Heterocyclic derivative as well as preparation method and application thereof

Abstract

The invention relates to a substituted heterocyclic derivative, a preparation method thereof and application of a pharmaceutical composition containing the derivative or a deuterated derivative in medicine. Specifically, the invention relates to substituted heterocyclic derivatives as shown in general formulas (I), (I-A) and (I-B), a preparation method and medicinal salts thereof, and application of the substituted heterocyclic derivatives as voltage-gated channel Nav 1.8 antagonists in prevention and / or treatment of Nav 1.8 related diseases, especially in the field of pain. Wherein the definitions of substituent groups in the general formulas (I), (I-A) and (I-B) are the same as the definitions in the specification.

Description

Technical Field

[0001] This application relates to a substituted heterocyclic derivative, a method for its preparation, and pharmaceutical compositions containing the derivative or a deuterated derivative, as well as their use as a therapeutic agent or in medicaments for the prevention of diseases mediated by the voltage-gated channel Nav 1.8. Background Technology

[0002] Pain is a clinical manifestation mediated by multiple factors. Its occurrence is often related to actual or potential tissue damage. It can be classified in different ways based on its intensity, pathogenesis, and manifestation. According to the duration of the illness, it can be divided into acute pain and chronic pain. Currently, pain has become the third largest health problem after cardiovascular and cerebrovascular diseases and tumors. It not only causes suffering for patients but also often leads to psychological stress and emotional disorders, increases the occurrence of complications, and in severe cases, even prevents independent living. In the 21st century, pain has been recognized by the World Health Organization and the International Association for the Study of Pain as the "fifth vital sign" in addition to the four major vital signs of respiration, pulse, body temperature, and blood pressure, thus reflecting the importance of pain research in the field of life and health science research. In recent years, with the increasing advancement of science and technology and basic research, people have gained a deeper understanding and awareness of pain. However, there is still a significant disconnect between basic research in pain science and clinical treatment, especially the physiological and pathological mechanisms of pain, particularly the generation, maintenance, and regulation mechanisms of pathological pain, which remain unclear, and related clinical treatment effects are not satisfactory.

[0003] Currently, opioids and non-opioids remain the mainstream medications for pain management. Opioids, such as morphine and oxycodone, are primarily used to treat acute pain and cancer pain, but they carry serious adverse risks such as addiction and respiratory depression. Non-opioids, such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), are used to treat mild to moderate pain, but they have some gastrointestinal and cardiovascular side effects. Antidepressants (such as tricyclic antidepressants, duloxetine, venlafaxine, and bupropion), antiepileptic drugs (such as gabapentin and pregabalin), and other central nervous system stimulants can also be used to treat chronic or neuropathic pain. Because these drugs were originally used to treat other diseases and are not specific for pain management, and because they have significant side effects, continuous exploration is needed in the field of pain management to find drugs with better therapeutic effects. Numerous studies have reported that voltage-gated sodium ion channels play a crucial role in pain transmission.

[0004] Nine sodium ion channels are currently known in humans, namely Nav1.1-Nav1.9. Based on their sensitivity to tetrodotoxin (TTX), they are classified into tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-insensitive (TTX-R) channels. Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.6, and Nav1.7 are TTX-S channels; Nav1.1, Nav1.2, Nav1.3, and Nav1.6 are mainly expressed in the central nervous system, Nav1.7 is mainly distributed in the peripheral nervous system, and Nav1.4 is expressed in skeletal muscle. Nav1.5, Nav1.8, and Nav1.9 are TTX-R channels; Nav1.5 is mainly expressed in cardiomyocytes, and Nav1.8 and Nav1.9 are mainly found in the dorsal root ganglia of the peripheral nervous system. In humans and mice, the absence or mutation of voltage-gated sodium ion channels Nav1.7 or Nav1.8 can lead to loss of pain sensation or abnormal pain, thus Nav1.7 and Nav1.8 are considered promising analgesic targets. While Nav1.7 has been known for some time, no drugs targeting it are currently on the market, and clinical trials have stalled due to side effects or efficacy issues. However, the release of Phase 3 clinical data for the Nav1.8 drug VX-548 demonstrates the safety and efficacy of targeting Nav1.8 in clinical settings.

[0005] The gene encoding Nav1.8 is SCN10A, located in the 3p21-22 region of human chromosome 1. Studies have found that the human and rat Nav1.8 genes share up to 93% homology. Nav1.8 is composed of α and β subunits. The α subunit is the main functional unit. Each α subunit consists of four homologous domains surrounding a center, forming the central pore of Nav1.8. Each domain contains six α-helical transmembrane structures (S1-S6). The β subunit mainly has four isoforms (β1-β4). In humans, the β subunits are mainly β1 and β3, which play an auxiliary role in the localization and stability of α on the cell membrane, and are also involved in the inactivation and voltage sensitivity of the α subunit. Although a great deal of research has been conducted in recent years on the regulation of Nav1.8 expression and how it participates in pain regulation, the regulatory mechanism of Nav1.8 expression remains unclear. What is clear is that Nav1.8 plays an important role in chronic neuropathic and chronic inflammatory pain, and also has some role in chronic visceral pain and cancer pain, but its role in acute and subacute inflammatory pain and neuropathic pain is not well understood.

[0006] Nav1.8 is currently one of the most popular targets for targeted pain therapy, attracting numerous researchers both domestically and internationally. Vertex's compound VX-548 has made the most progress, having already submitted a marketing application for the treatment of moderate to severe acute pain. Therefore, the rapid identification and active advancement of compounds with differentiated properties into clinical trials is urgently needed. Summary of the Invention

[0007] To address the aforementioned technical problems, this application provides a substituted heterocyclic derivative or its stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt of general formula (I):

[0008]

[0009] in:

[0010] Ring A, ring B, and ring C are each independently selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups;

[0011] L is selected from single bond, -NR x -、-CR x R y -、-O-、-S-;

[0012] X is selected from -NR x -、-CR x R y -、-O-、-S-、-S(O)- or -S(O)2-, X is preferably -O-、-S-;

[0013] R1, R2, R3, R4, R5, R6, R9, R x R y Each group is independently selected from hydrogen, deuterium, tritium, halogen, carboxyl, amino, hydroxyl, cyano, amide, alkoxy, alkylamino, mercapto, alkyl, alkenyl, =O, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -S(O). r R a -O-(CH2) t1 -[O-(CH2) t2 ] e -O-(CH2) t3 R a The -O-(CH2) t1 -[O-(CH2) t2 ] e -O-(CH2) t3 R a The O in the group may optionally be replaced by one or more S or N groups, wherein the amino, hydroxy, amide, alkoxy, alkylamino, mercapto, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -S(O) group is...r R a -O-(CH2) t1 -[O-(CH2) t2 ] e -O-(CH2) t3 R a Optionally composed of one or more radicals selected from deuterium, tritium, alkyl, haloalkyl, halogen, amino, hydroxyl, cyano, formyl, acetyl, deuterated alkyl, tritated alkyl, -S(O). r R a -C(O)NR a R b Substituted by cycloalkyl, heterocycloalkyl, aryl, heteroaryl or alkoxy substituents;

[0014] Alternatively, any two or two R9s selected from R1, R2, R3, R4, R5, R6, and R9, together with the atoms attached to them, form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group may optionally be further substituted by one or more substituents selected from hydroxyl, amino, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, and =O.

[0015] R7 and R8 can be the same or different, and each can be independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, halogen, nitro, cyano, hydroxyl, amide, cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, =O, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a C(O)OR b -NR a R b -NR a S(O) r R b -NR a C(O)R b -NR a C(O)NR b R c -NR a C(S)NR b R c -NR a S(O) r NR b R c -C(=NR) a )NR b R c -C(=NR) a )Rb -C(=NR) a )NR b OR c -C(=NR) a )NR b NR c -C(O)NR a OR b -C(O)NR a NR b R c -C(O)NR a R b -C(O)C(O)NR a R b -S(=NR) a )(O)R b -S(=NR) a )NR b R c -S(=NR) a )R b -S(=NR) a )(O)NR b R c -S(O) r NR a R b -S(O) r R a -Si(O)NR a R b 、-Si(R a 3. -P(O) s R a R b -OR a cycloalkylalkyl, heterocyclicalkyl, -alkylene-O-alkylene-cycloalkyl, -alkylene-O-cycloalkyl, -O-alkylene-heteroaryl, or -O-alkylene-heterocyclic, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, and heterocyclicalkyl are each independently and optionally selected by one or more R 01 Replaced;

[0016] R 01 Whether identical or different, each is independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, halogen, nitro, cyano, hydroxyl, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR aC(O)OR b 、-NR a R b 、-NR a S(O) r R b 、-NR a C(O)R b 、-NR a C(O)NR b R c 、-NR a C(S)NR b R c 、-NR a S(O) r NR b R c 、-C(=NR a )NR b R c 、-C(=NR a )R b 、-C(=NR a )NR b OR c 、-C(=NR a )NR b NR c 、-C(O)NR a OR b 、-C(O)NR a NR b R c 、-C(O)NR a R b 、-C(O)C(O)NR a R b 、-S(=NR a )(O)R b 、-S(=NR a )NR b R c 、-S(=NR a )R b 、-S(=NR a )(O)NR b R c 、-S(O) r NR a R b 、-S(O) r R a 、-Si(O)NR a R b 、-Si(R a )3、-P(O) s R a Rb -OR a The alkyl, heterocyclic, alkylene-O-alkylene-cycloalkyl, alkylene-O-cycloalkyl, alkylene-Hydroaryl, or alkylene-Hydroaryl groups may be further substituted by one or more substituents selected from deuterium, =O, halogen, hydroxyl, cyano, amino, aminoalkyl, acetyl, alkyl, alkenyl, alkynyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0017] Alternatively, R7, R8, together with the atoms they are attached to, form cycloalkyl and heterocycloalkyl groups, which may optionally be further substituted by one or more substituents selected from hydroxyl, amino, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, and =O.

[0018] Alternatively, R8, R9 and the atoms connected to them can be linked by single bonds, double bonds, cycloalkyl groups, or heterocyclic alkyl groups to form a macrocycle, which can be replaced by substituents of halogen, amino, hydroxyl, cyano, amide, alkoxy, mercapto, alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl groups.

[0019] R a R b R c Each is independently selected from hydrogen atom, hydroxyl, amino, alkyl, alkoxy, cycloalkyl, heterocyclic, heteroalkenyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, heteroalkenyl, aryl or heteroaryl may optionally be further substituted by one or more substituents selected from alkyl, halogen, nitro, cyano, amino, carboxyl, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, and substituents;

[0020] Or R a R b R c Any two links form a saturated or unsaturated heterocycle, which is further substituted by one or more substituents selected from alkyl, halogen, nitro, cyano, amino, carboxyl, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, etc.

[0021] n is 0, 1, or 2;

[0022] m can be 0, 1, 2, 3, 4, or 5;

[0023] p is 0, 1, 2 or 3;

[0024] t1 can be 0, 1, 2, or 3;

[0025] t2 can be 0, 1, 2, or 3;

[0026] t3 can be 0, 1, 2, or 3;

[0027] e can be 0, 1, 2, or 3;

[0028] r is 0, 1, or 2;

[0029] s is 0 or 1.

[0030] A preferred embodiment of this application provides a compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof, which is a compound of general formula (II) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof:

[0031]

[0032] The definitions of R1, R2, R3, R4, R5, R6, R7, R8, R9, X, L, ring A, ring B, ring C, n, m and p are as described in general formula (I).

[0033] A preferred embodiment of this application provides a compound of general formula (II) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, which is a compound of general formula (III) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof:

[0034]

[0035] The definitions of R1, R2, R3, R4, R5, R6, R7, R8, R9, X, ring A, ring B, ring C, n, m and p are as described in general formula (I).

[0036] A preferred embodiment of this application provides a compound of general formula (III) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, which is a compound of general formula (IV) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof:

[0037]

[0038] The definitions of R1, R2, R3, R4, R5, R6, R7, R8, R9, ring A, ring B, n, m and p are as described in general formula (I).

[0039] A preferred embodiment of this application provides a compound of general formula (III) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, which is a compound of general formula (V) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof:

[0040]

[0041] in:

[0042] X is selected from -S-, -S(O)-, or -S(O)2;

[0043] The definitions of R1, R2, R3, R4, R5, R6, R7, R8, R9, ring A, ring B, n, m, and p are as described in general formula (I).

[0044] A preferred embodiment of this application provides a compound of general formula (III) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, which is a compound of general formula (VI) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof:

[0045]

[0046] Among them: R1, R2, R3, R4, R5, R6, R7, R8, R9, R x The definitions of ring A, ring B, n, m and p are as described in general formula (I).

[0047] A preferred embodiment of this application provides a compound of general formula (IV) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically usable salt thereof, which is a compound of general formula (VII) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically usable salt thereof:

[0048]

[0049] Where: R1, R2, R3, R4, R5, R6, R7, R a R b The definitions of R9, ring A, ring B, n, m and p are as described in general formula (I).

[0050] This application provides a substituted heterocyclic derivative or its stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt of general formula (IA):

[0051]

[0052] in:

[0053] Ring D is selected from aryl, heteroaryl, heterocyclic alkyl, and fused rings;

[0054] Ring E is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups;

[0055] T is selected from single bonds, heteroaromatic rings, etc. The aforementioned heteroaryl rings, It can be one or more R 02 Replaced by, R 02 Selected from deuterium, tritium, halogen, amino, hydroxyl, nitro, cyano, amide, alkoxy, mercapto, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl;

[0056] L is selected from single bond, -NR x -、-CR x R y -、-O-、-S-;

[0057] X is selected from -NR x -、-CR x R y -、-O-、-S-、-S(O)- or -S(O)2-, X is preferably -O-、-S-;

[0058] R1, R2, R3, R4, R5, R6, R8, R x R y Each group is independently selected from hydrogen, deuterium, tritium, halogen, carboxyl, amino, hydroxyl, cyano, amide, alkoxy, alkylamino, mercapto, alkyl, alkenyl, heteroalkyl, =O, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -S(O). r R a -O-(CH2) t1 -[O-(CH2) t2 ] e -O-(CH2) t3 R a The -O-(CH2) t1 -[O-(CH2) t2 ] e -O-(CH2) t3 R a The O in the group may optionally be replaced by one or more S or N groups, wherein the amino, hydroxy, amide, alkoxy, alkylamino, mercapto, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -S(O) group is... r R a -O-(CH2) t1 -[O-(CH2) t2 ] e -O-(CH2) t3 R aOptionally composed of one or more radicals selected from deuterium, tritium, alkyl, haloalkyl, halogen, amino, hydroxyl, cyano, formyl, acetyl, deuterated alkyl, tritated alkyl, -S(O). r R a -C(O)NR a R b Substituted by cycloalkyl, heterocycloalkyl, aryl, heteroaryl or alkoxy substituents;

[0059] Alternatively, any two or two R8s selected from R1, R2, R3, R4, R5, R6, and R8, together with the atoms attached to them, form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group may optionally be further substituted by one or more substituents selected from hydroxyl, amino, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, and =O.

[0060] R7 is selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, halogen, nitro, cyano, hydroxyl, amide, cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, =O, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a C(O)OR b -NR a R b -NR a S(O) r R b -NR a C(O)R b -NR a C(O)NR b R c -NR a C(S)NR b R c -NR a S(O) r NR b R c -C(=NR) a )NR b R c -C(=NR) a )R b -C(=NR) a )NR b OR c -C(=NR) a )NR b NR c -C(O)NR a ORb -C(O)NR a NR b R c -C(O)NR a R b -C(O)C(O)NR a R b -S(=NR) a )(O)R b -S(=NR) a )NR b R c -S(=NR) a )R b -S(=NR) a )(O)NR b R c -S(O) r NR a R b -S(O) r R a -Si(O)NR a R b 、-Si(R a 3. -P(O) s R a R b -OR a cycloalkylalkyl, heterocyclicalkyl, -alkylene-O-alkylene-cycloalkyl, -alkylene-O-cycloalkyl, -O-alkylene-heteroaryl, or -O-alkylene-heterocyclic, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, and heterocyclicalkyl are each independently and optionally selected by one or more R 01 Replaced;

[0061] R 01 Whether identical or different, each is independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, halogen, nitro, cyano, hydroxyl, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a C(O)OR b -NR a R b -NR a S(O) r R b -NR a C(O)R b -NRa C(O)NR b R c 、-NR a C(S)NR b R c 、-NR a S(O) r NR b R c 、-C(=NR a )NR b R c 、-C(=NR a )R b 、-C(=NR a )NR b OR c 、-C(=NR a )NR b NR c 、-C(O)NR a OR b 、-C(O)NR a NR b R c 、-C(O)NR a R b 、-C(O)C(O)NR a R b 、-S(=NR a )(O)R b 、-S(=NR a )NR b R c 、-S(=NR a )R b 、-S(=NR a )(O)NR b R c 、-S(O) r NR a R b 、-S(O) r R a 、-Si(O)NR a R b 、-Si(R a )3、-P(O) s R a R b 、-OR aThe alkyl, heterocyclic, alkylene-O-alkylene-cycloalkyl, alkylene-O-cycloalkyl, alkylene-Hydroaryl, or alkylene-Hydroaryl groups may be further substituted by one or more substituents selected from deuterium, =O, halogen, hydroxyl, cyano, amino, aminoalkyl, acetyl, alkyl, alkenyl, alkynyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0062] Alternatively, R7, R8, and the atoms connected to them can be linked by single bonds, double bonds, cycloalkyl groups, or heterocycloalkyl groups to form a macrocycle, which can be replaced by substituents of halogen, amino, hydroxyl, cyano, amide, alkoxy, mercapto, alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl groups.

[0063] Alternatively, the two R7s together with the atoms they are attached to form a cycloalkyl or heterocycloalkyl group, which may optionally be further substituted by one or more substituents selected from hydroxyl, amino, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, =O.

[0064] R a R b R c Each is independently selected from hydrogen atom, hydroxyl, amino, alkyl, alkoxy, cycloalkyl, heterocyclic, heteroalkenyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, heteroalkenyl, aryl or heteroaryl may optionally be further substituted by one or more substituents selected from alkyl, halogen, nitro, cyano, amino, carboxyl, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, and substituents;

[0065] Or R a R b R c Any two links form a saturated or unsaturated heterocycle, which is further substituted by one or more substituents selected from alkyl, halogen, nitro, cyano, amino, carboxyl, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, etc.

[0066] m and q are 0, 1, 2, 3, 4 or 5;

[0067] r is 0, 1, or 2;

[0068] t1 can be 0, 1, 2, or 3;

[0069] t2 can be 0, 1, 2, or 3;

[0070] t3 can be 0, 1, 2, or 3;

[0071] e can be 0, 1, 2, or 3;

[0072] s is 0 or 1.

[0073] A preferred embodiment of this application provides a compound of general formula (IA) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof, which is a compound of general formula (II-A) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof:

[0074]

[0075] The definitions of R1, R2, R3, R4, R5, R6, R7, R8, T, ring D, m, and q are as described in general formula (IA).

[0076] This application provides a substituted heterocyclic derivative or its stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt of general formula (IB):

[0077]

[0078] Ring F is selected from aryl, heteroaryl, and fused rings;

[0079] The ring G is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups;

[0080] L is selected from single bond, -NR x -、-CR x R y -、-S-;

[0081] X is selected from -NR x -、-CR x R y -、-O-、-S-、-S(O)- or -S(O)2-, X is preferably -O-、-S-;

[0082] R1, R2, R3, R4, R5, R6, R8, R x R y Each group is independently selected from hydrogen, deuterium, tritium, halogen, carboxyl, amino, hydroxyl, cyano, amide, alkoxy, alkylamino, mercapto, alkyl, alkenyl, heteroalkyl, =O, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -S(O). r R a -O-(CH2) t1 -[O-(CH2) t2 ] e -O-(CH2) t3 R aThe -O-(CH2) t1 -[O-(CH2) t2 ] e -O-(CH2) t3 R a The O in the group may optionally be replaced by one or more S or N groups, wherein the amino, hydroxy, amide, alkoxy, alkylamino, mercapto, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -S(O) group is... r R a -O-(CH2) t1 -[O-(CH2) t2 ] e -O-(CH2) t3 R a Optionally composed of one or more radicals selected from deuterium, tritium, alkyl, haloalkyl, halogen, amino, hydroxyl, cyano, formyl, acetyl, deuterated alkyl, tritated alkyl, -S(O). r R a -C(O)NR a R b Substituted by cycloalkyl, heterocycloalkyl, aryl, heteroaryl or alkoxy substituents;

[0083] Alternatively, any two or two R8s selected from R1, R2, R3, R4, R5, R6, and R8, together with the atoms attached to them, form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group may optionally be further substituted by one or more substituents selected from hydroxyl, amino, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, and =O.

[0084] The condition is that when L is selected from a single bond and ring G is selected from aryl or heteroaryl, and the condition that any two atoms of R3, R5, R6, and R8 connected to them form a cycloalkyl or heterocycloalkyl group is not met, ring F is selected only from benzoxyheterocyclic boranes.

[0085] R7 is selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, halogen, nitro, cyano, hydroxyl, amide, cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, =O, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a C(O)OR b -NR a R b -NR a S(O) r R b -NR aC(O)R b 、-NR a C(O)NR b R c 、-NR a C(S)NR b R c 、-NR a S(O) r NR b R c 、-C(=NR a )NR b R c 、-C(=NR a )R b 、-C(=NR a )NR b OR c 、-C(=NR a )NR b NR c 、-C(O)NR a OR b 、-C(O)NR a NR b R c 、-C(O)NR a R b 、-C(O)C(O)NR a R b 、-S(=NR a )(O)R b 、-S(=NR a )NR b R c 、-S(=NR a )R b 、-S(=NR a )(O)NR b R c 、-S(O) r NR a R b 、-S(O) r R a 、-Si(O)NR a R b 、-Si(R a )3、-P(O) s R a R b 、-OR acycloalkylalkyl, heterocyclicalkyl, -alkylene-O-alkylene-cycloalkyl, -alkylene-O-cycloalkyl, -O-alkylene-heteroaryl, or -O-alkylene-heterocyclic, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, and heterocyclicalkyl are each independently and optionally selected by one or more R 01 Replaced;

[0086] R 01 Whether identical or different, each is independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, halogen, nitro, cyano, hydroxyl, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a C(O)OR b -NR a R b -NR a S(O) r R b -NR a C(O)R b -NR a C(O)NR b R c -NR a C(S)NR b R c -NR a S(O) r NR b R c -C(=NR) a )NR b R c -C(=NR) a )R b -C(=NR) a )NR b OR c -C(=NR) a )NR b NR c -C(O)NR a OR b -C(O)NR a NR b R c -C(O)NR a R b -C(O)C(O)NR a R b -S(=NR)a )(O)R b -S(=NR) a )NR b R c -S(=NR) a )R b -S(=NR) a )(O)NR b R c -S(O) r NR a R b -S(O) r R a -Si(O)NR a R b 、-Si(R a 3. -P(O) s R a R b -OR a The alkyl, heterocyclic, alkylene-O-alkylene-cycloalkyl, alkylene-O-cycloalkyl, alkylene-Hydroaryl, or alkylene-Hydroaryl groups may be further substituted by one or more substituents selected from deuterium, =O, halogen, hydroxyl, cyano, amino, aminoalkyl, acetyl, alkyl, alkenyl, alkynyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0087] Alternatively, R7, R8, and the atoms connected to them can be linked by single bonds, double bonds, cycloalkyl groups, or heterocycloalkyl groups to form a macrocycle, which can be replaced by substituents of halogen, amino, hydroxyl, cyano, amide, alkoxy, mercapto, alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl groups.

[0088] Alternatively, the two R7s together with the atoms they are attached to form a cycloalkyl or heterocycloalkyl group, which may optionally be further substituted by one or more substituents selected from hydroxyl, amino, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, =O.

[0089] R a R b R cEach is independently selected from hydrogen atom, hydroxyl, amino, alkyl, alkoxy, cycloalkyl, heterocyclic, heteroalkenyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, heteroalkenyl, aryl or heteroaryl may optionally be further substituted by one or more substituents selected from alkyl, halogen, nitro, cyano, amino, carboxyl, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, and substituents;

[0090] Or R a R b R c Any two links form a saturated or unsaturated heterocycle, which is further substituted by one or more substituents selected from alkyl, halogen, nitro, cyano, amino, carboxyl, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, etc.

[0091] m and q are 0, 1, 2, 3, 4 or 5;

[0092] r is 0, 1, or 2;

[0093] t1 can be 0, 1, 2, or 3;

[0094] t2 can be 0, 1, 2, or 3;

[0095] t3 can be 0, 1, 2, or 3;

[0096] e can be 0, 1, 2, or 3;

[0097] s is 0 or 1.

[0098] In one specific implementation, R1, R2, R3, R4, and R5 are each independently selected from hydrogen atoms, methyl groups, and trifluoromethyl groups.

[0099] In one specific implementation, R6 is selected from halogens and methoxy groups.

[0100] In one specific implementation, ring A and ring B are selected from 5-6 aryl and 5-6 heteroaryl groups.

[0101] In one specific embodiment, ring A and ring B are selected from 5-6 membered cycloalkyl and 5-6 membered heterocycloalkyl.

[0102] In one specific embodiment, ring A is selected from 5-6 aryl and 5-6 heteroaryl, ring B is selected from 5-6 aryl and 5-6 heteroaryl, ring C is aryl and heteroaryl, and the definitions of the remaining R1, R2, R3, R4, R5, R6, R7, R8, R9, L, X, n, p, and m are as defined above for the general formula (I).

[0103] In one specific embodiment, ring A is selected from 5-6 aryl and 5-6 heteroaryl, ring B is selected from 5-6 aryl and 5-6 heteroaryl, ring C is aryl, and the definitions of the remaining R1, R2, R3, R4, R5, R6, R7, R8, R9, L, X, n, p, and m are as defined above for the general formula (I).

[0104] In one specific implementation, X is selected from -O- and -S-, and L is selected from single bonds and -NR. x -、-CR x R y -、-S-、The definitions of the remaining rings A, B, C, R1, R2, R3, R4, R5, R6, R7, R8, R9, n, p, and m are as described above for the definitions in general formula (I).

[0105] In one specific implementation, X is selected from -O-, and L is selected from single bond, -CR x R y - The definitions of the remaining rings A, B, C, R1, R2, R3, R4, R5, R6, R7, R8, R9, n, p, and m are as described above for the definitions in general formula (I).

[0106] In one specific embodiment, ring C is aryl, R9 is selected from hydrogen atom, halogen, alkyl, cycloalkyl, m is selected from 2, 3, 4, 5, and L is selected from single bond, -NR x -、-CR x R y -、-S-、The definitions of the remaining rings A, ring B, R1, R2, R3, R4, R5, R6, R7, R8, n, p, and X are as described above for the definitions in general formula (I).

[0107] In one specific embodiment, cyclic C is aryl, R9 is selected from hydrogen atom, halogen, alkyl, cycloalkyl, m is selected from 2, 3, 4, and L is selected from single bond, -NR x -、-CR x R y -、-S-、The definitions of the remaining rings A, ring B, R1, R2, R3, R4, R5, R6, R7, R8, n, p, and X are as described above for the definitions in general formula (I).

[0108] In one specific embodiment, cyclic C is aryl, R9 is selected from hydrogen atom, halogen, alkyl, cycloalkyl, m is selected from 2, 3, 4, and L is selected from single bond, -CR x R y - The definitions of the remaining rings A, B, R1, R2, R3, R4, R5, R6, R7, R8, n, p, and X are as described above for the definitions in general formula (I).

[0109] In one specific embodiment, X is selected from -O-, -S-, R1, R2, R3, R4, R5, and R6 are all selected from hydrogen atoms, halogens, hydroxyl groups, alkoxy groups, alkyl groups, trifluoromethyl groups, and amide groups. The definitions of the remaining rings A, B, C, R7, R8, R9, n, p, m, and L are as defined above for the general formula (I).

[0110] In one specific embodiment, X is selected from -O-, -S-, R1, R3, R4, and R5 are all selected from hydrogen atom, halogen, hydroxyl, alkoxy, alkyl, amide group, and trifluoromethyl, R2 and R6 are selected from trifluoromethyl and amide group, and the definitions of the remaining ring A, ring B, ring C, R7, R8, R9, n, p, m, and L are as defined above for the general formula (I).

[0111] In one specific embodiment, X is selected from -O-, -S-, R1, R3, R4, and R5 are all selected from hydrogen atoms, halogens, hydroxyl groups, alkoxy groups, alkyl groups, and amide groups, R2 and R6 are trifluoromethyl groups and amide groups, and L is selected from single bonds and -NR groups. x -、-CR x R y -、-S-、The definitions of the remaining rings A, B, C, R7, R8, R9, n, p, and m are as described above for the definitions in general formula (I).

[0112] In one specific embodiment, X is selected from -O-, R1, R2, R3, R4, R5, and R6 are all selected from hydrogen atoms, halogens, hydroxyl groups, alkoxy groups, alkyl groups, trifluoromethyl groups, and amide groups, and the definitions of the remaining rings A, B, C, R7, R8, R9, n, p, m, and L are as defined above for the general formula (I).

[0113] In one specific embodiment, X is selected from -O-, R1, R3, R4, and R5 are all selected from hydrogen atom, halogen, hydroxyl, alkoxy, alkyl, amide group, and trifluoromethyl, R2 and R6 are selected from trifluoromethyl and amide group, and the definitions of the remaining ring A, ring B, ring C, R7, R8, R9, n, p, m, and L are as defined above for the general formula (I).

[0114] In one specific embodiment, X is selected from -O-, R1, R3, R4, and R5 are all selected from hydrogen atoms, halogens, hydroxyl groups, alkoxy groups, alkyl groups, and amide groups, R2 and R6 are trifluoromethyl groups and amide groups, and L is selected from single bonds and -NR groups. x -、-CR x R y -、-S-、The definitions of the remaining rings A, B, C, R7, R8, R9, n, p, and m are as described above for the definitions in general formula (I).

[0115] In one specific implementation, in general formula (I), R8 is selected from hydroxyl groups.

[0116] In one specific embodiment, in general formula (I), R8 is selected from amide groups.

[0117] In one specific implementation, in general formula (I), R8 is selected from halogens.

[0118] In one specific embodiment, in general formula (I), R8 is selected from alkoxy groups, wherein one or more hydrogen atoms in the alkoxy group are replaced by hydroxyl groups.

[0119] In one specific implementation, in general formula (I), R8 is selected from carboxyl groups.

[0120] In one specific implementation, in general formula (I), R8 is selected from cyano.

[0121] In one specific implementation, in general formula (I), R8 is selected from hydrogen atoms.

[0122] In one specific embodiment, in general formula (I), R8 is selected from heteroalkyl groups.

[0123] In one specific embodiment, in general formula (I), R8 is selected from heteroalkyl groups, wherein one or more hydrogen atoms in the heteroalkyl group are replaced by hydroxyl groups.

[0124] In one specific embodiment, in general formula (I), R8 is selected from heteroalkyl groups, wherein one or more hydrogen atoms in the heteroalkyl group are replaced by amino or hydroxyl groups.

[0125] In one specific embodiment, in general formula (I), R8 is selected from heterocyclic alkyl groups.

[0126] In one specific embodiment, in general formula (I), R8 is selected from four-membered heterocyclic alkyl groups.

[0127] In one specific embodiment, in general formula (I), R8 is selected from a four-membered heterocyclic alkyl group, wherein one hydrogen atom of the four-membered heterocyclic alkyl group is replaced by a hydroxyl group.

[0128] In one specific embodiment, in general formula (I), R8 is selected from alkyl groups, wherein one or more hydrogen atoms in the alkyl group are replaced by halogens.

[0129] In one specific embodiment, in general formula (I), R8 is selected from alkyl groups, wherein one or more hydrogen atoms in the alkyl group are replaced by hydroxyl groups.

[0130] In one specific implementation, in general formula (I), R8 is selected from =0.

[0131] In one specific implementation, in general formula (I), R8 is selected from amino groups.

[0132] In one specific implementation, in general formula (I), R8 is selected from -S(O). r R a r is 1, R a It is an alkyl or amino group.

[0133] In one specific embodiment, in general formula (I), R8 is selected from six-membered heterocyclic alkyl groups.

[0134] In one specific embodiment, in general formula (I), R8 is selected from amino groups, wherein one or more hydrogen atoms in the amino group are substituted with heterocyclic alkyl groups.

[0135] In one specific embodiment, in general formula (I), R8 is selected from amino groups, wherein one or more hydrogen atoms in the amino group are replaced by hydroxyl and amide groups.

[0136] In one specific embodiment, in general formula (I), R8 is selected from alkoxy groups, wherein one or more hydrogen atoms in the alkoxy group are replaced by hydroxyl groups.

[0137] In one specific implementation, in general formula (I), R8 is selected from -C(O)NR a OR b R a For hydrogen atoms, R b It is an alkyl group, and the alkyl group is replaced by two hydroxyl groups.

[0138] In one specific implementation, in general formula (I), R8 is selected from -C(O)NR a R b R a For hydrogen atoms, R b It is a heteroalkenyl group, and the heteroalkenyl group is substituted by one or two amino groups.

[0139] In one specific embodiment, in general formula (I), R7, R8 together with the atoms they are connected to form a heterocyclic alkyl group, wherein one hydrogen atom of the heterocyclic alkyl group is replaced by a hydroxyalkyl group.

[0140] In one specific implementation, in general formula (I), R8 is selected from -S(O). r NR a R b R a For amino group, R b The hydrogen atom is replaced by the =O atom.

[0141] In one specific implementation, in general formula (I), R8 is selected from -NR a R b R a For hydroxyl group, R bIt is an alkyl group, in which hydrogen atoms are replaced by carboxyl groups and multiple hydroxyl groups.

[0142] In one specific implementation, in general formula (I), R8 is selected from -NR a R b R a For hydroxyl group, R b It is an alkyl group, in which hydrogen atoms are replaced by multiple hydroxyl groups.

[0143] In one specific embodiment, in general formula (I), R8 is selected from alkyl groups, wherein one or more hydrogen atoms in the alkyl group are replaced by amide groups.

[0144] In one specific implementation, in general formula (I), R7 is selected from hydrogen atoms.

[0145] In one specific implementation, in general formula (I), R7 is selected from hydroxyl groups.

[0146] In one specific embodiment, in general formula (I), R7 is selected from alkyl groups.

[0147] In one specific implementation, in general formula (I), R7 is selected from =0.

[0148] In one specific embodiment, in general formula (I), R7 is selected from heteroalkyl groups.

[0149] In one specific implementation, in general formula (I), X is selected from -O-.

[0150] In one specific implementation, in general formula (I), X is selected from -S-.

