WO2020199683A1 - 氮杂环取代的磺酰基苯甲酰胺衍生物、其制法与医药上的用途 - Google Patents

氮杂环取代的磺酰基苯甲酰胺衍生物、其制法与医药上的用途 Download PDF

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WO2020199683A1
WO2020199683A1 PCT/CN2019/128925 CN2019128925W WO2020199683A1 WO 2020199683 A1 WO2020199683 A1 WO 2020199683A1 CN 2019128925 W CN2019128925 W CN 2019128925W WO 2020199683 A1 WO2020199683 A1 WO 2020199683A1
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alkyl
compound
ring
pharmaceutically acceptable
stereoisomer
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French (fr)
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周福生
谢婧
赵金柱
黄栋
许峰
沈思达
兰炯
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上海海雁医药科技有限公司
扬子江药业集团有限公司
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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • 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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/44—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a carbon atom of an unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/31—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/08—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with a hetero atom directly attached to the ring nitrogen atom
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    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the field of medical technology. Specifically, the present invention particularly relates to a sulfonyl benzamide derivative substituted by a nitrogen heterocycle, a preparation method thereof, and application as a sodium ion channel (especially Nav1.7) inhibitor, and a pharmaceutical composition prepared therefrom And medicinal composition.
  • 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 or NR a0 R b0 ;
  • R 1 is an optionally substituted 5- to 6-membered monocyclic heteroaryl group or a C 6-10 aryl group; wherein the optional substitution refers to unsubstituted or substituted by 1, 2 or 3 substituents selected from the following group Substitution: halogen, C 1-10 alkyl, halogenated C 1-10 alkyl, C 1-10 alkoxy, halogenated C 1-10 alkoxy, C 3-10 cycloalkyl or -O-( CH 2) q -R a; wherein R a is hydrogen, C 1-10 alkyl, halo C 1-10 alkyl, substituted NR a0 R b0, C 3-8 cycloalkyl or optionally 4 to 6 Saturated single heterocyclic ring;
  • R 2 is hydrogen, hydroxyl, cyano or C 1-10 alkyl
  • R 3 , R 4 , R 5 , and R 6 are each independently hydrogen, halogen, C 1-10 alkyl, halogenated C 1-10 alkyl, C 1-10 alkoxy or C 3-8 cycloalkyl ;
  • L is a bond, O, NH, -(CH 2 ) p -or -O-(CH 2 ) p ;
  • n 0, 1 or 2;
  • n 1, 2 or 3;
  • p and q are each independently 1, 2 or 3;
  • R a0 and R b0 are each independently hydrogen or C 1-8 alkyl
  • 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.
  • the 5- to 6-membered monocyclic heteroaryl group is selected from: thiophene ring, N-alkylpyrrole ring, furan ring, thiazole ring, imidazole ring, oxazole ring, Pyrrole ring, pyrazole ring, triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring or pyrazine ring.
  • the C 6-10 aryl group is a phenyl group.
  • R 2 is hydrogen or C 1-10 alkyl.
  • R 3 , R 4 , R 5 , and R 6 are each independently hydrogen, halogen (preferably fluorine or chlorine) or C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl).
  • R 3 and R 6 are hydrogen.
  • R 3 and R 6 are hydrogen, and R 4 and R 5 are each independently hydrogen, halogen (preferably fluorine or chlorine) or C 3-8 cycloalkyl ( Preferably, it is C 3-6 cycloalkyl).
  • R 1 is optionally substituted pyridine or phenyl; wherein said optionally substituted refers to unsubstituted or substituted by 1, 2 or 3 selected from the following group Group substitution: halogen, C 1-10 alkyl, halogenated C 1-10 alkyl, C 1-10 alkoxy, halogenated C 1-10 alkoxy, C 3-10 cycloalkyl or -O- (CH 2 ) q -R a ; wherein Ra is a C 1-10 alkyl group or a halogenated C 1-10 alkyl group, and q is 1, 2 or 3.
  • L is O or -O-(CH 2 ) p , and p is 1, 2 or 3.
  • R 1 and R 2 are as defined above.
  • the compound in formula (I), is a compound selected from Examples 1-35.
  • 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 inventors unexpectedly discovered that the nitrogen heterocyclic ring substituted sulfonyl benzamide derivative of the present invention has a high inhibitory activity on Nav1.7, and is expected to be developed into a wide range of pain treatments. 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 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 bi-heterocyclic ring refers to a bridged heterocyclic ring containing two rings containing 8 to 10 ring atoms, in which 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 (for example, 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 different compound structures 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 invention have statistically significant effects of inhibiting cold stimulation hyperalgesia.
  • 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(diphenylphosphorferrocene]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 is di(tri Methylsilyl) lithium amide
  • Pd 2 (dba) 3 is tris(dibenzylideneacetone)
  • room temperature refers to about 20-25°C.
  • Step 1 Add z-1-1 (614mg, 3.05mmol, 1.0eq), 7mL 1,4-dioxane to a 50mL round bottom flask, add 4M HCl/1,4-dioxane dropwise at room temperature The ring solution (3 mL, 12 mmol, 3.93 eq) was stirred at room temperature overnight, and the solvent was removed by rotary evaporation to obtain a white solid z-1-2 (414 mg, 98.6%), which was directly used in the next reaction. MS m/z(ESI): N/A.
  • Step 2 Add 4-bromo-2-chloro-1-(trifluoromethoxy)benzene (206mg, 0.748mmol, 1.0eq), z-1-2 (152mg, 1.105mmol, 1.48eq) to the 50mL sealed tube ), Pd 2 dba 3 (66mg, 0.072mmol, 0.1eq), binap (90mg, 0.145mmol, 0.19eq), potassium tert-butoxide (253mg, 2.255mmol, 3.01eq) and 10mL 1,4-dioxane , Degas by bubbling with Ar 2 for 5 min, heating the oil bath to 90° C., stirring and reacting for 15 h.
  • Step 3 Add z-1-3 (54mg, 0.183mmol, 1.2eq), 3mL THF to a 50mL round bottom flask, place it in an ice bath to cool, add NaH (18mg, 60%, 0.45mmol, 2.96eq), After stirring for 0.5h, 1-a (41mg, 0.152mmol, 1.0eq) was added and stirred at room temperature overnight.
  • Add 20mL of water, adjust pH 5 to 6 with 1M HCl, extract with ethyl acetate (20mL x 2), combine the organic phases, dry with anhydrous sodium sulfate, filter and concentrate, and purify the residue with preparative high performance liquid chromatography to obtain white Solid Z-1 (16 mg, 19.3%).
