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WO2024099269A1 - Arylamide compound, pharmaceutical composition comprising same, use thereof - Google Patents

Arylamide compound, pharmaceutical composition comprising same, use thereof Download PDF

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Publication number
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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WIPO (PCT)
Prior art keywords
mmol
compound
yield
substituted
title compound
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Application number
PCT/CN2023/129942
Other languages
French (fr)
Chinese (zh)
Inventor
阳怀宇
叶阳亮
王昆
张少英
张乾森
莫奕青
梅良和
Original Assignee
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/en

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    • C07C233/80—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
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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

Provided are following compound (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 pharmaceutical composition comprising the compound. Further provided are a use of the compound as a potassium channel regulator, a use of the compound in preparation of a drug for diseases associated with a potassium channel, and a corresponding pharmaceutical composition.

Description

芳基酰胺化合物、包含其的药物组合物及其用途Arylamide compound, pharmaceutical composition containing the same and use thereof 技术领域Technical Field
本发明属于化学及生物医药技术领域，具体涉及一种新骨架的酰胺类衍生物、其制备方法及用途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
背景技术Background technique
Kv7钾通道是一类电压依赖性钾离子通道，具有低阈值激活、慢激活和非失活的特点。Kv7钾通道具有五个家族成员(Kv7.1-Kv7.5，或称KCNQ1-KCNQ5)，所有的Kv7钾通道成员具有相似的结构，即由四个亚基组成一个功能性通道，每个亚基包含六个跨膜片段(S1-S6)。其S1-S4是电压感受区，在感受膜电位变化和控制构象改变等方面具有重要作用；S5-S6是通道孔区的主要组成部分，是钾通道开放剂的主要组合和作用区域。KV7.1钾通道是一种非神经元通路，分布于外周组织，在心脏中表达，以介导心肌Iks，其突变可导致Long Q-T综合征。Kv7.2-Kv7.5钾通道是神经元M电流的基础，广泛分布于神经系统中，具有多种生理活性。电压门控钾离子通道KCNQ2主要在神经系统中表达，它与电压门控钾离子通道KCNQ3组装成异源四聚体，共同介导M-current(IKM)。IKM是一种慢激活、慢去活和非失活的电流，在维持静息膜电位、减少兴奋性刺激所触发的内在放电和重复动作电位放电方面发挥重要作用。1998年首次在良性家族性新生儿惊厥患者家族中发现了KCNQ2基因突变，揭示了KCNQ2通道与癫痫疾病的相关性。大量的临床研究发现，KCNQ2基因突变与癫痫、良性家族性新生儿惊厥或新生儿癫痫性脑病、周围神经过度兴奋(PNH或肌强直或神经性肌强直)等疾病的发作有关。KCNQ2通道在痛觉感受传导通路的各级神经元以及涉及疼痛的大脑区域表达则提示KCNQ2通道作为镇痛靶点的可能性。功能实验证明在神经性疼痛、骨关节炎疼痛、骨癌痛等模型中，KCNQ2表达量下调，激活KCNQ2通道可缓解神经性疼痛和纤维肌痛。此外，KCNQ2通道活性的调控还与帕金森病、缺血、精神分裂症、平滑肌疾病和抑郁等神经疾病相关。鉴于IKM在中枢和外周神经系统中控制神经元兴奋性方面具有的重要作用，KCNQ2通道被认为是神经系统疾病和代谢性疾病新药开发的重要药理靶点，开发KCNQ2通道调节剂对于治疗疼痛、癫痫或神经性疾病具有潜在应用价值。KCNQ4钾通道高度表达于耳蜗和脑干听觉核的外毛细胞，其突变可能导致遗传性耳聋。KCNQ5钾通道在骨骼肌和脑中高度表达，其突变可能导致视网膜病变等。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. In 1998, 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. 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. Functional experiments have shown that 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. In addition, the regulation of KCNQ2 channel activity is also associated with neurological diseases such as Parkinson's disease, ischemia, schizophrenia, smooth muscle diseases, and depression. Given the important role of IKM in controlling neuronal excitability in the central and peripheral nervous systems, 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.
瑞替加滨是钾离子通道的激动剂，作为一种新型的抗癫痫药物用于辅助治疗部分发作性癫痫在2011年被批准上市，但其靶点选择性差会引起一系列副作用如视网膜色素沉积、皮肤变色和尿潴留等。BMS-204352、ICA-069673、NH29、ZnPy、ML213等一系列具有不同骨架的化合物被报道可以激活KCNQ2通道，在小鼠癫痫发作模型中部分化合物显示抗惊厥作用，但目前仍缺乏大量的临床前资料，考虑到这些新分子中绝大多数尚未开始临床试验，或者像ICA-069673这样已经进入临床II期研究的分子，因为耐受性和药代动力学等原因未能进行下一步临床研究，目前还无法预测它们是否会成功进入市场。
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. Considering that most of these new molecules have not yet started clinical trials, or molecules such as ICA-069673 that have entered clinical phase II studies have not been able to proceed to the next clinical study due to tolerability and pharmacokinetics, it is currently impossible to predict whether they will successfully enter the market.
发明内容Summary of the invention
目前，市场上除了瑞替加滨，虽然已有许多钾离子通道的小分子激动剂被发现，但是尚无其他成功上市的产品。通过计算机辅助药物设计结合理性设计和改造的方法，我们发现了一类具有成药前景的新骨架钾通道的小分子调节剂，并完成了体内外活性的相关研究。为了解决现有技术的上述问题，发明人经过锐意研究，深入探索，开发了一种具有钾通道调节剂的作用的化合物，并对其药理活性进行了深入测试。At present, in addition to retigabine, many small molecule agonists of potassium channels have been discovered on the market, but no other products have been successfully launched. Through computer-aided drug design combined with rational design and modification methods, we have discovered a class of small molecule modulators of new skeleton potassium channels with drug development prospects, and completed relevant studies on in vivo and in vitro activities. In order to solve the above-mentioned problems of the prior art, the inventors have developed a compound with the function of a potassium channel modulator through in-depth research and exploration, and conducted in-depth tests on its pharmacological activity.
具体而言，本发明提供式(I)所示的酰胺化合物或者其药学上可接受的盐、酯、光学异构体、互变异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药，
Specifically, 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,
环A为下述式(II)表示的环结构，
Ring A is a ring structure represented by the following formula (II),
“—”划过的环结构的表达方式，表示连接位点于该环结构上任意能够成键的位置，虚线表示的键表示存在或者不存在；The expression of a ring structure crossed by “—” indicates that the 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选自CRa或N；X2选自CRa、N或O、S、Se、NRa、C(Ra)2；X3不存在，或者选自CRa、N或NRa、O、S、Se、C(Ra)2；X4选自CRa、N或者NRa、C(Ra)2；X5选自CRa、N或O、S、Se、NRa、C(Ra)2；X6和X7表示C原子，X8选自C或N，X2～X7所形成的环为芳香性的或非芳香性； 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;
m为0～4的整数，各R1相同或不同，且各自独立地选自卤素、-CN、C1-C6烷基、C2-C6烯基、C2-C6炔基、饱和或部分不饱和的C3-6环烃基、5-10元螺环烷基、饱和或部分不饱和的3-10元杂环基、5-10元螺杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基、-ORa、-NHRa、-C(O)NHRa、-C(＝O)Ra、-OC(＝O)Ra、-C(＝O)ORa、-ORa、-SRa、-S(＝O)Ra、-S(＝O)2Ra、-S(＝O)2N(Ra)2、-N(Ra)2、-NRa-C(＝O)Ra、-NRa-C(＝O)ORa、-NRa-S(＝O)2-Ra、-NRa-C(＝O)-N(Ra)2、-C1-6亚烷基-S(＝O)2Ra、-C1-6亚烷基-CN、-C1-6亚烷基-S(＝O)Ra、-C1-6亚烷基-N(Ra)2、-C1-6亚烷基-ORa、-C1-6亚烷基-NRa-C(＝O)ORa、-C1-6亚烷基-NRa-C(＝O)Ra、-C1-6亚烯基-ORa和-O-C1-6亚烷基-N(Ra)2；R1中的CH2可以被-O-、-S-或-C(＝O)-替换，R1中的H可以被羟基、卤素或C1-C3烷氧基所取代，R1中的环烃基、螺环烷基、杂环基、螺杂环基、芳基、杂芳基、芳烷基可以被卤素、-CN或C1-C3烷基所取代；两个相邻的R1之间可以连接并与环A的组成原子共同形成环结构；m is an integer from 0 to 4, each R1 is the same or different and is independently selected from halogen, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated or partially unsaturated C3-6 cycloalkyl, 5-10 membered spirocycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, 5-10 membered spiroheterocyclyl, C6-10 aryl, 5-14 membered heteroaryl, C6-12 aralkyl, -ORa , -NHRa, -C (O) NHRa , -C(＝O) Ra , -OC(＝O)Ra, -C(＝O) ORa , -ORa , -SRa , -S(＝O) Ra, -S(＝O)2Ra, -S(＝O)2N(Ra)2, -N(Ra)2 , -NRa , -C ( ＝ O ) Ra , -NRa -C(＝O)OR a , -NR a -S(＝O) 2 -R a , -NR a -C(＝O)-N(R a ) 2 , -C1-6 alkylene-S(＝O) 2 R a , -C1-6 alkylene-CN, -C1-6 alkylene-S(＝O)R a , -C1-6 alkylene-N(R a ) 2 , -C1-6 alkylene-OR a , -C1-6 alkylene-NR a -C(＝O)OR a , -C1-6 alkylene-NR a -C(＝O)R a , -C1-6 alkenylene-OR a and -O-C1-6 alkylene-N(R a ) 2 ; CH 2 in R 1 may be replaced by -O-, -S- or -C(＝O)-, H in R 1 may be substituted by hydroxy, halogen or C1-C3 alkoxy, R The cycloalkyl, spirocycloalkyl, heterocyclyl, spiroheterocyclyl, aryl, heteroaryl, aralkyl in 1 may be substituted by halogen, -CN or C1-C3 alkyl; two adjacent R 1s may be connected and form a ring structure together with the constituent atoms of ring A;
L1为化学键或者NH；L2为化学键或者选自C1-6亚烷基、C2-6亚烯基、C2-6亚炔基、饱和或部分不饱和的C3-10亚环烃基、-O-、-C(＝O)O-、-NRa-、-NRaC(＝S)-、-NRaC(＝O)-、-NRaS(＝O)-、-NRaS(＝O)2-、-S-中的一种或多种组合而成的二价基团； L1 is a chemical bond or NH; L2 is a chemical bond or a divalent group selected from one or more of C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, saturated or partially unsaturated C3-10 cycloalkylene, -O- , -C( = O)O-, -NRa- , -NRaC(=S)-, -NRaC(=O)-, -NRaS(=O)-, -NRaS (=O) 2- , and -S-;
Ra独立地选自H、C1-C10烷基、C1-C10卤代烷基、饱和或部分不饱和的C3-6环烃基、饱和或部分不饱和的3-10元杂环基或者C6-10芳基，Ra中的CH2可以被-O-或-S-替换，Ra中的H可以被羟基、卤素或C1-C3烷氧基所取代；条件是，L1和L2不同时为化学键，L1为化学键时，L2为-NRa-； 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- ;
Ar1选自取代或未取代的C6～C30芳基、取代或未取代的C3～C30杂芳基中的一种；Ar 1 is selected from a substituted or unsubstituted C6-C30 aryl group, a substituted or unsubstituted C3-C30 heteroaryl group;
R2独立地选自取代或未取代的C1-C6烷基、羟基、卤素、氰基、氨基、C1-C6烷基取代氨基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C6环烷基、取代或未取代的C3-C6杂环基、取 代或未取代的苯基、取代或未取代的5-6元的杂芳基、S(O)2Rb1、S(O)2NH2、S(O)2NHRb1、S(O)2NRb1Rb2、NHS(O)2Rb1、NRb1S(O)2Rb2、S(O)(NH)Rb1、S(O)(NRb1)Rb2、C(O)Rb1、C(O)ORb1、OC(O)Rb1、NHC(O)Rb1、NRb1C(O)Rb2、NHC(O)ORb1、NRb1C(O)ORb2、C(O)NH2、C(O)NHRb1、C(O)NRb1Rb2、C(O)NHS(O)2Rb1、S(O)2NHC(O)Rb1；Rb1和Rb2分别独立地选自H、取代或未取代的C1-C3的烷基、取代或未取代的3-6元的环烷基或杂环基，或者Rb1和Rb2连同它们所连接的N原子形成3-7元的杂环基；n为0-4的整数，n为2以上时，多个R2可以相同的也可以不同，两个相邻的R2之间可以连接并与Ar1的组成原子共同形成五元环、或者六元环；上述的取代或未取代是指基团中的H被选自卤素、氰基、硝基、羟基、氨基、醛基、酯基、C1～C30烷基、C1～C30烷氧基、C2～C20杂环烷基、C1～C30烷基硅基、C6～C30芳基、C6～C30芳氧基、C3～C30杂芳基、C6～C30芳基氨基或C3～C30杂芳基氨基中的一种或者至少两种的组合以上的基团所取代，或者指基团中的-CH2-中的两个H被替换成氧代＝O 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(O)R b1 ; R b1 and R b2 are independently selected from H, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted 3-6-membered cycloalkyl or heterocyclic group, or R b1 and R b2 together with the nitrogen atom to which they are connected form a 3-7-membered heterocyclic group; n is an integer of 0-4, and when n is 2 or more, multiple R 2 may be the same or different, and two adjacent R 2 may be connected and connected to Ar 1 together form a five-membered ring or a six-membered ring; the above-mentioned substitution or unsubstitution means that the H in the group is substituted by a group selected from one or a combination of at least two of halogen, cyano, nitro, hydroxyl, amino, aldehyde, ester, C1-C30 alkyl, C1-C30 alkoxy, C2-C20 heterocycloalkyl, C1-C30 alkylsilyl, C6-C30 aryl, C6-C30 aryloxy, C3-C30 heteroaryl, C6-C30 arylamino or C3-C30 heteroarylamino, or means that two H in -CH2- in the group are replaced by oxo=O
条件是，不为以下的具体化合物：
Provided that it is not the following specific compound:
在本发明优选的实施方式中，式(1)中环A表示的结构选自以下结构：
In a preferred embodiment of the present invention, the structure represented by ring A in formula (1) is selected from the following structures:
在本发明优选的实施方式中，m为0～3的整数，R1选自卤素、-CN、羟基、取代或未取代的C1-C6直链烷基、或者任选被卤素、C1～C3的烷基、C1～C3的烷氧基取代的以下基团，
In a preferred embodiment of the present invention, m is an integer of 0 to 3, and 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,
上述的取代或未取代是指基团中的H被选自卤素、氰基、硝基、羟基、氨基、醛基、酯基、C1～C30烷基、C1～C30烷氧基、C2～C20杂环烷基、C1～C30烷基硅基、C6～C30芳基、C6～C30芳氧基、C3～C30杂芳基、C6～C30芳基氨基或C3～C30杂芳基氨基中的一种或者至少两种的组合以上的基团所取代，或者指基团中的-CH2-中的两个H被替换成氧代＝O；The above substitution or unsubstitution means that the H in the group is substituted by one or a combination of at least two of halogen, cyano, nitro, hydroxyl, amino, aldehyde, ester, C1-C30 alkyl, C1-C30 alkoxy, C2-C20 heterocycloalkyl, C1-C30 alkylsilyl, C6-C30 aryl, C6-C30 aryloxy, C3-C30 heteroaryl, C6-C30 arylamino or C3-C30 heteroarylamino, or that two H in -CH 2 - in the group are replaced by oxo=O;
在本发明优选的实施方式中，Ar1为以下基团中的一种或这些基团稠合的组合：In a preferred embodiment of the present invention, Ar 1 is one of the following groups or a fused combination of these groups:
苯基、萘基、蒽基、苯并蒽基、菲基、苯并菲基、芘基、窟基、茈基、荧蒽基、并四苯基、并五苯基、苯并芘基、联苯基、偶苯基、三联苯基、三聚苯基、四联苯基、芴基、螺二芴基、二氢菲基、二氢芘基、四氢芘基、顺式或反式茚并芴基、三聚茚基、异三聚茚基、螺三聚茚基、螺异三聚茚基所组成的群组中的基团。具体地，联苯基选自2-联苯基、3-联苯基和4-联苯基；三联苯基包括对-三联苯基-4-基、对-三联苯基-3-基、对-三联苯基-2-基、间-三联苯基-4-基、间-三联苯基-3-基和间-三联苯基-2-基；所述萘基包括1-萘基或2-萘基；蒽基选自由1-蒽基、2-蒽基和9-蒽基；所述芴基选自由1-芴基、2-芴基、3-芴基、4-芴基和9-芴基；所述芘基选自由1-芘基、2-芘基和4-芘基；并四苯基选自由1-并四苯基、2-并四苯基和9-并四苯基、呋喃基、噻吩基、吡咯基、吡啶基、苯并呋喃基、苯并噻吩基、异苯并呋喃基、异苯并噻吩基、吲哚基、异吲哚基、二苯并呋喃基、二苯并噻吩基、咔唑基及其衍生物、喹啉基、异喹啉基、吖啶基、菲啶基、苯并-5，6-喹啉基、苯并-6，7-喹啉基、苯并-7，8-喹啉基、吩噻嗪基、吩嗪基、吡唑基、吲唑基、咪唑基、苯并咪唑基、萘并咪唑基、菲并咪唑基、吡啶并咪唑基、吡嗪并咪唑基、喹喔啉并咪唑基、嗯唑基、苯并嗯唑基、萘并嗯唑基、蒽并嗯唑基、菲并嗯唑基、1，2-噻唑基、1，3-噻唑基、苯并噻唑基、哒嗪基、苯并哒嗪基、嘧啶基、苯并嘧啶基、喹喔啉基、1，5-二氮杂蒽基、2，7-二氮杂芘基、2，3-二氮杂芘基、1，6-二氮杂芘基、1，8-二氮杂芘基、4，5-二氮杂芘基、4，5，9，10-四氮杂茈基、吡嗪基、吩嗪基、吩噻嗪基、萘啶基、氮杂咔唑基、苯并咔啉基、菲咯啉基、1，2，3-三唑基、1，2，4-三唑基、苯并三唑基、1，2，3-噁二唑基、1，2，4-嗯二唑基、1，2，5_嗯二唑基、1，2，3-噻二唑基、1，2，4-噻二唑基、1，2，5-噻二唑基、1，3，4-噻二唑基、1，3，5-三嗪基、1，2， 4-三嗪基、1，2，3-三嗪基、四唑基、1，2，4，5-四嗪基、1，2，3，4-四嗪基、1，2，3，5-四嗪基、嘌呤基、蝶啶基、吲嗪基、苯并噻二唑；氮丙啶基、环氧基、吡咯烷基、四氢呋喃基、四氢吡喃基、噻唑烷基、哌啶基、哌嗪基、吗啉基、二氧杂戊环基、二氧杂己环基、二硫杂戊环基、二硫杂己环基。A group selected from the group consisting of phenyl, naphthyl, anthracenyl, benzanthryl, phenanthryl, triphenanthrenyl, pyrenyl, chrysene, peryl, fluoranthenyl, tetraphenyl, pentacene, benzopyrenyl, biphenyl, phenylene, terphenyl, triphenylene, quaterphenylene, fluorenyl, spirobifluorenyl, dihydrophenanthryl, dihydropyrenyl, tetrahydropyrenyl, cis- or trans-indenofluorenyl, trimerized indenyl, isotrimerized indenyl, spirotrimerized indenyl, and spiroisotrimerized indenyl. Specifically, 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 selected from the group consisting of 1-naphthyl, 2-naphthyl and 9-naphthyl, furyl, thienyl, pyrrolyl, pyridyl, benzofuranyl, benzothienyl, isobenzofuranyl, isobenzothienyl, indolyl, isoindolyl, dibenzofuranyl, dibenzothienyl, carbazolyl and its derivatives, quinolyl, isoquinolyl, acridinyl, phenanthridinyl, benzo-5,6-quinolyl, benzo-6,7-quinolyl, benzo-7,8-quinolyl, phenothiazinyl, phenazinyl, pyraz ... 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, pyrazinyl, phenazinyl, phenothiazinyl, naphthyridinyl, azacarbazolyl, benzocarbolinyl, phenanthrolinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzotriazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,3,5-triazinyl, 1,2, 4-triazinyl, 1,2,3-triazinyl, tetrazolyl, 1,2,4,5-tetrazinyl, 1,2,3,4-tetrazinyl, 1,2,3,5-tetrazinyl, purinyl, pteridinyl, indolizinyl, benzothiadiazole; aziridinyl, epoxy, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, dioxolanyl, dioxanyl, dithiolanyl, dithiolanyl.
在本发明优选的实施方式中，Ar1为以下基团中的一种或这些基团的组合：
In a preferred embodiment of the present invention, Ar 1 is one of the following groups or a combination of these groups:
在本发明优选的实施方式中，n为0～2的整数，R2选自以下基团：F、I、Cl、Br、OMe、OH、NH2、CN。In a preferred embodiment of the present invention, n is an integer of 0 to 2, and R 2 is selected from the following groups: F, I, Cl, Br, OMe, OH, NH 2 , and CN.
表示连接的位置，“—”划过的环结构的表达方式，表示连接位点于该环结构上任意能够成键的位置。 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.
在本发明进一步优选的实施方式中，Ar1为苯基，n为1，R2为F、Cl、Br、或I，m为0～2的整数，R1为卤素、环丙基、甲基、乙基、异丙基、叔丁基、环丁基、二氟甲氧基、三氟甲氧基、亚甲基炔基、甲氧基、亚甲基氰基、二氟甲基、乙酰基，式(II)表示的环结构为选自下述环结构中的基团：
In a further preferred embodiment of the present invention, 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:
在初步的药理实验中，本发明化合物表现出作为钾离子通道调节剂的用途，综上，本发明还提供上述化合物及其各种衍生物质(药学上可接受的无机或有机盐，水合物或溶剂合物)等，以及含有本发明化合物为主要活性成分的药物组合物可用于制备缓解和治疗与钾离子通道相关的疾病的药物中的应用。In preliminary pharmacological experiments, the compounds of the present invention have shown their use as potassium ion channel modulators. In summary, 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.
本发明优先实施方式中，钾离子通道优选的是指2型电压门控钾离子通道KCNQ2，有时也简称为KCNQ2通道。In a preferred embodiment of the present invention, the potassium ion channel preferably refers to a type 2 voltage-gated potassium ion channel KCNQ2, sometimes also referred to as a KCNQ2 channel.
本发明实施方式中，调节剂优选是激活剂，或称激动剂。In the embodiment of the present invention, the regulator is preferably an activator, or agonist.
一般而言，与钾离子通道相关疾病是指中枢神经系统疾病或病症，这些疾病或病症包括发作性疾病、焦虑症、神经性疼痛和偏头痛、神经变性疾病、中风、可卡因滥用、尼古丁戒断症状、乙醇戒断症状、耳鸣和阿尔兹海默症，郁症、衰老过程中的睡眠障碍、神经发育障碍。其中，所述发作性疾病选自急性发作性疾病、惊厥、癫痫持续状态、癫痫症如癫痫综合征和癫痫发作、新生儿痉挛、新生儿癫痫发作、良性家族性新生儿癫痫(KCNQ2-BFNE)、癫痫性脑病(KCNQ2-NEE)、良性家族性新生儿惊厥1型(BFNC)、良性家族性新生儿癫痫发作1(BFNS1)、与缺氧缺血性损伤相关的新生儿癫痫发作、癫痫性痉挛、癫痫性脑病、婴儿早期癫痫性脑病7(EIEE7)、精神运动发育迟缓的婴儿早期癫痫性脑病、全面强直癫痫发作、苍白球形态异常、呼吸暂停、脑水肿、肌张力障碍、面部红斑、肌张力低下、热性癫痫发作、胼胝体发育不全、高度节律失调、局灶性阵挛性癫痫发作、全面强直阵挛性癫痫发作、肌纤维颤搐、痉挛性四肢轻瘫和肌纤维颤搐；Generally speaking, 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. wherein the 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, generalized tonic-clonic seizures, myokymia, spastic quadriplegia and myokymia;
所述焦虑症选自焦虑和与下述疾病相关的疾病和病症：惊恐发作、广场恐怖症、伴有广场恐 怖症的惊恐障碍、无广场恐怖症的惊恐障碍、无惊恐障碍史的广场恐怖症、特定性恐惧症、社交恐惧症和其它特定性恐惧症、强迫症、创伤后应激障碍、急性应激障碍、广泛性焦虑症、由一般躯体病症引起的焦虑症、物质诱导的焦虑症、离别焦虑症、适应失调、表现焦虑、疑病障碍、由一般躯体病症引起的焦虑症和物质诱导的焦虑症和未有特殊说明的焦虑症；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;
所述神经性疼痛和偏头痛选自异常性疼痛、痛觉过敏性疼痛、幻痛、与糖尿病性神经病变相关的神经性疼痛、与三叉神经痛相关的神经性疼痛与坐骨神经痛相关的神经性疼痛与偏头痛相关的神经性疼痛；或，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,
所述神经变性疾病选自Alzheimer's病、Huntington's舞蹈病、多发性硬化症、肌萎缩性侧索硬化、Creutzfeld-Jakob's、Parkinson's病、由AIDS引起的或由风疹病毒、疱疹病毒、疏螺旋体属或未知病原体感染诱导的脑病、外伤诱导的神经变性性病变、神经元兴奋过度状态如在药物戒断或中毒症状中以及外周神经系统的神经变性疾病如多发性神经病和多发性神经炎。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.
所述抑郁症选自双相抑郁、产后抑郁、严重的抑郁症、精神抑郁症、非典型抑郁症、精神忧郁症、难治性抑郁症、亨廷顿氏病有关的抑郁症、多发性硬化症有关的抑郁症或焦虑症有关的抑郁症。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.
所述神经发育障碍选自发育迟缓、智力障碍、非综合征性智力障碍、自闭症谱系障碍(ASD)。The neurodevelopmental disorder is selected from the group consisting of developmental delay, intellectual disability, non-syndromic intellectual disability, and autism spectrum disorder (ASD).
上述医药用途中，所述式(I)化合物的施用剂量为0.1-200mg/kg。In the above-mentioned medical use, the dosage of the compound of formula (I) is 0.1-200 mg/kg.
本发明的化合物中各基团的具体例和优选例，以及本发明化合物的具体例子，与上述医药用途中化合物中各基团的具体例和优选例、化合物的优选例相同，在此不赘述。The specific examples and preferred examples of each group in the compound of the present invention, as well as the specific examples of the compound of the present invention, are the same as the specific examples and preferred examples of each group in the compound for medical use, as well as the preferred examples of the compound, and are not repeated here.
本发明还提供一种药物组合物，其包含预防或治疗有效量的式(I)所示的化合物或者其药学上可接受的盐、酯、光学异构体、互变异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药，以及药学上可接受的载体，所述药物组合物优选为固体制剂、半固体制剂、液体制剂或气态制剂。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.
本发明的一个实施方式中，所述的药物组合物的剂型为口服剂型或注射剂，所述口服剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂；所述注射剂包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的本发明的化合物或者其药学上可接受的盐、酯、光学异构体、互变异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药无菌粉末。In one embodiment of the present invention, the dosage form of the pharmaceutical composition is an oral dosage form or an injection, and 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.
相比于现有技术，本发明具有如下优势：Compared with the prior art, the present invention has the following advantages:
这类化合物与瑞替加滨相比，具有全新骨架类型，且其理化性质更稳定，不易被氧化，产生如色素沉着等副作用。瑞替加滨在结构上有一个三胺基苯环，理化性质不稳定，容易被氧化。目前的研究普遍认为瑞替加滨被氧化是产生色素沉积的主要原因。且本发明的化合物具有比瑞替加滨更好的抗癫痫效果。。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. .
具体实施方式Detailed ways
以下说明本发明其他各要素进行更加详细的说明。The other elements of the present invention are described below in more detail.
定义definition
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。Unless otherwise defined below, the meanings of all technical terms and scientific terms used herein are intended to be the same as those generally understood by those skilled in the art. Reference to the technology used herein is intended to refer to the technology generally understood in the art, including those changes in technology or replacement of equivalent technology that are obvious to those skilled in the art. Although it is believed that the following terms are well understood by those skilled in the art, the following definitions are still set forth to better explain the present invention.
本发明中，-In the present invention, -
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。The terms "comprises," "comprising," "having," "containing," or "involving" and other variations thereof herein are inclusive or open-ended and do not exclude additional unrecited elements or method steps.
如本文中所使用，术语“亚烷基”表示饱和二价烃基，优选表示具有1、2、3、4、5或6个碳原子的饱和二价烃基，例如亚甲基、亚乙基、亚丙基或亚丁基。As used herein, the term "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.
如本文中所使用，术语“烷基”定义为线性或支化饱和脂肪族烃。在一些实施方案中，烷基具有1至12个，例如1至6个碳原子。例如，如本文中所使用，术语“C1-6烷基”指1至6个碳原子的 线性或支化的基团(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基或正己基)，其任选地被1或多个(诸如1至3个)适合的取代基如卤素取代(此时该基团被称作“卤代烷基”)(例如CH2F、CHF2、CF3、CCl3、C2F5、C2Cl5、CH2CF3、CH2Cl或-CH2CH2CF3等)。术语“C1-4烷基”指1至4个碳原子的线性或支化的脂肪族烃链(即甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)。As used herein, the term "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), which is optionally substituted with 1 or more (e.g., 1 to 3) 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.). The term "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).
如本文中所使用，术语“烯基”意指线性的或支化的单价烃基，其包含一个双键，且具有2-6个碳原子(“C2-6烯基”)。所述烯基为例如乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基和4-甲基-3-戊烯基。当本发明的化合物含有烯基时，所述化合物可以纯E(异侧(entgegen))形式、纯Z(同侧(zusammen))形式或其任意混合物形式存在。As used herein, the term "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. When the compound of the present invention contains an alkenyl group, the compound may exist in the pure E (entgegen) form, the pure Z (zusammen) form or any mixture thereof.
如本文中所使用，术语“炔基”表示包含一个或多个三键的单价烃基，其优选具有2、3、4、5或6个碳原子，例如乙炔基或丙炔基。As used herein, the term "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.
如本文中所使用，术语“环烷基”指饱和的单环或多环(诸如双环)烃环(例如单环，诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基，或双环，包括螺环、稠合或桥连系统(诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基或双环[5.2.0]壬基、十氢化萘基等))，其任选地被1或多个(诸如1至3个)适合的取代基取代。所述环烷基具有3至15个碳原子。例如，术语“C3-6环烷基”指3至6个成环碳原子的饱和的单环或多环(诸如双环)烃环(例如环丙基、环丁基、环戊基或环己基)，其任选地被1或多个(诸如1至3个)适合的取代基取代，例如甲基取代的环丙基。As used herein, the term "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. The cycloalkyl has 3 to 15 carbon atoms. For example, the term " 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.
如本文中所使用，术语“亚环烃基”、“环烃基”和“烃环”是指具有例如3-10个(适合地具有3-8个，更适合地具有3-6个)环碳原子的饱和(即，“亚环烷基”和“环烷基”)或不饱和的(即在环内具有一个或多个双键和/或三键)单环或多环烃环，其包括但不限于(亚)环丙基(环)、(亚)环丁基(环)、(亚)环戊基(环)、(亚)环己基(环)、(亚)环庚基(环)、(亚)环辛基(环)、(亚)环壬基(环)、(亚)环己烯基(环)等。As used herein, the terms "cycloalkylene", "cycloalkyl" and "hydrocarbon ring" refer 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.
如本文中所使用，术语“杂环基”、“亚杂环基”和“杂环”是指具有例如3-10个(适合地具有3-8个，更适合地具有3-6个)环原子、其中至少一个环原子是选自N、O和S的杂原子且其余环原子是C的饱和(即，杂环烷基)或部分不饱和的(即在环内具有一个或多个双键和/或三键)环状基团。例如，“3-10元(亚)杂环(基)”是具有2-9个(如2、3、4、5、6、7、8或9个)环碳原子和独立地选自N、O和S的一个或多个(例如1个、2个、3个或4个)杂原子的饱和或部分不饱和(亚)杂环(基)。亚杂环基和杂环(基)的实例包括但不限于：(亚)环氧乙烷基、(亚)氮丙啶基、(亚)氮杂环丁基(azetidinyl)、(亚)氧杂环丁基(oxetanyl)、(亚)四氢呋喃基、(亚)二氧杂环戊烯基(dioxolinyl)、(亚)吡咯烷基、(亚)吡咯烷酮基、(亚)咪唑烷基、(亚)吡唑烷基、(亚)吡咯啉基、(亚)四氢吡喃基、(亚)哌啶基、(亚)吗啉基、(亚)二噻烷基(dithianyl)、(亚)硫吗啉基、(亚)哌嗪基或(亚)三噻烷基(trithianyl)。所述基团也涵盖双环系统，包括螺环、稠合或桥连系统(诸如8-氮杂螺[4.5]癸烷、3，9-二氮杂螺[5.5]十一烷、2-氮杂双环[2.2.2]辛烷等)。亚杂环基和杂环(基)可任选地被一个或多个(例如1个、2个、3个或4个)适合的取代基取代。As used herein, the terms "heterocyclyl", "heterocyclylene" and "heterocycle" refer 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. For example, 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. Examples of heterocyclyl and heterocyclic (base) 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.
如本文中所使用，术语“(亚)芳基”和“芳环”指具有共轭π电子系统的全碳单环或稠合环多环芳族基团。例如，如本文中所使用，术语“C6-10(亚)芳基”和“C6-10芳环”意指含有6至10个碳原子的芳族基团，诸如(亚)苯基(苯环)或(亚)萘基(萘环)。(亚)芳基和芳环任选地被1或多个(诸如1至3个)适合的取代基(例如卤素、-OH、-CN、-NO2、C1-6烷基等)取代。As used herein, the terms "(ylidene)aryl" and "aromatic ring" refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π electron system. For example, as used herein, the terms "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.).
如本文中所使用，术语“(亚)杂芳基”和“杂芳环”指单环、双环或三环芳族环系，其具有5、6、8、9、10、11、12、13或14个环原子，特别是1或2或3或4或5或6或9或10个碳原子，且其包含至少一个可以相同或不同的杂原子(所述杂原子是例如氧、氮或硫)，并且，另外在每一种情况下可为苯并稠合的。特别地，“(亚)杂芳基”或“杂芳环”选自(亚)噻吩基、(亚)呋喃基、(亚)吡咯基、(亚)噁唑基、(亚)噻唑基、(亚)咪唑基、(亚)吡唑基、(亚)异噁唑基、(亚)异噻唑基、(亚)噁二唑基、(亚)三唑基、(亚)噻二唑基等，以及它们的苯并衍生物；或(亚)吡啶基、(亚)哒嗪基、(亚)嘧啶基、(亚)吡嗪基、(亚)三嗪基等，以及它们的苯并衍生物。As used herein, the terms "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. In particular, "(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.
如本文中所使用，术语“芳烷基”优选表示芳基或杂芳基取代的烷基，其中所述芳基、杂芳基和烷基如本文中所定义。通常，所述芳基可具有6-14个碳原子，所述杂芳基可具有5-14个环原子，并且所述烷基可具有1-6个碳原子。示例性芳烷基包括但不限于苄基、苯基乙基、苯基丙基、苯基丁基。 As used herein, the term "aralkyl" preferably refers to an alkyl substituted with an aryl or heteroaryl, wherein the aryl, heteroaryl and alkyl are as defined herein. Typically, the aryl may have 6-14 carbon atoms, the heteroaryl may have 5-14 ring atoms, and the alkyl may have 1-6 carbon atoms. Exemplary aralkyls include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
作为更具体地术语解释如下：As a more specific explanation of the terms are as follows:
“烷基”指饱和脂肪族烃基团，包括1-20个碳原子，或1-10个碳原子，或1-6个碳原子，或1-4个碳原子，或1-3个碳原子，或1-2个碳原子饱和直链或支链的单价烃基，其中烷基可以独立任选地被一个或多个本发明所描述地取代基所取代。烷基基团更近一步地实例包括，包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是任选取代或未取代的。"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. Further examples of 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.
“烯基”指2-12个碳原子，或2-8个碳原子，或2-6个碳原子，或2-4个碳原子直链或支链的一价烃基，其中至少一个C-C为sp2双键，其中烯基的基团可以独立任选地被1个或多个本发明所描述的取代基所取代，其中具体的实例包括，但并不限于乙烯基、烯丙基和烯丁基等等。烯基可以是任选取代或未取代的。"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.
“环烷基”是指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包括3至20个碳原子，优选包括3至12个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实施例包括，但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。环烷基可以是任选取代的或未取代的。"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.
“螺环烷基”指5至18元，两个或两个以上环状结构，且单环之间彼此共用一个碳原子(称螺原子)的多环基团，环内含有1个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺、双螺或多螺环烷基，优选为单螺和双螺环烷基，优选为4元/3元、4元/4元、4元/5元、4元/6元、5元/5元或5元/6元。“螺环烷基”的非限制性实施例包括但不限于：
"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 π electron aromatic system. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of spiro atoms shared between the rings, 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. Non-limiting examples of "spirocycloalkyl" include, but are not limited to:
“稠环烷基”指5至18元，含有两个或两个以上环状结构彼此公用一对碳原子的全碳多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，优选为6至12元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。“稠环烷基”的非限制性实施例包括但不限于：
"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 π 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:
“桥环烷基”指5至18元，含有两个或两个以上环状结构，彼此共用两个不直接相连接碳原子的全碳多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，优选为6至12元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。“桥环烷基”的非限制性实施例包括但不限于：
"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 π 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. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to:
所述环烷基环可以稠合于芳基、杂芳基或杂环基环上，其中与母体结构连接在一起的环为环烷基，非限制性实施例包括茚满基、四氢萘基、苯并环庚烷基等。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.
“杂环基”、“杂环”或“杂环的”在本申请中可交换使用，本申请中可交换使用，都是指包含3-12个环原子的饱和或部分不饱和的单环、双环或三环的非芳香性杂环基，其中至少一个环原子原子是杂原子，如氧、氮、硫原子等。优选具有5至7元单环或7至10元双-或三环，其可以包含1，2或3个选自氮、氧和/或硫中的原子。“杂环基”的实例包括但不限于吗啉基，氧杂环丁烷基，硫代 吗啉基，四氢吡喃基，1，1-二氧代-硫代吗啉基，哌啶基，2-氧代-哌啶基，吡咯烷基，2-氧代-吡咯烷基，哌嗪-2-酮，8-氧杂-3-氮杂-双环[3.2.1]辛基和哌嗪基。所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基。杂环基可以是任选取代的或未取代的。"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. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiophene. Morpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and piperazinyl. The heterocyclyl ring 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.
“螺杂环基”指5至18元，两个或两个以上环状结构，且单环之间彼此共用一个原子的多环基团，环内含有1个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，其中一个或多个环原子选自氮、氧、硫或S(O)m的杂原子，其余环原子为碳，m＝1或2。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。“螺杂环基”的非限制性实施例包括但不限于：
"Spiro heterocyclyl" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one atom shared between the monocyclic rings, containing one or more double bonds in the ring, but no ring has a completely conjugated π electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S(O) m heteroatoms, and the remaining ring atoms are carbon, m = 1 or 2. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between rings, 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. Non-limiting examples of "spiro heterocyclyl" include, but are not limited to:
“稠杂环基”指含有两个或两个以上环状结构彼此公用一对原子的全碳多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，其中一个或多个环原子选自氮、氧、硫或S(O)m的杂原子，其余环原子为碳，m＝1或2。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。“稠杂环基”的非限制性实施例包括但不限于：
"Fused heterocyclic group" refers to an all-carbon polycyclic group containing two or more cyclic structures that share a pair of atoms, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S(O) m heteroatoms, and the remaining ring atoms are carbon, m = 1 or 2. Preferably 6 to 14 members, more preferably 7 to 10 members. According 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. Non-limiting examples of "fused heterocyclic group" include, but are not limited to:
“桥杂环基”指5至18元，含有两个或两个以上环状结构，彼此共用两个不直接相连接的原子的多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，其中一个或多个环原子选自氮、氧、硫或S(O)m的杂原子，其余环原子为碳，m＝1或2。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。“桥杂环基”的非限制性实施例包括但不限于：
"Bridged heterocyclic group" refers to a polycyclic group with 5 to 18 members, containing two or more cyclic structures, sharing two 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 π electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S(O) m heteroatoms, and the remaining ring atoms are carbon, m = 1 or 2. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclic groups" include, but are not limited to:
“芳基”是指含有一个或者两个环的碳环芳香系统，其中所述环可以以稠合的方式连接在一起。术语“芳基”包括比如苯基、萘基、四氢萘基的芳香基团。优选芳基为C6-C10芳基，更优选芳基为苯基和萘基，最优选为苯基。芳基可以是取代或未取代的。所述“芳基”可与杂芳基、杂环基或环烷基稠合，其中与母体结构连接在一起的为芳基环，非限制性实施例包括但不限于：
"Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be connected together in a fused manner. The term "aryl" includes aromatic groups such as phenyl, naphthyl, and tetrahydronaphthyl. Preferably, 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:
“杂芳基”是指芳香族5至6元单环或9至10元双环，其可以包含1至4个选自氮、氧和/或硫中的原子。“杂芳基”的实施例包括但不限于呋喃基，吡啶基，2-氧代-1，2-二氢吡啶基、哒嗪基、嘧啶基、吡嗪基、噻吩基、异噁唑基、噁唑基、噁二唑基、咪唑基、吡咯基、吡唑基、三唑基、四唑基、噻唑基、异噻唑基、1，2，3-噻二唑基、苯并间二氧杂环戊烯基、苯并咪唑基、吲哚基、异吲哚基、1，3-二氧代-异吲哚基、喹啉基、吲唑基、苯并异噻唑基、苯并噁唑基和苯并异噁唑基。杂芳基可以是任选取代或未取代的。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，非限制性实施例包括但不限于：
"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, quinolyl, indazolyl, benzisothiazolyl, benzoxazolyl and benzisoxazolyl. 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:
“烷氧基”是指(烷基-O-)的基团。其中，烷基见本文有关定义。C1-C6的烷氧基为优先选择。其实例包括，但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等。"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.
“卤代烷基”指具有一个或者多个卤素取代基的烷基，其中烷基基团具有如本发明所述的含义。卤代烷基的实例包括，但并不限于氟甲基、二氟甲基、三氟甲基、全氟乙基、1,1-二氯乙基、1,2-二氯丙基等。"Haloalkyl" refers to an alkyl group having one or more halogen substituents, wherein the alkyl group has the meaning as described herein. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, 1,1-dichloroethyl, 1,2-dichloropropyl, and the like.
“羟基”指-OH基团。"Hydroxy" refers to an -OH group.
“卤素”是指氟、氯、溴和碘，优选氟、氯和溴。"Halogen" refers to fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred.
“氨基”指-NH2。"Amino" refers to -NH2 .
“氰基”指-CN。"Cyano" refers to -CN.
“硝基”指-NO2。"Nitro" refers to -NO2 .
“苄基”指-CH2-苯基。"Benzyl" refers to -CH2 -phenyl.
“羧基”指-C(O)OH。"Carboxy" refers to -C(O)OH.
“乙酰基”指-C(O)CH3或Ac。"Acetyl" refers to -C(O) CH3 or Ac.
“羧酸酯基”指-C(O)O(烷基)或(环烷基)，其中烷基、环烷基的定义如上所述。"Carboxylate" refers to -C(O)O(alkyl) or (cycloalkyl) wherein alkyl and cycloalkyl are as defined above.
如本文中所使用，术语“卤代”或“卤素”基团定义为包括F、Cl、Br或I。As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.
如本文中所使用，术语“含氮杂环”指饱和或不饱和的单环或双环基团，其在环中具有2、3、4、5、6、7、8、9、10、11、12或13个碳原子和至少一个氮原子，其还可任选地包含一个或多个(例如一个、两个、三个或四个)选自N、O、C＝O、S、S＝O和S(＝O)2的环成员，其通过所述含氮杂环中的氮原子以及任一其余环原子与分子的其余部分连接，所述含氮杂环任选地为苯并稠合的，并且优选通过所述含氮杂环中的氮原子以及所稠合的苯环中的任一碳原子与分子的其余部分连接。As used herein, the term "nitrogen-containing heterocycle" refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms and at least one nitrogen atom in the ring, which may optionally contain one or more (e.g., one, two, three or four) ring members selected from N, O, C=O, S, S=O and S(=O) 2 , which is connected to the rest of the molecule via the nitrogen atom in the nitrogen-containing heterocycle and any remaining ring atoms, the nitrogen-containing heterocycle is optionally benzo-fused, and is preferably connected to the rest of the molecule via the nitrogen atom in the nitrogen-containing heterocycle and any carbon atom in the fused benzene ring.
术语“取代”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。The term "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.
如果取代基被描述为“任选地被取代”，则取代基可(1)未被取代或(2)被取代。如果取代基的碳被描述为任选地被取代基列表中的一个或多个取代，则碳上的一个或多个氢(至存在的任何氢的程度)可单独和/或一起被独立地选择的任选的取代基替代。如果取代基的氮被描述为任选地被取代基列表中的一个或多个取代，则氮上的一个或多个氢(至存在的任何氢的程度)可各自被独立地选择的任选的取代基替代。If a substituent is described as being "optionally substituted," the 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.
如果取代基被描述为“独立地选自”一组，则各取代基独立于另一者被选择。因此，各取代基可与另一(其他)取代基相同或不同。If substituents are described as being "independently selected" from a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.
如本文中所使用，术语“一个或多个”意指在合理条件下的1个或超过1个，例如2个、3个、4个、5个或10个。As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.
除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.
当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环中的任一成环原子。When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.
本发明还包括所有药学上可接受的同位素标记的化合物，其与本发明的化合物相同，除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。适合包含入本发明的化合物中的同位素的实例包括(但不限于)氢的同位素(例如氘(2H)、氚(3H))；碳的同位素(例如11C、13C及14C)；氯的同位素(例如36Cl)；氟的同位素(例如18F)；碘的同位素(例如123I及125I)；氮的同位素(例如13N及15N)；氧的同位素(例如15O、17O及18O)；磷的同位素(例如32P)；及硫的同位素(例如35S)。某些同位素标记的本发明的化合物(例如掺入放射性同位素的那些)可用于药物和/或底物组织分布研究(例如分析)中。放射性同位素氚(即3H)及碳-14(即14C)因易于掺入且容易检测而特别可用于该目的。用正电子发射同位素(例如11C、 18F、15O及13N)进行取代可在正电子发射断层显像术(PET)研究中用于检验底物受体占据情况。被同位素标记的本发明的化合物可通过与描述于随附路线和/或实施例及制备中的那些类似的方法通过使用适当的被同位素标记的试剂代替之前采用的非标记的试剂来制备。本发明的药学上可接受的溶剂合物包括其中结晶溶剂可被同位素取代的那些，例如，D2O、丙酮-d6或DMSO-d6。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. Examples of 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 ). Certain isotopically labeled compounds of the invention (e.g., those incorporating radioactive isotopes) 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 .
“取代的”如果没有特殊说明，则指基团中的一个或多个氢原子，优选为最多5个，更优选为1-3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"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.
本说明书所述的“取代”或“取代的”，如无特别指出，均是指基团可被一个或多个选自以下的基团取代：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、疏基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、＝O、-C(O)Rb、-OC(O)Rb、-NRbRb、-C(O)NRbRb、-NRbC(O)Rb、-S(O)NRbRb或-S(O)2NRbRb，其中，Rb的定义如通式(I)中所述。As used herein, “substituted” or “substituted”, unless otherwise specified, means that a group may be substituted by one or more groups selected from the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =O, -C(O) Rb , -OC (O) Rb , -NRbRb , -C(O) NRbRb , -NRbC (O) Rb , -S (O) NRbRb or -S(O) 2NRbRb , wherein Rb is as defined in the general formula (I).
此处使用的“儿科病人”一词是指在诊断或治疗时未满16岁的病人。“儿童”一词还可分为以下几个亚类：新生儿(从出生到出生第一个月)；婴儿(1个月至两岁)；儿童(2岁至12岁)；青少年(12岁至21岁(直到但不包括22岁生日))。Berhman RE，Kliegman R，Arvin AM，Nelson we.尼尔森儿科教科书，第15版。费城：W.B.Saunders公司，1996年；Rudolph AM，等人。鲁道夫的儿科，第21版。纽约：McGrow-Hill，2002年；和Avery MD，第一LR。儿科医学，第二版。巴尔的摩：Williams&Wilkins；1994。As used herein, 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.
如本文所用，化合物的“有效量”是指足以激动钾离子通道的量。As used herein, an "effective amount" of a compound refers to an amount sufficient to agonize potassium ion channels.
如本文所用，化合物的“治疗有效剂量”是指足以改善或以某种方式减少症状、停止或逆转病情进展、或激动钾离子通道的量。这种剂量可以作为单一剂量使用，也可以按照一种方案服用，从而有效。As used herein, 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.
如此处所用，“治疗”是指以任何方式改善或以其他方式改变患者的病情、紊乱或疾病的症状或病理。As used herein, "treating" means ameliorating or otherwise altering in any way the symptoms or pathology of a patient's condition, disorder or disease.
如本文所述，“通过使用某一特定化合物或药物组合物来改善某一特定疾病的症状”是指可归因于或与该组合物的使用有关的任何减少，不论是永久性的还是暂时性的、持久的或暂时性的。As used herein, "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.
本发明中立体化学的定义和惯例的使用通常参考以下文献：The definitions and conventions used in this invention for stereochemistry are generally based on the following references:
S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-HillBook Company,New York；and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,New York,1994.本发明的化合物可以包含不对称中心或手性中心，因此存在不同的立体异构体。本发明的化合物所有的立体异构形式，包括但绝不限于，非对映体，对映异构体，阻转异构体，和它们的混合物，如外消旋混合物，组成了本发明的一部分。非对映异构体可以以其物理化学差异为基础，通过层析、结晶、蒸馏或升华等方法被分离为个别非对映异构体。对映异构体可以通过分离，使手性异构混合物转化为非对映异构混合物，其方式是与适当光学活性化合物(例如手性辅助剂，譬如手性醇或Mosher氏酰氯)的反应，分离非对映异构体，且使个别非对映异构体转化为相应的纯对映异构体。本发明的中间体与化合物也可以不同互变异构形式存在，且所有此种形式被包含在本发明的范围内。很多有机化合物都以光学活性形式存在，即它们有能力旋转平面偏振光的平面。在描述光学活性化合物时，前缀D、L或R、S用来表示分子手性中心的绝对构型。前缀d、l或(+)、(-)用来命名化合物平面偏振光旋转的符号，(-)或l是指化合物是左旋的，前缀(+)或d是指化合物是右旋的。这些立体异构体的原子或原子团互相连接次序相同，但是它们的立体结构不一样。特定的立体异构体可以是对映体，异构体的混合物通常称为对映异构体混合物。50：50的对映体混合物被称为外消旋混合物或外消旋体，这可能导致化学反应过程中没有立体选择性或立体定向性。术语“外消旋混合物”和“外消旋体”是指等摩尔的两个对映异构体的混合物，缺乏光学活性。S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. 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. 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. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, 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. Specific 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. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that lacks optical activity.
“互变异构体”或“互变异构的形式”是指不同能量的结构的同分异构体可以通过低能垒互相转化。例如质子互变异构体(即质子移变的互变异构体)包括通过质子迁移的互变，如酮式-烯醇式和亚胺-烯胺的同分异构化作用。原子价(化合价)互变异构体包括重组成键电子的互变。除非其他方面表明，本发明所描述的结构式包括所有的同分异构形式(如对映异构，非对映异构，和几何异构)：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体，和(Z)、(E)的构象异构体。 因此，本发明的化合物的单个立体化学异构体或其对映异构体，非对映异构体，或几何异构体的混合物都属于本发明的范围。"Tautomers" or "tautomeric forms" refer to structural isomers of different energies that can be interconverted via a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. Valence (chemical valence) tautomers include interconversions by reorganization of bonding electrons. Unless otherwise indicated, 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.
“药学上可接受的盐”指本发明化合物的盐，这类盐用于人或动物体内时具有安全性和有效性。化合物的盐可以通过在纯的溶液或合适的惰性溶解中用足量的碱或酸获得相应的加成盐。可药用的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐等，可药用的酸加成盐包括无机酸盐和有机酸盐，所述的无机酸和有机酸包括盐酸、氢溴酸、碳酸、碳酸氢根、磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸一氢根、乙酸、马来酸、丙二酸、琥珀酸、饭丁烯二酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸和甲磺酸等(参见Berge et al.,“Pharmaceutical Salts”,Journal of Pharmaceutical Science 66:1-19(1977))。"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., and 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)).
本文中可使用实线实楔形或虚楔形描绘本发明的化合物的化学键。使用实线以描绘键连至不对称碳原子的键欲表明，包括该碳原子处的所有可能的立体异构体(例如，特定的对映异构体、外消旋混合物等)。使用实或虚楔形以描绘键连至不对称碳原子的键欲表明，存在所示的立体异构体。当存在于外消旋混合物中时，使用实及虚楔形以定义相对立体化学，而非绝对立体化学。除非另外指明，否则本发明的化合物意欲可以立体异构体(其包括顺式及反式异构体、光学异构体(例如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、构象异构体、阻转异构体及其混合物)的形式存在。本发明的化合物可表现一种以上类型的异构现象，且由其混合物(例如外消旋混合物及非对映异构体对)组成。In this article, 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. Unless otherwise indicated, 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).
本发明涵盖本发明的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。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.
还应当理解，本发明的某些化合物可以游离形式存在用于治疗，或适当时，以其药学上可接受的衍生物形式存在。在本发明中，药学上可接受的衍生物包括但不限于，药学上可接受的盐、酯、溶剂合物、N-氧化物、代谢物、螯合物、络合物、包合物或前药，在将它们向需要其的患者给药后，能够直接或间接提供本发明的化合物或其代谢物或残余物。因此，当在本文中提及“本发明的化合物”时，也意在涵盖化合物的上述各种衍生物形式。It should also be understood that certain compounds of the present invention may exist in free form for treatment, or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, 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.
本发明的化合物的药学上可接受的盐包括其酸加成盐及碱加成盐，包括但不限于含有氢键或配位键的盐。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.
适合的酸加成盐由形成药学可接受盐的酸来形成。实例包括乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环己氨磺酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、海苯酸盐、盐酸盐/氯化物、氢溴酸盐/溴化物、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐(naphthylate)、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、糖二酸盐、硬脂酸盐、丁二酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐及昔萘酸盐(xinofoate)。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, phosphate/hydrogenphosphate/dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, and xinofoate.
适合的碱加成盐由形成药学可接受盐的碱来形成。实例包括铝盐、精氨酸盐、苄星青霉素盐、钙盐、胆碱盐、二乙胺盐、二乙醇胺盐、甘氨酸盐、赖氨酸盐、镁盐、葡甲胺盐、乙醇胺盐、钾盐、钠盐、氨丁三醇盐及锌盐。Suitable base addition salts are formed with bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts.
适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts：Properties，Selection，and Use”(Wiley-VCH，2002)。用于制备本发明的化合物的药学上可接受的盐的方法为本领域技术人员已知的。For a review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.
如本文中所使用，术语“酯”意指衍生自本申请中各个通式化合物的酯，其包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本发明的化合物)。本发明的化合物本身也可以是酯。As used herein, the term "ester" 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). The compounds of the present invention themselves may also be esters.
本发明的化合物可以溶剂合物(优选水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。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. The amount of polar solvents, in particular water, may exist in a stoichiometric or non-stoichiometric ratio.
本领域技术人员会理解，由于氮需要可用的孤对电子来氧化成氧化物，因此并非所有的含氮杂环都能够形成N-氧化物；本领域技术人员会识别能够形成N-氧化物的含氮杂环。本领域技术人员还会认识到叔胺能够形成N-氧化物。用于制备杂环和叔胺的N-氧化物的合成方法是本领域技术人员熟知的，包括用过氧酸如过氧乙酸和间氯过氧苯甲酸(MCPBA)、过氧化氢、烷基过氧化氢如 叔丁基过氧化氢、过硼酸钠和双环氧乙烷(dioxirane)如二甲基双环氧乙烷来氧化杂环和叔胺。这些用于制备N-氧化物的方法已在文献中得到广泛描述和综述，参见例如：T.L.Gilchrist，Comprehensive Organic Synthesis，vol.7，pp 748-750；A.R.Katritzky和A.J.Boulton，Eds.，Academic Press；以及G.W.H.Cheeseman和E.S.G.Werstiuk，Advances in Heterocyclic Chemistry，vol.22，pp 390-392，Those skilled in the art will appreciate that not all 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. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include the use of peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as Tert-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyl dioxirane are used to oxidize heterocycles and tertiary amines. These methods for preparing N-oxides have been widely described and reviewed in the literature, see for example: TL Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; AR Katritzky and AJ Boulton, Eds., Academic Press; and GW H Cheeseman and ES G Werstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392,
A.R.Katritzky和A.J.Boulton，Eds.，Academic Press。In A. R. Katritzky and A. J. Boulton, Eds., Academic Press.
在本发明的范围内还包括本发明的化合物的代谢物，即在给药本发明的化合物时体内形成的物质。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。Also included within the scope of the present invention are 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. Thus, 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.
本发明在其范围内进一步包括本发明的化合物的前药，其为自身可具有较小药理学活性或无药理学活性的本发明的化合物的某些衍生物当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本发明的化合物。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其他信息可参见“Pro-drugs as Novel Delivery Systems”，第14卷，ACS Symposium Series(T.Higuchi及V.Stella)。本发明的前药可例如通过用本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design of Prodrugs”，H.Bundgaard(Elsevier，1985)中所述)”的某些部分替代本发明的化合物中存在的适当官能团来制备。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. Typically such 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)).
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在T.W.Greene&P.G.M.Wuts，Protective Groups in Organic Synthesis，JohnWiley&Sons，1991中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，在适当的后续阶段可以移除保护基。The present invention also encompasses compounds of the present invention containing 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.
术语“约”是指在所述数值的±10％范围内，优选±5％范围内，更优选±2％范围内。The term "about" means within ±10% of the stated numerical value, preferably within ±5%, more preferably within ±2%.
本发明的优选化合物Preferred compounds of the present invention
已经记载本发明化合物的通式和优选范围。进一步优选地，本发明化合物的具体例子可以选自如下结构的任意一种，但是并不限于以下化合物：The general formula and preferred range of the compounds of the present invention have been described. Further preferably, the specific examples of the compounds of the present invention can be selected from any one of the following structures, but are not limited to the following compounds:
表1示例化合物列表：






Table 1 Example compound list:






