Pyridone compounds as Nav1.8 inhibitors

Abstract

The invention provides a compound as shown in a formula (II), and a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof. The compound has a relatively good Nav1.8 inhibition effect;

Description

[0001] The present invention claims:

[0002] Priority to the prior application, patent application number 202410338790.8, filed with the State Intellectual Property Office of China on March 22, 2024, entitled “Pyridinone compounds as Nav1.8 inhibitors”;

[0003] Priority to the prior application, patent application number 202410888098.2, filed with the State Intellectual Property Office of China on July 3, 2024, entitled “Pyridinone compounds as Nav1.8 inhibitors”;

[0004] The entire contents of the above-mentioned prior applications are incorporated into the present application by reference. Technical Field

[0005] The present invention belongs to the field of medicine and relates to pyridone compounds as Nav1.8 inhibitors and their uses. Specifically, the present invention relates to substituted pyridone compounds, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, and pharmaceutical compositions thereof as Nav1.8 inhibitors and their use in the preparation of drugs for treating, alleviating or preventing pain. Background Art

[0006] Pain is "an unpleasant sensory and emotional feeling, accompanied by actual or potential tissue damage, and it is a subjective feeling." Pain can serve as a warning signal, alerting the body to potential dangers, and plays an indispensable protective role in the body's normal life activities. At the same time, pain is also a common clinical symptom. After the external stimulus that causes pain disappears, intense or persistent pain can cause physiological dysfunction and seriously affect the quality of life of the living organism. According to statistics, about one-fifth of the world's people suffer from moderate to severe chronic pain. In 2018, the global analgesic market was approximately US$36 billion and is expected to reach US$56 billion in 2023. Among them, acute, moderate and severe pain will grow steadily at a compound annual growth rate of 2.5% in the future, and the chronic pain market will grow at a compound annual growth rate of about 18%. Chronic pain is the main driving force for the continued growth of the global pain market in the next decade.

[0007] Pain originates from nociceptors in the peripheral nervous system. These are free nerve endings that are widely distributed throughout the skin, muscles, joints, and visceral tissues of the body. They can convert perceived thermal, mechanical, or chemical stimuli into nerve impulses (action potentials) and transmit them via afferent nerve fibers to their cell bodies located in the dorsal root ganglia (DRG), ultimately transmitting them to higher nerve centers, causing pain sensation. The generation and conduction of action potentials in neurons, in turn, rely on voltage-gated sodium channels (NaV) on the cell membrane. When the cell membrane depolarizes, sodium channels activate and open, causing an influx of sodium ions, further depolarizing the cell membrane and leading to the generation of action potentials. Therefore, inhibiting abnormal sodium channel activity can help treat and relieve pain.

[0008] Human sodium channels are transmembrane ion channels composed of a 260kD α subunit and a 30-40kD β subunit. They are classified into nine subtypes based on the α subunits: Nav1.1 to Nav1.9. Nav1.5, Nav1.8, and Nav1.9 are tetrodotoxin (TTX)-insensitive sodium channels. Nav1.5 is primarily found in cardiomyocytes, while Nav1.8 and Nav1.9 are found in the peripheral nervous system. Nav1.8 is a key ion channel involved in chronic pain, atrial fibrillation, and Budd-Chiari syndrome, making it a highly selective target for pain treatment.

[0009] The gene encoding Nav1.8, SCN10A, is located in the human chromosome 3p21-22 region and primarily encodes the α subunit. Studies have found that the human and rat Nav1.8 genes share up to 93% homology. Nav1.8 is primarily present in trigeminal ganglion neurons and DRG neurons, exhibiting electrophysiological characteristics of slow inactivation and rapid recovery. In Nav1.8-expressing neurons, the rise of the action potential is primarily composed of Nav1.8 currents. In models of neuropathic pain, nerve injury increases Nav1.8 expression in axons and neuronal cell bodies. Nav1.8 antisense oligonucleotides significantly alleviate pain while simultaneously reducing Nav1.8 expression. Intra-paw injection of carrageenan in rats increases Nav1.8 expression in DRG neurons. Nav1.8 knockout mice fail to exhibit normal visceral inflammatory pain. Gain-of-function mutations in the human Nav1.8 gene cause peripheral neuropathic pain. Based on a series of animal experiments and human genetic evidence, selective inhibition of Nav1.8 has the potential to become a new analgesic therapy that can be used to treat various types of pain, including inflammatory pain, neuralgia, postoperative pain, and cancer pain.

[0010] The main disadvantage of some known Nav's inhibitors is their poor therapeutic window, which may be the result of their lack of isotype selectivity. Since Nav1.8 is mainly limited to neurons that perceive pain, selective Nav1.8 blockers are unlikely to induce adverse reactions common to non-selective Nav's blockers. Therefore, there is still a need to develop new Nav1.8 selective inhibitors in this area, preferably Nav channel inhibitors with better selectivity for Nav1.8, more effectiveness, increased metabolic stability, increased solubility and fewer side effects. Summary of the Invention

[0011] The present invention aims to propose a Nav1.8 inhibitor that can be used to prepare a drug for treating, alleviating or preventing pain, including acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.

[0012] In the first aspect of the present invention, the present invention provides a compound represented by formula (II), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (II):

[0013]

[0014] in,

[0015] Ring B is selected from a 5-6 membered heteroaromatic ring, wherein the heteroatom or heteroatom group in the 5-6 membered heteroaromatic ring is selected from S, S(=O), S(=O)2, P(=O)2, O, N + -O - , N or NH;

[0016] R 0 Selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -NR 3 R 4 、-C(=O)NR 3 R 4 、-C(=NR 5 )NR 3 R 4 、-OR 4 、-S(=O)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ;

[0017] Ring A is selected from C 3-12Cycloalkyl, 4-12 membered heterocycloalkenyl, 3-12 membered heterocyclyl, C 6-12 Aryl and 5-12 membered heteroaryl;

[0018] R 1 Selected from H, halogen, hydroxy, cyano, oxo, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -(C 1-6 alkyl)-C 3-12 Cycloalkyl, -(C 2-6 alkenyl)-C 3-12 Cycloalkyl, -(C 2-6 Alkynyl)-C 3-12 Cycloalkyl, -NR 3 R 4 、-C(=O)NR 3 R 4 、C 3-12 Cycloalkyl, 4-12 membered heterocycloalkenyl, 3-12 membered heterocyclyl, C 6-12 Aryl, 5-12 membered heteroaryl; wherein, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R A replaced by;

[0019] R A Selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-6 Alkyl, =CR 3 R 4 、C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0020] R 2 and R 2’ Each independently selected from H, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl, 5-12 membered heteroaryl; wherein, the C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R B replaced by;

[0021] R B Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0022] Or, R 2 Together with ring A,

[0023]

[0024] Among them, Z 1 and Z 2 Each independently selected from a single bond, -CR 3 R 4 -, -CH=, -NH-, -N=, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2- or -S(=O)(=NH)-;

[0025] Or, R 2’ Together with ring A,

[0026]

[0027] Among them, Y 1 and Y 2 Each independently selected from a single bond, -CR 3 R 4 -, -CH=, -NH-, -N=, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2- or -S(=O)(=NH)-;

[0028] represents a single bond or a double bond;

[0029] R 3 、R 4 and R 5 Each independently selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl, 5-12 membered heteroaryl; wherein, the C1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R C replaced by;

[0030] Or, R 3 、R 4 Together with the atoms to which they are attached, they form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, the C 3-12 Cycloalkyl or 3-12 membered heterocyclic group is optionally substituted by one or more R C replaced by;

[0031] R C Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0032] n is selected from 0, 1, 2, 3, 4, 5 and 6;

[0033] m is selected from the group consisting of 0, 1, 2, 3, 4, 5 and 6.

[0034] In an optional embodiment of the present invention, the compound represented by formula (II), its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, is a compound represented by formula (I):

[0035]

[0036] in,

[0037] X 3a N or CR 3a ;

[0038] X 4a N or CR 4a ;

[0039] X 5a N or CR 5a ;

[0040] X 6a N, N + -O - or CR 6a ;

[0041] R 3a 、R 4a 、R 5a 、R 6aEach independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -NR 3 R 4 、-C(=O)NR 3 R 4 、-C(=NR 5 )NR 3 R 4 、-OR 4 、-S(=O)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ; Among them, R 3 、R 4 、R 5 As defined above;

[0042] In some embodiments, R 3a 、R 4a 、R 5a 、R 6a Each is independently selected from the following structures:

[0043] In some embodiments, R 6a Selected from C 1-6 Alkoxy and -S(=O)(=NH)-(C 1-6 Alkyl), the C 1-6 The alkoxy group is substituted with 1, 2, 3, 4, 5 or 6 hydroxy groups.

[0044] In some embodiments, X 3a and X 5a CH, X 5a Selected from N and CF.

[0045] In some embodiments, R 3a 、R 4a 、R 5a 、R 6a Each is independently selected from the following structures:

[0046] In some embodiments, R 3a 、R 4a 、R 5a are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C1-6 Alkoxy or C 1-6 haloalkoxy;

[0047] R 6a H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -NR 3 R 4 、-C(=O)NR 3 R 4 、-C(=NR 5 )NR 3 R 4 、-OR 4 、-S(=O)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ;

[0048] Ring A is selected from C 3-12 Cycloalkyl, 4-12 membered heterocycloalkenyl, 3-12 membered heterocyclyl, C 6-12 Aryl and 5-12 membered heteroaryl;

[0049] R 1 Selected from H, halogen, hydroxy, cyano, oxo, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -(C 1-6 alkyl)-C 3-12 Cycloalkyl, -(C 2-6 alkenyl)-C 3-12 Cycloalkyl, -(C 2-6 Alkynyl)-C 3-12 Cycloalkyl, -NR 3 R 4 、-C(=O)NR 3 R 4 、C 3-12 Cycloalkyl, 4-12 membered heterocycloalkenyl, 3-12 membered heterocyclyl, C 6-12 Aryl, 5-12 membered heteroaryl; wherein, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R A replaced by;

[0050] R A Selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-6 Alkyl, =CR 3 R 4 、C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0051] R 2 and R 2’ Each independently selected from H, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl, 5-12 membered heteroaryl; wherein, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R B replaced by;

[0052] R B Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0053] Or, R 2 Together with ring A,

[0054]

[0055] Among them, Z 1 and Z 2 Each independently selected from a single bond, -CR 3 R 4 -, -CH=, -NH-, -N=, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2- or -S(=O)(=NH)-;

[0056] Or, R 2’ Together with ring A,

[0057]

[0058] Among them, Y 1 and Y 2 Each independently selected from a single bond, -CR 3 R 4 -, -CH=, -NH-, -N=, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2- or -S(=O)(=NH)-;

[0059] Indicates a single bond or a double bond;

[0060] R 3 、R 4 and R 5 Each independently selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl, 5-12 membered heteroaryl; wherein, the C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R C replaced by;

[0061] Or, R 3 、R 4 Together with the atoms to which they are attached, they form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, the C 3-12 Cycloalkyl or 3-12 membered heterocyclic group is optionally substituted by one or more R C replaced by;

[0062] R C Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0063] n is selected from 0, 1, 2, 3, 4, 5 and 6.

[0064] In an optional embodiment of the present invention, R 2 For H.

[0065] In an optional embodiment of the present invention, R 2’ H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0066] In an optional embodiment of the present invention, R 2’ is H, methyl, difluoromethyl, or trifluoromethyl.

[0067] In an optional embodiment of the present invention, the group fragment Selected from Among them, X 3a N or CR 3a ;X 4a N or CR 4a ;X 5a N or CR 5a ;X 6a N, N + -O - or CR 6a ;

[0068] R 3a 、R 4a 、R 5a 、R 6a Each independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -NR 3 R 4 、-C(=O)NR 3 R 4 、-C(=NR 5 )NR 3 R 4 、-OR 4 、-S(=O)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ; Among them, R 3 、R 4 、R 5 As defined above;

[0069] In some embodiments, R 6a Selected from C 1-6 Alkoxy and -S(=O)(=NH)-(C 1-6 Alkyl), the C 1-6 The alkoxy group is substituted with 1, 2, 3, 4, 5 or 6 hydroxy groups.

[0070] In some embodiments, X 3a and X 5a CH, X 5a Selected from N and CF.

[0071] In some embodiments, R 3a 、R 4a 、R 5a 、R 6a Each is independently selected from the following structures:

[0072] In some embodiments, R 3a 、R 4a 、R 5a 、R 6a Each is independently selected from the following structures:

[0073] In some embodiments, R 3a 、R 4a 、R 5a are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; R 6a H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -NR 3 R 4 、-C(=O)NR 3 R 4 、-C(=NR 5 )NR 3 R 4 、-OR 4 、-S(=O)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ; W is selected from S, S(=O), S(=O)2, P(=O)2, O or NH.

[0074] In an optional embodiment of the present invention, the group fragment Selected from Among them, R 4a 、R 5a are each independently selected from H, halogen, C 1-6 Alkyl, R 6a -OCH2CH(OH)CH2OH, -C(=O)NHR 3 、-C(=NH)NHR 3 、-S(=O)2R 3 、-S(=O)2NHR 3or -S(=O)(=NH)R 3 , R 3 H, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one or more R C Replaced by R C The definition of is as described in the present invention.

[0075] In an optional embodiment of the present invention, the group fragment Selected from

[0076]

[0077] In an optional embodiment of the present invention, the group fragment Selected from Among them, R 6a is -OCH2CH(OH)CH2OH, -OCH2CH2OH, -C(=O)NHR 3 、-C(=NH)NHR 3 、-S(=O)2R 3 、-S(=O)2NHR 3 or -S(=O)(=NH)R 3 , R 3 H, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one or more R C Replaced by R C The definition of is as described in the present invention.

