WO2020169042A1 - 6-氧代-1,6-二氢哒嗪类前药衍生物、其制备方法及其在医药上的应用 - Google Patents

6-氧代-1,6-二氢哒嗪类前药衍生物、其制备方法及其在医药上的应用 Download PDF

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Publication number
WO2020169042A1
WO2020169042A1 PCT/CN2020/075790 CN2020075790W WO2020169042A1 WO 2020169042 A1 WO2020169042 A1 WO 2020169042A1 CN 2020075790 W CN2020075790 W CN 2020075790W WO 2020169042 A1 WO2020169042 A1 WO 2020169042A1
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general formula
alkyl
pharmaceutically acceptable
alkoxy
cooh
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PCT/CN2020/075790
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English (en)
French (fr)
Inventor
杨方龙
郁楠
池江涛
刘志伟
贺峰
陶维康
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Priority to JP2021547265A priority Critical patent/JP2022521483A/ja
Priority to MX2021009539A priority patent/MX2021009539A/es
Priority to BR112021014178-2A priority patent/BR112021014178A2/pt
Priority to CN202080005987.XA priority patent/CN112996776B/zh
Priority to US17/431,007 priority patent/US20220162169A1/en
Priority to AU2020224245A priority patent/AU2020224245A1/en
Application filed by Jiangsu Hengrui Medicine Co Ltd, Shanghai Hengrui Pharmaceutical Co Ltd filed Critical Jiangsu Hengrui Medicine Co Ltd
Priority to CA3129600A priority patent/CA3129600A1/en
Priority to EP20760294.7A priority patent/EP3929181A4/en
Priority to KR1020217028610A priority patent/KR20210131357A/ko
Publication of WO2020169042A1 publication Critical patent/WO2020169042A1/zh
Anticipated expiration legal-status Critical
Priority to ZA2021/06711A priority patent/ZA202106711B/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/14—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/22—Nitrogen and oxygen atoms
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present disclosure belongs to the field of medicine, and relates to a 6-oxo-1,6-dihydropyridazine prodrug derivative, a preparation method thereof, and application in medicine.
  • the present disclosure relates to a 6-oxo-1,6-dihydropyridazine prodrug derivative represented by general formula (I), a preparation method thereof, and a pharmaceutical composition containing the derivative, and The use as a Na V inhibitor and its use in preparing medicines for treating and/or reducing pain and pain-related diseases.
  • Pain is a complex physical and psychological activity and one of the most common symptoms in clinical practice.
  • the International Association for the Study of Pain defines pain as "an unpleasant feeling and emotional feeling accompanied by substantial or potential tissue damage. It is a subjective feeling.” Pain can be used as a warning signal to remind The body pays attention to potential dangers and has an indispensable protective effect on the body's normal life activities. At the same time, pain is also a common clinical symptom. After the external stimulus that caused the pain disappears, strong or long-lasting pain can cause disorders of physiological functions and seriously affect the quality of life of the living body. Statistics show that about one-fifth of people in the world suffer from moderate to severe chronic pain.
  • action potentials nerve impulses
  • DRG dorsal root ganglia
  • the generation and conduction of action potentials in neurons relies on voltage-gated sodium channels (Na V ) on the cell membrane. When the cell membrane is depolarized, the sodium ion channel is activated and the channel opens, causing the influx of sodium ions, further depolarizing the cell membrane, leading to the generation of action potentials. Therefore, inhibiting abnormal sodium ion channel activity is helpful for the treatment and relief of pain.
  • Na V voltage-gated sodium channels
  • Na V is a type of transmembrane ion channel protein. These proteins consist of an alpha subunit with a molecular weight of 260kD and a beta subunit with a molecular weight of 30-40kD. According to the different ⁇ subunits, it can be divided into 9 subtypes, Na V ll ⁇ Na V 1.9. Different subtypes show different tissue distribution and electrophysiological and pharmacological characteristics (Rush AM, et al. J. Physiol. 2007, 579, 1-14). According to whether it can be effectively inhibited by nanomolar tetrodotoxin (TTX), sodium ion channels are classified into TTX sensitive (TTX-S) and TTX insensitive (TTX-R).
  • TTX-S TTX sensitive
  • TTX-R TTX insensitive
  • Na V 1.1, Na V 1.2, Na V 1.3, and Na V 1.7 are TTX-S type, and the coding genes are located in human chromosome 2q23-24, and they are expressed in large amounts in neurons.
  • Na V 1.5, Na V 1.8 and Na V 1.9 are TTX-R type, and the coding gene is located on human chromosome 3p21-24.
  • Na V 1.5 is mainly present in cardiomyocytes
  • Na V 1.8 and Na V 1. 9 are present in the peripheral nervous system (Goldin A.L., et al. Annu. Rev. Physiol. 2001, 63, 871-894).
  • Both Na V 1.4 and Na V 1.6 are of the TTX-S type, which are abundant in the skeletal muscle and central nervous system respectively (Fozzard HA, et al. Physiol. Rev. 1996, 76, 887-926). Local anesthetic lidocaine for pain by inhibiting Na V.
  • Non-selective Na V inhibitors such as lamotrigine, lacosamide, and mexiletine have been successfully used to treat chronic pain.
  • Na V 1.8 is TTX-R type
  • the coding gene is SCN10A, which mainly exists in trigeminal ganglion neurons and DRG neurons, and has the electrophysiological characteristics of slow inactivation and rapid recovery (Dib-Hajj SD, et al. Annu .Rev.Neurosci.2010,33,325–347).
  • the rise of action potential is mainly composed of Na V 1.8 current.
  • nerve damage will increase the expression level of Na V 1.8 in axons and neuron cell bodies (Sleeper AA, et al. J. Neurosci. 2000, 20, 7279-7289).
  • Na V 1.8 antisense oligonucleotides can significantly relieve pain while reducing the expression of Na V 1.8 (Yoshimura N., et al. J. Neurosci. 2001, 21, 8690-8696).
  • carrageenan was injected into the paws of rats, the expression of Na V 1.8 in DRG neurons increased (Tanaka M., et al. G. NeuroReport 1998, 9, 967-972).
  • Na V 1.8 knockout mice cannot show normal visceral inflammation pain (Kerr BJ, et al. NeuroReport 2001, 12, 3077-3080).
  • the human gene Na V 1.8 gain generation function mutations leads to peripheral neuropathic pain (Faber CG, et al.Proc.Natl.Acad.Sci.USA 2012,109,19444-19449) .
  • selective inhibition of Na V 1.8 has the potential to become a new type of analgesic therapy, which can be used for the treatment of inflammatory pain, nerve pain, postoperative pain, cancer pain and other types of pain.
  • Na V inhibitors used in clinical practice can inhibit sodium channels expressed in the heart and central nervous system, so the therapeutic window is narrow and the application range is limited.
  • Na V 1.8 is mainly distributed in the peripheral nervous system, so selective inhibition of Na V 1.8 can effectively reduce side effects.
  • the purpose of the present disclosure is to provide a compound represented by general formula (I), or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof,
  • M is selected from O atom, CR 4 R 5 and S atom;
  • Ring A is aryl or heteroaryl
  • R 1 is the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, deuterated alkyl, alkoxy, deuterated alkoxy, halogenated alkyl, halogenated alkoxy, cyano, amino, nitro, Hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 2 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, deuterated alkyl, alkoxy, deuterated alkoxy, halogenated alkyl, halogenated alkoxy, cyano, amino, nitro, Hydroxyl, hydroxyalkyl, cycloalkyl, cycloalkyloxy, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each any Selected from alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by one or more substituents;
  • R 3 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl And heteroaryl groups;
  • R 4 and R 5 are the same or different, and are each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl , Heterocyclyl, aryl and heteroaryl;
  • R w is selected from hydrogen atom, alkyl group, -C(O)R 6 , -S(O) 2 OH, -S(O) 2 O - Q + , -PO(OH) 2 , -PO(OH)O - Q +, -PO (O - ) 2 2Q + and -PO (O -) 2 W 2+ ;
  • Q + is a monovalent pharmaceutically acceptable cation;
  • W 2+ cation is a pharmaceutically acceptable divalent;
  • R 6 is selected from alkyl, alkoxy, alkenyl, carboxyl and carboxylate, wherein each of said alkyl, alkoxy and alkenyl is optionally selected from hydroxyl, amino, carboxyl and carboxylate. Substituted by one or more substituents;
  • n 0, 1, 2, 3 or 4;
  • s 0, 1, 2, 3 or 4;
  • t 0, 1, or 2.
  • the purpose of the present disclosure is to provide a compound represented by general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or In the form of a mixture or its pharmaceutically acceptable salt,
  • M is selected from O atom, CR 4 R 5 and S atom;
  • Ring A is aryl or heteroaryl
  • R 1 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, deuterated alkyl, alkoxy, deuterated alkoxy, halogenated alkyl, halogenated alkoxy, cyano, amino, nitro, Hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 2 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, deuterated alkyl, alkoxy, deuterated alkoxy, halogenated alkyl, halogenated alkoxy, cyano, amino, nitro, Hydroxyl, hydroxyalkyl, cycloalkyl, cycloalkyloxy, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each any Selected from alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by one or more substituents;
  • R 3 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl And heteroaryl groups;
  • R 4 and R 5 are the same or different, and are each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl , Heterocyclyl, aryl and heteroaryl;
  • R w is selected from hydrogen atom, alkyl group, -C(O)R 6 , -S(O) 2 OH, -S(O) 2 O - Q + , -PO(OH) 2 , -PO(OH)O - Q + and -PO (O -) 2 W 2+ ;
  • Q + is a monovalent pharmaceutically acceptable cation;
  • W 2+ cation is a pharmaceutically acceptable divalent;
  • R 6 is selected from alkyl, alkoxy, alkenyl, carboxyl and carboxylate, wherein each of said alkyl, alkoxy and alkenyl is optionally selected from hydroxyl, amino, carboxyl and carboxylate. Substituted by one or more substituents;
  • n 0, 1, 2, 3 or 4;
  • s 0, 1, 2, 3 or 4;
  • t 0, 1, or 2.
  • Some embodiments of the present disclosure provide a compound represented by general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer , Or its mixture form, or its pharmaceutically acceptable salt,
  • M is selected from O, CR 4 R 5 or S;
  • Ring A is aryl or heteroaryl
  • R 1 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, hetero Cyclic, aryl and heteroaryl;
  • R 2 are the same or different and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, ring Alkyloxy, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, cycloalkyloxy, heterocyclyl, aryl and heteroaryl are optionally selected from alkyl One or more substituents in, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Replaced by
  • R 3 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl And heteroaryl groups;
  • R 4 and R 5 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocycle Group, aryl and heteroaryl;
  • R w is selected from hydrogen atom, alkyl group, -C(O)R 6 , -S(O) 2 OH, -S(O) 2 O - Q + , -PO(OH) 2 , -PO(OH)O - Q + and -PO (O -) 2 W 2+ ;
  • Q + is a monovalent pharmaceutically acceptable cation;
  • W 2+ cation is a pharmaceutically acceptable divalent;
  • R 6 is selected from alkyl, alkoxy, alkenyl, carboxy and carboxylate, wherein said alkyl, alkoxy and alkenyl are optionally selected from one of hydroxy, amino, carboxy and carboxylate Or more substituents;
  • n 0, 1, 2, 3 or 4;
  • s 0, 1, 2, 3 or 4;
  • t 0, 1, or 2.
  • Some embodiments of the present disclosure provide a compound represented by general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer , Or its mixture form, or its pharmaceutically acceptable salt,
  • M is selected from O, CR 4 R 5 or S;
  • Ring A is aryl or heteroaryl
  • R 1 is the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, hetero Cyclic, aryl and heteroaryl;
  • R 2 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, hetero Cyclic, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally selected from alkyl, haloalkyl, halogen, amino, nitro, cyano Substituted by one or more substituents in the group, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 3 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl And heteroaryl groups;
  • R 4 and R 5 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocycle Group, aryl and heteroaryl;
  • R w is selected from hydrogen atom, alkyl group and -C(O)R 6 ;
  • R 6 is selected from alkyl, alkoxy, alkenyl and carboxy, wherein said alkyl, alkoxy and alkenyl are optionally substituted by one or more substituents selected from hydroxyl, amino and carboxy;
  • n 0, 1, 2, 3 or 4;
  • s 0, 1, 2, 3 or 4;
  • t 0, 1, or 2.
  • the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer In the form of a compound, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl or pyridyl.
  • the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer Body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R w is selected from a hydrogen atom, -C(O)CH 3 , -C(O)CH(OH)CH 3 , -C(O)CH(CH 3 ) 2 , -C(O)OCH 2 CH 3 , -C(O)CH 2 COOH, -C(O)CH 2 CH 2 COOH, -C(O)CH(OH)CH 2 COOH, -C( O)CH 2 CH(OH)COOH, -C(O)CH(OH)CH(OH)COOH, -C(O)-CH CH-COOH, -C(O)-COOH, -S(O) 2 OH and -C(O)CH 2 NH 2 ; preferably selected from -C(O)CH 3 , -C(
  • the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer Body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R w is selected from a hydrogen atom, -C(O)CH 3 , -C(O)CH(OH)CH 3 , -C(O)CH(CH 3 ) 2 , -C(O)OCH 2 CH 3 , -C(O)CH 2 COOH, -C(O)CH 2 CH 2 COOH, -C(O)CH(OH)CH 2 COOH, -C( O)CH 2 CH(OH)COOH, -C(O)CH(OH)CH(OH)COOH, -C(O)-CH CH-COOH, -C(O)-COOH and -C(O) CH 2 NH 2 ; preferably selected from -C(O)CH 2 COOH, -C(O)CH 3 , -C
  • the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein M is O.
  • the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer Forms, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by the general formula (II), or tautomers, mesosomes, racemates, and enantiomers thereof , Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • R 1 , R 2 , R 3 , R w , n, s and t are as defined in the general formula (I).