本发明的典型化合物包括但不限于如上表格中的化合物，本发明中的化合物命名遵循系统命名，或者，使用ChemDraw软件进行命名。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.
实施例Example
下面通过具体实施例对本发明的方法进行说明，以使本发明技术方案更易于理解、掌握，但本发明并不局限于此。The method of the present invention is described below through specific embodiments to make the technical solution of the present invention easier to understand and grasp, but the present invention is not limited thereto.
下述实施例中1H NMR图谱是用Bruker仪器(400MHz)测定而得，化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm)。1H NMR的表示方法：s＝单峰，d＝双重峰，t＝三重峰，q＝四重峰，m＝多重峰，br＝宽峰，dd＝双重峰的双重峰，dt＝三重峰的双重峰。若提供偶合常数时，其单位为Hz。The 1 H NMR spectra in the following examples were obtained using a Bruker instrument (400 MHz) and the chemical shifts are expressed in ppm. Tetramethylsilane was used as an internal standard (0.00 ppm). 1 H NMR notation: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, dd = doublet of doublets, dt = doublet of triplet. When coupling constants are provided, the unit is Hz.
质谱是用LC/MS仪测定得到，离子化方式为ESI。The mass spectrum was obtained by LC/MS using ESI as the ionization method.
高效液相色谱仪型号：安捷伦1260、赛默飞U3000；色谱柱型号：Waters xbrige C18(4.6*150mm,3.5μm)；流动相：A:ACN,B:Water(0.1％H3PO4)；流速：1.0mL/min；梯度：5％A for 1min,increase to 20％A within 4min,increase to 80％A within 8min,80％A for 2min,back to 5％A within 0.1min；波长：220nm；柱温箱：35℃。HPLC model: Agilent 1260, Thermo Fisher U3000; chromatographic column model: Waters xbrige C18 (4.6*150 mm, 3.5 μm); 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.
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.2mm-0.3mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm。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.
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.
在下列实例中，除非另有指明，所有温度为摄氏温度，除非另有指明，各种起始原料和试剂来自市售或者是根据已知的方法合成，市售原料和试剂均不经进一步纯化直接使用，除非另有指明，市售厂家包括但不限于国药集团，百灵威科技有限公司，梯希爱(上海)化成工业发展有限公司，上海毕得医药科技有限公司和上海迈瑞尔化学科技有限公司等。In the following examples, unless otherwise indicated, all temperatures are in degrees Celsius. Unless otherwise indicated, various starting materials and reagents are commercially available or synthesized according to known methods. Commercially available materials and reagents are used directly without further purification. Unless otherwise indicated, commercial manufacturers include but are not limited to Sinopharm Group, J&K Technology Co., Ltd., TCI (Shanghai) Chemical Industry Development Co., Ltd., Shanghai Bid Pharmaceutical Technology Co., Ltd. and Shanghai Myrel Chemical Technology Co., Ltd.
CD3OD：氘代甲醇；CDCl3：氘代氯仿；DMSO-d6：氘代二甲基亚砜；Pd2(dba)3：三(二亚苄基丙酮)二钯；Pd(dppf)Cl2：[1,1'-双(二苯基膦基)二茂铁]二氯化钯；XantPhos：4,5-双二苯基膦-9,9-二甲基氧杂蒽；XPhos：2-二环己基磷-2,4,6-三异丙基联苯；HATU：2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；EDCI：1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐；DMAP：4-二甲氨基吡啶；PE：石油醚；EA：乙酸乙酯；DCM：二氯甲烷；MeOH：甲醇；DMF：N,N-二甲基甲酰胺；DIPEA：N,N-二异丙基乙胺；DPPA：叠氮磷酸二苯酯；BOC：叔丁氧羰基；TLC：薄层色谱法； HPLC：高效液相色谱法；purity：纯度；Rf：薄层色谱法中原点到斑点中心的距离与原点到溶剂前沿的距离的比值。CD 3 OD: deuterated methanol; CDCl 3 : deuterated chloroform; DMSO-d 6 : deuterated dimethyl sulfoxide; Pd 2 (dba) 3 : tris(dibenzylideneacetone)dipalladium; Pd(dppf)Cl 2 ：[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium; XantPhos: 4,5-bis(diphenylphosphino)ferrocene-9,9-dimethylxanthene; XPhos: 2-dicyclohexylphospho-2,4,6-triisopropylbiphenyl; HATU: 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate; EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; DMAP: 4-dimethylaminopyridine; PE: petroleum ether; EA: ethyl acetate; DCM: dichloromethane; MeOH: methanol; DMF: N,N-dimethylformamide; DIPEA: N,N-diisopropylethylamine; DPPA: diphenylphosphoryl azide; BOC: tert-butyloxycarbonyl; TLC: thin layer chromatography; HPLC: high performance liquid chromatography; purity: purity; R f : the ratio of the distance from the origin to the center of the spot to the distance from the origin to the solvent front in thin layer chromatography.
氢气氛围是指反应瓶连接一个约1L容积的氢气气球。Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1L.
实施例中无特殊说明，反应中的溶液是指水溶液。Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.
实施例中无特殊说明，反应的温度为室温，为20℃-30℃。Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C-30°C.
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系或薄层色谱法的展开剂体系包括：A：石油醚和乙酸乙酯体系；B：二氯甲烷和甲醇体系；C：正己烷：乙酸乙酯；其中溶剂的体积比根据化合物的极性不同而不同，也可以加入少量的酸性或碱性试剂进行调节，如醋酸或三乙胺等。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.
药物化学实验部分Medicinal Chemistry Experiment Section
实施例1N-(1,2-二氢苊-5-基)-4-氟苯甲酰胺1
Example 1 N-(1,2-dihydroacenaphthene-5-yl)-4-fluorobenzamide 1
第一步1,2-二氢苊-5-胺1bStep 1,2-Dihydroacenaphthene-5-amine 1b
5-硝基苊1a(1.00g,5.02mmol)溶于乙醇(20mL)中，室温下加入湿钯碳(0.15g,10％)，氢气置换三次，在氢气球下，室温搅拌过夜后，TLC显示原料消失，硅藻土过滤，乙醇洗，滤液浓缩，粗品经硅胶柱层析纯化，得到白色固体标题化合物1b(0.60g,收率71％)。LC-MS:m/z＝170.1[M+H]+ 5-Nitroacenaphthene 1a (1.00 g, 5.02 mmol) was dissolved in ethanol (20 mL), wet palladium carbon (0.15 g, 10%) was added at room temperature, hydrogen was replaced three times, and stirred at room temperature overnight under a hydrogen balloon. TLC showed that the raw material disappeared, diatomaceous earth was filtered, ethanol was washed, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to obtain the title compound 1b as a white solid (0.60 g, yield 71%). LC-MS: m/z = 170.1 [M + H] +
1H NMR(400MHz,DMSO-d6)δ7.70(d,J＝8.4Hz,1H),7.31-7.25(m,1H),7.18(d,J＝6.8Hz,1H),7.00(d,J＝7.2Hz,1H),6.60(d,J＝7.2Hz,1H),5.39(s,2H),3.31-3.25(m,2H),3.21-3.15(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.70 (d, J = 8.4 Hz, 1H), 7.31-7.25 (m, 1H), 7.18 (d, J = 6.8 Hz, 1H), 7.00 (d, J = 7.2 Hz, 1H), 6.60 (d, J = 7.2 Hz, 1H), 5.39 (s, 2H), 3.31-3.25 (m, 2H), 3.21-3.15 (m, 2H).
第二步N-(1,2-二氢苊-5-基)-4-氟苯甲酰胺1cStep 2 N-(1,2-dihydroacenaphthene-5-yl)-4-fluorobenzamide 1c
将化合物1b(450mg,2.66mmol)溶于二氯甲烷(10mL)中，室温下加入4-氟苯甲酸(485mg,3.46mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(660mg,3.46mmol)和4-二甲氨基吡啶(33mg,0.27mmol)，室温搅拌1小时后，TLC显示原料消失，反应液加水淬灭，二氯甲烷萃取，稀盐酸洗，无水硫酸钠干燥，过滤，浓缩，粗品经硅胶柱层析纯化，得到白色固体产物得到白色固体标题化合物1c(580mg,收率75％)。Compound 1b (450 mg, 2.66 mmol) was dissolved in dichloromethane (10 mL), and 4-fluorobenzoic acid (485 mg, 3.46 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (660 mg, 3.46 mmol) and 4-dimethylaminopyridine (33 mg, 0.27 mmol) were added at room temperature. After stirring at room temperature for 1 hour, TLC showed that the starting material disappeared. The 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.
LC-MS:m/z＝292.1[M+H]+(99.37％purity,220nm)LC-MS: m/z = 292.1 [M+H] + (99.37% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),8.15(dd,J＝8.4,5.2Hz,2H),7.62(d,J＝8.4Hz,1H),7.55(d,J＝7.2Hz,1H),7.49-7.45(m,1H),7.42-7.36(m,2H),7.35-7.32(m,2H),3.42-3.32(m,4H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.34 (s, 1H), 8.15 (dd, J=8.4, 5.2 Hz, 2H), 7.62 (d, J=8.4 Hz, 1H), 7.55 (d, J=7.2 Hz, 1H), 7.49-7.45 (m, 1H), 7.42-7.36 (m, 2H), 7.35-7.32 (m, 2H), 3.42-3.32 (m, 4H).
第三步4-氟-N-(4-硝基-1,2-二氢苊-5-基)苯甲酰胺1dStep 3 4-Fluoro-N-(4-nitro-1,2-dihydroacenaphthene-5-yl)benzamide 1d
将化合物1c(291mg,1.0mmol)溶于乙酸(8mL)中，冰水浴冷却至5℃，缓慢加入三水合硝酸铜(483mg,2.0mmol)至反应中。加毕，升至室温反应4小时，TLC(PE:EA＝5:1,Rf＝0.3)检测反应已完成。反应液加水稀释，饱和碳酸钠溶液调节pH＝7～8。水相用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，粗品经硅胶柱层析纯化得到黄色固体标题化合物1d(148mg,收率44％)。Compound 1c (291 mg, 1.0 mmol) was dissolved in acetic acid (8 mL), cooled to 5 ° C in an ice-water bath, and copper nitrate trihydrate (483 mg, 2.0 mmol) was slowly added to the reaction. After the addition, the temperature was raised to room temperature for 4 hours. TLC (PE: EA = 5: 1, R f = 0.3) detected that the reaction was complete. The reaction solution was diluted with water and the pH was adjusted to 7-8 with saturated sodium carbonate solution. 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.
LC-MS:m/z＝337.1[M+H]+ LC-MS: m/z = 337.1 [M + H] +
第四步N-(1,2-二氢苊-5-基)-4-氟苯甲酰胺1Step 4: N-(1,2-dihydroacenaphthene-5-yl)-4-fluorobenzamide 1
参照第一步合成方法合成得到棕色固体标题化合物1(45mg,收率71％)。The title compound 1 (45 mg, yield 71%) was synthesized as a brown solid by referring to the first step synthesis method.
LC-MS:m/z＝307.2[M+H]+(99.33％purity,220nm)LC-MS: m/z = 307.2 [M + H] + (99.33% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ9.68(s,1H),8.23-8.10(m,2H),7.36(t,J＝8.8Hz,2H),7.28-7.21(m,1H),7.10(d,J＝8.4Hz,1H),6.95(d,J＝6.4Hz,1H),6.90(s,1H),5.21(s,2H),3.30-3.15 (m,4H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.68 (s, 1H), 8.23-8.10 (m, 2H), 7.36 (t, J = 8.8 Hz, 2H), 7.28-7.21 (m, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 6.4 Hz, 1H), 6.90 (s, 1H), 5.21 (s, 2H), 3.30-3.15 (m,4H).
实施例2Example 2
N-(1,2-二氢苊-5-基)-[1,2,4]三唑并[4,3-a]吡啶-7-甲酰胺2
N-(1,2-dihydroacenaphthene-5-yl)-[1,2,4]triazolo[4,3-a]pyridine-7-carboxamide 2
第一步[1,2,4]三唑并[4,3-a]吡啶-7-羧酸2bFirst step [1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid 2b
[1,2,4]三唑并[4,3-a]吡啶-7-羧酸乙酯2a(150mg,0.78mmol)溶于甲醇(2mL)和四氢呋喃(2mL)的混合液中，室温下加入2N的氢氧化钠水溶液(2mL)，室温搅拌4小时后，TLC显示原料消失，加1N稀盐酸调节pH至2～3后，乙酸乙酯萃取(10mL x3)，饱和食盐水(20mL)洗，无水硫酸钠干燥，过滤，浓缩得到淡棕色固体标题化合物2b(120mg,收率94％)。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.
LC-MS:m/z＝164.1[M+H]+ LC-MS: m/z = 164.1 [M + H] +
第二步N-(1,2-二氢苊-5-基)-[1,2,4]三唑并[4,3-a]吡啶-7-甲酰胺2Step 2 N-(1,2-dihydroacenaphthene-5-yl)-[1,2,4]triazolo[4,3-a]pyridine-7-carboxamide 2
将化合物2b(40mg,0.25mmol)溶于N,N-二甲基甲酰胺(2mL)中，室温下加入1,2-二氢苊-5-胺1b(40mg,0.24mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(60mg,0.31mmol)和4-二甲氨基吡啶(4mg,0.03mmol)，TLC显示原料消失，反应液加水淬灭，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，过柱纯化得到白色固体标题化合物2(20mg,收率25％)。Compound 2b (40 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 1,2-dihydroacenaphthene-5-amine 1b (40 mg, 0.24 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (60 mg, 0.31 mmol) and 4-dimethylaminopyridine (4 mg, 0.03 mmol) were added at room temperature. TLC showed that the starting material disappeared. The 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%).
LC-MS:m/z＝315.1[M+H]+(96.93％purity,220nm)LC-MS: m/z = 315.1 [M+H] + (96.93% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.83(s,1H),9.06(s,1H),8.43(d,J＝2.0Hz,1H),7.78(d,J＝8.4Hz,1H),7.65(d,J＝7.2Hz,1H),7.50(t,J＝7.6Hz,1H),7.36(d,J＝5.6Hz,2H),6.88(s,1H),3.40(d,J＝7.2Hz,4H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.53 (s, 1H), 9.83 (s, 1H), 9.06 (s, 1H), 8.43 (d, J=2.0 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.65 (d, J=7.2 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 7.36 (d, J=5.6 Hz, 2H), 6.88 (s, 1H), 3.40 (d, J=7.2 Hz, 4H).
实施例3-11Example 3-11
表2参照实施例2的第二步合成方法合成实施例3-11的化合物，区别是投入不同类型的取代苯甲酸：

Table 2 The compounds of Examples 3-11 were synthesized by referring to the second step synthesis method of Example 2, except that different types of substituted benzoic acid were added:

实施例12Example 12
N-(7-环丙基-1-甲基-1H-吲唑-3-基)-4-氟苯甲酰胺12
N-(7-cyclopropyl-1-methyl-1H-indazol-3-yl)-4-fluorobenzamide 12
第一步2-(7-溴-1H-吲唑-3-基)异二氢吲哚-1,3-二酮12cStep 1: 2-(7-bromo-1H-indazol-3-yl)isoindoline-1,3-dione 12c
将7-溴-1H-吲唑-3-胺12a(200mg,0.94mmol)溶于1,4-二氧六环(3mL)中，加入邻苯二甲酸酐12b(168mg,1.13mmol)，加毕，反应液升温至120℃反应5小时，TLC检测反应已完成。冷却接浓缩，粗品加二氯甲烷打浆，收集滤饼，干燥得到白色固体标题化合物12c(283mg,收率88％)。7-Bromo-1H-indazole-3-amine 12a (200 mg, 0.94 mmol) was dissolved in 1,4-dioxane (3 mL), and phthalic anhydride 12b (168 mg, 1.13 mmol) was added. After the addition was completed, the reaction solution was heated to 120°C for 5 hours. The reaction was completed by TLC. After cooling, the mixture was concentrated. The crude product was slurried with dichloromethane, and the filter cake was collected and dried to obtain the title compound 12c (283 mg, yield 88%) as a white solid.
第二步2-(7-溴-1-甲基-1H-吲唑-3-基)异二氢吲哚-1,3-二酮12dStep 2 2-(7-bromo-1-methyl-1H-indazol-3-yl)isoindoline-1,3-dione 12d
化合物12c(100mg,0.29mmol)溶于N,N-二甲基甲酰胺(2mL)中，加碘甲烷(50mg,0.35mmol)和碳酸钾(120mg,0.87mmol)，TLC检测反应已完成。反应液加水,乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，硅胶制备板纯化得到白色固体题化合物12d(80mg,收率77％)。Compound 12c (100 mg, 0.29 mmol) was dissolved in N,N-dimethylformamide (2 mL), and iodomethane (50 mg, 0.35 mmol) and potassium carbonate (120 mg, 0.87 mmol) were added. TLC detected that the reaction was complete. The reaction solution was added with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and purified on a silica gel preparation plate to obtain the title compound 12d (80 mg, yield 77%) as a white solid.
LC-MS:m/z＝356.0/358.0[M+H]+ LC-MS: m/z＝356.0/358.0[M+H] +
第三步7-溴-1-甲基-1H-吲唑-3-胺12eStep 3 7-Bromo-1-methyl-1H-indazol-3-amine 12e
将化合物12d(80mg,0.22mmol)溶于乙醇(5mL)中，在30℃下，加入水合肼(85％,20mg,0.34mmol)至反应中，此反应在30℃下反应3小时后，TLC检测反应已完成。反应液加水，二氯甲烷 萃取，饱和食盐水洗涤，无水硫酸钠干燥得到白色固体标题化合物12e(26mg,收率51％)。Compound 12d (80 mg, 0.22 mmol) was dissolved in ethanol (5 mL) and hydrazine hydrate (85%, 20 mg, 0.34 mmol) was added to the reaction at 30°C. After the reaction was allowed to proceed for 3 hours at 30°C, the reaction was complete as determined by TLC. Water and dichloromethane were added to the reaction solution. The residue was extracted, washed with saturated brine, and dried over anhydrous sodium sulfate to give the title compound 12e (26 mg, yield 51%) as a white solid.
第四步7-环丙基-1-甲基-1H-吲唑-3-胺12fStep 4: 7-Cyclopropyl-1-methyl-1H-indazol-3-amine 12f
将化合物12e(26mg,0.12mmol)溶于1,4-二氧六环(3mL)和水(1.5mL)中，加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(2mg,0.002mmol)，环丙基硼酸21b(31mg,0.36mmol)和碳酸铯(117mg,0.36mmol)至反应中，氮气置换三次，此反应升温至100℃下反应3小时，TLC检。冷却，反应液加水，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，粗品经硅胶制备板(石油醚:乙酸乙酯＝1:1)纯化得到黄色固体12f(21mg,收率98％)。Compound 12e (26 mg, 0.12 mmol) was dissolved in 1,4-dioxane (3 mL) and water (1.5 mL), and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (2 mg, 0.002 mmol), cyclopropylboronic acid 21b (31 mg, 0.36 mmol) and cesium carbonate (117 mg, 0.36 mmol) were added to the reaction, and nitrogen was replaced three times. The reaction was heated to 100°C for 3 hours and checked by TLC. After cooling, the reaction solution was added with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was purified by silica gel preparation plate (petroleum ether: ethyl acetate = 1:1) to obtain yellow solid 12f (21 mg, yield 98%).
LC-MS:m/z＝188.2[M+H]+ LC-MS: m/z = 188.2 [M + H] +
第五步N-(7-环丙基-1-甲基-1H-吲唑-3-基)-4-氟苯甲酰胺12Step 5: N-(7-cyclopropyl-1-methyl-1H-indazol-3-yl)-4-fluorobenzamide 12
将化合物12f(21mg,0.11mmol)溶于二氯甲烷(2mL)中，加入对氟苯甲酸(18mg,0.13mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(27mg,0.14mmol)和4-二甲氨基吡啶(2mg,0.02mmol)，TLC检测反应，粗品经硅胶制备板纯化得到淡黄色固体12(10.0mg,收率29％)。Compound 12f (21 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL), and p-fluorobenzoic acid (18 mg, 0.13 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (27 mg, 0.14 mmol) and 4-dimethylaminopyridine (2 mg, 0.02 mmol) were added. The reaction was monitored by TLC, and the crude product was purified by silica gel preparation plate to obtain a light yellow solid 12 (10.0 mg, yield 29%).
LC-MS:m/z＝310.2[M+H]+(97.88％purity,220nm)LC-MS: m/z = 310.2 [M+H] + (97.88% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.18-8.08(m,2H),7.48(d,J＝8.4Hz,1H),7.37(t,J＝8.8Hz,2H),7.09(d,J＝6.8Hz,1H),7.01-6.92(m,1H),4.37(s,3H),2.55-2.51(m,1H),1.08-1.00(m,2H),0.87-0.80(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.71 (s, 1H), 8.18-8.08 (m, 2H), 7.48 (d, J=8.4 Hz, 1H), 7.37 (t, J=8.8 Hz, 2H), 7.09 (d, J=6.8 Hz, 1H), 7.01-6.92 (m, 1H), 4.37 (s, 3H), 2.55-2.51 (m, 1H), 1.08-1.00 (m, 2H), 0.87-0.80 (m, 2H).
实施例13Example 13
N-(7-乙基-1-甲基-1H-吲唑-3-基)-4-氟苯甲酰胺13
N-(7-ethyl-1-methyl-1H-indazol-3-yl)-4-fluorobenzamide 13
参照实施例12的第四步和第五步的合成方法合成实施例13，反应原料为乙基硼酸和12e：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:
LC-MS:m/z＝298.2[M+H]+(99.79％purity,220nm)LC-MS: m/z = 298.2 [M+H] + (99.79% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),8.19-8.06(m,2H),7.52-7.43(m,1H),7.42-7.33(m,2H),7.23-7.10(m,1H),7.05-6.94(m,1H),4.21(s,3H),3.18-3.06(m,2H),1.35-1.29(m,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.70 (s, 1H), 8.19-8.06 (m, 2H), 7.52-7.43 (m, 1H), 7.42-7.33 (m, 2H), 7.23-7.10 (m, 1H), 7.05-6.94 (m, 1H), 4.21 (s, 3H), 3.18-3.06 (m, 2H), 1.35-1.29 (m, 3H).
实施例14-17Examples 14-17
表3参照实施例12的第二步到第五步的合成实施例14-17的化合物：

Table 3 Compounds of Synthetic Examples 14-17 from the second step to the fifth step of Example 12:

