Sodium channel modulator

Abstract

Provided in the present invention are a compound as represented by formula I which can be used as a sodium channel modulator, and a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. Further provided are a pharmaceutical composition containing the compound and the stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a carrier or an excipient, and the pharmaceutical use thereof as an NaV1.8 inhibitor (against, for example, pain, respiratory diseases, neurological disorders, and mental diseases).

Description

Sodium channel modulators Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a sodium channel modulator for inhibiting the Nav1.8 target and its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof and the use of such modulators to inhibit voltage-gated sodium channels, especially Nav1.8 channels. Background Technology

[0002] Pain is "an unpleasant sensory and emotional experience accompanied by actual or potential tissue damage; it is a subjective feeling." Pain can serve as a warning signal, alerting the body to potential dangers and playing an indispensable protective role in normal bodily functions. At the same time, pain is also a common clinical symptom; after the external stimulus that triggered the pain disappears, intense or persistent pain can cause physiological dysfunction and seriously affect the quality of life of living individuals.

[0003] Pain originates from nociceptors in the peripheral nervous system. These are free nerve endings, widely distributed throughout the skin, muscles, joints, and internal organs. They convert perceived thermal, mechanical, or chemical stimuli into nerve impulses (action potentials), which are transmitted via afferent nerve fibers to the cell body of the dorsal root ganglion (DRG), ultimately reaching higher nerve centers and causing pain. The generation and conduction of action potentials in neurons depend on voltage-gated sodium channels (NaV) on the cell membrane. When the cell membrane depolarizes, sodium channels are activated, opening and causing an influx of sodium ions, further depolarizing the cell membrane and leading to the generation of action potentials. Therefore, inhibiting abnormal sodium channel activity can help treat and alleviate pain.

[0004] NaVs mediate the rapid rise of action potentials in many excitable cell types, such as neurons, skeletal muscle cells, and cardiomyocytes, and thus participate in the initiation of signal transduction in these cells. Voltage-gated sodium channels (NaVs) are logical targets for pain management given their important role in neuronal transmission in sensory neurons (Ruiz et al., 2015). In general, there are nine known subtypes of voltage-gated sodium channels (NaVs) that form the major pore-forming α subunit. Nav1.1, Nav1.2, and Nav1.3 are primarily expressed in the central nervous system (CNS), while Nav1.4 and Nav1.5 are abundant in skeletal and cardiac muscle. Nav1.6 has been shown to be expressed in both the peripheral nervous system (PNS) and the CNS, while Nav1.7, Nav1.8, and Nav1.9 are generally considered to be confined to the PNS (Yu and Catterall, 2003). Non-selective sodium channel inhibitors are available as antiarrhythmics, anticonvulsants, and local anesthetics, but none are suitable for the general treatment of chronic pain. The Nav channel family is highly homologous, and obtaining selective drug-like ligands is a significant challenge. However, the identification of selective inhibitors of specific isotypes holds promise for many disorders.

[0005] Because both Nav1.7 and Nav1.8 isoforms are present on pain receptors in the PNS, they have attracted considerable attention as targets for pain treatment (Jukic et al., 2014). Given the extensive human genome validation of Nav1.7 (Bennett and Woods, 2014) and the discovery of a class of selective inhibitors (McCormack et al., 2013), significant efforts have been made targeting this pathway (Vetter et al., 2017). However, disappointing human clinical trials of several selective Nav1.7 inhibitors (Donnell et al., 2018; Zakrzewska et al., 2017) have led to the proposal of Nav1.8 as an alternative target (Han et al., 2016).

[0006] The pore-forming α subunit of the Nav1.8 sodium channel is encoded by the SCN10A gene and is primarily (but not exclusively) expressed in dorsal root ganglion (DRG) neurons, as well as in trigeminal and nodal ganglion neurons (Akopian et al., 1996; Shields et al., 2012). These neurons mediate most of the inward sodium currents during the depolarization phase of the neuronal action potential, which is crucial for action potential transmission and repetitive firing (Akopian et al., 1999). Rodent SCN10A gene knockout and knock-down studies indicate that Nav1.8 is involved in inflammatory and neuropathic pain (Dong et al., 2007). Heterozygous gain-of-function mutations in SCN10A result in aberrant firing of DRG neurons and are associated with small fiber neuropathy of pain in humans, further linking Nav1.8 to the function of pain-sensory neurons (Faber et al., 2012).

[0007] Furthermore, because Nav1.8 expression is limited to peripheral neurons, particularly those that sense pain (e.g., dorsal root ganglia), Nav1.8 inhibitors are less likely to be associated with the common side effects of other sodium channel modulators and do not produce the abuse tendencies seen in opioid therapy. Therefore, targeting the underlying biology of pain through selective Nav1.8 inhibition represents a novel approach to analgesic drug development with the potential to address the urgent unmet need for safe and effective treatment of acute and chronic pain.

[0008] The inventors have discovered that some voltage-gated sodium channel inhibitors have limitations as therapeutic agents, such as due to therapeutic window defects (e.g., due to lack of NaV isoselectivity, low potency, and / or other reasons). Therefore, there remains a need in the art to develop novel Nav1.8 selective inhibitors, preferably Nav channel inhibitors with stronger Nav1.8 inhibitory activity, better selectivity, higher efficacy, better metabolic absorption, better pharmacokinetics, stronger analgesic activity, and fewer side effects. Summary of the Invention

[0009] Invention Overview

[0010] The present invention aims to propose a Nav1.8 inhibitor with stronger inhibitory activity, which can be used to prepare drugs for treating, relieving or preventing pain, including neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, visceral pain, cancer pain, etc.

[0011] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0012] On the one hand, the present invention provides a compound as shown in Formula I, its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof.

[0013] in,

[0014] X is selected from O or S;

[0015] Ring Q is phenyl or a 5-6 membered heteroaryl group;

[0016] Each R A They may be the same or different, and each is independently selected from H, deuterium, halogen, -CN, -OH, nitro, -(CH2)n-NR7R8, -CONR m R n The following groups are used: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, deuterated C1-C6 alkyl, C1-C6 hydroxyalkyl, carboxyl, -(CH2)n-6-10 aryl, -(CH2)n-3-8 heterocyclic, wherein the -(CH2)n-NR7R8, carboxyl, -(CH2)n-6-10 aryl, and -(CH2)n-3-8 heterocyclic groups may optionally be substituted with one or more halogens, CN, -C1-C6 alkyl-CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, -OH, C1-C6 hydroxyalkyl, -(CH2)n-NR7R8, C1-C6 alkoxy, oxo, and -COOR9;

[0017] r and n are independently selected from 0, 1, 2, 3, 4, and 5, respectively;

[0018] R7, R8, and R9 are each independently selected from the following groups: non-existent, H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkyl-substituted C1-C6 hydroxyalkyl, -(CH2)n-6-10 aryl, and -(CH2)n-3-8 heterocyclic groups. The C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 alkyl-substituted C1-C6 hydroxyalkyl groups are also selected from the following groups. The alkyl, -(CH2)n-6-10 aryl, and -(CH2)n-3-8 heterocyclic groups may be optionally substituted with one or more halogens, CN, -C1-C6 alkyl-CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, -OH, C1-C6 hydroxyalkyl, -(CH2)n-NR7R8, C1-C6 alkoxy, oxo, -NR7R8, and -COOR9.

[0019] Alternatively, R7 and R8 may form a 3-8 membered heterocyclic group with the nitrogen atom attached to them, wherein the 3-8 membered heterocyclic group may be optionally substituted with one or more halogens, CN, -C1-C6 alkyl-CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, -OH, C1-C6 hydroxyalkyl, C1-C6 alkoxy, oxo, amino, C1-C6 alkylamino, or -COOR9;

[0020] R m and R n Each is independently selected from non-existent, H, C1-C6 alkyl, C1-C6 haloalkyl, or R. m and R n Together with the N atom they belong to, they form 4-6 membered heterocyclic groups;

[0021] A is selected from N and CR1;

[0022] B is selected from N and CR2;

[0023] U is selected from N and CR3;

[0024] Y is selected from N and CR4;

[0025] Z is selected from N and CR5;

[0026] A, B, U, Y, and Z are not all N at the same time;

[0027] R1, R2, R3, R4, and R5 may be the same or different, and are independently selected from H, deuterium, halogen, hydroxyl, cyano, amino, amide, nitro, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclic, and aryl. The C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclic, and aryl groups may be optionally surrounded by one or more R groups. 02 replace;

[0028] Each R 02 They may be the same or different, and each is independently selected from deuterium, halogen, hydroxyl, cyano, oxo, amino, amide, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl substitutions;

[0029] R a R bThe same or different, and each independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, cyano, amino, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C1-C6 hydroxyalkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclic, 3- to 10-membered cycloalkyloxy, and 3- to 10-membered heterocyclic oxy; wherein the 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclic, 3- to 10-membered cycloalkyloxy, and 3- to 10-membered heterocyclic oxy are optionally surrounded by one or more R 01 replace;

[0030] The condition is R a R b They are not both hydrogen;

[0031] R c R d The same or different, and each independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, cyano, amino, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C1-C6 hydroxyalkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclic, 3- to 10-membered cycloalkyloxy, and 3- to 10-membered heterocyclic oxy; wherein the 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclic, 3- to 10-membered cycloalkyloxy, and 3- to 10-membered heterocyclic oxy are optionally surrounded by one or more R 01 replace;

[0032] Or, R a R b Together with the carbon atom attached to it, it forms a cycloalkyl or heterocyclic group; or, R c R d Together with the carbon atom attached thereto, they form a cycloalkyl or heterocyclic group; wherein each of the cycloalkyl or heterocyclic groups is independently and optionally surrounded by one or more R atoms. 01 replace;

[0033] Each R 01 They may be the same or different, and each is independently selected from deuterium, halogen, hydroxyl, cyano, oxo, amino, amide, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0034] As a preferred technical solution, the compound and its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof described in this invention are compounds represented by general formula II:

[0035] The groups are as defined above.

[0036] As a preferred technical solution, ring Q is selected from...

[0037] in End and of End connection.

[0038] As a preferred technical solution, R A Selected from H, methyl, trifluoromethyl, amino, cyano, methoxy, ethylamino, carboxyl, chlorine, hydroxyl, formamide,

[0039] As a preferred technical solution, R1 is selected from C1-C6 alkoxy groups.

[0040] As a more preferred technical solution, R1 is a methoxy group.

[0041] As a preferred technical solution, R2 is selected from halogens.

[0042] As a more preferred technical solution, R2 is fluorine.

[0043] As a preferred technical solution, R3 is selected from halogens.

[0044] As a more preferred technical solution, R3 is fluorine.

[0045] As a preferred technical solution, R a Selected from C1-C6 alkyl groups, and R b For H.

[0046] As a more preferred technical solution, R a It is methyl, and R b For H.

[0047] As a preferred technical solution, R c Selected from halogenated C1-C6 alkyl groups.

[0048] As a more preferred technical solution, R c It is trifluoromethyl.

[0049] As a preferred technical solution, R d Selected from C1-C6 alkyl groups.

[0050] As a more preferred technical solution, R d It is a methyl group.

[0051] The present invention also provides the following compounds, stereoisomers, tautomers, or pharmaceutically acceptable salts thereof:

[0052] The present invention also provides compounds represented by the following formulas, their stereoisomers, tautomers, or pharmaceutically acceptable salts thereof.

[0053] X is selected from O or S; ring Q is phenyl or 5-6 membered heteroaryl; other groups are defined as described in any of the preceding items.

[0054] The present invention also provides compounds as shown in formulas II-1 and II-2, their stereoisomers, tautomers, or pharmaceutically acceptable salts thereof.

[0055] Ring Q is phenyl or a 5-6 membered heteroaryl group; other groups are defined as described in any of the preceding items.

[0056] The present invention also provides compounds as shown below, their stereoisomers, tautomers, or pharmaceutically acceptable salts thereof.

[0057] The present invention also provides a method for preparing a compound as shown in Formula II, characterized by comprising the following steps:

[0058] In a solvent, compound i-1 and compound i-2 undergo a condensation reaction to obtain compound II-1. Compound II-1 is then subjected to a cyclization reaction in a solvent to obtain the compound shown in formula II, with each group defined as described in any of the preceding items.

[0059] The present invention also provides a pharmaceutical composition comprising any of the compounds described above and their stereoisomers, tautomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0060] The present invention also provides the use of compounds of any one of the above claims, stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof in the preparation of medicaments for inhibiting diseases or conditions associated with voltage-gated sodium channels, wherein the voltage-gated sodium channels are preferably Nav1.8 channels.

[0061] The present invention also provides the use of any of the compounds described above, their stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof in the preparation of medicaments for treating and / or reducing symptoms of conditions, diseases, or disorders associated with increased Nav1.8 activity or expression.

[0062] As a preferred technical solution, the condition, disease, or disorder associated with increased Nav1.8 activity or expression is preferably selected from: pain, respiratory diseases, neurological disorders, and mental illnesses, and combinations thereof.

[0063] As a preferred technical solution, the pain is preferably from the following categories: neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, idiopathic pain, traumatic pain, surgical pain, postoperative surgical pain, childbirth pain, labor pain, neurogenic bladder disorder, ulcerative colitis, intestinal pain, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, toothache, peripheral nerve injury, and combinations thereof.

[0064] As a preferred technical solution, the musculoskeletal pain is selected from osteoarthritis pain.

[0065] As a preferred technical solution, the acute pain is selected from acute postoperative pain.

[0066] As a preferred technical solution, the neuropathic pain is selected from postherpetic neuralgia, small fiber neuropathy, idiopathic small fiber neuropathy, diabetic neuropathy, and diabetic peripheral neuropathy.

[0067] As a preferred technical solution, the postoperative pain is preferably one or more of the following: pain from bunion removal surgery, pain from abdominoplasty, or pain from hernia repair surgery.

[0068] The inventors discovered that these compounds are highly effective Nav1.8 inhibitors with extremely strong Nav1.8 inhibitory activity, better selectivity, superior pharmacokinetic exposure, exceptionally significant analgesic effect, longer duration of analgesia, and better oral absorption. They can be used to prepare for the prevention and / or treatment of indications related to Nav1.8 inhibition, including and / or reduction of conditions, diseases, or disorders associated with increased Nav1.8 activity or expression, such as: neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, idiopathic pain, traumatic pain, surgical pain, postoperative pain, labor pain, labor pain, neurogenic bladder disorder, ulcerative colitis, enteropathic pain, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, toothache, peripheral nerve injury, and combinations thereof.

[0069] This invention was made based on the above findings.

[0070] Invention Details

[0071] The various aspects and features of the present invention will be further described below.

[0072] Since the compounds according to the present invention can exist in stereoisomeric forms, the present invention includes all stereoisomeric forms.

[0073] The compounds of this invention have an asymmetric center. Compounds containing asymmetric substitution atoms in this invention can be isolated into optically active or racemic forms. Those skilled in the art know how to prepare the optically active forms, for example, through racemic resolution or synthesis from optically active starting materials. Unless otherwise specified, this invention includes all chiral, diastereomers, and racemates. Methods for preparing the compounds of this invention and their intermediates are part of this invention. All stereoisomers and tautomers of the compounds of this invention are also part of this invention.

[0074] The term “optional” or “optionally” means that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation.

[0075] "alkyl" refers to a group having 1 to 10 carbon atoms, either straight-chain or branched, saturated hydrocarbon groups ("C1-C10 alkyl"). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C1-C8 alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C1-C6 alkyl"), 1 to 5 carbon atoms ("C1-C5 alkyl"), 1 to 4 carbon atoms ("C1-C4 alkyl"), 1 to 3 carbon atoms ("C1-C3 alkyl"), 1 to 2 carbon atoms ("C1-C2 alkyl"), or 1 carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C2-C6 alkyl"). Examples of C1-C6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Each alkyl group may be optionally substituted independently, i.e., unsubstituted (“unsubstituted alkyl”) or substituted with one or more substituents; for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or substituted with 1 substituent (“substituted alkyl”).

[0076] The term "alkenyl" refers to a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms connected to the rest of the molecule by single bonds, such as, but not limited to, vinyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl, etc.

[0077] The term "alkynyl" refers to a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms connected to the rest of the molecule by single bonds, such as, but not limited to, ethynyl, propynyl, butynyl, pent-1-en-4-ynyl, etc.

[0078] As described herein, the terms “halogen,” “halogenated,” “halogenated,” etc., refer to fluorine, chlorine, bromine, or iodine, particularly fluorine, chlorine, and bromine, with fluorine and chlorine being especially preferred.

[0079] "Haloalkyl" refers to an alkyl group as described herein (e.g., C1-C6 alkyl) in which one or more hydrogen atoms are replaced by a halogen (e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloro-fluoroalkyl, chloro-difluoroalkyl, and 2-fluoroisobutyl. "Cyclopropylmethylene" refers to a methylene terminus with other structures attached.

[0080] "Alkoxy" refers to an alkyl group (e.g., C1-C6 alkyl) as described herein, which is attached to the molecule by an oxygen atom. This includes portions in which the alkyl moiety can be straight-chain or branched, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and n-hexoxy.

[0081] "Cycloalkyl" is a monocyclic saturated cycloalkyl group having 3 to 10 ring carbon atoms ("C3-10 cycloalkyl" or "C3-C10 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C3-8 cycloalkyl" or "C3-C8 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C3-6 cycloalkyl" or "C3-C6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms ("C5-6 cycloalkyl" or "C5-C6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms ("C5-10 cycloalkyl" or "C5-C10 cycloalkyl"). Examples of C5-C6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-C6 cycloalkyl groups include the aforementioned C5-C6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-C8 cycloalkyl groups include the aforementioned C3-C6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each example of a cycloalkyl group is independently either unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”).

[0082] "Heterocyclic alkyl" refers to a group in which one or more C atoms in the above "cycloalkyl" are replaced by heteroatoms such as N, O, S, and P.

[0083] The term "alkylamino" refers to an amino-NRdRe with an alkyl-NH2 structure or a substituted amino-NRdRe, wherein Rd and Re are each independently hydrogen or an alkyl group as described above. For example, the term "monoalkylamino" refers to a substituted amino-NRdRe, wherein one of Rd and Re is hydrogen and the other is an alkyl group as described above; "dialkylamino" refers to a substituted amino-NRdRe, wherein Rd and Re are each independently an alkyl group as described above.

[0084] The term "haloalkylamino" refers to an amino-NRdRe with an alkyl-NH2 structure or a substituted amino-NRdRe, wherein Rd and Re are each independently hydrogen or a haloalkyl group as described above. For example, the term "monohaloalkylamino" refers to a substituted amino-NRdRe, wherein one of Rd and Re is hydrogen and the other is a haloalkyl group as described above; "dihaloalkylamino" refers to a substituted amino-NRdRe, wherein Rd and Re are each independently a haloalkyl group as described above.

[0085] The term "heterocyclic group" refers to a stable 3- to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen, and sulfur. Unless otherwise specified in this specification, the heterocyclic group can be a monocyclic, bicyclic, tricyclic, or more ring system, which may include fused ring systems, bridged ring systems, or spirocyclic systems; the nitrogen, carbon, or sulfur atoms in the heterocyclic group may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclic group may be partially or fully saturated. The heterocyclic group may be connected to the remainder of the molecule via a carbon atom or a heteroatom through a single bond. In heterocyclic groups containing fused rings, one or more rings may be aryl or heteroaryl as defined below, provided that the connection point with the remainder of the molecule is a non-aromatic ring atom. For the purposes of this invention, the heterocyclic group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged, or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged, or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of heterocyclic groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]nonane-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptane-2-yl, azacyclic butyl, pyranyl, tetrahydropyranyl, thiaranyl, tetrahydrofuranyl, oxazinyl, dioxocyclopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, quinazinyl, thiazoalkyl, etc. Heterocyclic groups in this document include the heterocyclic alkyl groups described above.

