WO2024012425A1 - 作为ripk1抑制剂的杂环化合物 - Google Patents

作为ripk1抑制剂的杂环化合物 Download PDF

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WO2024012425A1
WO2024012425A1 PCT/CN2023/106682 CN2023106682W WO2024012425A1 WO 2024012425 A1 WO2024012425 A1 WO 2024012425A1 CN 2023106682 W CN2023106682 W CN 2023106682W WO 2024012425 A1 WO2024012425 A1 WO 2024012425A1
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alkyl
hydrogen
methyl
nitrogen
fluorine
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孔祥龙
周超
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Nanjing Innocare Pharma Tech Co Ltd
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Definitions

  • the present invention relates to heterocyclic compounds, pharmaceutical compositions containing them and their use as receptor-interacting protein kinase-1 (RIPKl) inhibitors. More specifically, the present invention provides novel heterocyclic compounds as RIPK1 inhibitors, pharmaceutical compositions containing such compounds, and methods of using the compounds to treat or prevent related diseases and dysfunctions mediated by RIPK1. The invention also relates to methods for preparing said compounds.
  • RIPKl receptor-interacting protein kinase-1
  • Receptor-interacting protein kinase 1 is a serine/threonine protein kinase involved in innate immune signaling.
  • RIPK1 is a 76 kDa protein with an N-terminal kinase domain, a C-terminal death domain and an intermediate domain with RHIM (receptor interacting protein homotypic interaction motif).
  • the C-terminal death domain mediates homodimerization and heterodimerization with other death domain-containing proteins, and the N-terminal kinase domain mediates trans-autophosphorylation to promote autoactivation.
  • RIPK1 has dual immunoregulatory effects. On the one hand, it can serve as a scaffold to promote the activation of MAPK and NF- ⁇ B signaling pathways, thereby promoting inflammatory response, cell survival, and inhibiting apoptosis; on the other hand, abnormally regulated RIPK1 activity will cause cell necrosis.
  • RIPK1 is a master regulator of cellular determinants of NF- ⁇ B signaling in response to a wide range of inflammatory and pro-death stimuli in human disease (Degterev, A., et.al. PNAS, 2019,116(20),9714-9722).
  • RIPK1 is widely expressed in various cell types, and is most abundant in adipose, endothelial, and perivascular cell clusters. It is also expressed in immune cell clusters (dendritic cells, macrophages, and T cells). Studies have found that activation of RIPK1 kinase is present in pathological samples from autoimmune diseases and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). Anti-tumor necrosis factor- ⁇ (TNF- ⁇ ) drugs have achieved significant clinical success in the treatment of human peripheral inflammatory diseases such as rheumatoid arthritis, colitis, and psoriasis.
  • ALS amyotrophic lateral sclerosis
  • AD Alzheimer's disease
  • TNF- ⁇ Anti-tumor necrosis factor- ⁇
  • TNFR2 tumor necrosis factor receptor 2
  • RIPK1 inhibitors can safely improve harmful TNF responses in the central nervous system without affecting TNFR2. Therefore, RIPK1 inhibitors may become alternatives to TNF antibodies to make up for the deficiency of TNF antibodies.
  • Necrostatin-1 a small molecule inhibitor of RIPK1 known in the art, can effectively block programmed cell necrosis (Degterev et al. Nat. Chem. Biol. 2005; 1:112-119.) , showing effective therapeutic effects in a variety of inflammatory diseases.
  • GSK2982772 is being developed for peripheral autoimmune diseases such as psoriasis, rheumatoid arthritis (RA) and ulcerative colitis.
  • the brain-penetrating RIPK1 inhibitor DNL-788 is used in amyotrophic lateral sclerosis and more. These trials lay the foundation for advancing the clinical application of RIPK1 inhibitors.
  • RIPK1 inhibitors are of great significance to the field, especially in inhibiting inflammatory diseases (such as Crohn's disease, ulcerative colitis, etc.), sepsis and acute ischemic injury (such as sepsis, severe Covid-19 , acute ischemic injury to the brain, etc.), tumors, autoimmune diseases (such as psoriasis, rheumatoid arthritis, systemic lupus erythematosus, etc.) and neurodegenerative diseases (such as multiple sclerosis, Huntington's disease, Duchenne muscular dystrophy, frontotemporal dementia, Alzheimer's disease, Parkinson's disease, etc. (Lauren M.etc.al.Nature Reviews Drug Discovery, 19 (2020), 553–571).
  • inflammatory diseases such as Crohn's disease, ulcerative colitis, etc.
  • sepsis and acute ischemic injury such as sepsis, severe Covid-19 , acute ischemic injury to the brain, etc.
  • tumors such as psori
  • the present invention relates to compounds of formula (I), or optical isomers or pharmaceutically acceptable salts thereof,
  • R 1 is selected from hydrogen, halogen, cyano, Or a 5- to 10-membered heteroaryl optionally substituted by C1-C10 hydroxyalkyl, wherein R is selected from C1-C8 alkyl, containing one to three heteroatoms selected from nitrogen, oxygen and sulfur.
  • - to 10-membered heteroaryl containing one to two elements selected from nitrogen, oxygen and 3- to 10-membered heterocyclyl groups of sulfur heteroatoms
  • the alkyl, heteroaryl, heterocyclyl groups are unsubstituted or substituted by one to three substituents, wherein each of the substituents is independently Selected from hydroxyl, amino, halogen, C1-C10 alkyl, C1-C10 alkoxy, (C1-C10) alkyl-C(O)- or 3-10 membered heterocyclyl; preferably, R 1 is selected Since hydrogen, halogen, Or a 5- to 6-membered heteroaryl optionally substituted by C1-C6 hydroxyalkyl, wherein R is selected from C1-C8 alkyl, containing one to three heteroatoms selected from nitrogen, oxygen and sulfur.
  • - to 6-membered heteroaryl 4- to 6-membered heterocyclyl containing one to two heteroatoms selected from nitrogen, oxygen and sulfur, wherein the alkyl, heteroaryl and heterocyclyl are not Substituted or substituted by one to three substituents, wherein each of the substituents is independently selected from hydroxyl, amino, halogen, C1-C6 alkyl, C1-C6 alkoxy, (C1-C6)alkyl-C( O)-; further preferably, R 1 is selected from hydrogen, Or pyridyl substituted by C1-C4 hydroxyalkyl, wherein R a is selected from C1-C4 alkyl, 5- to 6-membered heteroaryl containing one to three heteroatoms selected from nitrogen and oxygen, containing one to Two 4- to 6-membered heterocyclyl groups selected from nitrogen and oxygen heteroatoms, wherein the alkyl group, heteroaryl group, and heterocyclyl group are unsubstituted or substituted by one to
  • R 2 is selected from hydrogen, C1-C8 alkyl or C1-C8 deuterated alkyl; preferably, R 2 is selected from hydrogen, C1-C6 alkyl or C1-C6 deuterated alkyl; further preferably, R 2 is selected from From hydrogen, C1-C4 alkyl or C1-C4 deuterated alkyl; most preferably, R 2 is selected from hydrogen, methyl or deuterated methyl;
  • R 3 is selected from hydrogen or halogen; preferably, R 3 is selected from hydrogen, fluorine, chlorine or bromine; further preferably, R 3 is selected from hydrogen, fluorine, chlorine; most preferably, R 3 is selected from hydrogen or fluorine;
  • R 4 is selected from hydrogen, halogen or cyano; preferably, R 4 is selected from hydrogen, fluorine, chlorine, bromine or cyano; further preferably, R 4 is selected from hydrogen, fluorine, chlorine or cyano; most preferably, R 4 is selected from hydrogen, fluorine or cyano;
  • L is selected from O, S, NH or C (R b R c ), where R b and R c are each independently selected from hydrogen, fluorine or C1-C4 alkyl, or R b and R c can be connected to a common carbon
  • the present invention relates to a compound of formula (I) as described above, or an optical isomer or pharmaceutically acceptable salt thereof, wherein:
  • R 1 is selected from hydrogen, halogen, Or a 5- to 6-membered heteroaryl optionally substituted by C1-C6 hydroxyalkyl, wherein R is selected from C1-C8 alkyl, containing one to three heteroatoms selected from nitrogen, oxygen and sulfur.
  • R 2 is selected from hydrogen, C1-C8 alkyl or C1-C8 deuterated alkyl
  • R 3 is selected from hydrogen and halogen
  • R 4 is selected from hydrogen, halogen or cyano
  • L is selected from O or C (R b R c ), where R b and R c are each independently selected from hydrogen, fluorine, or C1-C4 alkyl.
  • the present invention relates to a compound of formula (I) as described above, or an optical isomer or pharmaceutically acceptable salt thereof, wherein:
  • R 1 is selected from hydrogen, Or a 5- to 6-membered heteroaryl optionally substituted by C1-C4 hydroxyalkyl, wherein R a is selected from C1-C6 alkyl, 5-containing one to three heteroatoms selected from nitrogen, oxygen and sulfur.
  • 6-membered heteroaryl 4- to 6-membered heterocyclyl containing one to two heteroatoms selected from nitrogen, oxygen and sulfur, wherein the alkyl, heteroaryl and heterocyclyl are unsubstituted or substituted by one to three substituents, wherein each of the substituents is independently selected from hydroxyl, amino, halogen, C1-C6 alkyl, C1-C6 alkoxy, (C1-C6)alkyl-C(O )-;
  • R 2 is selected from hydrogen, C1-C6 alkyl or C1-C6 deuterated alkyl
  • R 3 is selected from hydrogen, fluorine, chlorine and bromine
  • R 4 is selected from hydrogen, fluorine, chlorine, bromine or cyano
  • L is selected from O or -CH2- .
  • the present invention relates to a compound of formula (I) as described above, or an optical isomer or pharmaceutically acceptable salt thereof, wherein:
  • R 1 is selected from hydrogen, Or pyridyl substituted by C1-C4 hydroxyalkyl, wherein R a is selected from C1-C4 alkyl, 5- to 6-membered heteroaryl containing one to three heteroatoms selected from nitrogen and oxygen, containing one to Two 4- to 6-membered heterocyclyl groups selected from nitrogen and oxygen heteroatoms, wherein the alkyl group, heteroaryl group, and heterocyclyl group are unsubstituted or substituted by one to three substituents, wherein the The substituents are each independently selected from hydroxyl, amino, halogen, C1-C4 alkyl, C1-C4 alkoxy, (C1-C4)alkyl-C(O)-;
  • R 2 is selected from hydrogen, C1-C4 alkyl or C1-C4 deuterated alkyl
  • R 3 is selected from hydrogen, fluorine or chlorine
  • R 4 is selected from hydrogen, fluorine, chlorine or cyano
  • L is selected from O or -CH2- .
  • the present invention relates to a compound of formula (I) as described above, or an optical isomer or pharmaceutically acceptable salt thereof, wherein:
  • R 1 is selected from hydrogen, where R a is selected from
  • R 2 is selected from hydrogen, methyl or deuterated methyl
  • R 3 is selected from hydrogen or fluorine
  • R 4 is selected from hydrogen, fluorine or cyano
  • L is selected from O or -CH2- .
  • the present invention relates to a compound of formula (I) as described above, or an optical isomer or pharmaceutically acceptable salt thereof, selected from:
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I or an isomer thereof or a pharmaceutically acceptable salt thereof in any embodiment of the present invention, optionally one or more other RIPK1 inhibitor, and one or more pharmaceutically acceptable carriers.
  • the present invention also relates to the compound of formula I according to any embodiment of the present invention, its optical isomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to the present invention for the preparation of treatment or prevention of RIPK1-mediated diseases. or use in medicines for diseases or conditions caused by programmed cell necrosis.
  • the present invention also relates to the use of the compound of formula I or its optical isomer or its pharmaceutically acceptable salt according to any embodiment of the present invention in the preparation of a medicament for the treatment or prevention of RIPK1-mediated Related diseases, such as: ulcerative colitis, Crohn's disease, pancreatitis, psoriasis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, systemic lupus erythematosus, Non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, systemic inflammatory response syndrome, cerebrovascular accident, Huntington's disease, Alzheimer's disease, Parkinson's disease , asthma, multiple sclerosis, cancer (such as pancreatic cancer), bacterial infections, hematological malignancies, solid organ malignancies, etc. Especially rheumatoid arthritis, ulcerative colitis
  • the present invention also relates to the use of the pharmaceutical composition according to the present invention in the preparation of medicaments, wherein the medicaments are used to treat or prevent related diseases mediated by RIPK1, such as ulcerative colitis, Crohn's disease disease, pancreatitis, psoriasis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, systemic lupus erythematosus, non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, Autoimmune hepatobiliary diseases, systemic inflammatory response syndrome, cerebrovascular accidents, Huntington's disease, Alzheimer's disease, Parkinson's disease, asthma, multiple sclerosis, cancer (such as pancreatic cancer), bacterial infections, Hematological malignancies, solid organ malignancies, etc. Especially rheumatoid arthritis, Ulcerative colitis, psoriasis, Alzheimer’
  • the present invention also relates to a method for treating or preventing related diseases mediated by RIPK1, which includes administering to a patient in need a therapeutically effective amount of a compound described in any embodiment of the present invention or an optical isomer thereof or a pharmaceutical thereof.
  • the related diseases such as: ulcerative colitis, Crohn's disease, pancreatitis, psoriasis, atopic dermatitis, rheumatoid arthritis , spondyloarthritis, gout, systemic lupus erythematosus, non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, systemic inflammatory response syndrome, cerebrovascular accident, Huntington's disease , Alzheimer's disease, Parkinson's disease, asthma, multiple sclerosis, cancer (such as pancreatic cancer), bacterial infections, hematological malignancies, solid organ malignancies, etc.; especially rheumatoid arthritis, ulcerative Colitis, psoriasis, Alzheimer’s and more.
  • the related diseases such as: ulcerative colitis, Crohn's disease, pancreatitis, psoriasis, atopic derma
  • Another aspect of the invention relates to a compound described in any one of the embodiments of the invention, or an isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt thereof, for use in the treatment of or Prevention of related diseases mediated by RIPK1, such as ulcerative colitis, Crohn's disease, pancreatitis, psoriasis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, systemic Lupus erythematosus, non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, systemic inflammatory response syndrome, cerebrovascular accident, Huntington's disease, Alzheimer's disease, Parkinson's disease, asthma, multiple sclerosis, cancer (e.g. pancreatic cancer), bacterial infections, hematological malignancies, solid organ malignancies, etc.; especially rheuma
  • a pharmaceutical composition which includes a compound of formula I or an optical isomer thereof or a pharmaceutically acceptable salt thereof, optionally one of the compounds of formula I described in any embodiment of the present invention. or a variety of other RIPK1 inhibitors, and one or more pharmaceutically acceptable carriers, diluents and excipients for the treatment or prevention of related diseases mediated by RIPK1, such as ulcerative colon inflammation, Crohn's disease, pancreatitis, psoriasis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, systemic lupus erythematosus, non-alcoholic steatohepatitis, alcoholic steatohepatitis, Autoimmune hepatitis, autoimmune hepatobiliary disease, systemic inflammatory response syndrome, cerebrovascular accident, Huntington's disease, Alzheimer's disease, Parkinson's disease, asthma, multiple sclerosis
  • the drug can be in any pharmaceutical dosage form, including but not limited to tablets, capsules, solutions, freeze-dried preparations, and injections.
  • the pharmaceutical preparations of the present invention may be administered in the form of dosage units containing a predetermined amount of active ingredient per dosage unit.
  • dosage units may contain, for example, 0.5 mg to 1 gram, preferably 1 mg to 700 mg, particularly preferably 5 mg to 300 mg, of a compound of the invention, or medicament, depending on the condition treated, the method of administration and the age, weight and condition of the patient.
  • the formulations may be administered in dosage unit form containing a predetermined amount of the active ingredient per dosage unit.
  • Preferred dosage unit formulations are those containing a daily dose or sub-dose, or corresponding fractions thereof, of the active ingredient as indicated above.
  • pharmaceutical preparations of this type can be prepared using methods well known in the pharmaceutical field.
  • the pharmaceutical formulations of the invention may be suitable for administration by any suitable method desired, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) administration methods.
  • Such formulations can be prepared by combining, for example, the active ingredient with one or more excipients or one or more auxiliaries using all methods known in the pharmaceutical art.
  • the invention also provides methods of preparing said compounds.
  • R 3 and R 4 are as mentioned above;
  • Dissolve compounds (I) and (II) in a solvent such as dioxane
  • a neutral gas such as nitrogen or argon
  • a base such as cesium carbonate
  • catalyst such as copper iodide
  • ligand such as N, N-dimethylglycine
  • R 3 and R 4 are as mentioned above;
  • Compound (IX) is dissolved in a solvent (such as water), a base (such as sodium hydroxide or lithium hydroxide, etc.) is added, and the temperature is stirred at room temperature to 80°C for 12 to 24 hours to obtain compound (X);
  • a solvent such as water
  • a base such as sodium hydroxide or lithium hydroxide, etc.
