110 mg, yield 100%) as a yellow liquid. LCMS: 371.0 [M - H] - .

[0229] Preparation of intermediate 55b:

[0230]

[0231] Step 1: (2R,3S,4S,5R)-3-(3,4-difluoro-2-difluoromethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid difluoromethyl ester (55a)

[0232] To a single-necked reaction flask, 1b (50 mg, 0.15 mmol, 1.0 eq) and acetonitrile (5 mL) were added. Aqueous solution of potassium hydroxide (99 mg, 1.8 mmol, 12.0 eq) in water (11 mL) was added, and difluoromethyl trifluoromethanesulfonate (88 mg, 0.44 mmol, 3.0 eq) was added. The reaction was carried out at room temperature for half an hour. The reaction was terminated by LCMS detection when most of the raw materials were completely reacted. The reaction system was adjusted to pH = 5 with 1N hydrochloric acid, extracted with ethyl acetate, and the ethyl acetate layer was taken, concentrated and purified by column chromatography (PE:EA = 0 - 100%) to obtain compound 55a (30 mg). LCMS: m / z (254 nm): 441.0 [M + H] + 。

[0233] Step 2: (2R,3S,4S,5R)-3-(3,4-difluoro-2-difluoromethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (55b)

[0234] Intermediate 55b was prepared by a synthetic method similar to that of intermediate 1d (LCMS: m / z (254 nm): 389.1 [M - H] - 。

[0235] Example 1: (2R,3S,4S,5R)-3-(3,4-difluoro-2-trideuteriomethoxyphenyl)-4,5-dimethyl-N-(3-oxoisoindolin-5-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0236]

[0237] Add 1d (0.16 g, 0.45 mmol, 1.0 eq), 4-aminobenzene-1,2-dicarboxamide (0.12 g, 0.67 mmol, 1.5 eq), HATU (0.255 g, 0.67 mmol, 1.5 eq), triethylamine (0.113 g, 1.12 mmol, 2.5 eq) and DMF (2 mL) to a single-neck reaction flask, and react at 30 °C for 16 h. The reaction was detected to be complete by LCMS, extracted with water and ethyl acetate, the ethyl acetate layer was taken, concentrated, and eluted by column chromatography (MeOH / DCM = 0 - 20%) to obtain Example 1 (0.22 g, 94% yield). 1 H NMR (400 MHz, CD3OD) δ 7.82 (d, J = 2.0 Hz, 1H), 7.73 (dd, J = 8.4, 2.1 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.15–7.09 (m, 1H), 6.97 (dd, J = 17.0, 9.3 Hz, 1H), 5.06 (d, J = 10.5 Hz, 1H), 4.34–4.27 (m, 1H), 2.78 (dd, J = 15.4, 7.8 Hz, 1H), 1.66 (s, 3H), 0.81 (d, J = 7.4 Hz, 3H).

[0238] Example 54: 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(fluoromethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)phthalimide

[0239] Replace 1d with intermediate 54b, and prepare Example 54 by a synthetic method similar to that of Example 1. ESI-MS m / z = 534.1 (M+1) + 。 1 H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 7.74–7.66 (m, 4H), 7.49 (d, J = 8.3 Hz, 1H), 7.37–7.24 (m, 4H), 5.90 (dd, J = 5.9, 2.5 Hz, 1H), 5.76 (dd, J = 6.2, 2.5 Hz, 1H), 5.11 (d, J = 10.4 Hz, 1H), 4.32 (dd, J = 10.3, 7.7 Hz, 1H), 2.84–2.75 (m, 1H), 1.59 (s, 3H), 0.74 (d, J = 6.0 Hz, 3H).

[0240] Example 55: 4-((2R,3S,4S,5R)-3-(3,4-Difluoro-2-(difluoromethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)phthalimide

[0241] Replace 1d with intermediate 55b and prepare Example 55 by a synthetic method similar to that of Example 1. ESI-MS m / z = 552.1 (M+1) + 。 1 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 7.73–7.66 (m, 4H), 7.53–7.08 (m, 6H), 5.13 (d, J = 10.3 Hz, 1H), 4.27 (dd, J = 10.1, 7.7 Hz, 1H), 2.79–2.72 (m, 1H), 1.59 (s, 3H), 0.76 (d, J = 6.1 Hz, 3H).

[0242] Table 1: Using the corresponding reagents as raw materials, prepare the following compounds according to the operations similar to those described in Example 1.

[0243]

[0244]

[0245]

[0246]

[0247]

[0248] Example 12:

[0249]

[0250] Step 1: 4-({[(2R,3S,4S,5R)-3-{3,4-Difluoro-2-[(trideuteriomethyl)oxy]phenyl}-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]carbonyl}amino)pyridine-2-carboxamide (12a)

[0251] Prepare intermediate 12a according to the operations similar to those described in Example 1. LCMS: [M+H] + = 477.2.

[0252] Step 2: 2-formamido-4-({[(2R,3S,4S,5R)-3-{3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl}-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]carbonyl}amino)-1-methylpyridin-1-ium (Example 12)

[0253] Into a microwave tube, compound 12a (42 mg, 0.08 mmol, 1.0 eq), methyl iodide (1 mL), and acetonitrile (2 mL) were successively added. The reaction solution was reacted at 80 °C for 16 h under nitrogen protection. After the reaction was monitored by LCMS and completed, the reaction mixture was concentrated, and the residue was purified by preparative separation (0.01% ammonia water) to obtain compound 12 (12 mg, 27% yield). LCMS: [M+H] + = 492.2.

[0254] Example 15: (2R,3S,4S,5R)-N-[2-(aminothiomethylidene)pyridin-4-yl]-3-{3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl}-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0255]

[0256] Compound 12a (30 mg, 0.06 mmol, 1.0 eq) was dissolved in toluene (20 mL), Lawesson's reagent (26 mg, 0.06 mmol, 1.0 eq) was added, and the temperature was raised to 110 °C for reaction for 24 h. After the reaction was completed, the solvent was removed by concentration, and Example 15 (15 mg, 48% yield) was prepared by thin-layer chromatography. LCMS: [M+H] + = 493.2.

[0257] Example 22:

[0258]

[0259] Step 1: 2-(benzylthio)-4-bromopyridine (22b)

[0260] Dissolve compound benzyl mercaptan 22a (2.0 g, 16.1 mmol, 1.0 eq) in anhydrous tetrahydrofuran (30 mL), and add sodium hydride (640 mg, 16.1 mmol, 1.0 eq) under nitrogen protection at 0 °C. Stir the reaction solution at 0 °C for 30 minutes. Add a solution of compound 4-bromo-2-fluoropyridine (2.8 g, 16.1 mmol, 1.0 eq) in anhydrous tetrahydrofuran (10 mL) at this temperature. After the addition is complete, stir at 0 °C for 1.5 hours. Monitor the reaction of the starting materials by LCMS. After the reaction of the starting materials is complete, add water (50 mL) to the reaction solution, extract with ethyl acetate (20 mL × 3), then wash with saturated brine, dry over anhydrous sodium sulfate and concentrate. The residue is purified by silica gel column (petroleum ether / ethyl acetate = 50 / 1) to obtain compound 2-(benzylthio)-4-bromopyridine 22b (4.3 g, 95% yield) as a pink oil. LCMS: [M+H] + = 280.0

[0261] Step 2: 4-Bromopyridine-2-sulfonyl chloride (22c)

[0262] Dissolve compound 2-(benzylthio)-4-bromopyridine 22b (4.3 g, 15.3 mmol, 1.0 eq) in dichloromethane: acetic acid: water = 7:1:2 (80 mL), and add 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (1.1 g, 7.2 mmol, 0.7 eq). React the reaction solution under nitrogen protection at 25 °C for 16 hours. Monitor the reaction of the starting materials by TLC. After the reaction of the starting materials is complete, add water (20 mL) to the reaction solution, extract with dichloromethane (20 mL × 3), then wash with saturated brine, dry over anhydrous sodium sulfate and concentrate. Dilute with dichloromethane and filter. Rotate the filtrate to dryness to obtain crude compound 4-bromopyridine-2-sulfonyl chloride 22c (4.5 g, 92% yield) as a yellow oil.

