WO2020140959A1 - 6-氧代-1,6-二氢哒嗪类衍生物、其制备方法及其在医药上的应用 - Google Patents

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

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WO2020140959A1
WO2020140959A1 PCT/CN2020/070186 CN2020070186W WO2020140959A1 WO 2020140959 A1 WO2020140959 A1 WO 2020140959A1 CN 2020070186 W CN2020070186 W CN 2020070186W WO 2020140959 A1 WO2020140959 A1 WO 2020140959A1
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Prior art keywords
racemate
compound
general formula
pharmaceutically acceptable
alkoxy
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PCT/CN2020/070186
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English (en)
French (fr)
Inventor
杨方龙
郁楠
池江涛
贺峰
陶维康
Original Assignee
江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Application filed by 江苏恒瑞医药股份有限公司, 上海恒瑞医药有限公司 filed Critical 江苏恒瑞医药股份有限公司
Priority to KR1020217023256A priority Critical patent/KR20210112336A/ko
Priority to US17/419,664 priority patent/US20220073471A1/en
Priority to MX2021007970A priority patent/MX2021007970A/es
Priority to CN202080005993.5A priority patent/CN112955436B/zh
Priority to EP20736089.2A priority patent/EP3907218A4/en
Priority to AU2020205139A priority patent/AU2020205139A1/en
Priority to CA3125244A priority patent/CA3125244A1/en
Priority to JP2021538728A priority patent/JP2022515909A/ja
Priority to BR112021012909-0A priority patent/BR112021012909A2/pt
Publication of WO2020140959A1 publication Critical patent/WO2020140959A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • 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
    • C07D237/20—Nitrogen atoms

Definitions

  • the present disclosure belongs to the field of medicine, and relates to a 6-oxo-1,6-dihydropyridazine derivative, its preparation method and its application in medicine.
  • the present disclosure relates to 6-oxo-1,6-dihydropyridazine derivatives represented by general formula (I), methods for preparing the same, and pharmaceutical compositions containing the derivatives, and their inhibition as Na V Use of the agent and its use in the preparation of a medicament for the treatment and/or alleviation of pain and pain-related diseases.
  • Pain is a complex physical and psychological activity and one of the most common clinical symptoms.
  • the International Pain Research Association defines pain as "an unpleasant sensation and emotional sensation, accompanied by substantial or potential tissue damage, it is a subjective sensation". Pain can be used as a warning signal to remind the body to pay 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 stimuli that cause pain disappear, strong or long-lasting pain will cause physiological function disorders, which seriously affect the quality of life of the living body. Statistics show that about one-fifth of the world's people suffer from moderate to severe chronic pain.
  • action potentials nerve impulses
  • DRG dorsal root ganglia
  • Na V voltage-gated sodium channels
  • Na V is a type of transmembrane ion channel protein. These proteins are composed of an alpha subunit with a molecular weight of 260 kD and a beta subunit with a molecular weight of 30-40 kD. According to 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 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 on human chromosome 2q23-24, and they are expressed in large numbers in neurons.
  • Na V 1.5, Na V 1.8 and Na V 1.9 are of the TTX-R type, and the coding gene is located on human chromosome 3p21-24.
  • Na V 1.5 mainly exists in cardiomyocytes
  • Na V 1.8 and Na V 1.9 exist in the peripheral nervous system (GoldinA.L., et al.Annu.Rev.Physiol.2001,63,871–894.).
  • Both Na V 1.4 and Na V 1.6 are TTX-S type, which are abundant in 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 a TTX-R type and the coding gene is SCN10A, which is mainly present in trigeminal ganglion neurons and DRG neurons, and has the characteristics of slow inactivation and rapid recovery (Dib-Hajj SD, et al. Annu .Rev.Neurosci.2010,33,325–347.).
  • the rise in action potential is mainly composed of Na V 1.8 current.
  • nerve damage increases Na V 1.8 expression levels in axons and neuronal cell bodies (Sleeper AA, et al. J. Neurosci. 2000, 20, 7279–7289).
  • Na V 1.8 antisense oligonucleotides can significantly reduce pain while reducing Na V 1.8 expression (Yoshimura N., et al. J. Neurosci. 2001, 21, 8690-8696). After intra-paw injection of carrageenan, 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 inflammatory pain (Kerr BJ, et al. NeuroReport 2001, 12, 3077–3080). A functional gain mutation in the human Na V 1.8 gene causes peripheral neuralgia (Faber CG, et al. Proc. Natl. Acad. Sci.
  • Na V inhibitors used in the clinic due to lack of subtype selectivity, can inhibit sodium ion channels expressed in the heart and central nervous system, so the therapeutic window is narrow and the scope of application 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. Therefore, it is necessary to develop Na V 1.8 inhibitors with higher activity, better selectivity, better pharmacokinetic properties and fewer side effects.
  • the purpose of the present disclosure is to provide a compound represented by the general formula (I), or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or the 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 an aryl or heteroaryl group, and the aryl or heteroaryl group is optionally fused with a cycloalkyl or heterocyclic group;
  • R 1 is the same or different and is independently selected from hydrogen atom, halogen, alkyl, deuterated alkyl, deuterated alkoxy, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, Hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 2 is the same or different, and is independently selected from hydrogen atom, halogen, alkyl, alkoxy, deuterated alkyl, deuterated alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, Hydroxy, hydroxyalkyl, cycloalkyl, cycloalkyloxy, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optional Is selected from one of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Or substituted by multiple substituents;
  • R 3 is the same or different and is independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aromatic Radicals and heteroaryls;
  • R 4 and R 5 are the same or different and are independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl , Heterocyclic, aryl and heteroaryl;
  • n 0, 1, 2, 3 or 4;
  • s 0, 1, 2, 3 or 4;
  • t 0, 1, or 2.
  • M is selected from O atom, CR 4 R 5 and S atom;
  • Ring A is aryl or heteroaryl
  • R 1 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl base;
  • R 2 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, cycloalkyloxy, heterocyclyl , Aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally selected from alkyl, haloalkyl, halogen, amino, nitro, cyano, Substituted by one or more substituents of hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 3 is selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 4 and R 5 are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic Radicals, aryls and heteroaryls;
  • n 0, 1, 2, 3 or 4;
  • s 0, 1, 2, 3 or 4;
  • t 0, 1, or 2.
  • M is selected from O, CR 4 R 5 and S;
  • Ring A is aryl or heteroaryl
  • R 1 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl base;
  • R 2 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl
  • the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally selected from alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, Substituted by one or more substituents in haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 3 is selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 4 and R 5 are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic Radicals, aryls and heteroaryls;
  • 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 a tautomer, a racemate, a racemate, an enantiomer, or a diastereomer In the form of a compound or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein M is an O atom.
  • the compound represented by the general formula (I), or a tautomer, a racemate, a racemate, an enantiomer, or a diastereomer Isomer or a mixture thereof, or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II), or a tautomer, a racemate, a racemate, an enantiomer, a non- Enantiomers or their mixtures, or their pharmaceutically acceptable salts:
  • R 1 , R 2 , R 3 , n, s and t are as defined in the general formula (I).
  • the compound represented by the general formula (I), or a tautomer, a racemate, a racemate, an enantiomer, or a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III), or a tautomer, a racemate, a racemate, an enantiomer , Diastereomers or their mixtures, or their pharmaceutically acceptable salts:
  • M is selected from O atom, CH 2 and S atom;
  • R 1a is halogen; preferably selected from Cl, Br or F;
  • R 1b is selected from halogen, alkyl, alkoxy, haloalkyl and haloalkoxy; preferably haloalkyl;
  • R 2 , R 3 , s and t are as defined in the general formula (I).
  • the compound represented by the general formula (I), or a tautomer, a racemate, a racemate, an enantiomer, or a diastereomer In the form of a compound or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is the same or different, and each is independently selected from a hydrogen atom, a halogen, an alkyl group, and a halogenated alkyl group.
  • the compound represented by the general formula (I), or a tautomer, a racemate, a racemate, an enantiomer, or a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 2 is the same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, deuterated alkyl, alkoxy, deuterated alkoxy, Hydroxy, haloalkyl, haloalkoxy, cycloalkyl, and cycloalkyloxy; preferably, R 2 is the same or different, and each is independently selected from a hydrogen atom, halogen, C 1-6 alkyl, deuterated C 1 -6 alkyl, C 1-6 alkoxy, deuterated C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, hydroxy, C 3-6 cycloalkane Group and C 3-6 cycloalkyl
  • the compound represented by the general formula (I), or a tautomer, a racemate, a racemate, an enantiomer, or a diastereomer Or a pharmaceutically acceptable salt thereof wherein R 2 is the same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, alkoxy, deuterated alkoxy, hydroxyl, haloalkyl, Haloalkoxy, cycloalkyl, and cycloalkyloxy; preferably, R 2 is the same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkane Group and cycloalkyloxy.
  • the compound represented by the general formula (I), or a tautomer, a racemate, a racemate, an enantiomer, or a diastereomer Isomer or a mixture thereof, or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IV), or its tautomer, meso, racemate, enantiomer, non- Enantiomers or their mixtures, or their pharmaceutically acceptable salts:
  • R 1a is halogen
  • R 1b is selected from halogen, alkyl, alkoxy, haloalkyl and haloalkoxy;
  • R 2a is alkoxy or deuterated alkoxy
  • R 2b is selected from a hydrogen atom, halogen, alkyl, alkoxy and haloalkoxy;
  • R 3 and t are as defined in the general formula (I).
  • the compound represented by the general formula (I), or a tautomer, a racemate, a racemate, an enantiomer, or a diastereomer In the form of a compound or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 is a hydrogen atom.
  • Typical compounds of general formula (I) include, but are not limited to:
  • Another aspect of the present disclosure provides a compound represented by the general formula (IA),
  • X is halogen; preferably Cl;
  • Rings A, M, R 1 , R 2 , R 3 , n, s and t are as defined in the compound of general formula (I).
  • the compound of general formula (IA) is an intermediate for preparing the compound of general formula (I).
  • Another aspect of the present disclosure provides a compound represented by general formula (IIA),
  • X is halogen; preferably Cl;
  • Rings A, R 1 , R 2 , R 3 , n, s and t are as defined in the compound of general formula (II).
  • the compound of general formula (IIA) is an intermediate for preparing the compound of general formula (II).
  • Another aspect of the present disclosure provides a compound represented by general formula (IB),
  • Y is halogen; preferably F;
  • R 1 , R 3 , n and t are as defined in the compound of general formula (I).
  • the compound of general formula (IB) is an intermediate for preparing the compound of general formula (I).
  • Another aspect of the present disclosure provides a compound represented by general formula (IIIA),
  • X is halogen; preferably Cl;
  • R 1a , R 1b , R 2 , R 3 , s and t are as defined in the compound of the general formula (III).
  • the compound of general formula (IIIA) is an intermediate for preparing the compound of general formula (III).
  • X is halogen; preferably Cl;
  • R 1a , R 1b , R 2a , R 2b , R 3 , s and t are as defined in the compound of general formula (IV).
  • the compound of general formula (IVA) is an intermediate for preparing the compound of general formula (IV).
  • Another aspect of the present disclosure provides a compound represented by the general formula (IIIB),
  • Y is halogen; preferably F;
  • R 1a , R 1b , R 3 and t are as defined in the compound of general formula (III).
  • the compound of general formula (IIIB) is an intermediate for preparing the compound of general formula (III).
  • Typical compounds of intermediates including but not limited to:
  • Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (I), the method comprising:
  • the compound of formula (I) is obtained from the reaction of the compound of formula (IA);
  • X is halogen; preferably Cl;
  • Rings A, M, R 1 , R 2 , R 3 , n, s and t are as defined in the compound of general formula (I).
  • Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (I), the method comprising:
  • Y is halogen; preferably F;
  • Rings A, M, R 1 , R 2 , R 3 , n, s and t are as defined in the compound of general formula (I).
  • Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (II), the method comprising:
  • X is halogen; preferably Cl;
  • R 1 , R 2 , R 3 , n, s and t are as defined in the compound of general formula (II).
  • Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (II), the method comprising:
  • Y is halogen; preferably F;
  • R 1 , R 2 , R 3 , n, s and t are as defined in the compound of general formula (II).
  • Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (III), the method comprising:
  • the compound of general formula (III) is obtained by reacting the compound of general formula (IIIA);
  • X is halogen; preferably Cl;
  • R 1a , R 1b , R 2 , R 3 , s and t are as defined in the compound of the general formula (III).
  • Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (III), the method comprising:
  • Y is halogen; preferably F;
  • R 1a , R 1b , R 2 , R 3 , s and t are as defined in the compound of the general formula (III).
  • Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (IV), the method comprising:
  • the compound of formula (IV) is obtained from the reaction of the compound of formula (IVA);
  • X is halogen; preferably Cl;
  • R 1a , R 1b , R 2a , R 2b , R 3 and t are as defined in the compound of general formula (IV).
  • Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (IV), the method comprising:
  • Y is halogen; preferably F;
  • R 1a , R 1b , R 2a , R 2b , R 3 and t are as defined in the compound of general formula (IV).
  • Another aspect of the present disclosure relates to a pharmaceutical composition containing the compound represented by the general formula (I) as described above, or a tautomer, a racemate, a racemate, an enantiomer thereof Forms, 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 pharmaceutical composition, which includes combining the compound represented by the general formula (I) as described above, or a tautomer, a racemate, a racemate, a The enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof are mixed with 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 a tautomer, a racemate, a racemate, an enantiomer, or a diastereomer , Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or the use of a pharmaceutical composition as described above in the preparation of a medicament for inhibiting a voltage-gated sodium ion channel in a subject.
  • the voltage-gated sodium ion 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 a tautomer, a racemate, a racemate, an enantiomer, or a diastereomer , Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above is prepared for the treatment and/or alleviation of pain and pain-related diseases, multiple sclerosis, Xia-Ma-Tu San's synthesis Use in medicines for symptoms, incontinence or arrhythmia.
  • the pain is preferably 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 of inhibiting voltage-gated sodium channels in a subject, the method comprising administering to a patient in need thereof a compound represented by the general formula (I) of the present disclosure as described above, or a tautomer thereof , A racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.
  • the voltage-gated sodium ion channel is preferably Na V 1.8.
  • the present disclosure also relates to a method of treating and/or alleviating pain and pain-related diseases, multiple sclerosis, Xia-Ma-Tuchan syndrome, incontinence or arrhythmia, the method comprising administering the present disclosure to a patient in need thereof
  • the pain is preferably 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 general formula (I), or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof , Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, which is used as a medicine.
  • a compound represented by general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof , Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, which is used as a medicine.
  • the present disclosure also relates to a compound represented by general formula (I), or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof , Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, which is used as a drug for inhibiting a voltage-gated sodium ion channel 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 a tautomer, a racemate, a racemate, an enantiomer, or a 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, Xia-Ma-Tu San's synthesis Use in medicines for symptoms, incontinence or arrhythmia.
  • the pain is preferably 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 trigeminal neuralgia, postherpetic neuralgia, diabetic neuralgia, painful HIV-related sensory neuralgia, burn syndrome, pain after amputation, 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 injury, brachial plexus avulsion Injury, 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 bowel 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 this disclosure includes 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 may be 0.1-1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following ingredients: filler (diluent), binder, wetting agent, disintegrant or excipient Wait.