  • Step 1 Add 3,4-dichlorobromobenzene (1g, 4.46mmol, 1.0eq), z-2-1 (977mg, 8.92mmol, 2eq), Pd 2 dba 3 (259mg, 0.45 mmol, 0.1eq), binap (280mg, 0.45mmol, 0.1eq), potassium tert-butoxide (1g, 8.92mmol, 2.0eq) and 20mL 1,4-dioxane, replaced with Ar 2 balloon three times and protected, The oil bath was heated to 100°C, and the reaction was stirred for 15h.
  • Step 2 Add z-2-2 (350mg, 1.6mmol), 15mL THF to a 100mL round bottom flask, place it in an ice bath to cool, slowly add NaH (200mg, 60%, 4.8mmol, 3eq), after the addition is complete The reaction was stirred under ice bath for 10 min, then z-2-3 (500 mg, 1.6 mmol, 1.0 eq) was added, and the reaction was stirred under ice bath for 1 h.
  • Step 3 Add z-2-4 (200mg, 0.39mmol, 1.0eq), cyclopropylboronic acid (67mg, 0.78mmol, 2eq), Pd 2 (dppf)Cl 2 (29mg, 0.04mmol) to a 100mL round bottom flask , 0.1eq), cesium carbonate (254mg, 0.78mmol, 2eq), 10mL 1,4-dioxane and 1mL water, replaced with Ar 2 balloon three times and protected, the oil bath was heated to 100°C, and the reaction was stirred for 15h.
  • Compounds Z-5 to Z-32 can be prepared according to the method in Example 2.
  • Step 1 Combine (R)-pyrrolidin-2-yl methanol (275mg, 2.723mmol), 4-bromo-2-chloro-1-(trifluoromethoxy)benzene (500mg, 1.815mmol), Pd2(dba )3 (164.8mg, 0.180mmol), BINAP (224.2mg, 0.36mmol), t-BuOK (407.3mg, 3.63mmol) were added to dry 1,4-dioxane (15ml), and the mixture was heated to 90°C After stirring overnight, the mixture was detected by LC-MS and concentrated under reduced pressure.
  • Step 2 Add (R)-(1-(3-chloro-4-(trifluoromethoxy)phenyl)pyrrolidin-2-yl)methanol (150mg, 0.508mmol) to DMF (5ml), Then NaH (61 mg, 1.524 mmol) was added, after stirring for a few minutes, 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (137 mg, 0.508 mmol) was added, and the mixture was stirred overnight.
  • Compounds Z-34 and Z-35 can be prepared according to the method in Example 33.
  • 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.

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Abstract

涉及氮杂环取代的磺酰基苯甲酰胺衍生物、其制法与医药上的用途。具体地，公开了式（I）化合物或其药学上可接受的盐、立体异构体、溶剂化合物或前药，及其制备方法和应用。

Description

氮杂环取代的磺酰基苯甲酰胺衍生物、其制法与医药上的用途 技术领域
本发明属于医药技术领域。具体地，本发明特别涉及一种氮杂环取代的磺酰基苯甲酰胺衍生物及其制备方法和作为钠离子通道(特别是Nav1.7)抑制剂的应用，以及由其制备的药物组合物和药用组合物。
背景技术
最近，英国的Cox等在Nature上首次报道了编码电压门控Nav1.7通道的SCN9A基因突变导致遗传个体无痛症的出人意料研究结果。该遗传突变的个体先天失去痛觉，但机体的其它功能完全正常，此外最近的研究表明，表达在DRG神经元的电压门控Nav1.7通道参与痛信号的产生并发挥控制痛觉信号传入的闸门功能。该研究提示Nav1.7通道可能会成为选择性治疗疼痛并无副作用的药物靶点。
Nav1.7(PN1，SCN9A)VGSC对河豚毒素的阻断敏感，其主要表达于末梢交感神经元和感觉神经元。SCN9A基因已由多种物种(包括人类、大鼠及兔)复制，并且显示人与大鼠基因之间的氨基酸有约90％的一致性。
越来越多的身体证据表明Nav1.7在多种疼痛状态(包括急性、慢性、炎性和/或神经性疼痛)中扮演重要的角色，在人类中，Nav1.7蛋白质积累于神经瘤，特别是引起疼痛的神经瘤。Nav1.7功能增加的突变(不论是遗传性或偶发性)已被认为涉及原发性红斑性肢痛(一种特征为四肢的灼痛和发炎的疾病)，和突发性极度疼痛症。有关非选择性钠通道阻断剂利多卡因和美西律可缓和遗传性红斑性肢痛的症状，以及卡马西平可有效地减低PEPD的侵袭的次数和严重度的报道结果与上述观察相一致。Nav1.7在疼痛中扮演的角色的其他证据可见于SCN9A基因的功能丧失的突变的显型。后续的研究已显示会导致SCN9A基因的功能丧失与CIP显型的许多不同的突变。
由于Nav1.7特异地在DRG感觉神经元表达而不在心肌细胞和中枢神经系统等其它组织表达，因此研发其特异阻断剂用于治疗慢性痛，不仅可能提高疗效，且副作用也会大大减少，并且Nav1.7离子通道的选择性抑制剂几乎可用于各种疼痛的治疗。
