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WO2025209562A1 - Composé de pyridone de tétrahydrofurane servant d'inhibiteur de nav1.8 - Google Patents

Composé de pyridone de tétrahydrofurane servant d'inhibiteur de nav1.8

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Publication number
WO2025209562A1
WO2025209562A1 PCT/CN2025/087032 CN2025087032W WO2025209562A1 WO 2025209562 A1 WO2025209562 A1 WO 2025209562A1 CN 2025087032 W CN2025087032 W CN 2025087032W WO 2025209562 A1 WO2025209562 A1 WO 2025209562A1
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Prior art keywords
alkyl
alkoxy
halogen
haloalkyl
membered
Prior art date
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Application number
PCT/CN2025/087032
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English (en)
Chinese (zh)
Inventor
张学军
李金平
徐招兵
杨辉
贾一民
安丹
杨俊�
李莉娥
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
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Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
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Publication of WO2025209562A1 publication Critical patent/WO2025209562A1/fr
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Anticipated expiration legal-status Critical

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom

Definitions

  • patent application number 202410405961.4 filed with the State Intellectual Property Office of China on April 3, 2024, entitled “Tetrahydrofuranpyridone compounds as Nav1.8 inhibitors”;
  • patent application number 202410725452.X filed with the State Intellectual Property Office of China on June 5, 2024, entitled “Tetrahydrofuranpyridone compounds as Nav1.8 inhibitors”;
  • patent application number 202411231872.9 filed with the State Intellectual Property Office of China on September 3, 2024, entitled “Tetrahydrofuran pyridone compounds as Nav1.8 inhibitors”;
  • the present invention belongs to the field of medicine and relates to tetrahydrofuran pyridone compounds as Nav1.8 inhibitors and their uses. Specifically, the present invention relates to substituted tetrahydrofuran 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.
  • 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.
  • action potentials nerve impulses
  • DRG dorsal root ganglia
  • 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.
  • NaV voltage-gated sodium channels
  • Human sodium channels are transmembrane ion channels composed of a 260kD ⁇ subunit and a 30-40kD ⁇ subunit. They are classified into nine subtypes based on the ⁇ 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.
  • Nav1.8 The gene encoding Nav1.8, SCN10A, is located in the human chromosome 3p21-22 region and primarily encodes the ⁇ 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.
  • 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.
  • Nav1.8 is mainly limited to neurons that perceive pain, selective Nav1.8 blockers are unlikely to induce the 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 effective, increased metabolic stability, increased solubility and fewer side effects.
  • 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.
  • R D is selected from H, halogen, hydroxy, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;
  • Y is selected from O, S or NH
  • R1 is selected from H, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C6-12 aryl, 5-12 membered heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C6-12 aryl and 5-12 membered heteroaryl are each independently optionally substituted with one or more RA ;
  • R 3 , R 4 and R 5 are each independently selected from H, halogen, hydroxyl, 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 membered heteroaryl are each independently optionally substituted by one or more R C ;
  • R C is selected from H, halogen, hydroxy, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;
  • R 5b1 and R 5b2 are each independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 haloalkyl;
  • R 5b1 and R 5b2 together with the atoms to which they are attached form a C 3-6 saturated ring, which is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 ;
  • R 4b1 and R 5b1 together with the atoms to which they are attached form a C 3-6 saturated ring, which is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 ;
  • X 3c is selected from N or CR 3c ;
  • X 4c is selected from N or CR 4c ;
  • X 6c is selected from N or CR 6c ;
  • R 4c is selected from H, halogen, C 1-6 alkyl, or C 1-6 haloalkyl;
  • L 1 is a bond or -O-
  • n is selected from 0, 1, 2, 3, 4, 5 and 6.
