WO2020052509A1 - Sulfonamide compound serving as sodium channel blocker and uses thereof - Google Patents

Sulfonamide compound serving as sodium channel blocker and uses thereof Download PDF

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WO2020052509A1
WO2020052509A1 PCT/CN2019/104852 CN2019104852W WO2020052509A1 WO 2020052509 A1 WO2020052509 A1 WO 2020052509A1 CN 2019104852 W CN2019104852 W CN 2019104852W WO 2020052509 A1 WO2020052509 A1 WO 2020052509A1
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pain
ethyl
amino
chloro
benzenesulfonamide
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PCT/CN2019/104852
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French (fr)
Chinese (zh)
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万剑飞
强晓明
吴红丽
柯潇
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成都康弘药业集团股份有限公司
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Definitions

  • the invention relates to a sulfonamide compound having dual inhibitory activities on sodium ion channels, in particular on Nav1.3 and Nav1.7 sodium ion channels, and uses thereof.
  • Voltage-gated sodium channels are a type of microporous transmembrane glycoprotein widely distributed on excitable cell membranes such as neurons. They are mainly responsible for the transmembrane transport of Na + . The most important ion channel required for normal electrophysiological functions. Voltage-gated sodium channels are composed of an alpha subunit and multiple beta subunits, of which the alpha subunit is the main functional unit. Nine subtypes have been found (Nav1.1 to Nav1.9). It consists of four highly similar homologous domains surrounding a center to form the central pore of the ion channel. Each domain has six alpha helix transmembrane fragments (S1-S6).
  • the amino acid sequence of S4 is highly conserved and is considered It is a voltage sensor for voltage-gated sodium channels.
  • Extensive homology exists in voltage-gated sodium channels in different animals, but there are also large differences.
  • sodium ion channels are divided into TTX-sensitive (TTX-S) and TTX-insensitive (TTX-R).
  • TTX-R type sodium ion channels include Nav1.5, Nav1.8, and Nav1.9, and the rest are TTX-S type sodium ion channels.
  • VGSC subtype Expressed genes Main organization distribution Dysfunction / Indication Nav1.1 SCN1A CNS, PNS Pain, epilepsy, neurodegeneration Nav1.2 SCN2A CNS Neurodegeneration, epilepsy Nav1.3 SCN3A CNS Pain, epilepsy Nav1.4 SCN4A Skeletal muscle Muscle rigidity Nav1.5 SCN5A Myocardium Related to arrhythmia Nav1.6 SCN8A CNS Pain, dyskinesia Nav1.7 SCN9A PNS pain Nav1.8 SCN10A PNS pain
  • Nav1.1, Nav1.6, Nav1.7, Nav1.8, and Nav1.9 are expressed in neurons of DRG in normal adult animals, while Nav1.3 is highly expressed in immature neurons.
  • the nociceptors on the dorsal root ganglion convert various nociceptive thermal, mechanical, and chemical signals into electrical impulses and transmit them to the central nervous system.
  • Nav determines the generation and transmission of action potentials, and its functional changes change the excitability of neurons. And pain conduction has important effects.
  • the subtypes currently known to be closely related to pain include: Nav1.3, Nav1.7, Nav1.8, Nav1.9.
  • Nav1.7 is a transmembrane protein encoded by SCN9A, which is specifically expressed in peripheral sensory nerve endings and sympathetic ganglion neurons, and is mainly expressed on large diameter DRG neurons and unmyelinated small diameter DRG, that is, 85% of the damage Expressed on the sexy receptor, which shows that Nav1.7 has a very critical role in pain transmission.
  • Animal model studies show that in carrageenan and complete Freund's adjuvant (CFA) -induced inflammatory pain models, Nav1.7 protein or mRNA expression increases, and these changes occur mainly in DRG neurons or afferent neurons. An increase in TTX-S current in DRG neurons was also detected in the carrageenan inflammatory pain model.
  • CFA complete Freund's adjuvant
  • Nav1.7 protein expression increased. Knockdown of Nav1.7 in DRG can alleviate thermal hyperalgesia, mechanical hyperalgesia and cold hyperalgesia in animals. Recent research also found that Nav1.7 in DRG and sympathetic ganglia are involved in different types of pain information transmission, respectively. After Nav1.7 in the DRG of the mice was conditioned knockout, the basic mechanical pain valve and thermal pain valve were significantly increased, and the inflammatory pain caused by 4% formaldehyde was also relieved. In human disease research, when the SCN9A gene mutation causes Nav1.7 to be inactivated after opening, resulting in enhanced function, it is a "function-enhancing mutation", which triggers primary erythema limb pain (PE).
  • PE primary erythema limb pain
  • Nav1.3 is a fast-restarting voltage-gated sodium channel that is normally expressed only in developing sensory neurons and the central nervous system of adults, and at low levels in the adult peripheral nervous system.
  • peripheral nerve injury such as spinal nerve cut, ligation, or chronic compression injury can lead to a large up-regulation of Nav1.3 expression in dorsal root ganglion neurons. This phenomenon indicates that Nav1.3 is involved in the occurrence and maintenance of peripheral neuralgia.
  • Pryde D.C. et al. Reported that a series of aryl ether selective Nav1.3 inhibitors can be used to treat pain (Pryde D.C. et al. MedChemComm, 2017, 8, 1255-1267).
  • WO2006122014A2 discloses a class of bicyclic Nav1.3 blockers, which can be used to treat chronic pain, acute pain, inflammatory pain, and anxiety and depression.
  • Samad et al. Demonstrated the potential of Nav1.3 knockout for pain treatment in rat models and suggested gene therapy as a potential treatment option (Samad, OAet al. Mol. Ther. 2013, 21, 49-56 ). More and more researchers believe that Nav1.3 is also a very promising target for the development of analgesics.
  • Nav1.8 and Nav1.9 both belong to the TTX-R sodium channel and are also expressed in DRG in adult animals. They are thought to be involved in pain, but the exact mechanism is not yet clear.
  • Nav1.1 and Nav1.2 are highly expressed in the brain and are essential for normal brain function (Ray, C.K. el. J. Biol. Chem. 2004, 279, 46234-46241). Studies have shown that some loss of function caused by the Nav1.1 mutation can cause epilepsy (Yu, F.H. et al. Nat. Neuroscience, 2006, 9, 1142-1149). Therefore, although Nav1.1 is also expressed in the peripheral nervous system and inhibition of Nav1.1 is beneficial for pain relief, it may also cause side effects such as anxiety or excessive excitement.
  • Nav1.4 is mainly expressed in skeletal muscle. Inhibition of Nav1.4 may cause the adverse effects of muscle rigidity and even paralysis.
  • Nav1.5 is mainly expressed in cardiac muscle cells, including atria, ventricles, sinoatrial nodes, and atrioventricular nodes. Inhibition of Nav1.5 may cause arrhythmia syndromes, including prolonged QT interval, Brugada syndrome, sudden nocturnal sudden death syndrome, and sudden infant death syndrome (Liu, H. et al. Am. J. Pharmacogenomics, 2003, 3, 173-179). And Nav1.6 may be related to movement disorders.
  • Nav1.7 is a very promising target for the treatment of pain or pain-related diseases, and it is also the most studied sodium ion channel.
  • some clinically highly selective Nav1.7 blockers are clinically effective.
  • the pain effect is not very good, probably due to the upregulation of Nav1.3 expression in the peripheral nervous system to mediate the pain signal compensatively.
  • WO2012125973A reports the application of Nav1.3 and Nav1.7 with strong and selective peptides in the prevention and treatment of pain.
  • protein and peptide drugs often limit their wide application due to limitations such as stability and single mode of administration. Therefore, it is an important research direction to study new types of small molecule dual inhibitors of Nav1.3 and Nav1.7 with stronger potency and less side effects.
  • the object of the present invention is to provide a sulfonamide compound having dual inhibitory activity on sodium ion channels, especially Nav1.3 and Nav1.7 sodium ion channels, and uses thereof.
  • the present invention provides a solvate, tautomer or pharmaceutically acceptable salt thereof represented by the following formula I:
  • R 1 is selected from a 5-10 membered aromatic heterocyclic ring or -CONHR 2 containing up to 3 N, O, and S heteroatoms, and optionally, the 5-10 membered aromatic heterocyclic ring is substituted by halogen, C 1-6 alkyl , -OC 1-6 alkyl, C 1-6 haloalkyl, -OC 1-6 haloalkyl, cyano substituted;
  • R 2 is selected from C 1-4 alkyl
  • X 1 does not exist or is -NH-;
  • R 3 and R 4 are independently selected from hydrogen or halogen, and at least one of R 3 and R 4 is halogen;
  • X 2 is NH or O
  • Z is-(CH 2 ) n- , and when X 2 is NH, n is an integer of 1-2, when X 2 is O, n is an integer of 0-2;
  • X 3 , X 4 , X 5 , X 6 is selected from N or CR 5 , and at most 1 of X 3 , X 4 , X 5 , X 6 is N;
  • R 5 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, cyano;
  • R 6 is selected from hydrogen or C 1-4 alkyl
  • R 7 is selected from-(CH) z NR 8 R 9 , R 8 and R 9 are independently hydrogen or C 1-4 alkyl, wherein z is an integer of 1-4, or -NR 8 R 9 forms the following structure:
  • X 7 is absent or selected from CHR 10 , NR 10 or O, and y is an integer of 0-5; R 10 is selected from hydrogen or C 1-4 alkyl.
  • R 1 is selected from a 5-6 membered aromatic heterocyclic ring containing up to 3 N, O, S heteroatoms, and optionally, a 5-6 membered aromatic heterocyclic ring is Halogen, C 1-6 alkyl, -OC 1-6 alkyl, C 1-6 haloalkyl, -OC 1-6 haloalkyl, cyano substituted.
  • R 1 is selected from a 5-6 membered monocyclic aromatic heterocyclic ring containing up to 3 N, O, S heteroatoms, optionally, a 5-6 membered monocyclic aromatic heterocycle
  • the ring aromatic heterocyclic ring is substituted with halogen.
  • R 1 is selected from a 5-membered aromatic heterocycle containing up to 3 N, O, S heteroatoms, and optionally, the 5-membered aromatic heterocycle is substituted with halogen.
  • R 1 is selected from
  • R 2 is -CH 3 .
  • X 2 is -NH.
  • the compounds of Formula I, X 3, X 4, X 5, X 6 are CH.
  • R 5 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy base.
  • R 5 is selected from hydrogen, halogen, methyl, methoxy, trifluoromethyl, trifluoromethoxy.
  • X 7 is absent or selected from CH 2 , O, -NCH 3 , and y is an integer from 1-4.
  • z is 2 or 3.
  • the compound of formula I is selected from:
  • a second object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising the compound according to the first object of the present invention, a solvate, a tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable Excipients.
  • a third object of the present invention is to provide a compound according to the first object of the present invention, the use of a solvate, tautomer or pharmaceutically acceptable salt thereof in the preparation of a medicament for treating pain.
  • the pain is selected from the group consisting of neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, childbirth pain, neurogenic bladder pain, ulcerative colon Inflammatory pain, chronic pain, persistent pain, peripheral-mediated pain, central-mediated pain, migraine, sinus headache, tension headache, phantom limb pain, tooth pain, pain in peripheral nerve injury, or a combination thereof.
  • the pain is selected from the group consisting of: neuropathic pain, inflammatory pain.
  • the pain is associated with a disease or condition selected from the group consisting of: HIV, HIV treatment-induced neuropathy, trigeminal neuralgia, postherpetic neuralgia, acute pain, heat sensitivity, sarcoidosis, Irritable bowel syndrome, Crohn's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, atherosclerosis Sclerosis, paroxysmal dystonia, myasthenic syndrome, myotonia, malignant fever, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia Disease, sodium channel toxin-related diseases, familial erythematous limb pain, primary erythematous limb pain, familial rectal pain, cancer, epilepsy, partial and systemic tonic seizures, restless leg syndrome, arrhythmia , Fibromyalgi
  • a fourth object of the present invention is to provide a compound according to the first object of the present invention, a method of treating a pain in a mammal by a solvate, tautomer or pharmaceutically acceptable salt thereof, comprising administering to a mammal in need A therapeutically effective amount of a compound according to the first object of the invention.
  • the pain is selected from the group consisting of: neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, childbirth pain, neurogenic bladder pain, ulcerative colon Inflammatory pain, chronic pain, persistent pain, peripheral-mediated pain, central-mediated pain, migraine, sinus headache, tension headache, phantom limb pain, tooth pain, pain in peripheral nerve injury, or a combination thereof.
  • the pain is selected from the group consisting of: neuropathic pain, inflammatory pain.
  • the pain is associated with a disease or condition selected from the group consisting of: HIV, HIV treatment-induced neuropathy, trigeminal neuralgia, postherpetic neuralgia, acute pain, heat sensitivity, sarcoidosis, Irritable bowel syndrome, Crohn's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, atherosclerosis Sclerosis, paroxysmal dystonia, myasthenic syndrome, myotonia, malignant fever, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia Disease, sodium channel toxin-related diseases, familial erythematous limb pain, primary erythematous limb pain, familial rectal pain, cancer, epilepsy, partial and systemic tonic seizures, restless leg syndrome, arrhythmia , Fibromyalgi
  • alkyl itself or as part of another substituent means (unless otherwise stated) a straight or branched chain hydrocarbon group having the specified number of carbon atoms (ie, C 1-8 means one to eight carbons ).
  • alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like .
  • aromatic heterocycle refers to having 5 to 10 heterocyclic atoms, preferably 5 or 6-membered monocyclic aromatic heterocycles or 8 to 10-membered bicyclic aromatic heterocycles; and having 1 to 10 carbon atoms in addition to carbon atoms. 3 heteroatom groups.
  • Heteroatom means nitrogen, oxygen or sulfur.
  • 5- to 6-membered monocyclic aromatic heterocyclic ring refers to a single heteroaryl ring containing 5 to 6 ring atoms, and includes, but is not limited to, a thiophene ring, an N-alkylpyrrole ring, a furan Ring, thiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, isoxazole ring, oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine Ring etc.
  • 8 to 10 membered bicyclic aromatic heterocyclic ring refers to a biheteroaryl ring containing 8 to 10 ring atoms, including, for example, but not limited to: a benzofuran ring, a benzothiophene ring, an indole Ring, isoindole ring, quinoline ring, isoquinoline ring, indazole ring, benzothiazole ring, benzimidazole ring, quinazoline ring, quinoxaline ring, perylene ring, phthalazine ring.
  • substituted refers to the replacement of any one or more hydrogen atoms on a specific atom with a substituent, and can include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • it means that two hydrogen atoms are substituted.
  • Carbonyl substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • halogen itself or as part of another substituent means, unless otherwise specified, a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl is intended to include monohaloalkyl and polyhaloalkyl.
  • C 1-4 haloalkyl is intended to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl, and the like.
  • alkoxy represents the above-mentioned alkyl group having a specific number of carbon atoms connected through an oxygen bridge, and unless otherwise specified, C 1-6 alkoxy includes C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy. Examples of alkoxy include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, n-pentoxy and S- Pentyloxy.
  • a wavy line that intersects a bond in a chemical structure indicates the point of attachment of the bond, whose wavy bond in the chemical structure intersects the rest of the molecule.
  • a structure depicted herein is also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometrically isomeric (or conformational)) forms of the structure; for example, each asymmetric The central R and S configurations, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers of these compounds as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures are within the scope of the present invention. Unless otherwise specified, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • the structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the structure of the present invention, except that hydrogen is replaced by deuterium or tritium or carbon is replaced by 13 C- or 14 C-enriched carbon, are within the scope of the present invention.
  • solvate refers to the physical association of a compound of the present application with one or more solvent molecules; the physical association involves various degrees of ionic and covalent bonds, including hydrogen bonding; in some cases below, for example, when one or more solvent molecules are introduced into the crystal lattice of a crystalline solid, the solvate will be able to be separated; “solvate” encompasses the solution phase and separable solvates; non-limiting examples of suitable solvents include but are not limited to, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine; "hydrate” is where the solvent molecule is H 2 O solvate.
  • composition is intended to encompass a product containing a specified amount of a specified ingredient, as well as any product derived directly or indirectly from a combination of a specified amount of a specified ingredient.
  • pharmaceutically acceptable means that the carrier, diluent or excipient must be compatible with the other ingredients in the formulation and not harmful to the recipient of the drug.
  • the term "pharmaceutically acceptable salt” is intended to include the preparation of salts of the active compounds with relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base either pure or in a suitable inert solvent.
  • the salt derived from a pharmaceutically acceptable inorganic base include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese salts, manganese, potassium, sodium, zinc, and the like.
  • Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines (including substituted amines, cyclic amines, naturally occurring amines, etc.), such as arginine, betaine, caffeine, bile Base, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethyl Piperidine, glucosamine, glucosamine, histidine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, Theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.
  • arginine betaine
  • caffeine bile Base
  • N N'-dibenzylethylenedi
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either pure or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include derivatives derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid Or phosphorous acid, etc., and derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, Salts of benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and the like
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium capable of delivering an effective amount of the active substance of the present invention without interfering with the biological activity of the active substance and without toxic side effects to the host or patient.
  • Representative carriers include water, oil, Vegetables and minerals, cream base, lotion base, ointment base, etc. These bases include suspending agents, tackifiers, transdermal enhancers, and the like. Their formulations are well known to those skilled in the field of cosmetics or topical medicine. For additional information on the carrier, see Remington: Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
  • compositions comprising a compound of formula I are usually formulated according to standard pharmaceutical practice as a pharmaceutical composition.
  • Typical formulations are prepared by mixing a compound of the invention with a diluent, carrier or excipient.
  • Suitable diluents, carriers and excipients are well known to those skilled in the art and are described in detail in, for example, Gennaro, Alfonso R., et al., Remington: The Science and Practice of Pharmacy, 21st Ed., Philadelphia: Lippincott, Williams & Wilkins, 2005 ).
  • the formulation may also include buffering agents, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacity agents, glidants, processing aids, colorants, sweeteners, One or more of fragrance, flavor, diluent, and other known additives.
  • compositions can be administered in any convenient use form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches and the like.
  • Such compositions may contain conventional components in pharmaceutical formulations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and additional active agents.
  • the compounds of the invention can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, and epidural Externally as well as intranasally, and if needed for local treatment, intralesional administration.
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, intracerebral, intraocular, intralesional, or subcutaneous administration.
  • an "effective amount" of a compound or a pharmaceutically acceptable composition is an amount effective to treat or reduce the severity of one or more of the following diseases: neuropathic pain, inflammatory pain, visceral pain, Cancer pain, chemotherapy pain, traumatic pain, surgical pain, childbirth pain, neurogenic bladder pain, ulcerative colitis pain, chronic pain, persistent pain, peripheral-mediated pain, central-mediated pain, migraine, sinus Headache, tension headache, phantom limb pain, toothache, peripheral nerve injury pain, or a combination thereof; postoperative pain, chronic headache or labor pain; HIV, HIV-induced neuropathy, trigeminal neuralgia, postherpetic neuralgia, acute Pain, heat sensitivity, sarcoidosis, irritable bowel syndrome, Crohn's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, joints Inflammation, rheumatoid arthritis, atherosclerosis, paroxysmal dystonia, myasthenic
  • the exact amount required will vary from subject to subject, depending on the type, age and general state of the subject, the severity of the infection, the particular drug, the mode of administration, and the like. It is understood that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level of any particular patient or organism will depend on a variety of factors, including the severity of the condition and condition being treated; the activity of the specific compound employed; the specific composition employed; the age, weight, General health, gender, and diet; time of administration, route of administration, and excretion rate of the specific compound used; duration of treatment; drugs used in combination with or concurrent with the specific compound used; and well-known in the medical field other factors.
  • a series of sulfonamide derivatives with novel structure are provided, which have dual inhibitory activities against Nav1.7 and Nav1.3 at the same time, and can be used as drugs for a wide range of pain treatments.
  • reaction solution was slowly poured into a saturated solution at 0 ° C
  • the ammonium chloride solution was extracted with ethyl acetate (100 mL ⁇ 3), and the organic layers were combined, washed with a saturated sodium chloride solution (50 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the obtained solid was extracted with saturated NaHCO 3 solution (10mL) and ethyl acetate (20mL). The aqueous layer was then ethyl acetate. (10 mL x 3) extraction, the organic layers were combined, washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the operation process is the same as that in Example 1, except that 1,2,4-thiadiazole-5-amine in step c is replaced with thiazol-2-amine to obtain 4-((4-chloro-2-((2- ( Ethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (thiazol-2-yl) -benzenesulfonamide, ESI-MS (m / z): 502.1 [M + H] + .
  • the operation process is the same as in Example 1, except that 1,2,4-thiadiazole-5-amine in step c is replaced with thiazol-4-amine to obtain 4-((4-chloro-2-((2- ( Ethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (thiazol-4-yl) -benzenesulfonamide, ESI-MS (m / z): 502.1 [M + H] + .
  • the operation process is the same as in Example 1, except that the 1,2,4-thiadiazole-5-amine in step c is replaced with 1,2,4-oxadiazole-3-amine to obtain 4-((4-chloro 2-((2- (ethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (1,2,4-oxadiazol-3-yl) -benzenesulfonamide , ESI-MS (m / z): 487.0 [M + H] + .
  • the operation process is the same as in Example 1, except that the (2-aminoethyl) (ethyl) t-butyl carbamate in step a is replaced by ethyl (2-methylamino) (ethyl) t-butyl carbamate.
  • the operation process is the same as in Example 1, except that (2-aminoethyl) (ethyl) t-butyl carbamate in step a was replaced with (3-aminopropyl) (ethyl) t-butyl carbamate, respectively.
  • the operation process is the same as in Example 1, except that (2-aminoethyl) (ethyl) t-butyl carbamate in step a was replaced with (3-aminopropyl) (ethyl) t-butyl carbamate, respectively.
  • the operation process is the same as in Example 1, except that (2-aminoethyl) (ethyl) t-butyl carbamate in step a was replaced with (3-aminopropyl) (ethyl) t-butyl carbamate, respectively.
  • step c The 1,2,4-thiadiazole-5-amine in step c was replaced with 1,2,4-oxadiazole-3-amine to obtain 4-((4-chloro-2-((3- (ethyl Amino) propyl) amino) benzyl) amino) -2,5-difluoro-N- (1,2,4-oxadiazol-3-yl) -benzenesulfonamide, ESI-MS (m / z) : 501.1 [M + H] + .
  • the operation process is the same as in Example 1, except that (2-aminoethyl) (ethyl) t-butyl carbamate in step a was replaced with (3-aminopropyl) (ethyl) t-butyl carbamate, respectively.
  • step a The operation procedure is the same as in Example 1, except that the (2-aminoethyl) (ethyl) carbamic acid tert-butyl ester in step a is replaced with N 1 , N 1 -dimethyl-1,2-ethylenediamine, Substituting 1,2,4-thiadiazole-5-amine with 1,2,4-oxadiazole-3-amine in step c to obtain 4-((4-chloro-2-((2- ( Dimethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (1,2,4-oxadiazol-3-yl) -benzenesulfonamide, ESI-MS (m / z): 487.0 [M + H] + .
  • the operation procedure is the same as in Example 1, except that the (2-aminoethyl) (ethyl) carbamic acid tert-butyl ester in step a is replaced with N 1 , N 1 -dimethyl-1,2-ethylenediamine, Substitute 1,2,4-thiadiazole-5-amine in step c with thiazol-2-amine to obtain 4-((4-chloro-2-((2- (dimethylamino) ethyl) amino ) Benzyl) amino) -2,5-difluoro-N- (thiazol-2-yl) -benzenesulfonamide, ESI-MS (m / z): 502.1 [M + H] + .
  • the operation process is the same as in Example 1, except that the (2-aminoethyl) (ethyl) carbamic acid tert-butyl ester in step a is replaced with 2-morpholinylethylamine, and 1, 2, 4 in step c are replaced.
  • -Thiadiazol-5-amine was replaced with 1,2,4-oxadiazol-3-amine to give 4-((4-chloro-2-((2-morpholinethyl) amino) benzyl) amino ) -2,5-difluoro-N- (1,2,4-oxadiazol-3-yl) -benzenesulfonamide, ESI-MS (m / z): 529.0 [M + H] + .
  • the operation process is the same as in Example 1, except that (2-aminoethyl) (ethyl) t-butyl carbamate in step a was replaced with (3-aminopropyl) (ethyl) t-butyl carbamate, respectively.
  • the operation process is the same as in Example 1, except that 4-chloro-2-fluorobenzonitrile in step a is replaced with 2-fluoro-4-trifluoromethylbenzonitrile, and 1, 2, 4 in step c are replaced.
  • -Thiadiazole-5-amine is replaced with 5-fluorothiazol-2-amine to give 4-((2-((2- (ethylamino) ethyl) amino) -4- (trifluoromethyl) benzyl) (Amino) -2,5-difluoro-N- (5-fluorothiazol-2-yl) -benzenesulfonamide, ESI-MS (m / z): 554.0 [M + H] + .
  • the operation process is the same as in Example 1, except that (2-aminoethyl) (ethyl) t-butyl carbamate in step a was replaced with (3-aminopropyl) (ethyl) t-butyl carbamate, respectively.
  • Example 2 The operation was the same as in Example 1, except that 4-chloro-2-fluorobenzonitrile in step a was replaced with 2-fluoro-4-methoxybenzonitrile to obtain 4-((2-((2- ( Ethylamino) ethyl) amino) -4-methoxybenzyl) amino) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide, ESI -MS (m / z): 499.0 [M + H] + .
  • the operation process is the same as in Example 1, except that (2-aminoethyl) (ethyl) t-butyl carbamate in step a was replaced with (3-aminopropyl) (ethyl) t-butyl carbamate, respectively.
  • the operation process is the same as in Example 1, except that (2-aminoethyl) (ethyl) t-butyl carbamate in step a was replaced with (3-aminopropyl) (ethyl) t-butyl carbamate, respectively.
  • the operation process is the same as in Example 1, except that (2-aminoethyl) (ethyl) t-butyl carbamate in step a was replaced with (3-aminopropyl) (ethyl) t-butyl carbamate, respectively.
  • the operation process is the same as in Example 1, except that 4-chloro-2-fluorobenzonitrile in step a is replaced with 2-fluoro-4-trifluoromethylbenzonitrile, and 1, 2, 4 in step c are replaced.
  • -Thiadiazole-5-amine is replaced with 5-chlorothiazol-2-amine
  • 2,4,5-trifluorophenyl-1-sulfonyl chloride in step d is replaced with 2-chloro-4,5-difluoro Phenyl-1-sulfonyl chloride substitution to give 2-chloro-N- (5-chlorothiazol-2-yl) -4-((2-((2- (ethylamino) ethyl) amino) -4- ( Trifluoromethyl) benzyl) amino) -5-fluorobenzenesulfonamide, ESI-MS (m / z): 586.1 [M + H] + .
  • the operation process is the same as in Example 1, except that the (2-aminoethyl) (ethyl) t-butyl carbamate in step a is replaced by ethyl (2-methylamino) (ethyl) t-butyl carbamate.
  • step a The operation procedure is the same as in Example 1, except that the (2-aminoethyl) (ethyl) tert-butyl carbamate in step a is respectively ethyl (2-methylaminoethyl) (ethyl) tert-butyl carbamate
  • 4-chloro-2-fluorobenzonitrile was replaced with 2-fluoro-4-methoxybenzonitrile
  • 2,4,5-trifluorophenyl-1-sulfonyl chloride in step d was replaced with 2- Replacement of chloro-4,5-difluorophenyl-1-sulfonyl chloride to give 2-chloro-4-((2-((2- (ethylamino) ethyl) (methyl) amino) -4-methoxy Benzyl) amino) -5-fluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide, ESI-MS (m /
  • the operation process is the same as in Example 1, except that the (2-aminoethyl) (ethyl) t-butyl carbamate in step a is replaced with (3-aminopropyl) (ethyl) t-butyl carbamate, 4 -Chloro-2-fluorobenzonitrile was replaced with 5-chloro-2-fluorobenzonitrile, and 2,4,5-trifluorophenyl-1-sulfonyl chloride in step d was replaced with 2-chloro-4,5 -Difluorophenyl-1-sulfonyl chloride to give 2-chloro-4-((5-chloro-2-((3- (ethylamino) propyl) amino) benzyl) amino) -5-fluoro- Preparation of N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide, ESI-MS (m / z): 533.1 [M + H
  • the operation process is the same as in Example 1, except that the (2-aminoethyl) (ethyl) t-butyl carbamate in step a is replaced by ethyl (2-methylamino) (ethyl) t-butyl carbamate.
  • 4-chloro-2-fluorobenzonitrile was replaced with 2-fluorobenzonitrile, and 1,2-4-thiadiazole-5-amine in step c was replaced with 5-chloro-thiazole-2-amine.
  • step d The 2,4,5-trifluorophenyl-1-sulfonyl chloride in step d was replaced with 2-chloro-4,5-difluorophenyl-1-sulfonyl chloride to obtain 2-chloro-N- (5-chloro Thiazol-2-yl) -4-((2-((2- (ethylamino) ethyl) (methyl) amino) benzyl) amino) -5-fluoro-benzenesulfonamide, ESI-MS (m / z): 532.0 [M + H] + .
  • the operation process is the same as in Example 1, except that 2,4,5-trifluorophenyl-1-sulfonyl chloride in step d is replaced with 2,4-difluorophenyl-1-sulfonyl chloride to obtain 4-(( 4-chloro-2-((2- (ethylamino) ethyl) amino) benzyl) amino) -2-fluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide , ESI-MS (m / z): 484.9 [M + H] + .
  • the operation process is the same as in Example 1, except that (2-aminoethyl) (ethyl) t-butyl carbamate in step a was replaced with (3-aminopropyl) (ethyl) t-butyl carbamate, respectively.
  • the operation process is the same as in Example 1, except that (2-aminoethyl) (ethyl) t-butyl carbamate in step a was replaced with (3-aminopropyl) (ethyl) t-butyl carbamate, respectively.
  • Example 2 The operation was the same as in Example 1, except that 4-chloro-2-fluoro-benzonitrile in step a was replaced with 4-chloro-2-fluoro-phenylacetonitrile to obtain 4-((4-chloro-2-(( 2- (ethylamino) ethyl) amino) phenethyl) amino) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide, ESI-MS (m / z): 517.1 [M + H] + .
  • the operation process is the same as steps a-b in the first embodiment.
  • step f in Example 1 The operation process is the same as step f in Example 1, except that (2-((5-chloro-2-(((4- (N- (2,4-dimethoxybenzyl) -N- (1, 2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorophenyl) amino) methyl) phenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester (2-((5-chloro-2-((((4- (N- (2,4-dimethoxybenzyl) -N- (1,2,4-thiadiazol-5-yl) amine Sulfonyl) -2,5-difluorophenyl) amino) methyl) phenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester was substituted to give 4-((4-chlor
  • the operation process is the same as step a in Example 1.
  • the preparation process is the same as step c in Example 1.
  • the preparation process is the same as step d in Example 1.
  • the obtained solid was extracted with saturated NaHCO 3 solution (10 mL) and ethyl acetate (20 mL x 4). The organic layers were combined. It was washed with saturated sodium chloride (40 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure.
  • Example 36 The operation was the same as in Example 36, except that the (2-aminoethyl) (ethyl) carbamic acid tert-butyl ester in step a was replaced with 2- (pyrrol-1-yl) ethylamine to obtain 4-((4- Chloro-2-((2- (pyrrole-1-yl) ethyl) amino) benzyloxy) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl)- Phenylsulfonamide, ESI-MS (m / z): 529.9 [M + H] + .
  • step c in Example 36 The operation was the same as step c in Example 36, except that (2-((tert-butoxycarbonyl) (5-chloro-2-cyanophenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester Substituting (2-((5-chloro-2-cyanophenyl) (methyl) amino) ethyl) (ethyl) carbamate to give (2-((2- (aminomethyl) -5-chlorophenyl) (methyl) amino) ethyl) (ethyl) -t-butyl carbamate, ESI-MS (m / z): 342.2 [M + H] + .
  • step d in Example 36 The operation was the same as step d in Example 36, except that (2-((2- (aminoethyl) -5-chlorophenyl) (tert-butoxycarbonyl) amino) ethyl) (ethyl) -carbamic acid Tert-butyl ester was replaced with (2-((2- (aminomethyl) -5-chlorophenyl) (methyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester, ESI-MS (m / z): 343.2 [M + H] + .
  • the preparation process is the same as step e in Example 36.
  • the preparation process is the same as step f in Example 36.
  • the preparation process is the same as step g in Example 36, except that (2-((tert-butoxycarbonyl) (5-chloro-2- (hydroxymethyl) phenyl) amino) ethyl) (ethyl) -carbamic acid Tert-butyl ester was replaced with (2-((5-chloro-2- (hydroxymethyl) phenyl) (methyl) amino) ethyl) (ethyl) carbamic acid tert-butyl ester to give (2-((5 -Chloro-2-((4- (N- (2,4-dimethoxybenzyl) -N- (1,2,4-thiadiazol-5-yl) sulfonamido) -2,5 -Difluorophenoxy) methyl) phenyl) (meth) amino) ethyl) (ethyl) -tert-butyl carbamate, ESI-MS (m / z): 768.1 [
  • the preparation process is the same as step h in Example 36, except that (2-((tert-butoxycarbonyl) (ethyl) amino) ethyl) (5-chloro-2-((4- (N- (2,4 -Dimethoxybenzyl) -N- (1,2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorophenoxy) methyl) benzyl) -carbamic acid Tert-butyl ester is used for (2-((5-chloro-2-((4- (N- (2,4-dimethoxybenzyl) -N- (1,2,4-thiadiazole-5- Sulfonamide) -2,5-difluorophenoxy) methyl) phenyl) (methyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester to obtain 4-((4 -Chloro-2-((2-
  • Example 38 The operation was the same as in Example 38, except that 1,1,2,4-thiadiazole-5-amine in step e was replaced with 5-fluoro-thiazole-2-amine to obtain 4-((4-chloro-2- ( (2- (ethylamino) ethyl) (methyl) amino) benzyloxy) -2,5-difluoro-N- (5-fluorothiazol-2-yl) -benzenesulfonamide, ESI-MS (m / z): 535.1 [M + H] + .
  • Example 38 The operation was the same as in Example 38, except that the 4-chloro-2-fluorobenzonitrile in step b was replaced with 2-fluoro-4-methoxybenzonitrile, and the 1, 2, 4- in step e Replace thiadiazole-5-amine with 5-fluorothiazol-2-amine to give 4-((2-((2- (ethylamino) ethyl) (methyl) amino) -4- (methoxy) Benzyloxy) -2,5-difluoro-N- (5-chlorothiazol-2-yl) -benzenesulfonamide, ESI-MS (m / z): 547.0 [M + H] + .
  • Example 38 The operation was the same as in Example 38, except that the 4-chloro-2-fluorobenzonitrile in step b was replaced with 2-fluoro-4-trifluoromethylbenzonitrile, and 2,4,5 in step f -Trifluorophenyl-1-sulfonyl chloride was replaced with 2-chloro-4,5-difluorophenyl-1-sulfonyl chloride to give 2-chloro-4-((2-((2- (ethylamino) ethyl (Methyl) amino) -4- (trifluoromethyl) benzyloxy) -5-fluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide, ESI- MS (m / z): 567.9 [M + H] + .
  • Example 38 The operation was the same as in Example 38, except that the 4-chloro-2-fluorobenzonitrile in step b was replaced with 2-fluoro-4-trifluoromethylbenzonitrile, and 1,2,4 in step e -Thiadiazole-5-amine is replaced with 5-chlorothiazol-2-amine, and 2,4,5-trifluorophenyl-1-sulfonyl chloride in step f is replaced with 2-chloro-4,5-difluoro Phenyl-1-sulfonyl chloride substitution to give 2-chloro-4-((2-((2- (ethylamino) ethyl) (methyl) amino) -4- (trifluoromethyl) benzyloxy) -5-fluoro-N- (5-chlorothiazol-2-yl) -benzenesulfonamide, ESI-MS (m / z): 601.0 [M + H] + .
  • Example 36 The operation was the same as in Example 36, except that (2-aminoethyl) (ethyl) carbamic acid tert-butyl ester in step a was replaced with 2- (pyrrol-1-yl) ethylamine, and 4-chloro-2 -Fluorobenzonitrile was replaced with 2-fluoro-4-trifluoromethoxybenzonitrile to give 4-((2-((2- (pyrrole-1-yl) ethyl) amino) -4- (tri Fluoromethoxy) benzyloxy) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide, ESI-MS (m / z): 580.0 [ M + H] + .
  • Example 36 The operation was the same as that in Example 36, except that 4-chloro-2-fluorobenzonitrile in step a was replaced with 2-fluoro-4-trifluoromethoxybenzonitrile, and 1, 2 in step e, 4-thiadiazole-5-amine was replaced with 1,2,4-thiadiazole-3-amine to give 4-((2-((2- (ethylamino) ethyl) amino) -4- (tri Fluoromethoxy) benzyloxy) -2,5-difluoro-N- (1,2,4-oxadiazol-3-yl) -benzenesulfonamide, ESI-MS (m / z): 538.1 [ M + H] + .
  • Example 48 The operation was the same as that in Example 48, except that (2-aminoethyl) (ethyl) carbamic acid tert-butyl ester in a was replaced with 2- (pyrrol-1-yl) ethylamine to obtain 4-((4-chloro -2-((2- (pyrrole-1-yl) ethyl) amino) benzyloxy) -2,5-difluoro-N- (methylcarbamoyl) -benzenesulfonamide, ESI-MS (m / z): 525.1 [M + Na] + .
  • Example 2 The operation was the same as in Example 1, except that 4-chloro-2-fluoro-benzonitrile in step a was replaced with 5-chloro-3-fluoropyridine-2-carbonitrile to obtain 4-(((5-chloro- 3-((2- (ethylamino) ethyl) amino) pyridin-2-yl) methyl) amino) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl ) -Benzenesulfonamide, ESI-MS (m / z): 504.1 [M + H] + .
  • step a in Example 1 The operation process is the same as step a in Example 1, except that 4-chloro-2-fluorobenzonitrile is replaced with 4-chloro-2-fluoro-1-nitrobenzene to obtain (2-((5-chloro- 2-nitrophenyl) amino) ethyl) (ethyl) -t-butyl carbamate.
  • step b in Example 36 The operation was the same as step b in Example 36, except that (2-((5-chloro-2-cyanophenyl) amino) ethyl) (ethyl) carbamic acid tert-butyl ester was used (2-((5 -Chloro-2-nitrophenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester to obtain (2-((tert-butoxycarbonyl) (5-chloro-2-nitrophenyl) Amino) ethyl) (ethyl) -t-butyl carbamate.
  • step d in Example 36 The operation was the same as step d in Example 36, except that ((2-((2- (aminoethyl) -5-chlorophenyl) (tert-butoxycarbonyl) amino) ethyl) (ethyl) -amino Tert-butyl formate was replaced with (2-((2-amino-5-chlorophenyl) (tert-butoxycarbonyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester to obtain (2-((tert Butoxycarbonyl) (5-chloro-2-hydroxyphenyl) amino) ethyl) (ethyl) -t-butyl carbamate.
  • the operation process is the same as in Example 1, except that the (2-aminoethyl) (ethyl) carbamic acid tert-butyl ester in step a is replaced with 2- (homoperidin-1-yl) ethylamine to obtain 4- ((2-((2- (Homopiperidin-1-yl) ethyl) amino) -4-chlorobenzyl) amino) -2,5-difluoro-N- (1,2,4-thiadi Azol-5-yl) -benzenesulfonamide, ESI-MS (m / z): 557.2 [M + H] + .
  • the operation process is the same as in Example 1, except that 1, 2, 4-thiadiazole-5-amine in step c is replaced with pyrimidine-4-amine to obtain 4-((4-chloro-2-((2- ( Ethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (pyrimidin-4-yl) -benzenesulfonamide, ESI-MS (m / z): 497.2 [M + H] + .
  • the operation process is the same as in Example 1, except that 1, 2, 4-thiadiazole-5-amine in step c is replaced with 6-fluoropyridin-2-amine to obtain 4-((4-chloro-2-(( 2- (ethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (6-fluoropyridin-2-yl) -benzenesulfonamide, ESI-MS (m / z): 514.0 [M + H] + .
  • step a in Example 1 The operation was the same as step a in Example 1, except that 4-chloro-2-fluoro-benzonitrile was replaced with 4-chloro-2-fluoro-benzoic acid methyl ester to obtain 2-((2-((tert-butyl Oxycarbonyl) (ethyl) amino) ethyl) amino) -4-chlorobenzoic acid methyl ester.
  • step d in Example 1 The operation process is the same as step d in Example 1, except that 2,4,5-trifluoro-benzenesulfonyl chloride is replaced with 2,5-difluoro-4-nitrobenzene-1-sulfonyl chloride to obtain N- (2 , 4-dimethoxybenzyl) -2,5-difluoro-4-nitro-N- (1,2,4-thiadiazol-5-yl) benzenesulfonamide.
