CN117447460A - Heterocyclic compounds as RIPK1 inhibitors - Google Patents

Heterocyclic compounds as RIPK1 inhibitors Download PDF

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CN117447460A
CN117447460A CN202210820411.XA CN202210820411A CN117447460A CN 117447460 A CN117447460 A CN 117447460A CN 202210820411 A CN202210820411 A CN 202210820411A CN 117447460 A CN117447460 A CN 117447460A
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alkyl
hydrogen
methyl
nitrogen
fluorine
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孔祥龙
周超
郑之祥
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Nanjing Innocare Pharma Tech Co ltd
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Nanjing Innocare Pharma Tech Co ltd
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Priority to PCT/CN2023/106682 priority patent/WO2024012425A1/en
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Abstract

The present invention relates to compounds, pharmaceutical compositions containing them, and methods for their preparation, and their use as RIPK1 inhibitors. The compound is a compound shown in a formula (I), or an optical isomer or a pharmaceutically acceptable salt thereof. The invention also relates to the use of said compounds for the treatment or prevention of related diseases and disorders mediated by RIPK1 and to methods of using the same for the treatment of said diseases.

Description

Heterocyclic compounds as RIPK1 inhibitors
Technical Field
The present invention relates to heterocyclic compounds, pharmaceutical compositions containing them and their use as inhibitors of receptor-interacting protein kinase-1 (RIPKl). More particularly, the present invention provides novel heterocyclic compounds which are inhibitors of RIPK1, pharmaceutical compositions containing such compounds and methods of using the compounds in the treatment or prevention of related diseases and disorders mediated by RIPK 1. The invention also relates to a method for preparing said compounds.
Background
Receptor-interacting protein kinase 1 (Receptor-interacting protein kinase 1, RIPK 1) is a serine/threonine protein kinase involved in natural immune signaling. RIPK1 is a 76kDa protein with an N-terminal kinase domain, a C-terminal death domain and an intermediate domain with RHIM (receptor interacting protein homotypic interacting motif). Wherein 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 double immunoregulation function, and can be used as a bracket to promote MAPK and NF- κB signal channels to activate, thereby promoting inflammatory reaction and cell survival and inhibiting apoptosis; on the other hand, abnormally regulated RIPK1 activity will cause cell necrosis. RIPK1 is the primary regulator of cellular determinants of NF- κb signaling and death response in response to a wide range of inflammatory and pro-mortal stimuli in human disease (degerev, a., et. al PNAS, 2019, 116 (20), 9714-9722).
RIPK1 is widely expressed in various cell types, most abundantly in adipose, endothelial, perivascular cell clusters, and also in immune cell clusters (dendritic cells, macrophages and T cells). It was found that activation of RIPK1 kinase is present in pathological samples of neurodegenerative diseases such as autoimmune diseases, amyotrophic Lateral Sclerosis (ALS) and Alzheimer's Disease (AD). Anti-tumor necrosis factor-alpha (TNF-alpha) drugs have achieved significant clinical success in the treatment of human peri-inflammatory diseases such as rheumatoid arthritis, colitis, psoriasis, and the like. However, since tumor necrosis factor receptor 2 (TNFR 2) mediates nerve regeneration, treatment of central nervous system diseases is an unsafe factor. RIPK1 inhibitors safely ameliorate adverse TNF responses in the central nervous system without affecting TNFR 2. Thus, RIPK1 inhibitors may be a drug replacing TNF antibodies to compensate for the deficiencies of TNF antibodies.
Studies have shown that the RIPK1 small molecule inhibitor Necrostatin-1 (Nec-1), known in the art, can effectively block cell programmed necrosis (Degterev)et al. Nat. Chem. Biol.2005:112-119.), shows potent therapeutic effects in a variety of inflammatory diseases. GSK2982772 is being developed for use in peripheral autoimmune diseases such as psoriasis, rheumatoid Arthritis (RA) and ulcerative colitis. The brain penetration RIPK1 inhibitor DNL-788 is used for amyotrophic lateral sclerosis and the like. These experiments lay the foundation for advancing the clinical application of RIPK1 inhibitors.
RIPKl inhibitors are of great importance to the art, especially in inhibiting inflammatory diseases (e.g. Crohn's disease, ulcerative colitis etc.), sepsis and acute ischemic injury (e.g. sepsis, severe Covid-19, cerebral acute ischemic injury etc.), tumours, autoimmune system diseases (e.g. psoriasis, rheumatoid arthritis, systemic lupus erythematosus etc.) and neurodegenerative diseases (e.g. multiple sclerosis, huntington's disease, du's muscular dystrophy, frontotemporal dementia, alzheimer's disease, parkinson's disease etc.) and the like (Lauren M.etc. al.Nature Reviews Drug Discovery, 19(2020), 553–571）。
Thus, there remains a need to develop small molecule RIPK1 inhibitors with excellent activity.
Disclosure of Invention
The present invention relates to compounds of formula (I), or an optical isomer or a pharmaceutically acceptable salt thereof,
wherein:
R 1 selected from hydrogen, halogen, cyano,Or a 5-to 10-membered heteroaryl optionally substituted with C1-C10 hydroxyalkyl, wherein R a Selected from C1-C8 alkyl, 5-to 10-membered heteroaryl containing one to three heteroatoms selected from nitrogen, oxygen and sulfur, 3-to 10-membered heterocyclyl containing one to two heteroatoms selected from nitrogen, oxygen and sulfur, and said alkyl, heteroaryl, heterocyclyl being unsubstituted or mono-substitutedTo three substituents, wherein each substituent is independently selected from hydroxy, amino, halogen, C1-C10 alkyl, C1-C10 alkoxy, (C1-C10) alkyl-C (O) -or 3-to 10-membered heterocyclyl; preferably, R 1 Selected from hydrogen, halogen, (-) -and->Or a 5-to 6-membered heteroaryl optionally substituted with C1-C6 hydroxyalkyl, wherein R a A 5-to 6-membered heteroaryl group containing one to three heteroatoms selected from nitrogen, oxygen and sulfur, a 3-to 8-membered heterocyclyl group containing one to two heteroatoms selected from nitrogen, oxygen and sulfur, wherein said alkyl, heteroaryl, heterocyclyl groups are unsubstituted or substituted with one to three substituents, wherein each of said substituents is independently selected from hydroxy, amino, halogen, C1-C8 alkyl, C1-C8 alkoxy, (C1-C8) alkyl-C (O) -; further preferably, R 1 Selected from hydrogen, & lt & gt>Or a 5-to 6-membered heteroaryl optionally substituted with C1-C4 hydroxyalkyl, wherein R a A 5-to 6-membered heteroaryl group containing one to three heteroatoms selected from nitrogen, oxygen and sulfur, a 4-to 6-membered heterocyclyl group containing one to two heteroatoms selected from nitrogen, oxygen and sulfur, wherein said alkyl, heteroaryl, heterocyclyl groups are unsubstituted or substituted with one to three substituents, wherein each of said substituents is independently selected from hydroxy, amino, halogen, C1-C6 alkyl, C1-C6 alkoxy, (C1-C6) alkyl-C (O) -; still further preferably, R 1 Selected from hydrogen, & lt & gt>Or pyridyl substituted by C1-C4 hydroxyalkyl, wherein R a Selected from C1-C4 alkyl, 5-to 6-membered heteroaryl containing one to three heteroatoms selected from nitrogen and oxygen, 4-to 6-membered heterocyclyl containing one to two heteroatoms selected from nitrogen and oxygen, wherein said alkyl, heteroaryl, heterocyclyl are unsubstituted or substituted with one to three substituents, wherein each of said substituents is independently selected from hydroxy, amino, halogenC1-C4 alkyl, C1-C4 alkoxy, (C1-C4) alkyl-C (O) -; most preferably, R 1 Selected from hydrogen,、/>Wherein R is a Selected from the group consisting of
R 2 Selected from hydrogen, C1-C8 alkyl or C1-C8 deuterated alkyl; preferably, R 2 Selected from hydrogen, C1-C6 alkyl or C1-C6 deuterated alkyl; further preferably, R 2 Selected from hydrogen, C1-C4 alkyl or C1-C4 deuterated alkyl; most preferably, R 2 Selected from hydrogen, methyl or deuterated methyl;
R 3 selected from hydrogen or halogen; preferably, R 3 Selected from hydrogen, fluorine, chlorine or bromine; further preferably, R 3 Selected from hydrogen, fluorine, chlorine; most preferably, R 3 Selected from hydrogen or fluorine;
R 4 selected from hydrogen, halogen or cyano; preferably, R 4 Selected from hydrogen, fluorine, chlorine, bromine or cyano; further preferably, R 4 Selected from hydrogen, fluorine, chlorine or cyano; most preferably, R 4 Selected from hydrogen, fluorine or cyano;
l is selected from O, S, NH or C (R) b R c ) Wherein R is b And R is c Each independently selected from hydrogen, fluorine or C1-C4 alkyl, or R b 、R c Can form a 3-membered saturated carbocyclic ring together with the carbon atoms to which they are commonly attached; preferably, L is selected from O or C (R b R c ) Wherein R is b And R is c Each independently selected from hydrogen, fluorine or C1-C4 alkyl; most preferably, L is selected from O or-CH 2 -。
Preferably, the present invention relates to a compound of formula (I), as described above, or an optical isomer or a pharmaceutically acceptable salt thereof, wherein:
R 1 selected from the group consisting ofHydrogen, halogen,Or a 5-to 6-membered heteroaryl optionally substituted with C1-C6 hydroxyalkyl, wherein R a A 5-to 6-membered heteroaryl group containing one to three heteroatoms selected from nitrogen, oxygen and sulfur, a 3-to 8-membered heterocyclyl group containing one to two heteroatoms selected from nitrogen, oxygen and sulfur, wherein said alkyl, heteroaryl, heterocyclyl groups are unsubstituted or substituted with one to three substituents, wherein each of said substituents is independently selected from hydroxy, amino, halogen, C1-C8 alkyl, C1-C8 alkoxy, (C1-C8) alkyl-C (O) -;
R 2 Selected from hydrogen, C1-C8 alkyl or C1-C8 deuterated alkyl;
R 3 selected from hydrogen, halogen;
R 4 selected from hydrogen, halogen or cyano;
l is selected from O or C (R) b R c ) Wherein R is b And R is c Each independently selected from hydrogen, fluorine or C1-C4 alkyl.
More preferably, the present invention relates to a compound of formula (I), as described above, or an optical isomer or a pharmaceutically acceptable salt thereof, wherein:
R 1 selected from hydrogen,Or a 5-to 6-membered heteroaryl optionally substituted with C1-C4 hydroxyalkyl, wherein R a A 5-to 6-membered heteroaryl group containing one to three heteroatoms selected from nitrogen, oxygen and sulfur, a 4-to 6-membered heterocyclyl group containing one to two heteroatoms selected from nitrogen, oxygen and sulfur, wherein said alkyl, heteroaryl, heterocyclyl groups are unsubstituted or substituted with one to three substituents, wherein each of said substituents is independently selected from hydroxy, amino, halogen, C1-C6 alkyl, C1-C6 alkoxy, (C1-C6) alkyl-C (O) -;
R 2 selected from hydrogen, C1-C6 alkyl or C1-C6 deuterated alkyl;
R 3 selected from hydrogen, fluorine, chlorine, bromine;
R 4 selected from hydrogen, fluorine, chlorine, bromine or cyano;
l is selected from O or-CH 2 -。
Further preferred, the present invention relates to a compound of formula (I), as described above, or an optical isomer or a pharmaceutically acceptable salt thereof, wherein:
R 1 Selected from hydrogen,Or pyridyl substituted by C1-C4 hydroxyalkyl, wherein R a A 5-to 6-membered heteroaryl group selected from C1-C4 alkyl, containing one to three heteroatoms selected from nitrogen and oxygen, a 4-to 6-membered heterocyclyl group containing one to two heteroatoms selected from nitrogen and oxygen, wherein said alkyl, heteroaryl, heterocyclyl groups are unsubstituted or substituted with one to three substituents, wherein each of said substituents is independently selected from hydroxy, amino, halogen, C1-C4 alkyl, C1-C4 alkoxy, (C1-C4) alkyl-C (O) -;
R 2 selected from hydrogen, C1-C4 alkyl or C1-C4 deuterated alkyl;
R 3 selected from hydrogen, fluorine or chlorine;
R 4 selected from hydrogen, fluorine, chlorine or cyano;
l is selected from O or-CH 2 -。
Still preferably, the present invention relates to a compound of formula (I), as described above, or an optical isomer or a pharmaceutically acceptable salt thereof, wherein:
R 1 selected from hydrogen,、/>Wherein R is a Selected from the group consisting of
R 2 Selected from hydrogen, methyl or deuterated methyl;
R 3 selected from hydrogen or fluorine;
R 4 selected from hydrogen, fluorine or cyano;
l is selected from O or-CH 2 -。
Most preferably, the present invention relates to a compound of formula (I), as described above, or an optical isomer or a pharmaceutically acceptable salt thereof, selected from:
。
the present invention further relates to pharmaceutical compositions comprising a compound of formula I as described in any one of the embodiments of the present invention, or an isomer or pharmaceutically acceptable salt thereof, optionally one or more additional RIPK1 inhibitors, and one or more pharmaceutically acceptable carriers.