  • the compound of the present invention, its tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug is a compound represented by formula (V)
  • A is selected from H, C 1-6 alkyl or C 3-12 cycloalkyl; wherein the C 1-6 alkyl and C 3-12 cycloalkyl are each independently optionally substituted by one or more R D ;
  • R D is selected from H, halogen, hydroxy, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;
  • Y is selected from O or S
  • Z is N or CR 2 ;
  • RA is selected from H, halogen, hydroxy, cyano, nitro, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy;
  • R2 is independently selected from H, halogen, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C6-12 aryl, 5-12 membered heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl , C1-6 alkoxy, C3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C6-12 aryl and 5-12 membered heteroaryl are each independently optionally substituted by one or more R B ;
  • RB is selected from H, halogen, hydroxy, cyano, nitro, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy;
  • R 3 , R 4 together with the atoms to which they are attached, form a C 3-12 cycloalkyl group or a 3-12 membered heterocyclyl group, wherein the C 3-12 cycloalkyl group and the 3-12 membered heterocyclyl group are optionally substituted with one or more R C ;
  • R C is selected from H, halogen, hydroxy, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;
  • R 5b1 and R 5b2 are each independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 haloalkyl;
  • R 5b1 and R 5b2 together with the atoms to which they are attached form a C 3-6 saturated ring, which is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 ;
  • R 4b1 and R 5b1 together with the atoms to which they are attached form a C 3-6 saturated ring, which is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 ;
  • R 6b is selected from H, -OH, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy;
  • X 2c is selected from N or CR 2c ;
  • R 6c is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxy;
  • RA is selected from H, halogen, hydroxy, cyano, nitro, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy;
  • RB is selected from H, halogen, hydroxy, cyano, nitro, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy;
  • R 4b1 and R 4b2 are each independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 haloalkyl;
  • R 4b1 and R 4b2 together with the atoms to which they are attached form a C 3-6 saturated ring, which is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 ;
  • R 5b1 and R 5b2 are each independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 haloalkyl;
  • R 4b1 and R 5b1 together with the atoms to which they are attached form a C 3-6 saturated ring, which is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 ;
  • R 7b is selected from H, -OH, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy;
  • L 2 is a bond or -(C 1-6 alkyl)-
  • the compound of the present invention is a compound represented by formula (IV)
  • A is selected from C 1-6 alkyl or C 3-12 cycloalkyl; wherein the C 1-6 alkyl and C 3-12 cycloalkyl are each independently optionally substituted by one or more R D ;
  • R D is selected from H, halogen, hydroxy, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;
  • R1 is selected from H, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C6-12 aryl, 5-12 membered heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C6-12 aryl and 5-12 membered heteroaryl are each independently optionally substituted with one or more RA ;
  • RA is selected from H, halogen, hydroxy, cyano, nitro, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy;
  • R2 is independently selected from H, halogen, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C6-12 aryl, 5-12 membered heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl , C1-6 alkoxy, C3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C6-12 aryl and 5-12 membered heteroaryl are each independently optionally substituted by one or more R B ;
  • R 3 , R 4 and R 5 are each independently selected from H, halogen, hydroxyl, 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 membered heteroaryl are each independently optionally substituted by one or more R C ;
  • R C is selected from H, halogen, hydroxy, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;
  • R 4b1 and R 4b2 are each independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 haloalkyl;
  • R 4b1 and R 4b2 together with the atoms to which they are attached form a C 3-6 saturated ring, which is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 ;
  • R 5b1 and R 5b2 together with the atoms to which they are attached form a C 3-6 saturated ring, which is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 ;
  • R 6b is selected from H, -OH, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy;
  • L 2 is a bond or -(C 1-6 alkyl)-
  • n is selected from 0, 1, 2, 3, 4, 5 and 6.
  • the compound of the present invention is a compound represented by formula (III)
  • Z is N or CR 2 ;
  • X 6a is N, N + —O — , or CR 6a ;
  • R1 is selected from H, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C6-12 aryl, 5-12 membered heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C6-12 aryl and 5-12 membered heteroaryl are each independently optionally substituted with one or more RA ;
  • RA is selected from H, halogen, hydroxy, cyano, nitro, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy;
  • R2 is independently selected from H, halogen, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C6-12 aryl, 5-12 membered heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl , C1-6 alkoxy, C3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C6-12 aryl and 5-12 membered heteroaryl are each independently optionally substituted by one or more R B ;
  • RB is selected from H, halogen, hydroxy, cyano, nitro, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy;
  • R 3 , R 4 and R 5 are each independently selected from H, halogen, hydroxyl, 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 membered heteroaryl are each independently optionally substituted by one or more R C ;
  • R 3 , R 4 together with the atoms to which they are attached, form a C 3-12 cycloalkyl group or a 3-12 membered heterocyclyl group, wherein the C 3-12 cycloalkyl group and the 3-12 membered heterocyclyl group are optionally substituted with one or more R C ;
  • R C is selected from H, halogen, hydroxy, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;
  • R 4b1 and R 4b2 together with the atoms to which they are attached form a C 3-6 saturated ring, which is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 ;
  • R 5b1 and R 5b2 are each independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 haloalkyl;
  • R 7b is selected from H, -OH, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy;
  • X 5c is selected from N or CR 5c ;
  • X 6c is selected from N or CR 6c ;
  • R 3c is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -(C 1-6 alkylene)-(C 1-6 alkoxy);
  • R 4c is selected from H, halogen, C 1-6 alkyl, or C 1-6 haloalkyl;
  • R 6c is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxy;
  • L 2 is a bond or -(C 1-6 alkyl)-.