此外，该蛋白家族的成员之一的Nav1.5和Nav1.2也是重要的一类离子型通道，NaV1.5主要在心肌细胞中表达(Raymond，C.K.等，op.cit.)，包括心房、心室、窦房结、房室结和心脏浦肯野纤维。心脏动作电位的迅速升支和通过心脏组织的迅速脉冲传导由于NaV1.5的开启。NaV1.5功能的异常可导致多种心律失常的形成。人体NaV1.5的突变导致多种心律不齐综合征，包括，例如，长QT3(LQT3)、Brugada综合征(BS)、遗传性心脏传导缺陷、突发性猝死综合征(SUNDS)和婴儿猝死综合征(SIDS)(Liu，H.等，Am.J.Pharmacogenomics(2003)，3(3)：173-9)。已经将钠通道阻断剂治疗广泛用于治疗心律失常。因此抑制Nav1.5通道会产生心脏毒性。此外NaV1.2在大脑中高度表达(Raymond，C.K. 等，J.Biol.Chem.(2004)，279(44)：46234-41)并且对正常的大脑功能是重要的。因此抑制Nav1.2通道会对大脑产生抑制毒性。
因此，鉴于目前可用药剂有限的效力和不可接受的副作用，迫切需要开发更加安全有效的镇痛药，使其具有较高功效和较少副作用。而Nav1.7离子通道是开发无成瘾性镇痛药物的重要靶标，开发具有Nav1.7离子通道高度选择性且具有良好药代动力学特征的抑制剂十分必要。
发明内容
本发明的目的是提供一种Nav1.7离子通道选择性抑制剂及其在医药上应用。
本发明第一方面，提供一种式(I)所示的化合物，或其药学上可接受的盐、溶剂化物、立体异构体或前药：
Figure PCTCN2019128925-appb-000001
式中，
R 0为C 1-10烷基或NR a0R b0；
R 1为任选取代的5至6元单环杂芳基或C 6-10芳基；其中所述任选取代是指未取代的或被1、2或3个选自下组的取代基取代：卤素、C 1-10烷基、卤代C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷氧基、C 3-10环烷基或-O-(CH 2) q-R a；其中R a为氢、C 1-10烷基、卤代C 1-10烷基、NR a0R b0、C 3-8环烷基或任选取代的4至6元饱和单杂环；
R 2为氢、羟基、氰基或C 1-10烷基；
R 3、R 4、R 5、R 6各自独立地为氢、卤素、C 1-10烷基、卤代C 1-10烷基、C 1-10烷氧基或C 3-8环烷基；
L为一个键、O、NH、-(CH 2) p-或-O-(CH 2) p；
n为0、1或2；
m为1、2或3；
p、q各自独立地为1、2或3；
R a0、R b0各自独立地为氢或C 1-8烷基；
在另一优选例中，式(I)中，所述4至6元饱和单杂环选自：氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1，1-二氧化物或四氢吡喃。
在另一优选例中，式(I)中，所述5至6元单环杂芳基选自：噻吩环、N-烷基吡咯环、呋喃环、噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、四唑环、异噁唑环、噁二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环或吡嗪环。
在另一优选例中，式(I)中，所述C 6-10芳基为苯基。
在另一优选例中，式(I)中，R 2为氢或C 1-10烷基。
在另一优选例中，式(I)中，R 3、R 4、R 5、R 6各自独立地为氢、卤素(优选为氟或氯)或C 3-8环烷基(优选为C 3-6环烷基)。
在另一优选例中，式(I)中，R 3、R 6为氢。
在另一优选例中，式(I)中，R 3、R 6为氢，且R 4、R 5各自独立地为氢、卤素(优选为氟或氯)或C 3-8环烷基(优选为C 3-6环烷基)。
在另一优选例中，式(I)中，R 1为任选取代的吡啶或苯基；其中所述任选取代是指未取代的或被1、2或3个选自下组的取代基取代：卤素、C 1-10烷基、卤代C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷氧基、C 3-10环烷基或-O-(CH 2) q-R a；其中R a为C 1-10烷基或卤代C 1-10烷基，q为1、2或3。
在另一优选例中，式(I)中，n为1或2；m为1或2。
在另一优选例中，式(I)中，n为0；m为2或3。
在另一优选例中，式(I)中，L为O或-O-(CH 2) p，p为1、2或3。
在另一优选例中，式(I)中，结构
Figure PCTCN2019128925-appb-000002
选自如下结构：
Figure PCTCN2019128925-appb-000003
其中，R 1、R 2如上述所定义。
在另一优选例中，式(I)中，所述化合物为选自实施例1-35的化合物。
本发明第二方面提供了一种药物组合物，所述组合物包括本发明第一方面所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药；以及药学可接受的载体。
本发明第三方面提供了如本发明第一方面所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，或本发明第二方面所述药物组合物在制备治疗疾病或病症的药物中的应用。
在另一优选例中，所述疾病或病症选自疼痛、抑郁症、心血管疾病、呼吸系统疾病、精神疾病或其组合。
在另一优选例中，所述疾病或病症选自与HIV相关的疼痛、HIV治疗诱导的神经病变、三叉神经痛、带状疱疹后神经痛、急性疼痛、热敏感、结节病、肠易激综合征、g罗恩病、与多发性硬化(MS)有关的疼痛、肌萎缩性侧索硬化(ALS)、糖尿病性神经病变、周围神经病变、关节炎、类风湿性关节炎、骨关节炎、动脉粥样硬化、突发性张力障碍、肌无力综合征、肌强直、恶性高热、囊性纤维化、假性醛固酮增多症、横纹肌溶解症、甲状腺功能减 退、双相抑郁症、焦虑症、精神分裂症、钠通道毒素相关病症、家族性红斑性肢痛症、原发性红斑性肢痛症，家族性直肠疼痛、癌症、癫痫、局部和全身强直性发作、不宁腿综合征、心律失常、纤维肌痛、在由中风或神经损伤导致的缺血性疾病状态下的神经保护、快速性心律失常、心房颤动和心室颤动。
在另一优选例中，所述疼痛选自神经性疼痛、炎性疼痛、内脏疼痛、癌症疼痛、化疗疼痛、创伤疼痛、手术疼痛、手术后疼痛、生产疼痛、分娩疼痛、牙痛、慢性疼痛、持续性疼痛、外周介导的疼痛、中枢介导的疼痛、慢性头痛、偏头痛、窦性头痛、紧张性头痛、幻肢痛、周围神经损伤、三叉神经痛、带状疱疹后神经痛、急性疼痛、家族性红斑性肢痛症、原发性红斑性肢痛症、家族性直肠疼痛或纤维肌痛或其组合。
本发明第四方面提供了一种治疗哺乳动物疾病或病症的方法，所述方法包括给需要的对象(如哺乳动物)施用治疗有效量的本发明第一方面所述的化合物，或其药学上可接受的盐、溶剂化物、立体异构体或前药，或本发明第二方面所述的药物组合物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过广泛而深入的研究，意外地发现了本发明的氮杂环取代的磺酰基苯甲酰胺衍生物对Nav1.7具有较高的抑制活性，有望开发成用于广泛疼痛的治疗的药物。在此基础上，发明人完成了本发明。