The invention also relates to the use of a compound of formula I according to any one of the embodiments of the invention, an optical isomer thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to the invention for the manufacture of a medicament for the treatment or prophylaxis of a RIPK1 mediated disease or condition or a disease or condition resulting from programmed necrosis of cells.
The present invention also relates to the use of a compound of formula I according to any one of the embodiments of the present invention, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture 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, nonalcoholic 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 infection, hematological malignancy, solid organ malignancy, and the like. In particular rheumatoid arthritis, ulcerative colitis, psoriasis, alzheimer's disease and the like.
The invention also relates to the use of a pharmaceutical composition according to the invention for the preparation of a medicament for the treatment or prophylaxis of a related disorder mediated by RIPK1, such as ulcerative colitis, crohn's disease, pancreatitis, psoriasis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, systemic lupus erythematosus, non-alcoholic steatohepatitis, autoimmune hepatitis, autoimmune liver and gall 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 infection, hematological malignancy, solid organ malignancy, etc. In particular rheumatoid arthritis, ulcerative colitis, psoriasis, alzheimer's disease and the like.
The present invention also relates to a method of treating or preventing a related disorder mediated by RIPK1, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of the embodiments of the invention, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the invention, for example: ulcerative colitis, crohn's disease, pancreatitis, psoriasis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, systemic lupus erythematosus, nonalcoholic 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 infection, hematological malignancy, solid organ malignancy, and the like; in particular rheumatoid arthritis, ulcerative colitis, psoriasis, alzheimer's disease and the like.
A further aspect of the invention relates to a compound as 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 or prophylaxis of a disease associated with RIPK1, such as ulcerative colitis, crohn's disease, pancreatitis, psoriasis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, systemic lupus erythematosus, non-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 infection, hematological malignancy, solid organ malignancy, and the like; in particular rheumatoid arthritis, ulcerative colitis, psoriasis, alzheimer's disease and the like.
Another aspect of the invention relates to pharmaceutical compositions comprising a compound of formula I as described in any one of the embodiments of the invention or an optical isomer thereof or a pharmaceutically acceptable salt thereof, optionally one or more other RIPK1 inhibitors, and one or more pharmaceutically acceptable carriers, diluents and excipients, for the treatment or prophylaxis of diseases associated with RIPK1, such as ulcerative colitis, crohn's disease, pancreatitis, psoriasis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, systemic lupus erythematosus, non-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 (e.g. pancreatic cancer), bacterial infections, hematological malignancies, solid organ malignancies, and the like; in particular rheumatoid arthritis, ulcerative colitis, psoriasis, alzheimer's disease and the like.
According to the present invention, the drug may be any pharmaceutical dosage form including, but not limited to, tablets, capsules, solutions, lyophilized formulations, injections.
The pharmaceutical formulations of the present invention may be administered in dosage unit form containing a predetermined amount of active ingredient per dosage unit. Such units may contain, for example, from 0.5 mg to 1 g, preferably from 1 mg to 700 mg, particularly preferably from 5 mg to 300 mg of a compound of the invention, or the pharmaceutical formulation may be administered in dosage unit form containing a predetermined amount of active ingredient per dosage unit, depending on the disorder being treated, the method of administration and the age, weight and condition of the patient. Preferred dosage unit formulations are those containing a daily dose or divided dose, or a corresponding fraction thereof, of the active ingredient as indicated above. In addition, this type of pharmaceutical formulation may be prepared using methods well known in the pharmaceutical arts.
The pharmaceutical formulations of the invention may be adapted for administration by any desired suitable method, 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) methods. Such formulations may be prepared using all methods known in the pharmaceutical arts by, for example, combining the active ingredient with one or more excipients or one or more adjuvants.
Preparation flow
The invention also provides a method for preparing the compound.
Scheme 1
R 3 And R is R 4 Is as defined above;
the first step:
dissolving the compounds (I) and (II) in a solvent (such as dioxane) at room temperature, adding a base (such as cesium carbonate), a catalyst (such as cuprous iodide) and a ligand (such as copper iodide) under the protection of an inert gas (such as nitrogen or argon)N,N-dimethylglycine), pumping vacuum nitrogen for three times, and reacting for 2-20 hours under the heating of an oil bath (100-130 ℃) to obtain a compound (V);
and a second step of:
dissolving the compounds (III) and (IV) in a solvent (e.g.)N,NAdding alkali (such as potassium carbonate) into dimethylformamide, and reacting for 2-20 hours under the heating of an oil bath (100-130 ℃) to obtain a compound (V);
and a third step of:
dissolving the compound (V) in a solvent (such as water) at room temperature, adding alkali (such as sodium hydroxide or lithium hydroxide, etc.), and stirring for 1-5 hours at the temperature of room temperature to 50 ℃ to obtain a compound (VI);
scheme 2
R 3 And R is R 4 Is as defined above;
the first step:
adding a compound (I), a bisboronic acid pinacol ester, a base (such as potassium acetate) and a catalyst (such as 1,1' -bis-diphenylphosphino ferrocene palladium dichloride) into a solvent (such as dimethyl sulfoxide) under the protection of nitrogen, vacuumizing the system, replacing the system with nitrogen for three times, and stirring for 12-24 hours at the temperature of 60-100 ℃ to obtain a compound (VII);
And a second step of:
adding a compound (VII), a compound (VIII), alkali (such as sodium carbonate) and a catalyst (such as 1,1' -bis-diphenylphosphino ferrocene palladium dichloride) into a solvent (such as dioxane) under the protection of nitrogen, vacuumizing the system, replacing nitrogen for three times, and stirring for 12-24 hours at the temperature of 80-120 ℃ to obtain a compound (IX);
and a third step of:
dissolving the compound (IX) in a solvent (such as water), adding alkali (such as sodium hydroxide or lithium hydroxide, etc.), and stirring at room temperature to 80 ℃ for 12-24 hours to obtain a compound (X);
scheme 3
R a 、R 2 、R 3 、R 4 And L are as defined above, X is halogen;
the first step:
compound (XI) (synthesis reference:Journal of Medicinal Chemistry(2017) 60 (4), 1247-1261), (XII) and a base (e.g. potassium carbonate or cesium carbonate) are dissolved in a solvent (e.gN,N-dimethylformamide), stirring for 2-6 hours at room temperature to 60 ℃ to obtain a compound (XIII);
and a second step of:
the compounds (XIII) and (XIV) are dissolved in a solvent (such as dioxane) and a base (such asN,NDiisopropylethylamine), a catalyst (such as bis (triphenylphosphine) palladium dichloride and cuprous iodide), pumping vacuum nitrogen for three times, and stirring for 12-24 hours at the temperature of 60-120 ℃ to obtain a compound (XV);
And a third step of:
dissolving the compound (XV) in acid (such as formic acid), and stirring for 2-6 hours at the temperature of room temperature to 60 ℃ to obtain a compound (XVI);
fourth step:
the compound (XVI), the compound (VI) or the compound (X), a condensing agent (e.g., 2- (7-azabenzotriazol)N,N,N',N' -tetramethylurea hexafluorophosphate), a base (e.g., triethylamine) in a solvent (e.g.N,N-dimethylformamide) and stirring at room temperature to 60 ℃ for 2 to 16 hours to obtain a compound (XIX);
fifth step:
dissolving the compound (XIII) in a solvent (such as dioxane), adding an acid (such as hydrochloric acid), and stirring at room temperature to 60 ℃ for 2 to 3 hours to obtain a compound (XVII);
sixth step:
the compound (XVII), the compound (VI) or the compound (X), a condensing agent (e.g., 2- (7-azabenzotriazol)N,N,N',N' -tetramethylurea hexafluorophosphate), a base (e.g., triethylamine) in a solvent (e.g.N,N-dimethylformamide), stirring for 2-16 hours at room temperature to 60 ℃ to obtain a compound (XVIII);
seventh step:
dissolving the compounds (XVIII) and (XIV) in a solvent (such as dioxane), adding alkali (such as triethylamine) and a catalyst (such as ditriphenylphosphine palladium dichloride and cuprous iodide) under the protection of inert gas (such as nitrogen or argon), vacuumizing the system, replacing nitrogen for three times, and stirring at 60-120 ℃ for 12-24 hours to obtain the compound (XIX);
Scheme 4
R 1 Selected from the group consisting of
R 2 、R 3 、R 4 And L are as defined above, X is halogen;
the first step:
adding the compound (XVIII), the bisboronic acid pinacol ester, alkali (such as potassium acetate) and a catalyst (such as 1,1' -bis-diphenylphosphino ferrocene palladium dichloride) into a solvent (such as dioxane) under the protection of nitrogen, vacuumizing the system, replacing nitrogen for three times, and stirring for 4-12 hours at the temperature of 60-100 ℃ to obtain a compound (XX);
and a second step of:
carrying out Suzuki coupling reaction: adding a compound (XX), a compound (XXI), alkali (such as sodium carbonate) and a catalyst (such as 1,1' -bis-diphenylphosphino ferrocene palladium dichloride) into a solvent (such as dioxane) under the protection of nitrogen, vacuumizing the system, replacing nitrogen for three times, and stirring at 80-120 ℃ for 4-12 hours to obtain the compound (XXII).
Detailed Description
Definition of the definition
Unless stated to the contrary, the following terms used in the specification and claims have the following meanings. The groups not specifically defined in the present invention have meanings commonly represented in the art as known to those skilled in the art.
The expression "Cx-Cy" as used in the present invention means a range of carbon atom numbers, wherein x and y are both integers, for example, C3-C8 cycloalkyl represents cycloalkyl having 3 to 8 carbon atoms, -C0-C2 alkyl represents alkyl having 0 to 2 carbon atoms, wherein-C0 alkyl means a chemical single bond.
In the present invention, the term "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms, which may be, for example, straight and branched chain groups of 1 to 18 carbon atoms, 1 to 12 carbon atoms, 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-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, and various branched isomers thereof, and the like. The alkyl group may be optionally substituted or unsubstituted.
In the present invention, the term "alkoxy" refers to an alkyl-O-group, wherein alkyl has the meaning defined above.
In the present invention, the term "hydroxyalkyl" refers to an alkyl-OH group, i.e. a group in which any position of the alkyl group (including straight chain alkyl groups and branched chain alkyl groups) is substituted with a hydroxyl group, wherein alkyl has the meaning as defined above.
In the present invention, the term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group comprising 3 to 20 ring atoms, which may be, for example, 3 to 16, 3 to 12, 3 to 10, 3 to 8 or 3 to 6 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen or heteroatoms of S (O) m (where m is an integer from 0 to 2), but excluding the ring portion of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, more preferably the heterocyclyl ring contains 3 to 10 ring atoms, more preferably 3 to 8 ring atoms, most preferably 5-membered ring or 6-membered ring, of which 1 to 4 are heteroatoms, more preferably 1 to 3 are heteroatoms, most preferably 1 to 2 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, azetidinyl, morpholinyl, 2-morpholinyl, dihydropyrazolyl, and the like. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups. The heterocyclyl group may be optionally substituted or unsubstituted.
In the present invention, the term "heteroaryl" refers to heteroaromatic systems containing from 1 to 4 heteroatoms, including oxygen, sulfur and nitrogen, from 5 to 14 ring atoms. Preferably 5-to 10-membered. More preferably, the heteroaryl group is 5-or 6-membered, such as pyrazolyl, imidazolyl, triazolyl, pyrazinyl, oxazolyl, isoxazolyl, pyridinyl, and the like. Heteroaryl groups may be optionally substituted or unsubstituted.
In the present invention, the term "halogen" refers to fluorine, chlorine, bromine or iodine.
In the present invention, "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.