  • the compound of the present invention is a compound represented by formula (II)
  • A is selected from C 1-6 alkyl or C 3-12 cycloalkyl; wherein the C 1-6 alkyl and C 3-12 cycloalkyl are each independently optionally substituted by one or more R D ;
  • R D is selected from H, halogen, hydroxy, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;
  • X 6a is N, N + —O — , or CR 6a ;
  • R 6a is H, halogen, hydroxy, 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) 2 R 3 , -S( ⁇ O) 2 NR 3 R 4 or -S( ⁇ O)( ⁇ NR 5 )R 3 ;
  • RA is selected from H, halogen, hydroxy, cyano, nitro, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy;
  • R2 is independently selected from H, halogen, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C6-12 aryl, 5-12 membered heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl , C1-6 alkoxy, C3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C6-12 aryl and 5-12 membered heteroaryl are each independently optionally substituted by one or more R B ;
  • R 3 , R 4 and R 5 are each independently selected from H, halogen, hydroxyl, 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 membered heteroaryl are each independently optionally substituted by one or more R C ;
  • R 3 , R 4 together with the atoms to which they are attached, form a C 3-12 cycloalkyl group or a 3-12 membered heterocyclyl group, wherein the C 3-12 cycloalkyl group and the 3-12 membered heterocyclyl group are optionally substituted with one or more R C ;
  • R 4b1 and R 4b2 are each independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 haloalkyl;
  • R 5b1 and R 5b2 are each independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 haloalkyl;
  • R 5b1 and R 5b2 together with the atoms to which they are attached form a C 3-6 saturated ring, which is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 ;
  • X 2c is selected from N or CR 2c ;
  • X 3c is selected from N or CR 3c ;
  • X 4c is selected from N or CR 4c ;
  • X 5c is selected from N or CR 5c ;
  • X 6c is selected from N or CR 6c ;
  • R 3c is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -(C 1-6 alkylene)-(C 1-6 alkoxy);
  • R 4c is selected from H, halogen, C 1-6 alkyl, or C 1-6 haloalkyl;
  • R 5c is selected from H, halogen, C 1-6 alkyl, or C 1-6 haloalkyl
  • L 1 is a bond or -O-
  • L 2 is a bond or -(C 1-6 alkyl)-.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 4b1 , R 4b2 , R 5b1 , R 5b2 , R 6b , R 7b , RA and A are as defined herein.
  • the compound of the present invention, its tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug is represented by Formula (II-A), Formula (II-C), Formula (II-D) or Formula (II-E):
  • X 5a is N or CR 5a ;
  • X 6a is N, N + —O — , or CR 6a ;
  • X 3a is N or CR 3a ;
  • R 6a is H, halogen, hydroxy, cyano, 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) 2 R 3 , -S( ⁇ O) 2 NR 3 R 4 or -S( ⁇ O)( ⁇ NR 5 )R 3 ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 4b1 , R 4b2 , R 5b1 , R 5b2 , R 6b , R 7b and A are as defined in the present invention.
  • the compound of the present invention is a compound represented by formula (II-A), formula (II-C) or formula (II-D):
  • R 3a , R 4a , and R 5a are each independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 4b1 , R 4b2 , R 5b1 , R 5b2 , R 6b , R 7b and A are as defined in the present invention.
  • X3a , X4a , X5a , X6a , R1 , R2 , R4b1 , R4b2 , R5b1 , R5b2 , R6b , R7b and A are as defined in the present invention.
  • X3a , X4a , X5a , X6a , R1 , R2 , R4b1 , R4b2 , R5b1 , R5b2 , R6b , R7b and A are as defined in the present invention.
  • the compound of the present invention is a compound represented by formula (I):
  • X3a , X4a, X5a , X6a , R1 , R2 , R4b1 , R4b2 , R5b1 , R5b2 , R6b , R7b , X2c , X3c , X4c , X5c and X6c are as defined in the present invention.
  • the compound of the present invention is a compound represented by formula (I):
  • X 3a is N or CR 3a ;
  • X 4a is N or CR 4a ;
  • X 5a is N or CR 5a ;
  • X 6a is N, N + —O — , or CR 6a ;
  • R 6a is H, halogen, hydroxy, 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) 2 R 3 , -S( ⁇ O) 2 NR 3 R 4 or -S( ⁇ O)( ⁇ NR 5 )R 3 ;
  • R1 is selected from H, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C6-12 aryl, 5-12 membered heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C6-12 aryl and 5-12 membered heteroaryl are each independently optionally substituted with one or more RA ;
  • R2 is independently selected from H, halogen, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C6-12 aryl, 5-12 membered heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl , C1-6 alkoxy, C3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C6-12 aryl and 5-12 membered heteroaryl are each independently optionally substituted by one or more R B ;
  • RB is selected from H, halogen, hydroxy, cyano, nitro, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy;
  • R 3 , R 4 and R 5 are each independently selected from H, halogen, hydroxyl, 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 membered heteroaryl are each independently optionally substituted by one or more R C ;
  • R C is selected from H, halogen, hydroxy, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;
  • R 4b1 and R 4b2 together with the atoms to which they are attached form a C 3-6 saturated ring, which is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 ;
  • R 5b1 and R 5b2 are each independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl or C 1 -C 6 haloalkyl;
  • R 7b is selected from H, -OH, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy;
  • X 2c is selected from N or CR 2c ;
  • X 3c is selected from N or CR 3c ;
  • X 4c is selected from N or CR 4c ;
  • X 5c is selected from N or CR 5c ;
  • X 6c is selected from N or CR 6c ;
  • R 4c is selected from H, halogen, C 1-6 alkyl, or C 1-6 haloalkyl;
  • R 6c is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxy;
  • L 2 is a bond or -(C 1-6 alkyl)-.
