WO2022228413A1 - Composé pour inhiber la mort cellulaire programmée et son procédé de préparation - Google Patents

Composé pour inhiber la mort cellulaire programmée et son procédé de préparation Download PDF

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WO2022228413A1
WO2022228413A1 PCT/CN2022/089186 CN2022089186W WO2022228413A1 WO 2022228413 A1 WO2022228413 A1 WO 2022228413A1 CN 2022089186 W CN2022089186 W CN 2022089186W WO 2022228413 A1 WO2022228413 A1 WO 2022228413A1
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alkylene
methyl
alkyl
compound
esi
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PCT/CN2022/089186
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Chinese (zh)
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王召印
曹津睿
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中国科学院上海有机化学研究所
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Priority to CN202280030675.3A priority Critical patent/CN117222628A/zh
Publication of WO2022228413A1 publication Critical patent/WO2022228413A1/fr

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Definitions

  • the present invention provides an inhibitor for inhibiting programmed cell necrosis, in particular to a preparation method thereof, and methods and uses for treating and preventing inflammatory and degenerative diseases.
  • Programmed necrosis is a highly inflammatory form of cell death that can be induced by a variety of promoting factors, such as necrosis factor (TNF) and FAS ligands. This process can occur in a variety of cells and is considered to be the main mode of cell death under pathological conditions, directly associated with a variety of inflammatory and degenerative diseases. These diseases include neurodegenerative diseases, stroke, coronary heart disease, myocardial infarction, retinal degenerative diseases, inflammatory bowel disease, kidney disease, liver disease, and many other related diseases.
  • TNF necrosis factor
  • FAS ligands FAS ligands.
  • diseases include neurodegenerative diseases, stroke, coronary heart disease, myocardial infarction, retinal degenerative diseases, inflammatory bowel disease, kidney disease, liver disease, and many other related diseases.
  • RIPK1 receptor interacting protein kinase 1
  • RIPK1 receptor interacting protein kinase 1
  • RIPK1 is a master regulator of cellular determinants of NF- ⁇ B signaling in response to a wide range of inflammatory and pro-lethal stimuli in human disease.
  • RIPK1 inhibitors can provide more effective necroptosis inhibition for the prevention and treatment of inflammatory and degenerative diseases related thereto.
  • the purpose of the present invention is to provide a novel RIPK1 inhibitor that inhibits programmed cell necrosis.
  • Another object of the present invention is to provide a preparation method of the inhibitor.
  • the first aspect of the present invention provides a compound represented by general formula I, or various isomers thereof (such as stereoisomers or tautomers thereof) and pharmaceutically acceptable salts or pro- medicine:
  • Y is CH 2 or CH 2 CH 2 ;
  • Z is O, NR 4A , CR a R b or absent;
  • Ring B is C 3 -C 6 cycloalkyl, phenyl, C 3 -C 6 cycloalkane acyl group, 5-6 membered heteroaryl or 5-6 membered non-aromatic heterocyclic group;
  • Each R 1 is independently H, halogen, -OH, -CN, -COOH, C 1 -C 6 alkyl, -C 0 -C 6 alkyleneoxy C 1 -C 6 alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 10 alkoxyalkyl, C 2 -C 10 haloalkoxyalkyl, C 1 -C 6 hydroxyalkane radical, -C 0 -C 6 alkylene-SC 1 -C 6 alkylene-, -C 0 -C 6 alkylene-C 6 -C 10 aryl, -C 0 -C 6 alkylene-XC 6 -C 10 aryl, -C 0 -C 6 alkylene-5-10-membered heteroaryl, -C 0 -C 6 alkylene-X-5-10-membered heteroaryl, -C
  • R 3 is H, C 1 -C 6 alkyl or -C 0 -C 3 alkylene-C 3 -C 6 cycloalkyl;
  • R 4A is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl
  • n 0, 1, 2 or 3;
  • Ring A is a C 6 -C 10 aromatic ring or a 5-10 membered heteroaromatic ring
  • L is C 0 -C 6 alkylene, C 2 -C 6 alkenylene, C 3 -C 6 cycloalkylene, benzene ring, 5-6 membered heteroaromatic ring or 5-6 membered non-aromatic heterocyclic ring ; L is optionally substituted by 1-3 R 5 ;
  • R 5 is each independently H, halogen, -OH, -CN, carbonyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy ;
  • Each R 6 is independently hydrogen, C 1 -C 10 alkyl, -C 0 -C 6 alkylene-C 6 -C 10 aryl, -C 0 -C 6 alkylene-5-10 membered heteroaryl group, -C 0 -C 6 alkylene-3-10 membered non-aromatic heterocyclic group, -C 0 -C 6 alkylene-C 3 -C 10 cycloalkyl, or -C 0 -C 6 alkylene Alkyl-C 1 -C 10 alkoxy; R 6 are each independently unsubstituted or substituted with 1, 2, 3 or 4 R f ;
  • R f is independently at each occurrence halogen, -OH, carbonyl, -CN, -COOH, C 1 -C 6 alkyl, -C 0 -C 6 alkyleneoxy C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 10 alkoxyalkyl, C 2 -C 10 haloalkoxyalkyl, C 1 - C 6 hydroxyalkyl, -C 0 -C 6 alkylene -C 3 -C 10 cycloalkyl, -C 0 -C 6 alkylene -SC 1 -C 6 alkyl, -SF 5 , -C 0 -C 6 alkylene-COR c , -C 0 -C 6 alkylene-CO 2 C 1 -C 6 alkyl, -C 0 -C 6 alkylene
  • R a , R b and R c are each independently hydrogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 Alkenyl, substituted or unsubstituted C 6 -C 10 aryl, or substituted or unsubstituted C 3 -C 10 heteroaryl; R a and R b may together form three to Eight-membered ring or four- to eight-membered heterocycle; the three- to eight-membered ring or four- to eight-membered heterocycle can be substituted by one or more R e ;
  • R e is independently halogen, -OH, -CN, carbonyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, two Adjacent R e or two R e attached to the same carbon atom together form a three- to eight-membered ring or a four- to eight-membered heterocycle;
  • Each of the above heterocycles and each heteroaryl has 1, 2, 3 or 4 heteroatoms, selected from sulfur, oxygen, N, NH or NR g ;
  • R g is C 1 -C 10 alkyl, C 1 -C 10 heteroalkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, or C 3 -C 10 heteroaryl;
  • Each X is independently O, S, SO, S(O) 2 , NH, CO, CH2 , CF2 , CH( CH3 ), CH(OH), or N( CH3 ).
