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WO2022171111A1 - Composé bicyclique fusionné hétéroaryle utile en tant qu'inhibiteur de la rip1-kinase et ses utilisations - Google Patents

Composé bicyclique fusionné hétéroaryle utile en tant qu'inhibiteur de la rip1-kinase et ses utilisations Download PDF

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Publication number
WO2022171111A1
WO2022171111A1 PCT/CN2022/075609 CN2022075609W WO2022171111A1 WO 2022171111 A1 WO2022171111 A1 WO 2022171111A1 CN 2022075609 W CN2022075609 W CN 2022075609W WO 2022171111 A1 WO2022171111 A1 WO 2022171111A1
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Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
cyclopropyl
disease
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PCT/CN2022/075609
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English (en)
Inventor
Yuhua Ji
Yeyu Cao
Dawei Ma
Jinlong ZHAO
Ning Yan
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Zai Lab (Us) Llc
Shanghai Insititute Of Organic Chemistry, Chinese Academy Of Sciences
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Publication of WO2022171111A1 publication Critical patent/WO2022171111A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems

Definitions

  • This application relates to compounds that inhibit cell necrotic and/or receptor-interacting protein-1 (RIP1) kinases and uses thereof.
  • RIP1 receptor-interacting protein-1
  • RIP1 kinase has been found to be a central regulator of cell signaling, which functions in a variety of cellular pathways related to both cell survival and death.
  • the cell death regulated by RIP1 kinase include apoptosis and necroptosis.
  • RIP1 kinase inhibitors could provide therapeutic benefit in a subject with RIP1 kinase-mediated diseases or disorders, including but not limited to myocardial infarction, stroke, atherosclerosis, ischemia-reperfusion injury, inflammatory bowel diseases, psoriasis, rheumatoid arthritis, retinal degeneration and a number of other inflammatory diseases, hematological and solid organ malignancies, pancreatic cancer, bacterial infections and viral infections (including, but not limited to, tuberculosis and influenza) and Lysosomal storage diseases.
  • diseases or disorders including but not limited to myocardial infarction, stroke, atherosclerosis, ischemia-reperfusion injury, inflammatory bowel diseases, psoriasis, rheumatoid arthritis, retinal degeneration and a number of other inflammatory diseases, hematological and solid organ malignancies, pancreatic cancer, bacterial infections and viral infections (including, but not limited to, tuberculo
  • a pre-clinical candidate of an RIP1 kinase inhibitor is also desired to possess an in vitro activity at a certain level against animal cell lines so that the candidate can be dosed at an appropriate amount to carry out the pre-clinical study without foreseen negative impact on the animal’s health.
  • the existing RIP1 kinase inhibitors show poor in vitro activity against animal cell lines. This therefore creates difficulties for conducting pre-clinical studies.
  • This application provides RIP1 kinase inhibitors that can demonstrate satisfactory in vitro potency against both human and animal cell lines.
  • one of R and R’ is H and the other is a 6-membered heteroaryl substituted by one or more R 1 , a fused bicyclic 9-membered heteroaryl, or phenyl, wherein each of the fused bicyclic 9-membered heteroaryl and phenyl is optionally substituted by one or more R 1 , wherein the 6-membered heteroaryl comprises one or two heteroatom that is N,
  • R 1 is independently selected from oxo, -F, -Cl, -Br, -I, -C 3-5 cycloalkyl, -C 1-5 alkyl substituted by 1-5 F, -C 1-5 alkyl, -OR 2 , -NR 3 R 4 , and -CONH 2 , provided that when R is a 6-membered heteroaryl, R is not substituted by -C 1-5 alkyl alone,
  • R 2 is -C 1-5 alkyl, -C 3-5 cycloalkyl, or -CH 2 C 3-5 cycloalkyl, wherein the -C 1-5 alkyl is optionally substituted by 1-5 F,
  • R 3 is H or -C 1-3 alkyl
  • R 4 is H, -C 1-5 alkyl, -C 3-5 cycloalkyl, 5-6 membered heterocycyl, or -CH 2 C 3-5 cycloalkyl, wherein the C 1-5 alkyl is optionally substituted by 1-5 F, or R 3 and R 4 together with the N to which they are attached form a 4-12 membered heterocyclyl optionally substituted by a group selected from -C 3-5 cycloalkyl and -C 1-5 alkyl optionally substituted by 1-5 F,
  • R 5 and R 6 are independently H, -CD 3 , -C 1-3 alkyl optionally substituted by 1-3 F, or cyclopropyl,
  • R 7 is -CH 3 , -CD 3 , or cyclopropyl
  • R 8 is H, F or Cl.
  • composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • the disease or disorder mediated by RIP1-kinase include cancer and inflammatory diseases.
  • the disease or disorder include inflammatory bowel diseases, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, osteoarthritis, spondylarthritis, gout, systemic onset juvenile idiopathic arthritis (SoJIA) , psoriatic arthritis) , systemic lupus erythematosus (SLE) , Sjogren's syndrome, systemic scleroderma, anti-phospholipid syndrome (APS) , vasculitis, liver damage/diseases (non-alcohol steatohepatitis, alcohol steatohepatitis, autoimmune hepatitis autoimmune hepatobiliary diseases, primary scle
  • cisplatin acute kidney injury (AKI) ) , Celiac disease, autoimmune idiopathic thrombocytopenic purpura, transplant rejection, ischemia reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome (SIRS) , cerebrovascular accident (CVA, stroke) , myocardial infarction (MI) , atherosclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) , spinal muscular atropy (SMA) , allergic diseases (including asthma and atopic dermatitis) , multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme (ICE, also known as caspase-1) associated fever syndrome, chronic obstructive pulmonary disease (COPD) , tumor necrosis factor receptor-associated periodic syndrome (TRAPS) , periodontitis, linear
  • a dash ( "-" ) at the left hand side of a substituent is used to indicate a point of attachment for a substituent.
  • -CONH 2 is attached through the carbon atom.
  • alkyl herein refers to a straight or branched hydrocarbon chain.
  • the symbol of C subscripted with a number range that precedes the term “alkyl” stands for the number of carbons in the alkyl.
  • C 1-5 alkyl represents an alkyl containing 1, 2, 3, 4, or 5 carbon atoms.
  • Examples of C 1-5 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, and pentyl.
  • cycloalkyl refers to a saturated and partially unsaturated cyclic hydrocarbon group only having carbon atom as the ring atom.
  • the symbol of C subscripted with a number range that precedes the term “cycloalkyl” stands for the carbon ring numbers in the cycloalkyl.
  • C 3-5 cycloalkyl represents a cycloalkyl containing 3, 4, or 5 carbon ring atoms, i.e., cyclopropyl, cyclobutyl, or cyclopentyl.
  • the ring may be saturated or have one or more double bonds (i.e. partially unsaturated) , but not fully conjugated.
  • heteroaryl refers to 5-to 8-membered aromatic, monocyclic rings containing one or more, for example, from 1 to 4, or, in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon; 8-to 12-membered fused bicyclic rings containing one or more, for example, from 1 to 4, or, in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring.
  • heteroaryl include, but are not limited to, pyridinyl, pyrazinyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolinyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothienyl, furyl, benzofuryl, benzoimidazolinyl, indolinyl, pyridizinyl, triazolyl, quinolinyl, pyrazolyl, and 5, 6, 7, 8-tetrahydroisoquinoline.
  • heterocyclyl is meant a single, fused, spiro, or bridged bicyclic or multicyclic, ring, with 5 to 12 ring atoms, containing at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen.
  • ring system When there is more than one ring system, at least one of the rings is saturated or not fully conjugated, contains at least one heteroatom, and is the point of attachment ring.
  • the point of the attachment may be carbon or heteroatom in the heterocyclic ring.
  • heterocyclyl includes but are not limited to pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydro-furanyl, 5, 6, 7, 8-tetrahydroimidazo [1, 2-a] pyrazinyl, tetrahydro-2H-pyranyl, 8-oxa-3-azabicyclo [3.2.1] octanyl, 3-oxa-9-azaspiro [5.5] undecanyl, 7-oxa-2-azaspiro [3.5] nonanyl, and 2-oxa-7-azaspiro [3.5] nonanyl.