  • step c in Example 51 The operation was the same as step c in Example 51, except that (2-((tert-butoxycarbonyl) (5-chloro-2-nitrophenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester Replace with N- (2,4-dimethoxybenzyl) -2,5-difluoro-4-nitro-N- (1,2,4-thiadiazol-5-yl) benzenesulfonamide, N- (2,4-dimethoxybenzyl) -2,5-difluoro-4-amino-N- (1,2,4-thiadiazol-5-yl) benzenesulfonamide was obtained.
  • reaction solution was poured into water, extracted with ethyl acetate (10 mL x 3), and the organic layers were combined, followed by saturated aqueous ammonium chloride solution (10 mL x 3), water (10 mL), and saturated chloride. It was washed with aqueous sodium solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • step f in Example 1 The operation process is the same as step f in Example 1, except that (2-((5-chloro-2-(((4- (N- (2,4-dimethoxybenzyl) -N- (1, 2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorophenyl) amino) methyl) phenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester (2-((tert-butoxycarbonyl) (ethyl) amino) ethyl) (5-chloro-2-((4- (N- (2,4-dimethoxybenzyl) -N- (1 , 2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorophenyl) carbamoyl) phenyl) carbamic acid tert-butyl ester to obtain N- (4
  • step a in Example 1 The operation process is the same as step a in Example 1, except that 4-chloro-2-fluorobenzonitrile is replaced with 4-chloro-2-fluoro-1-nitrobenzene to obtain (2-((5-chloro- 2-nitrophenyl) amino) ethyl) (ethyl) -t-butyl carbamate.
  • step b in Example 36 The operation was the same as step b in Example 36, except that (2-((5-chloro-2-cyanophenyl) amino) ethyl) (ethyl) carbamic acid tert-butyl ester was used (2-((5 -Chloro-2-nitrophenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester to obtain (2-((tert-butoxycarbonyl) (5-chloro-2-nitrophenyl) Amino) ethyl) (ethyl) -t-butyl carbamate.
  • Step f Preparation of methyl 4- (chlorosulfonyl) -2,5-difluorobenzoate
  • step d in Example 1 The operation process is the same as step d in Example 1, except that 2,4,5-trifluoro-benzenesulfonyl chloride is replaced with 4- (chlorosulfonyl) -2,5-difluorobenzoic acid methyl ester to obtain 4- ( N- (2,4-dimethoxybenzyl) -N- (1,2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorobenzoate.
  • reaction was stirred at room temperature for 20 hours. After the reaction was completed, the reaction solution was poured into water, extracted with ethyl acetate (10 mL x 3), and the organic layers were combined, followed by saturated ammonium chloride solution (10 mL x 3), water (10 mL), and saturated. It was washed with sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • step f in Example 1 The operation process is the same as step f in Example 1, except that (2-((5-chloro-2-(((4- (N- (2,4-dimethoxybenzyl) -N- (1, 2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorophenyl) amino) methyl) phenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester (2-((tert-butoxycarbonyl) (ethyl) amino) ethyl) (5-chloro-2- (4- (N- (2,4-dimethoxybenzyl) -N- (1, 2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorobenzamide) phenyl) -carbamic acid tert-butyl ester to give 4- (N- (1,2,4 -Th
  • step d in Example 1 The operation was the same as step d in Example 1, except that 2,4,5-trifluoro-benzenesulfonyl chloride was replaced with 4-bromo-2,5-difluoro-benzenesulfonyl chloride to obtain 4-bromo-N- ( 2,4-dimethoxybenzyl) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide.
  • step f in Example 1 The operation process is the same as step f in Example 1, except that (2-((5-chloro-2-(((4- (N- (2,4-dimethoxybenzyl) -N- (1, For 2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorophenyl) amino) methyl) phenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester (2-((tert-butoxycarbonyl) (ethyl) amino) ethyl) (5-chloro-2-((4- (N- (2,4-dimethoxybenzyl) -N- (1 , 2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorophenyl) amino) phenyl) -carbamic acid tert-butyl ester to obtain 4-((4
  • step f in Example 1 The operation process is the same as step f in Example 1, except that (2-((5-chloro-2-(((4- (N- (2,4-dimethoxybenzyl) -N- (1, For 2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorophenyl) amino) methyl) phenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester (2-((5-chloro-2-((4- (N- (2,4-dimethoxybenzyl) -N- (1,2,4-thiadiazol-5-yl) sulfonamide Group) -2,5-difluorobenzamide) methyl) phenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester to obtain 4- (N- (1,2,4-thiophene) Dia
  • step b in Example 1 The operation was the same as step b in Example 1, except that (2-((5-chloro-2-cyanophenyl) amino) ethyl) (ethyl) carbamic acid tert-butyl ester was treated with 4-cyano-N -(2,4-dimethoxybenzyl) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl) benzenesulfonamide substitution to give 4- (aminomethyl ) -N- (2,4-dimethoxybenzyl) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide.
  • Membrane voltage clamp electrophysiology allows direct measurement and quantification of blockade of voltage-gated sodium channels (NaV), as well as determination of time and voltage dependence of blockade, which has been interpreted as resting, open, and Differential binding of inactive states (Hille, B. et al., Journal of General Physiology (1977), 69: 497-515).
  • the representative compound of the present invention is a stable HEK293 cell line (purchased from Kyowa Cell Bank) transfected with a specific ion channel, and the effect of the compound on the ion channel current is measured by a manual patch clamp test.
  • the manual patch clamp experiment protocol is as follows:
  • the HEK293 cell line stably expressed by hNav1.7 sodium channel was cultured in DMEM medium containing 10% fetal bovine serum and 0.2 mg / mL Hygromycin B.
  • the culture temperature was 37 ° C and the concentration of CO 2 was 5%. After the stage, the cells are passaged. The method is to remove the old medium and wash it once with PBS, then add 1 mL of Trypsin-EDTA solution, and incubate at 37 ° C for one minute.
  • the CHO cell line stably expressed by hNav1.5 sodium channel was cultured in F12 medium containing 10% fetal bovine serum at a culture temperature of 37 ° C and a CO2 concentration of 5%. After the cells had grown to a certain stage, the cells were passaged. The method is to remove the old medium and wash it once with PBS, then add 1mL de 0.25% -Trypsin-EDTA solution, and incubate for one minute at 37 ° C.
  • the HEK293 cell line stably expressed by hNav1.3 sodium channel was cultured in DMEM medium containing 10% fetal bovine serum and 1.2 mg / mL G418 at a culture temperature of 37 ° C and a CO 2 concentration of 5%; when the cells grew to a certain stage Then, passaging the cells, the method is to remove the old medium and wash it once with PBS, then add 1mL of Trypsin-EDTA solution, and incubate at 37 ° C for one minute.
  • the compound prepared in the examples of the present invention was dissolved in dimethyl sulfoxide (DMSO) and prepared into a 10 mM DMSO stock solution for experiments.
  • the whole cell patch clamp records the hNav1.7, hNav1.5, and hNav1.3 sodium channel current voltage stimulation schemes as follows: When a whole cell seal is formed, the cell voltage is clamped at -120mV, the clamp voltage is depolarized to 0mV for 20 milliseconds, and then The voltage was restored to -75mV for 8 seconds, then the cell membrane potential was restored to -120mV for 20ms, then the depolarization was reduced to 0mV for 20ms, and finally the clamp voltage was returned to -120mV for 30ms, repeated every 20 seconds Data were collected to observe the effect of the drug on the peak currents of hNav1.7, hNav1.5 and hNav1.3 sodium channels.
  • a capillary electrode tube (BF150-86-10, Sutter Instruments) was drawn into a recording electrode using a microelectrode drawing instrument (P97, Sutter Instruments).
  • a microelectrode manipulator (86PW420600, MCI Instruments) was operated under an inverted microscope (AE31E, Motic) to contact the recording electrode with the cells, and suction was applied under negative pressure to form a G ⁇ seal. After forming a G ⁇ seal, perform fast capacitance compensation, then continue to apply negative pressure, suck through the cell membrane to form a whole-cell recording mode, and then perform slow capacitance compensation and record the membrane capacitance and series resistance.
  • hNav1.7 IC 50 : + (> 1 ⁇ M), ++ (100nM ⁇ 1 ⁇ M), +++ (50 ⁇ 100nM), ++++ ( ⁇ 50nM)
  • hNav1.5 IC 50 : + (> 1 ⁇ M), ++ (100nM ⁇ 1 ⁇ M), +++ (50 ⁇ 100nM), ++++ ( ⁇ 50nM)
  • hNav1.3 IC 50 : + (> 1 ⁇ M), ++ (100nM ⁇ 1 ⁇ M), +++ (50 ⁇ 100nM), ++++ ( ⁇ 50nM)
  • Example 27 ++++ +++ Example 62 + +++ Example 28 ++++ +++ Example 63 ++ + Example 29 ++++++++++ Example 64 ++++ + Example 30 ++++ ++ Example 65 +++ + Example 31 ++++ ++++ Example 66 ++++ + Example 32 ++++++++++ Zh Zh Zh Example 33 +++ ++++++ Zh Zh Zh Example 34 +++ ++++++ Zh Zh Zh Example 35 ++++ ++++++++ Zh Zh Zh
  • Formalin-induced plantar pain in mice is widely used in behavioral pharmacology research related to inflammatory pain, which mainly reflects moderate to severe acute and chronic pain caused by chemical stimulation. Its pain behavior is divided into two different pains.
  • the phase phases of the mechanism are the first phase and the second phase.
  • the first phase mainly reflects the acute pain caused by the chemical stimuli directly acting on the nociceptors
  • the second phase mainly reflects the inflammatory response of peripheral tissues and Spinal dorsal horn-induced functional changes should cause delayed, continuous nociceptive pain.
  • This model can better simulate clinical chronic pain, and it is currently recognized at home and abroad as a relatively reliable animal pain model.
  • the present invention uses a formalin-induced mouse plantar pain model to measure the analgesic activity of a representative compound. Experimental materials and reagents
  • SPF-grade Kunming mice were provided by Chengdu Dashuo Experimental Animal Co., Ltd. (Certificate No .: SCXK (Sichuan) 2015-030).
  • the feeding environment was alternated with 12h light and 12h dark, and the ambient temperature was controlled at 22-25 ° C.
  • the compound disclosed by the present invention has a purity of> 98%, and it is used at a concentration required before use.
  • the remaining reagents are commercially available analytical grade.
  • mice Take 110 Kunming mice, all males, weighing 22-26g, randomly divided into 11 groups, 10 in each group.
  • the normal saline group was the blank control group
  • the formalin group was the model control group
  • the rest were the experimental group.
  • the mice were placed in a transparent glass box for 30 minutes before the day of administration.
  • the experimental group was administered with the test compound 30 mg / kg by gavage.
  • the control group was given the same amount of blank vehicle by gavage.
  • 25 ⁇ L of 5% formalin was subcutaneously injected into the left hind plantar of the mice with a micro syringe, and the mice in the blank control group were injected 25 ⁇ L of normal saline subcutaneously into the left hind plantar of the mice.
  • the stopwatch observes and records the pain response of mice (the time of licking / biting the injection foot) every 5 minutes, in which 0-10min is the acute phase and is also called the first phase, and 10-40min is the continuous phase and is also called the second phase.
  • the first phase of formalin-induced mouse plantar pain model mainly reflects the acute pain produced by chemical stimuli directly acting on nociceptors
  • the second phase mainly reflects the inflammatory response of peripheral tissues and the spinal dorsal horn mediator. Delayed, continuous nociceptive pain caused by changes in the function of the liver can better simulate human clinical diseases such as chronic neuropathic pain. Therefore, the analgesic effect of the compound of the present invention on the second phase is mainly examined.
  • the formula for calculating the pain relief rate is: [[1- (pain response time in the experimental group-pain response time in the blank group) / (pain response time in the model group-pain response time in the blank group)] ⁇ 100% ⁇ .
  • GraphPad Prism software was used for statistical analysis. The experimental data were expressed as mean standard deviation. The experimental results are shown in Table 3.
  • Example 1 Numbering Second-phase pain relief rate (%) Example 1 65.8 ⁇ 9.5 Example 2 40.7 ⁇ 9.8 Example 3 60.0 ⁇ 10.2 Example 8 52.6 ⁇ 6.3 Example 15 55.3 ⁇ 12.5 Example 17 67.1 ⁇ 18.0 Example 18 68.5 ⁇ 17.1 Example 23 53.0 ⁇ 15.8 Example 41 65.0 ⁇ 7.2 Example 52 30.2 ⁇ 2.7 PF-05089771 22.4 ⁇ 11.3
  • the compound disclosed in the present invention can significantly reduce the licking / biting time and has a significant analgesic effect in the second phase.
  • the disclosed dual inhibitors of Nav1.7 and Nav1.3 have stronger analgesic effects.

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Abstract

Provided in the present invention are a sulfonamide compound serving as a sodium channel blocker and uses thereof. The compound simultaneously provides dual inhibitory activity with respect to Nav1.7 and Nav1.3 and is applicable as a medicament for widespread pain treatment.

Description

作为钠通道阻滞剂的磺酰胺类化合物及其用途Sulfonamides as sodium channel blockers and uses thereof 技术领域Technical field
本发明涉及对钠离子通道，特别是对Nav1.3和Nav1.7钠离子通道具有双重抑制活性的磺酰胺类化合物及其用途。The invention relates to a sulfonamide compound having dual inhibitory activities on sodium ion channels, in particular on Nav1.3 and Nav1.7 sodium ion channels, and uses thereof.
背景技术Background technique
电压门控钠通道(voltage-gated sodium channels,VGSCs)是神经元等可兴奋细胞膜上广泛分布的一种微孔跨膜糖蛋白，主要负责Na +的跨膜转运，是神经元产生兴奋性、发挥正常电生理功能所需的最主要离子通道。电压门控钠通道由一个α亚基和多个β亚基组成，其中α亚基是主要的功能性单位，目前已发现9种亚型(Nav1.1～Nav1.9)。其由4个高度相似的同源结构域围绕一个中心，形成离子通道的中央孔，每个结构域有6个α螺旋跨膜片段(S1-S6)，其中S4的氨基酸序列高度保守，被认为是电压门控钠通道的电压感受器。β亚基有4种亚型(β1-β4)，对α亚基在膜上的定位及稳定性起辅助作用，并参与调节α亚基的电压敏感性和失活过程。不同动物的电压门控钠通道存在广泛的同源性，但也存在很大差异。根据被河豚毒素(TTX)阻断的敏感性将钠离子通道分为TTX敏感型(TTX-S)和TTX不敏感型(TTX-R)。TTX-R型钠离子通道包括Nav1.5、Nav1.8和Nav1.9，其余均为TTX-S型钠离子通道。 Voltage-gated sodium channels (VGSCs) are a type of microporous transmembrane glycoprotein widely distributed on excitable cell membranes such as neurons. They are mainly responsible for the transmembrane transport of Na + . The most important ion channel required for normal electrophysiological functions. Voltage-gated sodium channels are composed of an alpha subunit and multiple beta subunits, of which the alpha subunit is the main functional unit. Nine subtypes have been found (Nav1.1 to Nav1.9). It consists of four highly similar homologous domains surrounding a center to form the central pore of the ion channel. Each domain has six alpha helix transmembrane fragments (S1-S6). The amino acid sequence of S4 is highly conserved and is considered It is a voltage sensor for voltage-gated sodium channels. There are four subtypes of β subunits (β1-β4), which assist the positioning and stability of the α subunit on the membrane, and participate in regulating the voltage sensitivity and inactivation of the α subunit. Extensive homology exists in voltage-gated sodium channels in different animals, but there are also large differences. According to the sensitivity of being blocked by tetrodotoxin (TTX), sodium ion channels are divided into TTX-sensitive (TTX-S) and TTX-insensitive (TTX-R). TTX-R type sodium ion channels include Nav1.5, Nav1.8, and Nav1.9, and the rest are TTX-S type sodium ion channels.
生理学及药理学研究(Catterall,WA.et al.Pharmacol.Rev.2005,57,397-409)已经证明哺乳动物9种钠通道的表达特性和药理学特征如表1所示：Physiological and pharmacological studies (Catterall, WA. Et al. Pharmacol. Rev. 2005, 57, 397-409) have proven that the expression characteristics and pharmacological characteristics of nine mammalian sodium channels are shown in Table 1:
表1Table 1
VGSC亚型VGSC subtype 表达基因Expressed genes 主要组织分布Main organization distribution 功能异常/适应症Dysfunction / Indication
Nav1.1Nav1.1 SCN1ASCN1A CNS、PNSCNS, PNS 疼痛、癫痫、神经变性Pain, epilepsy, neurodegeneration
Nav1.2Nav1.2 SCN2ASCN2A CNSCNS 神经变性、癫痫Neurodegeneration, epilepsy
Nav1.3Nav1.3 SCN3ASCN3A CNSCNS 疼痛、癫痫Pain, epilepsy
Nav1.4Nav1.4 SCN4ASCN4A 骨骼肌Skeletal muscle 肌强直Muscle rigidity
Nav1.5Nav1.5 SCN5ASCN5A 心肌Myocardium 与心律不齐有关Related to arrhythmia
Nav1.6Nav1.6 SCN8ASCN8A CNSCNS 疼痛、运动障碍Pain, dyskinesia
Nav1.7Nav1.7 SCN9ASCN9A PNSPNS 疼痛pain
Nav1.8Nav1.8 SCN10ASCN10A PNSPNS 疼痛pain
Nav1.9Nav1.9 SCN11ASCN11A PNSPNS 疼痛pain
其中，Nav1.1、Nav1.6、Nav1.7、Nav1.8和Nav1.9在正常成年动物DRG的神经元中表达，而Nav1.3在非成熟神经元中表达较高。背根神经节上的伤害感受器将各种伤害性热、机械、化学信号转化成电脉冲传递至中枢神经系统，而Nav决定了动作电位的产生和传播，其功能性改变对神经元的兴奋性及痛觉传导具有重要影响。目前已知与疼痛密切相关的亚型包括：Nav1.3、Nav1.7、Nav1.8、Nav1.9。Among them, Nav1.1, Nav1.6, Nav1.7, Nav1.8, and Nav1.9 are expressed in neurons of DRG in normal adult animals, while Nav1.3 is highly expressed in immature neurons. The nociceptors on the dorsal root ganglion convert various nociceptive thermal, mechanical, and chemical signals into electrical impulses and transmit them to the central nervous system. Nav determines the generation and transmission of action potentials, and its functional changes change the excitability of neurons. And pain conduction has important effects. The subtypes currently known to be closely related to pain include: Nav1.3, Nav1.7, Nav1.8, Nav1.9.
Nav1.7是SCN9A编码的跨膜蛋白，特异性表达于外周感觉神经末梢和交感神经节神经元，并主要在大直径DRG神经元和无髓鞘小直径DRG上表达，即在85％的伤害性感受器上表达，这说明Nav1.7对痛觉传导具有非常关键的作用。动物模型研究表明，在角叉菜胶和完全弗氏佐剂(CFA)诱导炎性痛模型中，Nav1.7蛋白或mRNA表达增加，而这些改变主要发生在DRG神经元或传入神经元。在角叉菜胶炎性痛模型中还同时检测到DRG神经元中TTX-S电流增加。在大鼠糖尿病神经痛模型中，Nav1.7蛋白表达增加。敲低DRG中的Nav1.7可使动物热痛敏、机械痛敏和冷痛觉超敏得以缓解。近期的研究还发现，DRG和交感神经节中的Nav1.7分别参与不同类型的疼痛信息传递。条件性敲除小鼠DRG中的Nav1.7后，基础机械痛阀和热痛阀显著升高，同时4％甲醛引起的炎性痛也得以缓解。而在人类疾病研究中，当SCN9A基因突变导致Nav1.7开放后不易失活，导致其功能增强，属于“功能增强型突变”，从而引发原发性红斑肢痛症(PE)。当SCN9A基因出现无效突变，Nav1.7完全失去功能，即出现功能缺失型突变时，导致先天性无痛症(CIP)，患者完全丧失感知疼痛的能力。干预Nav1.7表达或给予Nav1.7抑制剂可产生镇痛作用。同时研究还表明，以Nav1.7为靶点的药物毒副作用较小。上述表明，Nav1.7对痛觉信号传导和维持具有核心作用，已经成为镇痛药物研发非常重要的靶点。当前，多家制药公司和科研机构进行选择性Nav1.7阻滞剂研究(Sun,S.Y.et al.Bioorg.Med.Chem.Lett.2014,24,4397-4401；Dimauro,E.F.et al.J.Med.Chem.2016,59,7818-7839；Wu,Y.J.et al.J.Med.Chem.2017,60,2513-2525；Jennifer,M.F.J.Med.Chem.2016,59,3373-3391；Marx,I.E.et al.ACS Med.Chem.Lett.2017,8,378；WO2017184658、WO2017082688、WO2017058821、WO2017106871、WO2017172802、WO2016040315、WO2013102826)。Nav1.7 is a transmembrane protein encoded by SCN9A, which is specifically expressed in peripheral sensory nerve endings and sympathetic ganglion neurons, and is mainly expressed on large diameter DRG neurons and unmyelinated small diameter DRG, that is, 85% of the damage Expressed on the sexy receptor, which shows that Nav1.7 has a very critical role in pain transmission. Animal model studies show that in carrageenan and complete Freund's adjuvant (CFA) -induced inflammatory pain models, Nav1.7 protein or mRNA expression increases, and these changes occur mainly in DRG neurons or afferent neurons. An increase in TTX-S current in DRG neurons was also detected in the carrageenan inflammatory pain model. In a rat model of diabetic neuralgia, Nav1.7 protein expression increased. Knockdown of Nav1.7 in DRG can alleviate thermal hyperalgesia, mechanical hyperalgesia and cold hyperalgesia in animals. Recent research also found that Nav1.7 in DRG and sympathetic ganglia are involved in different types of pain information transmission, respectively. After Nav1.7 in the DRG of the mice was conditioned knockout, the basic mechanical pain valve and thermal pain valve were significantly increased, and the inflammatory pain caused by 4% formaldehyde was also relieved. In human disease research, when the SCN9A gene mutation causes Nav1.7 to be inactivated after opening, resulting in enhanced function, it is a "function-enhancing mutation", which triggers primary erythema limb pain (PE). When the SCN9A gene has an invalid mutation and Nav1.7 completely loses its function, that is, a loss-of-function mutation occurs, it causes congenital analgesia (CIP), and the patient completely loses the ability to perceive pain. Intervention of Nav1.7 expression or administration of Nav1.7 inhibitors can produce analgesic effects. At the same time, research also shows that drugs with Nav1.7 as the target have less toxic and side effects. The above shows that Nav1.7 has a core role in pain signal transmission and maintenance, and has become a very important target for the development of analgesics. Currently, a number of pharmaceutical companies and research institutions are conducting selective Nav1.7 blocker research (Sun, SYet. Bioorg. Med. Chem. Lett. 2014, 24, 4397-4401; Dimauro, EFetal. J. Med.Chem. 2016, 59, 7818-7839; Wu, YJet, J. Med. Chem. 2017, 60, 2513-2525; Jennifer, MFJMed. Chem. 2016, 59, 3373-3391; Marx, IE et al. ACS Med. Chem. Lett. 2017, 8, 378; WO2017184658, WO2017082688, WO2017058821, WO2017106871, WO2017172802, WO2016040315, WO2013102826).
Nav1.3是一种快速再启动电压门控钠通道，正常状态下仅在发育中的感觉神经元和成人的中枢神经系统表达，在成人周围神经系统中低水平表达。但在周围神经损伤，如脊神经切断、结扎或发生慢性压缩性损伤等，可导致Nav1.3在背根神经节神经元中的表达大量上调。这一现象表明Nav1.3参与了周围神经痛的发生和维持。Pryde D.C.等报道了一系列芳基醚类选择性Nav1.3抑制剂可用于治疗疼痛(Pryde D.C.et al.MedChemComm,2017,8,1255-1267)。 WO2006122014A2公开了一类双环类Nav1.3阻滞剂，可用于治疗慢性疼痛、急性疼痛、炎性痛以及焦虑和抑郁等疾病。Samad等人证明了Nav1.3敲除在大鼠模型中用于疼痛治疗的潜力，并建议将基因治疗作为潜在的治疗选择(Samad,O.A.et al.Mol.Ther.2013,21,49-56)。越来越多研究者认为Nav1.3也是开发镇痛药物非常有潜力的靶点。Nav1.3 is a fast-restarting voltage-gated sodium channel that is normally expressed only in developing sensory neurons and the central nervous system of adults, and at low levels in the adult peripheral nervous system. However, peripheral nerve injury, such as spinal nerve cut, ligation, or chronic compression injury can lead to a large up-regulation of Nav1.3 expression in dorsal root ganglion neurons. This phenomenon indicates that Nav1.3 is involved in the occurrence and maintenance of peripheral neuralgia. Pryde D.C. et al. Reported that a series of aryl ether selective Nav1.3 inhibitors can be used to treat pain (Pryde D.C. et al. MedChemComm, 2017, 8, 1255-1267). WO2006122014A2 discloses a class of bicyclic Nav1.3 blockers, which can be used to treat chronic pain, acute pain, inflammatory pain, and anxiety and depression. Samad et al. Demonstrated the potential of Nav1.3 knockout for pain treatment in rat models and suggested gene therapy as a potential treatment option (Samad, OAet al. Mol. Ther. 2013, 21, 49-56 ). More and more researchers believe that Nav1.3 is also a very promising target for the development of analgesics.
Nav1.8和Nav1.9均属于TTX-R类的钠离子通道，在成年动物DRG中也均有表达，被认为也参与了疼痛，但其确切机制尚不十分清楚。Nav1.1和Nav1.2高表达于脑中并且对正常脑功能至关重要(Ray,C.K.el al.J.Biol.Chem.2004,279,46234-46241)。研究表明，Nav1.1突变引起的一些功能丧失可造成癫痫(Yu,F.H.et al.Nat.Neuroscience,2006,9,1142-1149)。因此，尽管Nav1.1还表达于周围神经系统中并且抑制Nav1.1有利于疼痛的缓解，但也有可能引起焦虑或过度兴奋等副作用。Nav1.4主要表达于骨骼肌中，抑制Nav1.4可能引起肌强直，甚至瘫痪的不良影响。Nav1.5主要表达于心肌细胞中，包括心房、心室、窦房结、房室结等。抑制Nav1.5可能造成心律不齐综合征，包括QT间期延长、Brugada综合征、突发性夜间意外猝死综合征和婴儿猝死综合征等(Liu,H.et al.Am.J.Pharmacogenomics,2003,3,173-179)。而Nav1.6可能与运动障碍有关。Nav1.8 and Nav1.9 both belong to the TTX-R sodium channel and are also expressed in DRG in adult animals. They are thought to be involved in pain, but the exact mechanism is not yet clear. Nav1.1 and Nav1.2 are highly expressed in the brain and are essential for normal brain function (Ray, C.K. el. J. Biol. Chem. 2004, 279, 46234-46241). Studies have shown that some loss of function caused by the Nav1.1 mutation can cause epilepsy (Yu, F.H. et al. Nat. Neuroscience, 2006, 9, 1142-1149). Therefore, although Nav1.1 is also expressed in the peripheral nervous system and inhibition of Nav1.1 is beneficial for pain relief, it may also cause side effects such as anxiety or excessive excitement. Nav1.4 is mainly expressed in skeletal muscle. Inhibition of Nav1.4 may cause the adverse effects of muscle rigidity and even paralysis. Nav1.5 is mainly expressed in cardiac muscle cells, including atria, ventricles, sinoatrial nodes, and atrioventricular nodes. Inhibition of Nav1.5 may cause arrhythmia syndromes, including prolonged QT interval, Brugada syndrome, sudden nocturnal sudden death syndrome, and sudden infant death syndrome (Liu, H. et al. Am. J. Pharmacogenomics, 2003, 3, 173-179). And Nav1.6 may be related to movement disorders.
综上所述，Nav1.7是治疗疼痛或者疼痛相关疾病非常有潜力的靶点，也是当前研究的最多的钠离子通道，但临床上一些高选择性Nav1.7阻滞剂在临床上的镇痛效果不是十分理想，可能是由于在外周神经系统中Nav1.3的表达上调代偿性地介导疼痛信号。WO2012125973A报道了对Nav1.3和Nav1.7具有强效和选择性的多肽预防和治疗疼痛方面的应用。但蛋白、多肽类药物往往由于存在稳定性、给药方式单一等局限性往往限制了其广泛应用。因此，研究新型、效力更强、副作用更小的Nav1.3和Nav1.7小分子双重抑制剂是重要的研究方向。In summary, Nav1.7 is a very promising target for the treatment of pain or pain-related diseases, and it is also the most studied sodium ion channel. However, some clinically highly selective Nav1.7 blockers are clinically effective. The pain effect is not very good, probably due to the upregulation of Nav1.3 expression in the peripheral nervous system to mediate the pain signal compensatively. WO2012125973A reports the application of Nav1.3 and Nav1.7 with strong and selective peptides in the prevention and treatment of pain. However, protein and peptide drugs often limit their wide application due to limitations such as stability and single mode of administration. Therefore, it is an important research direction to study new types of small molecule dual inhibitors of Nav1.3 and Nav1.7 with stronger potency and less side effects.
发明内容Summary of the Invention
本发明的目的是提供对钠离子通道，特别是Nav1.3和Nav1.7钠离子通道具有双重抑制活性的磺酰胺类化合物及其用途。The object of the present invention is to provide a sulfonamide compound having dual inhibitory activity on sodium ion channels, especially Nav1.3 and Nav1.7 sodium ion channels, and uses thereof.
为了实现上述目的，本发明提供了由下式I，其溶剂化物、互变异构体或药学上可接受的盐：To achieve the above object, the present invention provides a solvate, tautomer or pharmaceutically acceptable salt thereof represented by the following formula I:
Figure PCTCN2019104852-appb-000001
Figure PCTCN2019104852-appb-000001
其中：among them:
其中，R 1选自至多包含3个N、O、S杂原子的5-10元芳杂环或-CONHR 2，任选地，5-10元芳杂环被卤素、C 1-6烷基、-OC 1-6烷基、C 1-6卤代烷基、-OC 1-6卤代烷基、氰基取代； Wherein R 1 is selected from a 5-10 membered aromatic heterocyclic ring or -CONHR 2 containing up to 3 N, O, and S heteroatoms, and optionally, the 5-10 membered aromatic heterocyclic ring is substituted by halogen, C 1-6 alkyl , -OC 1-6 alkyl, C 1-6 haloalkyl, -OC 1-6 haloalkyl, cyano substituted;
R 2选自C 1-4烷基； R 2 is selected from C 1-4 alkyl;
X 1不存在或为-NH-； X 1 does not exist or is -NH-;
R 3、R 4独立地选自氢或者卤素，且R 3、R 4至少1项为卤素； R 3 and R 4 are independently selected from hydrogen or halogen, and at least one of R 3 and R 4 is halogen;
X 2为NH或O； X 2 is NH or O;
Z为-(CH 2) n-，且当X 2为NH，n为1-2的整数，当X 2为O，n为0-2的整数； Z is-(CH 2 ) n- , and when X 2 is NH, n is an integer of 1-2, when X 2 is O, n is an integer of 0-2;
X 3、X 4、X 5、X 6选自N或CR 5，且X 3、X 4、X 5、X 6至多1项为N； X 3 , X 4 , X 5 , X 6 is selected from N or CR 5 , and at most 1 of X 3 , X 4 , X 5 , X 6 is N;
R 5选自氢、卤素、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、氰基； R 5 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, cyano;
R 6选自氢或C 1-4烷基； R 6 is selected from hydrogen or C 1-4 alkyl;
R 7选自-(CH) zNR 8R 9，R 8、R 9独立地为氢或C 1-4烷基，其中z为1-4的整数，或-NR 8R 9形成如下结构： R 7 is selected from-(CH) z NR 8 R 9 , R 8 and R 9 are independently hydrogen or C 1-4 alkyl, wherein z is an integer of 1-4, or -NR 8 R 9 forms the following structure:
Figure PCTCN2019104852-appb-000002
其中X 7不存在或选自CHR 10、NR 10或O，y为0-5的整数；R 10选自氢或C 1-4烷基。
Figure PCTCN2019104852-appb-000002
Wherein X 7 is absent or selected from CHR 10 , NR 10 or O, and y is an integer of 0-5; R 10 is selected from hydrogen or C 1-4 alkyl.
在另一实施方案中，在式I的化合物中，R 1选自至多包含3个N、O、S杂原子的5-6元芳杂环，任选地，5-6元芳杂环被卤素、C 1-6烷基、-OC 1-6烷基、C 1-6卤代烷基、-OC 1-6卤代烷基、氰基取代。 In another embodiment, in the compound of Formula I, R 1 is selected from a 5-6 membered aromatic heterocyclic ring containing up to 3 N, O, S heteroatoms, and optionally, a 5-6 membered aromatic heterocyclic ring is Halogen, C 1-6 alkyl, -OC 1-6 alkyl, C 1-6 haloalkyl, -OC 1-6 haloalkyl, cyano substituted.
在另一实施方案中，在式I的化合物中，R 1为选自至多包含3个N、O、S杂原子的5-6元单环芳杂环，任选地，5-6元单环芳杂环被卤素取代。 In another embodiment, in the compound of Formula I, R 1 is selected from a 5-6 membered monocyclic aromatic heterocyclic ring containing up to 3 N, O, S heteroatoms, optionally, a 5-6 membered monocyclic aromatic heterocycle The ring aromatic heterocyclic ring is substituted with halogen.
在另一实施方案中，在式I的化合物中，R 1选自至多包含3个N、O、S杂原子的5元芳杂环，任选地，5元芳杂环被卤素取代。 In another embodiment, in the compound of Formula I, R 1 is selected from a 5-membered aromatic heterocycle containing up to 3 N, O, S heteroatoms, and optionally, the 5-membered aromatic heterocycle is substituted with halogen.
在另一实施方案中，在式I的化合物中，R 1选自
Figure PCTCN2019104852-appb-000003
Figure PCTCN2019104852-appb-000004
In another embodiment, in the compound of Formula I, R 1 is selected from
Figure PCTCN2019104852-appb-000003
Figure PCTCN2019104852-appb-000004
在另一实施方案中，在式I的化合物中，R 2为-CH 3。 In another embodiment, in the compound of Formula I, R 2 is -CH 3 .
在另一实施方案中，在式I的化合物中，X 2为-NH。 In another embodiment, in the compound of Formula I, X 2 is -NH.
在另一实施方案中，在式I的化合物中，X 3、X 4、X 5、X 6均为CH。 In another embodiment, the compounds of Formula I, X 3, X 4, X 5, X 6 are CH.
在另一实施方案中，在式I的化合物中，R 5选自氢、卤素、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基。 In another embodiment, in the compound of Formula I, R 5 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy base.
在另一实施方案中，在式I的化合物中，R 5选自氢、卤素、甲基、甲氧基、三氟甲基、三氟甲氧基。 In another embodiment, in the compound of Formula I, R 5 is selected from hydrogen, halogen, methyl, methoxy, trifluoromethyl, trifluoromethoxy.
在另一实施方案中，在式I的化合物中，X 7不存在或选自CH 2、O、-NCH 3，y为1-4的整数。 In another embodiment, in the compound of Formula I, X 7 is absent or selected from CH 2 , O, -NCH 3 , and y is an integer from 1-4.
在另一实施方案中，在式I的化合物中，-NR 8R 9形成如下结构： In another embodiment, in the compound of Formula I, -NR 8 R 9 forms the structure:
Figure PCTCN2019104852-appb-000005
Figure PCTCN2019104852-appb-000005
在另一实施方案中，在式I的化合物中，z为2或3。In another embodiment, in the compound of Formula I, z is 2 or 3.
在另一实施方案中，式I的化合物选自：In another embodiment, the compound of formula I is selected from:
Figure PCTCN2019104852-appb-000006
Figure PCTCN2019104852-appb-000006
Figure PCTCN2019104852-appb-000007
Figure PCTCN2019104852-appb-000007
Figure PCTCN2019104852-appb-000008
Figure PCTCN2019104852-appb-000008
本发明的第二目的在于提供一种药物组合物，所述组合物包含本发明第一目的所述的化合物，其溶剂化物、互变异构体或药学上可接受的盐和药学上可接受的赋形剂。A second object of the present invention is to provide a pharmaceutical composition comprising the compound according to the first object of the present invention, a solvate, a tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable Excipients.
本发明的第三目的在于提供本发明第一目的所述的化合物，其溶剂化物、互变异构体或药学上可接受的盐在制备用于治疗疼痛的药物中的用途。A third object of the present invention is to provide a compound according to the first object of the present invention, the use of a solvate, tautomer or pharmaceutically acceptable salt thereof in the preparation of a medicament for treating pain.
在另一实施方案中，疼痛选自由以下组成的组：神经性疼痛、炎性疼痛、内脏痛、癌症疼痛、化疗疼痛、创伤疼痛、手术疼痛、分娩疼痛、神经源性膀胱疼痛、溃疡性结肠炎疼痛、慢性疼痛、持续性疼痛、外周介导性疼痛、中枢介导性疼痛、偏头痛、窦性头痛、紧张性头痛、幻肢痛、牙痛、外周神经损伤疼痛或其组合。In another embodiment, the pain is selected from the group consisting of neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, childbirth pain, neurogenic bladder pain, ulcerative colon Inflammatory pain, chronic pain, persistent pain, peripheral-mediated pain, central-mediated pain, migraine, sinus headache, tension headache, phantom limb pain, tooth pain, pain in peripheral nerve injury, or a combination thereof.
在另一实施方案中，疼痛选自由以下组成的组：神经性疼痛、炎性疼痛。In another embodiment, the pain is selected from the group consisting of: neuropathic pain, inflammatory pain.
在另一实施方案中，疼痛与选自由以下组成的组的疾病或病状相关：HIV、HIV治疗诱导的神经病变、三叉神经痛、疱疹后神经痛、急性疼痛、热敏感性、结节病、肠易激综合症、克罗恩病、多发性硬化(MS)、肌萎缩性脊髓侧索硬化症(ALS)、糖尿病性神经病变、外周神 经病变、关节炎、类风湿性关节炎、动脉粥样硬化、阵发性肌张力障碍、肌无力综合征、肌强直、恶性高热症、囊性纤维化、假性醛固酮增多症、横纹肌溶解症、甲状腺功能减退症、双相抑郁、焦虑、精神分裂症、钠通道毒素相关疾病、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、部分性和全身性强直发作、不宁腿综合征、心律失常、纤维肌痛、由中风或神经创伤引起的局部缺血状态下的神经保护、心房纤颤和心室纤颤。In another embodiment, the pain is associated with a disease or condition selected from the group consisting of: HIV, HIV treatment-induced neuropathy, trigeminal neuralgia, postherpetic neuralgia, acute pain, heat sensitivity, sarcoidosis, Irritable bowel syndrome, Crohn's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, atherosclerosis Sclerosis, paroxysmal dystonia, myasthenic syndrome, myotonia, malignant fever, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia Disease, sodium channel toxin-related diseases, familial erythematous limb pain, primary erythematous limb pain, familial rectal pain, cancer, epilepsy, partial and systemic tonic seizures, restless leg syndrome, arrhythmia , Fibromyalgia, neuroprotection in ischemia caused by stroke or neurotrauma, atrial fibrillation and ventricular fibrillation.
本发明的第四目的在于提供本发明第一目的所述的化合物，其溶剂化物、互变异构体或药学上可接受的盐治疗哺乳动物中疼痛的方法，包括向有需要的哺乳动物施用治疗有效量的本发明第一目的所述的化合物。A fourth object of the present invention is to provide a compound according to the first object of the present invention, a method of treating a pain in a mammal by a solvate, tautomer or pharmaceutically acceptable salt thereof, comprising administering to a mammal in need A therapeutically effective amount of a compound according to the first object of the invention.
在另一实施方案中，疼痛选自由以下组成的组：神经性疼痛、炎性疼痛、内脏痛、癌症疼痛、化疗疼痛、创伤疼痛、手术疼痛、分娩疼痛、神经源性膀胱疼痛、溃疡性结肠炎疼痛、慢性疼痛、持续性疼痛、外周介导性疼痛、中枢介导性疼痛、偏头痛、窦性头痛、紧张性头痛、幻肢痛、牙痛、外周神经损伤疼痛或其组合。In another embodiment, the pain is selected from the group consisting of: neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, childbirth pain, neurogenic bladder pain, ulcerative colon Inflammatory pain, chronic pain, persistent pain, peripheral-mediated pain, central-mediated pain, migraine, sinus headache, tension headache, phantom limb pain, tooth pain, pain in peripheral nerve injury, or a combination thereof.