  • the heteroaryl group is selected from, but not limited to: thienyl, pyridyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrimidinyl, thiazolyl, isothiazolyl, indium dolyl, triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl.
  • the compound of general formula I is the compound represented by formula II:
  • Z 1 and Z 3 are independently N or CR 7 respectively;
  • R 7 is H, halogen, methyl, halomethyl;
  • Z 2 is N or CR 1 ;
  • R 1 , R 2 , R 3 , X, Y, Z, L, Ring B and n are as defined in Formula I.
  • the compound of general formula I is the compound shown in formula III:
  • Z 4 and Z 5 are independently CR 1 , O, S, N or NR 1 ; R 1 , R 2 , R 3 , X, Y, Z, L, ring B and n are as defined in general formula I described.
  • the compound of general formula I is the compound shown in formula IV:
  • X is O, S or CH 2 ;
  • the compound of general formula I is the compound represented by formula V:
  • R 1 , R 2 , X, Z, L, ring B and n are as defined in Formula I.
  • the compound of general formula I is the compound shown in formula VI:
  • X is O, S or CH 2 ;
  • n 0, 1 or 2;
  • n 0, 1, 2, 3 or 4.
  • the compound of general formula I is the compound shown in formula VII:
  • R 1 and R 2 are as defined in general formula I;
  • X is O, S or CH 2 ;
  • n 0, 1 or 2;
  • n is an integer of 0, 1, 2, 3, or to 4.
  • R in the compounds of general formula I to VII is selected from the following groups:
  • the compound of general formula I is:
  • the compounds of general formula I to VII include all stereoisomers.
  • the stereoisomers are cis-trans isomers.
  • the compound is a racemate.
  • the stereoisomer is an enantiomer.
  • any one or more hydrogen atoms in the compound can be replaced by deuterium atoms.
  • the compounds of general formula I to VII include their prodrugs.
  • the pharmaceutically acceptable salts of general formula I to VII are selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, mesylate, trifluoromethane Sulfonate, benzenesulfonate, p-toluenesulfonate (toluenesulfonate), 1-naphthalenesulfonate, 2-naphthalenesulfonate, acetate, trifluoroacetate, malate, tartaric acid Salt, citrate, lactate, oxalate, succinate, fumarate, maleate, benzoate, salicylate, phenylacetate, mandelate.
  • the second aspect of the present invention provides the preparation method of the compound of general formula I described in the first aspect, wherein the method is selected from one of the following schemes.
  • Compounds of (Formula I) are prepared by reacting a fast radical compound (a) containing an R6 group with an aryl halide (Formula Ia- 1 , wherein the halogen is Cl, Br, or I) under Sonogashira coupling conditions.
  • the coupling reaction is carried out in the presence of a metal catalyst (including, but not limited to, a metal palladium catalyst and a metal copper catalyst) and a base, and in a suitable solvent at a temperature (eg, at about 85°C to 120°C). .
  • the reaction can also be promoted by microwave radiation.
  • the metal palladium catalyst includes, but is not limited to, bis(triphenylphosphino) palladium(II) dioxide, oxyallyl palladium(II) dimer, [1,1'-bis(diphenylphosphino)dimer Ferrocene]palladium dioxide ((dppf) PdCl2 ), palladium(II) acetate.
  • the metallic copper catalyst includes, but is not limited to, cuprous iodide. Examples of suitable bases that may be used include, but are not limited to, triethylamine, pyridine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
  • Non-limiting examples of solvents include N,N-dimethylformamide, dimethylacetamide, methanol, ethanol, acetonitrile, dimethoxyethane, dimethylsulfoxide, dioxane, tetrahydrofuran, ethyl acetate Glycol dimethyl ether, toluene.
  • Reaction of Boc-L-serine with a suitably substituted 1-fluoro-2-nitrobenzene with a base affords 1-1, followed by reduction of the nitro group to amine 1-2 (reduction conditions such as but not limited to Zn/AcOH, Fe /NH 4 Cl/EtOH, Zn/NH 4 Cl/EtOH,), and use a condensation reagent for intramolecular condensation to obtain (formula I-3) intermediate (the condensation reagent is, for example, but not limited to, HOAT, HOBT, HATU, EDCI, BOP, TCFH, NMI), the compound of formula 1-3 is methylated to give 1-4, followed by removal of the Boc protecting group under acidic conditions (such as but not limited to CF 3 CO 2 H, HCl) to give the free amine 1-5 .
  • acidic conditions such as but not limited to CF 3 CO 2 H, HCl
  • Reaction of Boc-L-cysteine with a suitably substituted 1-fluoro-2-nitrobenzene with a base affords 1-20, followed by reduction of the nitro group to the amine 1-21 (reduction conditions such as but not limited to Zn/ AcOH, Fe/NH 4 Cl/EtOH, Zn/NH 4 Cl/EtOH,), and use a condensation reagent for intramolecular condensation to obtain (formula I-22) intermediate (the condensation reagent is, for example, but not limited to, HOAT, HOBT, HATU , EDCI, BOP, TCFH/NMI), the compound of formula I-22 is methylated to obtain I-23 and then under acidic conditions (such as but not limited to TFA, HCl), the Boc protection is removed to obtain trifluoroacetate I-24 .
  • the condensation reagent is, for example, but not limited to, HOAT, HOBT, HATU , EDCI, BOP, TCFH/NMI
  • Reaction of 1-23 or 1-24 with alkynyl compounds (a) containing different R6 groups under Sonogashira coupling conditions affords 1-25 or 1-26, respectively.
  • the acid (b) is condensed with an amide condensation reagent (such as but not limited to HOAT, EDCI, HATU, TCFH) using an amide condensation reagent to obtain the final product I.