术语定义
如本文所用，“C 1-10烷基”指包含1至10个碳原子的直链和支链的饱和的脂族烃基，如下定义类似；更优选为C 1-8烷基，非限制性的例子包括：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；更优选为C 1-6烷基，最优选为C 1-3烷基。
如本文所用，“C 1-10烷氧基”指-O-(C 1-10烷基)，其中烷基的定义如上所述。优选C 1-8烷氧基，更优选C 1-6烷氧基，最优选C 1-3烷氧基。非限制性实施例包含甲氧基、乙氧基、丙氧 基、异丙氧基、丁氧基、叔丁氧基、异丁氧基、戊氧基等。
如本文所用，“C 3-8环烷氧基”指-O-(C 3-8环烷基)，其中环烷基的定义如上所述。优选C 3-6环烷氧基。非限制性实施例包含环丙氧基、环丁氧基、环戊氧基、环己氧基等。
如本文所用，“卤素”指氟、氯、溴或碘。
如本文所用，“卤代”指基团中一个或多个(如1、2、3、4或5个)氢被卤素所取代。
例如，“卤代C 1-10烷基”指烷基被一个或多个(如1、2、3、4或5个)卤素取代，其中烷基的定义如上所述。优选为卤代C 1-8烷基，更优选为卤代C 1-6烷基，最优选为卤代C 1-3烷基。卤代C 1-10烷基的例子包括(但不限于)一氯乙基、二氯甲基、1，2－二氯乙基、一溴乙基、一氟乙基、一氟甲基、二氟甲基、三氟甲基等。
又例如，“卤代C 1-10烷氧基”指烷氧基被一个或多个(如1、2、3、4或5个)卤素取代，其中烷氧基的定义如上所述。优选为卤代C 1-8烷氧基，更优选为卤代C 1-6烷氧基，最优选为卤代C 1-3烷氧基。包括(但不限于)三氟甲氧基、三氟乙氧基、一氟甲氧基、一氟乙氧基、二氟甲氧基、二氟乙氧基等。
又例如，“卤代C 3-8环烷基”指环烷基被一个或多个(如1、2、3、4或5个)卤素取代，其中环烷基的定义如上所述。优选为卤代C 3-6环烷基。包括(但不限于)三氟环丙基、一氟环丙基、一氟环己基、二氟环丙基、二氟环己基等。
如本文所用，“氘代C 1-8烷基”指烷基被一个或多个(如1、2、3、4或5个)氘原子取代，其中烷基的定义如上所述。优选为氘代C 1-6烷基，更优选为氘代C 1-3烷基。氘代C 1-20烷基的例子包括(但不限于)单氘代甲基、单氘代乙基、二氘代甲基、二氘代乙基、三氘代甲基、三氘代乙基等。
如本文所用，“一个键”指由其连接的两个基团通过一个共价键连接。
如本文所用，“环烷基”指饱和或部分不饱和单环环状烃基，“C 3-8环烷基”是指包含3至8个碳原子的环烃基，可优选为C 3-6环烷基，定义类似；环烷基的非限制性实施例包括环丙基、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，优选环丙基、环戊基、环己烯基。
如本文所用，“螺环”是指单环之间共用一个碳原子(称螺原子)的多环基团，这些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。根据环的数目将螺环分为双螺环或多螺环，优选为双螺环。更优选为4元/5元、5元/5元或5元/6元双螺环。例如：
Figure PCTCN2019128925-appb-000004
如本文所用，“螺杂环”指单环之间共用一个原子(称螺原子)的多环烃，其中一个或两个环原子选自氮、氧或S(O) n(其中n是整数0至2)的杂原子，其余环原子为碳。这些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。根据环的数目将螺杂环分为双螺杂环或多螺杂环，优选双螺杂环。更优选为4元/5元、5元/5元或5元/6元双螺杂环。例如：
Figure PCTCN2019128925-appb-000005
如本文所用，“桥环”是指共用两个或两个以上碳原子的多环基团，共用的碳原子称为桥头碳，两个桥头碳之间可以是碳链，也可以是一个键，称为桥。这些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。优选为双环或三环桥环。例如：
Figure PCTCN2019128925-appb-000006
如本文所用，“桥杂环”指共用两个或两个以上原子的多环基团，其中一个或多个环原子选自氮、氧或S(O) n(其中n是整数0至2)的杂原子，其余环原子为碳。这些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。优选为双环或三环桥杂环。例如：
Figure PCTCN2019128925-appb-000007
如本文所用，“8至10元双环”是指含8至10个环原子的含两个环的桥环，双环可为饱和全碳双环或部分不饱和的全碳双环，8至10元双环的实例包括(但不限于)：
Figure PCTCN2019128925-appb-000008
如本文所用，“8至10元双杂环”是指含8至10个环原子的含两个环的桥杂环，其中1、 2、3、4或5个环碳原子被选自氮、氧或硫的杂原子所取代。8至10元双杂环的实例包括(但不限于)四氢喹啉环、四氢异喹啉环、十氢喹啉环等。
如本文所用，“C 6-10芳基”和“C 6-10芳环”可互换使用，均指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，指含有6至10个碳原子的芳基；优选苯基和萘基，更优选苯基。
如本文所用，“氨基”指NH 2，“氰基”指CN，“硝基”指NO 2，“苄基”指-CH 2-苯基，“氧代基”指＝O，“羧基”指-C(O)OH，“乙酰基”指-C(O)CH 3，“羟甲基”指-CH 2OH，“羟乙基”指-CH 2CH 2OH或-CHOHCH 3，“羟基”指-OH，“硫醇”指SH，“亚环丙基”结构为：
Figure PCTCN2019128925-appb-000009
如本文所用，“杂芳基环”与“杂芳基”可互换使用，是指具有5到10个环原子，优选5或6元单环杂芳基或8至10元双环杂芳基；环阵列中共享6、10或14个π电子；且除碳原子外还具有1到5个杂原子的基团。“杂原子”是指氮、氧或硫。
如本文所用，“3至7元(4至7元)饱和或部分不饱和单环”是指含3至7个环原子的饱和或部分不饱和的全碳单环。3至7元饱和或部分不饱和单环的实例包括(但不限于)：环丙基环、环丁基环、环戊基环、环戊烯基环、环己基环、环己烯基环、环己二烯基环、环庚基环、环庚三烯基环、环辛基环等。
如本文所用，“5至6元单环杂芳基环”和“5至6元单环杂芳基”可互换使用，均是指含5至6个环原子的单杂芳基环，例如包括(但不限于)：噻吩环、N-烷环吡咯环、呋喃环、噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、1,2,3-三唑环、1,2,4-三唑环、1,2,5-三唑环、1,3,4-三唑环、四唑环、异噁唑环、噁二唑环、1,2,3-噁二唑环、1,2,4-噁二唑环、1,2,5-噁二唑环、1,3,4-恶二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环等。
