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WO2022171111A1 - Heteroaryl-fused bicyclic compound as rip1-kinase inhibitors and uses thereof - Google Patents

Heteroaryl-fused bicyclic compound as rip1-kinase inhibitors and uses thereof 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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French (fr)
Inventor
Yuhua Ji
Yeyu Cao
Dawei Ma
Jinlong ZHAO
Ning Yan
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Shanghai Institute of Organic Chemistry of CAS
Zai Lab US LLC
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Shanghai Institute of Organic Chemistry of CAS
Zai Lab US LLC
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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

A compound of formula I below as RIP1 kinase inhibitor and uses thereof.

Description

HETEROARYL-FUSED BICYCLIC COMPOUND AS RIP1-KINASE INHIBITORS AND USES THEREOF
This application claims the priority of the PCT/CN2021/076564, filed on February 10, 2021, the contents of which are incorporated herein by its entirety.
TECHNICAL FIELD
This application relates to compounds that inhibit cell necrotic and/or receptor-interacting protein-1 (RIP1) kinases and uses thereof.
BACKGROUND
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.
Studies have shown that 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.
In addition to having high potency in in vitro assay against human cell lines, 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, however, 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.
SUMMARY
Provided is a compound of formula I or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022075609-appb-000001
wherein
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 3R 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 2C 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 2C 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, and
R 8 is H, F or Cl.
Also provided is a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
Also provided is a method of inhibiting RIP1-kinase in a subject in need thereof, comprising administering a therapeutically effective amount of a composition comprising the compound of formula I or a pharmaceutically acceptable salt thereof.
Also provided is a method of treating a disease or disorder mediated by RIP1-kinase in a subject in need thereof, comprising administering a therapeutically effective amount of a composition comprising the compound of formula I or a pharmaceutically acceptable salt thereof.
The disease or disorder mediated by RIP1-kinase include cancer and inflammatory diseases. For example, 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 sclerosing cholangitis (PSC) , acetaminophen toxicity, hepatotoxicity) , kidney damage/injury (nephritis, renal transplant, surgery, administration of nephrotoxic drugs e.g. 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 ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematological and solid organ malignancies, bacterial infections and viral infections (such as tuberculosis and influenza) , and Lysosomal storage diseases.
DETAILED DESCRIPTION
I. Definitions
A dash ( "-" ) at the left hand side of a substituent is used to indicate a point of attachment for a substituent. For example, -CONH 2 is attached through the carbon atom.
The term "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. Fr example, 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.
The term "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. For example, 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.
The term "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.
Exemplary 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.
The term “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. 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.
Exemplary 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.
‘Oxo” means = (O) group.
“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.
As used herein, 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.
The terms “treating” , “treatment” , or “treat” (of) a disease 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.
The term “subject” as used herein 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. In those situations, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or  by resolution of the racemates or mixtures of diastereomers. 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. Where compounds described herein exist in various tautomeric forms, the term "compound" is intended to include all tautomeric forms of the compound.
II. Compounds and Uses Thereof
Provided is a compound of formula I or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022075609-appb-000002
wherein
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 3R 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 2C 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 2C 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, and
R 8 is H, F or Cl.
In some embodiments, R’ is phenyl optionally substituted by one or more R 1. In some embodiments, R’ is unsubstituted phenyl.
In some embodiments, R is a pyridine, pyrimidine, pyridazine or pyrazine substituted with one or more R 1. In some embodiments, R is imidazo [1, 2-a] pyridine optionally substituted by one or more R 1.
In some embodiments, R is
Figure PCTCN2022075609-appb-000003
Figure PCTCN2022075609-appb-000004
In some embodiments, R is
Figure PCTCN2022075609-appb-000005
In some embodiments, R is
Figure PCTCN2022075609-appb-000006
In some embodiments, 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, 
Figure PCTCN2022075609-appb-000007
In some embodiments, R 1 is -F, -Cl, -CF 3, cyclopropyl, -OCH 3, -O-iPr, -OCF 3, -OCHF 2, -OCH 2CF 3, -O-cyclopropyl, -NH-cyclopropyl, -N (CH 3) -cyclopropyl, -CONH 2, -O-CH 2-cyclopropyl, -NH-CH 2-cyclopropyl, -NH-tertbutyl, 
Figure PCTCN2022075609-appb-000008
Figure PCTCN2022075609-appb-000009
In some embodiments, R 1 is -CF 3, cyclopropyl, -NH-cyclopropyl, -O-cyclopropyl, -CONH 2, -OCH 3, -O-iPr, 
Figure PCTCN2022075609-appb-000010
In some embodiments, R 1 is
Figure PCTCN2022075609-appb-000011
Figure PCTCN2022075609-appb-000012
In some embodiments, R 5 is H. In some embodiments, R 5 is -CH 3.