  • an amide condensation reagent such as but not limited to HOAT, EDCI, HATU, TCFH
  • Boc-L-cysteine reacts with a suitably substituted thiophene derivative I-27 to obtain I-28, the nitro group of compound I-28 is reduced to obtain I-29, and then intramolecular condensation is performed to obtain compound I -30, I-30 was alkylated to obtain I-31, then reacted with NIS to obtain iodide I-31, deprotected Boc under acidic conditions to obtain I-35, and then carried out Sonogashira coupling reaction and amide with reference to Scheme 7 Condensation reaction (condensation reagents such as but not limited to HOAT, EDCI, HATU, TCFH) yields the final product I.
  • Condensation reaction condensation reagents such as but not limited to HOAT, EDCI, HATU, TCFH
  • the third aspect of the present invention provides the use of the compounds of the general formula I to the general formula VII described in the first aspect, for:
  • the disease mediated by programmed cell necrosis is cancer, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, and macular degeneration , pancreatitis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, systemic lupus erythematosus, Sjögren's syndrome, provincial scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, non- Alcoholic fatty liver hepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune ITP, transplant rejection, ischemia-reperfusion injury of solid organs, sepsis, Systemic Inflammatory Response Syndrome, Cerebrovascular Accident, Myocardial Infar
  • alkyl refers to a monovalent saturated aliphatic hydrocarbon group, having from 1 to 10 carbon atoms, including straight and branched chain hydrocarbon groups, such as methyl (ie, CH3- ), ethyl (ie, CH3CH2- ) , n-propyl (ie CH 3 CH 2 CH 2 -), isopropyl (ie (CH 3 ) 2 CH-), n-butyl (ie CH 3 CH 2 CH 2 CH 2 -), isobutyl (ie (CH 3 ) 2 CHCH 2 -), sec-butyl (ie (CH 3 )(CH 3 CH 2 )CH-), tert-butyl (ie (CH 3 ) 3 C-), n-pentyl (ie CH 3 CH2CH2CH2CH2- ) , neopentyl ( ie ( CH3 ) 3CCH2- ) .
  • aryl refers to a monovalent aromatic carbocyclic group of 6 to 20 (preferably 6 to 14) carbon atoms having a single ring (eg, phenyl) or a fused ring (eg, naphthyl). or anthracenyl), if the point of attachment is on an aromatic carbon, the fused ring may be non-aromatic (e.g. 2-benzoxazolone, 2H-1,4-benzoxazin-3(4H)-one-7 - base, etc.).
  • Preferred aryl groups include phenyl and naphthyl.
  • cycloalkyl refers to a cyclic alkyl group having 3 to 10 carbon atoms, having a monocyclic or polycyclic ring (including fused systems, bridged ring systems and spiro ring systems).
  • one or more of the rings may be cycloalkyl, heterocyclic, aryl, or heteroaryl, so long as the point of attachment is through the cycloalkyl ring.
  • suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • heteroaryl refers to an aromatic group having 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur in the ring, such heteroaryl radicals may be monocyclic (eg, pyridyl or furyl) or fused (eg, indolizinyl or benzothienyl), wherein the fused ring may be non-aromatic and/or contain a heteroatom , as long as the point of attachment is through an atom of an aromatic heteroaryl group.
  • the ring atom nitrogen and/or sulfur of the heteroaryl group is optionally oxidized to an N-oxide (N-O), a sulfinyl group or a sulfonyl group.
  • N-O N-oxide
  • Preferred heteroaryl groups include pyridyl, pyrrolyl, indolyl, thienyl and furyl.
  • substituted heteroaryl refers to a heteroaryl group substituted with 1 to 5, preferably 1 to 3, more preferably 1 to 2, substituents selected from and substituted The same substituents as defined for the aryl group.
  • heterocycle or “heterocyclic” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated, partially saturated or unsaturated group (but not aromatic), Has a single ring or a fused ring (including bridged ring system and spiro ring system), with 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, sulfur or oxygen in the ring, in the fused ring system, one or Multiple rings can be cycloalkyl, aryl, or heteroaryl, so long as the point of attachment is through a non-aromatic ring.
  • the nitrogen and/or sulfur atoms of the heterocyclic group are optionally oxidized to provide N-oxide, sulfinyl and sulfonyl moieties.
  • substituted heterocyclic or “substituted heterocycloalkyl” or “substituted heterocyclyl” refers to a heterocyclyl group substituted with 1 to 5 (eg 1 to 3) substituents group, the substituents are the same as those defined for substituted cycloalkyl.
  • the substituent is selected from, but not limited to, the following chemical groups: halogen, -C 1-6 alkyl, -C 3-8 cycloalkyl, -C 1-6 haloalkyl, -C 3-8 halogen Cycloalkyl, -C 1-6 alkoxy, -C 3-8 cycloalkoxy, -C 1-6 alkylthio, -C 0-6 alkylene-OH, nitro, aldehyde, -SF 5 , -C 0-6 alkylene-NR a R b , -C 0-6 alkylene-carboxy, -C 0-6 alkylene-COR a , -C 0-6 alkylene- CO 2 R a , -C 0-6 alkylene-CONR d Re , -C 0-6 alkylene-SO 2 R a , -C 0-6 alkylene-SO 2 NR d Re , - P(O)(OMe
  • C 0-6 alkylene means having no alkylene group or having C 1-6 alkylene group.
  • stereoisomer refers to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
  • Prodrug refers to any derivative of an example compound that, when administered to a subject, is capable of providing, directly or indirectly, an example compound or its active metabolite or residue.
  • Particularly preferred derivatives and prodrugs are those that, when administered to a subject, increase the bioavailability of an example compound (eg, an orally administered compound is more readily absorbed into the bloodstream) or increase the parent compound relative to the parent species
  • Derivatives and prodrugs for delivery to biological compartments such as the brain or lymphatic system.
  • Prodrugs include ester forms of the compounds of the present invention.
  • the present invention includes all stereoisomers of the compounds.
  • the present invention includes all tautomers of the compounds.
  • the present invention also includes deuterated compounds resulting from the substitution of any one or more of the hydrogen atoms in the compound with its stable isotope deuterium.
  • the present invention also provides active ingredients within a safe and effective amount of the compounds of general formula I and general formula VII, and a pharmaceutically acceptable carrier.
  • the “active ingredient” in the present invention refers to the compounds of the general formula I to the general formula VII of the present invention.
  • the "active ingredients" and pharmaceutical compositions of the present invention can be used as inhibitors of programmed necrosis-mediated diseases. In another preferred example, it is used to prepare a medicament for preventing and/or treating a disease mediated by programmed cell necrosis.
