Sodium channel modulators and their applications

Abstract

The present invention provides a sodium channel modulator and its application, and the sodium channel modulator of the present invention has a novel structure and has excellent in vitro inhibitory activity against Nav1.8. The compound of the present invention or a pharmaceutically acceptable salt thereof can be used to treat sodium channel-related diseases, including pain, multiple sclerosis, peroneal muscular atrophy, incontinence, pathological cough, or arrhythmia.

Description

[Technical Field]

[0001] This application claims priority from Chinese Patent Application No. 202211036306.3 filed on August 28, 2022, Chinese Patent Application No. 202211374105.4 filed on November 3, 2022, and Chinese Patent Application No. 202310334077.1 filed on March 31, 2023. This application cites the above Chinese patent applications in their entirety.

[0002] The present invention relates to the pharmaceutical field, specifically to sodium channel modulators, their preparation methods and therapeutic uses in the treatment of diseases. [Background technology]

[0003] Pain is a complex, unpleasant sensation typically caused by physical injury, illness, or adverse external stimuli. For clinical research, the International Association for the Study of Pain (IASP) defines pain as "an unpleasant sensory and emotional experience experienced when actual or threatened tissue damage occurs or occurs during such damage." Pain can act as a warning signal, alerting the body to potential danger and playing a protective role essential for normal life activities. Pain is also a common clinical symptom. Even after the external stimuli that cause pain have disappeared, if pain persists for a long time or is severe, it can disrupt physiological functions and seriously affect the body's quality of life. According to data, approximately one-fifth of people worldwide suffer from moderate to severe chronic pain.

[0004] Pain originates from nociceptors in the peripheral nervous system. Nociceptors are free nerve endings widely distributed throughout the body in the skin, muscles, joints, and visceral tissues. They convert perceived thermal, mechanical, or chemical stimuli into nerve impulses (action potentials), which are transmitted via afferent nerve fibers to cell bodies in the dorsal root ganglia (DRG) and ultimately to higher nervous centers, causing pain. Furthermore, the generation and conduction of action potentials in neurons depend on voltage-gated sodium channels (VGSCs) on the cell membrane. When the cell membrane is depolarized, sodium ion channels are activated, opening the channels and allowing sodium ions to inflow, further depolarizing the cell membrane and generating an action potential. Therefore, inhibiting abnormal sodium ion channel activity contributes to the treatment and relief of pain.

[0005] Voltage-gated sodium channels are widely present in the plasma membranes of excitable cells such as neurons and skeletal muscle cells. They are transmembrane glycoprotein complexes composed of an α subunit and multiple β subunits. The α subunit is the functional carrier of the sodium ion channel and consists of 1700-2000 amino acids. The β subunit mainly plays an auxiliary role and can modify the kinetics and voltage dependence of the ion channel. Sodium ion channels can be classified according to their different α subunits. Currently, in mammals, there are only 10 types of sodium ion channels: v 1(Na v 1.1~Na v Nine sodium ion channels (1.9) have been identified. Different subtypes exhibit different tissue distribution, electrophysiological characteristics, and pharmacological properties. Depending on whether they can be effectively inhibited by nanomolar concentrations of tetrodotoxin (TTX), sodium ion channels are divided into TTX-sensitive (TTX-S) and TTX-resistant (TTX-R) types. Among them, Na v 1.1, Na v 1.2, Na v 1.3 and Na v1.7 is a TTX-S type, the coding gene of which is located on human chromosome 2q23-24 and is abundantly expressed in neurons. v 1.5, Na v 1.8 and Na v 1.9 is a TTX-R type, and the coding gene is located on human chromosome 3p21-24. v 1.5 is mainly present in cardiac myocytes, and Na v 1.8, Na v 1.9 is present in the peripheral nervous system (PNS).

[0006] Na v 1.8 is an important ion channel involved in chronic pain, atrial fibrillation, and Busia syndrome, and is a highly selective target for treating pain. As a carrier of sodium currents, it has been shown to sustain the firing of action potentials in neurons in the small dorsal root ganglion, as well as to be involved in the spontaneous firing of electrical signals in injured neurons, for example, to promote 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, etc. PF-01247324, A-803467, and PF-06305591 have drawbacks such as low selectivity, poor pharmacokinetic data, and low bioavailability. Summary of the Invention

[0007] A first aspect of the present invention is a compound of formula I [ka] or a pharmaceutically acceptable salt thereof, and if chiral centers are present, the compound further includes its stereoisomers, racemates.

[0008] In some embodiments of the invention, the compound is further as shown in formula IA or IB. [ka]

[0009] In the above compound, R a1 , R a2 , R a3 are each independently hydrogen, halogen, hydroxyl, C1-C5 alkyl, C1-C5 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, -N(R c3 R c4 ) m wherein said alkyl, alkoxy, cycloalkyl, cycloalkoxy is optionally substituted by one or more of halogen, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, amino.

[0010] In some embodiments of the present invention, any two adjacent R a1 , R a2 , R a3 are linked to form a 5- to 7-membered ring, which may be a saturated or unsaturated carbocyclic or heterocyclic ring, and the heterocyclic ring may optionally contain one or more N, O, S(=O) m The 5- to 7-membered ring may contain a heteroatom and may be optionally substituted with one or more of halogen, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, and amino.

[0011] In some specific embodiments of the present invention, R a1 , R a2 , R a3 are each independently selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, difluoromethoxy, and amino.

[0012] In some specific embodiments, any two adjacent R a1 , R a2 , R a3 are linked to form a 5- or 6-membered carbocyclic or heterocyclic ring.

[0013] In some specific embodiments, the 5- or 6-membered heterocycle is one or two N, O, S(=O) m Contains heteroatoms.

[0014] In some specific embodiments, the 5- or 6-membered carbocyclic or heterocyclic ring is optionally substituted with one or more halogen, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, amino.

[0015] In the above compound, R b1 , R b2 , R b3 , R b4 are each independently selected from hydrogen, halogen, hydroxyl, C1-C5 alkyl, and C1-C5 alkoxy, wherein the alkyl and alkoxy are optionally substituted with one or more of halogen, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, and amino.

[0016] In a specific embodiment of the present invention, R b1 , R b2 , R b3 , R b4 are each independently selected from hydrogen, methyl, trifluoromethyl, ethyl, methoxy, and ethoxy.

[0017] In some specific embodiments, R b1 , R b2 are each independently selected from hydrogen, methyl, and trifluoromethyl.

[0018] In some specific embodiments, R b3 , R b4 are each independently selected from hydrogen, methyl, and trifluoromethyl.

[0019] In some specific embodiments, R b1 , R b2 , R b3 , R b4Any two of these may be linked to form a 3- to 7-membered ring, and the 3- to 7-membered ring may be a saturated or unsaturated carbocyclic or heterocyclic ring, and the heterocyclic ring may optionally contain one or more N, O, S(=O) m The 3- to 7-membered ring containing a heteroatom may be optionally further substituted with one or more halogen, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, or amino.

[0020] In some specific embodiments, R b1 , R b2 are linked to form a 3- to 7-membered saturated carbocyclic ring, which may be optionally substituted with one or more halogen, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, or amino.

[0021] In some specific embodiments, R b1 , R b2 are linked to form a three-membered saturated carbocyclic ring, which may be optionally substituted with one or more halogen, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, amino.

[0022] In some specific embodiments, R b3 , R b4 are linked to form a 3- to 7-membered saturated carbocyclic ring, which may be optionally substituted with one or more halogen, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, or amino.

[0023] In some specific embodiments, R b1 , R b2 and R b3 , R b4 Any two of these may be linked to form a 3- to 7-membered ring, and the 3- to 7-membered ring may be optionally substituted with one or more of halogen, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, and amino.

[0024] In some specific embodiments, R b1 , Rb2 and R b3 , R b4 Any two of these may be linked to form a 3- to 7-membered saturated carbocyclic ring, which may be optionally substituted with one or more of halogen, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, and amino.

[0025] In some specific embodiments, R b1 , R b2 and R b3 , R b4 Any two of these may be linked to form a 3- to 6-membered saturated carbocyclic ring, which may be optionally substituted with one or more of halogen, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, and amino.

[0026] In the present invention, R b1 , R b2 and R b3 , R b4 The concatenation of any two of b1 and R b3 , R b1 and R b4 , R b2 and R b3 , R b2 and R b4 may be a concatenation of

[0027] M1 and M2 are independently C, O, or S(=O) m , N.R. n is selected from, where R n is optionally selected from hydrogen, C1-C5 alkyl, and in one specific embodiment, R n is optionally selected from hydrogen, methyl or ethyl.

[0028] In the above compounds of the present invention, ring A has a structure such as A1. [ka] [ka] represents a single or double bond as long as the principles of chemical bond formation are not violated.

[0029] X1, X2, X3, X4, and X5 each independently represent a bond, C, N, O, C=O, or S(=O). m is selected from.

[0030] Unless the principles of chemical bond formation are violated, when X1, X2, X3, X4, and X5 are selected from "bonds", this means that they are directly connected in the form of a bond. For example, when X2 is selected from a bond, X1 is directly connected to X3 via a bond, and in this case, ring A is a 5-membered ring.

[0031] In some specific 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.

[0032] In some specific embodiments of the present invention, X1, X2, X3, X4, X5 are all selected from C atoms.

[0033] In some specific embodiments of the present invention, X1, X2, X3, X4, X5 optionally contain one or two N atoms.

[0034] In some specific embodiments of the present invention, X1, X2, X3, X4, X5 optionally contain one C=O.

[0035] In some specific embodiments of the present invention, X1, X2, X3, X4, and X5 optionally include one S(=O)2.

[0036] In some specific embodiments of the present invention, X1, X2, X3, X4, and X5 are optionally selected from a bond, C, S, and O.

[0037] In some specific embodiments of the present invention, ring A has the following structure: [ka]

[0038] In the above compounds of the present invention, ring A has a structure such as A2. [ka] In the formula, as long as the principles of chemical bond formation are not violated, [ka] optionally represents a single bond or a double bond. X1, X2, X3, and X4 have the same definition as in Formula A1. When X1, X2, X3, and X4 are selected from "bonds," they represent being directly linked in the form of a bond. For example, when X3 is selected from a bond, X2 is directly linked to X4 via a bond to form a 5-membered ring, and Y1 and Y2 may be the same or different and may be arbitrarily selected from C atoms or N atoms.

[0039] In some specific embodiments of the present invention, X1, X2, X3, and X4 in formula A2 are each independently selected from a bond, C, N, and C=O.

[0040] In some specific embodiments of the present invention, X1, X2, X3, and X4 in formula A2 are each independently selected from a bond, C, N, and O.

[0041] In some specific embodiments of the present invention, X1, X2, X3, and X4 in formula A2 each independently represent a bond, C, N, S(=O) m is selected from.

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

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

[0044] R c1 , R c2 are each independently hydrogen, halogen, cyano, hydroxyl, amino, C1-C5 alkyl, C1-C5 alkoxy, -S(=O) m -R c3 R c4 , -C(=O)-NR c3 R c4 , -C(=S)-NR c3 R c4 , -N(R c3 R c4 ) m , -P(=O) m -R c3 R c4 , -C(=N)-NR c3 R c4 , -S(=O)2NR c3 R c4 , -CH2NR c3 R c4 , -S(=O)(=NR c3 )R c4 wherein the C1-C5 alkyl and C1-C5 alkoxy may be further substituted by one or more substituents optionally selected from halogen, hydroxyl, cyano, amino, C1-C5 alkyl and C1-C5 alkoxy.

[0045] R c1 , R c2 is substituted at any substitutable position on ring A, including substitution at X, X, X, X, Y, Y. In some specific embodiments of the present invention, R c1 , R c2 is substituted on a carbon atom, and in some specific embodiments of the invention, R c1 , R c2 is substituted on the heteroatom.

[0046] R c3 , R c4are each independently selected from hydrogen, hydroxyl, amino, C1-C5 alkyl, C1-C5 alkoxy, and a 3- to 7-membered ring, or R c3 , R c4 are linked to form a 3- to 7-membered ring, and the 3- to 7-membered ring may be a saturated or unsaturated carbocyclic or heterocyclic ring, and the heterocyclic ring may optionally contain one or more N, O, S(=O) m The 3- to 7-membered ring containing a heteroatom may be optionally further substituted with one or more halogen, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, or amino.

[0047] R c1 , R c2 is the substituent -S(=O) m -R c3 R c4 When m=2, R c3 or R c4 One of them does not exist.

[0048] In some specific embodiments of the present invention, the compounds of formula I described above are further shown as general formula II. [ka] In the formula, M1, ring A, R a1 , R a2 , R a3 , R b1 , R b2 , R b3 , R b4 , R c1 , R c2 is as defined above.

[0049] In some specific embodiments of the present invention, R c1 , R c2 are each independently hydrogen, hydroxyl, 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, [ka] is selected from.

[0050] In some specific embodiments of the present invention, R c1 , R c2 are each independently selected from hydrogen, fluorine, chlorine, amino, cyano, and —C(═O)NH 2 .

[0051] In the above compounds of the present invention, m and n are optionally 0, 1 or 2.

[0052] In a specific embodiment of the invention, a specific compound of the invention has the structure: [ka] JPEG2025529931000012.jpg233169 JPEG2025529931000013.jpg228169 JPEG2025529931000014.jpg227169 JPEG2025529931000015.jpg245169 JPEG2025529931000016.jpg242169 JPEG2025529931000017.jpg236169 JPEG2025529931000018.jpg237169

[0053] A second aspect of the present invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, in the preparation of a medicament for inhibiting a voltage-gated sodium channel, the voltage-gated sodium channel being Nav1.8.

[0054] A third aspect of the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, in the preparation of a medicament for treating, preventing or alleviating a voltage-gated sodium channel-associated disorder, including, but not limited to, pain, multiple sclerosis, peroneal muscular atrophy (Charcot-Marie-Tooth syndrome), incontinence, pathological cough, or cardiac arrhythmia.

[0055] The pain includes acute pain, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain, and visceral pain. Accordingly, the present invention further provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating, preventing, or alleviating pain.

[0056] A fourth aspect of the present invention provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt or stereoisomer thereof, and pharmaceutically acceptable additives, including fillers, disintegrants, surfactants, and solubilizers.

[0057] The pharmaceutical compositions of the compound of formula I or its pharmaceutically acceptable salts according to the present invention can be administered by various known methods, for example, orally, topically, rectally, parenterally, by inhalation or injection, etc. The pharmaceutical compositions can be prepared into dosage forms such as tablets, capsules, bagged granules, sugar-coated tablets, powders, granules, lozenges, powder injections, liquids or suppositories.

[0058] A fifth aspect of the present invention provides a use of a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt or stereoisomer thereof in the preparation of a medicament for treating, preventing or alleviating a voltage-gated sodium channel-associated disorder, including, but not limited to, pain, multiple sclerosis, peroneal muscular atrophy (Charcot-Marie-Tooth syndrome), incontinence, pathological cough, cardiac arrhythmia, etc.

[0059] The pain includes acute pain, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, and visceral pain. Thus, the present invention further provides a use of a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating, preventing, or alleviating pain. DETAILED DESCRIPTION OF THE INVENTION

[0060] Terminology "Halogen" or "halogen atom" includes fluorine, chlorine, bromine, and iodine. In the present invention, preferred halogens are fluorine and chlorine.

[0061] "C1-C5 alkyl" refers to a straight or branched chain alkyl group containing 1 to 5 carbon atoms, specifically, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, etc. Preferred C1-C5 alkyl is C1-C3 alkyl, including methyl, ethyl, propyl, and isopropyl.

[0062] "C1-C5 alkoxy" refers to a straight-chain or branched-chain alkoxy group containing 1 to 5 carbon atoms, specifically, for example, methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, etc. Preferred C1-C5 alkoxy is C1-C3 alkoxy, including methoxy, ethoxy, propoxy, and isopropoxy. "C3-C6 cycloalkyl" refers to a cycloalkyl group containing 3 to 6 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl may be further substituted with one or more substituents such as halogen, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, and amino.

[0063] "C3-C6 cycloalkoxy" refers to a cycloalkoxy group containing 3 to 6 carbon atoms, including cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy. The cycloalkoxy may be further substituted with one or more substituents such as halogen, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, and amino.

[0064] The term "3- to 7-membered ring" refers to a saturated or unsaturated ring containing 3 to 7 carbon atoms, such as a 3-, 4-, 5-, 6-, or 7-membered ring. In the present invention, the carbon atoms on the ring may be one or more of C(=O), N, O, S(=O) m to form a 3- to 7-membered heterocyclic ring, which may be optionally further substituted with one or more of halogen, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, amino, and m is 0, 1, or 2.

[0065] The term "5- to 7-membered ring" refers to a saturated or unsaturated ring containing 5 to 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 on the ring may be one or more N, O, S(=O) m to form a 5- to 7-membered heterocyclic ring, which may be optionally further substituted with one or more of halogen, hydroxyl, cyano, C1-C5 alkyl, C1-C5 alkoxy, amino, and m is 0, 1, or 2.

[0066] "Multiple" may be 2, 3, 4 or more. In the present invention, those substituted with multiple halogens may be, for example, trifluoromethyl or difluoromethyl.

[0067] The alkyl, alkoxy, cycloalkyl, cycloalkoxy, 5- to 7-membered ring, and 3- to 7-membered ring described in the present invention may be optionally substituted with one or more deuterium atoms, halogen atoms, hydroxyl, cyano, oxo, C1-C5 alkyl, C1-C5 alkoxy, and amino.