如本文所用，“8至10元双环杂芳基环”和“8至10元双环杂芳基”可互换使用，均是指含8至10个环原子的双杂芳基环，例如包括(但不限于)：苯并呋喃、苯并噻吩、吲哚、异吲哚、喹啉、异喹啉、吲唑、苯并噻唑、苯并咪唑、喹唑啉、喹喔啉、噌啉、酞嗪、吡啶并[3,2-d]嘧啶、吡啶并[2,3-d]嘧啶、吡啶并[3,4-d]嘧啶、吡啶并[4,3-d]嘧啶、1,8-萘啶、1,7-萘啶、1,6-萘啶、1,5-萘啶。
如本文所用，“4至6元饱和单杂环”是指4至6元单环中的1、2或3个碳原子被选自氮、氧或S(O) t(其中t是整数0至2)的杂原子所取代，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳；优选4至6元，更优选5至6元。4至6元饱和单杂环的实例包括(但不限于)氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、吡咯啉、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1，1-二氧化物、四氢吡喃等。
如本文所用，“取代的”指基团中的一个或多个氢原子，优选为1～5个氢原子彼此独立地被相应数目的取代基取代，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。
如本文所用，“任选取代的”是指基团未被取代基取代，或者基团中的一个或多个氢原子，优选为1～5个氢原子彼此独立地被相应数目的取代基取代，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。
如本文所用，本文任一基团可以是取代的或未取代的。上述基团被取代时，取代基优选为1至5个以下基团，独立地选自CN、卤素、C 1-10烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 1-10烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、C 1-8烷基取代的胺基、胺基、卤代C 1-8烷基取代的胺基、乙酰基、羟基、羟甲基、羟乙基、羧基、硝基、C 6-10芳基(优选苯基)、C 3-8环烷氧基(优选为C 3-6环烷氧基)、C 2-10烯基(优选为C 2-6烯基，更优选为C 2-4烯基)、C 2-10炔基(优选为C 2-6炔基，更优选为C 2-4炔基)、-CONR a0R b0、-C(O)OC 1-10烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-CHO、-OC(O)C 1-10烷基(优选为-OC(O)C 1-6烷基，更优选为-OC(O)C 1-3烷基)、-SO 2C 1-10烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-SO 2C 6-10芳基(优选为-SO 2C 6芳基，如-SO 2-苯基)、-COC 6-10芳基(优选为-COC 6芳基，如-CO-苯基)、4至6元饱和或不饱和单杂环、4至6元饱和或不饱和单环、5至6元单环杂芳基环、8至10元双环杂芳基环、螺环、螺杂环、桥环或桥杂环，其中R a0、R b0各自独立地为氢或C 1-3烷基。
本文以上所述的各类取代基团其自身也是可以被本文所描述的基团取代。
本文所述的4至6元(5至6元)饱和单杂环被取代时，取代基的位置可处在它们可能的化学位置，示例性的单杂环的代表性的取代情况如下所示：
Figure PCTCN2019128925-appb-000010
Figure PCTCN2019128925-appb-000011
Figure PCTCN2019128925-appb-000012
其中“Sub”表示本文所述的各类取代基；
Figure PCTCN2019128925-appb-000013
表示与其他原子的连接。
除非另有定义，当本发明所述的4至6元饱和单杂环为取代基时，其自身也可以为取代或被1、2或3个选自下组的取代基所取代：卤素、羟基、C 1-3烷基、O＝、NR a0R b0、羟甲基、羟乙基、羧基、-C(O)OC 1-3烷基、乙酰基、卤代C 1-3烷基、C 1-3烷氧基、C 3-6环烷基、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、噻吩环、N-烷基吡咯环、呋喃环、噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、四唑环、异噁唑环、噁二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环；其中R a0、R b0各自独立地为氢或C 1-3烷基。
所述“药学上可接受的盐”包括药学可接受的酸加成盐和药学可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其他副作用的，与无机酸或有机酸所形成的盐。
“药学可接受的碱加成盐”，包括但不限于无机碱的盐如钠盐，钾盐，钙盐和镁盐等。包括但不限于有机碱的盐，比如铵盐，三乙胺盐，赖氨酸盐，精氨酸盐等。
本发明中提及的“溶剂化物”是指本发明的化合物与溶剂形成的配合物。它们或者在溶剂中反应或者从溶剂中沉淀析出或者结晶出来。例如，一个与水形成的配合物称为“水合物”。式(I)化合物的溶剂化物属于本发明范围之内。
本发明式(I)所示的化合物可以含有一个或多个手性中心，并以不同的光学活性形式存在。当化合物含有一个手性中心时，化合物包含对映异构体。本发明包括这两种异构体和异构体的混合物，如外消旋混合物。对映异构体可以通过本专业已知的方法拆分，例如结晶以及手性色谱等方法。当式(I)化合物含有多于一个手性中心时，可以存在非对映异构体。本发明包括拆分过的光学纯的特定异构体以及非对映异构体的混合物。非对映异构体可由本专业已知方法拆分，比如结晶以及制备色谱。
本发明包括上述化合物的前药。前药包括已知的氨基保护基和羧基保护基，在生理条件下被水解或经由酶反应释放得到母体化合物。具体的前药制备方法可参照(Saulnier，M.G.；Frennesson，D.B.；Deshpande，M.S.；Hansel，S.B and Vysa，D.M.Bioorg.Med.Chem Lett.1994，4，1985-1990；和Greenwald，R.B.；Choe，Y.H.；Conover，C.D.；Shum，K.；Wu，D.；Royzen，M.J.Med.Chem.2000，43，475.)。