[0086] The term "aryl" refers to a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms (preferably 6 to 10 carbon atoms). For the purposes of this invention, the aryl group can be a monocyclic, bicyclic, tricyclic, or more cyclic system, and can be fused with cycloalkyl or heterocyclic groups as defined above, provided that the aryl group is connected to the rest of the molecule via single bonds through atoms on the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, etc.

[0087] The term "heteroaryl" refers to a 5- to 16-membered conjugated cyclic group having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically indicated in this specification, a heteroaryl group can be a monocyclic, bicyclic, tricyclic, or more cyclic system, and can be fused with cycloalkyl or heterocyclic groups as defined above, provided that the heteroaryl group is connected to the remainder of the molecule via single bonds through atoms on the aromatic ring. The nitrogen, carbon, or sulfur atom in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. For the purposes of this invention, the heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur, more preferably a stable 5- to 10-membered aromatic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, but are not limited to, those described above. Thiophene, furan ring, etc.

[0088] Unless otherwise stated, when referring to a specifically named aryl (e.g., phenyl), heterocyclic (e.g., pyrrolyl, piperidinyl, and morpholinyl), or heteroaryl (e.g., tetrazolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, and furanyl), the reference is intended to include a ring having, where appropriate, 0 to 3, preferably 0 to 2, substituents selected from the substituents listed above for aryl heterocyclic and / or heteroaryl groups.

[0089] The term "one or more" (e.g., in the definition of substituents in the general formula compounds of the present invention) means "one, two, three or four, especially one, two, three or four, more especially one, two or three, and even more especially one or two".

[0090] As described herein, the term "pharmaceutically acceptable salt" means that the salt is not only physiologically acceptable to the subject, but can also refer to a synthetic substance with pharmaceutical value, such as a salt formed as an intermediate during chiral resolution. Although such intermediate salts cannot be directly administered to the subject, they can play a role in obtaining the end product of this invention. Specifically, this includes acid (organic and inorganic acid) addition salts or base addition salts (including organic and inorganic bases).

[0091] "Pharmaceutically acceptable carriers" include, but are not limited to, any adjuvant, carrier, excipient, flow aid, sweetener, diluent, preservative, dye / coloring agent, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that is permitted by the relevant government regulatory authority to be acceptable for human or animal use.

[0092] As described herein, the term "disease" refers to a physical condition of the subject that is related to the disease described in this invention. Examples include peripheral arterial diseases and neurodegenerative diseases described in this invention.

[0093] The term "pain" refers to acute and chronic pain, malignant chronic bone pain, rheumatoid arthritis, osteoarthritis, spinal stenosis, neuropathic low back pain, myofascial pain syndrome, fibromyalgia, temporomandibular joint pain, chronic visceral pain, abdominal pain, pancreatic pain, IBS pain, chronic and acute headaches, migraines, tension headaches, cluster headaches, chronic and acute neuropathic pain, postherpetic neuralgia, diabetic neuropathy, HIV-related neuropathy, trigeminal neuralgia, Charcot-Mali-Tuss neuropathy, and hereditary sensory nerve pain. Diseases, peripheral nerve injury, painful neuroma, ectopic proximal and distal discharges, radiculopathy, chemotherapy-induced neuropathic pain, radiotherapy-induced neuropathic pain, persistent / chronic postoperative pain (e.g., after amputation, thoracotomy, or cardiac surgery), post-mastectomy pain, central pain, spinal cord injury pain, post-stroke pain, thalamic pain, phantom pain (e.g., after amputation of the lower limb, upper limb, or breast), intractable pain, acute pain, acute postoperative pain, acute musculoskeletal pain, arthralgia, mechanical low back pain, neck pain, Tendinitis, injury pain, exercise pain, acute visceral pain, pyelonephritis, appendicitis, cholecystitis, intestinal obstruction, hernia, chest pain, heart pain, pelvic pain, renal colic, acute obstetric pain, labor pain, cesarean section pain, acute inflammatory pain, burn pain, traumatic pain, acute intermittent pain, endometriosis, acute herpes zoster pain, sickle cell anemia, acute pancreatitis, breakthrough pain, orofacial pain, sinusitis pain, dental pain, multiple sclerosis (MS) pain, depression pain, leprosy pain, Behcet's disease. Pain, painful lipopathy, venous pain, Guillain-Barré pain, leg and toe movement pain, Hagland syndrome, erythromelalgia, Fabry disease pain, bladder and genitourinary disorders, urinary incontinence, pathological cough, overactive bladder, bladder pain syndrome, interstitial cystitis (IC), prostatitis, complex regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II, generalized pain, paroxysmal extreme pain, pruritus, tinnitus, or pain caused by angina.

[0094] The pharmaceutically acceptable compositions of the present invention can be administered orally, rectally, parenterally, intracerebrospinally, vaginally, intraperitoneally, topically (e.g., by powder, ointment, or drops), sublingually, or as oral or nasal sprays to humans and other animals, depending on the severity of the condition being treated. In some embodiments, the compounds, salts, and compositions of the present invention can be administered orally or parenterally at dose levels of about 0.001 mg / kg to about 1000 mg / kg, once or more daily, to effectively achieve the desired therapeutic effect.

[0095] Dosage forms can be liquid, solid, or semi-solid. Liquid dosage forms can include solutions (including true solutions and colloidal solutions), emulsions (including o / w, w / o, and double emulsions), suspensions, injections (including aqueous injections, powder injections, and infusions), eye drops, nasal drops, lotions, and liniments, etc.; solid dosage forms can include tablets (including regular tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, and orally disintegrating tablets), capsules (including hard capsules, soft capsules, and enteric-coated capsules), granules, powders, microcapsules, pellets, suppositories, films, patches, aerosols, and sprays, etc.; semi-solid dosage forms can include ointments, gels, and pastes, etc.

[0096] To achieve the purpose of medication and enhance the therapeutic effect, the drug or drug composition of the present invention can be administered using any known method of administration.

[0097] The compounds or compositions of the present invention can be taken alone or in combination with other therapeutic or symptomatic drugs. When the compounds of the present invention have a synergistic effect with other therapeutic drugs, their dosage should be adjusted according to the actual situation.

[0098] Beneficial technical effects

[0099] The inventors discovered that the compounds of this invention exhibit inhibitory activity against human Nav1.8 ion channels in CHO cells comparable to or better than the positive control; they demonstrate better selectivity for Nav subtype ion channels; they are well absorbed orally in rats, with 24-hour in vivo exposure levels significantly superior to the positive control compound; and their analgesic effect and duration of analgesia are comparable to or better than VX-548. This invention provides a class of Nav1.8 inhibitor compounds with novel structures, high activity, good selectivity, superior pharmacokinetic exposure, better analgesic effect, longer duration of analgesia, and fewer side effects. These compounds show promising applications in the prevention and / or treatment of Nav1.8 inhibition-related indications such as pain, respiratory diseases, neurological disorders, and mental illnesses. Detailed Implementation

[0100] The following examples are intended to help those skilled in the art better understand the technical solutions of the present invention, but the scope of protection of the present invention includes, but is not limited to, these examples.

[0101] For all the following embodiments, standard operations and methods known to those skilled in the art were used. Unless otherwise stated, all temperatures are expressed in °C (degrees Celsius). The structures of the compounds were determined by nuclear magnetic resonance spectroscopy (NMR) and / or mass spectrometry (MS).

[0102] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are expressed in parts per million (ppm). NMR was determined using a Brukeravance-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents and tetramethylsilane (TMS) as an internal standard.

[0103] Liquid chromatography-mass spectrometry (LC-MS) was performed using an ACQUITY UPLC ultra-high pressure liquid chromatograph for the liquid phase and a Xevo G2-SQtof mass spectrometer for the mass spectrometry phase.

[0104] The starting materials used in the examples of this invention are known and commercially available, and can also be synthesized using or according to methods known in the art.

[0105] Example 1: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one (Compound 1)

[0106] Step 1: Synthesis of (2R,3S,4S,5R)-N-(4-amino-2-oxo-1,2-dihydropyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0107] 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-benzo[d]imidazolium-6-carboxylic acid (21.24 mg, 0.06 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (34 mg, 0.09 mmol, 1.5 eq) and N,N-diisopropylethylamine (39 mg, 0.3 mmol, 5.0 eq) were added. The mixture was reacted at room temperature for 10 minutes, and then 3,4-diaminopyridine-2(1H)-one (9.7 mg, 0.12 mmol, 2.0 eq) was added. The reaction was continued at room temperature for 1 hour. After the reaction was complete, ethyl acetate and water were added for extraction, and the organic phase was concentrated to give a yellow solid (2R,3S,4S,5R)-N-(4-amino-2-oxo-1,2-dihydropyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (15.0 mg, yield 47%), which was used directly in the next step of the reaction. LCMS (ESI) [M+H]+: 462.14.

[0108] Step 2: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one

[0109] Weigh (2R,3S,4S,5R)-N-(4-amino-2-oxo-1,2-dihydropyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (15.0 mg, 0.032 mmol, 1.0 eq.) and add it to ethanol (1 mL) and sodium hydroxide aqueous solution (1 mL, 10% wt.). React at 80 °C for 2 hours. After the reaction is complete, the reaction solution is concentrated directly to prepare and purify a white solid 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one (3.0 mg, yield 21%). LCMS(ESI)[M+H]+:444.1353. 1H NMR (400MHz, DMSO) δ11.15(s,1H),7.14–7.01(m,3H),6.49–6.44(m,1H),5.60(d,J=11.2Hz,1 H), 4.50 (s, 1H), 3.96 (d, J = 2.1Hz, 3H), 2.86 (p, J = 7.5Hz, 1H), 1.63 (s, 3H), 0.80–0.73 (m, 3H). 19 F NMR (376MHz, DMSO) delta -72.9, -137.51, -154.41.

[0110] Example 2: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-5-methyl-1,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one (compound 2)

[0111] Step 1: Synthesis of 4-methoxy-1-methyl-3-nitropyridine-2(1H)-one

[0112] 4-Hydroxy-3-nitropyridine-2(1H)-one (430 mg, 2.7 mmol, 1.0 eq) was dissolved in acetonitrile (5 mL), potassium carbonate (1.1 g, 8.1 mmol, 3 eq) was added, followed by dropwise addition of iodomethane (1 g, 6.75 mmol, 2.5 eq). The reaction was carried out under nitrogen protection at 60 °C. After the reaction was completed, water and ethyl acetate were added for extraction. The organic phases were combined, dried, concentrated, and separated by normal-phase column chromatography to give solid 4-methoxy-1-methyl-3-nitropyridine-2(1H)-one (50 mg, 10% yield). LCMS (TOF MS ES+) m / z [M+H]+: 185. 1 H NMR (400MHz, DMSO-d6) δ7.48 (d, J = 8.0 Hz, 1H), 6.19 (d, J = 8.0 Hz, 1H), 3.77 (s, 3H), 3.42 (s, 3H).

[0113] Step 2: Synthesis of 4-amino-1-methyl-3-nitropyridine-2(1H)-one

[0114] 4-Methoxy-1-methyl-3-nitropyridine-2(1H)-one (45 mg, 0.24 mmol, 1.0 eq) was dissolved in an amine-methanol solution (3 mL, 7 mol / L) and reacted at room temperature for 4 hours under nitrogen protection. After the reaction was complete, water and ethyl acetate were added for extraction. The organic phases were combined, dried, concentrated, filtered, and then subjected to column chromatography to obtain solid 4-amino-1-methyl-3-nitropyridine-2(1H)-one (30 mg, yield 75%). LCMS (TOF MS ES+) m / z [M+H]+: 170. 1 H NMR (400MHz, DMSO-d6) δ7.75 (d, J = 8.0 Hz, 1H), 7.46 (s, 2H), 6.08 (d, J = 8.0 Hz, 1H), 3.40 (s, 3H).

[0115] Step 3: Synthesis of 3,4-diamino-1-methylpyridin-2(1H)-one

[0116] 4-Amino-1-methyl-3-nitropyridine-2(1H)-one (27 mg, 0.16 mmol, 1.0 eq) was dissolved in methanol (3 mL), Pd / C was added, and the mixture was purged with hydrogen three times. The mixture was stirred at room temperature for 4 hours. After the reaction was complete as monitored by TLC, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated to obtain solid 3,4-diamino-1-methylpyridine-2(1H)-one (20 mg, 90% yield), which was used directly in the next step of the reaction. LCMS (TOF MS ES+) m / z [M+H]+: 140. 1 H NMR (400MHz, DMSO-d6) δ7.71 (d, J = 8.0 Hz, 1H), 6.83 (s, 2H), 5.93 (d, J = 8.0 Hz, 1H), 4.08 (s, 2H), 3.37 (s, 3H).

[0117] Step 4: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-5-methyl-1,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one

[0118] 3,4-Diamino-1-methylpyridin-2(1H)-one (9 mg, 0.066 mmol, 1.5 eq) and 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-benzo[d]imidazolium-6-carboxylic acid (16 mg, 0.044 mmol, 1.0 eq) were dissolved in phosphorus oxychloride (3 mL) and reacted at room temperature. After the reaction was complete, saturated sodium bicarbonate aqueous solution and ethyl acetate were added for extraction. The organic phase was concentrated, and the mixture was prepared and separated by HPLC to obtain a white solid 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-5-methyl-1,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one (3 mg, yield 15%). LCMS (TOF MS ES+) m / z [M+H]+: 458. 1 H NMR (400MHz, DMSO) δ11.15(s,1H),7.14–7.01(m,3H),6.49–6.44(m,1H),5.60(d,J=11.2Hz,1H),4 .50(s,1H),3.96(d,J=2.1Hz,3H),3.35(s,3H).2.92-2.85(m,1H),1.63(s,3H),0.80–0.73(m,3H).

[0119] Example 3: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-6-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine (compound 3)

[0120] Step 1: Synthesis of 5-nitro-2-(trifluoromethyl)pyridine-4-ol

[0121] 2-(trifluoromethyl)pyridin-4-ol (2.0 g, 12.26 mmol, 1.0 eq) was dissolved in sulfuric acid (6.0 mL). Fuming nitric acid (6.0 mL) was slowly added dropwise under ice bath conditions. After the addition was complete, the mixture was brought to room temperature and stirred for 15 minutes. The reaction solution was then poured into a sealed tube and reacted at 120 °C for 12 hours. After the reaction was complete, the reaction solution was cooled to room temperature and then slowly poured into ice water. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a yellow oily 5-nitro-2-(trifluoromethyl)pyridin-4-ol (2.5 g, yield 97.97%), which was used directly in the next reaction. LCMS (ESI) [M+H]+: 209.1 H NMR (400MHz, DMSO) δ9.09 (s, 1H), 7.46 (s, 1H).

[0122] Step 2: Synthesis of 4-chloro-5-nitro-2-trifluoromethylpyridine

[0123] 5-Nitro-2-(trifluoromethyl)pyridin-4-ol (1.0 g, 4.81 mmol, 1.0 eq) and phosphorus oxychloride (1.0 mL) were added to a vial and reacted at 80 °C for 1 hour. After the reaction was complete, the reaction solution was cooled to room temperature and slowly added to cold water. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried, and concentrated to give a yellow oily 4-chloro-5-nitro-2-trifluoromethylpyridine (550.0 mg, yield 50.52%). 1 H NMR (400MHz, DMSO) δ9.42 (s, 1H), 8.57 (s, 1H).

[0124] Step 3: Synthesis of 5-nitro-2-(trifluoromethyl)pyridine-4-amine

[0125] A yellow, oily solution of 4-chloro-5-nitro-2-trifluoromethylpyridine (300.0 mg, 1.32 mmol, 1.0 eq) and an ammonia-methanol solution (1.5 mL) were added to a vial and reacted at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated and purified by normal-phase column chromatography (petroleum ether and ethyl acetate, volume ratio 90:10) to obtain a yellow solid 5-nitro-2-(trifluoromethyl)pyridine-4-amine (100.0 mg, yield 36.46%). LCMS (ESI) [M+H]+: 208. 1 H NMR (400MHz, DMSO) δ9.07(s,1H),8.54–8.18(m,2H),7.38(s,1H).

[0126] Step 4: Synthesis of 6-(trifluoromethyl)pyridine-3,4-diamine

[0127] A yellow solid 5-nitro-2-(trifluoromethyl)pyridine-4-amine (100.0 mg, 0.48 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10.0 mL), and 5% wet palladium on carbon (100.0 mg) was added. The system was purged with hydrogen three times, and the reaction was carried out at room temperature for 2 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to obtain a yellow solid 6-(trifluoromethyl)pyridine-3,4-diamine (60.0 mg, yield 70.16%), which was directly used in the next step of the reaction. LCMS (ESI) [M+H]+: 208. 1H NMR (400MHz, DMSO) δ7.69(s,1H),6.82(s,1H),5.75(s,2H),5.10(s,2H).

[0128] Step 5: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-6-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine

[0129] Yellow solid 6-(trifluoromethyl)pyridine-3,4-diamine (12.0 mg, 67.74 μmol, 1.2 eq), (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (20.0 mg, 56.45 μmol, 1.0 eq), ammonium chloride (36.24 mg, 0.67 mmol, 12.0 eq) and phosphorus oxychloride (200.0 μL) were added to a vial, and the reaction was carried out at 100 °C for 12 hours. After the reaction was complete, the reaction solution was cooled to room temperature, slowly poured into cold water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried, concentrated under vacuum, and purified to prepare the synthesis of the pale yellow solid 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-6-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine (3.0 mg, yield 10.73%). LCMS (ESI) [M+H]+: 496.13. 1 H NMR (400MHz, DMSO) δ9.00(s,1H),8.03(s,1H),7.19(t,J=7.4Hz,1H),7.15–7.07(m,1H),5.86(d,J=11.0Hz,1H) ,4.50(m,J=11.0,7.5Hz,1H),3.95(d,J=2.2Hz,3H),2.90(d,J=7.5Hz,1H),1.66(s,3H),0.81(d,J=7.5Hz,3H).

[0130] Example 4: Synthesis of 6-chloro-2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-imidazo[4,5-c]pyridine (compound 4) and 6-chloro-2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-imidazo[4,5-c]pyridine (compound 46)

[0131] Step 1: Synthesis of 2-chloro-5-nitropyridine-4-amine

[0132] 2-Chloro-N-(4-methoxybenzyl)-5-nitropyridine-4-amine (200 mg, 0.69 mmol, 1.0 eq) was added to trifluoroacetic acid (4 mL) and stirred at 65 °C for 4 hours. After the reaction was complete, the reaction solution was concentrated and purified by normal-phase column chromatography (petroleum ether: ethyl acetate 5:1) to obtain a pale yellow solid 2-chloro-5-nitropyridine-4-amine (102 mg, yield 87.23%). LCMS (ESI) [MH]-: 171.99. 1 H NMR (400MHz, DMSO-d6) δ6.97(s,1H),8.86(s,1H),8.09(s,2H).

[0133] Step 2: Synthesis of (2R,3S,4S,5R)-N-(2-chloro-5-nitropyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0134] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (62 mg, 0.173 mmol, 1.0 eq), 2-chloro-5-nitropyridine-4-amine (30.0 mg, 0.173 mmol, 1.0 eq), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (75.0 mg, 0.198 mmol, 1.1 eq), and N,N-diisopropylethylamine (44.0 mg, 0.433 mmol, 2.5 eq) were added to dichloromethane (5 mL) and stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated and subjected to normal-phase column chromatography (petroleum ether:ethyl acetate 5:1) to give a yellow oil (2R,3S,4S,5R)-N-(2-chloro-5-nitropyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (52 mg, yield 59.01%). LCMS (ESI) [M+H]+: 510.1.