In some embodiments, R 6 is H. In some embodiments, R 6 is -CH 3.
In some embodiments, R 7 is -CH 3. In some embodiments, R 8 is H. In some embodiments, 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:
Figure PCTCN2022075609-appb-000013
Figure PCTCN2022075609-appb-000014
Figure PCTCN2022075609-appb-000015
Figure PCTCN2022075609-appb-000016
Figure PCTCN2022075609-appb-000017
Figure PCTCN2022075609-appb-000018
Figure PCTCN2022075609-appb-000019
Also provided is a compound selected from the following compounds or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022075609-appb-000020
Figure PCTCN2022075609-appb-000021
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.
Comparing with compounds containing R group substituted on the phenyl ring next to the methyl substituted nitrogen on the seven membered ring fused to the phenyl, the compound of formula I may have superior in vitro activity against both human and animal cell lines.
Compounds disclosed herein (the term “compound (s) disclosed herein” includes pharmaceutically acceptable salt thereof) 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. For oral administration, 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.
In addition to oral administration, 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. When prepared for unit dosage form, 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.
Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th ed., 2000) .
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. For example, 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, autoimmune hepatitis autoimmune hepatobiliary diseases, primary sclerosing cholangitis (PSC) , acetaminophen toxicity, hepatotoxicity) , kidney damage/injury (nephritis, renal transplant, surgery, administration of nephrotoxic drugs e.g. 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 ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematological and solid organ malignancies, bacterial infections and viral infections (such as tuberculosis and influenza) , and Lysosomal storage diseases.
In some embodiments, 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, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic diseases, asthma, atopic dermatitis, multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme associated fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, and periodontitis.
In some embodiments, the disease or disorder is selected from inflammatory bowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis, arthritis, rheumatoid arthritis, osteoarthritis, and psoriasis.
The compound disclosed herein may be administered in combination with other anti-inflammatory agents known for any indications above. These anti-inflammatory agents can be small molecules or antibodies. Exemplary anti-inflammatory agents include corticosteroids, 5-aminosalicyclic acid, tofacitinib, rituximab, adalimumab, etc.
EXAMPLES
The following examples are illustrative in nature and are in no way intended to be limiting.
Example 1
Synthesis of the Compounds
Scheme A below describes an illustrative synthetic scheme for preparation of the compounds disclosed herein.
Figure PCTCN2022075609-appb-000022
Scheme A
Preparation of compound (2)
Figure PCTCN2022075609-appb-000023
A solution of compound (1) (97.9 g, 477 mmol, 1.05 eq) in DMF (1200 mL) was cooled to 0-5 ℃ using an ice batch. Then NaH (40.0 g, 1.00 mol, 60%purity, 2.2 eq) was added in portions while keeping the internal temperature below 10 ℃ under N 2 over a period of 1 hr. During the addition, a pipeline was used to discharge the  crashed out H 2. After the addition, the mixture was stirred at 5-10 ℃ for 0.5 hr. Then a solution of 4-bromo-1-fluoro-2-nitro-benzene (100 g, 454 mmol, 1 eq) in DMF (300 mL) was added dropwise. After the addition, the mixture was allowed to warm to 25 ℃ and stirred at 25 ℃ for 2 hrs. LCMS showed the reaction was completed. The mixture was re-cooled to ～0 ℃, poured into ice water (1.5 L) , extracted with EtOAc (1L) . The extract was discarded. The aqueous layer was acidified with 2 N HCl to pH～4-5, extracted with EtOAc (1Lx2) . The combined extracts were dried over Na 2SO 4, filtered and the filtrate was concentrated to give compound (2) (220 g, 434 mmol, 95.5%yield, 80%purity) as yellow gum, which was directly used in the next step without further purification.
