Fused ring derivative, preparation method therefor and use thereof

Abstract

The present invention relates to a fused ring derivative, a preparation method therefor and a use thereof. Specifically, provided are a compound as shown in general formula (I), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, and a preparation method therefor, used for preventing and / or treating related diseases mediated by a voltage-gated sodium channel inhibitor.

Description

Cyclic derivatives, preparation methods and uses thereof

[0001] This application claims priority to Chinese patent application No. 202410176775.8, filed on February 8, 2024, priority to Chinese patent application No. 202410534111.4, filed on April 30, 2024, priority to Chinese patent application No. 202411197221.2, filed on August 29, 2024, and priority to Chinese patent application No. 202411733273.7, filed on November 29, 2024. This application incorporates the entirety of the aforementioned Chinese patent applications. Technical Field

[0002] The present invention belongs to the field of medicine, and in particular relates to a paracyclic derivative, a preparation method and use thereof. Background Art

[0003] Pain is the third most common health concern after cardiovascular and cerebrovascular diseases and cancer. Commonly used analgesics are primarily nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids. However, NSAIDs have a weak analgesic effect and a ceiling effect. Opioid analgesics are also commonly addictive and suffer from severe abuse. Overall, the analgesic market still has significant unmet demand.

[0004] Electrical signals underlie a range of physiological processes, including pain signaling, and sodium ion channels are the primary triggers of these signals. Voltage-gated sodium channels (NaV) are multisubunit transmembrane glycoproteins expressed on cell membranes, composed of α and β subunits. The α subunit is a functional unit, consisting of four homologous transmembrane domains, each containing six transmembrane hydrophobic α-helices (S1-S6). S1-S4 form the voltage receptor, which regulates the hydrophilicity of the sodium ion channel between S5 and S6, causing cellular depolarization or hyperpolarization and completing transmembrane signaling. In humans, there are nine different α subunit isoforms, designated NaV1.1 to 1.9. Abnormal inactivation or activation of these subtypes is associated with a variety of neurological, cardiovascular, and muscular diseases. Among these, the four subtypes associated with pain are primarily NaV1.3, NaV1.7, NaV1.8, and NaV1.9. NaV1.7 is present in sympathetic ganglion neurons and peripheral sensory neurons. NaV1.8 and NaV1.9 are expressed only in peripheral sensory neurons. Abnormal activation of these channels can cause analgesia or allodynia, providing potential targets for non-addictive analgesia.

[0005] NaV1.8 is a tetrodotoxin-insensitive sodium channel primarily expressed on nociceptive neurons. It plays a key role in pain signaling in the peripheral nervous system and is a primary selective target for pain treatment. Because NaV1.8 is primarily distributed in pain-sensing neurons, the use of selective NaV1.8 inhibitors is unlikely to result in the common adverse reactions of non-selective NaV inhibitors. More importantly, NaV1.8 does not participate in central nervous system-related activities, so NaV1.8 inhibitors do not have the addictive potential of opioids and will not affect motor function.

[0006] To date, numerous companies worldwide have entered the research field of Nav1.8 inhibitors, including Vertex Pharmaceuticals, Pfizer, GSK, Merck, Hengrui Medicine, Shanghai Jiyu Pharmaceuticals, Shenzhen Haibo Pharmaceuticals, and Guangzhou Fermion Technology. However, the development of Nav1.8 inhibitors has been challenging, with both Vertex Pharmaceuticals' VX-150 and Pfizer's PF-04531083 discontinued in Phase 2 clinical trials. Currently, there are only a few Nav1.8 inhibitors under development globally, including Vertex's VX-548, Hengrui Medicine's HRS-4800, Jimin Kexin's JMKX000623, Haibo Pharmaceuticals' HBW-004285, and Fermion Technology's FZ008-145. Vertex Pharmaceuticals' VX-548 is the most advanced. VX-548 is an oral selective NaV1.8 inhibitor developed by Vertex Pharmaceuticals. Compared with other NaV ion channels, it is highly selective for NaV1.8 and selectively produces an inhibitory effect. Compared with opioids, this drug class provides better analgesia while avoiding side effects such as addiction. On January 30, 2024, Vertex Pharmaceuticals announced the latest data from the Phase III clinical trial of VX-548 for the treatment of moderate to severe acute pain. The study achieved the primary endpoints of NPRS and SPID48, showing significant improvement compared to placebo.

[0007] Therefore, there is an urgent need to develop new analgesic Nav1.8 inhibitors with advantages such as obvious blocking effect on NaV1.8 and / or good pharmacokinetic properties to meet the huge market demand. Summary of the Invention

[0008] The technical problem to be solved by the present invention is that there are relatively few types of existing NaV1.8 blockers. To this end, the present invention provides a paracyclic derivative, a preparation method and its use. This type of compound has good NaV1.8 inhibitory activity and can be used to treat and / or prevent diseases mediated by NaV1.8 inhibitors, such as pain, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, postoperative pain and visceral pain, cough, pathological cough, multiple sclerosis, Chuck-Male-Doucet syndrome, incontinence or arrhythmia, etc., providing a new option for the treatment of such diseases or alleviating their severity.

[0009] The object of the present invention is to provide a compound represented by general formula (I), its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof,

[0010] in:

[0011] X is O or S;

[0012] Ring B is C 3-8 Cycloalkyl or a 3-8 membered heterocyclic group containing 1-4 heteroatoms selected from N, O and S;

[0013] R b are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy or C 1-6 haloalkoxy;

[0014] R1 and R2 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy or C 1-6 haloalkoxy;

[0015] Ring C is C 6-10 Aryl or a 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S;

[0016] R c are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl or C 1-6 Alkoxy; wherein the C 1-6 Alkyl or C 1-6The alkoxy group is optionally further substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, cyano, amino, nitro and oxo;

[0017] Ring A is C 6-10 aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, 5-10 membered heterocyclic group containing 1-4 heteroatoms selected from N, O and S, or

[0018] R a are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, -(CH2) n OR aa 、-(CH2) n NR aa R bb 、-(CH2) n C(O)R aa 、-(CH2) n C(O)OR aa 、-(CH2) n C(O)NR aa R bb 、-(CH2) n S(O)NR aa R bb 、-(CH2) n C(O)NR bb (CH2) n1 OP(O)(OR aa )2、-(CH2) n OP(O)(OR aa )2、-(CH2) n OC(O)(CH2) n1 COOR aa or -(CH2) n C(=NR cc )NR aa R bb ;

[0019] R aa 、R bb and R cc are independently hydrogen, deuterium, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, cyano, amino, nitro and oxo;

[0020] x is an integer from 0 to 6;

[0021] y is an integer from 0 to 6;

[0022] z is an integer from 0 to 6;

[0023] n is an integer from 0 to 3; and

[0024] n1 is an integer from 0 to 3.

[0025] In a further preferred embodiment of the present invention, X is O or S, preferably O.

[0026] In a further preferred embodiment of the present invention, the ring B is C 3-8 Cycloalkyl or a 3-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O and S; preferably cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or tetrahydropyranyl.

[0027] In a further preferred embodiment of the present invention, said R b are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy; preferably hydrogen or C 1-3 Alkyl; more preferably hydrogen or methyl.

[0028] In a further preferred embodiment of the present invention, said R1 and R2 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy; preferably hydrogen or C 1-3 Alkyl; more preferably hydrogen, methyl, ethyl or isopropyl.

[0029] In a further preferred embodiment of the present invention, the ring C is C 6-10 Aryl or a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S; preferably phenyl or pyridyl, more preferably the following groups:

[0030] In a further preferred embodiment of the present invention, said R c are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-3Alkyl or C 1-3 Alkoxy, wherein the C 1-3 Alkyl or C 1-3 The alkoxy group is optionally further substituted with one or more deuterium or halogen; preferably hydrogen, deuterium, halogen, C 1-3 Alkyl or C 1-3 Alkoxy, wherein the C 1-3 Alkyl or C 1-3 The alkoxy group is optionally further substituted with one or more deuterium or halogen; more preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, -OCF3, -OCHF2, -OCH2F, -OCD2F, -CD3, -OCD3 or -OCDF2.

[0031] In a further preferred embodiment of the present invention, said R c are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy or C 1-6 Halogenated alkoxy; preferably hydrogen, deuterium, halogen, hydroxy, cyano, amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy or C 1-3 more preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, -CD3, -OCD3 or -OCDF2.

[0032] In a further preferred embodiment of the present invention, the ring A is C 6-10 aryl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O and S or Preferably, phenyl, pyridyl, dihydropyridyl, dihydropyridazinyl, piperidinyl or More preferably, the following groups:

[0033] In a further preferred embodiment of the present invention, said R a are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3Haloalkoxy, -(CH2) n OR aa 、-(CH2) n NR aa R bb 、-(CH2) n C(O)OR aa 、-(CH2) n C(O)NR aa R bb 、-(CH2) n S(O)NR aa R bb 、-(CH2) n C(O)NR bb (CH2) n1 OP(O)(OR aa )2、-(CH2) n OP(O)(OR aa )2、-(CH2) n OC(O)(CH2) n1 COOR aa or -(CH2) n C(=NR cc )NR aa R bb ; preferably hydrogen, halogen, oxo, C 1-3 Alkyl, -OR aa 、-NR aa R bb 、-C(O)OR aa 、-C(O)NR aa R bb 、-S(O)NR aa R bb 、-C(O)NR bb -CH2-OP(O)(OR aa )2、-CH2OP(O)(OR aa )2, -CH2OC(O)(CH2)2COOR aa or -C(=NR cc )NR aa R bb; More preferably, it is hydrogen, fluorine, chlorine, bromine, cyano, oxo, methyl, -C(O)NH2, -S(O)NH2, -C(O)NH-CH2-OP(O)(OH)2, -O-CH2CH(OH)(CH2OH), -C(O)OCH3, -N(CH2OH)2, -CH2OP(O)(OH)2, -CH2OC(O)(CH2)2COOH, -C(=NH)NH2, -C(=N-CH3)NH2, -C(=N-OH)NH2 or -C(=N-OCH3)NH2.

[0034] In a further preferred embodiment of the present invention, said R a are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, -(CH2) n OR aa 、-(CH2) n NR aa R bb 、-(CH2) n C(O)R aa 、-(CH2) n C(O)OR aa 、-(CH2) n C(O)NR aa R bb 、-(CH2) n OP(O)(OR aa )2、-(CH2) n OC(O)(CH2) n1 COOR aa or -(CH2) n C(=NR cc )NR aa R bb ; preferably hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -(CH2) n OR aa 、-(CH2) n NR aa R bb 、-(CH2) n C(O)OR aa、-(CH2) n C(O)NR aa R bb 、-(CH2) n OP(O)(OR aa )2、-(CH2) n OC(O)(CH2) n1 COOR aa or -(CH2) n C(=NR cc )NR aa R bb ; preferably hydrogen, halogen, oxo, C 1-3 Alkyl, -OR aa 、-NR aa R bb 、-C(O)OR aa 、-C(O)NR aa R bb 、-CH2OP(O)(OR aa )2, -CH2OC(O)(CH2)2COOR aa or -C(=NR cc )NR aa R bb ; More preferably, it is hydrogen, fluorine, chlorine, bromine, oxo, methyl, -C(O)NH2, -O-CH2CH(OH)(CH2OH), -C(O)OCH3, -N(CH2OH)2, -CH2OP(O)(OH)2, -CH2OC(O)(CH2)2COOH, -C(=NH)NH2, -C(=N-CH3)NH2, -C(=N-OH)NH2 or -C(=N-OCH3)NH2.

[0035] In a further preferred embodiment of the present invention, said R aa 、R bb and R cc are independently hydrogen, deuterium, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more hydroxy groups; preferably hydrogen, hydroxy, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more hydroxy groups; more preferably hydrogen, hydroxy, methyl, methoxy, -CH2OH or -CH2CH(OH)(CH2OH).

[0036] In a further preferred embodiment of the present invention, x is an integer of 0-4; preferably 1, 2 or 3.

[0037] In a further preferred embodiment of the present invention, y is an integer of 0-4; preferably 1, 2 or 3.

[0038] In a further preferred embodiment of the present invention, z is an integer of 0-4; preferably 1, 2 or 3.

[0039] In a further preferred embodiment of the present invention, n is an integer of 0-2; preferably 0 or 1.

[0040] In a further preferred embodiment of the present invention, n1 is an integer of 0-2; preferably 1 or 2.

[0041] In a further preferred embodiment of the present invention, the For the following groups: Preferably

[0042] In a further preferred embodiment of the present invention, the for Preferably

[0043] In a further preferred embodiment of the present invention, the for Preferably

[0044] In a further preferred embodiment of the present invention, the general formula (I) further has a structure represented by the general formula (II):

[0045] in:

[0046] Ring B is C 3-8 Cycloalkyl or a 3-8 membered heterocyclic group containing 1-4 heteroatoms selected from N, O and S;

[0047] R b are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C1-6 Deuterated alkoxy or C 1-6 haloalkoxy;

[0048] R1 and R2 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy or C 1-6 haloalkoxy;

[0049] Ring C is C 6-10 Aryl or a 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S;

[0050] R c are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy or C 1-6 haloalkoxy;

[0051] Ring A is C 6-10 Aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, or 5-10 membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S;

[0052] R a are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, -(CH2) n OR aa 、-(CH2) n NR aa R bb 、-(CH2) n C(O)R aa 、-(CH2) n C(O)OR aa 、-(CH2) n C(O)NR aa R bb 、-(CH2) n C(NH2)(=N)R aa or -(CH2)n C(NH2)(=N)OR aa ;

[0053] R aa and R bb are independently hydrogen, deuterium, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, cyano, amino, nitro and oxo;

[0054] x is an integer from 0 to 6;

[0055] y is an integer from 0 to 6;

[0056] z is an integer from 0 to 6; and

[0057] n is an integer from 0 to 3.

[0058] In a further preferred embodiment of the present invention, the ring B is C 3-8 Cycloalkyl or 3-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O and S; preferably cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or tetrahydropyranyl. b are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy; preferably hydrogen or C 1-3 Alkyl; more preferably hydrogen or methyl.

[0059] In a further preferred embodiment of the present invention, said R1 and R2 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy; preferably hydrogen or C 1-3 Alkyl; more preferably hydrogen, methyl, ethyl or isopropyl;

[0060] In a further preferred embodiment of the present invention, the ring C is C 6-10 Aryl or a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S; preferably phenyl or pyridyl; more preferably the following groups:

[0061] In a further preferred embodiment of the present invention, said R care independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy or C 1-3 Halogenated alkoxy; preferably hydrogen, halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; more preferably hydrogen, fluorine, methyl, ethyl, deuterated methyl, deuterated ethyl, methoxy, ethoxy, deuterated methoxy or deuterated ethoxy.

[0062] In a further preferred embodiment of the present invention, the ring A is C 6-10 Aryl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, or 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O and S; preferably phenyl, pyridyl, dihydropyridyl, pyridonyl or pyridine-N-oxide; more preferably the following groups:

[0063] In a further preferred embodiment of the present invention, said R a are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -(CH2) n OR aa 、-(CH2) n NR aa R bb 、-(CH2) n C(O)OR aa 、-(CH2) n C(O)NR aa R bb 、-(CH2) n C(NH2)(=N)R aa or -(CH2) n C(NH2)(=N)OR aa ; preferably hydrogen, halogen, oxo, C 1-3 Alkyl, -OR aa 、-NR aa R bb 、-C(O)OR aa 、-C(O)NR aa R bb、-C(NH2)(=N)R aa or -C(NH2)(=N)OR aa More preferably, it is hydrogen, fluorine, chlorine, bromine, oxo, methyl, -C(O)NH2, -O-CH2CH(OH)(CH2OH), -C(O)OCH3, -N(CH2OH)2, -C(NH2)(=N)H, -C(NH2)(=N)OH or -C(NH2)(=N)OCH3;

[0064] In a further preferred embodiment of the present invention, said R aa and R bb are independently hydrogen, deuterium, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more hydroxy groups; preferably hydrogen, hydroxy, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more hydroxy groups; more preferably hydrogen, hydroxy, methyl, methoxy, -CH2OH or -CH2CH(OH)(CH2OH).

[0065] In a further preferred embodiment of the present invention, x is an integer from 0 to 4, preferably 1, 2 or 3; y is an integer from 0 to 4, preferably 1, 2 or 3; z is an integer from 0 to 4, preferably 1, 2 or 3; and n is an integer from 0 to 1, preferably 0.

[0066] In a further preferred embodiment of the present invention, the For the following groups:

[0067] In a further preferred embodiment of the present invention, the for

[0068] In a further preferred embodiment of the present invention, the for

[0069] In a further preferred embodiment of the present invention, the general formula (I) further has a structure represented by the general formula (III):

[0070] in:

[0071] Ring B is C3-8 Cycloalkyl or a 3-8 membered heterocyclic group containing 1-4 heteroatoms selected from N, O and S;

[0072] R b are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0073] R1 and R2 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0074] R3, R4 and R5 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0075] Ring A is C 6-10 Aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, or 5-10 membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S;

[0076] R a are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(CH2) n OR aa 、-(CH2) n NR aa R bb 、-(CH2) n C(O)R aa 、-(CH2) n C(O)OR aa or -(CH2) n C(O)NR aa R bb ;

[0077] R aa and R bb are independently hydrogen, deuterium, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, cyano, amino, nitro and oxo;

[0078] x is an integer from 0 to 6;

[0079] y is an integer from 0 to 6; and

[0080] n is an integer from 0 to 3.

[0081] In a further preferred embodiment of the present invention, the general formula (I) further has a structure represented by the general formula (III):

[0082] in:

[0083] The ring B is C 3-8 Cycloalkyl or a 3-8 membered heterocyclic group containing 1-4 heteroatoms selected from N, O and S;

[0084] R b are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0085] R1 and R2 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0086] R3, R4 and R5 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0087] Ring A is a 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S, or a 5-10 membered heterocyclic group containing 1-4 heteroatoms selected from N, O and S;

[0088] R a are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(CH2)n OR aa 、-(CH2) n NR aa R bb 、-(CH2) n C(O)R aa 、-(CH2) n C(O)OR aa or -(CH2) n C(O)NR aa R bb ;

[0089] R aa and R bb are independently hydrogen, deuterium, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, cyano, amino, nitro and oxo;

[0090] x is an integer from 0 to 6;

[0091] y is an integer from 0 to 6; and

[0092] n is an integer from 0 to 3.

[0093] In a further preferred embodiment of the present invention, the ring B is C 3-6 Cycloalkyl; preferably cyclobutyl or cyclopentyl.

[0094] In a further preferred embodiment of the present invention, said R b are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy; preferably hydrogen or C 1-3 Alkyl; more preferably hydrogen or methyl.

[0095] In a further preferred embodiment of the present invention, y is an integer of 0-4; preferably 1, 2 or 3.

[0096] In a further preferred embodiment of the present invention, said R1 and R2 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy; preferably hydrogen or C 1-3 Alkyl; more preferably hydrogen or methyl.

[0097] In a further preferred embodiment of the present invention, said R3, R4 and R5 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy; preferably halogen or C 1-3 Alkoxy; more preferably fluoro or methoxy.

[0098] In a further preferred embodiment of the present invention, the ring A is a phenyl group, a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, or a 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O and S; preferably a phenylpyridyl group, a dihydropyridyl group, a pyridonyl group or a pyridine-N-oxide group; more preferably the following groups:

[0099] In a further preferred embodiment of the present invention, the ring A is a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, or a 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O and S; preferably a pyridyl group, a dihydropyridyl group or a pyridine-N-oxide group; more preferably the following groups:

[0100] In a further preferred embodiment of the present invention, said R a are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -(CH2) n OR aa 、-(CH2) n NR aa R bb or -(CH2) n C(O)NR aa R bb ; preferably hydrogen, halogen, oxo, C 1-3 Alkyl, -OR aa 、-NR aa R bb or -C(O)NR aa R bb ; More preferably, it is hydrogen, fluorine, chlorine, bromine, oxo, methyl, -C(O)NH2, -O-CH2CH(OH)(CH2OH) or -N(CH2OH)2.

[0101] In a further preferred embodiment of the present invention, said R aa and R bb are independently hydrogen, deuterium, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more hydroxy groups, preferably hydrogen or C 1-6 Alkyl; more preferably hydrogen, -CH2OH or -CH2CH(OH)(CH2OH).

[0102] In a further preferred embodiment of the present invention, x is an integer of 0-4; preferably 1, 2 or 3.

[0103] In a further preferred embodiment of the present invention, n is an integer from 0 to 1; preferably 0.

[0104] In a further preferred embodiment of the present invention, the general formula (III) further has a structure shown by the general formula (IV):

[0105] wherein m is an integer from 0 to 3; Ring A, R1, R3, R4, R5, R a 、R aa 、R bb , x and n are as described above.

[0106] In a further preferred embodiment of the present invention, in the structure represented by the general formula (IV), m is 3, and the remaining rings A, R1, R3, R4, R5, R a 、R aa 、R bb , x and n are as described above.

[0107] In a further preferred embodiment of the present invention, the general formula (III) further has a structure represented by the general formula (IV-A) or the general formula (IV-B):

[0108] wherein m is an integer from 0 to 3; Ring A, R1, R3, R4, R5, R a 、R aa 、R bb , x and n are as described above.

[0109] In a further preferred embodiment of the present invention, the For the following groups:

[0110] In a further preferred embodiment of the present invention, the for

[0111] It should be understood that, based on the above definition of general formula (I), in other preferred embodiments of the present invention, in the structures represented by general formulas other than general formula (I), such as general formula (II), general formula (III), or general formula (IV), the R a It can also be independently -(CH2) n S(O)NR aa R bb or -(CH2) n C(O)NR bb (CH2) n1 OP(O)(OR aa )2, preferably -S(O)NH2 or -C(O)NH-CH2-OP(O)(OH) 2。

[0112] It should be understood that, based on the above definition of general formula (I), in other preferred embodiments of the present invention, in the structures represented by general formulas other than general formula (I), such as general formula (II), general formula (III), or general formula (IV), the R c Alternatively, the corresponding positions may be independently C optionally further substituted with one or more deuterium or halogen. 1-6 Alkyl or C 1-6 Alkoxy; preferably C optionally further substituted by one or more deuterium or halogen 1-3 Alkyl or C 1-3 Alkoxy; more preferably -OCD2F or -OCDF 2。

[0113] In a further preferred embodiment of the present invention, the general formula (I) further has a structure represented by the general formula (V):

[0114] in:

[0115] X is O or S; preferably O;

[0116] R1 is hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy or C 1-6 Halogenated alkoxy; preferably hydrogen, deuterium, halogen, hydroxy, cyano, amino, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; more preferably hydrogen, methyl, ethyl or isopropyl;

[0117] R b are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy or C 1-6 Halogenated alkoxy; preferably hydrogen, deuterium, halogen, hydroxy, cyano, amino, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; more preferably hydrogen or methyl;

[0118] Ring C is C 6-10 Aryl or a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S; preferably phenyl or pyridyl; more preferably the following groups:

[0119] R c are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted by one or more substituents independently selected from deuterium, halogen, hydroxyl, cyano, amino, nitro and oxo; preferably hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-3 Alkyl or C 1-3 Alkoxy, wherein the C 1-3 Alkyl or C 1-3 The alkoxy group is optionally further substituted with one or more deuterium or halogen; more preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, -OCF3, -OCHF2, -OCH2F, -OCD2F, -CD3, -OCD3 or -OCDF2;

[0120] Ring A is C 6-10 aryl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O and S or Preferably, phenyl, pyridyl, dihydropyridyl, dihydropyridazinyl, piperidinyl or More preferably, the following groups: More preferred are the following groups:

[0121] R a are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, -(CH2) n OR aa 、-(CH2) n NR aa R bb 、-(CH2) n C(O)R aa 、-(CH2) n C(O)OR aa 、-(CH2) n C(O)NR aa R bb 、-(CH2) n S(O)NR aa R bb 、-(CH2) n C(O)NR bb (CH2) n1 OP(O)(OR aa )2、-(CH2) n OP(O)(OR aa )2、-(CH2) n OC(O)(CH2) n1 COOR aa or -(CH2) n C(=NR cc )NR aa R bb ; preferably hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -(CH2) n OR aa 、-(CH2) n NR aa R bb 、-(CH2) n C(O)OR aa 、-(CH2) n C(O)NR aa R bb 、-(CH2) n S(O)NR aa Rbb 、-(CH2) n C(O)NR bb (CH2) n1 OP(O)(OR aa )2、-(CH2) n OP(O)(OR aa )2、-(CH2) n OC(O)(CH2) n1 COOR aa or -(CH2) n C(=NR cc )NR aa R bb More preferably, it is hydrogen, fluorine, chlorine, bromine, cyano, oxo, methyl, -C(O)NH2, -S(O)NH2, -C(O)NH-CH2-OP(O)(OH)2, -O-CH2CH(OH)(CH2OH), -C(O)OCH3, -N(CH2OH)2, -CH2OP(O)(OH)2, -CH2OC(O)(CH2)2COOH, -C(=NH)NH2, -C(=N-CH3)NH2, -C(=N-OH)NH2 or -C(=N-OCH3)NH2;

[0122] R aa 、R bb and R cc are independently hydrogen, deuterium, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more substituents independently selected from deuterium, halogen, hydroxyl, cyano, amino, nitro and oxo; preferably hydrogen, deuterium, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more hydroxy groups; more preferably hydrogen, hydroxy, methyl, methoxy, -CH2OH or -CH2CH(OH)(CH2OH);

[0123] x is an integer from 0 to 6; preferably an integer from 0 to 4; more preferably 1, 2 or 3;

[0124] y is an integer of 0-6; preferably an integer of 0-4; more preferably 1, 2 or 3;

[0125] z is an integer from 0 to 6; preferably an integer from 0 to 4; more preferably 1, 2 or 3;

[0126] n is an integer of 0-3; preferably an integer of 0-2; more preferably 0 or 1;

[0127] n1 is an integer from 0 to 3; preferably an integer from 0 to 2; more preferably 1 or 2; and

[0128] p is an integer from 0 to 3.

[0129] In a further preferred embodiment of the present invention, the general formula (V) further has a structure shown by the general formula (VI):

[0130] in:

[0131] R3, R4 and R5 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted by one or more substituents independently selected from deuterium, halogen, hydroxyl, cyano, amino, nitro and oxo; preferably hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-3 Alkyl or C 1-3 Alkoxy, wherein the C 1-3 Alkyl or C 1-3 The alkoxy group is optionally further substituted with one or more deuterium or halogen; more preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, -OCF3, -OCHF2, -OCH2F, -OCD2F, -CD3, -OCD3 or -OCDF2;

[0132] Ring A, R a , R1, x and p are as described above.

[0133] In a further preferred embodiment of the present invention, the general formula (VI) further has a structure represented by the general formula (VI-A), (VI-B), (VI-C) or (VI-D):

[0134] Among them: Ring A, R a , R1, R3, R4, R5, x and p are as described above.

[0135] In a further preferred embodiment of the present invention, the general formula (VI) further has a structure shown by the general formula (VII):

[0136] in:

[0137] R6 is hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 Alkyl, C1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, -(CH2) n OR aa 、-(CH2) n NR aa R bb 、-(CH2) n C(O)R aa 、-(CH2) n C(O)OR aa 、-(CH2) n C(O)NR aa R bb 、-(CH2) n S(O)NR aa R bb 、-(CH2) n C(O)NR bb (CH2) n1 OP(O)(OR aa )2、-(CH2) n OP(O)(OR aa )2、-(CH2) n OC(O)(CH2) n1 COOR aa or -(CH2) n C(=NR cc )NR aa R bb ; preferably hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -(CH2) n OR aa 、-(CH2) n NR aa R bb 、-(CH2) n C(O)OR aa 、-(CH2) n C(O)NR aa R bb 、-(CH2) n S(O)NR aa R bb 、-(CH2) n C(O)NR bb (CH2) n1OP(O)(OR aa )2、-(CH2) n OP(O)(OR aa )2、-(CH2) n OC(O)(CH2) n1 COOR aa or -(CH2) n C(=NR cc )NR aa R bb More preferably, it is hydrogen, fluorine, chlorine, bromine, cyano, oxo, methyl, -C(O)NH2, -S(O)NH2, -C(O)NH-CH2-OP(O)(OH)2, -O-CH2CH(OH)(CH2OH), -C(O)OCH3, -N(CH2OH)2, -CH2OP(O)(OH)2, -CH2OC(O)(CH2)2COOH, -C(=NH)NH2, -C(=N-CH3)NH2, -C(=N-OH)NH2 or -C(=N-OCH3)NH2; further preferably, it is cyano, -C(O)NH2, -C(O)NH-CH2-OP(O)(OH)2, -C(=NH)NH2, -C(=N-CH3)NH2, -C(=N-OH)NH2 or -C(=N-OCH3)NH2;

[0138] R aa 、R bb and R cc are independently hydrogen, deuterium, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more substituents independently selected from deuterium, halogen, hydroxyl, cyano, amino, nitro and oxo; preferably hydrogen, deuterium, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more hydroxy groups; more preferably hydrogen, hydroxy, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more hydroxy groups; further preferably hydrogen, hydroxy, methyl, methoxy, -CH2OH or -CH2CH(OH)(CH2OH);

[0139] n is an integer of 0-3; preferably an integer of 0-2; more preferably 0 or 1;

[0140] n1 is an integer from 0 to 3; preferably an integer from 0 to 2; more preferably 1 or 2;

[0141] R1, R3, R4, R5 and p are as described above.

[0142] In a further preferred embodiment of the present invention, the general formula (VII) further has the structure represented by the general formula (VII-A), (VII-B), (VII-C), or (VII-D):

[0143] wherein: R1, R3, R4, R5, R6 and p are as described above. In a further preferred embodiment of the present invention, the general formula (VI) further has a structure shown in the general formula (VIII):

[0144] in:

[0145] R7 is hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, -(CH2) n OR aa 、-(CH2) n NR aa R bb 、-(CH2) n C(O)R aa 、-(CH2) n C(O)OR aa 、-(CH2) n C(O)NR aa R bb 、-(CH2) n S(O)NR aa R bb 、-(CH2) n C(O)NR bb (CH2) n1 OP(O)(OR aa )2、-(CH2) n OP(O)(OR aa )2、-(CH2) n OC(O)(CH2) n1 COOR aa or -(CH2) n C(=NR cc )NR aa Rbb ; preferably hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -(CH2) n OR aa 、-(CH2) n NR aa R bb 、-(CH2) n C(O)OR aa 、-(CH2) n C(O)NR aa R bb 、-(CH2) n S(O)NR aa R bb 、-(CH2) n C(O)NR bb (CH2) n1 OP(O)(OR aa )2、-(CH2) n OP(O)(OR aa )2、-(CH2) n OC(O)(CH2) n1 COOR aa or -(CH2) n C(=NR cc )NR aa R bb More preferably, it is hydrogen, fluorine, chlorine, bromine, cyano, oxo, methyl, -C(O)NH2, -S(O)NH2, -C(O)NH-CH2-OP(O)(OH)2, -O-CH2CH(OH)(CH2OH), -C(O)OCH3, -N(CH2OH)2, -CH2OP(O)(OH)2, -CH2OC(O)(CH2)2COOH, -C(=NH)NH2, -C(=N-CH3)NH2, -C(=N-OH)NH2 or -C(=N-OCH3)NH2; further preferably, it is cyano, -C(O)NH2, -C(O)NH-CH2-OP(O)(OH)2, -C(=NH)NH2, -C(=N-CH3)NH2, -C(=N-OH)NH2 or -C(=N-OCH3)NH2;

[0146] R aa 、R bb and R cc are independently hydrogen, deuterium, hydroxyl, C 1-6 Alkyl or C 1-6Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more substituents independently selected from deuterium, halogen, hydroxyl, cyano, amino, nitro and oxo; preferably hydrogen, deuterium, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more hydroxy groups; more preferably hydrogen, hydroxy, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more hydroxy groups; further preferably hydrogen, hydroxy, methyl, methoxy, -CH2OH or -CH2CH(OH)(CH2OH);

[0147] n is an integer of 0-3; preferably an integer of 0-2; more preferably 0 or 1;

[0148] n1 is an integer from 0 to 3; preferably an integer from 0 to 2; more preferably 1 or 2;

[0149] R1, R3, R4, R5 and p are as described above.