[0135] Step 3: Synthesis of (2R,3S,4S,5R)-N-(5-amino-2-chloropyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0136] (2R,3S,4S,5R)-N-(2-chloro-5-nitropyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (50.0 mg, 0.097 mmol, 1.0 eq), iron powder (28 mg, 0.49 mmol, 5.0 eq), and ammonium chloride (53.0 mg, 0.97 mmol, 10.0 eq) were added to ethanol (6 mL) and water (2 mL) and reacted at 80 °C for 1 hour. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to give a yellow solid (2R,3S,4S,5R)-N-(5-amino-2-chloropyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (28 mg, yield 59.5%). LCMS (ESI) [M+H]+: 480.1.

[0137] Step 4: Synthesis of 6-chloro-2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-imidazo[4,5-c]pyridine (compound 46)

[0138] (2R,3S,4S,5R)-N-(5-amino-2-chloropyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (28 mg, 0.059 mmol, 1.0 eq) was added to acetic acid (2 mL) and stirred at 65 °C for 6 hours. After the reaction was complete, the reaction solution was directly concentrated to obtain a yellow solid 6-chloro-2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-imidazo[4,5-c]pyridine (compound 46, 23 mg, yield 85.35%), which was directly used in the next step of the reaction. LCMS (ESI) [M+H]+: 462.09. 1 H NMR (400MHz, DMSO-d6) δ8.67(s,1H),7.62(s,1H),7.17(t,J=7.7Hz,1H),7.16–7.05(m,1H),5.78(d,J=11.0Hz, 1H), 4.47 (dd, J=11.0, 7.6Hz, 1H), 3.94 (d, J=2.1Hz, 3H), 2.87 (q, J=7.5Hz, 1H), 1.64 (s, 3H), 0.83–0.76 (m, 3H). 19 F NMR(376MHz, DMSO-d6)δ-72.90,-137.55,-154.48.

[0139] Step 5: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-imidazo[4,5-c]pyridine-6-amine

[0140] The following ingredients were added: 6-chloro-2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-imidazo[4,5-c]pyridine (20 mg, 0.043 mmol, 1.0 eq), benzophenone imine (12 mg, 0.065 mmol, 1.5 eq), and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) 12 mg (0.0043 mmol, 0.1 eq), tris(dibenzylacetone)dipalladium (4.0 mg, 0.0043 mmol, 0.1 eq), and sodium tert-butoxide (12.5 mg, 0.129 mmol, 3.0 eq) were added to toluene (2 mL), the mixture was purged with nitrogen three times, and stirred at 80 °C for 3 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered through silica gel, and washed with ethyl acetate. The filtrate was concentrated, the residue was dissolved in methanol (3 mL), and ammonium hydroxide (1 mL) was added. The mixture was stirred at room temperature for 18 hours. After the reaction was complete, the reaction solution was concentrated and purified by high-performance liquid chromatography (HPLC) to obtain the synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-imidazo[4,5-c]pyridine-6-amine (compound 4, 2.0 mg, yield 10.44%). LCMS (ESI) [M+H]+: 443.14. 1 H NMR(400MHz,DMSO-d6)δ12.40(s,1H),8.80(s,1H),7.37–7.26(m,2H),6.93(s,1H),6.1 8(s,1H),6.09(s,1H),5.24(s,1H),3.87(s,3H),2.42(s,1H),1.40(s,3H),1.05(s,3H). 19 F NMR (376MHz, DMSO-d6) δ -72.93, -137.61 (m, J = 20.7, 8.5, 7.2Hz), -154.51 (d, J = 20.8Hz).

[0141] Example 5: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-imidazo[4,5-c]pyridine-6-carboxynitrile (compound 5)

[0142] Step 1: Synthesis of 4-[(4-methoxybenzyl)amino]-5-nitropyridinecarboxynitrile

[0143] 2-Chloro-N-(4-methoxybenzyl)-5-nitropyridine-4-amine (300 mg, 1.02 mmol, 1.0 eq) was dissolved in N-methylpyrrolidone (5.0 mL), and zinc cyanide (1.2 g, 10.21 mmol, 10.0 eq) and tetrakis(triphenylphosphine)palladium (236.07 mg, 0.2 mmol, 0.2 eq) were added. The system was purged with nitrogen three times, and the reaction was carried out at 120 °C for 16 hours. After the reaction was completed, the mixture was washed with saturated sodium chloride, extracted with ethyl acetate, and purified by normal phase to give a yellow solid 4-[(4-methoxybenzyl)amino]-5-nitropyridinecarboxynitrile (150 mg, yield 66.32%). LCMS (ESI) [M+H]+: 285.14. 1 H NMR (400MHz, DMSO) δ9.06 (s, 1H), 7.68 (s, 1H), 7.35–7.32 (m, 2H), 6.93–6.90 (m, 2H), 4.65 (d, J = 6.3Hz, 2H), 3.73 (s, 3H).

[0144] Step 2: Synthesis of 4-amino-5-nitropyridinecarboxynitrile

[0145] 4-[(4-methoxybenzyl)amino]-5-nitropyridinecarboxynitrile (150.0 mg, 0.67 mmol, 1.0 eq) was dissolved in trifluoroacetic acid (1 mL) and reacted at 60 °C for 16 hours. After the reaction was complete, the pH was adjusted to 7-8 with saturated sodium bicarbonate solution, and the mixture was extracted three times with ethyl acetate. The organic phase was concentrated and purified by normal-phase column chromatography to give a yellow solid 4-amino-5-nitropyridinecarboxynitrile (60.0 mg, yield 59.06%). LCMS (ESI) [M+H]+: 165.07. 1 H NMR (400MHz, DMSO) δ9.01 (s, 1H), 7.44 (s, 1H).

[0146] Step 3: Synthesis of (2R,3S,4S,5R)-N-(2-cyano-5-nitropyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0147] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (68.04 mg, 0.2 mmol, 1.1 eq) was added to dichloromethane (4 mL), followed by the addition of one drop of N,N-dimethylformamide, and then oxalyl chloride (0.05 mL, 3.0 eq). The mixture was reacted at room temperature for 2 hours, then concentrated. Under ice bath conditions, a solution of 4-amino-5-nitropyridinecarboxynitrile (50 mg, 0.2 mmol, 1.0 eq) and triethylamine (0.1 mL, 3.0 eq) in dichloromethane (1 mL) was added, and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, the sample was washed with saturated sodium chloride, extracted with ethyl acetate, and purified by normal-phase column chromatography to give a white solid (2R,3S,4S,5R)-N-(2-cyano-5-nitropyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (30.0 mg, yield 47.06%). LCMS (ESI) [M+H]+: 50 1.15. 1 H NMR(500MHz,Chloroform-d)δ9.55(s,1H),9.03(s,1H),8.47(s,1H),7.09–7.03(m,1H),6.99(m,J=10.1,9.2,4.8Hz,1H),5 .08(dd,J=7.6,0.8Hz,1H),3.98–3.91(m,1H),3.89(s,3H),2.53–2.43(m,1H),1.32(m,J=3.3Hz,3H),1.10(d,J=6.4Hz,3H).

[0148] Step 4: Synthesis of (2R,3S,4S,5R)-N-(5-amino-2-cyanopyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0149] (2R,3S,4S,5R)-N-(2-cyano-5-nitropyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (30 mg, 0.06 mmol, 1.0 eq) was added to ethanol (1 mL) and water (0.2 mL), followed by the addition of iron powder (17 mg, 0.3 mmol, 5.0 eq) and ammonium chloride (17 mg, 0.3 mmol, 5.0 eq), and the reaction was carried out at 80 °C for 12 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated and purified by normal-phase column chromatography to obtain a white solid (2R,3S,4S,5R)-N-(5-amino-2-cyanopyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (20 mg, yield 80.8%). LCMS (ESI) [M+H]+: 471.13. 1 H NMR(500MHz,Chloroform-d)δ8.97(s,1H),7.81(s,1H),7.59(s,1H),7.09–7.03(m,1H),6.99(m,J=10.1,9.2,4.8Hz,1H),5.09(dd,J=7.5,0.7 Hz,1H),4.60(s,2H),4.03–3.96(m,1H),3.87(s,3H),2.47(m,J=10.3,5.7,4.3,2.3,1.1Hz,1H),1.32(m,J=3.3Hz,3H),1.10(d,J=6.4Hz,3H).

[0150] Step 5: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-imidazo[4,5-c]pyridine-6-carboxynitrile

[0151] (2R,3S,4S,5R)-N-(5-amino-2-cyanopyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (20 mg, 0.06 mmol, 1.0 eq) was added to acetic acid (2 mL) and reacted at 60 °C for 12 hours. After the reaction was complete, the mixture was neutralized with saturated sodium bicarbonate, extracted with ethyl acetate, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate to prepare a white solid 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-imidazo[4,5-c]pyridin-6-carboxynitrile (5 mg, yield 40.2%). LCMS(ESI)[M+H]+:453.13. 1 H NMR(500MHz,Chloroform-d)δ8.43(s,1H),7.70(s,1H),7.13–7.07(m,1H),6.99(m,J=10.1,9.1,4.8Hz,1H),5.66( dd,J=7.3,0.7Hz,1H),4.16–4.09(m,1H),3.87(s,3H),2.97–2.87(m,1H),1.48–1.43(m,3H),1.16(d,J=6.2Hz,3H).

[0152] Example 6: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-5-(1H-imidazol-2-yl)-1H-benzo[d]imidazole (compound 6)

[0153] Step 1: Synthesis of tert-butyl 2-bromo-1H-imidazolium-1-carboxylic acid

[0154] 2-Bromo-1H-imidazolium (1.0 g, 6.8 mmol, 1.0 eq) was dissolved in anhydrous N,N-dimethylformamide (10 mL), followed by the addition of triethylamine (2.07 g, 20.4 mmol, 3.0 eq) and dropwise addition of di-tert-butyl dicarbonate (2.23 g, 10.2 mmol, 1.5 eq). The reaction was carried out at room temperature for 4 hours. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the combined organic phases were washed three times with saturated sodium chloride aqueous solution. The organic phase was dried, concentrated, and separated by normal column chromatography to obtain liquid 2-bromo-1H-imidazolium-1-carboxylic acid tert-butyl ester (1.23 g, 73% yield). LCMS (TOF MS ES+) m / z [M+H]+: 247.0. 1H NMR (400MHz, Chloroform-d) δ7.45 (d, J = 7.5 Hz, 1H), 7.17 (d, J = 7.5 Hz, 1H), 1.61 (s, 9H).

[0155] Step 2: Synthesis of [1-(tert-Butoxycarbonyl)-1H-imidazol-2-yl]boronic acid

[0156] 1.0 g (4.05 mmol, 1.0 eq) of 2-bromo-1H-imidazolium-1-carboxylic acid tert-butyl ester was dissolved in anhydrous tetrahydrofuran (10 mL). The mixture was purged with nitrogen, and n-butyllithium (1.94 mL, 4.86 mmol, 1.2 eq, 2.5 mol / L) was slowly added dropwise at -70 °C. After the addition was complete, the reaction was continued at -70 °C for 0.5 h. Then, trimethyl borate (630.8 mg, 6.07 mmol, 1.5 eq) was added dropwise, and the reaction was continued at -70 °C for 1 h. After the reaction was complete as monitored by TLC, saturated ammonium chloride aqueous solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, concentrated, and purified by normal column chromatography to obtain solid [1-(tert-butyloxycarbonyl)-1H-imidazolium-2-yl]boronic acid (453 mg, yield 53%). LCMS (TOF MS ES+) m / z [MH]-: 211.1. 1H NMR (400MHz, DMSO-d6) δ 7.51 (d, J = 7.5Hz, 1H), 7.35 (d, J = 7.5Hz, 1H), 1.52 (s, 9H).

[0157] Step 3: Synthesis of tert-butyl 2-(3-amino-4-nitrophenyl)-1H-imidazolium-1-carboxylic acid

[0158] [1-(tert-Butoxycarbonyl)-1H-imidazol-2-yl]boronic acid (300 mg, 1.42 mmol, 1.0 eq), 5-bromo-2-nitroaniline (367 mg, 1.70 mmol, 1.2 eq), and potassium carbonate (586 mg, 4.25 mmol, 3.0 eq) were added to dioxane (5 mL) and water (1 mL). 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (II) (30 mg) was added, and the system was purged with nitrogen three times. The reaction was carried out at 100 °C for 12 hours. After the reaction was complete, a saturated aqueous sodium chloride solution was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and separated by normal-phase column chromatography to obtain 2-(3-amino-4-nitrophenyl)-1H-imidazol-1-carboxylic acid tert-butyl ester (173 mg, yield 40.2%). LCMS(TOF MS ES+)m / z[M+H]+:305.1.1H NMR (400MHz, Chloroform-d) δ 8.06-7.99 (m, 2H), 7.64 (d, J = 7.5Hz, 1H), 7.42-7.40 (m, 1H), 6.92 (d, J = 2.0Hz, 1H), 6.91 (s, 2H), 1.63 (s, 9H).

[0159] Step 4: Synthesis of tert-butyl 2-(3,4-diaminophenyl)-1H-imidazolium-1-carboxylic acid

[0160] 2-(3-amino-4-nitrophenyl)-1H-imidazolium-1-carboxylic acid tert-butyl ester (170 mg, 0.558 mmol, 1.0 eq), iron powder (93.6 mg, 1.68 mmol, 3.0 eq), and ammonium chloride (179 mg, 3.35 mmol, 6.0 eq) were added to ethanol (5 mL) and water (1 mL). The system was purged with nitrogen three times, and the reaction was carried out at 70 °C for 4 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated and purified by normal-phase column chromatography to obtain 2-(3,4-diaminophenyl)-1H-imidazolium-1-carboxylic acid tert-butyl ester (73 mg, yield 47%). LCMS (TOF MS ES+) m / z [M+H]+: 275.1. 1 H NMR(400MHz,DMSO-d6)δ7.92(d,J=7.5Hz,1H),7.63(d,J=7.7Hz,1H),7.03-6.97(m,1H ), 6.74 (d, J = 2.0Hz, 1H), 6.56 (d, J = 7.6Hz, 1H), 5.70 (s, 2H), 5.25 (s, 2H), 1.53 (s, 9H).

[0161] Step 5: Synthesis of tert-butyl 2-{3-amino-4-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido]phenyl}-1H-imidazolium-1-carboxylic acid

[0162] (2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (51.6 mg, 0.145 mmol, 1.0 eq), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (83.1 mg, 0.218 mmol, 1.5 eq) and diisopropylethylamine (47.1 mg, 0.364 mmol, 2.5 eq) were dissolved in dichloromethane (3 mL), stirred at 23 °C for 30 minutes, and then 2-(3,4-diaminophenyl)-1H-imidazolium-1-carboxylic acid tert-butyl ester (40 mg, 0.145 mmol, 1.0 eq) was added, and the mixture was reacted at 23 °C for 4 hours. After the reaction was complete, the reaction solution was added to a saturated ammonium chloride aqueous solution, extracted with dichloromethane, and the organic phase was dried and concentrated to give 2-{3-amino-4-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido]phenyl}-1H-imidazolium-1-carboxylic acid tert-butyl ester (63 mg, yield 70.7%). LCMS (TOF MS ES+) m / z [M+H]+: 611.2. 1 H NMR(400MHz,DMSO-d6)δ10.04(s,1H),8.02(s,2H),7.95(d,J=7.5Hz,1H),7 .64(d,J=7.5Hz,1H),7.30-7.28(m,1H),7.16(d,J=7.5Hz,1H),7.00(d,J=2. 0Hz,1H),6.97–6.80(m,2H),5.23(d,J=7.0Hz,1H),3.85(s,3H),3.53-3.49 (m,1H),2.33-2.26(m,1H),1.51(s,9H),1.26(s,3H),1.03(d,J=6.8Hz,4H).

[0163] Step 6: Synthesis of tert-butyl 2-{2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-benzo[d]imidazol-5-yl}-1H-imidazol-1-carboxylic acid

[0164] 2-{3-amino-4-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido]phenyl}-1H-imidazolium-1-carboxylic acid tert-butyl ester (63 mg, 0.103 mmol, 1.0 eq) was dissolved in acetic acid (2 mL) and reacted at 45 °C for 12 hours. After the reaction was completed, the reaction solution was concentrated to obtain 2-{2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-benzo[d]imidazolium-5-yl}-1H-imidazolium-1-carboxylic acid tert-butyl ester (72 mg), which was directly used in the next step of the reaction. LCMS(TOF MS ES+)m / z[M+H]+:593.2.

[0165] Step 7: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-5-(1H-imidazol-2-yl)-1H-benzo[d]imidazole

[0166] 2-{2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-benzo[d]imidazol-5-yl}-1H-imidazol-1-carboxylic acid tert-butyl ester (72 mg, 0.121 mmol, 1.0 eq) was dissolved in dioxane hydrochloride solution (3 mL, 4 M) and reacted at 25 °C for 4 hours. After the reaction was completed, the reaction solution was concentrated and purified to obtain 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-5-(1H-imidazol-2-yl)-1H-benzo[d]imidazolium (5.3 mg). LCMS (TOF MS ES+)m / z[M+H]+: 493.1. 1 H NMR (400MHz, DMSO-d6) δ12.20(s,1H),8.03(d,J=1.5Hz,1H),7.80(d,J=7.5Hz,1H),7.65-7.61(m,1H),7.27(s,2H),7.20-7.15(m,1 H),7.05-6.97(m,1H),5.41(d,J=7.0Hz,1H),3.85(s,3H),3.79-3.74(m,1H),2.33-2.23(m,1H),1.35(s,3H),1.03(d,J=6.8Hz,3H).

[0167] Example 7: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-6-methoxy-1H-imidazo[4,5-c]pyridine (compound 7)

[0168] Step 1: Synthesis of 2-methoxy-5-nitropyridine-4-amine

[0169] 2-Methoxy-N-(4-methoxybenzyl)-5-nitropyridine-4-amine (100 mg, 0.35 mmol, 1.0 eq) was added to trifluoroacetic acid (4 mL) and stirred at 65 °C for 4 hours. After the reaction was complete, the reaction solution was concentrated and separated by normal-phase column chromatography (petroleum ether and ethyl acetate, volume ratio 5:1) to obtain a yellow solid 2-methoxy-5-nitropyridine-4-amine (42 mg, yield 71.8%). LCMS (ESI) [M+H]+: 170.01. 1 H NMR (400MHz, DMSO-d6) δ8.82(s,1H),7.67(s,2H),6.15(s,1H),3.84(s,3H).

[0170] Step 2: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-methoxy-5-nitropyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0171] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (59.0 mg, 0.017 mmol, 1.0 eq) and one drop of N,N-dimethylformamide were added to dichloromethane (5 mL). Oxaloyl chloride (43 mg, 0.033 mmol, 2.0 eq) was slowly added dropwise under ice bath conditions, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated and dissolved in dichloromethane (2 mL) for later use. 2-Methoxy-5-nitropyridine-4-amine (28 mg, 0.017 mmol, 1.0 eq) and triethylamine (34 mg, 0.033 mmol, 2.0 eq) were added to dichloromethane (5 mL). After stirring at room temperature for 15 minutes, the prepared solution was added to the reaction system, and the reaction was carried out at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated and subjected to normal-phase column chromatography (petroleum ether:ethyl acetate 5:1) to give a white solid (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-methoxy-5-nitropyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (40 mg, yield 47.81%). LCMS (ESI) [M+H]+: 506.13.