[0068] As used herein, in any chemical structure or formula, a bold or dashed linear bond connecting a stereoisomeric center of a compound [ka] for example, [ka] indicates the relative stereochemistry of a stereoisomeric center relative to another stereoisomeric center connected by a bold or dashed linear bond.

[0069] As used herein, in any chemical structure or formula, a bold or dashed wedge bond connecting a stereoisomeric center of a compound [ka] for example, [ka] indicates the absolute stereochemistry of a stereoisomeric center and the relative stereochemistry of the stereoisomeric center relative to other stereoisomeric centers connected by bold or dashed wedge bonds.

[0070] As used herein, when used in connection with a chiral compound, the prefix "rel-" refers to a single enantiomer of unknown absolute configuration. In compounds with the prefix "rel-", the (R)- and (S)- designators in the chemical name reflect the relative stereochemistry of the compound, but do not necessarily reflect the absolute stereochemistry of the compound.

[0071] "Pharmaceutically acceptable salts" include, but are not limited to, acid addition salts formed by compounds of formula I with inorganic acids, such as, for example, hydrochloride, hydrobromide, phosphate, sulfate, nitrate, etc., and acid addition salts formed by compounds of formula I with organic acids, such as, formate, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, paratoluenesulfonate, 2-hydroxyethanesulfonate, benzoate, etc.

[0072] The compounds of the present invention further include tautomers, such as, for example, tautomers of enol and ketone structures of the same compound.

[0073] The present invention further provides specific compounds prepared by the following methods. Unless otherwise specified, the compounds, reagents, etc. used in the examples of the present invention are all purchased from authorized suppliers or synthesized by referring to the methods disclosed in the prior art. For the synthesis of some intermediate compounds, for example, when intermediates 1a, 16a, etc. are prepared by referring to the methods of the prior art, the methods described in WO2021113627A1 can be referenced.

[0074] Example 1 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(3-oxoisoindolin-5-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide [ka] A reaction flask was charged with rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1a, 100 mg, 0.28 mmol), dichloromethane (25 mL), and one drop of N,N-dimethylformamide. Under nitrogen protection and an ice-water bath, oxalyl chloride (72 mg, 0.56 mmol) was added dropwise. After the addition was complete, the ice-water bath was removed, the mixture was allowed to warm to room temperature, stirred for 1 hour, and concentrated to remove the reaction solvent. The residue was dissolved in dichloromethane (25 mL), and a solution of 6-aminoisoindolin-1-one (1b, 50 mg, 0.34 mmol) in dichloromethane (10 mL) was added dropwise at -10 °C. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was quenched with water (25 mL) and separated into layers. The aqueous phase was extracted twice with DCM. The combined organic phase was washed once with water and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give the desired product (102 mg, 75% yield). ESI-MS m / z calc. 484.4, found 485.1 (M+1). + . 1 H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 8.54 (s, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.76 (dd, J = 8.2, 1.9 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.23 - 7.12 (m, 1H), 5.14 (d, J = 10.4 Hz, 1H), 4.30 (s, 2H), 4.26 (dd, J = 10.4, 7.6 Hz, 1H), 3.95 (d, J = 1.9 Hz, 3H), 2.76 (dt, J = 14.7, 7.4Hz, 1H), 1.61 (s, 3H), 0.73 (d, J = 6.3 Hz, 3H).

[0075] Example 2 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(2-oxoisoindolin-6-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide Example 2 was obtained in the same manner as in Example 1, except that 6-aminoisoindolin-2-one was used instead of 6-aminoisoindolin-1-one in Example 1. ESI-MS m / z calc. 484.4, found 485.1 (M+1) + . 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 10.32 (s, 1H), 7.30 (s, 1H), 7.20 - 7.14 (m, 2H), 7.11 - 7.05 (m, 2H), 5.08 (d, J = 10.4 Hz, 1H), 4.27 - 4.19 (m, 1H), 3.95 (d, J = 2.0 Hz, 3H), 3.39 (s, 2H), 2.78 - 2.70 (m, 1H), 1.58 (s, 3H), 0.72 (d, J = 6.1 Hz, 3H).

[0076] Example 3 [ka] Step 1 3-Bromo-6-nitrobenzofuran-1(3H)one (3b) A 100 mL reaction flask was charged with 3a (3.0 g) and CCl4 (30 mL). NBS (3.28 g) and AIBN (275 mg) were added sequentially with stirring. The temperature was raised to 78 °C and stirring was continued for 12 h. The reaction was monitored by TLC until complete conversion of the starting material. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated and separated by column chromatography (EA / PE, 0% to 30%) to give 3.3 g of a yellow solid in 77% yield. LCMS: m / z (254 nm): 257.9 [M+H] +

[0077] Step 2 7-Nitrophthalazin-1(2H)-one (3c) A reaction flask was charged with 3b (1.0 g) and 5% HCl (5 mL / mmol) and stirred at 80 °C for 3 h. The reaction was monitored by TLC until complete conversion of the starting material. The reaction mixture was cooled to room temperature, and N2H4·H2O (274 mg) was added. The mixture was stirred at room temperature for 3 h. The reaction was monitored by TLC until complete conversion of the starting material. The reaction mixture was filtered and washed with water. The solid residue was separated by column chromatography to give 237 mg of a white solid, a 32% yield. LCMS: m / z (254 nm): 192.0 [M+H] +

[0078] Step 3 7-Aminophthalazin-1(2H)-one (3d) A reaction flask was charged with 3c (200 mg), MeOH (10 mL), and THF (10 mL). After stirring evenly, palladium on carbon (20 mg) was added, and the mixture was purged with hydrogen three times. The mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC until the starting material was completely converted. The reaction mixture was filtered through diatomaceous earth with suction, and the filtrate was concentrated to give 120 mg of a white solid in a 71% yield. LCMS: m / z (254 nm): 162.0 [M+H] +

[0079] Step 4 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-4-oxa-3,4-dihydrophthalazin-6-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Example 3) A 25 mL reaction flask was charged with 1a (30 mg), DMF (1 mL), HATU (49 mg), and DIPEA (22 mg) and stirred for 5 minutes. Then, 3d (17 mg) was added and stirred at room temperature for 12 hours. The reaction mixture was monitored by LCMS for essentially complete conversion of the starting material. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel plate chromatography (EA / PE, 50%) to give 11.2 mg of a white solid, a 26.6% yield. LCMS: m / z (254 nm): 498.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 10.71 (s, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.27 (s, 1H), 8.08 (dd, J = 8.6, 2.2 Hz, 1H), 7.89 (d, J = 8.6 Hz, 1H), 7.20 - 7.12 (m, 2H), 5.13 (d, J = 10.3 Hz, 1H), 4.29 (dd, J = 10.1, 7.8 Hz, 1H), 3.95 (d, J = 2.0 Hz, 3H), 2.84 - 2.72 (m, 1H), 1.62 (s, 3H), 0.74 (d, J = 6.1 Hz, 3H).

[0080] Example 4 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(4-oxo-3H-quinazolin-6-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (4) Example 4 was obtained in the same manner as in Example 1, except that 6-amino-3,4-dihydroquinazolin-4-one was used instead of 1b in Example 1. ESI-MS m / z calc. 484.4, found 485.1 (M+1) + . 1H NMR (400 MHz, DMSO-d6) δ 12.25 - 12.16 (m, 1H), 10.60 (s, 1H), 8.51 (d, J = 2.5 Hz, 1H), 8.11 - 7.94 (m, 2H), 7.67 (d, J = 8.8 Hz, 1H), 7.28 - 7.15 (m, 2H), 5.14 (d, J = 10.3 Hz, 1H), 4.32 (dd, J = 10.3, 7.6 Hz, 1H), 3.99 (d, J = 2.1 Hz, 3H), 2.81 (t, J = 7.5 Hz, 1H), 1.66 (s, 3H), 0.78 (dd, J = 7.4, 2.5 Hz, 3H).

[0081] Example 5 [ka] Step 1 Methyl 2-hydroxy-5-nitrobenzoate (5b) Methanol (50 mL) and 5a (5.0 g) were added to a three-neck 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 separated and concentrated to give 6.0 g of a white solid in 111% yield. ESI-MS m / z calc. 197.2, found 198.1 (M+1). + .

[0082] Step 2 (2-Hydroxy-5-nitrophenyl)methanehydroxamic acid (5c) Methanol (500 mL) and potassium hydroxide (21 g) were added to a reaction flask, and hydroxylamine hydrochloride (17.5 g) was added in an ice bath. The mixture was stirred for 1.5 h, filtered, and the filtrate was added to 5b (5 g). The reaction was allowed to proceed for 16 h, at which point the reaction was confirmed to be complete by LCMS. The mixture was concentrated to remove the methanol, and the pH was adjusted to 2 with hydrochloric acid. The mixture was extracted with water and ethyl acetate. The ethyl acetate layer was collected, dried, and concentrated to give 4.8 g of a pale yellow solid in 96% yield. ESI-MS m / z calc. 198.0, found 198.9 (M+1). + .

[0083] Step 3 5-Nitro-2,3-dihydrobenzo[d]isoxazol-3-one (5d) THF (100 mL) and 5c (2.76 g) were added to a reaction flask, and triphenylphosphine (4.8 g) was added under nitrogen protection. The mixture was stirred in an ice bath for 20 minutes, followed by DIAD (3.7 g). The reaction was allowed to proceed for 4 hours, and the reaction was confirmed to be complete by LCMS. The mixture was concentrated to remove the solvent, and water was added. The pH was adjusted to 13 with sodium hydroxide and extracted with DCM. The aqueous layer was taken, adjusted to pH 1 with hydrochloric acid, extracted with DCM, washed with saturated brine, and concentrated to give 1.6 g of a white solid in 64% yield. ESI-MS m / z calc. 180.0, found 181.0 (M+1). + .

[0084] Step 4 5-Amino-2,3-dihydrobenzo[d]isoxazol-3-one (5e) Methanol (50 mL), 5d (800 mg), and 5% palladium on carbon (200 mg) were added to a reaction flask and reacted under hydrogenation conditions for 36 h. The reaction was complete as detected by LCMS. The filtrate was filtered and concentrated to give 400 mg of a white solid in 60.6% yield. ESI-MS m / z calc. 150.0, found 151.0 (M+1). + .

[0085] Step 5 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(3-oxo-2H-benzo[d]isoxazol-5-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Example 5) Example 5 was obtained in the same manner as in Example 1, except that 5e was used instead of 1b in Example 1. ESI-MS m / z calc. 486.1, found 487.1 (M+1) + . 1 H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 10.30 (s, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.29 - 7.09 (m, 5H), 5.08 (d, J = 10.4 Hz, 1H), 4.36 - 4.23 (m, 1H), 3.99 (d, J = 2.1 Hz, 3H), 2.87 - 2.73 (m, 1H), 1.63 (s, 3H), 0.80 - 0.73 (m, 3H).

[0086] Example 6 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (6) Example 6 was obtained in the same manner as in Example 1, except that 7-amino-1,2,3,4-tetrahydroisoquinolin-1-one was used instead of 1b in Example 1. ESI-MS m / z calc. 498.2, found 499.2 (M+1) + . 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.11 (d, J = 2.3 Hz, 1H), 7.94 (d, J = 3.3 Hz, 1H), 7.75 (dd, J = 8.2, 2.4 Hz, 1H), 7.31 - 7.14 (m, 3H), 5.09 (d, J = 10.4 Hz, 1H), 4.28 (dd, J = 10.4, 7.6 Hz, 1H), 3.99 (d, J = 2.1 Hz, 3H), 3.37 (td, J = 6.5, 2.7 Hz, 2H), 2.87 (t, J = 6.6 Hz, 2H), 2.82 - 2.76 (m, 1H), 1.64 (s, 3H), 0.83 - 0.71 (m, 3H).

[0087] Example 8 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(1-oxo-2,3-dihydro-1H-isoindol-5-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide Example 8 was obtained in the same manner as in Example 1, except that 5-amino-2,3-dihydro-1H-isoindol-1-one was used instead of 1b in Example 1. ESI-MS m / z calc. 484.1, found 485.2 (M+1) + . 1 H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 8.45 (s, 1H), 7.98 (d, J = 6.5 Hz, 2H), 7.63 (d, J = 1.1 Hz, 2H), 7.31 - 7.12 (m, 3H), 5.14 (d, J = 10.3 Hz, 1H), 4.35 (s, 2H), 3.99 (d, J = 2.1 Hz, 3H), 2.93 (s, 2H), 2.77 (s, 2H), 1.64 (s, 3H), 0.78 (d, J = 7.4 Hz, 3H).

[0088] Example 9 [ka] Step 1 6-Aminophenylpropyl[d]isothiazol-3(2H)-one-1,2-dioxygen (9b) 9a (650 mg) and concentrated hydrochloric acid (9 mL) were added to a reaction flask in an ice bath, and zinc powder (1.1 g) was added in several portions within approximately 30 minutes. The mixture was stirred at room temperature for 2 hours, and LCMS confirmed that the starting material was essentially completely converted. Saturated sodium bicarbonate solution was added to the reaction mixture in an ice bath until it became slightly alkaline, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered to give 320 mg of a copper-colored solid (purity approximately 70%) in a 37.0% yield. LCMS: MS m / z (254 nm): 185.0 [M+H] + .

[0089] Step 2 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1,1-dioxo-2,3-dihydrobenzo[d]isothiazol-6-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Example 9) Example 9 was obtained in the same manner as in Example 3, except that 9b was used instead of 3b in Example 3. LCMS: Rt: 2.625 min; MS m / z (254 nm): 521.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 8.12 (d, J = 1.5 Hz, 1H), 7.82 (t, J = 4.7 Hz, 1H), 7.77 (dd, J = 8.4, 1.8 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.16 (t, J = 6.5 Hz, 2H), 5.09 (d, J = 10.3 Hz, 1H), 4.34 (d, J = 4.8 Hz, 2H), 4.26 (dd, J = 10.1, 7.8 Hz, 1H), 3.95 (d, J = 2.0 Hz, 3H), 2.78 (dd, J = 14.7, 7.4 Hz, 1H), 1.61 (s, 3H), 0.73 (d, J = 6.7 Hz, 3H).

[0090] Example 10 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (10) Example 10 was obtained in the same manner as in Example 1, except that 5-amino-2H-isoindole-1,3-dione was used instead of 1b in Example 1. ESI-MS m / z calc. 498.1, found 499.2 (M+1) + . 1 H NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H), 10.73 (s, 1H), 8.14 (d, J = 1.8 Hz, 1H), 7.94 (dd, J = 8.2, 1.8 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.27 - 7.11 (m, 2H), 5.11 (d, J = 10.1 Hz, 1H), 4.32 - 4.16 (m, 1H), 3.95 (d, J = 2.1 Hz, 3H), 2.85 - 2.71 (m, 1H), 1.61 (s, 3H), 0.74 (d, J = 7.4 Hz, 3H).

[0091] Example 12 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1,4-dioxo-2,3-dihydrobenzo[2,1-d][1,2]diazin-6-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (12) Example 12 was obtained in the same manner as in Example 1, except that 6-amino-1,2,3,4-tetrahydrobenzo[2,1-d][1,2]diazine-1,4-dione was used instead of 1b in Example 1. ESI-MS m / z calc. 513.1, found 514.1 (M+1) + . 1 H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 10.76 (s, 0H), 8.45 (s, 0H), 8.07 (s, 1H), 7.21 (dd, J = 8.6, 5.0 Hz, 1H), 5.16 (d, J = 10.2 Hz, 0H), 4.32 (dd, J = 10.3, 7.6 Hz, 1H), 3.98 (dd, J = 9.9, 2.1 Hz, 2H), 2.83 (q, J = 7.6 Hz, 0H), 1.66 (s, 2H), 0.83 - 0.62 (m, 2H).

[0092] Example 13 [ka] Step 1 5-Amino-2-carbamimidoylbenzoic acid (13b) Compound 4-aminophthalonitrile 13a (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 reacted at 100 °C for 1 hour under nitrogen protection. Completion of the reaction mixture was monitored by LCMS. The reaction mixture was cooled to room temperature and concentrated. The residue was separated and purified by prep-HPLC (0.01% FA) to give compound 5-amino-2-carbamimidoylbenzoic acid 13b (733 mg, 82% yield) as a yellow solid. LCMS: [M+H] + = 180.1

[0093] Step 2 4,7-Diaminophthalazin-1-ol (13c) 5-Amino-2-carbamimidoylbenzoic acid 13b (680 mg, 3.79 mmol, 1.0 eq) was dissolved in methanol (10 mL) and hydrazine hydrate (7 mL) was added. The reaction mixture was reacted at 25 °C for 4 hours. The completion of the reaction was monitored by LCMS. The reaction mixture was concentrated, and the residue was extracted with water (10 mL) and ethyl acetate (10 mL × 5). Then, it was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was filtered, and the filter cake was dried under vacuum to obtain compound 4,7-diaminophthalazin-1-ol 13c (100 mg, 13% yield) as a yellow solid. LCMS: [M+H] + = 177.1

[0094] Step 3 rel-(2R,3S,4S,5R)-N-(1-amino-4-oxo-3H-benzo[2,1-d][1,2]diazin-6-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Example 13) Compound 1a (50 mg, 0.14 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (2 mL), and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (64 mg, 0.17 mmol, 1.2 eq), N,N-diisopropylethylamine (27 mg, 0.21 mmol, 1.5 eq), and 13c (29 mg, 0.17 mmol, 1.2 eq) were added. The reaction mixture was allowed to react at 25 °C for 2 h. The completion of the reaction was monitored by LCMS. The reaction mixture was dissolved in water (10 mL), extracted with ethyl acetate (10 mL x 3), washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative separation (0.01% aqueous ammonia) to give compound 13 (21.41 mg, 29% yield) as a white solid. LCMS: [M+H] + = 513.1. 1 H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 10.69 (s, 1H), 8.49 (d, J = 2.0 Hz, 1H), 8.05 (dd, J = 8.8, 2.4 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.21-7.16 (m, 2H), 5.88 (s, 2H), 5.12 (d, J = 10.0 Hz, 1H), 4.30-4.25 (m, 1H), 3.96 (d, J = 2.0 Hz, 3H), 2.82-2.74 (m, 1H), 1.62 (s, 3H), 0.74 (d, J = 6.4 Hz, 3H). 19 FnmR (377 MHz, DMSO-d6) δ -73.36 (s, 3H), -138.16 (d, J = 20.7 Hz, 1H), -154.96 (d, J = 20.7 Hz, 1H).