Such substituents include, but are not limited to, the various groups described previously.
The claimed compounds include not only the compounds themselves, but also optical isomers of the compounds or pharmaceutically acceptable salts thereof.
The term "pharmaceutical composition" as used herein means a mixture containing one or more of the compounds of the present invention or optical isomers thereof or pharmaceutically acceptable salts thereof and other chemical components. Other components such as pharmaceutically acceptable carriers, diluents and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
The term "comprising" when used in the specification is comprised of ….
The term "room temperature" as used herein means 15-30deg.C.
The "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 readily apparent to pharmaceutical chemists, and are substantially non-toxic and provide desirable pharmacokinetic properties, palatability, absorption, distribution, metabolism, excretion, and the like.
Pharmaceutically acceptable salts of the invention can be synthesized by general chemical methods.
In general, salts can be prepared by reacting the free base or acid with an equivalent stoichiometric or excess of an acid (inorganic or organic) or base in a suitable solvent or solvent composition.
The "optical isomer" of the present invention includes the meso, racemate, enantiomer, diastereomer, mixture thereof, and the like of the compound of formula (I) of the present invention.
The invention includes any polymorph of the compound or salt thereof, and any hydrate or other solvate.
In the present invention, the term "patient" generally refers to a mammal, especially a human.
In the present invention, the term "therapeutically effective amount" is meant to include an amount of a compound of the present invention that is effective to treat or prevent a related disorder mediated by RIPK 1.
Examples
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
The structures of all the compounds of the invention can be changed by nuclear magnetic resonance 1 H NMR) and/or mass spectrometry detection (MS) identification.
1 H NMR chemical shifts (δ) are reported in PPM (parts per million ). NMR was performed by Bruker AVANCE III-400MHz spectrometer. Suitable solvents are selected from deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), deuterated dimethyl sulfoxide (DMSO)d 6 ) And the like, tetramethylsilane as an internal standard (TMS).
Low resolution Mass Spectrometry (MS) was determined by an Agilent 1260 HPLC/6120 mass spectrometer using Agilent ZORBAX XDB-C18, 4.6X10 mm,3.5 μm.
Gradient elution condition one: 0 min 95% solvent A1 and 5% solvent B1, 1-2 min 5% solvent A1 and 95% solvent B1;2.01-2.50 minutes 95% solvent A1 and 5% solvent B1. The percentage is the volume percentage of a certain solvent to the total solvent volume. Solvent A1:0.01% formic acid aqueous solution; solvent B1:0.01% formic acid in acetonitrile; the percentage is the volume percentage of solute in the solution.
The thin-layer silica gel plate is a tobacco stand yellow sea HSGF254 or Qingdao GF254 silica gel plate. Column chromatography generally uses 100-200 or 200-300 mesh silica gel of yellow sea as carrier.
Preparative liquid chromatography (prep-HPLC) using Waters SQD2 mass spectrometry directed to a high pressure liquid chromatography separator, XBridge-C18; 30X 150 mm preparation column, 5 μm;
the method comprises the following steps: acetonitrile-water (0.2% formic acid), flow rate 25 mL/min; the second method is as follows: acetonitrile-water (0.8% ammonium bicarbonate), flow rate 25 mL/min;
the known starting materials of the present invention may be synthesized using or according to methods known in the art or may be purchased from Acros Organics, aldrich Chemical Company, shaoshan chemical technology (Accela ChemBio Inc), shanghai Piobtained medicine, shanghai Ala Ding Huaxue, shanghai Michelson chemistry, carbofuran chemistry, an Naiji chemistry, and the like.
In the examples, if no special description exists, the solvent used in the reaction is anhydrous solvent, wherein the anhydrous tetrahydrofuran uses commercial tetrahydrofuran, sodium block is used as a water scavenger, benzophenone is used as an indicator, reflux is carried out to the solution under the protection of argon gas to form bluish violet, distillation and collection are carried out, the solution is stored at room temperature under the protection of argon gas, other anhydrous solvents are purchased from Angust chemical and carbofuran chemical, and all transfer and use of the anhydrous solvents are carried out under the protection of argon gas if no special description exists.
In the examples, unless otherwise specified, the reaction was carried out under an argon atmosphere or a nitrogen atmosphere.
An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume.
The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume.
The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times.
In the examples, the reaction temperature was room temperature and the temperature range was 15℃to 30℃unless otherwise specified.
The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using a system of developing agents of a: methylene chloride and methanol systems; b: petroleum ether and ethyl acetate systems. The volume ratio of the solvent is adjusted according to the polarity of the compound.
The system of eluent for column chromatography and the system of developing agent for thin layer chromatography used for purifying the compound include a: methylene chloride and methanol systems; b: petroleum ether and ethyl acetate systems. The volume ratio of the solvent is adjusted according to the polarity of the compound, and can be adjusted by adding a small amount of triethylamine, an acidic or alkaline reagent and the like.
The reagents used in the biological experiment of the invention are: DMSO (D5879-500 ML) is purchased from Sigma company, fetal Bovine Serum (FSP 500) is purchased from Excell Bio company, DPBS (14190-144), RPMI Medium 1640 (72400-047), cellTiter-Glo Luminescent Cell Viability Assay (CellTiter-Glo luminescence cell viability assay kit, G7571, G7573) is purchased from Promega company.
Preparation of intermediates
Intermediate 1
2-fluoro-5- (2-fluorophenoxy) benzoic acid
First step
2-fluoro-5- (2-fluorophenoxy) benzoic acid methyl ester
Methyl 5-bromo-2-fluorobenzoate (4.60 g,20.00 mmol), ortho-fluorophenol (4.50 g,40.00 mmol), cesium carbonate (13.00 g,40.00 mmol), cuprous iodide (0.77 g,4.00 mmol) andN,Ndimethylglycine (0.41 g,4.00 mmol) was added to 1, 4-dioxane (60 mL), and the mixture was replaced 3 times with nitrogen under vacuum, heated to 100℃under nitrogen and stirred overnight. After cooling, the pH was adjusted to about 4 with 1N hydrochloric acid, and extracted with ethyl acetate (100 mL ×3). The organic phase was combined and washed successively with water and saturated brine each 150 mL. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give methyl 2-fluoro-5- (2-fluorophenoxy) benzoate (3.20, g, crude product), yield: 60.5 Percent of the total weight of the composition. MS M/z (ESI) 265 [ M+1 ]]；
Second step
2-fluoro-5- (2-fluorophenoxy) benzoic acid
Methyl 2-fluoro-5- (2-fluorophenoxy) benzoate (3.20 g,12.10 mmol) was dissolved in aqueous sodium hydroxide (2N, 200 mmol, 100 mL) and tetrahydrofuran (100 mL), and heated to 50℃for reaction for 5 hours. Tetrahydrofuran was removed by concentrating under reduced pressure, the aqueous phase was adjusted to pH 3 with dilute hydrochloric acid (1N), the solids were precipitated, filtered, and the solids were collected and dried to give 2-fluoro-5- (2-fluorophenoxy) benzoic acid (2.40 g, gray solids). Yield: 79.2 Percent of the total weight of the composition.
MS m/z (ESI): 251 [M + 1]；
1 H NMR (400 MHz, CDCl 3 ) δ 7.59-7.52 (m, 1H), 7.25-7.00 (m, 6H)。
Intermediate 2
2-fluoro-5- (3-fluorophenoxy) benzoic acid
The synthesis step of intermediate 2 refers to intermediate 1, wherein in the first step m-fluorophenol is substituted for o-fluorophenol.
MS m/z (ESI)：251 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 7.67-7.65 (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)。
Intermediate 3
5- (3-cyanophenoxy) -2-fluorobenzoic acid
First step
5- (3-Cyanophenoxy) -2-fluorobenzoic acid methyl ester
Methyl 2-fluoro-5-hydroxybenzoate (0.30 g,1.76 mmol), m-fluorobenzonitrile (0.64 g,5.28 mmol), potassium carbonate (0.48 g,3.52 mmol) andN,Ndimethylformamide (5 mL) and heating to 130 o C stirring for 2 hours. Water (20, mL) was added to the mixture. Extracted with ethyl acetate (15 mL ×3). The organic phases were combined and washed with saturated brine (10 mL ×2). The organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC (Waters Xbridge-C18, 4.6X1250 mm,10 μm, CH 3 CN/H 2 Purification of O ((0.1% TFA) 40% -70%) afforded the target product methyl 5- (3-cyanophenoxy) -2-fluorobenzoate (45 mg, white solid). Yield: 9%. MS M/z (ESI): 272 [ M+1 ]];
Second step
5- (3-cyanophenoxy) -2-fluorobenzoic acid
Methyl 5- (3-cyanophenoxy) -2-fluorobenzoate (45 mg,0.17 mmol), lithium hydroxide (25 mg,1.02 mmol), water (3 mL) and tetrahydrofuran (3 mL) were mixed and stirred at room temperature for 1 hour. The mixture was adjusted to pH 2 with 1N hydrochloric acid and extracted with dichloromethane (15 mL X3). The organic phases were combined and washed with saturated brine (15 mL ×2). The organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the desired product 5- (3-cyanophenoxy) -2-fluorobenzoic acid (35 mg, white solid) was obtained by desolventizing under reduced pressure. Yield: 82 Percent of the total weight of the composition. MS M/z (ESI) 258 [ M+1 ].
Intermediate 4
5- (2-cyanophenoxy) -2-fluorobenzoic acid
The synthesis step of intermediate 4 refers to intermediate 3, wherein the first step replaces m-fluorobenzonitrile with o-fluorobenzonitrile.
MS m/z (ESI): 258 [M + 1];
1 H NMR (400 MHz, DMSO-d 6 ) δ 13.52 (bs, 1H), 7.92 (dd, J = 7.6, 1.6 Hz, 1H), 7.73-7.66 (m, 1H), 7.56-7.40 (m, 3H), 7.36-7.28 (m, 1H), 7.04 (d, J = 8.4 Hz, 1H)。
Intermediate 5
5- (3-cyanobenzyl) -2-fluorobenzoic acid
First step
2-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzoic acid methyl ester
To a mixture of the compound methyl 5-bromo-2-fluorobenzoate (0.93 g,4.00 mmol), pinacol biborate (2.00 g,8.00 mmol), potassium acetate (1.20 g,12.00 mmol) and 1,1' -bis-diphenylphosphino ferrocene palladium dichloride (0.15 g,0.20 mmol) was added dimethyl sulfoxide (10 mL). The vacuum was pulled and replaced 3 times with nitrogen, heated to 80 ℃ under nitrogen blanket and stirred overnight. After cooling, ethyl acetate (60 mL) was added, and the mixture was washed with water (60 mL ×2) and saturated brine (60 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (0-10% ethyl acetate/petroleum ether) to give methyl 2-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzoate (0.50, g, colorless oil). Yield: 44.2 Percent of the total weight of the composition. MS M/z (ESI): 281 [ M+1 ];
second step
5- (3-Cyanobenzyl) -2-fluorobenzoic acid methyl ester
To a mixture of methyl 2-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzoate (0.50 g,1.80 mmol), 3-cyanobenzyl bromide (0.35 g,1.80 mmol), sodium carbonate (0.57 g,5.40 mmol) and 1,1' -bis-diphenylphosphino ferrocene palladium dichloride (0.13 g,0.18 mmol) was added a mixture of 1, 4-dioxane and water (v/v=5/1, 6 mL). Vacuum nitrogen was applied to the mixture for 3 times, heated to 100deg.C and stirred overnight. After cooling, ethyl acetate (50 mL) was added, and the mixture was 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 purified by silica gel column (0-10% ethyl acetate/petroleum ether) to give methyl 4- (3-cyanobenzyl) -2-fluorobenzoate (0.30. 0.30 g, colorless oil). Yield: 62.9 Percent of the total weight of the composition. MS M/z (ESI) 270 [ M+1 ];
third step
5- (3-cyanobenzyl) -2-fluorobenzoic acid
Methyl 5- (3-cyanobenzyl) -2-fluorobenzoate (0.30 g,0.11 mmol) was added to a mixture of aqueous sodium hydroxide (1N, 5 mmol, 5 mL) and tetrahydrofuran (5 mL) and stirred overnight at room temperature. Tetrahydrofuran was concentrated under reduced pressure, the aqueous phase was adjusted to pH 3 with dilute hydrochloric acid (1N), and extracted with ethyl acetate (10 mL X2). 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. The residue was purified by preparative liquid chromatography (Waters Xbridge-C18, 4.6X1250 mm,10 μm, CH 3 CN/H 2 O ((0.1% TFA) 30% -75%) was purified to give 5- (3-cyanobenzyl) -2-fluorobenzoic acid (15 mg, white solid). Yield: 5.3 Percent of the total weight of the composition.
