CN114736197B - Imidazolidinone derivatives and their use - Google Patents

Imidazolidinone derivatives and their use Download PDF

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CN114736197B
CN114736197B CN202210659489.8A CN202210659489A CN114736197B CN 114736197 B CN114736197 B CN 114736197B CN 202210659489 A CN202210659489 A CN 202210659489A CN 114736197 B CN114736197 B CN 114736197B
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compound
disease
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CN114736197A (en
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何广卫
储昭兴
许勤龙
林高峰
李丰
莫佳佳
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Hefei Amvite Pharmaceutical Co ltd
Hefei Industrial Pharmaceutical Institute Co ltd
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Hefei Amvite Pharmaceutical Co ltd
Hefei Industrial Pharmaceutical Institute Co ltd
Nanjing Medical Industry Medical Technology Co ltd
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Abstract

The invention provides an imidazolinone derivative and application thereof, wherein the imidazolinone derivative is a compound with a structure shown in the following formula (I) or (II) or pharmaceutically acceptable salt and stereoisomer thereof. The compound has obvious RIP1 kinase inhibition activity and can be used for treatment and prevention of tumorRIP1 kinase-associated diseases, in particular various inflammatory diseases.
Figure 605267DEST_PATH_IMAGE001
Or

Description

Imidazolidinone derivatives and their use
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a class of imidazolinone derivatives for treating and/or preventing RIP1 kinase-related diseases. In addition, the invention also provides a preparation method of the imidazolidinone derivative and application of the imidazolidinone derivative in preparing a medicament for treating and/or preventing RIP1 kinase-related diseases.
Background
Receptor interacting protein 1(RIP1) kinase is a serine/threonine protein kinase that is involved in immune signaling. RIP1 kinase has been found to be closely related to the occurrence and development of various diseases in human body [ Najjar M, Saleh D, Zelic M, et al, RIPK1 and RIPK3 kinases Cell-Death Independent infection by Toll-Like Receptor 4[ J ]. Immunity, 2016, 45(1): 46-59 ]. Among the most closely related RIP1 are the apoptosis-related signal pathways. Meanwhile, in the TNF-induced inflammatory reaction, cell damage mediated by RIPK1-RIPK2 caused by a necrosis mechanism can cause death, the clinical relevance of RIP1 kinase for inhibiting sepsis is also found, and RIP1 becomes a potential therapeutic target of SIRS and sepsis. Meanwhile, RIP1 plays a key role in psoriasis, mainly associated with RIP1 being a TNF-mediated inflammatory driver. RIP1 kinase activity was originally thought to induce inflammation only by controlling programmed necrosis, but subsequent studies have shown that activated RIP1 kinase can also directly regulate the production and release of pro-inflammatory cytokines. In addition, RIP1 Kinase has been shown to be a key driver for inflammation downstream of other pathways (TNFR1, FasL, TRAIL, TLR3 and TLR4) [ christoffeffects Role DE, Li Y, Hitom J, et al a Novel Role for RIP1 Kinase in media TNF α Production [ J ]. Cell Death Dis, 2012, 3, e320 ], in addition to its effect downstream of TNFR 1. Thus, inhibition of RIP1 kinase may have broad therapeutic potential for a variety of inflammatory diseases, particularly psoriasis. The compound GSK2982772 is an RIP1 kinase inhibitor developed by glatiramer and is currently undergoing clinical trials for indications such as ulcerative colitis, rheumatoid arthritis and plaque psoriasis.
Figure 330456DEST_PATH_IMAGE001
Figure 982017DEST_PATH_IMAGE002
However, preliminary clinical test results show that GSK-2982772 is metabolized rapidly, has a very short half-life of only 2.3h in humans, and has side effects that lead to abnormal liver function. Therefore, there is still an urgent need for new drugs capable of treating and/or preventing RIP1 kinase-associated diseases in the clinic.
Disclosure of Invention
In order to achieve the above object, the present invention provides a compound having a structure represented by formula (I) or formula (II),
Figure 824071DEST_PATH_IMAGE003
or a pharmaceutically acceptable salt, stereoisomer thereof; wherein the content of the first and second substances,
X 1 selected from O, S, NH, N (C) 1 -C 6 Alkyl groups);
X 2 selected from NH, O, S;
R 1 、R 5 each independently selected from H, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkyl, hydroxy, halogen, cyano, NH 2 、C 1 -C 6 Alkyl C (O) NH-, C 1 -C 6 Alkoxy C (O) NH-, SO 2 -C 1 -C 6 Alkyl radical, wherein SO 2 -C 1 -C 6 Alkyl optionally substituted with cyano;
R 2 is selected from H or C 1 -C 6 An alkyl group;
R 3 、R 3 ' is H or R 3 、R 3 ' together form an oxo group;
R 4 、R 4 ' is H or R 4 、R 4 ' together form an oxo group; and R is 3 、R 3 ’、R 4 、R 4 ' not simultaneously H;
Figure 389920DEST_PATH_IMAGE004
represents a carbon-carbon single bond or a carbon-carbon double bond; when it represents a carbon-carbon double bond, R 3 Is H, R 3 ' absence, R 4 、R 4 ' together form an oxo group;
m and n are respectively integers selected from 0, 1,2, 3,4 or 5.
In another aspect, the present invention provides a pharmaceutical composition for treating and/or preventing a RIP1 kinase-associated disease, comprising a therapeutically effective amount of a compound having a structure represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer, or pharmaceutically acceptable carrier thereof.
In another aspect, the invention also provides application of the compound with the structure shown in formula (I) or pharmaceutically acceptable salts and stereoisomers thereof in preparation of medicines for treating and/or preventing diseases related to RIP1 kinase.
In another aspect, the present invention also provides a method for treating and/or preventing a RIP1 kinase-associated disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having a structure represented by formula (I) or a pharmaceutically acceptable salt, stereoisomer, or pharmaceutical composition comprising the same.
Advantageous effects
The inventor surprisingly finds that the compound provided by the invention can effectively inhibit the activity of RIP1 kinase, and compared with the existing known RIP1 kinase inhibitor, the compound provided by the invention has better RIP1 kinase inhibition activity.
The compounds of the present invention exhibit excellent anti-inflammatory activity. Compared to the prior known RIP1 kinase inhibitors, the compounds of the present invention show significantly better anti-inflammatory activity.
Compared with the prior known RIP1 kinase inhibitor, the compound has longer half-life period in human body and less side effect on liver.
Detailed Description
Definition of
As used in this specification, the following words and phrases are generally intended to have the meanings as set forth below, unless the context in which they are used indicates otherwise.
As used herein, the term "alkyl" refers to a monovalent group of a branched or unbranched saturated hydrocarbon chain having from 1 to 6 carbon atoms (more typically having from 1 to 4, or from 1 to 3 carbon atoms). The term is exemplified by groups such as methyl, ethyl, 1-propyl (n-propyl), 2-propyl (isopropyl), 1-butyl (n-butyl), 2-methyl-1-propyl (isobutyl), 2-butyl (sec-butyl), 2-methyl-2-propyl (tert-butyl), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, and the like, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl and the like.
As used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine.
As used herein, the term "alkoxy" refers to an "alkyl-O-" group, wherein alkyl is as defined herein. The term is exemplified by groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
As used herein, the term "haloalkyl" refers to an alkyl group wherein one or more hydrogen atoms are replaced with a halogen, wherein alkyl is as defined herein. The term is exemplified by the groups trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2, 2-trifluoroethyl, 1, -difluoroethyl, and the like.
As used herein, the term "therapeutically effective amount" refers to an amount sufficient to effect treatment, as defined below, when administered to a mammal in need of such treatment. The therapeutically effective amount will vary with the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration, and the like, which can be readily determined by one of ordinary skill in the art.
As used herein, the term "stereoisomer" refers to a compound having the same chemical composition and connectivity, but with atoms having different orientations in space that cannot be rotationally interchanged by a single bond. "stereoisomers" includes "diastereomers" and "enantiomers". "diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral characteristics, and reactivities. Mixtures of diastereomers can be separated under high resolution analytical procedures such as crystallization, electrophoresis, and chromatography. "enantiomers" refers to two stereoisomers that are non-overlapping mirror images of each other.
As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of a given compound, and which is not biologically or otherwise undesirable. Pharmaceutically acceptable salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloride, hydrobromide, sulfate, nitrate, phosphate, carbonate, bisulfate, hydrogenphosphate, dihydrogenphosphate, hydrogencarbonate, and the like. Salts derived from organic acids include formates, acetates, propionates, glycolates, pyruvates, oxalates, malates, malonates, succinates, maleates, fumarates, tartrates, citrates, benzoates, cinnamates, mandelates, methanesulfonates, ethanesulfonates, p-toluenesulfonates, salicylates, and the like.
As used herein, the term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith.
Compound (I)
In a particular embodiment, the compounds provided herein are of the structure shown in formula (I-A), (I-B), (I-C), (II-A), (II-B), or (II-C),
Figure 532188DEST_PATH_IMAGE005
Figure 400656DEST_PATH_IMAGE006
Figure 526743DEST_PATH_IMAGE007
Figure 538693DEST_PATH_IMAGE008
Figure 4309DEST_PATH_IMAGE009
Figure 466515DEST_PATH_IMAGE010
or a pharmaceutically acceptable salt, stereoisomer thereof; wherein the content of the first and second substances,
X 1 selected from O, S, NH, N (C) 1 -C 6 Alkyl groups);
X 2 selected from NH, O, S;
R 1 、R 5 each independently selected from H, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkyl, hydroxy, halogen, cyano, NH 2 、C 1 -C 6 Alkyl C (O) NH-, C 1 -C 6 Alkoxy C (O) NH-, SO 2 -C 1 -C 6 Alkyl radical, wherein SO 2 -C 1 -C 6 Alkyl is optionally substituted with cyano;
R 2 is selected from H or C 1 -C 6 An alkyl group;
R 3 、R 3 ' is H or R 3 、R 3 ' together form an oxo group;
R 4 、R 4 ' is H or R 4 、R 4 ' together form an oxo group; and R is 3 、R 3 ’、R 4 、R 4 ' not simultaneously H;
Figure 323307DEST_PATH_IMAGE011
represents a carbon-carbon single bond or a carbon-carbon double bond; when it represents a carbon-carbon double bond, R3 is H, R3 'is absent, R4, R4' together form an oxo group;
m and n are respectively integers selected from 0, 1,2, 3,4 or 5.
In a particular embodiment, X1 is selected from O, S, NH, NCH 3 (ii) a Preferably, X1 is selected from O, NH, NCH 3 。
In a particular embodiment, X2 is selected from NH, O, S; preferably, X2 is selected from NH or O.
In a specific embodiment, R1 is selected from H, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 1 -C 4 Haloalkyl, halogen, cyano, NH 2 、C 1 -C 4 Alkyl C (O) NH-, C 1 -C 4 Alkoxy C (O) NH-; preferably, R1 is selected from H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl, halogen, cyano, NH 2 、CH 3 C(O)NH-、CH 3 CH 2 C(O)NH-、CH 3 CH 2 CH 2 C(O)NH-、CH 3 OC(O)NH-、CH 3 CH 2 OC(O)NH-、CH 3 CH 2 CH 2 OC(O)NH-。
In a particular embodiment, R2 is selected from H or C 1 -C 4 An alkyl group; preferably, R2 is selected from H or methyl.
In a specific embodiment, R5 is selected from H, C1-C4 alkyl, C 1 -C 4 Alkoxy radical, C 1 -C 4 Haloalkyl, halogen, cyano, NH2, C 1 -C 4 Alkyl C (O) NH-, C 1 -C 4 Alkoxy C (O) NH-, SO2-C 1 -C 4 Alkyl radical, in which SO2-C 1 -C 4 Alkyl optionally substituted with cyano; preferably, R5 is selected from H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl, halogen, cyano, NH 2 、CH 3 C(O)NH-、CH 3 CH 2 C(O)NH-、CH 3 CH 2 CH 2 C(O)NH-、CH 3 OC(O)NH-、CH 3 CH 2 OC(O)NH-、CH 3 CH 2 CH 2 OC(O)NH-、SO 2 -CH 2 CH 2 CN; more preferably, R5 is selected from H, halogen, SO 2 -CH 2 CH 2 CN。
The invention also provides a compound with a structure shown in a formula (III),
Figure 529160DEST_PATH_IMAGE012
or a pharmaceutically acceptable salt, stereoisomer thereof; wherein, the first and the second end of the pipe are connected with each other,
X 1 selected from O, S, NH, N (C) 1 -C 6 Alkyl groups);
X 2 selected from NH, O, S;
l is selected from the group consisting of a bond, -CH 2 -、-C(O)-、-C(O)-CH 2 -;
R 1 、R 5 Each independently selected from H, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkyl, hydroxy, halogen, cyano, NH 2 、C 1 -C 6 Alkyl C (O) NH-, C 1 -C 6 Alkoxy C (O) NH-, SO 2 -C 1 -C 6 Alkyl radical, wherein SO 2 -C 1 -C 6 Alkyl optionally substituted with cyano;
R 2 is selected from H or C 1 -C 6 An alkyl group;
R 3 、R 3 ' is H or R 3 、R 3 ' together form an oxo group;
R 4 、R 4 ' is H or R 4 、R 4 ' together form an oxo group; and R is 3 、R 3 ’、R 4 、R 4 ' not simultaneously H;
R 6 selected from H or methyl;
m and n are respectively integers selected from 0, 1,2, 3,4 or 5.
In a particular embodiment, the compounds provided herein are compounds having a structure represented by formula (III-A), (III-B), or (III-C),
Figure 849283DEST_PATH_IMAGE013
or a pharmaceutically acceptable salt, stereoisomer thereof; wherein, X 1 、X 2 、L、R 1 、R 2 、R 5 、R 6 M, n are as defined in formula (III).
In a specific embodiment, X 1 Selected from O, S, NH, NCH 3 (ii) a Preferably, X 1 Selected from O, NH, NCH 3 。
In a specific embodiment, X 2 Selected from NH, O, S; preferably, X 2 Selected from NH or O.
In a particular embodiment, R 1 Selected from H, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 1 -C 4 Haloalkyl, halogen, cyano, NH 2 、C 1 -C 4 Alkyl C (O) NH-, C 1 -C 4 Alkoxy C (O) NH-; preferably, R 1 Selected from H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl, halogen, cyano, NH 2 、CH 3 C(O)NH-、CH 3 CH 2 C(O)NH-、CH 3 CH 2 CH 2 C(O)NH-、CH 3 OC(O)NH-、CH 3 CH 2 OC(O)NH-、CH 3 CH 2 CH 2 OC(O)NH-。
In a particular embodiment, R 2 Is selected from H or C 1 -C 4 An alkyl group; preferably, R 2 Selected from H or methyl.
In a particular embodiment, R 5 Selected from H, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 1 -C 4 Haloalkyl, halogen, cyano, NH 2 、C 1 -C 4 Alkyl C (O) NH-, C 1 -C 4 Alkoxy C (O) NH-, SO 2 -C 1 -C 4 Alkyl radical, wherein SO 2 -C 1 -C 4 Alkyl optionally substituted with cyano; preferably, R 5 Selected from H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy,Isopropoxy, trifluoromethyl, halogen, cyano, NH 2 、CH 3 C(O)NH-、CH 3 CH 2 C(O)NH-、CH 3 CH 2 CH 2 C(O)NH-、CH 3 OC(O)NH-、CH 3 CH 2 OC(O)NH-、CH 3 CH 2 CH 2 OC(O)NH-、SO 2 -CH 2 CH 2 CN; more preferably, R 5 Selected from H, halogen, SO 2 -CH 2 CH 2 CN。
In a particular embodiment, R 6 Selected from H, C 1 -C 4 An alkyl group; preferably, R 6 Selected from H and methyl.
In one embodiment, the compounds of the invention are selected from:
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or a pharmaceutically acceptable salt, stereoisomer thereof.
Pharmaceutical compositions and administration
The compounds provided according to the present invention, or pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, solvates thereof, are typically administered in the form of a pharmaceutical composition. The present invention therefore provides pharmaceutical compositions comprising a compound provided herein as an active ingredient together with one or more pharmaceutically acceptable carriers. The pharmaceutical compositions may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the art (e.g., Reminton's Pharmaceutical Sciences, machine Publishing Co., Philadelphia, PA 17) th Ed. (1985); and Modern pharmaceuticals, Marcel Dekker, Inc.3 rd Ed. （G.S.Banker & C.T.Rhodes，Eds.）。
The pharmaceutically acceptable carrier may be a solid or a liquid. Among the solid carriers may be one or more substances that act as excipients, diluents, sweeteners, solubilizers, lubricants, binders, tablet disintegrating agents, stabilizers, preservatives, or encapsulating material. The liquid carrier can be a solvent or a liquid dispersion medium. Suitable solid carriers include, but are not limited to, for example, cellulose, glucose, lactose, mannitol, magnesium stearate, magnesium carbonate, sodium saccharin, sucrose, dextrin, talc, starch, pectin, gelatin, tragacanth, acacia, sodium alginate, parabens, methylcellulose, sodium carboxymethylcellulose, low melting waxes, cocoa butter, and the like. Suitable liquid carriers include, but are not limited to, water, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol, and the like), vegetable oil (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycerol esters, agar, pyrogen-free water, isotonic saline, ringer's solution, and mixtures thereof.
The pharmaceutical composition according to the invention may be in any form suitable for the intended method of administration. For example, when used for oral use, they may be formulated as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs, solutions, sprays. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions. The pharmaceutical compositions of the present invention may be in the form of a sterile injectable preparation, for example a sterile injectable aqueous or oleaginous suspension. The pharmaceutical compositions of the invention may also be prepared in formulations suitable for intrapulmonary or intranasal administration, for example as aerosol or dry powder administration, as nasal drops or as nasal sprays. The pharmaceutical compositions of the present invention may also be formulated as suppositories suitable for rectal administration. The pharmaceutical composition of the present invention may also be prepared into transdermal preparations for topical administration, or eye drops suitable for ocular administration.
The pharmaceutical compositions of the present invention may be administered by intra-arterial injection, intravenous injection, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, single dose, or multiple dose.
The effective dose of the compounds of the invention will depend at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower dose) or against an active viral infection, the method of delivery and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. It is contemplated that about 0.0001 to about 100mg per kilogram body weight per day; typically from about 0.01 to about 10mg per kg body weight per day; more typically, from about 0.01 to about 5mg per kg body weight per day; most typically from about 0.05 to about 0.5mg per kilogram of body weight per day. For example, a candidate daily dose for an adult human of about 70kg body weight will be in the range of 1mg to 1000mg, preferably 5mg to 500mg, and may take the form of a single or multiple doses.
Indications of
The compounds of the present invention or pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, solvates thereof can be used for preventing and/or treating diseases related to RIP1 kinase. In particular, the compounds of the invention, or pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, solvates thereof, are useful for treating and/or preventing diseases associated with RIP1 kinase are inflammatory diseases, including inflammatory bowel disease (including crohn's disease and ulcerative colitis), psoriasis, allergic dermatitis, retinitis, macular degeneration, pancreatitis, arthritis (including rheumatoid arthritis, spondyloarthritis, osteoarthritis, systemic juvenile idiopathic arthritis, psoriatic arthritis), gout, systemic lupus erythematosus, sjogren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, liver diseases (including non-alcoholic steatohepatitis, autoimmune hepatitis, autoimmune liver and gall disease), cholangitis (e.g., primary sclerosing cholangitis), Nephritis, chronic kidney disease, acute liver failure, acute kidney injury, pruritus, celiac disease, autoimmune thrombocytopenic purpura, transplant rejection, solid organ ischemia-reperfusion injury, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial infarction, myocarditis, huntington's disease, alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, allergic diseases (including asthma and atopic dermatitis), multiple sclerosis, type I diabetes, wegener's granuloma, asthma, pulmonary sarcoidosis, behcet's disease, interleukin-1 converting enzyme-related fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-related periodic syndrome, and periodontitis.
In addition, the compounds of the present invention or pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, solvates thereof may also be used for the prevention and/or treatment of NEMO-deficiency syndrome, HOIL-1 deficiency syndrome, linear polyubiquitin chain complex deficiency syndrome, hematologic and solid organ malignancies, bacterial infections and viral infections (such as tuberculosis, influenza, etc.), lysosomal storage diseases (in particular gaucher disease, including ganglioside GM2 storage disease, α -mannosidosis, aspartylglucosaminuria, cholesteryl ester deposition disease, chronic hexosaminidase a deficiency, cystinosis, Danon disease, fabry disease, fucosidosis, galactosialidosis, GM1 ganglioside storage disease, mucopolysaccharidosis, pediatric free sialyl storage disease, neuro-induced diabetes, diabetes mellitus, or combinations thereof, Juvenile hexosaminidase a deficiency, krabbe's disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis, thioesterase deficiency, niemann-pick disease, neuronal ceroid lipofuscinosis, glycogen storage disease type ii, compact osteogenesis imperfecta, sandhoff's disease, sinderler disease, sialic acid storage disease, tay-sachs disease, and walman disease).
In addition, the compounds of the present invention or pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs and solvates thereof can also ameliorate damage or destruction of liver tissue resulting from acetaminophen overdose, or kidney tissue following kidney transplantation or administration of a nephrotoxic drug or substance (e.g., cisplatin).
Combination drug
Treatment of RIP1 kinase-associated diseases may be achieved by using the compounds of the invention as monotherapy, or in combination or concatameric therapy, e.g., in combination with other anti-inflammatory and/or anti-TNF agents, which may be administered in therapeutically effective amounts as known in the art. Thus, in addition to being used as a monotherapy, a compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate thereof, may also be used in combination with one or more additional active therapeutic agents. The compounds of the invention and the additional active therapeutic agents may be used either together or separately, and when used separately, may be administered simultaneously or sequentially in any order.
The additional therapeutic agents include corticosteroids (such as prednisone and budesonide), anti-TNF agents (including anti-TNF biologics (including etanercept adalimumab, infliximab, certolizumab, and golimumab)), 5-aminosalicylic and aminosalicylic acid agents, hydroxychloroquine, thiopurines (azathioprine, mercaptopurine), methotrexate, cyclophosphamide, cyclosporines, calcineurin inhibitors (cyclosporines, pimecrolimus, tacrolimus), mycophenolate mTOR inhibitors (temsirolimus, everolimus), JAK inhibitors (tofacitinib), SYK inhibitors (fosatinib), anti-IL 6 biologics (anti-IL 6. sup. 6R mAb), anti-IL 1 biologics (adalimumab linac canadensipricept secukinumab), anti-IL 12 and IL23 biologics (ekinumab), anti-IL 17 biologics (anti-IL 22 secukinumab), anti-IL 23 biologics (ekinumab), anti-IL 17 biologics (CD 22) Anti-integrin agents (natalizumab), vedolizumab anti-IFNa (sifamumab), anti-CD 20 biologicals (anti-CD 20mAbs (rituximab and ofatumumab)) or anti-CD 4 biologicals and other cytokine inhibitors or biologicals of T-cell or B-cell receptors or interleukins.
Treatment/prevention
In one embodiment, the present invention provides a method of treating and/or preventing a disease associated with RIP1 kinase, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, particularly a compound of any one of formulas (I) - (III) or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate, or pharmaceutical composition comprising the same. In additional embodiments, the present invention provides a method of inhibiting RIP1 kinase, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, particularly a compound of any one of formulas (I) - (III), or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate, or pharmaceutical composition comprising the same. In a further embodiment, the present invention provides a method of treating and/or preventing an inflammatory disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, in particular a compound of any one of formulae (I) - (III) or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate, or pharmaceutical composition comprising the same.
