WO2020192553A1 - Dérivé de formamide benzohétérocyclique substitué par sulfonyle, son procédé de préparation et son utilisation médicale - Google Patents

Dérivé de formamide benzohétérocyclique substitué par sulfonyle, son procédé de préparation et son utilisation médicale Download PDF

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WO2020192553A1
WO2020192553A1 PCT/CN2020/080216 CN2020080216W WO2020192553A1 WO 2020192553 A1 WO2020192553 A1 WO 2020192553A1 CN 2020080216 W CN2020080216 W CN 2020080216W WO 2020192553 A1 WO2020192553 A1 WO 2020192553A1
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compound
alkyl
ring
pharmaceutically acceptable
stereoisomer
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周福生
谢婧
黄栋
兰炯
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Yangtze River Pharmaceutical Group Co Ltd
Shanghai Haiyan Pharmaceutical Technology Co Ltd
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Yangtze River Pharmaceutical Group Co Ltd
Shanghai Haiyan Pharmaceutical Technology Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the invention belongs to the field of medical technology. Specifically, the present invention particularly relates to a sulfonyl-substituted benzoheterocyclic carboxamide derivative, a preparation method thereof, and application as a sodium ion channel (especially Nav1.7) inhibitor, and a pharmaceutical composition prepared therefrom And medicinal composition.
  • Tarantula venom peptide Pro-TX-II is a potent Nav1.7 inhibitor (Schmalhofer et al., Molecular Pharmacology 2008, 74, 1476-1484).
  • a series of benzazepine Nav1.7 blockers have been described to show activity in preclinical pharmacological models of pain (Williams et al., Biochemistry, 2007, 46(50), 14693-14703; McGowan et al., Anesth Analg , 2009, 109, 951-958).
  • Amino-thiazoles and amino-pyridines have been described as Nav1.7 inhibitors (WO2007109324), and isoxazoles are described as Nav1.7 inhibitors (WO2009010784).
  • CIP congenital analgesia
  • Nav1.7 (PN1, SCN9A) VGSC is sensitive to the blocking of tetrodotoxin, which is mainly expressed in peripheral sympathetic neurons and sensory neurons.
  • the SCN9A gene has been replicated in a variety of species (including humans, rats, and rabbits), and shows that the amino acids between human and rat genes have about 90% identity.
  • Nav1.7 plays an important role in a variety of pain states (including acute, chronic, inflammatory and/or neuropathic pain).
  • Nav1.7 protein accumulates in neuromas, Especially neuromas that cause pain.
  • Mutations that increase the function of Nav1.7 have been thought to involve primary erythematous limb pain (a disease characterized by burning and inflammation of the limbs), and sudden extreme pain.
  • the reported results of non-selective sodium channel blockers lidocaine and mexiletine can alleviate the symptoms of hereditary erythematous limb pain, and carbamazepine can effectively reduce the number and severity of PEPD attacks are consistent with the above observations .
  • Nav1.7 is specifically expressed in DRG sensory neurons but not in other tissues such as cardiomyocytes and central nervous system, the development of its specific blocker for the treatment of chronic pain may not only improve the efficacy, but also greatly reduce side effects. And the selective inhibitor of Nav1.7 ion channel can be used for almost all kinds of pain treatment.
  • NaV1.5 and Nav1.2 which are members of the protein family, are also important ion-type channels.
  • NaV1.5 is mainly expressed in cardiomyocytes (Raymond, CK, etc., op.cit.), including atria, The ventricle, sinoatrial node, atrioventricular node and heart Purkinje fibers.
  • the rapid ascent of the action potential of the heart and the rapid pulse conduction through the heart tissue are due to the opening of NaV1.5.
  • Abnormal function of NaV1.5 can lead to the formation of a variety of arrhythmias.
  • Human NaV1.5 mutations cause a variety of arrhythmia syndromes, including, for example, long QT3 (LQT3), Brugada syndrome (BS), inherited cardiac conduction defects, sudden death syndrome (SUNDS), and sudden infant death Syndrome (SIDS) (Liu, H. et al., Am. J. Pharmacogenomics (2003), 3(3): 173-9).
  • LQT3 long QT3
  • BS Brugada syndrome
  • SUNDS sudden death syndrome
  • SIDS sudden infant death Syndrome
  • NaV1.2 is highly expressed in the brain (Raymond, C.K., et al., J. Biol. Chem. (2004), 279(44):46234-41) and is important for normal brain function. Therefore, inhibiting the Nav1.2 channel will produce inhibitory toxicity to the brain.
  • the Nav1.7 ion channel is an important target for the development of non-addictive analgesics. It is necessary to develop an inhibitor with the Nav1.7 ion channel highly selective and with good pharmacokinetic characteristics.
  • the purpose of the present invention is to provide a selective inhibitor of Nav1.7 ion channel and its application in medicine.
