Novel sodium channel modulator compound and use thereof

Abstract

Provided are a novel sodium channel modulator compound and a use thereof. The sodium channel modulator has a completely new structure as shown in formula I, and exhibits excellent in vitro inhibitory effects against Nav 1.8. The compound or a pharmaceutically acceptable salt thereof can be used for treating sodium channel-related diseases, including diseases such as pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or arrhythmia.

Description

New sodium channel modulator compounds and their applications

[0001] This application claims the benefit of priority to Chinese Patent Application No. 2024101375145, filed on January 31, 2024, and Chinese Patent Application No. 2024115635044, filed on November 4, 2024. This application incorporates the entirety of the aforementioned Chinese patent applications. Technical Field

[0002] The present invention relates to the field of medicine, and in particular to a new sodium channel modulator compound, a preparation method thereof, and therapeutic use thereof in treating 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 accompanied by actual or potential tissue damage." Pain, as a warning signal, 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 dysfunction and seriously affect the quality of life of the living organism. Data show that about one in five people worldwide suffers from moderate or severe chronic pain.

[0004] Pain originates from nociceptors in the peripheral nervous system. These are free nerve endings widely distributed throughout the skin, muscles, joints, and visceral tissues of the body. They can convert perceived thermal, mechanical, or chemical stimuli into nerve impulses (action potentials) and transmit them via afferent nerve fibers to their cell bodies in the dorsal root ganglia (DRG), ultimately reaching higher nerve centers, causing pain sensation. The generation and conduction of action potentials in neurons, in turn, rely on voltage-gated sodium channels (VGSCs) on the cell membrane. When the cell membrane depolarizes, sodium channels activate and open, causing an influx of sodium ions, further depolarizing the cell membrane and leading to the generation of action potentials. Therefore, inhibiting abnormal sodium channel activity can help treat and relieve pain.

[0005] Voltage-gated sodium ion 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 one α subunit and several β subunits. The α subunit is the functional carrier of the sodium ion channel and is composed of 1700 to 2000 amino acids. The β subunit mainly plays an auxiliary role and can modify the dynamics and voltage gating dependence of the ion channel. Sodium ion channels can be classified according to the different α subunits. At present, 9 sodium ion channel subtypes have been identified in mammals, namely Na v 1(Na v 1.1~Na v 1.9). Different subtypes show different tissue distribution and electrophysiological and pharmacological characteristics. Based on whether they can be effectively inhibited by nanomolar tetrodotoxin (TTX), sodium ion channels are divided into TTX-sensitive (TTX-S) and TTX-resistant (TTX-R). v 1.1、Na v 1.2 Na v 1.3 and Na v 1.7 is TTX-S type, the encoding gene is located on human chromosome 2q23-24, and they are expressed in large quantities in neurons. v 1.5 Na v 1.8 and Na v 1.9 is TTX-R type, and the encoding gene is located on human chromosome 3p21-24. v 1.5 is mainly present in myocardial cells, Na v 1.8, Na v 1.9 exists in the peripheral nervous system (PNS).

[0006] N av 1.8 is an important ion channel involved in chronic pain, atrial fibrillation, and Budd-Chiari syndrome, and is a highly selective target for the treatment of pain. It has been shown to act as a carrier of sodium current, maintaining the action potential firing of neurons in the small dorsal root ganglion, and also participating in the spontaneous electrical signal firing of damaged neurons, such as driving the generation of neuropathic pain. v 1.8 Small molecule inhibitors include PF-01247324, A-803467, PF-06305591, VX-150, HRS-4800, JMKX-000623, HBW-004, and VX-548. 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 the first aspect of the present invention, there is provided a compound of formula I

[0008] or a pharmaceutically acceptable salt thereof, when a chiral center is present, the compound further includes stereoisomers and racemates thereof. In some embodiments of the present invention, the above compound is further represented by Formula IA or IB:

[0009] In the above compounds, R a1 、R a3 Each is independently selected from hydrogen, halogen, hydroxy, C1-C5 alkyl, C1-C5 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, -N(R c3 R c4 )m, and the alkyl, alkoxy, cycloalkyl, cycloalkoxy is optionally substituted by one or more halogen, hydroxy, cyano, C1-C5 alkyl, C1-C5 alkoxy, amino; R a2 Selected from one or more deuterium- or fluorine-substituted C1-C6 alkyl groups.

[0010] In some embodiments of the present invention, any two adjacent R a1 , Ra3 are connected to form a 5-7 membered ring, wherein the 5-7 membered ring can be a saturated or unsaturated carbocyclic ring or heterocyclic ring; the heterocyclic ring optionally contains one or more N, O, S (=O) m Heteroatoms; the 5-7 membered ring may be optionally substituted by one or more halogen, hydroxy, cyano, C1-C5 alkyl, C1-C5 alkoxy, amino.

[0011] In some embodiments of the present invention, R a1 、R a3 Each is independently selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, difluoromethoxy, and amino.

[0012] In some embodiments, R a2 Arbitrarily selected from 1, 2 or 3 deuterium or fluorine substituted methyl groups.

[0013] In some embodiments, any two adjacent R a1 、R a3 Connected to form a 5- or 6-membered carbocyclic or heterocyclic ring.

[0014] In some embodiments, the 5-membered or 6-membered heterocyclic ring contains one or two N, O, or S(═O)m heteroatoms.

[0015] 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.

[0016] 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.

[0017] 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.

[0018] In some embodiments, R b1 、R b2 Each is independently selected from hydrogen, methyl, trifluoromethyl;

[0019] In some embodiments, R b3 、R b4 Each is independently selected from hydrogen, methyl, and trifluoromethyl.

[0020] 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 heteroatoms; the 3-7 membered ring may be further optionally substituted with one or more halogen, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, or amino.

[0021] 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.

[0022] In some embodiments, R b1 、R b2 The three-membered ring can be connected to form a saturated three-membered carbon ring, and the three-membered ring can be optionally substituted by one or more halogen, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, and amino.

[0023] In some embodiments, R b3 、R b4 The 3-7 membered rings are connected to form a saturated carbon ring, and the 3-7 membered rings can be optionally substituted by one or more halogen, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, and amino groups.

[0024] In some embodiments, R b1 、R b2 With R b3 、R b4 Any two of them are 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 embodiments, R b1 、R b2 With R b3 、R b4 Any two of them are connected to form a 3-7 membered saturated carbon ring, and the 3-7 membered saturated carbon ring can be optionally substituted by one or more halogen, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, and amino.

[0026] In some embodiments, R b1 、R b2 With R b3 、R b4 Any two of them are connected to form a 3-6 membered saturated carbon ring, and the 3-6 membered saturated carbon ring can be optionally substituted by one or more halogen, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, and amino.

[0027] In the present invention, R b1 、R b2 With R b3 、R b4 Any two connections can be R b1 With R b3 、R b1 With R b4 、R b2 With R b3 、R b2 With R b4 connect.

[0028] M1, M2 are independently selected from C, O, S(=O) m NR n , where R n Optionally selected from hydrogen, C1-C5 alkyl; in one embodiment, R n Optionally selected from hydrogen, methyl or ethyl.

[0029] In the above compounds of the present invention, ring A has the structure of A1:

[0030] Any single or double bond can be represented, provided that it does not violate the principles of chemical bonding;

[0031] X1, X2, X3, X4, X5 are each independently selected from a bond, C, N, O, C=O, S(=O) m ;

[0032] X1, X2, X3, X4, and X5 are selected from a "bond" to indicate that they are directly connected in the form of a bond, provided that this does not violate the principles of chemical bonding. For example, when X2 is selected from a bond, X1 is directly connected to X3 through a bond, and in this case, ring A is a five-membered ring;

[0033] In some embodiments of the present invention, X1, X2, X3, X4, and X5 are each independently selected from a bond, C, N, C=O, and S(=O)2;

[0034] In some embodiments of the present invention, X1, X2, X3, X4, and X5 are all selected from C atoms;

[0035] In some specific embodiments of the present invention, any of X1, X2, X3, X4, and X5 contains one or two N atoms;

[0036] In some specific embodiments of the present invention, any of X1, X2, X3, X4, and X5 contains a C=O;

[0037] In some specific embodiments of the present invention, any of X1, X2, X3, X4, and X5 contains one S(=O)2;

[0038] In some embodiments of the present invention, X1, X2, X3, X4, and X5 are arbitrarily selected from a bond, C, S, or O;

[0039] In some embodiments of the present invention, Ring A has the following structure:

[0040] In the above compounds of the present invention, ring A has a structure such as A2

[0041] in, arbitrarily represents a single bond or a double bond, provided that it does not violate the principles of chemical bonding; X1, X2, X3, and X4 have the same definitions as in Formula A1. X1, X2, X3, and X4 are selected from "bonds" to indicate direct linkage via bonds. For example, when X3 is selected from a bond, X2 is directly linked to X4 via a bond to form a five-membered ring; Y1 and Y2 can be the same or different and can be selected from carbon atoms or nitrogen atoms.

[0042] In some embodiments of the present invention, in formula A2, X1, X2, X3, and X4 are each independently selected from a bond, C, N, or C=O;

[0043] In some embodiments of the present invention, in formula A2, X1, X2, X3, and X4 are each independently selected from a bond, C, N, and O;

[0044] In some embodiments of the present invention, X1, X2, X3, and X4 in formula A2 are each independently selected from a bond, C, N, S(=O) m ;

[0045] In some embodiments of the present invention, in formula A2, X1, X2, X3, and X4 are each independently selected from C, N, and C=O;

[0046] In some embodiments of the present invention, Ring A has the following structure:

[0047] R c1 、R c2 Each is 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 、-CH2NR c3 R c4 、-S(=O)(=NR c3 )R c4 ; and the C1-C5 alkyl group and the C1-C5 alkoxy group may be further substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, amino, C1-C5 alkyl group and C1-C5 alkoxy group;

[0048] R c1 、R c2 Any substitutable position on ring A is substituted, including substitution on X1, X2, X3, X4, Y1, and Y2; in some embodiments of the present invention, Rc1 、R c2 Substituted on a carbon atom; In some embodiments of the present invention, R c1 、R c2 Substitution on heteroatoms.

[0049] R c3 、R c4 Each is independently selected from hydrogen, hydroxy, amino, C1-C5 alkyl, C1-C5 alkoxy, 3-7 membered ring, or R c3 、R c4 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.

[0050] The substituent -S(=O) m -R c3 R c4 When m=2, R c4 Does not exist.

[0051] In some embodiments of the present invention, the compound of formula I described above is further represented by general formula II:

[0052] Among them: M1, Ring A, R a1 、R a2 、R a3 、R b1 、R b2 、R b3 、R b4 、R c1 、R c2 As defined above.

[0053] In some embodiments of the present invention, R c1 、R c2 Each is independently selected from hydrogen, hydroxy, amino, fluorine, 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,

[0054] In some embodiments of the present invention, R c1 、R c2Each is independently selected from hydrogen, fluorine, chlorine, amino, cyano, -C(=O)NH2. In the above compounds of the present invention, m and n are 0, 1 or 2.