  • the composition may contain from 0.1 to 99% by weight of 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 Elixir.
  • Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions. Such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, colorants and preservatives, To provide a pleasing and delicious medicinal preparation.
  • Tablets contain 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 they may be coated by known techniques that provide sustained release for a longer period of time by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract.
  • Oral formulations can also be provided in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or where 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 colorants, one or more flavoring agents and one or more sweeteners ⁇ Flavor.
  • Oil suspensions can be prepared by suspending the active ingredient in vegetable oil or mineral oil.
  • the oil suspension may contain a thickener.
  • the above 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, suspending agents or one or more preservatives for mixing. Suitable dispersing or wetting agents and suspending agents can illustrate the above examples. Other excipients such as sweeteners, flavoring agents and coloring agents can also be added.
  • the pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion.
  • the oily phase may be vegetable oil or mineral oil such as liquid paraffin or mixtures thereof. Suitable emulsifiers may be naturally occurring phospholipids or partial esters.
  • the emulsion may also contain sweeteners, flavoring agents, preservatives and antioxidants.
  • the pharmaceutical composition of the present disclosure may be in the form of a sterile injectable aqueous solution.
  • Acceptable vehicles or solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase.
  • the injection solution or microemulsion can be injected into the patient's bloodstream by local injection.
  • the pharmaceutical composition of the present disclosure may be in the form of sterile water for injection 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 described above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent.
  • sterile fixed oil can be conveniently used as a solvent or suspending 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 therefore will dissolve in the rectum to release the drug.
  • the dosage of a 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, the behavior of the patient , The patient's diet, administration time, administration method, excretion rate, drug combination, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dosage of the general formula (I) or pharmaceutically acceptable salts The type can be verified according to the traditional treatment plan.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a linear or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, and more preferably 1 to 6 carbons Atomic alkyl.
  • 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
  • lower alkyl groups containing 1 to 6 carbon atoms 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.
  • the alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any usable connection point.
  • the substituent is preferably one or more of the following groups, which are independently selected from Group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxygen, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
  • 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, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate groups.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
  • 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 cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Radicals, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused and bridged cycloalkyls.
  • spirocycloalkyl refers to a polycyclic group that shares a carbon atom (called a spiro atom) between 5- to 20-membered monocycles, which may contain one or more double bonds, but none of the rings is fully conjugated ⁇ electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • spirocycloalkyl groups are classified into monospirocycloalkyl groups, bispirocycloalkyl groups or polyspirocycloalkyl groups, preferably monospirocycloalkyl groups and dispirocycloalkyl groups. More preferably, it is 4 member/4 member, 4 member/5 member, 4 member/6 member, 5 member/5 member, or 5 member/6 member monospirocycloalkyl.
  • spirocycloalkyl include:
  • fused ring alkyl 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, where one or more rings may contain one or Multiple double bonds, but no ring has a completely conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl.
  • fused cycloalkyl include:
  • bridged cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has a complete Conjugated ⁇ electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
  • bridged cycloalkyls include:
  • the cycloalkyl ring includes a cycloalkyl group (including monocyclic, spiro, fused and bridged rings) as described above fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein it is connected to the parent structure
  • the rings together are cycloalkyl, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like; phenylcyclopentyl, tetrahydronaphthyl are preferred.
  • Cycloalkyl can be optionally substituted or unsubstituted, when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxyl or carboxylate groups.
  • groups are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocyclo
  • heterocyclic group refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), but does not include the ring portion 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, dihydropyryl Hydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably tetrahydropyranyl, piperidinyl, pyrrolidinyl.
  • Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group that shares an atom (called a spiro atom) between 5 and 20 membered single rings, where one or more ring atoms are selected from nitrogen, oxygen, or S(O ) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan.
  • Spiro heterocyclic groups are classified into mono-spiro heterocyclic groups, di-spiro heterocyclic groups or poly-spiro heterocyclic groups according to the number of shared spiro atoms between rings, preferably mono-spiro heterocyclic groups and di-spiro heterocyclic groups. More preferably, it is 4 member/4 member, 4 member/5 member, 4 member/6 member, 5 member/5 member, or 5 member/6 member monospiro heterocyclic group.
  • Non-limiting examples of spiro heterocyclic 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 has a completely 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 remaining rings
  • the atom is carbon. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclic groups include:
  • bridged heterocyclic group refers to a 5- to 14-membered, polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common
  • 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 remaining ring atoms are carbon. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic bridge heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
  • bridged heterocyclic groups include:
  • the heterocyclic ring includes heterocyclic groups as described above (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring, wherein The rings connected together are heterocyclic groups.
  • Non-limiting examples 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, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxyl or carboxylate groups.
  • aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups with a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene And naphthyl.
  • the aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclic group, or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include :
  • the aryl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate groups.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen.
  • Heteroaryl groups are preferably 5- to 10-membered, containing 1 to 3 heteroatoms; more preferably 5- or 6-membered, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridine Pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and pyridazinyl, etc., preferably pyridazinyl and pyridinyl; more preferably pyridazinyl.
  • the heteroaryl ring includes a heteroaryl ring as described above fused to an aryl, heterocyclic group 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, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, oxo, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, Non-limiting examples of cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups include
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, where alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, where alkyl is as defined above.
  • deuterated alkoxy refers to an alkoxy group substituted with one or more deuterium atoms, wherein the alkoxy group is as defined above.
  • cycloalkylalkyl refers to an alkyl group substituted with one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.
  • cycloalkyloxy refers to -O-cycloalkyl, wherein cycloalkyl is as defined above.
  • heterocyclylalkyl refers to an alkyl group substituted with one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.
  • arylalkyl refers to an alkyl group substituted with one or more aryl groups, where aryl and alkyl are as defined above.
  • hydroxyl refers to the -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino means -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.
  • acyl halide refers to a compound containing a -C(O)-halogen group.
  • the compounds of the present disclosure may also include isotopic derivatives thereof.
  • isotopic derivative refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms.
  • having the structure of the present disclosure in addition to replacing hydrogen with "deuterium” or “tritium”, or replacing fluorine with an 18 F-fluoro label ( 18 F isotope), or using 11 C-, 13 C-, or 14 C-rich Compounds with carbon ( 11 C-, 13 C-, or 14 C-carbon labeling; 11 C-, 13 C-, or 14 C-isotope) replacing 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 in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamics, pharmacokinetics, or receptor studies.
  • the compounds of the present disclosure also include 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. A person skilled in the art can refer to the relevant literature to synthesize the compound of formula (I) in deuterated form.
  • commercially available deuterated starting materials can be used, or they can be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, tri-deuterated Borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane etc.
  • heterocyclic group optionally substituted with 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 with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted refers to one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only at their possible chemical positions, and those skilled in the art can determine (through experiment or theory) possible or impossible substitutions without undue effort. For example, an amino group or hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (eg, olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein or a physiological/pharmaceutically acceptable salt or prodrug thereof with 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, facilitate the absorption of the active ingredient and thus exert the biological activity.
  • “Pharmaceutically acceptable salts” refers to salts of the compounds of the present disclosure, such salts are safe and effective when used in mammals, and have due biological activity.
  • the present disclosure provides a compound represented by general formula (I), or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, Or a method for preparing a pharmaceutically acceptable salt thereof, including the following steps:
  • X is halogen; preferably Cl;
  • Y is halogen; preferably F;
  • Rings A, M, R 1 , R 2 , R 3 , n, s and t are as defined in the compound of general formula (I).
  • the compound of formula (ID) and the compound of formula (IC) react under basic conditions to obtain the compound of formula (IA);
  • the compound of formula (IA) is reacted under basic conditions to obtain the compound of formula (I).
  • the reagents that provide basic conditions include organic bases and inorganic bases.
  • the organic bases include but are not limited to pyridine, hexahydropyridine, triethylamine, N,N-diisopropylethylamine, n-butyl lithium, Lithium diisopropylamide, potassium acetate, sodium tert-butoxide or potassium tert-butoxide
  • the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium carbonate, potassium acetate, cesium carbonate , Sodium hydroxide and lithium hydroxide.
  • 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-methylpyrrolidone, N,N-dimethylformamide and mixtures thereof.
  • the present disclosure provides a compound represented by general formula (I), or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, Or a method for preparing a pharmaceutically acceptable salt thereof, including the following steps:
  • X is halogen; preferably Cl;
  • Y is halogen; preferably F;
  • Rings A, M, R 1 , R 2 , R 3 , n, s and t are as defined in the compound of general formula (I).
  • the reagents that provide basic conditions include organic bases and inorganic bases.
  • the organic bases include but are not limited to pyridine, hexahydropyridine, triethylamine, N,N-diisopropylethylamine, n-butyl lithium, Lithium diisopropylamide, potassium acetate, sodium tert-butoxide or potassium tert-butoxide
  • the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium carbonate, potassium acetate, cesium carbonate , Sodium hydroxide and lithium hydroxide.
  • 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-methylpyrrolidone, N,N-dimethylformamide and mixtures thereof.
  • the present disclosure provides a compound represented by general formula (II), or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, Or a method for preparing a pharmaceutically acceptable salt thereof, including the following steps:
  • X is halogen; preferably Cl;
  • Y is halogen; preferably F;
  • R 1 , R 2 , R 3 , n, s and t are as defined in the compound of general formula (II).
  • the compound of formula (ID) and the compound of formula (IIC) react under basic conditions to obtain the compound of formula (IIA);
  • the reagents that provide basic conditions include organic bases and inorganic bases.
  • the organic bases include but are not limited to pyridine, hexahydropyridine, triethylamine, N,N-diisopropylethylamine, n-butyl lithium, Lithium diisopropylamide, potassium acetate, sodium tert-butoxide or potassium tert-butoxide
  • the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium carbonate, potassium acetate, cesium carbonate , Sodium hydroxide and lithium hydroxide.
  • 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-methylpyrrolidone, N,N-dimethylformamide and mixtures thereof.
  • the present disclosure provides a compound represented by general formula (II), or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, Or a method for preparing a pharmaceutically acceptable salt thereof, including the following steps:
  • Y is halogen; preferably F;
  • R 1 , R 2 , R 3 , n, s and t are as defined in the compound of general formula (II).
  • the reagents that provide basic conditions include organic bases and inorganic bases.
  • the organic bases include but are not limited to pyridine, hexahydropyridine, triethylamine, N,N-diisopropylethylamine, n-butyl lithium, Lithium diisopropylamide, potassium acetate, sodium tert-butoxide or potassium tert-butoxide
  • the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium carbonate, potassium acetate, cesium carbonate , Sodium hydroxide and lithium hydroxide.
  • 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-methylpyrrolidone, N,N-dimethylformamide and mixtures thereof.
  • the present disclosure provides a compound represented by general formula (III), or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, Or a method for preparing a pharmaceutically acceptable salt thereof, including the following steps:
  • X is halogen; preferably Cl;
  • R 1a , R 1b , R 2 , R 3 , s and t are as defined in the compound of the general formula (III).
  • the reagents that provide basic conditions include organic bases and inorganic bases.
  • the organic bases include but are not limited to pyridine, hexahydropyridine, triethylamine, N,N-diisopropylethylamine, n-butyl lithium, Lithium diisopropylamide, potassium acetate, sodium tert-butoxide or potassium tert-butoxide
  • the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium carbonate, potassium acetate, cesium carbonate , Sodium hydroxide and lithium hydroxide; preferably potassium acetate.
  • 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-methylpyrrolidone, N,N-dimethylformamide and mixtures thereof.
  • the present disclosure provides a compound represented by general formula (III), or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, Or a method for preparing a pharmaceutically acceptable salt thereof, including the following steps:
  • Y is halogen; preferably F;
  • R 1a , R 1b , R 2 , R 3 , s and t are as defined in the compound of the general formula (III).
  • the reagents that provide basic conditions include organic bases and inorganic bases.
  • the organic bases include but are not limited to pyridine, hexahydropyridine, triethylamine, N,N-diisopropylethylamine, n-butyl lithium, Lithium diisopropylamide, potassium acetate, sodium tert-butoxide or potassium tert-butoxide
  • the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium carbonate, potassium acetate, cesium carbonate , Sodium hydroxide and lithium hydroxide; preferably cesium carbonate.
  • 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-methylpyrrolidone, N,N-dimethylformamide and mixtures thereof.
  • the present disclosure provides a compound represented by general formula (IV), or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, Or a method for preparing a pharmaceutically acceptable salt thereof, including the following steps:
  • X is halogen; preferably Cl;
  • R 1a , R 1b , R 2a , R 2b , R 3 and t are as defined in the compound of general formula (IV).
  • the reagents that provide basic conditions include organic bases and inorganic bases.
  • the organic bases include but are not limited to pyridine, hexahydropyridine, triethylamine, N,N-diisopropylethylamine, n-butyl lithium, Lithium diisopropylamide, potassium acetate, sodium tert-butoxide or potassium tert-butoxide
  • the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium carbonate, potassium acetate, cesium carbonate , Sodium hydroxide and lithium hydroxide; preferably potassium acetate.
  • 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-methylpyrrolidone, N,N-dimethylformamide and mixtures thereof.
  • the present disclosure provides a compound represented by general formula (IV), or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, Or a method for preparing a pharmaceutically acceptable salt thereof, including the following steps:
  • Y is halogen; preferably F;
  • Ring A, R 1a , R 1b , R 2a , R 2b , R 3 and t are as defined in the compound of general formula (IV).
  • the reagents that provide basic conditions include organic bases and inorganic bases.
  • the organic bases include but are not limited to pyridine, hexahydropyridine, triethylamine, N,N-diisopropylethylamine, n-butyl lithium, Lithium diisopropylamide, potassium acetate, sodium tert-butoxide or potassium tert-butoxide
  • the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium carbonate, potassium acetate, cesium carbonate , Sodium hydroxide and lithium hydroxide; preferably cesium carbonate.
  • 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-methylpyrrolidone, 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).
  • the measurement of NMR was performed by Bruker AVANCE-400 nuclear magnetic instrument.
  • 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) Methylsilane
  • the MS was measured with a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • ESI FINNIGAN LCQAd
  • HPLC High performance liquid chromatography analysis uses Agilent HPLC 1200DAD, Agilent HPLC1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatograph.
  • High-performance liquid phase preparation uses Waters 2767, Waters 2767-SQ Detector2, Shimadzu LC-20AP and Gilson-281 preparative chromatographs.
  • the 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 specification of the thin-layer chromatography (TLC) silica gel plate is 0.15mm ⁇ 0.2mm, and the specification of the thin-layer chromatography separation and purification product is 0.4mm ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Yantai Yellow Sea silica gel 200-300 mesh silica gel as a carrier.
  • the known starting materials of this disclosure can be synthesized using or following 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 be carried out under an argon atmosphere or a nitrogen atmosphere.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.
  • the pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenation instrument and a clear blue QL-500 hydrogen generator or an HC2-SS hydrogenation instrument.