The invention provides the use of a compound of the invention, in particular a compound of any one of formulae (I) - (III), or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate thereof, as active therapeutic substance in the manufacture of a medicament for the treatment and/or prevention of a disease associated with RIP1 kinase. More particularly, the present invention provides the use of a compound of the invention, in particular a compound of any one of formulae (I) - (III) or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate thereof, as active therapeutic substance for the manufacture of a medicament for the treatment and/or prevention of an inflammatory disease. More particularly, the invention provides the use of a compound of the invention, in particular a compound of any one of formulae (I) to (III), in the manufacture of a medicament for the treatment and/or prophylaxis of inflammatory bowel disease (including crohn's disease and ulcerative colitis), psoriasis, allergic dermatitis, retinitis, macular degeneration, pancreatitis, arthritis (including rheumatoid arthritis, spondyloarthritis, osteoarthritis, systemic juvenile idiopathic arthritis, psoriatic arthritis), gout, systemic lupus erythematosus, sjogren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, liver disease (including non-alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease), cholangitis (e.g. primary sclerosing cholangitis), nephritis, chronic kidney disease, inflammatory bowel disease, allergic dermatitis, retinitis, macular degeneration, pancreatitis, arthritis (including rheumatoid arthritis, spondyloarthritis, osteoarthritis, systemic juvenile idiopathic arthritis, psoriatic arthritis), gout, systemic lupus erythematosus, sjogren's syndrome, Sjogren's syndrome, systemic sclerosis, chronic nephropathies, chronic myelopathies, and/or a combination of such as mentioned above, Acute liver failure, acute kidney injury, pruritus, celiac disease, autoimmune thrombocytopenic purpura, transplant rejection, solid organ ischemia reperfusion injury, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial infarction, myocarditis, huntington's disease, alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, allergic diseases (including asthma and atopic dermatitis), multiple sclerosis, type I diabetes, wegener's granuloma, asthma, pulmonary sarcoidosis, behcet's disease, interleukin-1 converting enzyme-related fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-related periodic syndrome, and periodontitis. More particularly, the present invention provides the use of a compound of the invention, in particular any one of the compounds of formulae (I) to (III), in the manufacture of a medicament for the treatment and/or prophylaxis of NEMO-deficient syndrome, HOIL-1 deficient syndrome, linear polyubiquitin chain complex deficient syndrome, hematological and solid organ malignancies, bacterial and viral infections (e.g., tuberculosis, influenza, etc.), lysosomal storage diseases (in particular gaucher disease, including ganglioside GM2 storage disease, α -mannosidosis, aspartylglucosaminuria, cholesteryl ester deposition disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, galactoside storage disease, sialyl storage disease, GM1 ganglioside storage disease, mucositis, neuronosis, and/or a, Pediatric free sialic acid storage disease, juvenile hexosaminidase a deficiency, krabbe's disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis, thioesterase deficiency, niemann-pick disease, neuronal ceroid lipofuscinosis, glycogen storage disease type ii, compact osteogenesis imperfecta, sandhoff disease, sinderler disease, sialyl storage disease, tay-sachs disease, and walman disease). More particularly, the present invention provides the use of a compound of the present invention, in particular a compound of any one of formulae (I) - (III), in the manufacture of a medicament for the treatment and/or prophylaxis of liver tissue damage or destruction resulting from acetaminophen overdose, or kidney tissue damage or destruction following kidney transplantation or administration of a nephrotoxic drug or substance, such as cisplatin.
The present invention will be further described with reference to the following specific examples, which are not intended to limit the scope of the present invention. Modifications or adaptations to those skilled in the art may be made in light of the teachings of the present invention without departing from the spirit and scope thereof.
Abbreviations used in the examples of the present invention have the following respective meanings.
(Boc) 2 O Carbonic anhydride di-tert-butyl ester
CDI N, N' -carbonyldiimidazole
DIAD Diisopropyl azodicarboxylate
DMAP 4-dimethylaminopyridine
DMF Dimethyl formamide
DMSO Dimethyl sulfoxide
DPPA Azoic acid diphenyl ester
EDC or EDCI 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
HATU 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate
HBTU O-benzotriazole-N,N,N’,N’-tetramethylurea-hexafluoro-phosphate
HOBt Hydroxybenzotriazoles
NaH Sodium hydride
NaHMDS Sodium hexamethyldisilazide
PPh 3 Triphenylphosphine and its use
TLC Thin layer chromatography
TFAA Trifluoroacetic anhydride
T 3 P 1-propylphosphoric acid cyclic anhydride
[ examples ] A method for producing a compound
Example 1 Compounds(R)-4- (2-fluorobenzyl) -N-((S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of oxazepine-3-yl) -2-oxoimidazoline-1-carboxamide
Step 1 Compound 3N- (tert-butoxycarbonyl) -O- (2-nitrophenyl) -L-synthesis of serine
Figure 759786DEST_PATH_IMAGE079
NaH (9.75 g, 244 mmol) was slowly added to 250 mL of DMF, and after cooling to 0 deg.C, a solution of Compound 1(27.00 g, 122 mmol) in 50 mL of DMF was added dropwise at controlled temperature with vigorous evolution of gas. When no gas was generated further, 2-nitrofluorobenzene (12.85 g, 122 mmol) was added dropwise. After dropping, the mixture was stirred at 0 ℃ for 5min and then transferred to room temperature for reaction overnight. TLC (dichloromethane: methanol =10:1) monitored the starting material for substantial reaction completion. The reaction solution was poured into a mixed solution of ethyl acetate (1000 mL) and 0.5mol/L aqueous HCl (1000 mL), liquid-separated, the aqueous phase was extracted with ethyl acetate (500 mL × 2), the organic phases were combined, washed with water (800 mL × 3), then washed with saturated brine (1000 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (dichloromethane: methanol = 200: 1 to 20:1) to give compound 3(18.50 g, yield 46.5%) as a yellow solid.
Step 2 Compound 4 namelyO- (2-aminophenyl) -N- (tert-butyloxycarbonyl) substituted benzeneL-synthesis of serine
Figure 769330DEST_PATH_IMAGE080
Compound 3(10.81 g, 33 mmol) was dissolved in 120 mL of methanol, 10% Pd/C (0.90 g) was added, and the reaction was allowed to proceed overnight at room temperature under a 15 Psi hydrogen atmosphere. The reaction was complete as detected by TLC (dichloromethane: methanol =10: 1). Filter through a pad of celite, wash the filter cake with methanol (30 mL), and concentrate the filtrate to give compound 4 as a brown solid (9.88 g, 98% yield).
Step 3 Synthesis of Compound 5, tert-butyl (S) - (4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,5] oxazepin-3-yl) carbamate
Figure 255544DEST_PATH_IMAGE081
Compound 4(9.88 g, 33 mmol) was dissolved in 100 mL DMSO, cooled to 10 deg.C, diisopropylethylamine (6.46 g, 50 mmol) and HATU (15.21 g, 40 mmol) were added and stirred for 5 min. The reaction was transferred to room temperature for 3h and checked by TLC (dichloromethane: methanol =10:1) for completion. The reaction was poured into 400 mL of water, and a solid precipitated, stirred for 10 min, filtered, and the filter cake was washed with water (50 mL. times.2). The filter cake was dried and purified by column chromatography (petroleum ether: ethyl acetate =20:1 to 5:1) to obtain compound 5(7.50 g, yield 80%) as a brown solid.
1 HNMR(400MHz, CDCl 3 )δ(ppm): 9.90(s, 1H),7.12-7.05(m, 5H), 4.33-4.24(m, 3H), 1.36(s, 9H)
Step 4 Compound 6 i(S)- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]] [1,5]Synthesis of tert-butyl oxazepine-3-yl) carbamate
Figure 59552DEST_PATH_IMAGE082
Compound 5(6.50 g, 23 mmol) was dissolved in 100 mL DMF, cesium carbonate (15.23 g, 46 mmol) was added, and methyl iodide (4.00g, 28 mmol) was added dropwise under nitrogen atmosphere and reacted at room temperature overnight. The reaction was essentially complete as detected by TLC (petroleum ether: ethyl acetate =5: 1). The reaction was poured into 500 mL of ice water, solid precipitated, stirred for 10 min, filtered and the filter cake washed with water (50 mL x 2). The filter cake was dried and purified by column chromatography (petroleum ether: ethyl acetate =50:1 to 5:1) to obtain compound 6(3.90 g, yield 49%) as a white solid.
Step 5 Compound 7 is(S)-3-amino-5-methyl-2, 3-dihydrobenzo [ b ]] [1,5]Oxazepin-4 (5)H) -synthesis of keto hydrochloride
Figure 585211DEST_PATH_IMAGE083
Compound 6(1.00 g, 3.4 mmol) was dissolved in 40 mL of dichloromethane, cooled to 0 deg.C, 10 min of HCl gas was bubbled in, and then reacted for 1 h. The reaction was complete as detected by TLC (petroleum ether: ethyl acetate =5: 1). Direct concentration afforded compound 7 as a pale yellow solid (0.92 g, 99% yield).
1 HNMR (400MHz, DMSO-d 6 ) δ (ppm): 8.63(s, 2H), 7.53-7.51(m, 1H), 7.36-7.25(m, 3H), 4.64-4.59(m, 1H), 4.49-4.43(m, 1H), 4.24-4.19(m, 1H), 3.35(s, 3H).
Step 6 Synthesis of Compound 8, 2- ((tert-Butoxycarbonyl) amino) -3- (2-fluorophenyl) propionic acid
Figure 8233DEST_PATH_IMAGE084
To a 250 mL single-necked flask were added 2-amino-3- (2-fluorophenyl) propionic acid (5.00 g, 30.0 mmol), 100 mL of a water/tetrahydrofuran mixed solution (water: tetrahydrofuran =1:1), and (Boc) in this order 2 O (10.00g, 45.0 mmol) and sodium bicarbonate (5.00 g, 60.0 mmol) were reacted at room temperature for 12h under nitrogen. After completion of the reaction was monitored by TLC (dichloromethane: methanol =50:1), tetrahydrofuran was distilled off under reduced pressure. Then using stoneOil ether (50 mL. times.3) and the aqueous phase collected. The aqueous phase was adjusted to pH 4 with saturated aqueous citric acid, extracted with ethyl acetate (100 mL. times.3), washed with saturated brine (50 mL. times.3), the organic phase was collected, dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to give compound 8(7.80 g, yield 97.0%) which was used as it was in the next step.
Step 7 Synthesis of Compound 9, tert-butyl (1- ((4-methoxybenzyl) amino) -1-oxo-3- (2-fluorophenyl) propan-2-yl) carbamate
Figure 975052DEST_PATH_IMAGE085
To a 250 mL one-neck flask was added compound 8(5.30 g,20 mmol), HATU (9.12 g, 24 mmol), and dichloromethane (70 mL), stirred at room temperature for 10 minutes, followed by diisopropylethylamine (5.16 g, 40 mmol), p-methoxybenzylamine (2.74 g,20 mmol), and stirred at room temperature under nitrogen atmosphere for 1 h. TLC detected the reaction was complete, 500 mL dichloromethane was added, washed with saturated brine (200 mL x3), the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated to 100 mL, a solid precipitated, filtered off with suction, and the filtered solid was dried in vacuo to give compound 9 as a white solid (6.70g, 89.5% yield).
Step 8 Compound 10, 2-amino-3- (2-fluorophenyl) -NSynthesis of (4-methoxybenzyl) propionamide
Figure 340175DEST_PATH_IMAGE086
To a 100 mL single-neck flask was added compound 9(6.70g, 17.4 mmol), 120 mL of a 3N ethyl acetate hydrochloride solution, stirred at room temperature under a nitrogen atmosphere for 1h, the reaction was concentrated to dryness, and then 50 mL of ethyl acetate and 50 mL of a saturated sodium bicarbonate solution were added and stirred for 0.5 h. The organic layer was washed with brine (3 mL × 3), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 10 as a white solid (4.30g, yield 89.0%).
Step 9 Compound 11, i.e., 3- (2-fluorophenyl) -N- (4-methoxybenzyl) propyl-1, 2-diamineSynthesis of (2)
Figure 608257DEST_PATH_IMAGE087
To a 100 mL one-neck flask was added compound 10(4.30g, 15.1 mmol), 1N borane in tetrahydrofuran (45.3 mL, 45.3 mmol), and stirred at 60 ℃ under nitrogen for 22 h. The reaction was checked by TLC for completion, 6N aqueous hydrochloric acid was added to the reaction mixture, stirred for 10 min, concentrated to remove THF, extracted twice with ethyl acetate (100 mL × 2), the aqueous phase was adjusted to pH = 7 with saturated sodium bicarbonate solution to precipitate a solid, filtered with suction, washed, and dried by 45 ℃ forced air to obtain compound 11 as a white solid (2.50 g, yield 61.4%).
Step 10 Synthesis of Compound 12, 4- (2-fluorobenzyl) -1- (4-methoxybenzyl) imidazolin-2-one
Figure 225183DEST_PATH_IMAGE088
To a 100 mL single-neck flask, Compound 11(2.50 g, 9.2 mmol), CDI (1.8 g, 11.1 mmol), and tetrahydrofuran (40 mL) were added, stirred at 25 ℃ for 2h under a nitrogen atmosphere, the reaction mixture was concentrated to remove the tetrahydrofuran, and 50 mL of ethyl acetate and 50 mL of water were added and the layers were separated. The organic layer was washed with saturated brine (30 mL × 3), and the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to flash chromatography (petroleum ether: ethyl acetate =1:1) to obtain compound 12(1.90 g, yield 70.0%) as a white solid.
Step 11 Synthesis of Compound 13, 4- (2-fluorobenzyl) Imidazolin-2-one
Figure 374405DEST_PATH_IMAGE089
To a 100 mL single-neck flask was added compound 12(1.9 g, 6.4 mmol), TFA (20mL), and stirred at 50 ℃ under nitrogen for 3 h. The reaction was complete by TLC, concentrated to remove trifluoroacetic acid, adjusted to pH7 with saturated sodium bicarbonate solution, extracted three times with ethyl acetate (40 mLx3), the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and isolated by flash chromatography (20 g, petroleum ether: ethyl acetate =1:1) to give compound 13 as a white solid (808 mg, yield 72.0%).
Step 12 Synthesis of Compound 14, 4- (2-fluorobenzyl) -2-oxoimidazoline-1-carbonyl chloride
Figure 661161DEST_PATH_IMAGE090
Compound 13(360 mg, 2.04 mmol) was dissolved in tetrahydrofuran (9 mL), and then activated carbon (50 mg) was added, and a tetrahydrofuran solution (1 mL) of trichloromethyl chloroformate (303 mg, 1.53 mmol) was added dropwise at ordinary temperature, followed by replacement with nitrogen gas 3 times and installation of a dry tube, and the temperature was raised to 66 ℃ for 12 hours. TLC (dichloromethane: methanol =20:1) detected the starting material was completely reacted. Cooled to room temperature, filtered through celite, and concentrated to give compound 14 as a pale yellow oil (630 mg, 60.0% yield).
Step 13 Compound (of example 1)R) -4- (2-fluorobenzyl) -N-((S) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of oxazepine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 833516DEST_PATH_IMAGE091
Compound 7(350 mg, 1.80 mmol) was dissolved in tetrahydrofuran (10mL), purged with nitrogen 3 times, then a solution of compound 14(1.0 g, 2.34 mmol) in tetrahydrofuran (10mL) was added, the mixture was heated to 45 ℃ for 30min and then transferred to room temperature for reaction for 3 h. TLC (dichloromethane: ethyl acetate =1:1) detected the starting material was completely reacted. Directly filtering, concentrating the filtrate, mixing, and performing column chromatography (SiO) 2 And petroleum ether, ethyl acetate =2:1) to obtain a crude product A and a crude product B. Crude a was isolated with thick prep plates (petroleum ether: ethyl acetate =1:1) to give the compound of example 1 as a white solid (100 mg, yield 13.3%), melting point:<100℃。
1 H NMR(400 MHz, CDCl 3 ) δ(ppm): 8.73(d, J=6.8Hz, 1H), 6.96-7.22(m, 8H), 4.79-4.87(m, 2H), 4.50-4.55(m, 1H), 4.16-4.22(m, 1H), 3.84-3.92(m, 2H), 3.52-3.56(m, 1H), 3.34(s, 3H), 2.86-2.90(m, 1H), 2.68-2.73(m, 1H);
13 C NMR(100 MHz, CDCl 3 ) δ169.25, 162.36, 159.92, 157.24, 152.63, 150.10, 136.49, 131.52, 131.48, 129.28, 129.20, 127.36, 125.54, 124.56, 124.52, 123.19, 123.13, 122.97, 112.83, 115.88, 115.64, 77.62, 50.07, 48.62, 47.34, 35.78, 35.38;
ESI C 21 H 21 FN 4 O 4 m/z: 412.90 (M + +H)。
example 2 Compounds(S)-4- (2-fluorobenzyl) -N-, ((S) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of oxazepine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 847608DEST_PATH_IMAGE092
Referring to the synthetic method of example 1, crude B was isolated using thick prep plates (petroleum ether: ethyl acetate =1:1) to give the compound of example 2 as a white solid (90 mg, yield 12.0%), melting point: 202.1-205.1 ℃.
1 H NMR(400 MHz, CDCl 3 ) δ(ppm): 8.72(d, J=7.2Hz, 1H), 6.97- 7.23(m, 8H), 4.76-4.84(m, 2H), 4.52-4.56(m, 1H), 4.17-4.23(m, 1H), 3.84-3.91(m, 2H), 3.53-3.57(m, 1H), 3.33(s, 3H), 2.87-2.91(m, 1H), 2.71-2.76(m, 1H);
13 C NMR (100 MHz, CDCl 3 ) δ 169.23, 162.38, 159.94, 157.25, 152.62, 150.11, 136.48, 131.47, 131.43, 129.25, 129.17, 127.35, 125.54, 124.52, 124.48, 123.21, 123.12, 122.97, 112.81, 115.86, 115.65, 77.64, 50.09, 48.59, 47.32, 35.74, 35.37;
ESI C 21 H 21 FN 4 O 4 m/z: 412.85 (M + +H)。
Example 3 Compound (A)R)-4- (4-fluorobenzyl) -N-((S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Oxazepin-3-yl) Synthesis of (E) -2-oxoimidazoline-1-carboxamide
Figure 789020DEST_PATH_IMAGE093
Referring to the synthesis method of example 1, substituting 2-amino-3- (2-fluorophenyl) propionic acid with 2-amino-3- (4-fluorophenyl) propionic acid, 98 mg of the compound of example 3 was obtained in 4.0% yield.
1 H NMR (400 MHz, CDCl 3 )δ ppm 8.82 (d, J=7.28 Hz, 1 H), 7.34-7.45 (m, 1 H), 7.16-7.25 (m, 7 H), 4.98 (s, 1 H), 4.87-4.94 (m, 1 H), 4.58-4.62 (m, 1 H), 4.24-4.29 (m, 1 H), 4.00-4.09 (m, 1 H), 3.90-3.98 (m, 1 H), 3.62-3.66 (m, 1 H), 3.42 (s, 3 H), 3.06 (dd, J=13.55, 5.27 Hz, 1 H), 2.86 (dd, J=13.55, 8.28 Hz, 1 H)；
13 C NMR (100 MHz, CDCl 3 ) δ: 169.24, 157.17, 152.64, 150.12, 136.51, 134.14, 133.85, 131.47, 130.04, 128.89, 127.31, 125.54, 123.19, 122.84, 77.62, 50.10, 48.05, 47.40, 39.93, 35.38；
ESI C 21 H 21 FN 4 O 4 m/z: 412.90 (M + +H)。
Example 4 Compound (I)S) -4- (4-fluorobenzyl) -N-((S) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of oxazepine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 479633DEST_PATH_IMAGE094
Referring to the synthesis procedure of example 1, 2-amino-3- (2-fluorophenyl) propionic acid was replaced with 2-amino-3- (4-fluorophenyl) propionic acid to give 120mg of the compound of example 4 in a yield of 4.7% and a melting point of 99.8 to 102.4 ℃.
1 H NMR (400 MHz, CDCl 3 )δ ppm 8.82 (d, J=7.30 Hz, 1 H), 7.35-7.43 (m, 1 H), 7.15-7.25 (m, 7 H), 4.98 (s, 1 H), 4.85-4.93 (m, 1 H), 4.60-4.65 (m, 1 H), 4.25-4.31 (m, 1 H), 4.00-4.09 (m, 1 H), 3.90-3.98 (m, 1 H), 3.62-3.66 (m, 1 H), 3.40 (s, 3 H), 3.06 (dd, J=13.60, 5.54 Hz, 1 H), 2.89 (dd, J=13.55, 8.28 Hz, 1 H)；
13 C NMR (100 MHz, CDCl 3 ) δ: 169.22, 157.22, 152.67, 150.12, 136.50, 134.20, 133.87, 131.41, 130.05, 128.86, 127.27, 125.55, 123.20, 122.82, 77.65, 50.12, 48.05, 47.38, 39.91, 35.36；
ESI C 21 H 21 FN 4 O 4 m/z: 412.90 (M + +H)。
Example 5 Compounds(R)-4- (2-chlorobenzyl) -N-((S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 873705DEST_PATH_IMAGE095
Referring to the synthesis procedure of example 1, 2-amino-3- (2-fluorophenyl) propionic acid was replaced with 2-amino-3- (2-chlorophenyl) propionic acid to give example 5 compound 160 mg as a white solid in 17.1% yield with melting point 203.6-204.2 ℃.
1 H NMR (400 MHz, CDCl 3 ) δ 8.80 (d, J = 7.2 Hz, 1H), 7.21 (d, J = 2.7 Hz, 2H), 7.19 (dd, J = 4.3, 1.2 Hz, 1H), 7.18 – 7.10 (m, 3H), 7.02 (ddd, J = 10.7, 5.8, 2.5 Hz, 2H), 5.08 (s, 1H), 4.89 (dt, J = 11.3, 7.4 Hz, 1H), 4.60 (dd, J = 9.7, 7.4 Hz, 1H), 4.31 – 4.21 (m, 1H), 3.99 – 3.83 (m, 2H), 3.59 (dd, J = 9.6, 4.4 Hz, 1H), 3.41 (s, 3H), 2.79 (ddd, J = 21.6, 13.8, 6.7 Hz, 2H);
13 C NMR (100 MHz, CDCl 3 ) δ 169.22, 157.24, 152.60, 150.11, 136.48, 131.74, 130.55, 127.36, 125.55, 123.19, 122.83, 116.00, 115.79, 77.61, 50.04, 47.30, 41.34, 35.37;
ESI C 21 H 21 ClN 4 O 4 m/z: 428.85 (M + +H)。
Example 6 Compounds(S)-4- (2-chlorobenzyl) -N-, ((S) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 894751DEST_PATH_IMAGE096
Referring to the synthesis method of example 1, substituting 2-amino-3- (2-fluorophenyl) propionic acid with 2-amino-3- (2-chlorophenyl) propionic acid, 98 mg of the compound of example 6 was obtained as a white solid, in a yield of 10.5%, melting point 175.4-176.3 ℃.
1 H NMR (400 MHz, CDCl 3 ) 8.79 (d, J = 7.2 Hz, 1H), 7.21 (dd, J = 4.6, 2.5 Hz, 3H), 7.20 – 7.17 (m, 1H), 7.17 – 7.12 (m, 2H), 7.03 (t, J = 8.7 Hz, 2H), 5.19 (s, 1H), 4.89 (dd, J = 18.6, 7.3 Hz, 1H), 4.72 – 4.56 (m, 1H), 4.34 – 4.21 (m, 1H), 3.93 (dd, J = 17.6, 8.0 Hz, 2H), 3.61 (dd, J = 9.3, 3.8 Hz, 1H), 3.42 (s, 3H), 2.87 (dd, J = 13.6, 5.2 Hz, 1H), 2.78 (dd, J = 13.7, 7.7 Hz, 1H);
13 C NMR(100 MHz, CDCl 3 ) δ 169.23, 157.32, 152.60 (s), 150.12, 136.47, 131.71, 130.59, 127.37, 125.54, 123.20, 122.81, 115.95, 115.73, 77.62, 50.10, 49.86, 47.24, 41.35, 35.37;
ESI C 21 H 21 ClN 4 O 4 m/z: 428.85 (M + +H)。
Example 7 Compounds(R)-4- (4-chlorobenzyl) -N-((S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 566034DEST_PATH_IMAGE097
Referring to the synthesis procedure of example 1, 2-amino-3- (2-fluorophenyl) propionic acid was replaced with 2-amino-3- (4-chlorophenyl) propionic acid to give the compound of example 7 as a white solid 77 mg, yield 12.3%, m.p. 144.1-146.0 ℃.
