WO2024099269A1 - Composé arylamide, composition pharmaceutique le comprenant, son utilisation - Google Patents

Composé arylamide, composition pharmaceutique le comprenant, son utilisation Download PDF

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WO2024099269A1
WO2024099269A1 PCT/CN2023/129942 CN2023129942W WO2024099269A1 WO 2024099269 A1 WO2024099269 A1 WO 2024099269A1 CN 2023129942 W CN2023129942 W CN 2023129942W WO 2024099269 A1 WO2024099269 A1 WO 2024099269A1
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mmol
compound
yield
substituted
title compound
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PCT/CN2023/129942
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English (en)
Chinese (zh)
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阳怀宇
叶阳亮
王昆
张少英
张乾森
莫奕青
梅良和
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华东师范大学
苏州中科新药篮生物医药科技有限公司
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Publication of WO2024099269A1 publication Critical patent/WO2024099269A1/fr

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Definitions

  • the present invention belongs to the field of chemical and biomedical technology, and specifically relates to an amide derivative with a new skeleton, a preparation method thereof and its use
  • Kv7 potassium channel is a type of voltage-dependent potassium ion channel with the characteristics of low threshold activation, slow activation and non-inactivation.
  • Kv7 potassium channel has five family members (Kv7.1-Kv7.5, or KCNQ1-KCNQ5). All Kv7 potassium channel members have similar structures, that is, a functional channel composed of four subunits, each subunit contains six transmembrane segments (S1-S6). Its S1-S4 is the voltage sensing area, which plays an important role in sensing membrane potential changes and controlling conformational changes; S5-S6 is the main component of the channel pore area, which is the main combination and action area of potassium channel openers.
  • KV7.1 potassium channel is a non-neuronal pathway distributed in peripheral tissues and expressed in the heart to mediate myocardial Iks. Its mutation can lead to Long Q-T syndrome.
  • Kv7.2-Kv7.5 potassium channels are the basis of neuronal M currents, widely distributed in the nervous system, and have multiple physiological activities.
  • Voltage-gated potassium channel KCNQ2 is mainly expressed in the nervous system. It assembles into heterotetramers with voltage-gated potassium channel KCNQ3 to mediate M-current (IKM). IKM is a slow-activating, slow-deactivating and non-inactivating current that plays an important role in maintaining resting membrane potential and reducing intrinsic discharges and repetitive action potential discharges triggered by excitatory stimuli.
  • KCNQ2 gene mutations were first discovered in a family of patients with benign familial neonatal seizures, revealing the correlation between KCNQ2 channels and epilepsy.
  • a large number of clinical studies have found that KCNQ2 gene mutations are associated with the onset of epilepsy, benign familial neonatal seizures or neonatal epileptic encephalopathy, peripheral nerve hyperexcitability (PNH or myotonia or neuromyotonia) and other diseases.
  • PNH or myotonia or neuromyotonia peripheral nerve hyperexcitability
  • the expression of KCNQ2 channels in neurons at all levels of the pain perception pathway and in brain regions involved in pain suggests the possibility of KCNQ2 channels as analgesic targets.
  • KCNQ2 expression is downregulated in models of neuropathic pain, osteoarthritis pain, and bone cancer pain, and activation of KCNQ2 channels can relieve neuropathic pain and fibromyalgia.
  • the regulation of KCNQ2 channel activity is also associated with neurological diseases such as Parkinson's disease, ischemia, schizophrenia, smooth muscle diseases, and depression.
  • KCNQ2 channels are considered to be important pharmacological targets for the development of new drugs for neurological and metabolic diseases.
  • the development of KCNQ2 channel modulators has potential application value in the treatment of pain, epilepsy, or neurological diseases.
  • KCNQ4 potassium channels are highly expressed in the outer hair cells of the cochlea and the auditory nucleus of the brainstem, and their mutations may lead to hereditary deafness.
  • KCNQ5 potassium channels are highly expressed in skeletal muscle and brain, and their mutations may lead to retinal lesions, etc.
  • Retigabine is a potassium channel agonist. It was approved for marketing in 2011 as a new type of anti-epileptic drug for the adjuvant treatment of partial-onset epilepsy. However, its poor target selectivity can cause a series of side effects such as retinal pigment deposition, skin discoloration and urine retention. A series of compounds with different skeletons, such as BMS-204352, ICA-069673, NH29, ZnPy, and ML213, have been reported to activate KCNQ2 channels. Some compounds show anticonvulsant effects in mouse epileptic seizure models, but there is still a lack of a large amount of preclinical data.