  • the hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated 3 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 process in the examples uses thin layer chromatography (TLC), the developing agent used in the reaction, the eluent system of column chromatography used for purifying the compound, and the developing agent 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, and a small amount of triethylamine and acetic acid can also be added Such as alkaline or acid reagents for adjustment.
  • TLC thin layer chromatography
  • the compound 4,5-dichloro-2-fluorobenzoic acid 1a (1.5 g, 7.18 mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) was dissolved in thionyl chloride (10 mL) and reacted at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound 1b (1.6 g), and the product was directly used in the next reaction without purification.
  • the crude compound 1b (1.6 g, 7.03 mmol), 6-chloropyridazin-4-amine (500 mg, 3.86 mmol, Nanjing Pharmaceutical Technology Co., Ltd.) was dissolved in pyridine (10 mL), and the reaction was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and purified by using silica gel column chromatography with developing system B to obtain the title compound 1c (650 mg) as a white solid, yield: 53%.
  • the temperature of the ice bath was reduced to 0°C, 50 mL of methanol was added, and hydrogen peroxide (30 wt%, 11 mL) and 10% sodium hydroxide solution (50 mL) were added dropwise. After the dropwise addition, 400 mL of saturated sodium chloride solution was added, and extracted with ethyl acetate (200 mL ⁇ 3). The organic phase was washed with a saturated sodium bicarbonate solution (150 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with the developer system B to obtain the title compound 12b (1.0 g), yield: 74%.
  • the polished and bright magnesium bar (760mg, 31.7mmol, Shanghai Sinopharm Group Chemical Reagent Co., Ltd.) was shredded, added to tetrahydrofuran (80mL), and protected by argon gas. At room temperature, trimethylchlorosilane (345 mg, 3.17 mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) was added dropwise.
  • 1-bromo-4-fluoro-2-methylbenzene 13a 1.5g, 7.9mmol, Shaoyuan Technology (Shanghai) Co., Ltd.
  • compound 13a 4.5g, 23.7mmol, Shaoyuan Technology (Shanghai) Co., Ltd.
  • the product was used in the next reaction without purification.
  • Tetrahydrofuran (100 mL) and lithium hexamethyldisilazide (1M, 120 mL, 120 mmol, Titan Chemical) were cooled to -78°C under argon protection.
  • 4-bromo-2-chloro-1-(trifluoromethyl)benzene 13c 25g, 96.36mmol, Shaoyuan Technology (Shanghai) Co., Ltd.
  • N,N-dimethylformamide (14.1g, 192.9mmol, Bailingwei Technology Co., Ltd.) was added dropwise, and the temperature was gradually raised to room temperature for 16 hours. Water was added and extracted with ethyl acetate (50 mL ⁇ 3).
  • 1-fluoro-3-(trifluoromethoxy)benzene 14a (5g, 27.76mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) was dissolved in sulfuric acid (20mL), cooled in an ice bath, and potassium nitrate (7g, 69.2mmol)), the ice bath was naturally warmed to room temperature overnight.
  • the reaction solution was poured into ice water, stirred for 30 minutes, extracted three times with ethyl acetate, dried over sodium sulfate, and spin-dried to obtain a crude product mixture (5.8 g) containing compound 14b.
  • the crude compound 14b mixture (5.8 g, 25.7 mmol) was dissolved in methanol (80 mL), replaced with nitrogen, a palladium-carbon catalyst (1.54 g, 14.47 mmol) was added, hydrogen was replaced three times, and the hydrogenation reaction was performed at room temperature overnight.
  • the reaction solution was filtered, concentrated, and purified by using silica gel column chromatography with developing system A to obtain a crude product mixture (3.5 g) containing the title compound 14c.
  • the compound 14c mixture (3.4g, 17.4mmol) was dissolved in acetonitrile (40mL), copper bromide (4.67g, 20.9mmol, Shaoyuan Technology (Shanghai) Co., Ltd.), tert-butyl nitrite (2.16g, 20.9mmol) was added ).
  • the reaction was carried out at 60°C for 0.5 hours, and the reaction solution was filtered and concentrated under reduced pressure. Purification was carried out by using silica gel column chromatography with developing system A to obtain a mixture (1.3 g) containing the title compound 14d.
  • the compound 14j-containing mixture (65 mg, 0.12 mmol) was dissolved in acetic acid (3 mL), potassium acetate (60 mg, 0.61 mmol) was added, and the reaction was carried out at 130°C for 2 hours.
  • the reaction solution was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters 2767-SQ Detector 2, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 14 (8 mg), yield: 11%.
  • Example 2 Using the synthetic route of Example 1, the first step raw material 4,5-dichloro-2-fluorobenzoic acid was replaced with the compound 4-chloro-2,5-difluorobenzoic acid to obtain the title compound 18 (22 mg).
  • Example 2 Using the synthetic route of Example 1, the first step raw material 4,5-dichloro-2-fluorobenzoic acid was replaced with the compound 4-chloro-2,5-difluorobenzoic acid, and the third step raw material 2-methoxy The 4-fluorophenol was replaced with 2-methyl-4fluorophenol to prepare the title compound 19 (9 mg) as a white solid.
  • Example 2 Using the synthetic route of Example 1, the first step raw material 4,5-dichloro-2-fluorobenzoic acid was replaced with the compound 2-fluoro-5-(trifluoromethoxy)benzoic acid to obtain the title compound 22( 5mg).
  • Example 2 Using the synthetic route of Example 1, the first step raw material 4,5-dichloro-2-fluorobenzoic acid was replaced with the compound 5-chloro-2-fluorobenzoic acid to prepare the title compound 23 (14 mg).
  • Example 2 Using the synthetic route of Example 1, the first step raw material 4,5-dichloro-2-fluorobenzoic acid was replaced with the compound 2-fluoro-5-(trifluoromethoxy)benzoic acid to obtain the title compound 24( 7mg).
  • Example 2 Using the synthetic route of Example 1, the starting material 4,5-dichloro-2-fluorobenzoic acid was replaced with the compound 2,5-difluorobenzoic acid to prepare the title compound 25 (20 mg).
  • Example 2 Using the synthetic route of Example 1, the first step raw material 4,5-dichloro-2-fluorobenzoic acid was replaced with the compound 2,5-difluorobenzoic acid, and the third step raw material 2-methoxy-4-fluoro The phenol was replaced with 2-methyl-4fluorophenol to prepare the title compound 26 (20 mg).
  • the temperature of the ice bath was lowered to 0°C, methanol (50 mL) was added, hydrogen peroxide (30 wt%, 10 mL) and 10% sodium hydroxide solution (40 mL) were added dropwise, and the mixture was stirred at room temperature for 1 hour.
  • Saturated sodium thiosulfate solution 50 mL was slowly added dropwise to the reaction solution, and extracted with ethyl acetate (200 mL ⁇ 3).
  • the compound 1-(5-fluoro-2-hydroxyphenyl) ethyl-1-one 36a (3g, 19.5mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was dissolved in anhydrous methanol (20mL) and slowly added in portions Sodium borohydride (1.1g, 29.1mmol), react at room temperature for 1 hour. Concentrate under reduced pressure, add ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product of the title compound 36b (3.2 g), yield: 100%.
  • Example 35 Using the synthetic route of Example 35, the first step raw material deuterated methyl iodide was replaced with the compound bromocyclopentane to prepare the title compound 40 (30 mg).
  • Example 35 Using the synthetic route of Example 35, the first step raw material deuterated methyl iodide was replaced with the compound iodoisopropane to prepare the title compound 42 (100 mg).
  • Test Example 1 Determination of Nav1.8 inhibitory activity of the disclosed compounds
  • the purpose of the experiment was to investigate the effect of the compound on the Na V 1.8 ion channel in the in vitro experiment.
  • the Na V 1.8 ion channel was stably expressed on HEK293 cells. After the Na V 1.8 current has stabilized, comparing the Na V 1.8 current before and after application of the compound, the effect of the compound on the Na V 1.8 ion channel can be obtained.
  • Patch clamp amplifier patch PC-505B (WARNER instruments)/MultiClamp 700A (Axon instruments)
  • the extracellular fluid is: NaCl, 137; KCl, 4; CaCl 2 , 1.8; MgCl 2, 1; HEPES, 10; glucose 10; pH 7.4 (NaOH titration).
  • the intracellular fluid (mM) was 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.
  • test compound was stored at 9 mM in dimethyl sulfoxide (DMSO). Re-dissolve in extracellular fluid on the day of testing and prepare to the required concentration.
  • DMSO dimethyl sulfoxide
  • the data will be stored in the computer system for analysis.
  • pCLAMP10 Molecular Devices, Union, City, CA
  • Current stability means that the current changes within a limited range over time.
  • the magnitude of the current after stabilization is used to calculate the effect of the compound on this solubility.
  • the inhibitory activity of the disclosed compounds on Nav1.8 was determined by the above test, and the measured IC 50 values are shown in Table 1.
  • Rats were used as test animals, and the compounds of Example 2, Example 11, Compound 12, Example 15, Compound 31, and Compound 33 were administered to rats by intragastric administration using the LC/MS/MS method.
  • the drug concentration in the plasma at different times after the compound.
  • the pharmacokinetic behavior of the compounds of the present disclosure in rats was studied to evaluate their pharmacokinetic characteristics.
  • SD rats were fasted and administered by gavage overnight.
  • the dosage was 2.0 mg/kg, and the volume was 10.0 mL/kg.
  • Rats were given the compound of Example 2, the compound of Example 11, the compound of Example 12, the compound of Example 15, the compound of Example 31 and the compound of Example 33 by intragastric administration before and after administration 0.5, 1.0, 2.0, At 4.0, 6.0, 8.0, 11.0, and 24.0 hours, 0.2 mL of blood was collected from the orbit, placed in a heparinized test tube, centrifuged at 4°C and 10,000 rpm for 10 minutes to separate the plasma, stored at -20°C, and fed 2 hours after administration.
  • test compound content in rat plasma after intragastric administration of different concentrations of drugs take 25 ⁇ L of rat plasma at each time after administration, add 30 ⁇ L of internal standard solution, 175 ⁇ L of acetonitrile, vortex to mix for 5 minutes, and centrifuge for 10 minutes (3700 rpm), 0.5 ⁇ L of the supernatant of the plasma sample was taken for LC/MS/MS analysis.