  • a “safe and effective amount” refers to an amount of the active ingredient sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of active ingredient/dose, more preferably 10-200 mg of active ingredient/dose.
  • the "one dose” is a tablet or capsule.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gel substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility” as used herein means that the components of the composition can be blended with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients.
  • the compounds of the preferred embodiments will be administered in a therapeutically effective amount by any one of the acceptable modes of administration of agents having similar effects.
  • the actual amount of the compound of the preferred embodiment ie, the active ingredient
  • the drug may be administered several times a day, preferably, once or twice a day. All of these factors are within the consideration of the attending physician.
  • a therapeutically effective dose may generally be a total daily dose administered to a patient in one or divided doses, eg, about 0.001 to about 1000 mg/kg body weight per day, preferably about 1.0 to about 30 mg/kg body weight.
  • Dosage unit compositions can contain dosage factors thereof to form the daily dose. The choice of dosage form depends on various factors, such as the mode of administration and the bioavailability of the drug substance.
  • the compounds of the preferred embodiments can be administered as pharmaceutical compositions by any of the following routes: oral, systemic (eg, transdermal, intranasal, or via suppository), or parenteral (eg, intramuscular, intravenous or subcutaneous).
  • the preferred mode of administration is oral, and a convenient daily dose can be adjusted according to the degree of bitterness.
  • the compositions may take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable composition.
  • Another preferred mode of administration of the compounds of the preferred embodiments is by inhalation. This is an efficient method of delivering therapeutic agents directly to the respiratory tract (see, eg, US Pat. No. 5,607,915).
  • Suitable pharmaceutically acceptable carriers or excipients include, for example, processing agents and drug delivery modifiers and enhancers, such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose , sodium methylcellulose, carboxymethylcellulose, glucose, hydroxypropyl-B-cyclodextrin, polyvinylpyrrolidone, low-melting wax, ion exchange resin, etc., and any combination of two or more thereof.
  • Liquid and semi-solid excipients can be selected from glycerol, propylene glycol, water, ethanol and various oils including petroleum, animal, vegetable or synthetic sources such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • Preferred liquid carriers especially for injectable solutions, include water, saline, aqueous dextrose and glycols.
  • Other suitable pharmaceutically acceptable excipients are described in Remington's Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991), incorporated herein by reference.
  • salts refers to non-toxic acid or alkaline earth metal salts of compounds of general formula I. These salts can be prepared in situ during the final isolation and purification of the compound of general formula I, or by reacting a suitable organic or inorganic acid or base with a basic or acidic functional group, respectively.
  • Representative salts include, but are not limited to: acetate, adipate, alginate, citrate, aspartate, benzoate, besylate, bisulfate, butyrate , camphorate, camphorsulfonate, digluconate, cyclopentane propionate, lauryl sulfate, ethanesulfonate, glucose heptanoate, glycerophosphate, hemisulfate, heptanoic acid Salt, Caproate, Fumarate, Hydrochloride, Hydrobromide, Hydroiodide, 2-Hydroxyethanesulfonate, Lactate, Maleate, Mesylate, Niacinate , 2-naphthyl sulfonate, oxalate, pamoate, pectate, thiocyanate, 3-phenylpropionate, picrate, pivalate, propionate, Succinate, sulfate, tartrate, thio
  • nitrogen-containing basic groups can be quaternized with the following reagents: alkyl halides, such as methyl, ethyl, propyl, butyl chlorides, bromides and iodides; dialkyl sulfates , such as dimethyl, diethyl, dibutyl and dipentyl sulfates; long-chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkanes base halides such as benzyl and phenethyl bromide, etc. Water- or oil-soluble or dispersible products are thus obtained.
  • alkyl halides such as methyl, ethyl, propyl, butyl chlorides, bromides and iodides
  • dialkyl sulfates such as dimethyl, diethyl, dibutyl and dipentyl sulfates
  • Base addition salts can be prepared in situ during the final isolation and purification of the compound of general formula I, or by separating the carboxylic acid moiety with a suitable base such as a pharmaceutically acceptable metal cation hydroxide, carbonate or carbonic acid. Hydrogen salts) or ammonia, or organic primary, secondary or tertiary amines.
  • Pharmaceutically acceptable salts include, but are not limited to, alkali and alkaline earth metal-based cations, such as sodium, lithium, potassium, calcium, magnesium, aluminum, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including , but not limited to: ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc.
  • Other representative organic amines for forming base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.
  • EA Ethyl acetate.
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • DCM dichloromethane
  • DIBAL diisobutylaluminum hydride
  • DIEA diisopropylethylamine
  • DMAP N,N-Dimethylaminopyridine
  • DME 1,2-dimethoxyethane
  • DMF N,N-dimethylformamide
  • DMPE 1,2-bis(dimethylphosphine)ethane
  • DMSO dimethyl sulfoxide
  • DPPB 1,4-bis(diphenylphosphino)butane
  • DPPE 1,2-bis(diphenylphosphino)ethane
  • DPPF 1,1'-bis( diphenylphosphine) ferrocene
  • DPPM 1,1'-bis(diphenylphosphino)methane
  • DI 1,1'-bis(diphenylpho
  • Reverse-phase HPLC purification conditions Waters micromass ZQ 4000 (MAA050 model) was used as mass detector, Waters 2487UV was used as detector, and HPLC-MS analysis was performed on Waters HPLC 2790.
  • the chromatographic column used was Phenometria OOB-4605-E0 (5U-XB-C18-100A, 50 ⁇ 4.6 mm).
  • the mobile phases were eluent A (water, 0.05% TFA) and eluent B (CH 3 CN, 0.05% TFA) at a rate of 1 ml/min.
  • the initial conditions were 90% A for 1 minute, then 90% A decreased linearly to 10% A in 5 minutes, and then rose from 10% A to 90% A in 1 minute, for a total run time of 7 minutes.
  • the mobile phase gradient and run time can be adjusted appropriately.