  • the present invention provides an amide compound represented by formula (I) or a pharmaceutically acceptable salt, ester, optical isomer, tautomer, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, chelate, complex, inclusion compound or prodrug thereof,
  • Ring A is a ring structure represented by the following formula (II),
  • connection site is at any position on the ring structure that can form a bond, and the bond represented by the dotted line indicates existence or non-existence;
  • X1 is selected from CR a or N;
  • X2 is selected from CR a , N or O, S, Se, NR a , C(R a ) 2 ;
  • X3 is absent or selected from CR a , N or NR a , O, S, Se, C(R a ) 2 ;
  • X4 is selected from CR a , N or NR a , C(R a ) 2 ;
  • X5 is selected from CR a , N or O, S, Se, NR a , C(R a ) 2 ;
  • X6 and X7 represent C atoms, X8 is selected from C or N, and the ring formed by X2 to X7 is aromatic or non-aromatic;
  • L1 is a chemical bond or NH
  • Ra is independently selected from H, C1-C10 alkyl, C1-C10 haloalkyl, saturated or partially unsaturated C3-6 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclic group or C6-10 aryl, CH2 in Ra may be replaced by -O- or -S-, and H in Ra may be replaced by hydroxyl, halogen or C1-C3 alkoxy; provided that L1 and L2 are not chemical bonds at the same time, and when L1 is a chemical bond, L2 is -NRa- ;
  • Ar 1 is selected from a substituted or unsubstituted C6-C30 aryl group, a substituted or unsubstituted C3-C30 heteroaryl group;
  • R2 is independently selected from substituted or unsubstituted C1-C6 alkyl, hydroxy, halogen, cyano, amino, C1-C6 alkyl substituted amino, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 heterocyclyl, b1 , C(O) R b1 , C (O)OR b1 , OC (O)R b1 , NHC (O)R b1 , NR b1 C (O)R b2 , NHC ( O )OR b1 , NR b1 C(O)OR b2 , C( O ) NH 2 , C(O) NHR b1 , C( O)NR b1 R b2 , C (O) NHS (O) 2 R b1 , S ( O) 2 NHC(
  • the structure represented by ring A in formula (1) is selected from the following structures:
  • m is an integer of 0 to 3
  • R1 is selected from halogen, -CN, hydroxyl, substituted or unsubstituted C1-C6 straight chain alkyl, or the following groups optionally substituted by halogen, C1-C3 alkyl, C1-C3 alkoxy,
  • Ar 1 is one of the following groups or a fused combination of these groups:
  • the biphenyl group is selected from 2-biphenyl, 3-biphenyl and 4-biphenyl;
  • the terphenyl group includes p-terphenyl-4-yl, p-terphenyl-3-yl, p-terphenyl-2-yl, m-terphenyl-4-yl, m-terphenyl-3-yl and m-terphenyl-2-yl;
  • the naphthyl group includes 1-naphthyl or 2-naphthyl;
  • the anthracenyl group is selected from 1-anthracenyl, 2-anthracenyl and 9-anthracenyl;
  • the fluorenyl group is selected from 1-fluorenyl, 2-fluorenyl, 3-fluorenyl, 4-fluorenyl and 9-fluorenyl;
  • the pyrenyl group is selected from 1-
  • the invention relates to a naphthyl radical
  • oxazolyl indazolyl, imidazolyl, benzimidazolyl, naphthoimidazolyl, phenanthroimidazolyl, pyridoimidazolyl, pyrazinoimidazolyl, quinoxalin imidazolyl, oxazolyl, benzoxazolyl, naphthoxazolyl, anthrazolyl, phenanthroxazolyl, 1,2-thiazolyl, 1,3-thiazolyl, benzothiazolyl, pyridazinyl, benzopyridazinyl, pyrimidinyl, benzopyrimidinyl, quinoxalinyl, 1,5-diazaanthryl, 2,7-diazapyrenyl, 2,3-diazapyrenyl, 1,6-diazapyrenyl, 1,8-diazapyrenyl, 4,5-diazapyrenyl, 4,5,9,10-tetraazaperyl
  • Ar 1 is one of the following groups or a combination of these groups:
  • n is an integer of 0 to 2
  • R 2 is selected from the following groups: F, I, Cl, Br, OMe, OH, NH 2 , and CN.
  • connection site Indicates the position of connection.
  • the expression of a ring structure with a “—” crossed out indicates that the connection site is at any position on the ring structure that can form a bond.
  • Ar 1 is phenyl, n is 1, R 2 is F, Cl, Br, or I, m is an integer from 0 to 2, R 1 is halogen, cyclopropyl, methyl, ethyl, isopropyl, tert-butyl, cyclobutyl, difluoromethoxy, trifluoromethoxy, methylene alkynyl, methoxy, methylene cyano, difluoromethyl, acetyl, and the ring structure represented by formula (II) is a group selected from the following ring structures:
  • the compounds of the present invention have shown their use as potassium ion channel modulators.
  • the present invention also provides the above-mentioned compounds and their various derivative substances (pharmaceutically acceptable inorganic or organic salts, hydrates or solvates), etc., as well as pharmaceutical compositions containing the compounds of the present invention as main active ingredients, which can be used for the preparation of drugs for alleviating and treating diseases related to potassium ion channels.
  • the potassium ion channel preferably refers to a type 2 voltage-gated potassium ion channel KCNQ2, sometimes also referred to as a KCNQ2 channel.
  • the regulator is preferably an activator, or agonist.
  • potassium channel-related diseases refer to central nervous system diseases or disorders, which include seizure disorders, anxiety disorders, neuropathic pain and migraine, neurodegenerative diseases, stroke, cocaine abuse, nicotine withdrawal symptoms, ethanol withdrawal symptoms, tinnitus and Alzheimer's disease, depression, sleep disorders in the aging process, and neurodevelopmental disorders.
  • paroxysmal disorder is selected from acute paroxysmal disorders, convulsions, status epilepticus, epilepsy such as epileptic syndrome and epileptic seizures, neonatal spasms, neonatal epileptic seizures, benign familial neonatal epilepsy (KCNQ2-BFNE), epileptic encephalopathy (KCNQ2-NEE), benign familial neonatal convulsions type 1 (BFNC), benign familial neonatal seizures 1 (BFNS1), neonatal epileptic seizures associated with hypoxic-ischemic injury, epileptic spasms, epileptic encephalopathy, early infantile epileptic encephalopathy 7 (EIEE7), early infantile epileptic encephalopathy with psychomotor retardation, generalized tonic seizures, globus pallidus morphologic abnormalities, apnea, cerebral edema, dystonia, facial erythema, hypotonia, febrile seizures, corpus callosum dysgenesis, hyperrhythmia, focal clonic seizures
  • the anxiety disorder is selected from anxiety and diseases and conditions associated with the following diseases: panic attack, agoraphobia, agoraphobia panic disorder with agoraphobia, panic disorder without agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia and other specific phobias, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder caused by general medical condition, substance-induced anxiety disorder, separation anxiety disorder, adjustment disorder, performance anxiety, hypochondriasis, anxiety disorder caused by general medical condition and substance-induced anxiety disorder, and anxiety disorder not otherwise specified;
  • the neuropathic pain and migraine are selected from allodynia, hyperalgesic pain, phantom pain, neuropathic pain associated with diabetic neuropathy, neuropathic pain associated with trigeminal neuralgia, neuropathic pain associated with sciatica, and neuropathic pain associated with migraine; or,
  • the neurodegenerative disease is selected from Alzheimer's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, Creutzfeld-Jakob's, Parkinson's disease, encephalopathy caused by AIDS or induced by rubella virus, herpes virus, Borrelia or unknown pathogen infection, trauma-induced neurodegenerative lesions, neuronal hyperexcitability states such as in drug withdrawal or poisoning symptoms, and neurodegenerative diseases of the peripheral nervous system such as polyneuropathy and polyneuritis.
  • the depression is selected from bipolar depression, postpartum depression, major depressive disorder, dysthymia, atypical depression, melancholia, refractory depression, depression associated with Huntington's disease, depression associated with multiple sclerosis or depression associated with anxiety disorders.