  • R a , R 2 , R 3 , R 4 and L are as mentioned above, and X is halogen;
  • Compound (XVI), compound (VI) or compound (X), a condensing agent (such as 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluoro Phosphate ester) and a base (such as triethylamine) are dissolved in a solvent (such as N,N-dimethylformamide), and stirred at room temperature to 60°C for 2 to 16 hours to obtain compound (XIX);
  • a condensing agent such as 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluoro Phosphate ester
  • a base such as triethylamine
  • Compound (XVII), compound (VI) or compound (X), a condensing agent (such as 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluoro Phosphate ester) and a base (such as triethylamine) are dissolved in a solvent (such as N,N-dimethylformamide), and stirred at room temperature to 60°C for 2 to 16 hours to obtain compound (XVIII);
  • a condensing agent such as 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluoro Phosphate ester
  • a base such as triethylamine
  • R 1 is selected from
  • R 2 , R 3 , R 4 and L are as mentioned above, and X is halogen
  • Cx-Cy used in the present invention represents the range of carbon atoms, where x and y are integers, for example, C3-C8 cycloalkyl represents a cycloalkyl group with 3-8 carbon atoms, -C0 -C2 alkyl represents an alkyl group having 0-2 carbon atoms, where -C0 alkyl refers to a chemical single bond.
  • alkyl refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms, for example, 1 to 18 carbon atoms, 1 to 12 carbon atoms , straight and branched chain groups of 1 to 8 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, and various branched isomers thereof.
  • Alkyl groups may be optionally substituted or unsubstituted.
  • alkoxy refers to an alkyl-O- group, where alkyl has the meaning defined above.
  • hydroxyalkyl refers to an alkyl-OH group, that is, a group in which any position of the alkyl group (including straight-chain alkyl and branched-chain alkyl groups) is substituted by a hydroxyl group, wherein the alkyl group has the above-mentioned defined meaning.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, which includes 3 to 20 ring atoms, such as 3 to 16, 3 to 12, 3 to 10, 3 to 8 or 3 to 6 ring atoms, one or more of which are selected from nitrogen, oxygen or heteroatoms of S(O)m (where m is an integer from 0 to 2), but excluding - The ring part of O-O-, -O-S- or -S-S-, and the remaining ring atoms are carbon. Preferably it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms.
  • the heterocyclyl ring contains 3 to 10 ring atoms, more preferably 3 to 8 ring atoms, and most preferably a 5- or 6-membered ring. Ring, in which 1 to 4 are heteroatoms, more preferably 1 to 3 are heteroatoms, and most preferably 1 to 2 are heteroatoms.
  • monocyclic heterocyclyl groups include oxetanyl, oxetanyl, azetidinyl, morpholinyl, 2-morpholinyl, dihydropyrazolyl, and the like.
  • Polycyclic heterocyclyl groups include spirocyclic, fused cyclic and bridged cyclic heterocyclyl groups. Heterocyclyl groups may be optionally substituted or unsubstituted.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms include oxygen, sulfur and nitrogen. Preferably it is 5- to 10-yuan. More preferably, the heteroaryl group is 5-membered or 6-membered, such as pyrazolyl, imidazolyl, triazolyl, pyrazinyl, oxazolyl, isoxazolyl, pyridyl, etc. Heteroaryl groups may be optionally substituted or Not superseded.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • a heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but need not be present. This description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .
  • the substituents include, but are not limited to, the various groups described above.
  • the compounds claimed in the present invention include not only the compound itself, but also optical isomers of the compound or pharmaceutically acceptable salts thereof.
  • the "pharmaceutical composition” of the present invention means a mixture containing one or more compounds of the present invention or their optical isomers or pharmaceutically acceptable salts thereof and other chemical components.
  • Other components include pharmaceutically acceptable carriers, diluents and excipients.
  • the purpose of pharmaceutical compositions is to facilitate administration to living organisms and facilitate the absorption of active ingredients to exert biological activity.
  • Root temperature mentioned in the present invention refers to 15-30°C.
  • “Pharmaceutically acceptable salts” of the present invention are discussed in Berge, et al., “Pharmaceutically acceptable salts", J. Pharm. Sci., 1977, 66, 1-19, and are useful to medicinal chemists. It will be apparent that the salts are substantially non-toxic and provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion, etc.
  • the pharmaceutically acceptable salts of the present invention can be synthesized by general chemical methods.
  • salts can be prepared by reacting the free base or acid with an equal or excess stoichiometric amount of acid (inorganic or organic) or base in a suitable solvent or solvent combination.
  • optical isomers examples include meso, racemate, enantiomers, diastereomers, mixtures thereof, etc. of the compound of formula (I) of the present invention.
  • the present invention includes any polymorph of the compound or salt thereof as well as any hydrates or other solvates.
  • the term "patient” generally refers to mammals, especially humans.
  • the term "therapeutically effective amount” refers to an amount of a compound of the present invention that can effectively treat or prevent related diseases mediated by RIPK1.
  • the structures of all compounds of the present invention can be identified by nuclear magnetic resonance ( 1 H NMR) and/or mass spectrometry (MS).
  • MS mass spectrometry
  • the thin-layer silicone sheet is Yantai Huanghai HSGF254 or Qingdao GF254 silicone sheet.
  • Column chromatography generally uses Yantai Huanghai 100-200 or 200-300 mesh silica gel as the carrier.
  • Preparative liquid chromatography used Waters SQD2 mass spectrometry-guided high-pressure liquid chromatography separator, XBridge-C18; 30X 150mm preparative column, 5 ⁇ m;
  • Method 1 Acetonitrile-water (0.2% formic acid), flow rate 25mL/min;
  • Method 2 Acetonitrile-water (0.8% ammonium bicarbonate), flow rate 25mL/min;
  • the known starting materials of the present invention can be synthesized according to methods known in the art, or can be purchased from Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Shanghai Bide Pharmaceutical, Shanghai Accela Latin Chemical, Shanghai Merrill Chemical, Bailingwei Chemical, Anaiji Chemical and other companies.
  • the solvents used in the reaction are all anhydrous solvents.
  • Commercially available tetrahydrofuran is used as anhydrous tetrahydrofuran.
  • Sodium block is used as a water remover, and benzophenone is used as an indicator.
  • the solution is refluxed under argon protection. It is blue-purple, collected by distillation, and stored at room temperature under argon protection.
  • Other anhydrous solvents were purchased from Anaiji Chemical and Bailingwei Chemical. The transfer and use of all anhydrous solvents must be carried out under argon protection unless otherwise specified.
  • Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1L.
  • the hydrogen atmosphere refers to the reaction bottle connected to a hydrogen balloon with a volume of about 1L.
  • the hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated three times.
  • reaction temperature is room temperature, and the temperature range is 15°C-30°C.
  • the reaction progress in the examples was monitored by thin layer chromatography (TLC).
  • the developing solvent systems used in the reaction were A: methylene chloride and methanol system; B: petroleum ether and ethyl acetate system. The volume ratio of solvents is adjusted according to the polarity of the compounds.
  • the eluent system of column chromatography and the developing agent system of thin layer chromatography used to purify the compound include A: methylene chloride and methanol system; B: petroleum ether and ethyl acetate system.
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and acidic or alkaline reagents can also be added for adjustment.
  • DMSO D5879-500ML
  • Fetal Bovine Serum FSP500
  • DPBS 14190-144
  • RPMI Medium 1640 72400-047
  • Luminescent Cell Viability Assay Luminescent cell viability detection kit, G7571, G7573 was purchased from Promega Company.
  • intermediate 2 refers to intermediate 1, in which m-fluorophenol is used instead of o-fluorophenol in the first step.
  • intermediate 4 refers to intermediate 3, in which o-fluorobenzonitrile is used instead of m-fluorobenzonitrile in the first step.
  • 5-(3-cyanobenzyl)-2-fluorobenzoic acid methyl ester (0.30g, 0.11mmol) was added to a mixture of sodium hydroxide aqueous solution (1N, 5mmol, 5mL) and tetrahydrofuran (5mL), at room temperature Stir overnight. Concentrate under reduced pressure to remove tetrahydrofuran, adjust the pH of the aqueous phase to about 3 with dilute hydrochloric acid (1N), and extract with ethyl acetate (10 mL ⁇ 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Example 1 The synthesis steps of Examples 2 to 6 are referred to Example 1.
  • reaction solution was filtered and spun to dryness, quenched with 10 mL of water, and extracted with ethyl acetate (10 mL ⁇ 2).
  • the combined organic phases were washed with saturated brine (10 mL).
  • the organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was spin-dried to obtain crude product.
  • 2,2-Dimethyl-4-(trimethylsilyl)-3-butyn-1-ol (0.52g, 3.00mmol) (synthesis reference J.Am.Chem.Soc. (2020) , 142(47), 20048–20057) was dissolved in 15 mL of methylene chloride, imidazole (0.41g, 6.00mmol) was added, and then tert-butyldiphenylsilyl chloride (1.07g, 3.90mmol) was slowly added in batches. After the addition was completed, the reaction was stirred at room temperature for 48 hours. After the reaction is completed, add 50 mL of methylene chloride to dilute.
  • reaction solution was filtered and spun to dryness, quenched with 10 mL of water, and extracted with ethyl acetate (10 mL ⁇ 2).
  • the combined organic phases were washed with saturated brine (10 mL).
  • the organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and desolvated under reduced pressure to obtain the crude product.
  • the combined organic phases were washed with saturated brine (10 mL).
  • the organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and desolvated under reduced pressure to obtain the crude product.
  • reaction solution was bubbled with nitrogen for ten minutes. Heat to 85°C under nitrogen protection and stir for 8 hours. Spin the reaction liquid to dryness, add water (20 mL) to dilute, and extract with ethyl acetate (20 mL ⁇ 2). The combined organic phases were washed with saturated brine (20 mL ⁇ 2). Dry with anhydrous sodium sulfate, filter, and spin the filtrate to obtain a crude product.
  • Example 8 For the synthesis steps of Examples 31 to 42, refer to Example 8.
  • the reaction solution was diluted with ethyl acetate (50 mL), washed with water (50 mL ⁇ 2) and saturated brine (50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the residue was separated and purified using a silica gel column (0-20% ethyl acetate/petroleum ether) to obtain the target product (S)-N-(7-bromo-5-methyl-4-one-2,3,4,5 -Tetrahydrobenzo[b][1,4]oxaza -3-yl)-2-fluoro-5-(2-fluorophenoxy)benzamide (0.53 g, white solid). Yield: 64.6%.
  • reaction solution was filtered and spun to dryness.
  • Ethyl acetate (20 mL) and water (20 mL) were added for extraction.
  • the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and spun to dryness.
  • 1,1'-Bisdiphenylphosphine ferrocene palladium dichloride (59 mg, 0.08 mmol) and sodium carbonate (32 mg, 0.30 mmol) were added.
  • the reaction solution was bubbled with nitrogen for ten minutes, heated and stirred at 100°C for 14 hours under nitrogen protection.
  • the reaction solution was filtered and spun to dryness, ethyl acetate (5 mL) and water (5 mL) were added, and the organic phase was separated. The organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered and spun to dryness.
  • Example 44 For the synthesis steps of Example 44, refer to Example 43.
  • U-937 cells (purchased from Nanjing Kebai Biotechnology Co., Ltd., Cat. No. CBP60277) were cultured in a cell culture incubator containing 5% CO2 at 37°C in 1640 culture medium. They were spread on a 384-well white plate and the compounds were tested 4 times. Gradient serial dilution, the final starting concentration is 2000nM, 100ng/mL TNF ⁇ , Q-VD-Oph (10 ⁇ M) and test drugs were incubated with cells for 48h. GSK2982772 was used as a positive control substance, and DMSO was used in the control wells. The viability of the cells was determined using ATP-based viability assay using Cell-TiterGlo kit (purchased from Promega Company).
  • the EC 50 value is defined as the compound concentration that produces 50% of the maximum effect concentration.
  • the 4-parameter logistic equation is used to fit the drug activity data.
  • the XLfit 5.4 software of IDBS Company analyzes and calculates the EC 50 .
  • L-929 cells purchased from Nanjing Kebai Biotechnology Co., Ltd., Cat. No. CBP60878, were cultured in a cell culture incubator containing 5% CO2 at 37°C in MEM culture medium, and spread on a 384-well white plate. The compounds were tested 4 times. Gradient serial dilution, the final starting concentration is 10000nM, 40ng/mL TNF ⁇ , Q-VD-Oph (10 ⁇ M) and test drugs were incubated with cells for 24h. GSK2982772 was used as a positive control substance, and DMSO was used in the control wells. Cell viability was determined using the Cell-TiterGlo kit ATP-based viability assay.
  • the EC 50 value is defined as the compound concentration that produces 50% of the maximum effect concentration.
  • the 4-parameter logistic equation is used to fit the drug activity data.
  • the XLfit 5.4 software of IDBS Company analyzes and calculates the EC 50 .
  • HT-29 cells purchased from Nanjing Kebai Biotechnology Co., Ltd., product number CBP30001L
  • the cells were spread on a 384-well white plate, and the compounds were tested for 4 Two-fold gradient serial dilution, the final starting concentration is 500nM, 100ng/mL TNF ⁇ , Q-VD-Oph (10 ⁇ M), SM-164 (1 ⁇ M) and the test drug were incubated with the cells for 48h, GSK2982772 was used as a positive control substance, control Wells with DMSO.
  • Cell viability was determined using the Cell-TiterGlo kit ATP-based viability assay.
  • the EC 50 value is defined as the compound concentration that produces 50% of the maximum effect concentration.
  • the 4-parameter logistic equation is used to fit the drug activity data.
  • the XLfit 5.4 software of IDBS Company analyzes and calculates the EC 50 .
  • I2.1 cells are Jurkat cells with FADD gene knockout and are suitable for studying programmed necrosis of cells under TNF ⁇ -induced conditions.
  • I2.1 cells purchased from ATCC, Cat. No. CRL-2572 were cultured at 37°C. In a cell culture incubator containing 5% CO2 , in 1640 culture medium, spread on a 384-well white plate. The compound was diluted 4 times in a gradient series. The final starting concentration was 500 nM. TNF ⁇ of 40 ng/mL and the test drug were incubated with the cells for 24 days. hours, GSK2982772 was used as a positive control substance, and DMSO (D5879-500ML, purchased from Sigma) was used in the control wells.
  • DMSO D5879-500ML
  • the cell viability was measured based on changes in ATP content using the Cell-TiterGlo kit.
  • the EC 50 value is defined as the compound concentration that produces 50% of the maximum effect concentration.
  • the 4-parameter logistic equation is used to fit the drug activity data.
  • the XLfit 5.4 software of IDBS Company analyzes and calculates the EC 50 .
  • Table 1 Cell activity detection results of the compounds of the embodiments of the present invention
  • the compounds of the embodiments of the present invention can effectively inhibit programmed cell necrosis, and therefore have effective inhibitory activity of RIPK1, and can therefore be used to treat or prevent related diseases and dysfunctions mediated by RIPK1, such as rheumatoid arthritis. arthritis, ulcerative Colitis, psoriasis, Alzheimer’s, multiple sclerosis, amyotrophic lateral sclerosis and more.