[0078] In an optional embodiment of the present invention, the group fragment Selected from

[0079]

[0080] In an optional embodiment of the present invention, ring A is a 6-membered heterocycloalkenyl, a 6-membered heterocyclyl, a 6-membered heteroaryl, a 5-membered heteroaryl or a phenyl group; preferably, ring A is a pyridyl, a 1,2-dihydropyridyl, a phenyl or a thienyl group.

[0081] In an optional embodiment of the present invention, R 1 H, halogen, oxo, C 1-6 Alkyl, C 2-6 Alkynyl, C1-6 Alkoxy, C 3-12 Cycloalkyl, -(C 2-6 Alkynyl)-C 3-12 Cycloalkyl; wherein said C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl and -(C 2-6 Alkynyl)-C 3-12 The cycloalkyl groups are each independently optionally substituted with one or more R A Replaced by; R A Selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, =CR 3 R 4 ; R 3 and R 4 The definition of is as described in the present invention. In an optional embodiment of the present invention, R 1 H, halogen, oxo, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl; wherein said C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy and C 3-12 The cycloalkyl groups are each independently optionally substituted with one or more R A Replaced by; R A Selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy.

[0082] In an optional embodiment of the present invention, the group fragment for where R 2b 、R 3b 、R 4b and R 5b are each independently selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl; wherein said C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy and C 3-12 The cycloalkyl groups are each independently optionally substituted with one or more RA Replaced by; R A Selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy.

[0083] In an optional embodiment of the present invention, the group fragment for where R 2b 、R 3b 、R 4b and R 5b Each independently selected from H, Cl, methyl, tert-butyl or

[0084] In an optional embodiment of the present invention, the group fragment for

[0085] In an optional embodiment of the present invention, the group fragment for where R 3b and R 5b Each independently selected from

[0086] In an optional embodiment of the present invention, the group fragment for

[0087]

[0088] In an optional embodiment of the present invention, the group fragment for where R 1b 、R 2b 、R 3b 、R 4b and R 5b are each independently selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 4-7 Cycloalkyl, 4-7 membered heterocyclic group, -(C 2-6 Alkynyl)-C 3-12 Cycloalkyl; the C 1-6 Alkyl, C 2-6 Alkynyl, C 4-7 Cycloalkyl, 4-7 membered heterocyclic group, -(C 2-6 Alkynyl)-C 3-12 The cycloalkyl groups are each independently optionally substituted with one or more R A Replaced by; R ASelected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, =CR 3 R 4 ; R 3 and R 4 The definition of is as described in the present invention.

[0089] In an optional embodiment of the present invention, the group fragment for where R 1b 、R 2b 、R 3b 、R 4b and R 5b are each independently selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 4-7 Cycloalkyl, 4-7 membered heterocyclic group; the C 1-6 Alkyl, C 2-6 Alkynyl, C 4-7 Cycloalkyl, 4-7 membered heterocyclic group are each independently optionally substituted by one or more R A Replaced by; R A Selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy.

[0090] In an optional embodiment of the present invention, the group fragment for where R 1b 、R 2b 、R 3b 、R 4b and R 5b Each independently selected from H, F, Cl, methyl, difluoromethyl, trifluoromethyl, tert-butyl,

[0091] In an optional embodiment of the present invention, the group fragment for where R 1b 、R 2b 、R 3b 、R 4b and R 5b Each independently selected from H, F, Cl, methyl, difluoromethyl, trifluoromethyl, tert-butyl,

[0092] In an optional embodiment of the present invention, the group fragment for

[0093]

[0094] In an optional embodiment of the present invention, the group fragment for

[0095]

[0096] In an optional embodiment of the present invention, the group fragment for

[0097] In an optional embodiment of the present invention, the compound represented by formula (II), its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, is a compound represented by formula (I) or formula (II-A):

[0098]

[0099] in,

[0100] X 3a N or CR 3a ;

[0101] X 4a N or CR 4a ;

[0102] X 5a N or CR 5a ;

[0103] X 6a N, N + -O - or CR 6a ;

[0104] R 3a 、R 4a 、R 5a are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0105] R 6a H, halogen, hydroxyl, C 1-6 Alkyl, C1-6 Alkoxy, -NR 3 R 4 、-C(=O)NR 3 R 4 、-C(=NR 5 )NR 3 R 4 、-OR 4 、-S(=O)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ;

[0106] W is selected from S, S(=O), S(=O)2, P(=O)2, O or NH;

[0107] Ring A, R 1 、R 2 、R 2’ 、R 3 、R 4 、R 5 and n are as defined in the present invention.

[0108] In an optional embodiment of the present invention, the compound represented by formula (II), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is a compound represented by formula (IA), formula (IB) or formula (IC):

[0109]

[0110] in,

[0111] X 3a N or CR 3a ;

[0112] X 4a N or CR 4a ;

[0113] X 5a N or CR 5a ;

[0114] X 6a N, N + -O - or CR 6a ;

[0115] R 3a 、R 4a 、R 5a are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C1-6 Alkoxy or C 1-6 haloalkoxy;

[0116] R 6a H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -NR 3 R 4 、-C(=O)NR 3 R 4 、-C(=NR 5 )NR 3 R 4 、-OR 4 、-S(=O)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ;

[0117] Among them, ring A, R 1 、R 3 、R 4 、R 5 、R C and n are as defined in the present invention;

[0118] Ring B is C 3-6 Cycloalkyl; p is selected from 1, 2, 3, 4, 5 and 6.

[0119] In an optional embodiment of the present invention, the compound represented by formula (I), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is a compound represented by formula (IA), formula (IB) or formula (IC):

[0120]

[0121]

[0122] Among them, X 3a 、X 4a 、X 5a 、X 6a , Ring A, R 1 、R C and n are as defined in the present invention;

[0123] Ring B is C 3-6 Cycloalkyl; p is selected from 1, 2, 3, 4, 5 and 6.

[0124] In an optional embodiment of the present invention, the compound has any one of the following structures, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of any one of the structures:

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131] In an optional embodiment of the present invention, the compound has any one of the following structures, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of any one of the structures:

[0132]

[0133]

[0134]

[0135]

[0136] In the second aspect of the present invention, a pharmaceutical composition is provided, which comprises a therapeutically effective amount of the above-mentioned compound, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs and a pharmaceutically acceptable pharmaceutical carrier, diluent or excipient.

[0137] In the third aspect of the present invention, the present invention proposes the use of the above-mentioned compound, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs or the above-mentioned pharmaceutical composition in the preparation of drugs related to inhibiting voltage-gated sodium ion channels, wherein the voltage-gated sodium ion channels include Nav1.1 to Nav1.9, for example, Nav1.5, Nav1.8 and Nav1.9, preferably Nav1.8.

[0138] According to a specific embodiment of the present invention, the use of the above-mentioned compound or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above-mentioned pharmaceutical composition in the preparation of a drug, the drug can be used to treat, relieve or prevent pain, and the pain includes acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.

[0139] In a fourth aspect, the present invention provides a method for inhibiting voltage-gated sodium ion channels, or preventing and / or treating diseases related to voltage-gated sodium ion channels, comprising the steps of administering to a subject in need thereof the compound of formula I described in the first aspect of the present invention, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition described in the second aspect of the present invention.

[0140] The voltage-gated sodium ion channels include Nav1.1 to Nav1.9, for example, Nav1.5, Nav1.8 and Nav1.9, preferably Nav1.8. The diseases associated with the voltage-gated sodium ion channels are pain, including acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.

[0141] Beneficial effects:

[0142] According to the embodiments of the present invention, the present invention has at least one of the following technical effects:

[0143] Provided are Nav1.8 inhibitors with novel structure, excellent pharmacokinetic properties, and good efficacy or drugability, which can be used to effectively treat Nav1.8-related diseases and conditions.

[0144] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention.

[0145] Terms and Definitions

[0146] Unless otherwise specified, the terms and definitions used in this application, including the specification and claims, are as follows.

[0147] Those skilled in the art will understand that, according to the conventions used in the art, in the structural formula of this application, Used to depict chemical bonds, which are the points where a moiety or substituent is attached to a core or backbone structure.

[0148] Unless otherwise specified, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0149] Unless otherwise specified, the term "pharmaceutically acceptable salts" refers to salts of pharmaceutically acceptable non-toxic acids or bases including salts of inorganic acids and bases, and organic acids and bases.

[0150] In addition to pharmaceutically acceptable salts, the present invention also contemplates other salts that may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or that may be useful in the identification, characterization, or purification of the compounds of the present invention.

[0151] Unless otherwise specified, the term "pharmaceutical composition" means a mixture of one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism.

[0152] Unless otherwise specified, the term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients enhance the handling properties of pharmaceutical formulations, i.e., by increasing flowability and / or cohesiveness, making the formulation more suitable for direct compression.

[0153] Unless otherwise specified, the term "prodrug" refers to a compound of the present invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the present invention are prepared by modifying functional groups within the compound. These modifications can be removed by conventional procedures or in vivo to yield the parent compound. Prodrugs include compounds in which a hydroxyl or amino group within a compound of the present invention is attached to any group. When a prodrug of a compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group or free amino group, respectively.

[0154] Unless otherwise specified, the term "stereoisomer" refers to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0155] Depending on the choice of raw materials and methods, the compounds of the present invention may exist in the form of one of the possible isomers or a mixture thereof, for example as pure optical isomers, or as a mixture of isomers, such as a racemic and diastereomeric mixture, depending on the number of asymmetric carbon atoms. When describing an optically active compound, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are the symbols used to specify the rotation of plane polarized light caused by the compound, where (–) or L indicates that the compound is left-handed. Compounds prefixed with (+) or D are right-handed. With respect to a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of the isomers are often referred to as mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. Many geometric isomers of alkenes, C=N double bonds, etc. can also exist in the compounds described herein, and all such stable isomers are contemplated by the present invention. When the compounds described herein contain olefinic double bonds, unless otherwise specified, such double bonds include both E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in either the cis- or trans- configuration.

[0156] When the bonds to chiral carbon atoms in the present formulae are depicted as straight lines, it is understood that both the (R) and (S) configurations of the chiral carbon atoms and the enantiomerically pure compounds and mixtures thereof are encompassed within the scope of the formulae. The diagrammatic representations of racemates and enantiomerically pure compounds herein are adapted from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, wedge-shaped bonds and dashed bonds are used to represent the absolute configuration of a stereocenter.

[0157] Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. Compounds of the invention containing asymmetrically substituted carbon atoms can be separated in optically active form or racemic form. Resolution of a racemic mixture of a compound can be carried out by any of a number of methods known in the art. An exemplary method includes fractional recrystallization using a chiral resolving acid that is an optically active, salified organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids such as the D and L forms of β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include α-methyl-benzylamine (e.g., S and R forms or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. The resolution of the racemic mixture can also be carried out by eluting on a chromatographic column filled with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). High performance liquid chromatography (HPLC) can also be used to carry out supercritical fluid chromatography (SFC). The selection of specific methods and elution conditions, chromatographic column selection can be selected by those skilled in the art according to the structure of the compound and test results. Further, optically pure starting materials or reagents of known configuration can also be used to obtain any enantiomer or diastereomer of the compound described in the present invention through stereoorganic synthesis.

[0158] Unless otherwise specified, the term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist as two or more interconvertible species. Prototropic tautomers arise from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually produce a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0159] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicates the relative configuration of a stereocenter.

[0160] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture with physical and chemical properties consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0161] In embodiments of the present invention, protons can occupy two or more positions of the cyclic form of the heterocyclic ring system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, tetrazole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically fixed to one form by appropriate substitution. For example:

[0162]

[0163] Due to resonance, the hydrogen atoms of the tetrazole nitrogen can be on any of the four nitrogen atoms.

[0164] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0165] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For the oral dosage forms of the present invention, an "effective amount" of an active substance in the composition means the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, 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 experimentation.

[0166] Unless otherwise specified, the terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

[0167] Unless otherwise specified, the term "substituted" means that any one or more (two, three or more) hydrogen atoms on a particular atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is a keto group (i.e., =O), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups. When the substituent is limited to one or more, the plurality includes two, three or more.

[0168] Unless otherwise specified, the terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0169] The term "optionally substituted" means that the group may be substituted or not substituted, and unless otherwise specified, the type and number of the substituents may be any based on chemical feasibility.

[0170] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. For example, R 1 Be g R a When g is 2, 3 or 4, each R a Are independent options and can be the same or different.

[0171] In addition, combinations of substituents and / or their variants are permitted only if such combinations result in stable compounds. In addition, when multiple rings (parallel rings, spiro rings, or bridged rings) are substituted with substituents, each hydrogen atom on the ring may be substituted.

[0172] Unless otherwise specified, the term “C 1-6 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl groups include C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4, C6 and C5 alkyl, etc.; which can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Examples of C1-6 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.

[0173] Unless otherwise specified, the term “C 1-3 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0174] The term "halo" by itself or as part of another substituent is used interchangeably with the term "halogen-substituted."

[0175] Unless otherwise specified, "haloalkyl" or "halo-substituted alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogens.

[0176] Unless otherwise specified, “C 2-6 "Alkenyl" is used to refer to a linear or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-6 Alkenyl groups include C 2-4 、C 2-3 , C4, C3 and C2 alkenyl, etc.; which may be monovalent, divalent or polyvalent. 2-6 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperyl, hexadienyl, and the like.