  • the neurodevelopmental disorder is selected from the group consisting of developmental delay, intellectual disability, non-syndromic intellectual disability, and autism spectrum disorder (ASD).
  • ASD autism spectrum disorder
  • the dosage of the compound of formula (I) is 0.1-200 mg/kg.
  • the present invention also provides a pharmaceutical composition, comprising a preventive or therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt, ester, optical isomer, tautomer, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, chelate, complex, inclusion compound or prodrug thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is preferably a solid preparation, a semisolid preparation, a liquid preparation or a gaseous preparation.
  • the dosage form of the pharmaceutical composition is an oral dosage form or an injection
  • the oral dosage form includes capsules, tablets, pills, powders and granules.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures; the injection comprises a physiologically acceptable sterile aqueous or anhydrous solution, dispersion, suspension or emulsion, and a compound of the present invention or a pharmaceutically acceptable salt, ester, optical isomer, tautomer, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, chelate, complex, inclusion compound or prodrug sterile powder for re-dissolving into a sterile injectable solution or dispersion.
  • the present invention has the following advantages:
  • this type of compound Compared with retigabine, this type of compound has a completely new skeleton type, and its physical and chemical properties are more stable, and it is not easily oxidized, resulting in side effects such as pigmentation.
  • Retigabine has a triaminobenzene ring in its structure, and its physical and chemical properties are unstable and easily oxidized.
  • Current research generally believes that the oxidation of retigabine is the main cause of pigmentation. And the compounds of the present invention have better anti-epileptic effects than retigabine. .
  • alkylene refers to a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.
  • alkyl is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, such as 1 to 6 carbon atoms. For example, as used herein, the term “C1-6 alkyl” refers to a 1 to 6 carbon atom group.
  • a linear or branched group e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl
  • suitable substituents such as halogen (in which case the group is referred to as a "haloalkyl” ) (e.g., CH2F , CHF2 , CF3 , CCl3 , C2F5 , C2Cl5 , CH2CF3 , CH2Cl or -CH2CH2CF3 , etc.).
  • C1-4alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl , n -butyl, isobutyl, sec-butyl or tert-butyl).
  • alkenyl means a linear or branched monovalent hydrocarbon group containing one double bond and having 2 to 6 carbon atoms (“ C2-6 alkenyl”).
  • the alkenyl group is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl.
  • the compound of the present invention contains an alkenyl group, the compound may exist in the pure E (enthafen) form, the pure Z (zusammen) form or any mixture thereof.
  • alkynyl denotes a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl or propynyl.
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents.
  • monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclonon
  • the cycloalkyl has 3 to 15 carbon atoms.
  • C3-6cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) of 3 to 6 ring carbon atoms, which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.
  • cycloalkylene refers to saturated (i.e., “cycloalkylene” and “cycloalkyl") or unsaturated (i.e., having one or more double bonds and/or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbon atoms, including but not limited to (cyclo)propyl (ring), (cyclo)butyl (ring), (cyclo)pentyl (ring), (cyclo)hexyl (ring), (cyclo)heptyl (ring), (cyclo)octyl (ring), (cyclo)nonyl (ring), (cyclo)hexenyl (ring) and the like.
  • heterocyclyl refers to a saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double bonds and/or triple bonds within the ring) cyclic group having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring atoms, wherein at least one ring atom is a heteroatom selected from N, O and S and the remaining ring atoms are C.
  • a “3-10 membered (sub)heterocyclyl” is a saturated or partially unsaturated (sub)heterocyclyl having 2-9 (e.g., 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and one or more (e.g., 1, 2, 3 or 4) heteroatoms independently selected from N, O and S.
  • heterocyclyl and heterocyclic examples include, but are not limited to: (sub) oxirane, (sub) aziridine, (sub) azetidinyl, (sub) oxetanyl, (sub) tetrahydrofuranyl, (sub) dioxolyl (dioxolinyl), (sub) pyrrolidinyl, (sub) pyrrolidonyl, (sub) imidazolidinyl, (sub) pyrazolidinyl, (sub) pyrrolinyl, (sub) tetrahydropyranyl, (sub) piperidinyl, (sub) morpholinyl, (sub) dithianyl (dithianyl), (sub) thiomorpholinyl, (sub) piperazinyl or (sub) trithianyl (trithianyl).
  • the group also encompasses bicyclic systems, including spiro, fused or bridged systems (such as 8-azaspiro [4.5] decane, 3,9-diazaspiro [5.5] undecane, 2-azabicyclo [2.2.2] octane, etc.).
  • the heterocyclylene and heterocyclyl groups may be optionally substituted with one or more (eg, 1, 2, 3 or 4) suitable substituents.
  • (ylidene)aryl and “aromatic ring” refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated ⁇ electron system.
  • C 6-10 (ylidene)aryl and “C 6-10 aromatic ring” mean an aromatic group containing 6 to 10 carbon atoms, such as (ylidene)phenyl (benzene ring) or (ylidene)naphthyl (naphthalene ring).
  • the (ylidene)aryl and aromatic ring are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.).
  • suitable substituents e.g., halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.
  • heteroaryl(ene) and “heteroaromatic ring” refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom which may be identical or different (the heteroatom being for example oxygen, nitrogen or sulfur) and, in each case additionally may be benzo-fused.
  • (ylidene)heteroaryl or “heteroaromatic ring” is selected from (ylidene)thiophenyl, (ylidene)furanyl, (ylidene)pyrrolyl, (ylidene)oxazolyl, (ylidene)thiazolyl, (ylidene)imidazolyl, (ylidene)pyrazolyl, (ylidene)isoxazolyl, (ylidene)isothiazolyl, (ylidene)oxadiazolyl, (ylidene)triazolyl, (ylidene)thiadiazolyl, etc., and their benzo derivatives; or (ylidene)pyridinyl, (ylidene)pyridazinyl, (ylidene)pyrimidinyl, (ylidene)pyrazinyl, (ylidene)triazinyl, etc., and their benzo derivatives.
  • aralkyl preferably refers to an alkyl substituted with an aryl or heteroaryl, wherein the aryl, heteroaryl and alkyl are as defined herein.
  • the aryl may have 6-14 carbon atoms
  • the heteroaryl may have 5-14 ring atoms
  • the alkyl may have 1-6 carbon atoms.