在另一实施方案中，疼痛选自由以下组成的组：神经性疼痛、炎性疼痛。In another embodiment, the pain is selected from the group consisting of: neuropathic pain, inflammatory pain.
在另一实施方案中，疼痛与选自由以下组成的组的疾病或病状相关：HIV、HIV治疗诱导的神经病变、三叉神经痛、疱疹后神经痛、急性疼痛、热敏感性、结节病、肠易激综合症、克罗恩病、多发性硬化(MS)、肌萎缩性脊髓侧索硬化症(ALS)、糖尿病性神经病变、外周神经病变、关节炎、类风湿性关节炎、动脉粥样硬化、阵发性肌张力障碍、肌无力综合征、肌强直、恶性高热症、囊性纤维化、假性醛固酮增多症、横纹肌溶解症、甲状腺功能减退症、双相抑郁、焦虑、精神分裂症、钠通道毒素相关疾病、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、部分性和全身性强直发作、不宁腿综合征、心律失常、纤维肌痛、由中风或神经创伤引起的局部缺血状态下的神经保护、心房纤颤和心室纤颤。In another embodiment, the pain is associated with a disease or condition selected from the group consisting of: HIV, HIV treatment-induced neuropathy, trigeminal neuralgia, postherpetic neuralgia, acute pain, heat sensitivity, sarcoidosis, Irritable bowel syndrome, Crohn's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, atherosclerosis Sclerosis, paroxysmal dystonia, myasthenic syndrome, myotonia, malignant fever, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia Disease, sodium channel toxin-related diseases, familial erythematous limb pain, primary erythematous limb pain, familial rectal pain, cancer, epilepsy, partial and systemic tonic seizures, restless leg syndrome, arrhythmia , Fibromyalgia, neuroprotection in ischemia caused by stroke or neurotrauma, atrial fibrillation and ventricular fibrillation.
定义definition
如本文所用，术语“烷基”自身或作为另一取代基的部分意指(除非另外说明)具有指定碳原子数目的直链或支链烃基(即，C 1-8意指一至八个碳)。烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基、正庚基、正辛基等。 As used herein, the term "alkyl" itself or as part of another substituent means (unless otherwise stated) a straight or branched chain hydrocarbon group having the specified number of carbon atoms (ie, C 1-8 means one to eight carbons ). Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like .
如本文所用，术语“芳杂环”是指具有5到10个杂环原子，优选5或6元单环芳杂环或8至10元双环芳杂环；且除碳原子外还具有1到3个杂原子的基团。“杂原子”是指氮、氧或硫。As used herein, the term "aromatic heterocycle" refers to having 5 to 10 heterocyclic atoms, preferably 5 or 6-membered monocyclic aromatic heterocycles or 8 to 10-membered bicyclic aromatic heterocycles; and having 1 to 10 carbon atoms in addition to carbon atoms. 3 heteroatom groups. "Heteroatom" means nitrogen, oxygen or sulfur.
如本文所用，“5至6元单环芳杂环”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、异噁唑环、噁二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环等。As used herein, "5- to 6-membered monocyclic aromatic heterocyclic ring" refers to a single heteroaryl ring containing 5 to 6 ring atoms, and includes, but is not limited to, a thiophene ring, an N-alkylpyrrole ring, a furan Ring, thiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, isoxazole ring, oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine Ring etc.
如本文所用，“8至10元双环芳杂环”是指含8至10个环原子的双杂芳基环，例如包括(但不限于)：苯并呋喃环、苯并噻吩环、吲哚环、异吲哚环、喹啉环、异喹啉环、吲唑环、苯并噻唑环、苯并咪唑环、喹唑啉环、喹喔啉环、噌啉环、酞嗪环。As used herein, "8 to 10 membered bicyclic aromatic heterocyclic ring" refers to a biheteroaryl ring containing 8 to 10 ring atoms, including, for example, but not limited to: a benzofuran ring, a benzothiophene ring, an indole Ring, isoindole ring, quinoline ring, isoquinoline ring, indazole ring, benzothiazole ring, benzimidazole ring, quinazoline ring, quinoxaline ring, perylene ring, phthalazine ring.
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为羰基(即＝O)时，意味着两个氢原子被取代。羰基取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "substituted" refers to the replacement of any one or more hydrogen atoms on a specific atom with a substituent, and can include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of. When a substituent is a carbonyl group (ie, = 0), it means that two hydrogen atoms are substituted. Carbonyl substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
如本文所用，术语“卤素”自身或作为另一取代基的部分，意指(除非另外说明)氟、氯、溴或碘原子。另外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“C 1-4卤代烷基”意在包括三氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基、二氟甲基等。 As used herein, the term "halogen" itself or as part of another substituent means, unless otherwise specified, a fluorine, chlorine, bromine or iodine atom. In addition, the term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "C 1-4 haloalkyl" is intended to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl, and the like.
如本文所用，“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基，除非另有规定，C 1-6烷氧基包括C 1、C 2、C 3、C 4、C 5和C 6的烷氧基。烷氧基的例子包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。 As used herein, "alkoxy" represents the above-mentioned alkyl group having a specific number of carbon atoms connected through an oxygen bridge, and unless otherwise specified, C 1-6 alkoxy includes C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy. Examples of alkoxy include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, n-pentoxy and S- Pentyloxy.
如本文所用，在化学结构中与键相交的波浪线指示键的附连点，其在化学结构中的波浪键与分子的其余部分相交。As used herein, a wavy line that intersects a bond in a chemical structure indicates the point of attachment of the bond, whose wavy bond in the chemical structure intersects the rest of the molecule.
除非另有规定，本文所描绘的结构也意味着包括该结构的所有异构(例如对映异构、非对映异构和几何异构(或构象异构))形式；例如每一不对称中心的R与S构型，(Z)与(E)双键异构体，和(Z)与(E)构象异构体。因此，这些化合物的单一立体化学异构体以及对映异构、非对映异构和几何异构(或构象异构)混合物都属于本发明的范围。除非另有规定，本发明化合物的所有互变异构形式都属于本发明的范围。另外，除非另有规定，本文所描绘的结构也意味着包括仅在一个或多个同位素富集原子的存在上有所不同的化合物。例如，除了氢被氘或氚代替或者碳被 13C-或 14C-富集的碳代替以外具有本发明结构的化合物都属于本发明的范围。 Unless otherwise specified, a structure depicted herein is also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometrically isomeric (or conformational)) forms of the structure; for example, each asymmetric The central R and S configurations, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers of these compounds as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures are within the scope of the present invention. Unless otherwise specified, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise specified, the structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention, except that hydrogen is replaced by deuterium or tritium or carbon is replaced by 13 C- or 14 C-enriched carbon, are within the scope of the present invention.
如本文所用，“溶剂化物”是指本申请化合物与一个或多个溶剂分子的物理缔合；该物理缔合涉及各种程度的离子键和共价键，其包括氢键；在某些情况下，例如当将一个或多个溶剂分子引入到结晶固体的晶格中时，溶剂化物将能够被分离；“溶剂化物”涵盖溶液相和可分离的溶剂化物；合适的溶剂非限制性实例包括但不限于异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸和乙醇胺等；“水合物”为其中溶剂分子为H 2O的溶剂化物。 As used herein, "solvate" refers to the physical association of a compound of the present application with one or more solvent molecules; the physical association involves various degrees of ionic and covalent bonds, including hydrogen bonding; in some cases Below, for example, when one or more solvent molecules are introduced into the crystal lattice of a crystalline solid, the solvate will be able to be separated; "solvate" encompasses the solution phase and separable solvates; non-limiting examples of suitable solvents include but are not limited to, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine; "hydrate" is where the solvent molecule is H 2 O solvate.
如本文所用，术语“组合物”意欲涵盖包含规定量的规定成分的产品，以及直接或间接 源于规定量的规定成分的组合的任何产品。短语“药学上可接受的”意指载体、稀释剂或赋形剂必须与制剂中的其它成分相容并且对其药物接受者无害。As used herein, the term "composition" is intended to encompass a product containing a specified amount of a specified ingredient, as well as any product derived directly or indirectly from a combination of a specified amount of a specified ingredient. The phrase "pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients in the formulation and not harmful to the recipient of the drug.
如本文所用，术语“药学上可接受的盐”意在包括用相对无毒的酸或碱制备活性化合物的盐。当本发明化合物含有相对酸性官能团时，可通过将此类化合物的中性形式与足量的纯的或在合适的惰性溶剂中的所需碱接触获得碱加成盐。衍生自药学上可接受的无机碱的盐的实例包括铝、铵、钙、铜、铁、亚铁、锂、镁、锰盐、亚锰、钾、钠、锌等。衍生自药学上可接受的有机碱的盐包括伯胺、仲胺和叔胺(包括取代的胺、环胺、天然存在的胺等)的盐，诸如精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺、葡萄糖胺、组氨酸、异丙基胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。当本发明化合物含有相对碱性官能团时，可通过将此类化合物的中性形式与足量的纯的或在合适的惰性溶剂中的所需酸接触获得酸加成盐。药学上可接受的酸加成盐的实例包括衍生自无机酸如盐酸、氢溴酸、硝酸、碳酸、一氢碳酸、磷酸、一氢磷酸、二氢磷酸、硫酸、一氢硫酸、氢碘酸或亚磷酸等，以及衍生自相对无毒的有机酸如乙酸、丙酸、异丁酸、丙二酸、苯甲酸、琥珀酸、辛二酸、富马酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、甲烷磺酸等的盐。还包括氨基酸诸如精氨酸等的盐以及有机酸如葡糖醛酸或半乳糖醛酸。As used herein, the term "pharmaceutically acceptable salt" is intended to include the preparation of salts of the active compounds with relatively non-toxic acids or bases. When the compounds of the invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base either pure or in a suitable inert solvent. Examples of the salt derived from a pharmaceutically acceptable inorganic base include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese salts, manganese, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines (including substituted amines, cyclic amines, naturally occurring amines, etc.), such as arginine, betaine, caffeine, bile Base, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethyl Piperidine, glucosamine, glucosamine, histidine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, Theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When the compounds of the invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either pure or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include derivatives derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid Or phosphorous acid, etc., and derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, Salts of benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and the like. Also included are salts of amino acids such as arginine, and organic acids such as glucuronic acid or galacturonic acid.
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参见Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium capable of delivering an effective amount of the active substance of the present invention without interfering with the biological activity of the active substance and without toxic side effects to the host or patient. Representative carriers include water, oil, Vegetables and minerals, cream base, lotion base, ointment base, etc. These bases include suspending agents, tackifiers, transdermal enhancers, and the like. Their formulations are well known to those skilled in the field of cosmetics or topical medicine. For additional information on the carrier, see Remington: Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
包含式I化合物的组合物通常根据作为药物组合物的标准药学实践配制。典型的制剂通过将本发明化合物与稀释剂、载体或赋形剂混合制备。合适的稀释剂、载体和赋形剂对于本领域技术人员为熟知的并且详细描述于如Gennaro,Alfonso R.等，Remington:The Science and Practice of Pharmacy，21st Ed.,Philadelphia:Lippincott,Williams&Wilkins，2005)。制剂还可以包括缓冲剂、稳定剂、表面活性剂、湿润剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、不透明剂、助流剂、加工助剂、着色剂、增甜剂、芳香剂、调味剂、稀释剂和其它已知的添加剂中的一种或多种。Compositions comprising a compound of formula I are usually formulated according to standard pharmaceutical practice as a pharmaceutical composition. Typical formulations are prepared by mixing a compound of the invention with a diluent, carrier or excipient. Suitable diluents, carriers and excipients are well known to those skilled in the art and are described in detail in, for example, Gennaro, Alfonso R., et al., Remington: The Science and Practice of Pharmacy, 21st Ed., Philadelphia: Lippincott, Williams & Wilkins, 2005 ). The formulation may also include buffering agents, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacity agents, glidants, processing aids, colorants, sweeteners, One or more of fragrance, flavor, diluent, and other known additives.
本发明化合物可以以任何便利的使用形式被施用，如片剂、粉末、胶囊、溶液、分散体、 悬浮液、糖浆剂、喷雾剂、栓剂、凝胶剂、乳剂、贴剂等。此类组合物可以包含药物制剂中常规的组分，如稀释剂、载体、pH调节剂、增甜剂、填充剂和另外的活性剂。The compounds of the invention can be administered in any convenient use form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches and the like. Such compositions may contain conventional components in pharmaceutical formulations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and additional active agents.
本发明化合物可以通过任何合适的方式施用，包括口服、局部(包括颊部和舌下)、直肠、阴道、透皮、肠胃外、皮下、腹膜内、肺内、皮肤内、鞘内和硬膜外以及鼻内，并且，如果需要用于局部治疗，病灶内施用。肠胃外输注包括肌肉内、静脉内、动脉内、腹膜内、大脑内、眼内、病灶内或皮下施用。The compounds of the invention can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, and epidural Externally as well as intranasally, and if needed for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, intracerebral, intraocular, intralesional, or subcutaneous administration.
如本文所用，化合物或药学上可接受的组合物的“有效量”是就治疗一种或多种如下疾病或者减轻其严重性而言有效的量：神经性疼痛、炎性疼痛、内脏痛、癌症疼痛、化疗疼痛、创伤疼痛、手术疼痛、分娩疼痛、神经源性膀胱疼痛、溃疡性结肠炎疼痛、慢性疼痛、持续性疼痛、外周介导性疼痛、中枢介导性疼痛、偏头痛、窦性头痛、紧张性头痛、幻肢痛、牙痛、外周神经损伤疼痛或其组合；术后疼痛、慢性头痛或产痛；HIV、HIV治疗诱导的神经病变、三叉神经痛、疱疹后神经痛、急性疼痛、热敏感性、结节病、肠易激综合症、克罗恩病、多发性硬化(MS)、肌萎缩性脊髓侧索硬化症(ALS)、糖尿病性神经病变、外周神经病变、关节炎、类风湿性关节炎、动脉粥样硬化、阵发性肌张力障碍、肌无力综合征、肌强直、恶性高热症、囊性纤维化、假性醛固酮增多症、横纹肌溶解症、甲状腺功能减退症、双相抑郁、焦虑、精神分裂症、钠通道毒素相关疾病、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、部分性和全身性强直发作、不宁腿综合征、心律失常、纤维肌痛、由中风或神经创伤引起的局部缺血状态下的神经保护、心房纤颤和心室纤颤；关节炎或快速心律失常。As used herein, an "effective amount" of a compound or a pharmaceutically acceptable composition is an amount effective to treat or reduce the severity of one or more of the following diseases: neuropathic pain, inflammatory pain, visceral pain, Cancer pain, chemotherapy pain, traumatic pain, surgical pain, childbirth pain, neurogenic bladder pain, ulcerative colitis pain, chronic pain, persistent pain, peripheral-mediated pain, central-mediated pain, migraine, sinus Headache, tension headache, phantom limb pain, toothache, peripheral nerve injury pain, or a combination thereof; postoperative pain, chronic headache or labor pain; HIV, HIV-induced neuropathy, trigeminal neuralgia, postherpetic neuralgia, acute Pain, heat sensitivity, sarcoidosis, irritable bowel syndrome, Crohn's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, joints Inflammation, rheumatoid arthritis, atherosclerosis, paroxysmal dystonia, myasthenic syndrome, myotonia, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism Disease, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel toxin-related diseases, familial erythematous limb pain, primary erythematous limb pain, familial rectal pain, cancer , Epilepsy, partial and systemic tonic seizures, restless leg syndrome, arrhythmia, fibromyalgia, neuroprotection in ischemia caused by stroke or neurotrauma, atrial fibrillation and ventricular fibrillation; arthritis; Or tachyarrhythmia.
所需确切的量将因受治疗者而异，依赖于受治疗者的种类、年龄与一般状态、感染的严重性、特定药物、其给药的方式等。被理解的是，本发明化合物和组合物的总每日用量将由主治医师在合理的医学判断范围内决定。任意特定患者或生物体的具体有效剂量水平将依赖于多种因素，包括所治疗的病症和病症的严重性；所采用的具体化合物的活性；所采用的具体组合物；患者的年龄、体重、一般健康状况、性别和饮食；给药的时间、给药的途径和所采用的具体化合物的排泄速率；治疗的持续时间；与所采用的具体化合物联合或同时使用的药物；和医药领域熟知的其他因素。The exact amount required will vary from subject to subject, depending on the type, age and general state of the subject, the severity of the infection, the particular drug, the mode of administration, and the like. It is understood that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level of any particular patient or organism will depend on a variety of factors, including the severity of the condition and condition being treated; the activity of the specific compound employed; the specific composition employed; the age, weight, General health, gender, and diet; time of administration, route of administration, and excretion rate of the specific compound used; duration of treatment; drugs used in combination with or concurrent with the specific compound used; and well-known in the medical field other factors.
化合物经人工或者Chemdraw软件命名，市售化合物采用供应商目录名称。Compounds are named by human or Chemdraw software, and commercially available compounds use supplier catalog names.
与现有技术相比，本发明的主要优点在于：Compared with the prior art, the main advantages of the present invention are:
提供了一系列结构新颖的磺酰胺类衍生物，其同时对Nav1.7和Nav1.3具有双重抑制活性，可用作广泛疼痛治疗的药物。A series of sulfonamide derivatives with novel structure are provided, which have dual inhibitory activities against Nav1.7 and Nav1.3 at the same time, and can be used as drugs for a wide range of pain treatments.
具体实施方式detailed description
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。实施例(制备)中描述的化学反应可容易地被修改以制备许多本发明的其它化合物，并且用于制备本发明化合物的替代方法被认为在本发明的范围内。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。The present invention will be further described below with reference to specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions in the following examples are usually performed according to the conventional conditions or the conditions recommended by the manufacturer. The chemical reactions described in the examples (preparations) can be easily modified to prepare many other compounds of the invention, and alternative methods for preparing the compounds of the invention are considered to be within the scope of the invention. Unless otherwise defined, the terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the present invention.
实施例1Example 1
4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备4-((4-chloro-2-((2- (ethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (1,2,4-thiadiazole-5 -Yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000009
Figure PCTCN2019104852-appb-000009
步骤a)：(2-((5-氯-2-氰基苯基)氨基)乙基)(乙基)氨基甲酸叔丁酯的制备Step a): Preparation of (2-((5-chloro-2-cyanophenyl) amino) ethyl) (ethyl) t-butyl carbamate
将(2-氨乙基)(乙基)-氨基甲酸叔丁酯(3.01g，15.988mmol)、4-氯-2-氟-苯甲腈(2.48g，15.988mmol)、碳酸钠(3.39g，31.976mmol)和DMSO(40mL)加入反应瓶中，升温至50℃搅拌反应12小时，冷却至室温，加水(100mL)稀释，以乙酸乙酯(50mL x 3)萃取，合并有机层，依次用水(30mL x 3)、饱和氯化钠溶液(40mL)洗涤,无水硫酸钠干燥，过滤，减压浓缩，所得粗品用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1:1v/v)，得(2-((5-氯-2-氰基苯基)氨基)乙基)(乙基)氨基甲酸叔丁酯，收率67.0％，ESI-MS(m/z)：324.2[M+H] +。 (2-Aminoethyl) (ethyl) -carbamic acid tert-butyl ester (3.01 g, 15.988 mmol), 4-chloro-2-fluoro-benzonitrile (2.48 g, 15.988 mmol), sodium carbonate (3.39 g (31.976 mmol) and DMSO (40 mL) were added to the reaction flask, heated to 50 ° C and stirred for 12 hours, cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, and sequentially (30mL x 3), washed with saturated sodium chloride solution (40mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1: 1v / v), (2-((5-chloro-2-cyanophenyl) amino) ethyl) (ethyl) carbamic acid tert-butyl ester, yield 67.0%, ESI-MS (m / z) : 324.2 [M + H] + .
步骤b)：(2-((2-(氨甲基)-5-氯苯基)氨基)乙基)(乙基)氨基甲酸叔丁酯的制备Step b): Preparation of (2-((2- (aminomethyl) -5-chlorophenyl) amino) ethyl) (ethyl) carbamic acid tert-butyl ester
将B 2H 6/四氢呋喃溶液(43mL，1M)加入(2-((5-氯-2-氰基苯基)氨基)乙基)(乙基)氨基甲酸叔丁酯(3.4g，10.499mmol)的四氢呋喃溶液(50mL)中，升温至回流反应0.5小时，用甲醇(20ml)缓慢小心地淬灭反应，继续回流反应0.5小时，冷却至室温，减压浓缩，制备型HPLC纯化，得(2-((2-(氨甲基)-5-氯苯基)氨基)乙基)(乙基)氨基甲酸叔丁酯，收率71.0％， 1H NMR(400MHz,DMSO-d 6)δ:6.93(s,1H),6.58(dd,J 1＝1.6Hz,J 2＝7.6Hz,2H),6.20(brs, 1H),5.94(brs,1H),3.79(s,2H),3.52-3.40(m,2H),3.26(s,4H),1.47(s,9H),1.12(t,J＝7.2Hz,3H),ESI-MS(m/z):311.1[M-16] +。 Add a solution of B 2 H 6 / tetrahydrofuran (43 mL, 1M) to (2-((5-chloro-2-cyanophenyl) amino) ethyl) (ethyl) carbamic acid tert-butyl ester (3.4 g, 10.499 mmol ) In a tetrahydrofuran solution (50 mL), the temperature was raised to reflux for 0.5 hours, and the reaction was slowly and carefully quenched with methanol (20 ml). The reflux reaction was continued for 0.5 hours, cooled to room temperature, concentrated under reduced pressure, and purified by prep. -((2- (aminomethyl) -5-chlorophenyl) amino) ethyl) (ethyl) carbamic acid tert-butyl ester, yield 71.0%, 1 H NMR (400 MHz, DMSO-d 6 ) δ: 6.93 (s, 1H), 6.58 (dd, J 1 = 1.6 Hz, J 2 = 7.6 Hz, 2H), 6.20 (brs, 1 H), 5.94 (brs, 1H), 3.79 (s, 2H), 3.52- 3.40 (m, 2H), 3.26 (s, 4H), 1.47 (s, 9H), 1.12 (t, J = 7.2Hz, 3H), ESI-MS (m / z): 311.1 [M-16] + .
步骤c)：N-(2,4-二甲氧基苄基)-1,2,4-噻二唑-5-胺的制备Step c): Preparation of N- (2,4-dimethoxybenzyl) -1,2,4-thiadiazole-5-amine
将1,2,4-噻二唑-5-胺(3.0g，29.665mmol)、2,4-二甲氧基-苯甲醛(6.41g，38.565mmol)和甲苯(100ml)加入反应瓶中，使用Dean-Stark装置并升温至回流反应16小时，冷却至室温，减压蒸除溶剂，所得粗品以甲醇(80mL)溶解，0℃缓慢分批次加入硼氢化钠(2.0g，53.395mmol)，室温搅拌15小时。反应结束后，减压浓缩，残余物用水(100mL)稀释，以乙酸乙酯(80mL×3)萃取，合并有机层，用饱和氯化钠(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压蒸干，所得粗品经硅胶层析柱纯化(洗脱剂：甲醇/二氯甲烷＝1:100v/v)，得N-(2,4-二甲氧基苄基)-1,2,4-噻二唑-5-胺，收率72.1％，ESI-MS(m/z):252.1[M+H] +。 Add 1,2,4-thiadiazole-5-amine (3.0 g, 29.665 mmol), 2,4-dimethoxy-benzaldehyde (6.41 g, 38.565 mmol) and toluene (100 ml) to the reaction flask. Using a Dean-Stark device and heating to reflux for 16 hours, cooling to room temperature, evaporating the solvent under reduced pressure, the obtained crude product was dissolved in methanol (80 mL), and sodium borohydride (2.0 g, 53.395 mmol) was slowly added in portions at 0 ° C. Stir for 15 hours at room temperature. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (80 mL × 3). The organic layers were combined, washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate. Evaporate to dryness under reduced pressure. The obtained crude product is purified by silica gel chromatography (eluent: methanol / dichloromethane = 1: 100 v / v) to obtain N- (2,4-dimethoxybenzyl) -1,2. , 4-thiadiazole-5-amine, yield 72.1%, ESI-MS (m / z): 252.1 [M + H] + .
步骤d)：N-(2,4-二甲氧基苄基)-2,4,5-三氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备Step d): N- (2,4-dimethoxybenzyl) -2,4,5-trifluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide preparation
在-60℃条件下，将N-(2,4-二甲氧基苄基)-1,2,4-噻二唑-5-胺(3.21g，12.774mmol)的2-甲基四氢呋喃溶液(35mL)缓慢加入NaHMDS(1M，19.15mL)的2-甲基四氢呋喃悬浮液中，反应体系升温至0℃搅拌反应1小时，冷却至-60℃，将2,4,5-三氟-苯磺酰氯(2.5g，10.858mmol)的2-甲基四氢呋喃(25mL)中缓慢滴加到反应体系中，升温至20℃搅拌反应12小时，反应结束后，将反应液缓慢倾入0℃的饱和氯化铵溶液中，以乙酸乙酯(100mL×3)萃取，合并有机层，以饱和氯化钠溶液(50mL×2)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得粗品用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1:1v/v)，得N-(2,4-二甲氧基苄基)-2,4,5-三氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺，收率18.8％， 1H NMR(400MHz,CDCl 3)δ：8.22(s,1H),7.62(dt,J＝6.4，9.2Hz,1H),7.20(d,J＝8.8Hz,1H),6.94(dt,J＝6.4,9.2Hz,1H),6.37(dd,J＝2.4,8.4Hz,1H),6.23(d,J＝2.4Hz,1H),5.35(s,2H),3.77(s,3H),3.71(s,3H)，ESI-MS(m/z)：446.1[M+H] +。 A solution of N- (2,4-dimethoxybenzyl) -1,2,4-thiadiazole-5-amine (3.21 g, 12.774 mmol) in 2-methyltetrahydrofuran at -60 ° C (35mL) was slowly added to the 2-methyltetrahydrofuran suspension of NaHMDS (1M, 19.15mL), the reaction system was heated to 0 ° C and stirred for 1 hour, cooled to -60 ° C, and 2,4,5-trifluoro-benzene Sulfonyl chloride (2.5 g, 10.858 mmol) in 2-methyltetrahydrofuran (25 mL) was slowly added dropwise to the reaction system, and the temperature was raised to 20 ° C and the reaction was stirred for 12 hours. After the reaction was completed, the reaction solution was slowly poured into a saturated solution at 0 ° C The ammonium chloride solution was extracted with ethyl acetate (100 mL × 3), and the organic layers were combined, washed with a saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was silica gel Purification by column chromatography (eluent: petroleum ether / ethyl acetate = 1: 1 v / v) to obtain N- (2,4-dimethoxybenzyl) -2,4,5-trifluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide, yield 18.8%, 1 H NMR (400 MHz, CDCl 3 ) δ: 8.22 (s, 1H), 7.62 (dt, J = 6.4 , 9.2Hz, 1H), 7.20 (d, J = 8.8Hz, 1H), 6.94 (dt, J = 6.4, 9.2Hz, 1H), 6.37 (dd, J = 2.4, 8.4Hz, 1H), 6.23 (d , J = 2.4Hz, 1H), 5.35 (s, 2H), 3.77 (s, 3H), 3.7 1 (s, 3H), ESI-MS (m / z): 446.1 [M + H] + .
步骤e)：(2-((5-氯-2-(((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯基)氨基)甲基)苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯的制备Step e): (2-((5-chloro-2-(((4- (N- (2,4-dimethoxybenzyl) -N- (1,2,4-thiadiazole-5 -Yl) sulfonamido) -2,5-difluorophenyl) amino) methyl) phenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester
将(2-((2-(氨甲基)-5-氯苯基)氨基)乙基)(乙基)氨基甲酸叔丁酯(300mg，0.915mmol),N-(2,4-二甲氧基苄基)-2,4,5-三氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺(408mg，0.915mmol)、 碳酸钾(253mg，1.830mmol)和干燥DMSO(6mL)，氮气保护下25℃反应15小时，反应结束后，加水(30mL)稀释，以乙酸乙酯(20mL x 3)萃取，合并有机层，依次用水(10mL x 3)、饱和氯化钠溶液(30mL)洗涤,无水硫酸钠干燥，过滤，减压浓缩，所得粗品用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1:1v/v)，得(2-((5-氯-2-(((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯基)氨基)甲基)苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯，收率69.7％，ESI-MS(m/z)：775.3[M+Na] +。 Tert-butyl (2-((2- (aminomethyl) -5-chlorophenyl) amino) ethyl) (ethyl) carbamate (300 mg, 0.915 mmol), N- (2,4-dimethyl (Oxybenzyl) -2,4,5-trifluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide (408 mg, 0.915 mmol), potassium carbonate (253 mg, 1.830 mmol ) And dry DMSO (6mL), under nitrogen protection for 15 hours at 25 ° C. After the reaction, dilute with water (30mL), extract with ethyl acetate (20mL x 3), combine the organic layers, and use water (10mL x 3), It was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1: 1 v / v) to obtain (2-((5-chloro-2-((((4- (N- (2,4-dimethoxybenzyl) -N- (1,2,4-thiadiazol-5-yl) sulfonate Amido) -2,5-difluorophenyl) amino) methyl) phenyl) amino) ethyl) (ethyl) -t-butyl carbamate, yield 69.7%, ESI-MS (m / z) : 775.3 [M + Na] + .
步骤f)：4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备Step f): 4-((4-chloro-2-((2- (ethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (1,2,4-thia Preparation of Diazol-5-yl) -benzenesulfonamide
将(2-((5-氯-2-(((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯基)氨基)甲基)苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯(49mg，0.065mmol)加入反应瓶中，加入盐酸二氧六环溶液(2M，1.5mL)，室温搅拌2.5小时，反应结束后，抽滤，所得固体用饱和NaHCO 3溶液(10mL)和乙酸乙酯(20mL)萃取，水层再用乙酸乙酯(10mL x 3)萃取，合并有机层，以饱和氯化钠溶液(40mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得粗品以乙酸乙酯(5mL)超声粉碎打浆，抽滤，所得固体40℃真空干燥得4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺，收率31.6％， 1H NMR(400MHz,DMSO-d 6)δ:7.83(s,1H),7.28(dd,J 1＝11.6,J 2＝6.4Hz,1H),7.04(d,J＝8.0Hz,1H),6.81(s,1H),6.66(s,1H),6.61(d,J＝8.0Hz,1H),6.29(dd,J 1＝11.6,J 2＝6.4Hz,1H),5.54-5.53(m,1H),4.19(d,J＝5.6Hz,2H),3.37-3.36(m,2H),3.03-3.00(m,2H),2.91(q,J＝7.2Hz,2H),1.17-1.14(m,3H)，ESI-MS(m/z)：503.1[M+H] +。 Put (2-((5-chloro-2-(((4- (N- (2,4-dimethoxybenzyl) -N- (1,2,4-thiadiazol-5-yl) Sulfonyl) -2,5-difluorophenyl) amino) methyl) phenyl) amino) ethyl) (ethyl) -t-butyl carbamate (49 mg, 0.065 mmol) was added to the reaction flask, and hydrochloric acid was added Dioxane solution (2M, 1.5mL), stirred at room temperature for 2.5 hours. After the reaction, suction filtration was performed. The obtained solid was extracted with saturated NaHCO 3 solution (10mL) and ethyl acetate (20mL). The aqueous layer was then ethyl acetate. (10 mL x 3) extraction, the organic layers were combined, washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained solid was dried under vacuum at 40 ° C to obtain 4-((4-chloro-2-((2- (ethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (1,2, 4-thiadiazol-5-yl) -benzenesulfonamide, yield 31.6%, 1 H NMR (400 MHz, DMSO-d 6 ) δ: 7.83 (s, 1H), 7.28 (dd, J 1 = 11.6, J 2 = 6.4Hz, 1H), 7.04 (d, J = 8.0Hz, 1H), 6.81 (s, 1H), 6.66 (s, 1H), 6.61 (d, J = 8.0Hz, 1H), 6.29 (dd, J 1 = 11.6, J 2 = 6.4 Hz, 1H), 5.54-5.53 (m, 1H), 4.19 (d, J = 5.6 Hz, 2H), 3.37-3.36 (m, 2H), 3.03-3.00 (m, 2H), 2.91 (q, J = 7 .2Hz, 2H), 1.17-1.14 (m, 3H), ESI-MS (m / z): 503.1 [M + H] + .
实施例2Example 2
4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(噻唑-2-基)-苯磺酰胺的制备4-((4-chloro-2-((2- (ethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (thiazol-2-yl) -benzenesulfonamide preparation
Figure PCTCN2019104852-appb-000010
Figure PCTCN2019104852-appb-000010
操作过程同实施例1，只是将步骤c中的1,2,4-噻二唑-5-胺用噻唑-2-胺替代，得4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(噻唑-2-基)-苯磺酰胺，ESI-MS(m/z)：502.1[M+H] +。 The operation process is the same as that in Example 1, except that 1,2,4-thiadiazole-5-amine in step c is replaced with thiazol-2-amine to obtain 4-((4-chloro-2-((2- ( Ethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (thiazol-2-yl) -benzenesulfonamide, ESI-MS (m / z): 502.1 [M + H] + .
实施例3Example 3
4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-N-(5-氯噻唑-2-基)-2,5-二氟-苯磺酰胺的制备4-((4-chloro-2-((2- (ethylamino) ethyl) amino) benzyl) amino) -N- (5-chlorothiazol-2-yl) -2,5-difluoro-benzene Preparation of sulfonamide
Figure PCTCN2019104852-appb-000011
Figure PCTCN2019104852-appb-000011
操作过程同实施例1，只是将步骤c中的1,2,4-噻二唑-5-胺用5-氯-噻唑-2-胺替代，得4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-N-(5-氯噻唑-2-基)-2,5-二氟-苯磺酰胺， 1H NMR(400MHz,DMSO-d 6)δ:8.96(s,1H),7.53(s,1H),7.37(dd,J 1＝11.6,J 2＝6.4Hz,1H),7.30(s,1H),7.08(d,J＝8.0Hz,1H),6.69(d,J＝2.0Hz,1H),6.63(m,1H),6.46(dd,J 1＝11.6,J 2＝6.4Hz,1H),4.31(s,2H),3.45(t,J＝5.6Hz,2H),3.14-3.08(m,2H),3.03-3.00(m,2H),1.23(t,J＝7.2Hz,3H)，ESI-MS(m/z)：536.2[M+H] +。 The operation was the same as in Example 1, except that 1,1,2,4-thiadiazole-5-amine in step c was replaced with 5-chloro-thiazole-2-amine to obtain 4-((4-chloro-2- ( (2- (ethylamino) ethyl) amino) benzyl) amino) -N- (5-chlorothiazol-2-yl) -2,5-difluoro-benzenesulfonamide, 1 H NMR (400 MHz, DMSO- d 6 ) δ: 8.96 (s, 1H), 7.53 (s, 1H), 7.37 (dd, J 1 = 11.6, J 2 = 6.4 Hz, 1H), 7.30 (s, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.69 (d, J = 2.0 Hz, 1H), 6.63 (m, 1H), 6.46 (dd, J 1 = 11.6, J 2 = 6.4 Hz, 1H), 4.31 (s, 2H), 3.45 (t, J = 5.6Hz, 2H), 3.14-3.08 (m, 2H), 3.03-3.00 (m, 2H), 1.23 (t, J = 7.2Hz, 3H), ESI-MS (m / z) : 536.2 [M + H] + .
实施例4Example 4
4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(5-氟噻唑-2-基)-苯磺酰胺的制备4-((4-chloro-2-((2- (ethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (5-fluorothiazol-2-yl) -benzene Preparation of sulfonamide
Figure PCTCN2019104852-appb-000012
Figure PCTCN2019104852-appb-000012
操作过程同实施例1，只是将步骤c中的1,2,4-噻二唑-5-胺用5-氟-噻唑-2-胺替代，得4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(5-氟噻唑-2-基)-苯磺酰胺，ESI-MS(m/z)：520.1[M+H] +。 The operation was the same as in Example 1, except that 1,1,2,4-thiadiazole-5-amine in step c was replaced with 5-fluoro-thiazole-2-amine to obtain 4-((4-chloro-2- ( (2- (ethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (5-fluorothiazol-2-yl) -benzenesulfonamide, ESI-MS (m / z) : 520.1 [M + H] + .
实施例5Example 5
4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(噻唑-4-基)-苯磺酰胺的制备4-((4-chloro-2-((2- (ethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (thiazol-4-yl) -benzenesulfonamide preparation
Figure PCTCN2019104852-appb-000013
Figure PCTCN2019104852-appb-000013
操作过程同实施例1，只是将步骤c中的1,2,4-噻二唑-5-胺用噻唑-4-胺替代，得4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(噻唑-4-基)-苯磺酰胺，ESI-MS(m/z)：502.1[M+H] +。 The operation process is the same as in Example 1, except that 1,2,4-thiadiazole-5-amine in step c is replaced with thiazol-4-amine to obtain 4-((4-chloro-2-((2- ( Ethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (thiazol-4-yl) -benzenesulfonamide, ESI-MS (m / z): 502.1 [M + H] + .
实施例6Example 6
4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(1,2,4-噁二唑-3-基)-苯磺酰胺的制备4-((4-chloro-2-((2- (ethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (1,2,4-oxadiazole-3 -Yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000014
Figure PCTCN2019104852-appb-000014
操作过程同实施例1，只是将步骤c中的1,2,4-噻二唑-5-胺用1,2,4-噁二唑-3-胺替代，得4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(1,2,4-噁二唑-3-基)-苯磺酰胺，ESI-MS(m/z):487.0[M+H] +。 The operation process is the same as in Example 1, except that the 1,2,4-thiadiazole-5-amine in step c is replaced with 1,2,4-oxadiazole-3-amine to obtain 4-((4-chloro 2-((2- (ethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (1,2,4-oxadiazol-3-yl) -benzenesulfonamide , ESI-MS (m / z): 487.0 [M + H] + .
实施例7Example 7
4-((4-氯-2-((2-(乙氨基)乙基)(甲基)氨基)苄基)氨基)-2,5-二氟-N-(1,2,4-噁二唑-3-基)-苯磺酰胺的制备4-((4-chloro-2-((2- (ethylamino) ethyl) (methyl) amino) benzyl) amino) -2,5-difluoro-N- (1,2,4-ox Preparation of Diazol-3-yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000015
Figure PCTCN2019104852-appb-000015
操作过程同实施例1，只是分别将步骤a中的(2-氨基乙基)(乙基)氨基甲酸叔丁酯用乙基(2-甲氨基)(乙基)氨基甲酸叔丁酯替代，将步骤c中的1,2,4-噻二唑-5-胺用1,2,4-噁二唑-3-胺替代，得4-((4-氯-2-((2-(乙氨基)乙基)(甲基)氨基)苄基)氨基)-2,5-二氟-N-(1,2,4-噁二唑-3-基)-苯磺酰胺，ESI-MS(m/z):501.2[M+H] +。 The operation process is the same as in Example 1, except that the (2-aminoethyl) (ethyl) t-butyl carbamate in step a is replaced by ethyl (2-methylamino) (ethyl) t-butyl carbamate. Substituting 1,2,4-thiadiazole-5-amine with 1,2,4-oxadiazole-3-amine in step c to obtain 4-((4-chloro-2-((2- ( Ethylamino) ethyl) (methyl) amino) benzyl) amino) -2,5-difluoro-N- (1,2,4-oxadiazol-3-yl) -benzenesulfonamide, ESI-MS (m / z): 501.2 [M + H] + .
实施例8Example 8
4-((4-氯-2-((3-(乙氨基)丙基)氨基)苄基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备4-((4-chloro-2-((3- (ethylamino) propyl) amino) benzyl) amino) -2,5-difluoro-N- (1,2,4-thiadiazole-5 -Yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000016
Figure PCTCN2019104852-appb-000016
操作过程同实施例1，只是将步骤a中的(2-氨基乙基)(乙基)氨基甲酸叔丁酯用(3-氨基丙基)(乙基)氨基甲酸叔丁酯替代，得4-((4-氯-2-((3-(乙氨基)丙基)氨基)苄基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺， 1H NMR(400MHz,DMSO-d 6)δ:8.74(s,2H),8.49(s,1H),7.39-7.35(m,2H),7.10(d,J＝8.0Hz,1H),6.65-6.53(m,2H),6.49(dd,J 1＝12.4,J 2＝6.8Hz,1H),4.24(s,2H),3.23(t,J＝6.4Hz,2H),2.93-2.89(m,4H),1.95-1.79(m,2H),1.20(t,J＝7.2Hz,3H)，ESI-MS(m/z):517.0[M+H] +。 The operation was the same as in Example 1, except that (2-aminoethyl) (ethyl) t-butyl carbamate in step a was replaced with (3-aminopropyl) (ethyl) t-butyl carbamate to obtain 4 -((4-chloro-2-((3- (ethylamino) propyl) amino) benzyl) amino) -2,5-difluoro-N- (1,2,4-thiadiazole-5- ) -Benzenesulfonamide, 1 H NMR (400MHz, DMSO-d 6 ) δ: 8.74 (s, 2H), 8.49 (s, 1H), 7.39-7.35 (m, 2H), 7.10 (d, J = 8.0 Hz, 1H), 6.65-6.53 (m, 2H), 6.49 (dd, J 1 = 12.4, J 2 = 6.8 Hz, 1H), 4.24 (s, 2H), 3.23 (t, J = 6.4 Hz, 2H) , 2.93-2.89 (m, 4H), 1.95-1.79 (m, 2H), 1.20 (t, J = 7.2 Hz, 3H), ESI-MS (m / z): 517.0 [M + H] + .