实施例18Embodiment 18
N-(2-氨基-5-环丙基萘-1-基)-4-氟苯甲酰胺18
N-(2-amino-5-cyclopropylnaphthalen-1-yl)-4-fluorobenzamide 18
第一步N-(5-溴-2-硝基萘-1-基)乙酰胺18bStep 1: N-(5-bromo-2-nitronaphthalen-1-yl)acetamide 18b
将N-(5-溴萘-1-基)乙酰胺18a(1.50g,5.68mmol)分散于二氯甲烷(20mL)中，加入醋酸酐(3.48g,34.09mmol)与五水合硝酸铋(2.76g,5.69mmol)。加毕，室温搅拌2小时。TLC检测显示反应已完成。反应液以饱和碳酸氢钠水溶液淬灭，加乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得棕色固体标题化合物18b(334mg，收率19％)。Disperse N-(5-bromonaphthalen-1-yl)acetamide 18a (1.50 g, 5.68 mmol) in dichloromethane (20 mL), add acetic anhydride (3.48 g, 34.09 mmol) and bismuth nitrate pentahydrate (2.76 g, 5.69 mmol). After addition, stir at room temperature for 2 hours. TLC detection shows that the reaction is complete. The 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.
LC-MS:m/z＝309.0[M+H]+ LC-MS: m/z = 309.0 [M + H] +
第二步5-溴-2-硝基萘-1-胺18cStep 2 5-Bromo-2-nitronaphthalene-1-amine 18c
将化合物18b(200mg,0.65mmol)分散于乙醇(1mL)中，室温下加入浓盐酸(2mL)，反应液加热至90℃搅拌。TLC检测。冷却，以饱和碳酸氢钠水溶液调节pH＝8，乙酸乙酯萃取，饱和食盐水洗，干燥，粗品经硅胶柱层析纯化得到黄色固体18c(123mg，收率71％)。Compound 18b (200 mg, 0.65 mmol) was dispersed in ethanol (1 mL), concentrated hydrochloric acid (2 mL) was added at room temperature, and the reaction solution was heated to 90°C and stirred. TLC detection was performed. The mixture was cooled, pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried, and the crude product was purified by silica gel column chromatography to obtain a yellow solid 18c (123 mg, yield 71%).
第三步N-(5-溴-2-硝基萘-1-基)-4-氟苯甲酰胺18dStep 3 N-(5-bromo-2-nitronaphthalen-1-yl)-4-fluorobenzamide 18d
将化合物18c(123mg,0.46mmol)溶解于吡啶(4mL)中，加入4-二甲氨基吡啶(10mg,0.08mmol)，降温至0℃，加入对氟苯甲酰氯(250mg,1.58mmol)。加毕，加热至80℃。TLC检测。冷却，浓缩，粗品经硅胶柱层析纯化得到橙色固体18d(101mg，收率56％)。Compound 18c (123 mg, 0.46 mmol) was dissolved in pyridine (4 mL), 4-dimethylaminopyridine (10 mg, 0.08 mmol) was added, the temperature was lowered to 0°C, and p-fluorobenzoyl chloride (250 mg, 1.58 mmol) was added. After the addition, the mixture was heated to 80°C. TLC was performed. The mixture was cooled and concentrated, and the crude product was purified by silica gel column chromatography to obtain an orange solid 18d (101 mg, yield 56%).
LC-MS:m/z＝389.0[M+H]+ LC-MS: m/z = 389.0 [M + H] +
第四步N-(2-氨基-5-溴萘-1-基)-4-氟苯甲酰胺18eStep 4: N-(2-amino-5-bromonaphthalen-1-yl)-4-fluorobenzamide 18e
将化合物18d(101mg,0.26mmol)分散于乙醇(2mL)与水(2mL)中，加入还原铁粉(146mg,2.61mmol)与氯化铵(140mg,2.62mmol)，加毕，加热至80℃搅拌。TLC检测。反应液趁热过滤，滤液加水稀释，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，粗品经硅胶柱层析纯化得到淡黄色固体18e(25mg，收率27％)。Compound 18d (101 mg, 0.26 mmol) was dispersed in ethanol (2 mL) and water (2 mL), and reduced iron powder (146 mg, 2.61 mmol) and ammonium chloride (140 mg, 2.62 mmol) were added. After addition, the mixture was heated to 80 °C and stirred. TLC was performed. The reaction solution was filtered while hot, the filtrate was diluted with water, 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 a light yellow solid 18e (25 mg, yield 27%).
第五步N-(2-氨基-5-环丙基萘-1-基)-4-氟苯甲酰胺18Step 5: N-(2-amino-5-cyclopropylnaphthalen-1-yl)-4-fluorobenzamide 18
参照实施例12的第四步的方法合成得到化合物18(3.4mg，收率15％)。Compound 18 (3.4 mg, yield 15%) was synthesized by referring to the fourth step of Example 12.
LC-MS:m/z＝321.2[M+H]+(92.21％purity,220nm)LC-MS: m/z = 321.2 [M+H] + (92.21% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ9.87(s,1H),8.24-8.14(m,3H),7.47-7.34(m,3H),7.30-7.18(m,2H),6.94(d,J＝6.8Hz,1H),2.39-2.29(m,1H),1.11-0.92(m,2H),0.75-0.64(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.87 (s, 1H), 8.24-8.14 (m, 3H), 7.47-7.34 (m, 3H), 7.30-7.18 (m, 2H), 6.94 (d, J=6.8 Hz, 1H), 2.39-2.29 (m, 1H), 1.11-0.92 (m, 2H), 0.75-0.64 (m, 2H).
实施例19Embodiment 19
N-(1,2-二氢苊-5-基)四唑并[1,5-a]吡啶-7-甲酰胺19
N-(1,2-dihydroacenaphthene-5-yl)tetrazo[1,5-a]pyridine-7-carboxamide 19
第一步2-溴-N-(1,2-二氢苊-5-基)异烟酰胺19bStep 1: 2-Bromo-N-(1,2-dihydroacenaphthene-5-yl)isonicotinamide 19b
将1,2-二氢苊-5-胺1b(100mg,0.59mmol)溶于N,N-二甲基甲酰胺(2mL)中，室温下加入2-溴异烟酸19a(100mg,0.59mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(147mg,0.77mmol)和4-二甲氨基吡啶(7mg,0.06mmol)，室温搅拌16小时，TLC检测，反应液加水淬灭，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，过柱得到淡绿色固体19b(15mg,收率82％)。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%).
LC-MS:m/z＝353.0,355.0[M+H]+ LC-MS: m/z = 353.0, 355.0 [M + H] +
第二步(Z)-N-(1,2-二氢苊-5-基)-2-腙-1,2-二氢吡啶-4-甲酰胺19cStep 2 (Z)-N-(1,2-dihydroacenaphthene-5-yl)-2-hydrazone-1,2-dihydropyridine-4-carboxamide 19c
将化合物19b(170mg,0.48mmol)溶于乙醇(3mL)中，室温下加入水合肼(384mg,9.60mmol,80％)，加毕，油浴加热回流过夜后，TLC检测，反应液冷却，加水淬灭，过滤，得到类白色固体标题化合物19c(32mg,收率22％)。Compound 19b (170 mg, 0.48 mmol) was dissolved in ethanol (3 mL), and hydrazine hydrate (384 mg, 9.60 mmol, 80%) was added at room temperature. After the addition was completed, the mixture was heated under reflux in an oil bath overnight, and then detected by TLC. The reaction solution was cooled, quenched with water, and filtered to obtain the title compound 19c (32 mg, yield 22%) as an off-white solid.
LC-MS:m/z＝305.1[M+H]+ LC-MS: m/z = 305.1 [M + H] +
第三步N-(1,2-二氢苊-5-基)四唑并[1,5-a]吡啶-7-甲酰胺19Step 3 N-(1,2-dihydroacenaphthene-5-yl)tetrazo[1,5-a]pyridine-7-carboxamide 19
将化合物19c(32mg,0.11mmol)溶于醋酸(3mL)和水(1mL)的混合溶液中，室温下加入亚硝酸钠(23mg,0.33mmol)，室温搅拌2小时后，TLC监控，反应液加饱和碳酸钠水溶液，过滤，收集固体，粗品经Prep-HPLC纯化得到黄色固体标题化合物19(10mg,收率29％)。Compound 19c (32 mg, 0.11 mmol) was dissolved in a mixed solution of acetic acid (3 mL) and water (1 mL), and sodium nitrite (23 mg, 0.33 mmol) was added at room temperature. After stirring at room temperature for 2 hours, the reaction solution was monitored by TLC, and saturated aqueous sodium carbonate solution was added to the reaction solution. The solid was filtered and collected. The crude product was purified by Prep-HPLC to obtain the title compound 19 (10 mg, yield 29%) as a yellow solid.
LC-MS:m/z＝316.1[M+H]+(99.59％purity,220nm)LC-MS: m/z = 316.1 [M+H] + (99.59% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),9.47(d,J＝6.8Hz,1H),8.95(s,1H),7.93(d,J＝6.8Hz,1H),7.73(d,J＝8.4Hz,1H),7.64(d,J＝7.2Hz,1H),7.51(t,J＝7.6Hz,1H),7.37(d,J＝6.8Hz,2H),3.40(s,4H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.83 (s, 1H), 9.47 (d, J = 6.8 Hz, 1H), 8.95 (s, 1H), 7.93 (d, J = 6.8 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 7.2 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.37 (d, J = 6.8 Hz, 2H), 3.40 (s, 4H).
实施例20Embodiment 20
N-(2,2-二甲基-1,2-二氢苊-5-基)-4-氟苯甲酰胺20
N-(2,2-dimethyl-1,2-dihydroacenaphthene-5-yl)-4-fluorobenzamide 20
第一步5-溴-2,2-二甲基苊-1(2H)-酮20bStep 1 5-Bromo-2,2-dimethylacenaphthene-1(2H)-one 20b
将5-溴-1(2H)-苊酮20a(600mg,2.43mmol)加到四氢呋喃(6mL)中，温度降到0℃，分批加入氢化钠(292mg,7.29mmol,60％)，加毕，回到室温搅拌30分钟，加入碘甲烷(1380mg,9.72mmol)。继续室温搅拌1小时，TLC检测。反应液加水(30mL)淬灭，乙酸乙酯(30mL x2)萃取，水(30mL)洗，饱和食盐水(30mL)洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(石油醚/乙酸乙酯＝1-5)纯化得到白色固体标题化合物20b(632mg,收率95％)。5-Bromo-1(2H)-acenaphthene 20a (600 mg, 2.43 mmol) was added to tetrahydrofuran (6 mL), the temperature was lowered to 0°C, sodium hydride (292 mg, 7.29 mmol, 60%) was added in batches, after addition, the mixture was returned to room temperature and stirred for 30 minutes, iodomethane (1380 mg, 9.72 mmol) was added. Stirring was continued at room temperature for 1 hour, and TLC was used for detection. The reaction solution was quenched with water (30 mL), extracted with ethyl acetate (30 mL x 2), washed with water (30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1-5) to obtain the title compound 20b (632 mg, yield 95%) as a white solid.
第二步(2,2-二甲基-1-氧代-1,2-二氢苊-5-基)氨基甲酸叔丁酯20cStep 2 Tert-butyl (2,2-dimethyl-1-oxo-1,2-dihydroacenaphthene-5-yl)carbamate 20c
将化合物20b(550mg,2.00mmol)，氨基甲酸叔丁酯(469mg,4mmol)，Pd2(dba)3(275mg,0.30mmol)，Xantphos(22mg,0.036mmol)和碳酸铯(69mg,0.72mmol,Purity 100％)加到甲苯(2mL)中，反应液加热至100℃TLC检测。反应液冷却到室温，加水淬灭，乙酸乙酯萃取，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩。粗品经pre-TLC纯化得到白色固20c(473mg,收率76％)。Compound 20b (550 mg, 2.00 mmol), tert-butyl carbamate (469 mg, 4 mmol), Pd 2 (dba) 3 (275 mg, 0.30 mmol), Xantphos (22 mg, 0.036 mmol) and cesium carbonate (69 mg, 0.72 mmol, Purity 100%) were added to toluene (2 mL), and the reaction solution was heated to 100°C for TLC detection. The reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by pre-TLC to obtain a white solid 20c (473 mg, yield 76%).
第三步2,2-二甲基-1,2-二氢苊-5-胺20dStep 3 2,2-Dimethyl-1,2-dihydroacenaphthene-5-amine 20d
将化合物20c(460mg,1.48mmol)，水合肼(521mg,85％)和氢氧化钾(497mg,8.85mmol)加到乙二醇(46mL)中，氮气保护下，反应液加热至200℃回流反应8小时。TLC检测，冷却，加水淬灭，过滤，滤饼水洗，干燥，得到淡黄色固体标题化合物20d(244mg,粗品)，直接用于下一步。Compound 20c (460 mg, 1.48 mmol), hydrazine hydrate (521 mg, 85%) and potassium hydroxide (497 mg, 8.85 mmol) were added to ethylene glycol (46 mL), and the reaction solution was heated to 200°C and refluxed for 8 hours under nitrogen protection. TLC detection, cooling, quenching with water, filtering, washing the filter cake with water, and drying to obtain the title compound 20d (244 mg, crude product) as a light yellow solid, which was directly used in the next step.
LC-MS：m/z＝198.2[M+H]+ LC-MS: m/z = 198.2 [M + H] +
第四步N-(2,2-二甲基-1,2-二氢苊-5-基)-4-氟苯甲酰胺20Step 4: N-(2,2-dimethyl-1,2-dihydroacenaphthene-5-yl)-4-fluorobenzamide 20
将化合物20d(50mg,0.25mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(72mg,0.38mmol)，对氟苯甲酸(46mg,0.33mmol)和4-二甲氨基吡啶(3mg,0.025mmol)加到二氯甲烷(1mL)中，室温下搅拌反应2小时。TLC检测，加水淬灭，乙酸乙酯萃取，水洗，无水硫酸钠干燥，浓缩，粗品经纯化得到白色固体标题化合物20(68mg,两步收率70％)。Compound 20d (50 mg, 0.25 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg, 0.38 mmol), p-fluorobenzoic acid (46 mg, 0.33 mmol) and 4-dimethylaminopyridine (3 mg, 0.025 mmol) were added to dichloromethane (1 mL) and stirred at room temperature for 2 hours. TLC detection, quenching with water, extraction with ethyl acetate, washing with water, drying over anhydrous sodium sulfate, concentration, and purification of the crude product to obtain the title compound 20 (68 mg, two-step yield 70%) as a white solid.
LC-MS：m/z＝320.2[M+H]+；(99.68％purity,220nm)LC-MS: m/z=320.2 [M+H] + ; (99.68% purity, 220 nm)
1H NMR(400MHz,DMSO-d6):δ10.35(s,1H),8.15(dd,J＝8.8,5.6Hz,2H),7.65(d,J＝8.4Hz,1H),7.59(d,J＝7.6Hz,1H),7.52-7.48(m,1H),7.39(t,J＝8.8Hz,2H),7.34-7.31(m,2H),3.26(s,2H),1.43(s,6H). 1 H NMR (400 MHz, DMSO-d 6 ): δ10.35 (s, 1H), 8.15 (dd, J=8.8, 5.6 Hz, 2H), 7.65 (d, J=8.4 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.52-7.48 (m, 1H), 7.39 (t, J=8.8 Hz, 2H), 7.34-7.31 (m, 2H), 3.26 (s, 2H), 1.43 (s, 6H).
实施例21Embodiment 21
N-(5-环丙基萘-1-基)-4-氟苯甲酰胺21
N-(5-cyclopropylnaphthalen-1-yl)-4-fluorobenzamide 21
第一步5-环丙基萘-1-胺21cStep 1 5-Cyclopropylnaphthalene-1-amine 21c
参照实施例12的第四步的方法合成得到化合物21c(350mg，粗品)，直接投入下一步反应。Compound 21c (350 mg, crude product) was synthesized by referring to the method of step 4 of Example 12 and directly used in the next step reaction.
LC-MS:m/z＝184.1[M+H]+ LC-MS: m/z = 184.1 [M + H] +
第二步N-(5-环丙基萘-1-基)-4-氟苯甲酰胺21Step 2 N-(5-cyclopropylnaphthalen-1-yl)-4-fluorobenzamide 21
将化合物21c(50mg,粗品)和对氟苯甲酸(57mg,0.40mmol)溶于二氯甲烷(3mL)中，室温下加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(78mg,0.40mmol)和催化量4-二甲氨基吡啶，室温搅拌。TLC检测。反应液加饱和碳酸氢钠水溶液中和，二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得到白色固体标题化合物21(10mg,收率8％)Compound 21c (50 mg, crude product) and p-fluorobenzoic acid (57 mg, 0.40 mmol) were dissolved in dichloromethane (3 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (78 mg, 0.40 mmol) and catalytic amount of 4-dimethylaminopyridine were added at room temperature, and stirred at room temperature. TLC detection was performed. The 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.
LC-MS:m/z＝306.1[M+H]+；(93.71％purity,220nm)LC-MS: m/z=306.1 [M+H] + ; (93.71% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),8.36(d,J＝7.2Hz,1H),8.18-8.14(m,2H),7.84(d,J＝8.4Hz,1H),7.65-7.59(m,2H),7.45-7.38(m,3H),7.30(d,J＝6.8Hz,1H),1.11-1.07(m,2H),0.85-0.84(m,1H),0.76-0.72(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.45 (s, 1H), 8.36 (d, J = 7.2 Hz, 1H), 8.18-8.14 (m, 2H), 7.84 (d, J = 8.4 Hz, 1H), 7.65-7.59 (m, 2H), 7.45-7.38 (m, 3H), 7.30 (d, J = 6.8 Hz, 1H), 1.11-1.07 (m, 2H), 0.85-0.84 (m, 1H), 0.76-0.72 (m, 2H).
实施例22Embodiment 22
N-(5-环丙基萘-1-基)-5-氟吡啶酰胺22
N-(5-cyclopropylnaphthalen-1-yl)-5-fluoropicolinamide 22
参照实施例21的第二步合成方法合成得到化合物22。Compound 22 was synthesized by referring to the second step synthesis method of Example 21.
LC-MS：m/z＝307.1[M+H]+；(98.28％purity,210nm)LC-MS: m/z=307.1 [M+H] + ; (98.28% purity, 210 nm)
1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),8.80(d,J＝2.8Hz,1H),8.34(d,J＝8.4Hz,1H),8.27(dd,J＝8.4,4.4Hz,1H),8.04-7.99(m,1H),7.87-7.82(m,2H),7.63(t,J＝8.0Hz,1H),7.47(t,J＝8.0Hz,1H),7.32(d,J＝7.2Hz,1H),2.47-2.40(m,1H),1.11-1.06(m,2H),0.76-0.73(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.78 (s, 1H), 8.80 (d, J = 2.8 Hz, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.27 (dd, J = 8.4, 4.4 Hz, 1H), 8.04-7.99 (m, 1H), 7.87-7.82 (m, 2H), 7.63 (t, J = 8.0 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.32 (d, J = 7.2 Hz, 1H), 2.47-2.40 (m, 1H), 1.11-1.06 (m, 2H), 0.76-0.73 (m, 2H).
实施例23Embodiment 23
N-(5-乙基萘-1-基)-4-氟苯甲酰胺23
N-(5-ethylnaphthyl)-4-fluorobenzamide 23
第一步5-乙烯基萘-1-胺23bStep 1 5-vinylnaphthalene-1-amine 23b
室温下，将化合物21a(300mg,1.35mmol)，乙烯基三氟硼酸钾23a(271mg,2.03mmol)，三乙胺(682mg,6.74mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(46mg,0.056mmol)依次加入到1,4-二氧六环(6mL)和水(1.5mL)的混合溶液中，氮气保护下加热至90℃反应3小时。TLC监测。冷却，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得到黄色固体标题化合物23b(187mg,收率82％)。At room temperature, compound 21a (300 mg, 1.35 mmol), potassium vinyl trifluoroborate 23a (271 mg, 2.03 mmol), triethylamine (682 mg, 6.74 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (46 mg, 0.056 mmol) were added to a mixed solution of 1,4-dioxane (6 mL) and water (1.5 mL) in sequence, and heated to 90 ° C under nitrogen protection for 3 hours. TLC monitoring. Cool, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate, and the crude product is purified by silica gel column chromatography to obtain the title compound 23b (187 mg, yield 82%) as a yellow solid.
LC-MS：m/z＝170.1[M+H]+ LC-MS: m/z = 170.1 [M + H] +
1H NMR(400MHz,CDCl3)δ7.80(d,J＝8.4Hz,1H),7.60(dd,J＝14.4,8.4Hz,2H),7.50-7.42(m,2H),7.33(t,J＝7.6Hz,1H),6.81(d,J＝7.2Hz,1H),5.77(dd,J＝17.6,1.2Hz,1H),5.46(dd,J＝10.8,1.2Hz,1H),4.16(s,2H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.80 (d, J = 8.4 Hz, 1H), 7.60 (dd, J = 14.4, 8.4 Hz, 2H), 7.50-7.42 (m, 2H), 7.33 (t, J = 7.6 Hz, 1H), 6.81 (d, J = 7.2 Hz, 1H), 5.77 (dd, J = 17.6, 1.2 Hz, 1H), 5.46 (dd, J = 10.8, 1.2 Hz, 1H), 4.16 (s, 2H).
第二步5-乙基萘-1-胺23cStep 2 5-Ethylnaphthalen-1-amine 23c
参照实施例1的第一步合成方法合成得到化合物23c(181mg,收率95％)。Compound 23c (181 mg, yield 95%) was synthesized by referring to the first step of the synthesis method in Example 1.
第三步N-(5-乙基萘-1-基)-4-氟苯甲酰胺23Step 3 N-(5-ethylnaphthyl-1-yl)-4-fluorobenzamide 23
参照实施例21的第二步合成方法合成得到化合物23。(268mg,收率86％)。Compound 23 was synthesized by referring to the second step synthesis method of Example 21 (268 mg, yield 86%).
LC-MS:m/z＝294.1[M+H]+(98.33％purity,210nm)LC-MS: m/z = 294.1 [M+H] + (98.33% purity, 210 nm)
1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),8.17(dd,J＝8.0,6.0Hz,2H),8.06-8.04(m,1H),7.85(d,J＝8.4Hz,1H),7.61-7.58(m,2H),7.48-7.39(m,4H),3.12(q,J＝7.6Hz,2H),1.33(t,J＝7.6Hz,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.46 (s, 1H), 8.17 (dd, J=8.0, 6.0 Hz, 2H), 8.06-8.04 (m, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.61-7.58 (m, 2H), 7.48-7.39 (m, 4H), 3.12 (q, J=7.6 Hz, 2H), 1.33 (t, J=7.6 Hz, 3H).
实施例24Embodiment 24
N-(5-(环戊-1-烯-1-基)萘-1-基)-4-氟苯甲酰胺24
N-(5-(Cyclopent-1-en-1-yl)naphthalen-1-yl)-4-fluorobenzamide 24
第一步5-(环戊-1-烯-1-基)萘-1-胺24bStep 1 5-(Cyclopent-1-en-1-yl)naphthalen-1-amine 24b
将1-氨基-5-溴萘21a(500mg,2.2mmol)溶解于1,4-二氧六环(10mL)和水(5mL)的混合液中，室温下依次加入1-环戊烯硼酸频哪醇酯24a(1.31g,6.58mmol)和碳酸铯(2.2g,6.58mmol)氮气置换三次，再加入Pd(dppf)Cl2(50mg,催化量)，加毕，氮气保护下，升温至100℃反应2小时，TLC检测，反应液降至室温搅拌，反应液加水淬灭，二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥，粗品经Prep-TLC纯化得黄色油状标题化合物24b(855mg，粗品)，直接用于下一步。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. The 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.
LC-MS:m/z＝210.2[M+H]+ LC-MS: m/z = 210.2 [M + H] +
第二步N-(5-(环戊-1-烯-1-基)萘-1-基)-4-氟苯甲酰胺24Step 2 N-(5-(cyclopent-1-en-1-yl)naphthalen-1-yl)-4-fluorobenzamide 24
参照实施例21的第二步合成方法合成得到化合物24。。Compound 24 was synthesized by referring to the second step synthesis method of Example 21.
LC-MS:m/z＝332.2[M+H]+；(96.93％purity,210nm)LC-MS: m/z=332.2 [M+H] + ; (96.93% purity, 210 nm)
1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.19-8.15(m,2H),8.07-8.05(m,1H),7.90(d,J＝8.4Hz,1H),7.59-7.47(m,3H),7.43-7.39(m,3H),5.95(s,1H),2.81-2.77(m,2H),2.65-2.61(m,2H),2.12-2.04(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.48 (s, 1H), 8.19-8.15 (m, 2H), 8.07-8.05 (m, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.59-7.47 (m, 3H), 7.43-7.39 (m, 3H), 5.95 (s, 1H), 2.81-2.77 (m, 2H), 2.65-2.61 (m, 2H), 2.12-2.04 (m, 2H).
实施例25Embodiment 25
N-(5-环戊基萘-1-基)-4-氟苯甲酰胺25
N-(5-cyclopentylnaphth-1-yl)-4-fluorobenzamide 25
第一步5-(环戊-1-烯-1-基)萘-1-胺25aFirst step 5-(Cyclopent-1-en-1-yl)naphthalen-1-amine 25a
参照实施例1的第一步合成方法合成得到化合物25a(204mg，收率68％)。Compound 25a (204 mg, yield 68%) was synthesized by referring to the first step of the synthesis method in Example 1.
LC-MS:m/z＝212.2[M+H]+ LC-MS: m/z = 212.2 [M + H] +
第二步N-(5-环戊基萘-1-基)-4-氟苯甲酰胺25Step 2 N-(5-cyclopentylnaphthalen-1-yl)-4-fluorobenzamide 25
参照实施例21的第二步合成方法合成得到化合物25。Compound 25 was synthesized by referring to the second step synthesis method of Example 21.
LC-MS:m/z＝334.1[M+H]+(99.84％purity,220nm)LC-MS: m/z = 334.1 [M+H] + (99.84% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),8.18-8.15(m,3H),7.85(dd,J＝6.4,2.0Hz 1H),7.60-7.57(m,2H),7.49-7.45(m,2H),7.43-7.38(m,2H),3.86-3.78(m,1H),2.17(s,2H),1.81-1.71(m,6H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.45 (s, 1H), 8.18-8.15 (m, 3H), 7.85 (dd, J=6.4, 2.0 Hz 1H), 7.60-7.57 (m, 2H), 7.49-7.45 (m, 2H), 7.43-7.38 (m, 2H), 3.86-3.78 (m, 1H), 2.17 (s, 2H), 1.81-1.71 (m, 6H).
实施例26Embodiment 26
5-((5-环丙基萘-1-基)氨基甲酰基)-2-氟苯甲酸26
5-((5-cyclopropylnaphthalen-1-yl)carbamoyl)-2-fluorobenzoic acid 26
第一步3-溴-N-(5-环丙基萘-1-基)-4-氟苯甲酰胺26bStep 1 3-Bromo-N-(5-cyclopropylnaphthalen-1-yl)-4-fluorobenzamide 26b
将5-环丙基萘-1-胺26a(300mg,1.6mmol)和3-溴-4-氟苯甲酸(467mg,2.1mmol)溶解在二氯甲烷(6mL)中，再依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(408mg,2.1mmol)和4-二甲氨基吡啶(20mg,0.16mmol)，加毕，反应液升温至30℃搅拌2小时，TLC(石油醚/乙酸乙酯＝3/1)监测显示反应完全。冷却，加水(6mL)淬灭，有白色固体析出，吸走有机相，残余物加甲醇(3mL)溶解，超声打浆得白色固体，白色固体再用水(8mL)打浆得白色固体标题化合物26b(400mg,收率64％)。5-Cyclopropylnaphthalene-1-amine 26a (300 mg, 1.6 mmol) and 3-bromo-4-fluorobenzoic acid (467 mg, 2.1 mmol) were dissolved in dichloromethane (6 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (408 mg, 2.1 mmol) and 4-dimethylaminopyridine (20 mg, 0.16 mmol) were added in sequence. After the addition, the reaction solution was heated to 30°C and stirred for 2 hours. TLC (petroleum ether/ethyl acetate = 3/1) monitoring showed that the reaction was complete. 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.
第二步5-((5-环丙基萘-1-基)氨基甲酰基)-2-氟苯甲酸26Step 2 5-((5-cyclopropylnaphthalen-1-yl)carbamoyl)-2-fluorobenzoic acid 26
参照实施例21的第二步合成方法合成得到化合物26。(7.3mg,收率10％)。Compound 26 was synthesized by referring to the second step synthesis method of Example 21 (7.3 mg, yield 10%).
LC-MS：m/z＝348.1[M-H]-(98.96％purity,254nm)LC-MS: m/z = 348.1 [MH] - (98.96% purity, 254 nm)
1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.43-8.39(m,1H),8.35(d,J＝8.0Hz,1H),8.10-8.03(m,1H),7.83(d,J＝8.4Hz,1H),7.64-7.57(m,2H),7.43(t,J＝8.4Hz,1H),7.28(t,J＝7.6Hz,2H),2.47-2.40(m,1H),1.10-1.06(m,2H),0.76-0.72(m,2H).(羧酸氢未出峰) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.49 (s, 1H), 8.43-8.39 (m, 1H), 8.35 (d, J = 8.0 Hz, 1H), 8.10-8.03 (m, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.64-7.57 (m, 2H), 7.43 (t, J = 8.4 Hz, 1H), 7.28 (t, J = 7.6 Hz, 2H), 2.47-2.40 (m, 1H), 1.10-1.06 (m, 2H), 0.76-0.72 (m, 2H). (Carboxylic acid hydrogen peak not seen)
实施例27Embodiment 27
N-(8-环丙基喹啉-4-基)-4-氟苯甲酰胺27
N-(8-Cyclopropylquinolin-4-yl)-4-fluorobenzamide 27
第一步8-环丙基喹啉-4-醇27bStep 1 8-Cyclopropylquinolin-4-ol 27b
参照实施例12的第四步的方法合成得到黄色油状标题化合物27b(447mg,收率27％)。The title compound 27b (447 mg, yield 27%) was synthesized as a yellow oil by referring to the method of the fourth step of Example 12.
LC-MS:m/z＝186.2[M+H]+ LC-MS: m/z = 186.2 [M + H] +
第二步4-氯-8-环丙基喹啉27cStep 2 4-Chloro-8-cyclopropylquinoline 27c
将化合物27b(440mg,2.38mmol)溶解于1,2-二氯乙烷中，室温下滴加三氯氧磷(1mL)，加毕，缓慢升温至80℃，TLC检测原料。冷却，浓缩，饱和碳酸氢钠溶液调节至pH＝8，乙酸乙酯萃取，干燥，浓缩，粗品经硅胶柱层析纯化得到棕色油状标题化合物27c(332mg,收率69％)。Compound 27b (440 mg, 2.38 mmol) was dissolved in 1,2-dichloroethane, and phosphorus oxychloride (1 mL) was added dropwise at room temperature. After the addition was completed, the temperature was slowly raised to 80°C, and the raw material was detected by TLC. The mixture was cooled, concentrated, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, dried, and concentrated. The crude product was purified by silica gel column chromatography to obtain the title compound 27c (332 mg, yield 69%) as a brown oil.
LC-MS:m/z＝204.1[M+H]+ LC-MS: m/z = 204.1 [M + H] +
第三步(8-环丙基喹啉-4-基)氨基甲酸叔丁酯27dStep 3: tert-Butyl (8-cyclopropylquinolin-4-yl)carbamate 27d
将化合物27c(280mg,1.37mmol)溶解于盐酸1,4-二氧六环(3mL)中，室温下依次加入碳酸铯(896mg,2.75mmol)，氨基甲酸叔丁酯(210mg,1.79mmol)，X-Phos(60mg,0.13mmol)与醋酸钯(10mg,0.045mmol)。氮气保护，升温至100℃反应1.5小时，TLC检测。将冷却，加水稀释，乙酸乙酯萃取，无水硫酸钠干燥，经柱层析纯化得到黄色固体27d(360mg,收率92％)。Compound 27c (280 mg, 1.37 mmol) was dissolved in 1,4-dioxane hydrochloride (3 mL), and cesium carbonate (896 mg, 2.75 mmol), tert-butyl carbamate (210 mg, 1.79 mmol), X-Phos (60 mg, 0.13 mmol) and palladium acetate (10 mg, 0.045 mmol) were added in sequence at room temperature. The mixture was protected by nitrogen and heated to 100 °C for 1.5 hours, and then detected by TLC. The mixture was cooled, diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain a yellow solid 27d (360 mg, yield 92%).
第四步8-环丙基喹啉-4-胺27eStep 4: 8-Cyclopropylquinolin-4-amine 27e
将化合物27d(360mg,1.27mmol)溶解于二氯甲烷(2mL)中，室温下滴加三氟乙酸(1mL)。加毕，室温搅拌，TLC检测。反应液用饱和碳酸氢钠水溶液，二氯甲烷/异丙醇混合溶剂萃取，无水硫酸钠干燥，浓缩得到淡黄色固体标题化合物27e(251mg,粗品)，直接用于下一步。Compound 27d (360 mg, 1.27 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added dropwise at room temperature. After addition, the mixture was stirred at room temperature and tested by TLC. The reaction solution was extracted with a saturated aqueous sodium bicarbonate solution and a dichloromethane/isopropanol mixed solvent, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 27e (251 mg, crude product) as a light yellow solid, which was used directly in the next step.
第五步N-(8-环丙基喹啉-4-基)-4-氟苯甲酰胺27Step 5 N-(8-cyclopropylquinolin-4-yl)-4-fluorobenzamide 27
参照实施例21的第二步合成方法合成得到化合物27。Compound 27 was synthesized by referring to the second step synthesis method of Example 21.
LC-MS:m/z＝307.1[M+H]+(99.90％purity,210nm)LC-MS: m/z = 307.1 [M+H] + (99.90% purity, 210 nm)
1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),8.93(d,J＝4.8Hz,1H),8.19-8.15(m,2H),8.01(d,J＝8.4Hz,1H),7.90(d,J＝4.8Hz,1H),7.50(t,J＝8.0Hz,1H),7.41(t,J＝8.8Hz,2H),7.26-7.23(m,1H),3.28-3.21(m,1H),1.13-1.09(m,2H),0.86-0.82(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.67 (s, 1H), 8.93 (d, J = 4.8 Hz, 1H), 8.19-8.15 (m, 2H), 8.01 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 4.8 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.41 (t, J = 8.8 Hz, 2H), 7.26-7.23 (m, 1H), 3.28-3.21 (m, 1H), 1.13-1.09 (m, 2H), 0.86-0.82 (m, 2H).
实施例28Embodiment 28
N-(5-(3,6-二氢-2H-吡喃-4-基)萘-1-基)-4-氟苯甲酰胺28
N-(5-(3,6-dihydro-2H-pyran-4-yl)naphthalen-1-yl)-4-fluorobenzamide 28
第一步5-(3,6-二氢-2H-吡喃-4-基)萘-1-胺28bFirst step 5-(3,6-dihydro-2H-pyran-4-yl)naphthalen-1-amine 28b
将5-溴萘-1-胺21a(300mg,1.4mmol)和3,6-二氢-2H-吡喃-4-硼酸频哪醇酯28a(851mg,4.1mmol)溶解在1,4-二氧六环和水的混合溶液中，依次加入碳酸铯(1.3g,4.1mmol)和Pd(dppf)Cl2(110mg,0.14mmol)，加毕，氮气保护下，升温至100℃，TLC监控。冷却，加水稀释，乙酸乙酯萃取，饱和盐水洗，干燥，浓缩。粗品经硅胶柱层析纯化淡粉色固体8b(300mg,收率99％)。5-Bronaphthalene-1-amine 21a (300 mg, 1.4 mmol) and 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester 28a (851 mg, 4.1 mmol) were dissolved in a mixed solution of 1,4-dioxane and water, and cesium carbonate (1.3 g, 4.1 mmol) and Pd(dppf)Cl 2 (110 mg, 0.14 mmol) were added in sequence. After the addition, the temperature was raised to 100°C under nitrogen protection and monitored by TLC. The mixture was cooled, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried, and concentrated. The crude product was purified by silica gel column chromatography to obtain a light pink solid 8b (300 mg, yield 99%).
LC-MS：m/z＝226.1[M+H]+ LC-MS: m/z = 226.1 [M + H] +
第二步N-(5-(3,6-二氢-2H-吡喃-4-基)萘-1-基)-4-氟苯甲酰胺28Step 2 N-(5-(3,6-dihydro-2H-pyran-4-yl)naphthalen-1-yl)-4-fluorobenzamide 28
参照实施例21的第二步合成方法合成得到化合物28。Compound 28 was synthesized by referring to the second step synthesis method of Example 21.
LC-MS：m/z＝348.1[M+H]+(99.76％purity,220nm)LC-MS: m/z=348.1 [M+H] + (99.76% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.19-8.15(m,2H),7.96-7.91(m,2H),7.59-7.55(m,2H),7.51(t,J＝7.2Hz,1H),7.43-7.36(m,3H),5.84(s,1H),4.30(d,J＝2.4Hz,2H),3.94(t,J＝5.2Hz,2H),2.45(s,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.48 (s, 1H), 8.19-8.15 (m, 2H), 7.96-7.91 (m, 2H), 7.59-7.55 (m, 2H), 7.51 (t, J=7.2 Hz, 1H), 7.43-7.36 (m, 3H), 5.84 (s, 1H), 4.30 (d, J=2.4 Hz, 2H), 3.94 (t, J=5.2 Hz, 2H), 2.45 (s, 2H).
实施例29Embodiment 29
4-氟-N-(5-(四氢-2H-吡喃-4-基)萘-1-基)苯甲酰胺29
4-Fluoro-N-(5-(tetrahydro-2H-pyran-4-yl)naphthalen-1-yl)benzamide 29
第一步5-(3,6-二氢-2H-吡喃-4-基)萘-1-胺29aFirst step 5-(3,6-dihydro-2H-pyran-4-yl)naphthalen-1-amine 29a
参照实施例1的第一步合成方法合成得到棕色油状标题化合物29a(86mg，收率85％)。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.
LC-MS:m/z＝228.2[M+H]+ LC-MS: m/z = 228.2 [M + H] +
第二步4-氟-N-(5-(四氢-2H-吡喃-4-基)萘-1-基)苯甲酰胺29Step 2 4-Fluoro-N-(5-(tetrahydro-2H-pyran-4-yl)naphthalen-1-yl)benzamide 29
参照实施例21的第二步合成方法合成得到化合物29。Compound 29 was synthesized by referring to the second step synthesis method of Example 21.
LC-MS:m/z＝350.2[M+H]+(97.48％purity,220nm)LC-MS: m/z = 350.2 [M+H] + (97.48% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.58(s,1H),8.21-8.18(m,3H),7.86(d,J＝7.6Hz,1H),7.61-7.55(m,2H),7.52-7.46(m,2H),7.40(t,J＝8.8Hz,2H),4.01(d,J＝11.2Hz,2H),3.71-3.61(m,3H),1.88-1.77(m,4H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.58 (s, 1H), 8.21-8.18 (m, 3H), 7.86 (d, J=7.6 Hz, 1H), 7.61-7.55 (m, 2H), 7.52-7.46 (m, 2H), 7.40 (t, J=8.8 Hz, 2H), 4.01 (d, J=11.2 Hz, 2H), 3.71-3.61 (m, 3H), 1.88-1.77 (m, 4H).
实施例30Embodiment 30
N-(5-环丙基萘-1-基)-3-(二甲氨基)-4-氟苯甲酰胺30
N-(5-cyclopropylnaphth-1-yl)-3-(dimethylamino)-4-fluorobenzamide 30
第一步3-(二甲氨基)-4-氟苯甲酸甲酯30bStep 1 Methyl 3-(dimethylamino)-4-fluorobenzoate 30b
将3-氨基-4-氟苯甲酸甲酯30a(500mg,2.96mmol)和多聚甲醛(888mg,29.60mmol)溶于乙酸(30mL)中，反应液冷却至0℃，加入氰基硼氢化钠(558mg,8.88mmol)，加毕，缓慢恢复至室温下搅拌反应4小时。LCMS检测反应完全，反应液加乙酸乙酯稀释，水洗，饱和碳酸氢钠溶液洗，无水硫酸钠干燥，浓缩得到白色固体标题化合物30b(522mg,粗品)，直接用于下一步。3-Amino-4-fluorobenzoic acid methyl ester 30a (500 mg, 2.96 mmol) and paraformaldehyde (888 mg, 29.60 mmol) were dissolved in acetic acid (30 mL), the reaction solution was cooled to 0°C, sodium cyanoborohydride (558 mg, 8.88 mmol) was added, and the mixture was slowly returned to room temperature and stirred for 4 hours. LCMS detected that the reaction was complete, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 30b (522 mg, crude product) as a white solid, which was used directly in the next step.
LC-MS：m/z＝198.2[M+H]+ LC-MS: m/z = 198.2 [M + H] +
第二步3-(二甲氨基)-4-氟苯甲酸30cStep 2 3-(Dimethylamino)-4-fluorobenzoic acid 30c
将化合物30b(200mg,1.01mmol)溶于甲醇(2mL)和水(0.5mL)的混合溶剂中，温度降到0℃，加入氢氧化钠固体(404mg,10.1mmol)，加毕，缓慢恢复至室温搅拌反应1小时。LCMS检测反应 完全，反应液用饱和柠檬酸溶液调节pH到6，加乙酸乙酯稀释，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经pre-TLC纯化得到白色固体标题化合物30c(178mg,收率86％)。Compound 30b (200 mg, 1.01 mmol) was dissolved in a mixed solvent of methanol (2 mL) and water (0.5 mL), the temperature was lowered to 0°C, solid sodium hydroxide (404 mg, 10.1 mmol) was added, and after the addition, the mixture was slowly returned to room temperature and stirred for 1 hour. The reaction was detected by LCMS The reaction solution was adjusted to pH 6 with saturated citric acid solution, diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by pre-TLC to give the title compound 30c (178 mg, yield 86%) as a white solid.
LC-MS：m/z＝184.1[M+H]+ LC-MS: m/z = 184.1 [M + H] +
第三步N-(5-环丙基萘-1-基)-3-(二甲氨基)-4-氟苯甲酰胺30Step 3 N-(5-cyclopropylnaphthalen-1-yl)-3-(dimethylamino)-4-fluorobenzamide 30
参照实施例21的第二步合成方法合成得到化合物30。Compound 30 was synthesized by referring to the second step synthesis method of Example 21.
LC-MS：m/z＝349.2[M+H]+ LC-MS: m/z = 349.2 [M + H] +
1H NMR(400MHz,DMSO-d6):δ10.40(s,1H),8.36(d,J＝8.4Hz,1H),7.82(d,J＝8.8Hz,1H),7.65-7.61(m,3H),7.57(d,J＝7.2Hz,1H),7.44(t,J＝8.0Hz,1H),7.31-7.26(m,2H),2.86(s,6H),2.48-2.39(m,1H),1.15-1.01(m,2H),0.76-0.72(m,2H).1H NMR (400 MHz, DMSO-d 6 ): δ 10.40 (s, 1H), 8.36 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.65-7.61 (m, 3H), 7.57 (d, J = 7.2 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.31-7.26 (m, 2H), 2.86 (s, 6H), 2.48-2.39 (m, 1H), 1.15-1.01 (m, 2H), 0.76-0.72 (m, 2H).
实施例31Embodiment 31
N-(5-环丙基萘-1-基)-4-氟-3-(2-羟基乙氧基)苯甲酰胺31
N-(5-cyclopropylnaphth-1-yl)-4-fluoro-3-(2-hydroxyethoxy)benzamide 31
第一步4-氟-3-羟基苯甲酸甲酯31bStep 1 Methyl 4-fluoro-3-hydroxybenzoate 31b
将4-氟-3-羟基苯甲酸31a(1.0g,6.41mmol)溶解于甲醇中，加入2滴浓硫酸，加热至80℃，TLC检测。冷却，浓缩得到灰色固体粗品31b(1.6g)，直接用于下一步。4-Fluoro-3-hydroxybenzoic acid 31a (1.0 g, 6.41 mmol) was dissolved in methanol, 2 drops of concentrated sulfuric acid were added, and the mixture was heated to 80°C and tested by TLC. The mixture was cooled and concentrated to obtain a gray solid crude product 31b (1.6 g), which was used directly in the next step.
第二步2-(2-溴乙氧基)四氢-2H-吡喃胺31dStep 2 2-(2-bromoethoxy)tetrahydro-2H-pyranamine 31d
将2-溴乙烷-1-醇31c(1.0g,8.0mmol)溶解于二氯甲烷中，冰浴，加入3,4-二氢-2H-吡喃(0.81g,9.6mmol)与催化量的对甲苯磺酸一水合物。室温搅拌，TLC检测。反应液加水淬灭，二氯甲烷萃取，饱和食盐水洗，干燥，粗品经硅胶柱层析纯化得到无色液体31d(1.1g,收率63％)。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%).
第三步4-氟-3-(2-((四氢-2H-吡喃-2-基)氧基)乙氧基)苯甲酸甲酯31eStep 3: Methyl 4-fluoro-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoate 31e
将化合物31b(0.30g,1.76mmol)溶解于乙腈中，室温下加入31d(0.37g,1.76mmol)与碳酸钾(0.49g,3.52mmol)，反应液加热至80℃，TLC检测，冷却，加水淬灭，乙酸乙酯萃取，饱和食盐水洗，干燥，浓缩，粗品经硅胶柱层析纯化得到无水油状31e(0.26g,收率49％)。Compound 31b (0.30 g, 1.76 mmol) was dissolved in acetonitrile, and 31d (0.37 g, 1.76 mmol) and potassium carbonate (0.49 g, 3.52 mmol) were added at room temperature. The reaction solution was heated to 80°C, detected by TLC, cooled, quenched with water, extracted with ethyl acetate, washed with saturated brine, dried, concentrated, and the crude product was purified by silica gel column chromatography to obtain anhydrous oil 31e (0.26 g, yield 49%).
第四步4-氟-3-(2-((四氢-2H-吡喃-2-基)氧基)乙氧基)苯甲酸31fStep 4: 4-Fluoro-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzoic acid 31f
将化合物31e(0.26g,0.86mmol)溶解于甲醇(4mL)中，加入1N的氢氧化钠水溶液(2.5mL)，加热至80℃搅拌反应1小时，TLC检测。冷却，以稀盐酸调节pH＝6，加乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩得到白色固体标题化合物31f(0.23g,粗品)，直接用于下一步。Compound 31e (0.26 g, 0.86 mmol) was dissolved in methanol (4 mL), 1N sodium hydroxide aqueous solution (2.5 mL) was added, heated to 80°C and stirred for 1 hour, and then detected by TLC. After cooling, the pH was adjusted to 6 with dilute hydrochloric acid, and extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 31f (0.23 g, crude product) as a white solid, which was used directly in the next step.
LC-MS:m/z＝283.1[M-H]- LC-MS: m/z = 283.1 [MH] -
第五步N-(5-环丙基萘-1-基)-4-氟-3-(2-((四氢-2H-吡喃-2-基)氧基)乙氧基)苯甲酰胺31gStep 5: N-(5-cyclopropylnaphthalen-1-yl)-4-fluoro-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzamide 31 g
参照实施例21的第二步合成方法合成得到化合物31gCompound 31g was synthesized by referring to the second step synthesis method of Example 21
LC-MS:m/z＝448.1[M-H]- LC-MS: m/z = 448.1 [MH] -
第六步N-(5-环丙基萘-1-基)-4-氟-3-(2-羟基乙氧基)苯甲酰胺31Step 6 N-(5-cyclopropylnaphthalen-1-yl)-4-fluoro-3-(2-hydroxyethoxy)benzamide 31
将化合物31g(0.10g,0.22mmol)溶解于甲醇(2mL)中，室温下加入对甲苯磺酸吡啶盐(催化量)，加毕，加热至80℃搅拌，TLC检测。冷却，加水淬灭，二氯甲烷萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经Prep-HPLC纯化得到白色固体标题化合物31(57mg,收率70％)。Compound 31g (0.10g, 0.22mmol) was dissolved in methanol (2mL), and p-toluenesulfonic acid pyridinium salt (catalytic amount) was added at room temperature. After the addition was completed, the mixture was heated to 80°C with stirring and detected by TLC. The mixture was cooled, quenched with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-HPLC to obtain the title compound 31 (57mg, yield 70%) as a white solid.
LC-MS:m/z＝366.1[M+H]+(95.01％purity,220nm)LC-MS: m/z = 366.1 [M+H] + (95.01% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.37(d,J＝8.4Hz,1H),7.88-7.82(m,2H),7.73-7.69(m,1H),7.65-7.58(m,2H),7.46-7.38(m,2H),7.30(d,J＝7.2Hz,1H),4.96(t,J＝5.2Hz,1H),4.19(t,J＝4.8Hz,2H),3.79(q,J＝5.2Hz,2H),2.47-2.41(m,1H),1.11-1.06(m,2H),0.77-0.73(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.43 (s, 1H), 8.37 (d, J = 8.4 Hz, 1H), 7.88-7.82 (m, 2H), 7.73-7.69 (m, 1H), 7.65-7.58 (m, 2H), 7.46-7.38 (m, 2H), 7.30 (d, J = 7.2 Hz, 1H), 4.96 (t, J = 5.2 Hz, 1H), 4.19 (t, J = 4.8 Hz, 2H), 3.79 (q, J = 5.2 Hz, 2H), 2.47-2.41 (m, 1H), 1.11-1.06 (m, 2H), 0.77-0.73 (m, 2H).
实施例32Embodiment 32
N-(5-环丙基-8-甲基萘-1-基)-4-氟苯甲酰胺32
N-(5-cyclopropyl-8-methylnaphthalen-1-yl)-4-fluorobenzamide 32
第一步N-(5-溴萘-1-基)吡啶酰胺32bFirst step N-(5-bromonaphthalen-1-yl)pyridine amide 32b
将5-溴萘-1-胺21a(500mg,2.3mmol)和吡啶-2-甲酸32a(360mg,2.9mmol)溶解在二氯甲烷(10mL)中，再依次加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(560mg,2.9mmol)和4-二甲氨基吡啶(27mg,0.23mmol)，加毕，TLC监控。冷却，加水淬灭，二氯甲烷萃取，饱和盐水洗，无水硫酸钠干燥，浓缩得粗品。粗品经打浆得淡黄色固体32b(430mg,收率58％)。5-Bronaphthalene-1-amine 21a (500 mg, 2.3 mmol) and pyridine-2-carboxylic acid 32a (360 mg, 2.9 mmol) were dissolved in dichloromethane (10 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (560 mg, 2.9 mmol) and 4-dimethylaminopyridine (27 mg, 0.23 mmol) were added in sequence. After addition, TLC was monitored. The mixture was cooled, quenched with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was slurried to obtain a light yellow solid 32b (430 mg, yield 58%).
第二步N-(5-溴-8-甲基萘-1-基)吡啶酰胺32cStep 2 N-(5-bromo-8-methylnaphthalen-1-yl)picolinamide 32c
将化合物32b(330mg,1.0mmol)和碘甲烷(572mg,4.0mmol)溶解在1,4-二氧六环中，室温下加入乙酸钾(198mg,2.0mmol)和醋酸钯(34mg,0.15mmol)，焖罐130℃搅拌，TLC监控。冷却，加乙酸乙酯稀释，过滤，滤液浓缩，硅胶柱层析纯化得白色固体32c(300mg,收率：87％)。Compound 32b (330 mg, 1.0 mmol) and iodomethane (572 mg, 4.0 mmol) were dissolved in 1,4-dioxane, potassium acetate (198 mg, 2.0 mmol) and palladium acetate (34 mg, 0.15 mmol) were added at room temperature, the mixture was stirred at 130°C, and monitored by TLC. The mixture was cooled, diluted with ethyl acetate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain a white solid 32c (300 mg, yield: 87%).
LC-MS：m/z＝341.0[M+H]+ LC-MS: m/z = 341.0 [M+H] +
1H NMR(400MHz,CDCl3)δ10.53(s,1H),8.67(d,J＝4.8Hz,1H),8.37(d,J＝7.6Hz,1H),8.26(d,J＝8.4Hz,1H),8.10(d,J＝7.2Hz,1H),7.97-7.93(m,1H),7.67(d,J＝7.6Hz,1H),7.62(t,J＝8.0Hz,1H),7.54-7.51(m,1H),7.12(d,J＝7.6Hz,1H),2.93(s,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 10.53 (s, 1H), 8.67 (d, J = 4.8 Hz, 1H), 8.37 (d, J = 7.6 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 7.2 Hz, 1H), 7.97-7.93 (m, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.54-7.51 (m, 1H), 7.12 (d, J = 7.6 Hz, 1H), 2.93 (s, 3H).
第三步5-溴-8-甲基萘-1-胺32dStep 3 5-Bromo-8-methylnaphthalene-1-amine 32d
将化合物32c(370mg,1.1mmol)溶解在乙醇(6mL)和水(0.6mL)的混合溶剂中，室温下加入氢氧化钠固体(435mg,10.8mmol)，加毕，反应液升温至85℃搅拌30小时，TLC显示反应完全。冷却，加水淬灭，乙酸乙酯萃取，饱和盐水洗，无水硫酸钠干燥，浓缩得粗品。粗品经硅胶柱层析纯化得褐色液体标题化合物32d(180mg,收率70％)。Compound 32c (370 mg, 1.1 mmol) was dissolved in a mixed solvent of ethanol (6 mL) and water (0.6 mL), and solid sodium hydroxide (435 mg, 10.8 mmol) was added at room temperature. After addition, the reaction solution was heated to 85°C and stirred for 30 hours. TLC showed that the reaction was complete. The mixture was cooled, quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain the title compound 32d (180 mg, yield 70%) as a brown liquid.
LC-MS：m/z＝236.0[M+H]+ LC-MS: m/z = 236.0 [M + H] +
1H NMR(400MHz,CDCl3)δ7.74(dd,J＝8.4,0.8Hz,1H),7.57(d,J＝7.6Hz,1H),7.32(t,J＝8.0Hz,1H),6.95(d,J＝7.6Hz,1H),6.75(dd,J＝7.2,0.8Hz,1H),4.37(s,2H),2.95(s,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.74 (dd, J = 8.4, 0.8 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 6.95 (d, J = 7.6 Hz, 1H), 6.75 (dd, J = 7.2, 0.8 Hz, 1H), 4.37 (s, 2H), 2.95 (s, 3H).
第四步5-环丙基-8-甲基萘-1-胺32eStep 4: 5-cyclopropyl-8-methylnaphthalene-1-amine 32e
参照实施例12的第四步的方法合成得到褐色液体标题化合物32e(50mg,收率75％)。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.
LC-MS:m/z＝198.2[M+H]+ LC-MS: m/z = 198.2 [M + H] +
1H NMR(400MHz,CDCl3)δ7.90(dd,J＝8.4,0.8Hz,1H),7.31-7.27(m,1H),7.10(d,J＝7.2Hz,1H),7.03(d,J＝7.2Hz,1H),6.72(dd,J＝7.2,0.8Hz,1H),4.34(s,2H),2.97(s,3H),2.23-2.16(m,1H),1.03-0.98(m,2H),0.71-0.67(m,2H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.90 (dd, J = 8.4, 0.8 Hz, 1H), 7.31-7.27 (m, 1H), 7.10 (d, J = 7.2 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 6.72 (dd, J = 7.2, 0.8 Hz, 1H), 4.34 (s, 2H), 2.97 (s, 3H), 2.23-2.16 (m, 1H), 1.03-0.98 (m, 2H), 0.71-0.67 (m, 2H).
第五步N-(5-环丙基-8-甲基萘-1-基)-4-氟苯甲酰胺32Step 5: N-(5-cyclopropyl-8-methylnaphthalen-1-yl)-4-fluorobenzamide 32
参照实施例21的第二步合成方法合成得到化合物32。Compound 32 was synthesized by referring to the second step synthesis method of Example 21.
LC-MS：m/z＝320.2[M+H]+(98.07％purity,210nm)LC-MS: m/z = 320.2 [M+H] + (98.07% purity, 210 nm)
1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.46(d,J＝7.6Hz,1H),8.15-8.11(m,2H),7.61(t,J＝7.6Hz,1H),7.44-7.38(m,3H),7.18(s,2H),2.68(s,3H),2.39-2.32(m,1H),1.08-1.03(m,2H),0.71-0.68(m,2H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.43 (s, 1H), 8.46 (d, J=7.6 Hz, 1H), 8.15-8.11 (m, 2H), 7.61 (t, J=7.6 Hz, 1H), 7.44-7.38 (m, 3H), 7.18 (s, 2H), 2.68 (s, 3H), 2.39-2.32 (m, 1H), 1.08-1.03 (m, 2H), 0.71-0.68 (m, 2H).
实施例33Embodiment 33
N-(5-环丙基异喹啉-1-基)-4-氟苯甲酰胺33
N-(5-cyclopropylisoquinolin-1-yl)-4-fluorobenzamide 33
第一步5-溴异喹啉-1-胺33bStep 1 5-Bromoisoquinolin-1-amine 33b
在一个25mL单口圆底烧瓶中，加入5-溴-1-氯异喹啉33a(100mg,0.41mmol)，乙酰胺(485mg,8.21mmol)与无水碳酸钾(283mg,2.05mmol)，加热至180℃搅拌4小时，将反应体系冷却至室温，TLC检测。向反应体系中加水稀释，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得到棕色固体标题化合物33b(48mg，收率52％)。In a 25mL single-mouth round-bottom flask, 5-bromo-1-chloroisoquinoline 33a (100 mg, 0.41 mmol), acetamide (485 mg, 8.21 mmol) and anhydrous potassium carbonate (283 mg, 2.05 mmol) were added, heated to 180°C and stirred for 4 hours, the reaction system was cooled to room temperature, and TLC was detected. Water was added to dilute the reaction system, 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 33b (48 mg, yield 52%) as a brown solid.
第二步5-环丙基异喹啉-1-胺33cStep 2 5-Cyclopropylisoquinolin-1-amine 33c
参照实施例12的第四步的方法合成得到化合物33c(30mg，收率76％)。Compound 33c (30 mg, yield 76%) was synthesized by referring to the fourth step of Example 12.
第三步N-(5-环丙基异喹啉-1-基)-4-氟苯甲酰胺33Step 3 N-(5-cyclopropylisoquinolin-1-yl)-4-fluorobenzamide 33
将化合物33c(28mg,0.15mmol)溶解于二氯甲烷(1mL)中，0℃下加入三乙胺(31mg,0.30mmol)，滴加对氟苯甲酰氯(36mg,0.23mmol)。加毕，升温至室温搅拌，TLC检测，浓缩，粗品经硅胶柱层析纯化得到白色固体标题化合物33(8mg，收率17％)。Compound 33c (28 mg, 0.15 mmol) was dissolved in dichloromethane (1 mL), triethylamine (31 mg, 0.30 mmol) was added at 0°C, and p-fluorobenzoyl chloride (36 mg, 0.23 mmol) was added dropwise. After the addition, the mixture was heated to room temperature and stirred, and the mixture was tested by TLC. The mixture was concentrated and the crude product was purified by silica gel column chromatography to obtain the title compound 33 (8 mg, yield 17%) as a white solid.
LC-MS:m/z＝307.2[M+H]+(99.89％purity,220nm)LC-MS: m/z = 307.2 [M+H] + (99.89% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ8.36-8.13(m,4H),8.11-7.98(m,1H),7.62-7.53(m,2H),7.38(t,J＝8.8Hz,2H),2.47-2.38(m,1H),1.14-1.07(m,2H),0.81-0.75(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.36-8.13 (m, 4H), 8.11-7.98 (m, 1H), 7.62-7.53 (m, 2H), 7.38 (t, J=8.8 Hz, 2H), 2.47-2.38 (m, 1H), 1.14-1.07 (m, 2H), 0.81-0.75 (m, 2H).
实施例34Embodiment 34
N-(7-环丙基-1-(环丙基甲基)-1H-吲唑-3-基)-4-氟苯甲酰胺34
N-(7-cyclopropyl-1-(cyclopropylmethyl)-1H-indazol-3-yl)-4-fluorobenzamide 34
第一步7-环丙基-1H-吲唑-3-胺34aStep 1 7-Cyclopropyl-1H-indazol-3-amine 34a
参照实施例12的第四步的方法合成得到化合物34a。Compound 34a was synthesized by referring to the fourth step of Example 12.
LC-MS:m/z＝174.2[M+H]+ LC-MS: m/z = 174.2 [M + H] +
第二步N-(7-环丙基-1H-吲唑-3-基)-4-氟苯甲酰胺34bStep 2 N-(7-cyclopropyl-1H-indazol-3-yl)-4-fluorobenzamide 34b
将化合物34a(380mg,2.19mmol)溶解于吡啶(2mL)，冷却至0℃，滴加对氟苯甲酰氯(347mg,2.19mmol)，在此温度下搅拌30分钟，TLC监控，加水淬灭，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化，得棕色固体标题化合物34b(325mg,收率50％)。Compound 34a (380 mg, 2.19 mmol) was dissolved in pyridine (2 mL), cooled to 0°C, p-fluorobenzoyl chloride (347 mg, 2.19 mmol) was added dropwise, and stirred at this temperature for 30 minutes. The mixture was monitored by TLC, quenched with water, 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 34b (325 mg, yield 50%) as a brown solid.
LC-MS:m/z＝296.1[M+H]+ LC-MS: m/z = 296.1 [M + H] +
第三步N-(7-环丙基-1-(环丙基甲基)-1H-吲唑-3-基)-4-氟苯甲酰胺34Step 3 N-(7-cyclopropyl-1-(cyclopropylmethyl)-1H-indazol-3-yl)-4-fluorobenzamide 34
将化合物34b(30mg,0.10mmol)溶于N,N-二甲基甲酰胺(3mL)中，氮气置换，冷却至0℃加入氢化钠(8.00mg,0.2mmol,60％)保温搅拌5分钟，加入溴甲基环丙烷(13.5mg,0.10mmol)，加毕，室温反应，TLC监控，加水淬灭，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经Prep-TLC纯化得类白色固体标题化合物34(21mg,收率60％)。Compound 34b (30 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (3 mL), replaced with nitrogen, cooled to 0°C, added with sodium hydride (8.00 mg, 0.2 mmol, 60%), stirred for 5 minutes, added with bromomethylcyclopropane (13.5 mg, 0.10 mmol), reacted at room temperature, monitored by TLC, quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 34 (21 mg, yield 60%) as an off-white solid.
LC-MS:m/z＝350.2[M+H]+(99.00％purity,220nm)LC-MS: m/z = 350.2 [M+H] + (99.00% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.77(s,1H),8.20-8.10(m,2H),7.49(d,J＝8.0Hz,1H),7.40(t,J＝8.8Hz,2H),7.13(d,J＝6.8Hz,1H),7.00(d,J＝7.6Hz,1H),4.64(d,J＝6.8Hz,2H),2.44-2.31(m,1H),1.44-1.32(m,1H),1.10-0.99(m,2H),0.90-0.80(m,2H),0.57-0.38(m,4H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.77 (s, 1H), 8.20-8.10 (m, 2H), 7.49 (d, J=8.0 Hz, 1H), 7.40 (t, J=8.8 Hz, 2H), 7.13 (d, J=6.8 Hz, 1H), 7.00 (d, J=7.6 Hz, 1H), 4.64 (d, J=6.8 Hz, 2H), 2.44-2.31 (m, 1H), 1.44-1.32 (m, 1H), 1.10-0.99 (m, 2H), 0.90-0.80 (m, 2H), 0.57-0.38 (m, 4H).
实施例35 Embodiment 35
N-(1-乙基-1H-吲唑-4-基)-4-氟苯甲酰胺35
N-(1-ethyl-1H-indazol-4-yl)-4-fluorobenzamide 35
第一步1-乙基-4-硝基-1H-吲唑35bStep 1-Ethyl-4-nitro-1H-indazole 35b
参照实施例34的第三步的方法合成得到淡黄色固体标题化合物35b(194mg，收率33％)。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.
LC-MS:m/z＝192.2[M+H]+ LC-MS: m/z = 192.2 [M + H] +
第二步1-乙基-1H-吲唑-4-胺35cStep 2 1-Ethyl-1H-indazol-4-amine 35c
参照实施例18的第四步合成方法合成得到化合物35c(136mg，收率70％)。Compound 35c (136 mg, yield 70%) was synthesized by referring to the fourth step synthesis method of Example 18.
LC-MS:m/z＝162.2[M+H]+ LC-MS: m/z = 162.2 [M + H] +
第三步N-(1-乙基-1H-吲唑-4-基)-4-氟苯甲酰胺35Step 3 N-(1-ethyl-1H-indazol-4-yl)-4-fluorobenzamide 35
将化合物35c(50mg,0.31mmol)溶解于二氯甲烷(2mL)中，加入对氟苯甲酸(46mg,0.33mmol)，EDCI(77mg,0.40mmol)与DMAP(4mg,0.03mmol)，室温搅拌16小时，TLC检测，反应液浓缩，粗品Pre-TLC纯化，冻干，得到白色固体标题化合物35(64.9mg，收率74％)。Compound 35c (50 mg, 0.31 mmol) was dissolved in dichloromethane (2 mL), and p-fluorobenzoic acid (46 mg, 0.33 mmol), EDCI (77 mg, 0.40 mmol) and DMAP (4 mg, 0.03 mmol) were added. The mixture was stirred at room temperature for 16 hours, and the reaction mixture was detected by TLC. The reaction solution was concentrated, and the crude product was purified by Pre-TLC and freeze-dried to obtain the title compound 35 (64.9 mg, yield 74%) as a white solid.
LC-MS:m/z＝284.1[M+H]+(99.86％purity,210nm)LC-MS: m/z = 284.1 [M+H] + (99.86% purity, 210 nm)
1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.20(s,1H),8.09(dd,J＝8.4,5.6Hz,2H),7.51(d,J＝7.2Hz,1H),7.46(d,J＝8.4Hz,1H),7.42-7.33(m,3H),4.43(q,J＝7.2Hz,2H),1.40(t,J＝7.2Hz,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.42 (s, 1H), 8.20 (s, 1H), 8.09 (dd, J=8.4, 5.6 Hz, 2H), 7.51 (d, J=7.2 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.42-7.33 (m, 3H), 4.43 (q, J=7.2 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H).
实施例36Embodiment 36
N-(1-乙基-1H-苯并[d]咪唑-4-基)-4-氟苯甲酰胺36
N-(1-ethyl-1H-benzo[d]imidazol-4-yl)-4-fluorobenzamide 36
第一步4-硝基-1H-苯并[d]咪唑36bStep 1 4-Nitro-1H-benzo[d]imidazole 36b
将3-硝基邻苯二胺36a(1.00g,6.53mmol)溶于甲酸，加毕，升温至105℃，TLC检测。反应液降至室温，浓缩，粗品用饱和碳酸氢钠水溶液调节pH至中性，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得到黄色油状物标题化合物36b(482mg，收率45％)。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.
LC-MS:m/z＝164.1[M+H]+ LC-MS: m/z = 164.1 [M + H] +
第二步到第四步参考实施例35的第一步到第三步的合成方法，以化合物36b为物料，合成得到白色粉末标题化合物36(45mg，收率66％)。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.
LC-MS:m/z＝284.2[M+H]+(99.46％purity,210nm)LC-MS: m/z = 284.2 [M+H] + (99.46% purity, 210 nm)
1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),8.27(s,1H),8.14-8.04(m,2H),7.82(d,J＝7.6Hz,1H),7.45-7.33(m,3H),7.27(t,J＝8.0Hz,1H),4.37-4.25(m,2H),1.43(t,J＝7.2Hz,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.27 (s, 1H), 8.14-8.04 (m, 2H), 7.82 (d, J=7.6 Hz, 1H), 7.45-7.33 (m, 3H), 7.27 (t, J=8.0 Hz, 1H), 4.37-4.25 (m, 2H), 1.43 (t, J=7.2 Hz, 3H).
实施例37Embodiment 37
N-(4-环丙基萘-1-基)-4-氟苯甲酰胺37
N-(4-cyclopropylnaphthalen-1-yl)-4-fluorobenzamide 37
参照实施例35的第三步合成方法合成得到化合物37(50mg,收率12％)。Compound 37 (50 mg, yield 12%) was synthesized by referring to the third step synthesis method of Example 35.
LC-MS:m/z＝306.2[M+H]+(99.70％purity,220nm)LC-MS: m/z = 306.2 [M + H] + (99.70% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.45(d,J＝8.0Hz,1H),8.19-8.11(m,2H),7.99(d,J＝8.4Hz,1H),7.66-7.54(m,2H),7.46(d,J＝7.6Hz,1H),7.39(t,J＝8.8Hz,2H),7.30(d,J＝7.6Hz,1H),2.47-2.38(m,1H),1.12-1.04(m,2H),0.79-0.71(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.37 (s, 1H), 8.45 (d, J = 8.0 Hz, 1H), 8.19-8.11 (m, 2H), 7.99 (d, J = 8.4 Hz, 1H), 7.66-7.54 (m, 2H), 7.46 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 8.8 Hz, 2H), 7.30 (d, J = 7.6 Hz, 1H), 2.47-2.38 (m, 1H), 1.12-1.04 (m, 2H), 0.79-0.71 (m, 2H).
实施例38Embodiment 38
5-环丙基-N-(4-氟苯基)-1-萘酰胺38
5-Cyclopropyl-N-(4-fluorophenyl)-1-naphthamide 38
第一步5-环丙基-1-萘甲酸38bStep 1 5-Cyclopropyl-1-naphthoic acid 38b
参照实施例12的第四步的方法合成得到黄色固体标题化合物38b(39mg，收率23％)。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.
第二步5-环丙基-N-(4-氟苯基)-1-萘酰胺38Step 2 5-Cyclopropyl-N-(4-fluorophenyl)-1-naphthamide 38
参照实施例37的第二步合成方法合成得到化合物38。(19.4mg，收率35％)。Compound 38 was synthesized by referring to the second step synthesis method of Example 37 (19.4 mg, yield 35%).
LC-MS:m/z＝306.2[M+H]+(97.99％purity,220nm)LC-MS: m/z = 306.2 [M+H] + (97.99% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.58(s,1H),8.56(d,J＝8.4Hz,1H),7.99(d,J＝8.8Hz,1H),7.87-7.78(m,2H),7.75(d,J＝6.8Hz,1H),7.72-7.63(m,1H),7.48(t,J＝7.6Hz,1H),7.34(d,J＝6.8Hz,1H),7.21(t,J＝8.8Hz,2H),2.48-2.41(m,1H),1.12-1.04(m,2H),0.75-0.72(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.58 (s, 1H), 8.56 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.87-7.78 (m, 2H), 7.75 (d, J = 6.8 Hz, 1H), 7.72-7.63 (m, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.34 (d, J = 6.8 Hz, 1H), 7.21 (t, J = 8.8 Hz, 2H), 2.48-2.41 (m, 1H), 1.12-1.04 (m, 2H), 0.75-0.72 (m, 2H).
实施例39Embodiment 39
N-(8-环丙基喹唑啉-4-基)-4-氟苯甲酰胺39
N-(8-Cyclopropylquinazolin-4-yl)-4-fluorobenzamide 39
参考实施例33第二步到第三步的合成方法，以8-溴喹唑啉-4-胺为原料，合成得到白色固体粉末标题化合物39(1.65mg,收率6％)。Referring to the synthesis method from the second step to the third step of Example 33, 8-bromoquinazolin-4-amine was used as the raw material to synthesize the title compound 39 (1.65 mg, yield 6%) as a white solid powder.
LC-MS:m/z＝308.1[M+H]+(87.98％purity,220nm)LC-MS: m/z = 308.1 [M+H] + (87.98% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ8.87-8.56(m,1H),8.30(s,2H),8.02-7.88(m,1H),7.58(t,J＝7.6Hz,1H),7.47-7.42(m,1H),7.42-7.24(m,3H),3.11-2.95(m,1H),1.17-1.08(m,2H),0.93-0.81(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.87-8.56 (m, 1H), 8.30 (s, 2H), 8.02-7.88 (m, 1H), 7.58 (t, J=7.6 Hz, 1H), 7.47-7.42 (m, 1H), 7.42-7.24 (m, 3H), 3.11-2.95 (m, 1H), 1.17-1.08 (m, 2H), 0.93-0.81 (m, 2H).
实施例40Embodiment 40
N-(2-氰基-5-环丙基萘-1-基)-4-氟苯甲酰胺40
N-(2-cyano-5-cyclopropylnaphthalen-1-yl)-4-fluorobenzamide 40
第一步2-溴-5-环丙基萘-1-胺40aStep 1: 2-Bromo-5-cyclopropylnaphthalene-1-amine 40a
将化合物21c(200mg,1.09mmol)溶于N,N-二甲基甲酰胺(2mL)中，冷却至0℃，加入N-溴代丁二酰亚胺(NBS)(194mg,1.09mmol)，保温反应1小时，TLC监控，加水(30mL)淬灭，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析棕色固体40a(183mg,收率64％)。Compound 21c (200 mg, 1.09 mmol) was dissolved in N,N-dimethylformamide (2 mL), cooled to 0°C, and N-bromosuccinimide (NBS) (194 mg, 1.09 mmol) was added. The mixture was kept warm for 1 hour and monitored by TLC. The mixture was quenched by adding water (30 mL), extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography to obtain a brown solid 40a (183 mg, yield 64%).
LC-MS:m/z＝262.1[M+H]+ LC-MS: m/z = 262.1 [M + H] +
第二步N-(2-溴-5-环丙基萘-1-基)-4-氟苯甲酰胺40bStep 2 N-(2-Bromo-5-cyclopropylnaphthalen-1-yl)-4-fluorobenzamide 40b
将化合物40a(100mg,0.38mmol)溶于二氯甲烷中，加入三乙胺(76.90mg,0.76mmol)，冰浴，滴加对氟苯甲酰氯(90.38mg,0.57mmol)，加毕，升至室温，TLC检测，加水淬灭，二氯甲烷萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，硅胶柱层析纯化得类白色固体标题40b(64mg,收率44％)。Compound 40a (100 mg, 0.38 mmol) was dissolved in dichloromethane, triethylamine (76.90 mg, 0.76 mmol) was added, and the mixture was placed in an ice bath. p-Fluorobenzoyl chloride (90.38 mg, 0.57 mmol) was added dropwise. After the addition was completed, the mixture was warmed to room temperature, and tested by TLC. The mixture was quenched with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain the title 40b (64 mg, yield 44%) as an off-white solid.
LC-MS:m/z＝384.0[M+H]+ LC-MS: m/z = 384.0 [M + H] +
第三步N-(2-氰基-5-环丙基萘-1-基)-4-氟苯甲酰胺40Step 3 N-(2-cyano-5-cyclopropylnaphthalen-1-yl)-4-fluorobenzamide 40
将化合物40b(64mg,0.17mmol)溶于N-甲基吡咯烷酮(1mL)中，加入氰化亚铜(22.84mg,0.26mmol)，加毕，微波190℃反应，TLC检测反应，加水和氯化铁，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得棕色固体标题化合物40(14mg,收率25％)。Compound 40b (64 mg, 0.17 mmol) was dissolved in N-methylpyrrolidone (1 mL), and cuprous cyanide (22.84 mg, 0.26 mmol) was added. After the addition was completed, the mixture was reacted in a microwave at 190°C. The reaction was monitored by TLC. Water and ferric chloride were added, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography to obtain the title compound 40 (14 mg, yield 25%) as a brown solid.
LC-MS:m/z＝331.1[M+H]+(97.04％purity,220nm)LC-MS: m/z = 331.1 [M+H] + (97.04% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ12.91(s,0.6H),10.96(s,0.3H),9.00-8.54(m,1H),8.50-8.41(m,2H),8.23-8.14(m,1H),7.99-7.91(m,1H),7.70-7.57(m,1H),7.56-7.39(m,3H),2.48-2.42(m,1H),1.16-1.07(m,2H),0.83-0.75(m,2H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.91 (s, 0.6H), 10.96 (s, 0.3H), 9.00-8.54 (m, 1H), 8.50-8.41 (m, 2H), 8.23-8.14 (m, 1H), 7.99-7.91 (m, 1H), 7.70-7.57 (m, 1H), 7.56-7.39 (m, 3H), 2.48-2.42 (m, 1H), 1.16-1.07 (m, 2H), 0.83-0.75 (m, 2H).
实施例41Embodiment 41
(5-环丙基-1-(4-氟苯甲酰胺基)萘-2-基)(甲基磺酰基)酰胺41
(5-cyclopropyl-1-(4-fluorobenzamido)naphthalen-2-yl)(methylsulfonyl)amide 41
第一步N-(5-环丙基-2-(甲磺酰胺基)萘-1-基)-4-氟苯甲酰胺41The first step is N-(5-cyclopropyl-2-(methylsulfonamido)naphthalen-1-yl)-4-fluorobenzamide 41
将化合物18(30mg,0.094mmol)溶于二氯甲烷(2mL)和四氢呋喃(0.1mL)，加毕，加入吡啶(22.31mg,0.28mmol)，冷却至0℃，滴加甲基磺酰氯(16.15mg,0.14mmol)和催化量DMAP，加毕，升至室温，TLC检测，加淬灭，二氯甲烷萃取，无水硫酸钠干燥，浓缩，粗品经Prep-TLC(PE:EA＝4:1)纯化得白色固体标题化合物41(12mg,收率32％)。Compound 18 (30 mg, 0.094 mmol) was dissolved in dichloromethane (2 mL) and tetrahydrofuran (0.1 mL). After the addition was completed, pyridine (22.31 mg, 0.28 mmol) was added, and the mixture was cooled to 0°C. Methanesulfonyl chloride (16.15 mg, 0.14 mmol) and a catalytic amount of DMAP were added dropwise. After the addition was completed, the mixture was warmed to room temperature, tested by TLC, quenched, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Prep-TLC (PE:EA=4:1) to obtain the title compound 41 (12 mg, yield 32%) as a white solid.
LC-MS:m/z＝399.1[M+H]+(99.73％purity,220nm)LC-MS: m/z = 399.1 [M+H] + (99.73% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.09(s,1H),9.38(s,1H),8.43(d,J＝9.2Hz,1H),8.20(dd,J＝8.8,5.6Hz,2H),7.80(d,J＝9.2Hz,1H),7.66(d,J＝8.4Hz,1H),7.47-7.38(m,3H),7.25(d,J＝6.8Hz,1H),2.98(s,3H),2.47-2.39(m,1H),1.12-1.04(m,2H),0.78-0.70(m,2H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.09 (s, 1H), 9.38 (s, 1H), 8.43 (d, J=9.2 Hz, 1H), 8.20 (dd, J=8.8, 5.6 Hz, 2H), 7.80 (d, J=9.2 Hz, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.47-7.38 (m, 3H), 7.25 (d, J=6.8 Hz, 1H), 2.98 (s, 3H), 2.47-2.39 (m, 1H), 1.12-1.04 (m, 2H), 0.78-0.70 (m, 2H).
实施例42，43Embodiment 42, 43
4-氟-N-(4-(甲氨基)-1,2-二氢苊-5-基)苯甲酰胺424-Fluoro-N-(4-(methylamino)-1,2-dihydroacenaphthene-5-yl)benzamide 42
N-(4-(二甲氨基)-1,2-二氢苊-5-基)-4-氟苯甲酰胺43
N-(4-(Dimethylamino)-1,2-dihydroacenaphthene-5-yl)-4-fluorobenzamide 43
4-氟-N-(4-(甲氨基)-1,2-二氢苊烯-5-基)苯甲酰胺42 4-Fluoro-N-(4-(methylamino)-1,2-dihydroacenaphthylene-5-yl)benzamide 42
将化合物1(36mg,0.12mmol)溶解于N,N-二甲基甲酰胺(2mL)中，室温下加入碳酸钾(60mg,0.42mmol)与碘甲烷(88mg,0.62mmol)，室温搅拌3小时，TLC检测，反应液加水，乙酸乙酯萃取，无水硫酸钠干燥。浓缩，粗品经pre-TLC纯化得到类白色固体状标题化合物42(12mg,收率31％)。Compound 1 (36 mg, 0.12 mmol) was dissolved in N,N-dimethylformamide (2 mL), potassium carbonate (60 mg, 0.42 mmol) and iodomethane (88 mg, 0.62 mmol) were added at room temperature, stirred at room temperature for 3 hours, detected by TLC, the reaction solution was added with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by pre-TLC to obtain the title compound 42 (12 mg, yield 31%) as an off-white solid.
LC-MS:m/z＝321.2[M+H]+(92.52％purity,254nm)LC-MS: m/z = 321.2 [M + H] + (92.52% purity, 254 nm)
1H NMR(400MHz,DMSO-d6)δ9.65(s,1H),8.18(dd,J＝8.4,5.6Hz,2H),7.37(t,J＝8.8Hz,2H),7.29-7.20(m,1H),7.05(d,J＝8.4Hz,1H),6.96-6.90(m,2H),5.51-5.43(m,1H),3.31(s,4H),2.83(d,J＝4.8Hz,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.65 (s, 1H), 8.18 (dd, J=8.4, 5.6 Hz, 2H), 7.37 (t, J=8.8 Hz, 2H), 7.29-7.20 (m, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.96-6.90 (m, 2H), 5.51-5.43 (m, 1H), 3.31 (s, 4H), 2.83 (d, J=4.8 Hz, 3H).
N-(4-(二甲氨基)-1,2-二氢苊-5-基)-4-氟苯甲酰胺43N-(4-(Dimethylamino)-1,2-dihydroacenaphthene-5-yl)-4-fluorobenzamide 43
LC-MS:m/z＝335.2[M+H]+(98.45％purity,220nm)LC-MS: m/z = 335.2 [M+H] + (98.45% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ9.88(s,1H),8.24-8.09(m,2H),7.44-7.32(m,3H),7.27-7.19(m,2H),7.15(d,J＝6.8Hz,1H),2.77(s,6H).(4H包在水峰里) 1 H NMR (400MHz, DMSO-d 6 )δ9.88(s,1H),8.24-8.09(m,2H),7.44-7.32(m,3H),7.27-7.19(m,2H),7.15(d,J＝6.8Hz,1H),2.77(s,6H).(4H is included in the water peak)
实施例44Embodiment 44
4-氟-N-(4-(甲磺酰胺基)-1，2-二氢苊烯-5-基)苯甲酰胺44
4-Fluoro-N-(4-(methylsulfonamido)-1,2-dihydroacenaphthylene-5-yl)benzamide 44
第一步4-氟-N-(4-(甲磺酰胺基)-1，2-二氢苊烯-5-基)苯甲酰胺44Step 1 4-Fluoro-N-(4-(methylsulfonyl)-1,2-dihydroacenaphthylene-5-yl)benzamide 44
化合物1(40mg,0.13mmol)溶解于二氯甲烷(1mL)，降温至0℃，加入甲基磺酰氯(22mg,0.20mmol)与吡啶(20mg,0.26mmol)，加毕，升至室温反应，TLC检测，反应液浓缩，粗品经prep-TLC纯化得到类白色固体状标题化合物44(23mg,收率46％)。Compound 1 (40 mg, 0.13 mmol) was dissolved in dichloromethane (1 mL), cooled to 0°C, and methylsulfonyl chloride (22 mg, 0.20 mmol) and pyridine (20 mg, 0.26 mmol) were added. After the addition was completed, the temperature was raised to room temperature for reaction, and the reaction solution was detected by TLC. The reaction solution was concentrated and the crude product was purified by prep-TLC to obtain the title compound 44 (23 mg, yield 46%) as an off-white solid.
LC-MS:m/z＝385.1[M+H]+(93.56％purity,220nm)LC-MS: m/z = 385.1 [M+H] + (93.56% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),9.19(s,1H),8.23-8.13(m,2H),7.51-7.38(m,5H),7.31(d,J＝6.4Hz,1H),3.39(s,4H),2.95(s,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.01 (s, 1H), 9.19 (s, 1H), 8.23-8.13 (m, 2H), 7.51-7.38 (m, 5H), 7.31 (d, J=6.4 Hz, 1H), 3.39 (s, 4H), 2.95 (s, 3H).
实施例45Embodiment 45
4-氟-N-(4-(3-甲基脲基)-1,2-二氢苊烯-5-基)苯甲酰胺45
4-Fluoro-N-(4-(3-methylureido)-1,2-dihydroacenaphthylene-5-yl)benzamide 45
第一步N-甲基-1H-咪唑-1-甲酰胺45bFirst step N-methyl-1H-imidazole-1-carboxamide 45b
将甲胺盐酸盐(500mg,7.40mmol)溶解于N,N-二甲基甲酰胺(1.5mL)和乙腈(4.0mL)混合溶液中，加入羰基二咪唑45a(1.32g,8.14mmol)，加毕，室温搅拌3小时，TLC(DCM:MeOH＝10:1,Rf＝0.2)检测，反应液过滤，收集滤饼，干燥得到白色固体状标题化合物45b(313mg,收率34％)。Methylamine hydrochloride (500 mg, 7.40 mmol) was dissolved in a mixed solution of N,N-dimethylformamide (1.5 mL) and acetonitrile (4.0 mL), and carbonyldiimidazole 45a (1.32 g, 8.14 mmol) was added. After the addition, the mixture was stirred at room temperature for 3 hours and detected by TLC (DCM:MeOH=10:1, R f =0.2). The reaction solution was filtered, and the filter cake was collected and dried to obtain the title compound 45b (313 mg, yield 34%) as a white solid.
第二步4-氟-N-(4-(3-甲基脲基)-1,2-二氢苊烯-5-基)苯甲酰胺45Step 2 4-Fluoro-N-(4-(3-methylureido)-1,2-dihydroacenaphthylene-5-yl)benzamide 45
将化合物1(50mg,0.16mmol)溶解于四氢呋喃(4mL)中，加入三乙胺(33mg,0.33mmol)和化合物45b(23mg,0.18mmol)，加毕，氮气保护下加热回流6小时，TLC检测。冷却，浓缩，粗品经Prep-TLC(DCM:MeOH＝5:1)纯化得到白色固体状标题化合物45(13mg,收率22％)。Compound 1 (50 mg, 0.16 mmol) was dissolved in tetrahydrofuran (4 mL), triethylamine (33 mg, 0.33 mmol) and compound 45b (23 mg, 0.18 mmol) were added, and the mixture was heated under reflux for 6 hours under nitrogen protection and detected by TLC. The mixture was cooled and concentrated, and the crude product was purified by Prep-TLC (DCM: MeOH = 5: 1) to obtain the title compound 45 (13 mg, yield 22%) as a white solid.
LC-MS:m/z＝364.2[M+H]+(98.52％purity,254nm)LC-MS: m/z = 364.2 [M + H] + (98.52% purity, 254 nm)
1H NMR(400MHz,DMSO-d6)δ10.05(s,1H),8.21(dd,J＝8.8,5.6Hz,2H),8.06(d,J＝18.8Hz, 2H),7.44-7.35(m,3H),7.25(d,J＝8.4Hz,1H),7.17(d,J＝6.8Hz,1H),6.90-6.83(m,1H),3.35(s,4H),2.64(d,J＝4.8Hz,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.05 (s, 1H), 8.21 (dd, J＝8.8, 5.6 Hz, 2H), 8.06 (d, J＝18.8 Hz, 2H), 7.44-7.35 (m, 3H), 7.25 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 6.8 Hz, 1H), 6.90-6.83 (m, 1H), 3.35 (s, 4H), 2.64 (d, J = 4.8 Hz, 3H).
实施例46Embodiment 46
(5-(4-氟苯甲酰氨基)-1,2-二氢苊-4-基)氨基甲酸甲酯46
Methyl (5-(4-fluorobenzamido)-1,2-dihydroacenaphthene-4-yl)carbamate 46
第一步(5-(4-氟苯甲酰氨基)-1,2-二氢苊-4-基)氨基甲酸甲酯46The first step is methyl (5-(4-fluorobenzamido)-1,2-dihydroacenaphthene-4-yl)carbamate 46
将化合物1(54mg,0.18mmol)和N,N-二异丙基乙胺(34mg,0.26mmol)溶于二氯甲烷(3mL)中，滴加氯甲酸甲酯(20mg,0.21mmol)加毕，室温反应，TLC检测，加水淬灭，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品Prep-TLC纯化得白色固体粉末46(11.58mg,收率18％)。Compound 1 (54 mg, 0.18 mmol) and N,N-diisopropylethylamine (34 mg, 0.26 mmol) were dissolved in dichloromethane (3 mL), and methyl chloroformate (20 mg, 0.21 mmol) was added dropwise. The reaction was carried out at room temperature, and the mixture was detected by TLC. 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 white solid powder 46 (11.58 mg, yield 18%).
LC-MS:m/z＝365.2[M+H]+(95.25％purity,220nm)LC-MS: m/z = 365.2 [M + H] + (95.25% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),8.96(s,1H),8.21-8.11(m,2H),7.69(s,1H),7.47-7.35(m,4H),7.27(d,J＝6.4Hz,1H),3.66(s,3H),3.38(s,4H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.00 (s, 1H), 8.96 (s, 1H), 8.21-8.11 (m, 2H), 7.69 (s, 1H), 7.47-7.35 (m, 4H), 7.27 (d, J=6.4 Hz, 1H), 3.66 (s, 3H), 3.38 (s, 4H).
实施例47Embodiment 47
N-(7-环丙基-1-甲基-1H-吲哚-3-基)-4-氟苯甲酰胺47
N-(7-cyclopropyl-1-methyl-1H-indol-3-yl)-4-fluorobenzamide 47
第一步7-溴-1-甲基吲哚47bStep 1 7-Bromo-1-methylindole 47b
7-溴吲哚47a(300mg,1.53mmol)溶于无水四氢呋喃(6mL)，降温至0℃，分批加入钠氢(92mg,2.29mmol,60％)，加毕，继续搅拌20分钟，滴加碘甲烷(435mg,3.06mmol)。加毕，升至室温反应16小时。TLC监控。滴加饱和氯化铵溶液淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(PE)得到桔色固体标题化合物47b(298mg,收率93％)。7-Bromoindole 47a (300 mg, 1.53 mmol) was dissolved in anhydrous tetrahydrofuran (6 mL), cooled to 0°C, and sodium hydrogen sulfide (92 mg, 2.29 mmol, 60%) was added in batches. After the addition was completed, stirring was continued for 20 minutes, and iodomethane (435 mg, 3.06 mmol) was added dropwise. After the addition was completed, the temperature was raised to room temperature and reacted for 16 hours. TLC monitoring was performed. Saturated ammonium chloride solution was added dropwise to quench the reaction, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography (PE) to obtain the title compound 47b (298 mg, yield 93%) as an orange solid.
第二步1-(7-溴-1-甲基-1H-吲哚-3-基)-2，2，2-三氟乙烷-1-酮47cStep 2 1-(7-Bromo-1-methyl-1H-indol-3-yl)-2,2,2-trifluoroethane-1-one 47c
化合物47b(198mg,0.94mmol)溶于二氯甲烷(5mL)，滴加三氟乙酸酐(800mg,3.81mmol)。滴毕，室温反应40分钟，TLC监控。滴加饱和碳酸氢钠溶液淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，浓缩得到浅褐色固体标题化合物47c(270mg,收率94％)Compound 47b (198 mg, 0.94 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic anhydride (800 mg, 3.81 mmol) was added dropwise. After the addition, the mixture was reacted at room temperature for 40 minutes and monitored by TLC. Saturated sodium bicarbonate solution was added dropwise to quench the reaction, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 47c (270 mg, yield 94%) as a light brown solid.
第三步7-溴-1-甲基吲哚-3-羧酸47dStep 3 7-Bromo-1-methylindole-3-carboxylic acid 47d
化合物47c(270mg,0.88mmol)和氢氧化钠(353mg,8.83mmol)依次加入到乙醇(1mL)和水(6mL)中，加热回流。TLC监控。冷却，浓缩，粗品加水(8mL)稀释，浓盐酸调节pH＝2。将析出的沉淀过滤，水洗，收集滤饼，干燥得到白色固体47d(196mg,收率88％)。Compound 47c (270 mg, 0.88 mmol) and sodium hydroxide (353 mg, 8.83 mmol) were added to ethanol (1 mL) and water (6 mL) in sequence and heated to reflux. TLC was monitored. The mixture was cooled and concentrated, and the crude product was diluted with water (8 mL). The pH was adjusted to 2 with concentrated hydrochloric acid. The precipitate was filtered, washed with water, and the filter cake was collected and dried to obtain a white solid 47d (196 mg, yield 88%).
第四步7-溴-1-甲基-1H-吲哚-3-基氨基甲酸苄酯47eStep 4 Benzyl 7-bromo-1-methyl-1H-indol-3-ylcarbamate 47e
化合物47d(100mg,0.39mmol)，叠氮磷酸二苯酯(152mg,0.55mmol)，三乙胺(120mg,1.19mmol)和苄醇(85mg,0.79mmol)依次加入到无水甲苯(2mL)中，加热回流。TLC监控。冷却，浓缩， 粗品经硅胶柱层析得到白色固体标题化合物47e(142mg,收率101％)Compound 47d (100 mg, 0.39 mmol), diphenylphosphoryl azide (152 mg, 0.55 mmol), triethylamine (120 mg, 1.19 mmol) and benzyl alcohol (85 mg, 0.79 mmol) were added to anhydrous toluene (2 mL) in sequence and heated to reflux. TLC monitoring. Cooling and concentration. The crude product was purified by silica gel column chromatography to obtain the title compound 47e (142 mg, yield 101%) as a white solid.
第五步7-环丙基-1-甲基-1H-吲哚-3-基氨基甲酸苄酯47fStep 5 Benzyl 7-cyclopropyl-1-methyl-1H-indol-3-ylcarbamate 47f
参照实施例12的第四步的方法合成得到黄色油状标题化合物47f(75mg,收率71％)。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.
第六步N-(7-环丙基-1-甲基-1H-吲哚-3-基)-4-氟苯甲酰胺47Step 6 N-(7-cyclopropyl-1-methyl-1H-indol-3-yl)-4-fluorobenzamide 47
参照实施例1的第一步合成方法合成得到白色固体标题化合物47(8mg,收率24％)。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.
LC-MS:m/z＝309.2[M+H]+(99.37％purity,220nm)LC-MS: m/z = 309.2 [M+H] + (99.37% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.11(s,1H),8.12-8.03(m,2H),7.74-7.66(m,2H),7.40-7.31(m,2H),6.94-6.83(m,2H),4.19(s,3H),2.55-2.51(m,1H),1.02-0.95(m,2H),0.83-0.76(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.11 (s, 1H), 8.12-8.03 (m, 2H), 7.74-7.66 (m, 2H), 7.40-7.31 (m, 2H), 6.94-6.83 (m, 2H), 4.19 (s, 3H), 2.55-2.51 (m, 1H), 1.02-0.95 (m, 2H), 0.83-0.76 (m, 2H).
实施例48Embodiment 48
4-氟-N-(5-甲氧基萘-1-基)苯甲酰胺48
4-Fluoro-N-(5-methoxynaphthalen-1-yl)benzamide 48
第一步5-甲氧基萘-1-胺48bFirst step 5-methoxynaphthalen-1-amine 48b