[0263] Step 3: 4-Bromopyridine-2-sulfonamide (22d)

[0264] Add ammonia water (10 mL) to compound 4-bromopyridine-2-sulfonyl chloride 22c (3.0 g, 9.4 mmol, 1.0 eq). React the reaction solution at 25 °C for 1 hour. Monitor the reaction of the starting materials by LCMS. After the reaction of the starting materials is complete, concentrate the reaction solution. The residue is purified by silica gel column (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 4-bromopyridine-2-sulfonamide 22d (1.7 g, 77% yield) as a gray solid. LCMS: [M+H] + = 238.9

[0265] Step 4: tert-Butyl ((4-bromopyridin-2-yl)sulfonyl)carbamate (22e)

[0266] Compound 4-bromopyridine-2-sulfonamide 22d (500 mg, 2.1 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), and triethylamine (213 mg, 2.1 mmol, 1.0 eq), 4-dimethylaminopyridine (13 mg, 0.10 mmol, 0.05 eq) and di-tert-butyl dicarbonate (483 mg, 2.2 mmol, 1.05 eq) were added. The reaction mixture was stirred at 25 °C for 1 h. The reaction was monitored by LCMS until the starting material was consumed. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give tert-butyl ((4-bromopyridin-2-yl)sulfonyl)carbamate 22e (611 mg, 85% yield) as a yellow oil. LCMS: [M+Na] + = 359.0

[0267] Step 5: tert-butyl ((4-bromopyridin-2-yl)sulfonyl)(methyl-d3)carbamate (22f)

[0268] tert-Butyl ((4-bromopyridin-2-yl)sulfonyl)carbamate 22e (200 mg, 0.59 mmol, 1.0 eq) was dissolved in anhydrous N,N-dimethylformamide (5 mL), and potassium carbonate (123 mg, 0.88 mmol, 1.5 eq) and iodomethane-d3 (94 mg, 0.65 mmol, 1.1 eq) were added. The reaction mixture was stirred at 60 °C for 2 h. The reaction was monitored by LCMS until the starting material was consumed. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 22f (130 mg, 62% yield) as a white solid. LCMS: [M+Na] + = 376.0

[0269] Step 6: (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (22g)

[0270] 4-Aminobenzene-1,2-dicarboxamide in Example 1 was replaced with ammonium chloride, and Intermediate 22g was obtained by a method similar to that in Example 1. LCMS: [M+H] + = 357.1

[0271] Step 7: ({[4-({[(2R,3S,4S,5R)-3-{3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl}-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]carbonyl}amino)pyridin-2-yl]dioxo-yl-λ 6-thiol}(trideuteriomethyl)amino)methanoic acid 2-methylpropan-2-yl ester (22h)

[0272] Compound 22f (70 mg, 0.20 mmol, 1.0 eq) was dissolved in dioxane (5 mL), and compound 22g (139 mg, 0.24 mmol, 1.2 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23 mg, 0.04 mmol, 0.1 eq), cesium carbonate (128 mg, 0.39 mmol, 2.0 eq) and palladium(II) acetate (3 mg, 0.02 mmol, 0.1 eq) were added. The reaction mixture was stirred at 105 °C under nitrogen for 16 h. LCMS was used to monitor the completion of the reaction of the starting materials. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 22h (65 mg, 51% yield) as a yellow oil. LCMS: [M+H] + = 630.2

[0273] Step 8: (2R,3S,4S,5R)-3-{3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl}-N-(2-{dioxo[(trideuteriomethyl)amino]-λ 6 -thiol}pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0274] 22h (50 mg, 0.08 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), and p-toluenesulfonic acid (13.7 mg, 0.08 mmol, 1.0 eq) was added. The reaction mixture was stirred at 25 °C for 16 h. LCMS was used to monitor the completion of the reaction of the starting materials. The reaction mixture was concentrated, and the residue was purified by preparative separation (0.05% NH3) to give Example 82 (10.0 mg, 24% yield). LCMS: [M+H] + = 530.2

[0275] Example 23:

[0276]

[0277] Step 1: tert-Butyl ((4-bromopyridin-2-yl)sulfonyl)(ethyl)carbamate (23a)

[0278] Compound tert-butyl ((4-bromopyridin-2-yl)sulfonyl)carbamate 22e (200 mg, 0.59 mmol, 1.0 eq) was dissolved in anhydrous N,N-dimethylformamide (5 mL), and potassium carbonate (123 mg, 0.88 mmol, 1.5 eq) and iodoethane (101 mg, 0.65 mmol, 1.1 eq) were added. The reaction mixture was allowed to react at 60°C for 2 hours. LCMS confirmed the completion of the reaction. Water (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (10 mL x 3). The mixture was then washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified on a silica gel column (petroleum ether / ethyl acetate = 10 / 1) to afford compound tert-butyl ((4-bromopyridin-2-yl)sulfonyl)(ethyl)carbamate 23a (130 mg, 60% yield) as a yellow oil. LCMS: [M+Na] + =387.0

[0279] Step 2: (ethyl{[4-({[(2R,3S,4S,5R)-3-{3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl}-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]carbonyl}amino)pyridin-2-yl]dioxy-λ 6 -sulfanyl}amino)methane acid-2-methylprop-2-yl ester (23b)

[0280] Compound 23a (130 mg, 0.35 mmol, 1.0 eq) was dissolved in dioxane (5 mL), and 22 g (197 mg, 0.39 mmol, 1.2 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (41 mg, 0.07 mmol, 0.2 eq), cesium carbonate (231 mg, 0.71 mmol, 2.0 eq), and palladium acetate (6 mg, 0.03 mmol, 0.1 eq) were added. The reaction mixture was incubated at 105°C under nitrogen for 16 hours. LCMS analysis confirmed the complete reaction of the starting material. The reaction mixture was concentrated, and the residue was purified on a silica gel column (petroleum ether / ethyl acetate = 4 / 1) to afford 23b (100 mg, 44% yield) as a yellow oil. LCMS: [M+H] + =641.2.