MS m/z (ESI): 256 [M + 1]；
1 H NMR (400 MHz, CDCl 3 ) δ 7.86-7.80 (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)。
Intermediate 6
(S) -3-amino-7- ((3-hydroxyoxetan-3-yl) ethynyl) -5-methyl-2, 3-dihydrobenzo [ b ] [1,4] oxazepin-4 (5H) -ketoacid salt
First step
(S) - (7- ((3-hydroxyoxetan-3-yl) ethynyl) -5-methyl-4-carbonyl-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) carbamic acid tert-butyl ester
The compound is%S) - (7-bromo-5-methyl-4-carbonyl-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) carbamic acid tert-butyl ester (0.30 g,0.81 mmol) (synthetic reference:Journal of Medicinal Chemistry(2017) 60 (4), 1247-1261) and 3-ethynyloxetan-3-ol (0.24 g,2.43 mmol), cuprous iodide (30 mg,0.16 mmol), bis-triphenylphosphine palladium dichloride (60 mg,0.08 mmol),N,NDiisopropylethylamine (3 mL) and 1, 4-dioxane (6 mL) were mixed. Under nitrogen protection, the mixture is heated to 100 ℃ and stirred for 16 hours. The reaction solution was dried by filtration, and 10% mL water was added thereto. 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, the drying agent was removed by filtration, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate=3:1) to give the desired product [ (-) S) - (7- ((3-hydroxyoxetan-3-yl) ethynyl) -5-methyl-4-carbonyl-2, 3,4, 5-tetrahydrobenzo [b][1,4]Tert-butyl oxazepin-3-yl) carbamate (0.29, g, yellow solid). Yield: 92 Percent of the total weight of the composition.
MS m/z (ESI): 333 [M - 55];
1 H NMR (400 MHz, DMSO-d 6 ) δ 7.60 (d, J = 1.6 Hz, 1H), 7.36 (dd, J = 8.0, 1.6 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 6.65 (s, 1H), 4.77 (d, J = 6.4 Hz, 2H), 4.61 (d, J = 6.4 Hz, 2H), 4.42-4.26 (m, 4H), 3.29 (s, 3H), 1.35 (s, 9H)；
Second step
(S) -3-amino-7- ((3-hydroxyoxetan-3-yl) ethynyl) -5-methyl-2, 3-dihydrobenzo [b][1,4]Oxazepine-4 (5)H) -ketoformate salt
The compound is%S) - (7- ((3-hydroxyoxetan-3-yl) ethynyl) -5-methyl-4-carbonyl-2, 3,4, 5-tetrahydrobenzo [b][1,4]Tert-butyl oxazepin-3-yl) carbamate (0.29 g,0.74 mmol) and formic acid (5 mL) were mixed. Stirring was carried out at room temperature for 3 hours. To this mixture was added water (20 mL) for dilution, and the aqueous phase was washed with ethyl acetate (10 mL ×2). Obtaining the target product through freeze drying of water phaseS) -3-amino-7- ((3-hydroxyoxetan-3-yl) ethynyl) -5-methyl-2, 3-dihydrobenzo [b][1,4]Oxazepine-4 (5)H) -ketoformate (233 mg, crude). MS M/z (ESI): 289 [ M+1 ]]。
Intermediate 7
(S) -3-amino-7-bromo-5- (tridentate methyl) -2, 3-dihydrobenzo [b][1,4]Oxazepine-4 (5)H) -ketone hydrochloride
First step
(S) - (7-bromo-5- (tridentate methyl) -4-carbonyl-2, 3,4, 5-tetrahydrobenzo [ e.g.)b][1,4]Oxazepin-3-yl) carbamic acid tert-butyl ester
The compound is% S) - (7-bromo-4-carbonyl-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) carbamic acid tert-butyl ester (0.10 g,0.28 mmol) (synthetic reference:Journal of Medicinal Chemistry(2017) 60 (4), 1247-1261) and deuterated iodomethane (49 mg,0.33 mmol), cesium carbonate (0.13 g,0.39 mmol) andN,Ndimethylformamide (2 mL). Stir at room temperature for 3 hours. Pouring the mixture into 10 mL water, separating out solid, filtering, and drying the solid to obtain target product base(S) - (7-bromo-5- (tridentate methyl) -4-carbonyl-2, 3,4, 5-tetrahydrobenzo [ e.g.)b][1,4]Tert-butyl oxazepin-3-yl) carbamate (0.10, g, brown solid). Yield: 95 Percent of the total weight of the composition.
MS m/z (ESI): 374 & 376 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 7.30-7.27 (m, 2H), 7.00 (d, J = 8.4 Hz, 1H), 5.44 (d, J = 7.2 Hz, 1H), 4.67-4.57 (m, 1H), 4.54-4.50 (m, 1H), 4.16-4.11 (m, 1H), 1.38 (s, 9H)；
Second step
(S) -3-amino-7-bromo-5- (tridentate methyl) -2, 3-dihydrobenzo [b][1,4]Oxazepine-4 (5)H) -ketone hydrochloride
The compound is%S) - (7-bromo-5- (tridentate methyl) -4-carbonyl-2, 3,4, 5-tetrahydrobenzo [ e.g.)b][1,4]Tert-butyl oxazepin-3-yl) carbamate (50 mg,0.13 mmol) and hydrogen chloride (1, 4) -dioxane solution (4N, 8 mmol, 2 mL) were mixed. Stirring is carried out for 2 hours at normal temperature. The mixture is decompressed and spin-dried to obtain the target productS) -3-amino-7-bromo-5- (tridentate methyl) -2, 3-dihydrobenzo [b][1,4]Oxazepine-4 (5)H) Ketone hydrochloride (36.5 mg, crude). MS m/z (ESI): 274 & 276 [M + 1];
Intermediate 8
(S)-N- (7-bromo-5-methyl-4-keto-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -2-fluoro-5- (2-fluorophenoxy) benzamide
First step
(S) -3-amino-7-bromo-5-methyl-2, 3-dihydrobenzo [b][1,4]Oxazepine-4 (5)H) -ketone hydrochloride
The compound is%S) - (7-bromo-5-methyl-4-keto-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) carbamic acid tert-butyl ester (synthetic reference:Journal of Medicinal Chemistry(2017) 60 (4), 1247-1261) (1.00 g,2.70 mmol) of hydrogen chloride 1, 4-dioxySix-ring solution (4M, 40 mmol, 10 mL) was stirred at room temperature for 2 hours and desolventized under reduced pressure to give [ (]S) -3-amino-7-bromo-5-methyl-2, 3-dihydrobenzo [b][1,4]Oxazepine-4 (5)H) Ketone hydrochloride (0.83 g, yellow solid). Crude product. MS m/z (ESI) 271& 273 [M + 1]；
Second step
(S)-N- (7-bromo-5-methyl-4-keto-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -2-fluoro-5- (2-fluorophenoxy) benzamide
The compound 2-fluoro-5- (2-fluorophenoxy) benzoic acid (intermediate 1) (0.48 g,1.90 mmol),S) -3-amino-7-bromo-5-methyl-2, 3-dihydrobenzo [b][1,4]Oxazepine-4 (5)H) Ketone hydrochloride (0.50 g,1.6 mmol), triethylamine (0.50 g,4.80 mmol) and 2- (7-azabenzotriazol)N,N,N',N' -tetramethyl urea hexafluorophosphate (0.90 g,2.40 mmol) was dissolved in N,NDimethylformamide (5 mL). The reaction was carried out at room temperature overnight. The reaction solution was diluted with ethyl acetate (50 mL). Then washed with water (50 mL ×2) and saturated brine (50 mL), respectively. The organic phase is dried by anhydrous sodium sulfate, filtered, the filtrate is concentrated under reduced pressure, and the residue is separated and purified by a silica gel column (0-20% ethyl acetate/petroleum ether) to obtain the productS)-N- (7-bromo-5-methyl-4-keto-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -2-fluoro-5- (2-fluorophenoxy) benzamide (0.53 g, white solid). Yield: 64.6 Percent of the total weight of the composition.
MS m/z (ESI): 503 & 505 [M + 1]；
1 H NMR (400 MHz, CDCl 3 ) 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)。
The step of synthesis of intermediates 9-13 refers to intermediate 8.
Intermediate 9
(S)-N- (7-bromo-5-methyl-4-keto-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -2-fluoro-5-phenoxybenzamides
MS m/z (ESI): 485&487 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 7.81 (dd, J = 11.8, 6.4 Hz, 1H), 7.65-7.51 (m, 1H), 7.39-7.29 (m, 4H), 7.16-7.04 (m, 4H), 6.96 (d, J = 8.0 Hz, 2H), 5.12-5.02 (m, 1H), 4.82-4.74 (m, 1H), 4.31-4.20 (m, 1H), 3.43 (s, 3H)。
Intermediate 10
(S)-N- (8-bromo-5-methyl-4-keto-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -2-fluoro-5-phenoxybenzamides
MS m/z (ESI): 485&487 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 7.87-7.77 (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)。
Intermediate 11
(S)-N- (7-bromo-5-deuteromethyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -2-fluoro-5-phenoxybenzamides
MS m/z (ESI): 488 & 490 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 7.76-7.72 (m, 1H), 7.58-7.44 (m, 1H), 7.27 (d, J = 3.6 Hz, 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)。
Intermediate 12
(S)-N- (7-bromo-5)Deuterated methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -3-phenoxybenzamides
MS m/z (ESI): 506 &508 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 7.77-7.72 (m, 1H), 7.46 (d, J = 4.8 Hz, 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)。
Intermediate 13
(S)-N- (7-bromo-5-methyl-4-keto-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -3-phenoxybenzamides
MS m/z (ESI): 467 & 469 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 7.49-7.48 (d, J = 7.6 Hz, 1H), 7.44 (s, 1H), 7.41-7.33 (m, 5H), 7.18-7.13 (m, 3H), 7.09-7.07 (d, J = 9.2 Hz, 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)。
Preparation of the Compounds of examples
Example 1
(S)-2-fluoro-5- (2-fluorophenoxy) eneN- (7- ((3-hydroxyoxetan-3-yl) ethynyl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) benzamide
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The compound is%S) -3-amino-7- ((3-hydroxyoxetan-3-yl) ethynyl) -5-methyl-2, 3-dihydrobenzo [b][1,4]Oxazepine-4 (5)H) Ketoformate (0.23 g, crude) (inIntermediate 6) and 2-fluoro-5- (2-fluorophenoxy) benzoic acid (intermediate 1) (0.20 g,0.80 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.31 g,1.60 mmol), 1-hydroxybenzotriazole (0.22 g,1.60 mmol),N,NDiisopropylethylamine (0.33 g,3.20 mmol) andN,Ndimethylacetamide (9 mL) in a mixture. Stirring was carried out at room temperature for 5 hours. After the mixture was dried by spin-drying, it was quenched with 10 mL water and extracted with ethyl acetate (10 mL ×2). The organic phases were combined and washed with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the filtrate was concentrated to give a crude product. The crude product is purified by a silica gel preparation plate (petroleum ether/ethyl acetate=1:1) to obtain the target product @S) -2-fluoro-5- (2-fluorophenoxy) eneN- (7- ((3-hydroxyoxetan-3-yl) ethynyl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazepin-3-yl) benzamide (0.11, g, white solid). Yield: 29 Percent of the total weight of the composition.
MS m/z (ESI): 521 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 7.87-7.83 (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)。
The synthetic procedure of examples 2 to 6 is referred to in example 1.