将5-氨基-1-萘酚48a(100mg,0.63mmol)溶于N,N-二甲基甲酰胺中，降温至0℃，分批加入钠氢(60％,30mg,0.75mmol)，滴加用N,N-二甲基甲酰胺稀释的碘甲烷(134mg,0.94mmol)，加毕，TLC检测(PE/EA＝5:1,Rf＝0.3)反应完全，加水(15mL)淬灭，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品Prep-TLC纯化得到淡棕色粉末标题化合物48b(62mg,收率57％)。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. After the addition was completed, TLC detection (PE/EA=5:1, Rf=0.3) showed that the reaction was complete, and water (15 mL) was added to quench, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC to give the title compound 48b (62 mg, yield 57%) as a light brown powder.
LC-MS:m/z＝174.2[M+H]+ LC-MS: m/z = 174.2 [M + H] +
第二步4-氟-N-(5-甲氧基萘-1-基)苯甲酰胺48Step 2 4-Fluoro-N-(5-methoxynaphthalen-1-yl)benzamide 48
参照实施例40的第二步合成方法合成得到化合物48。白色粉末状固体(75mg,收率71％)。Compound 48 was synthesized by referring to the second step synthesis method of Example 40. White powdery solid (75 mg, yield 71%).
LC-MS:m/z＝296.2[M+H]+(99.04％purity,220nm)LC-MS: m/z = 296.2 [M+H] + (99.04% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.23-8.04(m,3H),7.63-7.58(m,1H),7.57-7.36(m,5H),7.02(d,J＝7.6Hz,1H),3.99(s,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.43 (s, 1H), 8.23-8.04 (m, 3H), 7.63-7.58 (m, 1H), 7.57-7.36 (m, 5H), 7.02 (d, J=7.6 Hz, 1H), 3.99 (s, 3H).
实施例49Embodiment 49
N-(5-氰基萘-1-基)-4-氟苯甲酰胺49
N-(5-cyanonaphthalen-1-yl)-4-fluorobenzamide 49
第一步5-氨基-1-萘腈49aStep 1 5-Amino-1-naphthocarbonitrile 49a
将1-氨基-5-溴萘21a(100mg,0.45mmol)溶于DMF(2mL)中，氮气换气，加入锌粉(95mg,0.81mmol)和四(三苯基膦)钯(104mg,0.090mmol)，加毕，氮气换气，升温至90℃，TLC(PE:EA＝5:1,Rf＝0.2)检测原料反应完，加水淬灭，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经Prep-TLC纯化得黄色固体标题化合物49a(20mg,收率26％)。1-Amino-5-bromonaphthalene 21a (100 mg, 0.45 mmol) was dissolved in DMF (2 mL), and the mixture was ventilated with nitrogen. Zinc powder (95 mg, 0.81 mmol) and tetrakis(triphenylphosphine)palladium (104 mg, 0.090 mmol) were added. After the addition was completed, the mixture was ventilated with nitrogen and the temperature was raised to 90°C. TLC (PE:EA＝5:1, R f ＝0.2) detected that the reaction of the raw material was complete. 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 49a (20 mg, yield 26%) as a yellow solid.
第二步N-(5-氰基萘-1-基)-4-氟苯甲酰胺49Step 2 N-(5-cyanonaphthalen-1-yl)-4-fluorobenzamide 49
参照实施例40的第二步合成方法合成得到白色固体标题化合物49(20mg,收率57％)。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.
LC-MS:m/z＝291.1[M+H]+(99.76％purity,220nm)LC-MS: m/z = 291.1 [M+H] + (99.76% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),8.37(d,J＝8.4Hz,1H),8.26-8.14(m,3H),8.08 (d,J＝8.0Hz,1H),7.89-7.77(m,2H),7.71(t,J＝8.0Hz,1H),7.42(t,J＝8.8Hz,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.70 (s, 1H), 8.37 (d, J＝8.4 Hz, 1H), 8.26-8.14 (m, 3H), 8.08 (d, J = 8.0 Hz, 1H), 7.89-7.77 (m, 2H), 7.71 (t, J = 8.0 Hz, 1H), 7.42 (t, J = 8.8 Hz, 2H).
实施例50Embodiment 50
5-(4-氟苯甲酰胺基)-1-萘甲酸甲酯50
5-(4-Fluorobenzamido)-1-naphthoic acid methyl ester 50
第一步N-(5-溴萘-1-基)-4-氟苯甲酰胺50aThe first step: N-(5-bromonaphthalen-1-yl)-4-fluorobenzamide 50a
参照实施例40的第二步合成方法合成得到化合物50a(262mg,收率84％)。Compound 50a (262 mg, yield 84%) was synthesized by referring to the second step synthesis method of Example 40.
第二步5-(4-氟苯甲酰胺基)-1-萘甲酸甲酯50Step 2 5-(4-fluorobenzamido)-1-naphthoic acid methyl ester 50
将化合物50a(100mg,0.29mmol)溶解于甲醇(3mL)中，加入三乙胺(60mg,0.58mmol)与Pd(dppf)Cl2二氯甲烷络合物(25mg,0.03mmol)，加毕，一氧化碳置换3次，加热至60℃反应18小时，TLC检测原料。冷却，浓缩，粗品经Prep-TLC纯化得到白色固体状50(36mg,收率38％)。Compound 50a (100 mg, 0.29 mmol) was dissolved in methanol (3 mL), and triethylamine (60 mg, 0.58 mmol) and Pd(dppf)Cl 2 dichloromethane complex (25 mg, 0.03 mmol) were added. After addition, carbon monoxide was replaced three times, and the mixture was heated to 60°C for 18 hours. The raw material was detected by TLC. The mixture was cooled and concentrated, and the crude product was purified by Prep-TLC to obtain 50 as a white solid (36 mg, yield 38%).
LC-MS:m/z＝324.2[M+H]+(99.08％purity,220nm)LC-MS: m/z = 324.2 [M + H] + (99.08% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.57(s,1H),8.66(d,J＝8.4Hz,1H),8.26(d,J＝8.8Hz,1H),8.21-8.11(m,3H),7.74-7.60(m,3H),7.42(t,J＝8.8Hz,2H),3.97(s,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.57 (s, 1H), 8.66 (d, J=8.4 Hz, 1H), 8.26 (d, J=8.8 Hz, 1H), 8.21-8.11 (m, 3H), 7.74-7.60 (m, 3H), 7.42 (t, J=8.8 Hz, 2H), 3.97 (s, 3H).
实施例51Embodiment 51
4-氟-N-(6-甲氧基萘-1-基)苯甲酰胺
4-Fluoro-N-(6-methoxynaphthalen-1-yl)benzamide
第一步6-甲氧基萘-1-胺51bStep 1 6-methoxynaphthalen-1-amine 51b
氮气保护下，将5-氨基-2-萘酚51a(100mg,0.63mmol)溶于DMF(3mL)中，降温至0℃，分批加入钠氢(60％,30mg,0.75mmol)，加毕，继续反应1小时，滴加用DMF(0.5mL)稀释的碘甲烷(134mg,0.94mmol)，加毕，升至室温反应5小时，TLC检测，加水淬灭，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品Prep-TLC纯化得淡棕色粉末标题化合物51b(81mg,收率74％)。Under nitrogen protection, 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.
LC-MS:m/z＝174.2[M+H]+ LC-MS: m/z = 174.2 [M + H] +
第二步4-氟-N-(6-甲氧基萘-1-基)苯甲酰胺51Step 2 4-Fluoro-N-(6-methoxynaphthalen-1-yl)benzamide 51
参照实施例40的第二步合成方法合成得到白色粉末状固体化合物51(114mg,收率82％)。Referring to the second step synthesis method of Example 40, a white powdery solid compound 51 (114 mg, yield 82%) was obtained.
LC-MS:m/z＝296.2[M+H]+(99.46％purity,220nm)LC-MS: m/z = 296.2 [M+H] + (99.46% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),8.20-8.11(m,2H),7.88(d,J＝9.2Hz,1H),7.76(d,J＝8.4Hz,1H),7.50(t,J＝7.6Hz,1H),7.44-7.35(m,4H),7.19(dd,J＝9.2,2.4Hz,1H),3.89(s,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.41 (s, 1H), 8.20-8.11 (m, 2H), 7.88 (d, J=9.2 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 7.44-7.35 (m, 4H), 7.19 (dd, J=9.2, 2.4 Hz, 1H), 3.89 (s, 3H).
实施例52Embodiment 52
N-(6-环丙基萘-1-基)-4-氟苯甲酰胺52
N-(6-cyclopropylnaphthalen-1-yl)-4-fluorobenzamide 52
第一步6-溴萘-1-胺52bStep 1 6-bromonaphthalene-1-amine 52b
参照实施例18的第四步合成方法合成得到化合物52b(78mg,收率88％)。Compound 52b (78 mg, yield 88%) was synthesized by referring to the fourth step synthesis method of Example 18.
第二步6-环丙基萘-1-胺52cStep 2 6-Cyclopropylnaphthalene-1-amine 52c
参照实施例12的第四步的方法合成得到粉色结晶体标题化合物52c(35mg,收率83％)。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.
第三步N-(6-环丙基萘-1-基)-4-氟苯甲酰胺52Step 3 N-(6-cyclopropylnaphthalen-1-yl)-4-fluorobenzamide 52
参照实施例40的第二步合成方法合成得到白色固体化合物52(40mg,收率69％)。Referring to the second step synthesis method of Example 40, a white solid compound 52 (40 mg, yield 69%) was obtained.
LC-MS:m/z＝306.2[M+H]+(99.01％purity,254nm)LC-MS: m/z = 306.2 [M+H] + (99.01% purity, 254 nm)
1H NMR(400MHz,DMSO-d6)δ10.40(s,1H),8.20-8.11(m,2H),7.85(d,J＝8.8Hz,1H),7.79-7.72(m,1H),7.69-7.64(m,1H),7.53-7.46(m,2H),7.44-7.35(m,2H),7.26(dd,J＝8.8,1.6Hz,1H),2.15-2.05(m,1H),1.07-1.00(m,2H),0.84-0.77(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.40 (s, 1H), 8.20-8.11 (m, 2H), 7.85 (d, J=8.8 Hz, 1H), 7.79-7.72 (m, 1H), 7.69-7.64 (m, 1H), 7.53-7.46 (m, 2H), 7.44-7.35 (m, 2H), 7.26 (dd, J=8.8, 1.6 Hz, 1H), 2.15-2.05 (m, 1H), 1.07-1.00 (m, 2H), 0.84-0.77 (m, 2H).
实施例53Embodiment 53
N-(7-环丙基苯并[d]异恶唑-3-基)-4-氟苯甲酰胺53
N-(7-Cyclopropylbenzo[d]isoxazol-3-yl)-4-fluorobenzamide 53
第一步3-环丙基-2-氟苯腈53bStep 1 3-Cyclopropyl-2-fluorobenzonitrile 53b
参照实施例12的第四步的方法合成得到化合物53b(208mg,收率52％)。Compound 53b (208 mg, yield 52%) was synthesized by referring to the method of step 4 of Example 12.
第二步7-环丙基苯并[d]异恶唑-3-胺53cStep 2 7-Cyclopropylbenzo[d]isoxazol-3-amine 53c
将乙酰氧肟酸(194mg,2.58mmol)溶于DMF(3mL)中，冷却至0℃，加入叔丁醇钾(290mg,2.58mmol)，加毕，升至室温反应1小时。加入化合物53b(208mg,1.29mmol)，加毕，室温反应16小时，TLC检测，加水淬灭，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(PE:EA＝10:1-5:1-3:1)纯化得到黄色固体标题化合物53c(35mg,收率16％)。Acetohydroxamic acid (194 mg, 2.58 mmol) was dissolved in DMF (3 mL), cooled to 0°C, potassium tert-butoxide (290 mg, 2.58 mmol) was added, and the mixture was heated to room temperature for 1 hour. Compound 53b (208 mg, 1.29 mmol) was added, and the mixture was reacted at room temperature for 16 hours. The mixture was tested by TLC, quenched with water, 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 (PE:EA=10:1-5:1-3:1) to obtain the title compound 53c (35 mg, yield 16%) as a yellow solid.
LC-MS:m/z＝175.2[M+H]+ LC-MS: m/z = 175.2 [M + H] +
第三步N-(7-环丙基苯并[d]异恶唑-3-基)-4-氟苯甲酰胺53Step 3 N-(7-cyclopropylbenzo[d]isoxazol-3-yl)-4-fluorobenzamide 53
参照实施例40的第二步合成方法合成得到白色固体化合物53(24mg,收率41％)。Referring to the second step synthesis method of Example 40, a white solid compound 53 (24 mg, yield 41%) was obtained.
LC-MS:m/z＝297.2[M+H]+(94.41％purity,210nm)LC-MS: m/z = 297.2 [M+H] + (94.41% purity, 210 nm)
1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),8.19-8.12(m,2H),7.75-7.68(m,1H),7.47-7.38(m,2H),7.31-7.22(m,2H),2.33-2.25(m,1H),1.13-1.06(m,2H),0.99-0.93(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.49 (s, 1H), 8.19-8.12 (m, 2H), 7.75-7.68 (m, 1H), 7.47-7.38 (m, 2H), 7.31-7.22 (m, 2H), 2.33-2.25 (m, 1H), 1.13-1.06 (m, 2H), 0.99-0.93 (m, 2H).
实施例54Embodiment 54
N-(4-氨基-1,2-二氢苊-5-基)-3,4-二氟苯甲酰胺54
N-(4-amino-1,2-dihydroacenaphthene-5-yl)-3,4-difluorobenzamide 54
第一步N-(1,2-二氢蒽-5-基)-3,4-二氟苯甲酰胺54aStep 1 N-(1,2-dihydroanthracen-5-yl)-3,4-difluorobenzamide 54a
参照实施例35的第三步合成方法合成得到化合物54a(2.28g,收率85％)。Compound 54a (2.28 g, yield 85%) was synthesized by referring to the third step synthesis method of Example 35.
LC-MS:m/z＝310.1[M+H]+ LC-MS: m/z = 310.1 [M + H] +
第二步3,4-二氟-N-(4-硝基-1,2-二氢蒽-5-基)苯甲酰胺54bStep 2 3,4-Difluoro-N-(4-nitro-1,2-dihydroanthracen-5-yl)benzamide 54b
将化合物54a(200mg 0.65mmol)溶于乙酸(5.5mL)中，冰水浴冷却至5℃，缓慢加入三水合硝 酸铜(312mg，1.29mmol)，加毕，升至室温反应4小时，TLC(PE/EA＝5:1,Rf＝0.3)检测反应完全，反应液加水(10mL)淬灭，饱和碳酸钠溶液调节pH＝8，乙酸乙酯(10mL x 3)萃取，饱和食盐水(15mL)洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(二氯甲烷)纯化得到黄色固体标题化合物54b(69mg,收率30％)。Compound 54a (200 mg, 0.65 mmol) was dissolved in acetic acid (5.5 mL), cooled to 5°C in an ice-water bath, and nitric acid trihydrate was slowly added. After the addition of copper iodide (312 mg, 1.29 mmol), the temperature was raised to room temperature for 4 hours. The reaction was complete as detected by TLC (PE/EA=5:1, R f =0.3). The reaction solution was quenched with water (10 mL), and the pH was adjusted to 8 with saturated sodium carbonate solution. The product was extracted with ethyl acetate (10 mL x 3), washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane) to give the title compound 54b (69 mg, yield 30%) as a yellow solid.
LC-MS:m/z＝355.1[M+H]+ LC-MS: m/z = 355.1 [M + H] +
第三步N-(4-氨基-1,2-二氢苊-5-基)-3,4-二氟苯甲酰胺54Step 3 N-(4-amino-1,2-dihydroacenaphthene-5-yl)-3,4-difluorobenzamide 54
参照实施例1的第一步合成方法合成得到白色固体粉末标题化合物54(4.31mg,收率7.4％)。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.
LC-MS:m/z＝325.1[M+H]+(97.25％purity,214nm)LC-MS: m/z = 325.1 [M+H] + (97.25% purity, 214 nm)
1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),8.19-8.11(m,1H),8.01-7.93(m,1H),7.67-7.57(m,1H),7.28-7.22(m,1H),7.08(d,J＝8.4Hz,1H),6.95(d,J＝6.4Hz,1H),6.89(s,1H),5.31(s,2H),3.31-3.20(m,4H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.76 (s, 1H), 8.19-8.11 (m, 1H), 8.01-7.93 (m, 1H), 7.67-7.57 (m, 1H), 7.28-7.22 (m, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.95 (d, J=6.4 Hz, 1H), 6.89 (s, 1H), 5.31 (s, 2H), 3.31-3.20 (m, 4H).
实施例55Embodiment 55
N-(7-环丙基-2-甲基-2H-吲唑-3-基)-4-氟苯甲酰胺55
N-(7-cyclopropyl-2-methyl-2H-indazol-3-yl)-4-fluorobenzamide 55
第一步7-溴-2-甲基-2H-吲唑55bStep 1 7-Bromo-2-methyl-2H-indazole 55b
将7-溴-1H-吲唑55a(3.50g,17.58mmol)溶于甲苯(30mL)中，加入硫酸二甲酯(2.44g,19.34mmol)，加毕，升温至110℃反应4小时，TLC检测。冷却，滴加饱和碳酸氢钠水溶液淬灭，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(PE:EA＝20:1-10:1-3:1)纯化得白色结晶体标题化合物55b(2.85g,收率77％)。7-Bromo-1H-indazole 55a (3.50 g, 17.58 mmol) was dissolved in toluene (30 mL), and dimethyl sulfate (2.44 g, 19.34 mmol) was added. After the addition was completed, the temperature was raised to 110°C for reaction for 4 hours, and TLC was used for detection. The mixture was cooled, quenched by dropwise addition of 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 (PE:EA=20:1-10:1-3:1) to obtain the title compound 55b (2.85 g, yield 77%) as white crystals.
第二步7-溴-2-甲基-2H-吲唑-3-羧酸甲酯55cStep 2 7-Bromo-2-methyl-2H-indazole-3-carboxylic acid methyl ester 55c
将化合物55b(500mg,2.37mmol)溶于无水四氢呋喃(15mL)中，氮气置换，冷却至-60℃，缓慢滴加二异丙基氨基锂(2M,1.4mL,2.80mmol)，滴毕，升温至0℃搅拌15分钟，再冷却至-60℃，一次性加入氯甲酸甲酯(269mg,2.84mmol)，加毕，升至室温反应16小时，TLC(PE:EA＝5:1,Rf＝0.4)检测反应已完成，加水淬灭，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(PE:EA＝10:1-8:1)纯化得类白色固体标题化合物55c(334mg,收率52％)。Compound 55b (500 mg, 2.37 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), replaced with nitrogen, cooled to -60°C, and lithium diisopropylamide (2 M, 1.4 mL, 2.80 mmol) was slowly added dropwise. After the addition was completed, the temperature was raised to 0°C and stirred for 15 minutes. The mixture was then cooled to -60°C and methyl chloroformate (269 mg, 2.84 mmol) was added all at once. After the addition was completed, the temperature was raised to room temperature and reacted for 16 hours. The reaction was completed as detected by TLC (PE:EA=5:1, R f =0.4). 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 silica gel column chromatography (PE:EA=10:1-8:1) to obtain the title compound 55c (334 mg, yield 52%) as an off-white solid.
第三步7-溴-2-甲基-2H-吲唑-3-羧酸55dStep 3 7-Bromo-2-methyl-2H-indazole-3-carboxylic acid 55d
将化合物55c(334mg,1.24mmol)溶于甲醇(5mL)和四氢呋喃(3mL)中，加入氢氧化钠水溶液(2.5mL,5.0mmol,2N)，室温反应2小时，TLC监控。反应液加水稀释，用稀盐酸调节pH＝4，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩得到淡黄色固标题化合物55d(310mg,收率98％)。Compound 55c (334 mg, 1.24 mmol) was dissolved in methanol (5 mL) and tetrahydrofuran (3 mL), and sodium hydroxide aqueous solution (2.5 mL, 5.0 mmol, 2 N) was added, and the mixture was reacted at room temperature for 2 hours and monitored by TLC. The reaction solution was diluted with water, and the pH was adjusted to 4 with dilute hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 55d (310 mg, yield 98%) as a light yellow solid.
第四步(7-溴-2-甲基-2H-吲唑-3-基)氨基甲酸苄酯55eStep 4: Benzyl (7-bromo-2-methyl-2H-indazol-3-yl)carbamate 55e
将化合物55d(240mg,0.94mmol)溶于甲苯(3mL)中，加入三乙胺(190mg,1.88mmol)、苯甲醇(132mg,1.22mmol)和DPPA(517mg,1.88mmol)，加毕，升温至90℃反应16小时，TLC检测，冷却，倒入水，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化 得到类白色固体标题化合物55e(240mg,收率71％)。Compound 55d (240 mg, 0.94 mmol) was dissolved in toluene (3 mL), and triethylamine (190 mg, 1.88 mmol), benzyl alcohol (132 mg, 1.22 mmol) and DPPA (517 mg, 1.88 mmol) were added. After the addition was completed, the temperature was raised to 90°C for reaction for 16 hours, and the mixture was tested by TLC. The mixture was cooled, poured into water, 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. The title compound 55e was obtained as an off-white solid (240 mg, yield 71%).
第五步(7-环丙基-2-甲基-2H-吲唑-3-基)氨基甲酸苄酯55fStep 5: Benzyl (7-cyclopropyl-2-methyl-2H-indazol-3-yl)carbamate 55f
参照实施例12的第四步的方法合成得到黄色固体标题化合物55f(137mg,收率64％)。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.
LC-MS:m/z＝322.2[M+H]+ LC-MS: m/z = 322.2 [M + H] +
第六步7-环丙基-2-甲基2H-吲唑-3-胺55gStep 6 7-cyclopropyl-2-methyl 2H-indazole-3-amine 55g
将33％氢溴酸醋酸溶液(2mL)冷却至0℃，缓慢加入化合物55f(130mg,0.40mmol)中，加毕，升至室温反应1小时，TLC检测，滴加饱和碳酸钠水溶液调节pH＝8，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得到类白色固体55g(34mg,收率45％)。A 33% hydrobromic acid acetic acid solution (2 mL) was cooled to 0°C and slowly added to compound 55f (130 mg, 0.40 mmol). After the addition was completed, the temperature was raised to room temperature and reacted for 1 hour. After TLC detection, a saturated aqueous sodium carbonate solution was added dropwise to adjust the pH to 8. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography to obtain 55 g (34 mg, yield 45%) of an off-white solid.
LC-MS:m/z＝188.2[M+H]+ LC-MS: m/z = 188.2 [M + H] +
第七步N-(7-环丙基-2-甲基-2H-吲唑-3-基)-4-氟苯甲酰胺55Step 7 N-(7-cyclopropyl-2-methyl-2H-indazol-3-yl)-4-fluorobenzamide 55
将化合物55g(34mg,0.18mmol)溶于二氯甲烷(2mL)中，加入DIPEA(23mg,0.18mmol)，冷却至0℃，加入对氟苯甲酰氯(29mg,0.18mmol)，加毕，升温至室温反应16小时，TLC检测，加水淬灭，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经Prep-TLC(PE:EA＝1:1)纯化得到类白色固体标题化合物55(30mg,收率54％)。Compound 55g (34 mg, 0.18 mmol) was dissolved in dichloromethane (2 mL), DIPEA (23 mg, 0.18 mmol) was added, and the mixture was cooled to 0°C. p-Fluorobenzoyl chloride (29 mg, 0.18 mmol) was added. After the addition was complete, the mixture was warmed to room temperature and reacted for 16 hours. The mixture was tested by TLC, 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 (PE:EA=1:1) to give the title compound 55 (30 mg, yield 54%) as an off-white solid.
LC-MS:m/z＝310.2[M+H]+(98.10％purity,220nm)LC-MS: m/z = 310.2 [M+H] + (98.10% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),8.22-8.12(m,2H),7.50-7.40(m,2H),7.30(d,J＝8.4Hz,1H),6.96-6.87(m,1H),6.80(d,J＝6.8Hz,1H),4.00(s,3H),2.44-2.34(m,1H),1.04-0.95(m,4H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.74 (s, 1H), 8.22-8.12 (m, 2H), 7.50-7.40 (m, 2H), 7.30 (d, J=8.4 Hz, 1H), 6.96-6.87 (m, 1H), 6.80 (d, J=6.8 Hz, 1H), 4.00 (s, 3H), 2.44-2.34 (m, 1H), 1.04-0.95 (m, 4H).
实施例56Embodiment 56
N-(5-环丙基-2-甲基萘-1-基)-4-氟苯甲酰胺56
N-(5-cyclopropyl-2-methylnaphthalen-1-yl)-4-fluorobenzamide 56
第一步5-环丙基-2-甲基萘-1-胺56aStep 1 5-Cyclopropyl-2-methylnaphthalen-1-amine 56a
将2-溴-5-环丙基萘-1-胺40a(100mg,0.38mmol)，三甲基环三硼氧烷(96mg,0.76mmol)，碳酸钾(105mg,0.763mmol)依次加入到二氧六环(3mL)中，加入Pd(dppf)Cl2二氯甲烷络合物(31mg,0.038mmol)，氮气保护下微波加热反应，TLC监控。冷却，倒入水中，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩。粗品经Prep-TLC纯化得到白色固体粉末56a(45mg,收率60％)。2-Bromo-5-cyclopropylnaphthalene-1-amine 40a (100 mg, 0.38 mmol), trimethylcyclotriboroxane (96 mg, 0.76 mmol), potassium carbonate (105 mg, 0.763 mmol) were added to dioxane (3 mL) in sequence, and Pd(dppf)Cl 2 dichloromethane complex (31 mg, 0.038 mmol) was added. The reaction was heated in a microwave under nitrogen protection and monitored by TLC. The mixture was cooled, poured into 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 a white solid powder 56a (45 mg, yield 60%).
LC-MS:m/z＝198.2[M+H]+ LC-MS: m/z = 198.2 [M + H] +
第二步N-(5-环丙基-2-甲基萘-1-基)-4-氟苯甲酰胺56Step 2 N-(5-cyclopropyl-2-methylnaphthalen-1-yl)-4-fluorobenzamide 56
参照实施例40的第二步合成方法合成得到化合物56(32mg,收率47％)。Compound 56 (32 mg, yield 47%) was synthesized by referring to the second step synthesis method of Example 40.
LC-MS:m/z＝320.2[M+H]+(96.85％purity,220nm)LC-MS: m/z = 320.2 [M+H] + (96.85% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),8.32(d,J＝8.8Hz,1H),8.18(dd,J＝8.8,5.6Hz,2H),7.73(d,J＝8.4Hz,1H),7.55(d,J＝8.8Hz,1H),7.44-7.35(m,3H),7.22(d,J＝7.2Hz,1H),2.47-2.39(m,1H),2.36(s,3H),1.07(d,J＝8.4Hz,2H),0.73(d,J＝4.4Hz,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.26 (s, 1H), 8.32 (d, J=8.8 Hz, 1H), 8.18 (dd, J=8.8, 5.6 Hz, 2H), 7.73 (d, J=8.4 Hz, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.44-7.35 (m, 3H), 7.22 (d, J=7.2 Hz, 1H), 2.47-2.39 (m, 1H), 2.36 (s, 3H), 1.07 (d, J=8.4 Hz, 2H), 0.73 (d, J=4.4 Hz, 2H).
实施例57Embodiment 57
N-(7-环丙基-1-甲基-1H-吲唑-3-基)-3,4-二氟苯甲酰胺57
N-(7-cyclopropyl-1-methyl-1H-indazol-3-yl)-3,4-difluorobenzamide 57
第一步N-(7-环丙基-1-甲基-1H-吲唑-3-基)-3，4-二氟苯甲酰胺57First step N-(7-cyclopropyl-1-methyl-1H-indazol-3-yl)-3,4-difluorobenzamide 57
化合物12f(50mg,0.27mmol)溶解于乙酸乙酯中，室温下加入119a(85mg,0.53mmol)、吡啶(127mg,1.60mmol)和1-丙基磷酸酐(50％,509mg,0.80mmol)，升温至70℃，TLC检测，冷却，加水，乙酸乙酯萃取，饱和食盐水洗，粗品经Prep-TLC纯化得到白色固体状57(32mg,收率36％)。Compound 12f (50 mg, 0.27 mmol) was dissolved in ethyl acetate, and 119a (85 mg, 0.53 mmol), pyridine (127 mg, 1.60 mmol) and 1-propylphosphoric anhydride (50%, 509 mg, 0.80 mmol) were added at room temperature. The temperature was raised to 70 ° C, and TLC was detected. After cooling, water was added, and the mixture was extracted with ethyl acetate and washed with saturated brine. The crude product was purified by Prep-TLC to obtain 57 (32 mg, yield 36%) as a white solid.
LC-MS:m/z＝328.2[M+H]+(96.60％purity,220nm)LC-MS: m/z = 328.2 [M+H] + (96.60% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),8.18-8.06(m,1H),8.00-7.91(m,1H),7.69-7.58(m,1H),7.48(d,J＝8.0Hz,1H),7.09(d,J＝7.2Hz,1H),7.01-6.93(m,1H),4.37(s,3H),2.55-2.51(m,1H),1.09-0.98(m,2H),0.88-0.80(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.84 (s, 1H), 8.18-8.06 (m, 1H), 8.00-7.91 (m, 1H), 7.69-7.58 (m, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.09 (d, J=7.2 Hz, 1H), 7.01-6.93 (m, 1H), 4.37 (s, 3H), 2.55-2.51 (m, 1H), 1.09-0.98 (m, 2H), 0.88-0.80 (m, 2H).
实施例58Embodiment 58
N-(7-环丙基-1-甲基-1H-吲唑-3-基)-3-氟苯甲酰胺58
N-(7-cyclopropyl-1-methyl-1H-indazol-3-yl)-3-fluorobenzamide 58
参考实施例57的合成方法，以化合物12f和3-氟苯甲酸为原料，合成得到白色固体标题化合物58(36mg,收率43％)。Referring to the synthesis method of Example 57, compound 12f and 3-fluorobenzoic acid were used as raw materials to synthesize the title compound 58 (36 mg, yield 43%) as a white solid.
LC-MS:m/z＝310.2[M+H]+(94.53％purity,220nm)LC-MS: m/z = 310.2 [M+H] + (94.53% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),7.98-7.74(m,2H),7.66-7.54(m,1H),7.53-7.38(m,2H),7.15-7.05(m,1H),7.01-6.90(m,1H),4.37(s,3H),2.44-2.26(m,1H),1.10-0.96(m,2H),0.90-0.73(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.81 (s, 1H), 7.98-7.74 (m, 2H), 7.66-7.54 (m, 1H), 7.53-7.38 (m, 2H), 7.15-7.05 (m, 1H), 7.01-6.90 (m, 1H), 4.37 (s, 3H), 2.44-2.26 (m, 1H), 1.10-0.96 (m, 2H), 0.90-0.73 (m, 2H).
实施例59Embodiment 59
N-(7-环丙基-1-甲基-1H-吲唑-3-基)-2,4-二氟苯甲酰胺59
N-(7-cyclopropyl-1-methyl-1H-indazol-3-yl)-2,4-difluorobenzamide 59
参考实施例57的合成方法，以化合物12f和2,4-二氟苯甲酸99a为原料，合成得到黄色固体标题化合物59(57mg,收率68％)。Referring to the synthesis method of 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.
LC-MS:m/z＝328.1[M+H]+(94.96％purity,254nm)LC-MS: m/z = 328.1 [M+H] + (94.96% purity, 254 nm)
1H NMR(400MHz,DMSO-d6)δ10.69(s,1H),7.89-7.76(m,1H),7.54(d,J＝8.0Hz,1H),7.50-7.39(m,1H),7.29-7.20(m,1H),7.10(d,J＝7.2Hz,1H),7.01(t,J＝8.0Hz,1H),4.36(s,3H),2.49-2.45(m,1H),1.07-1.00(m,2H),0.87-0.79(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.69 (s, 1H), 7.89-7.76 (m, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.50-7.39 (m, 1H), 7.29-7.20 (m, 1H), 7.10 (d, J=7.2 Hz, 1H), 7.01 (t, J=8.0 Hz, 1H), 4.36 (s, 3H), 2.49-2.45 (m, 1H), 1.07-1.00 (m, 2H), 0.87-0.79 (m, 2H).
实施例60Embodiment 60
N-(5-环丙基萘-1-基)-2,4-二氟苯甲酰胺60
N-(5-cyclopropylnaphthalen-1-yl)-2,4-difluorobenzamide 60
参照实施例35的第三步合成方法合成得到化合物60(36mg,收率70％)。Compound 60 (36 mg, yield 70%) was synthesized by referring to the third step synthesis method of Example 35.
LC-MS:m/z＝324.1[M+H]+(98.70％purity,210nm)LC-MS: m/z = 324.1 [M+H] + (98.70% purity, 210 nm)
1H NMR(400MHz,CDCl3)δ8.81(d,J＝15.2Hz,1H),8.40-8.26(m,2H),8.16(d,J＝7.2Hz,1H),7.82(d,J＝8.4Hz,1H),7.61(t,J＝8.0Hz,1H),7.51-7.44(m,1H),7.33(d,J＝6.8Hz,1H),7.13-7.06(m,1H),7.05-6.96(m,1H),2.42-2.31(m,1H),1.13-1.06(m,2H),0.82-0.75(m,2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.81 (d, J = 15.2 Hz, 1H), 8.40-8.26 (m, 2H), 8.16 (d, J = 7.2 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.51-7.44 (m, 1H), 7.33 (d, J = 6.8 Hz, 1H), 7.13-7.06 (m, 1H), 7.05-6.96 (m, 1H), 2.42-2.31 (m, 1H), 1.13-1.06 (m, 2H), 0.82-0.75 (m, 2H).
实施例61Embodiment 61
2-氰基-N-(5-环丙基萘-1-基)-4-氟苯甲酰胺61
2-Cyano-N-(5-cyclopropylnaphthalen-1-yl)-4-fluorobenzamide 61
参考实施例60的合成方法，以化合物21c和2-氰基-4-氟苯甲酸为原料，合成得到类白色固体标题化合物61(49mg,收率55％)。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.
LC-MS:m/z＝331.2[M+H]+(99.25％purity,254nm)LC-MS: m/z = 331.2 [M+H] + (99.25% purity, 254 nm)
1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),8.65-8.52(m,1H),8.20(dd,J＝8.4,2.4Hz,1H),8.06-7.97(m,1H),7.75-7.62(m,2H),7.61-7.57(m,1H),7.49-7.28(m,3H),2.49-2.43(m,1H),1.15-1.07(m,2H),0.81-0.73(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.25 (s, 1H), 8.65-8.52 (m, 1H), 8.20 (dd, J=8.4, 2.4 Hz, 1H), 8.06-7.97 (m, 1H), 7.75-7.62 (m, 2H), 7.61-7.57 (m, 1H), 7.49-7.28 (m, 3H), 2.49-2.43 (m, 1H), 1.15-1.07 (m, 2H), 0.81-0.73 (m, 2H).
实施例62Embodiment 62
N-(8-环丙基异喹啉-4-基)-4-氟苯甲酰胺62
N-(8-Cyclopropylisoquinolin-4-yl)-4-fluorobenzamide 62
第一步8-溴-4-碘异喹啉62bStep 1 8-Bromo-4-iodoisoquinoline 62b
将8-溴异喹啉62a(200mg,0.96mmol)溶于1,2-二氯乙烷中，加入碘(487mg,1.92mmol)和过氧叔丁醇(260mg,2.88mmol)，加毕，升温至85℃反应6小时，TLC检测。冷却，滴加饱和硫代硫酸钠溶液淬灭，乙酸乙酯萃取，浓缩，粗品用乙酸乙酯打浆得黄色固体62b(234mg,收率73％)。8-Bromoisoquinoline 62a (200 mg, 0.96 mmol) was dissolved in 1,2-dichloroethane, and iodine (487 mg, 1.92 mmol) and tert-butyl peroxide (260 mg, 2.88 mmol) were added. After addition, the temperature was raised to 85°C for 6 hours, and TLC was used for detection. The mixture was cooled, quenched by adding saturated sodium thiosulfate solution dropwise, extracted with ethyl acetate, concentrated, and the crude product was slurried with ethyl acetate to obtain a yellow solid 62b (234 mg, yield 73%).
第二步N-(8-溴异喹啉-4-基)-4-氟苯甲酰胺62cStep 2 N-(8-Bromoisoquinolin-4-yl)-4-fluorobenzamide 62c
将化合物62b(50mg,0.15mmol)溶于DMF(2mL)中，加入对氟苯甲酰胺(52mg,0.37mmol)、碳酸铯(98mg,0.30mmol)、(1R,2R)-N,N'-二甲基-1,2-环己烷二胺(17mg,0.12mmol)和碘化亚铜(23mg,0.12mmol)，加毕，氮气保护下升温至90℃反应16小时，TLC检测，冷却，过滤，滤液加水稀释，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经Prep-TLC(DCM:MeOH＝10:1)纯化得到类白色固体标题化合物62c(27mg,收率52％)。Compound 62b (50 mg, 0.15 mmol) was dissolved in DMF (2 mL), and p-fluorobenzamide (52 mg, 0.37 mmol), cesium carbonate (98 mg, 0.30 mmol), (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (17 mg, 0.12 mmol) and cuprous iodide (23 mg, 0.12 mmol) were added. After the addition was completed, the temperature was raised to 90°C under nitrogen protection and reacted for 16 hours. The mixture was tested by TLC, cooled, filtered, and the filtrate was diluted 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 (DCM:MeOH=10:1) to give the title compound 62c (27 mg, yield 52%) as an off-white solid.
第三步N-(8-环丙基异喹啉-4-基)-4-氟苯甲酰胺62Step 3 N-(8-cyclopropylisoquinolin-4-yl)-4-fluorobenzamide 62
参照实施例12的第四步的方法合成得到白色固体标题化合物62(5mg,收率21％)。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.
LC-MS:m/z＝307.1[M+H]+(99.38％purity,220nm)LC-MS: m/z = 307.1 [M+H] + (99.38% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.55(s,1H),9.75(s,1H),8.62(s,1H),8.22-8.13(m,2H),7.84 (d,J＝8.8Hz,1H),7.72-7.66(m,1H),7.47-7.37(m,3H),2.71-2.61(m,1H),1.19-1.10(m,2H),0.89-0.79(m,2H). 1 H NMR (400 MHz, DMSO-d 6 )δ10.55(s,1H),9.75(s,1H),8.62(s,1H),8.22-8.13(m,2H),7.84 (d, J = 8.8 Hz, 1H), 7.72-7.66 (m, 1H), 7.47-7.37 (m, 3H), 2.71-2.61 (m, 1H), 1.19-1.10 (m, 2H), 0.89-0.79 (m, 2H).
实施例63Embodiment 63
N-(5-环丙基异喹啉-1-基)-3,4-二氟苯甲酰胺63
N-(5-cyclopropylisoquinolin-1-yl)-3,4-difluorobenzamide 63
参照实施例35的第三步合成方法合成得到白色固体标题化合物63(42mg,收率81％)。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.
LC-MS:m/z＝325.1[M+H]+(93.24％purity,220nm)LC-MS: m/z = 325.1 [M+H] + (93.24% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ14.86(s,0.5H),11.08(s,0.5H),8.88-8.43(m,1H),8.33-8.09(m,2H),8.04-7.45(m,5H),2.47-2.31(m,1H),1.15-1.03(m,2H),0.83-0.72(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 14.86 (s, 0.5H), 11.08 (s, 0.5H), 8.88-8.43 (m, 1H), 8.33-8.09 (m, 2H), 8.04-7.45 (m, 5H), 2.47-2.31 (m, 1H), 1.15-1.03 (m, 2H), 0.83-0.72 (m, 2H).
实施例64Embodiment 64
N-(5-环丙基异喹啉-1-基)-2,4-二氟苯甲酰胺64
N-(5-cyclopropylisoquinolin-1-yl)-2,4-difluorobenzamide 64
参考实施例63的合成方法，以化合物33c和2,4-二氟苯甲酸99a为原料，合成得到白色固体标题化合物64(25mg,收率48％)。Referring to the synthesis method of Example 63, compound 33c and 2,4-difluorobenzoic acid 99a were used as raw materials to synthesize the title compound 64 (25 mg, yield 48%) as a white solid.
LC-MS:m/z＝325.1[M+H]+(95.88％purity,220nm)LC-MS: m/z = 325.1 [M+H] + (95.88% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),8.44-8.28(m,1H),8.17(d,J＝5.6Hz,1H),7.96(d,J＝8.4Hz,1H),7.89-7.78(m,1H),7.63-7.55(m,1H),7.54-7.47(m,1H),7.47-7.37(m,1H),7.33-7.17(m,1H),2.48-2.40(m,1H),1.15-1.03(m,2H),0.83-0.70(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.00 (s, 1H), 8.44-8.28 (m, 1H), 8.17 (d, J=5.6 Hz, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.89-7.78 (m, 1H), 7.63-7.55 (m, 1H), 7.54-7.47 (m, 1H), 7.47-7.37 (m, 1H), 7.33-7.17 (m, 1H), 2.48-2.40 (m, 1H), 1.15-1.03 (m, 2H), 0.83-0.70 (m, 2H).
实施例65Embodiment 65
N-(5-环丙基异喹啉-1-基)-3-氟苯甲酰胺65
N-(5-cyclopropylisoquinolin-1-yl)-3-fluorobenzamide 65
参考实施例63的合成方法，以化合物33c和3-氟苯甲酸为原料，合成得到白色固体标题化合物65(32mg,收率39％)。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.
LC-MS:m/z＝307.1[M+H]+(97.41％purity,220nm)LC-MS: m/z = 307.1 [M+H] + (97.41% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ11.14(br,1H),8.53-7.75(m,5H),7.65-7.52(m,3H),7.51-7.42(m,1H),2.47-2.35(m,1H),1.14-1.04(m,2H),0.83-0.71(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.14 (br, 1H), 8.53-7.75 (m, 5H), 7.65-7.52 (m, 3H), 7.51-7.42 (m, 1H), 2.47-2.35 (m, 1H), 1.14-1.04 (m, 2H), 0.83-0.71 (m, 2H).
实施例66Embodiment 66
3-氰基-N-(5-环丙基萘-1-基)-4-氟苯甲酰胺66
3-Cyano-N-(5-cyclopropylnaphthalen-1-yl)-4-fluorobenzamide 66
参考实施例60的合成方法，以化合物21c和3-氰基-4-氟苯甲酸为原料，合成得到白色固体标题化合物66(34mg,收率64％)。Referring to the synthesis method of Example 60, compound 21c and 3-cyano-4-fluorobenzoic acid were used as raw materials to synthesize the title compound 66 (34 mg, yield 64%) as a white solid.
LC-MS:m/z＝331.1[M+H]+(98.08％purity,220nm)LC-MS: m/z = 331.1 [M+H] + (98.08% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.62(s,1H),8.65(dd,J＝6.4,2.4Hz,1H),8.47-8.41(m,1H),8.40-8.35(m,1H),7.90(d,J＝8.4Hz,1H),7.77(t,J＝9.2Hz,1H),7.67-7.61(m,2H),7.47-7.42(m,1H), 7.31(d,J＝6.8Hz,1H),2.48-2.40(m,1H),1.12-1.05(m,2H),0.78-0.72(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.62 (s, 1H), 8.65 (dd, J = 6.4, 2.4 Hz, 1H), 8.47-8.41 (m, 1H), 8.40-8.35 (m, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.77 (t, J = 9.2 Hz, 1H), 7.67-7.61 (m, 2H), 7.47-7.42 (m, 1H), 7.31 (d, J = 6.8 Hz, 1H), 2.48-2.40 (m, 1H), 1.12-1.05 (m, 2H), 0.78-0.72 (m, 2H).
实施例67Embodiment 67
N-(5-环丙基萘-1-基)-4-氟-3-(甲基磺酰基)苯甲酰胺67
N-(5-cyclopropylnaphth-1-yl)-4-fluoro-3-(methylsulfonyl)benzamide 67
参考实施例60的合成方法，以化合物21c和3-甲砜基-4-氟苯甲酸为原料，合成得到白色固体标题化合物67(43mg,收率70％)。With reference to the synthesis method of Example 60, compound 21c and 3-methylsulfonyl-4-fluorobenzoic acid were used as raw materials to synthesize the title compound 67 (43 mg, yield 70%) as a white solid.
LC-MS:m/z＝384.1[M+H]+(97.28％purity,220nm)LC-MS: m/z = 384.1 [M+H] + (97.28% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.77(s,1H),8.59-8.54(m,1H),8.53-8.47(m,1H),8.38(d,J＝8.0Hz,1H),7.84(d,J＝8.4Hz,1H),7.77(t,J＝9.2Hz,1H),7.68-7.58(m,2H),7.49-7.40(m,1H),7.31(d,J＝7.2Hz,1H),3.42(s,3H),2.48-2.40(m,1H),1.12-1.05(m,2H),0.77-0.71(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.77 (s, 1H), 8.59-8.54 (m, 1H), 8.53-8.47 (m, 1H), 8.38 (d, J=8.0 Hz, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.77 (t, J=9.2 Hz, 1H), 7.68-7.58 (m, 2H), 7.49-7.40 (m, 1H), 7.31 (d, J=7.2 Hz, 1H), 3.42 (s, 3H), 2.48-2.40 (m, 1H), 1.12-1.05 (m, 2H), 0.77-0.71 (m, 2H).
实施例68Embodiment 68
N-(7-环丙基-1-甲基-1H-吲唑-3-基)-3,5-二氟苯甲酰胺68
N-(7-cyclopropyl-1-methyl-1H-indazol-3-yl)-3,5-difluorobenzamide 68
参考实施例57的合成方法，以化合物12f和3,5-二氟苯甲酸为原料，合成得到白色固体标题化合物68(79mg,收率45％)。With reference to the synthesis method of Example 57, compound 12f and 3,5-difluorobenzoic acid were used as raw materials to synthesize the title compound 68 (79 mg, yield 45%) as a white solid.
LC-MS:m/z＝328.1[M+H]+(97.45％purity,220nm)LC-MS: m/z = 328.1 [M+H] + (97.45% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),7.82-7.74(m,2H),7.61-7.53(m,1H),7.51(d,J＝8.0Hz,1H),7.11(d,J＝7.2Hz,1H),7.02-6.95(m,1H),4.37(s,3H),2.56-2.52(m,1H),1.08-1.00(m,2H),0.88-0.81(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.91 (s, 1H), 7.82-7.74 (m, 2H), 7.61-7.53 (m, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.11 (d, J=7.2 Hz, 1H), 7.02-6.95 (m, 1H), 4.37 (s, 3H), 2.56-2.52 (m, 1H), 1.08-1.00 (m, 2H), 0.88-0.81 (m, 2H).
实施例69Embodiment 69
N-(7-环丙基-1-甲基-1H-吲唑-3-基)-2,3-二氟苯甲酰胺69
N-(7-cyclopropyl-1-methyl-1H-indazol-3-yl)-2,3-difluorobenzamide 69
参考实施例57的合成方法，以化合物12f和2,3-二氟苯甲酸为原料，合成得到白色固体标题化合物69(94mg,收率54％)。With reference to the synthesis method of Example 57, compound 12f and 2,3-difluorobenzoic acid were used as raw materials to synthesize the title compound 69 (94 mg, yield 54%) as a white solid.
LC-MS:m/z＝328.2[M+H]+(97.42％purity,220nm)LC-MS: m/z = 328.2 [M+H] + (97.42% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),7.70-7.59(m,1H),7.55(d,J＝8.0Hz,2H),7.41-7.31(m,1H),7.11(d,J＝6.8Hz,1H),7.02(t,J＝8.0Hz,1H),4.36(s,3H),2.50-2.45(m,1H),1.08-0.97(m,2H),0.88-0.79(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.84 (s, 1H), 7.70-7.59 (m, 1H), 7.55 (d, J=8.0 Hz, 2H), 7.41-7.31 (m, 1H), 7.11 (d, J=6.8 Hz, 1H), 7.02 (t, J=8.0 Hz, 1H), 4.36 (s, 3H), 2.50-2.45 (m, 1H), 1.08-0.97 (m, 2H), 0.88-0.79 (m, 2H).
实施例70Embodiment 70
N-(7-环丙基-1-甲基-1H-吲唑-3-基)-3,4,5-三氟苯甲酰胺70
N-(7-cyclopropyl-1-methyl-1H-indazol-3-yl)-3,4,5-trifluorobenzamide 70
参考实施例57的合成方法，以化合物12f和3,4,5-三氟苯甲酸为原料，合成得到白色固体标题化合物70(110mg,收率60％)。With reference to the synthesis method of Example 57, compound 12f and 3,4,5-trifluorobenzoic acid were used as raw materials to synthesize the title compound 70 (110 mg, yield 60%) as a white solid.
LC-MS:m/z＝346.2[M+H]+(96.42％purity,220nm) LC-MS: m/z = 346.2 [M + H] + (96.42% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.07-7.97(m,2H),7.50(d,J＝8.0Hz,1H),7.11(d,J＝7.2Hz,1H),7.01-6.95(m,1H),4.37(s,3H),2.56-2.52(m,1H),1.07-1.00(m,2H),0.88-0.80(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.93 (s, 1H), 8.07-7.97 (m, 2H), 7.50 (d, J=8.0 Hz, 1H), 7.11 (d, J=7.2 Hz, 1H), 7.01-6.95 (m, 1H), 4.37 (s, 3H), 2.56-2.52 (m, 1H), 1.07-1.00 (m, 2H), 0.88-0.80 (m, 2H).
实施例71Embodiment 71
N-(2-氯-5-环丙基萘-1-基)-4-氟苯甲酰胺71
N-(2-chloro-5-cyclopropylnaphthalen-1-yl)-4-fluorobenzamide 71
第一步2-氯-5-环丙基萘-1-胺71aStep 1: 2-Chloro-5-cyclopropylnaphthalene-1-amine 71a
将化合物21c(100mg,0.55mmol)溶于DMF(1mL)中，冷却至0℃，缓慢加入N-氯代丁二酰亚胺(73.4mg,0.55mmol)，加毕，升温反应3小时，TLC检测，加水淬灭，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层纯化得棕色固体标题化合物71a(35mg,收率29％)。Compound 21c (100 mg, 0.55 mmol) was dissolved in DMF (1 mL), cooled to 0°C, and N-chlorosuccinimide (73.4 mg, 0.55 mmol) was slowly added. After the addition was complete, the temperature was raised to react for 3 hours, and the mixture was detected by TLC. 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 silica gel column chromatography to obtain the title compound 71a (35 mg, yield 29%) as a brown solid.
LC-MS:m/z＝218.1[M+H]+ LC-MS: m/z = 218.1 [M + H] +
第二步N-(2-氯-5-环丙基萘-1-基)-4-氟苯甲酰胺71Step 2 N-(2-chloro-5-cyclopropylnaphthalen-1-yl)-4-fluorobenzamide 71
将化合物71a(28mg,0.13mmol)溶于二氯甲烷(1mL)中，加入三乙胺(26.3mg,0.26mmol)，冷却至0℃，滴加对氟苯甲酰氯(30.9mg,0.20mmol)，加毕，升温至室温，反应3小时，TLC(PE:EA＝10:1,Rf＝0.2)检测反应已完成，加水淬灭，二氯甲烷萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(PE:EA＝50:1-20:1-10:1)纯化得类白色固体标题化合物71(64mg,收率44％)。Compound 71a (28 mg, 0.13 mmol) was dissolved in dichloromethane (1 mL), triethylamine (26.3 mg, 0.26 mmol) was added, and the mixture was cooled to 0°C. p-Fluorobenzoyl chloride (30.9 mg, 0.20 mmol) was added dropwise. After the addition was completed, the mixture was warmed to room temperature and reacted for 3 hours. The reaction was completed as detected by TLC (PE:EA＝10:1, R f ＝0.2). The mixture was quenched with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (PE:EA＝50:1-20:1-10:1) to obtain the title compound 71 (64 mg, yield 44%) as an off-white solid.
LC-MS:m/z＝340.1[M+H]+(95.94％purity,210nm)LC-MS: m/z = 340.1 [M+H] + (95.94% purity, 210 nm)
1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.45(d,J＝9.2Hz,1H),8.22-8.14(m,2H),7.81-7.72(m,2H),7.52(t,J＝7.6Hz,1H),7.46-7.38(m,2H),7.34(d,J＝7.2Hz,1H),2.47-2.40(m,1H),1.13-1.05(m,2H),0.79-0.72(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.49 (s, 1H), 8.45 (d, J = 9.2 Hz, 1H), 8.22-8.14 (m, 2H), 7.81-7.72 (m, 2H), 7.52 (t, J = 7.6 Hz, 1H), 7.46-7.38 (m, 2H), 7.34 (d, J = 7.2 Hz, 1H), 2.47-2.40 (m, 1H), 1.13-1.05 (m, 2H), 0.79-0.72 (m, 2H).
实施例72Embodiment 72
N-(7-环丙基-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺72
N-(7-cyclopropyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 72
第一步N-(7-环丙基-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺72First step N-(7-cyclopropyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 72
将化合物34b(80mg,0.27mmol)溶解于N,N-二甲基甲酰胺(2mL)，室温下加入3-溴丙炔(39mg,0.33mmol)和碳酸钾(75mg,0.54mmol)，室温搅拌，TLC检测，加水淬灭，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，经制备HPLC(三氟乙酸)纯化得白色固体72(18mg,收率20％)。Compound 34b (80 mg, 0.27 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 3-bromopropyne (39 mg, 0.33 mmol) and potassium carbonate (75 mg, 0.54 mmol) were added at room temperature. The mixture was stirred at room temperature and detected by TLC. The mixture was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC (trifluoroacetic acid) to obtain 72 (18 mg, yield 20%) as a white solid.
LC-MS:m/z＝334.2[M+H]+(99.10％purity,220nm)LC-MS: m/z = 334.2 [M+H] + (99.10% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.88(s,1H),8.15(dd,J＝8.4,5.6Hz,2H),7.53(d,J＝8.4Hz,1H),7.39(t,J＝8.8Hz,2H),7.17(d,J＝7.2Hz,1H),7.04(t,J＝8.0Hz,1H),5.56(d,J＝1.6Hz,2H),3.44(s,1H),2.49-2.44(m,1H),1.10-1.05(m,2H),0.89-0.83(m,2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.88 (s, 1H), 8.15 (dd, J = 8.4, 5.6 Hz, 2H), 7.53 (d, J = 8.4 Hz, 1H), 7.39 (t, J = 8.8 Hz, 2H), 7.17 (d, J = 7.2 Hz, 1H), 7.04 (t, J = 8.0 Hz, 1H), 5.56 (d, J = 1.6 Hz, 2H), 3.44 (s, 1H), 2.49-2.44 (m, 1H), 1.10-1.05 (m, 2H), 0.89-0.83 (m, 2H)
实施例73Embodiment 73
N-(7-环丙基-1-((四氢呋喃-2-基)甲基)-1H-吲唑-3-基)-4-氟苯甲酰胺73
N-(7-cyclopropyl-1-((tetrahydrofuran-2-yl)methyl)-1H-indazol-3-yl)-4-fluorobenzamide 73
参考实施例94的合成方法，以34b和2-溴甲基四氢呋喃为原料，合成得到灰色固体物73(21mg,收率55％)。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%).
LC-MS:m/z＝380.2[M+H]+(98.09％purity,254nm)LC-MS: m/z = 380.2 [M+H] + (98.09% purity, 254 nm)
1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),8.15(dd,J＝8.8,5.6Hz,2H),7.48(d,J＝8.0Hz,1H),7.38(t,J＝8.8Hz,2H),7.12(d,J＝6.8Hz,1H),6.98(t,J＝7.6Hz,1H),4.92(dd,J＝14.4,7.2Hz,1H),4.65(dd,J＝14.4,4.4Hz,1H),4.34-4.25(m,1H),3.76-3.69(m,1H),3.63-3.56(m,1H),2.48-2.41(m,1H),2.02-1.94(m,1H),1.86-1.73(m,3H),1.06-1.00(m,2H),0.94-0.88(m,1H),0.80-0.74(m,1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.78 (s, 1H), 8.15 (dd, J＝8.8, 5.6 Hz, 2H), 7.48 (d, J＝8.0 Hz, 1H), 7.38 (t, J＝8.8Hz,2H),7.12(d,J＝6.8Hz,1H),6.98(t,J＝7.6Hz,1H),4.92(dd,J＝14.4,7.2Hz,1H),4.65(dd, J＝14.4, 4.4Hz,1H),4.34-4.25(m,1H),3.76-3.69(m,1H),3.63-3.56(m,1H),2.48-2.41(m,1H),2.02-1.94(m,1H) ,1.86-1.73(m,3H),1.06-1.00(m,2H),0.94-0.88(m,1H),0.80-0.74(m,1H).
实施例74Embodiment 74
N-(7-环丙基-1-异丁基-1H-吲唑-3-基)-4-氟苯甲酰胺74
N-(7-cyclopropyl-1-isobutyl-1H-indazol-3-yl)-4-fluorobenzamide 74
参考实施例94的合成方法，以化合物34b和溴代异丁烷为原料，合成得到类白色固体标题化合物74(19mg,收率54％)。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.
LC-MS:m/z＝352.2[M+H]+(96.57％purity,220nm)LC-MS: m/z = 352.2 [M+H] + (96.57% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.75(s,1H),8.18-8.10(m,2H),7.49(d,J＝8.0Hz,1H),7.38(t,J＝9.2Hz,2H),7.12(d,J＝7.2Hz,1H),7.00(t,J＝7.6Hz,1H),4.55(d,J＝7.6Hz,2H),2.40-2.23(m,2H),1.09-1.02(m,2H),0.92(d,J＝6.7Hz,6H),0.87-0.81(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.75 (s, 1H), 8.18-8.10 (m, 2H), 7.49 (d, J=8.0 Hz, 1H), 7.38 (t, J=9.2 Hz, 2H), 7.12 (d, J=7.2 Hz, 1H), 7.00 (t, J=7.6 Hz, 1H), 4.55 (d, J=7.6 Hz, 2H), 2.40-2.23 (m, 2H), 1.09-1.02 (m, 2H), 0.92 (d, J=6.7 Hz, 6H), 0.87-0.81 (m, 2H).
实施例75Embodiment 75
N-(1-(氰基甲基)-7-环丙基-1H-吲唑-3-基)-4-氟苯甲酰胺75
N-(1-(Cyanomethyl)-7-cyclopropyl-1H-indazol-3-yl)-4-fluorobenzamide 75
参考实施例94的合成方法，以化合物34b和溴乙腈为原料，合成得到白色固体标题化合物75(18mg,收率54％)。Referring to the synthesis method of Example 94, compound 34b and bromoacetonitrile were used as raw materials to synthesize the title compound 75 (18 mg, yield 54%) as a white solid.
LC-MS:m/z＝335.2[M+H]+(91.69％purity,254nm)LC-MS: m/z = 335.2 [M+H] + (91.69% purity, 254 nm)
1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),8.18-8.12(m,2H),7.58(d,J＝8.0Hz,1H),7.42-7.36(m,2H),7.24(d,J＝7.2Hz,1H),7.10(t,J＝8.0Hz,1H),5.97(s,2H),2.47-2.40(m,1H),1.15-1.09(m,2H),0.89-0.84(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.98 (s, 1H), 8.18-8.12 (m, 2H), 7.58 (d, J=8.0 Hz, 1H), 7.42-7.36 (m, 2H), 7.24 (d, J=7.2 Hz, 1H), 7.10 (t, J=8.0 Hz, 1H), 5.97 (s, 2H), 2.47-2.40 (m, 1H), 1.15-1.09 (m, 2H), 0.89-0.84 (m, 2H).
实施例76Embodiment 76
N-(7-环丙基-1-(2-(二甲基氨基)乙基)-1H-吲唑-3-基)-4-氟苯甲酰胺76
N-(7-cyclopropyl-1-(2-(dimethylamino)ethyl)-1H-indazol-3-yl)-4-fluorobenzamide 76
参考实施例94的合成方法，以化合物34b和N,N-二甲胺基溴乙烷氢溴酸盐为原料，合成得 到白色固体标题化合物76(21mg,收率57％)。Referring to the synthesis method of Example 94, compound 34b and N,N-dimethylaminoethyl bromide hydrobromide were used as raw materials to synthesize The title compound 76 (21 mg, yield 57%) was obtained as a white solid.
LC-MS:m/z＝367.2[M+H]+(97.47％purity,220nm)LC-MS: m/z = 367.2 [M+H] + (97.47% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),8.19-8.09(m,2H),7.51(d,J＝8.0Hz,1H),7.45-7.34(m,2H),7.15(d,J＝7.2Hz,1H),7.02(t,J＝7.6Hz,1H),4.88(t,J＝7.2Hz,2H),2.96-2.82(m,2H),2.46-2.39(m,1H),2.33(s,6H),1.10-1.01(m,2H),0.91-0.84(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.80 (s, 1H), 8.19-8.09 (m, 2H), 7.51 (d, J=8.0 Hz, 1H), 7.45-7.34 (m, 2H), 7.15 (d, J=7.2 Hz, 1H), 7.02 (t, J=7.6 Hz, 1H), 4.88 (t, J=7.2 Hz, 2H), 2.96-2.82 (m, 2H), 2.46-2.39 (m, 1H), 2.33 (s, 6H), 1.10-1.01 (m, 2H), 0.91-0.84 (m, 2H).
实施例77Embodiment 77
N-(7-环丙基-1-(3,3,3-三氟丙基)-1H-吲唑-3-基)-4-氟苯甲酰胺77
N-(7-cyclopropyl-1-(3,3,3-trifluoropropyl)-1H-indazol-3-yl)-4-fluorobenzamide 77
第一步N-(7-环丙基-1-(3，3，3-三氟丙基)-1H-吲唑-3-基)-4-氟苯甲酰胺77First step N-(7-cyclopropyl-1-(3,3,3-trifluoropropyl)-1H-indazol-3-yl)-4-fluorobenzamide 77
将化合物34b(121mg,0.41mmol)溶于DMF(1mL)中，加入叔丁醇钾(92mg,0.82mmol)和1-碘-3,3,3-三氟丙烷(1836.5mg,8.20mmol)，加毕，微波升温至130℃反应2小时，TLC检测，加水淬灭，乙酸乙酯萃取，浓缩，粗品经过Prep-TLC纯化得白色固体标题化合物77(78mg,收率49％)。Compound 34b (121 mg, 0.41 mmol) was dissolved in DMF (1 mL), and potassium tert-butoxide (92 mg, 0.82 mmol) and 1-iodo-3,3,3-trifluoropropane (1836.5 mg, 8.20 mmol) were added. After the addition, the temperature was raised to 130°C in a microwave oven for 2 hours. The reaction was detected by TLC, and the mixture was quenched with water. The mixture was extracted with ethyl acetate and concentrated. The crude product was purified by Prep-TLC to obtain the title compound 77 (78 mg, yield 49%) as a white solid.
LC-MS:m/z＝392.2[M+H]+(99.90％purity,220nm)LC-MS: m/z = 392.2 [M+H] + (99.90% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.77(s,1H),8.20-8.11(m,2H),7.47(t,J＝8.8Hz,2H),7.31(d,J＝8.4Hz,1H),6.98-6.90(m,1H),6.82(d,J＝6.8Hz,1H),4.55(t,J＝7.2Hz,2H),3.09-2.94(m,2H),2.46-2.36(m,1H),1.05-0.97(m,4H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.77 (s, 1H), 8.20-8.11 (m, 2H), 7.47 (t, J=8.8 Hz, 2H), 7.31 (d, J=8.4 Hz, 1H), 6.98-6.90 (m, 1H), 6.82 (d, J=6.8 Hz, 1H), 4.55 (t, J=7.2 Hz, 2H), 3.09-2.94 (m, 2H), 2.46-2.36 (m, 1H), 1.05-0.97 (m, 4H).
实施例78Embodiment 78
N-(2-乙酰氨基-5-环丙基萘-1-基)-4-氟苯甲酰胺78
N-(2-Acetylamino-5-cyclopropylnaphthalen-1-yl)-4-fluorobenzamide 78
第一步N-(2-乙酰氨基-5-环丙基萘-1-基)-4-氟苯甲酰胺78The first step is N-(2-acetylamino-5-cyclopropylnaphthalen-1-yl)-4-fluorobenzamide 78
将化合物18(30mg,0.094mmol)溶于四氢呋喃(1mL)中，冷却至0℃，滴加乙酸酐(19.2mg,0.19mmol)，加毕，升至室温反应5小时，反应液有固体析出，TLC(PE:EA＝2:1,Rf＝0.5)检测反应已完成，过滤，收集滤饼得白色固体标题化合物78(14mg,收率41％)。Compound 18 (30 mg, 0.094 mmol) was dissolved in tetrahydrofuran (1 mL), cooled to 0°C, and acetic anhydride (19.2 mg, 0.19 mmol) was added dropwise. After the addition was completed, the temperature was raised to room temperature and reacted for 5 hours. Solid precipitated from the reaction solution. TLC (PE:EA=2:1, R f =0.5) detected that the reaction was complete. The solution was filtered and the filter cake was collected to obtain the title compound 78 (14 mg, yield 41%) as a white solid.
LC-MS:m/z＝363.1[M+H]+(92.90％purity,254nm)LC-MS: m/z = 363.1 [M+H] + (92.90% purity, 254 nm)
1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),9.66(s,1H),8.37(d,J＝9.2Hz,1H),8.20-8.12(m,2H),7.96(d,J＝9.2Hz,1H),7.64(d,J＝8.4Hz,1H),7.45-7.33(m,3H),7.22(d,J＝7.2Hz,1H),2.46-2.39(m,1H),2.09(s,3H),1.11-1.04(m,2H),0.78-0.70(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.01 (s, 1H), 9.66 (s, 1H), 8.37 (d, J = 9.2 Hz, 1H), 8.20-8.12 (m, 2H), 7.96 (d, J = 9.2 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.45-7.33 (m, 3H), 7.22 (d, J = 7.2 Hz, 1H), 2.46-2.39 (m, 1H), 2.09 (s, 3H), 1.11-1.04 (m, 2H), 0.78-0.70 (m, 2H).
实施例79Embodiment 79
N-(8-环丙基-2-甲基喹唑啉-4-基)-4-氟苯甲酰胺79
N-(8-Cyclopropyl-2-methylquinazolin-4-yl)-4-fluorobenzamide 79
第一步2-氨基-3-溴苯甲酰胺79bStep 1: 2-Amino-3-bromobenzamide 79b
2-氨基-3-溴苯甲酸79a(1.0g,4.63mmol)，氯化铵(792mg,14.82mmol)，1-羟基苯并三唑(HOBT)(813mg,6.02mmol)，DIPEA(3.6g,27.88mmol)，EDCI(1.15g,6.02mmol)依次加入到DMF(15mL)中，室温反应16小时。TLC检测。将反应液倒入水中，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得到黄色固体标题化合物79b(716mg,收率72％).2-Amino-3-bromobenzoic acid 79a (1.0 g, 4.63 mmol), ammonium chloride (792 mg, 14.82 mmol), 1-hydroxybenzotriazole (HOBT) (813 mg, 6.02 mmol), DIPEA (3.6 g, 27.88 mmol), EDCI (1.15 g, 6.02 mmol) were added to DMF (15 mL) in sequence and reacted at room temperature for 16 hours. TLC detection. The reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 79b (716 mg, yield 72%) as a yellow solid.
LC-MS:m/z＝215.1/217.1[M+H]+ LC-MS: m/z＝215.1/217.1[M+H] +
第二步8-溴-2-甲基喹唑啉-4(3H)酮79cStep 2 8-Bromo-2-methylquinazolin-4(3H)one 79c
将化合物79b(200mg,0.93mmol)，醋酸(112mg,1.87mmol)和原乙酸三乙酯(453mg,2.79mmol)依次加入到乙醇(5mL)中，加热回流16小时。TLC监控，冷却，浓缩，粗品用甲基叔丁基醚打浆得到白色固体标题化合物79c(125mg,收率56％)。Compound 79b (200 mg, 0.93 mmol), acetic acid (112 mg, 1.87 mmol) and triethyl orthoacetate (453 mg, 2.79 mmol) were added to ethanol (5 mL) in sequence and heated under reflux for 16 hours. TLC monitoring, cooling, concentration, and the crude product was slurried with methyl tert-butyl ether to obtain the title compound 79c (125 mg, yield 56%) as a white solid.
LC-MS:m/z＝239.1/241.1[M+H]+ LC-MS: m/z＝239.1/241.1[M+H] +
第三步8-溴-4-氯-2-甲基喹唑啉79dStep 3 8-Bromo-4-chloro-2-methylquinazoline 79d
将化合物79c(125mg,0.52mmol)和DIPEA(338mg,2.62mmol)加入到无水甲苯(3mL)中，加热至90℃，滴加三氯氧磷(241mg,1.57mmol)。加毕，继续在90℃反应16小时。TLC监控。冷却，浓缩，粗品加饱和碳酸氢钠水溶液(15mL)和乙酸乙酯(10mL)分层，分出有机相，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(PE:EA＝20:1)纯化得到白色固体标题化合物79d(106mg,收率79％)。Compound 79c (125 mg, 0.52 mmol) and DIPEA (338 mg, 2.62 mmol) were added to anhydrous toluene (3 mL), heated to 90°C, and phosphorus oxychloride (241 mg, 1.57 mmol) was added dropwise. After addition, the reaction was continued at 90°C for 16 hours. TLC monitoring was performed. The mixture was cooled and concentrated. The crude product was layered with saturated sodium bicarbonate aqueous solution (15 mL) and ethyl acetate (10 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (PE:EA=20:1) to obtain the title compound 79d (106 mg, yield 79%) as a white solid.
第四步8-溴-2-甲基喹唑啉-4-胺79eStep 4: 8-Bromo-2-methylquinazolin-4-amine 79e
将化合物79d(106mg,0.41mmol)溶于四氢呋喃(1mL)中，降温至0℃，滴加氨水(1mL,25-28％)，加毕，升至室温反应16小时。TLC(PE:EA＝1:1，新点Rf＝0.3)显示原料转化完全。将反应液浓缩，粗品加水(15mL)稀释，将沉淀过滤，水(5mL)洗，收集滤饼，干燥得到白色固体标题化合物79e(107mg,粗品)。Compound 79d (106 mg, 0.41 mmol) was dissolved in tetrahydrofuran (1 mL), cooled to 0°C, and aqueous ammonia (1 mL, 25-28%) was added dropwise. After addition, the mixture was warmed to room temperature and reacted for 16 hours. TLC (PE:EA=1:1, new spot R f =0.3) showed that the raw material was completely converted. The reaction solution was concentrated, and the crude product was diluted with water (15 mL). The precipitate was filtered, washed with water (5 mL), and the filter cake was collected and dried to obtain the title compound 79e (107 mg, crude product) as a white solid.
LC-MS:m/z＝238.0/240.0[M+H]+ LC-MS: m/z＝238.0/240.0[M+H] +
第五步8-环丙基-2-甲基喹唑啉-4-胺79fStep 5 8-Cyclopropyl-2-methylquinazoline-4-amine 79f
将化合物79e(107mg,0.45mmol)，环己基硼酸21b(155mg,1.80mmol)，Pd(dppf)Cl2二氯甲烷络合物(36mg,0.044mmol)，碳酸铯(293mg,0.90mmol)依次加入到二氧六环(2mL)和水(1mL)中，氮气保护下，升温至95℃反应18小时。TLC监控。冷却，倒入水中，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得到黄色固体标题化合物79f(45mg,两步收率55％)Compound 79e (107 mg, 0.45 mmol), cyclohexylboronic acid 21b (155 mg, 1.80 mmol), Pd(dppf)Cl 2 dichloromethane complex (36 mg, 0.044 mmol), cesium carbonate (293 mg, 0.90 mmol) were added to dioxane (2 mL) and water (1 mL) in sequence, and the temperature was raised to 95 °C under nitrogen protection for 18 hours. TLC monitoring. Cool, pour into water, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate, and the crude product was purified by silica gel column chromatography to obtain the title compound 79f (45 mg, two-step yield 55%) as a yellow solid.
LC-MS:m/z＝200.2[M+H]+ LC-MS: m/z = 200.2 [M + H] +
第六步N-(8-环丙基-2-甲基喹唑啉-4-基)-4-氟苯甲酰胺79Step 6 N-(8-cyclopropyl-2-methylquinazolin-4-yl)-4-fluorobenzamide 79
参照实施例35的第三步合成方法合成得到白色固体标题化合物79(55mg,收率74％) Referring to the third step of the synthesis method of Example 35, the title compound 79 (55 mg, yield 74%) was synthesized as a white solid
LC-MS:m/z＝322.1[M+H]+(95.74％purity,220nm)LC-MS: m/z = 322.1 [M+H] + (95.74% purity, 220 nm)
1H NMR(400MHz,CDCl3)δ14.99(s,1H),8.53(d,J＝8.0Hz,1H),8.45(dd,J＝8.4,5.6Hz,2H),7.46(t,J＝7.6Hz,1H),7.28-7.24(m,1H),7.19-7.11(m,2H),3.10-3.00(m,1H),2.68(s,3H),1.20-1.13(m,2H),0.86-0.79(m,2H). 1 H NMR (400 MHz, CDCl 3 ) δ 14.99 (s, 1H), 8.53 (d, J = 8.0 Hz, 1H), 8.45 (dd, J = 8.4, 5.6 Hz, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.28-7.24 (m, 1H), 7.19-7.11 (m, 2H), 3.10-3.00 (m, 1H), 2.68 (s, 3H), 1.20-1.13 (m, 2H), 0.86-0.79 (m, 2H).
实施例80Embodiment 80
4-氟-N-(5-丙酰胺邻苯二甲酸-1-基)苯甲酰胺80
4-Fluoro-N-(5-propionamidophthalic acid-1-yl)benzamide 80
第一步N-(5-氨基萘-1-基)丙酰胺80bStep 1: N-(5-aminonaphthalen-1-yl)propionamide 80b
将丙酸(210mg,2.84mmol)溶解于N,N-二甲基甲酰胺(5mL)中，依次加入EDCI(606mg,3.16mmol)和4-二甲氨基吡啶(39mg,0.31mmol)，室温搅拌30分钟后，加入1,5-萘二胺80a(500mg,3.16mmol)，室温搅拌16小时，TLC监控，加水淬灭，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化，得棕色固体标题化合物80b(270mg,收率40％)。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 mixture was stirred at room temperature for 16 hours, monitored by TLC, quenched with water, 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 80b (270 mg, yield 40%) as a brown solid.
第二步N-(5-氰基萘-1-基)-4-氟苯甲酰胺80Step 2 N-(5-cyanonaphthalen-1-yl)-4-fluorobenzamide 80
参照实施例35的第三步合成方法合成得灰色固体标题化合物80(22mg,收率18％)。Referring to the third step of the synthesis method of Example 35, the title compound 80 (22 mg, yield 18%) was synthesized as a grey solid.
LC-MS:m/z＝337.1[M+H]+(98.09％purity,210nm)LC-MS: m/z = 337.1 [M+H] + (98.09% purity, 210 nm)
1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),9.91(s,1H),8.21-8.12(m,2H),8.01(d,J＝8.4Hz,1H),7.83(d,J＝8.4Hz,1H),7.69(d,J＝7.6Hz,1H),7.63-7.53(m,2H),7.51(t,J＝8.0Hz,1H),7.44-7.37(m,2H),2.55-2.51(m,2H),1.17(t,J＝7.6Hz,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.48 (s, 1H), 9.91 (s, 1H), 8.21-8.12 (m, 2H), 8.01 (d, J=8.4 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.63-7.53 (m, 2H), 7.51 (t, J=8.0 Hz, 1H), 7.44-7.37 (m, 2H), 2.55-2.51 (m, 2H), 1.17 (t, J=7.6 Hz, 3H).
实施例81Embodiment 81
4-氟-N-(5-(3-甲基丁酰胺基)萘-1-基)苯甲酰胺81
4-Fluoro-N-(5-(3-methylbutyramido)naphthalen-1-yl)benzamide 81
参考实施例80的合成方法，以化合物80a和3-甲基丁酸为原料，合成得到灰色固体标题化合物81(40mg,收率91％)。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.
LC-MS:m/z＝365.2[M+H]+(97.92％purity,254nm)LC-MS: m/z = 365.2 [M+H] + (97.92% purity, 254 nm)
1H NMR(400MHz,DMSO-d6)δ10.51(s,1H),9.96(s,1H),8.23-8.14(m,2H),8.04-7.98(m,1H),7.84(d,J＝8.4Hz,1H),7.68(d,J＝7.2Hz,1H),7.64-7.56(m,2H),7.52(t,J＝8.0Hz,1H),7.45-7.36(m,2H),2.42-2.31(m,2H),2.23-2.10(m,1H),1.03(d,J＝6.8Hz,6H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.51 (s, 1H), 9.96 (s, 1H), 8.23-8.14 (m, 2H), 8.04-7.98 (m, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.68 (d, J=7.2 Hz, 1H), 7.64-7.56 (m, 2H), 7.52 (t, J=8.0 Hz, 1H), 7.45-7.36 (m, 2H), 2.42-2.31 (m, 2H), 2.23-2.10 (m, 1H), 1.03 (d, J=6.8 Hz, 6H).
实施例82Embodiment 82
N-(5-氰基萘-1-基)-4-氟苯甲酰胺82
N-(5-cyanonaphthalen-1-yl)-4-fluorobenzamide 82
第一步N-(5-氰基萘-1-基)-4-氟苯甲酰胺82The first step is N-(5-cyanonaphthalen-1-yl)-4-fluorobenzamide 82
将化合物50a(500mg,1.45mmol)溶解于N,N-二甲基甲酰胺(10mL)，依次加入氰化锌(256mg, 2.17mmol)，1,1'-双(二苯基膦)二茂铁(96mg,0.17mmol)和Pd2(dba)3(66mg,0.072mmol)，氮气保护下，加热100℃搅拌16小时，TLC(PE:EA＝5:1,Rf＝0.3)显示原料反应完全，冷却，加水(30mL)淬灭，加乙酸乙酯(50mL)淬灭，室温搅拌30分钟后，硅藻土过滤，乙酸乙酯萃取(20mL x3)，饱和食盐水(50mL x3)洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(PE:EA＝10:1-3:1)纯化，得棕色固体标题化合物82(410mg,收率97％)。Compound 50a (500 mg, 1.45 mmol) was dissolved in N,N-dimethylformamide (10 mL), and zinc cyanide (256 mg, 2.17mmol), 1,1'-bis(diphenylphosphino)ferrocene (96mg, 0.17mmol) and Pd2 (dba) 3 (66mg, 0.072mmol), heated at 100℃ with stirring for 16 hours under nitrogen protection, TLC (PE:EA＝5:1, Rf ＝0.3) showed that the raw materials reacted completely, cooled, quenched with water (30mL), quenched with ethyl acetate (50mL), stirred at room temperature for 30 minutes, filtered with celite, extracted with ethyl acetate (20mL x3), washed with saturated brine (50mL x3), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (PE:EA＝10:1-3:1) to obtain the title compound 82 (410mg, yield 97%) as a brown solid.
LC-MS:m/z＝291.1[M+H]+(98.83％purity,254nm)LC-MS: m/z = 291.1 [M+H] + (98.83% purity, 254 nm)
1H NMR(400MHz,DMSO-d6)δ10.65(s,1H),8.36(d,J＝8.8Hz,1H),8.23(d,J＝7.2Hz,1H),8.20-8.15(m,2H),8.08(d,J＝8.4Hz,1H),7.86(t,J＝7.6Hz,1H),7.80(d,J＝7.2Hz,1H),7.74-7.68(m,1H),7.42(t,J＝8.8Hz,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.65 (s, 1H), 8.36 (d, J=8.8 Hz, 1H), 8.23 (d, J=7.2 Hz, 1H), 8.20-8.15 (m, 2H), 8.08 (d, J=8.4 Hz, 1H), 7.86 (t, J=7.6 Hz, 1H), 7.80 (d, J=7.2 Hz, 1H), 7.74-7.68 (m, 1H), 7.42 (t, J=8.8 Hz, 2H).
实施例83Embodiment 83
((5-(4-氟苯甲酰胺基)萘-1-基)甲基)氨基甲酸叔丁酯83
tert-Butyl ((5-(4-fluorobenzamido)naphthalen-1-yl)methyl)carbamate 83
第一步(5-(4-氟苯甲酰氨基)萘-1-基)甲基)氨基甲酸叔丁酯胺83The first step is (5-(4-fluorobenzamido)naphthalen-1-yl)methyl)carbamic acid tert-butyl ester 83
将化合物82(200mg,0.69mmol)分散于甲醇(10mL)中，室温下加入二碳酸二叔丁酯(226mg,1.04mmol)和雷尼镍(50mg)，在氢气球下，室温搅拌2小时，TLC(PE:EA＝5:1,Rf＝0.2)显示原料反应完全，过滤，浓缩，粗品经硅胶柱层析(PE:EA＝10:1-2:1)纯化，得棕色固体标题化合物83(205mg,收率75％)。Compound 82 (200 mg, 0.69 mmol) was dispersed in methanol (10 mL), di-tert-butyl dicarbonate (226 mg, 1.04 mmol) and Raney nickel (50 mg) were added at room temperature, and the mixture was stirred at room temperature for 2 hours under a hydrogen balloon. TLC (PE:EA＝5:1, R f ＝0.2) showed that the raw material had reacted completely. The mixture was filtered and concentrated, and the crude product was purified by silica gel column chromatography (PE:EA＝10:1-2:1) to obtain the title compound 83 (205 mg, yield 75%) as a brown solid.
LC-MS:m/z＝412.2[M+H2O]+(95.42％purity,220nm)LC-MS: m/z = 412.2 [M + H 2 O] + (95.42% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.19-8.14(m,2H),8.09-8.04(m,1H),7.92(d,J＝8.4Hz,1H),7.62-7.58(m,2H),7.52-7.46(m,2H),7.44-7.38(m,3H),4.62(d,J＝5.6Hz,2H),1.41(s,9H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.48 (s, 1H), 8.19-8.14 (m, 2H), 8.09-8.04 (m, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.62-7.58 (m, 2H), 7.52-7.46 (m, 2H), 7.44-7.38 (m, 3H), 4.62 (d, J=5.6 Hz, 2H), 1.41 (s, 9H).
实施例84Embodiment 84
4-氟-N-(5-((3-甲基丁酰胺基)甲基)萘-1-基)苯甲酰胺84
4-Fluoro-N-(5-((3-methylbutyramido)methyl)naphthalen-1-yl)benzamide 84
第一步(5-(4-氟苯甲酰氨基)萘-1-基)甲基)氨基甲酸叔丁酯胺84aThe first step is tert-butyl (5-(4-fluorobenzamido)naphthalen-1-yl)methyl)carbamate 84a
参照实施例27第四步的方法合成得到化合物84a(150mg,收率98％)。Compound 84a (150 mg, yield 98%) was synthesized by referring to the method of step 4 of Example 27.
LC-MS:m/z＝293.1[M-H]- LC-MS: m/z = 293.1 [MH] -
第二步4-氟-N-(5-((3-甲基丁酰胺基)甲基)萘-1-基)苯甲酰胺84Step 2 4-Fluoro-N-(5-((3-methylbutyramido)methyl)naphthalen-1-yl)benzamide 84
将化合物84a(30mg,0.10mmol)溶解于二氯甲烷(2mL)，加入吡啶(24mg,0.30mmol)，冷却至0℃，滴入异戊酰氯(15mg,0.12mmol)，升至室温搅拌16小时，TLC(PE:EA＝2:1,Rf＝0.2)显示原料少量剩余，加水(10mL)淬灭，乙酸乙酯萃取(10mL x3)，饱和食盐水(20mL x3)洗，无水硫酸钠干燥，浓缩，粗品经Pre-TLC(PE:EA＝1:1)纯化得白色固体标题化合物84(18mg,收率51％)。Compound 84a (30 mg, 0.10 mmol) was dissolved in dichloromethane (2 mL), pyridine (24 mg, 0.30 mmol) was added, and the mixture was cooled to 0°C. Isovaleryl chloride (15 mg, 0.12 mmol) was added dropwise. The mixture was heated to room temperature and stirred for 16 hours. TLC (PE:EA＝2:1, R f ＝0.2) showed that a small amount of starting material remained. Water (10 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Pre-TLC (PE:EA＝1:1) to obtain the title compound 84 (18 mg, yield 51%) as a white solid.
LC-MS:m/z＝379.2[M+H]+(94.21％purity,220nm)LC-MS: m/z = 379.2 [M+H] + (94.21% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.37(t,J＝5.6Hz,1H),8.17(dd,J＝8.8,5.6Hz,2H),8.06-8.01(m,1H),7.95-7.90(m,1H),7.61-7.57(m,2H),7.51-7.45(m,2H),7.40(t,J＝8.8Hz,2H),4.76(d,J＝5.6Hz,2H),2.06-2.01(m,3H),0.88(d,J＝6.4Hz,6H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.48 (s, 1H), 8.37 (t, J=5.6 Hz, 1H), 8.17 (dd, J=8.8, 5.6 Hz, 2H), 8.06-8.01 (m, 1H), 7.95-7.90 (m, 1H), 7.61-7.57 (m, 2H), 7.51-7.45 (m, 2H), 7.40 (t, J=8.8 Hz, 2H), 4.76 (d, J=5.6 Hz, 2H), 2.06-2.01 (m, 3H), 0.88 (d, J=6.4 Hz, 6H).
实施例85Embodiment 85
(5-(4-氟苯甲酰胺基)萘-1-基)氨基甲酸乙酯85
Ethyl (5-(4-fluorobenzamido)naphthalen-1-yl)carbamate 85
第一步(5-溴萘-1-基)氨基甲酸乙酯85aFirst step Ethyl (5-bromonaphthalen-1-yl)carbamate 85a
将1-氨基-5-溴萘21a(800mg,3.60mmol)溶解于二氯甲烷(20mL)中，加入吡啶(570mg,7.21mmol)，冷却至0℃，滴入氯甲酸乙酯(430mg,3.96mmol)，升至室温搅拌16小时，TLC(PE:EA＝5:1,Rf＝0.4)显示原料少量剩余，加水(20mL)淬灭，乙酸乙酯萃取(10mL x3)，饱和食盐水(20mL x3)洗，无水硫酸钠干燥，浓缩，加入二氯甲烷(5mL)打浆，得淡粉色固体标题化合物85a(230mg,收率22％)。1-Amino-5-bromonaphthalene 21a (800 mg, 3.60 mmol) was dissolved in dichloromethane (20 mL), pyridine (570 mg, 7.21 mmol) was added, and the mixture was cooled to 0°C. Ethyl chloroformate (430 mg, 3.96 mmol) was added dropwise. The mixture was warmed to room temperature and stirred for 16 hours. TLC (PE:EA=5:1, R f =0.4) showed that a small amount of starting material remained. Water (20 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, concentrated, and slurried with dichloromethane (5 mL) to give the title compound 85a (230 mg, yield 22%) as a light pink solid.
LC-MS:m/z＝294.0/296.0[M+H]+ LC-MS: m/z＝294.0/296.0[M+H] +
第二步(5-(4-氟苯甲酰胺基)萘-1-基)氨基甲酸乙酯85Step 2 (5-(4-fluorobenzamido)naphthalen-1-yl)carbamate 85
将化合物85a(150mg,0.51mmol)溶解于1,4-二氧六环(3mL)，依次加入对氟苯甲酰胺(47mg,0.34mmol)，Xantphos(41mg,0.07mmol)，Pd2(dba)3(31mg,0.056mmol)和碳酸铯(222mg,0.68mmol)，氮气保护下，加热90℃搅拌16小时，TLC(PE:EA＝2:1,Rf＝0.2)显示原料少量剩余，冷却，硅藻土过滤，加水(10mL)淬灭，乙酸乙酯萃取(10mL x3)，饱和食盐水(20mL x3)洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(PE:EA＝5:1-2:1)纯化得白色固体80mg，加入乙酸乙酯(5mL)打浆，收集固体，得白色固体标题化合物85(32mg,收率18％)。Compound 85a (150 mg, 0.51 mmol) was dissolved in 1,4-dioxane (3 mL), and p-fluorobenzamide (47 mg, 0.34 mmol), Xantphos (41 mg, 0.07 mmol), Pd 2 (dba) 3 (31 mg, 0.056 mmol) and cesium carbonate (222 mg, 0.68 mmol) were added in sequence. The mixture was heated at 90°C with stirring for 16 hours under nitrogen protection. TLC (PE:EA＝2:1, R f ＝0.2) showed that a small amount of starting material remained. The mixture was cooled, filtered through celite, quenched with water (10 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (PE:EA＝5:1-2:1) to obtain 80 mg of a white solid. Ethyl acetate (5 mL) was added to slurry, and the solid was collected to obtain the title compound 85 (32 mg, yield 18%) as a white solid.
LC-MS:m/z＝353.2[M+H]+(98.60％purity,210nm)LC-MS: m/z = 353.2 [M+H] + (98.60% purity, 210 nm)
1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),9.57(s,1H),8.20-8.13(m,2H),8.01(d,J＝8.0Hz,1H),7.81(d,J＝8.4Hz,1H),7.64-7.55(m,3H),7.55-7.48(m,1H),7.44-7.37(m,2H),4.17(q,J＝6.8Hz,2H),1.28(t,J＝7.2Hz,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.47 (s, 1H), 9.57 (s, 1H), 8.20-8.13 (m, 2H), 8.01 (d, J=8.0 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.64-7.55 (m, 3H), 7.55-7.48 (m, 1H), 7.44-7.37 (m, 2H), 4.17 (q, J=6.8 Hz, 2H), 1.28 (t, J=7.2 Hz, 3H).
实施例86Embodiment 86
(5-(4-氟苯甲酰氨基)萘-1-基)氨基甲酸甲酯86
Methyl (5-(4-fluorobenzamido)naphthalen-1-yl)carbamate 86
参考实施例85的合成方法，以化合物21a和氯甲酸甲酯为原料，合成得到白色固体标题化合物86(16mg,收率13％)。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.
LC-MS:m/z＝339.1[M+H]+(91.25％purity,220nm)LC-MS: m/z = 339.1 [M+H] + (91.25% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),9.61(s,1H),8.20-8.13(m,2H),8.01(d,J＝8.0Hz,1H),7.82(d,J＝8.4Hz,1H),7.65-7.56(m,3H),7.55-7.48(m,1H),7.44-7.37(m,2H),3.71(s,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.47 (s, 1H), 9.61 (s, 1H), 8.20-8.13 (m, 2H), 8.01 (d, J=8.0 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.65-7.56 (m, 3H), 7.55-7.48 (m, 1H), 7.44-7.37 (m, 2H), 3.71 (s, 3H).
实施例87Embodiment 87
(5-(4-氟苯甲酰胺基)萘-1-基)甲基)氨基甲酸乙酯87
Ethyl (5-(4-fluorobenzamido)naphthalen-1-yl)methyl)carbamate 87
参考实施例84第二步的合成方法，以化合物84a和氯甲酸乙酯为原料，合成得到白色固体标题化合物87(16mg,收率45％)。 Referring to the synthesis method of the second step of Example 84, compound 84a and ethyl chloroformate were used as raw materials to synthesize the title compound 87 (16 mg, yield 45%) as a white solid.
LC-MS:m/z＝367.1[M+H]+(97.31％purity,220nm)LC-MS: m/z = 367.1 [M+H] + (97.31% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.50(s,1H),8.17(dd,J＝8.4,6.0Hz,2H),8.09-8.04(m,1H),7.92(d,J＝8.4Hz,1H),7.76(t,J＝5.6Hz,1H),7.61(d,J＝4.8Hz,2H),7.53-7.44(m,2H),7.41(t,J＝8.8Hz,2H),4.68(d,J＝5.6Hz,2H),4.04(q,J＝7.2Hz,2H),1.18(t,J＝6.8Hz,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.50 (s, 1H), 8.17 (dd, J=8.4, 6.0 Hz, 2H), 8.09-8.04 (m, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.76 (t, J=5.6 Hz, 1H), 7.61 (d, J=4.8 Hz, 2H), 7.53-7.44 (m, 2H), 7.41 (t, J=8.8 Hz, 2H), 4.68 (d, J=5.6 Hz, 2H), 4.04 (q, J=7.2 Hz, 2H), 1.18 (t, J=6.8 Hz, 3H).
实施例88Embodiment 88
(5-(4-氟苯甲酰氨基)萘-1-基)甲基氨基甲酸甲酯88
Methyl (5-(4-fluorobenzamido)naphthalen-1-yl)methylcarbamate 88
参考实施例84第二步的合成方法，以化合物84a和氯甲酸甲酯为原料，合成得到白色固体标题化合物88(12mg,收率34％)。Referring to the synthesis method of the second step of Example 84, compound 84a and methyl chloroformate were used as raw materials to synthesize the title compound 88 (12 mg, yield 34%) as a white solid.
LC-MS:m/z＝353.2[M+H]+(99.50％purity,210nm)LC-MS: m/z = 353.2 [M+H] + (99.50% purity, 210 nm)
1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.20-8.13(m,2H),8.08-8.02(m,1H),7.92(d,J＝8.0Hz,1H),7.81(t,J＝6.0Hz,1H),7.60(d,J＝4.8Hz,2H),7.53-7.44(m,2H),7.43-7.37(m,2H),4.68(d,J＝6.0Hz,2H),3.58(s,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.49 (s, 1H), 8.20-8.13 (m, 2H), 8.08-8.02 (m, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.81 (t, J=6.0 Hz, 1H), 7.60 (d, J=4.8 Hz, 2H), 7.53-7.44 (m, 2H), 7.43-7.37 (m, 2H), 4.68 (d, J=6.0 Hz, 2H), 3.58 (s, 3H).
实施例89Embodiment 89
4-氟-N-(4-(3-甲基丁酰胺基)萘-1-基)苯甲酰胺89
4-Fluoro-N-(4-(3-methylbutyramido)naphthalen-1-yl)benzamide 89
第一步4-氟-N-(4-硝基萘-1-基)苯甲酰胺89bStep 1 4-Fluoro-N-(4-nitronaphthalen-1-yl)benzamide 89b
参照实施例34的第二步的方法合成得到黄色固体标题化合物89b(104mg,收率32％)。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.
LC-MS:m/z＝311.1[M+H]+ LC-MS: m/z = 311.1 [M + H] +
第二步N-(4-氨基萘-1-基)-4-氟苯甲酰胺89cStep 2 N-(4-aminonaphthalen-1-yl)-4-fluorobenzamide 89c
参照实施例1的第一步合成方法合成得到咖啡色固体标题化合物89c(84mg,收率94％)。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.
LC-MS:m/z＝281.1[M+H]+ LC-MS: m/z = 281.1 [M + H] +
第三步4-氟-N-(4-(3-甲基丁酰胺基)萘-1-基)苯甲酰胺89Step 3 4-Fluoro-N-(4-(3-methylbutyramido)naphthalen-1-yl)benzamide 89
参考实施例84第二步的合成方法合成得到化合物89(44mg,收率67％)Compound 89 (44 mg, yield 67%) was synthesized by the synthesis method of the second step of Example 84
LC-MS:m/z＝365.2[M+H]+(98.01％purity,254nm)LC-MS: m/z = 365.2 [M+H] + (98.01% purity, 254 nm)
1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),9.91(s,1H),8.21-8.13(m,2H),8.08(d,J＝7.6Hz,1H),7.98(d,J＝8.0Hz,1H),7.67(d,J＝8.0Hz,1H),7.64-7.51(m,3H),7.40(t,J＝8.8Hz,2H),2.37(d,J＝7.2Hz,2H),2.23-2.11(m,1H),1.02(d,J＝6.8Hz,6H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.44 (s, 1H), 9.91 (s, 1H), 8.21-8.13 (m, 2H), 8.08 (d, J=7.6 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.64-7.51 (m, 3H), 7.40 (t, J=8.8 Hz, 2H), 2.37 (d, J=7.2 Hz, 2H), 2.23-2.11 (m, 1H), 1.02 (d, J=6.8 Hz, 6H).
实施例90Embodiment 90
(4-(4-氟苯甲酰胺基)萘-1-基)甲基)氨基甲酸乙酯90
Ethyl (4-(4-fluorobenzamido)naphthalen-1-yl)methyl)carbamate 90
第一步N-(4-溴萘-1-基)-4-氟苯甲酰胺90bStep 1 N-(4-bromonaphthalen-1-yl)-4-fluorobenzamide 90b
参照实施例35的第三步合成方法合成得到化合物90b(261mg,收率8％)。Compound 90b (261 mg, yield 8%) was synthesized by referring to the third step synthesis method of Example 35.
