Sodium channel modulators

Abstract

The invention provides a compound as shown in a formula I which can be used as a sodium channel regulator, and a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof. The invention also provides a pharmaceutical composition containing the compound and the stereoisomer, the tautomer or the pharmaceutically acceptable salt thereof and a carrier or excipient, and a pharmaceutical application of the pharmaceutical composition as a NaV1.8 inhibitor (such as pain, respiratory diseases, neurological disorders, mental diseases and the like).

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicinal chemistry, and particularly relates to a sodium channel modulator for inhibiting Nav1.8 target point and stereoisomers, tautomers or pharmaceutically acceptable salts thereof, a pharmaceutical composition thereof and the use of inhibiting voltage-gated sodium channels, especially Nav1.8 channels. BACKGROUND

[0002] Pain is a kind of unpleasant feeling and emotional feeling, accompanied by substantial or potential tissue damage, which is a subjective feeling. Pain can serve as a warning signal to alert the body to potential danger, and has an indispensable protective effect on normal life activities. At the same time, pain is also a common clinical symptom. After the external stimulus that causes pain disappears, strong or persistent pain will cause physiological function disorder and seriously affect the life quality of living beings.

[0003] Pain originates from nociceptors in the peripheral nervous system. It is a free nerve ending widely distributed in the skin, muscle, joint and visceral tissue of the whole body, which can convert the heat, mechanical or chemical stimuli into nerve impulses (action potentials) and transmit them to its cell body part located in the dorsal root ganglion (DRG) via afferent nerve fibers, and finally to the high-level nerve center, 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 is depolarized, the sodium ion channel is activated, the channel is opened, and the sodium ion influx is caused, which makes the cell membrane further depolarized, leading to the generation of action potential. Therefore, inhibiting abnormal sodium ion channel activity is helpful for the treatment and relief of pain.

[0004] NaVs mediate the rapid upstroke of the action potential in many excitable cell types, such as neurons, skeletal muscle cells, cardiac muscle cells, and thus are involved in the initiation of signaling in these cells. Voltage-gated sodium channels (NaVs), given their important role in neuronal conduction in sensory neurons, are a rational target for pain management (Ruiz et al., 2015). In total, there are nine known subtypes of the primary pore-forming a subunit of voltage-gated sodium channels (NaVs). The Navl. l, Navl.2, and Navl.3 subtypes are primarily expressed in the central nervous system (CNS), while Navl.4 and Navl.5 are abundant in skeletal and cardiac muscle. Navl.6 has been shown to be expressed in both the peripheral nervous system (PNS) and CNS, while Navl.7, Navl.8, and Navl.9 are generally considered to be restricted to the PNS (Yu and Catterall, 2003). Non-selective sodium channel inhibitors are available as antiarrhythmic agents, anticonvulsants, and local anesthetics, but none are suitable for general treatment of chronic pain. The Nav channel family is highly homologous, and obtaining a selective drug-like ligand is a significant challenge. However, the identification of selective inhibitors of specific isoforms has potential in a number of disorders.

[0005] Both Navl.7 and Navl.8 isoforms are present on nociceptors in the PNS, and they have attracted considerable interest as targets for the treatment of pain (Jukic et al., 2014). Given the extensive human genetic validation of Navl.7 (Bennett and Woods, 2014) and the discovery of a class of selective inhibitors (McCormack et al., 2013), there has been a significant effort directed at this channel (Vetter et al., 2017). However, several human clinical trials of selective Navl.7 inhibitors have been disappointing (Donnell et al., 2018; Zakrzewska et al., 2017), raising the alternative target of Navl.8 (Han et al., 2016).

[0006] The pore-forming alpha subunit of the Nav1.8 sodium channel is encoded by the SCN10A gene and is expressed primarily (but not exclusively) in dorsal root ganglion (DRG) neurons and in trigeminal and nodose ganglion neurons (Akopian et al., 1996; Shields et al., 2012). These neurons mediate the majority of the inward sodium current during the depolarizing phase of the neuronal action potential, which is critical for the propagation and repetitive firing of action potentials (Akopian et al., 1999). Rodent SCN10A knockout and knockdown studies indicate that Nav1.8 is involved in inflammatory and neuropathic pain (Dong et al., 2007). Heterozygous gain-of-function mutations in SCN10A lead to abnormal firing of DRG neurons and are associated with pain in small fiber neuropathy in humans, further linking Nav1.8 to the function of nociceptive 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 ganglion), Nav1.8 inhibitors are unlikely to be associated with the side effects common to other sodium channel modulators and do not produce the abuse liability similar to opioid therapy. Thus, targeting the underlying biology of pain through selective Nav1.8 inhibition represents a new approach to analgesic drug development with the potential to address the unmet need for safe and effective treatments for acute and chronic pain.

[0008] The inventors have found that some voltage-gated sodium channel inhibitors have limitations as therapeutic agents, for example due to poor therapeutic window (e.g., due to lack of NaV isoform selectivity, low potency, and / or other reasons). Thus, there remains a need in the art to develop new Nav1.8 selective inhibitors, preferably Nav channel inhibitors that are more potent, more selective, more efficacious, have good metabolic absorption, have good pharmacokinetics, have strong analgesic activity, and have fewer side effects for Nav1.8 inhibitory activity. SUMMARY SUMMARY

[0010] The present application aims to provide a Nav1.8 inhibitor with stronger inhibitory activity, which can be used for preparing a medicament for treating, alleviating or preventing pain, including neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, visceral pain, cancer pain, etc.

[0011] To solve the above technical problems, the present application adopts the following technical solutions:

[0012] In one aspect, the present application provides a compound as shown in formula I and stereoisomers, tautomers or pharmaceutically acceptable salts thereof,

[0013]

[0014] wherein,

[0015] X is selected from O or S;

[0016] Ring Q is phenyl or 5-6 membered heteroaryl;

[0017] each R A are the same or different, and each is independently selected from H, deuterium, halogen, -CN, -OH, nitro, -(CH2)n-NR7R8, -CONR m R n , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, deuterated C1-C6 alkyl, C1-C6 hydroxyalkyl, carboxyl, -(CH2)n-6-10 membered aryl, -(CH2)n-3-8 membered heterocyclyl, said -(CH2)n-NR7R8, carboxyl, -(CH2)n-6-10 membered aryl, -(CH2)n-3-8 membered heterocyclyl can be optionally substituted with 1 or more halogen, 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, -COOR9;

[0018] r and n are each independently selected from 0, 1, 2, 3, 4, 5;

[0019] R7, R8, R9 are each independently selected from absent, H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkyl substituted C1-C6 hydroxyalkyl, -(CH2)n-6-10 membered aryl, -(CH2)n-3-8 membered heterocyclyl, said C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkyl substituted C1-C6 hydroxyalkyl, -(CH2)n-6-10 membered aryl, -(CH2)n-3-8 membered heterocyclyl can be optionally substituted with 1 or more halogen, 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, -COOR9;

[0020] or R7, R8and the nitrogen atom to which they are attached form a 3-8 membered heterocyclyl group, optionally substituted with one or more halogen, CN, -Ci-C6alkyl-CN, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6haloalkoxy, -OH, Ci-C6hydroxyalkyl, Ci-C6alkoxy, oxo, amino, Ci-C6alkylamino, -COOR9;

[0021] R m and R n are each independently selected from absent, H, Ci-C6alkyl, Ci-C6haloalkyl, or R m and R n together with the N atom they are attached to form a 4-6 membered heterocyclyl group;

[0022] A is selected from N, CR1;

[0023] B is selected from N, CR2;

[0024] U is selected from N, CR3;

[0025] Y is selected from N, CR4;

[0026] Z is selected from N, CR5;

[0027] A, B, U, Y, Z are not simultaneously N;

[0028] R1, R2, R3, R4and R5are the same or different, and are each independently selected from H, deuterium, halogen, hydroxyl, cyano, amino, amido, nitro, Ci-C6alkyl, Ci-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, haloCi-C6alkyl, deuterated Ci-C6alkyl, deuterated Ci-C6alkoxy, haloCi-C6alkoxy, Ci-C6hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, which Ci-C6alkyl, Ci-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, haloCi-C6alkyl, deuterated Ci-C6alkyl, deuterated Ci-C6alkoxy, haloCi-C6alkoxy, Ci-C6hydroxyalkyl, cycloalkyl, heterocyclyl, aryl can be optionally substituted with 1 or more R 02 ;

[0029] each R 02 is the same or different, and is each independently selected from a deuterium atom, halogen, hydroxyl, cyano, oxo, amino, amido, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6haloalkoxy, Ci-C6hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0030] R a , R bthe same or different, and each independently selected from the group consisting of 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, 3-10 membered heterocyclyl, 3- to 10-membered cycloalkyloxy, and 3- to 10-membered heterocyclyloxy; said 3- to 10-membered cycloalkyl, 3-10 membered heterocyclyl, 3- to 10-membered cycloalkyloxy, and 3- to 10-membered heterocyclyloxy are optionally substituted with 1 or more R 01 substituted;

[0031] provided that R a , R b are not simultaneously hydrogen;

[0032] R c , R d the same or different, and each independently selected from the group consisting of 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, 3-10 membered heterocyclyl, 3- to 10-membered cycloalkyloxy, and 3- to 10-membered heterocyclyloxy; said 3- to 10-membered cycloalkyl, 3-10 membered heterocyclyl, 3- to 10-membered cycloalkyloxy, and 3- to 10-membered heterocyclyloxy are optionally substituted with 1 or more R 01 substituted;

[0033] or, R a , R b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl; or, R c , R d together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl; wherein said cycloalkyl or heterocyclyl are each independently optionally substituted with 1 or more R 01 substituted;

[0034] each R 01 the same or different, and each independently selected from the group consisting of deuterium, halogen, hydroxyl, cyano, oxo, amino, amido, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0035] As a preferred technical solution, the compound according to the present application and stereoisomers, tautomers or pharmaceutically acceptable salts thereof are compounds of general formula (II):

[0036]

[0037] wherein each group is as defined above.

[0038] As a preferred technical solution, wherein ring Q is selected from

[0039] wherein the end is connected with . the end.

[0040] As a preferred technical solution, wherein R A is selected from H, methyl, trifluoromethyl, amino, cyano, methoxy, ethylamino, carboxyl, chloro, hydroxyl, carboxamide,

[0041]

[0042] As a preferred technical solution, wherein R1 is selected from C1-C6 alkoxy.

[0043] As a more preferred technical solution, wherein R1 is methoxy.

[0044] As a preferred technical solution, wherein R2 is selected from halogen.

[0045] As a more preferred technical solution, wherein R2 is fluorine.

[0046] As a preferred technical solution, wherein R3 is selected from halogen.

[0047] As a more preferred technical solution, wherein R3 is fluorine.

[0048] As a preferred technical solution, wherein R a is selected from C1-C6 alkyl, and R b is H.

[0049] As a more preferred technical solution, R a is methyl, and R b is H.