[0281] Step 3: (2R,3S,4S,5R)-3-{3,4-difluoro-2-[(trideuterylmethyl)oxy]phenyl}-N-{2-[(ethylamino)dioxy]-λ 6 -thio]pyridin-4-yl}-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Example 23)

[0282] Compound 23b (100 mg, 0.16 mmol, 1.0 eq) was dissolved in hydrochloric acid / dioxane (4 M, 30 mL). The reaction mixture was stirred at 25 °C for 2 h. LCMS was used to monitor the completion of the reaction of the starting materials. The reaction mixture was concentrated, and the residue was purified by preparative separation (0.01% FA) to obtain Example 23 (39.5 mg, 47% yield) as a white solid. LCMS: [M+H] + = 541.2

[0283] Example 24:

[0284]

[0285] Step 1: 4-Bromo-N-(2,2,2-trifluoroethyl)pyridine-2-sulfonamide (24b)

[0286] 2,2,2-Trifluoroethan-1-amine (1.2 g, 11.7 mmol, 3.0 eq) was added to compound 4-bromopyridine-2-sulfonyl chloride 24a (1.0 g, 3.9 mmol, 1.0 eq). The reaction mixture was stirred at 25 °C for 1 h. LCMS was used to monitor the completion of the reaction of the starting materials. The reaction mixture was concentrated, and the residue was purified by silica gel column (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 4-bromo-N-(2,2,2-trifluoroethyl)pyridine-2-sulfonamide 24b (700 mg, 56% yield) as a white solid. LCMS: [M+H] + = 318.9

[0287] Step 2: tert-Butyl ((4-bromopyridin-2-yl)sulfonyl)(2,2,2-trifluoroethyl)carbamate (24c)

[0288] Compound 4-bromo-N-(2,2,2-trifluoroethyl)pyridine-2-sulfonamide 24b (700 mg, 2.2 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), and potassium carbonate (604 mg, 4.4 mmol, 2.0 eq), 4-dimethylaminopyridine (27 mg, 0.22 mmol, 0.1 eq) and di-tert-butyl dicarbonate (573 mg, 2.6 mmol, 1.2 eq) were added. The reaction mixture was stirred at 25 °C for 1 h. LCMS was used to monitor the completion of the reaction of the starting materials. The reaction mixture was concentrated, and the residue was purified by silica gel column (petroleum ether / ethyl acetate = 10 / 1) to obtain compound tert-Butyl ((4-bromopyridin-2-yl)sulfonyl)(2,2,2-trifluoroethyl)carbamate 24c (700 mg, 76% yield) as a yellow oil. LCMS: [M+Na] + = 441.0

[0289] Step 3: ([4-({[(2R,3S,4S,5R)-3-{3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl}-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]carbonyl}amino)pyridin-2-yl]dioxido-λ 6 -sulfanyl}(2,2,2-trifluoroethyl)amino)methanoic acid 2-methylpropan-2-yl ester (24d)

[0290] Dissolve compound 24c (100 mg, 0.24 mmol, 1.0 eq) in dioxane (5 mL), add compound 22g (154 mg, 0.26 mmol, 1.1 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (27 mg, 0.048 mmol, 0.2 eq), cesium carbonate (155 mg, 0.48 mmol, 2.0 eq) and palladium(II) acetate (4 mg, 0.024 mmol, 0.1 eq). The reaction mixture is reacted under nitrogen protection at 105 °C for 16 hours. Monitored by LCMS until the raw materials are completely reacted, the reaction solution is concentrated, and the residue is purified by silica gel column (dichloromethane / methanol = 10 / 1) to obtain compound 24d (80 mg, 48% yield) as a yellow oil. LCMS: [M+H] + = 695.2

[0291] Step 4: (2R,3S,4S,5R)-3-{3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl}-N-(2-{dioxido[(2,2,2-trifluoroethyl)amino]-λ 6 -sulfanyl}pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Example 24)

[0292] Dissolve compound 24d (80 mg, 0.11 mmol, 1.0 eq) in hydrochloric acid / dioxane (4M, 5 mL). The reaction mixture is reacted at 25 °C for 4 hours. Monitored by LCMS until the raw materials are completely reacted, the reaction mixture is concentrated, and the residue is purified by preparative separation (0.1% FA) to obtain Example 24 (15.4 mg, 22% yield). LCMS: [M+H] + = 595.1

[0293] Example 28:

[0294]

[0295] Step 1: 2-(benzylthio)-4-iodopyridine (28b)

[0296] Add benzyl mercaptan (2.9 g) and THF (50 mL) to a reaction flask, stir evenly, and add NaH (848 mg) portionwise under an ice bath. After addition, stir at room temperature for 1 hour. Add 28a (5 g) under an ice bath. After addition, continue to stir at room temperature for 3 hours. Monitor by LCMS until the raw materials are basically completely converted. Add water (like 10 mL) to the reaction solution, extract with ethyl acetate (10 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and separate by column chromatography (EA / PE, 0% - 10%) to obtain 6.6 g of a light red liquid 28b, with a yield of 90.1%. LCMS: m / z (254 nm): 327.9 [M+H] + .

[0297] Step 2: 4-Iodopyridine-2-sulfonyl chloride (28c)

[0298] Add 28b (3 g), DCM (30 mL), and DIPEA (3.8 g) to a reaction flask, and add dichlorohydantoin (6.9 g) portionwise under an ice bath. After addition, raise the temperature to room temperature and continue to stir for 4 hours. Monitor the reaction by LCMS until it is basically complete. Add water (50 mL) to the reaction solution, extract with dichloromethane (20 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and separate by column chromatography (EA / PE, 0% - 10%) to obtain 1.4 g of a pale yellow solid, with a yield of 24.2%. LCMS: m / z (254 nm): 303.9 [M+H] + .

[0299] Step 3: N,N-Bis(2,4-dibenzyl)-4-iodopyridine-2-sulfonamide (28d)

[0300] Add 28c (800 mg), N-methylpyrrolidone (7 mL), ammonium acetate (1.06 g), copper(II) acetylacetonate (107 mg), Ligand (115 mg), and cesium carbonate (1.34 g) to a reaction flask. Replace the gas with nitrogen three times and stir at 95 °C for 16 hours. Cool the reaction solution to room temperature, add water (like 20 mL), extract with ethyl acetate (20 mL×3), combine the organic phases, concentrate, and separate by column chromatography (EA / PE, 50% - 100%) to obtain 460 mg of a yellow oil, with a yield of 70.8%. LCMS: m / z (254 nm): 521.0 [M+H] + .

[0301] Step 4: 4-Amino-N,N-bis[(2,4-dimethoxyphenyl)methyl]pyridine-2-sulfonamide (28e)

[0302] Add 28d (800 mg), N-methylpyrrolidone (7 mL), ammonium acetate (1.06 g), copper(II) acetylacetonate (107 mg), Ligand (115 mg) and cesium carbonate (1.34 g) to a reaction flask. Replace the air with nitrogen three times and stir at 95 °C for 16 h. Cool the reaction mixture to room temperature, add water (20 mL), and extract with ethyl acetate (20 mL×3). Combine the organic phases, concentrate, and separate by column chromatography (EA / PE, 50% - 100%) to obtain 460 mg of a yellow oil with a yield of 70.8%. LCMS: m / z (254 nm): 410.2 [M+H] + 。

[0303] Step 5: rac-(2R,3R,4S,5R)-N-[2-({Bis[(2,4-dimethoxyphenyl)methyl]amino}dioxido-λ 6 -sulfanyl)pyridin-4-yl]-3-{3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl}-3a-methyl-5a-(trifluoromethyl)hexahydrocyclobuta[1,2-b]furan-2-carboxamide (28f)

[0304] Compound 28f was obtained by a method similar to that of Example 1. LCMS: MS m / z (254 nm): 825.3 [M+H] + 。

[0305] Step 6: rac-(2R,3R,4S,5R)-N-[2-(Aminodioxido-λ 6 -sulfanyl)pyridin-4-yl]-3-{3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl}-3a-methyl-5a-(trifluoromethyl)hexahydrocyclobuta[2,1-b]furan-2-carboxamide (Example 28)

[0306] Add 28f (50 mg), DCM (2 mL) and trifluoroacetic acid (146 mg) to a reaction flask and stir at room temperature for 12 h. Monitor the reaction by LCMS until the raw materials are almost completely converted. Concentrate the reaction mixture and separate by silica gel plate chromatography (EA / PE, 40%) to obtain 23 mg of a white solid with a yield of 74%. LC-MS: m / z (254 nm): 525.1 [M+H] + .