1H NMR: (400 MHz, DMSO-d 6)
δ ppm 9.09 (dd, J=4.31, 1.31 Hz, 1 H) , 8.42 -8.48 (m, 2 H) , 8.04 (t, J=9.85 Hz, 1 H) , 7.79 -7.86 (m, 1 H)
Preparation of compound (3)
Figure PCTCN2022075609-appb-000024
A solution of compound (2) (220 g, 434.36 mmol, 80%purity, 1 eq) and NH 4Cl (46.4 g, 869 mmol, 2 eq) in EtOH (1000 mL) and H 2O (300 mL) was heated to 70 ℃. Then Fe (97.0 g, 1.74 mol, 4 eq) was added in portions over a period of 1 h. After the addition, the mixture was stirred 80 ℃ for 1 h. LCMS showed the reaction was completed. The mixture was filtered through a pad of celite and the filtrate was concentrated to give brown residue. The residue was slurred in DCM (800 mL) , dried over Na 2SO 4, filtered and the filtrate was concentrated to give a crude compound (3) (160 g) as brown gum, which was directly used in the next step without further purification.
Preparation of compound (4)
Figure PCTCN2022075609-appb-000025
To a solution of compound (3) (160 g, 426 mmol, 1 eq) in EtOAc (1200 mL) was added DIPEA (165 g, 1.28 mol, 222 mL, 3 eq) and T 3P (271 g, 426 mmol, 253 mL, 50%purity, 1 eq) . The mixture was stirred at 25 ℃ for 16 h. LCMS showed the reaction was completed. To the mixture was added sat. NaHCO 3 (1500 mL) , filtered and the filtrate was separated. The EtOAc layer was washed with brine (500 mL) , dried over Na 2SO 4, filtered and the filtrate was concentrated to give brown residue. The residue was purified by column chromatography (SiO 2, petroleum ether/ethyl acetate=100/1 to 5/1) to give compound (4) (95 g, 266 mmol, 24.5%yield) was obtained as a yellow solid.
1H NMR: (400 MHz, CDCl 3)
δ ppm 8.44 (br s, 1 H) , 7.25 -7.30 (m, 1 H) , 7.20 (d, J=2.26 Hz, 1 H) , 7.02 (d, J=8.53 Hz, 1 H) , 5.55 (br d, J=6.53 Hz, 1 H) , 4.54 -4.75 (m, 2 H) , 4.24 (t, J=10.04 Hz, 1 H) , 1.45 (s, 9 H)
Preparation of compound (5)
Figure PCTCN2022075609-appb-000026
To a solution of compound (4) (87.0 g, 243 mmol, 1 eq) in DMF (700 mL) was added K 2CO 3 (67.3 g, 487 mmol, 2 eq) . The mixture was cooled to 0 ℃. Then MeI (50.1 g, 353 mmol, 21.9 mL, 1.45 eq) was added dropwise at 0 ℃. After the addition, the mixture was stirred at 25 ℃ for 18 h. The mixture was yellow and cloudy. TLC (petroleum ether/EtOAc-4/1, UV) and LCMS showed the reaction was completed. The mixture was poured into ice water (1500 mL) , filtered, the filter cake was washed with H 2O (500 mL) , EtOH (500 mL) , dried under vacuum to give compound (5) (87 g,  222 mmol, 91.4%yield, 95%purity) as a yellow solid, which was directly used in the next step without further purification.
1H NMR: (400 MHz, CDCl 3)
δ ppm 7.28 -7.35 (m, 2 H) , 7.02 (d, J=8.53 Hz, 1 H) , 5.47 (br d, J=6.78 Hz, 1 H) , 4.64 (dt, J=11.29, 7.28 Hz, 1 H) , 4.54 (dd, J=9.54, 7.28 Hz, 1 H) , 4.16 (dd, J=11.04, 9.79 Hz, 1 H) , 3.38 (s, 3 H) , 1.39 (s, 9 H)
Preparation of compound (6)
Figure PCTCN2022075609-appb-000027
To a solution of compound (5) (12 g, 32.3 mmol, 1 eq) , Pin 2B 2 (9.03 g, 35.5 mmol, 1.1 eq) in dioxane (200 mL) was added KOAc (4.76 g, 48.5 mmol, 1.5 eq) . The mixture was degassed and purged with N 2 for 2 minutes. Then Pd (dppf) Cl 2 (1.18 g, 1.62 mmol, 0.05 eq) was added under N 2. The resulting mixture was stirred at 100 ℃ under N 2 for 18 h. LCMS showed the reaction was completed. The mixture was filtered through a pad of celite and the filtrate was concentrated to give brown residue. The residue was purified by flash silica gel chromatography (
Figure PCTCN2022075609-appb-000028
120 g
Figure PCTCN2022075609-appb-000029
Silica Flash Column, Eluent of 0～30%Ethyl acetate/Petroleum ether gradient @85 mL/min) to give compound (6) (12.2 g, 29.2 mmol, 90.2%yield) as a white solid.