[0177] Unless otherwise specified, “C 2-3 "Alkenyl" is used to refer to a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-3 Alkenyl includes C3 and C2 alkenyl; the C 2-3 Alkenyl groups can be monovalent, divalent, or polyvalent. 2-3 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, and the like.

[0178] Unless otherwise specified, “C 2-6"Alkynyl" is used to represent a linear or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. 2-6 Alkynyl groups include C 2-4 、C 2-3 , C4, C3 and C2 alkynyl, etc. It can be monovalent, divalent or polyvalent. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.

[0179] Unless otherwise specified, “C 2-3 "Alkynyl" is used to represent a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. It may be monovalent, divalent or polyvalent. The C 2-3 Alkynyl groups include C3 and C2 alkynyl groups. 2-3 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like.

[0180] For the avoidance of doubt, the alkyl, alkenyl, and alkynyl groups as described herein may also serve as linking groups (i.e., groups that link two or more moieties of a compound as described), in which case the alkyl, alkenyl, and alkynyl groups may be monovalent, divalent, or multivalent, and such groups may be referred to as "alkylene," "alkylene," "alkenylene," "alkenylene," "alkynylene," and / or "alkynylene," respectively.

[0181] Unless otherwise specified, the term “C 1-6 "Alkoxy" refers to an alkyl group containing 1 to 6 carbon atoms which is attached to the rest of the molecule via an oxygen atom. 1-6 Alkoxy groups include C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6, C5, C4 and C3 alkoxy, etc. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexyloxy, and the like.

[0182] Unless otherwise specified, the term “C 1-3 "Alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 、C 2-3 , C3 and C2 alkoxy, etc. 1-3Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0183] Unless otherwise specified, the term “C 3-12 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 12 carbon atoms, including monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, fused and bridged rings. 3-12 Cycloalkyl groups include C 3-10 、C 3-8 、C 3-6 、C 3-5 、C 4-8 、C 4-6 、C 4-5 、C 5-8 or C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, and the like.

[0184] Unless otherwise specified, the term “C 3-8 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 8 carbon atoms, including monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, fused and bridged rings. 3-8 Cycloalkyl groups include C 3-6 、C 3-5 、C 4-8 、C 4-6 、C 4-5 、C 5-8 or C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, and the like.

[0185] Unless otherwise specified, the term “C 3-6 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic or bicyclic ring system. 3-6 Cycloalkyl groups include C 3-5 、C 4-5 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0186] Unless otherwise specified, the term "C 6-12 Aromatic ring" and "C 6-12 Aryl" can be used interchangeably, the term "C6-12 Aromatic ring" or "C 6-12 "Aryl" refers to a cyclic hydrocarbon group composed of 6 to 12 carbon atoms with a conjugated π electron system, which can be a monocyclic, fused bicyclic or fused tricyclic ring system, wherein at least one ring is aromatic and the other rings are any rings, which can be cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl. It can be monovalent, divalent or polyvalent, C 6-12 Aryl groups include C 6-10 、C 6-9 、C 6-8 、C 12 、C 10 and C6 aryl, etc. 6-12 Examples of aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc.). Unless otherwise specified, the term "4-12 membered heterocycloalkenyl" refers to a stable non-aromatic ring structure (monocyclic or polycyclic) containing at least one double bond and one or more heteroatoms independently selected from O, N, and S and specifying the number of ring atoms. The non-aromatic ring structure can have 4 to 12 ring members, and particularly 4 to 7 ring members. The fused heterocyclic ring system can contain carbocycles and need only contain one heterocycle.

[0187] Unless otherwise specified, Cn-n+m or Cn-Cn+m includes any one of n to n+m carbons, e.g., C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 , and C 12 , also includes any range from n to n+m, such as C 1-12 Including C 1-3 、C 1-6 、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C 6-12 , and C 9-12 Similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range from n to n+m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-7-membered ring, a 6-8-membered ring, and a 6-10-membered ring, etc.

[0188] Unless otherwise specified, the term "3-12 membered heterocyclyl" or "3-12 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 12 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, cyclic and bridged rings. In addition, with respect to the "3-12 membered heterocycloalkyl", heteroatoms can occupy the position at which the heterocycloalkyl is connected to the rest of the molecule. For example, 3-12 membered heterocycloalkyl includes, but is not limited to, 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered, 3-10-membered, 3-8-membered, 4-6-membered, etc. Examples of “3-12 membered heterocycloalkyl” include, but are not limited to, oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, and hexahydropyridazinyl.

[0189] Unless otherwise specified, the term "4-8 membered heterocycloalkyl" or "4-8 membered heterocyclyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 4 to 8 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, cyclic and bridged rings. In addition, with respect to the "6-8 membered heterocycloalkyl", heteroatoms can occupy the position at which the heterocycloalkyl is connected to the rest of the molecule. For example, 4-8 membered heterocycloalkyl includes but is not limited to 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 4-6-membered, etc. For example, 4-7 membered heterocyclyl includes but is not limited to 4-membered, 5-membered, 6-membered, 7-membered, 4-6-membered, etc. Examples of 4-8 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, and hexahydropyridazinyl.

[0190] Unless otherwise specified, the terms "5-12 membered heteroaromatic ring" and "5-12 membered heteroaryl" are used interchangeably herein, and the term "5-12 membered heteroaryl" refers to a cyclic group consisting of 5 to 12 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms independently selected from O, S and N, and the remainder are carbon atoms. It can be a monocyclic, fused bicyclic or fused tricyclic ring system, wherein each ring is aromatic. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p, where p is 1 or 2). The 5-12 membered heteroaryl can be attached to the rest of the molecule via a heteroatom or carbon atom. The 5-12 membered heteroaryl includes 5-10 membered, 5-8 membered, 5-7 membered, 5-6 membered, 5 membered and 6 membered heteroaryl groups, etc. Examples of the 5-12 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl), thiazolyl (including 2-thiazolyl, 4-thiazolyl) 1-oxazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-1-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indolyl (including 5-indolyl, etc.), isoquinolyl (including 1-isoquinolyl and 5-isoquinolyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.) or quinolyl (including 3-quinolyl and 6-quinolyl, etc.).

[0191] Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" are used interchangeably herein, and the term "5-6 membered heteroaryl" refers to a monocyclic group consisting of 5 to 6 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S, P and N, and the remainder are carbon atoms. Wherein the nitrogen atom is optionally quaternized, and the nitrogen, phosphorus and sulfur heteroatoms are optionally oxidized (i.e., NO, P(O)p, and S(O)p, p is 1 or 2). The 5-6 membered heteroaryl can be attached to the rest of the molecule via a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl), and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0192] Unless otherwise specified, the term "5,6-membered ring" refers to a 5-membered ring and a 6-membered ring.

[0193] Unless otherwise specified, the term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.

[0194] Additionally, it should be noted that, unless otherwise expressly stated, the term "independently" used in the present invention should be broadly construed to mean that the individual entities described are independent of one another and may independently represent the same or different specific groups. More specifically, the term "independently" can mean that specific options expressed by identical symbols in different groups do not affect each other, or that specific options expressed by identical symbols in the same group do not affect each other.

[0195] Unless otherwise specified, the term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0196] Unless otherwise specified, the term "therapeutically effective amount" means the amount of an active compound or drug that will elicit the biological or medical response that a researcher, veterinarian, physician, or other clinician is seeking in a tissue, system, animal, individual, or human, and includes one or more of the following: (1) prevent disease, e.g., prevent a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who is not yet experiencing or developing the pathology or symptoms of the disease. (2) inhibit disease, e.g., inhibit the disease, disorder, or condition (i.e., prevent further development of the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. (3) alleviate disease, e.g., alleviate the disease, disorder, or condition (i.e., reverse the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition.

[0197] As used herein, the term "treatment" and other similar synonyms include the following meanings:

[0198] (i) preventing a disease or condition from occurring in a mammal, particularly where such mammal is susceptible to the disease or condition but has not yet been diagnosed as having the disease or condition;

[0199] (ii) inhibiting the disease or condition, i.e., curbing its development;

[0200] (iii) alleviate the disease or condition, that is, cause regression of the disease or condition; or

[0201] (iv) Alleviate the symptoms of the disease or condition.

[0202] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0203] Additionally, it should be noted that, unless otherwise expressly stated, the term "independently" used in the present invention should be broadly construed to mean that the individual entities described are independent of one another and may independently represent the same or different specific groups. More specifically, the term "independently" can mean that specific options expressed by identical symbols in different groups do not affect each other, or that specific options expressed by identical symbols in the same group do not affect each other. DETAILED DESCRIPTION

[0204] Below, the scheme of the present invention will be explained in conjunction with embodiment.It will be understood by those skilled in the art that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.In the embodiment, if specific technology or conditions are not indicated, the technology or conditions described in the literature in this area or the product instructions are used.The reagents or instruments used are not indicated by the manufacturer, and are all conventional products that can be obtained by commercial purchase.

[0205] Unless otherwise specified, the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The unit of NMR shift is 10 -6 The solvents for NMR measurements include deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (MeOD), heavy water (D2O), etc., and tetramethylsilane (TMS) is the internal standard.

[0206] The abbreviations of the present invention are defined as follows:

[0207] PE: Petroleum Ether

[0208] EA: Ethyl Acetate

[0209] brine: saturated salt water (brine)

[0210] DMF: Dimethylformamide

[0211] NBS: N-Bromosuccinimide

[0212] BPO: Benzoyl Peroxide

[0213] NMO: N-Methoxyphthalimide

[0214] THF: Tetrahydrofuran

[0215] DCM: Dichloromethane

[0216] Dioxane:1,4-Dioxane

[0217] Xantphos: 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline

[0218] TLC: Thin layer chromatography

[0219] LC-MS: Liquid chromatography-mass spectrometry

[0220] M: molar concentration, for example, 1M hydrochloric acid means that there is 1 mol of HCl per liter of solution

[0221] N: equivalent concentration, for example, 2N hydrochloric acid means 2 mol / L hydrochloric acid solution

[0222] IC 50 : Half-maximal inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved

[0223] Example 1: Preparation of target compounds I-1A & I-1B

[0224] Synthesis of (R)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-(2,3-dihydroxypropoxy)-1,6-naphthyridin-4(1H)-one (I-1A)

[0225] Synthesis of (S)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-(2,3-dihydroxypropoxy)-1,6-naphthyridin-4(1H)-one (I-1B)

[0226]

[0227] The synthetic routes of target compounds I-1A & I-1B are as follows:

[0228]

[0229] Step 1: Synthesis of 4-(benzyloxy)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-1,6-naphthyridine 6-oxide

[0230]

[0231] At room temperature, 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.78 g, 5.75 mmol) and 4-(benzyloxy)-2-chloro-1,6-naphthyridine 6-oxide (1.50 g, 5.23 mmol) were dissolved in 1,4-dioxane (15 mL). Potassium phosphate (3.33 g, 15.7 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (408 mg, 523 μmol) were added. The atmosphere was replaced with nitrogen three times, and the temperature was raised to 80°C and stirred for 1 hour. After the reaction, the reaction solution was cooled to room temperature and slowly poured into water (30 mL), and then extracted with ethyl acetate (30 mL*3). The organic phase was washed with saturated sodium chloride solution (50 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was separated by column chromatography (petroleum ether: ethyl acetate 10:1 / 3:1) to obtain 4-(benzyloxy)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-1,6-naphthyridine 6-oxide (1.65 g, 72.7% yield).

[0232] LC-MS, M / Z(ESI):433.1[M+H] +

[0233] Step 2: Synthesis of 4-(benzyloxy)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-chloro-1,6-naphthyridine

[0234]

[0235] 4-(Benzyloxy)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-1,6-naphthyridine 6-oxide (1.50 g, 3.46 mmol) was dissolved in 1,2-dichloroethane (15 mL), and phosphorus oxychloride (1.33 g, 8.66 mmol) was added. The reaction mixture was stirred at 70°C for 2 hours. After completion of the reaction, the reaction mixture was added to saturated sodium bicarbonate solution (30 mL) and extracted with dichloromethane (10 mL x 3). The organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 50:1 / 10:1) to obtain 4-(benzyloxy)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-chloro-1,6-naphthyridine (0.620 g, 39.6% yield).

[0236] LC-MS, M / Z(ESI):451.1[M+H] +

[0237] Step 3: Synthesis of (R)-4-(benzyloxy)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-1,6-naphthyridine

[0238]

[0239] 4-(Benzyloxy)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-chloro-1,6-naphthyridine (200 mg, 443 μmol) and (R)-(-)-2,2-dimethyl-1,3-dioxolane-4-methanol (58.6 mg, 443 μmol) were dissolved in tetrahydrofuran (4 mL). The reaction solution was cooled to 0°C and then a 1 M solution of potassium tert-butoxide in tetrahydrofuran (0.53 mL, 532 μmol) was added. After nitrogen was replaced three times, the reaction solution was stirred at 25°C for 2 hours. After the reaction, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 mL*3). The organic phase was washed with saturated sodium chloride solution (5 mL) and dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 10:1) to give (R)-4-(benzyloxy)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-1,6-naphthyridine (140 mg, 57.7% yield).

[0240] LC-MS, M / Z(ESI):547.3[M+H] +

[0241] Step 4: Synthesis of (R)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-1,6-naphthyridin-4(1H)-one

[0242]

[0243] (R)-4-(Benzyloxy)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-1,6-naphthyridine (100 mg, 183 μmol) was dissolved in methanol (2 mL) and ethyl acetate (2 mL). Under argon, 10% wet palladium on carbon (10 mg) was added, and the hydrogen atmosphere was replaced three times. The reaction solution was stirred at 25°C for 0.5 hour. After completion of the reaction, the mixture was filtered and concentrated to give the crude product (R)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-1,6-naphthyridine-4(1H)-one (80.0 mg, crude).