[0055] In a specific embodiment of the present invention, the specific compound of the present invention has the following structure:

[0056] In a second aspect, the present invention provides a use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting a voltage-gated sodium channel, wherein the voltage-gated sodium channel is Nav1.8.

[0057] In a third aspect, the present invention provides a use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating, preventing or alleviating voltage-gated sodium channel-related diseases, wherein the related diseases include but are not limited to pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or arrhythmia.

[0058] The pain includes: acute pain, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, and visceral pain. Therefore, the present invention further provides a use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating, preventing, or alleviating pain.

[0059] In a fourth aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients include fillers, disintegrants, surfactants, and solubilizers.

[0060] The pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof of the present invention can be administered in various known ways, such as oral, topical, rectal, parenteral, inhalation or implantation. The pharmaceutical composition can be prepared into the form of tablets, capsules, bagged granules, dragees, powders, granules, lozenges, powder injections, liquid preparations or suppositories.

[0061] In a fifth aspect, the present invention provides a use of a compound of formula I or a pharmaceutically acceptable pharmaceutical composition thereof in the preparation of a medicament for treating, preventing or alleviating voltage-gated sodium channel-related diseases, wherein the voltage-gated sodium channel-related diseases include but are not limited to pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or arrhythmia.

[0062] The pain includes: acute pain, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, and visceral pain. Therefore, the present invention further provides a pharmaceutical combination containing a compound of formula I or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for treating, preventing, or alleviating pain. DETAILED DESCRIPTION

[0063] Explanation of terms

[0064] "Halogen" or "halogen atom" includes fluorine, chlorine, bromine and iodine; in the present invention, preferred halogen is fluorine or chlorine.

[0065] "C1-C5 alkyl" refers to a straight-chain or branched alkyl group containing 1-5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, etc.; the preferred C1-C5 alkyl group is C1-C3 alkyl, including methyl, ethyl, propyl, and isopropyl.

[0066] "C1-C5 alkoxy" refers to a straight-chain or branched alkoxy group containing 1-5 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, and tert-butoxy. Preferred C1-C5 alkoxy groups are C1-C3 alkoxy groups, including methoxy, ethoxy, propoxy, and isopropoxy. "C3-C6 cycloalkyl" refers to a cycloalkyl group containing 3-6 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl group may be further substituted with one or more of the following substituents: halogen, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, and amino.

[0067] "C3-C6 cycloalkoxy" refers to a cycloalkoxy group containing 3-6 carbon atoms, including cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy; the cycloalkoxy group may be further substituted with the following substituents: one or more halogens, hydroxyls, cyano groups, C1-C5 alkyl groups, C1-C5 alkoxy groups, and amino groups.

[0068] "3-7 membered ring" refers to a saturated or unsaturated ring containing 3-7 carbon atoms, such as a three-membered ring, a four-membered ring, a five-membered ring, a six-membered ring, or a seven-membered ring; in the present invention, the carbon atoms in the ring may be arbitrarily replaced by one or more C(=O), N, O, S(=O), m Substitution forms a 3-7 membered heterocyclic ring; the 3-7 membered ring may be further optionally substituted by one or more halogen, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, amino, and m is 0, 1, or 2.

[0069] "5-7 membered ring" refers to a saturated or unsaturated ring containing 5-7 carbon atoms, such as a 5-membered ring, a 6-membered ring, or a 7-membered ring; in the present invention, the carbon atoms in the ring may be arbitrarily replaced by one or more N, O, S (=O) m Substitution forms a 5-7 membered heterocyclic ring; the 5-7 membered ring may be further optionally substituted by one or more halogen, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, amino, and m is 0, 1, or 2.

[0070] "Multiple" can be two, three, four or more. In the present invention, multiple halogen substitutions can be trifluoromethyl, difluoromethyl.

[0071] The alkyl, alkoxy, cycloalkyl, cycloalkoxy, 5-7 membered ring, 3-7 membered ring described in the present invention may be optionally substituted with one or more deuterium, halogen, hydroxyl, cyano, oxo, C1-C5 alkyl, C1-C5 alkoxy, or amino groups.

[0072] As used herein, in any chemical structure or formula, a bold or hashed direct bond (respectively, ), such as in

[0073] middle,

[0074] Indicates the relative stereochemistry of a stereogenic center with respect to other stereogenic centers to which it is connected by bold or hashed direct bonds.

[0075] As used herein, in any chemical structure or formula, a bold or hashed wedge-shaped bond (respectively, ), such as in

[0076] middle,

[0077] Indicates the absolute stereochemistry of a stereogenic center and the relative stereochemistry of the stereogenic center with respect to the other stereogenic center to which it is connected by bold or hashed wedge bonds.

[0078] As used herein, the prefix "rel-" when used in conjunction with a chiral compound refers to a single enantiomer of unknown absolute configuration. In compounds with the "rel-" prefix, the (R)- and (S)- designators in the chemical name reflect the relative stereochemistry of the compound, but not necessarily the absolute stereochemistry of the compound.

[0079] “Pharmaceutically acceptable salts” include, but are not limited to, acid addition salts formed between a compound of formula (I) and an inorganic acid, such as hydrochloride, hydrobromide, phosphate, sulfate, nitrate, and the like; and acid addition salts formed between a compound of formula (I) and an organic acid, such as formate, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, and benzoate.

[0080] Compounds of the present invention For compounds The enol structure of is the same compound.

[0081] The general preparation method of the compounds of the present invention is as follows:

[0082] The compound of formula (A) reacts with the compound of formula (B) to obtain the compound of formula (IB-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 The definitions of and n are the same as those in the preceding text of the present invention.

[0083] The present invention further prepares specific compounds by the following method. Unless otherwise specified, the compounds, reagents, etc. used in the examples of the present invention were purchased from qualified suppliers or synthesized with reference to methods disclosed in the prior art. The synthesis of some intermediate compounds can refer to the method described in WO2022256660A1, such as the preparation of intermediate 1a with reference to the method of the prior art.

[0084] Synthesis of intermediate 1d:

[0085] Step 1: (2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1b)

[0086] To a single-necked reaction flask, (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 (25 mL) were added. The reaction mixture was reacted at 100°C under nitrogen for 18 hours. LCMS analysis indicated that most of the raw materials had reacted. The mixture was extracted with water and dichloromethane, and the dichloromethane layer was concentrated and purified by column chromatography (PE / EA = 0-100%) to afford compound 1b (1.2 g, 83.3% yield) as a yellow liquid. LCMS: m / z (254 nm): 339.3 [MH] - .

[0087] Step 2: (2R,3S,4S,5R)-3-(3,4-difluoro-2-trideuteromethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid trideuteromethyl ester (1c)

[0088] To a single-necked reaction flask, add 1b (0.5 g, 1.5 mmol, 1.0 eq), trideuteromethane (1.0 g, 7.4 mmol, 5.0 eq), potassium carbonate (1.9 g, 14.7 mmol, 10.0 eq), and acetonitrile (25 mL). The mixture was allowed to react at room temperature for 18 hours. LCMS confirmed the reaction was complete, and the mixture was extracted with water and ethyl acetate. The ethyl acetate layer was concentrated to afford compound 1c (0.7 g, crude) as a yellow liquid. LCMS: m / z (254 nm): 375.3 [M+H] + .

[0089] Step 3: (2R,3S,4S,5R)-3-(3,4-difluoro-2-trideuteromethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1d)

[0090] 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] - .

[0091] Synthesis of intermediate 3d:

[0092] Step 1: 3-Bromo-6-nitrobenzofuran-1(3H)-one (3b)

[0093] 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] +

[0094] Step 2: 7-nitrophthalazin-1(2H)-one (3c)

[0095] 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] +

[0096] Step 3: 7-aminophthalazin-1(2H)-one (3d)

[0097] 3c (200 mg), MeOH (10 mL), and THF (10 mL) were added to the reaction flask and stirred until uniform. Palladium / carbon (20 mg) was added and the atmosphere was replaced with hydrogen three times. The mixture was stirred at room temperature for 4 hours. TLC was used to monitor the reaction until the conversion of the starting material was complete. The reaction solution was filtered through celite and the filtrate was concentrated to obtain 120 mg of a white solid, with a yield of 71%. LCMS: m / z (254 nm): 162.0 [M+H] +

[0098] Synthesis of intermediate 5e:

[0099] Step 1: Methyl 2-hydroxy-5-nitrobenzoate (5b)

[0100] Methanol (50 mL) and 5a (5.0 g) were added to a three-necked flask, and thionyl chloride (10 mL) was slowly added dropwise. The mixture was reacted at 65°C for 16 hours, concentrated to dryness, and extracted with water and ethyl acetate. The ethyl acetate layer was concentrated to obtain 6.0 g of a white solid, with a yield of 111%. ESI-MS m / z: 198.1 (M+1) + .

[0101] Step 2: (2-Hydroxy-5-nitrophenyl)methanehydroxyamine (5c)

[0102] Methanol (500 mL) and potassium hydroxide (21 g) were added to the reaction flask. Hydroxylamine hydrochloride (17.5 g) was added under ice-cooling and stirred for 1.5 h. The filtrate was filtered and 5b (5 g) was added. The reaction was allowed to proceed for 16 h. LCMS confirmed the reaction was complete. The methanol was removed by concentration, and the pH was adjusted to 2 with hydrochloric acid. The mixture was extracted with water and ethyl acetate. The ethyl acetate layer was dried and concentrated to give 4.8 g of a light yellow solid (96% yield). ESI-MS m / z: 198.9 (M+1) + .

[0103] Step 3: 5-Nitro-2,3-dihydrobenzo[d]isoxazol-3-one (5d)

[0104] THF (100 mL) and 5c (2.76 g) were added to the reaction flask. Triphenylphosphine (4.8 g) was added under nitrogen protection. After stirring on ice for 20 minutes, DIAD (3.7 g) was added and the reaction was complete for 4 hours. LCMS confirmed the reaction was complete. The solvent was removed by concentration, water was added, the pH was adjusted to 13 with sodium hydroxide, and the product was extracted with DCM. The aqueous layer was taken, the pH was adjusted to 1 with hydrochloric acid, and the product was extracted with DCM. The product was washed with saturated brine and concentrated to give 1.6 g of a white solid in a 64% yield. ESI-MS m / z: 181.0 (M+1) + .

[0105] Step 4: 5-amino-2,3-dihydrobenzo[d]isoxazol-3-one (5e)

[0106] Methanol (50 mL), 5d (800 mg), and 5% palladium on carbon (200 mg) were added to the reaction flask and reacted under hydrogenation conditions for 36 h. LCMS confirmed the reaction was complete. The filtrate was filtered and concentrated to obtain 400 mg of a white solid, with a yield of 60.6%. ESI-MS m / z: 151.0 (M+1) + .