[0151] In one specific implementation, in general formula (I), X is selected from -S(O)2-.

[0152] In one specific implementation, in general formula (I), X is selected from -S(O)-.

[0153] In one specific implementation, in general formula (I), R1, R2, R3, R4, R5, R6, R7, R8, R9, L, X, n, p, and m are defined as described above for general formula (I).

[0154] In one specific embodiment, in general formula (I), R9 is selected from hydrogen, deuterium, tritium, halogen, carboxyl, amino, hydroxyl, cyano, amide, alkoxy, alkylamino, mercapto, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -S(O). r R a -O-(CH2) t1 -[O-(CH2) t2 ]e -O-(CH2) t3 R a The -O-(CH2) t1 -[O-(CH2) t2 ] e -O-(CH2) t3 R a The O in the group may optionally be substituted with one or more S groups, wherein the amino, hydroxy, amide, alkoxy, alkylamino, mercapto, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -S(O) group is a radical group. r R a -O-(CH2) t1 -[O-(CH2) t2 ] e -O-(CH2) t3 R a Optionally composed of one or more radicals selected from deuterium, tritium, alkyl, haloalkyl, halogen, amino, hydroxyl, cyano, formyl, acetyl, deuterated alkyl, tritated alkyl, -S(O). r R a -C(O)NR a R b It is substituted by substituents of cycloalkyl, heterocycloalkyl, aryl, heteroaryl or alkoxy.

[0155] In one specific embodiment, in general formula (I), R9 is selected from one or more halogens, alkoxy groups, and -S(O) groups. r R a -O-(CH2) t1 -[O-(CH2) t2 ] e -O-(CH2) t3 R a The -O-(CH2) t1 -[O-(CH2) t2 ] e -O-(CH2) t3 R a The O in the equation can be arbitrarily replaced by one or more S or N.

[0156] In one specific embodiment, in general formula (I), R9 is selected from an alkyl group and a methoxy group.

[0157] In one specific implementation, in general formula (I), R9 is selected from two halogens and one methoxy group.

[0158] In one specific implementation, in general formula (I), R9 is selected from three halogens.

[0159] In one specific embodiment, in general formula (I), R9 is selected from two halogens and one methoxy group, wherein the three hydrogen atoms in the methoxy group are replaced by deuterium.

[0160] In one specific embodiment, in general formula (I), R9 is selected from two halogens and one alkoxy group, wherein one or both hydrogen atoms of the alkoxy group are substituted with hydroxyl groups.

[0161] In one specific embodiment, in general formula (I), R9 is selected from two halogens and one alkoxy group, wherein one or both hydrogen atoms of the alkoxy group are substituted with an amide group.

[0162] In one specific embodiment, in general formula (I), R9 is selected from two halogens and one alkoxy group, wherein one hydrogen atom of the alkoxy group is substituted with a heteroalkyl group.

[0163] In one specific embodiment, in general formula (I), R9 is selected from two halogens and an alkoxy group, wherein one hydrogen atom of the alkoxy group is substituted by a heteroalkyl group containing an oxygen atom.

[0164] In one specific embodiment, in general formula (I), R9 is selected from two halogens and an alkoxy group, wherein one hydrogen atom of the alkoxy group is substituted by a tetra-heteroalkyl group containing an oxygen atom.

[0165] In one specific embodiment, in general formula (I), R9 is selected from two halogens and an alkoxy group, wherein one hydrogen atom of the alkoxy group is substituted by a five-membered heteroalkyl group containing an oxygen atom.

[0166] In one specific implementation, in general formula (I), R9 is selected from two halogens and one alkenyl group.

[0167] In one specific implementation, in general formula (I), R9 is selected from two halogens and one vinyl group.

[0168] In one specific implementation, in general formula (I), R9 is selected from two halogens and one alkyl group.

[0169] In one specific implementation, in general formula (I), R9 is selected from two halogens and one methyl group.

[0170] In one specific embodiment, in general formula (I), m is 3, R9 is selected from a halogen, and two R9 atoms together with the atoms attached to them form a cycloalkyl group.

[0171] In one specific embodiment, in general formula (I), m is 3, and R9 is selected from a halogen and two R9 atoms connected to them together to form a 5-membered cycloalkyl group.

[0172] In one specific implementation, in general formula (I), R9 is selected from two halogens and one alkoxy group, wherein the two hydrogen atoms in the alkoxy group are replaced by hydroxyl groups.

[0173] In one specific embodiment, in general formula (I), R9 is selected from an alkoxy group and an alkyl group, wherein the three hydrogen atoms in the alkyl group are replaced by halogens.

[0174] In one specific implementation, in general formula (I), R9 is selected from an alkoxy group and a methyl group, wherein the three hydrogen atoms in the methyl group are replaced by halogens.

[0175] In one specific implementation, in general formula (I), R9 is selected from two halogens and -O-(CH2). t1 -[O-(CH2) t2 ] e -O-(CH2) t3 R a Where t1 is 2, t2 is 2, e is 1, t3 is 0, and R a Selected from alkyl groups.

[0176] In one specific implementation, in general formula (I), R9 is selected from two halogens and -O-(CH2). t1 -[O-(CH2) t2 ] e -O-(CH2) t3 R a Where t1 is 2, e is 0, t3 is 0, and R a Selected from alkyl groups.

[0177] In one specific implementation, in general formula (I), R9 is selected from two halogens and -S(O). r R a r is 0, R a Selected from alkyl groups.

[0178] In one specific implementation, in general formula (I), R9 is selected from two halogens and -S(O). r R a r is 2, R a Selected from alkyl groups.

[0179] In one specific implementation, in general formula (I), R9 is selected from two halogens and -S(O). r R a r is 1, R a Selected from alkyl groups.

[0180] In one specific implementation, in general formula (I), R9 is selected from two halogens and -S-(CH2). t1 -[S-(CH2)t2 ] e -S-(CH2) t3 R a Where t1 is 2, t2 is 2, e is 1, t3 is 0, and R a Selected from alkyl groups.

[0181] In one specific implementation, in general formula (I), R9 is selected from two halogens and -S-(CH2). t1 -[S-(CH2) t2 ] e -S-(CH2) t3 R a Where t1 is 2, e is 0, t3 is 0, and R a Selected from alkyl groups.

[0182] In one specific implementation, m is 3 in general formula (I).

[0183] In one specific embodiment, in general formula (I), X is selected from -S-, and R9 is selected from one or more halogens, alkoxy groups, or -S(O). r R a -O-(CH2) t1 -[O-(CH2) t2 ] e -O-(CH2) t3 R a The -O-(CH2) t1 -[O-(CH2) t2 ] e -O-(CH2) t3 R a The O in the equation can be arbitrarily replaced by one or more S.

[0184] In one specific embodiment, in general formula (I), X is selected from -S-, and R9 is selected from an alkyl group and a methoxy group.

[0185] In one specific implementation, in general formula (I), X is selected from -S-, and R9 is selected from two halogens and one methoxy group.

[0186] In one specific implementation, in general formula (I), X is selected from -S- and R9 is selected from three halogens.

[0187] In one specific embodiment, in general formula (I), X is selected from -S-, and R9 is selected from two halogens and one methoxy group, wherein the three hydrogen atoms in the methoxy group are replaced by deuterium.

[0188] In one specific embodiment, in general formula (I), X is selected from -S-, R9 is selected from two halogens and one alkoxy group, wherein one or both hydrogen atoms of the alkoxy group are substituted with hydroxyl groups.

[0189] In one specific embodiment, in general formula (I), X is selected from -S-, R9 is selected from two halogens and one alkoxy group, wherein one or both hydrogen atoms of the alkoxy group are substituted with an amide group.

[0190] In one specific embodiment, in general formula (I), X is selected from -S-, R9 is selected from two halogens and one alkoxy group, wherein one hydrogen atom of the alkoxy group is substituted with a heteroalkyl group.

[0191] In one specific embodiment, in general formula (I), X is selected from -S-, R9 is selected from two halogens and an alkoxy group, wherein one hydrogen atom of the alkoxy group is substituted by a heteroalkyl group containing an oxygen atom.

[0192] In one specific embodiment, in general formula (I), X is selected from -S-, R9 is selected from two halogens and an alkoxy group, wherein one hydrogen atom of the alkoxy group is substituted by a tetra-heteroalkyl group containing an oxygen atom.

[0193] In one specific embodiment, in general formula (I), X is selected from -S-, R9 is selected from two halogens and an alkoxy group, wherein one hydrogen atom of the alkoxy group is substituted by a five-membered heteroalkyl group containing an oxygen atom.

[0194] In one specific implementation, in general formula (I), X is selected from -S-, and R9 is selected from two halogens and -O-(CH2). t1 -[O-(CH2) t2 ] e -O-(CH2) t3 R a Where t1 is 2, t2 is 2, e is 1, t3 is 0, and R a Selected from alkyl groups.

[0195] In one specific implementation, in general formula (I), X is selected from -S-, and R9 is selected from two halogens and -O-(CH2). t1 -[O-(CH2) t2 ] e -O-(CH2) t3 R a Where t1 is 2, e is 0, t3 is 0, and R a Selected from alkyl groups.

[0196] In one specific implementation, in general formula (I), X is selected from -S-, and R9 is selected from two halogens and one alkenyl group.

[0197] In one specific implementation, in general formula (I), X is selected from -S-, and R9 is selected from two halogens and one vinyl group.

[0198] In one specific embodiment, in general formula (I), X is selected from -S-, and R9 is selected from two halogens and one alkyl group.

[0199] In one specific implementation, in general formula (I), X is selected from -S-, and R9 is selected from two halogens and one methyl group.

[0200] In one specific embodiment, in general formula (I), m is 3, X is selected from -S-, R9 is selected from a halogen, and two R9 atoms together with them form a cycloalkyl group.

[0201] In one specific embodiment, in general formula (I), m is 3, X is selected from -S-, R9 is selected from a halogen, and two R9 atoms together with them form a 5-membered cycloalkyl group.

[0202] In one specific embodiment, in general formula (I), X is selected from -S-, and R9 is selected from two halogens and one alkoxy group, wherein the two hydrogen atoms in the alkoxy group are replaced by hydroxyl groups.

[0203] In one specific embodiment, in general formula (I), X is selected from -S-, R9 is selected from an alkoxy group and an alkyl group, and the three hydrogen atoms in the alkyl group are replaced by halogens.

[0204] In one specific embodiment, in general formula (I), X is selected from -S-, R9 is selected from an alkoxy group and a methyl group, and the three hydrogen atoms in the methyl group are replaced by halogens.

[0205] In one specific implementation, in general formula (I), X is selected from -S-, and R9 is selected from two halogens and -S(O). r R a r is 0, R a Selected from alkyl groups.

[0206] In one specific implementation, in general formula (I), X is selected from -S-, and R9 is selected from two halogens and -S(O). r R a r is 2, R a Selected from alkyl groups.

[0207] In one specific implementation, in general formula (I), X is selected from -S-, and R9 is selected from two halogens and -S(O). r R a r is 1, R a Selected from alkyl groups.

[0208] In one specific implementation, in general formula (I), X is selected from -S-, and R9 is selected from two halogens and -S(O). r R a r is 0, R a Selected from alkyl groups.

[0209] In one specific embodiment, ring F is selected from aryl, heteroaryl, and fused ring, ring G is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and the definitions of the remaining R1, R2, R3, R4, R5, R6, R7, R8, m, q, X, and L are as defined above for the general formula (IB).

[0210] In one specific embodiment, ring F is selected from heteroaryl and fused ring, ring G is selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and the definitions of the remaining R1, R2, R3, R4, R5, R6, R7, R8, m, q, X and L are as defined above for the general formula (IB).

[0211] In one specific embodiment, ring F is selected from aryl, heteroaryl, and fused ring, ring G is selected from aryl, and the definitions of the remaining R1, R2, R3, R4, R5, R6, R7, R8, m, q, X, and L are as defined above for the general formula (IB).

[0212] In one specific embodiment, ring F is selected from heteroaryl and fused ring, ring G is selected from aryl, and the definitions of the remaining R1, R2, R3, R4, R5, R6, R7, R8, m, q, X, and L are as defined above for the general formula (IB).

[0213] In one specific implementation, L is selected from single bond, -CR x R y - The definitions of the remaining rings F, G, R1, R2, R3, R4, R5, R6, R7, R8, m, q, and X are as described above for the general formula (IB).

[0214] In one specific implementation, L is selected from single bonds, and the definitions of the remaining rings F, G, R1, R2, R3, R4, R5, R6, R7, R8, m, q, and X are as defined above for the general formula (IB).

[0215] In one specific implementation, L is selected from -CR x R y - The definitions of the remaining rings F, G, R1, R2, R3, R4, R5, R6, R7, R8, m, q, and X are as described above for the general formula (IB).

[0216] In one specific embodiment, ring F is selected from aryl, heteroaryl, and fused ring; ring G is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and L is selected from single bond and -CR. x R y - The definitions of the remaining R1, R2, R3, R4, R5, R6, R7, R8, m, q, and X are as described above for the general formula (IB).

[0217] In one specific embodiment, ring F is selected from heteroaryl and fused ring, ring G is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and L is selected from single bond and -CR. x R y - The definitions of the remaining R1, R2, R3, R4, R5, R6, R7, R8, m, q, and X are as described above for the general formula (IB).

[0218] In one specific embodiment, ring F is selected from aryl, heteroaryl, or fused ring, ring G is selected from aryl, and L is selected from single bond or -CR. x R y - The definitions of the remaining R1, R2, R3, R4, R5, R6, R7, R8, m, q, and X are as described above for the general formula (IB).

[0219] In one specific embodiment, ring F is selected from heteroaryl and fused ring, ring G is selected from aryl, and L is selected from single bond and -CR. x R y - The definitions of the remaining R1, R2, R3, R4, R5, R6, R7, R8, m, q, and X are as described above for the general formula (IB).

[0220] In one specific embodiment, X is selected from -O-, -S-, R1, R2, R3, R4, R5, and R6 are all selected from hydrogen atoms, halogens, hydroxyl groups, alkoxy groups, alkyl groups, and trifluoromethyl groups, and the definitions of the remaining rings F, G, R7, R8, m, q, and L are as defined above for the general formula (IB).

[0221] In one specific embodiment, X is selected from -O-, -S-, R1, R3, R4, R5, and R6 are all selected from hydrogen atoms, halogens, hydroxyl groups, alkoxy groups, alkyl groups, and trifluoromethyl groups, R2 is trifluoromethyl, and the definitions of the remaining rings F, G, R7, R8, m, q, and L are as defined above for the general formula (IB).

[0222] In one specific embodiment, ring F is selected from heteroaryl and fused ring, ring G is selected from aryl, R7 and R8 are connected to the atoms thereto to form a macrocycle, and the definitions of the remaining R1, R2, R3, R4, R5, R6, R7, R8, m, q, X, and L are as defined above for the general formula (IB).

[0223] In one specific implementation, in the general formula (IB), X is selected from -O-.

[0224] In one specific implementation, in the general formula (IB), X is selected from -S-.

[0225] In this application, (R8) in formula (IB) m Equivalent to (R9) in equation (I) m In equation (IB), (R8) m The definition references (I) (R9) m The definition in [the document] is sufficient.

[0226] In this application, (R7) in formula (IB) q Equivalent to (R8) in equation (I) p In equation (IB), (R7) q The definition references (I) (R8) p The definition in [the document] is sufficient.

[0227] In one specific embodiment, ring D is selected from aryl, heteroaryl, and fused ring; ring E is selected from aryl; and the definitions of the remaining R1, R2, R3, R4, R5, R6, R7, R8, m, q, X, L, and T are as defined above for the general formula (IA).

[0228] In one specific implementation, L is selected from single bond, -NR x -、-CR x R y -, -O-, -S-, T is selected from single bond, amide group, alkoxy group, and the definitions of the remaining R1, R2, R3, R4, R5, R6, R7, R8, m, q, ring E, ring D, and X are as defined above for the general formula (IA).

[0229] In one specific implementation, X is selected from -O- and -S-, and the definitions of the remaining rings E, D, R1, R2, R3, R4, R5, R6, R7, R8, m, q, L, and T are as defined above for the general formula (IA).

[0230] In one specific implementation, L is selected from single bond, -NR x -、-CR x R y -, -O-, -S-, T is selected from single bond, amide group, alkoxy group, X is selected from -O-, -S-, and the remaining R1, R2, R3, R4, R5, R6, R7, R8, m, q, ring E, and ring D are defined as described above for the general formula (IA).

[0231] In one specific embodiment, X is selected from -O-, -S-, R1, R2, R3, R4, R5, and R6 are all selected from hydrogen atoms, halogens, hydroxyl groups, alkoxy groups, alkyl groups, and trifluoromethyl groups, and the remaining R7, R8, m, q, ring E, ring D, L, and T are defined as described above for the general formula (IA).

[0232] In one specific embodiment, X is selected from -O-, -S-, R1, R3, R4, R5, and R6 are all selected from hydrogen atoms, halogens, hydroxyl groups, alkoxy groups, alkyl groups, and trifluoromethyl groups, R2 is trifluoromethyl, and the remaining R7, R8, m, q, ring E, ring D, L, and T are defined as defined above for general formula (IA).

[0233] In one specific implementation, in the general formula (IA), X is selected from -O-.

[0234] In one specific implementation, in general formula (IA), R7 is selected from -S(O). r NR a R b R a For amino group, R b The hydrogen atom is replaced by the =O atom.

[0235] In one specific implementation, in general formula (IA), R7 is selected from -NR. a R b R a For hydroxyl group, R b It is an alkyl group, in which hydrogen atoms are replaced by carboxyl groups and multiple hydroxyl groups.

[0236] In one specific implementation, in general formula (IA), R7 is selected from -NR. a R b R a For hydroxyl group, R b It is an alkyl group, in which hydrogen atoms are replaced by multiple hydroxyl groups.

[0237] In one specific implementation, in the general formula (IA), X is selected from -S-.

[0238] In this application, (R) in formula (IA) 8)m Equivalent to (R) in equation (I) 9)m In formula (IA), (R) 8)m In the definition reference formula (I) (R) 9)m The definition in [the document] is sufficient.

[0239] In this application, (R7) in formula (IA) q Equivalent to (R8) in equation (I) p In equation (IA), (R7)q The definition references (I) (R8) p The definition in [the document] is sufficient.

[0240] In the preferred embodiment of this application, the compounds of general formulas (I), (IA), and (IB) are selected from:

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281] Or its stereoisomers, tautomers, deuterated derivatives, or medicinal salts thereof.

[0282] Note: If there is a difference between the drawn structure and the given name of the structure, the drawn structure will be given greater weight.

[0283] Furthermore, this application provides a pharmaceutical composition comprising an effective dose of a compound of general formula (I), (II), (III), (IV), (V), (VI), (VII), (IA), (II-A) or (IB) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or combination thereof.

[0284] This application provides the use of a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (IA), (II-A) or (IB) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a voltage-gated channel Nav 1.8 antagonist.

[0285] This application also provides the use of compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (IA), (II-A) or (IB) or their stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention and / or treatment of diseases mediated by voltage-gated channel Nav 1.8, wherein the Nav 1.8-mediated diseases are pain or pain-related diseases, multiple sclerosis, incontinence, pathological cough, peroneal muscular dystrophy or arrhythmia; wherein the Nav 1.8-mediated pain or pain-related diseases are selected from acute pain, chronic pain, inflammatory pain, postoperative pain, neuropathic pain, cancer pain, musculoskeletal pain, visceral pain, primary pain, and the postoperative pain is preferably selected from abdominoplasty pain and bunion removal pain.

[0286] This application further provides the use of compounds of general formula (I), (II), (III), (IV), (V), (VI), (VII), (IA), (II-A) or (IB) or their stereoisomers, tautomers, deuterated derivatives or their pharmaceutically usable salts, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention and / or treatment of pain or pain-related diseases, multiple sclerosis, incontinence, pathological cough, peroneal muscular dystrophy or arrhythmias.

[0287] This application provides the use of a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (IA), (II-A) or (IB) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for the prevention and / or treatment of acute pain, chronic pain, inflammatory pain, postoperative pain, neuropathic pain, cancer pain, musculoskeletal pain, visceral pain, primary pain, wherein the postoperative pain is preferably selected from medicaments for pain from abdominoplasty and pain from bunion removal.

[0288] The compounds of this application may optionally be in the form of a single optical isomer, a single enantiomer or a mixture of racemates, in the form of a tautomer, or in the form of a free base or an acid addition salt formed with a pharmacologically acceptable acid.

[0289] The compounds of this application may exist as tautomers. All tautomer forms of the compounds of this application are contemplated within the scope of this application.

[0290] Detailed description of the invention

[0291] Unless otherwise stated, some terms used in this application in the specification and claims are defined as follows:

[0292] When "alkyl" is used as a group or part of a group, it refers to a group consisting of C1-C2. 20 Straight-chain or branched aliphatic hydrocarbon groups. Preferably C1-C. 10 Alkyl groups, more preferably C1-C6 alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted.

[0293] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced by the same or different heteroatom groups, provided that the connection point with the rest of the molecule is through a carbon atom. In some embodiments, a heteroalkyl group may have 1 to 3 carbon atoms (e.g., C1-C3 heteroalkyl) or 1 to 6 carbon atoms (e.g., C1-C6 heteroalkyl) and one or more (e.g., 1, 2, or 3) heteroatoms or heteroatom groups, wherein the heteroatoms may be O, N, S, etc. "Heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. Heteroalkyl groups may be ethers, thioethers, sulfones, amines, or others. In some embodiments, a heteroalkyl group may have 1 to 20 carbon atoms, 1 to 15 carbon atoms, 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0294] "Alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl. Alkenyl groups can be optionally substituted or unsubstituted.

[0295] "Heteroalkenyl" refers to an alkenyl group in which at least one of its carbon atoms is replaced by a heteroatom such as N, O, or S. Heteroalkenyl can be a carbon radical or a heteroatom radical (i.e., the heteroatom can appear in the middle or at the end of the group) and can optionally be independently substituted by one or more substituents described herein.

[0296] "Alkyne group" refers to an aliphatic hydrocarbon group containing a single carbon-carbon triple bond, which can be straight-chain or branched. C2-C is preferred. 10 The alkynyl group is preferred, more preferably C2-C6 alkynyl, and most preferably C2-C4 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl. The alkynyl group may be substituted or unsubstituted.

[0297] "Cycloalkyl" refers to a saturated or partially saturated monocyclic, fused, bridged, or spirocyclic carbon ring. Preferably, it is C3-C. 12 Cycloalkyl groups, more preferably C3-C8 cycloalkyl groups, and most preferably C3-C6 cycloalkyl groups. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc., with cyclopropyl and cyclohexenyl being preferred. The cycloalkyl group may be optionally substituted or unsubstituted.

[0298] The terms “heterocyclic group,” “heterocyclic alkyl group,” “heterocyclic,” or “heterocyclic” are used interchangeably in this application and all refer to non-aromatic heterocyclic groups that can be saturated or partially saturated cyclic compounds in which one or more cyclic atoms are heteroatoms, such as boron, oxygen, nitrogen, sulfur, etc., including monocyclic, polycyclic, fused-ring, bridged-ring, and spirocyclic. Preferably, it has a 5- to 7-membered monocyclic or a 7- to 10-membered bicyclic or tricyclic ring, which may contain 1, 2, or 3 atoms selected from nitrogen, oxygen, and / or sulfur. Examples of “heterocyclic group” include, but are not limited to, morpholino, oxobutyryl, thiomorpholino, tetrahydrofuran, tetrahydropyran, 1,1-dioxo-thiomorpholino, piperidinyl, 2-oxo-piperidinyl, pyrrolyl, 2-oxo-pyrrolyl, piperazine-2-one, 8-oxa-3-aza-bicyclic [3.2.1]octyl, piperazine, and hexahydropyrimidine. The heterocyclic group can be substituted or unsubstituted.

[0299] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, and tetrahydronaphthyl aromatic groups. Preferably, the aryl group is C6-C. 10 Aryl, more preferably phenyl and naphthyl, most preferably phenyl. The aryl group can be substituted or unsubstituted.

[0300] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen, and / or sulfur. Examples of "heteroaryl" include, but are not limited to, furanyl, pyridinyl, 2-oxo-1,2-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiopheneyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrroleyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo[m]dioxacyclopentenyl, benzo[thiophene], benzimidazolyl, indolyl, isoyindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indolyl, benzisothiazolyl, benzo[oxazolyl], benzisothiazolyl. Heteroaryl groups may be substituted or unsubstituted. "Alkoxy" refers to an (alkyl-O-) group. Wherein, alkyl is defined in the relevant section of this document. C1-C6 alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[0301] A "fused ring" refers to a polycyclic group in which two or more cyclic structures share a pair of atoms. One or more rings may contain one or more double bonds, but at least one ring does not have a fully conjugated π-electron aromatic system. Conversely, at least one ring has a fully conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen, or sulfur heteroatoms, and the remaining ring atoms are carbon. The fused ring preferably comprises a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group with a monocyclic heterocyclic group or a monocyclic cycloalkyl group. It is preferably 7 to 14 quinary elements, more preferably 8 to 10 quinary elements.

[0302] "Hydroxy" refers to the -OH group.

[0303] "Halogens" refers to fluorine, chlorine, bromine, and iodine.

[0304] "Amino" refers to -NH2.

[0305] “Cyano” refers to -CN.

[0306] "Nitro" refers to -NO2.

[0307] "Carboxyl group" refers to -C(O)OH.

[0308] "DMSO" refers to dimethyl sulfoxide.

[0309] “BOC” refers to tert-butoxycarbonyl.

[0310] "TFA" refers to trifluoroacetic acid.

[0311] "THP" refers to tetrahydropyranyl.

[0312] “PMB” refers to p-methoxybenzyl.

[0313] “Bn” refers to benzyl.

[0314] "Hydroxyalkyl" refers to an alkyl group that is substituted with a hydroxyl group.

[0315] "Aminoalkyl" refers to an amino-substituted alkyl group.

[0316] "Halogenated alkyl" refers to alkyl groups that have been substituted with halogens.

[0317] "Alkylamino" refers to an amino group that is substituted with an alkyl group.

[0318] "Alkoxy" refers to an alkyl-substituted hydroxyl group.

[0319] "Amide group" refers to -NH-CO-, -CO-NH-, or -CO-NH2.

[0320] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0321] Unless otherwise specified, the term "substituted" or "substituted" in this specification means that the group can be substituted by one or more substituents selected from the following groups: alkyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, and hydroxyalkyl.

[0322] "Medicinal salts" refer to certain salts of the above-mentioned compounds that retain their original biological activity and are suitable for medicinal use. Medicinal salts of compounds represented by general formula (I) can be metal salts or amine salts formed with suitable acids.

[0323] Those skilled in the art will understand that salts of compounds of general formulas (I), (II), (III), (IV), (IA), (II-A), or (IB), including pharmaceutically acceptable salts, can be prepared. These salts can be prepared in situ during the final separation and purification of the compound, or by independently reacting a purified compound, in its free acid or free base form, with a suitable base or acid. Bases typically used to form pharmaceutically acceptable salts include organic or inorganic bases, and acids used to form pharmaceutically acceptable salts include organic or inorganic acids.

[0324] The pharmaceutically usable salts of this application can be synthesized from basic or acidic fractions using conventional chemical methods. Typically, these salts can be prepared by reacting the free acidic form of these compounds with a suitable stoichiometric amount of a base, or by reacting the free basic form of these compounds with a suitable stoichiometric amount of an acid. These reactions are typically carried out in water, in an organic solvent, or in a mixture of both. Typically, a non-aqueous medium, such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, is required where appropriate. A list of other suitable salts can be found in Remington's Pharmaceutical Sciences, 20th edition, Mack Publishing Company, Easton, Pa., (1985); and Stahl and Wermuth's Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, Weinheim, Germany, 2002).

[0325] "Deuterated derivatives" refer to compounds that contain deuterium bonded to carbon at at least one position, with the amount of carbon-bonded deuterium exceeding its natural content.

[0326] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0327] The pharmaceutical compositions disclosed in this application can be formulated for specific routes of administration, such as oral, parenteral, and rectal administration. Furthermore, the pharmaceutical compositions of this application can be prepared in solid form (non-limitingly including capsules, tablets, pills, granules, powders, or suppositories) or in liquid form (non-limitingly including solutions, suspensions, or emulsions). The pharmaceutical compositions can undergo conventional pharmaceutical processes (e.g., sterilization) and / or can contain conventional inert diluents, lubricants, or buffers, as well as excipients such as preservatives, stabilizers, wetting agents, emulsifiers, and buffers.

[0328] Typically, pharmaceutical compositions are tablets or capsules containing an active ingredient and

[0329] a) Diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, etc.;

[0330] b) Lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol; also included in tablets.

[0331] c) Adhesives, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone; and if necessary.

[0332] d) Disintegrants, such as starch, agar, alginate or its sodium salt, or effervescent mixtures; and / or

[0333] e) Absorbents, colorants, flavorings, and sweeteners.

[0334] According to methods known in the art, tablets can be film-coated or enteric-coated.

[0335] Suitable compositions for oral administration include an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the form of tablets, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions for oral use are prepared according to any method known in the art for preparing pharmaceutical compositions, and in order to provide a refined and palatable formulation, the composition may contain one or more agents selected from sweeteners, flavoring agents, coloring agents, and preservatives. Tablets may contain the active ingredient mixed with a non-toxic, pharmaceutically acceptable excipient suitable for preparing tablets. These excipients are, for example, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate); granulating and disintegrants (e.g., corn starch, or alginate); binders (e.g., starch, gelatin, or gum arabic); and lubricants (e.g., magnesium stearate, stearic acid, or talc). Tablets are either uncoated or coated using known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a prolonged effect over a longer period. For example, delaying materials such as glyceryl monostearate or glyceryl distearate can be used. Oral formulations can be presented in hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or in soft gelatin capsules, wherein the active ingredient is mixed with an aqueous or oily medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0336] Some injectable compositions are isotonic aqueous solutions or suspensions, and suppositories are advantageously prepared from fat emulsions or suspensions. The compositions may be sterilized and / or contain excipients such as preservatives, stabilizers, wetting or emulsifiers, dissolution promoters, salts and / or buffers for adjusting osmotic pressure. Furthermore, they may contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulation, or coating methods and contain approximately 0.1-75% or approximately 1-50% of the active ingredient.

[0337] Since water may promote the degradation of certain compounds, this application also provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of this application as active ingredients.

[0338] The anhydrous pharmaceutical compositions and dosage forms of this application can be prepared using anhydrous or low-water-content ingredients and low-water-content or low-humidity conditions. Anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous properties. Therefore, anhydrous compositions are packaged using materials known to prevent contact with water so that they can be contained in suitable formulation boxes. Examples of suitable packaging, without limitation, include airtight foil, plastics, unit-dose containers (e.g., tubular bottles), blister packs, and strip packs.

[0339] This application further provides pharmaceutical compositions and dosage forms comprising one or more agents that reduce the decomposition rate of the compound of this application as an active ingredient. Such agents (referred herein as "stabilizers") include, but are not limited to, antioxidants (e.g., ascorbic acid), pH buffers, or salt buffers.

[0340] For an individual weighing approximately 50-70 kg, the pharmaceutical composition or combination product of this application can be a unit dose of approximately 1-1000 mg of the active ingredient, or approximately 1-500 mg, or approximately 1-250 mg, or approximately 1-150 mg, or approximately 0.5-100 mg, or approximately 1-50 mg of the active ingredient. The therapeutically effective dose of the compound, pharmaceutical composition, or combination product thereof depends on the individual's species, weight, age, and individual circumstances, the condition or disease being treated, or its severity. A physician, clinician, or veterinarian of general skill can readily determine the effective amount of each active ingredient required for the prevention, treatment, or inhibition of the development of a condition or disease.

[0341] The term "stereoisomer" for a compound having a given stereochemical configuration refers to its opposite enantiomers and any diastereomers including its geometrical isomers (Z / E). For example, if a compound has an S,R,Z stereochemical configuration, its stereoisomers will include its opposite enantiomers having an R,S,Z configuration, and its diastereomers having S,S,Z, R,R,Z, S,R,E, R,S,E, S,S,E, and R,R,E configurations. If the stereochemical configuration of a compound is not specified, then "stereoisomer" refers to any of the possible stereochemical configurations of the compound.

[0342] Compounds of general formulas (I), (II), (III), (IV), or (V), their stereoisomers, or tautomers or complexes of their stereoisomers, may be administered alone or in combination with one or more pharmaceutically active compounds. Generally, one or more of these compounds are administered as a pharmaceutical composition (formulation) in combination with one or more pharmaceutically acceptable excipients. The choice of excipient depends on the specific administration method, the effect of the excipient on solubility and stability, and the nature of the dosage form, etc. Available pharmaceutical compositions and methods of their preparation can be found, for example, in ARGennaro (ed.), Remington: Pharmaceutical Science and Practice (20th edition, 2000).

[0343] The compounds of this application may contain asymmetric or chiral centers, and thus exist in different stereoisomer forms. It is contemplated that all stereoisomer forms of the compounds of this application, including but not limited to diastereomers, enantiomers, atropisomers, and geometric (conformal) isomers and mixtures thereof, such as racemic mixtures, are within the scope of this application.

[0344] Unless otherwise stated, the structure described in this application also includes all isomers of this structure (e.g., diastereomers, enantiomers, and trans-isomers and geometric (conformal) isomers; for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers). Therefore, individual stereoisomers of the compounds of this application, as well as mixtures of enantiomers, mixtures of diastereomers, and mixtures of geometric (conformal) isomers, are all within the scope of this application.

[0345] The term "stereoisomer" refers to isomers formed by different spatial arrangements of atoms in a molecule. Stereoisomers can be classified into two main categories: cis-trans isomers and enantiomers, or further divided into enantiomers and diastereomers. Stereoisomers are a type of isomer. Stereoisomers are isomers formed when atoms or groups of atoms in a molecule are connected in the same order but arranged differently in space.

[0346] The term "substantially enantiomerically pure" refers to an enantiomeric purity greater than 90% at a given stereocenter. Therefore, the term "substantially enantiomerically pure" means greater than 80% ee (enantiomer excess). For compounds existing as stereoisomers, such stereoisomers can be substantially enantiomerically pure at the stereocenter, or preferably can have an enantiomeric purity greater than 97%, or more preferably greater than 99%.

[0347] The method for synthesizing the compounds in this application

[0348] To achieve the objectives of this application, the following technical solution is adopted:

[0349] This application provides a method for preparing a compound of general formula (I) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, the method comprising:

[0350]

[0351] The compound represented by general formula (Ia) reacts with the compound represented by (Ib) in the presence of an acyl chloride to give the compound represented by general formula (Ic). The compound represented by general formula (Ic) then undergoes a cyclization reaction to give the compound represented by general formula (I).