[0095] Example 16 rel-2-Carbamoyl-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-1-methylpyridine-1-iodide [ka] Compound 16a (40 mg, 0.08 mmol, 1.0 eq), iodomethane (1 mL), and acetonitrile (2 mL) were added to a microwave tube in this order. The reaction mixture was reacted at 80°C for 16 hours under nitrogen protection. The completion of the reaction was monitored by LCMS, and the reaction mixture was concentrated. The residue was purified by preparative separation (0.01% aqueous ammonia) to give compound 16 (11.06 mg, 27% yield) as a white solid. LCMS: [M] + = 488.1. 1 H NMR (400 MHz, CDCl3) δ 11.38 (s, 1H), 9.92 (s, 1H), 8.83 (s, 1H), 8.69 (s, 1H), 8.12 (d, J = 12.8 Hz, 1H), 7.09-7.04 (m, 1H), 6.87-6.85 (m, 1H), 6.06 (s, 1H), 5.05 (d, J = 11.2 Hz, 1H), 4.31 (s, 3H), 4.27-4.20 (m, 1H), 3.97 (d, J = 2.6 Hz, 3H), 2.89-2.79 (m, 1H), 0.92 (s, 3H), 0.78 (d, J = 6.4 Hz, 3H).

[0096] Example 20 [ka] Step 1 4-(bis(4-methoxybenzyl)amino)-N-hydroxypicolinamide (20b) Compound 4-(bis(4-methoxybenzyl)amino)picolinic acid 20a (800 mg, 2.1 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (10 mL), N,N'-carbonyldiimidazole (411.32 mg, 2.5 mmol, 1.2 eq) was added, and the mixture was stirred at 25 °C for 2 h. Hydroxylamine hydrochloride (882.81 mg, 10.6 mmol, 5.0 eq) was then added. The reaction mixture was stirred at 25 °C for 2 h. The completion of the reaction was monitored by LCMS. The reaction mixture was poured into water, extracted with ethyl acetate, and the organic phase was washed with saturated brine. The organic phase was dried and concentrated. The residue was purified by silica gel column separation (dichloromethane / methanol = 10 / 1) to give compound 20b (500 mg, 60% yield) as a brown solid. LCMS: [M+H] + = 394.2

[0097] Step 2 4-Amino-N-hydroxypicolinamide (20c) Compound 20b (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. The completion of the reaction was monitored by LCMS, and the reaction mixture was concentrated. The residue was dissolved in dichloromethane, and an ethereal solution of hydrochloric acid (2 mL) was added and the mixture was concentrated to give compound 20c (260 mg, 93% yield) in the form of hydrochloride salt as a brown solid. LCMS: [M+H] + = 154.2

[0098] Step 3 rel-4-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-trifluoromethyltetrahydrofuran-2-carboxamido)-N-hydroxypicamide (Example 20) Compound 1a (50 mg, 0.14 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (2 mL) and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (80.48 mg, 0.21 mmol, 1.5 eq), 20c (64.8 mg, 0.42 mmol, 3.0 eq), and N,N-diisopropylethylamine (91.2 mg, 0.7 mmol, 5.0 eq) were added sequentially. The reaction mixture was stirred at 25 °C for 2 h. Completion was monitored by LCMS. The reaction mixture was poured into water, extracted with ethyl acetate, and the organic phase was washed with brine. The organic phase was dried and concentrated. The residue was purified by preparative separation (0.01% formic acid) to give compound 20 (4.41 mg, 6% yield) as a white solid. LCMS: [M+H] + = 490.1, 1 H NMR (400 MHz, CH3OD) δ 7.89 (d, J = 6.9 Hz, 1H), 7.26-7.16 (m, 2H), 6.97-6.90 (m, 1H), 6.79-6.64 (m, 1H), 5.17 (s,1H), 4.33-4.27 (m, 1H), 4.01 (d, J = 2.2 Hz, 3H), 2.84-2.77 (m, 1H), 1.64 (s, 3H), 0.80 (d, J = 6.2 Hz, 3H).

[0099] Example 21 [ka] Step 1 Toluene Methyl 4-(bis(4-methoxybenzyl)amino)picolinate (21a) Bis(4-methoxybenzyl)amine (4 g, 1.8 mmol, 1.0 eq), methyl 4-bromopicolinate (6.2 g, 2.4 mmol, 1.3 eq), 1,1′-[1,1′-dinaphthalene]-2,2′-diylbis[1,1-diphenyl-(ACI)phosphine] (580 mg, 0.09 mmol, 0.05 eq), palladium 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 to a microwave tube in this order and stirred at 100 °C for 4 h. The reaction was monitored for completion by LCMS. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column separation (petroleum ether / ethyl acetate = 1 / 1) to give 21a (3.2 g, 44% yield) as a yellow solid. LCMS: [M+H] + = 393.2

[0100] Step 2 4-(bis(4-methoxybenzyl)amino)picolinic acid (21b) Methyl 4-(bis(4-methoxybenzyl)amino)picolinate 21a (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 the mixture was stirred at 25 °C for 16 hours. The completion of the reaction was monitored by LCMS. The reaction mixture was poured into water, adjusted to a pH of ∼5 with 1N dilute hydrochloric acid, extracted with ethyl acetate, and washed with brine. The organic phase was dried and concentrated to give 4-(bis(4-methoxybenzyl)amino)picolinic acid 21b (2 g, 65% yield) as a yellow solid. LCMS: [M+H] + = 379.1

[0101] Step 3 4-(bis(4-methoxybenzyl)amino)-N-methoxypicolinamide (21c) Compound 4-(bis(4-methoxybenzyl)amino)picolinic acid 21b (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. The mixture was stirred at 25 °C for 2 h. Methoxyamine hydrochloride (221 mg, 10.6 mmol, 5.0 eq) was then added. The reaction mixture was stirred at room temperature for 2 h. The completion of the reaction was monitored by LCMS. The reaction mixture was poured into water, extracted with ethyl acetate, and the organic phase was washed with brine. The organic phase was dried and concentrated. The residue was purified by silica gel column separation (dichloromethane / methanol = 20 / 1) to give compound 4-(bis(4-methoxybenzyl)amino)-N-methoxypicolinamide 21c (140 mg, 65% yield) as a brown solid. LCMS: [M+H] + = 408.1

[0102] Step 4 4-Amino-N-methoxypicolinamide (21d) Compound 4-(bis(4-methoxybenzyl)amino)-N-methoxypicolinamide 21c (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. The completion of the reaction was monitored by LCMS, and the reaction mixture was concentrated. The residue was dissolved in dichloromethane, and ethereal hydrochloride (2 mL) was added and the mixture was concentrated to obtain compound 4-amino-N-methoxypicolinamide 21d (80 mg, 78% yield) in the hydrochloride form as a brown solid. LCMS: [M+H] + = 168.1

[0103] Step 5 rel-4-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-trifluoromethyltetrahydrofuran-2-formamidepicolinamide (Example 21) Compound 1a (50 mg, 0.14 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (2 mL) and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (80.48 mg, 0.21 mmol, 1.5 eq), 4-amino-N-methoxypicolinamide 21d (70.7 mg, 0.42 mmol, 3.0 eq), and N,N-diisopropylethylamine (91.2 mg, 0.7 mmol, 5.0 eq) were added sequentially. The reaction mixture was stirred at 25 °C for 2 h. After the majority of the starting material was reacted, the reaction mixture was poured into water, extracted with ethyl acetate, and the organic phase was washed with brine, dried, and concentrated. The residue was purified by preparative separation (0.01% formic acid) to give compound 21 (4.5 mg, 6% yield) as a white solid. LCMS: [M+H] + = 504.1. 1 H NMR (400 MHz, CH3OD) δ 8.53-8.43 (m, 1H), 8.23 ​​(s, 1H), 7.88 (s, 1H), 7.10 (d, J = 7.8 Hz, 1H), 7.02-6.93 (m, 1H), 5.06 (s, 1H), 4.37-4.29 (m, 1H), 3.99 (d, J = 2.2 Hz, 3H), 3.80 (s, 3H), 2.83-2.75 (m, 1H), 1.65 (s, 3H), 0.81 (d, J = 7.6 Hz, 3H).

[0104] Example 22 rel-(2R,3S,4S,5R)-N-[2-(aminothioylidenemethyl)pyridin-4-yl]-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide [ka] Compound 16a (30 mg, 0.06 mmol, 1.0 eq) was dissolved in toluene (20 mL), Lawesson's reagent (26 mg, 0.06 mmol, 1.0 eq) was added, and the mixture was heated to 110°C for 24 hours. After the reaction was completed, the mixture was concentrated to remove the solvent and purified by thin layer chromatography to give Example 22 (15 mg, 48% yield) as a yellow solid. LCMS: [M+H] + = 490.5. 1 H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1H), 10.21 (s, 1H), 9.93 (s, 1H), 8.89 - 8.71 (m, 1H), 8.49 (d, J = 5.4 Hz, 1H), 7.93 (s, 1H), 7.46 - 7.02 (m, 3H), 5.29 (d, J = 10.7 Hz, 1H), 4.27 (d, J = 8.9 Hz, 1H), 3.99 (d, J = 2.8 Hz, 3H), 2.75 (m, 1H), 1.64 (s, 3H), 0.75 (s, 3H).

[0105] Example 24 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-fluoro-2-oxo-1H-pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (24) Example 24 was obtained in the same manner as in Example 1, except that 4-amino-6-fluoro-1,2-dihydropyridin-2-one was used instead of 1b in Example 1. ESI-MS m / z calc. 464.1, found 465.1 (M+1) + . 1H NMR (400 MHz, Methanol-d4) δ 7.08 (t, J = 7.5 Hz, 1H), 7.01 - 6.93 (m, 1H), 6.83 (s, 1H), 6.75 (d, J = 1.4 Hz, 1H), 5.02 (d, J = 10.3 Hz, 1H), 4.30 (dd, J = 10.3, 8.0 Hz, 1H), 3.99 (d, J = 2.2 Hz, 3H), 2.87 - 2.70 (m, 1H), 1.63 (s, 3H), 0.80 (dd, J = 7.8, 2.4 Hz, 3H).

[0106] Example 25 [ka] Step 1 Methyl 2-cyano-5-nitrobenzoate (25b) A reaction flask was charged with 25a (3 g), cuprous cyanide (2 g), and DMF (30 mL). While stirring evenly, Pd2(dba)3 (527 mg) and dppf (638 mg) were added sequentially. The mixture was purged with nitrogen three times and stirred at 115 °C for 16 h. The reaction mixture was cooled to room temperature, water (70 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, concentrated, and separated by column chromatography (EA / PE, 0% to 15%) to give 2 g of a white solid in 84.4% yield. LCMS: m / z (254 nm): 207.0 [M+H] +

[0107] Step 2 2-Cyano-5-nitrobenzamide (25c) 25a (1 g) and ammonia methanol solution (7 M, 10 mL) were added to the reaction flask, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered with suction and washed with methanol to give 720 mg of a pale yellow solid, with a yield of 77.6%. LCMS: m / z (254 nm): 192.0 [M+H] +

[0108] Step 3 2-Cyano-5-aminobenzamide (25d) A reaction flask was charged with 25c (300 mg), MeOH (10 mL), and THF (10 mL). After stirring evenly, palladium on carbon (30 mg) was added, and the mixture was purged with hydrogen three times. The mixture was stirred at room temperature for 6 hours. The reaction was monitored by TLC until the starting material was completely converted. The reaction mixture was filtered through diatomaceous earth with suction, and the filtrate was concentrated to give 179 mg of a yellow solid in a 71% yield. LCMS: m / z (254 nm): 162.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 2H), 7.58 (d, 1H), 6.77 (d, 1H), 6.73 (dd, 1H), 5.99 (s, 2H).

[0109] Step 4 rel-(2R,3S,4S,5R)-N-(3-carbamoyl-4-cyanophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Example 25) Example 25 was obtained in the same manner as in Example 3, except that 25d was used instead of 3b in Example 3. 1 H NMR (400 MHz, DMSO) δ 10.87 (s, 1H), 7.26 - 7.20 (m, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.08 (dd, J = 17.3, 9.3 Hz, 1H), 6.85 (d, J = 2.0 Hz, 1H), 6.72 (dd, J = 8.4, 2.0 Hz, 1H), 6.39 (s, 2H), 5.22 (d, J = 10.6 Hz, 1H), 4.23 (dd, J = 10.5, 7.5 Hz, 1H), 3.90 (d, J = 2.0 Hz, 3H), 2.72 - 2.61 (m, 1H), 1.51 (s, 3H), 0.71 (d, J = 6.2 Hz, 3H).

[0110] Example 27 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(6-oxo-1H-1,2-diazin-3-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (27) Example 27 was obtained in the same manner as in Example 1, except that 6-amino-3H,2H-1,2-diazin-3-one was used instead of 1b in Example 1. ESI-MS m / z calc. 447.1, found 448.1 (M+1) + . 1 H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 10.75 (s, 1H), 7.88 (d, J = 10.1 Hz, 1H), 7.28 - 7.11 (m, 2H), 6.92 (d, J = 10.1 Hz, 1H), 5.14 (d, J = 10.4 Hz, 1H), 4.30 - 4.20 (m, 1H), 3.98 (t, J = 2.5 Hz, 3H), 2.78 (t, J = 7.5 Hz, 1H), 1.62 (s, 3H), 0.80 - 0.68 (m, 2H).

[0111] Example 29 rel-(2R,3S,4S,5R)-2-({[3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]carbonyl}amino)-1,3-thiazole-4-carboxamide (29) Example 29 was obtained in the same manner as in Example 3, except that 2-amino-1,3-thiazole-4-carboxamide was used instead of 3b in Example 3. ESI-MS m / z calc. 479.1, found 480.1 (M+1) + . 1H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 7.86 (s, 1H), 7.59 (s, 1H), 7.37 (s, 1H), 7.26 - 7.15 (m, 2H), 5.25 (d, J = 10.5 Hz, 1H), 4.30 (dd, J = 10.4, 7.6 Hz, 1H), 3.98 (d, J = 2.2 Hz, 2H), 2.82 (t, J = 7.5 Hz, 1H), 1.64 (s, 2H), 0.80 - 0.68 (m, 3).

[0112] Example 30 rel-(2R,3S,4S,5R)-4-({[3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]carbonyl}amino)benzene-1,2-dicarboxamide (30) Example 30 was obtained in the same manner as in Example 1, except that 4-aminobenzene-1,2-dicarboxamide was used instead of 1b in Example 1. ESI-MS m / z calc. 515.1, found 516.1 (M+1) + . 1 H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 7.76 - 7.60 (m, 4H), 7.49 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 20.8 Hz, 2H), 7.22 - 7.09 (m, 2H), 5.07 (d, J = 10.4 Hz, 1H), 4.24 (dd, J = 10.3, 7.6 Hz, 1H), 3.95 (d, J = 2.1 Hz, 2H), 2.76 (t, J = 7.5 Hz, 1H), 1.60 (s, 3H), 0.73 (d, J = 7.4Hz, 3H).

[0113] Example 30 was separated by chiral SFC using a Daicel CHIRALPAK IH_3 column, 3.0*150 mm, 3 μm particle size. Example 30-1 (RT = 1.6 min) had a specific rotation [α]20D = 35.4. Example 30-2 (RT = 3.0 min) had a specific rotation [α]20D = -35.5.

[0114] Example 31 rel-(2R,3S,4S,5R)-5-({[3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]carbonyl}amino)benzene-1,3-dicarboxamide Example 31 was obtained in the same manner as in Example 1, except that 5-aminobenzene-1,3-dicarboxamide was used instead of 1b in Example 1. ESI-MS m / z calc. 515.1, found 516.1 (M+1) + . 1 H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.23 ​​(d, J = 1.5 Hz, 2H), 8.10 (t, J = 1.6 Hz, 1H), 7.99 (d, J = 3.2 Hz, 2H), 7.47 (s, 2H), 7.26 - 7.20 (m, 2H), 5.14 (d, J = 10.5 Hz, 1H), 4.29 (dd, J = 10.5, 7.6 Hz, 1H), 3.99 (d, J = 2.1 Hz, 3H), 2.93 (s, 1H), 1.65 (s, 3H), 0.77 (d, J = 7.4 Hz, 3H).