[0050] As a preferred technical solution, wherein R c is selected from halogenated C1-C6 alkyl.

[0051] As a more preferred technical solution, R c is trifluoromethyl.

[0052] As a preferred technical solution, wherein R d is selected from C1-C6 alkyl.

[0053] As a more preferred technical solution, R d is methyl.

[0054] The present application also provides a compound as shown below and stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

[0055]

[0056]

[0057]

[0058] The present application also provides a compound as shown in the following formula and stereoisomers, tautomers or pharmaceutically acceptable salts thereof,

[0059]

[0060] X is selected from O or S; ring Q is phenyl or 5-6 membered heteroaryl; other group definitions are described in any of the preceding.

[0061] The present application also provides a compound as shown in formula II-1, II-2 and stereoisomers, tautomers or pharmaceutically acceptable salts thereof,

[0062]

[0063] Ring Q is phenyl or 5-6 membered heteroaryl; other group definitions are described in any of the preceding.

[0064] The present application also provides a compound as shown in any of the following formula and stereoisomers, tautomers or pharmaceutically acceptable salts thereof,

[0065]

[0066] The present application also provides a preparation method of a compound as shown in formula (II), characterized in that, comprising the following steps:

[0067]

[0068] The i-1 compound is condensed with the i-2 compound in a solvent to obtain a compound of formula II-1, and the compound of formula II-1 is further subjected to a ring closure reaction in a solvent to obtain a compound as shown in formula II, and the group definitions are described in any of the preceding.

[0069] The present application also provides a pharmaceutical composition comprising the compound as described in any of the preceding and stereoisomers, tautomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0070] The present application also provides the use of the compound as described in any of the preceding and stereoisomers, tautomers or pharmaceutically acceptable salts thereof and the pharmaceutical composition in the preparation of a drug for inhibiting a disease or disorder related to voltage-gated sodium channels, preferably selected from Nav1.8 channels.

[0071] The present application also provides the use of any one of the compounds as described above, and stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, in the manufacture of a medicament for treating and / or reducing symptoms of a condition, disease or disorder associated with increased Nav1.8 activity or expression.

[0072] As a preferred technical solution, the condition, disease or disorder associated with increased Nav1.8 activity or expression is preferably selected from the group consisting of pain, respiratory diseases, neurological disorders and psychiatric diseases, and combinations thereof.

[0073] As a preferred technical solution, the pain is preferably selected from the group consisting of neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, idiopathic pain, trauma pain, surgical pain, post-surgical pain, labor pain, parturient pain, neurogenic bladder disorder, ulcerative colitis, intestinal pain, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine, cluster headache, tension headache, phantom limb pain, dental pain, peripheral nerve injury, and combinations thereof.

[0074] As a preferred technical solution, the musculoskeletal pain is selected from the group consisting of osteoarthritic pain.

[0075] As a preferred technical solution, the acute pain is selected from the group consisting of acute postoperative pain.

[0076] As a preferred technical solution, the neuropathic pain is selected from the group consisting of post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy.

[0077] As a preferred technical solution, the post-surgical pain is preferably selected from one or more of bunionectomy pain, abdominoplasty pain, or hernia repair pain.

[0078] The inventors have found that such compounds are potent Nav1.8 inhibitors, have very strong Nav1.8 inhibitory activity, are better selective, have better pharmacokinetic exposure, have exceptionally obvious analgesic effect, have longer analgesic duration, have better oral absorption, and can be used for preparing a medicament for preventing and / or treating Nav1.8 inhibition related indications, including and / or reducing a condition, disease or disorder 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, trauma pain, surgical pain, post-surgical pain, labor pain, parturient pain, neurogenic bladder disorder, ulcerative colitis, intestinal pain, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine, cluster headache, tension headache, phantom limb pain, dental pain, peripheral nerve injury, and combinations thereof.

[0079] The present application was made based on the above findings. DETAILED DESCRIPTION

[0081] Various aspects and features of the present application are further described below.

[0082] The compounds according to the present application can exist in stereoisomeric forms, and the present application includes all stereoisomeric forms.

[0083] The compounds of the present application have asymmetric centers, and the compounds with asymmetric substituents can be isolated in optically active or racemic forms. Methods for the preparation of optically active forms are known to those skilled in the art, such as by resolution of racemic forms or by synthesis from optically active starting materials. Unless otherwise specified, specific chemical or isomeric forms of compounds of the present application are not limited to any particular stereochemistry or isomeric form, and include all chiral, diastereomeric, and racemic forms. Methods for the preparation of compounds of the present application and intermediates thereto are part of the present application. All stereoisomers, including geometric isomers, are intended to be covered by the present application.

[0084] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and this description includes instances where the event or circumstance occurs and instances where it does not.

[0085] "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having from 1 to 10 carbon atoms ("Ci-Cio alkyl"). In some embodiments, the alkyl group has from 1 to 8 carbon atoms ("Ci-C8alkyl"). In some embodiments, the alkyl group has from 1 to 6 carbon atoms ("Ci-C6alkyl"), the alkyl group has from 1 to 5 carbon atoms ("Ci-C5alkyl"), the alkyl group has from 1 to 4 carbon atoms ("Ci-C4alkyl"), the alkyl group has from 1 to 3 carbon atoms ("Ci-C3alkyl"), the alkyl group has from 1 to 2 carbon atoms ("Ci-C2alkyl") the alkyl group has 1 carbon atom ("Cialkyl"). In some embodiments, the alkyl group has from 2 to 6 carbon atoms ("C2-C6alkyl"). Examples of Ci-C6alkyl include methyl (Ci), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), t-butyl (C4), sec-butyl (C4), i-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanal (C5), t-amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Each instance of an alkyl group can be independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents; for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl").

[0086] The term "alkenyl" means a straight or branched hydrocarbon chain radical set of only 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, and being attached to the rest of the molecule by a single bond, such as, but not limited to, ethenyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl, and the like.

[0087] The term "alkynyl" means a straight or branched hydrocarbon chain radical set of only 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, and being attached to the rest of the molecule by a single bond, such as, but not limited to, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1- en-4-ynyl, and the like.

[0088] As described herein, the terms "halogen," "halo," "halogen," and the like mean fluorine, chlorine, bromine, or iodine, particularly fluorine, chlorine, bromine, particularly preferably fluorine, chlorine.

[0089] "Haloalkyl" refers to an alkyl group (e.g., C1-C6 alkyl) as described herein in which one or more hydrogen atoms are replaced by a halogen (e.g., mono-, di-, and tri-haloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloro-fluoroalkyl, chloro-difluoroalkyl, and 2-fluoroisobutyl. "Cyclopropylmethyl" refers to a methylene end attachment to other structure.

[0090] "Alkoxy" refers to an alkyl group (e.g., C1-C6 alkyl) as described herein attached to the molecule through an oxygen atom. This includes moieties in which the alkyl portion can be straight or branched, such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and n-hexoxy.

[0091] "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 foregoing C5-C6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-C8 cycloalkyl groups include the foregoing C3-C6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted ( "substituted cycloalkyl") with one or more substituents.

[0092] "Heterocycloalkyl" refers to a group in which one or more C atoms in the above "cycloalkyl" groups are replaced with a heteroatom such as N, O, S, P, etc.

[0093] The term "alkylamino" means a -alkyl-NH2structure or a substituted amino group -NRdRe, where each of Rdand Reis independently hydrogen or an alkyl group as described above. For example, the term "monoalkylamino" means a substituted amino group -NRdRe, where one of Rdand Reis hydrogen and the other is an alkyl group as described above; "dialkylamino" means a substituted amino group -NRdRe, where each of Rdand Reis independently an alkyl group as described above.

[0094] The term "haloalkylamino" means a -alkyl-NH2structure or a substituted amino group -NRdRe, where each of Rdand Reis independently hydrogen or a haloalkyl group as described above. For example, the term "monohaloalkylamino" means a substituted amino group -NRdRe, where one of Rdand Reis hydrogen and the other is a haloalkyl group as described above; "dihaloalkylamino" means a substituted amino group -NRdRe, where each of Rdand Reis independently a haloalkyl group as described above.

[0095] The term "heterocyclyl" means a stable 3- to 20-membered non-aromatic ring- system consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl group can be a monocyclic, bicyclic, tricyclic or more ring system, which can include fused, bridged or spiro ring systems; the nitrogen, carbon or sulfur atoms in the heterocyclyl group can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl can be partially or fully saturated. The heterocyclyl group can be attached to the remainder of the molecule via a carbon atom or a heteroatom and by a single bond. In a heterocyclyl group comprising fused rings, one or more of the rings can be an aryl or heteroaryl group as defined below, provided that the point of attachment to the remainder of the molecule is a non-aromatic ring atom. For the purposes of this application, the heterocyclyl group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged or spiro ring group comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spiro ring group comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclyl groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]nonan-7-yl, 2-oxa-6-aza-spiro[3.3]heptan-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxolanyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, and the like. Heterocyclyl groups herein include the heterocycloalkyl groups described above.

[0096] The term "aryl" means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms. For the purposes of this application, the aryl group can be a monocyclic, bicyclic, tricyclic or more ring system, and can also be fused with a cycloalkyl or heterocyclyl group as defined above, provided that the aryl group is attached to the remainder of the molecule via an atom on the aromatic ring by a single bond. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, 2,3-dihydro-lH-isoindolyl, 2-benzoxazolinonyl, 2H-l,4-benzoxazin-3(4H)-on-7-yl, and the like.

[0097] The term "heteroaryl" means a 5- to 16-membered, conjugated ring system having from 1 to 15 carbon atoms (preferably having from 1 to 10 carbon atoms) and from 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless specifically indicated otherwise in the specification, the heteroaryl group can be a monocyclic, bicyclic, tricyclic, or more ring ring system, and can also be fused with a cycloalkyl or heterocyclyl group as defined above, provided that the heteroaryl group is attached to the rest of the molecule via a single bond through an atom of the aromatic ring. The nitrogen, carbon, or sulfur atoms in the heteroaryl group can optionally be oxidized; the nitrogen atoms can optionally be quaternized. For the purposes of this application, the heteroaryl group is preferably a stable 5- to 12-membered aromatic radical containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, more preferably a stable 5- to 10-membered aromatic radical containing from 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or a 5- to 6-membered aromatic radical containing from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, but are not limited to thiophene, furan ring, and the like.

[0098] Unless otherwise indicated, when referring to a specifically named aryl group (e.g., phenyl), heterocyclyl group (e.g., pyrrolidinyl, piperidinyl, and morpholinyl), or heteroaryl group (e.g., tetrazolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, and furanyl), the reference is intended to include the ring as appropriate having from 0 to 3, preferably from 0 to 2, substituents selected from the group of substituents listed above for aryl, heterocyclyl, and / or heteroaryl.

[0099] The term "one or more" (e.g., in the definition of substituents of the generic compounds of the application) means "one, two, three, or four, especially one, two, three, or four, more especially one, two, or three, even more especially one or two."