[0172] Step 3: Synthesis of (2R,3S,4S,5R)-N-(5-amino-2-methoxypyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0173] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-methoxy-5-nitropyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (40.0 mg, 0.017 mmol, 1.0 eq) and palladium on carbon (50 mg, 53% water content) were added to methanol (5 mL), and the mixture was purged with hydrogen and reacted at room temperature for 1 hour. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to give a yellow solid crude product (2R,3S,4S,5R)-N-(5-amino-2-methoxypyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (28 mg, yield 74.4%), which was directly used in the next step of the reaction. LCMS(ESI)[M+H]+:476.15.

[0174] Step 4: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-6-methoxy-1H-imidazo[4,5-c]pyridine

[0175] (2R,3S,4S,5R)-N-(5-amino-2-methoxypyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (28 mg, 0.058 mmol, 1.0 eq) was added to acetic acid (2 mL) and stirred at 65 °C for 6 hours. After the reaction was complete, the reaction solution was concentrated directly to prepare and isolate a white solid 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-6-methoxy-1H-imidazo[4,5-c]pyridine (5.1 mg, yield 18.93%). LCMS (ESI) [M+H]+: 458.15. 1 H NMR (400MHz, DMSO-d6) δ12.22(s,1H),8.46(s,1H),7.18–7.05(m,2H),6.79(s,1H),5.69(d,J=11.1Hz,1H),4.45(dd,J =11.1,7.5Hz,1H),3.95(d,J=2.1Hz,3H),3.84(s,3H),2.87(m,J=7.5Hz,1H),1.64(s,3H),0.79(dd,J=7.7,2.6Hz,3H). 19 F NMR (376MHz, DMSO-d6) δ -72.93, -137.61 (m, J = 20.7, 8.5, 7.2Hz), -154.51 (d, J = 20.8Hz).

[0176] Example 8: Synthesis of 6-chloro-8-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-9H-purine (compound 8)

[0177] Step 1: Synthesis of 6-chloro-8-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-9H-purine

[0178] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (30 mg, 0.084 mmol, 1.0 eq), 6-chloropyrimidine-4,5-diamine (13.5 mg, 0.093 mmol, 1.1 eq.) and ammonium chloride (27 mg, 0.51 mmol, 6.0 eq.) were dissolved in phosphorus oxychloride (0.5 mL) and reacted at 100 °C for 2 hours. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to prepare and separate a white solid 6-chloro-8-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-9H-purine (2.0 mg, yield 5.10%). LCMS (ESI) [M+H]+: 463.10. 1 H NMR (400MHz, Methanol-d4) δ8.54(s,1H),7.08(m,J=8.5,5.7,2.2Hz,1H),6.89(m,J=8.9Hz,1H),5.70(d,J=11.1Hz ,1H),4.58(t,J=5.6Hz,1H),4.00(d,J=2.4Hz,3H),2.95(m,J=7.6Hz,1H),1.71(s,3H),0.87(m,J=7.6,2.4Hz,3H). 19 F NMR (376MHz, Methanol-d4) delta -75.63, -140.20, -156.99.

[0179] Example 9: Synthesis of 8-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-9H-purine-6-amine (compound 9)

[0180] 15.0 mg of 6-chloro-8-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-9H-purine was dissolved in ammonia-methanol solution (2 mL, 2 M) and reacted at 100 °C for 5 days. After the reaction was completed, the solution was concentrated under reduced pressure to prepare and isolate a white solid 8-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-9H-purine-6-amine (2.0 mg). LCMS (ESI) [M+H]+: 444.15.

[0181] Example 10: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-benzo[d]imidazol-6-ol (Compound 10)

[0182] Step 1: Synthesis of 4-[(tert-butyldimethylsilyl)oxy]-2-nitroaniline

[0183] 4-Amino-3-nitrophenol (500 mg, 3.25 mmol, 1.0 eq) was dissolved in dichloromethane (15 mL), followed by the sequential addition of diisopropylethylamine (1.3 g, 9.74 mmol, 3.0 eq) and tert-butyldimethylchlorosilane (582 mg, 3.9 mmol, 1.2 eq). The reaction was carried out at room temperature for 2 hours. After the reaction was complete, the mixture was washed with saturated sodium chloride, extracted with ethyl acetate, and purified in normal phase (90% petroleum ether, 10% ethyl acetate) to give a white solid 4-[(tert-butyldimethylsilyl)oxy]-2-nitroaniline (520 mg). LCMS (ESI) [M+H]+: 548.1. 1 H NMR (400MHz, DMSO) δ7.33 (d, J = 2.8 Hz, 1H), 7.20 (s, 2H), 7.08 (dd, J = 9.1, 2.8 Hz, 1H), 6.96 (d, J = 9.1 Hz, 1H), 0.94 (s, 9H), 0.17 (s, 6H).

[0184] Step 2: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(4-hydroxy-2-nitrophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0185] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (50 mg, 0.14 mmol, 1.0 eq) was added to phosphorus oxychloride (5 mL), followed by 4-[(tert-butyldimethylsilyl)oxy]-2-nitroaniline (42 mg, 0.15 mmol, 1.1 eq). The reaction was carried out at 50 °C for 3 hours. After the reaction was complete, the mixture was extracted with ethyl acetate and analyzed by TLC (petroleum ether / ethyl acetate = 3:1) to give a white solid (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(4-hydroxy-2-nitrophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (40 mg). LCMS(ESI)[M+H]+:491.1.

[0186] Step 3: Synthesis of (2R,3S,4S,5R)-N-(2-amino-4-hydroxyphenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0187] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(4-hydroxy-2-nitrophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (40 mg, 0.08 mmol, 1.0 eq) was added to methanol (5 mL), followed by palladium on carbon (40 mg, 0.08 mmol, 1.0 eq). The atmosphere was replaced with hydrogen, and the reaction was carried out at room temperature for 3 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain a yellow solid (2R,3S,4S,5R)-N-(2-amino-4-hydroxyphenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (30 mg), which was used directly in the next step of the reaction. LCMS (ESI) [M+H]+: 461.1.

[0188] Step 4: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-benzo[d]imidazol-6-ol

[0189] (2R,3S,4S,5R)-N-(2-amino-4-hydroxyphenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (30 mg, 0.06 mmol, 1.0 eq) was added to acetic acid (2 mL) and reacted at 60 °C for 12 hours. After the reaction was complete, the mixture was neutralized with saturated sodium bicarbonate, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under vacuum to prepare a white solid 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-benzo[d]imidazol-6-ol (7.0 mg). LCMS (ESI) [M+H]+: 443.1395. 1H NMR (400MHz, DMSO) δ12.29(s,1H),8.41(s,1H),7.30(d,J=8.1Hz,1H),7.19–6.98(m,2H),6.81(s,1H),6.64(d,J=8.1Hz,1H),5.61 (d, J=11.2Hz, 1H), 4.46 (dd, J=11.1, 7.6Hz, 1H), 3.96 (d, J=2.0Hz, 3H), 2.86 (t, J=7.5Hz, 1H), 1.63 (s, 3H), 0.78 (d, J=6.2Hz, 3H). 19 F NMR(376MHz, DMSO)δ-73.50(s),-137.65–-138.44(m),-155.18(s).

[0190] Example 11: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1,4-dihydro-5H-imidazo[4,5-b]pyridin-5-one (compound 38)

[0191] Step 1: Synthesis of 6-benzyloxy-3-nitropyridine-2-amine

[0192] Sodium hydride (460.90 mg, 11.52 mmol, 4.0 eq) was added to a two-necked flask, followed by NN-dimethylformamide (5 mL). The system was purged with nitrogen three times. Under ice bath conditions, benzyl alcohol (0.6 mL, 2.0 eq) was slowly added dropwise. The mixture was stirred at room temperature for 15 minutes. 6-Chloro-3-nitropyridine-2-amine (500 mg, 2.88 mmol, 1.0 eq) was dissolved in NN-dimethylformamide (1 mL) and then added dropwise to the above reaction solution. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, water was added, the mixture was stirred, and filtered. The filter cake was dried to give a yellow solid 6-benzyloxy-3-nitropyridine-2-amine (400 mg, yield 66.32%). LCMS (ESI) [M+H]+: 246.08. 1 H NMR (400MHz, DMSO) δ8.27 (d, J = 9.1 Hz, 1H), 8.18 (s, 2H), 7.51–7.47 (m, 2H), 7.41–7.34 (m, 3H), 6.19 (d, J = 9.1Hz, 1H), 5.39 (s, 2H).

[0193] Step 2: Synthesis of 6-(benzyloxy)pyridine-2,3-diamine

[0194] 6-Benzyloxy-3-nitropyridine-2-amine (400.0 mg, 1.63 mmol, 1.0 eq) was dissolved in isopropanol (4 mL) and water (1 mL). Iron powder (455 mg, 8.16 mmol, 5.0 eq) and ammonium chloride (436 mg, 8.16 mmol, 5.0 eq) were added, and the reaction was carried out at 100 °C for 4 hours under nitrogen protection. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated, and the crude product was purified by normal phase to give a brown oily 6-(benzyloxy)pyridine-2,3-diamine (240.0 mg, yield 59.06%). LCMS (ESI) [M+H]+: 216.07. 1 H NMR (400MHz, DMSO) δ7.41–7.37(m,2H),7.37–7.32(m,2H),7.30–7.26(m,1H),6.7 5(d,J=7.9Hz,1H),5.85(d,J=7.9Hz,1H),5.35(s,2H),5.13(s,2H),4.12(s,2H).

[0195] Step 3: Synthesis of (2R,3S,4S,5R)-N-[2-amino-6-(benzyloxy)pyridin-3-yl]-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0196] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (68.04 mg, 0.2 mmol, 1.0 eq), triethylamine (0.1 mL, 3.0 eq) and tripyrrolylphosphonium hexafluorophosphate bromide (195.04 mg, 0.3 mmol, 1.5 eq) were added to N,N-dimethylformamide (3 mL), and stirred for 15 minutes. Then, 6-(benzyloxy)pyridine-2,3-diamine (50 mg, 0.22 mmol, 1.1 eq) was added. After the reaction was complete, water was added for dilution, followed by extraction with ethyl acetate. The organic phase was washed with saturated sodium chloride, and the crude product was purified by normal-phase chromatography to obtain a yellow oil (2R,3S,4S,5R)-N-[2-amino-6-(benzyloxy)pyridin-3-yl]-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (50 mg, yield 47.06%). LCMS (ESI) [M+H]+: 552.15.

[0197] Step 4: Synthesis of 5-(benzyloxy)-2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-imidazo[4,5-b]pyridine

[0198] (2R,3S,4S,5R)-N-[2-amino-6-(benzyloxy)pyridin-3-yl]-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (30 mg, 0.06 mmol, 1.0 eq) was added to ethanol (7 mL), followed by the addition of 10% sodium hydroxide (7 mL), and the reaction was carried out at 85 °C for 2 hours. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride. The crude product was purified by normal phase to obtain colorless oil 5-(benzyloxy)-2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-imidazo[4,5-b]pyridine (30 mg, yield 80.8%). LCMS(ESI)[M+H]+:534.17. 1 H NMR (400MHz, DMSO-d6) δ13.22-12.76 (m, 1H), 7.89 (dd, J=32.6, 8.6Hz, 1H), 7.44 (d, J= 7.4Hz,2H),7.39–7.34(m,2H),7.31(s,1H),7.14–7.03(m,2H),6.73(dd,J=10.0,8.6H z,1H),5.64(dd,J=51.0,11.2Hz,1H),5.35(d,J=6.9Hz,2H),4.49(m,J=11.7,7.4Hz,1 H), 3.96 (d, J = 2.0Hz, 3H), 2.87 (m, J = 7.6, 2.5Hz, 1H), 1.65 (s, 3H), 0.81–0.76 (m, 3H). 19 F NMR(376MHz, DMSO-d6)δ-73.53,-138.21,-153.47–-155.89.

[0199] Step 5: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1,4-dihydro-5H-imidazo[4,5-b]pyridin-5-one

[0200] 5-(benzyloxy)-2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-imidazo[4,5-b]pyridine (30 mg, 0.02 mmol, 1.0 eq.) and 10% palladium on carbon (30 mg, 0.01 mmol, 0.3 eq.) were added to tetrahydrofuran (1 mL), purged with hydrogen, and stirred at room temperature for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was purified to obtain the solid product 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1,4-dihydro-5H-imidazo[4,5-b]pyridin-5-one (10 mg, yield 6.25%). LCMS (ESI) [M+H]+: 444.14. 1 H NMR (400MHz, DMSO) δ7.82–7.57(m,1H),7.12–7.02(m,2H),6.53–5.96(m,1H),5.60(d,J=11.5H z,1H),4.55–4.38(m,1H),3.96(d,J=2.1Hz,3H),2.84(s,1H),1.62(s,3H),0.80–0.74(m,3H). 19 F NMR(376MHz, DMSO-d6)δ-73.57,-138.24,-155.04.

[0201] Example 12: Synthesis of 2-[(2R.3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-3,5-dihydro-6H-imidazo[4,5-c]pyridin-6-one (compound 39)

[0202] Step 1: Synthesis of 2-methoxy-5-nitropyridine-4-amine

[0203] 2-Chloro-5-nitropyridine-4-amine (350.0 mg, 2.02 mmol, 1.0 eq.) was dissolved in methanol (4.0 mL), and sodium methoxide (560 μL, 3.02 mmol, 1.5 eq.) was added. The system was purged with nitrogen three times, and the reaction was carried out at 70 °C for 16 hours. After the reaction was completed, the reaction solution was washed with water, extracted with ethyl acetate, and the organic phases were combined. The solvent was removed under reduced pressure to obtain a yellow solid 2-methoxy-5-nitropyridine-4-amine (311.7 mg, yield 91.3%), which was directly used in the next step of the reaction. LCMS (ESI) [M+H] + :170.07. 1H NMR (400MHz, DMSO) δ8.82(s,1H),7.67(s,2H),6.16(s,1H),3.84(s,3H).

[0204] Step 2: Synthesis of 4-amino-5-nitropyridine-2(1H)-one

[0205] 2-Methoxy-5-nitropyridine-4-amine (310.0 mg, 1.84 mmol, 1.0 eq.) was dissolved in concentrated hydrochloric acid (10.0 mL) and reacted at 105 °C for 16 hours. After the reaction was complete, the hydrochloric acid was removed under reduced pressure, and the residue was dissolved in methanol and separated by LC-MS (90% dichloromethane, 10% methanol) to obtain a yellow solid 4-amino-5-nitropyridine-2(1H)-one (85.4 mg, yield 29.9%). LC-MS (ESI) [M+H] + :156.04. 1 H NMR (400MHz, DMSO) δ8.56(s,1H),7.22(s,2H),5.42(s,1H).

[0206] Step 3: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(5-nitro-2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0207] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (30.0 mg, 0.08 mmol, 1.0 eq.) was dissolved in N,N-dimethylformamide (1.0 mL), followed by the addition of 4-amino-5-nitropyridine-2(1H)-one (14.4 mg, 0.09 mmol, 1.1 eq.) and N,N-diisopropylethylamine (27.3 mg, 0.21 mmol, 2.5 eq.). The mixture was stirred at room temperature for 5 minutes, and finally N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (41.9 mg, 0.11 mmol, 1.3 eq.). The mixture was reacted at room temperature for 2 hours. After the reaction was complete, the reaction solution was washed with water, extracted with tert-butyl methyl ether, and the organic phases were combined. The solvent was removed under reduced pressure to give a yellow solid (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(5-nitro-2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (24.2 mg, yield 58.0%), which was used directly in the next reaction. LCMS(ESI)[M+H] + :492.12.

[0208] Step 4: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-3,5-dihydro-6H-imidazo[4,5-c]pyridin-6-one

[0209] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(5-nitro-2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (24.0 mg, 0.05 mmol, 1.0 eq.) was dissolved in ethanol / water (2 mL / 0.6 mL), and iron powder (46.4 mg, 0.83 mmol, 16.3 eq.) and ammonium chloride (44.4 mg, 0.83 mmol, 16.9 eq.) were added. The mixture was reacted at 80 °C for 2 hours. After the reaction was complete, insoluble matter was removed by filtration, and a white solid 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-3,5-dihydro-6H-imidazo[4,5-c]pyridin-6-one (2.5 mg, yield 11.5%) was prepared from the 1 / 1000 ammonium bicarbonate system. LCMS (ESI) [M+H] + :444.14. 1 H NMR(400MHz,MeOD)δ7.87(s,1H),7.10(t,J=7.4Hz,1H),6.95(m,J=8.9Hz,1H),6.35(s,1H),5.60(d,J=11.0Hz,1H), 4.35(dd,J=11.0,8.0Hz,1H), 3.99(d,J=2.5Hz,3H), 2.91(m,J=7.7Hz,1H), 1.68(s,3H), 0.86(dd,J=8.1,2.2Hz,3H).

[0210] Example 13: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-imidazo[4,5-b]pyridine-5-amine (compound 41)

[0211] Step 1: Synthesis of pyridine-2,3,6-triamine

[0212] Compound 3-nitropyridine-2,6-diamine (20 mg, 0.13 mmol, 1.0 eq) was mixed with 5% palladium on carbon (41 mg, 0.019 mmol, 0.15 eq.) and tetrahydrofuran (1 mL). The system was purged with hydrogen three times and stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was filtered, and the filter cake was washed several times with methanol. The filtrates were combined and concentrated under reduced pressure to obtain the purple solid product pyridine-2,3,6-triamine (16 mg, crude product). LCMS (ESI) [M+H]+: 125.08.

[0213] Step 2: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-imidazo[4,5-b]pyridine-5-amine

[0214] The compounds pyridine-2,3,6-triamine (16 mg, 0.13 mmol, 1.0 eq.), (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (46 mg, 0.13 mmol, 1.0 eq.), and ammonium chloride (17 mg, 0.32 mmol, 2.5 eq.) were added to phosphorus oxychloride (1 mL), heated to 100 °C, and stirred for 4 hours. After the reaction was complete, a saturated sodium bicarbonate aqueous solution was slowly added to quench the reaction. The mixture was extracted multiple times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified to obtain a yellow solid product, 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-imidazo[4,5-b]pyridine-5-amine (5.5 mg, yield 9.65%). LCMS (ESI) [M+H]+: 443.15. 1 H NMR(400MHz, DMSO-d6)δ12.41(s,1H),7.54(d,J=19.1,8.6Hz,1H),7.13–7.06(m,1H),7.05–6.95(m,1H),6.35(d,J=22.9,8.6Hz,1H),5 .87(s,2H),5.53(d,1H),4.50(dd,J=11.3,7.5Hz,1H),3.97(d,J=2.0Hz,3H),2.85(m,J=7.3Hz,1H),1.63(s,3H),0.77(d,J=7.6Hz,3H). 19 F NMR(376MHz, DMSO-d6)δ-73.49,-138.34,-155.09.