1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 8.65 (d, J=7.2Hz, 1H), 7.92 (s, 1H), 7.47-7.45 (m, 1H), 7.35-7.20 (m, 7H), 4.64-4.57 (m, 1H), 4.45-4.41 (m, 1H), 4.20-4.15 (m, 1H), 3.95-3.88 (m, 1H), 3.67-3.62 (m, 1H), 3.36-3.34 (m, 1H), 3.31 (s, 3H), 2.81-2.70 (m, 2H);
13 C NMR (100 MHz, CDCl 3 ) δ(ppm): 168.2, 156.3, 151.5, 149.0, 135.4, 133.5, 132.1, 129.4, 128.1, 126.3, 124.5, 122.2, 121.8, 76.6, 49.0, 48.8, 46.2, 40.4, 34.4;
ESI C 21 H 21 ClN 4 O 4 m/z: 428.80 (M + +H)。.
Example 8 Compounds(S)-4- (4-chlorobenzyl) -N- (C)(S) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Synthesis of azapine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 584806DEST_PATH_IMAGE098
Referring to the synthesis method of example 1, substituting 2-amino-3- (2-fluorophenyl) propionic acid with 2-amino-3- (4-chlorophenyl) propionic acid, 67 mg of the compound of example 8 was obtained as a white solid, in a yield of 10.7%, and a melting point of 210.5-212.2 ℃.
1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 8.59 (d, J=7.2Hz, 1H), 7.90 (s, 1H), 7.46-7.44 (m, 1H), 7.36-7.20 (m, 7H), 4.63-4.56 (m, 1H), 4.42-4.38 (m, 1H), 4.16-4.11 (m, 1H), 3.94-3.87 (m, 1H), 3.67-3.60 (m, 1H), 3.40-3.36 (m, 1H), 3.29 (s, 3H), 2.80-2.70 (m, 2H);
13 C NMR (100 MHz, CDCl 3 ) δ(ppm): 168.2, 156.3, 151.5, 149.0, 135.4, 133.4, 132.2, 129.4, 128.1, 126.4, 124.5, 122.2, 121.8, 76.6, 49.0, 48.7, 46.2, 40.4, 34.3;
ESI C 21 H 21 ClN 4 O 4 m/z: 428.80 (M + +H) 。
Example 9 Compounds(R)-4- (2, 6-fluorobenzyl) -N-((S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 590808DEST_PATH_IMAGE099
Referring to the synthesis procedure of example 1, substituting 2-amino-3- (2-fluorophenyl) propionic acid with 2-amino-3- (2, 6-difluorophenyl) propionic acid gave 160 mg of the compound of example 9 in 20.7% yield with a melting point of 129.9-133.6 ℃.
1 H NMR 400 MHz (DMSO-d 6 ) δ 8.67 (d, J=7.2Hz, 1H), 8.00 (s, 1 H), 7.45-7.47 (m, 1 H), 7.20-7.39 (m, 4 H), 7.05-7.11 (m, 2 H), 4.61-4.67 (m, 1 H), 4.42-4.46 (m, 1 H), 4.17-4.22 (m, 1 H), 3.89-3.90 (m, 1 H), 3.71-3.76 (m,1 H), 3.42-3.38 (m, 1 H), 3.31(s,3 H), 2.76-2.87 (m, 2 H);
13 C NMR 100 MHz (DMSO-d 6 ) δ169.11, 162.84, 162.75, 160.40, 160.31, 157.43, 152.66, 149.91, 136.76, 129.83, 129.73, 127.74, 126.15, 124.10, 122.82, 112.71, 112.51, 112.27, 112.15, 111.89, 77.45, 49.97, 47.92, 46.94, 35.19, 28.63；
ESI C 21 H 20 F 2 N 4 O 4 m/z: 430.90 (M + +H)。
Example 10 Compounds(S)-4- (2, 6-fluorobenzyl) -N-, ((S) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 822069DEST_PATH_IMAGE100
Referring to the synthesis of example 1, substituting 2-amino-3- (2-fluorophenyl) propionic acid with 2-amino-3- (2, 6-difluorophenyl) propionic acid provided example 10 compound 90mg, yield 11.6%, m.p. 193.8-194.8.
1 H NMR 400 MHz (DMSO-d 6 ) δ: 8.64 (d, J=7.2Hz, 1H), 8.00 (s, 1 H), 7.44-7.47 (m, 2 H), 7.21-7.40 (m, 4 H), 7.06-7.12 (m, 2 H), 4.60-4.67 (m, 1 H), 4.42-4.47 (m, 1 H), 4.17-4.22 (m, 1 H), 3.82-3.90 (m,1 H), 3.70-3.75 (m,1 H), 3.36-3.40 (m, 1 H), 3.30(s,3 H), 2.77-2.87 (m, 2 H);
13 C NMR 100 MHz (DMSO-d 6 ) δ 169.14, 162.83, 162.73, 160.45, 160.33, 157.42, 152.69, 149.95, 136.75, 129.82, 129.72, 127.75, 126.15, 124.09, 122.83, 112.54, 112.48, 112.41, 112.14, 111.89, 77.49, 49.89, 47.92, 46.95, 35.19, 28.68;
ESI C 21 H 20 F 2 N 4 O 4 m/z: 430.80 (M + +H)。
Example 11 Compounds(R)-4- (2, 4-fluorobenzyl) -N-((S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Synthesis of azapine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 49657DEST_PATH_IMAGE101
Referring to the synthesis method of example 1, 2-amino-3- (2-fluorophenyl) propionic acid was replaced with 2-amino-3- (2, 4-difluorophenyl) propionic acid to give example 11 compound 90mg as a white solid, yield 12.2%, melting point 103.5-106.5 ℃.
1 H NMR(400 MHz, CDCl 3 ) δ 8.77(d, J=7.2Hz, 1H), 7.11-7.21(m, 5H), 6.80-6.88(m, 2H), 5.03(s, 1H), 4.85-4.92(m, 1H), 4.57-4.62(m, 1H), 4.23-4.28(m, 1H), 3.90-3.94(m, 2H), 3.58-3.62(m, 1H), 3.41(s, 3H), 2.88-2.93(m, 1H), 2.73-2.79(m, 1H)；
13 C NMR(100 MHz, CDCl 3 ) δ168.21, 156.26, 151.56, 149.11, 135.48, 131.18, 131.12, 131.09, 131.03, 126.37, 124.55, 122.20, 121.83, 118.00, 117.96, 117.84, 117.80, 110.82, 110.79, 110.61, 110.58, 103.55, 103.29, 103.04, 76.61, 49.09, 47.58, 46.22, 34.37, 34.17；
ESI C 21 H 20 Cl 2 N 4 O 4 m/z: 462.80 (M + +H)。
Example 12 Compounds((S)-4- (2, 4-fluorobenzyl) -N-, ((S) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 363964DEST_PATH_IMAGE102
Referring to the synthesis method of example 1, 2-amino-3- (2-fluorophenyl) propionic acid was replaced with 2-amino-3- (2, 4-difluorophenyl) propionic acid to give 80 mg of the compound of example 12 as a white solid in a yield of 10.8% and a melting point of 96.9-99.9 ℃.
1 H NMR(400 MHz, CDCl 3 ) δ ppm 8.77(d, J=7.2Hz, 1H), 7.12-7.22(m, 5H), 6.81-6.88(m, 2H), 5.05(s, 1H), 4.84-4.90(m, 1H), 4.59-4.63(m, 1H), 4.24-4.29(m, 1H), 3.90-3.94(m, 2H), 3.57-3.63(m, 1H), 3.40(s, 3H), 2.89-2.93(m, 1H), 2.76-2.81(m, 1H)；
13 C NMR(100 MHz, CDCl 3 ) δ168.21, 156.30, 151.57, 149.12, 135.46, 131.13, 131.07, 131.04, 130.98, 126.38, 124.55, 122.21, 121.82, 118.01, 117.97, 117.85, 117.81, 110.77, 110.74, 110.57, 110.53, 103.54, 103.28, 103.02, 76.62, 49.10, 47.54, 46.21, 34.37, 34.14；
ESI C 21 H 20 Cl 2 N 4 O 4 m/z: 462.80 (M + +H)。
Example 13 Compounds(R)-4- (2, 6-chlorobenzyl) -N-((S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 732628DEST_PATH_IMAGE103
Referring to the synthesis procedure of example 1, 2-amino-3- (2-fluorophenyl) propionic acid was replaced with 2-amino-3- (2, 6-dichlorophenyl) propionic acid to give the compound of example 13 as a white solid 150 mg, yield 13.1%, m.p. 187.4-188.5 ℃.
1 H NMR(400 MHz, DMSO-d 6 ) δ(ppm): 8.71-8.73(m, 1H), 7.99(s, 1H), 7.46-7.48(m, 3H), 7.26-7.33(m, 3H), 7.21-7.23(m, 1H), 4.63-4.70(m, 1H), 4.44- 4.48 (m, 1H), 4.18-4.23(m, 1H), 3.95-4.01(m, 1H), 3.68-3.71(m, 1H), 3.49-3.53 (m, 1H), 3.32(s, 3H), 3.03-3.13(m, 2H);
13 C NMR(100 MHz, DMSO-d 6 ) δ 169.20, 157.53, 152.75, 149.99, 136.83, 135.70, 132.98, 130.10, 129.30, 127.81, 126.21, 124.18, 122.88, 77.52, 50.01, 47.44, 46.84, 36.90, 35.27;
ESI C 21 H 20 Cl 2 N 4 O 4 m/z: 462.80 (M + +H)。
Example 14 Compounds(S)-4- (2, 6-chlorobenzyl) -N-, ((S) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 642947DEST_PATH_IMAGE104
Referring to the synthesis of example 1, 2-amino-3- (2-fluorophenyl) propionic acid was replaced with 2-amino-3- (2, 6-dichlorophenyl) propionic acid to give 220 mg of the compound of example 14 as a white solid in 19.2%) with a melting point >250 ℃.
1 H NMR(400 MHz, DMSO-d 6 ) δ ppm 8.70-8.71(m, 1H), 7.99(s, 1H), 7.45-7.49(m, 3H), 7.22-7.34(m, 4H), 4.63-4.69(m, 1H), 4.45-4.50(m, 1H), 4.22-4.27(m, 1H), 3.95-4.02(m, 1H), 3.68-3.73(m, 1H), 3.50-3.53 (m, 1H), 3.31(s, 3H), 3.05-3.14(m, 2H)；
13 C NMR(100 MHz, DMSO-d 6 ) δ 169.69, 156.98, 152.36, 149.43, 136.29, 135.15, 132.48, 129.55, 128.75, 127.26, 125.67, 123.61, 122.37, 76.94, 49.44, 46.88, 46.37, 36.38, 34.71；
ESI C 21 H 20 Cl 2 N 4 O 4 m/z: 462.75 (M + +H)。
Example 15 Compounds(R)-4- (2, 4-chlorobenzyl) -N-((S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 475774DEST_PATH_IMAGE105
Referring to the synthesis procedure of example 1, 2-amino-3- (2-fluorophenyl) propionic acid was replaced with 2-amino-3- (2, 4-dichlorophenyl) propionic acid to give 81 mg of the compound of example 15 as a white solid, yield 13.7%, m.p. 102.4-103.3 ℃.
1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.81 (d, J=6.8Hz, 1H), 7.43 (d, J=1.6Hz, 1H), 7.26-7.15 (m, 6H), 5.03 (br, 1H), 4.95-4.88 (m, 1H), 4.64-4.60 (m, 1H), 4.31-4.25 (m, 1H), 4.03-3.93 (m, 2H), 3.66-3.62 (m, 1H), 3.43 (s, 3H), 3.05-3.01 (m, 1H), 2.89-2.84 (m, 1H);
13 C NMR (100 MHz, CDCl 3 ) δ(ppm): 168.2, 156.3, 151.5, 149.0, 135.4, 133.8, 133.0, 131.4, 131.2, 128.8, 126.6, 126.3, 124.5, 122.1, 121.8, 76.5, 49.0, 47.0, 46.2, 38.2, 34.4;
ESI C 21 H 20 Cl 2 N 4 O 4 m/z: 462.80 (M + +H)。
Example 16 Compounds(S)-4- (2, 4-chlorobenzyl) -N-, ((S) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 570768DEST_PATH_IMAGE106
Referring to the synthesis procedure of example 1, 2-amino-3- (2-fluorophenyl) propionic acid was replaced with 2-amino-3- (2, 4-dichlorophenyl) propionic acid to give 82 mg of the compound of example 16 as a white solid in 13.8% yield with melting point 151.7-152.6 ℃.
1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.82 (d, J=7.2Hz, 1H), 7.43 (d, J=2.0Hz, 1H), 7.26-7.16 (m, 6H), 5.02 (br, 1H), 4.93-4.86 (m, 1H), 4.66-4.62 (m, 1H), 4.32-4.27 (m, 1H), 4.06-3.93 (m, 2H), 3.66-3.62 (m, 1H), 3.42 (s, 3H), 3.06-3.02 (m, 1H), 2.92-2.87 (m, 1H);
13 C NMR (100 MHz, CDCl 3 ) δ(ppm): 168.1, 156.2, 151.5, 149.0, 135.4, 133.8, 133.0, 131.4, 131.1, 128.8, 126.5, 126.3, 124.5, 122.2, 121.8, 76.6, 49.0, 46.9, 46.2, 38.3, 34.3;
ESI C 21 H 20 Cl 2 N 4 O 4 m/z: 462.75 (M + +H)。
Example 17 Compounds(R)-4- ((2-cyanoethyl) sulfonyl) benzyl-N-((S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 800630DEST_PATH_IMAGE107
Referring to the synthesis of example 1, 2-amino-3- (2-fluorophenyl) propionic acid was replaced with 2-amino-3- (4- ((2-cyanoethyl) sulfonyl) phenyl) propionic acid to give 90mg of the compound of example 17 in 17.6% yield and mp 130.5-135.6 ℃.
1 H NMR 400 MHz (DMSO-d 6 ) δ 8.74 (d, J=7.2Hz, 1H), 7.90 (d, J=8.0Hz, 2H), 7.44 (d, J=8.4Hz, 2H), 7.14-7.23 (m, 4H),5.46 (s, 1 H), 4.84-4.90 (m, 1 H), 4.56-4.60 (m, 1 H), 4.22-4.27 (m, 1 H), 3.94-3.99 (m,2 H), 3.59-3.65 (m, 1 H), 3.35-3.44(m,5 H), 3.01-3.05 (m,1 H), 2.79-3.05 (m,3 H);
13 C NMR 100 MHz (DMSO-d 6 ) δ169.24, 157.22, 152.50, 150.07, 144.01, 136.40, 136.19, 130.74, 129.12, 127.44, 125.60, 123.26, 122.81, 115.72, 77.58, 51.26, 50.08, 49.56, 47.33, 42.07, 35.44, 12.34;
ESI C 21 H 20 Cl 2 N 4 O 4 m/z: 511.85 (M + +H)。
Example 18 Compounds(S)-4- ((2-cyanoethyl) sulfonyl) benzyl-N-, ((S) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 373694DEST_PATH_IMAGE108
Referring to the synthesis of example 1, 2-amino-3- (2-fluorophenyl) propionic acid was replaced with 2-amino-3- (4- ((2-cyanoethyl) sulfonyl) phenyl) propionic acid to give the compound of example 18 in 85 mg, 16.6% yield, mp 121.3-131.6 ℃.
1 H NMR 400 MHz (DMSO-d 6 ) δ (ppm): 8.72 (d, J=7.2Hz, 1H), 7.84 (d, J=8.4Hz, 2H), 7.39 (d, J=8.4Hz, 2H), 7.09-7.16 (m, 4H), 5.27 (s, 1 H), 4.77-4.83 (m, 1 H), 4.52-4.56 (m, 1 H), 4.17-4.22 (m, 1 H), 3.83-3.93 (m,2 H), 3.51-3.58 (m, 1 H), 3.29-3.35(m,5 H), 2.95-3.00 (m,1 H), 2.73-2.85 (m,3 H) ;
13 C NMR 100 MHz (DMSO-d 6 ) δ169.26, 157.24, 152.55, 150.09, 144.15, 136.39, 136.15, 130.73, 129.12, 127.45, 125.60, 123.23, 122.82, 115.69, 77.62, 51.28, 50.11, 49.58, 47.38, 42.19, 35.43, 12.35;
ESI-Mass for C 21 H 20 Cl 2 N 4 O 4 m/z: 511.85 (M + +H)。
Example 19 Compound (R) -4-benzyl-N-((R) 7- (trifluoromethyl) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of thiazepine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 388924DEST_PATH_IMAGE109
Reference example 1 Synthesis method substituting 2-nitrofluorobenzene with 1-fluoro-2-nitro-4- (trifluoromethyl) benzene and 2-amino-3- (2-fluorophenyl) propionic acid with 1-fluoro-2-nitro-4- (trifluoromethyl) benzene(R)-2-amino-3-phenylpropionic acid, prepared fromN- (tert-butyloxycarbonyl) -LReplacement of serine byN- (tert-butyloxycarbonyl) substituted benzeneLCysteine to give 125 mg of the compound of example 19 as an off-white solid, 34.5% yield, melting point: 201.3-206.2 ℃.
1 H NMR (400 MHz, CDCl 3 ): δ ppm 8.94 (d, J=7.6 Hz, 1 H), 7.80 (d, J=8.0 Hz, 1 H), 7.49-7.53 (m, 2 H), 7.29-7.37 (m, 3 H), 7.17-7.19 (m, 2 H), 5.03 (s, 1 H), 4.61-4.68 (m, 1 H), 3.89-3.98 (m, 2 H), 3.74-3.78 (m, 1 H), 3.59-3.67 (m, 1 H), 3.47 (s, 3 H), 3.02-3.08 (m, 1 H), 2.87-2.92 (m, 1 H), 2.74-2.79 (m, 1H)；
13 C NMR (100 MHz, CDCl 3 ): δ ppm 170.23, 157.16, 152.27, 146.90, 136.2jm6, 136.03, 132.83, 131.97, 129.03, 129.01, 127.27, 123.95, 123.91, 123.88, 121.26, 121.23, 50.26, 50.02, 47.37, 42.22, 38.56, 36.55;
ESI C 22 H 21 F 3 N 4 O 3 Sm/z: 479.14 (M + +H)。
Example 20 Compound (A)S) -4-benzyl-N-((R) -7- (trifluoromethyl) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of thiazepine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 654820DEST_PATH_IMAGE110
Referring to the synthesis method of example 1, 2-nitrofluorobenzene was replaced with 1-fluoro-2-nitro-4- (trifluoromethyl) benzene and 2-amino-3- (2-fluorophenyl) propionic acid was replaced with 1-fluoro-2-nitro-4- (trifluoromethyl) benzene(S)-2-amino-3-phenylpropionic acid, replacement of N- (tert-butoxycarbonyl) -L-serine by N- (tert-butoxycarbonyl) -L-cysteine to give a white solid119 mg of the compound of example 20 as such, yield 26.4%, melting point: is > 230 ℃.
1 H NMR (400 MHz, CDCl 3 ): δ ppm 8.90 (d, J=9.2 Hz, 1 H), 7.78 (d, J=8.0 Hz, 1 H), 7.46-7.50 (m, 2 H), 7.26-7.35 (m, 3 H), 7.16-7.18 (m, 2 H), 4.98 (s, 1 H), 4.57-4.64 (m, 1 H), 3.87-3.96 (m, 2 H), 3.74-3.78 (m, 1 H), 3.58-3.66 (m, 1 H), 3.43 (s, 3 H), 3.01-3.06 (m, 1 H), 2.87-2.92 (m, 1 H), 2.73-2.79 (m, 1H)；
13 C NMR (100 MHz, CDCl 3 ): δ ppm 170.22, 157.21, 152.24, 146.87, 136.25, 136.02, 132.81, 132.48, 131.96, 129.05, 129.01, 127.28, 123.94, 123.90, 121.29, 121.25, 50.27, 49.95, 47.33, 42.23, 38.58, 36.58；
ESI C 22 H 21 F 3 N 4 O 3 S m/z: 479.14 (M + +H)。
Example 21 Compound (I)R) -4-benzyl-N-((R) -7-methoxy-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b] [1,5]Synthesis of thiazepine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 811126DEST_PATH_IMAGE111
Referring to the synthesis method of example 1, 2-nitrofluorobenzene was replaced with 1-fluoro-2-nitro-4-methoxybenzene and 2-amino-3- (2-fluorophenyl) propionic acid was replaced with 1-fluoro-2-nitro-4-methoxybenzene(R)-2-amino-3-phenylpropionic acid, replacement of N- (tert-butoxycarbonyl) -L-serine with N- (tert-butoxycarbonyl) -L-cysteine provided 91 mg of the compound of example 21 as a white solid, 29.1% yield, melting point: 191.3 to 192.8 ℃.
1 H NMR(400 MHz, CDCl 3 ): δ ppm 8.84-8.86 (d, J=8 Hz, 1 H), 7.52-7.54 (d, J=8 Hz, 1 H), 7.26-7.34 (m, 3 H), 7.15-7.17 (m, 2 H), 6.75-6.80 (m, 2 H), 4.93 (s, 1 H), 4.58-4.63 (m, 1 H), 3.87-3.95 (m, 2 H), 3.82 (s, 3 H), 3.59-3.72 (m, 2 H), 3.40 (s, 3 H), 2.86-2.92 (m, 2 H), 2.73-2.78 (m, 1 H)；
13 C NMR(400 MHz, CDCl 3 ): δppm 170.73, 161.37, 157.25, 152.26, 147.41, 136.43, 136.13, 129.04, 128.99, 127.21, 118.08, 112.80, 110.73, 55.63, 50.63, 50.00, 47.37, 42.22, 38.96, 36.18；
ESI C 22 H 24 N 4 O 4 S m/z: 441.17 (M + +H)。
Example 22 Compound (A)S) -4-benzyl-N-((R) -7-methoxy-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b] [1,5]Synthesis of thiazepine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 843673DEST_PATH_IMAGE112
Referring to the synthesis method of example 1, 2-nitrofluorobenzene was replaced with 1-fluoro-2-nitro-4-methoxybenzene and 2-amino-3- (2-fluorophenyl) propionic acid was replaced with 1-fluoro-2-nitro-4-methoxybenzene(S)-2-amino-3-phenylpropionic acid, replacement of N- (tert-butoxycarbonyl) -L-serine with N- (tert-butoxycarbonyl) -L-cysteine provided 152 mg of the compound of example 22 as a white solid, 48.6% yield, melting point: 254.3-257.1 ℃.