Example 2
(S) -2-fluoro-5- (3-fluorophenoxy) eneN- (7- ((3-hydroxyoxetan-3-yl) ethynyl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) benzamide
MS m/z (ESI): 521 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 7.89-7.84 (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)。
Example 3
(S) -5- (3-cyanophenoxy) -2-fluoro-)N- (7- ((3-hydroxyoxetan-3-yl) ethynyl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) benzamide
MS m/z (ESI): 528 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 7.90 (dd, J = 12.0, 6.0 Hz, 1H), 7.63 (dd, J= 6.0, 2.8 Hz, 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)。
Example 4
(S) -5- (2-cyanophenoxy) -2-fluoro-)N- (7- ((3-hydroxyoxetan-3-yl) ethynyl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) benzamide
MS m/z (ESI): 528 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 7.89 (dd, J = 12.1, 6.2 Hz, 1H), 7.67 (d, J= 7.6 Hz, 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 = 8.5 Hz, 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)。
Example 5
(S) -5- (3-cyanobenzyl) -2-fluoro-)N- (7- ((3-hydroxyoxetan-3-yl) ethynyl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) benzamide
MS m/z (ESI): 526 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 7.88-7.77 (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)。
Example 6
(S)-N- (7- ((3-hydroxyoxetan-3-yl) ethynyl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -3-phenoxybenzamides
MS m/z (ESI): 485 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 7.41-7.38 (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)。
Example 7
(S) -2-fluoro-5- (2-fluorophenoxy) eneN- (5-methyl-4-keto-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) benzamide
The compound is%S)-N- (7-bromo-5-methyl-4-keto-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazepin-3-yl) -2-fluoro-5- (2-fluorophenoxy) benzamide (intermediate 8) (45 mg,0.08 mmol) and pinacol biborate (34 mg,0.13 mmol), potassium acetate (18 mg,0.16 mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (14 mg,0.016 mmol) and 1, 4-dioxane (3 mL) were mixed. Under the protection of nitrogenThen, the mixture was heated to 90℃and stirred for 16 hours. The reaction solution was dried by filtration, quenched with 10 mL water, and extracted with ethyl acetate (10 mL ×2). The combined organic phases were washed with saturated brine (10 mL). The organic phase is dried over anhydrous sodium sulfate, the drying agent is removed by filtration, the filtrate is dried by spin-drying to give the crude product, which is purified by preparative HPLC (Waters Xbridge-C18, 4.6X1250 mm,10 μm, CH 3 CN/H 2 O ((0.1% TFA) 40% -60%) purification to obtain debrominated target productS) -2-fluoro-5- (2-fluorophenoxy) eneN- (5-methyl-4-keto-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) benzamide (10 mg, white solid). Yield: 26 Percent of the total weight of the composition.
MS m/z (ESI): 425 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 7.88-7.83 (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)。
Example 8
(S) 2-fluoro-)N- (7- (3-hydroxy-3-methyl-1-butyn-1-yl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -5-phenoxybenzamides
Will be%S)-N- (7-bromo-5-methyl-4-keto-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazepin-3-yl) -2-fluoro-5-phenoxybenzamide (intermediate 9) (10 mg,0.02 mmol), 2-methylbut-3-yn-2-ol (42 mg,0.10 mmol) and anhydrous triethylamine (3 mL) were mixed. Cuprous iodide (4 mg,0.02 mmol) and ditriphenylphospholpalladium dichloride (2 mg,0.003 mmol) were added under nitrogen and replaced three times with nitrogen. Heating to 90 o Stirring at C for 16 hours. The residue was desolventized under reduced pressure, ammonia (8 mL) was added, and extracted with ethyl acetate (5 mL ×3). The combined organic phases were washed with saturated brine (5 mL ×2). The organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the solvent was removed under reduced pressure. Preparation of silica gel for residuePlate purification (petroleum ether/ethyl acetate=1:1) gives the desired product [ ]S) 2-fluoro-)N- (7- (3-hydroxy-3-methyl-1-butyn-1-yl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -5-phenoxybenzamide (6.2 mg, white solid). Yield: 64 Percent of the total weight of the composition.
MS m/z (ESI): 489 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 7.84 (dd, J = 12.0, 6.0 Hz, 1H), 7.66-7.55 (m, 1H), 7.42-7.20 (m, 4H), 7.18-7.06 (m, 4H), 6.97 (d, J = 8.0 Hz, 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)。
The synthetic procedure of examples 9 to 26 is referred to in example 8.
Example 9
(S) 2-fluoro-)N- (8- ((4-hydroxytetrahydro-2)H-pyran-4-yl) ethynyl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -5-phenoxybenzamides
MS m/z (ESI): 531 [M + 1];
1 H NMR (400 MHz, CD 3 OD) δ 7.42-7.33 (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)。
Example 10
(S) 2-fluoro-)N- (5-methyl-8- (3-morpholin-1-propyn-1-yl) -4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -5-phenoxybenzamides
MS m/z (ESI): 530 [M + 1];
1 H NMR (400 MHz, CD 3 OD) δ 7.40-7.33 (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)。
Example 11
(S)-N- (7- ((1-acetyl-3-methoxyazetidin-3-yl) ethynyl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -2-fluoro-5-phenoxybenzamides
MS m/z (ESI): 558 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) 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)。
Example 12
(S) -2-fluoro-5- (2-fluorophenoxy) eneN- (5-methyl-4-one-7- ((tetrahydro-2)H-pyran-4-yl) ethynyl) -2,3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) benzamide
MS m/z (ESI): 533 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) 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)。
Example 13
(S) 2-fluoro-)N- (7- ((3-hydroxyoxetan-3-yl) ethynyl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -5-phenoxybenzamides
MS m/z (ESI): 503 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 7.85 (dd, J = 12.0, 6.4 Hz, 1H), 7.65-7.53 (m, 1H), 7.37-7.24 (m, 4H), 7.21-7.06 (m, 4H), 6.96 (d, J = 7.8 Hz, 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)。
Example 14
(S) 2-fluoro-)N- (7- ((4-hydroxytetrahydro-2)H-pyran-4-yl) ethynyl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -5-phenoxybenzamides
MS m/z (ESI): 531 [M + 1];
1 H NMR (400 MHz, CD 3 OD) δ 7.39 (d, J = 1.6 Hz, 1H), 7.28-7.21 (m, 4H), 7.15-6.99 (m, 4H), 6.87 (d, J = 7.6 Hz, 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)。
Example 15
(S) -2-fluoro-5- (2-fluorophenoxy) eneN- (7- (3-hydroxy-3-methyl-1-butyn-1-yl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) benzamide
MS m/z (ESI)：507 [M + 1]
1 H NMR (400 MHz, CDCl 3 ) δ 7.88-7.83 (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)。
Example 16
(S) 2-fluoro-)N- (7- ((3-hydroxyoxetan-3-yl) ethynyl) -5- (tridentatomethyl) -4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -5-phenoxybenzamides
MS m/z (ESI): 506 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 7.86-7.82 (m, 1H), 7.60-7.58 (m, 1H), 7.35-7.31 (m, 4H), 7.18-7.08 (m, 4H), 6.96 (d, J = 7.6 Hz, 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)。
Example 17
(S) -2-fluoro-5-phenoxy-N- (5-methyl-4-one-7- ((tetrahydro-2)H-pyran-4-yl) ethynyl) -2,3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) benzamide
MS m/z (ESI): 515 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ7.85 (dd, J = 12.0, 6.4 Hz, 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, 7.2 Hz, 1H), 4.26 (dd, J = 10.8, 10.0 Hz, 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)。
Example 18
(S) -2-fluoro-5- (2-fluorophenoxy) eneN- (7- ((3-hydroxyoxetan-3-yl) ethynyl) -5- (tridentatomethyl) -4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazas(3-yl) benzamide
MS m/z (ESI): 524 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 7.87-7.83 (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)。
Example 19
(S) 2-fluoro-)N- (5-methyl-7- (3-morpholin-1-propyn-1-yl) -4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -5-phenoxybenzamide formate salt
MS m/z (ESI): 530 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 8.10 (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 = 8.7 Hz, 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)。
Example 20
(S) 2-fluoro-)N- (5-methyl-7- ((1-methyl-1)H-pyrazol-4-yl) ethynyl) -4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -5-phenoxybenzamides
MS m/z (ESI): 511 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 7.88-7.83 (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 = 8.0 Hz, 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)。
Example 21
(S) 2-fluoro-)N- (5-methyl-4-one-7- (pyridin-3-ylethynyl) -2,3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -5-phenoxybenzamides
MS m/z (ESI): 508 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 8.78 (d, J = 4.0 Hz, 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)。
Example 22
(S) -2-fluoro-5- (2-fluorophenoxy) eneN- (5-methyl-4-one-7- (pyridin-2-ylethynyl) -2,3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) benzamide
MS m/z (ESI)：526 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 8.64 (d, J = 4.0 Hz 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)。
Example 23
(S) 2-fluoro-)N- (5-methyl-4-one-7- (pyridin-2-ylethynyl) -2,3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -5-phenoxybenzamides
MS m/z (ESI): 508 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 8.65-8.63 (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 = 8.0 Hz, 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)。
Example 24
(S) 2-fluoro-)N- (5-methyl-7- ((1-methyl-1H-imidazol-4-yl) ethynyl) -4-keto-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazepin-3-yl) -5-phenoxybenzamides
MS m/z (ESI): 511 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 7.86 (dd, J = 12.0, 6.2 Hz, 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 = 7.8 Hz, 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)。
Example 25
(S) -2-fluoro-5- (2-fluorophenoxy) eneN- (5-methyl-7- ((1-methyl-1)H-1,2, 4-triazol-3-yl) ethynyl) -4-keto-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) benzamide
MS m/z (ESI)：530 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 8.06 (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)。
Example 26
(S) -2-fluoro-5- (2-fluorophenoxy) eneN- (5-methyl-7- ((1-methyl-1)H-pyrazol-4-yl) ethynyl) -4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) benzamide
MS m/z (ESI)：529 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 7.91-7.81 (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)。
Example 27
(S) 2-fluoro-)N- (7- (4-hydroxy-3, 3-dimethyl-1-butyn-1-yl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -5-phenoxybenzamides
First step
((2, 2-dimethyl-4- (trimethylsilyl) -3-butyn-1-yl) oxo) tert-butyldiphenylsilane
2, 2-dimethyl-4- (trimethylsilyl) -3-butyn-1-ol (0.52 g,3.00 mmol) (Synthesis reference)J. Am. Chem. Soc.(2020) 142 (47), 20048-20057) was dissolved in 15 mL dichloromethane, imidazole (0.41 g,6.00 mmol) was added followed by slow addition of t-butyldiphenylchlorosilane (1.07 g,3.90 mmol) in portions. After the addition was completed, the reaction was stirred at room temperature for 48 hours. After the reaction, 50 mL methylene chloride was added to dilute the mixture. The organic phase was separated, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Purification by column chromatography (petroleum ether) gave the target compound ((2, 2-dimethyl-4- (trimethylsilyl) -3-butyn-1-yl) oxo) tert-butyldiphenylsilane (1.01, g, none) Coloured liquid), yield 82.5%.
1 H NMR (400 MHz, CDCl 3 ) δ 7.71-7.69 (m, 4H), 7.43-7.36 (m, 6H), 3.49 (s, 2H), 1.23 (s, 6H), 1.07 (s, 9H), 0.14 (s, 9H)；
Second step
((2, 2-dimethyl-3-butyn-1-yl) oxo) tert-butyldiphenylsilane
(2, 2-dimethyl-4- (trimethylsilyl) -3-butyn-1-yl) oxo) tert-butyldiphenylsilane (1.01 g,2.45 mmol) was dissolved in a mixed solvent of methanol and dichloromethane (15 mL/15 mL), and potassium carbonate (0.51 g,3.67 mmol) was added. The reaction was stirred at room temperature for 4.8 hours. The reaction mixture was diluted with dichloromethane (25 mL). The organic phase was separated, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to give ((2, 2-dimethyl-3-butyn-1-yl) oxo) tert-butyldiphenylsilane (0.6 g, pale yellow oil), crude.
1 H NMR (400 MHz, CDCl 3 ) δ 7.71-7.69 (m, 4H), 7.44-7.36 (m, 6H), 3.51 (s, 2H), 2.08 (s, 1H), 1.26 (s, 6H), 1.07 (s, 9H)；
Third step
(S) - (7- (4- ((tert-butyldiphenylsilyl) oxo) -3, 3-dimethyl-1-butyn-1-yl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) carbamic acid tert-butyl ester
(2, 2-dimethyl-3-butyn-1-yl) oxo) tert-butyldiphenylsilane (0.15 g,0.41 mmol) and [. Sup.S) - (7-bromo-5-methyl-4-keto-2, 3,4, 5-tetrahydrobenzo [b][1,4]Dissolving tert-butyl oxazepin-3-yl carbamate (intermediate 9) (0.41 g,1.23 mmol) inN,NTo a mixed solvent of dimethylacetamide (5 mL) and triethylamine (5 mL) was added ditriphenylphosphine palladium dichloride (57 mg,0.08 mmol) and cuprous iodide (16 mg,0.08 mmol). Three times with nitrogen, heated to 85 ℃ and reacted for 5 hours under nitrogen protection. After completion of the reaction, the reaction mixture was cooled to room temperature, poured into water (50. 50 mL), and extracted with ethyl acetate (25. 25 mL ×3). The organic phase was washed with saturated brine (25 mL ×2), anhydrous sulfuric acid Drying sodium, filtering, concentrating filtrate, and purifying residue by column chromatography (petroleum ether: ethyl acetate=12:1) to obtain the final productS) - (7- (4- ((tert-butyldiphenylsilyl) oxo) -3, 3-dimethyl-1-butyn-1-yl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Tert-butyl oxazepin-3-yl) carbamate (0.25 g, pale yellow oil) was produced in 97% yield.