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Abstract

本发明涉及化合物、含有其的药物组合物、以及它们的制备方法,和其作为RIPK1抑制剂的用途。所述化合物为式(I)所示的化合物，或其光学异构体或药学上可接受的盐。本发明还涉及所述化合物用于治疗或预防由RIPK1介导的相关疾病和功能障碍的用途以及应用其治疗所述疾病的方法。

Description

作为RIPK1抑制剂的杂环化合物 技术领域
本发明涉及杂环化合物、含有其的药物组合物及其作为受体相互作用蛋白激酶-1(RIPKl)抑制剂的用途。更具体说，本发明提供了新的作为RIPK1抑制剂的杂环化合物、含有这类化合物的药物组合物和应用所述化合物治疗或预防由RIPK1介导的相关疾病和功能障碍的方法。本发明还涉及制备所述的化合物的方法。
背景技术
受体相互作用蛋白激酶1(Receptor-interacting protein kinase 1,RIPK1)是一种参与天然免疫信号传导的丝氨酸/苏氨酸蛋白激酶。RIPK1是一种76kDa的蛋白，具有一个N末端激酶结构域、一个C末端死亡结构域和一个具有RHIM(受体相互作用蛋白同型相互作用基序)的中间结构域。其中C端死亡结构域介导与其他含死亡结构域的蛋白质的同二聚和异二聚，N端激酶结构域介导反式自身磷酸化以促进自身激活。
RIPK1具有双重免疫调节作用，一方面可作为支架促进MAPK和NF-κB信号通路激活，从而促进炎症反应、细胞存活，并抑制细胞凋亡；另一方面，异常调控的RIPK1活性将造成细胞坏死。RIPK1是NF-κB信号转导与死亡反应的细胞决定因素的主要调节剂，NF-κB信号传导响应人类疾病中广泛的炎性和促死性刺激(Degterev,A.,et.al.PNAS,2019,116(20),9714-9722)。
RIPK1广泛表达于各种细胞类型中，在脂肪、内皮、血管周围细胞簇中表达最为丰富，在免疫细胞簇(树突细胞、巨噬细胞和T细胞)也有所表达。研究发现，自身免疫疾病以及肌萎缩侧索硬化症(ALS)和阿尔茨海默氏症(AD)等神经退行性疾病的病理样本中均存在RIPK1激酶的激活。抗肿瘤坏死因子-α(TNF-α)药物已在治疗人类外周炎性疾病如类风湿性关节炎、结肠炎和银屑病等方面取得重大临床成功。然而，由于肿瘤坏死因子受体2(TNFR2)介导神经再生，对中枢神经系统疾病的治疗是存在不安全的因素。RIPK1抑制剂在不影响TNFR2的情况下，能安全地改善中枢神经系统中有害TNF反应。因此， RIPK1抑制剂有可能成为替代TNF抗体的药物，以弥补TNF抗体的不足。
研究表明，本领域已知的RIPK1小分子抑制剂Necrostatin-1(Nec-1)可以有效地阻断细胞程序性坏死(Degterev et al.Nat.Chem.Biol.2005；1:112-119.)，在多种炎症疾病中表现出了有效的治疗作用。GSK2982772正在开发用于外周自身免疫性疾病，例如银屑病、类风湿性关节炎(RA)和溃疡性结肠炎。脑渗透RIPK1抑制剂DNL-788用于肌萎缩侧索硬化症等。这些试验为推进RIPK1抑制剂的临床应用奠定了基础。
RIPKl抑制剂对于本领域而言具有重要意义，尤其是在抑制炎症性疾病(例如克罗恩病、溃疡性结肠炎等)、脓毒症和急性缺血性损伤(例如败血症、重症Covid-19、脑急性缺血性损伤等)、肿瘤、自身免疫系统疾病(例如银屑病、类风湿性关节炎、系统性红斑狼疮等)和神经退行性疾病(例如多发性硬化症、亨廷顿氏病、杜氏肌营养不良、额颞叶痴呆、阿尔茨海默氏症、帕金森病等)等方面(Lauren M.etc.al.Nature Reviews Drug Discovery,19(2020),553–571)。
因此，仍然需要开发具有优异活性的小分子RIPK1抑制剂。
发明内容
本发明涉及式(I)化合物，或其光学异构体或药学上可接受的盐，
其中：
R1选自氢、卤素、氰基、或任选被C1-C10羟烷基所取代的5-至10-元杂芳基，其中Ra选自C1-C8烷基、含有一至三个选自氮、氧和硫的杂原子的5-至10-元杂芳基、含有一至两个选自氮、氧和 硫的杂原子的3-至10-元杂环基，且所述的烷基、杂芳基、杂环基为未取代的或被一至三个取代基取代，其中所述取代基各自独立地选自羟基、氨基、卤素、C1-C10烷基、C1-C10烷氧基、(C1-C10)烷基-C(O)-或3-10元的杂环基；优选地，R1选自氢、卤素、或任选被C1-C6羟烷基所取代的5-至6-元杂芳基，其中Ra选自C1-C8烷基、含有一至三个选自氮、氧和硫的杂原子的5-至6-元杂芳基、含有一至两个选自氮、氧和硫的杂原子的3-至8-元杂环基，其中所述的烷基、杂芳基、杂环基为未取代的或被一至三个取代基取代，其中所述取代基各自独立地选自羟基、氨基、卤素、C1-C8烷基、C1-C8烷氧基、(C1-C8)烷基-C(O)-；进一步优选地，R1选自氢、或任选被C1-C4羟烷基所取代的5-至6-元杂芳基，其中Ra选自C1-C6烷基、含有一至三个选自氮、氧和硫的杂原子的5-至6-元杂芳基、含有一至两个选自氮、氧和硫的杂原子的4-至6-元杂环基，其中所述的烷基、杂芳基、杂环基为未取代的或被一至三个取代基取代，其中所述取代基各自独立地选自羟基、氨基、卤素、C1-C6烷基、C1-C6烷氧基、(C1-C6)烷基-C(O)-；再进一步优选地，R1选自氢、或被C1-C4羟烷基所取代的吡啶基，其中Ra选自C1-C4烷基、含有一至三个选自氮和氧的杂原子的5-至6-元杂芳基、含有一至两个选自氮和氧的杂原子的4-至6-元杂环基，其中所述的烷基、杂芳基、杂环基为未取代的或被一至三个取代基取代，其中所述取代基各自独立地选自羟基、氨基、卤素、C1-C4烷基、C1-C4烷氧基、(C1-C4)烷基-C(O)-；最优选地，R1选自氢、 其中Ra选自
R2选自氢、C1-C8烷基或C1-C8氘代烷基；优选地，R2选自氢、C1-C6烷基或C1-C6氘代烷基；进一步优选地，R2选自氢、C1-C4烷基或C1-C4氘代烷基；最优选地，R2选自氢、甲基或氘代甲基；
R3选自氢或卤素；优选地，R3选自氢、氟、氯或溴；进一步优选地，R3选自氢、氟、氯；最优选地，R3选自氢或氟；
R4选自氢、卤素或氰基；优选地，R4选自氢、氟、氯、溴或氰基；进一步优选地，R4选自氢、氟、氯或氰基；最优选地，R4选自氢、氟或氰基；
L选自O、S、NH或C(RbRc)，其中Rb和Rc各自独立地选自氢、氟或C1-C4烷基，或者Rb、Rc可以与共同相连的碳原子一起形成3-元饱和碳环；优选地，L选自O或C(RbRc)，其中Rb和Rc各自独立地选自氢、氟或C1-C4烷基；最优选地，L选自O或-CH2-。
优选地，本发明涉及如上文所述的式(I)化合物，或其光学异构体或药学上可接受的盐，其中：
R1选自氢、卤素、或任选被C1-C6羟烷基所取代的5-至6-元杂芳基，其中Ra选自C1-C8烷基、含有一至三个选自氮、氧和硫的杂原子的5-至6-元杂芳基、含有一至两个选自氮、氧和硫的杂原子的3-至8-元杂环基，其中所述的烷基、杂芳基、杂环基为未取代的或被一至三个取代基取代，其中所述取代基各自独立地选自羟基、氨 基、卤素、C1-C8烷基、C1-C8烷氧基、(C1-C8)烷基-C(O)-；
R2选自氢、C1-C8烷基或C1-C8氘代烷基；
R3选自氢、卤素；
R4选自氢、卤素或氰基；
L选自O或C(RbRc)，其中Rb和Rc各自独立地选自氢、氟或C1-C4烷基。
更优选地，本发明涉及如上文所述的式(I)化合物，或其光学异构体或药学上可接受的盐，其中：
R1选自氢、或任选被C1-C4羟烷基所取代的5-至6元杂芳基，其中Ra选自C1-C6烷基、含有一至三个选自氮、氧和硫的杂原子的5-至6-元杂芳基、含有一至两个选自氮、氧和硫的杂原子的4-至6-元杂环基，其中所述的烷基、杂芳基、杂环基为未取代的或被一至三个取代基取代，其中所述取代基各自独立地选自羟基、氨基、卤素、C1-C6烷基、C1-C6烷氧基、(C1-C6)烷基-C(O)-；
R2选自氢、C1-C6烷基或C1-C6氘代烷基；
R3选自氢、氟、氯、溴；
R4选自氢、氟、氯、溴或氰基；
L选自O或-CH2-。
进一步优选地，本发明涉及如上文所述的的式(I)化合物，或其光学异构体或药学上可接受的盐，其中：
R1选自氢、或被C1-C4羟烷基所取代的吡啶基，其中Ra选自C1-C4烷基、含有一至三个选自氮和氧的杂原子的5-至6-元杂芳基、含有一至两个选自氮和氧的杂原子的4-至6-元杂环基，其中所述的烷基、杂芳基、杂环基为未取代的或被一至三个取代基取代，其中所述取代基各自独立地选自羟基、氨基、卤素、C1-C4烷基、C1-C4烷氧基、(C1-C4)烷基-C(O)-；
R2选自氢、C1-C4烷基或C1-C4氘代烷基；
R3选自氢、氟或氯；
R4选自氢、氟、氯或氰基；
L选自O或-CH2-。
再优选地，本发明涉及如上文所述的式(I)化合物，或其光学异构体或药学上可接受的盐，其中：
R1选自氢、其中Ra选自
R2选自氢、甲基或氘代甲基；
R3选自氢或氟；
R4选自氢、氟或氰基；
L选自O或-CH2-。
最优选地，本发明涉及如上文所述的式(I)化合物，或其光学异构体或药学上可接受的盐，其选自：




本发明进一步涉及药物组合物，所述药物组合物包括本发明任意一个实施方案中所述的式I化合物或其异构体或其药学上可接受的盐，任选的一种或多种其它RIPK1抑制剂，以及一种或多种药学上可接受的载体。
本发明还涉及根据本发明任意一个实施方案中所述的式I化合物，其光学异构体或其药学上可接受的盐或根据本发明的药物组合物在制备治疗或预防RIPK1介导的疾病或病症或者细胞程序性坏死导致的疾病或病症的药物中的用途。
本发明还涉及根据本发明任意一个实施方案中所述的式I化合物或其光学异构体或其药学上可接受的盐在制备药物中的用途，所述药物用于治疗或预防RIPK1介导的相关疾病，所述相关疾病如：溃疡性结肠炎、克罗恩氏病、胰腺炎、银屑病、特应性皮炎、类风湿性关节炎、脊椎关节炎、痛风、系统性红斑狼疮、非酒精性脂肪性肝炎、酒精性脂肪性肝炎、自身免疫性肝炎、自身免疫性肝胆疾病、全身性炎症反应综合征、脑血管意外、亨廷顿氏病、阿尔茨海默氏症、帕金森氏症、哮喘、多发性硬化症、癌症(例如胰腺癌)、细菌感染、血液恶性肿瘤、实体器官恶性肿瘤等。尤其是类风湿性关节炎、溃疡性结肠炎、银屑病、阿尔茨海默氏症等。
本发明还涉及根据本发明所述的药物组合物在制备药物中的用途，其中所述药物用于治疗或者预防由RIPK1介导的相关疾病，所述相关疾病例如溃疡性结肠炎、克罗恩氏病、胰腺炎、银屑病、特应性皮炎、类风湿性关节炎、脊椎关节炎、痛风、系统性红斑狼疮、非酒精性脂肪性肝炎、酒精性脂肪性肝炎、自身免疫性肝炎、自身免疫性肝胆疾病、全身性炎症反应综合征、脑血管意外、亨廷顿氏病、阿尔茨海默氏症、帕金森氏症、哮喘、多发性硬化症、癌症(例如胰腺癌)、细菌感染、血液恶性肿瘤、实体器官恶性肿瘤等。尤其是类风湿性关节炎、 溃疡性结肠炎、银屑病、阿尔茨海默氏症等。
本发明还涉及一种治疗或者预防由RIPK1介导的相关疾病的方法，其包括给予有需要的患者治疗有效量的本发明任意一个实施方案中所述的化合物或其光学异构体或其药学上可接受的盐、或本发明所述的药物组合物，所述相关疾病例如：溃疡性结肠炎、克罗恩氏病、胰腺炎、银屑病、特应性皮炎、类风湿性关节炎、脊椎关节炎、痛风、系统性红斑狼疮、非酒精性脂肪性肝炎、酒精性脂肪性肝炎、自身免疫性肝炎、自身免疫性肝胆疾病、全身性炎症反应综合征、脑血管意外、亨廷顿氏病、阿尔茨海默氏症、帕金森氏症、哮喘、多发性硬化症、癌症(例如胰腺癌)、细菌感染、血液恶性肿瘤、实体器官恶性肿瘤等；尤其是类风湿性关节炎，溃疡性结肠炎，银屑病，阿尔茨海默氏症等。
本发明的另一方面涉及本发明任意一个实施方案中所述的化合物、或其异构体、前药、溶剂合物、稳定的同位素衍生物或药学上可接受的盐，其用于治疗或者预防由RIPK1介导的相关疾病，所述相关疾病例如溃疡性结肠炎、克罗恩氏病、胰腺炎、银屑病、特应性皮炎、类风湿性关节炎、脊椎关节炎、痛风、系统性红斑狼疮、非酒精性脂肪性肝炎、酒精性脂肪性肝炎、自身免疫性肝炎、自身免疫性肝胆疾病、全身性炎症反应综合征、脑血管意外、亨廷顿氏病、阿尔茨海默氏症、帕金森氏症、哮喘、多发性硬化症、癌症(例如胰腺癌)、细菌感染、血液恶性肿瘤、实体器官恶性肿瘤等；尤其是类风湿性关节炎，溃疡性结肠炎，银屑病，阿尔茨海默氏症等。
本发明的另一方面涉及药物组合物，所述药物组合物包括本发明任意一个实施方案中所述的式I化合物或其光学异构体或其药学上可接受的盐，任选的一种或多种其它RIPK1抑制剂，以及一种或多种药学上可接受的载体、稀释剂和赋形剂，其用于治疗或者预防由RIPK1介导的相关疾病，所述相关疾病例如溃疡性结肠炎、克罗恩氏病、胰腺炎、银屑病、特应性皮炎、类风湿性关节炎、脊椎关节炎、痛风、系统性红斑狼疮、非酒精性脂肪性肝炎、酒精性脂肪性肝炎、自身免疫性肝炎、自身免疫性肝胆疾病、全身性炎症反应综合征、脑血管意外、亨廷顿氏病、阿尔茨海默氏症、帕金森氏症、哮喘、多发性硬化症、癌症(例如胰腺癌)、细菌感染、血液恶性肿瘤、实体器官恶性肿瘤等；尤其是类风湿性关节炎，溃疡性结肠炎，银屑病，阿尔茨海默氏症等。
根据本发明，所述药物可以是任何药物剂型，包括但不限于片剂、胶囊剂、溶液剂、冻干制剂、注射剂。
本发明的药物制剂可以以每剂量单位包含预定量的活性成分的剂量单位形式给药。这种单位可根据治疗的病症、给药方法和患者的年龄、体重和状况包含例如0.5毫克至1克，优选1毫克至700毫克，特别优选5毫克至300毫克的本发明的化合物，或药物制剂可以以每剂量单位包含预定量的活性成分的剂量单位形式给药。优选剂量单位制剂是包含如上指示的日剂量或分剂量或其相应分数的活性成分的那些。此外，可以使用制药领域中公知的方法制备这种类型的药物制剂。
本发明药物制剂可适于通过任何所需的合适方法给药，例如通过经口(包括口腔或舌下)、直肠、经鼻、局部(包括口腔、舌下或经皮)、阴道或肠胃外(包括皮下、肌内、静脉内或皮内)方法给药。可以使用制药领域中已知的所有方法通过例如将活性成分与一种或多种赋形剂或一种或多种辅助剂合并来制备这样的制剂。
制备流程
本发明还提供制备所述化合物的方法。
流程1
R3与R4的定义如前文所述；
第一步：
在室温，将化合物(I)和(II)溶解在溶剂(如二氧六环)中，在惰 性气体(如氮气或氩气)保护下，加入碱(如碳酸铯)、催化剂(如碘化亚铜)和配体(如N,N-二甲基甘氨酸)，体系抽真空氮气置换三次，在油浴加热(100～130℃)下反应2～20小时，得到化合物(V)；
第二步：
在室温，将化合物(III)和(IV)溶解在溶剂(如N,N-二甲基甲酰胺)中，加入碱(如碳酸钾)，在油浴加热(100～130℃)下反应2～20小时，得到化合物(V)；
第三步：
在室温将化合物(V)溶于溶剂(如水)中，加入碱(如氢氧化钠或氢氧化锂等)，在温度为室温～50℃搅拌1～5小时，得到化合物(VI)；
流程2
R3与R4的定义如前文所述；
第一步：
氮气保护下将化合物(I)、联硼酸频那醇酯、碱(如乙酸钾)以及催化剂(如1,1'-双二苯基膦二茂铁二氯化钯)加入溶剂(如二甲基亚砜)中，体系抽真空氮气置换三次，在温度为60～100℃下搅拌12～24小时，得到化合物(VII)；
第二步：
氮气保护下将化合物(VII)、化合物(VIII)、碱(如碳酸钠) 以及催化剂(如1,1'-双二苯基膦二茂铁二氯化钯)加入溶剂(如二氧六环)中，体系抽真空氮气置换三次，在温度为80～120℃下搅拌12～24小时，得到化合物(IX)；
第三步：
化合物(IX)溶于溶剂(如水)中，加入碱(如氢氧化钠或氢氧化锂等)，在温度为室温～80℃下搅拌12～24小时，得到化合物(X)；
流程3
Ra、R2、R3、R4与L的定义如前文所述，X为卤素；
第一步：
将化合物(XI)(合成参考：Journal of Medicinal Chemistry(2017),60(4),1247-1261)、(XII)和碱(如碳酸钾或碳酸铯)溶解在溶剂(如N,N-二甲基甲酰胺)中，在温度为室温～60℃下搅拌2～6小时，得到化合物(XIII)；
第二步：
化合物(XIII)和(XIV)溶解在溶剂(如二氧六环)中，在惰性气 体(如氮气或氩气)保护下，加入碱(如N,N-二异丙基乙胺)、催化剂(如双三苯基膦二氯化钯和碘化亚铜)，体系抽真空氮气置换三次，在温度为60～120℃下搅拌12～24小时，得到化合物(XV)；
第三步：
将化合物(XV)溶解在酸(如甲酸)中，在温度为室温～60℃下搅拌2～6小时，得到化合物(XVI)；
第四步：
将化合物(XVI)、化合物(VI)或化合物(X)、缩合剂(如2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯)、碱(如三乙胺)溶解在溶剂(如N,N-二甲基甲酰胺)中，在温度为室温～60℃下搅拌2～16小时，得到化合物(XIX)；
第五步：
将化合物(XIII)溶解在溶剂(如二氧六环)中，加入酸(如盐酸)，在温度为室温～60℃下搅拌2～3小时，得到化合物(XVII)；
第六步：
将化合物(XVII)、化合物(VI)或化合物(X)、缩合剂(如2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯)、碱(如三乙胺)溶解在溶剂(如N,N-二甲基甲酰胺)中，在温度为室温～60℃下搅拌2～16小时，得到化合物(XVIII)；
第七步：
化合物(XVIII)和(XIV)溶解在溶剂(如二氧六环)中，在惰性气体(如氮气或氩气)保护下，加入碱(如三乙胺)、催化剂(如双三苯基膦二氯化钯和碘化亚铜)，体系抽真空氮气置换三次，在温度为60～120℃下搅拌12～24小时，得到化合物(XIX)；
流程4
R1选自
R2、R3、R4与L的定义如前文所述，X为卤素；
第一步：
氮气保护下将化合物(XVIII)、联硼酸频那醇酯、碱(如乙酸钾)以及催化剂(如1,1'-双二苯基膦二茂铁二氯化钯)加入溶剂(如二氧六环)中，体系抽真空氮气置换三次，在温度为60～100℃下搅拌4～12小时，得到化合物(XX)；
第二步：
进行Suzuki偶联反应：在氮气保护下将化合物(XX)、化合物(XXI)、碱(如碳酸钠)以及催化剂(如1,1'-双二苯基膦二茂铁二氯化钯)加入溶剂(如二氧六环)中，体系抽真空氮气置换三次，在温度为80～120℃下搅拌4～12小时，得到化合物(XXII)。
具体实施方式
定义
除非有相反陈述，否则下列用在说明书和权利要求书中的术语具有下述含义。在本发明中未具体定义的基团具有本领域技术人员公知的本领域通常代表的含义。