  • “Pharmaceutically acceptable salt” refers to a salt form of a compound (e.g., a drug) having at least one group capable for salt formation that causes no significant adverse toxicological effects to the subject.
  • Pharmaceutically acceptable salts include, for example, salts prepared by reaction with an inorganic acid, organic acid, or a base depending on the nature of the compound (e.g., drug) .
  • the inorganic acid can be hydrochloric acid, hydrobromic acid, carbonic acid, sulfuric acid, phosphoric acid, and the like;
  • the organic acid can be fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, methanesulfonic acid and the like.
  • the base that can form a salt with an acid drug can be an amine containing compound or inorganic base such as sodium hydroxide, sodium carbonate, and the like.
  • Suitable pharmaceutically acceptable salt forms can e found in, for example, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Zürich: Wiley-VCH/VHCA, 2002; P.H. Stahl and C.G. Wermuth, Eds.
  • a “therapeutically effective amount” refers to the amount that, when administered to a subject for treatment of a disease, is sufficient to cause a desired treatment effect in the subject, including for example, alleviation of the symptoms or stop of the progression of the disease.
  • treating refers to slowing or arresting the development of a disease, providing relief from the symptoms or side-effects of the disease, and/or causing regression of the disease.
  • the terms also refers to reduction of the occurrence of the disease in the subject when compared with a subject without the treatment.
  • a “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • “A pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.
  • subject refers to animal (such as mammal) or human.
  • Compound of formula I and a pharmaceutically acceptable salt thereof as described herein include, but are not limited to, their solvates, optical isomers, racemates, and other mixtures thereof.
  • the single enantiomers or diastereomers i.e., optically active forms
  • Resolution of the racemates or mixtures of diastereomers can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high-pressure liquid chromatography (HPLC) column.
  • HPLC high-pressure liquid chromatography
  • one of R and R’ is H and the other is a 6-membered heteroaryl substituted by one or more R 1 , a fused bicyclic 9-membered heteroaryl, or phenyl, wherein each of the fused bicyclic 9-membered heteroaryl and phenyl is optionally substituted by one or more R 1 , wherein the 6-membered heteroaryl comprises one or two heteroatom that is N,
  • R 1 is independently selected from oxo, -F, -Cl, -Br, -I, -C 3-5 cycloalkyl, -C 1-5 alkyl substituted by 1-5 F, -C 1-5 alkyl, -OR 2 , -NR 3 R 4 , and -CONH 2 , provided that when R is a 6-membered heteroaryl, R is not substituted by -C 1-5 alkyl alone,
  • R 2 is -C 1-5 alkyl, -C 3-5 cycloalkyl, or -CH 2 C 3-5 cycloalkyl, wherein the -C 1-5 alkyl is optionally substituted by 1-5 F,
  • R 3 is H or -C 1-3 alkyl and R 4 is H, -C 1-5 alkyl, -C 3-5 cycloalkyl, 5-6 membered heterocycyl, or -CH 2 C 3-5 cycloalkyl, wherein the C1-5 alkyl is optionally substituted by 1-5 F, or R 3 and R 4 together with the N to which they are attached form a 4-12 membered heterocyclyl optionally substituted by a group selected from -C 3-5 cycloalkyl and -C 1-5 alkyl optionally substituted by 1-5 F,
  • R 5 and R 6 are independently H, -CD 3 , -C 1-3 alkyl optionally substituted by 1-3 F, or cyclopropyl,
  • R 7 is -CH 3 , -CD 3 , or cyclopropyl
  • R 8 is H, F or Cl.
  • R’ is phenyl optionally substituted by one or more R 1. In some embodiments, R’ is unsubstituted phenyl.
  • R is a pyridine, pyrimidine, pyridazine or pyrazine substituted with one or more R 1 .
  • R is imidazo [1, 2-a] pyridine optionally substituted by one or more R 1 .