  • the first aspect of the present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof:
  • R 0 is C 1-10 alkyl (preferably C 1-8 alkyl, more preferably C 1-3 alkyl) or NR a0 R b0 ;
  • R 1 , R 2 , and R 3 are each independently hydrogen, halogen (preferably fluorine or chlorine), C 1-10 alkyl, halogenated C 1-10 alkyl, C 1-10 alkoxy or C 3- 8 cycloalkyl;
  • R 4 , R 5 , and R 6 are each independently hydrogen, halogen (preferably fluorine or chlorine), C 1-10 alkyl, halogenated C 1-10 alkyl, -O-(CH 2 ) n -R a ;
  • L is CH 2 ;
  • Z 1 is N;
  • Z 2 is N;
  • Z 3 is CR c ;
  • Z 4 is N or CR d ;
  • R a is: hydrogen, C 1-10 alkyl, halogenated C 1-10 alkyl, NR a0 R b0 , C 3- which is unsubstituted or substituted with 1, 2 or 3 C 1-10 alkyl 8 -cycloalkyl, or unsubstituted or 4- to 6-membered saturated monocyclic heterocyclic ring substituted with 1, 2 or 3 C 1-10 alkyl groups;
  • R c and R d are each independently hydrogen, C 1-10 alkyl, halogenated C 1-10 alkyl, or C 3-8 cycloalkyl;
  • n 0, 1, 2 or 3;
  • R a0 and R b0 are each independently hydrogen or C 1-8 alkyl (preferably C 1-3 alkyl, more preferably methyl).
  • the 4- to 6-membered saturated monocyclic heterocycle is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine , Thiomorpholine, thiomorpholine-1,1-dioxide or tetrahydropyran.
  • R 0 is methyl
  • R 6 is hydrogen, halogen (preferably fluorine or chlorine) or -O- (CH 2) n -R a , wherein R a is methyl, ethyl, isopropyl, methyl-substituted ⁇ cyclopropyl or trifluoromethyl.
  • R 6 is halogen (preferably fluorine or chlorine) or -O- (CH 2) n -R a , wherein R a is trifluoromethyl, n is 0.
  • R 5 is halogen (preferably fluorine or chlorine).
  • R 4 is hydrogen
  • Z 4 is N or CH.
  • Z 4 is CH.
  • Z 4 is N.
  • R 1 , R 2 , and R 3 are each independently hydrogen or halogen (preferably fluorine or chlorine).
  • R 1 , R 2 , and R 3 are each independently hydrogen, fluorine or chlorine.
  • R 1 is hydrogen, chlorine or fluorine; R 2 and R 3 are hydrogen.
  • R c is hydrogen, C 1-10 alkyl or C 3-8 cycloalkyl.
  • R c is methyl or cyclopropyl.
  • Z 4 is N or CR d
  • R d is hydrogen or halogen (preferably fluorine or chlorine).
  • the compound is a compound selected from the following group:
  • the second aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof; and pharmacy Acceptable carrier.
  • the third aspect of the present invention provides the compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, or the pharmaceutical composition according to the second aspect of the present invention.
  • the disease or condition is selected from pain, depression, cardiovascular disease, respiratory system disease, mental disease or a combination thereof.
  • the disease or condition is selected from HIV-related pain, HIV treatment-induced neuropathy, trigeminal neuralgia, post-herpetic neuralgia, acute pain, heat sensitivity, sarcoidosis, bowel disease Acute syndrome, g-Rohn's disease, pain associated with multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, bone and joint Inflammation, atherosclerosis, sudden dystonia, myasthenia syndrome, myotonia, malignant hyperthermia, cystic fibrosis, pseudo-aldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety , Schizophrenia, sodium channel toxin-related disorders, familial erythematous limb pain, primary erythematous limb pain, familial rectal pain, cancer, epilepsy, local and general tonic seizures, restless legs syndrome, Arrhythmia,
  • the pain is selected from neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, postoperative pain, birth pain, childbirth pain, toothache, chronic pain, Persistent pain, peripheral-mediated pain, central-mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, peripheral nerve injury, trigeminal neuralgia, postherpetic neuralgia, acute Pain, familial erythematous limb pain, primary erythematous limb pain, familial rectal pain or fibromyalgia or a combination thereof.
  • the fourth aspect of the present invention provides a method for treating a mammalian disease or condition, the method comprising administering to a subject in need (such as a mammal) a therapeutically effective amount of the compound according to the first aspect of the present invention, or a pharmacologically Acceptable salts, solvates, stereoisomers or prodrugs, or the pharmaceutical composition according to the second aspect of the invention.
  • the present inventors unexpectedly discovered that the sulfonyl-substituted benzoheterocyclic carboxamide derivatives of the present invention have high inhibitory activity against Nav1.7, and are expected to be developed for the treatment of extensive pain drug. On this basis, the inventor completed the present invention.
  • C 1-10 alkyl refers to linear and branched saturated aliphatic hydrocarbon groups containing 1 to 10 carbon atoms, as defined below; more preferably C 1-8 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-methyl Propyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3- Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-
  • C 1-10 alkoxy refers to -O-(C 1-10 alkyl), where the definition of alkyl is as described above.
  • a C 1-8 alkoxy group is preferred, a C 1-6 alkoxy group is more preferred, and a C 1-3 alkoxy group is most preferred.
  • Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentoxy and the like.
  • C 3-8 cycloalkoxy refers to -O-(C 3-8 cycloalkyl), wherein cycloalkyl is defined as described above. Preferred is C 3-6 cycloalkoxy. Non-limiting examples include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • halo refers to the replacement of one or more (eg, 1, 2, 3, 4, or 5) hydrogens in a group with halogen.
  • halo C 1-10 alkyl means that an alkyl group is substituted with one or more (such as 1, 2, 3, 4, or 5) halogens, where the definition of alkyl is as described above. It is preferably a halogenated C 1-8 alkyl group, more preferably a halogenated C 1-6 alkyl group, and most preferably a halogenated C 1-3 alkyl group.
  • halogenated C 1-10 alkyl groups include (but are not limited to) monochloroethyl, dichloromethyl, 1,2-dichloroethyl, monobromoethyl, monofluoroethyl, monofluoromethyl, Difluoromethyl, trifluoromethyl, etc.
  • halogenated C 1-10 alkoxy means that the alkoxy group is substituted with one or more (such as 1, 2, 3, 4, or 5) halogens, wherein the definition of alkoxy is as described above. It is preferably a halogenated C 1-8 alkoxy group, more preferably a halogenated C 1-6 alkoxy group, and most preferably a halogenated C 1-3 alkoxy group. Including (but not limited to) trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy and the like.
  • halo C 3-8 cycloalkyl refers to a cycloalkyl group substituted with one or more (such as 1, 2, 3, 4, or 5) halogens, wherein the definition of cycloalkyl is as described above. Preferably, it is a halogenated C 3-6 cycloalkyl group. Including (but not limited to) trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl and the like.
  • deuterated C 1-8 alkyl refers to an alkyl group substituted with one or more (such as 1, 2, 3, 4, or 5) deuterium atoms, where the definition of the alkyl group is as described above. It is preferably a deuterated C 1-6 alkyl group, and more preferably a deuterated C 1-3 alkyl group. Examples of deuterated C 1-20 alkyl groups include (but are not limited to) mono-deuterated methyl, mono-deuterated ethyl, di-deuterated methyl, di-deuterated ethyl, tri-deuterated methyl, tri-deuterated ethyl Base etc.
  • a bond means that two groups connected by it are connected by a covalent bond.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon group
  • C 3-8 cycloalkyl refers to a cyclic hydrocarbon group containing 3 to 8 carbon atoms, which may preferably be C 3-6 Cycloalkyl, similar in definition; non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl Group, cycloheptatrienyl, cyclooctyl, etc., preferably cyclopropyl, cyclopentyl, and cyclohexenyl.
  • spirocyclic ring refers to a polycyclic group that shares one carbon atom (called a spiro atom) between single rings. These can contain one or more double bonds, but none of the rings have fully conjugated ⁇ electrons. system. According to the number of rings, spiro rings are classified into double spiro rings or multi spiro rings, preferably double spiro rings. More preferably, it is preferably a 4-membered/5-membered, 5-membered/5-membered or 5-membered/6-membered bispiro ring. E.g:
  • spiro heterocyclic ring refers to a polycyclic hydrocarbon sharing one atom (called a spiro atom) between single rings, wherein one or two ring atoms are selected from nitrogen, oxygen or S(O)n (where n is an integer 0 to 2) of heteroatoms, the remaining ring atoms are carbon. These can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. According to the number of rings, spiro heterocycles are classified into dispiro heterocycles or polyspiro heterocycles, and dispiro heterocycles are preferred. More preferably, it is a 4-membered/5-membered, 5-membered/5-membered or 5-membered/6-membered bispiro heterocyclic ring. E.g:
  • bridged ring refers to a polycyclic group that shares two or more carbon atoms.
  • the shared carbon atoms are called bridgehead carbons.
  • the two bridgehead carbons can be a carbon chain or a bond. , Called the bridge. These can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. Preferably it is a double ring or a triple ring bridged ring.
  • bridged heterocycle refers to a polycyclic group that shares two or more atoms, where one or more ring atoms are selected from nitrogen, oxygen, or S(O) n (where n is an integer from 0 to 2 ), the remaining ring atoms are carbon. These can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably a bicyclic or tricyclic bridged heterocyclic ring. E.g:
  • 8 to 10 membered bicyclic ring refers to a bridged ring containing two rings containing 8 to 10 ring atoms.
  • the bicyclic ring may be a saturated full carbon bicyclic ring or a partially unsaturated full carbon bicyclic ring, and an 8 to 10 membered bicyclic ring Examples include (but are not limited to):
  • 8 to 10 membered bicyclic heterocyclic ring refers to a two-ring bridged heterocyclic ring containing 8 to 10 ring atoms, wherein 1, 2, 3, 4 or 5 ring carbon atoms are selected from nitrogen , Oxygen or sulfur heteroatoms.
  • 8- to 10-membered biheterocycles include, but are not limited to, tetrahydroquinoline rings, tetrahydroisoquinoline rings, decahydroquinoline rings, and the like.