  • X 3a is N or CR 3a ;
  • X 5a is N or CR 5a ;
  • R 3a and R 4a are each independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 4b1 , R 4b2 , R 5b1 , R 5b2 , R 6b , R 7b , X 2c , X 3c , X 4c , X 5c and X 6c are as defined in the present invention.
  • the compound of the present invention is a compound represented by formula (IA), formula (IB), formula (IC) or formula (ID):
  • X 3a is N or CR 3a ;
  • X 4a is N or CR 4a ;
  • X 5a is N or CR 5a ;
  • X 6a is N, N + —O — , or CR 6a ;
  • R 6a is H, halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl substituted by one or more hydroxy groups, -NR 3 R 4 , -C( ⁇ O)NR 3 R 4 , -C( ⁇ NR 5 )NR 3 R 4 , -OR 4 , -S( ⁇ O) 2 R 3 , -S( ⁇ O) 2 NR 3 R 4 or -S( ⁇ O)( ⁇ NR 5 )R 3 ;
  • the compound of the present invention is a compound represented by formula (IA), formula (IB), formula (IC) or formula (ID):
  • X 3a is N or CR 3a ;
  • X 4a is N or CR 4a ;
  • X 5a is N or CR 5a ;
  • R 3a , R 4a , and R 5a are each independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 4b1 , R 4b2 , R 5b1 , R 5b2 , R 6b , R 7b , X 2c , X 3c , X 4c , X 5c and X 6c are as defined in the present invention.
  • the compound of the present invention is a compound represented by formula (IA), formula (IB) or formula (IC):
  • X 3a is N or CR 3a ;
  • X 4a is N or CR 4a ;
  • X 5a is N or CR 5a ;
  • X 6a is N, N + —O — , or CR 6a ;
  • R 6a is H, halogen, hydroxy, cyano, 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) 2 R 3 , -S( ⁇ O) 2 NR 3 R 4 or -S( ⁇ O)( ⁇ NR 5 )R 3 ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 4b1 , R 4b2 , R 5b1 , R 5b2 , R 6b , R 7b , X 2c , X 3c , X 4c , X 5c and X 6c are as defined in the present invention.
  • the compound of the present invention is a compound represented by formula (IA) or formula (IB):
  • R 1 is H, hydroxy or C 1-6 alkoxy; preferably, R 1 is H or hydroxy.
  • R 1 is H.
  • R2 is independently selected from H, halogen, hydroxy, cyano, C1-6 alkyl, C1-6 alkoxy; the C1-6 alkyl and C1-6 alkoxy are each independently optionally substituted by one or more RB ; RB is as defined in the present invention.
  • R2 is independently selected from H, halogen, hydroxy, C1-3 alkyl, C1-3 alkoxy; the C1-3 alkyl and C1-3 alkoxy are each independently optionally substituted with one or more RB ; RB is as defined in the present invention.
  • R 2 is independently selected from H, F, Cl, hydroxy, methyl, methoxy; the methyl and methoxy groups are each independently optionally substituted with one or more RB ; RB is as defined in the present invention.
  • RB is selected from H, F, Cl, hydroxy, C1-3 alkyl, and C1-3 alkoxy.