[0215] Example 14: Synthesis of 2-[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-benzo[d]imidazol-4-carboxylic acid (compound 43)

[0216] Step 1: Synthesis of methyl 2-amino-3-[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl]benzoate

[0217] The compound (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (30 mg, 0.083 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (1.0 mL), followed by the addition of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (49 mg, 0.12 mmol, 1.5 eq) and diisopropylethylamine (30 μl, 0.18 mmol, 2.0 eq). The reaction was carried out at room temperature for 0.5 h, followed by the addition of ethyl 4-amino-5-nitropropionate (17 mg, 0.11 mmol, 1.2 eq), and the reaction was carried out at room temperature for 3 h. After the reaction was complete, the sample was extracted with water and ethyl acetate, and separated by silica gel stencil using petroleum ether:ethyl acetate = 3:1 as the developing solvent, to give a white solid compound, methyl 2-amino-3-[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamate]benzoate (30 mg, yield 70.50%). LCMS (ESI) [M+H]+: 503.15. 1 H NMR(400MHz, DMSO-d6)δ9.52(s,1H),7.65(d,J=6.5Hz,1H),7.31(d,J=6.1Hz,1H),7.25–7.16(m,2H),6.58(t,J=7.9Hz,1H),6.26(s,2H),5.1 2(d,J=10.1Hz,1H),4.22(dd,J=10.1,7.7Hz,1H),3.94(d,J=2.1Hz,3H),3.80(s,3H),2.76(m,J=7.5Hz,1H),1.61(s,3H),0.76–0.70(m,3H). 19F NMR(376MHz, DMSO-d6)δ-72.77,-73.04,-137.36–-137.97,-138.21,-154.57.

[0218] Step 2: Synthesis of methyl 2-[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-benzo[d]imidazolium-4-carboxylic acid

[0219] Methyl 2-amino-3-[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido]benzoate (30 mg, 0.059 mmol, 1.0 eq) was added to acetic acid (1 mL) and reacted at 60 °C for 12 hours. After the reaction was complete, the mixture was neutralized with saturated sodium bicarbonate, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to give a yellow solid methyl 2-[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-benzo[d]imidazolium-4-carboxylic acid (25 mg, yield 86.45%). LCMS(ESI)[M+H]+:485.14.

[0220] Step 3: Synthesis of 2-[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-benzo[d]imidazol-4-carboxylic acid

[0221] Methyl 2-[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-benzo[d]imidazolium-4-carboxylic acid (25 mg, 0.051 mmol, 1.0 eq.) was dissolved in methanol (1 mL), and lithium hydroxide solution (2N, 0.5 mL) was added. The reaction was carried out at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated directly, neutralized with hydrochloric acid, and extracted with ethyl acetate to prepare and purify a white solid product 2-[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-benzo[d]imidazolium-4-carboxylic acid (9.5 mg, yield 39.13%). LCMS(ESI)[M+H]+:471.13. 1H NMR (400MHz, DMSO-d6) δ8.12(d,J=17.5Hz,1H),7.89–7.71(m,1H),7.60(d,J=19.6Hz,1H),7.18–7.07(m,2H),5.75(d,J=11.0Hz,1 H),4.51(dd,J=11.0,7.6Hz,1H),3.96(d,J=2.1Hz,3H),2.89(t,J=7.5Hz,1H),2.47–2.40(m,1H),1.66(s,3H),0.83–0.75(m,3H). 19 F NMR(376MHz, DMSO-d6)δ-68.69,-133.41,-150.34.

[0222] Example 15: Synthesis of 2-[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-4-(4-methylpiperazin-1-yl)-1H-imidazo[4,5-c]pyridine (compound 49)

[0223] Step 1: Synthesis of (2S,3R,4R,5S)-N-(4-amino-2-chloropyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0224] 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-benzo[d]imidazolium-6-carboxylic acid (50 mg, 0.14 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (80 mg, 0.21 mmol, 1.5 eq) and N,N-diisopropylethylamine (90 mg, 0.7 mmol, 5.0 eq) were added. The mixture was reacted at room temperature for 10 minutes, and then 2-chloropyridine-3,4-diamine (30 mg, 0.21 mmol, 1.5 eq) was added. The reaction was continued at room temperature for 1 hour. After the reaction was complete, ethyl acetate and water were added for extraction, and the organic phase was concentrated to obtain the crude product (2S,3R,4R,5S)-N-(4-amino-2-chloropyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (60 mg). LCMS (ESI) [M+H]+: 480.10.

[0225] Step 2: Synthesis of 4-chloro-2-2-[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-imidazo[4,5-c]pyridine

[0226] Weigh (2S,3R,4R,5S)-N-(4-amino-2-chloropyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (60.0 mg, 0.13 mmol, 1.0 eq.), add ethanol (2 mL) and sodium hydroxide aqueous solution (2 mL, 10% wt.), and react at 80 °C for 2 hours. After the reaction is complete, the reaction solution is concentrated under vacuum and separated by thin-layer chromatography (petroleum ether: ethyl acetate = 5:1) to give a white solid 4-chloro-2-2-[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-imidazo[4,5-c]pyridine (40 mg, yield 67%). LCMS(ESI)[M+H]+:462.82. 1 H NMR (400MHz, DMSO) δ13.45(s,1H),8.10(d,J=5.6Hz,1H),7.56(d,J=5.5Hz,1H),7.21–7.06(m,2H) ,5.84–5.73(m,1H),4.08-3.95(m,4H),2.89(t,J=7.5Hz,1H),1.65(s,3H),0.80(d,J=7.4Hz,3H).

[0227] Step 3: Synthesis of 2-[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-4-(4-methylpiperazin-1-yl)-1H-imidazo[4,5-c]pyridine

[0228] Weigh 30.0 mg (0.065 mmol, 1.0 eq.) of 4-chloro-2-2-[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-imidazo[4,5-c]pyridine, add 0.5 mL of 1-methylpiperazine, and react at 100 °C for 8 hours. After the reaction is complete, concentrate the reaction solution and purify to obtain the white solid target product 2-[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-4-(4-methylpiperazin-1-yl)-1H-imidazo[4,5-c]pyridine (13 mg, yield 38%). LCMS(ESI)[M+H]+:526.22. 1 H NMR (400MHz, DMSO) δ7.77(d,J=5.6Hz,1H),7.18-7.05(m,2H),6.82(d,J=5.6Hz,1H),5.72(d,J=11.3Hz,1H),4.45(dd,J=11.2,7.5Hz ,1H),3.98(s,4H),3.96(d,J=1.9Hz,3H),2.86(m,J=7.5Hz,1H),2.38(t,J=5.0Hz,4H),2.21(s,3H),1.66(s,3H),0.86-0.79(m,3H). 19 F NMR (376MHz, DMSO) delta -73.46, -138.34, -155.15.

[0229] Example 16: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-4-(3,4-dimethylpiperazin-1-yl)-1H-imidazo[4,5-c]pyridine (compound 50)

[0230] Step 1: Synthesis of 2-(3,4-dimethylpiperazin-1-yl)-3-nitropyridine-4-amine

[0231] 2-Chloro-3-nitropyridine-4-amine (100 mg, 0.55 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (2 mL), and cesium carbonate (275 mg, 0.85 mmol, 1.5 eq) and 1,2-dimethylpiperazine (100 mg, 0.85 mmol, 1.5 eq) were added. The reaction was carried out at 80 °C for 16 hours. After the reaction was completed, ethyl acetate and water were added for extraction. The organic phase was concentrated and purified by thin-layer chromatography to obtain 2-(3,4-dimethylpiperazin-1-yl)-3-nitropyridine-4-amine (200 mg). LCMS (ESI) [M+H]+: 252.14. 1 H NMR (400MHz, DMSO) δ7.97 (s, 1H), 7.67 (d, J = 5.7Hz, 1H), 7.29 (s, 2H), 6.22 (d ,J=5.7Hz,1H),2.91(s,3H),2.75(s,3H),2.19(s,3H),0.98(d,J=6.2Hz,3H).

[0232] Step 2: Synthesis of 2-(3,4-dimethylpiperazin-1-yl)pyridine-3,4-diamine

[0233] 2-(3,4-dimethylpiperazin-1-yl)-3-nitropyridine-4-amine (200 mg, 0.8 mmol, 1.0 eq) was dissolved in methanol (2 mL), and 10% palladium / carbon (30 mg) was added. Hydrogen gas was purged three times, and the reaction was carried out at room temperature for 1 hour. After the reaction was complete, the solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain a brown liquid, 2-(3,4-dimethylpiperazin-1-yl)pyridine-3,4-diamine (100 mg). LCMS (ESI) [M+H]+: 222.16. 1 H NMR (400MHz, DMSO) δ7.32(d,J=5.2Hz,1H),6.29(d,J=5.3Hz,1H),5.27(s,2H),4.12(m,J=5.3Hz,1H),4. 01 (s, 2H), 3.19 (d, J = 4.3Hz, 4H), 3.03 (m, J = 16.7, 11.6, 2.3Hz, 2H), 2.23 (s, 3H), 1.01 (d, J = 6.2Hz, 3H).

[0234] Step 3: Synthesis of (2R,3S,4S,5R)-N-(3-amino-2-(3,4-dimethylpiperazin-1-yl)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0235] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-benzo[d]imidazolium-6-carboxylic acid (30 mg, 0.08 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (80 mg, 0.21 mmol, 1.5 eq) and N,N-diisopropylethylamine (90 mg, 0.7 mmol, 5.0 eq) were added. The mixture was reacted at room temperature for 10 minutes, and then 2-(3,4-dimethylpiperazin-1-yl)pyridine-3,4-diamine (30 mg, 0.13 mmol, 1.5 eq) was added. The mixture was reacted at room temperature for 1 hour. After the reaction was complete, ethyl acetate and water were added for extraction. The organic phase was concentrated to obtain the crude product (2R,3S,4S,5R)-N-(3-amino-2-(3,4-dimethylpiperazin-1-yl)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (30 mg), which was directly used in the next reaction. LCMS (ESI) [M+H]+: 558.24.

[0236] Step 4: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-4-(3,4-dimethylpiperazin-1-yl)-1H-imidazo[4,5-c]pyridine

[0237] Weigh (2R,3S,4S,5R)-N-(3-amino-2-(3,4-dimethylpiperazin-1-yl)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (25.0 mg, 0.045 mmol, 1.0 eq.), add ethanol (2 mL) and 10% sodium hydroxide aqueous solution (2 mL), and react at 80 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under vacuum, and the white solid target 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-4-(3,4-dimethylpiperazin-1-yl)-1H-imidazo[4,5-c]pyridine (2.3 mg) was obtained by HPLC. LCMS (ESI) [M+H]+: 540.23. NMR(400MHz, DMSO-d6)δ12.80(s,1H),7.74(d,J=5.6Hz,1H),7.15(d,J=6.8Hz,1H),7.13–7.03(m,1H),6 .79(dd,J=5.7,1.4Hz,1H),5.71(d,J=11.2Hz,1H),4.88(q,J=15.6Hz,2H),4.43(q,J=7.3,4.9Hz,1H),3 .94(d,J=1.8Hz,3H),3.09–3.01(m,1H),2.84(t,J=7.4Hz,1H),2.79–2.62(m,2H),2.18(d,J=1.4Hz,3H) ,2.12(dd,J=11.3,7.9Hz,1H),2.02(s,1H),1.64(s,3H),0.98(dd,J=6.2,3.6Hz,3H),0.84–0.76(m,3H).

[0238] Example 17: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-4-(3-methylpiperazin-1-yl)-1H-imidazo[4,5-c]pyridine (compound 51)

[0239] Step 1: Synthesis of tert-butyl 4-(4-amino-3-nitropyridin-2-yl)-2-methylpiperazine-1-carboxylate

[0240] 2-Chloro-3-nitropyridin-4-amine (150 mg, 0.87 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (2 mL), and cesium carbonate (422 mg, 1.3 mmol, 1.3 eq) and tert-butyl 2-methylpiperazine-1-carboxylate (260 mg, 1.3 mmol, 1.5 eq) were added. The reaction was carried out at 80 °C for 16 hours. After the reaction was completed, ethyl acetate and water were added for extraction. The organic phase was concentrated and thin-layer chromatography was used to obtain tert-butyl 4-(4-amino-3-nitropyridin-2-yl)-2-methylpiperazine-1-carboxylate (260 mg). LCMS (ESI) [M-100+1]+: 238.13. 1 H NMR (400MHz, DMSO) δ7.70(d,J=5.7Hz,1H),7.30(s,2H),6.27(d,J=5.8Hz,1H),4.15(dd,J=6.9,3.5Hz,1H),3.67(m,J=13 .3,3.8Hz,1H),3.55–3.39(m,2H),3.31–3.17(m,1H),2.95–2.84(m,1H),2.01(s,1H),1.42(s,9H),1.09(d,J=6.6Hz,3H).

[0241] Step 2: Synthesis of tert-butyl 4-(3,4-diaminopyridin-2-yl)-2-methylpiperazine-1-carboxylate

[0242] 4-(4-amino-3-nitropyridin-2-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (260 mg, 0.77 mmol, 1.0 eq) was dissolved in methanol (2 mL), and 10% palladium / carbon (30 mg) was added. Hydrogen gas was purged three times, and the reaction was carried out at room temperature for 1 hour. After the reaction was complete, the solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain a black solid, 4-(3,4-diaminopyridin-2-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (220 mg), which was directly used in the next step of the reaction. LCMS (ESI) [M+H]+: 308.20. 1 H NMR (400MHz, DMSO) δ7.33(d,J=5.2Hz,1H),6.31(d,J=5.3Hz,1H),5.34(s,2H),4.20(s,1H),4.09(s,2H),3.77(m,J=13.0,2 .7Hz,1H),3.29–3.10(m,2H),3.02(m,J=12.1,1.9Hz,1H),2.73(m,J=12.1,3.8Hz,1H),1.44(s,9H),1.30(d,J=6.7Hz,3H).

[0243] Step 3: Synthesis of tert-butyl 4-{3-amino-4-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamate]pyridin-2-yl}-2-methylpiperazine-1-carboxylate

[0244] 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-benzo[d]imidazolium-6-carboxylic acid (50 mg, 0.14 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL), followed by the addition of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (76 mg, 0.21 mmol, 1.5 eq) and N,N-diisopropylethylamine (90 mg, 0.7 mmol, 5.0 eq). The mixture was reacted at room temperature for 10 minutes, and then 4-(3,4-diaminopyridin-2-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (70 mg, 0.21 mmol, 1.5 eq) was added. The mixture was reacted at room temperature for 1 hour. After the reaction was complete, ethyl acetate and water were added for extraction, and the organic phase was concentrated to give the crude product tert-butyl 4-{3-amino-4-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido]pyridin-2-yl}-2-methylpiperazine-1-carboxylate (30 mg). LCMS (ESI) [M+H]+: 644.28.

[0245] Step 4: Synthesis of tert-butyl 4-{3-amino-4-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamate]pyridin-2-yl}-2-methylpiperazine-1-carboxylate

[0246] Weigh 20.0 mg (0.05 mmol, 1.0 eq.) of 4-{3-amino-4-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido]pyridin-2-yl}-2-methylpiperazine-1-carboxylic acid tert-butyl ester, add 2 mL of ethanol and 2 mL of 10% sodium hydroxide aqueous solution, and react at 85 °C for 2 hours. After the reaction is complete, extract with ethyl acetate and water, and concentrate the organic phase to obtain a yellow solid crude product 4-{3-amino-4-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido]pyridin-2-yl}-2-methylpiperazine-1-carboxylic acid tert-butyl ester (20 mg). LCMS(ESI)[M-100+1]+:526.22.

[0247] Step 5: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-4-(3-methylpiperazin-1-yl)-1H-imidazo[4,5-c]pyridine

[0248] Weigh 30.0 mg, 0.032 mmol, 1.0 eq. of 4-{3-amino-4-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido]pyridin-2-yl}-2-methylpiperazine-1-carboxylic acid tert-butyl ester, add 0.5 mL of trifluoroacetic acid and 0.5 mL of dichloromethane, and react at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was concentrated under vacuum, and HPLC was used to prepare a white solid 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-(3-methylpiperazin-1-yl)-1H-imidazo[4,5-c]pyridine (10 mg). LCMS (ESI) [M+H]+: 526.22. 1H NMR (400MHz, DMSO-d6) δ12.84(s,1H),7.78(d,J=5.6Hz,1H),7.19–7.04(m,2H),6.84(d,J=5.6Hz,1H),5.71(d,J=11.2Hz,1H),5.04(t,J=14.7Hz,2 H),4.49–4.37(m,1H),3.94(d,J=1.9Hz,3H),3.12-2.97(m,3H),2.93–2.6 6(m,3H),1.64(s,3H),1.08(dd,J=6.4,3.9Hz,3H),0.81(d,J=7.4Hz,3H).

[0249] Example 18: Synthesis of ((R)-4-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)piperazin-2-yl)methanol (compound 71)

[0250] Step 1: Synthesis of (R)-2-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylic acid tert-butyl ester

[0251] (R)-2-hydroxymethylpiperazine-1-carboxylic acid tert-butyl ester (300 mg, 1.39 mmol, 1.0 eq) and imidazole (199 mg, 2.91 mmol, 2.1 eq) were added to dichloromethane (12 mL), purged with nitrogen, and a dichloromethane (4 mL) solution of tert-butyldimethylchlorosilane (419 mg, 2.77 mmol, 2.0 eq) was added dropwise at 0 °C. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, water was added, and the mixture was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain colorless oil (R)-2-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylic acid tert-butyl ester (432 mg, 94.22%), which was used directly in the next step. LCMS (ESI) [M+H]+: 331.23

[0252] Step 2: Synthesis of (R)-4-(4-amino-3-nitropyridin-2-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylic acid tert-butyl ester

[0253] 4-Amino-2-chloro-3-nitropyridine (170 mg, 0.98 mmol, 1.0 eq), (R)-2-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylic acid tert-butyl ester (420 mg, 1.27 mmol, 1.3 eq), and N,N-diisopropylethylamine (380 mg, 2.94 mmol, 3.0 eq) were added to N,N-dimethylformamide (10 mL), purged with nitrogen, and stirred at 100 °C for 16 hours. After the reaction was complete, the mixture was purified by reverse-phase column chromatography (water:acetonitrile = 1:4) to give yellow oil (R)-4-(4-amino-3-nitropyridine-2-yl)-2-((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylic acid tert-butyl ester (420 mg, 91.69%). LCMS(ESI)[M+H]+:468.26, 412.26, 368.26. 1 H NMR (400MHz, DMSO-d6) δ7.69(d,J=5.7Hz,1H),7.32(s,2H),6.26(d,J=5.7Hz,1H),3.97(s,1H),3.73–3.46(m,6H),3 .25(dd,J=13.4,4.0Hz,1H),3.00(ddd,J=13.0,9.5,3.5Hz,1H),1.42(s,9H),0.81(s,9H),-0.06(d,J=19.4Hz,6H).

[0254] Step 3: Synthesis of (R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(3,4-diaminopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0255] (R)-4-(4-amino-3-nitropyridin-2-yl)-2-((tert-butyldimethylsilyl)oxy)methyl)piperazin-1-carboxylic acid tert-butyl ester (420 mg, 0.898 mmol) and palladium on carbon (400 mg, 5%, 53% water content) were added to methanol (20 ml). The mixture was purged with hydrogen and reacted in a hydrogen balloon at room temperature for 1 hour. After the reaction was complete, the mixture was filtered through diatomaceous earth, and the filtrate was evaporated to dryness to give a white solid (R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(3,4-diaminopyridin-2-yl)piperazin-1-carboxylic acid tert-butyl ester (390 mg, 99.22%). LCMS (ESI) [M+H]+: 438.28. 1H NMR (400MHz, DMSO-d6) δ7.30(d,J=5.2Hz,1H),6.28(d,J=5.3Hz,1H),5.31(s,2H),4.12-3.90(m,4H),3.79(d,J=12.6Hz,2H),3.61(dd,J= 9.4, 5.3Hz, 1H), 3.38 (d, J = 12.1Hz, 1H), 3.16 (d, J = 12.0Hz, 2H), 2.60 (d, J = 12.1Hz, 1H), 1.42 (s, 9H), 0.86 (s, 9H), 0.05 (d, J = 10.3Hz, 6H).