[0244] LC-MS, M / Z(ESI):457.2[M+H] +

[0245] Step 5: Synthesis of (R)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-(2,3-dihydroxypropoxy)-1,6-naphthyridin-4(1H)-one (I-1A)

[0246]

[0247] (R)-2-(4-(tert-Butyl)-5-chloro-2-methylphenyl)-5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-1,6-naphthyridin-4(1H)-one (80.0 mg, 175 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (40.0 mg, 350 μmol) was added. The reaction solution was stirred at 25°C for 0.5 hours. After the reaction, the reaction mixture was concentrated to obtain a crude product, which was then purified by reverse phase chromatography (column: Phenomenex luna C18 150*25mm*10um; mobile phase: solvent A = water + 0.225% formic acid, B = acetonitrile; gradient: 32%-62%, 15 min) to obtain (R)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-(2,3-dihydroxypropoxy)-1,6-naphthyridin-4(1H)-one (I-1A) (41.9 mg, 57.3% yield).

[0248] LC-MS, M / Z(ESI):417.2[M+H] +

[0249] 1 H NMR (400MHz, DMSO-d6) δ11.85(s,1H),8.09(d,J=5.6Hz,1H),7.47(s,2H),7.02(d,J=6.0Hz,1H),6.07(s,1H),4.82-5.10(m,2H),4 .43(dd,J=10.8,5.2Hz,1H),4.21(dd,J=10.4,6.4Hz,1H),3.85(quin,J=6.0Hz,1H),3.46-3.64(m,2H),2.29(s,3H),1.47(s,9H).

[0250] Step 6: Synthesis of (S)-4-(benzyloxy)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-1,6-naphthyridine

[0251]

[0252] 4-(Benzyloxy)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-chloro-1,6-naphthyridine (200 mg, 443 μmol) and (S)-(+)-glycerol acetonide (58.6 mg, 443 μmol) were dissolved in tetrahydrofuran (4 mL). The reaction solution was cooled to 0°C and then a 1 M solution of potassium tert-butoxide in tetrahydrofuran (0.53 mL, 532 μmol) was added. After nitrogen was replaced three times, the reaction solution was stirred at 25°C for 2 hours. After the reaction, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 mL*3). The organic phase was washed with saturated sodium chloride solution (5 mL) and dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 100:1 / 10:1) to give (S)-4-(benzyloxy)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-1,6-naphthyridine (120 mg, 49.5% yield).

[0253] LC-MS, M / Z (ESI): 547.3 (M+H + )

[0254] Step 7: Synthesis of (S)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-1,6-naphthyridin-4(1H)-one

[0255]

[0256] (S)-4-(Benzyloxy)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-1,6-naphthyridine (110 mg, 201 μmol) was dissolved in methanol (2 mL) and ethyl acetate (2 mL). Under argon, 10% wet palladium on carbon (11.0 mg) was added. The hydrogen atmosphere was replaced three times, and the reaction mixture was stirred at 25°C for 0.5 h. After completion of the reaction, the mixture was filtered and concentrated to afford the crude product (S)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-1,6-naphthyridine-4(1H)-one (80.0 mg, crude).

[0257] LC-MS, M / Z (ESI): 457.2 (M+H + )

[0258] Step 8: Synthesis of (S)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-(2,3-dihydroxypropoxy)-1,6-naphthyridin-4(1H)-one (I-1B)

[0259]

[0260] (S)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-1,6-naphthyridin-4(1H)-one (80.0 mg, 175 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (40.0 mg, 350 μmol) was added. The reaction solution was stirred at 25 degrees for 0.5 hours. After the reaction, the reaction mixture was concentrated to obtain a crude product, which was then purified by reverse phase chromatography (column: Phenomenex luna C18 150*25mm*10um; mobile phase: solvent A = water + 0.225% formic acid, B = acetonitrile; gradient: 32%-62%, 15 min) to obtain (S)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-(2,3-dihydroxypropoxy)-1,6-naphthyridin-4(1H)-one (39.2 mg, 53.6% yield).

[0261] LC-MS, M / Z (ESI): 417.2 (M+H + )

[0262] 1 H NMR (400MHz, DMSO) δ11.85(s,1H),8.09(d,J=5.6Hz,1H),7.47(s,2H),7.02(d,J=6.0Hz,1H),6.07(s,1H),4.82-5.10(m,2H),4. 42(dd,J=10.8,5.2Hz,1H),4.21(dd,J=10.4,6.4Hz,1H),3.85(quin,J=6.0Hz,1H),3.49-3.64(m,2H),2.29(s,3H)1.47(s,9H).

[0263] Example 2: Preparation of target compound I-2

[0264] Synthesis of 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-(S-methylsulfonylimino)-1,6-naphthyridin-4(1H)-one (I-2)

[0265]

[0266] The synthetic route of target compound I-2 is as follows:

[0267]

[0268] Step 1: Synthesis of 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-chloro-1,6-naphthyridin-4(1H)-one

[0269]

[0270] Under nitrogen, 4-(benzyloxy)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-chloro-1,6-naphthyridine (180 mg, 0.40 mmol) was dissolved in dichloromethane (2 mL). The reaction mixture was cooled to 0°C, and a 1M solution of boron trichloride in dichloromethane (0.40 mL, 0.40 mmol) was added dropwise. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was slowly poured into saturated sodium bicarbonate solution (2 mL) and extracted with dichloromethane (2 mL x 3). The organic phase was washed with saturated sodium chloride solution (2 mL), dried over anhydrous sodium sulfate, and filtered and concentrated to yield the crude product 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-chloro-1,6-naphthyridine-4(1H)-one (72.0 mg, crude).

[0271] LC-MS, M / Z(ESI):361.1[M+H] +

[0272] Step 2: Synthesis of 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-(methylthio)-1,6-naphthyridin-4(1H)-one

[0273]

[0274] 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-chloro-1,6-naphthyridin-4(1H)-one (70 mg, 194 μmol) was dissolved in tetrahydrofuran (2 mL), and sodium thiomethoxide (67.9 mg, 969 μmol) was added. The reaction solution was stirred at 70°C for 2 hours. After the reaction, the reaction solution was added to water (3 mL) and extracted with ethyl acetate (2 mL*3). The organic phase was washed with saturated sodium chloride solution (3 mL) and dried over anhydrous sodium sulfate. It was then filtered and concentrated to obtain the crude product 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-(methylthio)-1,6-naphthyridin-4(1H)-one (70.0 mg, crude).

[0275] LC-MS, M / Z(ESI):373.1[M+H] +

[0276] Step 3: Synthesis of 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-(S-methylsulfonylimino)-1,6-naphthyridin-4(1H)-one (I-2)

[0277]

[0278] 2-(4-(tert-Butyl)-5-chloro-2-methylphenyl)-5-(methylthio)-1,6-naphthyridin-4(1H)-one (70 mg, 161 μmol) was dissolved in methanol (2 mL), and then ammonium carbamate (25.1 mg, 322 μmol) and diacetoxyiodobenzene (129 mg, 402 μmol) were added. The reaction solution was stirred at 25 °C for 1 hour. After the reaction, the reaction solution was added to water (2 mL), and then extracted with ethyl acetate (2 mL*3). The organic phase was washed with saturated sodium chloride solution (3 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was concentrated to obtain a crude product, which was purified by reverse phase preparation (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: solvent A = water + 0.225% trifluoroacetic acid, B = acetonitrile; gradient: 32%-62%, 15 min) to obtain 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-(S-methylsulfonylimino)-1,6-naphthyridin-4(1H)-one (I-2) (3.23 mg, 4.86% yield).

[0279] LC-MS, M / Z(ESI):404.1[M+H] +

[0280] 1 H NMR (400MHz, CDCl3) δ8.21(br s,1H),7.53(br s,1H),7.36(s,1H),7.31(br s,1H),6.43(br s,1H),3.77(br s,3H),2.32(s,3H),1.48(s,9H).

[0281] Example 3: Preparation of target compound I-3

[0282] Synthesis of 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-6-fluoro-5-(S-methylsulfonylimino)quinolin-4(1H)-one (I-3)

[0283]

[0284] The synthetic route of target compound I-3 is as follows:

[0285]

[0286] Step 1: Synthesis of tert-butyl 3,4-difluorophenylcarbamate

[0287]

[0288] 3,4-Difluoroaniline (40.0 g, 309 mmol) was dissolved in tetrahydrofuran (25 mL), and di-tert-butyl dicarbonate (2.58 g, 11.8 mmol) was slowly added. The reaction mixture was stirred at 25°C for 12 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated to obtain a crude product. The crude product was then purified by slurrying with petroleum ether (500 mL) to obtain tert-butyl 3,4-difluorophenylcarbamate (40.0 g, 56.0% yield).

[0289] 1 H NMR (400MHz, DMSO-d6) δ9.57(br s,1H),7.49-7.68(m,1H),7.27(dd,J=10.4,9.2Hz,1H),7.18(br d,J=9.01Hz,1H),1.46(s,9H).

[0290] Step 2: tert-Butyl (3,4-difluoro-2-iodophenyl)carbamate

[0291]

[0292] tert-Butyl 3,4-difluorophenylcarbamate (10.0 g, 43.6 mmol) was dissolved in tetrahydrofuran (200 mL). n-Butyl lithium (2.5 M, 38.3 mL) was slowly added dropwise at -78°C. The reaction mixture was stirred at -78°C for 30 minutes. Iodine (33.2 g, 130 mmol) was then added portionwise to the reaction mixture, and the mixture was stirred at -78°C for 2 hours. After completion of the reaction, the reaction mixture was diluted with saturated ammonium chloride solution (500 mL) and extracted with ethyl acetate (1 L x 3). The organic phase was washed with saturated sodium chloride solution (2 L), dried over anhydrous sodium sulfate, and filtered and concentrated to obtain the crude product. This was separated by column chromatography (mobile phase: petroleum ether:ethyl acetate = 100:1-20:1) to yield tert-butyl (3,4-difluoro-2-iodophenyl)carbamate (14.0 g, 90.3% yield).

[0293] 1 H NMR (400MHz, DMSO-d6) δ8.73(s,1H),7.43(dd,J=10,8.8Hz,1H),7.21(ddd,J=6.68,4.50,2.32Hz,1H),1.45(s,9H)

[0294] Step 3: Synthesis of 1-(6-amino-2,3-difluorophenyl)ethane-1-one

[0295]

[0296] Dissolve tert-butyl (3,4-difluoro-2-iodophenyl)carbamate (5.00 g, 14.0 mmol), tributyl(1-ethoxyethylene)tin (6.10 g, 16.9 mmol, 5.71 mL), and dichlorobis(triphenylphosphine)palladium (988 mg, 1.41 mmol) in dioxane (40 mL). Replace the atmosphere with nitrogen three times and stir at 100°C for 12 hours. After the reaction is complete, pour the reaction mixture into 1M hydrochloric acid (30 mL) and stir for 1 hour. After complete hydrolysis, the pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution, and then extracted with ethyl acetate (30*3 mL). The organic phase after extraction was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 100:1-2:1) to obtain 1-(6-amino-2,3-difluorophenyl)ethane-1-one (1.20 g, 49.8% yield).

[0297] 1 H NMR (400MHz, CDCl3) δ7.10 (q, J=9.34Hz, 1H), 6.36 (ddd, J=9.26, 3.88, 2.13Hz, 1H), 5.97 (s, 2H), 2.63 (d, J=8.0Hz, 3H)

[0298] Step 4: Synthesis of 1-(6-amino-3-fluoro-2-(methylthio)phenyl)ethane-1-one

[0299]

[0300] 1-(6-Amino-2,3-difluorophenyl)ethan-1-one (850 mg, 4.97 mmol) was dissolved in N,N-dimethylformamide (5 mL). Under nitrogen, sodium thiomethoxide (1.04 g, 14.90 mmol) was added. The mixture was stirred at 25°C for 0.5 hours. After the reaction was complete, the reaction solution was poured into ice water (10 mL) and extracted with ethyl acetate (30 x 3 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (mobile phase: petroleum ether:ethyl acetate = 100:1-5:1) to obtain 1-(6-amino-3-fluoro-2-(methylthio)phenyl)ethan-1-one (905 mg, 91.4% yield).

[0301] 1H NMR (400MHz, CDCl3) δ6.94 (t, J=8.76Hz, 1H), 6.6-6.7 (dd, J=8.82, 4.19Hz, 1H), 2.64 (s, 3H), 2.43 (s, 3H)

[0302] Step 5: Synthesis of N-(2-acetyl-4-fluoro-3-methylthiophenyl)-4-tert-butyl-5-chloro-2-methylbenzamide

[0303]

[0304] Dissolve 1-(6-amino-3-fluoro-2-(methylthio)phenyl)ethan-1-one (175 mg, 882 μmol), 4-(tert-butyl)-5-chloro-2-methylbenzoic acid (200 mg, 882 μmol), and N-methylimidazole (217 mg, 2.65 mmol) in N,N-dimethylformamide (1 mL). Under nitrogen, add N-(chloro(dimethylamino)methylene)-N-methylmethylammonium hexafluorophosphate (371 mg, 1.32 mmol), and stir at 25°C for 1 hour. After completion of the reaction, pour the reaction mixture into ice water (5 mL) and extract with ethyl acetate (10 x 3 mL). The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product. The product was purified by thin layer silica gel (petroleum ether:ethyl acetate=5:1) to give N-(2-acetyl-4-fluoro-3-methylthiophenyl)-4-tert-butyl-5-chloro-2-methylbenzamide (120 mg, 33.4% yield).