通常，本发明化合物或其药学可接受的盐、或其溶剂化物、或其立体异构体、或前药可 以与一种或多种药用载体形成适合的剂型施用。这些剂型适用于口服、直肠给药、局部给药、口内给药以及其他非胃肠道施用(例如，皮下、肌肉、静脉等)。例如，适合口服给药的剂型包括胶囊、片剂、颗粒剂以及糖浆等。这些制剂中包含的本发明的化合物可以是固体粉末或颗粒；水性或非水性液体中的溶液或是混悬液；油包水或水包油的乳剂等。上述剂型可由活性化合物与一种或多种载体或辅料经由通用的药剂学方法制成。上述的载体需要与活性化合物或其他辅料兼容。对于固体制剂，常用的无毒载体包括但不限于甘露醇、乳糖、淀粉、硬脂酸镁、纤维素、葡萄糖、蔗糖等。用于液体制剂的载体包括水、生理盐水、葡萄糖水溶液、乙二醇和聚乙二醇等。活性化合物可与上述载体形成溶液或是混悬液。
本发明的组合物以符合医学实践规范的方式配制，定量和给药。给予化合物的“治疗有效量”由要治疗的具体病症、治疗的个体、病症的起因、药物的靶点以及给药方式等因素决定。
如本文所用，“治疗有效量”是指将引起个体的生物学或医学响应，例如降低或抑制酶或蛋白质活性或改善症状、缓解病症、减缓或延迟疾病进程或预防疾病等的本发明化合物的量。
本发明的药物组合物中含有的本发明化合物或其药学上可接受的盐、或其溶剂化物、或其立体异构体的治疗有效量优选为0.1mg-5g/kg(体重)。
如本文所用，“药学可接受的载体”是指无毒、惰性、固态、半固态的物质或液体灌装机、稀释剂、封装材料或辅助制剂或任何类型辅料，其与患者相兼容，最好为哺乳动物，更优选为人，其适合将活性试剂输送到目标靶点而不终止试剂的活性。
如本文所用，“患者”是指一种动物，最好为哺乳动物，更好的为人。术语“哺乳动物”是指温血脊椎类哺乳动物，包括如猫、狗、兔、熊、狐狸、狼、猴子、鹿、鼠、猪和人类。
如本文所用，“治疗”是指减轻、延缓进展、衰减、预防，或维持现有疾病或病症(例如癌症)。治疗还包括将疾病或病症的一个或多个症状治愈、预防其发展或减轻到某种程度。
制备方法
下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press，1989)中所述的条件，或按照制造厂商所建议的条件。
除非另行定义，本文所用的术语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或同等的方法及材料皆可应用于本发明中。
本发明的式(I)化合物可根据具体化合物结构的不同，参照下列实施例中的示例性制备方法通过多种合成操作容易地进行制备，这些操作是所属领域技术人员熟练掌握的。制备过程中所使用的试剂和原料化合物均可市购得到，或本领域技术人员根据所设计的不同化合物结构参考已知方法制备得到。
与现有技术相比，本发明的主要优点在于：
本发明系列化合物结构新颖并具有较高的Nav1.7抑制活性和Nav1.7选择抑制活性。本发明系列化合物是具有统计学意义的抑制冷刺激痛觉超敏的效果。本发明系列化合物不仅具有明显的药代吸收效果和良好的生物利用度，而且具有明显的代谢稳定性，因此有望开发成 用于广泛疼痛治疗的药物。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。除非另行定义，本文所用的术语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或同等的方法及材料皆可应用于本发明中。
如本文所用，DMB为2，4-二甲氧基苄基，THF为四氢呋喃，EA为乙酸乙酯，PE为石油醚，Ac 2O为乙酸酐，NBS为N-溴代琥珀酰亚胺，DCM为二氯甲烷，AIBN为偶氮二异丁腈，Pd(dppf)Cl 2为1，1'-双(二苯基磷)二茂铁]二氯化钯，TFA为三氟乙酸，TBSCl为叔丁基二甲基氯硅烷，NCS为N-氯代丁二酰亚胺，DHP为二氢吡喃，LiAlH 4为氢化铝锂，PMB为对甲氧基苄基，LiHMDS为二(三甲基硅基)氨基锂，Pd 2(dba) 3为三(二亚苄基丙酮)二钯，RuPhos为2-二环己基磷-2'，6'-二异丙氧基-1，1'-联苯，DMAP为4-二甲氨基吡啶，THP为四氢吡喃，n-BuLi为正丁基锂，TMsOTf为三氟甲磺酸三甲基硅酯，TEBAC为三乙基苄基氯化铵，HATU为2-(7-偶氮苯并三氮唑)-N，N，N'，N'-四甲基脲六氟磷酸酯，DMF为二甲基甲酰胺，DMSO为二甲基亚砜，DIEA为N，N-二异丙基乙胺，BINAP为(2R，3S)-2，2'-双二苯膦基-1，1'-联萘。
如本文所用，室温是指约为20-25℃。
化合物1-a的制备
Figure PCTCN2019128925-appb-000014
在N 2保护条件下，将5-氯-2,4-二氟苯甲酸(7.8g，0.041mol)溶解在无水二氯甲烷(100mL)中，加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(11.65g，0.061mmol)，DMAP(11.07g，0.090mmol)。混合物在室温搅拌10分钟，加入甲基磺酰胺(4.82g，0.061mol)。混合物在室温搅拌18小时。向反应液中加150毫升水,混合物在室温搅拌0.5h，分出水相。水相用1N HCl水溶液调pH至3后，用二氯甲烷(3x 100mL)萃取,合并有机相，用饱和食盐水(200mL)洗，硫酸钠干燥，40℃旋干。粗品过柱(100-200目硅胶),淋洗液为石油醚：乙酸乙酯(1：1)，得到白色固体1-a(3.8g，35％)。MS m/z(ESI):270[M+H] +。 1H NMR(400MHz，CDCl 3)：δ12.41(s，1H)，8.00(t，J＝7.6Hz，1H)，7.74(t,J＝10.0Hz,1H),3.37(s，3H)。
实施例1 5-氯-2-(1-(3-氯-4-(三氟甲氧基)苯基)哌啶-4-基氧基)-4-氟-N-(甲基磺酰基)苯甲酰胺(Z-1)的制备
Figure PCTCN2019128925-appb-000015
步骤1：向50mL圆底烧瓶中加入z-1-1(614mg，3.05mmol，1.0eq)，7mL 1,4-二氧六环，室温下逐滴加入4M HCl/1,4-二氧六环溶液(3mL，12mmol，3.93eq)，室温搅拌过夜，旋蒸浓缩除去溶剂，得到白色固体z-1-2(414mg，98.6％)，直接用于下一步反应。MS m/z(ESI):N/A。
步骤2：向50mL封管中加入4-溴-2-氯-1-(三氟甲氧基)苯(206mg，0.748mmol，1.0eq)，z-1-2(152mg，1.105mmol,1.48eq)，Pd 2dba 3(66mg，0.072mmol，0.1eq)，binap(90mg,0.145mmol，0.19eq),叔丁醇钾(253mg，2.255mmol，3.01eq)和10mL 1,4-二氧六环，用Ar 2鼓泡脱气5min，油浴升温至90℃，搅拌反应15h。停止反应，反应液用硅藻土垫滤，滤液浓缩，combiflash过柱纯化(0-30％乙酸乙酯/石油醚)，得到黄色油状物z-1-3(94mg,42.5％)。MS m/z(ESI):296.0[M+H] +。