  • Exemplary aralkyls include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
  • Alkyl refers to a saturated aliphatic hydrocarbon group, comprising 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, or 1-2 carbon atoms, a saturated straight chain or branched monovalent hydrocarbon group, wherein the alkyl group may be independently optionally substituted with one or more substituents described herein.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc.
  • the alkyl group may be optionally substituted or unsubstituted.
  • Alkenyl refers to a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one CC is an sp2 double bond, wherein the alkenyl group may be independently optionally substituted with one or more substituents described herein, wherein specific examples include, but are not limited to, vinyl, allyl, and butylene, etc. Alkenyl may be optionally substituted or unsubstituted.
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring includes 3 to 20 carbon atoms, preferably includes 3 to 12 carbon atoms, more preferably includes 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyl includes cycloalkyl of spiro ring, condensed ring and bridge ring. Cycloalkyl can be optionally substituted or unsubstituted.
  • “Spirocycloalkyl” refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and one carbon atom (called spiro atom) shared between the monocyclic rings, containing one or more double bonds in the ring, but no ring has a completely conjugated ⁇ electron aromatic system. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members.
  • the spirocycloalkyl is divided into single spiro, double spiro or multi-spirocycloalkyl, preferably single spiro and double spirocycloalkyl, preferably 4/3 members, 4/4 members, 4/5 members, 4/6 members, 5/5 members or 5/6 members.
  • spirocycloalkyl include, but are not limited to:
  • “Fused cycloalkyl” refers to a 5 to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms, one or more rings may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl.
  • Non-limiting examples of "fused cycloalkyl” include, but are not limited to:
  • Bridged cycloalkyl refers to a 5 to 18-membered, all-carbon polycyclic group containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other, one or more rings may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl include, but are not limited to:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl and the like.
  • Heterocyclyl “heterocycle” or “heterocyclic” are used interchangeably in this application and refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic non-aromatic heterocyclic group containing 3-12 ring atoms, wherein at least one ring atom is a heteroatom, such as oxygen, nitrogen, sulfur, etc. Preferably, it has a 5-7 membered monocyclic or 7-10 membered bi- or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur.
  • heterocyclyl include, but are not limited to, morpholinyl, oxetanyl, thiophene.
  • heterocyclyl may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is the heterocyclyl.
  • the heterocyclyl may be optionally substituted or unsubstituted.
  • spiro heterocyclyl is divided into single spiro heterocyclyl, double spiro heterocyclyl or multi-spiro heterocyclyl, preferably single spiro heterocyclyl and double spiro heterocyclyl. More preferably 4/4, 4/5, 4/6, 5/5 or 5/6 monospiro heterocyclyl.
  • spiro heterocyclyl include, but are not limited to:
  • the number of constituent rings it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group.
  • fused heterocyclic group include, but are not limited to:
  • bridged heterocyclic groups include, but are not limited to:
  • Aryl refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be connected together in a fused manner.
  • aryl includes aromatic groups such as phenyl, naphthyl, and tetrahydronaphthyl.
  • the aryl is a C 6 -C 10 aryl, more preferably, the aryl is phenyl and naphthyl, and most preferably, phenyl.
  • the aryl may be substituted or unsubstituted.
  • the "aryl” may be fused with a heteroaryl, a heterocyclic group, or a cycloalkyl group, wherein the aryl ring is connected to the parent structure, and non-limiting examples include, but are not limited to:
  • Heteroaryl refers to an aromatic 5 to 6-membered monocyclic or 9 to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur.
  • the embodiment of “heteroaryl” includes, but is not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quino
  • Heteroaryl may be optionally substituted or unsubstituted.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples include but are not limited to:
  • Alkoxy refers to a group of (alkyl-O-), wherein alkyl is as defined herein.
  • C 1 -C 6 alkoxy is preferred, and examples thereof include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
  • Haloalkyl refers to an alkyl group having one or more halogen substituents, wherein the alkyl group has the meaning as described herein.
  • haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, 1,1-dichloroethyl, 1,2-dichloropropyl, and the like.
  • Hydrophilicity refers to an -OH group.
  • Halogen refers to fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred.
  • Amino refers to -NH2 .
  • Cyano refers to -CN.
  • Niro refers to -NO2 .
  • Benzyl refers to -CH2 -phenyl.
  • Carboxy refers to -C(O)OH.
  • Alcohol refers to -C(O) CH3 or Ac.
  • Carboxylate refers to -C(O)O(alkyl) or (cycloalkyl) wherein alkyl and cycloalkyl are as defined above.
  • halo or halogen group is defined to include F, Cl, Br, or I.
  • substituted means that one or more (e.g., one, two, three, or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that the normal valence of the designated atom in the present context is not exceeded and the substitution forms a stable compound. Combinations of substituents and/or variables are permitted only if such combinations form stable compounds.
  • substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the listed substituents, then one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and/or together, with independently selected optional substituents. If a nitrogen of a substituent is described as being optionally substituted with one or more of the listed substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.
  • each substituent is selected independently of the other.
  • each substituent may be the same as or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.
  • the point of attachment of a substituent may be from any suitable position of the substituent.
  • the present invention also includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature.
  • isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2H ), tritium ( 3H )); isotopes of carbon (e.g., 11C , 13C , and 14C ); isotopes of chlorine (e.g., 36Cl ); isotopes of fluorine (e.g., 18F ); isotopes of iodine (e.g., 123I and 125I ); isotopes of nitrogen (e.g., 13N and 15N ); isotopes of oxygen (e.g., 15O , 17O , and 18O ); isotopes of phosphorus (e.g., 32P ); and isotopes of sulfur (e.g., 35S ).
  • isotopes of hydrogen e.g., deuterium ( 2H ), tritium ( 3H
  • Certain isotopically labeled compounds of the invention are useful in drug and/or substrate tissue distribution studies (e.g., assays).
  • the radioactive isotopes tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) are particularly useful for this purpose due to their ease of incorporation and ready detection.
  • Substitution with 18 F, 15 O and 13 N) can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies.
  • Isotopically labeled compounds of the invention can be prepared by methods analogous to those described in the accompanying schemes and/or in the examples and preparations by using appropriate isotopically labeled reagents in place of the non-labeled reagents previously employed.
  • Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, for example, D 2 O, acetone-d 6 or DMSO-d 6 .
  • Substituted means, if not otherwise specified, that one or more hydrogen atoms, preferably up to 5, more preferably 1-3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g. olefinic) bond.