  • the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer Form, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by general formula (IIaa), or a tautomer, meso, racemate, or enantiomer , Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • R 1a is halogen; preferably, R 1a is Cl;
  • R 1b is a haloalkyl group; preferably, R 1b is CF 3 ;
  • R 2 , R 3 , R w , s and t are as defined in the general formula (I).
  • the compound represented by the general formula (IIaa), or its tautomer, meso, racemate, enantiomer, or diastereomer In the form of a compound, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1a is chlorine and R 1b is trifluoromethyl.
  • the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer R 1 is the same or different, and are each independently selected from hydrogen atom, halogen, alkyl and haloalkyl; preferably, R 1 is the same or different, and each independently Ground is selected from hydrogen atom, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl.
  • the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2;
  • the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer S is 0, 1 or 2; preferably 2 in the form of a mixture thereof or a pharmaceutically acceptable salt thereof.
  • the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer Form, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by general formula (III), or a tautomer, meso, racemate, or enantiomer thereof , Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • R w is as defined in the general formula (I).
  • the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer Form, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by the general formula (IV), or a tautomer, a mesosome, a racemate, or an enantiomer , Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • R 7 is selected from alkyl, deuterated alkyl and cycloalkyl; preferably, R 7 is selected from C 1-6 alkyl, deuterated C 1-6 alkyl and C 3-6 cycloalkyl; more preferably , R 7 is selected from methyl, deuterated methyl and cyclopropyl; and
  • R w is as defined in the general formula (I).
  • Typical compounds of general formula (I) include but are not limited to:
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method includes:
  • R w is -C(O)R 6 or -S(O) 2 OH
  • X is halogen or hydroxyl
  • Rings A, M, R 1 , R 2 , R 3 , R 6 , n, s, and t are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method includes:
  • R w is -C(O)R 6 ;
  • X is halogen;
  • R 6 is as defined in the general formula (I).
  • the above-mentioned preparation of the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, diastereomer further includes:
  • Rings A, M, R 1 , R 2 , R 3 , n, s and t are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II), or its tautomer, meso, racemate, enantiomer, diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method includes:
  • R w is -C(O)R 6 or -S(O) 2 OH
  • X is halogen or hydroxyl
  • R 1 , R 2 , R 3 , R 6 , n, s, and t are as defined in the general formula (II).
  • the above-mentioned preparation of the compound represented by the general formula (II), or its tautomer, meso, racemate, enantiomer, diastereomer further includes:
  • R 1 , R 2 , R 3 , n, s, and t are as defined in the general formula (II).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIaa), or its tautomer, meso, racemate, enantiomer, diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method includes:
  • R w is -C(O)R 6 or -S(O) 2 OH
  • X is halogen or hydroxyl
  • R 1a , R 1b , R 2 , R 3 , R 6 , s and t are as defined in the general formula (IIaa).
  • the above-mentioned preparation of the compound represented by the general formula (IIaa), or its tautomer, meso, racemate, enantiomer, diastereomer further includes:
  • R 1a , R 1b , R 2 , R 3 , s and t are as defined in the general formula (IIaa).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III), or its tautomer, meso, racemate, enantiomer, or diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method includes:
  • R w is -C(O)R 6 or -S(O) 2 OH
  • X is halogen or hydroxyl
  • R 6 is as defined in the general formula (III).
  • the above-mentioned preparation of the compound represented by the general formula (III), or its tautomer, meso, racemate, enantiomer, diastereomer further includes:
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV), or its tautomer, meso, racemate, enantiomer, or diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method includes:
  • R w is -C(O)R 6 or -S(O) 2 OH
  • X is halogen or hydroxyl
  • R 6 and R 7 are as defined in the general formula (IV).
  • the above-mentioned preparation of the compound represented by the general formula (IVA), or its tautomer, meso, racemate, enantiomer, diastereomer further includes:
  • R 7 is as defined in the general formula (IV).
  • compositions which contains the compound represented by the general formula (I) as described above, or its tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure also relates to a method for preparing the above-mentioned pharmaceutical composition, which comprises combining the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer
  • a pharmaceutically acceptable carrier diluent or excipient.
  • the present disclosure also relates to a compound represented by the general formula (I) as described above or its tautomer, meso, racemate, enantiomer, diastereomer, Or the use of a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above in the preparation of a medicament for inhibiting voltage-gated sodium channels in a subject.
  • the voltage-gated sodium channel is preferably Na V 1.8.
  • the present disclosure also relates to a compound represented by the general formula (I) as described above or its tautomer, meso, racemate, enantiomer, diastereomer, Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above in preparation for the treatment and/or alleviation of pain and pain-related diseases, multiple sclerosis, and Char-Martin-Tusan syndrome , Incontinence or arrhythmia drugs.
  • the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.
  • the present disclosure also relates to a method for inhibiting a voltage-gated sodium channel in a subject, the method comprising administering to a patient in need thereof the compound represented by the general formula (I) of the present disclosure or its tautomer, The meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.
  • the voltage-gated sodium channel is preferably Na V 1.8.
  • the present disclosure also relates to a method of treating and/or reducing pain and pain-related diseases, multiple sclerosis, Char-Martin-Tuson syndrome, incontinence or arrhythmia, the method comprising administering the present disclosure to patients in need
  • the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.
  • the present disclosure also relates to a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, for use as a medicine.
  • the present disclosure also relates to a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, which is used to inhibit voltage-gated sodium channels in a subject.
  • the voltage-gated sodium channel is preferably Na V 1.8.
  • the present disclosure also relates to a compound represented by the general formula (I) as described above or its tautomer, meso, racemate, enantiomer, diastereomer, Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, which is used for the treatment and/or alleviation of pain and pain-related diseases, multiple sclerosis, and Charma-Martin syndrome , Incontinence or arrhythmia.
  • the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.
  • the neuropathic pain described in the present disclosure is preferably selected from the group consisting of trigeminal neuralgia, postherpetic neuralgia, diabetic neuralgia, painful HIV-related sensory neuralgia, burn syndrome, post-amputation pain, pain after spinal cord injury, phantom Pain, painful neuroma, traumatic neuroma, Morton neuroma, nerve crush injury, spinal stenosis, carpal tunnel syndrome, nerve root pain, sciatica, nerve avulsion, brachial plexus avulsion Injuries, complex regional pain syndrome, neuralgia caused by drug therapy, neuralgia caused by cancer chemotherapy, neuralgia caused by antiretroviral therapy, primary small fiber neuropathy, primary sensory neuralgia, and trigeminal Autonomic headache.
  • the musculoskeletal pain described in the present disclosure is preferably selected from osteoarthritis pain, back pain, cold pain, burning pain and toothache.
  • the intestinal pain described in the present disclosure is preferably selected from inflammatory bowel disease pain, Crohn's disease pain or interstitial cystitis pain.
  • the inflammatory pain described in the present disclosure is preferably selected from rheumatoid arthritis pain and vulvar pain.
  • the idiopathic pain described in the present disclosure is preferably fibromyalgia.
  • the dosage of the compound or composition used in the treatment methods of the present disclosure will generally vary with the severity of the disease, the weight of the patient, and the relative efficacy of the compound.
  • a suitable unit dose can be 0.1-1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more auxiliary materials selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait.
  • auxiliary materials selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait.
  • the composition may contain 0.1 to 99% by weight of the active compound.
  • the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs.
  • Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions. Such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, In order to provide pleasing and delicious medicinal preparations.
  • the tablet contains the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing. These excipients can be inert excipients, granulating and disintegrating agents and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.
  • Oral preparations can also be provided in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or the active ingredient is mixed with a water-soluble carrier or oil vehicle or olive oil.
  • Aqueous suspensions contain the active substance and excipients suitable for the preparation of aqueous suspensions for mixing. Such excipients are suspending agents, dispersing agents or wetting agents.
  • the aqueous suspension may also contain one or more preservatives such as ethyl paraben or n-propyl paraben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents. Flavoring agent.
  • Oil suspensions can be formulated by suspending the active ingredients in vegetable oil or mineral oil.
  • the oil suspension may contain thickening agents.
  • the above-mentioned sweeteners and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
  • dispersible powders and granules suitable for preparing aqueous suspensions can be provided with active ingredients and dispersing or wetting agents for mixing, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can illustrate the above examples. Other excipients such as sweetening agents, flavoring agents and coloring agents may also be added.
  • the pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion.
  • the oil phase may be vegetable oil or mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers can be naturally occurring phospholipids or partial esters.
  • the emulsion may also contain sweetening agents, flavoring agents, preservatives and antioxidants.
  • the pharmaceutical composition of the present disclosure may be in the form of a sterile injectable aqueous solution.
  • Acceptable solvents or solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injection preparation may be a sterile oil-in-water injection microemulsion in which the active ingredient is dissolved in an oil phase. The injection or microemulsion can be injected into the patient's bloodstream by local large injections.
  • the pharmaceutical composition of the present disclosure may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration.
  • the suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above.
  • the sterile injection preparation may also be a sterile injection solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent.
  • sterile fixed oil can be conveniently used as a solvent or suspension medium.
  • the compounds of the present disclosure can be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and thus will melt in the rectum to release the drug.
  • the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, and the behavior of the patient , The patient’s diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, the best mode of treatment such as the mode of treatment, the daily dosage of compound (I) or the amount of pharmaceutically acceptable salt
  • the type can be verified according to the traditional treatment plan.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably containing 1 to 6 carbons Atom of the alkyl group.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • a lower alkyl group containing 1 to 6 carbon atoms non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Group, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl, etc.
  • Alkyl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available attachment point.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkanes Group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy, or carboxylate.
  • alkylene refers to a saturated linear or branched aliphatic hydrocarbon group, which has 2 residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is A straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 12 carbon atoms, more preferably an alkylene group containing 1 to 6 carbon atoms.
  • Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 -) CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), etc.
  • the alkylene group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment.
  • the substituent is preferably independently optionally selected from alkyl, alkenyl, alkynyl , Alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy Substituted by one or more substituents in the group, cycloalkylthio, heterocycloalkylthio and oxo.
  • alkenyl refers to an alkyl compound containing a carbon-carbon double bond in the molecule, wherein the definition of the alkyl group is as described above.
  • the alkenyl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, halogenated alkyl groups, hydroxyl groups, It is substituted by one or more substituents among hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.
  • alkenylene refers to an alkenyl group as described above, which has two residues derived from the removal of two hydrogen atoms from two different carbon atoms of the parent alkenyl group.
  • the alkenylene group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, halogenated alkyl groups, and hydroxyl groups. , Hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents.
  • alkoxy refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 Carbon atoms (e.g. 3, 4, 5 or 6 carbon atoms), most preferably 5 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.
  • spirocycloalkyl refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings. It may contain one or more double bonds, but none of the rings have complete conjugate ⁇ electronic system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyls, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has complete Conjugated ⁇ electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. It can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring includes the cycloalkyl as described above (including monocyclic, spiro, fused, and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein it is connected to the parent structure
  • the ring together is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.; preferably phenylcyclopentyl, tetrahydronaphthyl. Cycloalkyl groups may be optionally substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxy, or carboxylate.
  • groups are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthi
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably contains 5 to 6 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, di Hydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably tetrahydropyranyl, piperidinyl, and pyrrolidinyl.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • spiroheterocyclic group refers to a polycyclic heterocyclic group sharing one atom (called a spiro atom) between monocyclic rings of 5 to 20 members, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (where m is an integer of 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospiro heterocyclic group.
  • spiroheterocyclic groups include:
  • fused heterocyclic group refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the rest of the ring
  • the atom is carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • fused heterocyclic groups include:
  • bridged heterocyclic group refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common A conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclic groups include:
  • the heterocyclyl ring includes the heterocyclic group (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic ring) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the group is
  • the structures linked together are heterocyclic groups, non-limiting examples of which include:
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxy, or carboxylate.
  • aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) with a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene Base and naphthyl.
  • the aryl ring includes the aryl ring as described above fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include :
  • Aryl groups may be substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxy, or carboxylate.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl groups are preferably 5 to 10 members, containing 1 to 3 heteroatoms; more preferably 5 or 6 members, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridine Azolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and pyridazinyl, etc., preferably pyridazinyl and pyridinyl; more preferably pyridazinyl.
  • the heteroaryl ring includes the aforementioned heteroaryl ring fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, which is not limiting Examples include:
  • the heteroaryl group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, oxo, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, Cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate, non-limiting examples thereof include
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, where the alkyl group is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, where the alkyl group is as defined above.
  • deuterated alkoxy refers to an alkoxy group substituted with one or more deuterium atoms, where the alkoxy group is as defined above.
  • cycloalkyloxy refers to -O-cycloalkyl, where cycloalkyl is as defined above.
  • hydroxy refers to the -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH 2 .
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • carboxylate group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • carboxylate refers to -C(O)O - Q + , where Q + is a pharmaceutically acceptable monovalent positive ion (such as a metal ion or an ammonium ion, etc.).
  • acyl halide refers to a compound containing a -C(O)-halogen group.
  • Q + pharmaceutically acceptable monovalent cation
  • R y is H or C 1 -C 4 alkyl
  • alkali metal ions such as potassium, sodium, and lithium ions
  • dicyclohexylamine ion and N-methyl D-reduced glucosamine ion.
  • the term "pharmaceutically acceptable divalent cation” includes alkaline earth metal ions, such as calcium and magnesium ions, and divalent aluminum ions. It also includes amino acid cations, such as monovalent or divalent ions such as arginine, lysine, ornithine.
  • the pharmaceutically acceptable divalent cation (W 2+ ) can be replaced by two pharmaceutically acceptable monovalent cations (Q + ).
  • the compounds of the present disclosure may also include isotopic derivatives thereof.
  • isotopic derivative refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms.