  • C 6-10 aryl and C 6-10 aryl ring are used interchangeably, and both refer to all-carbon monocyclic or fused polycyclic rings with a conjugated ⁇ -electron system (that is, sharing adjacent The ring) group of a carbon atom pair refers to an aryl group containing 6 to 10 carbon atoms; phenyl and naphthyl are preferred, and phenyl is more preferred.
  • amino refers to NH 2
  • cyano refers to the CN
  • Niro refers to NO 2
  • benzyl refers to -CH 2 - phenyl
  • carboxy Refers to -C(O)OH
  • acetyl refers to -C(O)CH 3
  • hydroxymethyl refers to -CH 2 OH
  • hydroxyethyl refers to -CH 2 CH 2 OH or -CHOHCH 3
  • Hydroxy refers to -OH
  • thiol refers to SH
  • the structure of "cyclopropylene” is:
  • heteroaryl ring and “heteroaryl” are used interchangeably and refer to having 5 to 10 ring atoms, preferably 5 or 6 membered monocyclic heteroaryl or 8 to 10 membered bicyclic heteroaryl ;
  • the ring array shares 6, 10, or 14 ⁇ electrons; and in addition to carbon atoms, there are groups with 1 to 5 heteroatoms.
  • Heteroatom refers to nitrogen, oxygen, or sulfur.
  • 3 to 7-membered (4 to 7-membered) saturated or partially unsaturated monocyclic ring refers to a saturated or partially unsaturated, all-carbon monocyclic ring containing 3 to 7 ring atoms.
  • 3 to 7-membered saturated or partially unsaturated monocyclic rings include (but are not limited to): cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclopentenyl ring, cyclohexyl ring, cyclohexenyl ring, ring Hexadienyl ring, cycloheptyl ring, cycloheptatrienyl ring, cyclooctyl ring, etc.
  • 5- to 6-membered monocyclic heteroaryl ring and “5- to 6-membered monocyclic heteroaryl” are used interchangeably, and both refer to a mono-heteroaryl ring containing 5 to 6 ring atoms
  • Examples include (but are not limited to): thiophene ring, N-alkane pyrrole ring, furan ring, thiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2,3-triazole Ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, 1,2, 3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole
  • 8 to 10 membered bicyclic heteroaryl ring and “8 to 10 membered bicyclic heteroaryl ring” are used interchangeably, and both refer to a bicyclic heteroaryl ring containing 8 to 10 ring atoms, for example including (But not limited to): benzofuran, benzothiophene, indole, isoindole, quinoline, isoquinoline, indazole, benzothiazole, benzimidazole, quinazoline, quinoxaline, cinnoline, Phthalazine, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8 -Naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphth
  • 4- to 6-membered saturated monocyclic heterocyclic ring means that 1, 2, or 3 carbon atoms in a 4- to 6-membered monocyclic ring are selected from nitrogen, oxygen or S(O) t (where t is an integer 0
  • the heteroatom to 2 is substituted, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon; preferably 4 to 6 members, more preferably 5 to 6 members.
  • Examples of 4- to 6-membered saturated monocyclic heterocycles include (but are not limited to) azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, pyrroline, oxazolidine, piperazine , Dioxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, etc.
  • substituted refers to one or more hydrogen atoms in the group, preferably 1 to 5 hydrogen atoms are independently substituted with a corresponding number of substituents, more preferably 1 to 3 hydrogen atoms are independently substituted with each other Ground is substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort.
  • an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • any group herein may be substituted or unsubstituted.
  • the substituents are preferably 1 to 5 or less groups independently selected from CN, halogen, C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 Alkyl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkyl (preferably halogenated C 1- 6 alkyl, more preferably halogenated C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), C 1-8 alkyl substituted amino, amino, halogenated C 1-8 alkyl substituted amino, acetyl Group, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, nitro, C 6-10 ary
  • the “pharmaceutically acceptable salt” includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic acid or an organic acid that can retain the biological effectiveness of the free base without other side effects.
  • “Pharmaceutically acceptable base addition salts” include, but are not limited to, salts of inorganic bases such as sodium, potassium, calcium and magnesium salts. Including but not limited to salts of organic bases, such as ammonium salt, triethylamine salt, lysine salt, arginine salt and the like.
  • solvate refers to a complex formed by the compound of the present invention and a solvent. They either react in a solvent or precipitate or crystallize out of the solvent. For example, a complex formed with water is called a "hydrate”. Solvates of compounds of formula (I) fall within the scope of the present invention.
  • the compound represented by formula (I) of the present invention may contain one or more chiral centers and exist in different optically active forms.
  • a compound contains a chiral center
  • the compound contains enantiomers.
  • the present invention includes these two isomers and mixtures of isomers, such as racemic mixtures. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography.
  • diastereomers may exist.
  • the present invention includes the resolved optically pure specific isomers and mixtures of diastereomers. Diastereoisomers can be resolved by methods known in the art, such as crystallization and preparative chromatography.
  • the present invention includes prodrugs of the aforementioned compounds.