[0115] Example 32 [ka] Step 1 Methyl rel-(2R,3S,4S,5R)-4-({[3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]carbonyl}amino)pyridine-2-carboxylate (32a) Intermediate 32a was obtained in the same manner as in Example 3, except that methyl 4-aminopyridine-2-carboxylate was used instead of 3a in Example 3. ESI-MS m / z calc. 488.1, found 489.1 (M+1) + .

[0116] Step 2 rel-(2R,3S,4S,5R)-4-({[3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]carbonyl}amino)pyridine-2-carboxylic acid (32b) A reaction flask was charged with 32a (80 mg), THF (5 mL), water (5 mL), and sodium hydroxide (10 mg), and the mixture was allowed to react at room temperature for 2 hours. Completion of the reaction was monitored by TLC. The pH was adjusted to 1, and ethyl acetate was added for extraction. The organic phase was dried, concentrated, and purified by column chromatography to give 32b (75 mg, 98%). ESI-MS m / z calc. 474.1, found 473.1 (M-1). + .

[0117] Step 3 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-[2-(tetrahydroisoxazol-2-ylcarbonyl)pyridin-4-yl]-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Example 32) A reaction flask was charged with 32b (30 mg), tetrahydroisoxazole (10 mg), HATU (36 mg), diisopropylethylamine (20 mg), and DMF (1 mL). The mixture was allowed to react at room temperature for 17 hours, and the reaction was monitored by LCMS for completion. The mixture was extracted with water and ethyl acetate, and the organic phase was dried and concentrated. The product was purified by thin-layer chromatography to give Example 32 (20 mg, 60%). ESI-MS m / z calc. 529.1, found 530.2 (M+1). + . 1 H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.51 (d, J = 5.6 Hz, 1H), 8.02 (d, J = 27.4 Hz, 1H), 7.76 (s, 1H), 7.20 (dd, J = 9.7, 6.5 Hz, 2H), 5.14 (d, J = 10.2 Hz, 1H), 4.29 (dd, J = 10.2, 7.7 Hz, 1H), 3.98 (d, J = 2.2 Hz, 4H), 3.91 (d, J = 14.6 Hz, 0H), 2.85 (d, J = 63.6 Hz, 2H), 2.81 (t, J = 7.5 Hz, 1H), 2.32 (p, J = 7.0 Hz, 2H), 1.64 (s, 3H), 0.77 (d, J = 7.4 Hz, 3H).

[0118] Example 34 [ka] Step 1 2-Benzylthio-4-iodopyridine (34b) Benzyl mercaptan (2.9 g) and THF (50 mL) were added to a reaction flask and stirred evenly. NaH (848 mg) was added in several portions under ice bath conditions. After the addition was complete, the mixture was stirred at room temperature for 1 h. 34a (5 g) was added under ice bath conditions. After the addition was complete, the mixture was stirred at room temperature for 3 h. LCMS confirmed that the starting material was essentially completely converted. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (EA / PE, 0%-10%) to give 6.6 g of a pale red liquid in 90.1% yield. LCMS: MS m / z (254 nm): 327.9 [M+H] + .

[0119] Step 2 4-Iodopyridine-2-sulfonyl chloride (34c) A reaction flask was charged with 34b (3 g), DCM (30 mL), and DIPEA (3.8 g). Dichlorohydantoin (6.9 g) was added in portions under ice bath conditions. After the addition was complete, the mixture was warmed to room temperature and stirred for 4 h. The reaction was essentially complete as determined by LCMS. Water (50 mL) was added to the reaction mixture, which was then extracted with dichloromethane (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (EA / PE, 0%-10%) to give 1.4 g of a pale yellow solid in 24.2% yield. LCMS: MS m / z (254 nm): 585.0 [M+H] + .

[0120] Step 3 N,N-bis(2,4-dibenzyl)-4-iodopyridine-2-sulfonamide (34d) A reaction flask was charged with 34c (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 mixture was purged with nitrogen three times and stirred at 95 °C for 16 h. The reaction mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were concentrated and separated by column chromatography (EA / PE, 50% to 100%) to give 460 mg of a yellow oil in 70.8% yield. LCMS: MS m / z (254 nm): 475.1 [M+H] + .

[0121] Step 4 rel-(2R,3S,4S,5R)-N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfonyl)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (34e) Using 34d instead of 3b in Example 3, 34e was obtained in the same manner as in Example 3. LCMS: MS m / z (254 nm): 810.2 [M+H] + .

[0122] Step 5 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(2-sulfonylpyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Example 34) A reaction flask was charged with 34e (52 mg), DCM (2 mL), and trifluoroacetic acid (146 mg), and the mixture was stirred at room temperature for 12 hours. LCMS indicated essentially complete conversion of the starting material. The reaction mixture was concentrated and separated by silica gel plate chromatography (EA / PE, 40%) to give 24.5 mg of a white solid, a yield of 75.2%. LC-MS: MS m / z (254 nm): 510.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ1 H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.57 (d, J = 5.4 Hz, 1H), 8.26 (d, J = 1.8 Hz, 1H), 7.81 (dd, J = 5.5, 1.7 Hz, 1H), 7.41 (s, 2H), 7.23 - 7.11 (m, 2H), 5.12 (d, J = 10.1 Hz, 1H), 4.36 - 4.15 (m, 1H), 3.95 (d, J = 1.8 Hz, 3H), 2.93 - 2.66 (m, 1H), 1.61 (s, 3H), 0.73 (d, J = 6.1 Hz, 3H).

[0123] Example 59 [ka] Step 1 (3Z)-4-(3,4-difluoro-2-methoxyphenyl)-1,1,1-trifluoro-3-methylbutan-3-en-2-one (59a) 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 to the reaction flask in this order. The tube was sealed and reacted at room temperature for 2 h. The reaction was then heated to 75 °C and continued for 16 h. Completion of the reaction was monitored by TLC. The mixture was extracted with water and ethyl acetate. The ethyl acetate layer was collected, concentrated, and separated by column chromatography (PE:EA = 20:1) to give 59a (7.5 g, 92% yield) as a yellow liquid.

[0124] Step 2 rel-Ethyl-(2R,3S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methyl-5-(trifluoromethyl)-2,3-dihydrofuran-2-carboxylate (59b) Acetonitrile (25 mL), compound 59a (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 to a reaction flask in this order and allowed to react at room temperature for 16 hours. The completion of the reaction of compound 59a was monitored by TLC (PE:EA = 10:1). The filtrate was filtered, concentrated, and then column-separated (PE:EA = 20:1) to give 2.3 g of a yellow liquid (72% yield).

[0125] Step 3 rel-(2R,3S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methyl-5-(trifluoromethyl)-2,3-dihydrofuran-2-carboxylic acid (59c) Methanol (25 mL), water (25 mL), compound 59b (1.0 g, 2.7 mmol, 1.0 eq), and sodium hydroxide (0.54 g, 13.6 mmol, 5 eq) were added to a reaction flask in this order and reacted at 65 °C for 16 h. Completion of the reaction was monitored by LCMS. The mixture was concentrated to remove methanol, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was collected, dried, and concentrated to give 59c (0.8 g, 86% yield) as a yellow liquid.

[0126] Step 4 rel-(2R,3S)-4-({[3-(3,4-difluoro-2-methoxyphenyl)-4-methyl-5-(trifluoromethyl)-2,3-dihydrofuran-2-yl]carbonyl}amino)pyridine-2-carboxamide (59d) DMF (20 mL), 59c (0.8 g, 2.3 mmol, 1.0 eq), HATU (1.4 g, 3.5 mmol, 1.5 eq), triethylamine (0.7 g, 4.7 mmol, 2.0 eq), and 4-aminopyridine-2-carboxamide (0.5 g, 3.5 mmol, 1.5 eq) were added to a reaction flask in this order and allowed to react at room temperature for 16 h. The reaction was monitored for completion by TLC. The mixture was extracted with water and ethyl acetate. The ethyl acetate layer was collected, concentrated, and separated by column chromatography (PE:EA = 3:1 → 1:2) to give 59d (0.4 g, 40% yield) as a gray solid. MS: [M+H] + = 458. 1 H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.56 (d, J = 5.5 Hz, 1H), 8.33 (d, J = 2.1 Hz, 1H), 8.11 (s, 1H), 7.86 (dd, J = 5.6, 2.3 Hz, 1H), 7.66 (s, 1H), 7.31 - 7.21 (m, 1H), 7.10 (td, J = 6.9, 6.5, 3.1 Hz, 1H), 5.13 (d, J = 6.2 Hz, 1H), 4.73 (s, 1H), 3.94 (d, J = 1.9 Hz, 3H), 1.68 (d, J = 2.8 Hz, 3H), 0.88 (d, J = 6.9Hz, 1H)

[0127] Step 5 rel-(2R,3S)-4-({[4,5-dichloro-3-(3,4-difluoro-2-methoxyphenyl)-3a-methyl-5a-(trifluoromethyl)hexahydrocyclobut[2,1-b]furan-2-yl]carbonyl}amino)pyridine-2-carboxamide (59e) DCE (500 mL), 59d (500 mg, 1.1 mmol, 1.0 eq), and 1,2-dichloroethylene (2 mL) were added to a quartz reaction flask in this order, and the mixture was irradiated with light at 275 nm for 3 weeks. The reaction mixture was separated and purified by column chromatography. 75 mg of the starting material was recovered, and 20 mg of the product was obtained as a white solid, for a yield of 3.4%. MS: [M+H]+ = 554. 1 H NMR (400 MHz, Methanol-d4) δ 8.53 (d, J = 5.5 Hz, 1H), 8.31 (d, J = 2.1 Hz, 1H), 7.93 (dd, J = 5.5, 2.2 Hz, 1H), 7.12 - 7.05 (m, 2H), 5.41 (d, J = 6.0 Hz, 1H), 4.69 (q, J = 7.7 Hz, 2H), 4.61 (d, J = 6.0 Hz, 1H), 4.01 (d, J = 2.4 Hz, 3H), 0.95 - 0.93 (m, 3H).

[0128] Step 6 rel-(2R,3S)-4-({[3-(3,4-difluoro-2-methoxyphenyl)-3a-methyl-5a-(trifluoromethyl)hexahydrocyclobut[2,1-b]furan-2-yl]carbonyl}amino)pyridine-2-carboxamide (59) Toluene (15 mL), 59e (10 mg, 0.02 mmol, 1.0 eq), tributyltin (52 mg, 0.2 mmol, 10 eq), and AIBN (32 mg, 0.2 mmol, 10 eq) were added to the reaction flask in this order, sealed, and reacted at 100 °C for 36 h. Completion of the reaction was monitored by LCMS. Thin layer chromatography gave compound 59 (3.4 mg, 40% yield) as a white solid. MS: [M+H] + = 486. 1 H NMR (400 MHz, Chloroform-d) δ 8.94 (s, 1H), 8.50 (d, J = 5.4 Hz, 1H), 8.26 (s, 1H), 8.09 (s, 1H), 6.99 - 6.88 (m, 1H), 5.68 (s, 1H), 5.03 (s, 1H), 4.18 (s, 1H), 3.99 (d, J = 2.3 Hz, 2H), 2.56 (dd, J = 17.3, 6.7 Hz, 1H), 2.15 (t, J = 13.1 Hz, 1H), 1.92 (dd, J = 14.5, 6.3 Hz, 1H), 0.90 (s, 2H).

[0129] Example 79 rel-(2R,3S,4S,5)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-N-(1,1,3-trioxo-2,3-dihydro-1λ6-benzo[d][1,2]thiazol-6-yl)tetrahydrofuran-2-carboxamide (79) Example 79 was obtained in the same manner as in Example 1, except that 6-amino-2,3-dihydro-1λ6-benzo[d][1,2]thiazole-1,1,3-trione was used instead of 1b in Example 1. ESI-MS m / z calc. 534.5, found 533.5 (M-1) - . 1 H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.72 (dd, J = 8.2, 1.8 Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.17 (dd, J = 8.5, 5.2 Hz, 2H), 5.10 (d, J = 10.2 Hz, 1H), 4.26 (dd, J = 10.2, 7.6 Hz, 1H), 3.95 (d, J = 2.1 Hz, 3H), 2.77 (p, J = 7.5 Hz, 1H), 1.61 (s, 3H), 0.76 - 0.60 (m, 3H).

[0130] Example 80 [ka] Step 1 2-Bromo-3-fluoro-5-nitrobenzoic acid (80a) 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 completion of the reaction was monitored by LCMS. The reaction mixture was slowly poured into ice water and extracted with dichloromethane (50 mL × 3), and the organic phase was collected. The organic phase was washed with saturated brine (50 mL × 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 (800 mg, 13%) as a yellow solid. LCMS: [M+H] + = 263.9.

[0131] Step 2 Methyl 2-bromo-3-fluoro-5-nitrobenzoate (80b) Compound 2-bromo-3-fluoro-5-nitrobenzoic acid 80a (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. The completion of the reaction was monitored by LCMS. The reaction mixture was filtered to obtain the filtrate. The filtrate was concentrated to obtain compound methyl 2-bromo-3-fluoro-5-nitrobenzoate 80b (800 mg, 95%) as a yellow solid. LCMS: [M+H] + = 277.9.

[0132] Step 3 Dimethyl 3-fluoro-5-nitrobenzoate (80c) Compound methyl 2-bromo-3-fluoro-5-nitrobenzoate 80b (400 mg, 1.43 mmol, 1.0 eq) was dissolved in methanol (10 mL), and Pd(dppf)Cl (32 mg, 0.143 mmol, 0.1 eq) and EtN (437 mg, 4.32 mmol, 3.0 eq) were added. The reaction mixture was stirred at 80 °C under carbon monoxide (0.1 MPa) for 16 hours. The reaction mixture was concentrated to give a residue, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound dimethyl 3-fluoro-5-nitrobenzoate 80c (40 mg, 11%) as a brown oil. LCMS: [M+H] + = 258.1.

[0133] Step 4 3-Fluoro-5-nitrophthalic acid diammonium salt (80d) Compound dimethyl 3-fluoro-5-nitrobenzoate 80c (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 give a residue, which was washed with dichloromethane, filtered, and the solid was collected to give compound 3-fluoro-5-nitrophthalic acid diammonium salt 80d (20 mg, 57%) as a white solid. LCMS: [M+H] + = 228.1.

[0134] Step 5 3-Fluoro-5-aminophthalic acid diammonium salt (80e) Compound 3-fluoro-5-nitrophthalic acid diammonium salt 80d (20 mg, 0.088 mmol, 1.0 eq) was dissolved in methanol (5 mL). The reaction mixture was stirred under hydrogen gas at 25° C. for 1 hour. The reaction mixture was filtered, and the filtrate was collected and concentrated to give compound 3-fluoro-5-aminophthalic acid diammonium salt 80e (13 mg, 75%) as a yellow solid. LCMS: [M+H] + = 198.1.

[0135] Step 6 rel-5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-3-fluorophthalamine (Example 80) Compound 1a (28 mg, 0.079 mmol, 1.2 eq) was dissolved in DMF (3 mL), and compound 3-fluoro-5-aminophthalic acid diammonium salt (13 mg, 0.066 mmol, 1.0 eq) 80e, HATU (30 mg, 0.079 mmol, 1.2 eq), and DIEA (10 mg, 0.079 mmol, 1.2 eq) were added. The reaction mixture was stirred at 25° C. for 1 hour. Completion of the reaction was monitored by LCMS. The reaction mixture was purified by pre-HPLC (0.1% FA) to give Example 80 (2.9 mg, 5%) as a white solid. LCMS: [M+H] + = 534.2.1H NMR (400 MHz, CD3OD) δ 7.72 (dd, J = 2.0, 2.0 Hz, 1H), 7.63 - 7.61 (m, 1H), 7.15 - 7.08 (m, 1H), 7.01 - 6.94 (m, 1H), 5.06 (d, J = 10.4 Hz, 1H), 4.33 - 4.28 (m, 1H), 3.99 (d, J = 2.4 Hz, 3H), 2.85 - 2.71 (m, 1H), 1.65 (s, 3H), 0.83 - 0.80 (m, 3H).

[0136] Example 81 [ka] Step 1 2-Fluoro-5-nitrobenzenesulfonamide (81b) Compound 4-fluoronitrobenzene 81a (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 and 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 × 3). The organic phase was collected. The organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give 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 the completion of the reaction was confirmed by TLC, the reaction mixture was poured into water and extracted with ethyl acetate (50 mL × 3). The organic phase was collected. The organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=2 / 3) to obtain compound 2-fluoro-5-nitrobenzenesulfonamide 81b (400 mg, 13% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO) δ 8.56-8.53 (m, 2H), 8.06 (s, 2H), 7.86-7.65 (m, 1H).