[0107] Synthesis of intermediate 8b: 6-aminophenylpropionic acid [d] isothiazol-3 (2H) -one-1,2-dioxo

[0108] 8a (650 mg) and concentrated hydrochloric acid (9 mL) were added to the reaction flask under an ice bath. Zinc powder (1.1 g) was added portionwise over approximately 30 minutes and stirring was continued at room temperature for 2 hours. LCMS analysis indicated that the starting material was essentially converted. Saturated sodium bicarbonate solution was added to the reaction mixture under an ice bath until weakly alkaline. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered to obtain 320 mg of a tan solid (approximately 70% purity), with a yield of 37.0%. LCMS: MS m / z (254 nm): 185.0 [M+H] + .

[0109] Synthesis of intermediate 11c:

[0110] Step 1: 5-amino-2-[amino(nitrogenylidene)methyl]benzoic acid (11b)

[0111] Compound 4-aminophthalonitrile 11a (500 mg, 3.49 mmol, 1.0 eq) was dissolved in methanol:water (3:2) (5 mL) and sodium hydroxide (139 mg, 3.49 mmol, 1.0 eq) was added. The reaction mixture was incubated at 100°C under nitrogen for 1 hour. LCMS monitored the reaction completion. The reaction mixture was cooled to room temperature and concentrated. The residue was isolated and purified by prep-HPLC (0.01% FA) to afford compound 5-amino-2-carbamoylbenzoic acid 11b (733 mg, 82% yield) as a yellow solid. LCMS: [M+H] + =180.1

[0112] Step 2: 4,7-Diamino-1,2-dihydrobenzo[2,1-d][1,2]diazepine-1-one (11c)

[0113] 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 solution was reacted at 25°C for 4 hours. LCMS monitored the completion of the reaction, the reaction mixture was concentrated, and the residue was extracted with water (10 mL) and ethyl acetate (10 mL x 5), then washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was filtered, and the filter residue was vacuum dried to obtain compound 4,7-diaminophthalazin-1-ol 11c (100 mg, 13% yield) as a yellow solid. LCMS: [M+H] + =177.1

[0114] Synthesis of intermediate 13c:

[0115] Step 1: 4-(bis(4-methoxybenzyl)amino)-N-hydroxypicolinamide (13b)

[0116] Compound 4-(bis(4-methoxybenzyl)amino)picolinic acid 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 and stirred at 25°C for 2 hours. Hydroxylamine hydrochloride (882.81 mg, 10.6 mmol, 5.0 eq) was then added. The reaction solution was stirred at 25°C for 2 hours. LCMS monitored the completion of the reaction, poured into water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried, and concentrated. The residue was separated and 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

[0117] Step 2: 4-Amino-N-hydroxypicolinamide (13c)

[0118] 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 hours. LCMS monitored the reaction completion and the reaction mixture was concentrated. The residue was dissolved in dichloromethane, and ethereal hydrochloric acid (2 mL) was added and concentrated to afford the hydrochloride salt of compound 13c (260 mg, 93% yield) as a brown solid. LCMS: [M+H] + =154.2

[0119] Synthesis of intermediate 14d:

[0120] Step 1: Methyl 4-(bis(4-methoxybenzyl)amino)picolinate (14a)

[0121] 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′-dinaphthyl]-2,2′-diylbis[1,1-diphenyl-(ACI)phosphine (580 mg, 0.09 mmol, 0.05 eq), palladium acetate (210 mg, 0.09 mmol, 0.05 eq), cesium carbonate (12.06 g, 3.7 mmol, 2.0 eq), and toluene (40 mL) were added sequentially to a microwave tube and stirred at 100° C. for 4 hours. The reaction was monitored by LCMS, the reaction solution was filtered, and the filtrate was concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 14a (3.2 g, 44% yield) as a yellow solid. LCMS: [M+H] + =393.2

[0122] Step 2: 4-(Bis(4-methoxybenzyl)amino)picolinic acid (14b)

[0123] Compound 4-(bis(4-methoxybenzyl)amino)picolinic acid methyl ester 14a (3.2 g, 8.2 mmol, 1.0 eq) was dissolved in methanol / tetrahydrofuran / water (3 / 3 / 1) (30 mL). Lithium hydroxide monohydrate (1 g, 24.6 mmol, 3.0 eq) was added and stirred at 25°C for 16 hours. LCMS monitored the reaction completion. The reaction solution was poured into water, and the pH was adjusted to ~5 with 1N dilute hydrochloric acid. The solution was extracted with ethyl acetate, and the organic phase was washed with brine, dried, and concentrated to afford compound 4-(bis(4-methoxybenzyl)amino)picolinic acid 14b (2 g, 65% yield) as a yellow solid. LCMS: [M+H] + =379.1

[0124] Step 3: 4-(bis(4-methoxybenzyl)amino)-N-methoxypicolinamide (14c)

[0125] Compound 4-(bis(4-methoxybenzyl)amino)picolinic acid 14b (200 mg, 0.53 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (2 mL), and N,N′-carbonyldiimidazole (102.8 mg, 0.63 mmol, 1.2 eq) was added, and the mixture was stirred at 25°C for 2 hours. Methoxyamine hydrochloride (221 mg, 10.6 mmol, 5.0 eq) was then added. The reaction mixture was stirred at room temperature for 2 hours. LCMS monitored the completion of the reaction, and the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford compound 4-(bis(4-methoxybenzyl)amino)-N-methoxypicolinamide 14c (140 mg, 65% yield) as a brown solid. LCMS: [M+H] + =408.1

[0126] Step 4: 4-Amino-N-methoxypicolinamide (14d)

[0127] Compound 4-(bis(4-methoxybenzyl)amino)-N-methoxypicolinamide 14c (100 mg, 0.24 mmol, 1.0 eq) was dissolved in trifluoroacetic acid (2 mL). The reaction mixture was stirred at 60°C for 4 hours. LCMS monitored the reaction completion and the reaction mixture was concentrated. The residue was dissolved in dichloromethane, ethereal hydrochloric acid (2 mL) was added, and the mixture was concentrated to afford compound 4-amino-N-methoxypicolinamide 14d (80 mg, 78% yield) as a brown solid in the form of the hydrochloride salt. LCMS: [M+H] + =168.1

[0128] Synthesis of intermediate 18d:

[0129] Step 1: Methyl 2-cyano-5-nitrobenzoate (18b)

[0130] To a reaction flask, 18a (3 g), cuprous cyanide (2 g), and DMF (30 mL) were added. Pd2(dba)3 (527 mg) and dppf (638 mg) were added sequentially with stirring. The atmosphere was purged with nitrogen three times and stirred at 115°C for 16 hours. The reaction mixture was cooled to room temperature, water (70 mL) was added, and the mixture was extracted with ethyl acetate (40 mL x 3). The organic phases were combined, concentrated, and separated by column chromatography (EA / PE, 0% to 15%) to obtain 2 g of a white solid, in an 84.4% yield. LCMS: m / z (254 nm): 207.0 [M+H] +

[0131] Step 2: 2-Cyano-5-nitrobenzamide (18c)

[0132] To the reaction mixture was added 18b (1 g) and a 7 M ammonia methanol solution (10 mL) and stirred at room temperature for 16 hours. The reaction mixture was filtered and washed with methanol to obtain 720 mg of a pale yellow solid, a yield of 77.6%. LCMS: m / z (254 nm): 192.0 [M+H] +

[0133] Step 3: 2-Cyano-5-aminobenzamide (18d)

[0134] To the reaction flask, 18c (300 mg), MeOH (10 mL), and THF (10 mL) were added and stirred. Palladium / carbon (30 mg) was then added and the atmosphere was replaced with hydrogen three times. The mixture was stirred at room temperature for 6 hours. TLC was used to monitor the reaction until the conversion of the starting material was complete. The reaction solution was filtered through celite and the filtrate was concentrated to give 179 mg of a yellow solid, a yield of 71%. LCMS: m / z (254 nm): 162.0 [M+H]. + . 1 H NMR (400MHz, DMSO-d6) δ9.00 (s, 2H), 7.58 (d, 1H), 6.77 (d, 1H), 6.73 (dd, 1H), 5.99 (s, 2H).

[0135] Synthesis of intermediate 20f:

[0136] Step 1: 2-Bromo-3-fluoro-5-nitrobenzoic acid (20a)

[0137] Compound 2-bromo-3-fluorobenzoic acid (5 g, 22.8 mmol, 1.0 eq) was dissolved in concentrated sulfuric acid (15 mL) and fuming nitric acid (1 mL) was added at 0°C. The reaction mixture was stirred at 25°C for 4 hours and the reaction was complete after monitoring by LCMS. The reaction solution was slowly poured into ice water, extracted with dichloromethane (50 mL x 3), and the organic phase was collected. The organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified 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.

[0138] Step 2: Methyl 2-bromo-3-fluoro-5-nitrobenzoate (20b)

[0139] Compound 2-bromo-3-fluoro-5-nitrobenzoic acid 20a (800 mg, 3.03 mmol, 1.0 eq) was dissolved in methanol (5 mL) and thionyl chloride (1 mL) was added. The reaction mixture was stirred at 80°C for 6 hours. LCMS monitored the reaction completion. The reaction solution was filtered to obtain a filtrate. The filtrate was concentrated to obtain compound methyl 2-bromo-3-fluoro-5-nitrobenzoate 20b (800 mg, 95%) as a yellow solid. LCMS: [M+H] + =277.9.

[0140] Step 3: Dimethyl 3-fluoro-5-nitrobenzoate (20c)

[0141] Compound 2-bromo-3-fluoro-5-nitrobenzoic acid methyl ester 20b (400 mg, 1.43 mmol, 1.0 eq) was dissolved in methanol (10 mL), and Pd(dppf)Cl2 (32 mg, 0.143 mmol, 0.1 eq) and Et3N (437 mg, 4.32 mmol, 3.0 eq) were added. 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, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 3-fluoro-5-nitrobenzoic acid dimethyl ester 20c (40 mg, 11%) as a brown oil. LCMS: [M+H]+ = 258.1.

[0142] Step 4: 3-Fluoro-5-nitroammonium phthalate (20d)

[0143] Compound 3-fluoro-5-nitrobenzoic acid dimethyl ester 20c (40 mg, 0.155 mmol, 1.0 eq) was dissolved in ammonia methanol (5 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated to obtain a residue, which was washed with dichloromethane and filtered to obtain the solid compound 3-fluoro-5-nitrophthalammonium 20d (20 mg, 57%) as a white solid. LCMS: [M+H] = 228.1.

[0144] Step 5: 3-Fluoro-5-aminophthalate ammonium (20f)

[0145] Compound 3-fluoro-5-nitroammonium phthalate 20d (20 mg, 0.088 mmol, 1.0 eq) was dissolved in methanol (5 mL). The reaction mixture was stirred at 25°C for 1 hour in the presence of hydrogen. The reaction mixture was filtered, and the filtrate was collected and concentrated to obtain compound 3-fluoro-5-aminoammonium phthalate 20f (13 mg, 75%) as a yellow solid. LCMS: [M+H] + =198.1.