  • R is
  • R is
  • R is
  • R 1 is -F, -Cl, -C 1-2 alkyl substituted by 1-3 F, cyclopropyl, -O-C 1-3 alkyl optionally substituted by 1-3 F, -O-cyclopropyl, -NH-cyclopropyl, -N (CH 3 ) -cyclopropyl, -CONH 2 , -O-CH 2 -cyclopropyl, -NH-CH 2 -cyclopropyl, -NH-C 1-5 alkyl,
  • R 1 is -F, -Cl, -CF 3 , cyclopropyl, -OCH 3 , -O-iPr, -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -O-cyclopropyl, -NH-cyclopropyl, -N (CH 3 ) -cyclopropyl, -CONH 2 , -O-CH 2 -cyclopropyl, -NH-CH 2 -cyclopropyl, -NH-tertbutyl,
  • R 1 is -CF 3 , cyclopropyl, -NH-cyclopropyl, -O-cyclopropyl, -CONH 2 , -OCH 3 , -O-iPr,
  • R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 5 is H. In some embodiments, R 5 is -CH 3 .
  • R 6 is H. In some embodiments, R 6 is -CH 3 .
  • R 7 is -CH 3 .
  • R 8 is H.
  • R 8 is F or Cl.
  • the compound of formula I or a pharmaceutically acceptable thereof can be selected from the following compounds or a pharmaceutically acceptable salt thereof:
  • the compound of formula I and a pharmaceutically acceptable salt thereof possess in vitro activity against animal cell line that is improved over prior art compound. This improved activity is important in designing an appropriate dose for animal study which is essential in identifying pre-clinical and/or clinical candidates for drug development.
  • the compound of formula I may have superior in vitro activity against both human and animal cell lines.
  • compositions disclosed herein will be administered in a therapeutically effective amount by any of the accepted administration modes for agents that serve similar utilities.
  • Therapeutically effective amount of the compounds disclosed herein may range from 0.01 to 500 mg per kg subject body weight, which can be administered in single or multiple doses per day.
  • the compositions can be provided in the form of tablets or capsules containing 1.0 to 1000 mg of the compound disclosed herein, such as, 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, and 1000 mg of the compound disclosed herein.
  • the compound disclosed herein can also be administered as pharmaceutical compositions by, for example, transdermal, intranasal, suppository, intramuscular, intravenous or subcutaneous administration.
  • the pharmaceutical composition comprises the compound disclosed herein and a pharmaceutically acceptable excipient.
  • the pharmaceutical compositions can comprise from 1 mg to 1000 mg of the compound disclosed herein.
  • Exemplary solid pharmaceutical excipient includes starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e g, peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • the compounds discloses herein can be used to achieve therapeutic effects in a subject with disease or disorder mediated by RIP1 kinase, which include cancer and inflammatory diseases.
  • the disease or disorder can be selected from inflammatory bowel diseases, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, osteoarthritis, spondylarthritis, gout, systemic onset juvenile idiopathic arthritis (SoJIA) , psoriatic arthritis) , systemic lupus erythematosus (SLE) , Sjogren's syndrome, systemic scleroderma, anti-phospholipid syndrome (APS) , vasculitis, liver damage/diseases (non-alcohol steatohepatitis, alcohol steatohepatitis,
  • cisplatin acute kidney injury (AKI) ) , Celiac disease, autoimmune idiopathic thrombocytopenic purpura, transplant rejection, ischemia reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome (SIRS) , cerebrovascular accident (CVA, stroke) , myocardial infarction (MI) , atherosclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) , spinal muscular atropy (SMA) , allergic diseases (including asthma and atopic dermatitis) , multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme (ICE, also known as caspase-1) associated fever syndrome, chronic obstructive pulmonary disease (COPD) , tumor necrosis factor receptor-associated periodic syndrome (TRAPS) , periodontitis, linear
  • the disease or disorder is selected from inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, SoJIA, systemic lupus erythematosus, Sjogren's syndrome, systemic scleroderma, anti-phospholipid syndrome, vasculitis, osteoarthritis, non-alcohol steatohepatitis, alcohol steatohepatitis, autoimmune hepatitis autoimmune hepatobiliary diseases, primary sclerosing cholangitis, nephritis, Celiac disease, autoimmune ITP, transplant rejection, ischemia reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardi
  • the disease or disorder is selected from inflammatory bowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis, arthritis, rheumatoid arthritis, osteoarthritis, and psoriasis.