[0256] Step 4: Synthesis of (R)-4-(3-amino-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylic acid tert-butyl ester and (R)-4-(4-amino-3-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylic acid tert-butyl ester)

[0257] (R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(3,4-diaminopyridin-2-yl)piperazin-1-carboxylic acid tert-butyl ester (124 mg, 0.282 mmol, 1.0 eq), (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (100 mg, 0.282 mmol, 1.0 eq), O-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (140 mg, 0.367 mmol, 1.3 eq) and N,N-diisopropylethylamine (100 mg, 0.847 mmol, 3.0 eq) were added to dichloromethane (10 ml) and reacted at room temperature for 1 hour. After the reaction was complete, water was added, and the mixture was extracted with dichloromethane (20 ml * 3). The organic phase was collected, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a crude yellow oil (330 mg) of the condensation mixture, which was used directly in the next step. LCMS (ESI) [M+H]+: 774.36.

[0258] Step 5: Synthesis of (R)-4-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)-2-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester

[0259] The condensation mixture from the previous step (330 mg, 0.09 mmol) was added to acetic acid (5 ml) and stirred at 65°C for 6 hours. After the reaction was complete, the mixture was directly evaporated to dryness to give a yellow oil (R)-4-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)-2-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (56 mg). LCMS (ESI) [M+H]+: 642.26.

[0260] Step 6: Synthesis of ((R)-4-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)piperazin-2-yl)methanol

[0261] (R)-4-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)-2-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (56 mg, 0.08 mmol) was added to trifluoroacetic acid (5 ml) and stirred at room temperature for 1 hour. After the reaction was complete, the mixture was directly evaporated to dryness, and HPLC was used to prepare a white solid ((R)-4-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)piperazin-2-yl)methanol (14.3 mg, yield 30.26%). LCMS (ESI) [M+H]+: 542.21. 1H NMR(400MHz, DMSO-d6)δ7.75(d,J=5.5Hz,1H),7.20-7.14(m,1H),7.13–7.03(m,1H),6.79( d,J=5.6Hz,1H),5.69(d,J=11.2Hz,1H),4.99(d,J=12.3Hz,1H),4.86(d,J=12.2Hz,1H),4. 71(s,1H),4.42(dd,J=11.2,7.4Hz,1H),3.94(d,J=1.9Hz,3H),3.41(s,2H),3.30(s,1H),2 .98–2.81(m,2H),2.76–2.67(m,2H),2.64–2.53(m,1H),1.64(s,3H),0.83–0.77(m,3H).19F NMR (376MHz, DMSO-d6) δ-72.89, -137.73, -154.57 (d, J=20.6Hz).

[0262] Example 19: Synthesis of ((S)-4-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)piperazin-2-yl)methanol (compound 72)

[0263] Step 1: Synthesis of (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylic acid tert-butyl ester

[0264] (S)-2-hydroxymethylpiperazine-1-carboxylic acid tert-butyl ester (300 mg, 1.39 mmol, 1.0 eq) and imidazole (199 mg, 2.91 mmol, 2.1 eq) were added to dichloromethane (12 mL). A solution of tert-butyldimethylchlorosilane (419 mg, 2.77 mmol, 2.0 eq) in dichloromethane (4 mL) was added dropwise at 0°C, and the mixture was gradually stirred at room temperature for 2 hours. After the reaction was complete, water was added, and the mixture was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain colorless oil (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylic acid tert-butyl ester (440 mg, 95.97%), which was used directly in the next step. LCMS (ESI) [M+H]+: 331.23

[0265] Step 2: Synthesis of (S)-4-(4-amino-3-nitropyridin-2-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylic acid tert-butyl ester

[0266] 4-Amino-2-chloro-3-nitropyridine (170 mg, 0.98 mmol, 1.0 eq), (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylic acid tert-butyl ester (420 mg, 1.27 mmol, 1.3 eq), and N,N-diisopropylethylamine (380 mg, 2.94 mmol, 3.0 eq) were added to N,N-dimethylformamide (10 mL), purged with nitrogen, and stirred at 100 °C for 16 hours. After the reaction was complete, the mixture was purified by reverse-phase column chromatography (water:acetonitrile = 1:4) to give a yellow oil (S)-4-(4-amino-3-nitropyridine-2-yl)-2-((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylic acid tert-butyl ester (430 mg, 93.87%). LCMS(ESI)[M+H]+:468.26, 412.26, 368.26. 1 H NMR (400MHz, DMSO-d6) δ7.69(d,J=5.7Hz,1H),7.32(s,2H),6.26(d,J=5.7Hz,1H),3.96(s,1H),3.75-3.45(m,5H),3. 26(d,J=4.1Hz,1H),3.23(d,J=4.0Hz,1H),3.03-2.97(m,1H),1.42(s,9H),0.81(s,9H),-0.03(s,3H),-0.08(s,3H).

[0267] Step 3: Synthesis of tert-butyl (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(3,4-diaminopyridin-2-yl)piperazine-1-carboxylate

[0268] (S)-4-(4-amino-3-nitropyridin-2-yl)-2-((tert-butyldimethylsilyl)oxy)methyl)piperazin-1-carboxylic acid tert-butyl ester (430 mg, 0.919 mmol) and palladium on carbon (400 mg, 5%, 53% water content) were added to methanol (20 mL), and the mixture was purged with hydrogen and reacted in a hydrogen balloon at room temperature for 1 hour. After the reaction was complete, the mixture was filtered, and the filtrate was evaporated to dryness to give a white solid (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(3,4-diaminopyridin-2-yl)piperazin-1-carboxylic acid tert-butyl ester (402 mg, 99.89%). LCMS (ESI) [M+H]+: 438.28. 1H NMR (400MHz, DMSO-d6) δ7.32(d,J=5.2Hz,1H),6.30(d,J=5.3Hz,1H),5.33(s,2H),4.20-3.95(m,4H),3.81(d,J=12.9Hz,1H),3. 67–3.59(m,1H),3.40(d,J=12.2Hz,1H),3.21–3.14(m,2H),2.65-2.53(m,2H),1.44(s,9H),0.88(s,9H),0.07(d,J=10.4Hz,6H).

[0269] Step 4: Synthesis of (S)-4-(3-amino-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylic acid tert-butyl ester and (S)-4-(4-amino-3-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylic acid tert-butyl ester)

[0270] (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(3,4-diaminopyridin-2-yl)piperazin-1-carboxylic acid tert-butyl ester (124 mg, 0.282 mmol, 1.0 eq), (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (100 mg, 0.282 mmol, 1.0 eq), O-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (140 mg, 0.367 mmol, 1.3 eq) and N,N-diisopropylethylamine (100 mg, 0.847 mmol, 3.0 eq) were added to dichloromethane (10 ml) and reacted at room temperature for 1 hour. After the reaction was complete, water was added, and the mixture was extracted with dichloromethane (20 ml * 3). The organic phase was collected, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a crude yellow oil (345 mg) of the condensation mixture, which was used directly in the next step. LCMS (ESI) [M+H]+: 774.36.

[0271] Step 5: Synthesis of (S)-4-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)-2-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester

[0272] The condensation mixture from the previous step (345 mg, 0.523 mmol) was added to acetic acid (5 ml) and stirred at 65°C for 6 hours. After the reaction was complete, the mixture was directly evaporated to dryness to give a yellow oil (S)-4-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)-2-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (59 mg). LCMS (ESI) [M+H]+: 642.26.

[0273] Step 6: Synthesis of ((S)-4-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)piperazin-2-yl)methanol

[0274] (S)-4-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)-2-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (59 mg, 0.09 mmol) was added to trifluoroacetic acid (5 ml) and stirred at room temperature for 1 hour. After the reaction was complete, the mixture was directly evaporated to dryness, and HPLC was used to prepare a white solid ((S)-4-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)piperazin-2-yl)methanol (18.1 mg, yield 36.35%). LCMS (ESI) [M+H]+: 542.21. 1H NMR(400MHz,DMSO-d6)δ7.74(d,J=5.6Hz,1H),7.17-7.05(m,2H),6.78(d,J=5.6Hz,1H) ,5.69(d,J=11.2Hz,1H),5.03(d,J=12.3Hz,1H),4.94(d,J=12.0Hz,1H),4.43(dd,J=11. 2,7.5Hz,1H),3.94(d,J=1.9Hz,3H),2.91(d,J=11.1Hz,2H),2.88–2.79(m,1H),2.73–2 .62(m,3H),2.57(d,J=12.5Hz,2H),2.44(s,1H),1.64(s,3H),0.80(d,J=7.6Hz,3H).19F NMR(376MHz, DMSO-d6)δ-72.89,-137.73,-154.57.

[0275] Example 20: Synthesis of N-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)ethane-1,2-diamine (compound 81)

[0276] Step 1: Synthesis of (2R,3S,4S,5R)-N-(2-chloro-3-nitropyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0277] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (210 mg, 0.59 mmol, 1.0 eq.) and N,N-diisopropylethylamine (383.24 mg, 2.97 mmol, 5.0 eq.) were dissolved in dichloromethane (3.0 mL). 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (291 mg, 0.77 mmol, 1.3 eq.) was added, and the mixture was stirred at room temperature for 5 minutes. Then, 2-chloro-3-nitropyridine-4-amine (153.9 mg, 0.89 mmol, 1.3 eq.) was added, and the mixture was reacted at room temperature for 5 hours. After the reaction was complete, the reaction solution was washed with water, extracted with ethyl acetate, and the organic phases were combined and concentrated. The mixture was then purified by normal-phase column chromatography (petroleum ether:ethyl acetate = 20:1) to give a yellow solid (2R,3S,4S,5R)-N-(2-chloro-3-nitropyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (140.9 mg, yield 46.8%). LCMS (ESI) [M+H]+: 510.08. 1 H NMR (400MHz, DMSO) δ10.65(s,1H),8.53(d,J=5.6Hz,1H),7.99(d,J=5.6Hz,1H),7.17(dd,J=9.7,6.4Hz,2H),5.24(d,J=10.2Hz ,1H),4.19(dd,J=10.2,7.6Hz,1H),3.94(d,J=2.1Hz,3H),2.72(q,J=7.6Hz,1H),1.61(s,3H),0.71(dd,J=7.5,2.8Hz,3H).19F NMR (376MHz, DMSO) delta -72.94, -137.65, -154.63.

[0278] Step 2: Synthesis of tert-butyl(2-((4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamate)-3-nitropyridin-2-yl)amino)ethyl)carbamate

[0279] (2R,3S,4S,5R)-N-(2-chloro-3-nitropyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (100.0 mg, 0.20 mmol, 1.0 eq.), (2-aminoethyl)carbamate tert-butyl ester (37.7 mg, 0.24 mmol, 1.2 eq.), and triethylamine (49.7 mg, 0.49 mmol, 2.0 eq.) were dissolved in N,N-dimethylformamide (1.0 mL) and reacted at 80 °C for 1 hour. After the reaction was complete, ethyl acetate was added for dilution, the reaction solution was washed with saturated brine, the organic phase was concentrated, and purified by normal-phase column chromatography (petroleum ether: ethyl acetate = 3:1) to give a yellow solid tert-butyl(2-((4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamate)-3-nitropyridin-2-yl)amino)ethyl)carbamate (150.1 mg). LCMS (ESI) [M+H]+: 634.21, 1 H NMR (400MHz, DMSO) δ11.75(s,1H),8.63(s,1H),8.21(d,J=5.5Hz,1H),7.66(d,J=5. 5Hz,1H),7.34(t,J=7.4Hz,1H),7.17(d,J=8.8Hz,1H),6.94(t,J=5.6Hz,1H),5.29( d,J=11.0Hz,1H),4.21–4.16(m,1H),3.92(d,J=2.0Hz,3H),3.58(d,J=7.7Hz,2H),3 .16(q,J=5.9Hz,2H),1.67(s,3H),1.40(s,1H),1.35(s,9H),0.73–0.69(m,3H).19F NMR (376MHz, DMSO) delta -73.40, -138.15, -155.41.

[0280] Step 3: Synthesis of tert-butyl(2-((3-amino-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamate)pyridin-2-yl)amino)ethyl)carbamate

[0281] 150.0 mg, 0.24 mmol, 1.0 eq. of tert-butyl(2-((4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamate)-3-nitropyridin-2-yl)amino)ethyl)carbamate (3.0 mL) was dissolved in methanol, 5% palladium on carbon (150.0 mg) was added, and the mixture was purged with hydrogen three times. The reaction was carried out at room temperature for 16 hours. After the reaction was complete, the mixture was filtered, the filter cake was washed with methanol, and the filtrate was concentrated to give tert-butyl(2-((3-amino-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamate)pyridin-2-yl)amino)ethyl)carbamate (107.1 mg). LCMS (ESI) [M+H]+: 604.25.

[0282] Step 4: Synthesis of tert-butyl(2-((2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)amino)ethyl)carbamate

[0283] 107.0 mg, 0.18 mmol, 1.0 eq. of tert-butyl (2-((3-amino-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamate)pyridin-2-yl)amino)ethyl)carbamate (107.0 mg, 0.18 mmol, 1.0 eq.) was dissolved in 10% sodium hydroxide solution / ethanol (200 μL / 200 μL) and reacted at 70 °C for 2 hours. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, and separated. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to give a yellow solid tert-butyl(2-((2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)amino)ethyl)carbamate (70.0 mg). LCMS (ESI) [M+H]+: 586.24. 1H NMR (400MHz, DMSO) δ12.72 (s, 1H), 7.66 (d, J = 5.8Hz, 1H), 7.16–7.00 (m, 2H), 6.91(s,1H),6.68(d,J=5.8Hz,1H),6.52(s,1H),5.62(d,J=11.1Hz,1H),4.49 (t,J=9.5Hz,1H),3.97(d,J=2.1Hz,3H),3.47(q,J=6.2Hz,2H),3.17–3.12(m ,2H),2.88(p,J=7.5Hz,1H),1.64(s,3H),1.35(s,9H),0.81–0.76(m,3H).19F NMR (376MHz, DMSO) delta -73.47, -138.17, -154.92.

[0284] Step 5: Synthesis of N-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)ethane-1,2-diamine

[0285] 70.0 mg, 0.12 mmol, 1.0 eq. of tert-butyl(2-((2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)amino)ethyl)carbamate was dissolved in 2.0 mL of 4 M hydrochloric acid-1,4-dioxane solution and reacted at room temperature for 16 hours. After the reaction was complete, the mixture was filtered, and the organic phase was prepared under high pressure (1‰ trifluoroacetic acid aqueous solution / acetonitrile system) to give a yellow N-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)ethane-1,2-diamine (5.0 mg, yield 8.6%). LCMS (ESI) [M+H]+: 486.19. 1H NMR (400MHz, DMSO) δ13.65(s,1H),8.95(s,1H),8.20(t,J=5.7Hz,3H),7.66(d,J=6.9Hz,1H),7.12(dd,J=10.3,5.7Hz,3H),5.74(d,J=11.2Hz,1H), 4.55(dd,J=11.2,7.6Hz,1H),3.97(s,3H),3.96–3.88(m,2H),3.11(q,J= 5.9Hz,2H),2.93(p,J=7.5Hz,1H),1.69(s,3H),0.79(d,J=7.4Hz,3H).19F NMR (376MHz, DMSO) delta -73.54, -137.90, -154.79.

[0286] Example 21: Synthesis of (4-((2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)amino)piperidin-2-yl)methanol (compound 74)

[0287] Step 1: Synthesis of 1-(tert-butyl)-2-methyl-4-aminopiperidine-1,2-dicarboxylic acid ester

[0288] 1-(tert-butyl)-2-methyl-4-oxopiperidine-1,2-dicarboxylic acid ester (650.0 mg, 2.53 mmol, 1.0 eq.) and acetic acid (2 drops) were dissolved in methanol (6.5 mL). Ammonium acetate (1.9 g, 25.28 mmol, 10.0 eq.) was added in portions, and the reaction was carried out at room temperature for 1 hour. Sodium cyanoborohydride (635.4 mg, 10.11 mmol, 4.0 eq.) was added, and the reaction was carried out at room temperature for 48 hours. After the reaction was complete, the reaction solution was concentrated and diluted (150 mL) with a dichloromethane:methanol mixture of 9:1. The mixture was washed with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated to give a yellow solid 1-(tert-butyl)-2-methyl-4-aminopiperidine-1,2-dicarboxylic acid ester (580.5 mg, yield 88.8%). 1 H NMR (400MHz, DMSO) δ4.88–4.62(m,1H),3.66(d,J=5.1Hz,2H),3.60(s,3H),2.97–2.77( m,1H),2.21–1.93(m,2H),1.88–1.67(m,2H),1.59–1.45(m,2H),1.36(d,J=5.6Hz,9H).

[0289] Step 2: Synthesis of 1-(tert-butyl)-2-methyl-4-((4-amino-3-nitropyridin-2-yl)amino)piperidine-1,2-dicarboxylic acid ester

[0290] 1-(tert-butyl)-2-methyl-4-aminopiperidine-1,2-dicarboxylic acid ester (200.0 mg, 0.76 mmol, 1.0 eq.), 2-chloro-3-nitropyridin-4-amine (214.4 mg, 1.24 mmol, 1.6 eq.), and sodium carbonate (164.2 mg, 1.55 mmol, 2.0 eq.) were dissolved in N,N-dimethylformamide (2.0 mL) and reacted at 100 °C for 16 hours. After the reaction was complete, the mixture was filtered, and the filtrate was separated by reverse-phase chromatography (1‰ formic acid aqueous solution / acetonitrile system) to obtain a yellow solid 1-(tert-butyl)-2-methyl-4-((4-amino-3-nitropyridin-2-yl)amino)piperidine-1,2-dicarboxylic acid ester (165.5 mg, yield 54.0%). LCMS (ESI) [M+H]+: 396.23. 1 H NMR (400MHz, DMSO) δ8.52(d,J=7.3Hz,1H),6.12(d,J=5.9Hz,1H),5.76(s,2H),4.90–4.78(m,1H),4.07–3. 90(m,2H),3.70(d,J=4.6Hz,3H),3.07–2.89(m,1H),2.33(s,2H),1.97–1.76(m,2H),1.41(d,J=7.1Hz,9H).

[0291] Step 3: Synthesis of 1-(tert-butyl)-2-methyl-4-((4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-3-nitropyridin-2-yl)amino)piperidine-1,2-dicarboxylic acid ester

[0292] 1-(tert-butyl)-2-methyl-4-((4-amino-3-nitropyridin-2-yl)amino)piperidine-1,2-dicarboxylic acid ester (160.0 mg, 0.40 mmol, 1.0 eq.), (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (143.4 mg, 0.40 mmol, 1.0 eq.), and phosphorus oxychloride (93.12 mg, 0.61 mmol, 1.5 eq.) were dissolved in pyridine (2.0 mL) and reacted at room temperature for 1 hour. After the reaction was complete, the reaction solution was washed with 1M dilute hydrochloric acid, extracted with ethyl acetate, and purified by normal-phase column chromatography (petroleum ether: ethyl acetate = 5:1) to give a yellow solid 1-(tert-butyl)-2-methyl-4-((4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-3-nitropyridin-2-yl)amino)piperidine-1,2-dicarboxylic acid ester (150.8 mg, yield 51.5%). LCMS (ESI) [M+H]+: 732.32. 1 H NMR (400MHz, DMSO) δ11.65(d,J=5.3Hz,1H),8.22(d,J=5.6Hz,1H),8.17(t,J=6.7Hz,1H),7.65(dd, J=5.6,3.4Hz,1H),7.33(td,J=6.8,3.3Hz,1H),7.19–7.15(m,1H),5.28(d,J=10.9Hz,1H),4.91–4.7 9(m,1H),4.22–4.11(m,2H),3.92–3.90(m,3H),3.70(d,J=4.6Hz,3H),3.09–2.83(m,1H),2.75–2.7 0(m,1H),2.35–2.27(m,1H),1.91(s,2H),1.66(s,2H),1.42(s,3H),1.37(s,9H),0.73–0.70(m,3H).