[0146] Synthesis of intermediate 21c:

[0147] Step 1: 2-Fluoro-5-nitrobenzenesulfonamide (21b)

[0148] Compound p-fluoronitrobenzene 21a (2.0 g, 14.2 mmol, 1.0 eq) was dissolved in chlorosulfonic acid (10 mL). The reaction mixture was stirred at 110°C for 24 hours, then cooled to room temperature. The reaction mixture was slowly poured into an ice bath. After the ice had completely melted, the mixture was extracted with ethyl acetate (50 mL x 3), and the organic phase was collected. The organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was dissolved in ethyl acetate (60 mL), and aqueous ammonia (60 mL) was slowly added at 0°C. The reaction mixture was stirred at 25°C for 16 hours. After completion of the reaction as monitored by TLC, the reaction mixture was poured into water and extracted with ethyl acetate (50 mL x 3), and the organic phase was collected. The organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 3) to give compound 2-fluoro-5-nitrobenzenesulfonamide 21b (400 mg, 13% yield) as a yellow solid. 1 H NMR (400MHz, DMSO) δ 8.56-8.53 (m, 2H), 8.06 (s, 2H), 7.86-7.65 (m, 1H).

[0149] Step 2: 5-Amino-2-fluorobenzenesulfonamide (21c)

[0150] Compound 2-fluoro-5-nitrobenzenesulfonamide 21b (200 mg, 0.90 mmol, 1.0 eq) was dissolved in methanol (5 mL) and wet palladium on carbon (193 mg, 1.80 mmol, 2.0 eq) was added. The reaction mixture was stirred at 25°C for 1 hour in the presence of hydrogen. LCMS monitored the completion of the reaction. The reaction solution was filtered to obtain a filtrate. The filtrate was concentrated to obtain compound 5-amino-2-fluorobenzenesulfonamide 21c (160 mg, 92% yield) as a black solid. LCMS: [M+H] + =191.1

[0151] Preparation of intermediate 25g:

[0152] Step 1: (3Z)-4-(3,4-difluoro-2-methoxyphenyl)-1,1,1-trifluoro-3-methylbut-3-en-2-one (25a)

[0153] To a reaction flask, 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) were added sequentially. The mixture was sealed and reacted at room temperature for two hours. The temperature was then raised to 75°C and the reaction continued for 16 hours. TLC monitored the reaction for completion. The mixture was extracted with water and ethyl acetate. The ethyl acetate layer was concentrated and separated by column chromatography (PE:EA = 20:1) to afford 25a (7.5 g, 92% yield) as a yellow liquid.

[0154] Step 2: rac-(2R,3S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methyl-5-(trifluoromethyl)-2,3-dihydrofuran-2-carboxylic acid ethyl ester (25b)

[0155] 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) were added sequentially to a reaction flask and allowed to react at room temperature for 16 hours. TLC (PE:EA = 10:1) monitored the completion of the reaction of compound 25a. The filtrate was filtered, concentrated, and then separated on a column (PE:EA = 20:1) to yield 2.3 g of a yellow liquid (72% yield).

[0156] Step 3: rac-(2R,3S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methyl-5-(trifluoromethyl)-2,3-dihydrofuran-2-carboxamide (25c)

[0157] Compound 25b (5 g, 13.6 mmol, 1.0 eq) was dissolved in ammonia / methanol (7 M, 15 mL). The reaction mixture was allowed to react at 80°C for 16 hours. LCMS monitored the reaction completion. The reaction mixture was concentrated, and the residue was purified on a silica gel column (dichloromethane / methanol = 20 / 1) to afford compound 25c (3.8 g, 83% yield) as a white solid. LCMS: [M+H] + =338.0

[0158] 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)

[0159] Compound 25c (2.0 g, 5.9 mmol, 1.0 eq) was dissolved in dichloroethane (50 mL) and trimethyl(vinyl)silane (11.8 g, 11.8 mmol, 20.0 eq) was added. The reaction mixture was irradiated with a mercury lamp 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

[0160] 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)

[0161] Compound 25d (500 mg, 3.0 mmol, 1.0 eq) was dissolved in dimethyl sulfoxide (20 mL), and tetrabutylammonium fluoride trihydrate (6.4 g, 22.8 mmol, 20 eq) was added. The reaction mixture 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 give compound 25e (170 mg, 40% yield) as a yellow oil. LCMS: [M+H] + =366.1

[0162] 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)

[0163] Compound 25d (170 mg, 0.387 mmol, 1.0 eq) was dissolved in ethanol / water (3 mL + 1 mL) and potassium hydroxide (217 mg, 3.87 mmol, 10 eq) was added. The reaction solution was reacted at 100 ° C for 4 hours. LCMS monitored the completion of the reaction. 1 M dilute hydrochloric acid was added to the reaction solution, the pH was adjusted to 5-6, and the mixture was extracted with ethyl acetate (10 mL × 3), and the organic phase was collected. 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.

[0164] Step 5: rac-(1R,3R,4S,5R)-4-(3,4-difluoro-2-trideuteromethoxyphenyl)-5-methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxylic acid (25 g)

[0165] Intermediate 25g was prepared by a similar method to Intermediate 1d. LCMS: m / z (254 nm): 368.3 [MH] - .

[0166] Preparation of intermediate 33b: 5-bromo-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide

[0167] 4-Bromo-2-fluorobenzenesulfonyl chloride 33a (200 mg, 1.0 eq) was dissolved in THF (5 mL), cooled to 0°C, and under nitrogen, NaHMDS (0.9 mL, 1.0 M, 1.2 eq) was added dropwise. After 1 hour, a solution of tert-butyl thiazole-4-carbamate (161 mg, 1.1 eq) in THF (1 mL) was added. After slowly warming to room temperature, saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and dried by spin drying. The mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to afford 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.

[0168] Preparation of intermediate 34c:

[0169] Step 1: Benzyl (2-(S-methylsulfonylimino)pyridin-4-yl)carbamate (34b)

[0170] 34a (2.2 g, 8.0 mmol, 1.0 eq) was weighed into a reaction flask and iodophenyl diacetic acid (8.3 g, 25.7 mmol, 3.2 eq), aminoformamide (4.3 g, 56.2 mmol, 7.0 eq), dichloromethane (150 mL), and methanol (150 mL) were added. After 16 hours at room temperature, the reaction was complete as determined by LCMS. The reaction solution was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 0-100%) to afford 34b as a yellow solid (2.3 g, 94% yield). LCMS: [M+H] + =306.4.

[0171] Step 2: (4-aminopyridin-2-yl)(imino)(methyl)-1-6-sulfonic acid ketone (34c)

[0172] Compound 34b (300 mg, 0.98 mmol, 1.0 eq) was dissolved in methanol (10 mL) and palladium on carbon (314 mg, 2.95 mmol, 3.0 eq) was added. The reaction mixture was reacted under hydrogen at 25°C for 16 hours. LCMS monitored the reaction to be complete. The reaction mixture was filtered, and the filtrate was collected and concentrated to obtain a residue. The residue was 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.

[0173] Preparation of intermediate 35b:

[0174] Step 1: Benzyl (2-(N,S-dimethylsulfonylimino)pyridin-4-yl)carbamate (35a)

[0175] Compound 34b (300 mg, 0.98 mmol, 1.0 eq) was dissolved in acetonitrile (20 mL), and 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) were added. The reaction solution was reacted at 25 ° C for 16 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated to obtain a residue. The residue was 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.

[0176] Step 2: (4-aminopyridin-2-yl)(methyl)(methylimino)-1-6-sulfonic acid ketone (35b)

[0177] Compound 35a (300 mg, 0.94 mmol, 1.0 eq) was dissolved in methanol (10 mL) and palladium on carbon (300 mg, 2.82 mmol, 3.0 eq) was added. The reaction mixture was reacted at 25°C under hydrogen for 16 hours. LCMS monitored the reaction to be complete. The reaction mixture was filtered, and the filtrate was collected and concentrated to obtain a residue. The residue was 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.

[0178] Preparation of intermediate 42b:

[0179] Step 1: 2-(Methylthio)pyridin-4-amine (42b)

[0180] Sodium thiomethoxide (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 flash chromatography on silica gel eluting 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.

[0181] Step 2: 2-(Methylsulfonyl)pyridin-4-amine (42c)

[0182] 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 the reaction was completed, the mixture was concentrated under reduced pressure to obtain a mixture. The mixture was purified by column chromatography (dichloromethane / methanol=10 / 1) to obtain 2-(methylsulfonyl)pyridin-4-amine 42c (30 mg, 22% yield) as a yellow solid. LCMS: [M+H] + =173.0.

[0183] Preparation of Intermediate 43b: (4-aminopyridin-2-yl)dimethylphosphine oxide

[0184] In a microwave oven, 2-bromopyridin-4-amine 43a (200 mg, 1.16 mmol, 1.0 eq) was dissolved in 1,4-dioxane (3 mL). 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 microwaved at 130°C under a nitrogen atmosphere for 2 hours. After reaction completion, the reaction mixture was concentrated by LCMS, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to afford (4-aminopyridin-2-yl)dimethylphosphine oxide 43b (150 mg, 76% yield) as a yellow solid.

[0185] Preparation of intermediate 44d:

[0186] Step 1: 2-Amino-5-nitrobenzenesulfonamide (44b)

[0187] To a 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 aqueous ammonia (10 mL). The mixture was stirred at 120°C for 6 hours. TLC confirmed the complete conversion of the starting materials. The reaction solution was cooled to room temperature and poured into water to precipitate a solid. The mixture was filtered, the filter cake was washed with water, and dried to afford compound 44b (1.3 g, 71% yield) as a nitrogen-yellow solid. LCMS: 218.1 [M+H] + .

[0188] Step 2: 7-Nitro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (44c)

[0189] To the reaction flask, 44b (600 mg, 2.76 mmol, 1.0 eq) and trimethyl orthoformate (10 mL) were added and stirred at 140°C for 8 hours. TLC confirmed the near-complete conversion of the starting material. The reaction mixture was cooled to room temperature and poured into water, whereupon a solid precipitated. The mixture was filtered, the filter cake washed with water, and dried to afford compound 44c (230 mg, 37% yield) as a pale solid. LCMS: 228.1 [M+H] + .

[0190] Step 3: 7-Amino-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (44d)

[0191] To a reaction flask were added 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). The mixture was stirred at 75°C for 2 hours. LCMS analysis revealed that the starting material was essentially converted. The reaction mixture was filtered through Celite while hot, and the filtrate was concentrated and separated by column chromatography (MeOH / DCM, 0-10%) to afford compound 44d (82 mg, 47% yield) as a light yellow solid. LCMS: 198.2 [M+H] + .