  • anti-inflammatory agents can be small molecules or antibodies.
  • anti-inflammatory agents include corticosteroids, 5-aminosalicyclic acid, tofacitinib, rituximab, adalimumab, etc.
  • RIP1 inhibitors were tested using human monocytic U937 cells (ATCC, CRL-1593.2) in the necroptosis assay.
  • RPMI-1640 medium was added to 96 well cell culture plate (50 ⁇ L/well, including 10%FBS) . Then 0.5 ⁇ L of the diluted compounds or 100%DMSO were transferred into plates containing RPMI-1640 medium.
  • U937 cells at exponential phase were diluted to 5x105/mL in RPMI-1640 and seeded into assay plates (40 ⁇ L/well) . Cells were mixed with the compounds thoroughly and then incubated at RT (room temperature) for 1 hour.
  • hTNF ⁇ human tumor necrosis factor, Novoprotein, c008
  • QVD-Oph Selleck chemical, S7311
  • ATP content was measured via the addition of 50 ⁇ L Cell Titer-Glo Luminescent Cell Viability reagent (Promega Corporation) . Plates were incubated for 10 minutes followed by luminescence detection on BioTek.
  • L929 fibroblast cells ATCC, CRL6364
  • assay plates 100 ⁇ L/well
  • hTNF ⁇ human tumor necrosis factor, Novoprotein, c008
  • QVD-Oph (Selleck chemical, S7311) , a pan-caspase inhibitor, was added to the cell solution to achieve a final concentration of 50 ⁇ M. After 1-hour incubation at RT, the plates were incubated for 23 hours at 37°C, 5%CO2. The next day, cells were lysed and ATP content (viability) was measured via the addition of 50 ⁇ L Cell Titer-Glo Luminescent Cell Viability reagent (Promega Corporation) . Plates were incubated for 10 minutes followed by luminescence detection on BioTek. The ability of tested compound to rescue cells from TNF ⁇ /QVD induced necroptosis was represented as percent survival relative to 100%DMSO treated positive control wells. For concentration response experiments, normalized data were fitted and IC50 values determined using GraphPad Prism. All data are shown as mean ⁇ standard deviation of the mean.
  • RPMI-1640 medium 50 ⁇ L per well, including serum
  • a 0.5 ⁇ L solution containing the compound disclosed herein or control compound 7-Cl-O-Nec-1 and GSK2982772 (7-Cl-O-Nec-1 and GSK2982772 are known RIP1 kinase inhibitors) or a 0.5 ⁇ L 100%DMSO was added to each well, each compound has two replicate wells for each concentration.
  • Jurkat (FADD -/-) cells human-derived peripheral blood leukemia T cell line, FADD gene knocked out was cultured in vitro. After growing to logarithmic growth phase, the cells were collected and centrifuged at 1000 rpm for 5 minutes. The supernatant was discarded. The cells were resuspended in the fresh RPMI-1640 medium and the cell concentration was adjusted to 5 ⁇ 10 5 /mL. The cell suspension was added to the culture plate containing the compounds to be tested (40 ⁇ L per well) .
  • TNF tumor necrosis factor, final concentration 10ng/mL
  • cell culture medium 10 ⁇ L of TNF (tumor necrosis factor, final concentration 10ng/mL) diluted with cell culture medium was added to each well, placed in a cell culture incubator (37°C, 5%CO 2) for 20 or 24 hours, and 50 ⁇ L of Cell Titer-Glo solution was added to each well. After incubation at room temperature for 10 minutes, BioTek plate reader was used to detect the luminescence value to measure the intracellular ATP level. The ability of the tested compound in rescuing TNF-induced cell necrosis was represented as percent survival relative to 100%DMSO treated positive control wells. Graphpad Prism statistical software was used to calculate the compound’s IC50.

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Abstract

L'invention concerne un composé de formule I ci-après utile en tant qu'inhibiteur de la RIP1 kinase et ses utilisations.
PCT/CN2022/075609 2021-02-10 2022-02-09 Composé bicyclique fusionné hétéroaryle utile en tant qu'inhibiteur de la rip1-kinase et ses utilisations WO2022171111A1 (fr)

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