[0100] As used herein, the term "pharmaceutically acceptable salt" means that the salt is physiologically acceptable, but can also refer to a synthetic material that is pharmaceutically useful, e.g., as an intermediate in chiral resolution, while the salt itself can not be directly administered to a subject, but can be useful to the production of the end- product of the application. It specifically includes acid (organic and inorganic) addition salts or base (including organic and inorganic) addition salts.

[0101] A "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surface-active, wetting, dispersing, suspending, stabilizing agent, isotonic agent, solvent, or emulsor that is relevant for use in connection with the administration of a therapeutic agent to humans and to animals.

[0102] As described herein, the term "disease" refers to a physical state of the subject that is associated with the disease of the present application. For example, the arterial peripheral disease, neurodegeneration-related disease of the present application.

[0103] 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 headache pain, migraine, tension headache, cluster headache, chronic and acute neuropathic pain, post-herpetic neuralgia, diabetic neuropathy, HIV-related neuropathy, trigeminal neuralgia, Charcot-Marie-Tooth neuropathy, hereditary sensory neuropathy, peripheral nerve injury, painful neuroma, ectopic proximal and distal discharge, radiculopathy, chemotherapy-induced neuropathic pain, radiotherapy-induced neuropathic pain, persistent / chronic postsurgical pain (e.g., post-amputation, post-thoracotomy, post-cardiac surgery), post-mastectomy pain, central pain, spinal cord injury pain, post-stroke pain, thalamic pain, phantom pain (e.g., post-amputation of lower extremity, upper extremity, breast), intractable pain, acute pain, acute postoperative pain, acute musculoskeletal pain, joint pain, mechanical low back pain, neck pain, tendonitis, injury pain, exercise pain, acute visceral pain, pyelonephritis, appendicitis, cholecystitis, intestinal obstruction, hernia, chest pain, cardiac pain, pelvic pain, renal colic, acute obstetric pain, labor pain, cesarean section pain, acute inflammatory pain, burn pain, trauma 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, adiposis dolorosa, venous pain, Guillain-Barre pain, pain with leg and toe movement, Haglund syndrome, erythromelalgia, Fabry's disease pain, bladder and urogenital system diseases, 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, widespread pain, paroxysmal extreme pain, pruritis, tinnitus, or pain caused by angina.

[0104] The pharmaceutically acceptable compositions of the present application can be orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or via inhalation, as is appropriate to the disease condition being treated in accordance with the severity of the condition. In certain embodiments, the compounds, salts, and compositions of the present application can be administered orally or parenterally at dosage levels of about 0.001 mg / kg to about 1000 mg / kg, of subject body weight per day, one or more times per day, to obtain the desired therapeutic effect.

[0105] The administration form can be a liquid form, a solid form or a semi-solid form. The liquid form can be a solution (including true solution and colloidal solution), an emulsion (including o / w type, w / o type and multiple emulsion), a suspension, an injection (including water injection, powder injection and infusion), eye drops, nose drops, lotion and liniment, etc.; the solid form can be a tablet (including common tablet, enteric-coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, oral disintegrating tablet), a capsule (including hard capsule, soft capsule, enteric-coated capsule), a granule, a powder, a pellet, a drop pill, a suppository, a film, a patch, an aerosol (powder) mist, a spray, etc.; the semi-solid form can be an ointment, a gel, a paste, etc.

[0106] To achieve the purpose of administration and enhance the therapeutic effect, the drug or the pharmaceutical composition of the present application can be administered by any known administration method.

[0107] The compound or the composition of the present application can be taken alone or in combination with other therapeutic drugs or symptomatic drugs. When the compound of the present application has synergistic effect with other therapeutic drugs, the dosage thereof should be adjusted according to the actual situation.

[0108] Advantageous technical effects

[0109] The inventors found that the compound in the present application has equivalent or superior inhibitory activity on CHO cell human-derived Nav1.8 ion channel to the positive control; has better selectivity to Nav sub-type ion channels; has good oral absorption in rats, and the 24-hour in vivo exposure is much better than that of the positive control compound; has equivalent or better analgesic effect and analgesic duration to VX-548. The present application provides a class of Nav1.8 inhibitor compounds with novel structure, strong activity, good selectivity, better drug exposure, better analgesic effect, longer analgesic duration and fewer side effects, which has good application prospect in preventing and / or treating Nav1.8 inhibition-related indications such as pain, respiratory diseases, neurological disorders and mental diseases, etc. DETAILED DESCRIPTION

[0110] The following examples are helpful for those skilled in the art to better understand the technical solutions of the present application, but the protection scope of the present application includes but is not limited to this.

[0111] For all the following examples, standard operations and methods known to those skilled in the art can be used. Unless otherwise specified, all temperatures are in °C (degrees Celsius). The structure of the compound is determined by nuclear magnetic resonance spectrum (NMR) and / or mass spectrum (MS).

[0112] The structure of the compounds of the present application was determined by nuclear magnetic resonance (NMR) or / and liquid-mass spectrometry (LC-MS). NMR chemical shifts (δ) are in parts per million (ppm) units. Nuclear magnetic resonance was determined with a Bruker avance-400 type nuclear magnetic instrument, solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3), and tetramethylsilane (TMS) was used as an internal standard.

[0113] Liquid chromatography-mass spectrometry LC-MS measurement liquid phase part uses ACQUITY UPLC ultra-high pressure liquid chromatography, mass spectrometry part uses Xevo G2-SQ tof mass spectrometer.

[0114] The starting materials in the examples of the present application are known and can be purchased on the market, or can be synthesized using or according to methods known in the art.

[0115] 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)

[0116]

[0117] 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

[0118] To a solution of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-1H-benzo[d]imidazole-6-carboxylic acid (21.24 mg, 0.06 mmol, 1.0 eq) in dichloromethane (2 mL) was added 2-(7- azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (34 mg, 0.09 mmol, 1.5 eq) and N,N-diisopropylethylamine (39 mg, 0.3 mmol, 5.0 eq) and the reaction was stirred at room temperature for 10 min. Then 3,4-diaminopyridin-2(1H)-one (9.7 mg, 0.12 mmol, 2.0 eq) was added and the reaction was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was diluted with ethyl acetate and water. 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, 47% yield), which was used directly in the next step. LCMS (ESI) [M+H]+: 462.14.

[0119] 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

[0120] To a solution 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 (15.0 mg, 0.032 mmol, 1.0 eq.) in ethanol (1 mL) and aqueous sodium hydroxide (1 mL, 10% wt.) was added and the reaction was stirred at 80 °C for 2 h. After the reaction was completed, the reaction mixture was directly concentrated and purified by preparative HPLC to give 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, 21% yield) as a white solid. LCMS (ESI) [M+H]+: 444.1353. 1H NMR (400 MHz, DMSO) δ 11.15 (s, 1H), 7.14 - 7.01 (m, 3H), 6.49 - 6.44 (m, 1H), 5.60 (d, J = 11.2 Hz, 1H), 4.50 (s, 1H), 3.96 (d, J = 2.1 Hz, 3H), 2.86 (p, J = 7.5 Hz, 1H), 1.63 (s, 3H), 0.80 - 0.73 (m, 3H). 19 FNMR (376 MHz, DMSO) δ -72.9, -137.51, -154.41.

[0121] 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)

[0122]

[0123] Step 1: Synthesis of 4-methoxy-1-methyl-3-nitropyridin-2(1H)-one

[0124] Dissolve 4-hydroxy-3-nitropyridin-2(1H)-one (430 mg, 2.7 mmol, 1.0 eq) in acetonitrile (5 mL), add potassium carbonate (1.1 g, 8.1 mmol, 3 eq), then drop iodomethane (1 g, 6.75 mmol, 2.5 eq), react under nitrogen protection at 60 °C. After the reaction is completed, add water and extract with ethyl acetate, combine the organic phases, dry and concentrate, then separate by normal phase column to obtain solid 4-methoxy-1-methyl-3-nitropyridin-2(1H)-one (50 mg, yield 10%). LCMS (TOF MS ES+) m / z [M+H]+: 185. 1 H NMR (400 MHz, DMSO-d6) δ 7.48 (d, J = 8.0 Hz, 1H), 6.19 (d, J = 8.0 Hz, 1H), 3.77 (s, 3H), 3.42 (s, 3H).

[0125] Step 2: Synthesis of 4-amino-1-methyl-3-nitropyridin-2(1H)-one

[0126] To a solution of 4-methoxy-l-methyl-3-nitropyridin-2(lH)-one (45 mg, 0.24 mmol, 1.0 eq) in amine-methanol solution (3 mL, 7 mol / L) was added under nitrogen protection at room temperature for 4 hours. After the reaction was completed, water was added and extracted with ethyl acetate, the organic phase was combined, dried and concentrated, filtered and column chromatography to obtain solid 4-amino-l-methyl-3-nitropyridin-2(lH)-one (30 mg, yield 75%). LCMS (TOF MS ES+) m / z [M+H]+: 170. 1 H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J = 8.0 Hz, 1H), 7.46 (s, 2H), 6.08 (d, J = 8.0 Hz, 1H), 3.40 (s, 3H).

[0127] Step 3: Synthesis of 3,4-diamino-l-methylpyridin-2(lH)-one

[0128] To a solution of 4-amino-l-methyl-3-nitropyridin-2(lH)-one (27 mg, 0.16 mmol, 1.0 eq) in methanol solution (3 mL) was added Pd / C, replaced with hydrogen three times, stirred at room temperature for 4 hours. TLC monitoring reaction was complete, after the reaction was completed, filtered with diatomite, the filtrate was concentrated to obtain solid 3,4-diamino-l-methylpyridin-2(lH)-one (20 mg, yield 90%), which was directly used in the next reaction. LCMS (TOF MS ES+) m / z [M+H]+: 140. 1 H NMR (400 MHz, DMSO-d6) δ 7.71 (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).

[0129] 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-l,5-dihydro-4H- imidazo[4,5-c]pyridin-4-one

[0130] To a solution of 3,4-diamino-l-methylpyridin-2(lH)-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)-lH-benzo[d]imidazole-6-carboxylic acid (16 mg, 0.044 mmol, 1.0 eq) in phosphorus oxychloride (3 mL) was stirred at room temperature. After the reaction was completed, saturated aqueous sodium bicarbonate solution and ethyl acetate were added for extraction. The organic phase was concentrated and HPLC preparation separation was performed to obtain white solid 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl]-5-methyl-l,5-dihydro-4H-imidazo[4,5-c]pyridin-4- one (3 mg, yield 15%). LCMS (TOFMS ES+) m / z [M+H]+: 458. 1 H NMR (400 MHz, DMSO) δ 11.15 (s, 1H), 7.14 - 7.01 (m, 3H), 6.49 - 6.44 (m, 1H), 5.60 (d, J = 11.2 Hz, 1H), 4.50 (s, 1H), 3.96 (d, J = 2.1 Hz, 3H), 3.35 (s, 3H), 2.92 - 2.85 (m, 1H), 1.63 (s, 3H), 0.80 - 0.73 (m, 3H).