[0352] in:

[0353] W is selected from -NH2, -C(O)-CH3;

[0354] The definitions of R1, R2, R3, R4, R5, R6, R7, R8, R9, X, L, ring A, ring B, ring C, n, m, and q are as described in general formula (I).

[0355] This application provides a method for preparing a compound of general formula (IB) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, the method comprising:

[0356]

[0357] The compound represented by general formula (Ia) reacts with the compound represented by (Ib) in the presence of an acyl chloride to give the compound represented by general formula (IB);

[0358] in:

[0359] The definitions of R1, R2, R3, R4, R5, R6, R7, R8, X, ring F, ring G, m, and q are as described in the general formula (IB). Detailed Implementation

[0360] The following embodiments are used to further describe this application, but these embodiments are not intended to limit the scope of this application.

[0361] Example

[0362] The examples provide preparation and related structural identification data for representative compounds represented by formula (I). It must be noted that the following examples are illustrative of this application and not intended to limit its scope. 1 The 1H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used.1 H NMR representation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If the coupling constant is provided, the unit is Hz.

[0363] Mass spectrometry is performed using an LC / MS instrument, and the ionization method can be ESI or APCI.

[0364] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) are 0.15mm to 0.2mm in diameter, and the silica gel plates used for thin-layer chromatography separation and purification are 0.4mm to 0.5mm in diameter.

[0365] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0366] In the following examples, all temperatures are in Celsius unless otherwise specified. Unless otherwise specified, all starting materials and reagents are commercially available or synthesized according to known methods. Commercially available materials and reagents are used directly without further purification. Unless otherwise specified, they are purchased from manufacturers including but not limited to Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Guangzan Chemical Technology Co., Ltd., and Jingyan Chemical Technology Co., Ltd.

[0367] CD3OD: Deuterated methanol.

[0368] CDCl3: Deuterated chloroform.

[0369] DMSO-d6: Deuterated dimethyl sulfoxide.

[0370] D2O: Heavy water.

[0371] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0372] The compound was purified using a C18 reversed-phase column for preparative or semi-preparative purification, silica gel column chromatography eluent system, and thin-layer chromatography. The eluent system was selected from: A: petroleum ether and tetrahydrofuran system; B: acetonitrile and water system; C: petroleum ether and ethyl acetate system. The volume ratio of the solvent varied depending on the polarity of the compound and could be adjusted by adding a small amount of acidic or basic reagents, such as trifluoroacetic acid, acetic acid, or triethylamine.

[0373] Example 1

[0374] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxoroborane-6-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0375]

[0376] first step

[0377] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxoroborane-6-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0378] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a (10 mg, 28.23 μmol, prepared according to patent WO2022256660) was dissolved in dichloromethane (0.5 mL), and oxalyl chloride (5.37 mg, 42.34 μmol) and N,N-dimethylformamide (103.16 μg, 1.41 μmol) were added. The mixture was stirred at 20°C for 0.5 hours, concentrated under reduced pressure, and the crude product was dissolved in dichloromethane (1 mL). Triethylamine (3.43 mg, 33.87 μmol) and 6-aminobenzo[c][1,2]oxoborane-1(3H)-ol 1b (4.63 mg, 31.05 μmol) were added. The mixture was stirred at 20°C for 1 hour, and the reaction was monitored by LC-MS. After the reaction was completed, the reaction solution was directly purified by preparative separation (eluent: system B) through a C18 reversed-phase column to obtain (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxoborane-6-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 1 (2.59 mg), yield: 18.91%.

[0379] MS m / z(ESI): 486.1 [M+1]

[0380] 1H NMR (500MHz, CD3OD) δ7.70 (s, 1H), 7.59-7.52 (m, 1H), 7.24 (d, J = 8.2Hz, 1H), 7.04 (d, J = 2.3Hz, 1H), 6.88 (d, J = 7.8Hz, 1H), 4. 97-4.92(m,3H),4.21(dd,J=8.2,10.5Hz,1H),3.89(d,J=2.1Hz,3H),2.69(t,J=7.7Hz,1H),1.56(s,3H),0.76-0.67(m,3H).

[0381] Example 2

[0382] 4-((2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxybenzyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridineamide

[0383]

[0384]

[0385] first step

[0386] (3,4-Difluoro-2-methoxyphenyl)methanol

[0387] 2 g (10.63 mmol) of 3,4-difluoro-2-methoxybenzoic acid 2a was dissolved in 20 mL of tetrahydrofuran. A borane-tetrahydrofuran complex (1.83 g, 21.26 mmol) was added at 0 °C, and the mixture was stirred at 25 °C for 16 hours. The reaction was monitored by TLC. After completion, the reaction was quenched with 50 mL of methanol at 0 °C and concentrated under reduced pressure to give 1.7 g (3,4-difluoro-2-methoxyphenyl)methanol 2b) in 87.23% yield. This unpurified product was directly used in the next reaction.

[0388] 1 H NMR (400MHz, CD3OD) δ7.16 (ddd, J=2.3, 6.1, 8.6Hz, 1H), 6.95 (ddd, J=7.4, 8.7, 10.0Hz, 1H), 4.59 (s, 2H), 3.97 (d, J=2.0Hz, 3H).

[0389] Step 2

[0390] 1-(chloromethyl)-3,4-difluoro-2-methoxybenzene

[0391] (3,4-Difluoro-2-methoxyphenyl)methanol 2b (1.7 g, 9.27 mmol) was dissolved in dichloromethane (16 mL), and thionyl chloride (3.31 g, 27.82 mmol) and N,N-dimethylformamide (67.79 mg, 927.39 μmol) were added. The mixture was stirred at 25 °C for 2 hours. The reaction was monitored by TLC. The solution was concentrated under reduced pressure to give 1-(chloromethyl)-3,4-difluoro-2-methoxyphenyl 2c (1.7 g), yield: 95.18%. This solution was used directly in the next step without purification.

[0392] Step 3

[0393] 2-(3,4-Difluoro-2-methoxybenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane

[0394] 1-(chloromethyl)-3,4-difluoro-2-methoxybenzene 2c (1.7 g, 8.83 mmol) was dissolved in dioxane (20 mL), and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane) (6.72 g, 26.48 mmol), tetratetraphenylphosphine palladium (510.01 mg, 441.35 μmol), and potassium carbonate (3.66 g, 26.48 mmol) were added. The mixture was stirred at 80 °C for 16 hours under nitrogen protection. The reaction was monitored by TLC, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give 2-(3,4-difluoro-2-methoxybenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane 2d (2 g), yield: 79.75%.

[0395] 1 H NMR (400MHz, CDCl3) δ6.78-6.72(m,1H),6.71-6.64(m,1H),3.86(d,J=2.0Hz,3H),2.11(s,2H),1.17(s,12H).

[0396] Step 4

[0397] (4S,5R)-3-(3,4-difluoro-2-methoxybenzyl)-4-methoxy-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylic acid ethyl ester

[0398] Ethyl (4R,5R)-3-iodo-4-methoxy-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate 2e (200 mg, 526.18 μmol), 2-(3,4-difluoro-2-methoxybenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane 2d (298.98 mg, 1.05 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium chloride (38.50 mg, 52.62 μmol), cesium fluoride (159.85 mg, 1.05 mmol), and potassium carbonate (218.17 mg, 1.58 mmol) were dissolved in dioxane (5 mL) and stirred at 80 °C for 2 hours under nitrogen protection. The reaction was monitored by TLC, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give 2f (100mg) of ethyl (4S,5R)-3-(3,4-difluoro-2-methoxybenzyl)-4-methoxy-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate, yield: 46.32%.

[0399] MS m / z(ESI): 378.9 [M-32].

[0400] Step 5

[0401] (2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxybenzyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid ethyl ester

[0402] Ethyl (4S,5R)-3-(3,4-difluoro-2-methoxybenzyl)-4-methoxy-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate 2f (70.00 mg, 170.59 μmol) was dissolved in ethanol (3 mL), and wet palladium on carbon (36.31 mg, 170.59 μmol) and palladium hydroxide (23.96 mg, 170.59 μmol) were added. The mixture was stirred at 80 °C for 72 hours under hydrogen (50 psi). The reaction was monitored by LC-MS, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give 2 g (40 mg) of ethyl (2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxybenzyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate, yield: 56.86%.

[0403] MS m / z(ESI): 413.0 [M+1].

[0404] Step 6

[0405] (2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxybenzyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid

[0406] 2 g (35 mg, 84.88 μmol) of ethyl (2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxybenzyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate was dissolved in 1 mL of tetrahydrofuran. Potassium tert-butoxide (14.29 mg, 127.32 μmol) was added at 0 °C, and the mixture was stirred at 0 °C for 30 minutes. The reaction was monitored by LC-MS. The pH of the solution was adjusted to 5-6 with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxybenzyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 2h (30 mg), yield 91.97%. This product was used directly for the next reaction without purification.

[0407] MS m / z(ESI): 385.1 [M+1].

[0408] Step 7

[0409] 4-((2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxybenzyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamate)methyl pyridinecarboxylate

[0410] (2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxybenzyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 2h (27.00 mg, 70.26 μmol) was dissolved in dichloromethane (1 mL). N,N-dimethylformamide (1 drop) and oxaloyl chloride (13.38 mg, 105.39 μmol) were added at 0 °C, and the mixture was stirred at 25 °C for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (1 mL). Triethylamine (14.22 mg, 140.52 μmol) and methyl 4-aminopyridine-2-carboxylate 2i (12.83 mg, 84.31 μmol) were added at 0 °C, and the mixture was stirred at 25 °C for 1 hour. The reaction was monitored by LCMS. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 4-((2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxybenzyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamate)pyridinecarboxylate 2j (30 mg), yield: 82.36%. It was used directly in the next step of the reaction without purification.

[0411] MS m / z(ESI): 519.0 [M+1].

[0412] Step 8

[0413] 4-((2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxybenzyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridineamide

[0414] 4-((2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxybenzyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxylate 2j (30.00 mg, 57.87 μmol) was dissolved in ammonia solution (119.21 mg, 7.00 mmol) and stirred at 25 °C for 16 hours. The reaction was monitored by LC-MS, concentrated under reduced pressure, and the residue was preparatively separated by C18 reversed-phase column chromatography (eluent: system B) to give 4-((2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxybenzyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridineamide 2 (17.1 mg), yield: 70%.

[0415] MS m / z(ESI): 504.1 [M+1].

[0416] 1H NMR (400MHz, CD3OD) δ8.52(d,J=5.7Hz,1H),8.25(d,J=1.8Hz,1H),7.87(dd,J=2.0,5.7Hz,1H),7.01-6.95(m,1H),6.79-6.71(m,1H),4.46(d,J =10.3Hz,1H),3.96(d,J=2.1Hz,3H),3.87(d,J=5.1Hz,1H),3.45(s,3H) ,3.16-3.07(m,1H),3.07-3.00(m,1H),2.95-2.89(m,1H),1.48(s,3H).

[0417] Example 3

[0418] 4-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazol-5-yl)pyridineamide

[0419]

[0420] first step

[0421] Methyl 4-(2-bromoacetyl)pyridinecarboxylate

[0422] Methyl 4-acetylpyridinecarboxylate 3a (0.5 g, 2.79 mmol) was dissolved in hydrobromic acid (5 mL), and liquid bromine (491 mg, 3.07 mmol) was added at 0 °C. The mixture was stirred at 20 °C for 2 hours, and the reaction was monitored by LC-MS. After the reaction was completed, the mixture was quenched with water (15 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give methyl 4-(2-bromoacetyl)pyridinecarboxylate 3b (320 mg), yield: 44.43%.

[0423] MS m / z(ESI): 257.8 [M+1]

[0424] Step 2

[0425] 4-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazol-5-yl)methyl pyridinecarboxylate

[0426] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a (124 mg, 0.35 mmol) was dissolved in toluene (3 mL), ammonium carbonate (33.5 mg, 0.35 mmol) was added, and the mixture was stirred at 100 °C for 0.5 h. Then, methyl 4-(2-bromoacetyl)pyridinecarboxylate 3b (30 mg, 0.12 mmol) was added, and the mixture was stirred at 100 °C for 12 h. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system C) to give methyl 4-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazol-5-yl)pyridinecarboxylate 3c (30 mg), yield: 50.46%.

[0427] MS m / z(ESI): 512.1 [M+1]

[0428] Step 3

[0429] 4-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazol-5-yl)pyridineamide

[0430] 30 mg (0.06 mmol) of methyl 4-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazol-5-yl)pyridinecarboxylate 3c was dissolved in ammonia water (2 mL), and the mixture was stirred at 20 °C for 13 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was filtered, concentrated under reduced pressure, and preparatively separated by C18 reversed-phase column chromatography (eluent: system B) to give 14.5 mg (14.5 mg) of 4-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazol-5-yl)pyridineamide 3, yield: 49.68%.

[0431] MS m / z(ESI): 497.0 [M+1]

[0432] 1H NMR (400MHz, DMSO-d6) δ8.57(d,J=5.2Hz,1H),8.40(d,J=0.8Hz,1H),8.18(s,1H),8.10(s,1H),7.89(dd,J=5.2,1.4Hz,1H),7.73(s,1H),6.99-7. 16(m,2H),5.59(d,J=11.6Hz,1H),4.50(dd,J=11.2,7.6Hz,1H),3.98(d, J=1.6Hz,3H),2.85(q,J=7.6Hz,1H),1.63(s,3H),0.77(d,J=6.4Hz,3H).

[0433] Example 4

[0434] (14bS,15S,16R,17aR,Z)-11,12-difluoro-15,16-dimethyl-18-oxo-16-(trifluoromethyl)-8,9,14b,15,16,17a,18,19-octahydro-7H-benzo[b]furan[3,2-d]pyrido[4,3-h][1]oxa[7]azacyclotetradecane-2-carboxamide

[0435]

[0436] first step

[0437] (14bS,15S,16R,17aR,Z)-11,12-difluoro-15,16-dimethyl-18-oxo-16-(trifluoromethyl)-8,9,14b,15,16,17a,18,19-octahydro-7H-benzo[b]furan[3,2-d]pyrido[4,3-h][1]oxa[7]azacyclotetradecane-2-carboxamide

[0438] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(pent-4-en-1-oxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-5-vinylpyridineamide 3 (25 mg, 45.17 μmol) was dissolved in dichloromethane (2 mL), and [1,3-bis(2,4,6-trimethylphenyl)imidazoline-2-ylidene]-dichloro-[(2-isopropoxyphenyl)methylene]ruthenium (5.66 mg, 9.03 μmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was concentrated under reduced pressure and separated by C18 reversed-phase column (eluent: system B) to obtain (14bS,15S,16R,17aR,Z)-11,12-difluoro-15,16-dimethyl-18-oxo-16-(trifluoromethyl)-8,9,14b,15,16,17a,18,19-octahydro-7H-benzo[b]furan[3,2-d]pyrido[4,3-h][1]oxa[7]azacyclotetradecane-2-carboxamide 4 (10 mg), yield: 42.14%.

[0439] MS m / z(ESI): 526.3 [M+1]

[0440] 1 H NMR(400MHz, CDCl3)δ8.70(s,1H),8.33(s,1H),8.00(s,1H),7.95(s,1H),7.09-7.03(m, 1H),7.00-6.93(m,1H),6.72(s,1H),6.46-6.36(m,2H),4.83(d,J=10.4Hz,1H),4.40(t,J =10.5Hz,1H),4.19(d,J=7.7Hz,1H),3.87(d,J=8.1Hz,1H),2.75(dd,J=7.7,10.3Hz,1H), 2.61-2.54(m,1H),2.47-2.43(m,1H),2.12-1.98(m,2H),1.64(s,3H),0.90-0.85(d,3H).

[0441] Example 5

[0442] (14bS,15S,16R,17aR)-11,12-difluoro-15,16-dimethyl-18-oxo-16-(trifluoromethyl)-6,7,8,9,14b,15,16,17a,18,19-decahydro-5H-benzo[b]furan[3,2-d]pyrido[4,3-h][1]oxa[7]azacyclotetradecane-2-carboxamide

[0443]

[0444] first step

[0445] (14bS,15S,16R,17aR)-11,12-difluoro-15,16-dimethyl-18-oxo-16-(trifluoromethyl)-6,7,8,9,14b,15,16,17a,18,19-decahydro-5H-benzo[b]furan[3,2-d]pyrido[4,3-h][1]oxa[7]azacyclotetradecane-2-carboxamide

[0446] (14bS,15S,16R,17aR,Z)-11,12-difluoro-15,16-dimethyl-18-oxo-16-(trifluoromethyl)-8,9,14b,15,16,17a,18,19-octahydro-7H-benzo[b]furan[3,2-d]pyrido[4,3-h][1]oxa[7]azacyclotetradecane-2-carboxamide 4 (5 mg, 9.52 μmol) was dissolved in 1 mL of dioxane, and platinum dioxide (1.08 mg, 4.76 μmol) was added. The mixture was stirred at room temperature under hydrogen (15 psi) with the solution added. The reaction was stirred for 3 hours and monitored by LCMS. After the reaction was completed, the mixture was concentrated under reduced pressure and separated by C18 reversed-phase column (eluent: system B) to obtain (14bS,15S,16R,17aR)-11,12-difluoro-15,16-dimethyl-18-oxo-16-(trifluoromethyl)-6,7,8,9,14b,15,16,17a,18,19-decahydro-5H-benzo[b]furan[3,2-d]pyrido[4,3-h][1]oxa[7]azacyclotetradecane-2-carboxamide 5 (2.12 mg), yield: 42.24%.

[0447] MS m / z(ESI): 528.3 [M+1]

[0448] 1 H NMR (400MHz, CD3OD) δ8.55 (s, 1H), 8.03 (s, 1H), 7.25 (t, J = 6.3Hz, 1H), 7.07-6.9 5(m,1H),5.10-5.06(m,1H),4.65(d,J=5.2Hz,1H),4.37(dd,J=8.7,10.8Hz,1H), 3.70-3.62(m,1H),2.90-2.66(m,3H),2.20-2.09(m,1H),1.82(s,3H),1.79-1.7 1(m,2H),1.60(dd,J=7.9,14.3Hz,1H),1.51-1.42(m,2H),0.90(d,J=5.7Hz,3H).

[0449] Example 6

[0450] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxoroborane-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0451]

[0452] first step

[0453] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxoroborane-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0454] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a (40 mg, 112.91 μmol) was dissolved in dichloromethane (1 mL), and N,N-dimethylformamide (82.53 μg, 1.13 μmol) and oxalyl chloride (21.50 mg, 169.36 μmol) were added. The mixture was stirred at 25 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (1 mL). Triethylamine (34.28 mg, 338.73 μmol) and 4-aminobenzo[c][1,2]oxoborane-1(3H)-ol 6b (20.18 mg, 135.49 μmol) were added at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction was monitored by LC-MS. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The extract was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative separation using a C18 reversed-phase column (eluent: system B) to give (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxoboron-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 6 (14.21 mg), yield: 25.94%.

[0455] MS m / z(ESI): 485.9 [M+1].

[0456] 1H NMR (500MHz, CDCl3) δ8.18(s,1H),7.85(d,J=7.8Hz,1H),7.57(d,J=7.2Hz,1H),7.38(t,J=7.6Hz,1H),7.11(t,J=6.6Hz,1H),6.94-6.87(m,1H), 5.11-5.07(m,1H),5.07-5.01(m,2H),4.11(dd,J=8.0,10.8Hz,1H),4.01 (d,J=2.7Hz,3H),2.76(t,J=7.6Hz,1H),1.69(s,3H),0.83-0.78(m,3H).

[0457] Example 7

[0458] (2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxoborane-6-yl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0459]

[0460] first step

[0461] (2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxoborane-6-yl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0462] (2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 7a (40 mg, 108.03 μmol, prepared according to patent WO2022256660) and 6-aminobenzo[c][1,2]oxoborane-1(3H)-ol 1b (24.14 mg, 162.0 μmol) were prepared according to patent WO2022256660. 4 μmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (61.61 mg, 162.04 μmol), 1-hydroxy-7-azobenzotriazole (22.06 mg, 162.04 μmol), and N,N-diisopropylethylamine (55.85 mg, 432.12 μmol) were dissolved in N,N-dimethylformamide (2 mL). The mixture was stirred at 20 °C for 12 hours. The reaction was monitored by LCMS. After the reaction was completed, the reaction solution was filtered and washed with N,N-dimethylformamide (2 mL). The solution was concentrated under reduced pressure, and the residue was purified by preparative separation on a C18 reversed-phase column (eluent: system B) to obtain (2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxoborane-6-yl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 1 (10 mg), yield: 18%.

[0463] MS m / z (ESI): 502.2 [M+1]

[0464] 1 H NMR (400MHz, CDCl3) δ8.33(s,1H),7.84(s,1H),7.72(dd,J=8.2,2.0Hz,1H),7.33-7.29(m,2H),6.94-9.92(m,1H),5.08-5.05( m,3H),4.78-4.76(d,J=5.6Hz,1H),3.99(d,J=2.4Hz,3H),3.98-3.93(m,1H),3.85(d,J=4.8Hz,1H),2.99(s,3H),1.64(s,3H).

[0465] Example 8

[0466] (2R,3S,3aS,18aR)-6,7-difluoro-2,3-dimethyl-18-oxo-2-(trifluoromethyl)-2,3,3a,9,10,11,12,17,18,18a-decahydrobenzo[b]furan[3,2-d]pyrido[4,3-h][1]oxa[7]azacyclotridecane-15-carboxamide

[0467]

[0468] first step

[0469] 4-((2R,3S,4S,5R)-3-(2-(but-3-en-1-oxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-5-vinylpyridineamide

[0470] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-5-vinylpyridine amide 3e (30 mg, 61.80 μmol) was dissolved in N,N-dimethylformamide (2 mL), and cesium carbonate (60.41 mg, 185.41 μmol) and 4-bromobut-1-ene 8a (16.69 mg, 123.61 μmol) were added. The mixture was stirred at 20 °C for 16 hours. The reaction was monitored by LCMS. After the reaction was completed, water (30 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (eluent: system A) to give 4-((2R,3S,4S,5R)-3-(2-(but-3-en-1-oxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-5-vinylpyridine amide 8b (20 mg), yield: 59.98%.

[0471] MS m / z (ESI): 540.2 [M+1]

[0472] Step 2

[0473] (2R,3S,3aS,18aR,E)-6,7-difluoro-2,3-dimethyl-18-oxo-2-(trifluoromethyl)-2,3,3a,9,10,17,18,18a-octahydrobenzo[b]furan[3,2-d]pyrido[4,3-h][1]oxa[7]azacyclotridecane-15-carboxamide

[0474] 4-((2R,3S,4S,5R)-3-(2-(but-3-en-1-oxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)-5-vinylpyridine amide 8b (20 mg, 37.07 μmol) was dissolved in dichloromethane (2 mL), and [1,3-bis(2,4,6-trimethylphenyl)imidazolidine-2-ylidene]-dichloro-[(2-isopropoxyphenyl)methylene]ruthenium (4.65 mg, 7.41 μmol) was added. The mixture was stirred at 20 °C for 16 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by C18 reversed-phase column (eluent: system B) to give (2R,3S,3aS,18aR,E)-6,7-difluoro-2,3-dimethyl-18-oxo-2-(trifluoromethyl)-2,3,3a,9,10,17,18,18a-octahydrobenzo[b]furan[3,2-d]pyrido[4,3-h][1]oxa[7]azacyclotridecane-15-carboxamide 8c (10 mg), yield: 52.74%.

[0475] MS m / z(ESI): 512.2 [M+1]

[0476] Step 3

[0477] (2R,3S,3aS,18aR)-6,7-difluoro-2,3-dimethyl-18-oxo-2-(trifluoromethyl)-2,3,3a,9,10,11,12,17,18,18a-decahydrobenzo[b]furan[3,2-d]pyrido[4,3-h][1]oxa[7]azacyclotridecane-15-carboxamide

[0478] Dissolve ((2R,3S,3aS,18aR,E)-6,7-difluoro-2,3-dimethyl-18-oxo-2-(trifluoromethyl)-2,3,3a,9,10,17,18,18a-octahydrobenzo[b]furan[3,2-d]pyrido[4,3-h][1]oxa[7]azacyclotridecane-15-carboxamide 8c (9 mg, 17.60 μmol) in 0.6 mL of dichloromethane, add platinum dioxide (2.00 mg, 8.80 μmol), and stir at room temperature under hydrogen atmosphere (15 psi). Stir for 3 hours. Monitor the reaction with LCMS. After the reaction is complete, concentrate under reduced pressure and purify the residue by passing it through a C18 reversed-phase column (eluent: system B) to obtain (2R,3S,3aS,18aR)-6,7-difluoro-2,3-dimethyl-18-oxo-2-(trifluoromethyl)-2,3,3a,9,10,11,12,17,18,18a-decahydrobenzo[b]furan[3,2-d]pyrido[4,3-h][1]oxa[7]azacyclotridecane-15-carboxamide 8 (3.17 mg), yield: 35.08%.

[0479] MS m / z (ESI): 514.2 [M+1]

[0480] 1 H NMR (400MHz, CD3OD) δ8.51 (s, 1H), 7.99 (s, 1H), 7.21 (t, J = 6.7Hz, 1H), 7.03-6.95 (m, 1H), 4.77-4.66 (m, 2H), 4.59-4.53 (m, 1H), 4. 09(t,J=10.6Hz,1H),2.80-2.66(m,3H),2.07-1.98(m,1H),1.86-1.73(m,5H),1.47(dd,J=3.9,8.9Hz,1H),0.91(d,J=6.0Hz,3H).

[0481] Example 9

[0482] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridine-6-carboxamide

[0483]

[0484] first step

[0485] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazolium[4,5-c]pyridine-6-carboxylic acid methyl ester

[0486] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a (20 mg, 56.45 μmol) was dissolved in dichloromethane (0.5 mL). At 0 °C, N,N-dimethylformamide (1 drop) and oxaloyl chloride (10.75 mg, 84.68 μmol) were added, and the mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (0.5 mL). At 0 °C, triethylamine (11.43 mg, 112.91 μmol) and methyl 4,5-diaminopyridine-2-carboxylate 9a (11.32 mg, 67.75 μmol) were added, and the mixture was stirred at 25 °C for 1 hour. The reaction was monitored by LC-MS. After the reaction was complete, the residue was poured into water (20 mL), extracted with dichloromethane (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was dissolved in acetic acid (0.5 mL). The mixture was stirred at 80 °C for 16 hours. The reaction was monitored by LC-MS. After the reaction was complete, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give methyl 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazolium[4,5-c]pyridine-6-carboxylate 9b (15 mg), yield: 54.68%.

[0487] MS m / z(ESI): 486.0 [M+1].

[0488] Step 2

[0489] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridine-6-carboxylic acid

[0490] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazolium[4,5-c]pyridine-6-carboxylic acid methyl ester 9b (10 mg, 20.60 μmol) was dissolved in 0.5 mL of a mixed solution (methanol:tetrahydrofuran:water = 3:1:1), and lithium hydroxide (4.32 mg, 103.01 μmol) was added. The mixture was stirred at 25 °C for 1 hour. The reaction was monitored by LC-MS. After the reaction was completed, 10 mL of water was added, and the pH of the solution was adjusted to 6 with 1 M hydrochloric acid. The solution was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 9 c (6 mg) of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridine-6-carboxylic acid, with a yield of 61.79%. The solution was used directly for the next reaction without purification.

[0491] MS m / z(ESI): 472.0 [M+1].

[0492] Step 3

[0493] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridine-6-carboxamide

[0494] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridine-6-carboxylic acid 9c (6 mg, 12.73 μmol) was dissolved in dichloromethane (0.5 mL). Oxaloyl chloride (3.23 mg, 25.46 μmol) was added at 0 °C, and the mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (0.5 mL). This residue was then slowly added dropwise to ammonia water (273.00 mg, 1.95 mmol) at 0 °C, and the mixture was stirred at 25 °C for 1 hour. The reaction was monitored by LC-MS. After the reaction was completed, the product was poured into water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was preparatively separated by a C18 reversed-phase column (eluent: system B) to give 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridine-6-carboxamide 9 (2.56 mg), yield: 42.76%.

[0495] MS m / z(ESI): 471.1 [M+1].

[0496] 1 H NMR (400MHz, CD3OD) δ8.94(s,1H),8.40(s,1H),7.17(t,J=6.4Hz,1H),6.96(d,J=7.5Hz,1H),5.83(d,J=11.3Hz,1 H), 4.45 (dd, J = 8.0, 10.7Hz, 1H), 3.98 (d, J = 2.5Hz, 3H), 2.95 (t, J = 7.9Hz, 1H), 1.72 (s, 3H), 0.90 (d, J = 5.6Hz, 3H).

[0497] Example 10

[0498] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxoroborane-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0499]

[0500] first step

[0501] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxoroborane-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0502] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a (40 mg, 112.91 μmol, prepared according to patent WO2022256660) was dissolved in dichloromethane (1 mL), and N,N-dimethylformamide (82.53 μg, 1.13 μmol) and oxalyl chloride (21.50 mg, 169.36 μmol) were added at 0 °C, and the mixture was stirred at 25 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (1 mL). Triethylamine (34.28 mg, 338.73 μmol) and 5-aminobenzo[c][1,2]oxoborane-1(3H)-ol 10a (20.18 mg, 135.49 μmol) were added at 0 °C, and the mixture was stirred at 25 °C for 1 hour. The reaction was monitored by LC-MS. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). The extract was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by passing it through a C18 reversed-phase column (eluent: system B) to give (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxoboron-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 10 (21.97 mg), yield: 40.10%. MS m / z (ESI): 486.0 [M+1].

[0503] 1 H NMR (400MHz, CDCl3) δ8.50(s,1H),7.86(s,1H),7.70(d,J=8.0Hz,1H),7.30(dd,J=1.7,8.0Hz,1H),7.14-7.09(m,1H),6.95-6.87(m ,1H),5.06-5.02(m,3H),4.11(dd,J=8.1,10.8Hz,1H),4.00(d,J=2.7Hz,3H),2.76(q,J=7.7Hz,1H),1.69(s,3H),0.83-0.78(m,3H).

[0504] Example 11

[0505] 5-Chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthidium-4-ol

[0506]

[0507] first step

[0508] (2R,3S,4S,5R)-N-(3-acetyl-2-chloropyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl))tetrahydrofuran-2-carboxamide

[0509] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a (50 mg, 0.14 mmol) and 1-(4-amino-2-chloropyridin-3-yl)acetone 11a (48.15 mg, 0.28 mol) were dissolved in pyridine (1 mL). Phosphorus oxychloride (64.9 mg, 0.42 mmol) was added at 0 °C, and the mixture was stirred at 20 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, water (5 mL) was added to quench the reaction. The pH of the solution was adjusted to 9 with saturated sodium bicarbonate, and the solution was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (2R,3S,4S,5R)-N-(3-acetyl-2-chloropyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl))tetrahydrofuran-2-carboxamide 11b (50 mg), yield: 67.99%.

[0510] MS m / z(ESI): 507.1 [M+1]

[0511] Step 2

[0512] 5-Chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthidium-4-ol

[0513] (2R,3S,4S,5R)-N-(3-acetyl-2-chloropyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl))tetrahydrofuran-2-carboxamide 11b (50 mg, 0.10 mmol) was dissolved in toluene (5 mL), and sodium hydroxide (15.9 mg, 0.39 mmol) was added. The mixture was stirred at 110 °C for 3 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was diluted with water (15 mL), and the pH of the solution was adjusted to 2 with 1 M dilute hydrochloric acid. The solution was extracted with ethyl acetate (20 mL × 2). The pH of the aqueous phase was adjusted to 9 with saturated sodium bicarbonate, and the solution was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro)-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthid-4-ol 11 (34.3 mg), yield: 71.13%.

[0514] MS m / z(ESI): 489.1 [M+1]

[0515] 1 H NMR (400MHz, DMSO-d6) δ11.34-11.83(m,1H),8.31(d,J=6.0Hz,1H),7.59(d,J=5.6Hz,1H),7.04-7.34(m,2H),6.38(s,1H),5.43( d,J=11.2Hz,1H),4.25(dd,J=11.2,8.4Hz,1H),3.91(d,J=2.0Hz,3H),2.85(t,J=7.6Hz,1H),1.69(s,3H),0.77(d,J=6.4Hz,3H).

[0516] Example 12

[0517] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-5-carboxynitrile

[0518]

[0519] first step

[0520] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-5-carboxynitrile

[0521] 5-Chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro)-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthid-4-ol 11 (30 mg, 0.06 mmol), zinc cyanide (14.4 mg, 0.12 mmol), zinc powder (0.80 mg, 0.01 mmol), 1,1-bis(diphenylphosphino)ferrocene (6.80 mg, 0.01 mmol), and tris(dibenzylideneacetone)palladium (5.62 mg, 0.01 mmol) were added to N,N-dimethylacetamide (2 mL), and stirred at 120 °C for 14 hours under nitrogen protection. After the reaction was complete, the mixture was filtered, washed with ethyl acetate (10 mL × 3), diluted with water (20 mL), extracted with ethyl acetate (20 mL × 2), the organic layer of ethyl acetate was discarded, the aqueous phase was extracted with dichloromethane (20 mL × 5), the combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 12 (16 mg) of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-5-carboxynitrile, yield: 54.38%.

[0522] MS m / z(ESI): 480.2 [M+1]

[0523] 1 H NMR (400MHz, DMSO-d6) δ11.85(d,J=4.8Hz,1H),8.71(d,J=6.0Hz,1H),7.90(d,J=5.6Hz,1H),7.22-7.30(m,1H),7.11-7.21(m,1H),6.47( s,1H),5.50(d,J=11.2Hz,1H),4.26(dd,J=11.2,8.4Hz,1H),3.88-3.94(m,3H),2.86(q,J=7.6Hz,1H),1.70(s,3H),0.77(d,J=6.4Hz,3H).

[0524] Example 13

[0525] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl))tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-5-carboxamide

[0526]

[0527] first step

[0528] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-5-carboxamide

[0529] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-5-carboxynitrile 12 (10 mg, 20.86 μmol) was dissolved in toluene (2 mL), and trifluoroacetic acid (796.32 mg, 6.98 mmol) was added. The mixture was stirred at 65 °C for 8 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by preparative separation and purification using a C18 reversed-phase column (eluent: system B) to give 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl))tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-5-carboxamide 13 (3 mg), yield: 28%.