  • intermediate NN-1 (1eq), intermediate M-5 (1eq) and HATU(O-(7-azabenzotriazol-1-yl)-N,N,N′,N′ -Tetramethylurea hexafluorophosphate, 1.2eq) was dissolved in dichloromethane (the concentration of the reactant was 0.1M), DIEA (3eq) was added under an ice bath, the ice bath was removed after 10 minutes, and after stirring at room temperature for 2h, the addition of DIEA (3eq) was added.
  • Example 2 (T-2, yellow solid) was obtained using the same conditions as Example 1.
  • Example 4 was obtained using the same conditions as Example 3.
  • Example 5 Using M-7 and o-fluorophenethylamine as raw materials, use the same conditions as Example 3 to obtain Example 5.
  • Example 6 Using M-7 and 4-fluorophenethylamine as raw materials, using the same conditions as Example 3, through HPLC (mobile phase: A: H2O (+0.1% FA); B: MeCN; Separation conditions: 60% B; Flow rate: 10mL/min; Column: Water MSC18, 19 ⁇ 250 mm, 10 ⁇ m) was purified to obtain Example 6.
  • HPLC mobile phase: A: H2O (+0.1% FA); B: MeCN; Separation conditions: 60% B; Flow rate: 10mL/min; Column: Water MSC18, 19 ⁇ 250 mm, 10 ⁇ m
  • Example 7 (T-7) was obtained.
  • Example 8 Using M-7 and 3-chlorophenethylamine as raw materials, using the same conditions as Example 3, Example 8 (T-8) was obtained.
  • Example 10 (T-10) was obtained.
  • Example 11 (T-11) was obtained.
  • Example 12 Using M-7 and 3-fluorophenethylamine as raw materials, using the same conditions as Example 9, Example 12 was obtained.
  • Example 13 (T-13) was obtained.
  • Example 14 (T-14) was obtained.
  • Example 15 (T-15) was obtained.
  • Example 2 (50 mg), zinc cyanide (13.4 mg), PdPPh 3 (32.4 mg), and DMF (3 ml) were added to the reaction vessel, and a microwave reactor was used to react at 100 °C, and after one hour, a saturated solution was added at 0 °C. Sodium bicarbonate solution, the organic phase was extracted with EA, and the organic phase was washed 3 times with water. Concentrated under reduced pressure, separated by preparative HPLC (mobile phase: A, H2O (+0.1% TFA); B, MeCN; separation condition: 53% B; flow rate: 24 mL/min; chromatographic column: Water MSC18, 19 ⁇ 250 mm, 10 ⁇ m) to obtain Example 16 (T-16, white solid).
  • M-8 was dissolved in a solvent with THF:TFA ratio of 5:2, reacted at room temperature for 1 hour, and the solvent was spin-dried to obtain intermediate M-9. Go directly to the next step without purification.
  • Example 17 For the preparation method of Example 18, see Example 17, and the raw materials are M-4 and 2-alkynylpyridine.
  • the preparation method of embodiment 19 refers to embodiment 17, and takes raw material as M-5 and 3-methylbutynol-3, reacts under Sonogashira coupling conditions to obtain intermediate M-12, and then reacts with intermediate NN-4 One-step condensation to obtain the target compound T-19.
  • the target product T-20 is obtained by one-step condensation of intermediate M-12 and intermediate NN-2.
  • Example 21 (T-21) was obtained after HPLC purification.
  • Example 22 (T-22) was obtained.
  • Example 23 (T-23) was obtained.
  • Example 24 (T-24) was obtained.
  • Example 26 (T-26) was obtained.
  • Example 27 Using N-5 and NN-7 as raw materials, the same method as in Example 25 was used to obtain Example 27 (T-27).
  • Example 28 (T-28) was obtained.
  • Example 29 The preparation method of Example 29 (T-29) was the same as that of Example 17 using intermediates N-8 and N-9.
  • Example 21 (40mg), 4-alkynylpyridine (26.4mg), PdCl2 ( PPh3 ) 2 (7.9mg), CuI (4.3mg) were dissolved in DMF (2ml) and triethylamine (1ml) , under argon protection, heated to 85 °C, after 3 hours of reaction, cooled to room temperature, vacuum rotary evaporation to remove the solvent, HPLC separation (mobile phase: A, H2O (+0.1% TFA); B, MeCN; separation conditions : 55%B; Flow rate: 10mL/min; Column: Water MSC18, 19 x 250 mm, 10 ⁇ m) to give Example 30.
  • HPLC separation mobile phase: A, H2O (+0.1% TFA)
  • B MeCN
  • separation conditions 55%B
  • Flow rate 10mL/min
  • Example 31 was obtained in the same manner as Example 30.
  • Example 32 was obtained by the same method as Example 30.
  • Example 34 was obtained by the same method as Example 33.
  • Example 35 Using N-11 and NN-5 as starting materials, the same method as Example 33 was used to obtain Example 35.
  • Example 36 was obtained by the same method as Example 33.
  • Example 37 For the preparation method of Example 37, refer to Example 17, and take the raw material as N-5 and 3-methylbutynol-3, react under Sonogashira coupling conditions to obtain intermediate N-12, and then react with intermediate NN-4 One-step condensation to obtain the target compound (T-37).
  • Example 37 For the preparation method of Example 38, see Example 37.
  • the target compound (T-38) is obtained by one-step condensation of intermediate N-12 and intermediate NN-4.
  • the preparation method of embodiment 39 is referred to in embodiment 17, and is with raw material as N-5 and cyclopropyne, reacted under Sonogashira coupling conditions to obtain intermediate N-13, and then condensed with intermediate NN-4 in one step to obtain the target compound ( T-39).
  • Example 40 For the preparation method of Example 40 (T-40), please refer to Example 1.
  • the preparation method of the intermediate O-5 can refer to the literature (J.Med.Chem.2017,60,1247-1261).
  • MS-ESI: m/z 368.2 [M+H] + .
  • Example 41 For the preparation method of Example 41 (T-41), please refer to Example 1.
  • the preparation method of the intermediate P-5 can refer to the patent (BANDYOPADHYAY, Heterocyclic amides as kinase inhibitors. WO 2014/125444).
  • Example 41 Under ice bath, Example 41 (50mg) was dissolved in DMF (2ml), cesium carbonate (64.9mg) was added, MeI (0.011ml) was added, stirred at 0°C for 5min, returned to room temperature for reaction, after 2h, EA was added first , add ice water, extract three times with EA, combine the organic phases, wash three times with water and three times with saturated brine, add anhydrous sodium sulfate to dry the organic phase, and concentrate the organic phase.