[0131] 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)-lH-imidazo[4,5- c]pyridine (Compound 3)

[0132]

[0133] Step 1: Synthesis of 5-nitro-2-(trifluoromethyl)pyridin-4-ol

[0134] To a solution of 2-(trifluoromethyl)pyridin-4-ol (2.0 g, 12.26 mmol, 1.0 eq) in sulfuric acid (6.0 mL) was added fuming nitric acid (6.0 mL) dropwise at ice bath condition. After the addition was completed, the mixture was allowed to warm to room temperature and stirred for 15 min. Then the reaction mixture was poured into a sealed tube and heated at 120 °C for 12 h. After the reaction was completed, the reaction mixture was cooled to room temperature and then poured into ice water slowly. The mixture was extracted with ethyl acetate (3x). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 5-nitro-2-(trifluoromethyl)pyridin-4-ol (2.5 g, 97.97% yield) as a yellow oil, which was used directly in the next step. LCMS (ESI) [M+H]+: 209. 1 H NMR (400 MHz, DMSO) δ 9.09 (s, 1H), 7.46 (s, 1H).

[0135] Step 2: Synthesis of 4-chloro-5-nitro-2-trifluoromethylpyridine

[0136] To a solution of 5-nitro-2-(trifluoromethyl)pyridin-4-ol (1.0 g, 4.81 mmol, 1.0 eq) in sulfuric acid (6.0 mL) was added fuming nitric acid (6.0 mL) dropwise at ice bath condition. After the addition was completed, the mixture was allowed to warm to room temperature and stirred for 15 min. Then the reaction mixture was poured into a sealed tube and heated at 120 °C for 12 h. After the reaction was completed, the reaction mixture was cooled to room temperature and then poured into ice water slowly. The mixture was extracted with ethyl acetate (3x). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 5-nitro-2-(trifluoromethyl)pyridin-4-ol (2.5 g, 97.97% yield) as a yellow oil, which was used directly in the next step. LCMS (ESI) [M+H]+: 209. 1 H NMR (400 MHz, DMSO) δ 9.42 (s, 1H), 8.57 (s, 1H).

[0137] Step 3: Synthesis of 5-nitro-2-(trifluoromethyl)pyridin-4-amine

[0138] To a solution of 5-nitro-2-(trifluoromethyl)pyridin-4-ol (1.0 g, 4.81 mmol, 1.0 eq) in sulfuric acid (6.0 mL) was added fuming nitric acid (6.0 mL) dropwise at ice bath condition. After the addition was completed, the mixture was allowed to warm to room temperature and stirred for 15 min. Then the reaction mixture was poured into a sealed tube and heated at 120 °C for 12 h. After the reaction was completed, the reaction mixture was cooled to room temperature and then poured into ice water slowly. The mixture was extracted with ethyl acetate (3x). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 5-nitro-2-(trifluoromethyl)pyridin-4-ol (2.5 g, 97.97% yield) as a yellow oil, which was used directly in the next step. LCMS (ESI) [M+H]+: 209. 1 H NMR (400 MHz, DMSO) δ 9.42 (s, 1H), 8.57 (s, 1H).

[0139] Step 4: Synthesis of 6-(trifluoromethyl)pyridine-3,4-diamine

[0140] Yellow solid 5-nitro-2-(trifluoromethyl)pyridin-4-amine (100.0 mg, 0.48 mmol, 1.0 eq) was dissolved with tetrahydrofuran (10.0 mL), 5% wet palladium on carbon (100.0 mg) was added, the system was replaced with hydrogen three times, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction liquid was filtered, and the filtrate was concentrated to obtain yellow solid 6-(trifluoromethyl)pyridine-3,4-diamine (60.0 mg, yield 70.16%), which was directly used in the next step reaction. LCMS (ESI) [M+H]+: 208. 1 H NMR (400 MHz, DMSO) δ 7.69 (s, 1H), 6.82 (s, 1H), 5.75 (s, 2H), 5.10 (s, 2H).

[0141] 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

[0142] Yellow solid 6-(trifluoromethyl)pyridine-3,4-diamine (12.0 mg, 67.74 umol, 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 umol, 1.0 eq), ammonium chloride (36.24 mg, 0.67 mmol, 12.0 eq) and phosphorus oxychloride (200.0 ul) were added to a schlenk flask, and the reaction was carried out at 100 °C for 12 hours. After the reaction was completed, the reaction liquid was cooled to room temperature, slowly poured into cold water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried, concentrated in vacuum, and then prepared and separated to purify to obtain 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 (400 MHz, DMSO) δ 9.00 (s, 1H), 8.03 (s, 1H), 7.19 (t, J = 7.4 Hz, 1H), 7.15 - 7.07 (m, 1H), 5.86 (d, J = 11.0 Hz, 1H), 4.50 (m, J = 11.0, 7.5 Hz, 1H), 3.95 (d, J = 2.2 Hz, 3H), 2.90 (d, J = 7.5 Hz, 1H), 1.66 (s, 3H), 0.81 (d, J = 7.5 Hz, 3H).

[0143] 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]-lH- 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]-lH-imidazo[4,5-c]pyridine (Compound 46)

[0144]

[0145] Step 1: Synthesis of 2-chloro-5-nitropyridin-4-amine

[0146] To a solution of 2-chloro-N-(4-methoxybenzyl)-5-nitropyridin-4-amine (200 mg, 0.69 mmol, 1.0 eq) in trifluoroacetic acid (4 mL) was stirred at 65 °C for 4 h. After the reaction was completed, the reaction was concentrated and purified by normal phase column chromatography (petroleum ether: ethyl acetate 5: 1) to give 2-chloro-5-nitropyridin-4-amine (102 mg, yield 87.23%) as a beige solid. LCMS (ESI) [M-H]-: 171.99. 1 H NMR (400 MHz, DMSO-d6) δ 6.97 (s, 1H), 8.86 (s, 1H), 8.09 (s, 2H).

[0147] 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

[0148] (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-nitropyridin-4-amine (30.0 mg, 0.173 mmol, 1.0 eq), 2-(7-azabenzotriazol-1- yl)-N,N,N',N'-tetramethyluronium 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 into dichloromethane (5 mL) and stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was concentrated and purified by normal phase column chromatography (petroleum ether: ethyl acetate 5:1) to get (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%) as yellow oil. LCMS (ESI) [M+H]+: 510.1.

[0149] 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

[0150] (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 into ethanol (6 mL) and water (2 mL) and stirred at 80 °C for 1 h. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to get (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%) as yellow solid. LCMS (ESI) [M+H]+: 480.1.

[0151] 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)

[0152] (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 h. After the reaction was completed, the reaction was directly concentrated to give yellow solid 6-chloro-2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl]-lH-imidazo[4,5-c]pyridine (compound 46, 23 mg, yield 85.35%), which was directly used in the next step. LCMS (ESI) [M+H]+: 462.09. 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 7.62 (s, 1H), 7.17 (t, J = 7.7 Hz, 1H), 7.16 - 7.05 (m, 1H), 5.78 (d, J = 11.0 Hz, 1H), 4.47 (dd, J = 11.0, 7.6 Hz, 1H), 3.94 (d, J = 2.1 Hz, 3H), 2.87 (q, J = 7.5 Hz, 1H), 1.64 (s, 3H), 0.83 - 0.76 (m, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -72.90, -137.55, -154.48.

[0153] Step 5: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl]-lH-imidazo[4,5-c]pyridin-6-amine

[0154] To a solution of 6-chloro-2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-lH-imidazo[4,5-c]pyridine (20 mg, 0.043 mmol, 1.0 eq), benzophenone imine (12 mg, 0.065 mmol, 1.5 eq), 1,1'- binaphthalene-2,2'-diphenylphosphine (12 mg, 0.0043 mmol, 0.1 eq), tris(dibenzylideneacetone)dipalladium (4.0 mg, 0.0043 mmol, 0.1 eq) and sodium tert-butoxide (12.5 mg, 0.129 mmol, 3.0 eq) in toluene (2 mL) was purged with nitrogen for 3 times, stirred at 80 °C for 3 hours, the reaction was cooled to room temperature, the reaction mixture was diluted with ethyl acetate, filtered through silica gel, washed with ethyl acetate. The filtrate was concentrated, the residue was dissolved in methanol (3 mL) and added with ammonia hydroxide (1 mL), continued to stir at room temperature for 18 hours. After the reaction was completed, the reaction was concentrated, purified by high performance liquid chromatography to give 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl]-lH-imidazo[4,5-c]pyridine-6-carboxamide (Compound 4, 2.0 mg, yield 10.44 %). LCMS (ESI) [M+H]+: 443.14. 1 H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 8.80 (s, 1H), 7.37 - 7.26 (m, 2H), 6.93 (s, 1H), 6.18 (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 (376 MHz, DMSO-d6) δ -72.93, -137.61 (m, J = 20.7, 8.5, 7.2 Hz), -154.51 (d, J = 20.8 Hz).

[0155] Example 5: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl]-lH-imidazo[4,5-c]pyridine-6-carbonitrile (Compound 5)

[0156]

[0157] Step 1: Synthesis of 4-[(4-methoxybenzyl)amino]-5-nitropyridinecarbonitrile

[0158] To a solution of 2-chloro-N-(4-methoxybenzyl)-5-nitropyridin-4-amine (300 mg, 1.02 mmol, 1.0 eq) in N-methylpyrrolidone (5.0 mL) was added zinc cyanide (1.2 g, 10.21 mmol, 10.0 eq) and tetrakis(triphenylphosphine)palladium (236.07 mg, 0.2 mmol, 0.2 eq) and the system was purged with nitrogen for 3 times and reacted at 120 °C for 16 h. After the reaction was completed, it was washed with saturated sodium chloride, extracted with ethyl acetate and purified by normal phase to obtain 4-[(4-methoxybenzyl)amino]-5-nitropyridinecarbonitrile (150 mg, yield 66.32%) as a yellow solid. LCMS (ESI) [M+H]+: 285.14. 1 H NMR (400 MHz, DMSO) δ 9.06 (s, 1H), 7.68 (s, 1H), 7.35 - 7.32 (m, 2H), 6.93 - 6.90 (m, 2H), 4.65 (d, J = 6.3 Hz, 2H), 3.73 (s, 3H).

[0159] Step 2: Synthesis of 4-amino-5-nitropyridinecarbonitrile

[0160] To a solution of 4-[(4-methoxybenzyl)amino]-5-nitropyridinecarbonitrile (150.0 mg, 0.67 mmol, 1.0 eq) in trifluoroacetic acid (1 mL) was added and reacted at 60 °C for 16 h. After the reaction was completed, the pH was adjusted to 7-8 by adding saturated sodium bicarbonate solution and extracted with ethyl acetate for 3 times. The organic phase was concentrated and purified by normal phase column to obtain 4-amino-5-nitropyridinecarbonitrile (60.0 mg, yield 59.06%) as a yellow solid. LCMS (ESI) [M+H]+: 165.07. 1 H NMR (400 MHz, DMSO) δ 9.01 (s, 1H), 7.44 (s, 1H).