[0150] In a further preferred embodiment of the present invention, the general formula (VIII) further has the structure represented by the general formula (VIII-A), (VIII-B), (VIII-C), or (VIII-D):

[0151] wherein: R1, R3, R4, R5, R7 and p are as described above.

[0152] In a further preferred embodiment of the present invention, For the following groups: Preferably

[0153] In a further preferred embodiment of the present invention, For the following groups: Preferably

[0154] In a further preferred embodiment of the present invention, the compound is any of the following structures:

[0155] The present invention also provides a method for preparing the compound represented by general formula (I), its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof, comprising:

[0156] The compound represented by general formula (I-1), its stereoisomer, its tautomer or its salt and the compound represented by general formula (I-2), its stereoisomer or its tautomer undergo amidation reaction to prepare the compound represented by general formula (I), its stereoisomer, its tautomer or its pharmaceutically acceptable salt;

[0157] Among them, X, ring A, ring B, ring C, R1, R2, R a 、R b 、R c , x, y and z are as described above.

[0158] The present invention also provides a method for preparing the compound represented by general formula (II), its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof, comprising:

[0159] The compound represented by the general formula (II-1), its stereoisomer, its tautomer or its salt and the compound represented by the general formula (I-2), its stereoisomer or its tautomer undergo an amidation reaction to prepare the compound represented by the general formula (II), its stereoisomer, its tautomer or its pharmaceutically acceptable salt;

[0160] Among them, ring A, ring B, ring C, R1, R2, R a 、R b 、R c , x, y and z are as described above.

[0161] The present invention also provides a method for preparing a compound represented by general formula (III), its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof, comprising:

[0162] The compound represented by the general formula (III-1), its stereoisomer, its tautomer or its salt and the compound represented by the general formula (I-2), its stereoisomer or its tautomer undergo an amidation reaction to prepare the compound represented by the general formula (III), its stereoisomer, its tautomer or its pharmaceutically acceptable salt;

[0163] Among them, ring A, ring B, R1, R2, R3, R4, R5, R a 、R b , x and y are as described above.

[0164] The present invention also provides a method for preparing a compound represented by general formula (IV), its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof, comprising:

[0165] The compound represented by the general formula (IV-1), its stereoisomer, its tautomer or its salt and the compound represented by the general formula (I-2), its stereoisomer or its tautomer undergo an amidation reaction to prepare the compound represented by the general formula (IV), its stereoisomer, its tautomer or its pharmaceutically acceptable salt;

[0166] Among them, ring A, R1, R3, R4, R5, R a , x and m are as described above.

[0167] The present invention also provides a method for preparing a compound represented by general formula (V), its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof, comprising:

[0168] The compound represented by the general formula (V-1), its stereoisomer, its tautomer or its salt and the compound represented by the general formula (I-2), its stereoisomer or its tautomer undergo an amidation reaction to prepare the compound represented by the general formula (V), its stereoisomer, its tautomer or its pharmaceutically acceptable salt;

[0169] Among them, X, ring A, ring C, R1, R a 、R b 、R c , x, y, z and p are as described above.

[0170] The preparation method can be synthesized using commercially available raw materials through known methods.

[0171] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound represented by the above-mentioned general formula, its stereoisomers, its tautomers or pharmaceutically acceptable salts, and at least one pharmaceutical excipient selected from pharmaceutically acceptable carriers, diluents and excipients.

[0172] In some preferred embodiments of the present invention, the pharmaceutical composition can be administered in any of the following ways: oral, spray inhalation, rectal, nasal, buccal, topical, parenteral, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal or intracranial injection or infusion, or by means of an explanted reservoir, wherein oral, intraperitoneal or intravenous administration is preferred.

[0173] For oral administration, the compounds of the present application can be formulated into any orally acceptable dosage form, including but not limited to tablets, capsules, aqueous solutions, or aqueous suspensions. Carriers used in tablet formulations typically include lactose and corn starch, and lubricants such as magnesium stearate may also be added. Diluents used in capsule formulations typically include lactose and dried corn starch. Aqueous suspension formulations typically combine the active ingredient with a suitable emulsifier and suspending agent. If desired, sweeteners, flavorings, or coloring agents may be added to these oral formulations.

[0174] Tablets include, but are not limited to, lozenges, sublingual tablets, buccal patches, chewable tablets, dispersible tablets, effervescent tablets, rapid-release, sustained-release, or controlled-release tablets, and enteric-coated tablets.

[0175] When used topically, especially to treat affected areas or organs that are easily accessible by topical application, such as eyes, skin, or lower intestinal neurological diseases, the compounds of the present application can be prepared into different topical preparations according to the different affected areas or organs, as described below.

[0176] For topical ophthalmic administration, the compounds of the present invention may be formulated as a micronized suspension or solution in an isotonic, sterile saline solution of a defined pH, with or without the addition of a preservative such as benzyl alkanoate chloride. For ophthalmic use, the compounds may also be formulated in an ointment such as petrolatum.

[0177] When applied topically to the skin, the compounds of the present invention may be formulated into suitable ointments, lotions, or creams, wherein the active ingredient is suspended or dissolved in one or more carriers. Carriers for ointments include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax, and water; carriers for lotions or creams include, but are not limited to, mineral oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0178] The present invention also provides a use of the compounds represented by the general formulae, their stereoisomers, their tautomers or pharmaceutically acceptable salts, or the pharmaceutical compositions in the preparation of drugs for preventing and / or treating diseases mediated by voltage-gated sodium channel inhibitors.

[0179] The voltage-gated sodium channel is NaV1.8.

[0180] The present invention also provides a use of the compounds represented by the general formulae, their stereoisomers, their tautomers or pharmaceutically acceptable salts, or the pharmaceutical compositions in the preparation of drugs for preventing and / or treating pain, cough, multiple sclerosis, Chuck-Male-Dodds syndrome, incontinence, arrhythmia or alleviating their severity.

[0181] The present invention also relates to a method for treating diseases mediated by voltage-gated sodium channel inhibitors, which comprises administering a therapeutically effective amount of the compound of the present invention, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof to a mammal.

[0182] The present invention also relates to a method for treating pain, cough, multiple sclerosis, Chuck-Mare-Dodds syndrome, incontinence, arrhythmia or alleviating the severity thereof, which comprises administering to a mammal a therapeutically effective amount of a compound of the present invention, its stereoisomers, its tautomers or a pharmaceutically acceptable salt thereof.

[0183] In one embodiment, the present invention also provides a method for treating a disease mediated by a voltage-gated sodium channel inhibitor in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0184] In some embodiments of the invention, the pain is selected from one or more of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, postoperative pain, and visceral pain.

[0185] In some embodiments of the present invention, the cough is a pathological cough.

[0186] Detailed description of the invention

[0187] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. In the event of a conflict, the definitions provided herein shall prevail. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient. All patents, published patent applications, and publications cited herein are incorporated herein by reference.

[0188] The term "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms. 1-20 The alkyl group is preferably an alkyl group having 1 to 8 carbon atoms (i.e., C 1-8 alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6 Alkyl), further preferably an alkyl having 1 to 3 carbon atoms (ie, C 1-3 Non-limiting examples include: 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, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethyl Pentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, n-undecyl or n-pentadecyl, and various branched chain isomers thereof. The alkyl group is optionally further substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, cyano, amino, nitro and oxo.

[0189] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic hydrocarbon substituent (i.e., monocyclic cycloalkyl) or polycyclic hydrocarbon substituent (i.e., polycyclic cycloalkyl) having from 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, i.e., C 3-20 The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 carbon atoms (i.e., C 3-12 cycloalkyl), more preferably a cycloalkyl having 3 to 8 carbon atoms (i.e., C 3-8cycloalkyl), further preferably a cycloalkyl having 3 to 6 carbon atoms (i.e., C 3-6 cycloalkyl), most preferably a cycloalkyl having 3 to 5 carbon atoms (i.e., C 3-5 Cycloalkyl), or a cycloalkyl having 5 to 6 carbon atoms (i.e., C 3-5 Cycloalkyl). Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl. Non-limiting examples of polycyclic cycloalkyls include spirocycloalkyls, fused cycloalkyls, and bridged cycloalkyls. The cycloalkyls may be optionally substituted or unsubstituted. When substituted, the substituents may be substituted at any available attachment point. The substituents are preferably one or more of the following groups independently selected from deuterium, halogen, hydroxyl, amino, nitro, cyano, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, or haloalkoxy.

[0190] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocyclic hydrocarbon substituent (i.e., monocyclic heterocyclyl) or polycyclic heterocyclic hydrocarbon substituent (i.e., polycyclic heterocyclyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3-20 membered heterocyclyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, P(O), m and S(O) n (wherein m and n are integers of 0-2) heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. The heterocyclic group preferably has 3 to 12 ring atoms (i.e., a 3-12-membered heterocyclic group), wherein 1 to 4 heteroatoms are selected from N, O and S atoms, more preferably has 3 to 8 ring atoms (i.e., a 3-8-membered heterocyclic group), wherein 1 to 4, 1 to 3 or 1 to 2 heteroatoms are selected from N, O and S atoms, further preferably has 3 to 6 ring atoms (i.e., a 3-6-membered heterocyclic group), wherein 1 to 4, 1 to 3 or 1 to 2 heteroatoms are selected from N, O and S atoms, and most preferably has 5 to 6 ring atoms (i.e., a 5-6-membered heterocyclic group), wherein 1 to 4, 1 to 3 or 1 to 2 heteroatoms are selected from N, O and S atoms. Non-limiting examples of the monocyclic heterocyclic group include: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, dihydropyridinyl dihydropyridazinyl etc. Non-limiting examples of the polycyclic heterocyclic group include: spiroheterocyclic group, fused heterocyclic group and bridged heterocyclic group. The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from deuterium, halogen, hydroxyl, amino, nitro, cyano, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy or haloalkoxy.

[0191] The term "aryl" refers to an all-carbon monocyclic group (i.e., monocyclic aryl) or a fused polycyclic group (i.e., polycyclic aryl) having a conjugated π electron system, which has 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) carbon atoms (i.e., C 6-14 The aryl group is preferably an aryl group having 6 to 12 carbon atoms (i.e., C 6-12 aryl), more preferably an aryl group having 6 to 10 carbon atoms (i.e., C 6-10 The monocyclic aryl group is, for example, phenyl. Non-limiting examples of the polycyclic aryl group include naphthyl, anthracenyl, and phenanthrenyl. The aryl group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point. The substituent is preferably one or more of the following groups independently selected from deuterium, halogen, hydroxyl, amino, nitro, cyano, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, or haloalkoxy.

[0192] The term "heteroaryl" refers to a monocyclic heteroaryl group (i.e., a monocyclic heteroaryl) or a fused polycyclic heteroaryl group (i.e., a polycyclic heteroaryl) having a conjugated π electron system, which has 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 5-14 membered heteroaryl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, N(O)r, P(O), m and S(O) n (wherein r, m, n are integers from 0 to 2) heteroatoms, preferably heteroatoms selected from nitrogen, oxygen, or sulfur, but excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. The heteroaryl group is preferably a 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O or S. The monocyclic heteroaryl group is preferably a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, non-limiting examples of which include: furyl, pyranyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridonyl, pyrazinyl, pyridazinyl, pyrid ... The polycyclic heteroaryl group is preferably a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, a 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O or S, and C 6-10 Aryl or C 6-10 The 5- to 10-membered heteroaryl group is preferably an aryl group containing 1 to 4 heteroatoms selected from N, O or S, further preferably a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O or S and a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O or S, a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O or S and a phenyl group or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O or S, non-limiting examples of which include indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, thienophenyl, quinazolinyl, benzothiazolyl, carbazolyl, thienopyridyl, pyridothiphenyl, pyridopyrrolyl and the like. The heteroaryl group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from deuterium, halogen, hydroxy, amino, nitro, cyano, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy or haloalkoxy.

[0193] The term "halo" or "halogen" or "halo" is understood to mean a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom, preferably a fluorine, chlorine or bromine atom.

[0194] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above. Non-limiting examples include: fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, chlorofluoromethyl, dichloromethyl, bromofluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, bromodifluoromethyl, bromochlorofluoromethyl, dibromofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 2,2-dichloroethyl, 2-bromo-2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2, 2,2-trichloroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2-chloro-2-fluoroethyl, 2-bromo-2,2-dichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 2-chloro-1,1,2,2-tetrafluoroethyl, 1,2-dichloro-1,2,2-trifluoroethyl, 2-bromo-1,1,2,2-tetrafluoroethyl, etc., preferably fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl. The haloalkyl group may be further substituted with one or more deuteriums.

[0195] The term "deuterated alkyl" refers to an alkyl group substituted by one or more deuterium, wherein alkyl is as defined above. The deuterated alkyl group may be further substituted by one or more halogens.

[0196] The term "alkoxy" refers to -O-(alkyl) or -O-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above, and have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) carbon atoms (i.e., C 1-10 The alkoxy group is preferably an alkoxy group having 1 to 8 carbon atoms (i.e., C 1-8 Alkoxy), more preferably an alkoxy having 1 to 6 carbon atoms (ie, C 1-6 Alkoxy), most preferably alkoxy having 1 to 3 carbon atoms (ie C 1-3 Alkoxy). Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc. The alkoxy group is optionally further substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, cyano, amino, nitro and oxo.

[0197] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above. Non-limiting examples of halomethoxy include: fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, chlorofluoromethoxy, dichloromethoxy, bromofluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy, trichloromethoxy, bromodifluoromethoxy, bromochlorofluoromethoxy, dibromofluoromethoxy, etc.; preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy. Non-limiting examples of haloethoxy include: 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy, 2-chloro-2-fluoroethoxy, 2,2-dichloroethoxy, 2-bromo-2-fluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, 2-bromo-2,2-difluoroethoxy, 2-bromo-2- Chloro-2-fluoroethoxy, 2-bromo-2,2-dichloroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, 1-chloro-1,2,2,2-tetrafluoroethoxy, 2-chloro-1,1,2,2-tetrafluoroethoxy, 1,2-dichloro-1,2,2-trifluoroethoxy, 2-bromo-1,1,2,2-tetrafluoroethoxy, etc.; preferably 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy. The haloalkoxy group may be further substituted with one or more deuterium groups.

[0198] The term "deuterated alkoxy" refers to an alkoxy group substituted by one or more deuterium groups, wherein alkoxy is as defined above. The deuterated alkoxy group may be further substituted by one or more halogen groups.

[0199] The term "hydroxy" refers to -OH.

[0200] The term "amino" refers to -NH2.

[0201] The term "nitro" refers to -NO2.

[0202] The term "cyano" refers to -CN.

[0203] The term "oxo" or "oxo" refers to =0.

[0204] “CDI” refers to carbonyldiimidazole. “Pd-C” refers to platinum-carbon. “DIBAL-H” refers to diisobutylaluminum hydride. “TMSCN” refers to trimethylsilyl cyanide. “MeOH” refers to methanol. “EtOH” refers to ethanol. “DMF” refers to N,N-dimethylformamide. “HATU” refers to 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate. “DIEA” refers to N,N-diisopropylethylamine. “THF” refers to tetrahydrofuran. “DMSO” refers to dimethyl sulfoxide. “MeCN” or “ACN” refers to acetonitrile. “DMAP” refers to 4-dimethylaminopyridine. “DCM” refers to dichloromethane. “mCPBA” refers to meta-chloroperbenzoic acid. “TEA” refers to triethylamine. “TMSCl” refers to trimethylchlorosilane. “DIPEA” refers to N,N-diisopropylethylamine. "IPA" refers to isopropyl alcohol. "NMP" refers to N-methylpyrrolidone. "EA" refers to ethyl acetate. "PE" refers to petroleum ether. "FA" refers to formic acid.

[0205] The terms "include," "comprising," "having," "containing," or "involving," and their variations herein, are inclusive or open-ended and do not exclude other unrecited elements or method steps. Those skilled in the art will understand that the above terms, such as "comprising," encompass the meaning of "consisting of."

[0206] The term "one or more" or the similar expression "at least one" may mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

[0207] When the lower limit and upper limit of a numerical range are disclosed, any value and any included range falling within the range are specifically disclosed. In particular, each range of values ​​disclosed herein should be understood to mean each value and range encompassed within the broader range.

[0208] Herein, "Z" and "-Z-" both represent the same specific group and can be used interchangeably.

[0209] The expression mn used herein refers to the range from m to n and the subranges and individual point values ​​therein. For example, the expression "C2-C8" or "C 2-8 " covers the range of 2-8 carbon atoms and should be understood to also cover any subranges and each point value therein, such as C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, etc., as well as C2, C3, C4, C5, C6, C7, C8, etc. For example, the expression "C3-C 10 ” or “C 3-10 " should also be understood in a similar manner, for example, any sub-ranges and point values ​​contained therein may be encompassed, such as C3-C9, C6-C9, C6-C8, C6-C7, C7-C 10 , C7-C9, C7-C8, C8-C9, etc. and C3, C4, C5, C6, C7, C8, C9, C 10 For example, the expression "C1-C6" or "C 1-6 " covers a range of 1-6 carbon atoms and should be understood to also cover any subranges and each point value therein, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, etc., as well as C1, C2, C3, C4, C5, C6, etc. For another example, the expression "three-membered to ten-membered" should be understood to cover any subranges and each point value therein, such as three-membered to five-membered, three-membered to six-membered, three-membered to seven-membered, three-membered to eight-membered, four-membered to five-membered, four-membered to six-membered, four-membered to seven-membered, four-membered to eight-membered, five-membered to seven-membered, five-membered to eight-membered, six-membered to seven-membered, six-membered to eight-membered, nine-membered to ten-membered, etc., as well as three, four, five, six, seven, eight, nine, ten-membered, etc. Other similar expressions herein should be understood in a similar manner.

[0210] As used herein, different expressions such as “X is selected from A, B or C”, “X is selected from A, B and C”, “X is A, B or C”, and “X is A, B and C” all convey the same meaning, that is, X can be any one or more of A, B, and C.

[0211] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, "cycloalkyl optionally substituted with alkyl" means that alkyl may but need not be present, and the description includes both the case where the cycloalkyl is substituted with alkyl and the case where the cycloalkyl is not substituted with alkyl.

[0212] The terms "substituted" and "substituted" refer to one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom being replaced by a selection from the designated group, provided that the normal valence of the designated atom in the current situation is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form stable compounds. When a substituent is described as not being present, it is understood that the substituent can be one or more hydrogen atoms, provided that the structure allows the compound to reach a stable state. When each carbon atom in a group is described as optionally substituted by a heteroatom, the proviso is that the normal valence of all atoms in the group in the current situation is not exceeded and a stable compound is formed.

[0213] If a substituent is described as being "optionally substituted with...", the substituent may be unsubstituted or substituted. If an atom or group is described as being optionally substituted with one or more of the substituents listed, one or more hydrogen atoms on the atom or group may be replaced by independently selected, optional substituents. When the substituent is oxo (i.e., =0), this means that two hydrogen atoms are replaced. When the substituent is hydrogen, this may also mean that the corresponding group is "non-substituted" or "unsubstituted." Unless otherwise specified, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0214] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

[0215] When any variable (e.g., R), as well as variables with labels (e.g., R1, R2, R3, R4, R5, R6, R7, etc.) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. For example, if a group is substituted with 0, 1, 2, 3, or 4 R substituents, the group may be optionally substituted with up to four R substituents, and the options for each R substituent at each occurrence are independent of each other.

[0216] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. All such compounds of the present invention, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, are within the scope of the present invention. Additional asymmetric carbon atoms may be present in the substituents of the compounds of the present invention. All such isomers and mixtures thereof are within the scope of the present invention. In certain embodiments, preferred compounds are those isomers that exhibit superior biological activity. Purified or partially purified isomers and stereoisomers of the compounds of the present invention, or racemic mixtures or diastereomeric mixtures, are also within the scope of the present invention. Purification and separation of such substances can be achieved by standard techniques known in the art. The terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of one another. The terms "cis-trans isomers" or "geometric isomers" are derived from the inability to rotate freely about double bonds or single bonds between ring carbon atoms. The term "diastereomers" refers to stereoisomers with two or more chiral centers that are not mirror images of each other. The terms "(D)" or "(+)" indicate dextrorotatory rotation, "(L)" or "(-)" indicate levorotatory rotation, and "(DL)" or "(±)" indicate racemic rotation. The terms "tautomers" or "tautomeric forms" refer to isomers with different functional groups that are in dynamic equilibrium at room temperature and readily interconvert into each other. If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers, also called prototropic tautomers, include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversion by reshuffling of some of the bonding electrons. A specific example of keto-enol tautomerization is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0217] The compounds of the present invention include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, for example, respectively. 2 H (deuterium, D), 3 H (tritium, T), 11 C. 13 C.14 C. 15 N. 17 O. 18 O. 32 P. 33 P. 33 S. 34 S. 35 S. 36 S. 18 F. 36 Cl, 82 Br, 123 I. 124 I. 125 I. 129 I and 131 I, etc., preferably deuterium.

[0218] All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this disclosure. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom, wherein the deuterium replacement may be partial or complete, wherein partial deuterium replacement means that at least one hydrogen is replaced by at least one deuterium.

[0219] The term "pharmaceutically acceptable" refers to a substance that is, within the scope of normal medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit-risk ratio, and effective for its intended use.

[0220] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity.

[0221] The term "pharmaceutical composition" refers to a composition containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, as well as other components, such as a physiologically / pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0222] The term "pharmaceutically acceptable carrier" refers to substances that are non-irritating to organisms and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0223] The term "administration" or "administering" refers to a method that enables a compound or composition to be delivered to a desired biological site of action. These methods include, but are not limited to, oral or parenteral (including intracerebroventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, and the like. In particular, injection or oral administration.

[0224] As used herein, the term "treating" includes alleviating, alleviating or ameliorating a disease or symptom, preventing other symptoms, ameliorating or preventing the underlying metabolic factors of a symptom, inhibiting a disease or symptom, for example, preventing the disease or symptom from developing, alleviating a disease or symptom, promoting remission of a disease or symptom, or stopping the symptoms of a disease or symptom, and extends to include prevention. "Treatment" also includes achieving a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit refers to the eradication or amelioration of the condition being treated. In addition, a therapeutic benefit is achieved by eradicating or ameliorating one or more physiological signs associated with the underlying disease, and although the patient may still have the underlying disease, an improvement in the patient's disease is observed. A prophylactic benefit refers to the use of a composition by a patient to prevent the risk of a certain disease, or when a patient develops one or more physiological symptoms of a disease, even though the disease has not yet been diagnosed.

[0225] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating or preventing a target disorder, disease, or condition. The term "neuropsychiatric disorder" refers to a general term encompassing neurological and / or psychiatric disorders.

[0226] With respect to a drug, pharmaceutical unit, or active ingredient, the terms "effective amount," "therapeutically effective amount," or "prophylactically effective amount" refer to a sufficient amount of the drug or pharmaceutical agent to achieve the desired effect with acceptable side effects. The determination of an effective amount varies from person to person, depending on the individual's age and general condition, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine testing.

[0227] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0228] The term "room temperature" or "RT" refers to a temperature from 10-40°C. In some embodiments, "room temperature" refers to a temperature from 15-30°C; in other embodiments, "room temperature" refers to a temperature from 18-25°C.

[0229] "Equivalent" or its abbreviation "eq" refers to the equivalent amount of other raw materials required based on the equivalent relationship of chemical reactions, with the basic raw material used in each step as the benchmark (1 equivalent).

[0230] In the context of the present invention, when or whether the words "about" or "approximately" are used, they mean within 10%, suitably within 5%, and particularly within 1% of a given value or range. Alternatively, for those of ordinary skill in the art, the term "about" or "approximately" means within an acceptable standard error of the mean. Whenever a number having a value of N is disclosed, any number having a value of N + / - 1%, N + / - 2%, N + / - 3%, N + / - 5%, N + / - 7%, N + / - 8% or N + / - 10% is expressly disclosed, where "+ / -" means plus or minus.

[0231] The following detailed description of the invention is intended to illustrate non-limiting embodiments so that other technical personnel in the art can more fully understand the technical solutions, principles and practical applications of the present invention, so that other technical personnel in the art can modify and implement the present invention in many forms to best adapt it to the requirements of specific uses. Beneficial effects

[0232] The present invention discloses a class of voltage-gated sodium channel NaV1.8 inhibitor compounds with a novel structure. These compounds have excellent NaV1.8 inhibitory activity and can be used to treat and / or prevent diseases mediated by NaV1.8 inhibitors, such as pain, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, postoperative pain and visceral pain, cough, pathological cough, multiple sclerosis, Chuck-Marie-Doucet syndrome, incontinence, or arrhythmias, providing a new option for treating or alleviating the severity of such diseases.

[0233] In some embodiments, the compound of this invention has good blocking effect to NaV1.8. In some embodiments, the compounds of this invention have good pharmacokinetic properties (such as suitable half-life and duration of action, good blood drug concentration, area under the drug curve and / or bioavailability). In some embodiments, the compounds of this invention have improved in vivo pharmacodynamic effects, and / or improved safety (lower toxicity and / or less side effect), and / or good patient compliance, and / or are less likely to produce more excellent drug properties such as tolerance.

[0234] Specifically, the results of the NaV1.8 blocking activity experiments of the present disclosure show that the compounds of the present invention have a significant blocking effect on NaV1.8 and are effective NaV1.8 inhibitors. The results of the rat pharmacokinetic experiments show that the compounds of the present invention exhibit good drug metabolism properties and have a suitable half-life t 1 / 2 , and the maximum blood concentration C max Area under the curve (AUC) (0-t) Metabolic parameters showed good results. DETAILED DESCRIPTION

[0235] The embodiments of the present invention will be described in detail below with reference to the examples, but those skilled in the art will appreciate that the following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention. Where specific conditions are not specified in the examples, the methods are carried out according to conventional conditions or the conditions recommended by the manufacturer. Where the reagents or instruments used are not specified by manufacturer, they are all conventional products that can be obtained commercially. Unless otherwise specified, the ratios or percentages used herein are by weight.

[0236] Example

[0237] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS).

[0238] NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed on an AVANCE III 400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as the solvents, with tetramethylsilane (TMS) as the internal standard.

[0239] Liquid chromatography-mass spectrometry (LC-MS) was performed using a Shimadzu LCMS2020 mass spectrometer, and HPLC was performed using a Shimadzu LC20A liquid chromatograph.

[0240] Reversed phase chromatography column Luknova C18 50μm, 20~150g.

[0241] Normal phase chromatography column Biotage 40-63μm 4-220g.

[0242] The thin layer chromatography silica gel plate used was Yantai Jiangyou silica gel plate, the specification used for TLC was 0.2mm±0.03mm, and the specification used for thin layer chromatography separation and purification products was 0.4mm-0.5mm.

[0243] Synthesis of key intermediates

[0244] Intermediate 10-1: Synthesis of 2-hydroxy-2-methylcyclopentyl-1-one

[0245] Step 1: Synthesis of compound a-2

[0246] Dissolve compound a-1 (25 g, 210 mmol) in water (500 mL) and heat to 100°C. Dissolve ferric chloride (68.5 g, 422 mmol) in 150 mL of water and slowly add to the reaction mixture. Continue the reaction at 100°C for 1 hour. After TLC, cool to room temperature and adjust the pH to approximately 7 with saturated ammonium sulfate. Extract three times with ethyl acetate. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain the crude product, compound a-2 (18.5 g, 88% yield), which is used directly in the next step.

[0247] Step 2: Synthesis of compound 10-1

[0248] Compound a-2 (18.5 g, 190 mmol) was dissolved in tetrahydrofuran (500 mL) and cooled to 0°C. Methylmagnesium bromide (190 mL, 570 mmol) was slowly added to the reaction under nitrogen, and the reaction was continued at 0°C for 1 hour. After TLC confirmed the reaction was complete, saturated ammonium chloride was added to the reaction mixture in an ice bath to quench the reaction. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, compound 10-1 (8.9 g, 41% yield), which was used directly in the next step.

[0249] Example 1. Synthesis of 4-(3-(3,4-difluoro-2-methoxyphenyl)hexahydro-2H-cyclopentadienyl[b]furan-2-carboxamide)picolinamide (Compound 1)

[0250] Synthesis route:

[0251] Step 1: Synthesis of compound 1-2

[0252] Dissolve 2-methoxy-3,4-difluorophenylacetic acid (19.8 g, 98.1 mmol) and carbonyldiimidazole (14.59 g, 236 mmol) in acetonitrile (400 mL) and react at 0°C under nitrogen for 1 hour. Compound 1-1 (13 g, 129 mmol) and potassium carbonate (96.8 g, 700 mmol) were then added, and the temperature was slowly raised to 35°C for overnight reaction. Cesium carbonate (48 g, 148 mmol) was added and the reaction continued for 16 hours. Ethyl acetate was added for dilution, and the mixture was washed sequentially with water and saturated brine. The organic phase was dried and then spin-dried to dryness. The crude product was purified by column chromatography (EA in PE: 1%-20%) to afford compound 1-2 (2.35 g, 7.4% yield) as a white solid.

[0253] Step 2: Synthesis of Compounds 1-3

[0254] Compound 1-2 (2.35 g, 8.20 mmol) was dissolved in a mixture of tetrahydrofuran (27.5 mL) and methanol (110 mL) and cooled to -40°C under nitrogen. Nickel chloride hexahydrate (3.08 g, 13.0 mmol) and sodium borohydride (8.5 g, 44.4 mmol) were added sequentially and the reaction continued for 1 hour. TLC confirmed the reaction was complete, and the filtrate was filtered. The filtrate was diluted with water, extracted with dichloromethane, dried, and concentrated to afford the crude product of compound 1-3 (2.20 g, 92.9% yield).

[0255] Step 3: Synthesis of Compounds 1-4

[0256] Compound 1-3 (2.20 g, 8.20 mmol) was dissolved in dichloromethane (24 mL). 1 M diisobutylaluminum hydride (16.6 mL, 16.6 mmol) was added at -78°C under an inert atmosphere and the reaction was continued for 0.5 h. The mixture was quenched with water, filtered, and the filtrate was concentrated to afford the crude product of compound 1-4 (1.9 g, 85.7% yield), which was directly processed into the next step.

[0257] Step 4: Synthesis of Compounds 1-5

[0258] Compound 1-4 (1.90 g, 7.03 mmol) was dissolved in dichloromethane (47 mL). Triethylamine (2.75 g, 25.8 mmol) and 4-dimethylaminopyridine (1.26 g, 10.1 mmol) were added sequentially, followed by the slow dropwise addition of acetic anhydride (4.51 g, 42.0 mmol). The mixture was reacted at room temperature for 16 hours. After dilution with dichloromethane, the mixture was washed sequentially with water and saturated brine. The organic phase was dried and concentrated to obtain a crude product of compound 1-5 (2.06 g, 93.8% yield), which was directly carried out to the next step.

[0259] Step 5: Synthesis of Compounds 1-6

[0260] Compound 1-5 (2.06 g, 6.06 mmol) was dissolved in dichloromethane (75 mL). Trimethylsilyl cyanide (2.03 g, 68.1 mmol) and boron trifluoride etherate (15.6 g, 110 mmol) were added sequentially at -40°C and the reaction continued for 2 hours. The reaction was quenched with water, extracted with dichloromethane, concentrated, and separated by column chromatography (EA in PE: 1%-15%) to afford compound 1-6 (1.07 g, 58.1% yield) as a white solid.