  • the compound of the present disclosure has good pharmacokinetic absorption and obvious pharmacokinetic advantages.

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Abstract

6-氧代-1,6-二氢哒嗪类衍生物、其制备方法及其在医药上的应用。特别地，通式(I)所示的6-氧代-1,6-二氢哒嗪类衍生物、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/或预防疼痛和疼痛相关疾病的药物中的用途。其中通式(I)的各取代基与说明书中的定义相同。

Description

6-氧代-1,6-二氢哒嗪类衍生物、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，本公开涉及通式(I)所示的6-氧代-1,6-二氢哒嗪类衍生物、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离子通道(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、癌症疼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 PCTCN2020070186-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，所述芳基或杂芳基任选与环烷基或杂环基稠合；
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、氘代烷氧基、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、氘代烷基、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；
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，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 PCTCN2020070186-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、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；
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，提供一种通式(I)所示的化合物：
Figure PCTCN2020070186-appb-000003
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选自O、CR 4R 5和S；
环A为芳基或杂芳基；
R 1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；
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选自苯基、
Figure PCTCN2020070186-appb-000004
和吡啶基。
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M选自O原子、CH 2和S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M为O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，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 PCTCN2020070186-appb-000005
其中：
R 1、R 2、R 3、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，为其为通式(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 PCTCN2020070186-appb-000006
其中：
M选自O原子、CH 2和S原子；
R 1a为卤素；优选选自Cl、Br或F；
R 1b选自卤素、烷基、烷氧基、卤代烷基和卤代烷氧基；优选为卤代烷基；且
R 2、R 3、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，其中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、卤代烷基和卤代烷氧基。
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。
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、氘代烷基、烷氧基、氘代烷氧基、羟基、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、氘代C 1-6烷基、C 1-6烷氧基、氘代C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基、C 3-6环烷基和C 3-6环烷基氧基；更优选地，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烷氧基和氘代C 1-6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、羟基、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、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基和环烷基氧基。
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、卤代烷基和卤代烷氧基。
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s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，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 PCTCN2020070186-appb-000007
其中：
R 1a为卤素；
R 1b选自卤素、烷基、烷氧基、卤代烷基和卤代烷氧基；
R 2a为烷氧基或氘代烷氧基；
R 2b选自氢原子、卤素、烷基、烷氧基和卤代烷氧基；且
R 3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R 1a为氯原子，R 1b为三氟甲基。
通式(I)的典型化合物，包括但不限于：
Figure PCTCN2020070186-appb-000008
Figure PCTCN2020070186-appb-000009
Figure PCTCN2020070186-appb-000010
Figure PCTCN2020070186-appb-000011
Figure PCTCN2020070186-appb-000012
Figure PCTCN2020070186-appb-000013
Figure PCTCN2020070186-appb-000014
Figure PCTCN2020070186-appb-000015
Figure PCTCN2020070186-appb-000016
Figure PCTCN2020070186-appb-000017
Figure PCTCN2020070186-appb-000018
Figure PCTCN2020070186-appb-000019
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。
本公开另一方面提供一种通式(IA)所示的化合物，
Figure PCTCN2020070186-appb-000020
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：
X为卤素；优选为Cl；且
环A、M、R 1、R 2、R 3、n、s和t如通式(I)化合物中所定义。通式(IA)化合物为制备通式(I)化合物的中间体。
本公开另一方面提供一种通式(IIA)所示的化合物，
Figure PCTCN2020070186-appb-000021
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：
X为卤素；优选为Cl；且
环A、R 1、R 2、R 3、n、s和t如通式(II)化合物中所定义。通式(IIA)化合物 为制备通式(II)化合物的中间体。
本公开另一方面提供一种通式(IB)所示的化合物，
Figure PCTCN2020070186-appb-000022
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：
Y为卤素；优选为F；且
R 1、R 3、n和t如通式(I)化合物中所定义。通式(IB)化合物为制备通式(I)化合物的中间体。
本公开另一方面提供一种通式(IIIA)所示的化合物，
Figure PCTCN2020070186-appb-000023
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：
X为卤素；优选为Cl；且
M、R 1a、R 1b、R 2、R 3、s和t如通式(III)化合物中所定义。通式(IIIA)化合物为制备通式(III)化合物的中间体。
本公开另一方面提供一种通式(IVA)所示的化合物，
Figure PCTCN2020070186-appb-000024
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：
X为卤素；优选为Cl；且
R 1a、R 1b、R 2a、R 2b、R 3、s和t如通式(IV)化合物中所定义。通式(IVA)化合物为制备通式(IV)化合物的中间体。
本公开另一方面提供一种通式(IIIB)所示的化合物，
Figure PCTCN2020070186-appb-000025
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：
Y为卤素；优选为F；且
R 1a、R 1b、R 3和t如通式(III)化合物中所定义。通式(IIIB)化合物为制备通式(III)化合物的中间体。
中间体的典型化合物，包括但不限于：
Figure PCTCN2020070186-appb-000026
Figure PCTCN2020070186-appb-000027
Figure PCTCN2020070186-appb-000028
Figure PCTCN2020070186-appb-000029
本公开的另一方面涉及一种备通式(I)所示的化合物的方法，所述方法包括：
Figure PCTCN2020070186-appb-000030
由通式(IA)化合物反应得到通式(I)化合物；
其中：
X为卤素；优选为Cl；且
环A、M、R 1、R 2、R 3、n、s和t如通式(I)化合物中所定义。
本公开的另一方面涉及一种备通式(I)所示的化合物的方法，所述方法包括：
Figure PCTCN2020070186-appb-000031
通式(IB)化合物和通式(IC)化合物反应得到通式(I)化合物；
其中：
Y为卤素；优选为F；且
环A、M、R 1、R 2、R 3、n、s和t如通式(I)化合物中所定义。
本公开的另一方面涉及一种备通式(II)所示的化合物的方法，该方法包括：
Figure PCTCN2020070186-appb-000032
通式(IIA)化合物反应得到通式(II)化合物；
其中：
X为卤素；优选为Cl；且
R 1、R 2、R 3、n、s和t如通式(II)化合物中所定义。
本公开的另一方面涉及一种备通式(II)所示的化合物的方法，所述方法包括：
Figure PCTCN2020070186-appb-000033
通式(IB)化合物和通式(IIC)化合物反应得到通式(II)化合物；
其中：
Y为卤素；优选为F；且
R 1、R 2、R 3、n、s和t如通式(II)化合物中所定义。
本公开的另一方面涉及一种备通式(III)所示的化合物的方法，所述方法包括：
Figure PCTCN2020070186-appb-000034
由通式(IIIA)化合物反应得到通式(III)化合物；
其中：
X为卤素；优选为Cl；且
M、R 1a、R 1b、R 2、R 3、s和t如通式(III)化合物中所定义。
本公开的另一方面涉及一种备通式(III)所示的化合物的方法，所述方法包括：
Figure PCTCN2020070186-appb-000035
通式(IIIB)化合物和通式(IIIC)化合物反应得到通式(III)化合物；
其中：
Y为卤素；优选为F；且
M、R 1a、R 1b、R 2、R 3、s和t如通式(III)化合物中所定义。
本公开的另一方面涉及一种备通式(IV)所示的化合物的方法，所述方法包括：
Figure PCTCN2020070186-appb-000036
由通式(IVA)化合物反应得到通式(IV)化合物；
其中：
X为卤素；优选为Cl；且
R 1a、R 1b、R 2a、R 2b、R 3和t如通式(IV)化合物中所定义。
本公开的另一方面涉及一种备通式(IV)所示的化合物的方法，所述方法包括：
Figure PCTCN2020070186-appb-000037
通式(IIIB)化合物和通式(IVC)化合物反应得到通式(IV)化合物；
其中：
Y为卤素；优选为F；且
R 1a、R 1b、R 2a、R 2b、R 3和t如通式(IV)化合物中所定义。
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离子通道的药物中的用途。所述的电压门控钠离子通道优选为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。所述的疼痛优选选自慢性疼痛、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。所述的电压门控钠离子通道优选为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。所述的疼痛优选选自慢性疼痛、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，其用作药物。
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，其用于作抑制受试者电压门控钠离子通道的药物。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、失禁或心律失常的药物中的用途。所述的疼痛优选选自慢性疼痛、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包括纤维肌痛。
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
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“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 PCTCN2020070186-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 PCTCN2020070186-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 PCTCN2020070186-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 PCTCN2020070186-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 PCTCN2020070186-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 PCTCN2020070186-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 PCTCN2020070186-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 PCTCN2020070186-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 PCTCN2020070186-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 PCTCN2020070186-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“环烷基烷基”指烷基被一个或多个环烷基取代，其中环烷基和烷基如上所定义。
术语“环烷基氧基”指-O-环烷基，其中环烷基如上所定义。
术语“杂环基烷基”指烷基被一个或多个杂环基取代，其中杂环基和烷基如上所定义。
术语“芳基烷基”指烷基被一个或多个芳基取代，其中芳基和烷基如上所定义。
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“酰卤”指含有-C(O)-卤素的基团的化合物。
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。
本公开的化合物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。
“可药用的盐”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、或其可药用的盐制备方法，包括以下步骤：
Figure PCTCN2020070186-appb-000048
其中：
X为卤素；优选为Cl；
Y为卤素；优选为F；且
环A、M、R 1、R 2、R 3、n、s和t如通式(I)化合物中所定义。
第一步，通式(ID)化合物和通式(IC)化合物在碱性条件下，发生反应得到通式(IA)化合物；
第二步，通式(IA)化合物在碱性条件下，反应得到通式(I)的化合物。
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、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、叔丁醇钠或叔丁醇钾，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。
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-甲基吡咯烷酮、N,N-二甲基甲酰胺及其混合物。
方案二
本公开提供一种通式(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、或其可药用的盐制备方法，包括以下步骤：
Figure PCTCN2020070186-appb-000049
其中：
X为卤素；优选为Cl；
Y为卤素；优选为F；且
环A、M、R 1、R 2、R 3、n、s和t如通式(I)化合物中所定义。
第一步，通式(ID)化合物在碱性条件下，反应得到通式(IB)化合物；
第二步，通式(IB)化合物和通式(IC)化合物在碱性条件下，发生反应得到通式(I)化合物。
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、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、叔丁醇钠或叔丁醇钾，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。
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-甲基吡咯烷酮、N,N-二甲基甲酰胺及其混合物。
方案三
本公开提供一种通式(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 PCTCN2020070186-appb-000050
其中：
X为卤素；优选为Cl；
Y为卤素；优选为F；且
R 1、R 2、R 3、n、s和t如通式(II)化合物中所定义。
第一步，通式(ID)化合物和通式(IIC)化合物在碱性条件下，发生反应得到通式(IIA)化合物；
第二步，通式(IIA)化合物在碱性条件下，反应得到通式(II)的化合物。
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、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、叔丁醇钠或叔丁醇钾，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。
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-甲基吡咯烷酮、N,N-二甲基甲酰胺及其混合物。
方案四
本公开提供一种通式(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 PCTCN2020070186-appb-000051
其中：
Y为卤素；优选为F；且
R 1、R 2、R 3、n、s和t如通式(II)化合物中所定义。
通式(IB)化合物和通式(IIC)化合物在碱性条件下，发生反应得到通式(II)化合物。
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、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、叔丁醇钠或叔丁醇钾，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。
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-甲基吡咯烷酮、N,N-二甲基甲酰胺及其混合物。
方案五
本公开提供一种通式(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 PCTCN2020070186-appb-000052
其中：
X为卤素；优选为Cl；且
M、R 1a、R 1b、R 2、R 3、s和t如通式(III)化合物中所定义。
通式(IIIA)化合物在碱性条件下，反应得到通式(III)的化合物。
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、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、叔丁醇钠或叔丁醇钾，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；优选为醋酸钾。
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-甲基吡咯烷酮、N,N-二甲基甲酰胺及其混合物。
方案六
本公开提供一种通式(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 PCTCN2020070186-appb-000053