[0307] Example 29:

[0308]

[0309] Compound ((4-bromopyridin-2-yl)sulfonyl)(methyl)carbamic acid tert-butyl ester (29a)

[0310] Compound 22e (100 mg, 0.30 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (5 mL), and potassium carbonate (82 mg, 0.59 mmol, 2.0 eq) and methyl iodide (50 mg, 0.35 mmol, 1.2 eq) were added. The reaction mixture was stirred at 60 °C for 2 h. After monitoring the reaction completion of the starting material by LCMS, water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). Then, the organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 16 / 1) to obtain 29a (100 mg, 96% yield) as a white solid. LCMS: [M+Na] + = 373.0.

[0311] Step 2: rac-(3aR,3S,5aR)-3-{3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl}-3a-methyl-5a-(trifluoromethyl)hexahydrocyclobuta[1,2-b]furan-2-carboxamide (29b)

[0312] Intermediate 29b was prepared according to the synthetic method of intermediate 1c. LCMS: [M+H] + = 369.1.

[0313] Step 3: rac-(2R,3R,4S,5R)-{[(4-{[(3-{3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl}-3a-methyl-5a-(trifluoromethyl)hexahydrocyclobuta[2,1-b]furan-2-yl)carbonyl]amino}pyridin-2-yl)dioxido-λ 6 -sulfanyl](methyl)amino}methanoic acid 2-methylpropan-2-yl ester (29c)

[0314] Compound 29a (55 mg, 0.15 mmol, 1.1 eq) was dissolved in dioxane (5 mL), and compound 29b (52 mg, 0.14 mmol, 1.0 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (15 mg, 0.027 mmol, 0.2 eq), cesium carbonate (89 mg, 0.27 mmol, 2.0 eq), and palladium(II) acetate (2 mg, 0.013 mmol, 0.1 eq) were added. The reaction mixture was stirred at 105 °C under nitrogen atmosphere for 16 h. After monitoring the reaction completion of the starting material by LCMS, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 29c (70 mg, 80% yield) as a yellow oil. LCMS: [M+H] + = 639.2.

[0315] Step 4: rac-(2R,3R,4S,5R)-3-{3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl}-3a-methyl-N-{2-[(methylamino)dioxido-λ 6 -sulfanyl]pyridin-4-yl}-5a-(trifluoromethyl)hexahydrocyclobuta[2,1-b]furan-2-carboxamide (Example 29)

[0316] Dissolve compound 29c (70 mg, 0.11 mmol, 1.0 eq) in hydrochloric acid / dioxane (4 M, 10 mL). The reaction solution was reacted at 25 °C for 4 hours. LCMS monitored the completion of the reaction of the starting material. The reaction mixture was concentrated, and the residue was purified by preparative separation (0.01% FA) to obtain Example 29 (4.2 mg, 7.1% yield). LCMS: [M+H] + = 539.1

[0317] Example 30:

[0318] [[ID=I3]]

[0319] Step 1: 1-(4-bromopyridin-2-yl)-2-fluoroethan-1-one (30b)

[0320] In a reaction flask, dissolve compound 1-(4-bromopyridin-?yl)ethan-1-one 30a (300 mg, 1.50 mmol, 1.00 eq) in toluene (3 mL), add tert-butyldimethylsilyl trifluoromethanesulfonate (595 mg, 2.25 mmol, 1.50 eq) and triethylamine (326 mg, 3.22 mmol, 2.15 eq). The reaction solution was stirred at 80 °C for 2 hours. The reaction solution was concentrated, add acetonitrile (3 mL) and a selective fluorinating reagent (537 mg, 1.51 mmol, 1.01 eq). The reaction solution was stirred at 25 °C for 1 hour. LCMS monitored the completion of the reaction of the starting material. The reaction solution was concentrated, and the residue was purified by a silica gel column (petroleum ether / ethyl acetate = 50 / 1) to obtain compound 30b (176 mg, 54% yield) as a white solid. LCMS: [M+H] + = 218.0

[0321] Step 2: 1-(4-bromopyridin-2-yl)-2-fluoroethan-1-ol (30c)

[0322] In a reaction flask, compound 30b (176 mg, 0.81 mmol, 1.00 eq) was dissolved in methanol (5 mL), and sodium borohydride (60 mg, 1.60 mmol, 1.98 eq) was added at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. After monitoring the completion of the reaction of the starting material by LCMS, the reaction mixture was concentrated, and the residue was purified by silica gel column (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 30c (145 mg, 81% yield) as a yellow oil. LCMS: [M+H] + = 220.0.

[0323] Step 3: 4-Bromo-2-(1-((tert-butyldimethylsilyl)oxy)-2-fluoroethyl)pyridine (30d)

[0324] In a reaction flask, compound 30c (130 mg, 0.59 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (5 mL), and imidazole (149 mg, 2.18 mmol, 3.7 eq) and tert-butyldimethylchlorosilane (151 mg, 1.00 mmol, 1.7 eq) were added. The reaction mixture was stirred at 25 °C for 16 h. After monitoring the completion of the reaction of the starting material by LCMS, the reaction mixture was diluted with water (15 mL), extracted with ethyl acetate (10 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column (petroleum ether / ethyl acetate = 20 / 1) to obtain compound 30d (173 mg, 87% yield) as a colorless oil. LCMS: [M+H] + = 334.0.

[0325] Step 4: rac-(2R,3R,4S,5R)-3-{3,4-Difluoro-2-[(trideuteriomethyl)oxy]phenyl}-N-[2-(1-fluoro-4,4,5,5-tetramethyl-3-oxa-4-silahexan-2-yl)pyridin-4-yl]-3a-methyl-5a-(trifluoromethyl)hexahydrocyclobuta[2,1-b]furan-2-carboxamide (30e)

[0326] In a reaction flask, compound 30d (151 mg, 0.45 mmol, 1.5 eq) was dissolved in anhydrous 1,4-dioxane (5 mL), and cesium carbonate (196 mg, 0.60 mmol, 2.0 eq), 25g (110 mg, 0.30 mmol, 1.0 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (35 mg, 0.06 mmol, 0.2 eq) and palladium acetate (5 mg, 0.03 mmol, 0.1 eq) were added. The reaction mixture was reacted at 105 °C for 16 h under a nitrogen atmosphere. When the reaction of the starting materials was monitored by LCMS to be complete, the reaction mixture was diluted with water (15 mL), extracted with ethyl acetate (10 mL x 3), then washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 30e (193 mg, 98% yield) as a colorless oil. LCMS: [M+H] + = 622.3.