[0192] Preparation of intermediate 54b:

[0193] 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)

[0194] 1b (100 mg, 0.29 mmol, 1.0 eq), fluoroiodomethane (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 allowed to react at room temperature for 18 hours. LCMS monitored the complete reaction (no MS response was observed for the product). Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to afford crude compound 54a (0.145 g, crude) as a yellow liquid.

[0195] 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)

[0196] 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 allowed to react at room temperature for 16 hours. LCMS monitored the complete reaction. The reaction solution was concentrated and adjusted to pH 1 with hydrochloric acid (2 M). Water (10 mL) was added and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (EA / PE, 0-100%) to afford compound 54b (110 mg, 100% yield) as a yellow liquid. LCMS: 371.0 [MH] - .

[0197] Preparation of intermediate 55b:

[0198] Step 1: (2R,3S,4S,5R)-3-(3,4-difluoro-2-difluoromethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid difluoromethyl ester (55a)

[0199] To a single-necked reaction flask, 1b (50 mg, 0.15 mmol, 1.0 eq) and acetonitrile (5 mL) were added, followed by a solution of potassium hydroxide (99 mg, 1.8 mmol, 12.0 eq) in water (11 mL) and difluoromethyl trifluoromethanesulfonate (88 mg, 0.44 mmol, 3.0 eq). The mixture was allowed to react at room temperature for half an hour. LCMS analysis indicated that most of the starting materials had reacted completely, and the reaction was terminated. The reaction system was adjusted to pH 5 with 1N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by column chromatography (PE:EA = 0-100%) to afford compound 55a (30 mg). LCMS: m / z (254 nm): 441.0 [M+H]+ .

[0200] Step 2: (2R,3S,4S,5R)-3-(3,4-difluoro-2-difluoromethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (55b)

[0201] Intermediate 55b was prepared using a similar synthetic method to that of Intermediate 1d (LCMS: m / z (254 nm): 389.1 [MH]-).

[0202] Example 1: (2R,3S,4S,5R)-3-(3,4-difluoro-2-trideuteromethoxyphenyl)-4,5-dimethyl-N-(3-oxoisoindolin-5-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0203] To a single-necked reaction flask, 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) were added and reacted at 30°C for 16 hours. LCMS confirmed the reaction was complete, and the product was extracted with water and ethyl acetate. The ethyl acetate layer was concentrated and eluted by column chromatography (MeOH / DCM = 0-20%) to afford Example 1 (0.22 g, 94% yield). 1 H NMR (400MHz, CD3OD) δ7.82 (d, J=2.0Hz, 1H), 7.73 (dd, J=8.4, 2.1Hz, 1H), 7.59 (d, J=8.4Hz, 1H), 7.157.09 (m, 1H), 6.97 (dd, J= 17.0, 9.3Hz, 1H), 5.06 (d, J=10.5Hz, 1H), 4.344.27 (m, 1H), 2.78 (dd, J=15.4, 7.8Hz, 1H), 1.66 (s, 3H), 0.81 (d, J=7.4Hz, 3H).

[0204] Example 54: 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(fluoromethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)phthalamide

[0205] Example 54 was prepared by a method similar to Example 1, using intermediate 54b instead of 1d. ESI-MS m / z=534.1 (M+1) + . 1H NMR (400MHz, DMSO-d6) δ10.43 (s, 1H), 7.747.66 (m, 4H), 7.49 (d, J=8.3Hz, 1H), 7.37-7.24 (m, 4H), 5.90 (dd, J=5.9, 2.5Hz, 1H), 5.76 (dd, J=6.2, 2.5Hz, 1H), 5.11 (d, J=10.4Hz, 1H), 4.32 (dd, J=10.3, 7.7Hz, 1H), 2.842.75 (m, 1H), 1.59 (s, 3H), 0.74 (d, J=6.0Hz, 3H).

[0206] Example 55: 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(difluoromethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)phthalamide

[0207] Example 55 was prepared by a method similar to Example 1, using intermediate 55b instead of 1d. ESI-MS m / z=552.1 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ10.43 (s, 1H), 7.737.66 (m, 4H), 7.537.08 (m, 6H), 5.13 (d, J=10.3H z, 1H), 4.27 (dd, J=10.1, 7.7Hz, 1H), 2.792.72 (m, 1H), 1.59 (s, 3H), 0.76 (d, J=6.1Hz, 3H).

[0208] Table 1: The following compounds were prepared using the corresponding reagents as starting materials and following procedures similar to those described in Example 1.

[0209] Example 12:

[0210] 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)

[0211] Intermediate 12a was prepared by a procedure similar to that described in Example 1. LCMS: [M+H] + =477.2.

[0212] 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-methylpyridinium-1-ol ion (Example 12)

[0213] Compound 12a (42 mg, 0.08 mmol, 1.0 eq), iodomethane (1 mL), and acetonitrile (2 mL) were added sequentially to a microwave tube. The reaction mixture was reacted at 80°C under nitrogen for 16 hours. LCMS monitored the completion of the reaction. The reaction mixture was concentrated, and the residue was purified by preparative separation (0.01% ammonia water) to afford compound 12 (12 mg, 27% yield). LCMS: [M+H] + =492.2.

[0214] Example 15: (2R,3S,4S,5R)-N-[2-(aminosulfanylidenemethyl)pyridin-4-yl]-3-{3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl}-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0215] Compound 12a (30 mg, 0.06 mmol, 1.0 eq) was dissolved in toluene (20 mL), and Lawesson's reagent (26 mg, 0.06 mmol, 1.0 eq) was added. The temperature was raised to 110°C and the reaction was allowed to proceed for 24 hours. After the reaction was complete, the solvent was removed by concentration and thin-layer chromatography to obtain Example 15 (15 mg, 48% yield). LCMS: [M+H] + =493.2.

[0216] Example 22:

[0217] Step 1: 2-(Benzylthio)-4-bromopyridine (22b)

[0218] Compound benzylmercaptan 22a (2.0 g, 16.1 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (30 mL) and sodium hydroxide (640 mg, 16.1 mmol, 1.0 eq) was added at 0°C under nitrogen. The reaction mixture was stirred at 0°C for 30 minutes. At the same temperature, a solution of 4-bromo-2-fluoropyridine (2.8 g, 16.1 mmol, 1.0 eq) in anhydrous tetrahydrofuran (10 mL) was added dropwise, and the mixture was stirred at 0°C for 1.5 hours. LCMS confirmed the completion of the reaction. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The mixture was then washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified on a silica gel column (petroleum ether / ethyl acetate = 50 / 1) to afford compound 2-(benzylthio)-4-bromopyridine 22b (4.3 g, 95% yield) as a pink oil. LCMS: [M+H] + =280.0

[0219] Step 2: 4-Bromopyridine-2-sulfonyl chloride (22c)

[0220] Compound 2-(Benzylthio)-4-bromopyridine 22b (4.3 g, 15.3 mmol, 1.0 eq) was dissolved in 80 mL of dichloromethane:acetic acid:water (7:1:2) and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (1.1 g, 7.2 mmol, 0.7 eq) was added. The reaction mixture was allowed to react at 25°C under nitrogen for 16 hours. TLC confirmed the completion of the reaction. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL x 3). The mixture was then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, diluted with dichloromethane, filtered, and the filtrate was spin-dried to afford crude 4-bromopyridine-2-sulfonyl chloride 22c (4.5 g, 92% yield) as a yellow oil.

[0221] Step 3: 4-Bromopyridine-2-sulfonamide (22d)

[0222] Aqueous ammonia (10 mL) was added to 4-bromopyridine-2-sulfonyl chloride 22c (3.0 g, 9.4 mmol, 1.0 eq). The reaction mixture was allowed to react at 25°C for 1 hour. LCMS monitored the complete reaction. The reaction mixture was concentrated, and the residue was purified on a silica gel column (petroleum ether / ethyl acetate = 1 / 1) to afford 4-bromopyridine-2-sulfonamide 22d (1.7 g, 77% yield) as a gray solid. LCMS: [M+H] + =238.9

[0223] Step 4: tert-Butyl ((4-bromopyridin-2-yl)sulfonyl)carbamate (22e)

[0224] 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 allowed to react at 25°C for 1 hour. LCMS monitored the reaction completion of the starting material. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound tert-butyl ((4-bromopyridin-2-yl)sulfonyl)carbamate 22e (611 mg, 85% yield) as a yellow oil. LCMS: [M+Na] + =359.0

[0225] Step 5: Tert-butyl ((4-bromopyridin-2-yl)sulfonyl)(methyl-d3)carbamate (22f)

[0226] 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 deuterated iodomethane (94 mg, 0.65 mmol, 1.1 eq) were added. The reaction mixture was reacted at 60°C for 2 hours. LCMS monitoring 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 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 22f (130 mg, 62% yield) as a white solid. LCMS: [M+Na] + =376.0

[0227] Step 6: (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (22 g)

[0228] Ammonium chloride was used to replace 4-aminobenzene-1,2-dicarboxamide in Example 1, and a similar method was used to obtain 22 g of the intermediate. LCMS: [M+H] + =357.1.

[0229] 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]dioxy-λ 6-sulfanyl}(trideuteriomethyl)amino)methanoic acid-2-methylprop-2-yl ester (22h)

[0230] 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 acetate (3 mg, 0.02 mmol, 0.1 eq) were added. The reaction mixture was reacted at 105°C under nitrogen for 16 hours. LCMS monitoring confirmed the completion of the reaction. The reaction mixture was concentrated, and the residue was purified on a silica gel column (petroleum ether / ethyl acetate = 5 / 1) to afford 22h (65 mg, 51% yield) as a yellow oil. LCMS: [M+H] + =630.2.

[0231] Step 8: (2R,3S,4S,5R)-3-{3,4-difluoro-2-[(trideuteromethyl)oxy]phenyl}-N-(2-{dioxyylidene[(trideuteromethyl)amino]-λ 6 -thio}pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0232] 22h (50 mg, 0.08 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL) and p-toluenesulfonic acid (13.72 mg, 0.08 mmol, 1.0 eq) was added. The reaction mixture was allowed to react at 25°C for 16 hours. LCMS confirmed the complete reaction of the starting material. The reaction mixture was concentrated and the residue was purified by preparative separation (0.05% NH3) to afford Example 82 (10.0 mg, 24% yield). LCMS: [M+H] + =530.2.

[0233] Example 23:

[0234] Step 1: tert-Butyl ((4-bromopyridin-2-yl)sulfonyl)(ethyl)carbamate (23a)

[0235] 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

[0236] 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)

[0237] 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 reacted at 105°C under nitrogen for 16 hours. LCMS monitored the reaction completion of the starting material. The reaction solution 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.

