WO2023138317A1 - Composé ayant une activité inhibitrice de ripk1, son procédé de préparation et son utilisation - Google Patents

Composé ayant une activité inhibitrice de ripk1, son procédé de préparation et son utilisation Download PDF

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WO2023138317A1
WO2023138317A1 PCT/CN2022/142343 CN2022142343W WO2023138317A1 WO 2023138317 A1 WO2023138317 A1 WO 2023138317A1 CN 2022142343 W CN2022142343 W CN 2022142343W WO 2023138317 A1 WO2023138317 A1 WO 2023138317A1
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alkyl
aryl
membered heteroaryl
membered
disease
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段文虎
耿美玉
张贺峰
艾菁
兰垚瀚
戴阳
金泽宸
彭霞
方晨
季寅淳
冯大智
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Shanghai Institute of Materia Medica of CAS
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Definitions

  • the present invention relates to compounds with receptor-interacting protein kinase 1 inhibitory activity, their preparation methods and uses thereof, especially the use of the series of compounds or pharmaceutical compositions containing the series of compounds and therapeutic agents for treating inflammatory diseases, ischemic diseases, neurodegenerative diseases, tumors and other diseases and diseases related to receptor-interacting protein kinase 1.
  • Protein kinases are proteins (enzymes) that regulate various cellular functions by phosphorylating specific amino acids on proteins. Proteins regulate their activity and ability to bind to their chemical components through conformational changes.
  • the activity of a protein kinase refers to the rate at which a kinase binds a phosphate group to a substrate, which rate can be measured by measuring the amount of substrate converted to a product over a period of time. Phosphorylation of the substrate occurs at the activation site of the protein kinase.
  • protein kinases can be divided into five categories: serine/threonine protein kinases, tyrosine protein kinases, histidine protein kinases, tryptophan protein kinases and aspartyl/glutamyl protein kinases.
  • serine/threonine protein kinase is a class of enzymes that can catalyze the phosphorylation of serine/threonine residues on various substrate proteins
  • tyrosine kinase is a kind of protein enzyme that can catalyze the transfer of adenosine triphosphate to protein tyrosine residues.
  • Pathological conditions associated with protein kinases include inflammatory diseases, immune diseases, cardiovascular diseases, and tumors, among others.
  • Cell death mainly includes apoptosis, necroptosis, pyroptosis, ferroptosis, and cell death processes related to autophagy and unprogrammed necrosis.
  • Necroptosis also known as programmed cell death or programmed necrosis, is a new type of cell death discovered in recent years.
  • Necroptosis a highly inflammatory form of cell death that results in the release of danger-associated molecular patterns from cells, is considered an important pathological factor in a variety of degenerative and inflammatory diseases. These diseases include neurodegenerative diseases, stroke, coronary heart disease, myocardial infarction, retinal degenerative diseases, inflammatory bowel disease, kidney disease, liver disease, and various other related diseases.
  • Receptor-interacting protein kinase 1 (RIPK1) and RIPK3 are homologous serine/threonine kinases, which are key elements in mediating cell necroptosis.
  • RIPK1 kinase is recognized as a potential therapeutic target for necroptosis-related diseases.
  • the first RIPK1 inhibitor Necrostatin-1 (Nec-1) and its analogues have shown clear curative effects on a variety of degenerative diseases, inflammation, cancer and other diseases in preclinical studies.
  • Alzheimer's disease Parkinson's disease, Huntington's disease, age-related macular degeneration, etc.
  • it has a protective effect on psoriasis, retinitis pigmentosa, inflammatory bowel disease, autoimmune disease, acute pancreatitis and sepsis/systemic inflammatory response syndrome induced by bombesin
  • it can effectively relieve ischemic brain injury, ischemic myocardial injury, retinal ischemia/reperfusion injury, photoreceptor cell necrosis induced by retinal detachment, glaucoma, renal ischemia-reperfusion injury, and cisplatin-induced Renal injury and traumatic brain injury:
  • At least partial remission of other diseases associated with RIPK1-dependent apoptosis, necrosis or cytokine production including hematological and solid organ malignancies, bacterial and viral infections (including tuberculosis, influenza, etc.) and lysosomal storage disorders (
  • kinase inhibitors especially RIPK1 kinase inhibitors
  • the existing inhibitors targeting necroptosis-related kinases have defects of varying degrees, such as poor selectivity, unsatisfactory in vivo inhibitory activity, poor pharmacokinetic properties, low oral bioavailability, etc., and some cannot enter the central nervous system through the blood-brain barrier.