[0261] Step 6: Synthesis of Compounds 1-7

[0262] Compound 1-6 (1.07 g, 3.83 mmol) was dissolved in methanol (30 mL) and water (6 mL), and potassium hydroxide (1.94 mg, 34.6 mmol) was added. The mixture was reacted at 55°C for 16 hours. The reaction solution was adjusted to pH 1-2 with 2N hydrochloric acid, diluted with water, extracted with dichloromethane, and concentrated to obtain a crude product of compound 1-7 (1.07 g, 93.6% yield).

[0263] Step 7: Synthesis of Compounds 1-8

[0264] Compound 1-7 (75 mg, 0.26 mmol) was dissolved in dichloromethane (2 mL). A catalytic amount of N,N-dimethylformamide was added at 0°C, followed by the slow addition of oxalyl chloride (0.08 mL, 0.08 mmol). The reaction was allowed to react for 0.5 hours. The reaction mixture was concentrated and the concentrate was dissolved in dichloromethane. Triethylamine (185 mg, 1.37 mmol), 4-dimethylaminopyridine (3 mg, 0.02 mmol), and methyl 4-amino-2-picolinate (85 mg, 0.41 mmol) were added sequentially. The reaction was allowed to react overnight at room temperature for 16 hours. After TLC analysis, the reaction was concentrated and purified by column chromatography (EA in PE: 5%-50%) to afford compound 1-8 (58 mg, 53.3% yield) as a white solid.

[0265] Step 9: Synthesis of Compound 1 To compound 1-9 was added 10 mL of 7 M amine methanol solution, stirred at room temperature overnight for 16 h, and filtered to obtain compound 1 (48 mg, yield 85%).

[0266] 1 H NMR (400MHz, DMSO-d6) δ10.46 (s, 1H), 8.45 (d, J = 2.1Hz 1H),8.28(d,J=2.2Hz,1H),8.11(s,1H),7.77(s,1H),7.51(s,1H),7.26–6.99(m,2H),4.84(m, 1H),4.72(m,1H),3.85(d,J=1.8Hz,3H),3.78(d,J=1.7Hz,1H),2.96(m,1H),1.82–1.12(m,6H).

[0267] MS m / z(ESI):418.1[M+H] +

[0268] Example 2, 3-(3,4-difluoro-2-methoxyphenyl)-N-(6-oxo-1,6-dihydropyridin-3-yl)hexahydro-2H-cyclopenta[b]furan-2-carboxamide (Compound 2)

[0269] Synthesis route:

[0270] Step 1: Synthesis of compound 2-1

[0271] Compound 1-7 (150 mg, 0.52 mmol) was dissolved in dichloromethane (4.00 mL). A catalytic amount of N,N-dimethylformamide was added at 0°C, followed by the slow addition of oxalyl chloride (0.16 mL, 1.6 mmol) and the reaction was allowed to proceed for 1 hour. The reaction mixture was concentrated and the concentrate was dissolved in dichloromethane. Triethylamine (370 mg, 2.74 mmol), 4-dimethylaminopyridine (6 mg, 0.04 mmol), and 6-(benzyloxy)pyridin-3-amine (250 mg, 1.25 mmol) were added sequentially and the reaction was allowed to proceed overnight at room temperature. After TLC analysis, the reaction was concentrated and purified by column chromatography (EA in PE: 5% to 50%) to afford compound 2-1 (210 mg, 92.3% yield) as a white solid.

[0272] MS m / z(ESI):481.5[M+H] + .

[0273] Step 2: Synthesis of compound 2

[0274] Compound 2-1 was dissolved in tetrahydrofuran (10.0 mL), 20 mg of 10% wet palladium carbon was added, and the mixture was stirred overnight under hydrogen atmosphere. After filtration, the mixture was purified by column chromatography to obtain compound 2 (83.7 mg, yield 46.8%).

[0275] 1 H NMR (400MHz, DMSO-d6) δ11.39(s,1H),9.70(s,1H),7.80(d,J=2.9Hz,1H),7.56(dd,J=9.7,2.9Hz,1H),7.28–7.11(m,2H),6.32(d,J=9.7Hz, 1H),4.83(td,J=5.4,2.6Hz,1H),4.71(d,J=9.4Hz,1H),3.90(d,J=1.7Hz,3H),3.85(d,J=8.7Hz,1H),3.01–2.90(m,1H),1.84–1.11(m,6H).

[0276] MS m / z(ESI):391.4[M+H] + .

[0277] Example 3, 3-(3,4-difluoro-2-methoxyphenyl)-N-(2-oxo-1,2-dihydropyridin-4-yl)hexahydro-2H-cyclopenta[b]furan-2-carboxamide (Compound 4)

[0278] Synthesis route:

[0279] Step 1: Synthesis of compound 4-1

[0280] Compound 1-7 (150 mg, 0.52 mmol) was dissolved in dichloromethane (4.00 mL). A catalytic amount of N,N-dimethylformamide was added at 0°C, followed by the slow addition of oxalyl chloride (0.16 mL, 1.6 mmol) and the reaction was allowed to proceed for 1 hour. The reaction mixture was concentrated and the concentrate was dissolved in dichloromethane. Triethylamine (370 mg, 2.74 mmol), 4-dimethylaminopyridine (6 mg, 0.04 mmol), and 4-amino-2-pyridinylmethyl-2-(benzyloxy)pyridin-4-amine (251 mg, 1.25 mmol) were added sequentially and the reaction was allowed to proceed overnight at room temperature. After TLC analysis, the reaction was concentrated and purified by column chromatography (EA in PE: 5% to 50%) to afford compound 4-1 (170 mg, 74.7% yield) as a white solid.

[0281] MS m / z(ESI):481.5[M+H] + .

[0282] Step 2: Synthesis of compound 4

[0283] Compound 4-1 was dissolved in tetrahydrofuran (10.0 mL), 20 mg of 10% wet palladium carbon was added, and the mixture was stirred overnight under hydrogen atmosphere. After filtration, the mixture was purified by column chromatography to obtain compound 4 (41.8 mg, yield 23.9%).

[0284] 1 H NMR (400MHz, DMSO-d6) δ11.22(s,1H),9.94(s,1H),7.36–7.10(m,3H),6.73(d,J=2.1Hz,1H),6.45(dd,J=7.3,2.2H z,1H),4.85(td,J=5.4,2.5Hz,1H),4.74(d,J=9.4Hz,1H),3.96–3.85(m,4H),3.05–2.93(m,1H),1.85–1.09(m,6H).

[0285] MS m / z(ESI):391.4[M+H] + .

[0286] Example 4, 4-(3-(3,4-difluoro-2-methoxyphenyl)hexahydro-2H-cyclopenta[b]furan-2-carboxamido)pyridine 1-oxide (Compound 6)

[0287] Synthesis route:

[0288] Step 1: Synthesis of compound 6-1

[0289] Compound 1-7 (150 mg, 0.46 mmol) was dissolved in dichloromethane (4.00 mL). A catalytic amount of N,N-dimethylformamide was added at 0°C, followed by the slow addition of oxalyl chloride (0.16 mL, 1.6 mmol) and the reaction was allowed to proceed for 1 hour. The reaction mixture was concentrated and the concentrate was dissolved in dichloromethane. Triethylamine (370 mg, 2.74 mmol), 4-dimethylaminopyridine (6 mg, 0.04 mmol), and 4-aminopyridine (200 mg, 2.13 mmol) were added sequentially and the reaction was allowed to proceed overnight at room temperature. After TLC analysis, the reaction was concentrated and purified by column chromatography (EA in PE: 5% to 50%) to afford compound 6-1 (160 mg, 86.5% yield) as a white solid.

[0290] MS m / z(ESI):375.4[M+H] + .

[0291] Step 2: Synthesis of compound 6

[0292] Compound 6-1 was dissolved in dichloromethane (6.0 mL), and m-chloroperbenzoic acid (315 mg, 1.82 mmol) was added. The mixture was stirred overnight under nitrogen. The reaction was quenched with water, extracted with dichloromethane, concentrated, and separated by column chromatography (EA in PE: 1%-20%) to obtain compound 6 (32.7 mg, 19.6% yield).

[0293] 1 H NMR (400MHz, DMSO-d6) δ10.40(d,J=3.7Hz,1H),8.10(d,J=6.9Hz,2H),7.72(d,J=6.8Hz,2H),7.31–7.08(m,2H),4.86(td,J=5. 4,2.4Hz,1H),4.79(d,J=9.3Hz,1H),3.96–3.84(m,3H),3.42(d,J=11.5Hz,1H),2.99(td,J=8.5,4.3Hz,1H),1.85–1.11(m,6H).

[0294] MS m / z(ESI):391.4[M+H] + .

[0295] Example 5, 4-(3-(3,4-difluoro-2-methoxyphenyl)-6a-methylhexahydro-2H-cyclopentadienyl[b]furan-2-carboxamide)picolinamide (Compound 10)

[0296] Synthesis route:

[0297] Step 1: Synthesis of compound 10-2

[0298] Dissolve 2-methoxy-3,4-difluorophenylacetic acid (20.6 g, 102 mmol) and carbonyldiimidazole (20 g, 123 mmol) in acetonitrile (460 mL) and react at 0°C under nitrogen for 1 hour. Compound 10-1 (7.7 g, 67.5 mmol) and cesium carbonate (33 g, 101 mmol) were then added sequentially, and the temperature was slowly raised to 80°C, allowing the reaction to proceed overnight for 16 hours. Ethyl acetate was added for dilution, and the mixture was washed sequentially with water and saturated brine. The organic phase was dried and then spin-dried to dryness. The crude product was purified by column chromatography (EA in PE: 1%-20%) to afford compound 10-2 (7.83 g, 41% yield) as a white solid.

[0299] Step 2: Synthesis of compound 10-3

[0300] Compound 10-2 (7.83 g, 28 mmol) was dissolved in a mixture of tetrahydrofuran (80 mL) and methanol (400 mL) and cooled to -40°C under nitrogen. Nickel chloride hexahydrate and sodium borohydride were added sequentially, and the reaction was continued for 1 hour. TLC confirmed the reaction was complete, and the filtrate was filtered. The filtrate was diluted with water, extracted with dichloromethane, dried, and concentrated to afford the crude product of compound 10-3 (7.2 g, 91% yield).

[0301] Step 3: Synthesis of compound 10-4

[0302] Compound 10-3 (1 g, 3.5 mmol) was dissolved in dichloromethane (15 mL). 1 M diisobutylaluminum hydride (5 mL, 5 mmol) was added at -78°C under an inert atmosphere and the reaction was continued for 0.5 h. The mixture was quenched with saturated aqueous ammonium chloride, filtered, and the filtrate was concentrated to afford the crude product of compound 10-4 (1 g, 99% yield), which was directly carried out to the next step.

[0303] Step 4: Synthesis of compound 10-5

[0304] Compound 10-4 (1 g, 3.5 mmol) was dissolved in dichloromethane (15 mL), and 4-dimethylaminopyridine (650 mg, 5.32 mmol) was added sequentially, followed by the slow dropwise addition of acetic anhydride (2.26 g, 22.1 mmol). The reaction was allowed to react overnight at room temperature for 16 h. After dilution with dichloromethane, the mixture was washed sequentially with water and saturated brine. The organic phase was dried and concentrated to afford the crude product of compound 10-5 (1.44 g, yield >100%), which was directly carried out to the next step.

[0305] Step 5: Synthesis of compound 10-6

[0306] Compound 10-5 (1.4 g, 4.3 mmol) was dissolved in dichloromethane. Trimethylsilyl cyanide (0.53 mL, 11.18 mmol) and boron trifluoride etherate (1.4 mL, 30.1 mmol) were added sequentially at -40°C and the reaction continued for 2 hours. The reaction was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and concentrated to afford the crude product, compound 10-6 (0.98 g, 78% yield).

[0307] Step 6: Synthesis of compound 10-7

[0308] Compound 10-6 (0.98 g, 3.3 mmol) was dissolved in methanol (40 mL), and 2M potassium hydroxide solution (40 mL) was slowly added to the reaction mixture. The reaction mixture was allowed to react overnight at 55°C for 16 h. The pH of the reaction mixture was adjusted to 3-4 with 2N hydrochloric acid, diluted with water, extracted with dichloromethane, and concentrated to obtain the crude product of compound 10-7 (440 mg, 43% yield).

[0309] Step 7: Synthesis of compound 10-8

[0310] Compound 10-7 (440 mg, 1.41 mmol) was dissolved in dichloromethane (15 mL). A catalytic amount of N,N-dimethylformamide was added at 0°C, followed by the slow addition of oxalyl chloride (0.36 mg, 4.23 mmol) and the reaction was allowed to proceed for 1 hour. The reaction mixture was concentrated and the concentrate was dissolved in dichloromethane. Triethylamine (722 mg, 7.15 mmol), 4-dimethylaminopyridine (18 mg, 0.14 mmol), and methyl 4-amino-2-picolinate (327 mg, 2.15 mmol) were added sequentially. The reaction was allowed to proceed overnight at room temperature for 16 hours. After TLC analysis, the reaction was concentrated and purified by column chromatography (EA in PE: 5%-50%) to afford compound 10-8 (300 mg, 48% yield) as a white solid.

[0311] Step 8: Synthesis of compound 10

[0312] To compound 10-8 (100 mg) was added 10 mL of 7 M amine methanol solution, stirred at room temperature overnight for 16 h, and filtered to obtain compound 10 (83 mg, yield 84%).

[0313] 1H NMR (400MHz, DMSO-d6) δ10.42(s,1H),8.48(d,J=5.5Hz,1H),8.32(d,J=2.0Hz,1H),8.06(d,J=2.0 Hz,1H),7.86(dd,J=5.5,2.2Hz,1H),7.61(d,J=2.0Hz,1H),7.41–7.04(m,2H),4.86(d,J=10.7Hz, 1H),3.98(dd,J=10.6,7.7Hz,1H),3.92(d,J=1.7Hz,3H),2.61(dd,J=15.8,7.3Hz,1H),1.91(dt,J =12.3,6.3Hz,1H),1.74--1.62(m,2H),1.52--1.46(s,4H),1.42-1.32(m,1H),1.28--1.21(m,1H).

[0314] MS m / z(ESI):432.1[M+1].

[0315] Compound 10 was separated by chiral chromatography to obtain compound 10a and compound 10b. The specific experimental parameters are as follows:

[0316] Chromatographic column: DAICELCHIRALPAK IH; column size: 250*50 10μm; mobile phase A: supercritical CO2; mobile phase B: IPA (7.0 mol / L MEOH containing 0.1% ammonia); mobile phase gradient: A:B:75:25; detection wavelength: 214nm; flow rate: 140mL / min; column temperature: RT.

[0317] Compound 10: 770 mg, after splitting:

[0318] Compound 10b: 392 mg, >98% ee, retention time 0.852 min;

[0319] Compound 10a: 379 mg, >98% ee, retention time: 3.324 min.

[0320] Example 6. Synthesis of Compound 11

[0321] Synthesis route:

[0322] Compound 10-7 (80 mg, 0.26 mmol) was dissolved in dichloromethane (10 mL). A catalytic amount of N,N-dimethylformamide was added at 0°C, followed by the slow addition of oxalyl chloride (98 mg, 0.77 mmol) and the reaction was allowed to proceed for 1 hour. The reaction system was concentrated, and the concentrate was dissolved in dichloromethane (10 mL) and dimethyl sulfoxide (3 mL). Triethylamine (130 mg, 1.28 mmol), 4-dimethylaminopyridine (4 mg, 0.03 mmol), and the free amine of 2-hydroxy-5-aminopyridine hydrochloride (113 mg, 0.77 mmol) were added sequentially. The reaction was continued in an ice bath for 1 hour. After completion of the reaction, the mixture was concentrated by TLC and purified by column chromatography to afford compound 11 (24 mg, 23% yield).

[0323] 1 H NMR (400MHz, DMSO-d6) δ11.34(s,1H),9.62(s,1H),7.80(d,J=2.8Hz,1H),7.51(dd,J=9.7 ,2.9Hz,1H),7.24–7.06(m,2H),6.32(d,J=9.7Hz,1H),4.75(d,J=10.7Hz,1H),3.91(d,J= 1.7Hz,3H),3.90–3.78(m,1H),2.57(dd,J=15.9,7.3Hz,1H),1.87(dt,J=12.3,6.3Hz,1H) ,1.75–1.56(m,2H),1.51–1.47(m,1H),1.46(s,3H),1.39–1.28(m,1H),1.27–1.16(m,1H).

[0324] MS m / z(ESI):405.2[M+H] + .

[0325] Example 7. Synthesis of Compound 13

[0326] Synthesis route:

[0327] Compound 10-7 (300 mg, 0.96 mmol) was dissolved in dichloromethane (10 mL). A catalytic amount of N,N-dimethylformamide was added at 0°C, followed by the slow addition of oxalyl chloride (381 mg, 2.87 mmol) and the reaction was allowed to proceed for 1 hour. The reaction system was concentrated, and the concentrate was dissolved in dichloromethane. Triethylamine (505 mg, 4.8 mmol), 4-dimethylaminopyridine (13 mg, 0.1 mmol), and methyl 4-amino-2-picolinate (300 mg, 1.44 mmol) were added sequentially and the reaction was allowed to proceed overnight at room temperature. After TLC analysis, the reaction was concentrated and purified by column chromatography to afford compound 13-1 (380 mg, 80% yield) as a white solid.

[0328] Compound 13-1 (380 mg, 0.77 mmol) was dissolved in THF (10 mL), and a catalytic amount of palladium on carbon was added at room temperature. After hydrogen exchange, the reaction was allowed to proceed overnight at room temperature. After TLC detection, the reaction was complete, filtered, concentrated, and purified by column chromatography to obtain compound 13 (130 mg, yield 42%).

[0329] 1 H NMR (400MHz, DMSO-d6) δ11.23(s,1H),9.95(s,1H),7.27(d,J=7.2Hz,1H),7.18–7.09(m,2H) ,6.71(d,J=2.0Hz,1H),6.41(dd,J=7.2,2.1Hz,1H),4.79(d,J=10.7Hz,1H),3.99–3.93(m,1H ),3.91(d,J=1.8Hz,3H),2.59(dd,J=16.0,7.2Hz,1H),1.88(dt,J=12.3,6.3Hz,1H),1.73–1 .56(m,2H),1.49(dd,J=12.3,6.0Hz,1H),1.45(s,3H),1.41–1.30(m,1H),1.26–1.16(m,1H).

[0330] MS m / z(ESI):405.2[M+H] + .

[0331] Example 8. Synthesis of Compound 15

[0332] Synthesis route:

[0333] Compound 10-7 (300 mg, 0.96 mmol) was dissolved in dichloromethane (10 mL). A catalytic amount of N,N-dimethylformamide was added at 0°C, followed by the slow addition of oxalyl chloride (381 mg, 2.87 mmol) and the reaction was allowed to proceed for 1 hour. The reaction system was concentrated, and the concentrate was dissolved in dichloromethane. Triethylamine (505 mg, 4.8 mmol), 4-dimethylaminopyridine (13 mg, 0.1 mmol), and 4-aminopyridine (141 mg, 1.44 mmol) were added sequentially, and the reaction was continued in an ice bath for 1 hour. After TLC analysis, the reaction was concentrated and purified by column chromatography to afford compound 15-1 (270 mg, 73% yield).

[0334] Compound 15-1 (270 mg, 0.77 mmol) was dissolved in dichloromethane (15 mL), and m-chloroperbenzoic acid (482 mg, 2.78 mmol) was added at room temperature. The reaction was allowed to react overnight. After TLC, the reaction was quenched with water, extracted with dichloromethane, dried, filtered, concentrated, and purified by column chromatography to obtain compound 15 (145 mg, 47% yield).

[0335] 1 H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.17–8.01(m,2H),7.88–7.52(m,2H),7 .30–6.91(m,2H),4.83(d,J=10.7Hz,1H),3.96(dd,J=10.6,7.7Hz,1H),3.92( d,J=1.8Hz,3H),2.59(dd,J=16.0,7.2Hz,1H),1.96–1.83(m,1H),1.75–1.61( m,2H),1.53–1.48(m,1H),1.47(s,3H),1.42–1.30(m,1H),1.29–1.19(m,1H).

[0336] MS m / z(ESI):405.2[M+H] + .

[0337] Example 9, 4-(4-(3,4-difluoro-2-methoxyphenyl)-1-methyl-2-oxabicyclo[3.2.0]heptane-3-carboxamide)picolinamide (Compound 28)

[0338] Synthesis route:

[0339] Step 1: Synthesis of compound 28-2

[0340] 2,3-Pentanedione (3.08 mL, 30 mmol) was dissolved in acetonitrile (300 mL), stirred at room temperature under N2 atmosphere, and irradiated with 405 nm lamp beads for 16 h. The solution was concentrated by column chromatography (PE:EA=3:1) to obtain compound 28-2 (2.84 g, 95% yield).

[0341] Step 2: Synthesis of compound 28-3

[0342] 2-Methoxy-3,4-difluorophenylacetic acid (6.3 g, 31.3 mmol) and carbonyldiimidazole (6.1 g, 37.5 mmol) were dissolved in acetonitrile (90 mL) and reacted at 0°C under nitrogen for 1 hour. Compound 28-2 (3.8 g, 37.5 mmol) and cesium carbonate (12.2 g, 37.5 mmol) were then added sequentially, and the temperature was slowly raised to 35°C and allowed to react overnight. Ethyl acetate was added to dilute the mixture, and the mixture was washed sequentially with water and saturated brine. The organic phase was dried and then spin-dried. The crude product was purified by column chromatography (EA in PE: 1%-20%) to obtain compound 28-3 (1.4 g, 17% yield) as a white solid.

[0343] Step 3: Synthesis of compound 28-4

[0344] Compound 28-3 (1.7 g, 6.5 mmol) was dissolved in a mixture of tetrahydrofuran (6 mL) and methanol (30 mL) and cooled to -78°C under nitrogen. Nickel chloride hexahydrate (2.3 g, 9.8 mmol) and sodium borohydride (1.2 g, 32.5 mmol) were added sequentially and the reaction continued for 1 hour. The reaction was complete as determined by TLC. The mixture was filtered, and the filtrate was diluted with water, extracted with dichloromethane, dried, and concentrated to afford the crude product of compound 28-4 (1.5 g, 88% yield).

[0345] Step 4: Synthesis of compound 28-5

[0346] Compound 28-4 (1.5 g, 5.7 mmol) was dissolved in dichloromethane (50 mL). 1 M diisobutylaluminum hydride (11.4 mL, 11.4 mmol) was added at -78°C under an inert atmosphere and the reaction was continued for 1 hour. The mixture was quenched with water, filtered, and the filtrate was concentrated to obtain the crude product of compound 28-5, which was directly carried out to the next step.

[0347] Step 5: Synthesis of compound 28-6

[0348] Compound 28-5 was dissolved in dichloromethane (30 mL), 4-dimethylaminopyridine (32.5 mg, 2.67 mmol) was added, and acetic anhydride (1.36 g, 13.4 mmol) was slowly added dropwise. After addition, the mixture was reacted at room temperature for 2 hours. After dilution with dichloromethane, the mixture was washed with water and saturated brine in sequence. The organic phase was dried and concentrated to obtain the crude product of compound 28-6, which was directly carried out to the next step.

[0349] Step 6: Synthesis of compound 28-7

[0350] Compound 28-6 was dissolved in dichloromethane. Trimethylsilyl cyanide (0.83 mL, 6.7 mmol) and boron trifluoride etherate (377 mg, 2.7 mmol) were added sequentially at 0°C and the reaction was continued for 2 hours. The reaction was quenched with water, extracted with dichloromethane, concentrated, and separated by column chromatography (EA in PE: 1% to 15%) to afford compound 28-7, which was directly carried out to the next step.

[0351] Step 7: Synthesis of compound 28-8

[0352] Compound 28-7 was dissolved in methanol (5 mL) and water (1 mL) and reacted at 55° C. for 72 hours. The reaction solution was adjusted to pH 3-4 with 2N hydrochloric acid, diluted with water, extracted with dichloromethane, and concentrated to obtain a crude product of compound 28-8 (102 mg, yield 95%).

[0353] Step 8: Synthesis of compound 28-9

[0354] Compound 28-8 (102 mg, 0.34 mmol) was dissolved in dichloromethane (5 mL). A catalytic amount of N,N-dimethylformamide was added at 0°C, followed by the slow addition of oxalyl chloride (0.1 mL, 1.0 mmol) and the reaction was allowed to proceed for 1 hour. The reaction mixture was concentrated and the concentrate was dissolved in dichloromethane. Triethylamine (17 mg, 1.7 mmol), 4-dimethylaminopyridine (4 mg, 0.03 mmol), and methyl 4-amino-2-picolinate (77 mg, 0.51 mmol) were added sequentially and the reaction was allowed to proceed overnight at room temperature. After TLC analysis, the reaction was concentrated and purified by column chromatography (EA in PE: 5%-50%) to afford compound 28-9 (60 mg, 41% yield) as a white solid.

[0355] Step 9: Synthesis of compound 28

[0356] To compound 28-9 was added 7 mL of 7 M amine methanol solution, stirred overnight, and rotary evaporated to obtain compound 28 (40 mg, yield 69%).

[0357] 1H NMR (400MHz, DMSO-d6) δ10.37(s,1H),8.50(d,J=5.5Hz,1H),8.39(d,J=2.1Hz,1H ),8.07(d,J=2.8Hz,1H),7.91(dd,J=5.5,2.2Hz,1H),7.62(d,J=2.9Hz,1H),7.25 –7.20(m,2H),4.81(d,J=5.2Hz,1H),4.22(dd,J=7.4,5.1Hz,1H),3.92(d,J=1.8H z,3H),2.61(t,J=7.2Hz,1H),1.22–1.06(m,2H),0.83–0.74(m,1H),0.53(m,4H).

[0358] MS m / z(ESI):418.1[M+1].

[0359] Example 10, 4-(3-(3,4-difluoro-2-methoxyphenyl)octahydrobenzofuran-2-carboxamide)picolinamide (Compound 37)

[0360] Synthesis route:

[0361] Step 1: Synthesis of compound 37-2

[0362] Dissolve 2-methoxy-3,4-difluorophenylacetic acid (14.39 g, 71.3 mmol) and carbonyldiimidazole (14.59 g, 90 mmol) in 10 mL of water and react at 0°C under nitrogen for 1 hour. Compound 37-1 (8.6 g, 75 mmol) and cesium carbonate (34.21 g, 105 mmol) were then added sequentially. The temperature was slowly raised to 50°C and the reaction was allowed to proceed overnight for 16 hours. Ethyl acetate was added to dilute the mixture, and the mixture was washed sequentially with water and saturated brine. The organic phase was dried and then spin-dried to dryness. The crude product was purified by column chromatography (EA in PE: 1%-20%) to afford compound 37-2 (12.9 g, 67% yield) as a white solid.

[0363] Step 2: Synthesis of compound 37-3

[0364] Compound 37-2 (560 mg, 2 mmol) was dissolved in a mixture of tetrahydrofuran (6 mL) and methanol (20 mL) and cooled to -40°C under nitrogen. Nickel chloride hexahydrate (712 mg, 3 mmol) and sodium borohydride (317 mg, 10 mmol) were added sequentially and the reaction continued for 1 hour. TLC confirmed the reaction was complete, and the filtrate was filtered. The filtrate was diluted with water, extracted with dichloromethane, dried, and concentrated to afford the crude product of compound 37-3 (550 mg, 97% yield).

[0365] 1 H NMR(400MHz,Chloroform-d)δ7.13(ddd,J=8.4,5.7,2.2Hz,1H),6.85(td,J=9.2,7.6Hz,1H),4.62(q,J=3.2Hz,1H),4.27(d,J=6.2Hz,1H),4.00 (d,J=2.7Hz,3H),2.66–2.53(m,1H),2.33–2.23(m,1H),1.64(dt,J=13. 4,4.0Hz,2H),1.59–1.53(m,1H),1.45–1.30(m,1H),1.18–0.87(m,3H).

[0366] Step 3: Synthesis of compound 37-4

[0367] Compound 37-3 (550 mg, 1.95 mmol) was dissolved in dichloromethane (15 mL). 1 M diisobutylaluminum hydride (5 mL, 5 mmol) was added at -78°C under an inert atmosphere and the reaction was continued for 2 hours. The mixture was quenched with water, filtered, and the filtrate was concentrated to obtain the crude product of compound 37-4 (250 mg, 52% yield), which was directly carried out to the next step.

[0368] Step 4: Synthesis of compound 37-5

[0369] Compound 37-5 (250 mg, 0.88 mmol) was dissolved in dichloromethane (10 mL). Triethylamine (178 mg, 1.76 mmol) and 4-dimethylaminopyridine (21 mg, 0.18 mmol) were added sequentially, followed by the slow dropwise addition of acetic anhydride (180 mg, 1.76 mmol). The mixture was reacted at room temperature for 1 hour. After dilution with dichloromethane, the mixture was washed sequentially with water and saturated brine. The organic phase was dried and concentrated to afford the crude product of compound 37-6 (270 mg, 94% yield), which was directly carried out to the next step.

[0370] Step 5: Synthesis of compound 37-6

[0371] Compound 37-5 (270 mg, 0.83 mmol) was dissolved in dichloromethane. Trimethylsilyl cyanide (246 mg, 2.48 mmol) and boron trifluoride etherate (352 mg, 2.48 mmol) were added sequentially at 0°C and the reaction continued for 2 hours. The reaction was quenched with water, extracted with dichloromethane, concentrated, and separated by column chromatography (EA in PE: 1%-15%) to afford compound 37-6 (170 mg, 70% yield) as a white solid.

[0372] 1H NMR(400MHz,Chloroform-d)δ6.92–6.76(m,2H),4.99(d,J=9.7Hz,1H),4.43(q,J=2.8Hz,1H),4.16(dd,J=9.7,5.9Hz,1H),4.03(d,J=2.6Hz,3H),2.4 3–2.33(m,1H),2.13–2.05(m,1H),1.69–1.57(m,2H),1.53–1.45(m,1H),1 .42–1.30(m,1H),1.14–1.03(m,1H),1.02–0.95(m,1H),0.94–0.84(m,1H).

[0373] Step 6: Synthesis of compound 37-7

[0374] Compound 37-6 (150 mg, 0.5 mmol) was dissolved in methanol (5 mL) and water (1 mL), and potassium hydroxide (280 mg, 5 mmol) was added and reacted at 60°C for 48 hours. The reaction solution was adjusted to pH 3-4 with 2N hydrochloric acid, diluted with water, extracted with dichloromethane, and concentrated to obtain the crude product of compound 37-7 (150 mg, 96% yield).

[0375] Step 7: Synthesis of compound 37-8

[0376] Compound 37-7 (150 mg, 0.48 mmol) was dissolved in dichloromethane (5 mL). A catalytic amount of N,N-dimethylformamide was added at 0°C, followed by the slow addition of oxalyl chloride (191 mg, 1.5 mmol) and the reaction was allowed to proceed for 1 hour. The reaction mixture was concentrated and the concentrate was dissolved in dichloromethane. Triethylamine (251 mg, 2.5 mmol), 4-dimethylaminopyridine (6 mg, 0.05 mmol), and methyl 4-amino-2-picolinate (114 mg, 0.75 mmol) were added sequentially. The reaction was allowed to proceed overnight at room temperature for 16 hours. After TLC analysis, the reaction was concentrated and purified by column chromatography (EA in PE: 5%-50%) to afford compound 37-8 (160 mg, 72% yield) as a white solid.