[0137] Step 2 5-Amino-2-fluorobenzenesulfonamide (81c) Compound 2-fluoro-5-nitrobenzenesulfonamide 81b (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 gas. Completion of the reaction was monitored by LCMS. The reaction mixture was filtered to obtain the filtrate. The filtrate was concentrated to obtain compound 5-amino-2-fluorobenzenesulfonamide (160 mg, 92% yield) as a black solid. LCMS: [M+H] + =191.1

[0138] Step 3 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(4-fluoro-3-sulfonatophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Example 81) Compound (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a (50 mg, 0.14 mmol, 1.0 eq) was dissolved in dichloromethane (3 mL), and compound 5-amino-2-fluorobenzenesulfonamide 81c (32 mg, 0.17 mmol, 1.2 eq), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (64 mg, 0.17 mmol, 1.2 eq), and N,N-diisopropylethylamine (22 mg, 0.17 mmol, 1.2 eq) were added. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated to give a residue, which was purified by preparative separation (0.1% formic acid) to give the compound (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(4-fluoro-3-sulfonatophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (2.3 mg, 3% yield) as a white solid. LCMS: [M+H] + = 527.1. 1 H NMR (400 MHz, DMSO) δ 10.61 (s, 1H), 8.57 (s, 1H), 8.23-8.21 (m, 1H), 7.93-7.86 (m, 1H), 7.72 (s, 1H), 7.46-7.39 (m, 1H), 7.29-7.18 (m, 2H), 5.13 (d, J = 10.4 Hz, 1H), 4.35-4.25 (m, 1H), 4.01 (d, J = 2.4 Hz, 3H), 2.85-2.79 (m, 1H), 1.66 (s, 3H), 0.79 (d, J = 5.6 Hz, 3H).

[0139] Example 82 [ka] Step 1 2-(benzylthio)-4-bromopyridine (82b) Compound benzyl mercaptan 82a (2.0 g, 16.1 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (30 mL), and sodium hydride (640 mg, 16.1 mmol, 1.0 eq) was added at 0° C. under nitrogen protection. The reaction mixture was stirred at 0° C. for 30 minutes. At the same temperature, a solution of compound 4-bromo-2-fluoropyridine (2.8 g, 16.1 mmol, 1.0 eq) in anhydrous tetrahydrofuran (10 mL) was added. After the dropwise addition was completed, the mixture was stirred at 0° C. for 1.5 hours. The reaction completion of the raw material was monitored by LCMS. Water (50 mL) was added to the reaction mixture, which was then 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 give compound 2-(benzylthio)-4-bromopyridine 82b (4.3 g, 95% yield) as a pink oil. LCMS: [M+H] + = 280.0

[0140] Step 2 4-Bromopyridine-2-sulfonyl chloride (82c) Compound 2-(benzylthio)-4-bromopyridine 82b (4.3 g, 15.3 mmol, 1.0 eq) was dissolved in dichloromethane:acetic acid:water (7:1:2) (80 mL) 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 reacted at 25 °C under nitrogen protection for 16 h. Completion of the reaction mixture was monitored by TLC. Water (20 mL) was added to the reaction mixture, which was then extracted with dichloromethane (20 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, diluted with dichloromethane, filtered, and the filtrate was centrifuged to give crude compound 4-bromopyridine-2-sulfonyl chloride (4.5 g, 92% yield) as a yellow oil.

[0141] Step 3 4-Bromopyridine-2-sulfonamide (82d) Aqueous ammonia (10 mL) was added to compound 4-bromopyridine-2-sulfonyl chloride 82c (3.0 g, 9.4 mmol, 1.0 eq). The reaction mixture was allowed to react at 25° C. for 1 hour. The reaction completion of the raw material was monitored by LCMS. The reaction mixture was concentrated, and the residue was purified on a silica gel column (petroleum ether / ethyl acetate=1 / 1) to give compound 4-bromopyridine-2-sulfonamide 82d (1.7 g, 77% yield) as a gray solid. LCMS: [M+H] + = 238.9

[0142] Step 4 tert-Butyl ((4-bromopyridin-2-yl)sulfonyl)carbamate (82e) Compound 4-bromopyridine-2-sulfonamide 82d (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. The reaction completion of the raw material was monitored by LCMS. The reaction mixture was concentrated, and the residue was purified on a silica gel column (dichloromethane / methanol = 10 / 1) to give compound tert-butyl ((4-bromopyridin-2-yl)sulfonyl)carbamate 82e (611 mg, 85% yield) as a yellow oil. LCMS: [M+Na] + = 359.0

[0143] Step 5 tert-Butyl ((4-bromopyridin-2-yl)sulfonyl) (methyl-d3)carbamate (82f) Compound tert-butyl ((4-bromopyridin-2-yl)sulfonyl)carbamate 82e (200 mg, 0.59 mmol, 1.0 eq) was dissolved in anhydrous N,N-dimethylformamide (5 mL), and potassium carbonate (123 mg, 0.88 mmol, 1.5 eq) and iodomethane-d3 (94 mg, 0.65 mmol, 1.1 eq) were added. The reaction mixture was reacted at 60 °C for 2 h. Completion of the reaction was monitored by LCMS. 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 using a silica gel column (petroleum ether / ethyl acetate = 10 / 1) to give 82f (130 mg, 62% yield) as a white solid. LCMS: [M+Na] + = 376.0

[0144] Step 6 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (82g) Using ammonium chloride instead of 1b in Example 1, intermediate 82g was obtained in the same manner as in Example 1. LCMS: [M+H] + =354.3.

[0145] Step 7 rel-tert-butyl((4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)sulfonyl)(methyl-d3)carbamate (82h) Compound 82f (70 mg, 0.20 mmol, 1.0 eq) was dissolved in dioxane (5 mL) and compound 82g (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 heated at 105 °C under nitrogen protection for 16 h. The reaction completion of the raw material was monitored by LCMS. The reaction mixture was concentrated, and the residue was purified on a silica gel column (petroleum ether / ethyl acetate = 5 / 1) to give 82h (65 mg, 52% yield) as a yellow oil. LCMS: [M+H] + = 627.2

[0146] Step 8 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(2-(N-(methyl-d3)aminosulfonyl)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Example 82) 82h (50 mg, 0.08 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL) and paratoluenesulfonic acid (13.72 mg, 0.08 mmol, 1.0 eq) was added. The reaction was allowed to proceed at 25° C. for 16 hours. Completion of the starting material was monitored by LCMS, and the reaction mixture was concentrated and the residue was purified by preparative separation (0.05% NH) to give Example 82 (10.0 mg, 24% yield) as an off-white solid. LCMS: [M+H] + = 527.1 1H NMR (400 MHz, CH3OD) δ 8.54 (d, J = 5.6 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 7.86 (dd, J = 5.6, 2.0 Hz, 1H), 7.14-7.09 (m, 1H), 7.02-6.94 (m, 1H), 5.08 (d, J = 10.4 Hz, 1H), 4.32 (dd, J = 10.4, 8.4 Hz, 1H), 3.99 (d, J = 2.4 Hz, 3H), 2.80 (p, J = 7.6 Hz, 1H), 1.65 (s, 3H), 0.83-0.79 (m, 3H).

[0147] Example 83 [ka] Step 1 tert-Butyl ((4-bromopyridin-2-yl)sulfonyl)(ethyl)carbamate (83a) Compound tert-butyl ((4-bromopyridin-2-yl)sulfonyl)carbamate 82e (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 ethyl iodide (101 mg, 0.65 mmol, 1.1 eq) were added. The reaction mixture was reacted at 60 °C for 2 hours. Completion of the reaction was monitored by LCMS. 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 using a silica gel column (petroleum ether / ethyl acetate = 10 / 1) to give compound tert-butyl ((4-bromopyridin-2-yl)sulfonyl)(ethyl)carbamate 83a (130 mg, 60% yield) as a yellow oil. LCMS: [M+Na] + = 387.0

[0148] Step 2 rel-tert-butyl((4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)sulfonyl)(ethyl)carbamate (83b) Compound 83a (130 mg, 0.35 mmol, 1.0 eq) was dissolved in dioxane (5 mL) and 82g (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 protection for 16 h. The reaction completion of the raw material was monitored by LCMS. The reaction mixture was concentrated, and the residue was purified on a silica gel column (petroleum ether / ethyl acetate = 4 / 1) to give 83b (100 mg, 44% yield) as a yellow oil. LCMS: [M+H] + = 638.2

[0149] Step 3 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(N-ethylaminosulfonyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Example 83) Compound 83b (100 mg, 0.16 mmol, 1.0 eq) was dissolved in hydrochloric acid / dioxane (4 M, 30 mL). The reaction mixture was allowed to react at 25° C. for 2 hours. Completion of the starting material was monitored by LCMS, and the reaction mixture was concentrated. The residue was purified by preparative separation (0.01% FA) to give Example 83 (39.5 mg, 47% yield) as a white solid. LCMS: [M+H] + = 538.1 1H NMR (400 MHz, DMSO) δ 10.88 (s, 1H), 8.59 (d, J = 5.2 Hz, 1H), 8.27 (d, J = 1.6 Hz, 1H), 7.91-7.75 (m, 2H), 7.18-7.15 (m, 2H), 5.13 (d, J = 10.0 Hz, 1H), 4.28-4.23 (m, 1H), 3.95 (d, J = 2.4 Hz, 3H), 2.97-2.86 (m, 2H), 2.80-2.75 (m, 1H), 1.61 (s, 3H), 0.97 (t, J = 7.2 Hz, 3H), 0.73 (d, J = 6.0 Hz, 3H).

[0150] Example 84 [ka] Step 1 4-Bromo-N-(2,2,2-trifluoroethyl)pyridine-2-sulfonamide (84b) Compound 2,2,2-trifluoroethan-1-amine (1.2 g, 11.7 mmol, 3.0 eq) was added to compound 4-bromopyridine-2-sulfonyl chloride 84a (1.0 g, 3.9 mmol, 1.0 eq). The reaction mixture was allowed to react at 25° C. for 1 hour. The reaction completion of the raw material was monitored by LCMS. The reaction mixture was concentrated, and the residue was purified on a silica gel column (petroleum ether / ethyl acetate=10 / 1) to give compound 4-bromo-N-(2,2,2-trifluoroethyl)pyridine-2-sulfonamide 84b (700 mg, 56% yield) as a white solid. LCMS: [M+H] + = 318.9

[0151] Step 2 tert-Butyl ((4-bromopyridin-2-yl)sulfonyl)(2,2,2-trifluoroethyl)carbamate (84c) Compound 4-bromo-N-(2,2,2-trifluoroethyl)pyridine-2-sulfonamide 84b (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 h. Completion of the reaction mixture was monitored by LCMS. The reaction mixture was concentrated, and the residue was purified on a silica gel column (petroleum ether / ethyl acetate = 10 / 1) to give compound tert-butyl ((4-bromopyridin-2-yl)sulfonyl)(2,2,2-trifluoroethyl)carbamate 84c (700 mg, 76% yield) as a yellow oil. LCMS: [M+Na] + = 441.0

[0152] Step 3 rel-tert-butyl((4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)sulfonyl)(2,2,2-trifluoroethyl)carbamate (84d) Compound 84c (100 mg, 0.24 mmol, 1.0 eq) was dissolved in dioxane (5 mL) and compound 82g (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 mmL, 0.1 eq) were added. The reaction mixture was reacted at 105 °C under nitrogen protection for 16 h. The reaction completion of the raw material was monitored by LCMS. The reaction mixture was concentrated, and the residue was purified on a silica gel column (dichloromethane / methanol = 10 / 1) to give compound 84d (80 mg, 48% yield) as a yellow oil. LCMS: [M+H] + = 692.1

[0153] Step 4 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(2-(N-(2,2,2-trifluoroethyl)aminosulfonyl)pyridin-4-yl)-5-trifluoromethyltetrahydrofuran-2-carboxamide (Example 84) Compound 84d (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. Completion of the starting material was monitored by LCMS, and the reaction mixture was concentrated. The residue was purified by preparative separation (0.1% FA) to give Example 84 (15.4 mg, 22% yield) as a white solid. LCMS: [M+H] + = 592.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.84 (t, J = 6.8 Hz, 1H), 8.59 (d, J = 5.2 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 7.87 - 7.84 (m, 1H), 7.20 - 7.14 (m, 2H), 5.13 (d, J = 10.4 Hz, 1H), 4.28 - 4.23 (m, 1H), 3.95 (d, J = 2.24Hz, 3H), 3.84 - 3.75 (m, 2H), 2.82 - 2.72 (m, 1H), 1.61 (s, 3H), 0.73 (d, J = 6.0 Hz, 3H).

[0154] Example 85 Synthesis of compound 85 [ka] Step 1 rel-(2R,3S)-3-(3,4-difluoro-2-methoxyphenyl)-4-methyl-5-(trifluoromethyl)-2,3-dihydrofuran-2-carboxamide (85a) Compound 59b (5 g, 13.6 mmol, 1.0 eq) was dissolved in ammonia / methanol (7 M, 15 mL). The reaction mixture was reacted at 80° C. for 16 hours. The reaction completion of the raw material was monitored by LCMS, and the reaction mixture was concentrated. The residue was purified on a silica gel column (dichloromethane / methanol = 20 / 1) to give compound 85a (3.8 g, 83% yield) as a white solid. LCMS: [M+H] + = 338.0

[0155] Step 2 rel-(1R,3R,4R,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-1-(trifluoromethyl)-6-(trimethylsilyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamide (85b) Compound 85a (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 and reacted at 25°C for 16 hours. The reaction mixture was concentrated, and the residue was purified by fractionation (0.01% FA / ACN = 1 / 1) to give compound 85b (600 mg, 23% yield) as a yellow oil. LCMS: [M+H] + = 438.2

[0156] Step 3 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxamide (85c) Compound 85b (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 / ACN=3 / 2) to give compound 85c (170 mg, 40% yield) as a yellow oil. LCMS: [M+H] + = 366.1

[0157] Step 4 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxylic acid (85d) Compound 85c (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 mixture was heated at 100°C for 4 hours. Completion of the reaction was monitored by LCMS. 1M diluted hydrochloric acid was added to the reaction mixture to adjust the pH to 5-6, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was collected and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 85d (100 mg, 70% yield) as a yellow oil. LCMS: [M+H] + = 367.1

[0158] Step 5 rel-(1R,3R,4S,5R)-N-(3-carbamoyl-4-fluorophenyl)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxamide (Example 85) Compound 85d (50 mg, 0.14 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), and compound 5-amino-2-fluorobenzamide (25 mg, 0.16 mmol, 1.2 eq), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (62 mg, 0.16 mmol, 1.2 eq), and N,N-diisopropylethylamine (21 mg, 0.16 mmol, 1.2 eq) were added. The reaction was stirred at 25°C for 2 hours. Completion of the reaction was monitored by LCMS. The reaction was concentrated to give a residue. The residue was purified by preparative separation (0.01% FA) to give Example 85 (7.5 mg, 9% yield) as a white solid. LCMS: [M+H] + = 503.1. 1H NMR (400 MHz, CD3OD) δ 7.91-7.89 (m, 1H), 7.72-7.67 (m, 1H), 7.11-7.06 (m, 1H), 7.03-6.95 (m, 1H), 6.93-6.84 (m, 1H), 4.96 (d, J = 7.6 Hz, 1H), 4.22 (d, J = 7.6 Hz, 1H), 3.88 (d, J = 2.0 Hz, 3H), 2.42-2.34 (m, 1H), 2.33-2.25 (m, 1H), 2.16-2.09 (m, 1H), 1.83-1.75 (m, 1H), 0.81 (d, J = 1.2 Hz, 3H).

[0159] Example 85 was separated by chiral SFC using a Daicel CHIRALPAK IH_3 column, 3.0*150 mm, 3 μm particle size, to give Example 85-1 (RT=1.4 min) and Example 85-2 (RT=2.0 min).

[0160] Example 86 rel-4-((1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-1-(trifluoromethyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamide)phthalamide (86) Prepared in a similar manner to step 5 of example 85 to give example 86. LCMS: [M+H] + = 528.1. 1 H NMR (400 MHz, MeOD) δ 7.89 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.05 (dd, J = 25.2, 18.0 Hz, 2H), 5.10 (d, J = 8.0 Hz, 1H), 4.36 (d, J = 8.0 Hz, 1H), 4.07-3.92 (m, 3H), 2.68 (s, 1H), 2.46-2.17 (m, 2H), 1.98-1.80 (m, 1H), 1.32 (s, 1H), 0.93 (s, 3H).

[0161] Example 87 [ka] Step 1 rel-(1R,3R,4S,5R)-2-(2-(3,4-dimethoxybenzyl)aminosulfonyl)pyridin-4-yl)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxamide (87a) Compound 85d (60 mg, 0.16 mmol, 1.0 eq) was dissolved in anhydrous pyridine (3 mL), and compound 4-amino-N,N-bis(3,4-dimethoxybenzyl)pyridine-2-sulfonamide 34e (78 mg, 0.16 mmol, 1.0 eq) and phosphorus oxychloride (100 mg, 0.66 mmol, 4.0 eq) were added. The reaction mixture was reacted at 0 °C for 1.5 hours. Completion of the reaction mixture was monitored by LCMS. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 87a (120 mg, 89% yield) as a yellow oil.

[0162] Step 2 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(2-aminosulfonylpyridin-4-yl)-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxamide (Example 87) Compound 87a (120 mg, 0.15 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) was added. The reaction mixture was allowed to react at 25° C. for 4 hours. Completion of the reaction mixture was monitored by LCMS, and the reaction mixture was concentrated. The residue was purified by preparative separation (0.05% FA) to give Example 87 (17.2 mg, 23% yield) as a white solid. LCMS: [M+H] + = 522.1. 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.59 (d, J = 5.6 Hz, 1H), 8.32 (d, J = 2.0 Hz, 1H), 7.90-7.88 (m, 1H), 7.44 (s, 2H), 7.23-7.15 (m, 1H), 7.12-7.07 (m, 1H), 5.16 (d, J = 8.0 Hz, 1H), 4.23 (d, J = 8.0 Hz, 1H), 3.93 (d, J = 2.0 Hz, 3H), 2.44-2.35 (m, 2H), 2.18-2.10 (m, 1H), 1.87-1.80 (m, 1H), 0.82 (s, 3H).