  • the object of the present invention is to provide RIPK1 kinase inhibitors.
  • the first aspect of the present invention provides a compound represented by general formula (I) or its stereoisomers, enantiomers, diastereomers, atropisomers, optical isomers, racemates, tautomers or pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates or solvates thereof, and isotope-labeled compounds thereof,
  • Cy 1 is selected from the following group:
  • R at each occurrence is independently selected from: H, D, halogen, CD 3 , C1-C8 alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkoxy, cyano, amino, C1-C8 alkyl substituted amino, hydroxyl, mercapto, C1-C8 alkylthio;
  • Cy 2 is selected from the following groups substituted by 0-5 R 8 : C3-C14 cycloalkyl, C6-C14 membered aryl, 6-14 membered heteroaryl, or 3-14 membered heterocyclic group;
  • R4 at each occurrence is independently selected from: H, D, CH3 , CD3 ;
  • Each dashed line independently represents a single bond or a double bond
  • Z 2 is selected from C(R z2 ) 2 , N, CR z2 ; each R z2 is independently H, halogen, hydroxyl, optionally substituted C1-C8 alkyl, or two R z2 form an optionally substituted C3-C6 carbocycle or 3-6 membered heterocycle together with the carbon atoms to which they are attached,
  • R z2 , R z1 together with the carbon atoms they are connected to form an optionally substituted C3-C6 carbocycle or 3-6 membered heterocycle;
  • Z 3 and Z 4 are selected from C, CH, N;
  • Ring A is a C6-C14 membered aromatic ring, a 5-membered heteroaromatic ring, a 6-14 membered heteroaromatic ring, a C3-C14 carbocyclic ring or a 3-14 membered heterocyclic ring;
  • n is selected from 1, 2, 3, 4;
  • R 1 is independently selected from H, D, "R 7 -C ⁇ C-", R 1a at each occurrence; preferably, at least one R 1 on ring A is a substituent of "R 7 -C ⁇ C-";
  • R 1a , R 7 are independently at each occurrence R 1a1 substituted by 0-5 R 1a2 ;
  • R 1a1 and R 1a2 can be optionally replaced by 0-5 R 1a3 ;
  • R 2 does not exist, or R 2 is in the ortho position of Z 4 , and forms an optionally substituted or unsubstituted 5-6 membered heterocyclic ring with R 3 and the atoms they are connected to;
  • R 3 is selected from: H, D, CH 3 , CD 3 ;
  • Y is O, S, NR y , wherein R y and R 3 form an optionally substituted 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring together with the atoms they are connected to;
  • R 6 is selected from: CD 3 , C1-C8 alkyl, halogenated C1-C8 alkyl, C6-C14 aryl;
  • R 1a1 , R 1a2 In each occurrence independently selected from the group consisting of: H, D, halogen, C1-C8 alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkoxy, C1-C6 alkoxy substituted C1-C6 alkoxy, C2-C8 alkenyl, halogenated C2-C8 alkenyl, C2-C8 alkenyloxy, halogenated C2-C8 alkenyloxy, C2-C8 alkynyl, halogenated C2-C8 alkyne C2-C8 alkynyloxy, halogenated C2-C8 alkynyloxy, C3-C14 cycloalkyl, (C3-C14 cycloalkyl)-(C1-C8 alkyl)-, (C3-C14 cycloalkyl) oxy, (C3-C14 cycloalkyl
  • At least one R 1 is R 7 -C ⁇ C-". That is, m is 1, R 1 is R 7 -C ⁇ C-"; m is 2, 3 or 4, and one R 1 is R 7 -C ⁇ C-", and other R 1 are independently selected from H, D, "R 7 -C ⁇ C-", R 1a .