[0327] Step 5: rac-(2R,3R,4S,5R)-3-{3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl}-N-[2-(2-fluoro-1-hydroxyethyl)pyridin-4-yl]-3a-methyl-5a-(trifluoromethyl)hexahydrocyclobuta[2,1-b]furan-2-carboxamide (Example 30)

[0328] Compound 30e (193 mg, 0.31 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL), and a tetrahydrofuran solution of tetrabutylammonium fluoride (0.4 mL) was added. The reaction mixture was reacted at 25 °C for 3 h. When the reaction of the starting materials was monitored by LCMS to be complete, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), then washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column (petroleum ether / ethyl acetate = 1 / 1) and preparative separation purification (0.1% FA) to obtain Example 30 compound (68.5 mg, 41.3% yield). LCMS: [M+H] + = 508.2.

[0329] Example 31:

[0330]

[0331] Step 1: tert-Butyl (S)-(4-bromopyridin-2-yl)methyl(tetrahydrofuran-3-yl)carbamate (31c)

[0332] In a single-necked flask, dissolve compound 4-bromopyridinecarbaldehyde 31a (100 mg, 0.54 mmol, 1.0 eq) in 1,2-dichloroethane (5 mL), add (S)-tetrahydrofuran-3-amine 31b (61 mg, 0.70 mmol, 1.3 eq), acetic acid (32.38 mg, 0.54 mmol, 1.0 eq) and sodium triacetoxyborohydride (171 mg, 0.81 mmol, 1.5 eq). Stir the reaction mixture at 25 °C for 3 h. Then add di-tert-butyl dicarbonate (176 mg, 0.81 mmol, 1.5 eq) to the reaction mixture. Stir the reaction mixture at 25 °C for 0.5 h. Monitor the reaction by LCMS until the raw materials are completely reacted, concentrate the reaction mixture, and purify the residue by silica gel column (petroleum ether / ethyl acetate = 4 / 1) to obtain compound 31c (170 mg, 88% yield) as a yellow oil.

[0333] Step 2: rac-(4-(2R,3R,4S,5R)-{[(4-{[(3-{3,4-difluoro-2-[(trideuteromethyl)oxy]phenyl}-3a-methyl-5a-(trifluoromethyl)hexahydrocyclobuta[2,1-b]furan-2-yl)carbonyl]amino}pyridin-2-yl)methyl][(3S)-tetrahydrofuran-3-yl]amino}methanoic acid-2-methylpropyl-2-yl ester (31d)

[0334] In a single-necked flask, dissolve compound 31c (65 mg, 0.18 mmol, 1.0 eq) in anhydrous 1,4-dioxane (5 mL), add cesium carbonate (107 mg, 0.33 mmol, 2.0 eq), compound 29b (60 mg, 0.16 mmol, 1.0 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (19 mg, 0.03 mmol, 0.2 eq) and palladium acetate (2.7 mg, 0.02 mmol, 0.1 eq). React the reaction mixture at 105 °C under a nitrogen atmosphere for 16 h. Monitor the reaction by LCMS until the raw materials are completely reacted, dilute the reaction mixture with water (15 mL), extract with ethyl acetate (10 mL × 3), then wash with saturated brine, dry over anhydrous sodium sulfate and concentrate. Purify the residue by silica gel column (petroleum ether / ethyl acetate = 20 / 1) to obtain compound 31d (30 mg, 29% yield) as a yellow oil. LCMS: [M+H] + = 645.2.

[0335] Step 3: rac-(2R,3R,4S,5R)-3-{3,4-difluoro-2-[(trideuteromethyl)oxy]phenyl}-N-[2-({[(3S)-tetrahydrofuran-3-yl]amino}methyl)pyridin-4-yl]-3a-methyl-5a-(trifluoromethyl)hexahydrocyclobuta[2,1-b]furan-2-carboxamide (Example 31)

[0336] Compound 31d (30 mg, 0.05 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at 25 °C for 3 h. LCMS monitored the completion of the reaction of the starting material. The reaction mixture was concentrated, and the residue was purified by preparative separation (0.1% FA) to obtain Example 31 (5 mg, 18% yield). LCMS: [M+H] + = 545.2

[0337] Example 32: rac-(2R,3R,4S,5R)-3-{3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl}-3a-methyl-5a-(trifluoromethyl)-N-[2-(5-aza-2-oxahexan-6-yl)pyridin-4-yl]hexahydrocyclobuta[2,1-b]furan-ide-2-carboxamide

[0338]

[0339] Example 32 was prepared in a similar manner to Example 31. LCMS: [M+H] + = 533.2

[0340] Example 36:

[0341]

[0342] Step 1: 2-bromo-1-(5-bromopyridin-2-yl)ethan-1-one (36b)

[0343] 1-(5-Bromopyridin-2-yl)ethan-1-one 36a (2.0 g, 0.01 mmol, 1.0 eq) was dissolved in methanol (10 mL) and acetic acid (15 mL), cooled to 0 °C, 30% hydrobromic acid in acetic acid solution (2.8 mL) was added, and bromine (1.6 g, 0.01 mmol, 1.0 eq) in acetic acid (5 mL) was added dropwise. The reaction mixture was brought to room temperature and then heated to 70 °C and stirred for 1 h. LCMS analysis showed the completion of the reaction. The mixture was concentrated under reduced pressure, and the residue was crystallized from isopropanol to obtain 36b (1.0 g, 32% yield) as a yellow solid. LCMS: [M+H] + = 278.9

[0344] Step 2: 1-(5-bromopyridin-2-yl)ethane-1,2-diol (36c)

[0345] A solution of 2-bromo-1-(5-bromopyridin-2-yl)ethanone 36b (1.0 g, 3.6 mmol, 1.0 eq) and sodium formate (1.0 g, 14.4 mmol, 4.0 eq) in ethanol (10 mL) was heated to 50 °C and reacted for 3 hours. After the reaction was completed, it was cooled to room temperature and the solvent was evaporated under reduced pressure. The mixture was quenched with water (10 mL) and extracted with dichloromethane (50 mL × 3). The combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was taken up in methanol (10 mL) and cooled to 0 °C. Sodium borohydride (0.4 g, 10.8 mmol, 3.0 eq) was added portionwise and the mixture was stirred at 0 °C for 1 hour. The pH was adjusted to 2 by adding concentrated hydrochloric acid and the solvent was removed under reduced pressure. It was extracted 3 times with dichloromethane (50 mL) and saturated aqueous sodium bicarbonate (10 mL). The combined organic phases were dried over sodium sulfate. The residue was purified by silica gel column (petroleum ether / ethyl acetate = 4 / 1) to give compound 36c (350 mg, 42% yield) as a yellow solid. LCMS: [M+H] + = 218.0.

[0346] Step 3: 5-Bromo-2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine (36d)

[0347] 1-(5-Bromopyridin-2-yl)ethane-1,2-diol 36c (100 mg, 0.46 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (5 mL), and 2,2-dimethoxypropane (48 mg, 0.46 mmol, 1.0 eq) and p-toluenesulfonic acid (7.9 mg, 0.05 mmol, 0.1 eq) were added. The mixture was stirred at 25 °C for 24 hours. LCMS analysis showed that the reaction was complete. The mixture was quenched with water (50 mL) and then extracted with dichloromethane (50 mL × 3). The combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by eluting with ethyl acetate in petroleum ether from 0 - 50% to give 5-bromo-2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine 36d (60 mg, 48% yield) as a yellow oil. LCMS: [M+H] + = 258.0.