MS m/z (ESI)：627 [M + 1]；
1 H NMR (400 MHz, CDCl 3 ) δ 7.81-7.76 (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)；
Fourth step
(S) -3-amino-7- (4- ((tert-butyldiphenylsilyl) oxo) -3, 3-dimethyl-1-butyn-1-yl) -5-methyl-2, 3-dihydrobenzo [b][1,4]Oxazepine-4- (5)H) -ketotrifluoroacetate salt
Will be%S) - (7- (4- ((tert-butyldiphenylsilyl) oxo) -3, 3-dimethyl-1-butyn-1-yl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Tert-butyl oxazepin-3-yl) carbamate (50 mg,0.08 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (2 mL) was added. The reaction was carried out at room temperature for 1 hour. Adding dichloromethane (10 mL) into the concentrated residue, concentrating again to obtain the target compoundS) -3-amino-7- (4- ((tert-butyldiphenylsilyl) oxo) -3, 3-dimethyl-1-butyn-1-yl) -5-methyl-2, 3-dihydrobenzo [b][1,4]Oxazepine-4- (5)H) Ketone trifluoroacetate (50 mg, pale yellow oil), crude. MS m/z (ESI): 527 [ M+1 ] ]；
Fifth step
(S) 2-fluoro-)N- (7- (4- ((tert-butyldiphenylsilyl) oxo) -3, 3-dimethyl-1-butyn-1-yl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -5-phenoxybenzamides
2-fluoro-5-phenoxybenzoic acid (23 mg,0.096 mmol) was dissolved inN,NIn dimethylformamide (3 mL)1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (31 mg,0.16 mmol), 4-dimethylaminopyridine (22 mg,0.16 mmol) andN,Ndiisopropylethylamine (31 mg,0.24 mmol). Stirring at room temperature for 5 min, and addingS) -3-amino-7- (4- ((tert-butyldiphenylsilyl) oxo) -3, 3-dimethylbut-1-yn-1-yl) -5-methyl-2, 3-dihydrobenzo [b][1,4]Oxazepine-4 (5)H) -ketotrifluoroacetate salt (crude 50 mg, 0.08 mmol)N,NDimethylformamide (2 mL) solution, at room temperature for 5 hours. After completion of the reaction, the mixture was poured into water (30 mL), and extracted with ethyl acetate (25 mL ×3). The combined organic phases were washed with saturated brine (25 mL ×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by thin layer chromatography (petroleum ether: ethyl acetate=10:1) to give [ - ]S) 2-fluoro-)N- (7- (4- ((tert-butyldiphenylsilyl) oxo) -3, 3-dimethyl-1-butyn-1-yl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazepin-3-yl) -5-phenoxybenzamide (35 mg, pale yellow oil) was produced in 59% yield.
MS m/z (ESI)：741 [M + 1]；
1 H NMR (400 MHz, CDCl 3 ) δ 7.86-7.83 (m, 1H), 7.72 (d, J = 6.4 Hz, 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 = 8.0 Hz, 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)；
Sixth step
(S) 2-fluoro-)N- (7- (4-hydroxy-3, 3-dimethyl-1-butyn-1-yl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -5-phenoxybenzamides
Will be%S) 2-fluoro-)N- (7- (4-hydroxy-3, 3-dimethyl-1-butyn-1-yl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -5-phenoxybenzamide (35 mg,0.047 mmol) was dissolved in tetrahydrofuran (5 mL), tetrabutylammonium fluoride (0.5 mL, 1M tetrahydrofuran solution) was added and heated to 50deg.CThe reaction was carried out for 5 hours. After completion of the reaction, the mixture was cooled to room temperature, concentrated, and ethyl acetate (30 mL) was added to the residue to dissolve the mixture, which was then washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by thin layer chromatography (petroleum ether: ethyl acetate=1:1) to give the title compound [. Sup.S) 2-fluoro-)N- (7- (4-hydroxy-3, 3-dimethyl-1-butyn-1-yl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -5-phenoxybenzamide (21 mg, pale yellow solid) was produced in 89% yield.
MS m/z (ESI)：503 [M + 1]；
1 H NMR (400 MHz, CDCl 3 ) δ 7.88-7.83 (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)。
Example 28
(S) 2-fluoro-)N- (7- (3-hydroxypropyn-1-yl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [ e.g.) b][1,4]Oxazepin-3-yl) -5-phenoxybenzamides
First step
(S)-N- (7- (3- ((tert-butyldimethylsilyl) oxo) -1-propyn-1-yl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -2-fluoro-5-phenoxybenzamides
The compound is%S)-N- (7-bromo-5-methyl-4-keto-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -2-fluoro-5-phenoxybenzamide (intermediate 9) (20 mg,0.04 mmol) and tert-butyldimethyl (prop-2-yn-1-yloxy) silane (70 mg,0.41 mmol), cuprous iodide (7.6 mg,0.04 mmol), palladium acetate (1 mg,0.004 mmol), triphenylphosphine (20 mg,0.08 mmol) and triethylamine (3 mL) were mixed. Heated to 80℃under nitrogen and stirred for 4 hours. The reaction solution was filtered and dried by spin-drying, quenched with 10 mL water,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, the drying agent was removed by filtration, and the crude product was obtained by desolventizing under reduced pressure. Purifying the crude product with silica gel preparation plate (petroleum ether/ethyl acetate=10:1) to obtain the target product [ ]S)-N- (7- (3- ((tert-butyldimethylsilyl) oxo) -1-propyn-1-yl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazepin-3-yl) -2-fluoro-5-phenoxybenzamide (14 mg, white solid). Yield: 59 Percent of the total weight of the composition. MS M/z (ESI): 575 [ M+1 ]];
Second step
(S) 2-fluoro-)N- (7- (3-hydroxy-1-propyn-1-yl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -5-phenoxybenzamides
The compound is%S)-N- (7- (3- ((tert-butyldimethylsilyl) oxo) -1-propyn-1-yl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -2-fluoro-5-phenoxybenzamide (14 mg,0.024 mmol), tetrabutylammonium fluoride (7 mg,0.024 mmol), and tetrahydrofuran (2 mL) were mixed. Stirring was carried out at room temperature for 1 hour. The mixture was quenched with 1 mL ammonia, diluted with water (20 mL) and extracted with dichloromethane (10 mL ×2). The combined organic phases were washed with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the crude product was obtained by desolventizing under reduced pressure. Purifying the crude product with silica gel preparation plate (petroleum ether/ethyl acetate=5:1) to obtain the target product [ ]S) 2-fluoro-)N- (7- (3-hydroxy-1-propyn-1-yl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -5-phenoxybenzamide (10.1, mg, yellow solid). Yield: 90.9 Percent of the total weight of the composition.
MS m/z (ESI): 461 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 7.86-7.82 (m, 1H), 7.60-7.58 (m, 1H), 7.34-7.28 (m, 4H), 7.14-7.09 (m, 4H), 6.97 (d, J = 7.6 Hz, 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)；
Example 29
(S) 2-fluoro-)N- (7- ((3-fluorooxetan-3-yl) ethynyl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -5-phenoxybenzamides
The compound is%S) 2-fluoro-)N- (7- ((3-hydroxyoxetan-3-yl) ethynyl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -5-phenoxybenzamide (example 13) (25 mg,0.05 mmol) was dissolved in dichloromethane (3 mL), the reaction was evacuated and replaced 3 times with nitrogen. Cooled to-78 ℃ under nitrogen protection, diethylaminosulfur trifluoride (16 mg,0.10 mmol) was added dropwise, and stirred at-78 ℃ for 3 hours. After the reaction was completed, 10 mL saturated aqueous ammonium chloride solution and 10 mL methylene chloride were added. The organic phase was separated, washed with 10. 10 mL saturated brine, dried over anhydrous sodium sulfate, filtered and dried by spin-drying. Purifying the crude product by using a silica gel preparation plate (petroleum ether/ethyl acetate=3:1) to obtain a target product [ ]S) 2-fluoro-)N- (7- ((3-fluorooxetan-3-yl) ethynyl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -5-phenoxybenzamide (6 mg, yellow solid), yield: 24.1 Percent of the total weight of the composition.
MS m/z (ESI): 505 [M + 1]；
1 H NMR (400 MHz, CDCl 3 ) δ 7.86-7.81 (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)。
Example 30
(S)-N- (7- ((1-acetyl-3-hydroxyazetidin-3-yl) ethynyl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazepin-3-yl) -2-fluoro-5-phenoxybenzamides
First step
(S) -1-acetyl-3- ((3- (2-fluoro-5-phenoxybenzamido) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-7-yl) ethynyl) azetidin-3-yl acetate
Will be%S)-N- (7-bromo-5-methyl-4-keto-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -2-fluoro-5-phenoxybenzamide (intermediate 9) (58 mg,0.12 mmol), 1-acetyl-3-ethynylazetidin-3-ylacetate (70 mg,0.60 mmol), dissolved inN,NDimethylacetamide (2 mL) and triethylamine (1 mL) were added with ditolylphosphine palladium dichloride (14 mg,0.02 mmol) and copper iodide (6 mg,0.03 mmol). The reaction solution was bubbled with nitrogen for ten minutes. Heating to 85 under nitrogen o C stirring for 8 hours. The reaction mixture was dried by spinning, diluted with water (20 mL), and extracted with ethyl acetate (20 mL ×2). The combined organic phases were washed with saturated brine (20 mL ×2). Drying with anhydrous sodium sulfate, filtering, spin-drying the filtrate to obtain crude product, and purifying the crude product with silica gel preparation plate (petroleum ether/ethyl acetate=5:1) to obtain the final productS) -1-acetyl-3- ((3- (2-fluoro-5-phenoxybenzamido) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazepin-7-yl) ethynyl azetidin-3-yl acetate (18 mg, yellow solid) in 23.6% yield. MS M/z (ESI): 586 [ M+1 ]]；
Second step
(S)-N- (7- ((1-acetyl-3-hydroxyazetidin-3-yl) ethynyl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -2-fluoro-5-phenoxybenzamides
The compound is%S) -1-acetyl-3- ((3- (2-fluoro-5-phenoxybenzamido) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-7-yl) ethynyl azetidin-3-yl acetate (18 mg,0.03 mmol) was dissolved in methanol (2 mL). 2N aqueous lithium hydroxide (0.5. 0.5 mL) was added with stirring, and stirring was continued at room temperature for 2 hours after the completion of the dropwise addition. Diluting with water (10 mL), extracting with dichloromethane (10 mL), and collecting the organic phase with saturated saline (1)0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin-drying. The crude product was purified by plate preparation on silica gel (petroleum ether/ethyl acetate=2:1) to give [ - ]S)-N- (7- ((1-acetyl-3-hydroxyazetidin-3-yl) ethynyl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -2-fluoro-5-phenoxybenzamide (3.8, mg, yellow oil) was produced in 21.1% yield.
MS m/z (ESI): 544 [M + 1];
1 H NMR (400 MHz, CD 3 OD) δ 7.51 (d, J = 2.0 Hz, 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)。
The synthetic procedure of examples 31 to 42 is referred to in example 8.