  • the compound represented by general formula (I) has the structure:
  • the compound shown in general formula (I) has the structure shown in formula (II):
  • the compound is selected from formulas (IV-1), (IV-2), (IV-4), (IV-5), (IV-6), (IV-7), (IV-9):
  • Cy 3 is selected from formulas (III-1) to (III-14):
  • Z 5 is selected from CR 1 or N; R 1 , m, Z 1 , R 3 are as defined above; preferably, Z 5 is selected from CH or N; when m is 1, R 1 is R 7 -C ⁇ C-; R 7 is as defined above.
  • the compound is selected from formulas (V-1), (V-2), (V-3), (V-4):
  • Z 5 is selected from CR 1 or N; R 1a1 , R 1 , R 3 , Z 1 , Cy 1 , Cy 2 and R 5 are as defined above.
  • the compound is selected from:
  • Z 5 is selected from CH or N; R 1 is a C1-C8 alkyl group; R 1a1 , R 3 , Z 1 , Cy 2 , and R 5 are as defined above.
  • R 1 is independently selected from the following group at each occurrence: H, D, methyl,
  • the compound is the compound listed in claim 5.
  • the second aspect of the present invention provides the preparation method of the compound shown in formula (I) described in the first aspect, and the synthesis step includes at least one of Reaction Formula 1 and Reaction Formula 2:
  • R 4 , R 1 , m, R 2 , R 3 , Y, Z 1 , Z 2 , Z 3 , Z 4 , dotted line, and Cy 1 are as defined above.
  • the third aspect of the present invention provides a pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and one or more compounds described in the first aspect or stereoisomers, enantiomers, diastereomers, atropisomers, optical isomers, racemates, tautomers or pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates or solvates thereof, and isotope-labeled compounds thereof.
  • a fourth aspect of the present invention provides a receptor-interacting protein kinase 1 (RIPK1) inhibitor, comprising one or more compounds described in the first aspect or their stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates or solvates thereof, or the pharmaceutical composition described in the third aspect.
  • RIPK1 receptor-interacting protein kinase 1
  • the fifth aspect of the present invention provides the use of the compound described in the first aspect or its stereoisomer, enantiomer, diastereoisomer, atropisomer, optical isomer, racemate, tautomer or pharmaceutically acceptable salt thereof, its prodrug, its hydrate or solvate, its isotope-labeled compound or the pharmaceutical composition described in the third aspect, characterized in that it is used for the preparation of medicines, and the medicines are used for: 1) detection and/or prevention and/or treatment of kinase-related diseases; 2) detection and/or 3) Detect and/or prevent and/or treat diseases related to ischemia and/or reperfusion injury; 4) Detect and/or prevent and/or treat degenerative diseases; 5) Detect and/or prevent and/or treat tumor-related diseases; 6) Detect and/or prevent and/or treat diseases related to cell necrosis; 7) Detect and/or prevent and/or treat diseases related to metabolism;
  • the sixth aspect of the present invention provides the use of the compound described in the first aspect or its stereoisomer, enantiomer, diastereomer, atropisomer, optical isomer, racemate, tautomer or pharmaceutically acceptable salt thereof, its prodrug, its hydrate or solvate, its isotope-labeled compound, or the pharmaceutical composition described in the third aspect, characterized in that it is used to prepare a drug for detection and/or prevention and/or treatment of a disease selected from the following group:
  • Systemic juvenile idiopathic arthritis, Behcet's disease, interleukin-1 converting enzyme-related febrile syndrome, sepsis, alopecia areata, allergic disease, allergic disease, hepatitis B, hepatitis C, multiple sclerosis, pulmonary sarcoidosis, pulmonary fibrosis, pneumonia, mycobacterial infection, celiac disease, Sjogren's syndrome, osteoarthritis, hidradenitis suppurativa, necrotizing enterocolitis, acute pancreatitis, spondyloarthritis, colitis, Crohn's disease, antiphosphorus Lipid syndrome, Crohn's disease, ulcerative colitis, rheumatoid arthritis, bacterial infection, influenza, chronic obstructive pulmonary disease, viral infection, sepsis, dermatitis, staphylococcal infection, autoimmune disease, systemic lupus erythematosus, systemic inflammatory response syndrome, systemic scleroderma
  • the kinase inhibitor has excellent RIPK1 inhibitory activity, so it can be used to prepare pharmaceutical compositions for detection and/or prevention and/or treatment of cell death and/or related diseases.
  • the inventors have completed the present invention.