[0530] MS m / z(ESI): 498.2 [M+1]

[0531] 1 H NMR(400MHz, CDCl3)δ8.97(s,1H),8.85-8.82(m,1H),8.74-8.68(m,1H),7.31-7.28(m,1H),7.26-7.11(m,2H),6.92-6.80(m,1H),6.56 -6.49(m,1H),5.82(d,J=10.8Hz,1H),4.29-4.24(m,1H),3.93(d,J=2.8Hz,3H),2.90-2.82(m,1H),1.77(s,3H),0.91(d,J=6.0Hz,3H).

[0532] Example 14

[0533] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthidium-4-ol

[0534]

[0535]

[0536] first step

[0537] (2R,3S,4S,5R)-N-(3-acetylpyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0538] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a (20 mg, 0.06 mmol) and 1-(4-aminopyridin-3-yl)acetone 14a (15.4 mg, 0.11 mol) were dissolved in pyridine (1 mL), and phosphorus oxychloride (26.0 mg, 0.17 mmol) was added at 0 °C. The mixture was stirred at 20 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, water (5 mL) was added to quench the reaction. The pH of the solution was adjusted to 9 with saturated sodium bicarbonate. The solution was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to obtain (2R,3S,4S,5R)-N-(3-acetylpyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 14b (20 mg). This unpurified solution was directly used in the next step of the reaction.

[0539] MS m / z(ESI): 473.1 [M+1]

[0540] Step 2

[0541] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthidium-4-ol

[0542] (2R,3S,4S,5R)-N-(3-acetylpyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 14b (20 mg, 0.04 mmol) and sodium hydroxide (6.77 mg, 0.17 mmol) were dissolved in toluene (5 mL), and the mixture was stirred at 110 °C for 3 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was filtered, concentrated under reduced pressure, and the residue was preparatively separated by C18 reversed-phase column chromatography (eluent: system B) to give 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthidium-4-ol 14 (10.7 mg), yield: 55.62%. MS m / z (ESI): 455.2 [M+1]

[0543] 1 H NMR (400MHz, DMSO-d6) δ11.76-12.33(m,1H),9.24(s,1H),8.66(d,J=6.4Hz,1H),7.87(d,J=6.4Hz,1H),7.23-7.31(m,1H),7.11-7.21(m,1 H),6.51(s,1H),5.52(d,J=11.2Hz,1H),4.29(s,1H),3.91(d,J=2.0Hz,3H),2.88(quin,J=7.6Hz,1H),1.71(s,3H),0.78(d,J=6.4Hz,3H).

[0544] Example 15

[0545] 4-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4H-1,2,4-triazol-3-yl)pyridineamide

[0546]

[0547] first step

[0548] 4-Cyanopyridine-2-carboxamide

[0549] Methyl 4-cyanopyridine-2-carboxylate 15a (30 mg, 185.02 μmol) was dissolved in ammonia (0.5 mL) and stirred at room temperature for 0.5 hours. The reaction was monitored by LCMS. After the reaction was completed, the solution was concentrated under reduced pressure to obtain 4-cyanopyridine-2-carboxamide 15b (25 mg), yield: 91.84%. This amide was used directly for the next reaction without purification.

[0550] MS m / z (ESI): 148.1 [M+1]

[0551] Step 2

[0552] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazide

[0553] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a (20 mg, 56.45 μmol) was dissolved in ethanol (0.5 mL), and hydrazine hydrate (16.62 mg, 282.27 μmol) was added. The mixture was stirred at 85 °C for 16 hours. The reaction was detected by LCMS. After the reaction was completed, 10 mL of water was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonylhydrazine 15c (10 mg), yield: 48.10%. The mixture was not purified and was directly used in the next step of the reaction.

[0554] MS m / z(ESI): 369.1 [M+1]

[0555] Step 3

[0556] 4-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4H-1,2,4-triazol-3-yl)pyridineamide

[0557] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbazide 15c (10 mg, 27.15 μmol) was dissolved in n-butanol (0.5 mL), potassium carbonate (1.88 mg, 13.58 μmol) and 4-cyanopyridine-2-carboxamide 15b (11.98 mg, 81.46 μmol) were added, and the mixture was stirred at 110 °C for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure. The residue was then separated by C18 reversed-phase column chromatography (eluent: system B) to give 15 (2.12 mg) of 4-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4H-1,2,4-triazol-3-yl)pyridineamide, yield: 15.7%.

[0558] MS m / z(ESI): 498.2 [M+1]

[0559] 1H NMR(500MHz,CD3OD)δ8.61(d,J=4.9Hz,1H),8.56(s,1H),7.98(dd,J=1.7,5.0Hz,1H),6.95(t,J=6.5Hz,1H),6.87-6.79(m,1H), 5.59(d,J=11.1Hz,1H),4.48(s,3H),4.41(s,1H),3.92(d,J=2.3Hz,3H),2.82(t,J=7.6Hz,1H),1.58(s,3H),0.80-0.75(m,3H).

[0560] Example 16

[0561] 4-((2'R,4S,4'S,5'R)-7,8-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2'H-spiro[benzodihydropyran-4,3'-furan]-2'-carbamoyl)pyridine amide

[0562]

[0563] first step

[0564] (5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one

[0565] (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one 16a (500 mg, 1.55 mmol) was dissolved in dichloromethane (5 mL), and boron tribromide (777.46 mg, 3.10 mmol) was added dropwise. The mixture was stirred at 0 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, saturated sodium bicarbonate solution (10 mL) was added dropwise to quench the reaction. The mixture was extracted with dichloromethane (10 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one 16b (400 mg), yield: 83.64%. This mixture was used directly in the next reaction without purification.

[0566] MS m / z(ESI): 309.0 [M+1]

[0567] Step 2

[0568] (3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one

[0569] (5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one 16b (400 mg, 1.30 mmol) was dissolved in 18 mL of a mixed solution (methanol:tetrahydrofuran = 5:1), nickel dichloride hexahydrate (616.98 mg, 2.60 mmol) was added, followed by sodium borohydride (1.56 g, 41.14 mmol), and the mixture was stirred at -40 °C for 4 hours. The reaction was monitored by LC-MS. After the reaction was completed, the reaction was quenched by adding water and saturated sodium bicarbonate solution (10 mL) at 0 °C. The mixture was extracted with dichloromethane (30 mL × 3). The organic layer was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was preparatively separated by C18 reversed-phase column chromatography (eluent: system B) to give (3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one 16c (200 mg), yield: 49.68%.

[0570] MS m / z(ESI): 311.0 [M+1]

[0571] Step 3

[0572] (4S,4'S,5'R)-7,8-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)spiro[benzodihydropyran-4,3'-tetrahydrofuran]-2'-one

[0573] (3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one 16c (200 mg, 644.71 μmol) was dissolved in dimethyl sulfoxide (8 mL), and cesium carbonate (840.24 mg, 2.58 mmol) and 1,2-dibromoethane 16d (605.58 mg, 3.22 mmol) were added. The mixture was stirred at 60 °C for 16 hours. The reaction was monitored by LC-MS. After the reaction was completed, the pH of the solution was adjusted to 7 with 1 M hydrochloric acid, filtered, and concentrated under reduced pressure. The residue was preparatively separated by a C18 reversed-phase column (eluent: system B) to give (4S,4'S,5'R)-7,8-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)spiro[benzodihydropyran-4,3'-tetrahydrofuran]-2'-one 16e (100 mg), yield: 46.13%.

[0574] MS m / z(ESI): 337.0 [M+1]

[0575] Step 4

[0576] (4S,4'S,5'R)-7,8-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2'H-spiro[benzodihydropyran-4,3'-furan]-2'-ol

[0577] (4S,4'S,5'R)-7,8-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)spiro[benzodihydropyran-4,3'-tetrahydrofuran]-2'-one 16e (345 mg, 1.03 mmol) was dissolved in toluene (5 mL), and diisobutylaluminum hydride (364.80 mg, 2.57 mmol) was added dropwise. The mixture was stirred at -78 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the reaction was quenched by slowly adding 20 mL of saturated sodium potassium tartrate solution at 0 °C. The mixture was extracted with ethyl acetate (20 mL × 2), the organic layers were combined, washed with 10 mL × 2 of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 16 f (340 mg) of (4S,4'S,5'R)-7,8-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2'H-spiro[benzodihydropyran-4,3'-furan]-2'-ol, yield: 97.96%. MS m / z (ESI): 321.1 [M-17]

[0578] Step 5

[0579] (4S,4'S,5'R)-7,8-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2'H-spiro[benzodihydropyran-4,3'-furan]-2'-ylacetate

[0580] (4S,4'S,5'R)-7,8-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2'H-spiro[benzodihydropyran-4,3'-furan]-2'-ol 16f (340 mg, 1.03 mmol) was dissolved in toluene (5 mL), and acetic anhydride (126.76 mg, 1.24 mmol), triethylamine (115.17 mg, 1.14 mmol), and N,N-dimethylpyridin-4-amine (12.64 mg, 103.47 μmol) were added. The mixture was stirred at 0 °C for 2 hours. The reaction was monitored by TLC. After the reaction was completed, ammonium chloride (10 mL) was added to quench the reaction. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 16 g (350 mg) of (4S,4'S,5'R)-7,8-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2'H-spiro[benzodihydropyran-4,3'-furan]-2'-yl acetate: yield: 88.95%.

[0581] 1 H NMR (400MHz, CD3OD) δ6.96-6.90(m,1H),6.66(dt,J=7.4,9.5Hz,1H),6.30(s,1H),4.43-4.36(m,1H),4.32-4.24( m,1H),2.63(d,J=7.5Hz,1H),2.11-2.07(m,1H),2.02(s,3H),2.00-1.94(m,1H),1.54(s,3H),0.85-0.80(m,3H).

[0582] Step 6

[0583] (2'R,4S,4'S,5'R)-7,8-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2'H-spiro[benzodihydropyran-4,3'-furan]-2'-carboxynitrile

[0584] (2'R,4S,4'S,5'R)-7,8-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2'H-spiro[benzodihydropyran-4,3'-furan]-2'-carboxynitrile

[0585] 16 g (200 mg, 525.89 μmol) of ((4S,4'S,5'R)-7,8-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2'H-spiro[benzodihydropyran-4,3'-furan]-2'-yl acetate) was dissolved in 2 mL of dichloromethane. Trimethylsilaneformonitrile (130.43 mg, 1.31 mmol) and boron trifluoride diethyl ether (243.39 mg, 788.84 μmol) were added sequentially, and the mixture was stirred at 20 °C for 0.5 hours. TLC monitoring was performed. The reaction was controlled, and after completion, water (10 mL) was added, followed by extraction with dichloromethane (10 mL × 3). The organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (2'R,4S,4'S,5'R)-7,8-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2'H-spiro[benzodihydropyran-4,3'-furan]-2'-carboxynitrile 16h (180 mg), yield: 98.56%. This was carried out directly in the next reaction without purification.

[0586] 1 H NMR (400MHz, CD3OD) δ6.97-6.89(m,1H),6.76-6.68(m,1H),5.43-5.37(m,1H),4.55-4.47(m,1H),4.28-4. 18(m,1H),2.60-2.48(m,1H),2.36-2.25(m,1H),2.20-2.13(m,1H),1.62-1.52(m,3H),0.81-0.77(m,3H).

[0587] Step 7

[0588] ((2'R,4S,4'S,5'R)-7,8-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2'H-spiro[benzodihydropyran-4,3'-furan]-2'-formamide

[0589] (2'R,4S,4'S,5'R)-7,8-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2'H-spiro[benzodihydropyran-4,3'-furan]-2'-carboxynitrile (180 mg, 518.31 μmol) was dissolved in dimethyl sulfoxide (1 mL), potassium carbonate (298.47 mg, 2.16 mmol) and hydrogen peroxide (489.73 mg, 4.32 mmol) were added, and the mixture was stirred at 20 °C for 16 hours. The reaction was monitored by TLC. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give ((2'R,4S,4'S,5'R)-7,8-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2'H-spiro[benzodihydropyran-4,3'-furan]-2'-carboxamide 16i (80 mg), yield: 50.70%. It was used directly in the next reaction without purification.

[0590] Step 8

[0591] Methyl 4-((2'R,3'S,4'S,5'R)-7,8-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2'H-spiro[benzodihydropyran-4,3'-furan]-2'-ylcarbamate)pyridinecarboxylic acid

[0592] Dissolve ((2'R,4S,4'S,5'R)-7,8-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2'H-spiro[benzodihydropyran-4,3'-furan]-2'-carboxamide 16i (80 mg, 219.00 μmol) in dioxane (2 mL), add cesium carbonate (214.06 mg, 657.00 μmol), methyl 4-bromopyridine-2-carboxylate 16j (56.77 mg, 262.80 μmol), and the dichloromethyl adduct of [9,9-dimethyl-4,5-bis(diphenylphospho)oxanthracene][2-amino-1,1-diphenyl]palladium(II)methanesulfonate. (20.77 mg, 21.90 μmol), stirred at 100 °C for 16 hours. The reaction was monitored by LCMS. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 16 kJ (80 mg) of methyl 4-((2'R,3'S,4'S,5'R)-7,8-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2'H-spiro[benzodihydropyran-4,3'-furan]-2'-ylcarboxamido)pyridinecarboxylic acid, yield: 73.00%. The unpurified solution was directly used in the next step of the reaction.

[0593] MS m / z(ESI): 501.1 [M+1]

[0594] Step 9

[0595] 4-((2'R,4S,4'S,5'R)-7,8-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2'H-spiro[benzodihydropyran-4,3'-furan]-2'-carbamoyl)pyridine amide

[0596] 16kJ (80mg, 159.87μmol) of methyl 4-((2'R,3'S,4'S,5'R)-7,8-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2'H-spiro[benzodihydropyran-4,3'-furan]-2'-ylcarboxamido)pyridinecarboxylic acid was dissolved in ammonia water (2.40mL), and the mixture was stirred at 20°C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was then subjected to preparative separation using a C18 reversed-phase column (eluent: system B) to yield 4-((2'R,4S,4'S,5'R)-7,8-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2'H-spiro[benzodihydropyran-4,3'-furan]-2'-formamide)pyridineamide 16 (25 mg), yield: 32.22%.

[0597] MS m / z(ESI): 486.1 [M+1]

[0598] 1 H NMR (400MHz, CD3OD) δ8.52-8.47(m,1H),8.33-8.29(m,1H),7.94(dd,J=2.2,5.5Hz,1H),7.18-7.10(m,1H),6.87-6.78(m,1H),5.2 8-5.23(m,1H),4.53-4.46(m,1H),4.25-4.15(m,1H),2.56-2.47(m,1H),2.08-2.01(m,2H),1.76-1.72(m,3H),0.92-0.85(m,3H).

[0599] Example 17

[0600] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridineamide

[0601]

[0602]

[0603] first step

[0604] (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-3,4,5-trimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one

[0605] (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one 17a (300 mg, 925.23 μmol, prepared according to patent WO2022256660) was dissolved in N,N-dimethylformamide (3 mL). Iodomethane (393.98 mg, 2.78 mmol) and sodium tert-butoxide (97.81 mg, 1.02 mmol) were added at 0 °C, and the mixture was stirred at 0 °C for 2 hours. The reaction was monitored by LC-MS. Pour into water (20 mL) and extract with ethyl acetate (20 mL × 3). Dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by column chromatography (eluent: system A) to give (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-3,4,5-trimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one 17b (260 mg), yield: 83.07%.

[0606] MS m / z(ESI): 339.0 [M+1]

[0607] Step 2

[0608] (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-ol

[0609] (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-3,4,5-trimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one 17b (260 mg, 768.62 μmol) was dissolved in toluene (5 mL), and diisobutylaluminum hydride (273.28 mg, 1.92 mmol) was added at -78 °C. The mixture was stirred at 25 °C for 1 hour. The reaction was monitored by TLC. Water (20 mL) was added at 0 °C, and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-ol 17c (250 mg), yield: 95.58%. The product was used directly for the next reaction without purification.

[0610] 1 H NMR(400MHz,CD3OD)δ7.00-6.95(m,1H),6.88(dt,J=7.6,9.4Hz,1H),5.69(s,1H),4.06(d, J=3.5Hz,3H),2.69(q,J=7.6Hz,1H),1.57(d,J=0.8Hz,3H),1.47(s,3H),0.81-0.76(m,3H).

[0611] Step 3

[0612] (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-acetate

[0613] (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-ol 17c (250 mg, 734.68 μmol) was dissolved in toluene (5 mL), followed by the addition of acetic anhydride (82.50 mg, 808.15 μmol), 4-dimethylaminopyridine (8.98 mg, 73.47 μmol), and triethylamine (81.78 mg, 808.15 μmol). The mixture was stirred at 25 °C for 1 hour. The reaction was monitored by TLC. Pour into water (20 mL) and extract with ethyl acetate (20 mL × 3). Dry the combined organic layers with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-acetate 17d (270 mg), yield: 96.13%. It was used directly for the next reaction without purification.

[0614] Step 4

[0615] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxynitrile

[0616] (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-acetate 17d (270 mg, 706.21 μmol) was dissolved in dichloromethane (3 mL). Boron trifluoride diethyl ether (150.35 mg, 1.06 mmol) and trimethylcyanosilanes (175.15 mg, 1.77 mmol) were added at -78 °C, and the mixture was stirred at 25 °C for 1 hour under nitrogen protection. The reaction was monitored by TLC. The reaction mixture was poured into water (20 mL) and extracted with dichloromethane (20 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxynitrile 17e (200 mg), yield: 81.08%. It was carried out directly in the next step without purification.

[0617] 1 H NMR (400MHz, CD3OD) δ7.00-6.93(m,1H),6.86(s,1H),5.27(s,1H),4.11(d,J=3.6Hz ,3H),2.84(d,J=7.6Hz,1H),1.74(s,3H),1.64(d,J=0.7Hz,3H),0.82-0.77(m,3H).

[0618] Step 5

[0619] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0620] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxynitrile 17e (100 mg, 286.29 μmol) was dissolved in dimethyl sulfoxide (2 mL), and potassium carbonate (197.83 mg, 1.43 mmol) and hydrogen peroxide (324.60 mg, 2.86 mmol) were added. The mixture was stirred at 25 °C for 16 hours. The reaction was monitored by TLC. At 0 °C, saturated sodium sulfite solution (2 mL) was added, diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (eluent: system A) to give (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 17f (90 mg), yield: 85.59%.

[0621] MS m / z(ESI): 368.0 [M+1].

[0622] Step 6

[0623] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamate)pyridinecarboxylic acid

[0624] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 17f (50 mg, 136.12 μmol) and methyl 4-bromopyridine-2-carboxylate 16j (35.29 mg, 163.35 μmol) were dissolved in dichloromethane (1 mL), and cesium carbonate (133.06 mg, 408.37 μmol) and [9,9-dimethyl-4,5-bis(diphenylphospho)oxanthracene][2-amino-1,1-diphenyl]palladium(II) methanesulfonate (12.91 mg, 13.61 μmol) were added. The mixture was stirred at 100 °C for 16 hours under nitrogen protection. The reaction was monitored by LC-MS. After the reaction was complete, the pH of the solution was adjusted to 5-6 with 1M hydrochloric acid at 0℃, and extracted with ethyl acetate (20 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (eluent: system C) to give 17 g (50 mg) of 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxylic acid, yield: 75.21%. MS m / z (ESI): 489.0 [M+1]

[0625] Step 7

[0626] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridineamide

[0627] 17 g (40 mg, 81.90 μmol) of 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxylic acid was dissolved in 1 mL of N,N-dimethylformamide. Ammonium chloride (21.90 mg, 409.50 μmol), N,N-diisopropylethylamine (52.92 mg, 409.50 μmol), and 2-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphate (62.28 mg, 163.80 μmol) were added, and the mixture was stirred at 25 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the reaction mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated sodium chloride solution (10 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by preparative separation using a C18 reversed-phase column (eluent: system B) to give 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridineamide 17 (13.28 mg), yield: 33.27%.

[0628] MS m / z(ESI): 488.1 [M+1]

[0629] 1 H NMR (400MHz, DMSO) δ10.18(s,1H),8.51(d,J=5.6Hz,1H),8.46(d,J=2.0Hz,1H),8.14(s,1H),8.01(dd,J=2.1,5.6Hz,1H),7.67(s,1H), 7.56-7.50(m,1H),7.14-7.05(m,1H),5.24(s,1H),4.00(s,3H),2.76(d,J=7.5Hz,1H),1.72(s,3H),1.55(s,3H),0.69(d,J=6.6Hz,3H).

[0630] Example 18

[0631] 6-Chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,5-naphthidium-4-ol

[0632]

[0633] first step

[0634] 1-(3-amino-6-chloropyridin-2-yl)acetone

[0635] 3-Amino-6-chloropyridinium 18a (200 mg, 1.30 mmol) was dissolved in tetrahydrofuran (3 mL), and methylmagnesium bromide (465.89 mg, 3.91 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 2 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction was quenched by adding saturated ammonium chloride solution at 0 °C. The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system A) to give 1-(3-amino-6-chloropyridin-2-yl)acetone 18b (100 mg), yield: 45.01%. MS m / z (ESI): 171.0 [M+1]

[0636] Step 2

[0637] (2R,3S,4S,5R)-N-(2-acetyl-6-chloropyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0638] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a (50 mg, 141.14 μmol) and 1-(3-amino-6-chloropyridin-2-yl)acetone 18b (28.89 mg, 169.36 μmol) were dissolved in dichloromethane (1 mL), and pyridine (55.82 mg, 705.68 μmol) and phosphorus trichloride (43.28 mg, 282.27 μmol) were added at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction was monitored by LC-MS. After the reaction was complete, the reaction mixture was poured into water (20 mL) and extracted with dichloromethane (20 mL × 3). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give (2R,3S,4S,5R)-N-(2-acetyl-6-chloropyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 18c (70 mg), yield: 97.85%. MS m / z (ESI): 507.1 [M+1]

[0639] Step 3

[0640] 6-Chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,5-naphthidium-4-ol

[0641] (2R,3S,4S,5R)-N-(2-acetyl-6-chloropyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 18c (50 mg, 98.65 μmol) was dissolved in toluene (2 mL), sodium hydroxide (15.78 mg, 394.59 μmol) was added, and the mixture was stirred at 110 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system A) to give 18 (45 mg) of 6-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,5-naphthidium-4-ol, yield: 93.32%.

[0642] MS m / z(ESI): 489.0 [M+1]

[0643] 1 H NMR (400MHz, DMSO-d6) δ8.23(d,J=8.8Hz,1H),7.74(d,J=8.9Hz,1H),7.29(t,J=6.5Hz,1H),7.18-7.08(m,1H),6.87(s,1H),5.56(d ,J=11.2Hz,1H),4.27(dd,J=7.9,11.0Hz,1H),3.89(d,J=1.9Hz,3H),2.84(quin,J=7.6Hz,1H),1.69(s,3H),0.80(d,J=6.2Hz,3H).

[0644] Example 19

[0645] 6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-8-hydroxy-1,5-naphthidine-2-carboxamide

[0646]

[0647] first step

[0648] 6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-8-hydroxy-1,5-naphthidine-2-carboxamide

[0649] 6-Chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,5-naphthidium-4-ol 18 (10 mg, 20.46 μmol) was dissolved in N,N-dimethylacetamide (0.5 mL), and zinc cyanide (4.80 mg, 40.91 μmol), zinc powder (267.53 μg, 4.09 μmol), 1,1-bis(diphenylphosphino)ferrocene (2.27 mg, 4.09 μmol) and tris(dibenzylacetone)palladium (1.87 mg, 2.05 μmol) were added. The mixture was stirred at 110 °C for 16 hours. The reaction was monitored by LC-MS. After the reaction was completed, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by preparative separation using a C18 reversed-phase column (eluent: system B) to give 6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-8-hydroxy-1,5-naphthidine-2-carboxamide 19 (3.23 mg), yield: 31.74%.

[0650] MS m / z(ESI): 498.0 [M+1].

[0651] 1 H NMR (400MHz, DMSO-d6) δ8.77(s,1H),8.37(d,J=8.8Hz,1H),8.29(d,J=8.7Hz,1H),7.76(s,1H),7.32(t,J=6.5Hz,1H),7.22(s,1H),7.16-7. 07(m,1H),5.63(d,J=11.2Hz,1H),4.34(dd,J=7.6,11.1Hz,1H),3.89(d,J=1.9Hz,3H),2.90-2.81(m,1H),1.71(s,3H),0.81(d,J=6.7Hz,3H)

[0652] Example 20

[0653] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)quinoline-4-ol

[0654]

[0655] first step

[0656] (2R,3S,4S,5R)-N-(2-acetylphenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0657] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a (50.00 mg, 141.14 μmol) was dissolved in pyridine (1 mL), followed by 1-(2-aminophenyl)ethane-1-one 20a (28.61 mg, 211.70 μmol), and then phosphorus trichloride (64.92 mg, 423.41 μmol). The mixture was stirred at 25 °C for 1.5 hours under nitrogen protection. The reaction was monitored by LC-MS. After the reaction was completed, the reaction solution was quenched with water (5 mL), and the pH of the solution was adjusted to 9 with saturated sodium bicarbonate. The solution was extracted with ethyl acetate (20 mL × 3), the organic layers were combined, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (2R,3S,4S,5R)-N-(2-acetylphenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 20b (50 mg), yield: 75.15%. It was used directly in the next step of the reaction without purification.

[0658] MS m / z(ESI): 472.2 [M+1].

[0659] Step 2

[0660] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)quinoline-4-ol

[0661] (2R,3S,4S,5R)-N-(2-acetylphenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 20b (50 mg, 106.06 μmol) was dissolved in toluene (1.5 mL), and sodium hydroxide (16.97 mg, 424.25 μmol) was added. The mixture was stirred at 110 °C for 1.5 h under nitrogen protection. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by HPLC (eluent: system B) to give 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)quinoline-4-ol 20 (32.43 mg), yield: 67.44%.

[0662] MS m / z(ESI): 454.1 [M+1].

[0663] 1 H NMR(400MHz,DMSO-d6)δ12.23-11.07(m,1H),8.03(dd,J=1.1,8.1Hz,1H),7 .79-7.73(m,1H),7.72-7.66(m,1H),7.39-7.32(m,1H),7.29-7.22(m,1H),7 .19-7.09(m,1H),6.36(s,1H),5.56-5.47(m,1H),4.31-4.27(m,1H),3.91(d ,J=2.1Hz,3H),2.90-2.80(m,1H),1.76-1.65(m,3H),0.79(d,J=6.3Hz,3H).

[0664] Example 21

[0665] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-6-oxide

[0666]

[0667] first step

[0668] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-6-oxide

[0669] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthid-4-ol 14 (0.05 g, 0.11 mmol) was dissolved in dichloromethane (0.5 mL), and m-chloroperoxybenzoic acid (55.8 mg, 0.28 mmol) was added at 0 °C. The mixture was stirred at 25 °C for 6 hours. The reaction was monitored by LC-MS. After the reaction was complete, the sample was filtered and separated by C18 reversed-phase column chromatography (eluent: system B) to give 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-6-oxide 21 (4.56 mg), yield: 72.63%. MS m / z (ESI): 471.1 [M+1]

[0670] 1 H NMR (400MHz, DMSO-d6) δ8.60(d,J=2.0Hz,1H),8.38(dd,J=7.2,2.0Hz,1H),7.79(d,J=7.6Hz,1H),7.22-7.31(m,1H),7.10-7.19(m,1H),6.43(br s,1H),5.51(d,J=11.6Hz,1H),4.24(dd,J=11.2,8.4Hz,1H),3.91(d,J=2.0Hz,3H),2.85(quin,J=7.6Hz,1H),1.70(s,3H),0.75-0.81(m,3H).

[0671] Example 22

[0672] 3-((2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidin-5-yl)oxy)propane-1,2-diol

[0673]

[0674] first step

[0675] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-((2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methoxy)-1,6-naphthidium-4-ol

[0676] Sodium hydride (12.27 mg, 306.85 μmol) was added to 0.5 mL of tetrahydrofuran containing 5-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro)-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthidium-4-ol 11 (50 mg, 102.28 μmol) and (2,2-dimethyl-1,3-dioxolane-4-yl)methanol 22a (14.87 mg, 112.51 μmol) at 0 °C, and stirred at 25 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the reaction was quenched by adding water (2 mL) at 0 °C, extracted with dichloromethane (5 mL × 3), the organic layers were combined, washed with saturated sodium chloride aqueous solution (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-((2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methoxy)-1,6-naphthidium-4-ol 22b (40 mg), yield: 66.90%. It was carried out directly in the next step without purification.

[0677] MS m / z (ESI): 585.2 [M+1]

[0678] Step 2

[0679] 3-((2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidin-5-yl)oxy)propane-1,2-diol

[0680] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-1,6-naphthidium-4-ol 22b (30 mg, 51.32 μmol) was dissolved in 0.8 mL of 2 M hydrochloric acid / 1,4-dioxane solution and reacted at 25 °C for 3 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure. The residue was then purified by HPLC (elution buffer: system B) to give 3-((2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidium-5-yl)oxy)propane-1,2-diol 22 (9.38 mg), yield: 33.57%.

[0681] MS m / z (ESI): 545.2 [M+1]

[0682] 1 H NMR(500MHz,CD3OD)δ8.10(d,J=5.3Hz,1H),7.30-7.07(m,2H),7.05-6.89(m,1H),6.27(s,1H),5.43(d,J=10.8Hz,1H),4.66- 4.37(m,2H),4.23(t,J=9.2Hz,1H),4.02(s,1H),3.98-3.81(m,3H),3.70(s,2H),2.95-2.74(m,1H),1.71(s,3H),0.89(s,3H).

[0683] Example 23

[0684] 7-Chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,8-naphthidium-4-ol

[0685]

[0686] first step

[0687] 2-Amino-6-chloro-N-methoxy-N-methylnicotinamide

[0688] 2-Amino-6-chloronicotinic acid 23a (2 g, 11.59 mmol) was dissolved in N,N-dimethylformamide (40 mL), and N-methoxymethylamine hydrochloride (1.13 g, 11.59 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (6.61 g, 17.38 mmol), 1-hydroxy-7-azobenzotriazole (1.58 g, 11.59 mmol) and N,N-diisopropylethylamine (4.49 g, 34.77 mmol) were added. The mixture was stirred at 25 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was diluted with water (50 mL), extracted with ethyl acetate (40 mL × 2), and the organic layers were combined. The residue was washed with saturated sodium chloride solution (40 mL × 2), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: system A) to give 2-amino-6-chloro-N-methoxy-N-methylnicotinamide 23b (2.1 g), yield: 84.03%. MS m / z (ESI): 216.1 [M+1].

[0689] Step 2

[0690] 1-(2-amino-6-chloropyridin-3-yl)ethane-1-one

[0691] 2-Amino-6-chloro-N-methoxy-N-methylnicotinamide 23b (1 g, 4.64 mmol) was dissolved in tetrahydrofuran (12 mL), and methyl magnesium bromide (1.94 g, 16.23 mmol) was added at 0 °C under nitrogen protection. The mixture was stirred at 0 °C for 4 hours. The reaction was monitored by LC-MS. After the reaction was completed, ammonium chloride solution (50 mL) was added, and the mixture was extracted with ethyl acetate (50 × 2 mL). The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 1-(2-amino-6-chloropyridin-3-yl)ethane-1-one 23c (400 mg), yield: 50.56%.

[0692] MS m / z(ESI): 171.0 [M+1].

[0693] Step 3

[0694] (2R,3S,4S,5R)-N-(3-acetyl-6-chloropyridin-2-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0695] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a (180 mg, 508.09 μmol) was dissolved in pyridine (3 mL), and 1-(2-amino-6-chloropyridin-3-yl)ethyl-1-one 23c (104.01 mg, 609.71 μmol) was added. Phosphorus oxychloride (233.72 mg, 1.52 mmol) was added to the mixture, and the mixture was stirred at 25 °C for 1.5 h under nitrogen protection. The reaction was monitored by LC-MS. After the reaction was completed, water (5 mL) was added, the pH was adjusted to 9 with sodium bicarbonate aqueous solution, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (2R,3S,4S,5R)-N-(3-acetyl-6-chloropyridin-2-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 23d (200 mg), yield: 77.66%. It was used directly in the next reaction without purification.

[0696] MS m / z(ESI): 507.1 [M+1].

[0697] Step 4

[0698] 7-Chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,8-naphthidium-4-ol

[0699] (2R,3S,4S,5R)-N-(3-acetyl-6-chloropyridin-2-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 23d (100 mg, 197.30 μmol) was dissolved in toluene (2 mL), and potassium tert-butoxide (66.42 mg, 591.89 μmol) was added. The mixture was stirred at 110 °C for 2 hours under nitrogen protection. The reaction was monitored by LC-MS. After the reaction was completed, water (10 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was preparatively separated by C18 reversed-phase column chromatography (eluent: system B) to give 7-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,8-naphthidium-4-ol 23 (90 mg), yield: 93.32%.

[0700] MS m / z(ESI): 489.0 [M+1].

[0701] 1 H NMR (400MHz, CDCl3) δ9.20 (s, 1H), 8.53 (d, J = 8.3Hz, 1H), 7.35-7.30 (m, 1H), 6.98-6.90 (m, 2H), 5.99-5.90 (m, 1H) ,5.45(d,J=11.1Hz,1H),4.13-4.02(m,1H),3.98-3.88(m,3H),2.81-2.67(m,1H),1.71(s,3H),0.91-0.81(m,3H).

[0702] Example 24

[0703] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3H-imidazo[4,5-b]pyridine-5-carboxamide

[0704]

[0705] first step

[0706] 6-Amino-5-nitromethylene ester

[0707] 6-Bromo-3-nitropyridine-2-amine 24a (1 g, 4.59 mmol) was dissolved in 20 mL of a mixed solution (N,N-dimethylformamide:methanol = 1:1), and palladium acetate (30.89 mg, 137.61 μmol), triphenylphosphine (48.12 mg, 183.48 μmol) and triethylamine (1.86 g, 18.35 mmol) were added. The mixture was stirred at 60 °C for 16 hours under a carbon monoxide (50 psi) atmosphere. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the reaction solution was poured into water (50 mL). It was then extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give 6-amino-5-nitromethylene ester 24b (340 mg), yield: 37.60%.

[0708] MS m / z(ESI): 198.1 [M+1].

[0709] Step 2

[0710] Methyl 5,6-diaminopyridinecarboxylate

[0711] 6-Amino-5-nitromethylene ester 24b (340 mg, 1.72 mmol) was dissolved in methanol (4 mL), and palladium on carbon (183.53 mg, 172.46 μmol) was added. The mixture was stirred at 25 °C for 16 hours under a hydrogen atmosphere (50 psi). The reaction was monitored by LC-MS. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system A) to give methyl 5,6-diaminopyridinecarboxylate 24c (200 mg), yield: 69.37%.