Example 31
(S) -2-fluoro-5- (2-fluorophenoxy) eneN- (5-methyl-7- (oxazol-5-ylethynyl) -4-one-2, 3,4, 5-tetrahydrobenzo [ e.g.)b][1,4]Oxazepin-3-yl) benzamide
MS m/z (ESI)：516 [M + 1]；
1 H NMR (400 MHz, CDCl 3 ) δ 7.90 (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)。
Example 32
(S) -2-fluoro-5- (2-fluorophenoxy) eneN- (5-methyl-7- ((2-methyl-2)H-1,2, 3-triazol-4-yl) ethynyl) -4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) benzamide
MS m/z (ESI): 530 [M + 1]；
1 H NMR (400 MHz, CDCl 3 ) δ 7.88-7.83 (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)。
Example 33
(S)-N- (7- (3-amino-3-methyl-1-butyn-1-yl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -2-fluoro-5-phenoxybenzamides
MS m/z (ESI): 488 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 7.86-7.81 (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)。
Example 34
(S) 2-fluoro-)N- (5-methyl-7- (oxetan-3-ylethynyl) -4-one-2, 3,4, 5-tetrahydrobenzo [ e.g.)b][1,4]Oxazepin-3-yl) -5-phenoxybenzamides
MS m/z (ESI): 487 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 7.86-7.82 (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)。
Example 35
(S) -2-fluoro-5- (2-fluorophenoxy) eneN- (5-methyl-7- (oxetan-3-ylethynyl) -4-one-2, 3,4, 5-tetrahydrobenzo [ e.g.)b][1,4]Oxazepin-3-yl) benzamide
MS m/z (ESI): 505 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 7.87-7.82 (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)。
Example 36
(S) -2-fluoro-5- (2-fluorophenoxy) eneN- (5-methyl-7- (oxazol-4-ylethynyl) -4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) benzamide
MS m/z (ESI)：516 [M + 1]；
1 H NMR (400 MHz, CDCl 3 ) δ 7.95 (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)。
Example 37
(S) -2-fluoro-5- (2-fluorophenoxy) eneN- (5-methyl-7- ((1-methyl-1)H-1,2, 3-triazol-4-yl) ethynyl) -4-one-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazepin-3-yl) benzamide
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MS m/z (ESI): 530 [M + 1]；
1 H NMR (400 MHz, CDCl 3 ) δ 7.88-7.83 (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)。
Example 38
(S) -2-fluoro-5- (2-fluorophenoxy) eneN- (5-methyl-7- ((1-methyl-1)H-imidazol-4-yl) ethynyl) -4-one-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) benzamide
MS m/z (ESI): 529 [M + 1]；
1 H NMR (400 MHz, CDCl 3 ) δ 7.88-7.83 (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)。
Example 39
(S) 2-fluoro-)N- (5-methyl-7- ((1-methyl-1)H-1,2, 4-triazol-3-yl) ethynyl) -4-keto-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -5-phenoxybenzamides
MS m/z (ESI): 512 [M + 1]；
1 H NMR (400 MHz, CDCl 3 ) δ 8.07 (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)。
Example 40
(S) -2-fluoro-5- (2-fluorophenoxy) eneN- (5-deuteromethyl-7- ((1-methyl-1)H-1,2, 4-triazol-3-yl) ethynyl) -4-keto-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) benzamide
MS m/z (ESI)：533 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 8.09 (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)。
Example 41
(S) -2-fluoro-5- (2-fluorophenoxy) eneN- (5-methyl-7- ((1-ethyl-1)H-1,2, 4-triazol-3-yl) ethynyl) -4-keto-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) benzamide
MS m/z (ESI)：544 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 8.17 (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 = 7.2 Hz, 3H)。
Example 42
(S) -2-fluoro-5- (2-fluorophenoxy) eneN- (5-deuteromethyl-7- ((1-ethyl-1)H-1,2, 4-triazol-3-yl) ethynyl) -4-keto-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) benzamide
MS m/z (ESI)：547 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 8.09 (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 = 7.2 Hz, 3H)。
Example 43
(S) -2-fluoro-5- (2-fluorophenoxy) eneN- (7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Oxazas(3-yl) benzamide
First step
(S) -3-amino-7-bromo-5-methyl-2, 3-dihydrobenzo [b][1,4]Oxazepine-4 (5) H) -ketone hydrochloride
The compound is%S) - (7-bromo-5-methyl-4-keto-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) carbamic acid tert-butyl ester (1.00 g,2.70 mmol) (synthetic reference:J. Med.. Chem.(2017) 60 (4), 1247-1261) adding 1, 4-dioxane solution of hydrogen chloride (4M, 10 mL), stirring at room temperature for 2 hours, and removing solvent under reduced pressure to obtain the target productS) -3-amino-7-bromo-5-methyl-2, 3-dihydrobenzo [b][1,4]Oxazepine-4 (5)H) Ketone hydrochloride (0.83 g, yellow solid). Crude product. MS m/z (ESI) 271& 273 [M + 1]；
Second step
(S)-N- (7-bromo-5-methyl-4-keto-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -2-fluoro-5- (2-fluorophenoxy) benzamide
The compound 2-fluoro-5- (2-fluorophenoxy) benzoic acid (0.48 g,1.90 mmol)S) -3-amino-7-bromo-5-methyl-2, 3-dihydrobenzo [b][1,4]Oxazepine-4 (5)H) Ketone hydrochloride (0.50 g,1.60 mmol), triethylamine (0.50 g,4.80 mmol) and 2- (7-azabenzotriazol)N,N,N',N' -tetramethyl urea hexafluorophosphate (0.90 g,2.40 mmol) was dissolved inN,NDimethylformamide (5 mL), reacted overnight at room temperature. The reaction solution was diluted with ethyl acetate (50 mL), which was washed with water (50 mL ×2) and then with saturated brine (50 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Separating and purifying the residue by a silica gel column (0-20% ethyl acetate/petroleum ether) to obtain a target product S)-N- (7-bromo-5-methyl-4-keto-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -2-fluoro-5- (2-fluorophenoxy) benzamide (0.53 g, white solid). Yield: 64.6 Percent of the total weight of the composition.
MS m/z (ESI): 503 & 505 [M + 1]；
1 H NMR (400 MHz, CDCl 3 ) 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)；
Third step
(S) -2-fluoro-5- (2-fluorophenoxy) eneN- (5-methyl-4-one-7- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -2,3,4, 5-tetrahydrobenzo [ b ]][1,4]Oxazepin-3-yl) benzamide
The compound is%S)-N- (7-bromo-5-methyl-4-keto-2, 3,4, 5-tetrahydrobenzo [b][1,4]Oxazepin-3-yl) -2-fluoro-5- (2-fluorophenoxy) benzamide (0.41 g,0.81 mmol) and pinacol biborate (0.41 g,1.62 mmol) were dissolved in dioxane (10 mL). 1,1' -Didiphenylphosphino ferrocene Palladium dichloride (59 mg,0.08 mmol) and Potassium acetate (0.24 g,2.45 mmol) were added, and the reaction solution was bubbled with nitrogen for ten minutes under nitrogen protection of 100 o C heating and stirring for 4 hours. The reaction mixture was filtered and dried, and ethyl acetate (20 mL) and water (20 mL) were added thereto for extraction. The organic phase was washed with saturated brine (20. 20 mL), dried over anhydrous sodium sulfate, filtered and dried. Purifying the crude product by a silica gel column (ethyl acetate/petroleum ether=1:3) to obtain the target product [ ]S) -2-fluoro-5- (2-fluorophenoxy) eneN- (5-methyl-4-one-7- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -2,3,4, 5-tetrahydrobenzo [ b ] ][1,4]Oxazepin-3-yl) benzamide (0.36 g, white solid). Yield: 80 Percent of the total weight of the composition.
MS m/z (ESI): 551 [M + 1];
1 H NMR (400 MHz, CDCl 3 ) δ 7.91-7.81 (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)；
Fourth step
(S) -2-fluoro-5- (2-fluorophenoxy) eneN- (7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Oxazepin-3-yl) benzoatesAmides and their use
The compound is%S) -2-fluoro-5- (2-fluorophenoxy) eneN- (5-methyl-4-one-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2,3,4, 5-tetrahydrobenzo [ b ]][1,4]Oxazepin-3-yl) benzamide (55 mg,0.10 mmol) and 2- (5-bromopyridin-2-yl) -2-propanol (22 mg,0.10 mmol) were dissolved in dioxane (2 mL) and water (0.2 mL). 1,1' -Didiphenylphosphino 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, and the reaction solution was subjected to 100 minutes under nitrogen protection o C heating and stirring for 14 hours. The reaction solution was filtered and dried, ethyl acetate (5 mL) and water (5 mL) were added, and an organic phase was separated. The organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered and dried. The crude product was purified by plate preparation on silica gel (petroleum ether/ethyl acetate=1:1) to give the desired product [ (]S) -2-fluoro-5- (2-fluorophenoxy) eneN- (7- (6- (2-hydroxypropan-2-yl) pyridin-3-yl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [ b ] ][1,4]Oxazepin-3-yl) benzamide (26 mg, white solid). Yield: 46 Percent of the total weight of the composition.
MS m/z (ESI): 560 [M + 1]；
1 H NMR (400 MHz, CDCl 3 ) δ 8.70 (s, 1H), 7.90-7.84 (m, 2H), 7.55-7.53 (m, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.44-7.39 (m, 2H), 7.30 (d, J = 8.0 Hz, 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)。
Example 44
(S) -2-fluoro-5- (2-fluorophenoxy) eneN- (7- (6- (2-hydroxy-2-methylpropyl) pyridin-3-yl) -5-methyl-4-one-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Oxazepin-3-yl) benzamide
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Synthetic procedure for example 44 reference is made to example 43.
MS m/z (ESI)：574 [M + 1]；
1 H NMR (400 MHz, CDCl 3 ) δ 8.72 (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)。
Biological experiments
Example 1U-937 Programming necrosis of cells
The experimental method comprises the following steps: u-937 cells (available from Nanjing Corp. Bai Biotechnology Co., ltd., cat. No. CBP 60277) were cultured at 37℃with 5% CO 2 In 1640 medium, spread on 384 Kong Baiban, compound was serially diluted in 4-fold gradient, final initial concentration of 2000nM, 100ng/mL TNFα, Q-VD-Oph (10. Mu.M) and test drug incubated with cells for 48h, GSK2982772 was used as positive control, control wells were DMSO. Wherein viability of the cells was determined using Cell-TiterGlo kit (purchased from Promega corporation) based on an ATP viability assay. Cell viability assay values represent the percentage of cell viability of the drug-loaded wells compared to the control wells, where higher values represent stronger cell viability (drug action viability calculation = drug treated wells/control wells x 100%). EC (EC) 50 Values were defined as the concentration of compound that produced 50% of the maximum effect concentration, and the EC was calculated using a 4-parameter logistic equation to fit the drug action vitality data, XLfit 5.4 software analysis by IDBS company 50 。
Example 2 Programming necrosis of L-929 cells
The experimental method comprises the following steps: l-929 cells (available from Nanjing Corp. Bai Biotechnology Co., ltd., cat. No. CBP 60878) were cultured at 37℃with 5% CO 2 In MEM medium, spread on 384 Kong Baiban, compound was serially diluted in 4-fold gradients with final initial concentration of 10000nM, 40ng/mL TNFα, Q-VD-Oph (10. Mu.M) and test drug incubated with cells for 24h, GSK2982772 was used as positive control, control wells were DMSO. Wherein viability of the cells is determined using a Cell-TiterGlo kit based on an ATP viability assay. The viability assay value of the cells represents the percentage of cell viability of the drug-loaded wells compared to the control wells, wherein a higher value represents a stronger cell viability (drug action viability calculation = drugTreated wells/control wells × 100%). EC (EC) 50 Values were defined as the concentration of compound that produced 50% of the maximum effect concentration, and the EC was calculated using a 4-parameter logistic equation to fit the drug action vitality data, XLfit 5.4 software analysis by IDBS company 50 。
EXAMPLE 3 Programming necrosis of HT-29 cells
The experimental method comprises the following steps: HT-29 cells (available from Nanjing Corp. Bai Biotechnology Co., ltd., cat. No. CBP 30001L) were cultured at 37℃with 5% CO 2 In 1640 medium, cells were plated in 384 Kong Baiban, the compounds were serially diluted in 4-fold gradients, final initial concentrations of 500nM, 100ng/mL TNFα, Q-VD-Oph (10. Mu.M), SM-164 (1. Mu.M) and test drug were incubated with the cells for 48h, GSK2982772 was used as positive control, control wells were DMSO.
Wherein viability of the cells is determined using a Cell-TiterGlo kit based on an ATP viability assay. Cell viability assay values represent the percentage of cell viability of the drug-loaded wells compared to the control wells, where higher values represent stronger cell viability (drug action viability calculation = drug treated wells/control wells x 100%). EC (EC) 50 Values were defined as the concentration of compound that produced 50% of the maximum effect concentration, and the EC was calculated using a 4-parameter logistic equation to fit the drug action vitality data, XLfit 5.4 software analysis by IDBS company 50 。
EXAMPLE 4 programmed necrosis of I2.1 cells
I2.1 cells are Jurkat cells with FADD gene knockout, and are suitable for studying the programmed necrosis of cells under TNFa-induced conditions.