1 HNMR(400 MHz, CDCl 3 ):δppm 8.85-8.87 (d, J=8 Hz, 1 H), 7.51-7.53 (d, J=8 Hz, 1 H), 7.14-7.34 (m, 3 H), 6.75-7.80 (m, 2 H), 6.78-6.81 (m, 1 H), 6.75-6.76 (m, 1 H), 4.87 (s, 1 H), 4.58-4.63 (m, 1 H), 3.64-3.94 (m, 2 H), 3.83 (s, 3 H), 3.64-3.70 (m, 2 H), 3.40 (s, 3 H), 2.84-2.92 (m, 2 H), 2.70-2.76 (m, 1 H)；
13 C NMR(400 MHz, CDCl 3 ):δppm 170.70, 161.36, 157.26, 152.23, 147.40, 136.41, 136.10, 129.05, 128.97, 127.22, 118.08, 112.81, 110.73, 55.63, 50.65, 49.92, 47.34, 42.23, 38.96, 36.18；
ESI C 22 H 24 N 4 O 4 Sm/z: 441.17 (M + +H)。
Example 23 Compound (R) -4-benzyl-N-((R) -7-fluoro-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]] [1,5]Synthesis of thiazepine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 894500DEST_PATH_IMAGE113
Referring to the synthesis method of example 1, 2-nitrofluorobenzene was replaced with 1, 4-difluoro-2-nitrobenzene, and 2-amino-3- (2-fluorophenyl) propionic acid was replaced with 1, 4-difluoro-2-nitrobenzene(R)-2-amino-3-phenylpropionic acid, replacement of N- (tert-butoxycarbonyl) -L-serine with N- (tert-butoxycarbonyl) -L-cysteine provided 145 mg of the compound of example 23 as a white solid, yield 27.4%, melting point: 233.4-236.7 deg.C, [ alpha ]]
Figure 596877DEST_PATH_IMAGE114
=-309.80º。
1 H NMR (400 MHz, DMSO-d 6 ):δ ppm 8.73 (d, J=7.55 Hz, 1 H), 7.91 (s, 1 H), 7.69 (dd, J 1 =8.56 Hz, J 2 =6.29 Hz, 1 H), 7.52 (dd, J 1 =9.95 Hz, J 2 =2.64 Hz, 1 H), 7.25-7.32 (m, 2 H), 7.15-7.24 (m, 4 H), 4.31-4.38 (m, 1 H), 3.87-3.94 (m, 1 H), 3.60 (t, J=9.69 Hz, 1 H),3.52 (dd, J 1 =11.20 Hz, J 2 =6.67 Hz, 1 H), 3.32-3.36 (m, 4 H), 2.95 (t, J=11.46 Hz, 1 H), 2.77-2.85 (m, 1 H), 2.65-2.72 (m, 1 H)；
13 C NMR (100 MHz, DMSO-d 6 ): δppm170.25, 164.73, 162.27, 157.54, 152.26, 148.23, 148.12, 137.20, 136.92, 129.85, 128.85, 127.01, 122.51, 115.10, 114.89, 113.08, 112.83, 50.23, 49.07, 46.41, 41.03, 38.53, 36.04；
ESI C 21 H 21 FN 4 O 3 S m/z: 429.16 (M + +H)。
Example 24 Compound (S) -4-benzyl-N-((R) -7-fluoro-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b] [1,5]Thiazepin-3-yl) -Synthesis of 2-oxoimidazoline-1-carboxamide
Figure 489746DEST_PATH_IMAGE115
Referring to the synthesis method of example 1, 2-nitrofluorobenzene was replaced with 1, 4-difluoro-2-nitrobenzene, and 2-amino-3- (2-fluorophenyl) propionic acid was replaced with 1, 4-difluoro-2-nitrobenzene(S)-2-amino-3-phenylpropionic acid, replacement of N- (tert-butoxycarbonyl) -L-serine with N- (tert-butoxycarbonyl) -L-cysteine provided example 24 compound 151 mg as a white solid, 28.5% yield, melting point: alpha at 205.9-214.6 ℃, [ alpha ]]
Figure 545558DEST_PATH_IMAGE116
=-382.61º。
1 H NMR (400 MHz, DMSO-d 6 ):δ ppm 8.70 (d, J=7.53 Hz, 1H), 7.93 (s, 1H),7.70 (dd, J 1 =8.53 Hz, J 2 =6.27 Hz, 1H), 7.52 (dd, J 1 =10.04 Hz, J 2 =2.51 Hz, 1H),7.26-7.33 (m, 2H), 7.11-7.25 (m, 4H), 4.30-4.37 (m, 1H), 3.87-3.94 (m, 1H), 3.58 (t, J=9.79 Hz, 1H),3.50 (dd, J 1 =11.04 Hz, J 2 =6.78 Hz, 1H), 3.35-3.37 (m, 1H), 3.29 (s, 3H), 2.93 (t, J=11.42 Hz, 1H), 2.77-2.85 (m, 1H), 2.64-2.73 (m, 1H)；
13 C NMR (100 MHz, DMSO-d 6 ): δppm170.28, 164.72, 162.26, 157.56, 152.22, 148.23, 148.12, 137.18, 137.09, 136.91, 129.83, 128.82, 127.00, 122.48, 115.10, 114.88, 113.08, 112.84, 50.24, 49.07, 46.43, 41.10, 38.51, 36.05；
ESI C 21 H 21 FN 4 O 3 Sm/z: 429.16 (M + +H)。
Example 25 Compounds(R)-N-((R) -7-amino-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,5]Synthesis of azelnine-3-yl) -4-benzyl-2-oxoimidazoline-1-carboxamide
Figure 473063DEST_PATH_IMAGE117
Referring to the synthesis method of example 1, 2-nitrofluorobenzene was replaced with 3-nitro-4-fluoroaniline and 2-amino-3- (2-fluorophenyl) propionic acid was replaced with 3-nitro-4-fluoroaniline(R)-2-amino-3-phenylpropionic acid, replacement of N- (tert-butoxycarbonyl) -L-serine with (R) -N- (tert-butoxycarbonyl) -L-cysteine provided example 25 compound 44 mg, 54.5%) as a light yellow solid, melting point: 232.7-240.8 deg. C, [ alpha ]]
Figure 346341DEST_PATH_IMAGE118
=-117.14º。
1 H NMR(400 MHz, CDCl 3 ): δ ppm 8.84 (d, J=8.0 Hz, 1 H), 7.31-7.37 (m, 3 H), 7.24-7.28 (m, 1 H), 7.1 (d, J=7.2 Hz, 2 H), 6.56 (d, J=2.4 Hz, 1 H), 6.51 (dd, J 1 =8.0 Hz, J 2 =2.4 Hz, 1 H), 4.91 (s, 1 H), 4.60-4.66 (m, 1 H), 3.85-3.96 (m, 2 H), 3.58-3.67 (m, 2 H), 3.37 (s, 3 H), 2.79-2.91 (m, 2 H), 2.68-2.78 (m, 1 H) (LDS7-26-1, 20190223)。
13 C NMR (400 MHz, CDCl 3 ): δ 169.88, 156.15, 151.23, 147.65, 146.31, 135.44, 135.13, 128.00, 126.24, 113.76, 112.90, 109.59, 49.71, 49.00, 46.44, 41.27, 38.12, 35.04 .
ESI C 21 H 23 N 5 O 3 S m/z: 426.18 (M + +H)。
Example 26 Compounds(R)-N-((S) -7-amino-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,5]Synthesis of azelnine-3-yl) -4-benzyl-2-oxoimidazoline-1-carboxamide
Figure 975774DEST_PATH_IMAGE119
Referring to the synthesis method of example 1, 2-nitrofluorobenzene was replaced with 3-nitro-4-fluoroaniline, and 2-ammonia was addedReplacement of 3- (2-fluorophenyl) propionic acid by(S)-2-amino-3-phenylpropionic acid, replacement of N- (tert-butoxycarbonyl) -L-serine with (R) -N- (tert-butoxycarbonyl) -L-cysteine gave 72 mg of the compound of example 26 as a pale purple solid, yield 33.1%, melting point: 253.1 to 258.6 deg.C, [ alpha ]]
Figure 287807DEST_PATH_IMAGE118
=-140.54º。
1 H NMR(400 MHz, CDCl 3 ): δ ppm 8.82 (d, J=8.0 Hz, 1 H), 7.30-7.37 (m, 3H), 7.24-7.27 (m, 1 H), 7.15–7.17 (m, 2 H), 6.55 (d, J=2.4 Hz, 1 H), 6.49-6.52 (dd, J 1 =8.0 Hz, J 2 =2.5 Hz, 1H), 4.97 (s, 1 H), 4.58-4.64 (m, 1 H), 3.85-3.95 (m, 3 H), 3.64-3.69 (m, 1 H), 3.59-3.62 (m, 1 H), 3.35 (s, 3 H), 2.81-2.91 (m, 2 H), 2.75 (m, 1H) (LDS8-26-1, 20190319)。
13 C NMR (400 MHz, CDCl 3 ): δ ppm 169.88, 156.15, 151.23, 147.65, 146.31, 135.44, 135.13, 128.00, 126.24, 113.76, 112.90, 109.59, 49.71, 49.00, 46.44, 41.27, 38.12, 35.04 (LDS8-26-2, 20190320)。
ESI C 21 H 23 N 5 O 3 Sm/z: 426.18 (M + +H)。
Example 27 Compounds(R)-4-benzyl-N-, ((R)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]] [1,5]Synthesis of thiazepine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 882868DEST_PATH_IMAGE120
Referring to the synthesis procedure of example 1, substituting 2-amino-3- (2-fluorophenyl) propionic acid with 2-amino-3-phenylpropionic acid and substituting N- (tert-butoxycarbonyl) -L-serine with N- (tert-butoxycarbonyl) -L-cysteine gave 120mg of the compound of example 27 in 24.0% yield with a melting point>250℃，[α]
Figure 989364DEST_PATH_IMAGE116
=-89.24º。
1 H NMR(400 MHz, DMSO-d 6 ) δ(ppm): 8.73(d, J=7.6Hz, 1H), 7.92(s, 1H), 7.65-7.67(m, 1H), 7.52-7.58(m, 2H), 7.19-7.34(m, 5H), 4.31-4.37(m, 1H), 3.87-3.94(m, 1H), 3.51-3.60(m, 2H), 3.33-3.34(m, 1H), 3.30(s, 3H), 2.93-2.98(m, 1H), 2.78-2.83(m, 1H) , 2.66-2.71(m, 1H);
13 C NMR(100 MHz, DMSO-d 6 ) δ(ppm):170.13, 157.53, 152.25, 146.50, 136.93, 135.54, 131.24, 129.85, 128.84, 127.99, 127.00, 126.70, 125.38, 50.08, 49.06, 46.40, 41.02, 38.45, 36.18;
ESI C 21 H 22 N 4 O 3 Sm/z:(M + +H) 410.85。
Example 28 Compounds(S)-4-benzyl-N-, ((R)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]] [1,5]Synthesis of thiazepine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 794509DEST_PATH_IMAGE121
Referring to the synthesis method of example 1, substituting 2-amino-3- (2-fluorophenyl) propionic acid with 2-amino-3-phenylpropionic acid and substituting N- (t-butoxycarbonyl) -L-serine with N- (t-butoxycarbonyl) -L-cysteine gave 150 mg of the compound of example 28 as a white solid in 21.1% yield, melting point 195.4-196.9 ℃, [ alpha ] - α]
Figure 893921DEST_PATH_IMAGE118
=-182.99º。
1 H NMR(400 MHz, DMSO-d 6 ) δ(ppm): 8.69(d, J=7.6Hz, 1H), 7.91(s, 1H), 7.65-7.67(m, 1H), 7.51-7.57(m, 2H), 7.19-7.34(m, 5H), 4.30-4.37(m, 1H), 3.87-3.93(m, 1H), 3.48-3.60(m, 2H), 3.33-3.37(m, 1H), 3.29(s, 3H), 2.90-2.96(m, 1H), 2.78-2.83(m, 1H) , 2.67-2.72(m, 1H);
13 C NMR(100 MHz, DMSO-d 6 ) δ(ppm):169.15, 156.54, 151.20, 145.48, 135.91, 134.52, 130.24, 128.83, 127.81, 126.99, 126.00, 125.68, 124.39, 49.06, 48.04, 45.40, 40.07, 37.42, 35.19;
ESI C 21 H 22 N 4 O 3 Sm/z:(M + +H) 410.85。
Example 29 Compounds(R)-4-benzyl-N-, ((S)-1-methyl-4-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b][1,5]Synthesis of diazepin-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 796018DEST_PATH_IMAGE122
Referring to the synthesis method of example 1, 2-amino-3- (2-fluorophenyl) propionic acid was replaced with 2-amino-3-phenylpropionic acidN- (tert-butyloxycarbonyl) substituted benzeneLReplacement of-serine with (S) -3-amino-2- ((tert-butoxycarbonyl) amino) propionic acid gave 120mg of the compound of example 29 as a pale yellow solid, yield 29.2%, melting point 118.9-120.1 ℃.
1 H NMR(400 MHz, DMSO-d 6 ) δ(ppm): 9.91 (s, 1H), 8.64-8.66 (m, 1H), 7.89 (s, 1H), 7.27-7.31 (m, 2H), 7.15-7.24 (m, 4H), 7.07-7.09 (m, 1H), 6.95-7.01 (m, 1H), 4.27- 4.33 (m, 1H), 3.89-3.95 (m, 1H), 3.60-3.65 (m, 1H), 3.27-3.39 (m, 3H), 2.81-2.85 (m, 1H), 2.68-2.73 (m, 4H);
13 C NMR(100 MHz, DMSO-d 6 ) δ(ppm):170.82, 157.61, 152.67, 143.16, 136.98, 131.80, 129.83, 128.86, 127.00, 126.42, 122.92, 122.64, 119.65, 64.17, 49.39, 49.10, 46.55, 41.10, 41.00;
ESI C 21 H 23 N 5 O 3 m/z: 393.90 (M + +H)。
Example 30 Compounds(S)-4-benzyl-N-, ((S)-1-methyl-4-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b][1,5]Synthesis of diazepin-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 620885DEST_PATH_IMAGE123
Referring to the synthesis method of example 1, 2-amino-3- (2-fluorophenyl) propionic acid was replaced with 2-amino-3-phenylpropionic acidN- (tert-butyloxycarbonyl) substituted benzeneLReplacement of-serine with (S) -3-amino-2- ((tert-butoxycarbonyl) amino) propionic acid gave 150 mg of the compound of example 30 as a white solid in 25.1% yield with a melting point of 128.7-131.0 ℃.
1 H NMR(400 MHz, DMSO-d 6 ) δ(ppm): 9.90 (s, 1H), 8.59-8.61 (m, 1H), 7.90 (s, 1H), 7.28-7.32 (m, 2H), 7.16-7.24 (m, 4H), 7.08-7.09 (m, 1H), 6.94-7.01 (m, 1H), 4.25- 4.31 (m, 1H), 3.89-3.95 (m, 1H), 3.59-3.64 (m, 1H), 3.24-3.41 (m, 3H), 2.79-2.84 (m, 1H), 2.68-2.74 (m, 4H);
13 C NMR (100 MHz, DMSO-d 6 ) δ(ppm):170.78, 157.64, 152.62, 143.16, 136.93, 131.80, 129.86, 128.82, 127.06, 126.41, 122.91, 122.63, 119.64, 64.16, 49.37, 49.04, 46.48, 41.10, 41.04;
ESI C 21 H 23 N 5 O 3 m/z：393.90 (M + +H)。
Example 31 Compounds(R)-4-benzyl-N-((S)-1, 5-dimethyl-2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b] [1,5]Synthesis of diazepin-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 975643DEST_PATH_IMAGE124
Referring to the synthesis method of example 1, 2-amino-3- (2-fluorophenyl) propionic acid was replaced with 2-amino-3-phenylpropionic acidN- (tert-butyloxycarbonyl) substituted benzeneL-serine was replaced with (S) -3- (methylamino) -2- ((tert-butoxycarbonyl) amino) propionic acid to give 120mg of the compound of example 31 as a white solid in 13.2% yield, m.p. 162.2-165.5 ℃.
1 H NMR(400 MHz, CDCl 3 ) δ(ppm): 8.81-8.83(m, 1H), 7.27-7.35(m, 3H), 7.14-7.24(m, 4H), 7.05-7.09(m, 2H), 4.91(s, 1H), 4.58-4.64(m, 1H), 3.86-3.96(m, 2H), 3.60-3.63(m, 1H), 3.43-3.47(m, 1H), 3.34-3.40(m, 4H), 2.85-2.89(m, 1H), 2.71-2.76(m, 4H);
13 C-NMR(100 MHz, DMSO-d 6 ) δ(ppm):170.41, 157.30, 152.64, 143.78, 136.70, 136.21, 129.05, 129.00, 127.21, 127.06, 123.34, 123.14, 119.49, 64.28, 50.02, 49.91, 47.45, 42.24, 40.85, 36.12;
ESI C 22 H 25 N 5 O 3 m/z: 407.90 (M + +H)。
Example 32 Compounds(S)-4-benzyl-N-((S)-1, 5-dimethyl-2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b] [1,5]Synthesis of diazepin-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 567162DEST_PATH_IMAGE125
Referring to the synthesis method of example 1, 2-amino-3- (2-fluorophenyl) propionic acid was replaced with 2-amino-3-phenylpropionic acidN- (tert-butyloxycarbonyl) substituted benzeneLReplacement of-serine with (S) -3- (methylamino) -2- ((tert-butoxycarbonyl) amino) propionic acid gave 92 mg of the compound of example 32 as a white solid in 9.1% yield, melting point>250℃。
1 H NMR(400 MHz, CDCl 3 ) δ(ppm): 8.80-8.82(m, 1H), 7.27-7.35(m, 3H), 7.13-7.24(m, 4H), 7.05-7.08(m, 2H), 4.97(s, 1H), 4.56-4.62(m, 1H), 3.86-3.96(m, 2H), 3.59-3.63(m, 1H), 3.44-3.48(m, 1H), 3.35-3.40(m, 4H), 2.86-2.90(m, 1H), 2.73-2.79(m, 4H);
13 C NMR(100 MHz, DMSO-d 6 ) δ(ppm):170.42, 157.31, 152.62, 143.79, 136.69, 136.17, 129.05, 128.96, 127.20, 127.04, 123.34, 123.11, 119.45, 64.29, 49.93, 49.92, 47.41, 42.25, 40.84, 36.09 ;
ESI C 22 H 25 N 5 O 3 m/z: 407.90 (M + +H)。
Example 33 Compounds(R) -N- ((S) -7-acetylamino-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,5]Synthesis of azapine-3-yl) -4-benzyl-2-oxoimidazoline-1-carboxamide
Step 1
Referring to the synthesis method of example 1, 2-nitrofluorobenzene was replaced with 3-nitro-4-fluoroaniline to give intermediate compound 15.
Step 2
Figure 307453DEST_PATH_IMAGE126
A25 mL single neck flask was charged with intermediate compound 15(121 mg, 0.25 mmol) and dichloromethane (4 mL), TEA (0.18 mL, 1.25 mmol) was added dropwise, stirred to clear, AcCl (0.02 mL, 0.26 mmol) was added dropwise at 0 deg.C, and after addition, the reaction was allowed to proceed at room temperature for half an hour. TLC (dichloromethane: methanol =20:1) detected the starting material was completely reacted. The system was concentrated directly, the prep plate separated (dichloromethane: methanol =15:1) to give the crude, and slurried with n-hexane: dichloromethane =3:1(1.5 mL) to give 90mg of the compound of example 33 as a white solid, yield 79.7%, melting point: is >250 ℃.
1 HNMR (400 MHz, DMSO-d 6 ) δ ppm 10.07(s, 1H), 8.67-8.65(d, J=8 Hz, 1H), 7.93(s, 1H), 7.67 (d, J=1 Hz, 1H), 7.39-7.36(m, 1H), 7.31-7.27(m, 2H), 7.23-7.20(m, 3H), 7.14-7.12(d, J=8 Hz, 1H), 4.64-4.59(m, 1H), 4.41-4.37(m, 1H), 4.15-4.10(m, 1H), 3.92(m, 1H), 3.64-3.60(m, 1H), 3.36-3.32(m, 1H), 3.26(s, 3H), 2.85-2.80(m, 1H), 2.73-2.68(m, 1H), 2.04(s, 3H)；
13 C NMR (400 MHz, DMSO-d 6 ) δ ppm 168.79, 168.33, 157.04, 152.21, 144.68, 136.77, 136.44, 136.06, 129.36, 128.37, 126.52, 122.28, 117.56, 113.79, 76.93, 49.49, 48.60, 46.01, 40.53, 34.66, 23.91；
ESI C 23 H 25 N 5 O 5 m/z: 451.90 (M + +H)。
Example 34 Compounds(S)-N-((S)-7-acetylamino-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,5]Azapine-3-yl) -4-benzyl-2-oxoimidazolineSynthesis of (E) -1-carboxamide
Figure 21331DEST_PATH_IMAGE127
Step 1
The synthetic procedure of step 1 of example 33 was repeated, and intermediate compound 15' was also obtained during the separation and purification of intermediate compound 15.
Figure 676435DEST_PATH_IMAGE128
Step 2
Referring to the synthesis procedure of step 2 of example 33, intermediate compound 15' was used instead of intermediate compound 15 to give 86 mg, 73.3% of the compound of example 34 as a white solid, melting point: is >250 ℃.
1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.06(s, 1H), 8.61(d, J = 7.3 Hz, 1H), 7.92(s, 1H), 7.66(d, J = 2.5 Hz, 1H), 7.38(dd, J = 8.8, 2.4 Hz, 1H), 7.32–7.27(m, 2H), 7.22 (dd, J = 5.0, 2.7 Hz, 3H), 7.14(d, J = 8.7 Hz, 1H), 4.61(dt, J = 11.2, 7.4 Hz, 1H), 4.37(dd, J = 9.8, 7.4 Hz, 1H), 4.10(dd, J = 11.3, 9.9 Hz, 1H), 3.92(s, 1H), 3.61(dd, J = 10.4, 9.1 Hz, 1H), 3.38(dd, J = 9.9, 4.7 Hz, 1H), 3.26(d, J = 3.8 Hz, 3H), 2.81(dd, J = 13.8, 5.0 Hz, 1H), 2.71(dd, J = 13.5, 7.4 Hz, 1H), 2.04(s, 3H)；
13 C NMR (400 MHz, DMSO-d 6 ) δ 168.80, 168.32, 157.07, 152.16, 144.68, 136.76, 136.41, 136.05, 129.36, 128.33, 126.51, 122.27, 117.57, 113.80, 76.90, 49.48, 48.56, 45.97, 40.59, 34.67 (s), 23.90;
ESI C 23 H 25 N 5 O 5 m/z: 451.90 (M + +H)。
Example 35 Compound (A)(S)-3- ((R) -4-benzyl-2-oxoimidazoline-1-carboxamide-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]] [1,5]Synthesis of azapine-7-yl) carbamic acid ethyl ester
Figure 540486DEST_PATH_IMAGE129
Referring to the synthesis method of example 33, the acetyl chloride was replaced with ethyl chloroformate to obtain 71 mg of the compound of example 35 as a white solid in a yield of 43.7% and a melting point of 117.3 to 119.2 ℃, [ alpha ], (α)]
Figure 886016DEST_PATH_IMAGE118
=-100.06º。
1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.83(d, J = 7.1 Hz, 1H), 7.52(s, 1H), 7.32(dd, J = 16.6, 9.0 Hz, 3H), 7.18–7.13(m, 2H), 7.08(d, J = 8.7 Hz, 1H), 7.00(dd, J = 8.6, 2.6 Hz, 1H), 6.69(s, 1H), 4.95–4.85(m, 2H), 4.57(dd, J = 9.7, 7.5 Hz, 1H), 4.27–4.18(m, 3H), 3.93(dt, J = 13.8, 6.9 Hz, 2H), 3.62(dd, J = 9.5, 4.3 Hz, 1H), 3.41(s, 3H), 2.88(dd, J = 13.7, 4.9 Hz, 1H), 2.74(dd, J= 13.6, 8.2 Hz, 1H), 1.32(t, J = 7.1 Hz, 3H);
13 C NMR (400 MHz, CDCl 3 ) δ 168.34, 156.28, 152.59, 151.67, 144.55, 135.70, 135.09, 134.68, 128.00, 126.23, 121.86, 116.25, 112.52, 76.61, 49.11, 46.45, 41.19, 34.32, 30.57, 21.63, 13.52, 13.10;
ESI C 24 H 27 N 5 O 6 m/z: 481.85 (M + +H)。
Example 36 Compound ((S)-3-((S)-4-benzyl-2-oxoimidazoline-1-carboxamido) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b] [1,5]Synthesis of ethyl azepin-7-yl) carbamate
Figure 291502DEST_PATH_IMAGE130
Reference example 34Replacing acetyl chloride with ethyl chloroformate gave 83 mg of example 36 compound as a white solid, 31.4%, melting point: alpha at 250 deg.c]
Figure 417590DEST_PATH_IMAGE116
=-182.19º。
1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.81(d, J = 7.3 Hz, 1H), 7.52(s, 1H), 7.36–7.30(m, 2H), 7.29–7.26(m, 1H), 7.17(dd, J = 6.3, 4.8 Hz, 2H), 7.08(d, J= 8.7 Hz, 1H), 7.00(dd, J = 8.7, 2.6 Hz, 1H), 6.62(s, 1H), 4.87(dd, J = 12.8, 5.7 Hz, 2H), 4.59(dd, J = 9.7, 7.4 Hz, 1H), 4.29–4.19(m, 3H), 3.99–3.88(m, 2H), 3.62(dd, J = 9.7, 4.4 Hz, 1H), 3.41(d, J = 5.1 Hz, 3H), 2.89(dd, J = 13.3, 4.8 Hz, 1H), 2.80–2.73(m, 1H), 1.36–1.29(m, 3H)。
13 C NMR (400 MHz, CDCl 3 ) δ 169.36, 157.30, 153.61, 152.68, 145.56, 136.69, 136.05, 135.72, 129.02, 127.24, 122.85, 117.22, 113.56, 77.64, 50.20, 49.93, 47.37, 42.22, 35.33, 14.54;
ESI C 24 H 27 N 5 O 6 m/z: 481.90 (M + +H)。
Example 37 Compounds(R)-4-benzyl-N-((S) -7-cyano-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,5]Synthesis of azapine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 898381DEST_PATH_IMAGE131
Referring to the synthesis method of example 1, substituting 2-nitrofluorobenzene with 3-nitro-4-fluorobenzonitrile gave 78 mg of the compound of example 37 as a white solid in 16.2% yield with a melting point of 116.7-121.7 ℃.