在本发明中使用的表示方式“Cx-Cy”表示碳原子数的范围，其中x和y均为整数，例如C3-C8环烷基表示具有3-8个碳原子的环烷基，-C0-C2烷基表示具有0-2个碳原子的烷基，其中-C0烷基是指化学单键。
在本发明中,术语“烷基”指饱和的脂族烃基团，包括1至20个碳原子的直链和支链基团，例如可以是1至18个碳原子、1至12个碳原子、1至8个碳原子、1至6个碳原子或1至4个碳原子的直链和支链基团。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、及其各种支链异构体等。烷基可以是任选取代的或未取代的。
在本发明中,术语“烷氧基”指烷基-O-基团，其中烷基具有前文所定义的含义。
在本发明中,术语“羟烷基”指烷基-OH基团，即烷基(包含直链烷基和支链烷基)的任意位置被羟基取代的基团，其中烷基具有前文所定义的含义。
在本发明中,术语“杂环基”指饱和或部分不饱和单环或多环环状烃基，其包括3至20个环原子，例如可以是3至16个、3至12个、3至10个、3至8个或3至6个环原子，其中一个或多个环原子选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包括3至12个环原子，其中1～4个是杂原子，更优选杂环基环包含3至10个环原子、更优选包括3至8个环原子，最优选5元环或6元环，其中1～4个是杂原子，更优选1～3个是杂原子，最优选1～2个是杂原子。单环杂环基的非限制性实例包含氧杂环丁烷基、氧杂环己烷基、氮杂环丁烷基、吗啉基、2-吗啉基、二氢吡唑基等。多环杂环基包括螺环、稠环和桥环的杂环基。杂环基可以是任选取代的或未取代的。
在本发明中，术语“杂芳基”指包含1至4个杂原子，5至14个环原子的杂芳族体系，其中杂原子包括氧、硫和氮。优选为5-至10-元。更优选杂芳基是5-元或6-元的，例如吡唑基、咪唑基、三唑基、吡嗪基、噁唑基、异噁唑基、吡啶基等。杂芳基可以是任选取代的或 未取代的。
在本发明中，术语“卤素”指氟、氯、溴或碘。
在本发明中,“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
所述取代基包括但不限于前文所述的各种基团。
本发明要求保护的化合物不仅包括所述化合物本身，还包括所述化合物的光学异构体或其药学上可接受的盐。
本发明所述“药物组合物”表示含有一种或多种本发明所述化合物或其光学异构体或其药学上可接受的盐及其他化学组分的混合物。其他组分例如药学上可接受的药学可接受的载体、稀释剂和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
当在说明书中使用时，术语“包含”包括“由…组成”。
本发明所述“室温”是指15-30℃。
本发明所述“药学上可接受的盐”在Berge，et al.，“Pharmaceutically acceptable salts”，J.Pharm.Sci.,1977,66,1-19中有讨论，并对药物化学家来说是显而易见，所述的盐是基本上无毒性的，并能提供所需的药代动力学性质、适口性、吸收、分布、代谢或排泄等。
本发明药学上可接受的盐可通过一般的化学方法合成。
一般情况下，盐的制备可以通过游离碱或酸与等化学当量或者过量酸(无机酸或有机酸)或碱在合适的溶剂或溶剂组合物中反应制得。
本发明所述“光学异构体”包括本发明的式(I)化合物的内消旋体、外消旋体、对映异构体、非对映异构体、其混合物形式等。
本发明包括所述化合物或其盐的任何多晶型物以及任何水合物或其它溶剂合物。
在本发明中，术语“患者”通常指哺乳动物，尤其是人。
在本发明中，术语“治疗有效量”是指包括可有效治疗或预防由RIPK1介导的相关疾病的本发明化合物的量。
实施例
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
本发明所有化合物的结构可通过核磁共振(1H NMR)和/或质谱检测(MS)鉴定。
1H NMR化学位移(δ)以PPM(parts per million，百万分之几)记录。NMR通过Bruker AVANCE III-400MHz光谱仪进行。合适的溶剂选自氘代氯仿(CDCl3)、氘代甲醇(CD3OD)、氘代二甲亚砜(DMSO-d6)等，四甲基硅烷作为内标(TMS)。
低分辨率质谱(MS)由Agilent 1260HPLC/6120质谱仪测定，使用Agilent ZORBAX XDB-C18，4.6×50mm，3.5μm。
梯度洗脱条件一：0分钟:95％溶剂A1和5％溶剂B1,1-2分钟:5％溶剂A1和95％溶剂B1；2.01-2.50分钟:95％溶剂A1和5％溶剂B1。百分数为某一溶剂占总溶剂体积的体积百分数。溶剂A1：0.01％甲酸水溶液；溶剂B1：0.01％甲酸的乙腈溶液；百分数为溶质占溶液的体积百分数。
薄层硅胶板是烟台黄海HSGF254或青岛GF254硅胶板。柱层析一般使用烟台黄海100-200或200-300目硅胶作为载体。
制备液相色谱(prep-HPLC)使用Waters SQD2质谱导向高压液相色谱分离仪,XBridge-C18；30X 150mm制备柱，5μm；
方法一：乙腈-水(0.2％甲酸),流速25mL/分钟；方法二：乙腈-水(0.8％碳酸氢铵),流速25mL/分钟；
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、上海毕得医药、上海阿拉丁化学、上海迈瑞尔化学、百灵威化学、安耐吉化学等公司。
实施例中如无特殊说明，反应所用溶剂均为无水溶剂，其中无水四氢呋喃使用市售四氢呋喃，以钠块为除水剂，以二苯甲酮作为指示剂，氩气保护下回流至溶液呈蓝紫色，蒸馏收集，氩气保护下室温储存，其他无水溶剂购自安耐吉化学及百灵威化学，所有无水溶剂的转移和使用如无特殊说明，均需在氩气保护下进行。
实施例中如无特殊说明，反应均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
氢化反应通常抽真空，充入氢气，反复操作3次。
实施例中如无特殊说明，反应的温度为室温，温度范围是15℃-30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有A：二氯甲烷和甲醇体系；B：石油醚和乙酸乙酯体系。溶剂的体积比根据化合物的极性不同而进行调节。
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂的体系包括A：二氯甲烷和甲醇体系；B：石油醚和乙酸乙酯体系。溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和酸性或碱性试剂等进行调节。
本发明生物实验使用的试剂为：DMSO(D5879-500ML)购自Sigma公司，Fetal Bovine Serum(FSP500)购自ExCell Bio公司，DPBS(14190-144)、RPMI Medium 1640(72400-047)、Luminescent Cell Viability Assay(发光法细胞活力检测试剂盒，G7571，G7573)购自Promega公司。
中间体的制备
中间体1
2-氟-5-(2-氟苯氧基)苯甲酸
第一步
2-氟-5-(2-氟苯氧基)苯甲酸甲酯
将化合物5-溴-2-氟苯甲酸甲酯(4.60g，20.00mmol)、邻氟苯酚(4.50g，40.00mmol)、碳酸铯(13.00g，40.00mmol)、碘化亚铜(0.77g，4.00mmol)和N,N-二甲基甘氨酸(0.41g，4.00mmol)加入 1,4-二氧六环(60mL)，抽真空氮气置换3次，在氮气保护下加热至100℃搅拌过夜。冷却后用1N盐酸调pH至4左右，用乙酸乙酯(100mL×3)萃取。合并有机相依次用水和饱和食盐水各150mL洗涤。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得2-氟-5-(2-氟苯氧基)苯甲酸甲酯(3.20g，粗产物)，产率：60.5％。MS m/z(ESI):265[M+1]；
第二步
2-氟-5-(2-氟苯氧基)苯甲酸
将2-氟-5-(2-氟苯氧基)苯甲酸甲酯(3.20g，12.10mmol)溶于氢氧化钠水溶液(2N，200mmol,100mL)和四氢呋喃(100mL)中，加热至50℃反应5小时。减压浓缩除去四氢呋喃，水相用稀盐酸(1N)调pH至3左右，固体析出，过滤，收集固体后干燥得2-氟-5-(2-氟苯氧基)苯甲酸(2.40g，灰色固体)。产率：79.2％。
MS m/z(ESI):251[M+1]；
1H NMR(400MHz,CDCl3)δ7.59-7.52(m,1H),7.25-7.00(m,6H)。
中间体2
2-氟-5-(3-氟苯氧基)苯甲酸
中间体2的合成步骤参考中间体1，其中第一步用间氟苯酚代替邻氟苯酚。
MS m/z(ESI)：251[M+1]；
1H NMR(400MHz,CDCl3)δ7.67-7.65(m,1H),7.34-7.23(m,2H),7.20-7.16(m,1H),6.86-6.82(m,1H),6.78-6.75(m,1H),6.72-6.68(m,1H)。
中间体3
5-(3-氰基苯氧基)-2-氟苯甲酸
第一步
5-(3-氰基苯氧基)-2-氟苯甲酸甲酯
将2-氟-5-羟基苯甲酸甲酯(0.30g，1.76mmol)，间氟苯腈(0.64g，5.28mmol)，碳酸钾(0.48g，3.52mmol)和N,N-二甲基甲酰胺(5mL)混合，加热至130℃搅拌2小时。加水(20mL)至此混合物。用乙酸乙酯(15mL×3)萃取。合并有机相，用饱和食盐水(10mL×2)洗。将有机相用无水硫酸钠干燥，过滤除去干燥剂，减压脱溶。残余物用制备HPLC(Waters Xbridge-C18，4.6×250mm，10μm，CH3CN/H2O((0.1％TFA)40％-70％)纯化得到目标产物甲基5-(3-氰基苯氧基)-2-氟苯甲酸甲酯(45mg，白色固体)。产率：9％。MS m/z(ESI):272[M+1]；
第二步
5-(3-氰基苯氧基)-2-氟苯甲酸
将5-(3-氰基苯氧基)-2-氟苯甲酸甲酯(45mg，0.17mmol)，氢氧化锂(25mg，1.02mmol)，水(3mL)和四氢呋喃(3mL)混合，在室温下搅拌1小时。此混合物用1N盐酸调pH大约为2，用二氯甲烷(15mL×3)萃取。合并有机相，用饱和食盐水(15mL×2)洗涤。将有机相用无水硫酸钠干燥，过滤除去干燥剂，减压脱溶，得到目标产物5-(3-氰基苯氧基)-2-氟苯甲酸(35mg，白色固体)。产率：82％。MS m/z(ESI):258[M+1]。
中间体4
5-(2-氰基苯氧基)-2-氟苯甲酸
中间体4的合成步骤参考中间体3，其中第一步用邻氟苯腈代替间氟苯腈。
MS m/z(ESI):258[M+1]；
1H NMR(400MHz,DMSO-d6)δ13.52(bs,1H),7.92(dd,J＝7.6,1.6Hz,1H),7.73-7.66(m,1H),7.56-7.40(m,3H),7.36-7.28(m,1H),7.04(d,J＝8.4Hz,1H)。
中间体5
5-(3-氰基苯甲基)-2-氟苯甲酸
第一步
2-氟-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲酸甲酯
在化合物5-溴-2-氟苯甲酸甲酯(0.93g，4.00mmol)、联硼酸频那醇酯(2.00g，8.00mmol)、乙酸钾(1.20g，12.00mmol)和1,1'-双二苯基膦二茂铁二氯化钯(0.15g，0.20mmol)的混合物中加入二甲基亚砜(10mL)。抽真空用氮气置换3次，在氮气保护下加热至80℃搅拌过夜。冷却后加入乙酸乙酯(60mL)，用水(60mL×2)和饱和食盐水(60mL)洗涤。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱(0～10％乙酸乙酯/石油醚)分离纯化得到产物2-氟-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲酸甲酯(0.50g，无色油状物)。产率：44.2％。MS m/z(ESI):281[M+1]；
第二步
5-(3-氰基苯甲基)-2-氟苯甲酸甲酯
在2-氟-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲酸甲酯(0.50g，1.80mmol)、3-氰基苄溴(0.35g，1.80mmol)、碳酸钠(0.57g，5.40mmol)和1,1'-双二苯基膦二茂铁二氯化钯(0.13g，0.18mmol)的混合物中加入1,4-二氧六环和水混合液(v/v＝5/1，6mL)。抽真空氮气置换3次，加热至100℃搅拌过夜。冷却后加入乙酸乙酯(50mL)，用水(50mL×2)和饱和食盐水(50mL)洗涤。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱(0～10％乙酸乙酯/ 石油醚)分离纯化得到产物4-(3-氰基苯甲基)-2-氟苯甲酸甲酯(0.30g，无色油状物)。产率：62.9％。MS m/z(ESI):270[M+1]；
第三步
5-(3-氰基苯甲基)-2-氟苯甲酸
将5-(3-氰基苯甲基)-2-氟苯甲酸甲酯(0.30g，0.11mmol)加入氢氧化钠水溶液(1N，5mmol,5mL)和四氢呋喃(5mL)的混合物中，在室温下搅拌过夜。减压浓缩出去四氢呋喃，水相用稀盐酸(1N)调节pH至3左右，用乙酸乙酯萃取(10mL×2)。有机相合并后用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用制备液相色谱(Waters Xbridge-C18，4.6×250mm，10μm，CH3CN/H2O((0.1％TFA)30％-75％)纯化得5-(3-氰基苯甲基)-2-氟苯甲酸(15mg，白色固体)。产率：5.3％。
MS m/z(ESI):256[M+1]；
1H NMR(400MHz,CDCl3)δ7.86-7.80(m,1H),7.56-7.50(m,1H),7.48-7.39(m,3H),7.39-7.33(m,1H),7.18-7.09(m,1H),4.03(s,2H)。
中间体6
(S)-3-氨基-7-((3-羟基氧杂环丁烷-3-基)乙炔基)-5-甲基-2,3-二氢苯并[b][1,4]氧氮杂-4(5H)-酮甲酸盐
第一步
(S)-(7-((3-羟基氧杂环丁烷-3-基)乙炔基)-5-甲基-4-羰基-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)氨基甲酸叔丁酯
将化合物(S)-(7-溴-5-甲基-4-羰基-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)氨基甲酸叔丁酯(0.30g，0.81mmol)(合成参考文献：Journal of Medicinal Chemistry(2017),60(4),1247-1261)和3-乙炔基氧杂环丁烷-3-醇(0.24g，2.43mmol)、碘化亚铜(30mg，0.16mmol)、双三苯基膦二氯化钯(60mg，0.08mmol)、N,N-二异丙基乙胺(3mL) 和1，4-二氧六环(6mL)混合。在氮气保护下，加热至100℃搅拌16小时。将反应液过滤旋干，加入10mL水。用乙酸乙酯(10mL×2)萃取。合并有机相用饱和食盐水(10mL)洗涤。将有机相用无水硫酸钠干燥，过滤除去干燥剂，粗品用柱层析纯化(石油醚/乙酸乙酯＝3：1)得到目标产物(S)-(7-((3-羟基氧杂环丁烷-3-基)乙炔基)-5-甲基-4-羰基-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)氨基甲酸叔丁酯(0.29g，黄色固体)。产率：92％。
MS m/z(ESI):333[M-55]；
1H NMR(400MHz,DMSO-d6)δ7.60(d,J＝1.6Hz,1H),7.36(dd,J＝8.0,1.6Hz,1H),7.20(d,J＝8.0Hz,1H),6.65(s,1H),4.77(d,J＝6.4Hz,2H),4.61(d,J＝6.4Hz,2H),4.42-4.26(m,4H),3.29(s,3H),1.35(s,9H)；
第二步
(S)-3-氨基-7-((3-羟基氧杂环丁烷-3-基)乙炔基)-5-甲基-2,3-二氢苯并[b][1,4]氧氮杂-4(5H)-酮甲酸盐
将化合物(S)-(7-((3-羟基氧杂环丁烷-3-基)乙炔基)-5-甲基-4-羰基-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)氨基甲酸叔丁酯(0.29g，0.74mmol)和甲酸(5mL)混合。在常温下搅拌3小时。向此混合物加水(20mL)稀释，水相用乙酸乙酯(10mL×2)洗涤。水相冷冻干燥得到目标产物(S)-3-氨基-7-((3-羟基氧杂环丁烷-3-基)乙炔基)-5-甲基-2,3-二氢苯并[b][1,4]氧氮杂-4(5H)-酮甲酸盐(233mg，粗品)。MS m/z(ESI):289[M+1]。
中间体7
(S)-3-氨基-7-溴-5-(三氘代甲基)-2,3-二氢苯并[b][1,4]氧氮杂-4(5H)-酮盐酸盐
第一步
(S)-(7-溴-5-(三氘代甲基)-4-羰基-2,3,4,5-四氢苯并[b][1,4]氧氮杂 -3-基)氨基甲酸叔丁酯
将化合物(S)-(7-溴-4-羰基-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)氨基甲酸叔丁酯(0.10g，0.28mmol)(合成参考文献：Journal of Medicinal Chemistry(2017),60(4),1247-1261)和氘代碘甲烷(49mg，0.33mmol)、碳酸铯(0.13g，0.39mmol)和N,N-二甲基甲酰胺(2mL)混合。在室温下搅拌3小时。将此混合物倒入10mL水中，有固体析出，过滤，固体干燥得到目标产物基(S)-(7-溴-5-(三氘代甲基)-4-羰基-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)氨基甲酸叔丁酯(0.10g，棕色固体)。产率：95％。
MS m/z(ESI):374&376[M+1]；
1H NMR(400MHz,CDCl3)δ7.30-7.27(m,2H),7.00(d,J＝8.4Hz,1H),5.44(d,J＝7.2Hz,1H),4.67-4.57(m,1H),4.54-4.50(m,1H),4.16-4.11(m,1H),1.38(s,9H)；