  • the term "pediatric patient” refers to a patient who is less than 16 years of age at the time of diagnosis or treatment.
  • the term "child” may also be divided into the following subcategories: neonates (from birth to the first month of life); infants (1 month to 2 years); children (2 years to 12 years); adolescents (12 years to 21 years (up to but not including the 22nd birthday)).
  • Berhman RE Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st ed. New York: McGrow-Hill, 2002; and Avery MD, 1st LR. Pediatric Medicine, 2nd ed. Baltimore: Williams &Wilkins; 1994.
  • an "effective amount" of a compound refers to an amount sufficient to agonize potassium ion channels.
  • the "therapeutically effective dose” of a compound refers to an amount sufficient to improve or in some way reduce symptoms, stop or reverse the progression of a disease, or stimulate potassium channels. This dose can be used as a single dose or taken according to a regimen to be effective.
  • treating means ameliorating or otherwise altering in any way the symptoms or pathology of a patient's condition, disorder or disease.
  • amelioration of the symptoms of a particular disease by administration of a particular compound or pharmaceutical composition refers to any reduction, whether permanent or temporary, lasting or transient, attributable to or associated with the administration of that composition.
  • the compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute part of the present invention.
  • Diastereoisomers can be separated into individual diastereomers on the basis of their physical chemical differences by methods such as chromatography, crystallization, distillation or sublimation.
  • Enantiomers can be separated to convert a chiral isomeric mixture into a diastereomeric mixture by reacting with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers into the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • the intermediates and compounds of the present invention may also exist in different tautomeric forms, and all such forms are included within the scope of the present invention.
  • optically active forms i.e., they have the ability to rotate the plane of plane polarized light.
  • the prefixes D, L or R, S are used to indicate the absolute configuration of the chiral center of the molecule.
  • the prefixes d, l or (+), (-) are used to name the sign of rotation of the plane of polarized light of the compound, (-) or l means that the compound is left-handed, and the prefix (+) or d means that the compound is right-handed.
  • These stereoisomers have the same order of attachment of atoms or groups of atoms to each other, but their stereostructures are different.
  • Stereoisomers may be enantiomers, and mixtures of isomers are usually called enantiomeric mixtures.
  • a 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during chemical reactions.
  • racemic mixture and “racemate” refer to an equimolar mixture of two enantiomers that lacks optical activity.
  • Tautomers or “tautomeric forms” refer to structural isomers of different energies that can be interconverted via a low energy barrier.
  • proton tautomers i.e., prototropic tautomers
  • Valence (chemical valence) tautomers include interconversions by reorganization of bonding electrons.
  • the structural formulas described herein include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Therefore, single stereochemical isomers of the present compounds or mixtures of their enantiomers, diastereomers, or geometric isomers are within the scope of the invention.
  • “Pharmaceutically acceptable salts” refer to salts of the compounds of the present invention, which are safe and effective when used in humans or animals. Salts of compounds can be obtained by using a sufficient amount of base or acid in a pure solution or a suitable inert solvent to obtain the corresponding addition salt.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts, etc.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts and organic acid salts.
  • the inorganic and organic acids include hydrochloric acid, hydrobromic acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, acetic acid, maleic acid, malonic acid, succinic acid, butenedioic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid and methanesulfonic acid, etc. (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)).
  • solid lines can be used Solid wedge Virtual wedge Depicting chemical bonds of the compounds of the invention.
  • the use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.).
  • the use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomer shown is present. When present in a racemic mixture, the solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry.
  • the compounds of the invention are intended to exist in the form of stereoisomers, which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof.
  • the compounds of the invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).
  • the present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • compositions of the present invention may exist in free form for treatment, or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, chelates, complexes, inclusion compounds or prodrugs, which, after being administered to a patient in need thereof, can directly or indirectly provide a compound of the present invention or a metabolite or residue thereof. Therefore, when referring to "compounds of the present invention” herein, it is also intended to cover the above-mentioned various derivative forms of the compound.
  • Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof, including but not limited to salts containing hydrogen bonds or coordinate bonds.
  • Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hyaluronate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,
  • Suitable base addition salts are formed with bases which form pharmaceutically acceptable salts.
  • bases include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts.
  • esters means an ester derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in free acid or alcohol form).
  • physiologically hydrolyzable esters which can be hydrolyzed under physiological conditions to release the compounds of the present invention in free acid or alcohol form.
  • the compounds of the present invention themselves may also be esters.
  • the compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol.
  • polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol.
  • the amount of polar solvents, in particular water may exist in a stoichiometric or non-stoichiometric ratio.
  • nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires an available lone pair of electrons to oxidize to an oxide; those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides.
  • metabolites of the compounds of the present invention i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound.
  • the present invention includes metabolites of the compounds of the present invention, including compounds prepared by contacting the compounds of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.
  • the present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have less pharmacological activity or no pharmacological activity and can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered into or onto the body.
  • prodrugs will be functional group derivatives of the compounds that are easily converted into the desired therapeutically active compounds in vivo. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella).
  • Prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties” (e.g., as described in “Design of Prodrugs", H. Bundgaard (Elsevier, 1985)).
  • the present invention also encompasses compounds of the present invention containing protecting groups.
  • protecting groups In any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example, those described in T.W.Greene & P.G.M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups may be removed at an appropriate subsequent stage using methods known in the art.
  • Typical compounds of the present invention include but are not limited to the compounds in the above table.
  • the naming of the compounds in the present invention follows the systematic naming, or is named using ChemDraw software.
  • the mass spectrum was obtained by LC/MS using ESI as the ionization method.
  • HPLC model Agilent 1260, Thermo Fisher U3000; chromatographic column model: Waters xbrige C18 (4.6*150 mm, 3.5 ⁇ m); mobile phase: A: ACN, B: Water (0.1% H 3 PO 4 ); flow rate: 1.0 mL/min; gradient: 5% A for 1 min, increase to 20% A within 4 min, increase to 80% A within 8 min, 80% A for 2 min, back to 5% A within 0.1 min; wavelength: 220 nm; column oven: 35°C.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.2mm-0.3mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.
  • Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1L.
  • the solution in the reaction refers to an aqueous solution.
  • reaction temperature is room temperature, 20°C-30°C.