[0712] 1 H NMR (400MHz, CD3OD) δ7.38 (d, J = 7.9 Hz, 1H), 6.83 (d, J = 7.9 Hz, 1H), 3.85 (s, 3H).

[0713] Step 3

[0714] 5-Amino-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamate)methyl pyridinecarboxylate

[0715] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a (50 mg, 141.14 μmol) and methyl 5,6-diaminopyridinecarboxylate 24c (23.59 mg, 141.14 μmol) were dissolved in N,N-dimethylformamide (1 mL), and N,N-diisopropylethylamine (127.69 mg, 987.95 μmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphate (80.50 mg, 211.70 μmol) were added. The mixture was stirred at 25 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was complete, the mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 5-amino-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamate)pyridinecarboxylate 24d (50 mg), yield: 70.37%. This product was used directly for the next reaction without purification. MS m / z (ESI): 504.1 [M+1].

[0716] Step 4

[0717] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester

[0718] Methyl 5-amino-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxylate 24d (40 mg, 79.46 μmol) was dissolved in acetic acid (1 mL) and stirred at 80 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, saturated sodium bicarbonate solution was added to adjust the pH to 8-9. The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 24e (30 mg), yield: 77.78%. It was used directly in the next step of the reaction without purification.

[0719] MS m / z(ESI): 486.2 [M+1].

[0720] Step 5

[0721] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3H-imidazo[4,5-b]pyridine-5-carboxamide

[0722] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester 24e (30 mg, 61.80 μmol) was dissolved in ammonia water (1 mL) and stirred at 25 °C for 16 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was separated by C18 reversed-phase column chromatography (eluent: system B) to give 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3H-imidazo[4,5-b]pyridine-5-carboxamide 24 (23.76 mg), yield: 81.73%. MS m / z (ESI): 471.0 [M+1].

[0723] 1 H NMR (400MHz, DMSO) δ8.07(d,J=8.2Hz,1H),7.95(d,J=8.3Hz,2H),7.54(s,1H),7.21-7.15(m,1H),7.15-7.08(m,1H),5.80(d, J=11.1Hz,1H),4.50(dd,J=7.5,11.0Hz,1H),3.95(d,J=2.1Hz,3H),2.89(t,J=7.5Hz,1H),1.67(s,3H),0.81(d,J=6.2Hz,3H).

[0724] Example 25

[0725] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0726]

[0727] first step

[0728] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0729] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester 24e (6 mg, 12.36 μmol) was dissolved in 0.4 mL of a mixed solution (methanol:water = 3:1), and lithium hydroxide (1.56 mg, 37.08 μmol) was added. The mixture was stirred at 25 °C for 1 hour. LC-MS monitoring was performed. After the reaction was complete, the pH of the solution was adjusted to 5-6 with 2M hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by preparative separation using a C18 reversed-phase column (eluent: system B) to give 25 (2.88 mg) of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid, yield: 49.43%.

[0730] MS m / z(ESI): 472.0 [M+1].

[0731] 1 H NMR (400MHz, CD3OD) δ8.17-8.07(m,2H),7.19-7.13(m,1H),7.00-6.90(m,1H),5.83-5.77(m,1H),4.46(d d,J=7.9,11.0Hz,1H),4.01-3.95(m,3H),2.95(quin,J=7.7Hz,1H),1.74-1.69(m,3H),0.93-0.87(m,3H).

[0732] Example 26

[0733] 7-Chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthidium-4-ol

[0734]

[0735] first step

[0736] 1-(6-chloro-4-((2,4-dimethoxybenzyl)amino)pyridin-3-yl)ethyl ketone

[0737] At 0 °C, 1-(4,6-dichloropyridin-3-yl)acetone 26a (5 g, 26.31 mmol) was dissolved in acetonitrile (100 mL), and triethylamine (7.99 g, 78.94 mmol) and (2,4-dimethoxyphenyl)methylamine 26b (4.62 g, 27.63 mmol) were added. The mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LCMS until completion. The mixture was diluted with water (200 mL), filtered, washed with water, and dried under vacuum to give 1-(6-chloro-4-((2,4-dimethoxybenzyl)amino)pyridin-3-yl)acetone 26c (7.9 g), yield: 93.60%. This unpurified mixture was directly used in the next step of the reaction.

[0738] MS m / z(ESI): 320.9 [M+1]

[0739] Step 2

[0740] 1-(4-amino-6-chloro-3-pyridyl)acetone

[0741] 1-(6-chloro-4-((2,4-dimethoxybenzyl)amino)pyridin-3-yl)acetone 26c (7.6 g, 23.69 mmol) was dissolved in dichloromethane (50 mL), and trifluoroacetic acid (27.02 g, 236.93 mmol) was added. The mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LCMS until completion. The pH of the reaction solution was adjusted to 8 with saturated sodium bicarbonate aqueous solution, and the solution was extracted with dichloromethane (100 mL × 3). The organic phase was dried, filtered, and concentrated to obtain 1-(4-amino-6-chloro-3-pyridinyl)acetone 26d (2.6 g), yield: 64.33%. This product was used directly in the next reaction without purification.

[0742] MS m / z(ESI): 171.0 [M+1]

[0743] Step 3

[0744] (2R,3S,4S,5R)-N-(5-acetyl-2-chloropyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0745] At 0 °C, (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a (0.17 g, 566.11 μmol) was dissolved in dichloromethane (1 mL), and oxalyl chloride (53.74 mg, 423.41 μmol) and N,N-dimethylformamide (206.32 μg, 2.82 μmol) were added dropwise. After stirring at 0°C for 30 minutes, the reaction was completed and concentrated under reduced pressure. The residue was diluted with dichloromethane (0.5 mL). 26 d of 1-(4-amino-6-chloro-3-pyridyl) ethyl ketone (52.97 mg, 310.50 μmol) and N-ethyl-N-isopropylpropyl-2-amine (109.44 mg, 846.82 μmol) in dichloromethane (2 mL) cooled in ice water were added dropwise, and the mixture was stirred at 25°C for 1 hour. The reaction was monitored by LCMS until it was complete. The organic layer was washed with water (2 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (2R,3S,4S,5R)-N-(5-acetyl-2-chloropyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 26e (140 mg), yield: 97.85%. It was used directly in the next step of the reaction without purification.

[0746] MS m / z(ESI): 507.0 [M+1]

[0747] Step 4

[0748] 7-Chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthidium-4-ol

[0749] (2R,3S,4S,5R)-N-(5-acetyl-2-chloropyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 26e (140 mg, 276.22 μmol) was dissolved in toluene (2 mL), and sodium hydroxide (44.19 mg, 1.10 mmol) was added. The mixture was stirred at 110 °C for 3 hours. The reaction was monitored by LC-MS until completion. The pH of the solution was adjusted to 7 with 1 M hydrochloric acid, and the solution was extracted with ethyl acetate (2 mL × 3). The organic phase was dried, filtered, concentrated under reduced pressure, and the residue was obtained by C1... 18Preparative separation by reversed-phase column chromatography (eluent: system B) yielded 26 (8.3 mg) of 7-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthidium-4-ol, yield: 6.14%. MS m / z (ESI): 489.0 [M+1]

[0750] 1 H NMR(400MHz,CD3OD)δ9.06(s,1H),7.72(s,1H),7.19-7.16(m,1H),7.02-6.99(m,1H),6.23(s,1H),5.5 1(d,J=11.2Hz,1H),4.26-4.21(m,1H),3.94(s,3H),2.88-2.85(m,1H),1.72(s,3H),0.90-0.87(m,3H).

[0751] Example 27

[0752] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-7-carboxamide

[0753]

[0754] first step

[0755] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-7-carboxamide

[0756] A solution of 7-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthid-4-ol 26 (50 mg, 102.28 μmol) in N,N-dimethylformamide (0.5 mL) was added to zinc powder (0.05 g, 764.64 μmol), zinc cyanide (0.03 g, 255.48 μmol), and 1,1'-bis(di-tert-butylphosphine)ferrocene palladium dichloride (6.67 mg, 10.23 μmol). The mixture was stirred at 100 °C for 16 hours under nitrogen protection. The reaction was monitored by LC-MS until completion. The reaction solution was diluted with water (5 mL), extracted with ethyl acetate (5 mL × 3), dried, filtered, and concentrated under reduced pressure. The residue was analyzed by C1... 18Preparative separation by reversed-phase column chromatography (eluent: system B) yielded 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-7-carboxamide 27 (10 mg), yield: 19.66%.

[0757] MS m / z(ESI): 498.0 [M+1]

[0758] 1 H NMR(400MHz,DMSO-d6)δ11.68(s,1H),9.11(s,1H),8.38(s,1H),8.28(s,1H),7.81(s,1H),7.31-7.27(m,1H),7.19-7.13(m,1H ),6.44(s,1H),5.51(d,J=11.2Hz,1H),4.28-4.24(m,1H),3.89(s,3H),2.87-2.83(m,1H),1.72(s,3H),0.78(d,J=7.2Hz,3H).

[0759] Example 28

[0760] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-7-nitrile

[0761]

[0762] first step

[0763] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-7-nitrile

[0764] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-7-carboxamide 27 (7 mg, 102.28 μmol) was dissolved in tetrahydrofuran (1 mL), and triethylamine (56.96 mg, 562.91 μmol) and trifluoroacetic anhydride (29.56 mg, 140.73 μmol) were added. The mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LCMS until completion. The pH of the reaction solution was adjusted to 7 with saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phase was dried, filtered, and concentrated under reduced pressure. The residue was obtained by C...18 Preparative separation by reversed-phase column chromatography (eluent: system B) yielded 28 (2.8 mg) of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-7-onitrile, yield: 41.5%.

[0765] MS m / z(ESI): 480.0 [M+1]

[0766] 1 H NMR(400MHz,CD3OD)δ9.30(s,1H),8.16(s,1H),7.20-7.17(m,1H),7.05-7.00(m,1H),6.36(s,1H),5.5 5(d,J=11.2Hz,1H),4.27-4.22(m,1H),3.94(s,3H),2.92-2.84(m,1H),1.73(s,3H),0.91-0.88(m,3H).

[0767] Example 29

[0768] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-2,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridineamide

[0769]

[0770] first step

[0771] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-2,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-nitrile

[0772] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-onitrile 29a (80 mg, 238.61 μmol) and iodomethane (50.80 mg, 357.92 μmol) were dissolved in tetrahydrofuran (2 mL). Bis(trimethylsilyl)aminopotassium (57.12 mg, 286.34 μmol) was added dropwise at -78 °C, and the mixture was stirred at -78 °C for 3 hours. The reaction was monitored by LC-MS. After the reaction was completed, water and 2 mL of ammonium chloride solution were added at 0 °C to quench the reaction. The mixture was extracted with dichloromethane (5 mL × 3). The combined organic layers were washed with saturated sodium chloride aqueous solution (2 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-2,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-onitrile 29b (60 mg), yield: 71.99%. This product was used directly in the next step of the reaction without purification.

[0773] MS m / z(ESI): 323.1 [M-26]

[0774] Step 2

[0775] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-2,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0776] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-2,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-onitrile 29b (60 mg, 171.77 μmol) was dissolved in dimethyl sulfoxide (1 mL), potassium carbonate (118.70 mg, 858.87 μmol) and hydrogen peroxide (194.76 mg, 1.72 mmol) were added, and the mixture was stirred at 20 °C for 16 hours. The reaction was monitored by LC-MS. After the reaction was completed, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The extract was washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-2,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 29c (50 mg), yield: 79.25%. The extract was not purified and proceeded directly to the next step of the reaction.

[0777] MS m / z(ESI): 368.1 [M+1]

[0778] Step 3

[0779] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-2,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)methyl pyridinecarboxylate

[0780] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-2,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 29c (50 mg, 136.12 μmol) was dissolved in 1,4-dioxane (1 mL), and [9,9-dimethyl-4,5-bis(diphenylphospho)oxanthracene][2-amino-1,1-diphenyl]palladium(II)methanesulfonic acid (12.91 mg, 13.61 μmol), methyl 4-bromopyridine-2-carboxylate 16j (44.11 mg, 204.19 μmol) and cesium carbonate (133.06 mg, 408.37 μmol) were added. The mixture was stirred at 100 °C for 16 hours. The reaction was monitored by LC-MS. After the reaction was completed, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The extract was washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-2,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxylate 29d (30 mg), yield: 43.86%.

[0781] MS m / z(ESI): 503.1 [M+1]

[0782] Step 4

[0783] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-2,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridineamide

[0784] Methyl 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-2,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxylate 29d (20 mg, 39.81 μmol) was dissolved in ammonia water (135.34 mg, 7.96 mmol) and stirred at 20 °C for 16 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was filtered, concentrated under reduced pressure, and the residue was purified by HPLC (elution: system B) to give 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-2,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxamide 29 (10.19 mg), yield: 52.52%.

[0785] MS m / z(ESI): 488.1 [M+1]

[0786] 1 H NMR (400MHz, CD3OD) δ8.77-8.10(m,2H),7.94(s,1H),7.43-7.18(m,1H),7.15-6.74(m,1 H), 4.61 (s, 1H), 3.95 (s, 3H), 2.76 (d, J = 1.8Hz, 1H), 1.55 (d, J = 16.5Hz, 6H), 0.95 (s, 3H).

[0787] Example 30

[0788] 4-((1R,3R,3aR,9bS)-6,7-difluoro-3-methyl-3-(trifluoromethyl)-1,3a,4,9b-tetrahydro-3H-furano[3,4-c]chroman-1-carbamoyl)pyridine amide

[0789]

[0790]

[0791] first step

[0792] (R)-4-(bromomethyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)furan-2(5H)-one

[0793] (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one 16a (1 g, 3.10 mmol) was dissolved in 1,2-dichloroethane (10 mL), and azobisisobutyronitrile (102 mg, 0.62 mmol) and N-bromosuccinimide (608 mg, 3.41 mmol) were added. The mixture was stirred at 80 °C for 16 hours, and the reaction was monitored by TLC. After the reaction was completed, water (20 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give (R)-4-(bromomethyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)furan-2(5H)-one 30a (0.6 g), yield: 47.74%.

[0794] MS m / z(ESI): 401.0 [M+1]

[0795] Step 2

[0796] (R)-4-(bromomethyl)-3-(3,4-difluoro-2-hydroxyphenyl)-5-methyl-5-(trifluoromethyl)furan-2(5H)-one

[0797] (R)-4-(bromomethyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)furan-2(5H)-one 30a (1.2 g, 2.99 mmol) was dissolved in dichloromethane (10 mL), and boron tribromide (1.12 g, 4.49 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 1 hour, and the reaction was monitored by LCMS. After the reaction was completed, water (10 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give (R)-4-(bromomethyl)-3-(3,4-difluoro-2-hydroxyphenyl)-5-methyl-5-(trifluoromethyl)furan-2(5H)-one 30b (1.0 g), yield: 85.21%.

[0798] MS m / z(ESI): 387.0 [M+1]

[0799] Step 3

[0800] (R)-6,7-difluoro-3-methyl-3-(trifluoromethyl)-3,4-dihydro-1H-furano[3,4-c]chroman-1-one

[0801] (R)-4-(bromomethyl)-3-(3,4-difluoro-2-hydroxyphenyl)-5-methyl-5-(trifluoromethyl)furan-2(5H)-one 30b (1 g, 2.58 mmol) was dissolved in tetrahydrofuran (10 mL), sodium hydrogen (517 mg, 12.9 mmol) was added at -78 °C, and the mixture was stirred at -78 °C for 0.5 hours. The reaction was monitored by LCMS. Quenching with water (15 mL), extraction with ethyl acetate (20 mL × 3), combining the organic phases, washing with saturated sodium chloride solution (30 mL), drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying the residue by column chromatography (eluent: system A) to give (R)-6,7-difluoro-3-methyl-3-(trifluoromethyl)-3,4-dihydro-1H-furano[3,4-c]chroman-1-one 30c (0.4 g), yield: 50.57%.

[0802] MS m / z(ESI): 307.0 [M+1]

[0803] Step 4

[0804] (3R,3aR,9bS)-6,7-difluoro-3-methyl-3-(trifluoromethyl)-3,3a,4,9b-tetrahydro-1H-furano[3,4-c]chroman-1-one

[0805] (R)-6,7-difluoro-3-methyl-3-(trifluoromethyl)-3,4-dihydro-1H-furano[3,4-c]chroman-1-one 30c (0.2 g, 0.65 mmol) was dissolved in tetrahydrofuran (1 mL) and methanol (5 mL). Nickel chloride hexahydrate (310 mg, 1.31 mmol) and sodium borohydride (371 mg, 9.80 mmol) were added at -40 °C, and the mixture was stirred at -40 °C for 0.5 hours. The reaction was monitored by LCMS. After the reaction was completed, saturated ammonium chloride (10 mL) was added at -40 °C to quench the reaction. The mixture was extracted with dichloromethane (20 mL × 3), and the organic phases were combined. The organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give (3R,3aR,9bS)-6,7-difluoro-3-methyl-3-(trifluoromethyl)-3,3a,4,9b-tetrahydro-1H-furano[3,4-c]chroman-1-one 30d (0.19 g), yield: 94.38%.

[0806] MS m / z(ESI): 309.0 [M+1]

[0807] Step 5

[0808] (3R,3aR,9bS)-6,7-difluoro-3-methyl-3-(trifluoromethyl)-3,3a,4,9b-tetrahydro-1H-furano[3,4-c]chroman-1-ol

[0809] Dissolve (3R,3aR,9bS)-6,7-difluoro-3-methyl-3-(trifluoromethyl)-3,3a,4,9b-tetrahydro-1H-furano[3,4-c]chroman-1-one 30d (200 mg, 0.65 mmol) in toluene (5 mL), add diisobutylaluminum hydrogen (230.73 mg, 1.62 mmol) dropwise, and stir at -78 °C for 2 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was quenched with water (20 mL) at 0 °C, extracted with ethyl acetate (20 mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (3R,3aR,9bS)-6,7-difluoro-3-methyl-3-(trifluoromethyl)-3,3a,4,9b-tetrahydro-1H-furano[3,4-c]chroman-1-ol 30e (160 mg), yield 79.48%. It was not purified and directly proceeded to the next step of the reaction.

[0810] MS m / z(ESI): 293.1 [M-17]

[0811] Step 6

[0812] (3R,3aR,9bS)-6,7-difluoro-3-methyl-3-(trifluoromethyl)-3,3a,4,9b-tetrahydro-1H-furano[3,4-c]chromo-1-ylacetate

[0813] (3R,3aR,9bS)-6,7-difluoro-3-methyl-3-(trifluoromethyl)-3,3a,4,9b-tetrahydro-1H-furano[3,4-c]chroman-1-ol 30e (160 mg, 0.58 mmol) was dissolved in toluene (1 mL), and acetic anhydride (71.1 mg, 0.70 mmol), triethylamine (64.6 mg, 0.64 mmol), and N,N-dimethylpyridin-4-amine (7.09 mg, 0.06 mol) were added. The mixture was stirred at 0 °C for 2 hours. The reaction was monitored by TLC. After the reaction was completed, 10 mL of saturated ammonium chloride solution was added at 0 °C to quench the reaction. The mixture was then diluted with 10 mL of water and extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 30 f (120 mg) of (3R,3aR,9bS)-6,7-difluoro-3-methyl-3-(trifluoromethyl)-3,3a,4,9b-tetrahydro-1H-furano[3,4-c]chroman-1-yl acetate, yield: 58.71%. The product was not purified and was directly used in the next step of the reaction.

[0814] 1 H NMR(400MHz,CD3OD)δ6.95-6.88(m,1H),6.75(ddd,J=7.2,8.9,10.1Hz,1H),6.18-6.13(m,1H),4.40-4.3 1(m,1H),3.95-3.86(m,1H),3.80-3.73(m,1H),2.88-2.80(m,1H),2.10-2.06(m,3H),1.58-1.53(m,3H).

[0815] Step 7

[0816] (1R,3R,3aR,9bS)-6,7-difluoro-3-methyl-3-(trifluoromethyl)-3,3a,4,9b-tetrahydro-1H-furano[3,4-c]chromene-1-nitrile

[0817] Dissolve trimethylsilane nitrile (112 mg, 1.14 mmol) and boron trifluoride diethyl ether (210 mg, 0.68 mmol) in dichloromethane (2 mL), and slowly add dropwise to a solution of (3R,3aR,9bS)-6,7-difluoro-3-methyl-3-(trifluoromethyl)-3,3a,4,9b-tetrahydro-1H-furano[3,4-c]chroman-1-yl acetate 30f (160 mg, 0.45 mmol) in dichloromethane (2 mL). Stir at -78 to 20 °C for 0.5 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was extracted with dichloromethane (10 mL) and water (10 mL) to separate the organic phase. The organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 30 g (50 mg) of (1R,3R,3aR,9bS)-6,7-difluoro-3-methyl-3-(trifluoromethyl)-1,3a,4,9b-tetrahydro-3H-furano[3,4-c]chromene-1-onitrile, yield: 34.48%. The product was not purified and was directly used in the next step of the reaction.

[0818] 1 H NMR (400MHz, CD3OD) δ7.13-7.02(m,1H),7.00-6.89(m,1H),5.62-5.51(m,1H),4. 49-4.40(m,1H),4.16-4.08(m,1H),4.03-3.94(m,1H),2.86-2.75(m,1H),1.48(br s,3H).

[0819] Step 8

[0820] (1R,3R,3aR,9bS)-6,7-difluoro-3-methyl-3-(trifluoromethyl)-1,3a,4,9b-tetrahydro-3H-furano[3,4-c]chromene-1-carboxamide

[0821] 30 g (45 mg, 0.14 mmol) of (1R,3R,3aR,9bS)-6,7-difluoro-3-methyl-3-(trifluoromethyl)-1,3a,4,9b-tetrahydro-3H-furano[3,4-c]chromene-1-onitrile was dissolved in dimethyl sulfoxide (1 mL), potassium carbonate (97.4 mg, 0.70 mol) and hydrogen peroxide (160 mg, 1.41 mmol) were added, and the mixture was stirred at 20 °C for 1 hour. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was extracted with water (10 mL) and ethyl acetate (10 mL) to separate the organic phase. The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (1R,3R,3aR,9bS)-6,7-difluoro-3-methyl-3-(trifluoromethyl)-1,3a,4,9b-tetrahydro-3H-furano[3,4-c]chromene-1-carboxamide 30h (40 mg), yield: 84.14%. It was used directly for the next reaction without purification.

[0822] MS m / z(ESI): 338.1 [M+1]

[0823] Step 9

[0824] 4-((1R,3R,3aR,9bS)-6,7-difluoro-3-methyl-3-(trifluoromethyl)-1,3a,4,9b-tetrahydro-3H-furano[3,4-c]chromene-1-carboxamido)methyl pyridinecarboxylate

[0825] (1R,3R,3aR,9bS)-6,7-difluoro-3-methyl-3-(trifluoromethyl)-1,3a,4,9b-tetrahydro-3H-furano[3,4-c]chromene-1-carboxamide 30h (40 mg, 118.61 μmol) was dissolved in dioxane (0.8 mL) solution, and cesium carbonate (116 mg, 0.36 mmol), methyl 4-bromopyridine-2-carboxylate 16j (38.4 mg, 0.18 mmol), and methanesulfonic acid (9,9-dimethyl-4,5-bis(diphenylphosphine)(2-amino-1,1-biphenyl-2-yl)palladium(II) (11.2 mg, 0.01 mmol). The mixture was stirred at 100 °C for 16 hours. The reaction was monitored by LCMS, and the reaction mixture was extracted with water (10 mL) and ethyl acetate (10 mL). The organic phase was separated, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 4-((1R,3R,3aR,9bS)-6,7-difluoro-3-methyl-3-(trifluoromethyl)-1,3a,4,9b-tetrahydro-3H-furano[3,4-c]chromene-1-carboxamido)pyridinecarboxylate 30i (25 mg), yield: 44.62%, which was carried out directly in the next step without purification.

[0826] MS m / z(ESI): 473.1 [M+1]

[0827] Step 10

[0828] 4-((1R,3R,3aR,9bS)-6,7-difluoro-3-methyl-3-(trifluoromethyl)-1,3a,4,9b-tetrahydro-3H-furano[3,4-c]chroman-1-carbamoyl)pyridine amide

[0829] 4-((1R,3R,3aR,9bS)-6,7-difluoro-3-methyl-3-(trifluoromethyl)-1,3a,4,9b-tetrahydro-3H-furano[3,4-c]chromen-1-carboxamido) methyl pyridinecarboxylate 30i (20 mg, 0.04 mmol) was dissolved in ammonia-methanol (0.67 mL) and stirred at 20 °C for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by C18 reverse-phase column chromatography (eluent: system B) to give 4-((1R,3R,3aR,9bS)-6,7-difluoro-3-methyl-3-(trifluoromethyl)-1,3a,4,9b-tetrahydro-3H-furano[3,4-c]chromen-1-carboxamido) pyridine amide 30 (2 mg), yield: 10.33%.

[0830] MS m / z(ESI): 458.0 [M+1]

[0831] 1 H NMR(400MHz,CD3OD)δ8.57(d,J=5.6Hz,1H),8.36-8.40(m,1H),7.96-8.02(m,1H),7.03-7.11(m,1H), 6.77-6.88(m,1H),4.64(s,1H)4.52-4.58(m,1H),4.04-4.13(m,2H),2.90-2.96(m,1H),1.69(s,3H).

[0832] Example 31

[0833] (2R,3S,3aS,17aR)-6,7-difluoro-2,3-dimethyl-17-oxo-2-(trifluoromethyl)-3,3a,9,10,11,16,17,17a-octahydro-2H-benzo[b]furano[3,2-d]pyrido[4,3-h][1,7]oxazacyclododecane-14-carboxamide

[0834]

[0835]

[0836] first step

[0837] 4-Amino-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)pyridinecarboxylate methyl ester

[0838] Methyl 4-amino-5-bromo-pyridine-2-carboxylate 31a (1 g, 4.33 mmol) and tert-butyldimethylpropynoxysilane 31b (884.62 mg, 5.19 mmol) were dissolved in 1,4-dioxane (10 mL) solution. Bis(triphenylphosphine)palladium(ii) chloride (303.79 mg, 432.81 μmol), cuprous iodide (82.43 mg, 432.81 μmol), and triethylamine (1.31 g, 12.98 mmol) were added and stirred at 85 °C for 16 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. After the reaction was completed, the residue was purified by column chromatography (eluent: system A) to give methyl 4-amino-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)pyridinecarboxylate 31c (310 mg), yield: 22.35%.

[0839] MS m / z(ESI): 320.9 [M+1].

[0840] Step 2

[0841] 5-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)methyl pyridinecarboxylate

[0842] At 0 °C, (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a (0.26 g, 733.91 μmol) was dissolved in dichloromethane (3 mL), and oxalyl chloride (139.73 mg, 1.10 mmol) and N,N-dimethylformamide (536.44 μg, 7.34 μmol) were added dropwise. The mixture was stirred at 0 °C. Stir for 30 minutes, concentrate under reduced pressure, and dilute the residue with dichloromethane (1.0 mL). Under ice-water cooling, slowly add a solution of methyl 4-amino-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)pyridinecarboxylate 31c (258.7 mg, 807.30 μmol) and N,N-diisopropylethylamine (379.41 mg, 2.94 mmol) in dichloromethane (1 mL). Stir at room temperature for 1 hour. The reaction was monitored by LCMS. After the reaction was completed, the organic layer was washed with water (1 mL × 3), the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give methyl 5-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxylate 31d (350 mg), yield: 72.62%.

[0843] 1 H NMR (400MHz, CDCl3) δ9.47(s,1H),9.06(s,1H),8.70(s,1H),7.12-7.08(m,1H),6.96-6.89(m,1H),5.07(d,J=11.2Hz,1 H),4.64(s,2H),4.00(s,3H),3.95(s,3H),2.79-2.73(m,1H),1.70(s,3H),0.94(s,9H),0.80-0.78(m,3H),0.17(s,6H).

[0844] Step 3

[0845] 5-(3-((tert-butyldimethylsilyl)oxy)propyl)-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)methyl pyridinecarboxylate

[0846] Palladium on carbon (283.59 mg, 432.81 μmol) was added to a methanol (5 mL) and tetrahydrofuran (5 mL) solution of methyl pyridinecarboxylate 31d (350 mg, 532.96 μmol). The reaction solution was stirred at 25 °C for 16 hours under a hydrogen atmosphere (15 psi). The reaction was monitored by LCMS. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give methyl 5-(3-((tert-butyldimethylsilyl)oxy)propyl)-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridinecarboxylate 31e (280 mg), yield: 79.51%. It was used directly in the next step of the reaction without purification.

[0847] MS m / z(ESI): 661.3 [M+1]

[0848] Step 4

[0849] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-5-(3-hydroxypropyl)pyridinecarboxylate

[0850] Tetrabutylammonium fluoride (110.8 mg, 423.77 μmol) was added to a tetrahydrofuran (5 mL) solution of methyl 5-(3-((tert-butyldimethylsilyl)oxy)propyl)-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamate)pyridinecarboxylate 31e (280 mg, 423.77 μmol), and the mixture was stirred at 25 °C for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give methyl 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-5-(3-hydroxypropyl)pyridinecarboxylate 31f (150mg), yield: 64.77%.

[0851] MS m / z (ESI): 547.2 [M+1]

[0852] Step 5

[0853] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)-5-(3-hydroxypropyl)pyridineamide

[0854] Ammonia-methanol (311.08 mg, 18.30 mmol) was added to a solution of methyl 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-5-(3-hydroxypropyl)pyridinecarboxylate 31f (100 mg, 182.99 μmol) in dichloromethane (2 mL). The mixture was stirred at 25 °C for 16 hours, and the reaction was monitored by LC-MS. After the reaction was completed, the solution was concentrated under reduced pressure to obtain 31 g (97 mg) of 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-5-(3-hydroxypropyl)pyridine amide, yield: 99.74%. The amide was used directly for the next reaction without purification.

[0855] MS m / z(ESI): 532.1 [M+1].

[0856] Step 6

[0857] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-5-(3-hydroxypropyl)pyridineamide

[0858] At -30°C, boron tribromide (91.45 mg, 365.02 μmol) was added dropwise to a solution of 31 g (7 mg, 102.28 μmol) of 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-5-(3-hydroxypropyl)pyridineamide in 1 mL of dichloromethane. The mixture was stirred for 2 hours at -30°C to 25°C, and the reaction was monitored by LC-MS. After the reaction was complete, the reaction mixture was... The solution was adjusted to pH 7 with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane (5 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-5-(3-hydroxypropyl)pyridineamide 31h (40 mg), yield: 42.35%.

[0859] MS m / z(ESI): 518.1 [M+1].

[0860] Step 7

[0861] (2R,3S,3aS,17aR)-6,7-difluoro-2,3-dimethyl-17-oxo-2-(trifluoromethyl)-3,3a,9,10,11,16,17,17a-octahydro-2H-benzo[b]furano[3,2-d]pyrido[4,3-h][1,7]oxazacyclododecane-14-carboxamide

[0862] Under nitrogen protection, diisopropyl azodicarbonate (10.16 mg, 50.25 μmol) and triphenylphosphine (13.18 mg, 50.25 μmol) were added to a 2 mL solution of 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-5-(3-hydroxypropyl)pyridineamide (31 h, 20 mg, 38.65 μmol) in tetrahydrofuran. The reaction mixture was stirred at 50 °C for 4 h under nitrogen atmosphere. The reaction was monitored by LCMS until completion. The mixture was quenched with water (2 mL), extracted with ethyl acetate (2 mL × 2), dried, filtered, concentrated under reduced pressure, and the residue was analyzed by C. 18 Reversed-phase column chromatography was used for preparative separation and purification (eluent: system B) to give (2R,3S,3aS,17aR)-6,7-difluoro-2,3-dimethyl-17-oxo-2-(trifluoromethyl)-3,3a,9,10,11,16,17,17a-octahydro-2H-benzo[b]furano[3,2-d]pyrido[4,3-h][1,7]oxazacyclododecane-14-carboxamide 31 (3.4 mg), yield: 17.61%.

[0863] MS m / z(ESI): 500.1 [M+1].

[0864] 1 H NMR (400MHz, CD3OD) δ8.55(s,1H),7.84(s,1H),7.22-7.18(m,1H),7.06-7.02(m,1H),5.02-4.99(m,1H),4.61-4. 25(m,2H),2.99-2.95(m,1H),2.73-2.68(m,2H),2.04-1.88(m,2H),1.73(s,3H),1.33-1.26(m,1H),1.00(s,3H).

[0865] Example 32

[0866] 6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-8-hydroxy-1,5-naphthidine-2-nitrile

[0867]

[0868]

[0869] first step

[0870] 6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-8-hydroxy-1,5-naphthidine-2-nitrile

[0871] 6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-8-hydroxy-1,5-naphthidine-2-carboxamide 19 (10 mg, 20.10 μmol) was dissolved in tetrahydrofuran (0.5 mL), followed by the addition of trifluoroacetic anhydride (6.33 mg, 30.16 μmol) and triethylamine (4.07 mg, 40.21 μmol). The mixture was stirred at 25 °C for 2 hours, and the reaction was monitored by LC-MS. The mixture was then poured into... Extracted in water (20 mL) and with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by passing it through a C18 reversed-phase column (eluent: system B) to give 32 (3.21 mg) of 6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-8-hydroxy-1,5-naphthidine-2-onitrile, yield: 33.31%.

[0872] MS m / z(ESI): 480.1 [M+1].

[0873] 1 H NMR (400MHz, CD3OD) δ8.42(d,J=8.8Hz,1H),8.09(d,J=8.9Hz,1H),7.23(t,J=6.5Hz,1H),7.19-7.00(m,1H),6.55(s,1H),5.59(d, J=11.2Hz,1H),4.29(dd,J=7.9,11.0Hz,1H),3.94(d,J=1.9Hz,3H),2.91(quin,J=7.6Hz,1H),1.74(s,3H),0.92(d,J=6.2Hz,3H).

[0874] Example 33

[0875] 7-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-hydroxy-1,8-naphthidine-2-nitrile

[0876]

[0877]

[0878] first step

[0879] 7-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-hydroxy-1,8-naphthidine-2-nitrile

[0880] 7-Chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,8-naphthid-4-ol 23 (20 mg, 40.91 μmol) was dissolved in N,N-dimethylacetamide (1.5 mL), and zinc cyanide (9.61 mg, 81.83 μmol), zinc (535.07 μg, 8.18 μmol), and 1,1-bis(tert-butylphosphine)ferrocene palladium chloride (2.67 mg, 4.09 μmol) were added. The mixture was stirred at 120 °C for 12 hours under nitrogen protection, and the reaction was monitored by LC-MS. After the reaction was complete, the mixture was filtered, washed with ethyl acetate (20 mL × 3), diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative separation using a C18 reversed-phase column (elution buffer: system B) to give 33 (3.15 mg) of 7-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-hydroxy-1,8-naphthidine-2-onitrile, yield: 16.06%.