第二步
(S)-3-氨基-7-溴-5-(三氘代甲基)-2,3-二氢苯并[b][1,4]氧氮杂-4(5H)-酮盐酸盐
将化合物(S)-(7-溴-5-(三氘代甲基)-4-羰基-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)氨基甲酸叔丁酯(50mg，0.13mmol)和氯化氢(1，4)-二氧六环溶液(4N，8mmol,2mL)混合。常温下搅拌2小时。将此混合物减压旋干得到目标产物(S)-3-氨基-7-溴-5-(三氘代甲基)-2,3-二氢苯并[b][1,4]氧氮杂-4(5H)-酮盐酸盐(36.5mg，粗品)。MS m/z(ESI):274&276[M+1]；
中间体8
(S)-N-(7-溴-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-2-氟-5-(2-氟苯氧基)苯甲酰胺
第一步
(S)-3-氨基-7-溴-5-甲基-2,3-二氢苯并[b][1,4]氧氮杂-4(5H)-酮盐酸盐
将化合物(S)-(7-溴-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)氨基甲酸叔丁酯(合成参考文献：Journal of Medicinal Chemistry(2017),60(4),1247-1261)(1.00g，2.70mmol)加入氯化氢1,4-二氧六环溶液(4M，40mmol,10mL)，在室温下搅拌2小时，减压脱溶，得到(S)-3-氨基-7-溴-5-甲基-2,3-二氢苯并[b][1,4]氧氮杂-4(5H)-酮盐酸盐(0.83g，黄色固体)。粗品。MS m/z(ESI):271&273[M+1]；
第二步
(S)-N-(7-溴-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-2-氟-5-(2-氟苯氧基)苯甲酰胺
将化合物2-氟-5-(2-氟苯氧基)苯甲酸(中间体1)(0.48g，1.90mmol)，(S)-3-氨基-7-溴-5-甲基-2,3-二氢苯并[b][1,4]氧氮杂-4(5H)-酮盐酸盐(0.50g，1.6mmol)，三乙胺(0.50g，4.80mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(0.90g，2.40mmol)溶于N,N-二甲基甲酰胺(5mL)。在室温下反应过夜。反应液用乙酸乙酯稀释(50mL)。然后分别用水(50mL×2)和饱和食盐水(50mL)洗涤。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱分离纯化(0～20％乙酸乙酯/石油醚)，得到(S)-N-(7-溴-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-2-氟-5-(2-氟苯氧基)苯甲酰胺(0.53g，白色固体)。产率：64.6％。
MS m/z(ESI):503&505[M+1]；
1H NMR(400MHz,CDCl3)7.87-7.77(m,1H),7.56-7.50(m,1H),7.39-7.32(m,2H),7.20-7.01(m,7H),5.12-5.00(m,1H),4.81-4.72(m,1H),4.30-4.20(m,1H),3.43(s,3H)。
中间体9-13的合成步骤参考中间体8。
中间体9
(S)-N-(7-溴-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-2-氟-5-苯氧基苯甲酰胺
MS m/z(ESI):485&487[M+1]；
1H NMR(400MHz,CDCl3)δ7.81(dd,J＝11.8,6.4Hz,1H),7.65-7.51(m,1H),7.39-7.29(m,4H),7.16-7.04(m,4H),6.96(d,J＝8.0Hz,2H),5.12-5.02(m,1H),4.82-4.74(m,1H),4.31-4.20(m,1H),3.43(s,3H)。
中间体10
(S)-N-(8-溴-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-2-氟-5-苯氧基苯甲酰胺
MS m/z(ESI):485&487[M+1]；
1H NMR(400MHz,CDCl3)δ7.87-7.77(m,1H),7.62-7.57(m,1H),7.40-7.29(m,4H),7.14-7.06(m,4H),6.99-6.93(m,2H),5.14-5.03(m,1H),4.83-4.76(m,1H),4.31-4.23(m,1H),3.42(s,3H)。
中间体11
(S)-N-(7-溴-5-氘代甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-2-氟-5-苯氧基苯甲酰胺
MS m/z(ESI):488&490[M+1]；
1H NMR(400MHz,CDCl3)δ7.76-7.72(m,1H),7.58-7.44(m,1H),7.27(d,J＝3.6Hz,2H),7.25(s,1H),7.05-6.98(m,4H),6.91-6.89(m,3H),5.07-4.92(m,1H),4.72-4.68(m,1H),4.24-4.14(m,1H)。
中间体12
(S)-N-(7-溴-5-氘代甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-3-苯氧基苯甲酰胺
MS m/z(ESI):506&508[M+1]；
1H NMR(400MHz,CDCl3)δ7.77-7.72(m,1H),7.46(d,J＝4.8Hz,1H),7.28(s,1H),7.12-6.93(m,8H),4.99-4.95(m,1H),4.78-4.62(m,1H),4.20-4.15(m,1H)。
中间体13
(S)-N-(7-溴-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-3-苯氧基苯甲酰胺
MS m/z(ESI):467&469[M+1]；
1H NMR(400MHz,CDCl3)δ7.49-7.48(d,J＝7.6Hz,1H),7.44(s,1H),7.41-7.33(m,5H),7.18-7.13(m,3H),7.09-7.07(d,J＝9.2Hz,1H),7.02-7.00(m,2H),5.07-5.01(m,1H),4.79-4.75(m,1H),4.26-4.21(m,1H),3.42(s,3H)。
实施例化合物的制备
实施例1
(S)-2-氟-5-(2-氟苯氧基)-N-(7-((3-羟基氧杂环丁烷-3-基)乙炔基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺
将化合物(S)-3-氨基-7-((3-羟基氧杂环丁烷-3-基)乙炔基)-5-甲基-2,3-二氢苯并[b][1,4]氧氮杂-4(5H)-酮甲酸盐(0.23g，粗品)(中间体6)和2-氟-5-(2-氟苯氧基)苯甲酸(中间体1)(0.20g，0.80mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.31g，1.60mmol)、1-羟基苯并三唑(0.22g，1.60mmol)、N,N-二异丙基乙胺(0.33g，3.20mmol)和N,N-二甲基乙酰胺(9mL)混合。在常温下搅拌5小时。将此混合物旋干后，用10mL水淬灭，用乙酸乙酯(10mL×2)萃取。合并有机相并用饱和食盐水(10mL)洗涤。将有机相用无水硫酸钠干燥，过滤除去干燥剂，滤液浓缩得粗品。该粗品用硅胶制备板(石油醚/乙酸乙酯＝1：1)纯化得到目标产物(S)-2-氟-5-(2-氟苯氧基)-N-(7-((3-羟基氧杂环丁烷-3-基)乙炔基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺(0.11g，白色固体)。产率：29％。
MS m/z(ESI):521[M+1]；
1H NMR(400MHz,CDCl3)δ7.87-7.83(m,1H),7.54-7.52(m,1H),7.34-7.30(m,2H),7.20-7.02(m,7H),5.11-5.01(m,1H),4.95-4.93(m,2H),4.83-4.76(m,3H),4.30-4.25(m,1H),3.44(s,3H)。
实施例2到6的合成步骤参考实施例1。
实施例2
(S)-2-氟-5-(3-氟苯氧基)-N-(7-((3-羟基氧杂环丁烷-3-基)乙炔基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺
MS m/z(ESI):521[M+1]；
1H NMR(400MHz,CDCl3)δ7.89-7.84(m,1H),7.64-7.62(m,1H),7.35-7.23(m,3H),7.19-7.12(m,3H),6.83-6.78(m,1H),6.75-6.72(m,1H),6.68-6.64(m,1H),5.10-5.04(m,1H),4.94-4.93(m,2H),4.83-4.79(m,3H),4.32-4.27(m,1H),3.44(s,3H)。
实施例3
(S)-5-(3-氰基苯氧基)-2-氟-N-(7-((3-羟基氧杂环丁烷-3-基)乙炔基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺
MS m/z(ESI):528[M+1]；
1H NMR(400MHz,CDCl3)δ7.90(dd,J＝12.0,6.0Hz,1H),7.63(dd,J＝6.0,2.8Hz,1H),7.46-7.36(m,2H),7.35-7.29(m,2H),7.25-7.13(m,5H),5.12-5.01(m,1H),4.97-4.88(m,2H),4.84-4.74(m,3H),4.37-4.22(m,1H),3.44(s,3H)。
实施例4
(S)-5-(2-氰基苯氧基)-2-氟-N-(7-((3-羟基氧杂环丁烷-3-基)乙炔基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺
MS m/z(ESI):528[M+1]；
1H NMR(400MHz,CDCl3)δ7.89(dd,J＝12.1,6.2Hz,1H),7.67(d,J＝7.6Hz,2H),7.50-7.48(m,1H),7.36-7.29(m,2H),7.26-7.21(m,2H),7.20-7.13(m,2H),6.85(d,J＝8.5Hz,1H),5.11-5.01(m,1H),4.97-4.90(m,2H),4.85-4.74(m,3H),4.39-4.22(m,1H),3.45(s,3H)。
实施例5
(S)-5-(3-氰基苯甲基)-2-氟-N-(7-((3-羟基氧杂环丁烷-3-基)乙炔基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺
MS m/z(ESI):526[M+1]；
1H NMR(400MHz,CDCl3)δ7.88-7.77(m,2H),7.53-7.48(m,1H),7.43-7.37(m,3H),7.35-7.31(m,2H),7.27-7.23(m,2H),7.19-7.08(m,1H),5.12-5.04(m,1H),4.95-4.93(m,2H),4.85-4.79(m,3H),4.34-4.23(m,1H),4.00(s,2H),3.44(s,3H)。
实施例6
(S)-N-(7-((3-羟基氧杂环丁烷-3-基)乙炔基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-3-苯氧基苯甲酰胺
MS m/z(ESI):485[M+1]；
1H NMR(400MHz,CDCl3)δ7.41-7.38(m,2H),7.28-7.19(m,6H),7.10-7.07(m,3H),6.98-6.92(m,2H),4.98-4.96(m,1H),4.90-4.80(m,2H),4.78-4.66(m,2H),4.63-4.55(m,1H),4.27-4.11(m,1H),3.34(s,3H)。
实施例7
(S)-2-氟-5-(2-氟苯氧基)-N-(5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺
将化合物(S)-N-(7-溴-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-2-氟-5-(2-氟苯氧基)苯甲酰胺(中间体8)(45mg，0.08mmol)和联硼酸频那醇酯(34mg，0.13mmol)、醋酸钾(18mg，0.16mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(14mg，0.016mmol)和1,4-二氧六环(3mL)混合。在氮气保护下，加热至90℃搅拌16小时。将反应液过滤旋干，用10mL水淬灭，用乙酸乙酯(10mL×2)萃取。合并有机相用饱和食盐水(10mL)洗涤。将有机相用无水硫酸钠干燥，过滤除去干燥剂，滤液旋干得粗品，粗品用制备HPLC(Waters Xbridge-C18，4.6×250mm，10μm，CH3CN/H2O((0.1％TFA)40％-60％)纯化得到脱溴的目标产物(S)-2-氟-5-(2-氟苯氧基)-N-(5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺(10mg，白色固体)。产率：26％。
MS m/z(ESI):425[M+1]；
1H NMR(400MHz,CDCl3)δ7.88-7.83(m,1H),7.56-7.49(m,1H),7.25-7.16(m,4H),7.16-7.07(m,4H),7.06-7.02(m,1H),5.13-5.00(m,1H),4.82-4.78(m,1H),4.31-4.19(m,1H),3.44(s,3H)。
实施例8
(S)-2-氟-N-(7-(3-羟基-3-甲基-1-丁炔-1-基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-5-苯氧基苯甲酰胺
将(S)-N-(7-溴-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-2-氟-5-苯氧基苯甲酰胺(中间体9)(10mg，0.02mmol)，2-甲基丁-3-炔-2-醇(42mg，0.10mmol)和无水三乙胺(3mL)混合。在氮气保护下加入碘化亚铜(4mg，0.02mmol)和双三苯基磷二氯化钯(2mg，0.003mmol)，用氮气置换三次。加热至90℃下搅拌16小时。减压脱溶，残余物加入氨水(8mL)，用乙酸乙酯(5mL×3)萃取。合并有机相用饱和食盐水(5mL×2)洗涤。将有机相用无水硫酸钠干燥，过滤除去干燥剂，减压脱溶。残余物用制备硅胶板纯化(石油醚/乙酸乙酯＝1：1)得到目标产物(S)-2-氟-N-(7-(3-羟基-3-甲基-1-丁炔-1-基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-5-苯氧基苯甲酰胺(6.2mg，白色固体)。产率：64％。
MS m/z(ESI):489[M+1]；
1H NMR(400MHz,CDCl3)δ7.84(dd,J＝12.0,6.0Hz,1H),7.66-7.55(m,1H),7.42-7.20(m,4H),7.18-7.06(m,4H),6.97(d,J＝8.0Hz,2H),5.14-4.99(m,1H),4.86-4.71(m,1H),4.35-4.13(m,1H),3.43(s,3H),1.63(s,6H)。
实施例9到26的合成步骤参考实施例8。
实施例9
(S)-2-氟-N-(8-((4-羟基四氢-2H-吡喃-4-基)乙炔基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-5-苯氧基苯甲酰胺
MS m/z(ESI):531[M+1]；
1H NMR(400MHz,CD3OD)δ7.42-7.33(m,5H),7.30-7.10(m,4H),7.01-6.95(m,2H),5.05-4.96(m,1H),4.67-4.59(m,1H),4.44-4.34(m,1H),3.97-3.88(m,2H),3.78-3.65(m,2H),3.40(s,3H),2.05-1.95(m,2H),1.89-1.77(m,2H)。
实施例10
(S)-2-氟-N-(5-甲基-8-(3-吗啉-1-丙炔-1-基)-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-5-苯氧基苯甲酰胺
MS m/z(ESI):530[M+1]；
1H NMR(400MHz,CD3OD)δ7.40-7.33(m,5H),7.30-7.10(m,4H),7.01-6.96(m,2H),5.06-4.94(m,1H),4.66-4.59(m,1H),4.42-4.33(m,1H),3.78-3.71(m,4H),3.55(s,2H),3.40(s,3H),2.71-2.62(m,4H)。
实施例11
(S)-N-(7-((1-乙酰基-3-甲氧基氮杂环丁烷-3-基)乙炔基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-2-氟-5-苯氧基苯甲酰胺
MS m/z(ESI):558[M+1]；
1H NMR(400MHz,CDCl3)δ7.87-7.81(m,1H),7.61-7.57(m,1H),7.36-7.31(m,4H),7.20-7.10(m,4H),7.00-6.95(m,2H),5.13-5.03(m,1H),4.86-4.75(m,1H),4.40-4.36(m,1H),4.33-4.22(m,3H),4.18-4.12(m,1H),3.45(s,3H),3.43(s,3H),1.93(s,3H)。
实施例12
(S)-2-氟-5-(2-氟苯氧基)-N-(5-甲基-4-酮-7-((四氢-2H-吡喃-4-基)乙炔基)-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺
MS m/z(ESI):533[M+1]；