  • the reaction progress in the embodiment is monitored by thin layer chromatography (TLC), and the developing solvent used in the reaction, the eluent system of column chromatography or the developing solvent system of thin layer chromatography used for purifying the compound includes: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: n-hexane: ethyl acetate; wherein the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagent, such as acetic acid or triethylamine, can also be added for adjustment.
  • TLC thin layer chromatography
  • reaction solution was quenched with water, extracted with dichloromethane, washed with dilute hydrochloric acid, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain a white solid product to obtain the title compound 1c (580 mg, yield 75%) as a white solid.
  • the aqueous phase was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was purified by silica gel column chromatography to obtain the title compound 1d (148 mg, yield 44%) as a yellow solid.
  • the title compound 1 (45 mg, yield 71%) was synthesized as a brown solid by referring to the first step synthesis method.
  • Ethyl [1,2,4]triazolo[4,3-a]pyridine-7-carboxylate 2a (150 mg, 0.78 mmol) was dissolved in a mixture of methanol (2 mL) and tetrahydrofuran (2 mL). A 2N aqueous sodium hydroxide solution (2 mL) was added at room temperature. After stirring at room temperature for 4 hours, TLC showed that the starting material disappeared. 1N dilute hydrochloric acid was added to adjust the pH to 2-3, and the mixture was extracted with ethyl acetate (10 mL x 3). The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound 2b (120 mg, yield 94%) as a light brown solid.
  • reaction solution was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain the title compound 2 as a white solid (20 mg, yield 25%).
  • Example 13 was synthesized by referring to the synthesis method of the fourth and fifth steps of Example 12, and the reaction raw materials were ethylboric acid and 12e:
  • reaction solution is quenched with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product is purified by silica gel column chromatography to obtain the title compound 18b (334 mg, yield 19%) as a brown solid.
  • 1,2-Dihydroacenaphthene-5-amine 1b (100 mg, 0.59 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 2-bromoisonicotinic acid 19a (100 mg, 0.59 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (147 mg, 0.77 mmol) and 4-dimethylaminopyridine (7 mg, 0.06 mmol) were added at room temperature. The mixture was stirred at room temperature for 16 hours, and detected by TLC. The reaction solution was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and passed through a column to obtain a light green solid 19b (15 mg, yield 82%).
  • reaction solution was neutralized with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 21 (10 mg, yield 8%) as a white solid.
  • Compound 22 was synthesized by referring to the second step synthesis method of Example 21.
  • compound 21a 300 mg, 1.35 mmol
  • potassium vinyl trifluoroborate 23a 271 mg, 2.03 mmol
  • triethylamine 682 mg, 6.74 mmol
  • [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex 46 mg, 0.056 mmol
  • 1,4-dioxane 6 mL
  • water 1.5 mL
  • Compound 23 was synthesized by referring to the second step synthesis method of Example 21 (268 mg, yield 86%).
  • 1-Amino-5-bromonaphthalene 21a (500 mg, 2.2 mmol) was dissolved in a mixture of 1,4-dioxane (10 mL) and water (5 mL).
  • 1-Cyclopenteneboronic acid pinacol ester 24a (1.31 g, 6.58 mmol) and cesium carbonate (2.2 g, 6.58 mmol) were added in sequence at room temperature.
  • the atmosphere was replaced with nitrogen three times, and Pd(dppf)Cl 2 (50 mg, catalytic amount) was added. After the addition was completed, the temperature was raised to 100°C under nitrogen protection and reacted for 2 hours.
  • the reaction solution was cooled to room temperature and stirred.
  • reaction solution was quenched with water, extracted with dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate.
  • the crude product was purified by Prep-TLC to obtain the title compound 24b (855 mg, crude product) as a yellow oil, which was directly used in the next step.
  • Compound 24 was synthesized by referring to the second step synthesis method of Example 21.
  • Compound 25 was synthesized by referring to the second step synthesis method of Example 21.
  • the mixture was cooled and quenched with water (6 mL). A white solid precipitated. The organic phase was sucked away, and the residue was dissolved in methanol (3 mL). The white solid was slurried with ultrasonic beating to obtain a white solid. The white solid was slurried with water (8 mL) to obtain the title compound 26b (400 mg, yield 64%) as a white solid.
  • Compound 27 was synthesized by referring to the second step synthesis method of Example 21.
  • Compound 28 was synthesized by referring to the second step synthesis method of Example 21.
  • the title compound 29a (86 mg, yield 85%) was synthesized as a brown oil by referring to the first step of the synthesis method in Example 1.
  • Compound 29 was synthesized by referring to the second step synthesis method of Example 21.
  • 3-Amino-4-fluorobenzoic acid methyl ester 30a 500 mg, 2.96 mmol
  • paraformaldehyde 888 mg, 29.60 mmol
  • acetic acid 30 mL
  • sodium cyanoborohydride 558 mg, 8.88 mmol
  • Compound 30 was synthesized by referring to the second step synthesis method of Example 21.
  • 2-Bromoethane-1-ol 31c (1.0 g, 8.0 mmol) was dissolved in dichloromethane, and then added with 3,4-dihydro-2H-pyran (0.81 g, 9.6 mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate in an ice bath. The mixture was stirred at room temperature and detected by TLC. The reaction solution was quenched with water, extracted with dichloromethane, washed with saturated brine, and dried. The crude product was purified by silica gel column chromatography to obtain a colorless liquid 31d (1.1 g, yield 63%).
  • Step 4 4-Fluoro-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoic acid 31f
  • Step 5 N-(5-cyclopropylnaphthalen-1-yl)-4-fluoro-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzamide 31 g
  • the title compound 32e (50 mg, yield 75%) was synthesized as a brown liquid by referring to the method of the fourth step of Example 12.
  • Compound 32 was synthesized by referring to the second step synthesis method of Example 21.
  • the title compound 35b (194 mg, yield 33%) was synthesized as a pale yellow solid by referring to the method of the third step of Example 34.
  • 3-Nitro-o-phenylenediamine 36a (1.00 g, 6.53 mmol) was dissolved in formic acid, and the temperature was raised to 105°C for TLC detection. The reaction solution was cooled to room temperature and concentrated. The crude product was adjusted to neutral pH with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 36b (482 mg, yield 45%) as a yellow oil.
  • the second to fourth steps were prepared by referring to the first to third steps of Example 35, and compound 36b was used as the raw material to obtain the title compound 36 (45 mg, yield 66%) as a white powder.