[0163] Example 88 Synthesis of compound 88 [ka] Step 1 Compound tert-butyl((4-bromopyridin-2-yl)sulfonyl)(methyl)carbamate (88a) Compound tert-butyl ((4-bromopyridin-2-yl)sulfonyl)carbamate 82e (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. Completion of the reaction was monitored by LCMS. 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 using a silica gel column (petroleum ether / ethyl acetate = 16 / 1) to give 88a (100 mg, 96% yield) as a white solid. LCMS: [M+Na] + = 373.0

[0164] Step 2 rel-tert-butyl((4-((1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-1-(trifluoromethyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamido)pyridin-2-yl)sulfonyl)(methyl)carbamate (88b) Compound 88a (53 mg, 0.15 mmol, 1.1 eq) was dissolved in dioxane (5 mL) and compound 85c (50 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 mmL, 0.1 eq) were added. The reaction mixture was reacted at 105 °C under nitrogen protection for 16 h. The reaction completion of the raw material was monitored by LCMS. The reaction mixture was concentrated, and the residue was purified on a silica gel column (dichloromethane / methanol = 10 / 1) to give compound 88b (70 mg, 80% yield) as a yellow oil. LCMS: [M+H] + = 636.2

[0165] Step 3 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(2-(N-methylaminosulfonyl)pyridin-4-yl)-1-(trifluoromethyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamide (Example 88) Compound 88b (70 mg, 0.11 mmol, 1.0 eq) was dissolved in hydrochloric acid / dioxane (4 M, 10 mL). The reaction mixture was allowed to react at 25° C. for 4 hours. Completion of the starting material was monitored by LCMS, and the reaction mixture was concentrated. The residue was purified by preparative separation (0.01% FA) to give Example 88 (4.2 mg, 7.1% yield) as a white solid. LCMS: [M+H] + = 536.1. 1H NMR (400 MHz, CD3OD) δ 8.54 (d, J = 5.6 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 7.81 (dd, J = 2.4, 2.0 Hz, 1H), 7.32-7.26 (m, 1H), 7.06-6.95 (m, 1H), 5.24 (d, J = 10.4 Hz, 1H), 3.92 (d, J = 1.6 Hz, 3H), 3.84 (d, J = 10.8 Hz, 1H), 2.63 (s, 3H), 2.58-2.51 (m, 1H), 2.48-2.39 (m, 1H), 2.15-2.08 (m, 1H), 1.49-1.48 (m, 1H), 1.29 (s, 3H).

[0166] Example 89 Synthesis of compound 89 [ka] Step 1 1-(4-Bromopyridin-2-yl)-2-fluoroethan-1-one (89b) Compound 1-(4-bromopyridin-2-yl)ethan-1-one 89a (300 mg, 1.50 mmol, 1.00 eq) was dissolved in toluene (3 mL) in a reaction flask, 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 mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated, and acetonitrile (3 mL) and a selective fluorine reagent (537 mg, 1.51 mmol, 1.01 eq) were added. The reaction mixture was stirred at 25 °C for 1 h. The reaction completion of the raw material was monitored by LCMS. The reaction mixture was concentrated, and the residue was purified on a silica gel column (petroleum ether / ethyl acetate = 50 / 1) to give compound 89b (176 mg, 54% yield) as a white solid. LCMS: [M+H] + = 218.0.

[0167] Step 2 1-(4-Bromopyridin-2-yl)-2-fluoroethan-1-ol (89c) Compound 89a (176 mg, 0.81 mmol, 1.00 eq) was dissolved in methanol (5 mL) in a reaction flask, and sodium borohydride (60 mg, 1.60 mmol, 1.98 eq) was added at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was monitored by LCMS for completion of the raw material. The reaction mixture was concentrated, and the residue was purified on a silica gel column (petroleum ether / ethyl acetate = 3 / 1) to give compound 89c (145 mg, 81% yield) as a yellow oil. LCMS: [M+H] + = 220.0.

[0168] Step 3 4-Bromo-2-(1-((tert-butyldimethylsilyl)oxy)-2-fluoroethyl)pyridine (89d) Compound 89c (130 mg, 0.59 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (5 mL) in a reaction flask, 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 mixture was stirred at 25 °C for 16 h. The reaction mixture was monitored for completion by LCMS. The reaction mixture was diluted with water (15 mL), extracted with ethyl acetate (10 mL x 3), 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 give compound 89d (173 mg, 87% yield) as a colorless oil. LCMS: [M+H] + = 334.0.

[0169] Step 4 rel-(1R,3R,4S,5R)-N-(2-(1-((tert-butyldimethylsilyl)oxy)-2-fluoroethyl)pyridin-4-yl)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-1-(trifluoromethyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamide (89e) Compound 89d (151 mg, 0.45 mmol, 1.5 eq) was dissolved in anhydrous 1,4-dioxane (5 mL) in a reaction flask, and cesium carbonate (196 mg, 0.60 mmol, 2.0 eq), 85c (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 heated at 105 °C for 16 h under a nitrogen atmosphere. The reaction completion of the raw material was monitored by LCMS. The reaction mixture was diluted with water (15 mL), extracted with ethyl acetate (10 mL x 3), 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 give compound 89e (193 mg, 98% yield) as a colorless oil. LCMS: [M+H] + = 619.3

[0170] Step 5 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-N-(2-(2-fluoro-1-hydroxyethyl)pyridin-4-yl)-5-methyl-1-(trifluoromethyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamide (Example 89) Compound 89e (193 mg, 0.31 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL) and a solution of tetrabutylammonium fluoride in tetrahydrofuran (0.4 mL) was added. The reaction mixture was allowed to react at 25° C. for 3 hours. The reaction completion of the raw material was monitored by LCMS. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL×3), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column (petroleum ether / ethyl acetate=1 / 1) and fractionated (0.1% FA) to give Example 89 (68.5 mg, 41.3% yield) as a white solid. LCMS: [M+H] + = 505.1. 1H NMR (400 MHz, DMSO-d6) δ 10.64 (d, J = 3.6 Hz, 1H), 8.39 (d, J = 5.6 Hz, 1H), 7.85 (t, J = 2.4 Hz, 1H), 7.61 (d, J = 5.6 Hz, 1H), 7.19 (dd, J = 16.8, 8.8 Hz, 1H), 7.12-7.06 (m, 1H), 5.95 (s, 1H), 5.11 (d, J = 8.4 Hz, 1H), 4.80 (d, J = 19.6 Hz, 1H), 4.66 (ddd, J = 47.6, 9.6, 2.8 Hz, 1H), 4.50 (ddd, J = 47.6, 9.2, 6.0 Hz, 1H), 4.23 (d, J = 8.4 Hz, 1H), 3.93 (d, J = 2.0 Hz, 3H), 2.46-2.35 (m, 2H), 2.21-2.13 (m, 1H), 1.87-1.78 (m, 1H), 0.81 (s, 3H).

[0171] Example 90 Synthesis of Compound 90 [ka] Step 1 tert-Butyl (S)-(4-bromopyridin-2-yl)methyl(tetrahydrofuran-3-yl)carbamate (90c) In a single-neck flask, 4-bromopicolinaldehyde 90a (100 mg, 0.54 mmol, 1.0 eq) was dissolved in 1,2-dichloroethane (5 mL), and (S)-tetrahydrofuran-3-amine 90b (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. Next, di-tert-butyl dicarbonate (176 mg, 0.81 mmol, 1.5 eq) was added to the reaction mixture. The reaction mixture was stirred at 25°C for 0.5 hours. The reaction completion of the raw material was monitored by LCMS, the reaction mixture was concentrated, and the residue was purified by silica gel column (petroleum ether / ethyl acetate=4 / 1) to give compound 90c (170 mg, 88% yield) as a yellow oil.

[0172] Step 2 rel-tert-butyl(4-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxamido)pyridin-2-yl)methyl((S)-tetrahydrofuran-3-yl)carbamate (90d) Compound 90c (65 mg, 0.18 mmol, 1.0 eq) was dissolved in anhydrous 1,4-dioxane (5 mL) in a single-neck flask, and cesium carbonate (107 mg, 0.33 mmol, 2.0 eq), compound 85c (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 reacted at 105°C for 16 hours under a nitrogen atmosphere. The reaction completion of the raw material was monitored by LCMS, and the reaction mixture was diluted with water (15 mL), extracted with ethyl acetate (10 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified on a silica gel column (petroleum ether / ethyl acetate = 20 / 1) to give compound 90d (30 mg, 29% yield) as a yellow oil.

[0173] Step 3 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(2-((S)-tetrahydrofuran-3-amino)methyl)pyridin-4-yl)-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxamide (Example 90) Compound 90d (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. Completion of the reaction mixture was monitored by LCMS, and the reaction mixture was concentrated. The residue was purified by preparative separation (0.1% FA) to give Example 90 (1.7 mg, 6% yield) as a white solid. LCMS: [M+H] + = 542.2. 1 H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.46 (d, J = 5.6 Hz, 1H), 7.59 (s, 1H), 7.52 (d, J = 4.8 Hz, 1H), 6.96 (d, J = 5.6 Hz, 2H), 6.93-6.87 (m, 1H), 5.02 (d, J = 6.4 Hz, 1H), 4.20 (s, 1H), 4.00 (d, J = 2.4 Hz, 3H), 3.96 (s, 2H), 3.86-3.72 (m, 4H), 3.55 (s, 1H), 2.59-2.52 (m, 1H), 2.25-2.14 (m, 3H), 1.91-1.90 (m, 1H), 0.90 (s, 3H).

[0174] Example 91 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-N-(2-methoxyethylamino)methylpyridin-4-yl)-5-methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxamide (91) Prepared in the same manner as in Example 90, using 2-methoxyethan-1-amine instead of 90b to give Example 91. LCMS: [M+H] + = 530.2.1 H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 7.57-7.53 (m, 2H), 6.97-6.86 (m, 2H), 5.01 (d, J = 6.8 Hz, 1H), 4.20 (s, 1H), 4.00 (s, 3H), 3.58 (t, J = 4.8 Hz, 2H), 3.38 (s, 3H), 2.95 (t, J = 4.8 Hz, 2H), 2.57-2.50 (m, 1H), 2.19-2.10 (m, 3H), 1.94-1.89 (m, 2H), 0.90 (s, 3H).

[0175] Example 92: [ka] Step 1 5-Bromo-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide (92b) 4-Bromo-2-fluorobenzenesulfonyl chloride 92a (200 mg, 1.0 eq) was dissolved in THF (5 mL), cooled to 0 °C, and under nitrogen protection, NaHMDS (0.9 mL, 1.0 M, 1.2 eq) was added dropwise. After 1 h, a solution of tert-butyl thiazol-4-ylcarbamate (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 * 3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, centrifuged, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 5-bromo-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide 92b (150 mg, 60% yield) as a white solid. LCMS: [M+H] + =336.8, 338.8.

[0176] Step 2 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-N-(4-fluoro-3-(N-(thiazol-4-yl)aminosulfonyl)phenyl)-5-methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxamide (Example 92) 85c (30 mg, 0.08 mmol, 1.0 eq) was dissolved in 1,4-dioxane (5 mL) and 92b (42 mg, 0.12 mmol, 1.5 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (9.5 mg, 0.016 mmol, 0.2 eq), cesium carbonate (80 mg, 0.25 mmol, 3 eq), and palladium acetate (1.8 mg, 0.008 mmol, 0.1 eq) were added. The mixture was stirred at 105 °C for 16 h. The filtrate was concentrated under reduced pressure and purified by preparative separation (0.1% FA) to give Example 92 (2.4 mg, 4% yield) as a white solid. LCMS: [M+H] + = 622.1. 1 HNMR (400MHz, MeOD) δ 8.53 (s, 1H), 8.01-8.00 (m, 1H), 7.74-7.72 (m, 1H), 7.10-7.06 (m, 1H), 6.99-6.96 (m, 1H), 6.92-6.86 (m, 1H), 6.67 (s, 1H), 4.95-4.93 (m, 1H), 4.21-4.19 (m, 1H), 3.87 (s, 3H), 2.41-2.22 (m, 2H), 2.14-2.07 (m, 1H), 1.81-1.74 (m, 1H), 0.80 (s, 3H).

[0177] Example 93 Synthesis of Compound 93 [ka] Step 1 Benzyl (2-(S-methylsulfonimidoyl)pyridin-4-yl)carbamate (93b) 93a (2.2 g, 8.0 mmol, 1.0 eq) was weighed into a reaction flask, and (diacetoxyiodo)benzene (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 h of reaction at room temperature, the reaction was confirmed to be complete by LCMS. The reaction solution was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 0-100%) to give 93b (2.3 g, 94% yield) as a yellow solid. LCMS: [M+H] + = 306.4.

[0178] Step 2 (4-Aminopyridin-2-yl)(imino)(methyl)-1-6-sulfonic acid ketone (93c) Compound 93b (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 gas at 25° C. for 16 hours. Completion of the reaction was monitored by LCMS. The reaction mixture was filtered, and the filtrate was collected and concentrated to give a residue. The residue was purified on a silica gel column (dichloromethane / methanol=10 / 1) to give compound 93c (100 mg, 59% yield) as a white solid. LCMS: [M+H] + = 172.1.

[0179] Step 3 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-1-(trifluoromethyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamide (Example 93) Compound 85d (50 mg, 0.14 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), and compound 93c (28 mg, 0.16 mmol, 1.2 eq), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (62 mg, 0.16 mmol, 1.2 eq), and N,N-diisopropylethylamine (35 mg, 0.27 mmol, 2.0 eq) were added. The reaction was stirred at 25°C for 2 hours. Completion of the reaction was monitored by LCMS. The reaction was concentrated to give a residue. The residue was purified by preparative separation (0.01% FA) to give Example 93 (8.2 mg, 11.6% yield) as a white solid. LCMS: [M+H] + = 520.1. 1 H NMR (400 MHz, CD3OD) δ 8.06 (d, J = 5.6 Hz, 1H), 7.33 (s, 1H), 7.01-6.96 (m, 2H), 6.71-6.68 (m, 1H), 4.92 (d, J = 5.6 Hz, 1H), 4.88-4.84 (m, 3H), 4.19 (s, 1H), 3.95-3.93 (m, 3H), 2.45-2.18 (m, 2H), 2.18-1.97 (m, 1H), 1.79-1.73 (m, 1H), 0.85 (d, J = 5.2 Hz, 3H).

[0180] Example 94 Synthesis of compound 94 [ka] Step 1 Benzyl (2-(N,S-dimethylsulfonimidoyl)pyridin-4-yl)carbamate (94a) Compound 93b (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 mixture was reacted at 25°C for 16 hours. Completion of the reaction was monitored by LCMS. The reaction mixture was concentrated to give a residue. The residue was purified on a silica gel column (dichloromethane / methanol = 30 / 1) to give compound 94a (300 mg, 95% yield) as a colorless oil. LCMS: [M+H] + = 320.1.

[0181] Step 2 (4-Aminopyridin-2-yl)(methyl)(methylimino)-1-6-sulfonic acid ketone (94b) Compound 94a (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 under hydrogen gas at 25° C. for 16 hours. Completion of the reaction was monitored by LCMS. The reaction mixture was filtered, and the filtrate was collected and concentrated to give a residue. The residue was purified on a silica gel column (dichloromethane / methanol=10 / 1) to give compound 94b (150 mg, 86% yield) as a white solid. LCMS: [M+H] + = 186.1.

[0182] Step 3 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-N-(2-(N,S-dimethylsulfonyl)pyridin-4-yl)-5-methyl-1-(trifluoromethyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamide (Example 94) Compound 85d (50 mg, 0.14 mmol, 1.0 eq) was dissolved in anhydrous pyridine (3 mL), and compound 94b (30 mg, 0.16 mmol, 1.2 eq) was added. After homogeneous mixing, phosphorus oxychloride (84 mg, 0.55 mmol, 4.0 eq) was added at 0°C. The reaction mixture was stirred at 0°C for 15 min. Completion of the reaction was monitored by LCMS. The reaction mixture was poured into water, extracted with ethyl acetate, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and concentrated to give the residue. The residue was purified by preparative separation (0.01% FA) to give Example 94 (14.2 mg, 16% yield) as a white solid. LCMS: [M+H] + = 534.0. 1 H NMR (400 MHz, CD3OD) δ 8.62 (d, J = 5.2 Hz, 1H), 8.48 (t, J = 1.6 Hz, 1H), 7.95 (dd, J = 2.0, 2.0 Hz, 1H), 7.11-7.04 (m, 1H), 7.02-6.95 (m, 1H), 5.11 (d, J = 8.0 Hz, 1H), 4.34 (d, J = 7.6 Hz, 1H), 3.98 (t, J = 2.4 Hz, 3H), 3.22 (s, 3H), 2.57 (s, 3H), 2.52-2.45 (m, 1H), 2.39-2.31 (m, 1H), 2.22-2.17 (m, 1H), 1.93-1.84 (m, 1H), 0.90 (d, J = 1.2H, 3H).