实施例9Example 9
4-((4-氯-2-((3-(乙氨基)丙基)氨基)苄基)氨基)-2,5-二氟-N-(噻唑-2-基)-苯磺酰胺的制备4-((4-chloro-2-((3- (ethylamino) propyl) amino) benzyl) amino) -2,5-difluoro-N- (thiazol-2-yl) -benzenesulfonamide preparation
Figure PCTCN2019104852-appb-000017
Figure PCTCN2019104852-appb-000017
操作过程同实施例1，只是分别将步骤a中的(2-氨基乙基)(乙基)氨基甲酸叔丁酯用(3-氨基丙基)(乙基)氨基甲酸叔丁酯替代，将步骤c中的1,2,4-噻二唑-5-胺用噻唑-2-胺替代，得4-((4-氯-2-((3-(乙氨基)丙基)氨基)苄基)氨基)-2,5-二氟-N-(噻唑-2-基)-苯磺酰胺，ESI-MS(m/z):516.1[M+H] +。 The operation process is the same as in Example 1, except that (2-aminoethyl) (ethyl) t-butyl carbamate in step a was replaced with (3-aminopropyl) (ethyl) t-butyl carbamate, respectively. Substitute 1,2,4-thiadiazole-5-amine in step c with thiazol-2-amine to give 4-((4-chloro-2-((3- (ethylamino) propyl) amino) benzyl (Amino) amino) -2,5-difluoro-N- (thiazol-2-yl) -benzenesulfonamide, ESI-MS (m / z): 516.1 [M + H] + .
实施例10Example 10
4-((4-氯-2-((3-(乙氨基)丙基)氨基)苄基)氨基)-2,5-二氟-N-(噻唑-4-基)-苯甲酰胺的制备4-((4-chloro-2-((3- (ethylamino) propyl) amino) benzyl) amino) -2,5-difluoro-N- (thiazol-4-yl) -benzamide preparation
Figure PCTCN2019104852-appb-000018
Figure PCTCN2019104852-appb-000018
操作过程同实施例1，只是分别将步骤a中的(2-氨基乙基)(乙基)氨基甲酸叔丁酯用(3-氨基丙基)(乙基)氨基甲酸叔丁酯替代，将步骤c中的1,2,4-噻二唑-5-胺用噻唑-4-胺替代，得4-((4-氯-2-((3-(乙氨基)丙基)氨基)苄基)氨基)-2,5-二氟-N-(噻唑-4-基)-苯磺酰胺，ESI-MS(m/z):515.9[M+H] +。 The operation process is the same as in Example 1, except that (2-aminoethyl) (ethyl) t-butyl carbamate in step a was replaced with (3-aminopropyl) (ethyl) t-butyl carbamate, respectively. Substitute 1,2,4-thiadiazole-5-amine in step c with thiazol-4-amine to obtain 4-((4-chloro-2-((3- (ethylamino) propyl) amino) benzyl (Amino) amino) -2,5-difluoro-N- (thiazol-4-yl) -benzenesulfonamide, ESI-MS (m / z): 515.9 [M + H] + .
实施例11Example 11
4-((4-氯-2-((3-(乙氨基)丙基)氨基)苄基)氨基)-2,5-二氟-N-(1,2,4-噁二唑-3-基)-苯磺酰胺的制备4-((4-chloro-2-((3- (ethylamino) propyl) amino) benzyl) amino) -2,5-difluoro-N- (1,2,4-oxadiazole-3 -Yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000019
Figure PCTCN2019104852-appb-000019
操作过程同实施例1，只是分别将步骤a中的(2-氨基乙基)(乙基)氨基甲酸叔丁酯用(3-氨基丙基)(乙基)氨基甲酸叔丁酯替代，将步骤c中的1,2,4-噻二唑-5-胺用1,2,4-噁二唑-3-胺替代，得4-((4-氯-2-((3-(乙氨基)丙基)氨基)苄基)氨基)-2,5-二氟-N-(1,2,4-噁二唑-3-基)-苯磺酰胺，ESI-MS(m/z):501.1[M+H] +。 The operation process is the same as in Example 1, except that (2-aminoethyl) (ethyl) t-butyl carbamate in step a was replaced with (3-aminopropyl) (ethyl) t-butyl carbamate, respectively. The 1,2,4-thiadiazole-5-amine in step c was replaced with 1,2,4-oxadiazole-3-amine to obtain 4-((4-chloro-2-((3- (ethyl Amino) propyl) amino) benzyl) amino) -2,5-difluoro-N- (1,2,4-oxadiazol-3-yl) -benzenesulfonamide, ESI-MS (m / z) : 501.1 [M + H] + .
实施例12Example 12
4-((4-氯-2-((2-(乙氨基)丙基)氨基)苄基)氨基)-N-(5-氯噻唑-2-基)-2,5-二氟-苯磺酰胺的制备4-((4-chloro-2-((2- (ethylamino) propyl) amino) benzyl) amino) -N- (5-chlorothiazol-2-yl) -2,5-difluoro-benzene Preparation of sulfonamide
Figure PCTCN2019104852-appb-000020
Figure PCTCN2019104852-appb-000020
操作过程同实施例1，只是分别将步骤a中的(2-氨基乙基)(乙基)氨基甲酸叔丁酯用(3-氨 基丙基)(乙基)氨基甲酸叔丁酯替代，将步骤c中的1,2,4-噻二唑-5-胺用5-氯-噻唑-2-胺替代，得4-((4-氯-2-((2-(乙氨基)丙基)氨基)苄基)氨基)-N-(5-氯噻唑-2-基)-2,5-二氟-苯磺酰胺的制备，ESI-MS(m/z):550.0[M+H] +。 The operation process is the same as in Example 1, except that (2-aminoethyl) (ethyl) t-butyl carbamate in step a was replaced with (3-aminopropyl) (ethyl) t-butyl carbamate, respectively. Substitute 1,2,4-thiadiazole-5-amine in step c with 5-chloro-thiazole-2-amine to obtain 4-((4-chloro-2-((2- (ethylamino) propyl ) Amino) benzyl) amino) -N- (5-chlorothiazol-2-yl) -2,5-difluoro-benzenesulfonamide, ESI-MS (m / z): 550.0 [M + H] + .
实施例13Example 13
4-((4-氯-2-((2-(二甲氨基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(1,2,4-噁二唑-3-基)-苯磺酰胺的制备4-((4-chloro-2-((2- (dimethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (1,2,4-oxadiazole- Preparation of 3-yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000021
Figure PCTCN2019104852-appb-000021
操作过程同实施例1，只是分别将步骤a中的(2-氨基乙基)(乙基)氨基甲酸叔丁酯用N 1,N 1-二甲基-1,2-乙二胺替代，将步骤c中的1,2,4-噻二唑-5-胺用1,2,4-噁二唑-3-胺替代，得4-((4-氯-2-((2-(二甲氨基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(1,2,4-噁二唑-3-基)-苯磺酰胺，ESI-MS(m/z):487.0[M+H] +。 The operation procedure is the same as in Example 1, except that the (2-aminoethyl) (ethyl) carbamic acid tert-butyl ester in step a is replaced with N 1 , N 1 -dimethyl-1,2-ethylenediamine, Substituting 1,2,4-thiadiazole-5-amine with 1,2,4-oxadiazole-3-amine in step c to obtain 4-((4-chloro-2-((2- ( Dimethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (1,2,4-oxadiazol-3-yl) -benzenesulfonamide, ESI-MS (m / z): 487.0 [M + H] + .
实施例14Example 14
4-((4-氯-2-((2-(二甲氨基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(噻唑-2-基)-苯磺酰胺的制备4-((4-chloro-2-((2- (dimethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (thiazol-2-yl) -benzenesulfonamide Preparation
Figure PCTCN2019104852-appb-000022
Figure PCTCN2019104852-appb-000022
操作过程同实施例1，只是分别将步骤a中的(2-氨基乙基)(乙基)氨基甲酸叔丁酯用N 1,N 1-二甲基-1,2-乙二胺替代，将步骤c中的1,2,4-噻二唑-5-胺用噻唑-2-胺替代，得4-((4-氯-2-((2-(二甲氨基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(噻唑-2-基)-苯磺酰胺，ESI-MS(m/z):502.1[M+H] +。 The operation procedure is the same as in Example 1, except that the (2-aminoethyl) (ethyl) carbamic acid tert-butyl ester in step a is replaced with N 1 , N 1 -dimethyl-1,2-ethylenediamine, Substitute 1,2,4-thiadiazole-5-amine in step c with thiazol-2-amine to obtain 4-((4-chloro-2-((2- (dimethylamino) ethyl) amino ) Benzyl) amino) -2,5-difluoro-N- (thiazol-2-yl) -benzenesulfonamide, ESI-MS (m / z): 502.1 [M + H] + .
实施例15Example 15
4-((4-氯-2-((2-(吡咯-1-基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备4-((4-chloro-2-((2- (pyrrole-1-yl) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (1,2,4-thiadi Preparation of azole-5-yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000023
Figure PCTCN2019104852-appb-000023
操作过程同实施例1，只是将步骤a中的(2-氨基乙基)(乙基)氨基甲酸叔丁酯用2-(吡咯-1-基)乙胺替代，得4-((4-氯-2-((2-(吡咯-1-基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺， 1H NMR(400MHz,DMSO-d 6)δ:9.42(s,1H),7.84(s,1H),7.28-7.25(m,1H),7.07(d,J＝8.0Hz,1H),6.76(s,1H),6.72-6.60(m,2H),6.32-6.25(m,1H),5.57(s,1H),4.17(d,J＝5.6Hz,2H),3.66-3.32(m,2H),3.23-2.85(m,4H),2.03-1.77(m,4H)，ESI-MS(m/z):529.0[M+H] +。 The operation was the same as in Example 1, except that the (2-aminoethyl) (ethyl) carbamic acid tert-butyl ester in step a was replaced with 2- (pyrrol-1-yl) ethylamine to obtain 4-((4- Chloro-2-((2- (pyrrole-1-yl) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl) -Benzenesulfonamide, 1 H NMR (400 MHz, DMSO-d 6 ) δ: 9.42 (s, 1H), 7.84 (s, 1H), 7.28-7.25 (m, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.76 (s, 1H), 6.72-6.60 (m, 2H), 6.32-6.25 (m, 1H), 5.57 (s, 1H), 4.17 (d, J = 5.6Hz, 2H), 3.66-3.32 (m, 2H), 3.23-2.85 (m, 4H), 2.03-1.77 (m, 4H), ESI-MS (m / z): 529.0 [M + H] + .
实施例16Example 16
4-((4-氯-2-((2-吗啉乙基)氨基)苄基)氨基)-2,5-二氟-N-(1,2,4-噁二唑-3-基)-苯磺酰胺的制备4-((4-chloro-2-((2-morpholinethyl) amino) benzyl) amino) -2,5-difluoro-N- (1,2,4-oxadiazol-3-yl ) -Benzenesulfonamide
Figure PCTCN2019104852-appb-000024
Figure PCTCN2019104852-appb-000024
操作过程同实施例1，只是分别将步骤a中的(2-氨基乙基)(乙基)氨基甲酸叔丁酯用2-吗啉基乙胺替代，将步骤c中的1,2,4-噻二唑-5-胺用1,2,4-噁二唑-3-胺替代，得4-((4-氯-2-((2-吗啉乙基)氨基)苄基)氨基)-2,5-二氟-N-(1,2,4-噁二唑-3-基)-苯磺酰胺，ESI-MS(m/z):529.0[M+H] +。 The operation process is the same as in Example 1, except that the (2-aminoethyl) (ethyl) carbamic acid tert-butyl ester in step a is replaced with 2-morpholinylethylamine, and 1, 2, 4 in step c are replaced. -Thiadiazol-5-amine was replaced with 1,2,4-oxadiazol-3-amine to give 4-((4-chloro-2-((2-morpholinethyl) amino) benzyl) amino ) -2,5-difluoro-N- (1,2,4-oxadiazol-3-yl) -benzenesulfonamide, ESI-MS (m / z): 529.0 [M + H] + .
实施例17Example 17
4-((2-((3-(乙氨基)丙基)氨基)苄基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备4-((2-((3- (ethylamino) propyl) amino) benzyl) amino) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl)- Preparation of benzenesulfonamide
Figure PCTCN2019104852-appb-000025
Figure PCTCN2019104852-appb-000025
操作过程同实施例1，只是分别将步骤a中的(2-氨基乙基)(乙基)氨基甲酸叔丁酯用(3-氨基丙基)(乙基)氨基甲酸叔丁酯替代，将4-氯-2-氟苯甲腈用2-氟-苯甲腈替代，得4-((2-((3-(乙 氨基)丙基)氨基)苄基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺， 1H NMR(400MHz,DMSO-d 6)δ:8.83(s,2H),8.48(s,1H),7.38(dd,J 1＝11.2,J 2＝6.4Hz,2H),7.15-7.13(m,2H),6.79(s,1H),6.71(s,1H),6.55(dd,J 1＝12.4,J 2＝6.8Hz,1H),4.37(s,2H),3.27(t,J＝6.4Hz,2H),3.03-2.83(m,4H),2.04-1.87(m,2H),1.20(t,J＝7.2Hz,3H)，ESI-MS(m/z):483.2[M+H] +。 The operation process is the same as in Example 1, except that (2-aminoethyl) (ethyl) t-butyl carbamate in step a was replaced with (3-aminopropyl) (ethyl) t-butyl carbamate, respectively. 4-chloro-2-fluorobenzonitrile was replaced with 2-fluoro-benzonitrile to give 4-((2-((3- (ethylamino) propyl) amino) benzyl) amino) -2,5- Difluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide, 1 H NMR (400 MHz, DMSO-d 6 ) δ: 8.83 (s, 2H), 8.48 (s, 1H ), 7.38 (dd, J 1 = 11.2, J 2 = 6.4 Hz, 2H), 7.15-7.13 (m, 2H), 6.79 (s, 1H), 6.71 (s, 1H), 6.55 (dd, J 1 = 12.4, J 2 = 6.8Hz, 1H), 4.37 (s, 2H), 3.27 (t, J = 6.4Hz, 2H), 3.03-2.83 (m, 4H), 2.04-1.87 (m, 2H), 1.20 ( t, J = 7.2 Hz, 3H), ESI-MS (m / z): 483.2 [M + H] + .
实施例18Example 18
4-((2-((2-(乙氨基)乙基)氨基)-4-(三氟甲氧基)苄基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备4-((2-((2- (ethylamino) ethyl) amino) -4- (trifluoromethoxy) benzyl) amino) -2,5-difluoro-N- (1,2,4 -Thiadiazol-5-yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000026
Figure PCTCN2019104852-appb-000026
操作过程同实施例1，只是将步骤a中的4-氯-2-氟苯甲腈用2-氟-4-三氟甲氧基苯甲腈替代，得4-((2-((2-(乙氨基)乙基)氨基)-4-(三氟甲氧基)苄基)氨基)-2,5-二氟-N-(1,2,4-噻二唑5-基)-苯磺酰胺， 1H NMR(400MHz,DMSO-d 6)δ:8.12(s,1H),7.84(s,1H),7.29(dd,J 1＝11.6,J 2＝6.4Hz,1H),7.12(d,J＝8.0Hz,1H),6.81(s,1H),6.63-6.50(m,1H),6.29(dd,J 1＝11.6,J 2＝6.4Hz,1H),5.85(t,J＝5.6Hz,1H),4.19(d,J＝5.6Hz,2H),3.40-3.37(m,2H),3.09(t,J＝6.4Hz,1H),3.01(q,J＝7.2Hz,2H),1.17(t,J＝7.2Hz,3H)，ESI-MS(m/z):553.0[M+H] +。 The operation was the same as in Example 1, except that 4-chloro-2-fluorobenzonitrile in step a was replaced with 2-fluoro-4-trifluoromethoxybenzonitrile to obtain 4-((2-((2 -(Ethylamino) ethyl) amino) -4- (trifluoromethoxy) benzyl) amino) -2,5-difluoro-N- (1,2,4-thiadiazol 5-yl)- Benzenesulfonamide, 1 H NMR (400 MHz, DMSO-d 6 ) δ: 8.12 (s, 1H), 7.84 (s, 1H), 7.29 (dd, J 1 = 11.6, J 2 = 6.4 Hz, 1 H), 7.12 (d, J = 8.0 Hz, 1H), 6.81 (s, 1H), 6.63-6.50 (m, 1H), 6.29 (dd, J 1 = 11.6, J 2 = 6.4 Hz, 1H), 5.85 (t, J = 5.6Hz, 1H), 4.19 (d, J = 5.6Hz, 2H), 3.40-3.37 (m, 2H), 3.09 (t, J = 6.4Hz, 1H), 3.01 (q, J = 7.2Hz, 2H ), 1.17 (t, J = 7.2 Hz, 3H), ESI-MS (m / z): 553.0 [M + H] + .
实施例19Example 19
4-((2-((2-(乙氨基)乙基)氨基)-4-(三氟甲基)苄基)氨基)-2,5-二氟-N-(5-氟噻唑-2-基)-苯磺酰胺的制备4-((2-((2- (ethylamino) ethyl) amino) -4- (trifluoromethyl) benzyl) amino) -2,5-difluoro-N- (5-fluorothiazole-2 -Yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000027
Figure PCTCN2019104852-appb-000027
操作过程同实施例1，只是分别将步骤a中的4-氯-2-氟苯甲腈用2-氟-4-三氟甲基苯甲腈替代，将步骤c中的1,2,4-噻二唑-5-胺用5-氟噻唑-2-胺替代得4-((2-((2-(乙氨基)乙基)氨基)-4-(三氟甲基)苄基)氨基)-2,5-二氟-N-(5-氟噻唑-2-基)-苯磺酰胺，ESI-MS(m/z):554.0[M+H] +。 The operation process is the same as in Example 1, except that 4-chloro-2-fluorobenzonitrile in step a is replaced with 2-fluoro-4-trifluoromethylbenzonitrile, and 1, 2, 4 in step c are replaced. -Thiadiazole-5-amine is replaced with 5-fluorothiazol-2-amine to give 4-((2-((2- (ethylamino) ethyl) amino) -4- (trifluoromethyl) benzyl) (Amino) -2,5-difluoro-N- (5-fluorothiazol-2-yl) -benzenesulfonamide, ESI-MS (m / z): 554.0 [M + H] + .
实施例20Example 20
4-((2-((3-(乙氨基)丙基)氨基)-4-(三氟甲基)苄基)氨基)-2,5-二氟-N-(5-氟噻唑-2-基)-苯磺酰 胺的制备4-((2-((3- (ethylamino) propyl) amino) -4- (trifluoromethyl) benzyl) amino) -2,5-difluoro-N- (5-fluorothiazole-2 -Yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000028
Figure PCTCN2019104852-appb-000028
操作过程同实施例1，只是分别将步骤a中的(2-氨基乙基)(乙基)氨基甲酸叔丁酯用(3-氨基丙基)(乙基)氨基甲酸叔丁酯替代，将4-氯-2-氟苯甲腈用2-氟-4-三氟甲基苯甲腈替代，将步骤c中的1,2,4-噻二唑-5-胺用5-氟噻唑-2-胺替代，得4-((2-((3-(乙氨基)丙基)氨基)-4-(三氟甲基)苄基)氨基)-2,5-二氟-N-(5-氟噻唑-2-基)-苯磺酰胺，ESI-MS(m/z):568.1[M+H] +。 The operation process is the same as in Example 1, except that (2-aminoethyl) (ethyl) t-butyl carbamate in step a was replaced with (3-aminopropyl) (ethyl) t-butyl carbamate, respectively. 4-chloro-2-fluorobenzonitrile was replaced with 2-fluoro-4-trifluoromethylbenzonitrile, and 1,2,4-thiadiazole-5-amine in step c was replaced with 5-fluorothiazole- 2-amine substitution to give 4-((2-((3- (ethylamino) propyl) amino) -4- (trifluoromethyl) benzyl) amino) -2,5-difluoro-N- ( 5-fluorothiazol-2-yl) -benzenesulfonamide, ESI-MS (m / z): 568.1 [M + H] + .
实施例21Example 21
4-((2-((2-(乙氨基)乙基)氨基)-4-甲氧基苄基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备4-((2-((2- (ethylamino) ethyl) amino) -4-methoxybenzyl) amino) -2,5-difluoro-N- (1,2,4-thiadiazole -5-yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000029
Figure PCTCN2019104852-appb-000029
操作过程同实施例1，只是将步骤a中的4-氯-2-氟苯甲腈用2-氟-4-甲氧基苯甲腈替代，得4-((2-((2-(乙氨基)乙基)氨基)-4-甲氧基苄基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺，ESI-MS(m/z):499.0[M+H] +。 The operation was the same as in Example 1, except that 4-chloro-2-fluorobenzonitrile in step a was replaced with 2-fluoro-4-methoxybenzonitrile to obtain 4-((2-((2- ( Ethylamino) ethyl) amino) -4-methoxybenzyl) amino) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide, ESI -MS (m / z): 499.0 [M + H] + .
实施例22Example 22
4-((2-((3-(乙氨基)丙基)氨基)-4-甲氧基苄基)氨基)-2,5-二氟-N-(1,2,4-噁二唑-3-基)-苯磺酰胺的制备4-((2-((3- (ethylamino) propyl) amino) -4-methoxybenzyl) amino) -2,5-difluoro-N- (1,2,4-oxadiazole -3-yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000030
Figure PCTCN2019104852-appb-000030
操作过程同实施例1，只是分别将步骤a中的(2-氨基乙基)(乙基)氨基甲酸叔丁酯用(3-氨基丙基)(乙基)氨基甲酸叔丁酯替代，将4-氯-2-氟苯甲腈用2-氟-4-甲氧基苯甲腈替代，将步骤 c中的1,2,4-噻二唑-5-胺用1,2,4-噁二唑-3-胺，得4-((2-((3-(乙氨基)丙基)氨基)-4-甲氧基苄基)氨基)-2,5-二氟-N-(1,2,4-噁二唑-3-基)-苯磺酰胺，ESI-MS(m/z):497.0[M+H] +。 The operation process is the same as in Example 1, except that (2-aminoethyl) (ethyl) t-butyl carbamate in step a was replaced with (3-aminopropyl) (ethyl) t-butyl carbamate, respectively. 4-chloro-2-fluorobenzonitrile was replaced with 2-fluoro-4-methoxybenzonitrile, and 1,2,4-thiadiazole-5-amine in step c was replaced with 1,2,4- Oxadiazol-3-amine to give 4-((2-((3- (ethylamino) propyl) amino) -4-methoxybenzyl) amino) -2,5-difluoro-N- ( 1,2,4-oxadiazol-3-yl) -benzenesulfonamide, ESI-MS (m / z): 497.0 [M + H] + .
实施例23Example 23
4-((2-((3-(乙氨基)丙基)氨基)-4-氟苄基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备4-((2-((3- (ethylamino) propyl) amino) -4-fluorobenzyl) amino) -2,5-difluoro-N- (1,2,4-thiadiazole-5 -Yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000031
Figure PCTCN2019104852-appb-000031
操作过程同实施例1，只是分别将步骤a中的(2-氨基乙基)(乙基)氨基甲酸叔丁酯用(3-氨基丙基)(乙基)氨基甲酸叔丁酯替代，将4-氯-2-氟苯甲腈用2,4-二氟苯甲腈替代，得4-((2-((3-(乙氨基)丙基)氨基)-4-氟苄基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺，ESI-MS(m/z):501.1[M+H] +。 The operation process is the same as in Example 1, except that (2-aminoethyl) (ethyl) t-butyl carbamate in step a was replaced with (3-aminopropyl) (ethyl) t-butyl carbamate, respectively. 4-chloro-2-fluorobenzonitrile was replaced with 2,4-difluorobenzonitrile to give 4-((2-((3- (ethylamino) propyl) amino) -4-fluorobenzyl) amino ) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide, ESI-MS (m / z): 501.1 [M + H] + .
实施例24Example 24
4-((2-((3-(乙氨基)丙基)氨基)-4-甲基苄基)氨基)-2,5-二氟-N-(噻唑-2-基)-苯磺酰胺的制备4-((2-((3- (ethylamino) propyl) amino) -4-methylbenzyl) amino) -2,5-difluoro-N- (thiazol-2-yl) -benzenesulfonamide Preparation
Figure PCTCN2019104852-appb-000032
Figure PCTCN2019104852-appb-000032
操作过程同实施例1，只是分别将步骤a中的(2-氨基乙基)(乙基)氨基甲酸叔丁酯用(3-氨基丙基)(乙基)氨基甲酸叔丁酯替代，将4-氯-2-氟苯甲腈用2-氟-4-甲基苯甲腈替代，将步骤c中的1,2,4-噻二唑-5-胺用噻唑-2-胺替代，得4-((2-((3-(乙氨基)丙基)氨基)-4-甲基苄基)氨基)-2,5-二氟-N-(噻唑-2-基)-苯磺酰胺，ESI-MS(m/z):496.1[M+H] +。 The operation process is the same as in Example 1, except that (2-aminoethyl) (ethyl) t-butyl carbamate in step a was replaced with (3-aminopropyl) (ethyl) t-butyl carbamate, respectively. 4-chloro-2-fluorobenzonitrile was replaced with 2-fluoro-4-methylbenzonitrile, and 1,2,4-thiadiazole-5-amine in step c was replaced with thiazol-2-amine, 4-((2-((3- (ethylamino) propyl) amino) -4-methylbenzyl) amino) -2,5-difluoro-N- (thiazol-2-yl) -benzenesulfonate Amide, ESI-MS (m / z): 496.1 [M + H] + .
实施例25Example 25
2-氯-N-(5-氯噻唑-2-基)-4-((2-((2-(乙氨基)乙基)氨基)-4-(三氟甲基)苄基)氨基)-5-氟苯磺酰胺的制备2-chloro-N- (5-chlorothiazol-2-yl) -4-((2-((2- (ethylamino) ethyl) amino) -4- (trifluoromethyl) benzyl) amino) Of -5-fluorobenzenesulfonamide
Figure PCTCN2019104852-appb-000033
Figure PCTCN2019104852-appb-000033
操作过程同实施例1，只是分别将步骤a中的4-氯-2-氟苯甲腈用2-氟-4-三氟甲基苯甲腈替代，将步骤c中的1,2,4-噻二唑-5-胺用5-氯噻唑-2-胺替代，将步骤d中的2,4,5-三氟苯基-1-磺酰氯用2-氯-4,5-二氟苯基-1-磺酰氯替代，得2-氯-N-(5-氯噻唑-2-基)-4-((2-((2-(乙氨基)乙基)氨基)-4-(三氟甲基)苄基)氨基)-5-氟苯磺酰胺，ESI-MS(m/z):586.1[M+H] +。 The operation process is the same as in Example 1, except that 4-chloro-2-fluorobenzonitrile in step a is replaced with 2-fluoro-4-trifluoromethylbenzonitrile, and 1, 2, 4 in step c are replaced. -Thiadiazole-5-amine is replaced with 5-chlorothiazol-2-amine, and 2,4,5-trifluorophenyl-1-sulfonyl chloride in step d is replaced with 2-chloro-4,5-difluoro Phenyl-1-sulfonyl chloride substitution to give 2-chloro-N- (5-chlorothiazol-2-yl) -4-((2-((2- (ethylamino) ethyl) amino) -4- ( Trifluoromethyl) benzyl) amino) -5-fluorobenzenesulfonamide, ESI-MS (m / z): 586.1 [M + H] + .
实施例26Example 26
2-氯-4-((4-氯-2-((2-(乙氨基)乙基)(甲基)氨基)苄基)氨基)-5-氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备2-chloro-4-((4-chloro-2-((2- (ethylamino) ethyl) (methyl) amino) benzyl) amino) -5-fluoro-N- (1,2,4- Preparation of thiadiazol-5-yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000034
Figure PCTCN2019104852-appb-000034
操作过程同实施例1，只是分别将步骤a中的(2-氨基乙基)(乙基)氨基甲酸叔丁酯用乙基(2-甲氨基)(乙基)氨基甲酸叔丁酯替代，将步骤d中的2,4,5-三氟苯基-1-磺酰氯用2-氯-4,5-二氟苯基-1-磺酰氯替代，得2-氯-4-((4-氯-2-((2-(乙氨基)乙基)(甲基)氨基)苄基)氨基)-5-氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺，ESI-MS(m/z):533.0[M+H] +。 The operation process is the same as in Example 1, except that the (2-aminoethyl) (ethyl) t-butyl carbamate in step a is replaced by ethyl (2-methylamino) (ethyl) t-butyl carbamate. Substituting 2,4,5-trifluorophenyl-1-sulfonyl chloride in step d with 2-chloro-4,5-difluorophenyl-1-sulfonyl chloride to obtain 2-chloro-4-((4 -Chloro-2-((2- (ethylamino) ethyl) (methyl) amino) benzyl) amino) -5-fluoro-N- (1,2,4-thiadiazol-5-yl)- Benzenesulfonamide, ESI-MS (m / z): 533.0 [M + H] + .
实施例27Example 27
2-氯-4-((2-((2-(乙氨基)乙基)(甲基)氨基)-4-甲氧基苄基)氨基)-5-氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备2-chloro-4-((2-((2- (ethylamino) ethyl) (methyl) amino) -4-methoxybenzyl) amino) -5-fluoro-N- (1,2, Preparation of 4-thiadiazol-5-yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000035
Figure PCTCN2019104852-appb-000035
操作过程同实施例1，只是分别将步骤a中的(2-氨基乙基)(乙基)氨基甲酸叔丁酯用乙基(2-甲氨基乙基)(乙基)氨基甲酸叔丁酯替代，4-氯-2-氟苯甲腈用2-氟-4-甲氧基苯甲腈替代，将步骤d中的2,4,5-三氟苯基-1-磺酰氯用2-氯-4,5-二氟苯基-1-磺酰氯替代，得2-氯-4-((2-((2-(乙氨基)乙基)(甲基)氨基)-4-甲氧基苄基)氨基)-5-氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺，ESI-MS(m/z):529.0[M+H] +。 The operation procedure is the same as in Example 1, except that the (2-aminoethyl) (ethyl) tert-butyl carbamate in step a is respectively ethyl (2-methylaminoethyl) (ethyl) tert-butyl carbamate Instead, 4-chloro-2-fluorobenzonitrile was replaced with 2-fluoro-4-methoxybenzonitrile, and 2,4,5-trifluorophenyl-1-sulfonyl chloride in step d was replaced with 2- Replacement of chloro-4,5-difluorophenyl-1-sulfonyl chloride to give 2-chloro-4-((2-((2- (ethylamino) ethyl) (methyl) amino) -4-methoxy Benzyl) amino) -5-fluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide, ESI-MS (m / z): 529.0 [M + H] + .
实施例28Example 28
2-氯-4-((5-氯-2-((3-(乙氨基)丙基)氨基)苄基)氨基)-5-氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备2-chloro-4-((5-chloro-2-((3- (ethylamino) propyl) amino) benzyl) amino) -5-fluoro-N- (1,2,4-thiadiazole- Preparation of 5-yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000036
Figure PCTCN2019104852-appb-000036
操作过程同实施例1，只是分别将步骤a中的(2-氨基乙基)(乙基)氨基甲酸叔丁酯用(3-氨基丙基)(乙基)氨基甲酸叔丁酯替代，4-氯-2-氟苯甲腈用5-氯-2-氟苯甲腈替代，将步骤d中的2,4,5-三氟苯基-1-磺酰氯用2-氯-4,5-二氟苯基-1-磺酰氯替代，得2-氯-4-((5-氯-2-((3-(乙氨基)丙基)氨基)苄基)氨基)-5-氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备，ESI-MS(m/z):533.1[M+H] +。 The operation process is the same as in Example 1, except that the (2-aminoethyl) (ethyl) t-butyl carbamate in step a is replaced with (3-aminopropyl) (ethyl) t-butyl carbamate, 4 -Chloro-2-fluorobenzonitrile was replaced with 5-chloro-2-fluorobenzonitrile, and 2,4,5-trifluorophenyl-1-sulfonyl chloride in step d was replaced with 2-chloro-4,5 -Difluorophenyl-1-sulfonyl chloride to give 2-chloro-4-((5-chloro-2-((3- (ethylamino) propyl) amino) benzyl) amino) -5-fluoro- Preparation of N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide, ESI-MS (m / z): 533.1 [M + H] + .
实施例29Example 29
2-氯-N-(5-氯噻唑-2-基)-4-((2-((2-(乙氨基)乙基)(甲基)氨基)苄基)氨基)-5-氟-苯磺酰胺的制备2-chloro-N- (5-chlorothiazol-2-yl) -4-((2-((2- (ethylamino) ethyl) (methyl) amino) benzyl) amino) -5-fluoro- Preparation of benzenesulfonamide
Figure PCTCN2019104852-appb-000037
Figure PCTCN2019104852-appb-000037
操作过程同实施例1，只是分别将步骤a中的(2-氨基乙基)(乙基)氨基甲酸叔丁酯用乙基(2-甲氨基)(乙基)氨基甲酸叔丁酯替代，4-氯-2-氟苯甲腈用2-氟苯甲腈替代，将步骤c中的1,2,4-噻二唑-5-胺用5-氯-噻唑-2-胺替代，将步骤d中的2,4,5-三氟苯基-1-磺酰氯用2-氯-4,5-二氟苯基-1-磺酰氯替代，得2-氯-N-(5-氯噻唑-2-基)-4-((2-((2-(乙氨基)乙基)(甲基)氨基)苄基)氨基)-5-氟-苯磺酰胺，ESI-MS(m/z):532.0[M+H] +。 The operation process is the same as in Example 1, except that the (2-aminoethyl) (ethyl) t-butyl carbamate in step a is replaced by ethyl (2-methylamino) (ethyl) t-butyl carbamate. 4-chloro-2-fluorobenzonitrile was replaced with 2-fluorobenzonitrile, and 1,2-4-thiadiazole-5-amine in step c was replaced with 5-chloro-thiazole-2-amine. The 2,4,5-trifluorophenyl-1-sulfonyl chloride in step d was replaced with 2-chloro-4,5-difluorophenyl-1-sulfonyl chloride to obtain 2-chloro-N- (5-chloro Thiazol-2-yl) -4-((2-((2- (ethylamino) ethyl) (methyl) amino) benzyl) amino) -5-fluoro-benzenesulfonamide, ESI-MS (m / z): 532.0 [M + H] + .
实施例30Example 30
4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-2-氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备4-((4-chloro-2-((2- (ethylamino) ethyl) amino) benzyl) amino) -2-fluoro-N- (1,2,4-thiadiazol-5-yl) -Benzenesulfonamide preparation
Figure PCTCN2019104852-appb-000038
Figure PCTCN2019104852-appb-000038
操作过程同实施例1，只是分别将步骤d中的2,4,5-三氟苯基-1-磺酰氯用2,4-二氟苯基-1-磺酰氯替代，得4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-2-氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺，ESI-MS(m/z):484.9[M+H] +。 The operation process is the same as in Example 1, except that 2,4,5-trifluorophenyl-1-sulfonyl chloride in step d is replaced with 2,4-difluorophenyl-1-sulfonyl chloride to obtain 4-(( 4-chloro-2-((2- (ethylamino) ethyl) amino) benzyl) amino) -2-fluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide , ESI-MS (m / z): 484.9 [M + H] + .
实施例31Example 31
4-((2-((3-(乙氨基)丙基)氨基)-4-甲基苄基)氨基)-3-氟-N-(噻唑-2-基)-苯磺酰胺的制备Preparation of 4-((2-((3- (ethylamino) propyl) amino) -4-methylbenzyl) amino) -3-fluoro-N- (thiazol-2-yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000039
Figure PCTCN2019104852-appb-000039
操作过程同实施例1，只是分别将步骤a中的(2-氨基乙基)(乙基)氨基甲酸叔丁酯用(3-氨 基丙基)(乙基)氨基甲酸叔丁酯替代，将4-氯-2-氟苯甲腈用2-氟-4-甲基苯甲腈替代，将步骤c中的1,2,4-噻二唑-5-胺用噻唑-2-胺替代，将步骤d中的2,4,5-三氟苯基-1-磺酰氯用3,4-二氟苯基-1-磺酰氯替代，得4-((2-((3-(乙氨基)丙基)氨基)-4-甲基苄基)氨基)-3-氟-N-(噻唑-2-基)-苯磺酰胺，ESI-MS(m/z):478.1[M+H] +。 The operation process is the same as in Example 1, except that (2-aminoethyl) (ethyl) t-butyl carbamate in step a was replaced with (3-aminopropyl) (ethyl) t-butyl carbamate, respectively. 4-chloro-2-fluorobenzonitrile was replaced with 2-fluoro-4-methylbenzonitrile, and 1,2,4-thiadiazole-5-amine in step c was replaced with thiazol-2-amine, Substituting 2,4,5-trifluorophenyl-1-sulfonyl chloride in step d with 3,4-difluorophenyl-1-sulfonyl chloride to obtain 4-((2-((3- (ethylamino ) Propyl) amino) -4-methylbenzyl) amino) -3-fluoro-N- (thiazol-2-yl) -benzenesulfonamide, ESI-MS (m / z): 478.1 [M + H] + .
实施例32Example 32
4-((4-氯-2-((3-(乙氨基)丙基)氨基)苄基)氨基)-N-(5-氯噻唑-2-基)-3-氟-苯磺酰胺的制备4-((4-chloro-2-((3- (ethylamino) propyl) amino) benzyl) amino) -N- (5-chlorothiazol-2-yl) -3-fluoro-benzenesulfonamide preparation
Figure PCTCN2019104852-appb-000040
Figure PCTCN2019104852-appb-000040
操作过程同实施例1，只是分别将步骤a中的(2-氨基乙基)(乙基)氨基甲酸叔丁酯用(3-氨基丙基)(乙基)氨基甲酸叔丁酯替代，将步骤c中的1,2,4-噻二唑-5-胺用5-氯-噻唑-2-胺替代，将步骤d中的2,4,5-三氟苯基-1-磺酰氯用3,4-二氟苯基-1-磺酰氯替代，得4-((4-氯-2-((3-(乙氨基)丙基)氨基)苄基)氨基)-N-(5-氯噻唑-2-基)-3-氟-苯磺酰胺，ESI-MS(m/z):532.2[M+H] +。 The operation process is the same as in Example 1, except that (2-aminoethyl) (ethyl) t-butyl carbamate in step a was replaced with (3-aminopropyl) (ethyl) t-butyl carbamate, respectively. Replace 1,2,4-thiadiazole-5-amine in step c with 5-chloro-thiazole-2-amine, and use 2,4,5-trifluorophenyl-1-sulfonyl chloride in step d Substitution of 3,4-difluorophenyl-1-sulfonyl chloride to give 4-((4-chloro-2-((3- (ethylamino) propyl) amino) benzyl) amino) -N- (5- (Chlorothiazol-2-yl) -3-fluoro-benzenesulfonamide, ESI-MS (m / z): 532.2 [M + H] + .
实施例33Example 33
4-((4-氯-2-((2-(乙氨基)乙基)氨基)苯乙基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备4-((4-chloro-2-((2- (ethylamino) ethyl) amino) phenethyl) amino) -2,5-difluoro-N- (1,2,4-thiadiazole- Preparation of 5-yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000041
Figure PCTCN2019104852-appb-000041
操作过程同实施例1，只是将步骤a中的4-氯-2-氟-苯甲腈用4-氯-2-氟-苯乙腈替代，得4-((4-氯-2-((2-(乙氨基)乙基)氨基)苯乙基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺，ESI-MS(m/z):517.1[M+H] +。 The operation was the same as in Example 1, except that 4-chloro-2-fluoro-benzonitrile in step a was replaced with 4-chloro-2-fluoro-phenylacetonitrile to obtain 4-((4-chloro-2-(( 2- (ethylamino) ethyl) amino) phenethyl) amino) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide, ESI-MS (m / z): 517.1 [M + H] + .
实施例34Example 34
4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯胺磺酰胺的制备4-((4-chloro-2-((2- (ethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (1,2,4-thiadiazole-5 -Yl) -aniline sulfonamide
Figure PCTCN2019104852-appb-000042
Figure PCTCN2019104852-appb-000042
步骤a-b)：(2-((2-(氨甲基)-5-氯苯基)氨基)乙基)(乙基)氨基甲酸叔丁酯的制备Step a-b): Preparation of (2-((2- (aminomethyl) -5-chlorophenyl) amino) ethyl) (ethyl) carbamic acid tert-butyl ester
操作过程同实施例1的步骤a-b。The operation process is the same as steps a-b in the first embodiment.