  • isotopic derivative refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms.
  • in addition to using "deuterium” or “tritium” instead of hydrogen, or using 18 F-fluorine label ( 18 F isotope) instead of fluorine, or using 11 C-, 13 C-, or 14 C-rich Compounds in which a set of carbons ( 11 C-, 13 C-, or 14 C-carbon labels; 11 C-, 13 C-, or 14 C-isotopes) replace carbon atoms are within the scope of the present disclosure.
  • Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of diseases, or as tracers for pharmacodynamics,
  • the present disclosure also includes compounds of formula (I) in various deuterated forms. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the compound of formula (I) in deuterated form with reference to relevant literature. Commercially available deuterated starting materials can be used when preparing the deuterated form of the compound of formula (I), or they can be synthesized using conventional techniques using deuterated reagents. Deuterated reagents include but are not limited to deuterated borane and tri-deuterated. Borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but need not be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group .
  • Substituted refers to one or more hydrogen atoms in the group, preferably at most 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, and other components such as physiological/pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredients and thus the biological activity.
  • “Pharmaceutically acceptable salt” refers to the salt of the compound of the present disclosure. Such salt is safe and effective when used in the body of a mammal, and has due biological activity.
  • the preparation method of medicinal salt includes the following steps:
  • a compound of general formula (IB) and formaldehyde solution are heated and refluxed in a suitable solvent (preferably methanol) to obtain a compound of general formula (IA);
  • R w is -C(O)R 6 or -S(O) 2 OH
  • X is halogen or hydroxyl
  • Rings A, M, R 1 , R 2 , R 3 , R 6 , n, s, and t are as defined in the general formula (I).
  • the reagents that provide alkaline conditions include organic bases and inorganic bases.
  • the organic bases include but are not limited to pyridine, hexahydropyridine, 4-dimethylaminopyridine, triethylamine, N,N-diisopropylethyl Amine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide and potassium tert-butoxide
  • the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, carbonic acid Potassium, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide; preferably 4-dimethylaminopyridine or N,N-diisopropylethylamine.
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 ,4-Dioxane, water, N,N-dimethylformamide and mixtures thereof.
  • the compound represented by the general formula (II) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or
  • the preparation method of medicinal salt includes the following steps:
  • a compound of general formula (IIB) and formaldehyde solution are heated and refluxed in a suitable solvent (preferably methanol) to obtain a compound of general formula (IIA);
  • the second step the compound of general formula (IIA) and R w -X, Or sulfur trioxide pyridine, optionally reacted under alkaline conditions to obtain a compound of general formula (II).
  • R w is -C(O)R 6 or -S(O) 2 OH
  • X is halogen or hydroxyl
  • R 1 , R 2 , R 3 , R 6 , n, s, and t are as defined in the general formula (II).
  • the reagents that provide alkaline conditions include organic bases and inorganic bases.
  • the organic bases include but are not limited to pyridine, hexahydropyridine, 4-dimethylaminopyridine, triethylamine, N,N-diisopropylethyl Amine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide and potassium tert-butoxide
  • the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, carbonic acid Potassium, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide; preferably 4-dimethylaminopyridine or N,N-diisopropylethylamine.
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 ,4-Dioxane, water, N,N-dimethylformamide and mixtures thereof.
  • the preparation method of medicinal salt includes the following steps:
  • a compound of general formula (IIaa-B) and formaldehyde solution are heated and refluxed in a suitable solvent (preferably methanol) to obtain a compound of general formula (IIaa-A);
  • R w is -C(O)R 6 or -S(O) 2 OH
  • X is halogen or hydroxyl
  • R 1a , R 1b , R 2 , R 3 , R 6 , s and t are as defined in the general formula (IIaa).
  • the reagents that provide alkaline conditions include organic bases and inorganic bases.
  • the organic bases include but are not limited to pyridine, hexahydropyridine, 4-dimethylaminopyridine, triethylamine, N,N-diisopropylethyl Amine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide and potassium tert-butoxide
  • the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, carbonic acid Potassium, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide; preferably 4-dimethylaminopyridine or N,N-diisopropylethylamine.
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 ,4-Dioxane, water, N,N-dimethylformamide and mixtures thereof.
  • the preparation method of medicinal salt includes the following steps:
  • compound 1h and formaldehyde solution are heated and refluxed in a suitable solvent (preferably methanol) to obtain compound 1;
  • R w is -C(O)R 6 or -S(O) 2 OH
  • X is halogen or hydroxyl
  • R 6 is as defined in the general formula (III).
  • the reagents that provide alkaline conditions include organic bases and inorganic bases.
  • the organic bases include but are not limited to pyridine, hexahydropyridine, 4-dimethylaminopyridine, triethylamine, N,N-diisopropylethyl Amine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide and potassium tert-butoxide
  • the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, carbonic acid Potassium, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide; preferably 4-dimethylaminopyridine or N,N-diisopropylethylamine.
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 ,4-Dioxane, water, N,N-dimethylformamide and mixtures thereof.
  • the compound represented by the general formula (IV) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or
  • the preparation method of medicinal salt includes the following steps:
  • general formula (IVB) and formaldehyde solution are heated and refluxed in a suitable solvent (preferably methanol) to obtain general formula (IVA);
  • R w is -C(O)R 6 or -S(O) 2 OH
  • X is halogen or hydroxyl
  • R 6 and R 7 are as defined in the general formula (IV).
  • the reagents that provide alkaline conditions include organic bases and inorganic bases.
  • the organic bases include but are not limited to pyridine, hexahydropyridine, 4-dimethylaminopyridine, triethylamine, N,N-diisopropylethyl Amine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide and potassium tert-butoxide
  • the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, carbonic acid Potassium, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide; preferably 4-dimethylaminopyridine or N,N-diisopropylethylamine.
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1 ,4-Dioxane, water, N,N-dimethylformamide and mixtures thereof.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four Methylsilane (TMS).
  • HPLC High performance liquid chromatography analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatograph.
  • HPLC preparation uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
  • CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of thin layer chromatography separation and purification products is 0.4mm ⁇ 0.5mm.
  • the silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the known starting materials of the present disclosure can be synthesized by or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Darui Chemicals and other companies.
  • reaction can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere refers to the reaction flask connected to an argon or nitrogen balloon with a volume of about 1L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.
  • the hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated three times.
  • the microwave reaction uses the CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the examples adopts thin-layer chromatography (TLC).
  • the developing reagent used in the reaction, the eluent system of column chromatography used in the purification of the compound and the developing reagent system of thin-layer chromatography include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, D: acetone, E: dichloromethane/acetone system, F: ethyl acetate/dichloromethane system , G: ethyl acetate/dichloromethane/n-hexane, H: ethyl acetate/dichloromethane/acetone, the volume ratio of the solvent is adjusted according to the polarity of the compound, a small amount of triethylamine and acetic acid can also be added Wait for alkaline or acidic reagents to adjust.
  • the crude compound 1d (3.92 g, 10.81 mmol) was dissolved in methanol (30 mL), water (10 mL) and sodium hydroxide (1.3 g, 32.5 mmol) were added, and the reaction was carried out for 16 hours.
  • the reaction solution was concentrated, 10 mL of water was added, and the pH was adjusted to 1 with concentrated hydrochloric acid. It was extracted with ethyl acetate (20 mL ⁇ 3), and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with the developing solvent system A to obtain the title compound 1e (3.67 g), yield: 97%.
  • Example 2 Using the synthetic route of Example 2, replacing the raw material succinic anhydride with acetyl chloride (Sinopharm Chemical Reagent Co., Ltd.), the title compound 4 (60 mg) was prepared, and the yield: 55%.
  • test examples are not meant to limit the scope of the present disclosure.
  • Test Example 1 Room temperature solubility of the compound of the present disclosure in a pH 7.4 PBS solution
  • Reagents dimethyl sulfoxide (analytical grade), ethanol (analytical grade), acetonitrile (chromatographic grade), NaH 2 PO 4 ⁇ 2H 2 O (analytical grade), Na 2 HPO 4 ⁇ 12H 2 O (analytical grade), acetic acid Ammonium (analytical grade), sodium hydroxide, sodium chloride (analytical grade).
  • the LC/MS/MS method was used to determine the drug concentration in plasma at different times after the SD rats were orally administered the compound of Example 2, Example 6 and Compound of Example 7. To study the pharmacokinetic behavior of the compound of the present disclosure in SD rats and evaluate its pharmacokinetic characteristics.
  • Example 2 Weigh an appropriate amount of the sample of Example 2, add 5% DMSO + 5% Tween 80 + 90% physiological saline, and add in order to obtain a colorless, clear and transparent solution.
  • Example 2 Weigh an appropriate amount of the sample of Example 2 and add 0.5% sodium carboxymethyl cellulose (containing 0.5% Tween 80) to obtain a white uniform suspension.
  • the dosage of the compound of Example 2 was 2 mg/kg, the dosage volume was 10 mL/kg, and the dosage concentration was 0.2 mg/mL (formulation: 5% DMSO + 5% tween80 +90% normal saline); the administration dose of the compound of Example 2 is 10, 30, 100 mg/kg, the administration volume is 10 mL/kg, and the administration concentration is 1, 3, 10 mg/mL (formulation: 0.5% carboxymethyl Sodium cellulose (containing 0.5% Tween 80)).
  • the administration dose of the compound of Example 6 is 100, 300, and 900 mg/kg, the administration volume is 10 mL/kg, and the administration concentration is 10, 30, and 90 mg/mL.
  • the administration dose of the compound of Example 7 is 10, 30, 100 mg/kg, the administration volume is 10 mL/kg, and the administration concentration is 1, 3, and 10 mg/mL.
  • the plasma samples were analyzed by LC/MS/MS to determine the concentration of compound 2 and compound 1h, the concentration of compound 6 and compound 6c, and the concentration of compound 7 and compound 7d, which were not detected in rats.
  • the compound of Example 2 the compound of Example 6 and the compound of Example 7, the following data is the pharmacokinetic data of its metabolite compounds 1h, 6c and 7d.
  • Example 2 was transformed into Compound 1h in vivo;
  • Example 6 was transformed into Compound 6c in vivo;
  • Example 7 was transformed into Compound 7d in vivo.
  • the pharmacokinetic absorption of the compound of the present disclosure is good and has obvious pharmacokinetic advantages.
  • Test Example 3 Determination of the inhibitory activity of the compound of the present disclosure on Nav1.8
  • the purpose of the experiment is to study the effect of the compound on the Na V 1.8 ion channel in an in vitro experiment, and the Na V 1.8 ion channel is stably expressed on HEK293 cells. After the Na V 1.8 current is stable, comparing the Na V 1.8 current before and after the compound application, the influence of the compound on the Na V 1.8 ion channel can be obtained.
  • Patch clamp amplifier patch clamp PC-505B (WARNER instruments)/MultiClamp 700A (Axon instrument).
  • Extracellular fluid of: NaCl, 137; KCl, 4 ; CaCl 2, 1.8; MgCl 2, 1; HEPES, 10; glucose 10; pH 7.4 (NaOH titration).
  • Intracellular fluid (mM) is aspartic acid, 140; MgCl2, 2; EGTA 11; HEPES, 10; pH 7.2 (CsOH titration). All test compound and control compound solutions contained 1 ⁇ M TTX.
  • the storage concentration of the test compound is 9 mM, dissolved in dimethyl sulfoxide (DMSO). Re-dissolve in the extracellular fluid on the day of the test and prepare the required concentration.
  • DMSO dimethyl sulfoxide
  • the data will be stored in the computer system for analysis. Data collection and analysis will use pCLAMP 10 (Molecular Devices, Union City, CA), and management personnel will review the analysis results.
  • Current stability means that the current changes within a limited range over time. The magnitude of the current stabilized is used to calculate the effect of the compound's solubility.
  • the inhibitory activity of the compounds of the present disclosure on Nav1.8 was determined by the above test, and the measured IC 50 value is shown in Table 3.