1H NMR(400MHz,CDCl3)δ7.79-7.89(m,1H),7.57-7.49(m,1H),7.29-7.21(m,3H),7.20-7.00(m,6H),5.11-4.99(m,1H),4.78-4.76(m,1H),4.29-4.21(m,1H),3.95-3.93(m,2H),3.60-3.50(m,2H),3.41(s,3H),2.89-2.77(m,1H),1.99-1.87(m,2H),1.82-1.71(m,2H)。
实施例13
(S)-2-氟-N-(7-((3-羟基氧杂环丁烷-3-基)乙炔基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-5-苯氧基苯甲酰胺
MS m/z(ESI):503[M+1]；
1H NMR(400MHz,CDCl3)δ7.85(dd,J＝12.0,6.4Hz,1H),7.65-7.53(m,1H),7.37-7.24(m,4H),7.21-7.06(m,4H),6.96(d,J＝7.8Hz,2H),5.12-4.98(m,1H),4.99-4.85(m,2H),4.84-4.72(m,3H),4.36-4.22(m,1H),3.43(s,3H),3.34(s,1H)。
实施例14
(S)-2-氟-N-(7-((4-羟基四氢-2H-吡喃-4-基)乙炔基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-5-苯氧基苯甲酰胺
MS m/z(ESI):531[M+1]；
1H NMR(400MHz,CD3OD)δ7.39(d,J＝1.6Hz,1H),7.28-7.21(m,4H),7.15-6.99(m,4H),6.87(d,J＝7.6Hz,2H),4.91-4.87(m,1H),4.55-4.44(m,1H),4.33-4.21(m,1H),3.85-3.69(m,2H),3.65-3.47(m,2H),3.29(s,3H),1.81-1.78(m,2H),1.73-1.71(m,2H)。
实施例15
(S)-2-氟-5-(2-氟苯氧基)-N-(7-(3-羟基-3-甲基-1-丁炔-1-基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺
MS m/z(ESI)：507[M+1]
1H NMR(400MHz,CDCl3)δ7.88-7.83(m,1H),7.54-7.53(m,1H),7.28-7.27(m,1H),7.16-7.04(m,7H),5.07-5.02(m,1H),4.81-4.77(m,1H),4.29-4.23(m,1H),3.43(s,3H),1.33(s,6H)。
实施例16
(S)-2-氟-N-(7-((3-羟基氧杂环丁烷-3-基)乙炔基)-5-(三氘代甲基)-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-5-苯氧基苯甲酰胺
MS m/z(ESI):506[M+1]；
1H NMR(400MHz,CDCl3)δ7.86-7.82(m,1H),7.60-7.58(m,1H),7.35-7.31(m,4H),7.18-7.08(m,4H),6.96(d,J＝7.6Hz,2H),5.12-5.02(m,1H),4.95-4.93(m,2H),4.82-4.79(m,3H),4.31-4.26(m,1H)。
实施例17
(S)-2-氟-5-苯氧基-N-(5-甲基-4-酮-7-((四氢-2H-吡喃-4-基)乙炔基)-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺
MS m/z(ESI):515[M+1]；
1H NMR(400MHz,CDCl3)δ7.85(dd,J＝12.0,6.4Hz,1H),7.61-7.57(m,1H),7.35-7.26(m,4H),7.14-7.09(m,4H),6.99-6.94(m,2H),5.09-5.02(m,1H),4.79(dd,J＝9.6,7.2Hz,1H),4.26(dd,J＝10.8,10.0Hz,1H),3.98-3.91(m,2H),3.59-3.51(m,2H),3.43(s,3H),2.89-2.81(m,1H),1.94-1.88(m,2H),1.82-1.72(m,2H)。
实施例18
(S)-2-氟-5-(2-氟苯氧基)-N-(7-((3-羟基氧杂环丁烷-3-基)乙炔基)-5-(三氘代甲基)-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺
MS m/z(ESI):524[M+1]；
1H NMR(400MHz,CDCl3)δ7.87-7.83(m,1H),7.56-7.51(m,1H),7.34-7.29(m,2H),7.21-6.99(m,7H),5.11-5.01(m,1H),4.95-4.93(m,2H),4.83-4.76(m,3H),4.33-4.23(m,1H)。
实施例19
(S)-2-氟-N-(5-甲基-7-(3-吗啉-1-丙炔-1-基)-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-5-苯氧基苯甲酰胺甲酸盐
MS m/z(ESI):530[M+1]；
1H NMR(400MHz,CDCl3)δ8.10(s,1H),7.86-7.84(m,1H),7.65-7.51(m,1H),7.40-7.28(m,4H),7.19-7.06(m,4H),6.97(d,J＝8.7Hz,2H),5.15-4.97(m,1H),4.85-4.78(m,1H),4.35-4.20(m,1H),3.90-3.77(m,4H),3.62(s,2H),3.44(s,3H),2.96-2.61(m,4H)。
实施例20
(S)-2-氟-N-(5-甲基-7-((1-甲基-1H-吡唑-4-基)乙炔基)-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-5-苯氧基苯甲酰胺
MS m/z(ESI):511[M+1]；
1H NMR(400MHz,CDCl3)δ7.88-7.83(m,1H),7.65(s,1H),7.62-7.58(m,1H),7.57(s,1H),7.35-7.31(m,4H),7.17-7.08(m,4H),6.97(d,J＝8.0Hz,2H),5.14-5.04(m,1H),4.83-4.79(m,1H),4.32-4.23(m,1H),3.92(s,3H),3.45(s,3H)。
实施例21
(S)-2-氟-N-(5-甲基-4-酮-7-(吡啶-3-基乙炔基)-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-5-苯氧基苯甲酰胺
MS m/z(ESI):508[M+1]；
1H NMR(400MHz,CDCl3)δ8.78(d,J＝4.0Hz,1H),8.58-7.56(m,1H),7.90-7.80(m,2H),7.63-7.57(m,1H),7.43-7.40(m,2H),7.36-7.28(m,3H),7.22-7.17(m,1H),7.16-7.09(m,3H),7.01-6.94(m,2H),5.13-5.07(m,1H),4.85-4.81(m,1H),4.33-4.27(m,1H),3.48(s,3H)。
实施例22
(S)-2-氟-5-(2-氟苯氧基)-N-(5-甲基-4-酮-7-(吡啶-2-基乙炔基)-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺
MS m/z(ESI)：526[M+1]；
1H NMR(400MHz,CDCl3)δ8.64(d,J＝4.0Hz 1H),7.93-7.81(m,1H),7.73-7.69(m,1H),7.59-7.52(m,2H),7.50-7.42(m,2H),7.29-7.23(m,1H),7.20-7.03(m,7H),5.14-5.02(m,1H),4.87-4.77(m,1H),4.32-4.27(m,1H),3.46(s,3H)。
实施例23
(S)-2-氟-N-(5-甲基-4-酮-7-(吡啶-2-基乙炔基)-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-5-苯氧基苯甲酰胺
MS m/z(ESI):508[M+1]；
1H NMR(400MHz,CDCl3)δ8.65-8.63(m,1H),7.89-7.84(m,1H),7.73-7.69(m,1H),7.62-7.57(m,1H),7.55-7.53(m,1H),7.50-7.44(m,2H),7.36-7.30(m,2H),7.29-7.25(m,1H),7.19(d,J＝8.0Hz,1H),7.13-7.09(m,3H),6.99-6.94(m,2H),5.14-5.05(m,1H),4.85-4.81(m,1H),4.32-4.27(m,1H),3.46(s,3H)。
实施例24
(S)-2-氟-N-(5-甲基-7-((1-甲基-1H-咪唑-4-基)乙炔基)-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-5-苯氧基苯甲酰胺
MS m/z(ESI):511[M+1]；
1H NMR(400MHz,CDCl3)δ7.86(dd,J＝12.0,6.2Hz,1H),7.64-7.57(m,1H),7.46(s,1H),7.41-7.29(m,4H),7.22-7.05(m,5H),6.96(d,J＝7.8Hz,2H),5.13-5.00(m,1H),4.86-4.75(m,1H),4.33-4.19(m,1H),3.71(s,3H),3.44(s,3H)。
实施例25
(S)-2-氟-5-(2-氟苯氧基)-N-(5-甲基-7-((1-甲基-1H-1,2,4-三唑-3-基)乙炔基)-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺
MS m/z(ESI)：530[M+1]；
1H NMR(400MHz,CDCl3)δ8.06(s,1H),7.88-7.83(m,1H),7.56-7.51(m,1H),7.51-7.42(m,2H),7.19-7.03(m,6H),5.10-5.03(m,1H),4.86-4.78(m,1H),4.31-4.26(m,1H),3.97(s,3H),3.44(s,3H)。
实施例26
(S)-2-氟-5-(2-氟苯氧基)-N-(5-甲基-7-((1-甲基-1H-吡唑-4-基)乙炔基)-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺
MS m/z(ESI)：529[M+1]；
1H NMR(400MHz,CDCl3)δ7.91-7.81(m,1H),7.58(s,1H),7.50(s,1H),7.45-7.43(m,1H),7.28-7.22(m,2H),7.14-6.92(m,7H),5.05-4.95(m,1H),4.73-4.68(m,1H),4.28-4.12(m,1H),3.84(s,3H),3.37(s,3H)。
实施例27
(S)-2-氟-N-(7-(4-羟基-3,3-二甲基-1-丁炔-1-基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-5-苯氧基苯甲酰胺
第一步
((2,2-二甲基-4-(三甲基甲硅烷基)-3-丁炔-1-基)氧代)叔丁基二苯基硅烷
将2,2-二甲基-4-(三甲基甲硅烷基)-3-丁炔-1-醇(0.52g，3.00mmol)(合成参考文献J.Am.Chem.Soc.(2020),142(47),20048–20057)溶解于15mL二氯甲烷中，加入咪唑(0.41g，6.00mmol)，然后分批缓慢加入叔丁基二苯基氯硅烷(1.07g，3.90mmol)。加完后在室温搅拌反应48小时。反应结束后加入50mL二氯甲烷稀释。分离出有机相用饱和食盐水(25mL)洗涤，无水硫酸钠干燥，过滤，浓缩。柱层析(石油醚)纯化得到目标化合物((2,2-二甲基-4-(三甲基甲硅烷基)-3-丁炔-1-基)氧代)叔丁基二苯基硅烷(1.01g，无色液体)，收率82.5％。
1H NMR(400MHz,CDCl3)δ7.71-7.69(m,4H),7.43-7.36(m,6H),3.49(s,2H),1.23(s,6H),1.07(s,9H),0.14(s,9H)；
第二步
((2,2-二甲基-3-丁炔-1-基)氧代)叔丁基二苯基硅烷
将((2,2-二甲基-4-(三甲基甲硅烷基)-3-丁炔-1-基)氧代)叔丁基二苯基硅烷(1.01g，2.45mmol)溶解于甲醇和二氯甲烷混合溶剂中(15mL/15mL)，加入碳酸钾(0.51g，3.67mmol)。在室温下搅拌反应4.8小时。反应液加入二氯甲烷(25mL)稀释。分离所得有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到((2,2-二甲基-3-丁炔-1-基)氧代)叔丁基二苯基硅烷(0.6g，浅黄色油状物)，粗品。
1H NMR(400MHz,CDCl3)δ7.71-7.69(m,4H),7.44-7.36(m,6H),3.51(s,2H),2.08(s,1H),1.26(s,6H),1.07(s,9H)；
第三步
(S)-(7-(4-((叔丁基二苯基甲硅烷基)氧代)-3,3-二甲基-1-丁炔-1-基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)氨基甲酸叔丁酯
将((2,2-二甲基-3-丁炔-1-基)氧代)叔丁基二苯基硅烷(0.15g，0.41mmol)和(S)-(7-溴-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)氨基甲酸叔丁酯(中间体9)(0.41g，1.23mmol)溶解于N,N-二甲基乙酰胺(5mL)和三乙胺(5mL)的混合溶剂中，加入双三苯基膦二氯化钯(57mg，0.08mmol)和碘化亚铜(16mg，0.08mmol)。用氮气置换三次，加热至85℃在氮气保护下反应5小时。反应结束后冷却至室温，将反应液倒入水中(50mL)，用乙酸乙酯(25mL×3)萃取。有机相用饱和食盐水洗涤(25mL×2)，无水硫酸钠干燥，过滤，滤液浓缩，残余物用柱层析纯化(石油醚：乙酸乙酯＝12：1)得到(S)-(7-(4-((叔丁基二苯基甲硅烷基)氧代)-3,3-二甲基-1-丁炔-1-基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)氨基甲酸叔丁酯(0.25g，浅黄色油状物)，收率97％。
MS m/z(ESI)：627[M+1]；
1H NMR(400MHz,CDCl3)δ7.81-7.76(m,4H),7.47-7.41(m,7H),7.27(s,1H),7.10-7.08(m,1H),5.61(s,1H),4.72-4.69(m,1H),4.63-4.59(m,1H),4.24-4.16(m,1H),3.66(s,2H),3.40(s,3H),1.45(s,9H),1.40(s,3H),1.39(s,3H),1.16(s,9H)；
第四步
(S)-3-氨基-7-(4-((叔丁基二苯基甲硅烷基)氧代)-3,3-二甲基-1-丁炔-1-基)-5-甲基-2,3-二氢苯并[b][1,4]氧氮杂-4-(5H)-酮三氟乙酸盐
将(S)-(7-(4-((叔丁基二苯基甲硅烷基)氧代)-3,3-二甲基-1-丁炔-1-基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)氨基甲酸叔丁酯(50mg，0.08mmol)溶解于二氯甲烷(10mL)中，加入三氟乙酸(2mL)。在室温下反应1小时。浓缩后残留物中加入二氯甲烷(10mL)，再次浓缩得到目标化合物(S)-3-氨基-7-(4-((叔丁基二苯基甲硅烷基)氧代)-3,3-二甲基-1-丁炔-1-基)-5-甲基-2,3-二氢苯并[b][1,4]氧氮杂-4-(5H)-酮三氟乙酸盐(50mg，浅黄色油状物)，粗品。MS m/z(ESI)：527[M+1]；
第五步
(S)-2-氟-N-(7-(4-((叔丁基二苯基甲硅烷基)氧代)-3,3-二甲基-1-丁炔-1-基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-5-苯氧基苯甲酰胺
将2-氟-5-苯氧基苯甲酸(23mg，0.096mmol)溶解于N,N-二甲基甲酰胺(3mL)中，加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(31mg，0.16mmol)，4-二甲基氨基吡啶(22mg，0.16mmol)和N,N二异丙基乙胺(31mg，0.24mmol)。在室温下搅拌5分钟后加入(S)-3-氨基-7-(4-((叔丁基二苯基甲硅烷基)氧代)-3,3-二甲基丁-1-炔-1-基)-5-甲基-2,3-二氢苯并[b][1,4]氧氮杂-4(5H)-酮三氟乙酸盐(50mg粗品，0.08mmol)的N,N-二甲基甲酰胺(2mL)溶液，在室温下反应5小时。反应结束后倒入水(30mL)中，用乙酸乙酯萃取(25mL×3)。合并有机相用饱和食盐水(25mL×2)洗涤，用无水硫酸钠干燥，过滤，滤液浓缩。残余物用薄层色谱纯化(石油醚：乙酸乙酯＝10：1)得到(S)-2-氟-N-(7-(4-((叔丁基二苯基甲硅烷基)氧代)-3,3-二甲基-1-丁炔-1-基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-5-苯氧基苯甲酰胺(35mg，浅黄色油状物)，收率59％。
MS m/z(ESI)：741[M+1]；
1H NMR(400MHz,CDCl3)δ7.86-7.83(m,1H),7.72(d,J＝6.4Hz,4H),7.61-7.59(m,1H),7.44-7.30(m,8H),7.26-7.24(m,2H),7.12-7.08(m,4H),6.76-6.56(d,J＝8.0Hz,2H),5.05-5.02(m,1H),4.82-4.80(m,1H),4.28-4.25(m,1H),3.60(s,2H),3.39(s,3H),1.35(s,3H),1.34(s,3H),1.16(s,9H)；
第六步