步骤c)：N-(2,4-二甲氧苄基)-2,4,5-三氟-N-(1,2,4-噻二唑-5-基)-苯胺磺酰胺的制备Step c): Preparation of N- (2,4-dimethoxybenzyl) -2,4,5-trifluoro-N- (1,2,4-thiadiazol-5-yl) -aniline sulfonamide
在-10℃氮气保护下，将磺酰氯(1.93mL，23.876mmol)的干燥二氯甲烷溶液(20mL)缓慢滴加到DIPEA(7.7g，59.690mmol)的干燥二氯甲烷溶液(40mL)中，缓慢升温至室温反应30分钟，加入N-(2,4-二甲氧基苄基)-1,2,4-噻二唑-5-胺(3.0g，11.938mmol)，升温至回流反应9小时，减压蒸除溶剂，残余物以乙腈(30mL)溶解，再在0℃加入2,4,5-三氟苯胺(1.17g，7.959mmol)和无水碳酸钾(2.47g，17.907mmol)，升温至60℃反应20小时，反应结束后，减压浓缩，残余物以乙酸乙酯溶解(100mL)，依次用水(30mL x 2)、饱和氯化铵溶液(30mL x 2)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3：1v/v)，得N-(2,4-二甲氧苄基)-2,4,5-三氟-N-(1,2,4-噻二唑-5-基)-苯胺磺酰胺，收率25.5％，ESI-MS(m/z):461.0[M+H] +。 A dry dichloromethane solution (20 mL) of sulfonyl chloride (1.93 mL, 23.876 mmol) was slowly added dropwise to a dry dichloromethane solution (40 mL) of DIPEA (7.7 g, 59.690 mmol) under nitrogen at -10 ° C. Slowly warm to room temperature and react for 30 minutes. Add N- (2,4-dimethoxybenzyl) -1,2,4-thiadiazole-5-amine (3.0 g, 11.938 mmol) and warm to reflux. 9 After hours, the solvent was distilled off under reduced pressure. The residue was dissolved in acetonitrile (30 mL), and 2,4,5-trifluoroaniline (1.17 g, 7.959 mmol) and anhydrous potassium carbonate (2.47 g, 17.907 mmol) were added at 0 ° C. The temperature was raised to 60 ° C for 20 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with water (30 mL x 2), saturated ammonium chloride solution (30 mL x 2), and dried. Dry over sodium sulfate, filter, and concentrate under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3: 1 v / v) to obtain N- (2,4-dimethoxybenzyl) ) -2,4,5-trifluoro-N- (1,2,4-thiadiazol-5-yl) -aniline sulfonamide, yield 25.5%, ESI-MS (m / z): 461.0 [M + H] + .
步骤d)：(2-((5-氯-2-(((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)胺磺酰胺基)-2,5-二氟苯基)氨基)甲基)苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯的制备Step d): (2-((5-chloro-2-(((4- (N- (2,4-dimethoxybenzyl) -N- (1,2,4-thiadiazole-5 -Yl) sulfamido) -2,5-difluorophenyl) amino) methyl) phenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester
操作过程同实施例1中的步骤e，只是将N-(2,4-二甲氧基苄基)-2,4,5-三氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺用N-(2,4-二甲氧基苄基)-2,4,5-三氟-N-(1,2,4-噻二唑-5-基)-苯胺磺酰胺替代，得(2-((5-氯-2-(((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)胺磺酰胺基)-2,5-二氟苯基)氨基)甲基)苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯，ESI-MS(m/z):790.1[M+Na] +。 The operation process is the same as step e in Example 1, except that N- (2,4-dimethoxybenzyl) -2,4,5-trifluoro-N- (1,2,4-thiadiazole- 5-yl) -benzenesulfonamide for N- (2,4-dimethoxybenzyl) -2,4,5-trifluoro-N- (1,2,4-thiadiazol-5-yl) -Aniline sulfonamide substitution to give (2-((5-chloro-2-((((4- (N- (2,4-dimethoxybenzyl) -N- (1,2,4-thiadi Azole-5-yl) aminosulfonamido) -2,5-difluorophenyl) amino) methyl) phenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester, ESI-MS (m / z): 790.1 [M + Na] + .
步骤e)：4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯胺磺酰胺的制备Step e): 4-((4-chloro-2-((2- (ethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (1,2,4-thia Preparation of diazol-5-yl) -aniline sulfonamide
操作过程同实施例1中的步骤f，只是将(2-((5-氯-2-(((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯基)氨基)甲基)苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯用(2-((5-氯-2-(((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)胺磺酰胺基)-2,5-二氟苯基)氨基)甲基)苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯替代，得4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯胺磺酰胺， 1H NMR(400MHz,DMSO-d 6)δ:11.60(s，1H),7.85(s,1H),7.28-7.25(m,1H),7.03(d,J＝8.0Hz,1H),6.75(s,1H),6.66(s,1H),6.61(d,J＝8.0Hz,1H),6.31-6.29(m,1H),5.65-5.59(m,1H),4.51(d,J＝5.6Hz,2H),3.45-3.40(m,2H),3.15-3.00(m,4H),1.16-1.14(m,3H)，ESI-MS(m/z):518.0[M+H] +。 The operation process is the same as step f in Example 1, except that (2-((5-chloro-2-(((4- (N- (2,4-dimethoxybenzyl) -N- (1, 2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorophenyl) amino) methyl) phenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester (2-((5-chloro-2-((((4- (N- (2,4-dimethoxybenzyl) -N- (1,2,4-thiadiazol-5-yl) amine Sulfonyl) -2,5-difluorophenyl) amino) methyl) phenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester was substituted to give 4-((4-chloro-2- ((2- (ethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl) -aniline sulfonamide, 1 H NMR (400MHz, DMSO-d 6 ) δ: 11.60 (s, 1H), 7.85 (s, 1H), 7.28-7.25 (m, 1H), 7.03 (d, J = 8.0Hz, 1H), 6.75 (s, 1H), 6.66 (s, 1H), 6.61 (d, J = 8.0Hz, 1H), 6.31-6.29 (m, 1H), 5.65-5.59 (m, 1H), 4.51 (d, J = 5.6Hz, 2H ), 3.45-3.40 (m, 2H), 3.15-3.00 (m, 4H), 1.16-1.14 (m, 3H), ESI-MS (m / z): 518.0 [M + H] + .
实施例35Example 35
4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(5-氯噻唑-2-基)-苯胺磺酰胺的制备4-((4-chloro-2-((2- (ethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (5-chlorothiazol-2-yl) -aniline Preparation of sulfonamide
Figure PCTCN2019104852-appb-000043
Figure PCTCN2019104852-appb-000043
操作过程同实施例34，只是将步骤c中的N-(2,4-二甲氧基苄基)-1,2,4-噻二唑-5-胺用N-(2,4-二甲氧基苄基)-5-氯噻唑-2-胺替代，得4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(5-氯噻唑-2-基)-苯胺磺酰胺，ESI-MS(m/z):551.2[M+H] +。 The procedure was the same as that in Example 34, except that N- (2,4-dimethoxybenzyl) -1,2,4-thiadiazole-5-amine was used in step c with N- (2,4-di Substitution of methoxybenzyl) -5-chlorothiazole-2-amine to give 4-((4-chloro-2-((2- (ethylamino) ethyl) amino) benzyl) amino) -2,5 -Difluoro-N- (5-chlorothiazol-2-yl) -aniline sulfonamide, ESI-MS (m / z): 551.2 [M + H] + .
实施例36Example 36
4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄氧基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备4-((4-chloro-2-((2- (ethylamino) ethyl) amino) benzyloxy) -2,5-difluoro-N- (1,2,4-thiadiazole-5- ) -Benzenesulfonamide
Figure PCTCN2019104852-appb-000044
Figure PCTCN2019104852-appb-000044
步骤a)：(2-((5-氯-2-氰基苯基)氨基)乙基)(乙基)氨基甲酸叔丁酯的制备Step a): Preparation of (2-((5-chloro-2-cyanophenyl) amino) ethyl) (ethyl) t-butyl carbamate
操作过程同实施例1中的步骤a。The operation process is the same as step a in Example 1.
步骤b)：(2-((叔丁氧羰基)(5-氯-2-氰基苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯的制备Step b): Preparation of (2-((tert-butoxycarbonyl) (5-chloro-2-cyanophenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester
将(2-((5-氯-2-氰基苯基)氨基)乙基)(乙基)氨基甲酸叔丁酯(1.8g，5.559mmol)、4-二甲氨基吡啶(1.0g，8.339mmol)、Boc 2O(1.82g，8.339mmol)和无水乙腈(36mL)加入反应瓶中，室温搅拌反应20小时，反应结束后，减压蒸除乙腈，残余物加乙酸乙酯溶解(100mL)，依次用饱和氯化铵水溶液(20mL)、0.05N的盐酸(20mL x 2)、饱和碳酸氢钠水溶液(20mL x 2)和饱和氯化钠水溶液(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝4:1v/v)，收率75.6％，得(2-((叔丁氧羰基)(5-氯-2-氰基苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯，ESI-MS(m/z):424.1[M+H] +。 Tert-butyl (2-((5-chloro-2-cyanophenyl) amino) ethyl) (ethyl) carbamate (1.8 g, 5.559 mmol), 4-dimethylaminopyridine (1.0 g, 8.339 mmol), Boc 2 O (1.82 g, 8.339 mmol) and anhydrous acetonitrile (36 mL) were added to the reaction flask, and the reaction was stirred at room temperature for 20 hours. After the reaction was completed, the acetonitrile was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL). ), Washed with saturated aqueous ammonium chloride solution (20mL), 0.05N hydrochloric acid (20mL x 2), saturated aqueous sodium bicarbonate solution (20mL x 2), and saturated aqueous sodium chloride solution (20mL) in this order, dried over anhydrous sodium sulfate, Filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4: 1 v / v), the yield was 75.6%, and (2-((tert-butoxycarbonyl) ( 5-chloro-2-cyanophenyl) amino) ethyl) (ethyl) -t-butyl carbamate, ESI-MS (m / z): 424.1 [M + H] + .
步骤c)：(2-((2-(氨甲基)-5-氯苯基)(叔丁氧羰基)氨基)乙基)(乙基)-氨基甲酸叔丁酯的制备Step c): Preparation of (2-((2- (aminomethyl) -5-chlorophenyl) (tert-butoxycarbonyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester
将B 2H 6/四氢呋喃溶液(1M，20mL)滴加到(2-((叔丁氧羰基)(5-氯-2-氰基苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯(1.75g，4.128mmol)的四氢呋喃(35mL)中，升温至回流反应0.5小时，以甲醇(20ml)缓慢小心的淬灭，继续回流0.5小时，冷却至室温，减压浓缩，粗品经制备HPLC纯化，得(2-((2-(氨甲基)-5-氯苯基)(叔丁氧羰基)氨基)乙基)(乙基)-氨基甲酸叔丁酯，收率68.0％，ESI-MS(m/z):428.1[M+H] +。 B 2 H 6 / tetrahydrofuran solution (1M, 20 mL) was added dropwise to (2-((tert-butoxycarbonyl) (5-chloro-2-cyanophenyl) amino) ethyl) (ethyl) -carbamic acid Tert-butyl ester (1.75 g, 4.128 mmol) in tetrahydrofuran (35 mL) was heated to reflux for 0.5 hours, quenched slowly and carefully with methanol (20 ml), continued to reflux for 0.5 hours, cooled to room temperature, concentrated under reduced pressure, and the crude product was Preparative HPLC purification, (2-((2- (aminomethyl) -5-chlorophenyl) (tert-butoxycarbonyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester, yield 68.0% , ESI-MS (m / z): 428.1 [M + H] + .
步骤d)：(2-((叔丁氧羰基)(5-氯-2-(羟甲基)苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯的制备Step d): Preparation of (2-((tert-butoxycarbonyl) (5-chloro-2- (hydroxymethyl) phenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester
在0℃将(2-((2-(氨甲基)-5-氯苯基)(叔丁氧羰基)氨基)乙基)(乙基)-氨基甲酸叔丁酯(428mg，1.000mmol)加入醋酸(2mL)和水(2mL)混合溶剂中，搅拌混匀，加入亚硝酸钠(828mg，12.000mmol)，室温搅拌反应1小时，将反应液倾入乙酸乙酯和水(30mL/20mL)的混合物中，分取有机层，依次用饱和的碳酸氢钠水溶液(10mL)和饱和氯化钠水溶液(10mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，粗品以甲醇(4mL)溶解，加入水(1mL)和碳酸钾(276mg，2.000mmol)，升温至60℃反应20小时，反应结束后，减压蒸除溶剂，残余物以乙酸乙酯溶解，依次用水和饱和氯化钠洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝2：1v/v)，得(2-((叔丁氧羰基)(5-氯-2-(羟甲基)苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯，收率50.4％，ESI-MS(m/z):429.1[M+H] +。 (2-((2- (aminomethyl) -5-chlorophenyl) (tert-butoxycarbonyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester (428 mg, 1.000 mmol) at 0 ° C Add acetic acid (2mL) and water (2mL) to a mixed solvent, stir and mix, add sodium nitrite (828mg, 12.000mmol), stir the reaction for 1 hour at room temperature, and pour the reaction solution into ethyl acetate and water (30mL / 20mL). From the mixture, the organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate (10 mL) and a saturated aqueous solution of sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was dissolved in methanol (4 mL). After adding water (1mL) and potassium carbonate (276mg, 2.000mmol), the temperature was raised to 60 ° C for 20 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and saturated sodium chloride in this order. , Dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2: 1 v / v) to obtain (2-((tert-butoxycarbonyl) ) (5-Chloro-2- (hydroxymethyl) phenyl) amino) ethyl) (ethyl) -t-butyl carbamate, yield 50.4%, ESI-MS (m / z): 429.1 [M + H] + .
步骤e)：N-(2,4-二甲氧基苄基)-1,2,4-噻二唑-5-胺的制备Step e): Preparation of N- (2,4-dimethoxybenzyl) -1,2,4-thiadiazole-5-amine
制备过程同实施例1中的步骤c。The preparation process is the same as step c in Example 1.
步骤f)：N-(2,4-二甲氧基苄基-2,4,5-三氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备Step f): Preparation of N- (2,4-dimethoxybenzyl-2,4,5-trifluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide
制备过程同实施例1中的步骤d。The preparation process is the same as step d in Example 1.
步骤g)：(2-((叔丁氧羰基)(乙基)氨基)乙基)(5-氯-2-((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯氧基)甲基)苄基)-氨基甲酸叔丁酯的制备Step g): (2-((tert-butoxycarbonyl) (ethyl) amino) ethyl) (5-chloro-2-((4- (N- (2,4-dimethoxybenzyl)- Preparation of N- (1,2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorophenoxy) methyl) benzyl) -carbamic acid tert-butyl ester
将NaH(7mg，0.303mmol)加入反应瓶中，抽真空氮气保护，加入无水四氢呋喃(10mL)，冷却至-25℃，将(2-((叔丁氧羰基)(5-氯-2-(羟甲基)苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯(100mg，0.233mmol)的THF溶液(2mL)加入反应瓶中，搅拌反应30min，再将N-(2,4-二甲氧基苄基-2,4,5-三氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺(114mg，0.256mmol)的THF溶液(2mL)缓慢加入反应瓶中，加毕，升温至室温反应15小时，反应结束后向反应体系加入水(10mL)，减压蒸除四氢呋喃，残余物以乙酸乙酯(20mL x 3)萃取，合并有机层，用饱和氯化钠(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得粗品经制备薄层层析纯化(展开剂：石油醚/乙酸乙酯＝1.5/1v/v)，得(2-((叔丁氧羰基)(乙基)氨基)乙基)(5-氯-2-((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯氧基)甲基)苄基)-氨基甲酸叔丁酯，收率45.7％，ESI-MS(m/z)：876.2[M+Na] +。 Add NaH (7mg, 0.303mmol) to the reaction flask, evacuate nitrogen to protect, add anhydrous tetrahydrofuran (10mL), cool to -25 ° C, and remove (2-((tert-butoxycarbonyl) (5-chloro-2- (Hydroxymethyl) phenyl) amino) ethyl) (ethyl) -t-butyl carbamate (100 mg, 0.233 mmol) in THF (2 mL) was added to the reaction flask, and the reaction was stirred for 30 min. Then N- (2 A solution of 1,4-dimethoxybenzyl-2,4,5-trifluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide (114 mg, 0.256 mmol) in THF ( 2mL) was slowly added to the reaction flask. After the addition was completed, the temperature was raised to room temperature for 15 hours. After the reaction was completed, water (10mL) was added to the reaction system, and tetrahydrofuran was distilled off under reduced pressure. The organic layer was washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (developing solvent: petroleum ether / ethyl acetate = 1.5 / 1v / v ) To give (2-((tert-butoxycarbonyl) (ethyl) amino) ethyl) (5-chloro-2-((4- (N- (2,4-dimethoxybenzyl) -N -(1,2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorophenoxy) methyl) benzyl) -carbamic acid tert-butyl ester, yield 47.5%, ESI -MS (m / z): 8 76.2 [M + Na] + .
步骤h)：4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄氧基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备Step h): 4-((4-chloro-2-((2- (ethylamino) ethyl) amino) benzyloxy) -2,5-difluoro-N- (1,2,4-thiadi Preparation of azole-5-yl) -benzenesulfonamide
将(2-((叔丁氧羰基)(乙基)氨基)乙基)(5-氯-2-((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯氧基)甲基)苄基)-氨基甲酸叔丁酯(80mg，0.094mmol)加入反应瓶中，加入1.5mL盐酸二氧六环溶液，室温搅拌反应2.5小时，反应结束后抽滤，所得固体 用饱和的NaHCO 3溶液(10mL)和乙酸乙酯(20mL x 4)萃取，合并有机层，用饱和氯化钠(40mL)洗涤，无水硫酸钠干燥，过滤，减压蒸干，所得粗品以乙酸乙酯(5mL)用超声粉碎打浆，抽滤，真空干燥得4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄氧基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺，收率42.0％, 1H NMR(400MHz,DMSO-d 6)δ:7.86(s,1H),7.40(dd,J 1＝6.4,J 2＝11.6Hz,1H),7.06(d,J＝8.0Hz,1H),6.74(s,1H),6.71(s,1H),6.62(d,J＝8.0Hz,1H),6.31(dd,J 1＝6.4,J 2＝11.6Hz,1H),5.54-5.53(m,1H),4.89(d,J＝5.6Hz,2H),3.39-3.33(m,2H),3.07-3.00(m,2H),2.86(q,J＝7.2Hz,2H),1.16(t,J＝7.2Hz,3H)，ESI-MS(m/z):504.0[M+H] +。 (2-((tert-Butoxycarbonyl) (ethyl) amino) ethyl) (5-chloro-2-((4- (N- (2,4-dimethoxybenzyl) -N- ( 1,2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorophenoxy) methyl) benzyl) -carbamic acid tert-butyl ester (80 mg, 0.094 mmol) was added to the reaction flask To the reaction solution was added 1.5 mL of dioxane hydrochloride solution, and the reaction was stirred at room temperature for 2.5 hours. After the reaction was completed, suction filtration was performed. The obtained solid was extracted with saturated NaHCO 3 solution (10 mL) and ethyl acetate (20 mL x 4). The organic layers were combined. It was washed with saturated sodium chloride (40 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The obtained crude product was pulverized and pulverized with ethyl acetate (5 mL) with ultrasound, suction filtered, and dried under vacuum to obtain 4-((4-chloro -2-((2- (ethylamino) ethyl) amino) benzyloxy) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide, Yield: 42.0%, 1 H NMR (400 MHz, DMSO-d 6 ) δ: 7.86 (s, 1H), 7.40 (dd, J 1 = 6.4, J 2 = 11.6 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.74 (s, 1H), 6.71 (s, 1H), 6.62 (d, J = 8.0 Hz, 1H), 6.31 (dd, J 1 = 6.4, J 2 = 11.6 Hz, 1H), 5.54 -5.53 (m, 1H), 4.89 (d, J = 5.6Hz, 2H), 3.39-3.33 (m, 2H), 3.07-3.00 (m, 2H), 2.86 (q, J = 7.2Hz, 2H), 1.16 (t, J = 7.2Hz, 3H), ESI-MS (m / z): 504.0 [M + H] + .
实施例37Example 37
4-((4-氯-2-((2-(吡咯-1-基)乙基)氨基)苄氧基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备4-((4-chloro-2-((2- (pyrrol-1-yl) ethyl) amino) benzyloxy) -2,5-difluoro-N- (1,2,4-thiadiazole -5-yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000045
Figure PCTCN2019104852-appb-000045
操作过程同实施例36，只是将步骤a中的(2-氨基乙基)(乙基)氨基甲酸叔丁酯用2-(吡咯-1-基)乙胺替代，得4-((4-氯-2-((2-(吡咯-1-基)乙基)氨基)苄氧基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺，ESI-MS(m/z)：529.9[M+H] +。 The operation was the same as in Example 36, except that the (2-aminoethyl) (ethyl) carbamic acid tert-butyl ester in step a was replaced with 2- (pyrrol-1-yl) ethylamine to obtain 4-((4- Chloro-2-((2- (pyrrole-1-yl) ethyl) amino) benzyloxy) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl)- Phenylsulfonamide, ESI-MS (m / z): 529.9 [M + H] + .
实施例38Example 38
4-((4-氯-2-((2-(乙氨基)乙基)(甲基)氨基)苄氧基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备4-((4-chloro-2-((2- (ethylamino) ethyl) (methyl) amino) benzyloxy) -2,5-difluoro-N- (1,2,4-thiadi Preparation of azole-5-yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000046
Figure PCTCN2019104852-appb-000046
步骤a)：乙基(2-(甲氨基)乙基)氨基甲酸叔丁酯的制备Step a): Preparation of tert-butyl ethyl (2- (methylamino) ethyl) carbamate
将(2-氨基乙基)(乙基)氨基甲酸叔丁酯(3.0g，15.935mmol)和甲苯(50mL)加入反应瓶中，搅拌溶解，室温条件下缓慢滴加苯甲醛(2.2g，20.716mmol)，加毕，使用Dean-Stark装置并升温至150℃反应1.5小时，冷却至室温，滴加对甲苯磺酸甲酯(3.1g，16.413mmol)的甲苯溶液(15mL)，加毕，再升温至回流反应15小时，冷却至80℃，加入水(40mL)反应30分钟。反应结束后，冷却至室温，分取水层，加入2M的氢氧化钾水溶液(40mL)，再以二氯甲烷(30mL x 3)萃取，合并有机层，无水硫酸钠干燥，过滤，减压浓缩，得乙基(2-(甲氨基)乙基)氨基甲酸叔丁酯，收率40.5％，ESI-MS(m/z)：203.0[M+H] +。 Add tert-butyl (2-aminoethyl) (ethyl) carbamate (3.0 g, 15.935 mmol) and toluene (50 mL) to the reaction flask, stir to dissolve, and slowly add benzaldehyde (2.2 g, 20.716) at room temperature. mmol), add Dean-Stark device and raise the temperature to 150 ° C for 1.5 hours, cool to room temperature, dropwise add a toluene solution (15 mL) of methyl p-toluenesulfonate (3.1 g, 16.413 mmol). The temperature was raised to reflux for 15 hours, cooled to 80 ° C, and water (40 mL) was added to react for 30 minutes. After completion of the reaction, cool to room temperature, separate the aqueous layer, add 2M aqueous potassium hydroxide solution (40 mL), and extract with dichloromethane (30 mL x 3). Combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. To obtain tert-butyl ethyl (2- (methylamino) ethyl) carbamate, yield 40.5%, ESI-MS (m / z): 203.0 [M + H] + .
步骤b)：(2-((5-氯-2-氰基苯基)(甲基)氨基)乙基)(乙基)氨基甲酸叔丁酯的制备Step b): Preparation of (2-((5-chloro-2-cyanophenyl) (methyl) amino) ethyl) (ethyl) carbamic acid tert-butyl ester
操作过程同实施例36中的步骤a，只是将(2-氨基乙基)(乙基)氨基甲酸叔丁酯用乙基(2-(甲氨基)乙基)氨基甲酸叔丁酯替代，ESI-MS(m/z)：338.0[M+H] +。 The operation was the same as step a in Example 36, except that tert-butyl (2-aminoethyl) (ethyl) carbamate was replaced with tert-butyl ethyl (2- (methylamino) ethyl) carbamate. ESI -MS (m / z): 338.0 [M + H] + .
步骤c)：(2-((2-(氨甲基)-5-氯苯基)(甲基)氨基)乙基)(乙基)-氨基甲酸叔丁酯的制备Step c): Preparation of (2-((2- (aminomethyl) -5-chlorophenyl) (methyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester
操作过程同实施例36中的步骤c，只是将(2-((叔丁氧羰基)(5-氯-2-氰基苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯用(2-((5-氯-2-氰基苯基)(甲基)氨基)乙基)(乙基)氨基甲酸叔丁酯替代，得 (2-((2-(氨甲基)-5-氯苯基)(甲基)氨基)乙基)(乙基)-氨基甲酸叔丁酯，ESI-MS(m/z):342.2[M+H] +。 The operation was the same as step c in Example 36, except that (2-((tert-butoxycarbonyl) (5-chloro-2-cyanophenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester Substituting (2-((5-chloro-2-cyanophenyl) (methyl) amino) ethyl) (ethyl) carbamate to give (2-((2- (aminomethyl) -5-chlorophenyl) (methyl) amino) ethyl) (ethyl) -t-butyl carbamate, ESI-MS (m / z): 342.2 [M + H] + .
步骤d)：(2-((5-氯-2-(羟甲基)苯基)(甲基)氨基)乙基)(乙基)氨基甲酸叔丁酯的制备Step d): Preparation of (2-((5-chloro-2- (hydroxymethyl) phenyl) (methyl) amino) ethyl) (ethyl) carbamic acid tert-butyl ester
操作过程同实施例36中的步骤d，只是将(2-((2-(氨基乙基)-5-氯苯基)(叔丁氧羰基)氨基)乙基)(乙基)-氨基甲酸叔丁酯用(2-((2-(氨甲基)-5-氯苯基)(甲基)氨基)乙基)(乙基)-氨基甲酸叔丁酯替代，ESI-MS(m/z)：343.2[M+H] +。 The operation was the same as step d in Example 36, except that (2-((2- (aminoethyl) -5-chlorophenyl) (tert-butoxycarbonyl) amino) ethyl) (ethyl) -carbamic acid Tert-butyl ester was replaced with (2-((2- (aminomethyl) -5-chlorophenyl) (methyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester, ESI-MS (m / z): 343.2 [M + H] + .
步骤e)：N-(2,4-二甲氧基苄基)-1,2,4-噻二唑-5-胺的制备Step e): Preparation of N- (2,4-dimethoxybenzyl) -1,2,4-thiadiazole-5-amine
制备过程同实施例36中的步骤e。The preparation process is the same as step e in Example 36.
步骤f)：N-(2,4-二甲氧基苄基-2,4,5-三氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备Step f): Preparation of N- (2,4-dimethoxybenzyl-2,4,5-trifluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide
制备过程同实施例36中的步骤f。The preparation process is the same as step f in Example 36.
步骤g)：(2-((5-氯-2-((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯氧基)甲基)苯基)(甲基)氨基)乙基)(乙基)-氨基甲酸叔丁酯的制备Step g): (2-((5-chloro-2-((4- (N- (2,4-dimethoxybenzyl) -N- (1,2,4-thiadiazole-5- Sulfonamide) -2,5-difluorophenoxy) methyl) phenyl) (methyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester
制备过程同实施例36中的步骤g，只是将(2-((叔丁氧羰基)(5-氯-2-(羟甲基)苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯用(2-((5-氯-2-(羟甲基)苯基)(甲基)氨基)乙基)(乙基)氨基甲酸叔丁酯替代，得(2-((5-氯-2-((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯氧基)甲基)苯基)(甲基)氨基)乙基)(乙基)-氨基甲酸叔丁酯，ESI-MS(m/z):768.1[M+H] +。 The preparation process is the same as step g in Example 36, except that (2-((tert-butoxycarbonyl) (5-chloro-2- (hydroxymethyl) phenyl) amino) ethyl) (ethyl) -carbamic acid Tert-butyl ester was replaced with (2-((5-chloro-2- (hydroxymethyl) phenyl) (methyl) amino) ethyl) (ethyl) carbamic acid tert-butyl ester to give (2-((5 -Chloro-2-((4- (N- (2,4-dimethoxybenzyl) -N- (1,2,4-thiadiazol-5-yl) sulfonamido) -2,5 -Difluorophenoxy) methyl) phenyl) (meth) amino) ethyl) (ethyl) -tert-butyl carbamate, ESI-MS (m / z): 768.1 [M + H] + .
步骤h)：4-((4-氯-2-((2-(乙氨基)乙基)(甲基)氨基)苄氧基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备。Step h): 4-((4-chloro-2-((2- (ethylamino) ethyl) (methyl) amino) benzyloxy) -2,5-difluoro-N- (1,2, Preparation of 4-thiadiazol-5-yl) -benzenesulfonamide.
制备过程同实施例36中的步骤h，只是将(2-((叔丁氧羰基)(乙基)氨基)乙基)(5-氯-2-((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯氧基)甲基)苄基)-氨基甲酸叔丁酯用(2-((5-氯-2-((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯氧基)甲基)苯基)(甲基)氨基)乙基)(乙基)-氨基甲酸叔丁酯替代，得4-((4-氯-2-((2-(乙氨基)乙基)(甲基)氨基)苄氧基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺，收率47.0％， 1H NMR(400MHz,DMSO-d 6)δ:8.15(s,1H),7.35-7.30(m,1H),7.20(d,J＝8.0Hz,1H),6.95(s,1H),6.79(s,1H),6.75(d,J＝8.0Hz,1H),6.30-6.25(m,1H),4.20(d,J＝5.6Hz,2H),3.39-3.35(m,2H),3.15-2.98(m,4H),2.85(s,3H),1.15(t,J＝7.6Hz,3H)，ESI-MS(m/z):518.0[M+H] +。 The preparation process is the same as step h in Example 36, except that (2-((tert-butoxycarbonyl) (ethyl) amino) ethyl) (5-chloro-2-((4- (N- (2,4 -Dimethoxybenzyl) -N- (1,2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorophenoxy) methyl) benzyl) -carbamic acid Tert-butyl ester is used for (2-((5-chloro-2-((4- (N- (2,4-dimethoxybenzyl) -N- (1,2,4-thiadiazole-5- Sulfonamide) -2,5-difluorophenoxy) methyl) phenyl) (methyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester to obtain 4-((4 -Chloro-2-((2- (ethylamino) ethyl) (methyl) amino) benzyloxy) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl ) -Benzenesulfonamide, yield 47.0%, 1 H NMR (400 MHz, DMSO-d 6 ) δ: 8.15 (s, 1H), 7.35-7.30 (m, 1H), 7.20 (d, J = 8.0 Hz, 1H ), 6.95 (s, 1H), 6.79 (s, 1H), 6.75 (d, J = 8.0Hz, 1H), 6.30-6.25 (m, 1H), 4.20 (d, J = 5.6Hz, 2H), 3.39 -3.35 (m, 2H), 3.15-2.98 (m, 4H), 2.85 (s, 3H), 1.15 (t, J = 7.6Hz, 3H), ESI-MS (m / z): 518.0 [M + H ] + .
实施例39Example 39
4-((4-氯-2-((2-(乙氨基)乙基)(甲基)氨基)苄氧基)-2,5-二氟-N-(5-氟噻唑-2-基)-苯磺酰胺的制备4-((4-chloro-2-((2- (ethylamino) ethyl) (methyl) amino) benzyloxy) -2,5-difluoro-N- (5-fluorothiazol-2-yl ) -Benzenesulfonamide
Figure PCTCN2019104852-appb-000047
Figure PCTCN2019104852-appb-000047
操作过程同实施例38，只是将步骤e中的1,2,4-噻二唑-5-胺用5-氟-噻唑-2-胺替代，得4-((4-氯-2-((2-(乙氨基)乙基)(甲基)氨基)苄氧基)-2,5-二氟-N-(5-氟噻唑-2-基)-苯磺酰胺，ESI-MS(m/z):535.1[M+H] +。 The operation was the same as in Example 38, except that 1,1,2,4-thiadiazole-5-amine in step e was replaced with 5-fluoro-thiazole-2-amine to obtain 4-((4-chloro-2- ( (2- (ethylamino) ethyl) (methyl) amino) benzyloxy) -2,5-difluoro-N- (5-fluorothiazol-2-yl) -benzenesulfonamide, ESI-MS (m / z): 535.1 [M + H] + .
实施例40Example 40
2-氯-4-((4-氯-2-((2-(乙氨基)乙基)(甲基)氨基)苄氧基)-5-氟-N-(5-氯噻唑-2-基)-苯磺酰胺的制备2-chloro-4-((4-chloro-2-((2- (ethylamino) ethyl) (methyl) amino) benzyloxy) -5-fluoro-N- (5-chlorothiazole-2- ) -Benzenesulfonamide
Figure PCTCN2019104852-appb-000048
Figure PCTCN2019104852-appb-000048
操作过程同实施例38，只是分别将步骤e中的1,2,4-噻二唑-5-胺用5-氯噻唑-2-胺替代，将步骤f中的2,4,5-三氟苯基-1-磺酰氯用2-氯-4,5-二氟苯基-1-磺酰氯替代，得2-氯-4-((4-氯-2-((2-(乙氨基)乙基)(甲基)氨基)苄氧基)-5-氟-N-(5-氯噻唑-2-基)-苯磺酰胺，ESI-MS(m/z):567.1[M+H] +。 The operation was the same as that in Example 38, except that 1, 2, 4-thiadiazole-5-amine in step e was replaced with 5-chlorothiazol-2-amine, and 2, 4, 3, 3 in step f were replaced. Fluorophenyl-1-sulfonyl chloride was replaced with 2-chloro-4,5-difluorophenyl-1-sulfonyl chloride to give 2-chloro-4-((4-chloro-2-((2- (ethylamino ) Ethyl) (methyl) amino) benzyloxy) -5-fluoro-N- (5-chlorothiazol-2-yl) -benzenesulfonamide, ESI-MS (m / z): 567.1 [M + H ] + .
实施例41Example 41
4-((2-((2-(乙氨基)乙基)(甲基)氨基)-4-(三氟甲基)苄氧基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备4-((2-((2- (ethylamino) ethyl) (methyl) amino) -4- (trifluoromethyl) benzyloxy) -2,5-difluoro-N- (1,2 , 4-thiadiazol-5-yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000049
Figure PCTCN2019104852-appb-000049
操作过程同实施例38，只是将步骤b中的4-氯-2-氟苯甲腈用2-氟-4-三氟甲基苯甲腈替代，得4-((2-((2-(乙氨基)乙基)(甲基)氨基)-4-(三氟甲基)苄氧基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺， 1H NMR(400MHz,CDCl 3)δ:8.36(s,1H),8.27(br d,J＝1.5Hz,2H),7.73-7.61(m,2H),7.60-7.51(m,1H),6.81(s,1H),7.45-7.36(m,1H),5.39(s,2H),3.28-3.21(m,2H),3.20-3.10(m,2H),2.97(br d,J＝6.4Hz,2H),2.68(s,3H),1.14(t,J＝7.2Hz,3H)，ESI-MS(m/z):552.1[M+H] +。 The operation was the same as in Example 38, except that the 4-chloro-2-fluorobenzonitrile in step b was replaced with 2-fluoro-4-trifluoromethylbenzonitrile to obtain 4-((2-((2- (Ethylamino) ethyl) (methyl) amino) -4- (trifluoromethyl) benzyloxy) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl ) -Benzenesulfonamide, 1 H NMR (400 MHz, CDCl 3 ) δ: 8.36 (s, 1H), 8.27 (br d, J = 1.5 Hz, 2H), 7.73-7.61 (m, 2H), 7.60-7.51 ( m, 1H), 6.81 (s, 1H), 7.45-7.36 (m, 1H), 5.39 (s, 2H), 3.28-3.21 (m, 2H), 3.20-3.10 (m, 2H), 2.97 (br d , J = 6.4Hz, 2H), 2.68 (s, 3H), 1.14 (t, J = 7.2Hz, 3H), ESI-MS (m / z): 552.1 [M + H] + .
实施例42Example 42
4-((2-((2-(乙氨基)乙基)(甲基)氨基)-4-(甲氧基)苄氧基)-2,5-二氟-N-(5-氯噻唑-2-基)-苯磺酰胺的制备4-((2-((2- (ethylamino) ethyl) (methyl) amino) -4- (methoxy) benzyloxy) -2,5-difluoro-N- (5-chlorothiazole Preparation of -2-yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000050
Figure PCTCN2019104852-appb-000050
操作过程同实施例38，只是分别将步骤b中的4-氯-2-氟苯甲腈用2-氟-4-甲氧基苯甲腈替代，将步骤e中的1,2,4-噻二唑-5-胺用5-氟噻唑-2-胺替代，得4-((2-((2-(乙氨基)乙基)(甲基)氨基)-4-(甲氧基)苄氧基)-2,5-二氟-N-(5-氯噻唑-2-基)-苯磺酰胺，ESI-MS(m/z):547.0[M+H] +。 The operation was the same as in Example 38, except that the 4-chloro-2-fluorobenzonitrile in step b was replaced with 2-fluoro-4-methoxybenzonitrile, and the 1, 2, 4- in step e Replace thiadiazole-5-amine with 5-fluorothiazol-2-amine to give 4-((2-((2- (ethylamino) ethyl) (methyl) amino) -4- (methoxy) Benzyloxy) -2,5-difluoro-N- (5-chlorothiazol-2-yl) -benzenesulfonamide, ESI-MS (m / z): 547.0 [M + H] + .
实施例43Example 43
2-氯-4-((2-((2-(乙氨基)乙基)(甲基)氨基)-4-(三氟甲基)苄氧基)-5-氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备2-chloro-4-((2-((2- (ethylamino) ethyl) (methyl) amino) -4- (trifluoromethyl) benzyloxy) -5-fluoro-N- (1, Preparation of 2,4-thiadiazol-5-yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000051
Figure PCTCN2019104852-appb-000051
操作过程同实施例38，只是分别将步骤b中的4-氯-2-氟苯甲腈用2-氟-4-三氟甲基苯甲腈替代，将步骤f中的2,4,5-三氟苯基-1-磺酰氯用2-氯-4,5-二氟苯基-1-磺酰氯替代，得2-氯-4-((2-((2-(乙氨基)乙基)(甲基)氨基)-4-(三氟甲基)苄氧基)-5-氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺，ESI-MS(m/z):567.9[M+H] +。 The operation was the same as in Example 38, except that the 4-chloro-2-fluorobenzonitrile in step b was replaced with 2-fluoro-4-trifluoromethylbenzonitrile, and 2,4,5 in step f -Trifluorophenyl-1-sulfonyl chloride was replaced with 2-chloro-4,5-difluorophenyl-1-sulfonyl chloride to give 2-chloro-4-((2-((2- (ethylamino) ethyl (Methyl) amino) -4- (trifluoromethyl) benzyloxy) -5-fluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide, ESI- MS (m / z): 567.9 [M + H] + .
实施例44Example 44
2-氯-4-((2-((2-(乙氨基)乙基)(甲基)氨基)-4-(三氟甲基)苄氧基)-5-氟-N-(5-氯噻唑-2-基)-苯磺酰胺的制备2-chloro-4-((2-((2- (ethylamino) ethyl) (methyl) amino) -4- (trifluoromethyl) benzyloxy) -5-fluoro-N- (5- Preparation of chlorothiazole-2-yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000052
Figure PCTCN2019104852-appb-000052
操作过程同实施例38，只是分别将步骤b中的4-氯-2-氟苯甲腈用2-氟-4-三氟甲基苯甲腈替代，将步骤e中的1,2,4-噻二唑-5-胺用5-氯噻唑-2-胺替代，将步骤f中的2,4,5-三氟苯基-1-磺酰氯用2-氯-4,5-二氟苯基-1-磺酰氯替代，得2-氯-4-((2-((2-(乙氨基)乙基)(甲基)氨基)-4-(三氟甲基)苄氧基)-5-氟-N-(5-氯噻唑-2-基)-苯磺酰胺，ESI-MS(m/z):601.0[M+H] +。 The operation was the same as in Example 38, except that the 4-chloro-2-fluorobenzonitrile in step b was replaced with 2-fluoro-4-trifluoromethylbenzonitrile, and 1,2,4 in step e -Thiadiazole-5-amine is replaced with 5-chlorothiazol-2-amine, and 2,4,5-trifluorophenyl-1-sulfonyl chloride in step f is replaced with 2-chloro-4,5-difluoro Phenyl-1-sulfonyl chloride substitution to give 2-chloro-4-((2-((2- (ethylamino) ethyl) (methyl) amino) -4- (trifluoromethyl) benzyloxy) -5-fluoro-N- (5-chlorothiazol-2-yl) -benzenesulfonamide, ESI-MS (m / z): 601.0 [M + H] + .