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Abstract

一种通式(I)所示的6-氧代-1,6-二氢哒嗪类前药衍生物、其制备方法及含有该衍生物的药物组合物，以及其作为NaV抑制剂的用途和其在制备治疗和/或预防疼痛和疼痛相关疾病的药物中的用途。

Description

6-氧代-1,6-二氢哒嗪类前药衍生物、其制备方法及其在医药上的应用 技术领域
本公开属于医药领域，涉及一种6-氧代-1,6-二氢哒嗪类前药衍生物、其制备方法及其在医药上的应用。特别地，本公开涉及一种通式(I)所示的6-氧代-1,6-二氢哒嗪类前药衍生物、其制备方法及含有该衍生物的药物组合物，以及其作为Na V抑制剂的用途和其在制备治疗和/或减轻疼痛和疼痛相关疾病的药物中的用途。
背景技术
疼痛是一种复杂的生理心理活动，是临床上最常见的症状之一。国际疼痛研究协会将疼痛定义为“一种令人不快的感觉和情绪上的感受，伴有实质上的或潜在的组织损伤，它是一种主观感受。”疼痛可以作为一种警戒信号，提醒机体注意潜在的危险，对机体正常的生命活动具有不可或缺的保护作用。同时，疼痛也是一种常见的临床症状，在引发疼痛的外界刺激消失后，强烈或持久的疼痛会造成生理功能的紊乱，严重影响生命体的生活质量。统计数据显示，全世界约五分之一的人患有中度至重度慢性疼痛。
疼痛起源于周围神经系统的伤害感受器。这是一种游离的神经末梢，广泛分布于全身的皮肤、肌肉、关节和内脏组织中，它可以将感受到的热的、机械的或化学的刺激转化为神经冲动(动作电位)并经由传入神经纤维传递到其位于背根神经节(dorsal root ganglia，DRG)的胞体部分，最终传递到高级神经中枢，引起痛觉。而神经元中动作电位的产生和传导又依赖于细胞膜上的电压门控钠通道(voltage-gated sodium channels，Na V)。当细胞膜去极化时，钠离子通道激活，通道打开，引起钠离子内流，使细胞膜进一步去极化，导致动作电位的产生。因此，抑制异常的钠离子通道活动有助于疼痛的治疗、缓解。
Na V是一类跨膜离子通道蛋白。这些蛋白由分子量260kD的α亚基和分子量为30-40kD的β亚基组成。根据α亚基的不同可以分为9种亚型，Na Vl.l～Na V1.9。不同亚型表现出不同的组织分布和电生理、药理学特征(Rush A.M.,et al.J.Physiol.2007,579,1–14)。根据能否被纳摩尔河豚毒素(tetrodotoxin，TTX)有效抑制，钠离子通道被分为TTX敏感型(TTX-S)和TTX不敏感型(TTX-R)。其中，Na V1.1、Na V1.2、Na V1.3和Na V1.7为TTX-S型，编码基因位于人类染色体2q23-24，它们在神经元中大量表达。Na V1.5、Na V1.8和Na V1.9为TTX-R型，编码基因位于人类染色体3p21-24。其中，Na V1.5主要存在于心肌细胞中，Na V 1.8、Na V l.9存在于外周神经系统(GoldinA.L.,et al.Annu.Rev.Physiol.2001,63,871–894)。Na V1.4和Na V1.6都为TTX-S型，分别在骨骼肌和中枢神经系统中大量存在(Fozzard H.A., et al.Physiol.Rev.1996,76,887–926)。局部麻醉药利多卡因通过抑制Na V来止痛。而非选择性的Na V抑制剂，例如拉莫三嗪，拉科酰胺，美西律已经成功地用于治疗慢性疼痛。
Na V1.8为TTX-R型，编码基因为SCN10A，主要存在于三叉神经节神经元和DRG神经元中，具有慢速失活、迅速恢复的电生理特征(Dib-Hajj S.D.,et al.Annu.Rev.Neurosci.2010,33,325–347)。在表达Na V 1.8的神经元内，动作电位的上升主要由Na V1.8电流构成。在研究神经性疼痛的一些模型中，神经损伤会使Na V1.8在轴突和神经元胞体中的表达水平上升(Sleeper A.A.,et al.J.Neurosci.2000,20,7279–7289)。使用Na V1.8反义寡核苷酸在降低Na V1.8表达的同时可以明显地缓解疼痛(Yoshimura N.,et al.J.Neurosci.2001,21,8690-8696)。大鼠爪内注射角叉菜胶(carrageenan)后，DRG神经元中Na V1.8的表达有所上升(Tanaka M.,et al.G.NeuroReport 1998,9,967–972)。Na V1.8敲除小鼠不能表现出正常的内脏炎症痛(Kerr B.J.,et al.NeuroReport 2001,12,3077–3080)。人类的Na V1.8基因产生功能增益突变后，会导致外周神经痛(Faber C.G.,et al.Proc.Natl.Acad.Sci.USA 2012,109,19444–19449)。根据一系列动物实验以及人类基因证据，选择性抑制Na V1.8具有成为新型镇痛疗法的潜力，可以用于炎性疼痛，神经疼痛，手术后疼痛，癌痛等多种疼痛类型的治疗。
临床中使用的Na V抑制剂由于缺乏亚型选择性，能够抑制表达在心脏和中枢神经系统中的钠离子通道，因此治疗窗口较窄，应用范围受到限制。Na V1.8主要分布在外周神经系统，所以选择性地抑制Na V1.8可以有效地减少副作用。因此，有必要开发活性更高，选择性更好，药代动力学性质更佳，副作用更少的Na V1.8抑制剂。
发明内容
本公开的目的在于提供一种通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，
Figure PCTCN2020075790-appb-000001
其中：
M选自O原子、CR 4R 5和S原子；
环A为芳基或杂芳基；
R 1相同或不同，且各自独立地选自氢原子、卤素、烷基、氘代烷基、烷氧基、氘代烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
R 2相同或不同，且各自独立地选自氢原子、卤素、烷基、氘代烷基、烷氧基、氘代烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、环烷基氧基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自任选被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
R 4和R 5相同或不同，且各自独立地选自氢原子、氘原子、卤素、烷基、烷氧基、卤代烷基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
R w选自氢原子、烷基、-C(O)R 6、-S(O) 2OH、-S(O) 2O -Q +、-PO(OH) 2、-PO(OH)O -Q +、-PO(O -) 22Q +和-PO(O -) 2W 2+；Q +为药学上可接受的单价阳离子；W 2+为药学上可接受的二价阳离子；
R 6选自烷基、烷氧基、烯基、羧基和羧酸盐，其中所述的烷基、烷氧基和烯基各自任选被选自羟基、氨基、羧基和羧酸盐中的一个或多个取代基所取代；
n为0、1、2、3或4；
s为0、1、2、3或4；且
t为0、1或2。
本公开的目的在于提供一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，
Figure PCTCN2020075790-appb-000002
其中：
M选自O原子、CR 4R 5和S原子；
环A为芳基或杂芳基；
R 1相同或不同，且各自独立地选自氢原子、卤素、烷基、氘代烷基、烷氧基、 氘代烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
R 2相同或不同，且各自独立地选自氢原子、卤素、烷基、氘代烷基、烷氧基、氘代烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、环烷基氧基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自任选被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
R 4和R 5相同或不同，且各自独立地选自氢原子、氘原子、卤素、烷基、烷氧基、卤代烷基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
R w选自氢原子、烷基、-C(O)R 6、-S(O) 2OH、-S(O) 2O -Q +、-PO(OH) 2、-PO(OH)O -Q +和-PO(O -) 2W 2+；Q +为药学上可接受的单价阳离子；W 2+为药学上可接受的二价阳离子；
R 6选自烷基、烷氧基、烯基、羧基和羧酸盐，其中所述的烷基、烷氧基和烯基各自任选被选自羟基、氨基、羧基和羧酸盐中的一个或多个取代基所取代；
n为0、1、2、3或4；
s为0、1、2、3或4；且
t为0、1或2。
本公开的一些实施方案，提供一种通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，
Figure PCTCN2020075790-appb-000003
其中：
M选自O、CR 4R 5或S；
环A为芳基或杂芳基；
R 1相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、 卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
R 2相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、环烷基氧基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、环烷基氧基、杂环基、芳基和杂芳基任选被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
R 4和R 5相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
R w选自氢原子、烷基、-C(O)R 6、-S(O) 2OH、-S(O) 2O -Q +、-PO(OH) 2、-PO(OH)O -Q +和-PO(O -) 2W 2+；Q +为药学上可接受的单价阳离子；W 2+为药学上可接受的二价阳离子；
R 6选自烷基、烷氧基、烯基、羧基和羧酸盐，其中所述的烷基、烷氧基和烯基任选被选自羟基、氨基、羧基和羧酸盐中的一个或多个取代基所取代；
n为0、1、2、3或4；
s为0、1、2、3或4；且
t为0、1或2。
本公开的一些实施方案，提供一种通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，
Figure PCTCN2020075790-appb-000004
其中：
M选自O、CR 4R 5或S；
环A为芳基或杂芳基；
R 1相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
R 2相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
R 4和R 5相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
R w选自氢原子、烷基和-C(O)R 6；
R 6选自烷基、烷氧基、烯基和羧基，其中所述的烷基、烷氧基和烯基任选被选自羟基、氨基和羧基中的一个或多个取代基所取代；
n为0、1、2、3或4；
s为0、1、2、3或4；且
t为0、1或2。
在本公开一些实施方案中，所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中环A为苯基或吡啶基。
在本公开一些实施方案中，所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R w选自氢原子、-C(O)-烷基、-C(O)-烷氧基、-C(O)-亚烷基-COOH、-C(O)-亚烯基-COOH、-C(O)-COOH、-S(O) 2OH和-C(O)-亚烷基-NH 2，其中所述的烷基、烷氧基、亚烷基和亚烯基各自任选被一个或多个羟基所取代；优选地，R w选自氢原子、-C(O)-C 1-6烷基、-C(O)-C 1-6烷氧基、-C(O)-C 1-6亚烷基-COOH、-C(O)-C 2-6亚烯基-COOH、-C(O)-COOH、-S(O) 2OH和-C(O)-C 1-6亚烷基-NH 2，其中所述的C 1-6烷基、C 1-6烷氧基、C 1-6亚烷基和C 2-6亚烯基各自任选被一个或多个羟基所取代。
在本公开一些实施方案中，所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R w选自氢原子、-C(O)-烷基、-C(O)-烷氧基、-C(O)-亚烷基-COOH、-C(O)-亚烯基-COOH、-C(O)-COOH和-C(O)-亚烷基-NH 2，其中所述的烷基、烷氧基、亚烷基和亚烯基各自任选被一个或多个羟基所取代。
在本公开一些实施方案中，所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R w选自氢原子、-C(O)CH 3、-C(O)CH(OH)CH 3、-C(O)CH(CH 3) 2、-C(O)OCH 2CH 3、-C(O)CH 2COOH、-C(O)CH 2CH 2COOH、-C(O)CH(OH)CH 2COOH、 -C(O)CH 2CH(OH)COOH、-C(O)CH(OH)CH(OH)COOH、-C(O)-CH＝CH-COOH、-C(O)-COOH、-S(O) 2OH和-C(O)CH 2NH 2；优选选自-C(O)CH 2COOH、-C(O)CH 2CH 2COOH、-C(O)CH(OH)CH 2COOH、-C(O)CH 2CH(OH)COOH、-C(O)CH(OH)CH(OH)COOH、-C(O)-CH＝CH-COOH和-C(O)-COOH。
在本公开一些实施方案中，所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R w选自氢原子、-C(O)CH 3、-C(O)CH(OH)CH 3、-C(O)CH(CH 3) 2、-C(O)OCH 2CH 3、-C(O)CH 2COOH、-C(O)CH 2CH 2COOH、-C(O)CH(OH)CH 2COOH、-C(O)CH 2CH(OH)COOH、-C(O)CH(OH)CH(OH)COOH、-C(O)-CH＝CH-COOH、-C(O)-COOH和-C(O)CH 2NH 2；优选选自-C(O)CH 2COOH、-C(O)CH 2CH 2COOH、-C(O)CH(OH)CH 2COOH、-C(O)CH 2CH(OH)COOH、-C(O)CH(OH)CH(OH)COOH、-C(O)-CH＝CH-COOH和-C(O)-COOH。
在本公开一些实施方案中，所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中M为O。
在本公开一些实施方案中，所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，其为通式(II)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，
Figure PCTCN2020075790-appb-000005
其中：
R 1、R 2、R 3、R w、n、s和t如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，其为通式(IIaa)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，
Figure PCTCN2020075790-appb-000006
其中：
R 1a为卤素；优选地，R 1a为Cl；
R 1b为卤代烷基；优选地，R 1b为CF 3；
R 2、R 3、R w、s和t如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(IIaa)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R 1a为氯，R 1b为三氟甲基。
在本公开一些实施方案中，所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R 1相同或不同，且各自独立地选自氢原子、卤素、烷基和卤代烷基；优选地，R 1相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和卤代C 1-6烷基。
在本公开一些实施方案中，所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R 2相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基和环烷基氧基；优选地，R 2相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、氘代C 1-6烷氧基和C 3-6环烷基氧基。
在本公开一些实施方案中，所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R 2相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、氘代烷氧基、卤代烷基、卤代烷氧基、环烷基和环烷基氧基；优选的，R 2相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氘代烷氧基和环烷基氧基；更优选的，R 2相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基和氘代烷氧基。
在本公开一些实施方案中，所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中n为0、1或2；优选为2。
在本公开一些实施方案中，所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R 3为氢原子。
在本公开一些实施方案中，所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中s为0、1或2；优选为2。
在本公开一些实施方案中，所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，其为通式(III)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，
Figure PCTCN2020075790-appb-000007
其中：