1 H NMR(400 MHz, CDCl 3 ) δ (ppm): 8.85(d, J=6.8Hz, 1H), 7.50-7.53(m, 2H), 7.25-7.36(m, 4H), 7.15-7.17(m, 2H), 4.85-4.92(m, 2H), 4.62-4.65(m, 1H), 4.34-4.39(m, 1H), 3.90-3.98(m, 2H), 3.60-3.64(m, 1H), 3.43(s, 3H), 2.87-2.92(m, 1H), 2.72-2.77(m, 1H);
13 C NMR(100 MHz, CDCl 3 ) δ 168.83, 157.16, 153.67, 152.64, 137.58, 135.99, 131.20, 129.05, 129.00, 127.30, 127.08, 124.31, 117.68, 109.33, 77.60, 50.05, 49.79, 47.44, 42.20, 35.59;
ESI C 22 H 21 N 5 O 4 m/z: 419.85 (M + +H)。
Example 38 Compounds(S)-4-benzyl-N-((S) -7-cyano-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,5]Synthesis of azapine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 629576DEST_PATH_IMAGE132
Referring to the synthesis procedure of example 1, 2-nitrofluorobenzene was replaced with 3-nitro-4-fluorobenzonitrile to give example 38 compound 48 mg as a white solid in 9.9% yield with melting point >250 ℃.
1 H NMR(400 MHz, CDCl 3 ) δ(ppm): 8.83(d, J=7.2Hz, 1H), 7.50-7.52(m, 2H), 7.25-7.36(m, 4H), 7.16-7.18(m, 2H), 4.84-4.94(m, 2H), 4.62-4.66(m, 1H), 4.34-4.40(m, 1H), 3.90-3.98 (m, 2H), 3.60-3.63(m, 1H), 3.42(s, 3H), 2.88-2.92(m, 1H), 2.74-2.80(m, 1H);
13 C NMR(100 MHz, CDCl 3 ) δ 167.79, 156.15, 152.66, 151.60, 136.56, 134.93, 130.19, 128.01, 126.29, 126.08, 123.28, 116.68, 108.31, 76.60, 48.95, 48.77, 46.36, 41.23, 34.57；
ESI C 22 H 21 N 5 O 4 m/z:(M + +H) 419.85。
Example 39 Compounds(R)-4-benzyl-N-((S)-8-cyano-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 622940DEST_PATH_IMAGE133
Referring to the synthesis procedure of example 1, 2-nitrofluorobenzene was replaced with 3-fluoro-4-nitrobenzonitrile to give the compound of example 39 in 110 mg, 38% yield, m.p.: alpha at 99.6-102.3 ℃, [ alpha ]]
Figure 157696DEST_PATH_IMAGE116
=-86.42º。
1 H NMR 400 MHz (DMSO-d 6 ) δ(ppm) 8.67 (d, J=7.2Hz, 1H), 7.96 (s, 1 H), 7.76-7.79 (m, 2 H), 7.63 (d, J=8.4Hz, 1H), 7.27-7.31 (m, 2 H), 7.20-7.23 (m, 3 H), 4.61-4.66 (m, 1 H), 4.47-4.51 (m, 1 H), 4.26-4.31 (m, 1 H), 3.60-3.65 (m, 1 H), 3.34-3.37 (m, 1 H), 3.33 (s, 3 H), 2.80-2.85 (m, 1 H), 2.68-2.73 (m, 1 H);
13 C NMR 100 MHz (DMSO-d 6 ) δ 168.76, 157.03, 152.18, 149.36, 141.31, 136.41, 129.79, 129.36, 128.37, 126.53, 126.47, 124.60, 117.86, 108.94, 77.12, 49.53, 48.59, 46.00, 40.50, 40.14, 39.93, 34.63;
ESI C 22 H 21 N 5 O 4 m/z: 419.85 (M + +H)。
EXAMPLE 40 Compounds(S)-4-benzyl-N-((S)-8-cyano-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,5]Synthesis of azapine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 222604DEST_PATH_IMAGE134
Referring to the synthesis method of example 1, substituting 2-nitrofluorobenzene with 3-fluoro-4-nitrobenzonitrile gave 100mg of the compound of example 40 as a white solid in 38.5% yield, m.p.:>250℃，[α]
Figure 355776DEST_PATH_IMAGE118
=-155.36º。
1 H NMR 400 MHz (DMSO-d 6 ) δ 8.63 (d, J=7.2Hz, 1H), 7.96 (s, 1 H), 7.77-7.79 (m, 2 H), 7.62 (d, J=8.8Hz, 1H), 7.28-7.32 (m, 2 H), 7.22-7.23 (m, 3 H), 4.61-4.67 (m, 1 H), 4.46-4.50 (m, 1 H), 4.24-4.29 (m, 1 H), 3.89-3.96 (m, 1 H), 3.59-3.64 (m, 1 H), 3.32-3.36 (m, 4 H), 2.79-2.84 (m, 1 H), 2.68-2.73 (m, 1 H);
13 C NMR 100 MHz (DMSO-d6) δ 169.27, 157.54, 152.62, 149.86, 141.79, 136.90, 130.28, 129.85, 128.83, 127.01, 126.96, 125.09, 118.35, 109.45, 77.59, 50.02, 49.06, 46.46, 41.08, 35.14;
ESI C 22 H 21 N 5 O 4 m/z: 419.85 (M + +H)。
example 41 Compound (S) -4-benzyl-N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Synthesis of oxazepine-3-yl) -2-oxo-2, 3-dihydro-1H-imidazole-1-carboxamide
Figure 316779DEST_PATH_IMAGE135
Step 1 Synthesis of Compound 16, methyl 5-Benzyloxazol-4-carboxylate
Figure 135568DEST_PATH_IMAGE136
To a 250 mL single neck flask was added phenylacetic acid (11.4 g, 83.8 mmol), tetrahydrofuran (100 mL), CDI (16.3 g, 100.6 mmol), stirred at room temperature under nitrogen atmosphere for 3h, followed by addition of NaHMDS (42mL, 83.8 mmol, 2mol/L in THF), methyl isocyanoacetate (9.13 g, 92.2 mmol), followed by stirring at room temperature for 20 h, and TLC (dichloromethane: methanol =30:1) checked for reaction completion. Adding ethyl acetate (200 mL) and water (100 mL) into the reaction solution, separating the layers, extracting the aqueous phase with ethyl acetate (100 mL), combining the organic phases, washing with saturated brine (300 mL. times.3), drying the organic layer over anhydrous sodium sulfate, filtering, concentrating, and performing column chromatography (SiO) 2 Ethyl acetate =6:1) to give a colorless transparent liquidIntermediate compound 16(6.64 g, 36.8% yield).
1 HNMR(400 MHz, CDCl 3 ):δppm 7.74 (s,1H), 7.23-7.33 (m,5H), 4.40 (s,2H), 3.94(s,3H).
Step 2 Synthesis of Compound 17, 1-amino-3-phenylpropan-2-one hydrochloride
Figure 473008DEST_PATH_IMAGE137
Compound 16(6.64 g, 30.6 mmol), 3N ethanol hydrochloride solution (60 mL) was added to a 100 mL single-neck flask, stirred at 75 ℃ for 2h under nitrogen atmosphere, and the reaction was checked by TLC (petroleum ether: ethyl acetate =3:1) for completion. The reaction was concentrated to remove ethanol, and ethyl acetate (30 mL) was added and slurried for 30min, filtered, and dried under vacuum at room temperature to give intermediate compound 17(5.0 g, yield 88.3%) as a white solid.
1 H NMR(400 MHz, DMSO-d6):δppm 9.04 (s,2H), 7.20-7.35 (m,5H), 4.17 (s,2H), 3.83 (s,2H)
Step 3 Synthesis of Compound 18, 4-benzyl-1, 3-dihydro-2H-imidazol-2-one
Figure 585321DEST_PATH_IMAGE138
To a 100 mL single-neck flask was added compound 17(4.7g, 25.4mmol), water (80mL), KOCN (4.1g, 50.8mmol), stirred at 85 ℃ for 20 h under nitrogen atmosphere, and the reaction was checked by TLC (dichloromethane: methanol =20:1) for completion. The reaction was cooled, filtered, and the solid was slurried with ethyl acetate (20mL) for 30min, filtered, and dried in vacuo to give intermediate compound 18(1.7g, yield 38.6%) as a white solid.
1 HNMR(400 MHz, DMSO-d6):δppm 9.79 (s, 1H), 9.46 (s, 1H), 7.27-7.31 (m, 2H), 7.18-7.23 (m, 3H), 5.94 (s, 1H), 3.55 (s, 2H)。
Step 4 Synthesis of Compound 19, 4-benzyl-2-oxo-2, 3-dihydro-1H-imidazole-1-carbonyl chloride
Figure 999116DEST_PATH_IMAGE139
A50 mL single-neck flask was charged with compound 18(261mg, 1.5 mmol), tetrahydrofuran (4 mL), activated carbon (20mg), and a tetrahydrofuran solution (4 mL) of trichloromethyl chloroformate (158mg, 0.8mmol) was added dropwise at room temperature under a nitrogen atmosphere, followed by reaction at 65 ℃ for 20 hours. The reaction was complete by TLC (petroleum ether: ethyl acetate =1:1), the reaction solution was filtered through a pad of celite, and the filtrate was concentrated to give compound 19(520 mg, crude) as a yellow oil.
Step 5 example 41 Compound (I)S) -4-benzyl-N- (5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of oxazepine-3-yl) -2-oxo-2, 3-dihydro-1H-imidazole-1-carboxamide
Figure 259196DEST_PATH_IMAGE140
To a 50 mL single-necked flask was added intermediate compound 7(215 mg, 1.12 mmol), tetrahydrofuran (5 mL), N 2 A solution of 19(520 mg, 1.12 mmol) in THF (5 mL) was added dropwise to the mixture at room temperature under an atmosphere, and the mixture was reacted at 45 ℃ for 45 min and at room temperature for 3 hours. Filtering the reaction solution, concentrating to dryness, and performing column chromatography (SiO) 2 Petroleum ether: ethyl acetate =1:1) to yield 283 mg of crude product, which is then separated twice using a thick prep plate (dichloromethane: methanol =20:1) to yield 120mg of the first-order purified product, which is then separated using a thick prep plate (dichloromethane: ethyl acetate =1:1) to yield 90mg of the compound of example 41 as a white solid in 20.4% yield, melting point: 208.3 to 210.2 ℃.
1 H NMR(400 MHz, CDCl 3 ):δppm 9.35 (d, J=7.2 Hz, 1H), 9.10 (s,1H), 7.31-7.34 (m, 2H), 7.25-7.27 (m, 3H), 7.17-7.23 (m, 4H), 6.57 (t, J=1.2 Hz, 3 H), 4.90-4.96 (m, 1 H), 4.67-4.71 (m, 1 H), 4.27-4.33 (m, 1 H), 3.69 (s,2 H), 3.43 (s, 3 H)；
13 C NMR (100 MHz, CDCl 3 ): δppm 168.71, 153.26, 150.09, 149.54, 136.35, 136.18, 128.87, 128.83, 127.49, 127.14, 125.67, 123.25, 122.89, 104.52, 77.43, 50.38, 35.43, 31.97；
ESI C 21 H 20 N 4 O 4 m/z: 393.16 (M + +H)。
Example 42 CompoundsR-4-benzyl-N-((S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]] [1,5]Synthesis of azapine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 711911DEST_PATH_IMAGE141
Referring to the synthesis method of example 1, substituting 2-amino-3- (2-fluorophenyl) propionic acid with 2-amino-3-phenylpropionic acid provided example 42 compound 143 mg as a white solid in 56.1% yield, melting point: 99.2-102.6 deg.C, [ alpha ]]
Figure 6627DEST_PATH_IMAGE118
=-96.84º。
1 H NMR 400 MHz (DMSO-d 6 ) δ (ppm): 8.62 (d, J = 7.2 Hz, 1 H), 7.92 (s, 1 H), 7.42-7.47 (m, 1 H), 7.20-7.32 (m, 8 H), 4.57-4.64 (m, 1 H), 4.39-4.43 (m, 1 H), 4.12-4.18 (m, 1 H), 3.88-3.95 (m, 1 H), 3.58-3.63 (m, 1 H), 3.35-3.39 (m, 1 H), 3.29 (s, 3 H), 2.79-2.84 (m, 1 H), 2.68-2.73 (m, 1 H)；
13 C NMR 100 MHz (DMSO-d 6 ) δ(ppm): 168.23, 156.31, 151.66, 149.09, 135.47, 135.05, 128.06, 127.95, 126.34, 126.20, 124.53, 122.20, 121.80, 76.64, 49.06, 48.90, 46.34, 41.20, 34.36；
ESI C 21 H 22 N 4 O 4 m/z: 394.90 (M + +H)。
EXAMPLE 43 CompoundsS-5-benzyl-N-, ((S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]] [1,5]Synthesis of azapine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 325744DEST_PATH_IMAGE142
Referring to the synthesis of example 1, substituting 2-amino-3- (2-fluorophenyl) propionic acid with 2-amino-3-phenylpropionic acid provided the compound of example 43 as a white solid, 41mg, yield 16.1%, melting point: 197.5-200.6 deg.C, [ alpha ]]
Figure 276382DEST_PATH_IMAGE116
=-122.95º。 1 H NMR 400 MHz (DMSO-d 6 ) δ (ppm): 8.66 (d, J = 7.2 Hz, 1 H), 7.93 (s, 1 H), 7.44-7.47 (m, 1 H), 7.20-7.32 (m, 8 H), 4.58-4.65 (m, 1 H), 4.40-4.45 (m, 1 H), 4.15-4.20 (m, 1 H), 3.89-3.96 (m, 1 H), 3.59-3.64 (m, 1 H), 3.32-3.36 (m, 1 H), 3.30 (s, 3 H), 2.80-2.85 (m, 1 H), 2.67-2.73 (m, 1 H)；
13 C NMR 100 MHz (DMSO-d 6 ) δ(ppm): 169.28, 157.28, 152.70, 150.11, 136.50, 136.12, 129.04, 129.02, 127.37, 127.25, 125.56, 123.21, 122.85, 76.64, 50.09, 50.05, 47.45, 42.22, 35.40；
ESI C 21 H 22 N 4 O 4 m/z: 394.85 (M + +H)。
Example 44 Compound (C)R) -4-benzyl-N-((S) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2, 5-oxoimidazoline-1-carboxamide
Figure 752363DEST_PATH_IMAGE143
Step 1 Compound 20(Z)Synthesis of (E) -5-benzylideneimidazoline-2, 4-dione
Figure 168430DEST_PATH_IMAGE144
A50 mL single neck flask was charged with imidazolidine-2, 4-dione (2.00 g,20 mmol) and 20mL of water, stirred, partially dissolved, added with triethylamine (2.06 g,20 mmol) and benzaldehyde (2.40 g, 22 mmol), and allowed to react at 80 ℃ for 20 h. TLC (dichloromethane: methanol =10:1) showed the reaction was complete. Cooled to room temperature, filtered and the filter cake washed with water (10 mL. times.2). The filter cake was dried at 45 ℃ overnight to give compound 20 as a pale yellow solid (2.05 g, yield 53.0%).
Step 2 Synthesis of Compound 21, 5-Benzylimidazoline-2, 4-dione
Figure 579820DEST_PATH_IMAGE145
In a 50 mL single-neck flask, compound 20(2.05 g, 11 mmol) was dissolved in 60 mL of methanol, 10% Pd/C (200 mg) was added, and hydrogen (15 psi) was bubbled through and reacted for 12 h. TLC (petroleum ether: ethyl acetate =2:1) showed the reaction was complete. The reaction was filtered through a pad of celite and the filter cake was washed with methanol (10mL x 2). The filtrate was concentrated under reduced pressure to give off-white solid 21(1.87 g, yield 90.0%).
1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 10.41 (s, 1 H), 7.90 (s, 1 H), 7.30-7.18 (m, 5 H), 4.34-4.31(m, 1 H), 2.97-2.88 (m, 2 H)。
Step 3 Synthesis of Compound 22, 1- (4-Nitrophenyl-1-oxycarbonyl) -4-benzyl-2, 5-dioxoimidazoline
Figure 814492DEST_PATH_IMAGE146
In a 50 mL three-necked flask, compound 21(1.00 g, 5.2 mmol) was dissolved in 20mL of dichloromethane and cooled to 0 ℃. P-nitrophenyl chloroformate (1.05 g, 5.2 mmol) was dissolved in 5 mL of dichloromethane and added dropwise to the reaction mixture. The reaction was kept warm for 2h and then brought to room temperature for reaction overnight. TLC (dichloromethane: methanol =20:1) showed the reaction was complete. The reaction was quenched with 20mL of water, separated, the aqueous layer was extracted with dichloromethane (15 mL × 1), the organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (dichloromethane: methanol = 200: 1 to 40: 1) to obtain intermediate compound 22(900 mg, yield 55.0%).
Step 4 example 44 Compound (I)R) -4-benzyl-N-((S) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of oxazepine-3-yl) -2, 5-dioxoimidazoline-1-carboxamide
Figure 110475DEST_PATH_IMAGE147
Intermediate compound 7(250 mg, 1.1 mmol) was dissolved in 7 mL DMF and triethylamine (330 mg, 3.3 mmol) and compound 22(300 mg, 0.8mmol) were added. Heating to 80 ℃ under the protection of nitrogen, and reacting for 3 h. TLC (dichloromethane: methanol =20:1) showed the reaction was complete. The reaction was cooled to room temperature and quenched by the addition of 25 mL of 0.5mol/L HCl solution. A solid precipitated, and was stirred for 5min, filtered, and the cake was washed with water (20 mL. times.2). The filter cake was dried at 45 ℃ to give the crude product, which was separated via preparative plate (petroleum ether: ethyl acetate =1:1) to give the compound of example 44 (80 mg, yield 18.0%) as a white solid. Melting point 125.1-127.2 ℃.
1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 11.42 (m, 1H), 8.43-8.42 (m, 1H), 7.53-7.51 (m, 1H), 7.34-7.23 (m, 6H), 6.99-6.97 (m, 2H), 4.76-4.68 (m, 2H), 4.59-4.55(m, 1H), 4.31-4.25(m, 1H), 3.40 (s, 3 H), 3.30-3.27(m, 1H),3.05-3.02(m, 1 H)；
13 C NMR (100 MHz, CDCl 3 ) δ (ppm): 169.71, 168.00, 153.38, 149.72, 149.57, 135.69, 132.76, 129.24, 128.17, 127.15, 127.02, 125.21, 122.84, 122.34, 76.70, 60.79, 49.99, 35.05, 34.61;
ESI C 21 H 20 N 4 O 5 m/z: 408.85 (M + +H)。
Example 45 Compound (C)S) -4-benzyl-N-((S) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2, 4-dioxoimidazoline-1-carboxamide
Figure 379783DEST_PATH_IMAGE148
The procedure of example 44 was repeated to isolate the compound of example 45 (85 mg, yield 19.0%) as a white solid in the course of isolation of the preparation plate (petroleum ether: ethyl acetate =1: 1). Melting point >250 ℃.
1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 11.48 (m, 1 H), 8.49-8.47 (m, 1 H), 7.50-7.47 (m, 1 H), 7.35-7.24 (m, 6 H), 6.97-6.95 (m, 2H), 4.75-4.62 (m, 3 H), 4.34-4.29(m, 1H), 3.33(s, 3H), 3.09-3.08(m, 1H), 3.05-3.04(m, 1H)； 1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 8.58-8.57 (m, 1H), 7.80-7.79 (m, 1H), 7.25-7.20 (m, 7H), 7.04-7.01 (m, 2H), 4.93-4.87 (m, 1H), 4.77-4.72(m, 2H), 4.34-4.29(m, 1H), 3.55-3.50 (m, 1 H), 3.42(s, 3 H), 3.27-3.23(m, 1 H);
13 C NMR(100 MHz, CDCl 3 ) δ: 165.2, 163.47, 148.86, 145.23, 144.75, 130.89, 128.24, 124.31, 123.41, 122.40, 122.36, 120.52, 118.05, 117.64, 71.97, 55.79, 45.04, 30.29, 29.57;
ESI C 21 H 20 N 4 O 5 m/z: 408.90 (M + +H)。
Example 46 Compounds(R)-4- (3-fluorobenzyl) -N-((S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2, 5-dioxoimidazoline-1-carboxamide
Figure 962074DEST_PATH_IMAGE149
Referring to the synthesis procedure of example 44, substituting benzaldehyde with 3-fluorobenzaldehyde provided 190 mg of the compound of example 46 as an off-white solid in 33.3% yield with a mp 92.8-93.4 ℃.