LC-MS:m/z＝344.0/346.0[M+H]+ LC-MS: m/z＝344.0/346.0[M+H] +
第二步N-(4-氰基萘-1-基)-4-氟苯甲酰胺90cStep 2 N-(4-cyanonaphthalen-1-yl)-4-fluorobenzamide 90c
参照实施例82的合成方法合成得到化合物90c,LC-MS:m/z＝291.1[M+H]+ Compound 90c was synthesized by referring to the synthesis method of Example 82, LC-MS: m/z=291.1 [M+H] +
第三步(4-(4-氟苯甲酰氨基)萘-1-基)甲基)氨基甲酸叔丁酯90dStep 3 Tert-butyl (4-(4-fluorobenzamido)naphthalen-1-yl)methyl)carbamate 90d
参照实施例83的合成方法合成得到化合物90d(190mg,收率70％)。Compound 90d (190 mg, yield 70%) was synthesized by referring to the synthesis method of Example 83.
LC-MS:m/z＝393.1[M-H]- LC-MS: m/z = 393.1 [MH] -
第四步(N-(4-(氨甲基)萘-1-基)-4-氟苯甲酰胺90eStep 4 (N-(4-(Aminomethyl)naphthalen-1-yl)-4-fluorobenzamide 90e
参照实施例27第四步的方法合成得到化合物90e(130mg,收率92％)。Compound 90e (130 mg, yield 92%) was synthesized by referring to the method of step 4 of Example 27.
第五步(4-(4-氟苯甲酰氨基)萘-1-基)甲基)氨基甲酸乙酯90Step 5: Ethyl (4-(4-fluorobenzamido)naphthalen-1-yl)methyl)carbamate 90
参照实施例85第一步的方法合成得到化合物90(14mg,收率22％)。Compound 90 (14 mg, yield 22%) was synthesized by referring to the method of the first step of Example 85.
LC-MS:m/z＝365.1[M-H]-(98.22％purity,220nm)LC-MS: m/z = 365.1 [MH] - (98.22% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),8.24-8.12(m,3H),8.06-7.99(m,1H),7.81-7.74(m,1H),7.66-7.50(m,3H),7.49-7.36(m,3H),4.67(d,J＝6.0Hz,2H),4.04(q,J＝7.2Hz,2H),1.19(t,J＝7.2Hz,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.46 (s, 1H), 8.24-8.12 (m, 3H), 8.06-7.99 (m, 1H), 7.81-7.74 (m, 1H), 7.66-7.50 (m, 3H), 7.49-7.36 (m, 3H), 4.67 (d, J=6.0 Hz, 2H), 4.04 (q, J=7.2 Hz, 2H), 1.19 (t, J=7.2 Hz, 3H).
实施例91Embodiment 91
4-氟-N-(4-((3-甲基丁酰胺基)甲基)萘-1-基)苯甲酰胺91
4-Fluoro-N-(4-((3-methylbutyramido)methyl)naphthalen-1-yl)benzamide 91
参考实施例90第五步的合成方法，以化合物90e和异戊酰氯为原料，合成得到白色固体标题化合物91(31mg,收率48％)。With reference to the synthesis method of the fifth step of Example 90, compound 90e and isovaleryl chloride were used as raw materials to synthesize the title compound 91 (31 mg, yield 48%) as a white solid.
LC-MS:m/z＝379.2[M+H]+(95.05％purity,220nm)LC-MS: m/z = 379.2 [M+H] + (95.05% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),8.43-8.33(m,1H),8.23-8.09(m,3H),8.06-7.98(m,1H),7.63-7.51(m,3H),7.48(d,J＝7.6Hz,1H),7.41(t,J＝8.8Hz,2H),4.76(d,J＝5.6Hz,2H),2.09-1.97(m,3H),0.88(d,J＝6.4Hz,6H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.45 (s, 1H), 8.43-8.33 (m, 1H), 8.23-8.09 (m, 3H), 8.06-7.98 (m, 1H), 7.63-7.51 (m, 3H), 7.48 (d, J=7.6 Hz, 1H), 7.41 (t, J=8.8 Hz, 2H), 4.76 (d, J=5.6 Hz, 2H), 2.09-1.97 (m, 3H), 0.88 (d, J=6.4 Hz, 6H).
实施例92Embodiment 92
N-(7-环丙基-6-甲基-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺92
N-(7-cyclopropyl-6-methyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 92
第一步3-溴-2-氟-4-甲基苯甲醛肟92bStep 1 3-Bromo-2-fluoro-4-methylbenzaldehyde oxime 92b
将化合物3-溴-2-氟-4-甲基苯甲醛92a(800mg,3.69mmol)溶于四氢呋喃(20mL)和水(1mL)中，室温加入盐酸羟胺(512mg,7.37mmol)和碳酸钠(781mg,7.37mmol)，加毕，反应液25℃搅拌1小时，TLC检测原料反应完全。反应液加水稀释，乙酸乙酯萃取，饱和食盐水(50mL)洗，无水硫酸钠干燥，浓缩得白色固体标题化合物92b(1.18g,粗品)。Compound 3-bromo-2-fluoro-4-methylbenzaldehyde 92a (800 mg, 3.69 mmol) was dissolved in tetrahydrofuran (20 mL) and water (1 mL), and hydroxylamine hydrochloride (512 mg, 7.37 mmol) and sodium carbonate (781 mg, 7.37 mmol) were added at room temperature. After the addition, the reaction solution was stirred at 25°C for 1 hour. TLC showed that the reaction of the raw materials was complete. The 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.
第二步3-溴-2-氟-4-甲基苄腈92cStep 2 3-Bromo-2-fluoro-4-methylbenzonitrile 92c
将化合物92b(1.18g,粗品)溶于氯化亚砜(20mL)中，反应液25℃搅拌1小时，TLC(PE/EA＝10/1,Rf＝0.3)检测原料反应完全。反应液浓缩，除去氯化亚砜，粗品用碳酸氢钠水溶液(40mL)调节pH＝8，乙酸乙酯萃取(40mL x2)，饱和食盐水(40mL)洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(EA/PE＝1/20)纯化得白色固体标题化合物92c(768mg,两步收率97％)。1H NMR(400MHz,CDCl3)δ7.47(dd,J＝7.6,6.0Hz,1H),7.15(d,J＝7.6Hz,1H),2.51(s,3H).Compound 92b (1.18 g, crude product) was dissolved in thionyl chloride (20 mL), and the reaction solution was stirred at 25°C for 1 hour. TLC (PE/EA=10/1, R f =0.3) detected that the raw material reaction was complete. The reaction solution was concentrated to remove thionyl chloride. The crude product was adjusted to pH=8 with sodium bicarbonate aqueous solution (40 mL), extracted with ethyl acetate (40 mL x2), washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (EA/PE=1/20) to obtain the title compound 92c (768 mg, two-step yield 97%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ7.47 (dd, J=7.6, 6.0 Hz, 1H), 7.15 (d, J=7.6 Hz, 1H), 2.51 (s, 3H).
第三步3-环丙基-2-氟-4-甲基苄腈92dStep 3 3-Cyclopropyl-2-fluoro-4-methylbenzonitrile 92d
参照实施例12的第四步的方法合成得到化合物92d(570mg,收率91％)。Compound 92d (570 mg, yield 91%) was synthesized by referring to the method of step 4 of Example 12.
1H NMR(400MHz,CDCl3)δ7.34(dd,J＝7.6,6.4Hz,1H),7.02(d,J＝8.0Hz,1H),2.49(s,3H),1.67-1.59(m,1H),1.08-1.01(m,2H),0.79-0.71(m,2H). 1 H NMR (400 MHz, CDCl 3 ) δ7.34 (dd, J=7.6, 6.4 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 2.49 (s, 3H), 1.67-1.59 (m, 1H), 1.08-1.01 (m, 2H), 0.79-0.71 (m, 2H).
第四步7-环丙基-6-甲基1H-吲唑-3-胺92eStep 4 7-Cyclopropyl-6-methyl 1H-indazol-3-amine 92e
将化合物92d(752mg,4.29mmol)溶解于正丁醇(10mL)中，室温加入水合肼(80％,3.40g,54.33mmol)，加毕，反应液加热至120℃搅拌20小时，TLC(DCM/MeOH＝30/1,Rf＝0.8)检测有原料剩余，LCMS检测有目标产品。冷却，加水(30mL)淬灭，乙酸乙酯萃取(30mL x3)，水洗(20mLx3)，饱和食盐水(20mL)洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(MeOH/DCM＝1/50)纯化得黄色油状标题化合物92e(100mg,收率12％)。Compound 92d (752 mg, 4.29 mmol) was dissolved in n-butanol (10 mL), and hydrazine hydrate (80%, 3.40 g, 54.33 mmol) was added at room temperature. After addition, the reaction solution was heated to 120°C and stirred for 20 hours. TLC (DCM/MeOH=30/1, R f =0.8) detected the presence of residual raw materials, and LCMS detected the presence of the target product. The mixture was cooled, quenched with water (30 mL), extracted with ethyl acetate (30 mL x 3), washed with water (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (MeOH/DCM=1/50) to obtain the title compound 92e (100 mg, yield 12%) as a yellow oil.
LC-MS:m/z＝188.2[M+H]+ LC-MS: m/z = 188.2 [M + H] +
第五步N-(7-环丙基-6-甲基-1H-吲唑-3-基)-4-氟苯甲酰胺92fStep 5 N-(7-cyclopropyl-6-methyl-1H-indazol-3-yl)-4-fluorobenzamide 92f
参照实施例34的第二步的方法合成得到黄色固体标题化合物92f(121mg,收率73％)。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.
LC-MS:m/z＝310.1[M+H]+ LC-MS: m/z = 310.1 [M + H] +
1H NMR(400MHz,DMSO-d6)δ12.50(s,1H),10.73(s,1H),8.14(dd,J＝8.4,5.6Hz,2H),7.43(d,J＝8.4Hz,1H),7.37(t,J＝8.8Hz,2H),6.89(d,J＝8.0Hz,1H),2.48(s,3H),1.97-1.87(m,1H),1.14-1.05(m,2H),0.67-0.61(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.50 (s, 1H), 10.73 (s, 1H), 8.14 (dd, J=8.4, 5.6 Hz, 2H), 7.43 (d, J=8.4 Hz, 1H), 7.37 (t, J=8.8 Hz, 2H), 6.89 (d, J=8.0 Hz, 1H), 2.48 (s, 3H), 1.97-1.87 (m, 1H), 1.14-1.05 (m, 2H), 0.67-0.61 (m, 2H).
第六步N-(7-环丙基-6-甲基-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺92Step 6 N-(7-cyclopropyl-6-methyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 92
参照实施例72的第四步的方法合成纯化得淡黄色固体标题化合物92(14mg,收率11％)。Referring to the method of the fourth step of Example 72, the title compound 92 (14 mg, yield 11%) was synthesized and purified as a light yellow solid.
LC-MS:m/z＝348.2[M+H]+(93.11％purity,220nm)LC-MS: m/z = 348.2 [M+H] + (93.11% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.86(s,1H),8.14(dd,J＝8.4,5.6Hz,2H),7.43(d,J＝8.0Hz,1H),7.37(t,J＝8.8Hz,2H),6.96(d,J＝8.0Hz,1H),5.50(s,2H),2.22-2.13(m,1H),1.25-1.17(m, 2H),0.73-0.65(m,2H).(苯甲基3H和炔基1H分别被氘代试剂和水峰覆盖) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.86 (s, 1H), 8.14 (dd, J = 8.4, 5.6 Hz, 2H), 7.43 (d, J = 8.0 Hz, 1H), 7.37 (t, J = 8.8 Hz, 2H), 6.96 (d, J = 8.0 Hz, 1H), 5.50 (s, 2H), 2.22-2.13 (m, 1H), 1.25-1.17 (m, 2H), 0.73-0.65 (m, 2H). (Benzyl 3H and alkynyl 1H are covered by deuterated reagent and water peaks respectively)
实施例93Embodiment 93
N-(7-环丙基-5-甲基-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺93
N-(7-cyclopropyl-5-methyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 93
第一步3-溴-2-氟-5-甲基苯甲酰胺93bStep 1 3-Bromo-2-fluoro-5-methylbenzamide 93b
将3-溴-2-氟-5-甲基苯甲酸93a(1.5g,6.44mmol)悬浮于无水二氯甲烷(20mL)，氮气保护下降温至0℃，依次滴加草酰氯(1.1g,8.67mmol)和DMF(0.3mL)。加毕，反应液升至室温反应1小时。将反应液浓缩，粗品溶于无水四氢呋喃(10mL)，降温至0℃，滴加氨水(25％-28％,10mL)，滴毕，升至室温反应16小时。TLC(二氯甲烷:甲醇＝20:1,新点Rf＝0.4)显示原料转化完全。将反应液浓缩，将析出的沉淀过滤，水(10mL)洗，收集滤饼，干燥得到白色固体标题化合物93b(1.45g,收率97％)。3-Bromo-2-fluoro-5-methylbenzoic acid 93a (1.5 g, 6.44 mmol) was suspended in anhydrous dichloromethane (20 mL), cooled to 0°C under nitrogen protection, and oxalyl chloride (1.1 g, 8.67 mmol) and DMF (0.3 mL) were added dropwise in sequence. After the addition, the reaction solution was warmed to room temperature and reacted for 1 hour. The reaction solution was concentrated, the crude product was dissolved in anhydrous tetrahydrofuran (10 mL), cooled to 0°C, and ammonia water (25%-28%, 10 mL) was added dropwise. After the addition, the reaction solution was warmed to room temperature and reacted for 16 hours. TLC (dichloromethane: methanol = 20: 1, new point Rf = 0.4) showed that the raw material was completely converted. The reaction solution was concentrated, the precipitate was filtered, washed with water (10 mL), the filter cake was collected, and dried to obtain the title compound 93b (1.45 g, yield 97%) as a white solid.
第二步3-溴-2-氟-5-甲基苯腈93cStep 2 3-Bromo-2-fluoro-5-methylbenzonitrile 93c
氮气保护下，将化合物93b(1.39g,5.99mmol)溶于乙腈(20mL)，在室温缓慢滴加三氯氧磷(3.67g,23.94mmol)，滴毕，升温至80℃反应2小时。TLC监控。冷却，浓缩，粗品溶于乙酸乙酯，用饱和碳酸钠水溶液洗涤，无水硫酸钠干燥，浓缩得到黄色固体标题化合物93c(1.25g,收率98％)。Under nitrogen protection, compound 93b (1.39 g, 5.99 mmol) was dissolved in acetonitrile (20 mL), phosphorus oxychloride (3.67 g, 23.94 mmol) was slowly added dropwise at room temperature, and the temperature was raised to 80°C for 2 hours. TLC monitoring was performed. The mixture was cooled and concentrated, and the crude product was dissolved in ethyl acetate, washed with saturated sodium carbonate aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 93c (1.25 g, yield 98%) as a yellow solid.
第三步7-溴-5-甲基吲唑-3-胺93dStep 3 7-Bromo-5-methylindazol-3-amine 93d
参照实施例92的第四步的方法合成得到黄色固体标题化合物93d(516mg,收率39％)。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.
LC-MS：m/z＝226.0/228.0[M+H]+ LC-MS: m/z = 226.0/228.0 [M+H] +
第四步7-溴-3-(双(叔丁氧羰基)氨基)-5-甲基-1H-吲唑-1-羧酸叔丁酯93eStep 4: tert-butyl 7-bromo-3-(bis(tert-butyloxycarbonyl)amino)-5-methyl-1H-indazole-1-carboxylate 93e
将化合物93d(100mg,0.44mmol)和DMAP(11mg,0.090mmol)依次加入到四氢呋喃(4mL)中，加毕，室温滴加二碳酸二叔丁酯(483mg,2.21mmol)。滴毕，继续在室温反应16小时。TLC监控。将反应液浓缩，粗品经硅胶柱层析纯化得到发泡状标题化合物93e(194mg,收率83％)。Compound 93d (100 mg, 0.44 mmol) and DMAP (11 mg, 0.090 mmol) were added to tetrahydrofuran (4 mL) in sequence. After the addition, di-tert-butyl dicarbonate (483 mg, 2.21 mmol) was added dropwise at room temperature. After the addition, the reaction was continued at room temperature for 16 hours. TLC monitoring was performed. The reaction solution was concentrated and the crude product was purified by silica gel column chromatography to obtain the title compound 93e (194 mg, yield 83%) in a foamy state.
第五步3-(双(叔丁氧羰基)氨基)-7-环丙基-5-甲基-1H-吲唑-1-羧酸叔丁酯93fStep 5: tert-butyl 3-(bis(tert-butyloxycarbonyl)amino)-7-cyclopropyl-5-methyl-1H-indazole-1-carboxylate 93f
参照实施例12的第四步的方法合成得到化合物93f(105mg,收率58％)。Compound 93f (105 mg, yield 58%) was synthesized by referring to the fourth step of Example 12.
LC-MS：m/z＝488.3[M+H]+ LC-MS: m/z = 488.3 [M + H] +
第六步7-环丙基-5-甲基吲唑-3-胺93gStep 6 7-cyclopropyl-5-methylindazole-3-amine 93g
将化合物93f(105mg,0.22mmol)溶于二氧六环(1mL)，室温滴加氯化氢/二氧六环溶液(4M,1mL,4.0mmol)。滴毕，继续在室温反应4小时。TLC监控。将反应液浓缩，粗品用乙酸乙酯萃取，无水硫酸钠干燥，浓缩得到褐色液体标题化合物93g，粗品直接用于下一步。Compound 93f (105 mg, 0.22 mmol) was dissolved in dioxane (1 mL), and a hydrogen chloride/dioxane solution (4 M, 1 mL, 4.0 mmol) was added dropwise at room temperature. After the addition, the reaction was continued at room temperature for 4 hours. TLC monitoring was performed. The reaction solution was concentrated, and the crude product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain a brown liquid title compound 93 g, which was used directly in the next step.
LC-MS：m/z＝188.2[M+H]+ LC-MS: m/z = 188.2 [M + H] +
第七步2-(7-环丙基-5-甲基-1H-吲唑-3-基)异吲哚啉-1,3-二酮93h Step 7: 2-(7-cyclopropyl-5-methyl-1H-indazol-3-yl)isoindoline-1,3-dione 93h
将化合物93g(粗品)溶于二氧六环(1.5mL)，加入邻苯二甲酸酐(35mg,0.24mmol)。加毕，反应液加热至120℃反应4.5小时。TLC(PE:EA＝2:1,新点Rf＝0.4)显示原料转化完全。冷却，浓缩，粗品经硅胶柱层析纯化(PE:EA＝10:1-2:1)得到浅褐色固体标题化合物93h(48mg,两步收率70％)。Compound 93g (crude product) was dissolved in dioxane (1.5 mL) and phthalic anhydride (35 mg, 0.24 mmol) was added. After the addition, the reaction solution was heated to 120°C for 4.5 hours. TLC (PE:EA＝2:1, new spot R f ＝0.4) showed that the raw material was completely converted. The mixture was cooled and concentrated, and the crude product was purified by silica gel column chromatography (PE:EA＝10:1-2:1) to obtain the title compound 93h (48 mg, two-step yield 70%) as a light brown solid.
第八步2-(7-环丙基-5-甲基-1-丙基-2-炔基)-1H-吲唑-3-基)异吲哚啉-1,3-二酮93iStep 8 2-(7-cyclopropyl-5-methyl-1-propyl-2-ynyl)-1H-indazol-3-yl)isoindoline-1,3-dione 93i
参照实施例72的方法合成得到黄色固体标题化合物93i(45mg,收率84％)。The title compound 93i (45 mg, yield 84%) was synthesized as a yellow solid by referring to the method of Example 72.
LC-MS：m/z＝356.2[M+H]+ LC-MS: m/z = 356.2 [M + H] +
第九步7-环丙基-5-甲基-1-丙基-2-炔基-1-吲唑-3-胺93jStep 9 7-Cyclopropyl-5-methyl-1-propyl-2-alkynyl-1-indazol-3-amine 93j
将化合物93i(45mg,0.13mmol)溶于乙醇(1mL)中，滴加水合肼(80％,24mg,0.38mmol)。加毕，室温反应3小时。TLC(PE:EA＝1:1,新点Rf＝0.3)显示原料转化完全。将反应液过滤除去不溶物，滤液浓缩，粗品经pre-TLC(PE:EA＝1:1)纯化得到黄色固体标题化合物93j(15mg,收率53％)。Compound 93i (45 mg, 0.13 mmol) was dissolved in ethanol (1 mL), and hydrazine hydrate (80%, 24 mg, 0.38 mmol) was added dropwise. After addition, the mixture was reacted at room temperature for 3 hours. TLC (PE:EA＝1:1, new point R f ＝0.3) showed that the raw material was completely converted. The reaction solution was filtered to remove insoluble matter, and the filtrate was concentrated. The crude product was purified by pre-TLC (PE:EA＝1:1) to obtain the title compound 93j (15 mg, yield 53%) as a yellow solid.
第十步N-(7-环丙基-5-甲基-1-丙基-2-炔基)-1H-吲唑-3-基)-4-氟苯甲酰胺93Step 10: N-(7-cyclopropyl-5-methyl-1-propyl-2-ynyl)-1H-indazol-3-yl)-4-fluorobenzamide 93
参照实施例34的第二步的方法合成得到化合物93(12.5mg,收率54％)。Compound 93 (12.5 mg, yield 54%) was synthesized by referring to the second step of Example 34.
LC-MS:m/z＝348.2[M+H]+(95.13％purity,254nm)LC-MS: m/z = 348.2 [M+H] + (95.13% purity, 254 nm)
1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),8.14(dd,J＝8.8,5.2Hz,2H),7.38(t,J＝8.8Hz,2H),7.26(s,1H),6.99(s,1H),5.50(d,J＝2.0Hz,2H),3.43-3.39(m,1H),2.48-2.41(m,1H),2.33(s,3H),1.10-1.03(m,2H),0.89-0.83(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.79 (s, 1H), 8.14 (dd, J=8.8, 5.2 Hz, 2H), 7.38 (t, J=8.8 Hz, 2H), 7.26 (s, 1H), 6.99 (s, 1H), 5.50 (d, J=2.0 Hz, 2H), 3.43-3.39 (m, 1H), 2.48-2.41 (m, 1H), 2.33 (s, 3H), 1.10-1.03 (m, 2H), 0.89-0.83 (m, 2H).
实施例94Embodiment 94
N-(7-环丙基-1-(2-氟乙基)-1H-吲唑-3-基)-4-氟苯甲酰胺94
N-(7-cyclopropyl-1-(2-fluoroethyl)-1H-indazol-3-yl)-4-fluorobenzamide 94
第一步N-(7-环丙基-1-(2-氟乙基)-1H-吲唑-3-基)-4-氟苯甲酰胺94First step N-(7-cyclopropyl-1-(2-fluoroethyl)-1H-indazol-3-yl)-4-fluorobenzamide 94
参照实施例34的第三步的方法合成得到目标化合物94(28mg,收率82％)。The target compound 94 (28 mg, yield 82%) was synthesized by referring to the method of the third step of Example 34.
LC-MS:m/z＝342.1[M+H]+(96.78％purity,220nm)LC-MS: m/z = 342.1 [M+H] + (96.78% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.15(dd,J＝8.8,5.6Hz,2H),7.48(d,J＝8.0Hz,1H),7.38(t,J＝8.8Hz,2H),7.12(d,J＝6.8Hz,1H),6.98(t,J＝7.6Hz,1H),5.12(t,J＝4.7Hz,1H),5.05(t,J＝4.4Hz,1H),4.94(t,J＝4.8Hz,1H),4.83(t,J＝4.4Hz,1H),2.40-2.32(m,1H),1.08-1.02(m,2H),0.87-0.82(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.83 (s, 1H), 8.15 (dd, J=8.8, 5.6 Hz, 2H), 7.48 (d, J=8.0 Hz, 1H), 7.38 (t, J=8.8 Hz, 2H), 7.12 (d, J=6.8 Hz, 1H), 6.98 (t, J=7.6 Hz, 1H), 5.12 (t, J=4.7 Hz, 1H), 5.05 (t, J=4.4 Hz, 1H), 4.94 (t, J=4.8 Hz, 1H), 4.83 (t, J=4.4 Hz, 1H), 2.40-2.32 (m, 1H), 1.08-1.02 (m, 2H), 0.87-0.82 (m, 2H).
实施例95Embodiment 95
N-(7-环丙基-1-(3-氟丙基)-1H-吲唑-3-基)-4-氟苯甲酰胺95
N-(7-cyclopropyl-1-(3-fluoropropyl)-1H-indazol-3-yl)-4-fluorobenzamide 95
参考实施例94的合成方法，以化合物34b和1-溴-3-氟丙烷为原料，合成得到白色固体标题化合物95(21mg,收率59％)。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.
LC-MS:m/z＝356.2[M+H]+(99.17％purity,220nm)LC-MS: m/z = 356.2 [M+H] + (99.17% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),8.19-8.11(m,2H),7.51(d,J＝8.0Hz,1H),7.38(t,J＝8.8Hz,2H),7.15(d,J＝6.8Hz,1H),7.00(t,J＝7.6Hz,1H),4.87(t,J＝7.2Hz,2H),4.64(t,J＝ 5.6Hz,1H),4.52(t,J＝5.6Hz,1H),2.44-2.20(m,3H),1.09-1.01(m,2H),0.89-0.82(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.79 (s, 1H), 8.19-8.11 (m, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 8.8 Hz, 2H), 7.15 (d, J = 6.8 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 4.87 (t, J = 7.2 Hz, 2H), 4.64 (t, J = 5.6 Hz, 1H), 4.52 (t, J = 5.6 Hz, 1H), 2.44-2.20 (m, 3H), 1.09-1.01 (m, 2H), 0.89-0.82 (m, 2H).
实施例96Embodiment 96
N-(1-(丁-2-炔-1-基)-7-环丙基-1H-吲唑-3-基)-4-氟苯甲酰胺96
N-(1-(But-2-yn-1-yl)-7-cyclopropyl-1H-indazol-3-yl)-4-fluorobenzamide 96
参考实施例72的合成方法，以化合物34b和1-溴-2-丁炔为原料，合成得到白色固体标题化合物96(10mg,收率29％)。With reference to the synthesis method of Example 72, compound 34b and 1-bromo-2-butyne were used as raw materials to synthesize the title compound 96 (10 mg, yield 29%) as a white solid.
LC-MS:m/z＝348.2[M+H]+(99.43％purity,254nm)LC-MS: m/z = 348.2 [M+H] + (99.43% purity, 254 nm)
1H NMR(400MHz,DMSO-d6)δ10.86(s,1H),8.19-8.12(m,2H),7.51(d,J＝8.0Hz,1H),7.39(t,J＝9.2Hz,2H),7.15(d,J＝7.2Hz,1H),7.03(t,J＝7.6Hz,1H),5.50(d,J＝2.4Hz,2H),2.48-2.45(m,1H),1.77(t,J＝2.0Hz,3H),1.11-1.03(m,2H),0.91-0.83(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.86 (s, 1H), 8.19-8.12 (m, 2H), 7.51 (d, J=8.0 Hz, 1H), 7.39 (t, J=9.2 Hz, 2H), 7.15 (d, J=7.2 Hz, 1H), 7.03 (t, J=7.6 Hz, 1H), 5.50 (d, J=2.4 Hz, 2H), 2.48-2.45 (m, 1H), 1.77 (t, J=2.0 Hz, 3H), 1.11-1.03 (m, 2H), 0.91-0.83 (m, 2H).
实施例97Embodiment 97
N-(7-环丙基-1-(2-羟乙基)-1H-吲唑-3-基)-4-氟苯甲酰胺97
N-(7-cyclopropyl-1-(2-hydroxyethyl)-1H-indazol-3-yl)-4-fluorobenzamide 97
第一步N-(1-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-7-环丙基-1H-吲唑-3-基)-4-氟苯甲酰胺97aStep 1 N-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-cyclopropyl-1H-indazol-3-yl)-4-fluorobenzamide 97a
参照实施例34的第三步的方法合成得到黄色固体标题化合物97a(97mg,收率63％)。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.
LC-MS:m/z＝454.3[M+H]+ LC-MS: m/z = 454.3 [M + H] +
第二步N-(7-环丙基-1-(2-羟乙基)-1H-吲唑-3-基)-4-氟苯甲酰胺97Step 2 N-(7-cyclopropyl-1-(2-hydroxyethyl)-1H-indazol-3-yl)-4-fluorobenzamide 97
将化合物97a(110mg,0.24mmol)溶于1,4-二氧六环(2mL)中，冷却至0℃，加入氯化氢1,4-二氧六环溶液(4M,1mL)，加毕，升温至室温反应3小时，TLC(PE:EA＝1:1,Rf＝0.1)检测反应已完成。滴加饱和碳酸氢钠水溶液调节pH＝8，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，打浆，过滤，收集滤饼，干燥得白色固体标题化合物97(81mg,收率99％)。Compound 97a (110 mg, 0.24 mmol) was dissolved in 1,4-dioxane (2 mL), cooled to 0°C, and a 1,4-dioxane hydrogen chloride solution (4 M, 1 mL) was added. After the addition was complete, the mixture was heated to room temperature for 3 hours. TLC (PE:EA=1:1, R f =0.1) detected that the reaction was complete. Saturated sodium bicarbonate aqueous solution was added dropwise to adjust the pH to 8, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, slurried, filtered, and the filter cake was collected and dried to obtain the title compound 97 (81 mg, yield 99%) as a white solid.
LC-MS:m/z＝340.2[M+H]+(99.39％purity,210nm)LC-MS: m/z = 340.2 [M + H] + (99.39% purity, 210 nm)
1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),8.19-8.10(m,2H),7.48(d,J＝8.4Hz,1H),7.38(t,J＝8.9Hz,2H),7.11(d,J＝7.2Hz,1H),7.00-6.94(m,1H),4.96(t,J＝5.2Hz,1H),4.81(t,J＝6.4Hz,2H),3.85(q,J＝6.0Hz,2H),2.57-2.53(m,1H),1.07-1.00(m,2H),0.88-0.80(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.79 (s, 1H), 8.19-8.10 (m, 2H), 7.48 (d, J=8.4 Hz, 1H), 7.38 (t, J=8.9 Hz, 2H), 7.11 (d, J=7.2 Hz, 1H), 7.00-6.94 (m, 1H), 4.96 (t, J=5.2 Hz, 1H), 4.81 (t, J=6.4 Hz, 2H), 3.85 (q, J=6.0 Hz, 2H), 2.57-2.53 (m, 1H), 1.07-1.00 (m, 2H), 0.88-0.80 (m, 2H).
实施例98Embodiment 98
N-(7-环丙基-1-(2-(二氟甲氧基)乙基)-1H-吲唑-3-基)-4-氟苯甲酰胺98
N-(7-cyclopropyl-1-(2-(difluoromethoxy)ethyl)-1H-indazol-3-yl)-4-fluorobenzamide 98
第一步N-(7-环丙基-1-(2-(二氟甲氧基)乙基)-1H-吲唑-3-基)-4-氟苯甲酰胺98Step 1 N-(7-cyclopropyl-1-(2-(difluoromethoxy)ethyl)-1H-indazol-3-yl)-4-fluorobenzamide 98
将化合物97(30mg,0.09mmol)溶于乙腈(2mL)中，加入碘化亚铜(8mg,0.04mmol)和氟磺酰基二氟乙酸甲酯(68mg,0.35mmol)，加毕，氮气保护，微波加热至100℃反应30分钟，TLC(PE:EA＝1:1,Rf＝0.6)检测反应已完成。将冷却，倒入水中，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经Prep-TLC(PE:EA＝3:1)纯化得淡黄色固体标题化合物98(9mg,收率26％)。Compound 97 (30 mg, 0.09 mmol) was dissolved in acetonitrile (2 mL), and cuprous iodide (8 mg, 0.04 mmol) and methyl fluorosulfonyl difluoroacetate (68 mg, 0.35 mmol) were added. After the addition was completed, the mixture was protected by nitrogen and heated to 100°C in a microwave oven for 30 minutes. The reaction was completed as detected by TLC (PE:EA＝1:1, R f ＝0.6). The mixture was cooled, poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC (PE:EA＝3:1) to obtain the title compound 98 (9 mg, yield 26%) as a light yellow solid.
LC-MS:m/z＝390.2[M+H]+(95.26％purity,220nm)LC-MS: m/z = 390.2 [M+H] + (95.26% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),8.18(s,1H),8.17-8.11(m,2H),7.50(d,J＝8.0Hz,1H),7.43-7.33(m,2H),7.16(d,J＝7.2Hz,1H),7.04-6.97(m,1H),5.05(t,J＝5.2Hz,2H),4.59(t,J＝5.6Hz,2H),2.44-2.34(m,1H),1.09-1.01(m,2H),0.89-0.81(m,2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.82 (s, 1H), 8.18 (s, 1H), 8.17-8.11 (m, 2H), 7.50 (d, J = 8.0 Hz, 1H), 7.43-7.33 (m, 2H), 7.16 (d, J = 7.2 Hz, 1H), 7.04-6.97 (m, 1H), 5.05 (t, J = 5.2 Hz, 2H), 4.59 (t, J = 5.6 Hz, 2H), 2.44-2.34 (m, 1H), 1.09-1.01 (m, 2H), 0.89-0.81 (m, 2H)
实施例99Embodiment 99
N-(7-环丙基-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-2,4-二氟苯甲酰胺99
N-(7-cyclopropyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-2,4-difluorobenzamide 99
第一步2,4-二氟苯甲酰氯99bStep 1 2,4-Difluorobenzoyl chloride 99b
将2,4-二氟苯甲酸99a(150mg,0.95mmol)溶解于二氯甲烷(3mL)中，加入催化量N,N-二甲基甲酰胺(1滴)，冷却至0℃，滴入草酰氯(242mg,1.91mmol)，升至室温搅拌2小时，TLC显示原料反应完全，浓缩，得无色油状物标题化合物99b(165mg,收率98％)。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.
第二步N-(7-环丙基-1H-吲唑-3-基)-2,4-二氟苯甲酰胺99cStep 2 N-(7-cyclopropyl-1H-indazol-3-yl)-2,4-difluorobenzamide 99c
参照实施例34的第二步的方法合成得到白色固体标题化合物99c(140mg,收率86％)。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.
第三步N-(7-环丙基-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-2,4-二氟苯甲酰胺99Step 3 N-(7-cyclopropyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-2,4-difluorobenzamide 99
参照实施例72的方法合成得到白色固体标题化合物99(13mg,收率19％)。The title compound 99 (13 mg, yield 19%) was synthesized as a white solid by referring to the method of Example 72.
LC-MS:m/z＝352.1[M+H]+(96.39％purity,210nm)LC-MS: m/z = 352.1 [M+H] + (96.39% purity, 210 nm)
1H NMR(400MHz,CD3OD)δ7.92(dd,J＝15.2,8.0Hz,1H),7.64(d,J＝8.0Hz,1H),7.21(d,J＝7.2Hz,1H),7.19-7.11(m,2H),7.11-7.06(m,1H),5.57(d,J＝1.6Hz,2H),2.83(t,J＝2.4Hz,1H),2.57-2.48(m,1H),1.13-1.06(m,2H),0.92-0.86(m,2H). 1 H NMR (400 MHz, CD 3 OD) δ7.92 (dd, J=15.2, 8.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.21 (d, J=7.2 Hz, 1H), 7.19-7.11 (m, 2H), 7.11-7.06 (m, 1H), 5.57 (d, J=1.6 Hz, 2H), 2.83 (t, J=2.4 Hz, 1H), 2.57-2.48 (m, 1H), 1.13-1.06 (m, 2H), 0.92-0.86 (m, 2H).
实施例100Embodiment 100
N-(7-环丙基-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-3,4-二氟苯甲酰胺100
N-(7-cyclopropyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-3,4-difluorobenzamide 100
参考实施例99的合成方法，以3,4-二氟苯甲酸119a为原料，合成得到白色固体标题化合物 100(18mg,收率27％)。Referring to the synthesis method of Example 99, 3,4-difluorobenzoic acid 119a was used as the raw material to synthesize the title compound as a white solid 100 (18 mg, yield 27%).
LC-MS:m/z＝352.2[M+H]+(98.92％purity,220nm)LC-MS: m/z = 352.2 [M+H] + (98.92% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),8.17-8.10(m,1H),8.01-7.95(m,1H),7.69-7.60(m,1H),7.53(d,J＝8.0Hz,1H),7.17(d,J＝7.2Hz,1H),7.07-7.02(m,1H),5.56(d,J＝2.0Hz,2H),3.44(t,J＝2.4Hz,1H),2.49-2.44(m,1H),1.11-1.05(m,2H),0.89-0.84(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.98 (s, 1H), 8.17-8.10 (m, 1H), 8.01-7.95 (m, 1H), 7.69-7.60 (m, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.17 (d, J=7.2 Hz, 1H), 7.07-7.02 (m, 1H), 5.56 (d, J=2.0 Hz, 2H), 3.44 (t, J=2.4 Hz, 1H), 2.49-2.44 (m, 1H), 1.11-1.05 (m, 2H), 0.89-0.84 (m, 2H).
实施例101Embodiment 101
4-氟-N-(7-(1-甲基环丙基)-1-(丙-2-炔-1-基)-1H-吲唑-3-基)苯甲酰胺101
4-Fluoro-N-(7-(1-methylcyclopropyl)-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)benzamide 101
第一步7-(丙-1-烯-2-基)-1H-吲唑-3-胺101aFirst step 7-(Propan-1-en-2-yl)-1H-indazol-3-amine 101a
7-溴-1H-吲唑-3-胺12a(300mg,1.41mmol)溶解于1,4-二氧六环(10mL)和水(2mL)，依次加入异丙烯三氟硼酸钾(313mg,2.12mmol)，碳酸钠(373mg,3.52mmol)和Pd(dppf)Cl2二氯甲烷络合物(58mg,0.07mmol)，氮气保护下，加热至100℃搅拌16小时，TLC(PE:EA＝1:1,Rf＝0.2)显示原料反应完全，冷却，硅藻土过滤，乙酸乙酯(10mL)洗，加水(20mL)，乙酸乙酯萃取(10mL x3)，饱和食盐水(20mL x3)洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(PE:EA＝3:1-1:2)纯化得棕色油状标题化合物101a(220mg,收率90％)。7-Bromo-1H-indazol-3-amine 12a (300 mg, 1.41 mmol) was dissolved in 1,4-dioxane (10 mL) and water (2 mL). Potassium isopropylene trifluoroborate (313 mg, 2.12 mmol), sodium carbonate (373 mg, 3.52 mmol) and Pd(dppf)Cl 2 dichloromethane complex (58 mg, 0.07 mmol) were added in sequence. Under nitrogen protection, the mixture was heated to 100 °C and stirred for 16 hours. TLC (PE:EA＝1:1, R f ＝0.2) showed that the raw material was completely reacted. The mixture was cooled, filtered through celite, washed with ethyl acetate (10 mL), added with water (20 mL), extracted with ethyl acetate (10 mL x 3), and then heated to saturated brine (20 mL). x3), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (PE:EA＝3:1-1:2) to obtain the title compound 101a (220 mg, yield 90%) as a brown oil.
LC-MS:m/z＝174.2[M+H]+ LC-MS: m/z = 174.2 [M + H] +
第二步3-(双(叔丁氧基羰基)氨基)-7-(丙-1-烯-2-基)-1H-吲唑-1-羧酸叔丁酯101bStep 2 3-(bis(tert-butoxycarbonyl)amino)-7-(prop-1-en-2-yl)-1H-indazole-1-carboxylic acid tert-butyl ester 101b
将化合物101a(1.00g,5.77mmol)溶解于四氢呋喃(20mL)中，加入4-二甲氨基吡啶(0.14g,1.15mmol)，冷却至0℃，滴加二碳酸二叔丁酯(6.30g,28.85mmol)，升至室温搅拌16小时后，TLC(PE:EA＝10:1,Rf＝0.3)显示原料反应完全，加水(10mL)淬灭，乙酸乙酯萃取(10mL x3)，饱和食盐水(20mL x3)洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(PE:EA＝10:1)纯化得淡黄色固体标题化合物101b(1.63g,收率60％)。Compound 101a (1.00 g, 5.77 mmol) was dissolved in tetrahydrofuran (20 mL), 4-dimethylaminopyridine (0.14 g, 1.15 mmol) was added, and the mixture was cooled to 0°C. Di-tert-butyl dicarbonate (6.30 g, 28.85 mmol) was added dropwise. The mixture was heated to room temperature and stirred for 16 hours. TLC (PE:EA＝10:1, R f ＝0.3) showed that the reaction of the starting material was complete. The mixture was quenched by adding water (10 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (PE:EA＝10:1) to obtain the title compound 101b (1.63 g, yield 60%) as a light yellow solid.
LC-MS:m/z＝218.1[M-255]+ LC-MS: m/z = 218.1 [M-255] +
第三步(7-(1-甲基环丙基)-1H-吲唑-3-基)氨基甲酸叔丁酯101cStep 3: tert-Butyl (7-(1-methylcyclopropyl)-1H-indazol-3-yl)carbamate 101c
将化合物101b(0.90g,1.90mmol)溶解于无水1,2-二氯乙烷(5mL)中，冷却至0℃，滴加二乙基锌(38.0mL,1.0M in四氢呋喃)，在此温度搅拌30分钟后，滴加二碘甲烷(2.54g,9.50mmol)，加毕，升至室温搅拌16小时，TLC(PE:EA＝2:1,Rf＝0.4)显示原料反应完全，将反应液缓慢滴入饱和氯化铵水溶液(30mL)中淬灭，乙酸乙酯萃取(20mL x3)，饱和食盐水(30mL x3)洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(PE:EA＝10:1)纯化得淡黄色固体标题化合物101c(258mg,收率35％)。Compound 101b (0.90 g, 1.90 mmol) was dissolved in anhydrous 1,2-dichloroethane (5 mL), cooled to 0°C, and diethylzinc (38.0 mL, 1.0 M in tetrahydrofuran) was added dropwise. After stirring at this temperature for 30 minutes, diiodomethane (2.54 g, 9.50 mmol) was added dropwise. After the addition was complete, the mixture was heated to room temperature and stirred for 16 hours. TLC (PE:EA＝2:1, R f ＝0.4) showed that the reaction of the raw materials was complete. The 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. The crude product was purified by silica gel column chromatography (PE:EA＝10:1) to obtain the title compound 101c (258 mg, yield 35%) as a light yellow solid.
LC-MS:m/z＝288.1[M+H]+ LC-MS: m/z = 288.1 [M + H] +
第四步7-(1-甲基环丙基)-1H-吲唑-3-胺101dStep 4 7-(1-methylcyclopropyl)-1H-indazole-3-amine 101d
参照实施例27第四步的方法合成得到化合物101d(165mg,收率98％)。Compound 101d (165 mg, yield 98%) was synthesized by referring to the method of step 4 of Example 27.
LC-MS:m/z＝188.2[M+H]+ LC-MS: m/z = 188.2 [M + H] +
第五步4-氟-N-(7-(1-甲基环丙基)-1H-吲唑-3-基)苯甲酰胺101e Step 5: 4-Fluoro-N-(7-(1-methylcyclopropyl)-1H-indazol-3-yl)benzamide 101e
参照实施例34的第二步的方法合成得白色固体标题化合物101e(84mg,收率31％)。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.
LC-MS:m/z＝310.2[M+H]+ LC-MS: m/z = 310.2 [M + H] +
第六步N-(7-(二氟甲基)-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺101Step 6 N-(7-(difluoromethyl)-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 101
参照实施例72的方法合成纯化得白色固体标题化合物101(18mg,收率19％)。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.
LC-MS:m/z＝348.2[M+H]+(99.38％purity,220nm)LC-MS: m/z = 348.2 [M + H] + (99.38% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.19-8.12(m,2H),7.54(d,J＝8.0Hz,1H),7.38(t,J＝8.8Hz,3H),7.07(t,J＝8.0Hz,1H),5.54(s,2H),3.41-3.38(m,1H),1.50(s,3H),1.11-0.90(m,4H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.91 (s, 1H), 8.19-8.12 (m, 2H), 7.54 (d, J=8.0 Hz, 1H), 7.38 (t, J=8.8 Hz, 3H), 7.07 (t, J=8.0 Hz, 1H), 5.54 (s, 2H), 3.41-3.38 (m, 1H), 1.50 (s, 3H), 1.11-0.90 (m, 4H).
实施例102Embodiment 102
N-(7-(二氟甲氧基)-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺102
N-(7-(difluoromethoxy)-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 102
第一步1-溴-3-(二氟甲氧基)-2-氟苯102bStep 1-Bromo-3-(difluoromethoxy)-2-fluorobenzene 102b
将化合物3-溴-2-氟苯酚102a(1.3g,6.81mmol)溶于N,N-二甲基甲酰胺(20mL)中，室温加入二氟氯乙酸钠(2.0g,13.12mmol)和碳酸铯(4.4g,13.50mmol)，加毕，反应液加热至80℃反应2小时，TLC(PE/EA＝10/1,Rf＝0.6)检测原料反应完全。冷却，加水(160mL)稀释，乙酸乙酯萃取(50mL x2)，饱和食盐水(50mL)洗，无水硫酸钠干燥，浓缩得淡黄色油状标题化合物102b(1.58g,收率96％)。Compound 3-bromo-2-fluorophenol 102a (1.3 g, 6.81 mmol) was dissolved in N,N-dimethylformamide (20 mL), and sodium difluorochloroacetate (2.0 g, 13.12 mmol) and cesium carbonate (4.4 g, 13.50 mmol) were added at room temperature. After the addition, the reaction solution was heated to 80°C for 2 hours. TLC (PE/EA=10/1, R f =0.6) detected that the raw material had reacted completely. Cool, dilute with water (160 mL), extract with ethyl acetate (50 mL x 2), wash with saturated brine (50 mL), dry with anhydrous sodium sulfate, and concentrate to obtain the title compound 102b (1.58 g, yield 96%) as a light yellow oil.
1H NMR(400MHz,CDCl3)δ7.46-7.39(m,1H),7.21(t,J＝7.6Hz,1H),7.03(td,J＝8.4,1.2Hz,1H),6.56(t,J＝72.8,1H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.46-7.39 (m, 1H), 7.21 (t, J=7.6 Hz, 1H), 7.03 (td, J=8.4, 1.2 Hz, 1H), 6.56 (t, J=72.8, 1H).
第二步3-(二氟甲氧基)-2-氟苯腈102cStep 2 3-(Difluoromethoxy)-2-fluorobenzonitrile 102c
参照实施例82的合成方法合成得到化合物102c,(901mg,收率73％)。Compound 102c was synthesized by referring to the synthesis method of Example 82 (901 mg, yield 73%).
第三步7-(二氟甲氧基)-1H-吲唑-3-胺102dStep 3 7-(Difluoromethoxy)-1H-indazol-3-amine 102d
参照实施例92的第四步的方法合成得到淡黄色油状标题化合物102d(736mg,收率77％)。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.
LC-MS:m/z＝200.1[M+H]+ LC-MS: m/z = 200.1 [M + H] +
第四步N-(7-(二氟甲氧基)-1H-吲唑-3-基)-4-氟苯甲酰胺102eStep 4: N-(7-(difluoromethoxy)-1H-indazol-3-yl)-4-fluorobenzamide 102e
参照实施例34的第二步的方法合成得到黄色固体标题化合物102e(405mg,收率84％)。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.
LC-MS:m/z＝322.1[M+H]+ LC-MS: m/z = 322.1 [M + H] +
第五步N-(7-(二氟甲氧基)-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺102Step 5: N-(7-(difluoromethoxy)-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 102
参照实施例72的方法合成得到淡黄色固体标题化合物102(38mg,换算得收率29％)。The title compound 102 (38 mg, yield 29%) was synthesized as a pale yellow solid by referring to the method of Example 72.
LC-MS:m/z＝360.1[M+H]+(99.64％purity,254nm)LC-MS: m/z = 360.1 [M+H] + (99.64% purity, 254 nm)
1H NMR(400MHz,DMSO-d6)δ11.02(s,1H),8.16(dd,J＝8.8,5.6Hz,2H),7.59(d,J＝8.4Hz,1H),7.43(t,J＝73.2Hz,1H),7.39(t,J＝8.8Hz,2H),7.27-7.22(m,1H),7.16(t,J＝8.0Hz,1H),5.31(d,J＝2.0Hz,2H),3.42-3.38(m,1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.02 (s, 1H), 8.16 (dd, J=8.8, 5.6 Hz, 2H), 7.59 (d, J=8.4 Hz, 1H), 7.43 (t, J=73.2 Hz, 1H), 7.39 (t, J=8.8 Hz, 2H), 7.27-7.22 (m, 1H), 7.16 (t, J=8.0 Hz, 1H), 5.31 (d, J=2.0 Hz, 2H), 3.42-3.38 (m, 1H).
实施例103 Embodiment 103
4-氟-N-(7-甲氧基-1-(丙-2-炔-1-基)-1H-吲唑-3-基)苯甲酰胺103
4-Fluoro-N-(7-methoxy-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)benzamide 103
第一步7-甲氧基1H吲唑-3-胺103bStep 1 7-Methoxy 1H-indazol-3-amine 103b
参照实施例92的第四步的方法合成得到黄色发泡状标题化合物103b(231mg,收率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.
LC-MS:m/z＝164.1[M+H]+ LC-MS: m/z = 164.1 [M + H] +
第二步4-氟-N-(7-甲氧基-1H-吲唑-3-基)苯甲酰胺103cStep 2 4-Fluoro-N-(7-methoxy-1H-indazol-3-yl)benzamide 103c
参照实施例34的第二步的方法合成得到白色固体标题化合物103c(146mg,收率69％)。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.
LC-MS:m/z＝286.1[M+H]+ LC-MS: m/z = 286.1 [M + H] +
第三步4-氟-N-(7-甲氧基-1-(丙-2-炔-1-基)-1H-吲唑-3-基)苯甲酰胺103Step 3 4-Fluoro-N-(7-methoxy-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)benzamide 103
参照实施例72的方法合成得白色固体标题化合物103(49mg,收率72％)。The title compound 103 (49 mg, yield 72%) was synthesized as a white solid by referring to the method of Example 72.
LC-MS:m/z＝324.1[M+H]+(94.35％purity,210nm)LC-MS: m/z = 324.1 [M+H] + (94.35% purity, 210 nm)
1H NMR(400MHz,DMSO-d6)δ10.88(s,1H),8.19-8.10(m,2H),7.38(t,J＝9.2Hz,2H),7.24(d,J＝8.0Hz,1H),7.05(t,J＝7.6Hz,1H),6.93(d,J＝7.6Hz,1H),5.36(d,J＝2.4Hz,2H),3.98(s,3H),3.37-3.34(m,1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.88 (s, 1H), 8.19-8.10 (m, 2H), 7.38 (t, J=9.2 Hz, 2H), 7.24 (d, J=8.0 Hz, 1H), 7.05 (t, J=7.6 Hz, 1H), 6.93 (d, J=7.6 Hz, 1H), 5.36 (d, J=2.4 Hz, 2H), 3.98 (s, 3H), 3.37-3.34 (m, 1H).
实施例104Embodiment 104
4-氟-N-(7-异丙基-1-(丙-2-炔-1-基)-1H-吲唑-3-基)苯甲酰胺104
4-Fluoro-N-(7-isopropyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)benzamide 104
第一步7-异丙基-1H-吲唑-3-胺104aFirst step 7-isopropyl-1H-indazol-3-amine 104a
参照实施例1的第一步合成方法合成得到棕色固体标题化合物104a(140mg,收率87％)。The title compound 104a (140 mg, yield 87%) was synthesized as a brown solid by referring to the first step of the synthesis method in Example 1.
LC-MS:m/z＝176.2[M+H]+ LC-MS: m/z = 176.2 [M + H] +
第二步4-氟-N-(7-异丙基-1H-吲唑-3-基)苯甲酰胺104bStep 2 4-Fluoro-N-(7-isopropyl-1H-indazol-3-yl)benzamide 104b
参照实施例34的第二步的方法合成得到白色固体标题化合物104b(81mg,收率80％)。The title compound 104b (81 mg, yield 80%) was synthesized as a white solid by referring to the method of the second step of Example 34.
LC-MS:m/z＝298.2[M+H]+ LC-MS: m/z = 298.2 [M + H] +
第三步4-氟-N-(7-异丙基-1-(丙-2-炔-1-基)-1H-吲唑-3-基)苯甲酰胺104Step 3 4-Fluoro-N-(7-isopropyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)benzamide 104
参照实施例72的方法合成得白色固体标题化合物104(15mg,收率17％)。The title compound 104 (15 mg, yield 17%) was synthesized as a white solid by referring to the method of Example 72.
LC-MS:m/z＝336.2[M+H]+(94.17％purity,220nm)LC-MS: m/z = 336.2 [M+H] + (94.17% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.18-8.12(m,2H),7.51(d,J＝8.0Hz,1H),7.41-7.35(m,3H),7.14(t,J＝7.6Hz,1H),5.34(d,J＝2.4Hz,2H),3.78-3.70(m,1H),3.47(t,J＝2.0Hz,1H),1.38(d,J＝6.8Hz,6H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.83 (s, 1H), 8.18-8.12 (m, 2H), 7.51 (d, J=8.0 Hz, 1H), 7.41-7.35 (m, 3H), 7.14 (t, J=7.6 Hz, 1H), 5.34 (d, J=2.4 Hz, 2H), 3.78-3.70 (m, 1H), 3.47 (t, J=2.0 Hz, 1H), 1.38 (d, J=6.8 Hz, 6H).
实施例105Embodiment 105
N-(7-(二氟甲基)-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺105
N-(7-(Difluoromethyl)-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 105
第一步2-氟-3-甲酰基苄腈105bStep 1: 2-Fluoro-3-formylbenzonitrile 105b
将3-溴-2氟苯腈105a(1.00g,5.00mmol)溶解于无水四氢呋喃(15mL)中，冷却至0℃，滴入异丙基溴化镁(3.0mL,6.00mmol,2.0M in四氢呋喃)，滴毕，升至室温搅拌1小时后，冷却至0℃，滴入DMF(1.09g,14.95mmol)，升至室温搅拌3小时，TLC(PE:EA＝20:1,Rf＝0.2)显示原料反应完全，反应液冷却至0℃，加饱和氯化铵水溶液(20mL)淬灭，乙酸乙酯萃取(10mL x3)，饱和食盐水(20mL x 3)洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(PE:EA＝50:1-20:1)纯化得淡黄色固体标题化合物105b(616mg,收率83％)。3-Bromo-2-fluorobenzonitrile 105a (1.00 g, 5.00 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), cooled to 0°C, and isopropylmagnesium bromide (3.0 mL, 6.00 mmol, 2.0 M in tetrahydrofuran) was added dropwise. After the mixture was heated to room temperature and stirred for 1 hour, it was cooled to 0°C and DMF (1.09 g, 14.95 mmol) was added dropwise. The mixture was heated to room temperature and stirred for 3 hours. TLC (PE:EA=20:1, Rf =0.2) showed that the reaction of the raw materials was complete. The reaction solution was cooled to 0°C, quenched with saturated aqueous ammonium chloride solution (20 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (PE:EA=50:1-20:1) to obtain the title compound 105b (616 mg, yield 83%) as a light yellow solid.
1H NMR(400MHz,CDCl3)δ10.39(s,1H),8.17-8.11(m,1H),7.94-7.88(m,1H),7.45(t,J＝7.6Hz,1H). 1 H NMR (400 MHz, CDCl 3 ) δ 10.39 (s, 1H), 8.17-8.11 (m, 1H), 7.94-7.88 (m, 1H), 7.45 (t, J＝7.6 Hz, 1H).
第二步3-(二氟甲基)-2-氟苯腈105cStep 2 3-(Difluoromethyl)-2-fluorobenzonitrile 105c
将化合物105b(313mg,2.10mmol)溶解于二氯甲烷(5mL)中，冷却至0℃，滴入二乙胺基三氟化硫(1692mg,10.50mmol)，升至室温搅拌3小时，TLC(PE:EA＝20:1,Rf＝0.3)显示原料反应完全，反应液冷却至0℃，将反应液缓慢滴加至饱和碳酸钠水溶液(30mL)中淬灭，乙酸乙酯萃取(10mL x3)，饱和食盐水(20mL x 3)洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(PE:EA＝20:1)纯化得无色油状标题化合物105c(260mg,收率72％)。Compound 105b (313 mg, 2.10 mmol) was dissolved in dichloromethane (5 mL), cooled to 0°C, and diethylaminosulfur trifluoride (1692 mg, 10.50 mmol) was added dropwise. The mixture was heated to room temperature and stirred for 3 hours. TLC (PE:EA=20:1, Rf =0.3) showed that the reaction of the starting materials was complete. The reaction solution was cooled to 0°C, and the reaction solution was slowly added dropwise to a saturated aqueous sodium carbonate solution (30 mL) for quenching. The mixture was extracted with ethyl acetate (10 mL x 3), washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (PE:EA=20:1) to obtain the title compound 105c (260 mg, yield 72%) as a colorless oil.
1H NMR(400MHz,CDCl3)δ7.88(t,J＝7.2Hz,1H),7.78(t,J＝6.8Hz,1H),7.41(t,J＝8.0Hz,1H),6.92(t,J＝54.4Hz,1H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.88 (t, J = 7.2 Hz, 1H), 7.78 (t, J = 6.8 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 6.92 (t, J = 54.4 Hz, 1H).
第三步7-(二氟甲基)-1H-吲唑-3-胺105dStep 3 7-(Difluoromethyl)-1H-indazol-3-amine 105d
参照实施例92的第四步的方法合成得到淡黄色固体标题化合物105d(235mg,收率84％)。The title compound 105d (235 mg, yield 84%) was synthesized by referring to the method of the fourth step of Example 92 as a light yellow solid.
LC-MS:m/z＝184.1[M+H]+ LC-MS: m/z = 184.1 [M + H] +
第四步N-(7-(二氟甲基)-1H-吲唑-3-基)-4-氟苯甲酰胺105eStep 4: N-(7-(Difluoromethyl)-1H-indazol-3-yl)-4-fluorobenzamide 105e
参照实施例34的第二步的方法合成得到白色固体标题化合物105e(126mg,收率75％)。The title compound 105e (126 mg, yield 75%) was synthesized as a white solid by referring to the method of the second step of Example 34.
LC-MS:m/z＝306.1[M+H]+ LC-MS: m/z = 306.1 [M + H] +
第五步N-(7-(二氟甲基)-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺105Step 5 N-(7-(difluoromethyl)-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 105
参照实施例72的方法合成纯化得白色固体标题化合物105(39mg,收率28％)。The title compound 105 (39 mg, yield 28%) was synthesized and purified by referring to the method of Example 72 to obtain a white solid.
LC-MS:m/z＝344.1[M+H]+(98.82％purity,254nm)LC-MS: m/z = 344.1 [M+H] + (98.82% purity, 254 nm)
1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),8.20-8.13(m,2H),7.94(d,J＝8.0Hz,1H),7.75(d,J＝7.2Hz,1H),7.66-7.37(m,3H),7.28(t,J＝7.6Hz,1H),5.33(d,J＝1.6Hz,2H),3.40(s,1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.04 (s, 1H), 8.20-8.13 (m, 2H), 7.94 (d, J=8.0 Hz, 1H), 7.75 (d, J=7.2 Hz, 1H), 7.66-7.37 (m, 3H), 7.28 (t, J=7.6 Hz, 1H), 5.33 (d, J=1.6 Hz, 2H), 3.40 (s, 1H).
实施例106Embodiment 106
N-(7-环丙基-5-氟-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺106
N-(7-cyclopropyl-5-fluoro-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 106
第一步2-环丙基-4-氟-6-甲基苯胺106bStep 1: 2-Cyclopropyl-4-fluoro-6-methylaniline 106b
将化合物2-溴-4-氟-6-甲基苯胺106a(500mg,2.45mmol)溶于1,4-二氧六环(10mL)和水(1mL)中，加入环丙基三氟硼酸钾(725mg,4.90mmol)、碳酸铯(2395mg,7.35mmol)和Pd(dppf)Cl2二氯甲烷络合物(40mg,0.05mmol)，加毕，氮气保护性加热至100℃反应16小时，TLC(PE:EA＝4:1,Rf＝0.3)检测反应已完成。冷却，加水稀释，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥， 浓缩，粗品经硅胶柱层析(PE:EA＝30:1-20:1-15:1)纯化得黄色油状标题化合物106b(352mg,收率87％)。Compound 2-bromo-4-fluoro-6-methylaniline 106a (500 mg, 2.45 mmol) was dissolved in 1,4-dioxane (10 mL) and water (1 mL), and potassium cyclopropyl trifluoroborate (725 mg, 4.90 mmol), cesium carbonate (2395 mg, 7.35 mmol) and Pd(dppf)Cl 2 dichloromethane complex (40 mg, 0.05 mmol) were added. After addition, the mixture was heated to 100°C under nitrogen protection for 16 hours. TLC (PE:EA=4:1, R f =0.3) detected that the reaction was complete. Cool, dilute with water, extract with ethyl acetate, wash with saturated brine, and dry over anhydrous sodium sulfate. After concentration, the crude product was purified by silica gel column chromatography (PE:EA＝30:1-20:1-15:1) to give the title compound 106b (352 mg, yield 87%) as a yellow oil.
LC-MS:m/z＝166.1[M+H]+ LC-MS: m/z = 166.1 [M + H] +
第二步7-环丙基-5-氟-1H-吲唑106cStep 2 7-Cyclopropyl-5-fluoro-1H-indazole 106c
将化合物106b(350mg,2.12mmol)溶于醋酸(2mL)和水(1mL)中，冷却至0℃加入亚硝酸钠(175mg,2.54mmol)，加毕，升至室温反应1小时，TLC(PE:EA＝4:1,Rf＝0.2)检测反应已完成，将反应液浓缩，粗品经过硅胶柱层析(PE:EA＝20:1-10:1-5:1)纯化得黄色固体标题化合物106c(245mg,收率66％)。Compound 106b (350 mg, 2.12 mmol) was dissolved in acetic acid (2 mL) and water (1 mL), cooled to 0°C, and sodium nitrite (175 mg, 2.54 mmol) was added. After the addition was completed, the temperature was raised to room temperature and reacted for 1 hour. The reaction was completed as detected by TLC (PE:EA＝4:1, R f ＝0.2). The reaction solution was concentrated and the crude product was purified by silica gel column chromatography (PE:EA＝20:1-10:1-5:1) to obtain the title compound 106c (245 mg, yield 66%) as a yellow solid.
第三步7-环丙基-5-氟-3-碘-1H-吲唑106dStep 3 7-Cyclopropyl-5-fluoro-3-iodo-1H-indazole 106d
将化合物106c(195mg,1.11mmol)溶于DMF(2mL)中，加入碘(421mg,1.66mmol)和氢氧化钾(187mg,3.33mmol)，加毕，室温反应3小时，TLC检测，加水稀释，乙酸乙酯萃取，浓缩，粗品经硅胶柱层析(PE:EA＝20:1-10:1-8:1)纯化得黄色固体标题化合物106d(280mg,收率84％)。Compound 106c (195 mg, 1.11 mmol) was dissolved in DMF (2 mL), and iodine (421 mg, 1.66 mmol) and potassium hydroxide (187 mg, 3.33 mmol) were added. After the addition, the mixture was reacted at room temperature for 3 hours, and tested by TLC. The mixture was diluted with water, extracted with ethyl acetate, and concentrated. The crude product was purified by silica gel column chromatography (PE:EA=20:1-10:1-8:1) to obtain the title compound 106d (280 mg, yield 84%) as a yellow solid.
LC-MS:m/z＝303.0[M+H]+ LC-MS: m/z = 303.0 [M + H] +
第四步7-环丙基-5-氟-3-碘-1-(四氢2H-吡喃-2-基)-1H-吲唑106eStep 4: 7-cyclopropyl-5-fluoro-3-iodo-1-(tetrahydro 2H-pyran-2-yl)-1H-indazole 106e
将化合物106d(230mg,0.76mmol)溶于四氢呋喃(5mL)中，加入3,4-二氢-2H-吡喃(256mg,3.04mmol)和对甲苯磺酸(13mg,0.076mmol)，加毕，升温至80℃反应16小时，TLC(PE:EA＝4:1,Rf＝0.6)检测反应已完成，浓缩，粗品经硅胶柱层析纯化得白色固体标题化合物106e(174mg,收率59％)。Compound 106d (230 mg, 0.76 mmol) was dissolved in tetrahydrofuran (5 mL), and 3,4-dihydro-2H-pyran (256 mg, 3.04 mmol) and p-toluenesulfonic acid (13 mg, 0.076 mmol) were added. After the addition was completed, the temperature was raised to 80°C and the reaction was reacted for 16 hours. The reaction was completed as detected by TLC (PE:EA=4:1, R f =0.6). The mixture was concentrated and the crude product was purified by silica gel column chromatography to obtain the title compound 106e (174 mg, yield 59%) as a white solid.
第五步N-(7-环丙基-5-氟-1-(四氢2H-吡喃-2-基)-1H-吲唑-3-基)-4-氟苯甲酰胺106fStep 5 N-(7-cyclopropyl-5-fluoro-1-(tetrahydro 2H-pyran-2-yl)-1H-indazol-3-yl)-4-fluorobenzamide 106f
将化合物106e(160mg,0.41mmol)溶于甲苯(5mL)中，加入对氟苯甲酰胺(68mg,0.49mmol)、碳酸铯(401mg,1.23mmol)、XantPhos(47mg,0.08mmol)和Pd2(dba)3(38mg,0.04mmol)，加毕，氮气保护下升温至100℃反应16小时，TLC检测反应已完成。冷却，倒入水(30mL)中，乙酸乙酯萃取，浓缩，粗品经硅胶柱层析纯化得黄色固体标题化合物106f(68mg,收率42％)。Compound 106e (160 mg, 0.41 mmol) was dissolved in toluene (5 mL), and p-fluorobenzamide (68 mg, 0.49 mmol), cesium carbonate (401 mg, 1.23 mmol), XantPhos (47 mg, 0.08 mmol) and Pd 2 (dba) 3 (38 mg, 0.04 mmol) were added. After the addition, the temperature was raised to 100°C under nitrogen protection for 16 hours. The reaction was completed by TLC. The mixture was cooled, poured into water (30 mL), extracted with ethyl acetate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 106f (68 mg, yield 42%) as a yellow solid.
LC-MS:m/z＝398.2[M+H]+ LC-MS: m/z = 398.2 [M + H] +
第六步N-(7-环丙基-5-氟-1H-吲唑-3-基)-4-氟苯甲酰胺106gStep 6: N-(7-cyclopropyl-5-fluoro-1H-indazol-3-yl)-4-fluorobenzamide 106 g
参照实施例27第四步的方法合成得到化合物106g(52mg,收率98％)。Referring to the method of the fourth step of Example 27, compound 106 g (52 mg, yield 98%) was synthesized.
第七步N-(7-环丙基-5-氟-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺106Step 7 N-(7-cyclopropyl-5-fluoro-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 106
参照实施例72的方法合成得到白色固体标题化合物106(12mg,收率21％)。The title compound 106 (12 mg, yield 21%) was synthesized as a white solid by referring to the method of Example 72.
LC-MS:m/z＝352.1[M+H]+(95.32％purity,220nm)LC-MS: m/z = 352.1 [M+H] + (95.32% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.19-8.10(m,2H),7.38(t,J＝8.8Hz,2H),7.30-7.23(m,1H),7.09-7.03(m,1H),5.53(s,2H),3.51-3.45(m,1H),2.48-2.46(m,1H),1.15-1.06(m,2H),0.96-0.89(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.91 (s, 1H), 8.19-8.10 (m, 2H), 7.38 (t, J=8.8 Hz, 2H), 7.30-7.23 (m, 1H), 7.09-7.03 (m, 1H), 5.53 (s, 2H), 3.51-3.45 (m, 1H), 2.48-2.46 (m, 1H), 1.15-1.06 (m, 2H), 0.96-0.89 (m, 2H).
实施例107Embodiment 107
N-(6-氯-7-环丙基-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺107
N-(6-chloro-7-cyclopropyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 107
第一步3-溴-4-氯-2-氟苯胺107bStep 1 3-Bromo-4-chloro-2-fluoroaniline 107b
将3-溴-2-氟苯胺107a(5.0g,26.31mmol)溶于N,N-二甲基甲酰胺(40mL)中，加入N-氯代丁二 酰亚胺(3.5g,26.31mmol)，加毕，反应液25℃反应3小时，TLC检测反应完全(石油醚:乙酸乙酯＝10:1,Rf＝0.5)。反应液加水稀释，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(石油醚:乙酸乙酯＝50:1)纯化得棕色油状物标题化合物107b(3.7g,收率63％)。3-Bromo-2-fluoroaniline 107a (5.0 g, 26.31 mmol) was dissolved in N,N-dimethylformamide (40 mL) and N-chlorobutanediol was added. After the addition of imide (3.5 g, 26.31 mmol), the reaction solution was reacted at 25°C for 3 hours. The reaction was complete when detected by TLC (petroleum ether:ethyl acetate = 10:1, R f = 0.5). The reaction solution was diluted with water, 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 (petroleum ether:ethyl acetate = 50:1) to obtain the title compound 107b (3.7 g, yield 63%) as a brown oil.
第二步3-溴-4-氯-2-氟苯甲腈107cStep 2 3-Bromo-4-chloro-2-fluorobenzonitrile 107c
将化合物107b(1.0g,4.46mmol)溶于二氯甲烷(20mL)中，加入四氟硼酸亚硝(794mg,6.68mmol)加毕，反应液25℃反应1小时，加入氰化亚铜(803mg,8.97mmol)和四氟硼酸铜(1.4g,8.97mmol)的水溶液(5mL)，加毕，反应液室温反应2小时，TLC检测反应完全(石油醚:乙酸乙酯＝20:1,Rf＝0.6)。反应液加水稀释，二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(石油醚:乙酸乙酯＝50:1)纯化得棕色固体标题化合物107c(429mg,收率41％)。Compound 107b (1.0 g, 4.46 mmol) was dissolved in dichloromethane (20 mL), and nitroso tetrafluoroborate (794 mg, 6.68 mmol) was added. The reaction solution was reacted at 25°C for 1 hour, and an aqueous solution (5 mL) of cuprous cyanide (803 mg, 8.97 mmol) and copper tetrafluoroborate (1.4 g, 8.97 mmol) was added. The reaction solution was reacted at room temperature for 2 hours. TLC detected that the reaction was complete (petroleum ether: ethyl acetate = 20:1, R f = 0.6). The reaction solution was diluted with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1) to obtain the title compound 107c (429 mg, yield 41%) as a brown solid.
第三步4-氯-3-环丙基-2-氟苯甲腈107dStep 3 4-Chloro-3-cyclopropyl-2-fluorobenzonitrile 107d
参照实施例12的第四步的方法合成得棕色油状物标题化合物107d(298mg,收率83％)The title compound 107d (298 mg, yield 83%) was synthesized as a brown oil by referring to the fourth step of Example 12.
第四步6-氯-7-环丙基-1H-吲唑-3-胺107eStep 4: 6-Chloro-7-cyclopropyl-1H-indazole-3-amine 107e
参照实施例92的第四步的方法合成得白色固体标题化合物107e(78mg,收率25％)The title compound 107e (78 mg, yield 25%) was synthesized as a white solid by referring to the fourth step of Example 92.
LC-MS:m/z＝208.1[M+H]+ LC-MS: m/z = 208.1 [M + H] +
第五步N-(6-氯-7-环丙基-1H-吲唑-3-基)-4-氟苯甲酰胺107fStep 5 N-(6-chloro-7-cyclopropyl-1H-indazol-3-yl)-4-fluorobenzamide 107f
参照实施例34的第二步的方法合成得到粉色粉末状固体标题化合物107f(92mg,收率74％)The title compound 107f (92 mg, yield 74%) was synthesized as a pink powdery solid by referring to the second step of Example 34.
LC-MS:m/z＝330.1[M+H]+ LC-MS: m/z = 330.1 [M + H] +
第五步N-(6-氯-7-环丙基-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺107Step 5 N-(6-chloro-7-cyclopropyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 107
参照实施例72的方法合成得白色粉末状固体标题化合物107(22mg,收率21％)。The title compound 107 (22 mg, yield 21%) was synthesized as a white powdery solid by referring to the method of Example 72.
LC-MS:m/z＝368.1[M+H]+(99.59％purity,220nm)LC-MS: m/z = 368.1 [M+H] + (99.59% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),10.83(s,1H),8.20-8.09(m,4H),7.58(d,J＝8.4Hz,1H),7.48-7.31(m,5H),7.17(d,J＝8.8Hz,1H),7.02(d,J＝8.8Hz,1H),5.53(d,J＝2.0Hz,2H),5.21(d,J＝2.4Hz,2H),3.47(t,J＝2.4Hz,1H),3.41-3.40(m,1H),2.42-2.31(m,1H),2.28-2.16(m,1H),1.70-1.61(m,2H),1.35-1.26(m,2H),1.08-1.00(m,2H),0.89-0.78(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.00 (s, 1H), 10.83 (s, 1H), 8.20-8.09 (m, 4H), 7.58 (d, J＝8.4 Hz, 1H), 7.48- 7.31 (m, 5H), 7.17 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 5.53 (d, J = 2.0 Hz, 2H), 5.21 (d, J =2.4 Hz, 2H), 3.47 (t, J = 2.4 Hz, 1H), 3.41-3.40 (m, 1H), 2.42-2.31 (m, 1H), 2.28-2.16 (m, 1H), 1.70-1.61 ( m, 2H), 1.35-1.26 (m, 2H), 1.08-1.00 (m, 2H), 0.89-0.78 (m, 2H).
实施例108Embodiment 108
N-(5-氯-7-环丙基-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺108
N-(5-chloro-7-cyclopropyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 108
第一步4-氯-2-环丙基-6-甲基苯胺108bStep 1: 4-Chloro-2-cyclopropyl-6-methylaniline 108b
将2-溴-4-氯-6-甲基苯胺108a(3.0g,13.60mmol)溶于1,4-二氧六环(40mL)和水(4mL)的混合溶液中，依次加入环丙基三氟硼酸钾(4.0g,27.21mmol)、碳酸铯(13.3g，40.81mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(220mg，0.27mmol)，加毕，氮气保护下反应液加热至100℃反应16小时，TLC检测反应完全(石油醚:乙酸乙酯＝5:1,Rf＝0.5)。冷却，加水(30mL)稀释，乙酸乙酯(50mL)萃取，饱和食盐水洗涤(30mL)，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(石油醚：乙酸乙酯＝15:1)纯化得棕色固体标题化合物108b(1.7g,收率69％)。2-Bromo-4-chloro-6-methylaniline 108a (3.0 g, 13.60 mmol) was dissolved in a mixed solution of 1,4-dioxane (40 mL) and water (4 mL), and potassium cyclopropyltrifluoroborate (4.0 g, 27.21 mmol), cesium carbonate (13.3 g, 40.81 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (220 mg, 0.27 mmol) were added in sequence. After the addition was completed, the reaction solution was heated to 100°C under nitrogen protection for 16 hours. The reaction was completed by TLC detection (petroleum ether:ethyl acetate = 5:1, R f = 0.5). The mixture was cooled, diluted with water (30 mL), extracted with ethyl acetate (50 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=15:1) to give the title compound 108b (1.7 g, yield 69%) as a brown solid.
LC-MS:m/z＝182.1[M+H]+ LC-MS: m/z = 182.1 [M + H] +
第二步5-氯-7-环丙基-1H-吲唑108c Step 2 5-Chloro-7-cyclopropyl-1H-indazole 108c
将化合物108b(1.2g,6.60mmol)溶于醋酸(10mL)中，缓慢分批加入亚硝酸钠(501mg，7.26mmol)，加毕，反应液在25℃反应1小时，TLC检测反应完全(石油醚:乙酸乙酯＝5:1,Rf＝0.3)。反应液直接浓缩得黄色固体标题化合物108c(1.7g,粗品)，直接投入下一步使用。Compound 108b (1.2 g, 6.60 mmol) was dissolved in acetic acid (10 mL), and sodium nitrite (501 mg, 7.26 mmol) was slowly added in batches. After the addition was completed, the reaction solution was reacted at 25°C for 1 hour. TLC detected that the reaction was complete (petroleum ether: ethyl acetate = 5:1, R f = 0.3). The reaction solution was directly concentrated to obtain the title compound 108c (1.7 g, crude product) as a yellow solid, which was directly used in the next step.
LC-MS:m/z＝193.1[M+H]+ LC-MS: m/z = 193.1 [M + H] +
第三步5-氯-7-环丙基-3-碘-1H-吲唑108dStep 3 5-Chloro-7-cyclopropyl-3-iodo-1H-indazole 108d
将化合物108c(1.7g,粗品)溶于N,N-二甲基甲酰胺(20mL)中，加入氢氧化钾(1.5g，26.47mmol)和碘(3.4g,13.23mmol)，加毕，反应液25℃反应1小时，TLC检测反应完全(石油醚:乙酸乙酯＝7:1,Rf＝0.5)。反应液加水(30mL)稀释，乙酸乙酯(50mL)萃取，饱和食盐水洗涤(30mL)，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(石油醚:乙酸乙酯＝25:1)纯化得黄色固体标题化合物108d(1.6g,两步收率76％)。Compound 108c (1.7 g, crude product) was dissolved in N,N-dimethylformamide (20 mL), potassium hydroxide (1.5 g, 26.47 mmol) and iodine (3.4 g, 13.23 mmol) were added, and the reaction solution was reacted at 25°C for 1 hour. TLC detected that the reaction was complete (petroleum ether: ethyl acetate = 7:1, R f = 0.5). The reaction solution was diluted with water (30 mL), extracted with ethyl acetate (50 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 25:1) to obtain the title compound 108d (1.6 g, two-step yield 76%) as a yellow solid.
LC-MS:m/z＝319.0[M+H]+ LC-MS: m/z = 319.0 [M + H] +
第四步5-氯-7-环丙基-3-碘-1-(四氢-2H-吡喃-2-基)-1H-吲唑108eStep 4: 5-chloro-7-cyclopropyl-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 108e
将化合物108d(1.36g,4.26mmol)溶于四氢呋喃(20mL)中，加入3,4-二氢-2H-吡喃(539mg,6.40mmol)和对甲基苯磺酸(74mg,0.43mmol)，加毕，反应液加热至80℃反应12小时，TLC检测反应完全(石油醚:乙酸乙酯＝10:1,Rf＝0.6)。冷却，加水(20mL)稀释，乙酸乙酯(40mL)萃取，饱和食盐水洗涤(30mL)，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(石油醚:乙酸乙酯＝25:1)纯化得黄色固体标题化合物108e(1.4g,收率58％)。Compound 108d (1.36 g, 4.26 mmol) was dissolved in tetrahydrofuran (20 mL), and 3,4-dihydro-2H-pyran (539 mg, 6.40 mmol) and p-toluenesulfonic acid (74 mg, 0.43 mmol) were added. After the addition, the reaction solution was heated to 80°C for 12 hours. The reaction was complete when detected by TLC (petroleum ether: ethyl acetate = 10:1, R f = 0.6). The mixture was cooled, diluted with water (20 mL), extracted with ethyl acetate (40 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 25:1) to obtain the title compound 108e (1.4 g, yield 58%) as a yellow solid.
第五步N-(5-氯-7-环丙基-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)-4-氟苯甲酰胺108fStep 5 N-(5-chloro-7-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-4-fluorobenzamide 108f
将化合物108e(360mg,0.89mmol)和对氟苯甲酰胺(149mg,1.07mmol)溶于干燥甲苯(10mL)中，依次加入碳酸铯(882mg,2.68mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(206mg，0.36mmol)、三(二亚苄基丙酮)二钯(164mg，0.18mmol)，加毕，氮气保护，反应液加热至100℃反应16小时，TLC检测反应完全(石油醚:乙酸乙酯＝3:1,Rf＝0.4)。冷却，加水(15mL)稀释，乙酸乙酯(30mL)萃取，饱和食盐水洗涤(20mL)，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(石油醚:乙酸乙酯＝3:1)纯化得白色固体标题化合物108f(293mg,收率79％)。Compound 108e (360 mg, 0.89 mmol) and p-fluorobenzamide (149 mg, 1.07 mmol) were dissolved in dry toluene (10 mL), and cesium carbonate (882 mg, 2.68 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (206 mg, 0.36 mmol), and tris(dibenzylideneacetone)dipalladium (164 mg, 0.18 mmol) were added in sequence. After the addition was completed, the reaction solution was heated to 100°C for 16 hours under nitrogen protection. The reaction was complete by TLC detection (petroleum ether:ethyl acetate = 3:1, R f = 0.4). The mixture was cooled, diluted with water (15 mL), extracted with ethyl acetate (30 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the title compound 108f (293 mg, yield 79%) as a white solid.
LC-MS:m/z＝414.3[M+H]+ LC-MS: m/z = 414.3 [M + H] +
第六步N-(5-氯-7-环丙基-1H-吲唑-3-基)-4-氟苯甲酰胺108gStep 6: N-(5-chloro-7-cyclopropyl-1H-indazol-3-yl)-4-fluorobenzamide 108 g
参照实施例27第四步的方法合成得到化合物108g(196mg,收率83％)。Referring to the method of the fourth step of Example 27, compound 108 g (196 mg, yield 83%) was synthesized.
LC-MS:m/z＝330.1[M+H]+ LC-MS: m/z = 330.1 [M + H] +
第七步N-(5-氯-7-环丙基-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺108Step 7 N-(5-chloro-7-cyclopropyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 108
参照实施例72的方法合成得白色固体标题化合物108(21mg,收率18％)。The title compound 108 (21 mg, yield 18%) was synthesized as a white solid by referring to the method of Example 72.
LC-MS:m/z＝368.1[M+H]+(99.31％purity,220nm)LC-MS: m/z = 368.1 [M+H] + (99.31% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),8.15(dd,J＝8.8,5.6Hz,2H),7.61(d,J＝1.6Hz,1H),7.38(t,J＝8.8Hz,2H),7.14(s,1H),5.54(d,J＝2.0Hz,2H),3.47(s,1H),2.49-2.44(m,1H),1.13-1.06(m,2H),0.95-0.89(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.96 (s, 1H), 8.15 (dd, J=8.8, 5.6 Hz, 2H), 7.61 (d, J=1.6 Hz, 1H), 7.38 (t, J=8.8 Hz, 2H), 7.14 (s, 1H), 5.54 (d, J=2.0 Hz, 2H), 3.47 (s, 1H), 2.49-2.44 (m, 1H), 1.13-1.06 (m, 2H), 0.95-0.89 (m, 2H).
实施例109Embodiment 109
4-氟-N-(7-甲基-1-(丙-2-炔-1-基)-1H-吲唑-3-基)苯甲酰胺109
4-Fluoro-N-(7-methyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)benzamide 109
第一步7-甲基-1H-吲唑-3-胺109bFirst step 7-methyl-1H-indazol-3-amine 109b
参照实施例92的第四步的方法合成得到黄色粉末标题化合物109b(214mg,收率19％)。The title compound 109b (214 mg, yield 19%) was synthesized as a yellow powder by referring to the method of the fourth step of Example 92.
LCMS:m/z＝148.1[M+H]+ LCMS: m/z = 148.1 [M + H] +
第二步4-氟-N-(7-甲基-1H-吲唑-3-基)苯甲酰胺109cStep 2 4-Fluoro-N-(7-methyl-1H-indazol-3-yl)benzamide 109c
参照实施例34的第二步的方法合成得到黄色粉末标题化合物109c(163mg,收率89％)。The title compound 109c (163 mg, yield 89%) was synthesized as a yellow powder by referring to the method of the second step of Example 34.
LCMS:m/z＝270.1[M+H]+ LCMS: m/z = 270.1 [M + H] +
第三步4-氟-N-(7-甲基-1-(丙-2-炔-1-基)-1H-吲唑-3-基)苯甲酰胺109Step 3 4-Fluoro-N-(7-methyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)benzamide 109
参照实施例72的方法合成得到白色粉末标题化合物109(20mg,收率15％)。The title compound 109 (20 mg, yield 15%) was synthesized as a white powder by referring to the method of Example 72.
LC-MS:m/z＝308.1[M+1]+(98.45％purity,220nm)LC-MS: m/z = 308.1 [M + 1] + (98.45% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),8.15(dd,J＝8.0,5.6Hz,2H),7.51(d,J＝8.0Hz,1H),7.38(t,J＝8.4Hz,2H),7.19(d,J＝6.8Hz,1H),7.03(t,J＝7.6Hz,1H),5.38(s,2H),3.48(s,1H),2.80(s,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.82 (s, 1H), 8.15 (dd, J=8.0, 5.6 Hz, 2H), 7.51 (d, J=8.0 Hz, 1H), 7.38 (t, J=8.4 Hz, 2H), 7.19 (d, J=6.8 Hz, 1H), 7.03 (t, J=7.6 Hz, 1H), 5.38 (s, 2H), 3.48 (s, 1H), 2.80 (s, 3H).
实施例110Embodiment 110
N-(7-乙基-1-(丙-2-烯-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺110
N-(7-ethyl-1-(prop-2-en-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 110
第一步7-乙烯基-1H-吲唑-3-胺110aStep 1 7-vinyl-1H-indazol-3-amine 110a
将7-溴-1H-吲唑-3-胺12a(300mg,1.41mmol)溶于1,4-二氧六环(5mL)和水(1mL)的混合溶液中，加入碳酸钠(374mg,3.53mmol)和乙烯三氟硼酸钾(284mg,2.12mmol)，加毕，氮气保护下，加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(58mg,0.071mmol)，加毕，反应液升至100℃反应16小时，LCMS显示原料反应完全。冷却，加水稀释，乙酸乙酯(萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得黄棕色固体标题化合物110a(169mg,收率75％)。7-Bromo-1H-indazol-3-amine 12a (300 mg, 1.41 mmol) was dissolved in a mixed solution of 1,4-dioxane (5 mL) and water (1 mL), and sodium carbonate (374 mg, 3.53 mmol) and potassium ethylene trifluoroborate (284 mg, 2.12 mmol) were added. After the addition was completed, [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (58 mg, 0.071 mmol) was added under nitrogen protection. After the addition was completed, the reaction solution was heated to 100°C for 16 hours. LCMS showed that the raw material reacted completely. Cool, dilute with water, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and the crude product was purified by silica gel column chromatography to obtain the title compound 110a (169 mg, yield 75%) as a yellow-brown solid.
LCMS:m/z＝160.1[M+H]+ LCMS: m/z = 160.1 [M + H] +
第二步7-乙基-1H-吲唑-3-胺110bStep 2 7-Ethyl-1H-indazol-3-amine 110b
参照实施例1的第一步合成方法合成得到黄色粉末标题化合物110b(136mg,收率79％)。The title compound 110b (136 mg, yield 79%) was synthesized as a yellow powder by referring to the first step of the synthesis method in Example 1.
LCMS:m/z＝162.1[M+H]+ LCMS: m/z = 162.1 [M + H] +
第三步N-(7-乙基-1H-吲唑-3-基)-4-氟苯甲酰胺110cStep 3 N-(7-ethyl-1H-indazol-3-yl)-4-fluorobenzamide 110c
参照实施例34的第二步的方法合成得到黄棕色粉末标题化合物110c(177mg,收率74％)。The title compound 110c (177 mg, yield 74%) was synthesized as a yellow-brown powder by referring to the method of the second step of Example 34.
LCMS:m/z＝284.2[M+H]+ LCMS: m/z = 284.2 [M + H] +
第四步N-(7-乙基-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺110Step 4: N-(7-ethyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 110
参照实施例72的方法合成得类白色粉末标题化合物110(22mg,收率17％)。The title compound 110 (22 mg, yield 17%) was synthesized as an off-white powder by referring to the method of Example 72.
LC-MS:m/z＝322.2[M+1]+(96.19％purity,254nm)LC-MS: m/z = 322.2 [M + 1] + (96.19% purity, 254 nm)
1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),8.15(dd,J＝8.4,5.2Hz,2H),7.52(d,J＝8.0Hz,1H),7.39(t,J＝8.8Hz,2H),7.25(d,J＝6.8Hz,1H),7.10(t,J＝8.0Hz,1H),5.33(d,J＝2.4Hz,2H),3.47(t,J＝2.4Hz,1H),3.18(t,J＝7.2Hz,2H),1.35(t,J＝7.6Hz,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.84 (s, 1H), 8.15 (dd, J=8.4, 5.2 Hz, 2H), 7.52 (d, J=8.0 Hz, 1H), 7.39 (t, J=8.8 Hz, 2H), 7.25 (d, J=6.8 Hz, 1H), 7.10 (t, J=8.0 Hz, 1H), 5.33 (d, J=2.4 Hz, 2H), 3.47 (t, J=2.4 Hz, 1H), 3.18 (t, J=7.2 Hz, 2H), 1.35 (t, J=7.6 Hz, 3H).
实施例111Embodiment 111
4-氟-N-(7-氟-1-(丙-2-炔-1-基)-1H-吲唑-3-基)苯甲酰胺111
4-Fluoro-N-(7-fluoro-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)benzamide 111
第一步7-氟-1H-吲唑-3-胺111bStep 1 7-Fluoro-1H-indazol-3-amine 111b
参照实施例92的第四步的方法合成得类白色粉末标题化合物111b(1g,收率92％)。 The title compound 111b (1 g, yield 92%) was synthesized as an off-white powder by referring to the method of the fourth step of Example 92.
LCMS:m/z＝152.1[M+H]+ LCMS: m/z = 152.1 [M + H] +
1H NMR(400MHz,DMSO-d6)δ11.85(s,1H),7.52(d,J＝8.0Hz,1H),7.05(dd,J＝11.6,7.6Hz,1H),6.93-6.80(m,1H),5.49(s,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.85 (s, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.05 (dd, J=11.6, 7.6 Hz, 1H), 6.93-6.80 (m, 1H), 5.49 (s, 2H).
第二步4-氟-N-(7-氟-1H-吲唑-3-基)苯甲酰胺111cStep 2 4-Fluoro-N-(7-fluoro-1H-indazol-3-yl)benzamide 111c
参照实施例34的第二步的方法合成得到淡粉色粉末标题化合物111c(338mg,收率93％)。The title compound 111c (338 mg, yield 93%) was synthesized as a light pink powder by referring to the method of the second step of Example 34.
LCMS:m/z＝274.1[M+H]+ LCMS: m/z = 274.1 [M + H] +
第三步4-氟-N-(7-氟-1-(丙-2-炔-1-基)-1H-吲唑-3-基)苯甲酰胺111Step 3 4-Fluoro-N-(7-fluoro-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)benzamide 111
参照实施例72的方法合成得棕黄色粉末标题化合物111(93mg,收率58％)。The title compound 111 (93 mg, yield 58%) was synthesized as a brown-yellow powder by referring to the method of Example 72.
LC-MS:m/z＝310.1[M-1]-(93.54％purity,254nm)LC-MS: m/z = 310.1 [M-1] - (93.54% purity, 254 nm)
1H NMR(400MHz,DMSO-d6)δ11.03(s,1H),8.15(dd,J＝8.8Hz,5.2Hz,2H),7.56(d,J＝8.0Hz,1H),7.39(t,J＝8.8Hz,2H),7.31(dd,J＝12.4,7.6Hz,1H),7.16-7.09(m,1H),5.29(d,J＝2.4Hz,2H),3.45(t,J＝2.4Hz,1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.03 (s, 1H), 8.15 (dd, J=8.8 Hz, 5.2 Hz, 2H), 7.56 (d, J=8.0 Hz, 1H), 7.39 (t, J=8.8 Hz, 2H), 7.31 (dd, J=12.4, 7.6 Hz, 1H), 7.16-7.09 (m, 1H), 5.29 (d, J=2.4 Hz, 2H), 3.45 (t, J=2.4 Hz, 1H).
实施例112Embodiment 112
N-(7-氯-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺112
N-(7-chloro-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 112
第一步7-氯-1H-吲唑-3-胺112bStep 1 7-Chloro-1H-indazol-3-amine 112b
参照实施例92的第四步的方法合成得到类白色粉末标题化合物112b(830mg,收率77％)。The title compound 112b (830 mg, yield 77%) was synthesized by referring to the method of the fourth step of Example 92 as an off-white powder.
LCMS:m/z＝168.1[M+H]+ LCMS: m/z = 168.1 [M + H] +
第二步N-(7-氯-1H-吲唑-3-基)-4-氟苯甲酰胺112cStep 2 N-(7-chloro-1H-indazol-3-yl)-4-fluorobenzamide 112c
参照实施例34的第二步的方法合成得到类白色粉末标题化合物112c(329mg,收率47％)。The title compound 112c (329 mg, yield 47%) was synthesized as an off-white powder by referring to the method of the second step of Example 34.
第三步N-(7-氯-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺112Step 3 N-(7-chloro-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 112
参照实施例72的方法合成得白色粉末标题化合物112(25mg,收率21％)。The title compound 112 (25 mg, yield 21%) was synthesized as a white powder by referring to the method of Example 72.