  • Prodrugs include known amino protecting groups and carboxyl protecting groups, which are hydrolyzed under physiological conditions or released through enzymatic reactions to obtain the parent compound.
  • Specific preparation methods of prodrugs please refer to (Saulnier, MG; Frennesson, DB; Deshpande, MS; Hansel, SB and Vysa, DMBioorg. Med. Chem Lett. 1994, 4, 1985-1990; and Greenwald, RB; Choe, YH; Conover, CD; Shum, K.; Wu, D.; Royzen, MJ Med. Chem. 2000, 43, 475.).
  • the compound of the present invention or its pharmaceutically acceptable salt, or its solvate, or its stereoisomer, or prodrug can be administered in a suitable dosage form with one or more pharmaceutically acceptable carriers.
  • dosage forms are suitable for oral, rectal, topical, intraoral, and other parenteral administration (e.g., subcutaneous, intramuscular, intravenous, etc.).
  • dosage forms suitable for oral administration include capsules, tablets, granules, and syrups.
  • the compounds of the present invention contained in these formulations may be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water emulsions, and the like.
  • the above-mentioned dosage forms can be prepared from the active compound and one or more carriers or excipients through general pharmaceutical methods.
  • the above-mentioned carrier needs to be compatible with the active compound or other excipients.
  • commonly used non-toxic carriers include but are not limited to mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose and the like.
  • Carriers for liquid preparations include water, physiological saline, aqueous dextrose, ethylene glycol, polyethylene glycol, and the like.
  • the active compound can form a solution or a suspension with the aforementioned carriers.
  • composition of the present invention is formulated, quantified and administered in a manner that conforms to medical practice standards.
  • the "therapeutically effective amount" of the compound administered is determined by factors such as the specific condition to be treated, the individual to be treated, the cause of the condition, the target of the drug, and the mode of administration.
  • therapeutically effective amount refers to the amount of the compound of the present invention that will cause an individual's biological or medical response, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease, etc. the amount.
  • the therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof contained in the pharmaceutical composition of the present invention is preferably 0.1 mg-5 g/kg (body weight).
  • pharmaceutically acceptable carrier refers to a non-toxic, inert, solid, semi-solid substance or liquid filling machine, diluent, encapsulating material or auxiliary preparation or any type of excipient, which is compatible with the patient and most It is preferably a mammal, more preferably a human, which is suitable for delivering the active agent to the target target without terminating the activity of the agent.
  • patient refers to an animal, preferably a mammal, and more preferably a human.
  • mammal refers to warm-blooded spinal mammals, including cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, rats, pigs, and humans.
  • treating refers to reducing, delaying progression, attenuating, preventing, or maintaining an existing disease or condition (e.g., cancer). Treatment also includes curing one or more symptoms of the disease or condition, preventing its development, or alleviating to a certain degree.
  • the compound of formula (I) of the present invention can be easily prepared by various synthetic operations according to the specific compound structure with reference to the exemplary preparation methods in the following examples, and these operations are well mastered by those skilled in the art.
  • the reagents and raw material compounds used in the preparation process are all commercially available, or those skilled in the art can prepare them by referring to known methods according to the structure of different compounds designed.
  • the series of compounds of the invention have novel structures and high Nav1.7 inhibitory activity and Nav1.7 selective inhibitory activity.
  • the series of compounds of the present invention not only have obvious pharmacokinetic absorption effect and good bioavailability, but also have obvious metabolic stability, so they are expected to be developed into drugs for extensive pain treatment.
  • DMB 2,4-dimethoxybenzyl
  • THF tetrahydrofuran
  • EA ethyl acetate
  • PE petroleum ether
  • Ac 2 O acetic anhydride
  • NBS N-bromosuccinimide
  • DCM dichloromethane
  • AIBN azobisisobutyronitrile
  • Pd(dppf)Cl 2 is 1,1'-bis(diphenylphosphoferrocene]palladium dichloride
  • TFA is trifluoroacetic acid
  • TBSCl Is tert-butyldimethylchlorosilane
  • NCS N-chlorosuccinimide
  • DHP dihydropyran
  • LiAlH 4 is lithium aluminum hydride
  • PMB p-methoxybenzyl
  • LiHMDS di(tri Methylsilyl) lithium amide
  • Pd 2 (dba) 3 is tris(dibenzylideneacetone) dipall
  • room temperature refers to about 20-25°C.
  • Step a Add N-bromosuccinimide (3.15 g, 17.60 mmol) to a 50 ml acetonitrile solution of compound 2-a-1 (2 g, 16 mmol), and stir at room temperature for 4 hours. After the reaction is over, add sodium thiosulfate to wash, separate the organic phase, extract the aqueous phase with ethyl acetate, separate and combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, add petroleum ether to wash, filter, and dry the filter cake The compound 2-a-2 (2g) was obtained, which was directly used in the next reaction with a purity of 100% and a yield of 80%. MS m/z (ESI): 204[M+H] + .