  • X 3a is N or CR 3a ;
  • X 4a is N or CR 4a ;
  • X 5a is N or CR 5a ;
  • X 6a is N, N + —O — , or CR 6a ;
  • R 3a , R 4a , R 5a , and R 6a are each independently selected from H, halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, —NR 3 R 4 , —C( ⁇ O)NR 3 R 4 , —C( ⁇ NR 5 )NR 3 R 4 , —OR 4 , —S( ⁇ O) 2 R 3 , —S( ⁇ O) 2 NR 3 R 4
  • R 3a , R 4a , R 5a and R 6a are each independently selected from H, halogen, C 1-6 alkyl
  • R 6a and R 5a are each independently selected from cyano, -CH(OH)CH 2 OH, -OCH 2 CH(OH)CH 2 OH, -C( ⁇ O)NHR 3 , -C( ⁇ NH)NHR 3 , -S( ⁇ O) 2 R 3 , -S( ⁇ O) 2 NHR 3 , -S( ⁇ O)( ⁇ NH)R 3 or -OR 4
  • R 3 is H, hydroxy, C 1-6 alkyl or C 1-6 alkoxy, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with one or more R C ;
  • X 3a is N or CR 3a ;
  • X 4a is N or CR 4a ;
  • X 5a is N or CR 5a ;
  • X 6a is N, N + -O - , or CR 6a ;
  • R 3a , R 4a are each independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy;
  • R 5a and R 6a are each independently selected from H, halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl, 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) 2 R 3 , -S( ⁇ O) 2 NR 3 R 4 or
  • R 6a is independently selected from H, hydroxy, cyano,
  • R 5a is independently selected from H, hydroxy, cyano,
  • R 3 , R 4 , and R 5 are each independently selected from H, halogen, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy; and the C 1-6 alkyl and C 1-6 alkoxy are each independently optionally substituted with 1, 2, 3, 4, 5, or 6 H, halogen, or hydroxy.
  • R 3 , R 4 and R 5 are each independently selected from H, hydroxy, methyl,
  • R 4a is independently selected from H, halogen, and C 1-6 alkyl.
  • R 4a is independently selected from H, F, Cl, methyl, ethyl, n-propyl, isopropyl.
  • R 4a is H.
  • X 3a is N or CR 3a ;
  • X 4a is N or CR 4a ;
  • X 5a is N or CR 5a ;
  • X 6a is N, N + -O - , or CR 6a ;
  • R 3a , R 4a , and R 5a are each independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; and
  • R 6a is H, halogen, hydroxy, 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) 2 R 3 , -S( ⁇ O) 2 NR 3 R 4 , or -S( ⁇ O)( ⁇ NR 5 )R 3 ;
  • W is selected from
  • R 4a is H, halogen, or C 1-6 alkyl
  • R 6a and R 5a are each independently selected from H, halogen, C 1-6 alkyl, cyano, -CH(OH)CH 2 OH, -OCH 2 CH(OH)CH 2 OH, -C( ⁇ O)NHR 3 , -C( ⁇ NH)NHR 3 , -S( ⁇ O) 2 R 3 , -S( ⁇ O) 2 NHR 3 , -S( ⁇ O)( ⁇ NH)R 3 or -OR 4 ;
  • R 3 is H, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy, wherein the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with one or more RC , and RC is as defined herein;
  • R 4 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more RC , and RC is as defined herein
  • R 4a and R 5a are each independently selected from H, halogen, C 1-6 alkyl
  • R 6a is cyano, -CH(OH)CH 2 OH, -OCH 2 CH(OH)CH 2 OH, -C( ⁇ O)NHR 3 , -C( ⁇ NH)NHR 3 , -S( ⁇ O) 2 R 3 , -S( ⁇ O) 2 NHR 3 , -S( ⁇ O)( ⁇ NH)R 3 or -OR 4
  • R 3 is H, hydroxy, C 1-6 alkyl or C 1-6 alkoxy, said C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with one or more RC
  • RC is as defined in the present invention
  • R 4 is H or C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with one or more RC
  • RC is as defined in the present invention.
  • R 4a and R 5a are each independently selected from H, halogen, C 1-6 alkyl;
  • R 3 is H, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy, the C 1-6 alkyl and C 1-6 alkoxy being optionally substituted with one or more RC , and RC being as defined herein;
  • R 4 is H or C 1-6 alkyl, the C 1-6 alkyl being optionally substituted with one or more RC , and RC being as defined herein.
  • R 4b1 , R 4b2 , R 5b1 , R 5b2 , R 6b and R 7b are as defined in the present invention.
  • R 4b1 , R 4b2 , R 5b1 , R 5b2 , R 6b and R 7b are as defined in the present invention.
  • R 5b1 and R 5b2 are each independently selected from C 1-6 alkyl or C 1-6 haloalkyl; preferably, R 5b1 and R 5b2 are each independently selected from methyl or trifluoromethyl; more preferably, R 5b1 is methyl and R 5b2 is trifluoromethyl.
  • R 6b is H.
  • R 3c is H or halogen; preferably, R 3c is H, F or Cl; more preferably, R 3c is H or F.
  • R 4c is halogen; preferably, R 4c is F or Cl; more preferably, R 4c is F.
  • A is C 1-6 alkyl; preferably, A is methyl, ethyl, n-propyl or isopropyl; more preferably, A is methyl;
  • excipient refers to a pharmaceutically acceptable inert ingredient.
  • 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.
  • 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.
  • stereoisomer refers to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.
  • stereoisomers 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.
  • 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 ⁇ -camphorsulfonic acid.