[0377] Step 8: Synthesis of compound 37

[0378] To compound 37-8 was added 10 mL of 7 M amine methanol solution, stirred at room temperature overnight for 16 h, and filtered to obtain compound 37 (130 mg, yield 84%).

[0379] 1H NMR(400MHz,Chloroform-d)δ9.02(s,1H),8.45(d,J=5.5Hz,1H),8.21(dd,J=5.5,2.2Hz,1H),7.95(d,J=2.1Hz,1H),7. 84(d,J=3.0Hz,1H),7.10(ddd,J=8.0,5.5,1.9Hz,1H),6.88(td,J=9.2,7.6Hz,1H),5.67(d,J=3.0Hz,1H),4.95(d,J=10 .2Hz,1H),4.39(q,J=2.7Hz,1H),3.97(d,J=2.4Hz,3H),3.90(dd,J=10.2,5.6Hz,1H),2.47–2.34(m,1H),2.24–2.14(m, 1H),1.72–1.63(m,2H),1.60–1.52(m,1H),1.42(qt,J=12.1,2.4Hz,1H),1.17–1.06(m,1H),1.02(td,J=9.6,4.7Hz,2H).

[0380] MS m / z(ESI):447.2[M+1].

[0381] Example 11, 4-(3-(3,4-difluoro-2-methoxyphenyl)-7a-methyloctahydrobenzofuran-2-carboxamide)picolinyl (Compound 46)

[0382] Synthesis route:

[0383] Step 1: Synthesis of compound 46-2

[0384] 2-Methoxy-3,4-difluorophenylacetic acid (20 g, 99.1 mmol) and carbonyldiimidazole (19.25 g, 118.7 mmol) were dissolved in acetonitrile (400 mL) and reacted at 0°C under nitrogen for 1 hour. Compound 46-1 (19 g, 148 mmol) and cesium carbonate (48.4, 149 mmol) were then added sequentially. The temperature was slowly raised to 50°C and the reaction was allowed to proceed overnight for 16 hours. Ethyl acetate was added to dilute the mixture, and the mixture was washed sequentially with water and saturated brine. The organic phase was dried and then spin-dried to dryness. The crude product was purified by column chromatography (EA in PE: 1%-20%) to afford compound 46-2 (22 g, 76% yield) as a white solid.

[0385] Step 2: Synthesis of compound 46-3

[0386] Compound 46-2 (3.5 g, 11.9 mmol) was dissolved in a mixture of tetrahydrofuran (30 mL) and methanol (150 mL) and cooled to -40°C under nitrogen. Nickel chloride hexahydrate and sodium borohydride were added sequentially, and the reaction was continued for 1 hour. TLC confirmed the reaction was complete, and the filtrate was filtered. The filtrate was diluted with water, extracted with dichloromethane, dried, and concentrated to afford the crude product of compound 46-3 (3.4 g, 97% yield).

[0387] Step 3: Synthesis of compound 46-4

[0388] Compound 1-4 (3.4 g, 11.5 mmol) was dissolved in dichloromethane (80 mL). 1 M diisobutylaluminum hydride (23 mL, 23 mmol) was added at -78°C under an inert atmosphere and the reaction was continued for 2 hours. The mixture was quenched with water, filtered, and the filtrate was concentrated to afford the crude product of compound 46-4 (2.7 g, 79% yield), which was directly carried to the next step.

[0389] Step 4: Synthesis of compound 46-5

[0390] Compound 46-4 (2.7 g, 9.1 mmol) was dissolved in dichloromethane (50 mL). Triethylamine (1.8 g, 17.8 mmol) and 4-dimethylaminopyridine (110 mg, 0.94 mmol) were added sequentially, followed by the slow dropwise addition of acetic anhydride (1.85 g, 18.1 mmol). The mixture was reacted at room temperature for 1 hour. After dilution with dichloromethane, the mixture was washed sequentially with water and saturated brine. The organic phase was dried and concentrated to afford the crude product of compound 46-5 (3 g, 97% yield), which was directly carried out to the next step.

[0391] Step 5: Synthesis of compound 46-6

[0392] Compound 46-5 (3 g, 8.81 mmol) was dissolved in dichloromethane. Trimethylsilyl cyanide (3.4 mL, 26.4 mmol) and boron trifluoride etherate (3.2 mL, 26.4 mmol) were added sequentially at 0°C and the reaction continued for 2 hours. The reaction was quenched with water, extracted with dichloromethane, concentrated, and separated by column chromatography (EA in PE: 1%-15%) to afford compound 46-6 (1.9 g, 70% yield) as a white solid.

[0393] 1H NMR(400MHz,Chloroform-d)δ6.93–6.74(m,2H),5.01(d,J=9.9Hz,1H),4.48(dd,J=9.9,6.0Hz,1H),4.04(d,J=2.7 Hz,3H),2.27(dt,J=12.1,6.1Hz,1H),2.05–1.96(m,1H),1.62–1.24(m,7H),1.11–0.96(m,2H),0.83–0.72(m,1H).

[0394] Step 6: Synthesis of compound 46-7

[0395] Compound 46-6 (1.9 g, 6.2 mmol) was dissolved in methanol (40 mL) and water (8 mL), and potassium hydroxide (3.6 g, 64 mmol) was added. The mixture was reacted at 60°C for 48 hours. The pH of the reaction solution was adjusted to 3-4 with 2N hydrochloric acid, diluted with water, extracted with dichloromethane, and concentrated to obtain the crude product of compound 46-7 (1.9 g, 95% yield).

[0396] Step 7: Synthesis of compound 46-8

[0397] Compound 46-7 (300 mg, 0.92 mmol) was dissolved in dichloromethane (10 mL). A catalytic amount of N,N-dimethylformamide was added at 0°C, followed by the slow addition of oxalyl chloride (382 mg, 3.0 mmol) and the reaction was allowed to proceed for 1 hour. The reaction mixture was concentrated and the concentrate was dissolved in dichloromethane. Triethylamine (502 mg, 5.0 mmol), 4-dimethylaminopyridine (12 mg, 0.1 mmol), and methyl 4-amino-2-picolinate (228 mg, 1.5 mmol) were added sequentially. The reaction was allowed to proceed overnight at room temperature for 16 hours. After completion of the reaction by TLC, the mixture was concentrated and purified by column chromatography (EA in PE: 5%-50%) to afford compound 46-8 (250 mg, 59% yield) as a white solid.

[0398] Step 8: Synthesis of compound 46

[0399] To compound 46-8 was added 10 mL of 7 M amine methanol solution, stirred at room temperature overnight for 16 h, and filtered to obtain compound 46 (184.4 mg, yield 76%).

[0400] 1H NMR (400MHz, DMSO-d6) δ10.48(s,1H),8.47(d,J=5.5Hz,1H),8.37(d,J=2.2Hz,1H),8.05(d,J=2.9H z,1H),7.88(dd,J=5.6,2.2Hz,1H),7.60(d,J=2.9Hz,1H),7.25(td,J=7.2,5.9,1.9Hz,1H),7.12(q, J=9.2Hz,1H),5.07(d,J=9.8Hz,1H),4.32(dd,J=9.9,5.8Hz,1H),3.92(d,J=1.7Hz,3H),2.18(dt,J =11.7,6.3Hz,1H),1.99(d,J=14.3Hz,1H),1.56–1.43(m,3H),1.38–1.28(m,4H),1.10–0.85(m,3H).

[0401] MS m / z(ESI):461.2[M+1].

[0402] Compound 46 was separated by chiral chromatography to obtain compound 46a and compound 46b. The specific experimental parameters are as follows:

[0403] Chromatographic column: DAICELCHIRALPAK IH; column size: 250*50 10μm; mobile phase A: supercritical CO2; mobile phase B: IPA (7.0 mol / L MEOH containing 0.1% ammonia); mobile phase gradient: A:B:75:25; detection wavelength: 214nm; flow rate: 140mL / min; column temperature: RT.

[0404] Compound 46: 840 mg, after splitting:

[0405] Compound 46b: 418 mg, >98% ee, retention time 0.940 min;

[0406] Compound 46a: 406 mg, >98% ee, retention time: 4.187 min.

[0407] Example 12: Synthesis of 3-(3,4-difluoro-2-methoxyphenyl)-7a-methyl-N-(6-oxo-1,6-dihydropyridin-3-yl)octahydrobenzofuran-2-carboxamide (Compound 47)

[0408] Synthesis route:

[0409] Compound 47-1 was prepared using a similar route to compound 46, substituting the corresponding reactants. Compound 47-1 (380 mg, 0.73 mmol) was dissolved in 15 mL of tetrahydrofuran, and 10% palladium on carbon (38 mg) was added. The mixture was stirred overnight under 1 atmosphere of hydrogen. The mixture was filtered through Celite, concentrated, and separated by column chromatography (EtOH in EA: 0% to 5%) to afford compound 47 (180 mg, 59% yield).

[0410] 1 H NMR (400MHz, DMSO-d6) δ11.34(s,1H),9.67(s,1H),7.81(d,J=2.9Hz,1H),7.57(dd,J=9. 7,2.9Hz,1H),7.23(t,J=7.8Hz,1H),7.10(q,J=9.3Hz,1H),6.31(d,J=9.7Hz,1H),4.96(d ,J=9.9Hz,1H),4.24(dd,J=9.9,5.8Hz,1H),3.91(d,J=1.7Hz,3H),2.14(dt,J=11.8,6.2 Hz,1H),1.96(d,J=14.4Hz,1H),1.59–1.41(m,3H),1.36–1.24(s,4H),1.14–0.80(m,3H).

[0411] MS m / z(ESI):419.2[M+1].

[0412] Example 13. Synthesis of 3-(3,4-difluoro-2-methoxyphenyl)-7a-methyl-N-(2-oxo-1,2-dihydropyridin-4-yl)octahydrobenzofuran-2-carboxamide (Compound 49)

[0413] A similar route to that used to prepare compounds 46 and 47 was used, and the corresponding reactants were replaced to give compound 49 (134 mg, yield 61%).

[0414] 1H NMR (400MHz, DMSO-d6) δ11.21(s,1H),9.99(d,J=3.4Hz,1H),7.26(d,J=7.2Hz,1H),7.20(ddd ,J=8.2,5.9,2.1Hz,1H),7.17–7.03(m,1H),6.73(d,J=2.0Hz,1H),6.47(dt,J=7.4,1.7Hz,1H ),4.99(d,J=9.8Hz,1H),4.29(dd,J=9.9,5.8Hz,1H),3.92(d,J=1.8Hz,3H),2.17(dt,J=10.3 ,6.5Hz,1H),1.96(d,J=17.6Hz,1H),1.67–1.39(m,3H),1.35–1.28(m,4H),1.11–0.83(m,3H).

[0415] MS m / z(ESI):419.2[M+1].

[0416] Example 14. Synthesis of 4-(3-(3,4-difluoro-2-methoxyphenyl)-7a-methyloctahydrobenzofuran-2-carboxamide)pyridine-1-oxide (Compound 51)

[0417] Synthesis route:

[0418] Compound 51-1 was prepared using a similar route to compound 46, substituting the corresponding reactants. Compound 51-1 (250 mg, 0.62 mmol) was dissolved in 10 mL of dichloromethane, and m-chloroperbenzoic acid (427.9 mg, 2.48 mmol) was added. The mixture was stirred overnight at room temperature. After concentration, the mixture was separated by column chromatography (EtOH in EA: 0% to 14%) to afford compound 51 (103 mg, 39% yield).

[0419] 1H NMR (400MHz, DMSO-d6) δ10.43(s,1H),8.10(d,J=7.1Hz,2H),7.73(d,J=7.2Hz,2H ),7.23(ddd,J=8.4,5.9,2.0Hz,1H),7.11(q,J=9.1Hz,1H),5.04(d,J=9.9Hz,1H) ,4.30(dd,J=9.9,5.9Hz,1H),3.92(d,J=1.9Hz,3H),2.17(dt,J=11.8,6.4Hz,1H) ,1.98(d,J=13.7Hz,1H),1.61–1.40(m,3H),1.36–1.26(s,4H),1.11–0.80(m,3H).

[0420] MS m / z(ESI):419.2[M+1].

[0421] Example 15, N-(3-formyl-4-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)hexahydro-2H-cyclopenta[b]furan-2-carboxamide (Compound 55)

[0422] Synthesis route:

[0423] Step 1: Synthesis of compound 55-1

[0424] Compound 1-7 (150 mg, 0.52 mmol) was dissolved in dichloromethane (4.00 mL). A catalytic amount of N,N-dimethylformamide was added at 0°C, followed by the slow addition of oxalyl chloride (0.16 mL, 1.6 mmol) and the reaction was allowed to proceed for 1 hour. The reaction mixture was concentrated and the concentrate was dissolved in dichloromethane. Triethylamine (370 mg, 2.74 mmol), 4-dimethylaminopyridine (6 mg, 0.04 mmol), and methyl 2-fluoro-5-aminobenzoate (200 mg, 1.18 mmol) were added sequentially and the reaction was allowed to proceed overnight at room temperature. After TLC analysis, the reaction was concentrated and purified by column chromatography (EA in PE: 5% to 50%) to afford compound 55-1 (190 mg, 84.1% yield) as a white solid.

[0425] MS m / z(ESI):450.4[M+H] + .

[0426] Step 2: Synthesis of compound 55

[0427] To compound 55-1 was added 20 mL of 7 M amine methanol solution, stirred overnight, and filtered to obtain compound 55 (103.5 mg, yield 56.4%).

[0428] 1 H NMR(400MHz, DMSO-d6)δ10.06(s,1H),7.96(dd,J=6.5,2.8Hz,1H),7.85–7.47(m,3H),7.36–7.00(m,3H),4.92–4. 84(m,1H),4.75(d,J=9.4Hz,1H),3.93–3.85(m,3H),3.32–3.16(m,1H),2.98(t,J=7.7Hz,1H),1.88–1.06(m,6H).

[0429] MS m / z(ESI):435.4[M+H] + .

[0430] Example 16. Synthesis of Compound 56

[0431] Synthesis route:

[0432] Compound 10-7 (320 mg, 1.02 mmol) was dissolved in dichloromethane (10 mL). A catalytic amount of N,N-dimethylformamide was added at 0°C, followed by the slow addition of oxalyl chloride (0.39 mg, 3.08 mmol) and the reaction was allowed to proceed for 1 hour. The reaction mixture was concentrated, and the concentrate was dissolved in dichloromethane. Triethylamine (518 mg, 5.1 mmol), 4-dimethylaminopyridine (13 mg, 0.1 mmol), and methyl 4-amino-2-picolinate (266 mg, 1.53 mmol) were added sequentially, and the reaction was allowed to proceed overnight at room temperature. After TLC analysis, the reaction was concentrated and purified by column chromatography (EA in PE: 5%-50%) to afford compound 56-1 (148 mg, 56% yield) as a white solid.

[0433] To compound 56-1 (148 mg) was added 10 mL of 7 M amine methanol solution, stirred overnight, and filtered to obtain compound 56 (47 mg, yield 33%).

[0434] 1H NMR (400MHz, DMSO-d6) δ10.02 (s, 1H), 7.93 (dd, J = 6.5, 2.7Hz, 1H), 7.76-- 7.72(1,1H),7.64(s,2H),7.23–7.11(m,3H),4.80(d,J=10.7Hz,1H),3.99– 3.93(m,1H),3.91(d,J=1.7Hz,3H),2.72–2.55(m,1H),1.92-1.96(m,1H),1 .81–1.57(m,2H),1.53–1.45(m,4H),1.40-1.31(m,1H),1.27-1.19(m,1H).

[0435] MS m / z(ESI):449.2[M+H] + .

[0436] Example 17. Synthesis of N-(3-carbamoyl-4-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-7a-methyloctahydrobenzofuran-2-carboxamide (Compound 60)

[0437] A similar route to that used to prepare compound 46 was used, and the corresponding reactants were replaced to give compound 60 (72 mg, yield 57%).

[0438] 1 H NMR(400MHz,DMSO-d6)δ10.07(s,1H),8.00–7.97(m,1H),7.78–7.74(m,1H),7. 64(s,2H),7.30–7.16(m,2H),7.11(q,J=8.8Hz,1H),5.01(d,J=9.9Hz,1H),4.29 (dd,J=10.0,5.9Hz,1H),3.92(d,J=1.8Hz,3H),2.17(dt,J=11.7,6.2Hz,1H),1 .97(d,J=15.4Hz,1H),1.67–1.40(m,3H),1.36–1.27(s,4H),1.14–0.82(m,3H).

[0439] MS m / z(ESI):463.2[M+1].

[0440] Example 18: Synthesis of 4-(6a-methyl-3-phenylhexahydro-2H-cyclopenta[b]furan-2-carboxamido)picolinamide (Compound 61)

[0441] Synthesis route:

[0442] Step 1: Synthesis of compound 61-1

[0443] Phenylacetic acid (2.1 g, 13.14 mmol) and carbonyldiimidazole (2.1 g, 13.14 mmol) were dissolved in acetonitrile (20 mL) and reacted at 0°C under nitrogen for 0.5 hours. Compound 10-1 (1 g, 8.76 mmol) and cesium carbonate (5.71 g, 17.52 mmol) were then added sequentially, and the temperature was slowly raised to 80°C and allowed to react overnight. Ethyl acetate was added to dilute the mixture, and the mixture was washed sequentially with water and saturated brine. The organic phase was dried and then spin-dried to dryness. The crude product was purified by column chromatography (EA in PE: 1%-20%) to afford 61-1 (0.65 g, 35.76% yield) as a white solid.

[0444] Step 2: Synthesis of compound 61-2

[0445] Compound 61-1 (0.65 g, 28 mmol) was dissolved in a mixture of tetrahydrofuran (2 mL) and methanol (10 mL) and cooled to -40°C under nitrogen. Nickel chloride (1.07 g, 4.55 mmol) and sodium borohydride (0.172 g, 4.55 mmol) were added sequentially and the reaction continued for 1 hour. The reaction was complete as determined by TLC. The filtrate was filtered, diluted with water, extracted with dichloromethane, dried, concentrated, and purified by column chromatography to afford compound 61-2 (0.5 g, 76.21% yield).

[0446] Step 3: Synthesis of compound 61-3

[0447] Compound 61-2 (0.5 g, 2.31 mmol) was dissolved in dichloromethane (10 mL). 1 M diisobutylaluminum hydride (3.47 mL, 3.27 mmol) was added at -78°C under an inert atmosphere and the reaction was continued for 1 hour. The mixture was quenched with saturated aqueous ammonium chloride, filtered, and the filtrate was concentrated and purified to afford compound 61-3 (0.3 g, 59% yield).

[0448] Step 4: Synthesis of compound 61-4

[0449] Compound 61-3 (0.3 g, 1.37 mmol) was dissolved in dichloromethane (15 mL), and 4-dimethylaminopyridine (68 mg, 2.06 mmol) was added sequentially, followed by the slow dropwise addition of acetic anhydride (210 mg, 2.06 mmol). The reaction was allowed to proceed overnight at room temperature. After dilution with dichloromethane, the mixture was washed sequentially with water and saturated brine. The organic phase was dried, concentrated, and purified to afford compound 61-4 (310 mg, 86.7% yield).

[0450] Step 5: Synthesis of compound 61-5

[0451] Compound 61-4 (0.31 g, 4.3 mmol) was dissolved in dichloromethane. Trimethylsilyl cyanide (295 mg, 2.98 mmol) and boron trifluoride etherate (1.35 g, 9.53 mmol) were added sequentially at -78°C and the reaction was continued for 2 hours. The reaction was quenched by adding saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and concentrated to obtain the crude product compound 61-5 (0.23 g, yield 85%). Step 6: Synthesis of compound 61-6

[0452] Compound 61-4 (0.23 g, 3.3 mmol) was dissolved in methanol (3 mL), and 2 M potassium hydroxide solution (3 mL) was slowly added to the reaction mixture. The reaction mixture was allowed to react overnight at 55°C. The pH of the reaction mixture was adjusted to 3-4 with 2N hydrochloric acid, concentrated, and filtered. The filter cake was concentrated to obtain 0.21 mg of crude compound 61-6.

[0453] Step 7: Synthesis of compound 61-7

[0454] Compound 61-6 (0.21 g, 1.41 mmol) was dissolved in dichloromethane (5 mL). A catalytic amount of N,N-dimethylformamide was added at 0°C, followed by the slow addition of oxalyl chloride (337 mg, 1.71 mmol) and the reaction was allowed to proceed for 1 hour. The reaction mixture was concentrated and the concentrate was dissolved in dichloromethane. N,N-diisopropylethylamine (220 mg, 1.71 mmol) and 4-aminopyridineamide (140 mg, 1.02 mmol) were added sequentially and the reaction was allowed to proceed overnight at room temperature. After TLC analysis, the reaction was concentrated and purified by column chromatography (EA in PE: 5%-50%) to afford compound 61 (22 mg, 7.06% yield).

[0455] 1 H NMR (400MHz, DMSO-D6) δ10.44(s,1H),8.43(d,J=5.4Hz,1H),8.27(d,J=2.2Hz,1H),8.02( d,J=2.9Hz,1H),7.81(dd,J=5.5,2.2Hz,1H),7.57(d,J=2.8Hz,1H),7.27(d,J=5.0Hz,4H), 7.17(td,J=5.5,3.1Hz,1H),4.77(d,J=10.6Hz,1H),3.90(dd,J=10.5,7.3Hz,1H),2.59(dt ,J=9.0,6.8Hz,1H),1.92–1.86(m,1H),1.68–1.58(m,2H),1.44(s,4H),1.37–1.25(m,2H).

[0456] MS m / z(ESI):366.2[M+H] + .

[0457] Example 19. Synthesis of 4-(3-(4-fluorophenyl)hexahydro-2H-cyclopenta[b]furan-2-carboxamido)picolinamide (Compound 62)

[0458] Synthesis route:

[0459] A similar route to that used to prepare compound 61 was used to replace the phenylacetic acid in step 1 with p-fluorophenylacetic acid to obtain compound 62 (54.8 mg, yield 12.6%).

[0460] 1 H NMR (400MHz, DMSO-d6) δ10.38(s,1H),8.43(d,J=5.5Hz,1H),8.28(d,J=2.1Hz,1H),8.02( d,J=2.8Hz,1H),7.82(dd,J=5.5,2.2Hz,1H),7.57(d,J=2.9Hz,1H),7.35–7.29(m,2H),7. 13–7.08(m,2H),4.75(d,J=10.6Hz,1H),3.88(dd,J=10.6,7.3Hz,1H),2.56(dt,J=8.9,6. 9Hz,1H),1.88(dd,J=12.0,6.2Hz,1H),1.71–1.57(m,2H),1.44(s,3H),1.38–1.17(m,3H).

[0461] MS m / z(ESI):384.2[M+H] + .

[0462] Example 20: Synthesis of 4-(3-(3-fluorophenyl)-6a-methylhexahydro-2H-cyclopenta[b]furan-2-carboxamido)picolinamide (Compound 63)

[0463] Synthesis route:

[0464] A similar route to that used to prepare compound 61 was used to prepare compound 63 (45.2 mg, yield 14.16%) by replacing the phenylacetic acid in step 1 with m-fluorophenylacetic acid.

[0465] 1H NMR (400MHz, DMSO-d6) δ10.38(s,1H),8.43(t,J=5.0Hz,1H),8.28(d,J=2.2Hz,1H),8.09–7. 99(m,1H),7.82(dd,J=5.5,2.3Hz,1H),7.57(d,J=3.0Hz,1H),7.32(q,J=7.7Hz,1H),7.19–7 .09(m,2H),7.01(td,J=8.6,2.6Hz,1H),4.79(d,J=10.6Hz,1H),3.90(dd,J=10.6,7.4Hz,1H ),2.66–2.58(m,1H),1.97–1.84(m,1H),1.72–1.56(m,2H),1.44(s,3H),1.38–1.19(m,3H).

[0466] MS m / z(ESI):384.2[M+H] + .

[0467] Example 21. Synthesis of (E)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(N'-hydroxycarbamoyl)pyridin-4-yl)-6a-methylhexahydro-2H-cyclopenta[b]furan-2-carboxamide (Compound 64)

[0468] Synthesis route:

[0469] Step 1: Synthesis of compound 64-1

[0470] Compound 10-7 (1 g, 3.2 mmol) was dissolved in dichloromethane (30 mL). A catalytic amount of N,N-dimethylformamide was added at 0°C, followed by the slow addition of oxalyl chloride (1.22 g, 9.6 mmol) and the reaction was allowed to proceed for 0.5 hours. The reaction mixture was concentrated, and the concentrate was dissolved in dichloromethane. Triethylamine (1.62 g, 16 mmol), 4-dimethylaminopyridine (40 mg, 0.32 mmol), and 4-amino-2-cyanopyridine (573 mg, 4.8 mmol) were added sequentially, and the reaction was allowed to proceed overnight at room temperature. After TLC analysis, the reaction was concentrated and purified by column chromatography (EA in PE: 5%-50%) to afford compound 64-1 (500 mg, 38% yield) as a pale yellow solid.

[0471] Step 2: Synthesis of compound 64

[0472] Compound 64-1 (200 mg, 0.48 mmol) was dissolved in methanol (5 mL), and hydroxylamine hydrochloride (68 mg, 0.96 mmol) and N,N-diisopropylethylamine (94 mg, 0.72 mmol) were added. The mixture was stirred at room temperature overnight. After TLC, the reaction mixture was directly purified in batches using a reverse-phase column (aqueous phase: 0.1% FA; organic phase: acetonitrile) and lyophilized to obtain compound 64 (63 mg, 30% yield).

[0473] 1 H NMR (400MHz, DMSO-d6) δ10.31(s,1H),9.82(s,1H),8.40(d,J=5.6Hz,1H),8.17(d,J=1.9Hz,1H) ,7.65(dd,J=5.6,2.1Hz,1H),7.24–7.02(m,2H),5.78(s,2H),4.82(d,J=10.7Hz,1H),3.97(dd, J=10.7,7.6Hz,1H),3.91(d,J=1.8Hz,3H),2.60(dd,J=15.9,7.2Hz,1H),1.89(dt,J=12.4,6.4H z,1H),1.74–1.62(m,2H),1.51–1.46(m,1H),1.48(s,3H),1.41–1.30(m,1H),1.27–1.20(m,1H).

[0474] MS m / z(ESI):447.2[M+H] + .

[0475] Example 22. Synthesis of (E)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(N'-methoxycarbamoyl)pyridin-4-yl)-6a-methylhexahydro-2H-cyclopenta[b]furan-2-carboxamide (Compound 65)

[0476] Synthesis route:

[0477] Compound 64-1 (250 mg, 0.6 mmol) was dissolved in isopropanol (10 mL), and thioglycolic acid (112 mg, 1.2 mmol), methoxyamine hydrochloride (152 mg, 1.8 mmol), and N,N-diisopropylethylamine (315 mg, 2.4 mmol) were added. The mixture was heated to 80°C and stirred overnight. After TLC analysis of the reaction, the reaction solution was directly purified in batches using a reverse-phase column (aqueous phase: 0.1% FA; organic phase: acetonitrile) and lyophilized to obtain compound 65 (80 mg, 29% yield).

[0478] 1 H NMR (400MHz, DMSO-d6) δ10.37(s,1H),8.42(d,J=5.6Hz,1H),8.13(d,J=2.0Hz,1H),7.72(dd,J =5.6,2.1Hz,1H),7.28–7.00(m,2H),6.05(s,2H),4.83(d,J=10.8Hz,1H),3.96(dd,J=10.7,7.7 Hz,1H),3.92(d,J=1.8Hz,3H),3.78(s,3H),2.61(dd,J=15.9,7.2Hz,1H),1.89(dt,J=12.4,6.3 Hz,1H),1.79–1.59(m,2H),1.55–1.43(m,4H),1.41–1.30(m,1H),1.23(dt,J=13.3,6.6Hz,1H).

[0479] MS m / z(ESI):461.2[M+H] + .

[0480] Example 23. Synthesis of N-(2-aminoformylpyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-6a-methylhexahydro-2H-cyclopenta[b]furan-2-carboxamide (Compound 66)

[0481] Synthesis route:

[0482] Compound 64-1 (200 mg, 0.48 mmol) was dissolved in methanol (6 mL), and sodium methoxide (26 mg, 0.48 mmol) was added. The mixture was stirred at room temperature overnight. Subsequently, ammonium chloride (52 mg, 0.92 mmol) was added, and the temperature was raised to 70°C and stirred overnight. After TLC analysis of the reaction, the reaction solution was directly purified in batches using a reverse-phase column (aqueous phase: 10 mmol / L ammonium bicarbonate; organic phase: acetonitrile) and lyophilized to obtain compound 66 (11 mg, 5.3% yield).

[0483] 1H NMR (400MHz, DMSO-d6) δ10.43(s,1H),8.48(d,J=5.5Hz,1H),8.39(d,J=1.8Hz,1H),7. 81(dd,J=5.5,2.0Hz,1H),7.57(s,2H),7.22-7.11(m,2H),4.86(d,J=10.8Hz,2H),3.97 (dd,J=10.7,7.6Hz,1H),3.92(d,J=1.8Hz,3H),2.61(dd,J=15.8,7.3Hz,1H),1.93-1. 87(m,1H),1.76–1.57(m,2H),1.57–1.43(m,4H),1.37-1.33(m,1H),1.30–1.16(m,1H).

[0484] MS m / z(ESI):431.2[M+H] + .

[0485] Example 24. Synthesis of 4-(3-(3,4-difluoro-2-methoxyphenyl)-6a-ethylhexahydro-2H-cyclopenta[b]furan-2-carboxamido)picolinamide (Compound 67)

[0486] Synthesis route:

[0487] Using a similar route to compound 10, replacing the corresponding reactants, compound 67-8 (100 mg, 35.6% yield) was prepared. 10 mL of 7 M amine methanol solution was added to compound 67-8 (100 mg), stirred overnight, and filtered to obtain compound 67 (79 mg, 80% yield).

[0488] 1H NMR (400MHz, DMSO-d6) δ10.49(s,1H),8.47(d,J=5.5Hz,1H),8.29(d,J=2.0Hz,1H),8.06(d,J=2.0Hz,1H),7. 83(dd,J=5.5,2.2Hz,1H),7.61(d,J=2.0Hz,1H),7.24–7.09(m,2H),4.87(d,J=10.8Hz,1H),3.92(d,J=1.7Hz ,3H),3.89(d,J=7.9Hz,1H),2.67(dd,J=14.9,8.2Hz,1H),1.83(dd,J=13.0,6.5Hz,1H),1.80–1.69(m,3H),1 .69–1.57(m,1H),1.54–1.41(m,1H),1.39–1.28(m,1H),1.23(dq,J=13.1,6.6Hz,1H),1.01(t,J=7.3Hz,3H).

[0489] MS m / z(ESI):446.2[M+H] + .

[0490] Example 25. Synthesis of 4-(3-(3,4-difluoro-2-methoxyphenyl)-6a-isopropylhexahydro-2H-cyclopenta[b]furan-2-carboxamido)picolinamide (Compound 68)

[0491] Synthesis route:

[0492] Compound 68-8 (55 mg) was prepared by replacing the corresponding reactants using a similar route to compound 10. 10 mL of 7 M amine methanol solution was added to compound 68-8 (55 mg), stirred overnight, and filtered to obtain compound 68 (18.8 mg, yield 35%).

[0493] 1H NMR (400MHz, DMSO-d6) δ10.55(s,1H),8.47(d,J=2.2Hz,1H),8.26(d,J=2.0Hz,1H),8.06(s,1H ),7.81(dd,J=5.5,2.1Hz,1H),7.61(s,1H),7.22–7.15(m,2H),4.87(d,J=11.0Hz,1H),3.92(d ,J=1.5Hz,3H),3.90–3.85(m,1H),2.76(dd,J=14.0,8.3Hz,1H),2.11(dt,J=12.2,6.1Hz,1H), 2.03–1.87(m,2H),1.71–1.59(m,2H),1.47–1.41(m,1H),1.34–1.28(m,1H),1.08–1.01(m,6H).