[0305] LC-MS, M / Z(ESI):408.3[M+H] +

[0306] Step 6: Synthesis of 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-6-fluoro-5-(methylthio)quinolin-4(1H)-one

[0307]

[0308] N-(2-Acetyl-4-fluoro-3-methylthiophenyl)-4-tert-butyl-5-chloro-2-methylbenzamide (120 mg, 294 μmol) was dissolved in dioxane (10 mL). Sodium hydroxide (35.3 mg, 882 μmol) was added, and the atmosphere was replaced with nitrogen three times. The reaction was stirred at 110°C for 4 hours. After the reaction was complete, the reaction solution was poured into 1M hydrochloric acid (5 mL) and extracted with ethyl acetate (10 x 3 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified on thin-layer silica gel (petroleum ether:ethyl acetate = 1:1) to obtain 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-6-fluoro-5-(methylthio)quinolin-4(1H)-one (110 mg, 95.9% yield).

[0309] LC-MS, M / Z(ESI):390.1[M+H] +

[0310] Step 7: Synthesis of 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-6-fluoro-5-(S-methylsulfonylimino)quinolin-4(1H)-one (I-3)

[0311]

[0312] 2-(4-(tert-Butyl)-5-chloro-2-methylphenyl)-6-fluoro-5-(methylthio)quinolin-4(1H)-one (70.0 mg, 179 μmol) and ammonium carbamate (18.2 mg, 233 μmol) were dissolved in methanol (1 mL). The atmosphere was replaced with nitrogen three times, and diacetoxyiodobenzene (603 mg, 2.28 mmol) was added at 0°C. The reaction was stirred at 65°C for 12 hours. After the reaction was complete, the crude product was directly purified by thin-layer silica gel (petroleum ether: ethyl acetate = 1:1), and then purified by liquid phase preparation (column: Phenomenex LunaC18 150*25mm*10um; mobile phase: solvent A = water + 0.1% formic acid, B = acetonitrile; gradient: 28%-58%, 9 min) to obtain 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-6-fluoro-5-(S-methylsulfonylimino)quinolin-4(1H)-one (I-3) (0.31 mg, 0.38% yield).

[0313] LC-MS, M / Z(ESI):421.2[M+H] +

[0314] 1H NMR (400MHz, CDCl3) δ7.42-7.53(m,2H),7.37(s,2H),6.32(s,1H),3.4(d,J=5.6Hz,3H),2.35(br s,3H),1.51(s,9H)

[0315] Example 4: Preparation of target compound I-4

[0316] Synthesis of 9-tert-butyl-10-chloro-13-oxo-6H,7H,13H-isoquinoline[2,1-a]1,6-naphthyridine-1-carboxamide (I-4)

[0317]

[0318] The synthetic route of target compound I-4 is as follows:

[0319]

[0320] Step 1: Synthesis of 6-tert-butyl-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-one

[0321]

[0322] 6-(tert-Butyl)-3,4-dihydroisoquinolin-1(2H)-one (2.00 g, 9.84 mmol) was dissolved in sulfuric acid (40 mL), and N-chlorosuccinimide (1.45 g, 10.8 mmol) was added. The mixture was stirred at 25°C for 12 hours. After the reaction was complete, the reaction solution was slowly added to water (30 mL) at 0°C and extracted with ethyl acetate (30 x 3 mL). The organic phase was added to sodium bicarbonate (60 mL) and separated. The organic phase was dried, filtered, and concentrated to give a mixture of 6-(tert-butyl)-7-chloro-3,4-dihydroisoquinolin-1(2H)-one (2a) and 6-(tert-butyl)-5-chloro-3,4-dihydroisoquinolin-1(2H)-one as a white solid (2.45 g, 9.33 mmol, 94.80% yield). A mixture of 6-(tert-butyl)-7-chloro-3,4-dihydroisoquinolin-1(2H)-one and 6-(tert-butyl)-5-chloro-3,4-dihydroisoquinolin-1(2H)-one (500 mg) was subjected to supercritical fluid chromatography (column: DAICELCHIRALPAK AD 250×30 mm ID, 10 μm particle size: mobile phase A: [supercritical fluid carbon dioxide]; mobile phase B: i-PrOH (0.1% NH3H2O): gradient elution of 20% i-PrOH (0.1% NH3H2O) in supercritical fluid carbon dioxide from 0% to 40%; flow rate: 3 mL / min; detector: PDA); column temperature: 35°C; column pressure: 100 bar) to obtain 6-(tert-butyl)-7-chloro-3,4-dihydroisoquinolin-1(2H)-one (200 mg, 778 μmol, 37.0% yield).

[0323] LC-MS, M / Z(ESI):238.3[M+H] +

[0324] Step 2: Synthesis of N,9-di-tert-butyl-10-chloro-13-oxo-7,13-dihydro-6H-isoquinoline[2,1-a][1,6]naphthyridine-1-carboxamide

[0325]

[0326] 6-(tert-Butyl)-7-chloro-3,4-dihydroisoquinolin-1(2H)-one (50.0 mg, 210 μmol) and 3-acetyl-N-(tert-butyl)-4-chloropicolinamide (107 mg, 420 μmol) were dissolved in toluene (2 mL). 2-Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (20.0 mg, 42.0 μmol), bis(dibenzylideneacetone)palladium (12.0 mg, 21.0 μmol) and potassium phosphate (223 mg, 1.05 mmol) were added and the reaction was stirred at 100 °C under nitrogen atmosphere for 12 hours. After the reaction was completed, the reaction solution was concentrated to give a crude product, which was purified by thin layer chromatography (mobile phase: dichloromethane / methanol = 10 / 1) to give N,9-di-tert-butyl-10-chloro-13-oxo-7,13-dihydro-6H-isoquinoline[2,1-a][1,6]naphthyridine-1-carboxamide (60.0 mg, 274 μmol, 65.1% yield).

[0327] LC-MS, M / Z(ESI):438.2[M+H] +

[0328] Step 3: Synthesis of 9-tert-butyl-10-chloro-13-oxo-6H,7H,13H-isoquinoline[2,1-a]1,6-naphthyridine-1-carboxamide (I-4)

[0329]

[0330] N,9-di-tert-butyl-10-chloro-13-oxo-7,13-dihydro-6H-isoquinoline[2,1-a][1,6]naphthyridine-1-carboxamide (50.0 mg, 114 μmol) was dissolved in toluene (0.5 mL), tert-butyldimethylsilyl trifluoromethanesulfonate (603 mg, 2.28 mmol) was added, and the reaction was stirred at 65°C for 12 hours. After the reaction was complete, the mixture was dried and concentrated to give a crude product, which was purified by liquid phase preparation (column: Phenomenex luna C18 150*25mm*10um; mobile phase: solvent A = water + 0.1% formic acid, B = acetonitrile; gradient: 30%-60%, 9 min) to give 9-tert-butyl-10-chloro-13-oxo-6H,7H,13H-isoquinoline[2,1-a]1,6-naphthyridine-1-carboxamide (I-4) (15.0 mg, 36.7 μmol, 32.1% yield).

[0331] LC-MS, M / Z(ESI):382.0[M+H] +

[0332] 1H NMR(400MHz,MeOD)δ8.93(br d,1H,J=4.3Hz),8.44(br d,1H,J=5.1Hz),8.11(s,1H),7.64(s,1H),7.50(s,1H),4.70(t,2H,J=6.5Hz),3.33(t,2H,J=6.5Hz),1.56(s,9H)

[0333] Example 5: Preparation of target compound I-45

[0334] Synthesis of 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-3-methyl-4-oxo-1,4-dihydro-1,7-naphthyridine-5-carboxamide (I-45)

[0335]

[0336] The synthetic route of target compound I-45 is as follows:

[0337]

[0338] Step 1: Synthesis of 5-bromo-2-(4-tert-butyl-5-chloro-2-methylphenyl)-1,4-dihydro-1,7-naphthyridin-4-one (2)

[0339]

[0340] 4-(tert-Butyl)-5-chloro-2-methylbenzamide (1) (1 g, 4.43 mmol), 1-(3,5-dibromopyridin-4-yl)ethan-1-one (1.24 g, 4.43 mmol) were dissolved in toluene (15 mL), and then 4,5-bis(diphenylphosphino)-99-dimethyloxanthene (512 mg, 886 μmol), cesium carbonate (7.22 g, 22.2 mmol) and finally bis(dibenzylideneacetone)palladium (254 mg, 443 μmol) were added. The reaction was stirred at 100 ° C for 12 hours. After the reaction was completed, the reaction solution was filtered through celite, washed with ethyl acetate, and concentrated to obtain a residue. The residue was purified by thin layer chromatography (mobile phase: petroleum ether / ethyl acetate = 2:1, R f 0.43) to give 5-bromo-2-(4-tert-butyl-5-chloro-2-methylphenyl)-1,4-dihydro-1,7-naphthyridin-4-one (400 mg, 22.2% yield). LC-MS, M / Z (ESI): 406.9 [M+H + ]

[0341] Step 2: Synthesis of 2-(4-tert-butyl-5-chloro-2-methylphenyl)-4-oxo-1,4-dihydro-1,7-naphthyridine-5-carbonitrile

[0342]

[0343] 5-Bromo-2-(4-tert-butyl-5-chloro-2-methylphenyl)-1,4-dihydro-1,7-naphthyridin-4-one (350 mg, 862 μmol) was dissolved in N,N-dimethylformamide (4 mL). Methanesulfonic acid (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl)(2-methylamino-1,1-biphenyl-2-yl)palladium(II) (73.3 mg, 86.2 μmol) and zinc hydride (202 mg, 1.73 mmol) were added. The mixture was stirred at 140°C for 3 hours. After the reaction was complete, the reaction mixture was quenched by the addition of 50 mL of water at 0°C and extracted with ethyl acetate (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate and filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by thin layer chromatography (mobile phase: petroleum ether / ethyl acetate = 2:1, Rf was 0.43) to give 2-(4-tert-butyl-5-chloro-2-methylphenyl)-4-oxo-1,4-dihydro-1,7-naphthyridine-5-carbonitrile (200 mg, 66.6% yield).

[0344] LC-MS, M / Z(ESI):352.0[M+H + ]

[0345] Step 3: Synthesis of 3-bromo-2-(4-tert-butyl-5-chloro-2-methylphenyl)-4-oxo-1,4-dihydro-1,7-naphthyridine-5-carbonitrile

[0346]

[0347] 2-(4-tert-Butyl-5-chloro-2-methylphenyl)-4-oxo-1,4-dihydro-1,7-naphthyridine-5-carbonitrile (200 mg, 568 μmol) was dissolved in glacial acetic acid (2 mL), followed by the addition of N-bromosuccinimide (101 mg, 568 μmol). The reaction mixture was stirred at 60°C for 2 hours. After completion of the reaction, the pH of the reaction mixture was adjusted to 7 by the addition of 50 mL of aqueous sodium bicarbonate at 0°C, and extraction was performed by the addition of ethyl acetate (50 mL x 3). The organic layer was dried over anhydrous sodium sulfate and filtered. The filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin layer chromatography (silica, petroleum ether:ethyl acetate = 0:1) to give 3-bromo-2-(4-tert-butyl-5-chloro-2-methylphenyl)-4-oxo-1,4-dihydro-1,7-naphthyridine-5-carbonitrile (150 mg, 61.1% yield).

[0348] LC-MS, M / Z(ESI):432.1[M+H + ]

[0349] Step 4: Synthesis of 3-bromo-2-(4-tert-butyl-5-chloro-2-methylphenyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}-1,7-naphthyridine-5-carbonitrile

[0350]

[0351] 3-Bromo-2-(4-tert-butyl-5-chloro-2-methylphenyl)-4-oxo-1,4-dihydro-1,7-naphthyridine-5-carbonitrile (90.0 mg, 208 μmol) was dissolved in acetonitrile (1 mL). 2-(Trimethylsilyl)ethoxymethyl chloride (52.2 mg, 313 μmol) and cesium carbonate (204 mg, 626 μmol) were then added and stirred at 25°C for 12 hours. After the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The organic layer was dried over anhydrous sodium sulfate and filtered. The filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography (silica, petroleum ether:ethyl acetate = 2:1). 3-Bromo-2-(4-tert-butyl-5-chloro-2-methylphenyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}-1,7-naphthyridine-5-carbonitrile (90.0 mg, 76.8% yield) was obtained.

[0352] LC-MS, M / Z(ESI):562.1[M+H + ]

[0353] Step 5: Synthesis of 2-(4-tert-butyl-5-chloro-2-methylphenyl)-3-methyl-4-{[2-(trimethylsilyl)ethoxy]methoxy}-1,7-naphthyridine-5-carbonitrile

[0354]

[0355] 3-Bromo-2-(4-tert-butyl-5-chloro-2-methylphenyl)-4-{[2-(trimethylsilyl)ethoxy]methoxy}-1,7-naphthyridine-5-carbonitrile (90.0 mg, 160 μmol) was dissolved in dioxane / water (1 / 0.5 mL). Potassium phosphate (170 mg, 802 μmol) and methylboronic acid (67.2 mg, 1.12 mmol) were then added, followed by tetrakistriphenylphosphine palladium (37.1 mg, 32.1 μmol). The reaction was stirred at 100°C for 2 hours. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate and filtered. The filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography (silica, petroleum ether:ethyl acetate = 2:1). 2-(4-tert-Butyl-5-chloro-2-methylphenyl)-3-methyl-4-{[2-(trimethylsilyl)ethoxy]methoxy}-1,7-naphthyridine-5-carbonitrile (70.0 mg, 88.1% yield) was obtained.