[0348] Step 4: rac-(1R,3R,4S,5R)-3-{3,4-Difluoro-2-[(trideuteriomethyl)oxy]phenyl}-N-[6-(2,2-dimethyl-1,3-dioxol-4-yl)pyridin-3-yl]-3a-methyl-5a-(trifluoromethyl)hexahydrocyclobuta[2,1-b]furan-2-carboxamide (36e)

[0349] Dissolve 25 g (50 mg, 0.14 mmol, 1.0 eq) in 1,4-dioxane (5 mL), and add 5-bromo-2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine (53 mg, 0.21 mmol, 1.5 eq), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthrene (16 mg, 0.027 mmol, 0.2 eq), cesium carbonate (134 mg, 0.41 mmol, 3.0 eq) and palladium acetate (3.1 mg, 0.014 mmol, 0.1 eq). Stir the mixture at 105 °C for 16 h. After completion of the reaction, quench the mixture with water (50 mL), then extract with ethyl acetate (50 mL × 3). Dry the combined organic phases over sodium sulfate and filter. Concentrate the filtrate under reduced pressure. Purify by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 36e (50 mg, 67% yield) as a yellow oil. LCMS: [M+H] + = 546.2.

[0350] Step 5: rac-(1R,3R,4S,5R)-03-{3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl}-N-[6-(1,2-dihydroxyethyl)pyridin-3-yl]-3a-methyl-5a-(trifluoromethyl)hexahydrocyclobuta[2,1-b]furan-2-carboxamide (Example 36)

[0351] Dissolve 36e (50 mg, 0.0184 mmol, 1.0 eq) in hydrochloric acid / 1,4-dioxane (5 mL), and stir at 25 °C for 1 h. Concentrate the mixture under reduced pressure. Obtain Compound Example 36 (4.2 mg, 9% yield) by preparation (0.1% NH3). LCMS: [M+H] + = 506.2.

[0352] Example 40: rac-(2R,3R,4S,5R)-N-[6-(aminodioxido-λ 6 -sulfanyl)pyridin-3-yl]-3-{3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl}-3a-methyl-5a-(trifluoromethyl)hexahydrocyclobuta[2,1-b]furan-2-carboxamide

[0353]

[0354] Prepared Example 40 in a method similar to Example 28, LCMS: [M+H] + = 524.2.

[0355] Example 41:

[0356]

[0357] Step 1: tert-Butyl 4-(5-bromopyridin-2-yl)-3-oxopiperidine-1-carboxylate (41b)

[0358] Dissolve tert-butyl 3-oxopiperazine-1-carboxylate (1.37 g, 6.82 mmol, 1.2 eq) in DMF (15 mL), cool to 0 °C, add sodium hydride (341 mg, 8.52 mmol, 1.5 eq), and stir for 30 minutes. After adding 2-fluoro-5-bromopyridine 100a (1.0 g, 5.68 mmol, 1.0 eq), warm to 60 °C and stir for 16 hours. Add water, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with brine, dry over sodium sulfate, filter, concentrate in vacuo, and purify by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain tert-butyl 4-(5-bromopyridin-2-yl)-3-oxopiperidine-1-carboxylate 41b (560 mg, 27.7% yield) as a white solid. LCMS: [M+H]+ = 355.9, 357.9.

[0359] Step 2: rac-Tert-butyl 4-(4-((1R,3R,4S,5R)-4-(3,4-difluoro-2-trideuteriomethoxyphenyl)-5-methyl-1-(trifluoromethyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamido)pyridin-2-yl)-3-oxopiperazine-1-carboxylate (41c)

[0360] Dissolve compound 25g (50 mg, 0.14 mmol, 1.0 eq) in dioxane (5 mL), add 41b (65 mg, 0.18 mmol, 1.3 eq), cesium carbonate (133 mg, 0.41 mmol, 3.0 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11 mg, 0.03 mmol, 0.2 eq), and palladium acetate (3 mg, 0.01 mmol, 0.1 eq). The reaction mixture is reacted at 105 °C for 16 hours under a nitrogen atmosphere. Monitor the reaction by LCMS until the raw materials are completely reacted, concentrate the reaction mixture, and purify the residue by silica gel column (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 41c (50 mg, 57% yield) as a colorless oil. LCMS: [M+H] + = 644.3.

[0361] Step 3: rac-(1R,3R,4S,5R)-4-(3,4-Difluoro-2-trideuteriomethoxyphenyl)-5-methyl-N-(2-(2-oxopiperazin-1-yl)pyridin-4-yl)-1-(trifluoromethyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamide (41d)

[0362] Compound 41c (50 mg, 0.078 mmol, 1.0 eq) was dissolved in trifluoroacetic acid (5 mL), and the reaction mixture was stirred at 25 °C for 2 h. The reaction was monitored by LCMS until the starting material was consumed. The reaction mixture was concentrated to afford compound 41d (40 mg, 95% yield) as a white solid. LCMS: [M+H] + = 544.3.

[0363] Step 4: rac-(1R,3R,4S,5R)-4-(3,4-difluoro-2-trideuteriomethoxyphenyl)-5-methyl-N-(2-(4-methyl-2-oxopiperazin-1-yl)pyridin-4-yl)-1-(trifluoromethyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamide (Example 41)

[0364] Compound 41d (40 mg, 0.07 mmol, 1.0 eq) and paraformaldehyde (4 mg, 0.14 mmol, 2.0 eq) were dissolved in methanol (5 mL). The reaction mixture was stirred at 25 °C for 30 min, then sodium cyanoborohydride (8 mg, 0.14 mmol, 2.0 eq) was added, and the reaction mixture was stirred at 40 °C for 1 h. The reaction was monitored by LCMS until the starting material was consumed. The reaction mixture was concentrated, and the residue was purified by preparative separation (0.1% FA) to afford Example 41 (6.7 mg, 13% yield). LCMS: [M+H] + = 558.2.

[0365] Example 45:

[0366]

[0367] Step 1: 5-nitro-1,3-dioxoisoindolin-2-yl acetate (45b)

[0368] In a single-necked flask, 2-hydroxy-5-nitroisoindoline-1,3-dione 45a (300 mg, 1.44 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), then acetic anhydride (221 mg, 2.17 mmol, 1.5 eq) and pyridine (228 mg, 2.88 mmol, 2.0 eq) were added. The reaction mixture was stirred at 0 °C for 2 h. The reaction was monitored by LCMS until the starting material was consumed. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to afford compound 45b (300 mg, 83% yield) as a white solid. LCMS: [M+H] + = 251.0.

[0369] Step 2: 5-amino-1,3-dioxoisoindolin-2-yl acetate (45c)

[0370] In a single-necked flask, compound 45b (300 mg, 1.20 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (5 mL), and tetra(hydroxy)diborane (430 mg, 4.80 mmol, 4.0 eq) and 4,4'-bipyridine (19 mg, 0.12 mmol, 0.1 eq) were added. The reaction mixture was reacted at 0 °C for 20 minutes. LCMS monitoring showed that most of the starting materials had reacted. The reaction mixture was successively added with ethyl acetate (20 mL) and water (20 mL). The organic layer was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was separated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 45c (80 mg, 30% yield) as a yellow oil. LCMS: [M+H] + = 221.0.