其中：
Y为卤素；优选为F；且
M、R 1a、R 1b、R 2、R 3、s和t如通式(III)化合物中所定义。
通式(IIIB)化合物和通式(IIIC)化合物在碱性条件下，发生反应得到通式(III)化合物。
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、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、叔丁醇钠或叔丁醇钾，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；优选为碳酸铯。
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-甲基吡咯烷酮、N,N-二甲基甲酰胺及其混合物。
方案七
本公开提供一种通式(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 PCTCN2020070186-appb-000054
其中：
X为卤素；优选为Cl；且
R 1a、R 1b、R 2a、R 2b、R 3和t如通式(IV)化合物中所定义。
通式(IVA)化合物在碱性条件下，反应得到通式(IV)的化合物。
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、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、叔丁醇钠或叔丁醇钾，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；优选为醋酸钾。
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-甲基吡咯烷酮、N,N-二甲基甲酰胺及其混合物。
方案八
本公开提供一种通式(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 PCTCN2020070186-appb-000055
其中：
Y为卤素；优选为F；且
环A、R 1a、R 1b、R 2a、R 2b、R 3和t如通式(IV)化合物中所定义。
通式(IIIB)化合物和通式(IVC)化合物在碱性条件下，发生反应得到通式(IV)化合物。
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、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、叔丁醇钠或叔丁醇钾，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；优选为碳酸铯。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-甲基吡咯烷酮、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FINNIGAN LCQAd(ESI)质谱仪(生产商：Thermo，型号：Finnigan LCQ advantage MAX)。
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC1200VWD和Waters HPLC e2695-2489高压液相色谱仪。
手性HPLC分析测定使用Agilent 1260DAD高效液相色谱仪。
高效液相制备使用Waters 2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson-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
4,5-二氯-2-(4-氟-2-甲氧基苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)苯甲酰胺1
Figure PCTCN2020070186-appb-000056
第一步
4,5-二氯-2-氟苯甲酰氯1b
将化合物4,5-二氯-2-氟苯甲酸1a(1.5g,7.18mmol,韶远科技(上海)有限公司)溶于氯化亚砜(10mL)，80℃反应16小时。反应液减压浓缩，得到标题化合物1b(1.6g)，产品不经纯化直接用于下一步反应。
第二步
4,5-二氯-N-(6-氯哒嗪-4-基)-2-氟苯甲酰胺1c
将粗品化合物1b(1.6g,7.03mmol)，6-氯哒嗪-4-胺(500mg,3.86mmol，南京药石科技股份有限公司)溶于吡啶(10mL)，搅拌反应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1c(650mg)，白色固体，产率：53％。
MS m/z(ESI):321.9[M+1]
第三步
4,5-二氯-N-(6-氯哒嗪-4-基)-2-(4-氟-2-甲氧基苯氧基)苯甲酰胺1d
将化合物1c(100mg,0.31mmol)，4-氟-2-甲氧基苯酚(50mg,0.35mmol，韶远科技(上海)有限公司)和碳酸铯(153mg,0.47mmol)加入N,N-二甲基甲酰胺(10mL)，100℃反应2小时。冷却，硅藻土过滤，滤液减压浓缩，用硅胶柱色谱法以展开剂体系A纯化，到标题化合物1d(100mg)，产率：72％。
MS m/z(ESI):443.7[M+1]
第四步
4,5-二氯-2-(4-氟-2-甲氧基苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)苯甲酰胺1
将化合物1d(100mg,0.22mmol)和醋酸钾(45mg,0.46mmol)加入醋酸(5mL)，120℃反应1.5小时。反应液减压浓缩，用硅胶柱色谱法以展开剂体系A纯化，得到标题化合物1(70mg)，产率：73％。
MS m/z(ESI):425.8[M+1]
1H NMR(400MHz,DMSO-d 6)δ12.81(s,1H),10.85(s,1H),7.93(s,1H),7.91(d,1H),7.25-7.20(m,1H),7.11(dd,1H),6.88(s,1H),6.82-6.82(m,1H),5.73(s,1H),3.73(s,3H)。
实施例2
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2
Figure PCTCN2020070186-appb-000057
第一步
5-氯-2-氟-4-(三氟甲基)苯甲酸2b
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2a(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2b(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2c
将化合物2b(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2c(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2d
将化合物2c(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2d(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2e
将化合物2d(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2e(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2f
将化合物2e(3.67g,10.52mmol)加入氯化亚砜(20g,168.1mmol)，80℃反应2小时。反应液浓缩，得到标题化合物2f(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2g
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。加入化合物2f(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2g(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2
将化合物2g(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2(800mg)，产率：64％。
MS m/z(ESI):442.0[M+1]
1H NMR(400MHz,DMSO-d 6)δ12.83(s,1H),11.03(s,1H),8.07(s,1H),7.86(s,1H),7.05-7.25(m,5H),2.14(s,3H)。
实施例3
4,5-二氯-2-(4-氟-2-甲基苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)苯甲酰胺3
Figure PCTCN2020070186-appb-000058
采用实施例1的合成路线，将第三步原料4-氟-2-甲氧基苯酚替换为化合物4-氟-2-甲基苯酚，制备得标题化合物3(20mg)。
MS m/z(ESI):407.8[M+1]
1H NMR(400MHz,DMSO-d 6)δ12.82(s,1H),10.92(s,1H),7.99(s,1H),7.90(d,1H),7.21-7.18(m,2H),7.08-7.05(m,2H),6.99(s,1H),2.14(s,3H)。
实施例4
4,5-二氯-2-(4-氟苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)苯甲酰胺4
Figure PCTCN2020070186-appb-000059
采用实施例1的合成路线，将第三步原料4-氟-2-甲氧基苯酚替换为化合物4- 氟苯酚，制备得标题化合物4(55mg)。
MS m/z(ESI):395.8[M+1]
1H NMR(400MHz,DMSO-d 6)δ12.81(s,1H),10.89(s,1H),7.98(s,1H),7.88(d,1H),7.26-7.22(m,2H),7.19(s,1H),7.16-7.13(m,3H)。
实施例5
2-(4-氟-2-甲基苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(五氟乙基)苯甲酰胺5
Figure PCTCN2020070186-appb-000060
第一步
2-氟-4-(五氟乙基)苯甲酸5b
在氩气氛下，将4-溴-2-氟苯甲酸5a(2.19g,10mmol,百灵威科技有限公司)溶于二甲基亚砜(41mL)中。加入铜粉(6.36g,100mmol)，五氟碘乙烷(17.22g,70mmol,8.24mL,四川上氟科技有限公司)，封管120℃反应72小时。冷却，加入100mL水和100mL乙酸乙酯，搅拌均匀，过滤。滤液分层，水相用乙酸乙酯萃取(20mL×3)。合并有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液浓缩。用硅胶柱色谱法以展开剂体系B纯化，得到标题化合物5b(2.4g)，产率：93％。MS m/z(ESI):257.0[M-1]
第二步
2-氟-4-(五氟乙基)苯甲酰氯5c
将化合物5b(500mg,1.93mmol)加入氯化亚砜(8.19g,68.8mmol)，80℃反应16小时。反应液浓缩得到粗品标题化合物5c(535mg)，产品不经纯化直接用于下一步反应。
第三步
N-(6-氯哒嗪-4-基)-2-氟-4-(五氟乙基)苯甲酰胺5d
将粗品化合物5c(535mg,1.93mmol)，6-氯哒嗪-4-胺(150mg,1.16mmol)和吡啶(916mg,11.58mmol)溶于二氯甲烷(5mL)，反应16小时。加入50mL乙酸乙酯，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液浓缩。用硅胶柱色谱法以展 开剂体系B纯化，得到标题化合物5d(664mg)，产率：93％。
MS m/z(ESI):370.0[M+1]
第四步
2-氟-N-(6-氧代-1,6-二氢哒嗪)-4-(五氟乙基)苯甲酰胺5e
将化合物5d(400mg,1.08mmol)，乙酸钾(213mg,2.17mmol)加入乙酸(5mL)，130℃反应5小时。反应液浓缩，用硅胶柱色谱法以展开剂体系A纯化，得到标题化合物5e(190mg)，产率：50％。
MS m/z(ESI):352.0[M+1]
第五步
2-(4-氟-2-甲基苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(五氟乙基)苯甲酰胺5
将化合物5e(190mg,0.54mmol)，4-氟-2-甲基苯酚(103mg,0.82mmol)和碳酸铯(265mg,0.81mmol)加入N,N-二甲基甲酰胺(3mL)，100℃反应2小时。冷却，过滤，用高效液相色谱制备(Waters 2767-SQ Detecor2，洗脱体系：碳酸氢铵，水，乙腈)纯化，得到标题化合物5(89mg)，产率：36％。
MS m/z(ESI):458.1[M+1]
1H NMR(400MHz,CD 3OD):δ8.05(d,1H),7.92(d,1H),7.52(d,1H),7.49(d,1H),7.12(dd,1H),6.99-7.07(m,2H),6.93(s,1H),2.21(s,3H)。
实施例6
2-(2-甲基-4-(三氟甲氧基)苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺6
Figure PCTCN2020070186-appb-000061
第一步
2-氟-4-(三氟甲基)苯甲酰氯6b
将2-氟-4-(三氟甲基)苯甲酸6a(1.2g,5.76mmol，韶远化学科技(上海)有限公司)加入氯化亚砜(12mL)，80℃反应16小时。反应液浓缩，得到粗品标题化合物6b(1.3g)，产物不经纯化直接用于下一步反应。
第二步
N-(6-氯哒嗪-4-基)-2-氟-4-(三氟甲基)苯甲酰胺6c
将粗品化合物6b(1.3g,5.74mmol)，6-氯-4-氨基哒嗪(300mg,2.31mmol)，吡啶(916mg,11.58mmol)溶于二氯甲烷(5mL)，反应16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6c(475mg)，产率：64％。
MS m/z(ESI):320.0[M+1]
第三步
2-氟-N-(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(475mg,1.49mmol)，乙酸钾(292mg,2.98mmol)加入乙酸(5mL)中。120℃反应16小时。反应液浓缩，用硅胶柱色谱法以展开剂体系A纯化，得到标题化合物6d(300mg)，产率：67％。
MS m/z(ESI):302.0[M+1]
第四步
2-(2-甲基-4-(三氟甲氧基)苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺6
将化合物6d(100mg,0.33mmol)，2-甲基-4-(三氟甲氧基)苯酚(78mg,0.4mmol)和碳酸铯(216mg,0.66mmol)加入N,N-二甲基甲酰胺(3mL)。100℃反应8小时。冷却，过滤，滤液浓缩，用硅胶柱色谱法以展开剂体系A纯化，得到标题化合物6(60mg)，产率：38％。
MS m/z(ESI):473.8[M+1]
1H NMR(400MHz,CD 3OD):δ8.05(d,1H),7.92(d,1H),7.52(d,1H),7.49(d,1H),7.12(dd,1H),6.99-7.07(m,2H),6.93(s,1H),2.29(s,3H)。
实施例7
2-(4-氟-2-甲基苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-5-(三氟甲基)苯甲酰胺7
Figure PCTCN2020070186-appb-000062
第一步
2-氟-5-(三氟甲基)苯甲酰氯7b
将2-氟-5-(三氟甲基)苯甲酸7a(382mg,1.83mmol,上海毕得医药科技有限公 司)加入氯化亚砜(5mL)，80℃反应16小时。反应液浓缩，得到粗品标题化合物7b(400mg)，产品不经纯化直接用于下一步反应。
第二步
N-(6-氯哒嗪-4-基)-2-氟-5-(三氟甲基)苯甲酰胺7c
将粗品化合物7b(393mg,1.73mmol)，6-氯-4-氨基哒嗪(150mg,1.15mmol)和吡啶(458mg,5.79mmol)溶于二氯甲烷(5mL)，反应24小时。加入50mL乙酸乙酯，饱和氯化钠溶液洗涤，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(90mg)，产率：24％。
MS m/z(ESI):320.0[M+1]
第三步
N-(6-氯哒嗪-4-基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲酰胺7d
将化合物7c(90mg,0.28mmol)，4-氟-2-甲基苯酚(43mg,0.34mmol)和碳酸铯(183mg,0.56mmol)加入N,N-二甲基甲酰胺(3mL)中，100℃反应1小时。反应液过滤，滤液浓缩，用硅胶柱色谱法以展开剂体系A纯化，得到标题化合物7d(46mg)，产率：37％。
MS m/z(ESI):426.1[M+1]
第四步
2-(4-氟-2-甲基苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-5-(三氟甲基)苯甲酰胺7
将化合物7d(46mg,0.11mmol)和乙酸钾(21mg,0.21mmol)加入乙酸(1mL)，130℃反应4小时。反应液浓缩，用硅胶柱色谱法以展开剂体系A纯化，得到标题化合物7(16mg)，产率：36％。
MS m/z(ESI):407.9[M+1]
1H NMR(400MHz,CD 3OD):δ8.08-8.07(m,2H),7.77(dd,1H),7.52(d,1H),7.14-7.11(m,2H),7.05-7.00(m,1H),6.89(d,1H),2.21(s,3H)。
实施例8
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8
Figure PCTCN2020070186-appb-000063
采用实施例6的合成路线，将第三步原料2-甲基-4-(三氟甲氧基)苯酚替换为化合物4-氟-2-甲氧基苯酚，制得标题化合物8(20mg)。
MS m/z(ESI):424.1[M+1]
1H NMR(400MHz,CD 3OD):δ8.07(d,1H),7.94(d,1H),7.53-7.49(m,2H),7.26(q, 1H),7.03(dd,1H),6.97(s,1H),6.83-6.79(m,1H),2.89(s,3H)。
实施例9
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9
Figure PCTCN2020070186-appb-000064
采用实施例6的合成路线，将第三步原料2-甲基-4-(三氟甲氧基)苯酚替换为化合物4-氟-2-甲基苯酚，制得目标产物9(65mg)。
MS m/z(ESI):408.1[M+1]
1H NMR(400MHz,CD 3OD):δ8.05(d,1H),7.90(d,1H),7.54(d,1H),7.49(d,1H),7.11(dd,1H),6.99-7.07(m,2H),6.97(s,1H),2.22(s,3H)。
实施例10
N-(6-氧代-1,6-二氢哒嗪-4-基)-2-(4-(三氟甲氧基)苯氧基)-4-(三氟甲基)苯甲酰胺10
Figure PCTCN2020070186-appb-000065
采用实施例6的合成路线，将第三步原料2-甲基-4-(三氟甲氧基)苯酚替换为化合物4-三氟甲氧基苯酚，制得标题化合物10(18mg)。
MS m/z(ESI):460.0[M+1]
1H NMR(400MHz,CD 3OD):δ8.03(d,1H),7.93(d,1H),7.65-7.63(m,1H),7.43(d,1H),7.35-7.32(m,3H),7.19-7.16(m,2H)。
实施例11
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11
Figure PCTCN2020070186-appb-000066
第一步
5-氯-2-氟-4-(三氟甲基)苯甲酰氯11a
将化合物2b(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11a(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11b
将5-氨基哒嗪-3-酮(3.06g,24.8mmol,上海美迪西生物医药股份有限公司)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11a(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11b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11c
向含有化合物11b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11c(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)。
实施例12
5-氯-2-(2-环丙氧基-4-氟苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺12
Figure PCTCN2020070186-appb-000067
第一步
1-溴-2环丙氧基-4-氟苯12b
将2-溴-5-氟苯酚12a(2g,10.5mmol,韶远化学科技(上海)有限公司)，环丙基溴(5g,41.3mmol,上海泰坦科技股份有限公司),碳酸铯(7g,21.5mmol,韶远化学科技(上海)有限公司)，碘化钾(180mg,1.1mmol)加入N,N-二甲基甲酰胺(10mL)。置于微波反应器中在130℃反应1.5小时。反应液冷却至室温，加入乙酸乙酯(20mL)，用水洗涤(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12b(3.0g)，产率：70％。
第二步
2-环丙氧基-4-氟苯酚12c
将化合物12b(1.85g,8mmol)和硼酸三异丙酯(1.96g,10.4mmol,上海泰坦科技股份有限公司)加入20mL四氢呋喃。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,7.5mL,12mmol)，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50mL甲醇，滴加双氧水(30wt％,11mL)和10％氢氧化钠溶液(50mL)。滴加完毕再加入400mL饱和氯化钠溶液，用乙酸乙酯(200mL×3)萃取。有机相用饱和碳酸氢钠溶液(150mL)洗涤，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12b(1.0g)，产率：74％。
第三步
5-氯-2-(2-环丙氧基-4-氟苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺12
将化合物11b(700mg,2.1mmol)，化合物12c(300mg,1.78mmol)和碳酸铯(700mg,2.1mmol,韶远化学科技(上海)有限公司)加入7mL N-甲基吡咯烷酮,80℃ 反应1小时，反应液冷却至室温，加入乙酸乙酯(20mL)，用水洗涤(10mL×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12(300mg)，产率：30％。