[0356] LC-MS, M / Z(ESI):496.2[M+H + ]

[0357] Step 6: Synthesis of 2-(4-tert-butyl-5-chloro-2-methylphenyl)-3-methyl-4-{[2-(trimethylsilyl)ethoxy]methoxy}-1,7-naphthyridine-5-carboxamide

[0358]

[0359] 2-(4-tert-Butyl-5-chloro-2-methylphenyl)-3-methyl-4-{[2-(trimethylsilyl)ethoxy]methoxy}-1,7-naphthyridine-5-carbonitrile (60.0 mg, 121 μmol) was dissolved in dimethyl sulfoxide (1 mL). Potassium carbonate (66.9 mg, 484 μmol) was then added dropwise. Finally, 30% hydrogen peroxide (88.1 mg, 0.91 mmol) was added dropwise and stirred at 60°C for 12 hours. After the reaction was complete, sodium sulfite solution was added to remove excess hydrogen peroxide until the starch potassium iodide test paper did not turn blue. The pH was then adjusted to 7 with 10% sodium bicarbonate solution, and extraction was performed with ethyl acetate (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate and filtered. The filter cake was washed with ethyl acetate, and the filtrate was filtered and concentrated under reduced pressure to give 2-(4-tert-butyl-5-chloro-2-methylphenyl)-3-methyl-4-{[2-(trimethylsilyl)ethoxy]methoxy}-1,7-naphthyridine-5-carboxamide (50.0 mg, 80.4% yield).

[0360] LC-MS, M / Z(ESI):514.3[M+H + ]

[0361] Step 7: Synthesis of 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-3-methyl-4-oxo-1,4-dihydro-1,7-naphthyridine-5-carboxamide (I-45)

[0362]

[0363] 2-(4-tert-Butyl-5-chloro-2-methylphenyl)-3-methyl-4-{[2-(trimethylsilyl)ethoxy]methoxy}-1,7-naphthyridine-5-carboxamide (50.0 mg, 97.3 μmol) was dissolved in dichloromethane (0.5 mL), trifluoroacetic acid (55.4 mg, 486 μmol) was added, and the reaction was stirred at 25°C for 3 hours. After the reaction was complete, the crude product was dried and concentrated to give a crude product, which was purified by liquid phase preparation (column: Phenomenex luna C18 150*25mm*10um; mobile phase: solvent A = water + 0.225% formic acid, B = acetonitrile; gradient: 39%-59%, 10 min) to give 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-3-methyl-4-oxo-1,4-dihydro-1,7-naphthyridine-5-carboxamide (I-45) (1.76 mg, 4.57% yield).

[0364] 1 H NMR(400MHz,MeOD)δ8.97(s,1H)8.36(s,1H)7.54(s,1H)7.39(s,1H)2.19(s,3H)1.88(s,3H)

[0365] 1.54(s,9H)

[0366] LC-MS, M / Z(ESI):384.1[M+H + ]

[0367] Example 6: Preparation of target compound I-51

[0368] 2-[5-chloro-2-(difluoromethyl)-4-(2-methylprop-2-yl)phenyl]-7-fluoro-4-oxyylidene-1H-quinoline-5-carboxamide (I-51)

[0369]

[0370] The synthetic route of compound I-51 is as follows:

[0371]

[0372]

[0373] Step 1: Synthesis of 5-chloro-2-methyl-4-(2-methylprop-2-yl)phenol (2)

[0374]

[0375] Under ice-bath conditions, 5-chloro-2-methylphenol (1) (5.0 g, 35.07 mmol) was dissolved in n-heptane (50 mL) and tert-butyl alcohol (7.80 g, 104.15 mmol) was added. After the addition was complete, concentrated sulfuric acid (7.0 g, 69.44 mmol) was slowly added at the same temperature, and the temperature did not exceed 7°C during the addition. After the addition was complete, the reaction solution was reacted at room temperature for 16 hours. TLC (PE:EA=5:1) showed that the reaction was complete. H2O (50 mL) was added to the reaction solution, and then extracted with EtOAc (50 mL*3). The layers were separated and the organic phases were combined. The organic phase was washed with H2O (50 mL*2) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was separated by normal phase silica gel column chromatography (EtOAc / PE=0%-30%) to give 5-chloro-2-methyl-4-(2-methylprop-2-yl)phenol (2) (6.60 g; yield: 94.5%).

[0376] Step 2: Synthesis of 5-chloro-2-methyl-4-(2-methylprop-2-yl)phenyl trifluoromethanesulfonate (3)

[0377]

[0378] Under nitrogen protection and an ice bath, compound 2 (6.60 g, 33.22 mmol) and pyridine (5.26 g, 66.44 mmol) were weighed separately in DCM (70 mL), and Tf2O (12.17 g, 44.85 mmol) was slowly added. After the addition was complete, the temperature was slowly raised to room temperature and the mixture was reacted under these conditions for 16 hours. TLC (PE:EA=10:1) showed that the reaction was complete. H2O (30 mL) was added to the reaction solution, extracted, and separated. The aqueous phase was further extracted with DCM (40 mL*2), separated, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by normal phase silica gel column chromatography (EtOAc / PE=0%-50%) to obtain 5-chloro-2-methyl-4-(2-methylprop-2-yl)phenyl trifluoromethanesulfonate (3) (10.98 g; yield: 100%).

[0379] Step 3: Synthesis of methyl 5-chloro-2-methyl-4-(2-methylprop-2-yl)benzoate (4)

[0380]

[0381] At room temperature, compound 3 (5.0 g, 15.12 mmol), Pd(dppf)Cl2 (1.11 g, 1.51 mmol), and Et3N (4.60 g, 45.35 mmol) were weighed into anhydrous DMF (39 mL) and H2O (13 mL). The reaction mixture was evacuated and replaced with CO gas three times. The temperature was raised to 80°C and the reaction was allowed to proceed under a CO balloon pressure of 15 psi for 16 hours. TLC (PE:EA = 10:1) indicated the reaction was complete. H2O (30 mL) was added to the reaction mixture for dilution, followed by extraction with EtOAc (50 mL x 2). The organic phases were separated, combined, and washed with H2O (40 mL x 2) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was separated by normal phase silica gel column chromatography (EtOAc / PE = 0%-50%) to give methyl 5-chloro-2-methyl-4-(2-methylprop-2-yl)benzoate (4) (2.52 g; yield: 69.23%).

[0382] Step 4: Synthesis of methyl 2-(bromomethyl)-5-chloro-4-(2-methylprop-2-yl)benzoate (5)

[0383]

[0384] Under nitrogen, compound 4 (1.50 g, 6.23 mmol), NBS (1.11 g, 6.23 mmol), and BPO (46.5 mg, 0.62 mmol) were weighed into 20 mL of CCl. The reaction mixture was evacuated and replaced with nitrogen three times. The temperature was raised to 80°C and the reaction was continued under nitrogen for 16 hours. TLC (PE:EA = 10:1) indicated the reaction was complete. The reaction solution was diluted with H2O (10 mL), and then extracted with DCM (20 mL*2). The organic phases were separated and combined, and the organic phases were washed with brine (20 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by normal phase silica gel column chromatography (EtOAc / PE=0%-50%) to obtain methyl 2-(bromomethyl)-5-chloro-4-(2-methylprop-2-yl)benzoate (5) (1.80 g; yield: 90.45%).

[0385] Step 5: Synthesis of methyl 5-chloro-2-formyl-4-(2-methylprop-2-yl)benzoate (6)

[0386]

[0387] At room temperature, compound 5 (1.80 g, 5.63 mmol) and NMO (1.33 g, 11.26 mmol) were weighed into THF (20 mL). After weighing, the reaction solution was heated to 80°C and reacted under this condition for 16 hours. TLC (PE:EA = 10:1) showed that the reaction was complete. H2O (10 mL) was added to the reaction solution for dilution, and then extracted with DCM (20 mL*2). The organic phases were separated and combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by normal phase silica gel column chromatography (EtOAc / PE = 0%-50%) to obtain methyl 5-chloro-2-formyl-4-(2-methylpropan-2-yl)benzoate (6) (0.81 g; yield: 56.64%).

[0388] Step 6: Synthesis of methyl 5-chloro-2-(difluoromethyl)-4-(2-methylprop-2-yl)benzoate (7)

[0389]

[0390] Under nitrogen protection and an ice bath, compound 6 (0.50 g, 1.96 mmol) was weighed and dissolved in anhydrous DCM (5 mL). MeOH (6.43 mg, 0.20 mmol) and DAST (540.0 mg, 3.33 mmol) were added, respectively. After the addition was complete, the reaction mixture was reacted under the same conditions for 16 hours. TLC (PE:EA=10:1) showed that the reaction was complete. Saturated aqueous sodium bicarbonate solution (10 mL) was added to the reaction mixture to adjust the pH to neutral, and then the mixture was extracted with DCM (20 mL*2). The organic phases were separated and combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by normal phase silica gel column chromatography (EtOAc / PE=0%-50%) to give methyl 5-chloro-2-(difluoromethyl)-4-(2-methylprop-2-yl)benzoate (7) (0.40 g; yield: 73.66%).

[0391] Step 7: Synthesis of 5-chloro-2-(difluoromethyl)-4-(2-methylprop-2-yl)benzoic acid (8)

[0392]

[0393] At room temperature, compound 7 (0.25 g, 0.90 mmol) was dissolved in THF (2 mL), MeOH (0.5 mL), and H₂O (1 mL). Lithium hydroxide monohydrate (113.73 mg, 2.70 mmol) was then added. The reaction mixture was allowed to react for 16 hours under these conditions. TLC (PE:EA = 10:1) indicated completion of the reaction. The reaction solution was diluted with H2O (10 mL), extracted with EtOAc (10 mL*2), separated, and the organic phases were combined. The aqueous phase was adjusted to pH 3 with 1N HCl solution, and then extracted with EtOAc (10 mL*2). The organic phases were separated, combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by normal phase silica gel column chromatography (EtOAc / PE=0%-50%) to give 5-chloro-2-(difluoromethyl)-4-(2-methylprop-2-yl)benzoic acid (8) (0.24 g; crude product).

[0394] Step 8: Synthesis of 5-chloro-2-(difluoromethyl)-4-(2-methylprop-2-yl)benzene-1-carboxamide (9)

[0395]

[0396] Under nitrogen protection and an ice bath, compound 8 (0.24 g, 0.91 mmol) was weighed into anhydrous DCM (5 mL). DMF (6.70 mg, 0.09 mmol) and (COCl)2 (138.34 mg, 1.09 mmol) were added, respectively. After the addition was complete, the reaction mixture was allowed to react under these conditions for 1 hour. The reaction mixture was directly concentrated under reduced pressure to dryness to obtain a crude product. Under nitrogen protection and an ice bath, the crude product was diluted with anhydrous DCM (5 mL), and then ammonia (2 mL) was added. After the addition was complete, the reaction mixture was allowed to react under these conditions for 1 hour. TLC (PE:EA = 10:1) indicated that the reaction was complete. H2O (10 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (10 mL*2). The organic phases were separated and combined, and the organic phases were washed with brine (10 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 5-chloro-2-(difluoromethyl)-4-(2-methylprop-2-yl)benzene-1-carboxamide (9) (0.22 g; crude).

[0397] Step 9: Synthesis of methyl 2-acetyl-3-amino-5-fluorobenzoate (10-2)

[0398]

[0399] At room temperature, methyl 3-amino-2-bromo-5-fluorobenzoate (10-1) (2.0 g, 8.06 mmol) and tributyl(1-ethoxyvinyl)stannane (12) (3.50 g, 19.34 mmol) were weighed in anhydrous toluene (20 mL). Pd(dppf)Cl2 (0.94 g, 0.81 mmol) was then added. After the addition was complete, the reaction solution was evacuated and replaced with nitrogen three times. Finally, the reaction solution was heated to 100°C and reacted under nitrogen for 16 hours. TLC (PE:EA = 3:1) showed that the reaction was complete. The reaction solution was cooled to room temperature, and 6N HCl (10 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous KF solution (20 mL) was added to the reaction solution, and the mixture was stirred for 30 minutes. Saturated aqueous sodium bicarbonate solution was then added to adjust the pH to 8. The reaction solution was extracted with EtOAc (30 mL x 2), separated, and the organic phases were combined. The organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was separated by normal phase silica gel column chromatography (EtOAc / PE = 0%-50%) to give methyl 2-acetyl-3-amino-5-fluorobenzoate (10-2) (1.60 g; yield: 94.12%).

[0400] Step 10: Synthesis of methyl 2-acetyl-5-fluoro-3-iodobenzoate (10)

[0401]

[0402] On an ice bath, compound 10-2 (0.30 g, 1.42 mmol), KI (0.59 g, 3.55 mmol), and p-TsOH (0.73 g, 4.26 mmol) were weighed into ACN (3 mL) and H₂O (1 mL). NaNO₂ (0.20 g, 2.84 mmol) was then added. After complete addition, the reaction mixture was incubated on ice for 2 hours. TLC (PE:EA = 3:1) indicated completion of the reaction. The reaction mixture was cooled to room temperature, and the pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution. The reaction mixture was extracted with EtOAc (15 mL x 2), separated, and the organic phases combined. The organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was separated by normal phase silica gel column chromatography (EtOAc / PE = 0%-50%) to give methyl 2-acetyl-5-fluoro-3-iodobenzoate (10) (0.26 g; yield: 56.52%).