[0371] Step 3: rac-(2R,3S,4S,5R)-N-(2-acetoxy-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)-3-{3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl}-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (45d)

[0372] Compound 1d (100 mg, 0.28 mmol, 1.0 eq) was dissolved in anhydrous pyridine (3 mL), and compound 45c (62 mg, 0.28 mmol, 1.0 eq) and phosphorus oxychloride (173 mg, 1.13 mmol, 4.0 eq) were added. The reaction mixture was reacted at 0 °C for 1 hour. LCMS monitoring showed that the starting materials had reacted. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), then washed with saturated brine, filtered, the filtrate was concentrated, and the residue was separated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain compound 45d (100 mg, 64% yield) as a white solid. LCMS: [M+H] + = 560.2.

[0373] Step: (2R,3S,4S,5R)-3-{3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl}-N-(2-hydroxy-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Example 45)

[0374] Compound 45d (100 mg, 0.18 mmol, 1.0 eq) was dissolved in methanol (3 mL), and ammonia methanol solution (0.5 mL) was added. The reaction mixture was reacted at 25 °C for 10 minutes. The reaction was monitored by LCMS until the raw material was completely reacted. The reaction mixture was concentrated, and the residue was purified by preparative separation (0.1% FA) to obtain Example 45 (28.2 mg, 29% yield). LCMS: [M-H] - = 516.1.

[0375] Reference Compound 1:

[0376]

[0377] Reference Compound 1 was prepared by substituting Intermediate 1a for 1d in Example 1. ESI-MS m / z calc. 515.1, found 516.1 (M + 1) + . 1 H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 7.76–7.60 (m, 4H), 7.49 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 20.8 Hz, 2H), 7.22–7.09 (m, 2H), 5.07 (d, J = 10.4 Hz, 1H), 4.24 (dd, J = 10.3, 7.6 Hz, 1H), 3.95 (d, J = 2.1 Hz, 2H), 2.76 (t, J = 7.5 Hz, 1H), 1.60 (s, 3H), 0.73 (d, J = 7.4 Hz, 3H).

[0378] Biological activity test: In vitro inhibition of the compound on Nav 1.8: The inhibitory effect of the compound on Nav 1.8 in vitro was tested for IC 50 .

[0379] CHO cell line stably expressing Nav1.8 sodium channel was used for experimental detection. Gene information: Sodium channel, voltage-gated, type 8, alpha (SCN10A), cDNA strictly similar to GenBank accession number: NM_006514.

[0380] Before patch clamp detection, the cells were separated with 0.25%-Trypsin-EDTA, and 6.5×10 3 cells were plated on cover slips and cultured in a 24-well plate (final volume: 500 μL). After 18 hours, the test was carried out.

[0381] Liquids for electrophysiological recording: Extracellular fluid: K-007-1, 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, pH adjusted to 7.4 with NaOH. Intracellular fluid: Nav-001-2, 50 mM CsCl, 10 mM NaCl, 10 mM HEPES, 60 mM CsF, 20 mM EGTA, pH adjusted to 7.2 with CsOH. The extracellular fluid can be stored for 2 weeks. After the intracellular fluid is prepared, it is aliquoted into 1 mL tubes each and stored frozen at -20°C in a refrigerator. Freshly thawed intracellular fluid is used for each experiment every day. All intracellular fluid should be used up within three months. After three months, discard the old intracellular fluid and prepare a new batch.

[0382] Patch-clamp detection: The voltage stimulation protocol for recording Nav1.8 sodium current by whole-cell patch-clamp is as follows: After forming a whole-cell seal, the cell voltage is clamped at -120 mV for 30 ms. The clamped voltage is depolarized to 0 mV for 50 ms, and then the voltage is restored to -50 mV (the specific voltage refers to the half-inactivation voltage of the IV test) and maintained for 5 s. Then the cell membrane potential is restored to -120 mV and maintained for 20 ms, and then depolarized to 0 mV again for 50 ms, and finally restored to the clamped voltage of -120 mV and maintained for 30 ms. Data is collected every 20 ms. Observe the effect of the drug on the peak sodium current. The experimental data is collected by an EPC 10 amplifier (HEKA) and stored in the PatchMaster (HEKA) software.

[0383] A capillary glass tube is pulled into a recording electrode using a microelectrode puller. The electrode filled with intracellular fluid is inserted into the electrode holder, and 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 brought into contact with the cell surface, and negative pressure is applied to form a high-resistance seal (GΩ). At this time, fast capacitance compensation is performed, and then more negative pressure is applied to rupture the cell membrane to form a whole-cell recording mode. Then slow capacitance compensation is carried out, and experimental parameters such as membrane capacitance (Cm) and series resistance (Rs) are recorded. Leakage compensation is not applied.

[0384] Drug administration was started after the Nav1.8 current in whole-cell recording was stable. Each drug concentration was allowed to act for 5 min (or until the current was stable), and then the next concentration was tested. Multiple concentrations of each test compound were detected. The cover glass with cells was placed in the recording bath under an inverted microscope. The blank control external solution and the working solution of the compound to be tested were perfused through the recording bath from low concentration to high concentration in sequence by gravity perfusion to act on the cells, and a peristaltic pump was used for liquid exchange during the recording. The current detected in the external solution without the compound for each cell was used as its own control group. Each concentration was independently repeated and detected at least three times using at least three cells. All electrophysiological experiments were carried out at room temperature.

[0385] Data analysis: First, the current after the action of each drug concentration and the blank control current were normalized. Then, the inhibition rate corresponding to each drug concentration was calculated. And the mean (Mean), standard deviation (SD), and standard error (SE) of the inhibition rate for each concentration were calculated.

[0386] Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope))

[0387] The IC of each compound was calculated using the above equation. 50 value, and a non-linear fitting was performed on the dose-dependent effect, where IC 50 was the half-inhibitory concentration. The calculation of IC 50 and curve fitting were completed using GraphPad Prism software.

[0388] Table 2. Inhibitory activity of the compounds of the present invention against Nav 1.8

[0389] Example <![CDATA[IC 50 (nM)]]> 1 <0.5 54 <0.5 55 <0.5

[0390] The inhibitory effects of other compounds of the present invention against Nav 1.8 were tested using the same method, indicating that the compounds of the present invention have good inhibitory effects on Nav 1.8.

[0391] Liver microsome stability experiment of the compounds of the present invention:

[0392] First step: Preparation of the working solutions of the compound to be tested and the control compound: 5 μL of the stock solution (10 mM DMSO solution) was added to 495 μL of acetonitrile solution (i.e., 100 μM, 99% acetonitrile). Testosterone, diclofenac, and propafenone were used as controls in this experiment.

[0393] Step 2. Preparation of NADPH coenzyme working solution: β-Nicotinamide adenine dinucleotide phosphate reduced, tetrasodium salt; (Supplier: BONTAC, Product number: BT04); Weigh an appropriate amount of NADPH powder and dilute it into a 10 mM MgCl2 solution.

[0394] Step 3. Preparation of liver microsomes: Prepare a working solution of liver microsomes at 0.56 mg / mL with 100 mM potassium phosphate buffer.