  • C1 - C6 means having 1, 2, 3, 4, 5 or 6 carbon atoms
  • C1 - C8 means having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and so on.
  • 5-8 membered means having 5-8 ring atoms, and so on.
  • Substituent refers to an atom or group that can replace a hydrogen atom in a substituent.
  • substitution means that one or more hydrogen atoms on a specified group are replaced by a specified substituent.
  • the specific substituents are the corresponding substituents described above, or the substituents appearing in each embodiment.
  • a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position.
  • Alkyl means a saturated aliphatic hydrocarbon group, which may be straight or branched.
  • the alkyl groups may be independently substituted with one or more substituents described herein. Further examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 3-methylpentyl.
  • Alkyl groups can be optionally substituted or unsubstituted.
  • Alkenyl straight-chain or branched hydrocarbon group, wherein at least one CC is a sp 2 double bond, wherein the alkenyl group can be independently and optionally replaced by one or more substituents described in the present invention, wherein specific examples include, but are not limited to vinyl, allyl, butyl, etc. Alkenyl groups can be optionally substituted or unsubstituted.
  • Alkynyl refers to a straight-chain or branched hydrocarbon group, wherein at least one C-C is an sp triple bond, wherein the alkynyl group can be independently and optionally substituted by one or more substituents described in the present invention, and specific examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc. Alkynyl groups can be optionally substituted or unsubstituted.
  • Ring structure refers to a single or polycyclic structure. Usually two or more fragments connected to one atom in the ring structure are connected to form a closed structure, including but not limited to cycloalkane, heterocycloalkane, cyclic lactam, arene, heteroarene, ring, bridged ring, spiro ring and other structures, examples are as follows (but not limited to the following examples): cyclopropane, cyclobutane, oxetane, cyclopentane, cyclohexane, adamantane, cyclohexene, cyclooctyne, pyrazole, benzene, pyridine, 3,4-dihydro-1,4- Benzoxazepine-5(2H)-one, naphthalene, anthracene, phenanthrene, quinoline, pyrrolopyridine, pyrazolopyridine, indole
  • the ring structures may be optionally substituted or unsubstituted. When it appears as a substituent, it means that one or more hydrogen atoms on a monocyclic or polycyclic ring are removed so that it can serve as a substituent for a substituted substance.
  • Halogen refers to F, Cl, Br or I.
  • Halo means substituted with one or more halogens.
  • Aryl refers to a carbocyclic aromatic system containing one or more rings free of heteroatoms.
  • the aryl group may be fused to a heteroaryl, heterocyclyl, or other ring structure. Examples include (but are not limited to) the following examples: phenyl, naphthyl, tetrahydronaphthyl, wait.
  • the aryl group may be optionally substituted or unsubstituted.
  • aryl group is described as "C6-C14 aryl"
  • the aryl group can be optionally fused with other ring structures
  • the other ring structures refer to ring structures with 3-18 ring atoms, and the other ring structures may be optionally substituted or unsubstituted.
  • Heteroaryl refers to an aromatic ring structure containing one or more rings, which may contain one or more atoms selected from N, O or S. Alternatively, the aryl group may be fused to an aryl, heterocyclyl, cycloalkyl or other ring structure. Examples include (but are not limited to) the following examples: furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, wait.
  • the heteroaryl group can be optionally substituted or unsubstituted.
  • heteroaryl When the heteroaryl is described as "5-14 membered heteroaryl", it means that the heteroaryl ring connected to the parent structure has 5-14 ring atoms, but the heteroaryl may be fused with other ring structures, and the other ring structures refer to ring structures with 3-18 ring atoms, and the other ring structures may be optionally substituted or unsubstituted.
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the first ring structure where the cycloalkyl is directly attached to the substituent is non-aromatic.
  • monocyclic cycloalkyl groups (but not limited to the following examples): cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, cyclooctynyl, etc.
  • multicyclic cycloalkyl groups (but not limited to the following examples): spiro, fused and bridged cycloalkyls.
  • the cycloalkyl may be fused or form a spiro with an aryl, heterocyclyl, cycloalkyl or other ring structures.
  • the cycloalkyl group may be optionally substituted or unsubstituted.