[0293] Step 4: Synthesis of 1-(tert-butyl)-2-methyl-4-((3-amino-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)amino)piperidine-1,2-dicarboxylic acid ester

[0294] 1-(tert-butyl)-2-methyl-4-((4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-3-nitropyridin-2-yl)amino)piperidine-1,2-dicarboxylic acid ester (140.0 mg, 0.19 mmol, 1.0 eq.) was dissolved in methanol (3.0 mL), 5% palladium on carbon (150.0 mg) was added, and the mixture was purged with hydrogen three times. The reaction was carried out at room temperature for 16 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated to give a brown solid 1-(tert-butyl)-2-methyl-4-((3-amino-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)amino)piperidine-1,2-dicarboxylic acid ester (110.7 mg, yield 82.6%). LCMS (ESI) [M+H]+: 702.35. 1 H NMR (400MHz, CD3OD) δ7.53–7.39(m,1H),7.18(dq,J=7.1,3.4Hz,1H),6.99(q,J=8.8Hz,1H),6.83–6.63(m,1H ),5.11(dd,J=10.6,2.3Hz,1H),4.95(d,J=5.9Hz,1H),4.36–4.23(m,1H),4.08–4.02(m,1H),3.99(d,J=2.1H z,3H),3.84(d,J=10.2Hz,1H),3.77(d,J=3.8Hz,2H),3.36(d,J=2.2Hz,1H),3.31(s,3H),2.77(q,J=7.6Hz,1 H), 1.87 (d, J = 17.1Hz, 1H), 1.72 (d, J = 5.8Hz, 1H), 1.68 (s, 3H), 1.46 (d, J = 14.3Hz, 9H), 0.82 (d, J = 7.5Hz, 3H).

[0295] Step 5: Synthesis of 1-(tert-butyl)-2-methyl-4-((2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)amino)piperidine-1,2-dicarboxylic acid ester

[0296] 1-(tert-butyl)-2-methyl-4-((3-amino-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)amino)piperidine-1,2-dicarboxylic acid ester (90.0 mg, 0.13 mmol, 1.0 eq.) was dissolved in acetic acid (2.0 mL) and reacted at 80 °C for 2 hours. After the reaction was complete, acetic acid was neutralized in saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phase was concentrated and purified by normal-phase column chromatography (petroleum ether: ethyl acetate = 1:1.5) to give a yellow 1-(tert-butyl)-2-methyl-4-((2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)amino)piperidine-1,2-dicarboxylic acid ester (49.8 mg, yield 56.9%). LCMS (ESI) [M+H]+: 684.28. 1 H NMR(400MHz,DMSO)δ7.62(d,J=5.8Hz,1H),7.10–6.99(m,2H),6.69(dd,J=5.8,0.9Hz ,1H),5.61(d,J=11.3Hz,1H),4.90–4.75(m,1H),4.56(d,J=7.9Hz,1H),4.06–3.86(m ,5H),3.74–3.65(m,3H),3.17(s,1H),3.05(t,J=13.2Hz,1H),2.93–2.87(m,1H),2.2 8(s,1H),2.02–1.80(m,2H),1.66(s,3H),1.40(d,J=17.8Hz,9H),0.80–0.72(m,3H).

[0297] Step 6: Synthesis of tert-butyl 4-((2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)amino)-2-(hydroxymethyl)piperidine-1-carboxylic acid

[0298] 1-(tert-butyl)-2-methyl-4-((2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)amino)piperidine-1,2-dicarboxylic acid ester (30.0 mg, 0.04 mmol, 1.0 eq.) was dissolved in diethyl ether (1.0 mL), and lithium aluminum hydride (3.3 mg, 0.08 mmol, 2.0 eq.) was added at 0 °C. The mixture was then purged with nitrogen, and the temperature was slowly raised to room temperature for 3 hours. After the reaction was complete, the mixture was filtered, the filter cake was washed with diethyl ether, and the filtrate was concentrated to give a white solid tert-butyl 4-((2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)amino)-2-(hydroxymethyl)piperidine-1-carboxylic acid (23.0 mg, yield 79.9%). LCMS (ESI) [M+H]+: 656.29.

[0299] Step 7: Synthesis of (4-((2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)amino)piperidin-2-yl)methanol

[0300] 4-((2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)amino)-2-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (23.0 mg, 0.04 mmol, 1.0 eq.) was dissolved in 4M hydrochloric acid-1,4-dioxane solution (2.0 mL) and reacted at room temperature for 16 hours. After the reaction was completed, the product was directly concentrated, and the crude product was prepared under high pressure (1‰ trifluoroacetic acid system) to give white (4-((2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)amino)piperidin-2-yl)methanol (5.0 mg, yield 25.6%). LCMS (ESI) [M+H]+: 556.24. 1H NMR (400MHz, DMSO) δ7.60(d,J=5.8Hz,1H),7.02(d,J=9.1Hz,2H),6.63(d,J=5 .8Hz,1H),5.86(s,1H),5.58(s,1H),4.57(s,1H),4.44(dd,J=11.2,7.6Hz,1H ),4.31(s,1H),3.91(d,J=2.0Hz,3H),3.24(s,1H),2.80(dq,J=11.5,5.8Hz,4 H),1.72–1.59(m,3H),1.56(s,3H),1.38–1.27(m,1H),0.75–0.66(m,3H).19F NMR(376MHz, DMSO)δ-73.30,-137.76–-138.48,-154.54–-155.34.

[0301] Example 22: Synthesis of (4-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)piperazin-2-yl)methylamine (compound 78)

[0302] Step 1: Synthesis of 4-benzyl-1-(tert-butyl)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate

[0303] 2-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (2.0 g, 9.25 mmol, 1.0 eq) and triethylamine (1.9 g, 18.49 mmol, 2.0 eq) were dissolved in dichloromethane (50 mL). Benzyl chloroformate (2.4 g, 13.87 mmol, 1.5 eq) was added dropwise at 0°C. After the addition was complete, the mixture was gradually brought to room temperature and reacted for 4 hours. After the reaction was complete, the solvent was evaporated, and the mixture was purified by normal-phase column chromatography (petroleum ether: ethyl acetate = 1:1) to give colorless oil 4-benzyl-1-(tert-butyl)-2-(hydroxymethyl)piperazine-1,4-dicarboxylic acid ester (3.0 g, yield 92.58%). LCMS (ESI) [M+Na]+: 373.17. 1 H NMR(400MHz,Chloroform-d)δ7.35(d,5H),5.16(s,2H),4.10(d,3H),3.87(s,1H),3.59(s,2H),3.00(s,4H),1.46(s,9H).

[0304] Step 2: Synthesis of 4-benzyl-1-(tert-butyl)-2-((1,3-dioxoisoindoline-2-yl)methyl)piperazine-1,4-dicarboxylic acid ester

[0305] 4-Benzyl-1-(tert-butyl)-2-(hydroxymethyl)piperazine-1,4-dicarboxylic acid (2.5 g, 7.13 mmol, 1.0 eq), phthalimide (2.1 g, 14.27 mmol, 2.0 eq), and triphenylphosphine (5.61 g, 21.40 mmol, 3.0 eq) were dissolved in tetrahydrofuran (100 mL). Diethyl azodicarboxylate (3.73 g, 21.40 mmol, 3.0 eq) was added dropwise at 0°C. After the addition was complete, the mixture was gradually brought to room temperature and reacted for 3 hours. After the reaction was complete, the solvent was evaporated, and the mixture was purified by normal-phase column chromatography (petroleum ether: ethyl acetate = 17:3) to give a white solid 4-benzyl-1-(tert-butyl)-2-((1,3-dioxoisoindoline-2-yl)methyl)piperazine-1,4-dicarboxylic acid ester (3.2 g, yield 93.2%). LCMS(ESI)[M-100+H]+:380.2.

[0306] Step 3: Synthesis of 4-benzyl-1-(tert-butyl)-2-(((tert-butyloxycarbonyl)amino)methyl)piperazine-1,4-dicarboxylic acid ester

[0307] 4-Benzyl-1-(tert-butyl)-2-((1,3-dioxoisoindoline-2-yl)methyl)piperazine-1,4-dicarboxylic acid ester (3.2 g, 6.43 mmol, 1.0 eq) and hydrazine hydrate (604 mg, 9.65 mmol, 1.5 eq, 80%) were added to ethanol (100 ml) and reacted at 70 °C for 4 hours. After the reaction was complete, the mixture was cooled to 0°C, and di-tert-butyl dicarbonate (4.21 g, 19.19 mmol, 3.0 eq) was added dropwise. After the addition was complete, the mixture was gradually brought to room temperature and stirred for 2 hours. The reaction was monitored by TLC (using glycerol esters). The reaction was complete. The solvent was evaporated, ethyl acetate was added, and the mixture was filtered. The filtrate was collected, evaporated, and purified by normal-phase column chromatography (petroleum ether: ethyl acetate = 3:1) to give colorless oil 4-benzyl-1-(tert-butyl)-2-(((tert-butyloxycarbonyl)amino)methyl)piperazine-1,4-dicarboxylic acid ester (2.2 g, yield 76.09%). LCMS (ESI) [M-156+H]+: 294.16.

[0308] Step 4: Synthesis of tert-butyl 2-(((tert-butyloxycarbonyl)amino)methyl)piperazine-1-carboxylate

[0309] 1.5 g of 4-benzyl-1-(tert-butyl)-2-(((tert-butyloxycarbonyl)amino)methyl)piperazine-1,4-dicarboxylic acid ester was dissolved in 50.0 ml of tetrahydrofuran, and 240 mg of 5% palladium on carbon was added. The mixture was then purged with hydrogen and reacted at room temperature for 1 hour under a hydrogen balloon atmosphere. After the reaction was complete, the mixture was filtered, and the organic phase was evaporated to dryness to obtain a colorless oil, 940 mg of tert-butyl 2-(((tert-butyloxycarbonyl)amino)methyl)piperazine-1-carboxylic acid ester, yield 89.3%, which was used directly in the next step. LCMS(ESI)[M-200+H]+:116.2.1H NMR(400MHz,Chloroform-d)δ4.88(s,1H),4.07(s,1H),3.83(s,1H),3.52(dd,1H),3. 31(dt,1H),3.06–2.89(m,2H),2.84(dd,1H),2.68(td,1H),2.08(s,2H),1.44(d,18H).

[0310] Step 5: Synthesis of tert-butyl 4-(4-amino-3-nitropyridin-2-yl)-2-(((tert-butyloxycarbonyl)amino)methyl)piperazine-1-carboxylate

[0311] 2-Chloro-3-nitropyridin-4-amine (250 mg, 1.44 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (5.0 mL), and 2-(((tert-butyloxycarbonyl)amino)methyl)piperazine-1-carboxylic acid tert-butyl ester (546 mg, 1.73 mmol, 1.2 eq) and N,N-diisopropylethylamine (559 mg, 4.32 mmol, 3.0 eq) were added. The reaction was carried out at 100 °C for 16 hours. After the reaction was completed, the mixture was purified by reverse-phase column chromatography (acetonitrile:water (pure water) = 7:13) to give a yellow solid 4-(4-amino-3-nitropyridin-2-yl)-2-(((tert-butyloxycarbonyl)amino)methyl)piperazine-1-carboxylic acid tert-butyl ester (502 mg, yield 76.9%). LCMS(ESI)[M+1]+:453.2.1H NMR(400MHz,DMSO-d6)δ7.68(d,1H),7.28(s,2H),6.73(s,1H),6.26(d,1H),4.12(s,1H),3.66( dd,2H),3.25–3.12(m,3H),3.07(dd,1H),2.96(dt,1H),2.85(td,1H),1.40(s,9H),1.34(s,9H).

[0312] Step 6: Synthesis of tert-butyl 2-((tert-butyloxycarbonyl)amino)methyl)-4-(3,4-diaminopyridin-2-yl)piperazine-1-carboxylate

[0313] 500 mg of 4-(4-amino-3-nitropyridin-2-yl)-2-(((tert-butyloxycarbonyl)amino)methyl)piperazine-1-carboxylic acid tert-butyl ester was dissolved in tetrahydrofuran (20.0 mL), and 250.0 mg of 5% palladium on carbon was added. The mixture was purged with hydrogen and reacted at room temperature for 2 hours under a hydrogen balloon atmosphere. After the reaction was complete, the mixture was filtered, and the organic phase was evaporated to dryness and then purified by normal-phase column chromatography (petroleum ether: ethyl acetate = 1:1) to give 390 mg of brown oil 2-((tert-butyloxycarbonyl)amino)methyl)-4-(3,4-diaminopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (yield 65.9%). LCMS (ESI) [M+H]+: 423.26.

[0314] Step 7: Synthesis of the mixture 4-(3-amino-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)-2-(((tert-butyloxycarbonyl)amino)methyl)piperazine-1-carboxylic acid tert-butyl ester and 4-(4-amino-3-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)-2-(((tert-butyloxycarbonyl)amino)methyl)piperazine-1-carboxylic acid tert-butyl ester

[0315] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (102 mg, 0.29 mol, 1.1 eq) was dissolved in dichloromethane (2.0 mL), followed by the addition of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (129 mg, 0.34 mol, 1.3 eq) and N,N-diisopropylethylamine (101 mg, 0.78 mol, 3.0 eq). The mixture was reacted at room temperature for 2 minutes, and then 2-((tert-butyloxycarbonyl)amino)methyl)-4-(3,4-diaminopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (110 mg, 0.26 μmol, 1.0 eq) was added. The mixture was reacted at room temperature for 2.5 hours. After the reaction was complete, dichloromethane and water were added for extraction. The organic phase was washed three times with saturated sodium chloride, dried, and the solvent was evaporated to obtain a crude yellow oil mixture of 4-(3-amino-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)-2-(((tert-butyloxycarbonyl)amino)methyl)piperazine-1-carboxylic acid tert-butyl ester and 4-(4-amino-3-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)-2-(((tert-butyloxycarbonyl)amino)methyl)piperazine-1-carboxylic acid tert-butyl ester (300 mg), which was directly used in the next step. LCMS[M+H]+:755.4.

[0316] Step 8: Synthesis of tert-butyl 2-(((tert-butyloxycarbonyl)amino)methyl)-4-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)piperazine-1-carboxylic acid

[0317] 4-(3-amino-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)-2-(((tert-butyloxycarbonyl)amino)methyl)piperazine-1-carboxylic acid tert-butyl ester and 4-(4-amino-3-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)-2-(((tert-butyloxycarbonyl)amino)methyl)piperazine-1-carboxylic acid tert-butyl A mixture of butyl esters (200 mg) was added to a mixed solution of sodium hydroxide aqueous solution (10%, 3 ml) and ethanol (3 ml). The reaction was carried out at 80 °C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, and a yellow solid precipitated. After filtration and drying, a yellow solid of 2-(((tert-butyloxycarbonyl)amino)methyl)-4-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (147 mg) was directly used in the next step. LCMS (ESI) [M+1]+: 741.32.

[0318] Step 9: Synthesis of (4-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)piperazin-2-yl)methylamine

[0319] 147 mg of 2-(((tert-Butoxycarbonyl)amino)methyl)-4-(2-(((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)piperazine-1-carboxylic acid tert-butyl ester was added to a mixed solution of trifluoroacetic acid (5.0 mL) and dichloromethane (5 mL). The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the product was evaporated to dryness and a white solid (4-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)piperazin-2-yl)methylamine was obtained. HPLC showed 4.6 mg of product at the first retention time and 4.0 mg of product at the second retention time. LCMS (ESI) [M+H]+: 541.2, first retention time product: 1H NMR (400MHz, DMSO-d6) δ14.26 (s, 1H), 10.26 (s, 2H), 8.59 (s, 3H), 7.80 (d, J = 6.6Hz, 1H), 7.2 7-7.13(m,3H),5.81(d,J=11.2Hz,1H),5.06(d,J=14.2Hz,1H),4.97(d,J=14.4Hz,1H),4.49( dd,J=11.4,7.5Hz,1H),3.98(d,J=2.0Hz,3H),3.83(s,1H),3.65(d,J=12.4Hz,1H),3.54(s, 1H),3.38(s,1H),3.29(s,2H),2.93(p,J=7.1Hz,1H),1.72(s,3H),0.82(d,J=7.4Hz,3H).19F NMR(376MHz, DMSO-d6)δ-73.01,-137.45,-154.26–-154.59.

[0320] Example 23: Synthesis of 2-(4-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)piperazin-2-yl)acetonitrile (compound 58)

[0321] Step 1: Synthesis of tert-butyl 4-(4-amino-3-nitropyridin-2-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0322] 2-Chloro-3-nitropyridine-4-amine (150 mg, 0.87 mmol, 1.0 eq) was dissolved in N-methylpyrrolidone (4 mL), and tert-butyl-2-(cyanoethyl)piperazine-1-carboxylic acid ester (292 mg, 1.3 mmol, 1.5 eq) was added. The reaction was carried out at 100 °C for 3 hours. After the reaction was completed, ethyl acetate and water were added for extraction, the organic phase was evaporated to dryness, and the product was separated by normal column chromatography to give tert-butyl 4-(4-amino-3-nitropyridine-2-yl)-2-(cyanomethyl)piperazine-1-carboxylate (150 mg, yield 48%). LCMS (ESI) [M+H]+: 363.1. 1H NMR (400MHz, DMSO-d6) δ7.69(d,J=5.7Hz,1H),7.34(s,2H),6.30(d,J=5.8Hz,1H),4.47(s,1H),3.77(d,J=12.7 Hz,2H),3.27–3.18(m,1H),3.16(d,J=4.7Hz,2H),2.88(dd,J=18.3,5.9Hz,2H),2.82–2.74(m,1H),1.42(s,9H).

[0323] Step 2: Synthesis of tert-butyl 2-(cyanomethyl)-4-(3,4-diaminopyridin-2-yl)piperazine-1-carboxylate

[0324] 150 mg (0.41 mmol, 1.0 eq) of 4-(4-amino-3-nitropyridin-2-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester was dissolved in ethanol (2 ml) and water (2 ml). Iron powder (116 mg, 2.1 mmol, 5.0 eq) and ammonium chloride (217 mg, 4.1 mmol, 10.0 eq) were added, and the mixture was purged with nitrogen and reacted at 60 °C for 1 hour. After the reaction was complete, the solution was filtered, the filter cake was washed with ethyl acetate, and the filtrate was extracted with ethyl acetate. The organic phase was evaporated to dryness to give a yellow solid, 2-(cyanomethyl)-4-(3,4-diaminopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (100 mg, yield 72%). LCMS (ESI) [M+H]+: 333.2.