[0881] MS m / z(ESI): 480.2 [M+1].

[0882] 1H NMR (400MHz, CDCl3) δ9.38-9.24(m,1H),8.75-8.68(m,1H),7.73-7.62(m,1H),7.00-6.90(m,2H),6.02(s,1H),5. 48(d,J=11.2Hz,1H),4.14-4.06(m,1H),3.95(d,J=3.0Hz,3H),2.82-2.68(m,1H),1.74(s,3H),0.93-0.85(m,3H).

[0883] Example 34

[0884] 5-Carbamoyl-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-6-oxide

[0885]

[0886]

[0887] first step

[0888] 5-Carbamoyl-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4,6-dihydroxy-1,6-naphthidine-6-oxide

[0889] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-5-carboxamide 13 (0.05 g, 0.1 mmol) was dissolved in dichloromethane (5 mL), and m-chloroperoxybenzoic acid (51.0 mg, 0.25 mmol) was added. The mixture was stirred at 25 °C for 16 hours, and the reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was preparatively separated by a C18 reversed-phase column (eluent: system B) to give 34 (2.2 mg) of 5-carbamoyl-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-6-oxide, yield: 4.26%.

[0890] MS m / z (ESI): 514.2 [M+1]

[0891] 1H NMR (400MHz, CD3OD) δ8.38(d,J=7.2Hz,1H),7.88(d,J=7.2Hz,1H),7.13-7.23(m,1H),6.94-7.07(m,1H),6.26(s,1H) ,5.50(d,J=11.2Hz,1H),4.19-4.25(m,1H),3.94(d,J=2.4Hz,3H),2.83-2.92(m,1H),1.72(s,3H),0.85-0.95(m,3H).

[0892] Example 35

[0893] 4-((trans-2,3)-3-(4,4-difluoroazacycloheptan-1-yl)-5,5-dimethyltetrahydrofuran-2-carboxamido)pyridine amide

[0894]

[0895] first step

[0896] 3-((tert-butyldimethylsilyl)oxy)-2-diazobut-3-enoic acid ethyl ester

[0897] Ethyl 2-diazo-3-oxobutyrate 35a (3 g, 19.09 mmol) was dissolved in dichloromethane (40 mL) at 0 °C. Triethylamine (4.25 g, 42.00 mmol) was added, followed by the slow addition of [tert-butyl(dimethyl)silyl]trifluoromethanesulfonate (5.55 g, 21.00 mmol). The mixture was stirred at 0 °C for 0.5 h. The reaction was monitored by LC-MS. After the reaction was complete, the sample was washed with 30% sodium bicarbonate solution (100 mL), extracted with ethyl acetate (50 mL × 3), washed with water (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give ethyl 3-((tert-butyldimethylsilyl)oxy)-2-diazobut-3-enoate 35b (5 g), yield: 96.86%. This sample was used directly in the next step without purification.

[0898] 1 H NMR (500MHz, CDCl3) δ5.01 (d, J = 2.0Hz, 1H), 4.28-4.24 (m, 3H), 1.30 (t, J = 7.1Hz, 3H), 0.94-0.91 (m, 9H), 0.25-0.21 (m, 6H).

[0899] Step 2

[0900] Ethyl 2-diazo-5-hydroxy-5-methyl-3-oxohexanoate

[0901] Acetone (2.06 g, 35.50 mmol) was dissolved in dichloromethane (80 mL), and titanium chloride (6.73 g, 35.50 mmol) was added. The mixture was stirred at -78 °C for 10 minutes. Ethyl 3-((tert-butyldimethylsilyl)oxy)-2-diazobut-3-enoate 35b (4.00 g, 14.79 mmol) was added to the mixture, and the mixture was stirred at -78 °C for 1 hour. The reaction was monitored by LC-MS. After the reaction was completed, 80 mL of sodium bicarbonate aqueous solution was added to quench the reaction. The mixture was diluted with 80 mL of water and extracted with dichloromethane (40 mL × 2). The combined organic layers were washed with 50 mL of saturated sodium chloride aqueous solution, dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give ethyl 2-diazo-5-hydroxy-5-methyl-3-oxohexanoate 35c (780 mg), yield: 24.61%.

[0902] MS m / z(ESI): 215.0 [M+1].

[0903] Step 3

[0904] ethyl 5,5-dimethyl-3-oxotetrahydrofuran-2-carboxylate

[0905] Ethyl 2-diazo-5-hydroxy-5-methyl-3-oxohexanoate 35c (770.00 mg, 3.59 mmol) was dissolved in toluene (20 mL), and rhodium diacetoxy (7.94 mg, 35.94 μmol) was added. The mixture was stirred at 100 °C for 1 hour. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure to give ethyl 5,5-dimethyl-3-oxotetrahydrofuran-2-carboxylate 35d (650 mg), yield: 97.12%. This ester was used directly in the next step of the reaction without purification.

[0906] MS m / z(ESI): 187.0 [M+1].

[0907] Step 4

[0908] ethyl 3-(4,4-difluoroazacycloheptan-1-yl)-5,5-dimethyltetrahydrofuran-2-carboxylate

[0909] Ethyl 5,5-dimethyl-3-oxo-tetrahydrofuran-2-carboxylate 35d (300 mg, 1.61 mmol) was dissolved in methanol (8 mL) at 0 °C. 4,4-difluoroazacycloheptane (414.74 mg, 2.42 mmol) and sodium cyanoborohydride (303.74 mg, 4.83 mmol) were added, and the mixture was stirred at 25 °C for 12 hours. The reaction was monitored by LC-MS. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was preparatively separated by a C18 reversed-phase column (eluent: system B) to give ethyl 3-(4,4-difluoroazacycloheptane-1-yl)-5,5-dimethyltetrahydrofuran-2-carboxylate 35e (100 mg), yield: 20.33%.

[0910] MS m / z(ESI): 306.2 [M+1].

[0911] Step 5

[0912] (trans-2,3)-3-(4,4-difluoroazacycloheptane-1-yl)-5,5-dimethyltetrahydrofuran-2-carboxylic acid

[0913] Ethyl 3-(4,4-difluoroazacycloheptane-1-yl)-5,5-dimethyltetrahydrofuran-2-carboxylic acid 35e (30 mg, 98.24 μmol) was dissolved in tetrahydrofuran (3 mL), and potassium tert-butoxide (33.07 mg, 294.73 μmol) was added. The mixture was stirred at 25 °C for 72 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure to give (trans-2,3)-3-(4,4-difluoroazacycloheptane-1-yl)-5,5-dimethyltetrahydrofuran-2-carboxylic acid 35f (20 mg), yield: 73.41%. This product was used directly in the next step of the reaction without purification.

[0914] MS m / z(ESI): 278.1 [M+1].

[0915] Step 6

[0916] 4-((trans-2,3)-3-(4,4-difluoroazacycloheptan-1-yl)-5,5-dimethyltetrahydrofuran-2-carboxamido)methyl pyridinecarboxylate

[0917] (trans-2,3)-3-(4,4-difluoroazacycloheptane-1-yl)-5,5-dimethyl-tetrahydrofuran-2-carboxylic acid 35f (50 mg, 180.31 μmol) was dissolved in pyridine (1.5 mL), and methyl 4-aminopyridine-2-carboxylate 2i (41.15 mg, 270.46 μmol) and phosphorus oxychloride (82.94 mg, 540.92 μmol) were added. The mixture was stirred at 25 °C for 1.5 h. The reaction was monitored by LC-MS. After the reaction was completed, water (5 mL) was added to quench the reaction, and the solution was adjusted to pH 9 with saturated sodium bicarbonate. The mixture was then extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was preparatively separated by a C18 reversed-phase column (eluent: system B) to give 35 g (30 mg) of methyl 4-((trans-2,3)-3-(4,4-difluoroazacycloheptane-1-yl)-5,5-dimethyltetrahydrofuran-2-carboxamido)pyridinecarboxylate, yield: 40.44%. MS m / z (ESI): 412.1 [M+1].

[0918] Step 7

[0919] 4-((trans-2,3)-3-(4,4-difluoroazacycloheptan-1-yl)-5,5-dimethyltetrahydrofuran-2-carboxamido)pyridine amide

[0920] 35 g (40 mg, 97.22 μmol) of methyl 4-((trans-2,3)-3-(4,4-difluoroazacycloheptane-1-yl)-5,5-dimethyltetrahydrofuran-2-carboxamido)pyridinecarboxylate was dissolved in 3 mL of ammonia water and stirred at 25 °C for 12 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was preparatively separated by C18 reversed-phase column chromatography (eluent: system B) to give 35 g (30 mg) of 4-((trans-2,3)-3-(4,4-difluoroazacycloheptane-1-yl)-5,5-dimethyltetrahydrofuran-2-carboxamido)pyridine amide, yield: 77.84%.

[0921] MS m / z(ESI): 397.2 [M+1].

[0922] 1H NMR (400MHz, CD3OD) δ8.54-8.47(m,1H),8.34-8.28(m,1H),7.95-7.89(m,1H),4.41-4.34(m,1H),3.92-3.78(m,1H),2.89 -2.82(m,2H),2.81-2.75(m,2H),2.22-2.05(m,5H),1.91-1.83(m,1H),1.81-1.74(m,2H),1.40(s,3H),1.31-1.25(m,3H).

[0923] Example 36

[0924] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3H-imidazo[4,5-c]pyridine-4-carboxamide

[0925]

[0926] first step

[0927] Methyl 3,4-diaminopyridinecarboxylate

[0928] 2-Bromopyridine-3,4-diamine 36a (200 mg, 1.06 mmol) was dissolved in a mixture of methanol and N,N-dimethylformamide (methanol:N,N-dimethylformamide = 1:1) in 4 mL. Tetraphenylphosphine palladium (122.92 mg, 106.37 μmol) and triethylamine (538.17 mg, 5.32 mmol) were added, and the mixture was stirred at 80 °C for 16 hours under a carbon monoxide (50 psi) atmosphere. LC-MS showed the reaction was complete. The mixture was concentrated under reduced pressure and poured into water (50 mL). Extraction was performed with ethyl acetate (40 mL × 3). The combined organic layers were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was preparatively separated by a C18 reversed-phase column (eluent: system B) to give methyl 3,4-diaminopyridinecarboxylate 36b (50 mg), yield: 28.12%. MS m / z(ESI): 168.0 [M+1].

[0929] Step 2

[0930] 3-Amino-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)methyl pyridinecarboxylate

[0931] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a (50 mg, 141.14 μmol) and methyl 3,4-diaminopyridinecarboxylate 36b (23.59 mg, 141.14 μmol) were dissolved in N,N-dimethylformamide (0.2 mL), and N,N-diisopropylethylamine (127.69 mg, 987.95 μmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphate (80.50 mg, 211.70 μmol) were added. The mixture was stirred at 25 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography (eluent: system A) to give methyl 3-amino-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxylate 36c (20 mg), yield: 28.15%.

[0932] MS m / z(ESI): 504.1 [M+1].

[0933] Step 3

[0934] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3H-imidazo[4,5-c]pyridine-4-carboxylic acid methyl ester

[0935] Methyl 3-amino-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxylate 36c (20 mg, 39.73 μmol) was dissolved in acetic acid (0.5 mL) and stirred at 80 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3H-imidazo[4,5-c]pyridine-4-carboxylate 36d (15 mg), yield: 77.78%. It was used directly in the next step of the reaction without purification.

[0936] MS m / z(ESI): 486.0 [M+1].

[0937] Step 4

[0938] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3H-imidazo[4,5-c]pyridine-4-carboxamide

[0939] 36d (15 mg, 30.90 μmol) of methyl 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3H-imidazo[4,5-c]pyridine-4-carboxylate was dissolved in ammonia-methanol solution (0.5 mL) and stirred at 25 °C for 16 hours. The reaction was monitored by LC-MS. The residue was concentrated under reduced pressure and then separated by a C18 reversed-phase column (eluent: system B) to give 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3H-imidazo[4,5-c]pyridine-4-carboxamide 36 (8.56 mg), yield: 58.89%.

[0940] MS m / z(ESI): 471.1 [M+1].

[0941] 1 H NMR (400MHz, DMSO-d6) δ13.42-12.95(m,1H),8.35(d,J=5.2Hz,1H),8.29(s,1H),7.86(s,1H),7.16-7.05(m,2H),5. 98(d,J=11.2Hz,1H),4.71(s,1H),3.96(d,J=2.1Hz,3H),2.91(t,J=7.7Hz,1H),1.65(s,3H),0.79(d,J=6.4Hz,2H).

[0942] Example 37

[0943] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthidium-4-ol

[0944]

[0945] first step

[0946] 1-(4-amino-3-pyridyl)acetone

[0947] 1-(4-amino-6-chloro-3-pyridyl)acetone 26d (300 mg, 1.76 mmol) was dissolved in N,N-dimethylformamide (5 mL), and triethylamine (889.73 mg, 8.79 mmol), formic acid (404.73 mg, 8.79 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (128.67 mg, 175.85 μmol) were added. The mixture was stirred at 80 °C for 16 hours. TLC showed that the reaction was complete. The reaction was quenched by adding saturated ammonium chloride solution at 0 °C, and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give 1-(4-amino-3-pyridyl)acetone 37a (150 mg), yield: 62.65%.

[0948] Step 2

[0949] (2R,3S,4S,5R)-N-(3-acetylpyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0950] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a (30 mg, 84.68 μmol) and 1-(4-amino-3-pyridyl)acetone 37a (13.84 mg, 101.62 μmol) were dissolved in dichloromethane (1 mL), and pyridine (33.49 mg, 423.41 μmol) and phosphorus oxychloride (25.97 mg, 169.36 μmol) were added at 0 °C, and the mixture was stirred at 25 °C for 1 hour. LC-MS showed that the reaction was complete. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (2R,3S,4S,5R)-N-(3-acetylpyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 37b (30 mg), yield: 74.99%. It was used directly in the next step without purification.

[0951] MS m / z(ESI): 473.1 [M+1].

[0952] Step 3

[0953] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthidium-4-ol

[0954] (2R,3S,4S,5R)-N-(3-acetylpyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 37b (30 mg, 63.50 μmol) was dissolved in toluene (1 mL), and sodium hydroxide (10.16 mg, 254.02 μmol) was added. The mixture was stirred at 110 °C for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was filtered and concentrated under reduced pressure. The residue was separated by preparative separation using a C18 reversed-phase column (eluent: system B) to give 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthidium-4-ol 37 (11.97 mg), yield: 41.48%.

[0955] MS m / z(ESI): 455.1 [M+1].

[0956] 1 H NMR (400MHz, DMSO-d6) δ12.00(s,1H),9.24(s,1H),8.66(d,J=6.3Hz,1H),7.86(d,J=6.4Hz,1H),7.32-7.24(m,1H),7.21-7.12(m,1H),6.51( s,1H),5.53(d,J=11.3Hz,1H),4.29(dd,J=8.3,11.1Hz,1H),3.92(d,J=2.3Hz,3H),2.89(t,J=7.9Hz,1H),1.72(s,3H),0.79(d,J=6.7Hz,3H).

[0957] Example 38

[0958] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,5-naphthidium-4-ol

[0959]

[0960] first step

[0961] 1-(3-amino-pyridin-2-yl)ethyl ketone

[0962] 1-(3-amino-6-chloropyridin-2-yl)acetone 18b (10.00 mg, 58.62 μmol) was dissolved in N,N-dimethylformamide (0.5 mL), and triethylamine (29.66 mg, 293.09 μmol), formic acid (13.49 mg, 293.09 μmol) and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (4.29 mg, 5.86 μmol) were added. The mixture was stirred at 80 °C for 16 hours under nitrogen protection. The reaction was monitored by TLC until completion, then poured into water (20 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give 1-(3-amino-pyridin-2-yl)acetone 38a (5 mg), yield: 62.65%.

[0963] MS m / z(ESI): 137.0 [M+1].

[0964] Step 2

[0965] (2R,3S,4S,5R)-N-(2-acetylpyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0966] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a (10 mg, 28.23 μmol) and 1-(3-amino-pyridin-2-yl)acetone 38a (4.61 mg, 33.87 μmol) were dissolved in dichloromethane (0.5 mL), and pyridine (11.16 mg, 141.14 μmol) and phosphorus oxychloride (8.66 mg, 56.45 μmol) were added at 0 °C, and the mixture was stirred at 25 °C for 1 hour. LC-MS showed the reaction was complete. The solution was poured into water (20 mL), extracted with dichloromethane (20 mL × 3), and the combined organic layers were dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give (2R,3S,4S,5R)-N-(2-acetylpyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 38b (10 mg), yield: 74.99%.

[0967] MS m / z(ESI): 473.0 [M+1].

[0968] Step 3

[0969] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,5-naphthidium-4-ol

[0970] (2R,3S,4S,5R)-N-(2-acetylpyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 38b (10 mg, 21.17 μmol) was dissolved in toluene (0.5 mL), and sodium hydroxide (3.39 mg, 84.67 μmol) was added. The mixture was stirred at 110 °C for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was filtered and concentrated under reduced pressure. The residue was separated by preparative separation using a C18 reversed-phase column (eluent: system B) to give 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,5-naphthidium-4-ol 38 (4.38 mg), yield: 45.54%.

[0971] MS m / z(ESI): 455.1 [M+1].

[0972] 1 H NMR (400MHz, CD3OD) δ8.84(s,1H),8.57(d,J=8.7Hz,1H),8.01-7.89(m,1H),7.27-7.20(m,1H),7.06-6.98(m,1H),6.63(s,1H),5.65( d,J=11.2Hz,1H),4.29(dd,J=8.8,11.0Hz,1H),3.94(d,J=2.3Hz,3H),2.90(t,J=7.8Hz,1H),1.75(s,3H),0.92(dd,J=2.3,4.9Hz,3H).

[0973] Example 39

[0974] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthidine-4,5-diol

[0975]

[0976]

[0977] first step

[0978] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthidine-4,5-diol

[0979] 5-Chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthid-4-ol 11 (30 mg, 0.06 mmol), acetohydroxylamine (13.8 mg, 0.18 mmol), and potassium carbonate (25.4 mg, 0.18 mmol) were dissolved in dimethyl sulfoxide (0.5 mL) and stirred at 100 °C for 12 hours. The reaction was monitored by LC-MS until completion, filtered, and separated by C18 reversed-phase column (eluent: system B) to give 39 (5.38 mg) of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthidium-4,5-diol, yield: 17.77%.

[0980] MS m / z(ESI): 471.1 [M+1]

[0981] 1 H NMR(400MHz,DMSO-d6)δppm 11.87-12.39(m,1H),7.48(d,J=7.6Hz,1H),7.24-7.34(m,1H),7.08-7.15(m,1H),7.07(s,1H),6.60(d,J=7.2Hz,1H),5 .55(d,J=10.8Hz,1H),4.29-4.34(m,2H),3.88(d,J=2.0Hz,3H),2.75-2.88(m,1H),1.67(s,3H),0.79(d,J=6.4Hz,3H).

[0982] Example 40

[0983] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoroquinoline-4-ol

[0984]

[0985]

[0986] first step

[0987] (2R,3S,4S,5R)-N-(2-acetyl-3-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0988] 1-(2-amino-6-fluorophenyl)acetone 40a (45 mg, 293.82 μmol) and (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a (104.09 mg, 293.82 μmol) were dissolved in dichloromethane (2 mL), and phosphorus oxychloride (135.16 mg, 881.47 μmol) and pyridine (69.72 mg, 881.47 μmol) were added. The mixture was stirred at 20 °C for 1 hour. The reaction was monitored by LC-MS until completion, and the solution was poured into water (20 mL) and extracted with dichloromethane (20 mL × 3). The sample was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (2R,3S,4S,5R)-N-(2-acetyl-3-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 40b (100 mg, 204.33 μmol), yield: 69.54%. It was used directly in the next reaction without purification.

[0989] MS m / z(ESI): 490.1 [M+1]

[0990] Step 2

[0991] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoroquinoline-4-ol

[0992] (2R,3S,4S,5R)-N-(2-acetyl-3-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 40b (100 mg, 204.33 μmol) was dissolved in toluene (1 mL), and sodium hydroxide (32.69 mg, 817.32 μmol) was added. The mixture was stirred at 110 °C for 2 hours. The reaction was monitored by LC-MS until completion. The reaction was quenched by adding 5 mL of hydrochloric acid aqueous solution at 0 °C. The mixture was extracted with dichloromethane (5 mL × 3). The combined organic layers were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was preparatively separated by C18 reversed-phase column chromatography (eluent: system B) to give compound 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoroquinololin-4-ol 1 (42.56 mg, 90.29 μmol), yield: 44.19%.

[0993] MS m / z(ESI): 472.1 [M+1]

[0994] 1 H NMR (400MHz, CD3OD) δ7.82-7.58(m,2H),7.25-7.06(m,2H),7.04-6.89(m,1H),6.37(s,1H),5.56(d,J=11.2Hz, 1H), 4.27 (dd, J=8.6, 11.1Hz, 1H), 3.93 (d, J=2.5Hz, 3H), 2.87 (t, J=7.9Hz, 1H), 1.71 (s, 3H), 0.97-0.80 (m, 3H).

[0995] Example 41

[0996] 2-((3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridin-4-ol

[0997]

[0998] first step

[0999] 4-(benzyloxy)-2-chloro-6-methylpyridine

[1000] Sodium hydroxide (127 mg, 3.19 mmol) was dissolved in tetrahydrofuran (3 mL). Benzyl alcohol (313 mg, 2.90 mmol) was added at 0 °C, and the mixture was stirred for 0.5 hours. Then, 2-chloro-6-methyl-4-nitropyridine 41a (0.5 g, 2.90 mmol) was added, and the mixture was stirred at 25 °C for 2 hours. The reaction was monitored by LCMS until completion. The reaction was quenched with water (5 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system A) to give 4-(benzyloxy)-2-chloro-6-methylpyridine 41b (0.5 g), yield: 64.65%.

[1001] MS m / z(ESI): 234.1 [M+1]

[1002] Step 2

[1003] 4-(benzyloxy)-2-((3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridine

[1004] 4,4-Di-tert-butyl-2,2-dipyridine (17.2 mg, 0.06 mmol) and the nickel dichloride dimethoxyethane adduct (9.40 mg, 0.04 mmol) were dissolved in dimethyl sulfoxide (1 mL) and stirred at 25 °C for 0.5 hours. Then, 4-(benzyloxy)-2-chloro-6-methylpyridine 41b (0.1 g, 0.43 mmol) and (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2 1-Formic acid 1a (136 mg, 0.39 mmol), 2-tert-butyl-1,1,3,3-tetramethylguanidine (73.3 mg, 0.43 mmol), bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl]phenyl]iridium; 4-tert-butyl-2-(4-tert-butyl-2-pyridinyl)pyridine; hexafluorophosphate (9.60 mg, 0.01 mmol), phthalimide (63.0 mg, 0.43 mmol), under nitrogen protection, stirred at 25 °C for 16 hours using a photoreactor. The reaction was monitored by LCMS. After the reaction was complete, the mixture was filtered, concentrated under reduced pressure, and the residue was preparatively separated by a C18 reversed-phase column (eluent: system B) to give 4-(benzyloxy)-2-((3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridine 41c (40 mg), yield: 18.42%. MS m / z (ESI): 508.2 [M+1]

[1005] Step 3

[1006] 2-((3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridin-4-ol

[1007] 4-(benzyloxy)-2-((3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridine 41c (0.02 g, 0.04 mmol) and wet palladium on carbon (21.0 mg, 0.02 mmol) were dissolved in methanol (5 mL). The mixture was stirred at 25 °C for 4 hours, and the reaction was monitored by LCMS. After the reaction was completed, the mixture was filtered and separated by C18 reversed-phase column chromatography (eluent: system B) to give 2-((3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methylpyridine-4-ol 41 (7.7 mg), yield: 46.47%.

[1008] MS m / z(ESI): 418.2 [M+1]

[1009] 1 H NMR(400MHz,DMSO-d6)δppm 7.04-7.24(m,3H),6.88(d,J=2.0Hz,1H),5.59(dt,J=11.2,1.2Hz,1H),4.26-4.31(m,1H),3.9 2(d,J=2.0Hz,3H),2.85(quin,J=7.6Hz,1H),2.51(s,3H),1.66(s,3H),0.76(d,J=6.4Hz,3H).

[1010] Example 42

[1011] 7-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-hydroxy-1,8-naphthidine-2-carboxamide

[1012]

[1013] first step

[1014] 7-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-hydroxy-1,8-naphthidine-2-carboxamide

[1015] 7-Chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,8-naphthid-4-ol 23 (15 mg, 30.69 μmol) was dissolved in 1-methylpyrrolidone (1 mL) solution, and zinc cyanide (10.81 mg, 92.06 μmol), zinc (401.30 μg, 6.14 μmol) and 1,1-bis(tert-butylphosphine)ferrocene palladium chloride (2.00 mg, 3.07 μmol) were added. The mixture was stirred at 120 °C for 12 hours under nitrogen protection. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was then separated and purified by HPLC (eluent: system B) to give 7-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-hydroxy-1,8-naphthidine-2-carboxamide 42 (5 mg), yield: 32.76%.

[1016] MS m / z(ESI): 498.0 [M+1].

[1017] 1 H NMR (400MHz, CD3OD) δ8.71(d,J=8.2Hz,1H),8.13(d,J=8.2Hz,1H),7.26-7.19(m,1H),7.06-6.98(m,1H),6.38(s,1H),5.56( d,J=11.2Hz,1H),4.33(dd,J=8.5,11.3Hz,1H),3.95(d,J=2.5Hz,3H),2.92(t,J=7.9Hz,1H),1.76(s,3H),0.98-0.86(m,3H).

[1018] Example 43

[1019] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-7-(dimethylamino)-1,8-naphthidine-4-ol

[1020]

[1021] first step

[1022] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-7-(dimethylamino)-1,8-naphthidine-4-ol

[1023] 7-Chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,8-naphthid-4-ol 23 (50 mg, 102.28 μmol) was dissolved in N,N-dimethylacetamide (2 mL), and zinc cyanide (24.02 mg, 204.57 μmol), zinc (1.34 mg, 20.46 μmol), and 1,1-bis(tert-butylphosphine)ferrocene palladium chloride (6.67 mg, 10.23 μmol) were added. The mixture was stirred at 120 °C for 12 hours under nitrogen protection. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was then separated and purified by HPLC (eluent: system B) to give 43 (3 mg) of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-7-(dimethylamino)-1,8-naphthidium-4-ol, yield: 5.90%.

[1024] MS m / z(ESI): 498.2 [M+1].

[1025] 1 H NMR (400MHz, CD3OD) δ8.14(d,J=9.2Hz,1H),7.21-7.12(m,1H),7.06-6.95(m,1H),6.81(d,J=9.2Hz,1H),6.16(s,1H),5.44(d,J=11 .2Hz,1H),4.25(dd,J=8.4,11.1Hz,1H),3.93(d,J=2.4Hz,3H),3.23(s,6H),2.87(t,J=7.9Hz,1H),1.73(s,3H),0.95-0.81(m,3H).

[1026] Example 44

[1027] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,8-naphthidium-4-ol

[1028]

[1029] first step

[1030] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,8-naphthidium-4-ol

[1031] 7-Chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,8-naphthid-4-ol 23 (30.00 mg, 61.37 μmol) was dissolved in N,N-dimethylformamide (1 mL), and triethylamine (31.05 mg, 306.85 μmol), dichloro[1,1-bis(diphenylphosphine)ferrocene]palladium(II)dichloromethane adduct (4.49 mg, 6.14 μmol) and formic acid (0.05 mL) were added. The mixture was stirred at 110 °C for 12 hours under nitrogen protection. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was then separated by HPLC (eluent: system B) to give 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,8-naphthidium-4-ol 44 (10 mg), yield: 35.86%.

[1032] MS m / z(ESI): 455.0 [M+1].

[1033] 1 H NMR (400MHz, CDCl3) δ10.17-9.68(m,1H),8.73-8.63(m,2H),7.44-7.33(m,1H),7.06-6.88(m,2H),6.17-6.06(m,1H), 5.52-5.40(m,1H),4.18-4.09(m,1H),3.93(d,J=2.7Hz,3H),2.86-2.72(m,1H),1.82-1.67(m,3H),0.90-0.81(m,3H).

[1034] Example 45

[1035] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-6-methyl-1,6-naphthidium-5(6H)-one

[1036]

[1037] first step

[1038] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-6-methyl-1,6-naphthidium-5(6H)-one

[1039] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthidine-4,5-diol 39 (3 mg, 6.38 μmol) was dissolved in dimethyl sulfoxide (0.5 mL), and cesium carbonate (6.24 mg, 19.2 μmol) and methyl iodoform (2.72 mg, 19.2 μmol) were added. The mixture was stirred at 25 °C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was filtered and purified by C18 reversed-phase column chromatography (eluent: system B) to give 45 (2.59 mg) of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-6-methyl-1,6-naphthidium-5(6H)-one, yield: 83.82%.

[1040] MS m / z (ESI): 485.1 [M+1]

[1041] 1 H NMR (400MHz, CD3OD) δ7.70(d,J=7.6Hz,1H),7.16-7.27(m,1H),6.91-7.02(m,2H),6.77(d,J=7.6Hz,1H),5.54(d,J=1 0.8Hz,1H),4.19-4.32(m,1H),3.92(d,J=2.4Hz,3H),3.59(s,3H),2.79-2.96(m,1H),1.72(s,3H),0.87-0.91(m,3H).

[1042] Example 46

[1043] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-(3-hydroxyazacyclobutane-1-yl)-1,6-naphthidium-4-ol

[1044]

[1045] first step

[1046] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-(3-hydroxyazacyclobutane-1-yl)-1,6-naphthidium-4-ol

[1047] Under nitrogen protection, 5-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthid-4-ol 11 (20 mg, 40.91 μmol) and azacyclic butanol hydrochloride 46a (6.72 mg, 61.37 μmol) were dissolved in 1,4-dioxane (2 mL). Bis(tri-tert-butylphosphine)palladium (2.09 mg, 4.09 μmol) and sodium tert-butoxide (19.66 mg, 204.57 μmol) were added. The mixture was stirred at 110 °C for 3 hours, and the reaction was monitored by LC-MS. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was analyzed by C1... 18 Preparative separation by reversed-phase column chromatography (eluent: system B) yielded 46 (7.1 mg) of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-(3-hydroxyazacyclobutan-1-yl)-1,6-naphthidium-4-ol, yield: 33.03%.

[1048] MS m / z(ESI): 526.1 [M+1].

[1049] 1 H NMR (400MHz, CD3OD) δ7.78-7.76(m,1H),7.16-7.03(m,1H),7.02-6.99(m,2H),6.41(s,1H),5.50(d,J=11.2Hz,1H),4. 50-4.30(m,1H),4.29-4.25(m,3H),4.00(s,3H),3.67-3.63(m,2H),2.92-2.88(m,1H),1.72(s,3H),0.91-0.89(m,3H).

[1050] Example 47

[1051] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-(trifluoromethyl)quinoline-4-ol

[1052]

[1053] first step

[1054] 1-(2-((4-methoxybenzyl)amino)-6-(trifluoromethyl)phenyl)ethyl ketone

[1055] (4-Methoxyphenyl)methylamine (499.11 mg, 3.64 mmol) was dissolved in 1-methylpyrrolidone-2-one (5 mL), and cesium fluoride (552.68 mg, 3.64 mmol) and 1-(2-fluoro-6-(trifluoromethyl)phenyl)ethyl ketone 47a (250 mg, 1.21 mmol) were added. The mixture was stirred at 150 °C for 2 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with saturated sodium chloride aqueous solution (20 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 1-(2-((4-methoxybenzyl)amino)-6-(trifluoromethyl)phenyl)ethyl ketone 47b (80 mg), yield: 20.40%.

[1056] MS m / z(ESI): 324.0 [M+1].

[1057] Step 2

[1058] 1-(2-amino-6-(trifluoromethyl)phenyl)ethyl ketone

[1059] 1-(2-((4-methoxybenzyl)amino)-6-(trifluoromethyl)phenyl)ethyl ketone 47b (80 mg, 247.44 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at 25 °C for 12 hours, and the reaction was monitored by LCMS. The mixture was concentrated under reduced pressure to obtain 1-(2-amino-6-(trifluoromethyl)phenyl)ethyl ketone 47c (30 mg), yield: 59.68%. This product was not purified and was directly used in the next step of the reaction.

[1060] MS m / z(ESI): 204.0 [M+1].

[1061] Step 3

[1062] (2R,3S,4S,5R)-N-(2-acetyl-3-(trifluoromethyl)phenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[1063] 1-(2-amino-6-(trifluoromethyl)phenyl)ethyl ketone 47c (30 mg, 147.67 μmol) was dissolved in pyridine (1.5 mL), and (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a (50 mg, 141.14 μmol) was added. Then phosphorus oxychloride (64.92 mg, 423.41 μmol) was added, and the mixture was stirred at 25 °C for 1.5 hours. The reaction was monitored by LCMS. After the reaction was completed, water (5 mL) was added and the pH was adjusted to 9 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (2R,3S,4S,5R)-N-(2-acetyl-3-(trifluoromethyl)phenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 47d (10 mg), yield: 13.14%. This product was used directly for the next reaction without purification.

[1064] MS m / z(ESI): 540.1 [M+1].

[1065] Step 4

[1066] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-(trifluoromethyl)quinoline-4-ol

[1067] (2R,3S,4S,5R)-N-(2-acetyl-3-(trifluoromethyl)phenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 47d (10 mg, 18.54 μmol) was dissolved in toluene (1 mL), and sodium hydroxide (3.71 mg, 92.69 μmol) was added. The mixture was stirred at 110 °C under nitrogen protection. The reaction was monitored by LCMS for 1.5 hours, concentrated under reduced pressure, and the residue was preparatively separated by C18 reversed-phase column chromatography (eluent: system B) to give 47 (4.99 mg) of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-(trifluoromethyl)quinoline-4-ol, yield: 51.62%.

[1068] MS m / z(ESI): 522.1 [M+1].

[1069] 1H NMR (400MHz, CDCl3) δ7.92-7.79(m,2H),7.74-7.65(m,1H),7.09-6.99(m,1H),6.90-6.77(m,1H),6.58-6.47(m,1H),5.64 -5.48(m,1H),4.96-4.77(m,1H),4.15-4.04(m,1H),3.95-3.86(m,3H),2.84-2.70(m,1H),1.71(s,3H),0.91-0.79(m,3H).