R w如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，其为通式(IV)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，
Figure PCTCN2020075790-appb-000008
其中：
R 7选自烷基、氘代烷基和环烷基；优选地，R 7选自C 1-6烷基、氘代C 1-6烷基和C 3-6环烷基；更优选地，R 7选自甲基、氘代甲基和环丙基；且
R w如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(IV)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R 7为烷基或环烷基；优选为甲基或环丙基。
通式(I)的典型化合物，包括但不限于：
Figure PCTCN2020075790-appb-000009
Figure PCTCN2020075790-appb-000010
Figure PCTCN2020075790-appb-000011
Figure PCTCN2020075790-appb-000012
Figure PCTCN2020075790-appb-000013
Figure PCTCN2020075790-appb-000014
Figure PCTCN2020075790-appb-000015
Figure PCTCN2020075790-appb-000016
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐。
本公开的另一方面涉及一种制备通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法，该方法包括：
Figure PCTCN2020075790-appb-000017
通式(IA)化合物与R w-X、
Figure PCTCN2020075790-appb-000018
或三氧化硫吡啶反应得到通式(I)化合物的步骤；
其中：
R w为-C(O)R 6或-S(O) 2OH；
X为卤素或羟基；
Figure PCTCN2020075790-appb-000019
为单键或双键；且
环A、M、R 1、R 2、R 3、R 6、n、s和t如通式(I)中所定义。
本公开的另一方面涉及一种制备通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法，该方法包括：
通式(IA)化合物与R w-X或
Figure PCTCN2020075790-appb-000020
反应得到通式(I)化合物；
其中：R w为-C(O)R 6；X为卤素；R 6如通式(I)中所定义。
在本公开一个优选的实施方案中，上述制备通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法进一步包括：
Figure PCTCN2020075790-appb-000021
通式(IB)化合物与甲醛溶液反应得到通式(IA)化合物的步骤；
其中：
环A、M、R 1、R 2、R 3、n、s和t如通式(I)中所定义。
本公开的另一方面涉及一种制备通式(II)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法，该方法包括：
Figure PCTCN2020075790-appb-000022
通式(IIA)化合物与R w-X、
Figure PCTCN2020075790-appb-000023
或三氧化硫吡啶反应得到通式(II)化合物的步骤；
其中：
R w为-C(O)R 6或-S(O) 2OH；
X为卤素或羟基；
Figure PCTCN2020075790-appb-000024
为单键或双键；
R 1、R 2、R 3、R 6、n、s和t如通式(II)中所定义。
在本公开一个优选的实施方案中，上述制备通式(II)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法进一步包括：
Figure PCTCN2020075790-appb-000025
通式(IIB)化合物与甲醛溶液反应得到通式(IIA)化合物的步骤；
其中：
R 1、R 2、R 3、n、s和t如通式(II)中所定义。
本公开的另一方面涉及一种制备通式(IIaa)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用 的盐的方法，该方法包括：
Figure PCTCN2020075790-appb-000026
通式(IIaa-A)化合物与R w-X、
Figure PCTCN2020075790-appb-000027
或三氧化硫吡啶反应得到通式(IIaa)化合物的步骤；
其中：
R w为-C(O)R 6或-S(O) 2OH；
X为卤素或羟基；
Figure PCTCN2020075790-appb-000028
为单键或双键；且
R 1a、R 1b、R 2、R 3、R 6、s和t如通式(IIaa)中所定义。
在本公开一个优选的实施方案中，上述制备通式(IIaa)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法进一步包括：
Figure PCTCN2020075790-appb-000029
通式(IIaa-B)化合物与甲醛溶液反应得到通式(IIaa-A)化合物的步骤；
其中：
R 1a、R 1b、R 2、R 3、s和t如通式(IIaa)中所定义。
本公开的另一方面涉及一种制备通式(III)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法，该方法包括：
Figure PCTCN2020075790-appb-000030
化合物1与R w-X、
Figure PCTCN2020075790-appb-000031
或三氧化硫吡啶反应得到通式(III)化合物的步骤；
其中：
R w为-C(O)R 6或-S(O) 2OH；
X为卤素或羟基；
Figure PCTCN2020075790-appb-000032
为单键或双键；且
R 6如通式(III)中所定义。
在本公开一个优选的实施方案中，上述制备通式(III)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法还包括：
Figure PCTCN2020075790-appb-000033
化合物1h与甲醛溶液反应得到化合物1的步骤。
本公开的另一方面涉及一种制备通式(IV)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法，该方法包括：
Figure PCTCN2020075790-appb-000034
通式(IVA)与R w-X、
Figure PCTCN2020075790-appb-000035
或三氧化硫吡啶反应得到通式(IV)化合物；
其中：
R w为-C(O)R 6或-S(O) 2OH；
X为卤素或羟基；且
Figure PCTCN2020075790-appb-000036
为单键或双键；
R 6和R 7如通式(IV)中所定义。
在本公开一个优选的实施方案中，上述制备通式(IVA)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法进一步包括：
Figure PCTCN2020075790-appb-000037
通式(IVB)与甲醛溶液反应得到通式(IVA)的步骤；
其中：R 7如通式(IV)中所定义。
本公开的另一方面涉及一种药物组合物，其含有如上所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本公开还涉及一种制备上述药物组合物的方法，其包括将如上所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构 体、或其混合物形式、或其可药用的盐与药学上可接受的载体、稀释剂或赋形剂相混合。
本公开还涉及一种如上所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，或如上所述的药物组合物在制备抑制受试者电压门控钠通道的药物中的用途。所述的电压门控钠通道优选为Na V1.8。
本公开还涉及一种如上所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，或如上所述的药物组合物在制备用于治疗和/或减轻疼痛和疼痛相关疾病、多发性硬化症、夏-马-图三氏综合症、失禁或心律失常的药物中的用途。优选地，所述的疼痛选自慢性疼痛、急性疼痛、炎性疼痛、癌症疼痛、神经性疼痛、肌肉骨骼痛、原发性疼痛、肠痛和特发性疼痛。
本公开还涉及一种抑制受试者电压门控钠通道的方法，该方法包括向需要其的患者施用本公开如上所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，或如上所述的药物组合物。所述的电压门控钠通道优选为Na V1.8。
本公开还涉及一种治疗和/或减轻疼痛和疼痛相关疾病、多发性硬化症、夏-马-图三氏综合症、失禁或心律失常的方法，该方法包括向需要其的患者施用本公开如上所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，或如上所述的药物组合物。优选地，所述的疼痛选自慢性疼痛、急性疼痛、炎性疼痛、癌症疼痛、神经性疼痛、肌肉骨骼痛、原发性疼痛、肠痛和特发性疼痛。
本公开还涉及一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、或其可药用的盐，或如上所述的药物组合物，用作药物。
本公开还涉及一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、或其可药用的盐，或如上所述的药物组合物，其用于抑制受试者电压门控钠通道。所述的电压门控钠通道优选为Na V1.8。
本公开还涉及一种如上所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，或如上所述的药物组合物，其用于治疗和/或减轻疼痛和疼痛相关疾病、多发性硬化症、夏-马-图三氏综合症、失禁或心律失常。优选地，所述的疼痛选自慢性疼痛、急性疼痛、炎性疼痛、癌症疼痛、神经性疼痛、肌肉骨骼痛、原发性疼痛、肠痛和特发性疼痛。
本公开中所述的神经性疼痛优选选自三叉神经痛、疱疹后神经痛、糖尿病性 神经痛、痛性HIV相关性感觉神经痛、灼伤综合症、截肢术后疼痛、脊髓损伤后疼痛、幻痛、痛性神经瘤、创伤性神经瘤、莫顿(Morton)神经瘤、神经挤压损伤、脊管狭窄、腕管综合症、神经根痛、坐骨神经痛、神经撕脱伤、臂丛撕脱伤、复杂性区域疼痛综合征、药物疗法引起的神经痛、癌症化学疗法引起的神经痛、抗逆转录病毒疗法引起的神经痛、原发性小纤维神经病变、原发性感觉神经痛和三叉自主神经性头痛。
本公开中所述的肌肉骨骼痛优选选自骨关节炎疼痛、背痛、冷痛、灼烧疼痛和牙痛。
本公开中所述的肠痛优选选自发炎性肠病疼痛、克罗恩病疼痛或间质性膀胱炎疼痛。
本公开中所述的炎性疼痛优选选自类风湿性关节炎疼痛和外阴痛。
本公开中所述的特发性疼痛优选为纤维肌痛。
本公开治疗方法中所用化合物或组合物的剂量通常将随疾病的严重性、患者的体重和化合物的相对功效而改变。不过，作为一般性指导，合适的单位剂量可以是0.1～1000mg。
本公开的药物组合物除活性化合物外，可含有一种或多种辅料，所述辅料选自以下成分：填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方法的不同，组合物可含有0.1至99重量％的活性化合物。
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂，造粒剂和崩解剂和润滑剂。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒或橄榄油混合的软明胶胶囊提供口服制剂。
水悬浮液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此类赋形剂是悬浮剂，分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂例如尼泊金乙酯或尼泊金正丙酯、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。
油混悬液可通过使活性成分悬浮于植物油或矿物油中配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。
通过加入水可使适用于制备水混悬液的可分散粉末和颗粒提供活性成分和用 于混合的分散剂或湿润剂、悬浮剂或一种或多种防腐剂。适宜的分散剂或湿润剂和悬浮剂可说明上述的例子。也可加入其他赋形剂例如甜味剂、矫味剂和着色剂。
本公开的药物组合物也可以是水包油乳剂的形式。油相可以是植物油或矿物油例如液体石蜡或其混合物。适宜的乳化剂可以是天然产生的磷脂或偏酯。乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。
本公开的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳。可通过局部大量注射，将注射液或微乳注入患者的血流中。
本公开的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。
可按用于直肠给药的栓剂形式给予本公开化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、排泄的速率、药物的组合等；另外，最佳的治疗方式如治疗的模式、通式化合物(I)的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
术语定义
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙 基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“亚烷基”指饱和的直链或支链脂肪族烃基，其具有2个从母体烷的相同碳原子或两个不同的碳原子上除去两个氢原子所衍生的残基，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子，更优选含有1至6个碳原子的亚烷基。亚烷基的非限制性实例包括但不限于亚甲基(-CH 2-)、1,1-亚乙基(-CH(CH 3)-)、1,2-亚乙基(-CH 2CH 2)-、1,1-亚丙基(-CH(CH 2CH 3)-)、1,2-亚丙基(-CH 2CH(CH 3)-)、1,3-亚丙基(-CH 2CH 2CH 2-)、1,4-亚丁基(-CH 2CH 2CH 2CH 2-)等。亚烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基和氧代基中的一个或多个取代基所取代。
术语“烯基”指分子中含有碳碳双键的烷基化合物，其中烷基的定义如上所述。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自氢原子、烷基、烷氧基、卤素、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代。
术语“亚烯基”指如上所述的烯基，其具有2个从母体烯基的两个不同的碳原子上除去两个氢原子所衍生的残基。亚烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自氢原子、烷基、烷氧基、卤素、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基如上所定义。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧 基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子(例如3、4、5或6个碳原子)，最优选包含5至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2020075790-appb-000038
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2020075790-appb-000039
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更优选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2020075790-appb-000040
所述环烷基环包括如上所述的环烷基(包括单环、螺环、稠环和桥环)稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等；优选苯基并环戊基、四氢萘基。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；最优选包含3至8个环原子，其中1～3个是杂原子；最优选包含5至6个环原子，其中1～2或1～3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等，优选四氢吡喃基、哌啶基、吡咯烷基。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
Figure PCTCN2020075790-appb-000041
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其 中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
Figure PCTCN2020075790-appb-000042
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更优选为双环或三环。桥杂环基的非限制性实例包括：
Figure PCTCN2020075790-appb-000043
所述杂环基环包括如上所述的杂环基(包括单环、螺杂环、稠杂环和桥杂环)稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2020075790-appb-000044
等。
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。所述芳基环包括如上所述的芳基环稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连 接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2020075790-appb-000045