1H NMR: (400 MHz, CDCl 3)
δ ppm 7.57 -7.67 (m, 2 H) , 7.12 (d, J=8.44 Hz, 1 H) , 5.48 (br d, J=6.48 Hz, 1 H) , 4.51 -4.65 (m, 2 H) , 4.14 -4.21 (m, 1 H) , 3.42 (s, 3 H) , 1.39 (s, 9 H) , 1.34 (d, J=3.91 Hz, 12 H)
General procedure for preparation  of compound (7) (R is exemplified as   fluoropyridinyl)
Figure PCTCN2022075609-appb-000030
These series reactions were carried out using the following procedure.
A solution of compound (6) (150 mg, 358 umol, 1 eq) and 2-bromo-5-fluoro-pyridine (63.1 mg, 358 umol, 1 eq) in dioxane (5 mL) and H 2O (1.5 mL) was degassed with N 2 for 2 minutes. Then Pd-118 (11.7 mg, 17.9 umol, 0.05 eq) and Cs 2CO 3 (233 mg, 717 umol, 2 eq) was added under N 2. The resulting mixture was stirred at 90 ℃ for 2 h. LCMS showed the reaction was completed. The mixture was diluted with EtOAc (30 mL) , washed with water (30 mL) , dried over Na 2SO 4, filtered through a pad of silica gel, and the filtrate was concentrated to give compound (7) (130 mg, 335 umol, 93.6%yield) as a yellow solid, which was directly used in the next step without further purification.
General procedure for preparation of compound (8)
Figure PCTCN2022075609-appb-000031
These series reactions were carried out using the following condition.
A solution of compound (7) (130 mg, 335.57 umol, 1 eq) in HCl/dioxane (4 M, 10 mL, 119 eq) was stirred at 25 ℃ for 1 h. LCMS showed the reaction was completed. The mixture was concentrated to give compound (8) (108 mg, 333 umol, 99.4%yield, HCl salt) as a yellow solid, which was directly used in the next step without further purification.
General procedure for preparation of compound (9) (Cpd #33)
Figure PCTCN2022075609-appb-000032
These series reactions were carried out using the following condition.
To a solution of compound (8) (105 mg, 365 umol, 1 eq, HCl salt) and 5-benzyl-4H-1, 2, 4-triazole-3-carboxylic acid (81.7 mg, 402 umol, 1.1 eq) in DMF (5 mL) was added T 3P (302 mg, 475 umol, 282 uL, 50%purity, 1.3 eq) and DIPEA (142 mg, 1.10 mmol, 191 uL, 3 eq) . The mixture was stirred at 25 ℃ for 1 h. LCMS showed the reaction was completed. The mixture was diluted with sat. NaHCO 3 (30 mL) , extracted with EtOAc (30 mL*2) . The combined extracts was washed with brine (30 mL) , dried over Na 2SO 4, filtered and the filtrate was concentrated to give a crude product. The crude product was purified by prep-HPLC (column: YMC Triart C18 250*50mm*7um; mobile phase: [water (0.225%FA) -ACN] ; B%: 24%-64%, 9 min) , and then lyophilized under high vacuum to give compound (9) or cpd. #33 (68.7 mg, 144 umol, 39.5%yield, 99.3%purity) as a white solid.
Compounds in the Table 1 below were prepared by following procedures similar to those described above.