[1070] Example 48

[1071] 4-((2R,3S,3aS,6aR)-3a-(3,4-difluoro-2-hydroxyphenyl)-2,3-dimethyl-6-oxo-2-(trifluoromethyl)hexahydro-5H-furano[2,3-c]pyrrolo-5-yl)pyridineamide

[1072]

[1073] first step

[1074] (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one

[1075] (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one 16a (1 g, 3.10 mmol) was dissolved in a mixed solution of tetrahydrofuran (4 mL) and methanol (20 mL), and sodium borohydride (1.76 g, 46.55 mmol) and nickel dichloride hexahydrate (1.48 g, 6.21 mmol) were added. The mixture was stirred at -40 °C for 1 hour. The reaction was monitored by LCMS. After the reaction was completed, the reaction was quenched with ammonium chloride solution (40 mL), extracted with dichloromethane (80 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one 48a (660 mg), yield: 65.59%. It was carried out directly in the next step of the reaction without purification.

[1076] MS m / z(ESI): 325.0 [M+1]

[1077] Step 2

[1078] (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-3-(hydroxymethyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one

[1079] (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one 48a (0.8 g, 2.47 mmol) and paraformaldehyde (1.13 g, 12.58 mmol) were dissolved in N,N-dimethylformamide (3 mL), and sodium ethoxide (251.85 mg, 3.70 mmol) was added. The mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was quenched with ammonium chloride solution (20 mL), extracted with ethyl acetate (20 mL × 3), the organic layer was separated, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution: system A) to give (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-3-(hydroxymethyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one 48b (0.5 g), yield: 57.20%.

[1080] MS m / z(ESI): 355.0 [M+1]

[1081] Step 3

[1082] (3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one

[1083] At -40°C, (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-3-(hydroxymethyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one 48b (0.5 g, 1.41 mmol) was dissolved in dichloromethane (6 mL), and boron tribromide (1.06 g, 4.23 mmol) was added dropwise. The mixture was stirred at 25°C for 16 hours. The reaction was monitored by LCMS. The pH of the solution was adjusted to 4 with sodium bicarbonate, and the mixture was extracted with dichloromethane (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give (3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one 48c (0.48 g), yield: 99.96%. The mixture was carried out directly in the next step without purification.

[1084] MS m / z(ESI): 341.0 [M+1]

[1085] Step 4

[1086] (3S,4'S,5'R)-6,7-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2H,2'H-spiro[benzofuran-3,3'-furan]-2'-one

[1087] (3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one 48c (550 mg, 1.62 mmol) was dissolved in tetrahydrofuran (20 mL), and diisopropyl diazonium-1,2-dicarboxylate (424.93 mg, 2.10 mmol) and triphenylphosphine (551.19 mg, 2.10 mmol) were added. The mixture was stirred at 50 °C for 16 hours. The reaction was monitored by TLC, and the reaction was quenched at 0 °C with ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with saturated sodium chloride solution (10 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was preparatively separated by thin-layer chromatography (eluent: system A) to give (3S,4'S,5'R)-6,7-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2H,2'H-spiro[benzofuran-3,3'-furan]-2'-one 48d (350 mg), yield: 67.19%.

[1088] 1 H NMR(400MHz,CD3OD)δ6.90-6.93(m,1H),6.81-6.89(m,1H),4.98-5.01(m,1H) ,4.75-4.78(m,1H),2.97-3.05(m,1H),1.73-1.76(m,3H),1.02-1.07(m,3H).

[1089] Step 5

[1090] ((3S,4'S,5'R)-6,7-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2H,2'H-spiro[benzofuran-3,3'-furan]-2'-ol)

[1091] (3S,4'S,5'R)-6,7-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2H,2'H-spiro[benzofuran-3,3'-furan]-2'-one 48d (350 mg, 1.09 mmol) was dissolved in toluene (6 mL), and diisobutylaluminum hydride (615.42 mg, 4.33 mmol) was added dropwise. The mixture was stirred at -78 °C for 2 hours. The reaction was monitored by LCMS. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phase was separated, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (3S,4'S,5'R)-6,7-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2H,2'H-spiro[benzofuran-3,3'-furan]-2'-ol 48e (350 mg), yield: 99.38%. This was carried out directly in the next reaction without purification.

[1092] MS m / z (ESI): 307.1 [M-17]

[1093] Step 6

[1094] (3S,4'S,5'R)-6,7-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2H,2'H-spiro[benzofuran-3,3'-furan]-2'-ylacetate

[1095] (3S,4'S,5'R)-6,7-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2H,2'H-spiro[benzofuran-3,3'-furan]-2'-ol 48e (300 mg, 925.23 μmol) was dissolved in toluene (3 mL), and acetic anhydride (113.35 mg, 1.11 mmol), triethylamine (102.99 mg, 1.02 mmol), and N,N-dimethylpyridin-4-amine (11.30 mg, 92.52 μmol) were added. The mixture was stirred at 0 °C for 2 hours. The reaction was monitored by TLC, and the reaction was quenched by adding ammonium chloride (10 mL) at 0 °C. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (3S,4'S,5'R)-6,7-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2H,2'H-spiro[benzofuran-3,3'-furan]-2'-yl acetate 48f (330 mg), yield: 97.38%. This was carried out directly in the next reaction without purification.

[1096] 1H NMR(400MHz,CD3OD)δ7.04(dddd,J=1.6,3.2,4.9,6.7Hz,1H),6.77-6.85(m,1H),6.34-6.39(m,1H),4.75-4 .80(m,1H),4.64-4.69(m,1H),2.88-2.97(m,1H),2.12-2.16(m,3H),1.61-1.66(m,3H),0.94-1.02(m,3H).

[1097] Step 7

[1098] (2'R,3S,4'S,5'R)-6,7-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2H,2'H-spiro[benzofuran-3,3'-furan]-2'-nitrile

[1099] A 1 mL solution of trimethylsilyl nitrile (189.60 mg, 1.91 mmol) and boron trifluoride diethyl ether (336.95 mg, 1.09 mmol) in dichloromethane was added to a 1 mL solution of (3S,4'S,5'R)-6,7-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2H,2'H-spiro[benzofuran-3,3'-furan]-2'-yl acetate 48f (200 mg, 546.03 μmol) in dichloromethane. The mixture was stirred at -78 °C for 3 hours and then allowed to react at room temperature. The reaction was monitored by TLC. Water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 2). The organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 48 g (180 mg) of (2'R,3S,4'S,5'R)-6,7-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2H,2'H-spiro[benzofuran-3,3'-furan]-2'-nitrile, yield: 98.92%. The mixture was not purified and proceeded directly to the next step of the reaction.

[1100] 1 H NMR(400MHz,CD3OD)δ7.08-7.12(m,1H),6.93-6.99(m,1H),5.05-5.07(m,1H),4.63-4.6 5(m,1H),4.57-4.59(m,1H),2.55-2.63(m,1H),1.43-1.45(m,3H),0.94(d,J=1.8Hz,3H)

[1101] Step 8

[1102] (2'R,3S,4'S,5'R)-6,7-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2H,2'H-spiro[benzofuran-3,3'-furan]-2'-formamide

[1103] 48 g (160 mg, 480.12 μmol) of (2'R,3S,4'S,5'R)-6,7-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2H,2'H-spiro[benzofuran-3,3'-furan]-2'-nitrile was dissolved in dimethyl sulfoxide (2 mL), and potassium carbonate (331.78 mg, 2.40 mmol) and hydrogen peroxide (544.37 mg, 4.80 mmol) were added. The mixture was stirred at 20 °C for 1 hour, and the reaction was monitored by LC-MS. Add water (10 mL), extract with ethyl acetate (10 mL × 2), separate the organic phase, wash with saturated sodium chloride solution (10 mL), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure to give (2'R,3S,4'S,5'R)-6,7-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2H,2'H-spiro[benzofuran-3,3'-furan]-2'-carboxamide 48h (160 mg), yield: 94.87%. Proceed directly to the next step without purification.

[1104] MS m / z(ESI): 352.1 [M+1]

[1105] Step 9

[1106] 4-((2R,3S,3aS,6aR)-3a-(3,4-difluoro-2-hydroxyphenyl)-2,3-dimethyl-6-oxo-2-(trifluoromethyl)hexahydro-5H-furano[2,3-c]pyrrolo-5-yl)methyl pyridinecarboxylate

[1107] (2'R,3S,4'S,5'R)-6,7-difluoro-4',5'-dimethyl-5'-(trifluoromethyl)-4',5'-dihydro-2H,2'H-spiro[benzofuran-3,3'-furan]-2'-carboxamide 48h (100mg, 284.68μmol) was dissolved in dioxane (2mL), and cesium carbonate (278.27mg, 854.05μmol), methyl 4-bromopyridine-2-carboxylate 16j (73.80mg, 341.62μmol) and methanesulfonic acid (9,9-dimethyl-4,5-bis(diphenylphosphinethracene)(2-amino-1,1-biphenyl-2-yl)palladium(II) (27) were added. 0.00 mg (28.47 μmol) was stirred at 100 °C for 1 hour. The reaction was monitored by LCMS. After the reaction was completed, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 48 i (80 mg) of methyl 4-((2R,3S,3aS,6aR)-3a-(3,4-difluoro-2-hydroxyphenyl)-2,3-dimethyl-6-oxo-2-(trifluoromethyl)hexahydro-5H-furano[2,3-c]pyrrole-5-yl)pyridinecarboxylate, yield: 57.78%. The product was used directly for the next reaction without purification.

[1108] MS m / z(ESI): 487.1 [M+1]

[1109] Step 10

[1110] 4-((2R,3S,3aS,6aR)-3a-(3,4-difluoro-2-hydroxyphenyl)-2,3-dimethyl-6-oxo-2-(trifluoromethyl)hexahydro-5H-furano[2,3-c]pyrrolo-5-yl)pyridineamide

[1111] 4-((2R,3S,3aS,6aR)-3a-(3,4-difluoro-2-hydroxyphenyl)-2,3-dimethyl-6-oxo-2-(trifluoromethyl)hexahydro-5H-furano[2,3-c]pyrrolo-5-yl)methyl pyridinecarboxylate 48i (40 mg, 82.24 μmol) was dissolved in ammonia water (5.00 mL) and stirred at 20 °C for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was then separated by C18 reversed-phase column chromatography (eluent: system B) to give 4-((2R,3S,3aS,6aR)-3a-(3,4-difluoro-2-hydroxyphenyl)-2,3-dimethyl-6-oxo-2-(trifluoromethyl)hexahydro-5H-furano[2,3-c]pyrrolo-5-yl)pyridineamide 48 (3.88 mg), yield: 10.01%.

[1112] MS m / z(ESI): 472.1 [M+1]

[1113] 1 H NMR (400MHz, CD3OD) δ8.62(d,J=5.6Hz,1H),8.40(d,J=2.0Hz,1H),8.15(dd,J=2.1,5.7Hz,1H),7.05(s,1H),6.73-6.80(m, 1H), 5.24 (s, 1H), 4.72 (d, J = 10.8Hz, 1H), 4.14 (d, J = 11.0Hz, 1H), 2.76 (d, J = 7.3Hz, 1H), 1.47 (s, 3H), 1.17 (d, J = 6.3Hz, 3H).

[1114] Example 49

[1115] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-5-carboxylic acid

[1116]

[1117] first step

[1118] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-5-carboxylic acid methyl ester

[1119] 5-Chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthid-4-ol 11 (50 mg, 102.28 μmol) was dissolved in methanol (2 mL), and bis(diphenylphosphine)ferrocene]palladium(ii) dichloride (14.97 mg, 20.46 μmol) and triethylamine (51.75 mg, 511.42 μmol) were added. The mixture was stirred at 60 °C for 16 hours under a hydrogen atmosphere (15 psi), and the reaction was monitored by LCMS to indicate completion. The product was concentrated under reduced pressure to give methyl 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-5-carboxylic acid 49a (50 mg), yield: 95.40%. It was used directly in the next reaction without purification.

[1120] MS m / z(ESI): 513.0 [M+1].

[1121] Step 2

[1122] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-5-carboxylic acid

[1123] Methyl 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthyl-5-carboxylate 49a (30 mg, 58.55 μmol) was dissolved in a mixture of tetrahydrofuran (1 mL), water (0.3 mL), and methanol (0.3 mL), and sodium hydroxide (70.25 mg, 1.76 mmol) was added. The reaction mixture was stirred at 25 °C for 48 hours, and the reaction was monitored by LCMS to indicate completion. The solution was adjusted to pH 4 with 1M hydrochloric acid, concentrated under reduced pressure, and the residue was preparatively separated by a C18 reversed-phase column (eluent: system B) to give 49 (12 mg) of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-5-carboxylic acid, yield: 41.13%.

[1124] MS m / z(ESI): 499.0 [M+1].

[1125] 1 H NMR (400MHz, CD3OD) δ8.55(d,J=6.0Hz,1H),7.79(d,J=6.0Hz,1H),7.17-7.16(m,1H),7.04-6.99(m,1H),6.34(s ,1H),5.52(d,J=11.2Hz,1H),4.28-4.23(m,1H),3.94(s,3H),2.92-2.86(m,1H),1.73(s,3H),0.91-0.88(m,3H).

[1126] Example 50

[1127] 1-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthid-5-yl)ethane-1,2-diol

[1128]

[1129] first step

[1130] (S)-2,2-Dimethyl-1,3-dioxolane-4-carboxylic acid

[1131] Methyl (S)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid 50a (5.0 g, 31.2 mmol) was dissolved in a mixture of methanol (10.0 mL) and water (5.0 mL), and potassium hydroxide (3.5 g, 62.4 mmol) was added. The mixture was stirred at 25 °C for 2 hours. The reaction was monitored by TLC. The solution was diluted with water (10.0 mL), and the pH was adjusted to 1–2 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate (10 mL × 5). The combined organic layers were extracted and washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give (S)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid 50b (630 mg), yield: 13.81%.

[1132] 1 H NMR (400MHz, CDCl3) δ4.62 (dd, J = 7.6, 4.8Hz, 1H), 4.28-4.35 (m, 1H), 4.19-4.24 (m, 1H), 1.55 (s, 3H), 1.43 (s, 3H).

[1133] Step 2

[1134] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-(2,2-dimethyl-1,3-dioxacyclopentan-4-yl)-1,6-naphthidium-4-ol

[1135] Under nitrogen protection, 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (2.5 mg, 9.21 μmol) was dissolved in dimethyl sulfoxide (1.0 mL), and nickel dichloride dimethoxyethane adduct (1.4 mg, 6.14 μmol) was added. The mixture was stirred at 25 °C for 0.5 hours. 5-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthidium-4-ol 11 (30) (4S)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid 50b (9.9 mg, 67.51 μmol), 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (10.5 mg, 61.37 μmol), bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium, hexafluorophosphate (1.4 mg, 1.23 μmol), and phthalimide (9.0 mg, 61.37 μmol) were added to the reaction mixture. The reaction was carried out at 25 °C for 16 hours using photocatalysis. After the reaction was complete, water (5.0 mL) was added, and the mixture was extracted with ethyl acetate (3 mL × 3). The organic layer was washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (eluent: system A) to give 50 c (16 mg) of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-(2,2-dimethyl-1,3-dioxacyclopentan-4-yl)-1,6-naphthidium-4-ol, yield: 47.02%.

[1136] MS m / z (ESI): 555.4 [M+1].

[1137] Step 3

[1138] 1-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthid-5-yl)ethane-1,2-diol

[1139] 50c (16 mg, 28.85 μmol) of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-(2,2-dimethyl-1,3-dioxacyclopentan-4-yl)-1,6-naphthid-4-ol was dissolved in dichloromethane (2.0 mL), and 2,2,2-trifluoroacetic acid (65.8 mg, 577.09 μmol) was added. The mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LCMS, concentrated under reduced pressure, and the residue was preparatively separated by a C18 reversed-phase column (eluent: system B) to give 50 (3.03 mg) of 1-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidium-5-yl)ethane-1,2-diol, yield: 16.71%.

[1140] MS m / z (ESI): 515.1 [M+1].

[1141] 1 H NMR (400MHz, CD3OD): δ8.51(d,J=6.8Hz,1H),8.11(s,1H),7.13-7.21(m,1H),7.01(q,J=8.8Hz,1H),6.42(s,1H),6.18(s,1H),5.54(d d,J=11.2,2.8Hz,1H),4.24-4.31(m,1H),3.94-4.02(m,4H),3.77-3.84(m,1H),2.85-2.97(m,1H),1.72(s,3H),0.90(d,J=7.2Hz,3H).

[1142] Example 50-A

[1143] (R)-1-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidin-5-yl)ethane-1,2-diol 50-A

[1144] Example 50-B

[1145] (S)-1-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidin-5-yl)ethane-1,2-diol 50-B

[1146]

[1147] first step

[1148] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-((R)-2,2-dimethyl-1,3-dioxacyclopentan-4-yl)-1,6-naphthidium-4-ol 50c-A

[1149] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-((S)-2,2-dimethyl-1,3-dioxacyclopentan-4-yl)-1,6-naphthidium-4-ol 50c-B

[1150] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-(2,2-dimethyl-1,3-dioxacyclopentan-4-yl)-1,6-naphthidium-4-ol 50c (170 mg, 306.58 μmol) was purified by chiral resolution using SFC (column type: Phenomenex-Cellulose, 250 mm × 30 mm, 10 μm; mobile phase: A for CO2 and B for Ethanol; detection wavelength: 214 nm; column temperature: 40 °C) to obtain compounds with a single configuration (shorter retention time) and compounds with a single configuration (longer retention time).

[1151] Single-configuration compounds (shorter retention time):

[1152] 60 mg, yield: 35.3%, retention time 1.302 min, chiral purity 100% ee.

[1153] MS m / z (ESI): 555.2 [M+1]

[1154] Single-configuration compounds (longer retention time):

[1155] 60 mg, yield: 35.3%, retention time: 1.947 min, chiral purity: 98.24% ee.

[1156] MS m / z (ESI): 555.1 [M+1]

[1157] Step 2

[1158] (R)-1-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidin-5-yl)ethane-1,2-diol 50-A

[1159] (S)-1-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidin-5-yl)ethane-1,2-diol 50-B

[1160] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-((R)-2,2-dimethyl-1,3-dioxacyclopentan-4-yl)-1,6-naphthidium-4-ol 50c-A (50 mg, 90.17 μmol) or 2-((2R,3S,4S,5R)-3-(3 50 c-A of 4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-((S)-2,2-dimethyl-1,3-dioxacyclopentan-4-yl)-1,6-naphthid-4-ol 50 c-A (50 mg, 90.17 μmol) was dissolved in dichloromethane (1.0 mL), and 2,2,2-trifluoroacetic acid (205.6 mg, 1.80 mmol) was added. The mixture was stirred at 25°C for 16 hours, and the reaction was monitored by LCMS. The mixture was concentrated under reduced pressure, and the residue was preparatively separated using a C18 reversed-phase column (eluent: system B) to yield (R)-1-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidium-5-yl)ethane- 1,2-Diol 50-A (28.50 mg), yield: 50.29%; (S)-1-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthid-5-yl)ethane-1,2-diol 50-B (23.65 mg), yield: 41.73%.

[1161] MS m / z (ESI): 515.1 [M+1].

[1162] MS m / z (ESI): 515.1 [M+1].

[1163] 1H NMR (400MHz, CD3OD) δ8.52(d,J=6.0Hz,1H),7.60(d,J=6.0Hz,1H),7.11-7.19(m,1H ),6.95-7.04(m,1H),6.32(s,1H),5.73(dd,J=5.6,4.4Hz,1H),5.48(d,J=11.2Hz,1H ),4.25(dd,J=11.2,8.8Hz,1H),3.93-3.97(m,3H),3.90(dd,J=11.2,4.0Hz,1H),3.7 2(dd,J=11.2,6.0Hz,1H),2.87(quin,J=8.0Hz,1H),1.71(s,3H),0.84-0.93(m,3H).

[1164] MS m / z (ESI): 515.1 [M+1].

[1165] 1 H NMR(400MHz,CD3OD)δ8.52(d,J=6.0Hz,1H),7.61(d,J=6.0Hz,1H),7.12-7.18(m,1H) ,6.95-7.03(m,1H),6.32(s,1H),5.74(dd,J=5.6,4.0Hz,1H),5.48(d,J=11.2Hz,1H), 4.25(dd,J=11.2,8.4Hz,1H),3.95(d,J=2.4Hz,3H),3.90(dd,J=11.2,4.0Hz,1H),3. 72(dd,J=11.2,6.0Hz,1H),2.88(quin,J=8.0Hz,1H),1.71(s,3H),0.86-0.92(m,3H).

[1166] Example 51

[1167] 5-Chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,8-naphthidium-4-ol

[1168]

[1169] first step

[1170] 1-(2-amino-4-chloropyridin-3-yl)ethane-1-one

[1171] 4-Chloro-3-iodopyridin-2-amine 51a (500 mg, 1.96 mmol) and tributyl(1-ethoxyvinyl)stanane 51b (1.83 g, 5.07 mmol, 1.71 mL) were dissolved in dioxane (10 mL) solution, and bis(triphenylphosphine)palladium(II) dichloride (68.96 mg, 98.25 μmol) was added. The mixture was stirred at 70 °C for 16 hours. The reaction was monitored by LCMS. The mixture was cooled to 25 °C, and the pH of the solution was adjusted to 7 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (10 mL × 3). The extract was washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in dioxane (1 mL) solution, and hydrochloric acid (110.013 mg, 3.02 mmol) was added. The mixture was stirred at 50 °C for 5 hours. The reaction was monitored by LCMS. The pH of the solution was adjusted to 7 with saturated sodium bicarbonate solution, and extracted with dichloromethane (10 mL × 3). The organic layers were combined, washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative separation on a C18 reversed-phase column (eluent: system B) to give 51c (33 mg) of 1-(2-amino-4-chloropyridin-3-yl)ethane-1-one, yield: 38.43%. MS m / z (ESI): 171.1 [M+1]

[1172] Step 2

[1173] (2R,3S,4S,5R)-N-(3-acetyl-4-chloropyridin-2-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[1174] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a (62.30 mg, 175.85 μmol) and 1-(2-amino-4-chloropyridin-3-yl)acetone 51c (30 mg, 175.85 μmol) were dissolved in dichloromethane (1 mL), and phosphorus oxychloride (80.89 mg, 527.56 μmol) and pyridine (41.73 mg, 527.56 μmol) were added. The mixture was stirred at 20 °C for 1 hour. The reaction was monitored by LCMS, poured into water (5 mL), and extracted with dichloromethane (10 mL × 3). The sample was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (2R,3S,4S,5R)-N-(3-acetyl-4-chloropyridin-2-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 51d (40 mg), yield: 44.88%. It was used directly for the next reaction without purification.

[1175] MS m / z(ESI): 507.1 [M+1]

[1176] Step 3

[1177] 5-Chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,8-naphthidium-4-ol

[1178] (2R,3S,4S,5R)-N-(3-acetyl-4-chloropyridin-2-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 51d (40 mg, 78.92 μmol) was dissolved in toluene (1 mL), and sodium hydroxide (12.63 mg, 315.68 μmol) was added. The mixture was stirred at 110 °C for 2 hours. The reaction was monitored by LCMS. The reaction was quenched with water (5 mL) at 0 °C and extracted with dichloromethane (5 mL × 3). The organic layer was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,8-naphthidium-4-ol 51 (35 mg), yield: 90.72%. It was carried out directly in the next reaction without purification.

[1179] MS m / z(ESI): 489.1 [M+1]

[1180] 1 H NMR (400MHz, CD3OD) δ8.55(d,J=5.0Hz,1H),7.39(d,J=5.1Hz,1H),7.27-7.13(m,1H),7.06-6.96(m,1H),6.29(s,1H),5.49 (d,J=11.3Hz,1H),4.26(dd,J=8.5,11.0Hz,1H),3.94(d,J=2.4Hz,3H),2.92-2.80(m,1H),1.73(s,3H),0.93-0.86(m,3H).

[1181] Example 52

[1182] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,8-naphthidium-4,5-diol

[1183]

[1184]

[1185] first step

[1186] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,8-naphthidium-4,5-diol

[1187] 5-Chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,8-naphthid-4-ol 51 (30 mg, 61.37 μmol) and ethoxyxamic acid (13.82 mg, 184.11 μmol) were dissolved in dimethyl sulfoxide (0.5 mL), and potassium carbonate (25.45 mg, 184.11 μmol) was added. The mixture was stirred at 80 °C for 5 hours. The reaction was monitored by LC-MS. The residue was filtered, concentrated under reduced pressure, and then preparatively separated by a C18 reversed-phase column (eluent: system B) to give 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,8-naphthidium-4,5-diol 52 (21.23 mg), yield: 73.54%.

[1188] MS m / z(ESI): 471.0 [M+1]

[1189] 1 H NMR (500MHz, CD3OD) δ7.92(d,J=6.9Hz,1H),7.26(s,1H),6.93(d,J=8.2Hz,1H),6.86(s,1H),6.24(d,J=6.9Hz ,1H),5.48(d,J=10.8Hz,1H),4.25(t,J=8.9Hz,1H),3.91(s,3H),2.90-2.77(m,1H),1.70(s,3H),0.85(s,3H).

[1190] Example 53

[1191] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-(trifluoromethyl)-1,6-naphthidine-4-ol

[1192]

[1193] first step

[1194] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-(trifluoromethyl)-1,6-naphthidine-4-ol

[1195] 5-Chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthidium-4-ol 11 (50 mg, 102.28 μmol) was dissolved in N,N-dimethylacetamide (1.5 mL), and cuprous iodide (29.22 mg, 153.43 μmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate 53a (29.48 mg, 153.43 μmol) were added. The mixture was stirred at 85 °C for 20 hours under nitrogen protection. The reaction was monitored by LCMS, filtered, and passed through a C100000-dimethylamine solution. 18 Preparative separation by reversed-phase column chromatography (eluent: system B) yielded 53 (6.2 mg) of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-(trifluoromethyl)-1,6-naphthidium-4-ol, yield: 11.60%.

[1196] MS m / z(ESI): 523.0 [M+1]

[1197] 1 H NMR(400MHz, CDCl3)δ8.77(s,1H),8.65-8.63(m,1H),7.43-7.41(m,1H),6.93-6.90(m,2H),5.97(s,1H),5 .44-5.41(m,1H),4.09-4.04(m,1H),3.98-3.97(m,3H),2.75-2.73(m,1H),1.69(s,3H),0.86-0.84(m,3H).

[1198] Example 54

[1199] 3-((6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-8-hydroxy-1,5-naphthidin-2-yl)oxy)propane-1,2-diol

[1200]

[1201] first step

[1202] 1-(3-amino-6-chloropyridin-2-yl)ethane-1-one

[1203] 3-Amino-6-chloropyridine 54a (1 g, 6.51 mmol) was dissolved in tetrahydrofuran (10 mL), and methylmagnesium bromide (3.88 g, 32.56 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 2 hours. The reaction was monitored by LC-MS. A saturated ammonium chloride solution (20 mL) was added at 0 °C, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic layer was washed with a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give 1-(3-amino-6-chloropyridine-2-yl)ethane-1-one 54b (500 mg), yield: 45.01%.

[1204] MS m / z(ESI): 170.9 [M+1].

[1205] Step 2

[1206] (2R,3S,4S,5R)-N-(2-acetyl-6-chloropyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[1207] 1-(3-amino-6-chloropyridin-2-yl)ethane-1-one 54b (173.36 mg, 1.02 mmol) and (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a (300 mg, 846.82 μmol) were dissolved in dichloromethane (3 mL), and pyridine (401.90 mg, 5.08 mmol) and phosphorus oxychloride (259.69 mg, 1.69 mmol) were added at 0 °C, and the mixture was stirred at 25 °C for 1 hour. The reaction was monitored by LCMS. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). The combined organic layers were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give (2R,3S,4S,5R)-N-(2-acetyl-6-chloropyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 54c (400 mg), yield: 93.19%.

[1208] MS m / z(ESI): 507.0 [M+1].

[1209] Step 3

[1210] 6-Chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,5-naphthidium-4-ol

[1211] (2R,3S,4S,5R)-N-(2-acetyl-6-chloropyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 54c (400 mg, 789.19 μmol) was dissolved in toluene (6 mL), and sodium hydroxide (94.70 mg, 2.37 mmol) was added. The mixture was stirred at 110 °C for 2 hours. LC-MS showed that the reaction was complete. The residue was filtered and concentrated under reduced pressure. The residue was then purified by column chromatography (eluent: system A) to give 54 d (330 mg) of 6-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,5-naphthidium-4-ol, yield: 85.54%. MS m / z (ESI): 489.0 [M+1].

[1212] Step 4

[1213] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-((2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methoxy)-1,5-naphthidium-4-ol

[1214] Sodium hydrogen (18.16 mg, 454.00 μmol) was dissolved in tetrahydrofuran (1 mL), and (2,2-dimethyl-1,3-dioxane-4-yl)methanol 54e (20 mg, 151.33 μmol) was added at 0 °C. The mixture was stirred at 0 °C for 30 minutes. 6-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,5-naphthidium-4-ol 54d (51.78 mg, 105.93 μmol) was added to the reaction mixture, and the mixture was stirred at 70 °C for 16 hours. LCMS showed the reaction was complete. A saturated ammonium chloride solution (20 mL) was added at 0 °C, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layer was washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-((2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methoxy)-1,5-naphthidine-4-ol 55 f (60 mg), yield: 67.83%. This unpurified solution was directly used in the next reaction.

[1215] MS m / z (ESI): 585.2 [M+1].

[1216] Step 5

[1217] 3-((6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-8-hydroxy-1,5-naphthidin-2-yl)oxy)propane-1,2-diol

[1218] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-((2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methoxy)-1,5-naphthidium-4-ol 55f (60 mg, 102.65 μmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (307.00 mg, 2.69 mmol) was added. The mixture was stirred at 25 °C for 2 hours. LC-MS showed that the reaction was complete. The pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (20 mL × 3). The combined organic layers were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was preparatively separated by C18 reversed-phase column chromatography (eluent: system B) to give 54 (20 mg) of 3-((6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-8-hydroxy-1,5-naphthidin-2-yl)oxy)propane-1,2-diol, yield: 35.79%.

[1219] MS m / z(ESI): 545.1 [M+1].

[1220] 1 H NMR(400MHz,CD3OD)δ8.31-8.26(m,1H),7.38-7.34(m,1H),7.25-7.18(m, 1H),7.06-6.97(m,1H),6.85-6.79(m,1H),5.69-5.63(m,1H),4.60(dd,J= 1.9,4.3Hz,2H),4.31-4.25(m,1H),3.96(s,1H),3.94(d,J=2.4Hz,3H),3. 66-3.61(m,2H),2.94-2.86(m,1H),1.75-1.73(m,3H),0.93-0.89(m,3H).

[1221] Example 55

[1222] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthidine

[1223]

[1224] first step

[1225] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthidine

[1226] 4,4-Di-tert-butyl-2,2-dipyridine (4.89 mg, 18.23 μmol) and nickel dichloride dimethoxyethane adduct (2.67 mg, 12.15 μmol) were dissolved in dimethyl sulfoxide (1.0 mL), stirred at 25 °C for 0.5 h, and 2-chloro-1,6-naphthidine 55a (20 mg, 121.51 μmol) and (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a were added. (43.05 mg, 121.51 μmol), 2-tert-butyl-1,1,3,3-tetramethylguanidine (20.81 mg, 121.51 μmol), bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium (1+); 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine; hexafluorophosphate (2.73 mg, 2.43 μmol), phthalimide (17.88 mg, 121.51 μmol), photocatalytic reaction at 25 °C for 16 h. The reaction was monitored by LCMS. After the reaction was completed, the residue was filtered and then separated by C18 reversed-phase column chromatography (eluent: system B) to give 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthidine 55 (10.0 mg), yield: 18.86%.

[1227] MS m / z(ESI): 439.0 [M+1]

[1228] 1 H NMR(400MHz,CD3OD)δ9.58(s,1H),8.76-8.72(m,2H),8.17-8.11(m,2H),7.38-7.35(m,1H),6.98-6.94(m,1H ),5.81(d,J=11.2Hz,1H),4.35-4.30(m,1H),3.90(s,3H),2.94-2.88(m,1H),1.76(s,3H),0.94-0.91(m,3H).

[1229] Example 56

[1230] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-7-(trifluoromethyl)-1,6-naphthidine-4,5-diol

[1231]

[1232]

[1233] first step

[1234] (2-chloro-6-(trifluoromethyl)pyridin-4-yl)tert-butyl carbamate

[1235] 2-Chloro-6-(trifluoromethyl)pyridin-4-yl)amino 56a (1 g, 5.09 mmol) was dissolved in dichloromethane (10 mL), and di-tert-butyl carbonate (1.33 g, 6.11 mmol) and triethylamine (1.54 g, 15.26 mmol) were added. The mixture was stirred at 20 °C for 16 hours. The reaction was monitored by LCMS. Water (20 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 3). The organic layer was washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give (2-chloro-6-(trifluoromethyl)pyridin-4-yl)carbamate tert-butyl 56b (450 mg), yield: 29.81%. This unpurified product was directly used in the next step of the reaction.

[1236] MS m / z (ESI): 296.9 [M+1]

[1237] Step 2

[1238] (3-acetyl-2-chloro-6-(trifluoromethyl)pyridin-4-yl)tert-butyl carbamate

[1239] (2-chloro-6-(trifluoromethyl)pyridin-4-yl)tert-butyl carbamate 56b (250 mg, 842.68 μmol) and n-butyllithium (377.85 mg, 5.9 mmol) were dissolved in tetrahydrofuran (3 mL), and then N-methoxy-N-methylacetamide (434.49 mg, 4.21 mmol) was added dropwise at -78 °C, and the mixture was stirred at -78 °C for 3 hours. The reaction was monitored by LCMS. Water (10 mL) and 2 mL of ammonium chloride solution were added at 0 °C, and the mixture was extracted with dichloromethane (5 mL × 3). The organic layer was washed with saturated sodium chloride aqueous solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (3-acetyl-2-chloro-6-(trifluoromethyl)pyridin-4-yl)tert-butyl carbamate 56c (100 mg), yield: 35.04%. This product was used directly in the next step without purification.

[1240] MS m / z (ESI): 339.0 [M+1]

[1241] Step 3

[1242] 1-(4-amino-2-chloro-6-(trifluoromethyl)pyridin-3-yl)ethane-1-one

[1243] 56c (100 mg, 295.24 μmol) of tert-butyl (3-acetyl-2-chloro-6-(trifluoromethyl)pyridin-4-yl)carbamate was dissolved in 4M hydrochloric acid / dioxane (2 mL) and stirred at 20 °C for 3 hours. The reaction was monitored by LCMS, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system B) to give 56d (20 mg) of 1-(4-amino-2-chloro-6-(trifluoromethyl)pyridin-3-yl)ethane-1-one, yield: 28.39%.