实施例45Example 45
2-氯-N-(5-氯噻唑-2-基)-4-((2-((2-(乙氨基)乙基)(甲基)氨基)苄氧基)-5-氟-苯磺酰胺的制备2-chloro-N- (5-chlorothiazol-2-yl) -4-((2-((2- (ethylamino) ethyl) (methyl) amino) benzyloxy) -5-fluoro-benzene Preparation of sulfonamide
Figure PCTCN2019104852-appb-000053
Figure PCTCN2019104852-appb-000053
操作过程同实施例38，只是分别将步骤b中的4-氯-2-氟苯甲腈用2-氟苯甲腈替代，将步骤e中的1,2,4-噻二唑-5-胺用5-氯噻唑-2-胺替代，将步骤f中的2,4,5-三氟苯基-1-磺酰氯用2-氯-4,5-二氟苯基-1-磺酰氯替代，得2-氯-N-(5-氯噻唑-2-基)-4-((2-((2-(乙氨基)乙基)(甲基)氨基)苄氧基)-5-氟-苯磺酰胺，ESI-MS(m/z):533.1[M+H] +。 The operation was the same as in Example 38, except that the 4-chloro-2-fluorobenzonitrile in step b was replaced with 2-fluorobenzonitrile, and the 1,2,4-thiadiazole-5- Replace the amine with 5-chlorothiazole-2-amine, and replace the 2,4,5-trifluorophenyl-1-sulfonyl chloride in step f with 2-chloro-4,5-difluorophenyl-1-sulfonyl chloride Instead, 2-chloro-N- (5-chlorothiazol-2-yl) -4-((2-((2- (ethylamino) ethyl) (methyl) amino) benzyloxy) -5- Fluoro-benzenesulfonamide, ESI-MS (m / z): 533.1 [M + H] + .
实施例46Example 46
4-((2-((2-(吡咯-1-基)乙基)氨基)-4-(三氟甲氧基)苄氧基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备4-((2-((2- (pyrrole-1-yl) ethyl) amino) -4- (trifluoromethoxy) benzyloxy) -2,5-difluoro-N- (1,2 , 4-thiadiazol-5-yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000054
Figure PCTCN2019104852-appb-000054
操作过程同实施例36，只是分别将步骤a中的(2-氨基乙基)(乙基)氨基甲酸叔丁酯用2-(吡咯-1-基)乙胺替代，将4-氯-2-氟苯甲腈用2-氟-4-三氟甲氧基苯甲腈替代，得4-((2-((2-(吡咯-1-基)乙基)氨基)-4-(三氟甲氧基)苄氧基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺，ESI-MS(m/z):580.0[M+H] +。 The operation was the same as in Example 36, except that (2-aminoethyl) (ethyl) carbamic acid tert-butyl ester in step a was replaced with 2- (pyrrol-1-yl) ethylamine, and 4-chloro-2 -Fluorobenzonitrile was replaced with 2-fluoro-4-trifluoromethoxybenzonitrile to give 4-((2-((2- (pyrrole-1-yl) ethyl) amino) -4- (tri Fluoromethoxy) benzyloxy) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide, ESI-MS (m / z): 580.0 [ M + H] + .
实施例47Example 47
4-((2-((2-(乙氨基)乙基)氨基)-4-(三氟甲氧基)苄氧基)-2,5-二氟-N-(1,2,4-噁二唑-3-基)-苯磺酰胺的制备4-((2-((2- (ethylamino) ethyl) amino) -4- (trifluoromethoxy) benzyloxy) -2,5-difluoro-N- (1,2,4- Preparation of oxadiazol-3-yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000055
Figure PCTCN2019104852-appb-000055
操作过程同实施例36，只是分别将步骤a中的4-氯-2-氟苯甲腈用2-氟-4-三氟甲氧基苯甲腈替代，将步骤e中的1,2,4-噻二唑-5-胺用1,2,4-噻二唑-3-胺替代，得4-((2-((2-(乙氨基)乙基)氨基)-4-(三氟甲氧基)苄氧基)-2,5-二氟-N-(1,2,4-噁二唑-3-基)-苯磺酰胺，ESI-MS(m/z):538.1[M+H] +。 The operation was the same as that in Example 36, except that 4-chloro-2-fluorobenzonitrile in step a was replaced with 2-fluoro-4-trifluoromethoxybenzonitrile, and 1, 2 in step e, 4-thiadiazole-5-amine was replaced with 1,2,4-thiadiazole-3-amine to give 4-((2-((2- (ethylamino) ethyl) amino) -4- (tri Fluoromethoxy) benzyloxy) -2,5-difluoro-N- (1,2,4-oxadiazol-3-yl) -benzenesulfonamide, ESI-MS (m / z): 538.1 [ M + H] + .
实施例48Example 48
4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄氧基)-2,5-二氟-N-(甲氨基甲酰基)-苯磺酰胺的制备Preparation of 4-((4-chloro-2-((2- (ethylamino) ethyl) amino) benzyloxy) -2,5-difluoro-N- (methylcarbamoyl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000056
Figure PCTCN2019104852-appb-000056
步骤a-d)：(2-((叔丁氧羰基)(5-氯-2-(羟甲基)苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯的制备Steps a-d): Preparation of (2-((tert-butoxycarbonyl) (5-chloro-2- (hydroxymethyl) phenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester
操作过程同实施例36的步骤a-d。The operation procedure is the same as steps a-d of Example 36.
步骤e)：2,4,5-三氟-N-(甲氨基甲酰基)-苯磺酰胺的制备Step e): Preparation of 2,4,5-trifluoro-N- (methylcarbamoyl) -benzenesulfonamide
将2,4,5-三氟-苯磺酰胺(10.0g，47.357mmol)和干燥乙腈(50mL)加入反应瓶中，搅拌混匀，加入甲氨基甲酸苯酯(7.9g，52.291mmol)，再滴加DBU(10.86g，71.306mmol)，加毕，升温至回流反应8小时，减压蒸除溶剂，残余物以乙酸乙酯(300mL)溶解，有机层依次用0.1N盐酸(80mL)、饱和氯化钠水溶液(60mL x 2)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得粗品经正己烷/乙酸乙酯混合溶剂重结晶，得2,4,5-三氟-N-(甲氨基甲酰基)-苯磺酰胺，收率70.5％，ESI-MS(m/z):269.1[M+H] +。 Add 2,4,5-trifluoro-benzenesulfonamide (10.0g, 47.357mmol) and dry acetonitrile (50mL) to the reaction bottle, stir and mix, add phenyl carbamate (7.9g, 52.291mmol), and then DBU (10.86g, 71.306mmol) was added dropwise. After the addition was completed, the temperature was raised to reflux for 8 hours. The solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate (300mL). An aqueous solution of sodium chloride (60 mL x 2) was washed, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was recrystallized from a mixed solvent of n-hexane / ethyl acetate to obtain 2,4,5-trifluoro-N- ( Methylcarbamoyl) -benzenesulfonamide, yield 70.5%, ESI-MS (m / z): 269.1 [M + H] + .
步骤f)：N-(2,4-二甲氧基苄基)-2,4,5-三氟-N-(甲氨基甲酰基)-苯磺酰胺的制备Step f): Preparation of N- (2,4-dimethoxybenzyl) -2,4,5-trifluoro-N- (methylcarbamoyl) -benzenesulfonamide
在-10℃条件下，将2,4,5-三氟-N-(甲氨基甲酰基)-苯磺酰胺(4.0g，14.914mmol)、2,4-二甲氧基苯甲醇(3.26g，19.388mmol)、三苯基膦(5.87g，22.371mmol)和干燥四氢呋喃(80mL)加入反应瓶中，再缓慢滴加偶氮二甲酸二乙酯(3.38g，19.388mmol)的四氢呋喃溶液(15mL)，加毕，升温至室温搅拌反应2小时，再升温至40℃反应10小时，冷却至室温，加水(100mL)稀释，以二氯甲烷(50mL x 3)萃取，合并有机层，以饱和氯化钠 溶液(50mL x 2)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝2:1v/v)，得N-(2,4-二甲氧基苄基)-2,4,5-三氟-N-(甲氨基甲酰基)-苯磺酰胺，收率50.0％，ESI-MS(m/z):419.1[M+H] +。 At -10 ° C, 2,4,5-trifluoro-N- (methylcarbamoyl) -benzenesulfonamide (4.0 g, 14.914 mmol), 2,4-dimethoxybenzyl alcohol (3.26 g , 19.388 mmol), triphenylphosphine (5.87 g, 22.371 mmol) and dry tetrahydrofuran (80 mL) were added to the reaction flask, and then a solution of diethyl azodicarboxylate (3.38 g, 19.388 mmol) in tetrahydrofuran (15 mL) was slowly added dropwise. ). After the addition is complete, the mixture is warmed to room temperature and stirred for 2 hours, and then heated to 40 ° C for 10 hours, cooled to room temperature, diluted with water (100 mL), and extracted with dichloromethane (50 mL x 3). Sodium chloride solution (50mL x 2) was washed, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2: 1v / v) to obtain N- (2,4-dimethoxybenzyl) -2,4,5-trifluoro-N- (methylcarbamoyl) -benzenesulfonamide, yield 50.0%, ESI-MS (m / z) : 419.1 [M + H] + .
步骤g)：(2-((叔丁氧羰基)(乙基)氨基)乙基)(5-氯-2-((4-(N-(2,4-二甲氧基苄基)-N-(甲氨基甲酰基)磺酰胺基)-2,5-二氟苯氧基)甲基)苯基)-氨基甲酸叔丁酯的制备Step g): (2-((tert-butoxycarbonyl) (ethyl) amino) ethyl) (5-chloro-2-((4- (N- (2,4-dimethoxybenzyl)- Preparation of N- (methylcarbamoyl) sulfonamido) -2,5-difluorophenoxy) methyl) phenyl) -carbamic acid tert-butyl ester
操作过程同实施例36，只是将步骤g中的N-(2,4-二甲氧基苄基-2,4,5-三氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺用N-(2,4-二甲氧基苄基)-2,4,5-三氟-N-(甲氨基甲酰基)-苯磺酰胺替代，得(2-((叔丁氧羰基)(乙基)氨基)乙基)(5-氯-2-((4-(N-(2,4-二甲氧基苄基)-N-(甲氨基甲酰基)磺酰胺基)-2,5-二氟苯氧基)甲基)苯基)-氨基甲酸叔丁酯，ESI-MS(m/z):827.2[M+H] +。 The operation was the same as in Example 36, except that N- (2,4-dimethoxybenzyl-2,4,5-trifluoro-N- (1,2,4-thiadiazole-5) in step g -Yl) -benzenesulfonamide was replaced with N- (2,4-dimethoxybenzyl) -2,4,5-trifluoro-N- (methylcarbamoyl) -benzenesulfonamide to give (2- ((Tert-butoxycarbonyl) (ethyl) amino) ethyl) (5-chloro-2-((4- (N- (2,4-dimethoxybenzyl) -N- (methylcarbamoyl ) Sulfonamido) -2,5-difluorophenoxy) methyl) phenyl) -carbamic acid tert-butyl ester, ESI-MS (m / z): 827.2 [M + H] + .
步骤h)：4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄氧基)-2,5-二氟-N-(甲氨基甲酰基)-苯磺酰胺的制备Step h): 4-((4-chloro-2-((2- (ethylamino) ethyl) amino) benzyloxy) -2,5-difluoro-N- (methylcarbamoyl) -benzenesulfonate Preparation of amide
操作过程同实施例36，只是将步骤h中的(2-((叔丁氧羰基)(乙基)氨基)乙基)(5-氯-2-((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯氧基)甲基)苄基)-氨基甲酸叔丁酯用(2-((叔丁氧羰基)(乙基)氨基)乙基)(5-氯-2-((4-(N-(2,4-二甲氧基苄基)-N-(甲氨基甲酰基)磺酰胺基)-2,5-二氟苯氧基)甲基)苯基)-氨基甲酸叔丁酯替代，得4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄氧基)-2,5-二氟-N-(甲氨基甲酰基)-苯磺酰胺， 1H NMR(400MHz,DMSO-d 6)δ:7.25(dd,J 1＝11.6,J 2＝6.4Hz,1H),7.12(d,J＝8.0Hz,1H),6.73(s,1H),6.69(d,J＝8.0Hz,1H),6.44(brs,1H),6.25(dd,J 1＝12.0,J 2＝6.8Hz,1H),5.89-5.88(m,1H),4.50(d,J＝5.6Hz,2H),3.56-3.55(m,2H),3.00-2.95(m,4H),2.51(s,3H),1.42-1.40(m,3H),ESI-MS(m/z):499.0[M+Na] +。 The operation was the same as in Example 36, except that (2-((tert-butoxycarbonyl) (ethyl) amino) ethyl) (5-chloro-2-((4- (N- (2,4 -Dimethoxybenzyl) -N- (1,2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorophenoxy) methyl) benzyl) -carbamic acid (2-((tert-butoxycarbonyl) (ethyl) amino) ethyl) (5-chloro-2-((4- (N- (2,4-dimethoxybenzyl)- N- (methylcarbamoyl) sulfonamido) -2,5-difluorophenoxy) methyl) phenyl) -carbamic acid tert-butyl ester was substituted to give 4-((4-chloro-2-(( 2- (ethylamino) ethyl) amino) benzyloxy) -2,5-difluoro-N- (methylcarbamoyl) -benzenesulfonamide, 1 H NMR (400 MHz, DMSO-d 6 ) δ: 7.25 (dd, J 1 = 11.6, J 2 = 6.4 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.73 (s, 1H), 6.69 (d, J = 8.0 Hz, 1H), 6.44 ( brs, 1H), 6.25 (dd, J 1 = 12.0, J 2 = 6.8 Hz, 1 H), 5.89-5.88 (m, 1H), 4.50 (d, J = 5.6 Hz, 2H), 3.56-3.55 (m, 2H), 3.00-2.95 (m, 4H), 2.51 (s, 3H), 1.42-1.40 (m, 3H), ESI-MS (m / z): 499.0 [M + Na] + .
实施例49Example 49
4-((4-氯-2-((2-(吡咯-1-基)乙基)氨基)苄氧基)-2,5-二氟-N-(甲氨基甲酰基)-苯磺酰胺的制备4-((4-chloro-2-((2- (pyrrol-1-yl) ethyl) amino) benzyloxy) -2,5-difluoro-N- (methylcarbamoyl) -benzenesulfonamide Preparation
Figure PCTCN2019104852-appb-000057
Figure PCTCN2019104852-appb-000057
操作过程同实施例48，只是将a中的(2-氨基乙基)(乙基)氨基甲酸叔丁酯用2-(吡咯-1-基)乙胺替代，得4-((4-氯-2-((2-(吡咯-1-基)乙基)氨基)苄氧基)-2,5-二氟-N-(甲氨基甲酰基)-苯磺酰胺，ESI-MS(m/z):525.1[M+Na] +。 The operation was the same as that in Example 48, except that (2-aminoethyl) (ethyl) carbamic acid tert-butyl ester in a was replaced with 2- (pyrrol-1-yl) ethylamine to obtain 4-((4-chloro -2-((2- (pyrrole-1-yl) ethyl) amino) benzyloxy) -2,5-difluoro-N- (methylcarbamoyl) -benzenesulfonamide, ESI-MS (m / z): 525.1 [M + Na] + .
实施例50Example 50
4-(((5-氯-3-((2-(乙氨基)乙基)氨基)吡啶-2-基)甲基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备4-(((5-chloro-3-((2- (ethylamino) ethyl) amino) pyridin-2-yl) methyl) amino) -2,5-difluoro-N- (1,2, Preparation of 4-thiadiazol-5-yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000058
Figure PCTCN2019104852-appb-000058
操作过程同实施例1，只是将步骤a中的4-氯-2-氟-苯甲腈用5-氯-3-氟吡啶-2-甲腈替代，得4-(((5-氯-3-((2-(乙氨基)乙基)氨基)吡啶-2-基)甲基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺，ESI-MS(m/z):504.1[M+H] +。 The operation was the same as in Example 1, except that 4-chloro-2-fluoro-benzonitrile in step a was replaced with 5-chloro-3-fluoropyridine-2-carbonitrile to obtain 4-(((5-chloro- 3-((2- (ethylamino) ethyl) amino) pyridin-2-yl) methyl) amino) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl ) -Benzenesulfonamide, ESI-MS (m / z): 504.1 [M + H] + .
实施例51Example 51
4-(4-氯-2-((2-(乙氨基)乙基)氨基)苯氧基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备4- (4-chloro-2-((2- (ethylamino) ethyl) amino) phenoxy) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl ) -Benzenesulfonamide
Figure PCTCN2019104852-appb-000059
Figure PCTCN2019104852-appb-000059
步骤a)：(2-((5-氯-2-硝基苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯的制备Step a): Preparation of (2-((5-chloro-2-nitrophenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester
操作过程同实施例1中的的步骤a，只是将4-氯-2-氟苯甲腈用4-氯-2-氟-1-硝基苯替代，得(2-((5-氯-2-硝基苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯。The operation process is the same as step a in Example 1, except that 4-chloro-2-fluorobenzonitrile is replaced with 4-chloro-2-fluoro-1-nitrobenzene to obtain (2-((5-chloro- 2-nitrophenyl) amino) ethyl) (ethyl) -t-butyl carbamate.
步骤b)：(2-((叔丁氧羰基)(5-氯-2-硝基苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯的制备Step b): Preparation of (2-((tert-butoxycarbonyl) (5-chloro-2-nitrophenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester
操作过程同实施例36中的步骤b，只是将(2-((5-氯-2-氰基苯基)氨基)乙基)(乙基)氨基甲酸叔丁酯用(2-((5-氯-2-硝基苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯替代，得(2-((叔丁氧羰 基)(5-氯-2-硝基苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯。The operation was the same as step b in Example 36, except that (2-((5-chloro-2-cyanophenyl) amino) ethyl) (ethyl) carbamic acid tert-butyl ester was used (2-((5 -Chloro-2-nitrophenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester to obtain (2-((tert-butoxycarbonyl) (5-chloro-2-nitrophenyl) Amino) ethyl) (ethyl) -t-butyl carbamate.
步骤c)：(2-((2-氨基-5-氯苯基)(叔丁氧羰基)氨基)乙基)(乙基)-氨基甲酸叔丁酯的制备Step c): Preparation of (2-((2-amino-5-chlorophenyl) (tert-butoxycarbonyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester
将(2-((叔丁氧羰基)(5-氯-2-硝基苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯(1.0g，2.253mmol)和乙醇(30mL)加入反应瓶中，搅拌溶解，加入饱和氯化铵溶液(10mL)，再加入锌粉(737mg，11.265mmol)，升温至50℃搅拌反应15小时，冷却至室温，经过硅胶垫过滤除去不溶固体，滤饼用乙酸乙酯(50mL)洗涤，合并滤液，用乙酸乙酯(50mL)和水(100mL)萃取，有机层用饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1：1v/v)，得(2-((2-氨基-5-氯苯基)(叔丁氧羰基)氨基)乙基)(乙基)-氨基甲酸叔丁酯，收率70.0％，ESI-MS(m/z)：414.3[M+H] +。 (2-((tert-butoxycarbonyl) (5-chloro-2-nitrophenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester (1.0 g, 2.253 mmol) and ethanol (30 mL) Add to the reaction flask, stir to dissolve, add saturated ammonium chloride solution (10mL), and then add zinc powder (737mg, 11.265mmol), heat to 50 ° C and stir for 15 hours, cool to room temperature, filter through silica gel pad to remove insoluble solids, The filter cake was washed with ethyl acetate (50 mL), the filtrates were combined, extracted with ethyl acetate (50 mL) and water (100 mL), and the organic layer was washed with a saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and reduced. The solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1: 1 v / v) to obtain (2-((2-amino-5-chlorophenyl) (tert-butoxy Carbonyl) amino) ethyl) (ethyl) -t-butyl carbamate, yield 70.0%, ESI-MS (m / z): 414.3 [M + H] + .
步骤d)：(2-((叔丁氧羰基)(5-氯-2-羟基苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯的制备Step d): Preparation of (2-((tert-butoxycarbonyl) (5-chloro-2-hydroxyphenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester
操作过程同实施例36中的步骤d，只是将((2-((2-(氨基乙基)-5-氯苯基)(叔丁氧羰基)氨基)乙基)(乙基)-氨基甲酸叔丁酯用(2-((2-氨基-5-氯苯基)(叔丁氧羰基)氨基)乙基)(乙基)-氨基甲酸叔丁酯替代，得(2-((叔丁氧羰基)(5-氯-2-羟基苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯。The operation was the same as step d in Example 36, except that ((2-((2- (aminoethyl) -5-chlorophenyl) (tert-butoxycarbonyl) amino) ethyl) (ethyl) -amino Tert-butyl formate was replaced with (2-((2-amino-5-chlorophenyl) (tert-butoxycarbonyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester to obtain (2-((tert Butoxycarbonyl) (5-chloro-2-hydroxyphenyl) amino) ethyl) (ethyl) -t-butyl carbamate.
步骤e)：(2-((叔丁氧羰基)(乙基)氨基)乙基)(5-氯-2-(4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯氧基)苯基)-氨基甲酸叔丁酯的制备Step e): (2-((tert-butoxycarbonyl) (ethyl) amino) ethyl) (5-chloro-2- (4- (N- (2,4-dimethoxybenzyl) -N -(1,2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorophenoxy) phenyl) -carbamic acid tert-butyl ester
将(2-((叔丁氧羰基)(5-氯-2-羟基苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯(300mg，0.723mmol)、N-(2,4-二甲氧基苄基)-2,4,5-三氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺(322mg，0.724mmol)、碳酸钾(200mg，1.446mmol)和干燥DMSO(6mL)加入反应瓶中，氮气保护下于25℃反应15小时，反应结束后，加水(30mL)稀释，以乙酸乙酯(20mL x 3)萃取，合并有机层，依次用水(10mL x 3)、饱和氯化钠溶液(30mL)洗涤,无水硫酸钠干燥，过滤，减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1:1v/v)，得(2-((叔丁氧羰基)(乙基)氨基)乙基)(5-氯-2-(4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯氧基)苯基)-氨基甲酸叔丁酯，收率56.6％，ESI-MS(m/z)：840.2[M+H] +。 Tert-Butyl (2-((tert-butoxycarbonyl) (5-chloro-2-hydroxyphenyl) amino) ethyl) (ethyl) -carbamic acid (300 mg, 0.723 mmol), N- (2,4 -Dimethoxybenzyl) -2,4,5-trifluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide (322 mg, 0.724 mmol), potassium carbonate (200 mg (1.446 mmol) and dry DMSO (6 mL) were added to the reaction flask, and reacted at 25 ° C. for 15 hours under the protection of nitrogen. After the reaction, diluted with water (30 mL), extracted with ethyl acetate (20 mL x 3), and combined the organic layers. It was washed with water (10 mL x 3), saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1: 1 v / v) to give (2-((tert-butoxycarbonyl) (ethyl) amino) ethyl) (5-chloro-2- (4- (N- (2,4-dimethoxybenzyl) -)-N- (1,2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorophenoxy) phenyl) -carbamic acid tert-butyl ester, yield 56.6%, ESI-MS (m / z): 840.2 [M + H] + .
步骤f)：4-(4-氯-2-((2-(乙氨基)乙基)氨基)苯氧基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备Step f): 4- (4-chloro-2-((2- (ethylamino) ethyl) amino) phenoxy) -2,5-difluoro-N- (1,2,4-thiadiazole -5-yl) -benzenesulfonamide
将(2-((叔丁氧羰基)(乙基)氨基)乙基)(5-氯-2-(4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯氧基)苯基)-氨基甲酸叔丁酯(100mg)加入反应瓶中，加入三氟乙酸和二氯甲烷的混合液(4mL，v/v＝1:6)，室温搅拌反应1小时，反应结束后，减压蒸除过量三氟乙酸和二氯甲烷，残余物用饱和NaHCO 3溶液(10mL)和乙酸乙酯(20mL)萃取，水层再用乙酸乙酯萃取(10mL x 3)，合并有机层，以饱和氯化钠溶液(40mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得粗品经制备薄层纯化(展开剂：二氯甲烷/甲醇＝5：1)， 得4-(4-氯-2-((2-(乙氨基)乙基)氨基)苯氧基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺，ESI-MS(m/z)：490.0[M+H] +。 (2-((tert-butoxycarbonyl) (ethyl) amino) ethyl) (5-chloro-2- (4- (N- (2,4-dimethoxybenzyl) -N- (1 , 2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorophenoxy) phenyl) -carbamic acid tert-butyl ester (100 mg) was added to the reaction flask, and trifluoroacetic acid and A mixed solution of dichloromethane (4mL, v / v = 1: 6), the reaction was stirred at room temperature for 1 hour. After the reaction was completed, excess trifluoroacetic acid and dichloromethane were distilled off under reduced pressure. The residue was saturated with NaHCO 3 solution (10mL). ) And ethyl acetate (20 mL), the aqueous layer was extracted with ethyl acetate (10 mL x 3), the organic layers were combined, washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer (developing solvent: dichloromethane / methanol = 5: 1) to obtain 4- (4-chloro-2-((2- (ethylamino) ethyl) amino) phenoxy) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide, ESI-MS (m / z): 490.0 [M + H] + .
实施例52Example 52
4-((4-氯-2-((2-(4-甲基哌嗪-1-基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备4-((4-chloro-2-((2- (4-methylpiperazin-1-yl) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (1,2 , 4-thiadiazol-5-yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000060
Figure PCTCN2019104852-appb-000060
操作过程同实施例1，只是将步骤a中的(2-氨基乙基)(乙基)氨基甲酸叔丁酯用2-(4-甲基哌嗪-1-基)乙胺替代，得4-((4-氯-2-((2-(4-甲基哌嗪-1-基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺， 1H NMR(400MHz,DMSO-d 6)δ:7.87(s,1H),7.32(dd,J 1＝11.2,J 2＝6.4Hz,1H),7.09(d,J＝8.4Hz,1H),6.75-6.66(m,1H),6.65-6.57(m,2H),6.42(dd,J 1＝12.4,J 2＝6.8Hz,1H),5.34-5.23(m,1H),4.15(d,J＝5.6Hz,2H),3.50-3.29(m,2H),3.26-3.18(m,2H),3.14-2.80(m,4H),2.75-2.58(m,7H)，ESI-MS(m/z):558.1[M+H] +。 The operation was the same as in Example 1, except that the (2-aminoethyl) (ethyl) carbamic acid tert-butyl ester in step a was replaced with 2- (4-methylpiperazin-1-yl) ethylamine to obtain 4 -((4-chloro-2-((2- (4-methylpiperazin-1-yl) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (1,2, 4-thiadiazol-5-yl) -benzenesulfonamide, 1 H NMR (400 MHz, DMSO-d 6 ) δ: 7.87 (s, 1H), 7.32 (dd, J 1 = 11.2, J 2 = 6.4 Hz, 1H), 7.09 (d, J = 8.4Hz, 1H), 6.75-6.66 (m, 1H), 6.65-6.57 (m, 2H), 6.42 (dd, J 1 = 12.4, J 2 = 6.8 Hz, 1H) , 5.34-5.23 (m, 1H), 4.15 (d, J = 5.6Hz, 2H), 3.50-3.29 (m, 2H), 3.26-3.18 (m, 2H), 3.14-2.80 (m, 4H), 2.75 -2.58 (m, 7H), ESI-MS (m / z): 558.1 [M + H] + .
实施例53Example 53
4-((2-((2-(氮杂环丁烷-1-基)乙基)氨基)-4-氯苄基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)苯磺酰胺的制备4-((2-((2- (azetidin-1-yl) ethyl) amino) -4-chlorobenzyl) amino) -2,5-difluoro-N- (1,2, Preparation of 4-thiadiazol-5-yl) benzenesulfonamide
Figure PCTCN2019104852-appb-000061
Figure PCTCN2019104852-appb-000061
操作过程同实施例1，只是将步骤a中的(2-氨基乙基)(乙基)氨基甲酸叔丁酯用2-(氮杂环丁烷-1-基)乙胺替代，得4-((2-((2-(氮杂环丁烷-1-基)乙基)氨基)-4-氯苄基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)苯磺酰胺，ESI-MS(m/z):515.1[M+H] +。 The operation was the same as in Example 1, except that the (2-aminoethyl) (ethyl) carbamic acid tert-butyl ester in step a was replaced with 2- (azetidin-1-yl) ethylamine to obtain 4- ((2-((2- (azetidin-1-yl) ethyl) amino) -4-chlorobenzyl) amino) -2,5-difluoro-N- (1,2,4- Thiadiazol-5-yl) benzenesulfonamide, ESI-MS (m / z): 515.1 [M + H] + .
实施例54Example 54
4-((2-((2-(高哌啶-1-基)乙基)氨基)-4-氯苄基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备4-((2-((2- (Homopiperidin-1-yl) ethyl) amino) -4-chlorobenzyl) amino) -2,5-difluoro-N- (1,2,4- Preparation of thiadiazol-5-yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000062
Figure PCTCN2019104852-appb-000062
操作过程同实施例1，只是将步骤a中的(2-氨基乙基)(乙基)氨基甲酸叔丁酯用2-(高哌啶-1-基)乙基胺的替代，得4-((2-((2-(高哌啶-1-基)乙基)氨基)-4-氯苄基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺，ESI-MS(m/z):557.2[M+H] +。 The operation process is the same as in Example 1, except that the (2-aminoethyl) (ethyl) carbamic acid tert-butyl ester in step a is replaced with 2- (homoperidin-1-yl) ethylamine to obtain 4- ((2-((2- (Homopiperidin-1-yl) ethyl) amino) -4-chlorobenzyl) amino) -2,5-difluoro-N- (1,2,4-thiadi Azol-5-yl) -benzenesulfonamide, ESI-MS (m / z): 557.2 [M + H] + .
实施例55Example 55
4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(嘧啶-4-基)-苯磺酰胺的制备4-((4-chloro-2-((2- (ethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (pyrimidin-4-yl) -benzenesulfonamide preparation
Figure PCTCN2019104852-appb-000063
Figure PCTCN2019104852-appb-000063
操作过程同实施例1，只是将步骤c中的1,2,4-噻二唑-5-胺用嘧啶-4-胺替代，得4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(嘧啶-4-基)-苯磺酰胺，ESI-MS(m/z)：497.2[M+H] +。 The operation process is the same as in Example 1, except that 1, 2, 4-thiadiazole-5-amine in step c is replaced with pyrimidine-4-amine to obtain 4-((4-chloro-2-((2- ( Ethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (pyrimidin-4-yl) -benzenesulfonamide, ESI-MS (m / z): 497.2 [M + H] + .
实施例56Example 56
4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(吡嗪-2-基)-苯磺酰胺的制备4-((4-chloro-2-((2- (ethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (pyrazin-2-yl) -benzenesulfonamide Preparation
Figure PCTCN2019104852-appb-000064
Figure PCTCN2019104852-appb-000064
操作过程同实施例1，只是将步骤c中的1,2,4-噻二唑-5-胺用吡嗪-2-胺替代，得4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(吡嗪-2-基)-苯磺酰胺， 1H NMR(400MHz,DMSO-d 6)δ:8.26(s,1H),7.90(s,1H),7.35(dd,J 1＝11.6,J 2＝6.4Hz,1H),7.04(d,J＝8.0Hz,1H),6.73-6.58(m,3H),6.54(s,1H),6.20(dd,J 1＝11.6,J 2＝6.4Hz,1H),5.49(s,1H),4.15(d,J＝5.6Hz,2H),3.28(brs,2H),3.11-3.03(m,2H),2.98(q,J＝7.2Hz,2H),1.16(t,J＝7.2Hz,3H)，ESI-MS(m/z)：497.1[M+H] +。 The operation process is the same as in Example 1, except that the 1, 2, 4-thiadiazole-5-amine in step c is replaced with pyrazin-2-amine to obtain 4-((4-chloro-2-((2- (Ethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (pyrazin-2-yl) -benzenesulfonamide, 1 H NMR (400 MHz, DMSO-d 6 ) δ: 8.26 (s, 1H), 7.90 (s, 1H), 7.35 (dd, J 1 = 11.6, J 2 = 6.4 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.73-6.58 (m, 3H), 6.54 (s, 1H), 6.20 (dd, J 1 = 11.6, J 2 = 6.4 Hz, 1H), 5.49 (s, 1H), 4.15 (d, J = 5.6 Hz, 2H), 3.28 (brs , 2H), 3.11-3.03 (m, 2H), 2.98 (q, J = 7.2Hz, 2H), 1.16 (t, J = 7.2Hz, 3H), ESI-MS (m / z): 497.1 [M + H] + .
实施例57Example 57
4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(6-氟吡啶-2-基)-苯磺酰胺的制备4-((4-chloro-2-((2- (ethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (6-fluoropyridin-2-yl) -benzene Preparation of sulfonamide
Figure PCTCN2019104852-appb-000065
Figure PCTCN2019104852-appb-000065
操作过程同实施例1，只是将步骤c中的1,2,4-噻二唑-5-胺用6-氟吡啶-2-胺替代，得4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(6-氟吡啶-2-基)-苯磺酰胺，ESI-MS(m/z)：514.0[M+H] +。 The operation process is the same as in Example 1, except that 1, 2, 4-thiadiazole-5-amine in step c is replaced with 6-fluoropyridin-2-amine to obtain 4-((4-chloro-2-(( 2- (ethylamino) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (6-fluoropyridin-2-yl) -benzenesulfonamide, ESI-MS (m / z): 514.0 [M + H] + .
实施例58Example 58
N-(4-(N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯基)-4-氯-2-((2-(乙氨基)乙基)氨基)-苯甲酰胺的制备N- (4- (N- (1,2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorophenyl) -4-chloro-2-((2- (ethyl Preparation of amino) ethyl) amino) -benzamide
Figure PCTCN2019104852-appb-000066
Figure PCTCN2019104852-appb-000066
步骤a)：2-((2-((叔丁氧羰基)(乙基)氨基)乙基)氨基)-4-氯苯甲酸甲酯的制备Step a): Preparation of methyl 2-((2-((tert-butoxycarbonyl) (ethyl) amino) ethyl) amino) -4-chlorobenzoate
操作过程同实施例1中的步骤a，只是将4-氯-2-氟-苯甲腈用4-氯-2-氟-苯甲酸甲酯替代，得2-((2-((叔丁氧羰基)(乙基)氨基)乙基)氨基)-4-氯苯甲酸甲酯。The operation was the same as step a in Example 1, except that 4-chloro-2-fluoro-benzonitrile was replaced with 4-chloro-2-fluoro-benzoic acid methyl ester to obtain 2-((2-((tert-butyl Oxycarbonyl) (ethyl) amino) ethyl) amino) -4-chlorobenzoic acid methyl ester.
步骤b)：2-((叔丁氧羰基)(2-((叔丁氧羰基)(乙基)氨基)乙基)氨基)-4-氯苯甲酸甲酯的制备Step b): Preparation of 2-((tert-butoxycarbonyl) (2-((tert-butoxycarbonyl) (ethyl) amino) ethyl) amino) -4-chlorobenzoic acid methyl ester
将2-((2-((叔丁氧羰基)(乙基)氨基)乙基)氨基)-4-氯苯甲酸甲酯(1.02g，2.870mmol)，4-二甲氨基吡啶(527mg，4.310mmol)和干燥二氯甲烷(50mL)加入反应瓶中，缓慢加入Boc 2O(626mg，2.870mmol)，室温搅拌反应20小时，反应结束后，向反应体系加二氯甲烷(50mL)和饱和氯化铵溶液(100mL)，有机相用0.05N的盐酸(20mL x 2)、饱和氯化钠(30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10:1v/v)，得2-((叔丁氧羰基)(2-((叔丁氧羰基)(乙基)氨基)乙基)氨基)-4-氯苯甲酸甲酯，收率46.7％，ESI-MS(m/z):457.2[M+H] +。 Methyl 2-((2-((tert-butoxycarbonyl) (ethyl) amino) ethyl) amino) -4-chlorobenzoate (1.02 g, 2.870 mmol), 4-dimethylaminopyridine (527 mg, 4.310 mmol) and dry dichloromethane (50 mL) were added to the reaction flask, Boc 2 O (626 mg, 2.870 mmol) was slowly added, and the reaction was stirred at room temperature for 20 hours. After the reaction was completed, dichloromethane (50 mL) and saturated were added to the reaction system. Ammonium chloride solution (100 mL), the organic phase was washed with 0.05 N hydrochloric acid (20 mL x 2), saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. (Eluent: dichloromethane / methanol = 10: 1 v / v) to obtain 2-((tert-butoxycarbonyl) (2-((tert-butoxycarbonyl) (ethyl) amino) ethyl) amino)- Methyl 4-chlorobenzoate, yield 46.7%, ESI-MS (m / z): 457.2 [M + H] + .
步骤c)：2-((叔丁氧羰基)(2-((叔丁氧羰基)(乙基)氨基)乙基)氨基)-4-氯苯甲酸的制备Step c): Preparation of 2-((tert-butoxycarbonyl) (2-((tert-butoxycarbonyl) (ethyl) amino) ethyl) amino) -4-chlorobenzoic acid
将2-((叔丁氧羰基)(2-((叔丁氧羰基)(乙基)氨基)乙基)氨基)-4-氯苯甲酸甲酯(400mg，0.875mmol)和甲醇(10mL)加入反应瓶中，搅拌溶解，加入LiOH.H 2O(110mg，2.625mmol)的水溶液，室温搅拌2小时，反应结束后，减压蒸除甲醇，残余物加水(30mL)稀释，过滤除去少量不溶物，滤液以10％盐酸溶液调至pH＝3，过滤，所得滤饼水洗近中性，30℃真空干燥，得2-((叔丁氧羰基)(2-((叔丁氧羰基)(乙基)氨基)乙基)氨基)-4-氯苯甲酸，收率84.8％，ESI-MS(m/z):443.2[M+H] +。。 Methyl 2-((tert-butoxycarbonyl) (2-((tert-butoxycarbonyl) (ethyl) amino) ethyl) amino) -4-chlorobenzoate (400 mg, 0.875 mmol) and methanol (10 mL) Add to the reaction flask, stir to dissolve, add an aqueous solution of LiOH.H 2 O (110mg, 2.625mmol), and stir at room temperature for 2 hours. After the reaction is complete, evaporate the methanol under reduced pressure, dilute the residue with water (30mL), and filter to remove a small amount of insoluble The filtrate was adjusted to pH = 3 with a 10% hydrochloric acid solution and filtered. The obtained filter cake was washed with water and nearly neutral and dried under vacuum at 30 ° C to obtain 2-((tert-butoxycarbonyl) (2-((tert-butoxycarbonyl) ( Ethyl) amino) ethyl) amino) -4-chlorobenzoic acid, yield 84.8%, ESI-MS (m / z): 443.2 [M + H] + . .
步骤d)：苄基(2,5-二氟-4-硝基苯)硫醚的制备Step d): Preparation of benzyl (2,5-difluoro-4-nitrobenzene) sulfide
将1,2,4-三氟-5-硝基苯(10.0g，56.471mmol)、无水K 2CO 3(11.7g，84.707mmol)和干燥DMF(80mL)加入反应瓶中，再将苄硫醇(7.01g，56.471mmol)在0℃缓慢滴加到反应液中，加毕，缓慢升温到室温反应2小时。反应结束后，将反应倒入冰水中，过滤收集析出的黄色固体，用适量的水洗涤，干燥得到粗品苄基(2,5-二氟-4-硝基苯)硫醚，直接用于下一步反应，无需进一步纯化。 Add 1,2,4-trifluoro-5-nitrobenzene (10.0 g, 56.471 mmol), anhydrous K 2 CO 3 (11.7 g, 84.707 mmol) and dry DMF (80 mL) to the reaction flask, then add benzyl Thiol (7.01 g, 56.471 mmol) was slowly added dropwise to the reaction solution at 0 ° C. After the addition, the temperature was gradually raised to room temperature for 2 hours to react. After the reaction, the reaction was poured into ice water, and the precipitated yellow solid was collected by filtration, washed with an appropriate amount of water, and dried to obtain a crude benzyl (2,5-difluoro-4-nitrobenzene) sulfide, which was directly used in the next step. One step reaction without further purification.