Table 1: Compounds of formula I and analytical data thereof
Figure PCTCN2022075609-appb-000033
Figure PCTCN2022075609-appb-000034
Figure PCTCN2022075609-appb-000035
Figure PCTCN2022075609-appb-000036
Figure PCTCN2022075609-appb-000037
Figure PCTCN2022075609-appb-000038
Figure PCTCN2022075609-appb-000039
Figure PCTCN2022075609-appb-000040
Figure PCTCN2022075609-appb-000041
Figure PCTCN2022075609-appb-000042
Figure PCTCN2022075609-appb-000043
Figure PCTCN2022075609-appb-000044
Figure PCTCN2022075609-appb-000045
Figure PCTCN2022075609-appb-000046
Figure PCTCN2022075609-appb-000047
Figure PCTCN2022075609-appb-000048
Figure PCTCN2022075609-appb-000049
Figure PCTCN2022075609-appb-000050
Figure PCTCN2022075609-appb-000051
Figure PCTCN2022075609-appb-000052
Figure PCTCN2022075609-appb-000053
Figure PCTCN2022075609-appb-000054
Figure PCTCN2022075609-appb-000055
Figure PCTCN2022075609-appb-000056
Figure PCTCN2022075609-appb-000057
Figure PCTCN2022075609-appb-000058
Figure PCTCN2022075609-appb-000059
Example 2
In Vitro Cell Assays
The in vitro efficacy of the compounds disclosed herein as RIP1 inhibitors can be tested using cell lines in necroptosis assays.
Necroptosis Assay Using U937 Cells
The in vitro efficacy of RIP1 inhibitors were tested using human monocytic U937 cells (ATCC, CRL-1593.2) in the necroptosis assay. For the assay, RPMI-1640 medium was added to 96 well cell culture plate (50μL/well, including 10%FBS) . Then  0.5μL 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 (40μL/well) . Cells were mixed with the compounds thoroughly and then incubated at RT (room temperature) for 1 hour. hTNFα (human tumor necrosis factor, Novoprotein, c008) was added to the cell solution to achieve a final concentration of 20 ng/mL. QVD-Oph (Selleck chemical, S7311) , a pan-caspase inhibitor, was added to the cell solution to achieve a final concentration of 50μM . After 1-hour incubation at RT, the plates were incubated for 23 hours at 37℃, 5%CO2. On the next day, cells were lysed and ATP content (viability) was measured via the addition of 50 μL 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 compounds to rescue cells from TNFα/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.
Necroptosis Assay Using L929 Cells
The in vitro efficacy of RIP1 inhibitors were tested using mouse L929 fibroblast cells (ATCC, CRL6364) in the necroptosis assay. For the assay, L929 cells at exponential phase were diluted to 1x10 5/ml in MEM medium and seeded into assay plates (100μL/well) . Then 0.5μL of the diluted compounds or 100%DMSO were transferred into plates and incubated at RT for 1 hour. hTNFα (human tumor necrosis factor, Novoprotein, c008) was added to the cell solution to achieve a final concentration of 20 ng/mL. QVD-Oph (Selleck chemical, S7311) , a pan-caspase inhibitor, was added to the cell solution to achieve a final concentration of 50μM. After 1-hour incubation at RT, the plates were incubated for 23 hours at 37℃, 5%CO2. The next day, cells were lysed and ATP content (viability) was measured via the addition of 50 μL 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 TNFα/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.
TNF-induced Jurkat (FADD -/-) Cell Necrosis Assay
To a white 96-well cell culture plate was added RPMI-1640 medium (50 μL per well, including serum) . Then a 0.5μL 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 μL 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 μL per well) .
In the stimulation group, 10μL 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℃, 5%CO 2) for 20 or 24 hours, and 50μL 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.
The in vitro assay data obtained from the necroptosis assays described above are shown in Table 2 below.