  • Step b Add sodium nitrite (405 mg, 5.91 mmol) to 30 ml of acetic acid solution of compound 2-a-2 (1 g, 4.92 mmol), and stir at room temperature for 4 hours. After the reaction is over, add sodium hydroxide (50%) to adjust the pH to 7-8, separate the organic phase, extract with ethyl acetate, separate and combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 2-a -3 (1g), directly used in the next reaction, purity 100%, yield 80%, MS m/z (ESI): 215[M+H] + .
  • Step c To compound 2-a-3 (3g, 14mmol), 4-(bromomethyl)-2-chloro-1-(trifluoromethoxy)benzene (4.05g, 14mmol) in 60ml dimethylformaldehyde Cesium carbonate (10g, 30mmol) was added to the amide solution and stirred at room temperature for 4 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by Combi-flash column chromatography to obtain compound 2-a-4 (0.80g), which was directly used in the next reaction with a purity of 66% and a yield of 80%. MS m/ z(ESI): 423[M+H] + .
  • Step b Dissolve compound 6-a-3 (22.31g, 0.093mol) in acetic acid/toluene (500mL, 5% v/v) and add isoamyl nitrite (10.67g, 0.10mol) at 0°C, The reaction was stirred at 0°C for 1 hour. Potassium acetate (27.30g, 0.28mol) was added, the reaction was stirred at room temperature for 18 hours, 1 liter of saturated sodium chloride solution was added, extracted with ethyl acetate (3*1L), dried and spin-dried.
  • Step a Mix compound 7-a-1 (8g, 0.042mol) and aluminum trichloride (13.7g, 0.10mol) together, and stir at 60°C for 10 minutes. Then, acetyl chloride (4.90 g, 0.063 mol) was slowly added dropwise to the reaction system at 60°C, and after the addition, the reaction was stirred at 95°C for 6 hours. After the reaction, the system was cooled to -10°C, ice water (15g) was slowly added, extracted with ethyl acetate (3*100mL), dried and spin-dried to obtain a crude product (8g) of compound 7-a-2 as a yellow oil.
  • Step 1 Add sodium hydroxide (4N, 20ml) to 20ml of dioxane solution of compound 2-a (0.50g, 0.0012mol), and stir at room temperature for 1 to 2 hours. After the reaction was completed, hydrochloric acid (2N) adjusted the pH to 2 ⁇ 3, added ethyl acetate, separated the organic phase, washed with 25% brine, separated the organic phase, and concentrated under reduced pressure to obtain the crude compound 2-b (0.46g). MS m/z(ESI): 389.02[M+H]+
  • Step 2 Add DIPEA (N,N-diisopropylethylamine) (0.20g, 0.0016mol), HATU(2-(7) to 20ml dichloromethane solution of compound 2-b (0.25g, 0.00064mol) -Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate) (0.29g, 0.00077mol), methylsulfonamide (0.090g, 0.00095mol), room temperature Stir for 2 to 3 hours. After the reaction was completed, water was added, the organic phase was separated, and the solid was concentrated under reduced pressure to obtain 0.18 g of solid. After liquid phase separation and purification, solid compound Z-2 (38.65 mg) was obtained, with a yield of 12.9%. MS m/z(ESI): 466.7[M+H]+
  • Step 1 Compound 4-a (500mg, 2.58mmol), 4-(bromomethyl)-2-chloro-1-(trifluoromethoxy)benzene (745mg, 2.58mmol), cesium carbonate (1.68g, 5.16 mmol) in 10 ml of dimethylformamide solution, stirred at room temperature for 5 hours. After the reaction is over, pour into water, add dichloromethane for extraction, separate the organic phase, wash with water (4 ⁇ 20ml), separate the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. Purify by chromatography to obtain a white solid compound 4-b (754mg), directly used in the next reaction, purity 97%, MS m/z (ESI): 403[M+H] + .
  • Step 2 A mixture of compound 4-b (200 mg, 0.50 mmol) and lithium hydroxide (84 mg, 2 mmol) in 4 ml methanol and 1 ml aqueous solution was stirred at room temperature for 4 hours. At the end of the reaction, the reaction solution was concentrated under reduced pressure, water was added, and the pH was adjusted to 2 with hydrochloric acid, extracted with ethyl acetate, the combined organic phase was separated, washed with saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain white The solid compound 4-c (194 mg) was directly used in the next reaction with a purity of 100%. MS m/z (ESI): 389 [M+H] + .
  • Step 3 Compound 4-c (102mg, 0.26mmol), methylsulfonamide (24mg, 0.26mmol), HATU (2-(7-azobenzotriazole)-N, N, N', N' -Tetramethylurea hexafluorophosphate) (110 mg, 0.29 mmol), a mixture of triethylamine (54 mg, 0.53 mmol) in 3 ml of dichloromethane, stirred at room temperature for 4 hours.
  • Step 1 Compound 4-a (500mg, 2.58mmol), 4-(bromomethyl)-1,2-dichlorobenzene (619mg, 2.58mmol), cesium carbonate (1.68g, 5.15mmol) in 10ml dimethyl
  • the mixture of the formamide solution was stirred at room temperature for 4 hours. After the reaction is over, pour into water, extract with dichloromethane (2 ⁇ 30ml), separate and combine the organic phases, wash with water (4 ⁇ 20ml), separate the organic phase, wash with saturated brine (20ml), dry with anhydrous sodium sulfate, filter, and reduce the filtrate.