(S)-2-氟-N-(7-(4-羟基-3,3-二甲基-1-丁炔-1-基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-5-苯氧基苯甲酰胺
将(S)-2-氟-N-(7-(4-羟基-3,3-二甲基-1-丁炔-1-基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-5-苯氧基苯甲酰胺(35mg，0.047mmol)溶解在四氢呋喃(5mL)中，加入四丁基氟化铵(0.5mL，1M四氢呋喃溶液)，加热至50℃反应5小时。反应结束后冷却至室温，浓缩，残留物中加入乙酸乙酯(30mL)溶解，用饱和食盐水(25mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩。残余物用薄层色谱纯 化(石油醚：乙酸乙酯＝1：1)得到目标化合物(S)-2-氟-N-(7-(4-羟基-3,3-二甲基-1-丁炔-1-基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-5-苯氧基苯甲酰胺(21mg，浅黄色固体)，收率89％。
MS m/z(ESI)：503[M+1]；
1H NMR(400MHz,CDCl3)δ7.88-7.83(m,1H),7.60-7.58(m,1H),7.34-7.30(m,2H),7.28-7.26(m,2H),7.13-7.09(m,4H),6.97-6.96(m,2H),5.08-5.02(m,1H),4.81-4.77(m,1H),4.28-4.23(m,1H),3.51(s,2H),3.43(s,3H),1.32(s,3H),1.31(s,3H)。
实施例28
(S)-2-氟-N-(7-(3-羟基丙炔-1-基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-5-苯氧基苯甲酰胺
第一步
(S)-N-(7-(3-((叔丁基二甲基甲硅烷基)氧代)-1-丙炔-1-基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-2-氟-5-苯氧基苯甲酰胺
将化合物(S)-N-(7-溴-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-2-氟-5-苯氧基苯甲酰胺(中间体9)(20mg，0.04mmol)和叔丁基二甲基(丙-2-炔-1-氧基)硅烷(70mg，0.41mmol)、碘化亚铜(7.6mg，0.04mmol)、醋酸钯(1mg，0.004mmol)、三苯基膦(20mg，0.08mmol)和三乙胺(3mL)混合。在氮气保护下加热至80℃搅拌4小时。将反应液过滤旋干，用10mL水淬灭，用乙酸乙酯(10mL×2)萃取。合并有机相用饱和食盐水(10mL)洗涤。将有机相用无水硫酸钠干燥，过滤除去干燥剂，减压脱溶得粗品。粗品用硅胶制备板纯化(石油醚/乙酸乙酯＝10：1)得到目标产物(S)-N-(7-(3-((叔丁基二甲基甲硅烷基)氧代)-1-丙炔-1-基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-2-氟-5-苯氧基苯甲酰胺(14mg，白色固体)。 产率：59％。MS m/z(ESI):575[M+1]；
第二步
(S)-2-氟-N-(7-(3-羟基-1-丙炔-1-基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-5-苯氧基苯甲酰胺
将化合物(S)-N-(7-(3-((叔丁基二甲基甲硅烷基)氧代)-1-丙炔-1-基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-2-氟-5-苯氧基苯甲酰胺(14mg，0.024mmol)、四丁基氟化铵(7mg，0.024mmol)和四氢呋喃(2mL)混合。室温下搅拌1小时。此混合物用1mL氨水淬灭，加水(20mL)稀释，用二氯甲烷(10mL×2)萃取。合并有机相用饱和食盐水(10mL)洗涤。将有机相用无水硫酸钠干燥，过滤除去干燥剂，减压脱溶得粗品。粗品用硅胶制备板纯化(石油醚/乙酸乙酯＝5：1)得到目标产物(S)-2-氟-N-(7-(3-羟基-1-丙炔-1-基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-5-苯氧基苯甲酰胺(10.1mg，黄色固体)。产率：90.9％。
MS m/z(ESI):461[M+1]；
1H NMR(400MHz,CDCl3)δ7.86-7.82(m,1H),7.60-7.58(m,1H),7.34-7.28(m,4H),7.14-7.09(m,4H),6.97(d,J＝7.6Hz,2H),5.38-5.33(m,1H),5.09-5.03(m,1H),4.82-4.77(m,1H),4.50(s,2H),4.30-4.24(m,1H),3.43(s,3H)；
实施例29
(S)-2-氟-N-(7-((3-氟氧杂环丁烷-3-基)乙炔基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-5-苯氧基苯甲酰胺
将化合物(S)-2-氟-N-(7-((3-羟基氧杂环丁烷-3-基)乙炔基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-5-苯氧基苯甲酰胺(实施 例13)(25mg，0.05mmol)溶于二氯甲烷(3mL)中，反应体系抽真空，用氮气置换3次。在氮气保护下冷却至-78℃，滴加二乙胺基三氟化硫(16mg，0.10mmol)，在-78℃下搅拌3小时。反应结束后，加入10mL饱和氯化铵水溶液和10mL二氯甲烷。分出有机相用10mL饱和食盐水洗涤，无水硫酸钠干燥，过滤后旋干。粗产品用硅胶制备板纯化(石油醚/乙酸乙酯＝3：1)得到目标产物(S)-2-氟-N-(7-((3-氟氧杂环丁烷-3-基)乙炔基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-5-苯氧基苯甲酰胺(6mg，黄色固体)，产率：24.1％。
MS m/z(ESI):505[M+1]；
1H NMR(400MHz,CDCl3)δ7.86-7.81(m,1H),7.60-7.58(m,1H),7.36-7.30(m,4H),7.13-7.09(m,4H),6.97-6.95(m,2H),5.10-5.04(m,1H),4.98(s,2H),4.93(s,2H),4.83-4.78(m,1H),4.32-4.26(m,1H),3.44(s,3H)。
实施例30
(S)-N-(7-((1-乙酰基-3-羟基氮杂环丁烷-3-基)乙炔基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-2-氟-5-苯氧基苯甲酰胺
第一步
(S)-1-乙酰基-3-((3-(2-氟-5-苯氧基苯甲酰氨基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-7-基)乙炔基)氮杂环丁烷-3-基乙酸酯
将(S)-N-(7-溴-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-2-氟-5-苯氧基苯甲酰胺(中间体9)(58mg，0.12mmol)，1-乙酰基-3-乙炔基氮杂环丁烷-3-基乙酸酯(70mg，0.60mmol)，溶解在N,N-二甲基乙酰胺(2mL)和三乙胺(1mL)中，加入双三苯基膦二氯化 钯(14mg，0.02mmol)和碘化亚铜(6mg，0.03mmol)。反应液用氮气鼓泡十分钟。在氮气保护下加热至85℃搅拌8小时。将反应液旋干，加水(20mL)稀释，用乙酸乙酯(20mL×2)萃取。合并有机相用饱和食盐水(20mL×2)洗涤。用无水硫酸钠干燥，过滤，滤液旋干得粗产品，粗产品用硅胶制备板纯化(石油醚/乙酸乙酯＝5：1)得到(S)-1-乙酰基-3-((3-(2-氟-5-苯氧基苯甲酰氨基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-7-基)乙炔基)氮杂环丁烷-3-基乙酸酯(18mg，黄色固体)，收率23.6％。MS m/z(ESI):586[M+1]；
第二步
(S)-N-(7-((1-乙酰基-3-羟基氮杂环丁烷-3-基)乙炔基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-2-氟-5-苯氧基苯甲酰胺
将化合物(S)-1-乙酰基-3-((3-(2-氟-5-苯氧基苯甲酰氨基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-7-基)乙炔基)氮杂环丁烷-3-基乙酸酯(18mg，0.03mmol)溶解在甲醇(2mL)中。在搅拌下加入2N氢氧化锂(0.5mL)水溶液，滴加完毕，在室温下继续搅拌2小时。加水(10mL)稀释，用二氯甲烷(10mL)萃取，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液旋干。粗产品用硅胶制备板纯化(石油醚/乙酸乙酯＝2：1)得到(S)-N-(7-((1-乙酰基-3-羟基氮杂环丁烷-3-基)乙炔基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-2-氟-5-苯氧基苯甲酰胺(3.8mg，黄色油状)，产率21.1％。
MS m/z(ESI):544[M+1]；
1H NMR(400MHz,CD3OD)δ7.51(d,J＝2.0Hz,1H),7.36-7.31(m,4H),7.23-7.10(m,4H),6.96-6.94(m,2H),5.32-5.29(m,1H),4.99-4.95(m,1H),4.57-4.49(m,2H),4.39-4.34(m,1H),4.26-4.24(m,2H),3.37(s,3H),1.88(s,3H)。
实施例31到42的合成步骤参考实施例8。
实施例31
(S)-2-氟-5-(2-氟苯氧基)-N-(5-甲基-7-(噁唑-5-基乙炔基)-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺
MS m/z(ESI)：516[M+1]；
1H NMR(400MHz,CDCl3)δ7.90(s,1H),7.86-7.88(m,1H),7.55-7.51(m,1H),7.41-7.38(m,2H),7.36(s,1H),7.19-7.04(m,7H),5.18-5.04(m,1H),4.84-4.79(m,1H),4.33-4.29(m,1H),3.46(s,3H)。
实施例32
(S)-2-氟-5-(2-氟苯氧基)-N-(5-甲基-7-((2-甲基-2H-1,2,3-三唑-4-基)乙炔基)-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺
MS m/z(ESI):530[M+1]；
1H NMR(400MHz,CDCl3)δ7.88-7.83(m,1H),7.72(s,1H),7.54-7.52(m,1H),7.41-7.39(m,2H),7.18-7.01(m,7H),5.10-5.04(m,1H),4.83-4.78(m,1H),4.31-4.28(m,1H),4.25(s,3H),3.44(s,3H)。
实施例33
(S)-N-(7-(3-氨基-3-甲基-1-丁炔-1-基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-2-氟-5-苯氧基苯甲酰胺
MS m/z(ESI):488[M+1]；
1H NMR(400MHz,CDCl3)δ7.86-7.81(m,1H),7.64-7.55(m,1H),7.37-7.28(m,2H),7.28-7.22(m,2H),7.17-7.06(m,4H),6.98-6.95(m,2H),5.08-5.02(m,1H),4.81-4.77(m,1H),4.28-4.23(m,1H),3.43(s,3H),1.49(s,6H)。
实施例34
(S)-2-氟-N-(5-甲基-7-(氧杂环丁烷-3-基乙炔基)-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-5-苯氧基苯甲酰胺
MS m/z(ESI):487[M+1]；
1H NMR(400MHz,CDCl3)δ7.86-7.82(m,1H),7.61-7.56(m,1H),7.36-7.31(m,2H),7.29-7.27(m,2H),7.16-7.07(m,4H),6.98-6.95(m,2H),5.10-5.02(m,1H),4.91-4.83(m,2H),4.81-4.77(m,3H),4.29-4.24(m,1H),4.13-4.03(m,1H),3.44(s,3H)。
实施例35
(S)-2-氟-5-(2-氟苯氧基)-N-(5-甲基-7-(氧杂环丁烷-3-基乙炔基)-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺
MS m/z(ESI):505[M+1]；
1H NMR(400MHz,CDCl3)δ7.87-7.82(m,1H),7.54-7.52(m,1H),7.29-7.27(m,2H),7.17-7.03(m,7H),5.07-5.04(m,1H),4.91-4.87(m,2H),4.83-4.77(m,3H),4.29-4.24(m,1H),4.13-4.07(m,1H),3.44(s,3H)。
实施例36
(S)-2-氟-5-(2-氟苯氧基)-N-(5-甲基-7-(噁唑-4-基乙炔基)-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺
MS m/z(ESI)：516[M+1]；
1H NMR(400MHz,CDCl3)δ7.95(s,1H),7.90-7.82(m,2H),7.54-7.51(m,1H),7.41-7.38(m,2H),7.18-7.02(m,7H),5.11-5.07(m,1H),4.83-4.79(m,1H),4.29-4.24(m,1H),3.49(s,3H)。
实施例37
(S)-2-氟-5-(2-氟苯氧基)-N-(5-甲基-7-((1-甲基-1H-1,2,3-三唑-4-基)乙炔基)-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺
MS m/z(ESI):530[M+1]；
1H NMR(400MHz,CDCl3)δ7.88-7.83(m,1H),7.72(s,1H),7.54-7.52(m,1H),7.42-7.39(m,2H),7.14-7.02(m,7H),5.10-5.05(m,1H),4.83-4.79(m,1H),4.31-4.26(m,1H),4.15(s,3H),3.45(s,3H)。
实施例38
(S)-2-氟-5-(2-氟苯氧基)-N-(5-甲基-7-((1-甲基-1H-咪唑-4-基)乙炔基)-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺
MS m/z(ESI):529[M+1]；
1H NMR(400MHz,CDCl3)δ7.88-7.83(m,1H),7.73-7.45(m,2H),7.39-7.34(m,2H),7.27(s,1H),7.18-7.04(m,7H),5.09-5.03(m,1H),4.82-4.78(m,1H),4.29-4.24(m,1H),3.71(s,3H),3.43(s,3H)。
实施例39
(S)-2-氟-N-(5-甲基-7-((1-甲基-1H-1,2,4-三唑-3-基)乙炔基)-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-5-苯氧基苯甲酰胺
MS m/z(ESI):512[M+1]；
1H NMR(400MHz,CDCl3)δ8.07(s,1H),7.88-7.83(m,1H),7.60-7.58(m,1H),7.47-7.44(m,2H),7.35-7.30(m,2H),7.13-7.09(m,4H),6.97-6.95(m,2H),5.11-5.05(m,1H),4.84-4.80(m,1H),4.32-4.27(m,1H),3.96(s,3H),3.45(s,3H)。
实施例40
(S)-2-氟-5-(2-氟苯氧基)-N-(5-氘代甲基-7-((1-甲基-1H-1,2,4-三唑-3-基)乙炔基)-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺
MS m/z(ESI)：533[M+1]；
1H NMR(400MHz,CDCl3)δ8.09(s,1H),7.86(m,1H),7.55-7.51(m,1H),7.49-7.43(m,2H),7.20-6.99(m,7H),5.10-5.04(m,1H),4.83-4.79(m,1H),4.33-4.24(m,1H),3.97(s,3H)。
实施例41
(S)-2-氟-5-(2-氟苯氧基)-N-(5-甲基-7-((1-乙基-1H-1,2,4-三唑-3-基)乙炔基)-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺
MS m/z(ESI)：544[M+1]；
1H NMR(400MHz,CDCl3)δ8.17(s,1H),7.92-7.86(m,1H),7.54-7.50(m,1H),7.49-7.45(m,2H),7.21-7.03(m,7H),5.11-5.04(m,1H),4.84-4.77(m,1H),4.34-4.22(m,3H),3.45(s,3H),1.57(t,J＝7.2Hz,3H)。
实施例42
(S)-2-氟-5-(2-氟苯氧基)-N-(5-氘代甲基-7-((1-乙基-1H-1,2,4-三唑-3-基)乙炔基)-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺
MS m/z(ESI)：547[M+1]；
1H NMR(400MHz,CDCl3)δ8.09(s,1H),7.88-7.83(m,1H),7.56-7.51(m,1H),7.48-7.43(m,2H),7.20-7.02(m,7H),5.10-5.04(m,1H),4.84-4.79(m,1H),4.33-4.21(m,3H),1.56(t,J＝7.2Hz,3H)。