[0183] Example 95 Synthesis of Compound 95 [ka] Step 1 R-4-Bromo-2-(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridine (95c) 4-Bromo-2-fluoropyridine 95a (1.0 g, 5.7 mmol, 1.0 eq) and R-2,2-dimethyl-1,3-dioxolane-4-methanol 95b (0.9 g, 6.8 mmol, 1.2 eq) were dissolved in HCl / 1,4-dioxane (10 mL), and potassium tert-butoxide (1.9 g, 17.1 mmol, 0.1 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.4 g, 0.5 mmol, 0.1 eq), and palladium acetate (0.13 g, 0.5 mmol, 0.1 eq) were added. The reaction mixture was stirred at 105 °C for 16 h. The reaction completion of the raw material was monitored by LCMS. The reaction mixture was quenched by adding 1M dilute hydrochloric acid (4 mL), extracted with dichloromethane (10 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 95c (0.5 g, 30% yield) as a white solid. LCMS: [M+H] + = 288.0

[0184] Step 2 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-N-(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin-4-yl)-5-methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxamide (95d) 85c (500 mg, 1.37 mmol, 1.0 eq) was dissolved in 1,4-dioxane, and (R)-4-bromo-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridine 96b (592 mg, 2.0 mmol, 1.5 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (158 mg, 0.27 mmol, 0.2 eq), cesium carbonate (1.3 g, 4.1 mmol, 3.0 eq), and palladium acetate (31 mg, 0.14 mmol, 0.1 eq) were added. The reaction was stirred under nitrogen at 105 °C for 16 h. After completion of the reaction, the mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ethyl acetate:petroleum ether=1:3) to give compound 95d (100 mg, 30% yield) as a yellow solid. LCMS: [M+H]+ = 573.2.

[0185] Step 3 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-N-(2-(S)-2,3-dihydroxypropoxypyridin-4-yl)-5-methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxamide (Example 95) A mixture of 95d (100 mg, 0.17 mmol, 1.0 eq) was stirred at 25° C. for 1 hour. LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure. The compound was purified by preparative (0.1% FA) to give Example 95 (23.4 mg, 25% yield) as a white solid. LCMS: [M+H] + = 533.2. 1 HNMR (400MHz, DMSO-d6) δ 10.52 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.22-7.17 (m, 3H), 7.10-7.06 (m, 1H), 5.10 (d, J = 8.0 Hz, 1H), 4.88 (d, J = 8.0 Hz, 1H), 4.61 (t, J = 8.0 Hz, 1H), 4.25-4.21 (m, 2H), 4.12-4.08 (m, 1H), 3.93 (d, J = 4.0 Hz, 3H), 3.77-3.73 (m, 1H), 3.41 (t, J = 4.0 Hz, 2H), 2.45-2.36 (m, 1H), 2.32-2.29 (m, 1H), 2.19-2.12 (m, 1H), 1.86-1.79 (m, 1H), 0.81 (s, 3H).

[0186] Example 96 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-N-(2-(R)-2,3-dihydroxypropoxypyridin-4-yl)-5-methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxamide (96) Example 96 was prepared in the same manner as in Example 95, except that S-2,2-dimethyl-1,3-dioxolane-4-methanol was used instead of 95b. LCMS: [M+H] + = 533.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.02 (d, J = 5.7 Hz, 1H), 7.24-7.15 (m, 3H), 7.12- 7.06 (m, 1H), 5.11 (d, J = 8.0 Hz, 1H), 4.23 (dd, J = 9.7, 4.5 Hz, 2H), 4.10 (dd, J = 10.9, 6.3 Hz, 1H), 3.93 (d, J = 2.2 Hz, 3H), 3.77-3.59 (m, 5H), 2.43-2.29 (m, 2H), 2.20-2.11 (m, 1H), 1.83 (td, J = 10.7, 7.0 Hz, 1H), 0.81 (s, 3H).

[0187] Example 97 5-((1S,3R,4S,5S)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-1-(trifluoromethyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamido)picolinamide (97) Example 97 was prepared in a similar manner, using 5-aminopicolinamide instead of 5-amino-2-fluorobenzamide in Example 85. LCMS: [M+H] + = 486.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.87 (d, J = 2.0 Hz, 1H), 8.25 (dd, J = 8.6, 2.5 Hz, 1H), 8.01 (d, J = 8.6 Hz, 2H), 7.55 (s, 1H), 7.22-7.07 (m, 2H), 5.16 (d, J = 8.1 Hz, 1H), 4.25 (d, J = 8.1 Hz, 1H), 3.92 (dd, J = 8.0, 2.1 Hz, 4H), 2.20-1.81 (m, 2H), 0.82 (s, 4H).

[0188] Example 98 Synthesis of compound 98 [ka] Step 1 2-Bromo-1-(5-bromopyridin-2-yl)ethan-1-one (98b) 1-(5-Bromopyridin-2-yl)ethanone 98a (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. 30% hydrobromic acid in acetic acid (2.8 mL) was added, and bromine (1.6 g, 0.01 mmol, 1.0 eq) was added dropwise in acetic acid (5 mL). The reaction mixture was allowed to warm to room temperature, then heated to 70 °C and stirred for 1 h. LCMS analysis indicated the reaction was complete. The mixture was concentrated under reduced pressure, and the residue was crystallized from isopropanol to give 98b (1.0 g, 32% yield) as a yellow solid. LCMS: [M+H] + = 278.9.

[0189] Step 2 1-(5-Bromopyridin-2-yl)ethane-1,2-diol (98c) A solution of 2-bromo-1-(5-bromopyridin-2-yl)ethanone 98b (1.0 g, 3.6 mmol, 1.0 eq) and sodium formate (1.0 g, 14.4 mmol, 4.0 eq) in ethanol (10 mL) was heated to 50 °C and reacted for 3 h. After completion of the reaction, the mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The mixture was quenched with water (10 mL) and extracted with dichloromethane (50 mL × 3). The combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was taken up in methanol (10 mL) and cooled to 0 °C. Sodium borohydride (0.4 g, 10.8 mmol, 3.0 eq) was added in several portions, and the mixture was stirred at 0 °C for 1 h. The pH was adjusted to 2 with concentrated hydrochloric acid, the solvent was removed under reduced pressure, and the mixture was extracted three times with dichloromethane (50 mL) and saturated aqueous sodium bicarbonate (10 mL). The combined organic phase was dried over sodium sulfate. The residue was purified on a silica gel column (petroleum ether / ethyl acetate = 4 / 1) to give compound 98c (350 mg, 42% yield) as a yellow solid. LCMS: [M+H] + = 218.0.

[0190] Step 3 5-Bromo-2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine (98d) 1-(5-Bromopyridin-2-yl)ethane-1,2-diol 98c (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 paratoluenesulfonic acid (7.9 mg, 0.05 mmol, 0.1 eq) were added. The mixture was stirred at 25 °C for 24 h. LCMS analysis showed the reaction was complete. The mixture was quenched with water (50 mL) and then extracted with dichloromethane (50 mL × 3). The combined organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by eluting with ethyl acetate in petroleum ether from 0 to 50% to give a yellow oil, 5-bromo-2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine 98d (60 mg, 48% yield). LCMS: [M+H] += 258.0.

[0191] Step 4 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-N-(6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-5-methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxamide (98e) 85c (50 mg, 0.14 mmol, 1.0 eq) was dissolved in 1,4-dioxane (5 mL), and 5-bromo-2-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine (53 mg, 0.21 mmol, 1.5 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (16 mg, 0.027 mmol, 0.2 eq), cesium carbonate (134 mg, 0.41 mmol, 3.0 eq), and palladium acetate (3.1 mg, 0.014 mmol, 0.1 eq) were added. The mixture was stirred at 105 °C for 16 h. After the reaction was complete, the mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL × 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 98e (50 mg, 67% yield) as a yellow oil. LCMS: [M+H] + = 543.2.

[0192] Step 5 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-N-(6-(1,2-dihydroxyethyl)pyridin-3-yl)-5-methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxamide (Example 98) 98e (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 h. The mixture was concentrated under reduced pressure. Example 98 (4.2 mg, 9% yield) was obtained as a white solid by fractionation (0.1% NH). LCMS: [M+H] + = 503.2.1 H NMR(400MHz,CD3OD) δ 9.15(s, 1H), 8.49-8.47 (m, 1H), 7.89-7.87 (m, 1H), 7.12-7.07 (m, 1H), 7.03-6.96 (m, 1H), 5.15-5.14 (m, 1H), 4.95-4.93 (m, 1H), 4.34-4.31 (m, 1H), 3.98-3.97 (m, 3H), 3.84-3.76 (m, 2H), 2.54-2.46 (m, 1H), 2.40-2.33 (m, 1H), 2.25-2.17 (m, 1H), 1.93-1.86 (m, 1H), 0.91 (s, 3H).

[0193] Example 99 Synthesis of Compound 99 Prepared in a similar manner using 5-amino-N,N-bis(3,4-dimethoxybenzyl)pyridine-2-sulfonamide instead of 34e in example 87 to give example 99. LCMS: [M+H] + = 522.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.93 (d, J = 2.4 Hz, 1H), 8.31 (dd, J = 8.4, 2.4 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.40 (s, 2H), 7.23-7.16 (m, 1H), 7.13-7.09 (m, 1H), 5.17 (d, J = 8.0 Hz, 1H), 4.25 (d, J = 8.0 Hz, 1H), 3.93 (d, J = 2.4 Hz, 3H), 2.43-2.36 (m, 2H), 2.19-2.13 (m, 1H), 1.87-1.80 (m, 1H), 0.83 (s, 3H).

[0194] Example 100 Synthesis of Compound 100 [ka] Step 1 tert-Butyl 4-(5-bromopyridin-2-yl)-3-oxopiperidine-1-carboxylate (100b) 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 and stirred for 30 min. 2-Fluoro-5-bromopyridine 100a (1.0 g, 5.68 mmol, 1.0 eq) was added, and the mixture was heated to 60 °C and stirred for 16 h. Water was added, and the mixture was extracted with ethyl acetate (50 mL * 3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, centrifuged, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give tert-butyl 4-(5-bromopyridin-2-yl)-3-oxopiperidine-1-carboxylate 100b (560 mg, 27.7% yield) as a white solid. LCMS: [M+H]+ = 355.9, 357.9.

[0195] Step 2 rel-tert-butyl 4-(4-((1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-1-(trifluoromethyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamido)pyridin-2-yl)-3-oxopiperazine-1-carboxylate (100c) Compound 85c (50 mg, 0.14 mmol, 1.0 eq) was dissolved in dioxane (5 mL) and 100b (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) were added. The reaction mixture was stirred at 105 °C for 16 h under a nitrogen atmosphere. The reaction mixture was monitored for completion by LCMS. The reaction mixture was concentrated, and the residue was purified on a silica gel column (petroleum ether / ethyl acetate = 10 / 1) to give compound 100c (50 mg, 57% yield) as a colorless oil.

[0196] Step 3 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(2-(2-oxopiperazin-1-yl)pyridin-4-yl)-1-(trifluoromethyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamide (100d) Compound 100c (50 mg, 0.078 mmol, 1.0 eq) was dissolved in trifluoroacetic acid (5 mL), and the reaction mixture was allowed to react for 2 hours at 25° C. Completion of the reaction of the raw materials was monitored by LCMS, and the reaction mixture was concentrated to give compound 100d (40 mg, 95% yield) as a white solid.

[0197] Step 4 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(2-(4-methyl-2-oxopiperazin-1-yl)pyridin-4-yl)-1-(trifluoromethyl)-2-oxabicyclo[3.2.0]heptane-3-carboxamide (Example 100) Compound 100d (40 mg, 0.07 mmol, 1.0 eq) and paraformaldehyde (4 mg, 0.14 mmol, 2.0 eq) were dissolved in methanol (5 mL) and the reaction mixture was incubated at 25° C. for 30 minutes. Sodium cyanoborohydride (8 mg, 0.14 mmol, 2.0 eq) was added and the reaction mixture was incubated at 40° C. for 1 hour. The reaction completion of the raw material was monitored by LCMS. The reaction mixture was concentrated, and the residue was purified by preparative separation (0.1% FA) to give Example 100 (6.7 mg, 13% yield) as a white solid. LCMS: [M+H] + = 555.2. 1H NMR (400 MHz, MeOD) δ 8.33 (d, J = 5.6 Hz, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.64 (dd, J = 5.6, 2.0 Hz, 1H), 7.16-6.90 (m, 2H), 5.07 (d, J = 8.0 Hz, 1H), 4.33 (d, J = 8.0 Hz, 1H), 4.00-3.86 (m, 5H), 3.28 (s, 2H), 2.92-2.80 (m, 2H), 2.50-2.43 (m, 1H), 2.40 (s, 3H), 2.35-2.17 (m, 2H), 1.87 (td, J = 10.8, 6.4 Hz, 1H), 0.90 (s, 3H).

[0198] Example 101 Synthesis of Compound 101 [ka] Step 1 2-(Methylthio)pyridin-4-amine (101b) Methyl mercaptan sodium (1.9 g, 27.0 mmol, 1.7 eq) was dissolved in 1-methylpyrrolidone (10 mL) and 2-chloropyridin-4-amine 101a (2.0 g, 16.0 mmol, 1.0 eq) was added. The vessel was sealed and heated to 200 °C in a microwave oven for 15 min. Purification by silica gel high-performance chromatography eluting with 8% methanol / dichloromethane gave 2-(methylthio)pyridin-4-amine 101b (1.5 g, 55% yield) as a yellow solid. LCMS: [M+H] + = 141.0.

[0199] Step 2 2-(Methylsulfonyl)pyridin-4-amine (101c) 2-(Methylthio)pyridin-4-amine (100 mg, 0.7 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL) and metachloroperbenzoic 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 give a mixture. The mixture was purified by column chromatography (dichloromethane / methanol=10 / 1) to give 2-(methylsulfonyl)pyridin-4-amine 101c (30 mg, 22% yield) as a yellow solid. LCMS: [M+H] + = 173.0.

[0200] Step 3 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(2-methylsulfonyl)pyridin-4-yl)-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxamide (Example 101) 2-Methylsulfonylpyridin-4-amine 101c (14 mg, 0.082 mmol, 1.5 eq) was dissolved in anhydrous pyridine (5 mL), and 4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxylic acid 85d (20 mg, 0.055 mmol, 1.0 eq) and phosphorus oxychloride (25 mg, 0.16 mmol, 2.9 eq) were added. The mixture was stirred at 25 °C for 5 min. The filtrate was concentrated under reduced pressure. Purification by preparative filtration (0.1% NH3) gave compound 101 (3.4 mg, 9% yield) as a white solid. LCMS: [M+H] + = 521.1. 1H NMR (400 MHz, CD3OD) δ 8.62 (s, 1H), 8.48 (s, 1H), 8.01-7.99 (m, 1H), 7.10-7.06 (m, 1H), 7.03-6.96 (m, 1H), 5.13-5.11 (m, 1H), 4.34 (d, J = 6.4 Hz, 1H), 3.98 (d, J = 2.0 Hz, 3H), 3.21 (s, 3H), 2.51-2.45 (m, 1H), 2.38-2.31 (m, 1H), 2.23-2.17 (m, 1H), 2.03-2.00 (m, 1H), 1.93-1.85 (m, 1H), 0.91-0.88(m, 3H).

[0201] Example 102 Synthesis of Compound 102 [ka] Step 1 (4-aminopyridin-2-yl)dimethylphosphine oxide (102b) 2-Bromopyridin-4-amine 102a (200 mg, 1.16 mmol, 1.0 eq) was dissolved in 1,4-dioxane (3 mL) and 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 to a microwave tube. The reaction mixture was microwaved at 130 °C under a nitrogen atmosphere for 2 hours. The reaction completion of the raw material was monitored by LCMS, the reaction solution was concentrated, and the residue was purified by silica gel column (petroleum ether / ethyl acetate=8 / 1) to obtain a yellow solid, compound (4-aminopyridin-2-yl)dimethylphosphine oxide 102b (150 mg, 76% yield).

[0202] Step 2 rel-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-N-(2-(dimethylphosphoryl)pyridin-4-yl)-5-methyl-1-trifluoromethyl-2-oxabicyclo[3.2.0]heptane-3-carboxamide (102) 85d (50 mg, 0.14 mmol, 1.0 eq) was dissolved in anhydrous pyridine (3 mL), and compound (4-aminopyridin-2-yl)dimethylphosphine oxide 102b (23 mg, 0.14 mmol, 1.0 eq) and phosphorus oxychloride (84 mg, 0.55 mmol, 4.0 eq) were added. The reaction mixture was allowed to react at 0 °C for 1 hour. Completion of the reaction mixture was monitored by LCMS. The reaction mixture was diluted with water (10 mL) and 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 preparative separation (0.05% FA) to give compound 102 (15.8 mg, 22% yield) as a white solid. LCMS: [M+H] + = 519.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.63 (d, J = 5.6 Hz, 1H), 8.28 (dd, J = 6.8, 2.0 Hz, 1H), 7.85-7.82 (m, 1H), 7.23-7.16 (m, 1H), 7.13-7.07 (m, 1H), 5.13 (d, J = 8.0 Hz, 1H), 4.23 (d, J = 8.0 Hz, 1H), 3.93 (d, J = 2.0 Hz, 3H), 2.44-2.35 (m, 2H), 2.19-2.12 (m, 1H), 1.87-1.80 (m, 1H), 1.64 (s, 3H), 1.60 (s, 3H), 0.82 (s, 3H).