  • C3-C14 cycloalkyl it means that the cycloalkyl ring connected to the parent structure has 3-14 carbon atoms, but the cycloalkyl group can be fused with other ring structures or form a spiro ring.
  • the other ring structures refer to ring structures with 3-18 ring atoms, and the other ring structures can be optionally substituted or unsubstituted.
  • Heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic ring structure in which at least one ring atom is a heteroatom (eg, O, N, S atom, etc.). Examples include (but are not limited to) tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, tetrahydrothienyl, piperidinyl, piperazinyl, azetidinyl, azepanyl, morpholinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, and the like.
  • the heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring bonded to the parent structure is a heterocyclyl.
  • the heterocyclyl group may be optionally substituted or unsubstituted.
  • the description of the heteroalkyl group is "3-14 membered heterocyclic group” it means that the heterocyclic group connected to the parent structure has 3-14 ring atoms, but the heterocyclic group may be fused with other ring structures or form a spiro ring.
  • the other ring structures refer to ring structures with 3-18 ring atoms, and the other ring structures may be optionally substituted or unsubstituted.
  • Tautomer means that structural isomers with different energies can be interconverted beyond a low energy barrier.
  • proton tautomers i.e., proton shifts
  • proton migration such as 1H-indazole and 2H-indazole, 1H-benzo[d]imidazole and 3H-benzo[d]imidazole
  • valence tautomers include interconversions through some bonded electron recombination.
  • Stepoisomer refers to molecules that have atoms connected identically but arranged differently in space. For example, two compounds that contain a chiral center and have the same two-dimensional linkage, such as R-glyceraldehyde and S-glyceraldehyde, R-serine and S-serine.
  • Enantiomers means stereoisomers that are real and mirror images of each other and are not superimposable. Such as R-serine and S-serine.
  • Diastereoisomer means a stereoisomer whose molecules have two or more chiral centers and which are not mirror images of each other. Such as tartaric acid.
  • “Atropisomer” means a group of conformational isomers of a molecule resulting from hindered rotation about a single bond. For example, the individual stereoisomers of 6,6'-dinitro-2,2'-biphenyldicarboxylic acid.
  • Optical isomer refers to a compound in which two or more molecules have the same two-dimensional connection, but exhibit different optical rotation properties due to differences in configuration. Such as levamlodipine and dexamlodipine.
  • Racemate refers to compounds that have the same two-dimensional connection mode but are optical isomers of each other, and when mixed together, they finally appear as substances without optical activity. than racemic amlodipine.
  • amino acid acyl refers to a substituent in which the carboxyl group of an amino acid is converted into an acyl group and linked to a substituent through the acyl group.
  • the amino acids include, but are not limited to, ⁇ -amino acids, ⁇ -amino acids, ⁇ -amino acids, and ⁇ -amino acids.
  • Such amino acids include, but are not limited to, the following examples: glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, selenocysteine, pyrrolysine, beta-alanine, and the like.
  • glycosyl refers to a substituent of a monosaccharide or an oligosaccharide in the form of providing a hemiacetal hydroxyl group.
  • the monosaccharides include aldoses and ketoses.
  • the monosaccharides include triose, tetose, pentose, hexose and heptose.
  • the oligosaccharide also known as oligosaccharide, refers to a compound containing 2-11 monosaccharides, and each monosaccharide is polymerized through glycosidic bonds.
  • Examples of the monosaccharide or polysaccharide are as follows (but not limited to the following examples): erythrose, thulose, arabinose, ribose, xylose, lyxose, glucose, mannose, fructose, galactose, lactose, sucrose, maltose, ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin.
  • the pharmaceutically acceptable salt of the present invention may be a salt formed by an anion and a positively charged group on the compound of formula (I).
  • Suitable anions are chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumarate, glutamate, glucuronate, lactate, glutarate or maleate.
  • salts can be formed from cations with negatively charged groups on compounds of formula (I). Suitable cations include sodium, potassium, magnesium, calcium and ammonium, such as tetramethylammonium.