  • Example 42 T-42) was isolated as a white solid by preparative HPLC.
  • Example 44 T-44, white solid
  • Example 45 T-45, white solid was obtained using the same condensation conditions as Example 42.
  • Example 46 (T-46, white solid) was obtained using the same condensation conditions as Example 42.
  • Example 47 (T-47) was obtained.
  • Example 48 T-48, white solid.
  • Example 49 white solid.
  • Example 50 (T-50, white solid) was obtained using the same conditions as Example 42.
  • Example 51 T-51, white solid
  • Example 52 T-52, white solid.
  • reaction mixture was heated to 100°C and reacted for 2 hours.
  • the reaction solution was poured into ice water (10.0 mL), extracted with EA (20.0 mL), and the organic phase was dried over sodium sulfate, filtered, and concentrated to dryness.
  • Column chromatography separation and purification (mobile phase gradient is 0-80% ethyl acetate/petroleum ether) to obtain 173.0 mg of the target compound.
  • the product of the first step (173.0 mg, 0.46 mmol) was dissolved in dichloromethane (5.0 mL), and trifluoroacetic acid (1.0 mL) was added dropwise to the reaction system. Chloromethane (10.0 mL) was dissolved and the pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution. The organic phase was collected, dried over sodium sulfate, filtered, and concentrated to dryness to obtain 114.0 mg of the title compound.
  • the product of the third step (21.3 mg, 0.11 mmol) was dissolved in 1.0 mL of DMF, HATU (41.8 mg, 0.11 mmol), DIPEA (28.4 mg, 0.22 mmol) were added, the reaction was stirred at room temperature overnight, and then 10.0 mL of Saturated ammonium chloride and 15.0 mL of ethyl acetate, the organic phase was washed three times with 10.0 mL of saturated ammonium chloride, and then twice with 10.0 mL of saturated brine. The organic phase was retained and dried over anhydrous sodium sulfate.
  • reaction mixture was heated to 100°C. After 2 hours of reaction, the reaction solution was poured into ice water (10.0 mL), extracted with EA (20.0 mL), and the organic phase was dried over sodium sulfate, filtered, and concentrated to dryness. Separation and purification by column chromatography (mobile phase gradient 0-80% ethyl acetate/petroleum ether) gave 180.0 mg of the target compound.
  • the target compound was obtained by the same reaction conditions and method as the third step of Example 53.
  • the first step 1,3-dibromo-2-(bromomethyl)benzene
  • 1,3-Dibromo-2-methylbenzene (2.50g, 10.0mmol) was dissolved in carbon tetrachloride (40.0mL), AIBN (164.0mg, 1.0mmol) was added, NBS (1.78g, 10.0mmol) was added , replaced nitrogen, the reaction was heated to 80 ° C for 14 hours, the reaction system was cooled to room temperature, filtered through celite, spin-dried, and separated and purified by column chromatography (mobile phase gradient 0-5% ethyl acetate/petroleum ether) to obtain Target compound 2.75g. 1 H NMR (400MHz, CDCl 3 ): ⁇ 7.55(d, 2H), 7.04-7.00(t, 1H), 4.83(s, 2H).
  • the product of the second step (3.45 g, 7.42 mmol) was dissolved in dichloromethane (30 mL), TFA (6.0 mL) was added under ice bath, stirred for 1 hour under ice bath, the reaction was directly spin-dried, and dichloromethane (10 mL) was added. ) was dissolved, 1M aqueous sodium hydroxide solution was added to adjust the pH to about 9, extracted with dichloromethane (10 mL ⁇ 2), the organic phases were combined and dried with anhydrous sodium sulfate.
  • the product of the fourth step (2.32 g, 6.61 mmol) was dissolved in a mixture of 20.0 mL of tetrahydrofuran and 6.0 mL of water, placed in an ice bath to cool, and a solution of lithium hydroxide water (4.95 mL, 2M, 9.92 mmol) was added and stirred. Overnight, 1M dilute hydrochloric acid was added to adjust the pH to 6, then the reaction was directly spin-dried, and then toluene was used to carry water 3 times to obtain 2.2 g of the crude product of the target compound.
  • the fifth step product (34.0 mg, 0.08 mmol) and (S)-3-amino-5-methyl-7-(((1-methyl-1H-pyrazol-4-yl)ethynyl)-2, 3-Dihydrobenzo[b][1,4]oxa-4(5H)-one (20.0 mg, 0.068 mmol), dissolved in 1.0 mL of DMF, added HATU (33.0 mg, 0.088 mmol), DIPEA (26.0 mg, 0.20 mmol), the reaction was stirred at room temperature overnight, 10.0 mL of saturated ammonium chloride and 15.0 mL of ethyl acetate were added, the organic phase was washed three times with 10.0 mL of saturated ammonium chloride, and then with 10.0 mL of saturated common salt Wash twice with water.
  • the target compound was obtained under the same reaction conditions as the first to fifth steps in Example 57.
  • the product of the first step (1.13 g, 4.47 mmol) was dissolved in a mixture of 15.0 mL of tetrahydrofuran and 5.0 mL of water, placed in an ice bath to cool, and a solution of lithium hydroxide (1.34 mL, 4M, 5.36 mmol) was added, and after stirring overnight 1M diluted hydrochloric acid was added to adjust the pH to 6, then the reaction was directly spin-dried, and then toluene was used to bring water 3 times to obtain 1.20 g of the crude product of the target compound.
  • 2,6-Dimethylbenzonitrile (1.31g, 10.0mmol) was dissolved in methanol (30mL) and ammonia water (10mL), Raney nickel (1.5g) was added, heated to 50°C and stirred overnight after the reaction solution diatom Filtration with soil, spin-dried to obtain 1.40 g of crude product of the target compound.
  • Example 67 With intermediate (S)-3-(3-hydroxy-3-methylbut-1-yn-1 yl)-5-methyl-2,3-dihydrobenzo[b][1,4]thiazole Using the same conditions as Example 43, Example 67 was obtained using phenoline-4 (5 hydrogen) and NN-5 as starting materials.