  • Step 2 Add lithium hydroxide (72 mg, 1.70 mmol) to compound 5-b (150 mg, 0.43 mmol) in 8 ml of methanol and 2 ml of water, and stir overnight at room temperature. After the reaction was completed, most of the methanol was concentrated under reduced pressure, 10ml of water was added, the mixture was adjusted to pH 3, filtered, the filter cake was washed with water, and dried to obtain a white solid compound 5-c (127mg), which was directly used in the next reaction with a purity of 94.1%. The yield was 88.2%. MS m/z (ESI): 339.0 [M+H] + .
  • Step 3 To compound 5-c (127mg, 0.38mmol), methylsulfonamide (36mg, 0.38mmol), triethylamine (76mg, 0.75mmol) in 5ml dichloromethane solution was added HATU (2-(7- Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate) (157mg, 0.41mmol), stirred at room temperature for 2 hours.
  • HATU 3-(7- Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • Step 1 Add 4-(bromomethyl)-1,2-dichlorobenzene (0.46g, 0.0019mmol), cesium carbonate to 10ml dimethylformamide solution of compound 6-a (0.4g, 0.0017mol) (1.42g, 0.0043mol), stir at room temperature for 2-4 hours. After the reaction is over, pour into water, extract with ethyl acetate, separate and combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product, which is purified by Combi-flash column chromatography to obtain a white solid compound 6 b (0.17g), used directly in the next reaction. MS m/z (ESI): 386.98 [M+H] + .
  • Step 2 Add sodium hydroxide (4N, 16ml) to the 16ml dioxane solution of compound 6-b (0.15g, 0.00038mol), and stir at room temperature for 2 hours. After the reaction is over, adjust the pH to 2 ⁇ 3 with hydrochloric acid (2N), add ethyl acetate, separate the organic phase, wash with saturated brine, separate the organic phase, and concentrate under reduced pressure to obtain crude compound 6-c (0.13g), which is used directly in the next step reaction.
  • Step 3 Add HATU (2-(7-azobenzotriazole)-N,N,N',N'-tetrazolium to compound 6-c (0.13g, 0.00034mol) in 5ml dichloromethane solution Methylurea hexafluorophosphate) (0.16g, 0.00042mol), methylsulfonamide (0.049g, 0.00052mol), DIPEA (N,N-diisopropylethylamine) (0.11g, 0.00087mol), 30 Stir at Celsius for 1 to 2 hours. After the reaction was completed, water was added, the organic phase was separated, and the solid was concentrated under reduced pressure to obtain 0.11 g of solid. After liquid phase separation and purification, solid compound Z-6 (12.15 mg) was obtained with a yield of 7.9%. MS m/z(ESI): 449.96[M+H] +
  • Step 1 Add iodine (3.05g, 12mmol) and potassium hydroxide (1g, 18mmol) to the 10ml dimethylformamide solution of compound 9-a (1.06g, 6mmol), and stir at room temperature for 2 hours. After the reaction is over, add ethyl acetate, wash with saturated sodium thiosulfate, separate and combine the organic phase, wash with saturated sodium bicarbonate, separate and combine the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product, which is purified by chromatography The yellow solid compound 9-b (1.30 g) was directly used in the next reaction. The yield was 72%, and the purity was 74%. MS m/z (ESI): 302.9 [M+H] + .
  • Step 3 To a mixed solution of compound 9-c (600mg, 1.56mmol) in 6ml toluene and 1ml water was added trimethylboroxine (300mg, 2.34mmol), cesium carbonate (1g, 3.12mmol), four three Palladium phenylphosphorus (60mg), under the protection of argon, stirred overnight at 120°C.
  • Step 4 Add 2ml of hydrochloric acid/dioxane to compound 9-d (200mg, 0.73mmol) and stir at 40°C for 3 hours. After the reaction was completed, it was cooled to room temperature, and the solvent was concentrated under reduced pressure to obtain a yellow solid compound 9-e (150 mg), which was directly used in the next reaction with a yield of 100%. MS m/z (ESI): 191 [M+H] + .
  • Step 5 Add 4-(bromomethyl)-2-chloro-1-(trifluoromethoxy)benzene (274mg) to the solution of compound 9-e (150mg, 0.79mmol) in 4ml of anhydrous dimethylformamide , 0.95mmol), cesium carbonate (520mg, 1.58mmol), stirred at room temperature for 3 hours.
  • Step 6 Add sodium hydroxide (50 mg, 1.26 mmol) to compound 9-f (250 mg, 0.63 mmol) in 2 ml methanol and 2 ml aqueous solution, and stir at room temperature for 2 hours. After the reaction is over, adjust the pH to 1 with hydrochloric acid (1N), extract with ethyl acetate, separate and combine the organic phases, wash with saturated brine, separate the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a yellow solid compound 9-g (170mg), directly used in the next reaction, purity 44%, yield 70%.