  • “pharmaceutically acceptable salt” refers to the salts formed by the compound of formula (I) with an acid selected from the following group: hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, nitric acid, methanesulfonic acid, sulfamic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, oxalic acid, pyruvic acid, malic acid, glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid acid, ethanesulfonic acid, naphthalenedisulfonic acid, malonic acid, fumaric acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid,
  • the present invention provides a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and one or more therapeutically effective doses of the compound of the present invention or its stereoisomers, enantiomers, diastereomers, atropisomers, optical isomers, racemates, tautomers or pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates or solvates thereof, and isotope-labeled compounds thereof.
  • the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier.
  • safe and effective dose refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 50-200 mg of the compound of the present invention per dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low enough toxicity. "Compatibility” herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable carrier moieties include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
  • cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • talc such as ste
  • the pharmaceutical composition is injection, capsule, tablet, pill, powder or granule.
  • administration methods of the compounds or pharmaceutical compositions of the present invention are not particularly limited, and representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia; Potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; In capsules, tablets and pills, the dosage form may also contain
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • Examples of usable embedding components are polymeric substances and waxy substances.
  • the active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances and the like.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide and oils
  • compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.
  • the compound of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as antineoplastic drugs).
  • other pharmaceutically acceptable compounds such as antineoplastic drugs.
  • the treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage.
  • the daily dosage is usually 1-2000 mg, preferably 5-500 mg.
  • factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
  • HATU N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate
  • DMF N,N-Dimethylformamide
  • TEA Triethylamine
  • DIPEA Diisopropylethylamine
  • DMAC N,N-dimethylacetamide
  • Pd(dppf)Cl 2 [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
  • NBS N-bromosuccinimide
  • NMP N-methylpyrrolidone
  • Pd(PPh 3 ) 4 tetrakistriphenylphosphine palladium
  • DPPA diphenylphosphoryl azide
  • 4-DMAP 4-dimethylaminopyridine
  • NaBH 3 CN sodium cyanoborohydride
  • PTSA p-toluenesulfonic acid
  • MeOH methanol
  • EtOH ethanol
  • Boc 2 O di-tert-butyl dicarbonate
  • DMSO dimethyl sulfoxide
  • Pd(dppf)Cl 2 [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
  • reaction mixture was poured into water, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed five times with saturated sodium chloride, and finally the organic phase was dried over anhydrous sodium sulfate and concentrated, and purified by preparative thin layer chromatography to obtain I-1, yield: 47 mg, yield: 92.1%.
  • + indicates that the IC 50 is less than ( ⁇ ) 0.1 ⁇ M. It can be seen from Table 1 that the compound of the present invention has obvious inhibitory effect on RIPK1 enzyme.
  • I2.1 cell line the FADD mutant of human acute T-cell leukemia Jurkat cells, the FADD protein in the cells is missing, and TNF ⁇ alone can induce programmed necrosis in cells. It was detected by CCK-8 cell counting kit (Dojindo).
  • I2.1 cells in the logarithmic growth phase were inoculated into 96-well culture plates at an appropriate density. After culturing overnight, compounds of different concentrations were added first, and 20 ng/mL of TNF ⁇ was added to stimulate one hour later. Control wells without compounds and stimulating factors (positive control) and control wells without compounds and stimulating factors (negative control) were set. After the compound acted on the cells for 24 hours, the effect of the compound on the cell proliferation was detected using the CCK-8 cell counting kit (Dojindo). Add 10 ⁇ L of CCK-8 reagent to each well, place it in a 37°C incubator for 2-4 hours, and read it with a full-wavelength microplate microplate reader SpectraMax190, with a wavelength of 450nm.
  • the recovery rate (%) of the compound to programmed cell necrosis was calculated by the following formula:
  • IC50 values were calculated using GraphPad Prism software.

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Abstract

L'invention concerne un composé ayant une activité inhibitrice de RIPK1, son procédé de préparation et son utilisation. La structure du composé est telle que représentée dans la formule générale I, et la définition de chaque substituant est telle que décrite dans la description et les revendications. Le composé de la présente invention peut être utilisé pour traiter des affections et des maladies associées à la protéine kinase 1 interagissant avec le récepteur, telles que des maladies inflammatoires, des maladies ischémiques, des maladies neurodégénératives et des tumeurs.
PCT/CN2022/142343 2022-01-21 2022-12-27 Composé ayant une activité inhibitrice de ripk1, son procédé de préparation et son utilisation Ceased WO2023138317A1 (fr)

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