  • 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 ⁇ -camphorsulfonic acid.
  • the keto form predominates
  • phenols the enol form predominates
  • the present invention encompasses all tautomeric forms of the compounds.
  • 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 whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
  • the keto form predominates
  • phenols the enol form predominates
  • the present invention encompasses all tautomeric forms of the compounds. For example:
  • 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:
  • the hydrogen atoms of the tetrazole nitrogen can be on any of the four nitrogen atoms.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • the compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125I), or C-14 ( 14C). All isotopic variations of the compounds of the present invention (i.e., "isotopically labeled materials"), whether radioactive or not, are included within the scope of the present invention.
  • an effective amount or “therapeutically effective amount” refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect.
  • 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.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease, or condition.
  • 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.
  • Keto substitution does not occur on aromatic groups.
  • the substituent is limited to one or more, the plurality includes two, three, four or more.
  • any variable e.g., R
  • its definition at each occurrence is independent.
  • the group may be optionally substituted with up to two R, and each occurrence of R is an independent choice.
  • R is substituted with g Ra
  • each Ra is an independent choice and may be the same or different.
  • C 1-6 alkyl is used to represent a straight or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms.
  • the C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2, C 2-6 , C 2-4 , C 6 and C 5 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine).
  • C 1-6 alkyl groups 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 and the like.
  • C 1-3 alkyl refers to a linear or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, and can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine).
  • Examples of C 1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C2-6 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 within the group.
  • the C2-6 alkenyl group includes C2-4 , C2-3 , C4 , C3 , and C2 alkenyl groups, and may be monovalent, divalent, or polyvalent.
  • Examples of C2-6 alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentyladienyl, and hexadienyl.
  • C2-6 alkynyl is used to refer to 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 within the group.
  • the C2-6 alkynyl group includes C2-4 , C2-3 , C4 , C3 , and C2 alkynyl groups. It may be monovalent, divalent, or polyvalent. Examples of C2-6 alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and pentynyl.
  • C2-3 alkynyl refers to 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 within the group. It may be monovalent, divalent, or polyvalent.
  • the C2-3 alkynyl group includes C3 and C2 alkynyl groups. Examples of C2-3 alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like.
  • C 1-6 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.
  • C 1-3 alkoxy refers to an alkyl group containing 1 to 3 carbon atoms that is attached to the rest of the molecule via an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups.
  • Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 3-12 cycloalkyl or “C 3-12 saturated ring” refers to a saturated cyclic hydrocarbon group consisting of 3 to 12 carbon atoms, including monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, fused and bridged rings.
  • the C 3-12 cycloalkyl group includes 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 groups, etc.; and can be monovalent, divalent or polyvalent.
  • C 3-8 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, etc.
  • C3-8 cycloalkyl refers to a saturated cyclic hydrocarbon group consisting of 3 to 8 carbon atoms, including monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spirocyclic, fused, and bridged rings.
  • the C3-8 cycloalkyl group includes C3-6 , C3-5 , C4-8 , C4-6 , C4-5 , C5-8 , or C5-6 cycloalkyl groups, and can be monovalent, divalent, or polyvalent.
  • 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.
  • prevent disease e.g., prevent a disease, disorder, or condition in an individual who is susceptible
  • treatment and other similar synonyms include the following meanings:
  • 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.
  • N equivalent concentration, for example, 2N hydrochloric acid means 2 mol/L hydrochloric acid solution
  • Step 3 Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide
  • Step 4 Synthesis of N-(tert-butyl)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide
  • Step 5 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-1)
  • N-(tert-Butyl)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide 80.0 mg, 144 ⁇ mol
  • acetic acid (2 mL)
  • N-iodosuccinimide 29.2 mg, 130 ⁇ mol
  • reaction solution was poured into sodium bicarbonate (20 mL), the pH was adjusted to 7, and the product was extracted with ethyl acetate (10 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product.
  • Step 2 Synthesis of N-(tert-butyl)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide
  • N-(tert-Butyl)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-iodo-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (58.0 mg, 85.4 ⁇ mol) was dissolved in dioxane (2 mL), and methylboric acid (25.5 mg, 427 ⁇ mol), tetrakistriphenylphosphine palladium (19.7 mg, 17.1 ⁇ mol) and potassium phosphate (90.6 mg, 427 ⁇ mol) were added.
  • Step 3 Synthesis of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-4)
  • N-(tert-Butyl)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (20.0 mg, 35.2 ⁇ mol) was dissolved in toluene (1 mL), tert-butyldimethylsilyl trifluoromethylsulfonate (465 mg, 1.76 mmol) was added, and the mixture was stirred at 60°C for 1 hour.