[0395] Step 4. Preparation of the termination solution: Use cold (4 °C) acetonitrile containing 250 nM tolbutamide and 250 nM labetalol as internal standards as the termination solution.

[0396] Step 5. Experimental operation:

[0397] a. Add 445 μL of the liver microsome working solution (0.56 mg / mL) to the preheated T60 and NCF60 plates and stir well; Add 54 μL of the liver microsome working solution and 6 μL of the NADPH coenzyme working solution to the blank plate T0, and add 180 μL of the termination solution for standby.

[0398] b. Add 5 μL of the working solution of the test compound to the T60 and NCF60 plates with the liver microsome working solution.

[0399] c. Add 50 μL of phosphate buffer to the NCF60 plate.

[0400] d. Take out 54 μL from the T60 plate to the T0 plate as the sample at the 0-minute time point, and supplement 44 μL of the NADPH coenzyme working solution.

[0401] Table 3. Concentrations of each component in the final state of the reaction system

[0402] Component Concentration Microsome 0.5 mg / mL Test compound 1 μM Control compound 1 μM Acetonitrile 99％ DMSO 1％ NADPH 1 mM

[0403] e. At the 5-minute, 15-minute, 30-minute, 45-minute, and 60-minute time points, transfer 60 μL of the sample from the T60 plate to the termination plate in sequence.

[0404] f. At the 60-minute time point, transfer 60 μL of the sample from the NCF60 plate to the termination plate.

[0405] g. Mix all the sample plates well for 10 min, and centrifuge at 4 °C and 4000 rpm for 20 min; Take 80 μL of the supernatant, dilute it with 240 μL of high-purity water, and analyze it by LC-MS / MS.

[0406] Step 6. Data analysis: Calculate T1 / 2 and CLint(mic) (μL / min / mg) using the first-order kinetic equation.

[0407]

[0408] The experimental results of hepatic microsomal metabolic stability in monkeys, rats and humans are shown in Table 4. It can be seen from the table that Example 1 of the present invention has better metabolic stability compared with reference compound 1, and may have better pharmacokinetics, safety and efficacy.

[0409] Table 4. Experimental results of hepatic microsomal metabolic stability in monkeys, rats and humans

[0410]

[0411] The pharmacokinetics of the compounds of the present invention in rats:

[0412] Test article solvent: DMSO: Solutol HS15: Tween 80: Saline = 5:10:0.2:84.8 (v / v / v / v). Preparation method: Weigh appropriate amounts of the compound, and add DMSO, Solutol HS15, Tween 80 and normal saline in sequence to obtain a dosing preparation with a final concentration of 0.5 mg / mL for gavage administration to animals.

[0413] Male SD rats (source: Vital River Laboratory Animal Technology Co., Ltd.), 3 rats per group (180 - 250 g). After fasting for at least 12 hours (drinking water freely), they were given gavage administration with a dosing volume of 10 mL / kg. Blood samples of about 0.2 mL were collected from the jugular vein sinus before dosing and at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 10 h, and 24 h after dosing. The collected 0.2 mL of whole blood was placed in an EDTA-K2 anticoagulant tube pre-cooled in advance and centrifuged at 4°C (1500 - 1600 g) for 10 min. After separating the plasma, it was stored in a refrigerator at -90 to -60°C for bioanalysis of biological samples.

[0414] The pharmacokinetic parameters of rats are shown in Table 5. Compared with control compound 1, the compounds of the present invention have higher peak plasma drug concentrations and higher plasma exposures, indicating that the compounds provided by the present invention have better pharmacokinetic properties and more excellent application prospects in the treatment of pain.

[0415] Table 5. Pharmacokinetic parameters of rats

[0416]

Claims

1. A compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R a1 、R a3 each independently selected from hydrogen, halogen, hydroxy, C1-C5 alkyl, C1-C5 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, -N(R c3 R c4 ), m or any two adjacent R a1 、R a3 are connected to form a 5- to 7-membered ring, and the 5- to 7-membered ring may be a saturated or unsaturated carbocyclic or heterocyclic ring; the heterocyclic ring optionally contains one or more N, O, S(=O) m heteroatoms; R a2 selected from one or more deuterium- or fluorine-substituted C1-C6 alkyl groups; R b1 、R b2 、R b3 、R b4 are each independently selected from hydrogen, halogen, hydroxy, C1-C5 alkyl, C1-C5 alkoxy; or R b1 、R b2 、R b3 、R b4 any two of them are joined to form a 3- to 7-membered ring; M1 and M2 are independently selected from C, O, S(=O) m , N-R n , where R n is optionally selected from hydrogen, C1-C5 alkyl; ring A is A1 or A2: Any represents a single bond or a double bond X1, X2, X3, X4, and X5 are each independently selected from a bond, C, N, O, C=O, S(=O) m ; Y1 and Y2 may be the same or different and are each independently selected from a C atom or an N atom; R c1 and R c2 are each independently selected from hydrogen, halogen, cyano, hydroxy, amino, C1-C5 alkyl, C1-C5 alkoxy, -S(=O) m -R c3 R c4 , -C(=O)-NR c3 R c4 , -C(=S)-NR c3 R c4 , -N(R c3 R c4 ) m , -P(=O) m -R c3 R c4 , -C(=N)-NR c3 R c4 , -S(=O)2NR c3 R c4 , -C1-C5 alkylNR c3 R c4 , -S(=O)(=NR c3 )R c4 ; R c3 and R c4 are each independently selected from hydrogen, hydroxy, amino, C1-C5 alkyl, C1-C5 alkoxy, a 3-7 membered ring, or R c3 and R c4 are joined to form a 3-7 membered ring; m and n are each independently 0, 1 or 2; the alkyl, alkoxy, cycloalkyl, cycloalkoxy, 5- to 7-membered ring, and 3- to 7-membered ring may be optionally substituted with one or more deuterium, halogen, hydroxyl, cyano, oxo, C1-C5 alkyl, C1-C5 alkoxy, or amino groups.

2. The compound of formula I according to claim 1, R a1 , R a3 each independently selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, difluoromethoxy, amino.

3. The compound of formula I according to claim 1, R a2 is independently selected from methyl substituted with one, two or three deuterium or fluorine atoms.

4. The compound of formula I according to claim 1, wherein any two adjacent Rs a1 and R a3 are linked to form a 5- or 6-membered carbocyclic or heterocyclic ring.

5. The compound of formula I according to claim 1, R b1 , R b2 , R b3 , R b4 are each independently selected from hydrogen, methyl, trifluoromethyl, ethyl, methoxy, and ethoxy.

6. The compound of formula I according to claim 1, wherein R b1 , R b2 , R b3 , R b4 Any two of them are connected to form a 3-membered ring, 4-membered ring, or 5-membered ring.

7. The compound of formula I according to claim 1, wherein ring A has the following structure:

8. The compound of formula I according to claim 1, wherein formula I has the structure shown in formula I-A or formula I-B:

9. The compound of formula I according to claim 1 or 8, which has the following structure:

10. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable excipient.

11. Use of the pharmaceutical composition according to claim 10 or the compound of formula I according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof in the manufacture of a medicament for treating, preventing or alleviating a voltage-gated sodium channel-related disease.

12. The use according to claim 11, wherein the disease is pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or arrhythmia.

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