[0203] Example 103 Synthesis of Compound 103 [ka] Step 1 2-Amino-5-nitrobenzenesulfonamide (103b) A reaction flask was charged with 103a (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 h, and TLC monitored for essentially complete conversion of the starting material. The reaction mixture was cooled to room temperature and poured into water, resulting in the precipitation of a solid. The mixture was suction filtered, and the filter cake was washed with water and dried to give compound 103b (1.3 g, 71% yield) as a pale yellow solid. LCMS: 218.1 [M+H] + .

[0204] Step 2 7-Nitro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (103c) A reaction flask was charged with 103b (600 mg, 2.76 mmol, 1.0 eq) and trimethyl orthoformate (10 mL), and the mixture was stirred at 140° C. for 8 hours. Essentially complete conversion of the starting material was monitored by TLC. The reaction mixture was cooled to room temperature and poured into water, resulting in the precipitation of a solid. The mixture was suction filtered, and the filter cake was washed with water and dried to give compound 103c (230 mg, 37% yield) as a pale solid. LCMS: 228.1 [M+H] + .

[0205] Step 3 7-Amino-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (103d) A reaction flask was charged with 103c (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) and stirred at 75 °C for 2 h. LCMS indicated essentially complete conversion of the starting material. The reaction mixture was filtered hot through diatomaceous earth with suction, and the filtrate was concentrated and purified by column chromatography (MeOH / DCM, 0-10%) to give compound 103d (82 mg, 47% yield) as a pale yellow solid. LCMS: 198.2 [M+H] + .

[0206] Step 4 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1,1-dihydroxy-4H-benzo[e][1,2,4]thiadiazin-7-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Example 103) A reaction flask was charged with 1a (144 mg, 0.406 mmol, 1.0 eq), acetonitrile (3 mL), NMI (167 mg, 2.03 mmol, 5.0 eq), and TCFH (228 mg, 0.812 mmol, 2.0 eq) and stirred for 5 min. Then, 103d (80 mg, 0.406 mmol, 1.0 eq) was added and stirred at 60 °C for 12 h. The reaction mixture was monitored by LCMS for essentially complete conversion of the starting material. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (MeOH / DCM, 0-10%) to give Example 103 (63 mg, 29% yield) as a white solid. LCMS: 534.4 [M+H] + . 1H NMR (400 MHz, dmso-d6) δ 12.28 (s, 1H), 10.54 (s, 1H), 8.22 (d, J = 2.2 Hz, 1H), 7.93 (d, J = 2.3 Hz, 1H), 7.82 (dd, J = 9.0, 2.3 Hz, 1H), 7.30 (d, J = 9.0 Hz, 1H), 7.24 - 7.07 (m, 2H), 5.07 (d, J = 10.3 Hz, 1H), 4.25 (dd, J = 10.2, 7.7 Hz, 1H), 3.95 (d, J = 1.9 Hz, 3H), 2.85 - 2.70 (m, 1H), 1.61 (s, 3H), 0.72 (d, J = 6.2 Hz, 3H).

[0207] Example 104 Synthesis of Compound 104 [ka] Step 1 5-Nitro-1,3-dioxoisoindoline-2-iracetate (104b) In a single-neck flask, 2-hydroxy-5-nitroisoindoline-1,3-dione 104a (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 h. Completion of the reaction was monitored by LCMS. The reaction mixture was concentrated, and the residue was purified on a silica gel column (petroleum ether / ethyl acetate = 4 / 1) to give 104b (300 mg, 83% yield) as a white solid.

[0208] Step 2 5-Amino-1,3-dioxoisoindoline-2-iracetate (104c) In a single-neck flask, compound 104b (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 allowed to react at 0 °C for 20 min. After the reaction was completed by LCMS, ethyl acetate (20 mL) and water (20 mL) were added sequentially. 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 give compound 104c (80 mg, 30% yield) as a yellow oil.

[0209] Step 3 rel-5-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-trifluoromethyltetrahydrofuran-2-carboxamido)-1,3-dioxoisoindoline-2-acetate (104d) Compound 1a (100 mg, 0.28 mmol, 1.0 eq) was dissolved in anhydrous pyridine (3 mL), and compound 104c (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 allowed to react at 0 °C for 1 hour. The reaction completion of the raw material was monitored by LCMS. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), washed with saturated brine, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 104d (100 mg, 64% yield) as a white solid.

[0210] Step 4 rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-hydroxy-1,3-dioxoisoindolin-5-yl)-4,5-dimethyl-5-trifluoromethyltetrahydrofuran-2-carboxamide (Example 104) Compound 104d (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. Completion of the reaction mixture was monitored by LCMS, and the reaction mixture was concentrated. The residue was purified by preparative separation (0.1% FA) to give Example 104 (28.2 mg, 29% yield) as a white solid. LCMS: [MH] - = 513.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.14 (d, J = 1.6 Hz, 1H), 7.94 (dd, J = 8.0, 2.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.21-7.14 (m, 2H), 5.12 (d, J = 10.0 Hz, 1H), 4.29-4.25 (m, 1H), 3.95 (d, J = 2.0 Hz, 3H), 2.82-2.74 (m, 1H), 1.61 (s, 3H), 0.74 (d, J = 5.6 Hz, 3H). [Table 1] JPEG2025529931000057.jpg218169 JPEG2025529931000058.jpg219169 JPEG2025529931000059.jpg218169 JPEG2025529931000060.jpg221169 JPEG2025529931000061.jpg222169 JPEG2025529931000062.jpg220169 JPEG2025529931000063.jpg222169

[0211] Biological activity test 1: In vitro inhibitory effect of compounds on Nav1.8 For HEK293 cells stably expressing human Nav1.8, manual patch clamp was used. After the Nav1.8 current stabilized, the magnitude of the Nav1.8 current before and after compound administration was compared to determine the effect of the compound on the Nav1.8 channel.

[0212] Test compounds were dissolved in DMSO to prepare a 9 mM stock solution and then added to the extracellular solution at the desired concentration on the day of testing. The extracellular solution contained NaCl (137 mM), KCl (4 mM), CaCl (1.8 mM), MgCl (1 mM), HEPES (10 mM), and glucose (10 mM), with a pH of 7.4 (NaOH titration). All reagents were purchased from Sigma (St. Louis, MO).

[0213] Cells were clamped at -80 mV and depolarized to 10 mV with a 10 ms-duration square wave to acquire Nav1.8 currents, which were repeated every 5 seconds. The maximum current induced by the square wave was detected, and after the maximum current stabilized, test compounds (dissolved in extracellular solution at the desired concentration) were perfused. After stabilization, the blocking strength of the compounds against Nav1.8 was calculated based on the current before and after compound perfusion. pCLAMP 10 (Molecular Devices, Union City, CA) was used. Current stabilization refers to a limited range of change in current over time. [Table 2]

[0214] The inhibition rate / % of Nav1.8 at a concentration of 100 nM of other compounds of the present invention was measured by the same method, which showed that the compounds of the present invention have excellent sodium channel modulating activity (≧50%) and can be used to treat diseases related to sodium channel modulation.

[0215] Biological activity test 2: In vitro inhibitory activity of compounds against Nav1.8 (IC) 50 Measurement of Experiments and detection were 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.

[0216] Before patch clamp detection, cells were detached with 0.25% Trypsin-EDTA and 6.5 × 10 3 The cells were seeded onto cover glasses and cultured in 24-well plates (final volume: 500 μL). After 18 hours, experiments and detection were performed.

[0217] For electrophysiological recording, the extracellular solution was 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, and 1.25 mM NaH₂PO₄·2H₂O, adjusted to pH 7.4 with NaOH. The intracellular solution was Nav-001-2, 50 mM CsCl, 10 mM NaCl, 10 mM HEPES, 60 mM CsF, and 20 mM EGTA, adjusted to pH 7.2 with CsOH. The storage life of the extracellular solution was 2 weeks. After preparation, the intracellular solution was frozen and stored in a -20°C refrigerator in 1 mL aliquots per tube. Freshly thawed intracellular solution was used for each experiment. All intracellular solutions were to be used up within 3 months. If the use period exceeded 3 months, the old intracellular solutions were discarded and freshly prepared.

[0218] Patch clamp detection: The whole-cell patch clamp voltage stimulation protocol for recording Nav1.8 sodium currents was as follows: Once a whole-cell seal was formed, the cell voltage was clamped at -120 mV and held for 30 ms. The clamp voltage was depolarized to 0 mV and held for 50 ms, then returned to -50 mV (see the half-inactivation voltage for IV testing) and held for 5 s. Next, the cell membrane potential was returned to -120 mV and held for 20 ms, then depolarized to 0 mV and held for 50 ms. Finally, the clamp voltage was returned to -120 mV and held for 30 ms. Data were collected repeatedly every 20 ms. The effects of drugs on the peak sodium current were observed. Experimental data were collected using an EPC 10 amplifier (HEKA) and stored in the software PatchMaster (HEKA).

[0219] A glass capillary tube was drawn onto the recording electrode using a microelectrode drawing device. The electrode, filled with intracellular fluid, was attached to the electrode holder, and the microelectrode manipulator was used under an inverted microscope to immerse the electrode in the extracellular fluid, and the electrode resistance (Rpip) was recorded. The electrode was then brought into contact with the cell surface, and a high-resistance seal (GΩ) was formed by applying negative pressure and suction. Fast capacitance compensation was then performed, and the cell membrane was disrupted by suction while the negative pressure was maintained, forming a whole-cell recording mode. Experimental parameters such as membrane capacitance (Cm) and series resistance (Rs) were then recorded using slow capacitance compensation. No leakage compensation was performed.

[0220] Administration began after the Nav1.8 currents recorded from all cells stabilized. Each drug concentration was applied for 5 min (or until the current stabilized) before the next concentration was detected. Multiple concentrations were detected for each test compound. The cell-seeded coverslip was placed in a recording chamber under an inverted microscope, and blank control external solution and test compound working solution were perfused into the recording chamber by gravity perfusion, from low to high concentrations. Fluid exchange was performed using a peristaltic pump during recording. Currents detected in each cell in compound-free external solution served as its own control. Each concentration was measured independently three times using at least three cells. All electrophysiological experiments were performed at room temperature.

[0221] Data analysis: First, the current after each drug concentration was normalized to the blank control current.

number

number

[0222] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)) The IC of each compound in the above equation 50 Calculate IC values ​​and nonlinearly fit the dose-dependent effect, where IC 50 is the half-inhibitory concentration. IC 50 The calculation and curve fitting were completed by the software GraphPad Prism. [Table 3]

[0223] The inhibitory activity of other compounds of the present invention against Nav1.8 was measured by the same method, and it was shown that the compounds of the present invention have good inhibitory activity against Nav1.8.

[0224] Biological activity test 3: Beneficial effects of compounds on a mouse incision pain model Establishment of the model: Under isoflurane anesthesia and standard disinfection, a 0.5 cm longitudinal skin incision was made on the plantar surface of the left hind paw, approximately 0.2 cm distal to the tibiotalar joint, toward the toes. The plantaris muscle was isolated, slightly elevated, and then incised longitudinally, taking care not to disrupt the muscle's origin or insertion. The incision was then sutured horizontally with 5-0 nylon thread (two stitches).

[0225] Solvent: The solvent used for the test compounds was 5% DMSO + 10% Solutol + 85% Saline, and the solvent used for the positive compound TRV-130 was 10% ethanol + 10% cremophor + 80% water.

[0226] Control compound 1 is compound 7 in WO2021113627A1, and was synthesized with reference to the method of WO2021113627A1.

[0227] Administration method and frequency: The positive control compound TRV-130 was administered intravenously once daily, while the other groups were administered orally once daily.

[0228] Experimental grouping: After eliminating abnormal animals based on baseline PWT values ​​before modeling, eight animals were randomly selected for the sham surgery group, and eight animals per treatment group were surgically modeled, with the remaining animals designated as reserve animals. After surgery, the animals were regrouped according to their pre-treatment pain threshold (PWT). If an animal's PWT value was abnormal after surgery, an animal from the reserve animals was randomly selected for remodeling.

[0229] Measurement of mechanical pain threshold: Before modeling, the mechanical pain threshold was measured before modeling, and 2.5 hours after modeling, the mechanical pain threshold was measured before administration. After the measurements were completed, the drug was orally administered, and the mechanical pain threshold was measured 2 hours after administration. The measurement site was inside the surgical incision, and for each animal, measurements were taken three times at intervals of 3 to 5 minutes, and the average value was calculated.

[0230] Data analysis: Relevant data were compiled using Office Excel 2013 and GraphPad Prism 6.0, and the data were presented as mean ± SEM (standard error). One-way ANOVA was used for analysis, and Tukey's analysis method was used to test the significance of differences between groups. When comparing two groups, a two-sided t-test was performed for the two groups, and if p<0.05, there was a significant difference between the two groups. If there was a large difference in the small number of detected data within a group, GraphPad Prism 9.0 was used to perform identify outliers data analysis, and the difference value (Q=5%) could be excluded. During data statistics, for animals excluded from the efficacy experiment, all data related to that animal were excluded from the statistical analysis. [Table 4]

[0231] The experiments showed that the compounds of the present invention had higher pain thresholds (PWT) than the control compound 1 at different doses (8 mg / kg, 25 mg / kg, 75 mg / kg), and could effectively suppress pain.

Claims

1. Compounds of Formula I 【Chemical 1】 (In the formula, R ａ１ , R ａ２ , R ａ３ are each independently hydrogen, halogen, hydroxyl, C １ -C ５ Alkyl, C １ -C ５ Alkoxy, C ３ -C ６ Cycloalkyl, C ３ -C ６ Cycloalkoxy, —N(R ｃ３ R ｃ４ ) ｍ or any two adjacent R ａ１ , R ａ２ , R ａ３ are linked to form a 5- to 7-membered ring, which may be a saturated or unsaturated carbocyclic or heterocyclic ring, and which may optionally contain one or more N, O, S(=O) ｍ containing heteroatoms, R ｂ１ , R ｂ２ , R ｂ３ , R ｂ４ are each independently hydrogen, halogen, hydroxyl, C １ -C ５ Alkyl, C １ -C ５ alkoxy, or R ｂ１ , R ｂ２ , R ｂ３ , R ｂ４ any two of these are linked to form a 3- to 7-membered ring, M １ , M ２ are independently C, O, S(=O) ｍ , N-R ｎ is selected from the group consisting of ｎ is hydrogen, C １ -C ５ optionally selected from alkyl, Ring A is A1 or A2, 【Chemistry 2】 【Chemistry 3】 optionally represents a single or double bond, X １ , X ２ , X ３ , X ４ , X ５ are each independently a bond, C, N, O, C=O, or S(=O) ｍ is selected from Y １ , Y ２ may be the same or different and may be arbitrarily selected from C atoms or N atoms, R ｃ１ , R ｃ２ are each independently hydrogen, halogen, cyano, hydroxyl, amino, C １ -C ５ Alkyl, C １ -C ５ 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) ２ NR ｃ３ R ｃ４ , -C １ -C ５ Alkyl NR ｃ３ R ｃ４ , -S(=O)(=NR ｃ３ ) R ｃ４ is selected from R ｃ３ , R ｃ４ are each independently hydrogen, hydroxyl, amino, C １ -C ５ Alkyl, C １ -C ５ alkoxy, 3- to 7-membered ring, or R ｃ３ , R ｃ４ are linked to form a 3- to 7-membered ring, m and n are optionally 0, 1, or 2; The alkyl, alkoxy, cycloalkyl, cycloalkoxy, 5- to 7-membered ring, 3- to 7-membered ring may optionally contain one or more of deuterium, halogen, hydroxyl, cyano, oxo, C １ -C ５ Alkyl, C １ -C ５ may be substituted with alkoxy or amino) or a pharmaceutically acceptable salt or stereoisomer thereof.

2. R ａ１ , R ａ２ , R ａ３ 2. The compound of formula I according to claim 1, wherein each independently is selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, difluoromethoxy, amino.

3. Any two adjacent R ａ１ , R ａ２ , R ａ３ The compound of formula I according to claim 1, wherein: are linked to form a 5- or 6-membered carbocyclic or heterocyclic ring.

4. R ｂ１ , R ｂ２ , R ｂ３ , R ｂ４ 2. The compound of formula I according to claim 1, wherein each is independently selected from hydrogen, methyl, trifluoromethyl, ethyl, methoxy, and ethoxy.

5. R ｂ１ , R ｂ２ , R ｂ３ , R ｂ４ 2. The compound of formula I according to claim 1, wherein any two of:

6. 2. The compound of formula I of claim 1, wherein ring A has the structure: 【Chemistry 4】

7. The compound of formula I of claim 1, wherein said formula I has the structure shown in formula IA or formula IB: 【Chemistry 5】

8. 10. A compound of formula I according to claim 1 or 7, having the structure: 【Chemistry 6】 【change】 【change】 【change】 【change】 【change】 【change】 【change】

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

10. 10. Use of the pharmaceutical composition of claim 9 or the compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof of claim 1 in the preparation of a medicament for treating, preventing or alleviating a voltage-gated sodium channel-associated disease.

11. 11. The use according to claim 10, wherein the disease is pain, multiple sclerosis, peroneal muscular atrophy, incontinence, pathological cough, or arrhythmia.

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