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，含1至3个杂原子；更优选为5元或6元，含1至2个杂原子；优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基和哒嗪基等，优选为哒嗪基和吡啶基；更优选哒嗪基。所述杂芳基环包括如上所述的杂芳基环稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2020075790-appb-000046
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、氧代基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基，其非限制性实施例包括
Figure PCTCN2020075790-appb-000047
术语“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。
术语“氘代烷基”指烷基被一个或多个氘原子取代，其中烷基如上所定义。
术语“氘代烷氧基”指烷氧基被一个或多个氘原子取代，其中烷氧基如上所 定义。
术语“环烷基氧基”指-O-环烷基，其中环烷基如上所定义。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“羧基”指-C(O)OH。
术语“羧酸酯基”指-C(O)O(烷基)或-C(O)O(环烷基)，其中烷基、环烷基如上所定义。术语“羧酸盐”指-C(O)O -Q +，其中Q +为药学上可接受的单价正离子(例如金属离子或铵根离子等)。
术语“酰卤”指含有-C(O)-卤素的基团的化合物。
术语“药学上可接受的单价阳离子”(Q +)包括(例如N(R y) 4，其中R y为H或C 1-C 4烷基)、碱金属离子(例如钾、钠及锂离子)、二环己胺离子及N-甲基D-还原葡糖胺离子。
术语“药学上可接受的二价阳离子”(W 2+)包括碱土金属离子，例如钙及镁离子，以及二价铝离子。还包括氨基酸阳离子，例如精氨酸、赖氨酸、鸟氨酸等的单价或二价离子。药学上可接受的二价阳离子(W 2+)可以被两个药学上可接受的单价阳离子(Q +)替换。
本公开的化合物还可包含其同位素衍生物。术语“同位素衍生物”指结构不同仅在于存在一种或多种同位素富集原子的化合物。例如，具有本公开的结构，除了用“氘”或“氚”代替氢，或者用 18F-氟标记( 18F同位素)代替氟，或者用 11C-， 13C-，或者 14C-富集的碳( 11C-， 13C-，或者 14C-碳标记； 11C-， 13C-，或者 14C-同位素)代替碳原子的化合物处于本公开的范围内。这样的化合物可用作例如生物学测定中的分析工具或探针，或者可以用作疾病的体内诊断成像示踪剂，或者作为药效学、药动学或受体研究的示踪剂。
本公开还包括各种氘化形式的式(I)化合物。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的式(I)化合物。在制备氘代形式的式(I)化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3 个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用盐”是指本公开化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
本公开化合物的合成方法
为了完成本公开的目的，本公开采用如下技术方案：
方案一
本公开通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐制备方法，包括以下步骤：
Figure PCTCN2020075790-appb-000048
第一步，通式(IB)化合物与甲醛溶液，在适当的溶剂中(优选为甲醇)加热回流反应得到通式(IA)化合物；
第二步，通式(IA)化合物与R w-X、
Figure PCTCN2020075790-appb-000049
或三氧化硫吡啶，任选在碱性条件下反应得到通式(I)的化合物。
其中：
R w为-C(O)R 6或-S(O) 2OH；
X为卤素或羟基；
Figure PCTCN2020075790-appb-000050
为单键或双键；且
环A、M、R 1、R 2、R 3、R 6、n、s和t如通式(I)中所定义。
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于吡啶、六氢吡啶、4-二甲氨基吡啶、三乙胺、N,N-二异丙基乙胺、正丁基锂、二异 丙基氨基锂、醋酸钾、叔丁醇钠和叔丁醇钾，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、醋酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂；优选为4-二甲氨基吡啶或N,N-二异丙基乙胺。
上述反应优选在溶剂中进行，所用溶剂包括但不限于：乙酸、三氟乙酸、甲醇、乙醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物。
方案二
本公开通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐制备方法，包括以下步骤：
Figure PCTCN2020075790-appb-000051
第一步，通式(IIB)化合物与甲醛溶液，在适当的溶剂中(优选为甲醇)加热回流反应得到通式(IIA)化合物；
第二步，通式(IIA)化合物与R w-X、
Figure PCTCN2020075790-appb-000052
或三氧化硫吡啶，任选在碱性条件下反应得到通式(II)的化合物。
其中：
R w为-C(O)R 6或-S(O) 2OH；
X为卤素或羟基；
Figure PCTCN2020075790-appb-000053
为单键或双键；且
R 1、R 2、R 3、R 6、n、s和t如通式(II)中所定义。
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于吡啶、六氢吡啶、4-二甲氨基吡啶、三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠和叔丁醇钾，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、醋酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂；优选为4-二甲氨基吡啶或N,N-二异丙基乙胺。
上述反应优选在溶剂中进行，所用溶剂包括但不限于：乙酸、三氟乙酸、甲醇、乙醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚 砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物。
方案三
本公开通式(IIaa)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐制备方法，包括以下步骤：
Figure PCTCN2020075790-appb-000054
第一步，通式(IIaa-B)化合物与甲醛溶液，在适当的溶剂中(优选为甲醇)加热回流反应得到通式(IIaa-A)化合物；
第二步，通式(IIaa-A)化合物与R w-X、
Figure PCTCN2020075790-appb-000055
或三氧化硫吡啶，任选在碱性条件下反应得到通式(IIaa)的化合物。
其中：
R w为-C(O)R 6或-S(O) 2OH；
X为卤素或羟基；
Figure PCTCN2020075790-appb-000056
为单键或双键；且
R 1a、R 1b、R 2、R 3、R 6、s和t如通式(IIaa)中所定义。
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于吡啶、六氢吡啶、4-二甲氨基吡啶、三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠和叔丁醇钾，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、醋酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂；优选为4-二甲氨基吡啶或N,N-二异丙基乙胺。
上述反应优选在溶剂中进行，所用溶剂包括但不限于：乙酸、三氟乙酸、甲醇、乙醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物。
方案四
本公开通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐制备方法，包括以下步骤：
Figure PCTCN2020075790-appb-000057
第一步，化合物1h与甲醛溶液，在适当的溶剂中(优选为甲醇)加热回流反应得到化合物1；
第二步，化合物1与R w-X、
Figure PCTCN2020075790-appb-000058
或三氧化硫吡啶，任选在碱性条件下反应得到通式(III)的化合物。
其中：
R w为-C(O)R 6或-S(O) 2OH；
X为卤素或羟基；
Figure PCTCN2020075790-appb-000059
为单键或双键；且
R 6如通式(III)中所定义。
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于吡啶、六氢吡啶、4-二甲氨基吡啶、三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠和叔丁醇钾，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、醋酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂；优选为4-二甲氨基吡啶或N,N-二异丙基乙胺。
上述反应优选在溶剂中进行，所用溶剂包括但不限于：乙酸、三氟乙酸、甲醇、乙醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物。
方案五
本公开通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐制备方法，包括以下步骤：
Figure PCTCN2020075790-appb-000060
第一步，通式(IVB)与甲醛溶液，在适当的溶剂中(优选为甲醇)加热回流反应得到通式(IVA)；
第二步，通式(IVA)与R w-X、
Figure PCTCN2020075790-appb-000061
或三氧化硫吡啶，任选在碱性条件下反应得到通式(IV)的化合物。
其中：
R w为-C(O)R 6或-S(O) 2OH；
X为卤素或羟基；
Figure PCTCN2020075790-appb-000062
为单键或双键；且
R 6和R 7如通式(IV)中所定义。
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于吡啶、六氢吡啶、4-二甲氨基吡啶、三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠和叔丁醇钾，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、醋酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂；优选为4-二甲氨基吡啶或N,N-二异丙基乙胺。
上述反应优选在溶剂中进行，所用溶剂包括但不限于：乙酸、三氟乙酸、甲醇、乙醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物。
具体实施方式
以下结合实施例进一步描述本公开，但这些实施例并非限制着本公开的范围。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液质联用仪 (生产商：Agilent，MS型号：6110/6120 Quadrupole MS)、waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)、THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)。
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高压液相色谱仪。
手性HPLC分析测定使用Agilent 1260 DAD高效液相色谱仪。
高效液相制备使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281制备型色谱仪。
手性制备使用Shimadzu LC-20AP制备型色谱仪。
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，C：石油醚/乙酸乙酯体系，D：丙酮，E：二氯甲烷/丙酮体系，F：乙酸乙酯/二氯甲烷体系，G：乙酸乙酯/二氯甲烷/正己烷，H：乙酸乙酯/二氯甲烷/丙酮，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
5-氯-2-(4-氟-2-甲基苯氧基)-N-(1-(羟甲基)-6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺1
Figure PCTCN2020075790-appb-000063
第一步
5-氯-2-氟-4-(三氟甲基)苯甲酸1b
在氩气氛下，将2,2,6,6-四甲基哌啶(19.2g,135.93mmol，韶远科技(上海)有限公司)加入到四氢呋喃(200mL)中。降温至0℃，滴加正丁基锂(1.6M,85.1mL)，控制温度低于3°℃，约45分钟加完。0℃反应1小时。降温至-78℃，滴加化合物1-氯-4-氟-2-(三氟甲基)苯1a(18g,90.66mmol，上海泰坦科技股份有限公司)，反应3小时。加入过量干冰，自然升温至0℃，加入150mL冰水。分层，水相用浓盐酸调节pH为5～6，用乙酸乙酯(50mL)萃取，有机相减压浓缩。粗品用正己烷(50mL)洗涤，再用硅胶柱色谱法以展开剂体系A纯化，得到标题化合物1b(15g)，产率：68％。
MS m/z(ESI):241.1[M-1]。
第二步
5-氯-2-氟-4-(三氟甲基)苯甲酸甲酯1c
将化合物1b(5g,20.61mmol)加入到氯化亚砜(49.2g,413.55mmol)，80℃反应2小时。反应液减压浓缩，将得到的油状物滴加入到甲醇(100mL)中，室温反应1 小时。反应液减压浓缩，用硅胶柱色谱法以展开剂体系B纯化，得到标题化合物1c(2.78g)，产率：52％。
第三步
5-氯-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酸甲酯1d
将化合物1c(2.78g,10.83mmol)，4-氟-2-甲基-苯酚(1.5g,11.89mmol，上海毕得医药科技有限公司)和碳酸铯(6g,18.41mmol)加入N,N-二甲基甲酰胺(20mL)中，100℃反应1小时。降温抽滤，滤液浓缩，得到目标化合物1d(3.92g)，产品不经纯化直接用于下一步反应。
MS m/z(ESI):363.1[M+1]。
第四步
5-氯-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酸1e
将粗品化合物1d(3.92g,10.81mmol)溶于甲醇(30mL)，加入水(10mL)和氢氧化钠(1.3g,32.5mmol)，反应16小时。反应液浓缩，加入水10mL，用浓盐酸调节pH为1。乙酸乙酯萃取(20mL×3)，有机相用无水硫酸钠干燥。过滤，滤液减压浓缩，用硅胶柱色谱法以展开剂体系A纯化，得到标题化合物1e(3.67g)，产率：97％。
MS m/z(ESI):346.8[M-1]。
第五步
5-氯-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰氯1f
将化合物1e(3.67g,10.52mmol)加入氯化亚砜(20g,168.1mmol)，80℃反应2小时。反应液浓缩，得到粗品标题化合物1f(3.86g)，产品不经纯化直接用于下一步反应。
第六步
5-氯-N-(6-氯哒嗪-4-基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺1g
将4-二甲氨基吡啶(130mg,1.05mmol)和6-氯哒嗪-4-胺(1.51g,11.57mmol，南京药石科技股份有限公司)溶于吡啶(40mL)，用分子筛干燥。加入粗品化合物1f(3.86g,10.51mmol)，氩气保护，反应16小时。反应液减压浓缩，用硅胶柱色谱法以展开剂体系B纯化，得到标题化合物1g(1.3g)，产率：39％。
MS m/z(ESI):460.0[M+1]。
第七步
5-氯-2-(4-氟-2-甲基苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺1h
将化合物1g(1.3g,2.82mmol)和乙酸钾(555mg,5.65mmol)加入乙酸(20mL)，130℃反应3小时。反应液浓缩，用硅胶柱色谱法以展开剂体系B纯化，得到标题化合物1h(800mg)，产率：64％。
MS m/z(ESI):442.0[M+1]。
第八步
5-氯-2-(4-氟-2-甲基苯氧基)-N-(1-(羟甲基)-6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺1
将化合物1h(975mg,2.21mmol)加入到甲醇(12mL)，加入甲醛溶液(12g,147.87mmol,37wt％,国药集团化学试剂有限公司)，氩气保护加热回流16小时。反应液减压浓缩，抽滤得到滤饼，用水洗涤，干燥得到标题化合物1(1.0g)，产率：96％。
MS m/z(ESI):472.0[M+1]。
1H NMR(400MHz,DMSO-d 6)δ11.11(s,1H),8.08(s,1H),7.91(s,1H),7.10-7.22(m,2H),7.04-7.10(m,3H),6.66(t,1H),5.23(d,2H),2.13(s,3H)。
实施例2
4-((4-(5-氯-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲氧基)-4-氧代丁酸2
Figure PCTCN2020075790-appb-000064