  • Step 7 To compound 9-g (100mg, 0.26mmol) in 2ml 1,2-dichloroethane, methylsulfonamide (30mg, 0.31mmol), HATU (2-(7-azobenzotriazole) -N,N,N',N'-tetramethylurea hexafluorophosphate) (150mg, 0.39mmol), diisopropylethylamine (93mg, 0.72mmol), 4-dimethylaminopyridine (4mg, 0.030 mmol), stirring at 60 degrees Celsius for 1 hour.
  • Step 1 Compound 7-a (150mg, 0.72mmol), 4-(bromomethyl)-2-chloro-1-(trifluoromethoxy)benzene (209mg, 0.72mmol), cesium carbonate (469mg, 1.44mmol) ) In 5 ml of anhydrous dimethylformamide solution, stirred at room temperature for 4 hours.
  • Step 2 A mixture of compound 11-b (100 mg, 0.24 mmol) and lithium hydroxide (41 mg, 0.96 mmol) in 4 ml methanol and 1 ml aqueous solution was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, added with water, adjusted to pH 2 with hydrochloric acid, filtered, and the filter cake was collected and dried to obtain a white solid compound 11-c (91 mg), which was directly used in the next reaction with a purity of 81.5% and a yield of 94% . MS m/z (ESI): 403.1 [M+H] + .
  • Step 3 Compound 11-c (106mg, 0.26mmol), methylsulfonamide (50mg, 0.53mmol), HATU (2-(7-azobenzotriazole)-N, N, N', N' -Tetramethylurea hexafluorophosphate) (100mg, 0.26mmol), diisopropylethylamine (68mg, 0.53mmol), 4-dimethylaminopyridine (4mg, 0.026mmol) in 3ml dimethylformamide The mixture was stirred at 60 degrees Celsius for 24 hours.
  • Patch voltage clamp electrophysiology can directly measure and quantify the current blocking of voltage-gated sodium channels (various Navs) and determine the time and voltage dependence of the blocking. It has been interpreted as the resting, opening and The binding difference of the inactivation state reflects the inhibitory or activating effect of the compound (Hille, B., Journal of General Physiology (1977), 69:497-515).
  • the representative compounds of the present invention are carried out using manual patch clamp experiments.
  • the purpose of this study is to use the manual patch clamp method to test the effect of compounds on the ion channel currents on stable cell lines transfected with specific ion channels.
  • the stable cell line CHO-hNav1.7 used was from Genionics.
  • the manual patch clamp experiment protocol is as follows:
  • the positive control drug and the test compound are first dissolved in 100% DMSO (Sigma-Aldrich, D2650, and configured as a stock solution of a certain concentration (100nM, 1000nM). Before the experiment, the above-mentioned stock solution is serially diluted with DMSO, and then extracellular The solution is further diluted to obtain a test solution of the required concentration. The final concentration of DMSO in the extracellular solution does not exceed 0.30%.
  • the clamping potential is set at V 1/2 of the corresponding channel, that is, about 50% of the channels are in an inactive state. Then apply voltage to -120mV for 50ms. Then it depolarizes to -10mV, draws sodium current for 20ms, and finally returns to the clamping potential.
  • This kind of stimulation program can also be called a channel state-dependent voltage stimulation program.
  • the other is a non-inactivation stimulation program, which keeps the clamping potential at -120mV, gives a voltage stimulation to -10mV, and elicits a sodium current for 20ms, and finally returns to the clamping potential. That is to say, under the condition of this kind of stimulation program, all the channels have not experienced inactivation state, but directly activated from the resting state.
  • the time interval of the above two voltage stimulation procedures is 10s.
  • the inhibitory effect of the compound is calculated by the current change before and after the addition of the drug, and the IC 50 value is obtained by fitting the Hill equation. If the compound shows a certain multiple difference in the channel effect under the above two different voltage stimuli, then the compound is state-dependent on the channel.
  • test the representative compound of the present invention has a higher inhibitory activity on Nav1.7 at both 100nM (%) and 1000nM (%) concentrations.
  • the test results show that the representative compound of the present invention has a higher inhibitory activity on Nav1.7 .

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Abstract

La présente invention concerne un dérivé de formamide benzohétérocyclique substitué par sulfonyle, son procédé de préparation et son utilisation médicale. De façon spécifique, l'invention concerne un composé de formule (I) ou un sel pharmaceutiquement acceptable, un stéréoisomère, un composé de solvate ou un promédicament de celui-ci, un procédé de préparation associé, et leur utilisation ; la définition de chaque groupe dans la formule étant détaillée dans la description. (I)
PCT/CN2020/080216 2019-03-22 2020-03-19 Dérivé de formamide benzohétérocyclique substitué par sulfonyle, son procédé de préparation et son utilisation médicale Ceased WO2020192553A1 (fr)

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PCT/CN2020/080450 Ceased WO2020192588A1 (fr) 2019-03-22 2020-03-20 Dérivé d'alkylsulfamoyl indazole carboxamide, son procédé de préparation et son utilisation pharmaceutique

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