Table 2
Cpd# IC50 Jurkat IC50 U937 IC50 L929
  TNFα TNFα+QVD TNFα+QVD
1 1.82E-09 1.93E-09 6.67E-07
2 4.80E-10 6.08E-10 4.41E-07
3 1.28E-09 1.57E-09 7.60E-07
4 1.48E-09 1.80E-09 3.97E-06
5 1.32E-09 1.43E-09 7.40E-07
6 1.11E-09 9.84E-10 2.59E-08
7 1.09E-09 2.97E-09 1.67E-08
8 1.67E-09 1.71E-09 1.39E-07
9 7.37E-10 2.22E-09 1.06E-07
10 1.35E-09 4.71E-09 4.59E-07
11 6.93E-10 1.46E-09 7.13E-08
12 2.14E-10 4.73E-10 2.80E-07
13 5.64E-10 1.60E-09 3.13E-07
14 3.52E-07 4.52E-07 >2e-005
15 2.73E-10 7.47E-10 1.27E-06
16 8.13E-10 1.70E-09 4.60E-07
17 1.06E-09 1.82E-09 8.43E-07
18 6.58E-10 2.65E-09 1.31E-06
19 4.24E-10 1.43E-09 1.01E-06
20 8.23E-10 1.63E-09 1.68E-07
21 3.76E-10 8.82E-10 4.94E-08
22 3.85E-10 1.00E-09 5.52E-08
23 3.88E-10 1.10E-09 2.80E-08
24 5.65E-08 9.01E-08 >2e-005
25 8.13E-09 1.25E-08 7.05E-06
26 1.22E-09 2.22E-09 3.33E-07
27 1.48E-09 2.61E-09 1.43E-06
28 1.24E-09 1.71E-09 1.50E-07
29 1.28E-09 1.90E-09 8.54E-08
30 1.27E-09 3.80E-09 1.58E-07
31 3.45E-09 3.61E-09 >2e-005
32 3.41E-09 7.26E-09 >2e-005
33 1.39E-09 3.09E-09 8.98E-07
34 1.35E-09 2.18E-09 3.79E-07
35 1.75E-09 2.34E-09 2.75E-07
36 2.01E-09 4.37E-09 1.85E-07
37 1.87E-09 2.39E-09 2.25E-08
38 7.42E-10 2.21E-09 2.23E-08
39 2.48E-09 3.52E-09 2.31E-08
40 1.36E-09 2.79E-09 1.17E-07
41 3.37E-09 5.39E-09 2.59E-06
42 3.96E-09 7.33E-09 9.48E-07
43 4.30E-09 1.60E-09 3.40E-07
44 1.90E-09 2.50E-09 1.79E-06
45 1.09E-09 2.87E-09 3.74E-07
46 9.77E-08 1.52E-07 >2e-005
47 1.58E-09 2.47E-09 9.99E-07
48 9.71E-10 2.56E-09 3.25E-07
49 1.15E-09 2.10E-09 1.40E-06
50 9.64E-10 2.01E-09 1.27E-07
51 1.11E-09 1.75E-09 1.38E-06
52 8.50E-08 3.45E-08 >2e-005
53 4.16E-09 4.26E-09 >2e-005
54 1.27E-09 2.06E-09 9.13E-08
55 1.37E-09 2.35E-09 1.45E-08
56 1.21E-09 3.12E-09 5.50E-07
57 1.88E-09 3.48E-09 3.49E-07
58 1.06E-09   5.85E-08
59 1.05E-09 1.99E-09 1.02E-08
60 2.84E-09 3.28E-09 3.04E-07
61 1.59E-09 3.36E-09 2.01E-07
62 2.28E-09 2.90E-09 8.09E-07
63 8.97E-10 2.11E-09 8.60E-08
64 1.45E-09 2.42E-09 1.63E-07
65 1.09E-08 1.40E-08 >2e-005
66 1.02E-09 3.30E-09 5.24E-07
67 5.87E-10 7.26E-10 1.43E-08
68 2.18E-07 1.73E-07 >2e-005
69 1.89E-09 3.72E-09 2.94E-08
70 2.51E-09 4.80E-09 1.06E-07
71 1.46E-09 2.16E-09 7.14E-06
72 1.00E-09 1.30E-09 4.30E-08
73 2.70E-09 3.20E-09 7.40E-08
74 2.81E-09 4.70E-09 6.58E-08
75 1.18E-09 1.90E-09 4.08E-08
76 1.00E-09 1.64E-09 7.15E-08
77 1.39E-09 1.95E-09 3.15E-08
78 8.40E-10 1.65E-09 1.30E-07
79 1.08E-08 1.28E-08 1.53E-06
80 4.94E-09 6.64E-09 2.73E-06
It was found that the compounds with R group positioned meta to the amide group of the seven member ring have better efficacy in the necroptosis assays than the compounds with R group positioned next to the amide group of the seven member ring. This can be illustrated by the following data.
Figure PCTCN2022075609-appb-000060
Figure PCTCN2022075609-appb-000061

Claims (29)

  1. A compound of formula I or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022075609-appb-100001
    wherein
    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 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 3R 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 2C 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 2C 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 1-5 F, or cyclopropyl,
    R 7 is -CH 3, -CD 3, or cyclopropyl, and
    R 8 is H, F or Cl.