步骤3：向50mL圆底烧瓶中加入z-1-3(54mg，0.183mmol，1.2eq)，3mL THF，置于冰浴下冷却，加入NaH(18mg，60％，0.45mmol，2.96eq)，搅拌0.5h，加入1-a(41mg，0.152mmol，1.0eq)，室温搅拌过夜。加入20mL水，用1M HCl调节pH＝5 ～6，用乙酸乙酯萃取(20mL x 2)，合并有机相，无水硫酸钠干燥，过滤浓缩，残留物用制备型高效液相色谱纯化得到白色固体Z-1(16mg，19.3％)。MS m/z(ESI):545.1[M+H] +。 1H NMR(400MHz，DMSO-d 6)：δ11.69(s，1H)，7.71(d，J＝8.4Hz，1H)，7.44(d，J＝11.6Hz，1H)，7.34(dd，J 1＝9.2Hz,J 2＝1.0Hz,1H)，7.16(d，J＝2.8Hz，1H)，6.99(dd，J 1＝9.2Hz，J 2＝3.2Hz，1H)，4.75(m，1H)，3.52(m，2H)，3.27(m，2H)，3.21(s，3H),1.98(m，2H)，1.78(m，2H)。
实施例2 5-环丙基-2-(1-(3,4-二氯苯基)氮杂环丁烷-3-基氧基)-4-氟-N-(甲基磺酰基)苯甲酰胺(Z-2)的制备
Figure PCTCN2019128925-appb-000016
步骤1：向100mL圆底烧瓶中加入3,4-二氯溴苯(1g，4.46mmol，1.0eq)，z-2-1(977mg，8.92mmol,2eq)，Pd 2dba 3(259mg，0.45mmol，0.1eq)，binap(280mg,0.45mmol，0.1eq)，叔丁醇钾(1g，8.92mmol，2.0eq)和20mL 1,4-二氧六环，用Ar 2气球置换三次并保护，油浴升温至100℃，搅拌反应15h。停止反应，反应液倒入50mL水中，用二氯甲烷萃取(50mL x 2)，有机相拥无水硫酸钠干燥，过滤浓缩，combiflash过柱纯化，得到黄色固体z-2-2(400mg，41.3％)。MS m/z(ESI):218.0[M+H] +。
步骤2：向100mL圆底烧瓶中加入z-2-2(350mg，1.6mmol)，15mL THF，置于冰浴下 冷却，缓慢加入NaH(200mg，60％，4.8mmol，3eq)，加完后冰浴下搅拌反应10min，再加入z-2-3(500mg，1.6mmol，1.0eq)，冰浴下搅拌反应1h。反应液倒入50mL冰水中，用乙酸乙酯萃取(50mL x 2)，有机相拥无水硫酸钠干燥，过滤浓缩，combiflash过柱纯化，得到黄色固体z-2-4(200mg，24.3％)。MS m/z(ESI):511.0[M+H] +。
步骤3：向100mL圆底烧瓶中加入z-2-4(200mg，0.39mmol，1.0eq)，环丙基硼酸(67mg，0.78mmol,2eq)，Pd 2(dppf)Cl 2(29mg，0.04mmol，0.1eq)，碳酸铯(254mg,0.78mmol，2eq),10mL1,4-二氧六环和1mL水，用Ar 2气球置换三次并保护，油浴升温至100℃，搅拌反应15h。停止反应，反应液倒入50mL水中，用二氯甲烷萃取(50mL x 2)，有机相拥无水硫酸钠干燥，过滤浓缩，残留物用制备型高效液相色谱纯化得到白色固体Z-2(36mg，36％)。MS m/z(ESI):473.0[M+H] +。 1H NMR(400MHz，DMSO-d 6)：δ7.19(d，J＝7.6Hz，1H)，7.16(d，J＝6.8Hz，1H)，6.58(d，J＝2.0Hz，1H)，6.53(d，J＝9.6Hz，1H)，6.44(dd，J 1＝7.2Hz,J 2＝2.0Hz,1H),5.09(m，1H)，4.32(m，2H)，3.94(m，2H)，3.07(s，3H)，1.97(m，1H)，0.91(m，2H)，0.69(m，2H)。
实施例3-32
化合物Z-5至Z-32可参照实施例2的方法进行制备。
Figure PCTCN2019128925-appb-000017
Figure PCTCN2019128925-appb-000018
Figure PCTCN2019128925-appb-000019
Figure PCTCN2019128925-appb-000020
Figure PCTCN2019128925-appb-000021
实施例33 5-氯-2-((1-(3-氯-4-(三氟甲氧基)苯基)吡咯烷-2-基)甲氧基)-4-氟-N-(甲基磺酰基)苯甲酰胺(Z-33)的制备
Figure PCTCN2019128925-appb-000022
步骤1：将(R)-吡咯烷-2-基甲醇(275mg，2.723mmol)，4-溴-2-氯-1-(三氟甲氧基)苯(500mg，1.815mmol)，Pd2(dba)3(164.8mg，0.180mmol)，BINAP(224.2mg，0.36mmol)，t-BuOK(407.3mg，3.63mmol)加入到干燥1,4-二氧六环(15ml)中，混合物升温至90℃搅拌过夜，混合物经LC-MS检测后，减压浓缩，残余物经Combiflash(流动相PE:EA＝1:19－1:9)纯化后得黄色油状物(R)-(1-(3-氯-4-(三氟甲氧基)苯基)吡咯烷-2-基)甲醇(184mg，产率34.3％)。MS(ESI)296.0[M+H] +。
步骤2：将(R)-(1-(3-氯-4-(三氟甲氧基)苯基)吡咯烷-2-基)甲醇(150mg，0.508mmol)加入到DMF(5ml)中，再加入NaH(61mg，1.524mmol)，搅拌几分钟后加入5-氯-2,4-二氟 -N-(甲基磺酰基)苯甲酰胺(137mg，0.508mmol)，混合物搅拌过夜。混合物经LC-MS检测后，减压浓缩，残余物经Combiflash(流动相PE:EA＝1:9－1:4)纯化后得化合物Z-33(170mg，收率51.8％)，MS(ESI)545.0[M+H] +。
实施例34、35
化合物Z-34和Z-35可参照实施例33的方法进行制备。
Figure PCTCN2019128925-appb-000023
电生理学测定
测试例1 hNav1.7通道的手动膜片钳实验
膜片电压钳电生理学可以直接测量并定量电压门控钠通道(各种Nav)的电流阻断并可以测定阻断的时间和电压依赖，其已被解释为对钠通道的静息、开放和失活状态的结合差异来反映化合物的抑制或激活效应(Hille，B.，Journal of General Physiology(1977)，69：497-515)。
本发明代表性的化合物采用手动膜片钳实验进行，本研究的目的是应用手动膜片钳的方法在转染特定离子通道的稳定细胞株上测试化合物对该离子通道电流的作用。其使用的稳定细胞株CHO-hNav1.7来自Genionics公司。
手动膜片钳实验方案如下：
(一)溶液及化合物的配制：采用全细胞膜片钳技术记录hNav1.7电流。实验中，细胞外液的组成成分(mM)：HEPES：5，NaCl：40，KCl：3，CaCl 2：1，MgCl 2：1，CdCl 2：0.1，TEA-Cl：20。用NaOH调节pH值至7.3，同时用蔗糖调节渗透压至310-320mOsm，过滤后4℃保存。细胞内液的组成成分(mM)：HEPES：10，NaCl：10，CsOH：5，CsF：140，EGTA：1。用CsOH调节pH值至7.3，同时用蔗糖调节渗透压至280-290mOsm，过滤后-20℃保存。