[0161] 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

[0162] (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).

[0163] 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

[0164] (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 iron powder (17 mg, 0.3 mmol, 5.0 eq) and ammonium chloride (17 mg, 0.3 mmol, 5.0 eq), and reacted at 80 °C for 12 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated, and then purified by normal phase column to obtain 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 (500 MHz, Chloroform-d) δ 8.97 (s, 1H), 7.81 (s, 1H), 7.59 (s, 1H), 7.09 - 7.03 (m, 1H), 6.99 (m, J = 10.1, 9.2, 4.8 Hz, 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, 1.1 Hz, 1H), 1.32 (m, J = 3.3 Hz, 3H), 1.10 (d, J = 6.4 Hz, 3H).

[0165] Step 5: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-lH-imidazo[4,5-c]pyridine-6- carbonitrile

[0166] (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 h. After the reaction was completed, the reaction was neutralized with saturated sodium bicarbonate, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by preparative separation to obtain 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl]-lH-imidazo[4,5-c]pyridine-6-carbonitrile (5 mg, yield 40.2%) as a white solid. LCMS (ESI) [M+H]+: 453.13. 1 H NMR (500 MHz, Chloroform-d) δ 8.43 (s, 1H), 7.70 (s, 1H), 7.13 - 7.07 (m, 1H), 6.99 (m, J = 10.1, 9.1, 4.8 Hz, 1H), 5.66 (dd, J = 7.3, 0.7 Hz, 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 = 6.2 Hz, 3H).

[0167] Example 6: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-5-(lH-imidazol-2-yl)-lH- benzo[d]imidazole (Compound 6)

[0168]

[0169] Step 1: Synthesis of tert-butyl 2-bromo-lH-imidazole-l-carboxylate

[0170] tert-butyl 2-bromo-lH-imidazole-l-carboxylate (1.23 g, 5.0 mmol, 1.0 eq) was dissolved in anhydrous N,N-dimethylformamide (10 mL), triethylamine (1.41 g, 13.9 mmol, 2.8 eq) was added, and di-tert-butyl dicarbonate (1.41 g, 6.5 mmol, 1.3 eq) was added dropwise. The reaction was stirred at room temperature for 4 h. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution three times. The organic phase was dried and concentrated, and then purified by normal phase column separation to obtain 2-bromo-lH-imidazole-l-carboxylic acid tert-butyl ester (1.23 g, yield 73%) as a liquid. LCMS (TOF MS ES+) m / z [M+H]+: 247.0.1 H NMR (400 MHz, Chloroform-d) δ 7.45 (d, J = 7.5 Hz, 1H), 7.17 (d, J = 7.5 Hz, 1H), 1.61 (s, 9H).

[0171] Step 2: Synthesis of [1-(tert-butoxycarbonyl)-1H-imidazol-2-yl]boronic acid

[0172] tert-Butyl 2-bromo-1H-imidazole-1-carboxylate (1.0 g, 4.05 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (10 mL) and replaced with nitrogen, n-butyllithium (1.94 mL, 4.86 mmol, 1.2 eq, 2.5 mol / l) was slowly added dropwise at -70 °C, after the dropwise addition was completed, the reaction was continued at -70 °C for 0.5 hours, trimethyl borate (630.8 mg, 6.07 mmol, 1.5 eq) was added dropwise, after the dropwise addition was completed, the reaction was continued at -70 °C for 1 hour. After the reaction was completed by TLC monitoring, saturated aqueous ammonium chloride solution was added to quench, extracted with ethyl acetate three times, the organic phase was combined and concentrated, and purified by normal phase column separation to obtain solid [1-(tert-butoxycarbonyl)-1H-imidazol-2-yl]boronic acid (453 mg, yield 53%). LCMS (TOF MS ES+) m / z [M-H]": 211.1.1H NMR (400 MHz, DMSO-d6) δ 7.51 (d, J = 7.5 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 1.52 (s, 9H).

[0173] Step 3: Synthesis of tert-butyl 2-(3-amino-4-nitrophenyl)-1H-imidazole-1-carboxylate

[0174] To a solution of [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) in dioxane (5 mL) and water (1 mL) was added 1,1’- bis(diphenylphosphino)ferrocene palladium(II) dichloride (30 mg) and the system was purged with nitrogen three times. The reaction was stirred at 100 °C for 12 h. After the reaction was completed, saturated aqueous sodium chloride solution was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to give tert-butyl 2-(3-amino-4-nitrophenyl)-1H-imidazole-1-carboxylate (173 mg, 40.2% yield). LCMS (TOF MS ES+) m / z [M+H]+: 305.1.1H NMR (400 MHz, Chloroform-d) δ 8.06-7.99 (m, 2H), 7.64 (d, J = 7.5 Hz, 1H), 7.42-7.40 (m, 1H), 6.92 (d, J = 2.0 Hz, 1H), 6.91 (s, 2H), 1.63 (s, 9H).

[0175] Step 4: Synthesis of tert-butyl 2-(3,4-diaminophenyl)-1H-imidazole-1-carboxylate

[0176] To a solution of tert-butyl 2-(3-amino-4-nitrophenyl)-1H-imidazole-1-carboxylate (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) in ethanol (5 mL) and water (1 mL) was purged with nitrogen three times. The reaction was stirred at 70 °C for 4 h. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated and purified by column chromatography to give tert-butyl 2-(3,4-diaminophenyl)-1H-imidazole-1-carboxylate (73 mg, 47% yield). LCMS (TOF MS ES+) m / z [M+H]+: 275.1. 1 1H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 7.5 Hz, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.03-6.97 (m, 1H), 6.74 (d, J = 2.0 Hz, 1H), 6.56 (d, J = 7.6 Hz, 1H), 5.70 (s, 2H), 5.25 (s, 2H), 1.53 (s, 9H).

[0177] 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-imidazole-1-carboxylate

[0178] (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- azobenzo triazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (83.1 mg, 0.218 mmol, 1.5 eq) and diisopropyl ethylamine (47.1 mg, 0.364 mmol, 2.5 eq) were dissolved in dichloromethane (3 mL), stirred at 23 °C for 30 min, then tert-butyl 2-(3,4- diamino phenyl)-1H-imidazole-1-carboxylate (40 mg, 0.145 mmol, 1.0 eq) was added, and reacted at 23 °C for 4 h. After the reaction was completed, the reaction solution was added to saturated aqueous ammonium chloride solution, extracted with dichloromethane, and the organic phase was dried and 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-carboxamido]phenyl}-1H-imidazole-1- carboxylate (63 mg, yield 70.7%). LCMS (TOF MS ES+) m / z [M+H]+: 611.2. 1 H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.02 (s, 2H), 7.95 (d, J = 7.5 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.30 - 7.28 (m, 1H), 7.16 (d, J = 7.5 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H), 6.97 - 6.80 (m, 2H), 5.23 (d, J = 7.0 Hz, 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 = 6.8 Hz, 4H).

[0179] 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- imidazole-1-carboxylate

[0180] 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- imidazole-1 -carboxylate (63 mg, 0.103 mmol, 1.0 eq) was dissolved in acetic acid (2 mL) and reacted at 45 °C for 12 h. After the reaction was completed, the reaction solution was concentrated to give 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- imidazole-1 -carboxylate (72 mg), which was used directly in the next reaction. LCMS (TOF MS ES+) m / z [M+H]+: 593.2.

[0181] 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

[0182] 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- imidazole-1 -carboxylate (72 mg, 0.121 mmol, 1.0 eq) was dissolved in a hydrochloric acid dioxane solution (3 mL, 4 M) and reacted at 25 °C for 4 h. After the reaction was completed, the reaction solution was concentrated, and 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 (5.3 mg) was obtained by preparation separation and purification. LCMS (TOF MS ES+) m / z [M+H]+: 493.1. 1 H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 8.03 (d, J = 1.5 Hz, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.65 - 7.61 (m, 1H), 7.27 (s, 2H), 7.20 - 7.15 (m, 1H), 7.05 - 6.97 (m, 1H), 5.41 (d, J = 7.0 Hz, 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 = 6.8 Hz, 3H).

[0183] 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-lH-imidazo[4, 5- c]pyridine (Compound 7)

[0184]

[0185] Step 1: Synthesis of 2-methoxy-5-nitropyridin-4-amine

[0186] 2-methoxy-N-(4-methoxybenzyl)-5-nitropyridin-4-amine (100 mg, 0.35 mmol, 1.0 eq) was added to trifluoroacetic acid (4 mL) and stirred at 65 °C for 4 h. After the reaction was completed, the reaction was concentrated and separated by normal phase column chromatography (petroleum ether and ethyl acetate, volume ratio 5:1) to give 2-methoxy-5-nitropyridin-4-amine (42 mg, yield 71.8%) as a yellow solid. LCMS (ESI) [M+H]+: 170.01. 1 H NMR (400 MHz, DMSO-d6) d 8.82 (s, 1H), 7.67 (s, 2H), 6.15 (s, 1H), 3.84 (s, 3H).

[0187] 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

[0188] (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 into dichloromethane (5 mL), oxalyl chloride (43 mg, 0.033 mmol, 2.0 eq) was added dropwise under ice bath condition, and stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated, then dissolved with dichloromethane (2 mL) for standby. 2-methoxy-5-nitropyridin-4-amine (28 mg, 0.017 mmol, 1.0 eq) and triethylamine (34 mg, 0.033 mmol, 2.0 eq) were added into dichloromethane (5 mL), stirred at room temperature for 15 min, then the above prepared solution was added into the reaction system, and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated, and normal phase column chromatography (petroleum ether: ethyl acetate 5:1) was performed to obtain 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.

[0189] 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

[0190] (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 into methanol (5 mL), and hydrogen replacement was performed, and reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to obtain 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 reaction. LCMS (ESI) [M+H]+: 476.15.

[0191] 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-lH-imidazo[4,5- c]pyridine

[0192] (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 h. After the reaction was completed, the reaction was directly concentrated to give white solid 2-[(2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl]-6-methoxy-lH-imidazo[4,5-c]pyridine (5.1 mg, yield 18.93%). LCMS (ESI) [M+H]+: 458.15. 1 H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 8.46 (s, 1H), 7.18 - 7.05 (m, 2H), 6.79 (s, 1H), 5.69 (d, J = 11.1 Hz, 1H), 4.45 (dd, J = 11.1, 7.5 Hz, 1H), 3.95 (d, J = 2.1 Hz, 3H), 3.84 (s, 3H), 2.87 (m, J = 7.5 Hz, 1H), 1.64 (s, 3H), 0.79 (dd, J = 7.7, 2.6 Hz, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -72.93, -137.61 (m, J = 20.7, 8.5, 7.2 Hz), -154.51 (d, J = 20.8 Hz).