[0494] MS m / z(ESI):460.2[M+H] + .

[0495] Example 26. Synthesis of 4-(6a-methyl-3-(6-methylpyridin-3-yl)hexahydro-2H-cyclopenta[b]furan-2-carboxamido)picolinamide (Compound 69)

[0496] Synthesis route:

[0497] Compound 69-7 (60 mg, 41% yield) was prepared using a similar route to compound 61, replacing the phenylacetic acid in step 1 with 6-methyl-3-pyridineacetic acid. To compound 69-7 was added 7 mL of a 7 M amine methanol solution, stirred overnight, and rotary evaporated to afford compound 69 (40 mg, 69% yield).

[0498] 1H NMR(400MHz,Chloroform-d)δ8.71(s,1H),8.39–8.35(m,2H),8.10(td,J=5.6,2.2Hz,1H),7 .84(dd,J=4.1,2.2Hz,2H),7.46(dd,J=8.0,2.4Hz,1H),7.09(d,J=3.2Hz,1H),6.00(t,J=3. 8Hz,1H),4.40(d,J=10.3Hz,1H),2.86(dd,J=10.3,8.1Hz,1H),2.47(s,3H),2.37(t,J=7.8H z,2H),1.95(dq,J=13.3,7.4,6.8Hz,1H),1.78–1.68(m,3H),1.46(s,3H),1.41–1.36(m,1H).

[0499] MS m / z(ESI):381.2[M+H] + .

[0500] Example 27: Synthesis of methyl 4-(3-(2-methoxyphenyl)-7a-methyloctahydrobenzofuran-2-carboxamido)picolinate (Compound 70)

[0501] Synthesis route:

[0502] Compound 70-7 (67 mg, 16% yield) was prepared using a similar route to compound 46, replacing the reactant in step 1, 2-methoxy-3,4-difluorophenylacetic acid, with 2-methoxyphenylacetic acid. To compound 70-7 was added 10 mL of a 7 M amine methanol solution, stirred overnight, and filtered to afford compound 70 (46 mg, 72% yield).

[0503] 1 H NMR(400MHz,Chloroform-d)δ9.04(s,1H),8.43(d,J=5.2Hz,1H),8.25(d,J=5.2Hz,1H), 7.89(s,2H),7.42(d,J=7.3Hz,1H),7.24(d,J=7.8Hz,1H),6.98(t,J=7.5Hz,1H),6.85(d, J=8.0Hz,1H),5.62(s,1H),5.11(d,J=10.5Hz,1H),4.31(dd,J=10.6,5.6Hz,1H),3.82(s ,3H),2.39(q,J=7.6,7.2Hz,1H),2.08(d,J=14.4Hz,1H),1.60–1.48(m,7H),1.45(s,3H).

[0504] MS m / z(ESI):410.2[M+H] + .

[0505] Example 28. Synthesis of 4-(7a-methyl-3-phenyloctahydrobenzofuran-2-carboxamide)picolinamide (Compound 71)

[0506] Synthesis route:

[0507] Compound 71-8 was prepared using a similar route to compound 46, replacing the reactant 2-methoxy-3,4-difluorophenylacetic acid in step 1 with phenylacetic acid. To compound 71-8 was added 10 mL of a 7 M amine methanol solution, stirred overnight, and filtered to afford compound 71 (149 mg, 72% yield).

[0508] 1 H NMR(400MHz,Chloroform-d)δ8.98(s,1H),8.44–8.43(m,1H),8.26–8.19(m,1H),7.92–7.91(m,1H),7.85–7.84(m,1H),7.28–7.38(m,5H),5 .79(d,J=4.4Hz,2H),4.62(d,J=9.2Hz,1H),3.62–3.55(m,1H),2.95(s ,1H),2.88(s,1H),2.27–2.24(m,1H),1.81–1.54(m,5H),1.50(s,3H).

[0509] MS m / z(ESI):380.2[M+H] + .

[0510] Example 29. Synthesis of (Z)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(N'-hydroxyaminocarboxamido)pyridin-4-yl)-7a-methyloctahydrobenzofuran-2-carboxamide (Compound 72)

[0511] Synthesis route:

[0512] Using a similar route to prepare compounds 46 and 64

[0513] Step 1: Synthesis of compound 72-1

[0514] Compound 46-7 (2.2 g, 6.7 mmol) was dissolved in dichloromethane (65 mL). A catalytic amount of N,N-dimethylformamide was added at 0°C, followed by the slow addition of oxalyl chloride (2.6 mL) and the reaction was allowed to proceed for 0.5 hours. The reaction mixture was concentrated, and the concentrate was dissolved in dichloromethane. Triethylamine (3.85 g, 39.8 mmol), 4-dimethylaminopyridine (90 mg, 0.64 mmol), and 4-amino-2-cyanopyridine (1.2 g, 10 mmol) were added sequentially, and the reaction was allowed to proceed overnight at room temperature. After TLC analysis, the reaction was concentrated and purified by column chromatography (EA in PE: 5%-50%) to afford compound 72-1 (1.7 g, 59.0% yield) as a pale yellow solid.

[0515] Step 2: Synthesis of compound 72

[0516] Compound 72-1 (320 mg, 0.74 mmol) was dissolved in methanol (13 mL), and hydroxylamine hydrochloride (104 mg, 1.47 mmol) and N,N-diisopropylethylamine (144 mg, 1.09 mmol) were added. The mixture was stirred at room temperature overnight. After TLC analysis of the reaction, the reaction solution was directly purified in batches using a reverse-phase column (aqueous phase: 0.1% FA; organic phase: acetonitrile) and lyophilized to obtain compound 72 (150 mg, 43.5% yield).

[0517] 1 H NMR (400MHz, DMSO-d6) δ10.38(s,1H),9.81(s,1H),8.40(d,J=5.6Hz,1H),8.23(s,1H),7.68 (dd,J=5.6,2.0Hz,1H),7.24(ddd,J=8.5,5.9,1.8Hz,1H),7.19–7.06(m,1H),5.77(s,2H),5 .04(d,J=9.9Hz,1H),4.32(dd,J=9.9,5.8Hz,1H),3.92(d,J=1.8Hz,3H),2.18(dt,J=11.5,6 .4Hz,1H),1.98(d,J=13.9Hz,1H),1.64–1.42(m,3H),1.34–1.27(m,4H),1.16–0.84(m,3H).

[0518] MS m / z(ESI):461.2[M+H] + .

[0519] Example 30. Synthesis of (Z)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(N'-methoxycarbamoyl)pyridin-4-yl)-7a-methyloctahydrobenzofuran-2-carboxamide (Compound 73)

[0520] Synthesis route:

[0521] Using a similar route to compound 65, compound 72-1 (300 mg, 0.70 mmol) was dissolved in isopropanol (10 mL). Thioglycolic acid (129 mg, 1.38 mmol), methoxyamine hydrochloride (176 mg, 2.1 mmol), and N,N-diisopropylethylamine (363 mg, 2.8 mmol) were added. The mixture was heated to 80°C and stirred overnight. After TLC analysis of the reaction, the reaction solution was directly purified in batches using a reverse-phase column (aqueous phase: 0.1% FA; organic phase: acetonitrile) and lyophilized to obtain compound 73 (108 mg, 32.5% yield).

[0522] 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),8.41(d,J=5.6Hz,1H),8.23(d,J=2.0Hz,1H),7.73(dd,J =5.6,2.1Hz,1H),7.24(ddd,J=8.3,5.7,1.9Hz,1H),7.11(q,J=9.1Hz,1H),6.04(s,2H),5.05(d ,J=9.9Hz,1H),4.30(dd,J=9.9,5.8Hz,1H),3.92(d,J=1.9Hz,3H),3.77(s,3H),2.18(dt,J=11. 6,6.4Hz,1H),1.98(d,J=13.9Hz,1H),1.62–1.42(m,3H),1.34–1.23(m,4H),1.12–0.84(m,3H).

[0523] MS m / z(ESI):475.2[M+H] + .

[0524] Example 31. Synthesis of N-(2-aminoformylpyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-7a-methyloctahydrobenzofuran-2-carboxamide (Compound 74)

[0525] Synthesis route:

[0526] Using a similar route to compound 66, compound 72-1 (300 mg, 0.70 mmol) was dissolved in methanol (9 mL), and sodium methoxide (38 mg, 0.69 mmol) was added. The mixture was stirred at room temperature overnight. Subsequently, ammonium chloride (75 mg, 1.33 mmol) was added, and the temperature was raised to 70°C and stirred overnight. After TLC analysis of the reaction, the reaction solution was directly purified in batches using a reverse-phase column (aqueous phase: 10 mmol / L ammonium bicarbonate; organic phase: acetonitrile) and lyophilized to afford compound 74 (19 mg, 6.1% yield).

[0527] 1 H NMR(400MHz,DMSO-d6)δ10.40(s,1H),8.77–8.15(m,2H),7.81(d,J=5.4Hz,1H ),7.34–7.21(m,1H),7.12(q,J=8.9Hz,1H),6.93(s,2H),5.06(d,J=9.9Hz,1H ),4.31(dd,J=10.0,5.8Hz,1H),3.92(s,3H),2.18(dt,J=11.8,6.6Hz,1H),1. 98(d,J=13.9Hz,1H),1.59–1.43(m,3H),1.35–1.23(m,4H),1.11–0.83(m,3H).

[0528] MS m / z(ESI):445.2[M+H] + .

[0529] Example 32: Synthesis of 4-(3-(3,4-difluorophenyl)-7a-methyloctahydrobenzofuran-2-carboxamido)picolinamide (Compound 75)

[0530] Synthesis route:

[0531] A similar route to that used to prepare compound 46 was used to replace the reactant in step 1, 2-methoxy-3,4-difluorophenylacetic acid, with 3,4-difluorophenylacetic acid to obtain compound 75 (35 mg, yield 36.3%).

[0532] 1H NMR (400MHz, DMSO-d6) δ10.41(s,1H),8.50–8.44(m,1H),8.39(d,J=2.1Hz,1H),8.05( s,1H),7.90(dd,J=5.6,2.2Hz,1H),7.59(d,J=1.2Hz,1H),7.53–7.47(m,1H),7.41–7. 33(m,1H),7.22–7.16(m,1H),5.04(d,J=9.7Hz,1H),4.22(dd,J=9.8,6.0Hz,1H),2.18 (dt,J=12.3,9.1Hz,1H),2.00(d,J=13.6Hz,1H),1.81–1.16(m,7H),1.12–0.83(m,3H).

[0533] MS m / z(ESI):416.2[M+H] + .

[0534] Example 33. Synthesis of 4-(3-(4-fluorophenyl)-7a-methyloctahydrobenzofuran-2-carboxamido)picolinamide (Compound 76)

[0535] Synthesis route:

[0536] A similar route to that used to prepare compound 46 was used to replace the reactant in step 1, 2-methoxy-3,4-difluorophenylacetic acid, with p-fluorophenylacetic acid to obtain compound 76 (33 mg, yield 22.8%).

[0537] 1 H NMR (400MHz, DMSO-d6) δ10.48(s,1H),8.47(t,J=4.7Hz,1H),8.37(d,J=2.1Hz ,1H),8.05(s,1H),7.88(dd,J=5.5,2.1Hz,1H),7.59(s,1H),7.40–7.36(m,2H) ,7.15(q,J=8.7Hz,2H),5.01(d,J=9.7Hz,1H),4.22(dd,J=9.8,6.0Hz,1H),2. 26–2.09(m,1H),1.98(d,J=13.6Hz,1H),1.85–1.13(m,7H),1.12–0.84(m,3H).

[0538] MS m / z(ESI):398.2[M+H] + .

[0539] Example 34. Synthesis of 4-(3-(3-fluorophenyl)-7a-methyloctahydrobenzofuran-2-carboxamido)picolinamide (Compound 77)

[0540] Synthesis route:

[0541] A similar route to that used to prepare compound 46 was used to prepare compound 77 (59 mg, yield 61.4%) by replacing the reactant in step 1, 2-methoxy-3,4-difluorophenylacetic acid, with m-fluorophenylacetic acid.

[0542] 1 H NMR (400MHz, DMSO-d6) δ10.47(s,1H),8.47(t,J=4.8Hz,1H),8.39(d,J=2.1Hz,1H) ,8.05(s,1H),7.90(dd,J=5.5,2.2Hz,1H),7.59(s,1H),7.36(p,J=7.5Hz,1H),7.26 –7.11(m,2H),7.11–6.99(m,1H),5.05(d,J=9.7Hz,1H),4.25(dd,J=9.7,6.0Hz,1H ),2.27–2.09(m,1H),1.99(d,J=13.8Hz,1H),1.73–1.15(m,7H),1.10–0.78(m,3H).

[0543] MS m / z(ESI):398.2[M+H] + .

[0544] Example 35. Synthesis of 4-(3-(3,4-difluoro-2-methoxyphenyl)-8a-methyloctahydro-2H-cycloheptyl[b]furan-2-carboxamido)picolinamide (Compound 78)

[0545] Synthesis route:

[0546] Step 1: Synthesis of compound 78-2

[0547] Compound 78-1 (22.4 g, 200 mmol) was dissolved in 1,4-dioxane (100 mL), preheated to 80 ° C, and then selenium dioxide (33.4 g, 300 mmol) dissolved in a mixed solution of 1,4-dioxane (320 mL) and water (80 mL) was added. The temperature was raised to 90 ° C and the reaction was carried out for 7 hours. After cooling to room temperature, it was filtered through diatomaceous earth and washed with ethyl acetate. The organic phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then spin-dried to obtain 20 g of crude product of compound 78-2 (yield 80%).

[0548] Step 2: Synthesis of compound 78-3

[0549] Compound 78-2 (20 g, 158.7 mmol) was dissolved in dichloromethane (200 mL), and triethylamine (32 g, 316.8 mmol) and trimethylsilyl chloride (20 mL) were added dropwise successively. The reaction was monitored by TLC. After completion of the reaction, 3 M methylmagnesium bromide (104 mL) was added dropwise in an ice bath. The reaction was allowed to proceed for one hour. The reaction solution was then poured into a saturated aqueous ammonium chloride solution, and the pH of the aqueous phase was adjusted to acidic with 1N HCl. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then spin-dried. The crude product was purified by column chromatography (EA in PE: 0% to 10%) to give compound 78-3 (9 g, yield 41%) as a yellow oil.

[0550] Step 3: Synthesis of compound 78-4

[0551] 2-Methoxy-3,4-difluorophenylacetic acid (12 g, 59.4 mmol) and carbonyldiimidazole (11.8 g, 72.8 mmol) were dissolved in acetonitrile (300 mL) and reacted at 0°C under nitrogen for 1 hour. Compound 78-3 (8.6 g, 60.6 mmol) and cesium carbonate (29.7 g, 90.3 mmol) were then added sequentially, and the temperature was slowly raised to 80°C and allowed to react overnight. Ethyl acetate was added to dilute the mixture, and the mixture was washed sequentially with water and saturated brine. The organic phase was dried and then spin-dried to dryness. The crude product was purified by column chromatography (EA in PE: 1%-20%) to obtain compound 78-4 (6 g, 32% yield) as a white solid.

[0552] MS m / z(ESI):309.1[M+H] + .

[0553] Step 4: Synthesis of compound 78-5

[0554] Compound 78-4 (2.0 g, 6.5 mmol) was dissolved in a mixture of tetrahydrofuran (20 mL) and methanol (100 mL) and cooled to -40°C under nitrogen. Nickel chloride hexahydrate and sodium borohydride were added sequentially, and the reaction was continued for 1 hour. The reaction was determined to be complete by TLC. The filtrate was filtered, diluted with water, extracted with dichloromethane, dried, and concentrated to afford the crude product of compound 78-5 (2 g, 99% yield).

[0555] Step 5: Synthesis of compound 78-6

[0556] Compound 78-5 (2 g, 6.4 mmol) was dissolved in dichloromethane (40 mL). 1 M diisobutylaluminum hydride (12.8 mL, 12.8 mmol) was added at -78°C under an inert atmosphere and the reaction was continued for 2 hours. The mixture was quenched with water, filtered, and the filtrate was concentrated to obtain the crude product of compound 78-6 (2 g, 99% yield), which was directly used in the next step.

[0557] Step 6: Synthesis of compound 78-7

[0558] Compound 78-6 (2 g, 6.4 mmol) was dissolved in dichloromethane (40 mL). Triethylamine (1.3 g, 12.8 mmol) and 4-dimethylaminopyridine (80 mg, 0.66 mmol) were added sequentially, followed by the slow dropwise addition of acetic anhydride (1.3 g, 12.7 mmol). The mixture was reacted at room temperature for 1 hour. After dilution with dichloromethane, the mixture was washed sequentially with water and saturated brine. The organic phase was dried and concentrated to obtain the crude product of compound 78-7 (2 g, 88% yield), which was directly carried out to the next step.

[0559] Step 7: Synthesis of compound 78-8

[0560] Compound 78-7 (2 g, 5.6 mmol) was dissolved in dichloromethane. Trimethylsilyl cyanide (2.24 mL, 17.6 mmol) and boron trifluoride etherate (2.12 mL, 17.6 mmol) were added sequentially at -40°C and the reaction was continued for 1 hour. The reaction was quenched with water, extracted with dichloromethane, concentrated, and separated by column chromatography (EA in PE: 1%-15%) to afford compound 78-8 (900 mg, 50% yield) as a white solid.

[0561] Step 8: Synthesis of compound 78-9

[0562] Compound 78-8 (900 mg, 2.8 mmol) was dissolved in methanol (20 mL) and water (4 mL), and potassium hydroxide (1.256 g, 22 mmol) was added. The mixture was reacted at 60°C for 48 hours. The pH of the reaction solution was adjusted to 3-4 with 2N hydrochloric acid, diluted with water, extracted with dichloromethane, and concentrated to obtain 1 g of crude compound 78-9 (yield >100%).

[0563] Step 9: Synthesis of compound 78-10

[0564] Compound 78-9 (200 mg, 0.59 mmol) was dissolved in dichloromethane (5 mL). A catalytic amount of N,N-dimethylformamide was added at 0°C, followed by the slow addition of oxalyl chloride (0.2 mL) and the reaction was allowed to react for 1 hour. The reaction mixture was concentrated and the concentrate was dissolved in dichloromethane. Triethylamine (297.5 mg, 2.9 mmol), 4-dimethylaminopyridine (7 mg, 0.06 mmol), and methyl 4-amino-2-picolinate (134 mg, 0.88 mmol) were added sequentially and the reaction was allowed to react at room temperature overnight. After TLC analysis, the reaction was concentrated and purified by column chromatography (EA in PE: 5%-50%) to afford compound 78-10 (140 mg, 50% yield) as a white solid.

[0565] MS m / z(ESI):475.2[M+H] + .

[0566] Step 10: Synthesis of Compound 78

[0567] To compound 78-10 was added 5 mL of 7 M amine methanol solution, stirred overnight, and filtered to obtain compound 78 (54.2 mg, yield 40%).

[0568] 1 H NMR (400MHz, DMSO-d6) δ10.44(s,1H),8.46(d,J=5.5Hz,1H),8.31(d,J=2.1Hz,1H),8.05( d,J=2.8Hz,1H),7.84(dd,J=5.5,2.2Hz,1H),7.60(d,J=2.8Hz,1H),7.17–7.09(m,2H),4.8 8(d,J=10.4Hz,1H),4.21(dd,J=10.5,7.5Hz,1H),3.91(d,J=1.7Hz,3H),2.27–2.21(m,1H) ,1.91–1.86(m,1H),1.81–1.65(m,4H),1.46(s,3H),1.36–1.14(m,3H),1.11–0.87(m,2H).

[0569] MS m / z(ESI):460.2[M+H] + .

[0570] Compound 78 was separated by chiral chromatography to obtain compound 78a and compound 78b. The specific experimental parameters are as follows:

[0571] Chromatographic column: DAICELCHIRALPAK IH; column size: 250*50 10μm; mobile phase A: supercritical CO2; mobile phase B: IPA (7.0 mol / L MEOH containing 0.1% ammonia); mobile phase gradient: A:B:75:25; detection wavelength: 214nm; flow rate: 140mL / min; column temperature: RT.

[0572] Compound 78: 85 mg, after splitting:

[0573] Compound 78b: 30 mg, >98% ee, retention time 1.396 min;

[0574] Compound 78a: 33 mg, >98% ee, retention time: 3.483 min.

[0575] Example 36. Synthesis of 4-(3-(3,4-difluoro-2-methoxyphenyl)-8a-methyloctahydro-2H-cyclohepta[b]furan-2-carboxamido)pyridine 1-oxide (Compound 79)

[0576] Synthesis route:

[0577] Compound 79-1 (180 mg, 0.43 mmol) was dissolved in 10 mL of dichloromethane, and m-chloroperbenzoic acid (298.7 mg, 1.73 mmol) was added. The mixture was stirred at room temperature overnight. After concentration, the mixture was separated by column chromatography (ACN in H2O: 0% to 60%) to obtain compound 79 (63.2 mg, 34% yield).

[0578] 1 H NMR (400MHz, DMSO-d6) δ10.38(s,1H),8.09(d,J=7.5Hz,2H),7.68(d,J=7.5Hz,2H),7.29–7.03(m,2H),4.85(d,J=10.4Hz,1H),4.19(dd,J=10.4 ,7.5Hz,1H),3.90(d,J=1.7Hz,3H),2.25–2.20(m,1H),1.91–1.85(m,1H ),1.82–1.62(m,4H),1.44(s,3H),1.31–1.13(m,3H),1.12–0.86(m,2H).

[0579] MS m / z(ESI):433.2[M+H] + .

[0580] Example 37. Synthesis of 2-carbamoyl-4-(3-(3,4-difluoro-2-methoxyphenyl)-8a-methyloctahydro-2H-cyclohepta[b]furan-2-carboxamido)pyridine 1-oxide (Compound 80)

[0581] Synthesis route:

[0582] Compound 78 (166 mg, 0.36 mmol) was dissolved in 10 mL of dichloromethane, and m-chloroperbenzoic acid (249.6 mg, 1.44 mmol) was added. The mixture was stirred at room temperature overnight. After concentration, the mixture was separated by column chromatography (ACN in H2O: 0% to 60%) to obtain compound 80 (17 mg, 10% yield).

[0583] 1 H NMR (400MHz, DMSO-d6) δ10.62(d,J=4.6Hz,1H),10.57(s,1H),8.58(d,J=3.2Hz,1H),8.30( d,J=7.2Hz,1H),8.21(d,J=4.6Hz,1H),7.89(dd,J=7.2,3.3Hz,1H),7.17–7.09(m,2H),4.8 8(d,J=10.5Hz,1H),4.19(dd,J=10.5,7.5Hz,1H),3.91(d,J=1.8Hz,3H),2.30–2.13(m,1H) ,1.91–1.85(m,1H),1.81–1.68(m,4H),1.45(s,3H),1.27–1.18(m,3H),1.13–0.85(m,2H).

[0584] MS m / z(ESI):476.2[M+H] + .

[0585] Example 38. Synthesis of 4-(3-(3,4-difluoro-2-methoxyphenyl)-7a-methylhexahydro-2H-furo[2,3-c]pyran-2-carboxamido)picolinamide (Compound 81)

[0586] Synthesis route:

[0587] Step 1: Synthesis of compound 81-2

[0588] Compound 81-1 (5.0 g, 50.0 mmol) was dissolved in methanol (100 mL), potassium hydroxide (7.47 g, 133.5 mmol) was added, and the mixture was stirred in an ice bath. Iodine (13.9 g, 53.2 mmol) was dissolved in methanol (90 mL) and slowly added dropwise to the reaction mixture under nitrogen. After the addition was complete, the mixture was stirred at room temperature for 3 hours. After TLC detection, the reaction mixture was quenched with an appropriate amount of sodium bicarbonate solution, washed with saturated brine, and extracted three times with ethyl acetate (100 mL). The organic phase was dried and concentrated to obtain crude compound 81-2 (6.7 g).

[0589] Step 2: Synthesis of compound 81-3

[0590] Oxalyl chloride (6.83 g, 53.8 mmol) was dissolved in dichloromethane (150 mL), the system was purged with nitrogen, and cooled to -70°C. Dimethyl sulfoxide (4.1 g, 62.1 mmol) was slowly added, and the reaction system was stirred at -70°C for 10 minutes. Compound 81-2 (6.7 g, 41.4 mmol) was slowly added dropwise to the reaction system, and the reaction system was stirred at -70°C for 30 minutes. Finally, triethylamine (12.5 g, 124.2 mmol) was added, and the reaction system was stirred at -70°C to room temperature. After TLC analysis, the reaction solution was quenched with an appropriate amount of sodium bicarbonate solution, washed with saturated brine, and extracted twice with dichloromethane (100 mL). The organic phase was dried and concentrated to obtain the crude product, which was separated by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 81-3 (5.2 g, yield: 78.8%).

[0591] Step 3: Synthesis of compound 81-4

[0592] Compound 81-3 (5.2 g, 32.5 mmol) was dissolved in tetrahydrofuran (150 mL), the system was purged with nitrogen, and cooled to 0°C. Methyl Grignard reagent (32.5 mL, 97.5 mmol) was slowly added, and the reaction system was stirred at room temperature for 1 hour. After completion of the reaction by TLC, the reaction solution was quenched with an appropriate amount of ammonium chloride solution, washed with saturated brine, and extracted twice with ethyl acetate (150 mL). The organic phase was dried and concentrated to obtain a crude product, which was separated by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 81-4 (4.0 g, yield: 70.0%).

[0593] Step 4: Synthesis of compound 81-5

[0594] Compound 81-4 (2.0 g, 11.4 mmol) was dissolved in tetrahydrofuran / water (40 / 4 mL), concentrated hydrochloric acid (4 mL) was added, and the mixture was stirred at room temperature for 2 hours. After TLC analysis, the reaction solution was washed with saturated brine and extracted three times with ethyl acetate (50 mL). The organic phase was dried and concentrated to obtain crude compound 81-5 (1.5 g).

[0595] Step 5: Synthesis of compound 81-7

[0596] Compound 81-6 (2.0 g, 9.9 mmol) was dissolved in acetonitrile (40 mL), the atmosphere was purged with nitrogen, and the reaction mixture was cooled to 0°C. CDI (1.9 g, 11.9 mmol) was added, and the reaction system was stirred in an ice bath for 30 minutes. Cesium carbonate (4.8 g, 15.9 mmol) and compound 81-5 (1.7 g, 12.9 mmol) were then added, and the reaction system was stirred at 50°C overnight. After completion of the reaction, as determined by TLC, the reaction solution was washed with saturated brine and extracted three times with ethyl acetate (60 mL). The organic phase was dried and concentrated to obtain the crude product, which was then separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to afford compound 81-7 (800 mg, 27.5% yield).

[0597] Step 6: Synthesis of compound 81-8

[0598] Compound 81-7 (800 mg, 2.7 mmol) was dissolved in methanol (30 mL), the system was purged with nitrogen, and the mixture was cooled to -40°C. Nickel chloride hexahydrate (964.0 mg, 4.1 mmol) and sodium borohydride (410.0 mg, 10.8 mmol) were added, and the reaction system was stirred at -40°C. Equal amounts of nickel chloride and sodium borohydride were added every four hours. This was sufficient for the reaction to be complete. After TLC analysis, the reaction solution was washed with saturated brine and extracted three times with ethyl acetate (60 mL). The organic phase was dried and concentrated to obtain crude compound 81-8 (650 mg).

[0599] Step 7: Synthesis of compound 81-9

[0600] Compound 81-8 (650 mg, 2.2 mmol) was dissolved in tetrahydrofuran (20 mL), the system was purged with nitrogen, and the mixture was cooled to -78°C. Diisobutylaluminum hydride (2.3 mL, 2.3 mmol) was added, and the reaction system was stirred at -78°C for 1 hour. After TLC, the reaction solution was washed with saturated brine and extracted twice with ethyl acetate (50 mL). The organic phase was dried, filtered, and concentrated to obtain crude compound 81-9 (650 mg).

[0601] Step 8: Synthesis of Compound 81-10

[0602] Compound 81-9 (650 mg, 2.1 mmol) was dissolved in dichloromethane (20 mL), the atmosphere was purged with nitrogen, and the mixture was cooled to 0°C. Acetic anhydride (255 mg, 2.5 mmol), triethylamine (636 mg, 6.3 mmol), and DMAP (28 mg, 0.2 mmol) were added, and the reaction system was stirred at room temperature for 2 hours. After TLC, the reaction solution was quenched with saturated sodium bicarbonate, washed with saturated brine, and extracted twice with dichloromethane (40 mL). The organic phase was dried, filtered, and concentrated to obtain crude compound 81-10 (700 mg).

[0603] Step 9: Synthesis of Compound 81-11

[0604] Compound 81-10 (700 mg, 2.0 mmol) was dissolved in dichloromethane (20 mL), the atmosphere was purged with nitrogen, and the mixture was cooled to -78°C. TMSCN (248 mg, 2.5 mmol) and BF3OEt2 (355 mg, 2.5 mmol) were added, and the reaction system was stirred at -78°C for 1 hour. After completion of the reaction by TLC, the reaction solution was quenched with saturated sodium bicarbonate, washed with saturated brine, and extracted twice with dichloromethane (40 mL). The organic phase was dried, filtered, and concentrated to afford crude compound 81-11 (600 mg).

[0605] Step 10: Synthesis of Compound 81-12

[0606] Compound 81-11 (600 mg, 1.9 mmol) was dissolved in methanol (20 mL), and 2N potassium hydroxide solution (20 mL) was added. The reaction system was stirred at 55°C overnight. After TLC, the reaction solution was extracted with ethyl acetate. The aqueous phase was retained and adjusted to pH = 2 with 1N dilute hydrochloric acid. The solution was extracted twice with ethyl acetate (40 mL) and washed with saturated brine. The organic phase was dried, filtered, and concentrated to obtain crude compound 81-12 (520 mg).

[0607] Step 11: Synthesis of Compound 81-14

[0608] Compound 81-12 (300 mg, 0.9 mmol) was dissolved in dichloromethane (10 mL), oxalyl chloride (343 mg, 2.7 mmol) and a drop of DMF solution were added, and the reaction system was stirred at 0°C for 30 minutes. After TLC detection, the reaction solution was dried to obtain the acyl chloride for later use. Compound 81-13 (182 mg, 1.2 mmol) was dissolved in dichloromethane (10 mL), triethylamine (272 mg, 2.7 mmol) was added, and the acyl chloride for later use was dissolved in dichloromethane and added. The reaction system was stirred at room temperature for 30 minutes. After TLC detection, the reaction was washed with saturated brine and extracted twice with dichloromethane (20 mL). The organic phase was dried, filtered, and concentrated to obtain a crude product. The crude product was separated by column chromatography (dichloromethane:methanol = 97:3) to obtain compound 81-14 (260 mg, yield: 61.6%).

[0609] Step 12: Synthesis of Compound 81

[0610] Compound 81-14 (260 mg, 0.6 mmol) was dissolved in methanol (3 mL), 7N ammonia in methanol (15 mL) was added, and the reaction system was stirred at room temperature overnight. After TLC analysis, the reaction solution was dried to obtain a crude product, which was then separated using a reverse phase column (ammonium bicarbonate:acetonitrile = 35:65) to obtain compound 81 (40.0 mg, yield: 15.9%).