实施例43
(S)-2-氟-5-(2-氟苯氧基)-N-(7-(6-(2-羟基丙烷-2-基)吡啶-3-基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺
第一步
(S)-3-氨基-7-溴-5-甲基-2,3-二氢苯并[b][1,4]氧氮杂-4(5H)-酮盐酸盐
将化合物(S)-(7-溴-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)氨基甲酸叔丁酯(1.00g，2.70mmol)(合成参考：J.Med..Chem.(2017),60(4),1247-1261)加入氯化氢的1,4-二氧六环溶液(4M，10mL)，室温搅拌2小时，减压脱溶，得到目标产物(S)-3-氨基-7-溴-5-甲基-2,3-二氢苯并[b][1,4]氧氮杂-4(5H)-酮盐酸盐(0.83g，黄色固体)。粗品。MS m/z(ESI):271&273[M+1]；
第二步
(S)-N-(7-溴-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-2-氟-5-(2-氟苯氧基)苯甲酰胺
将化合物2-氟-5-(2-氟苯氧基)苯甲酸(0.48g，1.90mmol)，(S)-3-氨基-7-溴-5-甲基-2,3-二氢苯并[b][1,4]氧氮杂-4(5H)-酮盐酸盐(0.50g，1.60mmol)，三乙胺(0.50g，4.80mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(0.90g，2.40mmol)溶于N,N-二甲基甲酰胺(5mL)，室温反应过夜。反应液用乙酸乙酯稀释(50mL)，先后用水(50mL×2)和饱和食盐水(50mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱分离纯化(0～20％乙酸乙酯/石油醚)，得到目标产物(S)-N-(7-溴-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-2-氟-5-(2-氟苯氧基)苯甲酰胺(0.53g，白色固体)。产率：64.6％。
MS m/z(ESI):503&505[M+1]；
1H NMR(400MHz,CDCl3)7.87-7.77(m,1H),7.56-7.50(m,1H),7.39-7.32(m,2H),7.20-7.01(m,7H),5.12-5.00(m,1H),4.81-4.72(m, 1H),4.30-4.20(m,1H),3.43(s,3H)；
第三步
(S)-2-氟-5-(2-氟苯氧基)-N-(5-甲基-4-酮-7-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺
将化合物(S)-N-(7-溴-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)-2-氟-5-(2-氟苯氧基)苯甲酰胺(0.41g，0.81mmol)和联硼酸频那醇酯(0.41g，1.62mmol)溶解在二氧六环(10mL)中。加入1,1'-双二苯基膦二茂铁二氯化钯(59mg，0.08mmol)和醋酸钾(0.24g，2.45mmol)，反应液用氮气鼓泡十分钟，氮气保护下100℃加热搅拌4小时。反应液过滤后旋干，加入乙酸乙酯(20mL)和水(20mL)萃取。有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤后旋干。粗产品用硅胶柱纯化(乙酸乙酯/石油醚＝1：3)，得到目标产物(S)-2-氟-5-(2-氟苯氧基)-N-(5-甲基-4-酮-7-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺(0.36g，白色固体)。产率：80％。
MS m/z(ESI):551[M+1]；
1H NMR(400MHz,CDCl3)δ7.91-7.81(m,1H),7.71-7.62(m,2H),7.56-7.50(m,1H),7.22-7.01(m,7H),5.09-4.97(m,1H),4.85-4.74(m,1H),4.32-4.22(m,1H),3.47(s,3H),1.35(s,12H)；
第四步
(S)-2-氟-5-(2-氟苯氧基)-N-(7-(6-(2-羟基丙烷-2-基)吡啶-3-基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺
将化合物(S)-2-氟-5-(2-氟苯氧基)-N-(5-甲基-4-酮-7-(4,4,5,5-四甲基-1,3,2-二氧杂硼戊烷-2-基)-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺(55mg，0.10mmol)和2-(5-溴吡啶-2-基)-2-丙醇(22mg，0.10mmol)溶解在二氧六环(2mL)和水(0.2mL)中。加入1,1'-双二苯基膦二茂铁二氯化钯(59mg，0.08mmol)和碳酸钠(32mg，0.30mmol)。反应液用氮气鼓泡十分钟，氮气保护下100℃加热搅拌14小时。反应液过滤后旋干，加入乙酸乙酯(5mL)和水(5mL)，分离出有机相。有机相用饱和食盐水(5mL)洗涤，无水硫酸钠干燥，过滤后旋干。粗产品用硅胶制备板纯化(石油醚/乙酸乙酯＝1：1)，得到目标产物(S)-2-氟-5-(2-氟苯氧基)-N-(7-(6-(2-羟基丙烷-2-基)吡啶-3-基)-5-甲基-4- 酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺(26mg，白色固体)。产率：46％。
MS m/z(ESI):560[M+1]；
1H NMR(400MHz,CDCl3)δ8.70(s,1H),7.90-7.84(m,2H),7.55-7.53(m,1H),7.48(d,J＝8.0Hz,1H),7.44-7.39(m,2H),7.30(d,J＝8.0Hz,1H),7.19-7.02(m,6H),5.19-5.12(m,1H),4.85-4.81(m 2H),4.34-4.29(m,1H),3.50(s,3H),1.60(s,6H)。
实施例44
(S)-2-氟-5-(2-氟苯氧基)-N-(7-(6-(2-羟基-2-甲基丙基)吡啶-3-基)-5-甲基-4-酮-2,3,4,5-四氢苯并[b][1,4]氧氮杂-3-基)苯甲酰胺
实施例44的合成步骤参考实施例43。
MS m/z(ESI)：574[M+1]；
1H NMR(400MHz,CDCl3)δ8.72(s,1H),7.88-7.82(m,1H),7.80-7.76(m,1H),7.55-7.49(m,1H),7.43-7.38(m,2H),7.29-7.23(m,2H),7.18-7.03(m,6H),5.50(s,1H),5.15-5.08(m,1H),4.83-4.79(m,1H),4.31-4.27(m,1H),3.49(s,3H),2.98(s,2H),1.30(s,6H)。
生物学实验
实施例1 U-937细胞的程序性坏死
实验方法：U-937细胞(购自南京科佰生物科技有限公司，货号CBP60277)培养于37℃含5％CO2的细胞培养箱，1640培养基中，铺于384孔白板，化合物进行4倍梯度系列稀释，最终起始浓度为2000nM,100ng/mL TNFα、Q-VD-Oph(10μM)和受试药物与细胞共孵育48h，GSK2982772用作阳性对照品，对照孔用DMSO。其中细胞的活力使用Cell-TiterGlo试剂盒(购自Promega公司)基于ATP的生存力测定来确定。细胞的活力测定数值代表加药孔比对照孔细胞活力的百分比，其中数值越高代表细胞活力越强(药物作用活力计算＝药物处理孔/对照 孔*100％)。EC50值定义为产生最大效应浓度的50％的化合物浓度，使用4参数logistic方程拟合药物作用活力数据，IDBS公司的XLfit 5.4软件分析计算EC50。
实施例2 L-929细胞的程序性坏死
实验方法：L-929细胞(购自南京科佰生物科技有限公司，货号CBP60878)培养于37℃含5％CO2的细胞培养箱，MEM培养基中，铺于384孔白板，化合物进行4倍梯度系列稀释，最终起始浓度为10000nM,40ng/mL TNFα、Q-VD-Oph(10μM)和受试药物与细胞共孵育24h，GSK2982772用作阳性对照品，对照孔用DMSO。其中细胞的活力使用Cell-TiterGlo试剂盒基于ATP的生存力测定来确定。细胞的活力测定数值代表加药孔比对照孔细胞活力的百分比，其中数值越高代表细胞活力越强(药物作用活力计算＝药物处理孔/对照孔*100％)。EC50值定义为产生最大效应浓度的50％的化合物浓度，使用4参数logistic方程拟合药物作用活力数据，IDBS公司的XLfit 5.4软件分析计算EC50。
实施例3 HT-29细胞的程序性坏死
实验方法：HT-29细胞(购自南京科佰生物科技有限公司，货号CBP30001L)培养于37℃含5％CO2的细胞培养箱，1640培养基中，细胞铺于384孔白板，化合物进行4倍梯度系列稀释，最终起始浓度为500nM,100ng/mL TNFα、Q-VD-Oph(10μM)、SM-164(1μΜ)和受试药物与细胞共孵育48h，GSK2982772用作阳性对照品，对照孔用DMSO。
其中细胞的活力使用Cell-TiterGlo试剂盒基于ATP的生存力测定来确定。细胞的活力测定数值代表加药孔比对照孔细胞活力的百分比，其中数值越高代表细胞活力越强(药物作用活力计算＝药物处理孔/对照孔*100％)。EC50值定义为产生最大效应浓度的50％的化合物浓度，使用4参数logistic方程拟合药物作用活力数据，IDBS公司的XLfit 5.4软件分析计算EC50。
实施例4 I2.1细胞的程序性坏死
I2.1细胞是FADD基因敲除的Jurkat细胞，适合用于研究TNFα诱导条件下细胞的程序性坏死。
实验方法：I2.1细胞(购自ATCC,货号CRL-2572)培养于37℃ 含5％CO2的细胞培养箱，1640培养基中，铺于384孔白板，化合物进行4倍梯度系列稀释，最终起始浓度为500nM,40ng/mL的TNFα和受试药物与细胞共孵育24小时，其中GSK2982772用作阳性对照品，对照孔用DMSO(D5879-500ML，购自Sigma公司)。
其中细胞的活力使用Cell-TiterGlo试剂盒基于ATP含量变化来进行测定。细胞的活力测定数值代表加药孔比对照孔细胞活力的百分比，其中数值越高代表细胞活力越强(药物作用活力计算＝药物处理孔/对照孔*100％)。EC50值定义为产生最大效应浓度的50％的化合物浓度，使用4参数logistic方程拟合药物作用活力数据，IDBS公司的XLfit 5.4软件分析计算EC50。
细胞实验的结果见表1
表1：本发明实施例化合物的细胞活性检测结果

由上述实验结果可知，本发明的实施例化合物可有效抑制细胞程序性坏死，因而具有有效的抑制RIPKl的活性，因而可以用于治疗或预防由RIPK1介导的相关疾病和功能障碍，如类风湿性关节炎，溃疡性 结肠炎，银屑病，阿尔茨海默氏症，多发性硬化症，肌萎缩侧索硬化症等。
对于本领域技术人员来说，很明显，本公开不局限于上述说明性的实施例，并且在不背离本公开实质特性的条件下，其可以通过其它具体形式来具体实施。因此，期望在各方面都认为这些实施例是说明性的和非限制性的，应参照的是附加的权利要求，而不是上述实施例，且由此在权利要求的等效含义和范围内的所有变化都被包括在其中。

Claims (10)

  1. 式(I)化合物，或其光学异构体或药学上可接受的盐，
    其中：
    R1选自氢、卤素、氰基、或任选被C1-C10羟烷基所取代的5-至10-元杂芳基，其中Ra选自C1-C8烷基、含有一至三个选自氮、氧和硫的杂原子的5-至10-元杂芳基、含有一至两个选自氮、氧和硫的杂原子的3-至10-元杂环基，且所述的烷基、杂芳基、杂环基为未取代的或被一至三个取代基取代，其中所述取代基各自独立地选自羟基、氨基、卤素、C1-C10烷基、C1-C10烷氧基、(C1-C10)烷基-C(O)-或3-10元的杂环基；优选地，R1选自氢、卤素、或任选被C1-C6羟烷基所取代的5-至6-元杂芳基，其中Ra选自C1-C8烷基、含有一至三个选自氮、氧和硫的杂原子的5-至6-元杂芳基、含有一至两个选自氮、氧和硫的杂原子的3-至8-元杂环基，其中所述的烷基、杂芳基、杂环基为未取代的或被一至三个取代基取代，其中所述取代基各自独立地选自羟基、氨基、卤素、C1-C8烷基、C1-C8烷氧基、(C1-C8)烷基-C(O)-；进一步优选地，R1选自氢、或任选被C1-C4羟烷基所取代的5-至6-元杂芳基，其中Ra选自C1-C6烷基、含有一至三个选自氮、氧和硫的杂原子的5-至6-元杂芳基、含有一至两个选自氮、 氧和硫的杂原子的4-至6-元杂环基，其中所述的烷基、杂芳基、杂环基为未取代的或被一至三个取代基取代，其中所述取代基各自独立地选自羟基、氨基、卤素、C1-C6烷基、C1-C6烷氧基、(C1-C6)烷基-C(O)-；再进一步优选地，R1选自氢、或被C1-C4羟烷基所取代的吡啶基，其中Ra选自C1-C4烷基、含有一至三个选自氮和氧的杂原子的5-至6-元杂芳基、含有一至两个选自氮和氧的杂原子的4-至6-元杂环基，其中所述的烷基、杂芳基、杂环基为未取代的或被一至三个取代基取代，其中所述取代基各自独立地选自羟基、氨基、卤素、C1-C4烷基、C1-C4烷氧基、(C1-C4)烷基-C(O)-；最优选地，R1选自氢、 其中Ra选自
    R2选自氢、C1-C8烷基或C1-C8氘代烷基；优选地，R2选自氢、C1-C6烷基或C1-C6氘代烷基；进一步优选地，R2选自氢、C1-C4烷基或C1-C4氘代烷基；最优选地，R2选自氢、甲基或氘代甲基；
    R3选自氢或卤素；优选地，R3选自氢、氟、氯或溴；进一步优选地，R3选自氢、氟、氯；最优选地，R3选自氢或氟；
    R4选自氢、卤素或氰基；优选地，R4选自氢、氟、氯、溴或氰基；进一步优选地，R4选自氢、氟、氯或氰基；最优选地，R4选自氢、氟或氰基；
    L选自O、S、NH或C(RbRc)，其中Rb和Rc各自独立地选自氢、 氟或C1-C4烷基，或者Rb、Rc可以与共同相连的碳原子一起形成3-元饱和碳环；优选地，L选自O或C(RbRc)，其中Rb和Rc各自独立地选自氢、氟或C1-C4烷基；最优选地，L选自O或-CH2-。
  2. 根据权利要求1的式(I)化合物，或其光学异构体或药学上可接受的盐，
    其中：
    R1选自氢、卤素、或任选被C1-C6羟烷基所取代的5-至6-元杂芳基，其中Ra选自C1-C8烷基、含有一至三个选自氮、氧和硫的杂原子的5-至6-元杂芳基、含有一至两个选自氮、氧和硫的杂原子的3-至8-元杂环基，其中所述的烷基、杂芳基、杂环基为未取代的或被一至三个取代基取代，其中所述取代基各自独立地选自羟基、氨基、卤素、C1-C8烷基、C1-C8烷氧基、(C1-C8)烷基-C(O)-；
    R2选自氢、C1-C8烷基或C1-C8氘代烷基；
    R3选自氢、卤素；
    R4选自氢、卤素或氰基；
    L选自O或C(RbRc)，其中Rb和Rc各自独立地选自氢、氟或C1-C4烷基。
  3. 根据权利要求1的式(I)化合物，或其光学异构体或药学上可接受的盐，其中：
    R1选自氢、或任选被C1-C4羟烷基所取代的5-至6元杂芳基，其中Ra选自C1-C6烷基、含有一至三个选自氮、氧和硫的杂原子的5-至6-元杂芳基、含有一至两个选自氮、氧和硫的杂原子的4-至6-元杂环基，其中所述的烷基、杂芳基、杂环基为未取代的或被一至三个取代基取代，其中所述取代基各自独立地选自羟基、氨基、卤素、C1-C6烷基、C1-C6烷氧基、(C1-C6)烷基-C(O)-；
    R2选自氢、C1-C6烷基或C1-C6氘代烷基；
    R3选自氢、氟、氯、溴；
    R4选自氢、氟、氯、溴或氰基；
    L选自O或-CH2-。
  4. 根据权利要求1的式(I)化合物，或其光学异构体或药学上可接受的盐，其中：
    R1选自氢、或被C1-C4羟烷基所取代的吡啶基，其中Ra选自C1-C4烷基、含有一至三个选自氮和氧的杂原子的5-至6-元杂芳基、含有一至两个选自氮和氧的杂原子的4-至6-元杂环基，其中所述的烷基、杂芳基、杂环基为未取代的或被一至三个取代基取代，其中所述取代基各自独立地选自羟基、氨基、卤素、C1-C4烷基、C1-C4烷氧基、(C1-C4)烷基-C(O)-；
    R2选自氢、C1-C4烷基或C1-C4氘代烷基；
    R3选自氢、氟或氯；
    R4选自氢、氟、氯或氰基；
    L选自O或-CH2-。
  5. 根据权利要求1的式(I)化合物，或其光学异构体或药学上可接受的盐，其中：
    R1选自氢、其中Ra选自
    R2选自氢、甲基或氘代甲基；
    R3选自氢或氟；
    R4选自氢、氟或氰基；
    L选自O或-CH2-。
  6. 选自下列的化合物，或其光学异构体或药学上可接受的盐：




  7. 药物组合物，其包含根据权利要求1-6任一项的化合物或其光学异构体或药学上可接受的盐，任选的一种或多种其它RIPK1抑制剂，以及一种或多种药学上可接受的载体。
  8. 根据权利要求1-6任一项的化合物、其光学异构体或其药学上可接受的盐以及权利要求7所述的组合物在制备治疗或预防RIPK1介导的疾病或病症的药物中的用途。
  9. 根据权利要求8所述的用途，其中所述RIPK1介导的疾病或病症选自：类风湿性关节炎、克罗恩氏病、溃疡性结肠炎、胰腺炎、银屑病、特应性皮炎、脊椎关节炎、痛风、系统性红斑狼疮、非酒精性脂肪性肝炎、酒精性脂肪性肝炎、自身免疫性肝炎、自身免疫性肝胆疾病、全身性炎症反应综合征、脑血管意外、亨廷顿氏病、阿尔茨海默氏症、帕金森氏症、肌萎缩侧索硬化症、哮喘、多发性硬化症、胰腺癌、细菌感染、血液恶性肿瘤、实体器官恶性肿瘤等。
  10. 根据权利要求8所述的用途，其中所述RIPK1介导的疾病或病症选自类风湿性关节炎、溃疡性结肠炎、银屑病、阿尔茨海默氏症、多发性硬化症、肌萎缩侧索硬化症。
PCT/CN2023/106682 2022-07-13 2023-07-11 作为ripk1抑制剂的杂环化合物 Ceased WO2024012425A1 (zh)

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