  • Step 1 Synthesis of N-(tert-butyl)-3-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide
  • N-(tert-Butyl)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide 200 mg, 361 ⁇ mol was dissolved in acetic acid (4 mL), and N-chlorosuccinimide (43.4 mg, 325 ⁇ mol) was added. The reaction was stirred at 50 °C for 12 hours.
  • reaction solution was poured into sodium bicarbonate (50 mL), the pH was adjusted to 7, and the product was extracted with ethyl acetate (10 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product.
  • Step 2 Synthesis of 3-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-6)
  • Step 1 Synthesis of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-(methylsulfonyl)-1,6-naphthyridin-4(1H)-one
  • Step 2 Synthesis of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-1,6-naphthyridin-4(1H)-one
  • the starting material 3-bromo-4-chloro-N,N-bis(4-methoxybenzyl)pyridine-2-sulfonamide (1.19 g, 3.28 mmol), was dissolved in dioxane (20 mL). The reaction system was purged with nitrogen three times. Dichlorobis(triphenylphosphine)palladium (383 mg, 547 ⁇ mol) and tributyl(1-ethoxyethylene)tin (1.19 g, 3.28 mmol) were added at 25°C, respectively, and stirred at 110°C for 12 hours. After the reaction was complete, the mixture was concentrated to obtain the crude product.
  • Step 5 Synthesis of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-N,N-bis(4-methoxybenzyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-sulfonamide
  • Step 6 Synthesis of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-sulfonamide (target compound (I-9)
  • Step 3 Synthesis of (2R,3S,4S,5R)-N-(3-acetyl-2-(methylthio)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide
  • the crude product was diluted in dichloromethane (20 mL) and slowly added dropwise to a solution of 1-(4-amino-2-(methylthio)pyridin-3-yl)ethan-1-one (600 mg, 3.29 mmol) and triethylamine (666 mg, 6.58 mmol) in dichloromethane (20 mL) at 0°C. The mixture was then stirred at 25°C for 2 hours. After the reaction was complete, the reaction solution was concentrated to yield the crude product as a pale yellow oil.
  • Step 4 Synthesis of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-(methylthio)-1,6-naphthyridin-4(1H)-one
  • Step 5 Synthesis of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-(S-methylsulfonylimino)-1,6-naphthyridin-4(1H)-one (I-10)
  • Step 5 Synthesis of N-(tert-butyl)-2-((2R,3R)-3-cyclopropyl-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide
  • Step 1 Synthesis of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-hydroxy-1,6-naphthyridin-4(1H)-one (I-16)
  • Step 3 Synthesis of ethyl-(2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate
  • Step 8 Synthesis of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-20)
  • Step 1 Synthesis of N-(tert-butyl)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-hydroxy-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide
  • Step 2 Synthesis of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-hydroxy-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-25)
  • N-(tert-Butyl)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-hydroxy-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (40 mg, 70.2 ⁇ mol) was dissolved in toluene (5 mL), and tert-butyldimethylsilyl trifluoromethylsulfonate (185 mg, 702 ⁇ mol) was added. The reaction was stirred at 70°C for 1 hour.
  • Step 2 Synthesis of (4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl acetate
  • Step 5 Synthesis of 3-acetyl-N-(tert-butyl)-4-((4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinamide and N-(tert-butyl)-2-((4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide Under nitrogen protection, (4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (100 mg, 0.47 mmol), 3-acetyl-N-(tert-butyl)-4-chloropicolinamide (120 mg, 0.47 mmol), tripotassium phosphate (500 mg, 2.35 mmol), Pd(dba) 2 To a mixture of
  • Step 6 Synthesis of 2-((4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-63B)
  • Step 7 Synthesis of N-(tert-butyl)-2-((4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide
  • Step 8 Synthesis of 2-((4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-63B)
  • Step 1 Synthesis of (2R,3S,4S,5R)-N-(6-chloro-2-iodopyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide
  • Step 2 Synthesis of (2R,3S,4S,5R)-N-(2-acetyl-6-chloropyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxolane-2-carboxamide
  • Bis(triphenylphosphine)palladium dichloride (83.2 mg, 118 umol) was added at 25°C, and the mixture was stirred at 100°C for 8 hours. After completion of the reaction, saturated aqueous potassium fluoride solution (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was dissolved in tetrahydrofuran, and then 6M hydrochloric acid (5 mL) was added. The mixture was stirred at 25°C for 1 hour, then extracted with ethyl acetate (50 mL*3).