[0193] 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)

[0194]

[0195] 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

[0196] (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 completed, the reaction was quenched with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to isolate 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%) as a white solid. LCMS (ESI) [M+H]+: 463.10. 1 H NMR (400 MHz, Methanol-d4) δ 8.54 (s, 1H), 7.08 (m, J = 8.5, 5.7, 2.2 Hz, 1H), 6.89 (m, J = 8.9 Hz, 1H), 5.70 (d, J = 11.1 Hz, 1H), 4.58 (t, J = 5.6 Hz, 1H), 4.00 (d, J = 2.4 Hz, 3H), 2.95 (m, J = 7.6 Hz, 1H), 1.71 (s, 3H), 0.87 (m, J = 7.6, 2.4 Hz, 3H). 19 F NMR (376 MHz, Methanol-d4) δ -75.63, -140.20, -156.99.

[0197] Example 9: Synthesis of 8-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl]-9H-purin-6-amine (Compound 9)

[0198]

[0199] Step 1: Synthesis of 8-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl]-9H-purin-6-amine

[0200] To a solution of 6-chloro-8-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-9H-purine (15.0 mg) in ammonia- methanol solution (2 mL, 2 M) was heated at 100 °C for 5 days. After the reaction was completed, it was concentrated under reduced pressure, and preparative separation was performed to give 8-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl]-9H-purin-6-amine (2.0 mg) as a white solid. LCMS (ESI) [M+H]+: 444.15.

[0201] 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)

[0202]

[0203] Step 1: Synthesis of 4-[(tert-butyldimethylsilyl)oxy]-2-nitroaniline

[0204] To a solution of 4-amino-3-nitrophenol (500 mg, 3.25 mmol, 1.0 eq) in dichloromethane (15 mL) was added diisopropylethylamine (1.3 g, 9.74 mmol, 3.0 eq) and tert- butyldimethylsilyl chloride (582 mg, 3.9 mmol, 1.2 eq) successively, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, it was washed with saturated sodium chloride, extracted with ethyl acetate, and purified by normal phase (petroleum ether 90%, ethyl acetate 10%) to give 4-[(tert-butyldimethylsilyl)oxy]-2-nitroaniline (520 mg) as a white solid. LCMS (ESI) [M+H]+: 548.1. 1 HNMR (400 MHz, DMSO) δ 7.33 (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).

[0205] 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

[0206] (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) and reacted at 50 °C for 3 h. After the reaction was completed, water was added and extracted with ethyl acetate, and the crude was purified by flash column (petroleum ether / ethyl acetate = 3:1) to give (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) as a white solid. LCMS (ESI) [M+H]+: 491.1.

[0207] 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

[0208] (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), and the gas was replaced with hydrogen gas and reacted at room temperature for 3 h. After the reaction was completed, it was filtered and the filtrate was concentrated under vacuum to give (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) as a yellow solid, which was used directly in the next reaction. LCMS (ESI) [M+H]+: 461.1.

[0209] 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

[0210] (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 completed, the reaction was neutralized with saturated sodium bicarbonate, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo to prepare 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) as a white solid. LCMS (ESI) [M+H]+: 443.1395. 1 H NMR (400 MHz, DMSO) δ 12.29 (s, 1H), 8.41 (s, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.19 - 6.98 (m, 2H), 6.81 (s, 1H), 6.64 (d, J = 8.1 Hz, 1H), 5.61 (d, J = 11.2 Hz, 1H), 4.46 (dd, J = 11.1, 7.6 Hz, 1H), 3.96 (d, J = 2.0 Hz, 3H), 2.86 (t, J = 7.5 Hz, 1H), 1.63 (s, 3H), 0.78 (d, J = 6.2 Hz, 3H). 19 F NMR (376 MHz, DMSO) δ -73.50 (s), -137.65 - -138.44 (m), -155.18 (s).

[0211] 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)

[0212]

[0213] Step 1: Synthesis of 6-benzyloxy-3-nitropyridin-2-amine

[0214] Sodium hydride (460.90 mg, 11.52 mmol, 4.0 eq) was added to a flask, N.N- dimethylformamide (5 mL) was added, the system was replaced with nitrogen for 3 times, benzyl alcohol (0.6 mL, 2.0 eq) was slowly added dropwise under ice bath condition, stirred at room temperature for 15 minutes, then 6-chloro-3-nitropyridin-2-amine (500 mg, 2.88 mmol, 1.0 eq) was added dropwise, the reaction was carried out at room temperature for 2 hours, after the reaction was completed, water was added to filter to obtain yellow solid 6-benzyloxy-3-nitropyridin-2-amine (400 mg, yield 66.32%). LCMS (ESI) [M+H]+: 246.08. 1 HNMR (400MHz, DMSO) δ 8.27 (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 = 9.1 Hz, 1H), 5.39 (s, 2H).

[0215] Step 2: Synthesis of 6-(benzyloxy)pyridine-2,3-diamine

[0216] 6-benzyloxy-3-nitropyridin-2-amine (400.0 mg, 1.63 mmol, 1.0 eq) was dissolved in isopropyl alcohol (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, the reaction was carried out at 100 °C for 4 hours under nitrogen protection. After the reaction was completed, ethyl acetate was extracted, and normal phase purification was carried out to obtain 6-(benzyloxy)pyridine-2,3-diamine (240.0 mg, yield 59.06%) in the form of brown oil. LCMS (ESI) [M+H]+: 216.07. 1 HNMR (400MHz, DMSO) δ 7.41-7.37 (m, 2H), 7.37-7.32 (m, 2H), 7.30-7.26 (m, 1H), 6.75 (d, J = 7.9 Hz, 1H), 5.85 (d, J = 7.9 Hz, 1H), 5.35 (s, 2H), 5.13 (s, 2H), 4.12 (s, 2H).

[0217] 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

[0218] (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 tripyrrylphosphonium hexafluorophosphate (195.04 mg, 0.3 mmol, 1.5 eq) were added into N,N-dimethylformamide (3 mL), after stirring for 15 minutes, 6-(benzyloxy)pyridine-2,3-diamine (50 mg, 0.22 mmol, 1.1 eq) was added. After the reaction was completed, it was washed with saturated sodium chloride, extracted with ethyl acetate, and purified by normal phase to obtain 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.

[0219] 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

[0220] (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 into ethanol (7 mL), followed by the addition of 10% sodium hydroxide (7 mL), and reacted at 85 °C for 2 hours. After the reaction was completed, it was washed with saturated sodium chloride, extracted with ethyl acetate, and 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. 1H NMR (400 MHz, DMSO-d6) δ 13.22 - 12.76 (m, 1H), 7.89 (dd, J = 32.6, 8.6 Hz, 1H), 7.44 (d, J = 7.4 Hz, 2H), 7.39 - 7.34 (m, 2H), 7.31 (s, 1H), 7.14 - 7.03 (m, 2H), 6.73 (dd, J = 10.0, 8.6 Hz, 1H), 5.64 (dd, J = 51.0, 11.2 Hz, 1H), 5.35 (d, J = 6.9 Hz, 2H), 4.49 (m, J = 11.7, 7.4 Hz, 1H), 3.96 (d, J = 2.0 Hz, 3H), 2.87 (m, J = 7.6, 2.5 Hz, 1H), 1.65 (s, 3H), 0.81 - 0.76 (m, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -73.53, -138.21, -153.47 - -155.89.

[0221] Step 5: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-l,4-dihydro-5H- imidazo[4,5-b]pyridin-5-one

[0222] To 5-(benzyloxy)-2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-lH-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.) was added to tetrahydrofuran (1 mL), hydrogen replacement, stirring at room temperature for 2 hours. After the reaction was completed, filtration, the filtrate was prepared and purified to obtain solid product 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-l,4-dihydro-5H- imidazo[4,5-b]pyridin-5-one (10 mg, yield 6.25%). LCMS (ESI) [M+H]+: 444.14. 1 H NMR (400 MHz, DMSO) δ 7.82 - 7.57 (m, 1H), 7.12 - 7.02 (m, 2H), 6.53 - 5.96 (m, 1H), 5.60 (d, J = 11.5 Hz, 1H), 4.55 - 4.38 (m, 1H), 3.96 (d, J = 2.1 Hz, 3H), 2.84 (s, 1H), 1.62 (s, 3H), 0.80 - 0.74 (m, 3H). 19F NMR (376 MHz, DMSO-d6) δ -73.57, -138.24, -155.04.

[0223] 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)

[0224]

[0225] Step 1: Synthesis of 2-methoxy-5-nitropyridin-4-amine

[0226] 2-chloro-5-nitropyridin-4-amine (350.0 mg, 2.02 mmol, 1.0 eq.) was dissolved in methanol (4.0 mL), sodium methoxide (560 μL, 3.02 mmol, 1.5 eq.) was added, the system was replaced by nitrogen for 3 times, and reacted 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 yellow solid 2-methoxy-5-nitropyridin-4-amine (311.7 mg, yield 91.3%). LCMS (ESI) [M+H] + : 170.07. 1 H NMR (400 MHz, DMSO) δ 8.82 (s, 1H), 7.67 (s, 2H), 6.16 (s, 1H), 3.84 (s, 3H).

[0227] Step 2: Synthesis of 4-amino-5-nitropyridin-2(lH)-one

[0228] 2-methoxy-5-nitropyridin-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 completed, the hydrochloric acid was removed under reduced pressure, the residue was dissolved in methanol, and separated by a flash plate (dichloromethane 90%, methanol 10%) to obtain yellow solid 4-amino-5-nitropyridin-2(lH)-one (85.4 mg, yield 29.9%). LCMS (ESI) [M+H] + : 156.04. 1 H NMR (400 MHz, DMSO) δ 8.56 (s, 1H), 7.22 (s, 2H), 5.42 (s, 1H).

[0229] Step 3: Synthesis of (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-N-(5-nitro-2-oxo-l,2-dihydropyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran- 2-carboxamide

[0230] (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), 4-amino-5-nitropyridin-2(lH)-one (14.4 mg, 0.09 mmol, 1.1 eq.) and N,N-diisopropylethylamine (27.3 mg, 0.21 mmol, 2.5 eq.) were added, stirred at room temperature for 5 minutes, finally N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (41.9 mg, 0.11 mmol, 1.3 eq.) was added, reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was washed with water, extracted with tert-butyl methyl ether, the organic phases were combined, the solvent was removed under reduced pressure to obtain a yellow solid (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(5-nitro-2-oxo-l,2- dihydropyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (24.2 mg, yield 58.0%), which was directly used in the next step reaction. LCMS (ESI) [M+H] + : 492.12.