  • the first step 1-phenylcyclopropyl-amine
  • Benzonitrile (1 mL) was dissolved in tetrahydrofuran (60 mL), tetraisopropyl titanate (1.65 mL) was slowly added under dry ice ethanol bath cooling, and then ethylmagnesium bromide (2M, 5.2 mL) was slowly added dropwise to the reaction solution.
  • boron trifluoride ether solution (6 mL, 48%) was slowly added dropwise, then it was quenched with 40 mL 1N hydrochloric acid under ice-cooling, basified with NaOH (10%, 120 mL) aqueous solution, and the organic phase was separated.
  • the second step 2-oxo 2-((1-phenylcyclopropyl)amino)acetic acid
  • the third step using 2-oxo-2-((1-phenylcyclopropyl)amino)acetic acid and Q-11 as raw materials, see Example 51 for the preparation method of Example 84.
  • MS-ESI: m/z 500.1.
  • the first step 2-(methyl(phenethyl)amine)-2-oxoacetic acid
  • the first step (R)-2-oxo-2-((1-phenethyl)amine)acetic acid
  • the first step (S)-2-oxo-2-((1-phenethyl)amine)acetic acid
  • cerium trichloride (.512g) was mixed with tetrahydrofuran (200mL), cooled in a dry ice ethanol bath (-72°C), and methyllithium (1.3M) (20mL) was slowly added dropwise under nitrogen protection, reaction 1 After 1 hour, a solution of 2-chloro-6-fluorobenzonitrile (1.023 g) in (7 mL) tetrahydrofuran was slowly added dropwise, and the reaction was stirred at -72 °C for 4 hours, then warmed to 0 °C, and saturated with 20 (mL) of ammonium chloride. After quenching, the mixture was filtered and concentrated to give 2-(2-chloro-6-fluorophenyl)propan-2-amine (90 mg) by column chromatography.
  • the second step 2-((2-(2-chloro-6-fluorophenyl)propan-2-yl)amine)-2-oxoacetic acid
  • the third step using the products of the first step and the second step as raw materials, see Example 51 for the preparation method of Example 93.
  • MS-ESI: m/z 554.1.
  • Step 2 Dissolve 1g M-1 in ethanol/water (10ml/3ml), add 538.78mg ammonium chloride, 1.38g iron powder, react at 80°C for 20min, filter through celite while hot to remove insoluble matter, and concentrate the filtrate to obtain Product M-2.
  • the third step dissolve 5.61g M-2 in 30ml DMSO, then add 4.15ml TEA, then slowly add 11.602g HATU, react at room temperature for 3.5 hours, add 300ml ice water to the system, a yellow solid is precipitated in the system, and the system Stir in an ice bath for 30 min, filter, rinse the solid with water, collect the solid and dry to obtain intermediate M-3.
  • MS-ESI: m/z 355.0 [MH] ⁇ .
  • Step 4 Nitrogen protection. Under ice bath, M-3 (2.138g) was dissolved in DMF (10ml), cesium carbonate (2.739g) was added, MeI (0.458mL) was added, stirred at 0°C for 5min, the reaction was raised to room temperature for 3h, and added to the system. Ice water (40ml), a large amount of solids were precipitated, filtered, washed with water (40ml x 3), washed with ether (10ml x 2), dried to obtain white solid M-4.
  • the fifth step at room temperature, the intermediate M-4 (2.5g) was dissolved in dichloromethane/trifluoroacetic acid (15ml/3ml), reacted for 2 hours, the solvent was removed by vacuum rotary evaporation, and the pH was adjusted with saturated sodium bicarbonate solution to 8, and extracted with ethyl acetate (30 ml x 5), dried over anhydrous copper sulfate, and the solvent was removed by vacuum rotary evaporation to obtain an orange solid product M-5.
  • the sixth step choose a two-necked bottle as the reaction vessel, the system is strictly dewatered, protected by argon, add intermediate M-5 (1g), ultra-dry THF (20mL) and triethylamine (590 ⁇ L) to the system, replace the argon Three times, slowly inject oxalyl chloride monomethyl ester (381 ⁇ L) under dry ice ethanol bath cooling, stir for 5 minutes, return to room temperature, continue stirring for 10 minutes, add MeOH (0.2 eq) under ice bath after 0.5 h, a white solid is precipitated , was removed by filtration, the solid was washed with methyl tert-butyl ether, the filtrate was concentrated, and the filtrate was separated and purified by flash column chromatography (30-35% EA in PE) to obtain the orange solid product M-6.
  • intermediate N-5 The synthesis method of intermediate N-5 is basically the same as that of intermediate M-5.
  • the synthetic route of intermediate Q-5 is basically the same as that of M-5.
  • the first step After dissolving L-Boc-cysteine (14.5 g, 65.531 mmol) in 80 mL of ethanol at room temperature, NaHCO 3 (34 g, 242 mmol) was slowly added. Protected by N2 , 4-bromo-1-fluoro-nitrobenzene (8.3 mL, 66.4 mmol) was slowly added dropwise to the reaction solution, and the reaction was warmed to 80 °C.
  • the second step Intermediate Q-2 (0.47g), zinc powder (0.962g), ammonium chloride (0.962g, 14.683mmol) were dissolved in methanol (20mL). The reaction solution was heated and reacted at 75°C for 2.5 hours. After the reaction solution was filtered, the filter residue was washed with hot methanol solution, the filtrate was mixed and concentrated, and the liquid was separated with water and dichloromethane (30 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered again, and the filtrate was concentrated to obtain a white The solid is intermediate Q-2.
  • intermediate Q-2 (0.502g, 1.278mmol) was dissolved in DMF (20mL), followed by adding N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (i.e. TCFH, 0.49 g, 1.289 mmol), followed by the slow dropwise addition of N-methylimidazole (0.16 mL g, 2.0078 mmol).
  • TCFH N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate
  • the fourth step using the intermediate Q-3 as a raw material, and adopting the same synthesis conditions as the intermediate M-4 to carry out methylation to obtain the intermediate Q-4.
  • MS-ESI: m/z 331.0 [M+H-tBu] + .
  • the fifth step using the intermediate Q-4 as a raw material and adopting the same conditions as the intermediate M-5 to remove Boc to obtain the intermediate Q-5.