[0403] Step 11: Synthesis of 2-[5-chloro-2-(difluoromethyl)-4-(2-methylprop-2-yl)phenyl]-7-fluoro-4-oxyylidene-1H-quinoline-5-carboxylic acid (11)

[0404]

[0405] At room temperature, compound 9 (0.10 g, 0.38 mmol) and compound 10 (0.14 g, 0.42 mmol) were weighed into anhydrous dioxane (2 mL). Cs2CO3 (0.38 g, 1.14 mmol), Pd2(dba)3 (35.0 mg, 0.04 mmol), and Xantphos (44.0 mg, 0.08 mmol) were added, respectively. After complete addition, the reaction solution was evacuated and replaced with nitrogen three times. The reaction solution was heated to 100°C and reacted under nitrogen for 16 hours. TLC (PE:EA = 3:1) indicated the reaction was complete. The reaction solution was diluted with H2O (5 mL), and then extracted with EtOAc (10 mL*2). The organic phases were separated and combined, and the organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by normal phase silica gel column chromatography (EtOAc / PE=0%-50%) to give 2-[5-chloro-2-(difluoromethyl)-4-(2-methylprop-2-yl)phenyl]-7-fluoro-4-oxygen-1H-quinoline-5-carboxylic acid (11) (40.0 mg; yield: 24.84%).

[0406] Step 12: 2-[5-chloro-2-(difluoromethyl)-4-(2-methylprop-2-yl)phenyl]-7-fluoro-4-oxyylidene-1H-quinoline-5-carboxamide (I-51)

[0407]

[0408] Under nitrogen protection and ice bath, compound 11 (40.0 mg, 0.09 mmol) was weighed in anhydrous DCM (2 mL), and then DMF (0.67 mg, 0.009 mmol) and (COCl) 2 (13.71 mg, 0.11 mmol) were added respectively. After the addition, the reaction solution was reacted under the same conditions for 1 hour. The reaction solution was directly concentrated under reduced pressure and dried to obtain a crude product. Under nitrogen protection and ice bath, the crude product was diluted with anhydrous DCM (2 mL), and then ammonia water (2 mL) was added. After the addition, the reaction solution was reacted under the same conditions for 1 hour. TLC (PE: EA = 10: 1) showed that the reaction was complete. The reaction solution was directly concentrated under reduced pressure and dried to obtain a crude product. The crude product was purified by high performance liquid chromatography (Column: SunFire TM Prep C18 OBD TM5μm, 30X 150mm, Phase: ACN / H2O (0.5% FA) 40% ACN) was separated to obtain 2-[5-chloro-2-(difluoromethyl)-4-(2-methylprop-2-yl)phenyl]-7-fluoro-4-oxyylidene-1H-quinoline-5-carboxamide (I-51) (10.9 mg, yield: 28.87%).

[0409] 1 H NMR (400MHz, DMSO-d6): δ8.26(s,1H),7.81(s,1H),7.69(s,1H),7.28(d,2H,J=8.0Hz),6 .98(d,1H,J=8.0Hz),6.62(s,1H),6.04(d,1H,J=8.0Hz),5.31-5.29(m,1H),1.52(s,9H).

[0410] LC-MS, M / Z(ESI):423.26[M+H] +

[0411] Example 7: Preparation of target compound I-74

[0412] 2-(4-(tert-Butyl)-5-chloro-2-methylphenyl)-5-(2-hydroxyethoxy)-1,6-naphthyridin-4(1H)-one (target compound I-74)

[0413]

[0414] The synthetic route of target compound I-74 is as follows:

[0415]

[0416] Step 1: Synthesis of 4-(benzyloxy)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)-1,6-naphthyridine

[0417]

[0418] The starting materials, 4-(benzyloxy)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-chloro-1,6-naphthyridine (100 mg, 221 μmol) and 2-((tetrahydro-2H-pyran-2-yl)oxy)ethan-1-ol (64.7 mg, 443 μmol), were dissolved in tetrahydrofuran (4 mL). The reaction system was purged with nitrogen three times. Sodium hydride (13.2 mg, 332 μmol, 60% purity) was slowly added at 0°C, and then stirred at 0°C for 2 hours. After completion, the reaction was quenched by the addition of saturated ammonium chloride (10 mL), and the mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by thin layer chromatography (petroleum ether:ethyl acetate=0:1) to give 4-(benzyloxy)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)-1,6-naphthyridine (45.0 mg, 36% yield).

[0419] LC-MS, M / Z(ESI):561.2[M+H] + .

[0420] Step 2: Synthesis of 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-(2-hydroxyethoxy)-1,6-naphthyridin-4(1H)-one (I-74)

[0421]

[0422] 4-(Benzyloxy)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)-1,6-naphthyridine (25.0 mg, 44.5 μmol) was dissolved in anhydrous toluene (0.5 mL). Trifluoroacetic acid (25.4 mg, 222 μmol) was then added. The atmosphere was replaced with nitrogen three times, and the temperature was raised to 60°C and stirred for 12 hours. After completion of the reaction, the reaction solution was poured into saturated sodium bicarbonate (10 mL) at 0°C to quench the reaction. The mixture was then extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. It was separated and purified by high performance liquid chromatography (column: Phenomenex luna C18 150*25mm*10um; solvent: A=water+0.05% trifluoroacetic acid, B=acetonitrile; gradient: 18%-48%, 10 minutes) to obtain 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-(2-hydroxyethoxy)-1,6-naphthyridin-4(1H)-one (I-74) (3.00 mg, yield 8.0%).

[0423] LC-MS, M / Z(ESI):387.3[M+H]+ .

[0424] 1 H NMR(400MHz,MeOD)δ7.90(d,J=7.20Hz,1H),7.51(d,J=6.50Hz,2H),6.97-7.06(m,1H),6.77 (d,J=7.64Hz,1H),4.23(t,J=5.08Hz,2H),3.90(t,J=5.20Hz,2H),2.35(s,3H)1.53(s,9H).

[0425] Example 8: Preparation of target compound I-75

[0426] 2-(4-(tert-Butyl)-5-chloro-2-methylphenyl)-4-oxo-1,4-dihydrothieno[3,4-b]pyridine-5-carboxamide (target compound I-75)

[0427]

[0428] The synthetic route of target compound I-75 is as follows:

[0429]

[0430] Step 1: Synthesis of methyl 4-bromo-3-iodothiophene-2-carboxylate

[0431]

[0432] The raw materials 3-amino-4-bromothiophene-2-carboxylic acid methyl ester (5.00g, 21.2mmol) and diiodomethane (17.0g, 63.5mmol) were dissolved in acetonitrile (50mL), the reaction system was replaced with nitrogen three times, tert-butyl nitrite (3.28mg, 31.7mmol) was slowly added at 0°C, and then stirred at 50°C for 3 hours. After the reaction was completed, water (50mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified by thin layer chromatography (petroleum ether: ethyl acetate = 5:1, R fp1 =0.5), to give the compound 4-bromo-3-iodothiophene-2-carboxylic acid methyl ester (4.00 g, 54.4% yield).

[0433] LC-MS, M / Z (ESI): 347.8 (M+H + ).

[0434] Step 2: Synthesis of methyl 3-acetyl-4-bromothiophene-2-carboxylate

[0435]

[0436] The raw materials 4-bromo-3-iodothiophene-2-carboxylic acid methyl ester (4.00 g, 11.5 mmol) and tributyl (1-ethoxyethylene) tin (4.58 g, 12.7 mmol) were dissolved in N, N-dimethylformamide (40 mL), and the reaction system was replaced with nitrogen three times. At 25 ° C, lithium chloride (977 mg, 23.1 mmol) and tetrakistriphenylphosphine palladium (1.33 g, 1.15 mmol) were added, and then stirred at 50 ° C for 3 hours. The reaction was completed. Then add saturated potassium fluoride aqueous solution (40mL) to quench, extract with ethyl acetate (50mL*3), dry the combined organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. The crude product was dissolved in tetrahydrofuran (10mL), and then 2M dilute hydrochloric acid was added, stirred at 25°C for 1 hour, and then extracted with ethyl acetate (50mL*3), dried the combined organic phase with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified by thin layer chromatography (petroleum ether: ethyl acetate = 5:1, R fp1 =0.35), to give the compound 3-acetyl-4-bromothiophene-2-carboxylic acid methyl ester (1.80 g, 59.4% yield).

[0437] LC-MS, M / Z (ESI): 263.8 (M+H + ).

[0438] Step 3: Synthesis of 3-acetyl-4-bromothiophene-2-carboxylic acid

[0439]

[0440] The raw material, methyl 3-acetyl-4-bromothiophene-2-carboxylate (1.80 g, 6.84 mmol), was dissolved in tetrahydrofuran (18 mL). Sodium hydroxide (820 mg, 20.5 mmol) was dissolved in water (9 mL) at 0°C and the aqueous solution was slowly added to the reaction solution, followed by stirring at 25°C for 1 hour. After completion of the reaction, 1M dilute hydrochloric acid (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (40 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to yield 3-acetyl-4-bromothiophene-2-carboxylic acid (1.60 g, 93.9% yield).

[0441] LC-MS, M / Z(ESI):204.9(M-44-H + ).

[0442] Step 4: Synthesis of 3-acetyl-4-bromo-N-tert-butylthiophene-2-carboxamide

[0443]

[0444] The raw materials 3-acetyl-4-bromothiophene-2-carboxylic acid (1.60 g, 6.42 mmol) and tert-butylamine (939 mg, 12.8 mmol) were dissolved in dichloromethane (20 mL). At 25°C, N,N-diisopropylethylamine (2.49 g, 19.2 mmol) and n-butylphosphonic anhydride (9.26 g, 12.8 mmol, 50% content) were slowly added, and then stirred at 25°C for 1 hour. After the reaction was completed, water (20 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (40 mL*2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified by thin layer chromatography (petroleum ether: ethyl acetate = 3:1, R fp1 =0.4), to give the compound 3-acetyl-4-bromo-N-tert-butylthiophene-2-carboxamide (1.80 g, 92.1% yield).

[0445] LC-MS, M / Z (ESI): 304.8 (M+H + ).

[0446] Step 5: Synthesis of 3-acetyl-N-tert-butyl-4-(4-tert-butyl-5-chloro-2-methylbenzamide)thiophene-2-carboxamide

[0447]

[0448] The raw materials 4-(tert-butyl)-5-chloro-2-methylbenzamide (400 mg, 1.77 mmol) and 3-acetyl-4-bromo-N-tert-butylthiophene-2-carboxamide (593 mg, 1.95 mmol) were dissolved in dioxane (5 mL). Potassium phosphate (1.13 g, 5.32 mmol), cuprous iodide (33.7 mg, 177 umol), and N,N-dimethylethylenediamine (312 mg, 3.54 mmol) were added at 25°C. Under nitrogen protection, the mixture was stirred at 100°C for 5 hours. After completion of the reaction, water (5 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (10 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by thin layer chromatography (petroleum ether: ethyl acetate = 3:1, R fp1 =0.35), to give the compound 3-acetyl-N-tert-butyl-4-(4-tert-butyl-5-chloro-2-methylbenzamide)thiophene-2-carboxamide (175 mg, 21.9% yield).

[0449] LC-MS, M / Z (ESI): 449.1 (M+H + ).

[0450] Step 6: Synthesis of N-(tert-butyl)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4-oxo-1,4-dihydrothieno[3,4-b]pyridine-5-carboxamide

[0451]

[0452] The raw material 3-acetyl-N-tert-butyl-4-(4-tert-butyl-5-chloro-2-methylbenzamido)thiophene-2-carboxamide (150 mg, 334 umol) was dissolved in dioxane (5 mL). Sodium hydroxide (40.1 mg, 1.00 mmol) was added at 25°C, and then stirred at 60°C for 5 hours. After completion of the reaction, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. It was separated and purified by high performance liquid chromatography (column: Phenomenex luna C18 150*25mm*10um; solvent: A=water+0.05 volume of formic acid (99%), B=acetonitrile; gradient: 53%-83%, 10 minutes) to obtain the compound N-(tert-butyl)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4-oxo-1,4-dihydrothieno[3,4-b]pyridine-5-carboxamide (18.0 mg, 12.5% ​​yield).

[0453] LC-MS, M / Z (ESI): 431.1 (M+H + ).

[0454] Step 7: 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4-oxo-1,4-dihydrothieno[3,4-b]pyridine-5-carboxamide (target compound I-75)

[0455]

[0456] N-(tert-butyl)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4-oxo-1,4-dihydrothieno[3,4-b]pyridine-5-carboxamide (15.0 mg, 34.8 μmol) was dissolved in anhydrous toluene (0.5 mL), and then tert-butyldimethylsilyl trifluoromethanesulfonate (183 mg, 696 μmol) was added. After nitrogen replacement three times, the temperature was raised to 65°C and stirred for 2 hours. After the reaction was completed, the reaction solution was poured into saturated sodium bicarbonate (10 mL) at 0°C to quench, and the mixed solution was extracted with ethyl acetate (20 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified by thin layer chromatography (petroleum ether: ethyl acetate = 1:1, R fp1=0.35), to give 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-4-oxo-1,4-dihydrothieno[3,4-b]pyridine-5-carboxamide (target compound I-75) (8.80 mg, 66.7% yield).

[0457] 1 H NMR (400MHz, MeOD) δ7.69(s,1H),7.49(s,1H),7.45(s,1H),6.02(s,1H),2.35(s,3H),1.52(s,9H).

[0458] LC-MS, M / Z (ESI): 375.3 (M+H + ).