[1244] MS m / z (ESI): 238.9 [M+1]

[1245] Step 4

[1246] (2R,3S,4S,5R)-N-(3-acetyl-2-chloro-6-(trifluoromethyl)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[1247] Dissolve ((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a (22.27 mg, 62.87 μmol) and 1-(4-amino-2-chloro-6-(trifluoromethyl)pyridin-3-yl)ethane-1-one 56d (15 mg, 62.87 μmol) in dichloromethane (1 mL), then add phosphorus oxychloride (28.92 mg, 188.60 μmol) and pyridine (14.92 mg, 188.60 μmol). 60 μmol) was stirred at 20 °C for 1 hour. The reaction was monitored by LCMS, water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 3). The extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (2R,3S,4S,5R)-N-(3-acetyl-2-chloro-6-(trifluoromethyl)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 56e (20 mg), yield: 55.4%. The extract was used directly for the next step of the reaction without purification.

[1248] MS m / z(ESI): 575.1 [M+1]

[1249] Step 5

[1250] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-7-(trifluoromethyl)-1,6-naphthidine-4,5-diol

[1251] (2R,3S,4S,5R)-N-(3-acetyl-2-chloro-6-(trifluoromethyl)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 56e (20 mg, 34.79 μmol) was dissolved in toluene (1 mL), and sodium hydroxide (5.57 mg, 139.17 μmol) was added. The mixture was stirred at 110 °C for 2 hours. The reaction was monitored by LCMS. Water (5 mL) was added at 0 °C, and the mixture was extracted with 5 mL of dichloromethane (5 mL × 3). The organic layer was washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was preparatively separated by C18 reversed-phase column chromatography (eluent: system B) to give 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-7-(trifluoromethyl)-1,6-naphthidine-4,5-diol 56 (6.99 mg), yield: 36.08%.

[1252] MS m / z(ESI): 539.1 [M+1]

[1253] 1 H NMR (400MHz, CD3OD) δ7.29(s,1H),7.22(t,J=6.1Hz,1H),7.03-6.94(m,1H),6.79(s,1H),5.55(d,J=11.2Hz,1 H),4.24(dd,J=8.2,11.1Hz,1H),3.93(d,J=2.4Hz,3H),2.87(t,J=7.7Hz,1H),1.72(s,3H),0.92-0.84(m,3H).

[1254] Example 57

[1255] 5-Chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-7-(trifluoromethyl)-1,6-naphthidium-4-ol

[1256]

[1257]

[1258] first step

[1259] 5-Chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-7-(trifluoromethyl)-1,6-naphthidium-4-ol

[1260] (2R,3S,4S,5R)-N-(3-acetyl-2-chloro-6-(trifluoromethyl)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 56e (10 mg, 17.40 μmol) was dissolved in toluene (0.5 mL), and sodium hydroxide (2.78 mg, 69.58 μmol) was added. The mixture was stirred at 110 °C for 2 hours. The reaction was monitored by LCMS, quenched with 1 mL of hydrochloric acid aqueous solution at 0 °C, filtered, concentrated under reduced pressure, and the residue was preparatively separated by C18 reversed-phase column chromatography (eluent: system B) to give 57 (1.34 mg) of 5-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-7-(trifluoromethyl)-1,6-naphthidium-4-ol, yield: 13.83%.

[1261] MS m / z(ESI): 557.1 [M+1]

[1262] 1 H NMR(400MHz,CD3OD)δ8.06(s,1H),7.22-7.12(m,1H),7.06-6.96(m,1H),6.34(s,1H),5.50(d,J=11.2Hz,1H), 4.24(dd,J=8.5,11.1Hz,1H),4.00-3.94(m,3H),2.93-2.83(m,1H),1.72(s,3H),0.89(dd,J=2.1,7.6Hz,3H).

[1263] Example 58

[1264] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4,5-dihydroxy-1,6-naphthidine-1-oxide

[1265]

[1266] first step

[1267] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4,5-dihydroxy-1,6-naphthidine-1-oxide

[1268] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthidine-4,5-diol 39 (16 mg, 0.03 mmol) was dissolved in dichloromethane (0.2 mL), and m-chloroperoxybenzoic acid (10.4 mg, 0.05 mmol) was added at 0 °C. The mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LCMS. After the reaction was complete, the mixture was filtered and preparatively separated using a C18 reversed-phase column (eluent: system B) to give 58 (1 mg) of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4,5-dihydroxy-1,6-naphthidine-1-oxide, yield: 6.03%. MS m / z (ESI): 487.0 [M+1]

[1269] 1 H NMR (400MHz, CD3OD) δ7.66(d,J=7.5Hz,1H),7.35(t,J=7.0Hz,1H),7.22(s,1H),7.16(d,J=7.6Hz,1H),6.88-6.98(m, 1H), 6.31 (d, J = 10.5Hz, 1H), 4.23-4.36 (m, 1H), 3.95-3.98 (m, 3H), 2.88-3.01 (m, 1H), 1.72 (s, 3H) 0.85-0.91 (m, 3H).

[1270] Example 59

[1271] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4,5-dihydroxy-1,6-naphthidine-7-carboxylic acid

[1272]

[1273] first step

[1274] Methyl 5-acetyl-4-aminopyridinecarboxylate

[1275] 4-Amino-5-bromopyridinecarboxylate 59a (1 g, 4.33 mmol) was dissolved in dioxane (10 mL), and bis(triphenylphosphine)palladium(II) dichloride (151.89 mg, 216.41 μmol) and tributyl(1-ethoxyvinyl)stanane 51b (2.32 g, 6.42 mmol) were added. The mixture was stirred at 70 °C for 16 hours. The reaction was monitored by TLC until the starting material was completely reacted. 1 M dilute hydrochloric acid aqueous solution (20 mL) was added, and the mixture was stirred at 25 °C for 2 hours. The pH of the solution was adjusted to 8–9 with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (40 mL × 3). The organic layer was washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: system A) to give 5-acetyl-4-aminopyridinecarboxylate 59b (500 mg), yield: 59.49%.

[1276] Step 2

[1277] 5-Acetyl-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamate)methyl pyridinecarboxylate

[1278] Methyl 5-acetyl-4-aminopyridinecarboxylate 1c (213.77 mg, 1.10 mmol) and (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a (300 mg, 846.82 μmol) were dissolved in dichloromethane (6 mL). Pyridine (334.91 mg, 4.23 mmol) and phosphorus oxychloride (259.69 mg, 1.69 mmol) were added at 0 °C, and the mixture was stirred at 25 °C for 1 hour. The reaction was monitored by LCMS. Pour into water (20 mL), extract with dichloromethane (20 mL × 3), wash the combined organic layers with saturated sodium chloride solution (20 mL), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and the residue is purified by column chromatography (eluent: system A) to give methyl 5-acetyl-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxylate 59c (370 mg), yield: 82.37%.

[1279] MS m / z(ESI): 531.0 [M+1].

[1280] Step 3

[1281] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-7-carboxylic acid

[1282] Methyl 5-acetyl-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridinecarboxylate 59c (370 mg, 697.53 μmol) was dissolved in toluene (4 mL), and sodium hydroxide (83.70 mg, 2.09 mmol) was added. The mixture was stirred at 110 °C for 2 hours. The reaction was monitored by LCMS. The pH of the solution was adjusted to 5-6 with 1M dilute hydrochloric acid. The solution was extracted with ethyl acetate (40 mL × 3). The organic layer was washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 59d (300 mg) of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-7-carboxylic acid, yield: 86.29%. This product was used directly for the next step of the reaction without purification.

[1283] MS m / z(ESI): 499.0 [M+1].

[1284] Step 4

[1285] 7-Carboxy-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-6-oxide

[1286] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-7-carboxylic acid 59d (100 mg, 200.64 μmol) was dissolved in dichloromethane (1 mL), and m-chloroperoxybenzoic acid (61.10 mg, 300.96 μmol) was added. The mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LCMS. Saturated sodium sulfite solution (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layer was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (eluent: system C) to give 7-carboxy-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-6-oxide 59e (10 mg), yield: 9.69%.

[1287] MS m / z (ESI): 515.1 [M+1].

[1288] Step 5

[1289] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4,5-dihydroxy-1,6-naphthidine-7-carboxylic acid

[1290] 59e of 7-carboxy-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-1,6-naphthidine-6-oxide 59e (5 mg, 9.72 μmol) was dissolved in N,N-dimethylformamide (0.5 mL), and trifluoroacetic anhydride (20.42 mg, 97.20 μmol) was added. The mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LCMS. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic layer was washed with saturated sodium chloride solution (5 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was preparatively separated by C18 reversed-phase column chromatography (eluent: system B) to give 59 (1.25 mg) of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4,5-dihydroxy-1,6-naphthidine-7-carboxylic acid, yield: 25.00%.

[1291] MS m / z (ESI): 515.1 [M+1].

[1292] 1 HNMR(400MHz,CD3OD)δ7.46-7.35(m,1H),7.29-7.19(m,1H),7.10-6.88(m,2H),5.58-5.50(m,1H),4.2 5(dd,J=8.0,10.5Hz,1H),3.92(d,J=1.9Hz,3H),2.90-2.84(m,1H),1.72(s,3H),0.88(d,J=5.8Hz,3H).

[1293] Example 60

[1294] 5-Chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthidium-4,7-diol

[1295]

[1296] first step

[1297] 5-Chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthidium-4,7-diol

[1298] 0.05 g (0.1 mmol) of 5-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthid-4-ol 11 was dissolved in 3 mL of dichloromethane. Urea hydrogen peroxide (19.2 mg, 0.20 mmol) was added at 0 °C, and the mixture was stirred at 25 °C for 3 hours. The reaction was monitored by LC-MS. The solution was concentrated under reduced pressure and then preparatively separated using a C18 reversed-phase column (eluent: system B) to give 60 (1.0 mg) of 5-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthidium-4,7-diol, yield: 1.93%.

[1299] MS m / z(ESI): 505.0 [M+1]

[1300] 1H NMR (400MHz, CD3OD) δ7.40(d,J=7.2Hz,1H),6.86-7.00(m,2H),6.70(d,J=7.6Hz,1H),6.06(d,J=10.4 Hz,1H),4.19-4.32(m,1H),3.97(d,J=2.0Hz,3H),2.87-2.93(m,1H),1.66(s,3H),0.88-0.92(m,3H).

[1301] Example 61

[1302] 6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-hydroxy-2-methylnicotinamide

[1303]

[1304] first step

[1305] 4-(benzyloxy)-2-methylnicotinic acid methyl ester

[1306] 4-(benzyloxy)-3-iodo-2-methylpyridine 61a (2 g, 6.15 mmol) was dissolved in methanol (20 mL), and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (450 mg, 0.62 mmol) and triethylamine (1.87 g, 18.4 mmol) were added. The mixture was stirred at 80 °C for 12 hours under a carbon monoxide (50 psi) atmosphere. The reaction was monitored by LCMS, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give 4-(benzyloxy)-2-methylnicotinic acid methyl ester 61b (1.1 g), yield: 53.73%.

[1307] MS m / z(ESI): 258.3 [M+1]

[1308] Step 2

[1309] 4-(benzyloxy)-3-(methoxycarbonyl)-2-methylpyridine-1-oxide

[1310] 4-(benzyloxy)-2-methylnicotinic acid methyl ester 61b (1.1 g, 4.28 mmol) was dissolved in dichloromethane (15 mL), and m-chloroperoxybenzoic acid (1.30 g, 6.41 mmol) was added at 0 °C. The mixture was stirred at 25 °C for 12 hours, and the reaction was monitored by LCMS. The reaction was quenched with saturated sodium sulfite solution (5 mL), extracted with dichloromethane (10 mL × 3), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: C system) to give 4-(benzyloxy)-3-(methoxycarbonyl)-2-methylpyridine-1-oxide 61c (1.08 g), yield: 47.97%.

[1311] MS m / z(ESI): 274.1 [M+1]

[1312] Step 3

[1313] 4-(benzyloxy)-6-chloro-2-methylnicotinic acid methyl ester

[1314] 0.6 g (1.23 mmol) of 4-(benzyloxy)-3-(methoxycarbonyl)-2-methylpyridine-1-oxide 61c was dissolved in phosphorus oxychloride (2 mL), stirred at 110 °C for 12 hours, and the reaction was monitored by TLC. The reaction was quenched in water (2 mL), the pH was adjusted to 9 with saturated sodium bicarbonate aqueous solution, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give 4-(benzyloxy)-6-chloro-2-methylnicotinic acid methyl ester 61d (60 mg), yield: 28.09%.

[1315] Step 4

[1316] 4-(benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methylnicotinic acid methyl ester

[1317] 4,4-Di-tert-butyl-2,2-dipyridine (5.52 mg, 0.02 mmol) and nickel dichloride dimethoxyethane adduct (3.01 mg, 0.01 mmol) were dissolved in dimethyl sulfoxide (0.5 mL) and stirred at 25 °C for 0.5 hours. Then, methyl 4-(benzyloxy)-6-chloro-2-methylnicotinate 61d (40 mg, 0.14 mmol) and (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetracycline were added. Hydrofuran-2-carboxylic acid 1a (48.6 mg, 0.14 mmol), 2-tert-butyl-1,1,3,3-tetramethylguanidine (23.48 mg, 0.14 mmol), bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium, 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine, hexafluorophosphate (3.08 mg, 2.74 μmol), phthalimide (20.2 mg, 10.14 mmol), photocatalytic reaction at 25 °C for 16 h. The reaction was monitored by LCMS, filtered, and the residue was purified by column chromatography (eluent: system A) to give methyl 4-(benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methylnicotinic acid 61e (20 mg), yield: 25.79%.

[1318] MS m / z(ESI): 566.2 [M+1]

[1319] Step 5

[1320] 4-(benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methylnicotinic acid

[1321] 4-(benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methylnicotinic acid methyl ester 61e (20 mg, 0.04 mmol) was dissolved in a mixture of methanol (0.5 mL) and water (0.2 mL), and lithium hydroxide monohydrate (7.42 mg, 0.18 mmol) was added. The mixture was stirred at 50 °C for 6 hours, and the reaction was monitored by LCMS. The solution was concentrated under reduced pressure, the pH of which was adjusted to 3 with 1M hydrochloric acid, water (10 mL) was added, and the solution was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 61f (20 mg) of 4-(benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methylnicotinic acid, yield: 100%. It was used directly for the next reaction without purification.

[1322] MS m / z (ESI): 552.1 [M+1]

[1323] Step 6

[1324] 4-(benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methylnicotinamide

[1325] 4-(benzyloxy)-6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-2-methylnicotinic acid 61f (20 mg, 36.26 μmol) and N,N-diisopropylethylamine (14.1 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (0.2 mL) and dichloromethane (0.4 mL). Ammonium chloride (5.82 mg, 0.11 mmol) was added at 0 °C, and the mixture was stirred for 0.5 hours. Then, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (20.7 mg, 0.05 mmol) was added, and the mixture was stirred at 25 °C for 12 hours. The reaction was monitored by LCMS. The mixture was diluted with water (15 mL), extracted with dichloromethane (20 mL × 3), and the organic...

Claims

1. A compound of general formula (I) or a stereoisomer, tautomer, deuterated derivative thereof or a pharmaceutically acceptable salt thereof: in: Ring A, ring B, and ring C are each independently selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups; L is selected from single bond, -NR x -、-CR x R y -、-O-、-S-; X is selected from -NR x -、-CR x R y -、-O-、-S-、-S(O)- or -S(O)2-, X is preferably -O-、-S-; R1, R2, R3, R4, R5, R6, R9, R x R y Each group is independently selected from hydrogen, deuterium, tritium, halogen, carboxyl, amino, hydroxyl, cyano, amide, alkoxy, alkylamino, mercapto, alkyl, alkenyl, heteroalkyl, =O, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -S(O). r R a -O-(CH2) t1 -[O-(CH2) t2 ] e -O-(CH2) t3 R a The -O-(CH2) t1 -[O-(CH2) t2 ] e -O-(CH2) t3 R a The O in the group may optionally be replaced by one or more S or N groups, wherein the amino, hydroxy, amide, alkoxy, alkylamino, mercapto, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -S(O) group is... r R a -O-(CH2) t1 -[O-(CH2) t2 ] e -O-(CH2) t3 R a Optionally composed of one or more radicals selected from deuterium, tritium, alkyl, haloalkyl, halogen, amino, hydroxyl, cyano, formyl, acetyl, deuterated alkyl, tritated alkyl, -S(O). r R a -C(O)NR a R b Substituted by cycloalkyl, heterocycloalkyl, aryl, heteroaryl or alkoxy substituents; Alternatively, any two or two R9s selected from R1, R2, R3, R4, R5, R6, and R9, together with the atoms attached to them, form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group may optionally be further substituted by one or more substituents selected from hydroxyl, amino, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, and =O. R7 and R8 can be the same or different, and each can be independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, halogen, nitro, cyano, hydroxyl, amide, cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, =O, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a C(O)OR b -NR a R b -NR a S(O) r R b -NR a C(O)R b -NR a C(O)NR b R c -NR a C(S)NR b R c -NR a S(O) r NR b R c -C(=NR) a )NR b R c -C(=NR) a )R b -C(=NR) a )NR b OR c -C(=NR) a )NR b NR c -C(O)NR a OR b -C(O)NR a NR b R c -C(O)NR a R b -C(O)C(O)NR a R b -S(=NR) a )(O)R b -S(=NR) a )NR b R c -S(=NR) a )R b -S(=NR) a )(O)NR b R c -S(O) r NR a R b -S(O) r R a -Si(O)NR a R b 、-Si(R a 3. -P(O) s R a R b -OR a cycloalkylalkyl, heterocyclicalkyl, -alkylene-O-alkylene-cycloalkyl, -alkylene-O-cycloalkyl, -O-alkylene-heteroaryl, or -O-alkylene-heterocyclic, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, and heterocyclicalkyl are each independently and optionally selected by one or more R 01 Replaced; R 01 Whether identical or different, each is independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, halogen, nitro, cyano, hydroxyl, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a C(O)OR b -NR a R b -NR a S(O) r R b -NR a C(O)R b -NR a C(O)NR b R c -NR a C(S)NR b R c -NR a S(O) r NR b R c -C(=NR) a )NR b R c -C(=NR) a )R b -C(=NR) a )NR b OR c -C(=NR) a )NR b NR c -C(O)NR a OR b -C(O)NR a NR b R c -C(O)NR a R b -C(O)C(O)NR a R b -S(=NR) a )(O)R b -S(=NR) a )NR b R c -S(=NR) a )R b -S(=NR) a )(O)NR b R c -S(O) r NR a R b -S(O) r R a -Si(O)NR a R b 、-Si(R a 3. -P(O) s R a R b -OR a The alkyl, heterocyclic, alkylene-O-alkylene-cycloalkyl, alkylene-O-cycloalkyl, alkylene-Hydroaryl, or alkylene-Hydroaryl groups may be further substituted by one or more substituents selected from deuterium, =O, halogen, hydroxyl, cyano, amino, aminoalkyl, acetyl, alkyl, alkenyl, alkynyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; Alternatively, R7, R8, together with the atoms they are attached to, form cycloalkyl and heterocycloalkyl groups, which may optionally be further substituted by one or more substituents selected from hydroxyl, amino, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, and =O. Alternatively, R8, R9 and the atoms connected to them can be linked by single bonds, double bonds, cycloalkyl groups, or heterocyclic alkyl groups to form a macrocycle, which can be replaced by substituents of halogen, amino, hydroxyl, cyano, amide, alkoxy, mercapto, alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl groups. R a R b R c Each is independently selected from hydrogen atom, hydroxyl, amino, alkyl, alkoxy, cycloalkyl, heterocyclic, heteroalkenyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, heteroalkenyl, aryl or heteroaryl may optionally be further substituted by one or more substituents selected from alkyl, halogen, nitro, cyano, amino, carboxyl, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, and substituents; Or R a R b R c Any two links form a saturated or unsaturated heterocycle, which is further substituted by one or more substituents selected from alkyl, halogen, nitro, cyano, amino, carboxyl, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, etc. n is 0, 1, or 2; m can be 0, 1, 2, 3, 4, or 5; p is 0, 1, 2 or 3; t1 can be 0, 1, 2, or 3; t2 can be 0, 1, 2, or 3; t3 can be 0, 1, 2, or 3; e can be 0, 1, 2, or 3; r is 0, 1, or 2; s is 0 or 1.

2. The compound according to claim 1, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein the compound is a compound of general formula (II), or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof: in: The definitions of R1, R2, R3, R4, R5, R6, R7, R8, R9, X, L, ring A, ring B, ring C, n, m, and p are as described in claim 1.

3. The compound according to claim 2, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein the compound is a compound of general formula (III), or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof: in: The definitions of R1, R2, R3, R4, R5, R6, R7, R8, R9, X, ring A, ring B, ring C, n, m, and p are as described in claim 1.

4. The compound according to claim 3, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein the compound is a compound of general formula (IV), or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof: in: The definitions of R1, R2, R3, R4, R5, R6, R7, R8, R9, ring A, ring B, n, m, and p are as described in claim 1.

5. The compound according to claim 3, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein the compound is a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof of general formula (V): in: X is selected from -S-, -S(O)-, or -S(O)2; The definitions of R1, R2, R3, R4, R5, R6, R7, R8, R9, ring A, ring B, n, m, and p are as described in claim 1.

6. The compound according to claim 3, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein the compound is a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof of general formula (VI): in: R1, R2, R3, R4, R5, R6, R7, R8, R9, R x The definitions of ring A, ring B, n, m, and p are as described in claim 1.

7. The compound according to claim 3, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein the compound is a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof of general formula (VII): in: R1, R2, R3, R4, R5, R6, R7, R a R b The definitions of R9, ring A, ring B, n, m, and p are as described in claim 1.

8. A compound of general formula (IA) or a stereoisomer, tautomer, deuterated derivative thereof or a pharmaceutically acceptable salt thereof: in: Ring D is selected from aryl, heteroaryl, heterocyclic alkyl, and fused rings; Ring E is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups; T is selected from single bonds, heteroaryl rings, etc. The aforementioned heteroaryl rings, It can be one or more R 02 Replaced by, R 02 Selected from deuterium, tritium, halogen, amino, hydroxyl, nitro, cyano, amide, alkoxy, mercapto, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl; L is selected from single bond, -NR x -、-CR x R y -、-O-、-S-; X is selected from -NR x -、-CR x R y -、-O-、-S-、-S(O)- or -S(O)2-, X is preferably -O-、-S-; R1, R2, R3, R4, R5, R6, R8, R x R y Each group is independently selected from hydrogen, deuterium, tritium, halogen, carboxyl, amino, hydroxyl, cyano, amide, alkoxy, alkylamino, mercapto, alkyl, alkenyl, heteroalkyl, =O, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -S(O). r R a -O-(CH2) t1 -[O-(CH2) t2 ] e -O-(CH2) t3 R a The -O-(CH2) t1 -[O-(CH2) t2 ] e -O-(CH2) t3 R a The O in the group may optionally be replaced by one or more S or N groups, wherein the amino, hydroxy, amide, alkoxy, alkylamino, mercapto, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -S(O) group is... r R a -O-(CH2) t1 -[O-(CH2) t2 ] e -O-(CH2) t3 R a Optionally composed of one or more radicals selected from deuterium, tritium, alkyl, haloalkyl, halogen, amino, hydroxyl, cyano, formyl, acetyl, deuterated alkyl, tritated alkyl, -S(O). r R a -C(O)NR a R b Substituted by cycloalkyl, heterocycloalkyl, aryl, heteroaryl or alkoxy substituents; Alternatively, any two or two R8s selected from R1, R2, R3, R4, R5, R6, and R8, together with the atoms attached to them, form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group may optionally be further substituted by one or more substituents selected from hydroxyl, amino, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, and =O. R7 is selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, halogen, nitro, cyano, hydroxyl, amide, cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, =O, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a C(O)OR b -NR a R b -NR a S(O) r R b -NR a C(O)R b -NR a C(O)NR b R c -NR a C(S)NR b R c -NR a S(O) r NR b R c -C(=NR) a )NR b R c -C(=NR) a )R b -C(=NR) a )NR b OR c -C(=NR) a )NR b NR c -C(O)NR a OR b -C(O)NR a NR b R c -C(O)NR a R b -C(O)C(O)NR a R b -S(=NR) a )(O)R b -S(=NR) a )NR b R c -S(=NR) a )R b -S(=NR) a )(O)NR b R c -S(O) r NR a R b -S(O) r R a -Si(O)NR a R b 、-Si(R a 3. -P(O) s R a R b -OR a cycloalkylalkyl, heterocyclicalkyl, -alkylene-O-alkylene-cycloalkyl, -alkylene-O-cycloalkyl, -O-alkylene-heteroaryl, or -O-alkylene-heterocyclic, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, and heterocyclicalkyl are each independently and optionally selected by one or more R 01 Replaced; R 01 Whether identical or different, each is independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, halogen, nitro, cyano, hydroxyl, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a C(O)OR b -NR a R b -NR a S(O) r R b -NR a C(O)R b -NR a C(O)NR b R c -NR a C(S)NR b R c -NR a S(O) r NR b R c -C(=NR) a )NR b R c -C(=NR) a )R b -C(=NR) a )NR b OR c -C(=NR) a )NR b NR c -C(O)NR a OR b -C(O)NR a NR b R c -C(O)NR a R b -C(O)C(O)NR a R b -S(=NR) a )(O)R b -S(=NR) a )NR b R c -S(=NR) a )R b -S(=NR) a )(O)NR b R c -S(O) r NR a R b -S(O) r R a -Si(O)NR a R b 、-Si(R a 3. -P(O) s R a R b -OR a The alkyl, heterocyclic, alkylene-O-alkylene-cycloalkyl, alkylene-O-cycloalkyl, alkylene-Hydroaryl, or alkylene-Hydroaryl groups may be further substituted by one or more substituents selected from deuterium, =O, halogen, hydroxyl, cyano, amino, aminoalkyl, acetyl, alkyl, alkenyl, alkynyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; Alternatively, R7, R8, and the atoms connected to them can be linked by single bonds, double bonds, cycloalkyl groups, or heterocycloalkyl groups to form a macrocycle, which can be replaced by substituents of halogen, amino, hydroxyl, cyano, amide, alkoxy, mercapto, alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl groups. Alternatively, the two R7s together with the atoms they are attached to form a cycloalkyl or heterocycloalkyl group, which may optionally be further substituted by one or more substituents selected from hydroxyl, amino, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, =O. R a R b R c Each is independently selected from hydrogen atom, hydroxyl, amino, alkyl, alkoxy, cycloalkyl, heterocyclic, heteroalkenyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, heteroalkenyl, aryl or heteroaryl may optionally be further substituted by one or more substituents selected from alkyl, halogen, nitro, cyano, amino, carboxyl, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, and substituents; Or R a R b R c Any two links form a saturated or unsaturated heterocycle, which is further substituted by one or more substituents selected from alkyl, halogen, nitro, cyano, amino, carboxyl, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, etc. m and q are 0, 1, 2, 3, 4 or 5; r is 0, 1, or 2; t1 can be 0, 1, 2, or 3; t2 can be 0, 1, 2, or 3; t3 can be 0, 1, 2, or 3; e can be 0, 1, 2, or 3; s is 0 or 1.

9. The compound according to claim 8, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein the compound is a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof of general formula (II-A): in: The definitions of R1, R2, R3, R4, R5, R6, R7, R8, T, ring D, m, and q are as described in claim 5.

10. A compound of general formula (IB) or a stereoisomer, tautomer, deuterated derivative thereof or a pharmaceutically acceptable salt thereof: Ring F is selected from aryl, heteroaryl, and fused rings; Cyclomeric G is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups; L is selected from single bond, -NR x -、-CR x R y -、-S-; X is selected from -NR x -、-CR x R y -、-O-、-S-、-S(O)- or -S(O)2-, X is preferably -O-、-S-; R1, R2, R3, R4, R5, R6, R8, R x R y Each group is independently selected from hydrogen, deuterium, tritium, halogen, carboxyl, amino, hydroxyl, cyano, amide, alkoxy, alkylamino, mercapto, alkyl, alkenyl, heteroalkyl, =O, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -S(O). r R a -O-(CH2) t1 -[O-(CH2) t2 ] e -O-(CH2) t3 R a The -O-(CH2) t1 -[O-(CH2) t2 ] e -O-(CH2) t3 R a The O in the group may optionally be replaced by one or more S or N groups, wherein the amino, hydroxy, amide, alkoxy, alkylamino, mercapto, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -S(O) group is... r R a -O-(CH2) t1 -[O-(CH2) t2 ] e -O-(CH2) t3 R a Optionally composed of one or more radicals selected from deuterium, tritium, alkyl, haloalkyl, halogen, amino, hydroxyl, cyano, formyl, acetyl, deuterated alkyl, tritated alkyl, -S(O). r R a -C(O)NR a R b Substituted by cycloalkyl, heterocycloalkyl, aryl, heteroaryl or alkoxy substituents; Alternatively, any two or two R8s selected from R1, R2, R3, R4, R5, R6, and R8, together with the atoms attached to them, form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group may optionally be further substituted by one or more substituents selected from hydroxyl, amino, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, and =O. The condition is that when L is selected from a single bond and ring G is selected from aryl or heteroaryl, and the condition that any two atoms of R3, R5, R6, and R8 connected to them form a cycloalkyl or heterocycloalkyl group is not met, ring F is selected only from benzoxyheterocyclic boranes. R7 is selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, halogen, nitro, cyano, hydroxyl, amide, cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, =O, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a C(O)OR b -NR a R b -NR a S(O) r R b -NR a C(O)R b -NR a C(O)NR b R c -NR a C(S)NR b R c -NR a S(O) r NR b R c -C(=NR) a )NR b R c -C(=NR) a )R b -C(=NR) a )NR b OR c -C(=NR) a )NR b NR c -C(O)NR a OR b -C(O)NR a NR b R c -C(O)NR a R b -C(O)C(O)NR a R b -S(=NR) a )(O)R b -S(=NR) a )NR b R c -S(=NR) a )R b -S(=NR) a )(O)NR b R c -S(O) r NR a R b -S(O) r R a -Si(O)NR a R b 、-Si(R a 3. -P(O) s R a R b -OR a , cycloalkylalkyl, heterocyclicalkyl, -alkylene-O-alkylene-cycloalkyl, -alkylene-O-cycloalkyl, -O-alkylene-heteroaryl or -O-alkylene-heterocyclic, wherein, The alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, and heterocyclic alkyl groups are each independently and optionally influenced by one or more R groups. 01 Replaced; R 01 Whether identical or different, each is independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, halogen, nitro, cyano, hydroxyl, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R a -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a C(O)OR b -NR a R b -NR a S(O) r R b -NR a C(O)R b -NR a C(O)NR b R c -NR a C(S)NR b R c -NR a S(O) r NR b R c -C(=NR) a )NR b R c -C(=NR) a )R b -C(=NR) a )NR b OR c -C(=NR) a )NR b NR c -C(O)NR a OR b -C(O)NR a NR b R c -C(O)NR a R b -C(O)C(O)NR a R b -S(=NR) a )(O)R b -S(=NR) a )NR b R c -S(=NR) a )R b -S(=NR) a )(O)NR b R c -S(O) r NR a R b -S(O) r R a -Si(O)NR a R b 、-Si(R a 3. -P(O) s R a R b -OR a The alkyl, heterocyclic, alkylene-O-alkylene-cycloalkyl, alkylene-O-cycloalkyl, alkylene-Hydroaryl, or alkylene-Hydroaryl groups may be further substituted by one or more substituents selected from deuterium, =O, halogen, hydroxyl, cyano, amino, aminoalkyl, acetyl, alkyl, alkenyl, alkynyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; Alternatively, R7, R8, and the atoms connected to them can be linked by single bonds, double bonds, cycloalkyl groups, or heterocycloalkyl groups to form a macrocycle, which can be replaced by substituents of halogen, amino, hydroxyl, cyano, amide, alkoxy, mercapto, alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl groups. Alternatively, the two R7s together with the atoms they are attached to form a cycloalkyl or heterocycloalkyl group, which may optionally be further substituted by one or more substituents selected from hydroxyl, amino, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, =O. R a R b R c Each is independently selected from hydrogen atom, hydroxyl, amino, alkyl, alkoxy, cycloalkyl, heterocyclic, heteroalkenyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, heteroalkenyl, aryl or heteroaryl may optionally be further substituted by one or more substituents selected from alkyl, halogen, nitro, cyano, amino, carboxyl, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, and substituents; Or R a R b R c Any two links form a saturated or unsaturated heterocycle, which is further substituted by one or more substituents selected from alkyl, halogen, nitro, cyano, amino, carboxyl, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, etc. m and q are 0, 1, 2, 3, 4 or 5; r is 0, 1, or 2; t1 can be 0, 1, 2, or 3; t2 can be 0, 1, 2, or 3; t3 can be 0, 1, 2, or 3; e can be 0, 1, 2, or 3; s is 0 or 1.

11. The compound according to any one of claims 1 to 10, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, and R5 are each independently selected from hydrogen atoms, methyl groups, and trifluoromethyl groups.

12. The compound according to any one of claims 1 to 10, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein R6 is selected from halogens and methoxy groups.

13. The compound according to any one of claims 1 to 10, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein ring A and ring B are selected from 5-6 aryl and 5-6 heteroaryl groups.

14. The compound according to any one of claims 1 to 13, or its stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein the compound is:

15. A pharmaceutical composition comprising: The compound or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof according to any one of claims 1 to 14, and pharmaceutically acceptable carriers, excipients or combinations thereof.

16. Use of the compound or stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, or the pharmaceutical composition according to claim 15, in the preparation of a voltage-gated channel Nav1.8 antagonist.

17. Use of the compound or stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, or the pharmaceutical composition according to claim 15, in the preparation of a medicament for the prevention and / or treatment of diseases mediated by the voltage-gated channel Nav 1.8, wherein the diseases mediated by Nav 1.8 are pain or pain-related diseases, multiple sclerosis, incontinence, pathological cough, peroneal muscular dystrophy, or arrhythmia.

18. The use according to claim 17, wherein the pain mediated by Nav 1.8 or pain-related diseases are selected from acute pain, chronic pain, inflammatory pain, postoperative pain, neuropathic pain, cancer pain, musculoskeletal pain, visceral pain, and primary pain, and the postoperative pain is preferably selected from abdominoplasty pain and bunion removal pain.

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