MS m/z(ESI):484.0[M+1]
1H NMR(400MHz,DMSO-d 6):δ12.84(s,1H),10.99(s,1H),8.01(s,1H),7.87(s,1H),7.30-7.19(m,3H),6.96(s,1H),6.85-6.83(m,1H),3.90-3.88(m,3H),0.74-0.70(m,1H),0.40-0.38(m,1H)。
实施例13
5-氯-2-(4-氟-2-甲基苄基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺13
Figure PCTCN2020070186-appb-000068
第一步
(4-氟-2-甲基苯基)溴化镁13b
将打磨光亮的镁条(760mg,31.7mmol,上海国药集团化学试剂有限公司)，剪碎，加入四氢呋喃(80mL)中，氩气保护。室温下，滴入三甲基氯硅烷(345mg,3.17 mmol，韶远科技(上海)有限公司)。加入1-溴-4-氟-2-甲基苯13a(1.5g,7.9mmol，韶远科技(上海)有限公司)，加热引发反应后，再加入化合物13a(4.5g,23.7mmol，韶远科技(上海)有限公司)。加热45℃反应1小时，镁条全部消失，形成灰色均匀液体，得到标题化合物13b溶液(0.4M,80mL)，产物不经纯化，直接用于下一步反应。
第二步
2-溴-4-氯-5-(三氟甲基)苯甲醛13d
将四氢呋喃(100mL)和六甲基二硅基胺基锂(1M,120mL,120mmol,泰坦化学)在氩气保护冷却至-78℃。滴加4-溴-2-氯-1-(三氟甲基)苯13c(25g,96.36mmol，韶远科技(上海)有限公司)，保持低温反应2小时。滴加N,N-二甲基甲酰胺(14.1g,192.9mmol,百灵威科技有限公司)，逐渐升至室温反应16小时。加入水，乙酸乙酯萃取(50mL×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13d(3.14g)，产率：28％。
1H NMR(400MHz,CDCl 3)δ10.32(s,1H),8.23(s,1H),7.87(s,1H)。
第三步
(2-溴-4-氯-5-(三氟甲基)苯基)(4-氟-2-甲基苯基)甲醇13e
将化合物13d(900mg,3.13mmol)溶于四氢呋喃(10mL)，滴加现制的化合物13b溶液(7.97mmol,19.92mL)，室温反应1小时。加入饱和氯化铵溶液，乙酸乙酯萃取(10mL×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13e(900mg)，产率：72％。
1HNMR(400MHz,CD 3OD)δ8.04(s,1H),7.93(s,1H),7.0-7.03(m,1H),6.87-6.90(m,2H),6.17(s,1H),2.5(s,3H)。
第四步
1-溴-5-氯-2-(4-氟-2-甲基苄基)-4-(三氟甲基)苯13f
将化合物13e(4g,10.1mmol)溶于二氯甲烷(50mL)，冷却至0℃加入三氟醋酸(10mL,泰坦化学)，滴加三乙基硅烷(6mL,韶远科技(上海)有限公司)，0℃反应1小时。加水，乙酸乙酯萃取(10mL×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13f(3.2g)，产率83％。
第五步
5-氯-2-(4-氟-2-甲基苄基)-4-(三氟甲基)苯甲酸甲酯13g
将化合物13f(3.3g,8.64mmol)溶于甲醇(60mL)。加入醋酸钯(388.31mg,1.73mmol,百灵威科技有限公司)，1,1'-双(二苯基膦)二茂铁(960mg,1.73mmol,韶远科技(上海)有限公司)，三乙胺(2.63g,25.94mmol,上海国药集团化学试剂有限公司集团化学试剂有限公司)。反应体系连接一氧化碳气球，60℃反应16小时。硅藻土过滤，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13g(2.2 g)，产率71％。
MS m/z(ESI):359.1[M-1]
第六步
5-氯-2-(4-氟-2-甲基苄基)-4-(三氟甲基)苯甲酸13h
将化合物13g(2.2g,6.1mmol)溶于甲醇(40mL)和水(20mL)中，加入氢氧化钠溶液(5M，6mL,30mmol)，升温至40℃反应3小时。冷却，4M盐酸调节pH为2，二氯甲烷萃取(10mL×3)。有机相用无水硫酸钠干燥。过滤，滤液减压浓缩，得标题粗品化合物13h(2.1g),，产物不经纯化，直接用于下一步反应。
MS m/z(ESI):345.1[M-1]
第七步
5-氯-N-(6-氯哒嗪-4基)-2-(4-氟-2-甲基苄基)-4-(三氟甲基)苯甲酰胺13i
将化合物13h(300mg,0.87mmol)溶于二氯甲烷(15mL)中，滴加1滴N,N-二甲基甲酰胺，冰浴冷却下，滴加氯化亚砜(2mL,上海国药集团化学试剂有限公司集团化学试剂有限公司)，室温下过夜反应。反应液减压浓缩，将残余物溶于吡啶(2mL)中，加入4-氨基-6-氯哒嗪(168mg,1.3mmol,韶远科技(上海)有限公司)。室温下反应过夜，反应液减压浓缩。加入水(20mL)，用二氯甲烷萃取(10mL×3)。有机相用无水硫酸钠干燥。过滤，滤液减压浓缩，得标题粗品化合物13i(260mg)，产物不经纯化，直接用于下一步反应。
MS m/z(ESI):458.1[M+1]
第八步
5-氯-2-(4-氟-2-甲基苄基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺13
将化合物13i(260mg,0.57mmol)溶于乙酸(5mL)，加入乙酸钾(112mg,1.14mmol)，130℃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：碳酸氢铵，水，乙腈)纯化，得到标题化合物13(10mg)，两步产率：2.6％。
MS m/z(ESI):440.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ7.90-7.91(m,1H),7.81(m,1H),7.59(m,1H),7.39(m,1H),6.95-6.97(m,1H),6.85-6.88(m,1H),6.78-6.79(m,1H),4.63(m,1H),4.19(s,2H),2.20(s,3H)。
实施例14
5-氯-2-(2-氟-4-(三氟甲氧基)苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺14
Figure PCTCN2020070186-appb-000069
第一步
2-氟-1-硝基-4-(三氟甲氧基)苯14b
将1-氟-3-(三氟甲氧基)苯14a(5g,27.76mmol，韶远科技(上海)有限公司)溶于硫酸(20mL)，冰浴冷却，分批加入硝酸钾(7g,69.2mmol)),冰浴自然升温至室温过夜。反应液倒入冰水中，搅拌30分钟，乙酸乙酯萃取三次，硫酸钠干燥，旋干，得到含化合物14b的粗品混合物(5.8g)。
第二步
2-氟-4-(三氟甲氧基)苯胺14c
将化合物14b粗品混合物(5.8g,25.7mmol)溶于甲醇(80mL)，氮气置换，加入钯碳催化剂(1.54g,14.47mmol)，氢气置换三次，室温氢化反应过夜。反应液过滤，浓缩，用硅胶柱色谱法以展开剂体系A纯化，得到含标题化合物14c的粗品混合物(3.5g)。
第三步
1-溴-2-氟-4-(三氟甲氧基)苯14d
将化合物14c混合物(3.4g,17.4mmol)溶于乙腈(40mL)，加入溴化铜(4.67g,20.9mmol，韶远科技(上海)有限公司)，亚硝酸特丁酯(2.16g,20.9mmol)。60℃反应0.5小时，反应液过滤，减压浓缩。用硅胶柱色谱法以展开剂体系A纯化，得到含标题化合物14d混合物(1.3g)。
第四步
2-(2-氟-4-(三氟甲氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷14e
将含化合物14d混合物(3g,11.6mmol)溶于1,4-二氧六环(50mL)，加入联硼酸频那醇酯(4.4g,17.3mmol，韶远科技(上海)有限公司)，1,1-双(二-苯基磷基)二茂铁氯化钯(424mg,0.58mmol)，乙酸钾(3.41g,34.7mmol)，氩气置换三次，100℃反应过夜。反应液用硅藻土过滤，滤液减压浓缩，用硅胶柱色谱法以展开剂体系A纯化，得到含标题化合物14e(950mg)混合物。
第五步
2-氟-4-(三氟甲氧基)苯酚14f
将含化合物14e混合物(950mg,3.1mmol)溶于四氢呋喃(20mL)，加入氢氧化钠溶液(621mg,15.5mmol，5mL)。冰浴冷却，滴加双氧水(3.1mL)，室温反应过夜。有机相用饱和碳酸氢钠溶液(50mL)洗涤，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，得到含标题化合物14f混合物(220mg)。
第六步
5-氯-2-(2-氟-4-(三氟甲氧基)苯氧基)-4-(三氟甲基)苯甲酸甲酯14g
将化合物2c(300mg,1.2mmol)和含化合物14f混合物(229mg,1.2mmol)加入N,N-二甲基甲酰胺(5mL)，再加入碳酸铯(571mg,1.8mmol)，100℃反应1小时。冷却，反应液过滤，减压浓缩，用硅胶柱色谱法以展开剂体系B纯化，得到含标题化合物14g混合物(440mg)。
第七步
5-氯-2-(2-氟-4-(三氟甲氧基)苯氧基)-4-(三氟甲基)苯甲酸14h
将化合物14g(400mg,0.92mmol)溶于四氢呋喃(5mL)，加入氢氧化锂溶液(194mg,4.6mmol，1mL)，室温反应4小时。反应液减压浓缩，加入水(5mL)，用稀盐酸调节pH＝4,乙酸乙酯萃取三次(20mL×3)。有机相用无水硫酸钠干燥，过滤，减压浓缩，得到含标题化合物14h混合物(340mg)，直接用于下一步反应。
第八步
5-氯-2-(2-氟-4-(三氟甲氧基)苯氧基)-4-(三氟甲基)苯甲酰氯14i
将化合物14h(80mg,0.19mmol)溶于氯化亚砜(2mL)，80℃反应2小时。反应液减压浓缩，得到含标题化合物14i混合物(80mg)，直接用于下一步反应。
第九步
5-氯-N-(6-氯哒嗪-4-基)-2-(2-氟-4-(三氟甲氧基)苯氧基)-4-(三氟甲基)苯甲酰胺14j
将4氨基-6-氯哒嗪(31mg,0.24mmol，韶远科技(上海)有限公司)溶于四氢呋喃(3mL)，冰浴冷却，加入氢化钠(13mg,0.34mmol,60％purity)，反应30分钟。滴加化合物14i的四氢呋喃溶液(2mL)，氩气保护，室温反应过夜。加入水(10mL) 和乙酸乙酯(20mL)，有机相用无水硫酸钠干燥，减压浓缩。用硅胶柱色谱法以展开剂体系B纯化，得到含标题化合物14j混合物(65mg)。
第十步
5-氯-2-(2-氟-4-(三氟甲氧基)苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺14
将含化合物14j混合物(65mg,0.12mmol)溶于乙酸(3mL)，加入乙酸钾(60mg,0.61mmol)，130℃反应2小时。反应液减压浓缩，用高效液相色谱制备(Waters2767-SQ Detecor2，洗脱体系：碳酸氢铵，水，乙腈)纯化，得到标题化合物14(8mg)，产率：11％。
MS m/z(ESI):512.0[M+1]
H NMR(400MHz,CD 3OD):δ8.02(d,1H),8.00(s,1H),7.43(d,1H),7.40(s,1H),7.37-7.27(m,2H)，7.19(d,1H)。
实施例15
5-氯-2-(4-氟-2-(三氟甲氧基)苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺15
Figure PCTCN2020070186-appb-000070
第一步
1-甲氧基-2-(三氟甲氧基)苯15b
将2-(三氟甲氧基)苯酚15a(5g,28.1mmol,韶远科技(上海)有限公司)溶于 N,N-二甲基甲酰胺(50mL)，加入碘甲烷(4.78g,33.7mmol)和碳酸钾(7.75g,56.1594mmol)，80℃反应1小时。反应液中加入乙酸乙酯和水，水相乙酸乙酯萃取三次，有机相合并水洗四次，硫酸钠干燥，旋干得到标题化合物15b(5.1g)，产率：94％。
第二步
1-甲氧基-4-硝基-2-(三氟甲氧基)苯15c
硝酸钠(2.26g，26.6mmol)溶于三氟乙酸(50mL)，冰浴冷却，加入化合物15b(5.1g,26.5mmol)的三氟乙酸溶液(10mL)，冰浴反应1小时，室温反应3小时。反应液中加入水(50mL)和乙酸乙酯(50mL)，有机相用饱和碳酸氢钠洗涤至中性，无水硫酸钠干燥，减压浓缩，得到标题化合物15c(5.3g)，产率：84％。
第三步
4-甲氧基-3-(三氟甲氧基)苯胺15d
将化合物15c(5.3g,22.3mmol)溶于甲醇(100mL)，加入浓盐酸(0.5mL)，钯碳催化剂(500mg)，氢气置换三次，室温氢化反应4小时。反应液用硅藻土过滤，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15d(3.1g)，产率：67％。
第四步
4-氟-1-甲氧基-2-(三氟甲氧基)苯15e
将化合物15d(800mg,3.9mmol)加入水(15mL)，氟硼酸(1.51g,7.0mmol,40％purity)，盐酸(687mg,7.0mmol)的混合液中。冰浴冷却，滴加亚硝酸钠(280mg,4.06mmol,2mL)溶液，冰浴反应2小时。反应液过滤，滤饼烘干。氮气保护下，固体加热至130℃，逐渐溶解变红，反应1小时。反应体系冷却后，用二氯甲烷溶解，硫酸钠干燥，减压浓缩，得到标题化合物15e(600mg)，产率：74％。
第五步
4-氟-2-(三氟甲氧基)苯酚15f
将化合物15e(300mg,1.4mmol)，溶于二氯甲烷(5mL)，冰浴冷却，加入三溴化硼溶液(1M,7mL)，自然升至室温过夜。反应液滴加至甲醇中，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15f(100mg)，产率：36％。
第六步
5-氯-2-(4-氟-2-(三氟甲氧基)苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺15
将化合物15f(300mg,0.89mmol)加入N-甲基吡咯烷酮(3mL)，再加入化合物11b(140mg,0.71mmol)，碳酸铯(291mg,0.9mmol)，80℃反应1小时。反应液中加入水(10mL)和乙酸乙酯(20mL)，有机相用无水硫酸钠干燥，减压浓缩。用高效液相色谱制备(Waters 2767-SQ Detecor2，洗脱体系：碳酸氢铵，水，乙腈)纯化，得到标题化合物15(40mg)，产率：11％。
MS m/z(ESI):512.0[M+1]
H NMR(400MHz,CD 3OD):δ8.03(d,1H),8.01(s,1H),7.46(d,1H),7.37-7.35(m,1H),7.32-7.22(m,3H)。
实施例16
2-(4-氟-2-甲氧基苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-5-(三氟甲基)苯甲酰胺16
Figure PCTCN2020070186-appb-000071
采用实施例2的合成路线，将第二步原料5-氯-2-氟-4-(三氟甲基)苯甲酸替换为化合物2-氟-5-(三氟甲基)苯甲酸，第三步原料4-氟-2-甲基-苯酚替换为4-氟-2-甲氧基-苯酚，制得标题化合物16(27mg)。
MS m/z(ESI):424.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ12.81(s,1H),10.90(s,1H),7.95(d,2H),7.76(d,1H),7.21-7.33(m,2H),7.15(d,1H),6.72-6.90(m,2H),3.71(s,3H)。
实施例17
5-氯-2-((4-氟-2-甲氧基苯基)硫基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺17
Figure PCTCN2020070186-appb-000072
采用实施例2的合成路线，将第三步原料2-甲基-4-氟苯酚替换为2-甲氧基苯硫醇，制得标题化合物17(35mg)。
MS m/z(ESI):474.0[M+1]
1H NMR(400MHz,DMSO-d 6)δ12.90(s,1H),11.06(s,1H),8.12(s,1H),7.97(s,1H),7.59-7.55(m,1H),7.25(s,1H),7.16-7.13(m,2H),6.93-6.89(m,1H),3.74(s,3H)。
实施例18
4-氯-5-氟-2-(4-氟-2-甲氧基苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)苯甲酰胺18
Figure PCTCN2020070186-appb-000073
采用实施例1的合成路线，将第一步原料4,5-二氯-2-氟苯甲酸替换为化合物4-氯-2,5-二氟苯甲酸，制得标题化合物18(22mg)。
MS m/z(ESI):408.0[M+1]
1H NMR(400MHz,DMSO-d 6)δ12.81(s,1H),10.83(s,1H),7.90-7.89(d,1H),7.77-7.75(d,1H),7.19-7.16(m,2H),7.10-7.06(m,1H),6.90-6.81(m,1H),6.81-6.77(m,1H),3.71(s,3H)。
实施例19
4-氯-5-氟-2-(4-氟-2-甲基苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)苯甲酰胺19
Figure PCTCN2020070186-appb-000074
采用实施例1的合成路线，将第一步原料4,5-二氯-2-氟苯甲酸替换为化合物4-氯-2,5-二氟苯甲酸，第三步原料2-甲氧基-4-氟苯酚替换为2-甲基-4氟苯酚，制得标题化合物19(9mg)，白色固体。
MS m/z(ESI):392.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ12.81(s,1H),10.89(s,1H),7.87-7.86(d,1H),7.82-7.80(d,1H),7.18-7.14(m,2H),7.04-7.03(m,2H),7.00-6.93(m,1H),2.14(s,3H)。
实施例20
4-氯-2-(4-氟-2-甲基苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)苯甲酰胺20
Figure PCTCN2020070186-appb-000075
采用实施例2的合成路线，将第二步原料5-氯-2-氟-4-(三氟甲基)苯甲酸替换 为化合物4-氯-2-氟苯甲酸，制得标题化合物20(40mg)。
MS m/z(ESI):374.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ12.79(s,1H),10.83(s,1H),7.89(s,1H),7.67(d,1H),7.30(d,1H),7.14-7.22(m,2H),7.00-7.12(m,2H),6.74(s,1H),2.13(s,3H)。
实施例21
4-氯-2-(4-氟-2-甲氧基苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)苯甲酰胺21
Figure PCTCN2020070186-appb-000076
采用实施例2的合成路线，将第二步原料5-氯-2-氟-4-(三氟甲基)苯甲酸替换为化合物4-氯-2-氟苯甲酸，并将第三步原料2-甲基-4-氟苯酚替换为化合物2-甲氧基-4-氟苯酚，制得标题化合物21(40mg)。
MS m/z(ESI):390.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ12.79(s,1H),10.75(s,1H),7.92(s,1H),7.63(d,1H),7.18-7.30(m,3H),7.10(dd,1H),6.78-6.88(m,1H),6.64(s,1H),3.72(s,3H)。
实施例22
2-(4-氟-2-甲氧基苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-5-(三氟甲氧基)苯甲酰胺22
Figure PCTCN2020070186-appb-000077
采用实施例1的合成路线，将第一步原料4,5-二氯-2-氟苯甲酸替换为化合物2-氟-5-(三氟甲氧基)苯甲酸，制得标题化合物22(5mg)。
MS m/z(ESI):440.1[M+1]
1H NMR(400MHz,CD 3OD):δ8.05(d,1H),7.74(d,1H),7.54(d,1H),7.41-7.38(m,1H),7.26(q,1H),7.03-7.00(m,1H),6.89(d,1H),6.81-6.77(m,1H),3.81(s,3H)。
实施例23
5-氯-2-(4-氟-2-甲基苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)苯甲酰胺23
Figure PCTCN2020070186-appb-000078
采用实施例1的合成路线，将第一步原料4,5-二氯-2-氟苯甲酸替换为化合物5-氯-2-氟苯甲酸，制得标题化合物23(14mg)。
MS m/z(ESI):374.1[M+1]
1H NMR(400MHz,CD 3OD):δ8.05(d,1H),7.76(d,1H),7.49-7.46(m,2H),7.07(d,1H),7.01-6.98(m,2H),6.78(d,1H),2.22(s,3H)。
实施例24
2-(4-氟-2-甲基苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-5-(三氟甲氧基)苯甲酰胺24
Figure PCTCN2020070186-appb-000079
采用实施例1的合成路线，将第一步原料4,5-二氯-2-氟苯甲酸替换为化合物2-氟-5-(三氟甲氧基)苯甲酸，制得标题化合物24(7mg)。
MS m/z(ESI):424.1[M+1]
1H NMR(400MHz,CD 3OD):δ8.05(d,1H),7.71(d,1H),7.50(d,1H),7.44-7.41(m,1H),7.11-6.97(m,3H),6.87(d,1H),2.23(s,3H)。
实施例25
5-氟-2-(4-氟-2-甲氧基苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)苯甲酰胺25
Figure PCTCN2020070186-appb-000080
采用实施例1的合成路线，将第一步原料4,5-二氯-2-氟苯甲酸替换为化合物2，5-二氟苯甲酸，制得标题化合物25(20mg)。
MS m/z(ESI):374.0[M+1]
1H NMR(400MHz,DMSO-d 6)δ12.78(s,1H),10.77(s,1H),7.91(s,1H),7.45-7.55(m,1H),7.00-7.32(m,4H),6.65-6.85(m,2H),3.70(s,3H)。
实施例26
5-氟-2-(4-氟-2-甲基苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)苯甲酰胺26
Figure PCTCN2020070186-appb-000081
采用实施例1的合成路线，将第一步原料4,5-二氯-2-氟苯甲酸替换为化合物2，5-二氟苯甲酸，第三步原料2-甲氧基-4-氟苯酚替换为2-甲基-4氟苯酚，制得标题化合物26(20mg)。