阳性对照药和待测化合物先溶于100％DMSO(Sigma-Aldrich，D2650，配置成一定浓度(100nM，1000nM)的储备溶液。实验前用DMSO将上述储备溶液进行系列稀释，然后再用细胞外液进一步稀释得到所需浓度的测试溶液。细胞外液中DMSO最终浓度不超过0.30％。
(二)手动膜片钳实验：取细胞悬液加于35mm的培养皿中，置于倒置显微镜载物台上。待细胞贴壁后，用细胞外液灌流，流速为1–2mL/min。玻璃微电极由微电极拉制仪两步拉制， 其入水电阻值为2-5MΩ。通过Digidata 1440(Molecular Devices)和pCLAMP软件(10.2版，Molecular Devices)A/D–D/A数模转换，进行刺激发放及信号采集；膜片钳放大器(Multiclamp 700B，Molecular Devices)放大信号，滤波为4KHz。
在hNav1.7手动膜片钳实验中运用两种不同的电压刺激程序。
一种是失活刺激程序，钳制电位设置在相对应通道的V 1/2，即大约50％的通道处于失活状态。接着给予电压至-120mV，持续50ms。然后去极化至-10mV，持续20ms引出钠电流，最后回到钳制电位。这种刺激程序也可以称之为通道状态依赖的电压刺激程序。
另一种是非失活刺激程序，保持钳制电位在-120mV，给予电压刺激至-10mV，持续20ms引出钠电流，最后回到钳制电位。也就是说在该种刺激程序条件下，所有的通道都没有经历过失活状态，而是直接从静息状态进行激活。
上述两种电压刺激程序的时间间隔均为10s。化合物的抑制效应通过加药前后的电流变化来进行计算，而IC 50数值由Hill方程进行拟合所得。如果化合物在上述两种不同的电压刺激下显示出对通道效应有一定倍数的差异，那么该化合物对该通道是具有状态依赖性的。
数据分析
将每一个药物浓度作用后的电流和空白对照电流标准化(化合物峰拖尾电流/对照物峰拖尾电流)，然后计算每一个药物浓度对应的抑制率(1-(化合物峰拖尾电流/对照物峰拖尾电流))。对每一个浓度计算平均数和标准误差，并用以下的方程计算每种化合物的半抑制浓度：
抑制率＝1/(1+(IC 50/c) h)
用以上方程对剂量依赖效应进行非线性拟合，其中c代表药物浓度，IC 50为的半抑制浓度，h代表希尔系数。曲线拟合以及IC 50的计算利用IGOR软件完成。结果见表1。
表1 本发明代表性化合物在两种浓度下对Nav1.7的抑制率
化合物 100nM(％) 1000nM(％) 化合物 100nM(％) 1000nM(％)
Z-5 70.48 89.21 Z-6 70.60 98.40
Z-7 82.75 92.36 Z-14 72.27 94.64
Z-31 73.24 91.42 Z-33 60.47 81.47
从表1可以看出，本发明代表性化合物对Nav1.7具有较高的抑制活性。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种式(I)所示的化合物，或其药学上可接受的盐、溶剂化物、立体异构体或前药：
    Figure PCTCN2019128925-appb-100001
    式中，
    R 0为C 1-10烷基或NR a0R b0；
    R 1为任选取代的5至6元单环杂芳基或C 6-10芳基；其中所述任选取代是指未取代的或被1、2或3个选自下组的取代基取代：卤素、C 1-10烷基、卤代C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷氧基、C 3-10环烷基或-O-(CH 2) q-R a；其中R a为氢、C 1-10烷基、卤代C 1-10烷基、NR a0R b0、C 3-8环烷基或任选取代的4至6元饱和单杂环；
    R 2为氢、羟基、氰基或C 1-10烷基；
    R 3、R 4、R 5、R 6各自独立地为氢、卤素、C 1-10烷基、卤代C 1-10烷基、C 1-10烷氧基或C 3-8环烷基；
    L为一个键、O、NH、-(CH 2) p-或-O-(CH 2) p；
    n为0、1或2；
    m为1、2或3；
    p、q各自独立地为1、2或3；
    R a0、R b0各自独立地为氢或C 1-8烷基；
  2. 如权利要求1所述的化合物，或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，R 2为氢或C 1-10烷基。
  3. 如权利要求1所述的化合物，或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，R 3、R 6为氢，且R 4、R 5各自独立地为氢、卤素(优选为氟或氯)或C 3-8环烷基(优选为C 3-6环烷基)。
  4. 如权利要求1所述的化合物，或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，n为1或2；m为1或2。
  5. 如权利要求1所述的化合物，或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，n为0；m为2或3。
  6. 如权利要求1所述的化合物，或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，L为O或-O-(CH 2) p，p为1、2或3。
  7. 如权利要求1所述的化合物，或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，结构
    Figure PCTCN2019128925-appb-100002
    选自如下结构：
    Figure PCTCN2019128925-appb-100003
    其中，R 1、R 2如上述所定义。
  8. 如权利要求1所述的化合物，或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，所述化合物为选自实施例1-35的化合物，具体选自如下结构：
    Figure PCTCN2019128925-appb-100004
    Figure PCTCN2019128925-appb-100005
  9. 一种药物组合物，所述组合物包括权利要求1至8中任一项所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药；以及药学可接受的载体。
  10. 如权利要求1至8中任一项所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，或如权利要求9所述药物组合物在制备治疗疾病或病症的药物中的应用，所述疾病或病症选自疼痛、抑郁症、心血管疾病、呼吸系统疾病、精神疾病或其组合。
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