  • the title compound 38b (39 mg, yield 23%) was synthesized as a yellow solid by referring to the method of the fourth step of Example 12.
  • Compound 38 was synthesized by referring to the second step synthesis method of Example 37 (19.4 mg, yield 35%).
  • the first step is N-(5-cyclopropyl-2-(methylsulfonamido)naphthalen-1-yl)-4-fluorobenzamide 41
  • the first step is methyl (5-(4-fluorobenzamido)-1,2-dihydroacenaphthene-4-yl)carbamate 46
  • the title compound 47f (75 mg, yield 71%) was synthesized as a yellow oil by referring to the method of the fourth step of Example 12.
  • the title compound 47 (8 mg, yield 24%) was synthesized as a white solid by referring to the first step of the synthesis method in Example 1.
  • 5-Amino-1-naphthol 48a (100 mg, 0.63 mmol) was dissolved in N,N-dimethylformamide, cooled to 0°C, sodium hydrogen sulfide (60%, 30 mg, 0.75 mmol) was added in batches, and iodomethane (134 mg, 0.94 mmol) diluted with N,N-dimethylformamide was added dropwise.
  • Compound 48 was synthesized by referring to the second step synthesis method of Example 40. White powdery solid (75 mg, yield 71%).
  • the title compound 49 (20 mg, yield 57%) was synthesized as a white solid by referring to the second step synthesis method of Example 40.
  • 5-amino-2-naphthol 51a (100 mg, 0.63 mmol) was dissolved in DMF (3 mL), cooled to 0°C, and sodium hydrogen sulfide (60%, 30 mg, 0.75 mmol) was added in batches. After the addition was completed, the reaction was continued for 1 hour. Methyl iodide (134 mg, 0.94 mmol) diluted with DMF (0.5 mL) was added dropwise. After the addition was completed, the temperature was raised to room temperature and reacted for 5 hours. TLC detection was performed, the mixture was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Prep-TLC to obtain the title compound 51b (81 mg, yield 74%) as a light brown powder.
  • the title compound 52c (35 mg, yield 83%) was synthesized as pink crystals by referring to the method of the fourth step of Example 12.
  • the title compound 54 (4.31 mg, yield 7.4%) was synthesized as a white solid powder by referring to the first step of the synthesis method in Example 1.
  • Step 5 Benzyl (7-cyclopropyl-2-methyl-2H-indazol-3-yl)carbamate 55f
  • the title compound 55f (137 mg, yield 64%) was synthesized as a yellow solid by referring to the method of the fourth step of Example 12.
  • Example 57 compound 12f and 2,4-difluorobenzoic acid 99a were used as raw materials to synthesize the title compound 59 (57 mg, yield 68%) as a yellow solid.
  • Example 60 Referring to the synthesis method of Example 60, compound 21c and 2-cyano-4-fluorobenzoic acid were used as raw materials to synthesize the title compound 61 (49 mg, yield 55%) as an off-white solid.
  • the title compound 62 (5 mg, yield 21%) was synthesized as a white solid by referring to the method of the fourth step of Example 12.
  • the title compound 63 (42 mg, yield 81%) was synthesized as a white solid by referring to the third step synthesis method of Example 35.
  • Example 63 Referring to the synthesis method of Example 63, compound 33c and 3-fluorobenzoic acid were used as raw materials to synthesize the title compound 65 (32 mg, yield 39%) as a white solid.
  • Step 1 2-Chloro-5-cyclopropylnaphthalene-1-amine 71a
  • Example 94 Referring to the synthesis method of Example 94, 34b and 2-bromomethyltetrahydrofuran were used as raw materials to synthesize a gray solid 73 (21 mg, yield 55%).
  • Example 94 With reference to the synthesis method of Example 94, the title compound 74 (19 mg, yield 54%) was synthesized as an off-white solid using compound 34b and isobutyl bromide as raw materials.
  • the first step is N-(2-acetylamino-5-cyclopropylnaphthalen-1-yl)-4-fluorobenzamide 78
  • Step 5 8-Cyclopropyl-2-methylquinazoline-4-amine 79f
  • Propionic acid 210 mg, 2.84 mmol was dissolved in N,N-dimethylformamide (5 mL), and EDCI (606 mg, 3.16 mmol) and 4-dimethylaminopyridine (39 mg, 0.31 mmol) were added in sequence. After stirring at room temperature for 30 minutes, 1,5-naphthalenediamine 80a (500 mg, 3.16 mmol) was added.
  • the title compound 80 (22 mg, yield 18%) was synthesized as a grey solid.
  • Example 80 Referring to the synthesis method of Example 80, the title compound 81 (40 mg, yield 91%) was synthesized as a grey solid using compound 80a and 3-methylbutyric acid as raw materials.
  • the first step is N-(5-cyanonaphthalen-1-yl)-4-fluorobenzamide 82
  • the first step is (5-(4-fluorobenzamido)naphthalen-1-yl)methyl)carbamic acid tert-butyl ester 83
  • Embodiment 84 is a diagrammatic representation of Embodiment 84.
  • the first step is tert-butyl (5-(4-fluorobenzamido)naphthalen-1-yl)methyl)carbamate 84a
  • Step 2 4-Fluoro-N-(5-((3-methylbutyramido)methyl)naphthalen-1-yl)benzamide 84
  • Example 85 Referring to the synthesis method of Example 85, compound 21a and methyl chloroformate were used as raw materials to synthesize the title compound 86 (16 mg, yield 13%) as a white solid.
  • the title compound 89b (104 mg, yield 32%) was synthesized as a yellow solid by referring to the method of the second step of Example 34.
  • the title compound 89c (84 mg, yield 94%) was synthesized as a brown solid by referring to the first step of the synthesis method in Example 1.
  • reaction solution was diluted with water, extracted with ethyl acetate, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 92b (1.18 g, crude product) as a white solid.
  • the title compound 92f (121 mg, yield 73%) was synthesized as a yellow solid by referring to the method of the second step of Example 34.
  • the title compound 92 (14 mg, yield 11%) was synthesized and purified as a light yellow solid.
  • the title compound 93d (516 mg, yield 39%) was synthesized as a yellow solid by referring to the method of the fourth step of Example 92.