将化合物1(990mg,2.10mmol)加入二氯甲烷(20mL)，再加入丁二酸酐(300mg,3.00mmol,国药集团化学试剂有限公司)，4-二甲氨基吡啶(40mg,0.32mmol)，N,N-二异丙基乙胺(600mg,4.64mmol)，30℃反应5小时。反应液减压浓缩，用高效液相色谱制备(Waters 2767-SQ Detecor2，洗脱体系：乙酸铵，水，乙腈)纯化，得到标题化合物2，产率：68％。
MS m/z(ESI):572.0[M+1]。
1H NMR(400MHz,DMSO-d 6)δ12.23(s,1H),11.21(s,1H),8.08(s,1H),7.94(d,1H),7.28(d,1H),7.19(d,1H),7.05-7.09(m,3H),5.86(s,2H),2.40-2.53(m,4H),2.13(s,3H)。
实施例3
(4-(5-氯-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)异丁酸甲酯3
Figure PCTCN2020075790-appb-000065
采用实施例2的合成路线，将原料丁二酸酐替换为异丁酰氯(萨恩化学技术(上海)有限公司)，制得标题化合物3(60mg)，产率：52％。
MS m/z(ESI):542.1[M+1]。
1H NMR(400MHz,DMSO-d 6)δ11.21(s,1H),8.08(s,1H),7.94(s,1H),7.27(s,1H),7.19(d,1H),7.05-7.09(m,3H),5.87(s,2H),2.50-2.60(m,1H),2.13(s,3H),1.03(d,6H)。
实施例4
(4-(5-氯-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)乙酸甲酯4
Figure PCTCN2020075790-appb-000066
采用实施例2的合成路线，将原料丁二酸酐替换为乙酰氯(国药集团化学试剂有限公司)，制得标题化合物4(60mg)，产率：55％。
MS m/z(ESI):514.1[M+1]。
1H NMR(400MHz,DMSO-d 6)δ11.21(s,1H),8.08(s,1H),7.94(s,1H),7.28(d,1H),7.19(d,1H),7.05-7.09(m,3H),5.85(s,2H),2.13(s,3H),2.01(s,3H)。
实施例5
(4-(5-氯-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲基乙基碳酸酯5
Figure PCTCN2020075790-appb-000067
采用实施例2的合成路线，将原料丁二酸酐替换为氯代乙酸乙酯(国药集团化学试剂有限公司)，制得标题化合物5(15mg)，产率：13％。
MS m/z(ESI):544.1[M+1]。
1H NMR(400MHz,DMSO-d 6)δ11.22(s,1H),8.09(s,1H),7.94(d,1H),7.28(d,1H),7.19(d,1H),7.05-7.09(m,3H),5.89(s,2H),4.12(q,2H),2.13(s,3H),1.18(t,3H)。
实施例6
4-((4-(5-氯-2-(4-氟-2-甲氧基苯氧基)-4-(三氟甲基)苯甲酰胺基)-6-氧代哒嗪-1(6H)-基)甲氧基)-4-氧代丁酸6
Figure PCTCN2020075790-appb-000068
第一步
5-氯-2-氟-4-(三氟甲基)苯甲酰氯6a
将化合物1b(5.00g,20.6mmol)加入15mL氯化亚砜，80℃反应2小时。反应 液减压浓缩，得到粗品标题化合物6a(5.38g)，产物不经纯化，直接用于下一步反应。
第二步
5-氯-2-氟-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺6b
将5-氨基哒嗪-3-酮(3.06g,24.8mmol,采用专利申请“WO2016004417中说明书第100页的实施例386”公开的方法制备而得)溶于40mL N-甲基吡咯烷酮中，冷却至0℃，缓慢分批加入氢化钠(2.06g,51.5mmol,60％纯度)，0℃搅拌30分钟。将化合物6a(5.38g,20.6mmol)溶于3mL N-甲基吡咯烷酮，缓慢滴加入上述反应液中，室温搅拌过夜。含有标题化合物6b的反应液不经纯化直接用于下一步。
第三步
5-氯-2-(4-氟-2-甲氧基苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺6c
向含有化合物6b的反应液中直接加入4-氟-2-甲氧基苯酚(2.34g,16.5mmol，梯希爱(上海)化成工业发展有限公司)和碳酸铯(6.71g,20.6mmol,韶远化学科技(上海)有限公司)。60℃反应过夜，反应液冷却至室温，加入乙酸乙酯(250mL)，用水洗涤(100mL×3)。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以展开剂体系B纯化，得到标题化合物6c(3.0g)，产率：32％。
MS m/z(ESI):458.1[M+1]。
1H NMR(400MHz,DMSO-d 6):δ12.87(s,1H),11.03(s,1H),8.05(s,1H),7.92(s,1H),7.27(dd,1H),7.22(s,1H),7.15(dd,1H),7.00(s,1H),6.87-6.82(m,1H),3.71(s,3H)。
第四步
5-氯-2-(4-氟-2-甲氧基苯氧基)-N-(1-(羟甲基)-6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺6d
将化合物6c(3.00g,6.55mmol)加入到30mL甲醇，加入甲醛溶液(30mL,37wt％,国药集团化学试剂有限公司)，氩气保护加热回流16小时。反应液减压浓缩，抽滤得到滤饼，干燥得到标题化合物6d(2.90g)，产率：91％。
MS m/z(ESI):488.2[M+1]。
第五步
4-((4-(5-氯-2-(4-氟-2-甲氧基苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲氧基)-4-氧代丁酸6
将化合物6d(2.90g,5.94mmol)加入50mL二氯甲烷，再加入丁二酸酐(893mg,8.92mmol,国药集团化学试剂有限公司)，4-二甲氨基吡啶(110mg,0.89mmol)，N,N-二异丙基乙胺(1.54g,11.92mmol)，30℃反应过夜。反应液减压浓缩，用高效液相色谱制备(Waters 2767-SQ Detecor2，洗脱体系：乙酸铵，水，乙腈)纯化，得到标题化合物6(2.8g)，产率：80％。
MS m/z(ESI):588.1[M+1]。
1H NMR(400MHz,DMSO-d 6)δ12.22(s,1H),11.16(s,1H),8.03(s,1H),7.97(d,1H),7.31(s,1H),7.24(dd,1H),7.11(dd,1H),6.97(s,1H),6.84-7.79(m,1H),5.87(s,2H),2.52-2.41(m,4H),2.03(s,3H)。
实施例7
4-((4-(5-氯-2-(4-氟-2-(甲氧基-d 3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲氧基)-4-氧代丁酸7
Figure PCTCN2020075790-appb-000069
第一步
1-溴-4-氟-2-(甲氧基-d 3)苯7b
将2-溴-5-氟苯酚7a(1g,5.2mmol,韶远化学科技(上海)有限公司)，氘代碘甲烷(911mg,6.3mmol,萨恩化学技术(上海)有限公司)，碳酸钾(1.45g,10.5mmol)，加入N,N-二甲基甲酰胺(10mL)，搅拌反应6小时。反应液冷却至室温，加入乙酸乙酯(20mL)，用水洗涤(20mL×3)。合并有机相，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以展开剂体系A纯化，得到标题化合物7b(840mg)， 产率：71％。
1H NMR(400MHz,CDCl 3):δ7.49-7.45(m,1H),6.66-6.57(m,2H)。
第二步
4-氟-2-(甲氧基-d 3)苯酚7c
将化合物7b(840mg,4mmol)和硼酸三异丙酯(987mg,5.25mmol,上海泰坦科技股份有限公司)加入到四氢呋喃/甲苯混合溶液中(150mL/30mL)。将反应瓶内空气置换为氩气，降温至-78℃，缓慢滴加正丁基锂(1.6M,3.8mL,6.1mmol)，20分钟滴加完毕。自然升至室温，搅拌过夜。冰浴降温至0℃，加入甲醇(50mL)，滴加双氧水(30wt％,10mL)和10％氢氧化钠溶液(40mL)，室温搅拌1小时。反应液中缓慢滴加饱和硫代硫酸钠溶液(50mL)，用乙酸乙酯萃取(200mL×3)。有机相用饱和碳酸氢钠溶液(150mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以展开剂体系B纯化，得到标题化合物7c(570mg)，产率：97％。
MS m/z(ESI):144.0[M-1]。
1H NMR(400MHz,DMSO-d 6):δ8.89(s,1H),6.85-6.82(m,1H),6.76-6.72(m,1H),6.59-6.54(m,1H)。
第三步
5-氯-2-(4-氟-2-(甲氧基-d 3)苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺7d
将化合物6b(1g,2.98mmol)，化合物7c(433mg,2.98mmol)和碳酸铯(1.02g,3.13mmol,韶远化学科技(上海)有限公司)加入N-甲基吡咯烷酮(10mL)，80℃反应3小时。反应液冷却至室温，加入乙酸乙酯(20mL)，用水洗涤(10mL×3)。合并有机相，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以展开剂体系B纯化，得到标题化合物7d(280mg)，产率：20％。
MS m/z(ESI):461.0[M-1]。
1H NMR(400MHz,DMSO-d 6):δ12.87(s,1H),11.03(s,1H),8.06(s,1H),7.93(d,1H),7.29-7.23(m,2H),7.16-7.13(m,1H),7.01(s,1H),6.88-6.83(m,1H)。
第四步
5-氯-2-(4-氟-2-(甲氧基-d 3)苯氧基)-N-(1-(羟甲基)-6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺7e
将化合物7d(6.1g,13.2mmol)加入到60mL甲醇，加入甲醛溶液(60mL,37wt％,国药集团化学试剂有限公司)，氩气保护加热回流16小时。反应液减压浓缩，抽滤得到滤饼，干燥得到标题化合物7e(5.6g)，产率：86％。
MS m/z(ESI):491.2[M+1]。
第五步
4-((4-(5-氯-2-(4-氟-2-(甲氧基-d 3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪 -1(6H)-基)甲氧基)-4-氧代丁酸7
将化合物7e(3.43g,7mmol)加入80mL二氯甲烷，再加入丁二酸酐(1.05g,10.5mmol,国药集团化学试剂有限公司)，4-二甲氨基吡啶(1.09g,8.8mmol)，N,N-二异丙基乙胺(1.81g,14mmol)，30℃反应过夜。反应液减压浓缩，用高效液相色谱制备(Waters 2767-SQ Detecor2，洗脱体系：乙酸铵，水，乙腈)纯化，得到标题化合物7(2.7g)，产率：65％。
MS m/z(ESI):589.0[M-1],591.0[M+1]。
1H NMR(400MHz,DMSO-d 6)δ12.21(s,1H),11.93(s,1H),8.07(s,1H),8.02(d,1H),7.34(d,1H),7.30-7.26(m,1H),7.16-7.13(m,1H),7.01(s,1H),6.88-6.83(m,1H),5.91(s,2H),2.67-2.46(m,4H)。
实施例8
(4-(5-氯-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲基氢硫酸酯8
Figure PCTCN2020075790-appb-000070
采用实施例2的合成路线，将原料丁二酸酐替换为三氧化硫吡啶(韶远化学科技(上海)有限公司)，制得标题化合物8(30mg)。
MS m/z(ESI):550.0[M-1]。
1H NMR(400MHz,CD 3OD)δ7.98-7.97(m,2H),7.52-7.51(m,1H),7.12-7.09(m,1H),7.06-6.97(m,3H),5.88(s,2H),2.21(s,3H)。
实施例9
(E)-4-((4-(5-氯-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲氧基)-4-氧代丁-2-烯酸9
Figure PCTCN2020075790-appb-000071
采用实施例2的合成路线，将原料丁二酸酐替换为反丁烯二酸(韶远化学科技(上海)有限公司)，制得标题化合物9(10mg)。
MS m/z(ESI):570.1[M+1]。
1H NMR(400MHz,DMSO-d 6)δ12.22(s,1H),8.08(s,1H),7.96(s,1H),7.29(s,1H),7.19(d,1H),7.00-7.13(m,3H),6.60-6.75(m,2H),6.01(s,2H),2.13(s,3H)。
实施例10
3-((4-(5-氯-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲氧基)-3-氧代丙酸10
Figure PCTCN2020075790-appb-000072
采用实施例2的合成路线，将原料丁二酸酐替换为丙二酸(韶远化学科技(上海)有限公司)，制得标题化合物10(13mg)。
MS m/z(ESI):558.0[M+1]。
1H NMR(400MHz,DMSO-d 6)δ12.22(s,1H),8.09(s,1H),7.95(s,1H),7.29(s,1H),7.20(d,1H),7.00-7.13(m,3H),5.91(s,2H),3.41(s,2H),2.13(s,3H)。
实施例11
4-((4-(5-氯-2-(2-乙基-4-氟苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲氧基)-4-氧代丁酸11
Figure PCTCN2020075790-appb-000073
采用实施例6的合成路线，将第三步原料4-氟-2-甲氧基苯酚替换为2-乙基-4-氟苯酚(上海毕得医药科技有限公司)，制得标题化合物11(2.3g)。
MS m/z(ESI):584.0[M-1]。
1H NMR(400MHz,DMSO-d 6)δ12.23(br,1H),11.25(s,1H),8.12(s,1H),7.98-7.98(dd,1H),7.32-7.32(d,1H),7.25-7.23(d,1H),7.13-7.11(m,2H),7.10(s,1H),5.90(s, 2H),2.58-2.53(m,4H),2.49-2.46(m,2H),1.10-1.06(t,3H)。
实施例12
(4-(5-氯-2-(4-氟-2-(甲氧基-d 3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲基氢硫酸酯12
Figure PCTCN2020075790-appb-000074
采用实施例7的合成路线，将第五步原料丁二酸酐替换为三氧化硫吡啶(韶远化学科技(上海)有限公司)，制得标题化合物12(85mg)。
MS m/z(ESI):568.9[M-1]。
1H NMR(400MHz,DMSO-d 6)δ8.02(s,1H),7.89(d,1H),7.23-7.19(m,2H),7.09-7.05(m,2H),6.94(s,1H),6.80-6.76(m,1H),5.48(s,2H)。
实施例13
(E)-4-((4-(5-氯-2-(4-氟-2-(甲氧基-d 3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-6-氧代哒嗪-1(6H)-基)甲氧基)-4-氧代丁-2-烯酸13
Figure PCTCN2020075790-appb-000075
采用实施例7的合成路线，将第五步原料丁二酸酐替换为反丁烯二酸(韶远化学科技(上海)有限公司)，制得标题化合物13(11mg)。
MS m/z(ESI):587.0[M-1]。
1H NMR(400MHz,CD 3OD)δ7.95(d,1H),7.88(s,1H),7.46(d,1H),7.18-7.14(m,1H),6.95(s,1H),6.92-6.89(m,1H),6.79(d,1H),6.71-6.66(m,1H),6.56(d,1H),6.02(s,2H)。
理化性质
以下结合测试例进一步描述解释本公开，但这些测试例并非意味着限制本公 开的范围。
测试例1、本公开化合物在pH 7.4的PBS溶液中的室温溶解度
1.实验材料
试剂：二甲亚砜(分析纯)、乙醇(分析纯)、乙腈(色谱纯)、NaH 2PO 4·2H 2O(分析纯)、Na 2HPO 4·12H 2O(分析纯)、乙酸铵(分析纯)、氢氧化钠、氯化钠(分析纯)。
仪器：液相色谱仪。
2、实验步骤
2.1 pH 7.4 PBS溶液的配制：称取0.57g NaH 2PO 4·2H 2O、5.55g Na 2HPO 4·12H 2O和6.48g NaCl，加入超纯水，用1M NaOH或1M HCl调节pH至7.4±0.05，加水定容至1L。放置4℃冰箱保存(保存期限为6个月)。
2.2化合物PBS 7.4溶液的配制：称取适量待测化合物用DMSO或DMSO：乙腈：乙醇＝1:1:1溶解，配制10mM待测化合物储备液。精密量取10μL待测化合物储备液与990μL pH7.4PBS溶液于2mL样品瓶中，混匀，最终溶液DMSO浓度为1％(v/v)。该溶液平行配制两份，在平板床上室温振摇24小时，在5000rpm离心20min，上清液转移至液相色谱仪分析。
2.3参比溶液的配制：精密量取10μL待测样品储备液(浓度10mM，溶解在DMSO中)与990μL有机混合溶剂(通常为DMSO：乙腈：乙醇＝1:1:1)于2mL样品瓶中，混匀，得到澄清的100μM样品溶液。用0.45μm的有机相微孔滤膜过滤，续滤液进液相色谱仪分析。
3.数据处理
溶解度(μM)＝样品的峰面积/参比的峰面积*参比浓度(μM)*样品溶液稀释倍数取两次测量值得平均值作为最终溶解度。
表1本公开化合物在pH 7.4的PBS溶液中的溶解度
Figure PCTCN2020075790-appb-000076
结论：室温下，化合物1h、6c和7d在pH 7.4的PBS溶液中的溶解度差，而本公开的前药化合物在pH 7.4的PBS溶液中的溶解度得到了极大提高。