LC-MS:m/z＝328.1[M+1]+(96.39％purity,220nm)LC-MS: m/z = 328.1 [M + 1] + (96.39% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ11.02(s,1H),8.16(dd,J＝8.4,5.6Hz,2H),7.72(d,J＝8.0Hz,1H),7.55(d,J＝7.2Hz,1H),7.39(t,J＝8.4Hz,2H),7.16(t,J＝7.6Hz,1H),5.49(s,2H),3.44(s,1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.02 (s, 1H), 8.16 (dd, J=8.4, 5.6 Hz, 2H), 7.72 (d, J=8.0 Hz, 1H), 7.55 (d, J=7.2 Hz, 1H), 7.39 (t, J=8.4 Hz, 2H), 7.16 (t, J=7.6 Hz, 1H), 5.49 (s, 2H), 3.44 (s, 1H).
实施例113Embodiment 113
N-(7-环丙基-1-(丙-2-炔-1-基)-1H-吡唑并[3,4-c]吡啶-3-基)-4-氟苯甲酰胺113
N-(7-cyclopropyl-1-(prop-2-yn-1-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-fluorobenzamide 113
第一步2-溴-3-氟异烟酰氯113bStep 1: 2-Bromo-3-fluoroisonicotinyl chloride 113b
参照实施例99的第一步的方法合成得到化合物113b(2.65g,收率98％)。Compound 113b (2.65 g, yield 98%) was synthesized by referring to the first step of Example 99.
第二步2-溴-3-氟异烟酰胺113cStep 2 2-Bromo-3-fluoroisonicotinamide 113c
将化合物113b(2.65g,0.35mmol)溶解于四氢呋喃(3mL)，冷却至0℃，滴加氨水(25％-28％,20mL)中，滴毕，升至室温搅拌1小时，TLC(DCM:MeOH＝10:1,Rf＝0.5)显示原料反应完全。将反应 液浓缩，将析出的沉淀过滤，水(10mL)洗，收集滤饼，干燥得白色固体标题化合物113c(1.90g,收率78％)。Compound 113b (2.65 g, 0.35 mmol) was dissolved in tetrahydrofuran (3 mL), cooled to 0°C, and aqueous ammonia (25%-28%, 20 mL) was added dropwise. After the addition was completed, the mixture was heated to room temperature and stirred for 1 hour. TLC (DCM:MeOH=10:1, R f =0.5) showed that the reaction of the raw material was complete. The liquid was concentrated, the precipitate was filtered, washed with water (10 mL), and the filter cake was collected and dried to obtain the title compound 113c (1.90 g, yield 78%) as a white solid.
LC-MS:m/z＝219.0/221.0[M+H]+ LC-MS: m/z＝219.0/221.0[M+H] +
第三步2-溴-3-氟异烟腈113dStep 3 2-Bromo-3-fluoroisonicotinonitrile 113d
参照实施例93的第二步的方法合成得到化合物113d(1.22g,收率70％)。Compound 113d (1.22 g, yield 70%) was synthesized by referring to the method of the second step of Example 93.
1H NMR(400MHz,CDCl3)δ8.40(d,J＝4.8Hz,1H),7.53-7.48(m,1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.40 (d, J = 4.8 Hz, 1H), 7.53-7.48 (m, 1H).
第四步2-环丙基-3-氟异烟腈113eStep 4: 2-Cyclopropyl-3-fluoroisonicotinonitrile 113e
参照实施例12的第四步的方法合成得到化合物113e(810mg,收率86％)。Compound 113e (810 mg, yield 86%) was synthesized by referring to the fourth step of Example 12.
1H NMR(400MHz,CDCl3)δ8.37(d,J＝5.2Hz,1H),7.24(t,J＝4.8Hz,1H),2.42-2.33(m,1H),1.18-1.10(m,4H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.37 (d, J = 5.2 Hz, 1H), 7.24 (t, J = 4.8 Hz, 1H), 2.42-2.33 (m, 1H), 1.18-1.10 (m, 4H).
第五步7-(二氟甲基)-1H-吲唑-3-胺113fStep 5 7-(Difluoromethyl)-1H-indazol-3-amine 113f
参照实施例92的第四步的方法合成得到黄色固体标题化合物113f(0.67g,收率77％)。The title compound 113f (0.67 g, yield 77%) was synthesized by referring to the method of the fourth step of Example 92 as a yellow solid.
LC-MS:m/z＝175.1[M+H]+ LC-MS: m/z = 175.1 [M + H] +
第六步N-(7-环丙基-1H-[3,4-c]吡啶-3-基)-4-氟苯甲酰胺113gStep 6: N-(7-cyclopropyl-1H-[3,4-c]pyridin-3-yl)-4-fluorobenzamide 113 g
参照实施例34的第二步的方法合成得到白色固体标题化合物113g(220mg,收率86％)。Referring to the method of the second step of Example 34, 113 g (220 mg, yield 86%) of the title compound as a white solid was obtained.
LC-MS:m/z＝297.1[M+H]+ LC-MS: m/z = 297.1 [M + H] +
第七步N-(7-(二氟甲基)-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺113Step 7 N-(7-(difluoromethyl)-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 113
参照实施例72的方法合成得白色固体标题化合物113(26mg,收率29％)，另一产物经prep-HPLC(三氟乙酸)纯化得白色固体标题化合物113-P1(32mg,收率35％)。The title compound 113 (26 mg, yield 29%) was synthesized as a white solid by referring to the method of Example 72. The other product was purified by prep-HPLC (trifluoroacetic acid) to obtain the title compound 113-P1 (32 mg, yield 35%) as a white solid.
化合物113：Compound 113:
LC-MS:m/z＝335.1[M+H]+(99.31％purity,220nm)LC-MS: m/z = 335.1 [M+H] + (99.31% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),8.15(dd,J＝8.8,5.6Hz,2H),8.06(d,J＝5.6Hz,1H),7.48(d,J＝5.6Hz,1H),7.39(t,J＝8.8Hz,2H),5.59(d,J＝2.0Hz,2H),3.54(s,1H),2.83-2.74(m,1H),1.22-1.17(m,2H),1.15-1.08(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.04 (s, 1H), 8.15 (dd, J=8.8, 5.6 Hz, 2H), 8.06 (d, J=5.6 Hz, 1H), 7.48 (d, J=5.6 Hz, 1H), 7.39 (t, J=8.8 Hz, 2H), 5.59 (d, J=2.0 Hz, 2H), 3.54 (s, 1H), 2.83-2.74 (m, 1H), 1.22-1.17 (m, 2H), 1.15-1.08 (m, 2H).
化合物113-P1：Compound 113-P1:
LC-MS:m/z＝335.1[M+H]+(99.83％purity,220nm)LC-MS: m/z = 335.1 [M+H] + (99.83% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ11.32(s,1H),8.18(dd,J＝8.4,5.6Hz,2H),7.94(d,J＝6.8Hz,1H),7.77(d,J＝6.4Hz,1H),7.44(t,J＝8.8Hz,2H),5.52(d,J＝2.0Hz,2H),3.59(s,1H),2.87-2.78(m,1H),1.87-1.75(m,2H),1.58-1.48(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.32 (s, 1H), 8.18 (dd, J=8.4, 5.6 Hz, 2H), 7.94 (d, J=6.8 Hz, 1H), 7.77 (d, J=6.4 Hz, 1H), 7.44 (t, J=8.8 Hz, 2H), 5.52 (d, J=2.0 Hz, 2H), 3.59 (s, 1H), 2.87-2.78 (m, 1H), 1.87-1.75 (m, 2H), 1.58-1.48 (m, 2H).
实施例114Embodiment 114
N-(7-(二氟甲氧基)-5-甲基-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺114
N-(7-(difluoromethoxy)-5-methyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 114
第一步2-氟-5-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲腈114aStep 1: 2-Fluoro-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile 114a
将化合物93c(300mg,1.40mmol),联硼酸频那醇酯(463mg,1.82mmol)，乙酸钾(276mg,2.84mmol)和Pd(dppf)Cl2二氯甲烷络合物(58mg,0.070mmol)依次加入到二氧六环(8mL)中，氮气保护下加热至90℃反应2小时。TLC(PE:EA＝20:1,新点Rf＝0.1)显示原料转化完全。冷却，过滤，乙酸 乙酯(15mL)洗涤，滤液浓缩，粗品加水(15mL)稀释，乙酸乙酯萃取(10mL*3)，无水硫酸钠干燥，浓缩得到粗品标题化合物114a，直接用于下一步。Compound 93c (300 mg, 1.40 mmol), biboronic acid pinacol ester (463 mg, 1.82 mmol), potassium acetate (276 mg, 2.84 mmol) and Pd(dppf)Cl 2 dichloromethane complex (58 mg, 0.070 mmol) were added to dioxane (8 mL) in sequence and heated to 90°C for 2 hours under nitrogen protection. TLC (PE:EA=20:1, new point R f =0.1) showed that the raw material was completely converted. Cool, filter, and acetic acid The residue was washed with ethyl acetate (15 mL), the filtrate was concentrated, the crude product was diluted with water (15 mL), extracted with ethyl acetate (10 mL*3), dried over anhydrous sodium sulfate and concentrated to give the crude title compound 114a, which was used directly in the next step.
第二步2-氟-3-羟基-5-甲基苯腈114bStep 2 2-Fluoro-3-hydroxy-5-methylbenzonitrile 114b
将化合物114a(粗品)溶于四氢呋喃(5mL)中，降温至0℃，依次加入碳酸氢钠(471mg,5.61mmol)和双氧水(30％,2mL)，加毕，升至室温反应1.5小时。反应液加水(15mL)稀释，乙酸乙酯萃取(10mL*3)，合并的有机相用饱和硫代硫酸钠溶液(15mL)洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(PE：EA＝10:1-5:1)纯化得到白色固体标题化合物114b(139mg,两步收率66％)。Compound 114a (crude product) was dissolved in tetrahydrofuran (5 mL), cooled to 0°C, and sodium bicarbonate (471 mg, 5.61 mmol) and hydrogen peroxide (30%, 2 mL) were added in sequence. After addition, the mixture was heated to room temperature and reacted for 1.5 hours. The reaction solution was diluted with water (15 mL), extracted with ethyl acetate (10 mL*3), and the combined organic phase was washed with saturated sodium thiosulfate solution (15 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (PE: EA = 10: 1-5: 1) to obtain the title compound 114b (139 mg, two-step yield 66%) as a white solid.
1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),7.13-7.05(m,2H),2.24(s,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.59 (s, 1H), 7.13-7.05 (m, 2H), 2.24 (s, 3H).
第三步3-二氟甲氧基-2-氟-5-甲基苯腈114cStep 3 3-Difluoromethoxy-2-fluoro-5-methylbenzonitrile 114c
参照实施例102的第一步的方法合成得到黄色油状标题化合物114c(134mg,收率72％)。The title compound 114c (134 mg, yield 72%) was synthesized as a yellow oil by referring to the first step of Example 102.
1H NMR(400MHz,DMSO-d6)δ7.66(d,J＝5.2Hz,1H),7.62(d,J＝7.6Hz,1H),7.30(t,J＝72.4Hz,1H),2.35(s,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.66 (d, J = 5.2 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.30 (t, J = 72.4 Hz, 1H), 2.35 (s, 3H).
第四步7-二氟甲氧基-5-甲基吲唑-3-胺114dStep 4 7-difluoromethoxy-5-methylindazol-3-amine 114d
参照实施例92的第四步的方法合成得到黄色固体标题化合物114d(114mg,收率80％)。The title compound 114d (114 mg, yield 80%) was synthesized by referring to the method of the fourth step of Example 92 as a yellow solid.
LC-MS:m/z＝214.1[M+H]+ LC-MS: m/z = 214.1 [M + H] +
1H NMR(400MHz,DMSO-d6)δ11.62(s,1H),7.33(s,1H),7.26(t,J＝74.4Hz,1H),6.88(s,1H),5.32(s,2H),2.35(s,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.62 (s, 1H), 7.33 (s, 1H), 7.26 (t, J＝74.4 Hz, 1H), 6.88 (s, 1H), 5.32 (s, 2H), 2.35 (s, 3H).
第五步N-(7-(二氟甲氧基)-5-甲基-1H-吲唑-3-基)-4-氟苯甲酰胺114eStep 5: N-(7-(difluoromethoxy)-5-methyl-1H-indazol-3-yl)-4-fluorobenzamide 114e
参照实施例34的第二步的方法合成得到淡黄色固体标题化合物114e(167mg,收率94％)。The title compound 114e (167 mg, yield 94%) was synthesized as a pale yellow solid by referring to the method of the second step of Example 34.
LC-MS:m/z＝336.1[M+H]+ LC-MS: m/z = 336.1 [M + H] +
第六步N-(7-(二氟甲氧基)-5-甲基-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺114Step 6 N-(7-(difluoromethoxy)-5-methyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 114
参照实施例72的方法合成得到白色固体标题化合物114(18mg,收率32％)。The title compound 114 (18 mg, yield 32%) was synthesized as a white solid by referring to the method of Example 72.
LC-MS:m/z＝374.1[M+H]+(99.91％purity,254nm)LC-MS: m/z = 374.1 [M+H] + (99.91% purity, 254 nm)
1H NMR(400MHz,DMSO-d6)δ10.94(s,1H),8.15(dd,J＝8.8,5.6Hz,2H),7.62-7.21(m,4H),7.09(s,1H),5.26(d,J＝2.4Hz,2H),3.40-3.37(m,1H),2.40(s,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.94 (s, 1H), 8.15 (dd, J=8.8, 5.6 Hz, 2H), 7.62-7.21 (m, 4H), 7.09 (s, 1H), 5.26 (d, J=2.4 Hz, 2H), 3.40-3.37 (m, 1H), 2.40 (s, 3H).
实施例115Embodiment 115
N-(7-(二氟甲氧基)-5-甲基-1-丙基-1H-吲唑-3-基)-4-氟苯甲酰胺115
N-(7-(Difluoromethoxy)-5-methyl-1-propyl-1H-indazol-3-yl)-4-fluorobenzamide 115
第一步N-(7-(二氟甲氧基)-5-甲基-1-丙基-1H-吲唑-3-基)-4-氟苯甲酰胺115First step N-(7-(difluoromethoxy)-5-methyl-1-propyl-1H-indazol-3-yl)-4-fluorobenzamide 115
将化合物114e(30mg,0.89mmol)溶于N,N-二甲基甲酰胺(1.5mL)中，混合液降至0℃，加入钠氢(60％,7mg,0.18mmol)，搅拌十分钟后，加入溴丙烷(22mg,0.18mmol)，加毕，反应液升至25℃反应16小时，TLC监测。反应液加水淬灭，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经Pre-TLC纯化得类白色粉末标题化合物115(7mg,收率20％)。Compound 114e (30 mg, 0.89 mmol) was dissolved in N,N-dimethylformamide (1.5 mL), the mixture was cooled to 0°C, sodium hydrogen sulfide (60%, 7 mg, 0.18 mmol) was added, and after stirring for ten minutes, bromopropane (22 mg, 0.18 mmol) was added. After the addition was completed, the reaction solution was heated to 25°C and reacted for 16 hours, monitored by TLC. The reaction solution was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Pre-TLC to obtain the title compound 115 (7 mg, yield 20%) as an off-white powder.
LC-MS:m/z＝378.1[M+1]+(99.83％purity,220nm)LC-MS: m/z = 378.1 [M + 1] + (99.83% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),8.14(dd,J＝8.0,6.0Hz,2H),7.64-7.24(m,4H),7.03(s,1H),4.41(t,J＝7.2Hz,2H),2.38(s,3H),1.89-1.76(m,2H),0.86(t,J＝7.2Hz,3H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.81 (s, 1H), 8.14 (dd, J=8.0, 6.0 Hz, 2H), 7.64-7.24 (m, 4H), 7.03 (s, 1H), 4.41 (t, J=7.2 Hz, 2H), 2.38 (s, 3H), 1.89-1.76 (m, 2H), 0.86 (t, J=7.2 Hz, 3H).
实施例116Embodiment 116
N-(7-环丙基-5-甲基-1-丙基-1H-吲唑-3-基)-4-氟苯甲酰胺116
N-(7-cyclopropyl-5-methyl-1-propyl-1H-indazol-3-yl)-4-fluorobenzamide 116
第一步N-(7-环丙基-5-甲基-1H-吲唑-3-基)-4-氟苯甲酰胺116aFirst step N-(7-cyclopropyl-5-methyl-1H-indazol-3-yl)-4-fluorobenzamide 116a
参照实施例34的第二步的方法合成得到黄色固体标题化合物116a(390mg,收率83％)。The title compound 116a (390 mg, yield 83%) was synthesized as a yellow solid by referring to the method of the second step of Example 34.
LC-MS:m/z＝310.1[M+H]+ LC-MS: m/z = 310.1 [M + H] +
第二步N-(7-环丙基-5-甲基-1-丙基-1H-吲唑-3-基)-4-氟苯甲酰胺116Step 2 N-(7-cyclopropyl-5-methyl-1-propyl-1H-indazol-3-yl)-4-fluorobenzamide 116
参照实施例115的方法合成纯化得白色固体标题化合物116(16mg,收率47％)。The title compound 116 (16 mg, yield 47%) was synthesized and purified as a white solid by referring to the method of Example 115.
LC-MS:m/z＝352.2[M+H]+(97.18％purity,220nm)LC-MS: m/z = 352.2 [M+H] + (97.18% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),8.18-8.09(m,2H),7.37(t,J＝8.8Hz,2H),7.22(s,1H),6.95(s,1H),4.64(t,J＝7.2Hz,2H),2.37-2.29(m,4H),1.93-1.81(m,2H),1.07-1.00(m,2H),0.92(t,J＝7.6Hz,3H),0.87-0.81(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.67 (s, 1H), 8.18-8.09 (m, 2H), 7.37 (t, J=8.8 Hz, 2H), 7.22 (s, 1H), 6.95 (s, 1H), 4.64 (t, J=7.2 Hz, 2H), 2.37-2.29 (m, 4H), 1.93-1.81 (m, 2H), 1.07-1.00 (m, 2H), 0.92 (t, J=7.6 Hz, 3H), 0.87-0.81 (m, 2H).
实施例117Embodiment 117
N-(7-(二氟甲氧基)-1-丙基-1H-吲唑-3-基)-4-氟苯甲酰胺117
N-(7-(Difluoromethoxy)-1-propyl-1H-indazol-3-yl)-4-fluorobenzamide 117
第一步N-(7-(二氟甲氧基)-1-丙基-1H-吲唑-3-基)-4-氟苯甲酰胺117First step N-(7-(difluoromethoxy)-1-propyl-1H-indazol-3-yl)-4-fluorobenzamide 117
参照实施例115的方法合成得白色固体标题化合物117(17mg,收率50％)。The title compound 117 (17 mg, yield 50%) was synthesized as a white solid by referring to the method of Example 115.
LC-MS:m/z＝364.1[M+H]+(99.69％purity,220nm)LC-MS: m/z = 364.1 [M+H] + (99.69% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.18-8.11(m,2H),7.65-7.26(m,4H),7.18(d,J＝7.6Hz,1H),7.09(t,J＝8.0Hz,1H),4.45(t,J＝7.2Hz,2H),1.90-1.80(m,2H),0.88(t,J＝7.2Hz,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.90 (s, 1H), 8.18-8.11 (m, 2H), 7.65-7.26 (m, 4H), 7.18 (d, J=7.6 Hz, 1H), 7.09 (t, J=8.0 Hz, 1H), 4.45 (t, J=7.2 Hz, 2H), 1.90-1.80 (m, 2H), 0.88 (t, J=7.2 Hz, 3H).
实施例118Embodiment 118
4-氟-N-(7-甲氧基-1-丙基-1H-吲唑-3-基)苯甲酰胺118
4-Fluoro-N-(7-methoxy-1-propyl-1H-indazol-3-yl)benzamide 118
参照实施例115的方法合成得淡黄色固体标题化合物118(15mg,收率42％)。The title compound 118 (15 mg, yield 42%) was synthesized as a pale yellow solid by referring to the method of Example 115.
LC-MS:m/z＝328.1[M+H]+(98.26％purity,220nm)LC-MS: m/z = 328.1 [M+H] + (98.26% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.75(s,1H),8.18-8.09(m,2H),7.37(t,J＝8.8Hz,2H),7.20(d,J＝8.0Hz,1H),6.99(t,J＝7.6Hz,1H),6.87(d,J＝7.6Hz,1H),4.49(t,J＝6.8Hz,2H),3.96(s,3H),1.89-1.77(m,2H),0.85(t,J＝7.2Hz,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.75 (s, 1H), 8.18-8.09 (m, 2H), 7.37 (t, J=8.8 Hz, 2H), 7.20 (d, J=8.0 Hz, 1H), 6.99 (t, J=7.6 Hz, 1H), 6.87 (d, J=7.6 Hz, 1H), 4.49 (t, J=6.8 Hz, 2H), 3.96 (s, 3H), 1.89-1.77 (m, 2H), 0.85 (t, J=7.2 Hz, 3H).
实施例119Embodiment 119
N-(7-环丙基-5-甲基-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-3,4-二氟苯甲酰胺119
N-(7-cyclopropyl-5-methyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-3,4-difluorobenzamide 119
第一步3,4-二氟苯甲酰氯119bStep 1 3,4-Difluorobenzoyl chloride 119b
参照实施例99的第一步的方法合成得到无色油状物标题化合物119b(90mg,收率100％)。The title compound 119b (90 mg, yield 100%) was synthesized as a colorless oil by referring to the first step of Example 99.
第二步N-(7-环丙基-5-甲基-1H-吲唑-3-基)-3,4-二氟苯甲酰胺119cStep 2 N-(7-cyclopropyl-5-methyl-1H-indazol-3-yl)-3,4-difluorobenzamide 119c
参照实施例34的第二步的方法合成得到黄色固体标题化合物119c(63mg,收率57％)。The title compound 119c (63 mg, yield 57%) was synthesized as a yellow solid by referring to the method of the second step of Example 34.
第三步N-(7-环丙基-5-甲基-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-3,4-二氟苯甲酰胺119Step 3 N-(7-cyclopropyl-5-methyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-3,4-difluorobenzamide 119
参照实施例72的方法合成得到白色固体标题化合物119(18mg,收率26％)。The title compound 119 (18 mg, yield 26%) was synthesized as a white solid by referring to the method of Example 72.
LC-MS:m/z＝366.2[M+H]+(99.14％purity,220nm)LC-MS: m/z = 366.2 [M+H] + (99.14% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),8.15-8.08(m,1H),7.99-7.94(m,1H),7.63(dd,J＝18.8,8.4Hz,1H),7.27(s,1H),7.00(s,1H),5.51(d,J＝2.0Hz,2H),3.36-3.29(m,1H),2.48-2.40(m,1H),2.33(s,3H),1.09-1.02(m,2H),0.88-0.82(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.89 (s, 1H), 8.15-8.08 (m, 1H), 7.99-7.94 (m, 1H), 7.63 (dd, J=18.8, 8.4 Hz, 1H), 7.27 (s, 1H), 7.00 (s, 1H), 5.51 (d, J=2.0 Hz, 2H), 3.36-3.29 (m, 1H), 2.48-2.40 (m, 1H), 2.33 (s, 3H), 1.09-1.02 (m, 2H), 0.88-0.82 (m, 2H).
实施例120Embodiment 120
N-(7-(二氟甲氧基)-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-3,4-二氟苯甲酰胺120
N-(7-(difluoromethoxy)-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-3,4-difluorobenzamide 120
第一步N-(7-(二氟甲氧基)-1H-吲唑-3-基)-3,4-二氟苯甲酰胺120aFirst step: N-(7-(difluoromethoxy)-1H-indazol-3-yl)-3,4-difluorobenzamide 120a
参照实施例34的第二步的方法合成得白色固体标题化合物120a(81mg,收率80％)。The title compound 120a (81 mg, yield 80%) was synthesized as a white solid by referring to the method of the second step of Example 34.
第二步N-(7-(二氟甲氧基)-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-3,4-二氟苯甲酰胺120Step 2 N-(7-(difluoromethoxy)-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-3,4-difluorobenzamide 120
参照实施例72的方法合成纯化得白色固体标题化合物120(15mg,收率17％)。The title compound 120 (15 mg, yield 17%) was synthesized and purified by referring to the method of Example 72 to obtain a white solid.
LC-MS:m/z＝378.1[M+H]+(99.81％purity,220nm)LC-MS: m/z = 378.1 [M+H] + (99.81% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),8.18-8.09(m,1H),8.01-7.94(m,1H),7.70-7.23(m,4H),7.16(t,J＝8.0Hz,1H),5.31(d,J＝2.0Hz,2H),3.41-3.40(m,1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.11 (s, 1H), 8.18-8.09 (m, 1H), 8.01-7.94 (m, 1H), 7.70-7.23 (m, 4H), 7.16 (t, J=8.0 Hz, 1H), 5.31 (d, J=2.0 Hz, 2H), 3.41-3.40 (m, 1H).
实施例121Embodiment 121
N-(7-环丙基-5-甲基-1-(丙-2-炔-1-基)-1H-吡唑并[3,4-c]吡啶-3-基)-4-氟苯甲酰胺121
N-(7-cyclopropyl-5-methyl-1-(prop-2-yn-1-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-fluorobenzamide 121
第一步2-溴-3-氟-6-甲基异烟醛121b Step 1: 2-Bromo-3-fluoro-6-methylisonicotinaldehyde 121b
2-溴-3-氟-6-甲基吡啶121a(1.0g,5.26mmol)溶于无水四氢呋喃(15mL)中，降温至-60℃，滴加二异丙基氨基锂(2M,3.9mL,7.80mmol)，滴毕，继续在-60℃反应1小时，滴加DMF(577mg,7.89mmol)。反应液逐步升至室温反应2小时。TLC检测。滴加饱和氯化铵溶液(20mL)淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，浓缩得到黄色固体标题化合物121b(1.53g,粗品)。2-Bromo-3-fluoro-6-methylpyridine 121a (1.0 g, 5.26 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), cooled to -60 °C, and lithium diisopropylamide (2 M, 3.9 mL, 7.80 mmol) was added dropwise. After the addition was completed, the reaction was continued at -60 °C for 1 hour, and DMF (577 mg, 7.89 mmol) was added dropwise. The reaction solution was gradually warmed to room temperature and reacted for 2 hours. TLC detection was performed. Saturated ammonium chloride solution (20 mL) was added dropwise to quench the reaction, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 121b (1.53 g, crude product) as a yellow solid.
第二步2-溴-3-氟-6-甲基异烟醛肟121cStep 2: 2-Bromo-3-fluoro-6-methylisonicotinaldehyde oxime 121c
参照实施例92的第一步的方法合成得到黄色固体标题化合物121c(1.19g,粗品)。The title compound 121c (1.19 g, crude product) was synthesized by referring to the first step of Example 92 as a yellow solid.
第三步2-溴-3-氟-6-甲基异烟腈121dStep 3 2-Bromo-3-fluoro-6-methylisonicotinonitrile 121d
参照实施例92的第二步的方法合成得到黄色固体标题化合物121d(494mg,三步收率44％)。The title compound 121d (494 mg, three-step yield 44%) was synthesized by referring to the method of the second step of Example 92 to obtain a yellow solid.
第四步2-环丙基-3-氟-6-甲基异烟腈121eStep 4: 2-Cyclopropyl-3-fluoro-6-methylisonicotinonitrile 121e
参照实施例12的第四步的方法合成得到黄色固体标题化合物121e(129mg,收率100％)。The title compound 121e (129 mg, yield 100%) was synthesized by referring to the method of the fourth step of Example 12.
1H NMR(400MHz,DMSO-d6)δ7.55(d,J＝4.0Hz,1H),2.42(d,J＝0.8Hz,3H),2.36-2.28(m,1H),1.11-1.05(m,2H),1.03-0.98(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.55 (d, J = 4.0 Hz, 1H), 2.42 (d, J = 0.8 Hz, 3H), 2.36-2.28 (m, 1H), 1.11-1.05 (m, 2H), 1.03-0.98 (m, 2H).
第五步7-环丙基-5-甲基吡唑并[3,4-c]吡啶-3-胺121fStep 5: 7-Cyclopropyl-5-methylpyrazolo[3,4-c]pyridin-3-amine 121f
参照实施例92的第四步的方法合成得到黄色固体标题化合物121f(67.7mg,收率49％)。The title compound 121f (67.7 mg, yield 49%) was synthesized by referring to the method of the fourth step of Example 92 as a yellow solid.
LC-MS：m/z＝189.2[M+H]+ LC-MS: m/z = 189.2 [M + H] +
第六步N-(7-环丙基-5-甲基吡唑并[3,4-c]吡啶-3-基)-4-氟苯甲酰胺121gStep 6: N-(7-cyclopropyl-5-methylpyrazolo[3,4-c]pyridin-3-yl)-4-fluorobenzamide 121 g
参照实施例34的第二步的方法合成得到白色固体标题化合物121g(77mg,收率69％)。Referring to the method of the second step of Example 34, 121 g (77 mg, yield 69%) of the title compound as a white solid was obtained.
LC-MS：m/z＝311.1[M+H]+ LC-MS: m/z = 311.1 [M + H] +
第七步N-(7-环丙基-5-甲基-1-丙基-2-炔基)-1H-吡唑并[3,4-c]吡啶-3-基)-4-氟苯甲酰胺121Step 7: N-(7-cyclopropyl-5-methyl-1-propyl-2-ynyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-4-fluorobenzamide 121
参照实施例72的方法合成得到黄色固体标题化合物121(52mg,收率60％)。The title compound 121 (52 mg, yield 60%) was synthesized as a yellow solid by referring to the method of Example 72.
LC-MS:m/z＝349.1[M+H]+(99.34％purity,220nm)LC-MS: m/z = 349.1 [M+H] + (99.34% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),8.15(dd,J＝8.4,5.6Hz,2H),7.47-7.34(m,3H),5.59(d,J＝2.0Hz,2H),3.55(s,1H),2.84-2.74(m,1H),2.51(s,3H),1.27-1.21(m,2H),1.21-1.14(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.08 (s, 1H), 8.15 (dd, J=8.4, 5.6 Hz, 2H), 7.47-7.34 (m, 3H), 5.59 (d, J=2.0 Hz, 2H), 3.55 (s, 1H), 2.84-2.74 (m, 1H), 2.51 (s, 3H), 1.27-1.21 (m, 2H), 1.21-1.14 (m, 2H).
实施例122Embodiment 122
N-(5-氰基-7-(二氟甲氧基)-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺122
N-(5-cyano-7-(difluoromethoxy)-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 122
第一步5-溴-2-氟-3-羟基苯甲酸122bStep 1 5-Bromo-2-fluoro-3-hydroxybenzoic acid 122b
参照实施例114的第二步的方法合成得到化合物122b(0.86g,收率96％)。Compound 122b (0.86 g, yield 96%) was synthesized by referring to the method of the second step of Example 114.
LC-MS:m/z＝233.0/235.0[M-H]- LC-MS: m/z＝233.0/235.0[MH] -
第二步5-溴-2-氟-3-羟基苯甲酸甲酯122cStep 2 5-bromo-2-fluoro-3-hydroxybenzoic acid methyl ester 122c
参照实施例31的第一步的方法合成得到白色固体标题化合物122c(0.65g,收率71％)。The title compound 122c (0.65 g, yield 71%) was synthesized as a white solid by referring to the first step of Example 31.
第三步5-溴-2-氟-3-羟基苯甲酰胺122dStep 3 5-Bromo-2-fluoro-3-hydroxybenzamide 122d
参照实施例93的第一步的方法合成得到类白色固体标题化合物122d(270mg,收率77％)。The title compound 122d (270 mg, yield 77%) was synthesized by referring to the first step of Example 93 as an off-white solid.
1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),7.73(d,J＝46.8Hz,2H),7.17(dd,J＝7.2,2.4Hz,1H),7.11(dd,J＝5.2,2.8Hz,1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.60 (s, 1H), 7.73 (d, J=46.8 Hz, 2H), 7.17 (dd, J=7.2, 2.4 Hz, 1H), 7.11 (dd, J=5.2, 2.8 Hz, 1H).
第四步5-溴-2-氟-3-羟基苯甲腈122eStep 4: 5-Bromo-2-fluoro-3-hydroxybenzonitrile 122e
参照实施例93的第二步的方法合成得到棕色固体标题化合物122e(245mg,收率99％)。The title compound 122e (245 mg, yield 99%) was synthesized as a brown solid by referring to the method of the second step of Example 93.
1H NMR(400MHz,DMSO-d6)δ11.28(s,1H),7.59(dd,J＝4.4,2.4Hz,1H),7.43(dd,J＝7.6,2.4Hz,1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.28 (s, 1H), 7.59 (dd, J=4.4, 2.4 Hz, 1H), 7.43 (dd, J=7.6, 2.4 Hz, 1H).
第五步5-溴-3-(二氟甲氧基)-2-氟苯腈122fStep 5: 5-bromo-3-(difluoromethoxy)-2-fluorobenzonitrile 122f
参照实施例102的第一步的方法合成得到无水油状标题化合物122f(160mg,收率53％)。The title compound 122f (160 mg, yield 53%) was synthesized as an anhydrous oil by referring to the first step of Example 102.
1H NMR(400MHz,DMSO-d6)δ8.19(dd,J＝5.2,2.4Hz,1H),8.07(dd,J＝7.2,2.4Hz,1H),7.37(t,J＝72.4Hz,1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.19 (dd, J = 5.2, 2.4 Hz, 1H), 8.07 (dd, J = 7.2, 2.4 Hz, 1H), 7.37 (t, J = 72.4 Hz, 1H).
第六步5-溴-7-(二氟甲氧基)-1H-吲唑-3-胺122gStep 6 5-bromo-7-(difluoromethoxy)-1H-indazol-3-amine 122g
参照实施例92的第四步的方法合成得到类白色固体标题化合物122g(122mg,收率78％)。Referring to the method of the fourth step of Example 92, 122 g (122 mg, yield 78%) of the title compound was synthesized as an off-white solid.
LC-MS:m/z＝278.0/280.0[M+H]+ LC-MS: m/z＝278.0/280.0[M+H] +
第七步N-(5-溴-7-(二氟甲氧基)-1H-吲唑-3-基)-4-氟苯甲酰胺122hStep 7: N-(5-bromo-7-(difluoromethoxy)-1H-indazol-3-yl)-4-fluorobenzamide 122h
参照实施例34的第二步的方法合成得到类白色固体标题化合物122h(153mg,收率87％)。The title compound 122h (153 mg, yield 87%) was synthesized by referring to the method of the second step of Example 34 as an off-white solid.
LC-MS:m/z＝400.0[M+H]+ LC-MS: m/z = 400.0 [M + H] +
第八步N-(5-氰基-7-(二氟甲氧基)-1H-吲唑-3-基)-4-氟苯甲酰胺122iStep 8 N-(5-cyano-7-(difluoromethoxy)-1H-indazol-3-yl)-4-fluorobenzamide 122i
参照实施例82的合成方法合成得到化合物122i(32mg,收率77％)。Compound 122i (32 mg, yield 77%) was synthesized by referring to the synthesis method of Example 82.
LC-MS:m/z＝347.1[M+H]+ LC-MS: m/z = 347.1 [M + H] +
第九步N-(5-氰基-7-(二氟甲氧基)-1H-吲唑-3-基)-4-氟苯甲酰胺122Step 9 N-(5-cyano-7-(difluoromethoxy)-1H-indazol-3-yl)-4-fluorobenzamide 122
参照实施例72的方法合成得白色固体标题化合物122(18mg,收率31％)。The title compound 122 (18 mg, yield 31%) was synthesized as a white solid by referring to the method of Example 72.
LC-MS:m/z＝385.1[M+H]+(95.02％purity,210nm)LC-MS: m/z = 385.1 [M+H] + (95.02% purity, 210 nm)
1H NMR(400MHz,DMSO-d6)δ11.26(s,1H),8.28(s,1H),8.19-8.13(m,2H),7.73-7.32(m,4H),5.36(d,J＝2.4Hz,2H),3.48(t,J＝2.4Hz,1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.26 (s, 1H), 8.28 (s, 1H), 8.19-8.13 (m, 2H), 7.73-7.32 (m, 4H), 5.36 (d, J=2.4 Hz, 2H), 3.48 (t, J=2.4 Hz, 1H).
实施例123Embodiment 123
N-(7-(二氟甲氧基)-1-(丙-2-炔-1-基)-1H-吡唑并[4,3-b]吡啶-3-基)-4-氟苯甲酰胺123
N-(7-(difluoromethoxy)-1-(prop-2-yn-1-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-4-fluorobenzamide 123
第一步2-氯-4-二氟甲氧基-3-氟吡啶123bStep 1 2-Chloro-4-difluoromethoxy-3-fluoropyridine 123b
参照实施例102的第一步的方法合成得到无色透明油状物标题化合物123b(1.7g,收率64％)。The title compound 123b (1.7 g, yield 64%) was synthesized as a colorless transparent oil by referring to the method of the first step of Example 102.
LC-MS:m/z＝198.0[M+H]+ LC-MS: m/z = 198.0 [M + H] +
第二步4-(二氟甲氧基)-3-氟吡啶腈123cStep 2 4-(Difluoromethoxy)-3-fluoropyridinecarbonitrile 123c
参照实施例82的合成方法合成得到化合物123c(214mg,收率30％)。Compound 123c (214 mg, yield 30%) was synthesized by referring to the synthesis method of Example 82.
第三步7-(二氟甲氧基)-1H-吡唑并[4,3-b]吡啶-3-胺123dStep 3 7-(Difluoromethoxy)-1H-pyrazolo[4,3-b]pyridin-3-amine 123d
参照实施例92的第四步的方法合成得到黄色固体标题化合物123d(142mg,收率62％)。The title compound 123d (142 mg, yield 62%) was synthesized by referring to the method of the fourth step of Example 92 as a yellow solid.
LC-MS:m/z＝201.1[M+H]+ LC-MS: m/z = 201.1 [M + H] +
第四步N-(7-二氟甲氧基)-1H-吡唑并[4,3-b]吡啶-3-基)-4-氟苯甲酰胺123eStep 4: N-(7-difluoromethoxy)-1H-pyrazolo[4,3-b]pyridin-3-yl)-4-fluorobenzamide 123e
参照实施例34的第二步的方法合成得到淡黄色固体标题化合物123e(204mg,收率89％)。The title compound 123e (204 mg, yield 89%) was synthesized as a pale yellow solid by referring to the method of the second step of Example 34.
LC-MS:m/z＝323.1[M+H]+ LC-MS: m/z = 323.1 [M + H] +
第五步N-(7-二氟甲氧基)-1-丙基-2-丙基-1-吡唑并[4,3-b]吡啶-3-基)-4-氟苯甲酰胺123Step 5: N-(7-difluoromethoxy)-1-propyl-2-propyl-1-pyrazolo[4,3-b]pyridin-3-yl)-4-fluorobenzamide 123
参照实施例72的方法合成得到白色粉末状固体标题化合物123(34mg,收率15％)。The title compound 123 (34 mg, yield 15%) was synthesized as a white powdery solid by referring to the method of Example 72.
LC-MS:m/z＝361.1[M+H]+(94.05％purity,210nm)LC-MS: m/z = 361.1 [M+H] + (94.05% purity, 210 nm)
1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),8.51(d,J＝4.8Hz,1H),8.21-8.13(m,2H),7.80(t, J＝72.8Hz,1H),7.45(t,J＝8.8Hz,2H),7.10(d,J＝4.8Hz,1H),5.33(d,J＝2.4Hz,2H),3.53(t,J＝2.4Hz,1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.05 (s, 1H), 8.51 (d, J＝4.8 Hz, 1H), 8.21-8.13 (m, 2H), 7.80 (t, J＝72.8 Hz, 1H), 7.45 (t, J＝8.8 Hz, 2H), 7.10 (d, J＝4.8 Hz, 1H), 5.33 (d, J＝2.4 Hz, 2H), 3.53 (t, J＝2.4 Hz, 1H).
实施例124Embodiment 124
N-(7-(二氟甲氧基)-5-乙基-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺124
N-(7-(Difluoromethoxy)-5-ethyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 124
第一步N-(7-(二氟甲氧基)-5-乙烯基-1H-吲唑-3-基)-4-氟苯甲酰胺124aFirst step N-(7-(difluoromethoxy)-5-vinyl-1H-indazol-3-yl)-4-fluorobenzamide 124a
将N-(5-溴-7-(二氟甲氧基)-1H-吲唑-3-基)-4-氟苯甲酰胺122h(120mg,0.30mmol)溶于1,4-二氧六环(2mL)和水(0.4mL)的混合溶液中，加入碳酸钠(80mg,0.75mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(25mg,0.03mmol)，反应液升至100℃，TLC监控，反应液过滤，加水淬灭，乙酸乙酯萃取，饱和食盐水洗涤，干燥，浓缩，得棕色油状124a(146mg,粗品)。N-(5-bromo-7-(difluoromethoxy)-1H-indazol-3-yl)-4-fluorobenzamide 122h (120 mg, 0.30 mmol) was dissolved in a mixed solution of 1,4-dioxane (2 mL) and water (0.4 mL), and sodium carbonate (80 mg, 0.75 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (25 mg, 0.03 mmol) were added. The reaction solution was heated to 100°C and monitored by TLC. The reaction solution was filtered, quenched with water, extracted with ethyl acetate, washed with saturated brine, dried and concentrated to obtain brown oil 124a (146 mg, crude product).
LCMS:m/z＝348.1[M+H]+ LCMS: m/z = 348.1 [M + H] +
第二步N-(7-(二氟甲氧基)-5-乙基-1H-吲唑-3-基)-4-氟苯甲酰胺124bStep 2 N-(7-(Difluoromethoxy)-5-ethyl-1H-indazol-3-yl)-4-fluorobenzamide 124b
参照实施例1的第一步合成方法合成纯化得白色固体标题化合物124b(68mg,65％)。The title compound 124b (68 mg, 65%) was synthesized and purified by referring to the first step of the synthesis method in Example 1 to obtain a white solid.
LCMS:m/z＝350.1[M+H]+ LCMS: m/z = 350.1 [M + H] +
第三步N-(7-(二氟甲氧基)-5-乙基-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺124Step 3 N-(7-(difluoromethoxy)-5-ethyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 124
参照实施例72的方法合成得到淡黄色粉末标题化合物124(6.9mg,收率9％)。The title compound 124 (6.9 mg, yield 9%) was synthesized as a light yellow powder by referring to the method of Example 72.
LC-MS:m/z＝388.1[M+1]+(99.38％purity,210nm)LC-MS: m/z = 388.1 [M + 1] + (99.38% purity, 210 nm)
1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.15(dd,J＝8.4Hz,5.6Hz,2H),7.65-7.05(m,5H),5.27(s,2H),3.37(s,1H),2.70(q,J＝7.6Hz,2H),1.21(t,J＝7.6Hz,3H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.92 (s, 1H), 8.15 (dd, J = 8.4 Hz, 5.6 Hz, 2H), 7.65-7.05 (m, 5H), 5.27 (s, 2H), 3.37 (s, 1H), 2.70 (q, J = 7.6 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H)
实施例125Embodiment 125
N-(7-(二氟甲氧基)-1-(丙-2-炔-1-基)-5-丙基-1H-吲唑-3-基)-4-氟苯甲酰胺125
N-(7-(difluoromethoxy)-1-(prop-2-yn-1-yl)-5-propyl-1H-indazol-3-yl)-4-fluorobenzamide 125
第一步N-(5-溴-7-(二氟甲氧基)-1-(四氢2H-吡喃-2-基)-1H-吲唑-3-基)-4-氟苯甲酰胺125aFirst step N-(5-bromo-7-(difluoromethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-4-fluorobenzamide 125a
将化合物122h(420mg,1.05mmol)溶解于四氢呋喃(8mL)中，在室温下加入3,4-二氢-2H-吡喃(265mg,3.15mmol)和对甲苯磺酸(18mg,0.10mmol)，加热回流16小时，TLC(PE:EA＝20:1,Rf＝0.4)显示原料反应完全。冷却，加水(20mL)淬灭，乙酸乙酯萃取(10mL x3)，饱和食盐水(30mL x3)洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(PE:EA＝20:1-8:1)纯化，得类白色固体标题化合物125a(410mg,收率81％)。Compound 122h (420 mg, 1.05 mmol) was dissolved in tetrahydrofuran (8 mL), 3,4-dihydro-2H-pyran (265 mg, 3.15 mmol) and p-toluenesulfonic acid (18 mg, 0.10 mmol) were added at room temperature, and the mixture was heated to reflux for 16 hours. TLC (PE:EA＝20:1, R f ＝0.4) showed that the reaction of the raw materials was complete. The mixture was cooled, quenched with water (20 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (PE:EA＝20:1-8:1) to obtain the title compound 125a (410 mg, yield 81%) as an off-white solid.
LC-MS:m/z＝484.1/486.1[M+H]+ LC-MS: m/z＝484.1/486.1[M+H] +
第二步N-(5-烯丙基-7-(二氟甲氧基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)-4-氟苯甲酰胺125bStep 2 N-(5-allyl-7-(difluoromethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-4-fluorobenzamide 125b
将化合物125a(170mg,0.35mmol)溶于N,N-二甲基甲酰胺(2mL)中，依次加入烯丙基三丁基锡(139mg,0.42mmol)，氯化锂(45mg,1.05mmol)，四三苯基膦钯(40mg,0.035mmol)和2,6-二叔丁基 -4-甲基苯酚(2mg,0.01mmol)，加毕，反应液通入氮气五分钟，微波120℃反应1小时，LCMS显示原料反应完全。反应液浓缩，加水稀释，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得白色固体标题化合物125b(137mg,收率87％)。Compound 125a (170 mg, 0.35 mmol) was dissolved in N,N-dimethylformamide (2 mL), and allyl tributyltin (139 mg, 0.42 mmol), lithium chloride (45 mg, 1.05 mmol), tetrakistriphenylphosphine palladium (40 mg, 0.035 mmol) and 2,6-di-tert-butyl -4-Methylphenol (2 mg, 0.01 mmol), after addition, nitrogen was introduced into the reaction solution for five minutes, microwaved at 120°C for 1 hour, and LCMS showed that the raw material was completely reacted. The reaction solution was concentrated, diluted with water, 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 125b (137 mg, yield 87%) as a white solid.
LCMS:m/z＝446.2[M+H]+ LCMS: m/z = 446.2 [M + H] +
第三步N-(7-(二氟甲氧基)-5-丙基-1-(四氢-2H-吡喃-2-基)-1H-吲唑-3-基)-4-氟苯甲酰胺125cStep 3 N-(7-(Difluoromethoxy)-5-propyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-4-fluorobenzamide 125c
参照实施例1的第一步合成方法合成得到粗品灰色固体标题化合物125c(120mg,收率86％)。Referring to the first step of the synthesis method of Example 1, the crude title compound 125c (120 mg, yield 86%) was synthesized as a grey solid.
LCMS:m/z＝448.2[M+H]+ LCMS: m/z = 448.2 [M + H] +
第四步N-(7-(二氟甲氧基)-5-丙基-1H-吲唑-3-基)-4-氟苯甲酰胺125dStep 4: N-(7-(difluoromethoxy)-5-propyl-1H-indazol-3-yl)-4-fluorobenzamide 125d
参照实施例27第四步的方法合成得到化合物125d(86mg,收率87％)。Compound 125d (86 mg, yield 87%) was synthesized by referring to the method of step 4 of Example 27.
LCMS:m/z＝364.1[M+H]+ LCMS: m/z = 364.1 [M + H] +
第五步N-(7-(二氟甲氧基)-1-(丙-2-炔-1-基)-5-丙基-1H-吲唑-3-基)-4-氟苯甲酰胺125Step 5 N-(7-(difluoromethoxy)-1-(prop-2-yn-1-yl)-5-propyl-1H-indazol-3-yl)-4-fluorobenzamide 125
参照实施例72的方法合成得白色固体标题化合物125(27mg,收率28％)。The title compound 125 (27 mg, yield 28%) was synthesized as a white solid by referring to the method of Example 72.
LC-MS:m/z＝402.1[M+1]+(99.69％purity,220nm)LC-MS: m/z = 402.1 [M + 1] + (99.69% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.15(dd,J＝8.8Hz,5.6Hz,2H),7.62-7.23(m,4H),7.10(s,1H),5.27(d,J＝2.0Hz,2H),3.38(t,J＝2.4Hz,1H),2.64(t,J＝7.6Hz,2H),1.68-1.56(m,2H),0.90(t,J＝7.2Hz,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.93 (s, 1H), 8.15 (dd, J=8.8 Hz, 5.6 Hz, 2H), 7.62-7.23 (m, 4H), 7.10 (s, 1H), 5.27 (d, J=2.0 Hz, 2H), 3.38 (t, J=2.4 Hz, 1H), 2.64 (t, J=7.6 Hz, 2H), 1.68-1.56 (m, 2H), 0.90 (t, J=7.2 Hz, 3H).
实施例126：化合物129的合成过程Example 126: Synthesis of Compound 129
N-(5-环丙基-7-(二氟甲氧基)-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺129
N-(5-cyclopropyl-7-(difluoromethoxy)-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 129
第一步N-(5-环丙基-7-(二氟甲氧基)-1-(四氢2H-吡喃-2-基)-1H-吲唑-3-基)-4-氟苯甲酰胺129aFirst step N-(5-cyclopropyl-7-(difluoromethoxy)-1-(tetrahydro 2H-pyran-2-yl)-1H-indazol-3-yl)-4-fluorobenzamide 129a
参照实施例12的第四步的方法合成得到化合物129a(115mg,收率83％)。Compound 129a (115 mg, yield 83%) was synthesized by referring to the fourth step of Example 12.
LC-MS:m/z＝446.2[M+H]+ LC-MS: m/z = 446.2 [M + H] +
第二步N-(5-环丙基-7-(二氟甲氧基)-1H-吲唑-3-基)-4-氟苯甲酰胺129bStep 2 N-(5-cyclopropyl-7-(difluoromethoxy)-1H-indazol-3-yl)-4-fluorobenzamide 129b
参照实施例27第四步的方法合成得到化合物129b(110mg,收率92％)。Compound 129b (110 mg, yield 92%) was synthesized by referring to the method of step 4 of Example 27.
LC-MS:m/z＝362.1[M+H]+ LC-MS: m/z = 362.1 [M + H] +
第三步N-(5-环丙基-7-(二氟甲氧基)-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺129Step 3 N-(5-cyclopropyl-7-(difluoromethoxy)-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 129
参照实施例72的方法合成纯化得白色固体标题化合物129(18mg,收率27％)。The title compound 129 (18 mg, yield 27%) was synthesized and purified by referring to the method of Example 72 to obtain a white solid.
LC-MS:m/z＝400.2[M+H]+(99.39％purity,210nm)LC-MS: m/z = 400.2 [M + H] + (99.39% purity, 210 nm)
1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.17-8.12(m,2H),7.45(t,J＝73.2Hz,1H),7.38(t,J＝8.8Hz,2H),7.29(s,1H),6.94(s,1H),5.25(d,J＝2.4Hz,2H),3.36(t,J＝2.4Hz,1H),2.09-2.01(m,1H),0.98-0.92(m,2H),0.71-0.66(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.91 (s, 1H), 8.17-8.12 (m, 2H), 7.45 (t, J=73.2 Hz, 1H), 7.38 (t, J=8.8 Hz, 2H), 7.29 (s, 1H), 6.94 (s, 1H), 5.25 (d, J=2.4 Hz, 2H), 3.36 (t, J=2.4 Hz, 1H), 2.09-2.01 (m, 1H), 0.98-0.92 (m, 2H), 0.71-0.66 (m, 2H).
实施例127：化合物130的合成过程Example 127: Synthesis of Compound 130
N-(5-乙酰基-7-(二氟甲氧基)-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺130
N-(5-acetyl-7-(difluoromethoxy)-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 130
参考化合物129的合成方法，以化合物125a和三丁基(1-乙氧基乙烯)锡为原料，合成得到白色固体标题化合物130(19mg,收率23％)。With reference to the synthesis method of compound 129, compound 125a and tributyl(1-ethoxyethylene)tin were used as raw materials to synthesize the title compound 130 (19 mg, yield 23%) as a white solid.
LC-MS:m/z＝402.1[M+H]+(99.79％purity,220nm)LC-MS: m/z = 402.1 [M + H] + (99.79% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ11.19(s,1H),8.41(s,1H),8.18(dd,J＝8.8,5.6Hz,2H),7.71(s,1H),7.55(t,J＝72.8Hz,1H),7.40(t,J＝8.8Hz,2H),5.35(d,J＝2.0Hz,2H),3.45(s,1H),2.62(s,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.19 (s, 1H), 8.41 (s, 1H), 8.18 (dd, J=8.8, 5.6 Hz, 2H), 7.71 (s, 1H), 7.55 (t, J=72.8 Hz, 1H), 7.40 (t, J=8.8 Hz, 2H), 5.35 (d, J=2.0 Hz, 2H), 3.45 (s, 1H), 2.62 (s, 3H).
实施例128：化合物133的合成过程Example 128: Synthesis of Compound 133
N-(5-乙酰氨基-7-(二氟甲氧基)-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺133
N-(5-acetylamino-7-(difluoromethoxy)-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 133
参考化合物129的合成方法，以化合物125a和乙酰胺为原料，合成得到白色固体标题化合物133(9.0mg,HPLC第二个峰,收率14％)。Referring to the synthesis method of compound 129, compound 125a and acetamide were used as raw materials to synthesize the title compound 133 (9.0 mg, second peak by HPLC, yield 14%) as a white solid.
LC-MS:m/z＝417.2[M+H]+(99.42％purity,220nm)LC-MS: m/z = 417.2 [M+H] + (99.42% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),10.13(s,1H),8.17-8.12(m,2H),7.75(s,1H),7.59(s,1H),7.39(t,J＝73.2Hz,1H),7.42-7.36(m,2H),5.26(d,J＝2.0Hz,2H),3.34-3.33(m,1H),2.03(s,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.96 (s, 1H), 10.13 (s, 1H), 8.17-8.12 (m, 2H), 7.75 (s, 1H), 7.59 (s, 1H), 7.39 (t, J=73.2 Hz, 1H), 7.42-7.36 (m, 2H), 5.26 (d, J=2.0 Hz, 2H), 3.34-3.33 (m, 1H), 2.03 (s, 3H).
实施例129：化合物134的合成过程Example 129: Synthesis of Compound 134
N-(5,7-双(二氟甲氧基)-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺134
N-(5,7-bis(difluoromethoxy)-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 134
第一步3-(二氟甲氧基)-2-氟-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苄腈134aStep 1: 3-(Difluoromethoxy)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile 134a
参照实施例114的第一步的方法合成得到棕色油状标题化合物134a(粗品)，直接用于下一步反应。The title compound 134a (crude product) was synthesized as a brown oil by referring to the first step of Example 114 and was directly used in the next step.
第二步3-(二氟甲氧基)-2-氟-5-羟基苯甲腈134bStep 2 3-(Difluoromethoxy)-2-fluoro-5-hydroxybenzonitrile 134b
参照实施例114的第二步的方法合成得到白色固体标题化合物134b(170mg,两步收率65％)。The title compound 134b (170 mg, two-step yield 65%) was synthesized as a white solid by referring to the second step method of Example 114.
1H NMR(400MHz,DMSO-d6)δ10.56(s,1H),7.30(t,J＝72.4Hz,1H),7.13-7.07(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.56 (s, 1H), 7.30 (t, J＝72.4 Hz, 1H), 7.13-7.07 (m, 2H).
第三步3,5-双(二氟甲氧基)-2-氟苯腈134cStep 3 3,5-bis(difluoromethoxy)-2-fluorobenzonitrile 134c
参照实施例102的第一步的方法合成得无水油状标题化合物134c(48mg,收率32％)。The title compound 134c (48 mg, yield 32%) was synthesized as an anhydrous oil by referring to the first step of Example 102.
1H NMR(400MHz,DMSO-d6)δ7.82-7.80(m,1H),7.72(dd,J＝6.8,3.2Hz,1H),7.55(s,0.25H),7.50(s,0.25H),7.37(s,0.50H),7.32(s,0.50H),7.19(s,0.25H),7.13(s,0.25H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.82-7.80 (m, 1H), 7.72 (dd, J=6.8, 3.2 Hz, 1H), 7.55 (s, 0.25H), 7.50 (s, 0.25H), 7.37 (s, 0.50H), 7.32 (s, 0.50H), 7.19 (s, 0.25H), 7.13 (s, 0.25H).
第四步5,7-双(二氟甲氧基)-1H-吲唑-3-胺134dStep 4: 5,7-bis(difluoromethoxy)-1H-indazol-3-amine 134d
参照实施例92的第四步的方法合成得类白色固体标题化合物134d(32mg,收率64％)。Referring to the method of the fourth step of Example 92, the title compound 134d (32 mg, yield 64%) was synthesized as an off-white solid.
LC-MS:m/z＝266.1[M+H]+ LC-MS: m/z = 266.1 [M + H] +
第五步N-(7-(二氟甲氧基)-5-甲氧基-1H-吲唑-3-基)-4-氟苯甲酰胺134eStep 5: N-(7-(difluoromethoxy)-5-methoxy-1H-indazol-3-yl)-4-fluorobenzamide 134e
参照实施例34的第二步的方法合成得到类白色固体标题化合物134e(56mg,收率72％)。The title compound 134e (56 mg, yield 72%) was synthesized as an off-white solid by referring to the method of the second step of Example 34.
LC-MS:m/z＝388.1[M+H]+ LC-MS: m/z = 388.1 [M + H] +
第六步N-(5,7-双(二氟甲氧基)-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺134Step 6 N-(5,7-bis(difluoromethoxy)-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 134
参照实施例72的方法合成得到白色固体标题化合物134(16.50mg,收率28％)。The title compound 134 (16.50 mg, yield 28%) was synthesized as a white solid by referring to the method of Example 72.
LC-MS:m/z＝426.1[M+H]+(96.89％purity,220nm)LC-MS: m/z = 426.1 [M+H] + (96.89% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),8.17-8.12(m,2H),7.69(s,0.25H),7.51(s,0.50H),7.42-7.36(m,3.25H),7.33(s,0.25H),7.22(s,0.50H),7.17(s,1H),7.04(s,0.25H),5.30(d,J＝2.4Hz,2H),3.42(t,J＝2.4Hz,1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.06 (s, 1H), 8.17-8.12 (m, 2H), 7.69 (s, 0.25H), 7.51 (s, 0.50H), 7.42-7.36 (m, 3.25H), 7.33 (s, 0.25H), 7.22 (s, 0.50H), 7.17 (s, 1H), 7.04 (s, 0.25H), 5.30 (d, J=2.4 Hz, 2H), 3.42 (t, J=2.4 Hz, 1H).
实施例130：化合物135的合成过程Example 130: Synthesis of Compound 135
N-(7-(二氟甲氧基)-4-甲基-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺135
N-(7-(difluoromethoxy)-4-methyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 135
第一步3-溴-2-氟-6-甲基苯甲醛135bStep 1: 3-Bromo-2-fluoro-6-methylbenzaldehyde 135b
将4-溴-3-氟甲苯135a(5.00g,26.45mmol)溶于无水四氢呋喃(50mL)中，冷却至-78℃，滴加二异丙基氨基锂(20mL,40.00mmol,2M)，加毕，搅拌30分钟，加入DMF(5.80g,79.35mmol)，加毕，继续在-78℃反应2小时，TLC检测，加饱和氯化铵水溶液淬灭，加水稀释，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得白色固体135b(1.29g,收率22％)。4-Bromo-3-fluorotoluene 135a (5.00 g, 26.45 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), cooled to -78°C, and lithium diisopropylamide (20 mL, 40.00 mmol, 2 M) was added dropwise. After the addition was completed, the mixture was stirred for 30 minutes, and DMF (5.80 g, 79.35 mmol) was added. After the addition was completed, the reaction was continued at -78°C for 2 hours. After TLC detection, the mixture was quenched with saturated aqueous ammonium chloride solution, diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography to obtain a white solid 135b (1.29 g, yield 22%).
第二步3-溴-2-氟-6-甲基苯甲醛肟135cStep 2 3-Bromo-2-fluoro-6-methylbenzaldehyde oxime 135c
参照实施例92的第一步的方法合成得到白色粉末标题化合物135c(1.30g,收率94％)。The title compound 135c (1.30 g, yield 94%) was synthesized as a white powder by referring to the first step of Example 92.
第三步3-溴-2-氟-6-甲基苄腈135dStep 3 3-Bromo-2-fluoro-6-methylbenzonitrile 135d
参照实施例92的第二步的方法合成得到白色固体135d(850mg,收率99％)。Referring to the method of the second step of Example 92, a white solid 135d (850 mg, yield 99%) was obtained.
第四步2-氟-6-甲基-3-(4,4,5,5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)苄腈135eStep 4: 2-Fluoro-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile 135e
参照实施例114的第一步的方法合成得黑色油状物标题化合物135e(粗品)，直接用于下一步。The title compound 135e (crude product) was synthesized as a black oil by referring to the first step of Example 114 and was used directly in the next step.
第五步2-氟-3-羟基-6-甲基苄腈135fStep 5: 2-Fluoro-3-hydroxy-6-methylbenzonitrile 135f
参照实施例114的第二步的方法合成得到化合物135f(427mg,两步收率80％)Compound 135f (427 mg, two-step yield 80%) was synthesized by referring to the second step of Example 114
第六步3-(二氟甲氧基)-2-氟-6-甲基苄腈135gStep 6 3-(difluoromethoxy)-2-fluoro-6-methylbenzonitrile 135g
参照实施例102的第一步的方法合成得到黄色油状标题化合物135g(201mg,收率38％)。The title compound 135 g (201 mg, yield 38%) was synthesized as a yellow oil by referring to the method of the first step of Example 102.
第七步7-(二氟甲氧基)-4-甲基1H-吲唑-3-胺135hStep 7 7-(Difluoromethoxy)-4-methyl 1H-indazol-3-amine 135h
参照实施例92的第四步的方法合成得到白色固体标题化合物135h(208mg,收率98％)。The title compound 135h (208 mg, yield 98%) was synthesized as a white solid by referring to the method of the fourth step of Example 92.
第八步N-(7-(二氟甲氧基)-4-甲基-1H-吲唑-3-基)-4-氟苯甲酰胺135iStep 8 N-(7-(difluoromethoxy)-4-methyl-1H-indazol-3-yl)-4-fluorobenzamide 135i
参照实施例34的第二步的方法合成得到白色固体标题化合物135i(120mg,收率76％)。The title compound 135i (120 mg, yield 76%) was synthesized as a white solid by referring to the method of the second step of Example 34.
LC-MS:m/z＝336.1[M+H]+ LC-MS: m/z = 336.1 [M + H] +
第九步N-(7-(二氟甲氧基)-4-甲基-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺135Step 9 N-(7-(difluoromethoxy)-4-methyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 135
参照实施例72的方法合成得白色固体标题化合物135(47mg,收率35％)。The title compound 135 (47 mg, yield 35%) was synthesized as a white solid by referring to the method of Example 72.
LC-MS:m/z＝374.2[M+H]+(96.10％purity,254nm)LC-MS: m/z = 374.2 [M+H] + (96.10% purity, 254 nm)
1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),8.15-8.05(m,2H),7.57-7.17(m,3H),7.13(d,J＝7.6Hz,1H),6.91(d,J＝7.6Hz,1H),5.31(s,2H),3.40(s,1H),2.41(s,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.60 (s, 1H), 8.15-8.05 (m, 2H), 7.57-7.17 (m, 3H), 7.13 (d, J=7.6 Hz, 1H), 6.91 (d, J=7.6 Hz, 1H), 5.31 (s, 2H), 3.40 (s, 1H), 2.41 (s, 3H).
实施例131：化合物136的合成过程Example 131: Synthesis of Compound 136
N-(7-(二氟甲氧基)-6-甲基-1-(丙-2-炔-1-基)-1H-吲唑-3-基)-4-氟苯甲酰胺136
N-(7-(difluoromethoxy)-6-methyl-1-(prop-2-yn-1-yl)-1H-indazol-3-yl)-4-fluorobenzamide 136
参考化合物135的方法，以2-溴-3-氟甲苯为原料，合成得到白色固体136(29mg,收率32％)。Referring to the method of compound 135, 2-bromo-3-fluorotoluene was used as the starting material to synthesize white solid 136 (29 mg, yield 32%).
LC-MS:m/z＝374.1[M+H]+(98.68％purity,220nm)LC-MS: m/z = 374.1 [M+H] + (98.68% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),8.19-8.11(m,2H),7.58(d,J＝8.4Hz,1H),7.38(t,J＝8.8Hz,2H),7.24(t,J＝73.2Hz,1H),7.09(d,J＝8.4Hz,1H),5.26(d,J＝2.4Hz,2H),3.34(t,J＝ 2.0Hz,1H),2.42(s,3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.99 (s, 1H), 8.19-8.11 (m, 2H), 7.58 (d, J = 8.4 Hz, 1H), 7.38 (t, J = 8.8 Hz, 2H), 7.24 (t, J = 73.2 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 5.26 (d, J = 2.4 Hz, 2H), 3.34 (t, J = 2.0Hz,1H),2.42(s,3H).
实施例132：化合物142的合成过程Example 132: Synthesis of Compound 142
N-(8-环丙基-1-(丙-2-炔-1-基)-1,2,3,4-四氢喹啉-4-基)-4-氟苯甲酰胺142
N-(8-cyclopropyl-1-(prop-2-yn-1-yl)-1,2,3,4-tetrahydroquinolin-4-yl)-4-fluorobenzamide 142
第一步8-环丙基-2,3-二氢喹啉-4(1H)酮142bStep 1 8-Cyclopropyl-2,3-dihydroquinolin-4(1H)one 142b
参照实施例12的第四步的方法合成得到黄色油状标题化合物142b(49mg,收率99％)。The title compound 142b (49 mg, yield 99%) was synthesized as a yellow oil by referring to the method of the fourth step of Example 12.
LC-MS:m/z＝188.1[M+H]+ LC-MS: m/z = 188.1 [M + H] +
第二步8-环丙基-2,3-二氢喹啉-4(1H)-酮肟142cStep 2 8-Cyclopropyl-2,3-dihydroquinolin-4(1H)-one oxime 142c
参照实施例92的第一步的方法合成干燥得到白色固体标题化合物142c(47mg,收率89％)。The title compound 142c (47 mg, yield 89%) was synthesized and dried according to the method of the first step of Example 92 to obtain a white solid.
LC-MS:m/z＝203.2[M+H]+ LC-MS: m/z = 203.2 [M + H] +
第三步8-环丙基-1,2,3,4-四氢喹啉-4-胺142dStep 3 8-Cyclopropyl-1,2,3,4-tetrahydroquinolin-4-amine 142d
参照实施例1的第一步合成方法合成得到黄色固体标题化合物142d(41mg,收率94％)。The title compound 142d (41 mg, yield 94%) was synthesized as a yellow solid by referring to the first step of the synthesis method in Example 1.
第四步N-(8-环丙基-1,2,3,4-四氢喹啉-4-基)-4-氟苯甲酰胺142eStep 4: N-(8-cyclopropyl-1,2,3,4-tetrahydroquinolin-4-yl)-4-fluorobenzamide 142e
将化合物142d(41mg,0.22mmol)，对氟苯甲酸(37mg,0.26mmol)，EDCI(51mg,0.27mmol)，1-羟基苯并三唑(HOBT)(36mg,0.27mmol)和DIPEA(57mg,0.44mmol)依次加入到四氢呋喃(1.5mL)中，室温反应16小时。TLC监控。反应液加水稀释，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析纯化得到白色固体标题化合物142e(45mg,收率67％)。Compound 142d (41 mg, 0.22 mmol), p-fluorobenzoic acid (37 mg, 0.26 mmol), EDCI (51 mg, 0.27 mmol), 1-hydroxybenzotriazole (HOBT) (36 mg, 0.27 mmol) and DIPEA (57 mg, 0.44 mmol) were added to tetrahydrofuran (1.5 mL) in sequence and reacted at room temperature for 16 hours. TLC monitoring. The reaction solution was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 142e (45 mg, yield 67%) as a white solid.
1H NMR(400MHz,DMSO-d6)δ8.73(d,J＝8.0Hz,1H),8.04-7.93(m,2H),7.27(t,J＝8.8Hz,2H),6.85(d,J＝7.6Hz,1H),6.76(d,J＝7.2Hz,1H),6.43(t,J＝7.2Hz,1H),5.42(s,1H),5.25-5.17(m,1H),3.42-3.33(m,2H),1.97-1.89(m,2H),1.65-1.54(m,1H),0.86(d,J＝8.0Hz,2H),0.52-0.40(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.73 (d, J = 8.0 Hz, 1H), 8.04-7.93 (m, 2H), 7.27 (t, J = 8.8 Hz, 2H), 6.85 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 7.2 Hz, 1H), 6.43 (t, J = 7.2 Hz, 1H), 5.42 (s, 1H), 5.25-5.17 (m, 1H), 3.42-3.33 (m, 2H), 1.97-1.89 (m, 2H), 1.65-1.54 (m, 1H), 0.86 (d, J = 8.0 Hz, 2H), 0.52-0.40 (m, 2H).
第五步N-(8-环丙基-1-(丙-2-炔-1-基)-1,2,3,4-四氢喹啉-4-基)-4-氟苯甲酰胺142Step 5: N-(8-cyclopropyl-1-(prop-2-yn-1-yl)-1,2,3,4-tetrahydroquinolin-4-yl)-4-fluorobenzamide 142
参照实施例72的方法合成得到类白色固体标题化合物142(24mg,收率48％)。The title compound 142 (24 mg, yield 48%) was synthesized as an off-white solid by referring to the method of Example 72.
LC-MS:m/z＝349.2[M+H]+(96.36％purity,254nm)LC-MS: m/z = 349.2 [M+H] + (96.36% purity, 254 nm)
1H NMR(400MHz,DMSO-d6)δ8.79(d,J＝8.4Hz,1H),7.97(dd,J＝8.4,5.6Hz,2H),7.28(t,J＝8.8Hz,2H),6.96(d,J＝7.2Hz,1H),6.87(t,J＝7.6Hz,1H),6.71(d,J＝7.6Hz,1H),5.22(dd,J＝14.0,6.4Hz,1H),3.97-3.80(m,2H),3.43-3.34(m,1H),3.29-3.24(m,1H),3.19(s,1H),2.18-2.04(m,2H),1.93-1.82(m,1H),1.05-0.98(m,2H),0.74-0.67(m,2H). 1 H NMR (400 MHz, DMSO-d 6 )δ8.79(d,J＝8.4Hz,1H),7.97(dd,J＝8.4,5.6Hz,2H),7.28(t,J＝8.8Hz,2H),6.96(d,J＝7.2Hz,1H),6.87(t,J＝7.6Hz,1H),6.71(d,J＝7.6Hz,1H),5.22(dd,J＝14.0,6.4Hz,1H),3.97-3.80(m,2H),3.43-3.34(m,1H),3.29-3.24(m,1H),3.19(s,1H),2.18-2.04(m,2H),1.93-1.82(m,1H),1.05-0.98(m,2H),0.74-0.67(m,2H).
实施例133：化合物146的合成过程Example 133: Synthesis of Compound 146
N-(7-(二氟甲氧基)-1-(氧杂环乙烷-3-基)-1H-吲唑-3-基)-4-氟苯甲酰胺146
N-(7-(difluoromethoxy)-1-(oxane-3-yl)-1H-indazol-3-yl)-4-fluorobenzamide 146
参照实施例72的方法合成，原料使用3-溴环氧丁烷合成得到白色固体标题化合物146(18mg,收率31％)。The method of Example 72 was used for synthesis, and 3-bromobutylene oxide was used as the starting material to obtain the title compound 146 (18 mg, yield 31%) as a white solid.
LC-MS:m/z＝378.1[M+H]+(97.59％purity,220nm)LC-MS: m/z = 378.1 [M+H] + (97.59% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),8.17(dd,J＝8.8,5.6Hz,2H),7.60(d,J＝8.0Hz,1H),7.38(t,73.2Hz,1H),7.44-7.36(m,2H),7.22(d,J＝7.6Hz,1H),7.13(t,J＝8.0Hz,1H),6.16-6.06(m,1H),5.07(t,J＝6.4Hz,2H),4.99(t,J＝7.2Hz,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.10 (s, 1H), 8.17 (dd, J=8.8, 5.6 Hz, 2H), 7.60 (d, J=8.0 Hz, 1H), 7.38 (t, 73.2 Hz, 1H), 7.44-7.36 (m, 2H), 7.22 (d, J=7.6 Hz, 1H), 7.13 (t, J=8.0 Hz, 1H), 6.16-6.06 (m, 1H), 5.07 (t, J=6.4 Hz, 2H), 4.99 (t, J=7.2 Hz, 2H).
实施例134：化合物153的合成过程Example 134: Synthesis of Compound 153
N-(7-(二氟甲氧基)-1-异丙基-1H-吲唑-3-基)-4-氟苯甲酰胺153
N-(7-(Difluoromethoxy)-1-isopropyl-1H-indazol-3-yl)-4-fluorobenzamide 153
参照实施例72的方法合成，原料使用2-溴丙烷合成得到白色固体标题化合物153(18mg,收率27％)和153-P1(10mg,收率15％)。The reaction was synthesized by referring to the method of Example 72, and 2-bromopropane was used as the starting material to obtain the title compounds 153 (18 mg, yield 27%) and 153-P1 (10 mg, yield 15%) as white solids.
化合物153：Compound 153:
LC-MS:m/z＝364.1[M+H]+(99.41％purity,220nm)LC-MS: m/z = 364.1 [M+H] + (99.41% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.16(dd,J＝8.8,5.6Hz,2H),7.52(d,J＝8.0Hz,1H),7.44(t,J＝73.6Hz,1H),7.38(t,J＝8.8Hz,2H),7.20(d,J＝7.2Hz,1H),7.10(t,J＝8.0Hz,1H),5.30-5.21(m,1H),1.51(d,J＝6.4Hz,6H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.93 (s, 1H), 8.16 (dd, J=8.8, 5.6 Hz, 2H), 7.52 (d, J=8.0 Hz, 1H), 7.44 (t, J=73.6 Hz, 1H), 7.38 (t, J=8.8 Hz, 2H), 7.20 (d, J=7.2 Hz, 1H), 7.10 (t, J=8.0 Hz, 1H), 5.30-5.21 (m, 1H), 1.51 (d, J=6.4 Hz, 6H).
化合物153-P1：Compound 153-P1:
LC-MS:m/z＝364.1[M+H]+(98.72％purity,210nm)LC-MS: m/z = 364.1 [M+H] + (98.72% purity, 210 nm)
1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),8.17(dd,J＝8.4,5.6Hz,2H),7.57(t,J＝74.8Hz,1H),7.44(t,J＝8.8Hz,2H),7.40-7.35(m,1H),7.02-6.97(m,2H),4.86-4.78(m,1H),1.51(d,J＝6.8Hz,6H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.70 (s, 1H), 8.17 (dd, J=8.4, 5.6 Hz, 2H), 7.57 (t, J=74.8 Hz, 1H), 7.44 (t, J=8.8 Hz, 2H), 7.40-7.35 (m, 1H), 7.02-6.97 (m, 2H), 4.86-4.78 (m, 1H), 1.51 (d, J=6.8 Hz, 6H).
实施例135：化合物154的合成过程Example 135: Synthesis of Compound 154
N-(1-环丙基-7-(二氟甲氧基)-1H-吲唑-3-基)-4-氟苯甲酰胺154
N-(1-cyclopropyl-7-(difluoromethoxy)-1H-indazol-3-yl)-4-fluorobenzamide 154
第一步N-(1-环丙基-7-(二氟甲氧基)-1H-吲唑-3-基)-4-氟苯甲酰胺154First step N-(1-cyclopropyl-7-(difluoromethoxy)-1H-indazol-3-yl)-4-fluorobenzamide 154
参照实施例12的第四步的方法合成得到白色粉末标题化合物154(21mg,收率37％)。The title compound 154 (21 mg, yield 37%) was synthesized as a white powder by referring to the method of the fourth step of Example 12.
LC-MS:m/z＝362.1[M+1]+(99.87％purity,254nm)LC-MS: m/z = 362.1 [M + 1] + (99.87% purity, 254 nm)
1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.13(dd,J＝8.4Hz,5.6Hz,2H),7.55(d,J＝8.4Hz,1H),7.41(t,J＝74.0Hz,3H),7.24-7.20(m,1H),7.11(t,J＝8.0Hz,1H),3.98-3.89(m,1H),1.26-1.19(m,2H),1.13-1.06(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.90 (s, 1H), 8.13 (dd, J=8.4 Hz, 5.6 Hz, 2H), 7.55 (d, J=8.4 Hz, 1H), 7.41 (t, J=74.0 Hz, 3H), 7.24-7.20 (m, 1H), 7.11 (t, J=8.0 Hz, 1H), 3.98-3.89 (m, 1H), 1.26-1.19 (m, 2H), 1.13-1.06 (m, 2H).
实施例136：化合物160的合成过程Example 136: Synthesis of Compound 160
N-(1-环丁基-7-(二氟甲氧基)-1H-吲唑-3-基)-4-氟苯甲酰胺160
N-(1-cyclobutyl-7-(difluoromethoxy)-1H-indazol-3-yl)-4-fluorobenzamide 160
参照实施例72的方法合成，原料使用环丁基溴合成得到类白色固体标题化合物160(石油醚:乙酸乙酯＝1:1,Rf＝0.5,10mg,收率17％)。160-P1(石油醚:乙酸乙酯＝1:1,Rf＝0.7,5mg,收率9％)。The method of Example 72 was used to synthesize the title compound 160 (petroleum ether:ethyl acetate = 1:1, R f = 0.5, 10 mg, yield 17%) as an off-white solid. 160-P1 (petroleum ether:ethyl acetate = 1:1, R f = 0.7, 5 mg, yield 9%).
化合物160：Compound 160:
LC-MS:m/z＝376.1[M+1]+(95.51％purity,210nm)LC-MS: m/z = 376.1 [M + 1] + (95.51% purity, 210 nm)
1H NMR(400MHz,DMSO-d6)δ10.73(s,1H),8.21-8.11(m,2H),7.59(t,J＝74.4Hz,1H),7.44(t,J＝8.8Hz,2H),7.40-7.36(m,1H),7.03-6.95(m,2H),5.16-5.03(m,1H),2.77-2.64(m,2H),2.45-2.38(m,2H),1.92-1.82(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.73 (s, 1H), 8.21-8.11 (m, 2H), 7.59 (t, J=74.4 Hz, 1H), 7.44 (t, J=8.8 Hz, 2H), 7.40-7.36 (m, 1H), 7.03-6.95 (m, 2H), 5.16-5.03 (m, 1H), 2.77-2.64 (m, 2H), 2.45-2.38 (m, 2H), 1.92-1.82 (m, 2H).
化合物160-P1：Compound 160-P1:
LC-MS:m/z＝376.1[M+1]+(99.60％purity,254nm)LC-MS: m/z = 376.1 [M + 1] + (99.60% purity, 254 nm)
1H NMR(400MHz,DMSO-d6)δ10.95(s,1H),8.16(dd,J＝8.8Hz,5.6Hz,2H),7.53(d,J＝8.0Hz,1H),7.43(t,J＝73.6Hz,1H),7.39(t,J＝8.8Hz,2H),7.20(d,J＝7.6Hz,1H),7.09(t,J＝8.0Hz,1H),5.53-5.41(m,1H),2.73-2.59(m,2H),2.48-2.37(m,2H),1.90-1.77(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.95 (s, 1H), 8.16 (dd, J=8.8 Hz, 5.6 Hz, 2H), 7.53 (d, J=8.0 Hz, 1H), 7.43 (t, J=73.6 Hz, 1H), 7.39 (t, J=8.8 Hz, 2H), 7.20 (d, J=7.6 Hz, 1H), 7.09 (t, J=8.0 Hz, 1H), 5.53-5.41 (m, 1H), 2.73-2.59 (m, 2H), 2.48-2.37 (m, 2H), 1.90-1.77 (m, 2H).
实施例137：化合物164的合成过程Example 137: Synthesis of Compound 164
4-氟-N-(1-(丙-2-炔-1-基)-7-(三氟甲氧基)-1H-吲唑-3-基)苯甲酰胺164
4-Fluoro-N-(1-(prop-2-yn-1-yl)-7-(trifluoromethoxy)-1H-indazol-3-yl)benzamide 164
第一步2-氟-3-三氟甲氧基苯甲酰胺164bStep 1: 2-Fluoro-3-trifluoromethoxybenzamide 164b
参照实施例99的第一步的方法合成得到白色固体标题化合物164b(715mg,收率72％)。The title compound 164b (715 mg, yield 72%) was synthesized as a white solid by referring to the first step of Example 99.
第二步2-氟-3-(三氟甲氧基)苄腈164cStep 2 2-Fluoro-3-(trifluoromethoxy)benzonitrile 164c
参照实施例93的第二步的方法合成得到化合物164c。Compound 164c was synthesized by referring to the second step of Example 93.
第三步7-(三氟甲氧基)-1H-吲唑-3-胺164dStep 3 7-(Trifluoromethoxy)-1H-indazol-3-amine 164d
参照实施例92的第四步的方法合成得到白色固体标题化合物164d(131mg,两步收率67％)。The title compound 164d (131 mg, two-step yield 67%) was synthesized as a white solid by referring to the method of the fourth step of Example 92.
LC-MS:m/z＝218.1[M+H]+ LC-MS: m/z = 218.1 [M + H] +
第四步4-氟-N-(7-(三氟甲氧基)-1H-吲唑-3-基)苯甲酰胺164eStep 4: 4-Fluoro-N-(7-(trifluoromethoxy)-1H-indazol-3-yl)benzamide 164e
参照实施例34的第二步的方法合成得到灰色粉末状固体标题化合物164e(160mg,收率78％)。The title compound 164e (160 mg, yield 78%) was synthesized as a grey powdery solid by referring to the method of the second step of Example 34.
第五步4-氟-N-(1-(丙-2-炔-1-基)-7-(三氟甲氧基)-1H-吲唑-3-基)苯甲酰胺164Step 5 4-Fluoro-N-(1-(prop-2-yn-1-yl)-7-(trifluoromethoxy)-1H-indazol-3-yl)benzamide 164
参照实施例72的方法合成得到白色固体标题化合物164(22mg,收率20％)。The title compound 164 (22 mg, yield 20%) was synthesized as a white solid by referring to the method of Example 72.
LC-MS:m/z＝378.1[M+H]+(99.43％purity,210nm)LC-MS: m/z = 378.1 [M+H] + (99.43% purity, 210 nm)
1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),8.20-8.11(m,2H),7.75(d,J＝8.0Hz,1H),7.49(dd,J＝7.6,1.2Hz,1H),7.44-7.35(m,2H),7.22(t,J＝8.0Hz,1H),5.28(d,J＝2.4Hz,2H),3.44(t,J＝2.4Hz,1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.07 (s, 1H), 8.20-8.11 (m, 2H), 7.75 (d, J=8.0 Hz, 1H), 7.49 (dd, J=7.6, 1.2 Hz, 1H), 7.44-7.35 (m, 2H), 7.22 (t, J=8.0 Hz, 1H), 5.28 (d, J=2.4 Hz, 2H), 3.44 (t, J=2.4 Hz, 1H).
实施例138：化合物165的合成过程
Example 138: Synthesis of Compound 165
参照实施例72的方法合成，得到白色固体标题化合物165。The title compound 165 was synthesized according to the method of Example 72 to obtain a white solid.
LC-MS:m/z＝413.1[M+1]+(99.38％purity,210nm)LC-MS: m/z = 413.1 [M + 1] + (99.38% purity, 210 nm)
1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),8.52(dd,J＝4.4,1.2Hz,2H),8.15(dd,J＝8.8,5.6Hz,2H),7.62(d,J＝7.6Hz,1H),7.42-7.37(m,2H),7.37(t,J＝73.2Hz,1H),7.21(t,J＝7.6Hz,1H),7.15(t,J＝8.0Hz,1H),7.10-7.08(m,2H),5.76(s,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.00 (s, 1H), 8.52 (dd, J = 4.4, 1.2 Hz, 2H), 8.15 (dd, J = 8.8, 5.6 Hz, 2H), 7.62 (d, J = 7.6 Hz, 1H), 7.42-7.37 (m, 2H), 7.37 (t, J = 73.2 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H), 7.10-7.08 (m, 2H), 5.76 (s, 2H).
实施例139：化合物166的合成过程
Example 139: Synthesis of Compound 166
参照实施例72的方法合成，得到白色固体标题化合物166。The title compound 166 was synthesized according to the method of Example 72 to obtain the title compound 166 as a white solid.
LC-MS:m/z＝437.1[M+1]+(97.19％purity,220nm)LC-MS: m/z = 437.1 [M + 1] + (97.19% purity, 220 nm)
1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),8.14(dd,J＝8.8,5.6Hz,2H),7.82(d,J＝8.4Hz,2H),7.61(d,J＝8.0Hz,1H),7.38(t,J＝73.2Hz,1H),7.42-7.35(m,2H),7.31(d,J＝8.4Hz,2H),7.23-7.18(m,1H),7.13(t,J＝7.6Hz,1H),5.80(s,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.99 (s, 1H), 8.14 (dd, J=8.8, 5.6 Hz, 2H), 7.82 (d, J=8.4 Hz, 2H), 7.61 (d, J=8.0 Hz, 1H), 7.38 (t, J=73.2 Hz, 1H), 7.42-7.35 (m, 2H), 7.31 (d, J=8.4 Hz, 2H), 7.23-7.18 (m, 1H), 7.13 (t, J=7.6 Hz, 1H), 5.80 (s, 2H).
药理实验部分Pharmacological Experiments
测试例1KCNQ2的活性测试Test Example 1 Activity test of KCNQ2
1.质粒制备1. Plasmid Preparation
人源电压门控钾离子通道KCNQ2(NP_004509.2)的基因被克隆到pIRES2-EGFP表达载体上，在CHO-K1细胞中进行异源表达。The gene of human voltage-gated potassium channel KCNQ2 (NP_004509.2) was cloned into the pIRES2-EGFP expression vector and heterologously expressed in CHO-K1 cells.
2.细胞培养和转染2. Cell Culture and Transfection
CHO-K1细胞(购自中国科学院细胞库)培养采用DMEM/F12培养液，并加入10％胎牛血清，放入二氧化碳恒温培养箱进行培养(5％CO2 37℃)。细胞传代时采用25％胰酶消化，待细胞密度达80％～100％时，参照Lipofectamine 300实验操作说明书进行转染质粒：A管加入OPTI-MEM 125μL，lip3000 5μL；B管加入OPTI-MEM 125μL，质粒2.5μg，P3000 5μL，将A管和B管混合，静置15min后，滴加至6孔板中，转染24h后将细胞用胰酶消化，离心后用细胞外液重悬滴加至培养皿中，选择带有绿色荧光标记的细胞进行电生理测试。CHO-K1 cells (purchased from the cell bank of the Chinese Academy of Sciences) were cultured in DMEM/F12 medium and added with 10% fetal bovine serum, and placed in a carbon dioxide constant temperature incubator for culture (5% CO 2 37°C). Cells were digested with 25% trypsin during passage, and when the cell density reached 80% to 100%, plasmids were transfected according to the Lipofectamine 300 experimental operation manual: OPTI-MEM 125μL and lip3000 5μL were added to tube A; OPTI-MEM 125μL, plasmid 2.5μg, P3000 5μL were added to tube B, tube A and tube B were mixed, and after standing for 15min, they were added dropwise to a 6-well plate. After transfection for 24h, the cells were digested with trypsin, centrifuged, resuspended with extracellular fluid, and added dropwise to a culture dish, and cells with green fluorescent markers were selected for electrophysiological testing.
3.全细胞膜片钳实验3. Whole-cell patch clamp experiment
全细胞电生理实验记录在室温23～25℃条件下进行，采用HEKA EPC10膜片钳放大器，滤波为1kHz，采样频率为10kHz。膜片钳电极由水平电极拉制仪P-97经多步程序拉制完成，电阻为3～5MΩ。用于细胞记录的细胞外液为145mM NaCl、5mM KCl、1mM CaCl2、3mM MgCl2、10mM HEPES(pH 7.4,用NaOH调节)，细胞内液为150mM KCl、3mM MgCl2、5mM EGTA、10mM HEPES(pH 7.3,用KOH调节)。封接破膜后，先将电压钳制在-80mV，再采用Step记录模式，给予-90mV到+60mV(每隔10mV递增，每2s一个sweep)的一系列去极化电压引出外向电流，然后给予-120mV超级化电压引出尾电流并记录。然后启用Ramp记录模式，在-10mV电压下先给细胞外液进行记录，当通道电流稳定后给予化合物(本发明三唑类衍生物，作为钾离子通道调节剂)。给药时间至少3min，最后当药物作用稳定后，用细胞外液洗回。快速给药系统为RSC-200，速度约为0.2mL/min。Whole-cell electrophysiological experiments were recorded at room temperature of 23-25°C using a HEKA EPC10 patch clamp amplifier with a filter of 1kHz and a sampling frequency of 10kHz. The patch clamp electrodes were pulled by a horizontal electrode puller P-97 through a multi-step program, with a resistance of 3-5MΩ. The extracellular solution used for cell recording was 145mM NaCl, 5mM KCl, 1mM CaCl 2 , 3mM MgCl 2 , 10mM HEPES (pH 7.4, adjusted with NaOH), and the intracellular solution was 150mM KCl, 3mM MgCl 2 , 5mM EGTA, 10mM HEPES (pH 7.3, adjusted with KOH). After the membrane is broken, the voltage is first clamped at -80mV, and then the Step recording mode is adopted to give a series of depolarizing voltages from -90mV to +60mV (increased every 10mV, one sweep every 2s) to elicit outward currents, and then give a -120mV super voltage to elicit tail currents and record. Then enable the Ramp recording mode, first record the extracellular fluid at a voltage of -10mV, and give the compound (triazole derivatives of the present invention, as potassium channel regulators) when the channel current is stable. The administration time is at least 3min, and finally, when the drug effect is stable, it is washed back with extracellular fluid. The rapid drug delivery system is RSC-200, and the speed is about 0.2mL/min.
4.数据分析和统计4. Data Analysis and Statistics
采用Clampfit 10.4、GraphPad Prism 8.0.2等软件进行数据分析和作图。具体统计方法如下： Clampfit 10.4, GraphPad Prism 8.0.2 and other software were used for data analysis and graphing. The specific statistical methods are as follows:
(1)药物效应统计。通过记录-10mV下测试给药前后的稳定外向电流来判断药物的效应。给药前的稳定电流平均值记为Icontrol，给药后稳定电流平均值记为I。药物对通道作用效应表示为I/Icontrol。(1) Statistics of drug effects. The drug effect was determined by recording the stable outward current before and after drug administration at -10 mV. The average value of the stable current before drug administration was recorded as I control , and the average value of the stable current after drug administration was recorded as I control . The drug effect on the channel was expressed as I/I control .
(2)药物的剂量效应曲线拟合。用公式E＝Emax/(1+(EC50/C)P进行拟合，其中EC50是产生最大反应一半的药物浓度，P是Hill系数，C为药物浓度。(2) Fitting of drug dose-effect curve: The equation E = E max /(1 + (EC 50 /C) P was used for fitting, where EC 50 is the drug concentration that produces half of the maximum response, P is the Hill coefficient, and C is the drug concentration.
(3)电导-电压曲线(G-V curve)统计。通过记录一组去极化电压(-90mV至+60mV，每隔10mV递增)瞬间超极化到-120mV所激发的尾电流，来统计通道本身电压敏感性或者测试药物对通道电压敏感性的影响。以计算得到的最大电导Gmax作为标准进行归一化来统计每个电压下的G/Gmax。使用玻尔兹曼方程：G＝Gmin+(Gmax-Gmin)/(1+exp(V-V1/2)/S)进行拟合，Gmax为最大电导，Gmin为最小电导，V1/2为达到最大电导50％时的电压，S为斜率因子。(3) Conductance-voltage curve (GV curve) statistics. By recording a set of tail currents induced by instantaneous hyperpolarization from a depolarizing voltage (-90mV to +60mV, increasing by 10mV) to -120mV, the voltage sensitivity of the channel itself or the effect of the test drug on the voltage sensitivity of the channel is statistically analyzed. The calculated maximum conductance Gmax is used as the standard for normalization to calculate the G/ Gmax at each voltage. The Boltzmann equation: G= Gmin +( Gmax - Gmin )/(1+exp(VV1 /2 )/S) is used for fitting, where Gmax is the maximum conductance, Gmin is the minimum conductance, V1 /2 is the voltage at which the maximum conductance reaches 50%, and S is the slope factor.
采用配对t检验(Student’s paired t test)对数据进行统计分析，所有实验数据均以平均值±标准误(mean±S.E.M.)表示，P<0.05时认为两组之间的差异具有统计学意义。The data were statistically analyzed using the Student’s paired t test. All experimental data were expressed as mean ± standard error (mean ± S.E.M.). The difference between the two groups was considered statistically significant when P < 0.05.
试验结果见表4。The test results are shown in Table 4.
表4本发明中化合物在不同浓度下测试对电压门控钾离子通道KCNQ2通道电流的影响