  • Step 4 tert-butyl 7-bromo-3-(bis(tert-butyloxycarbonyl)amino)-5-methyl-1H-indazole-1-carboxylate 93e
  • Step 5 tert-butyl 3-(bis(tert-butyloxycarbonyl)amino)-7-cyclopropyl-5-methyl-1H-indazole-1-carboxylate 93f
  • Step 6 7-cyclopropyl-5-methylindazole-3-amine 93g
  • Step 7 2-(7-cyclopropyl-5-methyl-1H-indazol-3-yl)isoindoline-1,3-dione 93h
  • Step 8 2-(7-cyclopropyl-5-methyl-1-propyl-2-ynyl)-1H-indazol-3-yl)isoindoline-1,3-dione 93i
  • Step 9 7-Cyclopropyl-5-methyl-1-propyl-2-alkynyl-1-indazol-3-amine 93j
  • Step 10 N-(7-cyclopropyl-5-methyl-1-propyl-2-ynyl)-1H-indazol-3-yl)-4-fluorobenzamide 93
  • the target compound 94 (28 mg, yield 82%) was synthesized by referring to the method of the third step of Example 34.
  • Example 94 Referring to the synthesis method of Example 94, compound 34b and 1-bromo-3-fluoropropane were used as raw materials to synthesize the title compound 95 (21 mg, yield 59%) as a white solid.
  • Step 1 N-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-cyclopropyl-1H-indazol-3-yl)-4-fluorobenzamide 97a
  • the title compound 97a (97 mg, yield 63%) was synthesized as a yellow solid by referring to the method of the third step of Example 34.
  • 2,4-Difluorobenzoic acid 99a (150 mg, 0.95 mmol) was dissolved in dichloromethane (3 mL), and a catalytic amount of N,N-dimethylformamide (1 drop) was added. The mixture was cooled to 0°C, and oxalyl chloride (242 mg, 1.91 mmol) was added dropwise. The mixture was heated to room temperature and stirred for 2 hours. TLC showed that the reaction of the starting material was complete. The mixture was concentrated to give the title compound 99b (165 mg, yield 98%) as a colorless oil.
  • the title compound 99c (140 mg, yield 86%) was synthesized as a white solid by referring to the method of the second step of Example 34.
  • Step 2 3-(bis(tert-butoxycarbonyl)amino)-7-(prop-1-en-2-yl)-1H-indazole-1-carboxylic acid tert-butyl ester 101b
  • reaction solution was slowly dropped into saturated aqueous ammonium chloride solution (30 mL) for quenching, extracted with ethyl acetate (20 mL x 3), washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, and concentrated.
  • Step 5 4-Fluoro-N-(7-(1-methylcyclopropyl)-1H-indazol-3-yl)benzamide 101e
  • the title compound 101e (84 mg, yield 31%) was synthesized as a white solid by referring to the method of the second step of Example 34.
  • the title compound 101 (18 mg, yield 19%) was synthesized and purified by referring to the method of Example 72 to obtain a white solid.
  • the title compound 102d (736 mg, yield 77%) was synthesized by referring to the method of the fourth step of Example 92 as a light yellow oil.
  • the title compound 102e (405 mg, yield 84%) was synthesized as a yellow solid by referring to the method of the second step of Example 34.
  • Step 5 N-(7-(difluoromethoxy)-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 102
  • the title compound 102 (38 mg, yield 29%) was synthesized as a pale yellow solid by referring to the method of Example 72.
  • the title compound 103b (231 mg, yield 72%) was synthesized by referring to the method of the fourth step of Example 92 as a yellow foam.
  • the title compound 103c (146 mg, yield 69%) was synthesized as a white solid by referring to the method of the second step of Example 34.
  • Step 3 4-Fluoro-N-(7-methoxy-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)benzamide 103
  • the title compound 103 (49 mg, yield 72%) was synthesized as a white solid by referring to the method of Example 72.

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Abstract

L'invention concerne un composé (I) ou un sel pharmaceutiquement acceptable, un ester, un isomère optique, un tautomère, un stéréoisomère, un polymorphe, un solvate, un N-oxyde, un composé marqué par un isotope, un métabolite, un chélate, un complexe, un composé d'inclusion ou un promédicament de celui-ci, et une composition pharmaceutique comprenant le composé. L'invention concerne en outre une utilisation du composé en tant que régulateur de canal potassique, une utilisation du composé dans la préparation d'un médicament pour des maladies associées à un canal potassique, et une composition pharmaceutique correspondante.
PCT/CN2023/129942 2022-11-11 2023-11-06 Composé arylamide, composition pharmaceutique le comprenant, son utilisation WO2024099269A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003089404A1 (fr) * 2002-04-19 2003-10-30 Abbott Laboratories Amides du naphtalene utilises comme agents d'ouverture du canal potassique
WO2004096767A1 (fr) * 2003-04-25 2004-11-11 H. Lundbeck A/S Derives indole et indoline substitues
WO2009015667A1 (fr) * 2007-08-01 2009-02-05 H. Lundbeck A/S Utilisation d'agents d'ouverture kncq des canaux potassiques pour réduire des symptomes ou traiter des troubles et des états dans lesquels le système dopaminergique est détruit
CN101842011A (zh) * 2007-08-17 2010-09-22 安克进药物公司 作为钾通道调节剂的杂环
CN114380731A (zh) * 2022-03-09 2022-04-22 台州学院 一种kcnq钾离子通道激动剂、药物组合物及其应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003089404A1 (fr) * 2002-04-19 2003-10-30 Abbott Laboratories Amides du naphtalene utilises comme agents d'ouverture du canal potassique
WO2004096767A1 (fr) * 2003-04-25 2004-11-11 H. Lundbeck A/S Derives indole et indoline substitues
WO2009015667A1 (fr) * 2007-08-01 2009-02-05 H. Lundbeck A/S Utilisation d'agents d'ouverture kncq des canaux potassiques pour réduire des symptomes ou traiter des troubles et des états dans lesquels le système dopaminergique est détruit
CN101842011A (zh) * 2007-08-17 2010-09-22 安克进药物公司 作为钾通道调节剂的杂环
CN114380731A (zh) * 2022-03-09 2022-04-22 台州学院 一种kcnq钾离子通道激动剂、药物组合物及其应用

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Title
DATABASE REGISTRY 28 October 2021 (2021-10-28), ANONYMOUS: "Benzamide, N-(1,2-dihydro-4-methoxy-5-acenaphthylenyl)-4-methoxy- (CA INDEX NAME)", XP093170649, retrieved from STN Database accession no. 2719834-60-1 *

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