1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 11.50 (br, 1H), 8.42 (d, J = 6.78 Hz, 1H), 7.52 (dd, J 1 = 7.40 Hz, J 2 = 1.88 Hz, 1H), 7.24-7.35 (m, 4H), 7.07 (td, J 1 = 8.60 Hz, J 2 = 2.38 Hz, 1H), 6.84 (d, J = 7.53 Hz, 1 H), 6.79 (d, J = 9.79 Hz, 1 H), 4.69-4.78 (m, 2 H), 4.56(dd, J 1 = 9.79 Hz, J 2 = 7.28 Hz, 1 H), 4.30 (dd, J 1 = 11.04 Hz, J 2 = 10.04 Hz, 1 H), 3.36 (s, 3 H), 3.29 (d, J = 5.77 Hz, 1H), 3.09 (dd, J 1 = 13.80, J 2 = 2.51Hz, 1H)；
13 C NMR (100 MHz, DMSO-d 6 ) δ (ppm): 171.58, 168.17, 163.01, 160.59, 155.69, 150.16, 149.43, 137.24, 136.11, 130.21, 127.34, 125.70, 123.73, 122.30, 116.23, 116.02, 113.99, 113.78, 76.52, 60.34, 49.95, 34.83, 33.97；
ESI C 21 H 20 N 4 O 5 m/z: 426.85 (M + +H)。
Example 47 Compounds(S)-4- (3-fluorobenzyl) -N-((S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2, 5-dioxoimidazoline-1-carboxamide
Figure 933310DEST_PATH_IMAGE150
Example 47
Referring to the synthesis procedure of example 44, substituting benzaldehyde for 3-fluorobenzaldehyde, 200 mg of the compound of example 47 was obtained in 35.0% yield with a mp 132.8-134.1 ℃.
1 H NMR (400 MHz, DMSO-d 6 )δ (ppm): 11.56 (br, 1 H), 8.48 (d, J=6.55 Hz, 1 H), 7.46-7.51(m, 1 H), 7.27-7.36 (m, 4 H), 7.09 (td, J 1 =8.62, J 2 =2.14 Hz, 1 H), 6.81 (d, J=7.81 Hz, 1 H), 6.75 (d, J=9.82 Hz, 1 H), 4.69-4.75 (m, 2 H), 4.63 (dd, J 1 = 9.57, J 2 =7.30 Hz, 1 H), 4.30 (dd, J=11.08, 9.82 Hz, 1 H), 3.36 (d, J=6.04 Hz, 1 H), 3.33 (s, 3 H), 3.11 (dd, J 1 =13.85, J 2 = 2.27 Hz, 1 H);
13 C NMR (100 MHz, DMSO-d 6 ) δ: 171.68, 168.08, 163.05, 160.62, 155.60, 150.16, 149.40, 137.28, 136.03, 130.40, 130.31, 127.37, 125.73, 123.65, 122.41, 116.05, 115.84, 114.08, 113.88, 76.61, 60.16, 49.62, 34.73, 33.76);
ESI C 21 H 20 N 4 O 5 m/z: 426.85 (M + +H)。
Example 48 Compounds(R)-4- (3, 4-difluorobenzyl) -N-((S) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2, 5-dioxoimidazoline-1-carboxamide
Figure 16672DEST_PATH_IMAGE151
Referring to the synthesis procedure of example 44, substituting benzaldehyde with 3, 4-di-fluorobenzaldehyde, 102 mg of the compound from example 47 was obtained in 22.5% yield and 98.1-104.4 ℃ melting point.
1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 11.52 (s, 1H), 8.40 (d, J = 7.2Hz, 1H), 7.53-7.50 (m, 1H), 7.36-7.24 (m, 4H), 7.04-6.99 (m, 1H), 6.87-6.83 (m, 1H), 4.77-4.72(m, 1H), 4.70-4.68 (m, 1H), 4.58-4.54 (m, 1H), 4.33-4.28 (m, 1H), 3.36(s, 3H), 3.28-3.25(m, 1H), 3.10-3.06(m, 1H);
13 C NMR (100 MHz, CDCl 3 ) δ (ppm): 169.00, 167.50, 152.88, 150.42, 150.29, 150.19, 150.06, 149.24, 149.02, 147.95, 147.82, 147.72, 147.60, 135.14, 129.45, 129.41, 129.36, 126.71, 124.97, 124.93, 124.91, 124.87, 124.80, 122.38, 121.84, 117.77, 117.60, 116.65, 116.48, 76.12, 60.04, 49.57, 34.60, 33.32;
ESI C 21 H 18 F 2 N 4 O 5 m/z: 444.80 (M + +H)。
Example 49 Compound (I)S) -4- (3, 4-difluorobenzyl) -N-((S) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2, 5-dioxoimidazoline-1-carboxamide
Figure 891218DEST_PATH_IMAGE152
Referring to the synthesis method of example 44, benzaldehyde was replaced with 3, 4-di-fluorobenzaldehyde to obtain 101 mg of the compound of example 49 in 22.3% yield and 146.5-148.1 ℃ melting point.
1 H NMR (400 MHz, DMSO-d 6 ) δ(ppm): 11.59(s, 1H), 8.48(d, J=6.8Hz, 1H), 7.49-7.46(m, 1H), 7.41-7.26(m, 4H), 6.99-6.94(m, 1H), 6.83-6.79(m, 1H), 4.75-4.68(m, 2H), 4.64-4.60(m, 1H), 4.35-4.30(m, 1H), 4.33 (s, 3H), 3.31-3.29(m, 1H), 3.12-3.07(m, 1H);
13 C NMR (100 MHz, CDCl 3 ) δ(ppm) :169.40, 167.75, 153.30, 150.43, 150.30, 150.16, 150.04, 149.57, 148.97, 147.95, 147.83, 147.69, 147.57, 135.06, 129.72, 129.62, 126.73, 124.82, 124.67, 124.63, 124.61, 124.57, 122.33, 121.88, 117.61, 117.44, 116.61, 116.44, 76.13, 59.80, 49.33, 34.60, 33.02;
ESI C 21 H 18 F 2 N 4 O 5 m/z: 444.80 (M + +H)。
Example 50 Compounds(R)-3-benzyl-5-methyl-5-(s) (b)(S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]] [1,5]Synthesis of azapine-3-yl) amino) imidazoline-2, 4-dione
Figure 909990DEST_PATH_IMAGE153
Step 1 Synthesis of Compound 23, methyl (benzylcarbamoyl) serine
Figure 119254DEST_PATH_IMAGE154
Serine methyl ester hydrochloride (5.60 g, 0.0361 mol), triethylamine (7.60g, 0.075mol) were dissolved in acetonitrile (50 mL), and benzyl isocyanate (4.00g, 0.03 mol) was added, after addition, N 2 The displacement was performed 3 times, and the reaction was heated to 80 ℃ overnight. TLC (petroleum ether: ethyl acetate =5:1) detected the starting material was completely reacted. Cooling to room temperature, concentrating the reaction mixture to dryness, adding water (200 mL), extracting with dichloromethane (200 mL x4), concentrating the organic phase to dryness to give crude product, adding 200 mL dry ether, pulping, filtering, washing the filter cake with dry ether (50 mL), and drying to give off-white solid compound 23(5.01g, 66.0% yield).
1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 7.20-7.33 (m, 6 H), 6.72-6.75 (m, 1 H), 6.31 (d, J = 8.8 Hz, 1 H), 5.08 (t, J = 5.4 Hz, 1 H), 4.21-4.28 (m, 3 H), 3.72-3.77 (m, 1 H), 3.63 (s, 3 H), 3.55-3.6 (m, 1 H) 。
Step 2 Synthesis of Compound 24, 3-benzyl-5- (hydroxymethyl) imidazoline-2, 4-dione
Figure 458838DEST_PATH_IMAGE155
Intermediate compound 23(2.50 g, 0.99 mol) was dissolved in methanol (40 mL), concentrated hydrochloric acid (1mL, 1.19 mmol) was added, and after the addition was complete, the reaction was allowed to warm to 80 ℃ for overnight reaction. TLC (petroleum ether: ethyl acetate =2:1) detected the completion of the starting material reaction. Cooling to room temperature, solid precipitated, filtration, drying the filter cake to give 1.5 g of off-white solid while concentrating the filtrate to dryness, adding ether (20mL) and pulping, filtration, drying the filter cake to give 520 mg of off-white solid, and combining the two batches of off-white solid to give compound 24(2.02 g, 92.7% yield).
1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 8.17 (s, 1 H), 7.23-7.33 (m, 5 H), 5.13-5.15 (m, 1 H), 4.47-4.58 (m, 2 H), 4.14-4.15 (m, 1 H), 3.60-3.72 (m, 2 H), 3.07-3.10 (m, 1 H)。
Step 3 Synthesis of Compound 25, 3-benzyl-5-methylidene imidazoline-2, 4-dione
Figure 437158DEST_PATH_IMAGE156
Intermediate 24(750 mg, 3.41 mmol), PPh 3 (982 mg, 3.75 mmol) was dissolved in THF (15 mL), DIAD (757 mg, 3.75 mol) was added dropwise in ice bath, and after the addition was completed, the mixture was warmed to room temperature and stirred for reaction for 10 min, and triethylamine (361 mg, 3.58 mol) was added thereto and reacted overnight at room temperature. TLC (petroleum ether: ethyl acetate =2:1) detected the completion of the starting material reaction. The reaction was quenched with water (20mL), extracted with ethyl acetate (20mL x4), the organic phases combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated, sample stirred and isolated by flash preparative chromatography (petroleum ether: ethyl acetate =4: 1) to give compound 25 as a yellow oil (920 mg, yield 93.6%).
Step 4 example 50 Compound(R)-3-benzyl-5-methyl-5-(s) (((S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]] [1,5]Synthesis of azapine-3-yl) amino) imidazoline-2, 4-dione
Figure 502197DEST_PATH_IMAGE157
Under nitrogen protection, two drops of compound 25(500 mg, 2.48 mmol), 7(570 mg, 2.97 mmol), dichloromethane (15 mL) and triethylamine were added in this order to a 50 mL single-neck flask and reacted at 40 ℃ for 12 h. After the completion of the reaction was monitored by TLC (ethyl acetate: petroleum ether =2:1), water (5 mL) was added, followed by extraction with dichloromethane (20mL × 3), washing with a saturated sodium chloride solution, and collecting an organic phase. The reaction mixture was dried over anhydrous magnesium sulfate, filtered under suction, concentrated, and purified with a silica gel column (petroleum ether: ethyl acetate =1:1 to 1: 2) to obtain the compound of example 50 (60 mg, yield 6.14%) as a white solid. Melting point >250 deg.C, [ alpha ]]
Figure 464337DEST_PATH_IMAGE118
=-124.01º。
1 H NMR (400 MHz, CDCl 3 )δ(ppm): 7.13-7.25(m, 7H), 7.05-7.08(m, 1 H), 6.98-7.00(m, 1 H), 5.39(s, 1 H), 4.45-4.55(m, 2 H), 4.26-4.30 (m, 1H), 4.11-4.13(m, 1 H), 3.39-3.41(m, 1 H), 3.34(s, 3 H), 3.23-3.24 (m, 1 H), 1.49 (s, 3 H);
13 C NMR(100 MHz, CDCl 3 ) δ(ppm): 173.44, 172.80, 154.98, 149.99, 136.20, 135.75, 128.72, 127.80, 127.73, 127.58, 125.82, 123.24, 122.66, 122.96, 78.93, 73.66, 52.84, 42.08, 35.92, 25.11；
ESI C 21 H 22 N 4 O 4 m/z: 394.16 (M + +H)。
Example 51 Compounds(S)-3-benzyl-5-methyl-5- (((S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]] [1,5]Synthesis of azapine-3-yl) amino) imidazoline-2, 4-dione
Figure 76453DEST_PATH_IMAGE158
The synthesis method of example 50 was repeated, and in the process of obtaining the compound of example 50 by silica gel column purification (petroleum ether: ethyl acetate =1:1 to 1: 2), 55 mg of the compound of example 51 was isolated as an off-white solid in a yield of 5.63%, a melting point of 100.9 to 102.4 ℃, [ alpha ] -]
Figure 846963DEST_PATH_IMAGE116
=-135.92º。
1 H NMR (400 MHz, CDCl 3 )δ(ppm): 7.21-7.06(m, 9H), 5.43(s, 1H), 4.54-4.46(m, 2H), 4.32-4.27(m, 1H), 4.12-4.07(m, 1H), 3.37(s, 3H), 3.24-3.17(m, 1H), 2.80-2.77(m, 1H), 1.56(s, 3H)。
13 C NMR(100 MHz, CDCl 3 )δ(ppm): 173.26, 172.72, 154.70, 149.97, 136.24, 135.75, 128.63, 127.73, 127.71, 127.50, 125.78, 123.19, 122.65, 77.21, 73.62, 52.84, 42.08, 35.87, 25.27;
ESI C 21 H 22 N 4 O 4 m/z: 394.32 (M + +H)。
Example 52 Compounds (R)-3-benzyl-5- (((s))(S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1, 5]Synthesis of azapine-3-yl) amino) methyl) imidazoline-2, 4-dione
Figure 535433DEST_PATH_IMAGE159
Step 1 Synthesis of Compound 26, i.e., 3-benzyl-5-methylene-2, 4-dioxoimidazoline-1-carboxylic acid tert-butyl ester
Figure 204443DEST_PATH_IMAGE160
A50 mL single-neck flask was charged with approximately 80% of compound 25(794 mg, 3.90 mmol), DMAP (95 mg, 0.78 mmol), triethylamine (789 mg, 7.8 mmol) and dichloromethane (10mL) in that order. After the addition, Boc is dropwise added at 0 DEG C 2 O (1.29 g, 5.90 mmol) was stirred for 10 minutes and at room temperature for 3 hours. TLC (petroleum ether: ethyl acetate =5:1) detected the starting material was completely reacted. Direct concentration and column chromatography (petroleum ether: ethyl acetate =5:1) gave compound 26(130 mg, 11.0%) as a colorless oil.
1 H NMR (400 MHz, CDCl3): δ ppm 7.42(dd, J1=7.6 Hz, J2=1.6 Hz, 2 H), 7.35-7.28(m, 3 H), 6.02(d, J=1.0 Hz, 1 H), 5.87(d, J=1.0 Hz, 1 H), 4.74(s, 2 H), 1.59(s, 9 H)。
Step 2 Synthesis of Compound 27, tert-butyl 3-benzyl-5- ((((S) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,5] oxazepin-3-yl) amino) methyl) -2, 4-dioxoimidazoline-1-carboxylate
Figure 636561DEST_PATH_IMAGE161
To a 50 mL single-necked flask were added compound 26(250 mg, 0.83 mmol), compound 7(207 mg, 1.08 mmol) and dichloromethane (10mL) in that order. After addition, stir at 50 ℃ overnight. TLC (petroleum ether: ethyl acetate =3:1) detects about 40% remaining starting material. Direct concentration and column chromatography (petroleum ether: ethyl acetate =3:1) gave compound 27(290 mg, 70.7%) as a white solid.
Step 3 Compounds of example 52(R)-3-benzyl-5- (((s))(S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) amino) methyl) imidazoline-2, 4-dione (example 52)
Figure 906918DEST_PATH_IMAGE162
To a 50 mL single-necked flask were added compound 27(240 mg, 049 mmol) and a 4N HCl in ethyl acetate solution (7 mL) in that order. After the addition, the mixture was stirred at room temperature for 0.5 hour. TLC (petroleum ether: ethyl acetate =3:1) detected the starting material was completely reacted. Water (10mL) was added, and the mixture was washed with ethyl acetate (15 mL. times.3). The aqueous phase was collected, made basic with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (15 mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and separated on a thick preparative plate (petroleum ether: ethyl acetate =1:3) to give a first-order crude product, which was repeatedly separated three times on a thick preparative plate (petroleum ether: ethyl acetate =1:3) to give the pure compound of example 52 (54 mg, 24.3%) as a pale purple solid.
Melting point of 205.6-207.8 deg.C, [ alpha ]]
Figure 500710DEST_PATH_IMAGE118
=-138.10º。
1 HNMR (400 MHz, CDCl 3 ): δ ppm 7.34-7.36 (m, 2 H), 7.27-7.32 (m, 3 H), 7.17-7.24 (m, 3 H), 7.11-7.16 (m, 1 H), 5.68 (s, 1 H), 4.57-4.66 (m, 2 H), 4.27-4.32 (m, 1 H), 3.90-4.03 (m, 2 H), 3.64 (s, 1 H), 3.48-3.53 (m, 1 H), 3.39 (s, 3 H), 2.96 (dd, J 1 =8.4 Hz, J 2 =14.2 Hz, 1 H), 2.77 (dd, J 1 =3.2 Hz, J 2 =14.2 Hz, 1 H)；
13 C NMR (400 MHz, CDCl 3 ): δ ppm 171.13, 156.22, 149.23, 135.62, 134.93, 127.50, 126.83, 126.31, 124.55, 122.18, 121.70, 77.87, 57.78, 57.09, 49.18, 41.14, 34.43；
ESI C 21 H 22 N 4 O 4 m/z: 395.21 (M + +H)。
Example 53 Compounds(S)-3-benzyl-5- (((s))(S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) amino) methyl) imidazoline-2, 4-dione (example 53)
Figure 578387DEST_PATH_IMAGE163
The synthetic method of example 52 was repeated, and in the course of performing thick preparative plate separation (petroleum ether: ethyl acetate =1:3) to obtain the compound of example 52, the compound of example 53 (53 mg, 24.3%) was also isolated as a white solid in a yield of 48.6%. Melting point 260.6-265.3 deg.C, [ alpha ]]
Figure 96087DEST_PATH_IMAGE116
=-175.00º。
1 HNMR (400 MHz, CDCl 3 ): δ ppm 7.36-7.38 (m, 2 H), 7.29-7.33 (m, 3 H), 7.21-7.25 (m, 3 H), 7.14-7.17 (m, 1 H), 6.10 (s, 1 H), 4.58-4.68 (m, 1 H), 4.24 (dd, J 1 =7.6 Hz, J 2 =10.4 Hz, 1 H), 3.96 (dd, J 1 =10.6 Hz, J 2 =11.6 Hz, 1H), 3.90-3.93 (m, 1 H), 3.48 (dd, J 1 =7.6 Hz, J 2 =11.2 Hz, 1 H), 3.38 (s, 3 H), 3.15 (dd, J 1 =3.2 Hz, J 2 =14.2 Hz, 1 H), 2.62 (dd, J 1 =7.2 Hz, J 2 =14.2 Hz, 1H), 2.02 (s, 1 H)；
13 C NMR(400 MHz, CDCl 3 ): δ ppm 172.66, 157.07, 150.29, 136.54, 136.02, 128.46, 127.77, 127.46, 125.57, 123.20, 122.77, 78.95, 58.31, 57.46, 50.04, 42.12, 35.48；
ESI C 21 H 22 N 4 O 4 m/z: 395.21 (M + +H)。
Example 54 Compound 1-benzyl-N-((S) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2, 5-dioxoimidazoline-4-carboxamide
Figure 903506DEST_PATH_IMAGE164
Step 1 Synthesis of Compound 28, diethyl 2- (tert-Butoxycarbonyl) aminomalonate
Figure 340304DEST_PATH_IMAGE165
To a 250 mL single neck flask were added diethyl 2-aminomalonate (5.0 g, 23.6 mmol), sodium bicarbonate (2.084 g, 24.8 mmol), water (30 mL), dioxane (30 mL). Stirring at room temperature under nitrogen, clarifying, adding DMAP (28.8 mg, 0.236 mmol), and then adding 30 mL of a solution containing (Boc) dropwise 2 O (5.414 g, 24.8 mmol) in dioxane, about 1h after the addition, the reaction was continued for 18 h. TLC detection reaction raw material basically completely reacts. The reaction mixture was concentrated to remove dioxane, 60 mL of ethyl acetate was added thereto, the mixture was separated into layers, and the organic layer was washed with 20mL of 5% potassium hydrogensulfate, 20mL of saturated sodium hydrogencarbonate, 20mL of saturated brine, 20mL of water, and the organic layer was Na 2 SO 4 Drying, filtration and concentration gave compound 28 as a colorless clear oil (6.48 g, 100% yield).
Step 2 Synthesis of Compound 29, 2- ((tert-Butoxycarbonyl) amino) -3-ethoxy-3-oxomalonic acid
Figure 544758DEST_PATH_IMAGE166
To a 100 mL single-neck vial was added compound 28(6.48 g,23.6 mmol), ethanol (30 mL). 30 mL of an ethanol solution of potassium hydroxide (1.3 g, 23.6 mmol) was added dropwise under a nitrogen atmosphere, and the reaction was continued at room temperature for 24 hours after the addition was completed for about 1 hour. About 10% of the starting material remained as detected by TLC. Concentrating the reaction solution to remove ethanol, adding 20mL saturated sodium bicarbonate water solution to dissolve, extracting with ethyl acetate (20mL × 2) twice, adjusting pH of the water phase to 4 with saturated potassium bisulfate, extracting with ethyl acetate (40 mL × 2) twice, mixing the organic phases after adjusting pH, and adding anhydrous Na 2 SO 4 Drying, filtration and concentration gave compound 29 as a white solid (3.3 g, yield 56.7%).
Synthesis of compound 30, ethyl 2- ((tert-butoxycarbonyl) amino) -3- ((S) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,5] azepin-3-yl) amino) -3-oxopropanoate in step 3
Figure 318679DEST_PATH_IMAGE167
To a 100 mL one-neck flask were added compound 29(988 mg, 4mmol), HATU (1.82 g, 4.8 mmol), and dichloromethane (30 mL), stirred at room temperature for 10 minutes, added diisopropylethylamine (1.29 g, 10 mmol), compound 7(1.0 g, 4mmol), and stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was completed by TLC, the reaction solution was washed with saturated brine (10mL × 3), and the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and isolated by flash preparative chromatography (petroleum ether/ethyl acetate =5:1) to give compound 30(1.75 g, yield 98%) as a white solid.
Synthesis of compound 31, 2-amino-3- ((S) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] [1,5] azepin-3-yl) amino) -3-oxopropanoic acid ethyl ester hydrochloride, step 4
Figure 918288DEST_PATH_IMAGE168
To a 100 mL single-neck flask was added compound 30(750 mg, 1.78 mmol), 10mL of a 3N ethyl acetate hydrochloride solution, and the mixture was stirred at room temperature for 1h under a nitrogen atmosphere. The reaction was completed by TLC, and the reaction mixture was concentrated to dryness, and added with 20mL of ethyl acetate to continue concentrating once, to obtain compound 31 as a white solid (637 mg, yield 100%).
Step 5 Compound 32, i.e., 2- (3-Benzylpyrureido) -3-(s) ((R))(S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]] [1,5]Synthesis of ethyl azepin-3-yl) amino) -3-oxopropanoate
Figure 604615DEST_PATH_IMAGE169
To a 50 mL single-neck flask was added compound 31(340 mg, 0.95 mmol), benzyl isocyanate (189.5 mg, 1.43 mmol), TEA (288 mg, 2.85 mmol) and chloroform (10mL), and stirred at 60 ℃ for 1h under nitrogen. The reaction was completed by TLC (petroleum ether: ethyl acetate =1:1), the reaction solution was cooled to room temperature, washed three times with saturated brine (20mL × 3), and the organic layer was washed with anhydrous Na 2 SO 4 Drying, filtration, and flash chromatography (20 g, petroleum ether: ethyl acetate =1:1) isolated compound 32(366 mg, yield 87.6%) as a white solid.
Step 6 the Compound of example 54, 1-benzyl-N-((S) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2, 5-dioxoimidazoline-4-carboxamide
Figure 781519DEST_PATH_IMAGE170
To a 50 mL single-neck flask was added compound 32(366 mg, 0.77 mmol), sodium ethoxide (26 mg, 0.39 mmol) and ethanol (20mL), and stirred at 60 ℃ for 1h under nitrogen. The reaction was completed by TLC (dichloromethane: methanol =20:1), ethanol was removed by concentration under reduced pressure, 20mL ethyl acetate and 10mL water were added, the layers were separated, the organic phase was washed with saturated brine (10 mLx3), the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and separated on a thick prep. plate (dichloromethane: methanol =20:1) to give the compound of example 54 as a white solid (130 mg, yield 41.4%), melting point 108.2-109.8 ℃.