  2. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein R’ is phenyl optionally substituted by one or more R 1.
  3. The compound or a pharmaceutically acceptable salt thereof of claim 2, wherein R’ is unsubstituted phenyl.
  4. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein R is a pyridine, pyrimidine, pyridazine or pyrazine substituted with one or more R 1.
  5. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein R is imidazo [1, 2-a] pyridine optionally substituted by one or more R 1.
  6. The compound or a pharmaceutically acceptable salt thereof of claim 1 or 4, wherein R is
    Figure PCTCN2022075609-appb-100002
    Figure PCTCN2022075609-appb-100003
    and R 1 is as defined in claim 1.
  7. The compound or a pharmaceutically acceptable salt thereof of claim 1, R is
    Figure PCTCN2022075609-appb-100004
  8. The compound or a pharmaceutically acceptable salt thereof of claim 1 or 5, wherein R is
    Figure PCTCN2022075609-appb-100005
  9. The compound or a pharmaceutically acceptable salt thereof of any of claim 1, 2, and 4-6, wherein 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, 
    Figure PCTCN2022075609-appb-100006
  10. The compound or a pharmaceutically acceptable salt thereof of any of claim 1, 2, and 4-6, wherein R 1 is -F, -Cl, -CF 3, cyclopropyl, -OCH 3, -O-iPr, -OCF 3, -OCHF 2, -OCH 2CF 3, -O-cyclopropyl, -NH-cyclopropyl, -N (CH 3) -cyclopropyl, -CONH 2, -O-CH 2-cyclopropyl, -NH-CH 2-cyclopropyl, -NH-tertbutyl, 
    Figure PCTCN2022075609-appb-100007
  11. The compound or a pharmaceutically acceptable salt thereof of any of claim 1, 2, and 4-6, wherein R 1 is -CF 3, cyclopropyl, -NH-cyclopropyl, -O-cyclopropyl, -CONH 2, -OCH 3, -O-iPr, 
    Figure PCTCN2022075609-appb-100008
  12. The compound or a pharmaceutically acceptable salt thereof of any of claim 1, 2, and 4-6, wherein R 1 is
    Figure PCTCN2022075609-appb-100009
    Figure PCTCN2022075609-appb-100010
  13. The compound or a pharmaceutically acceptable salt thereof of any of claim 1-12, wherein R 5 is H.
  14. The compound or a pharmaceutically acceptable salt thereof of any of claim 1-12, wherein R 5 is -CH 3.
  15. The compound or a pharmaceutically acceptable salt thereof of any of claim 1-14, wherein R 6 is H.
  16. The compound or a pharmaceutically acceptable salt thereof of any of claim 1-14, wherein R 6 is CH 3.
  17. The compound or a pharmaceutically acceptable salt thereof of any of claim 1-16, wherein R 7 is CH 3.
  18. The compound or a pharmaceutically acceptable salt thereof of any of claim 1-17, wherein R 8 is H.
  19. The compound or a pharmaceutically acceptable salt thereof of any of claim 1-17, wherein R 8 is F or Cl.
  20. The compound or a pharmaceutically acceptable salt thereof of any of claim 1-19, wherein the compound is selected from the following compounds:
    Figure PCTCN2022075609-appb-100011
    Figure PCTCN2022075609-appb-100012
    Figure PCTCN2022075609-appb-100013
    Figure PCTCN2022075609-appb-100014
    Figure PCTCN2022075609-appb-100015
    Figure PCTCN2022075609-appb-100016
    Figure PCTCN2022075609-appb-100017
  21. A compound selected from the following compounds or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022075609-appb-100018
    Figure PCTCN2022075609-appb-100019
  22. A pharmaceutical composition comprising a compound of any of claims 1-21 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  23. A method of inhibiting RIP1-kinase in a subject in need thereof, comprising administering a therapeutically effective amount of a composition of claim 22.
  24. A method of treating a disease or disorder mediated by RIP1-kinase in a subject in need thereof, comprising administering a therapeutically effective amount of a composition of claim 22.
  25. The method of claim 24, wherein the disease or disorder mediated by RIP1-kinase is selected from cancer and inflammatory diseases.