步骤e)：2,5-二氟-4-硝基苯-1-磺酰氯的制备Step e): Preparation of 2,5-difluoro-4-nitrobenzene-1-sulfonyl chloride
将苄基(2,5-二氟-4-硝基苯)硫醚(10.0g，35.552mmol)和二氯甲烷(300mL)加入反应瓶中，0℃充分搅拌下缓慢滴加HCl(4M，275.00mL)和NaClO(9.26g，124.432mmol)，在0℃反应1小时，升温至10℃反应12小时。反应结束后，分取有机相，浓缩，所得固体在-30℃用石油醚(20mL)打浆得2,5-二氟-4-硝基苯-1-磺酰氯，收率52.8％，ESI-MS(m/z):258.0[M+H] +。 Benzyl (2,5-difluoro-4-nitrobenzene) sulfide (10.0 g, 35.552 mmol) and dichloromethane (300 mL) were added to the reaction flask, and HCl (4 M, 275.00 mL) and NaClO (9.26 g, 124.432 mmol), reacted at 0 ° C for 1 hour, and heated to 10 ° C for 12 hours. After the reaction, the organic phase was separated and concentrated. The obtained solid was slurried with petroleum ether (20 mL) at -30 ° C to obtain 2,5-difluoro-4-nitrobenzene-1-sulfonyl chloride. The yield was 52.8%. ESI- MS (m / z): 258.0 [M + H] + .
步骤f)：N-(2,4-二甲氧基苄基)-2,5-二氟-4-硝基-N-(1,2,4-噻二唑-5-基)苯磺酰胺的制备Step f): N- (2,4-dimethoxybenzyl) -2,5-difluoro-4-nitro-N- (1,2,4-thiadiazol-5-yl) benzenesulfonate Preparation of amide
操作过程同实施例1中的步骤d，只是将2,4,5-三氟-苯磺酰氯用2,5-二氟-4-硝基苯-1-磺酰氯替代，得到N-(2,4-二甲氧基苄基)-2,5-二氟-4-硝基-N-(1,2,4-噻二唑-5-基)苯磺酰胺。The operation process is the same as step d in Example 1, except that 2,4,5-trifluoro-benzenesulfonyl chloride is replaced with 2,5-difluoro-4-nitrobenzene-1-sulfonyl chloride to obtain N- (2 , 4-dimethoxybenzyl) -2,5-difluoro-4-nitro-N- (1,2,4-thiadiazol-5-yl) benzenesulfonamide.
步骤g)：N-(2,4-二甲氧基苄基)-2,5-二氟-4-氨基-N-(1,2,4-噻二唑-5-基)苯磺酰胺的制备Step g): N- (2,4-dimethoxybenzyl) -2,5-difluoro-4-amino-N- (1,2,4-thiadiazol-5-yl) benzenesulfonamide Preparation
操作过程同实施例51中的步骤c，只是将(2-((叔丁氧羰基)(5-氯-2-硝基苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯用N-(2,4-二甲氧基苄基)-2,5-二氟-4-硝基-N-(1,2,4-噻二唑-5-基)苯磺酰胺替代，得到N-(2,4-二甲氧基苄基)-2,5-二氟-4-氨基-N-(1,2,4-噻二唑-5-基)苯磺酰胺。The operation was the same as step c in Example 51, except that (2-((tert-butoxycarbonyl) (5-chloro-2-nitrophenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester Replace with N- (2,4-dimethoxybenzyl) -2,5-difluoro-4-nitro-N- (1,2,4-thiadiazol-5-yl) benzenesulfonamide, N- (2,4-dimethoxybenzyl) -2,5-difluoro-4-amino-N- (1,2,4-thiadiazol-5-yl) benzenesulfonamide was obtained.
步骤h)：(2-((叔丁氧羰基)(乙基)氨基)乙基)(5-氯-2-((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯基)氨甲酰基)苯基)氨基甲酸叔丁酯的制备Step h): (2-((tert-butoxycarbonyl) (ethyl) amino) ethyl) (5-chloro-2-((4- (N- (2,4-dimethoxybenzyl)- Preparation of N- (1,2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorophenyl) carbamoyl) phenyl) carbamate
将N-(2,4-二甲氧基苄基)-2,5-二氟-4-氨基-N-(1,2,4-噻二唑-5-基)苯磺酰胺(50mg，0.113mmol)、2-((叔丁氧羰基)(2-((叔丁氧羰基)(乙基)氨基)乙基)氨基)-4-氯苯甲酸(55mg，0.124mmol)、苯并三氮唑-1-基氧-三(四氢吡咯基)鏻鎓六氟磷酸盐(PyBOP，88mg，0.170mmol)、DIPEA(44mg，0.339mmol)和干燥DMSO(3mL)加入反应瓶中，室温搅拌反应15小时，反应结束后，将反应液倾入水中，乙酸乙酯萃取(10mL x 3)，合并有机层，依次用饱和氯 化铵水溶液(10mL x 3)、水(10mL)、饱和氯化钠水溶液(10mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得粗品经制备薄层纯化(展开剂：二氯甲烷/甲醇＝10：1v/v)，得(2-((叔丁氧羰基)(乙基)氨基)乙基)(5-氯-2-((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯基)氨甲酰基)苯基)氨基甲酸叔丁酯，收率45.0％，ESI-MS(m/z):867.1[M+H] +。 N- (2,4-dimethoxybenzyl) -2,5-difluoro-4-amino-N- (1,2,4-thiadiazol-5-yl) benzenesulfonamide (50 mg, 0.113 mmol), 2-((tert-butoxycarbonyl) (2-((tert-butoxycarbonyl) (ethyl) amino) ethyl) amino) -4-chlorobenzoic acid (55 mg, 0.124 mmol), benzotris Azozol-1-yloxy-tris (tetrahydropyrrolyl) phosphonium hexafluorophosphate (PyBOP, 88 mg, 0.170 mmol), DIPEA (44 mg, 0.339 mmol) and dry DMSO (3 mL) were added to the reaction flask and stirred at room temperature The reaction was carried out for 15 hours. After the reaction was completed, the reaction solution was poured into water, extracted with ethyl acetate (10 mL x 3), and the organic layers were combined, followed by saturated aqueous ammonium chloride solution (10 mL x 3), water (10 mL), and saturated chloride. It was washed with aqueous sodium solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer (developing solvent: dichloromethane / methanol = 10: 1 v / v) to obtain (2-((tert Butoxycarbonyl) (ethyl) amino) ethyl) (5-chloro-2-((4- (N- (2,4-dimethoxybenzyl) -N- (1,2,4-thia Diazol-5-yl) sulfonamido) -2,5-difluorophenyl) carbamoyl) phenyl) carbamic acid tert-butyl ester, yield 45.0%, ESI-MS (m / z): 867.1 [ M + H] + .
步骤i)：N-(4-(N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯基)-4-氯-2-((2-乙基氨基)乙基)氨基)苯甲酰胺的制备Step i): N- (4- (N- (1,2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorophenyl) -4-chloro-2-(( Preparation of 2-ethylamino) ethyl) amino) benzamide
操作过程同实施例1中的步骤f，只是将(2-((5-氯-2-(((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯基)氨基)甲基)苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯用(2-((叔丁氧羰基)(乙基)氨基)乙基)(5-氯-2-((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯基)氨甲酰基)苯基)氨基甲酸叔丁酯替代，得N-(4-(N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯基)-4-氯-2-((2-乙基氨基)乙基)氨基)苯甲酰胺，ESI-MS(m/z)：517.0[M+H] +。 The operation process is the same as step f in Example 1, except that (2-((5-chloro-2-(((4- (N- (2,4-dimethoxybenzyl) -N- (1, 2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorophenyl) amino) methyl) phenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester (2-((tert-butoxycarbonyl) (ethyl) amino) ethyl) (5-chloro-2-((4- (N- (2,4-dimethoxybenzyl) -N- (1 , 2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorophenyl) carbamoyl) phenyl) carbamic acid tert-butyl ester to obtain N- (4- (N- (1,2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorophenyl) -4-chloro-2-((2-ethylamino) ethyl) amino) benzene Formamide, ESI-MS (m / z): 517.0 [M + H] + .
实施例59Example 59
4-(N-(1,2,4-噻二唑-5-基)磺酰胺基)-N-(4-氯-2-((2-(乙氨基)乙基)氨基)苯基)-2,5-二氟-苯甲酰胺的制备4- (N- (1,2,4-thiadiazol-5-yl) sulfonamido) -N- (4-chloro-2-((2- (ethylamino) ethyl) amino) phenyl) -2,5-difluoro-benzamide
Figure PCTCN2019104852-appb-000067
Figure PCTCN2019104852-appb-000067
步骤a)：(2-((5-氯-2-硝基苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯的制备Step a): Preparation of (2-((5-chloro-2-nitrophenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester
操作过程同实施例1中的的步骤a，只是将4-氯-2-氟苯甲腈用4-氯-2-氟-1-硝基苯替代，得(2-((5-氯-2-硝基苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯。The operation process is the same as step a in Example 1, except that 4-chloro-2-fluorobenzonitrile is replaced with 4-chloro-2-fluoro-1-nitrobenzene to obtain (2-((5-chloro- 2-nitrophenyl) amino) ethyl) (ethyl) -t-butyl carbamate.
步骤b)：(2-((叔丁氧羰基)(5-氯-2-硝基苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯的制备Step b): Preparation of (2-((tert-butoxycarbonyl) (5-chloro-2-nitrophenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester
操作过程同实施例36中的步骤b，只是将(2-((5-氯-2-氰基苯基)氨基)乙基)(乙基)氨基甲酸叔丁酯用(2-((5-氯-2-硝基苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯替代，得(2-((叔丁氧羰基)(5-氯-2-硝基苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯。The operation was the same as step b in Example 36, except that (2-((5-chloro-2-cyanophenyl) amino) ethyl) (ethyl) carbamic acid tert-butyl ester was used (2-((5 -Chloro-2-nitrophenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester to obtain (2-((tert-butoxycarbonyl) (5-chloro-2-nitrophenyl) Amino) ethyl) (ethyl) -t-butyl carbamate.
步骤c)：(2-((2-氨基-5-氯苯基)(叔丁氧羰基)氨基)乙基)(乙基)-氨基甲酸叔丁酯的制备Step c): Preparation of (2-((2-amino-5-chlorophenyl) (tert-butoxycarbonyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester
将(2-((叔丁氧羰基)(5-氯-2-硝基苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯(2.0g，4.505mmol)和乙醇(60mL)加入反应瓶中，搅拌溶解，加入饱和的氯化铵(20mL)，再加入锌粉(1.47g，22.530mmol)，升温至50℃搅拌反应15小时，冷却至室温，经过硅胶垫过滤除去不溶固体，滤饼用乙酸乙酯(100mL)洗涤，合并滤液，用乙酸乙酯(100mL)和水(200mL)萃取，有机层用饱和氯化钠水溶液(200mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得粗品经硅胶柱层析纯化洗脱剂：石油醚/乙酸乙酯＝1:1v/v)，得(2-((2-氨基-5-氯苯基)(叔丁氧羰基)氨基)乙基)(乙基)-氨基甲酸叔丁酯，收率67.0％，ESI-MS(m/z)：414.3[M+H] +。 (2-((tert-Butoxycarbonyl) (5-chloro-2-nitrophenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester (2.0 g, 4.505 mmol) and ethanol (60 mL) Add to the reaction flask, stir and dissolve, add saturated ammonium chloride (20mL), and then add zinc powder (1.47g, 22.530mmol), warm to 50 ° C and stir for 15 hours, cool to room temperature, and filter through silica gel pad to remove insoluble solids The filter cake was washed with ethyl acetate (100 mL), the filtrates were combined, extracted with ethyl acetate (100 mL) and water (200 mL), and the organic layer was washed with a saturated sodium chloride aqueous solution (200 mL), dried over anhydrous sodium sulfate, and filtered, It was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column eluent: petroleum ether / ethyl acetate = 1: 1 v / v) to obtain (2-((2-amino-5-chlorophenyl) (tert-butoxy Carbonyl) amino) ethyl) (ethyl) -t-butyl carbamate, yield 67.0%, ESI-MS (m / z): 414.3 [M + H] + .
步骤d)：4-(苄硫基)-2,5-二氟苯甲酸的制备Step d): Preparation of 4- (benzylthio) -2,5-difluorobenzoic acid
将2,4,5-三氟苯甲酸(10.0g，56.789mmol)和DMF(100mL)加入反应瓶中，加入Cs 2CO 3(37.0g，113.578mmol)和苯甲硫醇(7.05g，56.789mmol)，升温至70℃反应5小时，反应结束后，冷却至室温后倾入水(1500mL)中，以乙酸乙酯(150mL x 3)萃取，水层用4N HCI(aq)调至pH＝1，析出的固体经过滤干燥得4-(苄硫基)-2,5-二氟苯甲酸，收率75.6％，ESI-MS(m/z)：281.0[M+H] +。 Add 2,4,5-trifluorobenzoic acid (10.0 g, 56.789 mmol) and DMF (100 mL) to the reaction flask, add Cs 2 CO 3 (37.0 g, 113.578 mmol) and benzothiol (7.05 g, 56.789 mmol), warmed to 70 ° C and reacted for 5 hours. After the reaction, cooled to room temperature, poured into water (1500 mL), and extracted with ethyl acetate (150 mL x 3). The aqueous layer was adjusted to pH = 1 with 4N HCI (aq). The precipitated solid was filtered and dried to obtain 4- (benzylthio) -2,5-difluorobenzoic acid. The yield was 75.6%. ESI-MS (m / z): 281.0 [M + H] + .
步骤e)：4-(苄硫基)-2,5-二氟苯甲酸甲酯的制备Step e): Preparation of methyl 4- (benzylthio) -2,5-difluorobenzoate
将4-(苄硫基)-2,5-二氟苯甲酸(12.0g，42.813mmol)和甲醇(100mL)加入反应瓶中，缓慢滴加浓H 2SO 4(840mg，8.563mmol)，加毕，升温至回流反应48小时，减压浓缩，用乙酸乙酯(200mL)稀释，依次用水(50mL)、饱和NaHCO 3水溶液(50mL)、饱和氯化钠水溶液(50mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，得4-(苄硫基)-2,5-二氟苯甲酸甲酯，收率90.2％，ESI-MS(m/z)：295.0[M+H] +。 Add 4- (benzylthio) -2,5-difluorobenzoic acid (12.0 g, 42.813 mmol) and methanol (100 mL) to the reaction flask, slowly add concentrated H 2 SO 4 (840 mg, 8.563 mmol) dropwise, and add After completion of the reaction, the reaction mixture was heated to reflux for 48 hours, concentrated under reduced pressure, diluted with ethyl acetate (200 mL), washed with water (50 mL), saturated aqueous NaHCO 3 solution (50 mL), and saturated aqueous sodium chloride solution (50 mL), and anhydrous sodium sulfate Dry, filter, and concentrate under reduced pressure to obtain methyl 4- (benzylthio) -2,5-difluorobenzoate. The yield was 90.2%. ESI-MS (m / z): 295.0 [M + H] + .
步骤f)：4-(氯磺酰基)-2,5-二氟苯甲酸甲酯的制备Step f): Preparation of methyl 4- (chlorosulfonyl) -2,5-difluorobenzoate
将4-(苄硫基)-2,5-二氟苯甲酸甲酯(8.0g，27.181mmol)和二氯甲烷(240mL)加入反应瓶中，在0℃充分搅拌下缓慢滴加HCl(4N，220.00mL)和NaClO(7.08g，95.134mmol)，在0℃反应1小时后升温至10℃反应12小时，反应结束后，分取有机层，减压浓缩，所得 粗品在-30℃用石油醚(16mL)超声打浆，得4-(氯磺酰基)-2,5-二氟苯甲酸甲酯，收率50.5％，ESI-MS(m/z):271.0[M+H] +。 Methyl 4- (benzylthio) -2,5-difluorobenzoate (8.0 g, 27.181 mmol) and dichloromethane (240 mL) were added to the reaction flask, and HCl (4N) was slowly added dropwise with sufficient stirring at 0 ° C. (220.00mL) and NaClO (7.08g, 95.134mmol), reacted at 0 ° C for 1 hour, and then heated to 10 ° C for 12 hours. After the reaction was completed, the organic layer was separated and concentrated under reduced pressure. The obtained crude product was -30 ° C with petroleum Ether (16 mL) was ultrasonically beaten to obtain methyl 4- (chlorosulfonyl) -2,5-difluorobenzoate. The yield was 50.5%. ESI-MS (m / z): 271.0 [M + H] + .
步骤g)：4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟-苯甲酸甲酯的制备Step g): 4- (N- (2,4-dimethoxybenzyl) -N- (1,2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluoro -Preparation of methyl benzoate
操作过程同实施例1中的步骤d，只是将2,4,5-三氟-苯磺酰氯用4-(氯磺酰基)-2,5-二氟苯甲酸甲酯替代，得到4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯甲酸甲酯。The operation process is the same as step d in Example 1, except that 2,4,5-trifluoro-benzenesulfonyl chloride is replaced with 4- (chlorosulfonyl) -2,5-difluorobenzoic acid methyl ester to obtain 4- ( N- (2,4-dimethoxybenzyl) -N- (1,2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorobenzoate.
步骤h)：4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯甲酸的制备Step h): 4- (N- (2,4-dimethoxybenzyl) -N- (1,2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluoro Preparation of benzoic acid
将4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯甲酸甲酯(2.5g，5.150mmol)和LiOH.H 2O(324mg，7.724mmol)加入到THF(20mL)和水(10mL)中，10℃反应1小时，反应结束后，以10％甲醇和二氯甲烷的混合溶液(500mL x 3)萃取，合并有机层，用饱和氯化钠洗涤，无水硫酸钠干燥，过滤，减压浓缩，得4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯甲酸，收率90.2％，ESI-MS(m/z)：472.0[M+H] +。 4- (N- (2,4-dimethoxybenzyl) -N- (1,2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorobenzoate Esters (2.5 g, 5.150 mmol) and LiOH.H 2 O (324 mg, 7.724 mmol) were added to THF (20 mL) and water (10 mL), and reacted at 10 ° C. for 1 hour. After the reaction was completed, 10% methanol and dichloride Extracted from a mixed solution of methane (500 mL x 3), combined the organic layers, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4- (N- (2,4-dimethoxybenzyl) ) -N- (1,2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorobenzoic acid, yield 90.2%, ESI-MS (m / z): 472.0 [ M + H] + .
步骤i)：(2-((叔丁氧羰基)(乙基)氨基)乙基)(5-氯-2-(4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯甲酰胺)苯基)氨基甲酸叔丁酯的制备Step i): (2-((tert-butoxycarbonyl) (ethyl) amino) ethyl) (5-chloro-2- (4- (N- (2,4-dimethoxybenzyl) -N -(1,2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorobenzamide) phenyl) carbamic acid tert-butyl ester
将4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯甲酸(50mg,0.106mmol)、(2-((2-氨基-5-氯苯基)(叔丁氧羰基)氨基)乙基)(乙基)-氨基甲酸叔丁酯(44mg,0.106mmol)、苯并三氮唑-1-基氧-三(四氢吡咯基)鏻鎓六氟磷酸盐(PyBOP，110mg，0.212mmol)、DIPEA(41mg，0.318mmol)和干燥DMSO(3mL)加入反应瓶中，室温搅拌反应20小时，反应结束后，将反应液倾入水中，乙酸乙酯萃取(10mL x 3)，合并有机层，依次用饱和氯化铵溶液(10mL x 3)、水(10mL)、饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得粗品经制备薄层纯化(展开剂：二氯甲烷/甲醇＝20：1v/v)，得(2-((叔丁氧羰基)(乙基)氨基)乙基)(5-氯-2-(4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯甲酰胺)苯基)氨基甲酸叔丁酯，收率40.1％，ESI-MS(m/z):867.2[M+H] +。 4- (N- (2,4-dimethoxybenzyl) -N- (1,2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorobenzoic acid ( 50mg, 0.106mmol), (2-((2-amino-5-chlorophenyl) (tert-butoxycarbonyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester (44mg, 0.106mmol), benzene Pyridazol-1-yloxy-tris (tetrahydropyrrolyl) phosphonium hexafluorophosphate (PyBOP, 110 mg, 0.212 mmol), DIPEA (41 mg, 0.318 mmol) and dry DMSO (3 mL) were added to the reaction flask. The reaction was stirred at room temperature for 20 hours. After the reaction was completed, the reaction solution was poured into water, extracted with ethyl acetate (10 mL x 3), and the organic layers were combined, followed by saturated ammonium chloride solution (10 mL x 3), water (10 mL), and saturated. It was washed with sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer (developing solvent: dichloromethane / methanol = 20: 1 v / v) to obtain (2- ( (Tert-butoxycarbonyl) (ethyl) amino) ethyl) (5-chloro-2- (4- (N- (2,4-dimethoxybenzyl) -N- (1,2,4- Thiadiazol-5-yl) sulfonamido) -2,5-difluorobenzamide) phenyl) carbamic acid tert-butyl ester, yield 40.1%, ESI-MS (m / z): 867.2 [M + H] + .
步骤j)：4-(N-(1,2,4-噻二唑-5-基)磺酰胺基)-N-(4-氯-2-((2-(乙氨基)乙基)氨基)苯基)-2,5-二氟苯甲酰胺的制备Step j): 4- (N- (1,2,4-thiadiazol-5-yl) sulfonamido) -N- (4-chloro-2-((2- (ethylamino) ethyl) amino ) Phenyl) -2,5-difluorobenzamide
操作过程同实施例1中的步骤f，只是将(2-((5-氯-2-(((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯基)氨基)甲基)苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯用(2-((叔丁氧羰基)(乙基)氨基)乙基)(5-氯-2-(4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺 酰胺基)-2,5-二氟苯甲酰胺)苯基)-氨基甲酸叔丁酯替代，得到4-(N-(1,2,4-噻二唑-5-基)磺酰胺基)-N-(4-氯-2-((2-(乙氨基)乙基)氨基)苄基)-2,5-二氟苯甲酰胺，ESI-MS(m/z)：517.1[M+H] +。 The operation process is the same as step f in Example 1, except that (2-((5-chloro-2-(((4- (N- (2,4-dimethoxybenzyl) -N- (1, 2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorophenyl) amino) methyl) phenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester (2-((tert-butoxycarbonyl) (ethyl) amino) ethyl) (5-chloro-2- (4- (N- (2,4-dimethoxybenzyl) -N- (1, 2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorobenzamide) phenyl) -carbamic acid tert-butyl ester to give 4- (N- (1,2,4 -Thiadiazol-5-yl) sulfonamido) -N- (4-chloro-2-((2- (ethylamino) ethyl) amino) benzyl) -2,5-difluorobenzamide, ESI-MS (m / z): 517.1 [M + H] + .
实施例60Example 60
4-((4-氯-2-((2-(乙氨基)乙基)氨基)苯基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备4-((4-chloro-2-((2- (ethylamino) ethyl) amino) phenyl) amino) -2,5-difluoro-N- (1,2,4-thiadiazole-5 -Yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000068
Figure PCTCN2019104852-appb-000068
步骤a)：4-溴-N-(2,4-二甲氧基苄基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备Step a): 4-bromo-N- (2,4-dimethoxybenzyl) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonate Preparation of amide
操作过程同实施例1中的步骤d，只是将2,4,5-三氟-苯磺酰氯用4-溴-2,5-二氟-苯磺酰氯代替，得4-溴-N-(2,4-二甲氧基苄基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺。The operation was the same as step d in Example 1, except that 2,4,5-trifluoro-benzenesulfonyl chloride was replaced with 4-bromo-2,5-difluoro-benzenesulfonyl chloride to obtain 4-bromo-N- ( 2,4-dimethoxybenzyl) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide.
步骤b)：(2-((叔丁氧羰基)(乙基)氨基)乙基)(5-氯-2-((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯基)氨基)苯基)-氨基甲酸叔丁酯的制备Step b): (2-((tert-butoxycarbonyl) (ethyl) amino) ethyl) (5-chloro-2-((4- (N- (2,4-dimethoxybenzyl)- Preparation of N- (1,2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorophenyl) amino) phenyl) -carbamic acid tert-butyl ester
将(2-((2-氨基-5-氯苯基)(叔丁氧羰基)氨基)乙基)(乙基)-氨基甲酸叔丁酯(450mg，1.087mmol)、4-溴-N-(2,4-二甲氧基苄基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺(660mg，1.304mmol)、Pd(OAc) 2(24mg，0.109mmol)、BINAP(136mg，0.218mmol)和Cs 2CO 3(1.06g，3.261mmol)分散到干燥的二氧六环(10mL)中，氮气保护回流反应15小时，反应结束后，冷却至室温，过滤，滤饼以乙酸乙酯(50mL)洗涤，再加入乙酸乙酯(50mL)和水(100mL)，萃取，有机层用饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20:1v/v)，得(2-((叔丁氧羰基)(乙基)氨基)乙基)(5-氯-2-((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯基)氨基)苯基)-氨基甲酸叔丁酯，收率66.5％。ESI-MS(m/z)：839.2[M+H] +。 Tert-Butyl (2-((2-amino-5-chlorophenyl) (tert-butoxycarbonyl) amino) ethyl) (ethyl) -carbamic acid (450 mg, 1.087 mmol), 4-bromo-N- (2,4-dimethoxybenzyl) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide (660 mg, 1.304 mmol), Pd ( OAc) 2 (24 mg, 0.109 mmol), BINAP (136 mg, 0.218 mmol) and Cs 2 CO 3 (1.06 g, 3.261 mmol) were dispersed in dry dioxane (10 mL), and the reaction was carried out under nitrogen at reflux for 15 hours. After finishing, cool to room temperature, filter, wash the filter cake with ethyl acetate (50 mL), add ethyl acetate (50 mL) and water (100 mL), extract, and wash the organic layer with saturated sodium chloride solution (100 mL). It was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20: 1 v / v) to obtain (2-((tert-butoxycarbonyl) (ethyl (Yl) amino) ethyl) (5-chloro-2-((4- (N- (2,4-dimethoxybenzyl) -N- (1,2,4-thiadiazol-5-yl ) Sulfonamido) -2,5-difluorophenyl) amino) phenyl) -carbamic acid tert-butyl ester, yield 66.5%. ESI-MS (m / z): 839.2 [M + H] + .
步骤c)：4-((4-氯-2-((2-(乙氨基)乙基)氨基)苯基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备Step c): 4-((4-chloro-2-((2- (ethylamino) ethyl) amino) phenyl) amino) -2,5-difluoro-N- (1,2,4-thia Preparation of Diazol-5-yl) -benzenesulfonamide
操作过程同实施例1中的步骤f，只是将(2-((5-氯-2-(((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4- 噻二唑-5-基)磺酰胺基)-2,5-二氟苯基)氨基)甲基)苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯用(2-((叔丁氧羰基)(乙基)氨基)乙基)(5-氯-2-((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯基)氨基)苯基)-氨基甲酸叔丁酯替代，得4-((4-氯-2-((2-(乙氨基)乙基)氨基)苯基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺，ESI-MS(m/z):489.1[M+H] +。 The operation process is the same as step f in Example 1, except that (2-((5-chloro-2-(((4- (N- (2,4-dimethoxybenzyl) -N- (1, For 2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorophenyl) amino) methyl) phenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester (2-((tert-butoxycarbonyl) (ethyl) amino) ethyl) (5-chloro-2-((4- (N- (2,4-dimethoxybenzyl) -N- (1 , 2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorophenyl) amino) phenyl) -carbamic acid tert-butyl ester to obtain 4-((4-chloro-2 -((2- (ethylamino) ethyl) amino) phenyl) amino) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide, ESI -MS (m / z): 489.1 [M + H] + .
实施例61Example 61
4-(N-(1,2,4-噻二唑-5-基)磺酰胺基)-N-(4-氯-2-((2-(乙氨基)乙基)氨基)苄基)-2,5-二氟-苯甲酰胺的制备4- (N- (1,2,4-thiadiazol-5-yl) sulfonamido) -N- (4-chloro-2-((2- (ethylamino) ethyl) amino) benzyl) -2,5-difluoro-benzamide
Figure PCTCN2019104852-appb-000069
Figure PCTCN2019104852-appb-000069
步骤a)：(2-((5-氯-2-((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯甲酰胺)甲基)苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯的制备Step a): (2-((5-chloro-2-((4- (N- (2,4-dimethoxybenzyl) -N- (1,2,4-thiadiazole-5- Sulfonamide) -2,5-difluorobenzamide) methyl) phenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester
将(2-((2-(氨甲基)-5-氯苯基)氨基)乙基)(乙基)氨基甲酸叔丁酯的(150mg，0.458mmol)、4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯甲酸(238mg，0.504mmol)、HATU(261mg，0.687mmol)、DIPEA(118mg，0.916mmol)和干燥DMSO(5mL)加入反应瓶中，氮气保护下25℃反应20小时，反应结束后，向反应体系加入饱和氯化铵溶液(20mL)，以乙酸乙酯(20mL x 3)萃取，合并有机层，用饱和氯化钠(30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得粗品经制备薄层纯化(展开剂：二氯甲烷/甲醇＝20:1v/v)，得(2-((5-氯-2-((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯甲酰胺)甲基)苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯，收率40.2％，ESI-MS(m/z):781.1[M+H] +。 Tert-butyl (2-((2- (aminomethyl) -5-chlorophenyl) amino) ethyl) (ethyl) carbamate (150 mg, 0.458 mmol), 4- (N- (2, 4-dimethoxybenzyl) -N- (1,2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorobenzoic acid (238 mg, 0.504 mmol), HATU (261 mg , 0.687 mmol), DIPEA (118 mg, 0.916 mmol) and dry DMSO (5 mL) were added to the reaction flask, and reacted at 25 ° C for 20 hours under nitrogen protection. After the reaction was completed, a saturated ammonium chloride solution (20 mL) was added to the reaction system to Extracted with ethyl acetate (20 mL x 3), combined organic layers, washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by preparing a thin layer (developing solvent: dichloromethane / Methanol = 20: 1v / v) to obtain (2-((5-chloro-2-((4- (N- (2,4-dimethoxybenzyl) -N- (1,2,4 -Thiadiazol-5-yl) sulfonamido) -2,5-difluorobenzamide) methyl) phenyl) amino) ethyl) (ethyl) -t-butyl carbamate, yield 40.2% , ESI-MS (m / z): 781.1 [M + H] + .
步骤b)：4-(N-(1,2,4-噻二唑-5-基)磺酰胺基)-N-(4-氯-2-((2-(乙氨基)乙基)氨基)苄基)-2,5-二氟-苯甲酰胺的制备Step b): 4- (N- (1,2,4-thiadiazol-5-yl) sulfonamido) -N- (4-chloro-2-((2- (ethylamino) ethyl) amino ) Benzyl) -2,5-difluoro-benzamide
操作过程同实施例1中的步骤f，只是将(2-((5-氯-2-(((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4- 噻二唑-5-基)磺酰胺基)-2,5-二氟苯基)氨基)甲基)苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯用(2-((5-氯-2-((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯甲酰胺)甲基)苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯替代，得4-(N-(1,2,4-噻二唑-5-基)磺酰胺基)-N-(4-氯-2-((2-(乙氨基)乙基)氨基)苄基)-2,5-二氟-苯甲酰胺，ESI-MS(m/z)：531.0[M+H] +。 The operation process is the same as step f in Example 1, except that (2-((5-chloro-2-(((4- (N- (2,4-dimethoxybenzyl) -N- (1, For 2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorophenyl) amino) methyl) phenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester (2-((5-chloro-2-((4- (N- (2,4-dimethoxybenzyl) -N- (1,2,4-thiadiazol-5-yl) sulfonamide Group) -2,5-difluorobenzamide) methyl) phenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester to obtain 4- (N- (1,2,4-thiophene) Diazol-5-yl) sulfonamido) -N- (4-chloro-2-((2- (ethylamino) ethyl) amino) benzyl) -2,5-difluoro-benzamide, ESI -MS (m / z): 531.0 [M + H] + .
实施例62Example 62
N-(4-(N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苄基)-4-氯-2-((2-(乙氨基)乙基)氨基)-苯甲酰胺的制备N- (4- (N- (1,2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorobenzyl) -4-chloro-2-((2- (ethyl Preparation of amino) ethyl) amino) -benzamide
Figure PCTCN2019104852-appb-000070
Figure PCTCN2019104852-appb-000070
步骤a)：4-氰基-N-(2,4-二甲氧基苄基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)苯磺酰胺的制备Step a): 4-cyano-N- (2,4-dimethoxybenzyl) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl) benzenesulfonate Preparation of amide
将N-(2,4-二甲氧基苄基)-2,4,5-三氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺(500mg，1.122mmol)、氰化钠(72mg，1.459mmol)和DMF(5mL)加入反应瓶中，室温搅拌反应12小时，将反应液倾入水中，以乙酸乙酯萃取(20mL x 3)，合并有机层，依次用水(10mL x 2)、饱和氯化钠(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5:1v/v)，得4-氰基-N-(2,4-二甲氧基苄基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)苯磺酰胺，收率70.5％，ESI-MS(m/z)：453.1[M+H] +。 N- (2,4-dimethoxybenzyl) -2,4,5-trifluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide (500 mg, 1.122 mmol), sodium cyanide (72 mg, 1.459 mmol) and DMF (5 mL) were added to the reaction flask, and the reaction was stirred at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate (20 mL x 3). It was washed with water (10 mL x 2) and saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 : 1v / v) to give 4-cyano-N- (2,4-dimethoxybenzyl) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl ) Benzenesulfonamide, yield 70.5%, ESI-MS (m / z): 453.1 [M + H] + .
步骤b)：4-(氨甲基)-N-(2,4-二甲氧基苄基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备Step b): 4- (aminomethyl) -N- (2,4-dimethoxybenzyl) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl ) -Benzenesulfonamide
操作过程同实施例1中的步骤b，只是将(2-((5-氯-2-氰基苯基)氨基)乙基)(乙基)氨基甲酸叔丁酯用4-氰基-N-(2,4-二甲氧基苄基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)苯磺酰胺替代，得4-(氨甲基)-N-(2,4-二甲氧基苄基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺。The operation was the same as step b in Example 1, except that (2-((5-chloro-2-cyanophenyl) amino) ethyl) (ethyl) carbamic acid tert-butyl ester was treated with 4-cyano-N -(2,4-dimethoxybenzyl) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl) benzenesulfonamide substitution to give 4- (aminomethyl ) -N- (2,4-dimethoxybenzyl) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide.
步骤c)：(2-((5-氯-2-((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苄基)氨甲酰基)苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯的制备Step c): (2-((5-chloro-2-((4- (N- (2,4-dimethoxybenzyl) -N- (1,2,4-thiadiazole-5- Sulfonamide) -2,5-difluorobenzyl) carbamoyl) phenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester
将4-(氨甲基)-N-(2,4-二甲氧基苄基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺(100mg，0.219mmol)、2-((2-((叔丁氧羰基)(乙基)氨基)乙基)氨基)-4-氯-苯甲酸(83mg，0.241mmol)、 HATU(125mg，0.329mmol)、DIPEA(57mg，0.438mmol)和干燥DMSO(3mL)加入反应瓶中，氮气保护下25℃反应15小时，反应结束后，向反应体系加入饱和氯化铵溶液(10mL)，以乙酸乙酯(10mL x 3)萃取，合并有机层，用饱和氯化钠(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得粗品经制备薄层纯化(展开剂：二氯甲烷/甲醇＝20:1v/v)，得(2-((5-氯-2-((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苄基)氨甲酰基)苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯，收率44.8％，ESI-MS(m/z):781.1[M+H] +。 4- (Aminomethyl) -N- (2,4-dimethoxybenzyl) -2,5-difluoro-N- (1,2,4-thiadiazol-5-yl) -benzene Sulfonamide (100 mg, 0.219 mmol), 2-((2-((tert-butoxycarbonyl) (ethyl) amino) ethyl) amino) -4-chloro-benzoic acid (83 mg, 0.241 mmol), HATU (125 mg , 0.329 mmol), DIPEA (57 mg, 0.438 mmol) and dry DMSO (3 mL) were added to the reaction flask, and reacted at 25 ° C for 15 hours under nitrogen protection. After the reaction was completed, a saturated ammonium chloride solution (10 mL) was added to the reaction system to Extracted with ethyl acetate (10 mL x 3), combined the organic layers, washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by preparing a thin layer (developing solvent: dichloromethane / Methanol = 20: 1v / v) to obtain (2-((5-chloro-2-((4- (N- (2,4-dimethoxybenzyl) -N- (1,2,4 -Thiadiazol-5-yl) sulfonamido) -2,5-difluorobenzyl) carbamoyl) phenyl) amino) ethyl) (ethyl) -t-butyl carbamate, yield 44.8% , ESI-MS (m / z): 781.1 [M + H] + .
步骤d)：N-(4-(N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苄基)-4-氯-2-((2-(乙氨基)乙基)氨基)-苯甲酰胺的制备Step d): N- (4- (N- (1,2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorobenzyl) -4-chloro-2-(( Preparation of 2- (ethylamino) ethyl) amino) -benzamide
操过程同实施例1中的步骤f，只是将(2-((5-氯-2-(((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苯基)氨基)甲基)苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯用(2-((5-氯-2-((4-(N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苄基)氨甲酰基)苯基)氨基)乙基)(乙基)-氨基甲酸叔丁酯，得N-(4-(N-(1,2,4-噻二唑-5-基)磺酰胺基)-2,5-二氟苄基)-4-氯-2-((2-(乙氨基)乙基)氨基)-苯甲酰胺，ESI-MS(m/z)：531.0[M+H] +。 The procedure is the same as step f in Example 1, except that (2-((5-chloro-2-(((4- (N- (2,4-dimethoxybenzyl) -N- (1, 2,4-thiadiazol-5-yl) sulfonamido) -2,5-difluorophenyl) amino) methyl) phenyl) amino) ethyl) (ethyl) -carbamic acid tert-butyl ester (2-((5-chloro-2-((4- (N- (2,4-dimethoxybenzyl) -N- (1,2,4-thiadiazol-5-yl) sulfonamide ) -2,5-difluorobenzyl) carbamoyl) phenyl) amino) ethyl) (ethyl) -t-butyl carbamate to give N- (4- (N- (1,2,4 -Thiadiazol-5-yl) sulfonamido) -2,5-difluorobenzyl) -4-chloro-2-((2- (ethylamino) ethyl) amino) -benzamide, ESI- MS (m / z): 531.0 [M + H] + .
实施例63Example 63
4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备4-((4-chloro-2-((2- (ethylamino) ethyl) amino) benzyl) amino) -N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide Preparation
Figure PCTCN2019104852-appb-000071
Figure PCTCN2019104852-appb-000071
操作过程同实施例1，只是将步骤d中的2,4,5-三氟苯基-1-磺酰氯用4-氟苯基-1-磺酰氯替代，得4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-N-(1,2,4-噻二唑-5-基)-苯磺酰胺，ESI-MS(m/z):467.1[M+H] +。 The operation was the same as in Example 1, except that 2,4,5-trifluorophenyl-1-sulfonyl chloride in step d was replaced with 4-fluorophenyl-1-sulfonyl chloride to obtain 4-((4-chloro- 2-((2- (ethylamino) ethyl) amino) benzyl) amino) -N- (1,2,4-thiadiazol-5-yl) -benzenesulfonamide, ESI-MS (m / z ): 467.1 [M + H] + .
实施例64Example 64
4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-2-氟-5-氰基-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备4-((4-chloro-2-((2- (ethylamino) ethyl) amino) benzyl) amino) -2-fluoro-5-cyano-N- (1,2,4-thiadiazole -5-yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000072
Figure PCTCN2019104852-appb-000072
操作过程同实施例1，只是将步骤d中的2,4,5-三氟-苯磺酰氯用5-氰基-2,4-二氟苯-1-磺酰氯替代，得4-((4-氯-2-((2-(乙氨基)乙基)氨基)苄基)氨基)-2-氟-5-氰基-N-(1,2,4-噻二唑-5-基)-苯磺酰胺，ESI-MS(m/z):510.0[M+H] +。 The operation was the same as in Example 1, except that 2,4,5-trifluoro-benzenesulfonyl chloride in step d was replaced with 5-cyano-2,4-difluorobenzene-1-sulfonyl chloride to obtain 4-(( 4-chloro-2-((2- (ethylamino) ethyl) amino) benzyl) amino) -2-fluoro-5-cyano-N- (1,2,4-thiadiazol-5-yl ) -Benzenesulfonamide, ESI-MS (m / z): 510.0 [M + H] + .
实施例65Example 65
4-((4-氯-2-((2-(3-甲基吡咯-1-基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备4-((4-chloro-2-((2- (3-methylpyrrole-1-yl) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (1,2, Preparation of 4-thiadiazol-5-yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000073
Figure PCTCN2019104852-appb-000073
操作过程同实施例1，只是将步骤a中的(2-氨基乙基)(乙基)氨基甲酸叔丁酯用2-(3-甲基吡咯-1-基)乙胺替代，得4-((4-氯-2-((2-(3-甲基吡咯-1-基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺，ESI-MS(m/z):543.1[M+H] +。 The operation was the same as in Example 1, except that (2-aminoethyl) (ethyl) carbamic acid tert-butyl ester in step a was replaced with 2- (3-methylpyrrole-1-yl) ethylamine to obtain 4- ((4-chloro-2-((2- (3-methylpyrrole-1-yl) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (1,2,4- Thiadiazol-5-yl) -benzenesulfonamide, ESI-MS (m / z): 543.1 [M + H] + .