[0238] Step 3: (2R,3S,4S,5R)-3-{3,4-difluoro-2-[(trideuterium methyl)oxy]phenyl}-N-{2-[(ethylamino)dioxy]-λ 6 -thio]pyridin-4-yl}-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Example 23)

[0239] Compound 23b (100 mg, 0.16 mmol, 1.0 eq) was dissolved in hydrochloric acid / dioxane (4 M, 30 mL). The reaction mixture was incubated at 25°C for 2 hours. LCMS confirmed the complete reaction. The reaction mixture was concentrated, and the residue was purified by preparative separation (0.01% FA) to afford Example 23 (39.5 mg, 47% yield) as a white solid. LCMS: [M+H] + =541.2.

[0240] Example 24:

[0241] Step 1: 4-Bromo-N-(2,2,2-trifluoroethyl)pyridine-2-sulfonamide (24b)

[0242] Compound 2,2,2-trifluoroethane-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 reacted at 25°C for 1 hour. LCMS monitored the reaction completion of the raw material reaction. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (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

[0243] Step 2: tert-Butyl ((4-bromopyridin-2-yl)sulfonyl)(2,2,2-trifluoroethyl)carbamate (24c)

[0244] 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 allowed to react at 25°C for 1 hour. LCMS monitored the reaction completion of the starting material. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (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

[0245] 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]dioxy-λ 6 -sulfanyl}(2,2,2-trifluoroethyl)amino)methanoic acid-2-methylprop-2-yl ester (24d)

[0246] Compound 24c (100 mg, 0.24 mmol, 1.0 eq) was dissolved in dioxane (5 mL), and 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 acetate (4 mg, 0.024 mmol, 0.1 eq) were added. The reaction mixture was reacted at 105°C under nitrogen for 16 hours. LCMS monitored the reaction completion of the raw material reaction. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 24d (80 mg, 48% yield) as a yellow oil. LCMS: [M+H] + =695.2.

[0247] Step 4: (2R,3S,4S,5R)-3-{3,4-difluoro-2-[(trideuterium methyl)oxy]phenyl}-N-(2-{dioxyethylene[(2,2,2-trifluoroethyl)amino]-λ 6 -thio}pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Example 24)

[0248] Compound 24d (80 mg, 0.11 mmol, 1.0 eq) was dissolved in hydrochloric acid / dioxane (4 M, 5 mL). The reaction mixture was allowed to react at 25°C for 4 hours. LCMS confirmed the complete reaction. The reaction mixture was concentrated and the residue was purified by preparative separation (0.1% FA) to afford Example 24 (15.4 mg, 22% yield). LCMS: [M+H] + =595.1.

[0249] Example 28:

[0250] Step 1: 2-Benzylthio-4-iodopyridine (28b)

[0251] Benzyl mercaptan (2.9 g) and THF (50 mL) were added to the reaction flask and stirred until homogeneous. NaH (848 mg) was added portionwise under ice-cooling. After addition, the mixture was stirred at room temperature for 1 hour. Compound 28a (5 g) was added under ice-cooling. After addition, the mixture was stirred at room temperature for 3 hours. LCMS analysis indicated that the starting material was nearly completely converted. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (EA / PE, 0% to 10%) to afford 6.6 g of compound 28b as a light red liquid in a 90.1% yield. LCMS: m / z (254 nm): 327.9 [M+H]. + .

[0252] Step 2: 4-Iodopyridine-2-sulfonyl chloride (28c)

[0253] 28b (3 g), DCM (30 mL), and DIPEA (3.8 g) were added to the reaction flask. Dichlorohydantoin (6.9 g) was added portionwise in an ice bath. After addition, the mixture was warmed to room temperature and stirred for 4 hours. LCMS analysis indicated that the reaction was essentially complete. Water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (EA / PE, 0%-10%) to afford 1.4 g of a light yellow solid in a 24.2% yield. LCMS: m / z (254 mm): 303.9 [M+H]. + .

[0254] Step 3: N,N-di(2,4-dibenzyl)-4-iodopyridine-2-sulfonamide (28d)

[0255] To a reaction flask were added 28c (800 mg), N-methylpyrrolidone (7 mL), ammonium acetate (1.06 g), copper acetylacetonate (107 mg), Ligand (115 mg), and cesium carbonate (1.34 g). The atmosphere was purged with nitrogen three times and stirred at 95°C for 16 hours. The reaction mixture was cooled to room temperature, water (20 mL) was added, and extraction was performed with ethyl acetate (20 mL x 3). The organic phases were combined, concentrated, and separated by column chromatography (EA / PE, 50% to 100%) to obtain 460 mg of a yellow oil in a yield of 70.8%. LCMS: m / z (254 nm): 521.0 [M+H] + .

[0256] Step 4: 4-amino-N,N-bis[(2,4-dimethoxyphenyl)methyl]pyridine-2-sulfonamide (28e)

[0257] To a reaction flask were added 28d (800 mg), N-methylpyrrolidone (7 mL), ammonium acetate (1.06 g), copper acetylacetonate (107 mg), Ligand (115 mg), and cesium carbonate (1.34 g). The atmosphere was purged with nitrogen three times and stirred at 95°C for 16 hours. The reaction mixture was cooled to room temperature, water (20 mL) was added, and extraction was performed with ethyl acetate (20 mL x 3). The organic phases were combined, concentrated, and separated by column chromatography (EA / PE, 50% to 100%) to obtain 460 mg of a yellow oil in a 70.8% yield. LCMS: m / z (254 nm): 410.2 [M+H] + .

[0258] Step 5: rac-(2R,3R,4S,5R)-N-[2-({bis[(2,4-dimethoxyphenyl)methyl]amino}dioxy-λ 6 -thio)pyridin-4-yl]-3-{3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl}-3a-methyl-5a-(trifluoromethyl)hexahydrocyclobutane[1,2-b]furan-2-carboxamide (28f)

[0259] A method similar to Example 1 was used to obtain 28f. LCMS: MS m / z (254 nm): 825.3 [M+H] + .

[0260] Step 6: rac-(2R,3R,4S,5R)-N-[2-(aminodioxy-λ 6 -thio)pyridin-4-yl]-3-{3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl}-3a-methyl-5a-(trifluoromethyl)hexahydrocyclobutane[2,1-b]furan-2-carboxamide (Example 28)

[0261] 28f (50 mg), DCM (2 mL), and trifluoroacetic acid (146 mg) were added to the reaction flask and stirred at room temperature for 12 hours. LCMS analysis showed that the starting material was nearly completely converted. The reaction solution was concentrated and separated by silica gel chromatography (EA / PE, 40%) to afford 23 mg of a white solid in a 74% yield. LC-MS: m / z (254 nm): 525.1 [M+H] + .

[0262] Example 29:

[0263] Step 1: Compound ((4-bromopyridin-2-yl)sulfonyl)(methyl)carbamic acid tert-butyl ester (29a)

[0264] 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 iodomethane (50 mg, 0.35 mmol, 1.2 eq) were added. The reaction mixture was reacted at 60°C for 2 hours. LCMS monitoring confirmed the completion of the reaction. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The mixture was then washed 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 afford 29a (100 mg, 96% yield) as a white solid. LCMS: [M+Na] + =373.0.

[0265] Step 2: rac-(3aR,3S,5aR)-3-{3,4-difluoro-2-[(trideuteromethyl)oxy]phenyl}-3a-methyl-5a-(trifluoromethyl)hexahydrocyclobutane[1,2-b]furan-2-carboxamide (29b)

[0266] According to the synthesis method of intermediate 1c, intermediate 29b was prepared. LCMS: [M+H] + =369.1.

[0267] Step 3: rac-(2R,3R,4S,5R)-{[(4-{[(3-{3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl}-3a-methyl-5a-(trifluoromethyl)hexahydrocyclobutane[2,1-b]furan-2-yl)carbonyl]amino}pyridin-2-yl)dioxy-λ 6 -thio](methyl)amino}methanoic acid-2-methylprop-2-yl ester (29c)

[0268] 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 acetate (2 mg, 0.013 mmol, 0.1 eq) were added. The reaction mixture was reacted at 105°C under nitrogen for 16 hours. LCMS monitored the reaction completion of the starting material. The reaction mixture was concentrated, and the residue was purified on a silica gel column (dichloromethane / methanol = 10 / 1) to obtain compound 29c (70 mg, 80% yield) as a yellow oil. LCMS: [M+H] + =639.2.

[0269] Step 4: rac-(2R,3R,4S,5R)-3-{3,4-difluoro-2-[(trideuteromethyl)oxy]phenyl}-3a-methyl-N-{2-[(methylamino)dioxy]phenyl-λ 6 -thio]pyridin-4-yl}-5a-(trifluoromethyl)hexahydrocyclobutane[2,1-b]furan-2-carboxamide (Example 29)

[0270] Compound 29c (70 mg, 0.11 mmol, 1.0 eq) was dissolved in hydrochloric acid / dioxane (4 M, 10 mL). The reaction mixture was incubated at 25°C for 4 hours. LCMS confirmed the complete reaction. The reaction mixture was concentrated, and the residue was purified by preparative separation (0.01% FA) to afford Example 29 (4.2 mg, 7.1% yield). LCMS: [M+H] + =539.1.

[0271] Example 30:

[0272] Step 1: 1-(4-bromopyridin-2-yl)-2-fluoroethane-1-one (30b)

[0273] In a reaction flask, compound 1-(4-bromopyridin-2-yl)ethane-1-one 30a (300 mg, 1.50 mmol, 1.00 eq) was dissolved in toluene (3 mL), and tert-butyldimethylsilyl trifluoromethanesulfonate (595 mg, 2.25 mmol, 1.50 eq) and triethylamine (326 mg, 3.22 mmol, 2.15 eq) were added. The reaction solution was stirred at 80 ° C for 2 hours. The reaction solution was concentrated, and acetonitrile (3 mL) and a selective fluorine reagent (537 mg, 1.51 mmol, 1.01 eq) were added. The reaction solution was stirred at 25 ° C for 1 hour. LCMS monitoring showed that the reaction of the raw materials was complete, the reaction solution was concentrated, and the residue was purified by 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.

[0274] Step 2: 1-(4-bromopyridin-2-yl)-2-fluoroethane-1-ol (30c)

[0275] 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 solution was stirred at 25°C for 16 hours. LCMS monitored the complete reaction of the starting material. The reaction solution was concentrated and the residue was purified on a silica gel column (petroleum ether / ethyl acetate = 3 / 1) to afford compound 30c (145 mg, 81% yield) as a yellow oil. LCMS: [M+H] + =220.0.

[0276] Step 3: 4-Bromo-2-(1-((tert-butyldimethylsilyl)oxy)-2-fluoroethyl)pyridine (30d)

[0277] 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-butyldimethylsilyl chloride (151 mg, 1.00 mmol, 1.7 eq) were added. The reaction solution was stirred at 25°C for 16 hours. LCMS monitoring showed that the reaction of the raw materials was complete. The reaction solution was diluted with water (15 mL) and 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 = 20 / 1) to obtain compound 30d (173 mg, 87% yield) as a colorless oil. LCMS: [M+H] + =334.0.