MS m/z(ESI):358.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ12.79(s,1H),10.85(s,1H),7.88(s,1H),7.50-7.60(m,1H),7.30-7.40(m,1H),7.08-7.19(m,2H),6.95-7.05(m,1H),6.80-6.95(m,2H),2.14(s,3H)。
实施例27
4-氯-2-(4-氟-2-甲基苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-5-(三氟甲基)苯甲酰胺27
Figure PCTCN2020070186-appb-000082
Figure PCTCN2020070186-appb-000083
第一步
1-氯-5-氟-4-硝基-2-(三氟甲基)苯27b
将2-氯-4-氟-1-(三氟甲基)苯27a(3g,15.1mmol,阿达玛斯试剂有限公司)溶于硫酸(30mL)，冷却至-10℃，分批加入硝酸钾(1.83g,18.1mmol)，-10℃反应1小时，室温反应过夜。将反应液倒入冰中，用乙酸乙酯(50mL×2)萃取，有机相用无水硫酸干燥，过滤，减压浓缩得到标题化合物27b(3.46g)，产率：94％。
第二步
1-氯-5-(4-氟-2-甲基苯氧基)-4-硝基-2-(三氟甲基)苯27c
将化合物27b(1g,4.1mmol)溶于N,N-二甲基甲酰胺(10mL)，加入4-氟-2-甲基苯酚(518mg,4.1mmol)和磷酸钾(2.61g,12.3mmol)，80℃反应1小时。反应液过滤，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27c(1.27g)，产率：88％。
第三步
4-氯-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯胺27d
将化合物27c(1.2g,3.4mmol)溶于乙醇(20mL)和水(10mL)，加入还原铁粉(1.15g,20.6mmol)和氯化铵(1.10g,20.6mmol)，80℃反应3小时。反应液过滤，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27d(900mg)，产率：82％。
第四步
1-溴-4-氯-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯27e
将化合物27d(1g,3.1mmol)溶于乙腈(10mL)，加入溴化铜(839mg,3.7mmol，阿达玛斯试剂有限公司)，亚硝酸特丁酯(387mg,3.7mmol)，回流2小时。反应液过滤，滤液减压浓缩，得到标题化合物27e(1g)，产率：83％。
第五步
4-氯-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲酸甲酯27f
将化合物27e(400mg,1.04mmol)溶于甲醇(10mL)，加入醋酸钯(47mg,0.21mmol)，1,1'-双(二苯基膦)二茂铁(116mg,0.21mmol)和三乙胺(317mg,3.1mmol)，一氧化碳置换三次。在一氧化碳气氛下，70℃反应过夜。反应液过滤，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27f(400mg)，产率：42％。
第六步
4-氯-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲酸27g
将化合物27f(480mg,1.3mmol)溶于四氢呋喃(5mL)和水(1mL)，加入氢氧化锂一水合物(170mg,4.0mmol)，室温反应过夜。反应液减压浓缩，加入少量水溶解，稀盐酸调节pH＝4。乙酸乙酯萃取(20mL×3)，有机相用无水硫酸钠干燥，减压浓缩，得到标题化合物27g(430mg)，产率：93％。
第七步
4-氯-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲酰氯27h
将化合物27g(200mg,0.57mmol)加入氯化亚砜(2mL)，80℃反应2小时。反应液减压浓缩，得到标题化合物27h(210mg)粗品，直接用于下一步反应。
第八步
4-氯-N-(6-氯吡啶-4-基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲酰胺27i
将化合物27h(230mg，0.73mmol)溶于吡啶(3mL)，加入4-氨基-6-氯哒嗪(95mg,0.73mmol)和4-二甲氨基吡啶(10mg,0.08mmol)，室温反应过夜。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27i(60mg)，产率：20％。
第九步
4-氯-2-(4-氟-2-甲基苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-5-(三氟甲基)苯甲酰胺27
将化合物27i(60mg,0.13mmol)溶于乙酸(2mL)，加入乙酸钾(25mg,0.25mmol)。130℃反应4小时。反应液减压浓缩，用高效液相色谱制备(Waters2767-SQ Detecor2，洗脱体系：碳酸氢铵，水，乙腈)纯化，得到标题化合物27(14mg)，产率：24％。
MS m/z(ESI):442.1[M+1]
1H NMR(400MHz,CD 3OD):δ8.18(s,1H),8.06(d,1H),7.52(d,1H),7.18-7.15(m,2H),7.09-7.06(m,1H),6.87(s,1H),2.21(s,3H)。
实施例28
5-氯-2-(4-氟-2-甲基苯氧基)-4-甲基-N-(6-氧代-1,6-二氢哒嗪-4-基)苯甲酰胺28
Figure PCTCN2020070186-appb-000084
采用实施例2的合成路线，将第二步原料5-氯-2-氟-4-(三氟甲基)苯甲酸替换为化合物5-氯-2-氟-4-甲基苯甲酸，制得标题化合物28(3mg)。
MS m/z(ESI):388.2[M+1]
1H NMR(400MHz,CD 3OD):δ8.03(d,1H),7.79(s,1H),7.48(d,1H),7.09-7.06(m,1H),7.00-6.96(s,2H),6.72(s,1H),2.33(s,3H),2.22(s,3H)。
实施例29
2-(4-氟-2-甲基苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4,6-双(三氟甲基)苯甲酰胺29
Figure PCTCN2020070186-appb-000085
采用实施例1的合成路线，将第一步原料5-氯-2-氟-4-(三氟甲基)苯甲酸替换为化合物2-氟-4,6-二(三氟甲基)苯甲酸，制得标题化合物29(2.4mg)。
MS m/z(ESI):476.0[M+1]
1H NMR(400MHz,CD 3OD)δ8.02(s,1H),7.82(s,1H),7.50(s,1H),7.00-7.20(m,4H),2.19(s,3H)。
实施例30
5-氯-N-(6-氧代-1,6-二氢哒嗪-4-基)-2-(邻甲苯基氧基)-4-(三氟甲基)苯甲酰胺30
Figure PCTCN2020070186-appb-000086
采用实施例2的合成路线，将第三步原料2-甲基-4-氟苯酚替换为2-甲基苯酚，制得标题化合物30(75mg)。
MS m/z(ESI):424.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ12.87(s,1H),11.08(s,1H),8.11(s,1H),7.88(d,1H),7.34-7.32(m,1H),7.27-7.23(m,1H),7.17-7.13(m,3H),7.02-7.00(m,1H),2.16(s,3H)。
实施例31
5-氯-2-(2-环丙基-4-氟苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺31
Figure PCTCN2020070186-appb-000087
第一步
2-环丙基-4-氟苯酚31b
将2-溴-4-氟苯酚31a(1.77g,9.26mmol,上海毕得医药科技有限公司)，磷酸三钾(6.89g,32.46mmol)，三环己基膦(260mg,0.93mmol)和环丙基硼酸(1.20g,13.97mmol,上海毕得医药科技有限公司)置于甲苯(40mL)/水(2mL)混合液中，氩气置换3次。再加入醋酸钯(105mg,0.46mmol)，氩气置换3次，100℃反应过夜。冷却，向反应液中加入乙酸乙酯(50mL)，水洗(50mL×3)。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到标题化合物31b粗品(1.41g)。
MS m/z(ESI):151.1[M-1]
第二步
5-氯-2-(2-环丙基-4-氟苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺31
将化合物11b(1.03g,3.06mmol)，化合物31b(0.47g,3.08mmol)和碳酸铯(1.01g,3.09mmol)加入N-甲基吡咯烷酮(10mL)中，60℃反应过夜。冷却，向反应液中加入乙酸乙酯(150mL)，水洗(50mL×3)。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用高效液相色谱制备(Waters 2767-SQ Detecor2，洗脱体系：碳酸氢铵，水，乙腈)纯化，得到标题化合物31(350mg)，产率：24％。
MS m/z(ESI):468.0[M+1]
1H NMR(400MHz,DMSO-d 6):δ12.87(s,1H),11.08(s,1H),8.10(s,1H),7.90(d,1H),7.21(s,1H),7.14(dd,1H),7.08-7.03(m,2H),6.87(dd,1H),2.01-1.94(m,1H),0.87-0.83(m,2H),0.71-0.67(m,2H)。
实施例32
5-氯-2-(2-乙氧基-4-氟苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺32
Figure PCTCN2020070186-appb-000088
采用实施例12的合成路线，将第一步原料环丙基溴替换为化合物碘乙烷室温反应，制得标题化合物32(200mg)。
MS m/z(ESI):472.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ12.83(s,1H),10.98(s,1H),8.02(s,1H),7.89(s,1H),7.00-7.28(m,4H),6.73-6.83(m,1H),3.99(q,2H),1.07(t,3H)。
实施例33
5-溴-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33
Figure PCTCN2020070186-appb-000089
采用实施例11的合成路线，将第一步原料5-氯-2-氟-4-(三氟甲基)苯甲酸替换为化合物5-溴-2-氟-4-(三氟甲基)苯甲酸反应，制得标题化合物33(126mg)。
MS m/z(ESI):486.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ12.84(s,1H),11.03(s,1H),8.19(s,1H),7.86-7.85(d,1H),7.21-7.16(m,2H),7.07-7.06(d,1H),2.13(s,3H)。
实施例34
2-(4-氟-2-甲基苯氧基)-5-甲基-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺34
Figure PCTCN2020070186-appb-000090
采用实施例11的合成路线，将第一步原料5-氯-2-氟-4-(三氟甲基)苯甲酸替换为化合物5-甲基-2-氟-4-(三氟甲基)苯甲酸，第三步原料2-甲氧基-4-氟苯酚替换为2-甲基-4-氟苯酚，制得标题化合物34(15mg)。
MS m/z(ESI):422.0[M+1]
1H NMR(400MHz,DMSO-d 6)δ12.83(s,1H),11.97(s,1H),7.89-7.88(d,1H),7.74(d,1H),7.19-7.18(m,2H),7.08-7.04(m,1H),7.00-6.97(m,2H),2.44(s,3H),2.15(s,3H)。
实施例35
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35
Figure PCTCN2020070186-appb-000091
第一步
1-溴-4-氟-2-(甲氧基-d 3)苯35b
将2-溴-5-氟苯酚12a(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)。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35b(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35c
将化合物35b(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，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35c(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35
将化合物11b(1g,2.98mmol)，化合物35c(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)。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35(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)。
实施例36
5-氯-2-(2-乙基-4-氟苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺36
Figure PCTCN2020070186-appb-000092
Figure PCTCN2020070186-appb-000093
第一步
4-氟-2-(1-羟乙基)苯酚36b
将化合物1-(5-氟-2-羟基苯基)乙-1-酮36a(3g,19.5mmol,韶远化学科技(上海)有限公司)溶于无水甲醇(20mL)，分批缓慢加入硼氢化钠(1.1g,29.1mmol)，室温反应1小时。减压浓缩，加入乙酸乙酯及水。有机相用无水硫酸钠干燥，过滤，减压浓缩，得标题化合物36b粗品(3.2g)，产率：100％。
MS m/z(ESI):155.1[M-1]
第二步
2-乙基-4-氟苯酚36c
将化合物36b(1.5g,9.6mmol)溶于二氯甲烷(15mL)，加入三氟乙酸(11g,96.5mmol,7.2mL)，滴加三乙基硅烷(11.2g,96.3mmol,15.4mL)，室温反应2小时。减压浓缩，加入二氯甲烷和水。有机相用无水硫酸钠干燥，过滤，减压浓缩得标题化合物36c粗品(1.38g)，产率：100％。
MS m/z(ESI):139.1[M-1]
第三步
5-氯-2-(2-乙基-4-氟苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺36
将化合物11b(100mg,0.3mmol)，化合物36c(42mg,0.3mmol)和碳酸铯(100mg,0.33mmol)加入N-甲基吡咯烷酮(2mL)中，60℃反应过夜。冷却，向反应液中加入乙酸乙酯(150mL)，水洗(50mL×3)。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用高效液相色谱制备(Waters 2767-SQ Detecor2，洗脱体系：碳酸氢铵，水，乙腈)纯化，得到标题化合物36(18mg)，产率：13％。
MS m/z(ESI):456.0[M+1]
1H NMR(400MHz,DMSO-d 6)δ12.88(s,1H),11.09(s,1H),8.12(s,1H),7.90-7.90(d,1H),7.25-7.20(m,2H),7.14(m,1H),7.11-7.10(m,2H),2.58-2.54(m,2H),1.10-1.06(m,3H)。
实施例37
5-氯-2-(2-(二氟甲氧基)-4-氟苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺37
Figure PCTCN2020070186-appb-000094
第一步
2-(二氟甲氧基)-4-氟-1-甲氧基苯37b
将5-氟-2-甲氧基苯酚37a(1g,7.03mmol,韶远化学科技(上海)有限公司)，二氟氯乙酸钠(2.68g,17.57mmol，韶远化学科技(上海)有限公司)，碳酸铯(4.58g,14.05mmol)加入N,N-二甲基甲酰胺(14mL)/水(1.5mL)混合溶剂中，100℃反应过夜。冷却，向反应液中加入二氯甲烷(100mL)，水洗(50mL×3)。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到标题化合物37b粗品(1.35g)。
第二步
2-(二氟甲氧基)-4-氟苯酚37c
将碘化钠(5.27g,35.15mmol，上海国药集团化学试剂有限公司)溶于乙腈(20mL)中，加入三甲基氯硅烷(3.82g,35.16mmol，上海国药集团化学试剂有限公司)，室温反应20分钟。再加入化合物37b(1.35g,7.0263mmol)，80℃反应过夜。冷却，向反应液中加入水(50mL)，乙酸乙酯萃取(50mL×3)。合并有机相，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37c(540mg)，产率：43％。
MS m/z(ESI):177.1[M-1]
第三步
5-氯-2-(2-二氟甲氧基)-4-氟苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺37
将化合物11b(1.02g,3.03mmol)，化合物37c(0.54g,3.03mmol)和碳酸铯(0.99g,3.13mmol)加入N-甲基吡咯烷酮(10mL)中，60℃反应过夜。冷却，向反应液中加入乙酸乙酯(150mL)，水洗(50mL×3)。有机相用无水硫酸钠干燥，过滤， 滤液减压浓缩，用高效液相色谱制备(Waters 2767-SQ Detecor2，洗脱体系：碳酸氢铵，水，乙腈)纯化，得到标题化合物37(450mg)，产率：30％。
MS m/z(ESI):493.9[M+1]
1H NMR(400MHz,DMSO-d 6):δ12.86(s,1H),11.0 6(s,1H),8.11(s,1H),7.89(d,1H),7.38(dd,1H),7.33(dd,1H),7.27(s,1H),7.23(t,1H),7.22-7.17(m,2H)。
实施例38
5-氯-2-(4-氟-2-羟基苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺38
Figure PCTCN2020070186-appb-000095
将化合物11(100mg,0.22mmol)置于二氯甲烷(2mL)中，冷却到-78℃，滴加三溴化硼(1M,1.09mL，阿达玛斯贝塔(上海)化学试剂有限公司)，升温至0℃，反应3小时。0℃补加三溴化硼(1M,1.09mL)，室温反应过夜。浓缩，向残余物中滴加入10mL甲醇，搅拌均匀，浓缩，用高效液相色谱制备(Waters 2767-SQ Detecor2，洗脱体系：碳酸氢铵，水，乙腈)纯化，得到标题化合物38(50mg)，产率：51％。
MS m/z(ESI):444.1[M+1]
1H NMR(400MHz,DMSO-d 6):δ12.88(s,1H),10.99(s,1H),10.47(s,1H),8.04(s,1H),7.94(s,1H),7.26-7.22(m,2H),6.97(s,1H),6.80(dd,1H),6.75-6.70(m,1H)。
实施例39
5-氯-2-((7-氟-2,3-二氢-1H-茚-4-基)氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺39
Figure PCTCN2020070186-appb-000096
第一步
4-氟苯基3-氯丙酸酯39b
将原料4-氟苯酚39a(15g,133.8mmol,韶远化学科技(上海)有限公司)溶于二氯甲烷(80mL)，加入吡啶(12g,151.7mmol)，冰水浴冷却下缓慢滴加3-氯丙酰氯(18.9g,134mmol,韶远化学科技(上海)有限公司)，滴完后室温搅拌1小时。加入饱和碳酸氢钠溶液(60mL)，用乙酸乙酯萃取(80mL×2)。合并有机相，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39b(25g)，产率：86％。
MS m/z(ESI):203.1[M+1]
第二步
4-氟-7-羟基-2,3-二氢-1H-茚-1-酮39c
将化合物39b(10g,49.4mmol)和三氯化铝(20g,150mmol,国药集团化学试剂有限公司)均匀混合，加热至100℃，搅拌15分钟。再加热至180℃反应3小时。反应冷却至室温，缓慢加入冰水中，加入乙酸乙酯，搅拌2小时。有机相用无水硫酸钠干燥，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39c(3g)，产率：37％。
MS m/z(ESI):167.3[M+1]
第三步
7-氟-2,3-二氢-1H-茚-4-醇39d
将化合物39c(8g,48.2mmol)溶于三氟酸(80mL)，加入三乙基硅烷(14g,120.4mmol)，80℃搅拌反应过夜。反应液减压浓缩，用硅胶柱色谱法以展开剂体系A纯化，得到标题化合物39d(6g)，产率：82％。
MS m/z(ESI):151.3[M-1]
第四步
5-氯-2-((7-氟-2,3-二氢-1H-茚-4-基)氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺39
将化合物11b(1.02g,3.03mmol)，化合物39d(0.54g,3.03mmol)和碳酸铯(0.99g,3.13mmol)加入N-甲基吡咯烷酮(10mL)中，60℃反应过夜。冷却，向反应液中加入乙酸乙酯(150mL)，水洗(50mL×3)。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用高效液相色谱制备(Waters 2767-SQ Detecor2，洗脱体系：碳酸氢铵，水，乙腈)纯化，得到标题化合物39(400mg)，产率：29％。
MS m/z(ESI):468.0[M+1]
1H NMR(400MHz,DMSO-d 6)δ12.86(s,1H),11.03(s,1H),8.08(s,1H),7.874-7.868(d,1H),7.27(m,1H),7.15(m,1H),7.04-7.00(m,1H),6.92-6.89(m,1H),2.92-2.88(m,2H),2.77-2.73(m,2H),2.05-1.99(m,2H)。
实施例40
5-氯-2-(2-(环戊氧基)-4-氟苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺40
Figure PCTCN2020070186-appb-000097
采用实施例35的合成路线，将第一步原料氘代碘甲烷替换为化合物溴代环戊烷，制得标题化合物40(30mg)。
MS m/z(ESI):511.9[M+1].