1 HNMR 400MHz(DMSO-d 6 ) δ(ppm): 8.88-8.91(m, 1H), 8.57(d, J = 29.6 Hz, 1H), 7.45-7.50(m, 1H), 7.20-7.34(m, 8 H), 4.88(dd, J 1 =1.2Hz, J 2 = 12Hz, 1H), 4.67-4.77(m, 1H), 4.46- 4.56(m, 2H), 4.23-4.38(m, 2H), 3.31 (s, 3H);
13 C-NMR 100MHz(DMSO-d 6 ) δ(ppm): 167.54, 167.51, 167.49, 167.36, 161.96, 161.61, 155.86, 155.55, 148.95, 148.93, 134.89, 134.32, 127.71, 127.09, 126.77, 124.81, 122.27, 121.89, 75.80, 75.76, 58.59, 58.39, 48.87, 48.65, 41.73, 34.51.
ESI C 21 H 20 N 4 O 5 m/z: 408.85 (M + +H)。
Example 55 Compound 1- (3-Fluorobenzyl) -N- ((S) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,5]Synthesis of azapine-3-yl) -2, 5-dioxoimidazoline-4-carboxamide
Figure 765655DEST_PATH_IMAGE171
Referring to the synthesis of example 54, benzyl isocyanate was replaced with 3-fluorobenzyl isocyanate to give the compound of example 55 (62 mg) as a white solid in 22% yield and melting point 92.2-93.1 ℃.
1 H NMR 400 MHz (DMSO-d 6 ) δ(ppm): 8.93-8.97 (m, 1 H), 8.61 (d, J = 30 Hz, 1 H), 7.46-7.50 (m, 1 H), 7.22-7.34 (m, 4 H), 7.02-7.10 (m, 3 H), 4.90 (dd, J 1 = 1.2 Hz, J 2 = 10.4 Hz, 1 H), 4.67-4.77 (m, 1 H), 4.49-4.58 (m, 2 H), 4.23-4.38 (m, 2 H), 3.32 (s, 3 H)。
13 C NMR 100 MHz (DMSO-d 6 ) δ (ppm): 167.59, 167.52, 167.42, 167.28, 163.03, 161.93, 161.56, 160.58, 155.73, 155.38, 148.93, 136.60, 136.53, 134.87, 126.79, 124.83, 123.20, 122.29, 121.89, 114.65, 114.43, 114.24, 114.00, 75.78, 58.73, 58.48, 48.91, 48.67, 41.14, 34.53；
ESI C 21 H 19 FN 4 O 5 m/z: 426.80 (M + +H)。
Example 56 Compound 1- (3, 4-difluorobenzyl) -N-((S) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azepin-3-yl) -2-, 5-dioxoimidazoline-4-carboxamide
Figure 796934DEST_PATH_IMAGE172
Referring to the synthesis procedure of example 54, benzyl isocyanate was replaced with 3, 4-difluorobenzyl isocyanate to give 240 mg of the compound of example 56 as a white solid), 50% yield, and 139.8-141.1 ℃ melting point.
1 H NMR 400 MHz (DMSO-d 6 ) δ(ppm): 8.94-8.98 (m, 1 H), 8.63 (d, J = 29.6 Hz, 1 H), 7.46-7.51 (m, 1 H), 7.22-7.43 (m, 5 H), 7.06-7.09 (m, 1 H), 4.90 (dd, J 1 = 0.8 Hz, J 2 = 10.4Hz, 1 H), 4.68-4.78 (m, 1 H), 4.48-4.57 (m, 2 H), 4.20-4.39 (m, 2 H), 3.32 (s, 3 H)；
13 C NMR 100 MHz (DMSO-d 6 ) δ (ppm): 167.59, 167.55, 167.37, 167.27, 161.92, 161.60, 155.71, 155.36, 148.94, 148.91, 148.04, 147.91, 134.86, 134.83, 131.21, 131.16, 131.12, 126.83, 124.86, 124.05, 124.01, 123.98, 123.95, 123.91, 122.29, 122.27, 121.92, 121.88, 116.96, 116.78, 116.60, 116.57, 116.42, 116.40, 77.57, 58.78, 58.58, 48.92, 48.68, 40.70, 34.53；
ESI C 21 H 18 F 2 N 4 O 5 m/z: 444.85 (M + +H)。
Example 57 Compounds(R)-3-benzyl-N-((S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2-oxooxazoline-5-carboxamide
Figure 169009DEST_PATH_IMAGE173
Step 1 Synthesis of Compound 33, 4- (benzyloxy) -3-hydroxy-4-oxobutanoic acid
Figure 583941DEST_PATH_IMAGE174
A500 mL single neck flask was charged with 2-hydroxysuccinic acid (20.0 g, 149 mmol) and pre-cooled to 0 ℃ TFAA (78.4 g, 372 mmol) and reacted at 0 ℃ for 4h under nitrogen. The reaction was turned from cloudy to clear and concentrated at 0 ℃. To the residue was added benzyl alcohol (234 g, 2.16 mol) and reacted at 25 ℃ for 4h under nitrogen. After completion of the reaction was monitored by TLC (dichloromethane: methanol =20:1), ethyl acetate (150 mL) was added to the above reaction solution, extracted with 10% sodium carbonate solution (150 mL × 3), and the aqueous phase was collected. The aqueous phase was adjusted to pH7 with 3N dilute hydrochloric acid, extracted with ethyl acetate (100 mL. times.3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL. times.3), the organic phase was collected, dried over anhydrous magnesium sulfate, filtered with suction, and concentrated to give compound 33(30.3 g, yield 90.4%) which was directly charged to the next reaction.
Step 2 Synthesis of Compound 34, benzyl 2-oxooxazoline-5-carboxylate
Figure 434086DEST_PATH_IMAGE175
To a 1L single-neck flask were added compound 33(29.30 g, 0.131 mol), toluene (300 mL), triethylamine (15.90 g, 0.157 mol) and DPPA (43.20 g, 0.157 mol) in that order, and reacted at 110 ℃ for 4h under nitrogen. TLC (petroleum ether: ethyl acetate =1:1) monitored after the reaction was completed, and concentrated. Water (200 mL) was added to the residue, extracted with ethyl acetate (100 mL. times.4), and the organic phases were combined. Saturated sodium chloride solution (100 mL × 4) was washed, the organic phase was collected, dried over anhydrous magnesium sulfate, filtered with suction, concentrated, and purified with silica gel column (petroleum ether: ethyl acetate =2:1 to 1.5: 1) to obtain compound 34(14.1 g, yield 48.6%) as an off-white solid.
1 H NMR (400 MHz, CDCl 3 ) δ(ppm): 7.27-7.31(m, 5H), 5.76 (s, 1H), 5.15-5.22 (m, 2H), 4.95-4.99 (m, 1H), 3.78-3.82 (m, 1H), 3.58-3.62 (m, 1H)。
Synthesis of Compound 35, benzyl 3-benzyl-2-oxooxazoline-5-carboxylate, in step 3
Figure 8286DEST_PATH_IMAGE176
To a 250 mL single neck flask were added compound 34(4.00 g, 18.1 mmol), acetone (80mL), potassium carbonate (5.00 g, 36.2 mmol) and benzyl bromide (10.2 g, 59.7 mmol) in that order and reacted at 25 ℃ for 40 h. After completion of the reaction monitored by TLC (petroleum ether: ethyl acetate =2:1), the reaction was filtered through a celite pad, concentrated, and purified by silica gel column (petroleum ether: ethyl acetate =3:1 to 2:1) to obtain compound 35(3.97 g, yield 70.5%) as a white solid.
Step 4 Synthesis of Compound 36, 3-benzyl-2-oxooxazoline-5-carboxylic acid
Figure 534952DEST_PATH_IMAGE177
A250 mL single neck flask was charged with compound 35(3.97 g, 12.8 mmol) and tetrahydrofuran (40 mL), stirred at 0 ℃ and added with potassium carbonate (7.05 g, 51.0 mmol) in water (40 mL), and reacted at 0 ℃ for 2h under nitrogen. After the completion of the reaction was monitored by TLC (petroleum ether: ethyl acetate =1:1), the reaction solution was adjusted to pH 2 with 3mol/L dilute hydrochloric acid, extracted with ethyl acetate (100 mL. times.3), washed with a saturated sodium chloride solution (2 mL. times.3), and the organic phase was collected, dried over anhydrous magnesium sulfate, filtered with suction, concentrated, and slurried with ethyl acetate (10 mL). Suction filtration, cake washing with ethyl acetate (2 mL. times.3), collection of the filter cake, at 45 ℃ to dry for 4h, white solid 36(1.11 g, yield 39.2%).
Step 5 example 57 Compounds namely(R)-3-benzyl-N-((S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2-oxooxazoline-5-carboxamide
Figure 155289DEST_PATH_IMAGE178
To a 100 mL single-neck flask were added compound 36(600 mg, 2.71 mmol), dichloromethane (20mL) and HATU (1.13 g, 2.96 mmol) in that order, and stirred at 25 ℃ for 20 min under nitrogen. Diisopropylethylamine (958 mg, 7.41 mmol) and 7(564 mg, 2.47 mmol) were added to the above reaction solution in this order, and reacted at 25 ℃ for 12 hours. After the completion of the reaction was monitored by TLC (petroleum ether: ethyl acetate =1: 2), water (20mL) was added to the reaction system, extraction was performed with ethyl acetate (20mL × 3), the organic phases were combined, washed with a saturated sodium chloride solution (5 mL × 3), dried over anhydrous magnesium sulfate, suction-filtered, and the filtrate was concentrated. Flash preparative chromatography purification (40 g, petroleum ether: ethyl acetate =1:1) afforded crude a and crude B. Crude a was purified by flash preparative chromatography (12 g, petroleum ether: ethyl acetate =1: 1.5) to give a purer product which was further purified by prep plate (petroleum ether: ethyl acetate =2:1) to give the compound of example 57 as a white solid (230 mg, yield 23.5%), melting point: alpha at 96.6-98.5 ℃, [ alpha ]]
Figure 356594DEST_PATH_IMAGE118
=-81.63º。
1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 8.57 (d, J=8.0Hz, 1H), 7.47-7.49 (m, 1H), 7.20-7.38 (m, 8H), 4.97-5.01 (m, 1H), 4.67-4.74 (m, 1H), 4.30-4.42 (m, 4H), 3.61-3.66 (m, 1H), 3.31- 3.35 (m, 4H)。
13 C NMR (100 MHz, CDCl 3 ) δ (ppm)34.5, 45.8, 47.3, 48.2, 69.6, 76.2, 121.9, 122.2, 124.7, 126.6, 127.1, 127.2, 127.9, 133.9, 135.0, 148.9, 155.0, 167.2, 167.5;
ESI C 21 H 21 N 3 O 5 m/z: 395.85 (M + +H)。
Example 58 Compounds(S)-3-benzyl-N-((S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2-oxooxazoline-5-carboxamide
Figure 113198DEST_PATH_IMAGE179
Crude product B obtained in example 57 was purified by flash preparative chromatography (12 g, petroleum ether: ethyl acetate =1: 1.5) to give a purer product which was further purified by prep plate (petroleum ether: ethyl acetate =2:1) to give the compound of example 58 (123 mg, yield 12.6%) as a white solid with a melting point >250 ℃, [ α ]]
Figure 499179DEST_PATH_IMAGE118
=-107.65º。
1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 8.59 (d, J = 8.0 Hz, 1H), 7.46-7.48 (m, 1H), 7.20-7.37 (m, 8H), 4.97-5.01 (m, 1H), 4.66-4.72 (m, 1H), 4.29-4.41 (m, 4H), 3.66-3.70 (m, 1H), 3.29-3.36 (m, 4H);
13 C NMR (100 MHz, CDCl 3 ) δ (ppm): 34.5, 45.9, 47.2, 48.1, 69.6, 76.0, 121.8, 122.2, 124.7, 126.6, 127.1, 127.2, 127.9, 133.9, 135.0, 148.9, 155.1, 167.2, 167.7;
ESI C 21 H 21 N 3 O 5 m/z: 395.90 (M + +H)。
Example 59 Compounds(R)-5-benzyl-N-((S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2-oxooxazoline-3-carboxamide
Figure 584642DEST_PATH_IMAGE180
Step 1 Synthesis of Compound 37, 5-Benzyloxazolin-2-one
Figure 776589DEST_PATH_IMAGE181
2-Phenyloxirane (4.50 g, 37.5 mmol) and methyl carbamate (3.37 g, 44.9 mmol) were added to a 25 mL single-neck flask, and triethylamine (759 mg, 7.50 mmol) was added dropwise to the reaction mixture under nitrogen, and the mixture was reacted at 120 ℃ for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature by TLC (petroleum ether: ethyl acetate =2:1), ethyl acetate (50 mL) was added thereto, and the mixture was washed with water (10mL × 3) and a saturated sodium chloride solution (10mL × 3) in this order to collect an organic phase. The extract was dried over anhydrous magnesium sulfate, filtered with suction, concentrated, and purified by a vacuum column (petroleum ether: ethyl acetate =5:1 to 1:1) to obtain compound 37(2.52 g, yield 32.2%) as a yellow solid.
Step 2 Synthesis of Compound 38, 4-nitrophenyl-5-benzyl-2-oxooxazoline-3-carboxylate
Figure 200748DEST_PATH_IMAGE182
To a 100 mL single-neck flask were added compound 37(1.26 g, 7.11 mmol), dichloromethane (40 mL), triethylamine (3 mL, 21.3 mmol) and p-nitrochloroformate (1.72 g, 8.53 mmol) in that order, and the mixture was reacted at room temperature for 4h under nitrogen. After the completion of the reaction was monitored by TLC (petroleum ether: ethyl acetate =4: 1), the reaction system was quenched by addition of water (20mL), the organic layer was separated, washed with a saturated sodium chloride solution (10 mL. times.3), and the organic phase was collected. The extract was dried over anhydrous magnesium sulfate, filtered with suction, concentrated, and purified by a vacuum column (petroleum ether: ethyl acetate =5:1 to 1:1) to obtain compound 38(1.16 g, yield 47.7%) as a yellow solid.
Step 3 the compound of example 59(R)-5-benzyl-N-((S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2-oxooxazoline-3-carboxamide (example 59)
Figure 819948DEST_PATH_IMAGE183
A50 mL single vial was charged with compound 38(1.06 g, 3.10 mmol), tetrahydrofuran (20mL) and compound 7(0.71 g, 3.72 mmol) in that order and reacted at 25 ℃ for 12h under nitrogen. TLC (petroleum ether: ethyl acetate =2:1) monitors the reaction, concentrates it, and purifies it by flash chromatography (petroleum ether: ethyl acetate =2:1) to obtain crude a and crude B. Crude product A was purified by preparative plate (petroleum ether: ethyl acetate = 1.5: 1) to giveTo a white solid, the compound of example 59 (211 mg, yield 30.6%), melting point 123.7-125.2 ℃, [ alpha ] -]
Figure 821402DEST_PATH_IMAGE118
=-80.56º。
1 H NMR (400 MHz, DMSO-d 6 ) δ(ppm): 8.38(d, J = 6.8 Hz, 1H), 7.47-7.45(m, 1H), 7.32-7.20(m, 8H), 4.93-4.86(m, 1H), 4.63-4.56(m, 1H), 4.47-4.43 (m, 1H), 4.27-4.22(m, 1H), 3.91-3.86(m, 1H), 3.54-3.49(m, 1H), 3.30(s, 3H), 3.00(d, J = 6.4 Hz, 1H);
13 C NMR (100 MHz, CDCl 3 ) δ(ppm): 167.7, 153.5, 150.0, 149.0, 135.2, 133.1, 128.3, 127.9, 126.5, 126.4, 124.6, 122.2, 121.8, 76.2, 73.5, 49.2, 45.7, 39.3, 34.4；
ESI C 21 H 21 N 3 O 5 m/z: 395.90(M + +H)。
EXAMPLE 60 Compounds(S)-5-benzyl-N–((S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of oxazepine-3-) -2-oxooxazoline-3-carboxamide
Figure 863045DEST_PATH_IMAGE184
The crude product B obtained in example 59 was purified by preparative plate (petroleum ether: ethyl acetate = 1.5: 1) to give the compound of example 60 as a white solid (280 mg, yield 22.9%), melting point:>250℃，[α]
Figure 594241DEST_PATH_IMAGE118
=-132.14º。
1 H NMR(400 MHz, DMSO-d 6 )δ(ppm): 8.35(d, J = 6.8 Hz, 1H), 7.47-7.45(m, 1H), 7.34-7.22(m, 8H), 4.95-4.88(m, 1H), 4.64-4.58(m, 1H), 4.49-4.44(m, 1H), 4.26-4.21(m, 1H), 3.91-3.86 (m, 1H), 3.60-3.56(m, 1H), 3.31(s, 3H), 3.02(d, J=6.4Hz, 1H);
13 C NMR(100 MHz, CDCl 3 )δ(ppm): 167.6, 153.5, 149.8, 149.0, 135.2, 133.0, 128.4, 127.8, 126.5, 126.4, 124.6, 122.2, 121.8, 76.2, 73.4, 49.2, 45.6, 39.4, 34.4.
ESI C 21 H 21 N 3 O 5 m/z: 395.90 (M + +H)。
example 61 Compound 4-benzyl-N-((S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -5-oxoimidazoline-1-carboxamide
Figure 135075DEST_PATH_IMAGE185
Step 1 Synthesis of Compound 39, i.e., (1-amino-1-oxo-3-phenylpropan-2-yl) carbamic acid tert-butyl ester
Figure 623825DEST_PATH_IMAGE186
Sequentially adding into a 500 mL single-mouth bottleN-tert-Butoxycarbonylphenylalanine (10.00g, 37.7 mmol), tetrahydrofuran (110 mL), HOBt (6.11 g, 45.3 mmol) and EDCI (10.80 g, 56.6 mmol) were stirred at room temperature under nitrogen for 1 h. Ammonia (110 mL) was added and the reaction was carried out at room temperature for 36 h under nitrogen. After completion of the reaction, TLC (dichloromethane: methanol =20:1) was carried out, the organic solvent was distilled off under reduced pressure, water (50 mL) was added, ethyl acetate (100 mL. times.3) was extracted, and the mixture was washed with saturated brine (20 mL. times.3), and the organic phase was collected and dried over anhydrous magnesium sulfate. Suction filtration, concentration of the filtrate, and purification by a reduced pressure column (dichloromethane: methanol =50:1) gave compound 39(7.00 g, 70.7% yield) as a white powder.
Step 2 Synthesis of Compound 40, i.e., tert-butyl 5-benzyl-4-oxoimidazoline-1-carboxylate
Figure 219891DEST_PATH_IMAGE187
A250 mL single-neck flask was charged with compound 39(3.50 g, 13.3 mmol), absolute ethanol (150 mL), triethylamine (1.34 g, 13.3 mmol), potassium carbonate (18.30 g, 132 mmol) and 37% aqueous formaldehyde (38 mL) in that order and reacted at 60 ℃ for 12h under nitrogen. After the reaction was monitored by TLC (dichloromethane: methanol =20:1), it was concentrated to dryness, and ethyl acetate (400 mL) was added. The mixture was washed successively with water (40 mL. times.3) and saturated brine (40 mL. times.3), and the organic phase was collected, dried over anhydrous magnesium sulfate, and filtered with suction. The filtrate was concentrated, purified by a vacuum column (dichloromethane: methanol =100: 1 to 50:1), and concentrated to obtain compound 40(4.21 g, yield 43.1%) as a white powder.
Step 3 Synthesis of Compound 41, 3- (tert-butyl) -1- (4-nitrophenyl) -4-benzyl-5-oxoimidazoline-1, 3-dicarboxylic acid ester
Figure 54861DEST_PATH_IMAGE188
To a 250 mL single-neck flask were added compound 40(4.21 g, 15.3 mmol), dichloromethane (130 mL) and triethylamine (4.66 g, 45.8 mmol) in that order. While stirring at room temperature, a solution of p-nitrochloroformate (3.68 g, 18.3 mmol) in methylene chloride (20mL) was added dropwise to the above reaction mixture, and the mixture was reacted at room temperature for 3 hours under nitrogen atmosphere. After completion of the reaction was monitored by TLC (dichloromethane: methanol =50:1), the reaction system was quenched with ice water (20mL), the organic layer was separated, washed with saturated brine (20 mL. times.3), the organic phase was collected, and dried over anhydrous magnesium sulfate. Suction filtration, concentration of the filtrate, purification by flash chromatography (dichloromethane: methanol =50:1), and concentration gave compound 41(2.80 g, yield 41.8%) as a white powder.
Step 4 Compound 42, 5-benzyl-3- (((s) ((S) -5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]] [1,5]Synthesis of azapine-3-yl) carbamoyl) -4-oxoimidazoline-1-carboxylic acid tert-butyl ester
Figure 687968DEST_PATH_IMAGE189
To a 250 mL single-neck flask were added compound 41(2.80 g, 6.36 mmol), DMF (25 mL) and triethylamine (1.93 g, 19.1 mmol) in that order. To the reaction mixture was added compound 7(1.45 g, 6.36 mmol) under stirring at room temperature, and the mixture was reacted at 75 ℃ for 3 hours under nitrogen atmosphere. TLC (dichloromethane: methanol =20:1) monitored reaction completion, saturated brine (50 mL) was added to the reaction system, ethyl acetate (25 mL × 4) was extracted, the organic phases were combined, washed with saturated brine (10mL × 4), and the organic phases were collected and dried over anhydrous magnesium sulfate. And (5) carrying out suction filtration and concentration to obtain a crude product. The crude product was slurried with ethyl acetate (10mL) to afford 42(1.65g, 40.3% yield).
Step 5 the compound of example 61, namely 4-benzyl-N-((S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -5-oxoimidazoline-1-carboxamide
Figure 726331DEST_PATH_IMAGE190
A50 mL single-neck flask was charged with compound 42(1.00 g, 2.02 mmol) and a 3N solution of hydrogen chloride in ethyl acetate (20mL) and reacted at room temperature for 1.5 h under a nitrogen blanket. After completion of the reaction, the reaction system was neutralized with a saturated sodium bicarbonate solution by TLC (dichloromethane: methanol =10:1), extracted with ethyl acetate (50 mL × 3), washed with a saturated saline solution (10mL × 3), and the organic phase was collected and dried over anhydrous magnesium sulfate. And (3) carrying out suction filtration, concentrating the filtrate, carrying out rapid preparative chromatography purification (40 g, dichloromethane: methanol =100: 1-20: 1), and concentrating to obtain a crude product. The crude product was purified on a preparation plate (dichloromethane: methanol =10:1) to give the compound of example 61 as a white solid (54 mg, yield 6.78%).
1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 8.23-8.19 (m, 1H), 7.40-7.37 (m, 1H), 7.28-7.13 (m, 9H), 4.30-4.23 (m, 1H), 4.03-3.97 (m, 1H), 3.92-3.80 (m, 2H), 3.63-3.57 (m, 2H), 3.27 (d, J = 2.8 Hz, 3H), 2.90-2.83 (m, 1H), 2.61-2.50 (m, 1H);
13 C NMR (100 MHz, CDCl 3 ) δ (ppm):173.42, 172.22, 149.32, 136.81, 135.74, 128.20, 127.81, 126.34, 125.93, 124.57, 122.29, 121.64, 76.23, 55.67, 55.49, 53.07, 39.95, 34.62；
ESI C 21 H 22 N 4 O 4 m/z: 394.90 (M + +H)。
Example 62 Compound 1-benzyl-N-((S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2-oxoimidazoline-4-carboxamide
Figure 876821DEST_PATH_IMAGE191
Example 62
Step 1 Synthesis of Compound 43, 3- ((benzyloxy) carbonyl) -2-oxoimidazoline-4-carboxylic acid
Figure 51450DEST_PATH_IMAGE192
To a 500 mL single-neck flask were added sodium hydroxide (5.26 g, 131.5 mmol) and purified water (200 mL) and dissolved with stirring at 0 ℃. Under the protection of nitrogen, bromine (6.31 g, 39.44 mmol) was slowly added dropwise to the reaction solution, and the addition was completed in 10 min. (benzyloxy) carbonyl asparagine (10.00g, 37.56 mmol) was slowly added to the reaction mixture, and after the addition was complete, the mixture was transferred to 50 ℃ for reaction for 3.5 h. After the completion of the reaction was monitored by TLC (methanol), the reaction solution was cooled to room temperature, washed with anhydrous ether (25 mL. times.3), and the aqueous phase was collected. The pH of the aqueous phase was adjusted to 1 with dilute hydrochloric acid (6N) and stirred at 0 ℃ for 2h, whereupon a solid gradually precipitated. The filter cake was washed with water (10 mL. times.3) by suction filtration, collected, and dried at 55 ℃ for 12h to give compound 43(7.8 g, yield 78.7%) as a white solid.