Table 4 Effects of the compounds of the present invention on the voltage-gated potassium channel KCNQ2 channel current at different concentrations

nd表示未统计。nd means not counted.
结论，可见本专利的化合物无论在高电压下(+50mv)和低电压下(-10mv)都可以对KCNQ2通道起到激活作用，提示这些化合物可能对癫痫，抑郁，镇痛，渐冻症等疾病治疗有较好作用。In conclusion, it can be seen that the compounds of this patent can activate KCNQ2 channels at both high voltage (+50mv) and low voltage (-10mv), suggesting that these compounds may have a good effect on the treatment of diseases such as epilepsy, depression, analgesia, and ALS.
测试例2 KCNQ2/3的活性测试Test Example 2 Activity test of KCNQ2/3
1.质粒制备1. Plasmid Preparation
人源电压门控钾离子通道KCNQ2(NP_004509.2)和KCNQ3的基因被分别克隆到pIRES2-EGFP表达载体上，在CHO-K1细胞中进行异源表达，其他测试方式和测试例1一样。The genes of human voltage-gated potassium channels KCNQ2 (NP_004509.2) and KCNQ3 were cloned into pIRES2-EGFP expression vectors, respectively, and heterologously expressed in CHO-K1 cells. Other test methods were the same as those in Test Example 1.
试验结果见表5。The test results are shown in Table 5.
表5本发明中化合物在不同浓度下测试对电压门控钾离子通道KCNQ2/3通道电流的影响
Table 5 Effects of the compounds of the present invention on the voltage-gated potassium channel KCNQ2/3 channel current at different concentrations
结论，可见本专利的化合物对KCNQ2/3通道起到激活作用，提示这些化合物可能对癫痫，抑郁，镇痛，渐冻症等疾病治疗有较好作用。In conclusion, it can be seen that the compounds of this patent have an activating effect on KCNQ2/3 channels, suggesting that these compounds may have a good effect on the treatment of diseases such as epilepsy, depression, analgesia, and ALS.
测试例3体内癫痫实验Test Example 3 In vivo epilepsy experiment
MES实验：MES experiment:
实验过程experiment procedure
1.分组：动物适应期结束后，小鼠禁食不禁水4h，随后根据体重随机分组。 1. Grouping: After the animal adaptation period, the mice were fasted but not watered for 4 hours and then randomly grouped according to body weight.
2.给药：按照分组进行给药，各组(N＝8)给予对应的受试物、Retigabine或者溶媒，口服给药。2. Administration: The drugs were administered orally according to the groups. Each group (N=8) was given the corresponding test substance, Retigabine or vehicle.
3.造模：将生理药理电子刺激仪设置为：配置8，类型：连续波输出，波数75，刺激电压为160V，给药后0.5h用生理盐水润湿动物耳朵，用耳夹电极刺激小鼠1次，观察并记录实验动物的行为学表现。3. Modeling: Set the physiological pharmacological electronic stimulator to: Configuration 8, Type: Continuous wave output, Wave number 75, Stimulation voltage 160V, Moisten the ears of the animals with physiological saline 0.5h after administration, stimulate the mice once with ear clip electrodes, and observe and record the behavioral performance of the experimental animals.
4.实验结束：动物吸入CO2安乐死。4. End of the experiment: Animals were euthanized by inhalation of CO2 .
评价指标Evaluation indicators
动物是否出现全身强直，呈现前肢屈曲、后肢伸直的直线状态。若动物出现全身强直状态，则表明化合物无抗癫痫保护作用。Whether the animal is in a state of general tonicity, showing a straight line with the forelimbs flexed and the hind limbs extended. If the animal is in a state of general tonicity, it indicates that the compound has no anti-epileptic protective effect.
数据统计Statistics
实验数据以率表示，用excel处理数据。试验结果见表6。The experimental data are expressed as rate and processed by Excel. The test results are shown in Table 6.
表6本发明的化合物的体内癫痫实验