The experimental method comprises the following steps: i2.1 cells (purchased from ATCC, cat. No. CRL-2572) were cultured at 37℃with 5% CO 2 In 1640 medium, spread on 384 Kong Baiban, 4-fold gradient serial dilutions of the compound, final initial concentration of 500nM, 40ng/mL of TNFα and test drug incubated with the cells for 24 hours, with GSK2982772 as positive control and control wells with DMSO (D5879-500 ML, from Sigma).
Wherein viability of the cells was determined based on ATP content variation using the Cell-TiterGlo kit. The measured value of the cell viability represents the drug-adding hole The higher the number represents the stronger the cell viability (drug action viability calculation = drug treated wells/control wells x 100%). EC (EC) 50 Values were defined as the concentration of compound that produced 50% of the maximum effect concentration, and the EC was calculated using a 4-parameter logistic equation to fit the drug action vitality data, XLfit 5.4 software analysis by IDBS company 50 。
The results of the cell experiments are shown in Table 1
Table 1: cell Activity assay results of the Compounds of the examples
Numbering of compounds EC 50 (nM)　U-937 EC 50 (nM)　L-929 EC 50 (nM)　HT-29 EC 50 (nM)　I2.1
1 4.07 23.64 0.81 0.97
2 22 1.3
3 48 7.9
4 41 1.65
5 689 13
6 6.3 167 5.45
7 283 5.45
8 5.6 112 4.6
9 7.3 322.5 3.2
10 11 374
11 5.2 53 6.4
12 13 2.8
13 10.1 21.95 0.98
14 6.2 63 1.12
15 11 377 1.6
16 10 0.77
17 8.8 3.1
18 5.6 0.65 0.74
19 9.17 119 1.23
20 8.1 4
21 21 6.2
22 11 2
23 10 12
24 25 25 6.47
25 4.95 2.85 2.45
26 14.6 1.04 4.4
27 15.5 267.25 3.52
28 22 428
29 13 202 2.5
30 5.4 119 6.5
31 22 8.7
32 24 3.4 31
33 228 3.3 4.5
34 33 3.2 3.2
35 33 3.5 5
36 23 4.4 4.1
37 12 1.2 2.2
38 11 3.2 3.8
39 4.9 7.7 3.6
40 9.4 18 14
41 6.7 13 21
42 7.3 0.36 0.36
43 51.5 4.2 1.7
44 43.8 5.0 3.6
From the above experimental results, it is apparent that the compounds of the present invention are effective in inhibiting apoptosis and thus have potent inhibitory activity against RIPKl, and thus can be used for treating or preventing related diseases and dysfunctions mediated by RIPK1, such as rheumatoid arthritis, ulcerative colitis, psoriasis, alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, etc.
It will be apparent to those skilled in the art that the present disclosure is not limited to the illustrative embodiments described above, and that it may be embodied in other specific forms without departing from the essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, reference being made to the appended claims rather than to the foregoing embodiments, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Claims (10)

1. A compound of formula (I), or an optical isomer or a pharmaceutically acceptable salt thereof,
wherein:
R 1 selected from hydrogen, halogen, cyano,Or a 5-to 10-membered heteroaryl optionally substituted with C1-C10 hydroxyalkyl, wherein R a A 5-to 10-membered heteroaryl group selected from C1-C8 alkyl, containing one to three heteroatoms selected from nitrogen, oxygen and sulfur, a 3-to 10-membered heterocyclyl group containing one to two heteroatoms selected from nitrogen, oxygen and sulfur, and said alkyl, heteroaryl, heterocyclyl group being unsubstituted or substituted with one to three substituents, wherein each of said substituents is independently selected from hydroxy, amino, halogen, C1-C10 alkyl, C1-C10 alkoxy, (C1-C10) alkyl-C (O) -or 3-10 membered heterocyclyl; preferably, R 1 Selected from hydrogen, halogen,Or a 5-to 6-membered heteroaryl optionally substituted with C1-C6 hydroxyalkyl, wherein R a A 5-to 6-membered heteroaryl group containing one to three heteroatoms selected from nitrogen, oxygen and sulfur, a 3-to 8-membered heterocyclyl group containing one to two heteroatoms selected from nitrogen, oxygen and sulfur, wherein said alkyl, heteroaryl, heterocyclyl groups are unsubstituted or substituted with one to three substituents, wherein each of said substituents is independently selected from hydroxy, amino, halogen, C1-C8 alkyl, C1-C8 alkoxy, (C1-C8) alkyl-C (O) -; further preferably, R 1 Selected from hydrogen, & lt & gt>Or optionally by C1-C4 hydroxyalkylSubstituted 5-to 6-membered heteroaryl, wherein R a A 5-to 6-membered heteroaryl group containing one to three heteroatoms selected from nitrogen, oxygen and sulfur, a 4-to 6-membered heterocyclyl group containing one to two heteroatoms selected from nitrogen, oxygen and sulfur, wherein said alkyl, heteroaryl, heterocyclyl groups are unsubstituted or substituted with one to three substituents, wherein each of said substituents is independently selected from hydroxy, amino, halogen, C1-C6 alkyl, C1-C6 alkoxy, (C1-C6) alkyl-C (O) -; still further preferably, R 1 Selected from hydrogen, & lt & gt>Or pyridyl substituted by C1-C4 hydroxyalkyl, wherein R a A 5-to 6-membered heteroaryl group selected from C1-C4 alkyl, containing one to three heteroatoms selected from nitrogen and oxygen, a 4-to 6-membered heterocyclyl group containing one to two heteroatoms selected from nitrogen and oxygen, wherein said alkyl, heteroaryl, heterocyclyl groups are unsubstituted or substituted with one to three substituents, wherein each of said substituents is independently selected from hydroxy, amino, halogen, C1-C4 alkyl, C1-C4 alkoxy, (C1-C4) alkyl-C (O) -; most preferably, R 1 Selected from hydrogen,、/>Wherein R is a Selected from the group consisting of
R 2 Selected from hydrogen, C1-C8 alkyl or C1-C8 deuterated alkyl; preferably, R 2 Selected from hydrogen, C1-C6 alkyl or C1-C6 deuterated alkyl; further preferably, R 2 Selected from hydrogen, C1-C4 alkyl or C1-C4 deuterated alkyl; most preferably, R 2 Selected from hydrogen, methyl or deuterated methyl;
R 3 selected from hydrogen or halogen; preferably, R 3 Selected from hydrogen,Fluorine, chlorine or bromine; further preferably, R 3 Selected from hydrogen, fluorine, chlorine; most preferably, R 3 Selected from hydrogen or fluorine;
R 4 selected from hydrogen, halogen or cyano; preferably, R 4 Selected from hydrogen, fluorine, chlorine, bromine or cyano; further preferably, R 4 Selected from hydrogen, fluorine, chlorine or cyano; most preferably, R 4 Selected from hydrogen, fluorine or cyano;
l is selected from O, S, NH or C (R) b R c ) Wherein R is b And R is c Each independently selected from hydrogen, fluorine or C1-C4 alkyl, or R b 、R c Can form a 3-membered saturated carbocyclic ring together with the carbon atoms to which they are commonly attached; preferably, L is selected from O or C (R b R c ) Wherein R is b And R is c Each independently selected from hydrogen, fluorine or C1-C4 alkyl; most preferably, L is selected from O or-CH 2 -。
2. A compound of formula (I) according to claim 1, or an optical isomer or a pharmaceutically acceptable salt thereof,
wherein:
R 1 selected from hydrogen, halogen,Or a 5-to 6-membered heteroaryl optionally substituted with C1-C6 hydroxyalkyl, wherein R a A 5-to 6-membered heteroaryl group containing one to three heteroatoms selected from nitrogen, oxygen and sulfur, a 3-to 8-membered heterocyclyl group containing one to two heteroatoms selected from nitrogen, oxygen and sulfur, wherein said alkyl, heteroaryl, heterocyclyl groups are unsubstituted or substituted with one to three substituents, wherein each of said substituents is independently selected from hydroxy, amino, halogen, C1-C8 alkyl, C1-C8 alkoxy, (C1-C8) alkyl-C (O) -;
R 2 Selected from hydrogen, C1-C8 alkyl or C1-C8 deuterated alkyl;
R 3 selected from hydrogen, halogen;
R 4 selected from hydrogen, halogen or cyano;
l is selected from O or C (R) b R c ) Wherein R is b And R is c Each independently selected from hydrogen, fluorine or C1-C4 alkyl.
3. A compound of formula (I) according to claim 1, or an optical isomer or a pharmaceutically acceptable salt thereof, wherein:
R 1 selected from hydrogen,Or a 5-to 6-membered heteroaryl optionally substituted with C1-C4 hydroxyalkyl, wherein R a A 5-to 6-membered heteroaryl group containing one to three heteroatoms selected from nitrogen, oxygen and sulfur, a 4-to 6-membered heterocyclyl group containing one to two heteroatoms selected from nitrogen, oxygen and sulfur, wherein said alkyl, heteroaryl, heterocyclyl groups are unsubstituted or substituted with one to three substituents, wherein each of said substituents is independently selected from hydroxy, amino, halogen, C1-C6 alkyl, C1-C6 alkoxy, (C1-C6) alkyl-C (O) -;
R 2 selected from hydrogen, C1-C6 alkyl or C1-C6 deuterated alkyl;
R 3 selected from hydrogen, fluorine, chlorine, bromine;
R 4 selected from hydrogen, fluorine, chlorine, bromine or cyano;
l is selected from O or-CH 2 -。
4. A compound of formula (I) according to claim 1, or an optical isomer or a pharmaceutically acceptable salt thereof, wherein:
R 1 selected from hydrogen,Or pyridyl substituted by C1-C4 hydroxyalkyl, wherein R a Selected from C1-C4 alkyl, 5-to 6-membered heteroaryl containing one to three heteroatoms selected from nitrogen and oxygen, 4-to 6-membered heterocyclyl containing one to two heteroatoms selected from nitrogen and oxygen, wherein said alkyl, heteroaryl, heterocyclyl are unsubstituted or substituted with one to three substituents, wherein each of said substituents is independently selected from hydroxy, aminoHalogen, C1-C4 alkyl, C1-C4 alkoxy, (C1-C4) alkyl-C (O) -;
R 2 selected from hydrogen, C1-C4 alkyl or C1-C4 deuterated alkyl;
R 3 selected from hydrogen, fluorine or chlorine;
R 4 selected from hydrogen, fluorine, chlorine or cyano;
l is selected from O or-CH 2 -。
5. A compound of formula (I) according to claim 1, or an optical isomer or a pharmaceutically acceptable salt thereof, wherein:
R 1 selected from hydrogen,、/>Wherein R is a Selected from the group consisting of
R 2 Selected from hydrogen, methyl or deuterated methyl;
R 3 selected from hydrogen or fluorine;
R 4 selected from hydrogen, fluorine or cyano;
l is selected from O or-CH 2 -。
6. A compound selected from the group consisting of the following, or an optical isomer or pharmaceutically acceptable salt thereof:
。
7. a pharmaceutical composition comprising a compound according to any one of claims 1-6, or an optical isomer or pharmaceutically acceptable salt thereof, optionally one or more other RIPK1 inhibitors, and one or more pharmaceutically acceptable carriers.
8. Use of a compound according to any one of claims 1-6, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, and a composition of claim 7 in the manufacture of a medicament for the treatment or prevention of a RIPK1 mediated disease or condition.
9. The use of claim 8, wherein the RIPK 1-mediated disease or condition is selected from the group consisting of: rheumatoid arthritis, crohn's disease, ulcerative colitis, pancreatitis, psoriasis, atopic dermatitis, spondyloarthropathies, gout, systemic lupus erythematosus, nonalcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, systemic inflammatory response syndrome, cerebrovascular accident, huntington's disease, alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, asthma, multiple sclerosis, pancreatic cancer, bacterial infection, hematological malignancy, solid organ malignancy, and the like.
10. The use according to claim 8, wherein the RIPK1 mediated disease or condition is selected from rheumatoid arthritis, ulcerative colitis, psoriasis, alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis.
CN202210820411.XA 2022-07-13 2022-07-13 Heterocyclic compounds as RIPK1 inhibitors Pending CN117447460A (en)

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