1H NMR(400MHz,DMSO-d 6)δ12.87(s,1H),10.99(s,1H),8.05(s,1H),7.95(s,1H),7.30-7.35(m,1H),7.29(s,1H),7.11(dd,1H),6.98(s,1H),6.77-6.86(m,1H),4.80-4.90(m,1H),1.72-1.85(m,2H),1.35-1.55(m,4H),1.15-1.35(m,2H)。
实施例41
5-氯-2-(2-环丁氧基-4-氟苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺41
Figure PCTCN2020070186-appb-000098
采用实施例35的合成路线，将第一步原料氘代碘甲烷替换为化合物溴代环丁烷，制得标题化合物41(110mg)。
MS m/z(ESI):498.0[M+1]
1H NMR(400MHz,DMSO-d 6):δ12.87(s,1H),11.02(s,1H),8.06(s,1H),7.94(s,1H),7.29-7.23(m,2H),7.09(s,1H),6.95-6.92(m,1H),6.92-6.83(m,1H),4.73-4.70(m,1H),2.37-2.33(m,2H),1.79-1.72(m,2H),1.68-1.52(m,2H)。
实施例42
5-氯-2-(4-氟-2-异丙基苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺42
Figure PCTCN2020070186-appb-000099
采用实施例35的合成路线，将第一步原料氘代碘甲烷替换为化合物碘代异丙烷，制得标题化合物42(100mg)。
MS m/z(ESI):485.9[M+1]
1H NMR(400MHz,DMSO-d 6):δ12.87(s,1H),11.00(s,1H),8.05(s,1H),7.95(s,1H),7.32-7.16(m,3H),7.01(s,1H),6.86-6.82(m,1H),4.67-4.62(m,1H),1.08(s,3H),1.06(s,3H)。
实施例43
2-(2-溴-4-氟苯氧基)-5-氯-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺43
Figure PCTCN2020070186-appb-000100
采用实施例11的合成路线，将第三步原料2-甲氧基-4-氟苯酚替换为2-溴-4-氟苯酚，制得标题化合物43(100mg)。
MS m/z(ESI):505.7[M+1]
1H NMR(400MHz,DMSO-d 6)δ12.86(s,1H),11.08(s,1H),8.14(s,1H),7.90(d,1H),7.75(dd,1H),7.36-7.26(m,3H),7.17(s,1H)。
实施例44
5-氯-2-(4-氟-2-(甲基-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44
Figure PCTCN2020070186-appb-000101
第一步
4-氟-1-甲氧基-2-(甲基-d 3)苯44b
将化合物1-氟-4-甲氧基苯(5g,39.6mmol,韶远科技(上海)有限公司)溶于四氢呋喃(50mL)，冷却至-10℃，滴加正丁基锂(2.5M,43.7mmol,17.5mL)。自然升温至室温反应1小时。冰浴冷却下，缓慢滴加碘甲烷-d3(5.8g,40mmol,韶远科技(上海)有限公司)，室温反应2小时。缓慢加入水(50mL)，乙酸乙酯萃取(20mL×3)。合并有机相，用无水硫酸钠干燥，过滤，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44b(1.5g)，产率：26％。
1H NMR(400MHz,CDCl 3)δ6.86-6.85(m,2H),6.73-6.69(m,1H),3.78(s,3H)。
第二步
4-氟-2-(甲基-d 3)苯酚44c
将化合物44a(1.5g,10.5mmol)加入二氯甲烷(30mL)，室温滴加三溴化硼的二氯甲烷溶液(1M,21.2mmol,21.2mL)，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A纯化，得到标题化合物44c(900mg)，产率：67％。
第三步
5-氯-2-(4-氟-2-(甲基-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44
将化合物11b(100mg,0.3mmol)，化合物44c(39mg,0.3mmol)和碳酸铯(100 mg,0.33mmol)加入N-甲基吡咯烷酮(2mL)中，60℃反应过夜。冷却，向反应液中加入乙酸乙酯(150mL)，水洗(50mL×3)。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用高效液相色谱制备(Waters 2767-SQ Detecor2，洗脱体系：碳酸氢铵，水，乙腈)纯化，得到标题化合物44(21mg)，产率：16％。
MS m/z(ESI):445.0[M+1]
1H NMR(400MHz,DMSO-d 6)δ8.09(s,1H),7.89-7.88(d,1H),7.23-7.21(d,1H),7.18-7.18(dd,1H),7.13(m,1H),7.10-7.08(m,2H)
实施例45
5-氯-2-(2-氯-4-氟苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺45
Figure PCTCN2020070186-appb-000102
采用实施例11的合成路线，将第三步原料2-甲氧基-4-氟苯酚替换为2-氯-4-氟苯酚，制得标题化合物45(40mg)。
MS m/z(ESI):461.8[M+1]
1H NMR(400MHz,DMSO-d 6)δ12.87(s,1H),11.08(s,1H),8.14(s,1H),7.89(d,1H),7.64(dd,1H),7.33-7.26(m,3H),7.17(s,1H)。
实施例46
5-氯-2-(2,4-二氟苯氧基)-N-(6-氧代-1,6-二氢哒嗪-4-基)-4-(三氟甲基)苯甲酰胺46
Figure PCTCN2020070186-appb-000103
采用实施例11的合成路线，将第三步原料2-甲氧基-4-氟苯酚替换为2,4-二氟苯酚，制得标题化合物46(70mg)。
MS m/z(ESI):445.8[M+1]
1H NMR(400MHz,DMSO-d 6)δ12.87(s,1H),11.10(s,1H),8.12(s,1H),7.89(d,1H),7.53-7.47(m,1H),7.38-7.32(m,2H),7.18-7.12(m,2H)。
生物学评价
以下结合测试例进一步描述解释本公开，但这些实施例并非意味着限制本公开的范围。
测试例1、本公开化合物对Nav1.8抑制活性的测定
实验的目的是为了调查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1。
表1 本公开化合物对Nav1.8通道活性抑制的IC 50
Figure PCTCN2020070186-appb-000104
Figure PCTCN2020070186-appb-000105
结论：本公开中的化合物对Nav1.8通道活性具有明显的抑制效果。
药代动力学评价
测试例2、本公开化合物的药代动力学测试
1、摘要
以大鼠为受试动物，应用LC/MS/MS法测定了大鼠灌胃给予实施例2化合物、实施例11化合物、实施例12化合物、实施例15化合物、实施例31化合物和实施例33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11化合物、实施例12化合物、实施例15化合物、实施例31化合物和实施例33化合物。
2.2试验动物
健康成年SD大鼠24只，雌雄各半，平均分成6组，每组4只，购自上海杰思捷实验动物有限公司。
2.3药物配制
称取一定量药物，加5％DMSO、5％tween 80和90％生理盐水配制成0.2mg/mL无色澄明溶液。
2.4给药
SD大鼠禁食过夜后灌胃给药，给药剂量均为2.0mg/kg，给药体积均为10.0 mL/kg。
3、操作
大鼠灌胃给药实施例2化合物、实施例11化合物、实施例12化合物、实施例15化合物、实施例31化合物和实施例33化合物，于给药前及给药后0.5，1.0，2.0，4.0，6.0，8.0，11.0，24.0小时由眼眶采血0.2mL，置于肝素化试管中，4℃、10000转/分钟离心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灌胃给药后大鼠血浆中的待测化合物含量：取给药后各时刻的大鼠血浆25μL，加入内标溶液30μL，乙腈175μL，涡旋混合5分钟，离心10分钟(3700转/分钟)，血浆样品取上清液0.5μL进行LC/MS/MS分析。
4、药代动力学参数结果
本公开化合物的药代动力学参数如下：
Figure PCTCN2020070186-appb-000106
结论：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。

Claims (20)

  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 PCTCN2020070186-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，所述芳基或杂芳基任选与环烷基或杂环基稠合；
    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、氘代烷氧基、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、氘代烷基、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；
    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选自苯基、
    Figure PCTCN2020070186-appb-100002
    和吡啶基。
  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M选自O原子、CH 2和S原子。
  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 PCTCN2020070186-appb-100003
    其中：
    R 1、R 2、R 3、n、s和t如权利要求1中所定义。
  5. 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 PCTCN2020070186-appb-100004
    其中：
    M选自O原子、CH 2和S原子；
    R 1a为卤素；
    R 1b选自卤素、烷基、烷氧基、卤代烷基和卤代烷氧基；且
    R 2、R 3、s和t如权利要求1中所定义。
  6. 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、卤代烷基和卤代烷氧基。
  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，其中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、羟基、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、氘代C 1-6烷基、C 1-6烷氧基、氘代C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基、C 3-6环烷基和C 3-6环烷基氧基；更优选地，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烷氧基和氘代C 1-6烷氧基。
  8. 根据权利要求1至7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s为2。
  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 PCTCN2020070186-appb-100005
    其中：
    R 1a为卤素；
    R 1b选自卤素、烷基、烷氧基、卤代烷基和卤代烷氧基；
    R 2a为烷氧基或氘代烷氧基；
    R 2b选自氢原子、卤素、烷基、烷氧基和卤代烷氧基；且
    R 3和t如权利要求1中所定义。
  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，其中所述化合物选自：
    Figure PCTCN2020070186-appb-100006
    Figure PCTCN2020070186-appb-100007
    Figure PCTCN2020070186-appb-100008
  12. 一种通式(IA)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 PCTCN2020070186-appb-100009
    其中：
    X为卤素；且
    环A、M、R 1、R 2、R 3、n、s和t如权利要求1中所定义。
  13. 根据权利要求12所述的通式(IA)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 PCTCN2020070186-appb-100010
    Figure PCTCN2020070186-appb-100011
  14. 一种通式(IB)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 PCTCN2020070186-appb-100012
    其中：
    Y为卤素；且
    R 1、R 3、n和t如权利要求1中所定义。
  15. 根据权利要求14所述的通式(IB)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 PCTCN2020070186-appb-100013
  16. 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，所述方法包括：
    Figure PCTCN2020070186-appb-100014
    由通式(IA)化合物反应得到通式(I)化合物；
    其中：
    X为卤素；且
    环A、M、R 1、R 2、R 3、n、s和t如权利要求1中所定义。
  17. 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，所述方法包括：
    Figure PCTCN2020070186-appb-100015
    通式(IB)化合物和通式(IC)化合物反应得到通式(I)化合物；
    其中：
    Y为卤素；且
    环A、M、R 1、R 2、R 3、n、s和t如权利要求1中所定义。
  18. 一种药物组合物，其含有根据权利要求1至11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。
  19. 根据权利要求1至11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18所述的药物组合物在制备抑制受试者电压门控钠离子通道的药物中的用途，优选地，所述的电压门控钠离子通道为Na V1.8。
  20. 根据权利要求1至11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18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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CN113277942A (zh) * 2021-05-25 2021-08-20 都创(上海)医药开发有限公司 一种基于微通道反应技术快速制备5-氯-2-氟-4-(三氟甲基)苯甲酸的方法
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WO2023205463A1 (en) 2022-04-22 2023-10-26 Vertex Pharmaceuticals Incorporated Heteroaryl compounds for the treatment of pain
WO2023205468A1 (en) 2022-04-22 2023-10-26 Vertex Pharmaceuticals Incorporated Heteroaryl compounds for the treatment of pain
WO2023205778A1 (en) 2022-04-22 2023-10-26 Vertex Pharmaceuticals Incorporated Heteroaryl compounds for the treatment of pain
WO2023205465A1 (en) 2022-04-22 2023-10-26 Vertex Pharmaceuticals Incorporated Heteroaryl compounds for the treatment of pain
WO2023207949A1 (zh) * 2022-04-25 2023-11-02 中国科学院上海药物研究所 并环类化合物及其应用
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