Step 2 Synthesis of Compound 44, i.e., tert-butyl 1-benzyloxycarbonyl-2-oxoimidazoline-5-carboxylate
Figure 386616DEST_PATH_IMAGE193
Under nitrogen, 43(6.80 g, 25.73 mmol), tert-butanol (5.72 g, 77.2 mmol), DMAP (315 mg, 2.57 mmol), EDC (5.92 g, 30.88 mmol) and dichloromethane (300 mL) were added successively to a 500 mL single-neck flask, reacted at 0 ℃ for 1h, and then transferred to room temperature for 12 h. TLC (petroleum ether: ethyl acetate =3: 2) monitored after completion of the reaction, the solvent was distilled off under reduced pressure, purified by silica gel column (petroleum ether: ethyl acetate =3: 1-1: 2), and the solvent was recovered under reduced pressure to give 44(3.4 g, yield 41.3%) as a white solid.
1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.41-7.30(m, 5H), 6.08(s, 1H), 5.30-5.22(m, 2H), 4.64-4.61(dd, J 1 = 3.6 Hz, J 2 = 10.0Hz, 1H), 3.74-3.69(m, 1H), 3.39-3.36(m, 1H), 1.62(s, 1H), 1.39(s, 9H), 1.26(s, 1H)。
Step 3 Synthesis of Compound 45, 1-benzyl-5- (tert-butyl) 3-benzyl-2-oxoimidazoline-1, 5-dicarboxylic acid ester
Figure 692702DEST_PATH_IMAGE194
44(1.00 g, 3.12 mmol), potassium carbonate (0.86 g, 6.24 mmol), acetone (40 mL) and benzyl bromide (1.76 g, 10.3 mmol) were added sequentially in a 100 mL single-neck flask under nitrogen protection and reacted at 25 ℃ for 3 d. TLC (petroleum ether: ethyl acetate =3: 2) monitored after the reaction was complete, suction filtered over celite pad, the filtrate was evaporated under reduced pressure to remove the solvent to give crude product, purified by flash chromatography (petroleum ether: ethyl acetate =10: 1-3: 2), and the solvent was recovered under reduced pressure to give intermediate 45 as an oil (0.90 g, yield 70.3%).
1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.44-7.42(m, 2H), 7.37-7.29(m, 6H), 7.25-7.23(m, 2H), 5.33-5.26(m, 2H), 4.58(d, J=15.2 Hz, 1H), 4.53-4.49(dd, J 1 = 3.6 Hz, J 2 = 10 Hz, 1H), 4.30(d, J = 15.2 Hz, 1H), 3.53-3.49(m, 1H), 3.17-3.14(dd, J 1 = 3.6 Hz, J 2 = 9.6 Hz, 1H), 1.34(s, 9H)。
Step 4 Synthesis of Compound 46, i.e., 1-benzyl-2-oxoimidazoline-4-carboxylic acid tert-butyl ester
Figure 833833DEST_PATH_IMAGE195
A25 mL single-neck flask was charged with 45(0.90 g, 2.19 mmol) and methanol (50 mL), 10% Pd/C (46%, 415 mg) was added under nitrogen, and after completion of the addition, hydrogen substitution was carried out three times to carry out reaction at room temperature for 2 hours. TLC (ethyl acetate: petroleum ether =2: 3) monitored the reaction was completed, and then filtered under suction through a celite pad, and the filtrate was evaporated under reduced pressure to remove the solvent to obtain 46(0.58 g, yield 95.7%) as a white solid.
Step 5 Synthesis of Compound 47, 1-benzyl-2-oxoimidazoline-4-carboxylic acid
Figure 535073DEST_PATH_IMAGE196
Under nitrogen, 46(0.58 g, 2.10 mmol), dichloromethane (10mL) and trifluoroacetic acid (5 mL, 67.3 mmol) were added to a 25 mL single-neck flask and reacted at room temperature for 12 h. TLC (petroleum ether: ethyl acetate =1: 2) monitored the completion of the reaction, and 2mol/L sodium bicarbonate solution (20mL) was added. Ethyl acetate (20 mL. times.3) was extracted and the organic phase was collected. The organic phases were washed successively with water (10 mL. times.3) and saturated sodium chloride solution (10 mL. times.3), and the organic layers were combined and dried over anhydrous magnesium sulfate. And (5) carrying out suction filtration, and carrying out reduced pressure evaporation to remove the solvent to obtain a crude product. Preparative plate purification (petroleum ether: ethyl acetate =1: 2) and solvent recovery under reduced pressure gave 47 as a white solid (126 mg, yield 27.3%).
Step 6 the compound of example 62, 1-benzyl-N-((S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2-oxoimidazoline-4-carboxamide
Figure 916507DEST_PATH_IMAGE197
47(64 mg, 0.29 mmol), dichloromethane (5 mL), HATU (123 mg, 0.35 mmol) and Diisopropylethylamine (DIPEA) (113 mg, 0.87 mmol) were added to a 25 mL single-neck flask under nitrogen and reacted at room temperature for 10 min. 7(73 mg, 0.32 mmol) was added to the above reaction mixture and reacted at room temperature for 12 hours. After completion of the reaction was monitored by TLC (dichloromethane: methanol =15:1), water (5 mL) was added to the reaction solution, dichloromethane (5 mL. times.3) was extracted, the organic phase was collected, washed with a saturated sodium chloride solution (5 mL. times.3), the organic layers were combined, and dried over anhydrous magnesium sulfate. And (4) carrying out suction filtration, and carrying out reduced pressure evaporation on the filtrate to remove the solvent to obtain a crude product. Preparative plate purification (dichloromethane: methanol =15:1) and solvent recovery under reduced pressure gave example 62 as a white solid (58 mg, yield 50.0%) melting point 173.4-175.6 ℃.
1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.68-7.66(d, J = 8.0 Hz, 1H), 7.35-7.27(m, 4H), 7.25-7.15(m, 5H), 5.55(d, J = 2.8Hz, 1H), 4.93-4.87(m, 1H), 4.54-4.50(m, 1H), 4.44-4.31(m, 2H), 4.26-4.21(m, 1H), 4.18-4.13(m, 1H), 3.69-3.64(m, 1H), 3.40(s, 3H), 3.25-3.22(m, 1H)；
13 C NMR (100 MHz, CDCl 3 ) δ (ppm): 170.76, 168.34, 160.44, 149.05, 135.44, 135.17, 127.69, 127.04, 126.64, 124.71, 122.28, 121.90, 75.86, 51.58, 47.97, 47.66, 46.37, 34.52；
ESI C 21 H 22 N 4 O 4 m/z: 394.90 (M + +H)。
Example 63 Compound 2- (1-benzyl-2, 5-dioxoimidazolin-4-yl) -N–((R) -5-methyl-2, 3,4, 5-tetrahydrobenzo [ b ]] [1,5]Synthesis of azapine-3-yl) acetamide
Figure 663883DEST_PATH_IMAGE198
Step 1 Synthesis of Compound 48, methyl 2- (2, 5-dioxoimidazolin-4-yl) acetate
Figure 15230DEST_PATH_IMAGE199
2- ((2, 5-dioxoimidazoline) -4-yl) acetic acid (2.00 g, 0.0126 mol) was dissolved in methanol (20mL), and sulfuric acid (1.24 g, 0.0126 mol) was added thereto and the reaction was refluxed for 3 hours. After cooling to room temperature, the reaction mixture was concentrated, water (10mL) was added, extraction was performed with ethyl acetate (10 mL. times.4), and the organic phase was concentrated to dryness to give 48(1.50 g, yield 69.1%) as a white solid.
1 H NMR(400 MHz, DMSO-d 6 ) δ (ppm): 10.65(s, 1 H), 7.88 (s, 1 H), 4.24-4.27 (m, 1 H), 3.61 (s, 3 H), 2.72 (d, J = 6.4 Hz, 2 H)。
Step 2 Synthesis of Compound 49, methyl 2- (1-benzyl-2, 5-dioxoimidazolin-4-yl) acetate
Figure 685157DEST_PATH_IMAGE200
Compound 48(1.30g, 7.56 mmol) and sodium methoxide (1.58 mL, 8.54 mmol) were dissolved in methanol (20mL) and replaced with nitrogen 3 times, heated to 60 ℃ for reaction for 1h, then benzyl bromide (1.42 g, 8.31mmol) was added and the temperature was controlled at 60 ℃ for reaction for 12 h. TLC (petroleum ether: ethyl acetate =2:1) detected the completion of the starting material reaction. Cooled to room temperature, the reaction mixture was concentrated to dryness, water (10mL) was added, and the mixture was stirred for 6 hours. Filtration and drying of the filter cake afforded 49 as a white solid (1.07 g, 54.0% yield).
1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.28-7.41 (m, 5 H), 5.82 (s, 2 H), 4.66 (d, J = 2.0 Hz, 2 H), 4.31-4.35 (m, 1 H), 3.70 (s, 3 H), 3.01-3.06 (m, 1 H), 2.54-2.61 (m, 1 H)。
Step 3 Synthesis of Compound 50, 2- (1-benzyl-2, 5-dioxoimidazolin-4-yl) acetic acid
Figure 221181DEST_PATH_IMAGE201
Compound 49(200 mg, 0.76 mmol) was dissolved in tetrahydrofuran (15 mL), and LiOH. H was added 2 O (77 mg, 1.83 mol) in water. After the addition, the reaction was stirred at room temperature for 3 hours. TLC (petroleum ether: ethyl acetate =2:1) detected the completion of the starting material reaction. The tetrahydrofuran was concentrated to remove tetrahydrofuran, 3mol/L HCl (10 drops) was added dropwise to adjust pH =1-2, extracted with ethyl acetate (10mL × 4), the organic phases were combined, washed with saturated brine (10mL), dried over anhydrous sodium sulfate, and concentrated to give yellow oil 50(220 mg, yield 87.3%).
Step 4 the Compound of example 63, namely 2-(1-benzyl-2, 5-dioxoimidazolin-4-yl) -N–((R) -5-methyl-2, 3,4, 5-tetrahydrobenzo [ b ]] [1,5]Synthesis of azapine-3-yl) acetamide
Figure 393536DEST_PATH_IMAGE202
Compound 50(220 mg, 0.682 mmol), 7(130 mg, 0.568 mmol), diisopropylethylamine (733 mg, 5.68 mmol) was dissolved in isopropanol (10mL) and stirred at room temperature for 10 min. Then adding T 3 P (542 mg, 0.853 mmol), and reacted at room temperature for 10 min. TLC (dichloromethane: methanol =20:1) detected the starting material was completely reacted. The reaction was concentrated to dryness, the residue was dissolved in ethyl acetate (30 mL), the organic phase was washed once with dilute 1 mol/L HCl (15 mL), saturated aqueous sodium bicarbonate (15 mL), saturated aqueous sodium chloride (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and plate-purified (dichloromethane: methanol =20:1) to give the compound of example 63 as an off-white solid (50 mg, yield 21.9%), melting point 103.1-104.4 ℃.
1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.36-7.39 (m, 2H), 7.27-7.33 (m, 3 H), 7.15-7.23 (m, 4 H), 6.77 (d, J = 3.2 Hz, 1 H), 6.31 (s, 1 H), 4.82-4.88(m, 1 H), 4.59-4.63 (m, 3H), 4.31- 4.34 (m,1 H) , 4.14-4.20 (m, 1 H), 3.39 (s, 3 H), 2.90-2.95(m, 1 H), 2.35-2.41(m, 1 H);
13 C NMR (100 MHz, CDCl 3 ) δ (ppm): 172.55, 169.17, 168.97, 156.62, 149.99, 135.95, 135.90, 128.69, 128.58, 127.97, 127.81, 125.78, 123.25, 122.96, 77.21, 54.13, 49.64, 42.29, 37.85, 35.55;
ESI C 22 H 22 N 4 O 5 m/z: 422.85 (M + +H)。
Example 64 Compounds(S)-5- (2-fluorobenzyl) -N-((S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 627203DEST_PATH_IMAGE203
Step 1 Synthesis of Compound 51, 4-Nitrophenyl 5- (2-fluorobenzyl) -3- (4-methoxybenzyl) -2-oxoimidazoline-1-carboxylic acid
Figure 693248DEST_PATH_IMAGE204
Intermediate compound 12(860 mg, 2.74 mmol) was dissolved in toluene (15 mL), and phenyl p-nitrochloroformate (2.2 g, 10.94 mmol), triethylamine (1.66 g, 16.41 mmol) and N were added 2 The replacement is carried out for 3 times, and the mixture is heated to 110 ℃ and reacted for 12 hours. TLC (dichloromethane: methanol =50:1) detected that the starting material was not completely reacted. Cooling to room temperature, adding water (20mL), quenching, extracting with ethyl acetate (20 mL. times.3), combining the organic phases, washing with saturated brine (30 mL. times.5), drying over anhydrous sodium sulfate, filtering, concentrating, mixing, and column chromatography (SiO) 2 Ethyl acetate =3:1) gave intermediate compound 51(450 mg, 34.3% yield) as a pale yellow oil.
1 H NMR (400 MHz, CDCl 3 )δ(ppm)：8.72 (d, J = 7.2 Hz, 1H), 6.97-7.23 (m, 8H), 4.76-4.84 (m, 2H), 4.52-4.56 (m, 1H), 4.17-4.23 (m, 1H), 3.84-3.91 (m, 2H), 3.53-3.57 (m, 1H), 3.33 (s, 3H), 2.87-2.91 (m, 1H), 2.71-2.76 (m, 1H)。
Step 2 Compound 52 is(S)-5- (2-fluorobenzyl) -3- (4-methoxybenzyl) -N -((S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1, 5]Synthesis of azapine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 275539DEST_PATH_IMAGE205
Compound 51(450 mg, 0.94 mmol) was dissolved in DMF (10mL), and compound 7(260 mg, 1.13 mmol) and triethylamine (380 mg, 3.76 mmol) were added and the mixture was replaced with nitrogen 3 times and heated to 80 ℃ for 2 h. TLC (Petroleum ether: ethyl acetate =2:1) detection of starting materialIt should be complete. Cooling to room temperature, quenching with water (20mL), extracting with ethyl acetate (20 mL. times.3), combining the organic phases, washing with saturated brine (50 mL. times.5), drying over anhydrous sodium sulfate, filtering, concentrating, mixing, and column chromatography (SiO) 2 Ethyl acetate =3:1) to give intermediate compound 52 as a clear oil (150 mg, yield 30.0%).
1 H NMR(400 MHz, CDCl 3 )δ(ppm)：9.04 (d, J = 6.8 Hz, 1H), 7.07-7.16 (m, 5H), 7.00-7.04 (m, 2H), 6.94-6.96 (m, 2H), 6.86-6.90 (m, 1H), 6.75-6.79 (m, 2H), 4.85-4.92 (m, 1H), 4.58-4.62 (m, 1H), 4.12-4.33 (m, 4H), 3.73 (s, 3H), 3.37 (s, 3H), 3.09-3.14 (m, 2H), 2.87-2.90 (m, 1H), 2.64-2.70 (m, 1H)。
Step 3 example 64 Compound i(S)-5- (2-fluorobenzyl) -N-((S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 246775DEST_PATH_IMAGE206
Intermediate compound 52(150 mg, 0.28 mmol) was dissolved in trifluoroacetic acid (10mL) and heated to 60 ℃ for 12 h. TLC (petroleum ether: ethyl acetate =1:1) detected the completion of the starting material reaction. Concentration removed trifluoroacetic acid, adjusted pH to around 8 with saturated sodium bicarbonate (8 mL), extracted with ethyl acetate (10mL × 3), combined organic phases, washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated on thick prep plates (petroleum ether: ethyl acetate =1:1) to give the compound of example 64 as a white solid (90 mg, yield 77.5%), m.p. 166.7-170.6 ℃.
1 H NMR(400 MHz, CDCl 3 ) δ (ppm): 8.92(d, J=7.2Hz, 1H), 7.15-7.24(m, 6H), 7.00-7.10(m, 2H), 4.92-4.99(m, 1H), 4.84(s, 1H), 4.64-4.68(m, 1H), 4.52-4.57(m, 1H), 4.25-4.31(m, 1H), 3.44(s, 3H), 3.39-3.41(m, 1H), 3.19-3.26(m, 2H), 2.85-2.91(m, 1H);
13 C NMR(100 MHz, CDCl 3 ) δ (ppm): 169.23, 162.57, 160.13, 157.93, 152.40, 150.14, 136.48, 131.90, 131.85, 128.79, 128.71, 127.42, 125.54, 124.47, 124.37, 123.44, 123.28, 123.25, 122.82, 115.63, 115.41, 77.65, 54.36, 50.11, 41.49, 35.39, 32.17;
ESI C 21 H 21 FN 4 O 4 m/z: 412.85 (M + +H)。
Example 65 Compounds(R)-5- (2-fluorobenzyl) -N-((S)-5-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,5]Synthesis of azapine-3-yl) -2-oxoimidazoline-1-carboxamide
Figure 533400DEST_PATH_IMAGE207
Example 64 was repeated using step 1 and step 2 in column chromatography (SiO) 2 Ethyl acetate =3:1) to give intermediate compound 53 during purification to intermediate compound 52 as a clear oil.
Figure 470263DEST_PATH_IMAGE208
Referring to the synthesis of example 64, step 3, intermediate compound 52 was replaced with intermediate compound 53 to give the compound of example 65 as a white solid (70 mg, yield 51.7%) with a melting point of 95.6-97.3 ℃.
1 H NMR(400 MHz, CDCl 3 ) δ(ppm):8.92(d, J=7.6Hz, 1H), 7.15-7.25(m, 6H), 7.00-7.09(m, 2H), 4.91-4.98(m, 1H), 4.79(s, 1H), 4.63-4.67(m, 1H), 4.55-4.60(m, 1H), 4.30-4.35(m, 1H), 3.41(s, 3H), 3.39-3.44(m, 1H), 3.19-3.23(m, 2H), 2.94-3.00(m, 1H);
13 C NMR(100 MHz, CDCl 3 ) δ(ppm):168.36, 161.61, 159.18, 157.00, 151.55, 149.07, 135.50, 130.80, 130.76, 127.83, 127.75, 126.34, 124.54, 123.32, 123.29, 122.36, 122.19, 121.85, 114.63, 114.41, 76.56, 53.11, 49.02, 40.59, 34.34, 31.15;
ESI C 21 H 21 FN 4 O 4 m/z: 412.85(M + +H)。
Example 66 biological Activity assay
A. The compound of the invention has the effect of inhibiting human RIP1 kinase
The positive control compound was GSK2982772, purchased from seleck Chemical co., Ltd; dimethyl sulfoxide (DMSO) (Sangon Biotech co., Ltd); RIP1 kinase (Husha Biotechnology Ltd.), ADP-Glo kinase assay kit (Promega (Beijing) Biotechnology Ltd.). All enzymatic reactions were carried out at 30 ℃ for 40 min. 50 μ L of the reaction mixture contained 40 mM Tris (pH 7.4), 10mM MgCl 2 0.1mg/mL BSA, 1mM DTT, 10. mu.M ATP, 0.2. mu.g/mL RIP1 kinase, and 100. mu.M lipid substrate (5% Glycerol). Compounds were diluted in 10% DMSO in water and 5. mu.L of the dilution was added to 50. mu.L of the reaction to give a final DMSO concentration of 1% and drug concentrations of 1, 3.3, 10, 33, 100, 333, 1000, 3300, 10000nM in all reactions, with two replicates per concentration. The assay was performed using an ADP-Glo kinase assay kit, kinase activity was measured by quantifying the amount of ATP in the solution after the kinase reduction reaction, and the fluorescent signal of the reaction correlated with the amount of ATP present and negatively correlated with kinase activity. The results of the experiment were converted to percent activity and dose-response curves, IC, were plotted 50 Values were calculated using Prime GraphPad software.
The experimental results are shown in the following table 1, and the compounds of the invention all show good activity of inhibiting RIP1 kinase. In particular, some compounds inhibited RIP1 kinase activity significantly better than the positive control GSK-2982772.
Figure 957876DEST_PATH_IMAGE209
Anti-inflammatory effect of compound on phorbol lipid-induced mouse ear swelling model
Male ICR mice (Henan Scout Biotechnology GmbH, Inc., license number: SCXK 2020 & ltsub.) 0005) are taken, the weight is 18-22g, the mice are adaptively fed for 7 days, and the mice are randomly divided into a blank group, a model group, a positive control dexamethasone group and a compound group of the invention, phorbol lipid (5 mu g/20 mu L/ear) is smeared for 30min and 15min after smearing, the right ear of each group of rats is respectively and uniformly smeared with a compound with a corresponding concentration or a positive control drug of 20 mu L/ear, the left ear of each group of rats is smeared with a solvent of 20 mu L (acetone + ethanol), and the two ears of the rats of the blank group and the model group are smeared with 20 mu L (acetone + ethanol) of equal dosage. Measuring ear swelling as an inflammation index by a thickness meter 6h after molding, and calculating swelling degree and inhibition rate by a calculation formula (swelling degree is the average thickness of right ear-average thickness of left ear); the inhibition ratio (%) was (average swelling degree in model group-average swelling degree in administration group)/average swelling degree in model group 100%).
The experimental results are shown in the following table 2, and compared with the model group, dexamethasone, GSK-2982772 and the compound of the invention can obviously reduce ear swelling caused by phorbol ester (P is less than 0.01). The anti-inflammatory activity of the compound of the invention is superior to that of the positive control GSK-2982772, and particularly, the anti-inflammatory activity of the compound 5, the compound 6, the compound 20, the compound 27, the compound 35 and the compound 42 in the examples is remarkably superior to that of the positive control GSK-2982772.
Figure 167140DEST_PATH_IMAGE210
All references mentioned herein are incorporated herein by reference. It is to be understood that many variations and modifications may be made to the present invention without departing from the spirit and scope of the disclosure.

Claims (5)

1. A compound selected from
Figure FDA0003756847690000011
Figure FDA0003756847690000021
Figure FDA0003756847690000031
Or a pharmaceutically acceptable salt, stereoisomer thereof.
2. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, and a pharmaceutically acceptable carrier.
3. Use of a compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or pharmaceutical composition according to claim 2, for the manufacture of a medicament for the treatment and/or prevention of a RIP1 kinase-associated disease.
4. The use according to claim 3, wherein the disease is an inflammatory disease.
5. The use according to claim 3, wherein the disease is selected from inflammatory bowel disease, Crohn's disease, ulcerative colitis, retinitis, macular degeneration, pancreatitis, periodontitis, pruritus, allergic dermatitis, urticaria, atopic dermatitis, seborrheic dermatitis, contact dermatitis, psoriasis, systemic lupus erythematosus, Sjogren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, spondyloarthritis, rheumatoid arthritis, gout, gaucher's disease, multiple sclerosis, chronic kidney disease, acute liver failure, acute kidney injury, cholangitis, autoimmune hepatitis, non-alcoholic steatohepatitis, transplant rejection, solid organ ischemia-reperfusion injury, sepsis, myocarditis, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic disease, Asthma, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme associated fever syndrome, chronic obstructive pulmonary disease, tumors.
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