Table 6 In vivo epilepsy test of the compounds of the present invention

结论，可见本发明的化合物的较瑞替加滨有更低的起效计量和更强的保护率，即有更强的抗癫痫作用。In conclusion, it can be seen that the compound of the present invention has a lower onset dose and a stronger protection rate than retigabine, that is, it has a stronger anti-epileptic effect.
在此试验中测试了本发明的一些化合物可增加电压门控钾离子通道KCNQ2以及KCNQ2/3通道的钾电流，同时使通道对低电压更敏感，即能使电压门控钾离子通道在更低的电压下打开，另一部分化合物虽然不显著影响电流，但与瑞替加滨类似，可以左移电压激活曲线(△V1/2为负值)，影响通道开发和关闭动力学等。预期可调节神经元网络的活性，因此本发明化合物可有效用于治疗调节神经元活性的疾病如癫痫、疼痛、抑郁、肌萎缩性侧索硬化症等。In this experiment, some compounds of the present invention were tested to increase the potassium current of the voltage-gated potassium ion channel KCNQ2 and KCNQ2/3 channels, and at the same time make the channels more sensitive to low voltage, that is, they can open the voltage-gated potassium ion channels at a lower voltage. Although another part of the compounds does not significantly affect the current, they can shift the voltage activation curve to the left (△V1/2 is a negative value) similar to retigabine, affecting the channel development and closing dynamics, etc. It is expected that the activity of the neuronal network can be regulated, so the compounds of the present invention can be effectively used to treat diseases that regulate neuronal activity such as epilepsy, pain, depression, amyotrophic lateral sclerosis, etc.
然而，本发明化合物的各种活性，也可能存在其他机理，本发明中对于机理的推测正确与否，并不影响本发明化合物的具体活性效果。相关的疾病的治疗或者缓解方面的治疗用途并不局限于上述实施例，即不意味着本发明必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了，对本发明的任何改进，对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等，均落在本发明的保护范围和公开范围之内。However, the various activities of the compounds of the present invention may also have other mechanisms, and whether the speculation on the mechanism in the present invention is correct or not does not affect the specific activity effects of the compounds of the present invention. The therapeutic uses in the treatment or relief of related diseases are not limited to the above embodiments, which does not mean that the present invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent replacement of the raw materials of the products of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the scope of protection and disclosure of the present invention.
以上详细描述了本发明的优选实施方式，但是，本发明并不限于上述实施方式中的具体细节，在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，这些简单变型均属于本发明的保护范围。The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, a variety of simple modifications can be made to the technical solution of the present invention, and these simple modifications all belong to the protection scope of the present invention.
另外需要说明的是，在上述具体实施方式中所描述的各个具体技术特征，在不矛盾的情况下，可以通过任何合适的方式进行组合，为了避免不必要的重复，本发明对各种可能的组合方式不再另行说明。 It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

Claims (9)

  1. 式(I)所示的酰胺化合物或者其药学上可接受的盐、酯、光学异构体、互变异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药，
    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,
    环A为下述式(II)表示的环结构，
    Ring A is a ring structure represented by the following formula (II),
    “—”划过的环结构的表达方式，表示连接位点于该环结构上任意能够成键的位置，虚线表示的键表示存在或者不存在；The expression of a ring structure crossed by “—” indicates that the 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选自CRa或N；X2选自CRa、N或O、S、Se、NRa、C(Ra)2；X3不存在，或者选自CRa、N或NRa、O、S、Se、C(Ra)2；X4选自CRa、N或者NRa、C(Ra)2；X5选自CRa、N或O、S、Se、NRa、C(Ra)2；X6和X7表示C原子，X8选自C或N，X2～X7所形成的环为芳香性的或非芳香性； 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;
    m为0～4的整数，各R1相同或不同，且各自独立地选自卤素、-CN、C1-C6烷基、C2-C6烯基、C2-C6炔基、饱和或部分不饱和的C3-6环烃基、5-10元螺环烷基、饱和或部分不饱和的3-10元杂环基、5-10元螺杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基、-ORa、-NHRa、-C(O)NHRa、-C(＝O)Ra、-OC(＝O)Ra、-C(＝O)ORa、-ORa、-SRa、-S(＝O)Ra、-S(＝O)2Ra、-S(＝O)2N(Ra)2、-N(Ra)2、-NRa-C(＝O)Ra、-NRa-C(＝O)ORa、-NRa-S(＝O)2-Ra、-NRa-C(＝O)-N(Ra)2、-C1-6亚烷基-S(＝O)2Ra、-C1-6亚烷基-CN、-C1-6亚烷基-S(＝O)Ra、-C1-6亚烷基-N(Ra)2、-C1-6亚烷基-ORa、-C1-6亚烷基-NRa-C(＝O)ORa、-C1-6亚烷基-NRa-C(＝O)Ra、-C1-6亚烯基-ORa和-O-C1-6亚烷基-N(Ra)2；R1中的CH2可以被-O-、-S-或-C(＝O)-替换，R1中的H可以被羟基、卤素或C1-C3烷氧基所取代，R1中的环烃基、螺环烷基、杂环基、螺杂环基、芳基、杂芳基、芳烷基可以被卤素、-CN或C1-C3烷基所取代；两个相邻的R1之间可以连接并与环A的组成原子共同形成环结构；m is an integer from 0 to 4, each R1 is the same or different and is independently selected from halogen, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated or partially unsaturated C3-6 cycloalkyl, 5-10 membered spirocycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, 5-10 membered spiroheterocyclyl, C6-10 aryl, 5-14 membered heteroaryl, C6-12 aralkyl, -ORa , -NHRa, -C (O) NHRa , -C(＝O) Ra , -OC(＝O)Ra, -C(＝O) ORa , -ORa , -SRa , -S(＝O) Ra, -S(＝O)2Ra, -S(＝O)2N(Ra)2, -N(Ra)2 , -NRa , -C ( ＝ O ) Ra , -NRa -C(＝O)OR a , -NR a -S(＝O) 2 -R a , -NR a -C(＝O)-N(R a ) 2 , -C1-6 alkylene-S(＝O) 2 R a , -C1-6 alkylene-CN, -C1-6 alkylene-S(＝O)R a , -C1-6 alkylene-N(R a ) 2 , -C1-6 alkylene-OR a , -C1-6 alkylene-NR a -C(＝O)OR a , -C1-6 alkylene-NR a -C(＝O)R a , -C1-6 alkenylene-OR a and -O-C1-6 alkylene-N(R a ) 2 ; CH 2 in R 1 may be replaced by -O-, -S- or -C(＝O)-, H in R 1 may be substituted by hydroxy, halogen or C1-C3 alkoxy, R The cycloalkyl, spirocycloalkyl, heterocyclyl, spiroheterocyclyl, aryl, heteroaryl, aralkyl in 1 may be substituted by halogen, -CN or C1-C3 alkyl; two adjacent R 1s may be connected and form a ring structure together with the constituent atoms of ring A;
    L1为化学键或者NH；L2为化学键或者选自C1-6亚烷基、C2-6亚烯基、C2-6亚炔基、饱和或部分不饱和的C3-10亚环烃基、-O-、-C(＝O)O-、-NRa-、-NRaC(＝S)-、-NRaC(＝O)-、-NRaS(＝O)-、-N RaS(＝O)2-、-S-中的一种或多种组合而成的二价基团； L1 is a chemical bond or NH; L2 is a chemical bond or a divalent group selected from one or more of C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, saturated or partially unsaturated C3-10 cycloalkylene, -O- , -C(=O)O-, -NRa- , -NRaC(=S)-, -NRaC (=O)-, -NRaS(=O)-, -NRaS (=O) 2- , and -S-;
    Ra独立地选自H、C1-C10烷基、C1-C10卤代烷基、饱和或部分不饱和的C3-6环烃基、饱和或部分不饱和的3-10元杂环基或者C6-10芳基，Ra中的CH2可以被-O-或-S-替换，Ra中的H可以被羟基、卤素或C1-C3烷氧基所取代；条件是，L1和L2不同时为化学键，L1为化学键时，L2为-NRa-； 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- ;
    Ar1选自取代或未取代的C6～C30芳基、取代或未取代的C3～C30杂芳基中的一种；Ar 1 is selected from a substituted or unsubstituted C6-C30 aryl group, a substituted or unsubstituted C3-C30 heteroaryl group;
    R2独立地选自取代或未取代的C1-C6烷基、羟基、卤素、氰基、氨基、C1-C6烷基取代氨基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C6环烷基、取代或未取代的C3-C6杂环基、取代或未取代的苯基、取代或未取代的5-6元的杂芳基、S(O)2Rb1、S(O)2NH2、S(O)2NHRb1、S(O)2NRb1Rb2、NHS(O)2Rb1、NRb1S(O)2Rb2、S(O)(NH)Rb1、S(O)(NRb1)Rb2、C(O)Rb1、C(O)ORb1、OC(O)Rb1、NHC(O)Rb1、NRb1C(O)Rb2、NHC(O)ORb1、NRb1C(O)ORb2、C(O)NH2、C(O)NHRb1、C(O)NRb1Rb2、C(O)NH S(O)2Rb1、S(O)2NHC(O)Rb1；Rb1和Rb2分别独立地选自H、取代或未取代的C1-C3的烷基、取代或未取代的3-6元的环烷基或杂环基，或者Rb1和Rb2连同它们所连接的N原子形成3-7元的杂环基；n为0-4的整数， n为2以上时，多个R2可以相同的也可以不同，两个相邻的R2之间可以连接并与Ar1的组成原子共同形成五元环、或者六元环；上述的取代或未取代是指基团中的H被选自卤素、氰基、硝基、羟基、氨基、醛基、酯基、C1～C30烷基、C1～C30烷氧基、C2～C20杂环烷基、C1～C30烷基硅基、C6～C30芳基、C6～C30芳氧基、C3～C30杂芳基、C6～C30芳基氨基或C3～C30杂芳基氨基中的一种或者至少两种的组合以上的基团所取代，或者指基团中的-CH2-中的两个H被替换成氧代＝O 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, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, S(O) 2Rb1 , S ( O) 2NH2 , S(O) 2NHRb1 , S(O) 2NRb1Rb2 , NHS(O) 2Rb1 , NRb1S (O) 2Rb2 , S(O)(NH) Rb1 , S(O ) ( NRb1 ) Rb2 , C(O) Rb1 , C ( O) ORb1 , OC(O) Rb1 , NHC(O) Rb1 , NRb1C (O) Rb2 , NHC(O) ORb1 , NRb1C (O) ORb2 , C(O) NH2 , C(O) NHRb1 , C(O) NRb1Rb2 , C(O)NHS(O) 2Rb1 , S(O) 2NHC (O) Rb1 ; Rb1 and Rb2 are independently selected from H, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted 3-6-membered cycloalkyl or heterocyclic group, or Rb1 and Rb2 together with the N atom to which they are connected form a 3-7-membered heterocyclic group; n is an integer of 0-4, When n is 2 or more, multiple R 2's may be the same or different, and two adjacent R 2's may be connected to form a five-membered ring or a six-membered ring together with the constituent atoms of Ar 1 ; the above-mentioned substitution or unsubstitution means that the H in the group is substituted by a group selected from one or a combination of at least two of halogen, cyano, nitro, hydroxyl, amino, aldehyde, ester, C1-C30 alkyl, C1-C30 alkoxy, C2-C20 heterocycloalkyl, C1-C30 alkylsilyl, C6-C30 aryl, C6-C30 aryloxy, C3-C30 heteroaryl, C6-C30 arylamino or C3-C30 heteroarylamino, or that two H's in -CH 2 - in the group are replaced by oxo=O
    条件是，不为以下的具体化合物：
    Provided that it is not the following specific compound:
  2. 如权利要求1所述的化合物或其药学上可接受的盐、酯、光学异构体、互变异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药，其中，式(1)中环A表示的结构选自以下结构：
    The compound according to claim 1 or its pharmaceutically acceptable salt, ester, optical isomer, tautomer, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, chelate, complex, inclusion compound or prodrug, wherein the structure represented by ring A in formula (1) is selected from the following structures:
    m为0～3的整数，R1选自卤素、-CN、羟基、取代或未取代的C1-C6直链烷基、或者任选被卤素、C1～C3的烷基、C1～C3的烷氧基取代的以下基团，
    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,
    上述的取代或未取代是指基团中的H被选自卤素、氰基、硝基、羟基、氨基、醛基、酯基、C1～C30烷基、C1～C30烷氧基、C2～C20杂环烷基、C1～C30烷基硅基、C6～C30芳基、C6～C30芳氧基、C3～C30杂芳基、C6～C30芳基氨基或C3～C30杂芳基氨基中的一种或者至少两种的组合以上的基团所取代，或者指基团中的-CH2-中的两个H被替换成氧代＝O；The above substitution or unsubstitution means that the H in the group is substituted by one or a combination of at least two of halogen, cyano, nitro, hydroxyl, amino, aldehyde, ester, C1-C30 alkyl, C1-C30 alkoxy, C2-C20 heterocycloalkyl, C1-C30 alkylsilyl, C6-C30 aryl, C6-C30 aryloxy, C3-C30 heteroaryl, C6-C30 arylamino or C3-C30 heteroarylamino, or that two H in -CH 2 - in the group are replaced by oxo=O;
    Ar1为以下基团中的一种或这些基团稠合的组合：Ar 1 is one of the following groups or a fused combination of these groups:
    苯基、萘基、蒽基、苯并蒽基、菲基、苯并菲基、芘基、窟基、茈基、荧蒽基、并四苯基、并五苯基、苯并芘基、联苯基、偶苯基、三联苯基、三聚苯基、四联苯基、芴基、螺二芴基、二氢菲基、二氢芘基、四氢芘基、顺式或反式茚并芴基、三聚茚基、异三聚茚基、螺三聚茚基、螺异三聚茚基所组成的群组中的基团。具体地，联苯基选自2-联苯基、3-联苯基和4-联苯基；三联苯基包括对-三联苯基-4-基、对-三联苯基-3-基、对-三联苯基-2-基、间-三联苯基-4-基、间-三联苯基-3-基和间-三联苯基-2-基；所述萘基包括1-萘基或2-萘基；蒽基选自由1-蒽基、2-蒽基和9-蒽基；所述芴基选自由1-芴基、2-芴基、3-芴基、4-芴基和9-芴基；所述芘基选自由1-芘基、2-芘基和4-芘基；并四苯基选自由1-并四苯基、2-并四苯基和9-并四苯基、呋喃基、噻吩基、吡咯基、吡啶基、苯并呋喃基、苯并噻吩基、异苯并呋喃基、异苯并噻吩基、吲哚基、异吲哚基、二苯并呋喃基、二苯并噻吩基、咔唑基及其衍生物、喹啉基、异喹啉基、吖啶基、菲啶基、苯并-5，6-喹啉基、苯并-6，7-喹啉基、苯并-7，8-喹啉基、吩噻嗪基、吩嗪基、吡唑基、吲唑基、咪唑基、苯并咪唑基、萘并咪唑基、菲并咪唑基、吡啶并咪唑基、吡嗪并咪唑基、喹喔啉并咪唑基、嗯唑基、苯并嗯唑基、萘并嗯唑基、蒽并嗯唑基、菲并嗯唑基、1，2-噻唑基、1，3-噻唑基、苯并噻唑基、哒嗪基、苯并哒嗪基、嘧啶基、苯并嘧啶基、喹喔啉基、1，5-二氮杂蒽基、2，7-二氮杂芘基、2，3-二氮杂芘基、1，6-二氮杂芘基、1，8-二氮杂芘基、4，5-二氮杂芘基、4，5，9，10-四氮杂茈基、 吡嗪基、吩嗪基、吩噻嗪基、萘啶基、氮杂咔唑基、苯并咔啉基、菲咯啉基、1，2，3-三唑基、1，2，4-三唑基、苯并三唑基、1，2，3-噁二唑基、1，2，4-嗯二唑基、1，2，5_嗯二唑基、1，2，3-噻二唑基、1，2，4-噻二唑基、1，2，5-噻二唑基、1，3，4-噻二唑基、1，3，5-三嗪基、1，2，4-三嗪基、1，2，3-三嗪基、四唑基、1，2，4，5-四嗪基、1，2，3，4-四嗪基、1，2，3，5-四嗪基、嘌呤基、蝶啶基、吲嗪基、苯并噻二唑；氮丙啶基、环氧基、吡咯烷基、四氢呋喃基、四氢吡喃基、噻唑烷基、哌啶基、哌嗪基、吗啉基、二氧杂戊环基、二氧杂己环基、二硫杂戊环基、二硫杂己环基。A group selected from the group consisting of phenyl, naphthyl, anthracenyl, benzanthryl, phenanthryl, triphenanthrenyl, pyrenyl, chrysene, peryl, fluoranthenyl, tetraphenyl, pentacene, benzopyrenyl, biphenyl, phenylene, terphenyl, triphenylene, quaterphenylene, fluorenyl, spirobifluorenyl, dihydrophenanthryl, dihydropyrenyl, tetrahydropyrenyl, cis- or trans-indenofluorenyl, trimerized indenyl, isotrimerized indenyl, spirotrimerized indenyl, and spiroisotrimerized indenyl. Specifically, 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 fluorene group includes 1-naphthyl or 2-naphthyl; the anthracenyl group includes 1-anthracenyl, 2-anthracenyl and 9-anthracenyl; the fluorene group includes 1-naphthyl or 2-naphth ... The radical is selected from 1-fluorenyl, 2-fluorenyl, 3-fluorenyl, 4-fluorenyl and 9-fluorenyl; the pyrenyl is selected from 1-pyrenyl, 2-pyrenyl and 4-pyrenyl; the naphthyl is selected from 1-naphthyl, 2-naphthyl and 9-naphthyl, furanyl, thienyl, pyrrolyl, pyridyl, benzofuranyl, benzothienyl, isobenzofuranyl, isobenzothienyl, indolyl, isoindolyl, dibenzofuranyl, dibenzothien ... benzothiophenyl, carbazolyl and its derivatives, quinolyl, isoquinolyl, acridinyl, phenanthridinyl, benzo-5,6-quinolyl, benzo-6,7-quinolyl, benzo-7,8-quinolyl, phenothiazinyl, phenazinyl, pyrazolyl, indazolyl, imidazolyl, benzimidazolyl, naphthioimidazolyl, phenanthioimidazolyl, pyridoimidazolyl, pyrazinoimidazolyl, quinoxalinoiimidazolyl, oxazolyl, benzoxazolyl, naphthioimidazolyl, phenanthioimidazolyl, pyridoimidazolyl, pyrazinoimidazolyl, quinoxalinoiimidazolyl, oxazolyl, benzoxazolyl, naphthioimidazolyl oxazolyl, anthrazolyl, phenanthrazolyl, 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, pyrazinyl, phenazinyl, phenothiazinyl, naphthyridinyl, azacarbazolyl, benzocarbolinyl, phenanthrolinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, benzotriazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,3,5-triazinyl, 1 , 2,4-triazinyl, 1,2,3-triazinyl, tetrazolyl, 1,2,4,5-tetrazinyl, 1,2,3,4-tetrazinyl, 1,2,3,5-tetrazinyl, purinyl, pteridinyl, indolizinyl, benzothiadiazole; aziridinyl, epoxy, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, dioxolanyl, dioxane, dithiolanyl, dithiolanyl.
  3. 如权利要求1或2所述化合物或其药学上可接受的盐、酯、光学异构体、互变异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药，Ar1为以下基团中的一种或这些基团的组合：
    The compound according to claim 1 or 2, 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, wherein Ar 1 is one of the following groups or a combination of these groups:
    n为0～2的整数，R2选自以下基团：F、I、Cl、Br、OMe、OH、NH2、CN，n is an integer of 0 to 2, R 2 is selected from the following groups: F, I, Cl, Br, OMe, OH, NH 2 , CN,
    表示连接的位置，“—”划过的环结构的表达方式，表示连接位点于该环结构上任意能够成键的位置。 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.
  4. 如权利要求1或2所述化合物或其药学上可接受的盐、酯、光学异构体、互变异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药，其中，The compound according to claim 1 or 2, 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, wherein:
    Ar1为苯基，n为1，R2为F、Cl、Br、或I，Ar 1 is phenyl, n is 1, R 2 is F, Cl, Br, or I,
    m为0～2的整数，R1为卤素、环丙基、甲基、乙基、异丙基、叔丁基、环丁基、二氟甲氧基、三氟甲氧基，亚甲基炔基、甲氧基、亚甲基氰基、二氟甲基、乙酰基，m is an integer of 0 to 2, R1 is halogen, cyclopropyl, methyl, ethyl, isopropyl, tert-butyl, cyclobutyl, difluoromethoxy, trifluoromethoxy, methylene alkynyl, methoxy, methylene cyano, difluoromethyl, acetyl,
    式(II)表示的环结构为选自下述环结构中的基团：
    The ring structure represented by formula (II) is a group selected from the following ring structures:
    L1为NH且L2为化学键，或者L1为化学键，L2为NH。 L1 is NH and L2 is a chemical bond, or L1 is a chemical bond and L2 is NH.
  5. 如权利要求1-4中任一项所述化合物或其药学上可接受的盐、酯、光学异构体、互变异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药，其中，所述化合物选自以下具体化合物：




    The compound according to any one of claims 1 to 4, 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, wherein the compound is selected from the following specific compounds:




  6. 式(I)所示的酰胺化合物或者其药学上可接受的盐、酯、光学异构体、互变异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药作为钾离子通道调节剂的用途，
    Use of 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 as a potassium ion channel modulator,
    环A为下述式(II)表示的环结构，
    Ring A is a ring structure represented by the following formula (II),
    “—”划过的环结构的表达方式，表示连接位点于该环结构上任意能够成键的位置，虚线表示的键表示存在或者不存在；The expression of a ring structure crossed by “—” indicates that the 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选自CRa或N；X2选自CRa、N或O、S、Se、NRa、C(Ra)2；X3不存在，或者选自CRa、N或NRa、O、S、Se、C(Ra)2；X4选自CRa、N或者NRa、C(Ra)2；X5选自CRa、N或O、S、Se、NRa、C(Ra)2；X6和X7表示C原子，X8选自C或N，X2～X7所形成的环为芳香性的或非芳香性； 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;
    m为0～4的整数，各R1相同或不同，且各自独立地选自卤素、-CN、C1-C6烷基、C2-C6烯基、C2-C6炔基、饱和或部分不饱和的C3-6环烃基、5-10元螺环烷基、饱和或部分不饱和的3-10元杂环基、5-10元螺杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基、-ORa、-NHRa、-C(O)NHRa、-C(＝O)Ra、-OC(＝O)Ra、-C(＝O)ORa、-ORa、-SRa、-S(＝O)Ra、-S(＝O)2Ra、-S(＝O)2N(Ra)2、-N(Ra)2、-NRa-C(＝O)Ra、-NRa-C(＝O)ORa、-NRa-S(＝O)2-Ra、-NRa-C(＝O)-N(Ra)2、-C1-6亚烷基-S(＝O)2Ra、-C1-6亚烷基-CN、-C1-6亚烷基-S(＝O)Ra、-C1-6亚烷基-N(Ra)2、-C1-6亚烷基-ORa、-C1-6亚烷基-NRa-C(＝O)ORa、-C1-6亚烷基-NRa-C(＝O)Ra、-C1-6亚烯基-ORa和-O-C1-6亚烷基-N(Ra)2；R1中的CH2可以被-O-、-S-或-C(＝O)-替换，R1中的H可以被羟基、卤素或C1-C3烷氧基所取代，R1中的环烃基、螺环烷基、杂环基、螺杂环基、芳基、杂芳基、芳烷基可以被卤素、-CN或C1-C3烷基所取代；两个相邻的R1之间可以连接并与环A的组成原子共同形成环结构；m is an integer from 0 to 4, each R1 is the same or different and is independently selected from halogen, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated or partially unsaturated C3-6 cycloalkyl, 5-10 membered spirocycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, 5-10 membered spiroheterocyclyl, C6-10 aryl, 5-14 membered heteroaryl, C6-12 aralkyl, -ORa , -NHRa, -C (O) NHRa , -C(＝O) Ra , -OC(＝O)Ra, -C(＝O) ORa , -ORa , -SRa , -S(＝O) Ra, -S(＝O)2Ra, -S(＝O)2N(Ra)2, -N(Ra)2 , -NRa , -C ( ＝ O ) Ra , -NRa -C(＝O)OR a , -NR a -S(＝O) 2 -R a , -NR a -C(＝O)-N(R a ) 2 , -C1-6 alkylene-S(＝O) 2 R a , -C1-6 alkylene-CN, -C1-6 alkylene-S(＝O)R a , -C1-6 alkylene-N(R a ) 2 , -C1-6 alkylene-OR a , -C1-6 alkylene-NR a -C(＝O)OR a , -C1-6 alkylene-NR a -C(＝O)R a , -C1-6 alkenylene-OR a and -O-C1-6 alkylene-N(R a ) 2 ; CH 2 in R 1 may be replaced by -O-, -S- or -C(＝O)-, H in R 1 may be substituted by hydroxy, halogen or C1-C3 alkoxy, R The cycloalkyl, spirocycloalkyl, heterocyclyl, spiroheterocyclyl, aryl, heteroaryl, aralkyl in 1 may be substituted by halogen, -CN or C1-C3 alkyl; two adjacent R 1s may be connected and form a ring structure together with the constituent atoms of ring A;
    L1为化学键或者NH；L2为化学键或者选自C1-6亚烷基、C2-6亚烯基、C2-6亚炔基、饱和或部分不饱和的C3-10亚环烃基、-O-、-C(＝O)O-、-NRa-、-NRaC(＝S)-、-NRaC(＝O)-、-NRaS(＝O)-、-N RaS(＝O)2-、-S-中的一种或多种组合而成的二价基团； L1 is a chemical bond or NH; L2 is a chemical bond or a divalent group selected from one or more of C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, saturated or partially unsaturated C3-10 cycloalkylene, -O- , -C(=O)O-, -NRa- , -NRaC(=S)-, -NRaC (=O)-, -NRaS(=O)-, -NRaS (=O) 2- , and -S-;
    Ra独立地选自H、C1-C10烷基、C1-C10卤代烷基、饱和或部分不饱和的C3-6环烃基、饱和或部分不饱和的3-10元杂环基或者C6-10芳基，Ra中的CH2可以被-O-或-S-替换，Ra中的H可以被羟基、卤素或C1-C3烷氧基所取代；条件是，L1和L2不同时为化学键，L1为化学键时，L2为-NRa-； 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- ;
    Ar1选自取代或未取代的C6～C30芳基、取代或未取代的C3～C30杂芳基中的一种；Ar 1 is selected from a substituted or unsubstituted C6-C30 aryl group, a substituted or unsubstituted C3-C30 heteroaryl group;
    R2独立地选自取代或未取代的C1-C6烷基、羟基、卤素、氰基、氨基、C1-C6烷基取代氨基、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C6环烷基、取代或未取代的C3-C6杂环基、取代或未取代的苯基、取代或未取代的5-6元的杂芳基、S(O)2Rb1、S(O)2NH2、S(O)2NHRb1、S(O)2NRb1Rb2、NHS(O)2Rb1、NRb1S(O)2Rb2、S(O)(NH)Rb1、S(O)(NRb1)Rb2、C(O)Rb1、C(O)ORb1、OC(O)Rb1、NHC(O)Rb1、NRb1C(O)Rb2、NHC(O)ORb1、NRb1C(O)ORb2、C(O)NH2、C(O)NHRb1、C(O)NRb1Rb2、C(O)NH S(O)2Rb1、S(O)2NHC(O)Rb1；Rb1和Rb2分别独立地选自H、取代或未取代的C1-C3的烷基、取代或未取代的3-6元的环烷基或杂环基，或者Rb1和Rb2连同它们所连接的N原子形成3-7元的杂环基；n为0-4的整数，n为2以上时，多个R2可以相同的也可以不同，两个相邻的R2之间可以连接并与Ar1的组成原子共同形成五元环、或者六元环；上述的取代或未取代是指基团中的H被选自卤素、氰基、硝基、羟基、氨基、醛基、酯基、C1～C30烷基、C1～C30烷氧基、C2～C20杂环烷基、C1～C30烷基硅基、C6～C30芳基、C6～C30芳氧基、C3～C30杂芳基、C6～C30芳基氨基或C3～C30杂芳基氨基中的一种或者至少两种的组合以上的基团所取代，或者指基团中的-CH2-中的两个H被替换成氧代＝O。 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, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, S(O) 2Rb1 , S ( O) 2NH2 , S(O) 2NHRb1 , S(O) 2NRb1Rb2 , NHS(O) 2Rb1 , NRb1S (O) 2Rb2 , S(O)(NH) Rb1 , S(O ) ( NRb1 ) Rb2 , C(O) Rb1 , C ( O) ORb1 , OC(O) Rb1 , NHC(O) Rb1 , NRb1C (O) Rb2 , 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)NH S(O) 2 R b1 , S(O) 2 NHC(O)R b1 ; R b1 and R b2 are independently selected from H, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted 3-6-membered cycloalkyl or heterocyclic group, or R b1 and R b2 together with the nitrogen atom to which they are connected form a 3-7-membered heterocyclic group; n is an integer of 0-4. When n is 2 or more, multiple R 2s may be the same or different, and two adjacent R 2s may be connected and connected to Ar 1 together form a five-membered ring or a six-membered ring; the above-mentioned substitution or unsubstitution means that the H in the group is substituted by a group selected from one or a combination of at least two of halogen, cyano, nitro, hydroxyl, amino, aldehyde, ester, C1-C30 alkyl, C1-C30 alkoxy, C2-C20 heterocycloalkyl, C1-C30 alkylsilyl, C6-C30 aryl, C6-C30 aryloxy, C3-C30 heteroaryl, C6-C30 arylamino or C3-C30 heteroarylamino, or means that two H in -CH2- in the group are replaced by oxo=O.
  7. 根据权利要求6所述的用途，其为在制备作为治疗或缓解与钾离子通道相关疾病的药物中的应用，The use according to claim 6, which is used in the preparation of a drug for treating or alleviating diseases related to potassium ion channels,
    优选地与钾离子通道相关疾病选自中枢神经系统疾病或病症，Preferably, the potassium channel-related disease is selected from central nervous system diseases or disorders,
    进一步优选地中枢神经系统疾病或病症选自发作性疾病、焦虑症、神经性疼痛和偏头痛、神经变性疾病、中风、可卡因滥用、尼古丁戒断症状、乙醇戒断症状、耳鸣和阿尔兹海默症，郁症、衰老过程中的睡眠障碍、神经发育障碍，Further preferably, the central nervous system disease or disorder is selected from the group consisting of 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, neurodevelopmental disorders,
    进一步优选地所述发作性疾病选自急性发作性疾病、惊厥、癫痫持续状态、癫痫症如癫痫综 合征和癫痫发作、新生儿痉挛、新生儿癫痫发作、良性家族性新生儿癫痫KCNQ2-BFNE、癫痫性脑病KCNQ2-NEE、良性家族性新生儿惊厥1型BFNC、良性家族性新生儿癫痫发作1BFNS1、与缺氧缺血性损伤相关的新生儿癫痫发作、癫痫性痉挛、癫痫性脑病、婴儿早期癫痫性脑病7EIEE7、精神运动发育迟缓的婴儿早期癫痫性脑病、全面强直癫痫发作、苍白球形态异常、呼吸暂停、脑水肿、肌张力障碍、面部红斑、肌张力低下、热性癫痫发作、胼胝体发育不全、高度节律失调、局灶性阵挛性癫痫发作、全面强直阵挛性癫痫发作、肌纤维颤搐、痉挛性四肢轻瘫和肌纤维颤搐；所述焦虑症选自焦虑和与下述疾病相关的疾病和病症：惊恐发作、广场恐怖症、伴有广场恐怖症的惊恐障碍、无广场恐怖症的惊恐障碍、无惊恐障碍史的广场恐怖症、特定性恐惧症、社交恐惧症和其它特定性恐惧症、强迫症、创伤后应激障碍、急性应激障碍、广泛性焦虑症、由一般躯体病症引起的焦虑症、物质诱导的焦虑症、离别焦虑症、适应失调、表现焦虑、疑病障碍、由一般躯体病症引起的焦虑症和物质诱导的焦虑症和未有特殊说明的焦虑症；所述神经性疼痛和偏头痛选自异常性疼痛、痛觉过敏性疼痛、幻痛、与糖尿病性神经病变相关的神经性疼痛、与三叉神经痛相关的神经性疼痛与坐骨神经痛相关的神经性疼痛与偏头痛相关的神经性疼痛；It is further preferred that the paroxysmal disease is selected from acute paroxysmal disease, convulsions, status epilepticus, epilepsy such as epileptic syndrome 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 epileptic seizures 1 BFNS1, neonatal epileptic seizures associated with hypoxic-ischemic injury, epileptic spasms, epileptic encephalopathy, early infantile epileptic encephalopathy 7EIEE7, early infantile epileptic encephalopathy with psychomotor retardation, generalized tonic seizures, globus pallidus morphological abnormalities, apnea, cerebral edema, dystonia, facial erythema, hypotonia, febrile seizures, corpus callosum agenesis, hyperrhythmia, focal clonic seizures, generalized tonic-clonic seizures, myokymia, spastic quadriplegia and myokymia; the anxiety disorder is selected from anxiety and Diseases and conditions associated with the following diseases: panic attack, 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 conditions, substance-induced anxiety disorder, separation anxiety disorder, adjustment disorder, performance anxiety, hypochondriasis, anxiety disorder caused by general medical conditions 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;
    进一步优选地所述神经变性疾病选自Alzheimer's病、Huntington's舞蹈病、多发性硬化症、肌萎缩性侧索硬化、Creutzfeld-Jakob's、Parkinson's病、由AIDS引起的或由风疹病毒、疱疹病毒、疏螺旋体属或未知病原体感染诱导的脑病、外伤诱导的神经变性性病变、神经元兴奋过度状态如在药物戒断或中毒症状中以及外周神经系统的神经变性疾病如多发性神经病和多发性神经炎；Further preferably, 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;
    进一步优选地所述抑郁症选自双相抑郁、产后抑郁、严重的抑郁症、精神抑郁症、非典型抑郁症、精神忧郁症、难治性抑郁症、亨廷顿氏病有关的抑郁症、多发性硬化症有关的抑郁症或焦虑症有关的抑郁症；Further preferably, the depression is selected from bipolar depression, postpartum depression, severe depression, dysthymia, atypical depression, melancholia, refractory depression, depression associated with Huntington's disease, depression associated with multiple sclerosis or depression associated with anxiety;
    进一步优选地所述神经发育障碍选自发育迟缓、智力障碍、非综合征性智力障碍、自闭症谱系障碍ASD。It is further preferred that the neurodevelopmental disorder is selected from developmental delay, intellectual disability, non-syndromic intellectual disability, and autism spectrum disorder ASD.
  8. 一种药物组合物，其包含预防或治疗有效量的权利要求1-5中任一项的化合物或者其药学上可接受的盐、酯、光学异构体、互变异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药，以及药学上可接受的载体。A pharmaceutical composition comprising a preventively or therapeutically effective amount of a compound according to any one of claims 1 to 5 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.
  9. 如权利要求7所述的药用组合物，其特征在于，所述的药物组合物的剂型为口服剂型或注射剂，The pharmaceutical composition according to claim 7, characterized in that the dosage form of the pharmaceutical composition is an oral dosage form or an injection,
    所述口服剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂，The oral dosage forms include capsules, tablets, pills, powders and granules. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
    所述注射剂包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的权利要求1-5中任一项的化合物或者其药学上可接受的盐、酯、光学异构体、互变异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药无菌粉末。 The injection comprises a physiologically acceptable sterile aqueous or anhydrous solution, dispersion, suspension or emulsion, and a compound according to any one of claims 1 to 5 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 reconstitution into a sterile injectable solution or dispersion.
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