  26. The method of claim 24, wherein the disease or disorder is 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, autoimmune hepatitis autoimmune hepatobiliary diseases,  primary sclerosing cholangitis (PSC) , acetaminophen toxicity, hepatotoxicity) , kidney damage/injury (nephritis, renal transplant, surgery, administration of nephrotoxic drugs e.g. 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 ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematological and solid organ malignancies, bacterial infections and viral infections (such as tuberculosis and influenza) , and Lysosomal storage diseases.
  27. The method of claim 24, wherein the disease or disorder is selected from inflammatory bowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis, arthritis, rheumatoid arthritis, osteoarthritis, and psoriasis.
  28. The method of any of claims 24-27, further comprising administering to the subject in need thereof an additional known anti-inflammatory agent.
  29. The method of claim 28, wherein the additional known anti-inflammatory agent is selected from corticosteroids, 5-aminosalicyclic acid, tofacitinib, rituximab, and adalimumab.
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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105121432A (en) * 2013-02-15 2015-12-02 葛兰素史密斯克莱知识产权发展有限公司 Heterocyclic amides as kinase inhibitors
WO2018007973A2 (en) * 2016-07-06 2018-01-11 Glaxosmithkline Intellectual Property Development Limited Process and intermediates for preparing benzoxazepines
CN107849023A (en) * 2015-07-02 2018-03-27 豪夫迈·罗氏有限公司 Bicyclic lactams and methods of use thereof
CN109071504A (en) * 2016-02-05 2018-12-21 戴纳立制药公司 Inhibitor of receptor-interacting protein kinase 1
WO2019213447A1 (en) * 2018-05-03 2019-11-07 Rigel Pharmaceuticals, Inc. Rip1 inhibitory compounds and methods for making and using the same
CN112028885A (en) * 2019-06-04 2020-12-04 察略盛医药科技(上海)有限公司 Heterocyclic lactam derivatives, preparation method and medical application thereof
CN112074519A (en) * 2018-04-20 2020-12-11 豪夫迈·罗氏有限公司 N- [ 4-oxo-2, 3-dihydro-1, 5-benzoxazepin-3-yl ] -5, 6-dihydro-4H-pyrrolo [1,2-B ] pyrazole-2-carboxamide derivatives and related compounds as RIP1 kinase inhibitors for the treatment of e.g. Irritable Bowel Syndrome (IBS)
WO2021046407A1 (en) * 2019-09-06 2021-03-11 Rigel Pharmaceuticals, Inc. Rip1 inhibitory compounds and methods for making and using the same
WO2021092336A1 (en) * 2019-11-07 2021-05-14 Rigel Pharmaceuticals, Inc. Heterocyclic rip1 inhibitory compounds

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105121432A (en) * 2013-02-15 2015-12-02 葛兰素史密斯克莱知识产权发展有限公司 Heterocyclic amides as kinase inhibitors
CN107849023A (en) * 2015-07-02 2018-03-27 豪夫迈·罗氏有限公司 Bicyclic lactams and methods of use thereof
CN109071504A (en) * 2016-02-05 2018-12-21 戴纳立制药公司 Inhibitor of receptor-interacting protein kinase 1
WO2018007973A2 (en) * 2016-07-06 2018-01-11 Glaxosmithkline Intellectual Property Development Limited Process and intermediates for preparing benzoxazepines
CN112074519A (en) * 2018-04-20 2020-12-11 豪夫迈·罗氏有限公司 N- [ 4-oxo-2, 3-dihydro-1, 5-benzoxazepin-3-yl ] -5, 6-dihydro-4H-pyrrolo [1,2-B ] pyrazole-2-carboxamide derivatives and related compounds as RIP1 kinase inhibitors for the treatment of e.g. Irritable Bowel Syndrome (IBS)
WO2019213447A1 (en) * 2018-05-03 2019-11-07 Rigel Pharmaceuticals, Inc. Rip1 inhibitory compounds and methods for making and using the same
CN112028885A (en) * 2019-06-04 2020-12-04 察略盛医药科技(上海)有限公司 Heterocyclic lactam derivatives, preparation method and medical application thereof
WO2021046407A1 (en) * 2019-09-06 2021-03-11 Rigel Pharmaceuticals, Inc. Rip1 inhibitory compounds and methods for making and using the same
WO2021092336A1 (en) * 2019-11-07 2021-05-14 Rigel Pharmaceuticals, Inc. Heterocyclic rip1 inhibitory compounds

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