[0611] 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H),8.48(d,J=5.6Hz,1H),8.35(s,1H),8.06(s,1H),7.87(dd,J=5.6,2 .0Hz,1H),7.61(s,1H),7.39–7.22(m,1H),7.14(dd,J=17.6,9.2Hz,1H),5.10(d,J=10.0Hz,1H),4.33(dd, J=10.0,5.6Hz,1H),3.94(d,J=1.2Hz,3H),3.86(d,J=12.8Hz,1H),3.75(dd,J=10.8,3.6Hz,1H),3.36(s,1 H),3.19(t,J=11.6Hz,1H),2.40(dt,J=12.0,6.4Hz,1H),1.47–1.08(m,4H),0.85(dd,J=13.6,6.4Hz,1H).

[0612] MS m / z(ESI):448.2[M+H] - .

[0613] Example 39, Synthesis of Compound 82

[0614] Referring to the synthetic route of compound 67, compound 82 (17 mg, yield 20%) was prepared.

[0615] 1 H NMR(400MHz,Chloroform-d)δ9.90(s,1H),8.61(d,J=4.9Hz,1H),8.54(d,J=1.1Hz,1H),7.43(dd,J= 5.0,1.0Hz,1H),7.22–7.15(m,1H),7.06(ddd,J=9.0,7.5,5.6Hz,1H),6.96(dddd,J=8.9,5.9,2.0,1. 0Hz,1H),6.74(s,2H),5.07(d,J=7.0Hz,1H),3.33(tt,J=7.2,1.2Hz,1H),2.12(q,J=7.0Hz,1H),1.96 –1.84(m,1H),1.83–1.70(m,2H),1.63–1.48(m,3H),1.40–1.29(m,1H),0.89(dd,J=25.0,6.8Hz,6H).

[0616] MS m / z(ESI):430.2[M+H] + .

[0617] Example 40, Synthesis of Compound 83

[0618] Synthesis route:

[0619] Referring to the synthetic route of compound 67, compound 83-6 (200 mg, 0.68 mmol) was dissolved in dichloromethane (10 mL). A catalytic amount of N,N-dimethylformamide was added at 0°C, followed by the slow addition of oxalyl chloride (257 mg, 2.00 mmol) and the reaction was allowed to proceed for 0.5 hours. The reaction mixture was concentrated, and the concentrate was dissolved in dichloromethane. Triethylamine (341 mg, 3.38 mmol), 4-dimethylaminopyridine (8 mg, 0.06 mmol), and methyl 4-amino-2-picolinate (154 mg, 1.01 mmol) were added sequentially, and the reaction was allowed to proceed overnight at room temperature. After TLC analysis, the reaction was concentrated and purified by column chromatography (EA in PE: 5%-50%) to afford compound 83-7 (105 mg, 36% yield) as a white solid.

[0620] To compound 83-7 (105 mg) was added 10 mL of 7 M amine methanol solution, stirred overnight, and filtered to obtain compound 83 (58 mg, yield 57%).

[0621] 1 H NMR (400MHz, DMSO-d6) δ10.42(s,1H),8.47(d,J=2.9Hz,1H),8.32(d,J=1.7Hz,1H),8.07(s,1H),7.84( dd,J=5.5,1.9Hz,1H),7.61(s,1H),7.48(d,J=5.9Hz,1H),7.42–7.38(m,1H),7.17(s,1H),4.85(d,J=1 0.6Hz,1H),3.83(dd,J=10.3,8.0Hz,1H),2.69(dd,J=15.4,7.7Hz,1H),1.95–1.87(m,1H),1.78–1.72( m,2H),1.67–1.60(m,2H),1.49–1.42(m,1H),1.39–1.33(m,1H),1.30–1.25(m,1H),1.01–0.97(m,3H).

[0622] MS m / z(ESI):416.2[M+H] + .

[0623] Example 41. Synthesis of Compound 84

[0624] Synthesis route:

[0625] Referring to the synthetic route of compound 83, compound 83-6 (400 mg, 1.35 mmol) was dissolved in dichloromethane (20 mL). A catalytic amount of N,N-dimethylformamide was added at 0°C, followed by the slow addition of oxalyl chloride (514 mg, 4.05 mmol) and the reaction was allowed to proceed for 0.5 hours. The reaction mixture was concentrated, and the concentrate was dissolved in dichloromethane. Triethylamine (685 mg, 6.75 mmol), 4-dimethylaminopyridine (17 mg, 0.14 mmol), and 4-amino-2-cyanopyridine (242 mg, 2.02 mmol) were added sequentially, and the reaction was allowed to proceed overnight at room temperature. After TLC analysis, the reaction was concentrated and purified by column chromatography (EA in PE: 5%-50%) to afford compound 84-1 (320 mg, 60% yield) as a white solid.

[0626] Compound 84-1 (320 mg, 0.81 mmol) was dissolved in methanol (15 mL), and sodium methoxide (44 mg, 0.81 mmol) was added. The mixture was stirred at room temperature overnight, followed by the addition of ammonium chloride (87 mg, 1.62 mmol). The temperature was raised to 70°C and stirred overnight. After TLC analysis of the reaction, the reaction solution was directly purified in batches using a reverse-phase column (aqueous phase: 10 mmol / L ammonium bicarbonate; organic phase: acetonitrile) and lyophilized to afford compound 84 (40 mg, 12% yield).

[0627] 1 H NMR (400MHz, DMSO-d6) δ8.47(d,J=5.4Hz,1H),8.39(s,1H),7.83–7.77(m,1H),7.46(dd,J=11.9,7.1 Hz,1H),7.37(dd,J=19.2,8.6Hz,1H),7.16(s,1H),4.85(d,J=10.7Hz,1H),3.90–3.75(m,1H),2.69(d d,J=15.3,7.5Hz,1H),1.83(dd,J=12.7,6.3Hz,1H),1.78–1.69(m,3H),1.65(dd,J=12.8,6.3Hz,1H), 1.46(dt,J=12.2,6.3Hz,1H),1.39–1.32(m,1H),1.28(dt,J=13.3,6.7Hz,1H),1.01(t,J=7.3Hz,3H).

[0628] MS m / z(ESI):415.2[M+H] + .

[0629] Example 42, Synthesis of Compound 85

[0630] Synthesis route:

[0631] Compound 10-2 (2.0 g, 7.14 mmol) was dissolved in dichloromethane (100 mL) and cooled to 0°C. Boron tribromide (22 mL, 21.4 mmol, 1 M) was slowly added to the reaction mixture under nitrogen, and the reaction was continued at 0°C for 1 h. After TLC analysis, the reaction was completed by slowly adding water in an ice bath to quench the reaction. The mixture was extracted three times with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (EA in PE: 1% to 25%) to obtain compound 85-1 (1.61 g, 85% yield) as a white solid.

[0632] Compound 85-1 (1.55 g, 5.83 mmol) was dissolved in acetonitrile (100 mL), and potassium carbonate (2.42 g, 17.5 mmol) and deuterated iodomethane (1.59 g, 11.7 mmol) were added in sequence. After the addition was complete, the reaction was allowed to react at room temperature overnight. After TLC detection, the reaction was completed, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (EA in PE: 1% to 25%) to obtain compound 85-2 (1.33 g, yield 81%) as a white solid.

[0633] Compound 85-8 was prepared using compound 85-2 as the starting material and referring to the synthetic route of compound 10. 10 mL of 7 M amine methanol solution was added to compound 85-8 (92 mg), stirred overnight, and filtered to obtain compound 85 (58 mg, yield 65%).

[0634] 1 H NMR(400MHz,DMSO-d6)δ10.41(s,1H),8.47(d,J=5.5Hz,1H),8.31(s,1H),8.06(s,1H) ,7.89–7.83(m,1H),7.61(s,1H),7.32–7.08(m,2H),4.85(d,J=10.7Hz,1H),3.97(dd,J =10.5,7.8Hz,1H),2.60(dd,J=15.4,7.7Hz,1H),1.90(dt,J=11.3,5.5Hz,1H),1.75–1 .62(m,2H),1.50(s,1H),1.48(s,3H),1.41–1.30(m,1H),1.24(dt,J=13.1,6.6Hz,1H).

[0635] MS m / z(ESI):435.2[M+H] + .

[0636] Example 43. Synthesis of Compound 86

[0637] Synthesis route:

[0638] Compound 86-1 was prepared by referring to the synthetic route of compound 85. Compound 86-1 (365 mg, 0.88 mmol) was dissolved in methanol (15 mL), and sodium methoxide (50 mg, 0.88 mmol) was added. The mixture was stirred at room temperature overnight, followed by the addition of ammonium chloride (95 mg, 1.76 mmol). The temperature was raised to 70°C and stirred overnight. After TLC analysis of the reaction, the reaction solution was directly purified in batches using a reverse-phase column (aqueous phase: 10 mmol / L ammonium bicarbonate; organic phase: acetonitrile) and lyophilized to afford compound 86 (22 mg, 6% yield).

[0639] 1 H NMR(400MHz,DMSO-d6)δ8.43(d,J=5.5Hz,1H),8.36(s,1H),7.79(dd,J=5.5,2.1H z,1H),7.21–7.11(m,2H),4.85(d,J=10.8Hz,1H),3.97(dd,J=10.7,7.6Hz,1H),2 .61(dd,J=15.9,7.2Hz,1H),1.89(dt,J=12.3,6.3Hz,1H),1.75–1.59(m,2H),1.5 1(d,J=6.2Hz,1H),1.48(s,3H),1.41–1.30(m,1H),1.24(dt,J=13.2,6.6Hz,1H).

[0640] MS m / z(ESI):434.2[M+H] + .

[0641] Example 44. Synthesis of Compound 87

[0642] Synthesis route:

[0643] Compound 67-7 (400 mg, 1.23 mmol) was dissolved in dichloromethane (20 mL). A catalytic amount of N,N-dimethylformamide was added at 0°C, followed by the slow addition of oxalyl chloride (468 mg, 3.68 mmol) and the reaction was allowed to proceed for 0.5 hours. The reaction mixture was concentrated and the concentrate was dissolved in dichloromethane. Triethylamine (620 mg, 6.13 mmol), 4-dimethylaminopyridine (15 mg, 0.12 mmol), and 4-amino-2-cyanopyridine (219 mg, 1.84 mmol) were added sequentially and the reaction was allowed to proceed overnight at room temperature. After TLC analysis, the reaction was concentrated and purified by column chromatography (EA in PE: 5%-50%) to afford compound 87-1 (320 mg, 61% yield) as a white solid.

[0644] Compound 87-1 (320 mg, 0.75 mmol) was dissolved in methanol (15 mL), and sodium methoxide (41 mg, 0.75 mmol) was added. The mixture was stirred at room temperature overnight, followed by the addition of ammonium chloride (81 mg, 1.50 mmol). The temperature was raised to 70°C and stirred overnight. After TLC analysis of the reaction, the reaction solution was directly purified in batches using a reverse-phase column (aqueous phase: 10 mmol / L ammonium bicarbonate; organic phase: acetonitrile) and lyophilized to afford compound 87 (41 mg, 5.3% yield).

[0645] 1 H NMR(400MHz,DMSO-d6)δ8.43(d,J=5.5Hz,1H),8.36(d,J=1.4Hz,1H),7.77(dd,J=5.5,2.1Hz,1H), 7.22–7.09(m,2H),6.95(s,2H),4.87(d,J=10.9Hz,1H),3.92(d,J=1.8Hz,3H),3.90–3.84(m,1H),2 .66(dd,J=14.7,8.3Hz,1H),1.83(dt,J=13.1,6.6Hz,1H),1.79–1.71(m,3H),1.64(dt,J=13.6,6.9 Hz,1H),1.50–1.42(m,1H),1.37–1.30(m,1H),1.23(dt,J=13.0,6.6Hz,1H),1.01(t,J=7.3Hz,3H).

[0646] MS m / z(ESI):445.2[M+H] + .

[0647] Example 45. Synthesis of Compound 88

[0648] Referring to the synthetic route of compound 85, compound 88 (173 mg, yield 51%) was prepared.

[0649] 1H NMR (400MHz, DMSO-d6) δ10.42(s,1H),8.47(d,J=5.6Hz,1H),8.31(d,J=2.0Hz,1H),8.06(d, J=2.0Hz,1H),7.85(dd,J=5.6,2.0Hz,1H),7.61(d,J=2.0Hz,1H),7.32–6.98(m,2H),4.85(d, J=10.8Hz,1H),4.14(q,J=6.8Hz,2H),4.00(dd,J=10.8,7.6Hz,1H),2.59(dd,J=16.0,7.2Hz ,1H),1.91(dt,J=12.0,6.0Hz,1H),1.79–1.59(m,2H),1.58–1.43(m,4H),1.41–1.20(m,5H).

[0650] MS m / z(ESI):446.2[M+H] + .

[0651] Example 46, Synthesis of Compound 89

[0652] Referring to the synthetic route of compound 85, compound 89 (34 mg, yield 39%) was prepared.

[0653] 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),8.47(d,J=5.6Hz,1H),8.30(d,J=2.0Hz,1H),8.06(d,J= 2.0Hz,1H),7.83(dd,J=5.6,2.0Hz,1H),7.61(d,J=2.0Hz,1H),7.36–7.05(m,2H),4.84(d,J=1 0.8Hz,1H),4.51(dt,J=12.0,6.0Hz,1H),4.02(dd,J=10.8,7.6Hz,1H),2.58(dd,J=16.0,7.2H z,1H),1.91(dt,J=11.2,6.0Hz,1H),1.72-1.66(m,2H),1.56–1.43(m,4H),1.38–1.18(m,8H).

[0654] MS m / z(ESI):460.2[M+H] + .

[0655] Example 47, Synthesis of Compound 90

[0656] Referring to the synthetic route of compound 85, compound 90 (49 mg, yield 49%) was prepared.

[0657] 1 H NMR (400MHz, DMSO-d6) δ10.54(s,1H),8.58(d,J=5.6Hz,1H),8.20(d,J=2.0Hz,1H) ,7.93(dd,J=5.6,2.0Hz,1H),7.54–7.00(m,2H),4.89(d,J=10.8Hz,1H),4.51(dd,J =12.0,6.0Hz,1H),4.01(dd,J=10.8,7.2Hz,1H),2.58(dd,J=16.0,7.2Hz,1H),1.9 4(dd,J=12.4,6.4Hz,1H),1.79–1.58(m,2H),1.56–1.41(m,4H),1.41–1.14(m,8H).

[0658] MS m / z(ESI):442.2[M+H] + .

[0659] Example 48, Synthesis of Compound 91

[0660] Referring to the synthetic routes of compounds 46 and 85, compound 91 (120 mg, yield 61%) was prepared.

[0661] 1 H NMR (400MHz, DMSO-d6) δ10.31(s,1H),8.46(d,J=5.5Hz,1H),8.33(d,J=2.2Hz,1 H),8.05(d,J=2.0Hz,1H),7.86(dd,J=5.5,2.0Hz,1H),7.60(s,1H),7.26(ddd,J =8.4,3.7,1.9Hz,1H),7.18(q,J=8.8Hz,1H),4.56(d,J=9.2Hz,1H),4.12(dd,J= 12.4,9.2Hz,1H),2.16(d,J=12.8Hz,1H),1.89–1.58(m,3H),1.49–0.98(m,8H).

[0662] MS m / z(ESI):449.2[M+H] + .

[0663] Example 49, Synthesis of Compound 92

[0664] Referring to the synthetic routes of compounds 90 and 91, compound 92 (75 mg, yield 36%) was prepared.

[0665] 1 H NMR (400MHz, DMSO-d6) δ10.48(s,1H),8.58(d,J=5.6Hz,1H),8.24(d,J=2.1Hz,1H),7.97(dd,J=5.7,2.1Hz,1H),7.27(ddd,J=8.2,5.9,2.0Hz,1H ),7.18(td,J=9.4,7.5Hz,1H),4.59(d,J=9.2Hz,1H),4.10(dd,J=12.4,9 .2Hz,1H),2.16(d,J=12.4Hz,1H),1.79–1.58(m,3H),1.51–1.10(m,8H).

[0666] MS m / z(ESI):431.1[M+H] + .

[0667] Example 50, Synthesis of Compound 93

[0668] Referring to the synthetic routes of compounds 74 and 91, compound 93 (82 mg, yield 47%) was prepared.

[0669] 1 H NMR(400MHz,DMSO-d6)δ10.36(s,3H),8.60(d,J=5.5Hz,1H),8.44(d,J=4.8H z,2H),8.11–7.83(m,1H),7.28(td,J=7.2,5.8,1.7Hz,1H),7.23–7.14(m,1H ),4.61(d,J=9.2Hz,1H),4.13(dd,J=12.4,9.3Hz,1H),2.17(d,J=12.5Hz,1H ),1.78(td,J=14.0,13.5,4.2Hz,1H),1.69–1.63(m,2H),1.53–1.16(m,8H).

[0670] MS m / z(ESI):448.2[M+H] + .

[0671] Example 51, Synthesis of Compound 94

[0672] Referring to the synthetic route of compound 46, compound 94 (103 mg, yield 59%) was prepared.

[0673] 1 H NMR(400MHz,Chloroform-d)δ8.99(s,1H),8.45(d,J=5.5Hz,1H),8.21(dd,J=5.5,2.2Hz,1H),7.94 (d,J=2.2Hz,1H),7.85(d,J=4.6Hz,1H),7.03–6.82(m,2H),5.86(d,J=4.4Hz,1H),4.62(d,J=9.5Hz ,1H),4.32–4.09(m,2H),4.04(dd,J=12.3,9.5Hz,1H),2.20(dd,J=12.4,3.6Hz,1H),1.82(dt,J=12 .7,3.4Hz,1H),1.77–1.69(m,2H),1.64(td,J=13.0,3.9Hz,1H),1.48(s,7H),1.36(t,J=7.0Hz,3H).

[0674] MS m / z(ESI):460.2[M+H] + .

[0675] Example 52: Synthesis of Compound 95

[0676] Referring to the synthetic route of compound 46, compound 95 (49 mg, yield 48%) was prepared.

[0677] 1 H NMR (400MHz, DMSO-d6) δ10.48(s,1H),8.58(d,J=5.6Hz,1H),8.22(d,J=2.1Hz,1H),7.95(dd,J=5.6,2.1Hz,1H),7.26(ddd,J=8.3,6. 0,2.0Hz,1H),7.21–7.10(m,1H),4.59(d,J=9.2Hz,1H),4.16–4.06(m,2H),4.06–3.97(m,1H),1.74–1.60(m,3H),1.48–1.15(m,12H).

[0678] MS m / z(ESI):442.2[M+H] + .

[0679] Example 53. Synthesis of Compound 96

[0680] Synthesis route:

[0681] Compound 67-2 (2.05 g, 6.97 mmol) was dissolved in dichloromethane (15 mL). Boron tribromide (20.9 mL, 20.9 mmol) was slowly added dropwise at 0°C. The reaction was allowed to proceed for 2 hours until the starting material was completely reacted. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and concentrated to afford compound 96-1 (1.2 g) as a yellow solid.

[0682] Compound 96-1 (1.2 g, 4.27 mmol) was dissolved in dichloromethane (15 mL). Potassium carbonate (1.77 g, 12.81 mmol) and deuterated iodomethane (1.23 g, 8.54 mmol) were added at room temperature. The reaction was allowed to proceed for 14 hours until the starting materials reacted completely. The mixture was extracted with water and dichloromethane and concentrated to afford compound 96-2 (1.28 g) as a yellow solid.

[0683] Compound 96 (213 mg, yield 69%) was finally prepared using compound 96-2 as the starting material and referring to the synthetic route of compound 67.

[0684] 1 H NMR(400MHz,Chloroform-d)δ8.88(s,1H),8.43(d,J=5.5Hz,1H),8.16(dd,J=5.6,2.2Hz, 1H),7.88(d,J=2.3Hz,2H),7.16–7.15(m,1H),6.89(td,J=9.3,7.5Hz,1H),5.82(d,J=4.4 Hz,1H),4.81(d,J=11.4Hz,1H),3.75(dd,J=11.4,7.6Hz,1H),2.78–2,72(m,1H),1.95–1. 75(m,5H),1.68–1.61(m,1H),1.56–1.51(m,1H),1.49–1.46(m,2H),1.12(t,J=7.4Hz,3H).

[0685] MS m / z(ESI):449.2[M+H] + .

[0686] Example 54. Synthesis of Compound 97

[0687] Referring to the synthetic route of compound 96, compound 97 (20 mg, yield 41%) was prepared.

[0688] 1H NMR (400MHz, DMSO-d6) δ10.35(s,0.7H),10.14(s,0.2H),8.47(dd,J=5.6,3.9Hz,1H),8.33(d,J=2.2Hz,1H),8.05(d,J=2.9Hz,1H) ,7.86(dt,J=5.6,2.1Hz,1H),7.60(d,J=3.0Hz,1H),7.47(dddd,J=12.6,7.7,5.0,2.1Hz,1H),7.39–7.30(m,1H),7.18(dd,J=8.9, 4.4Hz,1H),4.82(d,J=10.6Hz,0.7H),4.48(d,J=10.2Hz,0.2H),3.91(dd,J=10.6,7.4Hz,0.7H),3.09(t,J=9.3Hz,0.2H),2.61(dt ,J=9.0,7.0Hz,1H),1.99–1.80(m,1H),1.76–1.59(m,2H),1.48(d,J=2.2Hz,5H),1.42–1.35(m,1H),1.30(dt,J=13.2,7.0Hz,1H).

[0689] MS m / z(ESI):474.2[M+H] + .

[0690] Example 55. Synthesis of Compound 98

[0691] Referring to the synthetic route of compound 75, compound 98 (75 mg, yield 43%) was prepared.

[0692] 1H NMR (400MHz, DMSO-d6) δ10.35(s,0.7H),10.14(s,0.2H),8.47(dd,J=5.6,3.9Hz,1H),8.33(d,J=2.2Hz,1H),8.05(d,J=2.9Hz,1H) ,7.86(dt,J=5.6,2.1Hz,1H),7.60(d,J=3.0Hz,1H),7.47(dddd,J=12.6,7.7,5.0,2.1Hz,1H),7.39–7.30(m,1H),7.18(dd,J=8.9, 4.4Hz,1H),4.82(d,J=10.6Hz,0.7H),4.48(d,J=10.2Hz,0.2H),3.91(dd,J=10.6,7.4Hz,0.7H),3.09(t,J=9.3Hz,0.2H),2.61(dt ,J=9.0,7.0Hz,1H),1.99–1.80(m,1H),1.76–1.59(m,2H),1.48(d,J=2.2Hz,5H),1.42–1.35(m,1H),1.30(dt,J=13.2,7.0Hz,1H).

[0693] MS m / z(ESI):402.2[M+H] + .

[0694] Example 56. Synthesis of Compound 99

[0695] Referring to the synthetic route of compound 76, compound 99 (2 mg, yield 13%) was prepared.

[0696] 1 H NMR(400MHz,Chloroform-d)δ8.81(s,1H),8.49–8.34(m,2H),8.11(dd,J=5.6,2.2Hz,1H),7.86–7.67(m,3H),7.24(d,J=8.2Hz,1H),5.54( s,1H),4.47(d,J=9.3Hz,1H),3.57(dd,J=12.3,9.3Hz,1H),2.59(d,J=10.0Hz,3H),2.23(d,J=12.3Hz,1H),1.84–1.52(m,8H),1.44(s,3H).

[0697] MS m / z(ESI):395.2[M+H] + .

[0698] Example 57. Synthesis of Compound 100

[0699] Referring to the synthetic route of compound 46, compound 100 (32 mg, yield 35%) was prepared.

[0700] 1 H NMR (400MHz, Chloroform-d) δ8.85 (s, 1H), 8.39 (d, J = 5.6 Hz, 1H), 8.12 (dd, J = 5.6, 2. 2Hz,1H),7.85–7.76(m,2H),6.93(ddd,J=8.1,5.8,2.1Hz,1H),6.81(td,J=9.1,7.3H z,1H),5.65(s,1H),4.67–4.55(m,2H),3.97(dd,J=12.3,9.8Hz,1H),2.06(dd,J=12. 3,4.3Hz,1H),1.59–1.39(m,11H),1.27(dd,J=6.1,1.2Hz,3H),1.17(d,J=6.2Hz,3H).

[0701] MS m / z(ESI):474.2[M+H] + .

[0702] Example 58. Synthesis of Compound 101

[0703] Referring to the synthetic routes of compounds 46 and 92, compound 101 (60 mg, yield 41%) was prepared.

[0704] 1 H NMR(400MHz,Chloroform-d)δ8.82(s,1H),8.49(d,J=5.6Hz,1H),7.94(d,J=2.1Hz,1H ),7.60(dd,J=5.6,2.2Hz,1H),6.96–6.75(m,2H),4.70–4.54(m,2H),3.97(dd,J=12.3 ,9.7Hz,1H),2.08(dd,J=12.2,4.2Hz,1H),1.73(dd,J=12.6,3.3Hz,3H),1.55(td,J=1 3.0,3.9Hz,1H),1.49–1.31(m,7H),1.28(dd,J=6.2,1.2Hz,3H),1.19(d,J=6.1Hz,3H).

[0705] MS m / z(ESI):456.2[M+H] + .

[0706] Example 59. Synthesis of Compound 102

[0707] Referring to the synthetic route of compound 75, compound 102 (30 mg, yield 45%) was prepared.

[0708] 1 H NMR(400MHz,DMSO-d6)δ10.22(d,J=19.4Hz,1H),8.47(d,J=5.5Hz,1H),8.3 3(d,J=2.2Hz,1H),8.05(s,1H),7.86(dt,J=5.6,2.3Hz,1H),7.60(d,J=2.9 Hz,1H),7.53–7.04(m,3H),4.44(dd,J=26.8,9.7Hz,1H),3.77(dd,J=12.3, 9.4Hz,1H),2.25(d,J=11.6Hz,1H),1.84–1.13(m,10H),1.04–0.94(m,3H).

[0709] MS m / z(ESI):430.2[M+H] + .

[0710] Example 60, Synthesis of Compound 103

[0711] Referring to the synthetic route of compound 75, compound 103 (24 mg, yield 51%) was prepared.

[0712] 1 H NMR (400MHz, DMSO-d6) δ10.50(d,J=126.0Hz,1H),8.59(dd,J=5.6,1.7Hz,1H),8.26(dd,J=5.7,2.1Hz,1H),7.97(ddd,J=14.8,5.6,2.1Hz,1 H),7.53–7.11(m,3H),4.55–4.46(m,1H),3.76(dd,J=12.4,9.4Hz,1H),2.30–2.21(m,1H),1.82–1.12(m,10H),0.94(dt,J=43.0,7.4Hz,3H).

[0713] MS m / z(ESI):412.2[M+H] + .

[0714] Example 61. Synthesis of Compound 104

[0715] Synthesis route:

[0716] Compound 64-1 (200 mg, 0.48 mmol) was dissolved in isopropanol (10 mL), and thioglycolic acid (90 mg, 0.96 mmol), methylamine hydrochloride (99 mg, 1.44 mmol), and N,N-diisopropylethylamine (188 mg, 1.44 mmol) were added. The mixture was heated to 80°C and stirred overnight. After TLC analysis of the reaction, the reaction solution was directly purified in batches using a reverse-phase column (aqueous phase: 10 mmol / L ammonium bicarbonate; organic phase: acetonitrile) and lyophilized to obtain compound 104 (94 mg, 44% yield).

[0717] 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),8.41(d,J=5.6Hz,1H),8.38(d,J=1.8Hz,1H),7.75(dd,J=5. 6,2.1Hz,1H),7.36–7.06(m,2H),6.86(s,2H),4.84(d,J=10.8Hz,1H),3.96(dd,J=10.8,7.6Hz,1H) ,3.91(d,J=1.9Hz,3H),2.87(s,3H),2.60(dd,J=16.0,7.2Hz,1H),1.89(dt,J=12.2,6.3Hz,1H),1 .79–1.58(m,2H),1.53–1.49(m,1H),1.48(s,3H),1.41–1.31(m,1H),1.23(dt,J=13.1,6.6Hz,1H).

[0718] MS m / z(ESI):445.2[M+H] + .

[0719] Example 62: Synthesis of Compound 105

[0720] Synthesis route:

[0721] Compound 85-7 (150 mg, 0.48 mmol) was dissolved in dichloromethane (10 mL). A catalytic amount of N,N-dimethylformamide was added at 0°C, followed by the slow addition of oxalyl chloride (182 mg, 1.44 mmol) and the reaction was allowed to proceed for 0.5 hours. The reaction mixture was concentrated and the concentrate was dissolved in dichloromethane. Triethylamine (240 mg, 2.4 mmol), 4-dimethylaminopyridine (6 mg, 0.05 mmol), and 4-amino-2-cyanopyridine (85 mg, 0.72 mmol) were added sequentially and the reaction was allowed to proceed overnight at room temperature. After TLC analysis, the reaction was concentrated and purified by column chromatography (EA in PE: 5%-50%) to afford compound 106 (17.8 mg, 9% yield).

[0722] 1 H NMR (400MHz, DMSO-d6) δ10.53(s,1H),8.58(d,J=5.6Hz,1H),8.22(d,J=2.0Hz,1H),7.94(dd,J =5.6,2.1Hz,1H),7.21(t,J=7.4Hz,1H),7.13(dd,J=17.1,9.4Hz,1H),4.90(d,J=10.7Hz,1H), 3.96(dd,J=10.6,7.6Hz,1H),2.60(dd,J=16.0,7.2Hz,1H),1.92(dt,J=12.3,6.3Hz,1H),1.78 –1.59(m,2H),1.52(dd,J=13.2,7.0Hz,1H),1.48(s,3H),1.41–1.31(m,1H),1.29–1.21(m,1H).

[0723] MS m / z(ESI):417.2[M+H] + .

[0724] Example 63. Synthesis of Compound 106

[0725] Synthesis route:

[0726] Compound 85-1 (1.6 g, 6.24 mmol) was dissolved in tetrahydrofuran (30 mL) under nitrogen protection. Sodium hydroxide (2.5 g, 62.4 mmol) was slowly added at 0°C and the mixture was allowed to warm to room temperature for 0.5 hours. Heavy water (6.2 g, 312 mmol) was slowly added to the reaction mixture and the reaction was continued for 0.5 hours. Diethyl bromofluoromethylphosphonate (3.2 g, 12.28 mmol) was added to the reaction mixture and the reaction was continued for 1 hour. After TLC analysis, the reaction was diluted with ethyl acetate and washed sequentially with water and saturated brine. The organic phase was dried and then spin-dried. The crude product was purified by column chromatography to obtain compound 106-1 (880 mg, 44% yield) as a white solid.

[0727] Compound 106-8 was prepared by referring to the synthetic route of compound 85. To compound 106-8 (130 mg) was added 20 mL of 7 M amine methanol solution, stirred overnight, and filtered to obtain compound 106 (110 mg, yield 87%).

[0728] 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),8.48(d,J=5.5Hz,1H),8.33(d,J=2.0Hz,1H),8.05(t, J=10.1Hz,1H),7.85(dd,J=5.5,2.2Hz,1H),7.61(d,J=2.1Hz,1H),7.48–7.36(m,2H),4.91(d ,J=10.6Hz,1H),3.98(dd,J=10.6,7.6Hz,1H),2.71–2.53(m,1H),1.92(dt,J=12.4,6.4Hz,1 H),1.76–1.62(m,2H),1.56–1.49(m,1H),1.48(s,3H),1.42–1.33(m,1H),1.31–1.23(m,1H).

[0729] MS m / z(ESI):469.2[M+H] + .

[0730] Example 64. Synthesis of Compound 107

[0731] Referring to the synthetic routes of compounds 46 and 80, compound 107 (109 mg, yield 45%) was prepared.