[0231] 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

[0232] (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), 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, and the reaction was carried out at 80 °C for 2 hours. After the reaction was completed, the insoluble matter was removed by filtration, and the filtrate was prepared with a tenth of ammonium bicarbonate system to obtain 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%). LCMS (ESI) [M+H]: 444.14. + :444.14. 1 H NMR (400 MHz, MeOD) δ 7.87 (s, 1H), 7.10 (t, J = 7.4 Hz, 1H), 6.95 (m, J = 8.9 Hz, 1H), 6.35 (s, 1H), 5.60 (d, J = 11.0 Hz, 1H), 4.35 (dd, J = 11.0, 8.0 Hz, 1H), 3.99 (d, J = 2.5 Hz, 3H), 2.91 (m, J = 7.7 Hz, 1H), 1.68 (s, 3H), 0.86 (dd, J = 8.1, 2.2 Hz, 3H).

[0233] 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]pyridin-5-amine (Compound 41)

[0234]

[0235] Step 1: Synthesis of pyridine-2,3,6-triamine

[0236] Compound 3-nitropyridine-2,6-diamine (20 mg, 0.13 mmol, 1.0 eq) and 5% palladium on carbon (41 mg, 0.019 mmol, 0.15 eq.) and tetrahydrofuran (1 mL) were mixed, and the system was replaced with hydrogen gas for 3 times, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction liquid was filtered, and the filter cake was washed with methanol for several times, and the filtrate was combined and concentrated under reduced pressure to obtain purple solid product pyridine-2,3,6-triamine (16 mg, crude). LCMS (ESI) [M+H]+: 125.08.

[0237] Step 2: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-lH-imidazo[4,5-b]pyridin-5- amine

[0238] Compound 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), warmed to 100 °C, stirred for 4 h. After the reaction was completed, the reaction was quenched by slowly adding saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate several times, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the residue was prepared and purified to give yellow solid product 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl]-lH-imidazo[4,5-b]pyridin-5-amine (5.5 mg, yield 9.65 %). LCMS (ESI) [M+H]+: 443.15. 1 H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 7.54 (d, J = 19.1, 8.6 Hz, 1H), 7.13 - 7.06 (m, 1H), 7.05 - 6.95 (m, 1H), 6.35 (d, J = 22.9, 8.6 Hz, 1H), 5.87 (s, 2H), 5.53 (d, 1H), 4.50 (dd, J = 11.3, 7.5 Hz, 1H), 3.97 (d, J = 2.0 Hz, 3H), 2.85 (m, J = 7.3 Hz, 1H), 1.63 (s, 3H), 0.77 (d, J = 7.6 Hz, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -73.49, -138.34, -155.09.

[0239] Example 14: Synthesis of 2-[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-lH-benzo[d]imidazole-4-carboxylic acid (Compound 43)

[0240]

[0241] 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-carboxamido]benzoate

[0242] 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), 2-(7-azabenzotriazol-1- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (49 mg, 0.12 mmol, 1.5 eq) and diisopropylethylamine (30 μl, 0.18 mmol, 2.0 eq) were added, and the reaction was allowed to proceed at room temperature for 0.5 hours, then 4-amino-5-nitrophenylacetic acid ethyl ester (17 mg, 0.11 mmol, 1.2 eq) was added, and the reaction was allowed to proceed at room temperature for 3 hours. After the reaction was completed, extraction was performed with water and ethyl acetate, and separation was performed on a silica gel plate with a developing agent of petroleum ether: ethyl acetate = 3: 1 to obtain white solid compound 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, yield 70.50%). LCMS (ESI) [M+H]+: 503.15. 1 H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 7.65 (d, J = 6.5 Hz, 1H), 7.31 (d, J = 6.1 Hz, 1H), 7.25 - 7.16 (m, 2H), 6.58 (t, J = 7.9 Hz, 1H), 6.26 (s, 2H), 5.12 (d, J = 10.1 Hz, 1H), 4.22 (dd, J = 10.1, 7.7 Hz, 1H), 3.94 (d, J = 2.1 Hz, 3H), 3.80 (s, 3H), 2.76 (m, J = 7.5 Hz, 1H), 1.61 (s, 3H), 0.76 - 0.70 (m, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -72.77, -73.04, -137.36 - -137.97, -138.21, -154.57.

[0243] 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]imidazole-4-carboxylate

[0244] 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 h. After the reaction was completed, the reaction was neutralized with saturated sodium bicarbonate, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to give methyl 2-[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl]-1H-benzo[d]imidazole-4-carboxylate (25 mg, 86.45% yield) as a yellow solid. LCMS (ESI) [M+H]+: 485.14.

[0245] 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]imidazole-4-carboxylic acid

[0246] Methyl 2-[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl]-1H-benzo[d]imidazole-4-carboxylate (25 mg, 0.051 mmol, 1.0 eq.) was dissolved in methanol (1 mL), and a lithium hydroxide solution (2 N, 0.5 mL) was added, and the reaction was allowed to proceed at room temperature for 12 h. After the reaction was completed, the reaction was directly concentrated, neutralized with hydrochloric acid, extracted with ethyl acetate, and purified by preparative separation to obtain 2-[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-yl]-1H-benzo[d]imidazole-4-carboxylic acid (9.5 mg, 39.13% yield) as a white solid. LCMS (ESI) [M+H]+: 471.13. 1 H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 17.5 Hz, 1H), 7.89 - 7.71 (m, 1H), 7.60 (d, J = 19.6 Hz, 1H), 7.18 - 7.07 (m, 2H), 5.75 (d, J = 11.0 Hz, 1H), 4.51 (dd, J = 11.0, 7.6 Hz, 1H), 3.96 (d, J = 2.1 Hz, 3H), 2.89 (t, J = 7.5 Hz, 1H), 2.47 - 2.40 (m, 1H), 1.66 (s, 3H), 0.83 - 0.75 (m, 3H). 19F NMR (376 MHz, DMSO-d6) δ -68.69, -133.41, -150.34.

[0247] 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-l-yl)-lH- imidazo[4,5-c]pyridine (Compound 49)

[0248]

[0249] 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

[0250] Step 2: Synthesis of 4-chloro-2-[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-lH-imidazo[4,5-c]pyridine

[0251] Step 2: Synthesis of 4-chloro-2-[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-lH-imidazo[4,5-c]pyridine

[0252] Take (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 aqueous sodium hydroxide solution (2 mL, 10% wt.), and react at 80 °C for 2 hours. After the reaction is completed, the reaction solution is concentrated under vacuum, and thin layer chromatography is performed (petroleum ether: ethyl acetate = 5:1) to obtain 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%) as a white solid. LCMS (ESI) [M+H]+: 462.82. 1 H NMR (400 MHz, DMSO) δ 13.45 (s, 1H), 8.10 (d, J = 5.6 Hz, 1H), 7.56 (d, J = 5.5 Hz, 1H), 7.21 - 7.06 (m, 2H), 5.84 - 5.73 (m, 1H), 4.08 - 3.95 (m, 4H), 2.89 (t, J = 7.5 Hz, 1H), 1.65 (s, 3H), 0.80 (d, J = 7.4 Hz, 3H).

[0253] 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

[0254] Take 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 (30.0 mg, 0.065 mmol, 1.0 eq.), add 1-methylpiperazine (0.5 mL), and react at 100 °C for 8 hours. After the reaction is completed, the reaction solution is concentrated, and preparative purification is performed to obtain the 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%) as a white solid. LCMS (ESI) [M+H]+: 526.22. 1H 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.

[0255] 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)

[0256]

[0257] Step 1: Synthesis of 2-(3,4-dimethylpiperazin-1-yl)-3-nitropyridine-4-amine

[0258] 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).

[0259] Step 2: Synthesis of 2-(3,4-dimethylpiperazin-1-yl)pyridine-3,4-diamine

[0260] 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).

[0261] 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

[0262] 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.

[0263] 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

[0264] 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 completed, 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 prepared by HPLC. LCMS(ESI)[M+H]+:540.23.1HNMR(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=1.4 Hz,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).

[0265] 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)

[0266]

[0267] Step 1: Synthesis of tert-butyl 4-(4-amino-3-nitropyridin-2-yl)-2-methylpiperazine-1-carboxylate

[0268] 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).

[0269] Step 2: Synthesis of tert-butyl 4-(3,4-diaminopyridin-2-yl)-2-methylpiperazine-1-carboxylate

[0270] 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. 1H 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).

[0271] 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

[0272] 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 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.

[0273] 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

[0274] 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.

[0275] 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

[0276] 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).

[0277] 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)

[0278]

[0279] Step 1: Synthesis of (R)-2-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylic acid tert-butyl ester

[0280] (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). 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 (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

[0281] Step 2: Synthesis of (R)-4-(4-amino-3-nitropyridin-2-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylic acid tert-butyl ester

[0282] 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).

[0283] Step 3: Synthesis of (R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(3,4-diaminopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0284] (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), 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 through diatomaceous earth and evaporated to dryness to obtain 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).

[0285] 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)

[0286] (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.

[0287] 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

[0288] 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.

[0289] 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

[0290] (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).

[0291] 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)

[0292]

[0293] Step 1: Synthesis of (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylic acid tert-butyl ester

[0294] (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

[0295] Step 2: Synthesis of (S)-4-(4-amino-3-nitropyridin-2-yl)-2-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylic acid tert-butyl ester

[0296] 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).

[0297] Step 3: Synthesis of tert-butyl (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(3,4-diaminopyridin-2-yl)piperazine-1-carboxylate

[0298] (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 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. 1HNMR (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).

[0299] 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)

[0300] (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.

[0301] 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

[0302] 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.

[0303] 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

[0304] (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.

[0305] 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)

[0306]

[0307] 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

[0308] (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.

[0309] 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

[0310] (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).19FNMR(376MHz,DMSO)δ-73.40,-138.15,-155.41.

[0311] 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

[0312] 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.

[0313] 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

[0314] 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).19FNMR(376MHz,DMSO)δ-73.47,-138.17,-154.92.

[0315] 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

[0316] 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. 1HNMR (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.

[0317] 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)

[0318]

[0319] Step 1: Synthesis of 1-(tert-butyl)-2-methyl-4-aminopiperidine-1,2-dicarboxylic acid ester

[0320] 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 with a 9:1 dichloromethane:methanol mixture (150 mL). 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 to give a yellow solid 1-(tert-butyl)-2-methyl-4-aminopiperidine-1,2-dicarboxylic acid ester (580.5 mg, yield 88.8%). 1H 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).

[0321] Step 2: Synthesis of 1-(tert-butyl)-2-methyl-4-((4-amino-3-nitropyridin-2-yl)amino)piperidine-1,2-dicarboxylic acid ester

[0322] 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 product 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).

[0323] 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

[0324] 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).

[0325] 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

[0326] 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).

[0327] 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

[0328] 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 HNMR(400MHz,DMSO)δ7.62(d,J=5.8Hz,1H),7.10–6.99(m,2H),6.69(dd,J=5.8,0.9H z,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. 28(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).

[0329] 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

[0330] 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.

[0331] 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

[0332] 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 complete, the mixture was filtered, and the organic phase 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. 1HNMR (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,1 H),4.31(s,1H),3.91(d,J=2.0Hz,3H),3.24(s,1H),2.80(dq,J=11.5,5.8Hz, 4H),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.