[0325] Step 3: Synthesis of tert-butyl 4-(3-amino-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamate)pyridin-2-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0326] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-benzo[d]imidazolium-6-carboxylic acid (50 mg, 0.14 mmol, 1.0 eq) was dissolved in dichloromethane (2 ml), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (76 mg, 0.21 mmol, 1.5 eq) and N,N-diisopropylethylamine (90 mg, 0.7 mmol, 5.0 eq) were added. The mixture was reacted at room temperature for 10 minutes, and then 2-(cyanomethyl)-4-(3,4-diaminopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (70 mg, 0.21 mmol, 1.5 eq) was added and the mixture was reacted for 2 hours. After the reaction was complete, ethyl acetate and water were added for extraction. The organic phase was extracted using a large-scale TLC plate to give the product tert-butyl 4-(3-amino-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)-2-(cyanomethyl)piperazine-1-carboxylate (48 mg, yield 51%). LCMS (ESI) [M+H]+: 689.2.

[0327] Step 4: Synthesis of tert-butyl piperazine-1-carboxylate 2-(cyanomethyl)-4-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)piperazine-1-carboxylate

[0328] Take 4-(3-amino-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (48.0 mg, 0.07 mmol, 1.0 eq.) and sodium acetate (57.0 mg, 0.7 mmol, 10.0 eq.), add acetic acid (2 mL), The reaction was carried out at 80 °C for 12 hours. After the reaction was completed, ethyl acetate and water were added for extraction. The organic phase was evaporated to dryness to give the target crude product, 2-(cyanomethyl)-4-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (42 mg, yield 89%). LCMS (ESI) [M-100+1]+: 651.2.

[0329] Step 5: Synthesis of 2-(4-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)piperazin-2-yl)acetonitrile

[0330] Weigh 42.0 mg, 0.06 mmol, 1.0 eq. of 2-(cyanomethyl)-4-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)piperazine-1-carboxylic acid tert-butyl ester, add 0.5 mL of trifluoroacetic acid and 0.5 mL of dichloromethane, and react at room temperature. After 0.5 hours, the reaction was concentrated under vacuum. The crude product was then subjected to HPLC to obtain a white solid. The white solid was resolved by SFC to obtain the main peak product 2-(4-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-4-yl)piperazin-2-yl)acetonitrile (11 mg, yield 22%). LCMS (ESI) [M+H]+: 551.2, 1H NMR (400MHz, DMSO) δ13.01 (s, 1H), 7.84 (d, J = 5.6Hz, 1H), 7.24–7.05 (m, 2H), 6.95 ( d,J=5.6Hz,1H),5.70(d,J=11.3Hz,1H),5.01(dd,J=30.8,13.0Hz,2H),4.44(dd,J= 11.1,7.5Hz,1H),3.97(d,J=1.9Hz,3H),3.35–3.24(m,4H),3.06(s,1H),2.97(d,J= 6.1Hz,2H),2.92–2.84(m,1H),1.68(s,3H),1.25(s,1H),0.81(d,J=6.7Hz,3H).19F NMR (377MHz, DMSO) δ -72.91 (s), -73.00 (s), -137.65 (d, J = 14.3Hz), -154.50 (d, J = 19.6Hz).

[0331] The compounds listed in Table 1 below were prepared using methods similar to those described in the examples, with appropriate variations in the amounts of reactants and reagents, protection and deprotection, solvents, and reaction conditions. Characterization data for the compounds are summarized in Table 1 below.

[0332] Table 1: Structure and characterization of some compounds

[0333] Experimental Example 1: Test of the inhibitory activity of the compounds of the present invention on human Nav1.8 ion channels in CHO cells

[0334] Experimental Objective: The purpose of this test case is to test the effect of the compound on the human Nav1.8 ion channel.

[0335] Background and Principle: The sodium ion channel Nav1.8 is mainly expressed in dorsal root ganglion (DRG) neurons. Its physiological and functional characteristics determine that Nav1.8 channels can significantly affect the excitability of DRG neurons, thereby influencing human pain sensitivity. Nav1.8 is mainly distributed in pain-sensing neurons; therefore, selective Nav1.8 inhibitors are unlikely to induce the adverse reactions commonly seen with non-selective Nav1.8 inhibitors. More importantly, Nav1.8 does not participate in central nervous system-related activities, so Nav1.8 inhibitors do not pose addiction problems similar to opioids, nor do they affect motor function, making it a promising target for pain treatment. Patch-clamp techniques are microelectrode techniques that record the electrical activity of ion channels on biological membranes by clamping voltage or current. The principle is to use a glass microelectrode with a tip diameter of 1.5-3.0 μm to contact the cell membrane surface. By using negative pressure to attract, an impedance seal of more than gigahertz ohms is formed between the electrode tip and the cell membrane. At this time, the small region of the cell membrane (patch) under the electrode tip is electrically separated from its surroundings. Based on this, the potential is fixed (clamped), and the ion current of the ion channel on the patch is monitored and recorded.

[0336] Experimental procedure:

[0337] Cell Culture: A stable CHO cell line expressing the human Nav1.8 channel was used. Cells were cultured in Ham's F-12 nutrient mixture containing 10% fetal bovine serum and 10 μg / mL Blasticidin, 200 μg / mL Hygromycin B, and 100 μg / mL Zeocin at 37°C and 5% CO2. Cell Passaging: The old culture medium was removed and the cells were washed once with PBS. Then, 1 mL of 0.25% Trypsin-EDTA solution was added, and the cells were incubated at 37°C for approximately 1.5 min. When the cells detached from the bottom of the dish, approximately 5 mL of preheated (37°C) complete culture medium was added. The cell suspension was gently pipetted to separate aggregated cells. The cell suspension was transferred to sterile centrifuge tubes and centrifuged at 1000 rpm for 5 min to collect the cells. For expansion or maintenance culture, cells were seeded in 6 cm cell culture dishes at a density of 2.5 × 10⁶ cells per dish.5 6.5 × 10⁶ cells (final volume: 5 mL). To maintain cellular electrophysiological activity, cell density must not exceed 80%. Before patch-clamp assay, cells were separated with 0.25% Trypsin-EDTA, and 6.5 × 10⁶ cells were collected. 3 The cells were seeded onto a coverslip and cultured in a 24-well plate (final volume: 500 μL). After 18 hours, the cells were tested.

[0338] Patch-clamp assay: The voltage stimulation protocol for whole-cell patch-clamp recording of Nav1.8 currents is as follows: after whole-cell sealing, the cell voltage is clamped at -120 mV. First, the voltage is stepped from -110 mV to -20 mV in 10 mV increments and held for 5 s. Then, a 0 mV depolarization pulse is applied to measure the peak value of the inward current to obtain the half-inactivated voltage (Vhalf). The resting state and half-inactivated state of the current are detected using a dual-pulse mode. First, a first depolarization pulse (TP1) is applied to 0 mV for 50 ms to detect the sodium current in the resting state. Then, between the two depolarization pulses, the conditional voltage is adjusted to Vhalf and held for 5 s. Next, the voltage is restored to -120 mV and held for 20 ms to allow the unbound and inactivated channels to recover. A second depolarization pulse (TP2) is then applied to 0 mV for 50 ms to detect the sodium current in the half-inactivated state. Finally, the voltage was restored to a clamping voltage of -120mV, and data were repeatedly collected at 20-second intervals to observe the effect of the drug on the peak sodium current under two different conditions. Experimental data were acquired using an EPC 10 amplifier (HEKA) and stored in PatchMaster (HEKA) software. For data analysis, the peak sodium current (Peak current compound) and the peak current (Peak current Control) after each drug concentration were first normalized. Then, the inhibition rate corresponding to each drug concentration under different conditions was calculated, i.e., Inhibition% = (1 - (Peak current compound / Peak current Control)) * 100%. IC50 calculation and curve fitting were performed using GraphPad Prism software. The experimental results are shown in Table 2. The positive control compound used in this test was the commercially available VX-548, with the following structural formula:

[0339] Table 2. Nav1.8 inhibition rate test results (1 nM)

[0340] The experimental results show that the representative compound of this invention has the same or better inhibitory activity against human Nav1.8 ion channel in CHO cells as the positive control, and has strong application prospects in the field of Nav1.8 ion channel inhibition.

[0341] Experimental Example 2: Pharmacokinetic Test of the Compounds of the Present Invention in SD Rats

[0342] The pharmacokinetic characteristics of the compound of the present invention were investigated by gavage (PO) administration to male SD rats.

[0343] Specific experimental procedure:

[0344] The compound of this invention and VX-548 (commercially available) were administered by gavage (VX-548: 10 mg / kg; compound of this invention: 3 mg / kg). The PO solvent was 15% polyethylene glycol-15-hydroxystearate and 85% (0.5% sodium carboxymethyl cellulose). Blood samples were collected via jugular vein at 0 h before administration and at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration (by gavage). Approximately 0.02 mL of each sample was collected and anticoagulated with K2-EDTA. The samples were then placed on ice. Plasma sample processing: After collection, blood samples were placed on ice and centrifuged within 1 hour to separate the plasma (centrifugation conditions: 6800 rpm, 6 minutes, 2-8℃). Plasma samples were stored at -80℃ before analysis. Results analysis: The experimental results based on the blood drug concentration data at different time points are shown in Table 3 below.

[0345] Table 3: Pharmacokinetic Results in Male SD Rats

[0346] The experimental results show that the series of compounds of this invention are well absorbed orally in rats, and the 24-hour in vivo exposure is much better than that of the positive control compound VX-548.

[0347] Experimental Example 3: Analgesic effect of the compound of the present invention in a rat incision pain model

[0348] 1. Experimental Procedure:

[0349] 1.1 Animal Adaptation: Animals were placed in an acclimatization environment for 7 days after purchase, with free access to food. On days 5-7 of the acclimatization period, rats were placed on a metal pain assessment rack for 40-60 minutes to allow experimental personnel to have acclimatization contact with the animals (stroking the rats for 3-5 minutes) to reduce the stress response of the experimental animals to the experimental personnel.

[0350] 1.2 Baseline value determination: After the petting adaptation period, the baseline value of the animals was tested, and the animals were randomly grouped according to the baseline.

[0351] 1.3 Establishment of plantar incision pain model: On the first day after modeling, the animals in the Control and Model groups were given the same amount of Vehicle. The mechanical pain threshold of the animals in each group was measured before administration and at 1h, 3h and 6h after administration.

[0352] 2. Foot incision pain modeling

[0353] (1) Disinfection of surgical instruments;

[0354] (2) The animal was anesthetized and fixed in a prone position on the operating table;

[0355] (3) The lateral hind limb is flattened with the sole of the foot facing upwards, fixed with surgical tape, and disinfected;

[0356] (4) Use a blade to cut the skin fascia 0.5cm from the heel on the sole of the foot towards the toes, making a longitudinal incision of about 1cm;

[0357] (5) Insert one end of the curved forceps below the outer edge of the flexor digitorum brevis and push the forceps into the inner side of the muscle to lift the flexor digitorum brevis.

[0358] (6) Make a longitudinal incision in the muscle with a blade, making sure to cut the belly of the muscle in half;

[0359] (7) The skin is sutured with 7-0 sutures and then disinfected.

[0360] 3. Mechanical pain threshold (MPT) measurement

[0361] Pain assessment using the Ascending method:

[0362] (1) Place the test animals on a mechanical metal mesh frame and let them stand for 30-60 minutes. Once the animals are no longer looking around or exploring and are relatively quiet, start the test.

[0363] (2) After the test animal has settled down, the sole of the hind limb to be tested is slowly and gently stimulated with Von-Frey fibers to bend the fibers, and the animal's foot withdrawal response is observed for 2-3 seconds. The test animal is stimulated one by one in order of increasing fiber weight, with each fiber weight being stimulated 5 times consecutively, with an interval of at least 10 seconds between each stimulation. If there are fewer than 3 positive responses, the above operation is repeated with a larger fiber weight. When there are 3 or more positive responses on the first test, that fiber is the pain threshold for that animal (each animal is tested twice, and the average value is taken). If the animal exhibits foot lifting, avoidance, or foot licking behavior due to stimulation, it is marked as positive (×), while foot withdrawal response caused by body movement is not included; if there are no such behaviors, it is marked as negative (○).

[0364] (3) Fiber weight: Rat(g): 0.6, 1.0, 1.4, 2.0, 4.0, 6.0, 8.0, 10.0, 15.0, cut value 15.0g. The analgesic effects of intravenous injection of the test compound on incisional pain in rats are shown in Table 4:

[0365] Table 4: Effects of intravenous injection of the test compound on analgesia in rats with surgical pain model

[0366] Experimental results show that, at a dose of 10 mg / kg, compared with the model group, the pain threshold of the compounds of the present invention was significantly increased 1 hour after administration, and the analgesic effect and duration of analgesia of some compounds were comparable to or better than VX-548.

Claims

1. A compound of formula (I) and its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, in, X is selected from O or S; Ring Q is phenyl or a 5-6 membered heteroaryl group; Each R A They may be the same or different, and each is independently selected from H, deuterium, halogen, -CN, -OH, nitro, -(CH2)n-NR7R8, -CONR m R n The following groups are used: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, deuterated C1-C6 alkyl, C1-C6 hydroxyalkyl, carboxyl, -(CH2)n-6-10 aryl, -(CH2)n-3-8 heterocyclic, wherein the -(CH2)n-NR7R8, carboxyl, -(CH2)n-6-10 aryl, and -(CH2)n-3-8 heterocyclic groups may optionally be substituted with one or more halogens, CN, -C1-C6 alkyl-CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, -OH, C1-C6 hydroxyalkyl, -(CH2)n-NR7R8, C1-C6 alkoxy, oxo, and -COOR9; r and n are independently selected from 0, 1, 2, 3, 4, and 5, respectively; R7, R8, and R9 are each independently selected from the following groups: non-existent, H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkyl-substituted C1-C6 hydroxyalkyl, -(CH2)n-6-10 aryl, and -(CH2)n-3-8 heterocyclic groups. The C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C1-C6 alkyl-substituted C1-C6 hydroxyalkyl groups are also selected from the following groups. The alkyl, -(CH2)n-6-10 aryl, and -(CH2)n-3-8 heterocyclic groups may be optionally substituted with one or more halogens, CN, -C1-C6 alkyl-CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, -OH, C1-C6 hydroxyalkyl, -(CH2)n-NR7R8, C1-C6 alkoxy, oxo, -NR7R8, and -COOR9. Alternatively, R7 and R8 may form a 3-8 membered heterocyclic group with the nitrogen atom attached to them, wherein the 3-8 membered heterocyclic group may be optionally substituted with one or more halogens, CN, -C1-C6 alkyl-CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, -OH, C1-C6 hydroxyalkyl, C1-C6 alkoxy, oxo, amino, C1-C6 alkylamino, or -COOR9; R m and R n Each is independently selected from non-existent, H, C1-C6 alkyl, C1-C6 haloalkyl, or R. m and R n Together with the N atom they belong to, they form 4-6 membered heterocyclic groups; A is selected from N and CR1; B is selected from N and CR2; U is selected from N and CR3; Y is selected from N and CR4; Z is selected from N and CR5; A, B, U, Y, and Z are not all N at the same time; R1, R2, R3, R4, and R5 may be the same or different, and are independently selected from H, deuterium, halogen, hydroxyl, cyano, amino, amide, nitro, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclic, and aryl. The C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclic, and aryl groups may be optionally surrounded by one or more R groups. 02 replace; Each R 02 They may be the same or different, and each is independently selected from deuterium, halogen, hydroxyl, cyano, oxo, amino, amide, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl substitutions; R a R b The same or different, and each independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, cyano, amino, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C1-C6 hydroxyalkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclic, 3- to 10-membered cycloalkyloxy, and 3- to 10-membered heterocyclic oxy; wherein the 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclic, 3- to 10-membered cycloalkyloxy, and 3- to 10-membered heterocyclic oxy are optionally surrounded by one or more R 01 replace; The condition is R a R b They are not both hydrogen; R c R d The same or different, and each independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, cyano, amino, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C1-C6 hydroxyalkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclic, 3- to 10-membered cycloalkyloxy, and 3- to 10-membered heterocyclic oxy; wherein the 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclic, 3- to 10-membered cycloalkyloxy, and 3- to 10-membered heterocyclic oxy are optionally surrounded by one or more R 01 replace; Or, R a R b Together with the carbon atom attached to it, it forms a cycloalkyl or heterocyclic group; or, R c R d Together with the carbon atom attached thereto, they form a cycloalkyl or heterocyclic group; wherein each of the cycloalkyl or heterocyclic groups is independently and optionally surrounded by one or more R atoms. 01 replace; Each R 01 They may be the same or different, and each is independently selected from deuterium, halogen, hydroxyl, cyano, oxo, amino, amide, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl.

2. The compound according to claim 1, its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein the compound is a compound represented by general formula (II): in, Each group is as defined in claim 1.

3. The compound according to claim 1 or 2, its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein ring Q is selected from... in End and of End connection.

4. The compound according to any one of claims 1-3, its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein R A Selected from H, methyl, trifluoromethyl, amino, cyano, methoxy, ethylamino, chlorine, hydroxy, carboxyl, formamide, 5. The compound according to any one of claims 1-4, its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein R1 is selected from C1-C6 alkoxy groups, preferably, R1 is a methoxy group.

6. The compound according to any one of claims 1-5, its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein R2 is selected from halogens, preferably, R2 is fluorine.

7. The compound according to any one of claims 1-6, its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein R3 is selected from halogens, preferably, R3 is fluorine.

8. The compound according to any one of claims 1-7, its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein R a Selected from C1-C6 alkyl groups, and R b For H, preferably, R a It is methyl, and R b For H.

9. The compound according to any one of claims 1-8, its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein R c Selected from halogenated C1-C6 alkyl groups, preferably, R c It is trifluoromethyl.

10. The compound according to any one of claims 1-9, its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein R d Selected from C1-C6 alkyl groups, preferably, R d It is a methyl group.

11. The following compounds and their stereoisomers, tautomers, or pharmaceutically acceptable salts thereof:

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients.

13. Use of the compound of any one of claims 1 to 11, its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and the pharmaceutical composition of claim 12 in the preparation of a drug for inhibiting a voltage-gated sodium channel, wherein the voltage-gated sodium channel is preferably a Nav1.8 channel.

14. Use of the compounds of any one of claims 1 to 11, their stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and the pharmaceutical composition of claim 12 in the preparation of a medicament for treating and / or reducing conditions, diseases, or disorders associated with increased Nav1.8 activity or expression; wherein the conditions, diseases, or disorders associated with increased Nav1.8 activity or expression are preferably selected from: pain, respiratory diseases, neurological disorders, and mental illnesses, and combinations thereof; wherein the pain is preferably selected from neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, visceral pain, chemotherapy pain, cancer pain, idiopathic pain, traumatic pain, surgical pain, and surgical pain. Postoperative pain, labor pain, labor pain, neurogenic bladder disorder, ulcerative colitis, enteropathic pain, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, toothache, peripheral nerve injury, and combinations thereof; the musculoskeletal pain is preferably osteoarthritis pain; the acute pain is preferably acute postoperative pain; the neuropathic pain is preferably postherpetic neuralgia, small fiber neuropathy, idiopathic small fiber neuropathy, diabetic neuropathy, or diabetic peripheral neuropathy; the postoperative pain is preferably one or more of the following: pain from bunion excision, pain from abdominoplasty, or pain from hernia repair.

15. A compound as shown in formulas (I-1) and (I-2), its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, X is selected from O or S; ring Q is phenyl or 5-6 membered heteroaryl; other groups are defined as described in any one of claims 1-10.

16. A compound as shown in formulas (II-1) and (II-2), its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, Ring Q is phenyl or a 5-6 membered heteroaryl group; other groups are defined as described in any one of claims 1-10.

17. A compound as shown in any of the following descriptions, its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof.

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