  • the first step choose a two-necked bottle as the reaction vessel, under argon protection, add amine (1eq), THF (to make the amine concentration 1M) and triethylamine (1.2eq), and slowly inject into the system under a dry ice ethanol bath.
  • Oxalyl chloride monomethyl ester (1.1eq) was stirred for 10 minutes, then removed from the ice bath, returned to room temperature, and continued to stir for 10 minutes.
  • MeOH 0.2eq
  • was added under the ice bath the reaction solution was concentrated, the solid was removed by filtration, and the The solid was washed with butyl ether, the filtrate was concentrated, and the solid product was obtained by flash column chromatography (20-30% EA in PE).
  • R 2 of intermediate MM-1 The product is a white solid.
  • R2 of intermediate MM- 2 is: The product is a white solid.
  • R2 of intermediate MM- 4 is: The product was a pale yellow solid. MS-ESI: m/z 214.0 [M+H] + .
  • R2 of intermediate MM- 5 is: The product was a yellow solid. MS-ESI: m/z 246.0 [M+H] + .
  • (a) Cell culture Jurkat fadd-deficient cells were cultured with 10% fetal bovine serum FBS, 100 U/mL penicillin, 100 U/mL streptomycin plus RPMI 1640 medium. The cells were cultured in a cell incubator containing 5% CO 2 at 37°C, and all cells were cryopreserved using complete medium containing 5-10% DMSO. Change the medium for passage 3-4 times a week.
  • RPMI 1640 medium (GIBCO, USA), fetal bovine serum (GIBCO, USA), Human recombinant TNF (Novoprotein C008), Cell Titer-Glo Kit (Promega, USA), Nec-1s were combined by Ma Dawei of Shanghai Organic Institute into, compound GSK2982772 (Bide Reagent Company).
  • the cells were placed in a cell culture incubator for co-incubation for 13h (the cell death rate in the TNF- ⁇ group alone reached 65%), and the total volume of each well was 50 ⁇ L. Then follow the steps below to detect cell viability.
  • Example 36 0.06 Example 37 6.7 Example 38 13 Example 39 1.8 Example 40 152 Example 41 1418 Example 42 319 Example 43 ⁇ 0.1 Example 44 ⁇ 0.1 Example 45 ⁇ 0.1 Example 46 ⁇ 0.1 Example 47 ⁇ 0.1 Example 48 ⁇ 0.1 Example 49 ⁇ 0.1 Example 50 ⁇ 0.1 Example 51 ⁇ 0.1 Example 52 ⁇ 0.1 Example 53 32 Example 54 42 Example 55 184 Example 56 74 Example 57 7.8 Example 58 2.8 Example 59 >1000 Example 60 485 Example 61 ⁇ 1 Example 62 1.3 Example 63 77.8 Example 64 ⁇ 1 Example 65 156.6 Example 66 126.2 Example 67 542.8 Example 68 1.6 Example 69 twenty one Example 70 3.2 Example 71 3.4 Example 72 4.1 Example 73 ⁇ 1 Example 74 43 Example 75 ⁇ 1 Example 76 19 Example 77 ⁇ 1 Example 78 ⁇ 1 Example 79 ⁇ 1
  • Example 80 ⁇ 1
  • Example 81 ⁇ 1
  • Example 82 9.4
  • Example 83 ⁇ 1
  • Example 84 ⁇ 1
  • Example 85 ⁇ 1
  • Example 86 9.5
  • Example 88 ⁇ 1 Example 89 ⁇ 1
  • Example 90 2.7
  • Example 91 1.89
  • Example 92 ⁇ 1 Example 93 ⁇ 1
  • Example 94 3.1
  • Example 95 53 Example 96 1.74
  • Example 98 3.3
  • RIPK1 activity inhibition test was completed by NANOSYN Testing Service Company (3100 Central Expressway, Santa Clara, CA 95051).
  • the test compounds were dissolved in DMSO to a maximum height of 1 micromolar, and then sequentially diluted 3-fold, the concentration of DMSO in the test medium was kept at 1%, and IC 50 was obtained for a total of 12 test concentrations each.

Abstract

La présente invention concerne un inhibiteur de RIPK1 pour inhiber la mort cellulaire programmée et son procédé de préparation. L'inhibiteur de RIPK1 selon la présente invention est représenté par la formule générale I, dans laquelle X, Y, Z, L, R1, R2, R3, R4, le cycle A, le cycle B et n sont tels que définis dans la description et les revendications. La présente invention concerne en outre un procédé de préparation de formule générale I et un résultat d'essai d'activité de formule générale I pour inhiber la mort cellulaire programmée et RIPK1. Le composé de formule générale I selon la présente invention peut être utilisé pour préparer un médicament pour le traitement et la prévention de maladies inflammatoires et dégénératives.
PCT/CN2022/089186 2021-04-27 2022-04-26 Composé pour inhiber la mort cellulaire programmée et son procédé de préparation WO2022228413A1 (fr)

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CN105121432A (zh) * 2013-02-15 2015-12-02 葛兰素史密斯克莱知识产权发展有限公司 作为激酶抑制剂的杂环酰胺
CN106573006A (zh) * 2014-08-21 2017-04-19 葛兰素史密斯克莱知识产权发展有限公司 作为药物的rip1激酶抑制剂杂环酰胺
CN109843886A (zh) * 2016-10-17 2019-06-04 豪夫迈·罗氏有限公司 二环吡啶酮内酰胺及其使用方法
WO2021029632A1 (fr) * 2019-08-09 2021-02-18 Bisichem Co., Ltd. Composés hétéroaryle à cycles condensés utilisés en tant qu'inhibiteurs de ripk1

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105121432A (zh) * 2013-02-15 2015-12-02 葛兰素史密斯克莱知识产权发展有限公司 作为激酶抑制剂的杂环酰胺
CN106573006A (zh) * 2014-08-21 2017-04-19 葛兰素史密斯克莱知识产权发展有限公司 作为药物的rip1激酶抑制剂杂环酰胺
CN109843886A (zh) * 2016-10-17 2019-06-04 豪夫迈·罗氏有限公司 二环吡啶酮内酰胺及其使用方法
WO2021029632A1 (fr) * 2019-08-09 2021-02-18 Bisichem Co., Ltd. Composés hétéroaryle à cycles condensés utilisés en tant qu'inhibiteurs de ripk1

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