生物学评价
测试例2、本公开化合物的大鼠药代动力学测试
1、摘要
以SD大鼠为受试动物，应用LC/MS/MS法测定了SD大鼠口服给予实施例2化合物、实施例6化合物和实施例7化合物后不同时刻血浆中的药物浓度。研究本公开化合物在SD大鼠体内的药代动力学行为，评价其药动学特征。
2、试验方案
2.1试验药品
实施例2化合物、实施例6化合物和实施例7化合物。
2.2试验动物
SD大鼠40只，雌雄各半，平均分成10组，购自上海杰思捷实验动物有限公司，动物生产许可证号：SCXK(沪)2013-0006。
2.3药物配制
称取适量实施例2样品，加入5％DMSO+5％吐温80+90％生理盐水，按顺序依次加入得到无色澄清透明溶液。
称取适量实施例2样品，加入0.5％羧甲基纤维素钠(含0.5％吐温80)，得到白色均匀混悬液。
称取适量实施例6样品，加入到200mM(5％PVPK30+5％TPGS)Na 2HPO 4溶液(pH＝9)，得到均匀混悬液。
称取适量实施例7样品，加入到200mM(5％PVPK30+5％TPGS)Na 2HPO 4溶液(pH＝9)，得到均匀混悬液。
2.4给药
SD大鼠禁食过夜后灌胃给药，实施例2化合物给药剂量为2mg/kg，给药体积为10mL/kg，给药浓度为0.2mg/mL(配方：5％DMSO+5％tween80+90％生理盐水)；实施例2化合物给药剂量为10、30、100mg/kg，给药体积为10mL/kg，给药浓度为1、3、10mg/mL(配方：0.5％羧甲基纤维素钠(含0.5％吐温80))。实施例6化合物给药剂量为100、300、900mg/kg，给药体积为10mL/kg，给药浓度为10、30、90mg/mL。实施例7化合物给药剂量为10、30、100mg/kg，给药体积为10mL/kg，给药浓度为1、3、10mg/mL。
3、操作
禁食一夜后灌胃给药，于给药前及给药后0.5,1.0,2.0,4.0,6.0,8.0,11.0,24.0h由眼眶采血0.2ml，置于肝素化试管中，3500rpm离心10分钟分离血浆，于-20℃保存。给药后2小时进食。
测定不同浓度的药物SD大鼠给药后血浆中的待测化合物含量：取给药后各时刻的SD大鼠血浆25μL，加入内标喜树碱溶液50μL(100ng/mL)，乙腈200μL，涡旋混合5分钟，离心10分钟(3700转/分钟)，给药实施例2化合物(给药剂量2mg/kg组)的血浆样品取上清液3.0μL，给药实施例2化合物(给药剂量10、30、100mg/kg组)的血浆样品取上清液2.0μL，给药实施例6化合物的血浆样品取上清液0.2μL，给药实施例7化合物的血浆样品取上清液1μL进行LC/MS/MS分析。
4、SD大鼠药代动力学参数结果
灌胃给药后，使用LC/MS/MS分析血浆样品以测定化合物2和化合物1h的浓度，化合物6和化合物6c的浓度，以及化合物7和化合物7d的浓度，在大鼠体内未检测到实施例2化合物、实施例6化合物和实施例7化合物，以下数据为其代谢物化合物1h、6c和7d的药代数据。
表2本公开化合物的大鼠药代动力学参数
Figure PCTCN2020075790-appb-000077
结论：上述研究结果证实，在大鼠中，实施例2在体内转化为化合物1h；实施例6在体内转化为化合物6c；实施例7在体内转化为化合物7d。并且，本公开化合物的药代吸收良好，具有明显的药代动力学优势。
测试例3、本公开化合物对Nav1.8抑制活性的测定
实验的目的是为了研究化合物在离体实验中对Na V1.8离子通道的影响，Na V1.8离子通道稳定地表达在HEK293细胞上。在Na V1.8电流稳定后，比较化合物应用 前后Na V1.8电流的大小，可以得到化合物对Na V1.8离子通道的影响。
1、实验材料及仪器
1)膜片钳放大器：patch clamp PC-505B(WARNER instruments)/MultiClamp 700A(Axon instrument)。
2)数模转换器：Digidata 1440A(Axon CNS)/Digidata 1550A(Axon instruments)。
3)微操控仪：MP-225(SUTTER instrument)。
4)倒置显微镜：TL4(Olympus)。
5)玻璃微电极拉制仪：PC-10(NARISHIGE)。
6)微电极玻璃毛细管：B12024F(武汉微探科学仪器有限公司)。
7)二甲基亚砜(DMSO)D2650(Sigma-Aldrich)。
8)TTX AF3014(Affix Scientific)。
2、实验步骤
2.1化合物配制
配制细胞内外液的化合物除用于酸碱滴定的NaOH和KOH外，均从Sigma(St.Louis,MO)公司购买。细胞外液(mM)为:NaCl,137；KCl,4；CaCl 2,1.8；MgCl 2,1；HEPES,10；葡萄糖10；pH 7.4(NaOH滴定)。细胞内液(mM)为天冬氨酸,140；MgCl2,2；EGTA 11；HEPES,10；pH 7.2(CsOH滴定)。所有测试化合物和对照化合物溶液均含1μM TTX。
测试化合物的保存浓度为9mM，溶于二甲基亚砜(DMSO)。测试当天再溶于细胞外液，配制成要求浓度。
2.2手动膜片钳测试过程
1)化合物配制成指定浓度的溶液后，按浓度从从低到高顺序将药液依次加入各个管道，并对各个管道进行标记。
2)将细胞转移到灌流槽中，电极内施加正压，将电极尖端接触到细胞，抽气装置三通阀调成三通状态，然后对电极施加负压，使得电极与细胞形成高阻封接。继续施加负压，使得细胞膜破裂，形成电流通路。
3)待细胞破膜电流稳定后，依次进行不同的浓度的灌注。若电流稳定至少一分钟即可换下一个浓度进行灌流。每个浓度灌流时间不超过五分钟。
4)清洗灌流槽。按药液浓度从高到低进行冲洗，每个浓度药液冲洗20s。最后用细胞外液冲洗1min。
2.3测试电压方程(resting)及结果
将细胞钳制在–80mV，然后用持续10毫秒方波去极化到10mV，以得到Na V1.8电流。这一程序每5秒重复一次。检测方波引发的最大电流，待其稳定后，灌流测试化合物，当反应稳定后，计算阻断的强度。
3、数据分析
资料将存于计算机系统做分析。资料采集和分析将用pCLAMP 10(Molecular Devices,Union City,CA),管理人员将审查分析结果。电流稳定指的是电流随时间变化在有限的范围内。电流稳定后的大小说用来计算化合物在此溶度的作用。
本公开化合物对Nav1.8的抑制活性通过以上的试验进行测定，测得的IC 50值见表3。
表3本公开所述的前药化合物及其代谢物对Nav1.8通道活性抑制的IC 50
Figure PCTCN2020075790-appb-000078
结论：本公开所述的前药化合物及其代谢物对Nav1.8通道活性具有明显的抑制效果。

Claims (18)

  1. 一种通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，
    Figure PCTCN2020075790-appb-100001
    其中：
    M选自O原子、CR 4R 5和S原子；
    环A为芳基或杂芳基；
    R 1相同或不同，且各自独立地选自氢原子、卤素、烷基、氘代烷基、烷氧基、氘代烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
    R 2相同或不同，且各自独立地选自氢原子、卤素、烷基、氘代烷基、烷氧基、氘代烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、环烷基氧基、杂环基、芳基和杂芳基，其中所述烷基、环烷基、杂环基、芳基和杂芳基各自任选被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
    R 4和R 5相同或不同，且各自独立地选自氢原子、氘原子、卤素、烷基、烷氧基、卤代烷基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
    R w选自氢原子、烷基、-C(O)R 6、-S(O) 2OH、-S(O) 2O -Q +、-PO(OH) 2、-PO(OH)O -Q +、-PO(O -) 22Q +和-PO(O -) 2W 2+；Q +为药学上可接受的单价阳离子；W 2+为药学上可接受的二价阳离子；
    R 6选自烷基、烷氧基、烯基、羧基和羧酸盐，其中所述烷基、烷氧基和烯基各自任选被选自羟基、氨基、羧基和羧酸盐中的一个或多个取代基所取代；
    n为0、1、2、3或4；
    s为0、1、2、3或4；且
    t为0、1或2。
  2. 根据权利要求1所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，其中环A为苯基或吡啶基。
  3. 根据权利要求1或2所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，其中R w选自氢原子、-C(O)-烷基、-C(O)-烷氧基、-C(O)-亚烷基-COOH、-C(O)-亚烯基-COOH、-C(O)-COOH、-S(O) 2OH和-C(O)-亚烷基-NH 2，其中所述烷基、烷氧基、亚烷基和亚烯基各自任选被一个或多个羟基所取代；优选地，R w选自氢原子、-C(O)-C 1-6烷基、-C(O)-C 1-6烷氧基、-C(O)-C 1-6亚烷基-COOH、-C(O)-C 2-6亚烯基-COOH、-C(O)-COOH、-S(O) 2OH和-C(O)-C 1-6亚烷基-NH 2，其中所述C 1-6烷基、C 1-6烷氧基、C 1-6亚烷基和C 2-6亚烯基各自任选被一个或多个羟基所取代。
  4. 根据权利要求1至3中任一项所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，其中R w选自氢原子、-C(O)CH 3、-C(O)CH(OH)CH 3、-C(O)CH(CH 3) 2、-C(O)OCH 2CH 3、-C(O)CH 2COOH、-C(O)CH 2CH 2COOH、-C(O)CH(OH)CH 2COOH、-C(O)CH 2CH(OH)COOH、-C(O)CH(OH)CH(OH)COOH、-C(O)-CH＝CH-COOH、-C(O)-COOH、-S(O) 2OH和-C(O)CH 2NH 2，优选选自-C(O)CH 2COOH、-C(O)CH 2CH 2COOH、-C(O)CH(OH)CH 2COOH、-C(O)CH 2CH(OH)COOH、-C(O)CH(OH)CH(OH)COOH、-C(O)-CH＝CH-COOH和-C(O)-COOH。
  5. 根据权利要求1至4中任一项所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，其中M为O。
  6. 根据权利要求1至5中任一项所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，其为通式(II)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，
    Figure PCTCN2020075790-appb-100002
    其中：
    R 1、R 2、R 3、R w、n、s和t如权利要求1中所定义。
  7. 根据权利要求1至6中任一项所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，其为通式(IIaa)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，
    Figure PCTCN2020075790-appb-100003
    其中：
    R 1a为卤素；优选地，R 1a为Cl；
    R 1b为卤代烷基；优选地，R 1b为CF 3；且
    R 2、R 3、R w、s和t如权利要求1中所定义。
  8. 根据权利要求1至6中任一项所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，其中R 1相同或不同，且各自独立地选自氢原子、卤素、烷基和卤代烷基；优选地，R 1相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和卤代C 1-6烷基。
  9. 根据权利要求1至8中任一项所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其 可药用的盐，其中R 2相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、氘代烷氧基、卤代烷基、卤代烷氧基、环烷基和环烷基氧基；优选地，R 2相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、氘代C 1-6烷氧基和C 3-6环烷基氧基。
  10. 根据权利要求1至9中任一项所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，其中R 3为氢原子。
  11. 根据权利要求1至10中任一项所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，其为通式(III)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，
    Figure PCTCN2020075790-appb-100004
    其中：
    R w如权利要求1中所定义。
  12. 根据权利要求1至10中任一项所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，其为通式(IV)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，
    Figure PCTCN2020075790-appb-100005
    其中：
    R 7选自烷基、氘代烷基和环烷基；优选地，R 7选自C 1-6烷基、氘代C 1-6烷基和C 3-6环烷基；且
    R w如权利要求1中所定义。
  13. 根据权利要求1至12中任一项所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，其中所述化合物选自：
    Figure PCTCN2020075790-appb-100006
    Figure PCTCN2020075790-appb-100007
  14. 一种制备根据权利要求1所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐的方法，该方法包括：
    Figure PCTCN2020075790-appb-100008
    通式(IA)化合物与R w-X、
    Figure PCTCN2020075790-appb-100009
    或三氧化硫吡啶反应得到通式(I)化合物的步骤；
    其中：
    R w为-C(O)R 6或-S(O) 2OH；
    X为卤素或羟基；
    Figure PCTCN2020075790-appb-100010
    为单键或双键；且
    环A、M、R 1、R 2、R 3、R 6、n、s和t如权利要求1中所定义。
  15. 根据权利要求14所述的方法，该方法进一步包括：
    Figure PCTCN2020075790-appb-100011
    通式(IB)化合物与甲醛溶液反应得到通式(IA)化合物的步骤；
    其中：
    环A、M、R 1、R 2、R 3、n、s和t如权利要求1中所定义。
  16. 一种药物组合物，其含有根据权利要求1至13中任一项所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异 构体、或其混合物形式，或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  17. 根据权利要求1至13中任一项所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，或根据权利要求16所述的药物组合物在制备抑制受试者电压门控钠通道的药物中的用途，优选地，所述电压门控钠通道为Na V1.8。
  18. 根据权利要求1至13中任一项所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐，或根据权利要求16所述的药物组合物在制备治疗和/或减轻疼痛和疼痛相关疾病、多发性硬化症、夏-马-图三氏综合症、失禁或心律失常的药物中的用途，优选地，所述疼痛选自慢性疼痛、急性疼痛、炎性疼痛、癌症疼痛、神经性疼痛、肌肉骨骼痛、原发性疼痛、肠痛和特发性疼痛。
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WO2022037647A1 (zh) * 2020-08-19 2022-02-24 江苏恒瑞医药股份有限公司 一种选择性Nav抑制剂的结晶形式及其制备方法
WO2022037641A1 (zh) * 2020-08-19 2022-02-24 江苏恒瑞医药股份有限公司 一种选择性NaV抑制剂的前药及其晶型
CN112500353A (zh) * 2020-12-08 2021-03-16 北京晨光同创医药研究院有限公司 一种左西孟旦的前药化合物、制备方法及其应用
CN112500353B (zh) * 2020-12-08 2022-11-25 北京晨光同创医药研究院有限公司 一种左西孟旦的前药化合物、制备方法及其应用
WO2022179624A1 (zh) * 2021-02-26 2022-09-01 江苏恒瑞医药股份有限公司 一种选择性NaV抑制剂的可药用盐、结晶形式及其制备方法
CN116964065A (zh) * 2021-02-26 2023-10-27 江苏恒瑞医药股份有限公司 一种选择性NaV抑制剂的可药用盐、结晶形式及其制备方法

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CN112996776B (zh) 2024-03-15
AU2020224245A1 (en) 2021-08-05
BR112021014178A2 (pt) 2021-09-21
ZA202106711B (en) 2022-08-31
US20220162169A1 (en) 2022-05-26
MX2021009539A (es) 2021-11-04
TW202102480A (zh) 2021-01-16
KR20210131357A (ko) 2021-11-02
EP3929181A4 (en) 2022-10-26

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