  • Step 3 Synthesis of 6-chloro-2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxolan-2-yl]-1,4-dihydro-1,5-naphthyridin-4-one
  • Step 5 Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxolan-2-yl]-6-(1,2-dihydroxyethyl)-1,4-dihydro-1,5-naphthyridin-4-one (target compound I-66)
  • Step 4 Synthesis of methyl 5-( ⁇ [(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]carbonyl ⁇ amino)-6-acetylpyridine-2-carboxylate (7)
  • Step 5 Synthesis of 6-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-8-oxyylidene-5H-pyrido[3,2-b]pyridine-2-carboxylic acid (8)
  • Step 6 6-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-8-oxyylidene-5H-pyrido[3,2-b]pyridine-2-carboxamide (I-67)
  • reaction mixture was separated by HPLC (Column: SunFire TM Prep C18 OBD TM 5 ⁇ m, 30X 150mm, Phase: ACN/ H2O (0.5% FA) 40% ACN) to give 6-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-8-oxylidene-5H-pyrido[3,2-b]pyridine-2-carboxamide (I-67) (3.1 mg, yield: 6.23%).
  • Test Example 1 Detection of the inhibitory activity of compounds on Nav1.8 ion channels
  • test and control compound solutions contained 1 ⁇ M TTX.
  • the intracellular fluid 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.
  • 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.
  • DMSO dimethyl sulfoxide
  • Adjust the Stage to Patch control the leak within -200pA, and continue to apply negative pressure to rupture the cell membrane, forming a current path. Open the vacuum device and the extracellular solution valve to perfuse, observe the cell current, and start adding drugs when the cell current stabilizes (the current curves of at least 3 sweeps overlap). Add medicine from low concentration to high concentration, the adding time for each concentration should be no less than 2 minutes and wait until the current is stable before changing the concentration.
  • the test article is administered using a gravity-fed perfusion system.
  • the peak current amplitude is observed for at least 1 minute until it stabilizes.
  • 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.
  • 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.
  • 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.
  • the inhibitory activity (IC 50 ) of the drug on Nav1.8 ion channel was then calculated.
  • mice For the pharmacokinetic study in mice, three male ICR mice weighing 20-30 g were fasted overnight and orally administered with 10 mg/kg. Blood was collected before administration and at 5, 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours after administration. The blood samples were centrifuged at 6000 g for 3 minutes at 2-8°C, and the plasma was collected and stored at -20°C.
  • the plasma at each time point was taken, 10 times the amount of 50% methanol-acetonitrile solution containing the internal standard was added and mixed, vortexed for 5 minutes, centrifuged at 4000 rpm and 4°C for 10 minutes, the supernatant was taken and 1 times the amount of water was added and mixed, and an appropriate amount of the mixture was taken for LC-MS/MS analysis.
  • the main pharmacokinetic parameters were analyzed by non-compartmental model using WinNonlin 7.0 software.
  • mice show that the compound of the present invention has good pharmacokinetic properties in mice.
  • the plasma at each time point was taken, 10 times the amount of 50% methanol-acetonitrile solution containing the internal standard was added and mixed, vortexed for 5 minutes, centrifuged at 4000 rpm and 4°C for 10 minutes, the supernatant was taken and 1 times the amount of water was added and mixed, and an appropriate amount of the mixture was taken for LC-MS/MS analysis.
  • the main pharmacokinetic parameters were analyzed by non-compartmental model using WinNonlin 7.0 software.
  • Canine pharmacokinetic study was conducted using 3 male Beagle dogs weighing 7-11 kg, fasted overnight, and orally administered with 5 mg/kg. Blood was collected before administration and 5, 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours after administration. Blood samples were centrifuged at 6000g for 3 minutes at 2-8°C, and plasma was collected and stored at -20°C. Plasma was collected at each time point, added with 10 times the amount of 50% methanol-acetonitrile solution containing internal standard, mixed, vortexed for 5 minutes, centrifuged at 4000 rpm at 4°C for 10 minutes, and the supernatant was added with 1 times the amount of water and mixed. An appropriate amount of the mixture was taken for LC-MS/MS analysis. The main pharmacokinetic parameters were analyzed by non-compartmental model using WinNonlin 7.0 software.

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Abstract

La présente invention concerne un composé tel que représenté dans la formule (V), un tautomère, un stéréoisomère, un hydrate, un solvate, un sel pharmaceutiquement acceptable ou un promédicament de celui-ci. Le composé a un bon effet d'inhibition de Nav1.8.
PCT/CN2025/087032 2024-04-03 2025-04-03 Composé de pyridone de tétrahydrofurane servant d'inhibiteur de nav1.8 Pending WO2025209562A1 (fr)

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CN202410405961 2024-04-03
CN202410405961.4 2024-04-03
CN202410725452 2024-06-05
CN202410725452.X 2024-06-05
CN202410931168.8 2024-07-11
CN202410931168 2024-07-11
CN202411090328 2024-08-08
CN202411090328.7 2024-08-08
CN202411231872 2024-09-03
CN202411231872.9 2024-09-03
CN202411690310.0 2024-11-22
CN202411690310 2024-11-22

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