实施例66Example 66
4-((4-氯-2-((2-(4-甲基哌啶-1-基)乙基)氨基)苄基)氨基)-2,5-二氟-N-(1,2,4-噻二唑-5-基)-苯磺酰胺的制备4-((4-chloro-2-((2- (4-methylpiperidin-1-yl) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (1,2 , 4-thiadiazol-5-yl) -benzenesulfonamide
Figure PCTCN2019104852-appb-000074
Figure PCTCN2019104852-appb-000074
操作过程同实施例1，只是将步骤a中的(2-氨基乙基)(乙基)氨基甲酸叔丁酯用2-(4-甲基哌啶-1-基)乙胺替代，得4-((4-氯-2-((2-(4-甲基哌啶-1-基)乙基)氨基)苄基)氨基)-2,5-二氟 -N-(1,2,4-噻二唑-5-基)-苯磺酰胺，ESI-MS(m/z):557.1[M+H] +。 The operation was the same as in Example 1, except that (2-aminoethyl) (ethyl) carbamic acid tert-butyl ester in step a was replaced with 2- (4-methylpiperidin-1-yl) ethylamine to obtain 4 -((4-chloro-2-((2- (4-methylpiperidin-1-yl) ethyl) amino) benzyl) amino) -2,5-difluoro-N- (1,2, 4-thiadiazol-5-yl) -benzenesulfonamide, ESI-MS (m / z): 557.1 [M + H] + .
电生理学测定Electrophysiological measurement
膜片电压钳电生理学允许直接测量和定量电压门钠通道(NaV)的阻断，以及允许确定阻断的时间和电压依赖性，这已经被解释为与钠通道的静息状态、开启状态和失活状态的差异结合(Hille,B.et al.,Journal of General Physiology(1977),69:497-515)。Membrane voltage clamp electrophysiology allows direct measurement and quantification of blockade of voltage-gated sodium channels (NaV), as well as determination of time and voltage dependence of blockade, which has been interpreted as resting, open, and Differential binding of inactive states (Hille, B. et al., Journal of General Physiology (1977), 69: 497-515).
本发明的代表性化合物用转染特定离子通道的稳定HEK293细胞系(购自协和细胞库)，通过手动膜片钳试验测定化合物对离子通道电流的作用。The representative compound of the present invention is a stable HEK293 cell line (purchased from Kyowa Cell Bank) transfected with a specific ion channel, and the effect of the compound on the ion channel current is measured by a manual patch clamp test.
手动膜片钳实验方案如下：The manual patch clamp experiment protocol is as follows:
1)细胞培养1) Cell culture
Nav1.7Nav1.7
hNav1.7钠通道稳定表达的HEK293细胞系在含有10％胎牛血清及0.2mg/mL Hygromycin B的DMEM培养基中培养，培养温度为37℃，CO 2浓度为5％；当细胞生长到一定阶段后，进行细胞传代，其方法是除去旧培养基并用PBS洗一次，再加入1mL Trypsin-EDTA溶液，37℃孵育一分钟，当细胞从皿底分离，加入5mL 37℃预热的完全培养基，将细胞悬液用吸管轻轻吹打使聚集的细胞分离，将细胞悬液转移至无菌的离心管中，1000rmp离心5分钟收集细胞；用于扩增或维持培养，则将细胞接种于6cm细胞培养皿，每个细胞培养皿接种细胞量为2.5*10 5cells；膜片钳实验之前用Trypsin-EDTA分离，将3*10 3细胞铺到盖玻片上，在24孔板中培养(最终体积：500μL)，18小时后，进行实验检测。 The HEK293 cell line stably expressed by hNav1.7 sodium channel was cultured in DMEM medium containing 10% fetal bovine serum and 0.2 mg / mL Hygromycin B. The culture temperature was 37 ° C and the concentration of CO 2 was 5%. After the stage, the cells are passaged. The method is to remove the old medium and wash it once with PBS, then add 1 mL of Trypsin-EDTA solution, and incubate at 37 ° C for one minute. When the cells are separated from the bottom of the dish, add 5 mL of pre-warmed 37 ° C complete medium The cell suspension is gently blown with a pipette to separate the aggregated cells, the cell suspension is transferred to a sterile centrifuge tube, and the cells are collected by centrifugation at 1000 rpm for 5 minutes; for expansion or maintenance, the cells are seeded at 6 cm Cell culture dish, each cell culture dish is seeded with 2.5 * 10 5 cells; trypsin-EDTA was used to separate the patch-clamp experiments, 3 * 10 3 cells were spread on coverslips, and cultured in a 24-well plate (final Volume: 500 μL). After 18 hours, experimental detection was performed.
Nav1.5Nav1.5
hNav1.5钠通道稳定表达的CHO细胞系在含有10％胎牛血清的F12培养基中培养，培养温度为37℃，CO2浓度为5％；当细胞生长到一定阶段后，进行细胞传代，其方法是除去旧培养基并用PBS洗一次，再加入1mL de 0.25％-Trypsin-EDTA溶液，37℃孵育一分钟，当细胞从皿底分离，加入5mL 37℃预热的完全培养基，将细胞悬液用吸管轻轻吹打使聚集的细胞分离，将细胞悬液转移至无菌的离心管中，1000rmp离心5分钟收集细胞；用于扩增或维持培养，则将细胞接种于6cm细胞培养皿，每个细胞培养皿接种细胞量为2.5*105cells；膜片钳实验之前用Trypsin-EDTA分离，将3*10 3细胞铺到盖玻片上，在24孔板中培养(最终体积：500μL)，18小时后，进行实验检测。 The CHO cell line stably expressed by hNav1.5 sodium channel was cultured in F12 medium containing 10% fetal bovine serum at a culture temperature of 37 ° C and a CO2 concentration of 5%. After the cells had grown to a certain stage, the cells were passaged. The method is to remove the old medium and wash it once with PBS, then add 1mL de 0.25% -Trypsin-EDTA solution, and incubate for one minute at 37 ° C. When the cells are separated from the bottom of the dish, add 5mL of pre-warmed complete medium at 37 ° C and suspend the cells The solution was gently pipetted with a pipette to separate the aggregated cells, the cell suspension was transferred to a sterile centrifuge tube, and the cells were collected by centrifugation at 1000 rpm for 5 minutes; for expansion or maintenance, the cells were seeded in a 6 cm cell culture dish The amount of cells inoculated in each cell culture dish was 2.5 * 105 cells; before the patch-clamp experiment was separated with Trypsin-EDTA, 3 * 10 3 cells were spread on coverslips, and cultured in a 24-well plate (final volume: 500 μL), 18 After an hour, an experimental test was performed.
Nav1.3Nav1.3
hNav1.3钠通道稳定表达的HEK293细胞系在含有10％胎牛血清及1.2mg/mL G418的DMEM培养基中培养，培养温度为37℃，CO 2浓度为5％；当细胞生长到一定阶段后，进行 细胞传代，其方法是除去旧培养基并用PBS洗一次，再加入1mLTrypsin-EDTA溶液，37℃孵育一分钟，当细胞从皿底分离，加入5mL 37℃预热的完全培养基，将细胞悬液用吸管轻轻吹打使聚集的细胞分离，将细胞悬液转移至无菌的离心管中，1000rmp离心5分钟收集细胞；用于扩增或维持培养，则将细胞接种于6cm细胞培养皿，每个细胞培养皿接种细胞量为2.5*10 5cells；膜片钳实验之前用Trypsin-EDTA分离，将3*10 3细胞铺到盖玻片上，在24孔板中培养(最终体积：500μL)，18小时后，进行实验检测。 The HEK293 cell line stably expressed by hNav1.3 sodium channel was cultured in DMEM medium containing 10% fetal bovine serum and 1.2 mg / mL G418 at a culture temperature of 37 ° C and a CO 2 concentration of 5%; when the cells grew to a certain stage Then, passaging the cells, the method is to remove the old medium and wash it once with PBS, then add 1mL of Trypsin-EDTA solution, and incubate at 37 ° C for one minute. When the cells are separated from the bottom of the dish, add 5mL of pre-warmed 37 ° C complete medium The cell suspension is gently blown with a pipette to separate the aggregated cells, the cell suspension is transferred to a sterile centrifuge tube, and the cells are collected by centrifugation at 1000 rmp for 5 minutes; for expansion or maintenance, the cells are seeded in 6 cm cell culture The number of cells inoculated in each cell culture dish was 2.5 * 10 5 cells; before the patch-clamp experiment was separated with Trypsin-EDTA, 3 * 10 3 cells were spread on cover slips and cultured in 24-well plates (final volume: 500 μL), after 18 hours, experimental detection was performed.
2)制备化合物样品2) Preparation of compound samples
将本发明实施例中制备的化合物溶解于二甲亚砜(DMSO)并配成浓度为10mM的DMSO储备液用于实验。10mM的DMSO储备液用细胞外液(140mM NaCl，4mM KCl，1mM MgCl 2，2mM CaCl 2，5mM D-Glucose monohydrate，10mM HEPES，NaOH调节pH＝7.4)稀释至各种浓度，并使每种化合物中DMSO的最终浓度为0.1％或以下。 The compound prepared in the examples of the present invention was dissolved in dimethyl sulfoxide (DMSO) and prepared into a 10 mM DMSO stock solution for experiments. 10 mM DMSO stock solution was diluted to various concentrations with extracellular fluid (140 mM NaCl, 4 mM KCl, 1 mM MgCl 2 , 2 mM CaCl 2 , 5 mM D-Glucose monohydrate, 10 mM HEPES, NaOH adjusted pH = 7.4), and each compound The final concentration of medium DMSO is 0.1% or less.
3)膜片钳测量钠离子通道阻滞效应3) Patch clamp measurement of sodium ion channel block effect
全细胞膜片钳记录hNav1.7、hNav1.5和hNav1.3钠通道电流的电压刺激方案如下：当形成全细胞封接后细胞电压钳制于-120mV，钳制电压除极至0mV维持20毫秒，然后电压恢复至-75mV维持8秒，接着细胞膜电位恢复至-120mV，维持时间为20毫秒，然后再除极至0mV维持20毫秒，最后恢复至钳制电压-120mV，维持30毫秒，每隔20秒重复采集数据，观察药物对hNav1.7、hNav1.5和hNav1.3钠通道电流峰值的作用。The whole cell patch clamp records the hNav1.7, hNav1.5, and hNav1.3 sodium channel current voltage stimulation schemes as follows: When a whole cell seal is formed, the cell voltage is clamped at -120mV, the clamp voltage is depolarized to 0mV for 20 milliseconds, and then The voltage was restored to -75mV for 8 seconds, then the cell membrane potential was restored to -120mV for 20ms, then the depolarization was reduced to 0mV for 20ms, and finally the clamp voltage was returned to -120mV for 30ms, repeated every 20 seconds Data were collected to observe the effect of the drug on the peak currents of hNav1.7, hNav1.5 and hNav1.3 sodium channels.
用微电极拉制仪(P97，Sutter Instruments)将毛细玻璃管(BF150-86-10，Sutter Instruments)拉制成记录电极。在倒置显微镜(AE31E，Motic)下操纵微电极操纵仪(86PW420600，MCI Instruments)将记录电极接触到细胞上，给予负压抽吸，形成GΩ封接。形成GΩ封接后进行快速电容补偿，然后继续给予负压，吸破细胞膜，形成全细胞记录模式，然后进行慢速电容的补偿并记录膜电容及串联电阻。A capillary electrode tube (BF150-86-10, Sutter Instruments) was drawn into a recording electrode using a microelectrode drawing instrument (P97, Sutter Instruments). A microelectrode manipulator (86PW420600, MCI Instruments) was operated under an inverted microscope (AE31E, Motic) to contact the recording electrode with the cells, and suction was applied under negative pressure to form a GΩ seal. After forming a GΩ seal, perform fast capacitance compensation, then continue to apply negative pressure, suck through the cell membrane to form a whole-cell recording mode, and then perform slow capacitance compensation and record the membrane capacitance and series resistance.
当全细胞记录的hNav1.7、hNav1.5和hNav1.3电流稳定后开始给药，每个药物浓度作用至5分钟(或者电流至稳定)后检测下一个浓度，每一个测试化合物检测多个浓度。所有电生理实验在室温下进行。具体而言，每个化合物设置八个浓度，通过计算在用各浓度化合物处理细胞后产生的峰值电流相对于在用化合物处理之前产生的峰值电流的抑制百分比来确定化合物对钠通道的抑制百分比，并利用IGOR软件计算IC 50值。并如下评定化合物对hNav1.7、hNav1.5和hNav1.3的抑制IC 50： When the hNav1.7, hNav1.5, and hNav1.3 currents recorded in the whole cell are stabilized, dosing is started, and the next concentration is measured after each drug concentration is applied for 5 minutes (or the current is stabilized). Each test compound detects multiple concentration. All electrophysiological experiments were performed at room temperature. Specifically, eight concentrations were set for each compound, and the percentage inhibition of the sodium channel by the compound was determined by calculating the percentage inhibition of the peak current generated after treating the cells with each concentration of the compound relative to the peak current generated before the treatment with the compound. The IC 50 value was calculated using IGOR software. And compounds evaluated as follows hNav1.7, hNav1.5 hNav1.3 inhibition and IC 50:
hNav1.7：IC 50：+(>1μM)、++(100nM～1μM)、+++(50～100nM)、++++(<50nM) hNav1.7: IC 50 : + (> 1μM), ++ (100nM ～ 1μM), +++ (50 ～ 100nM), ++++ (<50nM)
hNav1.5：IC 50：+(>1μM)、++(100nM～1μM)、+++(50～100nM)、++++(<50nM) hNav1.5: IC 50 : + (> 1μM), ++ (100nM ～ 1μM), +++ (50 ～ 100nM), ++++ (<50nM)
hNav1.3：IC 50：+(>1μM)、++(100nM～1μM)、+++(50～100nM)、++++(<50nM) hNav1.3: IC 50 : + (> 1μM), ++ (100nM ～ 1μM), +++ (50 ～ 100nM), ++++ (<50nM)
结果表明，实施例中所有的化合物对与心脏功能障碍有关的hNav1.5钠通道的抑制活性的IC 50均大于10μM。而对hNav1.7和hNav1.3的抑制活性IC 50计算结果如下表2所示。 The results showed that all of the embodiments of the compounds to inhibit cardiac dysfunction associated with sodium channel activity hNav1.5 IC 50 greater than 10μM. While hNav1.7 and hNav1.3 inhibitory activity IC 50 results shown below in Table 2.
表2Table 2
实施例编号Example number IC 50(hNav1.7) IC 50 (hNav1.7) IC 50(hNav1.3) IC 50 (hNav1.3) 实施例编号Example number IC 50(hNav1.7) IC 50 (hNav1.7) IC 50(hNav1.3) IC 50 (hNav1.3)
实施例1Example 1 ++++++++ ++++++++ 实施例36Example 36 ++++++++ ++++++
实施例2Example 2 ++++++ ++++++++ 实施例37Example 37 ++++++ ++++++++
实施例3Example 3 ++++++++ ++++++++ 实施例38Example 38 ++++++++ ++++++++
实施例4Example 4 ++++++++ ++++++++ 实施例39Example 39 ++++++++ ++++++++
实施例5Example 5 ++++++++ ++++ 实施例40Example 40 ++++++++ ++++++++
实施例6Example 6 ++++++++ ++++++ 实施例41Example 41 ++++++++ ++++++++
实施例7Example 7 ++++++++ ++++++ 实施例42Example 42 ++++++++ ++++++++
实施例8Example 8 ++++++ ++++++++ 实施例43Example 43 ++++++++ ++++++++
实施例9Example 9 ++++ ++++++ 实施例44Example 44 ++++++++ ++++++++
实施例10Example 10 ++++++ ++++++ 实施例45Example 45 ++++++++ ++++++++
实施例11Example 11 ++++++++ ++++++++ 实施例46Example 46 ++++++ ++++++++
实施例12Example 12 ++++++++ ++++++ 实施例47Example 47 ++++++++ ++++++++
实施例13Example 13 ++++++++ ++++++ 实施例48Example 48 ++++++++ ++++++++
实施例14Example 14 ++++++ ++++++ 实施例49Example 49 ++++ ++++++++
实施例15Example 15 ++++++ ++++++++ 实施例50Example 50 ++++++ ++++
实施例16Example 16 ++++++ ++++++++ 实施例51Example 51 ++++++ ++++++
实施例17Example 17 ++++++++ ++++++++ 实施例52Example 52 ++++++ ++++++
实施例18Example 18 ++++++++ ++++++ 实施例53Example 53 ++++++ ++++
实施例19Example 19 ++++++++ ++++++++ 实施例54Example 54 ++++ ++++++
实施例20Example 20 ++++++++ ++++++++ 实施例55Example 55 ++++++ ++++++
实施例21Example 21 ++++++++ ++++++++ 实施例56Example 56 ++++ ++++++
实施例22Example 22 ++++++++ ++++++++ 实施例57Example 57 ++++ ++++++
实施例23Example 23 ++++++ ++++++++ 实施例58Example 58 ++ ++++
实施例24Example 24 ++++++++ ++++++++ 实施例59Example 59 ++ ++
实施例25Example 25 ++++++++ ++++++ 实施例60Example 60 ++++++++ ++
实施例26Example 26 ++++++++ ++++++++ 实施例61Example 61 ++ ++++++
实施例27Example 27 ++++++++ ++++++ 实施例62Example 62 ++ ++++++
实施例28Example 28 ++++++++ ++++++ 实施例63Example 63 ++++ ++
实施例29Example 29 ++++++++ ++++++++ 实施例64Example 64 ++++++++ ++
实施例30Example 30 ++++++++ ++++ 实施例65Example 65 ++++++ ++
实施例31Example 31 ++++++++ ++++++++ 实施例66Example 66 ++++++++ ++
实施例32Example 32 ++++++++ ++++++++  Zh  Zh  Zh
实施例33Example 33 ++++++ ++++++++  Zh  Zh  Zh
实施例34Example 34 ++++++ ++++++++  Zh  Zh  Zh
实施例35Example 35 ++++++++ ++++++++  Zh  Zh  Zh
动物体内镇痛活性测定Determination of analgesic activity in animals
福尔马林致小鼠足底疼痛模型Formalin-induced foot pain in mice
福尔马林致小鼠足底疼痛模型广泛用于炎性疼痛相关的行为药理学研究，主要反映化学物质刺激引起的中度至重度的急、慢性疼痛，其疼痛行为分为两个不同疼痛机制的时相期，分别为第一时相和第二时相，第一时相主要反映化学刺激物直接作用于伤害感受器产生的急性痛，第二时相主要反映外周组织的炎性反应及脊髓背角介导的功能变化引起的应迟发的、连续的伤害性疼痛。该模型能较好地模拟临床慢性疼痛，是目前国内外公认的、较为可靠的动物疼痛模型。本发明采用福尔马林致小鼠足底疼痛模型测定了代表性化合物的镇痛活性。实验材料与试剂Formalin-induced plantar pain in mice is widely used in behavioral pharmacology research related to inflammatory pain, which mainly reflects moderate to severe acute and chronic pain caused by chemical stimulation. Its pain behavior is divided into two different pains. The phase phases of the mechanism are the first phase and the second phase. The first phase mainly reflects the acute pain caused by the chemical stimuli directly acting on the nociceptors, and the second phase mainly reflects the inflammatory response of peripheral tissues and Spinal dorsal horn-induced functional changes should cause delayed, continuous nociceptive pain. This model can better simulate clinical chronic pain, and it is currently recognized at home and abroad as a relatively reliable animal pain model. The present invention uses a formalin-induced mouse plantar pain model to measure the analgesic activity of a representative compound. Experimental materials and reagents
SPF级昆明种小鼠由成都达硕实验动物有限公司(合格证号：SCXK(川)2015-030)提供，饲养环境12h光照/12h黑暗交替，环境温度控制于22-25℃；所选取的本发明公开的化合物纯度>98％，临用前配置所需浓度使用。其余试剂均为市售分析纯。SPF-grade Kunming mice were provided by Chengdu Dashuo Experimental Animal Co., Ltd. (Certificate No .: SCXK (Sichuan) 2015-030). The feeding environment was alternated with 12h light and 12h dark, and the ambient temperature was controlled at 22-25 ° C. The compound disclosed by the present invention has a purity of> 98%, and it is used at a concentration required before use. The remaining reagents are commercially available analytical grade.
实验方法：experimental method:
取昆明小鼠110只，全雄，体重22-26g，随机分为11组，每组10只，生理盐水组为空白对照组，福尔马林组为模型对照组，其余为给药实验组。实验当日给药之前将小鼠置于透明玻璃箱中适应30min，实验组灌胃给予受试化合物30mg/kg，对照组灌胃给予等剂量的空白溶媒，给药2h后，模型对照组和给药实验组以微量注射器于小鼠左后足底皮下注射5％福尔马林25μL，空白对照组小鼠于左后足底皮下注射生理盐水25μL，注射后立即放入透明玻璃箱中，用秒表以每5min为单位观察记录小鼠疼痛反应(舔/咬注射足的时间)，其中0-10min为急性阶段又称第一时相，10-40min为持续阶段又称第二时相。由于福尔马林致小鼠足底疼痛模型的第一时相主要反映化学刺激物直接作用于伤害感受器产生的急性痛，而第二时相主要反映外 周组织的炎性反应及脊髓背角介导的功能变化引起的应迟发的、连续的伤害性疼痛，能更好地模拟人类临床疾病如慢性神经病理性疼痛。因此，重点考察本发明的化合物对第二时相的镇痛作用。疼痛缓解率计算公式为：{[1-(实验组疼痛反应时间-空白组疼痛反应时间)/(模型组疼痛反应时间-空白组疼痛反应时间)]×100％}。采用GraphPad Prism软件进行统计分析，实验数据均以均数标准差表示，实验结果如表3所示Take 110 Kunming mice, all males, weighing 22-26g, randomly divided into 11 groups, 10 in each group. The normal saline group was the blank control group, the formalin group was the model control group, and the rest were the experimental group. . The mice were placed in a transparent glass box for 30 minutes before the day of administration. The experimental group was administered with the test compound 30 mg / kg by gavage. The control group was given the same amount of blank vehicle by gavage. In the medicine experiment group, 25 μL of 5% formalin was subcutaneously injected into the left hind plantar of the mice with a micro syringe, and the mice in the blank control group were injected 25 μL of normal saline subcutaneously into the left hind plantar of the mice. The stopwatch observes and records the pain response of mice (the time of licking / biting the injection foot) every 5 minutes, in which 0-10min is the acute phase and is also called the first phase, and 10-40min is the continuous phase and is also called the second phase. Because the first phase of formalin-induced mouse plantar pain model mainly reflects the acute pain produced by chemical stimuli directly acting on nociceptors, while the second phase mainly reflects the inflammatory response of peripheral tissues and the spinal dorsal horn mediator. Delayed, continuous nociceptive pain caused by changes in the function of the liver can better simulate human clinical diseases such as chronic neuropathic pain. Therefore, the analgesic effect of the compound of the present invention on the second phase is mainly examined. The formula for calculating the pain relief rate is: [[1- (pain response time in the experimental group-pain response time in the blank group) / (pain response time in the model group-pain response time in the blank group)] × 100%}. GraphPad Prism software was used for statistical analysis. The experimental data were expressed as mean standard deviation. The experimental results are shown in Table 3.
表3table 3
编号Numbering 第二时相疼痛缓解率(％)Second-phase pain relief rate (%)
实施例1Example 1 65.8±9.565.8 ± 9.5
实施例2Example 2 40.7±9.840.7 ± 9.8
实施例3Example 3 60.0±10.260.0 ± 10.2
实施例8Example 8 52.6±6.352.6 ± 6.3
实施例15Example 15 55.3±12.555.3 ± 12.5
实施例17Example 17 67.1±18.067.1 ± 18.0
实施例18Example 18 68.5±17.168.5 ± 17.1
实施例23Example 23 53.0±15.853.0 ± 15.8
实施例41Example 41 65.0±7.265.0 ± 7.2
实施例52Example 52 30.2±2.730.2 ± 2.7
PF-05089771PF-05089771 22.4±11.322.4 ± 11.3
上述结果表明，在第二时相中与模型对照组相比，本发明所公布的化合物能显著减少舔/咬时间，具有显著的镇痛作用。与高选择性Nav1.7抑制剂PF-05089771相比，本发明所公布的Nav1.7和Nav1.3双重抑制剂具有更强的镇痛作用。The above results show that, compared with the model control group, the compound disclosed in the present invention can significantly reduce the licking / biting time and has a significant analgesic effect in the second phase. Compared with the highly selective Nav1.7 inhibitor PF-05089771, the disclosed dual inhibitors of Nav1.7 and Nav1.3 have stronger analgesic effects.

Claims (24)

  1. 一种式I化合物，其溶剂化物、互变异构体或药学上可接受的盐：A compound of formula I, a solvate, tautomer or pharmaceutically acceptable salt thereof:
    Figure PCTCN2019104852-appb-100001
    Figure PCTCN2019104852-appb-100001
    其中，R 1选自至多包含3个N、O、S杂原子的5-10元芳杂环或-CONHR 2，任选地，5-10元芳杂环被卤素、C 1-6烷基、-OC 1-6烷基、C 1-6卤代烷基、-OC 1-6卤代烷基、氰基取代； Wherein R 1 is selected from a 5-10 membered aromatic heterocyclic ring or -CONHR 2 containing up to 3 N, O, and S heteroatoms, and optionally, the 5-10 membered aromatic heterocyclic ring is substituted by halogen, C 1-6 alkyl , -OC 1-6 alkyl, C 1-6 haloalkyl, -OC 1-6 haloalkyl, cyano substituted;
    R 2选自C 1-4烷基； R 2 is selected from C 1-4 alkyl;
    X 1不存在或为-NH-； X 1 does not exist or is -NH-;
    R 3、R 4独立地选自氢或者卤素，且R 3、R 4至少1项为卤素； R 3 and R 4 are independently selected from hydrogen or halogen, and at least one of R 3 and R 4 is halogen;
    X 2为NH或O； X 2 is NH or O;
    Z为-(CH 2) n-，且当X 2为NH，n为1-2的整数，当X 2为O，n为0-2的整数； Z is-(CH 2 ) n- , and when X 2 is NH, n is an integer of 1-2, when X 2 is O, n is an integer of 0-2;
    X 3、X 4、X 5、X 6选自N或CR 5，且X 3、X 4、X 5、X 6至多1项为N； X 3 , X 4 , X 5 , X 6 is selected from N or CR 5 , and at most 1 of X 3 , X 4 , X 5 , X 6 is N;
    R 5选自氢、卤素、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、氰基； R 5 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, cyano;
    R 6选自氢或C 1-4烷基； R 6 is selected from hydrogen or C 1-4 alkyl;
    R 7选自-(CH) zNR 8R 9，R 8、R 9独立地为氢或C 1-4烷基，其中z为1-4的整数，或-NR 8R 9形成如下结构： R 7 is selected from-(CH) z NR 8 R 9 , R 8 and R 9 are independently hydrogen or C 1-4 alkyl, wherein z is an integer of 1-4, or -NR 8 R 9 forms the following structure:
    Figure PCTCN2019104852-appb-100002
    其中X 7不存在或选自CHR 10、NR 10或O，y为0-5的整数；R 10选自氢或C 1-4烷基。
    Figure PCTCN2019104852-appb-100002
    Wherein X 7 is absent or selected from CHR 10 , NR 10 or O, and y is an integer of 0-5; R 10 is selected from hydrogen or C 1-4 alkyl.
  2. 根据权利要求1所述的化合物，其溶剂化物、互变异构体或药学上可接受的盐，其特征在于R 1选自至多包含3个N、O、S杂原子的5-6元单环芳杂环，任选地，5-6元单环芳杂环被卤素、C 1-6烷基、-OC 1-6烷基、C 1-6卤代烷基、-OC 1-6卤代烷基、氰基取代。 The compound according to claim 1, solvate, tautomer or pharmaceutically acceptable salt thereof, wherein one selected from up to contain three N, O, 5-6 membered monocyclic hetero atoms, R S Ring aromatic heterocyclic ring, optionally, 5-6 membered monocyclic aromatic heterocyclic ring is halogen, C 1-6 alkyl, -OC 1-6 alkyl, C 1-6 haloalkyl, -OC 1-6 haloalkyl Cyano substitution.
  3. 根据权利要求1所述的化合物，其溶剂化物、互变异构体或药学上可接受的盐，其特征在于R 1为选自至多包含3个N、O、S杂原子的5-6元单环芳杂环，任选地，5-6元单环芳杂环被卤素取代。 The compound according to claim 1, which is a solvate, tautomer or pharmaceutically acceptable salt thereof, characterized in that R 1 is a member selected from the group consisting of 5 to 6 members containing at most 3 heteroatoms of N, O, and S. A monocyclic aromatic heterocyclic ring, optionally, a 5-6 membered monocyclic aromatic heterocyclic ring is substituted with a halogen.
  4. 根据权利要求1所述的化合物，其溶剂化物、互变异构体或药学上可接受的盐，其特征在于R 1选自至多包含3个N、O、S杂原子的5元芳杂环，任选地，5元芳杂环被卤素取代。 The compound according to claim 1, solvate, tautomer or pharmaceutically acceptable salt thereof, wherein R 1, 5-membered aromatic heterocycle O, S hetero atoms selected from the group containing up to three N , Optionally, the 5-membered aromatic heterocyclic ring is substituted with halogen.
  5. 根据权利要求1所述的化合物，其溶剂化物、互变异构体或药学上可接受的盐，其特征在 于R 1选自
    Figure PCTCN2019104852-appb-100003
    Figure PCTCN2019104852-appb-100004
    The compound according to claim 1, solvate, tautomer or pharmaceutically acceptable salt thereof, wherein R 1 is selected
    Figure PCTCN2019104852-appb-100003
    Figure PCTCN2019104852-appb-100004
  6. 根据权利要求1所述的化合物，其溶剂化物、互变异构体或药学上可接受的盐，其特征在于R 2为-CH 3。 The compound according to claim 1, wherein the solvate, tautomer or pharmaceutically acceptable salt thereof is characterized in that R 2 is -CH 3 .
  7. 根据权利要求1所述的化合物，其溶剂化物、互变异构体或药学上可接受的盐，其特征在于X 2为-NH。 The compound according to claim 1, wherein solvate, tautomer or pharmaceutically acceptable salt is characterized in that X 2 is -NH.
  8. 根据权利要求1所述的化合物，其溶剂化物、互变异构体或药学上可接受的盐，其特征在于X 3、X 4、X 5、X 6均为CH。 The compound according to claim 1, wherein the solvate, tautomer or pharmaceutically acceptable salt thereof is characterized in that X 3 , X 4 , X 5 , and X 6 are all CH.
  9. 根据权利要求1所述的化合物，其溶剂化物、互变异构体或药学上可接受的盐，其特征在于R 5选自氢、卤素、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基。 The compound according to claim 1, which is a solvate, tautomer or pharmaceutically acceptable salt thereof, characterized in that R 5 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy group, C 1-4 haloalkyl, C 1-4 haloalkoxy.
  10. 据权利要求1所述的化合物，其溶剂化物、互变异构体或药学上可接受的盐，其特征在于R 5选自氢、卤素、甲基、甲氧基、三氟甲基、三氟甲氧基。 The compound according to claim 1, wherein the solvate, tautomer or pharmaceutically acceptable salt thereof is characterized in that R 5 is selected from hydrogen, halogen, methyl, methoxy, trifluoromethyl, tri Fluoromethoxy.
  11. 根据权利要求1所述的化合物，其溶剂化物、互变异构体或药学上可接受的盐，其特征在于R 6选自氢或甲基。 The compound according to claim 1, which is a solvate, tautomer or pharmaceutically acceptable salt thereof, characterized in that R 6 is selected from hydrogen or methyl.
  12. 根据权利要求1所述的化合物，其溶剂化物、互变异构体或药学上可接受的盐，其特征在于X 7不存在或选自CH 2、O、-NCH 3，y为1-4的整数。 The compound according to claim 1, which is a solvate, tautomer or pharmaceutically acceptable salt, characterized in that X 7 is absent or selected from CH 2 , O, -NCH 3 , and y is 1-4 Integer.
  13. 根据权利要求1所述的化合物，其溶剂化物、互变异构体或药学上可接受的盐，其特征在于-NR 8R 9形成如下的环结构： The compound according to claim 1, its solvate, tautomer or pharmaceutically acceptable salt, characterized in that -NR 8 R 9 forms the following ring structure:
    Figure PCTCN2019104852-appb-100005
    Figure PCTCN2019104852-appb-100005
  14. 根据权利要求1所述的化合物，其溶剂化物、互变异构体或药学上可接受的盐，其特征在于z为2或3。The compound according to claim 1, wherein solvate, tautomer or pharmaceutically acceptable salt is characterized in that z is 2 or 3.
  15. 根据权利要求1所述的化合物，其溶剂化物、互变异构体或药学上可接受的盐，其特征在于所述化合物选自：The compound according to claim 1, which is a solvate, tautomer or pharmaceutically acceptable salt thereof, characterized in that the compound is selected from:
    Figure PCTCN2019104852-appb-100006
    Figure PCTCN2019104852-appb-100006
    Figure PCTCN2019104852-appb-100007
    Figure PCTCN2019104852-appb-100007
    Figure PCTCN2019104852-appb-100008
    Figure PCTCN2019104852-appb-100008
  16. 一种药物组合物，其包含权利要求1-15中任一项所述的化合物，其溶剂化物、互变异构体或药学上可接受的盐和药学上可接受的赋形剂。A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, a solvate, a tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  17. 如权利要求1-15中任一项所述的化合物，其溶剂化物、互变异构体或药学上可接受的盐在制备用于治疗疼痛的药物中的用途。The compound according to any one of claims 1 to 15, the use of a solvate, tautomer or pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of pain.
  18. 如权利要求17所述的用途，其特征在于所述疼痛选自由以下组成的组：神经性疼痛、炎性疼痛、内脏痛、癌症疼痛、化疗疼痛、创伤疼痛、手术疼痛、分娩疼痛、神经源性膀胱疼痛、溃疡性结肠炎疼痛、慢性疼痛、持续性疼痛、外周介导性疼痛、中枢介导性疼痛、偏头痛、窦性头痛、紧张性头痛、幻肢痛、牙痛、外周神经损伤疼痛或其组合。The use according to claim 17, characterized in that the pain is selected from the group consisting of: neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, childbirth pain, neurogenic Bladder pain, ulcerative colitis pain, chronic pain, persistent pain, peripheral-mediated pain, central-mediated pain, migraine, sinus headache, tension headache, phantom limb pain, toothache, peripheral nerve injury pain Or a combination.
  19. 如权利要求18所述的用途，其特征在于所述疼痛选自由以下组成的组：神经性疼痛、炎性疼痛。The use according to claim 18, wherein the pain is selected from the group consisting of neuropathic pain and inflammatory pain.
  20. 如权利要求17所述的用途，其特征在于所述疼痛与选自由以下组成的组的疾病或病状相关：HIV、HIV治疗诱导的神经病变、三叉神经痛、疱疹后神经痛、急性疼痛、热敏感性、结节病、肠易激综合症、克罗恩病、多发性硬化(MS)、肌萎缩性脊髓侧索硬化症(ALS)、糖尿病性神经病变、外周神经病变、关节炎、类风湿性关节炎、动脉粥样硬化、阵发性肌张力障碍、肌无力综合征、肌强直、恶性高热症、囊性纤维化、假性醛固酮增多症、横纹肌溶解症、甲状腺功能减退症、双相抑郁、焦虑、精神分裂症、钠通道毒素相关疾病、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、部分性和全身性强直发作、不宁腿综合征、心律失常、纤维肌痛、由中风或神经创伤引起的局部缺血状态下的神经保护、心房纤颤和心室纤颤。The use according to claim 17, characterized in that the pain is associated with a disease or condition selected from the group consisting of: HIV, HIV treatment-induced neuropathy, trigeminal neuralgia, postherpetic neuralgia, acute pain, fever Sensitivity, sarcoidosis, irritable bowel syndrome, Crohn's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, class Rheumatoid arthritis, atherosclerosis, paroxysmal dystonia, myasthenic syndrome, myotonia, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, double Phase depression, anxiety, schizophrenia, sodium channel toxin-related diseases, familial erythematous limb pain, primary erythematous limb pain, familial rectal pain, cancer, epilepsy, partial and generalized tonic episodes, Leg syndrome, arrhythmia, fibromyalgia, neuroprotection in ischemia caused by stroke or nerve trauma, atrial fibrillation and ventricular fibrillation.
  21. 权利要求1-15中任一项所述的化合物，其溶剂化物、互变异构体或药学上可接受的盐治疗哺乳动物中疼痛的方法，其特征在于包括向有需要的哺乳动物施用治疗有效量式I化合物。A compound according to any one of claims 1-15, a solvate, tautomer or pharmaceutically acceptable salt thereof for treating pain in a mammal, characterized by comprising administering the treatment to a mammal in need thereof An effective amount of a compound of formula I.
  22. 如权利要求21所述的方法，其特征在于所述疼痛选自由以下组成的组：神经性疼痛、炎性疼痛、内脏痛、癌症疼痛、化疗疼痛、创伤疼痛、手术疼痛、分娩疼痛、神经源性膀胱疼痛、溃疡性结肠炎疼痛、慢性疼痛、持续性疼痛、外周介导性疼痛、中枢介导性疼痛、偏头痛、窦性头痛、紧张性头痛、幻肢痛、牙痛、外周神经损伤疼痛或其组合。The method of claim 21, wherein the pain is selected from the group consisting of neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, childbirth pain, neurogenic Bladder pain, ulcerative colitis pain, chronic pain, persistent pain, peripheral-mediated pain, central-mediated pain, migraine, sinus headache, tension headache, phantom limb pain, toothache, peripheral nerve injury pain Or a combination.
  23. 如权利要求22所述的方法，其特征在于所述疼痛选自由以下组成的组：神经性疼痛、炎性疼痛.The method of claim 22, wherein the pain is selected from the group consisting of: neuropathic pain, inflammatory pain.
  24. 如权利要求21所述的方法，其特征在于所述疼痛与选自由以下组成的组的疾病或病状相关：HIV、HIV治疗诱导的神经病变、三叉神经痛、疱疹后神经痛、急性疼痛、热敏感性、结节病、肠易激综合症、克罗恩病、多发性硬化(MS)、肌萎缩性脊髓侧索硬化症(ALS)、糖尿病性神经病变、外周神经病变、关节炎、类风湿性关节炎、动脉粥样硬化、阵发性肌张力障碍、肌无力综合征、肌强直、恶性高热症、囊性纤维化、假性醛固酮增多症、横纹肌溶解症、甲状腺功能减退症、双相抑郁、焦虑、精神分裂症、钠通道毒素相关疾病、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、部分性和全身性强直发作、不宁腿综合征、心律失常、纤维肌痛、由中风或神经创伤引起的局部缺血状态下的神经保护、心房纤颤和心室纤颤。The method of claim 21, wherein the pain is associated with a disease or condition selected from the group consisting of: HIV, HIV treatment-induced neuropathy, trigeminal neuralgia, postherpetic neuralgia, acute pain, fever Sensitivity, sarcoidosis, irritable bowel syndrome, Crohn's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, class Rheumatoid arthritis, atherosclerosis, paroxysmal dystonia, myasthenic syndrome, myotonia, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, double Phase depression, anxiety, schizophrenia, sodium channel toxin-related diseases, familial erythematous limb pain, primary erythematous limb pain, familial rectal pain, cancer, epilepsy, partial and generalized tonic episodes, Leg syndrome, arrhythmia, fibromyalgia, neuroprotection in ischemia caused by stroke or nerve trauma, atrial fibrillation and ventricular fibrillation.
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CN101218235A (en) * 2005-05-10 2008-07-09 沃泰克斯药物股份有限公司 Bicyclic derivatives as modulators of ion channels
CN104093716A (en) * 2011-10-31 2014-10-08 克赛农制药股份有限公司 Biaryl ether sulfonamides and their use as therapeutic agents
CN108349963A (en) * 2015-11-13 2018-07-31 株式会社大熊制药 sodium channel blockers

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101218235A (en) * 2005-05-10 2008-07-09 沃泰克斯药物股份有限公司 Bicyclic derivatives as modulators of ion channels
CN104093716A (en) * 2011-10-31 2014-10-08 克赛农制药股份有限公司 Biaryl ether sulfonamides and their use as therapeutic agents
CN108349963A (en) * 2015-11-13 2018-07-31 株式会社大熊制药 sodium channel blockers

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