[0459] Test Example 1: Detection of the inhibitory activity of compounds on Nav1.8 ion channels

[0460] All reagents, except NaOH and KOH for acid-base titration, were purchased from Sigma (St. Louis, MO). Final concentrations of test compounds were prepared on the day of the experiment and dissolved in extracellular fluid. The extracellular fluid (mM) consisted of: NaCl, 137; KCl, 4; CaCl₂, 1.8; MgCl₂, 1; HEPES, 10; glucose, 10; pH 7.4 (NaOH titration). All test and control compound solutions contained 1 μM TTX. The intracellular fluid (mM) consisted of: aspartic acid, 140; magnesium chloride, 2; ethylene glycol tetraacetic acid (EGTA), 11; and N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), 10. The pH was adjusted to 7.4 with cesium hydroxide.

[0461] The test compound was dissolved in dimethyl sulfoxide (DMSO) at a concentration of 9 mM and redissolved in the extracellular fluid on the day of the test to prepare the required concentration.

[0462] Electrophysiological experimental steps:

[0463] Transfer the cells to a perfusion tank and perfuse with extracellular solution. Thaw the intracellular solution on the day of the experiment. Electrodes were pulled using PC-10 (Narishige, Japan). Whole-cell patch clamp recordings were performed, with noise filtered at one-fifth the sampling frequency. Fill the electrode with intracellular solution to a quarter of the length of the electrode tube and install the electrode on the probe. Set the desired protocol, adjust the interface to Membrane test, and the Stage to Bath. Apply positive pressure to the electrode, touch the electrode tip to the cell, adjust the three-way valve of the aspirator to the three-way position, and then apply negative pressure to the electrode to form a high-resistance seal between the electrode and the cell. Adjust the Stage to Patch, control the leak to -200pA, and continue to apply negative pressure to rupture the cell membrane, establishing a current path. Open the aspirator and extracellular solution valves to allow perfusion, observe the cell current, and begin drug addition after the cell current stabilizes (at least three sweeps of overlapping current curves). Add drug from low to high concentrations, with each dose lasting at least 2 minutes. Wait until the current stabilizes before changing concentrations.

[0464] The test article is administered using a gravity-fed perfusion system. During the initial recording period, the peak current amplitude is observed for at least 1 minute until it stabilizes. During this period, the CV% of all peak current amplitudes should be less than 10% to exclude fluctuations in the initial current. The average of the peak current amplitudes recorded during the last 10 recordings during the initial recording period is used as the peak current of the negative control. After the initial current stabilizes, the test article is administered starting at a low concentration until the peak currents of the 10 recordings stabilize again or, after 5 minutes of continuous administration, the peak current remains unchanged after administration. "Stable" or "unchanged" is defined as follows: 1) if the absolute average of the peak current for 10 consecutive scans exceeds 200pA with a CV value of less than 10%, or 2) if the average of the peak current for 10 consecutive scans is between 200pA and 50pA with a CV value of less than 30%. The next higher concentration is then administered.

[0465] The average peak current of the last 10 scans for each concentration was used as the peak current for that concentration and was used for data analysis. If steady state was not achieved within 5 minutes, the average peak current of the last 10 scans at that time was used as the peak current for that concentration and was used for data analysis. The cell was discarded and not used for testing at higher concentrations. At least two cells were tested for each compound concentration.

[0466] Voltage pulse program:

[0467] The cell is clamped at –80 mV and then depolarized to 10 mV with a 10-ms square wave to elicit a NaV1.8 current. This procedure is repeated every 5 seconds. The maximum current evoked by the square wave is measured and, after stabilization, the test compound is perfused. Once the response stabilizes, the magnitude of the blockade is calculated.

[0468] Data processing and fitting:

[0469] Data acquisition and analysis will be performed using pCLAMP 10 (Molecular Devices, Union City, CA). Current stability refers to the ability of the current to vary within a limited range over time. The inhibitory activity (IC) of the drug against the Nav1.8 channel is calculated by plotting the dose-response relationship between the drug's concentration series and the stable current values ​​generated by its action on HEK293 / Nav1.8 cells. 50 ).

[0470] Table 1: Inhibitory activity of compounds on Nav1.8 ion channels

[0471]

[0472] In addition to the compounds in Table 1, the results are as follows:

[0473] Inhibitory activity IC of Nav1.8 ion channel 50 Compounds (nM) less than 20nM include: I-5, I-6, I-7, I-8, I-9, I-32, I-33, I-34, I-35, I-36, I-38, I-40 ,I-42,I-43,I-44,I-45,I-47,I-54,I-55,I-56,I-60,I-61,I-62,I-64,I-65,I-66.

[0474] Inhibitory activity IC of Nav1.8 ion channel 50 Compounds (nM) less than 10 μM and greater than or equal to 20 nM include: I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-24 ,I-25,I-26,I-29,I-37,I-39,I-41,I-46,I-49,I-50,I-51,I-52,I-53,I-57,I-58,I-59,I-69,I-70,I-71,I-72.

[0475] Inhibitory activity IC of Nav1.8 ion channel 50Compounds with an activity (nM) greater than or equal to 10 μM include: I-4, I-10, I-27, I-28, I-30, I-31, I-67, I-68, and I-73.

[0476] The test results show that the compound of the present invention has strong inhibitory activity on Nav1.8 ion channel.

[0477] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A compound, which is a compound represented by formula (II), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (II): in, Ring B is selected from a 5-6 membered heteroaromatic ring, wherein the heteroatom or heteroatom group in the 5-6 membered heteroaromatic ring is selected from S, S(=O), S(=O)2, P(=O)2, O, N + -O - , N or NH; R 0 Selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -NR 3 R 4 、-C(=O)NR 3 R 4 、-C(=NR 5 )NR 3 R 4 、-OR 4 、-S(=O)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ; Ring A is selected from C 3-12 Cycloalkyl, 4-12 membered heterocycloalkenyl, 3-12 membered heterocyclyl, C 6-12 Aryl and 5-12 membered heteroaryl; R 1 Selected from H, halogen, hydroxy, cyano, oxo, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -(C 1-6 alkyl)-C 3-12 Cycloalkyl, -(C 2-6 alkenyl)-C 3-12 Cycloalkyl, -(C 2-6 Alkynyl)-C 3-12 Cycloalkyl, -NR 3 R 4 、-C(=O)NR 3 R 4 、C 3-12 Cycloalkyl, 4-12 membered heterocycloalkenyl, 3-12 membered heterocyclyl, C 6-12 Aryl, 5-12 membered heteroaryl; wherein, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R A replaced by; R A Selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-6 Alkyl, =CR 3 R 4 、C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy; R 2 and R 2’ Each independently selected from H, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl, 5-12 membered heteroaryl; wherein, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R B replaced by; R B Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy; Or, R 2 Together with ring A, Among them, Z 1 and Z 2 Each independently selected from a single bond, -CR 3 R 4 -, -CH=, -NH-, -N=, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2- or -S(=O)(=NH)-; Or, R 2’ Together with ring A, Among them, Y 1 and Y 2 Each independently selected from a single bond, -CR 3 R 4 -, -CH=, -NH-, -N=, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2- or -S(=O)(=NH)-; Indicates a single bond or a double bond; R 3 、R 4 and R 5 Each independently selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl, 5-12 membered heteroaryl; wherein, the C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R C replaced by; Or, R 3 、R 4 Together with the atoms to which they are attached, they form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, the C 3-12 Cycloalkyl or 3-12 membered heterocyclic group is optionally substituted by one or more R C replaced by; R C Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy; n is selected from 0, 1, 2, 3, 4, 5 and 6; m is selected from the group consisting of 0, 1, 2, 3, 4, 5 and 6.

2. The compound of formula (II) according to claim 1, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, characterized in that: R 2 is H; and / or, R 2’ H, C 1-6 Alkyl or C 1-6 alkyl halide; and / or, R 2’ is H, methyl, difluoromethyl, or trifluoromethyl.

3. The compound of formula (II) according to claim 1, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, characterized in that: Group fragment Selected from Among them, X 3a N or CR 3a ;X 4a N or CR 4a ;X 5a N or CR 5a ;X 6a N, N + -O - or CR 6a ; R 3a 、R 4a 、R 5a 、R 6a Each independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -NR 3 R 4 、-C(=O)NR 3 R 4 、-C(=NR 5 )NR 3 R 4 、-OR 4 、-S(=O)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ; Among them, R 3 、R 4 、R 5 As defined in claim 1; Preferably, R 6a Selected from C 1-6 Alkoxy and -S(=O)(=NH)-(C 1-6 Alkyl), the C 1-6 The alkoxy group is substituted with 1, 2, 3, 4, 5 or 6 hydroxy groups; Preferably, X 3a and X 5a CH, X 5a Selected from N and CF; Preferably, R 3a 、R 4a 、R 5a are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; R 6a H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -NR 3 R 4 、-C(=O)NR 3 R 4 、-C(=NR 5 )NR 3 R 4 、-OR 4 、-S(=O)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ; W is selected from S, S(=O), S(=O)2, P(=O)2, O or NH; and / or, group fragments Selected from Among them, R 4a 、R 5a are each independently selected from H, halogen, C 1-6 Alkyl, R 6a is -OCH2CH(OH)CH2OH, -OCH2CH2OH, -C(=O)NHR 3 、-C(=NH)NHR 3 、-S(=O)2R 3 、-S(=O)2NHR 3 or -S(=O)(=NH)R 3 , R 3 H, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one or more R C Replaced by R C The definition of as claimed in claim 1; Preferably, the group fragment Selected from and / or, group fragments Selected from Among them, R 6a is -OCH2CH(OH)CH2OH, -OCH2CH2OH, -C(=O)NHR 3 、-C(=NH)NHR 3 、-S(=O)2R 3 、-S(=O)2NHR 3 or -S(=O)(=NH)R 3 , R 3 H, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one or more R C Replaced by R C The definition of as claimed in claim 1; Preferably, the group fragment Selected from 4. The compound of formula (II) according to claim 1, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, characterized in that: Ring A is a 6-membered heterocycloalkenyl, a 6-membered heterocyclyl, a 6-membered heteroaryl, a 5-membered heteroaryl or a phenyl group; preferably, Ring A is a pyridyl, a 1,2-dihydropyridyl, a phenyl or a thienyl group; and / or, R 1 H, halogen, oxo, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, -(C 2-6 Alkynyl)-C 3-12 Cycloalkyl; wherein said C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl and -(C 2-6 Alkynyl)-C 3-12 The cycloalkyl groups are each independently optionally substituted with one or more R A Replaced by; R A Selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, =CR 3 R 4 ; R 3 and R 4 The definition of as claimed in claim 1; and / or, group fragments for where R 2b 、R 3b 、R 4b and R 5b are each independently selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl; wherein said C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy and C 3-12 The cycloalkyl groups are each independently optionally substituted with one or more R A Replaced by; R A Selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy; and / or, group fragments for where R 2b 、R 3b 、R 4b and R 5b Each independently selected from H, Cl, methyl, tert-butyl or and / or, group fragments for and / or, group fragments for where R 3b and R 5b Each independently selected from and / or, group fragments for and / or, group fragments for where R 1b 、R 2b 、R 3b 、R 4b and R 5b are each independently selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 4-7 Cycloalkyl, 4-7 membered heterocyclic group, -(C 2-6 Alkynyl)-C 3-12 Cycloalkyl; the C 1-6 Alkyl, C 2-6 Alkynyl, C 4-7 Cycloalkyl, 4-7 membered heterocyclic group, -(C 2-6 Alkynyl)-C 3-12 The cycloalkyl groups are each independently optionally substituted with one or more R A Replaced by; R A Selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, =CR 3 R 4 ; R 3 and R 4 The definition of as claimed in claim 1; and / or, group fragments for where R 1b 、R 2b 、R 3b 、R 4b and R 5b Each independently selected from H, F, Cl, methyl, difluoromethyl, trifluoromethyl, tert-butyl, and / or, group fragments for and / or, group fragments for and / or, group fragments for 5. The compound of formula (II) according to claim 1, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, characterized in that: It is a compound represented by formula (I) or formula (II-A), in, X 3a N or CR 3a ; X 4a N or CR 4a ; X 5a N or CR 5a ; X 6a N, N + -O - or CR 6a ; R 3a 、R 4a 、R 5a are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; R 6a H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -NR 3 R 4 、-C(=O)NR 3 R 4 、-C(=NR 5 )NR 3 R 4 、-OR 4 、-S(=O)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ; W is selected from S, S(=O), S(=O)2, P(=O)2, O or NH; Ring A, R 1 、R 2 、R 2’ 、R 3 、R 4 、R 5 and n are as defined in claim 1.

6. The compound of formula (II) according to claim 1, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, characterized in that: It is a compound represented by formula (IA), formula (IB) or formula (IC): in, X 3a N or CR 3a ; X 4a N or CR 4a ; X 5a N or CR 5a ; X 6a N, N + -O - or CR 6a ; R 3a 、R 4a 、R 5a are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; R 6a H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -NR 3 R 4 、-C(=O)NR 3 R 4 、-C(=NR 5 )NR 3 R 4 、-OR 4 、-S(=O)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ; Among them, ring A, R 1 、R 3 、R 4 、R 5 、R C and n is defined as in claim 1; Ring B is C 3-6 Cycloalkyl; p is selected from 1, 2, 3, 4, 5 and 6.

7. The compound represented by formula (II) according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein: The compound represented by formula (II) is selected from the following compounds:

8. The compound represented by formula (II) according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein: The compound represented by formula (II) is selected from the following compounds:

9. A pharmaceutical composition, characterized in that The invention comprises the compound according to any one of claims 1 to 8, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug and a pharmaceutically acceptable excipient.

10. Use of the compound according to any one of claims 1 to 8, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the composition according to claim 9 in the preparation of a drug for inhibiting voltage-gated sodium ion channels; and / or, in the preparation of a drug for treating, alleviating or preventing pain; Preferably, the voltage-gated sodium ion channel is Nav1.8; Preferably, the pain includes acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.

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