[0732] 1H NMR(400MHz,Chloroform-d)δ11.08(d,J=5.7Hz,1H),9.71(d,J=13.9Hz,1H),8.48–8.38(m ,2H),8.17(d,J=7.2Hz,1H),7.08(ddd,J=8.1,5.5,2.0Hz,1H),6.87(td,J=9.2,7.4Hz,1H), 6.57(s,1H),5.02(d,J=10.2Hz,1H),4.28(dd,J=10.2,5.8Hz,1H),4.00(d,J=2.4Hz,3H),2. 28(dt,J=12.1,6.3Hz,1H),2.16–2.08(m,1H),1.68–1.48(m,4H),1.45(s,3H),1.37(m,3H).

[0733] MS m / z(ESI):462.2[M+H] + .

[0734] Example 65. Synthesis of Compound 108

[0735] Referring to the synthetic route of compound 96, compound 108 (31 mg, yield 37%) was prepared.

[0736] 1 H NMR(400MHz,Chloroform-d)δ8.99(s,1H),8.46(t,J=7.2Hz,1H),8.26(d,J=5.4 Hz,2H),7.96(d,J=6.2Hz,1H),7.15–7.12(m,1H),6.89(d,J=9.3Hz,1H),5.74(d ,J=3.2Hz,1H),4.83(d,J=9.4Hz,1H),4.21(d,J=31.2Hz,2H),3.78(s,1H),2.80 –2.79(m,1H),1.44–1.28(m,8H),1.24(d,J=12.0Hz,3H),1.14(t,J=7.2Hz,3H).

[0737] MS m / z(ESI):460.2[M+H] + .

[0738] Example 66. Synthesis of Compound 109

[0739] Referring to the synthetic route of compound 96, compound 109 (54 mg, yield 39%) was prepared.

[0740] 1 H NMR (400MHz, Chloroform-d) δ8.84(s,1H),8.55(d,J=5.5Hz,1H),7.99(d,J=1.9Hz,1H),7.60(dd,J=5.6,2.1Hz,1H),7.16–7.11(m,1H),6.93–6. 86(m,1H),4.82(d,J=11.4Hz,1H),3.75(dd,J=11.5,7.5Hz,1H),2.79–2 .73(m,1H),1.97–1.75(m,4H),1.68–1.56(m,4H),1.13(t,J=7.4Hz,3H).

[0741] MS m / z(ESI):431.2[M+H] + .

[0742] Example 67. Synthesis of Compound 110

[0743] Referring to the synthetic route of compound 96, compound 110 (22 mg, yield 44%) was prepared.

[0744] 1 H NMR(400MHz,Chloroform-d)δ8.84(s,1H),8.55(d,J=5.6Hz,1H),7.98(d,J=2.1Hz,1H),7.61(dd,J =5.6,2.1Hz,1H),7.13(ddd,J=8.3,5.7,2.0Hz,1H),6.89(td,J=9.2,7.4Hz,1H),4.81(d,J=11.5Hz ,1H),4.31–4.10(m,2H),3.77(dd,J=11.5,7.5Hz,1H),2.79(dt,J=8.7,7.0Hz,1H),1.97–1.75(m,4 H),1.65–1.52(m,4H),1.52(dd,J=12.8,6.5Hz,2H),1.27(d,J=12.0Hz,3H),1.13(t,J=7.4Hz,3H).

[0745] MS m / z(ESI):442.2[M+H] + .

[0746] Example 68, Synthesis of Compound 111

[0747] Synthesis route:

[0748] Compound 78-5 (1.2 g, 3.87 mmol) was dissolved in dichloromethane (15 mL). Boron tribromide (11.6 mL, 11.6 mmol) was slowly added dropwise at -50°C. The reaction was allowed to proceed for 2 hours until the starting material was completely reacted. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and concentrated to afford Compound 111-1 (1.25 g) as a yellow solid.

[0749] Compound 111-1 (1.25 g, 4.16 mmol) was dissolved in dichloromethane (15 mL). Potassium carbonate (1.7 g, 12.48 mmol) and iodoethane (1.2 g, 8.32 mmol) were added at room temperature. The reaction was allowed to proceed for 14 hours until the starting materials reacted completely. The mixture was extracted with water and dichloromethane and concentrated to afford compound 111-2 (1.4 g) as a yellow solid.

[0750] Compound 111-2 was used as the starting material, and the synthetic route of compound 78 or 96 was referred to finally prepare compound 111 (56 mg, yield 44%).

[0751] 1 H NMR (400MHz, Chloroform-d) δ8.81 (s, 1H), 8.45 (d, J = 5.6Hz, 1H), 8.24 (dd, J = 5.9, 2. 0Hz,1H),8.02(s,1H),7.90(d,J=2.1Hz,1H),6.99–6.82(m,2H),5.70(s,1H),4.53(d, J=10.6Hz,1H),4.28–4.03(m,2H),3.46(t,J=10.8Hz,1H),2.24–2.04(m,1H),2.04–1 .82(m,1H),1.76–1.61(m,7H),1.53–1.42(m,2H),1.50(s,4H),1.26(t,J=5.8Hz,3H).

[0752] MS m / z(ESI):474.2[M+H] + .

[0753] Example 69, Synthesis of Compound 112

[0754] Referring to the synthetic route of compound 82, compound 112 (90 mg, yield 17%) was prepared.

[0755] 1H NMR(500MHz,Chloroform-d)δ9.90(s,1H),8.74(d,J=5.0Hz,1H),8.67(d,J=1.0Hz,1 H),7.51(dd,J=4.9,1.0Hz,1H),7.14–7.01(m,2H),6.97(dddd,J=8.7,5.6,1.9,1.0H z,1H),5.07(d,J=6.9Hz,1H),3.43–3.36(m,1H),2.07(q,J=7.1Hz,1H),1.97(dt,J=1 2.7,6.9Hz,1H),1.85–1.46(m,5H),1.44–1.33(m,1H),0.89(dd,J=25.0,6.8Hz,6H).

[0756] MS m / z(ESI):412.2[M+H] + .

[0757] Example 70, Synthesis of Compound 113

[0758] Referring to the synthetic route of compound 68, compound 113 (6 mg, yield 21%) was prepared.

[0759] 1 H NMR(400MHz,CHLOROFORM-D)δ8.80(s,1H),8.47(d,J=5.7Hz,1H),8.26(d,J=5.6Hz,1H),8 .07(s,1H),7.92(s,1H),6.98–6.81(m,2H),5.64(s,1H),4.53(d,J=8.4Hz,2H),3.96(m,1H ),3.58–3.39(m,1H),2.84–2.62(m,1H),1.95(d,J=35.7Hz,3H),1.54–1.40(m,3H),1.27( dd,J=6.2,1.2Hz,3H),1.18(d,J=6.1Hz,3H),1.09(d,J=6.6Hz,3H),0.96(d,J=6.6Hz,3H).

[0760] MS m / z(ESI):488.2[M+H] + .

[0761] Example 71. Synthesis of Compound 114

[0762] Referring to the synthetic route of compound 68, compound 114 (7 mg, yield 35%) was finally prepared.

[0763] 1 H NMR(400MHz,CHLOROFORM-D)δ8.80(s,1H),8.47(d,J=5.7Hz,1H),8.26(d,J=5.6Hz,1H),8.07(s,1H),7.92(s,1H),6.98–6.81(m,2H),5.64(s,1H),4 .53(d,J=8.4Hz,2H),3.58–3.39(m,1H),2.84–2.62(m,1H),1.95(d,J=35. 7Hz,3H),1.54–1.40(m,3H),1.09(d,J=6.6Hz,3H),0.96(d,J=6.6Hz,3H).

[0764] MS m / z(ESI):463.2[M+H] + .

[0765] Example 72. Synthesis of Compound 115

[0766] Referring to the synthetic routes of compounds 93 and 104, compound 115 (43 mg, yield 32%) was prepared.

[0767] 1 H NMR(400MHz,DMSO-d6)δ10.19(s,1H),8.76–8.17(m,2H),7.76(dd,J=5.6,2.1Hz, 1H),7.27(ddd,J=8.2,6.0,1.9Hz,1H),7.18(td,J=9.4,7.4Hz,1H),6.58(s,2H), 4.54(d,J=9.3Hz,1H),4.11(dd,J=12.4,9.3Hz,1H),2.86(s,3H),2.16(d,J=11.9 Hz,1H),1.80(td,J=14.8,13.8,4.2Hz,1H),1.68–1.63(m,2H),1.50–1.13(m,8H).

[0768] MS m / z(ESI):462.2[M+H] + .

[0769] Example 73. Synthesis of Compound 116

[0770] Synthesis route:

[0771] Step 1: Synthesis of compound 116-2

[0772] Compound 116-1 (20 g, 139 mmol) and sodium bromate (250.3 g, 333 mmol) were dissolved in a mixed solution of acetonitrile (250 mL) and water (150 mL). A solution of sodium bisulfite (34.68 g, 333 mmol) dissolved in water (300 mL) was slowly added dropwise. The mixture was stirred at room temperature overnight. The reaction solution was extracted with ethyl acetate, and the organic phase was first washed with sodium thiosulfate solution and then with saturated brine, dried over anhydrous sodium sulfate, and then spin-dried. The crude product was purified by column chromatography (EA in PE: 10%) to give compound 116-2 (6 g, yield 32%) as a yellow oil.

[0773] Step 2: Synthesis of compound 116-3

[0774] Compound 116-2 (5.8 g, 42 mmol) was dissolved in tetrahydrofuran (116 mL), and 3 M methylmagnesium bromide (14 mL) was added dropwise under an ice bath. The reaction mixture was allowed to react for half an hour. The reaction solution was then poured into a saturated aqueous ammonium chloride solution to quench the mixture. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then spin-dried. The crude product was purified by column chromatography (EA in PE: 0% to 10%) to give compound 116-3 (5.3 g, yield 83%) as a yellow oil.

[0775] Step 3: Synthesis of compound 116-4

[0776] 2-Methoxy-3,4-difluorophenylacetic acid (6.5 g, 32.2 mmol) and carbonyldiimidazole (6.5 g, 40.1 mmol) were dissolved in acetonitrile (150 mL) and reacted at 0°C under nitrogen for 1 hour. Compound 116-3 (5 g, 32.1 mmol) and cesium carbonate (15.65 g, 47.6 mmol) were then added sequentially, and the temperature was slowly raised to 60°C and allowed to react overnight. Ethyl acetate was added to dilute the mixture, and the mixture was washed sequentially with water and saturated brine. The organic phase was dried and then spin-dried to dryness. The crude product was purified by column chromatography (EA in PE: 1%-20%) to afford compound 116-4 (1.4 g, 14% yield) as a white solid.

[0777] MS m / z(ESI):323.1[M+H] + .

[0778] Step 4: Synthesis of compound 116-5

[0779] Compound 116-4 (1.4 g, 4.4 mmol) was dissolved in a mixture of tetrahydrofuran (20 mL) and methanol (100 mL) and cooled to -40°C under nitrogen. Nickel chloride hexahydrate and sodium borohydride were added sequentially, and the reaction was continued for 1 hour. The reaction was determined to be complete by TLC. The filtrate was filtered, diluted with water, extracted with dichloromethane, dried, and concentrated to afford the crude product of compound 116-5 (1 g, 71% yield).

[0780] Step 5: Synthesis of compound 116-6

[0781] Compound 116-5 (1 g, 3.1 mmol) was dissolved in dichloromethane (20 mL). 1 M diisobutylaluminum hydride (6 mL, 6 mmol) was added at -78°C under an inert atmosphere and the reaction was continued for 2 hours. The mixture was quenched with water, filtered, and the filtrate was concentrated to obtain the crude product of compound 116-6 (1 g, 99% yield), which was directly used in the next step.

[0782] Step 6: Synthesis of compound 116-7

[0783] Compound 116-6 (1 g, 3.1 mmol) was dissolved in dichloromethane (20 mL). Triethylamine (620 mg, 6.1 mmol) and 4-dimethylaminopyridine (37 mg, 0.31 mmol) were added sequentially, followed by the slow dropwise addition of acetic anhydride (626 mg, 6.1 mmol). The mixture was allowed to react at room temperature for 1 hour. After dilution with dichloromethane, the mixture was washed sequentially with water and saturated brine. The organic phase was dried and concentrated to afford the crude product 116-7 (1.2 g, yield >100%), which was directly carried out to the next step.

[0784] Step 7: Synthesis of compound 116-8

[0785] Compound 116-7 (1.2 g, 3.2 mmol) was dissolved in dichloromethane (25 mL). Trimethylsilyl cyanide (1.3 mL, 10.2 mmol) and boron trifluoride etherate (1.3 mL, 10.2 mmol) were added sequentially at -40°C and the reaction was continued for 1 hour. The reaction was quenched with water, extracted with dichloromethane, and the organic phase was concentrated to obtain the crude product of compound 116-8 (1.1 g, yield >100%), which was directly carried out to the next step.

[0786] Step 8: Synthesis of compound 116-9

[0787] Compound 116-8 (1.1 g, 3.3 mmol) was dissolved in methanol (22 mL) and water (4.4 mL), and potassium hydroxide (3.3 g, 57.8 mmol) was added. The mixture was reacted at 60°C for 48 hours. The reaction solution was extracted with ethyl acetate to remove impurities, and the aqueous phase was adjusted to pH 3-4 with 2N hydrochloric acid, diluted with water, extracted with dichloromethane, and concentrated to obtain a crude product of compound 116-9 (200 mg, 17% yield).

[0788] Step 9: Synthesis of compound 116-10

[0789] Compound 116-9 (200 mg, 0.56 mmol) was dissolved in dichloromethane (5 mL). A catalytic amount of N,N-dimethylformamide was added at 0°C, followed by the slow addition of oxalyl chloride (0.2 mL) and the reaction was allowed to react for 1 hour. The reaction mixture was concentrated, and the concentrate was dissolved in dichloromethane. Triethylamine (283.3 mg, 2.8 mmol), 4-dimethylaminopyridine (6.7 mg, 0.06 mmol), and methyl 4-amino-2-picolinate (128 mg, 0.84 mmol) were added sequentially, and the reaction was allowed to react at room temperature overnight. After TLC analysis, the reaction was concentrated and purified by column chromatography (EA in PE: 5%-50%) to afford compound 116-10 (60 mg, 22% yield) as a white solid.

[0790] MS m / z(ESI):489.2[M+H] + .

[0791] Step 10: Synthesis of compound 116

[0792] To compound 116-10 was added 5 mL of 7 M amine methanol solution, stirred overnight, and filtered to obtain compound 116 (10 mg, yield 17%).

[0793] 1 H NMR (400MHz, Chloroform-d) δ9.03 (s, 1H), 8.44 (d, J = 5.7Hz, 1H), 8.21 (dd, J = 5.7, 2. 0Hz,1H),8.05–7.84(m,2H),7.07(ddd,J=8.3,5.6,2.1Hz,1H),6.90(q,J=9.1Hz,1H) ,5.70(s,1H),4.73(d,J=11.6Hz,1H),4.17(dd,J=11.5,6.2Hz,1H),3.99(d,J=2.6Hz ,3H),2.31(dd,J=9.9,6.2Hz,1H),2.11(td,J=13.6,4.4Hz,1H),1.90–1.09(m,14H).

[0794] MS m / z(ESI):474.2[M+H] + .

[0795] Example 74. Synthesis of Compound 117

[0796] Synthesis route:

[0797] Compound 117 (68 mg, yield 44%) was finally prepared using compound 78-5 as the starting material and referring to the synthetic route of compound 96.

[0798] 1 H NMR(400MHz,Chloroform-d)δ8.73(s,1H),8.44(d,J=5.5Hz,1H),8.19(dd,J=5.5,2.2Hz ,1H),7.86(t,J=4.4Hz,2H),7.02–6.77(m,2H),5.70(d,J=4.4Hz,1H),4.52(d,J=10.7Hz, 1H),3.41(t,J=10.7Hz,1H),2.35–2.29(m,1H),2.03(dd,J=13.6,10.6Hz,1H),1.82(dd,J =13.5,8.1Hz,1H),1.77–1.59(m,6H),1.59–1.51(m,1H),1.49(s,3H),1.43–1.33(m,1H).

[0799] MS m / z(ESI):463.2[M+H] + .

[0800] Example 75. Synthesis of Compound 118

[0801] Referring to the synthetic route of compound 117, compound 118 (26 mg, yield 24%) was finally prepared.

[0802] 1H NMR(400MHz,Chloroform-d)δ8.95(s,1H),8.45(d,J=5.4Hz,1H),8.19(d,J=5.3Hz,1H),8.06(s,1H),7.95(s,1H),7.24–7.17(m,1H),7.12(q,J=8.6Hz, 1H),5.67(s,1H),4.82(d,J=11.2Hz,1H),4.14(dd,J=11.2,7.2Hz,1H),2.3 7(dd,J=12.1,7.2Hz,1H),2.01(dd,J=14.0,8.4Hz,1H),1.91–0.90(m,12H).

[0803] MS m / z(ESI):497.2[M+H] + .

[0804] Compound 118 was separated by chiral chromatography to obtain compound 118a and compound 118b. The specific experimental parameters are as follows:

[0805] Chromatographic column: DAICELCHIRALPAK IH; column size: 250*50 10μm; mobile phase A: supercritical CO2; mobile phase B: IPA (7.0 mol / L MEOH containing 0.1% ammonia); mobile phase gradient: A:B:75:25; detection wavelength: 214nm; flow rate: 140mL / min; column temperature: RT.

[0806] Compound 118 was resolved to obtain Compound 118a and Compound 118b.

[0807] Example 76. Synthesis of Compound 119

[0808] Synthesis route:

[0809] Compound 119 (97 mg, yield 22%) was finally prepared using compound 118 as the starting material and referring to the synthetic route of compound 80.

[0810] 1H NMR(400MHz, DMSO-d6)δ10.62(d,J=4.6Hz,1H),10.59–10.50(m,1H),8.59(d,J=3.2Hz ,1H),8.30(d,J=7.2Hz,1H),8.22(d,J=4.7Hz,1H),7.89(dd,J=7.2,3.3Hz,1H),7.46– 7.39(m,1H),7.34–7.22(m,1H),4.92(d,J=10.4Hz,1H),4.19(dd,J=10.4,7.4Hz,1H), 2.23(d,J=7.6Hz,1H),1.96–1.61(m,7H),1.44(s,3H),1.27–1.18(m,2H),1.02(s,1H).

[0811] MS m / z(ESI):513.2[M+H] + .

[0812] Example 77. Synthesis of Compound 120

[0813] Synthesis route:

[0814] Compound 10-7 (300 mg, 0.96 mmol) was dissolved in dichloromethane (10 mL). A catalytic amount of N,N-dimethylformamide was added at 0°C, followed by the slow addition of oxalyl chloride (381 mg, 2.87 mmol) and the reaction was allowed to proceed for 1 hour. The reaction system was concentrated, and the concentrate was dissolved in dichloromethane. Triethylamine (505 mg, 4.8 mmol), 4-dimethylaminopyridine (13 mg, 0.1 mmol), and methyl 4-amino-2-picolinate (300 mg, 1.44 mmol) were added sequentially, and the reaction was allowed to proceed overnight at room temperature. After TLC analysis, the reaction was concentrated and purified by column chromatography to afford Compound 120-1 (280 mg, 59% yield) as a white solid.

[0815] Compound 120-1 (280 mg, 0.57 mmol) was dissolved in THF (10 mL), and a catalytic amount of palladium on carbon was added at room temperature. After hydrogen exchange, the reaction was allowed to proceed overnight at room temperature. After TLC detection, the reaction was complete, filtered, concentrated, and purified by column chromatography to obtain compound 120 (124 mg, 54% yield).

[0816] 1H NMR(400MHz, DMSO-d6)δ7.93(dd,J=26.8,7.6Hz,1H),7.38(d,J=15.9Hz,1H),7.21–7.08 (m,2H),4.64(dd,J=10.8,3.8Hz,1H),3.90(d,J=1.7Hz,3H),3.87(s,1H),3.82–3.74(m,1 H),3.26–3.09(m,1H),3.06–2.82(m,1H),2.31–2.10(m,2H),1.88–1.76(m,2H),1.75–1.5 4(m,3H),1.51–1.43(m,1H),1.41(d,J=1.9Hz,3H),1.37–1.27(m,1H),1.25–1.12(m,2H).

[0817] MS m / z(ESI):409.2[M+H] + .

[0818] Example 78, Synthesis of Compound 121

[0819] Referring to the synthetic routes of compounds 10 and 80, compound 121 (106 mg, yield 39%) was finally prepared.

[0820] 1 H NMR (400MHz, DMSO-d6) δ10.62(d,J=4.6Hz,1H),10.54(s,1H),8.57(d,J=3.2Hz,1H),8.3 0(d,J=7.1Hz,1H),8.22(d,J=4.6Hz,1H),7.90(dd,J=7.2,3.2Hz,1H),7.30–7.09(m,2H) ,4.85(d,J=10.7Hz,1H),4.01–3.94(m,1H),3.91(d,J=1.8Hz,3H),2.60(d,J=7.8Hz,1H) ,1.95–1.84(m,1H),1.76–1.57(m,2H),1.48(s,3H),1.30(ddt,J=46.0,13.4,6.4Hz,2H).

[0821] MS m / z(ESI):448.2[M+H] + .

[0822] Example 79, Synthesis of Compound 122

[0823] Referring to the synthetic routes of compounds 46 and 106, compound 122 (38 mg, yield 36%) was finally prepared.

[0824] 1 H NMR (400MHz, DMSO-d6) δ10.48(s,1H),8.70–8.34(m,2H),8.24–7.82(m,2H),7.74–7.36(m,3H),5.13(d,J=9.8Hz,1H),4.34(dd,J= 9.8,5.8Hz,1H),2.21(dt,J=11.7,6.2Hz,1H),2.07(s,2H),2.04–1.97(m,1H),1.61–1.44(m,3H),1.33(s,3H),1.14–0.83(m,3H).

[0825] MS m / z(ESI):483.2[M+H] + .

[0826] Compound 122 was separated by chiral chromatography to obtain compound 122a and compound 122b. The specific experimental parameters are as follows:

[0827] Chromatographic column: DAICELCHIRALPAK IH; column size: 250*50 10μm; mobile phase A: supercritical CO2; mobile phase B: IPA (7.0 mol / L MEOH containing 0.1% ammonia); mobile phase gradient: A:B:75:25; detection wavelength: 214nm; flow rate: 140mL / min; column temperature: RT.

[0828] Compound 122 was resolved to give Compound 122a and Compound 122b.

[0829] Example 80, Synthesis of Compound 123

[0830] Synthesis route:

[0831] Referring to the synthetic method of compound 80, compound 123 (17 mg, yield 28%) was finally prepared.

[0832] 1H NMR(400MHz,Chloroform-d)δ11.09(s,1H),9.34(s,1H),8.40–8.25(m,2H),8.18(d,J=7.2Hz,1H),7.26–7.20(m,1H),7.16–7.06(m,1H),6 .30(m,1H),4.99(d,J=10.3Hz,1H),4.32(dd,J=10.4,5.8Hz,1H),2.37(dt,J=11.9,6.1Hz,1H),2.11(d,J=15.4Hz,1H),1.73–0.84(m,11H).

[0833] MS m / z(ESI):499.2[M+H] + .

[0834] Example 81. Synthesis of Compound 124

[0835] Synthesis route:

[0836] Step 1: Synthesis of compound 124-1

[0837] Compound 49 (200 mg, 478 μmol) was dissolved in ethyl acetate (5 mL). Chloroacetyl chloromethyl ester (73.9 mg, 574 μmol) was slowly added dropwise to the reaction mixture under nitrogen. DBACO (80.4 mg, 717 μmol) and DMF (0.1 mL) were then added and allowed to react at room temperature for 4 hours. After the reaction was complete as determined by LCMS, the reaction solution was poured into 30 mL of water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford compound 124-1 (230 mg crude product), which was used directly in the next step.

[0838] MS m / z(ESI):467.15[M+H] + .

[0839] Step 2: Synthesis of compound 124-2

[0840] Compound 124-1 (230 mg, crude) was dissolved in DMF (5 mL), and potassium carbonate (97.7 mg, 707 μmol) and di-tert-butyl potassium phosphate (176 mg, 707 μmol) were added, followed by a small amount of tetrabutylammonium iodide (17 mg, 47.12 μmol). The mixture was reacted at 70°C for 4 hours. After the reaction was complete as determined by LCMS, the reaction solution was poured into 30 mL of water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 124-2 (310 mg, crude product), which was used directly in the next step.

[0841] MS m / z(ESI):641.27[M+H] + .

[0842] Step 3: Synthesis of compound 124

[0843] Compound 124-2 (330 mg, crude product) was dissolved in a mixture of acetonitrile (5 mL), acetic acid (5 mL), and water (5 mL) and stirred at 70°C for 4 hours. After completion of the reaction by TLC, the reaction solution was concentrated under reduced pressure and directly purified using a reverse-phase column (aqueous phase: 10 mmol / L ammonium bicarbonate; organic phase: acetonitrile) and lyophilized to afford compound 124 (33.8 mg, 18% yield).

[0844] 1 H NMR(400MHz,Chloroform-d)δ9.22(s,1H),7.50(d,J=7.6Hz,1H),7.23(s,3H),7.04(s,1H),6.89–6.69(m,2H),6.5 6(s,1H),5.44(s,1H),4.92(t,J=9.6Hz,1H),4.15(s,1H),3.89(s,3H),2.21(d,J=35.5Hz,1H),1.70–0.71(m,11H).

[0845] MS m / z(ESI):529.15[M+H] + .

[0846] Example 82, Synthesis of Compound 127

[0847] Synthesis route:

[0848] Compound 10-7 (600 mg, 1.92 mmol) was dissolved in dichloromethane (30 mL). A catalytic amount of N,N-dimethylformamide was added at 0°C, followed by the slow addition of oxalyl chloride (733 mg, 5.77 mmol) and the reaction was allowed to proceed for 1 hour. The reaction mixture was concentrated and the concentrate was dissolved in dichloromethane. Triethylamine (970 mg, 9.6 mmol), 4-dimethylaminopyridine (24 mg, 0.19 mmol), and 5-aminopyridazin-3-one (320 mg, 2.88 mmol) were added sequentially and the reaction was allowed to proceed overnight at room temperature. After TLC analysis, the reaction was concentrated and purified by column chromatography (5-10% MeOH in DCM) to afford compound 127 (31 mg, 4% yield).

[0849] 1 H NMR (400MHz, DMSO-d6) δ12.76 (s, 1H), 10.26 (s, 1H), 8.04 (d, J = 2.3Hz, 1H), 7 .24–7.07(m,3H),4.86(d,J=10.6Hz,1H),3.99–3.94(m,1H),3.91(d,J=1.7Hz ,3H),2.59(dt,J=17.5,8.6Hz,1H),1.91(dt,J=12.3,6.3Hz,1H),1.76–1.58( m,2H),1.53–1.48(m,1H),1.47(s,3H),1.39–1.32(m,1H),1.27–1.21(m,1H).

[0850] MS m / z(ESI):406.2[M+H] + .

[0851] Example 83. Synthesis of Compound 128

[0852] Synthesis route:

[0853] Compound 46-7 (700 mg, 2.14 mmol) was dissolved in dichloromethane (10 mL). A catalytic amount of N,N-dimethylformamide was added at 0°C, followed by the slow addition of oxalyl chloride (818 mg, 6.44 mmol) and the reaction was allowed to proceed for 1 hour. The reaction mixture was concentrated and the concentrate was dissolved in dichloromethane. Triethylamine (1.13 g, 10.7 mmol), 4-dimethylaminopyridine (26 mg, 0.214 mmol), and 5-aminopyridazin-3-one (356 mg, 3.21 mmol) were added sequentially and the reaction was allowed to proceed overnight at room temperature. After TLC analysis, the reaction was concentrated and purified by column chromatography (PE containing EA: 5-50%) to afford compound 128 (252 mg, 28% yield).

[0854] 1 H NMR(400MHz, DMSO-d6)δ8.11(t,J=1.9Hz,1H),7.28–7.17(m,2H),7.14–7.04(m,1H),5.07(d,J=9.7Hz,1H),4.30–4.26(m,1H), 3.92(s,3H),2.20–2.14(m,1H),2.00(d,J=13.7Hz,1H),1.57–1.39(m,3H),1.38–1.32(m,1H),1.31(s,3H),1.06–0.87(m,3H).

[0855] MS m / z(ESI):420.2[M+H] + .

[0856] Example 84. Synthesis of Compound 129

[0857] Synthesis route:

[0858] Compound 78-9 (200 mg, 0.59 mmol) was dissolved in dichloromethane (5 mL). A catalytic amount of N,N-dimethylformamide was added at 0°C, followed by the slow addition of oxalyl chloride (0.2 mL) and the reaction was allowed to react for 1 hour. The reaction mixture was concentrated, and the concentrate was dissolved in dichloromethane. A mixture of triethylamine (178.38 mg, 1.76 mmol), 4-dimethylaminopyridine (21.54 mg, 0.17 mmol), and 5-aminopyridazin-3-one (84.87 mg, 0.74 mmol) was slowly added dropwise. The reaction was allowed to react at room temperature for 2 hours. After TLC analysis, the reaction was concentrated and purified by column chromatography (CAN in H2O: 5-65%) to afford compound 129 (11 mg, 4.1% yield).

[0859] 1 H NMR (400MHz, DMSO-D6) δ12.76(s,1H),10.30(s,1H),8.04(d,J=2.3Hz,1H),7.18–7.11(m,3H),4.89(d,J=10.3Hz,1H),4.19( dd,J=10.3,7.5Hz,1H),3.92(d,J=1.7Hz,3H),2.24(t,J=9.1Hz,1H),1.80–1.67(m,5H),1.44(s,3H),1.22(d,J=15.8Hz,5H).

[0860] MS m / z(ESI):433.9[M+H] + .

[0861] Example 85. Synthesis of Compound 131

[0862] Synthesis route:

[0863] Compound 78-9 (700 mg, 0.59 mmol) was dissolved in dichloromethane (10 mL). A catalytic amount of N,N-dimethylformamide was added at 0°C, followed by the slow addition of oxalyl chloride (0.2 mL) and the reaction was allowed to react for 1 hour. The reaction mixture was concentrated, and the concentrate was dissolved in dichloromethane. A mixture of triethylamine (624.34 mg, 6.17 mmol), 4-amino-2-hydroxypyridine (294.40 mg, 2.67 mmol), and 4-dimethylaminopyridine (75.38 mg, 0.62 mmol) was slowly added dropwise. The reaction was allowed to react at room temperature for 2 hours. After TLC analysis, the reaction was concentrated and purified by column chromatography (CAN in H2O: 5-65%) to afford compound 131 (12 mg, 1.28% yield).

[0864] MS m / z(ESI):433.2[M+H] + .

[0865] Example 86. Synthesis of Compound 133

[0866] Synthesis route:

[0867] Compound 72-1 (180 mg, 0.42 mmol) was dissolved in 18 mL of xylene, and Lawesson's reagent (256.5 mg, 0.63 mmol) was added. The mixture was then microwaved at 120°C for 1 hour. After concentration, the mixture was separated by column chromatography (H₂O containing CAN: 0-60%) to afford compound 133 (48 mg, 36% yield) (22 mg, 36% yield).

[0868] 1 H NMR (400MHz, DMSO-d6) δ10.58(s,1H),10.12(s,1H),9.87(s,1H),8.83(d,J=2.1Hz, 1H),8.44(d,J=5.5Hz,1H),7.90(dd,J=5.5,2.2Hz,1H),7.24(ddd,J=8.3,5.9,1.9Hz ,1H),7.17–7.06(m,1H),5.07(d,J=9.9Hz,1H),4.32(dd,J=9.9,5.9Hz,1H),3.93(d ,J=1.8Hz,3H),2.19(dt,J=11.5,6.4Hz,1H),2.03–1.89(m,1H),1.67–0.73(m,10H).

[0869] MS m / z(ESI):462.2[M+H] + .