[0278] 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-silanhex-2-yl)pyridin-4-yl]-3a-methyl-5a-(trifluoromethyl)hexahydrocyclobutane[2,1-b]furan-2-carboxamide (30e)

[0279] 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), 25 g (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 under a nitrogen atmosphere for 16 hours. LCMS monitoring confirmed the completion of the reaction. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (10 mL x 3). The mixture was then washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified on a silica gel column (petroleum ether / ethyl acetate = 2 / 1) to afford compound 30e (193 mg, 98% yield) as a colorless oil. LCMS: [M+H] + =622.3.

[0280] 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)hexahydrocyclobutane[2,1-b]furan-2-carboxamide (Example 30)

[0281] 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 allowed to react at 25°C for 3 hours. LCMS monitoring confirmed the completion of the reaction. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) and preparative separation (0.1% FA) to obtain compound Example 30 (68.5 mg, 41.3% yield). LCMS: [M+H] + =508.2.

[0282] Example 31:

[0283] Step 1: (S)-tert-Butyl (4-bromopyridin-2-yl)methyl (tetrahydrofuran-3-yl)carbamate (31c)

[0284] In a single-necked flask, compound 4-bromopicolinaldehyde 31a (100 mg, 0.54 mmol, 1.0 eq) was dissolved in 1,2-dichloroethane (5 mL). (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) were added. The reaction mixture was stirred at 25°C for 3 hours. Di-tert-butyl dicarbonate (176 mg, 0.81 mmol, 1.5 eq) was then added to the reaction mixture. The reaction mixture was stirred at 25°C for 0.5 hours. LCMS monitored the reaction completion of the starting material reaction. The reaction mixture was concentrated, and the residue was purified on a silica gel column (petroleum ether / ethyl acetate = 4 / 1) to afford compound 31c (170 mg, 88% yield) as a yellow oil.

[0285] Step 2: rac-(4-(2R,3R,4S,5R)-{[(4-{[(3-{3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl}-3a-methyl-5a-(trifluoromethyl)hexahydrocyclobutane[2,1-b]furan-2-yl)carbonyl]amino}pyridin-2-yl)methyl][(3S)-tetrahydrofuran-3-yl]amino}methanoic acid-2-methylpropan-2-yl ester (31d)

[0286] In a single-necked flask, compound 31c (65 mg, 0.18 mmol, 1.0 eq) was dissolved in anhydrous 1,4-dioxane (5 mL). 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) were added. The reaction mixture was incubated at 105°C under a nitrogen atmosphere for 16 hours. LCMS monitoring confirmed the completion of the reaction. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (10 mL x 3). The mixture was then washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified on a silica gel column (petroleum ether / ethyl acetate = 20 / 1) to afford compound 31d (30 mg, 29% yield) as a yellow oil. LCMS: [M+H] + =645.2.

[0287] Step 3: rac-(2R,3R,4S,5R)-3-{3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl}-N-[2-({[(3S)-tetrahydrofuran-3-yl]amino}methyl)pyridin-4-yl]-3a-methyl-5a-(trifluoromethyl)hexahydrocyclobutane[2,1-b]furan-2-carboxamide (Example 31)

[0288] 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 allowed to react at 25°C for 3 hours. LCMS confirmed the complete reaction of the starting material. The reaction mixture was concentrated and the residue was purified by preparative separation (0.1% FA) to afford Example 31 (5 mg, 18% yield). LCMS: [M+H] + =545.2.

[0289] Example 32: rac-(2R,3R,4S,5R)-3-{3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl}-3a-methyl-5a-(trifluoromethyl)-N-[2-(5-aza-2-oxahex-6-yl)pyridin-4-yl]hexahydrocyclobutane[2,1-b]furan-2-carboxamide

[0290] Example 32 was prepared in a similar manner to Example 31. LCMS: [M+H] + =533.2.

[0291] Example 36:

[0292] Step 1: 2-Bromo-1-(5-bromopyridin-2-yl)ethan-1-one (36b)

[0293] 1-(5-Bromopyridin-2-yl)ethanone 36a (2.0 g, 0.01 mmol, 1.0 eq) was dissolved in methanol (10 mL) and acetic acid (15 mL) and cooled to 0°C. A 30% solution of hydrogen bromide in acetic acid (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 allowed to reach room temperature and then heated to 70°C and stirred for 1 hour. LCMS analysis indicated that the reaction was complete. The mixture was concentrated under reduced pressure and the residue was crystallized from isopropanol to give 36b (1.0 g, 32% yield) as a yellow solid. LCMS: [M+H] + =278.9.

[0294] Step 2: 1-(5-Bromopyridin-2-yl)ethane-1,2-diol (36c)

[0295] 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 for 3 hours. After the reaction was complete, 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 x 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. The mixture was extracted three times with dichloromethane (50 mL) and saturated aqueous sodium bicarbonate solution (10 mL). The combined organic phases were dried over sodium sulfate. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 36c (350 mg, 42% yield) as a yellow solid. LCMS: [M+H] + =218.0.

[0296] Step 3: 5-Bromo-2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine (36d)

[0297] 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 at 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.

[0298] Step 4: rac-(1R,3R,4S,5R)-3-{3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl}-N-[6-(2,2-dimethyl-1,3-dioxolane-4-yl)pyridin-3-yl]-3a-methyl-5a-(trifluoromethyl)hexahydrocyclobutane[2,1-b]furan-2-carboxamide (36e)

[0299] 25g (50mg, 0.14mmol, 1.0eq) was dissolved in 1,4-dioxane (5mL), and 5-bromo-2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine (53mg, 0.21mmol, 1.5eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (16mg, 0.027mmol, 0.2eq), cesium carbonate (134mg, 0.41mmol, 3.0eq) and palladium acetate (3.1mg, 0.014mmol, 0.1eq) were added. The mixture was stirred at 105°C for 16 hours. After the reaction was completed, the mixture was quenched with water (50mL) and then extracted with ethyl acetate (50mL×3). The combined organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Purification by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1) gave 36e (50 mg, 67% yield) as a yellow oil. LCMS: [M+H] + =546.2.

[0300] 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)hexahydrocyclobutane[2,1-b]furan-2-carboxamide (Example 36)

[0301] 36e (50 mg, 0.0184 mmol, 1.0 eq) was dissolved in hydrochloric acid / 1,4-dioxane (5 mL) and stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure. Compound Example 36 (4.2 mg, 9% yield) was obtained by preparative (0.1% NH3). LCMS: [M+H] + =506.2.

[0302] Example 40: rac-(2R,3R,4S,5R)-N-[6-(aminodioxy-λ 6 -thio)pyridin-3-yl]-3-{3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl}-3a-methyl-5a-(trifluoromethyl)hexahydrocyclobuta[2,1-b]furan-2-carboxamide

[0303] Example 40 was prepared in a manner similar to Example 28. LCMS: [M+H]+=524.2.

[0304] Example 41:

[0305] Step 1: tert-Butyl 4-(5-bromopyridin-2-yl)-3-oxopiperidine-1-carboxylate (41b)

[0306] tert-Butyl 3-oxo-1-piperazinecarboxylate (1.37 g, 6.82 mmol, 1.2 eq) was dissolved in DMF (15 mL), cooled to 0°C, and sodium hydride (341 mg, 8.52 mmol, 1.5 eq) was added. The mixture was stirred for 30 minutes. 2-Fluoro-5-bromopyridine 100a (1.0 g, 5.68 mmol, 1.0 eq) was added, and the temperature was raised to 60°C and stirred for 16 hours. Water was added and the mixture was extracted with ethyl acetate (50 mL*3). The organic phases were combined, washed with brine, dried over sodium sulfate, filtered, and dried by spin drying. The mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to afford 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.

[0307] Step 2: rac-tert-butyl 4-(4-((1R,3R,4S,5R)-4-(3,4-difluoro-2-trideuteromethoxyphenyl)-5-methyl-1-(trifluoromethyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamido)pyridin-2-yl)-3-oxopiperazine-1-carboxylate (41c)

[0308] Compound 25g (50 mg, 0.14 mmol, 1.0 eq) was dissolved in dioxane (5 mL) and added with 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 was incubated at 105°C under a nitrogen atmosphere for 16 hours. LCMS monitored the complete reaction of the starting material. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to afford compound 41c (50 mg, 57% yield) as a colorless oil. LCMS: [M+H] + =644.3.

[0309] Step 3: rac-(1R,3R,4S,5R)-4-(3,4-difluoro-2-trideuteromethoxyphenyl)-5-methyl-N-(2-(2-oxopiperazin-1-yl)pyridin-4-yl)-1-(trifluoromethyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamide (41d)

[0310] Compound 41c (50 mg, 0.078 mmol, 1.0 eq) was dissolved in trifluoroacetic acid (5 mL) and the reaction mixture was allowed to react at 25°C for 2 hours. LCMS monitored the completion of the reaction. The reaction mixture was concentrated to afford compound 41d (40 mg, 95% yield) as a white solid. LCMS: [M+H] + =544.3.

[0311] 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)

[0312] 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 allowed to react at 25°C for 30 minutes. Sodium cyanoborohydride (8 mg, 0.14 mmol, 2.0 eq) was added, and the reaction mixture was allowed to react at 40°C for 1 hour. LCMS monitored the completion of the reaction. 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.

[0313] Example 45:

[0314] Step 1: 5-Nitro-1,3-dioxoisoindolin-2-yl acetate (45b)

[0315] In a single-necked flask, compound 2-hydroxy-5-nitroisoindoline-1,3-dione 45a (300 mg, 1.44 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL) and 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 hours. LCMS monitored the reaction completion 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 compound 45b (300 mg, 83% yield) as a white solid. LCMS: [M+H] + =251.0.

[0316] Step 2: 5-amino-1,3-dioxoisoindolin-2-yl acetate (45c)

[0317] In a single-necked flask, compound 45b (300 mg, 1.20 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (5 mL), and tetrahydroxydiboron (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 incubated at 0°C for 20 minutes. LCMS indicated that most of the starting materials had reacted. Ethyl acetate (20 mL) and water (20 mL) were then added to the reaction mixture. The organic layer was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford compound 45c (80 mg, 30% yield) as a yellow oil. LCMS: [M+H] + =221.0.

[0318] Step 3: rac-(2R,3S,4S,5R)-N-(2-acetoxy-1,3-dioxyidene-2,3-dihydro-1H-isoindol-5-yl)-3-{3,4-difluoro-2-[(trideuteriomethyl)oxy]phenyl}-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (45d)

[0319] 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 reaction of the raw materials was complete. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3), then washed with saturated brine, filtered, and the filtrate was concentrated. 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.

[0320] Step: (2R,3S,4S,5R)-3-{3,4-difluoro-2-[(trideuterium methyl)oxy]phenyl}-N-(2-hydroxy-1,3-dioxyidene-2,3-dihydro-1H-isoindol-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Example 45)

[0321] 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 allowed to react at 25°C for 10 minutes. LCMS confirmed the complete reaction of the starting material. The reaction mixture was concentrated, and the residue was purified by preparative separation (0.1% FA) to afford Example 45 (28.2 mg, 29% yield). LCMS: [MH]- = 516.1.