[0333] 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)

[0334]

[0335] Step 1: Synthesis of 4-benzyl-1-(tert-butyl)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate

[0336] 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).

[0337] Step 2: Synthesis of 4-benzyl-1-(tert-butyl)-2-((1,3-dioxoisoindoline-2-yl)methyl)piperazine-1,4-dicarboxylic acid ester

[0338] 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.

[0339] Step 3: Synthesis of 4-benzyl-1-(tert-butyl)-2-(((tert-butyloxycarbonyl)amino)methyl)piperazine-1,4-dicarboxylic acid ester

[0340] 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.

[0341] Step 4: Synthesis of tert-butyl 2-(((tert-butyloxycarbonyl)amino)methyl)piperazine-1-carboxylate

[0342] 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).

[0343] Step 5: Synthesis of tert-butyl 4-(4-amino-3-nitropyridin-2-yl)-2-(((tert-butyloxycarbonyl)amino)methyl)piperazine-1-carboxylate

[0344] 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).

[0345] Step 6: Synthesis of tert-butyl 2-((tert-butyloxycarbonyl)amino)methyl)-4-(3,4-diaminopyridin-2-yl)piperazine-1-carboxylate

[0346] 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.

[0347] 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

[0348] (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.

[0349] 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

[0350] 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.

[0351] 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

[0352] 147 mg 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 was added to a mixture 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 mixture 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. 4.6 mg of the product at the first retention time and 4.0 mg of the product at the second retention time were obtained. 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.

[0353] 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.

[0354] Table 1: Structure and characterization of some compounds

[0355]

[0356]

[0357]

[0358]

[0359]

[0360] Experimental Example 1: Test of the inhibitory activity of the compounds of the present invention on human Nav1.8 ion channels in CHO cells

[0361] Experimental Objective: The purpose of this test case is to test the effect of the compound on the human Nav1.8 ion channel.

[0362] 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.

[0363] Experimental procedure:

[0364] 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.

[0365] 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:

[0366]

[0367] Table 2. Nav1.8 inhibition rate test results (1 nM)

[0368] Compounds Half-inactivated state (TP2, 1 nM) Compounds Half-inactivated state (TP2, 1 nM) VX-548 61.4％ 41 94.3％ 1 89.7％ 43 51.8％ 3 54.2％ 44 41.4％ 4 36.3％ 45 44.9％ 5 40.8％ 46 33.4％ 7 31.3％ 47 92.3％ 8 63.8％ 48 83.2％ 9 52.0％ 49 92.7％ 10 90.8％ 50 95.63％ 33 78.6％ 51 94.26％ 34 23.3％ 57 69.91％ 38 90.6％ 60 53.41％ 39 95.2％ 71 91.7％ 72 92.6％ 73 68.8％ 74 88.9％ 78 86.5％ 81 90.1％ 83 72.7％

[0369] 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.

[0370] Experimental Example 2: Pharmacokinetic Test of the Compounds of the Present Invention in SD Rats

[0371] The pharmacokinetic characteristics of the compound of the present invention were investigated by gavage (PO) administration to male SD rats.

[0372] Specific experimental procedure:

[0373] 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.

[0374] Table 3: Pharmacokinetic Results in Male SD Rats

[0375]

[0376] 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.

[0377] Experimental Example 3: Analgesic effect of the compound of the present invention in a rat incision pain model

[0378] 1. Experimental Procedure:

[0379] 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.

[0380] 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.

[0381] 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.

[0382] 2. Foot incision pain modeling

[0383] (1) Disinfection of surgical instruments;

[0384] (2) The animal was anesthetized and fixed in a prone position on the operating table;

[0385] (3) The lateral hind limb is flattened with the sole of the foot facing upwards, fixed with surgical tape, and disinfected;

[0386] (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;

[0387] (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.

[0388] (6) Make a longitudinal incision in the muscle with a blade, making sure to cut the belly of the muscle in half;

[0389] (7) Suture the skin with 7-0 sutures and disinfect.

[0390] 3. Measurement of Mechanical Pain Threshold (MPT)

[0391] Pain assessment using the Ascending method:

[0392] (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.

[0393] (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 (○).

[0394] (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:

[0395] Table 4: Effects of intravenous injection of test compounds on analgesia in rats with surgical pain model

[0396]

[0397] 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 as shown in formula (I) and stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein, X is selected from O or S; ring Q is phenyl or 5-6 membered heteroaryl; 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 each independently selected from 0, 1, 2, 3, 4, 5; R7, R8, R9 are each independently selected from absent, H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkyl substituted C1-C6 hydroxyalkyl, -(CH2)n-6-10 membered aryl, -(CH2)n-3-8 membered heterocyclyl, said C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkyl substituted C1-C6 hydroxyalkyl, -(CH2)n-6-10 membered aryl, -(CH2)n-3-8 membered heterocyclyl can be optionally substituted with 1 or more halogen, 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, -COOR9; NR7R8, -COOR9; or R7, R8 and the nitrogen atom to which they are attached form a 3-8 membered heterocyclyl, said 3-8 membered heterocyclyl is optionally substituted with one or more halogen, 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, -COOR9; R m and R n are each independently selected from the group consisting of absent, H, C1-C6alkyl, C1-C6haloalkyl, or R m and R n together with the N atom they are attached to form a 4-6 membered heterocyclyl; A is selected from N, CR1; B is selected from N, CR2; U is selected from N, CR3; Y is selected from N, CR4; Z is selected from N, CR5; A, B, U, Y, Z are not simultaneously N; R1, R2, R3, R4and R5are the same or different, each independently selected from the group consisting of H, deuterium, halogen, hydroxyl, cyano, amino, amido, nitro, C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, haloC1-C6alkyl, deuterated C1-C6alkyl, deuterated C1-C6alkoxy, haloC1-C6alkoxy, C1-C6hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, said C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, haloC1-C6alkyl, deuterated C1-C6alkyl, deuterated C1-C6alkoxy, haloC1-C6alkoxy, C1-C6hydroxyalkyl, cycloalkyl, heterocyclyl, aryl optionally substituted with 1 or more R 02 substituents; 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 are identical or different and each independently selected from the group consisting of H, halogen, Ci-C6-alkyl, Ci-C6-alkoxy, hydroxyl, cyano, amino, C2-C6-alkenyl, C2-C6-alkynyl, halogenated Ci-C6-alkyl, halogenated Ci-C6-alkoxy, Ci-C6-hydroxyalkyl, 3- to 10-membered cycloalkyl, 3-10 membered heterocyclyl, 3- to 10-membered cycloalkyloxy and 3- to 10-membered heterocyclyloxy; said 3- to 10-membered cycloalkyl, 3-10 membered heterocyclyl, 3- to 10-membered cycloalkyloxy and 3- to 10-membered heterocyclyloxy are optionally substituted by 1 or more R 01 ; provided that R a , R b are not simultaneously hydrogen; R c , R d are identical or different and each independently selected from the group consisting of H, halogen, Ci-C6-alkyl, Ci-C6-alkoxy, hydroxyl, cyano, amino, C2-C6-alkenyl, C2-C6-alkynyl, halogenated Ci-C6-alkyl, halogenated Ci-C6-alkoxy, Ci-C6-hydroxyalkyl, 3- to 10-membered cycloalkyl, 3-10 membered heterocyclyl, 3- to 10-membered cycloalkyloxy and 3- to 10-membered heterocyclyloxy; said 3- to 10-membered cycloalkyl, 3-10 membered heterocyclyl, 3- to 10-membered cycloalkyloxy and 3- to 10-membered heterocyclyloxy are optionally substituted by 1 or more R 01 ; or R a , R b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl; or R c , R d together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl; wherein each of said cycloalkyl or heterocyclyl is independently optionally substituted with one or more R 01 ; each R 01 the same or different, and each independently selected from deuterium, halogen, hydroxyl, cyano, oxo, amino, amido, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

2. The compound according to claim 1 and stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, which is a compound shown in general formula (II): wherein each group is as defined in claim 1.

3. The compounds according to claim 1 or 2, and stereoisomers, tautomers thereof, or pharmaceutically acceptable salts thereof, wherein ring Q is selected from wherein is connected to the end of .

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

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

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

8. The compounds according to any one of claims 1 to 7, wherein R a is selected from Ci-C6-alkyl, and R b is H, preferably R a is methyl, and R b is H. and the stereoisomers, tautomers or pharmaceutically acceptable salts thereof.

9. The compounds according to any one of claims 1-8, wherein R c is selected from haloC1-C6alkyl, preferably, R c is trifluoromethyl; and stereoisomers, tautomers or pharmaceutically acceptable salts thereof.

10. The compound according to any one of claims 1-9, wherein R d is selected from C1-C6 alkyl, preferably R d is methyl; and stereoisomers, tautomers or pharmaceutically acceptable salts thereof.

11. A compound as shown below and stereoisomers, tautomers, or pharmaceutically acceptable salts thereof:

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

13. Use of a compound according to any one of claims 1 to 11, and stereoisomers, tautomers thereof, or pharmaceutically acceptable salts thereof, and a pharmaceutical composition according to claim 12, for the manufacture of a medicament for inhibiting voltage-gated sodium channels, preferably selected from the group consisting of Navl.8 channels.

14. Use of a compound according to any one of claims 1 to 11, and stereoisomers, tautomers thereof, or pharmaceutically acceptable salts thereof, and a pharmaceutical composition according to claim 12, for the manufacture of a medicament for the treatment and / or reduction of a condition, disease or disorder associated with increased Navl.8 activity or expression; preferably said condition, disease or disorder associated with increased Navl.8 activity or expression is selected from the group consisting of pain, respiratory diseases, neurological disorders and psychiatric diseases and combinations thereof; preferably said pain is selected from the group consisting of neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, visceral pain, chemotherapy pain, cancer pain, idiopathic pain, trauma pain, surgical pain, post-surgical pain, labor pain, parturition pain, neurogenic bladder disorders, ulcerative colitis, intestinal pain, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine, cluster headache, tension headache, phantom limb pain, dental pain, peripheral nerve injury and combinations thereof; preferably said musculoskeletal pain is selected from the group consisting of osteoarthritic pain; preferably said acute pain is acute post-surgical pain; preferably said neuropathic pain is selected from the group consisting of post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, diabetic neuropathy, diabetic peripheral neuropathy; preferably said post-surgical pain is selected from the group consisting of one or more of bunionectomy pain, abdominoplasty pain or hernia repair pain.

15. A compound as represented by formula (I-1), (I-2) and stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, X is selected from O or S; ring Q is phenyl or 5-6 membered heteroaryl; the other radicals are as defined in any one of claims 1 to 10.

16. A compound as represented by formula (II-1), (II-2) and stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, ring Q is phenyl or 5-6 membered heteroaryl; the other radicals are as defined in any one of claims 1 to 10.

17. A compound according to any one of the following, and stereoisomers, tautomers thereof, or pharmaceutically acceptable salts thereof,

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