[0870] Example 87. Synthesis of Compound 134

[0871] Synthesis route:

[0872] Compound 72-1 (180 mg, 0.42 mmol) was dissolved in 18 mL of xylene, and Lawesson's reagent (256.5 mg, 0.63 mmol) was added. The mixture was reacted in a microwave oven at 120°C for 1 hour. After concentration, the mixture was separated by column chromatography (H₂O containing CAN: 0-60%) to obtain compound 134 (22 mg, 36% yield).

[0873] 1 H NMR (400MHz, DMSO-d6) δ10.13(s,1H),9.89(s,1H),8.72(s,1H),8.50(d,J=5.3Hz,1 H),7.89(dd,J=5.4,2.1Hz,1H),7.28(ddd,J=8.5,6.0,2.0Hz,1H),7.09(q,J=9.0Hz ,1H),5.26(d,J=9.5Hz,1H),4.54(dd,J=9.7,6.0Hz,1H),3.91(d,J=1.5Hz,3H),2.1 6(dt,J=11.9,6.2Hz,1H),2.03–1.92(m,1H),1.66–1.29(m,7H),1.16–0.77(m,3H).

[0874] MS m / z(ESI):478.1[M+H] + .

[0875] Example 88. Synthesis of Compound 135

[0876] Synthesis route:

[0877] Compound 106 (210 mg, 0.45 mmol) was dissolved in dichloromethane (20 mL), and m-chloroperbenzoic acid (309 mg, 1.79 mmol) was added at room temperature. The reaction was allowed to react overnight. After TLC, the reaction was quenched with water, extracted with dichloromethane, dried, filtered, concentrated, and purified by column chromatography to obtain compound 135 (68 mg, 31% yield).

[0878] 1H NMR (400MHz, DMSO-d6) δ10.62(d,J=4.3Hz,1H),10.52(s,1H),8.59(d,J=3.2Hz,1H),8.31(d,J =7.2Hz,1H),8.22(d,J=4.3Hz,1H),7.90(dd,J=7.2,3.2Hz,1H),7.51–7.34(m,2H),4.91(d,J=1 0.6Hz,1H),3.95(dd,J=10.5,7.7Hz,1H),2.57(dt,J=21.7,10.6Hz,1H),1.92(dt,J=12.5,6.4H z,1H),1.80–1.61(m,2H),1.55–1.49(m,1H),1.48(s,3H),1.31(dtt,J=26.7,13.4,6.7Hz,2H).

[0879] MS m / z(ESI):485.2[M+H] + .

[0880] The remaining compounds of the present invention can be prepared using commercially available raw materials with reference to the synthetic routes of Examples 1-88 above.

[0881] Biological test evaluation

[0882] The present invention is further described and explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0883] Test Example 1 Blocking activity experiment of the compound of the present invention on voltage-gated sodium ion channel 1.8 (NaV1.8)

[0884] 1. Purpose of the experiment

[0885] The patch clamp technique was used to detect the effects of the compounds of the present invention on NaV1.1-1.8 subtype currents.

[0886] 2. Preparation and Analysis of Drug Delivery Preparations

[0887] (1) Preparation method of drug delivery preparation stock solution

[0888] Vehicle control: Weigh an appropriate volume of DMSO as a stock solution.

[0889] Test compound: Weigh an appropriate amount of compound (actual amount = theoretical concentration * volume × molecular weight / purity). Calculate the required volume of DMSO according to the formula, and then convert the final amount of DMSO required. Dissolve the powder in the weighed DMSO. Calculate the actual stock concentration based on the final amount of DMSO used. The actual stock concentration will generally differ slightly from the theoretical concentration.

[0890] (2) Preparation method and concentration of drug preparation working solution

[0891] Before the NaV channel current test, the control and test compound stock solutions were diluted into 10 mL of extracellular fluid as working solution and sonicated for 20 min.

[0892] Alternatively, control and test compound stock solutions were further diluted into the extracellular fluid to achieve the final concentration tested. Visual inspection for precipitation was performed before testing, and the final DMSO concentration in the extracellular fluid did not exceed 0.30%. Five concentration gradients were tested for each compound, with two replicates for each concentration, depending on the actual situation.

[0893] 3. Experimental system

[0894] Experimental system 1:

[0895] (1) Cell culture

[0896] 1) The specific information of the CHO cell line stably expressing NaV1.8 channels is as follows: SCN10A: NM_006514.

[0897] 2) The cells were cultured in HAM'S / F-12 medium containing 10% fetal bovine serum, 10 μg / mL Blasticidin, 200 μg / mL Hygromycin B, and 100 μg / mL Zeocin at a temperature of 37° C. and a carbon dioxide concentration of 5%.

[0898] 3) Cell passaging: Remove old culture medium and wash once with PBS, then add 1 mL of 0.25%-Trypsin-EDTA solution and incubate at 37°C for 1.5 min. When the cells detach from the bottom of the dish, add 5 mL of complete culture medium preheated at 37°C. Gently pipette the cell suspension to separate the aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 1000 rpm for 5 minutes to collect the cells. For expansion or maintenance culture, seed the cells in a 6 cm cell culture dish with 2.5*105 cells seeded in each cell culture dish (final volume: 5 mL).

[0899] 4) To maintain the electrophysiological activity of cells, the cell density must not exceed 80%.

[0900] 5) Patch clamp assay: Before the experiment, cells were dissociated with 0.25% trypsin-EDTA and seeded into a 24-well plate with a cover slip in place at a density of 8 × 10 3 cells per well (final volume: 500 μL). Tetracycline was added, and the assay was performed the next day.

[0901] (2) Electrophysiological solution

[0902] Extracellular solution: 140 mM NaCl, 3.5 mM KCl, 2 mM CaCl2, 10 mM HEPES, 1.25 mM NaH2PO4, 1 mM MgCl2, 10 mM Glucose, pH = 7.4 (NaOH).

[0903] Intracellular solution: 50 mM CsCl, 10 mM NaCl, 10 mM HEPES, 20 mM EGTA, 60 mM CsF, pH = 7.2 (CsOH).

[0904] Experimental system 2:

[0905] (1) Cell culture

[0906] 1) HEK-293 cell lines stably expressing hNav1.8 / β1 sodium channel (WuXi Apptec, Nav1.8: AF117907; β1: NM_001037) were used.

[0907] 2) The cells were cultured in a cell culture incubator at 37°C and 5% carbon dioxide. The culture medium conditions are shown in the table below.

[0908] 3) Cell Passaging: When the cell density in the T75 flask is approximately 70-80%, discard the old culture medium and rinse the cells once with DPBS. Add 2 mL of 0.25% Trypsin-EDTA solution and incubate at 37°C for 1 minute. Gently tap the flask to detach the cells, then add 10 mL of complete culture medium to terminate the digestion. Dilute the cells as needed for expansion or maintenance culture.

[0909] 4) HEK-293 cells can be used for patch clamp experiments after being cultured for at least two days and reaching a cell density of approximately 75%. Cells should be induced with tetracycline (Sangon Biotech, T0422) at a concentration of 1 μg / mL for 24 hours prior to testing. Cells should be dissociated using TrypLE digestion enzyme and resuspended in extracellular medium at room temperature for testing.

[0910] (2) Electrophysiological recording solution

[0911] The following solutions were used for electrophysiological recordings. Extracellular solution was prepared at least one month in advance, and electrode solution was prepared in batches, aliquoted, and stored at -20°C until use.

[0912] 4. Patch Clamp Assay

[0913] Detection method 1:

[0914] The voltage stimulation protocol for whole-cell patch-clamp recordings of NaV channel currents was as follows: the cell membrane potential was first clamped at -130 mV. The voltage was then stepped to -40 mV or -20 mV in 10 mV steps for 8 seconds. The clamping voltage was maintained at -120 mV, and data were collected repeatedly every 20 seconds. The peak amplitude of the inward current was measured to determine the half-inactivation voltage.

[0915] The cell clamp potential was set at -120 mV. Resting and half-inactivation inhibition of sodium currents were measured using a double-pulse mode. The double-pulse mode consisted of two 0 mV depolarizing test pulses (TP1 and TP2) lasting 50 ms. The conditioning voltage between the two depolarizing pulses was set near the half-inactivation voltage (lasting 8 s). Before giving the second depolarizing pulse, the cell membrane potential was clamped to -120 mV for 20 ms to allow the channels in the inactivated state to recover without binding the compound. Data were collected repeatedly at intervals of 20 s, and the current peaks at the two test pulses were measured.

[0916] Experimental data were collected by an amplifier and stored in PatchMaster software. Recording electrodes were drawn from glass capillaries using a microelectrode puller. Under an inverted microscope, the microelectrode manipulator was used to place the recording electrode in contact with the cell. Negative pressure was applied to create a GΩ seal. After the GΩ seal was established, rapid capacitance compensation was performed. Further negative pressure was applied to rupture the cell membrane, establishing whole-cell recording mode. Slow capacitance compensation was then performed, and membrane capacitance and series resistance were recorded. No leakage compensation was applied.

[0917] When the NaV channel current recorded in the whole cell is stable, the drug is administered. After each drug concentration is applied for 5 minutes (or the current is stable), the next concentration is detected. Multiple concentrations are detected for each test compound. The coverslip with cells is placed in the recording bath in an inverted microscope. The test compound and the external solution without the compound are flowed through the recording chamber from low concentration to high concentration by gravity perfusion to act on the cells. A vacuum pump is used for liquid exchange during the recording. The current detected in the external solution without the compound for each cell serves as its own control group. Multiple cells are tested independently and repeatedly. All electrophysiological experiments are performed at room temperature.

[0918] Detection method 2:

[0919] (1) Experimental equipment

[0920] Compounds were tested using the whole-cell patch-clamp technique at room temperature. A Multiclamp 700B patch-clamp amplifier (Molecular Devices, USA) was used, and the amplifier output was digitized using a DigiData 1440A / DD / A board and low-pass filtered at 10 kHz. Recordings were controlled by PClamp10 software (Molecular Devices, USA). For quality control, the minimum seal resistance was set to 500 MOhms, and the minimum specific hNav1.8 current (before compound) was 0.4 nA. Glass microelectrodes were pulled and heat-polished from borosilicate glass capillaries (GC150tF-10, Harvard Apparatus Co., UK) using a programmable microneedle puller (NARISHIGE PC-10 Puller, Japan). The electrode tip resistance ranged from 2 to 5 MΩ.

[0921] The recorded cells were continuously perfused with extracellular fluid using a perfusion system (Warner Instrument Corporation, VC-6-PINCH, ~1 ml / min). The system was mounted on the platform of an inverted microscope (Nikon ECLIPSE Ti, Japan), and the perfusion head was manually positioned under the microscope.

[0922] (2) Experimental voltage setting

[0923] Starting from a -120mV holding potential, the voltage was adjusted to Vhalf for 8 seconds (pre-pulse) to inactivate the sodium channels, and then the voltage was adjusted back to the -120mV holding potential for 20 milliseconds. Afterwards, the voltage was adjusted to 0mV for 20 milliseconds to open the sodium channels. The peak current induced under the 0mV pulse was used for data analysis. Finally, the voltage was adjusted back to the -120mV holding potential again. During the test period (control and test compound), this voltage control program was repeated continuously every 15 seconds.

[0924] (3) Compound treatment

[0925] During the initial recording period, peak current amplitudes were monitored until stable (variation <5%) for a total of five sweeps. Once stable, perfusion with the lowest compound concentration was initiated and continued for five consecutive sweeps until the peak current stabilized again; if the peak current remained unchanged, perfusion was continued for 5 minutes. When the average current amplitude over five sweeps was greater than 200 pA, the current was defined as "stable" or "unchanged" if the coefficient of variation (CV) of the current amplitude over five sweeps was as follows: less than 5% for percent inhibition <70%; less than 10% for percent inhibition >70%. Higher concentrations of compound were used if necessary; otherwise, the experiment was terminated.

[0926] 5. Data Analysis

[0927] Data analysis was performed using Clampfit (V10, Molecular Devices, USA), Excel 2013 (Microsoft), and GraphPad Prism 7.0. Percent inhibition at each test compound concentration was calculated from the recorded current responses: (1 - peak current measured during compound perfusion / peak current measured during vehicle perfusion) × 100%. Curves were fitted using the following sigmoid dose-response (variable slope) equation:

[0928] I / Icontrol=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)), where X is the logarithm of the concentration, I / Icontrol is the normalized peak current amplitude, Top is 1, and Bottom is 0.

[0929] If the inhibition rate measured at the lowest concentration exceeded 50%, or the inhibition rate measured at the highest concentration was less than 50%, we would define the IC 50 Report as below the lowest concentration or above the highest concentration, respectively.

[0930] 5. Data Analysis

[0931] First, the current after each drug concentration was normalized to the blank control current, and then the blockade rate corresponding to each drug concentration was calculated. The mean and standard error were calculated for each concentration. All the above values ​​were calculated using Microsoft Excel. In addition, the half-inhibitory concentration of each compound was calculated using the following equation using IGOR software: Blockade rate = 1 / [1 + (IC 50 / c) h The dose-dependent effect was fitted nonlinearly using this equation, where c represents the drug concentration, IC 50 is the half-inhibitory concentration, and h represents the Hill coefficient. Curve fitting and IC 50 The calculations were performed using IGOR software.

[0932] 6. Experimental Results

[0933] The above schemes reveal that the compounds of the present invention have a half-blocking activity (IC 50 ) The specific results are shown in Table 1 below, where: Blocking activity IC 50 The results of A + Representative IC 50 Value ≤ 1nM, A represents 1nM<IC 50Value ≤ 10nM, B represents 10nM<IC 50 Value ≤ 50nM, C represents 50nM < IC 50 Value ≤ 100nM, D represents IC 50 Value>100nM.

[0934] The specific results are shown in Table 1 below:

[0935] Table 1 Experimental results of the NaV1.8 blocking activity of the compounds of the present invention

[0936] 7. Experimental Conclusion

[0937] The experimental results show that the compound of the present invention has a significant blocking effect on NaV1.8.

[0938] Test Example 2: In vivo pharmacokinetic study of the compound of the present invention in rats

[0939] 1. Purpose of the test:

[0940] The compound of the present invention was administered orally orally to male SD rats, and the blood concentration of the compound of the present invention in the rats was determined. The PK parameters were calculated, and the pharmacokinetic evaluation of the compound of the present invention was performed.

[0941] 2. Test materials:

[0942] (1) Test sample: Compounds of the present invention, homemade.

[0943] (2) Experimental animals: SD rats, SPF grade, male, purchased from Shanghai Jihui Experimental Animal Breeding Co., Ltd.

[0944] (3) Main test instruments:

[0945] 3. Experimental plan:

[0946] (1) Dosage information:

[0947] Drug preparation: Calculate the preparation volume based on the weight of the sample to be tested, add 5-10% DMSO and 40% PEG 400, and after the sample is fully dissolved, add 50-55% 20% β-cyclodextrin aqueous solution, mix thoroughly and set aside.

[0948] Route of administration: Oral gavage.

[0949] Frequency and duration of administration: Single dose.

[0950] (2) Test method:

[0951] SD rats were stratified by weight and randomly divided into groups of 3 rats per group. All rats were fasted overnight before the experiment. The drug was administered orally by gavage. At 0, 0.167, 0.333, 0.5, 1, 2, 4, 7, and 24 hours, 50 μL of blood was collected from the jugular vein of the rats into sample tubes containing sodium heparin, an anticoagulant, and placed on wet ice. The tubes were rotated at 4000 rpm. -1 The cells were centrifuged for 10 min to separate the plasma, which was then frozen and stored in a -80°C refrigerator until testing.

[0952] 4. Test results and analysis:

[0953] The concentration of plasma samples was determined by high performance liquid chromatography-tandem mass spectrometry (LC-MS / MS). After administration of the present invention, the blood concentration of CVL-751 in the animal plasma was detected, and the relevant pharmacokinetic parameters were calculated. The retention time of the compound and the internal standard, the chromatographic acquisition and the chromatographic integration were processed using the software Analyst (AB SCIEX), and the data statistics were processed using the software Microsoft Office. WinNonlin TM Plasma concentrations were calculated using a non-compartmental model using the pharmacokinetic software Version 6.3 (Pharsight, Mountain View, CA). Pharmacokinetic parameters were calculated using the linear-log trapezoidal method. The results are shown in Table 2.

[0954] Table 2 Pharmacokinetic test results of the compounds of the present invention in rats

[0955] 5. Test conclusion:

[0956] Compared to known Nav1.8 inhibitors including VX-548, the compounds of the present invention have a suitable half-life t 1 / 2 , good exposure AUC and maximum blood concentration C max , showing good pharmacokinetic properties.

Claims

1. A compound represented by general formula (I), a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, in: X is O or S; Ring B is C 3-8 Cycloalkyl or a 3-8 membered heterocyclic group containing 1-4 heteroatoms selected from N, O and S; R b are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy or C 1-6 haloalkoxy; R1 and R2 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy or C 1-6 haloalkoxy; Ring C is C 6-10 Aryl or a 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S; R c are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl or C 1-6 Alkoxy; wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, cyano, amino, nitro and oxo; Ring A is C 6-10 aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, 5-10 membered heterocyclic group containing 1-4 heteroatoms selected from N, O and S, or R a are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, -(CH2) n OR aa 、-(CH2) n NR aa R bb 、-(CH2) n C(O)R aa 、-(CH2) n C(O)OR aa 、-(CH2) n C(O)NR aa R bb 、-(CH2) n S(O)NR aa R bb 、-(CH2) n C(O)NR bb (CH2) n1 OP(O)(OR aa )2、-(CH2) n OP(O)(OR aa )2、-(CH2) n OC(O)(CH2) n1 COOR aa or -(CH2) n C(=NR cc )NR aa R bb ; R aa 、R bb and R cc are independently hydrogen, deuterium, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, cyano, amino, nitro and oxo; x is an integer from 0 to 6; y is an integer from 0 to 6; z is an integer from 0 to 6; n is an integer from 0 to 3; and n1 is an integer from 0 to 3.

2. The compound according to claim 1, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, wherein: One or more of the following conditions are met: (1) The ring B is C 3-8 Cycloalkyl or a 3-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O and S; preferably cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or tetrahydropyranyl; (2) R b are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy; preferably hydrogen or C 1-3 Alkyl; more preferably hydrogen or methyl; (3) R1 and R2 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy; preferably hydrogen or C 1-3 Alkyl; more preferably hydrogen, methyl, ethyl or isopropyl; (4) The ring C is C 6-10 Aryl or a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S; preferably phenyl or pyridyl; more preferably the following groups: (5) R c are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-3 Alkyl or C 1-3 Alkoxy, wherein the C 1-3 Alkyl or C 1-3 The alkoxy group is optionally further substituted with one or more deuterium or halogen; preferably hydrogen, deuterium, halogen, C 1-3 Alkyl or C 1-3 Alkoxy, wherein the C 1-3 Alkyl or C 1-3 The alkoxy group is optionally further substituted with one or more deuterium or halogen; more preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, -OCF3, -OCHF2, -OCH2F, -OCD2F, -CD3, -OCD3 or -OCDF2; (6) Ring A is C 6-10 aryl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O and S or Preferably, phenyl, pyridyl, dihydropyridyl, dihydropyridazinyl, piperidinyl or More preferably, the following groups: (7) R a are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -(CH2) n OR aa 、-(CH2) n NR aa R bb 、-(CH2) n C(O)OR aa 、-(CH2) n C(O)NR aa R bb 、-(CH2) n S(O)NR aa R bb 、-(CH2) n C(O)NR bb (CH2) n1 OP(O)(OR aa )2、-(CH2) n OP(O)(OR aa )2、-(CH2) n OC(O)(CH2) n1 COOR aa or -(CH2) n C(=NR cc )NR aa R bb ; preferably hydrogen, halogen, cyano, oxo, C 1-3 Alkyl, -OR aa 、-NR aa R bb 、-C(O)OR aa 、-C(O)NR aa R bb 、-S(O)NR aa R bb 、-C(O)NR bb -CH2-OP(O)(OR aa )2、-CH2OP(O)(OR aa )2, -CH2OC(O)(CH2)2COOR aa or -C(=NR cc )NR aa R bb More preferably, it is hydrogen, fluorine, chlorine, bromine, cyano, oxo, methyl, -C(O)NH2, -S(O)NH2, -C(O)NH-CH2-OP(O)(OH)2, -O-CH2CH(OH)(CH2OH), -C(O)OCH3, -N(CH2OH)2, -CH2OP(O)(OH)2, -CH2OC(O)(CH2)2COOH, -C(=NH)NH2, -C(=N-CH3)NH2, -C(=N-OH)NH2 or -C(=N-OCH3)NH2; (8) R aa 、R bb and R cc are independently hydrogen, deuterium, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more hydroxy groups; preferably hydrogen, hydroxy, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more hydroxy groups; more preferably hydrogen, hydroxy, methyl, methoxy, -CH2OH or -CH2CH(OH)(CH2OH); (9) x is an integer from 0 to 4, preferably 1, 2 or 3; (10) y is an integer from 0 to 4, preferably 1, 2 or 3; (11) z is an integer from 0 to 4, preferably 1, 2 or 3; (12) n is an integer from 0 to 2, preferably 0 or 1; (13) n1 is an integer from 0 to 2, preferably 1 or 2; (14) X is O or S.

3. The compound according to claim 1 or 2, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, wherein: One or both of the following conditions are met: (1) For the following groups: (2) for (3) for 4. The compound according to any one of claims 1 to 3, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, characterized in that: The general formula (I) further has a structure represented by the general formula (II): Ring B is C 3-8 Cycloalkyl or a 3-8 membered heterocyclic group containing 1-4 heteroatoms selected from N, O and S; R b are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy or C 1-6 haloalkoxy; R1 and R2 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy or C 1-6 haloalkoxy; Ring C is C 6-10 Aryl or a 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S; R c are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy or C 1-6 haloalkoxy; Ring A is C 6-10 Aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, or 5-10 membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S; R a are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, -(CH2) n OR aa 、-(CH2) n NR aa R bb 、-(CH2) n C(O)R aa 、-(CH2) n C(O)OR aa 、-(CH2) n C(O)NR aa R bb 、-(CH2) n C(NH2)(=N)R aa or -(CH2) n C(NH2)(=N)OR aa ; R aa and R bb are independently hydrogen, deuterium, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, cyano, amino, nitro and oxo; x is an integer from 0 to 6; y is an integer from 0 to 6; z is an integer from 0 to 6; and n is an integer from 0 to 3.

5. The compound according to any one of claims 1 to 4, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, characterized in that: The general formula (I) further has a structure represented by the general formula (III): in: Ring B is C 3-8 Cycloalkyl or a 3-8 membered heterocyclic group containing 1-4 heteroatoms selected from N, O and S; R b are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; R1 and R2 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; R3, R4 and R5 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; Ring A is C 6-10 Aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, or 5-10 membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S; R a are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(CH2) n OR aa 、-(CH2) n NR aa R bb 、-(CH2) n C(O)R aa 、-(CH2) n C(O)OR aa or -(CH2) n C(O)NR aa R bb ; R aa and R bb are independently hydrogen, deuterium, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, cyano, amino, nitro and oxo; x is an integer from 0 to 6; y is an integer from 0 to 6; and n is an integer from 0 to 3.

6. The compound according to claim 5, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, wherein: The general formula (III) further has the structure shown in the general formula (IV): wherein m is an integer from 0 to 3; Ring A, R1, R3, R4, R5, R a , and x as described in claim 5; Preferably, the general formula (I) further has a structure represented by the general formula (IV-A) or the general formula (IV-B): wherein m is an integer from 0 to 3; Ring A, R1, R3, R4, R5, R a and x as described in claim 5.

7. The compound according to any one of claims 1 to 3, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, characterized in that: The general formula (I) further has a structure represented by the general formula (V): in: X is O or S; preferably O; R1 is hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy or C 1-6 Halogenated alkoxy; preferably hydrogen, deuterium, halogen, hydroxy, cyano, amino, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; more preferably hydrogen, methyl, ethyl or isopropyl; R b are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy or C 1-6 Halogenated alkoxy; preferably hydrogen, deuterium, halogen, hydroxy, cyano, amino, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; more preferably hydrogen or methyl; Ring C is C 6-10 Aryl or a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S; preferably phenyl or pyridyl; more preferably the following groups: R c are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted by one or more substituents independently selected from deuterium, halogen, hydroxyl, cyano, amino, nitro and oxo; preferably hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-3 Alkyl or C 1-3 Alkoxy, wherein the C 1-3 Alkyl or C 1-3 The alkoxy group is optionally further substituted with one or more deuterium or halogen; more preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, -OCF3, -OCHF2, -OCH2F, -OCD2F, -CD3, -OCD3 or -OCDF2; Ring A is C 6-10 aryl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O and S or Preferably, phenyl, pyridyl, dihydropyridyl, dihydropyridazinyl, piperidinyl or More preferably, the following groups: R a are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, -(CH2) n OR aa 、-(CH2) n NR aa R bb 、-(CH2) n C(O)R aa 、-(CH2) n C(O)OR aa 、-(CH2) n C(O)NR aa R bb 、-(CH2) n S(O)NR aa R bb 、-(CH2) n C(O)NR bb (CH2) n1 OP(O)(OR aa )2、-(CH2) n OP(O)(OR aa )2、-(CH2) n OC(O)(CH2) n1 COOR aa or -(CH2) n C(=NR cc )NR aa R bb ; preferably hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -(CH2) n OR aa 、-(CH2) n NR aa R bb 、-(CH2) n C(O)OR aa 、-(CH2) n C(O)NR aa R bb 、-(CH2) n S(O)NR aa R bb 、-(CH2) n C(O)NR bb (CH2) n1 OP(O)(OR aa )2、-(CH2) n OP(O)(OR aa )2、-(CH2) n OC(O)(CH2) n1 COOR aa or -(CH2) n C(=NR cc )NR aa R bb More preferably, it is hydrogen, fluorine, chlorine, bromine, cyano, oxo, methyl, -C(O)NH2, -S(O)NH2, -C(O)NH-CH2-OP(O)(OH)2, -O-CH2CH(OH)(CH2OH), -C(O)OCH3, -N(CH2OH)2, -CH2OP(O)(OH)2, -CH2OC(O)(CH2)2COOH, -C(=NH)NH2, -C(=N-CH3)NH2, -C(=N-OH)NH2 or -C(=N-OCH3)NH2; R aa 、R bb and R cc are independently hydrogen, deuterium, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more substituents independently selected from deuterium, halogen, hydroxyl, cyano, amino, nitro and oxo; preferably hydrogen, deuterium, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more hydroxy groups; more preferably hydrogen, hydroxy, methyl, methoxy, -CH2OH or -CH2CH(OH)(CH2OH); x is an integer from 0 to 6; preferably an integer from 0 to 4; more preferably 1, 2 or 3; y is an integer of 0-6; preferably an integer of 0-4; more preferably 1, 2 or 3; z is an integer from 0 to 6; preferably an integer from 0 to 4; more preferably 1, 2 or 3; n is an integer of 0-3; preferably an integer of 0-2; more preferably 0 or 1; n1 is an integer from 0 to 3; preferably an integer from 0 to 2; more preferably 1 or 2; and p is an integer from 0 to 3.

8. The compound according to claim 7, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, wherein: The general formula (V) further has the structure shown in the general formula (VI): in: R3, R4 and R5 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted by one or more substituents independently selected from deuterium, halogen, hydroxyl, cyano, amino, nitro and oxo; preferably hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-3 Alkyl or C 1-3 Alkoxy, wherein the C 1-3 Alkyl or C 1-3 The alkoxy group is optionally further substituted with one or more deuterium or halogen; more preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, -OCF3, -OCHF2, -OCH2F, -OCD2F, -CD3, -OCD3 or -OCDF2; Ring A, R a , R1, x and p are as described in claim 7.

9. The compound, stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of claims 8, characterized in that: The general formula (VI) further has a structure represented by the general formula (VII) or (VIII): in: R6 and R7 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, -(CH2) n OR aa 、-(CH2) n NR aa R bb 、-(CH2) n C(O)R aa 、-(CH2) n C(O)OR aa 、-(CH2) n C(O)NR aa R bb 、-(CH2) n S(O)NR aa R bb 、-(CH2) n C(O)NR bb (CH2) n1 OP(O)(OR aa )2、-(CH2) n OP(O)(OR aa )2、-(CH2) n OC(O)(CH2) n1 COOR aa or -(CH2) n C(=NR cc )NR aa R bb ; preferably hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -(CH2) n OR aa 、-(CH2) n NR aa R bb 、-(CH2) n C(O)OR aa 、-(CH2) n C(O)NR aa R bb 、-(CH2) n S(O)NR aa R bb 、-(CH2) n C(O)NR bb (CH2) n1 OP(O)(OR aa )2、-(CH2) n OP(O)(OR aa )2、-(CH2) n OC(O)(CH2) n1 COOR aa or -(CH2) n C(=NR cc )NR aa R bb More preferably, it is hydrogen, fluorine, chlorine, bromine, cyano, oxo, methyl, -C(O)NH2, -S(O)NH2, -C(O)NH-CH2-OP(O)(OH)2, -O-CH2CH(OH)(CH2OH), -C(O)OCH3, -N(CH2OH)2, -CH2OP(O)(OH)2, -CH2OC(O)(CH2)2COOH, -C(=NH)NH2, -C(=N-CH3)NH2, -C(=N-OH)NH2 or -C(=N-OCH3)NH2; further preferably, it is cyano, -C(O)NH2, -C(O)NH-CH2-OP(O)(OH)2, -C(=NH)NH2, -C(=N-CH3)NH2, -C(=N-OH)NH2 or -C(=N-OCH3)NH2; R aa 、R bb and R cc are independently hydrogen, deuterium, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more substituents independently selected from deuterium, halogen, hydroxyl, cyano, amino, nitro and oxo; preferably hydrogen, deuterium, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more hydroxy groups; more preferably hydrogen, hydroxy, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further substituted with one or more hydroxy groups; further preferably hydrogen, hydroxy, methyl, methoxy, -CH2OH or -CH2CH(OH)(CH2OH); n is an integer of 0-3; preferably an integer of 0-2; more preferably 0 or 1; n1 is an integer from 0 to 3; preferably an integer from 0 to 2; more preferably 1 or 2; R1, R3, R4, R5 and p are as described in claim 8.

10. The compound according to any one of claims 5 to 9, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, characterized in that: One or both of the following conditions are met: (1) For the following groups: Preferably (2) for Preferably 11. The compound according to any one of claims 1 to 10, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is any of the following structures:

12. A method for preparing the compound according to any one of claims 1 to 11, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, characterized in that: include: The compound represented by general formula (I-1), its stereoisomer, its tautomer or its salt and the compound represented by general formula (I-2), its stereoisomer or its tautomer undergo amidation reaction to prepare the compound represented by general formula (I), its stereoisomer, its tautomer or its pharmaceutically acceptable salt; Among them, X, ring A, ring B, ring C, R1, R2, R a 、R b 、R c , x, y and z are as described in any one of claims 1-11.

13. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 11, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof, and at least one pharmaceutical excipient selected from pharmaceutically acceptable carriers, diluents and excipients.

14. A compound according to any one of claims 1 to 11, a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13 for the preparation of a medicament for preventing and / or treating a related disease mediated by a voltage-gated sodium channel inhibitor; wherein the voltage-gated sodium channel is NaV1.

8.

15. Use of the compound according to any one of claims 1 to 11, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 13 in the preparation of a medicament for preventing and / or treating pain, cough, multiple sclerosis, Chuck-Mare-Dodds syndrome, incontinence, arrhythmia or alleviating the severity thereof.

16. The use according to claim 15, characterized in that The pain is selected from one or more of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, postoperative pain and visceral pain; and the cough is pathological cough.

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