[0322] Reference compound 1:

[0323] Intermediate 1a was used to replace 1d in Example 1 to prepare reference compound 1, ESI-MS m / z calc. 515.1, found 516.1 (M+1) + . 1 H NMR (400MHz, DMSO-d6) δ10.42 (s, 1H), 7.767.60 (m, 4H), 7.49 (d, J = 8.2Hz, 1H), 7.30 (d, J = 20.8Hz, 2H), 7.227.09 (m, 2H), 5.07 (d , J=10.4Hz, 1H), 4.24 (dd, J=10.3, 7.6Hz, 1H), 3.95 (d, J=2.1Hz, 2H), 2.76 (t, J=7.5Hz, 1H), 1.60 (s, 3H), 0.73 (d, J=7.4Hz, 3H).

[0324] Biological activity test: In vitro inhibition of Nav 1.8 by the compound: IC of the inhibitory effect of the compound on Nav 1.8 in vitro 50 .

[0325] Experimental testing was performed using a CHO cell line stably expressing the Nav1.8 sodium channel. Gene information: Sodium channel, voltage-gated, type 8, alpha (SCN10A), cDNA strictly similar to GenBank accession number: NM_006514.

[0326] Before patch clamp testing, cells were detached with 0.25% Trypsin-EDTA and 6.5 × 10 3 The cells were plated on coverslips and cultured in 24-well plates (final volume: 500 μL). After 18 hours, the assay was performed.

[0327] Electrophysiological recording solutions: Extracellular solution: 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 by NaOH. Intracellular solution: Nav-001-2, 50 mM CsCl, 10 mM NaCl, 10 mM HEPES, 60 mM CsF, 20 mM EGTA, pH adjusted to 7.2 by CsOH. The extracellular solution has a shelf life of 2 weeks. After preparation, the intracellular solution is aliquoted into 1 mL tubes and stored frozen at -20°C. Freshly thawed intracellular solution is used daily for each experiment. All intracellular solution should be used within 3 months. After 3 months, discard the old intracellular solution and prepare a fresh one.

[0328] Patch clamp detection: The voltage stimulation protocol for whole-cell patch clamp recording of Nav1.8 sodium current is as follows: After the whole-cell seal is formed, the cell voltage is clamped at -120mV for 30ms. The clamping voltage is depolarized to 0mV and maintained for 50ms, and then the voltage is restored to -50mV (the specific voltage refers to the half-inactivation voltage of the IV test) and maintained for 5s. Then the cell membrane potential is restored to -120mV, maintained for 20ms, and then depolarized to 0mV again, maintained for 50ms, and finally restored to the clamping voltage of -120mV, maintained for 30ms. Data is collected repeatedly every 20ms. The effect of the drug on the peak of the sodium current is observed. The experimental data are collected by an EPC 10 amplifier (HEKA) and stored in the PatchMaster (HEKA) software.

[0329] Recording electrodes are drawn from capillary glass tubes using a microelectrode puller. The electrodes, filled with intracellular fluid, are placed in an electrode holder. Under an inverted microscope, the microelectrode manipulator is used to immerse the electrodes in extracellular fluid and record the electrode resistance (Rpip). The electrodes are placed in contact with the cell surface and negative pressure is applied to create a high-resistance seal (GΩ). Fast capacitance compensation is then performed, and negative pressure is continued to rupture the cell membrane, establishing whole-cell recording mode. Slow capacitance compensation is then performed, and experimental parameters such as membrane capacitance (Cm) and series resistance (Rs) are recorded. No leakage compensation is performed.

[0330] When the Nav1.8 current recorded in the whole cell is stable, the drug is administered. After each drug concentration is applied for 5 minutes (or the current is stable), the next concentration is detected. Multiple concentrations are detected for each test compound. The coverslip with cells is placed in a recording bath under an inverted microscope. The blank control external solution and the working solution of the test compound are passed through the recording bath from low concentration to high concentration by gravity perfusion to act on the cells. A peristaltic pump is used for liquid exchange during recording. The current detected for each cell in the external solution without the compound serves as its own control group. At least three cells are used for each concentration and the test is repeated three times independently. All electrophysiological experiments were performed at room temperature.

[0331] Data analysis: First, normalize the current after each drug concentration and the blank control current Then calculate the inhibition rate corresponding to each drug concentration The mean (Mean), standard deviation (SD) and standard error (SE) of the inhibition rate at each concentration were calculated. Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope))

[0332] The IC of each compound was calculated using the above equation 50 values, and a nonlinear fitting was performed for the dose-dependent effect, where IC 50 IC is the half inhibitory concentration. 50 Calculations and curve fitting were performed using GraphPad Prism software.

[0333] Table 2. Inhibitory activity of the compounds of the present invention against Nav 1.8

[0334] The same method was used to test the inhibitory effects of other compounds of the present invention on Nav 1.8, which showed that the compounds of the present invention had a good inhibitory effect on Nav 1.8.

[0335] Liver microsome stability test of the compound of the present invention:

[0336] Step 1: Preparation of working solutions of test compounds and control compounds: 5 μL of stock solution (10 mM in DMSO) 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.

[0337] Step 2: Prepare NADPH coenzyme working solution: β-nicotinamide adenine dinucleotide phosphate (reduced form), tetrasodium salt (supplier: BONTAC, product number: BT04). Weigh an appropriate amount of NADPH powder and dilute it to a 10 mM MgCl2 solution.

[0338] Step 3: Preparation of liver microsomes: Use 100 mM potassium phosphate buffer to prepare liver microsomes into a 0.56 mg / mL working solution.

[0339] Step 4: Preparation of stop solution: cold (4°C) acetonitrile to which 250 nM toluene butanamide and 250 nM labetalol as internal standards were added was used as the stop solution.

[0340] Step 5: Experimental operation:

[0341] a. Add 445 μL of liver microsome working solution (0.56 mg / mL) to the preheated T60 and NCF60 plates and stir thoroughly. Add 54 μL of liver microsome working solution and 6 μL of NADPH coenzyme working solution to the blank plate T0, and add 180 μL of stop solution for later use.

[0342] b. Add 5 μL of the working solution of the test compound to the T60 and NCF60 plates containing the liver microsome working solution.

[0343] c. Add 50 μL of phosphate buffer to the NCF60 plate.

[0344] d. Take out 54 μL from the T60 plate and transfer it to the T0 plate as the sample at the 0 minute time point, and add 44 μL of NADPH coenzyme working solution.

[0345] Table 3. Concentration of each component in the final state of the reaction system

[0346] e. At the 5-minute, 15-minute, 30-minute, 45-minute, and 60-minute time points, 60 μL of sample was transferred from the T60 plate to the stop plate.

[0347] f. At the 60 minute time point, transfer 60 μL of sample from the NCF60 plate to the stop plate.

[0348] g. All sample plates were thoroughly mixed for 10 min and centrifuged at 4°C, 4000 rpm for 20 min. 80 μL of supernatant was taken and diluted with 240 μL of high-purity water before analysis by LC-MS / MS.

[0349] Step 6. Data analysis: Calculate T1 / 2 and CLint(mic) (μL / min / mg) using the first-order kinetic equation.

[0350] The results of the metabolic stability experiments on monkey, rat and human liver microsomes are shown in Table 4. As can be seen from the table, Example 1 of the present invention has better metabolic stability than Reference Compound 1, and may have better pharmacokinetics, safety and efficacy.

[0351] Table 4. Metabolic stability test results of hepatic microsomes in monkeys, rats and humans

[0352] Pharmacokinetics of the compounds of the present invention in rats:

[0353] Test substance solvent: DMSO: Solutol HS15: Tween 80: Saline = 5:10:0.2:84.8 (v / v / v / v). Preparation method: Weigh appropriate amounts of compound and add DMSO, Solutol HS15, Tween 80, and saline in sequence to obtain a final concentration of 0.5 mg / mL for oral administration to animals.

[0354] Male SD rats (sourced from Weitong Lihua Laboratory Animal Technology Co., Ltd.) were fasted for at least 12 hours (with free access to water) and then gavage administered with a dose of 10 mL / kg. Approximately 0.2 mL of blood was collected from the jugular sinus before dosing, i.e., 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 a pre-chilled EDTA-K2 anticoagulant tube and centrifuged at 4°C (1500-1600 g) for 10 min. Plasma was separated and stored at -90 to -60°C for analysis.

[0355] The pharmacokinetic parameters of rats are shown in Table 5. Compared with the control compound 1, the compound of the present invention has a higher peak blood concentration and a higher plasma exposure, indicating that the compound provided by the present invention has better pharmacokinetic properties and has a better application prospect in the treatment of pain.

[0356] Table 5. Pharmacokinetic parameters in rats

Claims

1. Compounds of Formula I or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R a1 、R a3 Each is 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 Connected to form a 5-7 membered ring, the 5-7 membered ring can be a saturated or unsaturated carbocyclic ring 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; R b1 、R b2 、R b3 、R b4 Each is independently selected from hydrogen, halogen, hydroxy, C1-C5 alkyl, C1-C5 alkoxy; or R b1 、R b2 、R b3 、R b4 Any two are connected to form a 3-7 membered ring; M1, M2 are independently selected from C, O, S(=O) m NR n , where R n Optionally selected from hydrogen, C1-C5 alkyl; Ring A is A1 or A2: Any single or double bond X1, X2, X3, X4, 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 may be selected from C atoms or N atoms; R c1 、R c2 Each is 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 alkyl NR c3 R c4 、-S(=O)(=NR c3 )R c4 ; R c3 、R c4 Each is independently selected from hydrogen, hydroxy, amino, C1-C5 alkyl, C1-C5 alkoxy, 3-7 membered ring, or R c3 、R c4 Connect to form a 3-7 membered ring; m and n are 0, 1 or 2; The alkyl, alkoxy, cycloalkyl, cycloalkoxy, 5-7 membered ring, 3-7 membered ring can be optionally substituted with one or more deuterium, halogen, hydroxyl, cyano, oxo, C1-C5 alkyl, C1-C5 alkoxy, and amino groups.

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

3. The compound of formula I according to claim 1, R a2 Arbitrarily selected from 1, 2 or 3 deuterium or fluorine substituted methyl groups.

4. The compound of formula I according to claim 1, any two adjacent R a1 、R a3 Connected 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 Each is independently selected from hydrogen, methyl, trifluoromethyl, ethyl, methoxy, and ethoxy.

6. The compound of formula I according to claim 1, R b1 、R b2 、R b3 、R b4 Any two of them can be connected to form a 3-membered ring, a 4-membered ring, or a 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 the formula I has a structure as shown in formula IA or formula IB:

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

10. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt, 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 preparation of a medicament for treating, preventing or alleviating voltage-gated sodium channel-related diseases.

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